ROI] [eTe] le | Profile RU Rr TYoIFN fo] | Draft for Public Comment Comment Period Ends: February 17, 1998 U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES ‘ Public Health Service Agency for Toxic Substances and Disease Registry PUBLIC HEALTH LIBRARY / BERKELEY | LIBRARY UNIVERSITY OF \ GAUFORNIA DRAFT TOXICOLOGICAL PROFILE FOR IONIZING RADIATION Prepared by: Research Triangle Institute Under Contract No. 205-93-0606 Prepared for: U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry September 1997 IONIZING RADIATION DISCLAIMER The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry. CAT. FOR pUBLIC BEALT. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION . [< A i 12% Rz Tb UPDATE STATEMENT 1949 7 puéL Toxicological profiles are revised and republished as necessary, but no less than once every three years. For information regarding the update status of previously released profiles, contact ATSDR at: Agency for Toxic Substances and Disease Registry Division of Toxicology/Toxicology Information Branch 1600 Clifton Road NE, E-29 Atlanta, Georgia 30333 ***DRAFT FOR PUBLIC COMMENT*** FOREWORD The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects information for the hazardous substance described therein. Each peer-reviewed profile identifies and reviews the key literature that describes a hazardous substance 's toxicologic properties. Other pertinent literature is also presented, but is described in less detail than the key studies. The profile is not intended to be an exhaustive document; however, more comprehensive sources of specialty information are referenced. The focus of the profiles is on health and toxicologic information; therefore, each toxicological profile begins with a public health statement that describes, in nontechnical language, a substance's relevant toxicological properties. Following the public health statement is information concerning levels of significant human exposure and, where known, significant health effects. The adequacy of information to determine a substance's health effects is described in a health effects summary. Data needs that are of significance to protection of public health are identified by ATSDR and EPA. Each profile includes the following: (A) The examination, summary, and interpretation of available toxicologic information and epidemiologic evaluations on a hazardous substance to ascertain the levels of significant human exposure for the substance and the associated acute, subacute, and chronic health effects; (B) A determination of whether adequate information on the health effects of each substance is available or in the process of development to determine levels of exposure that present a significant risk to human health of acute, subacute, and chronic health effects; and (C) Where appropriate, identification of toxicologic testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans. The principal audiences for the toxicological profiles are health professionals at the Federal, State, and local levels; interested private sector organizations and groups; and members of the public. We plan to revise these documents in response to public comments and as additional data become available. Therefore, we encourage comments that will make the toxicological profile series of the greatest use. Comments should be sent to: Agency for Toxic Substances and Disease Registry Division of Toxicology Mail Stop E-29 Atlanta, Georgia 30333 Toxicological profiles are prepared in accordance with guidelines developed by the Agency for Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised and republished as necessary. vi This toxicological profile was developed by ATSDR pursuant to Section 104(i) (3) and (5) of the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund) for hazardous substances found at Department of Energy (DOE) waste sites. CERCLA directs ATSDR to prepare toxicological profiles for hazardous substances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that pose the most significant potential threat to human health, as determined by ATSDR and the EPA. ATSDR and DOE entered into a Memorandum of Understanding on November 4, 1992 which provided that ATSDR would prepare toxicological profiles for hazardous substances based upon ATSDR’s or DOE's identification of need. The current ATSDR priority list of hazardous substances at DOE NPL sites was announced in the Federal Register on July 24, 1996 (61 FR 38451). This profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been peer-reviewed. Staff of the Centers for Disease Control and Prevention and other Federal scientists have also reviewed the profile. In addition, this profile has been peer-reviewed by a nongovernmental panel and is being made available for public review. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR. RX he —— David Satcher, M.D., Ph.D Administrator Agency for Toxic Substances and Disease Registry IONIZING RADIATION vii CONTRIBUTORS CHEMICAL MANAGER(S)/AUTHORS(S): Sam Keith, M.S., CHP ATSDR, Division of Toxicology, Atlanta, GA H. Edward Murray, Ph.D. ATSDR, Division of Toxicology, Atlanta, GA Wayne Spoo, D.V.M Research Triangle Institute, Research Triangle Park, NC THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 1. Health Effects Review. The Health Effects Review Committee examines the health effects chapter of each profile for consistency and accuracy in interpreting health effects and classifying end points. 2. Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to substance-specific minimal risk levels (MRLs), reviews the health effects database of each profile, and makes recommendations for derivation of MRLs. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION ix PEER REVIEW A peer review panel was assembled for ionizing radiation. The panel consisted of the following members: 1. Herman Cember, Ph.D., Certified Health Physicist, 2119 Birch Lane, Lafayette, IN 47905; 2. Richard Toohey, Ph.D., Certified Health Physicist, Director, 114 Emory Lane, Oak Ridge, TN 37830; 3. Kenneth Mossman, Ph.D., Professor, Department of Microbiology, Arizona State University, 8046 East Kalil Drive, Scottsdale, AZ 85260-5700; 4. John Poston, Ph.D., Professor, Zachery Engineering Center, Department of Nuclear Engineering, Texas A&M University, College Station, TX 77843-3133; and 5. Darrell Fisher, Ph.D., Senior Scientist, 229 Saint, Richland, WA 99352. These experts collectively have knowledge of ionizing radiation's physical and chemical properties, toxico- kinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer review specified in Section 104(i)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as amended. Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer reviewers' comments and determined which comments will be included in the profile. A listing of the peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their exclusion, exists as part of the administrative record for this compound. A list of databases reviewed and a list of unpublished documents cited are also included in the administrative record. The citation of the peer review panel should not be understood to imply its approval of the profile's final content. The responsibility for the content of this profile lies with the ATSDR. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION Xi CONTENTS FOREWORD . Lotte eee eee eee eee eee eee eee v CONTRIBUTORS ©. ott eee eee ee ee ee eee eee vii PEER REVIEW . . ite eee eee ee ea ix LIST OF FIGURES . . ote eee ee eee ee eee XV LIST OF TABLES «o.oo eee eee eee ee eee Xvii 1. PUBLIC HEALTH STATEMENT . . eee eee 1 1.1 WHATIS IONIZING RADIATION? eee ieee 1 1.2 HOW DOES RADIOACTIVE MATERIAL ENTER AND SPREAD THROUGH THE ENVIRONMENT? tite ee eee eee eee eee een 6 1.3 HOW MIGHT I BE EXPOSED TO IONIZING RADIATION? . ......... iii. 7 1.4 HOW CAN IONIZING RADIATION ENTER AND LEAVEMY BODY? ................. 9 1.5 HOW CAN IONIZING RADIATION AFFECT MY HEALTH? ......................... 11 1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO IONIZING RADIATION? «ooo eee eee 13 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? .... ee eee 14 1.8 WHERE CAN I GET MORE INFORMATION? .........ooiiiiiiiiiiaiiin, 16 2. PRINCIPLES OF IONIZING RADIATION . ... oot eee eee 17 2.1 INTRODUCTION . . . tte ee ee eee ee eee eee 17 2.2 HISTORY, BACKGROUND INFORMATION, AND SCIENTIFIC PRINCIPLES OF IONIZING RADIATION . Lie eee 19 2.2.1 Historical Perspective on Ionizing Radiation . ................................. 19 2.2.2 Basic Information on Ionizing Radiation ..................................... 25 2.2.3 Principles of Radioactive Transformation .................................... 27 2.2.4 Interaction of Radiation with Matter ................... iii... 30 2.2.5 Characteristics of Emitted Radiation ........................................ 32 22.5.1 AlphaRadiation ............... oii 32 2.2.52 BetaRadiation .............. 33 2.2.5.3 GammaRadiation .............. 34 2.2.6 Estimation of Energy Deposition in Human Tissues ............................ 34 2.3 FUNDAMENTALS OF IONIZING RADIATION DOSIMETRY ..............c.oooo... 35 2.3.1 Dose Units ......io 35 2.3.2 Dosimetry Models ...........oo ii 36 2.3.3 Terms Used in Radiation Safety Practice and Regulation ........................ 38 2.4 BIOLOGICAL EFFECTS OF RADIATION .......ooi ieee 42 2.4.1 Radiation Effects at the Cellular Level ...................................... 44 2.4.2 Radiation Effects atthe Organ Level .................. ci... 45 ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 2.43 Acute and Delayed Somatic Effects ................ i 24.3.1 Acute Effects... 2.4.3.2 Delayed Effects ...... coo 2.4.4 Genetic Effects .......... 2.4.5 Teratogenic Effects ......... oo 2.4.6 Internal Exposure to Ionizing Radiation ..........................ccoueun... 2.4.6.1 Inhalation ........... co... 2.4.6.2 INGESHON . ttt tte 24.63 Dermal. ...... o.oo. 2.4.7 External Exposure to Ionizing Radiation ..................................... 2.5 MEASURING INTERNAL AND EXTERNAL SOURCES OF IONIZING RADIATION .... 2.5.1 Internal Radiation Measurements . . .............ouuuniiiinneinnnennnneennn.. 2.5.2 External Radiation Measurements .................ouuiiuniiniinninnennenn.. 2.5.3 Field Radiation and Contamination SUIVEYS ............c.uueeunnernnneennnnn. 2.5.3.1 Field Measurements of Ionizing Radiation ........................... 2.5.3.2 Laboratory Analysis of Environmental Samples ...................... 2.6 CONCLUSIONS . Lee ee ee eee 2.7 OTHER SOURCES OF INFORMATION . ....... cco iia 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION .............. coi... 3.1 INTRODUCTION . ... eee eee eee 3.2 HEALTH EFFECTS FROM EXPOSURE TO IONIZING RADIATION .................. 3.2.1 Acute (Immediate and Non-Carcinogenic) Effects from Ionizing Radiation EXpOSUIe . ooo 3.2.1.1 Gastrointestinal Effects ................ i. 3.2.1.2 Hematological and Lymphoreticular Effects ......................... 3.2.1.3 Reproductive Effects. ............. 3.2.1.4 Teratogenic/Embryotoxic Effects .................................. 3.2.1.5 Central Nervous System (CNS) Effects ............................ 3.2.1.6 Respiratory and Cardiovascular Effects ............................ 32.1.7 Ocular Effects ........... i 3.2.1.8 Dermal Effects ............. 3.2.1.9 Genotoxic Effects .......... 3.2.2 Carcinogenic Effects from Ionizing Radiation Exposure ....................... 322.1 Introduction .............oiiiiii 3.2.2.2 Nuclear Detonations of 1945 in Hiroshima and Nagasaki, Japan ........ 3.2.2.3 Human Exposures to Ra and ***Ra: The Radium Dial Painters . . ...... 3.2.2.4 Human Exposures to ***Ra via Injection ........................... 3.2.2.5 Other Human Cancer Studies ................c.coiiiiiiinn... 3.2.2.6 Laboratory Animal Reports ........................... 3.3 IDENTIFICATION OF DATA NEEDS ...... ie 3.4 CONCLUSIONS Lee ee eee ee ee eee 4. RADIATION ACCIDENTS Lee eee 4.1 PALOMARES, SPAIN . . ite ie 4.2 THULE, GREENLAND . ......coit ities 4.3 ROCKY FLATS, COLORADO .. coin 4.4 THREEMILE ISLAND, PENNSYLVANIA ........ ie 4.5 CHERNOBYL, UKRAINE . ... tte cian 4.6 KY SHT YM Loe ee ee ***DRAFT FOR PUBLIC COMMENT*** Xii IONIZING RADIATION xiii 4.7 WINDSCALE, UK. eee ee eee 187 4.8 TOMSK 188 4.9 LOST INDUSTRIAL OR MEDICAL SOURCES ...... iin, 188 4.10 IDENTIFICATION OF DATANEEDS .. .. een 189 4.11 CONCLUSIONS . ©. eee ee eee een 189 4.12 OTHER SOURCES OF INFORMATION . ........oii ieee 190 5. MECHANISMS OF BIOLOGICAL EFFECTS .... eee ein 193 5.1 INTRODUCTION . . .. ite eee eee ee ieee 193 5.2 EVIDENCE OF THE EFFECTS ON DNA ..... iii enn 194 5.3 INTERACTIONS OF IONIZING RADIATION WITHDNA .......................... 197 5.4 EFFECTS ON OTHER CELLULAR MACROMOLECULES ...................oo.... 202 5.5 MECHANISMS OF CARCINOGENESIS ........ enn 204 5.6 IDENTIFICATION OF DATANEEDS ........ ieee 208 57 SUMMARY 208 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION .................... 211 6.1 OVERVIEW 211 6.2 EXPOSURE TO NATURAL SOURCES OF EXTERNAL IONIZING RADIATION ....... 211 6.2.1 CosmiC Rays ....... ci 213 6.2.2 Earth's Crust ..........oiiiii i 214 6.2.2.1 Coal Production ............ iii, 214 6.2.2.2 Crude Oil and Natural Gas Production . . . .......................... 215 6.2.2.3 Phosphate Rock Products ....................................... 215 6.2.2.4 Sand... 216 6.2.3 Hot Springs and Caves .............couniiiiiineiiie iii 217 6.3 EXPOSURE FROM INTAKE OF NATURAL AND ANTHROPOGENIC RADIOACTIVE MATERIALS 217 6.3.1 Inhalation ............ 218 6.3.2 Oral... 221 6.3.3 Dermal ......... 222 6.4 EXPOSURE FROM NATURAL AND ANTHROPOGENIC RADIOACTIVE MATERIALS 223 6.4.1 Exposure from Nuclear Weapons ..................couiiuniiinnennnennnn.. 223 6.4.2 Exposure from Nuclear Weapons Testing ................oovuieeeeennnnn... 225 6.42.1 Atmospheric Testing ..............ccoiiiiiiiiiiiiiiinnnnnnnnn.. 228 6.4.2.2 Underground Testing ...............oiiiniiiiiniiinnennnnnnn.. 231 6.4.3 Exposure from the Nuclear Fuel Cycle ..................... civ... 231 6.4.4 Exposure from Medical and Dental X-rays, Radiopharmaceuticals, and Commercial Radionuclides ............. iii 235 6.4.5 Exposure from Consumer Products .................... coin. 238 6.4.6 Occupational Exposure ................ iii 246 6.5 ADEQUACY OFTHE DATABASE ..... ein 248 6.6 CONCLUSIONS . Lo ee ee ee en 248 7. REGULATIONS ee een 251 8. OBSERVED HEALTH EFFECTS FROM RADIATION AND RADIOACTIVE MATERIAL . Leia 261 ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION xiv 0. GLOSSARY iii 305 10. REFERENCES . .. ott ee eee eee ee eee ie 321 APPENDICES A. ATSDRMINIMAL RISK LEVEL ...... ieee A-1 B. USER'SGUIDE ... ite eee B-1 C. ACRONYMS, ABBREVIATIONS, ANDSYMBOLS ............ iii. C-1 ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION XV 1-1 2-1 2-2 2-3 2-5 2-6 2-7 2-8 4-1 4-2 4-4 6-1 6-2 LIST OF FIGURES Sources of Exposure to Ionizing Radiation to the Average U.S. Citizen ........................ 7 Decomposition of 100 pCi of 2P LL... uit 29 Whole-body COUNLET . ...... ott 55 Low Energy Germanium (LEGe) Based Lung Counter ......................0ooiiiiiiin... 56 Components of a Scintillation Detector . ............ iii 58 Liquid Scintillation Counting (LSC) System .............. iii... 59 Geiger-Mueller Counter with an Energy-compensated Gamma Probe ......................... 63 Geiger-Mueller Counter with a Beta/Gamma Pancake-type Detection Probe ................... 63 In-Situ Gamma Ray Spectrometer . . ...... o.oo. 64 Schematic of Three Mile Island Nuclear Reactor ........................... i. 181 Aerial View of the Damaged Chernobyl Reactor Facility .................................. 183 Hot Spots of Radioactivity in the Regions Surrounding the Chernobyl Facility ................ 184 A View of the Sarcophagus Covering the Chernobyl Reactor Facility ........................ 185 Sources of Exposure to Ionizing Radiation to the Average U.S. Citizen ...................... 211 Replicas of the “Little Boy” and “Fat Man” Bombs Dropped on Hiroshima and Nagasaki ....... 223 Schematic of the Nuclear Fuel Cycle ......... cee 231 ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION xvii 1-1 2-1 2-2 2-3 2-4 2-6 2-7 2-8 3-1 3-2 3-3 3-5 3-6 3-7 3-8 3-9 3-10 3-12 LIST OF TABLES Approximate Doses of Ionizing Radiation to Individuals .................................... 9 Characteristics of Nuclear Radiations ................ iii. 28 Effective Half-Lives of Selected Radionuclides in Major Adult Body Organs .................. 30 Quality Factors Used in USNRC Radiation Safety Regulations . ............................. 39 Tissue Weighting Factors Used by the USNRC and ICRP to Calculate Effective Dose ........... 40 Common and SI Units for Radiation Quantities .................c.uuinininenenennnnnnen nn. 42 Relative Radiosensitivity of Mammalian Cells .................... iii... 45 Common Analytical Methods for Measuring Radioactive Material Inside and Radiation Outside the Body . ........ oii 54 Some Internet WWW Sites Related to Tonizing Radiation .................................. 69 ATSDR Priority Listing of Radionuclides Present at Department of Energy NPL Sites ........... 72 Summary of Some Studies of Humans Exposed to Radionuclides ............................ 76 Summary of the Dose Response Effects of Ionizing Radiation in Humans ..................... 84 Genotoxicity of Ionizing Radiation In Vivo .................... iii 123 Genotoxicity of Ionizing Radiation In Vitro ................. iii. 126 Estimated Genetic Effects of 1 Rem of Ionizing Radiation per Generation .................... 131 Estimated Lower 95% Confidence Limits of Doubling Dose (in rem) from Chronic Radiation for Malformations, Stillbirths, Neonatal Deaths, and All Untoward Pregnancy Outcomes (Based on the Hiroshima and Nagasaki Atomic Bombing Data) ........................................ 134 Summary of Risks of Developing Cancer After Exposure to Ionizing Radiation ............... 138 Summary of Radiation Dose Response for Cancer Mortality by Site . ........................ 147 Incidence Estimates for Each of Four Leukemia Types by Exposure Category and Period (PET 10° PEISON-YEAIS) «veo tt eet e eee eee ee ee eee eee eee 149 Incidence Estimates for Each of Four Leukemia Types by Age, Exposure Category, and Time Period (per 10° PEISON-YEAIS) . .......tnttte tte ee eee eee eee eee eae 150 Distribution of Osteosarcomas in a Population of Female Dial Painters Exposed tO 22 RAANA PRA oo ott tee 155 ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION xviii 3-13 Distribution of Head Carcinomas in a Population of Female Dial Painters Exposed to *Ra ... . .. 156 3-14 Alpha Doses from Injected **Ra (in rads) by Age Group, Number, and Percentage of 3-15 4-1 5-1 5-2 5-3 6-1 6-3 6-4 7-1 7-2 7-3 8-1 8-3 8-4 Subpopulation Developing OSte0SarcOmMa ..............ueeiunee ruins einen. 158 Age Distribution, Alpha Dose (in rads), and % Incidence of Osteosarcomas Induced bY ZURAINJECHON «eee teeta ee eee eee eee 159 Internet WWW Sites Pertaining to Population Exposures to Ionizing Radiation ................ 191 Relative Sensitivities of Major Organs and Tissues to the Effects of Ionizing Radiation ......... 195 Some Effects of Ionizing Radiation on Molecules in Animal Tissues ........................ 203 Some Models That Describe the Induction of Cancer in Animals ........................... 205 Common Terms and Abbreviations . ................ iii. 212 Scientific UNIS . . . ooo 212 Radioactive Properties of Radon and its Daughter Products . . ............................ 219 Some Radiopharmaceuticals Used in Medicine . . . ................ooueuiunenennnnannnn... 239 Regulations and Guidelines Applicable to Ionizing Radiation .............................. 253 Regulations and Guidelines Applicable to 26Ra .................coiuiiiinneiinnnnnn... 256 Regulations and Guidelines Applicable to Strontium Isotopes .............................. 259 Observed Health Effects from Radiation and Radioactive Material—Inhalation ............... 265 Observed Health Effects from Radiation and Radioactive Material—Oral .................... 285 Observed Health Effects from Radiation and Radioactive Material—Dermal .................. 287 Observed Health Effects from Radiation and Radioactive Material—External ................. 288 ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 1 1. PUBLIC HEALTH STATEMENT This public health statement tells you about ionizing radiation and the effects of exposure. The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in the nation. These sites make up the National Priorities List (NPL) and are the sites targeted for long-term federal cleanup. However, it’s unknown how many of the 1,445 current or former NPL sites have been evaluated for the presence of ionizing radiation sources. As more sites are evaluated, the sites with ionizing radiation may increase. This information is important because exposure to ionizing radiation may harm you and because these sites may be sources of exposure. When a substance is released from a large area, such as an industrial plant, or from a container, such as a drum or bottle, it enters the environment. This release does not always lead to exposure. If you are exposed to ionizing radiation, many factors determine whether you’ll be harmed. These factors include the dose (how much), the duration (how long), and the type of radiation. You must also consider the other chemicals you’re exposed to and your age, sex, diet, family traits, lifestyle, and state of health. 1.1 WHAT IS IONIZING RADIATION? What lonizing Radiation Is. Ionizing radiation is energy that is carried by any of several types of particles and rays given off by radioactive material, X-ray machines, and nuclear reactions. These rays are a type of electromagnetic radiation. They have more energy than the other types of electromagnetic radiation, which include radio waves, microwaves, infrared light, visible light, and ultraviolet light. This energy can knock out electrons from molecules, such as water, protein, and DNA, with which it interacts. This process is called ionization and is the source of the name “ionizing radiation.” We cannot sense ionizing radiation, so we must use special instruments to learn whether we are being exposed to it and measure the level of radiation exposure. To explain ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 2 1. PUBLIC HEALTH STATEMENT what ionizing radiation is, we will start with a discussion of atoms, how they come to be radioactive, and how they give off ionizing radiation. Then, we will explain where radiation comes from. Finally, we will describe the more important types of radiation to which you may be exposed. Of the different types and sources of ionizing radiation, this profile will only discuss three types: alpha, beta, and gamma radiation. What lonizing Radiation Is Not. Ionizing radiation is not a substance like salt, air, water, or a hazardous chemical that we can eat, breathe, or drink or that can soak through our skin. However, these substances may become contaminated with radioactive material and people can be exposed to ionizing radiation from these radioactive contaminants. The Atom. Atoms are the basic building blocks of all elements. No one knows what an atom really looks like, but we have models of an atom that measurements support. We believe that an atom consists of one nucleus, made of protons and neutrons, and many smaller particles called electrons. The electrons normally circle the nucleus much like the planets circle the sun. The number of protons in the atom’s nucleus identifies which element it is. For example, an atom with one proton is hydrogen and an atom with 27 protons is cobalt. Each proton has a positive charge, and positive charges try to push away from one another. The neutrons neutralize this action and act as a kind of glue that holds the protons together in the nucleus. Neutrons also add to the weight of the atom, so an atom of cobalt that has 27 protons and 32 neutrons is called cobalt-59 because 27 and 32 equals 59. If one more neutron were added to this atom, it would be called cobalt-60. Cobalt-59 and cobalt-60 are isotopes of cobalt. Isotopes are forms of the same element, but differ in the number of neutrons within the nucleus. Since cobalt-60 is radioactive, it is called a radionuclide. How Does an Atom Become Radioactive? An atom is either stable (not radioactive) or unstable (radioactive). The ratio of neutrons to protons within the nucleus determines whether an atom is stable. In the case of heavy nuclei, stability occurs when the number of neutrons exceeds the number of protons. If there are too many or too few neutrons, the nucleus is unstable, and the atom is said to be radioactive. There are several ways an atom can become radioactive. An atom ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 3 1. PUBLIC HEALTH STATEMENT can be naturally radioactive, it can be made radioactive by natural processes in the environment, or it can be made radioactive by humans. Naturally occurring radioactive materials like potassium-40 and uranium-238 have existed since the earth was formed. Other naturally occurring radioactive materials such as carbon-14 and hydrogen-3 (tritium) are formed when radiation from the sun and stars bombards the earth’s atmosphere. Radioactive materials made by human industry are formed when stable atoms are bombarded by radiation from nuclear reactors or particle accelerators. For example, stable cobalt-59, found in the steel surrounding a nuclear reactor, is hit by neutrons coming from the reactor and can become radioactive cobalt-60. Any material that contains radioactive atoms is radioactive material. How Does a Radioactive Atom Give off lonizing Radiation? At some time in the future, each radioactive atom will transform into another element. This means that one of several reactions will take place in the nucleus to stabilize the neutron-proton ratio. If the neutron to proton ratio is too low, a neutron changes into a proton and throws out a negative “beta” (pronounced bay’ tah) particle. If the neutron to proton ratio is too high, a proton changes into a neutron and throws out a positive “beta” particle. In special cases, very heavy radioactive atoms transform by emitting an “alpha” (pronounced al’-fah) particle. Any excess energy that is left can be released as “gamma” rays, which are similar to X-rays. Other reactions are also possible, but the final result is to make a radioactive atom into a stable atom. Take radioactive cobalt-60 for examle. The neutron to proton ratio is high, and a neutron transforms into a proton, a beta particle, and two gamma rays. The result is a stable atom of nickel-60. How Long Can Radioactive Material Give Off Ionizing Radiation? The length of time atoms stay radioactive is measured by the half-life, or the time it takes one-half of the radioactive atoms to transform into another element which may or may not also be radioactive. After one half-life, 2 of the radioactive atoms remain; after two half lives, half of a half or 1/4 remain, then 1/8, 1/16, 1/32, 1/64, etc. This is a gradual decline. The half-life can be as short as a fraction of a second or as long as many billions of years. Each type of radioactive atom, or radionuclide, has its own unique half-life. Technetium-99m, which is used in nuclear medicine, has a 6-hour half-life. The “*NRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 4 1. PUBLIC HEALTH STATEMENT naturally occurring radionuclide, uranium-235, which is used in nuclear reactors, has a half-life of 700 million years. Potassium-40 (*°K) has a half-life of 13,000 million years. What Are the Three Types of Radiation? The three main types of ionizing radiation are called alpha, beta, and gamma. These are named for letters of the Greek alphabet, and they are often symbolized or abbreviated using the Greek letters o (alpha), (beta), and y (gamma). Alpha Radiation (or Alpha Particles). This type of radiation can be called either alpha radiation or alpha particles. Alpha radiation is a particle made of two protons and two neutrons that travels almost as fast as light through matter. The protons and neutrons make an alpha particle identical to a helium atom, but without the electrons. Although it is much too small to be seen with the best microscope, it is large compared with other types of radiation. The protons give it a large positive charge that pulls hard at the electrons of atoms it passes near. Each time the alpha particle pulls an electron off an atom in its path, the process of ionization occurs. The alpha particle loses some energy and slows down. It will finally take two electrons from other atoms at the end of its path and become a complete helium atom. This helium has no effect on the body. Because of its large mass and large charge, alpha particles ionize tissue very strongly. If the alpha particle is from radioactive material that is outside the body, it will lose all its energy before getting through the outer (dead) layer of your skin. This means that you can only be exposed to alpha radiation if you take radioactive material that produces alpha radiation into your body (for example, if you breathe it in or swallow it in food or drink). Once inside the body, this radioactive material can be mixed in the contents of the stomach and intestines, incorporated into a large particle, and deposited into the bone matrix, which would put it outside the range of living tissue. The alpha particles from this radioactive material can also damage living tissue. Beta Radiation (or Beta Particles). This type of radiation can be called either beta radiation or beta particles. Like alpha radiation, the beta type of ionizing radiation is a very small particle. Beta particles are high energy particles that are emitted from radioactive material with either a positive or negative charge, depending on the way they are made. Negative beta particles (called negatrons) originate in radioactive materials, like cobalt-60, that transform by changing a neutron ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 5 1. PUBLIC HEALTH STATEMENT into a proton. Beta particles with a positive charge (called positrons) are made by radioactive materials, like carbon-11, that transform by changing a proton into a neutron. Beta particles are smaller and much more penetrating than alpha particles. Positive beta particles have a positive charge, and negative beta particles have a negative charge. Some, such as those from tritium, can’t pass through the outer layer of dead skin. Most have enough energy, to pass through the dead outer layer of a person’s skin and expose the live tissue underneath. Beta radiation can also expose the body from within if the beta-emitting radionuclide is taken into the body. A beta particle loses its energy by ionizing atoms along its path. When their energy is spent, a negatron and a positron act differently. A negatron becomes an ordinary electron attached to some other atom it runs into, and has no more effects on the body. A positron collides with an ambient electron, and the two particles disappear. This electron-positron pair turns into a pair of gamma rays, which can affect other parts of the body. Gamma Radiation (or Gamma Rays). This type of radiation can be called either gamma radiation or gamma rays. Unlike alpha and beta radiation, gamma radiation is not a particle, but is aray. Itis a type of light you cannot see, much like radio waves, infrared light, ultraviolet light, and X-rays. When a radioactive atom transforms by giving off an alpha or a beta particle, it may also give off one or more gamma rays to release any excess energy. Gamma rays are bundles of energy that have no charge or mass. This allows them to travel very long distances through air, body tissue, and other materials. They travel so much farther than either alpha or beta radiation that the source of the gamma rays doesn’t have to be inside the body or near the skin. It can be relatively far away, like the radioactive materials in nearby construction materials, soil, and asphalt. A gamma ray may pass through the body without hitting anything, or it may hit an atom and give that atom all or part of its energy. This normally knocks an electron out of the atom (ionizes it). This electron then uses the energy it received from the gamma ray to ionize many other atoms by knocking electrons out of them as well. Since a gamma ray is pure energy, once it loses all its energy it no longer exists. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 6 1. PUBLIC HEALTH STATEMENT More information about alpha, beta, and gamma radiation can be found in Chapter 2 of this profile. 1.2 HOW DOES RADIOACTIVE MATERIAL ENTER AND SPREAD THROUGH THE ENVIRONMENT? Radioactive materials can be released to the air as particles or gases as a result of natural forces or from human industrial activities. People are most likely to be exposed to ionizing radiation that comes from natural sources, such as cosmic radiation from space and terrestrial radiation from radioactive materials in the ground. Ionizing radiation can also come from industrially produced radioactive materials (such as iridium-192), nuclear medicine (such as thyroid or bone scans using technetium-99m), the nuclear fuel cycle (producing fission products like cesium-137 and activation products such as cobalt-60), and production and testing of nuclear weapons. Radioactive material released into the air is carried by the wind and is spread by mixing with air. It can be diluted in the atmosphere and remain there for a long time. Radioactive gases remain in the air longer than radioactive particles. When the wind blows across land contaminated with radioactive materials, the particles that contain radioactive materials can be stirred up and returned to the atmosphere. Radioactive material on the ground can be incorporated into plants and animals, which may later be eaten by people. Water can contain man-made and naturally occurring radioactive materials that it dissolves from the soil it passes over or through. Rain also washes man-made and naturally occurring radioactive material out of the air. Radioactive material may be added to water through planned or accidental releases of liquid radioactive material from sources such as hospitals, research universities, manufacturing plants, or nuclear facilities. Radioactive material can also reach surface waters when airborne radioactive materials settle to the earth or are brought down by rain or snow, and when soil containing radioactive material is washed away into a river or lake. The movement of liquid radioactive material is limited by the size of the bodies of water into which the radioactive materials have drained. Like silt, some radioactive material may settle along the banks, or in the bottom, of ponds and rivers. Radioactive material may also concentrate in aquatic animals and ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 7 1. PUBLIC HEALTH STATEMENT plants. Eventually, radioactive material in liquid runoff that goes into rivers and streams may reach the oceans. Radioactive material moves very slowly in soil compared to the way it moves in air and water. Radioactive material will often stick to the surface of the soil. The organic material in soils can bind radioactive material, which slows its movement through the environment. If crops are watered with water containing radioactive material, the radioactive material may be taken up through the roots of the plant or may contaminate the outside of the plant. The plants may then be eaten by both animals and people. Radioactive materials that occur naturally in the soil (uranium, radium, thorium, potassium, tritium, and others) are also taken up by plants, and become available for intake by animals and people. More information about what happens to radioactive material when it enters the environment can be found in Chapters 5 and 6 of this profile. 1.3 HOW MIGHT | BE EXPOSED TO IONIZING RADIATION? The world is continually bathed with low levels of ionizing radiation, so all animals, plants, and other living creatures are exposed to small amounts of ionizing radiation every day. You are exposed to ionizing radiation from several sources every day, and you may be exposed from others at various times. Figure 1-1 is a pie graph showing all of the sources of radiation that the average American is exposed to every day. Most of your daily exposure to radiation is from radon (55%), which is found in all air, but at higher levels in indoor environments, such as schools and homes, and in the soil. You are Figure 1-1. Sources of Exposure to lonizing Radiation to the Average U.S. Citizen. (From NCRP Report 93, 1987) always exposed to radiation from cosmic sources ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 8 1. PUBLIC HEALTH STATEMENT (from outer space, 8%), terrestrial sources (rocks and soil, 8%), and natural internal sources (radioactive material normally inside your body, 10%). You may also be exposed to radiation from X-ray exams (11%), nuclear medicine exams (for example, thyroid scans, 4%), and consumer products (for example, TV and smoke detectors, 3%), as well as other sources. Less than 1% of the total ionizing radiation that people living in the United States are exposed to comes from their jobs, nuclear fallout, the nuclear fuel cycle, or other exposures. However, people in some types of jobs may have higher exposures (pilots and flight attendants, astronauts, industrial and nuclear power plant workers, X-ray personnel, medical personnel, etc.). Some groups of people have been exposed to higher-than-normal levels of ionizing radiation from weapons testing or accidents at nuclear facilities or military bases. Some of these exposures are discussed in Chapter 3 of this profile. Not everyone will be exposed to every source or the same percentage of radiation shown in Figure 1-1. For example, if you are not regularly X-rayed because of illness, you may receive less total exposure to radiation than what is shown. However, if you live in a town or city at a high altitude, you may be exposed to more radiation from outer space than someone who lives in a town or city near the ocean at sea-level. Table 1-1 shows you that where you live and what you do determines how much ionizing radiation you will receive. The units used to measure doses of ionizing radiation are the rem and the sievert (Sv) (1 Sv = 100 rem). These are large doses, so everyday doses are measured in the smaller units, millirem (mrem) and millisievert (mSv) (1 mSv = 100 mrem). The unit of absorbed dose is the rad and the gray (Gy). The average American is exposed to a small amount of ionizing radiation every year (about 3.6 millisievert or 360 millirem). However, the dose of ionizing radiation you receive may be different. One major reason is that background radiation depends on the type of soil, the altitude, the building materials, and the ventilation at your home, school, and office. Another major factor is the number of medical X-rays and nuclear medicine tests you get. More information about exposure to ionizing radiation can be found in Chapters 2 and 6 of this profile. **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 1. PUBLIC HEALTH STATEMENT Table 1-1. Approximate Doses of Ionizing Radiation to Individuals Approximate Doses of Activity Radiation Received Comments Average American Exposure to lonizing Radiation? Total yearly dose 360 mrem/yr From natural sources 300 mrem/yr From man-made sources 60 mrem/yr From nuclear power Less than 1 mrem/yr Approximate Doses of lonizing Radiation and Where You Live (Cosmic + Terrestrial) Kerala, India, resident 1300 mrem/yr Concentrated radioactive material in the soil Colorado state resident 179 mrem/yr High altitude above sea level Boston, Massachusetts, resident 100 mrem/yr Louisiana state resident 92 mrem/yr Low altitude above sea level Approximate Doses of lonizing Radiation Above Background Radiation and Some Activities® Anyone near a patient released after a Less than 500 Guidance for medical facilities. nuclear medicine test. mrem/patient. Quantity depends on the quantity of radioactive material. A person who works inside a nuclear 300 mrem/yr power plant A person who gets a full set of dental 40 mrem X-rays A flight attendant flying from New York 5 mrem/flight to Los Angeles Watching a color TV set 2-3 mrem/yr A person who lives directly outside of a 1 mrem/yr nuclear power plant A person who watches a truck carrying Less than 0.1 mrem/truck nuclear waste pass by “Taken from NCRP 1976a ®Taken from NCRP 1987b, 1987e, 1989a, 1989¢c mrem = millirem for each occasion; mrem/yr = millirem per year 1.4 HOW CAN IONIZING RADIATION ENTER AND LEAVE MY BODY? This question is easier to answer for chemicals than for ionizing radiation. You are exposed to chemicals only if they are on your skin or inside you. There is one more way you can be exposed to ionizing radiation—from sources at a distance. The answer to the question of how you can be exposed to ionizing radiation can be broken into two parts. One paragraph below describes ionizing radiation that comes from a source outside your body and some distance away (external radiation). The second paragraph describes ionizing radiation that comes from a source inside your body (internal radiation). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 10 1. PUBLIC HEALTH STATEMENT External radiation comes from natural and man-made sources of ionizing radiation that are outside your body. Part of the natural radiation is cosmic radiation from the stars. The rest is given off by radioactive materials in the soil and building materials that are around you. Asa result of human activities, higher levels of natural radioactive material are left in products or on the land. Examples of such activities are manufacturing fertilizer, burning coal in power plants, and mining and purifiying uranium. Ionizing radiation from human activities adds to your external radiation exposure. Some of this radiation is given off by X-ray machines, televisions, radioactive sources used in industry, and patients who have had nuclear medicine tests. The rest is given off by man-made radioactive materials in consumer products, industrial equipment, atom bomb fallout, and to a smaller extent by hospital waste and nuclear reactors. Gamma rays are the main type of ionizing radiation that are of concern when you are exposed to external sources of ionizing radiation. Gamma rays from natural and man-made sources pass through your body just like X-rays do, at the speed of light. In fact, gamma rays and X-rays are special bundles of light energy that you cannot see, feel, or smell. Many gamma rays speed directly through your body without hitting anything. When one hits a cell, it leaves a small bit of energy behind that can cause damage. Since a gamma ray is only a bundle of energy, it leaves nothing else behind. Other types of ionizing radiation, like alpha and beta particles, hit your body but normally do not have enough energy to get inside to harm you. Your external dose depends on the amount of energy that ionizing radiation gives to your body as it passes through. Exposure to external radiation does not make you radioactive. Internal radiation is ionizing radiation that natural and man-made radioactive materials give off while they are inside your body. You take radioactive materials into your body every day since they are in the air you breathe, the food you eat, and the water you drink. They can also be injected into you for medical purposes. Examples of natural radioactive materials that enter and leave your body every day include potassium-40, carbon-14, radium, and radon. Sometimes, natural conditions or industrial activities concentrate radioactive materials. If you are exposed to these, you will take in more radioactive material. Man-made radioactive materials can also get inside your body from any special nuclear medicine test that your doctor may give you and from the fallout from past nuclear weapons testing. Hospitals and nuclear reactors release radioactive “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 1 1. PUBLIC HEALTH STATEMENT materials in ways that keeps your exposure low. Radioactive materials build up in your body if you take them in faster than they leave. This is determined by how fast your body gets rid of them in urine and feces and by the rate of their radioactive transformation. In addition to gamma rays, these natural and man-made radioactive materials can give off alpha and beta particles. Since the radiation is formed inside your body, it exposes you from the inside. Many gamma rays escape your body without hitting anything. When a gamma ray does hit a cell, it transfers energy to the cell. If enough energy is transferred, the cell may be damaged. Alpha and beta particles travel short distances, giving energy to cells they hit and causing damage. They lose energy with each hit and, like a car with its brakes on, quickly come to a stop. Their energy is totally absorbed inside your body. When alpha particles come to a stop, they become helium that you breathe out later. When beta particles come to a stop they become electrons and attach to atoms near them. Your internal dose is a measure of the energy deposited by all the ionizing radiation that is produced inside your body. More information about how ionizing radiation enters and leaves your body can be found in Chapters 2, 3 and 5 of this profile. 1.5 HOW CAN IONIZING RADIATION AFFECT MY HEALTH? To protect the public from the harmful effects of ionizing radiation and to find ways to treat people who have been harmed, scientists use many tests. One way to see if radiation will hurt people is to learn how radioactive materials are absorbed, used, and released by the body; for radiation and radioactive materials, animal testing may be necessary. Animal testing may also be used to identify health effects such as cancer or birth defects. Without laboratory animals, scientists would lose a basic method to get information needed to make wise decisions to protect public health. Scientists have the responsibility to treat research animals with care and compassion. Laws today protect the welfare of research animals, and scientists must comply with strict animal care guidelines. “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 12 1. PUBLIC HEALTH STATEMENT Scientists have been studying the effects of ionizing radiation in humans and laboratory animals for many years. Studies so far have not shown that the low levels of ionizing radiation we are exposed to every day cause us any harm. We do know that exposure to massive amounts of ionizing radiation can cause great harm, so it is wise to not be exposed to any more ionizing radiation than what is necessary. Exposure to ionizing radiation can lead to many effects, like skin burns, hair loss, nausea, birth defects, illness, cancer, and death. How you are affected after exposure to ionizing radiation will depend on how much ionizing radiation you received and how long you were exposed. Increasing the size of the dose increases the severity of the effect. Ionizing radiation may also increase your chance of getting cancer. How likely you are to get cancer from ionizing radiation again depends on how much ionizing radiation you received and how long you were exposed. Increasing the size of the dose increases the chance of getting cancer. Scientists base radiation safety standards on what is called a “zero threshold” assumption. That is, they predict that any amount of a substance that can cause cancer (called a carcinogen), no matter how small of a dose, carries with it a corresponding increase in the chance of causing cancer. Increasing the size of the dose increases the likelihood of causing cancer. Cancers that are caused by radiation are completely indistinguishable from those that occur spontaneously or are caused by other carcinogens. The effects of internally deposited radioactive material are the same as those of external radiation. The effects depend on the size of the dose and how long you were exposed. The radiation absorbed dose, in turn, depends on the radioactive material, the quantity of activity, the type and energy of the radiation, the half life of the radioactive material, and how it was taken into your body. Only if the dose is great enough, can we expect harmful health effects. More information about the biological effects of ionizing radiation can be found in Chapters 2, 3, and 5 of this profile. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 13 1. PUBLIC HEALTH STATEMENT 1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER | HAVE BEEN EXPOSED TO IONIZING RADIATION? There are no easy or accurate medical tests that your doctor can perform to determine if you have been exposed to ionizing radiation. In fact, most doctors are not able to assess how much radiation you were exposed to. Tests for Recent Exposure to lonizing Radiation. A great degree of overexposure is necessary to cause the clinical signs or symptoms of radiation exposure. The two kinds of tests scientists use to see if you have been overexposed to ionizing radiation examine changes in blood cell counts and changes in your chromosomes. If you are exposed to no more than 10 rads of ionizing radiation, there are no detectable changes in blood cell counts. The most sensitive measure of radiation exposure involves a study of your chromosomes. This is a special test for low doses (relative to doses for clinically observable signs or symptoms) and is useful for doses greater than about three times the maximum annual permissible dose for radiation workers. Changes in the white blood cell count may be seen in people whose doses exceeded about five times the occupational maximum permissible annual dose. Greater radiation doses can be estimated using these two special tests. Doctors do not treat people who are exposed to ionizing radiation unless the dose is extremely large. In those cases, doctors usually treat the symptoms with pain killers, antibiotics, and blood transfusions as needed. More information on the changes that occur in your body and what doctors look for after you are exposed to ionizing radiation can be found in Chapter 2 of this profile. Tests for Radioactive Material Inside Your Body. Scientists can also examine your blood, feces, saliva, urine, and even your entire body to see if measuraable amounts of radioactive material are still in any part of your body. Different tests are used for different types of radioactive material. Several types of instruments are available to look for each type of radiation. These instruments are not available at your doctor’s office. They are normally large, heavy, and available only in laboratories. Equipment usually consists of a “detector,” electrical cables, and a “processor.” The detector contains material sensitive to one or more types of radiation, so the detector is chosen based on the type of radiation we want to measure. Alpha, beta, and gamma ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 14 1. PUBLIC HEALTH STATEMENT radiation have different energies that depend upon the radioactive atom they come from. Because of this, scientists can tell which type of radioactive material is on your skin or inside your body by measuring the different energies of the radiation. More information about the detection of ionizing radiation and biomarkers for ionizing radiation exposure can be found in Chapter 2 of this profile. 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? Recommendations and regulations are periodically updated as more information becomes available. For the most current information, check with the federalor state agency or organization that provides it. Some regulations and recommendations for ionizing radiation include the following: We have seen health effects from very high doses of ionizing radiation, but not at normal everyday levels. To be cautious, we assume that there could be some harmful effects at any dose, no matter how small. Because of its potential to cause harmful health effects in exposed people, regulations and guidelines have been established for ionizing radiation by state, national, and international agencies. The basic philosophy of radiation safety is to allow only a reasonable risk of harm using the concept of “as low as reasonably achievable” (ALARA). More specific information about the regulations in the United States and in your state can be found in Chapter 7 of this profile. Radiation protection standards for radiation workers and members of the public are recommended by the International Commission on Radiological Protection (ICRP) and the National Council on Radiation Protection and Measurements (NCRP). These standards are not regulations, but they provide the scientific basis for the making of regulations by federal agencies, such as the EPA, the Nuclear Regulatory Commission (NRC), and the Department of Energy (DOE), as well as by the individual states. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 15 1. PUBLIC HEALTH STATEMENT The EPA is responsible for federal radiation protection guidance for environmental radiation standards and regulations to implement specific statutory requirements, such as the Safe Drinking Water Act and the Clean Air Act. The NRC's regulations apply to all types of ionizing radiation that are emitted from special nuclear material (such as nuclear reactor fuel) and from by-product material (materials made radioactive in the use of special nuclear material), and from source material (material from which nuclear fuel is made). The NRC sets limits on the total exposure to ionizing radiation. NRC has also determined the amounts of different radioactive materials that will give these limiting doses if taken into the body. These are called Annual Limits on Intake (ALI) and derived air concentrations (DAC). The DOE has issued regulations for its facilities. States also regulate radioactive materials and other sources of radiation that are not regulated by the NRC. These include sources of natural radioactivity, such as radium, and radiation-producing machines, such as X-ray machines and radioactive material produced by particle accelerators. The current federal and state regulations limit radiation workers' doses to 0.05 Sv/year (5 rem/year). The limit for the unborn child of a female radiation worker is 0.005 Sv/year (0.5 rem/year). For the general public, the limit is 0.001 Sv/year (0.1 rem/year), with provisions for a limit of 0.005 Sv/year (0.5 rem/year) under special circumstances. EPA's National Emission Standards for Hazardous Air Pollutants (NESHAPS) contain regulations that limit the dose from radionuclides released to the air to 0.1 mSv/year (10 mrem/year). Based on the Safe Drinking Water Act, the EPA has issued drinking water standards for radionuclides, which include dose limits of 0.04 mSv/year (4 mrem/year) for man-made sources of beta and photon emitters. The EPA and NRC have been considering standards for cleaning up sites contaminated with radioactive materials. These would make sure the public exposure would not be more than about 0.15 to 0.25 mSv (15 to 25 mrem) per year. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 16 1. PUBLIC HEALTH STATEMENT 1.8 WHERE CAN | GET MORE INFORMATION? If you have any more questions or concerns, please contact your community or state health or environmental quality department or Agency for Toxic Substances and Disease Registry Division of Toxicology 1600 Clifton Road NE, Mailstop E-29 Atlanta, GA 30333 * Information line and technical assistance Phone: (404) 639-6000 Fax: (404) 639-6315 or 6324 ATSDR can also tell you the location of occupational and environmental health clinics. These clinics specialize in recognizing, evaluating, and treating illnesses resulting from exposure to hazardous substances. * To order toxicological profiles, contact National Technical Information Service 5285 Port Royal Road Springfield, VA 22161 Phone: (800) 553-6847 or (703) 487-4650 **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 17 2. PRINCIPLES OF IONIZING RADIATION 2.1 INTRODUCTION The term “radioactive material” is defined as any material containing radioactive atoms which emit ionizing radiation as they transform into stable or less radioactive atoms. The frequently used terms “radiation,” and “ionizing radiation” are defined in this toxicological profile as a specific form of radiation that possesses sufficient energy to remove electrons from the atomic or molecular orbital shells in the tissues that they penetrate (Borek 1993). This process is called ionization, and is the source of the name “ionizing radiation.” This penetration results in the ionization of atoms and molecules in the exposed tissue. When this energy is received in appropriate quantities and over a sufficient period time, it can result in tissue damage and disruption of cellular functions at the molecular level. Ionizing radiation can also affect deoxyribonucleic acids (DNA) and other intracellular structures. The clinical manifestations of ionizing radiation can be negligible (no effect), acute (occurring within several hours to several months after exposure), or delayed or latent (occurring several years after the exposure), depending on the dose and the rate which it was received. All organisms (i.e., bacteria, plants, or animals, including humans) are exposed each day to some amount of ionizing radiation. In the United States, as shown in Figure 1-1, 82% of the dose received from ionizing radiation comes from natural sources: 55% from radon; 8% from cosmic radiation; 8% from rocks and soil; and 11% from internal exposures to ionizing radiation from food and water consumed in the daily diet, such as potassium-40 (*’K). The remaining 18% of the daily dose may originate from anthropogenic sources; it is composed of medical X-ray exposure (11%), nuclear medicinal exposure (4%), consumer products (3%), and other sources (<1%). This last category includes occupational sources, nuclear fallout, the nuclear fuel cycle radioactive waste, and other miscellaneous exposures. Radiation dose is expressed in units of rads and millirad (1 rad = 1,000 millirad) or grays (Gy) and milligrays (mGy). For administrative, regulatory, and radiation safety purposes, a unit called the rem or the sievert (Sv) (1 rem = 0.01 Sv) is used. For beta and gamma radiation, 1 rad = 1 rem, while for alpha radiation, 1 rad = 20 rem. For the population of the United States, the average annual total effective dose equivalent (natural and anthropogenic), is approximately 360 mrem (3.6 mSv) per year (BEIR V 1990). Sources of ionizing radiation can also be found at many waste sites in the United States and abroad. A survey of the open literature found that it is quite comprehensive and replete with discussions pertaining to the biological and toxicological effects of ionizing radiation. Much of the information on the biological/ “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 18 2. PRINCIPLES OF IONIZING RADIATION toxicological effects of ionizing radiation was obtained from laboratory animal studies and human epidemiological studies (see Chapters 3, 4 and 5). The human data are mostly from studies of World War II atomic bomb survivors, medical patients exposed to radiation and radioactive material, and radium dial painters. A great deal is currently known about the biological, toxicological and toxicokinetic aspects of radionuclides, as well as the general mechanisms of action of ionizing radiation. It is clear that much remains to be learned about the specific mechanisms by which ionizing radiation exerts its effects, how these effects can be minimized in living tissues, and what the long-term effects of very low doses of ionizing radiation over long periods of time will be (see Chapter 3). However, we know enough to allow the use of radioactive materials and ionizing radiation in commerce, industry, science, and medicine. For the purposes of this toxicologic profile, discussions on the effects of ionizing radiation will be limited to the alpha (ct), beta () and gamma (7) radiation, since these three types of radiation are the most likely to be encountered at Department of Energy (DOE) hazardous waste sites (see Chapter 3, Table 3-1). This profile provides an in- depth discussion on the finer points of radiation biology and radiation toxicology. Chapters 3 and 5 provide the reader with a comprehensive overview of a representative cross-section of the available literature that pertains to the effects of ionizing radiation, both in humans and laboratory animals. Specific radionuclides will be used to demonstrate how toxicological effects can occur, but these effects can also be caused by other radionuclides that emit the same or other types of ionizing radiation (see Chapters 3 and 5). However, we know enough to allow us to safely use radioactive materials and ionizing radiation in commerce, industry, scient and medicine. Readers should consult the glossary of this toxicological profile (Chapter 9) to become familiar with the terminology used when discussing both the effects of exposure to ionizing radiation and the characteristics of these three forms of ionizing radiation. Several excellent texts and review documents are currently available in the open literature that provide important background material used in developing other sections of this profile (BEIR IV 1988; BEIR V 1990; Cember 1996; Faw and Shultis 1993; Harley 1991; Roesch 1987; UNSCEAR 1993). This toxicological profile contains Observed Health Effects from Radiation and Radioactive Material tables that summarize the effects of ionizing radiation for both humans and laboratory animals (see Chapter 8). It should be noted here that in radiation biology, the term "dose" has a very specific meaning. As discussed in more depth later in this chapter, the term "dose" used in these tables refers to the amount of radiation energy absorbed per unit mass by the organ, tissue, or cell; dose is typically expressed either in grays (Gy) or in rads (1 Gy = 100 rad). For example, estimation of the dose to lung tissue or specific cells in the lung from a given exposure to plutonium-239 (**Pu) is accomplished by modeling the sequence of events involved in the inhalation, deposition, clearance, and transformation of 23%Pu within the lung. While based on the current ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 19 2. PRINCIPLES OF IONIZING RADIATION understanding of lung morphometry and experimental data for other radionuclide toxicokinetics, different models make different assumptions about these processes, thereby resulting in different estimates of dose and risk coefficient. The units of measure in the studies that describe the health effects of ionizing radiation varied from one report to another. Some studies reported the amount of radioactive material introduced into the body (curies [Ci] or becquerels [Bq]) when describing the biological effects related to ionizing radiation, while other authors reported units of absorbed dose (rad, Gy) or dose equivalent (rem, Sv). Although the units did differ among the many reports, attempts were made to standardize the reporting of doses in units of rad in order to minimize confusion and provide a basis by which dose responses could be determined and evaluated. No Minimal Risk Levels (MRLs) have been derived for any route of exposure in this profile at this time. However, ATSDR is currently in the process of examining and critically evaluating the large database of health effects caused by exposure to ionizing radiation. During this evaluation process, ATSDR is also examining many other factors, including (1) which specific studies would lend themselves to be most suitable for deriving an MRL, and (2) what health effect(s) an MRL should be based upon (cataract formation, reduction in IQ, etc.). Any MRLs that are derived will be integrated into the final version of this profile. An understanding of the basic concepts in radiation physics, chemistry, and biology is important to the evaluation and interpretation of radiation-induced adverse health effects and to the derivation of radiation protection principles. This chapter presents a brief overview of radiation physics, chemistry, and biology and is based to a large extent on the reviews of Eichholz (1982), Hendee (1973), Early et al. (1979), Faw and Shultis (1993), Harley (1991) and Roesch (1987). 2.2 HISTORY, BACKGROUND INFORMATION, AND SCIENTIFIC PRINCIPLES OF IONIZING RADIATION 2.2.1 Historical Perspective on lonizing Radiation Ionizing radiation has been present since the earth was created. Before the 1890s, there were only natural sources of ionizing radiation such as radiation from cosmic sources, and radioactive material inside the body and in rocks, soil, and air. Since ionizing radiation cannot be observed using any of the five senses, any biological effects induced by these natural sources of ionizing radiation were not recognized by the people using these materials that emitted ionizing radiation or by the people living in communities where there were “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 20 2. PRINCIPLES OF IONIZING RADIATION elevated levels of radiation. Much of the radiation exposure was in the form of low-level cosmic and terrestrial radiation. About 1,800,000 years ago, the only natural "nuclear reactor” operated for about 100,000 years in the uranium-rich soil around what is now Oklo, Gabon. The first known use of uranium occurred in 79 AD, when Roman artisans were producing yellow-colored glass in a mosaic mural near Naples; this activity produced low levels of ionizing radiation. The first reports of adverse health effects that were likely due to ionizing radiation from inhaled radon gas probably occurred around 1400 AD, when a mysterious malady resulted in the deaths of miners at an early age in the mountains around Schneeberg and Joachimsthal in the Sudetenland (now Czechoslovakia). This mysterious disease was known as "mountain sickness." It was not until the discovery of mystery rays or “X-rays” in 1895 that people began to be aware of the almost magical presence of these invisible “rays” that could produce a visible effect on the body. In the summer of 1894, Wilhelm Konrad Roentgen began experiments with cathode ray tubes and on November 8, 1895 he observed that a few crystals of barium platinocyanide, which were lying on a table, produced a fluorescent glow. He subsequently discovered that some unknown component (“X”) from the cathode ray tube could also penetrate solid substances, and that “X-rays” had the same effect on a photographic plate as visible light. What followed was the first "Roentgen exposures," or “Roentgenograms,” which were photographs that were able to show the shapes of metal objects locked in a wooden case and the bones inside his wife’s hand. A month after his discovery, Roentgen sent a manuscript of his extraordinary findings to the Physical-Medical Association in Wuerzburg, titled Concerning a New Kind of Ray: Preliminary Report. Other periodicals such as Nature and Science subsequently published the report in the following year and Roentgen received wide acclaim for his discovery, both in the scientific and lay communities in the years to come. Others quickly found practical applications for these “X-rays” (also called “Roentgen rays”). In 1896, the first diagnostic X-ray in the United States was performed by E. Frost. Within the next 2 years, the first X-ray picture of a fetus still in utero was taken; this was followed by the first use of an X-ray in dentistry. Adverse health effects due to exposure to X-rays were soon reported, including a report by Thomas Edison asserting that eye injuries can be produced by exposure to X-rays, and other reports of alopecia (hair loss) and erythema (skin reddening). Roentgen’s discovery of X-rays was followed by Antoine Henri Becquerel’s discovery of radioactivity. Becquerel found that photographic plates that were lying near pitchblende (a uranium ore) were exposed despite being sealed in light-tight envelopes. The exposure, he found, was due to radiations emitted from the **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 21 2. PRINCIPLES OF IONIZING RADIATION pitchblende. Subsequent studies showed that there were three uniquely different radiations, which he called alpha, beta, and gamma. Later, it was shown that Roentgen’s X-rays and Becquerel’s gamma rays were exactly the same kind of radiation. After these discoveries, scientific interest in the properties of ionizing radiation began to increase dramatically. Radioactive thorium (Th) was discovered by Schmidt in 1898. A few months later, Marie and Pierre Curie isolated polonium (Po) from pitchblende, a variety of the mineral uraninite (largely UO,), which occurs as a constituent of quartz veins and is a source of radium (Ra) and uranium (U). The Curies later isolated radioactive ***Ra from pitchblende and explained the natural transformation of an unstable atom of a higher atomic number to one of a lower atomic number, referred to as transformation or “decay.” The Curies ultimately coined the word “radioactivity.” In the years to come, other notable scientists who contributed to this new area of science included: Villard (discovered gamma rays), Rutherford (discovered radioactive gas emanating from thorium and coined the term “half-life”), Becquerel (decomposition units of radioactivity), Planck (quantum theory), Einstein (mass-energy relationship; photoelectric effect), and Hess (reported the existence of “cosmic rays” [ionizing radiation] at high altitudes). “If it were ever possible to control at will the rate of disintegration of radio-elements, an enormous amount of energy could be obtained from a small amount of matter.” This statement, spoken by Ernest Rutherford in 1904, expressed the obvious future implications for the use of radionuclides (in particular uranium and plutonium) in generating large amounts of electric power and in the production of nuclear weapons approximately 40 years later. The use of the “atomic bomb” (although this term is somewhat of a misnomer) would make an important contribution to ending the second World War. Much scientific research needed to be performed to move from theory to application. The project responsible for taking many of the theoretical ideas on atomic energy proposed since Roentgen’s novel discovery and applying them in a real-world application that would result in the creation of the first atomic weapon was code named “The Manhattan Project.” The Manhattan Project was named for the Manhattan Engineer District of the U.S. Army Corps of Engineers, because much of the early theoretical research on the potential of nuclear energy was done at Columbia University and because the Manhattan District of the U.S. Army Corps of Engineers was located near Columbia University in New York City. Initiated by President Roosevelt on the recommendation of several physicists who had fled Europe, the program was slowly organized after nuclear fission was discovered by German scientists in 1938. Many U.S. scientists began to express the fear that the Germans, under their ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 22 2. PRINCIPLES OF IONIZING RADIATION dictator Adolf Hitler, would attempt to build a fission bomb which would pose a serious threat to the world. It was subsequently decided that the United States must be the first country to harness this new technology in order to maintain the future balance of world power. In 1942, Brigadier General Leslie Groves was chosen to lead the Manhattan Project. He immediately purchased a site at Oak Ridge, Tennessee, and constructed the facilities to extract and purify the SU isotope fuel needed to power the weapon. He secured a 550-square mile site in Eastern Washington State, later called the “Hanford Works,” for the highly secret reactor production and chemical refinement of plutonium metal. The first plutonium in gram quantities was produced by the Hanford “B” reactor in early 1945. (B Reactor has been designated a National Historic Site). He also appointed theoretical physicist J. Robert Oppenheimer as director of a weapons laboratory, built on an isolated plot of land at Los Alamos, New Mexico. In 1945, **U of adequate purity was shipped to Los Alamos and was used in the testing in the first of two prototype weapons. In the first prototype, one subcritical piece of uranium was fired at another subcritical piece down a gun barrel; the combined pieces formed a supercritical, explosive mass. The second prototype was constructed using plutonium. In the plutonium prototype, the plutonium was surrounded with explosives to compress it into a superdense, supercritical mass far faster than could be done in a gun barrel. The result was tested at Alamogordo, New Mexico, on July 16, 1945, and was the first detonation of an atomic-type weapon. Two more atomic weapons were subsequently manufactured in the United States and detonated over Hiroshima and Nagasaki, Japan, in August 1945. The use of these devices, the most destructive weapons at the time, brought the war in the Pacific to an end much more quickly, thus saving Allied soldiers who would have been lost in a ground invasion of the Japanese mainland using only the conventional weapons of the time. The two bombs detonated over Japan in the final days of World War II were made from two different types of explosive material. The Hiroshima bomb was made from the highly enriched >°U, extracted from ore containing the much more abundant isotope 28. This bomb, which was released over Japan's seventh largest city on 6 August 1945, contained approximately 60 kilograms of highly enriched uranium; its detonation destroyed 90% of the city. The explosive charge for the bomb detonated over Nagasaki 3 days later was provided by about 8 kg of 239Py and caused a similar amount of destruction. Both atomic devices were detonated in the air over the city; there was no ground impact as with conventional bombs of the day. The devastating effects of the bombs depended essentially upon the blast, shock, and heat released at the moment of the explosion, causing immediate fires and destructive blast pressures. Since the bombs were detonated at a height of some 600 meters above the ground, only a relatively small proportion of the radioactive fission products were deposited on the ground near the “ground zero” point below the site of ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 23 2. PRINCIPLES OF IONIZING RADIATION detonation. Some deposition occurred in areas near each city due to local rainfall soon after the explosions, specifically at positions a few kilometers to the east of Nagasaki and in areas to the west and northwest of Hiroshima. Generally, the majority of the fission products were carried into the upper atmosphere by the heat generated by the explosion. On the fallout’s return to earth, it contributed to human radiation exposure. In Hiroshima, with a resident civilian population of about 250,000 people, an estimated 45,000 died on the first day after the bombing and an additional 19,000 during the subsequent 4 months. In Nagasaki, with a resident population of about 174,000, an estimated 22,000 died on the first day and an additional 17,000 deaths were reported within the next 4 months. Unrecorded deaths of military personnel and foreign workers may have added to these estimates. Teratogenic effects on fetuses were severe among those heavily exposed, resulting in many birth deformities and stillbirths over the next 9 months. No genetic damage has been detected in the survivors’ children and grandchildren, despite careful and continuing investigation by a joint Japanese-U.S. foundation. Since then, some of the surviving adults developed leukemias and other cancers (see Chapter 3). The major source of exposure in both cities was from the penetrating gamma radiations. The atomic bombs used in Japan in 1945 and the bombs tested during the following 7 years depended on the fission of *5U or ***Pu, mostly ***Pu. For comparison, the explosive power of the Hiroshima bomb was about 15 kilotons (equivalent to 15,000 tons of trinitrotoluene [TNT]) and that of the Nagasaki bomb was approximately 25 kilotons. The total equivalent of all atmospheric weapon tests made by the end of 1951 was in the vicinity of 600 kilotons. After 1951, the atomic bombs being tested included hydrogen bombs, which became more sophisticated and had explosive effects about a thousand times greater than those of the Hiroshima and Nagasaki type bombs; by the end of 1962, the total of all atmospheric tests had risen from the 1951 value of 0.6 million tons of TNT equivalent, to about 500 million tons of TNT equivalent. This vast increase in scale was due to the testing of the “thermonuclear” weapons or “hydrogen bombs” or “H-bombs,” which depended not on the fission of a critical mass of fissile material alone, but on a two or three-stage process initiated by a fission reaction. Briefly, the hydrogen bomb uses the same process that the sun uses to release its tremendous amounts of energy. In the hydrogen bomb, the nuclei of two light atoms (usually hydrogen) are fused together to form a heavier atom, helium. A fission reaction, one where a heavier atom is split into lighter ones, generates the energy to trigger the fusion reaction. The United States exploded its first hydrogen bomb ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 24 2. PRINCIPLES OF IONIZING RADIATION in November 1952 at Eniwetok Atoll in the South Pacific. Atomic weapons development in the United States and in other nations has continued well into the 1990s. The development of the “atomic bombs” has frequently received more attention than the peaceful use of atomic energy and ionizing radiation. Peaceful uses of atomic substances emitting ionizing radiation have also been developed quite successfully over the years. An important application has been in the generation of safe, controlled and long-term power sources for the civilian population. Today, nearly 25% of the electricity generated in the U.S. (75% in Maine and 50% in South Carolina) comes from nuclear power. In countries like France and Japan, the use is higher. On December 20, 1951, the first usable electricity produced from nuclear energy was manufactured at the National Reactor Testing Station, now called the Idaho National Engineering and Environmental Laboratory (INEEL), in Idaho Falls, Idaho. The electricity produced lit four light bulbs across a room of the Experimental Breeder Reactor I (EBR-I). In 1953, these scientists demonstrated that a reactor could create more fuel than it used, "breeding" fuel as it created electricity. EBR- I operated as a research reactor until 1963, at which time EBR-II became active; EBR-II is now a historical monument. In July 1955, Arco, Idaho, became the first U.S. town to be powered by nuclear energy, supplied by power from the Borax-III reactor, an early prototype of a boiling water-type nuclear reactor. The Sodium Reactor Experiment in Santa Susana, California, generated the first power from a civilian nuclear reactor on July 12, 1957, using sodium as a substitute for water as the primary coolant. The first large-scale nuclear power plant in the world began operating in Shippingport, Pennsylvania, in December 1957. Nuclear reactors continue to be used today as a source of power for many states and countries; however, public concerns about nuclear reactor safety have intensified due to well-publicized accidents (see Chapters 4 and 6). Medical uses of radioactive elements emitting ionizing radiation have also been developed and have generally served to benefit mankind, playing a significant role in medical diagnosis and treatment. Controlled amounts of ionizing radiation, in the form of X-rays, have been used for a century as an aid in the diagnosis and treatment of both osseous and soft tissue diseases in humans and animals. Today, much is known about the health effects of high doses of X-rays, as well as other forms of ionizing radiation; however, this has not always been the case. In 1947, doctors in Israel treated ringworm of the scalp with 400 rad of X-rays to cause the hair to fall out (alopecia); it was later found that this treatment regimen led to the formation of thyroid tumors and brain cancers. Radium-224 (***Ra) was used in the treatment of ankylosing spondylitis in Germany in the 1940s; these treatments later were associated with an increased incidence of osteosarcomas. In addition to X-rays, radionuclides like iodine-131 (**'I) and metastable technecium 99 (®™Tc) have been used to successfully diagnose and/or treat a wide range of diseases found throughout the body. Laboratory **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 25 2. PRINCIPLES OF IONIZING RADIATION research has benefited from the use of radionuclides, typically in the form of radiolabeled tracers harnessed in radioimmunoassays for many drugs, hormones, chemicals, and toxicokinetic studies, as well as many other applications. 2.2.2 Basic Information on lonizing Radiation Ionizing radiation is any of several types of particles and rays given off by radioactive material, nuclear reactions and radiation producing machines. Ionizing radiation is odorless, tasteless, and invisible to the naked eye. All life on earth is exposed to low levels of ionizing radiation from terrestrial and cosmic sources every day. Itis called ionizing radiation because it changes or “ionizes” molecules that it comes into close contact with, including a number of macromolecules such as chromosomes and other genetic components. To explain exactly what ionizing radiation is, we begin at the atomic level with atoms, how they come to be radioactive, and how they give off ionizing radiation. Although there are several types of ionizing and non- ionizing radiation, this profile will only discuss three types of ionizing radiation: alpha, beta, and gamma radiation. This profile will not address non-ionizing radiation, such as radiowaves, microwaves, infrared light, and ultraviolet light. The materials we call elements are composed of atoms, which in turn are made up of neutrons, protons, and electrons. Protons (positively charged particles) and neutrons (neutral particles with no charge) reside in and primarily comprise the nucleus of any atom, while electrons exist in a “cloud” of orbits around the nucleus. A nuclide is the general term referring to any atom. The nuclide is characterized by the composition of its nucleus and hence by the number of protons and neutrons in the nucleus. All atoms of an element have the same number of protons (this is given by the atomic number) but may have different numbers of neutrons (this is reflected by the atomic mass or atomic weight of the element). Atoms with different atomic masses but the same atomic number are referred to as isotopes of an element. The typical numerical combination of protons and neutrons in most nuclides is such that the atom is said to be stable, meaning that the nuclide does not spontaneously gain or lose any of its inherent subcomponents (protons, neutrons, or electrons). However, if there are too few or too many neutrons, the nucleus of the atom is considered to be unstable, and will undergo one or more transformation processes in order to obtain and maintain a stable energy configuration. Unstable nuclides undergo a process referred to as radioactive transformation or “decay” in which particles and/or energy is emitted. These unstable atoms are called radionuclides, their emissions are called ionizing radiation, and the whole property is called radioactivity. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 26 2. PRINCIPLES OF IONIZING RADIATION The transformation of this unstable radionuclide results in the formation of a new nuclide, which is typically stable. For those radionuclides that are still radioactive, a series of one or more further transformations are needed to form a stable atom. This series of transformations, called a “decay” chain, is typical of the very heavy natural elements like uranium and thorium. For use as a point of reference, the first radionuclide in the chain is called the parent radionuclide with the subsequent products of the transformation called progeny, daughters, or transformation products. There are two general classifications of radiation and radionuclides: natural and man-made. Naturally occurring radionuclides exist in nature, and no additional energy is necessary to place them in an unstable state. Natural radioactivity is the property of many naturally occurring radionuclides especially among elements that are heavier than lead. Radionuclides such as Ra and **°U primarily emit alpha particles and are called alpha emitters. Some lighter radionuclides such as carbon-14 (*C) and tritium (*H) emit beta particles as they transform into a more stable atom. After emitting particles, most radionuclides still have some excess energy that they emit in the form of photons; these are referred to as y emitters. Natural radioactive atoms, which are heavier than lead (Pb), cannot attain a stable nucleus that is heavier than Pb, hence their respective transformation chains all end with a stable form of Pb. Everyone is exposed to background radiation from naturally occurring radionuclides throughout life. This background radiation is the major source of radiation exposure to man and arises from several sources. Natural background dose rates are frequently used as a standard of comparison for doses from various anthropogenic sources of ionizing radiation. Anthropogenic radioactive elements are produced either as a by-product of the fission of uranium atoms in a nuclear reactor or by bombarding stable atoms with high-velocity particles, such as protons, or with neutrons. These artificially produced radioactive elements usually transform by emission of positive or negative beta particles and one or more high-energy photons (gamma rays). Unstable (radioactive) atoms of any known element can be produced. Both naturally occurring and anthropogenic radionuclides have found numerous applications in diagnostic and therapeutic medicine, industrial products, consumer products, and in scientific and industrial research. Trace amounts of some specific radionuclides remain in, or have been redistributed in, the environment as a result of these applications and also from the production, use, and testing of nuclear weapons. **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 27 2. PRINCIPLES OF IONIZING RADIATION 2.2.3 Principles of Radioactive Transformation The stability of an atom is the result of the balance of the forces of the various components of the nucleus. If there are either too many or too few neutrons for a given number of protons, the resulting nucleus is unstable and will eventually undergo transformation. An atom that is unstable (a radionuclide) will eventually transform (transformation) into a stable atom or into another lighter radioactive species (daughters), by the release of some type of ionizing radiation. For some elements, a chain of daughter transformation products is produced until stable atoms are formed. Radionuclides can be characterized by the type and energy of the radiation emitted, the rate of transformation, and the mode of transformation. The mode of transformation indicates how the parent radionuclide undergoes its transformation. Radiations considered here, with the exception of X-rays, are released from the atom’s nucleus; X-rays are produced in the atom’s electron shells surrounding the nucleus. These radiations are produced when an excited (radioactive) nucleus reduces its excess energy by one of several processes that involve converting a proton into a neutron and positron, converting a neutron into a proton and negatron, emitting an alpha particle, capturing an orbital electron and converting a proton into a neutron, or fissioning into smaller atoms with the release of several neutrons. The atom is generally left with an amount of excess energy that can be released by emitting one or more gamma rays. During these transformations, the atom changes from one element into another, modifying the structure of the electron orbitals and in some cases emitting X-rays with energies characteristic of the new element. For example, the iron-55 (**Fe) nucleus captures an orbital electron, converts a proton into a neutron so that the atom becomes manganese-55 (**Mn), and Mn X-rays are emitted. The type of radiation may be categorized as charged particle (alpha, negatron, positron), uncharged particle (neutron), or electromagnetic radiation (gamma and X-ray). The type of radiation can also be characterized as directly ionizing (alpha, negatron, positron, proton, gamma, or X-ray) or as indirectly ionizing (neutron, gamma, or X-rays). Except for delayed neutrons emitted during the nuclear fission process, there are no radionuclides that emit neutrons. Californium-252 (**’Cf), which undergoes spontaneous nuclear fission as well as radioactive transformation, emits fast neutrons during the fission process. Neutrons, when necessary for neutron activation analysis or for radiography, are produced either in a nuclear reactor and accelerator, in a sealed 2*2Cf source, or in an encapsulated neutron source in which the radiation from a radionuclide interacts with an appropriate stable nucleus to “knock” a neutron out of the nucleus. An example of such a neutron source is a mixture of a finely powdered alpha emitter, such as *'°Po and beryllium (Be). The alpha particle interacts with the *Be isotope to produce '?C and a neutron. Table 2-1 summarizes the basic characteristics of the more common types of radiation encountered. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 28 2. PRINCIPLES OF IONIZING RADIATION Table 2-1. Characteristics of Nuclear Radiations Typical Path length Radiation Rest mass® Charge energy range Air Solid Comments Alpha (a) 4.00 amu +2 4-10 MeV 5-10cm 25-80 pm Identical to ionized He nucleus Negatron (7) 5.48x10™ amu; -1 0-4 Mev 0-1m 0-1 cm Identical to electron 0.51 MeV Positron (B*) 5.48x10™ amu; +1 0-4 Mev 0-1m 0-1 cm Identical to electron 0.51 Mev except for sign of charge Neutron 1.0086 amu; 0 0-15 MeV 0-100 m 0-100cm Free half-life: 16 min 939.55 MeV X-ray (gm. photon) - 0 5 keV-100 keV b b Photon from transition of an electron between atomic orbits Gamma (y) - 0 10 keV-3 MeV b b Photon from nuclear (em. photon) transformation 2 The rest mass (in amu) has an energy equivalent in MeV that is obtained using the equation E=mc?, where 1 amu = 9 32 MeV. ® path lengths are not applicable to x- and gamma rays since their intensities decrease exponentially amu = atomic mass unit; e.m. = electromagnetic; MeV = MegaElectron Volts Every radionuclide transforms at a constant rate with a value characteristic of that radionuclide, and is independent of the temperature, pressure, or chemical form in which it exists. The transformation rate is often expressed by the half-life (t;,). A high rate of transformation leads to a short half-life, while a long half-life means a slow rate of transformation. During one half-life, 50% of the radionuclide transforms; during the next half-life, 50% of the remaining radionuclide transforms, and so on. As an example, 32P has a half-life of about 14 days. If one starts with 100 pCi of **P on day 1, on day 14 there will be exactly one- half, or 50 uCi of **P remaining. After another 14 days pass, exactly 25 uCi of **P will remain, and so on. This transformation scheme is illustrated in Figure 2-1. Half lives of the various radionuclides range from fractions of a second to billions of years. The quantity of radioactive material is expressed in terms of activity, which is defined as the number of disintegrations (or transformations) in the radioactive material during 1 second or 1 minute. The traditional unit for measurement of activity is the curie (Ci). The curie was originally defined as the activity of 1 gram of **Ra, which is about 3.69x10'° transformations or decompositions per second (dps). Now it is defined as that quantity of radioactive material in which an average of 3.7x10'° atoms transform in 1 second. In the International System (SI), the unit of activity is the Bequerel (Bq). One Bq is defined as that quantity of radioactive material in which an average of 1 atom disintegrates in 1 second. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 29 2. PRINCIPLES OF IONIZING RADIATION 100 90 80 70 60 50 40 Microcuries (1Ci) of **P Remaining 20 10 0 14 28 42 56 70 84 98 Days Figure 2-1. Decomposition of 100 uCi of *2P. The activity of a radionuclide at time t may be calculated by the equation: — -0.693t/T(rad) A=Age where A is the activity in appropriate units, such as Ci, Bq, or dps, A, is the activity at time zero, t is the time that has elapsed, and T,,, is the radioactive half-life of the radionuclide. T,,, and t must be in the same time units. When radioactive material is inside a living organism, either naturally or as the result of an accidental intake, the radioactive material is eliminated by both radioactive transformation and biological removal. This introduces a rate constant called the biological half-life (T,,,), which is defined as the time required for the sum of all of the available biological processes to eliminate one-half of the retained radioactivity. This time is the same for both stable and radioactive isotopes of any given element since they behave identically in the body. The time required for a radioactive element to be halved as a result of the combined action of radioactive transformation and biological elimination is the effective half-life (T,;), and is described in the equation: Tex = (Thon X Toa) (Thion + Toa) : ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 30 2. PRINCIPLES OF IONIZING RADIATION Table 2-2 presents representative effective half-lives of some of the commonly encountered radionuclides. Table 2-2. Effective Half-Lives of Selected Radionuclides in Major Adult Body Organs Half-life Radionuclide Critical organ Physical Biological Effective Tritium (°H)® Whole body 12.3 yr 12d 11.97d lodine-131 (*') Thyroid 8d 138d 7.6d Strontium-90 (Sr) Bone 28 yr 50 yr 18 yr Plutonium-239 (**Pu) Bone 24,400 yr 200 yr 198 yr Lung 24,400 yr 500 yr 500 6 Cobalt-60 (*Co) Whole body 53yr 99.5d 95d Iron-55 (*Fe) Spleen 2.7 yr 600d 388d Iron-59 (*Fe) Spleen 45.1d 600d 419d Manganese-54 (*Mn) Liver 303d 25d 23d Cesium-137 (Cs) Whole body 30 yr 70d ~70 yr 2 Mixed in body water as tritiated water d = days; yr = years 2.2.4 Interaction of Radiation with Matter Both ionizing and non-ionizing radiation will interact with matter: it will lose kinetic energy to any solid, liquid, or gas through which it passes by several mechanisms and at different rates. The partial or complete transfer of energy to a medium by either electromagnetic (gamma) or particulate (alpha or beta) radiation may be sufficient to excite electrons or to “knock out” electrons from the absorber atoms or molecules. This process is called ionization and is the source of the name “ionizing radiation.” Compared to other types of radiation that may be absorbed, such as ultraviolet radiation, ionizing radiation deposits a relatively large amount of energy into a small volume of matter, possibly resulting in deleterious biological effects. The method by which ionizing radiation interacts with a biological medium to cause damage may be direct or indirect. A direct effect occurs when an ionizing event disrupts a critical molecule, such as an enzyme, DNA, or RNA, by knocking out an intramolecular bonding electron. Indirect effects occur when ionized or disrupted molecules, mainly water (since the body is about 67% water), recombine to form chemically toxic compounds, such as hydrogen peroxide (H,0,). Each type of radiation can be classified into high linear energy transfer (high LET) or low linear energy transfer (low LET) based on the amount of energy it loses per unit path length it travels. For example, an alpha particle is classified as high LET radiation because its large +2 charge and relatively large mass (about ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 31 2. PRINCIPLES OF IONIZING RADIATION 8,000 times that of an electron) causes it to move relatively slowly and interact strongly with any material it passes through. Beta particles, which are energetic electrons, are classified as low LET radiation. Even though they interact with matter in a manner similar to alpha particles, their smaller +1 charge and smaller mass result in a greater distance between ionizing collisions and, thus, a lower ionization density. Gamma rays are indirectly ionizing radiation. Depending on its energy, a gamma ray photon interacts with an absorber atom by one of three different mechanisms, which results in the production of lor 2 highly energetic electrons. These electrons (which are the primary ionizing particles in the case of X-ray or gamma radiation) dissipate their energy by interacting with other atoms in their path in exactly the same manner as beta particles (which are, in fact, electrons) and excite and ionize these atoms. Since the ionizations resulting from gamma radiation are due to electrons, gamma radiation is a low LET radiation. Both high and low LET interactions can cause significant damage to the DNA and can result in a wide array of biological effects. Ionizing radiation can also react with molecules other than DNA (lipids, proteins, water, etc.) to produce free radicals, which can then go on to adversely react with the DNA molecule. Regardless of the method of energy transfer, DNA is the primary molecule of concern for effects from low level radiation because DNA damage from ionizing radiation and from other sources is cumulative and can (but does not always) result in carcinogenesis or other adverse cellular events months or years after exposure. Further discussion of directly and indirectly ionizing forms of ionizing radiation is presented in Chapter 5. When cells are irradiated with ionizing radiation, chromosomal breaks are produced in one or more places on the chromosome, resulting in a small piece(s) of the original, intact chromosome being separated from the rest of the chromosomal structure. This may or may not result in the disruption of normal cellular functions, depending on which chromosome had the breakage and where on the chromosome the damage occurred. However, when the cell enters a mitotic cycle, these damaged chromosomal units will fail to replicate properly unless chromosomal repair mechanisms can repair the damage prior to entering mitosis. If the repair mechanisms fail to perfectly and seamlessly repair the damage to the chromosome, restoring it to its original structure prior to ionizing radiation damage, or if they do not repair the damage at all, the chromosome will not replicate properly. This results in critical portions of that chromosome being deleted during the replication cycle, and transmission of misinformation to cell progeny. It is clear that cells with short mitotic cycles (intestinal crypt cells, fetal cells, and other rapidly dividing cells) have less time for repair mechanisms to reverse the damage to the nuclear DNA inflicted by ionizing radiation. This makes chromosomal anomalies more likely to be present during the frequent mitotic cycles, and increases the chances for abnormal cell functions in cell progeny whose DNA was damaged by radiation or by any other agent. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 32 2. PRINCIPLES OF IONIZING RADIATION When these broken chromosomes are examined more closely, the broken ends of the chromosome appear "sticky" and have the ability to rejoin with other broken chromosomes but not with intact and undamaged chromosomes. Once chromosomal breakage occurs, a broken fragment can: (1) rejoin with the chromosome it was originally joined to, and no abnormalities will be observed at the next mitosis; (2) not rejoin and cause gene deletions to occur at the next mitosis; or (3) join another broken fragment and give rise to new, distorted chromosomes (Hall 1988). Chromosomal repair mechanisms have been known to exist for many years; without them the everyday damage that can occur to the entire organism's DNA could prove lethal. Chromosomal repair mechanisms provide a useful method of minimizing the adverse DNA effects of ionizing radiation (or any other chemical) on the genome, providing that the dose of radiation is not so large as to overwhelm the inherent repair mechanisms; however, like many other biological functions, their efficiency at performing this task is not always 100%. Minor damage left unrepaired or damage that was not completely or correctly repaired can result in mutations that involve either a single gene or multiple genes. Point mutations and small deletions usually involve a small number of bases (~20 to 60), whereas large base deletions or base rearrangements may involve several hundred or many thousands of bases. The proportion of deletions obviously tends to increase in frequency as the number of hits from the ionizing radiation source increases (Borek 1993). An important type of change to DNA at the molecular level that is frequently produced by ionizing radiation is the removal of a base, forming an apurinic or apyrimidinic site. The deletion or total destruction of DNA bases, the destruction of deoxyribose residues, and the deamination of cytosine or adenine are but a few of the many ways ionizing radiation can alter DNA at the molecular level. A more in-depth discussion of the alterations at the DNA level by ionizing radiation, including a few of the known DNA repair mechanisms, is presented in BEIR V (1990) and in Chapter 5 of this toxicological profile. 2.2.5 Characteristics of Emitted Radiation 2.2.5.1 Alpha Radiation An alpha particle is composed of two protons and two neutrons, or the equivalent of a helium nucleus. When a parent radionuclide emits an alpha particle, its atomic mass number decreases by four and its atomic number decreases by two, resulting in the formation of a different element. In nature, alpha particles come from the radioactive transformation of heavy elements, such as uranium, radium, thorium, and radon, where long transformation chains produce several alpha particles until the resulting nuclide has a stable configuration. A specific radionuclide emits alpha particles of discrete energies and relative intensities, ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 33 2. PRINCIPLES OF IONIZING RADIATION making it possible to identify each radionuclide by its alpha energy distribution spectrum on a standard alpha spectrometer system. The alpha particle’s electrical charge of +2 and mass number of 4 atomic mass units (amu), both of which are larger than most other types of radiation, cause it to interact strongly with matter. This slow-moving, highly charged particle spends a relatively long time in the vicinity of each atom it passes; this enables it to pull electrons easily off those atoms. With a mass about 7,200 times that of the electrons, each interaction has only a small effect on its velocity, but the strong interaction with each atom it encounters causes a high density of ionization throughout its short path. As a result of these characteristics, the particle has little penetrating power compared with other types of radiation. Typically, an alpha particle cannot penetrate an ordinary sheet of notebook paper. The range of an alpha particle (the distance the charged particle travels from the point of origin to its resting point) is approximately 5-10 cm in air; the range decreases dramatically to a few micrometers in biological tissues (see Table 2-1). These properties cause « emitters to be hazardous only if there is internal contamination (i.e., if the radionuclide is ingested, inhaled, or otherwise absorbed internally) (see Table 2-2). Once its energy is expended, the alpha particle will combine with two electrons to become a helium atom, which is not assimilated into biological material. 2.2.5.2 Beta Radiation Atomic nuclei that are excessively rich or excessively deficient in neutrons will transform by emission of a beta particle from the nucleus (beta transformation). A beta particle is a high-velocity electron ejected from a transforming nucleus. The particle may be either a negatively charged electron, termed a negatron (Bp), ora positively charged electron, termed a positron (B*). Although the precise definition of "f emission" refers to both B* and f°, common usage of the term generally applies only to the negatively charged particle (8); the term positron emission is commonly used to refer to the f* particle. Beta minus or negatron (B) transformation is a process by which a radionuclide with a neutron excess achieves stability. In this case, a neutron is converted into a proton, a negatron (f°), and an antineutrino (see glossary). This nuclear transformation results in the formation of a different element with one more proton, one fewer neutron, and the same mass number as the original nucleus. The energy spectrum of a beta particle emission ranges from a certain maximum down to zero, with the mean energy of the spectrum being about one-third of the maximum. Negatron-emitting radionuclides can cause injury to the skin and superficial body tissues (more so than alpha particles) but present more of an internal contamination hazard. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 34 2. PRINCIPLES OF IONIZING RADIATION Beta positive (B*), or positron, transformation occurs when there are too many protons in the nucleus. In this case, a proton is converted into a neutron, and a positron (B*) is emitted, accompanied by a neutrino (see glossary). This nuclear transformation results in the formation of a different element with one more neutron, one fewer proton, and the same atomic mass number as the original nucleus. The positron is a very reactive species which, when sufficiently slowed through successive ionizing collisions, will combine with an electron. At this point, the electron-positron pair is annihilated, with their combined mass being converted into energy in the form of two gamma ray photons of 0.51 MeV each. The gamma radiation resulting from the annihilation (see glossary) of the positron makes all positron-emitting isotopes more of an external radiation hazard than pure (3 emitters of equal energy. The neutrino in B* transformation and the antineutrino in p transformation are not known to produce any biological damage. 2.2.5.3 Gamma Radiation Radioactive transformation by alpha, beta, or positron emission or by electron capture often leaves the nucleus in an excited energy state with some residual energy. The nucleus cannot remain in this elevated energy state indefinitely, and will eventually release this energy and achieve ground state, or the lowest possible stable energy level. The energy released is in the form of gamma radiation (high-energy photons) and has an energy equal to the change in the energy state of the nucleus. Gamma radiation and X-rays are types of electromagnetic radiations that behave identically but differ in their origin; gamma emissions originate in the nucleus while X-rays originate in the electron orbital structure, or from the slowing down or stopping of highly energetic beta particles or electrons. The X-rays that originate in the orbital structure are called characteristic X-rays, while those due to stopping high speed electrons are called bremsstrahlung. 2.2.6 Estimation of Energy Deposition in Human Tissues Animals can be exposed externally from radiation sources outside the body, or exposure can be from internally deposited sources inside the body. An exposure can be further classified as "acute" or "chronic" depending on how long an individual or organ was exposed to the radiation. Internal exposures occur when radionuclides that have entered the body through the inhalation, ingestion, or dermal pathways undergo radioactive transformation resulting in the deposition of energy to internal cells and organs. This radioactive material may be eliminated quickly (hours to days) or may result in a long-term retention pattern of the radionuclide (weeks to years). External exposures occur when radiation enters the body directly from sources located outside the body, such as radiation emitters from radionuclides on ground surfaces, dissolved in water, or dispersed in the air. In general, external exposures are from material emitting gamma-type ionizing “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 35 2. PRINCIPLES OF IONIZING RADIATION radiation, which readily penetrate the skin and internal organs. Beta and alpha ionizing radiation from external sources are far less penetrating and deposit their energy primarily on the skin's outer layer. High levels of beta contamination of the skin may lead to skin burns. However, the beta contribution of the total body dose from external radiation, compared to that contributed by gamma rays, may be small. Characterizing the radiation dose to persons or laboratory animals as a result of exposure to radiation is a complex issue. However, through the use of physiologically-based mathematical models, the dose from both external and internal exposure can be estimated with a sufficient degree of accuracy to establish reliable radiation safety standards. More information on the health effects of both internal and external forms of ionizing radiation and the effects that ionizing radiation have on matter is presented in Chapters 3 and 5 of this toxicological profile. 2.3 FUNDAMENTALS OF IONIZING RADIATION DOSIMETRY 2.3.1 Dose Units The term “dose” has a specific meaning in radiation biology. Dose pertains to the amount of energy that the ionizing radiation deposits in an organ or tissue rather than to how much ionizing radiation passes through it. The unit of absorbed dose is the rad, with 1 rad = 100 ergs/gram = 0.01 Joule (J) per kg in any medium. The SI unit of absorbed dose is the gray (Gy), which is equivalent to 100 rad or 1 J/kg. Dose is related to the quantity of radioactive material (becquerels or curies), but the energy and intensity of the radiation. For internally deposited radionuclides, physiologically based biokinetic models are used to describe the distribution and retention (or clearance) of radionuclides taken into the body. This information, together with the physical data on the type and energy of the radiation, allows the calculation of the absorbed dose at different sites. The roentgen (R) is the unit of X-ray or gamma radiation exposure related to the intensity of an X-ray or gamma radiation field, and is measured by the amount of ionization caused in air by X-ray or gamma radiation. One roentgen equals 2.58x10* Coulomb per kg of air. In the case of gamma radiation, over the commonly encountered range of photon energy, the energy deposition in tissue for a dose of 1 R is about 0.0096 J/kg of tissue. Although the roentgen is a unit of X-ray exposure, not dose, it continues to be used in X-ray or gamma radiation dosimetry because an exposure of 1 R leads to a dose of approximately 1 rad. An ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 36 2. PRINCIPLES OF IONIZING RADIATION exposure of 1 R is considered as a dose equivalent of 1 rem (0.01 sievert). The dose equivalent, the rem, and the sievert are discussed below in Section 2.3.3. Health physics survey meters that are used to measure external X-ray or gamma radiation are usually calibrated in units of mR (milliroentgens) per hour. Internal and external exposures from radiation sources are usually received over extended periods of time. External doses are more easily and directly determined than internal doses. External doses are measured directly with radiation dosimeters or calculated from hand-held survey meter readings as the product of the exposure time and the dose rate in rad/unit time. Internal doses, however, are calculated with data obtained from measurements of radiation emissions from the body or from excreta samples in counts/unit time. The radioactive material(s) are identified and their radiation characteristics are used to calculate the activity inside the body in curies. Application of physiologically based biokinetic models are then used to calculate the dose from the radioactive materials take into the body. For radiation safety purposes and for regulatory requirements, the dose is multiplied by a unitless quality factor for that radiation to convert rads to rems. The potential inhalation hazard from atmospheric rad isotopes 2*’Rn and 2*°Rn (thoron) is due to their short- lived progeny. The concentration of these short-lived progeny (*'*Po through 2'* Po from 2??Rn and 2'*Po through 2'?Po from **’Rn) is measured by the working level (WL). One WL is defined as any combination of short-lived radon daughters per L of air that will result in the emission of 1.3x10° MeV of alpha energy. An activity concentration of 100 picocuries (pCi) of radon-222 (***Rn) per L of air, in equilibrium with its daughters, corresponds approximately to a potential alpha energy concentration of 1 WL. The WL unit for thoron (**°Rn) daughters at 50% equilibrium is 14.8 pCi thoron/L. Thoron daughters in radioactive equilibrium with thoron at a concentration of 7.43 pCi/L represents 1 WL. The potential alpha energy exposure to radon progeny is commonly expressed in working level months (WLM) units. One WLM corresponds to exposure to a concentration of 1 WL for the reference period of 170 hours. 2.3.2 Dosimetry Models Physiologically based biokinetic dosimetry models are used to estimate the dose from radioactive substances taken into the body. The models for internal dosimetry consider the quantity of radionuclides entering the body, the factors affecting their movement or transport through the body, the distribution and retention of radionuclides in the body, and the energy deposited in organs and tissues from the radiation that is emitted during spontaneous transformation processes. The dose pattern for radioactive materials in the body may be strongly influenced by the route of entry of the material. For industrial workers, inhalation of radioactive particles with pulmonary deposition and puncture wounds with subcutaneous deposition have been the most ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 37 2. PRINCIPLES OF IONIZING RADIATION frequent exposure routes. The models for external dosimetry consider only the photon doses to organs of individuals who are immersed in air or are exposed to a contaminated ground surface. Ingestion. Ingestion of radioactive materials is most likely to occur from contaminated foodstuffs and water, or by the eventual ingestion of inhaled compounds initially deposited in the lung (mucociliary clearance pathway). Ingestion of radioactive material may result in toxic effects as a result of either absorption of the radionuclide from the intestine, irradiation of the gastrointestinal tract during passage through the tract, or a combination of both. The fraction of radioactive material absorbed from the gastrointestinal tract is variable, depending on the specific element, its chemical and physical form, the diet, and the individual’s own metabolic and physiological factors. The absorption of some elements is influenced by age, usually with higher absorption rates in very young animals. Inhalation. The inhalation route of exposure has long been recognized as being of major importance for both nonradioactive and radioactive materials. The deposition site of particles within the lung is largely dependent upon the size of the particles being inhaled. After the particle is deposited, the retention will depend upon the physical and chemical properties of the dust, the physiological status of the lung, and the site of deposition. There are at least three distinct mechanisms that operate simultaneously to remove or clear radioactive material from the lung. Ciliary clearance acts only in the upper respiratory tract (i.e., trachea and the major and minor conducting airways of the lung). Cilia are short hairlike filaments that grow out of the lining cells of the upper respiratory tract and are covered by the layer of mucous in the upper respiratory tract. The cilia move in a synchronized beating motion that pushes the mucous blanket, on which the large sized inhaled particles are deposited, upwards into the throat. There the particles can be coughed up or swallowed. The second and third mechanisms act mainly in the deep respiratory tract and include phagocytosis and systemic absorption following dissolution of a particle. Phagocytosis is the engulfing of foreign bodies by alveolar macrophages and their subsequent removal either up the ciliary "escalator" or by entrance into the lymphatic system. Dosimetric lung models are reviewed by NCRP (1994), James (1987, 1994) and James and Roy (1987). Internal emitters. The absorbed dose from an internally deposited radionuclide is the energy that its radiations deposit in tissue. The dose to an organ or tissue is a function of its mass, the quantity of radioactive material introduced into the organism, the fraction that incorporates into that tissue, the effective half-life, and the energy and type of radiation. Since alpha and beta particles travel only short distances, all of the alpha particle energy and all or most of the beta particle energy is absorbed in the tissue that contains the radioactive material. Many common radionuclides also emit gamma rays that are so penetrating that a ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 38 2. PRINCIPLES OF IONIZING RADIATION significant number escape from that tissue and interact with remote portions of the body, or even pass out of the body entirely without interacting. For this reason, the gamma radiation dose to an organ considers both the dose from radioactive material in that organ plus the exposure from the gamma emitter deposited in other organs in the body. For a radionuclide distributed uniformly throughout an infinitely large medium, the concentration of absorbed energy must be equal to the concentration of energy emitted by the isotope. An infinitely large medium may be approximated by a tissue mass whose dimensions exceed the range of the particle. All of the alpha radiation (due to its very short traveling distance in biological tissue) and most of the beta radiation will be absorbed in the organ (or tissue) of reference. Common isotope emissions are of the penetrating types of ionizing radiation (alpha, beta, and gamma), and a substantial fraction may travel great distances within tissue (some beta and many gamma types), leaving the tissue without interacting. The dose to an organ or tissue is a function of the effective retention half-time, the rate of energy released in the tissue, the amount of radioactivity initially introduced, and the mass of the organ or tissue. 2.3.3 Terms Used in Radiation Safety Practice and Regulation Health physics. Health physics is that area of environmental health engineering that is devoted to radiation safety. The scientific and engineering aspects of health physics deal with the measurement of radiation and radioactivity, the establishment of dose-response relationships for radiation exposure, movement of radioactivity through the environment, the design of radiologically safe processes and equipment, and the maintenance of a radiologically safe environment. The health physicist is the professional who deals with radiation safety. Relative biological effectiveness (RBE). The toxicity of a given absorbed radiation dose depends on the LET of the radiation: The higher the LET, the more toxic is the radiation and the smaller is the dose needed to produce a specific biological end point. To account for this LET effect, radiobiologists use the term relative biological effectiveness (RBE). The RBE for any radiation is simply the ratio of the dose from 200 keV X-rays required for a given biological effect to the dose that would produce the same effect with that radiation. The term RBE is restricted in application to radiobiology. Although the RBE is considered in setting radiation safety standards, it is not used explicitly in the practice of health physics. Quality factor (Q). For health physics purposes, a normalizing factor, called the quality factor (Q), is applied to the radiation absorbed dose to account for the RBE of the different radiations. The numerical values for the quality factors are determined by a committee of experts, and are based on a conservative upper limit of the RBE for the biological effect believed to be of the greatest interest to humans. Values for Q that ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 39 2. PRINCIPLES OF IONIZING RADIATION are used in the USNRC safety standards in the Code of Federal Regulations (CFR) 10, Part 20, are listed below in Table 2-3. Table 2-3. Quality Factors Used in USNRC Radiation Safety Regulations Type of radiation Quality factor (Q) Alpha particles, multiple charged particles, fission fragments, and heavy charged particles 20 X-rays, gamma rays, electrons, negatrons, or positrons 1 Thermal neutrons 2 Fast neutrons, neutrons of unknown energy, or high-energy protons 10 Source: USNRC 1997a Dose equivalent (H). The normalizing factor, Q, is used as a multiplier of the radiation absorbed dose to give the dose equivalent. The dose equivalent, symbolized by H, is called the rem in the traditional system of units and the sievert (Sv) in SI units. One hundred rems is equal to one sievert. H=DxQ Effective dose equivalent (Hg). The effective dose equivalent is used for radiation safety purposes and for regulatory purposes to account for the relative susceptibility of the various organs and tissues to radiation- induced nondeterministic effects (principally cancer) in cases of non-uniform irradiation. The basis for the effective dose equivalent concept is that the probability of a nondeterministic effect from non-uniform irradiation should be equal to that due to uniform whole body irradiation. This is accomplished by multiplying the dose equivalent, H, to each irradiated tissue or organ by a tissue weighting factor, W, and then summing these products for all the irradiated tissues. Hg, = (the sum of) W; x Hy W; represents the fraction of the probability of a nondeterministic effect resulting from irradiation of that tissue to the total probability of a nondeterministic effect when the whole body is uniformly irradiated. The values for W; used by the USNRC and ICRP are listed below in Table 2-4. For occupational exposure, the USNRC specifies an upper limit of 5 rems (5,000 millirems) in 1 year for the effective dose equivalent. The regulations also specify an upper annual limit of 50 rems (50,000 millirems) for all organs and tissues except the lens of the eye, for which an annual maximum of 15 rems (15,000 millirems) is prescribed. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 40 2. PRINCIPLES OF IONIZING RADIATION Table 2-4. Tissue Weighting Factors Used by the USNRC and ICRP to Calculate Effective Dose Tissue USNRC Weighting factor ICRP Weighting factor Whole body 1.00% - Gonads 0.25 0.20 Breast 0.15 0.05 Red bone marrow 0.12 0.12 Lung 0.12 0.12 Thyroid 0.03 0.05 Bone surface 0.03 0.01 Colon - 0.12 Stomach - 0.12 Bladder - 0.05 Liver - 0.05 Esophagus oe 0.05 Remainder 0.30" 0.05 aThe whole body weighting factor was introduced by the USNRC and is not addressed by either the ICRP or the NCRP. ®0.30 results from 0.006 being assigned to each of the five remaining organs (excluding the skin and lens of the eye) that receve the highest doses. Source: ICRP 1995; USNRC 1997a Absorbed dose. The energy imparted by ionizing radiation per unit mass of irradiated material is called the absorbed dose. The units of absorbed dose are the rad and the gray (Gy). (See “Units of radiation dose” for more information on absorbed dose). ALARA. This acronym for “As Low As is Reasonably Achievable” refers to the practice of making every effort to keep exposure to radiation as far below the dose limit as possible while still achieving the purpose for which the radiation is licensed to be used. ALI. This acronym for “Annual Limit on Intake” is the derived limit for the amount of radioactive material taken into the body of an adult worker by inhalation or ingestion in a year. For a given radionuclide, ALI is defined as the smaller of the intakes that would result in a committed effective dose equivalent of 5 rems and a committed dose equivalent of 50 rems to any individual organ or tissue. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 41 2. PRINCIPLES OF IONIZING RADIATION External dose. Radiation dose from a radiation source originating from outside of the body. Internal dose. Radiation dosed from a radiation source originating from inside the body. Weighting factor (W;). This factor is used for radiation safety purposes to account for the different sensitivities of the various organs and tissues to the induction of nondeterministic radiation effects. Units of radioactive material. The following two units are commonly used when describing the quantity of radioactivity: Becquerel (Bq). A SI unit of measure for radioactive material; one becquerel equals that quantity of radioactive material in which one atom disintegrates in one second. Curie (Ci). The conventional unit used to measure the quantity of radioactive material. The curie is equal to that quantity of radioactive material in which 37 billion atoms transform per second. This is approximately the activity of 1g of radium. Units of radiation dose. The International Commission on Radiation Units and Measurements (ICRU 1980), International Commission on Radiological Protection (ICRP 1984), and National Council on Radiation Protection and Measurements (NCRP 1985) now recommend that the traditional units: rad, roentgen, curie, and rem be replaced by the SI units: gray (Gy), coulomb per kilogram (C/kg), becquerel (Bq), and sievert (Sv), respectively. However, the regulations used in the United States are written with the traditional units. The following four dosimetric units are commonly used: Gray (Gy). The SI unit of absorbed dose. One gray = 1 J/kg = 100 rad. Rad. The unit of absorbed dose. One rad = 100 erg/g = 0.01 Gy. Sievert (Sv). The SI unit of dose equivalent, equal to absorbed dose in grays multiplied by the quality factor. One Sv = 100 rem. Rem. The conventional unit of dose equivalent. One rem = 0.01 Sv. The relationship between the traditional units and the international system of units (SI) for radiological quantities is shown in Table 2-5. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 42 2. PRINCIPLES OF IONIZING RADIATION Table 2-5. Common and SI Units for Radiation Quantities Quantity Traditional units Sl units Relationship Activity (A) curie (Ci) becquerel (Bq) 1 Ci=3.7x10" Bq 1Bqg=1dps 1Ci=3.7x10" Bq Absorbed dose (D) rad gray (Gy) 1 rad = 0.01 Gy 1 Gy = 1 Jkg" Dose equivalent (H) rem sievert (Sv) 1rem=0.01Sv 1Sv=1Jkg" dps = transformations per second; JKg" = Joules per kilogram; S™ = per second Source: Shleien 1992 Other terms used in discussions of radiation protection and regulation include: bioassay, collective dose, embryo/fetus, eye dose equivalent, public dose, shallow dose equivalent, total effective dose equivalent, whole body, and working level. These terms and their definitions may be found in Chapter 9. 2.4 BIOLOGICAL EFFECTS OF RADIATION When biological tissue is exposed to ionizing radiation, a chain of cellular events occurs as the ionizing radiation passes through the biological tissue matrix. A number of theories have been put forth to describe the interaction of radiation with the biologically important molecules in mammalian cells and to explain the resulting damage to biological systems from those interactions. Many factors may modify the response of a living organism to a given dose of radiation. Factors related to the exposure include the dose rate, the energy and type of radiation, and the temporal pattern of the exposure. Biological considerations include factors such as species, age, sex, the portion of the body tissues exposed, and repair mechanisms. The genome (the DNA) is considered to be the primary target molecule for ionizing radiation toxicity. Molecular damage, which includes damage to the DNA, can occur in one of two ways from an exposure to ionizing radiation. First, ionizing radiation can interact directly with the DNA, resulting in single or double- strand DNA breaks or unbonding base pairs. Second, ionizing radiations can interact directly with other surrounding molecules within or outside of the cell, such as water, to produce free radicals and active oxygen species. These reactive molecules, in turn, interact with the DNA and/or other molecules within the cell (cell membranes, mitochondria, lipids, proteins, etc.) to produce a wide range of damage at the cellular and tissue levels of the organism. High LET radiation is an efficient producer of free radicals and H,O,, both of which act indirectly on macromolecules. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 43 2. PRINCIPLES OF IONIZING RADIATION Regardless of how the DNA is damaged, the mammalian body has remarkable abilities to repair its DNA without outside interventions. Mammalian DNA repair schemes, classified as either direct or indirect repair mechanisms, include many mechanisms such as nucleotide excision (via endonuclease), base excision (via DNA glycosylase), and mismatch repair. The success or failures of these inherent DNA repair systems depend on many factors, such as the dose of ionizing radiation received and the tissue that received the radiation. Depending on the dose and the tissue exposed, inherent DNA repair mechanisms may be highly successful, resulting in total repair of the DNA. These mechanisms may fail completely if the repair mechanism is overwhelmed with very high doses of radiation, or may fail to repair all of the DNA damage caused by lower doses of ionizing radiation. This failure can result in cell death due to necrosis or apoptosis, altered cell function, or the development of neoplastic cells several years after the damage occurred. DNA repair systems may be able to adequately repair the damage done to the DNA by reactive molecules (free radicals), but do nothing to protect the irradiated cell from damage by these reactive species to other cellular structures (membranes, mitochondria, etc.) (Zajtchuk 1989). Other repair mechanisms must be employed to protect the cell against these injuries. Several protective strategies have been devised to minimize the damage from free radicals and reactive oxygen species that occur in cells exposed to sources of high-level ionizing radiation. Some of these methods include hypoxia, which decreases the amount of oxygen available to form such reactive species; hypothermia; the use of scavenging agents (aminothiols, vitamins A, E, and C); and eicosanoids. These methods have been used in special cases, such as in radiation therapy of tumors, to protect the surrounding healthy tissue. Genetic methods (repair by hydrogen transfer, regeneration) are also being investigated (Zajtchuk 1989). The study of the mechanisms by which ionizing radiation exerts its toxicological effects is an important and constantly evolving field of toxicology. More information on the mechanisms of action of ionizing radiation can be found in Chapter 5 of this toxicological profile. Several excellent reviews of the biological effects of radiation have been published, and the reader is referred to these for a more in-depth discussion (BEIR V 1990; ICRP 1984; Kondo 1993; Rubin and Casarett 1968). A general overview of the health effects of alpha, beta, and gamma types of ionizing radiation in some types of biological tissue is presented below; more in-depth information on the health effects of ionizing radiation is presented in Chapters 3 and 5 of this toxicological profile. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 44 2. PRINCIPLES OF IONIZING RADIATION 2.4.1 Radiation Effects at the Cellular Level According to Mettler and Moseley (1985), at acute doses up to 10 rad, single-strand breaks in DNA may be produced. These single-strand breaks may be repaired rapidly. With doses in the range of 50 to 500 rad (0.5-5 Gy), irreparable double-strand DNA breaks are likely, resulting in cellular reproductive death after one or more divisions of the irradiated cell. At large doses of radiation, usually greater than 500 rad (5 Gy), direct cell death before division (interphase death) may occur from the direct interaction of free radicals with essential cellular macromolecules. Morphological changes at the cellular level, the severity of which are dose-dependent, may also be observed at this dose level. Specific clinical symptoms and other health effects associated with different doses of ionizing radiation are discussed in Chapter 3 of this profile. The sensitivity of various cell types within an organism may vary widely, depending on specific cell and tissue characteristics. According to the Bergonie-Tribondeau law, the sensitivity of cell lines is directly proportional to their mitotic rate and inversely proportional to the degree of differentiation (Mettler and Moseley 1985). This means that cells that undergo frequent mitosis under normal physiologic circumstances or are not well-differentiated in histologic cell-type characteristics will tend to be more susceptible to the effects of ionizing radiation than those cells in which the converse is true. Rubin and Casarett (1968) devised a classification system that categorized cells according to type, function, and mitotic activity. The five categories range from the most sensitive type, "vegetative intermitotic cells," found in the stem cells of the bone marrow and the gastrointestinal tract, to the least sensitive cell type, "fixed postmitotic cells," found in striated muscles or long-lived neural tissues. This classification system is show in Table 2-6. Cellular changes in susceptible cell types may result in cell death; extensive cell death may produce irreversible damage to an organ or tissue, or may result in the death of the individual. If the cells recover, altered metabolism and function may be the ultimate sequelae, and the damage imposed may be repaired to a normal state, produce some characteristic manifestation of clinical symptoms, or result in apoptosis. If the cells are adequately repaired and relatively normal function is restored, the more subtle DNA alterations may also be expressed at a later time as mutations and/or tumors. More information on the genetic effects of ionizing radiation is presented in Chapter 5 of this profile. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 2. PRINCIPLES OF IONIZING RADIATION 45 Table 2-6. Relative Radiosensitivity of Mammalian Cells Class Category Characteristics Cell types | Vegetative intermitotic cells Il Differentiation intermitotic cells ll} Multipotential connective tissue cells Iv Reverting postmitotic cells Vv Fixed postmitotic cells Rapidly dividing, short-lived; daughter cells with either differentiate or form more cells like the parent cell Somewhat less radiosensitive than Class | cells; rapid proliferation rates, but daughter cells become more radioresistant than the parent cell Cells divide regularly in response to injury and irritation Normally do not undergo cell division Cells that will not divide; highly radioresistant Hemocytoblast, lymphoblast, erythroblast, myelobalst, primitive intestinal crypt cell, type A spermatogonia, primitive oogonia, lymphocytes Type B spermatogonia, oogonia, cells of the intermediate stages of erythropoiesis and myelopoiesis Endothelium, fibroblast, mesenchymal cells. Epithelial cells of salivary glands, liver, kidney, pancreas, lung; parenchymal cells of sweat glands and endocrine glands. Interstitial cells of testis and ovary Mature nerve cells, muscle cells, sperm, erythrocytes. Source: Sander and Kathren 1983 2.4.2 Radiation Effects at the Organ Level In most organs and tissues, the injury and the underlying mechanism for that injury are complex and involve a combination of events. The extent and severity of this tissue injury depend on the dose and the radiosensitivity of the various cell types in that organ system. Rubin and Casarett (1968) describe and schematically display the events following radiation in several organ system types. These include: a rapid renewal system, such as the gastrointestinal mucous; a slow renewal system, such as the pulmonary epithelium; and a nonrenewable system, such as neural or muscle tissue. In the rapid renewal system, organ injury results from the direct destruction of highly radiosensitive cells, such as the stem cells in the bone marrow. Injury may also result from constriction of the microcirculation and from edema and inflammation of the basement membrane, which is called the histohematic barrier (HHB), which may progress to fibrosis. In slow renewal and nonrenewable systems, the radiation may have little effect on the parenchymal cells, but ultimate parenchymal atrophy and death over several months result from HHB fibrosis and occlusion of the microcirculation. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 46 2. PRINCIPLES OF IONIZING RADIATION 2.4.3 Acute and Delayed Somatic Effects 2.4.3.1 Acute Effects The result of acute exposure to radiation is commonly referred to as Acute Radiation Syndrome (ARS). This effect is seen only after exposures to relatively high doses (> 100 rad, >1.0 Gy), which would only be expected to occur in the event of a serious nuclear accident or close to a nuclear weapon detonation. The four stages of acute radiation syndrome are prodrome (or initial), latent stage, manifest illness stage, and recovery or death. The prodromal phase is characterized by nausea, vomiting, malaise and fatigue, increased temperature, and blood changes. The latent stage is similar to an incubation period. Subjective symptoms may subside, but changes may be taking place within the blood-forming organs and elsewhere that will subsequently give rise to the next stage. The manifest illness stage gives rise to signs and symptoms specifically associated with the radiation injury: hair loss, fever, infection, hemorrhage, severe diarrhea, prostration, disorientation, and cardiovascular collapse. Convulsions are possible at extreme doses. The severity and time of onset of the signs and symptoms depend upon the radiation dose received (see Chapter 3), with the time of onset decreasing with increasing dose. 2.4.3.2 Delayed Effects The level of exposure to radiation and radioactive materials that may be encountered in the environment is expected to be too low to result in the acute effects described above. The amount of radiation absorbed from ionizing radiation in the environment may produce long-term effects that manifest themselves years after the original exposure and may be due to a single elevated exposure or a continuous low-level exposure. Exposure to ionizing radiation has resulted in a number of adverse health effects. The rapidly dividing cells in the developing fetus put it at a higher risk of the adverse biological effects of ionizing radiation than a post-partum child, who in turn is more radiosensitive than an adult. External alpha and beta radiation are of little concern due to the protection afforded by the mother’s body tissues and the placental sac; however, gamma radiation can provide a more uniform exposure to the fetus. Analysis of the human data from the children exposed in utero by the bombing of Hiroshima and Nagasaki suggests that the cells of the developing central nervous system are the cells most sensitive to the effects of ionizing radiation in the developing human fetus. The major clinical effect on these susceptible cells is impaired intelligence and mental retardation that is observed during childhood development, mainly for those fetuses exposed to doses of radiation during weeks 8-15 after conception. A “no effect” threshold exists for doses in the range of ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 47 2. PRINCIPLES OF IONIZING RADIATION 20-40 rad (0.2-0.4 Gy); at a dose of 100 rad (1 Gy), the frequency of observed mental retardation would be 43% (BEIR V 1990). The lens of the eye is also quite susceptible to the effects of ionizing radiation, with sufficient exposure of the lens to ionizing radiation resulting in cataract formation, which can range from mild visual impairment to blindness. The lens fibers are normally transparent and function in focusing light entering from the pupil onto the retina; however, after exposure to large doses of ionizing radiation, these cells fail to divide to produce lens fibers of the appropriate length or transparency. This results in increased opacity of the crystalline lens of the eye (cataracts). Cataracts can be induced with as little as 200 rad (2 Gy) of X-ray irradiation (Adams and Wilson 1993). Data from those victims exposed to large doses of ionizing radiation after the bombings of Hiroshima and Nagasaki give a cataract threshold of 60-150 rad (0.6-1.5 Gy); however, typical human exposure over a long period of time is thought to have a threshold greater than 800 rad (8 Gy) (BEIR V 1990). Sufficient evidence exists in both human populations and laboratory animals to establish that ionizing radiation can be carcinogenic and that the incidence of cancer increases by increasing the dose of ionizing radiation. Human data are extensive and include epidemiological studies of atomic bomb survivors, many types of radiation-treated patients, underground miners, and radium dial painters. Reports on the survivors of the atomic bomb explosions at Hiroshima and Nagasaki, Japan (with whole-body external radiation doses of 0 to more than 200 rad), indicate that cancer mortality has increased in that exposed population compared to control (non-exposed) individuals (Kato and Schull 1982). The use of X-rays (at doses of approximately 100 rad) in the medical treatment for ankylosing spondylitis and other benign conditions and diagnostic purposes, such as breast conditions, has resulted in excess cancers in the irradiated organs (BEIR 1980, 1990; UNSCEAR 1977, 1988). Leukemia has been observed in children exposed in utero to doses of 0.2 to 20 rad (BEIR 1980, 1990; UNSCEAR 1977, 1988). The medical use of Thorotrast® (colloidal thorium dioxide) resulted in increases in the incidence of cancers of the liver, bone, and lung (ATSDR 1990b; BEIR 1980, 1990). Occupational exposure to ionizing radiation provides further evidence of the ability of radiation to cause cancer. Numerous studies of underground miners exposed to radon and radon daughters (which are « emitters), in combination with silica dust, diesel fumes, and other potential toxicants in uranium and other hard rock mines, have demonstrated increases in lung cancer in exposed workers, especially smokers (Harley 1990b, 1996¢). Workers who ingested **Ra while painting watch dials had an increased incidence of osteogenic sarcoma (ATSDR 1990d). Animal studies indicate that, depending on the radiation dose and the exposure schedule, ionizing radiation can induce cancer in nearly any tissue or organ in the body. However, radiation has not been shown to cause cancer of the prostate, uterus, testis, and mesentery in humans (Sanders ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 48 2. PRINCIPLES OF IONIZING RADIATION and Kathren 1983). Radiation-induced cancers in humans are found to occur in the hemopoietic system, lung, thyroid, hepatic, bone, skin, and many other tissues. The effects of sex, age, smoking, and other susceptibility factors have also been reviewed (BEIR V 1990). Generally, cancer rates after exposure to ionizing radiation are age-dependent and increase with age. The effect of smoking on lung cancer incidences in those individuals who also have prolonged exposure to inhaled alpha emitters indicate a multiplicative risk (or near multiplicative risk); however, this may not be the case for acute exposures to X-rays or gamma rays. In contrast, the data on lung cancer and smoking in the Japanese atomic bomb survivors indicate an additive risk (no interaction between radiation and smoking). It is not presently clear how a person’s sex influences cancer rates. Males appear to be more susceptible to lung and non-sex-specific cancers than are females; however, this may be related to the male’s increased exposure to carcinogens and promoting agents in occupational situations, as well as a number of lifestyle factors, and not necessarily due to increased exposure to ionizing radiation. Laboratory animal data show that high doses of ionizing radiation are carcinogenic and mutagenic, and can result in cell lethality. This raises a question about the relationship between high and low doses. There is some uncertainty regarding the shape of the dose response curve with regard to extrapolating from effects seen at high doses down to low doses or doses received over protracted periods of time. If one assumes that the dose-response relationship is linear, then the expectation would be a proportional decrease in the incidence of the effect being measured (cancer, reciprocal chromosome translocations, locus mutations, life- span shortening, etc.) as the dose or dose rate of radiation decreases; however, this has not always been the case, particularly in the case of low LET radiation exposure. A higher-than-expected reduction in the adverse effect compared to the reduction predicted using a linear dose response model is likely due to the cell’s ability to more effectively repair itself as the dose of radiation decreases. To account for this, a compensation factor or Dose Rate Effectiveness Factor (DREF) can be incorporated into these models to extrapolate cancer risk from high to low doses or low dose rates. For low LET radiation, DREF factors from 2 to 10 have been suggested, with a DREF of 2.5 for human leukemia. Assumptions about DREF are largely based on laboratory animal data. A comprehensive discussion of radiation-induced cancer is found in BEIR IV (1988), BEIR V (1990), and UNSCEAR (1988) and in Chapters 3 and 5 of this toxicological profile. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 49 2. PRINCIPLES OF IONIZING RADIATION 2.4.4 Genetic Effects All genes have a natural and spontaneous mutation rate, but radiation can induce additional genetic damage, such as gene mutations and a variety of chromosomal aberrations, by causing changes in the structure, number, or genetic content of chromosomes in the cell nucleus. The evidence for the mutagenicity of ionizing radiation is derived from studies in laboratory animals, primarily mice (BEIR 1980, 1988, 1990; UNSCEAR 1982, 1986, 1988). Evidence for genetic effects in humans is derived from tissue cultures of human lymphocytes from persons exposed to ingested or inhaled radionuclides (ATSDR 1990d, 1990e). Evidence for mutagenesis in human germ cells (cells of the ovaries or testis) is not conclusive (BEIR 1980, 1988, 1990; UNSCEAR 1977, 1986, 1988). Chromosome aberrations following radiation exposure have been demonstrated in humans and in experimental animals (BEIR 1980, 1988, 1990; UNSCEAR 1982, 1986, 1988). However, no genetic effects have been observed in any human population exposed to any radiation at any dose level. More information on the genetic effects of ionizing radiation can be found in Chapters 3 and 5 of this toxicological profile. 2.4.5 Teratogenic Effects There is sufficient evidence to suggest that some forms of ionizing radiation produce teratogenic effects in animals. Rapidly multiplying cells tend to be more sensitive to the adverse effects of ionizing radiation than slowly multiplying cells. It appears that the developing fetus is more sensitive to radiation than the mother and is most sensitive to radiation-induced damage during the early stages of organ development due to the rapid cellular proliferations occurring at that time. The type of malformation depends on the stage of development and the cells that are undergoing the most rapid differentiation at the time. Studies of mental retardation, microcephaly, and growth retardation in children exposed in utero to radiation from the atomic bombs at Hiroshima and Nagasaki provide sufficient evidence that radiation may produce teratogenic effects in human fetuses (Otake and Schull 1984; Zajtchuk 1989). The damage to the child was found to be related to the dose that the fetus received in utero. Chapters 3 and 8 contain more information on the teratogenic effects of ionizing radiation. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 50 2. PRINCIPLES OF IONIZING RADIATION 2.4.6 Internal Exposure to lonizing Radiation For the purposes of this profile, internal exposure is defined as the energy deposited in the body by the transformation of radioactive material that is inside the body. The pathways by which radioactive materials enter the body include inhalation, ingestion, dermal absorption, and injection. The material’s solubility and chemical nature and not its radioactive properties determine the degree to which the material will stay in place or redistribute throughout the body; thus, the dose is determined from the types and energies of emitted radiation, the rates of radioactive transformation and biological elimination, and the distribution of the material throughout the body, regardless of the route of entry. The exposure to one part of the body is the sum of the exposures to that part from radiation emitted from all parts. 2.4.6.1 Inhalation Inhalation is an important route by which exposure to radionuclides can occur. Many of the inhalation studies discussed in Chapter 3 are further indexed by no-observed-adverse-effect level (NOAEL) and lowest- observed-adverse-effect level (LOAEL) in Chapter 8 of this toxicological profile. It is important to recognize that the total amounts of ionizing radiation absorbed at a specific site, such as the lungs and any surrounding structures, are dependent upon the physicochemical characteristics of the radioactive element or the particle to which the radioactive element is bound or incorporated when deposited in the respiratory tract. In many of the studies reported in Chapters 3 and 8 of this profile, laboratory animals were exposed to a radionuclide that was bound to a particle of some type. The radionuclide “piggy-backing” on that particle was inhaled for a designated period of time, the initial lung burden was determined, and the health effects on the animal observed over a period of days or over its lifespan. Particle kinetics are a major determinant in the size of the total absorbed radiation dose that lung tissue and other tissues and organs receive from inhaled radioactive material. Several excellent reviews are available that discuss the deposition and clearance of inhaled particles in humans and in laboratory animals (Gore and Patrick 1978; Lippmann and Esch 1988; Lippman and Schlesinger 1984; Schlesinger 1989; Snipes 1989; Stahlhofen et al. 1980, 1981). A brief review is presented below. In addition to inhalation exposure to medically related radionuclides, the public is regularly exposed to radionuclides such as uranium, thorium, radon gas, and radon daughters bound to dust particles. Particle deposition and clearance mechanisms are a complex set of variables, with many interspecies differences; however, some generalities have been reported (Snipes 1989). As a rule of thumb, the larger the particle inhaled, the more likely that particle is to be deposited in the upper airways (nasal tract and upper conducting airways); the smaller the particle, the more likely that alveolar and deep penetration of the particle **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 51 2. PRINCIPLES OF IONIZING RADIATION into the lung will occur, regardless of the particle's solubility. Particles that are soluble in the lung fluid milieu generally have shorter residence times or biological half-lives than those that are insoluble in that same matrix. These concepts are important when considering inhaled particles containing a radionuclide component. For example, particles that are 3 pm in diameter and that are also insoluble (such as fused aluminosilicate particles [FAP]) laden with a radionuclide such as '*‘Ce are likely to be largely deposited deep in the lung (bronchioles and alveoli). Retention of particles deep within the lung may be due to a number of factors, including the lack of cilia and decreased amounts of mucous in the smaller airways when compared to larger airways (trachea and bronchi) (Snipes et al. 1996). These insoluble particles are also likely to be cleared slowly from the respiratory tract over a period of several months or years, thereby subjecting the tissues around that particle to long-term doses of ionizing radiation. On the other hand, particles that are very large (10-12 pm and above) may never reach the deep lung and will either lodge in the nasal cavity or be cleared by mucociliary clearance from the conducting airways, resulting in very little exposure to ionizing radiation in the respiratory tract (but may increase the dose to the gastrointestinal or nasal tract). Soluble particles will dissolve, releasing the material into the surrounding tissue, where it will behave toxicokinetically like its nonradioactive counterpart. Leaching of radionuclides from insoluble particles has also been reported to occur. Other factors that influence particle clearance include: (1) particle characteristics, such as geometric size, shape, density, hygroscopicity, and electrical charge; (2) respiratory tract characteristics, such as the individual airway caliber, branching patterns of the conducting (tracheobronchial) airway tree, and the path length to the terminal airways, all of which contribute further to the disposition of particles in the respiratory tract; (3) ventilation rates (mode of breathing [oral, nasal, oronasal], respiratory rate, tidal volume, interlobular distribution of ventilated air, length of respiratory pauses, etc.); and (4) other factors (lung disease, age of the animal, irritant exposure, etc.) which also play significant roles in how long a particle remains lodged in the respiratory tract. Finally, several natural body mechanisms function to clear the respiratory tract of these foreign bodies. Such mechanisms include sneezing, coughing, mucociliary transport, dissolution (for soluble and some insoluble particles), and removal by macrophages and interstitial pathways; these function to decrease the particle residence time in the respiratory tract, thereby decreasing the total dose of ionizing radiation to the tissues (Schlesinger 1989). These deposition and clearance mechanisms are clearly of paramount importance when discussing the dose of a radionuclide to lung tissue and in relating that dose to a corresponding health-related effect. **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 52 2. PRINCIPLES OF IONIZING RADIATION 2.4.6.2 Ingestion Oral exposure to radionuclides may occur after a release of radioactive effluents into the air or water supply (see Chapter 6); after the detonation of a nuclear device, where particles from the fallout can immediately contaminate food and water supplies (McClellan 1982); or as a secondary exposure via the mucociliary clearance mechanism from the respiratory tract after an inhalation exposure. Radionuclides present in radioactive fallout can also enter the soil and later be incorporated into animal and plant life, entering the food chain by an indirect route. There is little literature available that describes the toxicity of ionizing radiation in humans when the oral route was the primary route of exposure. The main source of information on oral toxicity of a radionuclide is the experience of the radium dial painters who "tipped" their paint brushes with their lips and/or tongues, subsequently ingesting radioactive radium. The radium in the paint contained both the long-lived *’Ra and the shorter-lived 22%Ra isotopes. Some of these exposed individuals later developed bone sarcomas and head carcinomas that appeared from 5 to 50 years after their first exposure to these isotopes (Mays 1988; Spiess and Mays 1970). On the other hand, millions of humans have been given tons of microcuries of radioiodine orally to aid in the diagnosis of thyroid disorders, with no apparent harmful effects. For most radionuclides present at chemical waste sites containing low-levels of radioactive isotopes, oral exposure is not a major route of exposure; however, the oral exposure route cannot be completely disregarded because of the potential for groundwater contamination and uptake by plants following erosion of ground cover from a contaminated site. 2.4.6.3 Dermal Dermal exposure to radionuclides is a minor route of exposure at low-level radioactive waste sites. Swimming or bathing in water containing soluble radioactive elements in the water itself or water-soluble radioactive elements in sediment or sludge are potential routes of exposure in highly contaminated areas. Contact with tritiated water is another situation in which skin absorption of a radionuclide can be significant. In general, and depending on the specific physical properties of the radionuclide that may reside on the skin, the percutaneous absorption of radionuclides from particles is usually negligible (especially if the skin is thoroughly washed immediately), with long-term biological effects being demonstrated locally at the level of the dermis (and its vasculature) and epidermis; however, these effects depend greatly on the dose and length of exposure. More soluble forms of the radionuclides may result in a small percentage of the nuclide being ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 53 2. PRINCIPLES OF IONIZING RADIATION absorbed if it was not removed from the skin's surface. This absorption may, in turn, exert biological effects on other organ systems than those seen locally on the skin. 2.4.7 External Exposure to lonizing Radiation External radiation is another major source of exposure to ionizing radiation. External radiation is defined here as radiation exposure from a radioactive source that is outside of the body. Common natural sources are terrestrial radiation (originating from the soil, water, building materials, and air) and cosmic radiation from outer space. Common sources of anthropogenic external radiation include medical and dental X-rays, consumer products, licensed radioactive sources, and being near someone undergoing a medical radionuclide treatment. Technologically enhanced sources consist of concentration of naturally radioactive elements, such as uranium mine and mill tailings or the uranium containing slag from phosphate rock processing. In situations involving external exposure to ionizing radiation, radionuclides that are y emitters are of greatest importance. Alpha particles travel only a few inches in the air and are not capable of penetrating a piece of paper or the straturi corneum, the dead outer layer of the skin. Beta emitters are more energetic than alpha particles (they can travel a few feet through the air) but can be stopped with aluminum foil or glass. In contrast, y-emitting radionuclides have air penetration ranges of several meters or more and are capable of irradiating the whole body instead of localizing to a specific tissue. 2.5 MEASURING INTERNAL AND EXTERNAL SOURCES OF IONIZING RADIATION The radiation from internally deposited radionuclides can not be measure directly. Instead, the radioactivity within the body is determined by bioassay methods, and then applying the data obtained to physiologically- based biokinetic models to calculate the dose. In the case of external radiation, dose rates can be directly measured with appropriate instruments, and the total dose is determined simply by multiplying the dose rate by the exposure time. Total dose from external sources can be easily measured. This is usually done with a personal monitoring device, such as an electronic dosimeter, a pocket dosimeter and film badge, or a thermoluminescent dosimeter (TLD). Table 2-7 lists some of the methods and instruments used by the health physicist to determine a person’s radiation dose. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 54 2. PRINCIPLES OF IONIZING RADIATION Table 2-7. Common Analytical Methods for Measuring Radioactive Material Inside and Radiation Outside the Body Sample matrix Preparation method Device used Reference Whole body, portion of Position individual in front of Multichannel analyzer with Nal NCRP 1978 body, or organ (a-, B- x- or detector with area of interest detector for up to a few y-radiation) shielded from extraneous radiation y-emitters, a germanium detector for any number of y-emitters, or a planar germanium detector for a-emitters that also emit X-rays. Urine, blood or feces Put any solids into solution; do Liquid scintillation for a- or Jia etal. chemical separation if multiple B-emitters; alpha 1994 radioactive elements are present; spectroscopy for a-emitters; deposit thin layer on a planchet or GM counter for high-energy mix with liquid scintillation cocktail. B- or y-emitters; multichannel analyzer for y-emitters. Personal monitoring: None TLD Lynch et al. external radiation dose (B- 1994 and y-radiation) Personal monitoring: None Film badge Shapiro external radiation dose (B- 1990c and y-radiation) Contamination monitoring: None GM counter NCRP 1978 surfaces, skin, clothing, shoes (B- and y-radiation) Contamination monitoring: None Proportional counter NCRP 1978 surfaces, skin, clothing (a-radiation) o = alpha; B = beta; y = gamma; GM = Geiger-Mueller 2.5.1 Internal Radiation Measurements Entry of radioactive materials into the body may occur through any combination of inhalation, oral, injection, or dermal routes of exposure. Measurement of the quantities of radioactive material in the body are performed by in vivo or in vitro methods or a combination of in vivo and in vitro techniques. These types of measurements, called bioassays, are used to determine the type, quantity, location, and retention of radionuclides in the body. In vivo techniques measure the quantities of internally deposited radionuclides directly, while in vitro analyses are performed on the materials excreted or removed from the body. A synopsis of the analytical methods used to measure the quantity of radioactivity both inside and outside of the body is presented in Table 2-7. **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 55 2. PRINCIPLES OF IONIZING RADIATION One in vivo or direct method of measuring radionuclides in the body is performed with a radiation detection system and its associated electronics, called a whole-body counter (see Figure 2-2). This system measures the emission of gamma rays or X-rays from internally deposited radionuclides. The use of whole-body counters is limited to assessment of radionuclides that emit X-ray or gamma radiation as these counters are insensitive to the alpha and beta particles emitted from radionuclides. Whole-body counting systems can vary from single, unshielded detectors that Figure 2-2. Whole Body Counter. The linear geometry Nal based . . WBC pictured here is designed to maximize sensitivity and accuracy for can be used in the field to shielded multi- intemally deposited fission/activation products such as isotopes of Cs and . Co. Photograph courtesy of Canberra Nuclear/Packard BioScience Co. detector scanning systems (NCRP 1987). The complexity of whole-body counting systems is dependent upon their intended uses and the radionuclides to be measured, as well as the accuracy and precision required of the measurement. Examples of types of detectors used include solid, inorganic scintillators (e.g., sodium iodide), and semiconductors (e.g., germanium detectors). If the radionuclide(s) present in the body are unknown, the ability to resolve the energies of the gamma rays also requires the use of a multichannel analyzer and computer for timely spectral analysis (NCRP 1987). Equipment for whole-body counting varies from facility to facility and is based the need of each facility. Equipment changes also continue as the state of the art advances. Commonly, a chair-type counter, equipped with a single large detector, is used; however, the subject can remain standing during the count, as shown in Figure 2-2. The detector is placed a short distance from the body, such as over the chest when a lung count is desired. Multiple, fixed position detectors may also be used for measurement (e.g., lung and thyroid detectors). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 56 2. PRINCIPLES OF IONIZING RADIATION If a particular portion of the body requires monitoring (such as the lungs) after exposure to alpha particle emitters such as uranium, plutonium, and americium, a low-energy germanium lung counter can be used to maximize detection sensitivity for X-rays or gamma rays that are emitted from such internally deposited radionuclides (see Figure 2-3). Typical count time for the instrument shown in Figure 2-3 is 15-30 minutes. Another detector variation consists of moving one or several detectors along the length of the subject, or moving the subject in relation to a fixed detector, and determining radioactivity in the body as a function of the position of the detector (NCRP 1987). Photons from the radionuclides exit the tissues (i.e., the body) and enter the detector. The emissions then interact with the detector. In the case of a sodium iodide detector, the Nal crystal produces flashes of light (scintillations). The intensity of each scintillation is proportional to the interaction energy of the photon producing it. Photomultiplier tubes convert the light energy to an electrical pulse with an output voltage proportional to the intensity of the scintillation. The output pulses are then amplified and sorted by energy level. If a germanium semiconductor detector is used, the photon interaction directly produces an electrical impulse whose magnitude is proportional to the photon’s energy. With either detector, qualitative and quantitative analyses of the energy profiles are then performed to identify and measure the radioactive source. Examples of radionuclides that may be readily detected using whole-body counting techniques are '*Cs, *’Cs, **Co, 0Co, ! I, technetium-99m’{™ Tc), and xenon-133 (***Xe). Special equipment and techniques are also available to measure a-emitting radionuclides like **°Pu where it is actually the isotope’s low energy X-rays Figure 2-3. Low Energy Germanium (LEGe) Based Lung Counter. This that are detected. instrument is designed to maximize sensitivity for internally deposited U, Pu and Am isotopes. Germanium is used to provide the system with the ability to resolve the differences between photons which are close in energy to each other. . . Photograph courtesy of Canberra Nuclear/Packard BioScience Co. In vivo counting systems are calibrated using tissue-equivalent phantoms. These phantoms have shapes similar to the human torso and are made of polystyrene or other tissue equivalent material. Standard radioactive sources of known activities are inserted into the phantom at locations or geometries approximating internal depositions of particular radionuclides in the human body. Relationships are thus determined between the radiations detected and the known activity in the phantom (ANSI N13.30 1989; DOE 1983). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 57 2. PRINCIPLES OF IONIZING RADIATION The American National Standards Institute (ANSI) Draft Standard N13.30 (1989) was developed in an effort to establish performance criteria for accuracy and precision for bioassays. The sensitivity of a whole-body counting system is specified by the Acceptable Minimum Detectable Activity (AMDA). AMDAs have been established by the standard, taking into consideration good laboratory practices (GLPs), need, and available technology (ANSI N13.30 1989). When a whole-body counting facility can measure a minimum detectable activity that is less than or equal to the AN ST AMDA, the performance requirements for the AMDA of the ANSI standard are considered to have been met. For radionuclides that transform by alpha or beta particle emission and do not emit readily measurable gamma rays, in vitro or indirect analyses can be performed. In vitro analyses may also be performed in support of an in vivo monitoring program, or in cases where the size of an operation does not justify the cost of a whole-body counting facility. These analyses usually use urine, but other body materials such as feces, blood, or tissue samples may also be used. Urine sample analysis provides a rapid means of determining whether an intake of radioactive material has occurred; however, fecal, blood or tissue analyses are not routinely performed. Radionuclides that are often assessed using in vitro techniques are *H, *C, various isotopes of uranium and plutonium, and many other 3- or e-emitting radionuclides. Gamma ray measurements of excreta may not require chemical processing and separation prior to counting due to the penetrating characteristic of gamma radiation. For alpha and beta radiation measurements, the energy spectra of the various radionuclides overlap; in such cases, chemical separation of samples prior to quantification of the radioactivity may be required. If only the total activity, not the identity of the radionuclide, is needed, gross alpha and gross beta quantification can be performed with minimal sample preparation. There are no standard chemical separation or preparation procedures for in vitro analysis that are recommended by any recognized authority; however, there are a large number of acceptable procedures available and in use at a large variety of laboratories and facilities, with DOE and EPA laboratories having some standard procedures that they routinely follow (Draft ANSI N13.30 1989). Regardless of the procedures used by each laboratory, the methods should be capable of meeting the AMDAs identified by Draft ANSI N13.30 (1989). Detectors commonly used to quantify alpha, beta, and gamma radiation in in vitro samples include liquid scintillation detectors (Figures 2-4 and 2-5), Geiger-Mueller (GM) detectors (Figure 2-6), gas-filled proportional counters, and semiconductor detectors. In scintillation counters, photons from the radionuclides exit the sample (i.e., urine, feces, tissue) and interact with the scintillator (e.g., toluene for «- and B-emitters; Nal crystals for y-emitters) to produce flashes of light (scintillations). Photomultiplier tubes convert the light ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 58 2. PRINCIPLES OF IONIZING RADIATION energy into an electrical pulse with an output voltage proportional to the intensity of the radiation interaction. The output pulses are then amplified and sorted by energy level. Nal(Tl) Crystal 2 Al20O 3 Reflector Optical Window Optical Coupling Fluid Sprayed ALO3 Reflector 7 # A oil Mumetal Magnetic Shield Spun Aluminum Body ; Photomultiplier: A NN, SS Spun Aluminum Cap Figure 2-4. Components of a Scintillation Detector (adapted from http://tweedledee.wonderiand.caltech.edu/~derose/labs/exp12.html) GM counting systems consist of a gas-filled detector tube, associated electronics, and a counting circuit and display. The tube end can have a thin covering (window) that allows low-energy particles to enter the tube. An incident particle from a radionuclide that enters the tube window and interacts with at least one gas molecule initiates a series of ionizations that result in the generation of a voltage pulse of about 1 volt. The charge multiplication results in a signal of about 1 volt in a typical GM counter. These electrical pulses produced by the incident radiation trigger a circuit which counts the pulses. The GM counter is not capable of discriminating among various energy forms (alpha, beta, gamma) of radiation; the instrument simply records the number of excitations. However, the use of different window coverings allows the user to discriminantly monitor different energy spectra. An aluminum window 0.1 mm thick will stop all beta particles emitted from '*C; to measure alpha particles, an aluminum window thickness of less than 0.02 mm is required. Gamma radiation does not require a special window as it will penetrate the tube from all directions (Shapiro 1990). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 59 2. PRINCIPLES OF IONIZING RADIATION Gas-filled proportional counters are used to measure low-energy (alpha and beta) particles; they are particularly well-suited for low-level alpha measurements due to their large counting areas and low background. Like the GM counters, the signal produced in proportional counters is a result of an electrical charge resulting from the ionization of the gas by the incident particle. Electrons released by the ionization are drawn toward the positively charged central wire. As they travel toward the wire, the electrons collide with other gas molecules, producing more ionizations and an amplification effect. At certain operating voltages, the amplified charge produced is proportional to the energy absorbed in the detector. Alpha particles, due to their larger size and lower speed, interact with more gas molecules over a given path-length than beta particles. Thus, the alpha-to-beta particle pulse height ratio is substantial (Shapiro 1990). Proportional detectors use this difference to distinguish between alpha and beta particles, based on pulse-height discrimination. Semiconductor detectors are characterized by their use of crystalline silicon or germanium as the ionization i medium. A sensitive volume is produced | in the crystal by electrochemical means. The interaction of ionizing radiation with the crystallin lattice within the sensitive volume generates electrons by ionization, and the collection of these electrons leads to an electrical output pulse whose size is proportional to the energy of the ionizing radiation. A semiconductor detector requires only about one-tenth as much energy to produce an ionization as other types of detectors. This leads to a great increase in the detector’s resolving power (i.e., in the ability of the detector to Figure 2-5. Liquid Scintillation Counting (LSC) System. separate pulses from particles whose 7 Photograph courtesy of Canberra/Packard BioScience Co. energy differences are very small. For this reason, semiconductor detectors find their main use in nuclear spectroscopy, where they can separate and accurately identify various radionuclides. Several types of semiconductor systems are available, including in- situ spectrometers and both portable and stationary systems equipped with multichannel analyzers (Cember 1996; Shapiro 1990). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 60 2. PRINCIPLES OF IONIZING RADIATION 2.5.2 External Radiation Measurements People who are occupationally exposed to radiation are routinely monitored for external radiation dose (i.e., radiation sources located outside of the body) by several different devices called dosimeters. The most commonly used personal monitoring dosimeters are thermoluminescent dosimeters (TLDs) and nuclear emulsion monitors (film badges), which can be used to measure exposure to 3, X-ray, and y radiation sources. The TLDs and the film badges are integrating devices that measure the dose over the period the TLD or film badge is used or worn. The most widely used thermoluminescent material for measuring beta and gamma radiation is lithium fluoride crystals. The energy absorbed from the radiation raises the electrons in the lattice structure of the crystal to a higher energy level, where a portion are trapped by added impurities. The electrons remain in these excited states until the TLD is heated to a sufficiently high temperature to return the material to its normal energy level with the emission of light (Lynch et al. 1994). The light emitted can be measured and is proportional to the radiation dose to which the TLD was exposed. Automated systems for measuring the light output from the heated TLDs are known as TLD readers and are commercially available. A TLD is normally worn from 1 day to 3 months before being processed and is then available to be used again (Shapiro 1990). When individuals are exposed to mixed radiation fields (e.g., mixtures of beta/gamma radiation), measurements for each radiation type must be performed. Film badges (or TLDs) are commonly used to monitor personal exposures to 3, X-ray, and y radiation, but not ¢ radiation. Due to the limited range of beta particles in tissue, the exposure of concern is primarily to the skin, although betas whose energy exceeds 0.8 MeV can penetrate to the lens of the eye. Penetrating X-ray and gamma radiation pose exposure concerns for the whole body, including the lens of the eye. These types of radiation are assessed simultaneously using multiple TLDs individually covered with absorbers of various materials, or a strip of film with sections covered with absorbers, that account for attenuation in tissues covering the area of interest. The skin dose, called the shallow dose equivalent (SDE), is measured with the dosimeter behind 7 mg/cm? of material representing the dead skin layer above live tissue. The dose to the lens of the eye, called the eye dose equivalent (EDE), is measured behind 300 mg/cm? of material equal to the thickness of the cornea plus liquid that covers the lens. The whole-body dose, called the deep dose equivalent (DDE), is measured behind 1,000 mg/cm?. This is equal to about 1 cm of tissue or the depth inside the body where scattered radiation causes the dose to be the highest. For example, most TLDs and film badges have a small beta window shielded only by a thin sheet of mylar, and a gamma ray detection area consisting of one or more sections shielded with thin sheets of plastic, metal (like copper, aluminum, steel, tin, or lead), or combinations of ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 61 2. PRINCIPLES OF IONIZING RADIATION these. The radiation exposure of the film is determined by the degree of darkening of the photographic film. A densitometer is used to read the film darkening, which is proportional to the absorbed dose of the film (Shapiro 1990). In addition to wearing TLDs and film badges, many radiation workers also carry self-indicating pocket dosimeters to provide the wearer an indication of the radiation dose received during the day. Because the pocket dosimeters may be read by the individual locally, it gives the worker the necessary information to prevent an overexposure; the worker can leave an area before a particular radiation dose is exceeded. The dosimeters, which are usually worn beside the primary dosimeter, typically measure X-ray or y radiation as well as beta rays with energies exceeding 1 MeV; by coating the interior of the chamber with boron, the devices may also be made to monitor thermal neutron exposure. There are two types of pocket dosimeters. The condenser-type dosimeter is an indirect reading dosimeter; an additional device, referred to as a charger- reader, is needed to charge and read the dosimeter. The dosimeter is basically a capacitor with an exterior wall made of an electrically conducting plastic and an interior central wire which is insulated from the outer wall. Using the charger-reader, a positive charge is placed on the central wire. When exposed to X-ray or vy radiation, the ionizations discharge the unit. The amount of charge remaining in the dosimeter at any point is inversely proportional to the ionization produced in the cavity. The degree of discharge is measured by attaching the dosimeter to the charger-reader, which is calibrated in milliroentgens. The second type of pocket dosimeter is a direct-reading type; no additional equipment is needed to assess the degree of exposure. In this instrument, a quartz fiber is electrostatically displaced by charging it to a potential of about 200 V. As with the other dosimeter, ionizations caused by radiation discharge the fiber. As the fiber loses its charge, it returns to its original position. The relative position of the fiber is calibrated to an exposure scale, usually in the range of 0 to 200 mR. The position of the fiber against the scale may be viewed through the end of the instrument. Pocket dosimeters gradually discharge over time due to cosmic radiation and charge leakage across the insulating material. Because of the natural discharging and the potential for malfunction due to dropping the device, they are typically worn in duplicate and are read and recharged daily (Cember 1996). Miniature digital alarm systems are also available. These detectors feature solid-state Si detectors, a microprocessor to monitor X-ray and gamma radiation, dose, dose rates, and dose history. In addition, these systems are light-weight, programmable, and feature audible alarms and visible LED warning indicators (Dositec 1997). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 62 2. PRINCIPLES OF IONIZING RADIATION 2.5.3 Field Radiation and Contamination Surveys Ionizing radiation in the environment arises from four basic sources: (1) natural radioactivity from uranium, thorium, and other primordial radiation nuclides; (2) cosmic rays and radionuclides produced by cosmic-ray interactions in the atmosphere; (3) contaminants from nuclear-weapons fallout; and (4) effluent from nuclear and medical facilities (NCRP 1985). Two methods are routinely used for measurement of ionizing radiation in the environment: (1) field surveys using portable survey instruments, and (2) analysis of samples procured in the field that are returned to the laboratory for quantification. 2.5.3.1 Field Measurements of lonizing Radiation External radiation measurements can also be performed by the use of portable, hand-held survey instruments. The primary purpose of some types of survey instruments is to measure the radiation levels to which people are exposed, while others detect any contamination that may be present on an individual's skin, clothing, shoes or in the environment. Various types of radiation detectors (e.g., Geiger-Mueller or scintillation) are coupled with a count rate meter designed to detect alpha, beta, and gamma forms of ionizing radiation. The count rate meter has a scale with a needle indicator or digital display that provides an immediate readout of levels of radiation or contamination that may be present in units of milliroentgens per hour (mR/hr) (1 mR = 1 millirem) or counts per minute (cpm). The two most frequently used GM survey meters are the GM thin end window type probe (Figure 2-6) and the GM "pancake" type detector (Figure 2-7). The pancake detector typically has a probe detection area which is larger than that of an end window detector; thus, the pancake detector gives a background radiation reading of 70-100 cpm, while the end window GM detector gives background count rates of approximately 40-50 cpm (Shapiro 1990). The typical survey meter for identifying alpha contamination uses a zinc sulfide scintillator material that can reliably detect 200-500 dpm per 100 cm? (DOE 1988). This unit of measure has been chosen by regulatory agencies for control purposes. The alpha reading may be inaccurately low if the surface is irregular, porous, or damp since these conditions can attenuate the alpha particles. Recent developments in large area gas and gas-flow proportional counter technology have enabled these detectors to achieve higher sensitivities than alpha scintillator detectors and acceptance in decommissioning operations. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 63 2. PRINCIPLES OF IONIZING RADIATION Field surveys can be either qualitative in nature to provide a go/no-go indication for excess radiation levels, or quantitative to provide a numerical value for the level and possible identification of the radionuclides present. Most field surveys involve the use of a calibrated, portable, hand-held survey meter equipped with a count-rate meters or digital display that provides an immediate reading of Figure 2-6. Geiger-Mueller Counter with an Energy-compensated or Gamma Probe. the radiation field strength or the surface contamination level. Attached to the survey meter is a radiation detector that is chosen for its sensitivity to the radiation of interest. Typical alpha radiation detectors use the alpha scintillator material ZnS and gas-flow surface contamination monitors. Typical beta radiation detectors are GM detectors and gas-flow surface contamination monitors. Gamma radiation detectors include a wide range of equipment types such as the GM sodium iodide counters, which are highly sensitive and are used mainly to search for and detect radiation; ion chambers for measuring the radiation dose rate; pressurized ion chambers; and plastic scintillators for low levels. Specialty instruments are available for more detailed field work, but these generally require special skills and training. The in-situ germanium spectrometer is a multichannel analyzer with a germanium detector that can identify a range of y-emitting isotopes and quantify their concentration in surface soil. The Laser Ablation Inductively Coupled Figure 2-7. Geiger-Mueller Counter with a Beta/gamma Pancake- type Detection Probe. Plasma (LRAD) -mass spectrometer (LA-ICP- MS) can measure 0.3 pCi/g of ?**U in soil. The Long Range Alpha Detector (LRAD) can measure alpha soil contamination down to 10 pCi/g. The Field Instrument for Detection of Low Energy Radiation (FIDLER) can measure plutonium and americium surface contamination. The field X-ray fluorescence spectrometer can measure the relative concentration of metal atoms in soil or water down to the parts per million (ppm) range. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 64 2. PRINCIPLES OF IONIZING RADIATION The purpose of making measurements with field survey instruments is to provide timely information on the presence and levels of ionizing radiation fields or radioactive materials. Measurements of ionizing radiation fields or loose radioactive material can be made in the field with portable instrumentation (Figure 2-8). Similar surveys can also be performed on persons when contamination is suspected since both environmental surveys and personnel surveys use many of the same types of portable instrumentation. Accurate quantification of radioactivity in environmental media may be made with portable instrumentation, such as the in-situ gamma ray spectrometer shown in Figure 2-8, or samples may be collected and subjected to laboratory analyses. . Semi-permanent instruments or liguld nitrogen reservoir {io ratain crystal at -196°C) high-purity germanium detector instruments placed in the field {suspanded 1 m above the surface} for extended periods of time are sometimes used for measuring mirdature, modular multichannel analyzer ambient environmental radiation levels or to detect changes in field of view axtends to approx. 10m ambient environmental radiation levels, such as around nuclear soil surface | assembk facilities. Pressurized ionization chambers (PICs) are often used as a standard for measuring Figure 2-8. In-Situ Gamma Ray Spectrometer gamma radiation levels in mR. (adapted from http://www.em.doe.gov/rainplum/fig16.html) . Readings are recorded on a real- time strip chart recorder or on a magnetic card, and can be arranged to transmit these data to a central site for computer processing. Several types of portable survey instruments using ionization chamber detectors are also used. For ionization chamber detectors to be used for ambient environmental radiation monitoring, the detection sensitivity must be several prad/hour (Kathren 1984). Ion chamber survey meters typically exhibit long response times, particularly at low radiation levels, requiring up to several minutes to record a detectable measurement above background levels at low radiation levels. GM counters and both plastic and Nal scintillators have also been used for field measurements of ambient radiation. These instruments have detection capability down to several urad/hour. These instruments are rugged and have a shorter time constant than a pressurized ion chamber (PIC), making them more suitable than PICs when numerous environmental measurements are to be made. Counter type survey meters count particles, while the response of dose measuring instruments is proportional to the amount of energy absorbed ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 65 2. PRINCIPLES OF IONIZING RADIATION by the gas in the ion chamber. Counter type survey meters, such as GM and scintillation counters, therefore, are very energy dependent when used to measure dose. They can be used to reliably measure dose or dose rate only for radiation whose energy is the same as the energy of the calibration source. Energy flattening filters are sometimes used in GM survey meters to compensate for the energy dependence (Kathren 1984; NCRP 1976, 1985). The energy response problem can largely be overcome by taking paired PIC and GM or Nal readings at several points to develop factors for converting GM or Nal readings to true exposure levels in mR/hr (EPA 1994). Scintillation detectors and semiconductor detectors can also be used for field monitoring for detection and quantification of gamma radiation. When used in conjunction with a multichannel analyzer and computing capabilities, it is possible to determine whether the radiation fields originate from terrestrial radiation, cosmic radiation, or anthropogenic radiation, or from a combination of these sources. These instruments are useful for environmental monitoring around reactor sites and sites undergoing remediation for unrestricted use by the public. The very short range of the alpha particle makes it necessary for the distance between the x-emitting source and the alpha detector to be very small. It also requires that the detector window be very thin to enable passage of the alpha particle into the detector. Portable alpha monitors are available based on the principle of gas proportional counters or scintillation counters. A scintillation detectory that is frequently used is silver- activated ZnS. The ZnS detector is relatively insensitive to beta or gamma radiation and exhibits a low background count, thus permitting discrimination of alpha from beta or gamma radiation. Gas-filled proportional counters are particularly well-suited for low-level alpha measurements due to their large counting areas and low background. Proportional detectors can distinguish between alpha and beta particles based on pulse-height discrimination (NCRP 1978; Shapiro 1990). Detection of plutonium in the environment is needed due to several accidents that have occurred in the past (see Section 3.5). Plutonium transforms by « emission with a small percentage of accompanying X-rays with energies in the region of 17 keV from the excited *’Np daughter. Due to the difficulties associated with measurement of alpha particles, an instrument called a FIDLER (Field Instrument for Detection of Low Energy Radiation) was developed. This instrument measures the 17 keV photons associated with the transformation of **Pu using a 5-inch diameter crystal of Nal, 1/16th of an inch thick. FIDLER measurements are also made of the 60 keV photons from americium-241 (**' Am), which is often associated with plutonium as an impurity (Kathren 1984). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 66 2. PRINCIPLES OF IONIZING RADIATION Large-scale environmental monitoring for contamination is sometimes carried out on roads and railroad tracks using scintillation detectors mounted on vehicles. The detectors are shielded on the sides and tops and are suspended above the ground surface. In addition, aerial surveys for radioactivity are useful for mineral exploration, special studies of uranium fields, nuclear facilities monitoring, fallout measurements, etc. The detector of choice for most of these measurements is the scintillator, usually a large single crystal (Kathren 1984) or multiple smaller detectors with summed responses. The correlation of airborne measurements with ground-level data indicates that the average exposure rates in a strip of land 400 meters wide under the flight lines are accurate to within £20% (NCRP 1976). In addition to the use of survey instruments, environmental radiation is also measured with passive integrating detectors such as film badges or TLDs. TLDs are superior to film badges in energy dependence, angular dependence of ionizing radiation incident upon the dosimeter, permissible time in the field, resistance to environmental conditions, and lower limit of detection (10 mrad for film compared with 1 mrad for TLD) (Kathren 1984; NCRP 1976). Several phosphors are available for environmental measurements, including LiF, CaF,, CaSO, (Kathren 1984; NCRP 1976) and Al,O,. In the field, TLDs do not require a great deal of protection; however, some phosphors may exhibit light and humidity sensitivity. Consequently, it is useful to package the TLD in some sort of light and water-tight material that will protect the TLD from dirt and precipitation. A good source of information on the applicability, operation, specificity, sensitivity, cost, and cost of operation is the draft Multi-Agency Radiation Survey and Site Investigation Manual (MARSSIM) being jointly prepared by EPA, NRC, and DOE as a consensus guide for conducting the final status survey in releasing a radiation site for unrestricted public use. 2.5.3.2 Laboratory Analysis of Environmental Samples Analytical methods for the quantification of radioactive material in environmental samples include the matrices of air, water, sediment, food, vegetation, and other biota. In many cases, particularly in occupational settings, the radionuclide(s) are known so the analysis can be confined to that particular radionuclide(s). If the radioactivity in a sample is from an unknown radionuclide(s), the sample should be examined for & and p/y-emitting nuclides. Environmental samples usually involve measurement of low levels of specific radionuclides in the presence of naturally occurring radionuclides. Consequently, the analyzing analytical instrumentation should be highly sensitive and the effect of natural background radiation levels on the detectors should be minimized. Background reductions are usually achieved mechanically by the use of shields around the detectors and electronically by pulse size discrimination (NCRP 1978). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 67 2. PRINCIPLES OF IONIZING RADIATION Preparation of various environmental media for analysis of radioactive content may require concentrating the radioactive material from a large sample into a small volume to increase the sensitivity of the analysis or reducing the sample to a form more suitable for counting. Standardization of chemical methods for preparation of all sample matrices and for sample counting for all radionuclides has not been achieved. Such standardization may not even be desirable, because variations of a single procedure may be used to advantage even in a single laboratory. For example, solvent extraction may be used for samples with high salt content whereas ion exchange chromatography may be used for samples with low salt content. However, some standardized methods for environmental sample preparation have been developed in laboratories for analysis of radionuclides in various matrices (EPA 1984) and in drinking water (EPA 1980). These should be used unless experience has indicated otherwise. Chemical separation techniques and nuclear instrumentation for assessment of several radionuclides in various matrices can be found in the ATSDR profiles for uranium, plutonium, and radium (ATSDR 1990c, 1990e, 1990f). There are several methods in use for quantification of alpha particles. If the identity of the a-emitting radionuclide is not needed or is already known, alpha activity of samples can be quantified by gross or "total" alpha counting (NCRP 1985). However, the short range of alpha particles in liquid and solid samples usually requires physical and/or chemical separation of the radionuclide from the matrix as described by EPA procedures (EPA 1980, 1984). Since the energies of the radionuclides that transformation by « emission are unique, when the identity as well as the quantity of the «-emitting radionuclide(s) in a sample are needed, o.-spectroscopy or mass spectrometry can be used (NCRP 1985) and in the procedures manuals of the DOE’s Environmental Measurements Laboratory and the Los Alamos National Laboratory. For environmental samples containing radionuclides that emit gamma rays, scintillation detectors (sodium iodide) and semiconductor detectors (germanium) are commonly used. These detectors, along with the appropriate electronics, computers and software, can be used to identify and/or quantify y-emitting radionuclides (Kathren 1984; Knoll 1989; NCRP 1985). A number of radionuclides, including *H, "*C, **P, 3S, **Ca, **Sr, **Sr, and *°Y, emit only beta radiation (NCRP 1985). Liquid scintillation counting systems are widely used for the assay of low levels of f-emitting radionuclides and can be used to quantify all of the radionuclides listed above. GM detectors are also often used for quantification of beta particles; however, GM detectors cannot be used to quantify *H and *C because of the very low beta energies of these two nuclides. Another instrument used for assessment of beta particles in environmental samples is the gas-flow proportional counter. Gas-flow proportional counters can readily quantify the B-emitting radionuclides identified above, as well as *H and '“C, either when the detector ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 68 2. PRINCIPLES OF IONIZING RADIATION window is very thin (in the case of '*C) or when the detector is windowless (in the case of *H). In general, liquid scintillation, gas-flow proportional and GM counters provide data on total beta activity, although some liquid scintillation counters have some ability to resolve energy spectra. Also, solid organic scintillators, which are usually made from plastic but may also be made of crystals of anthracene and trans-stilbene, may be used to quantify and identify beta particles (Knoll 1989). 2.6 CONCLUSIONS Low levels of ionizing radiation have always been present; however, only in the past 100 years have humans discovered its ubiquitous presence and learned to harness and manipulate its power. Ionizing radiation is a highly specialized area of toxicology that requires an extensive knowledge and understanding of radiation physics, dose, transformation, and biology. Ionizing radiation interacts in unique ways with matter to yield carcinogenic and non-carcinogenic responses after acute and chronic exposures. During the 20th century, scientists and governments have developed uses for radionuclides both for peaceful purposes, such as medical diagnosis and treatment and electrical power generation, and for destructive purposes, such as weapons technology. Much research has been performed in defining the different types of radiation, how ionizing radiation interacts with matter, and how to measure both the radioactivity as well as the radiation dose from a given exposure. All of this and other information has been used in correlating the absorbed dose, from short- term high doses to long-term low doses, to toxicological manifestations ranging from almost immediate death after an initial exposure to the induction of carcinogenesis years after a non-lethal exposure. This chapter summarized some of the more important information about ionizing radiation. The remainder of this toxicological profile discusses in more depth the biological and toxicological effects and mechanisms of action of ionizing radiation (Chapters 3 and 5), sources of population exposure (Chapter 6), and regulatory aspects specific to ionizing radiation (Chapter 7). Observed Health Effects from Radiation and Radioactive Material tables for ionizing radiation are presented in Chapter 8. 2.7 OTHER SOURCES OF INFORMATION The Internet World Wide Web (WWW) sites listed in Table 2-8 may provide more information on the general principles and health effects of the different forms and doses of ionizing radiation. However, one should clearly understand that information obtained from internet sources should not be considered as having been peer reviewed unless separately authenticated. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 69 2. PRINCIPLES OF IONIZING RADIATION Table 2-8. Some Internet WWW Sites Related to Ionizing Radiation HyperText Transfer Protocol (HTTP) address http://www.uic.com.au/ral.htm http://www.dne.bnl.gov/CoN/index.html http://www.nci.nih.gov/intra/dce/whatwekn.html http://www.nci.nih.gov/intra/dce/available.html http://radefx.bcm.tmc.edu/ http://www.em.doe.gov/cgi-bin/tc/tindex.html http://www.rerf.or.jp/ http://www.ohre.doe.gov/ http://www.hps.org http://www.epa.gov/narel/index.html http://www.epa.gov/narel/erd-online.html http://www.nrc.gov/ Web page contents A beginner's reference for ionizing radiation. Radionuclide information on half-life, transformation energies, etc. General information on the known health effects of ionizing radiation. Downloadable peer-reviewed references on some health effects of ionizing radiation Baylor College of Medicine Radiation Effects Homepage. Health effects documents, downloadable software, Chernobyl information, links to other radiation-related sites. DOE Environmental Management. Public information access and links to DOE research laboratories Radiation Effects Research Foundation. Human health impact of the atomic bomb release on Hiroshima and Nagasaki, Japan. DOE “cold war” radiation research using human subjects. Health Physics Society. Involved in the development, dissemination, and application of radiation protection. Concerned with understanding, evaluating, and controlling the risks from radiation exposure relative to the benefits derived. Reports nationwide radionuclide concentrations in air, drinking water, surface water, precipitation, and milk NRC. Nuclear waste, nuclear reactors in operation, and rule-making procedures. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 7 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION 3.1 INTRODUCTION Ionizing radiation is a form of radiation that possesses sufficient energy to remove electrons from their atomic or molecular orbital shells in the tissues they penetrate (Borek 1993). These ionizations, received in sufficient quantities over a period of time, can result in tissue damage and disruption of cellular function at the molecular level. Of particular interest is their effect on deoxyribonucleic acids (DNA). A special issue to consider when examining the health effects caused by ionizing radiation is the concept of dose. The dose delivered to tissue from ionizing radiation can either be acute (with the energy from the radiation being absorbed over a few hours or days) or chronic (in that the energy is absorbed over a longer period of months, years, or over a lifetime). The dose becomes particularly important when the exposure is to radioactive materials inside the body. The distinction between acute and chronic exposure must consider both the intake rate and the physical, chemical, and biological aspects of the radionuclide kinetics. For radioactive materials with effective half-lives longer than a day, even if the intake is prompt (minutes to a few days), the energy is deposited in tissue over a period longer than a few days, so that the exposure to the surrounding tissue is of a chronic duration. Very few radioactive materials can deliver a large acute radiation dose; however those which can are typically associated with medical diagnostics and therapeutics (i.e., “™Tc or X-rays). Depending on the size and duration of the dose, the effects of ionizing radiation can either be acute (occurring within several hours to several months after exposure) or delayed (occurring several years after the exposure). Readers should keep in mind the principles of dose when interpreting Tables 8-1 to 8-4, found in Chapter 8 (“Observed Health Effects from Radiation and Radioactive Material”) in this profile. For example, Table 8-1 lists the observed health effects from radiation and radioactive material using inhalation as the route of exposure. Entry 109 shows a study in which Beagle dogs were exposed for 2 to 22 minutes to **SrCl,. Although this animal received the total amount of radionuclide within 2 to 22 minutes (an acute duration of exposure), the radionuclide is absorbed and redistributes to other tissues (in this case, bone) and remains there for a protracted period of time (chronic exposure). Delayed effects of osteosarcoma and other tumors were found in almost half of these animals (Gillett et al. 1987b). Without a clear understanding of both the dose and the toxicokinetics of the radionuclide, one may conclude from this table that a 2 to 22 minute dose of radiation from *’SrCl, will cause bone cancer in dogs. The more appropriate conclusion to draw from this ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 72 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION study is that after a 2 to 22 minute dose of radiation from **SrCl,, the radionuclide appeared to have redistributed from the lungs to the bones, and given its long physical t,,, of 28.6 years, irradiated the surrounding tissues for a lengthy period of time to produce a cancerous end point. Sources of ionizing radiation can be found at many waste sites in the United States and abroad. Exposure to these sources may have potential adverse health effects, depending on the isotope and the absorbed dose. The predominant radionuclides found at Department of Energy (DOE) National Priorities List (NPL) waste sites are listed in Table 3-1. Table 3-1. ATSDR Priority Listing of Radionuclides Present at Department of Energy NPL Sites Ranking # Isotope Primary emission Physical half-life Target tissue(s) for soluble forms 1 Thorium-232 a 1.4 x 10" years 2 Uranium-235 a 7.04 x 10% years Renal (proximal tubules) 3 Radium-228 B 5.76 years Skeleton 4 Uranium-238 a 4.46 x 10° years Renal (proximal tubules) 5 Radium-226 ao 1600 years Skeleton 6 Cobalt-60 B,vy 5.271 years Whole body 7 Krypton-85 B 10.72 years 8 Americium-241 a 432.2 years Lung 9 Uranium-234 a 2.45 x 10° years Renal (proximal tubules) 10 Potassium-40 B 1.26 x 10° years Skeleton 11 Europium-152 B 13.5 years 12 Neptunium-237 a 2.14 x 10° years 13 Cesium-137 By 30 years Whole body 14 Protactinium-231 a 3.25 x 10* years 15 Strontium-90 B 28.6 years Skeleton 16 Krypton-88 B 2.84 hours 17 Thallium-208 B 3.053 minutes 18 Thorium-228 o 1.913 years 19 Protactinium-234 B 6.69 hours 20 Argon-41 B 1.82 hours 21 Plutonium-239 a 24,131 years Bone surface 22 Krypton-87 Bly 76.3 minutes Whole body 23 Thorium-230 a 77,000 years Bone surface 24 Uranium-236 a 2.3415x 10” years Bone surface 25 Plutonium-238 ao 87.75 years Bone surface Source: Lide 1996; Schleien 1992 ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 73 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION The open scientific literature is filled with in-depth discussions and reviews on the effects of ionizing radiation in humans and animals, and it would be difficult, if not impractical, to justly summarize all of the known information about each radionuclide in every animal in this profile. Although the database of biological, radiological, toxicological, and toxicokinetic information is substantial and much is known, much remains to be learned about the specific mechanisms by which ionizing radiation exerts its effects, how these effects can be minimized in living tissues, and what the long-term effects of very low doses of ionizing radiation are over the normal human lifespan. In this profile, some of the information about the effects of ionizing radiation has been obtained from human epidemiological and medical studies, but most has come from studies conducted on laboratory animals. Because of this large database of information, and in an effort to provide a useable overview of the health effects caused by exposure to radionuclides, this toxicological profile will summarize the adverse effects of ionizing radiation from alpha (a), beta (B), and gamma (y) forms of ionizing radiation, using representative radionuclides to demonstrate the effects on specific organs and tissues. Other radionuclides with similar emissions and kinetics may produce similar end points. This profile will not provide an in-depth discussion of the more subtle points of radiation biology and toxicology. It will, however, provide the reader with a comprehensive and informative overview of a cross-section of the scientific literature that pertains to the adverse carcinogenic and non-carcinogenic effects of the «, B, and y forms of ionizing radiation, focusing on key human and animal studies and using representative radionuclides for illustration purposes. Readers are strongly urged to consult both the glossary and Chapter 2 of this profile to become familiar with the terminology used when discussing both the exposure to ionizing radiation and also for the characteristics of these three forms of ionizing radiation. Several excellent texts and review papers are also available in the open literature that provide the salient background material for many of the sections of this profile (BEIR IV 1988; BEIR V 1990; Faw and Shultis 1993; Harley 1991; Roesch 1987; UNSCEAR 1993). 3.2 HEALTH EFFECTS FROM EXPOSURE TO IONIZING RADIATION Ionizing radiation can lead to various effects, such as skin burns, hair loss, birth defects, illness, cancer, and death. The basic principle of toxicology, “the dose determines poison,” applies to the toxicology of ionizing radiation as well as to ail other branches of toxicology. In the case of threshold effects (“deterministic effects” in the language of radiation toxicology), such as skin burns, hair loss, sterility, nausea, cataracts, etc., a certain minimum dose (the threshold dose), usually on the order of hundreds or thousands of rad, must be exceeded in order for the effect to be expressed. Increasing the size of the dose after the threshold is exceeded increases the severity of the effect. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 74 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Ionizing radiation also increases the chance of getting cancer. Increasing the size of the dose increases the chance of cancer induction. In the case of carcinogens generally, whether chemical or radiological, we base our safety standards on a postulated zero threshold. That is, we postulate that any increment of carcinogen, no matter how small, carries with it a corresponding increase in the chance of causing cancer. Increasing the size of the dose increases the probability of inducing a cancer with that carcinogen. Cancers that are in fact caused by radiation are completely indistinguishable from those that occur spontaneously or are caused by other carcinogens. In a given population, such as the Japanese survivors of the atomic bombings of 1945, we identify the carcinogenicity of ionizing radiation only by measuring the frequency of occurrence of cancer. In the case of the survivors of the atomic bombings in Japan, we have seen no increase in cancer frequency among those persons whose radiation dose did not exceed 40 rad and no increase in leukemia among those whose radiation dose did not exceed 40 rad. Since we can not uniquely identify any cancer as having been caused by the radiation, and since we do not observe an increase in cancer frequency following low-level irradiation, we must calculate the cancer risk coefficient, that is, the probability of getting cancer per unit of radiation dose, by extrapolation of data from observations on populations that received high doses of radiation. The effects of internally deposited radioisotopes are the same as those of external radiation. The effects depend on the size of the dose. The dose of radiation absorbed, in turn, depends on the radiological parameters of the radionuclide, such as the quantity of activity, the type and energy of the radiation, and the half-life of the radionuclide, and also on the physiological parameters, such as the chemical form of the radionuclide that is taken in the body, the route of entry into the body, the metabolic pathways, and the residence time and the rate and route of elimination of the radionuclide. Only if the dose is great enough can we expect harmful health effects. For the purposes of this profile, we have divided the end points produced by ionizing radiation into those effects that were (at least initially) non-carcinogenic and those exposures that were carcinogenic. The non- carcinogenic effects were further subdivided by major organ systems affected plus teratogenic effects. This was primarily done to help the reader understand the broad scope of adverse health effects produced by ionizing radiation. This approach was also necessary to facilitate evaluating study designs found in the literature. Some studies exposed laboratory animals to radiation, determined the non-cancerous end points, and then sacrificed the animals to complete the study objectives. This would imply that cancer did not or would not develop after exposure to this radiation, which certainly may not be the case. Other studies exposed animals to radiation, observed the non-carcinogenic end points (if any), and then allowed the animals ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 75 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION to live out their normal lifespans to determine if cancer would develop. These latter studies provided more complete information on the overall effects of exposure to ionizing radiation. As discussed in Chapter 2 of this profile, no Minimal Risk Levels (MRLs) have been derived for any route of exposure in this profile at this time. However, ATSDR is currently in the process of examining and critically evaluating the large database of health effects caused by exposure to ionizing radiation. During this evaluation process, ATSDR is also examining many other factors, including (1) which specific studies would lend themselves to be most suitable for deriving an MRL, and (2) what health effect(s) an MRL should be based upon (cataract formation, reduction in IQ, etc.). Any MRLs that are derived will be integrated into the final version of this profile. 3.2.1 Acute (Immediate and Non-Carcinogenic) Effects from lonizing Radiation Exposure A considerable body of information is available in the open literature on the acute exposure, high-dose health effects of ionizing radiation. There are three circumstances in which a person may conceivably be exposed to acute high-level doses of ionizing radiation that would initially result in one or many immediate non- carcinogenic effects. One instance would involve being in the immediate proximity of an atomic blast, as were the Japanese populations of Hiroshima and Nagasaki in August 1945 or the Marshall Islands fallout victims injured from fallout from an atomic weapons blast on Bikini Atoll in March 1954. The second instance would be a laboratory or industrial accident. The third and most likely opportunity for exposure to high levels (or repeated doses) of ionizing radiation would involve medical sources in the treatment of disease (protracted exposures to X-rays, fluoroscopy, radioiodine therapy, etc.). People who volunteer to be exposed to ionizing radiation for the purpose of medical research also fall into the third category. People who have a large enough area of their body exposed to high doses of ionizing radiation in any of these situations may exhibit immediate signs known as acute radiation syndrome. In addition to radiation sickness, exposure to ionizing radiation can result in lens opacities (~0.2 Gy threshold and protracted exposure), and fetal and developmental anomalies. The acute and delayed effects of exposure to ionizing radiation in humans and laboratory animals have been studied quite extensively. Laboratory animal data has provided a large volume of information related to the health effects of ionizing radiation; however, the most useful information related to human health effects comes from controlled human exposure data. The data collected from the larger exposed populations, such as those from Hiroshima and Nagasaki or the radium dial painters, have provided valuable information on both “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 76 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION the acute and the delayed (long-term) health effects in humans exposed to ionizing radiation from certain radionuclides. A number of studies performed on smaller groups of people as early as the 1930s have been recently identified and made public (DOE 1995). These experiments will not be discussed in depth in this toxicological profile (for reasons listed below), but will be briefly summarized. Most of these exposures to sources of ionizing radiation were performed in small groups of human volunteers at a few institutions sponsored or supported by the Department of Energy (DOE), U.S. Energy Research and Development Administration (ERDA), the U.S. Atomic Energy Commission (AEC), the Manhattan Engineer District (MED), and the Office of Scientific Research and Development (OSRD). Other studies took place at universities, private hospitals, and other institutions. The bulk of these human studies could be grossly categorized as either tracer studies, metabolism studies, dose-response studies, or as experimental treatments for disease. Many of these studies listed in the DOE report are quite dated, which provided the challenge of assembling the appropriate documentation to describe the purpose of each experiment, reconstruct and describe the experimental designs, the dates and locations of the exposures, doses and routes of administration, the population size and how the populations were chosen, the use of informed consent among these individuals, and whether any of these individuals were followed through the remainder of their life in order to determine possible delayed effects from exposures to these radionuclides. In any case, these experiments yielded a useful database of information that described the health effects of radiation exposure in humans. Some of these studies are summarized in Table 3-2. Table 3-2. Summary of Some Studies of Humans Exposed to Radionuclides Number Purpose of of people Dose and route of Laboratory Year(s) Radionuclide experiment dosed exposure Result ANL 1931- **Ra Determine the NA 70-50 pg; In progress 1933 retention time of **Ra injected in humans ANL 1943- X-rays; Determine effects of 4 X-rays: 30 R White blood cell chemistry 1946 ¥P radiation, process 2p: route not was important in assessing chemicals and toxic specified the radiation sensitivity of metals in humans workers exposed to radiation ANL 1944- =p Study the metabolism 7 15-40 pCi; NA 1945 of hemoglobin in route not specified cases of polycythemia rubra vera ANL 1962 °H Study the uptake of 4 10 pCi; injected ~~ Similar growth was noted in ®H thymidine in both cancerous and non- tumors and the cancerous cells treated with effects of °H on °H tumors ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 77 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Table 3-2. Summary of Some Studies of Humans Exposed to Radionuclides (continued) Number Purpose of of people Dose and route of Laboratory Year(s) Radionuclide experiment dosed exposure Result ANL 1943- X-ray Study hematological 14 27-500 R; Reduction of white blood 1944 changes at varying external exposure cells formed in lymphoid doses of radiation tissue; routine monitoring of blood components not a practical way of assessing the usual occupational radiation exposures ANL 1948- T®As Determine effects of 24 17-90 mCi; ®As as effective as more 1953 "As on hematopoietic intravenous commonly used leukemia tissues in leukemia therapeutic agents. patients BNL 1950 | Determine the 12 4-360mCi or NA usefulness of *'l to 6-20 mCi; route treat patients with not specified Grave's Disease (metastatic carcinoma of the thyroid) BNL 1951 | Study interaction of 8 NA Maximum uptake of '*'l was the thyroid and "*'l in 30-60% of administered children with ) dose (3-5 pCi); no nephrotic syndrome impairment of | uptake in children with nephrotic syndrome. BNL 1952- “2K Examine formation 2 NA; injected route The amount of CSF 1953 ¥Cl and cycling of not specified produced daily is small and | (1 patient) cerebrospinal fluid fluid production is not solely (CSF) produced by the choroid plexus BNL 1963 *Fe Study iron absorption 9 1-10 pCi; oral Menstrual blood loss in in women with women with excessive various menstrual bleeding was 110-550 mL. histories Normal women lost 33-59 mL during menstruation. Heavy menstruating women had higher GIT absorption of iron than normal women BNL 1967 “Ca Study the role of 7 25 pCi; Diets high in Ca had a dietary Ca in intravenous small but positive impact on osteoporosis osteoporosis BNL Early ®Br Study the kinetics of 4 2.5 pCi; inhalation Concentrations of 1970s halothane halothane were initially high ***DRAFT FOR PUBLIC COMMENT*** in upper parts of the body and low in lower parts of the body. Diffusion equilibrium throughout the body was achieved in about 24 minutes. IONIZING RADIATION 78 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Table 3-2. Summary of Some Studies of Humans Exposed to Radionuclides (continued) Number Purpose of of people Dose and route of Laboratory Year(s) Radionuclide experiment dosed exposure Result HS 1963 | Determine uptake 8 NA. Dairy cows Uptake of '*'l in humans kinetics of "lin consumed 5 mg was characterized. humans to 2 gm/day |. Volunteers consumed milk produced by the cows exposed to 31in the diet. LBL 1942- X-ray Determine if blood 29 5-50 R, daily Significant deviations in 1946 cell changes could be dose white blood cell counts, used to indicate 100-300 R, total anemia formed in relation exposure in workers dose. to dose. on the Manhattan Whole body Project. external exposure. LBL 1948- X-ray Determine the effects > 1 8,000-10,000 Pituitary is extremely 1949 of radiation on the rad; external resistant to X-rays. pituitary gland during exposure treatment of cancers of other tissues LBL 1949- X-ray Effect of radiation on 3 8,500-10,000 Pituitary is extremely 1950 the pituitary gland rad; external resistant to X-rays. and its effect on exposure advanced melanoma and breast cancer. LBL Early *Co Determine feasibility 35 5,000- 6,000 rad Non-infiltrating cancers 1950s of treating bladder over 7 days. were more successfully cancer using beads Beads were treated than were the labeled with ®Co placed inside the infiltrating bladder cancers. bladder cavity. LBL 1961 oy Determine the 1 200 rad to Therapy resulted in effectiveness of *Y in lymphatic tissue; temporary remission of the treatment of acute route not leukemia; little effect on leukemia in a child specified. peripheral blood cells and red blood cells. LLNL 1980s "N Determine the uptake 11 NA. Doses inthe NA “Ar and clearance of mCi range. nitrogen gas in order Route was via to better understand inhalation. “decompression Absorbed dose to sickness” in deep-sea the lungs divers. estimated to be 0.3-0.5 rad. LANL 1955 NA Obtain information 4 <15 R; No significant internal needed to plan for the Inhalation and deposition of fission safe and effective use external routes products or unfissioned Pu of military aircraft near were the likely were detected in urine or “mushroom clouds” routes of via whole-body counting. during combat exposure. operation - LANL 1961- ®Sr Determine the 2 70 pCi; Absorption of ®Sr across 1962 cutaneous absorption dermal exposure the skin was low, and kinetics of ®Sr through human skin ***DRAFT FOR PUBLIC COMMENT*** ranged from 0.2% to 0.6% total absorption. IONIZING RADIATION 79 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Table 3-2. Summary of Some Studies of Humans Exposed to Radionuclides (continued) Number Purpose of of people Dose and route of Laboratory Year(s) Radionuclide experiment dosed exposure Result OR 1956- %Co Study efficacy of total- 194 50-300 R, one Higher frequency of 1973 "Cs body irradiation on person received remissions after 150 R the treatment of 500 R; external compared to 250 R. Total leukemia, exposure body irradiation survived as polycythemia rubra long-but not longer-than vera, and lymphoma patients treated with non- radiation treatments OR 1953- 2% Study the distribution NS. 4-50 mg; 99% of injected uranium 1957 2%y and excretion of intravenously cleared the blood within 20 uranium in humans hrs and the remainder either deposited in the skeleton and kidneys or excreted via the urine OR 1945 2p Study effects of beta 10 140-1,180 rad; Threshold dose of beta rays on skin external exposure. radiation that resulted in mild tanning was about 200 rad. Erythema resulted after a dose of 813 rad uc 1937- X-rays Study the effect of 116 ~~ 1,100-2,930 rad; Claimed that moderate 1954 X-rays for the external exposure irradiation of the stomach treatment of gastric reduced acid secretion and ulcers was a valuable adjunct to conventional gastric ulcer therapy. Therapy was later discontinued due to risks outweighing benefits uc 1959 S'Cr Determine feasibility 24 2-5 mCi; 16 had good or favorable of using implanted Implanted within results; the remainder of radiation sources in cancerous tissues patients had questionable the treatment of or unfavorable results. cancer Implants were generally well tolerated. uc 1960s Various. Gain information in 10 0.2-0.7 pCi actual No gastrointestinal Fallout civil defense planning fallout; 0.4-14 pCi symptoms were reported. contains prior to nuclear fallout simulated fallout. Studies provided a basis for many alpha, Subjects ingested estimating the systemic beta, and of actual fallout uptake and internal gamma from Nevada test radiation dose that could emitting site, as well as result from the ingestion of radionuclides. simulated fallout fallout after nuclear bomb Simulated particles detonation. fallout contained 83r, '¥Ba, or Cg UR 1946- UU Determine dose level 6 6.4-70.9 uCi’kkg U excretion occurred 1947 =U at which renal injury is intravenously mainly via the urine and first detectable; 70-85% was eliminated measure U with 24 hrs. Acidosis elimination and excretion rates ***DRAFT FOR PUBLIC COMMENT*** decreased U excretion. Humans tolerated U at doses as high as 70 pg/kg IONIZING RADIATION 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION 80 Table 3-2. Summary of Some Studies of Humans Exposed to Radionuclides (continued) Number Purpose of of people Dose and route of Laboratory Year(s) Radionuclide experiment dosed exposure Result UR 1956 Rn Determine radiation 2 0.025 uCi; Average retention of Rn doses to different inhalation and daughter products in parts of the normal atmospheric dust respiratory tract from was 25%; retention in inhaled ??Rn filtered air was 75%. Radiation exposure to the lungs was due to radon daughter products rather than by #*Rn itself. UR 1966- 2"?Pb Study absorption of 4 1 pCi intravenous Lead might be released 1967 lead from the and/or 5 pCi orally from binding sites only gastrointestinal tract when red blood cells die. and determine the radiation hazard and chemical toxicity of ingested lead. MISC 1950s "| Study the 2 100 pCi; oral 3] concentration in transmission of "*'l'in maternal milk was high maternal breast milk enough to allow significant to nursing infants uptake in the thyroids of nursing infants. '*'l tracers should be used with caution when nursing infants. MISC 1953 | Study uptake of ™*'I NA 100-200 pCi Pregnant women were by the thyroids of (maternal dose); scheduled for abortion prior human embryos route not specified to receiving '*'l. Results indicated that it would be unwise to administer '*'l for diagnostic or therapeutic purposes while pregnant. MISC 1963- X-rays Determine the effects 60 7.5-400 rad; Doses of 7.5 rad yielded no 1973 of radiation on human external exposure adverse effect on testicular testicular function function. 27 rad inhibited generation of sperm, and 75 rad destroyed existing sperm cells. Doses of 100-400 rad produced temporary sterility. All persons eventually recovered to pre-exposure levels prior to vasectomy. Source: Human Radiation Experiments Associated with the U.S. Department of Energy and its Predecessors. U.S. Department of Energy, Assistant Secretary for Environment, Safety, and Health, Washington, DC, July, 1995. Document #DOE/EH-0491 ANL = Argonne National Laboratory; BNL = Brookhaven National Laboratory; HS = Hanford Sites; LBL = Lawrence Berkeley Laboratory; LLNL = Lawrence Livermore National Laboratory; LANL = Los Alamos National Laboratory; ORS = Oak Ridge Sites; UCLA = University of California, Los Angeles; UCACRH = University of Chicago Argonne Cancer Research Hospital; UR = University of Rochester; MISC = Other miscellaneous studies performed at other institutions; NA = information not available. **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 81 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION All cells that comprise the body’s tissues and organ systems are not equally sensitive to the biological effects of ionizing radiation; their sensitivity is affected by age at the time of exposure, sex, health status, and other factors. Cells which are rapidly growing and dividing, such as those found in the gastrointestinal tract, bone marrow, reproductive and lymphoid tissues, and fetal nerve cells are more sensitive to the cytotoxic effects of ionizing radiation. Tissues that undergo little cell growth and mitosis under normal conditions (such as those found in the central nervous system, the adrenal, adipose, and connective tissues, and the kidney) are more resistant to these effects, requiring much more of an acute dose to be absorbed before outward toxicological effects may be observed. Why are these growing and dividing cells the most sensitive to the effects of ionizing radiation? The answer relates to the effect on the genome of the cell. Simply put, ionizing radiation may damage the cell’s DNA (which the cell must rely on to manufacture proteins and enzymes, perform routine cell functions, and maintain cell integrity and homeostasis) to the point that normal cell functions are markedly decreased or stopped, resulting in cell damage and death. Once damaged, the cell can either repair the damage or die. When precursor cells in the hematopoietic system (which multiply quite frequently to replenish aging leukocytes) are damaged or die, leukopenia may result in the peripheral blood, leaving the body susceptible to infections and disease. Similarly, the cells lining the gastrointestinal tract, which normally have high turnover rates, will fail to multiply and replace dying cells, making the body susceptible to malabsorption syndromes and secondary bacterial infections. Fetal nervous system cells go through a period of rapid development between weeks 8-15, during which time they are more sensitive to radiation damage. Mechanisms by which ionizing radiation affects cells are described in greater detail in Chapter 5 of this profile. Acute Radiation Syndrome (ARS). The acute radiation syndrome (ARS) is seen in individuals following acute hole body doses of 100 or rad. The degree of ARS in humans is roughly classified by the absorbed dose and the time over which the energy from the radiation is deposited in tissue. It consists of the subclinical syndrome (25-100 rad), the acute hematopoietic syndrome (100-800 rad), the gastrointestinal syndrome (800-3,000 rad), and the central nervous system/cerebral syndrome (>3,000 rad). If the energy is deposited over more than a few days (i.e., at a lower dose rate), the severity of the effects may be greatly reduced. At doses below 25 rad, no symptoms or clinical signs are caused by ionizing radiation, and even the most sensitive assessments do not detect biological changes. Lifetime radiation exposure from radioactive NPL waste sites, nuclear power plant operations, consumer products, natural background radiation, and most hospital nuclear medical tests should be at the low end of this range. Each of these syndromes and the tissues they are most likely to affect are briefly discussed below. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 82 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Subclinical Response (25-100 rad). This phase is characterized by very few, if any, clinical or hematological manifestations of illness. There are no visible symptoms from this level of radiation exposure. At around 50 rad, there may be transient changes in formed elements of the blood in sensitive individuals. At 100 rad, most individuals express transient hematopoietic manifestations. Clinical Response (100 to >3,000 rad). 100-200 Rad. This phase of ARS is characterized by mild, but non-specific signs of toxicity. Acute clinical signs of toxicity appear within 3—6 hours of receiving the dose; these initially consist of nausea and vomiting. Within 7-15 days after exposure, a moderate leukopenia appears; however, blood cell counts eventually return to normal within 4-6 weeks after exposure. There is no perceptible decrease in mental capabilities. Rest and self-care are generally all that is needed for these individuals to fully recover. Any treatment which is offered could include antibiotics and supportive care, much the same as one may treat cold or flu symptoms. Hematopoietic Syndrome (100-800 rad). This form of ARS is characterized by four phases. The first phase, the prodromal phase, typically lasts about 2-3 days and is characterized by fatigue, listlessness, and lethargy that progresses to headache, anorexia, nausea, and vomiting within approximately 8 hours after initial exposure, depending on the dose. Laboratory findings are limited to varying alterations in the peripheral blood, with the earliest changes demonstrated as a marked lymphopenia about 1 day after exposure. The second stage, the latent phase, begins on the third to fourth day and may last up to 3 weeks from the time of initial exposure. This phase is marked by a progressive decrease in total blood leukocyte counts and hair loss (epilation) toward the third week. The third phase, the symptomatic or bone marrow depression phase, is present 18-21 days after exposure. Chills, fever, malaise, a swollen oropharynx, gingivitis, bleeding gums, petechiae, ecchymoses, anemia, and acute infectious diseases are quite characteristic of persons in this phase. The leukopenia and thrombocytopenia due to destruction of stem cells in the red marrow undermine the body's natural defenses against disease, leaving the body susceptible to acute infections and illnesses. Depending on the dose and the aggressiveness of the treatment protocols, the clinical picture can vary from serious to fatal. The fourth phase, the recovery phase, is marked by a general improvement of the patient over a 3-6 month period. For doses from 100 to 600 rad, the prognosis for recovery is good; doses of 600-800 rad are somewhat more dangerous, but many victims are expected to survive. The LD, for whole body irradiation is estimated to be between 350 and 400 rad (3.5-4.0 Gy) ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 83 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Gastrointestinal Syndrome (800-3,000 rad). The prodromal phase of this syndrome is very abrupt in onset, characterized by diarrhea, which typically subsides after several days, followed by a short latent period. Symptoms then return, which include white blood cell depression as seen in the hematopoietic form of ARS, nausea, vomiting, diarrhea, fever, and massive electrolyte imbalances, which ultimately will result in death. Treatments are palliative. Persons exposed to doses of > 1,000 rad are expected to die, although aggressive medical intervention may improve survival rates. There is one exception. If the dose is fractionated, as with bone marrow transplant patients who receive a standard whole body dose of 1,575 rad and are well-managed, the individual should be able to handle the dose quite well. Central Nervous System Syndrome (>3,000 rad). Symptoms in this syndrome classically have a quick onset, and include violent nausea and vomiting, diarrhea, irrational behavior, circulatory system collapse, and neuromuscular incoordination occurring within a few minutes after receipt of the dose of ionizing radiation. Convulsions, coma, and death, probably due to enzyme inactivation or alterations in the electrical responses within the heart, usually ensue within 48 hours after the receipt of the dose. The phases of acute toxicity of ionizing radiation discussed above are summarized in Table 3-3. Studies of Acute Effects. As can be observed from Table 3-3, the overt signs of toxicity from absorbed doses of ionizing radiation follow a dose-response relationship as long as the radiation dose rate is high. Individuals exposed to single acute doses of ionizing radiation that are less than 100 rad experience few if any significant clinical signs of toxicity; however, as the dose is doubled (200 rad), some systems begin to show signs of overt toxicity. At this dose, the cells that multiply the most rapidly (gastrointestinal cells, blood-forming cells) are only being mildly affected (nausea/vomiting, leukopenia). Red blood cell precursors are also likely to be affected at this dose; however, because of the lifespan of a peripheral red blood cell (60-120 days, depending on the species of animal), marked anemia may not become clinically evident for several days or weeks after exposure. Cells which proliferate more slowly (e.g., the cells of the central nervous system, connective tissues, etc.) are largely unaffected. As the dose increases to 600 rad, more severe changes in the hematopoietic and gastrointestinal systems are present, in the form of more intense vomiting for longer durations and severe leukopenia. Infections are of a greater concern, since the main barriers of protection from foreign organisms (gastrointestinal cell barriers, neutrophils, lymphocytes) are severely compromised or non-functional. Coagulapathies begin to appear due to platelet anomalies (pupura, hemorrhage) as well as hair follicle death (hair epilation). Also at this dose, the first signs of central nervous system disruption begin to appear, with short periods of decreased cognitive abilities. As the dose of ionizing ***DRAFT FOR PUBLIC COMMENT*** +x INTFWWNOD 21789Nd HOH 14VHQ wx Table 3-3. Summary of the Dose Response Effects of lonizing Radiation in Humans Phase Subclinical range Feature 100-800 rad (sublethal ranges) Over 800 rad (lethal range) 0-100 rad 100-200 rad 200-600 rad 600-800 rad 800-3000 rad >3000 rad Initial Phase Incidence of None 5-50% 50-100% 75-100% 90-100% 100% nausea and vomiting Time of onset 3-6 hours 2—4 hours 1-2 hours <1hr <1hr Duration <24 hours <24 hours <48 hours <48 hours 48 hours Mental and 100% 100% Able to perform Able to perform simple Progressive incapacitation physical routine tasks. and routine tasks. capabilities Cognitive abilities Significant incapacitation impaired for 6-20 in upper part of dose hours. range. Lasts more than 24 hours. Latent Phase Duration > 2 weeks 7-15 days 0-7 days 0-2 days None Secondary Signs and None Moderate Severe leukopenia; pneumonia; purpura, Diarrhea; fever; Convulsions; phase symptoms leukopenia hemorrhage; infection; hair loss (epilation) at disturbance of tremor; ataxia; about 300 rads electolyte lethargy balance Time of onset >2 weeks Several days to 2 weeks 2-3 days after exposure Critical period None 4-6 weeks 5-14 days 1-48 hours after exposure Organ system None Hematopoietic and Hematopoietic and Gastrointestinal Central nervous affected respiratory tissues respiratory tissues tract;respiratory system tissues Hospitalization Percentage None <5% 90% 100% 100% 100% Duration 45-60 days 60-90 days 90-120 days 2 weeks 2 days Incidence of None None 0-80% 90-100% 90-100% death Average time to 3 weeks to 2 months 1-2 weeks 2 days death Medical therapy None Hematologic Blood transfusions and antibiotics Maintenance of Sedatives surveillance electrolyte balance Source: adapted from Medical Aspects of Nuclear Weapons and Their Effects on Medical Operations 1990 NOILYIAQVH DNIZINOI 40 S103443 HLTV3H 40 AHVIWANS '€ NOILVIAv4d ONIZINOI v8 IONIZING RADIATION 85 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION radiation increases beyond 800 rad, a dose-dependent increase in the severity of the hematological, gastrointestinal, and central nervous system toxicity occurs, and death will likely ensue due to catastrophic multi-organ failure, including complete destruction of the blood forming cells in the red marrow and destruction of the basement cells in the lining of the intestinal walls. Death has been reported after receiving single or multiple doses of ionizing radiation, regardless of whether the radiation source was outside or inside the body. Most of these studies have the common theme of very high doses (several hundred to several thousands of rad) being administered over a relatively short period of time (acute exposure), usually over the course of minutes or hours. This was seen in the human case report by Stavem et al. (1985) in which a worker was exposed to 2,250 rad within a few minutes time, resulting in death due to acute radiation sickness (depressed leukocyte counts, vomiting, diarrhea, etc). Many reports were located on animals that inhaled large doses of soluble and insoluble particles. The inhalation studies pointed to a number of immediate or near-immediate causes of death, including bone marrow hypoplasia (Gillette et al. 1987a); radiation pneumonitis and fibrosis (Brooks et al. 1992; Hahn et al. 1981, 1987; Lundgren et al. 1991); and blood abnormalities, such as thrombocytopenia, neutropenia, lymphopenia, and anemia (McClellan et al. 1973). Death is most likely a result of these systems being adversely affected by the deleterious effects that ionizing radiation has on the cell functionality within these organ systems. The overwhelming damage that ionizing radiation induces on rapidly dividing (or undifferentiated) cells at these high doses (i.e., cell functional loss, necrosis, apoptosis, and death of precursor cells) leads to a decreased numbers of functional cells for an extended period of time, leaving the body highly susceptible to systemic infections that can lead to organ failure and death. There is no accepted mechanism of action to explain what leads to or contributes to radiation pneumonitis after an internal or external dose of ionizing radiation, although several hypotheses have been put forth. It has been suggested that the damage induced by ionizing radiation is principally vascular, with the sloughing of dead and dying endothelial cells causing capillary leakage, both interstitially and onto the alveolar surface. Another theory suggests that the damage to type II pneumocytes causes serious alterations in the amount of surfactant phospholipids, ultimately altering the normal functioning of the lung and leading to lung inflammation. A third theory suggests that type I pneumocytes necrose and slough, leaving denuded basement membranes and alveolar debris. Finally, a few researchers believe that the role of lymphocytes, the immune system, and the interaction of bacteria plays a major part in the induction of radiation pneumonitis (Coggle et al. 1986). Causes of death of the experimental animals later in life are primarily related to the cancerous effects (Boecker et al. 1988; Lloyd et al. 1994). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 86 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION The clinical signs of toxicity from absorbed doses of ionizing radiation follow the classic dose-response curve, with some organs more severely affected at each dose than are others. A number of studies have been summarized that describe the no-observed-adverse-effect level (NOAEL) and the lowest-observed-adverse- effect level (LOAEL) of ionizing radiation on multiple body systems. These data are summarized in the Observed Health Effects from Radiation and Radioactive Material tables in Chapter 8 of this profile. More specific information on some organ systems affected after receiving high doses of ionizing radiation is discussed in more detail below. 3.2.1.1 Gastrointestinal Effects Prominent gastrointestinal effects due to high acute doses of radiation can occur, usually after oral or whole- body exposures. Localized doses of external radiation, in the vicinity of 1,000 rad (10 Gy), have been reported to induce inflammation and swelling of the oral cavity, including the cheeks, soft and hard palate, tongue, and throat. The salivary glands are also sensitive to the effects of ionizing radiation. Those structures proximal to the stomach, having stratified squamous epithelial coverings, seem to be much less severely affected than the stomach, small and large intestines, and the colon, largely due to the lower cell turnover rates associated with this type of epithelium. The gastrointestinal structures that appear to be the most sensitive to the effects of ionizing radiation are those with high cell turnover rates, which include the epithelium covering the stomach and intestines. Very large doses (>1,000 rad) to the germinal epithelium of the stomach and intestines damage these cells, rendering them unable to divide and replace older, more senescent cells lining these structures. As a result, ulceration and hemorrhage may occur, leading to the gastrointestinal syndrome described in Table 3-3 (Adams and Wilson 1993). Numerous laboratory animal studies identified gastrointestinal effects after exposure to ionizing radiation. For example, male Swiss albino mice were injected with tritiated water with a specific activity of 10 mCi/mL, followed by maintenance on tritiated drinking water at 2.5 uCi/mL for 12 days. Mice were estimated to have cumulative doses of 116, 440, 1,320, 2,200, and 5,280 millirads for the 0.25, 1, 3, 5, and 12 days of treatment, respectively. A significant decrease in the total cell population and mitotic figure per crypt section was observed 6 hours after exposure; the decrease continued through day 1. After that, the total cell population stayed at a constant value (3-5 days), after which it showed a significant increase on day 12. The number of mitotic figures increased slightly on day 3 followed by a decrease on day 5, but these changes were not significant. On day 12, the mitosis also increased slightly. The number of pycnotic nuclei and necrotic cells increased significantly 6 and 24 hours after exposure, and then decreased on day 3. After that, they ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 87 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION increased again on day 5. The number of cells per villus column showed a significant decrease 6 hours after exposure; this decline continued up to day 5, when the cell count was 67.5% of normal. After this the count showed a significant increase on day 12. The villus height was reduced slightly 6 hours after exposure, then significantly from day 1 to 5. The height was 81% of normal at day 5, and at day 12 it was 91.5% of the normal controls. In summary, all of the parameters studied showed partial recovery towards normal on day 12 at the doses tested (Kumar et al. 1983). Gastrointestinal effects have also been described after inhalation exposure to radionuclides. Gastrointestinal effects are most likely due to inhaled particles lodging in the nasopharyngeal mucus and in the tracheo- bronchial mucus layers of the conducting airways of the lungs and then being carried up the airways, where they enter the pharynx and are swallowed. Several reports are present in the literature that describe such gastrointestinal effects after inhalation exposure. Gillett et al. (1987a) exposed young adult Beagle dogs (12-14 months old) once to soluble aerosols containing **SrCl,. Different airborne concentrations (2.16-418.5 pCi *°Sr/L) and exposure durations (2-22 minutes) were used to produce graded levels of initial lung burdens. Seventy-two Beagle dogs were exposed and another 25 unexposed dogs served as controls. The long-term retained burden ranged from 1.0 to 118.8 uCi *Sr/kg body weight. Clinical signs of radiation-induced illness appeared about 2 weeks after exposure. The first signs, fever and anorexia, including bloody diarrhea, developed during the last 48 hours before death. In another study, Hahn et al. (1975) studied the effects of *°Y laden particles clearing to the gastrointestinal tract after an acute-duration inhalation exposure. Ten Beagle dogs were exposed by nose-only inhalation to aerosols of *°Y in fused clay particles; three control dogs were exposed to fused clay only. Gastrointestinal burdens ranged from 8 to 34 mCi. A rapid initial decrease in body burden occurred (typical of an insoluble material deposited by inhalation) and was largely due to the clearance of particles from the upper respiratory tract through the gastrointestinal tract by way of mucociliary clearance mechanisms in the respiratory tract. Four out of 6 dogs with 18-34 mCi gastrointestinal burden developed a mucoid diarrhea. The dog with the highest exposure developed hemorrhagic diarrhea. Two out of 7 dogs exposed to 18-32 mCi gastrointestinal tract burden (32-50 mCi whole-body burden) developed colitis. At necropsy, lesions were found to be confined to the colon, except for one dog with ulcerative esophagitis. No gross lesions were seen in the stomachs or small intestines of any of the dogs; no histologic lesions were found. In the dogs with colitis, ulcerative and atrophic foci were scattered in the terminal third of the colon. Loss of mucosal epithelial cells and collapse of the lamina propria were the most severe pathologic alterations in the colon. The colon received the highest radiation dose in the two exposed dogs, although the stomach and small intestines also received significant doses. Of the two dogs sacrificed at 8 days postexposure, the only lesions that were seen at necropsy were in ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 88 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION the colon of the dog that received 3,200-5,700 rad estimated. No lesions were seen in the intestines of the dog that received 2,800 rad or less. Lesions were most likely in response to a high dose of ionizing radiation due to the long transit time of the radiolabeled material through the colon (increased exposure time). Similar effects from external gamma radiation have been reported. In one human case report, Stavem et al. (1985) described a 64-year-old male worker who accidentally received a large dose of gamma radiation in a plant for sterilizing medical equipment. He was exposed for only a few minutes and was most likely exposed to a mean whole-body dose of 2,250 rad. The worker developed ARS. Histologically, the mucosa of the gastrointestinal tract (and respiratory tract) showed only a few mononuclear cells, and no granulocytes. There was slight atrophy of glands in the stomach, marked atrophy in the small intestine, and total atrophy of the glands in the large intestine. As in humans, laboratory animals exposed to extreme doses of external radiation exhibit effects on the exposed organ systems. A group of 12 male BALB/c mice was exposed to a single whole-body dose of 1,500 rad gamma rays from a ®’Co source. The degree of gastrointestinal motility and the condition of the abdominal blood vessels, spleen, and the contents of the stomach and intestine were examined 1 hour, 3 hours, 18 hours, and 3 days after irradiation. Gastrointestinal mobility was present at all times after the exposure; vascular dilatation was absent at all times; luminal contents were present 1-3 hours after the exposure and slightly present 18 hours to 3 days after the exposure. The mucosal surface displayed changes in the shape of the villi, with rudimentary villi being the most advanced type of collapse seen. Villous shape changes were seen at all time post-exposure. Changes in tissue structure were seen at the 18-hour time point including less distinct crypts with disintegrating cells present (Indran et al. 1991). ILjiri (1989), studying the influence of circadian rhythm on apoptosis, found that gamma (from '*’Cs) irradiation between 0900 and 1500 hours caused a higher incidence of apoptotic cells in the small intestine of male C57BL/6crSlc mice than irradiation between 2100 and 0300 hours, irrespective of dose rate; similar differences, but with lower incidences of apoptotic cells, were also noted in the descending colon. The mean lethal dose values for continuous irradiation with gamma rays were 21 rad for the cells of the small intestine and 38 rad for the cells of the descending colon, and the respective values for HTO (beta radiation) were 13 and 28 rad, indicating the high radiosensitivity of these target cells for apoptotic death. In summary, higher doses are required to see effects in the gastrointestinal tract than in bone marrow, and these start at dose rates in the range of 200-300 rad (2-3 Gy). The severity of effects follows a typical dose response relationship. The cells responsible for lining the tract frequently undergo mitosis, leaving them particularly susceptible to DNA damage, cell death, and altered cell kinetics that affect the cells ability to proliferate. These effects include karyorrhexis, pyknotic nuclei, necrosis, decreased number of cells/villus, ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 89 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION and changes in shapes of the villi and mucosal surfaces. The damage to the lining of epithelial cells results in the loss of the natural barrier between intestinal microbes and the body, making it susceptible to systemic infections, fluid imbalances and losses, bloody diarrhea, colitis, and a host of other clinical signs, depending on the dose of ionizing radiation that was received (Gillett et al. 1987a; Hahn et al. 1975; Kumar et al. 1983). Data for acute gastrointestinal effects in humans and laboratory animals from large doses of radiation are summarized in the Observed Health Effects from Radiation and Radioactive Material tables in Chapter 8 of this profile. 3.2.1.2 Hematological and Lymphoreticular Effects Hematological effects are one of the syndromes seen after acute exposures of bone marrow to ionizing radiation (see Table 3-3) at dose levels of about 50,000 millirads (50 rad). The magnitude of effect on hematopoiesis is dependent on the total dose absorbed, regardless of the route of exposure. As can be seen in Table 3-3, hematological symptoms begin to occur at doses of 100-200 rad. Like the gastrointestinal system, the hematopoetic system contains a large population of cells that requires the frequent replacement of senescent cells. To accommodate this need, a pool of precursor cells is present in the red marrow present within bone (e.g., ribs, pelvis, bertebrae, and ends of long bones), which undergo high rates of mitotic activity. This pool of cells is critical for the production of replacement cell populations for erythrocytes, granulocytes, lymphocytes, and thrombocytes. The dose of radiation received by stem cells, which are the germinal cells of the marrow, damages these cells, rendering them unable to divide and provide needed cell replacements, resulting in anemia, leukopenia, thrombocytopenia, septicemia, infections, and death. The severity of these lesions depends on the depression of bone marrow activity due to the total dose absorbed, with irreversible total destruction resulting from doses to the red marrow on the order of 800 or more rad (>8 Gy). As an example of hematological lesions in humans obtained after exposure to ionizing radiation, Klener et al. (1986) reports one case iit which a man was accidentally irradiated by a sealed *°Co source. His health status was followed for 11 years after the accident. A film dosimeter worn during the accident indicated an exposure of 159 rad. Twelve to 24 hours after the accident, the worker felt general malaise without vomiting; however, a blood count showed no marked deviations from normal. Eight days after the accident, he developed minor deviations in peripheral blood counts. Leukocyte values were lowest 31-49 days after exposure. The lymphocyte count was normal the first day after the accident, but decreased on days 19-23 ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 90 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION and day 49. Neutrophils with coarse granulations and hypersegmentation of nuclei were observed. In another acute exposure case, Stavem et al. (1985) reported on a 64-year-old male worker who was accidentally exposed to gamma radiation in a plant that used ionizing radiation for sterilization purposes. He was exposed for only a few minutes to an estimated 2,250 rad. The worker developed ARS, with the leukocyte count rapidly diminished to low values. Extensive chromosome injuries were demonstrated in cultured blood lymphocytes, and virtually no undamaged cells were found. The worker did not survive, dying 13 days after exposure; an autopsy found the bone marrow to be markedly hypocellular with a few scattered plasma cells. Hematological effects have been reported after inhalation exposures in laboratory animals, and again, the effects depend on the dose absorbed. Brooks et al. (1992) exposed male monkeys, divided into mature (5.00.5 kg) and immature (2.10.3 kg) groups, to an aerosol of 2**Pu (NO,), by nose-only inhalation to produce projected initial lung burdens of either 1.08, 0.27, or 0.1 uCi. No significant changes in blood lymphocyte numbers were observed. Gillett et al. (1987a) exposed young adult Beagle dogs (12-14 months old) to soluble aerosols containing *’SrCl,. A review of the hematological parameters of all dogs showed a similar, consistent, and dose-related pancytopenia in those animals having a long-term retained burden greater than 10 uCi *°Sr/kg. A profound dose-related depression of platelet counts was also found. Decreases in platelet numbers were manifested by 7 days and were maximal by 28 days. Platelet counts were depressed in all exposed groups as compared to controls when evaluation was extended to 1,000 days after exposure. Platelet counts among animals having a long-term retained burden greater than 40.5 pCi **Sr/kg frequently fell to less than 10% of pre-exposure values. Animals having slightly lower long-term retained burden also exhibited depressed but less severe thrombocytopenia. The degree of platelet depression was related to the degree of long-term retained *°Sr. Interestingly, the decline in platelet counts seen in dogs with a long-term retained burden of 27.0-118.8 uCi **Sr/kg at 1,000 days was also associated with the presence of hemangio- sarcomas. Thrombocytopenia and neutropenia persisted in all exposed dogs through 1,000 days after exposure. Lymphocyte numbers were also depressed in a dose-related manner at exposures greater than 10 pCi *°Sr/kg. Reduced erythrocyte mass occurred in dogs having a long-term retained burden greater than 10 pCi *Sr/kg between 14 and 21 days after exposure. Red blood cell counts fell to 70-80% of pre-exposure values, with maximal depression at 32 days. Hobbs et al. (1972) also observed dose-related clinical, hematological, serum chemical, and pathological alterations more than 1 year after intake. Thirty-three Beagle dogs were given lung burdens of 3,600, 1,800, 1,800, 1,200, 780, 400, 210, 110 and 0 pCi *°Y/kg body weight. Cumulative doses between 990 and 55,000 rad (9.9-550 Gy) to the lungs through the end of the study or the death of the animals were reported. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 91 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Dogs that had initial lung burdens of 670-760 uCi/kg and radiation doses to lung from 8,400 to 9,400 rad (8.4-9.4 Gy) and died within 31 days after intake had a dose-related depression of circulating lymphocytes (lymphopenia), as well as a marked marrow suppression and deletion of hemic elements. Rib marrow was found to be repopulated in dogs that died after 31 days. Exposure to primarily f and y radiation from external sources yields similar results. Seed et al. (1989) exposed male Beagle dogs to 7.5 rad/day gamma radiation for 150-300 days from a Co source. The irradiated dogs showed a suppression/recovery pattern for the five circulating types of cells studied (granulocytes, monocytes, platelets, erythrocytes, and lymphocytes), which was significantly different from the control animals. In a later study by Seed et al. (1993), female Beagle dogs were exposed to 7.5 rad/day gamma radiation for 150-300 days from a ®’Co source. Again, the irradiated dogs showed a suppression/ recovery pattern for the five circulating cell types (granulocytes, monocytes, platelets, erythrocytes, and lymphocytes) which was significantly different from the controls. It should be noted that these daily doses were high and would have likely been fatal if the entire dose was received within a few days. A large number of reports are available in the literature regarding immunological effects associated with radionuclides that have been inhaled using laboratory animals as models. Lymphopenia is a common sequela of exposure to ionizing radiation affecting the immune system of both humans and animals. Gillett et al. (1987a) exposed young adult Beagle dogs (12-14 months old) to soluble aerosols containing *°SrCl, and found that lymphocyte numbers were depressed in a dose-related manner at exposures greater than 10 uCi *Sr/kg. Benjamin et al. (1976) exposed 6 Beagle dogs, (3 males and 3 females, 17-20 months old) by nose-only inhalation to *°Y, '*‘Ce, or *Sr in fused-clay particles. Initial lung burdens lung burden were 560, 46, and 28 pCi/kg for *°Y, “Ce, and *°Sr, respectively. Cumulative absorbed dose at death or 44 weeks was 8,700, 42,000, and 39,000 rad for *°Y, '*‘Ce, and *°Sr exposures, respectively. Lymphopenia was observed in *°Y exposed dogs within several days after intake and was statistically significantly depressed though 8 weeks (except for 6 weeks) but returned to control levels by 16-20 weeks. No change in peripheral lymphocytes was observed. Lymphocyte counts in dogs exposed to '**Ce were significantly lower (lymphopenia) than controls from 4 to 28 weeks after exposure. In a study conducted by Lundgren et al. (1976), the effect of *°Y inhaled in fused-clay particles on the pulmonary clearance of inhaled Staphyloccus aureus in mice was investigated. Groups of male CFW mice were exposed to °°Y for 10-20 minutes. Aerosol concentrations ranged from 14.5 to 428 pCi/L air and the activity median aerodynamic diameter (AMAD) ranged from 0.7 to 1.4 um. The initial lung burden ranges of the groups were 2.54, 7-12, 20-47, and 50-76 pCi in experiment I and 5-7 and 8-12 pCi in experiment II. Pulmonary clearance of inhaled ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 92 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION S. aureus was suppressed in mice with an initial lung burdens of 20 uCi *°Y or greater at 2, 3, and 4 weeks after exposure. Lymphocyte counts were suppressed in the 20-47 pCi and 50-76 pCi groups at 2 weeks postexposure and in the 50-76 pCi group at 3 weeks after intake. Clearance of bacteria at a reduced rate was observed in 20-47 pCi mice at 2, 3, and 4 weeks and in 50-76 pCi mice at 2 and 3 weeks after intake. Similarly, Hobbs et al. (1972) observed dose-related pathological alterations more than 1 year postexposure in 33 Beagle dogs exposed to *°Y. Of the 33 dogs exposed, 21 with initial lung burdens from 670 to 5,200 uCi/kg and radiation doses to the lungs ranging from 8,400 to 55,000 rad (84-550 Gy) died between 7.5 and 163 days after intake. Tracheobronchial lymph nodes (TBLNG) in the early deaths showed marked lymphoid depletion, some sinus hemorrhage, and, later, phagocytosis of hemosiderin pigment. In the dogs that died 38 days or more postexposure, the nodes were enlarged and exhibited hyperplastic repopulation of lymphocytes. Hahn et al. (1976) also studied the effects of exposure on TBLNSs in 16 male and 14 female Beagle dogs exposed by nose-only inhalation to aerosols of '*Ce in fused-clay particles. Between 2 and 730 days postinhalation, the '**Ce dose to TBLNs ranged from 240 to 230,000 rad (2.4-2,300 Gy). The concentration of '**Ce in the TBLNs increased during the first year after exposure as a result of the translocation of '**Ce from the lungs via the lymphatics. Histologically, the changes were atrophic in nature. The cortex showed progressive reduction in size with increasing time after intake; by 730 days after intake, there was little cortex remaining. Fibrosis was first noted 128 days after intake and was more severe at each succeeding time period up to 730 days. There was also a loss in numbers of lymphocytes in the paracortical area 56 days after intake, although not as severe as the depletion of lymphocytes from the cortex. At later times the cortical and paracortical areas were nearly devoid of lymphocytes and were populated mainly by macrophages. Particles could be seen in macrophages 2 days after inhalation exposure. The authors note that since lymph nodes play a key role in immunologic responses associated with humoral antibody production and cell-mediated immunity and, in view of the severe atrophy and fibrosis in the TBLNS in the dogs in this study, the immunologic function in the TBLNs would seem to have been severely impaired. Lymphocytes are responsible for providing cell-mediated and humoral-mediated (antibodies) resistance to infection. Galvin et al. (1989) evaluated the cell-mediated and humoral immune responses to *°Pu0, in the blood and lung lavage fluid. Four Beagle dogs per group (8 total) were exposed to monodisperse aerosols (0.72-1.4 um AMAD) of ?**Pu0,, with initial lung burdens ranging from 0.51 to 0.95 pCi. Cumulative dose ranges were 1,400-2,400 rad to the lungs; 620,000-930,000 rad to the TBLNSs; 290,000-440,000 to the mediastinal lymph nodes; 200-300 rad to the sternal lymph nodes; and 2-3 rad to the spleen. The dog with the highest cumulative dose to the TBLNs (a massive 930,000 rad) was the only dog noted to have had ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 93 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION chronic lymphopenia; blood cell counts of the other 3 dogs showed normal lymphocyte counts. TBLNs of all dogs displayed severe diffuse fibrosis and atrophy with elimination of all lymphatic cells and follicles. Lymphatic vessels were moderately to markedly distended. The spleen and other peripheral lymph nodes were histologically normal. Systemic humoral response induced by lung immunization was not different in the age-matched and exposed groups. Peak humoral immune response (lung lavage, immunoglobulin G [IgG]) measured in immunized lung lobes of exposed and control dogs was significantly greater than saline- lavaged control lung lobes. Leukopenia (severe lymphopenia and granulocytopenia) and splenic congestion were found in one male worker who accidentally received a dose of 2,250 rad external source of gamma-ionizing radiation (Stavem et al. 1985). Mazur et al. (1991) exposed male Swiss mice to a single dose of 1,000 rad whole-body irradiation from a *°Co source. Spleen weights were significantly lower in the irradiated group during the 24-hour period. No statistically significant differences in acid phosphatase activity were seen in the spleens and livers of radiation-exposed mice; however, the acid phosphatase activity in the spleen and liver was statistically significantly higher in the irradiated rats as compared to controls. An increased activity of beta-glucuronidase was seen in the spleen, but the enzyme activity did not differ from controls in the liver. In summary, the hematological and lymphoreticular systems are target systems susceptible to the effects of ionizing radiation, the severity of which occurs in a dose-responsive manner. As was the case with the gastrointestinal tract, the hematological system is largely composed of rapidly dividing cells, making it more susceptible to the toxic effects of ionizing radiation than are the systems composed of more slowly dividing cells (central nervous system). The kinetics of the radionuclides determine the dose and, therefore, the extent and severity of the hematological lesions. It was noted in many of the studies that pancytopenia was one of the first major peripheral blood changes to occur. Neutrophils have a naturally short lifespan in the peripheral blood (12-48 hours) and depend upon constant replenishment by the bone marrow to adequately defend the body against infection. Acute high (sublethal) doses of ionizing radiation from an external source or from inhaled or ingested radionuclides that distribute to bone and irradiate the sensitive cells in the bone marrow will first noticeably affect the progenitor cells that produce leucocytes, since their turnover rates for this cell type are very high. Red blood cells that have longer lifespans in the peripheral blood and lower turnover rates will not have their immediate peripheral blood counts affected because of their long lifetime (3-4 months). Radionuclides that preferentially distribute to the bone for long periods of time will, if the dose is high, cause prolonged depression of most red and white blood cell types, due to constant irradiation of the bone marrow components. Anemias, thrombocytopenia, and leukopenias (all cell types) are also frequent ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 94 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION findings in such situations (Benjamin et al. 1976, 1979; Davila et al. 1992; Gillette et al. 1987a; Hahn et al. 1976; Hobbs et al. 1972). Animals administered sublethal doses of ionizing radiation have the ability to recover from these effects once the radiation source is removed (Gidali et al. 1985; Hobbs et al. 1972; Seed et al. 1989, 1993) or its dose rate is sufficiently reduced. The data for hematological and lymphoreticular effects in humans and laboratory animals are summarized in the Observed Health Effects from Radiation and Radioactive Material tables in Chapter 8 of this profile. Because of the high threshold dose for hematological effects, blood counting is not used to routinely monitor the health of radiation workers. 3.2.1.3 Reproductive Effects Cells that reproduce frequently, such as those found in intestinal crypts, bone marrow, and the reproductive systems of animals, are more radiosensitive than cells that are highly differentiated and reproduce slowly. This radiosensitivity is independent of the type of ionizing radiation or the source (internal or external). Specific cells in the reproductive tract of both males and females replicate at accelerated rates, making them more at risk to the effects of ionizing radiation. In males, the spermatogonia are the cells most sensitive to the effects of ionizing radiation. These are the germ cells responsible for producing spermatocytes and later, spermatids and mature sperm. Decreases in sperm numbers in semen are not immediate; in humans, decreased sperm counts are not seen until 30-45 days after significant exposures. Azospermia can occur 10 weeks after exposure to doses >100 rad; a dose of 250 rad may cause sterility for 1-2 years. A dose of 600 rad can cause permanent sterility (Adams and Wilson 1993). In females, the mature oocyte is less sensitive than male spermatogonia cells, but it is the most radiosensitive reproductive cell. Doses of 65-150 rad (0.65-1.5 Gy) have been reported to produce temporary sterility (Adams and Wilson 1993); however, a fractionated dose of 600-2,000 rad (6-20 Gy) can be tolerated (BEIR V 1990). Several studies were found in the literature that support these findings. In one human study, Birioukov et al. (1993) investigated the reproductive effects of ionizing radiation in 12 men (29-78 years old) with chronic radiation dermatitis caused by accidental exposure to beta and gamma radiation during and after the Chernobyl nuclear reactor accident. These men were examined for changes in sexual behavior, hormonal status, and spermatogenesis. All were diagnosed with ARS, which was categorized as first degree (100-200 rad), second degree, (200-350 rad, Group A), and third degree (350-550 rad, Group B) based on their location at the time of the incident. Of the 12 men evaluated, 9 reported decreased sexual potency, and ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 95 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION 3 refused to answer the question. Two patients reported impotentia coeundi, and 7 patients had decreased libido. The sperm of 7 patients were examined (5 refused to give a semen sample). All patients tested had normal semen pH values. Other sperm anomalies reported in both groups A and B included azoospermia, asthenospermia, and teratospermia. Others had slightly increased numbers of abnormal cells (morphological changes in the sperm head). Abnormal motility was present in all but one patient (in group B). Follicle- stimulating hormone was increased in 6 of 9 patients in group A and was normal in group B patients. Testosterone was decreased in 2 patients in each group. A decrease of luteinizing hormone and an increase of prolactin were measured only in 1 patient. Similar reproductive effects have been noted in laboratory animals. Ramaiya et al. (1994) performed a comparative estimation of the frequencies of genetic disorders induced in germ cells of male mice by a single or long-term exposure to incorporated *’Cs. Groups of 10 male mice were exposed to a single oral administration of 0.1, 0.5, 1.0, 2.0, and 3.0 pCi/g as '*’Cs. Groups of 10-30 males were also given daily injections of '*’Cs nitrate in phosphate buffer solution for 2 weeks at activity doses of 0.5, 2.0, and 5.0 pCi/g as 37Cs. The total absorbed dose to the testes during the 5 weeks after the single oral exposure was 10, 50, 100, 200, and 300 rad, respectively, while the total absorbed doses during the 5 weeks of multiple injections was 38, 154, and 385 rad, respectively. A decrease in the fertility of males was observed in the 2.0 and 3.0 uCi/g dose groups, beginning from the 4th week (190-197 rad and 285-295 rad, respectively). Complete, but temporary, sterility observed in animals exposed to 300 rad after 6 weeks was attributed to the death of spermatogonial cells. There was a significant increase in post-implantation embryo mortality and, correspondingly, in the dominant lethal mutation frequency, at a total dose of > 180 rad). Pinon-Lataillade et al. (1991) irradiated male Sprague-Dawley rats so that only the testes and surrounding organs were exposed to a gamma-ray beam of 900 rad. Groups of 6 irradiated rats and age-matched controls were sacrificed at 7, 15, 23, 34, 50, 71, 118, and 180 days after irradiation. Testis weight dropped to 85% of the control by day 7, and increased to 58% of the control by day 23, and continued to increase to 41% by day 34. Epididymal weight decreased to 88% of control by day 15 and increased to 63% by day 50, plateauing out at 55% of the control value. Spermatocytes were damaged, and by day 34, only elongated spermatids remained in a few tubules and very little regeneration of the seminiferous tubule had occurred. From day 15 after the irradiation, the epididymal content of androgen-binding protein (ABP) value dropped to 26% of the control and by day 34 it was back to only 14% of this value. From day 50 to the end, the ABP value remained below 10% of the control levels. No significant changes were observed in the weights of the seminal vesicles or in the concentrations of seminal vesicles. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 96 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Canlfi et al. (1990) exposed adult (3-5 month old) male Sprague-Dawley rats that were irradiated (whole body) from a "Ir gamma source of 8-10 Ci, with a dose rate of 0.3 rad/min, to 0.1, 1, or 10 rad. Fertility decreased significantly (25% and 66%) after exposure to 1 and 10 rad, respectively. The authors concluded that the primary site of radiation damage in the reproductive tract is the tubuli compartment of the testes and that spermatogonia were probably the first to be affected by the effects of *’Ir. The lack of meiotic activity in the immature male reproductive system is thought to make it less sensitive than the adult to radiation. A comparative estimation of the frequencies of genetic disorders induced in germ cells of male mice by a single or long-term exposure to incorporated '*’Cs or to external gamma radiation was performed in another study of acute duration. Groups of 10 male mice were exposed to a '*’Cs apparatus for a whole-body exposure to gamma radiation of 300 rad (0.675 rad/hour). Subsequent data on effective matings and embryo mortality were collected. Animals that mated exposed, during the second week of exposure, to external gamma radiation were noted to have a significant decrease in male fertility, and at 3 weeks the animals became sterile. During weeks 1 and 2, there was a significant increase in total and post-implantation embryo mortality (Ramaiya et al. 1994). Studies of longer exposure duration have demonstrated similar results. Searle et al. (1976) exposed 13 adult C3Hx101 hybrid male mice continuously to 1,128 rad *°Co gamma irradiation over 28 weeks (5.8 rad/day). There were significant reductions in testis mass (35% of controls) and epididymal sperm count (15% of controls). An increased percentage of abnormal sperm was observed in gamma-irradiated animals (17.1% versus 3.9% controls). The frequency of translocations was significantly higher than in controls. There was also good evidence for the induction of dominant lethal mutations, with an increase in pre-implantation loss from 16% (controls) to 28% (radiation exposed) and in post-implantation loss from 10% (control) to 22% (radiation exposed). In addition, Grahn and Carnes (1988) exposed groups of 4-13 male B6CF, mice to *°Co gamma-rays or fission neutrons at once-weekly doses for periods up to 60 weeks (10, 25, 40, 50, or 60 weeks of exposure and observations at 75, 90, and 99 weeks). Doses rates were 0, 5, 7.5, and 10 rad per week. An increased frequency of abnormal sperm was observed at all doses and all exposure durations. After exposure ended, frequencies of sperm abnormalities returned to near-normal levels. In summary, male reproductive organs are at risk for non-carcinogenic effects when exposed to high doses of ionizing radiation due to the relative high rates of cell divisions that occur in these organs. Sperm anomalies, temporary impotence, decreased libido, and hormonal imbalances have been reported in men exposed to 100-550 rad of ionizing radiation (Birioukov et al. 1993). Similar effects in laboratory animals, such as “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 97 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION decreased testes weights, decreased fertility, sterility, decreased sperm counts, chromosomal reciprocal transformations, sperm anomalies, and embryo mortality, have been reported at similar dose levels (Canfi et al. 1990; Grahn and Carnes 1988; Pinon-Lataillade et al. 1991; Ramaiya et al. 1994; Searle et al. 1976; Shevchenko et al. 1992). The data for reproductive effects in humans and laboratory animals are summarized in the Observed Health Effects from Radiation and Radioactive Material tables in Chapter 8 of this profile. 3.2.1.4 Teratogenic/Embryotoxic Effects The rapidly dividing cells in the developing fetus, like those in the reproductive system, are also at a much higher risk of the adverse biological effects of ionizing radiation, independent of the type of ionizing radiation, the source (internal versus external) or the route of exposure, than slowly dividing, differentiated cells. The vast majority of the available literature reported numerous toxicological end points on the developing fetus associated with external exposure to ionizing radiation. In cases of external exposure to the fetal animal, alpha and beta radiation are of little concern because they can not penetrate the mother’s body tissues and the placental sac. Gamma radiation is very penetrating and can expose the fetus. The embryo/ fetus is always uniformly exposed to external gamma rays from background radiation. There may be partial body exposure in instances where there is preferential uptake of a radionuclide, such as *Sr, during fetal bone development or by medical X-rays. Of most concern in cases of human exposure are the effects of embryo organogenesis and how these changes will affect the individual as a child and an adult. During the early days of development, the human embryo largely consists as a mass of undifferentiated cells, the cells most sensitive to the effects of ionizing radiation. These cells transform themselves into more specialized (differentiated) cells at specific times during gestation, with these cells developing into the more organized tissues later seen in the mature animal. The periods of central nervous system development in the human can be subdivided into four basic periods of development after conception: weeks 1-7, weeks 8-15, weeks 16-25, and »25 weeks. During weeks 1-7, the cells that will later differentiate into neurons are steadily multiplying. During weeks 8-15, the population of neurons rapidly increases, migrates to their functional sites, and loses their ability to further divide. Between weeks 16 and 25, these neurons continue to differentiate, but more importantly, they undergo synaptogenesis in order to communicate. From week 25 on, the neurons continue to differentiate into more mature neurons, with continued growth of the cerebrum (cognitive thought and motor skills) and cerebellum (motor coordination) (BEIR V 1990; ICRP 1986). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 98 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Analysis of the human data from the fetuses exposed to very high doses of radiation during the bombing of Hiroshima and Nagasaki suggests that the cells of the developing central nervous system are the cells most sensitive to the effects of ionizing radiation in the developing human fetus. The major clinical effect on these susceptible cells results in mental retardation that is observed after birth during childhood development. Human fetuses exposed to doses of ionizing radiation from 1 to 7 weeks after conception suffered no discernable ill effects after birth. For fetuses exposed to doses of radiation during weeks 8-15 after conception, a dose-dependent increase in mental retardation occurred in these individuals. Using the latest Japanese dose measurement system, termed DS86, dosimetry for fetuses exposed during the 8-15 week period of development, a “no effect” threshold exists for doses in the range of 2040 rad (0.2-0.4 Gy); at a dose of 100 rad (1 Gy), the frequency of observed mental retardation would be 43% (BEIR V 1988; ICRP 1986). Similar results were seen in fetuses exposed from weeks 16 to 25; however, the relative risk of mental retardation was significantly lower. No discernable adverse effects were observed in children exposed during weeks 25 and beyond. It has been suggested that these effects may not have been caused by radiation but by genetic variation, nutritional variation, bacterial and viral infections during pregnancy, and embryonic or fetal hypoxia (BEIR V 1990; ICRP 1986). Intelligence quotient (IQ) test scores of children fetally exposed to high radiation doses during each of these time frames support the supposition that exposure to ionizing radiation during fetal development may yield adverse effects. For fetuses exposed during the 0-7 week and 26+ week periods of development, no radiation-related effect on intelligence test scores was observed. For those exposed during weeks 8-15 and, to a lesser extent, weeks 16-25, marked dose-related decreases in intelligence test scores were noted, with lower scores noted as the dose of ionizing radiation increased above a 0.2-0.4 Gy threshold (BEIR V 1990). The data presented here suggest that the effects of mental retardation and impaired intelligence are dose- dependent and vary depending on when the fetus was exposed after conception. The developing fetal central nervous system seems resistant to the effects of ionizing radiation from 0 to 7 weeks and from weeks 28 and beyond, evidenced by no apparent changes in the frequency of mental retardation or decreases in intelligence test scores. The period of maximum susceptibility is between weeks 8 and 15 after conception, when the proliferation of developing neurons and their subsequent migration to specific areas of the cerebrum is at its peak. Disruption of these vital migrations and neuronal functions can have the obvious effects of mental retardation and, hence, a reduction in intelligence test scores later in life. Exposures during weeks 16-25 clearly have more effects on synaptogenesis than neuronal migration anomalies, producing defects in inter- neuronal communication pathways. Mental retardation and decreased intelligence test scores are also ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 99 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION produced if exposure occurs during this time frame. Little effect was noted if exposure occurred beyond 25 weeks, indicating that the majority of neuronal and synaptic development had already occurred and exposure to ionizing radiation had little, if any, effect on the existing cell populations of the central nervous system (BEIR V 1990). Embryo Organogenesis Defects and Body Weight Alterations. Beta and gamma sources of ionizing radiation have been demonstrated to induce embryo/organogenic defects in laboratory animals. As in the human fetus, the developing central nervous system of laboratory animals during specific stages of development is at varying risk after exposure to ionizing radiation. In laboratory animals, effects such as hydrocephaly, anencephaly, encephalocele, spina bifida, functional and behavioral effects, motor defects, hyperactivity, defects in learning, as well as a host of other defects have been reported (BEIR V 1990). For example, Bruni et al. (1994) studied the effects of low levels of ionizing radiation on embryogenesis. Pregnant Sprague- Dawley rats were exposed on gestational days 9.5, 15, and 18 to 50 rad of “°Co radiation lasting for 14-17 seconds. Irradiated rats and controls were sacrificed at prenatal intervals of 4 hours, 48 hours, and 10 days (term) after exposure. No statistically significant difference was seen in the number of embryos recovered per litter for control and irradiated embryos sacrificed 4 hours after exposure. With the exception of the neuroepithelium, no histopathological changes were observed in embryos in this group. In irradiated embryos, mitoses were reduced within the neuroepithelium; pyknosis and some necrosis of cells were apparent at this gestational interval. No significant difference was seen in the number of embryos recovered per litter, the crown-rump length, or the head length of irradiated embryos sacrificed 48 hours after irradiation compared to controls. Among the gross developmental abnormalities observed in embryos 48 hours after irradiation, excessive flexion of the embryo (seen in 3.7%) and abnormal flexion of the head (seen in 1.2%) were the only ones that appeared to possibly be radiation-induced. At term, no significant differences in litter size or resorption rates were observed in irradiated animals compared to the controls. Mean fetal body and placental weights were not significantly different. There was a higher incidence of developmental abnormalities in irradiated (9.7%) versus control (4%) fetuses, but this was not statistically significant. The most common anomalies were defects in ocular development; microphthalmia and anophthalmia were seen in 3% and 1.5% of irradiated fetuses, respectively. Scoliosis was also significant with a prevalence of 1%. Viscerally, abnormally positioned kidneys were found in 5.8% of irradiated fetuses and 7.1% of controls. Ureteric anomalies and hemorrhagic liver lesions were encountered in 2% and 11.5% of irradiated fetuses, respectively. No significant developmental differences were observed in the nervous system of irradiated versus control fetuses at term. The authors concluded that in utero exposure to 50 rad of gamma radiation during the period of early organogenesis can produce some irreversible defects that are discernable at term. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 100 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION External Malformations, Growth Retardation, and Death. Many other types of birth defects have been reported. Kusama and Hasegawa (1993) designed a study to precisely determine the radiosensitive period in the development of ICR mouse embryos during which external malformations and growth retardation tended to occur. Pregnant mice were treated with a single whole-body gamma radiation at a dose of 150 rad delivered at a dose rate of 20 rad/minute from a '*’Cs source. Death of the embryo/fetus, especially during the early period of organogenesis, was most frequent in mice irradiated between days 6.75 and 8.25 of gestation. There was no difference in radiosensitivity between male and female fetuses. Reduction of fetal body weight was found to be a good indicator of radiation effects. Body weights of all irradiated fetuses were significantly less than controls. The reduction in fetal body weights was marked in mice irradiated in the intermediate stage of organogenesis (between days 9.75 and 12.75 of gestation). The body weights of abnormal fetuses with external malformations other than exencephalia and eventration were not significantly different from those of fetuses without external malformations. Exencephalia appeared most often in mice irradiated between 6.5 and 8.75 days of gestation (0.6-21.7%) and at a low frequency between days 10.25 and 10.75 of gestation (0.5-1.5%). Cleft palate appeared in mice irradiated between days 8.25 and 12.75 of gestation (1.1-20.5%). Micromelia, ectrodactyly, and polydactyly were observed in fore- and hindpaws. The forepaw malformations appeared in fetuses exposed on days 10.25-12 of gestation (0.8—46.2%). Hindpaw malformations showed two periods of high sensitivity, from days 7.5 to 8.75 (0.6-3.8%) and from days 10.25 to 12 (0.6-28.9%) of gestation. Shortened and/or bent tails were observed in groups irradiated from days 7 to 11.5 of gestation (0.7-32.5%), with the peak frequency among those irradiated on day 9.25 of gestation. Other studies support the observation of increased incidences of birth defects after exposure to ionizing radiation. Devi et al. (1994) exposed the whole abdominal region of pregnant Swiss mice (n=25) to 5-50 rad of ®’Co gamma radiation (at a dose rate of 83 rad/min) on postcoitus day 11.5. Increased fetal mortality and retarded growth was seen among the 50 rad group. At this level, growth retardation was observed in 12% of fetuses, with body weight and body length decreased (7% and 3%, respectively). A significant reduction in head length, width, and brain weight was seen at 25 rad and above. A significant increase in the incidence of microphthalmia was also observed at 25 rad and above in 14% of fetuses. Zaman et al. (1992) also studied the effects of acute-duration prenatal exposure to ionizing radiation on myelination of the developing brain, as well as some physical parameters. Rats were treated with a single dose of gamma radiation (6.8, 15, or 150 rad) on the 20th day of gestation (i.e., offspring exposed on the 20th day of prenatal life). At day 30, absolute brain, kidney, heart, and spleen weights of the 150 rad treated group were significantly lower than that of any other treatment group. Relative brain, ovary, adrenal, kidney, liver, heart, spleen, and lung ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 101 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION weights showed no significant differences among different treatment groups. At postnatal day 52, brain weight of the 150-rad treated group was significantly lower than the other treatment groups and controls. No significant differences were seen in relative organ weights at day 52. The relative weight of the cerebral cortex was significantly less than controls in the 150 and 15 rad group at day 30 and in the 150 rad group on day 52 (9-11%). In addition, Reyners et al. (1992) evaluated the effects of radiation on brain development in pregnant Wistar rats exposed on gestation day (Gd) 15. Protracted gamma irradiation to total doses up to 80 rad was performed with a ®*Co source. The dose rate varied from 1 rad/day at 15 meters (m) to 13.3 rad/day. Exposure was carried out either from Gd 12 to 16 (4 days) or from Gd 14 to 20 (6 days). Co gamma irradiation protracted over 4 days from Gd 12 to 16 significantly reduced the brain weight in 3-month-old rats by 3%, 4%, and 13% after 160, 350, and 560 rad exposures. Animals irradiated for 6 days from Gd 14 to 20 also showed a significant reduction in the 3-month-old brain weight of 5%, 4%, and 7% after exposures to 17, 34, and 80 rad, respectively. The cingulum volume was also significantly decreased in the 80 rad group by 19%. Dental and Oral Cavity Development. Ionizing radiation can also affect dental and oral cavity development. Lee et al. (1989) irradiated Beagle dogs in utero at 8, 28, or 55 days postcoitus or postnatally at 2, 70, or 365 days postpartum. Whole-body *’Co gamma radiation doses ranged from 0 to 380 rad. After a threshold dose of 83 rad, there was an age-dependent dose-related increase in premolar hypodontia for dogs irradiated at 55 days postcoitus or 2 days postpartum. Dogs irradiated at 55 days postcoitus were the most sensitive, with fewer than 20% having normal teeth at doses above 83 rad. After irradiation at 28 days postcoitus, no effect was seen below doses of 120 rad. Similarly, Saad et al. (1991) exposed pregnant CD-1 Swiss albino mice to an external source of gamma rays on the 12th gestational day to a dose of 400 rad. All irradiated fetuses presented clefts of the secondary palate but usually not cleft lip. The development of the maxillary and mandibular incisors was retarded in irradiated fetuses and was in early bell stage, whereas controls had elaborated their matrices. Significant doses of ionizing radiation can also affect the fetal blood-forming organs. Koshimoto et al. (1994) mated female Wistar rats with male rats, and on the 13th, 14th, or 15th day of gestation, pregnant animals were irradiated externally with '*’Cs to a dose of 50-800 rad. Forty-eight hours later, the pregnant animals were sacrificed and the numbers of ovulations, implantations, and surviving fetuses were determined. Blood cell volume was measured, and fetal blood was collected. The numbers of erythrocytes and hepatocytes in the livers in the fetuses were counted. Gamma radiation did not significantly affect the number of ovulations per litter and implantation rate. The fetal survival rate at 400 and 800 rad was significantly ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 102 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION lower than for the controls (68.5% and 21.3%, respectively, as compared to 96.5% for controls). The number of blood cells in circulating blood after the fetuses were irradiated to 800 rad on day 15 was significantly lower than the controls, and the formation of micronuclei was significantly increased at 50 rad and above. The erythrocyte counts in the fetal liver were significantly lower than controls at 400 and 800 rad, and the ratio of the large hematocyte count to the small hematocyte count was significantly higher than controls at doses of 100 rad and above. Reproductive Tract. As in the adult animal, the in utero exposure to large doses of ionizing radiation can affect the forming reproductive tracts of male and female embryos. As an example, Inano et al. (1989) exposed pregnant rats to whole-body irradiation at Gd 20, with 260 rad gamma rays from a **Co source. It was found that the seminiferous tubules of the irradiated male offspring were remarkably atrophied with free germinal epithelium and contained only Sertoli cells. Female offspring also had atrophied ovaries. The testicular and ovarian weight in irradiated offspring were 18% and 34%, respectively, of controls. No oocytes or Graafian follicles were found in ovaries of the irradiated rats. Testicular tissue obtained from control and %0Co-irradiated rats was incubated with “C-labeled pregnenolone, progesterone, 17-alpha-hydroxy- progesterone, and androstenedione as a substrate. Intermediates for androgen production and catabolic metabolites were isolated after the incubation. The amounts of these metabolites produced by the irradiated testes were low in comparison with the control. The activities of delta[5]-3-beta-hydroxysteroid dehydrogenase, 17-alpha-hydroxylase, C(17, 20)-lyase, and delta[4]-5-alpha-reductase in the irradiated testes were 30-40% of those in nonirradiated testes. The activities of 17-beta- and 20-alpha-hydroxysteroid dehydrogenases were 72% and 52% of controls, respectively. The activity of delta[5]-3-beta-hydroxysteroid dehydrogenase of the irradiated ovary was only 19% of the control. The authors note that these results suggest that ®°Co irradiation of the fetus in utero markedly affects the production of steroid hormones in the testes, ovaries, and adrenal glands after birth. Behavioral Alterations. Behavioral changes have also been noted in laboratory animals after birth when exposed to certain doses of ionizing radiation during the embryo stages of development. Minamisawa et al. (1992) investigated social behavior, in particular aggressive behavior (AB), in mice exposed prenatally to ionizing radiation. Pregnant C57BL/6 mice (n=3) were exposed to whole-body gamma radiation from a '*’Cs source on Gd 14. The dose rate to the midline of the mouse was 25 rad per minute and doses of 0, 100, and 200 rad were given. AB in first-generation (F1) hybrid male offspring was studied. The number of instances of AB was significantly higher in the 100-rad group than in controls during the first 45 minutes of “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 103 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION observation. The AB of the 200-rad group was significantly more intensive than that of the control group. There is little information in the literature with which to compare these findings. In a similar study, Zaman et al. (1993) treated adult female Fischer 344 rats with a single dose of total-body gamma irradiation (6.8, 15, or 150 rad) on the 20th day of gestation (the offspring received the radiation doses on the 20th day of prenatal life). During the 3 weeks of the offspring’s postnatal life, changes in pivoting, crawling, negative geotaxis, cliff avoidance, hindlimb support, eye opening, and tooth eruption were studied. Pups irradiated with 150 rad exhibited significantly lower pivoting than any other group on days 15-16 of the observation period. No significant differences were observed between treatment groups for crawling, geotaxis, or hindlimb support when suspended. Cliff avoidance was recorded from days 3to 10 postnatally. Cliff avoidance was significantly different in the 15 and 150 rad groups compared to the 6.8 rad group and controls on day 8 only; however, the mean score was not significantly different in the 15 rad group. There was a dose-related delay in upperjaw tooth eruption for all three groups, but the only significant difference was observed between the control and 150-rad group. Data from this study suggest that radiation affects several of the tested locomotion parameters. Based on the data presented in this study, it appears that areas of cerebral cortex including the somatosensory and sensory cortex, the primary cortex, and the premotor cortex were adversely affected by doses of 150 rad of ionizing radiation. Sensorimotor Effects. Norton and Kimler (1987) also investigated the early postnatal behaviors involving sensorimotor integration and the thickness of the sensorimotor cortex in prenatally irradiated rats which received a dose of 100 rad (1 Gy) of ionizing radiation from a '*’Cs source. Performance in the negative geotaxis test was poorer in irradiated rats than in controls. Rats irradiated on Gd 17 were unable to equal the performance of either controls or rats irradiated on Gd 11 in the reflex suspension test. No gait alterations were seen in the irradiated rats. In a later study, Norton and Kimler (1990) exposed pregnant Sprague- Dawley rats to whole-body gamma radiation from a '3’Cs source on Gd 15 to doses of 25, 50, 75, or 100 rad (0.25, 0.5, 0.75, 1.0 Gy). The fetuses of irradiated dams were examined 24 hours after irradiation for changes in the cells of the cerebral mantle of the developing brain. Changes were seen in those rats treated with 50 or more rad. Cortical thickness of the cerebral mantle was not significantly altered. The number of pyknotic cells, the number of macrophages, the nuclear area, and the number of mitotic cells were altered in a dose-related way. The number of mitotic figures in the ventricular zone was significantly reduced and the number of macrophages was significantly increased in fetuses from the 50-, 75- and 100 rad (0.5, 0.75, and 1 Gy) treatment groups. The nuclear area in fetuses prenatally exposed to 100 rad (1 Gy) was significantly increased. In fetuses prenatally exposed to 50 rad (0.5 Gy), the nuclear area of subventricular zone cells was “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 104 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION significantly increased compared to controls 12 hours postirradiation but returned to almost the control value at 24 hours postirradiation. The number of macrophages in the ventricle and in the cortical mantle was significantly increased at 12 and 24 hours in fetuses prenatally exposed to 50 rad (0.5 Gy). Several vesicles containing nuclear fragments were present in each macrophage at these times. The number of mitotic figures in the ventricular zones was significantly increased at 3 and 6 hours postexposure and significantly decreased at 12 and 24 hours postexposure in fetuses prenatally exposed to 50 rad (0.5 Gy) compared to controls. Pyknotic cells developed rapidly after irradiation with 50 rad (0.5 Gy). At 3 hours postirradiation, the total number of pyknotic cells in the cortical mantle had increased from nearly 0 to 166. This number increased slightly from 3 to 6 hours and then declined from 12 to 24 hours. The number of pyknotic cells in the ventricular and subventricular zones decreased while the proportion in the intermediate and cortical plate zones increased. Both the percentage and number of pyknotic cells increased with time in the two latter zones. A positive correlation between the number of pyknotic cells and the number of macrophages developed with time. At 3 hours after irradiation, about 60% of pyknotic cells were found in the subventricular zone and about 25% in the intermediate zone and cortical plate. The number of such cells in the upper layers of the cortex steadily increased up to 24 hours, at which time about 70% of pyknotic cells were in these two layers. In summary, the developing fetus, with its rapidly dividing cell characteristics, has been an area of intense study relating to the effects of ionizing radiation, particularly for external exposures to ionizing radiation involving gamma radiation sources. For obvious reasons, laboratory animal models have been used to delineate many of these effects. Ionizing radiation, above a threshold dose of about 25 rad (0.25 Gy) can impair development of embryonic structures, in particular the structures of the central nervous system (brain). Ionizing radiation affects specific cells of the developing nervous system at specific times during its developmental process, although the exact mechanisms behind these alterations are not known. Many of these reports include descriptions of decreased fetal body weights (Devi et al. 1994; Minamisawa et al. 1990; Norton and Kimler 1987; Zaman et al. 1992) and developmental anomalies, such as necrosis of neuroepithelial cells, microphthalmia, anophthalmia, scoliosis, decreased myelination of the brain, hypodontia, cleft palate, micromelia, ectrodactyly, polydactyly, as well as many more defects (Bruni et al. 1994; Kusama and Hasegawa 1993; Lee et al. 1989; Reyners et al. 1992; Saad et al. 1991; Zaman et al. 1992) at doses of <300 rad {3 Gy). Social behavior changes have also been reporced in male mice at doses of 100 rad and higher (Minamisawa et al. 1992). Locomotor difficulties have also been reported (Norton and Kimler 1987, 1988; Zaman et al. 1993) as well as reproductive organ anomalies (Inano et al. 1989). From these animal studies, it is clear that the developing embryo and fetus are subject to damage from ionizing ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 105 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION radiation at doses greater than 25 to 50 rad (0.25- 0.5 Gy), in particular from external gamma radiation sources at doses greater than 25 to 50 rad (0:25-0.5 Gy). Data for developmental effects in humans and laboratory animals are summarized in the Observed Health Effects from Radiation and Radioactive Material tables in Chapter 8 of this profile. 3.2.1.5 Central Nervous System (CNS) Effects As a whole, the central nervous system of the adult human and laboratory animal is one organ system relatively resistant to the effects of ionizing radiation (see Table 3-2). In contrast to the rapidly dividing cells of the gastrointestinal and hematopoietic systems, the central nervous system has a relatively static population of cells, with cell mitosis occurring between long intervals of latency, if at all. This allows cells to be exposed to much larger doses of ionizing radiation because the cells have much more time to repair themselves before they multiply. The brain appears to be sensitive to ionizing radiation only at extremely large doses; a dose of approximately 1,500 rad is necessary to produce discernable deterministic effects. Necrosis of the brain (associated with demylination and cerebral vascular damage) may occur within 3 years after a 5,500 rad (55 Gy) dose received over a 6-week time frame. Demylination and necrosis of neurons in the white matter of the spinal cord can also develop within 6 months after exposure to high doses (>6,000 rad or 60 Gy) of ionizing radiation. These are extreme doses of radiation. Birioukov et al. (1993) reported that one man exposed to 200-350 rad (2-3.5 Gy) had clinical symptoms such as permanent headache and vision impairment after accidental exposure to beta and gamma radiation during and after the Chernobyl atomic power plant accident. Reports are available that describe the effects that ionizing radiation has on the nervous system of the developing embryo in laboratory animals (Minamisawa et al. 1992; Norton and Kimler 1987, 1990). Adverse effects have been reported from extremely high doses of ionizing radiation. Cockerham et al. (1986) explored the effects of ionizing radiation on early transient incapacitation (ETI) and performance decrement (PD). Rhesus monkeys (n=6) were exposed to a whole-body total dose of 10,000 rad (1,000 Gy) from a **Co source. Monkeys showed a decrease in blood flow in the motor cortex and the pons by 10 minutes postirradiation. Postirradiation blood flow to the reticular formation of the pons 60 minutes after sham-irradiation showed an overall increase in sham-irradiated animals while irradiated animals showed a significant decrease, to 49% below preirradiation levels by 10 minutes postirradiation. A slight recovery was seen at 20 minutes postirradiation, but blood flow gradually decreased to 48% of preirradiation values by 60 minutes postirradiation. Postirradiation ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 106 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION cortical blood flow in sham-irradiated animals showed a decrease to 87% for the 60-minute observation period while irradiated monkeys' cortical blood flow decreased to 63% of preirradiation levels by 10 minutes postirradiation. A sharp, partial recovery was seen in this group 20 minutes postirradiation followed by a decline to 66% below baseline at 60 minutes postirradiation. Within 10 minutes postirradiation, mean arterial blood pressure was decreased to 34% from the preirradiation mean in irradiated animals. A slight recovery was seen at 30 minutes postirradiation, followed by a decline to 71% 60 minutes postirradiation. Hippocampal cellular activity also showed highly disturbed electrical activity in rabbits exposed to a sublethal dose of 450 rad (with a dose rate of 14 rad/min) from a Co source. Bassant and Court (1978) exposed rabbits to a Co gamma ray source, with the mean absorbed dose of 450 rad (4.5 Gy). According to the authors, the LDj, for rabbits ranges from 600 to 650 rad. Following irradiation, the hippocampal cellular activity was highly disturbed, as described by the EEG activity. Data for neurological effects in humans and laboratory animals are summarized in the Observed Health Effects from Radiation and Radioactive Material tables in Chapter 8 of this profile. 3.2.1.6 Respiratory and Cardiovascular Effects The respiratory tract has long been known to be a target organ of both internal and external forms of ionizing radiation. Respiratory effects have been reported in humans (Stavem et al. 1985) who had received radiotherapy for breast cancer and those who had been accidentally overexposed, as well as in laboratory animals (Rezvani et al. 1989; Salovsky and Shopova 1992). No harmful effects have been seen in the millions of people who had received occasional diagnostic X-rays of the chest. However, repeated diagnostic X-rays of the chest led to a nine-fold increase in female breast cancer (Myrden and Hiltz 1969). Like the central nervous system, the respiratory tract can tolerate higher doses of ionizing radiation than other organ systems. Local injury is tolerated much more than diffuse injuries. Irradiation of large portions of one or both lungs initially results in alterations in blood flow, initially manifested as edema, and later as pneumonitis and pulmonary fibrosis, depending on the total dose received. Radiation pneumonitis, followed by pulmonary fibrosis (i.e., fibrosis of alveolar structures involving changes in the ratios of some pulmonary collagens), are two of the most commonly reported aberrations in laboratory animals following an inhalation of radioactive material (Benjamin et al. 1978, 1979; Brooks et al. 1992; Hahn et al. 1975, 1981; Lundgren et al. 1980a, 1991). **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 107 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION The precise mechanism behind the induction of radiation pneumonitis is not currently known; however, a vascular component (comprised of sloughing and of dead and dying endothelial cells that may lead to capillary leakage) has been suggested. Damage to type II pneumocytes, which can lead to serious alterations in the amount of surfactant phospholipids and to lung inflammation, has also been considered. The role of type I pneumocytes, which by necrosing and sloughing leave denuded basement membranes and alveolar debris, may also be significant. Any one or all of these mechanisms may be involved in the development of pneumonitis. Fibrosis is a serious sequela of pulmonary inflammation due to large populations of cells dying and not being replaced, and is seen in the lungs after exposure to ionizing radiation at moderate to high doses or to asbestos. A more in-depth discussion of radiation pneumonitis and subsequent fibrosis after exposure to ionizing radiation is available (Coggle et al. 1986). Most of the studies have focused on the effects of ionizing radiation on the lungs when associated with inhaled insoluble (and, to a lesser degree, soluble) particles. Most of these studies were acute inhalations of large quantities of radioactive material resulting in high initial lung burdens and cumulative radiation doses on the order of hundreds of rad. After the radioactive material was inhaled, clinical signs were related to the organ system which received the major radiation dose during and after redistribution of these particles had occurred. Important aspects of this redistribution related to whether these radionuclides were in a soluble or insoluble form and to the size of the inhaled particle. Soluble particles tended to dissolve in the lung matrix and redistribute based on chemical mechanisms; then they induced toxic effects in those organ systems. These soluble particles tended to deliver a higher dose rate to the lungs shortly after inhalation; the rate tended to decrease rapidly as the material was dissolved and the radionuclide redistributed to other organs via the normal lung clearance mechanisms. Soluble particles deposited in the respiratory tract tended to result in lower overall dose over time when compared to insoluble particles because they exposed the lung tissue for a shorter period of time. Unlike the soluble particles, the bulk of the inhaled insoluble particles tended to remain for long periods of time in the lungs (several days to several years), radiating the tissues and depositing large radiation doses to the tissue immediately around the particles. Some fraction of these particles would initially be coughed up or removed by the ciliary clearance mechanism and then swallowed during the first few days after exposure, thereby exposing the gastrointestinal tract as the particles passed through and cleared the body. In addition, smaller particles (1-3 pm) tended to penetrate to the deeper regions of the lungs (terminal bronchiles and alveoli) than did the larger (>6 um) particles, which are deposited in the upper respiratory tract (trachea, ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 108 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION conducting airways). The effect of inhaled radioactive particles, therefore, varied with the size distribution and solubility of the inhaled particles, as well as the type and quantity of the inhaled radioactivity. Respiratory insufficiency was a common finding in many studies following high radiation doses to the lungs This was manifested clinically as increased respiratory rates, increased abnormal lung sounds and cyanosis, decreased lung volumes, total lung capacity, and compliance (common but not pathoneumonic symptoms of pneumonia). These clinical symptoms were most likely related to inflammatory and fibrotic changes occurring within the lungs. This observation is supported by radiographic, gross, and histopathological evidence, such as increased radiographic focal or diffuse lung-field densities, and by interstitial, perivascular, peribronchial, and pleural fibrosis; emphysema; inflammation; vascular damage; fibrin exudation; congestion; and hemorrhage (Benjamin et al. 1976; Hahn et al. 1976; Lundgren et al. 1991). Numerous assessments of human exposure to inhaled radionuclides (with no dermal or oral component) have been identified in the open literature. One report involved a U.S. military airplane crash near Palomares, Spain, in January 1966. The aircraft was carrying 4 thermonuclear weapons containing **Pu; 2 of the devices were recovered. The other 2 devices detonated their conventional explosives and released fissile material upon ground impact. Partial ignition of the fissile material resulted in a cloud formation that contaminated approximately 2.25 km? of farmland. The deposition density of alpha emitters from the partial explosion was 32.4 uCi/m?; estimates of the inhaled and ingested dose from **’Pu and 240py were derived. Of the 714 people examined through 1988, 124 had urine concentrations of Pu greater than the minimum detection limits. An estimate from Iranzo et al. (1987) states that the 70-year committed effective dose for 55 of those 124 people, due to inhalation of radioactive particles, was 2 to 20 rem (0.02 to 0.2 Sv); however, no acute respiratory effects were reported and there has apparently been no long-term follow-up of these individuals. There is a considerable database available on the effects seen from inhaled radionuclides in laboratory animals. For example, Hobbs et al. (1972) exposed Beagle dogs to initial lung burdens of 3,600, 1,800, 1,200, 780, 400, 210, 110, and 0 pCi *°Y/kg body weight. The AMAD:s of the aerosols used ranged from 0.8 to 1.2 um. Death was reported in 21 of 33 dogs exposed within 7.5 and 163 days postexposure, with their initial lung burdens ranging from 670 to 5,200 pCi/kg (8,400 to 55,000 rad). Clinical signs of the dogs that died included progressive increase of respiratory rates, abnormal lung sounds on ausculation, anorexia, progressive weight loss, and eventual cyanosis of the mucous membrane. Additionally, thoracic radiographs showed marked, generally diffuse nodular increases in density of lung fields. The authors note that clinical ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 109 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION signs did not differ from high to low doses; however, the time to the onset and the duration of the illness varied considerably. A dose response could be demonstrated with these exposures: “acute symptoms” occurring 7-10 days after inhalation, with initial lung burdens of 1,700-5,200 uCi/kg and doses to the lungs of 21,000-55,000 rad; “subacute symptoms” with signs of respiratory insufficiency 3-4 weeks postexposure, initial lung burdens of 1,000-2,400 uCi/kg and doses to the lungs of 13,000-29,000 rad; “subacute to chronic symptoms” appearing at 6-8 weeks, which included a gradual deterioration in the animals’ condition. Animals in this group had initial lung burdens of 670-760 pCi/kg and radiation doses to the lungs of 8,400-9,400 rad. Pathological findings at necropsy included pulmonary and pleural fibrosis, occlusive pulmonary vascular lesions, metaplasia and/or hyperplasia of terminal bronchiole and alveolar epithelium, right heart dilation, and hypertrophy. Small indurated hemorrhagic areas near the ventricular junction were present in the right atria of the hearts of 7 of the 12 dogs that died 64-92 days postexposure. Infarctions of the right atria were found in some animals. Similarly, Muggenburg et al. (1988) exposed 216 Beagle dogs by inhalation to initial lung burdens of 3-54 pCi **Pu/kg monodisperse **Pu0, aerosols with AMADSs of 0.75, 1.5, or 3.0 pm, which produced a protracted alpha irradiation dose to the lungs. From the group of 78 dogs which survived to 7.1 years post-inhalation, 20 were selected for cardiorespiratory function tests and further clinical evaluation. Of these 20 dogs, 10 were selected because they had persistent respiratory frequencies of 40 breaths/min for more than 1 year (group I). The second 10 dogs were selected because they had similar or slightly lower plutonium lung burdens at the time of inhalation as the dogs in group I, but had normal respiratory frequencies (group II). Ten controls were used (group III). The average dose to the lungs through 2,600 days after inhalation for the dogs in group I ranged from 230 to 3,200 rad (2.3 to 32 Gy) and for the dogs in group II, from 80 to 1,570 rad (0.8 to 15.7 Gy). Respiratory tract injury was again first observed as an increased respiratory frequency on average 3.4 years after inhalation; this change in breathing pattern persisted for at least 1 year. Only the dogs in group I with signs of lung injury had a mild respiratory function disorder consisting of smaller lung volumes, decreased total lung capacity, vital capacity, functional residual capacity, reduced dynamic and quasistatic compliance, and increased respiratory frequency and minute volume. Carbon monoxide diffusing capacity was significantly reduced in both groups I and II. These findings indicate that alpha irradiation of the lungs of humans could produce restrictive lung disease at long times after initial inhalation. In addition to alterations in respiratory rates and respiratory function tests, pneumonitis and pulmonary fibrosis are two of the most commonly reported respiratory aberrations in animals (and humans) after ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 110 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION inhaling radionuclides (Coggle et al. 1986). Hahn et al. (1975) studied the radiation dose of °°Y to the upper respiratory tract in Beagles exposed by nose-only inhalation to aerosols of °%Y in fused clay. Initial whole- body burdens ranged from 23 to 65 mCi, with initial lung burdens ranging from 9 to 35 mCi. A rapid initial decrease in body burden, typical of an insoluble material deposited by inhalation, was due to the clearance of particles from the upper respiratory tract entering the gastrointestinal tract. Of the 7 dogs surviving 27-29 days, 6 dogs exposed to 14-35 mCi initial lung burden developed radiation pneumonitis. Radiation pneumonitis was characterized by accumulations of alveolar macrophages, bizarre alveolar lining cells, and alveolar hemorrhage; vasculitis was the most consistent histopathologic finding. Benjamin et al. (1976) exposed 6 Beagle dogs to a nose-only inhalation of *°Y, '*Ce, or **Sr in fused aluminosilicate particles (FAP). The initial lung burdens in uCi/kg were 560, 46, and 28 for *°Y, '*Ce, and *Sr, respectively. Deterioration in the health of the dogs exposed to *°Sr included an increased respiratory rate, dyspnea, cyanosis, and dry and moist rales. Increased radiographic focal or diffuse lung-field densities, with clear evidence of ventricular enlargement, was apparent. The lungs of dogs exposed to 0Y showed radiation pneumonitis characterized by interstitial, perivascular, peribronchial, and pleural fibrosis, focal emphysema, and acute and chronic inflammation with increased numbers of alveolar macrophages. Vascular damage included congestion, hemorrhage, fibrin exudation, and occasional vessels with fibrinoid necrosis or proliferation. Epithelial changes included denudation of terminal bronchioles and alveolar ducts, with regeneration of bizarre lining cells and proliferation of bizarre, hypertrophied alveolar lining cells. Adenomatous epithelial proliferation and squamous metaplasia were common findings in the *°Y dogs. Later, Benjamin et al. (1978) again exposed Beagles to 144Ce in FAP by nose-only inhalation using particle sizes 1.4-2.7 um. Initial lung burden ranges were 26-34, 24-33, 27-32, 30-35, and 26-31 pCi/kg body weight in dogs sacrificed or those that died between 1.4 and 1.9 years, 2.0 and 2.4 years, at 2.5 years, at 3.0 years, or at 4.1 years postexposure, respectively. The doses to the lungs to death for these groups of dogs were 27,000-47,000, 32,000-41,000, 35,000-43,000, 43,000-45,000, and 36,000-41,000 rad, respectively. By 2 years after exposure, more than 90% of the radiation dose had been delivered. Radiation pneumonitis and pulmonary fibrosis were evident in approximately 80% of the dogs that died. Other reports of radiation pneumonitis and/or pulmor.ry fibrosis have been described in dogs (Benjamin ei al. 1979; Hahn et al. 1976), monkeys (Brooks et al. 1992; Hahn et al. 1987; LaBauve et al. 1980), mice (Lundgren et al. 1980a, 1981, 1991), and hamsters (Lundgren et al. 1983). Some laboratory animal studies were found that dealt with the effects of external sources of ionizing radiation on the respiratory tract. In one study, Rezvani et al. (1989) determined the effects of external forms of ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 111 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION ionizing radiation on the diaphragmatic lobe of the left lung in female large white pigs irradiated with single doses of 900-1,470 rad of *Co gamma rays (at a dose rate of 80 rad/min). Standard lung function tests were performed prior to irradiation and at 4 and 13 weeks after irradiation, then at 13 week intervals up to 104 weeks. At 104 weeks after irradiation, the animals were sacrificed and the lungs were excised and examined for gross changes. A marked impairment in the ventilation capacity of the lungs 4 weeks after irradiation was seen, but was not considered to be dose-dependent. After a dose of 900 rad, the initial impairment in lung function was resolved within 13 weeks, while at 1,470 rad damage persisted. There was an elevation in the breathing rate at 4 weeks after irradiation, which was most marked in animals irradiated with the highest doses; however, the breathing rate returned to normal within 13 weeks of irradiation at all dose levels. At 104 weeks after irradiation, postmortem examination revealed only one case of adhesion between the lung and chest wall. In animals irradiated with 1,090 rad or greater, atrophy of the irradiated left lobe of the left lung was seen. This was particularly characteristic in all lungs irradiated with 1,470 rad in which the lungs showed severe atrophy. At 1,280 rad, a general and severe thickening of the interlobular septa was seen in some animals. The authors calculated a 50% effective dose (EDs) value for pathological changes (fibrosis and focal scarring) in the lungs of 1,112 rad. With regard to external exposure to ionizing radiation sources, Salovsky and Shopova (1992) exposed male Wistar rats to 0, 400, 800, or 1,500 rad in a single whole-body dose in order to gain an overview of the changes present in broncheoalveolar tissue after exposure to ionizing radiation. Eight animals of each group were sacrificed on days 1, 5, and 15. Prior to sacrifice, a broncheoalveolar lavage was performed. Broncheoalveolar lavage fluid was analyzed for lactase dehydrogenase (LDH), alkaline phosphatase (APH), acid phosphatase (AcPH), angiotensin converting enzyme (ACE), and protein content. LDH activity was decreased on day 1 in the 1,500 rad group. At day 5, the 400 and 800 rad group LDH levels were significantly decreased by 30% and 49%, respectively. No significant difference was observed at day 15. Both APH (31-41%) and AcPH (40-67%) were significantly decreased on day 1 in all irradiated groups. In the 800-rad group, APH was significantly increased on day 15 (203%). ACE activity was examined only on day 1, with a significant increase in ACE in the 800 (190%) and 1,500 (187%) rad groups. Protein content decreased significantly only in the 1,500 rad group, measured only on day 1. The authors provided little meaningful interpretation of the toxicological significance of these results. ACE is normally bound to lung endothelial cell surfaces, with increased concentrations suggesting endothelial cell injury. Increased protein content in the BALF indicates vascular permeability changes due to adverse events in the endothelial cells lining the capillaries. LDH, APH, and AcPH are normally intracellular enzymes, and their release into the extracellular domain indicates lung cellular membrane damage. From these data, it appears that LDH may “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 112 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION provide a non-specific biomarker of exposure to ionizing radiation shortly after exposure has occurred, whereas APH would be a non-specific biomarker of exposure at later time points after exposure, but not immediately after exposure, and may also be a relatively sensitive indicator to higher doses of ionizing radiation. In addition to pulmonary effects, cardiovascular effects have been reported after exposure to inhaled radioactive material. The study described earlier by Muggenburg et al. (1988) noted no abnormal cardiac function parameters in any of the dogs studied; however, Hobbs et al. (1972) reported cardiac lesions in 33 Beagle dogs exposed in groups to mean initial lung burdens of 3,600, 1,800, 1,200, 780, 400, 210, and 110, pCi of *°Y/kg body weight. Electrocardiogram changes, consistent with the right heart enlargement and/or conduction defect, were observed in 5 of the animals that died 64-92 days postexposure after receiving a dose of 8,400 rad. Pathological cardiac findings included right heart dilation and hypertrophy. Small indurated hemorrhagic areas near the ventricular junction were present in the right atria of the hearts of 7 of the 12 dogs that died 64-92 days postexposure. Infarcts of the right atria were also found in some animals. ECG changes occurred in 5 of 12 and hemorrhagic areas were found near the ventricular junction in the right atria of 7 of 12 dogs that died 64-92 days after exposure. Cockerham et al. (1986) explored the effects of ionizing radiation and ETI (the complete cessation of performance during the first 30 minutes after radiation exposure) and PD (the reduction in performance at the same time of ETI) in Rhesus monkeys exposed to 10,000 rad whole-body gamma radiation from a Co source. Irradiated monkeys showed a decrease in blood flow in the motor cortex and the pons by 10 minutes postirradiation. Postirradiation blood flow to the reticular formation of the pons 60 minutes after sham- irradiation showed an overall increase in sham-irradiated animals; irradiated animals showed a significant decrease to 51% below preirradiation levels by 10 minutes postirradiation. A slight recovery was seen at 20 minutes postirradiation, but blood flow gradually decreased to 48% of preirradiation values by 60 minutes postirradiation. Postirradiation cortical blood flow in sham-irradiated animals showed a 13% decrease for the 60-minute observation period while irradiated monkeys’ cortical blood flow decreased to 63% of preirradiation levels by 10 minutes postirradiation. A sharp, partial recovery was seen in this group 20 minutes postirradiation followed by a decline to 66% below baseline at 60 minutes postirradiation. Within 10 minutes after irradiation, mean arterial blood pressure was decreased 66% from the preirradiation mean in irradiated animals. A slight recovery was seen at 30 minutes postirradiation, followed by a decline to 71% at 60 minutes postirradiation. There was no significant difference in preirradiation systemic arterial plasma histamine levels of irradiated and sham-irradiated animals. Postirradiation, however, histamine levels ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 113 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION in the irradiated animals were significantly increased at 2 and 4 minutes postirradiation (96.8 and 73.2 times control values). The authors concluded that regional cerebral blood flow decreases postirradiation with the development of hypotension and may be associated temporally with the postirradiation release of histamine. The authors also noted that although a temporal relationship does seem to exist between cortical blood flow and ETI, the presence of other factors must not be excluded. Some chemical factors might be released by irradiation and cause the release of histamine from mast cells, producing ETI by acting as a neurotransmitter in the central nervous system. Durakovic (1986a) studied cardiac function in male Beagle dogs that received 3,000, 6,000, or 10,000 rad of gamma radiation applied bilaterally to the precordium. The electrocardiograms remained normal after irradiation at all dose levels. The atrium, right and left ventricle, and papillary muscle of every dog all showed focal areas of perivasculitis. No evidence of focal necrosis was observed. The left ventricular ejection fraction (LVEF) did not show statistically significant decreases until 58-70 days after the irradiation, when a marked impairment of heart function was finally observed. With regard to cardiovascular effects and external exposure to ionizing radiation, Stavem et al. (1985) reported a case of a 64-year-old male worker who accidentally received a large dose of gamma radiation in a plant that used ionizing radiation for sterilization purposes. He was exposed for only a few minutes. From spectroscopic analyses of electron-spin resonance in irradiated material, the following mean doses were estimated: whole body, 2,250 rad; bone marrow, 2,100 rad; and brain, 1,400 rad. The dose to nitroglycerin tablets that were in the worker's pocket at the time was 4,000 rad. The worker developed an ARS and an autopsy was performed after death. The left ventricle of the heart was hypertrophic and the anterior descending ramus of the coronary artery was markedly stenotic; however, it was not clear whether this was an age-related effect or directly related to the effects of the radiation. In summary, respiratory effects have been reported in humans (Stavem et al. 1985) as well as in laboratory animals (Rezvani et al. 1989; Salovsky and Shopova 1992) exposed to internal and external sources of ionizing radiation. Most research has focused on the effects of ionizing radiation on the lungs when associated with inhaled insoluble (and, to a lesser degree, soluble) particles. Again, these studies were acute, high-dose exposures resulting in high initial lung burdens on the order of several thousand pCi and which resulted in doses in the thousands of rad. After the radioactive material was inhaled, clinical signs were related to the organ system which received the major radiation dose during and after distribution. Soluble particles tended to dissolve in the lung and redistribute, depending on the radionuclide, to the liver or bone to “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 114 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION induce toxic effects in those organ systems. After an initial clearance phase from the lungs, from which a portion of the initial lung burden was transferred to the gastrointestinal tract, the balance of the insoluble particles tended to remain for long periods of time in the lung (several days to several years), irradiating the tissues closest to their immediate lung location and leaving the lungs very slowly. The effect of ionizing radiation on the lungs varied with the dose and length of exposure of the lung tissue. Respiratory insufficiency, manifested clinically as increased respiratory rates, increased abnormal lung sounds, and cyanosis, was a common finding in these studies (Hobbs et al. 1972; Muggenburg et al. 1988), in association with decreased lung volumes, total lung capacity, and compliance (common but not pathoneumonic symptoms of pneumonia) (Muggenburg et al. 1988). These clinical signs are most likely related to inflammatory and fibrotic changes occurring within the lungs. This observation is supported by radiographic, gross, and histopathological evidence, such as increased focal or diffuse radiographic lung-field densities, and by interstitial, perivascular, peribronchial, and pleural fibrosis; emphysema; inflammation; vascular damage; fibrin exudation; congestion; and hemorrhage (Benjamin et al. 1976; Hahn et al. 1976; Lundgren et al. 1991). Radiation pneumonitis, followed by pulmonary fibrosis (fibrosis of alveolar structures involving changes in the ratios of some pulmonary collagens), are two of the most commonly reported aberrations in laboratory animals following the inhalation of substances that emit ionizing radiation (Benjamin et al. 1978, 1979; Brooks et al. 1992; Hahn et al. 1975, 1981; Lundgren et al. 1980a, 1991). The precise mechanism behind the induction of radiation pneumonitis is not currently known; however, a vascular component (comprised of sloughing of dead and dying endothelial cells that may lead to capillary leakage) has been suggested. Damage to type II pneumocytes, which can lead to serious alterations in the amount of surfactant phospholipids and lung inflammation, has also been considered. The role of type I pneumocytes, that by necrosing and sloughing leave denuded basement membranes and alveolar debris, may also be significant. Alterations in cardiovascular functions could not be definitively linked to ionizing radiation after inhalation or external ionizing radiation exposures in laboratory animals (Durakovic 1986a; Hobbs et al. 1972; Muggenburg et al. 1988) or in one man exposed to external ionizing radiation (Stavem et al. 1985); however, some changes in regional cerebral blood flow were noted in one study (Cockerham et al. 1986) that used Rhesus monkeys as a model and these were probably linked to histamine release. It should be emphasized that all of these effects are due to very high radiation doses. Data for respiratory and cardiovascular effects in humans and laboratory animals are summarized in the Observed Health Effects from Radiation and Radioactive Material tables in Chapter 8 of this profile. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 115 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION 3.2.1.7 Ocular Effects The lens of the eye is among the most radiosensitive tissues in the body. Exposure of the lens to sufficient doses of ionizing radiation results in cataract formation, which can range from minimally detectable opacities that do not impair vision to blindness. The target cells in the lens are the epithelial cells on the interior surface of the anterior capsule of the lens. These cells differentiate into lens fibers, which are normally transparent. The function of the lens is to focus the light entering the pupil onto the retina. After exposure to ionizing radiation, these cells fail to divide to produce lens fibers of the appropriate length or transparency. These defective fibers then tend to migrate to the posterior pole of the lens, where they can be seen ophthal- mologically as a small, opaque dot. The appearance of the opacities can appear anytime between 0.5 and 35 years postexposure. Occurrence is affected by the dose, dose rate, and the type and energy of the radiation. Cataracts can be induced with as little as 2 Gy of X-ray irradiation (Adams and Wilson 1993). Data from those victims exposed to large doses of ionizing radiation after the bombings of Hiroshima and Nagasaki show a threshold of 0.6-1.5 Gy of low LET radiation. However, typical human exposures over a long period of time are thought to have a vision impairing threshold greater than 8 Gy (BEIR V 1990). Ham (1953) described the radiogenic cataracts in cyclotron physicists from mixed gamma-neutron doses of 700-1,000 rad to the lens. The effects of ionizing radiation on the eye have been reported in some human exposure cases. Klener et al. (1986) reported on a human case study in which a male technician was accidentally irradiated by a sealed ®°Co source he had been installing. His health status was followed for 11 years after the accident. A film dosimeter worn during the accident indicated it received an exposure of 159 rad, but the dose to his eye was not reported. Changes in the lens of the left eye began to appear gradually, leading to the deterioration of visual acuity. Later, opacities of the lens of the right eye were also found. Schweitzer et al. (1987) exposed Beagle dogs to single, bilateral, whole-body exposures to **Co gamma radiation at various stages during fetal ocular development. Dogs were irradiated during middle or late pregnancy at 28 or 55 days postcoitus (dpc) or as neonates on the second postpartum day (ppd), with mean whole-body doses ranging from 100 to 386 rad (1-3.86 Gy). The dose to the eyes was essentially equivalent to the whole-body dose. For dogs exposed on ppd 2, the most prominent fundic alteration on or before 70 days of age was a reduction in arterioles and a narrowing of the venules. The venules were dull, the tapetal fundus mottled in appearance, the nontapetal fundus lighter in color than controls, the optic disc paler, and the eyes characterized by a generalized slight haziness of the ocular media. Dogs sacrificed at 2-4 years ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 116 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION of age had more marked reductions in arterioles and attenuation of the venules. Tapetal hyperreflectivity was found, and homogeneity was often lost in affected eyes. General and focal degenerative lesions were evident as were color changes. Partial tapetal atrophy with increased pigmentation in the area previously occupied by tapetum was noted in some eyes. Loss of color and hyperreflectivity were related to focal loss of pigment and thinning of atrophic retinal foci. With severe retinal atrophy or degeneration, choroidal circulation was seen in the nontapetal fundus. Retinal lesions were progressive in severity and extent, and the degree of injury was similar for both eyes. A correlation was seen between lesions (mostly in the retina and lens) and radiation treatment, with respect to both age at exposure and radiation dose. Due to fixation and sectioning artifacts, most lenses couldn't be adequately evaluated histopathologically. Retinal dysplasias and atrophy were the most striking lesions seen. The stage of development at exposure had a marked effect on the distribution of retinal lesions. The most severe changes were seen in the portion of the retina undergoing differentiation at the time of the insult. In dogs sacrificed at 70 days of age, the lesions were primarily dysplasias, consisting of ectopic nuclear aggregates in the photoreceptor layer, retinal folds, and retinal rosettes. With increasing age, there appeared to be progression of the extent of the clinically evident lesions, and there was a change in the nature of the lesions from dysplasia to atrophy. This was accompanied by marked attenuation of the retinal vasculature. In dogs exposed on ppd 2, retinal degeneration was evident in all dogs sacrificed at 70 days, 2 years, or 4 years of age. Retinal dysplasias were evident in all dogs sacrificed at 70 days of age and in 4 of the 13 dogs sacrificed at 2 years. Retinal dysplasia was not evident in dogs sacrificed at 4 years. Atrophy in dogs exposed on ppd 2 was evident in 19 of the 20 dogs sacrificed at 70 days of age and in all dogs sacrificed at 2 and 4 years of age. Dysplasias included focal aggregates of nuclei in the rod and cone layer, retinal folds, and retinal rosettes. Atrophic changes included altered rosettes, as well as the rest of the retina, loss of rods and cones, and/or thinning of inner and outer nuclear layers. These lesions were bilateral and focal-to-diffuse in nature. They increased in severity with increasing radiation dose. In dogs exposed on ppd 2, central retinal lesions only were seen in 1 of the 20 dogs sacrificed at 70 days of age. None were seen in dogs sacrificed at 2 or 4 years. Central and peripheral retinal lesions were seen in 19 of the 20 dogs and in all dogs sacrificed at 70 days and at 2 or 4 years, respectively. In summary, ocular effects have been reported in both humans and laboratory animals after exposure to ionizing radiation. These effects range from mild opacities of the lens to cataract formation and alterations in both the posterior chamber of the eye and of the retinal structures. The effects are not immediate, and in people may occur several years after the initial exposure. “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 117 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION 3.2.1.8 Dermal Effects A transient erythema, the earliest sign of overexposure of the skin, occurs after a dose of about 300 rad. The erythema appears several hours after exposure, and disappears within a day. Much greater radiation doses lead to a second erythema several weeks later, which lasts for about a month. Greater doses lead to loss of hair, peeling of the skin (dry desquamation), blistering (wet desquamation), ulceration, and necrosis (Potten 1985). The USNRC limit for occupational exposure of the skin is 50,000 millirad. As with the ocular tissues, parts of the dermal system are also quite susceptible to the effects of ionizing radiation. Dermal lesions have also been described after internal or external radiation exposures. The skin has a susceptible cell population sensitive to the effects of ionizing radiation. The target cells are those comprising the germinal cells of the skin (stratum germinativum), also known as the basal cell layer, which is itself affected by the thickness of the various skin layers of the epidermis. Normally, the basal cells give rise to the outer layers of the skin (stratum granulosum, stratum lucidum, etc.) and finally form the outmost protective dead layer of the skin, the stratum corneum. The effects of ionizing radiation on the skin are directly proportional to the dose received by this germinal cell layer and to the type of radiation received. Alpha particles that deposit on the skin surface (stratum corneum) have little effect, given the short penetration range of this type of radiation. The bulk of the dose is absorbed by the stratum corneum, comprised of dead cells, phospholipids, waxes, and other large complex molecules (Riviere and Spoo 1995). Beta and gamma radiation, which can penetrate deeper to live cell layers, can produce erythema, indicating a vascular component manifested by vasodilation and probably mediated by histamine or other inflammatory mediators. As the dose increases, epilation, dry and/or moist desquamation, and necrosis can occur. The threshold dose of gamma radiation in humans required to produce skin erythema over an area of 10 cm? is 600-800 rad (6-8 Gy) for single doses and 3,000 rad (30 Gy) for multiple (fractionated) doses (Adams and Wilson 1993). The threshold dose increases with decreasing area of the irradiated skin. The dermis is less severely affected, given its population of less active cells, connective tissue, sebaceous glands, and nerve fibers. However, the endothelial cells associated with the dermal blood vessels are somewhat more susceptible and may play a role in the production of erythema after receiving doses of ionizing radiation. The long-term effects on the skin after receiving over 1,000 rad (10 Gy) of ionizing radiation include pigmentation, epidermal atrophy, dermal fibrosis, and atrophy of several dermal and epidermal structures, such as sweat and sebaceous glands and hair follicles. Hahn et al. (1975) reported the effects of ionizing radiation on the skin of Beagle dogs after inhalation exposure to *°Y in FAP. Four of the 7 dogs exposed to 14-22 mCi initial lung burden (32-40 mCi whole-body burden) developed a nasal dermatitis. Hobbs et al. (1972) observed dose-related clinical, ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 118 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION hematological, serum chemical, and pathological alterations more than 1 year postexposure in 33 Beagle dogs exposed to initial lung burdens of 3,600, 1,800, 1,200, 780, 400, 210, 110, and 0 uCi *°Y/kg body weight. Patches of radiation alopecia were found on the dorsum of the nose of four animals that died 70-91 days postexposure. These patches were characterized by a thinning of the outer epidermal layer of the skin, atrophy, and loss of hair follicles and hair shafts. Dermal collagen seemed unaffected. Nasal dermatitis, however, is unlikely to occur in humans for two reasons. First, these animals were exposed to very high activities of *°Y that are essentially out of the realm of possibility for humans. Second, these effects are likely to occur in animals with long snouts or muzzles Syrian golden (23) and white (24) hamsters (8 weeks of age) were exposed to a 8Kr source that was in direct contact with the skin. Delivered doses ranged from 2,000 to 10,000 rad (495 rads/min). Within 24 hours after radiation, erythematous reactions developed and persisted for several days postexposure. At sites where larger doses were applied, severe radiation dermatitis developed and sometimes resulted in ulcerative changes in the epidermis. Permanent epilation resulted at doses of 10,000 rad, and doses of 4,000 rad induced temporary epilation up to the 17th week in all males and most of the females. Growth of grey hair was subsequently observed in the exposed areas of all animals in the 4,000 rad dose group. Females receiving 2,000 rad showed about 12 weeks of epilation followed by growth of grey hair in most of them. Some males showed epilation for a short period of time, and the rest of the males showed initial and transient periods of epilation followed by growth of normal hair. Complete epilation occurred in white hamsters receiving 4,000 and 10,000 rad and recuperation of hair growth in these animals was not observed. A short period of epilation was observed, followed by growth of normal hair in animals exposed at the 2,000-rad level. Few animals showed complete epilation preceded or interrupted by periods of growth of normal hair. No spreading of the hair-greying effect of beta particles was observed in this experiment (Garcia and Shubik 1971). Similar results were found in pigs, whose skin is considered to be most like that of humans. Hopewell et al. (1986) studied the dose-response relationship as a function of an irradiated area of the skin by irradiating an area of skin in 3-4 month old large white pigs with *°Sr, "Tm, or '*’Pm sources, using different size radionuclide sources. These radionuclides emit beta particles with energies of 0.55, 0.97, and 0.22 MeV that can penetrate 2, 4, and 0.5 mm of tissue, respectively, compared with 0.007 mm for the stratum corneum. The size of the sources varied from 1 to 40 mm for %8r, from 0.1 to 19 mm for Tm, and from 2 to 15 mm for Pm. In the porcine model, the ED; values for moist desquamation for *’Sr varied from 2,750 rad for the 22.5-mm diameter source to 7,500 rad for the 5-mm source. An increase in source diameter to 40 mm did ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 119 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION not significantly change the EDs, value from that obtained with a 22.5-mm source. '*Tm irradiation in the pig produced no distinct area effect for sources 5-19 mm in diameter (EDs, for moist desquamation ~8,000 rad). Acute tissue necrosis was only achieved in pig skin by very high doses (ED; > 14,000 rad) from sources <2 mm in diameter. Irradiation of pig skin with ¥’Pm produced acute epithelial breakdown but only after high skin-surface doses (EDs, 55,000-72,500 rad for 15-2 mm sources). In a similar experiment, Hopewell et al. (1986) exposed SAS/4 randomly-bred male mice, 11-12 weeks old to *°Sr, Tm, and '*’Pm, again with the sources varying in size. *°Sr and "Tm exposure in the mouse resulted in a distinct field-size effect for sources 5-22.5 mm in diameter; the EDs, values for moist desquamation were 2,200-2,750 rad for the 22.5-mm source and 7,500-9,000 rad for the 5-mm source. There was a distinct source size effect; the EDj, values decreased as the source diameter increased. Acute tissue breakdown was only achieved in mouse skin by very high doses (EDs, > 14,000 rad) from sources of <2 mm in diameter from both types of beta emitters. The large differences in doses required to produce the same effect from the same size source by these three radionuclides may be due to differences in penetrating power. The lower energy beta particles deposit a larger portion of their dose in the dead layers of the stratum corneum, compared with live tissue, so the actual live tissue doses may be comparable for these radionuclides. A study by Song et al. (1968) examined the efficacy of several anti-inflammatory agents on the suppression of the early increase in radiation-induced vascular permeability to plasma protein in guinea pigs (radio- dermatitis is one limiting factor in radiation therapy because the skin is the first in line for exposure to absorb the energy). Albino male guinea pigs were exposed to 3,000 rep (1 rep=1 rad) of particles (750 rad/min) from a *°Sr and *°Y source. Immediately after irradiation, '*’I-labeled guinea pig serum albumin (15 pCi in 0.15-0.20 mL of saline) was injected into the blood. The peak increase in accumulation of vascular permeability as measured by plasma protein between the control and the 3,000-rad beta-irradiated skin was determined to occur at 18 hours. A significant increase in vascular permeability occurred in the control group receiving no anti-inflammatory drug, as demonstrated by an approximately 3- and 1.6-fold increase in the 18-hour accumulation of plasma protein in the irradiated epidermis and dermis, respectively. External exposure to ionizing radiation shows similar results in humans. Birioukov et al. (1993) reported on a case study in which 12 men developed different forms and stages of chronic radiation dermatitis caused by accidental exposure to beta and gamma radiation during and after the Chernobyl nuclear power plant accident. Nine of the men were close enough to the accident to receive doses ranging from 350-550 rad (2-3.5 Gy). Three men received doses ranging from 200-350 rad: two had worked in the contaminated zone for 2 months to 3 years and one was inside the power plant during the accident. All the men were diagnosed ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 120 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION with ARS of varying severity after the accident. All the men except one had chronic radiation dermatitis on the upper and lower extremities. The other patient had slight radiation dermatitis on the neck. Klener et al. (1986) reported another human case study in which a male technician was accidentally irradiated by a sealed 3,000 Ci (110 TBq) ®Co telotherapy source which he had been installing. A film dosimeter he was wearing during the accident indicated a dose of 159 rad; however, his whole body was highly non- uniformly irradiated. His health status was followed for 11 years after the accident. Eight days after the accident, he developed severe skin changes on the left hand (reddening and painful inflammation) that are not compatible with a dose of 159 rad. Clearly, his left hand (he was left-handed) suffered a very much greater dose than that shown on his film badge. Since he was left-handed, it seems likely that he severely over- exposed his left hand during his several unsuccessful attempts, and his final successful attempt, to place the source back into the container with improvised tools. He also suffered epilation in a small area of the left temporal region, with minor deviations in peripheral blood counts. In the following year, repeated surgery due to secondary skin defects of the left hand resulted in the loss of the second through fifth fingers; effects included serious trophic changes characterized by a smoothed discolored skin, hard swelling of deep skin layers, and disturbed local blood flow. In laboratory animal studies, Hulse (1966) exposed albino hairless mice to 750-1,500 rad of **Tl radiation (0.77 MeV beta particles) to determine if a nonepilating dose produced skin erythema. No visible changes in the skin of albino hairless mice were observed with a 750-rad exposure. Only slight erythema was noted in the 1,500-rad animal groups. Using slightly higher doses, Etoh et al. (1977) irradiated male albino guinea pigs at a total of 6 sites per animal. Maximum cell loss of recognizable basal cells of 20% on day 8, 60% on day 12, and 75% on day 15 occurred after irradiation with 1,000, 2,200, and 3,000 rad, respectively. The data for the 5,000-rad exposure were similar to data for 3,000 rad. Regeneration occurred from survivors within the irradiated area after 1,000 and 2,200 rad, and was completed in 5 days. No hyperplasia was seen at 1,000 rad, but a long-lived hyperplastic epidermis resulted after the higher doses. Lefaix et al. (1993) exposed large white pigs to a single dose of 12,000, 16,000, or 25,600 rad (120, 160, or 256 Gy) applied to the outer side of the right thigh; in another group, some animals were given single doses of 1,600, 3,200, 4,800, 6,400, 8,000, and 9,600 rad (16, 32, 48, 64, 80, and 96 Gy) applied to the back skin. Data were collected 30 weeks after exposure. No change in the skin surface was observed following an exposure of 1,600 rad (16 Gy). After a 3,200-rad (32 Gy) exposure, erythema was observed. After 4,800 rad (48 Gy), desquamation of the epidermis developed at the 12th week post-irradiation. At 6,400, 8,000, and 9,600 rad (64, 80, and 96 Gy) all showed a moderate erythema in the first 3-4 days, a distinct erythema after ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 121 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION 3-5 weeks, and moist desquamation after 7-12 weeks. Skin necrosis was observed during the 5th week following exposure to 12,000 and 16,000 rad (120 and 160 Gy), and cutaneous and muscular ulceration during the 6th week. The highest dose of 25,600 rad (256 Gy) caused skin necrosis at the end of the second week and well-delimited ulceration by the third week. After exposures of 12,000, 16,000, and 25,600 rad (120, 160, and 256 Gy), which all induced skin and skeletal muscle ulceration, and 6,400, 8,000, and 9,600 rad doses, which induced dried exudate crusts, damaged skeletal muscles healed by replacement fibrosis and scar formation. It should be noted that the 0.77 MeV “Tl beta particles can penetrate 300 mg/cm? of material, or approximately 0.3 cm of tissue, which is enough to penetrate all layers of the skin and continue to penetrate into the skeletal muscle. In summary, the dermal effects attributed to ionizing radiation appear to follow a dose-response curve (Etoh et al. 1977; Hulse 1966; Lefaix et al. 1993). Ionizing radiation affects the deep, rapidly multiplying cells of the epidermis (basal cells), which are at a mean depth of 0.007 cm below the outer surface layer of dead cells and which are responsible for the production of the more superficial layers of the epidermis. These basal cells are affected by ionizing radiation in a dose-responsive fashion as demonstrated. Other cells within the epidermis that multiply rapidly, such as cells that surround the hair follicle, can also be affected by ionizing radiation, resulting in epilation. Dermal effects of ionizing radiation seem to be most common after either a direct dermal exposure to a beta or gamma emitter or after external exposure scenarios; alpha emitters, due to their short penetration range, do not penetrate the upper, dead layers of the epidermis (stratum corneum). A clear dose-response relationship to the effects of ionizing radiation to the skin as a whole was demonstrated in humans and in animals. In humans, the earliest response is a mild, transitory erythema that appears several hours after a dose of about 300 rad (3 Gy). Responses ranged from mild epilation that led to the return of normal hair growth at a dose of 2,000 rad, to ulcerative dermatitis and permanent epilation at doses up to 10,000 rad (Garcia and Shubik 1971). Moist desquamation occurred in pigs dosed with 2,250-7,500 rad and acute tissue necrosis occurred at doses of 14,000 rad and above (Hopewell et al. 1986). Erythema and epilation, followed by serious trophic changes and altered skin blood flow, have also been reported in a man whose film badge showed a dose of 159 rad; however, the affected areas on the hand received a much higher dose than that reported on the film dosimeter (Klener et al. 1986). Men exposed to external ionizing radiation sources (200-550 rad) in the Chernobyl reactor accident also developed chronic dermatitis as a result of exposures to ionizing radiation. Data for dermal and ocular effects in humans and laboratory animals are summarized in the Observed Health Effects from Radiation and Radioactive Material tables in Chapter 8 of this profile. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 122 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION 3.2.1.9 Genotoxic Effects The scientific literature contains abundant information on the genotoxic effects of all forms of ionizing radiation from multiple routes of exposure. Several representative studies are summarized in Tables 3-4 and 3-5 that demonstrate the genotoxic end points that can be induced due to exposure(s) to ionizing radiation using in vivo and in vitro testing systems. However, it must be emphasized that genetic effects of radiation have never been seen in any human population exposed to any level of radiation. The data presented in Tables 3-4 and 3-5 show that genotoxicity is a major toxicological end point for exposure to ionizing radiation; specific end points consist of chromosomal aberrations and breaks, reciprocal translocations, deletions, sister chromatid exchanges, dominant lethal mutations, sperm anomalies, and mutations. DNA is a major target molecule during exposure to ionizing radiation; however, those alterations largely relate back to effects on the DNA molecule itself (see Chapter 5). Other macromolecules, such as lipids and proteins, are also at risk of damage when exposed to ionizing radiation. The genotoxicity of ionizing radiation is an area of intense study, as damage to the DNA is ultimately responsible for many of the adverse toxicological effects described so far in this chapter. Cells depend on their DNA for coding information to make specific enzymes, proteins, hormones, vasoactive substances, and a host of other chemicals in order to live. When the genetic information containing the “blueprint” for these substances is disturbed, cell homeostasis is disrupted, resulting in a wide-range of immediate and/or delayed toxicological effects in a number of organ systems, as described earlier in this chapter. Disruptions and changes of the cellular genome are also thonght to be responsible for the formation of cancer in both humans and laboratory animals. There are two types of interactions that ionizing radiation can have with the cellular DNA to produce the effects seen in Tables 3-4 and 3-5. These interactions can be classified as direct and indirect interactions. Direct interactions with DNA (as well as other macromolecules) involve an alpha particle, beta particle, or gamma ray knocking an electron out of the DNA molecule through an ionizing collision. This can break the intramolecular chemical bond that contains the vital information that must be transmitted to the daughter cells. Complete repair is normally expected, but if the damage goes unrepaired, the information encoded in the DNA structure is distorted, and faulty information is transmitted to the daughter cells during mitosis. These effects can result in the genetic effects listed in Tables 3-4 and 3-5. Indirect interactions of ionizing radiation with DNA are similar. Ionizing radiation here has no direct contact with the DNA; instead it interacts with smaller molecules, especially water, surrounding the DNA to produce highly reactive radicals ***DRAFT FOR PUBLIC COMMENT*** +»INIWWOD O119Nd HOS L4VHQ ux Table 3-4. Genotoxicity of lonizing Radiation /n Vivo Species (test system) End point Results Reference Radionuclide ALPHA PARTICLES Mammalian cells: Human peripheral blood Chromosomal aberrations + Pohl-Ruling and Fischer 1979 [222]Rn (E) lymphocytes Human peripheral blood Chromosome aberrations + Sasaki et al. 1987 [232]Th (I) lymphocytes Human peripheral blood Chromosome aberrations + Steinstrasser 1981 [232]Th (I) lymphocytes Monkey peripheral blood Chromosome aberrations + Brooks et al. 1992 [239]Pu (I) lymphocytes Monkey peripheral blood Chromosome aberrations + LaBauve et al. 1980 [239]Pu (I) lymphocytes Mouse germ cells (male) Chromosomal aberrations + Beechey et al. 1975 [239]Pu (1) Mouse germ cells (male) Chromosome fragmentation + Pomerantseva et al. 1989 [238]Pu (I) Mouse germ cells (male) Heritable reciprocal translocations + Generoso et al. 1985 [239]Pu (I) Mouse germ cells (male) Reciprocal translocations + Grahn et al. 1983 [239]Pu (I) Mouse germ cells (male) Reciprocal translocations + Pomerantseva et al. 1989 [238]Pu (I) Mouse germ cells (male) Reciprocal translocations + Searle et al. 1976 [238]Pu (I) Mouse germ cells (male) Dominant lethal mutations + Pomerantseva et al. 1989 [238]Pu (I) Mouse germ cells (male) Dominant lethal mutations + Searle et al. 1976 [238]Pu (I) Mouse Sperm abnormalities + Beechey et al. 1975 [239]Pu (I) Mouse Sperm abnormalities + Pomerantseva et al. 1989 [238]Pu (I) Mouse Sperm abnormalities + Searle et al. 1976 [238]Pu (I) BETA PARTICLES Invertebrate animal cells: Drosophila melanogaster (male) Large deletions + Fossett et al. 1994 HTO: [3]H (I) Plants: Brassica campestris T10 and Chromosome aberrations + Dasgupta 1970 [32]P, [35]S (E) T151 Vicia faba Chromosome breakage + Lazanyi 1965 [90]Sr-[90]Y (E) V. faba Sister chromatid exchange _ Kuglik and Slotova 1991 [BIH (I) V. faba Micronuclei + Kuglik and Slotova 1991 [31H (1) NOILYIAVH ONIZINOI 40 S103443 HLIVIH 40 AHVWANS '€ NOILYIAV4d ONIZINOI ech «»+LNJWWOD O178Nd HOS 14VHAuxx Table 3-4. Genotoxicity of lonizing Radiation In Vivo (continued) lymphocytes Species (test system) End point Results Reference Radionuclide Mammalian cells: Mouse liver cells Chromosome aberrations + Brooks et al. 1976 HTO: [3H (1) Mouse skin cells Unscheduled DNA synthesis + Ootsuyama and Tanooka 1986 [90]Sr-[90]Y (E) Mouse germ cells (male) Reciprocal translocations + Ramaiya et al. 1994 [137]Cs (I) Mouse germ cells (male) Reciprocal translocations + Shevchenko et al. 1989 [13111 (1) Mouse germ cells (male) Dominant lethal mutations + Ramaiya et al. 1994 [137]1Cs (I) Mouse germ cells (male) Dominant lethal mutations + Shevchenko et al. 1989 [13111 (1) Mouse germ cells (female) Dominant lethal mutations + Zhou et al. 1986 HTO: [3H (I) Mouse Sperm abnormalities + Shevchenko et al. 1989 [13171 (1) GAMMA RAYS: Vicia faba Chromosome breakage Lazanyi 1965 [60]Co (E) V. faba Sister chromatid exchange + Kuglik and Slotova 1991 [60]Co (E) V. faba Micronuclei + Kuglik and Slotova 1991 [60]Co (E) Mammalian cells: Human peripheral blood Chromosome aberrations + Bigatti et al. 1988 NS (E) lymphocytes Human peripheral blood Chromosome aberrations + Klener et al. 1986 [60]Co (E) lymphocytes Human peripheral blood Chromosome aberrations + Lloyd et al. 1994 [192]ir (E) lymphocytes Human peripheral blood Chromosome aberrations + Milkovic-Kraus et al. 1992 [60]Co (E) lymphocytes Human peripheral blood Chromosome aberrations + Natarajan et al. 1991 [137]Cs (E) lymphocytes Human peripheral blood Chromosome aberrations + Padovani et al. 1993 [137]Cs (E&l) lymphocytes Human peripheral blood Chromosome aberrations + Pohl-Ruling and Fischer 1979 NS (E) lymphocytes Human peripheral blood Chromosome aberrations + Stavem et al. 1985 NS (E) lymphocytes Human peripheral blood Chromosome aberrations + Stram et al. 1993 NS (E) NOILVYIAVd ONIZINOI 40 S103443 HLTV3IH 40 AHVNANS '€ NOILYIAV4d ODNIZINOI vel «»+LNIJWWOD O1789Nd HOH L4VHuxs Table 3-4. Genotoxicity of lonizing Radiation /n Vivo (continued) Species (test system) End point Results Reference Radionuclide Human bone marrow Chromosome aberrations + Stavem et al. 1985 NS (E) Chinese hamster liver cells Metaphase chromosomal + Brooks et al. 1971a, 1971b [60]Co (E) aberrations Mouse bone marrow (maternal) Chromosome breaks Ricoul and Dutrillaux 1991 [60]Co (E) Mouse fetal liver cells Chromosome breaks + Ricoul and Dutrillaux 1991 [60]Co (E) Human peripheral blood Reciprocal translocations + Maes et al. 1993 NS (E) lymphocytes Monkey germ cells (male) Reciprocal translocations + Tobari et al. 1988 [137]Cs (E) Mouse germ cells (male) Reciprocal translocations + Bayrakova et al. 1987 [60]Co (E) Mouse germ cells (male) Reciprocal translocations + Deluca et al. 1988 [60]Co (E) Mouse germ cells (male) Reciprocal translocations + Gilot-Delhalle et al. 1988 [60]Co (E) Mouse germ cells (male) Reciprocal translocations + Grahn and Carnes 1988 [60]Co (E) Mouse germ cells (male) Reciprocal translocations + Grahn et al. 1983 [60]Co (E) Mouse germ cells (male) Reciprocal translocations + Ramaiya et al. 1994 [137]Cs (E) Mouse germ cells (male) Reciprocal translocations + Searle et al. 1976 [60]Co (E) Mouse germ cells (male) Reciprocal translocations + Shevchenko et al. 1992 NS (E) Mouse germ cells (male) Dominant lethal mutations + Ramaiya et al. 1994 [137]Cs (E) Mouse germ cells (male) Dominant lethal mutations + Searle et al. 1976 [60]Co (E) Mouse germ cells (female) Dominant lethal mutations + Zhou et al. 1986 [60]Co (E) Mouse Sperm abnormalities + Grahn and Carnes 1988 [60]Co (E) Mouse Sperm abnormalities + Searle et al. 1976 [60]Co (E) Mouse Sperm abnormalities + Shevchenko et al. 1992 NS (E) Mouse bone marrow Micronuclei + Abraham et al. 1993 [60]Co (E) Mouse thymocytes DNA fragmentation + Sellins and Cohen 1987 [60]Co (E) Mouse liver cells DNA fragmentation _ Sellins and Cohen 1987 [60]Co (E) Pig skin fibroblasts Abnormal karyotypes + Sabatier et al. 1992 [192]Ir (E) + = Positive result; — = Negative result; (E) = External dose, ( I) = Internal dose; HTO = tritiated water. NOILYIAv4d ONIZINOI 40 S103443 HLTVIH 40 AHVWNINNS '€ NOILYIAVv4d ONIZINOI Sct Table 3-5. Genotoxicity of lonizing Radiation In Vitro »+LNFWWNOD O178Nd HOH L4VHQuxs Result Species (test system) End point With activation Without activation Reference Radionuclide ALPHA PARTICLES Prokaryotic organisms: Escherichia coli DNA double-strand breaks ND Wilkins 1971 [241]Am E. coli DNA single-strand breaks ND + Wilkins 1971 [241]Am Mammalian cells: Human peripheral blood lymphocytes Chromosome aberrations ND + DuFrain et al. 1979 [241]Am Human peripheral blood lymphocytes Chromosome aberrations ND + Fajgelj et al. 1991 [235]U Human peripheral blood lymphocytes Chromosome aberrations ND + Purrott et al. 1980 [238]Pu Human peripheral blood lymphocytes Chromosome aberrations ND + Takatsuji and Sasaki 1984 NS Human peripheral blood lymphocytes Chromosome aberrations ND + Takatsuiji et al. 1989 NS Human peripheral blood lymphocytes Chromosome aberrations ND + Wolff et al. 1991 [226]Ra Mouse bone marrow Chromosome aberrations ND + Kadhim et al. 1992 [238]Pu Mouse 10T1/2, 3T3 cells Chromosome aberrations ND + Nagasaswa et al. 1990a [238]Pu Chinese hamster ovary cells, K-1 Chromosome aberrations ND + Nagasawa et al. 1990b [238]Pu Human fibroblasts Chromosome breaks ND + Loucas and Geard 1994 NS Chinese hamster M3-1 cells Chromosome damage ND + Welleweerd et al. 1984 [238]Pu Human AT2BE cells and normal DNA double-strand breaks ND + Coquerelle et al. 1987 [241]Am fibroblasts Ehrlich ascites tumor cells DNA double-strand breaks ND + Blocher 1988 NS Chinese hamster cells, V79-4 DNA double-strand breaks ND Jenner et al. 1993 [238]Pu Human peripheral blood lymphocytes Sister chromatid exchange ND Aghamohammadi et al. [238]Pu 1988 Mouse 10T1/2, 3T3 cells Sister chromatid exchange ND Nagasawa et al. 1990a [238]Pu Chinese hamster ovary cells, K-1 Sister chromatid exchange ND + Nagasawa et al. 1990b [238]Pu Chinese hamster V79 cells Mutations ND Thacker 1986 NS NOILYIAV4 ONIZINOI 40 S103443 HLTVIH 40 AHYWNINNS '€ NOILYIAvd ONIZINOI 9cl Table 3-5. Genotoxicity of lonizing Radiation In Vitro (continued) NOILYIAv4d ONIZINOI »+LNFWWNOD O178Nd HOS 14VHQuxs Result Species (test system) End point With activation Without activation Reference Radionuclide BETA PARTICLES Eukaryotic organisms: Fungi: Saccharomyces cerevisiae PG-60 Mitotic recombination ND + Gracheva and Korolev [32]P 1974 Mammalian cells: Human peripheral blood lymphocytes Chromosome aberrations ND + Bocian et al. 1977 HTO: [3]H Human peripheral blood lymphocytes Chromosome aberrations ND + Ribas et al. 1994 HTO: [3]H Human peripheral blood lymphocytes Chromosome aberrations ND + Tanaka et al. 1994 HTO: [8H Human peripheral blood lymphocytes Chromosome aberrations ND + Vulpis 1984 HTO: [3]H Human peripheral blood lymphocytes Chromosome aberrations ND + Vulpis and Scarpa 1986 [90]Sr Human bone marrow cells Chromosome aberrations ND + Tanaka et al. 1994 HTO: [3]H Human spermatozoa and zona-free Chromosome aberrations ND + Kamiguchi et al. 1990 HTO: [3]H hamster oocytes fertilization system Human spermatozoa Chromosome aberrations ND + Mikamo et al. 1990, 1991 HTO: [3]H Human bone marrow cells Chromatid aberrations ND + Tanaka et al. 1994 HTO: [3]H Chinese hamster ovary cells DNA single-strand breaks ND + Cleaver 1977 [BIH Chinese hamster ovary cells DNA strand breaks ND + Dikomey and Franzke [3H 1986 Human peripheral blood lymphocytes Sister chromatid exchange ND + Crossen and Morgan [3H 1979 Human peripheral blood lymphocytes Sister chromatid exchange ND _ Ribas et al. 1994 HTO: [3]H Chinese hamster ovary cells Sister chromatid exchange ND + Roberts et al. 1987 [31H GAMMA RAYS Prokaryotic organisms: Escherichia coli K12 DNA double-strand breaks ND + Krisch et al. 1976 [125]1 Mammalian cells: Human peripheral blood lymphocytes Chromosome aberrations ND + Doggett and McKenzie [137]Cs 1983 Human peripheral blood lymphocytes Chromosome aberrations ND + Fajgelj et al. 1991 [235]U NOILYIAVH DNIZINOI 40 S103443 HLTVAH JO AHVWANS '€ Le) +»+INIWWNOD O178Nd HOH L4VH ux Table 3-5. Genotoxicity of lonizing Radiation In Vitro (continued) Result Species (test system) End point With activation Without activation Reference Radionuclide Human peripheral blood lymphocytes Chromosome aberrations ND Hintenlang 1993 [137]Cs Human peripheral blood lymphocytes Chromosome aberrations ND + lijima and Morimoto 1991 [137]Cs Human blood peripheral lymphocytes Chromosome aberrations ND + Tanaka et al. 1994 [60]Co Human blood peripheral lymphocytes Chromosome aberrations ND + Tanaka et al. 1994 [137]Cs Human blood peripheral lymphocytes Chromosome aberrations ND + Rueff et al. 1993 [60]Co Human blood peripheral lymphocytes Chromosome aberrations ND + Xiao et al. 1989 NS Human bone marrow cells Chromosome aberrations ND + Tanaka et al. 1994 [60]Co Human spermatozoa Chromosome aberrations ND + Mikamo et al. 1990, 1991 [137]Cs Human bone marrow cells Chromatid aberrations ND + Tanaka et al. 1994 [60]Co Human blood peripheral lymphocytes DNA strand breaks ND + Rueff et al. 1993 [60]Co Human lung carcinoma lines (HC12, DNA double-strand breaks ND + Cassoni et al. 1992 [60]Co HX149, HX147A7, HX148G7) Human AT2BE cells and normal DNA double-strand breaks ND + Coquerelle et al. 1987 [60]Co fibroblasts Mouse (BALB/c, SC3T3/W, Scid/St DNA double-strand breaks ND + Biedermann et al. 1991 [137]Cs cells) Chinese hamster cells, V79-4 DNA double-strand breaks ND Jenner et al. 1993 [60]Co Mouse thymocytes DNA fragmentation ND Sellins and Cohen 1987 [60]Co Human peripheral blood lymphocytes Sister chromatid exchange ND _ lijima and Morimoto 1991 [137]Cs Human spermatozoa and zona-free Micronuclei ND + Kamiguchi et al. 1991 [137]Cs hamster oocytes fertilization system Chinese V79 hamster cells Mutations ND + Thacker 1986 [60]Co NA = not applicable; ND = no data; — = negative results; + = positive results NOILVIQVH ONIZINOI 40 S103443 HLTV3H 40 AHVWINNS °C NOILYIAv4d ODNIZINOI 8cl IONIZING RADIATION 129 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION and ions, and the end-products of this reaction diffuse away from the site of interaction with the ionizing radiation and interact of the DNA breaking its molecular bonds just as with direct radiation. Misrepair and replication can then produce the adverse effects listed in Tables 3-4 and 3-5. More specific information about how ionizing radiation produces its effects on DNA and other macromolecules is presented in Chapter 5 of this profile. Regardless of the method (direct or indirect), the structure of the DNA molecule is damaged after exposure to ionizing radiation. Significant amounts of damage result in part or all of the DNA being rendered unusable for gene coding of essential enzymes, proteins, and other essential molecule formation through RNA pathways, as well as the inability of the DNA to successfully replicate during mitosis. DNA base damage is the most predominant type of DNA damage, followed (in decreasing order of incidence) by single strand breaks (which are four times more prevalent than base lesions), DNA-protein cross-linkages, and double- strand breaks. At the molecular level, an important type of change to DNA that is frequently produced by ionizing radiation is the removal of a base, forming an apurinic or apyrimidinic site. The deletion or total destruction of DNA bases, destruction of deoxyribose residues, and deamination of cytosine or adenine are but a few of the many ways ionizing radiation can alter the DNA at a molecular level. Minor damage left unrepaired or damage that was not completely or correctly repaired can result in mutations. A more in-depth discussion of the alterations at the DNA level by ionizing radiation, including some DNA repair mechanisms, are presented in BEIR V (1990) and in Chapter 5. Damage to genetic material in an organism may have one of several outcomes. First, enough damage can cause cell death. Second, the genetic material may be repaired by the cell’s native DNA repair mechanisms. If the damage is small and the DNA can be repaired correctly prior to the cell dividing, no adverse effects are likely to come from the genetic damage. Chromosomal repair mechanisms have likely existed since life began and our knowledge of these mechanisms has existed for many years. Without these repair mechanisms, the normal damage that occurs to the entire organisms's DNA every day spontaneously, and from other sources, such as mutagenic chemicals and background radiation, could be lethal. Chromosomal repair mechanisms provide a mechanism for minimizing the adverse DNA effects of ionizing radiation on the genome, providing that the dose of radiation is not so large as to overwhelm them. If the damage is reparable and the cell divides prior to the repair process taking place, or if the damage is so extensive it cannot be repaired by the normal mechanisms, the cell may die via apotosis or necrosis. The results range from no apparent effect on the organs if few or scattered cells die to the obvious consequences in damaged tissues at higher doses. Another alternative is that the DNA damage is not repaired, the cell lives and carries out its ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 130 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION normal functions, and then divides to produce progeny cells. If the progeny cells die, then the mutational event is considered a lethal mutation with no consequences. If the progeny cells live, then the cells will likely carry these genetic mutations forward into all future daughter cells. In-depth reviews of these mutation processes and their impact on the induction of cancer in animals and humans are available (Hoffman 1996; Pitot III and Dragan 1996; Sanders 1983; Sanders and Kathren 1983). If the cell survives the genetic damage induced by ionizing radiation and carries the mutations into future cell populations, two events can take place. First, the cell may carry the DNA defect and express an adverse event, such as altered protein and enzyme synthesis and defects in cellular metabolism. These defects can be numerous, depending largely on where on the genome the mutation takes place and how critical the normal gene is to normal cell function. The second event is multi-stage carcinogenesis, which is discussed in more detail later in Chapter 5. Both somatic and reproductive cell chromosomes are target tissues which can sustain damage after exposure to ionizing radiation. Damage to the human genome in exposed populations of humans has potentially serious implications. If genetic damage occurs in the reproductive cells (sperm and ova), this may result in decreased fertility, malformed fetuses, and certain hereditary diseases. These effects have been observed in animal studies but long-term follow-up of radiation-exposed human populations has not identified any genetic effects. As shown in Table 3-6, genetic diseases occur spontaneously (naturally) in approximately 5% of the population (excluding genetic contributions to heart, cancer, and other selected human diseases). Before one begins to determine whether human genetic damage can be caused by exposure to increasing doses of ionizing radiation, it is necessary to know what the normal, spontaneous, or “background” rates of genetic diseases are in the human population exposed to ambient levels of ionizing radiation. Several investigators have performed work to measure the spontaneous frequencies of genetic anomalies and spontaneous mutation rates of many genetic traits in humans throughout the world (Childs 1981; Czeizel and Sankaranarayanan 1984; Stevenson 1959, 1961; Stevenson and Kerr 1967). Difficulties are clearly inherent in such comprehensive studies. As an example, as our knowledge of human and animal genetics increases, discrepancies in the data may arise from changes in the classification of some genetic disorders. For example, Stevenson (1959) estimated that 30.7/1000 liv= births were due to autosomal dominant genetic disorders, while in a study 15 years later by Trimble and Doughty (1974) estimated that only 0.8/1000 live births for the same class of genetic disorders. It is thought that the data from the Stevenson (1959) data set included disorders now ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 131 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Table 3-6. Estimated Genetic Effects of 1 Rem of lonizing Radiation per Generation® Additional Cases/10° Liveborn } Offspring/rem/Generation Type of Disorder Current Incidence per Million Liveborn Offspring First Generation Equilibrium Autosomal dominant ° Clinically severe 2,500° 5-20° 25° Clinically mild 7,500° 1-15° 75° X-linked 400 <1 <5 Recessive 2,500 <1 Very slow increase Chromosomal Unbalanced Jranslacation 600" <5 Very little increase risomies 3,800 <1 <1 Congenital abnormalities 20,000-30,000 10) 10 - 100 Other disorders of Organs’ Heart" 600,000 Cancer 300,000 Not estimated Not estimated Selected others 300,000 ®Risks pertain to average population exposure of 1 rem per generation to a population with the spontaneous genetic burden of humans and a doubling dose for chronic exposure of 100 rem (1 Sv) ®Assumes that survival and reproduction are reduced by 20-80% relative to normal (s=0.2-0.8), which is consistent with the range of values in Table 2.2 in BEIR (1990). CApproximates incidence of severe dominant traits in Table 2-2 in BEIR (1990). PCalculated using Equations (2-7) in BEIR (1990) with s=0.2-0.8 for clinically severe and s = 0.01-0.2 for clinically mild. Calculated using Equations (2-1) in BEIR (1990), with the mutational component = 1. Assumes that survival and reproduction are reduced by 1-20 percent relative to normal (s=0.01-0.02). Obtained by subtracting an estimated 2,500 clinically severe dominant traits from an estimated total incidence of dominant traits of 10,000. "Estimated frequency from UNSCEAR (1982, 1986). ‘Most frequent result of chromosomal nondisjunction among liveborn children. Estimated frequency from UNSCEAR (1982, 1986). Based on worse-case assumption that mutational component results from dominant genes with an average s of 0.1: hence, using Equation 2.3 in BEIR (1990), excess cases <30,000 x 0.35 x 100" x 0.1 = 10. Calculated using Equation 2-1 in BEIR (1990), with the mutational component 5-35%. Lifetime prevalence estimates may vary according to diagnostic criteria and other factors. The values given for heart disease and cancer are round-number approximations for all varieties of the diseases, and the value for other selected traits approximates that for the tabulation in Table 2-4 of BEIR (1990). ™No implication is made that any form of heart disease is caused by radiation among exposed individuals. The effect, if any, results from mutations that may be induced by radiation and expressed in later generations, which contribute, along with other genes, to the genetic component of susceptibility. This is analogous to environmental risk factors that contribute to the environmental component of susceptibility. The magnitude of the genetic component in susceptibility to heart disease and other disorders with complex etiologies is unknown. Source: adapted from BEIR V 1990 ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 132 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION known to not be of an autosomal dominant etiology, resulting in an artificially high estimate in the 1959 report. Definitions of serious and mild genetic disease, size of the population sampled and the specific world location sampled, in addition to the frequencies of some genetic diseases tending to wax and wane over a number of years, will all significantly contribute to the problem of obtaining stable and accurate estimates of background genetic disease burdens in humans. Table 3-6 summarizes the current incidence of some generalized genetic anomalies (background levels of genetic disease) and the estimated genetic effects of 1 rem/year/generation of ionizing radiation on the genome of humans based on an assumed doubling dose of 100 rem (1 Sv) (BEIR V 1990). Determining the genotoxic effects of ionizing radiation in a population of humans is difficult. Several factors complicate making such predictions of genotoxic effects in humans. First, the genotoxic effects of ionizing radiation in humans must be detected in the offspring from the parent(s) that were irradiated. Given the normally long life cycle of humans compared to laboratory animal models, it may be a few weeks to many years before any genetic effects which may be induced by a dose of ionizing radiation would express themselves in the offspring of an exposed human population. The epidemiologic studies that are needed to accumulate a sufficient database of information after such an exposure would be both time consuming and expensive, with the final results most likely not being available for years after exposure. In addition, the effects induced by ionizing radiation on an exposed population may vary significantly by exposure location: all of the population may not have received a uniform whole body dose, and different individuals would have received different radiation doses, thus complicating the data collection process. Distance-from-exposure source and total organ dose received are only estimates and not a precise measurement. Age and sex distribution of the exposed population and their normal probabilities of producing children must also be accounted for and determined using relevant control populations. In addition to data from the atomic bombing of Hiroshima and Nagasaki in August, 1945, which showed no effects—neither somatic nor genetic—on children born to exposed parents (BEIR V 1990). Those studies, however, indicate that ionizing radiation does not produce genetic effects in humans in either the first or second generation. Many of the difficulties described above were encountered with the data collected from the exposures to ionizing radiation resulting from the atomic bombing at Hiroshima and Nagasaki, Japan; these exposures consisted primarily of external gamma radiation. The original dosimetry measurements from that exposure (T65D) have been revised (DS86) and are still undergoing revision to accurately determine the actual doses of ionizing radiation received by individuals who survived the atomic bomb explosion in August 1945. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 133 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Despite the difficulties associated with making such estimates for the genotoxic effects of ionizing radiation in humans, some assumptions about dose have been made and the risks of using these assumptions have been estimated. More information about how these estimates were determined have been reported (BEIR IV 1988; BEIR V 1990; UNSCEAR 1993). Today, there are two basic models employed for estimating the risk for radiation-induced hereditary disease for low doses of ionizing radiation and for doses of ionizing radiation in humans. Both models are linear, no- threshold models for dose response and will be briefly summarized here. The "Direct Method" for determining the risk of radiation-induced hereditary disease estimates the risk of inducing dominant mutations from induced mutations produced by high doses of ionizing radiation in laboratory animals, with the results later corrected for dosing rates. An estimate is then made of the proportion of deleterious dominant disorders in humans that involve similar defects. That estimate, when multiplied by the measured rate in animals, gives an estimate of the rate of induction of genetic defects of all dominant disorders in humans due to those doses of ionizing radiation used in the laboratory animal model. The direct method is used for first-generation dominant mutation estimation of genetic defects only; population genetic methods can be used thereafter to estimate the effects to be seen in succeeding generations. Given the many uncertainty estimates this method uses, the BEIR V committee did not use this method extensively in its genetic effects data analysis. The "Doubling Dose Method" requires fewer assumptions and estimates than the direct method. By definition, the "doubling dose" is the dose of ionizing radiation to the gonads (testes or ovaries) that, if delivered per generation to all members of a population would, at equilibrium after many generations, double the spontaneous burden that existed before exposure began (BEIR V 1990; Faw and Shultis 1993). This method uses the natural frequency of human hereditary disease in determining an estimate of the increased frequency of genetic alterations as a result of a sudden increase in ionizing radiation exposure to the general public. Compared to the direct method, the doubling dose method directly takes into account the effect of a genetic anomaly on all generations beyond the first generation. The problem of species extrapolation from animal to human is also somewhat circumvented; in theory this method relies entirely on a known estimate of a specific genetic mutation frequency in the human, although some of the doubling-dose estimates originate from data collected in the mouse animal model. Risk estimates of genetic disease using ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 134 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION the doubling dose method have been adopted by the latest BEIR committee; however, UNSCEAR still relies on the direct method of risk estimation. Risk estimates have been reported for humans exposed to doses of ionizing radiation, despite the difficulties with the availability of data. Using the epidemiological data gathered after the atomic bombing of Hiroshima and Nagasaki in August 1945, which encompasses nearly 50 years of data, together with data from studies with mice, some estimates of genetic disease risk using the doubling dose method can be derived for human exposures to ionizing radiation. These estimates are presented in Table 3-7. Table 3-7. Estimated Lower 95% Confidence Limits of Doubling Dose (in rem) from Chronic Radiation for Malformations, Stillbirths, Neonatal Deaths, and All Untoward Pregnancy Outcomes (Based on the Hiroshima and Nagasaki Atomic Bombing Data). All untoward Group Malformations Stillbirths Neonatal death outcomes All groups 96 124 90 60 Only mother exposed 277 32 23 29 Only father exposed 65 344 56 41 Combined 119 64 35 36 Both mother and father exposed 41 73 75 37 Source: adapted from BEIR V 1990 and Schull et al. 1981 NOTE: Data are the lower 95% confident limits of the doubling dose adjusted for concomitant sources of variation. For acute doubling doses, divide by 3. For all estimates adjusted for concomitant sources of variation, the range is 23-344, the median is 62, and the mean is 86. Table 3-7 provides the lower 95% confidence limits of the minimum doubling dose estimates (in rem) on adjusted data from those individuals that survived the atomic blasts of 1945, and are for chronic ionizing radiation exposures only. The human data set closely approximates the median values obtained in mice (data not shown), and overall may suggest that humans are somewhat more radioresistant than mice, implying lower risk. It should be clearly understood at this point that due to the data restrictions in this human population (discussed previously in this section), the human data may be biased in such a way as to yield an artificially lower number than that obtained using the mouse data. If large-scale human exposures to ionizing radiation occur in the future and are studied to any degree of depth, the data from these incidents will need to be closely scrutinized in order to determine if humans tend to be more resistant to the genotoxic effects of ionizing radiation when compared to other species or if such an observation is due to data anomalies. It should be emphasized that the numbers in the Table 3-6 are based on the application of actual doses to ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 135 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION models derived from animal experiments. In the case of the survivors of the atomic bombing, Dr. S.V. Neel, who had been studying the genetic effects of these bombings since 1946, concluded that “the children of the most highly irradiated population in the world’s history provide no statistically significant evidence that mutations were produced in their parents. . . . In particular, the studies should prove reassurance to that considerable group of exposed Japanese and their children, without whose magnificent cooperation these studies would have been impossible and who over the years have been subject to a barrage of exaggerations concerning the genetic risks involved” (Neel et al. 1990). In summary, the genetic materials that comprise living cells of both humans and laboratory animals are major targets for damage from sources of ionizing radiation. The severity of these lesions depend on the dose and type of ionizing radiation received and the extent to which these lesions can be repaired by the resident cellular repair systems. These lesions range from chromosomal aberrations and breaks, reciprocal translocations, deletions, sister chromatid exchanges, dominant lethal mutations, sperm anomalies, to lethal and non-lethal mutations of the genetic material. Of concern to risk assessors is ascertaining the amounts of ionizing radiation that result in changes in the prevalence of some hereditary diseases. The two models that currently exist for making these determinations have both strengths and weaknesses. The main difficultly with estimating genetic effects of radiation is that the frequency of the postulated effects, even for high radiation doses, is less than the annual statistical variability in the number of these that occur spontaneously. 3.2.2 Carcinogenic Effects from lonizing Radiation Exposure 3.2.2.1 Introduction Cancer is the major latent effect produced by ionizing radiation and the one that most people exposed to sources of ionizing radiation are concerned about. The ability of alpha, beta, and gamma radiation to produce cancer in virtually every tissue and organ in laboratory animals has been well-demonstrated. There is also a large database that exists for people exposed to ionizing radiation for diagnostic purposes, those treated for disease with radiation, occupational exposure populations, people that live in high background level regions, survivors of radiation accidents, and nuclear bombing survivors. It is presently not clear whether humans are more or less sensitive to the adverse effects of low-levels of ionizing radiation than are the laboratory animal models ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 136 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION It is important to note that the development of cancer is not an immediate effect, and may take several years to develop (referred to as the latent period or latency), if it develops at all. Important, too, is the fact that radiation-induced cancers are the same types that are normally found in unexposed individuals; however, after exposure to ionizing radiation, these cancer types may occur with some increasing frequency and therefore can be detected only by epidemiological means. These cancers occur only when those individuals reach an age when these cancers would normally be expected to develop (except for leukemia). For example, a female <10 years of age exposed to external ionizing radiation from the atomic blast, who survived the acute effects of the initial radiation exposure, would have an increased probability of developing breast cancer as a result of exposure to ionizing radiation, but not before the end of the latent period for this specific cancer. The same would be true for the other types of cancers. Radiation induced leukemia has the shortest latent period at 2 years, while other radiation induced cancers have latent periods >20 years. Radiation carcinogenesis has not been demonstrated in several types of human cells, possibly because the latent period exceeds the human lifespan. Raabe (1994) has developed two- and three-dimensional models of risk from constant levels of radiation exposure. The typical plot of lifespan vs. daily dose rate has three portions based on the cause of death, natural life-span, cancer, and acute radiation syndrome. According to Raabe, at low dose rates the animal’s natural life-span is the cause of death. As the daily dose rate increases, a threshold is reached where cancer deaths dominate in a dose-responsive manner. Similarly, at extreme dose rates, a threshold is reached where acute radiation syndrome is the cause of death. These are unique studies in that they are lifetime studies involving dose rates down to levels humans normally experience. The mechanism by which cancer is induced in living cells is complex and an area under intense study. The accepted theory states that the induction of cancer by exposure to ionizing radiation takes place in three steps. The first step is initiation, which is a mutational event caused by the effect of the ionizing radiation interacting with the cellular genome. This may involve a single gene or multiple genes on one or many chromosomes, and may involve the activation of an oncogene or the mutation and subsequent inactivation of tumor suppressor genes. The mechanism may stall at this point, with the gene(s) either undergoing repair or remaining mutated and dormant. If repair fails to take place at all, if the repair is unsuccessful, or if cell division occurs before repair is complete, and the cell remains viable through future cell generations, the gene(s) appear in the progeny cells and will then enter into the stage of promotion. The second step, promotion, is generally thought to be unrelated to the dose of radiation (initiation step) received, even though thyroid cancer in children from "*'I or external exposure may suggest otherwise; therefore, the latent period is clearly independent of the initial dose of the radiation received. This would be a plausible explanation of why cancers develop at the ages that they would normally develop in unexposed populations, with the increased ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 137 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION incidence of cancer related to the increased number of cell insults/injuries in the genome of the damaged cells. Several promotor agents have been identified, with some acting as both initiators and promotors. In the third step, cell transformation and proliferation, neoplasic cells are produced. More information on how ionizing radiation interacts with the genome and on the mechanisms by which cancer is induced after exposure to ionizing radiation is presented in Chapter 5 of this profile. A few human studies are available that describe the incidences and types of cancers produced by some radionuclides. Osteogenic sarcomas were found in people whose bone marrow doses exceeded 1,380 rad (13.8 Gy) of alpha radiation following exposure to *’Ra and ***Ra via several routes of exposure (Aub et al. 1952; Evans 1966; Martland 1931; Rowland et al. 1978; Woodard 1980). ??*Ra, used in the treatment of ankylosing spondylitis, has also been implicated in producing osteosarcomas (Chemelevsky 1986; Mays 1988; Spiess and Mays 1970, 1973; Wick et al. 1986). The largest cohort of humans available for study of the effects of external ionizing radiation and cancer is the group of people exposed to the varying degrees of ionizing radiation produced by the two atomic bombs detonated in Japan in August 1945. In this population, an increase in leukemia incidence rate was seen only in those persons whose dose exceeded 10 rad (0.1 Gy). An increased incidence of solid tumors was seen only in those whose dose exceeded 40 rad (0.4 Gy). Exposure to ionizing radiation can produce cancer at any site within the body; however, some sites appear to be more at risk than others. The BIER V (1990) committee report came to some conclusions about which sites are more at risk than others in humans, and these data are summarized in Table 3-8. The relative risk of death normalized to a dose of 100 rad (1 Gy) from several types of cancer among 75, 991 atomic bomb survivors whose radiation doses are known are given in Table 3-9. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 138 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Table 3-8. Summary of Risks of Developing Cancer After Exposure to lonizing Radiation Cancer Relative Risk (RR) Factors (low dose rate) per Organ or System BEIR Committee Conclusions About Risk 10° rad (10* Gy) ® Mammary/breast 1. The development of cancer from susceptible mammary 92.5 cells due to exposure to ionizing radiation depends on the hormonal status of these cells. 2. The age-distribution of radiogenic-induced breast cancers and those breast cancers from unknown causes is similar. 3. Women irradiated at <20 years of age are at higher risk than those irradiated later in life. 4. There is no evidence to suggest that radiogenic breast cancer will appear during the first 10 years after exposure to ionizing radiation. Peak incidences occur 15 to 20 years after exposure. 5. The data show little if any decrease in the yield of tumors when multiple radiation doses are compared to single, brief exposures to ionizing radiation. Lung 1. Absolute risk of lung cancer from exposure to ionizing 75.4 radiation is similar for both males and females. 2. The data suggest that smoking has a “greater than additive” effect on the development of lung cancer after exposure to ionizing radiation. Stomach/digestive 1. The incidence of stomach cancers increases with 49.3 system increased exposure to ionizing radiation. 2. Females are at greater risk for developing cancers than are males 3. The relative risk for developing cancer is higher for those exposed when 30 years of age or younger. 4. The baseline risk for digestive cancers increases with age; most of the excess cancers occur after middle age. Thyroid 1. Susceptibility to radiation-induced thyroid cancer is 32.1 greater in childhood. 2. Development of thyroid cancer is dependant on the hormonal status of the individual; sustained levels of TSH increase the risk of developing thyroid cancer. 3. For those exposed before puberty, the tumors do not appear until after sexual maturation. The risk is greatest for children exposed within the first 5 years of life. 4. Females are 2-3 times more susceptible than males to radiogenic (and spontaneous) thyroid cancer. 5. Radiogenic cancer of the thyroid is usually preceded by benign thyroid nodules and the frequency of hypothyroidism and goiter is increased in those exposed to large doses when very young. Esophagus 1. Increased incidences of cancer of the esophagus have 9.5 been observed to occur in humans receiving doses of ionizing radiation. 2. Little human data is available to make strong conclusions about the risk of developing esophageal cancer after exposure to ionizing radiation, although a risk estimate is available. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 139 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Table 3-8. Summary of Risks of Developing Cancer After Exposure to lonizing Radiation (continued) Cancer Relative Risk (RR) Factors (low dose rate) per Organ or System BEIR Committee Conclusions About Risk 10% rad (10° Gy) ® Small intestine Cancers of the small intestine have been produced in NR (duodenum, laboratory animals exposed to large doses of ionizing jejunum, ileum) radiation. None of the human epidemiological studies have conclusively demonstrated an increased risk of developing cancers of the small intestine after exposure to ionizing radiation. Large intestine (colon/rectum) Data imply that there is an increased risk of developing 178.5 either colon or rectal cancer after exposure to ionizing radiation Based on human exposure data, the development of colon or rectal cancer is not apparent until 15 years after exposure or longer. Skeleton Brain/central nervous system (CNS) Large doses of low-LET ionizing radiation can result in 1.3 the development of bone cancers. The data suggest a threshold of up to 4 Gy of low-LET radiation before increased bone cancers begin to occur. Increased incidences of CNS tumors have been NR observed in both humans and laboratory animals exposed to ionizing radiation. Tumors are both malignant and benign. The brain is considered to be relatively sensitive to developing cancer after exposure to ionizing radiation. Increases have been reported when irradiated during childhood at doses less than 1-2 Gy. Ovary and uterus There is no clear relationship between exposure to 23.8 ionizing radiation and the development of uterine or ovarian cancers Testis There is little human data available for studying the NR ielationship between exposure to ionizing radiation and testicular cancer. The existing data suggest that the testis is relatively insensitive to the carcinogenic effects of ionizing radiation. Prostate There is a weak association between cancer of the NR prostate and exposure to ionizing radiation. The relative risk of cancer of the prostate due to exposure to ionizing radiation is small. Urinary tract Exposure to ionizing radiation can cause cancer of the 49.7 bladder, as well as cancers of the kidney and other urinary structures. Women < 55 years old at the time of exposure are at greater risk than older women, with this risk increasing with time after exposure. Gender appears to have little effect on the incidence of bladder cancer mortality. “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 140 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Table 3-8. Summary of Risks of Developing Cancer After Exposure to lonizing Radiation (continued) Cancer Relative Risk (RR) Factors (low dose rate) per Organ or System BEIR Committee Conclusions About Risk 10° rad (10° Gy) Parathyroid glands 1. Increased incidences of hyperparathyroidism, parathyroid NR hyperplasia and parathyroid adenoma occur after exposure to ionizing radiation. 2. The data suggest that the incidences of hyperparathyroidism and parathyroid neoplasia increase with increasing doses of ionizing radiation. 3. Time to diagnosis normally is >30 years. Nasal cavity and 1. Little human data is available for analysis. Nasal and NR sinuses sinus tumors have been noted after human exposure to internally deposited ?°Ra and Th. 2. The latency of these tumors is at least 10 years. 3. The risk of developing nasal and sinus cavity tumors from routes other than from internalized sources of alpha ion radiation are extremely low. Skin 1. Increased incidences of basal cell and squamous cell 1.0 carcinomas of the skin have been reported after occupational and therapeutic exposures to ionizing radiation. 2. Incidence from radiation exposure may be 5 times greater if the skin is also exposed to sunlight and X-rays. Bone marrow 1. Examples include multiple myeloma, non-Hodgkins NR (leukemia, lymphoma, and chronic lymphocytic leukemia. lymphoma, and 2. Multiple myelomas are observed to form after irradiation multiple myeloma) of the bone marrow. 3. The latent period for multiple myeloma is considerably longer than that of leukemia. 4. In Japanese A-bomb survivors, an excess of multiple myeloma cases did not appear until 20 years after exposure. 5. Excess mortality from multiple myelomas has been observed at doses as low as 0.5-0.99 Gy 6. No other form for lymphoma has been consistently observed in human populations exposed to excess amounts of ionizing radiation. Pharynx, 1. Increased incidences of cancer do arise in these tissues NR hypopharynx, and after therapeutic radiation (i.e., ankylosing spondylitis) in larynx the 30-60 Gy range. Increases in these cancers were not statistically significant at the p<0.05 level. 2. There were no increases in the incidences of these cancers in the Japanese A-bomb survivors exposed to <1 Gy. 3. The risk of developing cancers of these tissues after exposure to ionizing radiation appears to be very low. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 141 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Table 3-8. Summary of Risks of Developing Cancer After Exposure to lonizing Radiation (continued) Cancer Relative Risk (RR) Factors (low dose rate) per Organ or System BEIR Committee Conclusions About Risk 10° rad (10° Gy) ® Salivary gland 1. The incidence of salivary gland tumors was increased in NR the Japanese A-bomb survivors, patients treated with X-rays to the head and neck during childhood, and women treated with '*'l when middle-aged. 2. Increases in salivary gland neoplasia are dose-dependant in the Japanese A-bomb survivors, but with no detectable increases in excess mortality. 3. The salivary gland appears to be particularly susceptible to the development of cancer after exposure to ionizing radiation. Pancreas 1. An association between cancer of the pancreas and NR exposure to ionizing radiation has been suggested in some literature reports. 2. The existing data suggest that the pancreas is relatively insensitive to the carcinogenic effects of ionizing radiation. # Values from EPA Report 402-R-96-016, Radiation Exposure and Risk Assessment Manual, June 1996. Sum of all values = 173.4 and will include other organs not listed here Source: summarized from BEIR V 1990 LET = linear energy transport; NR = RR factor not reported. The conclusions of the BEIR V (1990) report were based on many human exposures and their subsequent epidemiological studies over the past 70-80 years. Laboratory animal data have also proven to be invaluable assets in defining human risks after exposure to ionizing radiation, particularly to the respiratory tract of humans, and were included when relevant. The use of human epidemiological data is certainly a valuable tool in determining the long-term carcinogenic effects from exposure to ionizing radiation; however, there are hazards associated with its use. The BEIR V (1990) committee used human epidemiological data whenever possible; however, it also recognized its many limitations when attempting to draw conclusions about the carcinogenic effects of ionizing radiation. The main difficulty is that there have not observed any increase in cancer at low doses. For purposes of setting safety standards and public policy, we postulate mathematical models that are based on a zero threshold. Most of the literature examined reported the effects of ionizing radiation in laboratory animal species, such as monkeys, dogs, rats, pigs, mice, and guinea pigs. The short- and long-term effects of ionizing radiation in these animals as a result of this research have been well-outlined. When the laboratory animal data are examined more closely, the researcher and risk assessor are faced with a difficult and complex question: “Is this what happens when humans are exposed to this dose of ionizing radiation?” The answer will likely ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 142 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION depend on a number of variables, including the toxicological end point being examined (in this case, cancer); however, the definitive answer lies in actually exposing a population or populations of humans to varying doses of ionizing radiation and systematically and methodically studying the effects (if any) over the lifespan of the exposed individuals. The use of human subjects in scientific research is a highly regulated area and, for obvious moral reasons, is not a regularly accepted practice in the area of radiation biology. This leaves radiation biology risk assessors with three sources of information from which to determine the risks associated with ionizing radiation exposure in humans: (1) extrapolation of data from laboratory animal models (which is associated with many uncertainty factors), and (2) epidemiological studies, often associated with accidental or occupational exposure to radiation and radioactive material, and (3) data from patients who have received radiation diagnostic and radiotherapy treatments. The use of human data pools theoretically provides the most direct and informative approach to assessing the toxicity of exposure to ionizing radiation in humans. This would likely be the case in well-equipped laboratories using controlled exposure scenarios. In reality, much of the information regarding exposures to radiation does not use a controlled exposure situation. Much of the human information comes from epidemiology studies following the detonation of nuclear bombs (Hiroshima, Nagasaki, Bikini Atoll, etc.), from accidents involving the release of radionuclides (Palomares, Spain; Thule, Greenland; Rocky Flats, Colorado; and others), or from exposed radiation workers or patients. In these groups it is difficult to identify a suitable control population. Epidemiology is the study of the patterns of disease in groups of people. Epidemiologists attempt to determine the risk factors which cause health effects by comparing the rate of occurrence of a disease among exposed and non-exposed populations with similar attributes. Epidemiologists usually prefer to compare the rate of occurrence of the effects under consideration. The major questions asked are: (1) do the rates of occurrence differ between populations, and (2) are any noted differences a real effect or are they merely due to chance? In studying populations, epidemiologists must characterize the subjects based upon both the risk factor and the disease status. There are four main types of epidemiological studies: cohort, case-control, occupational, and cross-sectional. Cohort, case-control, and occupational studies are the most likely types of epidemiological studies to be conducted in the case of exposure to ionizing radiation. Cohort studies follow a group of initially healthy persons with differing levels of exposure or risk factors and compare the rate of occurrence of disease in each population over time. Because exposure is assessed prior to development of the effect, there is less chance ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 143 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION for bias; in addition, the relationship of other disease outcomes to the pre-assessed risk factors may also be studied after the fact. These studies are both expensive and time-consuming. In case-control studies, a population with a particular disease and a matched (except for the disease) disease-free population are assessed for exposure or risk factors in order to determine causality. By studying populations after the development of the disease, the causes of relatively rare diseases can be assessed without following thousands of people; thus, a case-control study is a quicker, less expensive study compared to the cohort design. However, there is more opportunity for bias due to the fact that the disease has already occurred prior to determining exposure or risk factors. Also, only one disease may be investigated per study. All epidemiological studies have inherent weaknesses due to the potential for bias in the experimental design or implementation. Common forms of bias include selection bias, recall bias, misclassification, and confounding factors. Selection bias occurs when subjects are not recruited uniformly. When information about health and exposure status is not collected consistently or reliably, this will also artificially affect the outcome of the study. Recall bias occurs when subjects do not uniformly report the incidence or severity of exposures or health effects. Misclassification refers to mislabeling or incorrectly characterizing a study participant with regard to the toxic end point or outcome (disease). A common type of misclassification occurs in patients with cancer; the cause of death in these subjects may be complicated and classified as the result of a secondary illness. Even when death is attributed to cancer(s), the specific cancer listed on the death certificate may be a secondary metastatic cancer. Exposure may also be misclassified, particularly when study subjects are aware that they are practicing risky behavior. Confounding refers to the interaction of multiple factors on a given effect and the possibility of attributing risk to an inappropriate factor. For example, when assessing the risk of a disease due to a factor such as the wire code of high power lines, one must consider that the wire code of power lines may be highly correlated with urbanization, heavy traffic, and increased pollution. In such a case, an association between power lines and disease must be investigated while taking these other factors into account; otherwise, the results may not be interpretable. One should both appreciate the unique data epidemiological studies provide and view such data with an objective and cautious eye. With these caveats in place, the following pages contain a synopsis of some of the more important human exposure scenarios that have occurred in the past involving alpha, beta, and gamma radiation. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 144 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION 3.2.2.2 Nuclear Detonations of 1945 in Hiroshima and Nagasaki, Japan The first atomic device was exploded in a test on July 16, 1945, in Alamagordo, New Mexico. The U.S. military, in an effort to bring a swifter end to the war and to avoid a costly ground invasion of Japan (actually planned for November 1945), detonated a **°U atomic bomb over the city of Hiroshima, Japan, on August 6, 1945. Three days later, another atomic device using **Pu was detonated over the city of Nagasaki, Japan. In both Hiroshima and Nagasaki, a total of 64,000 people within 1 km of the air detonation site (designated the "hypocenter," the point on the ground directly below where the bomb exploded in the air) were killed by a combination of the blast, intense heat, and to a much lesser extent gamma and neutron radiation emitted by these bombs. These effects accounted for 50%, 35%, and 15%, respectively, of the energy released by the bombs (Zajtchuk 1989). Persons 1-2 kilometers away from the hypocenter received up to several hundreds of rad of ionizing radiation and suffered the ill effects of the acute radiation syndrome. The doses dropped off fairly rapidly with distance. In Hiroshima, the dose at 1 km was on the order of 100 rad (1 Gy), dropping to approximately 1 rad (0.01 Gy) at 2 km. For Nagasaki, the doses were on the order of 1,000 rad (10 Gy) and 10 rad (0.1 Gy), respectively. Those who survived the immediate effects, including those who were far enough away or shielded from a portion of the radiation, were potential candidates for the latent effects of ionizing radiation. A more in-depth discussion of the events surrounding the creation of the atomic devices appears in Chapter 2 of this toxicological profile. A few years after the atomic bombs were detonated, an effort was begun to study the effects that the different doses of ionizing radiation had on the human populations of Hiroshima and Nagasaki. This study was instituted by the Atomic Bomb Casualty Commission (ABCC) in 1950; these effects continue to be monitored today by the Radiation Effects Research Foundation (RERF). Periodic reports are published on the effects of ionizing radiation in the human populations of these cities in the main study, called the Lifespan Study (LSS). The LSS includes 120,321 individuals living in Hiroshima and Nagasaki in 1950; of these, 91,228 were exposed at the time of the bombing (BEIR 1990). At the time of the bombing of both cities, it was clearly not possible to determine the exact doses of ionizing radiation each person had received; therefore, estimates had to be made as to the dose of radiation received by persons located at different distances from the hypocenter. The original dose estimates, called the Tentative 1965 Dose (T65D), used the air dose (gamma ray + neutron tissue kerma in air) adjusted for shielding by structures and natural terrain based on data obtained at the Nevada test sites, the Bare Reactor Exposure of Neutrons (BREN) experiment, and from large-scale shielding experiments. The accuracy of this ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 145 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION computational system was questioned in 1978. After re-examining the available data, a new system of dose estimation, the Dosimetry System 1986 (DS86), was created and is available in its final format (Roesch 1987). The DS86 system is considered to provide more accurate and sensitive radiation dose estimates than the T65D estimates because of improvements in assessing doses to building materials, like ceramic roof tiles; in modeling the doses to the human fetus; and in considering the reduction in the neutron component of the radiation dose caused by the high atmospheric humidity in Japan as compared to the Nevada desert. The DS86 data are currently being reevaluated, looking for opportunities to further improve the results. Based on the new dosimetry system, there are sufficient data from these large-scale human exposures to derive some conclusions about the cancer-inducing effects of external sources of ionizing radiation. A report by Shimizu et al. (1988) used the exposure data from 75,991 persons exposed to external ionizing radiation from the atomic bombs at Hiroshima and Nagasaki (based on the DS86 estimates of dose) to estimate the risk of developing cancer when humans are exposed to similar doses of ionizing radiation. Of these 75,991 exposed persons, 59,784 were distally exposed and 16,207 were proximally exposed to the explosions. These persons were followed to their time of death (for those people who died during the course of the study) for the period from 1950 to 1985, with the specific types of cancers found in these deceased individuals summarized in Table 3-9. As can be seen in Table 3-9, external (gamma) ionizing radiation induces site-specific cancers in some organs but not in others. This extensive data set indicates that leukemia (acute and chronic myeloid and acute lymphocytic, but not chronic lymphocytic), cancers of the esophagus, stomach, colon, lung, female breast, ovary, and bladder, and multiple myelomas have statistically significant increases in incidences after exposure to external ionizing radiation. The incidence of these types of cancer increases with the dose (as measured by estimated relative risk at 100 rad and excess risk per 10,000 individuals each exposed to 1 Gy [10* person- year Gy]). Conversely, incidences of cancers of the rectum, gallbladder, pancreas, uterus, and prostate, and incidences of malignant lymphoma do not appear to increase after exposure to ionizing radiation. A number of other conclusions can be drawn from the data sets that are presented in many extensive tables in the Shimizu et al. (1988) report. Due to the size of these data sets, much of the raw data has been omitted from this toxicological profile; however, the conclusions drawn from those data will be discussed here. Table 3-9 shows the risks associated with certain types of cancers over all age groups; however, when cancers are further classified by age at the time of death (ATD) and age at the time of the bombing (ATB), other ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 146 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION trends are noted. For ATB <10 years, the risk of stomach cancer appears to be greater for those younger ATD groups (as observed for all cancers), but this trend is not statistically significant. No definable trends are observed for breast, lung, and colon cancers; however, this is most likely due to the fact that in 1985, this age group had not yet reached the age where expression is likely. However, the relative risk of leukemia peaked at 6-8 years after the bombing and tends to decrease every year thereafter. In humans, cancers do not begin to appear immediately after exposure to ionizing radiation; it is only after some minimum latent period (defined in this study as the time from exposure to the time of observation) that cancers induced by the effects of ionizing radiation will occur. This is the case with leukemia and with solid tumors shown in Table 3-9. The incidence of radiation-induced leukemia began to occur 2-3 years after the detonation occurred, reached a peak within 6-8 years, and has been steadily declining ever since. A small (yet significant) excess in leukemia mortality still existed as of the writing of the Shimizu et al. (1988) report. This study also noted that there is some evidence to suggest that radiation-induced cancers increase significantly only when the survivors reach those ages at which cancers normally develop; thus, the minimum latent period is longer for the younger ATB groups. These data also have demonstrated that the latent period for all the cancers shown in Table 3-9 (except for leukemia) appears not to be dose-dependent; the latency period is not affected by the dose. The latency period, however, is shorter among the young who were exposed to higher doses within the first 10 years of life. For the solid tumors (all but leukemia), the data from this study suggest that the minimum latent period is 15-19 years for stomach cancer, 20-24 years for lung and breast cancers, 25-29 years for ovarian cancer, and 30-34 years for cancers of the colon and urinary tract and for multiple myeloma. Some benefits of following this group until the last individual dies are (1) the improvement of radiogenic cancer risk estimates and (2) the possibility of verifiying that certain cancer types that have not yet been observed at elevated rates may have very long latency periods. Other factors were examined in this cohort that may affect cancer rates. The relative risk of developing leukemia was not significantly different for males and females. For cancers other than leukemia, particularly those of the esophagus and lung, the relative risk is higher for females than for males. This is most likely due to the fact that the background occurrence for cancers other than leukemia is higher for males than females. As for the effect of smoking on the rate of development of lung cancers, the relative risk of lung cancer at 100 rad is greater for females than males. Adjusting for the effects of smoking in both males and females, the relative risk differences no longer are statistically significant. Also, no shortening of the lung cancer latency period was noted in male or female smokers. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION 147 Table 3-9. Summary of Radiation Dose Response for Cancer Mortality by Site®® Estimated Excess risk per 10* Number Statistical relative risk at person-year Gy Attributable risk Site of cancer of deaths p test’ 1 Gy (PY Gy) (%)¢ All malignant neoplasms 5936 0.0000 1.39 (1.23,1.46) 10.0 (8.36, 11.8) 10.2 (8.50, 12.0) Leukemia 202 0.0000 4.92(3.89,6.40) 2.29 (1.89, 2.73) 55.4 (45.7, 66.3) All cancers except 5734 0.0000 1.29 (1.23,1.36) 7.41 (5.83, 9.08) 7.86 (6.19, 9.64) leukemia Digestive organs and 3129 0.0000 1.24 (1.16, 1.33) 3.39 (2.27, 4.59) 6.58 (4.41, 8.91) peritoneum Esophagus 176 0.02 1.43 (1.09, 1.91) 0.34 (0.08, 0.67) 12.7 (2.92, 25.0) Stomach 2007 0.0000 1.23(1.13,1.34) 2.07 (1.19, 3.05) 6.26 (3.61, 9.23) Colon 232 0.0000 1.56 (1.25,1.98) 0.56 (0.26, 0.91) 15.1 (6.96, 24.7) Rectum 216 0.67 0.93 (, 1.27)! -0.07 (, 0.25)" -1.93 (, 7.12)! Liver (primary) 77 0.57 1.12 (0.87, 1.70) 0.05 (-0.05, 0.25) 3.90 (-4.38, 20.5) Gallbladder and bile ducts 149 0.13 1.37 (0.98, 1.96) 0.22 (-0.01, 0.53) 8.24 (-0.55, 19.5) Pancreas 191 0.53 0.89 (, 1.23)f -0.10 (, 0.20)" -3.01 (, 6.21)" Other (unspecified) 81 0.29 1.32 (0.87,2.14) 0.11 (-0.05, 0.35) 7.73 (-3.29, 24.2) Respiratory system 747 0.0000 1.40 (1.21,1.63) 1.29 (0.71, 1.96) 10.1 (5.50, 15.3) Lung 638 0.0000 1.46 (1.25,1.72) 1.25(0.70, 1.89) 11.4 (6.36, 17.1) Breast (female) 155 0.0000 2.00 (1.48,2.75) 1.02 (0.53, 1.60) 22.1 (11.4, 34.8) Cervix uteri and uterus 382 0.08 1.22 (1.01, 1.50) 0.60 (0.04, 1.29) 5.30 (0.34, 11.5) (female) Cervix uteri (female) 90 0.17 1.43 (0.93, 2.30) 0.26 (-0.04, 0.70) 10.0 (-1.68, 26.9) Ovary (female) 82 0.03 1.81 (1.16, 2.89) 0.45 (0.10, 0.90) 18.7 (3.97, 37.7) Prostate (male) 52 0.85 1.05 (, 1.73)! 0.03 (, 0.40)t 1.89 (, 24.8)1 Urinary tract 133 0.0000 2.02 (1.45,2.87) 0.55 (0.26, 0.89) 22.7 (10.8, 37.1) Malignant lymphoma 110 0.81 1.92 (, 1.40)! -0.02 (, 0.18)" -1.75 (, 13.6)" Multiple myeloma 36 0.002 2.86 (1.55,5.41) 0.21 (0.07, 0.39) 32.5 (11.3, 59.5) Liver (including not 590 0.02 1.24 (1.06, 1.47) 0.63 (0.07, 1.18) 7.02 (1.87, 13.2) specified as primary) Kidney 38 0.18 1.58 (0.91, 2.94) 0.09 (-0.02, 0.26) 15.7 (-2.77, 43.3) Bladder 90 0.003 2.13 (1.40, 3.28) 0.41 (0.16, 0.70) 23.6 (9.31, 40.8) Tongue 26 0.40 0.83 (, 1.49) -0.02 (, 0.06)" -5.35 (, 14.1)t Pharynx 23 0.61 0.83 (, 2.04)" -0.02 (, 0.09)! -6.14 (, 31.6)" Nose 44 0.58 0.84 (, 1.67)! -0.03 (, 0.12)" -4.04 (, 14.5) Larynx 46 0.16 1.51 (0.95, 2.68) 0.10 (-0.01, 0.29) 13.4 (-1.47, 37.1) Skin (except melanoma) 21 0.69 1.17 (, 2.47)t 0.02 (, 0.12) 5.60 (, 38.7)f Bone 27 0.65 1.22 (, 2.79) 0.02 (, 0.16)" 6.56 (, 42.9) Brain tumors 47 0.97 1.03 (0.51, 2.09) 0.01 (-0.12, 0.20) 1.0 (-13.0, 22.5) Tumors of central 14 0.08 3.09 (1.06, 9.74) 0.10 (0.00, 0.24) 35.9 (1.4, 82.2) nervous system (except brain) Other 907 0.03 1.20 (1.05, 1.38) 0.77 (0.19, 1.44) 5.65 (1.37, 10.5) # Adapted from Shimizu et al. 1988. Number in parentheses indicate 90% confidence intervals. ® Data includes Hiroshima and Nagasaki, Japan, both sexes (unless specifically otherwise stated), all ages at time of bombing (ATB), from 1950 to 1985. ¢ p-value based on the test for increasing trend in radiation dose. ? Based on 41,719 human subjects exposed to >1 rad (average = 29.5 rad). T Lower confidence limit not reported by study authors. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 148 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION The Shimizu et al. (1988) report addressed the occurrence of leukemia in the populations of Nagasaki and Hiroshima; however, the report did not elaborate on the specific types of leukemia found in those populations as a result of age and dose. Tomonaga et al. (1993) reported on the differential effects of atomic radiation in inducing major leukemia types in these two cities using the DS86 dosimetry system. That study included 766 leukemia cases (249 among LSS subjects) occurring as of the end of 1980 in people who were exposed within a 9-kilometer radius of the detonation hypocenter. Bone marrow and blood specimens of the registered cases were reassembled and re-examined for 493 of the 766 leukemia-diagnosed cases, including 177 of the 249 LSS cases, using the French-American-British classification system of leukemia diagnosis. Leukemias were further subclassified into a specific type of leukemia: acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and other leukemias (OTHER, including adult T-cell leukemia and other specifically diagnosed leukemias). Once a diagnosis was ascertained, the type of leukemia was correlated with the total body kerma received by that person, the city the dose was received in, the ATB, and the elapsed time since exposure. Incidence estimates for each type of leukemia by exposure category and period were determined (see Table 3-8) as well as incidence estimates for each type of leukemia by ATB, exposure category, and time period (see Table 3-9). Meaningful statistical analysis on the leukemia data set could not be performed and should be taken as descriptive only. Table 3-10 shows that for the three lowest exposure categories, incidence rates were either similar or slightly increased over time; the two highest dose categories had incidence rates for all types of leukemias declining over time. CML and OTHER leukemia incidence rates returned to background levels during the late 1970s, while at the highest exposure levels (> 150 rad), the overall incidence rates of ALL and AML were 4-5 times higher than background levels from 1976 to 1980. Table 3-11 shows that ATB seemed not to modify the temporal trends of leukemia in the 3 lowest exposure groups. The following is quoted from Tomonaga et al. (1993) regarding Tables 3-10 and 3-11: "In the two highest exposure groups, type-specific incidence rates declined with time in the youngest age-ATB group (0-15 years) for all types. In the young adult age-ATB group (16-35 years), however, this pattern held for ALL and CML in the two highest exposure categories and for OTHER in the 50-149.9 rad (0.5-1.499 Gy) group. The incidences of OTHER among those exposed to > 1,500 mGy (150 rad) and of AML among those exposed to 50-149.9 rad (0.5-1.499 Gy) held nearly constant in time and that of AML among those exposed to >150 rad (1.5 Gy) increased. Among older adults (i.e., >36 years old ATB), there was either no change or an increase in incidence over time for AML and OTHER in the two highest exposure categories. CML and OTHER rates declined with time in the 50-149.9 rad (0.5-1.499 Gy) group, and CML and CML and ALL declined with time in the > 150 rad (1.5 Gy) group. There was an increase over time in the excess rates of AML among ***DRAFT FOR PUBLIC COMMENT*** +»LNIWWOD O118Nd HOH L4VH ux Table 3-10. Incidence Estimates for Each of Four Leukemia Types by Exposure Category and Period (per 10° Person-years) Time period Leukemia Exposure Exposure type category (rad) category (Gy) 1951-55 1956-60 1961-65 1966-70 1971-75 1976-80 ALL 0 0 0.38 0.30 0.27 0.56 0.67 0.65 0.14.9 0.001-0.049 0.44 1.27 0.96 1.14 1.68 0.96 5.0-49.9 0.05-0.499 1.51 1.81 0.99 0.24 0.24 0.27 50.0-149.9 0.5-1.499 6.77 3.69 2.41 2.70 2.96 1.60 >150.0 21.5 57.82 30.81 9.89 20.99 7.88 285 CML 0 0 0.62 0.49 0.44 0.93 1.09 1.07 0.14.9 0.001-0.049 0.69 1.74 1.14 1.18 1.51 0.75 5.049.9 0.05-0.499 2.47 4.28 3.39 1.19 1.72 2.75 50.0-149.9 0.5-1.499 25.83 11.03 5.64 4.94 4.24 1.80 >150.0 >1.5 42.39 17.88 4.54 7.63 2.27 0.65 OTHER 0 0 0.80 0.64 0.56 1.20 1.41 1.39 0.14.9 0.001-0.049 0.03 0.16 0.26 0.67 2.15 2.67 5.0-49.9 0.05-0.499 0.13 0.48 0.79 0.57 1.73 5.73 50.0-149.9 0.5-1.499 7.28 2.74 1.24 0.96 0.73 0.27 >150.0 21.5 14.37 9.13 3.49 8.82 3.94 1.70 AML *® 0 0 3.03 (2.42) 2.40 (1.92) 2.12 (2.03) 4.51 (0.72) 5.33 (5.41) 5.23 (5.84) 0.1-4.9 0.001-0.049 0.47 (0.00) 1.97 (1.71) 2.17 (2.72) 3.77 (1.93) 8.09 (9.30) 6.73 (4.44) 5.049.9 0.05-0.499 2.07 (1.03) 4.26 (3.25) 4.01 (2.30) 1.67 (1.23) 2.87 (3.94) 5.45 (4.26) 50.0-149.9 0.5-1.499 18.08 (7.73) 10.93 (23.20) 7.92 (4.30) 9.84 (4.61) 11.96 (14.92) 7.19 (5.44) 2150.0 215 52.75 (54.41) 34.03 (11.48) 18.46 (12.13) 66.21 (77.74) 41.98 (14.02) 25.67 (30.86) NOILVIAv4d ONIZINOI *The values within parentheses are raw incidence estimates from the Life Span Study subjects in the extended cohort (LSS-E85). These values are presented for comparison with the distributed incidence estimates. ALL = acute lymphocytic leukemia; AML = acute myeloid leukemia; CML = chronic myeloid leukemia; OTHER = other leukemia including adult T-cell leukemia and other specifically diagnosed leukemia Source: Shimizu et al. 1988 NOILYIQvYd ONIZINOI 40 S103443 HLTV3IH 40 AHVYWANS € 6v1 «x LNTFWWOO O178Nd HO L4VHuxs Table 3-11. Incidence Estimates for Each of Four Leukemia Types by Age, Exposure Category, and Time Period (per 10° Person-years) Time period <15 years old ATB Leukemia Exposure Exposure type category (rad) category (Gy) 1951-55 1956-60 1961-65 1966-70 1971-75 1976-80 ALL 0 0 0.27 0.27 0.54 0.55 0.00 0.28 0.1-4.9 0.001-0.049 1.04 1.90 0.83 0.00 2.64 0.39 5.0-49.9 0.05-0.499 1.34 3.98 1.37 0.00 0.00 0.43 50.0-149.9 0.5-1.499 22.94 14.09 0.00 0.00 0.00 3.69 >150.0 >1.5 148.77 38.72 0.00 0.00 9.25 0.00 CML 0 0 0.15 0.15 0.31 0.31 0.00 0.16 0.1-4.9 0.001-0.049 0.57 0.90 0.34 0.00 0.82 0.10 5.0-49.9 0.05-0.499 0.76 3.26 1.63 0.00 0.00 1.54 50.0-149.9 0.5-1.499 30.28 14.56 0.00 0.00 0.00 1.43 >150.0 21.5 37.73 7.77 0.00 0.00 0.92 0.00 OTHER 0 0 0.18 0.19 0.38 0.39 0.00 0.20 0.14.9 0.001-0.049 0.02 0.08 0.07 0.00 1.12 0.36 5.0-49.9 0.05-0.499 0.04 0.35 0.36 0.00 0.00 3.08 50.0-149.9 0.5-1.499 8.20 3.48 0.00 0.00 0.00 0.21 >150.0 >1.5 12.29 3.81 0.00 0.00 1.54 0.00 AML ? 0 0 1.16 (0.00) 1.17 (1.78) 2.35 (3.59) 2.37 (0.00) 0.00 (0.00) 1.21 (1.84) 0.14.9 0.001-0.049 0.60 (0.00) 1.61 (0.00) 1.02 (2.26) 0.00 (0.00) 6.90 (6.89) 1.47 (2.32) 5.0-49.9 0.05-0.499 1.00 (0.00) 5.10 (3.17) 3.02 (0.00) 0.00 (0.00) 0.00 (0.00) 4.78 (3.27) 50.0-149.9 0.5-1.499 33.23 (27.04) 22.64 (27.39) 0.00 (0.00) 0.00 (0.00) 0.00 (0.00) 8.98 (0.00) >150.0 >1.5 52.75 (35.93) 23.20 (0.00) 0.00 (0.00) 0.00 (0.00) 0.00 (26.78) 0.00 (0.00) NOILYIAVH DNIZINOI 40 SL1O3443 HLIVIH 40 AHVAWNS '€ NOILYIAVv4d ONIZINOI 0S} Table 3-11. Incidence Estimates for Each of Four Leukemia Types by Age, Exposure Category, and Time Period (per 10° Person-years) (continued) Time period: 16-35 years old ATB +» LNIFWWOD O119Nd HOS L4VHQuxs Leukemia Exposure Exposure type category (rad) category (Gy) 1951-55 1956-60 1961-65 1966-70 1971-75 1976-80 ALL 0 0 0.24 0.12 0.00 0.38 0.79 0.41 0.14.9 0.001-0.049 0.00 1.08 0.48 1.58 1.51 1.73 5.0-49.9 0.05-0.499 1.23 0.84 0.28 0.51 0.20 0.21 50.0-149.9 0.5-1.499 3.71 1.07 3.58 2.59 1.38 1.45 >150.0 >1.5 25.54 7.74 12.74 14.48 10.32 0.00 CML 0 0 0.68 0.35 0.00 1.08 2.22 1.15 0.14.9 0.001-0.049 0.00 2.55 0.98 2.82 2.34 2.33 5.0-49.9 0.05-0.499 3.48 3.44 1.62 4.36 2.44 3.77 50.0-149.9 0.5-1.499 24.33 5.48 14.38 8.15 3.40 2.80 >150.0 21.5 32.17 7.72 10.05 9.05 5.10 0.00 OTHER 0 0 0.70 0.36 0.00 1.11 2.27 1.18 0.14.9 0.001-0.049 0.00 0.18 0.18 1.27 2.63 6.56 5.0-49.9 0.05-0.499 0.15 0.30 0.30 1.67 1.94 6.23 50.0-149.9 0.5-1.499 5.43 1.08 2.50 1.25 0.46 0.33 >150.0 >1.5 8.64 3.12 6.11 8.28 7.03 0.00 AML? 0 0 2.03 (2.12) 0.00 (0.00) 0.00 (0.00) 4.13 (2.28) 8.48 (6.88) 4.40 (2.38) 0.14.9 0.001-0.049 0.00 (0.00) 2.27 (6.08) 1.47 (0.00) 7.05 (0.00) 9.82 (9.78) 16.39 (10.13) 5.0-49.9 0.05-0.499 2.29 (3.57) 2.68 (3.63) 1.51 (3.71) 4.80 (3.78) 3.19 (7.76) 5.86 (4.02) 50.0-149.9 0.5-1.499 13.35 (0.00) 4.26 (11.88) 15.84 (12.10) 12.73 (12.36) 7.51 (12.74) 8.76 (13.35) >150.0 21.5 22.49 (29.61) 11.52 (0.00) 32.04 (0.00) 61.56 (62.25) 74.16 (32.21) 0.00 (0.00) NOILYIQYH ONIZINOI 40 S103443 HLTV3H 40 AHVINANS '€ NOILVYIAvY4 ONIZINOI ISH »LNIJWWOD O1189Nd HO 14VH.us and Time Period (per 10° Person-years) (continued) Table 3-11. Incidence Estimates for each of Four Leukemia Types by Age, Exposure Category, Exposure Time Period: >36 years old ATB Leukemia Exposure category type category (rad) (Gy) 1951-55 1956-60 1961-65 1966-70 1971-75 1976-80 ALL 0 0 0.42 0.38 0.33 0.67 0.83 1.32 0.14.9 0.001-0.049 0.42 0.89 1.32 1.25 1.12 0.32 5.0-49.9 0.05-0.499 1.34 1.36 1.24 0.00 0.34 0.21 50.0-149.9 0.5-1.499 2.99 1.91 1.22 3.15 6.09 0.00 >150.0 >1.5 35.92 45.26 8.57 39.40 0.00 13.12 CML 0 0 1.16 1.05 0.92 1.84 2.29 3.63 0.1-4.9 0.001-0.049 1.12 2.04 2.65 2.17 1.69 0.42 5.0-49.9 0.05-0.499 3.80 5.44 7.12 0.00 4.08 3.70 50.0-149.9 0.5-1.499 19.20 9.60 4.81 9.69 14.68 0.00 >150.0 >1.5 44.30 44.16 6.62 24.09 0.00 5.03 OTHER 0 0 1.97 1.79 1.57 3.13 3.90 6.18 0.14.9 0.001-0.049 0.05 0.24 0.79 1.62 3.16 1.97 5.0-49.9 0.05-0.499 0.27 0.80 2.17 0.00 5.38 10.13 50.0-149.9 0.5-1.499 7.12 3.14 1.39 2.47 3.31 0.00 >150.0 >1.5 19.74 29.64 6.69 36.61 0.00 17.30 AML? 0 0 4.59 (4.88) 4.18 (3.71) 3.66 (2.16) 7.29 (0.00) 9.08 (12.09) 1.21 (1.84) 0.14.9 0.001-0.049 0.62 (0.00) 1.88 (0.00) 4.10 (5.90) 5.63 (7.12) 7.36 (13.33) 1.47 (2.32) 5.0-49.9 0.05-0.499 2.59 (0.00) 4.41 (3.00) 6.85 (3.48) 0.00 (0.00) 5.53 (5.11) 4.78 (3.27) 50.0-149.9 0.5-1.499 10.91 (32.08) 7.73 (22.38) 5.48 (0.00) 15.67 (0.00) 33.64 (38.48) 8.98 (0.00) >150.0 >1.5 66.32 (37.48) 21.67 (43.75) 169.88 (215.98) 0.00 (0.00) 0.00 (0.00) NOILYIav4 ONIZINOI 3The values within parentheses are raw incidence estimates from the Life Span Study subjects in the extended cohort (LSS-E85). These values are presented for comparison with the distributed incidence estimates. ALL = acute lymphocytic leukemia; AML = acute myeloid leukemia; ATB = at time of bombing; CML = chronic myeloid leukemia; OTHER = other leukemia including adult T-cell leukemia and other specifically diagnosed leukemia. Source: Shimizu et al. 1988 NOILYIAV4d ONIZINOI 40 S103443 HLTV3H 40 AHVANINNS '€ cst IONIZING RADIATION 153 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION those exposed to very high radiation levels (> 150 rad [1.5 Gy]) at adult ages ATB. Thus age ATB appears to moderate the temporal patterns of incidence in the highest exposure groups." The authors summarized the study's findings by stating that the results of the incidence estimations for these types of leukemias suggest that the incidences for ALL, AML, CML, and OTHER were all greater in the higher dose categories. In the highest dose group, the estimated incidence of ALL tended to decrease with increasing ATB, while those of ALL, CML, and OTHER were less dependent on ATB. The risks of ALL and CML increased more rapidly with an increasing dose than did those of AML and OTHER. These findings suggest that ALL and CML leukemogeneses are more affected by atomic bomb radiation production than AML. 3.2.2.3 Human Exposures to ?*Ra and **Ra: The Radium Dial Painters Radium was one of the first radioactive isotopes discovered (see Chapter 2). Radium began to find its way into several medicines and concoctions around 1900; however, the highest exposures to radium involved its use in dial paint. Martland (1931) reported that approximately 800 females employed in a factory in New Jersey were painting the dials of watches and clocks with special luminous paint. The paint consisted of a crystalline, phosphorescent zinc sulfide, with the addition of varying amounts of radium and its progeny containing primarily ?Ra, ***Ra, and ??*Th, all in the form of insoluble sulfates in the paint. These young women had the habit of “tipping” the end of the paint brush to a point with their mouth and lips. This resulted in oral ingestion of small amounts of radium, mainly **’Ra (t,, = ~ 1,600 years) and ***Ra (t,,, = 5.75 years). In the women who died, deposits of these isotopes were found over the entire skeleton, and in particular in the cortical bone surface. Martland also estimated the total lifetime body burden of radium to be between 2 and 20 pg Ra in those exhibiting clinical signs of “radium poisoning.” Radiation toxicity seemed more evident in those individuals who worked at the factory for >1-2 years or who had swallowed the paint for >1-4 years. One of the main findings in this study was the increased incidence of death in some of the exposed women. Death was noted in 18 women in the study. Thirteen of the women who died also had jaw necrosis and anemias that developed within 4-6 years after they left the factory for other employment. The other 8 deaths occurred at a later date. Jaw necrosis and anemia occurred with less severity and at lower levels; however, these individuals did develop bone lesions which were characterized as radiation osteitis. Osteogenic sarcomas (scapula, knee, pelvis, femur, orbit) also developed in this study population. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 154 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION A study by Evans et al. (1966) at the Massachusetts Institute of Technology (MIT) reported on the incidence of tumors in individuals exposed to ***Ra and ***Ra in both the radium dial painter population and other populations exposed to alpha emitters. The study included approximately 5,000 or more persons, including chemists who inhaled or ingested radioactive compounds, patients receiving intravenous injections of **RaCl, those who ingested water containing ***Ra, and the female radium dial painters. As a group, the total duration of exposure was usually less than 1 year but in some cases was as long as 20 years. The basic conclusion from this study confirmed the study findings of both Martland (1931) and Rowland et al. (1978)— persons exposed to internalized radium (**‘Ra, ***Ra, **Ra) have an increased chance of developing tumors of the bone or of the paranasal sinuses but little, if any, chance of developing leukemia from any of the doses studied. The data also supported the conclusion that the time required to develop these sarcomas or carcinomas tended to increase as the total activity of radium decreased. When all measured cases were included, the skeletal dose at which tumors began to be observed was 1,200 rad (12 Gy) of alpha radiation. No tumors were observed in the population that received less than 1,200 rad (12 Gy, the “practical threshold”); however, the tumor incidences began to climb in a dose-responsive manner from 1,200 to 50,000 rad (12-500 Gy) skeletal dose. However, not all persons receiving a >1,200 rad (12 Gy) skeletal dose developed sarcomas or carcinomas; the tumor incidence at >1,200 rad (12 Gy) skeletal dose was placed at 40% at the time the study ended. Interestingly, the subpopulation of chemists (n=142) had yet to develop a single tumor, while the other subpopulations had developed many tumors (both sarcomas and carcinomas) throughout the course of the study. Rowland et al. (1978) performed a follow-up study on the incidences of osteosarcoma and “head carcinomas” (carcinomas originating in the mastoid air cells or paranasal sinuses) on this population of female dial painters. The data sets are shown in Tables 3-12 and 3-13. The exact number of luminous dial painters was not known; however, using statistics from the U.S. Department of Labor (DOL), it was estimated that approximately 2,000 individuals had been employed in the industry prior to 1929, with 1,474 workers identified who worked in the industry prior to 1930. Most of the dial workers were not located until as late as the 1960s. For the osteosarcoma analysis, the combined intake of radium (***Ra + 228 Ra) ranged from <0.5 to >2,500 pCi, with the time-weighted average ranging from 0.74 to 3,602 pCi. The average age at first exposure to these two isotopes ranged from 18.4 to 19.8 years. For the head carcinomas, the intake of *** Ra ranged from <0.5 to > 1,000 pCi, with the time-weighted average ranging from 0.71 to 1,577 uCi. The average age at first exposure ranged from 17.8 to 22.3 years. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 155 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Table 3-12. Distribution of Osteosarcomas in a Population of Female Dial Painters Exposed to ?*Ra and *’Ra Systemic intake® (**Ra + 2.5 **Ra)" Activity Activity Average age at Number of Person- Sarcomas per range weighted Number first exposure bone Person- yearsat 1,000 person-years (uCi) average of cases (years) sarcomas years risk at risk (10° years ™) (uCi) >2500 3602 16 18.5 4 299 219 18.3 1000-2499 1675 22 19.2 15 529 419 36.8 500-999 675 18 19.7 8 700 610 13.1 250-499 375 32 19.8 9 1409 1249 7.21 100-249 171 27 18.4 2 1299 1164 1.72 50-99 68.0 21 18.6 0.00 1082 977 0.00 25-49.9 35.2 45 19.5 0.00 2331 2106 0.00 10-24.9 16.3 71 19.2 0.00 3642 3287 0.00 5-9.9 7.04 66 19.1 0.00 3378 3048 0.00 2.5-4.9 3.63 83 18.8 0.00 4217 3802 0.00 1.0-2.49 1.56 101 18.9 0.00 5240 4735 0.00 0.5-0.99 0.74 52 18.4 0.00 2731 2471 0.00 <0.5 — 205 19.0 0.00 10535 9510 0.00 estimated amount that entered the blood after oral exposure ®dose adjustment factor for Ra (and daughters) energy (29.4 MeV) and t,, (1600 years), in relation to ?®Ra (and daughters) energy (10.6 MeV) and t,, (5.75 years) Source: Rowland et al. 1978 ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 156 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Table 3-13. Distribution of Head Carcinomas in a Population of Female Dial Painters Exposed to ?*Ra Systemic intake? (**Ra) Activity Carcinomas per weighted Average age at Number of Person- 1,000 person- Activity average Number first exposure head Person- years at years at risk range (pCi) (LCi) of cases (years) sarcomas years risk (10% years ™) >1000 1577 10 17.8 3 264 164 18.3 500-999 584 11 22.3 2 385 275 7.27 250-499 366 25 20.1 5 1062 812 6.16 100-249 176 31 18.3 5 1255 945 5.29 50-99 68.3 23 18.2 1 1123 893 1.12 25-49 35.5 34 18.8 1 1666 1326 0.75 10-24.9 15.9 59 19.0 0.00 3025 2435 0.00 5-9.9 6.99 41 18.4 0.00 2114 1704 0.00 2.5-4.9 3.52 70 19.6 0.00 3558 2858 0.00 1.0-2.49 1.55 145 19.3 0.00 7531 6081 0.00 0.5-0.99 0.71 73 18.7 0.00 3799 3069 0.00 <0.5 — 227 18.9 0.00 11624 9354 0.00 2 estimated amount that entered the blood after oral exposure Source: Rowland et al. 1978 The increased incidence of osteosarcoma in this exposed population can be attributed in part to radium’s distribution and elimination kinetics. Radium (independent of the isotope) has distribution patterns similar to those of calcium. Once ingested, radium distributes primarily to the bone surfaces and within 10 um from the osteogenic cells (the target cells for radium toxicity). The range of alpha particles in bone is estimated to be approximately 30-70 um (see Chapter 2), well within the range of these populations of radiosensitive cells but outside the range of red marrow cells from which leukemias would originate. The osteogenic cells initially receive a large intake of ionizing radiation after each dose of ***Ra and/or **Ra. Owing to the long t,, of both 2*Ra (~ 1,600 years) and ***Ra (5.75 years), both nuclides will eventually redistribute throughout the bone matrix over time, moving out of range of the osteogenic cells but continuing to irradiate other less sensitive cells and tissues within a 70-um radius of each atom of radium. A similar proximity of exposure scenario is likely true for the development of the head carcinomas in this population of exposed workers. The most likely explanation for the head carcinomas is that they are due to accumulation of **’Rn gas and radon ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 157 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION daughters in the air spaces. This explains the lack of effect of 22Ra and ***Ra, which transform through 2°Rn by short half-life transitions, and which produce much lower doses than from Rn (Rowland 1994). The data presented in both tables show that a dose response is present when comparing the weighted-average dose to the number of osteosarcomas or head carcinomas observed throughout the lifespan of these exposed individuals. In addition, the author of the study noted that a dose-squared-exponential function most closely described the bone sarcomas induced by these two radionuclides. In contrast, a linear dose-response function was found to best describe the head carcinoma data. 3.2.2.4 Human Exposures to ?*Ra via Injection During 1944-1951, injections of ***Ra were administered to approximately 2,000 German adults and children as a treatment modality for several debilitating diseases, including tuberculosis and ankylosis spondylitis. A report by Spiess and Mays (1970) summarized the health effects of 925 humans (708 adults and 217 children) injected with ***Ra who received alpha doses of up to 5,750 rad. The duration of treatment ranged from a few weeks to a few years, depending on the disease being treated. For this study, exposed individuals were classified by age and dose received during the treatment period(s). These subpopulations are shown in Tables 3-14 and 3-15. As was the case with *Ra and **Ra, the critical organ for toxicity for >*Ra was bone tissue, with an overall increased incidence of osteosarcoma in the exposed population. Tables 3-14 and 3-15 report the dose parameters and incidences of osteosarcomas induced by ***Ra by age distribution. As can be seen from these data, the lowest dose that resulted in a detectable osteosarcoma was 90 rad (in an adult). The incidence of osteosarcoma in this population increased in a dose-responsive fashion, with a 0.7% rise in incidence of osteosarcomas per 100 rad of 2*Ra skeletal dose in adults and a rise of 1.4% per 100 rad in all children (see Table 3-15). The ability of **Ra to induce bone tumors in males and females, with or without pre-existing bone disease, was equal in all instances. At the time of publication of the Speiss and Mays (1970) report, no head carcinomas or leukemias attributable to ***Ra exposure had been observed. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Table 3-14. Alpha Dose from Injected ?Ra (in rad) by Age Group, Number, and Percentage of Subpopulation Developing Osteosarcoma 158 Age at first injection of ?*Ra Dose range 1-5ye 6-10y 11-15 16-20y All children Adults (rad) Parameters ars ears years ears (1-20 years) (>20 years) 0-89 Average rad dose 46 ND 24 55 47 53 No. of persons 1 ND 1 3 5 210 % Bone sarcomas? 0.00 ND 0.00 0.00 0.00 0.00 90-199 Average rad dose 152 126 ND 148 146 139 No. of persons 2 1 ND 4 7 229 % Bone Sarcomas 0.00 0.00 ND 0.00 0.00 1.3 200-499 Average rad dose 446 397 344 342 363 306 No. of persons 2 9 7 17 35 214 % Bone sarcomas 0.00 0.00 29 0.00 5.7 1.9 500-999 Average rad dose 860 703 727 719 727 650 No. of persons 7 30 22 17 76 55 % Bone sarcomas 0.00 10 5 0.00 5.3 5.5 1000-1999 Average rad dose 1426 1381 1340 1246 1345 ND No. of persons 16 19 18 19 72 ND % Bone sarcomas 38 26 22 21 26.4 ND 2000-5750 Average rad dose 3491 3451 2550 3100 3329 ND No. of persons 9 9 3 1 22 ND % Bone sarcomas 22 67 0.00 0.00 36.4 ND All persons Average rad dose 1662 1207 984 747 1103 204 with a known dose of #'Ra No. of persons 37 68 51 61 217 708 % Bone sarcomas 22 21 14 7 15.2 1.4 a 9, of bone sarcomas as of 1969 ND = No data available Source: adapted from Speiss and Mays 1970 ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 159 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION Table 3-15. Age Distribution, Alpha Dose (in rad), and % Incidence of Osteosarcomas Induced by **Ra Injection Exposed Average dose % Incidence per Age (years) patients Sarcoma cases % Incidence (rad) 100 rad 1-5 37 8 21.6 1662 1.30 6-10 68 14 20.6 1207 1.70 11-15 51 7 13.7 984 1.39 16-20 61 4 6.6 747 0.88 All children 217 33 15.2 1103 1.38 Adults 708 10 1.4 204 0.69 Source: adapted from Speiss and Mays 1970 It is also of interest to note that the lowest alpha dose to induce osteosarcoma in this population exposed to 224Ra was 90 rad, significantly lower than the 1,200 rad (skeletal dose at death) required to induce osteo- sarcoma in the radium dial painters (**Ra and **Ra). The answer lies in the physical half-life of ***Ra, its distribution kinetics in the bone, and the total dose to the critical tissue. **‘Ra distributes in an identical fashion within the bone matrix as does *’Ra and **®Ra, with the initial deposition of each of these isotopes within 10 pm from the osteogenic cells on the bone surface. In cases of Ra and ***Ra exposure, the dose of radiation was initially received by the osteogenic cells; however, as time progressed, natural bone function and reorganization resulted in the movement of these isotopes (and other minerals) away from these target cells and into the mineral volume of the bone, out of the range of the alpha particles (50-70 pm) emitted by these isotopes. These longer-lived isotopes continued to transform for several years; however, they were out of range of the target tissues (osteogenic cells) and relatively innocuous relative to bone tumor formation. This was not the case with those exposed to ‘Ra. *>‘Ra follows identical distribution patterns as *’Ra and 228Ra- however, the half-life of 2‘Ra is 3.62 days and the dosimetery is quite different from other radium isotopes. The local dose to the skeleton of 224Ra within 0-10 pm is estimated to be nine times the average skeletal dose of 2“Ra (because the radiation dose is almost exclusively delivered to the osteogenic cells during **Ra’s short half-life). However, the dose from **Ra to the critical osteogenic cells is only 0.63 times the average skeletal dose, which is randomly distributed throughout the bone matrix, with the osteogenic cells only receiving a portion of the total dose to the skeleton. Using these numbers as crude conversion factors, the equations for determining an estimate of dose to the osteogenic cells for the radium dial painters and the 22%Ra injection population are: 90 rad x 9 = Dose to Target Cells from ***Ra = 810 rad 1,200 rad x 0.63 = Dose to Target Cells from “Ra = 760 rad **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 160 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION These equations show that the total dose to the target osteogenic cells of the bone from 22‘Ra and 22°Ra are approximately equal, and would explain any superficial dose discrepancies. Other studies of interest include those involving tinea capitis treatment (Albert et al. 1986: Harley et al. 1983; Ron and Modan 1984), uranium miners (NIH 1994), and iron miners (Radford and Renard 1984). 3.2.2.5 Other Human Cancer Studies Cancer data from other sources are also available in the open literature. Sorahan and Roberts (1993) performed a case-control study examining the association between childhood cancer and the occupational exposure of the child’s father to radiation. Data from the Oxford Survey of Childhood Cancers collected from 1953 to 1981 were used. There was a total of 15,279 cases and the same number of matched controls (matched for sex, date of birth, and local area). Estimates of exposure were completed based on job descriptions. Dose groups were: not exposed (<0.1 rem, 0.001 Sv), 0.1-0.4 rem (0.001-0.004 Sv), 0.5-0.9 rem (0.005-0.009 Sv), and > 1 rem (0.01 Sv). There were also 27 case fathers and 10 control fathers who had been exposed to radionuclides. Based on the information gathered, it was determined that 67 fathers of children with cancer and 50 fathers of controls were exposed to external forms of ionizing radiation within 6 months of conception of their children. Relative risks for estimated doses of external radiation and all childhood cancers were near one, and none of the specific types was statistically significant. Among fathers with likely exposure to radionuclides (from unsealed radioactive material), the relative risk for all childhood cancers was statistically significant at 2.87 (95% CI 1.15-7.13). There is considerable uncertainty associated with this value, and the findings are not supported by those in the studies of the survivors of the atomic bombings in Japan. Cancer incidence during the first 20 years of life among the children of parents who suffered a mean gonadal dose of 43 rem (43,000 millirem) was 43 cases in 31,150 offspring, and there were 49 cases among 41,066 offspring from the control population. For leukemia, there were 16 cases among 31,150 children of exposed parents and 21 cases among the 41,066 children from the unexposed controls (Yashimoto et al. 1991). In 1991, Matanoski (1991) reported on the health effects of low-level radiation exposure to shipyard workers. Many of the earlier human radiation studies had been of groups exposed to large doses of radiation where there was a clear dose response for cancer induction. The typical dose response curve assumes a linear no- threshold shape that starts with zero effect at zero dose and extends linearly upward to intersect the measured effect at doses above 10-40 rad (0.1-0.4 Gy). Previous attempts to demonstrate the shape of the curve at “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 161 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION low and occupational doses had not produced a clear result. The purpose of the Matinoski study was to better define the upper and lower bounds of risk associated with radiation exposure using a relatively large population group whose radiation doses had been measured carefully, many of which were elevated above ambient levels, and for which there was an adequate control population. The selected group was workers in public and private U.S. shipyards involved in the overhaul and refueling of nuclear-powered warships. Concern over the risk to these workers had been raised earlier in a limited study of deaths among Portsmouth, New Hampshire, shipyard workers (Najarian 1978). Also, a report had been released on an apparent leukemia excess among U.S. military veterans (Caldwell 1980). However, a subsequent cohort study by Rinsky (1981) did not observe a relationship between exposures and leukemia. These groups had received approximately the same radiation dose. The Matinoski study group involved workers at eight nuclear facilities throughout the United States, who had been occupationally exposed from 1957 through 1981. The workers were divided into dose groups and exposures lagged by 2 years for leukemia and lymphoma, and 5 years for lung cancer to account for disease latency. The numbers in each of the three major dose groups were: 32,510 non-radiation workers; 10,348 radiation workers whose doses were below 0.5 rem (0.005 Sv); and 27,872 radiation workers whose doses were over 0.5 rem (0.005 Sv). The data were statistically assessed using methods suggested by Gilbert (1983). In this manner it was estimated that the statistical power had a 79% probability of finding a risk of leukemia from cancer if the risks were as large as five times the linear model estimates in BEIR III. The SMRs (with 95% confidence interval) for those exposed to > 0.5 rem (0.005 Sv) were 0.91 (0.56,1.39) for leukemia and 0.82 (0.61,1.08) for all lymphatic and hematopoietic cancers; SMRs for the lower-dose group were similar. This indicates the risks of these diseases is lower among shipyard workers than in the general population. The risk of lung cancer, however, was significantly higher (p<0.5) in the non-nuclear work group and slightly higher in the nuclear work groups than for the public. Mesothelioma was selected as a biological marker for the presence of asbestos exposure in the population, and a high SMR for mesothelioma (>5 for radiation workers and 2.4 for non-radiation workers) suggests that the excess is due to asbestos exposure and not to radiation. The radiation worker population did not show a significant increase in the risk of any of the cancers studied, except for mesothelioma which was attributed to asbestos. The data suggest that there is not a consistent relationship between low radiation dose and leukemia, or lymphatic or hematopoietic neoplasms. In another human study, Checkoway et al. (1988) used a historical cohort mortality study of 8,375 workers at the Y-12 plant at Oak Ridge who were exposed to gamma radiation and/or alpha radiation by inhaling uranium compounds. The population studied included employees who had worked for at least 30 days between May 1947 and December 1974. The median duration of exposure in that study was 9.2 years. There ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 162 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION were 862 deaths in the cohort, which was composed of 6,781 white males. The majority of the cohort was followed for 10 years. Exposure from gamma radiation was measured with dosimeters or film badges, and internal alpha contamination was estimated with urinalysis (reported as cumulative radiation dose). Mortality was compared with both U.S. and Tennessee rates. For all causes there were fewer deaths than expected (Standardized Mortality Ratio [SMR] 0.89, 95% CI 0.84-0.96). These findings are consistent with the healthy worker effect. There were a total of 196 cancer deaths in the population compared to 193 expected, (SMR 1.01). Relative to U.S. white males, there were statistically significant excesses of lung cancer (SMR 1.36, 95% CI 1.09-1.67) and cancers of the brain and central nervous system (SMR 1.8, 95% CI 0.98-3.02). Cancer SMRs for Tennessee white males were lower than those for the U.S. white male referent population. A trend was observed for increasing lung cancer deaths with increasing radiation dose, although the trend was greater with a zero-year latency assumption than for a 10-year latency assumption. Mortality for brain and central nervous system cancers was unrelated to either the alpha or gamma dose. The authors point out that the dose-response trend for lung cancer mortality should be viewed with some caution because the rate ratio estimates are imprecise, as reflected by the wide confidence limits because of small numbers. Also, the dose-response gradients are reduced considerably when a 10-year latency is assumed. No data on cigarette smoking were included in the study. Other studies have also shown that the lung is the primary target organ of airborne radon when mixed with diesel fumes, cigarette smoke and silica dust related to uranium mining, but not from uranium itself (BEIR IV 1988), which was the most important exposure in this plant. Readers are encouraged to read about the effects of cancer induced by the chemical and radiological effects of uranium mining in the ATSDR (Draft) Toxicologic Profile for Uranium (1997). In a later related report, Kneale et al. (1981) reported on an attempt to answer criticism of previous reports of a study of cancer risks from radiation to workers at Hanford using the method of regression models in life-tables. The population included employees up to 1975 who wore film badges and included deaths through 1977. The dose was measured with a film badge. Some internal monitoring was also completed: individuals for whom internal monitoring was completed tended to have higher external exposures. Cause of deaths was classified into three categories: (1) cancers of radiosensitive tissues (stomach, large intestine, pancreas, other intestinal, pharynx, lung, breast, lymphoma, myeloma, myeloid leukemia, other reticuloendothelial system cancers, and thyroid); (2) other cancers; and (3) non-cancer. Previous reports aroused much controversy because the reported risk per unit of radiation dose for cancers of radiosensitive tissues was much greater than the generally accepted risk based on other studies which had been used in setting safety levels for exposure to low-level ionizing radiation. The estimated risk calculated from this study was about 10-20 times greater than would have been expected by extrapolating downward from higher ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 163 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION doses analyzed in previous studies, notably studies of the atomic bomb survivors. The authors suggested that after statistically controlling for a wide range of possible interfering factors, there was a significant downward curve at about 10 rem in the dose-response relation. Therefore, the agreement with other studies, conducted at higher doses, may be better than is widely assumed. The authors also point out that the findings on cancer latency (about 25 years) and the effect of exposure age (increasing risk with age) are in general agreement with other studies. The unexplained finding is a significantly higher dose for all workers than for workers who developed cancers in tissues that are supposed to have low sensitivity to cancer induction by radiation. The healthy worker effect was very large in this study—the SMR for all causes of death was 75. Therefore, the fact that living workers at Hanford have higher radiation doses than workers who died could reflect a healthy worker effect. Using a model that allowed for cancer latency and variation in sensitivity to radiation with age of exposure, investigators estimated a doubling dose for cancer of 15 rad with a 95% CI of 2-150 rad. The interval between cancer induction and death was estimated (maximum likelihood estimate) to be 25 years. The investigators also discuss the fact that Japanese bomb survivor data and ankylosing spondylitis data indicate that the doubling dose is about 200 rem. No records of smoking were available for the Hanford population. Internal monitoring showed evidence of internal exposure in only 225 of the Hanford workers; the investigators indicate that the effects were a result of external rather than internal radiation. The authors point out that the Hanford study cannot separate the greater radiobiological effects of neutrons from the lesser effects of gamma radiation. 3.2.2.6 Laboratory Animal Reports Cancer is a major latent biological effect of inhaling many of the various isotopes and physical forms of radioactive nuclides. The literature contains many references describing the onset and specific types of cancers that occur after inhalation exposure(s) (see the ATSDR profiles on uranium and radon for more complete information). The vast majority of the literature reports concerning the inhalation of radionuclides with the subsequent development of cancer dealt with alpha and beta particle emitters incorporated into soluble or insoluble particles of varying sizes for an acute duration of delivery (usually only a few minutes to achieve the desired initial lung burdens) followed by a long-term exposure of the tissues. Due to the large database describing the neoplasia associated with exposure to ionizing radiation, only a cross-section of these reports will be discussed in some detail here. Cancer has been reported in several species of laboratory animals after inhalation exposure to many different radionuclides, and will at least initially develop where the element would normally distribute within the body, ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 164 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION regardless of whether it was radioactive (see Table 3-1). For example, isotopes of strontium (**Sr and Sr) have strong affinities for bone; therefore, it is reasonable to expect that the initial site of neoplasia formation will be in bone tissues. Metastases may occur to more distant organs at a later time, depending on the type of tumor induced. For example, Gillett et al. (1987b) studied the late-occurring biologic effects in Beagle dogs given graded levels of **SrCl, via single brief inhalation exposures and then observed for their lifespans. The cumulative absorbed beta dose to bone ranged from 12 to 1,200 rad at 30 days and from 200 to 170,000 rad at 1,000 days after exposure. The most frequent cause of death in exposed dogs was primary bone cancer (30 of the 66 exposed dogs). Bone-tumor-related deaths occurred from 759 to 3,472 days after exposure. Four additional animals developed carcinomas in soft tissues adjacent to the bones of the skull (invasive baso-squamous carcinoma, transitional carcinomas of the nasal cavity, and an adenocarcinoma in the maxilloturbinate region). The remaining exposed and control dogs died from a variety of other causes not related to *°Sr exposure. Radiation-induced lesions were confined to the bone, bone marrow, and adjacent soft tissue. Forty-five primary bone tumors occurred in 31 of the 66 exposed dogs (47%). Metastasis occurred from 21 tumors, with the lungs being the most frequent site of metastasis (76%). Twenty-seven tumors were classified as different subtypes of osteosarcoma, 14 as hemangiosarcomas, 3 as fibrosarcomas, and 1 as a myxosarcoma. Using **' Am, Gillette et al. (1985) determined the retention, translocation, and excretion of inhaled monodisperse (1.8 um AMAD) or polydisperse aerosols (AMAD 0.75, 1.5, 3.0 um) and explored the development of osteosarcomas in dogs. **' Am was soluble and transported in blood and deposited in the liver and skeleton. Two years after exposure, 0.5-3.0% of the initial lung burden was present in the lung, while 10-47% was in the liver, and 10-36% in the skeleton. Four out of 15 dogs developed osteoblastic osteosarcomas < 1,000 days after exposure to **' Am. Three of these were in the 1.8-um polydisperse AMAD group and one was in the 3.0-um monodisperse AMAD group. Initial lung burdens for all 15 ranged from 1.0 to 6.2 pCi. Radiation doses in rad to 1,000 days for dogs ranged from 185 to 1,260 to the lungs, 180 to 1,070 to the liver, and 67 to 410 to the skeleton, while the skeletal doses to death for the 4 dogs developing osteosarcoma were 500, 300, 240, and 180 rad. Metastasis was evident in only 1 of the 4 dogs. Neoplastic formation after exposure to **Pu and **°Pu has been extensively studied in Beagles. Hahn et al. (1981) exposed 72 Beagle dogs by inhalation to monodisperse aerosols of ***PuO, measuring 1.5 um and another 72 dogs to particles measuring 3.0 um. Twenty-four control dogs inhaled an aerosol produced from a diluent solution. Equal numbers of males and females were used. Groups of 12 dogs were exposed to concentrations to produce initial lung burdens of 0.56, 0.28, 0.14, 0.07, 0.029, 0.01, and 0 pCi/kg. Mean ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 165 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION actual initial lung burdens were 0.97, 0.43, 0.26, 0.11, 0.055, 0.017, and 0 pCi/kg, respectively, for 1.5 um particles, and 1.2, 0.57, 0.30, 0.14, 0.069, 0.024, or 0 uCi/kg, respectively, for 3.0 um particles. Necropsy and histopathological examinations were performed at death. Primary bone cancers developed in Beagle dogs briefly exposed by inhalation to aerosols of **PuQ,. 2**Pu0, was initially deposited in the respiratory tract where it was retained with a half-time greater than 100 days. A portion of the ***Pu was solubilized and translocated to the liver and skeleton. Forty-six of 144 exposed dogs and 2 of 24 control dogs died (as of date of publication). Deaths unrelated to bone tumors are as follows: 7 of the 144 dogs died 536-1,213 days after exposure from severe radiation pneumonitis and pulmonary fibrosis (3,700-8,600 rad to lungs) and 4 of the 144 dogs died of pulmonary carcinomas 1,319-2,143 days after exposure (2,100-5,900 rad to lungs). Five years after exposure, 46 osteosarcomas developed in 35 of 144 exposed dogs. The cumulative absorbed radiation doses to the skeleton for these dogs ranged from 210 to 830 rad, and time from inhalation exposure to death ranged from 1,125 to 2,078 days. Of the 46 bone tumors, 22 originated in the vertebrae (49%), 12 in the humeri (26%), 6 in the pelvis (13%), and 6 in miscellaneous long and flat bones (13%). Most of the tumors were well-differentiated sarcomas. Only 10 of the tumors metastasized; the lung was the organ most often invaded. Bone tumors were associated with lesions of radiation osteodysplasia. The number of bone tumors found in this study indicated that inhaled ***PuQ, was an effective skeletal carcinogen. The authors noted that the rate of solubilization in the lungs and translocation to the bone may be factors in the radiation dose pattern and the type and location of bone tumors that developed after inhalation of ***Pu0Q,. In another study, Muggenburg et al. (1994) exposed 144 Beagle dogs to ***Pu0, aerosols; 72 of these dogs inhaled monodisperse aerosols of 2**PuO, with AMADSs of 1.5 um, and 72 dogs inhaled 3.0-um AMAD particles. For each particle size, dogs were exposed to achieve one of the following six graded activity levels of initial lung burden: 0.57, 0.27, 0.14, 0.08, 0.03, or 0.01 pCi of #**PuO,/kg. These dogs were observed for biological effects (cancerous and non-cancerous effects) over their natural lifespan. The ***PuQ, aerosol exposures resulted in initial lung burden ranging from 37 to 0.11 and from 1.50 to 0.01 pCi of ***PuO,/kg of body mass for the 1.5- and 3.0-um particles, respectively. The particles were found to dissolve slowly, resulting in translocation of the Pu to liver, bone, and other tissue sites. The principal late-occurring effects were tumors of the lung, skeleton, and liver. Lung tumors were detected in 47 of the exposed dogs; within this group, lung tumors were the primary cause of death in 8 dogs that died from 3.6 to 12.3 years after exposure. Twenty-seven dogs that died from bone tumors also had lung tumors. Lung tumors were primarily bronchoalveolar carcinomas and papillary adenocarcinomas. Skeletal tumors were detected in 92 dogs; of this group, bone tumors were the primary cause of death in 89 dogs that died from 3.1 to 13.2 years after exposure. These tumors were primarily osteosarcomas that occurred in the axial skeleton and head of the ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 166 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION humerus. Liver tumors were detected in 19 dogs and caused the death of 2 dogs that died from 6.6 to 13.2 years after exposure. Thirteen of these dogs had a variety of malignant liver tumors and 6 had only benign liver tumors. Risk factors estimated for these cancers were 2.8 lung cancers per 10° dog rad, 8.0 liver cancers per 10° rad, and 6.2 bone cancers per 10° rad. Using a different isotope of Pu, Muggenburg et al. (1988) exposed 216 Beagle dogs to ***PuO, aerosols. The 29PuQ, aerosols were monodisperse with AMADs of 0.75, 1.5, or 3.0 um. After exposure, all animals were matched by age and sex (6 males and 4 females in each group). Group I dogs had initial pulmonary burdens (IPBs) of 8.91-109.9 uCi of 2°PuO,/kg of body mass with a mean of 42.9 pCi/kg. Group II dogs had IPBs of 2.97-52.9 uCi of 2°PuO,/kg of body mass with a mean of 15.9 pCi/kg. The plutonium particles produced protracted alpha irradiation of the lungs over the course of several years. The average alpha dose to the lungs to 2,600 days after exposure for the dogs in group I ranged from 230 to 3,200 rad and for the dogs in group II, 80 to 1,570 rad. Five dogs died within 1 year of exposure. Lung carcinomas were observed in 3 dogs (2 males and 1 female) from group I (2,900-3,200 rad) and in 1 dog (male) from group II (1,000 rad). These 3 dogs from group I had the highest doses and had many small, dense, parenchymal scars and small foci of alveolar septal fibrosis scattered throughout the lungs. Alveolar epithelial hyperplasia was associated with many of the fibrotic foci. Oral melanoma was found in one dog (male) from group II that died (190 rad). The authors note that these findings indicate that alpha irradiation of the lungs of humans could produce restrictive lung disease at long times after initial exposure. Histopathology was performed on animals that died during the duration of this study. Other studies in dogs have demonstrated that exposure to **’Pu can induce lung cancer (Boecker et al. 1988; Galvin et al. 1989). In addition to Pu, other radionuclides have been shown to induce cancer in dogs. Hahn et al. (1977) reported on a series of lifespan studies initiated to study the biological effects of beta emitters using aerosols of insoluble fused-clay particles containing *°Y, °'Y, '*‘Ce, or **Sr. AMAD:s ranged from 0.8 to 2.7 pm and the duration of exposure was 2-48 minutes. *’Y exposures resulted in a range of initial lung burdens of 0 or 80-5,200 uCi/kg body weight; *'Y exposures resulted in a range of initial lung burdens of 0 or 11-360 pCi/kg; exposure to “Ce resulted in a range of initial lung burdens of 0 or 0.0024-210 uCi/kg; and Sr exposures resulted in a range of initial lung burdens of 0 or 3.7-94 pCi/kg. The approximate effective half-lives in the lungs of insoluble *°Y, °'Y, '*‘Ce, and *’Sr are 2.6, 50, 180, and 400 days, respectively. Dogs exposed to '**Ce or *°Sr generally had more active inflammation and pulmonary fibrosis than dogs exposed to %Y or °'Y, perhaps due to their longer average survival time after inhalation exposure and the influence of the continuous irradiation. Primary malignant lung tumors were found in 5 of the °'Y exposed dogs (cumulative **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 167 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION lung doses to death of 16,000-25,000 rad), 9 of the '**Ce exposed dogs (22,000-61,000 rad), and 14 of the *’Sr exposed dogs (34,000-68,000 rad). Several dogs died with primary hemangiosarcomas of the heart or mediastinum, and several died with primary bone tumors or epithelial tumors associated with the nasal cavity. Exposure to '**Ce or *Sr, with dose rates that decreased slowly, induced pulmonary hemangio- sarcomas. Pulmonary irradiation from *'Y, with a rapidly decreasing dose rate, resulted in bronchoalveolar carcinomas. Benjamin et al. (1978) exposed dogs to '**Ce in fused aluminosilicate particles with particle sizes ranging from 1.4 to 2.7 um. Radiation pneumonitis and pulmonary fibrosis were evident in 13 of 14 dogs that died. Additionally, there was one bronchoalveolar-squamous carcinoma and four pulmonary hemangiosarcomas. The authors note that the tumors observed developed within a time period when the dogs showed severe lymphopenia and also were likely to have immune suppression. The relationship between the two is not clear. These studies do suggest, however, that chronic pulmonary irradiation from internally deposited radionuclides may have a dual effect in terms of carcinogenesis. Other species exposed to Pu isotopes show similar results. Brooks et al. (1992) exposed male monkeys by nose-only inhalation to an aerosol of soluble **°Pu (NO,), to produce projected initial lung burdens of either 1.08, 0.27, or 0.1 pCi. Total skeletal Pu activity was nearly constant for the first year after dosing; however, the skeletal body burden at sacrifice increased with time up to 99 months after exposure to 1.08 uCi because of clearance from other organs. **°Pu in the liver peaked at 1 year and then decreased to about 10% of the peak value at 99 months postexposure. In the testes, Pu was localized in the interstitial tissue with only 0.01-0.002% of the projected lung burden remaining in the testes at 99 months after inhalation. Animals exposed to 1.08 pCi died (3 of the 8) of radiation-related pulmonary pneumonitis and fibrosis, and a primary papillary adenocarcinoma of the lung was identified in one animal in that group. Of two animals exposed at 0.27 pCi, one developed fibrosis and one developed fibrosis and pneumonitis. Of those exposed at 1.08 uCi, 6 developed pneumonitis, 9 developed fibrosis, 7 developed alveolar epithelial proliferation, and 1 developed lung cancer. Overall, results of this study indicate that the lungs, the bone, and the liver are the major sites of deposition following inhalation of soluble plutonium in monkeys. The primary biological effects, pneumonitis and pulmonary fibrosis, were seen in monkeys with large initial plutonium burdens. There was little indication of chromosome damage at levels of plutonium at which there were no major histological changes in the lungs. In contrast, Hahn et al. (1987) exposed 16 male Rhesus monkeys to particles laden with 2*°PuQ, via inhalation (AMAD 1.6 um) Initial lung burdens ranged from 0.0018 to 1.8 uCi. A pulmonary fibrosarcoma of bronchial origin was discovered in a Rhesus monkey that died of pulmonary fibrosis 9 years (3,277 days) ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 168 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION after inhalation of 2*°Pu0Q,, with a radiation dose to the lungs of 1,400 rad. The fibrosarcoma proliferated around the major bronchus of the right cardiac lung lobe and extended into the bronchial lumen and surrounding pulmonary parenchyma. The time-dose relationship for survival is consistent with that of dogs and baboons that inhaled plutonium dioxide and died with lung tumors. In addition to dogs and monkeys, induction of cancers in rats irradiated with different forms of ionizing radiation has also been studied. A lifespan study was conducted by Lundgren et al. (1981) in CFW random-bred male mice for the toxicity of *’Y (AMAD 0.7-1.4 pm) inhaled in insoluble fused alumino- silicate particles. Groups of 25-393 mice were exposed to achieve initial lung burdens of 1-10, 11-20, 21-30, 31-40, 41-50, 51-60, and 61-140 pCi. Exposures were 10-20 minutes. Control mice (n=763) were either unexposed, sham exposed, or exposed to nonradioactive Y in fused aluminosilicate particles. At death, animals were necropsied and major organs examined. Mean rad to the lungs to death were 1,100, 2,300, 3,800, 6,000, 7,200, 8,800, and 14,000 rad for initial lung burdens of 1-10, 11-20, 21-30, 31-40, 41-50, 51-60, and 61-140 uCi, respectively. The cumulative survival rates of mice in groups with initial lung burdens of 1-10 pCi (1,100 rad to lungs) and 11-20 pCi (2,300 rad to lungs) were not significantly different from that of controls. Initial lung burdens of more than 20 pCi (>3,000 rad to lungs) resulted in radiation pneumonitis and a significant shortening of the lifespan (p<0.05). Median survival time ranged from 12% to 2.1% of controls at initial lung burdens of more than 20 pCi, and median time of survival after exposure ranged from 66 to 12 days for these dose levels. Radiation pneumonitis was observed in 75-100% of mice at these dose levels. The incidences of all lung tumors and other lesions in exposed mice were similar to those of controls, except for pulmonary adenomas, which were found more frequently in groups of mice with initial lung burdens of 1-10 and 11-20 pCi. The authors note that the early occurring biological effects observed in mice in this study were similar to those observed in Beagle dogs exposed to *°Y in the same form. Hahn and Lundgren (1992) also studied lung neoplasms induced in rats by inhaled, internally deposited 144Ce0,. Fischer 344 rats were exposed once or repeatedly by inhalation to '**CeO, and observed over their natural lifespan. A group of 314 rats was exposed once, briefly, to '*“CeO, to achieve lung burdens of 0.06, 0.32, 1.16, or 6.48 uCi. Another group of 201 rats was repeatedly exposed briefly once every other month for 1 year (7 exposures) to initially establish and subsequently re-establish desired lung burdens in groups of 18-38 males and 19-38 females of 0.35, 1.30, 5.67, or 32.4 pCi. There was significant life shortening only in those rats exposed repeatedly at the highest radiation dose (32.4 pCi). In these rats, there was a high percentage of squamous cell carcinomas of the lungs, as well as much lower percentages of adenocarcinomas of the lungs, hemangiosarcomas of the lungs, and pleural mesotheliomas. At lower doses, adenocarcinomas ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 169 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION were the most predominant tumor, with alveolar, papillary, tubular, or undifferentiated adenocarcinomas most commonly observed histologically. The authors note that the lung neoplasms induced by this beta-emitting radionuclide are similar in nature to those induced by alpha-emitting radionuclides deposited in the lung in rats. However, the radiation-induced squamous cell carcinomas of the lungs differ from those induced by heavy particle loads of nonradioactive compounds. Many other studies also confirm the formation of cancers of the respiratory tract in laboratory animals (Benjamin et al. 1975, 1978, 1979; Boecker et al. 1988; Gillette et al. 1992; Hahn et al. 1976, 1980, 1988; Lundgren et al. 1974, 1980a, 1983, 1991; McClellan et al. 1973). Similar cancer data have been demonstrated after external exposure to radionuclides, particularly those that are beta and gamma emitters. Ootsuyama and Tanooka (1989) exposed female ICR mice to a source of beta irradiation with 40,000 pCi of **Sr and *’Y which delivered a surface dose rate of 228 rad/minute and a 20-80% lower dose rate to the top of the vertebrae. Mice were irradiated three times weekly at surface doses per exposure of 135, 150, 250, 350, 470, and 1,180 rad, respectively, and irradiation was continued until a palpable tumor appeared (up to 86 weeks). Tumors that formed in the irradiated area were of skin and bone origin. Most mice had either an osteosarcoma or a skin tumor, while some mice had both osteosarcomas and skin tumors. Osteosarcomas were induced most frequently with surface doses of 250-350 rad per exposure. These doses were 20-80% lower at the depth of the bone. The authors note that repetitive irradiation seems to be essential, or at least more effective, for induction of osteosarcomas, as well as for skin tumors, and that carcinogenic dose for osteosarcoma was less than that for skin tumors. Hulse (1966) irradiated female CBA/H mice with 2°*T1 and then allowed them to live out their natural life (unless they were moribund or sacrifice was deemed necessary). Nominal doses ranged from 750 to 12,000 rad. ***T1 particles have a low energy (mean 0.24 MeV) and a maximum range in soft tissue of 3 mm. Doses reaching the dermis and epidermis were 69-72% and 40-70%, respectively, of the nominal dose. Mice were irradiated on one or two zones. The single-zone exposure included the middle of the trunk, and the two-zone exposure included the thorax (with proximal forelimbs) and pelvis (with hindlimbs), with an intervening unirradiated gap of about 1 cm. In one group, two zones were arranged to be immediately adjacent (thorax-midtrunk, midtrunk-pelvis) with the potential for slight overlap due to the movement of the mice. The percentage of mice irradiated on one zone only and dying with skin tumors was 7, 25, 42, and 57 for the 1,500-, 3,000-, 6,000-, and 12,000-rad dose groups, respectively. In mice exposed to two separate zones, the percentage dying of skin tumors was 3, 17, and 50 for the 750-, 1,500-, and 3,000-rad dose ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 170 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION groups, respectively. Mice that were irradiated on two adjacent zones received 1,500 rad only. Twenty percent of these mice died with skin tumors. A total of 133 tumors arose in tissues which were affected by the irradiation, and 7 tumors arose in similar tissues outside the irradiated zones. There were 20 epidermal tumors: 2 benign and 18 squamous cell carcinomas, which were situated on the torso. There were 96 dermal tumors; 77 of those were malignant and of those 74 were fibrosarcomas. Five fibrosarcomas occurred beneath the irradiated skin and 12 breast tumors occurred. No tumors of the epidermis or dermis were seen in the unirradiated control mice. The maximum incidence of dermal tumors in all dose groups occurred during the third year after irradiation. In summary, cancer is a major latent biological effect in several studies identified in this profile after inhalation, ingestion, or external doses. Reports of cancer induction after oral exposure and the more unconventional exposure routes are numerous (Evans et al. 1966; Martland 1931; Raabe 1994; Rowland et al. 1978; Speiss and Mays 1970). Cancer has been reported in humans after exposure to varying degrees of ionizing radiation after the Hiroshima and Nagasaki atomic blasts (Shimizu et al. 1988), which has provided risk assessors a very unique data set to determine the short- and long-term biological effects of ionizing radiation in humans. Several other studies that monitored cancer death rates from ionizing radiation exposure in humans were also located (Checkoway et al. 1988; Kneale et al. 1981; Sorahan and Roberts 1993). Reports of humans receiving an acute inhalation, oral, dermal, or external dose of ionizing radiation (by aerosol or vapor) under controlled conditions were not identified in the open literature. Observed Health Effects from Radiation and Radioactive Material tables that describe Cancer Effect Levels (CELs) from exposure to ionizing radiation in humans and laboratory animals are provided in Chapter 8 of this profile. Many laboratory animal inhalation exposure studies were identified that described increased incidences of cancer developing in a variety of species after exposure to alpha, beta, and gamma forms of ionizing radiation. Many of these studies were selected for discussion in this profile because they were lifespan studies, concentrating on the effects of alpha (***Pu, #*°Pu) and beta (*°Sr, '*‘Ce, *'Y, '*’Cs). The main animal model, the Beagle dog, has lungs that are similar anatomically, physiologically, and morphologically to human lungs, making them an ideal lung model to study the potential effects of inhaled nuclides in humans. However, the Beagle’s nasopharageal structure is significantly different from a human’s; therefore, comparisons of nasal tissue and bone cancers between the species are not practical at this time. Many of these lifespan studies are currently ongoing; the final conclusions about the biological effects of these radionuclides will not be available for several years. These studies provide valuable insights into the long- term toxicity of many radionuclides that would be likely to be inhaled in soluble and insoluble forms during a ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 171 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION nuclear fallout or an acute exposure event, as well as low-level radionuclide exposure from fallout and radioactive species formed naturally in the atmosphere. Biennial reports of these lifespan studies that summarize the most recent findings from these laboratory animal studies are available. These animal studies, especially the Beagle dog studies, clearly demonstrate that the inhalation of very large quantities of radionuclides in soluble or insoluble forms, which results in very high absorbed doses to the lungs, has the potential to produce lung cancer and to induce cancers in other organs. These cancers are the same cancers that would normally appear with a lower frequency in an unexposed animal population; however, after exposure(s) to one or to a combination of radionuclides, the incidence of these naturally occurring cancers tend to increase, though the latent periods do not change. This observation was well- demonstrated by the studies performed by many investigators in which ***Pu0, and **Pu0Q, exposed dogs had increases in lung, skeletal and liver tumors after exposures to varying doses of these nuclides (Boecker et al. 1988; Brooks et al. 1992; Gillett et al. 1985; Hahn et al. 1987, 1981; Muggenburg et al. 1994). This trend, also noted with the cancers that were produced in those individuals exposed to external sources of ionizing radiation after the atomic blasts in Hiroshima and Nagasaki, Japan, in August 1945, is discussed in more detail below (Shimizu et al. 1988). The sites where these cancers occurred in exposed laboratory animals depended largely on (1) the dose, which depends on the quantity of radioactive material, (2) the physical properties of the particle (or vapor) they were incorporated into, (3) the solubility of the particle, (4) the particle size, and (5) the radiological and biological properties of the material. For example, for dogs exposed to insoluble aerosols of 2**Pu (1.5 and 3.0 pm), it may be reasonably surmised that these animals would develop lung tumors based on the radioactive t,, of the radionuclide, the insoluble nature of the particle, the small particle size (long retention times), the dose, and the cells at risk of receiving large doses of radiation within a short distance of the particle retention site. Lung tumors did in fact develop in these animals at an increased incidence rate many years after the initial exposure; however, liver and bone tumors also developed in conjunction with some of these lung tumors. Over a period of time, the particles slowly dissolved and the ?**Pu followed its kinetic pattern by redistributing to the hepatic and skeletal tissues, subsequently irradiating other susceptible tissues and inducing cancers of the liver and osteosarcomas of the bone (Muggenburg et al. 1994). Metastasis also is a factor in the appearance of cancer in some organs. Similar situations no doubt occur for other radionuclides and by other routes (oral, dermal, injection, etc.) as well. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 172 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION External exposure (exposure to sources of ionizing radiation other than by inhalation, oral or dermal exposure routes) has also been demonstrated to induce cancers in both humans and laboratory animals. A few human studies that involved external exposures to radiation and resulted in cancer were identified, but the best study available to date is the Life Span Study (LSS) currently being conducted by the Radiation Effects Research Foundation (RERF) with the survivors of the atomic bombings of Japan in 1945. A large database is available from the persons exposed to ionizing radiation after the atomic bombing of Hiroshima and Nagasaki. According to DS86 doses, the major type of radiation was gamma emissions, with lesser amounts of neutron radiation than originally anticipated using T65D dosimetry assumptions; the estimates of doses these individuals received are still being refined today. Exposures are considered to be mostly external ionizing radiation exposures, with much smaller amounts of ionizing radiation doses resulting from inhalation and oral exposure routes, due to very little fallout from those atomic blasts. In Nagasaki, however, survivors were exposed to the “Black Rain,” which is fallout radioactivity mixed in a rain shower. Many of these individuals received high doses to their unprotected skin and even to skin under water-saturated clothing due to the high-activity, beta-emitting fission products. This ongoing epidemiologic study provides an excellent source of data for use in studying the acute exposure effects of ionizing radiation in humans. As with cancers induced after inhalation exposures in laboratory animals, cancers in humans or animals exposed to external radiation do not appear immediately after the initial exposure. In the Hiroshima and Nagasaki atomic bombing survivors, and in the dog studies discussed above, there was no dose-dependent shortening of the latent periods for cancer induction, except possibly for those individuals exposed to ionizing radiation within the first 10 years of life (which was dose-dependent). This observation may reflect a higher sensitivity to the effects of ionizing radiation in very young humans; however, further data will need to be collected from this cohort exposed at the very early ages to determine whether this trend is real or an artifact of the data set. Cancers were also of the type that are normally found in unexposed individuals, but they occurred with some increasing frequency. These cancers occur only when those individuals reach an age when these cancers normally would be expected to develop (except for leukemia). For example, a female <10 years of age who was exposed to external gamma ionizing radiation from the atomic blast and survived the acute effects of the initial radiation exposure would have an increased probability of developing (and dying from) breast cancer as a result of the latent effects of ionizing radiation, but not before she reached the age at which the majority of unexposed women would be expected to start developing this specific neoplasia. The same would be true for the other types of cancers as well, except for leukemias. Deaths due to leukemia did exhibit a minimum latent period (2-3 years), with the incidence of the cancer increasing to a peak at 6-8 years after exposure and the incidence declining after that. A slightly significant increase in deaths due ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 173 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION to leukemia existed at least through 1980 (the cut-off date for much of the DS86 dosimetry system data), some 35 years after the initial exposure; this increase is independent of the age at which the initial exposure had occurred. In another report by Upton (1991) and in the report by Shimizu et al. (1988), the same cohort was reported to show linear dose-mortality relationship responses for cancers (other than leukemia) ranging from 0 to 300 rad. In the most recent reports on this cohort, the radiation-induced excess in the cumulative number of deaths from cancer has increased by more than 50% (Shimizu et al. 1988; Upton 1991). The increase in radiation-related deaths was found to be proportional to the increase in background cancer rates associated with the aging of this study population, with the excess relative risk for cancer mortality remaining relatively constant. Given this scenario, it now appears that the overall cancer mortality data in the Hiroshima and Nagasaki populations are more compatible with the multiplicative risk projection model rather than with the additive model. When examined for some solid cancers (i.e., breast and thyroid), the data tend to be linear, while linear-quadradic or quadratic functions best describe cancers at other sites (i.e., colon). In contrast, the dose-effect relationship for leukemia (excluding chronic lymphocytic leukemia) fits best with the linear- quadratic model. Cancer mortality due to ionizing radiation has been evaluated extensively (BEIR V 1990; Shimizu et al. 1988; Upton 1991). In summary, for the Japanese atomic bomb survivors, the relative risk for the whole exposed population (all ages and both sexes) for malignant neoplasms (including leukemia) for the years 1950-1985 has been estimated to be 1.39 (range 1.32-1.46) per 100 rad (1 Gy), corresponding to an absolute risk of 13.1 (10.1-15.9) excess deaths per million person rad (10* person-Gy)/year. When leukemia is excluded from the previous estimates, the relative risk for the whole exposed population (all ages and both sexes) for solid neoplasms is estimated to be 0.41 (0.32-0.51) per 100 rad (per Gy) Gy organ-absorbed dose, corresponding to a lower absolute risk of 10.13 excess cancer deaths per million person rad (10* person- Gy)/year organ-absorbed dose. When total cancer mortality (including leukemia) is re-examined on the basis of sex, sex ratios of radiation-induced cancers at specific sites are not significantly different from those of the unexposed general population. The relative risk for some epithelial tumors tends to be somewhat higher in females than in males (Upton 1991). Finally, when the data are re-examined as to cancer mortality and age at exposure, the current data suggest that the lifetime risk of developing radiation-induced cancer is substantially lower in those persons exposed during their adult years than in those exposed during childhood or adolescence, a conclusion supported by BEIR V (1990). This observation will require further study to ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 174 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION confirm. Several types of cancer were observed with increased frequencies in this exposed population and are summarized in Table 3-8. CELs from exposure to ionizing radiation in humans and laboratory animals are summarized in the Observed Health Effects from Radiation and Radioactive Material tables in Chapter 8 of this profile. 3.3 IDENTIFICATION OF DATA NEEDS The database appears to have a sufficient volume of information for regulators to allow workers to work safely with radiation sources. This is verified by the fact that the nuclear power industry has the best overall safety record of all industries. This good safety record, with a Standardized Mortality Ratio (SMR) of less than 100 is usually attributed to the “Healthy Worker Effect.” However, for scientific reasons, the following have been identified as potential data needs regarding health effects that may be associated with exposure to ionizing radiation: . Since somatic and reproductive cell chromosomes are radiosensitive tissues which can sustain damage after exposure to ionizing radiation, damage to the human genome in exposed populations has potentially serious implications. Better methods are needed by which to estimate the levels of exposure to ionizing radiation that may result in an increased risk of hereditary disease. . The mechanisms by which cancer is induced in living cells are complex and an area under intense study. More research is required to better understand the mechanisms by which cancer is induced after exposure to chemical carcinogens and to ionizing radiation. . Regarding radon exposure, several studies involving underground-miner surveys need to be completed and the data analyzed for the interaction between radon and smoking. These studies should also provide more information on radon dosimetry and narrow some uncertainties in applying the lung- cancer risk data derived from the miner data sets to estimation of risk of radon exposure in the general population. . Epidemiological studies need to continue in order to more firmly describe the risks of lung cancer in underground miners and the risks of indoor home radon exposure to those potentially exposed to radon and radon progeny. . Further modeling of the indoor air environment is needed to assess potential health consequences of indoor radon exposure. . The role of polonium in tobacco smoke and lung cancer should continue to be evaluated; this includes bronchial and lung dosimetry, identification and characterization of target cells, and the role of cofactors in the carcinogenic response. . The nonstochiastic acute and delayed health effects from polonium, particularly those affecting the renal, cardiovascular, and reproductive systems, should continue to be investigated. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 175 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION . More quantitative information regarding the **Ra, **Ra and **Ra human exposures is needed to more adequately evaluate the magnitude of some dosimetric uncertainties and what impact these uncertainties have on quantitative risk estimation. . The bone cancer information from all of the human ‘Ra, **Ra and ?**Ra exposures should be integrated and more adequately analyzed. . Research should continue on identifying the cells at risk after exposure to radium. This should include cell behavior over time, changes in cell behavior, location of cells in relation to the microenvironment of the radiation field, responses of the cell to the radiation, and the time course and distribution of radioactivity in the bone. . The dosimetery of the mastoids should be examined in order to calculate the risk per unit of epithelial tissue and per unit of cell dose. . Data should be obtained from the five major epidemiological studies of Throtrast-exposed patients and the data analyzed to develop risk models for liver and other cancers. . The dosimetry of the thorium isotopes at the cellular level in target organs should be closely examined. . The mechanism of uranium deposition and redistribution in bone should be further investigated in order to more accurately define the potential carcinogenic effect of natural uranium based on results obtained from enriched uranium or other alpha particle emitters. . The current epidemiological studies of worker populations exposed to transuranic elements should be continued. . The current lifespan studies with dogs should be completed and the results reported. . The current lifespan studies of the Japanese atomic bomb survivors should be continued and the results reported. . Studies should continue regarding the genetic effects of low-level exposure to ionizing radiation, particularly in the second generation offspring of the Japanese atomic bomb survivors. Better methods for extrapolating data from animal studies for applications in human genetic risk assessment are also needed. . Efforts to assess the carcinogenic risks of exposure to low levels of ionizing radiation, for both single dose and protracted and fractioned doses, should continue. . The carcinogenicity of neutron radiation exposure in human populations should continue to be examined. Similarly, the mutagenicity of low doses of neutron radiation should continued to be investigated in order to more comfortably predict the potential genetic risks observed in laboratory animals and extrapolate those findings to human populations. . Further research is needed to more accurately describe the dose-response relationship between pre-natal exposure to ionizing radiation and the effect of mental retardation, particularly in the population of Japanese atomic bomb survivors. “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 176 3. SUMMARY OF HEALTH EFFECTS OF IONIZING RADIATION 3.4 CONCLUSIONS This chapter has provided an overview of the health effects related to ionizing radiation exposure in humans and laboratory animals. These effects can be both non-carcinogenic and carcinogenic in nature. Non- carcinogenic effects primarily result in immediate effects, mainly to organs with rapidly dividing cells, which include the hematopoietic system, gastrointestinal tract, and central nervous system, or delayed effects such as cataracts and embryo/fetal development problems. Carcinogenic effects also may occur in any number of organ systems; however, this end point may not be expressed for several years after the initial exposure. The dose-response relationships for these effects are known from the massive amount of data from studies on both humans and animals. **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 177 4. RADIATION ACCIDENTS A number of accidents involving sources of ionizing radiation have occurred over the past 50 years. These accidents have resulted in a number of people being exposed to a variety of doses of ionizing radiation and, like those of the Hiroshima and Nagasaki blasts, involved multiple routes of exposure. Some of the more important accidents involving a significant exposure to ionizing radiation, including any known health effects, are discussed below. 4.1 PALOMARES, SPAIN From the 1950s through the late 1960s, the Strategic Air Command (SAC) conducted Operation Chrome Dome which, in the interest of national defense, required the Air Force to fly aircraft carrying nuclear weapons around the world 24 hours a day. On January 16, 1966, two B-52 airplanes carrying four thermonuclear weapons containing **’Pu flew to the southern fringes of the former Soviet Union. On their return trip to the United States, one collided in mid-air with a KC-135 aircraft during a refueling operation over Spain. After fire erupted on the planes, the B-52 broke apart and scattered all four nuclear weapons. The weapons were dispersed over Palomares, a town located in a remote area of Spain. The first weapon landed without incident on the beach near Palomares. The second and third weapons landed on the west and east sides of the village, respectively, and the high explosives on the weapons detonated and spread plutonium contamination throughout the area (there were no nuclear explosions). The last weapon landed in the Mediterranean Sea. Authorities located and recovered this weapon 8 weeks later (Civil Defense Technology Workshop 1995). Partial ignition of the fissile material from the two bombs that had been blown apart by their high explosive charges resulted in a cloud formation which was dispersed by a 35-mph wind. Approximately 2.25 km? of farmland, an area one-half mile long by one-sixteenth of a mile wide, was contaminated with plutonium at levels of 50-500 pg/m?. Initially, 630 acres of land were reported to be contaminated; however, an additional 20 acres were subsequently classified as contaminated due to resuspension by the wind. The primary form of income for the citizens of Palomares was their tomato crop. The U.S. government purchased the tomato crop for a total of $250,000. The mildly contaminated tomatoes were washed and served in the base camp or were sent to the U.S. military commissaries and dining facilities in Europe. Highly contaminated crops were dug up and burned in open-pit fires, which further spread the contamination. An agreement between the United States and Spain called for removing the top 10 cm (4 inches) of soil in areas contaminated with more than “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 178 4. RADIATION ACCIDENTS 32 pug/m?. This resulted in the removal of 1,100 m? of soil. The decontamination procedure required 747 people and 8 weeks of labor and resulted in the filling of 4,879 metal 55-gallon drums with contaminated soil. Soil contaminated with 700-60,000 cpm (counts per minute: 60,000 cpm corresponds to a contamination level of 462 pg/m?) was mixed with petroleum oil and plowed under to a depth of 8 inches, then covered over with another layer of top soil. The Air Force contracted 140 trucks to move 3,400 truck loads of replacement soil from a dry river bed. These actions essentially destroyed all of the indigenous population’s crop lands. All soil levels greater than 462 pg/m?, together with other contaminated materials, were transferred to the United States for burial. All but two of the barrels were shipped to the Savannah Naval Storage Facility in Aiken, South Carolina. The other two barrels were sent to Los Alamos National Laboratories in New Mexico, where they are still being monitored and tested (Civil Defense Technology Workshop 1995; Shapiro 1990; UNSCEAR 1993). No plutonium was found in the 100 residents of Palomares who were the most likely to have been exposed. The potential dose to the lungs, bone surface, and bone marrow of the local residents has been estimated to be much less than the ICRP recommended limits (Iranzo et al. 1987). Follow-up studies on this group of exposed individuals could provide useful information on the long-term effects of plutonium exposure in humans. The Spanish government, concerned about public perception and panic, prohibited the U.S. Air Force cleanup crews from wearing anti-contamination suits or full face masks. Only uniforms, hats, and surgical gloves with tape over the openings between gloves and clothing were permitted. Counter to U.S. recommendations, civilians were not restricted in their movements in or around the area. In the hilly, rocky area surrounding the detonation site of the third weapon, it proved impossible to reach the initial cleanup standards set by the Spanish Government, so the standards for this area were simply lowered to meet the conditions. Where the soil could not be removed, the workers soaked it with water. This area has never been restricted, and, although they were warned the area was contaminated, Spanish citizens continued to inhabit the area (Civil Defense Technology Workshop 1995). Six years after the incident, follow-up studies found that there was little change in the community and in exposed persons (Shapiro 1990). Of the 714 people examined through 1988, 124 had urine concentrations of plutonium greater than the minimum detection limits (MDL). 4.2 THULE, GREENLAND In January 1968, a U.S. Air Force plane experienced an on-board fire and subsequently crashed while attempting an emergency landing near Thule, Greenland. The plane was carrying four unarmed 1.1-megaton nuclear weapons; although the nuclear weapons did not detonate, the conventional explosives of the weapons ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 179 4. RADIATION ACCIDENTS exploded on impact, depositing an inventory of 1 TBq (27 Ci) 2**?*°Pu, 0.02 TBq (0.54 Ci) 23*Pu, and 0.1 TBq (0.27 Ci) **' Am; igniting fuel; and creating an intense fire that burned for almost 4 hours. The velocity of the crash and explosions resulted in the spread of plutonium-laden debris over an area approximately 100 by 700 m. The burning plutonium was converted mainly into insoluble oxides and dispersed as fine particles. Measurements of **>*Pu indicated that the radionuclides preferentially deposited in the fine-grained bottom sediments covering the basins in the vicinity of the crash site. Follow-up investigations found that plutonium levels in bivalves and crustacea to be increased by a factor of 10-1,000 over pre-accident levels (Aarkrog 1971, 1994; Handler 1992; Shapiro 1990; Smith et al. 1994). The cleanup effort, called project Crested Ice, lasted 8 months and resulted in the shipping of almost 240,000 tons of contaminated ice and snow to the United States. About 99% of the plutonium was contained in the blackened ice at the crash site; this was recovered by road graders and mechanized loaders scraping away the affected ice. A total of sixty-seven 25,000-gallon fuel tanks were filled with debris and four additional containers were used for storing contaminated recovery equipment and gear. The materials were shipped to the United States for disposal. Although low-level contamination was detected on land close to the crash site, it is believed that minimal amounts of plutonium escaped from the crash site. No long-term effects to neighboring populations are expected (Handler 1992; Shapiro 1990). 4.3 ROCKY FLATS, COLORADO The Rocky Flats Nuclear Weapons Plant, located approximately 15 miles from Denver, Colorado, occupies approximately 2 square miles of federally owned land. Approximately 2.2 million people from the 8-county Denver metropolitan area live within a 52-mile radius of the facility. As of December 1995, there were approximately 4,700 employees at the Rocky Flats facility. Since beginning operations in 1953, the plant has been a major processor of plutonium. During the Cold War, Rocky Flats was responsible for the fabrication of the hollow plutonium sphere, or "pit," that serves as nuclear fuel for nuclear warheads. Rocky Flats also was responsible for recycling plutonium retrieved from retired nuclear warheads. A high-tech machine shop produced other weapons parts from stainless steel, beryllium, depleted uranium, and other metals. Due to its proximity to an urban area and because its property boundaries border two creeks feeding public waters, the potential for public exposure to radiation following an accident at this plant is relatively high. Several significant incidents have occurred at this plant: two fires in 1957 and 1969 and leakage of ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 180 4. RADIATION ACCIDENTS plutonium-contaminated cutting oils from storage drums (Rocky Flats Citizens Advisory Board 1995; Shapiro 1990). Probably no individual location at the Rocky Flats site has received more notoriety than the site known as the 903 Pad. In the late 1950s and early 1960s, Rocky Flats stored barrels at this location which were filled with plutonium-contaminated oil left over from the pit manufacturing operations. Over time, many of the oil barrels had corroded, allowing the contaminated oil to spill out onto the ground. The leakage was first detected in 1964, and efforts to prevent the spread of leakage were initiated the same year. Managers at the site attempted to solve the problem by removing all of the barrels and cleaning up the storage area. However, the cleanup effort resulted in the disturbance of the contaminated soil, and the radioactive dust was picked up and spread further by the high winds that are common at Rocky Flats. The Health Advisory Panel overseeing the Dose Reconstruction Project for the Colorado Department of Public Health and Environment lists the 903 Pad as one of the major contributors to off-site contamination from Rocky Flats (Rocky Flats Citizens Advisory Board 1995; Shapiro 1990). The first of two major fires at the Rocky Flats facility occurred on the evening of September 11, 1957, when some of the plutonium on the glove box line of Room 180 in Building 771 spontaneously ignited. Although the area was designed to be fireproof, it was soon engulfed in flames. Firemen switched on ventilating fans, which ultimately spread the flames to contact more plutonium. Attempts to quench the fire with carbon dioxide also failed. Meanwhile, the filters designed to trap plutonium escaping up the stacks caught fire. The shift captain and other observers reported a billowing black cloud pouring some 80-160 feet into the air above the 150-foot-high stack. When the carbon dioxide gas failed to extinguish the fire, the firefighters began pouring water into the blaze. The fire was extinguished roughly 13 hours after it began. Some 14-20 kg of plutonium were estimated to have burned in the fire, not including plutonium liberated from the burning filters. In addition, the water used to extinguish the fire became contaminated with radioactive material, and approximately 30,000 gallons of it escaped unfiltered, spreading contamination into local streams and into the water table. Although some of the buildings were heavily contaminated, bomb-trigger production was back under way within a few days (Wasserman et al. 1982). The fire in 1969 also started with the spontaneous ignition of plutonium metal. Several kilograms of plutonium burned and the resulting smoke plume spread to surrounding areas. Soil samples collected from 15 locations ranged from background levels of 0.04 transformations per minute per gram of material (DPM/g) to 13.5 DPM/g in the top centimeter; 7 water samples ranged from 0.003 to 0.4 transformations or **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 181 4. RADIATION ACCIDENTS decompositions per minute per liter (DPM/L). Another study in 1970 of soil samples to a depth of 20 cm found levels as high as 2,000 mCi/km? at sites adjacent to the property boundaries (Shapiro 1990). Johnson (1981) examined the relation between cancer rates and plutonium exposures using cancer diagnosis data for 1969-1971 and plutonium exposures estimated from an analysis of soil samples collected near Rocky Flats in 1970. Johnson claimed to have found increases in many cancer types for persons in exposed areas, as compared with those for unexposed areas. However, a feasibility study for an epidemiologic study of persons who lived near the plant concluded that exposures were not high enough to be evaluated statistically (Dreyer et al. 1982). Cobb and co-workers (1982) compared plutonium concentrations in autopsy samples from persons who lived near Rocky Flats with those who lived far from the plant. A weak relation between plutonium concentrations in autopsy samples and distance from Rocky Flats was detected; however, these authors did not believe that the elevated concentrations could be conclusively linked to emissions from Rocky Flats. Crump et al. (1987) re-evaluated cancer diagnosis data for 1969-1971 and for 1979-1981 using the study designed by Johnson (1981). For both study periods, the authors found no increase in cancer rates for combined cancers, for radiation-sensitive cancers, or for cancers of the respiratory system in those living within 10 miles of Rocky Flats. A National Cancer Institute (NCI) study of cancer incidence and mortality around nuclear facilities in the United States found slight elevations for some cancers in some age groups among those living near the Rocky Flats facility; however, the study should be interpreted with caution because county-by-county cancer mortality data were used and because of limited information on potential confounding factors (Jablon et al. 1990). 4.4 THREE MILE ISLAND, PENNSYLVANIA On March 28, 1979, an accident occurred at the civilian nuclear reactor facility at Three Mile Island (TMI). Emergency Safety relief valve core coolant Figure 4-1 is a simplified diagram of the TMI pressurized water nuclear reactor design. Under normal ee Hot water operating conditions, the control rods are withdrawn outlet <+— Cold water from the reactor core to produce power, and water from Reactor — : inlet #1 the principal source (#1) circulates through the core and <+— Cold water . inlet #2 a primary heat exchange loop. A secondary water :. . . Wat source (#2) is in standby. To prevent a major accident, o it is imperative that the thermal core be submerged in Figure 4-1. Schematic of Three Mile Island Nuclear Reactor “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 182 4. RADIATION ACCIDENTS water at all times. Although the water should never be allowed to boil inside the pressure vessel, a pressure relief valve exists to release steam in the event of inadvertent boiling; during normal operation, this valve is closed. During shutdown, it is important that the cooling water continues to circulate through the core until the chain reaction dies out and heat production subsides. In the TMI incident, water from supply #1, which returns condensed steam from the generators, was interrupted because the feed water pumps that pumped water from the reactor to the reactor’s steam generators stopped. The loss of water flow resulted in a loss of cooling of the reactor core. The operators immediately switched on the emergency feedwater pumps. However, the water did not enter into the cooling loop because the valve was accidentally left closed the previous day (the reactor operators didn't realize this). Emergency water injection pumps started automatically, but an operator reduced the flow. The water overheated and steam bubbles began forming. The operators responded improperly, draining water out of the system, exacerbating the coolant problems. The fuel heated up and partially melted, releasing radioactive material into the remaining coolant, which continued flowing out of the reactor through the relief valve and onto the containment room floor (Eisenbud 1987; Shapiro 1990; http://www.ems.psu.edu/~radovic/ TMI html). The cleanup is still in progress at a cost that has already exceeded 1 billion dollars. The high cost is not only due to the cleanup itself, but to the research into the materials and their behavior during the accident. This has made the cleanup a huge research project. However, very little radioactivity was released to the environment. The main contaminants reaching the environment were **Xe and '*'I, with total releases of approximately 370 PBq (10 MCi) and 550 GBq (14.85 Ci), respectively. The average dose to the general public within 80 km was estimated to be 0.0015 rem (0.000015 Sv), and the highest dose was estimated to be 0.085 rem (0.00085 Sv), mainly in the form of external gamma radiation. In contrast, the average annual radiation dose from natural radiation is approximately 0.3 rem (0.003 Sv), of which 0.036 rem (0.00036 Sv) is from radioactive material naturally inside the human body (UNSCEAR 1993; http://www.ems.psu.edu/ ~radovic/TMLhtml). No radiation effects have been reported among the surrounding population. 4.5 CHERNOBYL, UKRAINE In April 1986, an accident at the civilian nuclear reactor facility at Chernobyl in the former USSR, resulted in the largest accidental release of radioactive material to date. The RBMK-1000 reactors utilized at Chernobyl have a design flaw that makes their operation at low power unstable. In this mode of operation, any increase ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 183 4. RADIATION ACCIDENTS in the production of steam can boost the rate of energy production in the reactor. If that extra energy generates still more steam, the result can be a runaway power surge. While performing an unauthorized engineering test, instabilities developed in the reactor system which could not be controlled; the operators had deliberately disabled safety systems that could have averted the reactor's destruction because the safety systems might have interfered with the results of the test. At 1:23 and 40 seconds on that morning, an operator pressed a button to activate the automatic protection system, but by this time it was too late. Within 3 seconds, the fission rate in the reactor dramatically increased to hundreds of times the normal operating level. The fuel temperature subsequently rose within seconds to beyond the melting point of uranium dioxide (2,760 °C; 5,000 °F). The resulting steam explosion lifted the 90-ton covering of the reactor, destroyed the roof, and ejected fuel from the » . Figure 4-2. Aerial View of the Damaged Chernobyl Reactor Facility facility (Figure 4-2). Molten nuclear (adapted from http://193.125.172.36/www-klae/POLYN/history. html) fuel and graphite from the reactor core caused fires in and around the reactor that burned for 10 days. Efforts to quench the flames included dumping 5,000 tons of various materials (boron carbide, dolomite, sand-clay mixture, and lead) by helicopter. By the time the fires were extinguished, 250 tons of graphite had been consumed by the fires (Shapiro 1990; Shcherbak 1996). The total release of radioactive material from Chernobyl was estimated to be 1-2 EBq (27-54 MCi). The major radionuclides released were *'T (630 PBq; 17.0 MCi), '**Cs (35 PBg; 0.95 MCi), and *’Cs (70 PBq; 1.9 MCi). A plume containing these radionuclides moved with the prevailing winds to the north and west, and then east around the world, transporting the radioactive material thousands of miles (Figure 4-3). The deposition on the ground varied considerably during the accident due to variations in temperature and other parameters during the release. "Cs was the main contributor to the radiation doses received by the population once the short-lived 3'T had decayed. The three main areas of '*’Cs contamination resulting from the Chernobyl accident were identified as the Central, Bryansk-Belarus, and Kaluga-Tula-Orel spots. The central spot, formed during the initial, active stage of the release, had ground depositions of *’Cs of more than 40 kBg/m? (1.1 pCi/m?) over large areas of ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 184 4. RADIATION ACCIDENTS Northern Ukraine and Southern Belarus. The most highly contaminated area was the 30-km zone surrounding the reactor, where '*’Cs ground depositions exceeded 1,500 kBg/m? (40.5 pCi/m?). The Bryansk-Belarus spot, centered 200 km to the north-northeast of the reactor, was formed as a result of rainfall on the region. The ground depositions of '*’Cs in the most highly contaminated areas reached 5,000 kBg/m (135.1 pC#m ) in some villages. The Kaluga-Tula-Orel spot, approximately 500 km northeast of the reactor in Russia, was also formed as a result of rainfall; the levels of '*’Cs deposition in this area were usually less than 600 kBg/m* (16.2 pCi/m?). Outside the three main hot spots there were many areas in the European territory of the former Soviet Union contaminated with '¥’Cs at levels ranging from 40 to 200 kBq/m? (1.1-5.4 uCi/m?). Overall, the territory of the former Soviet Union initially contained approximately 3,100 km* contaminated by'*’ Cs at levels exceeding 1,500 kBg/m? (40.5 pCi/m?); 7,200 km?* with levels of 600-1,500 kBg/m? (16.2-40.5 pCi/m); and 103,000 km? with levels of 40-200 kBg/h (1.1-5.4 uCi/m?) (NEA 1995). The regions affected included not only the Ukraine, Belarus, and Russia, but also Georgia, Poland, Sweden, Germany, Turkey, and other countries. Even such distant lands as the United States and Japan received measurable amounts of radioactive material. In Poland, Germany, Austria, and Hungary as well as in the Ukraine, some crops and oo Ootcatedossd one : Contes thas AQ mn milk were so contaminated they had to be destroyed, Arc Coen 47 Pededic Control Zone 58 16 Clow’ of Conk 137 while others were destroyed out of panic. In Finland, | Str Cwm 137 4 306 donee. Sweden, and Norway, carcasses of reindeer that had grazed on contaminated vegetation were destroyed (Shcherbak 1996; UNSCEAR 1993). Figure 4-3. Hot Spots of Radioactivity in the Regions Surrounding the Chernobyl Facility (adapted from http://www.osc.edu/ukraine_nonpub/htmis/maps.html) A total of 237 plant workers and firefighters suffered from ARS (Shapiro 1990). Within 3 months, the death toll from the incident was 30 persons; all of the deceased were either plant operators or firefighters (UNSCEAR 1993). Approximately 15,000 persons from the plant or surrounding communities lost their ability to work as a result of diseases attributed to radiation exposure, including: gastrointestinal (inflammatory immediately after the accident and ulcerative in later years); immunological; metabolic (5-6 year latency period); respiratory (chronic obstructive bronchitis); hemopoietic (increase or decrease in white blood cell numbers); and neuropathologies (reduced mental capacity, inability to estimate one’s own abilities). In addition, 12,000 children received large doses to the thyroid, and 9,000 persons were exposed in ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 185 4. RADIATION ACCIDENTS utero. A sharp increase in thyroid cancer among those who had been exposed as children is the only major public health effect documented to date. An investigation of brain damage in utero, performed by the International Programme on the Health Effects of the Chernobyl Accident IPHECA), found some evidence of retarded mental development and deviations in behavioral and emotional reactions in exposed children; however, the extent to which radiation contributed to these problems could not be determined due to the lack of individual dosimetry data (Bebeshko 1995; WHO 1995). By 1992, the frequency of occurrence of thyroid cancer had increased dramatically in the children of Belarus, but this data may be difficult to interpret because of endemic goiter in the population. More importantly, the pattern of the increases was not uniform but was correlated with those areas in the direct path of the radioactive fallout (Kazakov et al. 1992). Other health- related effects from the accident included: radiophobia, an increase in stress-related illnesses due to both fear of radiation and to the dislocation of people; poor diets due to stringent safeguards against potentially contaminated food, that may have led to vitamin deficiencies; the aborting of as many as 200,000 healthy fetuses because of concern that they might have been damaged in the womb by minor radiation exposures; and an increase in alcoholism following the accident (Atomic Energy Insights 1996). About 200,000 people involved in the initial cleanup received an average whole-body dose on the order of 10 rem (0.1 Sv). An exclusion zone (within 30 km [18.6 mi] of the reactor) was established which required the evacuation of 116,000 of the surrounding residents. Fewer than 10% of these people received doses greater than 5 rem (0.05 Sv), and the dose to more than 95% of these was less than 10 rem (0.15 Sv), but exceeded 30-40 rem (0.3-0.4 Sv) in some cases. In contrast, the Figure 4-4. A View of the Sarcophagus Covering the oo Chernobyl Reactor Facility average annual radiation dose from back- (adapted from http:/193.125.172.36/www-kiae/POLYN/history.html) ground radiation is approximately 0.36 rem (0.0036 Sv). A total of 786 settlements in Belarus, the Russian Federation, and the Ukraine were declared strict control zones. In the settlements, food consumption was restricted as a protective measure. Average exposure during the first year to persons in these settlements was 3.7 rem (0.037 Sv); in 2 subsequent years, average annual exposures were approximately 2.3 rem (0.023 Sv) (UNSCEAR 1993). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 186 4. RADIATION ACCIDENTS The collective dose (the sum of all individual doses) from the Chernobyl accident has been estimated to be 600,000 maneSv. The majority of this dose is expected to be received by the population in the former USSR (40%) and Europe (57%). The remainder (3%) is expected to be dispersed over other countries of the northern hemisphere (UNSCEAR 1993). Direct costs of the accident, due to loss of the facility, firefighting, and relocating citizens, approached $7 billion (Shapiro 1990). This figure does not include current or predicted future medical expenses. The explosion left approximately 180 metric tons of fuel exposed to the atmosphere. In an attempt to prevent the further escape of radiation, the Ukrainian government built a concrete covering over the entire facility, referred to as the sarcophagus (Figure 4-4), beginning in May 1986 and completed in November of that year. However, the sarcophagus is not leak-tight. It is feared that rainwater can enter the structure, causing structural failures, and that the approximately 10 metric tons of radioactive dust within the structure could potentially either exit the building dissolved in rainwater or be stirred up and propelled into the atmosphere (NEI 1995). 4.6 KYSHTYM In September 1957, a major accident occurred at the Chelyabinsk-40 military plutonium production facility near Kyshtym in the southern Ural mountains of the former Soviet Union. The facility, built in 1953, had a number of underground steel storage tanks equipped with cooling systems to store high-level waste so that it would not be dumped in the River Techna. These high-level wastes overheated when the cooling system failed. The heat buildup resulted in evaporation of the coolant water, which allowed the sediment to heat further and dry. The tank contents exploded on September 29, 1957, with an explosive power of 70-100 tons of TNT, which hurled the 2.5-m-thick concrete lid 25-30 m away. The radioactive cloud from the explosion reached about 1 km. Due to calm wind conditions, about 90% of the materials deposited locally, while 100 PBq (2.7 MCi) was dispersed away from the plant in an oblong fallout pattern about 300 km in length, including parts of Chelyabinsk, Sverdlovsk, and Tyumen counties. Almost all of the radioactive fallout occurred within the first 11 hours. A Russian emigre named Lev Tumerman wrote the Jerusalem Post that in 1960 he had driven through the Urals and had seen a road sign that "warned drivers not to stop for the next 30 kilometers and to drive through at maximum speed. On both sides of the road as far as one could see the land was ‘dead’; no villages, no towns, only the chimneys of destroyed houses, no cultivated fields or pastures, no herds, no people. . . . nothing" (UNSCEAR 1993; Wasserman et al. 1982; WISE 1996). **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 187 4. RADIATION ACCIDENTS The major contaminants released were '*Ce, **Zr, **Nb, and **Sr. Most fission products deposited on the ground, allowing the strontium isotopes to enter the food chain. A ban on food containing *°Sr at concentrations greater than 2.4 Bq/g (64.8 pCi/g) resulted in the destruction of 10,000 tons of agricultural produce in the first 2 years. All stores in Kamensk-Uralskiy which sold milk, meat, and other foodstuffs were closed as a precaution against consuming radioactive material, and new supplies were brought in 2 days later by train and truck. Approximately 10,000 people were evacuated from the high-contamination area, while approximately 260,000 people remained in less contaminated areas. The highest individual doses were experienced by those evacuated within a few days of the accident. These individuals received an average external dose of 17 rem (0.17 Sv) and an average internal (gastrointestinal) dose of 150 rem (1.5 Sv); the average effective dose equivalent was approximately 52 rem (0.52 Sv). The average 30-year committed dose for persons living in areas with a *°Sr density of 40-70 kBg/m? (1.1-1.9 pCi/km?) was estimated to be 2 rem (0.02 Sv) (CIA 1959; UNSCEAR 1993). 4.7 WINDSCALE, U.K. In October 1957, the first substantially publicized release of radioactive material from a nuclear reactor accident occurred at the Windscale nuclear weapons plant at Sellafield in the United Kingdom. During a routine release of stored energy from the graphite core of a carbon dioxide-cooled, graphite-moderated reactor, operator error allowed the fuel to overheat. This led to uranium oxidation and a subsequent graphite fire. Attempts to extinguish the fire with carbon dioxide were ineffective. In the end, water was applied directly to the fuel channels but not before the fire had burned for 3 days, resulting in the release of '*'I (740 TBq; 20 kCi), '¥’Cs (22 TBgq; 0.6 kCi), *'°Po (8.8 TBq; 0.2 kCi), '°Ru (3 TBq; 0.08 kCi), and '**Xe (1.2 PBq; 32.4 kCi). A part of the release consisted of flake-like uranium-oxide (reactor core material) varying in size from 1 to 25 cm (Schultz 1996; UNSCEAR 1993). The contamination of pastureland was widespread; for those in close proximity to the accident, the greatest threat of exposure was considered to be from "*'I via contaminated cow’s milk. Those living farther from the accident were exposed to significant amounts of *'I and *'°Po via milk consumption and air inhalation. The consumption of cow’s milk was quickly banned; this lessened the exposure to '*'I. The highest individual doses (approximately 100 mGy) were to the thyroids of children living near the accident site. The collective dose received in the United Kingdom and the rest of Europe was estimated to be 2,000 maneSv, of which 900 maneSv was from inhalation, 800 maneSv was from ingestion, and 300 man*Sv was from external ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 188 4. RADIATION ACCIDENTS exposure. The main radionuclides contributing to the exposures were *'I (37%), '°Po (37%), and *’Cs (15%) (UNSCEAR 1993). There has been no lasting impact on the health of the public from this accident. 4.8 TOMSK An incident occurred at a plant near Tomsk in the Russian federation in 1993 in which individual exposures were low and few in number. The Tomsk plant is one of Russia's three operating plutonium production reactors, all of which are over 30 years old and share design characteristics with Chernobyl-style reactors, including the lack of a containment structure. The Tomsk reactors were built to produce plutonium, but they also supply steam for the city's district heating plant. Reprocessing, which involves the use of chemical processes to separate uranium and plutonium from spent nuclear fuel, occurs at the plant. Under certain conditions, the chemical solutions can cause an explosion. In April 1993, a chemical tank at the Tomsk plant exploded, causing substantial damage to the facility and contaminating a largely unpopulated area of about 123 km?. The accident released about 40 Ci. The accident could have had more serious local consequences if the wind had carried the contamination to two large nearby cities. In June 1993, DOE officials visited Tomsk to investigate the accident. Although they were not permitted to view the chemical tank that had exploded, they did see other parts of the facility. Several operational errors, such as improper mixing of chemicals in the reprocessing tank, and possible design flaws, such as inadequate tank ventilation, were identified as contributors to the accident (GAO 1995; OTA 1994; UNSCEAR 1993). 4.9 LOST INDUSTRIAL OR MEDICAL SOURCES Four incidents in which sealed sources of radiation intended for industrial or medical use were lost or damaged have occurred since 1982. In 1983, an obsolete teletherapy machine from a hospital containing *Co was sold as scrap metal. As a result, steel products from Mexico and the United States were contaminated and approximately 1,000 people were exposed to an approximate dose of 0.025 rem (.25 Sv). About 80 people received doses as high as 0.3 rem (0.003 Sv), and 7 received doses of 300-700 rad (3-7 Gy) (UNSCEAR 1993). No deaths resulted from this exposure. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 189 4. RADIATION ACCIDENTS In 1984, a family in Morocco found and kept within their house a sealed radiography source containing “Ir. The resultant effective doses were estimated to be 800-2,500 rad (8-25 Gy); 8 members of the family died (UNSCEAR 1993). In Goiania, Brazil, in 1987, 54 people were hospitalized and 4 died after removing a teletherapy source containing '*’Cs from its enclosure. Individual doses were estimated to range up to 500 rad (5 Gy) (UNSCEAR 1993). In 1992, in the Shanxi province of China, three people in one family died after a member found a Co source. The Nuclear Regulatory Commission (NRC) has published a safety document that describes the acute health effects of these types of radiation accidents (NRC 1982). 4.10 IDENTIFICATION OF DATA NEEDS The following has been identified as a potential data need regarding health effects associated with exposure to ionizing radiation. A number of people have been exposed to increased doses of ionizing radiation as a result of the accidents discussed in this chapter. Some human data do exist on the health effects associated with acute exposure to ionizing radiation (see Chapters 3 and 5); however, most of the potential effects have been derived from laboratory animal data. It would be helpful to estimate the dose of radiation each of these individuals was exposed to and monitor these people over the long term to determine what health effects (if any) these doses of ionizing radiation had on lifespan, cancer rates, and reproductive effects. There is ongoing research in these areas. 4.11 CONCLUSIONS Although most radiation to which the public is exposed is of natural origin, that portion arising from human activities, particularly accidental releases, is perceived by the public to be very serious threat to health. For the majority of the world’s population, less than 1% of radiation exposure arises from nuclear weapons testing fallout and the generation of electricity in nuclear, coal (many coal-fired electric generating stations emit more radioactivity than do nuclear stations), and geothermal power plants. While military and civilian accidents have resulted in the exposure of certain populations to substantial amounts of radiation, the ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 190 4. RADIATION ACCIDENTS resulting increases in average exposures worldwide have been minor. Few exposures of general populations have been of sufficient size to produce quantifiable deleterious effects. The thyroid cancer rates (the only type of excess cancer seen to date) associated with the Chernobyl accident have begun to rise. After the Hiroshima and Nagasaki bombings, there was a surge of childhood leukemia cases into the 1950s (Pierce et al. 1996). There are also elevated incidence rates (but not dramatic increases) for other cancers in the population exposed by the Hiroshima and Nagasaki bombings. The circumstances and results of nuclear power plant accidents indicate that rapid mobilization of clean-up efforts, imposed dietary restrictions, and evacuation of residents (especially pregnant women) minimizes the public risk appreciably. Before a decision to evacuate is made, its potential benefit for reducing radiation exposure should be weighed against its potential to cause stress-related injuries. Three-Mile Island and Chernobyl are cases in which the evacuations caused a health detriment and a health benefit, respectively. 4.12 OTHER SOURCES OF INFORMATION This chapter provided a brief synopsis of population exposures to ionizing radiation. Readers are encouraged to read Chapters 2 through 6 of this toxicological profile for more in-depth information on the basic principles of ionizing radiation, the health effects of ionizing radiation, and the sources of population exposure to ionizing radiation. Further scientific information can be obtained from the United Nations specialized agencies, such as the World Health Organization (WHO), Geneva, Switzerland, and the International Atomic Energy Agency (IAEA), Vienna, Austria. Readers are also encouraged to visit the Internet World Wide Web (WWW) sites listed in Table 4-1 to obtain more information on the general principles and health effect issues involving the different types and doses of ionizing radiation. Some of these sites are sponsored by scientific organizations, while others are presented by advocacy groups. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 191 4. RADIATION ACCIDENTS Table 4-1. Internet WWW Sites Pertaining to Population Exposures to lonizing Radiation HyperText Transfer Protocol (HTTP) Address Web Page Contents http://www.hps.org http://www.rerf.or.jp http://www.sandia.gov/LabNews/LNO1-1 9-96/palo.html http://www.indra.com/rfcab/Newsletter. HTML http://www.greenpeace.org/~usa/reports/nuclear/arctconf.html http://193.125.172.36/www-kiae/POLY N/history.html http://www.osc.edu/ukraine_nonpubl/htmls/maps. html http://www.radek.slu.se/radio/chern.htm http://www.halcyon.com/blackbox/hw/accounts. html http://radefx.bcm.tmc.edu/default.htm The Health Physics Society, a scientific organization dealing with radiation safety. Atomic bomb survivor studies A newspaper for the employees of Sandia National Laboratories and recounts the Palomares incident. Rocky Flats Citizens Advisory Board newsletter Greenpeace Nuclear Campaign Report Russian Research Center report on the Chernobyl accident discusses the causes of the accident and its consequences. OSC-CEE-Ukrainian Server Image Gallery which contains an assortment of maps related to the Ukraine and Chernobyl A Swedish account of the effects of the Chernobyl accident on Sweden. Excerpts from the book Chernobyl: Insight from the Inside, contain anecdotal reports of health effects on the human and animal populations in Belarus and the Ukraine. Radiation Health Effects Research Resource page. A comprehensive page on radiation and health effects, including extensive literature searches on Chernobyl health effects. ***DRAFT FOR PUBLIC COMMENT"** IONIZING RADIATION 193 5. MECHANISMS OF BIOLOGICAL EFFECTS 5.1 INTRODUCTION A number of direct and indirect radiation interaction pathways can produce damage to the DNA of the cells receiving a dose of ionizing radiation. Cells depend on their DNA for coding information to make various classes of proteins that include enzymes, certain hormones, transport proteins, and structural proteins that support life. When the genetic information containing the “blueprint” for these substances is disrupted, cell homeostasis is disrupted, resulting in a wide-range of immediate and/or delayed toxicological effects. Direct and indirect interactions with DNA are ultimately responsible for the DNA alterations that adversely affect the structural and genetic integrity of the system. These alterations can be repaired, or can result in mutations in the genetic coding that can be passed on to daughter somatic cells or to progeny offspring from reproductive cells. These alterations can result in the wide range of somatic and reproductive effects described in greater detail in Chapter 3. The human body is composed of approximately 2x10"? cells, with each somatic (cells other than sperm and eggs) cell containing 23 pair of chromosomes. Each cell (except for red blood cells) contains a nucleus that houses these chromosomes. The total chromosomal content of a cell contains approximately 10° genes in a specialized macromolecule called deoxyribonucleic acid (DNA). DNA is composed of alternating sugar and phosphate groups, with the sugar attached to 1 of 4 possible nucleotide bases (adenosine, cytosine, guanine, thymidine). These bases attach to each other in a specific pattern: adenosine:thymidine and cytosine:guanine. Genetic sequences of the bases are read in groups of three (called a triplet), with a possibility of 64 config- urations or “words” in which to code information. Specialized cell structures called ribonucleic acids (RNA) are the cellular organelles that actually synthesize the proteins. RNA reads the codes from specific areas of the DNA and transcribes the information using cellular components (sugars, phosphates, amino acids, etc.) to manufacture specific enzymes, peptides, polypeptides, proteins, hormones and other necessary chemicals for normal life functions. When the genetic information containing the “blueprint” for these substances is disrupted, cell homeostasis is disrupted, with a wide range of non-carcinogenic and carcinogenic toxicological effects. These effects were described in some detail in Chapter 3. Ionizing radiation can disrupt the structure of the DNA (and other macromolecules), disrupting normal cell functions. Direct macromolecule damage from ionizing radiation involves energy transfer from an alpha particle, beta particle, or gamma ray of radiation to the molecule. The partial or complete transfer of energy to a medium by alpha, beta, or gamma radiation may be sufficient to excite DNA and other macromolecules and cause the ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 194 5. MECHANISMS OF BIOLOGICAL EFFECTS formation of ions; this process called “ionization” is the source of the name “ionizing radiation” (see Chapter 2). Compared to other types of radiation that may be absorbed, such as microwaves and ultraviolet radiation, ionizing radiation deposits a relatively large amount of energy into a small volume of space, possibly resulting in deleterious biological effects. Ionizing radiation exerts a number of adverse toxicological effects on many tissues in the body. The mechanism by which ionizing radiation exerts its toxicological effects is through interacting with and subsequently altering the DNA in the nucleus and other macromolecules of the irradiated cell. This toxicity occurs in addition to whatever chemical toxicological effects from internally deposited radionuclides that may be induced independently of the radiological toxicity. Chapter 3 described in some detail the biological effects of ionizing radiation in different organ systems in humans and laboratory animals and demonstrated that some systems or tissues are more sensitive to the effects of ionizing radiation than others. Chapter 3 also provided some general explanation for the presence of marked toxicity differences. DNA damage is the likely basis for lethality due to ionizing radiation; however, other molecules and cellular organelles may be adversely affected by exposure to ionizing radiation. These other molecular alterations may also result in adverse cellular activity and may be responsible of some of the biological responses observed after exposure to ionizing radiation. Ionizing radiation may act directly, via firsthand interaction with the DNA or other cell molecules, or indirectly by the production of other chemicals, such as free radicals, which can later interact with the DNA or other cell molecules to produce a biological effect. This chapter will provide an overview of the specific mechanisms that result in the non-carcinogenic and carcinogenic biological effects. 5.2 EVIDENCE OF THE EFFECTS ON DNA Before any mechanism of action of ionizing radiation on DNA can be presented, it is necessary to demonstrate that DNA is indeed the critical molecule after exposure to ionizing radiation. Indirect evidence is available that supports the current thinking that the radiological effect of ionizing radiation is on the nuclear DNA. First, cells that frequently undergo the mitotic processes are the most sensitive to the effects of ionizing radiation. This phenomenon is demonstrated in Table 5-1. As shown in Table 5-1, those cells that frequently undergo mitosis (or meiosis) have the highest sensitivity to the effects of ionizing radiation. As the frequency of cell replication (and hence DNA replication) decreases, the sensitivity to cell death from the effects of ionizing radiation also decreases. Structures that undergo less frequent mitotic cycles (myocytes, connective tissue, nervous tissue) are, relatively speaking, more resistant to ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 195 5. MECHANISMS OF BIOLOGICAL EFFECTS the effects of ionizing radiation. This observation gives indirect evidence that the critical molecule for radiation toxicity is the DNA. Table 5-1. Relative Sensitivities of Major Organs and Tissues to the Effects of lonizing Radiation Radiosensitivity category Organ system General cell type affected Frequency of mitosis High Lymphoreticular Lymphocytes Very frequent Hematological Immature hematopoietic cells Reproductive Spermatogonia Ovarian follicular cells Gastrointestinal Intestinal epithelium Esophageal epithelium Frequent Gastric mucosa Renal Urinary bladder epithelium Dermal Epidermal epithelial cells Mucous membranes Ocular Epithelium of optic lens Medium Multiple organs Endothelium Musculoskeletal Growing bone and Moderately frequently cartilaginous tissues Brain/CNS Glial cells Dermal Glandular epithelium of the breast Respiratory Pulmonary epithelium Renal Renal epithelium Hepatic Hepatic epithelium Gastrointestinal Pancreatic epithelium Endocrine Thyroid epithelium Adrenal epithelium Low Hematological Mature hematopoietic cells Infrequently/rarely Musculoskeletal Brain and peripheral nervous system (erythrocytes, neutrophils, eosinophils, basophils, macrophages) Myocytes Mature connective tissues Mature bone and cartilage Ganglion cells That the DNA is the most critical cellular component in radiation toxicology was demonstrated in early experiments in which either the cytoplasm of the cell (not the nuclear material) or the nucleus only were irradiated with high doses of alpha radiation (Munro 1970). Those experiments showed that, although some minor effects could be induced after exposing the cytoplasm to large amounts of alpha particle ionizing ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 196 5. MECHANISMS OF BIOLOGICAL EFFECTS radiation, the nucleus (and the genome) were many times more sensitive to the effects of ionizing radiation. These alterations are what ultimately gives rise to lethal or phenotypic genetic alterations of the DNA and may lead to the induction of many types of cancers in the irradiated individual (see Chapter 3 of this profile). Other evidence exists to support the thesis that ionizing radiation's toxicological effects are intimately related to nuclear DNA damage. For example, when non-radioactive thymidine is incorporated into the DNA of a cell, no change in the cell's lifespan is encountered; however, when the same thymidine is made radioactive using tritiated (*H), which emits short-range beta particles (see Chapter 2), cell lethality dramatically increases. Coupled with the other indirect evidence, this suggests that the beta particles are bombarding only the nuclear DNA, the alterations from which damage the DNA locally, resulting in increased incidences of cellular death. Additionally, work involving ionizing radiation sources in viruses and plants has shown a strong correlation between the chromosome volume of a cell with radiosensitivity—the higher the volume of chromosomal material, the greater the relative radiosensitivity of the cell. Also, a direct correlation has been demonstrated between aberrant chromosome formation at the first cell division after delivery of a dose of ionizing radiation to hamster cells. These and many other studies provide strong evidence that exposure to ionizing radiation has detrimental effects on the DNA of living cells (Hall 1988). It is also critical to understand how radiation interacts with biological matter (in this case DNA) when trying to understand the mechanism of action and the chain of events that occur at the molecular level. Linear Energy Transfer (LET) is an important concept in determining the relative biological and toxicological effects of alpha, beta and gamma radiation on tissue. The concepts of LET and relative biological effectiveness were discussed in some detail in Chapter 2. LET is defined as the rate per unit distance, measured in MeV/mm (KeV/um), at which the particle or photon transfers energy to the medium through which it travels (Faw and Shultis 1993). The LET is directly related to the quality factor (Q) that expresses the radiation’s effectiveness for damaging tissue. The damage that ionizing radiation inflicts on living cells depends on the dose to the tissue of interest and the LET of the radiation. Gamma rays are low LET radiation because of their lack of charge and mass, so they interact in a different manner in relation to energy transfers and matter alterations. In the case of gamma radiation, three types of interaction with matter typically take place. First, the photon can interact with an orbital electron and transfer all of its electromagnetic energy at once to an electron, subsequently ejecting the electron from the atom; this is called the "photoelectric effect." The second method, called the "Compton effect," occurs when only a portion of the total available energy from the photon is transferred to the electron; the balance is retained by ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 197 5. MECHANISMS OF BIOLOGICAL EFFECTS the photon and the photon changes direction (scattering). This scattering interaction may be repeated every time it interacts with other electrons in tissue, until finally the photon is absorbed in a photoelectric interaction. The third type of interaction, “pair production,” can occur only if the photon’s energy exceeds 1.02 MeV. In a pair production interaction, 1.02 MeV of the photon’s energy is converted to the mass of an electron-positron pair, and the balance of the photon’s energy appears as kinetic energy. These two beta-type particles interact with tissues (like low LET beta particles), but at the end of its path, the positron combines with an electron and both are annihilated, forming two 0.511 MeV photons, which interact like gamma rays. In all cases, the interaction of gamma radiation with matter produces low LET electrons. These electrons are the primary ionizing particles that transfer energy to the molecules of the absorbing medium. The evidence presented thus far indicates that the critical molecular site for both high and low LET ionizing radiation is the DNA. Research performed over the course of many years has demonstrated that ionizing radiation can interact either directly or indirectly with the cellular DNA to exert adverse biological effects through the energy transfers from a particle or photon. Regardless of the method, the genetic material is the primary target for ionizing radiation (Faw and Shultis 1993). 5.3 INTERACTIONS OF IONIZING RADIATION WITH DNA The two general types of interaction that ionizing radiation can have with all molecules (in particular the DNA of the cell) can be roughly classified into direct and indirect interactions. Each type produces adverse effects by specific pathways (or mechanisms). These pathways are discussed in more detail in this section. Direct interactions with cellular molecules, such as DNA, involve alpha, beta or gamma radiation coming into direct physical contact with the DNA molecule. Chapter 2 provides an overview of the different types of ionizing radiation and their ability to transfer their energies when interacting with biological matrices. The mechanism behind direct interactions with macromolecules and DNA is rather straightforward. In the case of DNA, both high and low LET radiation can directly collide with this large macromolecule and distort the DNA structure and remove large or small pieces of the molecules, resulting in the opening of purine rings (leading to depurination) and the breaking of phosphodiester bonds. The effects ultimately result in the genetic effects listed in Tables 3-4 and 3-5. Genotoxic effects are a major toxicological end point for exposure to ionizing radiation and are likely involved in the induction of cancer in humans. The data from Tables 3-4 and 3-5 demonstrate that the typical genotoxic effects associated with exposure of genetic material to ionizing radiation primarily consist of deletions, mutations, chromosomal aberrations, and breaks, ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 198 5. MECHANISMS OF BIOLOGICAL EFFECTS resulting in reciprocal translocations, sister chromatid exchanges, dominant lethal mutations, and sperm anomalies. When the cell enters a mitotic cycle, these damaged chromosomal units have an increased probability of failing to replicate properly due to structural damage unless chromosomal repair mechanisms can repair the damage prior to entering mitosis. If the repair mechanisms fail to perfectly and seamlessly repair the damage to the chromosome, restoring it to its original structure prior to ionizing radiation damage, or do not repair the damage at all, the chromosome may not replicate properly. This results in critical portions of that chromosome being deleted during the replication cycle, resulting in genetic mutations in cell progeny. Table 5-1 shows that the cells undergoing rapid mitotic cycles (intestinal crypt cells, fetal cells, and other rapidly dividing cells) have less time for repair mechanisms to reverse the damage to the nuclear DNA inflicted by ionizing radiation, making chromosomal anomalies more likely to be present during the frequent mitotic cycles and increasing the chances for cell death, genetic mutations, and abnormal cell functions in cell progeny. Ionizing radiation can affect other macromolecules in a similar fashion; these effects are discussed in Section 5.4. The indirect action of ionizing radiation occurs by a number of pathways which result in the production of cytotoxic compounds. In this scenario, ionizing radiation has no direct interaction with any macromolecules. Instead, ionizing radiation interacts with smaller molecules surrounding the DNA; the end-products of this reaction diffuse away from the site of interaction with the ionizing radiation and interact with macromolecules (DNA) to produce adverse effects. One way that ionizing radiation may indirectly cause damage is through its interaction with water. Water comprises approximately 60% of the total body mass of humans and laboratory animals and 75-80% of the chemical composition of the living cell. Results depend on whether oxygen is present during the interaction. When ionizing radiation comes into contact with water (and no oxygen), a series of unstable reactions occur: H,0 + IR — e+ H,0" (radiolysis reaction) e +H,0 —- H,00 —-OH +H’ H,0* — H*+ OH’ In this reaction, free cellular water interacts with an ionizing radiation source to produce one free electron and one ionized water molecule, a reaction commonly known as radiolysis. This free electron is highly reactive and interacts with another un-ionized water molecule to produce a negatively charged and highly unstable water molecule. This molecule quickly decomposes to form the OH" and the H' free radical; the H' radical is ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 199 5. MECHANISMS OF BIOLOGICAL EFFECTS very reactive and essentially reacts where it is formed, but the OH ion is more stable and can then diffuse out into the cellular fluid and interact with any number of macromolecules it encounters in its path, in this case molecules of DNA. The remaining H,O* molecule can also transform into a free and ionized hydrogen ion (potentially affecting intracellular or extracellular pH) and the hydroxyl radical. From these equations, four products of radiolysis can occur after ionizing radiation interacts with a water molecule: H’, OH’, H*, and OH". Of the molecules, 55% are either H" or OH" and are the most important species biologically; however, they have half-lives of approximately 10""" seconds, which is long enough to produce damage to DNA and other macromolecules. These ionized particles will interact with DNA, resulting in the addition or loss of atoms or pieces of molecules; this will ultimately result in structural degradation, cross-linking, breakage of chemical bonds, and a host of other adverse effects. H* or OH™ may also interact with each other, to form an innocuous water molecule. In the presence of water and oxygen, ionizing radiation can produce another set of reactions that have more potentially destructive capabilities within the cell. The radiolysis reaction, in the presence of tnolecular oxygen, results in the formation of three chemical entities: hydrogen peroxide (H,0,), hydroperoxy radicals (HO;"), and hydroperoxy ions (HO,"). All have potent oxidizing potential and half-lives of approximately 10" second. With an extended half-life (when compared to the 10! second half-lives of H', OH’, H*, and OH"), there is a greater potential for interacting with and inducing more damage to the DNA. Oxygen is therefore considered a radiosensitizing agent, associated with the production of relatively longer-lived and more potent by-products (hydrogen peroxide and hydroperoxy ions and radicals) than in tissues with lower oxygen tensions. The oxygen-water-ionizing radiation interactions have practical applications in clinical medicine. Radiotherapy is often used to treat large neoplastic masses in humans. Oxygen tension is lowest at the center of these large neoplastic masses, due to an inadequate blood supply to the neoplastic mass, compression from surrounding cells, or altered aerobic metabolism in these cancerous cells. Many of these masses may have liquified and necrotic centers as well. Low oxygen tension in these neoplastic masses may not result in the production of significant amounts of hydrogen peroxide and hydroperoxy ions/radicals to damage macromolecules within these abnormal cells and, therefore, may limit the efficacy of radiotherapy in these patients. Thus, ionizing radiation interacts by both direct and indirect mechanisms to damage the DNA molecule. Ionizing radiation frequently produces an important type of change to DNA at the molecular level by ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 200 5. MECHANISMS OF BIOLOGICAL EFFECTS removing a base to form an apurinic or apyrimidinic site. The deletion or total destruction of DNA bases, destruction of deoxyribose residues, and deamination of cytosine or adenine are a few of the many ways ionizing radiation can alter the DNA at a molecular level. The attack by reactive species or by a direct interaction by the ionizing radiation source itself results in the degradation of bases and sugars, breakage of the hydrogen and sugar-phosphate bonds, and cross-linkages, all of which are deleterious to the structural integrity of the DNA macromolecule. Significant amounts of damage make the DNA unable to successfully replicate during mitosis and/or unusable for gene coding of essential enzymes, proteins, and other molecule formation through RNA pathways. The magnitude of the damage is dose-dependant. A more in-depth discussion of the alterations at the DNA level by ionizing radiation, including a few of the known DNA repair mechanisms, is presented in BEIR V (1990). DNA base damage is the most predominant type of DNA damage, followed (in decreasing order of incidence) by single-strand breaks, DNA-protein cross-linkages, and double-strand breaks. In base damage, thymidine appears to be the most sensitive base, followed by cytosine, adenine, and guanine. Both single- and double- strand breaks occur after exposure to ionizing radiation. A 100-rad (1 Gy) dose of low LET ionizing radiation can produce 63-70 double-strand breaks per cell and 1,000 single-strand breaks (Cockerham et al. 1994). In addition, it was noted that there were 440 sites of multiple DNA strand lesions that are in close proximity to each other that interact in such a way to cause cell death (called Locally Multiple Damaged Sites, LMDS). It would appear that simple single- or double-strand breakage is responsible for cell death; however, in cases of genotoxicity after chemical exposure, single-strand breakages have numbered into the hundreds of thousands, implying that the relatively low number of single-strand breaks after exposure to ionizing radiation is not likely the primary cause of cell toxicity, probably because of the presence of repair systems. Double-strand breaks are likely too few to be of consequence for cell death, but they are critically important in cancer initiation. Given that there are only three types of damage to the DNA that could be responsible for cell death, this leaves LMDS as the primary cause for cell death (Faw and Shultis 1993). Strand breakage is also responsible for chromosomal anomalies, some of which were reported in Tables 3-4 and 3-5. DNA strand damage is a serious cellular event; however, the cell comes equipped with chromo- somal repair mechanisms. Without them, the damage that occurs to the entire organisms's DNA every day could prove lethal. Chromosomal repair mechanisms provide a mechanism for minimizing the adverse DNA effects of ionizing radiation on the genome, providing that the dose of radiation is not so large as to overwhelm the inherent repair mechanisms. However, like many other biological functions, they are not always 100% efficient at performing this task. Single-strand breaks stand a better chance for repair by the ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 201 5. MECHANISMS OF BIOLOGICAL EFFECTS cellular DNA repair enzymes (DNA ligase) than do double-strand breaks. First, with single-strand breaks, only one strand of the double-stranded DNA is broken, whereas both strands are broken with double-strand DNA damage. Because one strand is still intact, single-strand breaks are usually stable and within a reasonable distance from each other for repair enzymes to function; however, this is not always the case with double-strand DNA breaks. Secondly, there is a template on the adjacent strand in single-strand DNA breaks to determine where various bases go on the missing strand. Exposure to ionizing radiation that results in a double-strand break may have just broken the bonds of the nucleotides (perhaps easier to repair?), or it may have also destroyed large bits of DNA, leaving no template for repair enzymes to follow in order to replace the missing segments of DNA. Because single-strand breaks in DNA are more easily repaired, cells can tolerate much more of this type of strand breakage before the repair mechanisms are overwhelmed. With double-stranded DNA breaks, the DNA is in three or more pieces and may no longer be adjacent to the chromosome to which it is supposed to be attached. When cells are irradiated with ionizing radiation, chromosomal breaks are commonly produced in one or multiple places on the chromosome, and small pieces of the original, intact chromosome are separated from the rest of the parent chromosomal structure, resulting in chromosome and chromatid aberrations. The fragments may not be in close proximity to each other, making repairs difficult, if not impossible. Chromosomal aberrations and chromatid aberrations are the two most common types of chromosomal anomalies that can be visibly observed during the metaphase stage of the cycle. Chromosomal aberrations are a result of a cell that was irradiated early in the interphase cell cycle (G1 or early S phase), prior to the chromosome being duplicated. Chromatid aberrations are commonly observed when the damage was received in the later stages of interphase (late S or G2 phase) after the chromosome has duplicated and consists of 2 strands of chromatin. Specific radiation-induced aberrations in chromosome and chromatid structure have been discussed in more depth by Hall (1988). These aberrations may or may not result in the disruption of normal cellular functions, depending on which chromosome the breakage occurred on and where on the chromosome the damage occurred. However, when the cell enters a mitotic cycle, these damaged chromosomal units will ultimately fail to replicate properly unless chromosomal repair mechanisms can repair the damage prior to entering mitosis/meiosis. If the repair mechanisms fail to repair the damage to the chromosome, it is unlikely to replicate properly; this will result in critical portions of that chromosome being deleted during the mitotic cycle, leading to genetic mutations and deletions in cell progeny. These chromosomal breaks can best be seen microscopically during either the metaphase or anaphase portion of the cell cycle. Minor damage left unrepaired or damage that was not completely or correctly repaired can result in mutations. Mutations can involve either a single gene or multiple genes. Point mutations and small deletions usually involve a small number of bases (~20 to 60), whereas large base ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 202 5. MECHANISMS OF BIOLOGICAL EFFECTS deletions or base rearrangements may involve several hundred or many thousands of bases. The proportion of deletions obviously tends to increase in frequency as the number of hits from the ionizing radiation source increases (Borek 1993). The cells that undergo more frequent mitotic cycles (intestinal crypt cells, fetal cells, and other rapidly dividing cells) have less time for repair mechanisms to reverse the damage to the nuclear DNA inflicted by ionizing radiation. This makes chromosomal anomalies more likely to be present during the frequent mitotic cycles and increases the chances for genetic mutations and abnormal cell functions in cell progeny. When examined more closely, the broken ends of the chromosome appear "sticky" and have the ability to rejoin with other broken chromosomes. Once chromosomal breakage occurs, a broken fragment can: (1) rejoin with the chromosome it was originally joined to, producing no abnormalities at the next mitosis; (2) not rejoin and cause gene deletions to occur at the next mitosis; or (3) join another broken fragment and give rise to new, distorted chromosomes (Hall 1988). The DNA damage described in this section also occurs spontaneously. Environmental agents, including radiation, increase the rate at which this DNA damage occurs. Actually, the damage occurs at a much greater rate than is observed. However, the damage is repaired by many physiological mechanisms. Damage is expressed when the rate at which the damage is produced exceeds the body’s natural repair mechanisms. 5.4 EFFECTS ON OTHER CELLULAR MACROMOLECULES DNA is the most critical molecule for damage from ionizing radiation. A number of other critical cellular components have been reported; some effects on these molecules are outlined in Table 5-2. Table 5-2 shows that a wide range of molecules, varying in both size and molecular weight, can be adversely affected by exposure to ionizing radiation. The mechanisms by which each is affected are the direct and indirect effects of ionizing radiation discussed for DNA. The end results are broken chemical bonds, cross- linkages, and conformational changes. These changes may affect the molecule’s biological function; for example, a conformation change in the structure of an enzyme or protein could affect its ability to perform a critical function in a metabolic pathway and thereby halt a certain function. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 203 5. MECHANISMS OF BIOLOGICAL EFFECTS Table 5-2. Some Effects of lonizing Radiation on Molecules in Animal Tissues Molecule General effects Amino acids Production of ammonia, H,S, pyruvic acid, CO,, hydrogen molecules Carbohydrates Cleavage of glycosidic bonds, depolymerization of monomers, oxidation of terminal alcohols to aldehydes Deoxyribonucleic acid (DNA) Degradation from base loss and modification, breakage of hydrogen bonds and sugar-phosphate bonds; DNA-DNA and/or DNA-protein cross-linking; single- or double-strand breakage; formation of guanyl, thymidyl and sugar radicals Lipids Peroxidation and carbon bond rearrangement: conjugated diene formation, aldehyde formation, B-scission, lipid cross-linking, increased microviscosity, cell membrane rupture Proteins Degradation and modification of amino acids, chain scission, cross-linkage; denaturation, molecular weight modifications, changes in solubility Thiols Redox reactions, radical formation, cross-linkages, inhibit thiol from mediating damage to lipids Source: adapted from Cockerham et al. 1994. Amino acids and their larger counterparts, peptides, polypeptides, and proteins, are also susceptible to the effects of exposure to ionizing radiation. Exposure of these molecules to ionizing radiation frequently results in breakage of hydrogen bonds, disulfide bridges, and cross-linking with DNA or with other proteins. All of these effects can result in conformation changes and alterations in function. Exposure to ionizing radiation causes the depolymeration or glycogen and cleavage of a-glycosidic bonds within glycogen and other molecules containing «-glycosidic bonds. Glycogenesis and gluconeogenesis pathways within the cell are activated; insulin and blood glucose levels also rise due to increased release of insulin and adrenocorticoid release. Lipids are ubiquitous macromolecules that participate in a number of cell process. Lipids comprise cell membranes, disruption of which leads to disruptions of homeostasis, cellular dysfunction, and death. Lipids are also involved in the production of prostaglandins, which modulate a number of biological functions, including digestion, reproduction, and neural function. Lipid peroxidation occurs primarily through free- radical attacks at double-bond sites and at carbonyl groups. Lipid peroxidation starts a chain reaction within cells. When a lipid radical interacts with another organic molecule, that molecule is transformed to a free- radical state. Each newly transformed free-radical molecule then interacts with another molecule. Given this chain of events, the damage induced after lipid peroxidation can be formidable. Fortunately, animals have several mechanisms by which to slow or stop this chain reaction. A number of free-radical scavengers such as vitamin A, vitamin E, and thiols are available to inhibit the chain reactions. Other detoxification systems ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 204 5. MECHANISMS OF BIOLOGICAL EFFECTS that can inhibit the effects of lipid peroxidation include metallothionine, glutathione transferase, reduced NADPH-dependent glutathione reductase, selenium-dependant glutathione peroxidase, ferric manganese and copper-zinc superoxidase dismutases, and catalase. A more in-depth discussion on the specific mechanisms by which each system functions is available (Cockerham et al. 1994). Several of these systems and a number of chemicals have been more closely studied in order to potentially decrease the biological effects of exposure to moderate to high doses of radiation in humans and animals, but results have been mixed (Biambarresi and Walter 1989). 5.5 MECHANISMS OF CARCINOGENESIS No one is certain of the exact mechanism(s) by which cancer is produced, but over the years, several theories and models have been put forth that describe the events that scientists suggest must take place in order for cancer to occur. Some of the more traditional carcinogenesis models are briefly summarized in Table 5-3. A number of factors have been identified (such as diet; hormonal status; genetics; and exposure to some solvents, chemicals, and ionizing radiation) that appear to predispose some individuals to developing cancer. Both chemicals and ionizing radiation are known to induce many types of cancer and much of the evidence for this observation was discussed in Chapter 3 of this profile. Cancer is the major latent effect after exposure to ionizing radiation, with the critical molecule being the DNA. Cells depend on their DNA for coding information to make very specific enzymes, proteins, hormones, vasoactive substances, and a host of other chemicals in order to live. When the genetic information containing the “blueprint” for these substances is disrupted, cell homeostasis is disrupted, with a wide range of carcinogenic and non-carcinogenic toxicological effects that have been described in Chapter 3. Not all alterations in the genome will result in the expression of immediate adverse events. Lower levels of exposure to ionizing radiation may result in genetic damage, which includes gene deletions, point mutations, frameshift mutations, and “nonsense” coding of some genes on one or many chromosomes. These alterations occur by the same direct and/or indirect mechanisms outlined in Section 5.3. If these genes are not used by the cell or if their mutation or total absence is of little consequence to normal cell function, no immediate effects may be incurred. Cell function and homeostasis is not disrupted. These seemingly inconsequential genetic effects may initially seem to be of minimal importance. However, with spontaneous changes in the genetic apparatus of somatic cells continuing over time and with further exposure to environmental carcinogens, the amount of misinformation in the genetic apparatus continues to increase within the cell’s ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 205 5. MECHANISMS OF BIOLOGICAL EFFECTS DNA. If this misinformation affects the DNA coding that either controls or suppresses an oncogene, then oncogenic lesions may be initiated. The formation of cancer has been an area of intense research in the scientific community for centuries. In 1775, Percival Pott was the first to report that cancer could be caused by environmental factors. Pott described a number of cases of cancer in men employed as chimney sweeps sometime during their life. Pott concluded from his observations that their exposure to soot was in some way related to their developing cancer of the scrotum. Since that time, a number of chemical, environmental, and lifestyle factors have been identified as either be directly or indirectly implicated in producing different types of cancer. Many of these chemicals share similar physico-chemical and structural similarities. Table 5-3. Some Models That Describe the Induction of Cancer in Animals Model Model type and premise Model characteristics Single Hit* Mechanistic model: One “hit” is Tumor development depends only on the total dose sufficient for a cell to mutate and then received and not on the pattern of exposure; yields high transform into a neoplastic cell. estimations of risk compared to other models Multi-Hit Mechanistic model: A critical number ~~ May produce very high or very low “safe-dose” estimates; of hits must occur before the cell doesn’t easily account for dose-response relationships that becomes neoplastic. are linear at low doses; begins to curve as dose increases Multistage/ Mechanistic model (based on the Use of upper bounds results in a model less sensitive to Linearized model of Armitage and Doll 1957): A changes in data; multi-degree polynomials are fitted using Multistage progression of orderly events must only 2 or 3 dose levels; a constant dose rate is assumed (LMS) occur in a cell in order for cancer to (which is not always the case); does provide conservative occur. risk estimates MVK Mechanistic model; Two-stage model: ~~ Assumes tumors come from mutations of anti-oncogenes; Similar to the LMS, but it assumes that assumes 2 events must occur for malignant transformation; altered cells have a selective allows for cell kinetic information and mutations to be advantage over normal cells. incorporated into the model Probit Statistical model Estimates probability of a response at a given dose; may not reflect scientific observations of dose-response when extrapolating from a 50% response dose to a 1/1,000,000 risk estimate Logit Statistical model Derived from chemical kinetic data; used to derive “virtually safe doses” by some government agencies until the late 1970's; similar to Probit model Weibull Statistical model Used to derive “virtually safe doses” by some government agencies until the late 1970s; uses power transformations to describe the data; greater flexibility that either the Probit or Logit models; risk estimates range between the LMS and multihit mechanistic models; dose and time relationship are described ® A “hit” is defined as a critical cellular interaction, such as a gene mutation, that alters the cell's DNA (Faustman and Omenn 1996). Source: summarized from Faustman and Omenn 1996 and Rees and Hattis 1994 ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 206 5. MECHANISMS OF BIOLOGICAL EFFECTS Today, the formation of cancer from exposure to some chemicals is believed to be a multi-stage process that involves at least three distinct phases, events, or steps. Some chemicals or agents may be capable of inciting one, two, or all three of these steps. It is believed that exposure to ionizing radiation involves the same multi- step process as does the chemical carcinogen exposure. There are three general stages necessary for cancer formation. The first stage is initiation, which is characterized by the fixation of a somatic mutational event in the cell’s DNA. This damage may occur by direct, indirect, or a combination of the events described in Sections 5.2 and 5.3. This initiation may occur at one or multiple sites within the genome and can affect any gene on any chromosome in any exposed cell; which site is affected depends on where the damage occurs. Once exposed, certain outcomes are possible. In cases of high doses of radiation, the cell may sustain such extensive genetic damage that the cell is unable to perform its functions or sustain itself metabolically, in which case it simply dies. High doses may kill so many cells that the organism shows obvious signs and symptoms, but lower doses can kill few enough cells that effects are not readily observed. The cell may attempt to repair the damage using alkyltransferases, base excision repair, nucleotide excision repair, mismatch repair, or other innate repair mechanisms inherent to that cell. If all of the damage is repaired correctly, the cell is considered normal and not at risk for developing cancer. However, repair mechanisms are not always 100% effective and may result in incorrect repair or no repair at all. In this case, the cell may either live and tolerate the damage to the genetic material or undergo apoptosis (programmed cell death). Only the cells that continue to live and reproduce can potentially produce cancer. Since exposure to ionizing radiation can result in changes to a cell’s genetic apparatus, it can act as an initiating agent in the development of cancer. Additional information about the ability of ionizing radiation to inflict damage on the DNA structure is presented in Chapters 2, 3, and 5. Initiation requires at least a partial failure of gene repair mechanisms and one or more cell mitotic cycles before the genetic alteration can be “fixed” into place. Initiation is an irreversible process once this fixation occurs. Whatever the mechanism, the end product is a mutation of the cell’s DNA that the cell’s innate repair systems failed to restore to the normal genetic state. This mutation is considered an adverse event; however, the initiation or “genetic recoding” alone is not sufficient to produce cancer. The initiation step must be followed by the second stage, promotion. A promoting agent is one which stimulates the initiated (or pre-neoplastic) cell to divide or otherwise provides certain conditions that allow the preferential selection of mutated cells to survive over unmutated cells in the tissue. In contrast to initiation, the promotion step is a reversible step both at the DNA and cellular level, and depends on ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 207 5. MECHANISMS OF BIOLOGICAL EFFECTS continuous exposure to the promoting agent. This reversibility is a major characteristic of the promotion stage of carcinogenesis. For promoting agents, there is no evidence to suggest that these chemicals or other factors must interact directly with the DNA to affect cell proliferation. Promoters need not necessarily be carcinogenic agents themselves. Many chemicals (saccharin, phenobarbital, dioxins, cholic acid), as well as some hormones (estrogen and thyroid-stimulating hormone) are not carcinogenic themselves, but have been found to promote carcinogenesis after certain cells have undergone the initiation process in some species of animals. Promoting agents may also be species specific: what is a promoting agent for cancer in laboratory animals may not necessarily be a promoting agent in humans. Although some promoters are actually non- carcinogenic when administered by themselves, other promoters can act as both initiators and promoting agents. Ionizing radiation is an excellent example of an agent that can act as both an initiator (producing gene mutations and chromosomal alterations) and as a promoting agent by stimulating cell division after exposure. The last stage of carcinogenesis is called proliferation. Proliferation agents cause uncontrolled and extensive proliferation of abnormal cell types. During this stage, a specific phenotype of mutated cells is selected that effectively evades the host defense mechanisms and then undergoes massive proliferation. Arsenic salts, asbestos fibers, benzene, benzoyl peroxide, and hydroxyurea have all been identified as proliferation agents associated with cancer formation. This uncontrolled and extensive proliferation of abnormal cell types leads to the formation of solid tumors (adenomas, squamous cell carcinoma, adenocarcinomas, etc.) or non-solid tumors (leukemia, lymphoma, etc.) at one or multiple locations throughout the body. How locally invasive the tumor is (aggressiveness) or the ability of the tumor to relocate to sites distant from the site of initial formation (metastasis) depends on the type of tumor formed. Should the proliferations become widespread throughout the body or cause severely adverse effects on vital organ functions, the organism will eventually succumb to organ failure and die. Ionizing radiation is capable of acting as a proliferation agent in the formation of cancer in the skin of mice. Gene mutation is a key step in the formation of cancer. Any gene or any locus on the DNA can be affected by a genotoxic agent and undergo mutation; however, some genes may be more susceptible to mutations than others. Certain gene mutations and chromosomal irregularities are associated with specific cancers in humans and laboratory animals. These genes are called proto-oncogenes, oncogenes, and tumor suppressor genes. Proto-oncogenes are similar to viral oncogenes. Both proto-oncogenes and oncogenes are dominant genes that normally function to regulate cell growth, signal transduction, and nuclear transcription (Pitot III and Dragan 1996). Mutations in these genes result in the activation and subsequent neoplastic transformation of “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 208 5. MECHANISMS OF BIOLOGICAL EFFECTS cells containing these mutated genes. Conversely, tumor suppressor genes are recessive genes which normally function to slow cell growth. When these genes mutate, they lose this capacity to down-regulate cell growth, which results in the activation and subsequent neoplastic transformation of the mutated cells. Exposure to ionizing radiation may cause mutations in proto-oncogenes, oncogenes, and tumor suppressor genes. Environmental factors have also been shown to play a role in lung carcinogenesis, particularly in the promotion stage. These environmental factors include tobacco, silicon dust, diesel fumes, and possibly other toxicants found in the breathable air of mines. Other factors that have been related to chemically-induced cancers include alcohol use, food additives, diet, sexual behavior, occupation, air and water pollution, pharmaceuticals, and bacterial and viral infections. 5.6 IDENTIFICATION OF DATA NEEDS The following has been identified as a potential data need regarding health effects associated with exposure to ionizing radiation. Environmental factors, such as tobacco, silicon dust, diesel fumes, and possibly other toxicants found in the breathable air of mines, together with exposure to sources of ionizing radiation, have been shown to play a role in the development of lung cancer. More research is needed to determine possible interactions between other carcinogens and ionizing radiation. 5.7 SUMMARY This chapter summarized the major mechanisms by which ionizing radiation exerts it toxic effects on cell structure. Macromolecules, in particular DNA, are the critical molecules for damage from ionizing radiation. The method by which ionizing radiation interacts with a biological medium to cause ionization may be direct or indirect. Damage can occur due to direct ionization of the DNA molecule itself or indirectly through the formation of toxic products, such as free radicals, hydrogen peroxide, hydroperoxy radicals, and hydroperoxy ions, that diffuse from the site of formation and interact with any molecule in their path. Both direct and indirect DNA ionization occur and can lead to DNA damage. Since cells rely heavily on their DNA for instruction information, when the genetic information containing the “blueprint” for this information is disrupted, cell homeostasis is disrupted, and a wide range of biological responses is encountered. These “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 209 5. MECHANISMS OF BIOLOGICAL EFFECTS responses include non-carcinogenic and carcinogenic end points of toxicity. Other molecules, such as lipids, proteins, thiols, amino acids, and carbohydrates, can also be damaged when exposed to ionizing radiation. A number of models were presented that reflect possible mechanisms of cancer induction, as well as a brief discussion of the three steps of cancer formation. By knowing the specific mechanisms by which ionizing radiation produces carcinogenic and non-carcinogenic end points, research can focus on identifying biomarkers of effect with which to better assess the effects of low-level radiation exposure. ***DRAFT FOR PUBLIC COMMENT*** - ‘ . oo IONIZING RADIATION 211 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION 6.1 OVERVIEW Commonly used terms and scientific unit abbreviations used in this chapter are defined in Table 6-1 and Table 6-2, respectively. These and other terms may also be found in Chapter 9 of this toxicologic profile. All organisms (e.g., bacteria, plants, or animals, including humans) are exposed everyday to varying amounts of | ionizing radiation. Figure 6-1 depicts the average contributions from various sources of ionizing radiation to which the average U.S. citizen is exposed during his or her lifetime. In the United States, approximately 82% of the dose received from ionizing radiation comes from natural sources: 55% from radon, 8% from cosmic sources, another 8% from rocks and soil, and 11% from internal exposures to ionizing radiation from food and water consumed in the daily diet (largely potassium-40 [*°K]). The remaining 18% of the dose originates from Figure 6-1. Sources of Exposure to lonizing Radiation (adapted from NCRP 1987 Report #93) anthropogenic (man-made) sources such as medical X-ray exposure (11%), nuclear medicinal exposure (4%), and consumer products (3%). Less than 1% of the total ionizing radiation to the U.S. population comes from occupational sources, nuclear fallout, the nuclear fuel cycle, or other miscellaneous exposures. The total average annual effective dose equivalent for the population of the United States, natural and anthropogenic, is approximately 360 mrem (3.6 mSv) and is described further in Chapter 1 of this profile (BEIR V 1990). 6.2 EXPOSURE TO NATURAL SOURCES OF EXTERNAL IONIZING RADIATION The majority of exposure to radiation comes from natural sources; with the exception of indoor radon exposure (and to some extent exposure from terrestrial sources), exposure to natural radiation from natural sources is only moderately controllable. The average annual effective dose equivalent from all natural sources combined is approximately 300 millirem (3 mSv). Of this amount, approximately 98 millirem ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 212 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION Table 6-1. Common Terms and Abbreviations becquerel (Bq) curie (Ci) rad gray (Gy) rem roentgen (R) sievert (Sv) quality factor (Q) Sl unit for quantity of radioactive material; 1 Bq equals that quantity of radioactive material in which there is 1 transformation or disintegration per second (dps). Conventional unit for quantity of radioactive material. One Ci is the quantity of any radionuclide in which there are 37 billion transformations or disintegrations in 1 second. This is the activity of 1 gram of **Ra. The unit of absorbed dose equal to 0.01 Joule/kg in any medium. Sl unit of absorbed dose. Conventional unit for dose equivalent. The dose equivalent in rem is numerically equal to the absorbed dose in rad multiplied by the quality factor. Amount of ionization in air by X-ray and gamma radiation. One R equals 2.58x10™ coulomb per kg of air. The SI unit of dose equivalent. It is equal to the dose in grays times a quality factor; 1 Sv equals 100 rem. The linear-energy-transfer-dependent factor by which absorbed doses are multiplied to obtain (for radiation protection purposes) a quantity that expresses the effectiveness of the absorbed dose on a common scale for all ionizing radiation. Table 6-2. Scientific Units Prefix (symbol) Power of 10 Decimal Equivalent atto 107 0.000000000000000001 femto (f) 10 0.000000000000001 pico (p) 10" 0.000000000001 nano (n) 10° 0.000000001 micro (u) 10% 0.000001 milli (m) 103 0.001 centi (c) 102 0.01 deci (d) 10 0.1 kilo (k) 10° 1,000 mega (M) 10° 1,000,000 giga (G) 10° 1,000,000,000 tera (T) 10% 1,000,000,000,000 peta (P) 10" 1,000,000,000,000,000 exa (E) 10" 1,000,000,000,000,000,000 (98 mSv) is due to background radiation; this includes cosmic rays, 29 millirem (0.29 mSv); terrestrial gamma rays, 29 millirem (0.29 mSv); and radionuclides within the body, 40 millirem (0.40 mSv). Individual doses from natural sources may be much greater. The magnitude of natural exposures depends upon numerous factors such as geographic location, height above sea level, and the construction and ventilation of buildings. For instance, the average annual radiation dose received by a person living in Boston, Massachusetts, is approximately 300 mrad, while people living in Denver, Colorado, and Kerala, India, **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 213 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION receive average annual doses of approximately 600 mrad and 1500 mrad, respectively. The difference in these doses is due mainly to the increase in cosmic radiation at higher altitudes in the Colorado area and the greater concentrations of radioactive material found in the soils of the Colorado and Kerala areas (BEIR V 1990; Eisenbud 1987; Harvard Medical School 1996; UNSCEAR 1993). 6.2.1 Cosmic Rays Cosmic radiation is primarily composed of galactic radiation originating outside the solar system in addition to a varying degree of solar radiation. The primary cosmic rays that arrive in the upper atmosphere are high- energy subatomic particles — primarily protons, but also nuclei, electrons and X-rays — moving almost at the speed of light; these primary rays create secondary rays that bathe the atmosphere in radiation. Austrian physicist Victor Hess discovered cosmic rays in 1912 when he and two assistants flew a balloon to an altitude of 16,000 ft. Hess proved that the source of a mysterious radiation previously detected at ground level was actually coming from outside the atmosphere; he also found that the rate of decline in radiation as the balloon ascended was slower than would be expected if the radiation emanated from the earth. Only a small fraction of cosmic radiation originates from the sun; however, the proportion of cosmic radiation contributed by the sun increases during periods of increased sunspot and solar flare activity, which run in 11-year cycles. Cosmic rays bombard the periphery of the earth’s atmosphere at a rate of 2x10'® particles per second, at a density of about 25 rays per square inch, and at an energy flux of 2,000 MeV/cm?esec. These rays, referred to as “primary cosmic rays,” are deflected and slowed by particles in the earth’s atmosphere, creating “secondary cosmic rays” that often reach and even penetrate the earth’s surface. The interaction of cosmic rays with the atmosphere leads to the production of several cosmogenic radionuclides, notably carbon-14 (*C), tritium (*H) and beryllium-7 ("Be). Because of the shielding effect of the atmosphere and the earth’s geomagnetic fields, which tend to deflect cosmic ray particles towards the magnetic poles, the cosmic ray dose rate increases with altitude and latitude. The average annual dose from cosmic radiation in the United States is 29 mrem, but this value doubles for every 6,000-foot increase in altitude. Thus, the dose from cosmic rays received in Denver, Colorado, and Leadville, Colorado (altitudes of 1,600 m and 3,200 m, respectively), is approximately two and four times that received at sea level, respectively (Eisenbud 1987; Korff 1964; NASA 1995; Shapiro 1990; UNSCEAR 1993). At altitudes of 30,000 to 40,000 feet, where most jet aircraft fly, the cosmic ray dose rate is almost 1 millirem per hour. “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 214 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION 6.2.2 Earth's Crust Cosmogenic radionuclides contribute very little to background radiation compared to naturally occurring radioactive materials found in the earth’s crust, such as “°K, uranium and its progeny, and thorium and its progeny. Uranium, for example, is found in all types of soil and rock at concentrations ranging from 0.003 ppm in meteorites to 120 ppm in phosphate rock from Florida. Exposure to radioactive materials in the soil and earthen products occurs continuously since we are surrounded by these sources. The degree of exposure varies tremendously and is affected by such factors as geographic location, the types of materials used in building structures, and the degree of ventilation in dwellings. Some communities situated on soil with high concentrations of granite or mineral sand experience exposures many times the average. Examples include coastal areas in Espiritos Santos and Rio de Janeiro in Brazil; Kerala, on the southwest coast of India; and the Guangdong province in China. In Brazil, the black sand beaches are composed of monazite, a rare earth mineral containing 9% radioactive thorium. External radiation exposure from these sands may be as high as 5 mR/hr; permanent residents experience an average annual exposure of approximately 500 mrem. In Kerala, on the west coast of India, residents are exposed to 1,300-1,500 millirem annually, due to the presence of monazite sand. Apart from radiation exposures due to living in close proximity to the earth’s crust, people are also exposed to radiation when earth crust products (oil, coal, coal ash, minerals) are extracted, refined, and used. In general, the hazards of exposure to radioactive materials during the extraction and processing of earth materials are relatively small compared to the hazards of exposure to other chemicals. As a result, radiation exposure from these sources is not routinely monitored (Eisenbud 1987; UNSCEAR 1993). The radiation hazards associated with the mining of coal, oil, natural gas, phosphate rock products, and sand are discussed below. 6.2.2.1 Coal Production Exposure to radionuclides occurs during the mining and use of coal and coal ash. The methods of coal usage vary considerably among countries; on average worldwide, about 40% of coal is burned in electric power stations, 10% in dwellings, and 50% in other industries. Based on samples from 15 countries, the average concentrations of “°K, 28U, and **?Th in coal are 50, 20, and 20 Bg/kg (1.35, 0.54, and 0.54 nCi/kg), respectively. These concentrations may vary considerably, depending upon the mine location. For example, **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 215 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION concentrations of these radionuclides in China are 104, 36, and 30 Bg/kg (2.81, 0.97, and 0.81 nCi/kg), respectively. Coal mine exhaust typically contains radon; the estimated annual per person exposure from radon in coal mine dust is 0.1-2 nSv. The average annual per person exposures to radiation from coal-fired power plants and from domestic cooking with coal are about 0.2 millirem (2 pSv) and 0.04-0.8 millirem (0.4-8 pSv), respectively. About 280 million tons of coal ash are produced by power plants each year. Potential uses for the ash include fertilizers and building materials for roads and dwellings. Most U.S. power plants recover ash exhaust using scrubbers, electrostatic precipitators, or bag houses. The radioactive content of coal tends to concentrate in the ash, resulting in 5- to 10-fold increases in the concentration of lead-210 (*'°Pb) and polonium-210 (*'°Po) as compared to unburned coal. When fly ash is used in building materials, the degree of external exposure to radiation and the inhalation of radon gas increases directly with the amount of ash incorporated into these materials. The average annual exposure associated with living in concrete and wooden houses is 7 millirem (70 pSv) and 3 millirem (30 pSv), respectively. An EPA report published in 1979 estimated that the exposure to radioactive materials emitted from all 250 coal-fired power plants resulted in an additional 1.5 cancers per year (Eisenbud 1987; EPA 1979 as cited by Eisenbud; UNSCEAR 1982, 1988). 6.2.2.2 Crude Oil and Natural Gas Production About 3x10" kg of crude oil and 10'> m® of natural gas are produced worldwide annually. Oil-fired power plants use about 15% of all oil. Gas-fired power plants are estimated to use about 15% of all gas. Radon is present in natural gas; concentrations at well heads average approximately 40 pCi/L. The processing and blending of liquefied petroleum gas (LPG) tends to enhance radon concentrations, and the long-lived radon daughters (*'°Pb and *'°Po) tend to accumulate on LPG processing machinery, resulting in a risk of exposure to maintenance workers. The annual per person doses from crude oil and gas are estimated to be 0.001 millirem (10 nSv) and 0.0001 millirem (1 nSv), respectively. The estimated doses are extremely small and result from inhalation of radioactive particles and radon gas (Eisenbud 1987; UNSCEAR 1993). 6.2.2.3 Phosphate Rock Products Phosphate rock, the precursor of all phosphate products including fertilizer, is mined at a rate of 130 million tons per year worldwide. The worldwide use of fertilizer, estimated to be 30 million tons, constitutes the greatest source of “°K and **Ra mobility. In the United States, the application rate for fertilizers ranges from ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 216 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION 30 kg of phosphate per hectare (barley) to 150 kg/hectare (potatoes and tobacco) for commercial agricultural application, and possibly less for residential applications. Concentrations of “°K and ***Th in phosphate rock are similar to those in soil (a few grams per hundred grams of matrix and a few grams per million grams of matrix, respectively). Levels of **U and its transformation products are much higher in phosphate rock than in soil. Concentrations of ***U in phosphate deposits are typically about 1,500 Bq/kg (40.5 nCi/kg). The practice of using phosphate fertilizers has resulted in uranium concentrations in food at levels up to 8 ng/g. Exposure to the general public occurs near areas of mining and processing through waste effluent. Several end-products of phosphate processing, phosphogypsum and calcium silicate, are used for fertilizer, for back- fill and road-base material, in additives to concrete, in mine reclamation, and in the recovery of sulphur. Phosphogypsum is also used as a substitute for natural gypsum in the manufacture of cement, wallboard and plaster. The primary radioactive material in this matrix is **°Ra, which is found at concentrations of 900 Bq/kg (24.3 nCi/kg). Exposure to phosphate-borne radioactivity is greater in discharges into surface waters. The primary pathway of exposure to radioactivity in humans is through the consumption of fish and crustacea. Elevated concentrations of radon have been detected in structures built over reclaimed phosphate mines, and over unmined mineral deposits. Maximum annual individual doses near phosphate facilities range from 4 millirem (40 pSv) in the Netherlands to 600 millirem (6 mSv) in the United States. The average annual per person dose of “°K derived from fertilizers is approximately 0.2 millirem (2 uSv); maximum annual individual doses, from consumption of seafood, have been estimated at 15 millirem (150 pSv), with 2'°Po as the main contributor. The annual per person radiation dose from ?’Ra-laden phosphogypsum in building materials is estimated to be about 1 millirem (10 uSv) (Eisenbud 1987; Shapiro 1990; UNSCEAR 1982, 1988, 1993). 6.2.2.4 Sand Mineral sands, defined as sands with a specific gravity of more than 2.9, originate from eroded rock. These sands are mined in Australia, Bangladesh, Indonesia, Malaysia, Thailand, and Vietnam. The heavy mineral is extracted from the sand and is processed into, among other items, paint pigment, titanium metals, catalysts, and structural materials. The sand itself is used as abrasive material for sandblasting. The principal radioactive components are >*?Th and ***U. Exposure is mainly external through minerals spilled at the processing plants. Although information on exposures is scant, annual levels are estimated to be in the low puSv range (UNSCEAR 1993). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 217 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION 6.2.3 Hot Springs and Caves Geothermal energy, produced in Iceland, Italy, Japan, New Zealand, Russia, and the United States, is produced from steam or water from high-temperature areas of the earth’s crust. Mineral springs and spas, which are found in South America, Europe, Japan, and the United States, are also clustered around these high-temperature areas of the earth’s crust. The primary radionuclides of concern from this source are those of the uranium transformation chain. Of these, **Ra and **’Rn are considered to be the most important. The diffusion of radon from ordinary rock and soils and from radon-rich water can cause notably elevated radon concentrations in tunnels, caves, and spas. In Bad Gastein, Austria, approximately 5 million gallons of mineral water are distributed to hotels and spas daily, allowing the release of about 58 Ci of radon per year into the environment. In comparison with levels in outdoor air, the concentrations of radon and its transformation products in confined air spaces such as mines and caves are elevated. The average annual per person radiation dose from this source is estimated to be 0.0001 millirem (1 nSv); however, the doses received by those intentionally spending time in these environs (e.g., tourists, workers, miners) are expected to be higher (Eisenbud 1987; IARC 1988; UNSCEAR 1993). 6.3 EXPOSURE FROM INTAKE OF NATURAL AND ANTHROPOGENIC RADIOACTIVE MATERIALS Radioactive materials enter the body primarily by inhalation, ingestion, or dermal absorption. Although radioactive materials may also enter the body through punctures (either wounds or injections), this route of exposure will not be addressed in this toxicological profile. The effects induced by internally deposited nuclides or external radiation are classified as either "acute" (early-occurring effects of radiation, which appear within days or weeks after exposure) or "latent" (chronic or late-occurring effects of radiation, which appear months or years after exposure). Acute effects are not expected for such sources of radiation because they are not capable of producing high dose rates in a short period of time. However, they can cause latent effects. The most common latent effect noted after exposure to ionizing radiation is an increased probability of certain types of cancer. More information on the health effects of ionizing radiation can be found in Chapter 3 of this toxicological profile. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 218 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION 6.3.1 Inhalation The sources of radionuclides that contribute to inhalation radiation exposure include nuclear testing; nuclear reactor and medical gaseous waste; radioactive materials manufacturing; medical nuclide use; coal- and gas- burning power plants; airborne soil; and naturally emanating gases. The radionuclides (and their average concentrations) commonly found in the atmosphere include: ***Rn and 2°Rn (270 pCi/m? each); ?'°Pb (0.01 pCi/m*); *°Po (0.001 pCi/m?); **U (12x10 pCi/m*); *?Th (3x10 pCi/m?); Th; (4.5x107 pCi/m*); and **Th (3x10 pCi/m®), "*C and *H. In addition, smokers are exposed to radiation from the radionuclide *'°Po, which is found in tobacco; the resulting dose to the bronchial epithelium can be as high as 0.2 mSv per year (NCRP 1984; Shapiro 1990; UNSCEAR 1993). The largest dose of radiation from natural sources comes from the inhalation of **’Rn and Rn (thoron) gases. These colorless and odorless gases, which are in the uranium and thorium transformation chains, respectively, are continuously released from the soil. Worldwide, the total emanation rate of radon is estimated to be 50 Ci/sec; the total atmospheric content is estimated to be 25 MCi. The main factors controlling the rate of radon release and subsequent exposure are: ground porosity, ground cover, temperature, meteorological conditions, and the type of construction and ventilation properties of dwellings. The rate of radon emanation from soil is thought to increase with diminished atmospheric pressure and to decrease during periods of, or in areas of, elevated moisture. The health hazards of radon exposure were first recognized in the 1930s when radium miners in Scheenburg, Germany, and Joachimstal, Czechoslovakia, were found to have a high incidence of lung cancer. Over half of all miner deaths were attributed to lung cancer, and most of the miners were less than 50 years of age when they died. In the general U.S. population, the EPA estimates that radon exposure accounts for approximately 10% (17,000) of all lung cancers, while smoking accounts for approximately 85% (144,500) of all lung cancers. The average annual effective dose equivalent from radon is about 200 millirem (2 mSv), but individual doses may be much higher. It is estimated that 1-3% of all homes have radon levels in excess of 8 pCi/L. Approximately 50,000 to 100,000 homes in the U.S. have radon concentrations exceeding 20 pCi/L, which results in exposures equal to or exceeding the limit for occupational exposure. For radon, the 22°Rn doses are considerably lower than those of *’Rn, due to its short half-life (55 sec for 2’Rn versus 3.8 days for ??Rn). Both *°Rn and **’Rn have several short-lived progeny in their transformation chains (see Table 6-3), and radiation from these daughter products constitutes the hazard from radon. Thus, in assessing ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 219 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION the effects associated with radon exposure, one must consider the simultaneous and cumulative effect of the entire radon series (BEIR V 1990; Eisenbud 1987; LBL 1993; Shapiro 1990; NCI 1996; UNSCEAR 1993). Coal mine exhaust and the combustion products from the use of coal and oil typically contain radon and daughter products, which contribute doses of 0.001 millirem (10 nSv) or less. The average annual per person exposures to radiation from coal- and oil-fired power plants are about 0.2 millirem (2 uSv) and 0.001 millirem (10 nSv), respectively. The average annual per person exposure to radiation from domestic cooking and heating with coal is about 0.04—0.8 millirem (0.48 pSv); this dose originates primarily from radon and its daughter products (UNSCEAR 1993). Several radioactive by-products of the nuclear power industry may be inhaled and result in adverse health effects. During uranium fuel fabrication, uranium hexafluoride gas is enriched to increase the percentage of 250 and then converted into uranium oxide or metal. Depending upon the type of reactor fuel or nuclear weapons material being produced, uranium must be enriched to a minimum of 3% ***U. Emissions from fabrication facilities usually consist of the long-lived isotopes **U, #*5U, and 2**U, and the short-lived isotopes “Th, and protactinium-234m (**™Pa). The major route of exposure from this source is inhalation. More information about uranium is available in ATSDR's (Draft) Toxicological Profile for Uranium (ATSDR 1997). Other radioactive by-products of the nuclear power industry include the noble gases Table 6-3. Radioactive Properties of Radon and its Daughter Products Radiation energies (MeV) Radionuclide Half-life [od B y Radon-222 3.8 days 5.49 oe — Polonium-218 3.1 minutes 6.00 — —_— Lead-214 26.8 minutes — 0.67 0.30 0.73 0.35 Bismuth-214 19.9 minutes — 1.51 0.61 1.54 1.12 3.27 1.76 Polonium-214 164 pseconds 7.60 mm 0.8 Lead-210 22.3 years — 0.016 0.05 0.06 Bismuth-210 5 days — 1.16 — Polonium-210 138 days 5.31 re — Lead-206 No half-life; stable element Source: adapted from Schieien 1992 (includes radiations over 10% intensity) ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 220 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION 85Kr and xenon-133 (**Xe). ¥Kr is the primary radioactive gas released from pressurized water reactors (PWRs); boiling water reactors (BWRs) primarily release both 3Kr and **Xe. *Kr is not metabolized if inhaled when the steady-state body:atmosphere concentration ratio for 3Kr is 1:20. Thus, the internal dose from ®5Kr is negligible (Shapiro 1990; UNSCEAR 1993). Plutonium (Pu) has been introduced into the atmosphere from sources such as weapons testing (>5,000 kg [>320 kCi]) and the vaporization of energy power packs from a Russian satellite (***Pu from 20 kg enriched uranium; [0.27 TBq]) and U.S. satellites (**Pu from1 kg of enriched uranium [17 kCi]) that burned up upon re-entry. Air activity of Pu, monitored in New York, peaked in 1963 at a concentration of 1.7 fCi/m®. The cumulative inhalation intake from 1954 to 1975 averaged 43 pCi per person. Cumulative individual tissue doses (through the year 2000) due to inhalation are predicted to be: lungs, 1.6 mrad; liver, 1.7 mrad; and bone lining cells, 1.5 mrad (Shapiro 1990). Approximately 23 billion Ci of iodine-131 (**'I) have been introduced into the atmosphere as a result of nuclear weapons testing. In October 1961, the air concentration of *'I in the United States averaged 3.8 pCi/m®. This was estimated to result in an annual dose of 24 mrad to a 1-year-old child. In addition, studies of pregnant women who died suddenly of non-radiation-induced causes (e.g., car accidents) found that fetal tissue concentrations of *'I were 30% greater than those in maternal tissues (Shapiro 1990). Due to the short 8-day half-life of '*'I, there is no '*'I remaining in the atmosphere from nuclear weapons testing. Radioactive materials, both naturally occurring and fallout-derived, often become associated with particles; the potential for inhalation of radionuclides bound to particles, and the respective threat this poses to animals and humans, varies considerably. In regions downwind of nuclear weapons test sites or nuclear weapons production facilities, or areas with abnormally high concentrations of naturally occurring radionuclides (e.g. New York state or Denver, Colorado), the potential for inhalation of particulate-bound radionuclides increases. Although most inhaled radioactive particles are eliminated from the lungs by normal clearing mechanisms, some of the particles remain in the lungs for extended periods. Others are carried to lymph nodes by scavenger cells (Eisenbud 1987; Shapiro 1990). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 221 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION 6.3.2 Oral The sources of radionuclides that contribute to radiation exposure by ingestion include nuclear weapons testing, the accidental or intentional release of radioactivity from nuclear reactors, the release of medical or experimental radionuclides into sanitary sewers, and naturally occurring radionuclides (which normally represent the source of highest oral dose). For most radionuclides present at chemical waste sites containing low levels of radioactive nuclides, oral exposure is not a major route of exposure; however, the oral exposure cannot be completely disregarded because of the potential for surface water and groundwater contamination and uptake by plants and animals following erosion of ground cover from a contaminated site. Among the naturally occurring radionuclides, uranium, “°K, and **’Ra are found in soils and fertilizers; as a result, they are incorporated into foods consumed by animals and humans. The practice of using phosphate fertilizers has resulted in uranium concentrations in food at levels up to 8 ng/g, resulting in an estimated average annual intake of uranium from dietary sources of 0.14 mCi; as a result, the average skeletal content of uranium is estimated to be 25 pug, which is equivalent to approximately 8 pCi (Eisenbud 1987). The most important radionuclides that are ingested are “°K, ***Ra, and the transformation products of Ra. The body content of potassium is under strict homeostatic control and is maintained at a relatively constant level of about 140 g/70 kg. This amount of potassium contains approximately 0.1 pCi of “°K. Because the body controls the potassium balance, environmental variations have little effect on the “’K content in the body (Eisenbud 1987; Shapiro 1990). This natural “’K delivers a dose of 20 mrem/year to the gonads and other soft tissues and 15 mrem/year to bone. Significant amounts of radionuclides have been injected into the atmosphere as the result of nuclear weapons testing and warfare. The more significant isotopes include *', strontium-90 (°°Sr), strontium-89 (**Sr), cesium-137 ("*’Cs), and *H. Carbon and hydrogen inventories in the biosphere also contain a large amount of 'C and *H resulting from the interaction of cosmic rays with atmospheric gases. Radioactive particles resulting from fallout or cosmic rays can contaminate food supplies directly by foliar deposition, or indirectly by entry into the soil and subsequent incorporation into plants. Surface waters can be contaminated through soil runoff or direct contamination from the atmosphere. The degree of radionuclide incorporation into plants through root uptake varies considerably among radionuclides. For example, Cs and radium bind tightly to clay or organic minerals upon entering the soil and are not amenable to root uptake; thus, foliar deposition is the primary route for oral exposure to '*’Cs. Likewise, '*'I poses little threat through root uptake due to its ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 222 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION short half-life (8 days). The concentrations of radionuclides in food vary considerably across food types. The concentration of ***Ra ranges from 0.15 pCi/kg in cow’s milk to 2,000 pCi/kg in Brazil nuts. Concentrations of '¥’Cs range from 20 pCi/kg in cow’s milk to 5,000 pCi/kg in beef. More important than concentrations in foods is the rate of intake and absorption of a radionuclide. Individual intake varies considerably; for a given radionuclide and locality, intake may vary as much as 500-fold. Likewise, the extent of absorption varies among the various nuclides, from almost completely in the case of “°K, *’Cs, and '*'I, to very poorly (0.003%) in the case of Pu radionuclides. Many « emitters, such as **Ra, are taken up and retained in the bone, resulting in sustained « irradiation of the bone-forming cells and bone surface lining cells (Eisenbud 1987; McClellan 1982; Shapiro 1990). Approximately 23 billion Ci of *'T have been introduced into the atmosphere as a result of nuclear weapons testing. In 1962, the concentration of "*'I in milk in the United States averaged 32 pCi/L. Although about two-thirds of orally administered '*' is excreted in the urine within the first 24 hours, the remainder concentrates in the thyroid, resulting in localized high doses. It has been estimated that an infant receiving milk from cows that grazed on forage contaminated with 1 pCi *'I/m? will receive a dose to the thyroid of 30 rad (Shapiro 1990; UNSCEAR 1993). There is no longer any *'I in the atmosphere from nuclear weapons testing, due to its short 8-day half-life. The disposition of ingested strontium-90 (*°Sr) has been studied extensively due to its abundance (15 MCi of that introduced into the atmosphere as a result of nuclear weapons testing fell to the earth by January 1970), its long half-life (28 years), and its tendency to localize in bones. Metabolically, Sr follows the pathways of calcium (Ca); however, the body discriminates against Sr in favor of Ca. Because of this parallel metabolism, Sr concentrations are often expressed in units per mass of Ca. In 1965, bone levels of **Sr in 1- to 4-year-old Norwegian children averaged 11.8 pCi/g Ca. In New York City, bone levels of *’Sr in 1- to 2-year-olds varied from 7 pCi/g Ca in 1965 to 1.6 pCi/g Ca in 1975. In 5- to 19-year-olds, bone levels varied from 3 pCi/g Ca during 1956-1968 to 1.4 pCi/g Ca in 1975 (Shapiro 1990). 6.3.3 Dermal For the purposes of this profile, dermal exposure to radionuclides refers to exposures from a radionuclide placed in direct contact with skin surface. Dermal exposure is a minor route of exposure; however, the dermal route becomes more important in areas where a nuclear device has recently been detonated, and the radioactive fallout particles land on the skin. This occurred in the Marshall Islands in 1954, when a group of ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 223 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION 23 Japanese fishermen was inadvertently exposed to radioactive fallout resulting from U.S. nuclear weapons testing. After contact with *H- or *C-laden water, skin absorption of a radionuclide can also be measurable. Tritium, as tritiated water vapor, is readily absorbed into the body through the skin. In general, depending on the specific physical properties of the radionuclide that may reside on the skin, the percutaneous absorption of radionuclides from particles is negligible, especially if the skin is thoroughly washed immediately after exposure. The long-term biological effects of dermally absorbed radionuclides are limited to the level of the epidermis and dermis (and its vasculature). More soluble forms of the radionuclides may result in a small percentage of the nuclide being absorbed if it is not removed from the skin's surface. Generally, the skin is an effective barrier against absorption of radionuclides (except for tritiated water) into the body. The dermal exposure pathway is, therefore, a minor route of exposure at low-level radioactive waste sites. 6.4 EXPOSURE FROM NATURAL AND ANTHROPOGENIC RADIOACTIVE MATERIALS Radiation exposure may result from several anthropogenic sources, including the radioactive debris still remaining from atmospheric and underground detonation of nuclear weapons, electrical energy production, radiopharmaceuticals, and radionuclide production and use (Shapiro 1990; UNSCEAR 1993). 6.4.1 Exposure from Nuclear Weapons A large human cohort (86,572 people who survived the detonation of two atomic bombs in Japan in 1945) are being studied for the effects of external exposure to ionizing radiation. The first atomic bomb was successfully detonated on July 16, 1945, in Alamagordo, New Mexico. The U.S. military, in an effort to bring a swifter end to World War II and to avoid a costly ground invasion of Japan, detonated a ***U atomic bomb, nicknamed “Little Boy,” (see Figure 6-2) over the city of Hiroshima, Japan, on August 6, 1945. Three days later, an atomic bomb using 239py, Figure 6-2. Replicas of the “Little Boy” and “Fat Man” Bombs } Dropped on Hiroshima and Nagasaki (adapted from A-Bomb WWW nicknamed “Fat Man,” was detonated over the Museum, http://Awww.csi.ad.jp/ABOMB). city of Nagasaki, Japan. **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 224 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION The uranium used in the “Little Boy” bomb was enriched to >80% %5U. (Natural uranium contains 0.7% *U, and reactor fuel is enriched to 34% SU). The uranium bomb design of Little Boy used a standard explosion trigger, called the "gun" method, because it was originally made using a gun barrel. In this configuration, a sub-critical uranium mass, referred to as the “bullet,” was propelled inside the gun barrel toward a second sub-critical portion of the uranium mass (called the “target”), which was located at the end of the gun barrel. The target contained slightly less than the amount of uranium needed to achieve critical mass (the amount necessary to create a chain reaction). The instant the two subcritical pieces of uranium came together, super-criticality was attained, and an explosion with a force equivalent to 20,000 tons (20 kt) of trinitrotoluene (TNT) occurred. In the case of Little Boy, the bullet was a cylindrical stack of nine %5U wafers about 10 cm wide and 16 cm long, containing 40% of the bomb’s total ***U mass (25.6 kg). The target was a hollow cylinder 16 cm long and wide; it weighed 38.4 kg and was composed of two separate rings that were inserted into the bomb separately to prevent reaching critical mass during assembly. The complete Little Boy weapon was 10.5 feet long, 28-29 inches in diameter, and reportedly weighed between 8,900 and 9,700 pounds. The firing mechanism was so simple and was considered so failproof that it was not tested prior to its use over Hiroshima. The gun-type firing mechanism was, however, an unsafe weapon design, in that once the firing mechanism was loaded with high explosive, anything that ignited it would cause a nuclear explosion. Also, a crash or even an accidental drop of the bomb could have driven the bullet into the target, potentially resulting in a nuclear explosion. No other weapon of this design was ever tested, and although several Little Boy units were built, none ever entered the U.S. nuclear arsenal. The plutonium bomb, Fat Man, was dramatically different from the Little Boy design. The gun-type firing mechanism could not be used to unite two pieces of plutonium fast enough to achieve a nuclear blast; impurities in the plutonium would have caused premature detonation. Fat Man contained a ball of subcritical plutonium (plutonium core), which was surrounded with high explosives. The high explosives were cast into spheres, called lenses, and were wired so they would all fire at the same instant. The instantaneous pressure from all sides compressed the plutonium core in on itself, causing it to reach critical mass and create a nuclear blast. The combat configuration for the Fat Man bomb consisted of the implosion device encapsulated in a steel armor egg. Fat Man was 5 feet in diameter, 12 feet in length, and weighed 10,300 pounds (American Airpower Heritage Museum 1996; Sublette 1996). In Hiroshima and Nagasaki, a total of 64,000 people within 1 km of the hypocenter (the point on the ground directly below where the bomb exploded in the air) died on the first day. For bombs the size (approximate yield of 15 kilotons) and type of Little Boy, the energy released within the first minute after detonation was in ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 225 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION the forms of thermal radiation (35%), blast wave (60%), and ionizing radiation (5%); casualties (including fatalities) resulted from a combination of these effects. Two-thirds of those who died during the first day were burned. People close enough to suffer from radiation illness were also well within the lethal zones from blast and heat; thus, the proportion of survivors experiencing radiation illness (30%) was much smaller than the expected proportion based solely on exposure to radiation. People within 1-2 km of the hypocenter who initially survived the blast and received several hundred rad (several grays) of ionizing radiation, suffered the ill effects of the acute forms of radiation sickness. It is estimated that all persons whose bodies were exposed to a dose of 600 rad (6 Gy) and half of those whose radiation doses were 450 rad (4.5 Gy) died shortly thereafter, as a direct result of radiation exposure. Of those who survived the immediate radiation illness effects, a portion would suffer from the latent effects of ionizing radiation (the excess cancer death rate among the exposed population is on the order of 5% greater than that of an unexposed population). Given the estimated altitudes at which Little Boy and Fat Man detonated (1,900+50 ft. and 1,650+33 ft., respectively), very little radioactive material was deposited on the ground in the vicinity of ground zero; the majority was carried high into the atmosphere by heat convection. A small amount of fallout did occur in areas close to the cities due to rainfall that occurred shortly after the explosions; the affected areas were to the west and northwest of Hiroshima and a few miles east of Nagasaki. Fatality rates in the Hiroshima and Nagasaki attacks were 1-2 orders of magnitude greater than rates from conventional bombings because of the nearly instantaneous destruction of buildings and persons inflicted without warning, and because survivors were so incapacitated that they could not escape the rapidly ensuing fire storms. Approximately one-third of all Japanese bombing fatalities occurred in these two cities (Masse 1996; Sublette 1995, 1996; Uranium Information Center 1995). 6.4.2 Exposure from Nuclear Weapons Testing Nuclear explosions world wide were carried out above ground from 1945 to 1980, with the periods of greatest activity occurring from 1952 to 1958, and from 1961 to 1962. A total of 520 tests with an estimated total equivalent energy of 545 megatons (Mt) of TNT was performed, resulting in the release of 220 PBq (5.94 MCi) of radioactive material. The first U.S. testing of nuclear weapons after World War II was performed in the Marshall Islands in the Pacific Ocean from 1946 to 1948. The Soviet Union conducted its first weapons test in 1948. In the 1950s, as the frequency of weapons testing escalated, so did public concerns over radioactive fallout. In the fall of 1958, the United States, Britain, and Russia, declared a moratorium on weapons testing; however, Russia broke the agreement in 1961, and another rapid escalation in testing ensued. In 1963, the United States, Britain, and Russia, signed the Limited Test Ban Treaty, which ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 226 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION prohibited atmospheric testing. Although these three countries have remained faithful to the treaty, other countries such as France, China and India, have since conducted weapons testing (Eisenbud 1987; UNSCEAR 1993). The energy from nuclear weapons devices is generated by one or both of the following reactions: (1) the fission of **U or **°Pu in a chain reaction and (2) the fusion of the hydrogen isotopes deuterium and tritium. Fission-energized weapons accounted for 217 Mt of the total test yield, while fusion-energized weapons accounted for 328 Mt. There are many fission-related nuclides; of these, °°Sr, '*'I, and *’Cs are the radionuclides most commonly associated with weapons fallout. Fusion reactions produce helium and result in the neutron activation of surrounding substances; significant amounts of unused *H are typically liberated after detonation due to premature loss of critical mass. The most notable neutron activation product is '*C, which is formed from nitrogen (Radnet 1996; UNSCEAR 1993). The most important radionuclides associated with nuclear weapons testing exposures are '*C; '*’Cs; zirconium-95 (**Zr); niobium-95 (**Nb); *°Sr; ruthenium-106 ('°°Ru); manganese-54 (**Mn); '*‘Ce; *'I; and *H. In an effort to quantitate exposure resulting from nuclear testing, *°Sr deposition has been monitored worldwide at 50 to 200 stations in cooperation with the Environmental Measurements Laboratory (EML), and by a network of 26 stations organized by the United Kingdom Atomic Energy Authority. These data are compiled into a report called Environmental Radiation Data (ERD), which is distributed quarterly by the Office of Radiation and Indoor Air’s National Air and Radiation Environmental Laboratory (NAREL). The report contains data from the Environmental Radiation Ambient Monitoring System (ERAMS). ERAMS was established in 1973 by the EPA to provide air, surface and drinking water, and milk samples from which environmental radiation levels are derived. These samples are collected from locations that provide adequate population coverage and function to monitor fallout from nuclear devices and other radioactive contamination from the environment. Samples are subjected to analysis for gross alpha and beta emissions; gamma analyses for fission products; and more specific analysis for uranium plutonium, strontium, iodine, radium, and tritium (EPA 1997). In addition, **Zr deposition has been monitored as an indicator of exposure to short-lived radionuclides. Monitoring exposures to *H and 'C is more difficult due to the rapid recycling of these elements in the biosphere. Interhemispheric transfer is limited due to prevailing trade winds and the scavenging effect of precipitation in the tropics. The average total per person dose, for persons in the northern and southern hemispheres, for all 22 radionuclides resulting from nuclear testing is 440 and 310 millirad (4.4 and ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 227 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION 3.1 mSv), respectively. Worldwide, the average total dose is 370 millirad (3.7 mSv). However, as noted below, extreme variations in local exposures due to testing have been noted (UNSCEAR 1993). Radioactive debris from nuclear explosions falls into three categories: large particles, which fall out close to the explosion site within hours of the explosion; smaller particles, which penetrate the troposphere, behave like aerosols, and may not fall out for days; and the smallest particles, which penetrate the stratosphere, distribute worldwide, and fall out over many months or years. The greatest portion of fallout from nuclear weapons testing was deposited in the stratosphere (78%), while 10% and 12% were deposited in the troposphere and in the locality of the test, respectively. As of 1993, the total cumulative worldwide dose due to fallout was estimated to be 7x10° man*Sv. The cumulative dose will continue to climb, mainly due to long-lived “C (Eisenbud 1987; UNSCEAR 1993). Exposure to radiation from atmospheric testing is attributed to external exposure to radionuclides on the earth's surface, internal exposure from inhalation of gases or particulate matter, and ingestion of contaminated foods and water. Approximately 80% of radiation exposure from nuclear testing is estimated to be delivered through ingestion, with 16% and 4% of the dose delivered through external exposure and inhalation, respectively. Exposure through ingestion occurs primarily when there is immediate incorporation of radionuclides by plants and animals. Delayed incorporation of radionuclides through root uptake accounts for a small proportion of that ingested. The primary radionuclides of concern are *’Sr and "Cs. Within the first year, 45% of '*’Cs is transferred to the food chain (through milk, grain and meat). *’Sr enters the food chain primarily through milk and grain products. Exposure to '“C and *H is through ingestion and inhalation; however, the contribution of '*C and *H is trivial. The dose rate from naturally occurring '“C is about 1 millirem per year. At its peak effect, the dose rate from '“C due to weapons testing also was about 1 millirem per year, and is now decreasing. The dose from the tritium due to weapons is considered to be even less. At the peak, the additional *H contributed less than 0.1 millirem per year (UNSCEAR 1993). In addition to exposures from inhalation and ingestion, radiation exposure also occurs externally through particles deposited on the ground. Since the debris spends more time on the ground than in the air, the ratio of exposure from earthbound versus airborne particles ranges from 100 to 1,000,000 (UNSCEAR 1993). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 228 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION 6.4.2.1 Atmospheric Testing Nevada Test Site Fallout. A total of 100 surface or near-surface tests with a total explosive yield of about 1 Mt were performed at the Nevada test site between 1951 and 1962. The population around the site at this time was approximately 180,000 persons. Within this population, thyroid doses in children may have been as high as 100 rad (1 Gy). The collective dose received by this population was approximately 50,000 manerem (500 maneSv); 90% of this dose was delivered between 1953 and 1957. The dust from these tests also drifted over the United States, producing bands of exposure to radioactive material. Deposition of fallout varied considerably because of meteorological conditions. For example, the greatest (non-local) fallout levels from one of the Nevada test explosions occurred in Troy, New York, some 2,000 miles away, due to rainfall. The cumulative dose from gamma radiation in Troy, approximately 100 mrad, exceeded the doses received by any remote U.S. location for all of 1953 (Eisenbud 1987; UNSCEAR 1993). Bikini Atoll Fallout. Operation Crossroads was a series of nuclear weapons tests that began in the Marshall Islands, a group of atolls in the Pacific, on July 1, 1946. Prior to testing, the inhabitants of the Bikini Island Atoll were evacuated. The second test in this series, designated “Baker,” was a 21-kiloton bomb that was detonated underwater. This resulted in contamination of the surviving ships and the atoll itself. These tests and others prevented the return of the Bikini native population until 1969. Although the island was still contaminated at the time, it was thought that dietary restrictions and the importation of foods would allow safe habitation. However, body burdens of plutonium began to increase in the natives, resulting in their re-evacuation in 1978. During Operation Castle, another series of nuclear tests, the second test, “Bravo,” resulted in significant fallout and contamination of humans. Abrupt changes in wind direction after the 15-Mt detonation on March 1, 1954, resulted in the inadvertent exposure of residents of the Rongelap and Utirik islands, which lie 210 and 570 km to the east of Bikini, as well as exposure of a group of 23 Japanese fishermen whose boat was caught in the fallout approximately 80 miles downwind. Since the device was mounted on a barge situated in shallow water, a considerable amount of coral was incorporated into the fireball. The fishermen reported that the fallout particles resembled snow and that deposits of fallout on the boat were of sufficient depth to allow one to see footprints. Because they were unaware of the circumstances, the fishermen took no precautionary measures to minimize exposure; they remained on the contaminated boat until returning to port some 13 days later. Within 1-2 days after exposure to the fallout, the fishermen began to experience itching and burning sensations on exposed skin. By the third day, skin lesions and epilation began to develop; the skin lesions ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 229 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION became ulcerous in about 70% of the fishermen. Lesions were less severe in those who had worn protective clothing such as hats (ACHRE 1995; Eisenbud 1987). A more detailed description is available (Simon and Vetter 1997). Within 78 hours of the explosion, 82 and 159 persons were evacuated from Rongelap and Ultirik, respectively. However, as with the fishermen, the island inhabitants took no precautionary measures to minimize exposure to radioactive fallout. Within 1-2 days after exposure to fallout, itching and burning sensations on exposed skin were experienced by the natives of Rongelap, but not those of Utirik. Skin lesions and epilation occurred within 21 days of exposure, becoming ulcerous in about 25% of the Rongelaps; lesions were less severe in those who had worn protective clothing or bathed during the period prior to evacuation. The island of Utirik was not heavily contaminated, and its residents were allowed to return within a few months; however, the Rongelap residents were not allowed to return to their island until 1957, and they were monitored annually by U.S. medical teams thereafter. Despite the monitoring, fears among the island residents that exposure-related health problems were occurring prompted a second evacuation, initiated by the residents, in 1985. External doses, ranging from 10 to 190 rad (0.1 to 1.9 Sv), were mostly from short-lived radionuclides. Mean thyroid doses to adults, 9-year-olds, and 1-year-olds, were (1,300, 2,200, and 5,200 rad (12, 22, and 52 Gy), respectively. Maximum thyroid doses to these groups were 4,200, 8,200, and 20,000 rad (42, 82, and 200 Gy), respectively (Advisory Committee on Human Radiation Experiments 1995; Eisenbud 1987; National Academy of Sciences 1994; UNSCEAR 1993). Average gamma dose rates 3 feet above ground level on Rongelap island, estimated from a survey performed in July 1956, were 0.2-0.5 mR/hr (mean of 0.4 mR/hr) (Department of Energy, Accession Number: NV0050785). Environmental samples collected in 1964 revealed ***Pu concentrations of 11 pCi/g in a soil sample collected at a depth of 0.5-1.0 inch. A more extensive survey that included 14 of the atoll islands was performed in April and May of 1967. External radiation, as well as the radioactive content of food, vegetation, and soil, was quantified. On the islands closest to the detonations, the major contributor to the external gamma radiation field was °Co, which was associated with neutron activation of scrap metal; the major contributor to the external gamma radiation field on distant islands was '*’Cs. Additional samples were collected during the U.S. cleanup operations in 1969. **°Pu concentrations on Bikini Island ranged from 1.3 to 190 pCi/g. **°Pu concentrations on Eneu Island ranged from 0.5 to <3 pCi/g (DOE 1970). Measurements of gamma radiation exposure performed in June 1975 revealed highly variable exposure rates on Bikini island (10-20 pR/hr at the shore versus 30-100 uR/hr in the interior), while exposure rates on Eneu island were relatively constant (<10 pR/hr) over the entire island. Thirty-year cumulative doses were ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 230 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION estimated to be 0.057 and 0.027 Sv (5.7 and 2.7 rem) for those living on Bikini Island (interior portions) and Eneu Island, respectively (USERD 1975). Water samples collected from Eneu Island in 1975 revealed *°Sr and *’Cs at concentrations that would lead to a combined 30-year whole-body and skeletal dose of 25 mrem. Sampling of cistern water on Bikini Island during the same period revealed *’Sr concentrations, which would lead to a 30-year skeletal dose of 9.1 mrem, and *’Cs at concentrations that would lead to a 30-year whole- body dose of 1.9 mrem (DOE 1975). Whole-body counting of Bikini Island residents in 1974, 1977, and 1978 revealed that the major contributor to whole body doses was *’Cs. The average body burden for '*’Cs increased ten-fold between 1974 and 1977; body burden increased by 72% between 1977 and 1978. Nine persons had body burdens exceeding the federal standards for non-occupational dose in that year (0.5 rem/year); the highest body burdens were approximately twice the permissible levels (DOE 1978). Semipalatinsk Test Site Fallout (Russia). Approximately 10,000 people living near the Semipalatinsk test site in the Kazakh region of Russia were exposed to radioactive materials from atmospheric testing between the years of 1949 and 1962 and underground testing between 1964 and 1989, respectively. The collective doses to this population from external and internal radiation were estimated to be 260,000 and 200,000 manerem (2,600 and 2,000 maneSv), respectively (UNSCEAR 1993). Australian Test Site Fallout (United Kingdom). The United Kingdom performed a total of 12 nuclear tests at 3 sites in Australia with total explosive yields at each site of 100, 16, and 60 kilotons, respectively. The collective dose delivered to the Australian population was estimated to be 70,000 manerem (700 maneSv). In addition, several hundred smaller experiments were performed, resulting in the contamination of hundreds of square kilometers with a total of 24 kg of *°Pu. Potential annual exposures to individuals in these areas, assuming continuous habitation, is estimated to range from several hundred millirem to several thousand millirem (UNSCEAR 1993). Lop Nor Test Site (People’s Republic of China). China has performed more than 40 nuclear weapons tests. Approximately 23 tests were atmospheric; the last atmospheric test was performed on October 16, 1980. The remaining tests have been performed underground; the most recent test occurred on August 17, 1995. All Chinese nuclear testing occurs at the Lop Nor site, located in the Xinjian region in northwest China. China has not allowed independent assessments of the ecological or health impacts of its testing program; however, increased mortality rates due to fallout of radioactive materials have been reported by a political advocacy group in neighboring eastern Turkestan (Eastern Turkestan Information Bulletin 1996). Both the data and the claims are highly questionable. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 231 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION 6.4.2.2 Underground Testing About 1,400 underground nuclear tests have been performed worldwide, with a total explosive yield of 90 Mt. The frequency of underground testing increased dramatically after the 1963 signing of the Limited Test Ban Treaty, which banned atmospheric testing. Although well-contained explosions pose little risk of exposure, radioactive material can be released if the blast penetrates the surface or if inadvertent leaks occur due to ground structure damage or the gradual diffusion of gases. Of the 500 underground tests performed at the Nevada test site, only 32 led to off-site contamination. The total activity of *'I inadvertently released was about 5 PBq (135 kCi), which is about five orders of magnitude lower than that released during atmospheric testing. Based on calculations of theoretical yields, it is estimated that the total release of noble gases from underground testing resulted in a population dose of 500 manerem (5 maneSv). Of the noble gases, '**Xe is the predominant radionuclide. It is estimated that the total dose from *H resulting from underground testing is 0.1 manerem (0.001 maneSv) (UNSCEAR 1993). In addition to military-sponsored nuclear explosions, a series of about 100 test detonations was carried out during the 1960s for the purpose of developing peaceful applications for nuclear explosives (designated as Project Plowshare). As the benefits were far outweighed by the issues of contamination, the project was subsequently terminated. Of these tests, six were performed at the Nevada test site. The estimated collective dose delivered to the surrounding population (180,000 persons) from one of these tests (Sedan; 104 kt explosion) is estimated to be 300 manerem (3 man*Sv). As a result of the Schooner cratering experiment carried out in the United States in 1968, tungsten-181 (**'Tu) generated from the neutron shield was detected as far away as Europe. The estimated collective dose from this explosion to the population living in the 40°-50° latitude band of the northern hemisphere is estimated to be 2,000 manerem (20 man*Sv) (UNSCEAR 1993). Processing Milling Enrichment 6.4.3 Exposure from the Nuclear Fuel Cycle Fuel fabrication The nuclear fuel cycle refers to the mining, milling, enrichment, Mining Reprocessing and fabrication of fuel elements; the production of energy; and the recycling, transportation, and waste storage/disposal of . . . . Power generation radioactive materials used in nuclear weapons or reactor-grade Disposal JS nuclear fuel. The steps involved in the U fuel cycle are depicted RN sr . . . Spent fuel storage in Figure 6-3. The primary radionuclide components of nuclear P 9 Figure 6-3. Schematic of the Nuclear Fuel Cycle ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 232 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION weapons and reactors include Pu, #°U, #*U, and *H. Radionuclides associated with fuel mining, milling, power production, and waste reprocessing include (but are not limited to): °’Co, ?*Ra, ?*°Th, **?Rn, *°Rn, *H, '“C, ¥*Kr, 129, BY, Cs, 2*Th, #*"Pa, and "Cs. The various steps within this cycle provide multiple opportunities for the exposure of humans to these materials. Power production from nuclear plants has increased steadily since the industry’s birth in the 1950s. During the years between 1970 and 1989, the number of nuclear reactors worldwide increased from 77 to 426, and total nuclear power generation increased from 9 to 212 gigawatts per year. In 1989, nuclear power plants produced 17% of the world’s energy. The annual worldwide production of uranium from 1979 to 1989 ranged from 19,000 to 44,000 tons; from 1985 to 1990, the annual production was approximately 50,000 tons. Although there is little public information regarding the amount of radioactive materials produced for use as weapons, it has been estimated that the total dose commitment from these activities is much smaller than that caused by weapons testing. The atmospheric content of krypton-85 (**Kr), a by-product of plutonium extraction, has been used to estimate the plutonium stockpiles in both the United States and Russia. After adjusting for production and release of **Kr from nuclear reactors, it is estimated from the atmospheric content of ¥*Kr in plutonium stockpiles in both the United States and Russia is about 100 tons each. United Nations estimates from 1981 and 1990 state that nuclear arsenals are comprised of 40,000 weapons with a combined explosive power of 13,000 Mt. Tritium, which has a half-life of 12.32 years, must be continually produced to replace aging stockpiles. It is estimated that an annual production of 3 kg is sufficient to replace that lost by transformation in the United States. By inference, this would indicate a total U.S. stockpile of 55 kg and a world stockpile of about 110 kg (UNSCEAR 1993). Uranium ore typically contains uranium at concentrations ranging from a tenth of a percent to a few percent; thus, millions of tons of ore are mined and processed annually to meet the world’s needs. Radon is the predominant radionuclide released from uranium mines. Air discharged from mines contains radon in concentrations of approximately 0.5-20 pCi/min/1,000 ft’; these are point releases whose concentrations dilute quickly with distance from the release shaft and, thus, pose no additional health risk to the general public. Incomplete extraction of uranium during milling results in uranium concentrations in mill tailings of 0.001-0.01%. The presence of radon precursors (***Ra and ?*°Th) in mill tailings presents a potential long- term source for atmospheric contamination. The rate of radon emanation varies with meteorological factors ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 233 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION such as barometric pressure, wind velocity, and humidity. The rate of soil and mill tailings migration depends primarily on wind and water erosion of the site (Eisenbud 1987; UNSCEAR 1993). In both nuclear weapons and nuclear fuel production, after being mined and milled, uranium must be converted to uranium hexafluoride gas, which is then enriched and converted to uranium oxide or metal. If enrichment is carried to about 90%, the uranium may be used to make nuclear weapons or to fuel naval warships; alternatively, the uranium may be enriched by only a small percentage for use in nuclear energy facilities. Metallic uranium is capable of reacting with both air and water exothermically; because of this reactivity, the more stable uranium oxide is the most commonly used fuel in reactors. While this form is more stable, it has poor thermal conductivity, necessitating the use of small-diameter rods, pins, or plates. The fuel is in the form of high melting point ceramic pellets, about 0.5 inches in diameter and 1 inch long, in which UO,-enriched to 3-4% *°U is dispersed. These pellets are stacked end to end in zirconium alloy or stainless steel tubes about 12 feet long (called cladding) and then sealed to retain the fission products that are produced during operation. These fuel rods are then assembled in groups of 64—100 into fuel rod assemblies. About 500 of these assemblies make up the core of a nuclear power reactor. For a frame of reference, a single pellet contains the energy equivalent of about one ton of coal or 3 barrels of oil. Emissions from fabrication facilities usually consist of the long-lived isotopes **U, ***U, and 2**U, and the short-lived nuclides >*Th and 24mpa: however, the relative value of the refined and enriched uranium and the high level of accountability for uranium stock preclude any long-term or widespread loss of material. The major route of exposure from this source is inhalation (Eisenbud 1987; UNSCEAR 1993). During the energy production phase, radioactive contamination of the coolant occurs through small defects in the protective cladding surrounding the fuel pellets through fission of “tramp” uranium contamination on the surface of the fuel rods and through neutron activation of contaminants in the cooling medium. Fuel reprocessing allows the recovery of uranium and plutonium from the irradiated fuel pellets. Less than 10% of the nuclear fuel is consumed in a spend fuel rod. The radionuclides most commonly associated with reprocessing waste are: °H, '“C, Kr, '*’I, *'I, **Cs, '*'Cs and transuranium nuclides. At present, reprocessing is carried out in only a few countries, and only a small portion of the total fuel inventory is being reprocessed (4% from 1985 to 1990). The remainder is retrievably stored (UNSCEAR 1993). In general, the levels of radionuclide emissions from reactors are not detectable except at points close to effluent discharges; because of this, estimates of radionuclide discharge levels must be modeled. Based on such models, the total collective dose due to reactor discharges through 1989 was estimated to be ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 234 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION 370,000 manerem (3,700 maneSv). Doses to the general public resulting from nuclear power production vary widely. The annual dose to the most highly exposed person was estimated to be 0.1-2 millirem (1-20 uSv). A 1981 Nuclear Regulatory Commission (NRC) study of the doses received by 98 million people living within 80 km of 48 nuclear facilities concluded, on the basis of a zero threshold model, that only 0.02 excess fatal cancers per year could be attributed to exposures from nuclear facilities (NRC 1981). A study of the cancer rates in populations surrounding 62 U.S. nuclear facilities, performed by the National Cancer Institute (NCI) in 1990, found no evidence of a relationship between proximity to a nuclear facility and the occurrence of cancer (Eisenbud 1987; NCI 1990; UNSCEAR 1993). The effective dose from nuclear weapons research, development, and production is, at worst, less than 1% of the dose due to atmospheric testing. However, as noted below, extreme variations in local exposure from uranium processing plants have been reported. In the United States, the Hanford nuclear weapons facility has released a significant amount of radioactive material into the atmosphere and the Columbia River from its plutonium production and reprocessing plants. The majority of the radioactive material ("*'I) was released between 1944 and 1946 (18 PBq; 486 kCi), although additional releases are known to have occurred from 1947 to 1956 (2 PBq; 54kCi). Thyroid doses during the 1940s near production plants in the U.S. may have been as great as 1,000 rad (10 Gy). The Chelyabinsk-40 center, located near Kyshtym in the Soviet Union, was the first nuclear weapons processing facility in Russia. A uranium-graphite-moderated reactor and a fuel reprocessing plant were opened in 1948. Due to poor waste handling and the storage of radioactive wastes in the open, significant liquid releases (100 PBq; 2.7MCi) to the Techa River occurred from 1949 to 1956, with the majority of the releases (95%) occurring from March 1950 to November 1951. The main nuclides released included *°Sr, '*’Cs, **Zr, ®*Nb, and ruthenium and rare-earth nuclides. The population along the Techa River was exposed to both external and internal doses of radiation; a total of 20 settlements (7,500 people) were eventually evacuated. The average doses to persons living in the village of Metlino, 7 km downstream from the plant, were estimated to be as much as 140 rad (1.4 Sv) (UNSCEAR 1993). The reprocessing of nuclear fuel has been performed almost exclusively at government-owned facilities designed to meet military needs. Only one operable commercial reprocessing facility exists in the United States. As with nuclear reactors, the facility and the equipment used have been designed with numerous safeguards to prevent criticality and to ensure containment of radioactive material in the event of a non- nuclear explosion or system failure. The estimated collective dose due to reprocessing to date is estimated to be 460,000 manerem (4,600 maneSv); the main radionuclide constituents (>90%) of these releases have been 137Cs and Ru. Releases of gaseous **Kr and *H from reprocessing facilities have also been reported. The ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 235 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION main pathways of exposure are consumption of locally caught fish and shellfish, external (whole-body) irradiation from intertidal areas, and external (dermal) irradiation of fishermen handling pots and nets. Annual individual doses were estimated for critical populations living near three reprocessing plants (Sellafield, England; Cap de la Hage, France; and Tokai-Mura, Japan) for which records of radioactive effluent exist. For the critical population living near Sellafield, annual individual doses from ingestion were estimated to be approximately 350 millirem (3.5 mSv) during the early 1980s and declined to approximately 20 millirem (0.2 mSv) by 1986. The estimated doses in the same group due to external irradiation were estimated to be about 100 millirem (1 mSv) in the early 1980s and 30 millirem (0.3 mSv) by 1986. In contrast, annual individual doses for critical populations living near the Cap de la Hage and Tokai-Mura reprocessing plants were approximately 25 millirem (0.25 mSv) and 0.1 millirem (1 pSv) (Eisenbud 1987; UNSCEAR 1993). Solid wastes derived from reactor operations and from the handling, processing, and disposal of spent fuel are classified as low-, intermediate-, or high-level wastes. While low- and intermediate-level wastes had been packaged and placed into shallow burial sites, high-level waste disposal strategies have not yet been implemented. Some low-level wastes were packaged and disposed of at sea from 1946 to 1982. Exposure to buried wastes is thought to occur through groundwater migration from leakage at the burial site. The major radionuclide found in reactor waste leakage is '“C (UNSCEAR 1993). 6.4.4 Exposure from Medical and Dental X-rays, Radiopharmaceuticals, and Commercial Radionuclides Radioactive materials and other sources of ionizing radiation are widely used in the diagnosis and treatment of some diseases in human and veterinary medicine. In 1980, an estimated 300,000 X-ray units were being used for medical diagnoses and therapy; of these, approximately 170,000 were used in dentistry. The annual worldwide dose from diagnostic X-rays and fluoroscopy procedures is estimated to be 160,000,000 manerem (1,600,000 maneSv) and 194 million manerem (1,940,000 mansSv), respectively. Due to the usefulness of nuclear medicine, radioactive drugs and diagnostic compounds have become the greatest contributors to internal doses of ionizing radiation from anthropogenic sources today. Although the use of low to high levels of radiation may result in an increased risk for the development of cancers, it is accepted that under normal circumstances the overall benefits associated with medical diagnosis or treatment outweigh the risks of radiation-induced injury (UNSCEAR 1993). After many millions of diagnostic radionuclide procedures, we have found no increase in cancers from these procedures. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 236 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION The common sources of radiation exposure associated with radiotherapy and diagnosis include X-rays, thallium-201 (*'T1), technetium-99m (**"Tc), and '*'I. More exposures are related to diagnosis than to therapy, and the number of treatments per person increases as the level of health care improves. Also, the average dose per treatment tends to decrease as techniques and equipment improve. Overall, X-ray treatments deliver a higher average per person dose in industrialized nations (average of 0.3-2.2 mSv) than in countries with less developed health care (average exposure 0.02-0.2 mSv). On an individual basis, the dose increases with age, from 52 mrem/year in adolescents to 151 mrem/year in persons over 65 years of age. Exposures are usually lower for examinations of the extremities and skull and higher for examination of the gastrointestinal (GI) tract. In the United States, the average annual dose to the bone marrow from this source increased from 83 mrem in 1964 to 103 mrem in 1970. A person receiving a full set of dental X-rays would add approximately 40 mrem to his or her annual dose. On the other hand, the average annual dose per patient from the diagnostic use of radionuclides is lower in industrialized nations, largely because of greater use of "Tc. This radionuclide is preferred over '*'I because its shorter half-life (6 hours versus 8 days) gives a much lower patient dose. Its shorter half-life and higher cost make it more available in developed than in developing nations, where '*'I has frequent use. While the average dose (per individual) in patients undergoing radiotherapy is much greater than in patients undergoing diagnosis, the exposure group is much smaller, resulting in a lower overall population-at-risk. Unfortunately, serious exposures resulting from failures of equipment, procedures, or personnel errors (usually a result of not following procedures) sometimes occur, with several hundred failures out of several hundred million procedures per year worldwide. There are several emerging trends in diagnostic nuclear medicine. Some of these trends include: the introduction of radiolabeled monoclonal antibodies for imaging; the emergence of new compounds used in positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies; and the use of computed X-ray tomography. Radiolabeled monoclonal antibodies have proven useful in the localization of tumors and metastases; common radionuclides associated with these antibodies and their average effective dose equivalents are indium-111 (*"'In), 340 millirem (34 mSv); "I, 3,000 millirem (30 mSv); and *™Tc, 700 millirem (7 mSv). SPECT is used for tumor localization, brain and cardiac studies, and bone or abdominal imaging. PET, which uses nuclides such as ''C, can gather anatomical and physiological information that would otherwise be difficult to collect. Whole-body imaging using radiolabeled compounds (e.g., anticancer drugs) is becoming a common PET application (DOE 1996; Eisenbud 1987; Shapiro 1990; UNSCEAR 1993). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 237 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION The use of radiopharmaceuticals has stabilized in industrialized countries but is increasing in developing countries. Long-lived radionuclides are used more frequently in developing countries, while industrialized countries tend to use short-lived radionuclides. This results in increased exposures per examination among developing country patients compared to those of industrialized nations. For example, a typical thyroid scintigraphy with ®"Tc can give an effective dose of less than 0.1 rem (1 mSv), while the same procedure using "*'I gives 10 rem (100 mSv); however, ®"Tc is less readily available in developing countries. Although the average per patient dose equivalent is lower in developed (2-5 mSv) than in less developed countries (20 mSv), an apparently larger fraction of individuals in developed nations receive nuclear medicine treatment, so the average per capita annual dose from radiopharmaceuticals in developed countries (0.07 mSv) is an order of magnitude more than that of developing nations (0.004 mSv) (UNSCEAR 1993). Radionuclides are frequently produced and used in industry, medicine, and research. The number of users and frequency of radionuclide use are both steadily increasing. The number of establishments in J apan that generate and/or use radionuclides has increased from 100 in 1960 to 5,000 in 1990. The public may be exposed to radionuclides from these sources as a result of routine use or from being near someone who has recently received a nuclear medicine procedure, as well as improper handling, use, or disposal. In Japan, the usage of "C,'’L, °H, and "*'I has been estimated to be 5.2, 6.1, 14, and 34 GBq (0.14, 0.16, 0.38, and 0.92 Ci) per million persons, respectively. In contrast, the production of *C in the United States and Britain has been estimated to be 30 and 55 GBq (0.81 and 1.49 Ci) per million, respectively. The annual global production and usage of '*C has been estimated to be 30 GBq (810 mCi) per million persons, or a total of 0.05 Pbq (1.5 kCi). The total amount of '3'I. produced in Sweden for medical purposes was estimated to be 0.9 TBq (110 GBq [2.97 Ci] per million) in 1986, while the amount of '*'T discharged from Australian hospitals in 1988 and 1989 was estimated to be 2.9 TBq (190 GBq [5.13 Ci] per million) (UNSCEAR 1993). Information about some radionuclides used for medical applications are shown in Table 6-4. The release of radionuclides from medical, educational, and industrial sources is generally not detectable. It is believed that *H and noble gases are released to the air, while '“C release is through airborne and fluid effluents. The isotopes "*'I and '*’I are primarily released through liquid effluent. The annual collective dose from medical and radiopharmaceutical wastes to local populations is thought to be in the range of 10,000 manerem (100 maneSv). This level of exposure is relatively unimportant compared to that from other sources (Eisenbud 1987; UNSCEAR 1993). “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 238 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION 6.4.5 Exposure from Consumer Products Several consumer products, used both within the home and in many public areas, emit small amounts of radiation. Among these are ionization-type smoke detectors, television sets, and liquid propane gas (LPG) appliances. The first smoke detectors contained radium (approximately 20 pCi), but now contain americium- 241 (**' Am), which is more economical. While present-day detectors contain 0.5-1.0 uCi of >! Am, the original units contained approximately 79 pCi. In the 1980s, annual sales of smoke detectors approached 12 million, representing approximately 8.5 Ci of *! Am. Smoke detectors contain a small ionization chamber in which the air between two electrodes is ionized by the source radionuclide. This ionization allows the flow of current across the gap between the electrodes. When the flow is stopped by smoke particles, the interruption in current flow is interpreted by the detector to indicate the presence of smoke. Television sets accelerate electrons that bombard the screen; in the process, low-energy X-rays are emitted. The total annual dose associated with watching a color television has been estimated to be 2-3 mrad per year. Radon is found in LPG, which may be used in water heaters, stoves, and fireplaces; it has been estimated that exposure to radon in homes using natural gas results in an average annual dose of approximately 5 mrem in the United States. Among consumer products of the past are items which contained radium, such as medicines, tonics, luminous paints, and ceramic glazes. After its discovery in the early part of the 20th century, radium was used for many years in the treatment of rheumatism and mental disorders; oral solutions contained **Ra and ?**Ra at concentrations up to 2 uCi/60 mL, while ampules for intravenous administration contained 5-100 pg ***Ra and **®Ra. Radium was also used to produce luminescent paints that were applied to wristwatches, clocks, static eliminators, fire alarms, electron tubes, and military and educational products. During the peak years of production, approximately 3 million radium-laden timepieces were sold annually in the United States. The radium content of a man’s wristwatch ranged from 0.01 to 0.36 pCi, resulting in potential gonadal doses of 0.5—- 6 mrem/year. The annual skin dose under these watches has been estimated to be as great as 165 rem/year. Radium has been replaced with *H and prometium-147 ('¥’Pm), and watch cases are sufficiently thick to absorb the B emissions from these radionuclides. Uranium has been used as a coloring agent for ceramic glazes, resulting in doses to the hands of up to 20 mrad/hour. The dose from ceramics produced since 1944 is thought to be five-fold less than that from earlier pieces. For more than 40 years, 224Ra has been used in Europe to treat the symptoms of tuberculosis and ankylosing spondylitis. Although its use in children was curtailed in the 1950s, ?**Ra has been used for treating the pain associated with ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 239 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION Table 6-4. Some Radiopharmaceuticals Used in Medicine methanol; add aqueous sodium chloride Radionuclide Preparation Use Properties Tc Albumin Reduce pertechnetate "Tc [Primarily used for lung imaging. Also | The clearance half-life from the in the presence of human used for imaging of coronary, lungs of 14 to 15 hours. albumin, ascorbic acid, FeCl,, | urogenital, liver, gastrointestinal, and SnCl,. lymphatic, and peripheral circulation. "In Albumin Incubate "In with human Primarily used for lung imaging. Also |The clearance half-life from the albumin in phosphate at used for imaging of coronary, lungs of 14 to 15 hours. pH 3; adjust pH to 11 and urogenital, liver, gastrointestinal, heat. lymphatic, and peripheral circulation. "Mn Albumin Incubate "In with human | Primarily used for lung imaging. Also |The clearance half-life from the albumin in phosphate at used for imaging of coronary, lungs of 14 to 15 hours. pH 3; adjust pH to 11 and urogenital, liver, gastrointestinal, heat. lymphatic, and peripheral circulation. 23pp Albumin Incubate ionic 2®Pb with Primarily used for lung imaging. Also |The clearance half-life from the human albumin at pH 10 with | used for imaging of coronary, lungs of 14 to 15 hours. heat. urogenital, liver, gastrointestinal, lymphatic, and peripheral circulation. *'Cr Albumin Incubate *'CrCl, with human | Detection and quantitation of Cr (Ill) has strong affinity for albumin gastrointestinal protein loss and plasma proteins without placental localization affecting (binding to) red blood cells. 125] Albumin Mild iodination of human Diagnostic aid in determining total Longer shelf life than ™'l; emits albumin at 10 °C in slightly blood and plasma volumes no beta radiation (all gamma alkaline medium emissions); lower doses needed for correct resolution compared to "| 3 Albumin Mild iodination of human Diagnostic aid in determining total May cause sensitization. albumin at 10 °C in slightly blood and plasma volumes, alkaline medium _| circulation times, or cardiac output. 31 Albumin, Mild iodination of human Diagnostic study of the lungs, Aggregates block a small aggregated albumin at 10 °C in slightly especially the diagnosis of pulmonary | percentage (<0.5%) of the fine alkaline medium embolisms. capillaries. Disintegrating aggregates are cleared by phagocytic Kupffer cells in the liver. Thyroid uptake may be blocked by prior administration of Lugol’s solution. ¥THg Reflux allylurea with "Hg Diagnostic aid in scanning the brain | Rapidly cleared by the kidneys. Chlormerodrin | mercuric acetate in methanol; | for lesions. Also used for scanning | Provides smaller radiation add aqueous sodium chloride | kidneys for anatomical and functional | dose compared to "*'l albumin. abnormalities. A high tumor:background ratio is obtained within 4 hours, allowing quicker scans with greater resolution. Hg Reflux allylurea with Diagnostic aid in scanning the brain | Rapidly cleared by the kidneys. Chlormerodrin ~~ [#*®*Hg mercuric acetate in for lesions. Also used for scanning | Provides smaller radiation kidneys for anatomical and functional abnormalities. dose compared to "*'| albumin. A high tumor:background ratio is obtained within 4 hours, allowing quicker scans with greater resolution. “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 240 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION Table 6-4. Some Radiopharmaceuticals Used in Medicine (continued) carboxymethylcellulose vehicle. and peritoneal effusions. Radionuclide Preparation Use Properties ®p Chromic React Na,H*PO, with A neoplastic suppressant that Emits virtually no gamma phosphate chromic nitrate in a saline- provides palliative treatment of pleural | radiation; delivers 10-fold greater radiation dose per millicurie compared to '®Au. Because it remains in situ after injection, it may be injected directly into a malignancy. Cyanocobalamin of the molecule contains ¥Co. absorption and deposition of vitamin B,,, especially the diagnosis of pernicious anemia. %Co Neutron bombardment of Replaced radium in various The gamma radiation matches %Co therapeutic areas. that of radium very closely. 92) Neutron bombardment of '*'Ir | Replaced radium in various Provides softer (i.e., less therapeutic areas. May be enclosed |penetrating) radiation in nylon mesh for interstitial use. compared to radium. Co Vitamin B,, in which a portion | Diagnostic aid in studying the Co Cyanocobalamin Vitamin B,, in which a portion of the molecule contains ®Co. Diagnostic aid in studying the absorption and deposition of vitamin B,,, especially the diagnosis of pernicious anemia. Although the half-life is 5.24 years, ¥Co cyanocobalamin may decompose in storage; thus, frequent radiochemical analysis may be required. "3|n Ferric hydroxide "In is stirred with FeCI3 while titrated with 0.5 N NaOH to a pH of 11 to 12. While stirring, a 20% gelatin is added to attain a pH of 7.6 to 8.5 while heating in a boiling waterbath; preparation is then autoclaved. A diagnostic aid in lung imaging. Particles are in the 20 to 50 pm range. ®Fe Ferrous Citrate %Fe complexed with citrate. A diagnostic aid in studying the kinetics of iron metabolism. It may be administered directly into the bloodstream where it reacts with the metal-binding globulin. ®™Tc Ferrous hydroxide Add *™Tc to a vial containing ferrous sulfate; the hydroxide is precipitated with 0.1N NaOH at a pH of 7.5 to 10.7. Gelatin is added to stabilize the particles; final pH should be 7.110 8.3. A diagnostic aid in pulmonary scintigraphy. Most of the particles are in the 11 to 13 pm range; virtually all particles fall in the 3 to 50 pm range;. '%| Fibrinogen 125] in the form of I, ICl or I is combined with fibrinogen and is oxidized by chloramine-T, electrolytically or enzymatically. Unreacted iodine is removed by the addition of sodium thiosulfate A diagnostic aid in the localization of deep vein thromboses. Other applications include detection of renal transplant rejection, tumors, and the study of fibrinogen turnover. Accumulates in clots, the radiation is easily detected at the external surface of the affected limb. **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 241 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION Table 6-4. Some Radiopharmaceuticals Used in Medicine (continued) more, whereupon the indium is converted to the insoluble hydroxide. The particle size and stability are controlled by heating and the addition of a stabilizer (gelatin, mannitol, etc.). Radionuclide Preparation Use Properties Ga Gallium Ga is produced by proton |Used in the diagnosis of lesions of Concentrates in tumors of soft citrate irradiation of ¥Zn-enriched the lung, breast, maxillary sinuses tissues and bone. The half-life Zn0, and liver. A positive “Ga uptake is | of the isotope is 78 hours; the indicative of malignancies such as biological half-life of the citrate lymphomas, bronchogenic compound is 53 days. carcinoma, and Hodgkin’s disease. Also useful for placental localization and diagnosis of pancreatitis and disk space infection. BAU '®Au is prepared by neutron | Used as a neoplastic suppressant, [Particle sizes range from 2 to activation. The irradiated gold| esp. carcinomas of the prostate and |60 nm. Upon standing, the foil is then dissolved in aqua | cervix and tumors of the bladder. radiation may cause darkening regia. A colloidal dispersion is of the injection and glass produced by chemical container. reduction, the pH is adjusted to 4.3-7.5, and gelatin is added as a stabilizer. "In Indium A cadmium target is "In has been used as atagfora [Indium normally exists in chlorides bombarded with deuterons. | variety of compounds such as aqueous solution as a trivalent The "In is then etched from |transferrin, EDTA and DTPA (used in | cation. In aqueous solution the target with HCI, carrier cisternography), platelets (detection |InCl exists as a mixture of Fe* is added, and the of coronary thrombi), lymphocytes hydrated chlorides. mixture is precipitated with (monitoring cardiac antirejection NH,OH. The precipitate is therapy), and leukocytes (diagnosis dissolved in HCI and the ferric | of upper-abdominal infections). iron is removed by extraction with isopropyl ether. "3M Indium 13M is formed by the Used in blood-pool studies, including | Indium normally exists in Chloride radioactive transformation of | visualization of aneurysms, and aqueous solution as a trivalent "'®Sn. "Mn is separated from| placental scintigraphy; also used for cation. In aqueous solution "®Sn using sterile, pyrogen- | bone, liver, lung, brain, and renal InCl exists as a mixture of free dilute HCI. imaging. hydrated chlorides. Urinary excretion is low, resulting in low urinary bladder activity. "3M Indium "13M Indium chloride is Used in liver, spleen and bone hydroxide adjusted to a pH of 4 or marrow scintigraphy. 125) or "| Insulin Prepared by mild iodination with high-specific-activity radioactive iodine followed by purification via dialysis or other process. Used for in vitro assay of circulating insulin; study of in vivo insulin kinetics Longer shelf life than *'l; emits no beta radiation (all gamma emissions); lower doses needed for correct resolution compared to | “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 242 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION Table 6-4. Some Radiopharmaceuticals Used in Medicine (continued) Liothyronine exchanged with "*'l. The mixture is then purified by column or strip paper chromatography. function. Radionuclide Preparation Use Properties | Na lodobenzyl chloride is Used in the detection of renal Excreted almost exclusively by lodohippurate condensed with glycine with | malfunction. the kidneys. the aid of a dehydrochlorinating agent. The resulting o-iodohippuric acid is reacted with NaOH. 8mKr gas A transformation product of | Used for lung function, ventilation, 8'Rb, which is produced by [and perfusion. Also used in alpha bombardment of "Br. | radiocardiology. 25] or *¥| Synthetic liothyronine is Used for in vitro evaluation of thyroid | Binds to thyroxine-binding proteins. Due to the high specific activity, this compound may not be taken internally. The materials should be refrigerated or frozen and should be used within 2 weeks. 125] or 131) Levothyroxine Obtained by synthesis, with the I-tag in the 3'-position. Used to study the endogenous metabolism of thyroxine; to measure thyroxine-binding protein capacity. Binds to thyroxine-binding proteins. 125] or *¥'| Triolein and Oleic acid lodine monochloride is reacted with purified fat triolein in a carbon tetrachloride solution. The solvent and free iodine are removed and the product is diluted in peanut oil. lodinated oleic acid is prepared in a similar manner and has similar properties. Used as a diagnostic agent for measuring fat absorption. The iodine bond is stable in the GI tract but breaks once the compound is in the bloodstream "In Pentetate Indium Disodium Cyclotron-produced indium chlorides are mixed with pentetic acid at low pH (<3.5) to form an indium-DTPA chelate. A trisodium salt is formed by increasing the pH to 7.0-7.5. Used as a diagnostic aid for studies of cardiac output, glomerular filtration; used for cisternography and renal scintigraphy. Shelf-life is limited by the half- life of "In (67.5 hours). 83m n Pentetate Indium Trisodium Pentetic acid containing some ferric ion and HCI is mixed with "In. The resulting chelate is stabilized by increasing the pH to 7.0-7.5, resulting in the formation of a trisodium salt. Used as a diagnostic aid for studies of glomerular filtration; also used for brain scanning and kidney imaging, and cisternography of spinal fluid circulation. 18Yph Pentetate Ytterbium Trisodium Buffered, lyophilized pentetic acid is mixed with '®Yb. Used as a diagnostic aid for brain scanning and kidney imaging, and cisternographic diagnosis of CSF rhinorrhea. May be administered orally or intravenously. “2K Potassium Chloride By neutron bombardment of natural potassium. Used for tumor localization and studies of renal blood flow. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 243 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION Table 6-4. Some Radiopharmaceuticals Used in Medicine (continued) byproduct of uranium fission. Radionuclide Preparation Use Properties “K Potassium By alpha bombardment of a | Used as a diagnostic aid for heart Chloride natural argon target. imaging. 3" Rose Bengal [Prepared by thermal A diagnostic aid for liver function; Accumulates in the polygonal Sodium condensation of especially useful for differential cells of the liver and is excreted tetrachlorophthalic anhydride |diagnosis of hepatobiliary disease. via the biliary system. If liver with 2,4-diiodoresorcinol. function is impaired, it is The resulting phthalein is excreted via the kidneys. reacted with NaOH, and the purified product is labeled by isotope exchange Se Seleno- Extracted from yeast grown | Used for scintigraphy of the pancreas | Incorporated into newly- methionine on sulfur-free medium to -|and parathyroid glands; also used to |formed proteins. Blood levels which trace amounts of visualize the parotid and prostate decline to a minimum value at radiolabeled sodium selenite | glands. 20 to 45 minutes after IV have been added. injection; blood levels then rise Selenomethionine is to about 3/4 that seen at separated from separated 2 minutes postinjection. from the yeast proteins. ZNa Sodium By deuteron bombardment of | Used for determination of circulation |The usual required tracer dose Chloride Mg times, sodium space, and total is well within tolerated levels. exchangeable sodium. Emits positrons which are easily detected by coincidence counting. $'Cr Sodium By neutron bombardment of [Used as a biological tracer to Requires 15-60 minutes to Chromate enriched ¥Cr. measure red-cell volume, red-cell diffuse into red cells; binds to survival time, and whole-blood globin molecules. volume. Also used to detect blood cell loss due to hemolytic anemia or Gl bleeding. '8F Sodium By neutron bombardment of | Useful for bone imaging, especially Fluoride enriched Li in the form of areas of altered osteogenic activity. lithium carbonate. Contamination with °H must be removed prior to use. 3] Sodium By proton bombardment of | For diagnostic procedures in thyroid [Short half-life (13.2 hours) and lodide enriched "Te or by deuteron | function studies; for imaging of the | radiation characteristics result bombardment of enriched thyroid, liver, lung, and brain. in a smaller radiation dose '2Te or by transformation of compared to other iodine 2Xe. isotopes. 125] Sodium By neutron bombardment of |For diagnostic procedures in thyroid lodide xenon gas. function studies; for imaging of the thyroid, liver, and brain; treatment of deep-seated non-resectable tumors. 3] Sodium By neutron bombardment of |For diagnostic procedures in thyroid lodide enriched ®*'Te or as a function studies; a neoplastic suppressant. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 244 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION Table 6-4. Some Radiopharmaceuticals Used in Medicine (continued) reactor. *P is then separated by leaching with NaOH. Radionuclide Preparation Use Properties ®mTc Sodium Produced by the elution of | Used in the detection and localization | *™Tc has an ideal half-life Pertechnetate sodium pertechnetate of cranial lesions, thyroid and salivary | which is long enough for through a generator gland imaging, placenta localization, |diagnostic procedures but is containing ¥*Mo which decays | and blood pool imaging. short enough to minimize to ®*™Tc. radiation doses to the patient. Pertechnetate is readily absorbed by the thyroid; this can be blocked by preinfusion of potassium perchlorate. ®p Sodium By neutron bombardment of | A neoplastic and polycythemic Phosphate elemental sulfur in an atomic | suppressant; a diagnostic aid for the localization of certain ocular tumors. Sr Strontium By neutron bombardment of a strontium salt enriched in Sr. A diagnostic aid for scanning bones and bony structures to detect and define lesions and to study bone growth and abnormal formations. Has a long half-life (64 days), resulting in high bone doses and preventing multiple studies. ®mTe Albumin Albumin is tagged with a reduced form of the pertechnetate. The pertechnetate may be reduced by one of several methods. Diagnostic aid in determining total blood and plasma volumes, circulation times, or cardiac output. See earlier comment on *®™Tc. 9MTe Albumin, Aggregated Denatured human albumin is tagged with a reduced form of the pertechnetate. The pertechnetate may be reduced by one of several methods. Diagnostic aid in determining total blood and plasma volumes, circulation times, or cardiac output. Also useful for static blood-pool imaging, angiography, dynamic function tests and visualization of placental tissues. See earlier comment on *™Tc. ®™Tc is preferred over '*'l as the radioactive tag because of the smaller delivered dose. ®mT¢ Etidronate Acetic acid is treated with PCI; the disodium salt is formed when a solution of etidronic acid is adjusted to a pH of 8.5. Stannous chloride and sometimes a stabilizer such as sodium ascorbate are added. Useful for bone imaging. See earlier comment on ®™Tc. This compound is superior to '®F bone scans and to roentgen studies and is frequently more sensitive in detecting metastases to the bone. ®mTe Iminodiacetic Acid (IDA) Usually provided in kit form, the compound is reconstituted and tagged by adding sterile * Tc sodium pertechnetate. Useful for hepatobiliary imaging. See earlier comment on *™Tc. ®"T¢ Ferpentate Usually in kit form, the compound is made by adding a solution of ¥™T¢ sodium pertechnetate; the pH is adjusted with sodium hydroxide and a solution of pentetic acid is added. The chelate is formed by gentle mixing. Useful for kidney imaging. See earlier comment on *™Tc. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 245 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION Table 6-4. Some Radiopharmaceuticals Used in Medicine (continued) Radionuclide Preparation Use Properties "Tc Pentetate Prepared by adding sterile ®mTc pertechnetate saline solution to an aliquot of buffered stock solution of DTPA containing stannous chloride as a reducing agent. Instant DTPA ®™T¢ kits are available. Useful for brain and kidney visualization, for vascular dynamic studies for measurement of glomerular filtration and for lung ventilation studies. See earlier comment on *™Tc. DTPA is uniformly distributed throughout the extracellular space and is rapidly cleared by the kidneys without retention. ®mTe Pyrophosphate Sodium pyrophosphate, mixed with stannous tin, are combined with a solution of #mT¢ sodium pertechnetate. Used as a skeletal imaging agent; used to demonstrate areas of altered osteogenesis; also used as a cardiac imaging agent, as an adjunct in the diagnosis of myocardial infarction. See earlier comment on *™Tc. The pyrophosphate compound has been found to concentrate in muscle tissue, especially contused muscle tissue. 9™Te Sulfur Colloid A colloidal suspension of sulfur labeled with *™Tc. Used as a diagnostic aid for liver scanning. Also used in detection of intrapulmonary and lower GI bleeding, as well as visualization of the lungs by inhalation of the colloid. See earlier comment on *™Tc. Colloids are phagocytized by the liver. The plasma clearance is rapid (approximately 2.5 min). At least 80% of dose accumulates in the liver. ¥MTc Gluceptate Freshly eluted *™Tc sodium pertechnetate is added to sodium glucoheptonate in combination with stannous chloride. Useful as a renal imaging agent; possibly useful for localization of brain, lung, and gallbladder lesions. See earlier comment on ¥™Tc. Optimal results are obtained 1-2 hours after administration. %"Tc Sodium Methylene Diphosphonate Sodium methylene diphosphonate, available in kit form, is mixed with #mTc sodium pertechnetate. Useful for skeletal imaging. See earlier comment on *™Tc. When administered by IV, compound concentrates in areas of altered osteogenesis. $¥mTe Sodium Phosphates Polyphosphate polymer, available in kit form mixed with stannous chloride, is mixed with ¥mTc pertechnetate. Useful for bone and renal imaging. See earlier comment on *™Tc. #¥mTc Sodium Phytate Sodium phytate, available in kit form mixed with stannous chloride, is reconstituted with ®MmTc pertechnetate. Useful for liver and spleen imaging See earlier comment on *™Tc. Cleared rapidly from the blood by the reticuloendothelial system. Over 80% of compound localizes in the liver and spleen within 30 minutes of an iv injection. The addition of ionic calcium to the ®*™Tc stannous phytate mixture enhances splenic uptake. Te Tetracycline Tetracycline, available in kit form, is reconstituted with stannous chloride and #mTc pertechnetate. For imaging kidneys and gall bladder; myocardial imaging is possible with larger doses. See earlier comment on *™Tc. The compound localizes in the gall bladder. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 246 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION Table 6-4. Some Radiopharmaceuticals Used in Medicine (continued) Radionuclide Preparation Use Properties 20'T| Thallium Thallium target material is Used for myocardial perfusion Thallium mimics potassium Chloride bombarded with protons to [imaging for the localization of ions and is taken up by the produce ?*'Pb. The unused [myocardial ischemia and infarction; | cells of the heart; decreased thallium material is removed |used as an adjunct to angiography. [cell vitality is indicated by by ion exchange, and the Also useful for thyroid imaging, decreased thallium uptake. remaining 2°'Pb subsequently | particularly the detection of goiter and decays to #'Tl. thyroid carcinoma. 127Xe Xenon gas [Produced by proton As a gas, it is used for lung imaging | The biological half-life of the bombardment of cesium-133. | to detect alveolar blockage; also gas is approximately used for mapping cerebral blood 15 minutes. flow. 13Xe Xenon A product of nuclear fission; |As a gas, it is used for lung imaging | The biological half-life of the also formed by neutron to detect alveolar blockage; also gas is approximately activation of Xe. used for mapping cerebral blood 15 minutes. flow. Source: Remington's Pharmaceutical Sciences, 17th ed., 1985. ankylosing spondylitis. In two studies of patients treated with 224Ra, average calculated skeletal doses ranged from 0.65-4.2 Gy (Eisenbud 1987; Harley 1996; Harvard Medical School 1996; NCRP 1993). 6.4.6 Occupational Exposure Occupational exposure to radiation occurs when workers handle radioactive materials or are exposed to radiation sources (e.g., X-rays and radioactive sources). The history of occupational exposure to radioactivity is as old as its use. In the period between the discovery of X-rays and the early 1930s, more than 100 radiologists died of skin cancer, anemia, and possibly leukemia. The frequencies of anemia and noncancerous skin damage were also elevated. The concept of a “tolerance dose” was developed early, based initially upon the levels of exposure that resulted in erythema. Originally, limits of 5 R/month or 0.2 R/day were established, and these limits were successively lowered as the body of knowledge concerning radiation health effects grew. The current limit is 5 rem/year (0.05 Sv/year) to the whole body. While most exposure is external, internal exposure has occurred in several occupations, such as radium dial painters, powerplant workers, uranium miners, and nuclear medicine support staff. In the early 1900s, it was discovered that radium, when mixed with zinc sulfide causes the zinc sulfide to glow. This discovery spurred the development of radioluminescent paints, which consists of a mixture of finely powdered radium salt and zinc sulfide crystals in an appropriate volatile vehicle. This paint was used in the manufacture of dial faces, wristwatches, static eliminators, emergency exit signs, electron tubes, and ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 247 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION educational products. In 1924, bone cancers of the jaw were observed in radium dial painters employed at a northern New Jersey plant. It was determined that the young women were inadvertently ingesting radium due to the practice of lip-pointing the brush tips when painting fine numerals. A group of 24 dial painters ingested approximately 900-1300 pCi radium during the course of their careers, which resulted in the formation of bone cancers (see Chapter 3 of this toxicological profile) (Eisenbud 1987; Shapiro 1990; UNSCEAR 1993). Exposure to airborne uranium ore dust occurs in uranium miners and millers, while exposure to airborne elemental uranium or uranium salts occurs in uranium processors. Uranium ore contains other radionuclides including **Ra, **’Rn, **°Rn, *'®Po, *'*Po, and *'°Po. Radon diffuses from the rock into the mine air, where the radon progeny become attached to particles of dust or moisture and are inhaled into the lungs. In the 1800s, silver and uranium miners in Europe were dying of a mysterious malady; the illness was diagnosed as intrathoracic malignancy in 1879. At that time, it was estimated that the life expectancy of these miners was 20 years after entering the occupation. Death rates from lung cancer in these miners were much higher than expected; as early as 1942, the deaths were attributed to radon exposure. It has been estimated that as much as 40% of all lung cancers in miners may be due to exposure to radon and its progeny (Archer et al. 1973a; Gottlieb and Husen 1982; Lubin et al. 1969, 1995; Samet et al. 1984, 1986). Although radon and its transformation products have been implicated as causative agents in miners with lung cancer, it is difficult to isolate the cancer risk that may be specific to the miners’ exposure because they were concurrently exposed to other suspected carcinogens such as tobacco smoke, silica and other dusts, and diesel engine exhaust fumes (ACHRE 1995; Auerbach et al. 1978; Band et al. 1980; Lundin et al. 1969; Saccomanno et al. 1971, 1976, 1986; Whittemore and McMillan 1983). A study of 16 male Navajo uranium miners who developed lung cancer between February 1965 and May 1979 found that the mean cumulative radon exposure was 1,140 working level months (WLM) (Gottlieb and Husen 1982). The working level is a measure of atmospheric concentration of radon progeny. The WLM is a measure of total exposure. It is the product of the concentration, in WL’s and the exposure time, in months (1 working month = 170 hrs). One WLM corresponds to an alpha dose of approximately 1,000 millirad. An excess of lung cancer deaths was also found in uranium miners who had worked underground for at least one year in the Grants mineral belt area of New Mexico. Mean exposures in these studies ranged from 2.6 to 42 WLM from 1954 to 1966 and from 0.3 to 21.8 WLM from 1967 to 1982 (Acquavella et al. 1985; Samet et al. 1986). A study of 8,487 miners employed between 1948 and 1980 at the Beaver Edge uranium mine in Saskatchewan, Canada, found that workers were exposed to doses as high as 5 WLM (Howe et al. 1986). It ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 248 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION should be noted that, in several of these studies, exposure to dust and cigarette smoke was also found to be related in varying degrees to the incidence of cancer. With the discovery of fission and the development of particle accelerators (Cockcroft-Walton, Van de Graaff generator, cyclotron), numerous new radionuclides and new elements could be readily produced. The number of users and frequency of radionuclide use are both steadily increasing. Other professions in which radiation exposure presents a hazard include: commercial airline personnel (pilots and flight attendants), military pilots, astronauts, industrial and nuclear power plant workers, radiographers, and medical personnel. A person flying cross-country would add 5 mrem exposure per flight due to the increased levels of cosmic radiation associated with the increase in elevation; it has been estimated that pilots and flight attendants receive an annual dose that is approximately 160 mrem higher than that of the average population. Astronauts are exposed to intense radiation emanating from solar flares, the earth’s radiation belts, and ambient cosmic radiation. The average radiation doses for crews of the Apollo missions (5-12 days/mission) were 0.16—1.14 rad; for the Skylab missions, which lasted 20-90 days, the average doses were 1.67.7 rad. These relatively high doses of ionizing radiation may require further attention should persons begin living in the environments of outer space (space stations, interplanetary travel, etc.). The processing and blending of LPG tends to enhance radon concentrations, and the long-lived radon daughters (*'%Pb and *'°Po) tend to accumulate inside LPG processing machinery, resulting in a possible risk of exposure to maintenance workers. A nuclear power plant worker averages 300 mrem additional exposure per year, resulting in exposures about 80% higher than the average population (DOE 1996; Eisenbud 1987). 6.5 ADEQUACY OF THE DATABASE The database is considered to be adequate for use as the basis for radiation safety standards. 6.6 CONCLUSIONS The issue of radiation exposure is a matter of considerable concern to the general public; however, radiation exposure is inevitable as it is a natural part of the environment. Indeed, radioactive materials have always existed around and even within us. While the risk of exposure to radiation from anthropogenic sources exists, with the exception of locally high exposures, the average individual dose received from anthropogenic radiation is negligible compared to that received from natural sources. When assessing the risks associated ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 249 6. SOURCES OF POPULATION EXPOSURE TO IONIZING RADIATION with a radiation exposure, one must weigh the potential benefits (e.g., gain in quality of life related to medical diagnoses and treatments) against the potential detriments (acute radiation sickness, cancer, or both) associated with the exposure. Conversely, in situations presenting minimal risks of exposure to radioactive substances, one may also compare the potential risks associated with the use of alternatives. For example, in the case of nuclear power versus power from fossil fuels, one may want to weigh the risk of exposure to coal dust, radioactive materials, and combustion products associated with coal power versus the risk of exposure to nuclear power production. The regulations concerning radiation exposure limitations are based upon the studies and recommendations of numerous scientific organizations to ensure the health of occupational workers and the public. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 251 7. REGULATIONS Because of its potential to cause adverse health effects in exposed individuals, guidelines and regulations have been established for protection against ionizing radiation and for establishing safe limits for radionuclides in air and water by a number of international and national agencies. The health effects of ionizing radiation have been recognized since early in the twentieth century, and by 1928 the International X-Ray and Radium Protection Committee (now the International Commission on Radiological Protection [ICRP]) was established. In the United States, a year later, the Advisory Committee on X-Ray and Radiation Protection, now called the National Council on Radiation Protection and Measurements (NCRP), was formed. The NCRP was chartered in 1964 by the U.S. Congress to (1) disseminate information of public interest and recommend radiation levels to protect the public, (2) support cooperation among organizations concerned with radiation protection, (3) develop basic concepts about radiation protection, and (4) cooperate with the ICRP and the International Commission on Radiation Units and Measurements. Even though the NCRP is a nongovernmental organization, it provides recommendations that guide the establishment of federal radiation policies, agency requirements, and statutory laws. Through the governmental agencies that rely on NCRP recommendations, the work of this organization has a significant impact on the many activities in the United States involving the use of radiation and radioactive materials. In the United States, the Environmental Protection Agency (EPA) sets radiation safety policy and basic safety standard. The execution of this policy is assigned to the various regulatory agencies, including the EPA itself, for application to the specific activities that they regulate. The Nuclear Regulatory Commission (NRC), an independent government agency, regulates commercial nuclear power reactors; research/test/training reactors; fuel cycle facilities; and the transport, storage and disposal of nuclear materials and waste (NRC 1997). The EPA is responsible for protecting the public and the environment and for clean up of radioactively contaminated sites (EPA 1997). For exposure to radon and its daughters and gamma rays in underground or surface mines, the Mine Safety and Health Administration (Department of Labor) is responsible for protecting miners (MSHA 1997). The Food and Drug Administration (FDA) develops standards for equipment that emits ionizing radiation, such as radiographic and fluoroscopic equipment (FDA 1997). Transport of radioactive materials is regulated by the Department of Transportation (DOT) in conjunction with the NRC. DOT also enforces regulations concerning transport of radioactive materials. Coordinating government emergency response to accidents involving radioactive materials is the responsibility of the Federal Emergency Management Administration (FEMA). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 252 7. REGULATIONS International and national regulations and guidelines pertinent to human exposure to ionizing radiation are summarized in Table 7-1. National regulations governing the occupational exposure to ionizing radiation include EPA standards for uranium and thorium mills (40CFR 192), OSHA standards for ionizing radiation (29CFR 1910.1096), the DOE standards for occupational radiation protection (10CFR 835), and MSHA’s radon and gamma ray standards (60CFR 33719). National regulations concerning general population exposure to ionizing radiation have been developed by the EPA and NRC based upon the dose limit recommendations of the International Commission for Radiological Protection (ICRP 1997) and the National Council on Radiation Protection (NCRP 1991). Currently there are 29 "NRC Agreement States." An agreement state is any state that has entered into an agreement with the NRC under Section 274 of the Atomic Energy Act of 1954, as amended. The NRC relinquishes to these states the majority of its regulatory authority over source, by-product, and special nuclear material in quantities not sufficient to form a critical mass. However, the regulation of nuclear reactors is left to the NRC. In the remaining states, NRC still handles all of the inspection, enforcement, and licensing responsibilities. States can regulate exposure to workers from electronic sources, as well as from naturally occurring and accelerator-produced radioactive materials. State regulations for ***Ra and strontium isotopes are listed in Tables 7-2 and 7-3, respectively. The basic philosophy of radiation safety is to minimize unnecessary radiation exposure. The specific objectives of radiation safety guidance as stated by NCRP are (1) to prevent the occurrence of severe radiation-induced nonstochastic disease, and (2) to limit the risk of the nondeterministic effects, fatal cancer, and genetic effects to a reasonable level compared with nonradiation risks and in relation to societal needs, benefits gained, and economic factors. In addition to laws that set upper limits on radiation dose, the concept of ALARA (As Low As Reasonably Achievable) was introduced to ensure that a reasonable benefit will come as a result of the endeavor that causes the exposure. The goal is not to reach a dose of zero, but to obtain the appropriate balance between protection of public health and the costs (economic, social, etc.) for achieving desirable dose limits. The NRC has set dose limits for individual members of the public of 0.1 rem/year and for occupationally exposed workers, including the fetus of a pregnant worker, as shown in Table 7-1 (NRC 1996). More specific information on regulations pertaining to ionizing radiation exposure can be found in the references listed in Table 7-1 of this profile. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 7. REGULATIONS 253 Table 7-1. Regulations and Guidelines Applicable to lonizing Radiation Agency Description Information References INTERNATIONAL GUIDELINES a. Occupational ICRP Whole body 10 rem/5 years ICRP 1991 not to exceed 5 rem/year Equivalent dose to lens of eye 15 rem/year Equivalent dose to skin, hands and 50 rem/year feet Annual Limits of Intake 2 rem E (50) Bq b. General Population ICRP Effective dose limit and, if needed, 0.1 rem/year ICRP 1991 higher values provided that the annual average over 5 years does not exceed this limit Equivalent dose limit to lens of eye 1.5 rem/year Equivalent dose limit to skin, hands 5 rem/year and feet Equivalent dose to woman’s abdomen 0.2 rem NATIONA IDELINE a. Occupational NCRP*® Effective dose equivalent limit 5 rem/year NCRP 1993 (stochastic limits) not to exceed 1 rem x age of individual Equivalent dose limit to skin, hands, 5 rem/year and feet Dose equivalent limits for the lens of 15 rem/year the eyes (nonstochastic limits) Dose equivalent limits for all other 50 rem/year organs (nonstochastic limits) Guidance: Cumulative exposure 1 rem x age in years Annual Reference Levels of Intake 2rem (ARLI) E (50) Bq’ EPA® Effective dose equivalent (adult) 5 rem/year EPA 1987 Fed Reg Part II Lens of the eye 15 rem/year All other organs 50 rem/year Juvenile workers(<18 years old) 0.5 rem/year Pregnant workers 0.5 rem/gestation period b. General Population: EPA® Effective dose equivalent limit 0.1 rem/year EPA 1994a (Proposed regulation) Fed Reg Part lll NCRP* Effective dose equivalent limit, 0.1 rem/year NCRP 1993 continuous or frequent exposure Effective dose equivalent 0.5 rem/year limit,infrequent exposure Dose equivalent limits for lens of the 5 rem/year eye, skin, and extremities Dose equivalent limit for embryo-fetus ~~ 0.05 rem/month ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 7. REGULATIONS 254 Table 7-1. Regulations and Guidelines Applicable to lonizing Radiation (continued) Agency Description Information References NATIONAL GUIDELINES (cont.) c. Remedial action recommended NCRP Effective dose equivalent” >0.5 rem/year NCRP 1987 Exposure to radon and its decay >2 WLM/year products d. Education and training exposures NCRP*® Effective dose equivalent limit 0.1 rem/year NCRP 1987 Dose equivalent limit in a month 0.05 rem e. Neglible individual risk level NCRP* Effective dose equivalent per source 0.01 rem/year NCRP 1987 or practice f. Information EPA Section 112 of the Clean Air Act yes EPA 1983 (radionuclides) 48CFR 15076 EPA Carcinogen Classification (proposed) Group A° EPA 1994b NATIONAL REGULATIONS a. Occupational: NRC Total effective dose 5 rem/year NRC 1996 Deep dose equivalent plus committed 50 rem/year dose to any organ or tissue other than lens of the eye Eye lens dose equivalent 15 rem/year Skin or other extremity 50 rem/year Fetus of pregnant female 0.5 rem/year DOE Total effective dose 5 rem/year DOE 1997 Deep dose equivalent plus committed 50 rem/year dose to any organ or tissue other than lens of the eye Eye lens dose equivalent 15 rem/year Skin or other extremity 50 rem/year DOT Total effective dose 1.25 rem/3 months or DOT 1996 5 rem/year Dose to embryo-fetus 500 mrem/9 months 50 mrem/month MSHA Radon daughters, MSHA 1997 monitoring required 1/3 months >0.1 WL moitoring requred 1/week >0.3 WL Uranium mines, monitoring monthly 0.1 WL Gamma radiation dosimeters for all employees and records of cumulative individual exposure >0.002 roentgens/hr ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 7. REGULATIONS 255 Table 7-1. Regulations and Guidelines Applicable to lonizing Radiation (continued) Agency Description Information References NATIONAL REGULATIONS (cont.) b. General Population NRC Whole body 0.1 rem/year NRC 1991 10CFR20 Dose from external sources 0.002 rem/hour EPA Radiation Protection Guide (average 5 rem/30years EPA 1994a genetic dose) 0.5 rem/year Fed Reg Part lll DOE Effective dose equivalent limit from 0.1 rem/year DOE 1990 DOE activities Temporary increases in dose limit 0.5 rem/year from DOE activities Effective dose equivalent limit from 0.01 rem/year DOE activities (airborne) Effective dose equivalent limit from DOE activities (direct radiation) 0.025 rem/year DOT General public 2 mrem/hr DOT 1996 Cumulative dose, individual 100 mrem/week 500 mrem/year c. Water: EPA MCL for beta particles and photon 0.004 rem/year EPA 1994b activity (proposed) MCLG for beta particles and 0.0 photonactivity (proposed) DOE Effective dose equivalent limit from 0.004 rem/year DOE 1990 DOE activities (drinking water) STATE GUIDELINES/REGULATIONS FOR PUBLIC PROTECTION a. Virginia Acceptable ambient air concentrations ~~ 8.00 pg/m® (24 hours) NATICH 1992 Radionuclides 2 Sum of external and internal exposures ® Including background but excluding internal exposures © Sufficient evidence in epidemiologic studies to support causal association between exposure and cancer DOE = Department of Energy; DOT = Department of Transportation; EPA = Environmental Protection Agency; ICRP = International Commission on Radiological Protection; MCL = maximum contaminant level; MCLG = maximum contaminant level goal; MSHA = Mine Safety Health Administration; NATICH = National Air Toxics Information Clearing House; NCRP = National Council on Radiation Protection; NRC = Nuclear Regulatory Commission; WL = working level; WLM = working level month ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 256 7. REGULATIONS Table 7-2. Regulations and Guidelines Applicable to 2°Ra Agency Description Information References STATE a. Regulations: Water Quality Criteria: Human Health CELDs 1994 AK Drinking water 5 pCi/L AL Drinking water 5 pCi/L AZ Drinking water 5 pCi/L CA Drinking water 5 pCi/L co Drinking water 5 pCi/L. combined CT Drinking water 5 pCi/L DE Drinking water 5 pCi/L FL Drinking water 5 pCi/L combined GA Drinking water 5 pCi/L HI Drinking water 5 pCi/L IA Drinking water 5 pCi/L IN Drinking water 5 pCi/L KY Drinking water/waste management 5 pCi/L MD Drinking water 5 pCi/L ME Drinking water 5 pCi/L MT Drinking water 5 pCi/L NC Drinking water 5 pCi/L ND Drinking water 5 pCi/L NE Drinking water 5 pCi/L NH Drinking water 5 pCi/L combined NM Drinking water 5 pCi/L NY Drinking water 3 pCi/L - PR Drinking water 3 pCilL OH | Drinking water 5 pCilL OK Drinking water 5 pCi/L RI Drinking water 5 pCi/L SC Drinking water 5 pCi/L SD Drinking water 5 pCi/L TN Drinking water 5 pCi/L TX Drinking water 5 pCilL VA Drinking water 5 pCi/L ut Drinking water 5 pCi/L ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 7. REGULATIONS Table 7-2. Regulations and Guidelines Applicable to 226Ra (continued) 257 Agency Description Information References STATE (cont.) WA Drinking water 3 pCilL WV Drinking water 5 pCilL WY Drinking water 3 pCi/L combined Water Quality Criteria: Aquatic Life CELDs 1994 1A Raw water sources for potable water 5 pCilL MT None NC 5 pCi/L ND 5 pCi/L NH 5 pCilL PR 3 pCiL WV 5 pCilL WY 5 pCilL Water Quality Criteria: Agriculture CELDs 1994 AZ Private Agriculture 5 pCilL ND Irrigation 5 pCilL WY Not specified 5 pCiL Water Quality Criteria: Recreational CELDs 1994 ND Recreational (boating, fishing) 5 pCi/L NH Recreational 3 pCilL WY Not specified 5 pCilL Water Quality - Monitoring CELDs 1994 CA Drinking water 5 pCi/L FL Drinking water 5 pCilL IA Drinking water 1 pCilL ID Drinking water 5 pCilL IL Drinking water 5 pCilL IN Drinking water 3 pCiL MA Drinking water 5 pCilL MD Drinking water 1 pCilL Mi Drinking water 3 pCilL MO Drinking water 5 pCilL MT Drinkirig water Yes NC Drinking water 5 pCilL ND Drinking water 5 pCilL ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 7. REGULATIONS Table 7-2. Regulations and Guidelines Applicable to 2*Ra (continued) 258 _ Agency Description Information References STATE (cont.) NM Drinking water 1 pCilL NY Drinking water 5 pCi/L OH Drinking water 5 pCilL PR Drinking water 5 pCilL RI Drinking water 5 pCi/L SC Drinking water 5 pCilL SD Drinking water 5 pCi/L TN Drinking water 1 pCi/L TX Drinking water 5 pCi/L VA Drinking water 5 pCi/L uT Drinking water 5 pCi/L WA Drinking water 5 pCi/L WI Drinking water 5 pCi/L WV Drinking water 5 pCi/L Groundwater Quality Standards CELDs 1994 NE Groundwater 5 pCi/L NC Drinking, potable mineral water 5 pCi/L NY Not specified 3 pCi/L PR Not specified 3 pCi/L TN Not specified 5 pCi/L VA Not specified 5 pCi/L WY Not specified 5 pCi/L Groundwater Monitoring Parameters CELDs 1994 CA Hazardous waste facilities Yes CO Hazardous waste facilities 5 pCi/L IN Public supply 3 pCi/L NC Public supply 5 pCi/L NJ Hazardous waste facilities 5 pCi/L NM Public supply 1 pCi/L NY Hazardous facility 5 pCi/L SC Hazardous waste 5 pCi/L TN Not specified 5 pCi/L Wi Hazardous waste 5 pCi/L CELDS = Comprehensive Environmental Legislative Database ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 259 7. REGULATIONS Table 7-3. Regulations and Guidelines Applicable to Strontium Isotopes Agency Description Information References STATE a. Regulations: Water Quality Criteria - Human Health CELDs 1994 AZ Agricultural, public, aquatic 8 pCi/L AL Drinking water 8 pCi/L CA Drinking water 8 pCi/L co Drinking water 2 pCilL CT Drinking water - standard 8 pCi/L DE Drinking water - standard and monitoring 8 pCilL FL Drinking water 8 pCi/L GA Drinking water Yes HI Drinking water 8 pCi/L IA Drinking water 8 pCilL ID Drinking water 8 pCi/L IL Drinking water 8 pCi/L IN Drinking water 8 pCi/L Surface Water Quality Standards CELDs 1994 co 8 pCi/L Water Quality Monitoring CELDs 1994 AL Drinking water Yes AZ Drinking water Yes CA Drinking water 8 pCi co Drinking water 2pCi DE Drinking water 8 pCi GA Drinking water Yes HI Drinking water Yes IA Drinking water Yes ID Drinking water Yes IL Drinking water 8 pCi IN Drinking water Yes Groundwater Quality Standards CELDs 1994 CO Groundwater - Public 8 pCi/L IN Groundwater - Drinking 10 pCilL CELDS = Comprehensive Environmental Legislative Database ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 261 8. OBSERVED HEALTH EFFECTS FROM RADIATION AND RADIOACTIVE MATERIAL To help public health professionals and others address the needs of those who are exposed to radiation and radioactive material, the information in this section on ionizing radiation is organized first by route of exposure— inhalation, oral, dermal and external; and then by health effect—death, systemic, immunological, neurological, reproductive, developmental, genotoxic, and carcinogenic effects. The data for the observed effects from radiation and radioactive material are presented in the following tables. These tables are not meant to be exhaustive reviews of all of the literature that reports biological effects resulting from exposure to ionizing radiation. It does, however, provide health care professionals, persons exposed (or potentially exposed) to ionizing radiation in their occupations, and the general public an overview of the types of effects observed in each category. The tables report no-observed-adverse-effect levels (NOAELSs) or lowest-observed-adverse-effect levels (LOAELs), which reflect the actual doses (or concentration of radioactive material) used in the studies. LOAELS have been further classified into "less serious" or "serious" effects. "Serious" effects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute radiation sickness or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a considerable amount of judgment may be required in establishing whether an end point should be classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be insufficient data to decide whether the effect is indicative of significant dysfunction. However, the Agency has established guidelines and policies that are used to classify these end points. ATSDR believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between "less serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is considered to be important because it helps the users of the profiles to identify levels of exposure to ionizing radiation at which major health effects may start to appear. LOAELs or NOAELSs should also help in determining whether or not the effects vary with dose and/or duration, and place into perspective the possible significance of these effects to human health. The units of exposure in the studies on ionizing radiation reported in Tables 8-1 to 8-4 varied considerably from one report to another. In these studies, some authors reported units of absorbed dose (rad, Gy) or dose equivalent (rem, Sv), while other authors reported effects in terms of units of concentration, transformations (disintegrations) or activity (uCi/kg or Bq/kg, etc). Conversions between units is possible when given ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 262 8. OBSERVED HEALTH EFFECTS FROM RADIATION AND RADIOACTIVE MATERIALS specific information about the exposed animal, organ weights, and the nuclide; however, the specific information required to perform those conversions was, in many cases, not complete or not reported at all. Many of the activities reported in Ci or Bq could not be converted into a unit of absorbed dose (rad, Gy) to determine a dose-response relationship. Since these conversions were not practical, the unit information (rad, Gy, rem, Si) with the corresponding NOAEL or LOAEL are listed first under each heading (death, respiratory, gastrointestinal, etc). This information is then immediately followed by the studies that examined end points in terms of concentration or activity (uCi/kg or Bg/kg) for each organ system route of exposure. This provides the reader an opportunity to more clearly observe any dose-response effects resulting from exposure to ionizing radiation, both from an absorbed dose (rad, Gy) aspect as well as from a radionuclide activity (Ci, Bq) perspective. The significance of the exposure levels shown in Tables 8-1 to 8-4 may differ depending on the user's perspective. Public health officials and others concerned with appropriate actions to take at hazardous waste sites may want information on levels of exposure associated with more subtle effects in humans or animals (LOAELS) or exposure levels below which no adverse effects (NOAELs) have been observed. Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CEL) of ionizing radiation are also indicated in Tables 8-1 through 8-4. Estimates of exposure levels posing minimal risk to humans may be of interest to health professionals and citizens alike. Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have not been made for ionizing radiation, for the reasons outlined below. An MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration within a given route of exposure. MRLs are based on noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for acute, intermediate, and chronic duration exposures for inhalation and oral routes as well as for external exposure. Appropriate methodology does not exist to develop chemical MRLs for dermal exposure. Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990), uncertainties are always associated with these techniques. ATSDR acknowledges additional uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an example, acute inhalation MRLs may not be protective for health effects that are delayed in development or are acquired ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 263 8. OBSERVED HEALTH EFFECTS FROM RADIATION AND RADIOACTIVE MATERIALS following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic bronchitis. As these kinds of health effects data become available and methods to assess levels of significant human exposure improve, these MRLs will be revised. No Minimal Risk Levels (MRLs) have been derived for any route of exposure in this profile at this time. However, ATSDR is currently in the process of examining and critically evaluating the large database of health effects caused by exposure to ionizing radiation. During this evaluation process, ATSDR is also examining many other factors, including (1) which specific studies would lend themselves to be most suitable for deriving an MRL, and (2) what health effect(s) an MRL should be based upon (cataract formation, reduction in IQ, etc.). Any MRLs that are derived will be integrated into the final version of this profile. The tables of Observed Health Effects from Radiation and Radioactive Material consist of the following information: (1) Route of Exposure One of the first considerations when reviewing the toxicity of ionizing radiation using these tables and figures should be the relevant and appropriate route of exposure. When sufficient data exist, four tables are presented in the document by the four principal routes of exposure, i.e., inhalation, oral, dermal and external (Observed Health Effects from Radiation and Radioactive Materials tables 8-1, 8-2, 8-3 and 8-4, respectively). Not all studies will have data on each route of exposure. (2) Health Effect The major categories of health effects included in Observed Health Effects from Radiation and Radioactive Materials tables are death, systemic, immunological, neurological, developmental, reproductive, and cancer. NOAELSs and LOAELSs can be reported in the tables and figures for all effects but cancer. Systemic effects are further defined in the "System" column of the Observed Health Effects from Radiation and Radioactive Materials table. (3) Species The test species, whether animal or human, are identified in this column. (4) Duration/ Frequency of Administration The duration of the study and the weekly and daily exposure regimen are provided in this column. This permits comparison of NOAELs and LOAELSs from different studies. (5) System This column further defines the systemic effects. These systems include: respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and dermal/ocular. Other systems considered separately in these tables are immunological/lymphoreticular, neurological, reproductive, developmental, genotoxic, and cancer. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered in these systems. (6) NOAEL A No-Observed-Adverse-Effect Level (NOAEL) is the highest exposure level at which no harmful effects were seen in the organ system studied. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 264 8. OBSERVED HEALTH EFFECTS FROM RADIATION AND RADIOACTIVE MATERIALS (7) LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest dose used in the study that caused a harmful health effect. LOAELSs have been arbitrarily classified into "Less Serious" and "Serious" effects. These distinctions help readers identify the levels of exposure at which adverse health effects first appear and the gradation of effects with increasing dose. A brief description of the specific endpoint used to quantify the adverse effect accompanies the LOAEL. (8) CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious effects. (9) Chemical Form The nuclide, the chemical form (chloride, oxide, etc.) and the type of emission (alpha or beta particle and gamma ray) is indicated in this column. (10) Reference The complete reference citation is given in chapter 10 of the profile. ***DRAFT FOR PUBLIC COMMENT*** +LNIWWOD O1718Nd HOH L4vHQA... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation Duration/ LOAEL Entry Species Frequency of Reference Number (strain) Administration System NOAEL Less serious Serious Chemical Form Death 1 Rat 20 min 71 radM (decr. median survival time Lundgren et al. (Fischer- 344) in fibrotic vs non-fibrotic 1991 rats) Alpha Particles [239)PuO2 2 Rat 20 min 340 rad F (decr. median survival time Lundgren et al. (Fischer- 344) in fibrotic vs non-fibrotic 1991 rats) Alpha Particles [239]PuO2 3 Dog 3-46 min 8,400 rad (21/33 dogs died-7.5 to 163 Hobbs et al. (Beagle) d post-exposure) 1972 Beta Particles [s0]Y 4 Dog once 8700 rad (3/4 died) Benjamin et al. (Beagle) 1976 Beta Particles [90]Y 5 Dog once 10,000 (16/16 dogs died 12 to 163 McClellan et al. (Beagle) rad d post exp) 1970 Beta Particles [90]Y 6 Dog <70 min 15,000 (40/96 died <3 yrs post Boecker et al. (Beagle) rad exposure) 1988 Beta Particles [91]Y STVIH3LVIN 3AILOVOIAYYH ANV NOILYIAYH WOH S103443 HLTVIH a3AH3S80 8 NOILVIAQVH DNIZINOI S92 ++ LNIWWNOD OIN8Nd "Od 14VHQ... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Duration/ LOAEL Entry Species Frequency of Reference Number (strain) Administration System NOAEL Less serious Serious Chemical Form 7 Dog once 27,000 (14/16 died or were Benjamin et al. (Beagle) rad sacrificed due to severe 1978 condition within 5 yrs post Beta-Gamma exposure) Particles [144]Ce 8 Dog once 39,000 (1/4 died) Benjamin et al. (Beagle) rad 1976 Beta Particles [90]Sr 9 Dog once 42,000 (2/4 died) Benjamin et al. (Beagle) rad 1976 Beta Particles [144]Ce 10 Dog once 48,000 (9/9 dogs died 143-410d McClellan et al. (Beagle) rad post exposure) 1970 Beta Particles [144]Ce 11 Monkey once 270 nCiM (5/5 animals died 430- Hahn et al. (Rhesus) 4334 d after exposure) 1987 Alpha Particles [239]Pu02 12 Monkey once 1.08 uCiM (3/12 died) Brooks et al. (Cynomol- gus) 1992 Alpha Particles [239]Pu STIVIH3LVYN 3AILOVOIAYYH ANV NOILVIAvH WOH S103443 HLTV3H 3AY3Sa0 8 NOILVIAQVH ONIZINOI 992 «.LNIWWNOD D179Nd HOH 14vHQ... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Duration/ LOAEL Entry Species Frequency of Reference Number (strain) Administration System NOAEL Less serious Serious Chemical Form 13 Mouse 10-20 min 21 uCiM (survival 12% of controls, Lundgren et al. (CFW) with median survival of 66 1981 d) Beta Particles [s0]Y 14 Rat 1x2 mo 32.4 uCi (29.3-31.9% shortened life Hahn and (Fischer- 344) 1yr span) Lundgren 1992 (7x) Beta Particles [144]Ce02 15 Dog once 320uCi (5 dogs died, 93-279 d McClellan et al. (Beagle) post exposure) 1970 Beta Particles [144]Ce 16 Dog once 320 uCi (5 dogs died, 93- 279 d McClellan et al. (Beagle) post exposure) 1970 Beta Particles [144]Ce 17 Dog once 0.26 (death in 8/24 dogs over ~~ Hahn et al. (Beagle) uCilkg 1125-2143d 1981 post-exposure) Alpha Particles [238]Pu02 18 Dog once 0.97 (51/72 died) Benjamin et al. (Beagle) uCi/kg 1979 Beta Particles [90]SrCI2 NOILYIAYH ONIZINOI SAVIHILVYIN 3AILOVOIAVH ANV NOILYIQVH WOHL S103443 HLTV3H G3AH3SE0 8 192 «+INFWWOD O178Nd HOH 14VHQ... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Duration/ LOAEL Entry Species Frequency of Reference Number (strain) Administration System NOAEL Less serious Serious Chemical Form 19 Dog once 1.7 (27/72 died at 585+ d) McClellan et al. (Beagle) uCikg 1973 Beta Particles [90]SrCI2 20 Dog once 2.6 (43/55 died) Benjamin et al. (Beagle) uCi/kg 1979 Beta Particles [144]CeCI3 21 Dog once 14 uCi/kg (21/46 died) Benjamin et al. (Beagle) 1979 Beta Particles [91]YCI3 22 Dog 2-22 min 45.9 (death in 6/66 animals Gillett et al. (Beagle) uCikg within 32 d) 1987a Beta Particles [90]SrCI2 23 Dog once 74 uCi/kg (6/72 dogs died at 18-31 d) McClellan et al. (Beagle) 1973 Beta Particles [90]SrCI2 24 Dog <70 min NS (58/96 died >3 yrs post Boecker et al. (Beagle) exposure) 1988 Beta Particles [o1]Y SIVIHILYW IAILOVOIAVH NV NOILYIQYH WOHH S103443 HLTV3H G3AW3S80 8 NOILYIAYH ONIZINOI 89¢ «+LNIWWOD O1718Nd HOH 14vHQ... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Duration/ LOAEL Entry Species Frequency of Reference Number (strain) Administration System NOAEL Less serious Serious Chemical Form Systemic 25 Hamster 1-45 min Resp 40 radM (radiation pneumonitis in Lundgren et al. (Syrian) 8%) 1983 Alpha Particles [239]Pu0O2 26 Hamster 1yr Resp 220 radM (radiation pneumonitis in Lundgren et al. (Syrian) 7x/yr 40% and bronchiolar 1983 1-45 min/x epithelial hyperplasia in Alpha Particles 35%) [239]Pu02 27 Dog once Resp 3700 rad (severe radiation Hahn et al. (Beagle) pneumonitis and pulmonary 1981 fibrosis in 7/144) Alpha Particles [238]PuO2 28 Dog once Resp 8700 rad (pneumonitis, fibrosis, Benjamin et al. (Beagle) inflammation in 3/4 dogs) 1976 Beta Particles [s0]y 29 Dog once Resp 27,000 (pneumonitis and Benjamin et al. (Beagle) rad pulmonary fibrosis) 1978 Beta-Gamma Particles [144]Ce 30 Dog once Resp 39,000 (dyspnea and cyanosis; Benjamin et al. (Beagle) rad pneumonitis and fibrosis in 1976 1/4 dogs) Beta Particles [90]Sr SIVIH3LVIN 3AILOVOIAYH ANV NOILYIAvd WOHH S103443 HLTV3H d3AHY3S80 8 NOILYIAvH ONIZINOI 692 «+: LNIWWOD O118Nd HOH 14VHd... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Duration/ LOAEL Entry Species Frequency of Reference Number (strain) Administration System Less serious Serious Chemical Form 31 Dog once Resp 42,000 (pneumonitis, fibrosis, Benjamin et al. (Beagle) rad inflammation in 2/4 dogs) 1976 Beta Particles [144]Ce 32 Dog once Resp 230rad (decr. lung capacity & Muggenburg et (Beagle) compliance, & incr. al. 1988 respiratory frequency & Alpha Particles minute volume) [239]PuO2 33 Rat 20 min Resp 240rad (decr. functional residual Lundgren et al. (Fischer- 344) capacity and incr. 1991 percentage of forced Alpha Particles vital capacity, mild [239]PuO2 septal fibrosis, small focal scars, decr. in lung volume, incr. in connective tissue) 34 Dog 3-46 min Resp 8,400 rad (incr. resp. rate, Hobbs et al. (Beagle) pulmonary & pleural 1972 fibrosis, metaplastic Beta Particles and/or hyperplastic [90]Y lesions in terminal bronchiolar and alveolar regions) 35 Monkey once Resp 270 nCiM (pulmonary fibrosis) Hahn et al. (Rhesus) 1987 Alpha Particles [239]Pu0O2 SIVIHALYN JAILOVOIAYH ANY NOILYIAYH WOH S103443 HLTV3IH A3AH3S80 8 NOILYIAVYH ONIZINOI 0L2 +++LNJWWOD O178Nd HOH 14vHQ... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Duration/ LOAEL Entry Species Frequency of Reference Number (strain) Administration gystem NOAEL Less serious Serious Chemical Form 36 Monkey once Resp 1000 nCiM (radiation pneumonitis and LaBauve et al. (Rhesus) pulmonary fibrosis) 1980 Alpha Particles [239]Pu02 37 Monkey once Resp 210nCi M Hahn et al. (Rhesus) 1987 Alpha Particles [239]Pu02 38 Monkey once Resp 0.27 uCiM (2/2 fibrosis, 1/2 Brooks et al. (Cynomol- gus) pneumonitis) 1992 Alpha Particles [239]Pu 39 Mouse once Resp 4.8 uCiF (92%, 34%, and 59% Lundgren et al. (C57BL/6Y) radiation pneumonitis in 1980a 70-, 260-, and 450-day old Beta Particles mice) [144]Ce02 40 Mouse 10-20 min Resp 21uCiM (radiation pneumonitis in Lundgren et al. (CFW) 75-100% of mice) 1981 Beta Particles [90]Y 41 Dog 28-53 min Resp 24,000 (radiation pneumonitis in Hahn et al. (Beagle) uCi 6/7 dogs) 1975 Beta Particles [90]Y STVIH3LYW 3AILOVOIAYYH ANY NOILYIAVH WOHS S103443 HLTV3H A3AH3SE0 ‘8 NOILYIAVYd ONIZINOI Lie «+LNTFWWNOD J1718Nd HO4 14VH(... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Duration/ LOAEL Entry Species Frequency of Reference Number (strain) Administration System NOAEL Less serious Serious Chemical Form 42 Monkey once Resp 0.108 M Brooks et al. (Cynomol- gus) uCi 1992 Alpha Particles [239]Pu 43 Mouse once Resp 1.1uCi F Lundgren et al. (C57BL/6J) 1980a Beta Particles [144]Ce02 44 Dog once Resp 2.6 (3/55 radiation Benjamin et al. (Beagle) uCi’kg pneumonitis, pulmonary 1979 fibrosis) Beta Particles [144]CeCI3 45 Dog <1 hr Resp 33 uCi/kg (radiation pneumonitis) Hahn et al. (Beagle) 1976 Beta Particles [144]Ce 46 Dog 3-46 min Cardio 8,400rad (ECG changes in 5/12 Hobbs et al. (Beagle) and hemorrhagic areas 1972 near ventricular junction Beta Particles in right atria of 7/12 dogs [90]Y dying 64-92 d post exposure) 47 Dog once Cardio 3200 Muggenburg et (Beagle) rad al. 1988 Alpha Particles [239]Pu0O2 SIVIHILVYW 3AILOVOIAvH ANY NOILYIAvd WOYHd S103443 HLTV3H d3AY3S80 8 NOILYIAVYH ONIZINOI cle ««LNIWWOO O118Nd HOH L4VHQ... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Duration/ LOAEL Entry Species Frequency of Reference Number (strain) Administration System NOAEL Less serious Serious Chemical Form 48 Dog 28-53 min Gastro 3200 (colon lesion, ulcerative Hahn et al. (Beagle) rads and atrophic foci in 1/2 1975 dogs) Beta Particles [90]Y 49 Dog 28-53 min Gastro 32,000 uCi (colitis in 2/7 dogs) Hahn et al. (Beagle) 1975 Beta Particles [90]Y 50 Dog 2-22 min Gastro 45.9 uCi’kkg (diarrhea) Gillett et al. (Beagle) 1987a Beta Particles [90]SrCI2 51 Dog 3-46 min Hemato 8,400 rad (lymphopenia) Hobbs et al. (Beagle) 1972 Beta Particles [s01Y 52 Dog 3-46 min Hemato 8,400rad (suppression of bone Hobbs et al. (Beagle) marrow in deaths up to 1972 31d, repopulation of Beta Particles marrow in later deaths [90]Y 53 Monkey once Hemato 1.08 uCi M Brooks et al. (Cynomol- gus) 1992 Alpha Particles [239]Pu STVIHILVYIN 3AILOVOIAVH ANY NOILYIAVYH WOHH S103443 HL1V3H Q3AY3S90 8 NOILYIAQVH ONIZINOI €L2 ++ LINTFWWOD O178Nd HOH 14vHQ... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Duration/ LOAEL Entry Species Frequency of Reference Number (strain) Administration System NOAEL Less serious Serious Chemical Form 54 Dog once Hemato 0.97 (bone marrow aplasia) Benjamin et al. (Beagle) uCi/kg 1979 Beta Particles [90]SrCi2 55 Dog once Hemato 2.6-360 (9/55 bone marrow aplasia) Benjamin et al. (Beagle) uCikg 1979 Beta Particles [144]CeCI3 56 Dog once Hemato 14 (11/46 bone marrow Benjamin et al. (Beagle) uCi’kg aplasia) 1979 Beta Particles [91]YCI3 57 Dog 2-22 min Hemato 45.9 (bone marrow hypoplasia) Gillett et al. (Beagle) uCi/kg 1987a Beta Particles [90]SrCI2 58 Dog 2-22 min Hemato 9.99 uCilkg (decreased platelet Gillett et al. (Beagle) counts) 1987a Beta Particles [90]SrCI2 59 Hamster 1yr Hepatic 3900 radM (degenerative liver lesions Lundgren et al. (Syrian) 7x/yr in 40%) 1983 1-45 min/x Alpha Particles [239]Pu02 SIVIHILVYW JAILOVOIQVYYH ANY NOILYIaYH WOHH S103443 HLTV3H A3AH3S80 8 NOILVIAvHd ONIZINOI vie +» LNIJWWOD O118Nd HOH 14vHQ... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Duration/ LOAEL Entry Species Frequency of Reference Number (strain) Administration System NOAEL Less serious Serious Chemical Form 60 Dog 3-46 min Hepatic 8,400rad (moderate or marked Hobbs et al. (Beagle) centrilobular hepatic 1972 congestion in deaths Beta Particles >38d, no necrosis) [90]Y 61 Dog once Hepatic 2.6-360 (3/55 hepatic degeneration) Benjamin et al. (Beagle) uCikg 1979 Beta Particles [144]CeCI3 62 Dog 3-46 min Dermal 8,400rad (alopecia, atrophy and Hobbs et al. (Beagle) loss of hair follicles in 1972 4/33 dogs) Beta Particles [90]Y 63 Dog 28-53 min Dermal ? (nasal dermatitis in 4/7 Hahn et al. (Beagle) dogs) 1975 Beta Particles [90]Y 64 Dog 3-46 min Bd Wt 8,400 rad (anorexia and Hobbs et al. (Beagle) progressive weight loss) 1972 Beta Particles (90]Y 65 Dog 2-22 min Metab 459 uCikg (fever) Gillett et al. (Beagle) 1987a Beta Particles [90]SrCI2 STVIH3LVYW 3AILOVOIAVYH ANV NOILYIAYH WOYHH S103443 HLTV3H G3AH3S80 ‘8 NOILVIAv4d ONIZINOI Sle ++ LNFWWOD 0118Nd HOH 14VHQA... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Entry Number 66 67 68 69 70 71 Species Frequency of (strain) Administration Duration/ System Immunological/Lymphoreticular Dog (Beagle) Dog (Beagle) Dog (Beagle) Dog (Beagle) Dog (Beagle) Dog (Beagle) once once once once once once NOAEL LOAEL Less serious Serious 1400 rad 27,000 rad 39,000 rad 42,000 rad 520 rad (decr. response of lymphocytes to PHA in middle aged dogs) 740 rad (decr. response of lymphocytes to Con A and PHA in aged tumor bearing dogs) (fibrosis, atrophy, or hyperplasia in lymph nodes) (60% decr. in lymphocyte count) (lymphopenia and decr. in lymphocyte function) (lymphopenia and decr. in lymphocyte function) Reference Chemical Form Galvin et al. 1989 Alpha Particles [239]Pu0O2 Benjamin et al. 1978 Beta-Gamma Particles [144]Ce Benjamin et al. 1976 Beta Particles [90]Sr Benjamin et al. 1976 Beta Particles [144]Ce Davila et al. 1992 Alpha Particles [239]Pu0O2 Davila et al. 1992 Alpha Particles [239]PuO2 SIVIHILYN 3AILOVOIAVYH ANV NOILYIavH WOY4 S103443 HLTV3H 3AY3S80 8 NOILYIAVY DNIZINOI 9/2 ++ LNIWWOD O178Nd HOH 14VHA... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Duration/ LOAEL Entry Species Frequency of Reference Number (strain) Administration gygtem NOAEL Less serious Serious Chemical Form 72 Dog once 1400rad (incr. IgG in lung; Galvin et al. (Beagle) neutrophils six-fold 1989 higher in lungs) Alpha Particles [239]PuO2 73 Dog 3-46 min 8,400 rad (<38d, TBLN had Hobbs et al. (Beagle) marked lymphoid 1972 depletion; >38 d nodes Beta Particles were enlarged with [90]Y hyperplastic repopulation of lymphocytes) 74 Mouse 10-20 min 7 uCi M (incr. number vacuolated Lundgren et al. (CFW) macrophages) 1976 Beta Particles [90]Y 75 Mouse 10-20 min 8 uCi M (equivocal suppression Lundgren et al. (CFW) of pulmonary bacterial 1976 clearance at 2 and 3 wk Beta Particles post-exposure) [90]Y 76 Dog <1 hr 51 (severe atrophy and Hahn et al. (Beagle) uCi/kg fibrosis in both cortex and 1976 paracortex) Beta Particles [144]Ce Cancer 78 Dog once 180rad (CEL: osteoblastic Gillett et al. (Beagle) osteosarcomas in 4/15 1985 dogs) Beta Particles [241)AmO2 STVIH3LYIN 3AILOVOIAVYH ANV NOILYIAYH WOHH S103443 H1TV3H 3AH3SE0 8 NOILYIAVH ONIZINOI Ll2 ++«LINTFWNOD 0178Nd HOH L4VHQ... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Duration/ LOAEL Entry Species Frequency of Reference Number (strain) Administration System NOAEL Less serious Serious Chemical Form 79 Dog once 180rad (CEL: osteoblastic Gillett et al. (Beagle) osteosarcomas in 4/15 1985 dogs) Beta Particles [241)AmO2 80 Dog once 190 radM (CEL: oral melanoma) Muggenburg et (Beagle) al. 1988 Alpha Particles [239]Pu0O2 81 Dog once 200rad (CEL: 30 lung tumors Hahn et al. (Beagle) observed, 1.2 expected) 1988 Beta Particles [144]Ce 82 Dog once 210rad (CEL: osteosarcomasin Hahn et al. (Beagle) 35/144 exposed dogs) 1981 Alpha Particles [238]Pu0O2 83 Dog <70 min 310rad (CEL: 28/36 lung cancer) Boecker et al. (Beagle) 1988 Alpha Particles [239]PuO2 84 Dog once 800rad (CEL: nasal squamous cell Benjamin et al. (Beagle) carcinomas in 5/55) 1979 Beta Particles [144]CeCI3 SIVIH3LVIW 3AILOVOIAVH ANY NOILYIAVH WOHH S103443 HLTVIH Q3AY3S80 '8 NOILVYIAVYH ONIZINOI 8.2 «:LNIWWOD J178Nd HO4 1d4vHQ... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Duration/ LOAEL Entry Species Frequency of Reference Number (strain) Administration System NOAEL Less serious Serious Chemical Form 77 Dog once 860rad (CEL: 3/46 nasal Benjamin et al. (Beagle) - squamous cell carcinomas) 1979 Beta Particles [91]YCI3 85 Dog once 1000 rad (CEL: lung carcinoma) Muggenburg et (Beagle) al. 1988 Alpha Particles [239]Pu02 86 Dog once 1400 rad (CEL: lung tumorsin 3/4 Galvin et al. (Beagle) dogs) 1989 Alpha Particles [239]Pu02 87 Monkey once 1400 radM (CEL: pulmonary sarcoma Hahn et al. (Rhesus) in 1/12) 1987 Alpha Particles [239]Pu02 88 Dog once 1900 rad (CEL: 8 lung tumors Hahn et al. (Beagle) observed, 1.2 expected) 1988 Beta Particles [90]Y 98 Dog once 2,800 (CEL: 31 bone related Benjamin et al. (Beagle) rads sarcomas) 1979 Beta Particles [90]SrClI2 STVIH3LVIN SAILOVOIAYYH ANY NOILYIAVH WOHd S103443 HLTV3H d3A43S80 8 NOILYIAQYH ONIZINOI 6.2 ««LNIWWOD 0118Nd HO 14vHa... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Duration/ LOAEL Entry Species Frequency of Reference Number (strain) Administration System NOAEL Less serious Serious Chemical Form 89 Dog once 3100rad (CEL: 36 lung tumors Hahn et al. (Beagle) observed, 1.2 expected) 1988 Beta Particles [91)Y 99 Dog once 3200rad (CEL: 2 heart tumors) Hahn et al. (Beagle) 1988 Beta Particles [144]Ce 100 Dog once 3200 rad (CEL: 9 TBLN tumors) Hahn et al. (Beagle) 1988 Beta Particles [144]Ce 90 Dog <70 min 3500 rad (CEL: lung cancer in 32/56) Boecker et al. (Beagle) 1988 Beta Particles [91]Y 91 Dog 10-15 min 7,000rad (CEL: pulmonary Hahn et al. (Beagle) carcinomas and sarcomas) 1983 Beta Particles [90]Y, [91]Y, [144]Ce, [90]Sr 97 Dog once 7100 (CEL: 2/72 other Benjamin et al. (Beagle) rads carcinomas of the head) 1979 Beta Particles [90]SrCI2 SIVIHILVYIN 3AILOVOIAQVH ANV NOILYIAvYH WOHd S103443 HLTV3H 3AY3SE0 8 NOILVYIAVH ONIZINOI 082 «xINIFWWOD 01N18Nd HOS 14H... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Duration/ Entry Species Frequency of LOAEL Reference Number (strain) Administration system NOAEL Less serious Serlous Chemical Form 101 Dog once 7700rad (CEL: 14 heart tumors) Hahn et al. (Beagle) 1988 Beta Particles [90]Sr 102 Dog once 7700rad (CEL: 8 TBLN tumors) Hahn et al. (Beagle) 1988 Beta Particles [90]Sr 92 Dog once 8100rad (CEL: 1/55 bone related ~~ Benjamin et al. (Beagle) sarcomas) 1979 Beta Particles [144)CeCI3 103 Dog once 9600 rad (CEL: 1 heart tumor) Hahn et al. (Beagle) 1988 Beta Particles [91]Y 104 Dog once 9600 rad (CEL: 2 TBLN tumors) Hahn et al. (Beagle) 1988 Beta Particles [91]Y 93 Dog once 13000 (CEL: 1/72 nasal Benjamin et al. (Beagle) rad squamous cell carcinomas) 1979 Beta Particles [90]SrCI2 SIVIHILYN 3AILOVOIAYH ANY NOILYIQYH WOH S103443 HLTV3H d3AY3S80 8 NOILYIAYH ONIZINOI 182 ««LNJWWOD O178Nd HOH L4vHQ... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Duration/ Entry Species Frequency of Number (strain) Administration LOAEL Reference System NOAEL Less serious Serious Chemical Form 94 Dog 2-48 min 16,000 (CEL: bronchiolo-alveolar Hahn et al. (Beagle) rad carcinomas and pulmonary 1977 hemangiosarcomas) Beta Particles [s0]Y, [91]Y, [144]Ce, [90]ST 95 Dog once 18,000 (CEL: 28 lung tumors Hahn et al. (Beagle) rad observed, 1.2 expected) 1988 Beta Particles [90]Sr 96 Dog once 27,000 (CEL: pulmonary Benjamin et al. (Beagle) rad neoplasms in 5/16 dogs) 1978 Beta-Gamma Particles [144]Ce 105 Rat once 0.06 uCi (CEL: pulmonary Hahn and (Fischer- 344) adenocarcinoma in 1/35) Lundgren 1992 Beta Particles [144]Ce0O2 106 Rat 7x 0.35uCi (CEL: pulmonary Hahn and (Fischer- 344) 1x/2 mo adenocarcinoma and Lundgren 1992 1yr adenoma in 2/36) Beta Particles [144)Ce02 107 Mouse 10-20 min 1 uCiM (CEL: pulmonary Lundgren et al. (CFW) adenomas) 1981 Beta Particles [90]Y SIVIHILVIN 3AILOVOIAYYH ANV NOILYIAVYH WOHH S103443 HLTV3H d3AH3S80 8 NOILYIQVYH DNIZINOI [4:14 + INIFWWNOD 0118Nd HOS 14VH..e Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Duration/ LOAEL Entry Species Frequency of Reference Number (strain) Administration System NOAEL Less serious Serious Chemical Form 108 Monkey once 1.08 uCiM (CEL: lung cancerin 1/8) Brooks et al. (Cynomol- gus) 1992 Alpha Particles [239]Pu 109 Dog 2-22 min 7.02 (CEL: primary bone Gillett et al. (Beagle) uCi’kkg neoplasa in 30/66 dogs: 1987b osteosarcoma, Beta Particles hemangiosarcomas, [90]SrCI2 fibrosarcomas, myxosarcoma) 110 Dog once NS (CEL: 100/144 Gillett et al. (Beagle) osteosarcomas) 1988 Alpha Particles [238]PuO2 111 Dog once NS (CEL: 28/144 lung tumors) Gillett et al. (Beagle) 1988 Alpha Particles [238]Pu0O2 112 Dog once NS (CEL: lung tumors in Muggenburg et (Beagle) 47/144 dogs; al. 1994 bronchioalveolar Alpha Particles carcinomas & papillary [238]PUO2 adenocarcinomas) 113 Dog once NS (CEL: skeletal tumors in Muggenburg et (Beagle) 92/144; osteosarcomas) al. 1994 Alpha Particles [238]Pu0O2 SIVIHILVYN 3AILOVOIAVYH ANY NOILYIQYH WOHH S103443 HLTV3H d3AY3S80 8 NOILYIAVY4d DONIZINOI £82 «+ INTFWWOD 0118Nd HOH 14VHQ... Table 8-1. Observed Health Effects from Radiation and Radioactive Material: Inhalation (continued) Duration/ Entry Species Frequency of LOAEL Reference Number (strain) Administration System NOAEL Less serious Serious Chemical Form 114 Dog once NS (CEL: malignant liver Muggenburg et (Beagle) tumors in 13/144) al. 1994 Alpha Particles [238]Pu02 Bd Wt = body weight; Cardio = cardiovascular; CEL = cancer effect level; Con A = concanavalin A; d = day(s); decr = decrease; ECG = electrocardiograph; F = female; Gastro = gastrointestinal; Hemato = hematological; ILB = initial lung burden; incr = increase; LOAEL = lowest-observable-adverse-effect level, M = male; Metab = metabolism; min = minute(s); mo = month(s); NOAEL = no-observable-adverse-effect level; NS = not specified; PHA = phytohaemagglutinin; Resp = respiratory; skel = skeletal; TBLN = tracheobronchial lymph nodes; wk = week(s); yr = year(s); x = times SIVIHILVIN 3AILOVOIAQVYH ANY NOILYIavd WOHd S103443 HLTV3H A3AH3S80 8 NOILYIAYH ONIZINOI ¥8¢ ««INTFWWOD 2178Nd HOH 14VvHQa... Table 8-2. Observed Health Effects from Radiation and Radioactive Material: Oral Duration/ Frequency of LOAEL Entry Species/ Bon Reference Number (Strain) Route) System NOAEL Less Serious Serious Chemical Form Systemic 1 Human 4.7 yr Musc/skel 1,851 F Polednak and rad Famham 1980 (17-19 Alpha Particles yr age [226]Ra at expos.) 2 Human 4.7 yr Musc/skel 10,110 F Polednak and rad Famham 1980 (13-16 Alpha Particles yr age- [226]Ra at expos.) Reproductive 3 Mouse 2 wk 140rad (incr. embryo mortality) Ramaiya et al. (Hybrid) 1x/d 1994 Beta Particles [137]Cs 4 Mouse once 180rad (incr. post-implantation Ramaiya et al. (Hybrid) embryo mortality) 1994 Beta Particles [137]Cs 5 Mouse once 190 rad M (decreased fertility) Ramaiya et al. (Hybrid) 1994 Beta Particles [137]Cs SIVIH3LVYN 3AILOVOIAYYH ANV NOILYIAVYH WOYd S1O03443 HLTV3H d3AY3S80 ‘8 NOILVIAVH ONIZINOI S82 +INIFWWNOD J118Nd HOS L4VHQA... Table 8-2. Observed Health Effects from Radiation and Radioactive Material: Oral (continued) Duration/ Frequency of LOAEL Administration Entry Species/ (Specific Reference Number (Strain) Route) System NOAEL Less Serious Serious Chemical Form 6 Mouse 2 wk 350 rad M (reduced effective Ramaiya et al. (Hybrid) 1x/d mating) 1994 Beta Particles [137]Cs 7 Mouse once 100 rad M Ramaiya et al. (Hybrid) 1994 Beta Particles [137]Cs d = day(s); expos. = exposure; F = female; incr. = increase; LOAEL = lowest-observable-adverse-effect level; M = male; Musc/skel = musculoskeletal; NOAEL = no-observable-adverse-effect level; wk = week(s); yr = year(s) SIVIHILVIN 3AILOVOIAVYH ANV NOLLYIQYH WOHH S103443 HLTV3H d3AH3S80 ‘8 NOILYIAV4 ONIZINOI 982 «:LNJWWOD DIN8Nd HOS L4vHQ... Table 8-3. Observed Health Effects from Radiation and Radioactive Material: Dermal . LOAEL Duration/ Species/ Frequency of Reference (Strain) Administration gy giem NOAEL Less Serious Serious Chemical Form Systemic Hamster once Dermal 2000 rad (epilation) Garcia and (Syrian golden Shubik 1971 & white) Beta Particles [85]Kr Gn Pig once Dermal 3000 rep M (incr. vascular Song et al. 1968 (Albino) permeability) Beta Particles (90]Sr-[90]Y Cardio = cardiovascular; F = female; Gn pig = guinea pig; incr. = increase; LOAEL = lowest-observable-adverse-effect level; M = male; NOAEL = no-observable-adverse-effect level. SIVIH3LVIN 3AILOVOIAYH ANV NOILYIAYH WOHd S103443 HLTV3H Q3A4Y3S80 ‘8 NOILYIAv4 ONIZINOI 182 +:INIFWWOD O1718Nd HOH 14vHQ... Table 8-4. Observed Health Effects from Radiation and Radioactive Material: External Duration/ Frequency of LOAEL Entry Specles/ A on Reference Number (Strain) Route) System NOAEL Less Serious Serious Chemical Form Death 1 Rat once 10 rad M (1/9 died) Canfi et al. 1990 (Sprague- Gamma Ray Dawley) [192]ir 2 Mouse 3x/wk 150 rad F (13/21 died) Ootsuyama (ICR) <86 wk and Tanooka 1989 Beta Particles [90]Sr-[90]Y 3 Rat once 800 rad M (45% died through d 15) Salovsky and (Wistar) Shopova 1992 Gamma Ray NS 4 Human once 2250 rad M (death 13 d after exposure) Stavem et al. (occup) 1985 Gamma Ray Systemic 5 Pig once Resp 1280 rad F (severe thickening of Rezvani et al. (Large white) interlobular septa) 1989 Gamma Ray [60]Co 6 Rat once Resp 400 rad M (30% decr. in BALF LDH, Salovsky and (Wistar) 31% decr. in alkaline Shopova 1992 phosphatase, and 40% Gamma Ray decr. in acid NS phosphatase) STVIH3LYN JAILOVOIQYH ANY NOILYIQYH WOHS S103443 HLTV3H 3AH3SE0 ‘8 NOILVIAQVH ONIZINOI 882 «+INIJWWOD 0118Nd HOH 14VvHA... Table 8-4. Observed Health Effects from Radiation and Radioactive Material: External (continued) Duration/ Frequency of Administration LOAEL Entry Species/ (Specific Reference Number (Strain) Route) System Less Serious Serious Chemical Form 7 Human once Resp 2250 rad M (few mononuclear cells Stavem et al. (occup) and no granulocytes in 1985 resp. tract) Gamma Ray 8 Monkey 1.38 min Cardio 10,000 M (66% decr. blood pressure ~~ Cockerham et (Rhesus) rad 20 min post-exposure) al. 1986 Gamma Ray [60]Co 9 Human once Cardio 2250 rad M (hypertrophic ventricle) Stavem et al. (occup) 1985 Gamma Ray 10 Dog once Cardio 3000 rad M (focal area of Durakovic (Beagle) pervasculitis, reduction 1986a in LVEF) Gamma Ray [60]Co 11 Mouse 3-24 hr Gastro 2.5 rad/hr M (cell death in the crypts ljiri 1989 (Hybrid) of the small intestine Gamma Ray and descending colon) [137]Cs 12 Mouse once Gastro 1500 rad M (changes in villous Indran et al. (BALB/c) shape and reduction in 1991 height, tissue cell Gamma Ray disintegration) [60]Co 13 Human once Gastro 2250 rad M (atrophy of glands in Stavem et al. (occup) stomach, small 1985 intestine, and large Gamma Ray intestine; diarrhea) SIVIHILYIN IAILOVOIAYH ANY NOILYIQYH WOHH S103443 HLTV3H 3AH3S80 8 NOILYIAVYH ONIZINOI 682 «+ INIFWWOO 2178Nd HOH 14VHQA... Table 8-4. Observed Health Effects from Radiation and Radioactive Material: External (continued) Duration/ Frequency of LOAEL Administration Entry Specles/ "gp cific Reference Number (Strain) Route) System NOAEL Less Serious Serious Chemical Form 14 Monkey 1.38 min Hemato 10,000 M (arterial plasma histamine ~~ Cockerham et (Rhesus) rad level incr. 96.8- fold 2 min al. 1986 post-exposure) Gamma Ray [60]Co 15 Dog 150-300d Hemato 7.5 rad/d M (suppression/recovery Seed et al. 1989 (Beagle) 22 hr/d for granulocytes, Gamma Ray monocytes, leukocytes, [60]Co platelets, & erythrocytes) 16 Dog 150-300d Hemato 7.5rad/d F (suppression/recovery Seed et al. 1993 (Beagle) 22 hr/d for granulocytes, Gamma Ray monocytes, leukocytes, [60]Co platelets, & erythrocytes) 17 Mouse once Hemato 50 rad M (increase in proliferation Gidali et al. (hybrid) of femoral CFU-S, 1985 oscillation in Gamma Ray granulocytes and CFU-S) [60]Co 18 Human once Hemato * 159 rad M (decr. leukocyte, Klener et al. (occup) neutrophil, and 1986 lymphocyte counts) Gamma Ray [60]Co 19 Rat once Hemato 840 rad M (decrease in arachidonic Lognonne et al. (Sprague- acid incorporation into 1985 Dawley) membrane phospholipids Gamma Ray of platelets) [60]Co SIVIH3LVYA JAILOVOIAQYYH ANV NOILYIAYH WOH S103443 H1TV3H d3AH3S80 ‘8 NOILYIAVH ONIZINOI 062 «+«LNIJWWOD J178Nd HOH 14VHQA... Table 8-4. Observed Health Effects from Radiation and Radioactive Material: External (continued) Duration/ Frequency of LOAEL Administration Entry Species/ (Specific Reference Number (Strain) Route) System NOAEL Less Serious Serious Chemical Form 20 Human once Hemato 2250 rad M (decr. leukocyte count, Stavem et al. (occup) elevated serum 1985 creatinine, and Gamma Ray hypocellular bone marrow) 21 Mouse 0-177 min Hemato 12,000 F Hulse 1966 (CBA/H) rad Beta Particles [204]T1 22 Dog once Hepatic 400 rad M (signif. decrease in Durakovic (Beagle) SGOT) 1986b Gamma Ray [60]Co 23 Mouse once Hepatic 1000 rad M (incr. acid phosphatase Mazur et al. (Swiss) activity, decr. protein 1991 content) Gamma Ray [60]Co 24 Human once Renal 2250 rad M (anuria, enlarged Stavem et al. (occup) kidneys, and interstitial 1985 edema) Gamma Ray 25 Rat once Endocr 1.0 rad M (decr. in hypophyseal Canfi et al. 1990 (Sprague- and serum FSH) gamma ray Dawley) [192)ir 26 Human 2 mo-3 yr Endocr 200 rad M (decreased LH) Birioukov et al. 1993 Beta and Gamma SIVIH3LVYW 3AILOVOIAVYH ANV NOILYIAVH WOH S103443 HLTV3H 03AH3S80 8 NOILVIAVH ONIZINOI 162 +«LNIWWOD 2178Nd HOH 14VHJ... Table 8-4. Observed Health Effects from Radiation and Radioactive Material: External (continued) Duration/ Frequency of Administration LOAEL Entry Specles/ (Specific Reference Number (Strain) Route) System NOAEL Less Serious Serious Chemical Form 27 Rat once Endocr O.1rad M Canfi et al. 1990 (Sprague- gamma ray Dawley) [192]ir 28 Human once Dermal * 159 rad M (painful hard swelling of Klener et al. (occup) deep skin layers of hand 1986 resulting in amputation of Gamma Ray fingers) [60]Co 29 Human 2mo-3 yr Dermal 200 rad M (radiation dermatitis) Birioukov et al. 1993 Beta and Gamma 30 Gn Pig once Dermal 2200 rad M (hyperplastic epidermis) Etoh et al. 1977 (Albino) Beta Particles [90]Sr-[90]Y 31 Mouse 0-177 min ~~ Dermal 3000 rad F (radiation burns) Hulse 1966 (CBA/H) Beta Particles [204]TI 32 Pig 1x or 6x Dermal 12,000 (skin and skeletal muscle Lefaix et al. (Large white) rad ulcerations) 1993 Gamma Ray [192]ir 33 Human once Dermal * 159 rad M (reddening and Klener et al. (occup) inflammation of hand 1986 and epilation) Gamma Ray [60]Co SVIH3 LVN 3AILOVOIAVYH ANY NOILYIAVH WOYH S103443 HLIV3H d3AH3SE0 ‘8 NOILYIAVYd ONIZINOI c6e -+«INIFWWOD 2178Nd HO 14vHQ..s Table 8-4. Observed Health Effects from Radiation and Radioactive Material: External (continued) Duration/ Frequency of LOAEL Administration Entry Species/ (Specific Reference Number (Strain) Route) System NOAEL Less Serious Serious Chemical Form 34 Mouse 0-177 min Dermal 750 rad F (hair depigmentation and Hulse 1966 (CBA/H) hyperkeratotic areas) Beta Particles [204]TI 35 Mouse 0-177 min Dermal 1500 rad (slight erythema) Hulse 1966 (Albino) Beta Particles [204]T 36 Pig 1x or 6x Dermal 3200 rad (erythma) Lefaix et al. (Large white) 1993 Gamma Ray [(192]ir 37 Mouse 0-177 min ~~ Dermal 750 rad Hulse 1966 (Albino) Beta Particles [204]TI 38 Gn Pig once Dermal 1000 rad M Etoh et al. 1977 (Albino) Beta Particles [90]Sr-[90]Y 39 Pig 1x or 6x Dermal 1600 rad Lefaix et al. (Large white) 1993 Gamma Ray [192]ir 40 Human once Ocular 200rad (cataracts) Lipman et al. 1988 x-ray and beta SIVIH3ILVYA 3AILOVOIAVYH ANY NOILYIavH WOYH S103443 HLTV3H d3AH3S80 '8 NOILYIAV4d ONIZINOI £62 -+«LNIJWWOD O1N18Nd HO4 14vHQ... Table 8-4. Observed Health Effects from Radiation and Radioactive Material: External (continued) Duration/ Frequency of LOAEL Administration Entry Species/ (Specific Reference Number (Strain) Route) System NOAEL Less Serious Serious Chemical Form 41 Dog ped 2 Ocular 300rad (severe bilateral Schweitzer et (Beagle) degenerative retinal lesions al. 1987 in 99% of offspring) Gamma Ray [60]Co 42 Human once Ocular * 159 rad M (deterioration of visual Klener et al. (occup) acuity) 1986 Gamma Ray [60]Co 43 Human 2 mo-3 yr Ocular 200 rad M (vision impairment) Birioukov et al. 1993 Beta and Gamma 44 Rat Gd 13, 15 or Bd Wt 100 rad F Norton and (Sprague- 17 Kilmer 1988 Dawley) Gamma Ray [137]Cs 45 Rat Gd 15 Bd Wt 100 rad F Norton and (Sprague- Kimler 1990 Dawley) Gamma Ray [137]Cs 46 Rat Gd 20 Bd Wt 150 rad F Zaman et al. (Fischer- 344) 1992 Gamma Ray NS SIVIH3ILVIA 3AILOVOIAVYH ANV NOILYIavd WOHd S103443 HLTV3H A3AH3S80 8 NOILYIAVY ONIZINOI y62 «INIFWWOO 2178Nd HOH 14VvHQA... Table 8-4. Observed Health Effects from Radiation and Radioactive Material: External (continued) Duration/ Frequency of LOAEL Administration Entry Specles/ (Specific Reference Number (strain) Route) System NOAEL Less Serious Serious Chemical Form 47 Rat Gd 20 Bd Wt 150rad F Zaman et al. (Fischer- 344) 1993 Gamma Ray NS 48 Human once Metab * 159 rad M (irregular subfebrile Klener et al. (occup) temperatures) 1986 Gamma Ray [60]Co 49 Human once Metab 2250 rad M (fever) Stavem et al. (occup) 1985 Gamma Ray 50 Human 2 mo-3 yr Other 200 rad M (acute radiation sickness) Birioukov et al. 1993 Beta and Gamma Immunological/Lymphoreticular 51 Human once 2250 rad M (congestion and Stavem et al. (occup) hemorrhage of spleen) 1985 Gamma Ray 52 Mouse once 1000 rad M (decr. spleen wt & levels Mazur et al. (Swiss) of protein in spleen, incr. 1991 acid phosphatase Gamma Ray activity & activity of [60]Co beta- glucuronidase) SIVIHILVIA JAILOVOIAYH ANV NOILVIAvd WOH S103443 HLTV3H 3AH3SE0 8 NOILYIAV4 ONIZINOI s6c ++LNJWWOD 0118Nd HOH 14vHQ... Table 8-4. Observed Health Effects from Radiation and Radioactive Material: External (continued) Duration/ Frequency of LOAEL Ent Species! Administration N n A pecle (Specific Reference umber (Strain) Route) System NOAEL Less Serious Serious Chemical Form 53 Human once 2250 rad M (decr. number of Stavem et al. (occup) lymphocytes and 1985 hypocellular lymph Gamma Ray nodes) Neurological 54 Monkey 1.38 min 10,000 M (51 and 63% decr. blood Cockerham et (Rhesus) rad flow to reticular formation of al. 1986 pons & motor cortex, resp.) Gamma Ray [60]Co 55 Rabbit once 450 rad M (increased firing interval Bassant and (Burgundy in pyramidal cells) Court 1978 fawn) Gamma Ray [60]Co Reproductive 56 Mouse 10-50 wk 5 rad M (sperm abnormalities) Grahn and (B6C3F1) 1x/wk Cames 1988 20 min/x Gamma Ray [60]Co 57 Mouse 60 wk 5 rad M (sperm abnormalities) Grahn and (B6C3F1) 1x/wk Carnes 1988 20 min/x Gamma Ray [60]Co 58 Mouse 22-25d 80rad (incr. post-implantation Shevchenko et (NS) mortality in progeny) al. 1992 Gamma and beta SIVIHILYIN 3AILOVOIAVYYH ANY NOILYIAvd WOHd S103443 H1IV3H A3AH3S80 8 NOILYIAVd ONIZINOI 962 +«LNIWWOD O179Nd HOH 14VHA... Table 8-4. Observed Health Effects from Radiation and Radioactive Material: External (continued) Duration/ Frequency of LOAEL Administration Entry Species/ (Specific Reference Number (Strain) Route) System NOAEL Less Serious Serious Chemical Form 59 Human 2mo-3 yr 200 rad M (impotency, abnormal Birioukov et al. sperm, and decr. viability of 1993 spermatozoa) Beta and Gamma 60 Mouse once 300 rad (incr. total and Ramaiya et al. (Hybrid) post-implantation embryo 1994 mortality) Gamma Ray [137]Cs 61 Rat once 900 rad M (decr. testis wt, epididymal ~~ Pinon-Lataillade (Sprague- wt & epididymal content etal. 1991 Dawley) ABP & damaged Gamma Ray spermatocytes) (60]Co 62 Mouse 28 wk 1,128 rad (incr. pre- and post- Searle et al. (Hybrid) implantation loss) 1976 Gamma Ray [60]Co 63 Mouse 28 wk 1,128 rad M (85% reduced epididymal ~~ Searle et al. (Hybrid) sperm-count) 1976 Gamma Ray [60]Co 64 Rat once 1 rad M (25% decrease in fertility) Canfi et al. 1990 (Sprague- gamma ray Dawley) (192]ir 65 Mouse once 300 rad M (sterility and decr. fertility) Ramaiya et al. (Hybrid) 1994 Gamma Ray [137]Cs SIVIHILYN SAILOVOIAQYYH ANY NOILYIAVH WOHH S103443 HLTV3H 3AH3SE0 8 NOILYIAVYH ODNIZINOI 162 «+LNJWWOD 2178Nd HOH 14VHQ... Table 8-4. Observed Health Effects from Radiation and Radioactive Material: External (continued) Duration/ Frequency of LOAEL Administration Entry Species/ (Specific Reference Number (Strain) Route) System NOAEL Less Serious Serious Chemical Form 66 Mouse 22-25d 300 rad M (reversible sterility, Shevchenko et (NS) (environ) reduced testes mass) al. 1992 Gamma and beta 67 Mouse 28 wk 1,128 rad M (65% reduced testis Searle et al. (Hybrid) mass) 1976 Gamma Ray [60]Co 68 69 70 71 Developmental Rat once (Sprague- Dawley) Mouse Gd 11.5 (Swiss) Rat Gd 10 (Wistar) 3 sec Rat Gd 13, 15 or (Sprague- 17 Dawley) 1 rad'M (17% decr. pup weight at 25 rad 40 rad 75 rad weaning) (13.67% w/ microphthalmia; 2% decr. fetal head length and width; 5% decr. brain weight) (32.2% fetal mortality, 53 resorption sites) (decr. performance on functional tests; decr. motor activity PND 21; 11-23 % decr. thickness in 3 areas of cerebral cortex PND 21) Canfi et al. 1990 gamma ray [192)ir Devi et al. 1994 Gamma Ray [60]Co Roux et al. 1986 Gamma Ray [60]Co Norton and Kilmer 1988 Gamma Ray [137]Cs SIVIHILVA 3AILOVOIAYH ANY NOILYIAYH WOYH SL1O3443 HLTV3H Q3AY3S80 '8 NOILYIAVYd ONIZINOI 86¢ ++ LINTJWWOD 2178Nd HOH 14vHQ... Table 8-4. Observed Health Effects from Radiation and Radioactive Material: External (continued) Duration/ Frequency of LOAEL Entry Specles/ Administration Rel (Specific erence Number (Strain) Route) System NOAEL Less Serious Serious Chemical Form 72 Dog once 83 rad (premolar hypodontia) Lee et al. 1989 (Beagle) Gamma Ray [60]Co 73 Rat Gd 11or17 100rad (24% decr. body weight; Norton and (Sprague- 2 min decr. performance on reflex Kilmaer 1987 Dawley) suspension test; decr. Gamma Ray thickness of sensorimotor [437)cs cortex) 74 Mouse 7.5 min 150rad (exencephalia, cleft palate, Kusama and (ICR) open eyelid & paw Hasegawa 1993 malformations) Gamma Ray [137]Cs 75 Rat Gd 20 210rad (20% decr. body wt; 79% Suzuki et al. (Wistar) decr. testes, 72% ventral 1990 prostate, & 60% seminal Gamma Ray vesicle wits; disrupted [60]Co spermatogenesis & androgen production) 76 Rat Gd 13, 14, 400rad (31-79% decr. fetal survival) Koshimoto et (Wistar) or 15 al. 1994 Gamma Ray [137]Cs 77 Mouse Gd 12 400 rad F (clefts of the secondary Saad et al. 1991 (Swiss) palate) Gamma Ray [137]Cs NOILVIAQVH DNIZINOI SIVIH3ILVA JAILOVOIAQVYH ANV NOILYIAYH WOHH S103443 HLIV3H a3AH3SE0 8 662 «+ LNIWWNOD O118Nd HO4 14vHd... Table 8-4. Observed Health Effects from Radiation and Radioactive Material: External (continued) Duration/ Frequency of LOAEL Entry Specles/ Administration Referenc (Specific e Number (Strain) Route) System NOAEL Less Serious Serious Chemical Form 78 Mouse Gd 12 400 rad F (reduced litter size, head Saad et al. 1994 (Swiss) measurements, & incr. in Gamma Ray cleft palate) [137]Cs 79 Rat Gd 20 15 rad F (9-11 % decr. in pup Zaman et al. (Fischer- 344) relative cerebral cortex 1992 weight) Gamma Ray NS 80 Mouse Gd 11.5 50rad (1% incr. incidence of Devi et al. 1994 (Swiss) microphthalmia) Gamma Ray [60]Co 81 Rat Gd 15 50rad (incr. total no. pyknotic Norton and (Sprague- cells and no. of Kimler 1990 Dawley) macrophages in cortical Gamma Ray mantle; decr. no. mitotic [137]Cs figures in ventricular zone) 82 Rat 4or6d 56 rad F (13% decr. in brain Reyners et al. (Wistar) weight) 1991 Gamma Ray [60]Co 83 Rat Gd 13, 14, 100 rad (incr. ratio of large Koshimoto et (Wistar) or 15 hematocytes to small al. 1994 hematocytes) Gamma Ray [137]Cs SIVIHILV IAILOVOIAVH ANV NOILYIAvH WOHd S103443 HLTV3H Q3AH3SE0 8 NOILVIAVYH ONIZINOI 00€ Table 8-4. Observed Health Effects from Radiation and Radioactive Material: External (continued) +++LNIJWWOD O1718Nd HOH 14vHd... Duration/ Frequency of LOAEL Administration Ny Specles/ ~(gpecific Reference umber (Strain) Route) System NOAEL Less Serious Serious Chemical Form 84 Mouse Gd 14 100rad (9% decr. brain weight, Minamisawa et (C57BLS6) decr. area and length of al. 1990 cerebral hemispheres; Gamma Ray incr. area of superior [137]Cs colliculi and its proportion to cerebral hemisphere length) 85 Mouse Gd 14 100 rad (incr. no. of instances Minamisawa et (C57BL/6) 4-8 min of aggressive behavior in al. 1992 offspring; 16% decr. Gamma Ray offspring body weight at [137]Cs’ 3 mo of age) 86 Dog Gd 28 100rad (mild to moderate Schweitzer et (Beagle) degenerative retinal al. 1987 lesions in offspring) Gamma Ray [60]Co 87 Rat Gd 20 150 rad (altered pivoting, cliff Zaman et al. (Fischer- 344) avoidance and upper jaw 1993 tooth eruption in Gamma Ray offspring) NS 88 Dog Gd 55 160 rad (moderate to severe Schweitzer et (Beagle) bilateral degenerative al. 1987 retinal lesions in 75% of Gamma Ray offspring) [60]Co 89 Rat Gd 20 6.8rad F Zaman et al. (Fischer- 344) 1992 Gamma Ray NS STVIH3LVIN 3AILOVOIAVYYH ANV NOILYIAYH WOH S103443 HLTV3H A3AY3S80 8 NOILYIQVYH ONIZINOI L0€ ++ INJWWOD 0IN8Nd HOS 14YHQ... Table 8-4. Observed Health Effects from Radiation and Radioactive Material: External (continued) Duration/ Frequency of LOAEL Entry Species/ A eine" Reference Number (Strain) Route) System NOAEL Less Serious Serious Chemical Form 90 Rat Gd 20 6.8 rad Zaman et al. (Fischer- 344) 1993 Gamma Ray NS 91 Rat Gd 9.5 50 rad Bruni et al. 1994 (Sprague- 14-17 sec Gamma Ray Dawley) [60]Co 92 Rat Gd 20 NS (51-52% decr. body weight, Inano et al. istar 82% decr. testicular weight, 1989 (Wistar) - A 66% decr. ovarian weight) ~~ Gamma Ray [60]Co 93 Rat Gd 20 NS (decr. steroid hormone Inano et al. (Wistar) production) 1989 Gamma Ray [60]Co Cancer 94 Human NS 2.10rad (CEL: lung cancer) Mancuso et al. 1977 95 Human NS 2.10rad (CEL: pancreatic cancers) Mancuso et al. 1977 96 Human NS 2.10rad (CEL: myelomas) Mancuso et al. 1977 SIVIHILVYI 3AILOVOIAVYH ANV NOILYIAvd WOY4 S103443 HLTV3H 03AY3SE0 8 NOILYIAYYd ONIZINOI coe +++LNJWWOD O118Nd HOS L4vHAQ... Table 8-4. Observed Health Effects from Radiation and Radioactive Material: External (continued) Duration/ Frequency of LOAEL Admini i NontrY Speciles/ Tepe Reference umber (Strain) Route) System NOAEL Less Serious Serious Chemical Form 97 Human NS 15rad (CEL: estimated doubling Kneale et al. (occup) dose of cancers of 1981 radiosensitive tissues) Gamma Ray 98 Dog 10 min 16rad (CEL: cancers in 7 and Benjamin et al. (Beagle) neoplasms in 16 dogs out 1986 of 1,309; primarily Gamma Ray squamous papilloma of [60]Co eyelid) 99 Mouse 3x/wk 150 rad F (CEL: 23/96 Ootsuyama (ICR) <86 wk osteosaracomas, optimum and Tanooka dose for induction was 250 1989 to 350 cGy) Beta Particles [90]Sr-[90]Y 100 Mouse 0-177 min 1500 rad F (CEL: signif. incr. in benign Hulse 1966 (CBA/H) and malignant dermal Beta Particles tumors) [204]TI 101 Mouse 1 hr 2000 rad M (CEL: 20% skin tumor Charles et al. (SAS/4 incidence from 32 2-mm 1988 Albino) diameter source; 3% skin Beta Particles tumor incid. from 8 2-mm [(170]Th diam. source; 33% skin tumor incid. following uniform expos.) 102 Mouse 1 hr 2000 rad (CEL: (20% increase in Charles et al. (SAS/4 skin tumor incidence) 1988 Albino) Beta Particles [170]Th NOILYIAVH ONIZINOI SIVIH3LVIN SAILOVOIAYYH ANV NOILVIAYH WOYH S103443 HLIV3H 3AY3SE0 8 €0€ +.INTFWWOD 21N18Nd HOH 14vHQ... Table 8-4. Observed Health Effects from Radiation and Radioactive Material: External (continued) Duration/ Frequency of LOAEL Administration Entry Species/ (Specific Reference Number (Strain) Route) System NOAEL Less Serious Serious Chemical Form 103 Human NS 0-10 mSv (CEL: childhood cancers Sorahan and associated with paternal Roberts 1993 exposure to radionuclides) Ns 104 Human NS 0-10+ rem M (CEL: incr. lung cancer) Checkoway et y al. 1988 gamma and alpha [12)Y * The reported dose at a distant location on the body, so the actual dose to the effected tissue was probably much larger. BALF = bronchioalveolar lavage fluid; Bd Wt = body weight; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); decr = decrease, Endocr = endocrine; F = female; Gastro = gastrointestinal; Gd = gestational day; Gn pig = guinea pig; Hemato = hematological; hr = hour(s); incr = increase; LOAEL = lowest-observable-adverse-effect level; LVEF = left ventricular ejection fraction; M = male; Metab = metabolism; min = minute(s); mo = month(s); no. = number; NOAEL = no-observable-adverse-effect level; NS = not specified; occup = occupational; pcd = days post coitus; PND = post-natal day; Resp = respiratory; sec = second(s); SGOT = serum glutamic oxaloacetic transaminase; signif. = significant; wk = week(s); wt = weight; yr = year(s); x = times SIVIHILYW 3AILOVOIAVYH ANY NOILYIAYH WOHH S103443 HLTV3H A3AY3S80 8 NOILYIAVH ONIZINOI $0€ IONIZING RADIATION 305 9. GLOSSARY Absorbed Dose—The energy imparted by ionizing radiation per unit mass of irradiated material. The units of absorbed dose are the gray (Gy). (See also Rad, Gray, and Units, Radiological.) Absorbed Fraction—A term used in internal dosimetry. It is that fraction of energy radiated by the source organ that is absorbed by the target organ. For example, for '*'I in the thyroid (source organ), the absorbed fraction could be the fraction of gamma radiation absorbed in the liver (one of the target organs). Absorber—Any material that absorbs or lessens the intensity of ionizing radiation. Neutron absorbers (boron, hafnium, and cadmium) are used as material in control rods for reactors. Concrete, steel, and lead are typical absorbers for X-rays and gamma rays. A thin sheet of paper or metal will absorb or weaken alpha particles and all except the most energetic beta particles. Absorption—The process by which radiation imparts some or all of its energy to any material through which it passes. Absorption Ratio, Differential —The ratio of concentration of a nuclide in a given organ or tissue to the concentration that would be obtained if the same administered quantity of this nuclide were uniformly distributed throughout the body. Activation—The process of inducing radioactivity by neutron irradiation in a nuclear reactor. Activity—The number of nuclear transformations occurring in a given quantity of material per unit time. (See also Curie, Becquerel, and Units, Radiological, for more information on activity.) Activity Median Aerodynamic Diameter (AMAD)—The diameter of a unit density sphere with the same terminal settling velocity in air as that of the aerosol particulate whose activity is the median for the entire aerosol. Acute Exposure—An exposure to ionizing radiation for a duration of 2 days or less. Acute Radiation Syndrome—The symptoms which, taken together, characterize a person suffering from the effects of intense radiation. The effects occur within hours or weeks of exposure. ALARA—The acronym for “As Low As is Reasonably Achievable.” This term refers to the practice of making every effort to keep exposure to radiation as far below the dose limit as possible while still achieving the purpose for which radiation is licensed to be used. Alpha Particle—A charged particle emitted from the nucleus of certain radioactive atoms. An alpha particle has a mass of 4 atomic mass units (amu) and is equal in magnitude to that of a helium nucleus (i.e., two protons and two neutrons, and a charge of +2). Annihilation Radiation—The photons produced when an electron and a positron unite and cease to exist. The annihilation of a positron-electron pair results in the production of two photons, each of 0.51 MeV in energy (see pair production). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 306 9. GLOSSARY Annual Limit on Intake (ALI)—The derived limit for the amount of radioactive material taken into the body of an adult worker by inhalation or ingestion in a year. For a given radionuclide, ALI is defined as the smaller of the intakes that would result in a committed effective dose equivalent of 5 rems and a committed dose equivalent of 50 rems to any individual organ or tissue (See also Committed Effective Dose). Antineutrino— A neutral particle of rest mass near zero that is emitted during beta transformation (nucleus with a neutron excess) which occurs via the pathway by converting a neutron into a proton: n--->p + ¢ + anti-nu (¢), where n means neutron, p means proton, ¢” means electron, and anti-nu(e) means an antineutrino of the electron type. Artificial Radioactivity—The radioactivity produced by particle bombardment or electromagnetic irradiation in an accelerator or reactor and not existing in nature. Atomic Mass—The mass of a neutral atom of a nuclide, usually expressed in terms of "atomic mass units." The "atomic mass unit" is one-twelfth the mass of one neutral atom of carbon-12; equivalent to 1.6604x10%* gm. (Symbol: u) Atomic Mass Number—The total number of nucleons (neutron plus protons) in the nucleus of an atom. Atomic Number—The number of protons in the nucleus of an atom. The "effective atomic number" is calculated from the composition and atomic numbers of a compound or mixture. An element of this atomic number would interact with photons in the same way as the compound or mixture. (Symbol: Z). Atomic Weight—The weighted mean of the masses of the neutral atoms of an element expressed in atomic mass units. Background Radiation—Radiation resulting from cosmic rays and naturally occurring radioactive material. Background radiation is always present and its level can change with altitude and the amount of radioactive material present in soil and building materials. Becquerel (Bq)—A unit of measure for the quantity of radioactive material; one becquerel is that quantity of radioactive material in which one atom decays in one second. (See also Units, Radiological.) Beta Particle—A charged particle emitted from the nucleus of some radioactive atoms. A beta particle has a mass and charge equal in magnitude to that of the electron. The charge may be either +1 or -1. Bioassay—A determination of the kind, quantity, concentration, or location of radioactive material in the body by either direct measurement or the analysis and evaluation of materials excreted or removed from the body. Bone Seeker—Any compound or ion in the body that preferentially migrates into actively forming bone to become part of the hydroxy apetite mixture. Branching—The occurrence of two modes by which a radionuclide can undergo radioactive transformation. For example, 2'*Bi can undergo « or 6 transformation, %4Cu can undergo 6°, 6, or electron capture transformation. An individual atom of a nuclide exhibiting branching disintegrates by one mode only. The fraction disintegrating by a particular mode is the "branching fraction" for that mode. The "branching ratio" is the ratio of two specified branching fractions (also called multiple transformation or disintegration). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 307 9. GLOSSARY Bremsstrahlung—Electromagnetic radiation (photons) produced by the negative acceleration that a fast charged particle (usually an electron) undergoes from the effect of an electric or magnetic field, for instance, from the field of another charged particle (usually a nucleus). Bremsstrahlung is emitted when beta particles or electrons are stopped by a shield. Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces significant increases in the incidence of cancer (or tumors) between the exposed population and its appropriate control. Carcinogen—A chemical capable of inducing cancer. Carcinoma—A malignant neoplasm composed of epithelial cells, regardless of their derivation. Cataract—A clouding of the crystalline lens of the eye that obstructs the passage of light. Chronic Exposure—An exposure to ionizing radiation for 365 days or more, as specified in the ATSDR toxicological profiles. Collective Dose—The sum of the individual doses received in a given period of time by a specified population from exposure to a specified source of radiation, in units such as person * rems or person * Sv. Committed Dose Equivalent (H,;))—The dose equivalent to organs or tissues of reference (T) that will be received from an intake of radioactive material by an individual during the 50-year period following the intake. Committed Effective Dose—The International Commission for Radiological Protection (ICRP) term for committed effective dose equivalent. (See Committed Effective Dose Equivalent.) Committed Effective Dose Equivalent (Hys,)—The sum of the products of the weighting factors applicable to each of the body organs or tissues that are irradiated and the committed dose equivalent to the organs or tissues (His = },WiHys,). The committed effective dose equivalent is used in radiation safety because it implicitly includes the relative carcinogenic sensitivity of the various tissues. Compton Scattering—An attenuation process observed for X or gamma radiation in which an incident photon interacts with an orbital electron of an atom to produce a recoil electron and a scattered photon of energy less than the incident photon. Contamination, Radioactive—The deposition of radioactive material in any place where it is not desired. Cosmic Rays—High-energy particulate and electromagnetic radiations that originate outside the earth's atmosphere. Count (Radiation Measurements)—The external indication of a radiation-measuring device designed to enumerate ionizing events. It may refer to a single detected event or to the total number registered in a given period of time. This term can be used with equipment and geometry efficiencies to quantifiy the rate of transformation of ionizing events. “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 308 9. GLOSSARY Counter—A general description applied to radiation detection instruments or survey meters that detect and measure radiation. The signal that announces the detection of an ionization event is called a count. (See also Counter, Geiger-Mueller and Counter, Scintillation.) Counter, Geiger-Mueller—A highly sensitive, gas-filled radiation-measuring device that responds to individual ionizing particles. Counter, Scintillation—The combination of phosphor, a photmultiplier tube, and associated circuits for counting light emissions produced in the phosphors by ionizing radiation. Cumulative Dose—The total dose resulting from repeated exposures of radiation to the same region of the body, or to the whole body, over a period of time. (See Also Weighting Factor.) Curie (Ci) The quantity of radioactive material in which 37 billion transformations occur per second, which is approximately the activity of 1 gram of radium. Radium decays at a rate of 1.36 x 10"! grams/second. Decay Constant—See transformation constant. Decay Product (Daughter Product, Progeny)—Isotopes that are formed by the radioactive transformation of some other isotope. In the case of ***Ra, for example, there are 10 successive daughter products or progeny, ending in the stable isotope **°Pb. Decay, Radioactive—Transformation of the nucleus of an unstable nuclide by spontaneous emission of charged particles and/or photons. Deep Dose Equivalent (H,)—The dose equivalent at a tissue depth of 1 cm from external whole-body radiation. Delayed Health Effects—The health effects that manifest themselves after an extended period. Derived Air Concentration (DA C)—The concentration of a given radionuclide in the air which, if breathed by the reference man for one working year (2,000 hours) under conditions of light work, results in an intake of one ALL Detector—A material or device that is sensitive to radiation and can produce a response signal suitable for measurement or analysis. Deterministic Effects—Health effects for which there exists a definite threshold and which become more severe as the dose is increased. The dose response curve is sigmoid-shaped. Examples of deterministic effects are acute radiation syndrome and cataracts (previously referred to as non-stochastic effects) Developmental Toxicity—The occurrence of adverse effects on a developing organism that may result from exposure to a chemical or to ionizing radiation prior to conception (either parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the life span of the organism. Decay Constant—(see transformation constant) Disintegration, Nuclear—A spontaneous nuclear transformation (radioactivity) characterized by the emission of energy and/or mass from the nucleus. When large numbers of nuclei are involved, the process is characterized by a definite half-life. (See also Transformation, Nuclear.) **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 309 9. GLOSSARY Dose (or Radiation Dose)—A general term denoting the quantity of radiation or energy absorbed. A generic term meaning absorbed dose, dose equivalent, effective dose equivalent, committed dose equivalent, committed effective dose equivalent, or total effective dose equivalent. For special purposes it must be appropriately qualified. If unqualified, it refers to the absorbed dose. Dose Assessment—An estimate of the radiation dose to an individual or a population group usually by means of predictive modeling techniques, often supplemented by the results of measurement. Dose Conversion Factor—A factor (Sv/Bq or rem/Ci) that is multiplied by the intake quantity of a radionuclide (Bq or Ci) to estimate the committed dose equivalent from radiation (Sv or rem). The dose conversion factor depends on the route of entry (inhalation or ingestion), the lung clearance class (D, W, or Y) for inhalation, the fractional uptake from the small intestine to blood (f1) for ingestion, and the organ of interest. EPA provides separate dose conversion factor tables for inhalation and ingestion, and each provides factors for the gonads, breast, lung, red marrow, bone surface, thyroid, remainder, and effective whole body. Dose Equivalent (DE)—A quantity used in radiation protection. It expresses all radiations on a common scale for calculating the dose for purposes of radiation safety. It is defined as the product of the absorbed dose in rads and certain modifying factors. (The unit of dose equivalent is the rem. In SI units, the dose equivalent is the sievert, which equals 100 rem.) Dose, Fractionation—A method of dividing the radiation dose into fractions that are administered over a period of time. Dose, Radiation—The amount of energy imparted to matter by ionizing radiation per the unit mass of matter, usually expressed as the unit rad, or in SI units, 100 rads = 1 Gy (See also Absorbed Dose.) Dose Rate—The radiation dose delivered per unit time. The rate can be measured, for example, in Sieverts per hours or in rem per hour. Dosimetry—Quantification of radiation doses to individuals or populations resulting from specified exposures. Early Effects (of radiation exposure)—Effects which appear within 60 days of an acute exposure. Effective Dose (50 %)—The dose at which one would expect 50% of a population to have a predicted response to a drug or chemical. Effective Dose Equivalent (Hg)—The sum of the products of the dose equivalent to the organ or tissue (H) and the weighting factors (Wy) applicable to each of the body organs or tissues that are irradiated (HE = YW:Hy). The effective dose equivalent recognizes the carcinogenic radiosensitivity of the several different tissues of the body. Effective Half-Life (also effective half-time)—The time required for a radioactive element in an animal body to be diminished 50% as a result of the combined action of radioactive transformation and biological elimination. It is described by the following equation: Effective Half-Life = (Biological half-life x radioactive half-life) / (biological half-life + radioactive half-life). ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 310 9. GLOSSARY Electron—A stable elementary particle having an electric charge equal to +1.60210 x 10" Coulombs (C), and a rest mass equal to 9.1091 x 10?! kg. A positron is a positively charged "electron." (See Positron.) Electron Capture—A mode of radioactive transformation involving the capture of an orbital electron by its nucleus. Capture from a particular electron shell is designated as "K-electron capture," "L-electron capture,” and so on. The atom then emits X-rays. Electron Volt—A unit of energy equivalent to the energy gained by an electron in passing through a potential difference of one volt. It is the energy unit for an ionizing particle or photon often expressed as keV for thousand or kilo electron volts or MeV for million or mega electron volts. (symbolized: eV, as in 1eV=1.6x10"erg.) Embryo/Fetus—The developing human (or animal) from the time of conception up to the time of birth. Embryotoxicity and Fetal toxicity—Any toxic effect on the conceptus as a result of prenatal exposure to ionizing radiation a chemical; the distinguishing feature between the two terms is the stage of development during which the insult occurred. The terms, as used here, include malformations and variations, altered growth, and in utero death. Enriched Material—(1) Any material in which the relative amount of one or more isotopes of a constituent has been increased. (2) Uranium in which the percentage of *°U to total uranium of all isotopes is increased from 0.72% to a higher value. Equilibrium Fraction (F)— The fraction of radon-decay products present in air compared to unity, where unity represents complete radioactive equilibrium between the parent radionuclide and the decay products. The equilibrium fraction is used to estimate working levels based on measurement of radon only. Equilibrium, Radioactive—In a radioactive series, the state that prevails when the ratios between the activities of two or more successive members of the series remain constant. Excitation Energy—The energy required to change a system from its ground state to an excited state. Each different excited state has a different excitation energy. Excitation—The addition of energy to a system, thereby transferring it from its ground state to an excited state. Excitation of a nucleus, an atom, or a molecule can result from absorption or scattering of photons or from inelastic collisions with particles. The excited state of an atom is a metastable state and will return to the ground state by radiation of the excess energy. Exposure—A measure of the intensity of an X-ray or gamma ray field in air, whose value depends on the ionization produced in air by X or gamma radiation. External Dose—The amount of energy, expressed per unit mass of matter, imparted to an organism by ionizing radiation from a source outside the body. External Radiation—Radiation from a source outside the body; the radiation must penetrate the skin to produce biological damage. Eye Dose Equivalent—The dose of radiation received by the lens of the eye which is at a depth of 0.3 cm below the outside surface (cornea) of the eye, delivered by an external radiation source. **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 311 9. GLOSSARY Fission, Nuclear—A nuclear transformation characterized by the splitting of a nucleus into two or three other nuclei and two or three neutrons, and the release of a relatively large amount of energy. Gamma Ray—A short wavelength electromagnetic radiation of nuclear origin (range of energy from 10 keV to 9 MeV). Genetic Effect of Radiation—An inheritable change, chiefly mutations, produced by the absorption of ionizing radiation by germ cells. Gray (Gy)—The SI unit of the absorbed dose. One Gy equals the absorption of 1 joule of energy (about 1/4 of a calorie) per kilogram of absorber. One gray equals 100 rad. (See also Units.) Half-Life, Radioactive—The time required for a radioactive substance to lose 50% of its activity by transformation. Each radionuclide has a unique half-life. Half-Life, Biological (or biological half-time)—The time required for the body to eliminate one-half of any absorbed substance by regular physiological processes of elimination. It is the same for both stable and radioactive isotopes of a particular element. This is sometimes referred to as a biological half-time. ‘Half-Life, Effective—The time required for a radioactive element in an animal body to be diminished 50% as a result of the combined action of radioactive transformation and biological elimination. Half-Time (see Half-Life, Biological) High-LET—The characteristic ionization patterns by alpha particles, protons, or fast neutrons having a high relative specific ionization per unit path length. Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from exposure to agents such as radiation or chemicals. In Vitro—The condition of being isolated from a living organism and artificially maintained, as in a test tube. In Vivo—Any condition occurring within a living organism. Induced Radioactivity—The radioactivity produced in a substance after bombardment with neutrons or other particles. The resulting activity is “natural radioactivity” if formed by nuclear reactions occurring in nature, and “artificial radioactivity” if the reactions are caused by humans. Intensity—The amount of energy per unit time passing through a unit area perpendicular to the line of propagation at the point in question. Intermediate Exposure—An exposure to radiation for a duration of 3-364 days. Internal Conversion—One of the possible mechanisms of transformation from the metastable state (isomeric transition) in which the transition energy is transferred to an orbital electron, causing its ejection from the atom. The ratio of the number of internal conversion electrons to the number of gamma quanta emitted in the de-excitation of the nucleus is called the "conversion ratio." Internal Radiation— Radiation from radionuclides inside the body. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 312 9. GLOSSARY Ton—An atomic particle, atom or chemical radical bearing a net electrical charge, either negative or positive. Ton Pair—Two particles of opposite charge, usually referring to the electron and positive atomic or molecular residue resulting after the interaction of ionizing radiation with the orbital electrons of atoms. Ionization—The process by which a neutral atom or molecule acquires a positive or negative charge. Also the process by which ioniizng radiation (photons or particles) remove electrons from an atom. Ionizing Energy—The average energy lost by ionizing radiation in producing an ion pair. For air, the ionizing energy is about 33.73 eV. Ionizing Density—The number of ion pairs per unit volume. Ionization Path (Track)—The trail of ion pairs produced by ionizing radiation in its passage through matter. Ionization Potential —The energy, in electron-volts (eV) necessary to separate one electron from an atom, resulting in the formation of an ion pair. Ionizing Radiation—Any electromagnetic or particulate radiation capable of producing ions, directly or indirectly, in its passage through matter. Isotopes—Any nuclide of the same element having the same number of protons in their nuclei, and hence the same atomic number, but differing in the number of neutrons and therefore in the mass number. Almost identical chemical properties exist between isotopes of a particular element, but physical properties such as diffusion through a membrane may differ. This term should not be used as a synonym for nuclide. Joule—The unit for work and energy, equal to one newton expended along a distance of one meter (17 =IN x Im). There are 4.2 joules per calorie Kerma (k)—This term stands for kinetic energy released to matter. It is the sum of the initial kinetic energies of all the charged ionized particles liberated by uncharged ionizing particles in a mall of material, expressed as ergs/g (J/Kg). The special name of this unit is the rad (Gy). Labeled Compound—A compound consisting, in part, of labeled molecules. These are molecules including radionuclides in their structure. By observations of radioactivity or isotopic composition, this compound or its fragments may be followed through physical, chemical, or biological processes. Late Effects (of radiation exposure)—Any effects that appear 60 days or more following an acute exposure. Lethal Doses, (LD5y)—The dose of radiation or a chemical that has been found to cause death in 50% of a defined experimental animal population. Lethal Dose, 3, (LDs,30)—7The dose of radiation or a chemical which kills 50% of the population within 30 days. Linear Energy Transfer (LET)—The average amount of energy transferred locally to the medium per unit of particle track length. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 313 9. GLOSSARY Linear Hypothesis or Linear No Threshold (LNT) Hypothesis—The assumption that a dose-effect curve derived from data in the high dose and high dose-rate ranges may be extrapolated linearly through the low dose and low dose-rate ranges to zero, implying that, theoretically, any amount of radiation will cause some damage. Low-LET—The characteristic ionization patterns of electrons, X-rays, and gamma rays having a low relative specific ionization per unit path length compared to high LET. Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest dose of chemical in a study, or group of studies, that produces statistically or biologically significant increases in the frequency or severity of adverse effects between the exposed population and its appropriate control. Malformations—Any permanent structural changes that may adversely affect survival, development, or function. Mass Absorption Coefficient—The linear absorption coefficient per centimeter divided by the density of the absorber in grams per cubic centimeter. This is the fraction of incident radiation that is absorbed per unit mass of the absorber. Mass Numbers—The number of nucleons (protons and neutrons) in the nucleus of an atom. (Symbol: A) Maximum Permissible Dose Equivalent (MPD)—The greatest dose equivalent that a person or specified part of a person shall be allowed to receive in a given period of time. Median Lethal Dose (MLD)—The dose of radiation required to kill 50% of the individuals in a large group of animals or organisms within a specific period, usually 30 days. Also called LD; Megacurie—One million curies. Symbolized as MCi. Microcurie—One-millionth of a curie (3.7x10*) transformations per second. Symbolized as pCi. Millicurie—One-thousandth of a curie (3.7x107 transformations per second. Symbolized as mCi. Minimal Risk Level (MRL)—An estimate of daily human exposure to a dose of radiation or a chemical that is likely to be without an appreciable risk of adverse noncancerous effects over a specified duration of exposure. Monoenergetic Radiation—Radiation of a given type (alpha, neutron, gamma, etc.) in which all particles or photons originate with the same energy. Mutagen—A substance that causes mutations. Mutation—A mutation is a change in the genetic material in a body cell. Mutations can lead to birth defects, miscarriages, or cancer. Nanocurie—One-billionth of a curie. Symbolized as nCi. Natural Radioactivity—The property of radioactivity exhibited by more than 50 naturally occurring radionuclides. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 314 9. GLOSSARY Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to radiation or a chemical. Neutrino—A neutral particle of very nearly zero rest mass emitted during the beta-decay process. Non-deterministic Effects (stochastic effects) —Health effects which appear to be related to random events and not assumed to be a linear function of the dose. No-Observed-Adverse-Effect Level (NOAEL)—The dose of radiation or a chemical that produces no statistically or biologically significant increases in frequency or severity of adverse effects seen between the exposed population and its appropriate control. Effects may be produced at this dose, but they are not considered to be adverse. Nucleon—Generic name for a constituent particle of the nucleus. Applied to a proton or neutron. Nuclide—A species of atom characterized by the constitution of its nucleus. The nuclear constitution is specified by the number of protons (Z), number of neutrons (N), and energy content; or, alternatively, by the atomic number, (Z) mass number A =(N+Z), and atomic mass. To be regarded as a distinct nuclide, the atom must be capable of existing for a measurable time. Thus, nuclear isomers are separate nuclides, whereas promptly decaying excited nuclear states and unstable intermediates in nuclear reactions are not considered separate nuclides. Pair Production—An absorption process for X-ray and gamma radiation in which the incident photon is annihilated in the vicinity of the nucleus of the absorbing atom, and its energy is converted into an electron and positron pair. This reaction only occurs for incident photon energies exceeding 1.02 MeV, which is the energy equivalence of the masses of the positron and electron. Parent Radionuclide—A radionuclide which, upon transformation, yields a specified nuclide, either directly or as a later member of a radioactive series. Photoelectric Effect—An attenuation process observed for X-ray and gamma radiation in which an incident photon knocks out an orbital electron of an atom delivering all of its energy to produce a recoil electron, but with no scattered photon. Photon—A quantity of electomagnetic radiation whose energy content depends on the frequency or wavelength of the radiation. The equation is: E=hv. Photon energy for ionizing radiation purposes is usually measured in eV, keV and MeV. Picocurie—One- trillionith of a curie (3.7x10 transformations per second or 2.22 transformations per minute). Symbolized as pCi. Positron—A particle equal in mass to the electron (9.1091x10”' kg) and having an equal but positive charge (+1.60210x10" Coulombs). (See also Electron). Primary Ionization—(1) In collision theory, the ionization produced by the primary particles (photoelectron, Compton electron, or positron-electron pair) as contrasted with the total ionization, which includes the secondary ionization produced by delta rays; (2) In counter tubes, the total ionization produced by incident radiation without gas amplification. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 315 9. GLOSSARY Progeny—The transformation products resulting after a series of radioactive decays. Progeny can also be radioactive, and the chain continues until a stable nuclide is formed. Proton—An elementary nuclear particle with a positive electric charge equal numerically to the charge of the electron and a rest mass of 1.007277 atomic mass units. Public Dose—The dose received by a member of the public from exposure to radiation caused by a licensee or to any other source of radiation under the control of a licensee, excluding background and occupational doses. Quality—A term describing the distribution of the energy deposited by a particle along its tract; radiations that produce different densities of ionization per unit track length are said to have different qualities. Quality Factor (Q)—The linear-energy-transfer-dependent factor by which absorbed doses are multiplied to obtain (for radiation protection purposes) a quantity that expresses the biological effectiveness of the absorbed dose on a common scale for all ionizing radiation. Rad—The unit of absorbed dose equal to 0.01 J/kg in any medium. (See also Absorbed Dose.) Radiant Energy—The energy of electromagnetic radiation, such as radio waves, visible light, X- and gamma rays. Radiation—(1) The emission and propagation of energy through space or through a material medium in the form of waves: for instance, the emission and propagation of electromagnetic waves, or of sound and elastic waves. (2) The energy propagated through space or through a material medium such as waves; for example, energy in the form of electromagnetic waves or of elastic waves. The term radiation or radiant energy, when unqualified, usually refers to electromagnetic radiation. Such radiation commonly is classified, according to frequency, as with Hertzian, infrared, visible (light), ultraviolet, X-ray and gamma ray. (See also Photon.) (3) By extension, corpuscular emission, such as alpha and beta radiation, or rays of mixed or unknown type, such as cosmic radiation. Radioactivity—The property of certain nuclides to spontaneously transform into another element by emitting alpha or beta particles. Radioisotopes—A radioactive atomic species of an element with the same atomic number and usually identical chemical properties. Radionuclide—A radioactive species of an atom characterized by the constitution of its nucleus. Radiosensitivity—The relative susceptibility of cells, tissues, organs, organisms, or any living substance to the injurious action of radiation. Radiosensitivity and its antonym, radioresistance, are currently used in a comparative sense, rather than in an absolute one. Reaction (Nuclear)—An induced nuclear transformation (i.e., a process occurring when a nucleus comes in contact with a photon, an elementary particle, or another nucleus). In many cases, the reaction can be represented by the symbolic equation: X+a-Y+b or, in abbreviated form, X(a,b) Y, where X is the target nucleus, a is the incident particle or photon, b is an emitted particle or photon, and Y is the product nucleus. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 316 9. GLOSSARY Reference Man —A theoretical human male on which dosimetry calculations related to ionizing radiation exposure are based. Reference man is 70 kg and consists of detailed organ mass data for all major human body organs. Models, which can be other than 70 kg, are also available for different ages and for females (pregnant and non-pregnant). ; Relative Biological Effectiveness (RBE)—The RBE is a factor used to compare the biological effectiveness of absorbed radiation doses (i.e., rad) due to different types of ionizing radiation. More specifically, it is the experimentally determined ratio of an absorbed dose of a radiation in question to the absorbed dose of a reference radiation required to produce an identical biological effect in a particular experimental organism or tissue. (See also Quality Factor.) Rem—A unit of dose equivalent. The dose equivalent in rem is numerically equal to the absorbed dose in rad multiplied by the quality factor. It is used only in the context of radiation safety, administrative, and engineering design purposes. Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result from exposure to radiation or a chemical. The toxicity may be directed to the reproductive organs and/or the related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of this system. Roentgen (R)—A unit of exposure to photon radiation whose energy <3 MeV. One roentgen generates 2.58x10* Coulomb of charge per kilogram of air at standard temperature and pressure (0 °C, 1 atm). Scattered Radiation—Radiation that, during its passage through a substance, has been deviated in direction. It may also have been modified by a decrease in energy. Scientific Units Prefix (Symbol) Power of 10 Decimal Equivalent atto (a) 1078 0.000000000000000001 femto (f) 101 0.000000000000001 pico (p) 1012 0.000000000001 nano (n) 10° 0.000000001 micro (pu) 10° 0.000001 milli (m) 1073 0.001 centi (c) 102 0.01 deci (d) 10! 0.1 kilo (k) 10° 1,000.0 mega (M) 10° 1,000,000.0 giga (G) 10° 1,000,000,000.0 tera (T) 10"? 1,000,000,000,000.0 peta (P) 10% 1,000,000,000,000,000.0 exa (E) 10" 1,000,000,000,000,000,000.0 ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 317 9. GLOSSARY Secondary Radiation—Radiation that results from absorption of other radiation in matter. It may be either electromagnetic or particulate. Secular Equilibrium—If a parent element has a much longer half-life than its progeny (so that there is no appreciable change in its amount in the time interval required for later products to attain equilibrium), then after equilibrium is reached, equal numbers of atoms of all members of the series that are in equilibrium transform in unit time. This also means that each has the same activity measured in curies. This condition is never exactly attained, but is essentially established after 6 or 7 daughter half-lives. For example, the half- life of radium is about 1,600 years; of radon, approximately 3.82 days; and for each of the subsequent members, a few minutes. After about a month, the equilibrium amount of radon is present; then (and for a long time) all members of the series transform at the same number of atoms per unit time. Self-Absorption—The absorption of radiation (emitted by radioactive atoms) by the material in which the atoms are located (in particular, the absorption of radiation within a sample being assayed). Shallow Dose Equivalent (Hg)—The dose equivalent at a tissue depth of 0.007 cm averaged over an area of 1 cm? from external exposure of the skin or an extremity. SI Units—The International System of Units as defined by the General Conference of Weights and Measures in 1960. These units are generally based on the meter/kilogram/second units, with special quantities for radiation including the becquerel, gray, and sievert. Sickness, Radiation —(1) A syndrome characterized by nausea, vomiting, diarrhea, and psychic depression following exposure to appreciable doses of ionizing radiation within a short period of hours to weeks. Its mechanism is known, and remedies include fluid replacement, antibiotics, electrolyte replacement, and in some cases, marrow stem cell support. It usually appears a few hours after irradiation and may subside within a day. In nuclear medicine applications, it may be sufficiently severe to necessitate interrupting the treatment series or to incapacitate the patient. (2) The syndrome associated with intense acute exposure to ionizing radiations. The rapidity with which symptoms develop is a rough measure of the level of dose. Sievert—The SI unit of radiation dose equivalent. It is equal to dose in grays times a quality factor; 1 sievert equals 100 rem. Somatic Effects—Effects of radiation limited to the exposed individual, as distinguished from genetic effects, which may subsequently affects unexposed generations. Specific Activity—The total activity of a given nuclide per gram of an element. It is a measure of the concentration of radioactivity, which may be expressed as pCi/gram, Bq/m?, etc. Stable Isotope—A nonradioactive isotope of an element. Standard Mortality Ratio (SMR)—The ratio of the disease or accident mortality rate in a certain population compared with that in a standard population. The SMR is usually expressed in percent. Thus, an SMR is the mortality rate for the standard population. Stopping Power—The average rate of energy loss of a charged particle per unit thickness of a material or per unit mass of material traversed as a result of Coulomb interactions with electrons and with atomic nuclei. Stochastic effects—See Non-Deterministic Effects. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 318 9. GLOSSARY Surface-seeking Radionuclide—A bone-seeking radioactive material that is deposited and remains on the surface for a long period of time. This contrasts with a volume seeker, which deposits more uniformly throughout the bone volume. Target Theory (Hit Theory)—A theory explaining some biological effects of radiation on the basis that ionization, occurring in a discrete volume (the target) within the cell, directly causes a lesion that subsequently results in a physiological response to the damage at that location. One, two, or more "hits" (ionizing events within the target) may be necessary to elicit the response. Teratogen—Radiation or a chemical that can lead to birth defects. Tissue Dose—The absorbed dose received by tissue in the region of interest, expressed in Gray or rad. (See also Dose and Rad.) Total Effective Dose Equivalent (TEDE)—The sum of the deep dose equivalent (from external exposures) and the committed effective dose equivalent (from internal exposures). Total Ionization—The total electric charge of one sign on the ions produced by radiation in the process of losing its kinetic energy. For a given gas, the total ionization is closely proportional to the initial ionization, and is nearly independent of the nature of the ionizing radiation. It is frequently used as a measure of radiation energy absorbed per unit mass of gas. Total Organ Dose Equivalent (TODE)—The sum of the dose equivalent to an organ or tissue from external radiation and the committed dose equivalent to that organ or tissue from radioactive materials deposited within the body. Transformation Constant—The fraction of the number of atoms of a radioactive nuclide that transforms in unit time. A is the symbol for the transformation constant in the equation N=Nye*, where Nj, is the initial number of atoms present, and N is the number of atoms present after some time, t. Transformation, Nuclear—The process by which a nuclide is transformed into a different nuclide by absorbing or emitting a particle. Transient Equilibrium—If the half-life of the parent is short enough, so that the quantity present decreases appreciably during the period under consideration, but is still longer than that of successive members of the series, a stage of equilibrium will be reached after which all members of the series decrease in activity exponentially with the period of the parent. An example of this is radon (half-life of approximately 3.82 days), and successive members of the series to 2!°Pb. Transition, Isomeric—The process by which an excited nuclide decays to the ground state to produce an isomeric nuclide (i.e., one of the same mass number and atomic number) by the emission of a gamma ray. Tritium—The hydrogen isotope with one proton and two neutrons in the nucleus (Symbol: *H or T). Tritum is radioactive, with a half-life of 12.3 years; it emits very low energy beta particles. Unattached Fraction—That fraction of the radon daughters, usually 2'*Po (Radium A), that has not yet electrostatically attached to an airborne dust particle. As a free atom, it has a high probability of being retained within the lung and depositing alpha energy when it decays. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 319 9. GLOSSARY Units, Radiological Units Equivalents becquerel* 1 Bq = 1 transformation or disintegration per second = 2.7x10"" Ci curie 1 Ci = 3.7x10'° transformations or disintegrations per second = 3.7x10'° Bq gray* 1 Gy = 1J/kg = 100 rad rad 1 rad = 100 erg/g = 0.01 Gy sievert* 1 Sv =100 rem rem 1 rem = 0.01 sievert *International Units are designated as (SI). Weighting Factor (W,)—A dosimetric factor used in the practice of health physics (radiation safety) to account for the relative carcinogenic susceptibility of the various tissues. Whole Body—For the purposes of radiation exposure, the part of the body composed of the head, trunk, arms above the elbow, legs above the knee, and gonads. Working Level (WL)—A unit for measuring the atmospheric concentration of radon progeny. It corresponds to the equilibrium concentration of radion progeny due to 100 pCi radon per liter of air, or any combination of short-lived radon daughters in 1 liter of air that will result in the ultimate emission of 1.3x10° MeV of potential alpha energy. Working Level Month (WLM)—Inhalation of air with a concentration of 1 WL of radon daughters for 170 working hours results in an exposure of 1 WLM. X-rays—Penetrating electromagnetic radiations whose wave lengths are shorter than those of visible light. X-rays can be deliberately produced in X-ray machines, or are produced incidentally as bremsstrahlung whenever highly energetic beta rays or electrons are stopped in radiation shielding. These rays are sometimes called roentgen rays after their discoverer, W.C. Roentgen. **DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION 321 10. REFERENCES *Aarkrog. 1971. Environmental behavior of plutonium accidentally released at Thule, Greenland. Health Physics. 32:271-284. * Abraham SK, Sarma L, Kesavan PC. 1993. Protective effects of chlorogenic acid, curcumin and beta-carotene against gamma-radiation-induced in vivo chromosomal damage. Mutat Res 303(3):109-112. * Academy of Health and Science. 1995. Medical aspects of nuclear weapons and their effects on medical operations. United States Army, Subcourse MED477. (Retrieval in progress) *ACHRE. 1995. The uranium miners. Final report, Advisory Committee on Human Radiation Experiments. Chapter 12, section 2. (http://nattie.eh.doe.gov/systems/hrad/chap12_2.html). *Acquavella JP, Wiggs LD, Waxweiler RJ, et al. 1985. Mortality among workers at the Pantex Weapons Facility. Health Phys 48:735-746. *Adams GE, Wilson A. 1993. 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Personnel Dosimetry Performance Criteria for Testing, ANSIN13.11. *Archer VE, Wagoner JK, Lundin FE. 1973a. Lung cancer among uranium miners in the United States. Health Phys 25:351-371. *Archer VE, Wagoner JK, Lundin FE Jr. 1973b. Cancer mortality among uranium mill workers. J Occup Med (United States) 15:11-14. *Atomic Energy Insights. 1996. Chernobyl Health Effects: Best Available Data. Adams Atomic Engines, Tarpon Springs, vol. 2, No. 1. (http://ans.neep.wisc.edu/~ans/point_source/AE/apr96/effects.html). *ATSDR. 1990a. Subcommittee report on biological indicators of organ damage. Agency for Toxic Substances and Disease Registry, Centers for Disease Control and Prevention, Atlanta, GA. *ATSDR. 1990b. Toxicological profile for thorium. U.S. Department of Health and Human Services. Public Health Service. Agency for Toxic Substances and Disease Registry. Atlanta, GA. *ATSDR. 1990c. Toxicological profile for uranium. U.S. Department of Health and Human Services. Public Health Service. 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Exp Hematol 22(2):130-135. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION A-1 APPENDIX A ATSDR MINIMAL RISK LEVEL The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99-499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological profiles for each substance included on the priority list of hazardous substances; and assure the initiation of a research program to fill identified data needs associated with the substances. The toxicological profiles include an examination, summary, and interpretation of available toxicological information and epidemiologic evaluations of a hazardous substance. During the development of toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are used by ATSDR health assessors to identify contaminants and potential health effects that may be of concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or action levels. MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor approach. They are below levels that might cause adverse health effects in the people most sensitive to such effects. MRLs are derived for acute (1-14 days), intermediate (15-364 days), and chronic (365 days and longer) durations and for the oral, inhalation, and external routes of exposure. Currently, MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method suitable for this route of exposure. MRLs are generally based on the most sensitive end point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level above the MRL does not mean that adverse health effects will occur. “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION A-2 APPENDIX A MRLs are intended only to serve as a screening tool to help public health professionals decide where to look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health principle of prevention. Although human data are preferred, MRLs often must be based on animal studies because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes that humans are more sensitive to the effects of hazardous substance than animals and that certain persons may be particularly sensitive. Thus, the resulting MRL may be as much as a hundredfold below levels that have been shown to be nontoxic in laboratory animals. Proposed MRLs undergo a rigorous review process: Health Effects/ MRL Workgroup reviews within the Division of Toxicology, expert panel peer reviews, and agencywide MRL Workgroup reviews, with participation from other federal agencies and comments from the public. They are subject to change as new information becomes available concomitant with updating the toxicological profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published levels. For additional information regarding MRLs, please contact the Division of Toxicology, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road, Mailstop E-29, Atlanta, Georgia 30333. ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION MINIMAL RISK LEVEL (MRL) WORKSHEET There are presently no MRLs for Ionizing Radiation. ***DRAFT FOR PUBLIC COMMENT*** A-3 IONIZING RADIATION B-1 APPENDIX B USER'S GUIDE Chapter 1. Public Health Statement This chapter of the profile is a health effects summary written in non-technical language. Its intended audience is the general public, especially people living in the vicinity of a hazardous waste site or chemical release. If the Public Health Statement were separate from the rest of the document, it would still communicate to the lay public essential information about the chemical. The major headings in the Public Health Statement are useful to find specific topics of concern. The topics are written in a question and answer format. The answer to each question includes a sentence that will direct the reader to chapters in the profile that provide more information on the given topic. Chapter 2. Principles of Ionizing Radiation This chapter is an introductory discussion on the principles of ionizing radiation. It addresses what ionizing radiation is and provides a brief overview of the history of ionizing radiation as it pertains to health effects and uses, both peaceful and military. The chapter goes on to discuss the concept of radioactive transformation and the concept of half-life, characteristics of nuclear radiation, how radiation interacts with matter, ionizing radiation and DNA interactions, energy deposition in biological tissues, radiation dosimetry, and internal vs. external exposure. Chapter 2 also introduces the concept of the dose-response curve and the concept of acute and chronic (delayed) health effects, in addition to briefly summarizing the major health effects caused by exposure to ionizing radiation. This chapter concludes with a thorough discussion on how to measure ionizing radiation, both internally and externally, and in media using a variety of instrumentation. Chapter 3. Summary of Health Effects of Ionizing Radiation This chapter provides an overview of the health effects related to ionizing radiation exposure in humans and laboratory animals. The top 25 list of radionuclides present at Department of Energy (DOE) waste sites are identified and some information on their physical half-life and retention characteristics in the body are summarized. The health effects associated with exposure to ionizing radiation is summarized and divided into non-carcinogenic and carcinogenic responses for discussion purposes. A discussion of the non- carcinogenic health effects by major organ system was presented, followed by a discussion of the carcinogenic responses using data from both laboratory animal and the limited amount of human data available. The effects of ionizing radiation on teratogenesis, reproduction, genotoxicity, and ocular toxicities, including the available information on human risk assessments, are also addressed. Readers are encouraged to use Chapter 8 as a supplement to the discussion of the health effects presented in Chapter 3 of this profile. Chapter 4. Radiation Accidents This chapter discusses the major radiation accidents of this century, including health effects data, if such data were reported. “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION B-2 APPENDIX B Chapter 5. Mechanisms of Biological Effects This chapter discusses the major mechanisms by which ionizing radiation exerts it toxic effects on cellular activities. This discussion addresses the major target molecules of ionizing radiation, with emphasis on how ionizing radiation interacts with DNA. The concept of direct vs. indirect damage to DNA and other macromolecules is also introduced, followed by a discussion of how these mechanisms induce specific types of damage to macromolecules, cells, tissues, and organs to elicit a toxic or adverse event. A brief discussion of the mechanisms by which ionizing radiation induces cancer in laboratory animals and humans is presented, in addition to a number of models that reflect possible mechanisms of cancer induction and a brief discussion of the three steps of cancer formation. Chapter 6. Sources of Population Exposure to Ionizing Radiation There are many ways humans and animals can be exposed to ionizing radiation. This chapter addresses the potential for exposure to sources of ionizing radiation to the human population. Exposure to ionizing radiation is divided into natural external (cosmic rays, terrestrial, coal production, crude oil and natural gas, hot springs and caves, etc.), anthropogenic external (nuclear weapons, fallout, nuclear fuel cycle, medical, and occupational) and internal exposure (inhalation, oral and dermal routes). Discussion of the human health hazards associated with each type of exposure is also presented in this chapter. Chapter 7. Regulations This chapter provides a summary of the regulations pertaining to radionuclides. Chapter 8. Observed Health Effects from Radiation and Radioactive Material Tables 8-1 (inhalation exposure), 8-2 (oral exposure), 8-3 (dermal exposure), and 8-4 (external exposure) are used to summarize health effects associated with exposure to ionizing radiation. These levels cover the health effects observed at increasing dose concentrations and durations, the specific isotope used, and the differences in response by species. Use these tables for a quick review of the health effects and to locate data for a specific exposure scenario. The tables should be used in conjunction with the text in chapters 2, 3 and 4. All entries in these tables represent studies that provide reliable, quantitative estimates of No-Observed-Adverse-Effect Levels (NOAELs), Lowest-Observed-Adverse-Effect Levels (LOAELS), or Cancer Effect Levels (CELs). Chapter 9. Glossary This chapter contains of definitions and terminology pertaining to ionizing radiation and should be consulted when reviewing and interpreting the data present in chapters 2 through 8 of this toxicological profile. Chapter 10. References This chapter lists the references used to construct this profile or references that the reader may use to obtain more information on many of the topics discussed in this profile. “**DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION] C-1 AMAD ATSDR C CDC CEL CERCLA CFR cm CNS d DHHS ECG ED; EEG EPA EKG ERAMS ERD F F, ft g HPS hr IARC ICRP ILB IPB in kg L LCs NAREL NCRP ng APPENDIX C ACRONYMS, ABBREVIATIONS, AND SYMBOLS Activity Median Aerodynamic Diameter Agency for Toxic Substances and Disease Registry Centigrade Centers for Disease Control Cancer Effect Level Comprehensive Environmental Response, Compensation, and Liability Act Code of Federal Regulations centimeter central nervous system day Department of Health and Human Services electrocardiogram Effective Dose 50% electroencephalogram Environmental Protection Agency see ECG Environmental Radiation Ambient Monitoring System Environmental Radiation Data Fahrenheit first filial generation foot gram Health Physics Society hour International Agency for Research on Cancer International Commission on Radiological Protection Initial Lung Burden Initial Pulmonary Burden inch kilogram liter lethal concentration, 50% kill lethal dose, low lethal dose, 50% kill Lethal Dose 50%/30 days lowest-observed-adverse-effect level milligram minute milliliter millimeter Minimal Risk Level National Air and Radiation Environmental Laboratory National Council on Radiaiton Protection and Measurements nanogram ***DRAFT FOR PUBLIC COMMENT*** IONIZING RADIATION] C-2 APPENDIX C nm nanometer NPL National Priorities List NRC Nuclear Regulatory Commission NTIS National Technical Information Service NTP National Toxicology Program OSHA Occupational Safety and Health Administration PHS Public Health Service ppm parts per million sec second SCE sister chromatid exchange SMR standard mortality ratio STEL short term exposure limit STORET STORAGE and RETRIEVAL TWA time-weighted average U.S. United States yr year AE CEA wk week > greater than > greater than or equal to = equal to < less than < less than or equal to % percent o alpha p beta Y gamma H micro a Atto f Femto p Pico n Nano m Milli K Kilo M Mega G Giga T Tera P Peta E Exa Ci Curie mCi millicurie pCi picocurie Sv Seivert Gy Gray + U.S. GOVERNMENT PRINTING OFFICE: 1997-538-109 **DRAFT FOR PUBLIC COMMENT*** BERKELEY LIBRARIES CD8LA&a7LA0