a Ye a se 9 » a3? ” ° “ . a TT TS .r LEAD POISONING BY ABRAHAM CANTAROW, M.D. Associate Professor of Medicine, Jefferson Medical College Assistant Physician, Jefferson Hospital Biochemist, Jefferson Hospital Philadelphia, Pa. AND MAX TRUMPER, Pu.D. Lt.Commander, H-V (S), USNR. Naval Medical Research Institute, Bethesda, Md. Formerly Lecturer in Tozicology, Jefferson Medical College Consultant in Industrial Toxicology, Cynwyd, Pa. THE WILLIAMS & WILKINS COMPANY BALTIMORE 1944 ————u]e = i Corymigar ye "Tue Wirtrams & Witkins COMPANY 1 t . | Y L 2 ¥ \ aT Waren Bazes, 150 i ~ THE WiLL1ams & WILKINS COMPANY \ TO THE MEMORY OF HENRY LEFFMANN, SCIENTIST, SCHOLAR AND PHILOSOPHER 230220 Vii Da J fap wn FW [& YH Bh J gd fe ou Ne es | Fart ra PREFACE Lead poisoning is probably the most important of the known toxic haz- ards incident to the development of our civilization. Lead was among the first metals known to the early Egyptians, Hebrews and Phoenicians, and - certain of its toxic effects were familiar to Greek, Roman and Arabian physicians before the Christian era; lead colic and paralysis were mentioned by Dioscorides in the first century A.D. The usefulness of this metal in the erection of buildings is mentioned in the Old Testament and the term “plumbing” is an outgrowth of its use by the Romans in their famous water-carrying systems. Because of its peculiar properties, it has rendered invaluable service to man; the important role that it has played in the progress of civilization is indicated by its use in type, which has spread knowledge by means of the printed word, and by its contribution to the development, of the electrical and other industries. As is true of many other substances which man has adapted to his use, lead may be harmful as well as beneficial. Increased exposure to its toxic effects, growing out of its steadily increasing employment for household and industrial purposes, soon led to a comprehensive understanding of the clinical manifestations of lead poisoning. Modern interest in and clinical studies of this condition date from the 17th and 18th centuries, when, in addition to industrial plumbism, outbreaks of lead poisoning occurred throughout western Europe as a result of the addition of lead to wine to promote fermentation and because of its employment in the manufacture and storage of cider and in material for cooking-vessels and other household articles. The epoch-making treatise by Tanquerel des Planches, published in 1839, contained a remarkably accurate clinical description of lead poison- ing, and initiated a period of intensive clinical and experimental investiga- tion of this condition. The characteristic morphological effects of lead were fairly well established by the beginning of the present century, when attention was directed to the pathological physiology and biochemistry of lead poisoning. The significant contributions made in these fields in recent years, together with the growing interest in problems of public and indus- trial hygiene, have laid the foundation for effective control of this hazard. The expansion of industry during the past few decades is reflected in the tremendous increase in production and consumption of lead in the United States, from 270,000 tons in 1900 to about 750,000 tons annually in the period immediately preceding World War II. There are few industries that do not use lead or its alloys in some form. In a survey made by the vii viii PREFACE United States Public Health Service in 1940, of 16,803 industrial plants in 15 states, it was found that about 549, of the 1,500,000 workers in these plants were handling lead or its compounds. The actual decrease in in- cidence of severe lead poisoning in the face of this enormously increased exposure is due to the growing interest in industrial hygiene and the con- sequent wide-spread employment of adequate measures for safeguarding the health of workers in hazardous industries. Management and labor, through the services of industrial physicians, chemists, engineers and nurses, have co-operated to accomplish this end. Careful medical supervision and improved diagnostic procedures have facilitated recognition of cases of incipient plumbism that would formerly have been overlooked and neglected until the condition had become serious. Nevertheless, lead intoxication, because of its cumulative effects, is still probably the most prevalent industrial poisoning, forming the basis for a large proportion of the total claims for compensation for occupational diseases other than dermatoses. One of the most dangerous features of lead poisoning is the insidiousness of its development. Absorption, excretion and storage of excessive quan- tities of lead may continue for many years without significant manifesta- tions of intoxication. However, during this latent period the basis may be established for the subsequent occurrence of frank or obscure signs and symptoms of poisoning. Accurate diagnosis of lead poisoning depends to a large degree upon an appreciation of the extent of this hazard in industry and an understanding of the conditions under which the potential danger may become an actual one.. The clinician must also have a thorough appreciation of the pathological physiology and clinical manifestation of this condition as well as of the significance and limitations of findings ob- tained by laboratory methods. By no means least important is the neces- sity of obtaining an accurate history of the occupation of the patient and the conditions under which he worked. One might well adopt in this con- nection the motto of Ramazzini, the eminent 18th century physician: Medici munus plebios curantis est interrogare quas artes exerceant— “The duty of a physician attending the common people is to inquire what trades they practice”. We have culled from the enormous literature on this subject such data as in our opinion will contribute to a comprehensive understanding of the nature, prevention and management of lead poisoning. In presenting this information we have sought to reflect the consensus of authoritative opinion. However, on many controversial issues we have indicated our personal opinions, based on the study of hundreds of workers exposed to lead hazards in various industries. Personal experience has strengthened our conviction of the necessity for a more general appreciation of the extent PREFACE ix of the lead hazard and the importance of the early recognition of chronic lead poisoning. The authors are deeply indebted to Dr. Morris B. Jacobs, Senior Chem- ist, Department of Health, New York City, for contributing the section on “Determination of Lead”, to Dr. May R. Mayers, Division of Indus- trial Hygiene, New York State Department of Labor, for the section on “Industrial Control of Lead Poisoning (Prevention of Lead Poisoning)” and to Mr. L. H. Schroeder, Research Laboratories, National Lead Co., for the section on “Lead Products in Industry”. We are also indebted to the U. S. Public Health Service for permission to reprint Figures 1-4 from U. S. Public Health Bulletin No. 262. The opinions and views set forth in this book are those of the authors and are not to be considered as reflecting the policies of the Navy Department. Jefferson Medical College, A.C, Philadelphia, Pa. M.T. ) RAC an Bach fe LC Sdn hy Fhyl APP ET ad Wes Toa) Nem py Fa’ 0 at A Yai iE {A 1g yas adi 3, alas a GEL RR CONTENTS CHAPTER I ABSORPTION, TRANSPORTATION, DEPOSITION AND EXCRETION OF LEAD. ........ 1 ADROTPUION. (ion sbi fos salons nn.5 vfs ok Mirai shows 3 ee min on Te hE Sd, 1 Transportation and DepomtIon. . . .. oui iue iiss eubinhiiuys so vinings siiviate 8 Bloom Lond: ocr va xhu con ves sinnges so iv iaahise ie ot + 0d avn S ae a ate 8 Lotte BISSUSE. - ois sin sn a hniinn ass sai bigoinah o 4 swamp SIE a TE 12 Factors Influencing Distribution and Deposition. ..................... 13 POTIa) OF TERUIY: «20s iets sem sens sin wniicngins son.» x 4x ivnae tase pate y 16 Storage In Skelebon. 5. c.coo vids ors dilernu sds « 5 oid dawnt ambi usd 21 Deposition In Other Tissues... ... cus arsine veiiideis nila divoh 26 BROretOn. vs i. rina eh 3 aan ae 8 ¢ eee ey ee eames Se LEN 31 CHAPTER II PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY. .........coiviiiiiiiiinin ranean, 41 EOUPOAUOLION Ao. vo a Eos 's ie 4 sien opin winnie) AR 0 Sn For Sane Ceot gotl eS 41 Changes in Blood and Hematopoietic Funetion........................... 42 Stippling, Polychromasia, Reticulocytes....................cooeninn. 42 ABB, ovis v3 sn wins To sain ati mis wt Ly etn RE ens veut a eR SRE 45 BORO VIBITOW. ios Tans i rnaivinnigs vos wm dain sie bby 8 Eutals MS edbals ISR 48 Pigment Metabolism. .[. .. foiuvvs oe durin hives vive bas Tui sntamide aime 50 TBUROCYIRE. .. 1v.v vitrinite n vn suimvan's dn Swkidusninine son ko sd amd rn oh 53 PIOtalotl. . . «oposite 0% surge snninene vs By prenitonie'ds s 0 bin nwa oie 54 TPRAIOR: «co oindiis 1 voids irwinin vs sir Th Yin Bis + nal oi sar SR 54 Metaboli. +. o.oo sv viv bs noiim bss divas autos » wipes vba os § bw EAT ars 54 Growth and Buzyme ACbiVIbY......... vei. ins iin vais snnslenss Tannieinis bt Protein MetaliolISm. ..o..ov ov tim case ss wiiiishe sso sin wiimote abet tutery plodle 56 Carbohydrate Metabollsm. ........../..ccviivnin suv dees nmninlsiling avi 57 Tab MobabolIsmi- bcos Juii va ainan cuvhliin sv a sn sivnnsi sas aifonmnatiiy ie tein 57 Mineral MetabolISI. .o. ..iv vin vs Ji vvaes wi sninmiine sos vo sinumeit is Sumani 58 Badoorine GIADMS: . 5 .u uv. vii cvs npebiivdas os roaninsinm vs bron ans pho iom 59 RIN An ADDEOARZOS. «oc ov cx ne 05% 0 40h ws bie Sawn wn Ts Ss oo pd We Wales See 59 Effect-on Skalatal Muscle... .........0 cc deiie vi veiiomese sods levine 59 Effact on Nervous SYSLEIN... ..cc.ouiihivvmirs « dnmmgatnsy soon klehinn diiaiddentals 62 BRA. ht fo rom signin ns ov Sabin ntevn on a RATING Sorted heii deve le 63 MEIHtZRE. «ns oe ca nin a Se Sm bins 3 SS rae Te wie AE ag EAE 64 BOINBLIQOIAL 5. vinais 21s sn suas bi sims i+ & wns wiosiith, © on va BA aa rly 65 Nerve Roots and Peripheral Nerves..................coiviivnniinnnn. 65 DORSC OTIS. ini in ins vhosts Fh os 4 wins ule rioiis rah ore rte Shotd 68 Effection Smooth Muscle. . .... 0. c....ou.ciiioranme dans daub sine daises san 69 CHAPTER III PatHOLOGY AND PATHOLOGICAL PHYSI10LOGY (Continued). ..................... 72 Heart, Blood Vessels and Blood Pressure. .................ccoviivneennnnsn 72 AHMENEATY PIRO . vs secs ans v5 525 woniainins oa 54% a adabe tines 536 wales winjeioh siwselsisrobe 77 LoEIING, i ts ii ima rss v0 3 miwmn Thonn £4 we cae Soba pa a Ee a ear 0 Rr rd 77 xii CONTENTS Salivary Glands.» oo od ih Be Tah fie i seater 79 MLBBUR Ziti ih a7 55 inte 5 de wea 4 60 ave Sha into ortin. faint wid mrs: § 1H, we a talet hele 79 StomarhPand Intestines: . .. Ji vi. de A Sais sists rae bonus odes sh vias 80 BONER anITOMILE. .\. ooh css vn vs ahs win w Shri rosin Sa maids sone 2a a Te Phin Wiebe 81 RespIrat ORY Tratl 3. or. is» fit nr mmiirer Pye en as sri nS a ey wiwnin ak ay 83 Bonsde and BoprodUeEIon. 1. Lv. a «hss crienie « 45 antes tine Po sia'sinain warts matmins oe # Female Gonads. ant UIVEIUS. .. «cui priniing ss = «sia siphon sia ws syste sie ncsiaing fain 84 Sli TH CIE Re Br RE SR arn, YE WE SE ET ANE am 86 AVOID a1 TILL ns Saamhatie se deeb ma mais s § Bote wo pons sed Soeitrid fat o Vieth 87 on LT PRA Chay Se OS NEL SIL LDR Ep I TE 89 CT I RS ne RL or a EI 89 [OOXICTDIORB ION LRA, oi vrs nr Saab 2 Smite 5 ri 40 PASAT GE To sa AB nin 94 CHAPTER 1V CLINICAL MANIFESTATIONS: .ccvvovs. Svnnns suibwlieh oon aid aol sea diore av aia nippole valk atin # 99 DOE LIONA ro. 2.5 iis damn oh + 3s Sinrainbins ve ale hismmsls ooo nie wintrnad Po ile 99 AUMEREary ITrant. ohm hs ns cu Lak nian oon nts ws awe nes woe Kem ss he 102 Cardiovascular Syston... u. oh iis dood don 2a anviws wishes ss os sitconinleie se oh on 108 Eh a Ef SIE cr VS WEE ra Ne LN SLC 112 CHAPTER V OriNicar. ManiresTATIONS (Continued)..............ovivviiiiiiiiiiiiiiinnnes 117 INeUroUSEUIAr SYSEOIY. I... . Jo ui hve Suilonnins 45 34s 5 Soninin ss & 5nd + Role singe se Fine 117 Encephalopathy... oi oes sno s satiniide oo o's drmadin® comes Shakin tals oly 117 NASual DISLUTDANGEE. . ov +o ulovivs sis wuininns « o0 5 Saimin sie Soihs sient sisteolals ovis 124 PAPRTUSIS ob. cL LLL CA i esis E Ae rami © Filme ah 126 Sensory DIsturbanes. i... .. concn es mins ros singain ss snus striae 135 Cerebrospinal BIW. ... 05 tis cirnbinaives oo rlipnnn de vg walntdiitbenleams 136 etrabthyl Lead. . |... anidns 5 vain seo fn nme neon sa ss AEN OAR 137 CHAPTER VI CLINICAL MANIFESTATIONS (Continued). ............coviiviiiiiiiiiiiiinnn 140 Bone ad JOINER: 7... van scm sp hidisiarinsin + +s sein Tobnbiandid iis sh het aoe 140 IR ESPIPRLOTY TIPACY. vo fe i binant cn sims wp ooo Bip raid he ER ag Er Sef ld 142 Gental/SYBLON. 1... . ois s voi saan dune nate so sainardn's Saadin wie iNEAARY 142 Hematopoletio SYStOmE. 1... 2 cb ans nainrns on 1 5 5 dnaindivoy nds skits sb on eps 144 BIBI AY ov na nk Lee id Said See vd Peas aT 0 Ma Er ne 144 Polychromasia, Punctate Basophilia, Reticuloeytosis................. 146 Leucocytos and Pladelett.. . ...; a. dup cere mise wppiaivit Foe gions aides 151 Biomeat Metabolism. . oq. «i: vu Ware sins was Wh mwa pmin b « ia snide Lokilion 153 CHAPTER VII LEAD 18 BLOOD, BODY FLUIDS AND EXCRETIONS.......civviiuurivinnnnnnnnnnns 155 Eead/Contehtiof Blood: v. iv. ivshcssis is vesavansoasessinsinans rns seh 155 Jean Iria. i. a hn te Pen Binsin toe sa S100 Kor past Bins § Kibr 4 apie mph ke A RAE 158 OAT TECEE,. t beivnitin wm oo nll i ela a yay A ae 164 Lead in Cerebrospinal Fluid... ....00 0. Vis din fe diaivh vs ban ably Jie £onivie 4574 165 CHAPTER VIII NORMAL INTARE OF LBAD. vile he i va wei i dein ain aa yanian sue adam see obs SH said 167 CONTENTS xiii CHAPTER IX TREATMENT OF LEAD POISONING... 0 viii sssivetsennstnnanssnenssssvessssine 172 Industrial Control (by May R. Mayers) ............covvuviurnrensnncnnnns 172 Medical Supervision. ..... trv dn onion is Se seis bed viii halons oles 191 Symptomatic Treatment... oie sul venom sins raindiid vis Sin pv aia te iv vie t Glasotate 197 CHAPTER X OCCURRENCE OF CHRONIC LEAD POISONING. ........ciiiiiiiiiiiiiinnnnnnnnnnns 199 Occupations Involving Potential Lead Exposure.......................... 201 CHAPTER XI J/EAD PRODUCTS IN INDUSTRY. .....oiuivisuinmmis die smoswnniass se Cora sidemmnivinds 205 Primary Production of Lead. ..... ... 5 cine savior svkiviv oh vil S3alwaiieit d isis 205 Manufacture and Use of Lead Produets. ...............c. cove innenads ns 207 CHAPTER XII by Morris B. Jacobs PROCEDURES FOR DETERMINATION OF LEAD. ... . ..oiiiiiiii iii nanan 219 BATOPHRG liv B s+ i vase Tisch herd ein abound v Ta on Sinn i A PS rere Sle 3 rE 219 Qualitative and Quantitative Tests................cooiniiiiiniiiinninn. 221 s-Diphenylearbazide Method. :.... «ove edi Giddy wah SRNL Tah ls, 222 Dithizone Methods. . .... il resi vrubiossiss ss seed as sadn seielmieteinnteuitel ne 225 Blectrolytic Method. .. J... «oc vvatans Vals fun van visa sin salina smisineate sis aise 233 Polarographie Method. ......... cc ics avin nas'einnio ws va PAA Eablet 233 BIBLIOARAPIIY . . oor b's v sn ais Was winluiatii ala an inlet 4 0) Fata a9 A B10 oe WhaTiaTetcTend he 240 EOE Vt fh) aie es Ea mmr on w vem uion ve Sats a wtioassin hatraaie stn ot Ain io RAEN IGRI 258 NR Con fy: vv i a i 23 CHAPTER I ABSORPTION, TRANSPORTATION, DEPOSITION AND EXCRETION OF LEAD ABSORPTION Lead enters the body most commonly through the gastrointestinal and respiratory tracts, occasionally through the skin and the conjunctival and vaginal mucous membranes and, rarely, from the subcutaneous tissues. The absorption of lead from subcutaneous tissue, muscle and peritoneal space is chiefly of experimental rather than practical interest. The rela- tive importance of these possible portals of entry is a matter of great practical significance and has been the subject of intensive investigation. Cutaneous Absorption. Many early observers believed that lead may be absorbed in significant amounts through the skin (Manouvrier). This impression was based largely upon clinical observations and upon the ap- parently frequent occurrence of arthralgia and paralysis in parts of the body most exposed to lead. However, experimental studies do not support this belief, at least in the case of inorganic lead compounds (Siissmann) (Tanquerel des Planches). In this connection, it is possible, as suggested by Rand, that data regarding cutaneous absorption obtained in non- perspiring animals may not be strictly applicable to man. The possibility of entrance of inorganic lead salts by this route cannot be denied, especially if they are suspended in a lipid medium as in the case of cosmetics (Oliver?) and paint (Hamilton!). Brezine and Engling found stippling of the red blood cells of guinea pigs annointed with lead in lanolin and Siissmann found small amounts of lead in the feces and urine of cats and guinea pigs annointed with lead oxide mixed with animal fat. It is doubtful, however, whether this absorption was of sufficient magnitude to produce poisoning except of a very chronic nature. The consensus among modern authorities is that absorption of inorganic lead compounds through the intact skin is of little or no practical significance in contributing to the development of lead poisoning (Hamilton!; Oliver?; Legge and Goadby; Meillére; Aub, Fairhall, Minot and Reznikoff). This is not true, however, of certain organic lead compounds nor, per- haps, of solutions or suspensions of lead salts in fat solvents. For example, it has been shown that tetraethyl lead readily penetrates the intact skin of dogs and rabbits (Eldridge; Kehoe and Thamann?), and is capable of producing manifestations of acute lead poisoning following local application 1 2 . «ex i.aes so +"“LEAD POISONING to the skin. Eldridge states that this is probably the only substance which causes acute plumbism by absorption through the skin. Obviously, the broken or irritated skin surface does not offer the same barrier to absorption of lead as does the intact skin. The older literature (Tanquerel des Planches) contains many references to the occurrence of lead poisoning following the application of lead-containing lotions and ointments to ulcers, burns, skin eruptions and areas of inflammation. Plumbism has also followed the use of lead lotions as eye washes and in the bladder and vagina. In view of the frequency of otherwise inconsequential cuts and abrasions on the hands of workers in hazardous industries, the possibility of entrance of lead into the body by this route should not be entirely disregarded. Subcutaneous Absorption. There can be no doubt regarding the absorp- tion of lead from the subcutaneous tissues. Absorption through the broken skin surface belongs properly under this heading. Some observers have been able to produce fatal chronic lead poisoning in cats by the sub- cutaneous injection of lead compounds (Straub; Erlenmeyer’). On the other hand, Aub and his associates were unable to produce any toxic ef- fects by this means with the exception of the occasional development of a lead line. Absorption of the injected lead did, however, proceed for several weeks; the absence of toxic manifestations was attributed to the fact that absorption from the subcutaneous tissues occurs very slowly and gradually, so that a significant increase in the concentration of lead in the blood and tissue fluids is prevented by the processes of excretion and storage. The question of the subcutaneous absorption of lead occasionally ac- quires some practical importance in connection with the possible absorption of lead from bullets lodged in the tissues. There are several reports of the occurrence of plumbism from this unusual source (L. Lewin?; Bronvin; Machle; Clague and Watson; Loeper and Verpy; Oliver’; Haenish). After a careful investigation of this subject, Bonhoff concluded that little or no lead is absorbed from bullets in the subcutaneous tissues. However, Haenish recently reported a case of fatal acute plumbism apparently re- sulting from embedded shot after an asymptomatic latent period of twenty- two years. The shot was found to be disintegrating and the surrounding tissue was darkened. The literature dealing with lead absorption from bullets lodged in the tissues has been reviewed by Machle, who added two cases to the forty reported instances of lead poisoning from this cause (to 1940). He concluded that although poisoning from this source is rare, lead absorption can occur from bullets lodged in the tissues, particularly in bones at the joints. Alimentary Tract. It seems probable that the majority of lead com- ABSORPTION, TRANSPORTATION, EXCRETION OF LEAD 3 pounds, particularly those which are readily soluble, are absorbed to some extent from the mouth, pharynx, and esophagus (Flury). The amount of lead entering the body through these channels is usually inconsequential, but may be considerably increased in the presence of irritation or inflam- mation of the mucous membranes in these situations. However, the stomach and intestines obviously play a much more important rdle in this connection. The exact processes involved in the absorption of lead from the gastro- intestinal tract are not clearly understood. However, the fact that lead is invariably stored in the skeleton as a phosphate, regardless of the com- pound to which the organism was exposed, appears to indicate a condition of true solution during the processes of absorption or transportation (Aub, Minot, Fairhall and Reznikoff). For example, Minot? could detect no chromate in the bone following experimental insufflation of lead chromate. Some observers (Brouardel; Flury) believe that lead can be absorbed from any mucous surface, including the stomach, particularly in the presence of hyperacidity, ulceration or gastritis. However, recent studies (Shields, Mitchell and Keith) indicate that little or no absorption of lead occurs in this organ. The chief action of the stomach in this connection appears to consist in the solution of ingested lead compounds. Two factors have been emphasized as of importance in this regard: (a) the solubility of the compounds in the gastric juice and (b) the formation of insoluble compounds with ingested foods or products of gastric digestion. The lead salts which most commonly enter the gastrointestinal tract are the oxide, sulphide, carbonate, and chromate. Lead oxide and chromate are quite soluble in gastric juice and dilute hydrochloric acid, their solubility, as is the case with the majority of lead salts, increasing with increasing concentration of hydrochloric acid (Beck and Steigmiiller). Carlson and Woelfel reported the following range of solubility of lead salts in a given amount of gastric juice: carbonate 469, sulphate 9.5%, sulphide 2.59%. The solubility of lead is also increased in the presence of a high concentra- tion of carbon dioxide, perhaps through conversion to the relatively soluble carbonate (Auerbach and Pick). According to Legge and Goadby, lead salts entering the stomach may be converted to the chloride by the hydro- chloric acid of the gastric juice; in the presence of lactic, acetic and other organic acids, the corresponding salts may be formed. If the gastric acidity is low immediately following the entrance of lead into the stomach in con- junction with food, the former may be incorporated in the bolus of food and escape conversion or solution. These authors believe that the presence of lead salts in association with food in the stomach results in the formation of the albuminate or peptonate of lead, which are insoluble and cannot be absorbed as such from the stomach (Shicksal). Their experiments with 4 LEAD POISONING artificial juices suggest accordingly that lead is not absorbed as the chloride but that these organic compounds are first formed in the stomach and pass into the intestine where the lead is liberated from this combination as a result of breakdown of the organic radical during digestion. On the other hand, Flury states that whereas there is no doubt that lead chloride is formed in the stomach, there is no adequate evidence of the formation of lead albuminates or peptonates nor of the reaction of these substances with enzymes in the gastrointestinal tract. The observations of Shields, Mitchell and Keith indicate that lead is actively absorbed throughout the small intestine and probably also in the cecum and colon (rat). This is in accord with the general view (Legge and Goadby). Auerbach and Pick found that lead chromate and sulphate were’ converted to the carbonate in the presence of an excess of sodium bicarbonate, a reaction which is dependent upon the concentration of carbon dioxide. On this basis, it would appear that even relatively insoluble salts may be slowly converted to the more soluble carbonate when they come in contact with the intestinal secretions and particularly with pancreatic juice. This reaction may be facilitated, as suggested above, by the possible libera- tion of lead from its combination with protein molecules during the process of intestinal digestion of the latter. Lead sulphide may be formed as a result of reaction with hydrogen sulphide in the intestines. This, being relatively insoluble, is largely excreted, but Legge and Goadby believe that probably most of the lead is absorbed before it reaches the point in the in- testines where free sulphur or hydrogen sulphide exist in large amounts. It has been suggested that the absorption of lead from the intestines may be diminished by the administration of foods which depress or retard gastric secretion. Carlson advises the use of milk for this purpose but more recent studies have revealed no significant influence of milk upon the absorption of lead from the intestines (Aub, Fairhall, Minot and Reznikoff). Despite these negative findings, according to Flury, practical experience supports the view that milk and other foodstuffs exert a favorable influence in that they may slow up even if they do not diminish absorption. Harnack® claims that absorption of lead from the intestines is hindered by bile but Legge and Goadby found that, at least in vitro, bile favors the solubility of lead compounds. The gastrointestinal tract was for a long time regarded as the most important portal of entry of lead into the organism in clinical lead poisoning. Although there can be no doubt of its importance, the bulk of available evidence suggests that the respiratory tract is a more important avenue of absorption in industrial poisoning. This phase of the subject has been considered in detail by Aub and his associates. As stated by them, when lead enters the intestines a variable but usually large portion escapes absorption and passes out in the feces. A small fraction of the ABSORPTION, TRANSPORTATION, EXCRETION OF LEAD 5 remainder may be absorbed by the lymphatic system and thus enter the general circulation; however, the larger part of the absorbed lead probably enters the portal circulation and passes to the liver, where perhaps most of it enters the bile and is thus excreted into the bowel without ever having reached the systemic circulation. This cycle may be repeated many times, with the consequent entrance of relatively small quantities of lead into the general circulation and the tissues through the barrier imposed by the liver. As will be indicated below, the existence of this barrier in the path of absorption from the intestines is responsible for the fact that the respiratory tract is a much more dangerous route of absorption of this agent in the vast majority of cases. It is stated by Gant that an equivalent amount of lead is 10-100 times more toxic when inhaled than when swal- lowed. Weyrauch! believes that the liver is very efficient in removing lead from the portal blood, but is not so efficient in removing it from the systemic circulation. He believes that if absorption from the intestines has been rapid a considerable portion of the absorbed lead may reach the general circulation, from which it is not readily filtered out by the liver. It is conceivable that if only small amounts are slowly absorbed from the bowel, the greater part of that reaching the liver in the portal circulation may be excreted in the bile and subsequently undergo reabsorption and reexcretion, this enterohepatic circulation of the lead preventing sudden entrance of sufficient quantities into the systemic circulation to produce manifestations of acute intoxication. Interesting observations on the rates of absorption of lead from the bowel have been made by adding a radioactive isotope of lead (thorium B) to that ingested, its distribution in the tissues being fol- lowed by means of an electroscope and radiograph (Behrens!; Behrens and Baumann?; Miyasaki). Studies of Behrens.and his co-workers suggested that, in accord with the general opinion, absorption from the intestine oc- curs slowly, a maximum being reached in 10-20 hours in the great majority of cases. When relatively small doses were administered a maximum absorption or retention of about 20 per cent was obtained, this proportion diminishing as the quantity administered was increased. Miyasaki, using rather large doses, found that about 159, of the ingested lead was absorbed in three hours, the proportion absorbed decreasing when very large quan- tities were administered (mice). He found that absorption was inhibited by the presence of food, particularly milk, and suggested that milk may form a non-diffusible colloidal lead phosphate. This author regards the absorption of lead as a simple diffusion process and believes that a condition of equilibrium is reached between lead in the blood and in the intestines. Fees, using much smaller doses, found that over 90 per cent of the ingested lead was absorbed from the intestines of mice within one hour, suggesting 6 LEAD POISONING that the doses employed by Miyasaki and Behrens! were so large that most of the lead passed through the bowel in the feces unabsorbed. After twenty-four hours, only 50 per cent of the ingested lead could be found in the tissues, and 25 per cent was present in the bowel, the remaining 25 per cent having been eliminated in the urine and feces. As stated by Monier- Williams, these observations point clearly to rapid absorption from the intestinal tract and gradual excretion, perhaps to a large extent by the same route. It is pointed out, however, that mice are very tolerant to lead, and it may be that these data are not applicable to the absorption of lead from the intestine in man. Absorption from Respiratory Tract. The relation of dusty trades to the development of plumbism has been stressed since the middle of the seven- teenth century. Although the possibility of absorption of lead from the respiratory tract was suspected and even demonstrated by several early workers in this field, direct proof of the importance of this route has been furnished only comparatively recently. The early studies of Goadby and the critical observations of Minot and of Blumgart leave little doubt that even relatively insoluble lead compounds can be absorbed by the respiratory tract from the nasopharynx to the pulmonary alveoli. In the latter studies, the esophagus (cats) was ligated in order to obviate the possibility of en- trance of the ingested or insufflated material into the gastrointestinal tract. Minot found significant quantities of lead in various tissues within a few hours after the intratracheal injection of suspensions of finely divided lead carbonate, oxide, chromate, and sulphide in salt solution. Blumgart introduced particles of lead carbonate into the nasopharynx of dogs after insuring against the possibility of passage through the trachea or esophagus. He found 8-30.6 mg. of lead in the tissues (exclusive of the head) in 18-36 hours after the insufflation of 180-480 mg. of lead, thus demonstrating conclusively the possibility of rapid absorption of lead dust from the nasal passages. In a study of the comparative rates of absorption of lead by different routes, Aub and his associates found that the tissues (exclusive of lungs) contained approximately as much lead (16.7 to 72.4 mg.) in 19-94 hours after the insufflation of 250 mg. of lead (carbonate) as was present in the body 9-124 days after feeding 2000-11,400 mg. of lead (lead acetate solution) (5.8-88.9 mg., exclusive of gastrointestinal contents). Obviously, lead enters the systemic circulation and the tissues much more readily as a result of absorption from the respiratory tract than from the gastrointes- tinal tract. This was reflected also in the fact that the animals (cats) exposed to respiratory absorption developed manifestations of acute lead intoxication much more quickly and following much smaller doses than did those receiving lead by mouth. As stated by Aub, during long experiments the disproportion between the quantities of lead retained after absorption ABSORPTION, TRANSPORTATION, EXCRETION OF LEAD 7 from these two systems decreases, indicating that if time allows, excretory processes become important. Lead entering the body through the intes- tines may be excreted without being absorbed, or, following absorption, may be reexcreted by the liver in the bile without ever reaching the systemic circulation; on the other hand, when lead enters the organism through the respiratory passages, both absorption and excretion necessarily involve transportation in the systemic blood with the consequent greater likelihood of the development of acute intoxication and of widespread distribution of the lead throughout the tissues. Lehmann, Saito and Gfrori report experiments in which powdered white lead was inhaled through the nose and exhaled through the mouth. It was found that 36-43 per cent of the quantity inhaled went to the lungs, 2.8-10 per cent was exhaled and 51 per cent was caught in the nose and 3 per cent in the mouth. Although it is extremely difficult to avoid passage of lead into the gastrointestinal tract in such experiments, a considerable portion must have entered the respiratory passages, and the fact that 51 per cent was found in the nose is important in the light of the findings by Blumgart regarding the facility of absorption from the naso-pharynx. If lead enters the bronchioles and alveoli it probably remains there until it is absorbed and, consequently, probably the only effective defense against rather com- plete absorption of inhaled lead dusts is their expulsion by the action of the ciliated epithelium of the upper respiratory passages. Ehrismann found that a number of factors influenced the entrance of lead through the respiratory tract; among these were the quantity admin- istered, the duration of exposure, the size of the particles, the density of the suspension, the nature of the air current, humidity, temperature, and the degree of moisture of the mucous membranes of the respiratory passages. Several authors have observed that finer particles of lead dust enter the organism through this channel much more readily than coarser particles. According to Hipple, a large percentage of inhaled tetra-ethyl lead is re- turned during expiration. In subjects resting quietly, 16 per cent of the inspired lead remained in the lungs, whereas under conditions of mild ac- tivity 32 per cent was retained. These observations suggest that retention in the lungs is dependent to a large degree upon the depth of inspiration. The mechanism of absorption of lead from the respiratory tract is not clearly understood. As demonstrated by Fine, this may be accomplished in part by phagocytosis of lead by polymorphonuclear leukocytes and other phagocytic cells. Readily soluble lead compounds may be absorbed directly and, as stated by Oliver, gradual diffusion may occur from slowly dissolving particles in contact with the moist epithelium of the pulmonary alveoli. The possibility that certain lead compounds may be converted to lead carbonate in the presence of relatively high concentrations of CO, 8 LEAD POISONING may account for the ready absorption of relatively insoluble salts from the respiratory tract. In relation to the fact that a relatively high acidity is necessary for the solution of certain lead compounds of low solubility, Aub and his associates suggest that the penetration of CO, through cell mem- branes may permit the hydrogen-ion concentration within the cell to in- crease to the point where such solution becomes possible (Jacobs). It is interesting, in this connection, that metallic lead and lead oxide are strik- ingly soluble in blood serum (Fairhall) and that lead carbonate is more soluble in serum than in pure water. As pointed out by Oliver?, these observations are significant in view of the fact that manifestations of lead poisoning dccur very rapidly after exposure to lead fumes and lead oxide dust. TRANSPORTATION AND DEPOSITION OF LEAD Although there is no evidence that lead is an essential constituent of the body, many studies with improved technical methods indicate, as stated by Minot!, that the average individual in a modern community continually ingests or inhales small amounts of lead. Consequently, although the term “normal” may not be strictly applicable to lead as a constituent of the body tissues, it is important to recognize the fact that certain amounts of this element may be present in the blood and tissues of normal individuals who have not been exposed to unusual quantities of lead. This fact is of some medicolegal importance. Blood Lead Lead may be present in the blood of normal subjects. The range of values obtained by different investigators is presented in Table 1. The upper limit of normal (0.13 mg. per 100 cc.) given by Kehoe, Thamann and Cholak? is probably too high and, in our opinion, any value above 0.080 mg. per 100 cc. should be regarded as abnormal. There is evidence to suggest that the relative distribution of lead between the plasma and the red blood cells is of considerable significance. Aub and his associates believed that about 80 per cent of the blood lead was present in the plasma or serum. However, more recent evidence (Blumberg and Scott; Teisinger; Smith, Rathmell and Marcil; Weyrauch, Necke and Miiller) indicates that probably less than 10 per cent is contained in the plasma even under conditions of acute plumbism. Behrens and Pachur state that most of the blood lead is in the red corpuscles but that there appears to be a species difference in this connection, the smallest proportion being present in the serum of man and the largest in that of cattle. The partition seems to be dependent somewhat also upon the total amount, the percentage present in the serum increasing as the total blood lead con- ABSORPTION, TRANSPORTATION, EXCRETION OF LEAD 9 centration increases. These observers also found that the greater part of the serum lead is in a non-dialyzable colloid form, only a small proportion being dialyzable and ionized. Schmidt and Weyrauch found that the nuclei of the red blood cells at first exhibit a particular affinity for lead. Schmidt and Barth found about seven times as much lead in the stroma as in the hemoglobin of the red blood cells and they regard this observation as evidence of the lipid solubility of the circulating lead. The consensus of the majority of authorities is that the blood lead is largely adsorbed on the surface membrane of the red blood cells, the white blood cells and platelets being of little significance in this connection. According to Smith, if the blood is defibrinated, all of the lead under normal conditions should be contained in the cells and fibrin and none in | the serum (maximum normal values: cells and fibrin, 0.110 mg. per cent; TABLE 1 Lead in Blood of Normal Subjects Whole Blood Pb mg. per 100 cc. Blumberg andiSoolt. .... cota ini crs nie ste sd hain hie wnivinins ov 0.005-0.10 Kehoe, Thamann and Cholak®.......................... 0.0. 0.000-0.13 Kaplan and MeDonald. . ...x. «voir sion og davdvnnhe sd ¥ duavanite 0.0 -0.03 Willoughby and WHKING. «... ov we ioiitn vient 4s iran dois witint she isboete 0.000-0.090 Smith, Rathmell and Mazel... occu. ie ens curgrsiosios donnie saiv 0.010-0.060 Taegan: ANSON. o.oo ur si cnn mings ¢ or Bren aninninrs aru nest 0.015-0.080 IERRHORAL. ore rv» oe nrbiote os 5302 smo Hints vans visereje © s Lath pltwiein win 0.005-0.010 Tompeett BNA ANBETSOI. . 2. covers vrs sr gute sak snes smvnazeins os 0.040-0.070 Litener'and Weyranieh. |... Lo ola vim ddan dan ddan 0.010-0.030 BaBRY il DF hinds Wann ote bn hire Fin en heh npr il Eg 0.010-0.050 FRCISIBEOP NY. nis 5 5 isis nf otha 28 eels siniviass we aleine st mag bwisiinial slo sl aie 0.041-0.079 serum 0.000 mg. per cent; whole blood 0.060 mg. per cent). It is obvious, however, that a portion of the blood lead must be contained in the circu- lating plasma under both normal and abnormal conditions, for its presence in other body fluids and tissues and its excretion in the urine can be ex- plained only on this basis. Some of the plasma lead may, of course, be carried down with the fibrin clot and be incorporated in the cell-fibrin fraction when this method of separation is employed. Because of the fact that such analytic procedures necessarily involve measurement of ex- tremely small quantities of lead, it is difficult to obtain accurate informa- tion regarding the distribution of lead between the cells and plasma in the circulating blood. The use of anticoagulants for the purpose of separating cells and plasma introduces a possible error resulting from an alteration in the permeability of the cell membrane. However, the data reported by 10 LEAD POISONING Blumberg and Scott include figures obtained from the analysis of a sample of hemophilic blood in which the cells and plasma could be separated with- out the use of any artificial agent. / It ‘would appear that the bulk of evidence favors the view that the greater part, if not practically all of the blood lead is contained within the red blood cells. As stated by Minot, in view of the many difficulties in- volved, one should be conservative in interpreting as absolutely accurate figures now available regarding the concentration and distribution of blood lead. However, as she points out, while there is a considerable lack of agreement with regard to conditions present in normal blood, there is a reassuring difference between the blood of normal subjects and that of patients with lead poisoning. Opinion is divided regarding the form in which lead exists in the blood. Oliver? believed that it is present as the albuminate. As stated by Aub, Fairhall, Minot and Reznikoff, investigation of this problem is very difficult because even during plumbism the quantity of lead in the blood is so minute that isolation and identification are almost impossible. On the basis of extensive theoretical and experimental observations these authors conclude that lead exists in the blood plasma chiefly if not entirely as di-lead phos- phate in colloidal form, highly dispersed by the peptizing action of the plasma proteins. Jowett presented evidence that lead forms a complex inorganic phosphate containing calcium and chloride, while Teisinger was of the opinion that it circulates as an organic complex and not as the phos- phate. Maxwell and Bischoff and Kehoe and Thamann believe that lead is present in the blood in some form more active than the phosphate and the work of the former suggests that it may be carried as a diphosphogly- cerate. No final statement can be made in this connection at the present time but, as stated by Aub, in chemical systems such as those represented by the plasma and red blood cells an equilibrium of several such compounds is not unreasonable and any of these substances might conceivably remain ionized and dispersed in the presence of protein. ~——£ Lead may be present in any of the fluids of the body. Schmitt and Basse found it in the cerebrospinal fluid of normal subjects without undue ex- posure to lead in concentrations of 0.015 to 0.038 mg. per 100 cc. We have observed concentrations of 0.001-0.040 mg. per 100 cc. in hospital patients with no history of abnormal exposure to lead and no demonstrable disease of the meninges or central nervous system. Lead has been found in the cerebrospinal fluid of infants by Tada, Kasahara and Arimichi (see pp. 30, 165ff.). \ As has been stated (p. 8), the upper limit of normal blood lead concen- tration has been set at 0.01 to 0.13 mg. per 100 cc. of blood by different investigators. Much of this discrepancy can be attributed to differences ABSORPTION, TRANSPORTATION, EXCRETION OF LEAD 11 in analytic method. It seems advisable to regard 0.08 mg. per 100 cc. as being extreme upper limit of normal, although probably the great majority of normal subjects without undue exposure to lead will present values below 0.06 mg. per 100 cc. Litzner and Weyrauch? believe that the earliest objective manifestations of lead poisoning may appear with blood lead concentrations between 0.03 and 0.06 mg. per 100 cc. and that values above this level are usually accompanied by outspoken manifestations of lead poisoning. The highest concentration observed by Litzner and Weyrauch? was 0.5 mg. per 100 cc. but Smith, Rathmell and Marcil reported values up to 0.64 mg. per 100 cc. in clinical plumbism and 1.06 mg. per 100 cc. in a patient with carcinoma receiving active lead therapy. The relation of the concentration of lead in the blood to the development of symptoms of lead intoxication is considered in detail elsewhere (p. 155). There is some difference of opinion regarding the rapidity with which lead leaves the blood following its injection intravenously. According to Newman, when colloidal lead phosphate is injected intravenously in horses about 90 per cent leaves the blood stream in one hour and none can be demonstrated at the end of two hours following injection. Behrens and Giinther found that lead leaves the blood for the tissues of the guinea pig over a period of several hours, after which time the blood level tends to remain rather constant. After twenty-four hours, 16 to 50 per cent of the quantity injected could be recovered from the blood. Kasahara and Arimichi believe that the concentration of lead in the blood depends to a certain extent upon the age of the subject. This belief was based upon the observation that following intravenous injection of lead, lower concentra- tions were found in the blood of young than of mature rabbits. With the introduction of methods capable of determining accurately very small quantities of lead, attempts have been made to establish the relation- ship between disturbances in the partition of lead in the blood and the appearance of manifestations of lead intoxication. Behrens and Pachur found that the proportion of lead in the serum rose as the total blood lead concentration increased. The observations of Smith, Rathmell and Marcil suggest that the presence of lead in the serum fraction following defibrina- tion of the blood is related to the development of manifestations of lead intoxication more directly than is the concentration of lead in whole blood. Serum lead concentrations of 0.02 to 0.15 mg. per 100 cc. were observed in a group of 41 cases of acute or chronic active plumbism, 52 per cent of whom had whole blood lead concentrations either bordering on the normal or well within the normal range. On the other hand, no lead was found in the serum of 18 subjects with inactive lead poisoning (no symptoms), in all of whom the whole blood lead concentration was abnormally high (0.07 to 0.64 mg. per 100 cc.). This subject is discussed in detail elsewhere (p. 155). 12 LEAD POISONING Lead in Tissues The term normal is used here to signify the absence of undue exposure to lead. Much of the early data dealing with this problem must be discounted because of the common practice at that time of sweetening wine with lead acetate and the wide use of pewter dishes, lead pipes and lead medication. With the gradual elimination of sources of contamination of food and drink, the quantity of lead found in the tissues decreased and, as early as 1903, Meillere? could demonstrate lead only occasionally in the tissues of unex- posed subjects, most frequently in the hair, nails and bones. As recently as 1926, Aub and his associates stated that they found no lead in the bones in 19 of 26 cases without plumbism and with no recent industrial exposure to this element. Since then, however, by improved analytic methods, many observers have demonstrated lead in the tissues, particularly in the skeleton, of practically all normal subjects investigated. The source of this “normal” lead is discussed elsewhere (p. 167). It is interesting to note that lead has been found in the tissues of various wild and domestic animals (Pfrieme). Kehoe? # states that the average normal adult has about 100-400 mg. of lead in his tissues. It has been found in the tissues of still-born fetuses of mothers with no evidence of lead poisoning and with no history of undue exposure (Gant; Hansmann and Perry; Kehoe, Thamann, and Cholak?). This evidence of the transfer of lead across the placental membrane is supported by the results of observations upon animals (Morris et al; Bau- mann; Calvery). The following findings were reported by Gant in still- born fetuses: Liver, 0.047 to 0.049 mg. per 100 gms.; kidneys, 0.019 to 0.021 mg. ; sternum and ribs, 0.050 to 0.090 mg. Values two to three times as great as these were reported by Tompsett and Anderson!. Hansmann and Perry found lead in 62.59, of fetuses ranging in age from 11 to 24 weeks (trace to 25.7 mg. per 100 gm. dry weight). In two instances in which abortion was believed to be due to lead poisoning, the fetal tissues contained 8.6 and 25.7 mg. Pb per 100 gm. dry weight, the concentration in the remainder ranging from 0.0 to 0.9 mg. per 100 gm. Of fetuses from 43 months to term, 809, had lead in the ribs or liver or both. In the absence of probable lead poisoning, the concentration in the ribs was 0.000— 6.988 mg. per 100 gm. and in the liver 0.000-2.417 mg. per 100 gm., the former exceeding the latter in each instance. In one case of lead intoxica- tion (?), the fetal ribs contained 23.058 and the liver 4.650 mg. per 100 gm. During pregnancy, the immediate source of fetal lead is, of course, the maternal blood, and it appears to be present in the fetal tissues in con- centrations somewhat lower than those of the corresponding maternal tissues. After birth the child is exposed to additional sources of lead in food, drink, and the atmosphere under normal conditions. The presence ABSORPTION, TRANSPORTATION, EXCRETION OF LEAD 13 of lead in breast milk under experimental conditions has been demonstrated by Morris and his associates (see also p. 40). The concentration of lead in the tissues increases until the age of approximately two years (Kehoe, Thamann and Cholak?+#; Tompsett and Anderson!), thereafter remaining approximately constant under normal conditions. According to Gant, from pre-school age until very old age, lead maintains an average concen- tration of approximately 0.2 mg. per 100 gm. in the liver, 0.1 mg. in the kidneys, and 1.3 mg. in the sternum and ribs. Data reported by other observers (Barth; Roche-Lynch; Tompsett; Morris; Weyrauch and Miiller) indicate that much higher concentrations may be present in other portions of the skeleton, particularly the long bones, and that this concentration may gradually increase with increasing years. According to Morris, there is a significant increase with age in the lead content of four different human bones from different subjects, when expressed as milligrams of lead per kilogram of fresh bone, the increase being less marked in the rib and verte- bra than in the femur and tibia. The increase in the femur per year was 0.810 mg. per kilogram of fresh bone, in the rib 0.060 mg. and in the verte- bra 0.044 mg. On the other hand, Kehoe does not believe that available evidence justifies the conclusion that there is a progressive accumulation of lead in the skeleton throughout life. In his opinion, within certain re- stricted limits of lead intake, a state of dynamic equilibrium is maintained in the human body whereby lead intake and output are balanced over long periods of time, preventing progressive accumulation in the tissues. Data regarding the quantity of lead in the tissues of normal subjects are pre- sented in Table 2. The factors which influence the distribution of lead throughout the organ- ism are considered elsewhere (p. 16ff.). Suffice it to state here that during the period ranging from early childhood to old age, in the absence of undue exposure, the body is apparently in a state of equilibrium with regard to lead, excretion keeping pace with absorption, thus preventing any signifi- cant increase in its concentration in the tissues, with the possible exception of the solid portion of the bones. Factors Influencing Distribution and Deposition of Lead In the absence of more specific information than is at present available regarding the form in which lead exists in the circulating blood, no definite statement can be made regarding the possible influence of factors operating in the blood itself upon the concentration, distribution or deposition of lead in the tissues. There is evidence, however, that these phenomena are in- fluenced by a number of factors under physiological and pathological con- ditions. The effect of the majority of these factors is particularly demon- strable and important in the presence of abnormal exposure to lead and of 14 LEAD POISONING TABLE 2 Normal Tissue Lead (After Hansmann and Perry) Author Tissue Fresh Weight Dry Weight Ash mg. per 100 gm. | mg. per 100 gm. | mg. per 100 gm. Tompsett and Anderson Vertebra 0.2 - 1.47 (0.6 — 4.41 | 1.00- 7.35 Tompsett 0.46 — 1.65 | 1.38- 4.95 | 2.30 8.25 Maulbetsch 0.28 — 0.92 | 0.84- 2.76 | 1.4 — 4.6 Tompsett Femur 1.82 -10.83 | 5.46-32.5 | 9.1 — 54.1 Roche Lynch 2.356 -13.25 | 7.05-39.7 (11.7 - 66.2 Hansmann and Perry 2.583 7.749 12.915 Bagchi 1.2 -2.26({3.6-6.78|1.5- 3.0 Maulbetsch 0.07 - 0.66 | 0.21- 1.98 | 0.35- 3.3 Kehoe 0.8 - 3.59 Tompsett Tibia 1.53 - 9.65 | 4.59-28.95 | 7.65— 48.2 Bagchi 0.68 — 1.45 | 2.04- 4.35 | 3.4 - 7.25 Roche Lynch Humerus 4.1 -5.5 [12.3 -16.5 (20.5 - 27.5 Hansmann and Perry Rib 0.0 -2.88]|0.0-8.64|0.0-14.4 Tompsett 0.4 -1.75(1.2-5.25|2.0- 8.85 Tompsett and Anderson 0.15 — 1.29 | 0.42- 2.31 | 4.25- 23.1 Bagchi 0.82 - 0.85 | 2.46 2.55 | 4.1 — 4.25 Kehoe 0.39 - 1.11 Bagchi Skull 1.48 4.44 7.4 Maulbetech calvarium 0.08 — 0.44 | 0.24- 1.32 | 0.4 - 2.2 maxilla 0.44 - 1.22 | 1.32- 3.66 [ 2.2 - 6.1 Roche Lynch Teeth 4.25 24.75 | 4.71-27.47 | 5.86- 34.15 Maulbetsch 1.01 -5.65(1.12-6.27 | 1.4 - 7.8 Pfrieme 0.48 - 6.21 | 5.38- 6.90 | 0.67- 8.58 Bagchi 1.556 - 2.3 | 1.72- 2.55 | 2.13- 3.17 Hansmann and Perry Liver 0.00 — 4.20 | 0.00-21.03 | 0.0 210.3 Hijman 0.00 - 3.06 | 0.00-15.3 | 0.0 -153.0 Tompsett and Anderson 0.08 — 0.46 | 0.42- 2.31 | 4.25- 23.1 Roche Lynch 0.00 — 0.18 | 0.00- 0.90 | 0.00- 9.00 Weyrauch and Miller 0.02 - 0.24 | 0.10- 1.20 | 1.00- 12.0 infant 0.11 —- 0.04 children 0.05 — 0.297 Gant youth 0.07 - 0.237 middle age [0.112 0.307 aged 0.038- 0.208 Kehoe 0.05 — 0.94 ABSORPTION, TRANSPORTATION, EXCRETION OF LEAD 15 TABLE 2—Continued Author Tissue Fresh Weight | Dry Weight Ash mg. per 100 gm. | mg. per 100 gm. | mg. per 100 gm. Tompsett and Anderson | Kidney 0.072- 0.355] 0.36— 1.77 | 3.60- 17.7 Kehoe et al. 0.02 - 0.04 | 0.10- 0.20 { 1.0 — 2.0 Bagchi 0.037- 0.071] 0.18- 0.35 | 1.85- 3.55 Hijman 0.00 — 3.12 | 0.00-15.6 | 0.0 -156.0 infant 0.014- 0.028 children 0.038- 0.143 Gant youth 0.042- 0.168 middle age [0.054 0.115 aged 0.029- 0.108 Kehoe 0.02 - 0.08 Hijman Brain 0.00 — 0.36 [0.00- 2.4 [0.0-24.0 Weyrauch and Miiller 0.02 - 0.03 |0.133- 0.19 | 1.33- 1.99 Bagchi 0.00 — 0.01 [0.00- 0.06 | 0.0 — 0.66 Bertrand and Ciurea 0.04 — 0.06 Kehoe 0.01 —- 0.10 Hansmann and Perry Spleen 2.408 12.403 124.03 Tompsett and Anderson 0.06 — 0.59 | 0.31- 2.95 | 2.15- 29.5 Bagchi 0.03 - 0.05 | 0.15- 0.26 | 1.50- 2.60 Weyrauch and Miller 0.02 - 0.04 | 0.10- 0.20 | 1.0 = 2.0 Kehoe 0.01 — 0.07 Hansmann and Perry Pancreas 3.396 16.981 169.81 Bagchi Thyroid 0.04 — 0.06 | 0.20- 0.30 | 2.0 - 3.0 Tompsett and Anderson Lung 0.02 — 0.088] 0.13— 0.44 | 1.30- 4.40 Bagchi 0.03 - 0.06 | 0.15- 0.30 | 1.5 - 3.0 Bagchi Uterus 0.005- 0.047( 0.02- 0.23 | 0.25- 2.35 Bagchi Heart 0.045- 0.075| 0.22- 0.37 | 2.25- 3.75 Hansmann and Perry 3.45 17.27 172.7 Bagchi Muscle 0.014- 0.7 | 0.07- 0.35 | 0.70- 3.5 Roche Lynch Bone Marrow [1.756 - 5.0 Hansmann and Perry Placenta 0.392 1.959 19.59 Minot and Aub 0.00 — 2.08 | 0.00-10.4 | 0.0 -104.0 Bagchi 0.03 - 0.036] 0.15- 0.18 | 1.5 — 1.8 16 LEAD POISONING TABLE 2—Continued Author Tissue Fresh Weight Dry Weight Ash mg. per 100 gm. | mg. per 100 gm. | mg. per 100 gm. Bagchi Cartilage 0.045- 0.325 0.11- 0.81 | 9.0 — 65.0 Kehoe et al. 0.00 — 0.255 0.0 — 0.63 | 0.0 — 51.0 Bagchi Fat 0.0 0.0 0.0 Kehoe et al. 0.0 0.0 0.0 Kehoe et al. Ovary 0.0 0.0 0.0 Kehoe et al., Prostate 0.0 0.0 0.0 Kehoe et al. Bladder 0.0 0.0 0.0 Bagchi Testes 0.003- 0.04 | 0.01- 0.20 | 0.15- 2.0 abnormal quantities of lead in the tissues. However, they will be consid- ered here because of their possible relation to the normal intermediary metabolism of this substance. Influence of Portal of Entry on Distribution of Lead. Many of the early data regarding the distribution of lead in the various tissues is of purely historical interest because of the failure to recognize the influence of time and the portal of entry in this connection. Some observers stressed the significance of the lead content of the muscles (Gusserow; Rosenstein; Hitzig) and others that of the central nervous system (Heubel). It was recognized by some (Gusserow; Heubel) that the highest concentration of lead usually was found in the bones and data presented by Meillere? illustrated the difference in distribution of lead at various stages of plumb- ism and the apparent localization in the bones in chronic cases. The latter observation was also made by Prevost and Binet, who pointed out the fact that the liver contained relatively large quantities of lead in acute experi- mental plumbism induced by gastrointestinal absorption of lead. As stated by Aub and his associates, these observations were made under a variety of conditions and the analytic procedures employed were varied and often so inaccurate they could result in no clear concept of the fate of lead in the organism. More recent studies, under carefully controlled conditions and employing uniform methods, have added greatly to our understanding of this subject (Minot; Minot and Aub; Aub, Fairhall, Minot and Reznikoff; Behrens and Baumann; Weyrauch?). It is generally agreed that in chronic experiments employing the gastro- intestinal route of administration of lead the highest concentrations are found in the bones, smaller amounts in the liver and kidneys and the lowest ABSORPTION, TRANSPORTATION, EXCRETION OF LEAD 17 concentration in the muscles, heart, blood, lungs and brain. Within twenty-four hours after the oral administration of lead chloride to mice, Behrens! 2 found the largest quantity in the bones, a relatively large amount in the kidneys and very little in the liver. Schmidt, too, found more in the kidneys than in the liver of rabbits. Danckwortt and Jiirgens reported the highest concentration in the bones and smaller quantities in the spleen, brain, kidneys, bile, stomach, lungs, heart and liver, in order of decreasing concentration. Weyrauch! 2345 observed considerable deposition of lead in the kidneys and liver and also in the bones of rabbits seven hours after oral administration of white lead. Only traces were present in the muscles TABLE 3 Distribution of Lead in Cats after Absorption by Different Routes (After Aub, Fairhall, Minot and Reznikoff) Distribution of Total Lead Dura- Route of Absorption Hon of Ph jg Gastro-| ga: iy i Shales Liver | Muscle | Kidney inten oy Tract Cord days mg. % % % % % % Gastrointestin + 18 [24.85 | 40.9 | 21.8 | 12.4 | 11.3 | 10.8 | 0.0 i a aa a LA 124 [88.99 |85.5| 3.6 | 4.0| 2.4| 3.2 0.2 : 1 |16.72 90.5 | 6.0 0.0 ({:3.5 Respiratory Tractf........ { 4 42.64 | 89.0 | 10.3 07! 0.0 eg 132 5.7 {86.76.67 2.010.711 8.5{:0.0 Subcutaneous Injection... 149 29.2 |99.4| 00! 0.0! 0.6] 0.0] 0.0 * 50 mg. Pb (lead acetate) per kilogram by stomach tube every other day. t Single insufflation of 200-250 mg. Pb (suspension of lead carbonate in salt so- lution). t Single subcutaneous injection of 220 mg. of Pb (lead carbonate). and none could be detected in the lungs, brain and spleen. The quantity in the liver and kidneys diminished in 12 to 24 hours and, in chronic experi- ments, only minute amounts were present in the liver at the end of three weeks. The observation of a large amount of lead in the kidneys and the bones within a few hours after introduction into the intestines suggests that the liver does not invariably constitute a firm protective barrier to the entrance of lead into the general circulation. It is possible that the liver does not completely remove lead from the portal blood, but it is also possi- ble that some lead is absorbed from the bile directly into the general circula- tion by way of the intestinal lymphatics. "Parenteral administration has been employed extensively in experimental 18 LEAD POISONING animals. In both acute and chronic plumbism in dogs following subcutane- ous injection of lead salts, Weyrauch!+? found the largest deposits in the kidneys and smaller quantities in the bones and liver. Oppenheimer re- ported the largest quantity in the skeleton and less in the liver, kidneys, muscles, and brain. In 24 hours after the subcutaneous injection of radio- active lead, Lomholt! found extensive deposition in the liver, somewhat less in the kidneys, but only in the cortex, and also considerable amounts in the spleen. In new-born rats, the skeletal deposits occurred chiefly in the zones of ossification and in the periosteum, and more lead was found in the liver than the kidneys. Similar observations were reported by Behrens and by Christiansen, Hevesy and Lomholt. Colloidal preparations of lead, injected subcutaneously, are distributed in much the same manner as soluble lead salts. They are, however, more slowly absorbed. At the site of injection, Paroni! noted giant cells and mononuclear leukocytes and he also found lead granules in the lymph channels and lymph nodes a long time after injection. When injected intramuscularly, even readily soluble lead salts cause a rather marked local reaction, and absorption is relatively slow but not as slow as from avascular subcutaneous tissues (Flury?). Em- ploying this route, Lomholt' found the largest quantity of lead in the intestinal contents, the next higher concentration in the liver, about one- half as much in the kidneys and very little in the heart and blood. Unfortunately, it is difficult to interpret many of the data reported fol- lowing intravenous injection of lead because of the unusually large doses that have frequently been employed. The sudden introduction of rela- tively large quantities of lead into the blood stream creates conditions not at all comparable to those encountered in clinical exposure to lead, and results obtained under such conditions must be interpreted with caution. Behrens and Baumann showed that the distribution of lead in the tissues following intravenous administration depends upon the amount injected. With small doses, the largest quantities are found in the renal cortex and the liver, and much less in the bones, spleen, intestines and blood. With larger doses, most of the lead is deposited in the liver and only small quantities in the spleen and blood and very little in the bones, kidneys and intestines. According to Weyrauch?, after the intravenous injection of relatively large doses of lead nitrate in rabbits, the storage of lead parallels more or less the distribution of reticulo-endothelial cells. The largest quantity was deposited in the liver, and smaller amounts, in order of decreasing concen- tration, in the spleen, lungs, bones, kidneys, and blood. There was usually none in the intestines (exclusive of their contents) and none in the brain and muscles. However, Kisskalt and Friedmann reported significant amounts in the brains of rabbits after administration of lead acetate ABSORPTION, TRANSPORTATION, EXCRETION OF LEAD 19 intravenously. Early storage of lead in the reticulo-endothelial system appears to occur most strikingly following intravenous injection of colloidal lead preparations (Timm; Dilling and Haworth; Todd; Flury?; Weyrauch). Flury? found the largest amount in the liver, spleen and bone marrow, storage in the liver occurring chiefly in the Kupffer cells and, to a lesser extent, in the hepatic cells, while that in the kidney occurred chiefly in the epithelial cells of the convoluted tubules. According to Simon, the largest amounts are found in the kidneys, liver and intestines and none could be demonstrated in the central nervous system. Similar findings were re- ported by Orestano, who also found that following repeated intravenous injection of lead nitrate the brain contained more lead than the liver. Colloidal lead preparations are also absorbed readily from the intestines, serous cavities, the anterior chamber of the eye and the subcutaneous tissues (Simon; Chistoni and Milanesi). The distribution in the tissues of volatile organic lead preparations, such as methyl, ethyl and phenyl lead compounds, is somewhat different from that of the inorganic lead salts. According to Flinn, tetraethyl lead, which may enter the body through the skin and the lungs, may be retained in the organism for relatively long periods of time. Kehoe and Thamann showed that this substance circulates in the blood as such before being deposited and that its distribution in the tissues is similar to that of fat-soluble sub- stances. Disappearing rather quickly from the blood and kidneys of rab- bits there was an early increase in its concentration in the bones and muscles and, subsequently, a significant increase in the central nervous system, in which tissue it was found in high concentration in fatal cases. Eventually, the distribution of lead in the tissues resembles that which follows the ad- ministration of water-soluble preparations. According to Ehrenberg, triethyl lead is more toxic than triphenyl lead, the largest quantities of lead being found in the blood, large intestine and liver following injection of the former and in the central nervous system following administration of the latter. As stated by Aub and his associates, analysis of the data obtained fol- lowing absorption by the gastrointestinal tract, the respiratory tract and from the subcutaneous tissues reveals the following points of similarity: (a) the high percentage of total lead present in the skeleton and (b) the relatively uniform order of concentration in the soft tissues following ab- sorption from different situations, with the exception of those tissues directly in the path of absorption. The most obvious differences were (a) the much higher concentrations of lead in the liver and gastrointestinal tract following gastrointestinal absorption, and (b) the relatively large quantities of lead in the tissues within a very few hours or days following absorption from the respiratory tract as compared with the amount present 20 LEAD POISONING after much longer periods following absorption by the other routes. As pointed out by these authors, lead absorbed in the gastrointestinal tract is carried in the portal blood to the liver, which removes a large portion of it from the blood and excretes it in the bile into the intestine, where some of it is excreted in the feces and some reabsorbed, this entero-hepatic circulation continuing as long as lead is present in this situation. Considerable quan- tities of lead may be retained in the liver for relatively short periods of time, a small amount escaping into the general circulation and being distributed throughout the organism. This mechanism accounts for both the relatively small quantity of lead in the tissues other than the liver and intestines and TABLE 4 Percentage of Total Stored Pb in Organs (After Martini) Animal Plumbism Bones | Liver | Kidney | Blood Lungs Brain Oral % % % % % % Rabbit acute 12-18 30 44-60 8-13 oe font Cat acute- 47-68 10-30 5-6 ro 1-1.5 0.95 subacute Respiratory Tract Rabbit acute 11-29 13-40 30-56 | 3.8-9.5 — —_ Cat acute 32-86 5-11 0-0.18 — -_ — Parenteral Rabbit acute 22-30 10-17 51-54 6-7 oe ro Mouse 1 hour 7.7 26.2 48.5 18 or —_ Cat subacute 93 3.3 0.65 oe en — the late appearance of toxic manifestations following gastrointestinal ab- sorption (Aub, Fairhall, Minot and Reznikoff). On the other hand, lead absorbed from the subcutaneous tissue or the respiratory tract enters the systemic circulation directly and the liver receives only that portion con- tained in the hepatic artery blood. These data indicate that, if those tis- sues be excluded which lie directly in the path of absorption, the relative concentrations of lead in the soft tissues is approximately in direct ratio to their vascularity, the most striking phenomenon in this connection being the great affinity between lead and bone. It would appear, therefore, on the basis of these and similar observations, that regardless of the route of absorption, or whether the lead is in organic, inorganic or colloidal form, ABSORPTION, TRANSPORTATION, EXCRETION OF LEAD 21 the primary distribution in the tissues is essentially the same. Immediately after entering the general circulation it is distributed throughout the viscera, to the greatest extent in the liver, muscles, spleen and kidneys. After a few days, however, it gradually collects in increasing quantities in the bones, which eventually contain practically all of the lead retained in the body (Aub et al.; Weyrauch!—5; Behrens and Baumann; Kehoe and Thamann). According to Kehoe and Thamann, the same is true even of relatively stable organic compounds such as tetraethyl lead, in spite of its great solubility in the body lipids. Analysis of the tissues of animals several weeks after recovery from severe acute plumbism resulting from gastrointestinal administration of lead has revealed almost complete locali- zation of lead in the skeleton (Aub et al.). The following statements seem justified on the basis of these observations (Aub et al.): (1) Following its entrance into the general circulation, lead comes in contact with all of the body tissues, producing certain untoward reactions with consequent local damage if the proper conditions exist. (2) It is not stored for very long in the soft tissues, which may nevertheless be injured, but is eventually removed and reenters the general circulation. This is not necessarily due to an absence of chemical affinity between lead and these tissues, but merely implies that lead compounds resulting from interaction with these tissues are not retained. (3) This course of events may recur repeatedly until the lead entering the circulation is either excreted in the feces or urine or is stored in the skeleton. The fate of this skeletal deposit will be considered subsequently. Storage of Lead in the Skeleton. The work of Minot and Aub and their associates has demonstrated rather conclusively the similarity of behavior of lead and calcium as regards their deposition in and mobilization from the bones. No exact information is available regarding the form in which lead exists in the bones and the mechanism of its deposition. However, experimental observations of these authors and of Fairhall seem to warrant the following conclusions: (a) Under conditions of normal hydrogen-ion concentration, lead is deposited in the bones, possibly by adsorption, as the tri-lead phosphate in colloidal form. The remarkable capacity of bone for removing lead from solution or suspension is not dependent upon the protein content of the bones. (b) During the process, at least in vitro, calcium is liberated from the calcium phosphate of the bones and is replaced by lead. (c) The tri-lead phosphate thus deposited is quite inert and in- soluble under conditions of normal hydrogen-ion concentration, but any significant change in the latter toward either the acid or the alkaline side. allows it to be gradually transformed into di-lead phosphate, which is 100 times more soluble (Fairhall; Aub, Fairhall, Minot and Reznikoff). (d) This response to local changes in reaction of the tissues, particularly to 22 LEAD POISONING variations caused by lactic acid, may result in mobilization of lead within the organism and in manifestations of intoxication. It is believed by most authorities that this deposition occurs practically entirely in the solid portions of the bones and according to Aub, usually in the endosteum and occasionally near the capillary walls (Aub et al.; Behrens!; Roche-Lynch; Weyrauch!—%; Monier-Williams). On the other hand, Biichler found the highest concentrations in the spongiosa and marrow, with more in the flat than in the long bones. Certain interesting observations have been made regarding the distribution of lead in various portions of the skeleton. It has been found that flat bones (skull, pelvis, scapula) contain more lead than tubular bones (Danckwortt and Jiirgens; Biichler), the femurs and tibiae more than the ribs and vertebrae (Tomp- sett), the ends of long bones more than the shafts (Grant; Park et al.), and the teeth proportionately more than the bones (Maulbetsch and Rutis- hauser). In the teeth, lead appears to be localized principally in the dentin of the roots. Chemical analyses have shown that the concentration of lead is higher in the subepiphyseal zones than in the remainder of the shaft, particularly during the period of active growth (Caffey), and similar studies by Aub, Robb and Rossmeisl have shown that it is stored in relatively high concentration in the trabeculae, especially at the epiphyses. Following administration of radioactive lead in new-born mice, Lomholt demonstrated relatively large quantities in the bones, most of which was in the zones of calcification and in the periosteum, with very little in the marrow. Similar observations were made by Behrens and Baumann in young and growing mice and rats. Relatively large quantities of the radioactive lead were deposited in the sub-epiphyseal zones of the long bones, in a very narrow subperiosteal zone, at the costochondral junctions and in the dental pulp. There was very little in the marrow and none could be detected in the cartilage. By this ingenious procedure, these observers appear to have established the parallelism between the deposition of lead and of calcium in embryonal, growing and mature bones. It would also appear that the higher concentrations of lead in flat and in long bones may be due to the fact that the subperiosteal zone, in which lead appears to be deposited in large quantities, occupies a relatively large proportion of the total mass of the former than of the latter. The intimate relationship between the deposition of these two elements is indicated by other observations. No lead could be demonstrated in the bones of rachitic rats in the areas in which large quantities are usually deposited. Intensive storage was noted promptly following correction of the metabolic defect by administration of vitamin D. Increased deposition of lead was also noted in the callus at the site of fractures and also in regions of pathological calcification. The latter included (a) calcification of the convoluted tubules of the kidneys of ABSORPTION, TRANSPORTATION, EXCRETION OF LEAD 23 rats following ligation of the renal arteries, (b) calcification of the placenta and fetus following death in utero and (c) calcification in the heart, large vessels, kidneys and placenta in rats and mice following large doses of calcium gluconate and irradiated ergosterol. Increased deposition of lead (radioactive) was demonstrable in all of these areas of abnormal calcium deposition. The influence of age in this connection is of great interest and importance. In general, it may be stated that growing bones retain lead more avidly and at lower levels of lead intake than mature bones and the skeletal deposits are more stable in young than in mature animals (Shields, Mitchell and Keith; Kasahara and Nasu; Calvery). According to Calvery, the lead content of the femurs of dogs receiving 64 mg. of lead per kilogram of diet intake was as follows: young dogs (51-84 days), 126.5 mg. per 100 gms. of dry weight; half-grown dogs (208-226 days), 41.5-66.7 mg.; mature dogs, 19.4-22.4 mg. X-ray studies by Park, Jackson and Kajdi indicate that, in children, lead is deposited in the trabeculi of actively growing bones in close proximity to the cartilage. Similar studies by Caffey reveal that lead is deposited particularly in the growing portions of the skeleton of children, as evidenced by the appearance of a series of transverse lines in the di- aphyses and linear rings of density in ossification centers of the epiphyseal cartilages and carpal bones. These roentgenographic observations of bones suggest that lead may be repeatedly mobilized from these deposits and be redeposited along the epiphyseal lines of growth (Vogt! 2). The investigations of Aub and his associates upon the lead content of bone and urinary excretion of lead in animals and patients with plumbism demonstrated that a striking analogy exists in the metabolism of calcium and lead. These and subsequent studies appear to indicate that conditions which favor calcium retention simultaneously favor the deposition of lead in the bones and, conversely, factors which tend to produce mobilization of calcium from the bones also tend to liberate lead from its skeletal deposits. In other words, the stream of lead to and from the skeleton tends to follow that of calcium. Accordingly, the administration of large doses of calcium salts or a high calcium diet is accompanied by increased deposition of lead in the bones and a decrease in the quantity excreted in the urine (Aub et al. ; Minot). A similar increase in skeletal storage of lead has been observed following the administration of therapeutic doses of Vitamin D in young and particularly in rachitic animals (Calvery; Behrens and Baumann; Sobel et al.). Shelling believed that the production of this effect was dependent upon the maintenance of a high phosphate as much as, if not more than a high calcium intake. In view of the complexity of the problem of calcification, it seems clear, as pointed out by Sobel and his associates, that many factors must be taken into account in considering the factors 24 LEAD POISONING which may influence the deposition and mobilization of lead just as in the case of calcium and phosphorus. Among the most apparent of these factors are the intake of Vitamin D, the calcium and phosphorus content of the diet and of the blood, the stage of skeletal development, the condition of parathyroid and thyroid activity, and the state of the general nutrition and of acid-base equilibrium. It is generally believed that in the absence of significant abnormalities in other factors, a high intake of calcium and phosphorus favors the storage of lead in the bones. However, there are conflicting opinions on this point. For example, Calvery, Laug and Morris found that whereas a suitable concentration of calcium in the diet of dogs retarded the onset of manifestations of lead poisoning, it also diminished the storage of lead in the bones and soft tissues. Similar findings were obtained in rats by Grant, Calvery, Laug and Morris. Lederer and Bing, on the basis of studies on young albino rats, concluded that the amount of lead stored in the body is diminished by the addition of calcium carbonate to the diet, while the addition of phosphate has no significant effect. They believe that the beneficial effect of calcium appears to be due to the pre- vention of absorption of lead from the intestine, because the calcium content of the diet has no significant effect on the retention of lead administered by intraperitoneal injection. Sobel, Yuska, Peters and Kramer studied the effects of different calcium-phosphorus ratios upon the retention of lead by young rats (low calcium-low phosphorus; high calcium-low phosphorus; high phosphorus-low calcium). The greatest degree of lead deposition was obtained with the low calcium-low phosphorus diet, the addition of either calcium or phosphorus reducing the quantity of lead deposited. The addition of vitamin D increased the deposition of lead with all types of diet. They believe that the deposition of lead involves a process analagous to that of calcification and that maximal deposition occurs with a dietary lead- phosphorus ratio similar to the dietary calcium-phosphorus ratio that is optimal for calcification. Addition of either calcium or phosphorus to such diets diminishes lead deposition just as it diminishes calcification. It was concluded that lead deposition is directed by a system governed by the same laws as is calcium deposition but does not necessarily proceed in the same direction. It appeared that the influence of calcium on the deposition of lead is essentially competitive, because it tends to remove phosphorus available for lead deposition. These conclusions are criticized by Lederer and Bing, who state that the data presented are equally in harmony with the view that conditions which favor deposition of calcium salts in the bones also favor deposition of lead. In adult animals, Tompsett failed to observe any effect of vitamin D on the storage of lead in the body. Shields and Mitchell found that retention of lead was increased by diets low in calcium or in phosphorus or in both, an observation which, according to ABSORPTION, TRANSPORTATION, EXCRETION OF LEAD 25 the work of Lederer and Bing, could be due to factors affecting absorption from the gastrointestinal tract. It must be concluded that the most recent evidence suggests that whereas the mobilization of lead from the bones parallels that of calcium, both being influenced in a similar manner by similar factors, the deposition of lead in the bones appears to take place in inverse relation to that of calcium. As suggested above, this may be due to the competition of these two elements for phosphorus. As has been indicated, factors which favor the mobilization of calcium and phosphorus from the bones tend to affect lead in the same manner. Among these are (a) an inadequate intake of calcium and phosphorus, (b) parathyroid hormone, (c) large doses of Vitamin D, particularly in the pres- ence of a low calcium and phosphorus intake, (d) thyroxin, and (e) increase in the hydrogen-ion concentration of the body fluids, either spontaneous or induced by the administration of acidifying agents (Aub, Fairhall, Minot and Reznikoff; Flinn and Smith; Aub; Grant et al.; Schmitt and Taeger; Hunter and Aub; Robb and Rossmeisl). In addition, mobilization of lead stored in the bones is also favored by increased alkalinity of the surrounding tissue fluids. The explanation for this is suggested by the observation of Fairhall and Shaw that changes in reaction towards either the acid or alkaline side allow the very insoluble tri-lead phosphate to be gradually transformed into the di-lead phosphate, which is 100 times as soluble. Absorption of lead by the bones appears to be greatest between pH 7.4 and 7.8. The site of storage of lead in the bones appears to have some influence upon the facility with which it may be mobilized. In studying patients with chronic plumbism, Hunter and Aub found that the urinary excretion of lead was increased when parathyroid hormone was first given, but that subsequent administration produced little or no increase. They explained this phenomenon on the basis that the lead excreted after the first doses of the hormone is loosely bound in the bones or has been recently ingested, being therefore readily available. The observations of Aub, Robb and Rossmeisl suggest that this readily available or mobilizable lead may be that portion which is stored in the trabeculi rather than in the cortex of the bones. Data reported by Gant are of interest in this connection. He found 52 per cent more lead in the cortex than in the trabecular portion of the sternum in a subject without plumbism and 78 per cent more lead in the trabeculi than in the cortex in a subject with active chronic lead poisoning. This suggests that trabecular deposits of lead may be of greater significance than cortical deposits in active lead poisoning. Gant believes that recently ingested lead may be first deposited as a loosely-bound compound in the trabeculi, from which it may be easily liberated, thus supplying a constant stream to the tissues through the blood. In time, increasing quantities are 26 LEAD POISONING deposited in the cortex, from which lead is apparently less easily mobilized and where it may remain deposited for an indefinite period. Although attractive, this hypothesis regarding the more ready mobilization from the trabecular than from the cortical portions of the bones cannot be accepted without reserve, in view of the probability that a similar hypothesis regard- ing the mobilization of calcium lacks foundation (Jaffe, Bodansky and Blair; Cantarow). Other aspects of this subject will be considered in discussing the excretion of lead and the treatment of lead intoxication (pp. 37, 194). It may be pointed out here, however, that these observations explain the long-recog- nized tendency for the development of acute episodes of lead intoxication long after the time of original exposure. Although lead stored in the skeleton appears to be harmless, a portion of it, at least, is apparently rather unstable chemically and, under the influence of various events and conditions, may be released into the blood stream from time to time with the consequent development of manifestations of lead intoxication. It should also be pointed out that lead present in the blood stream at any given time may represent either absorption or mobilization, or both; in other words, the lead stream may be toward or away from the bones. This fact is of obvious medicolegal significance. Deposition in Other Tissues. Deposition of lead in tissues other than the skeleton has already been referred to in passing. It seems advisable to summarize here briefly the present views regarding the lead content of various tissues in lead poisoning. As has been indicated elsewhere (p. 18), some observers believe that reticulo-endothelial cells possess a peculiar affinity for lead and that this element is selectively stored in organs in which these cells are particularly concentrated. The validity of this hypothesis is questioned by Flury?, who believes that the frequently high lead content of the spleen and lungs, for example, especially after intravenous injection of lead preparations, is due chiefly to the unusually large amount of blood in these organs. Liver. The liver serves three important functions in regard to lead: (a) it removes lead from the portal blood following absorption from the intes- tines and thus constitutes a barrier to the immediate entrance of large quan- tities into the systemic circulation within a short period of time; (b) under certain circumstances, relatively large quantities of lead may be stored in the liver, usually for comparatively short periods of time; (c) it plays an important part in the excretion of lead (in bile). Apart from the quantity of lead entering the body, the lead content of the liver depends largely upon the avenue of entrance and the duration of exposure as well as the time which has elapsed since the last exposure. In general, the largest quantities are found in this organ in acute lead intoxica- tion resulting from gastrointestinal absorption. In gradual chronic lead ABSORPTION, TRANSPORTATION, EXCRETION OF LEAD 27 poisoning, by far the largest deposits occur in the skeleton, but the liver usually contains more than the other soft tissues. Although Behrens and Baumann found lead in the bile within several minutes after intravenous injection, lead usually remains in the liver for some time, a fact which explains the relatively late development of manifestations of lead intoxica- tion after ingestion of lead. According to Timm, when introduced into the portal circulation lead is removed from the blood by the Kupffer cells and then passes to the polygonal cells of the liver, being distributed chiefly in the peripheral zone of the lobules (Tada; Behrens and Baumann). Quite different findings are obtained when lead enters the body through the respiratory tract or by subcutaneous, intramuscular, intravenous or intraperitoneal injection. Following insufflation of lead, its concentration in the liver is usually not much higher than that in other organs, particularly after some time has elapsed. One hour after intravenous injection, Beh- rens and Baumann found about 50 per cent of the quantity administered in the bones and about 25 per cent in the liver; later the kidneys contained more than the liver. Kidney. As is true of the liver, the quantity of lead in the kidney de- pends to a large extent upon the route of entrance into the organism and upon time factors. Following absorption from the intestine, in the early stages of lead poisoning the kidneys contain less than the liver and later they usually contain more, as has been indicated above. It has been shown that the deposits occur chiefly in the cortex (P. Schmidt!; Behrens and Baumann). In guinea pigs, lead was found first in the lumens of the vessels and the basal portions of the cells of the convoluted tubules and later within the lumens of the tubules. Following intraportal injection of lead sulphide in rabbits. Timm found deposits usually in the cells of the ascending limb of the loop of Henle and smaller quantities in the convoluted tubules, with fine granular deposits in the glomerular cells. Similar findings were also obtained in chronic lead intoxication, with further deposits in the capillary endothelium. The localization of lead in the latter situation suggests that the renal damage in lead poisoning may be primarily vascular in origin (Weyrauch?). According to Behrens and Baumann, one hour after intravenous injection in the rat, lead is found first in the upper portion of Henle’s tubules and the glomeruli while the convoluted tubules and col- lecting tubules contained none. In the mouse, after twenty-two hours, although small amounts may be scattered throughout the parenchyma, the only sites of intensive deposition are in the glomeruli. These studies, made with radio-active lead compounds, revealed that deposition in the kidney and excretion in the urine do not occur simultaneously nor to the same degree and that excretion in the urine continues for some time after entrance of lead into the organism has ceased. Muscle. Several early observers reported relatively large quantities 28 LEAD POISONING of lead in the muscles but this is not in accord with the observations of the majority of recent investigators (Flury?). Although at times relatively large quantities have been found in chronic experiments, more frequently none can be demonstrated. According to Aub, Fairhall, Minot and Reznikoff, the comparative freedom of muscular tissue in this respect may be dependent upon the formation of lactic acid, which facilitates the solution of lead phosphate and renders its storage in significant amount impossible. Intestines. The intestines, exclusive of their contents, usually contain relatively large quantities of lead even if only small quantities have been TABLE 5 Distribution of Lead in Human Tissues in Plumbism (After Aub, Fairhall, Minot and Reznikoff) Case 1 Case 2 Case 3 Case 4 Con- | potal | Son [ Total | $92 | Total | So | Total mg. % | mg. | mg. % | mg. | mg. % | mg. | me. % | mg. iver oak dno eat od 5.11 | 22.99| 0.12 | 1.65 0.68 | 10.88] 0 0 RIANBY. 0 aviva fe via ds sess 1.00 | 0.97/0.35| 0.94] 2.45 | 7.84] 0 0 Spleen: £0500 a va de ill £a4 4 1.07 0.77/1.59 | 2.23] © 0 0 0 Pancreas... ..... coisa banitoby 10.00 [| 1.09] — —_— oe — 0 0 LL RE A IR BERS a) 0.56 | 0.30{ 0.32 | 0.99, — _ 0 0 ang... of a se 0.32 | 0.61) 0.29 | 4.41] © 0 — — CleTebrum. vu «sis Senna niles 0.36 | 2.91 ©O 0 0.22 | 3.200 — Rx Cerebellum and Medulla. .... 0.62 | 0.65 0.49 | 0.71) 0.30 | — x pt Spinal Cord and Peripheral NOYES 5. oo chews wins wwe ps — - — —_ — — Skeletal Muscle.............. - — —_ — —_ er — pe BEEIBEOL. vials Lviv ais ane 2's 45 15.30 (195.8 | 2.24 [280.0 | 7.16 [800.0 | 2.17 [243.0 Washed Gastrointestinal OPRCE: Jud vies wiarive bw lle 0.46 | 1.59] — ot ot — 0 0 BOO iv hidinne s's rut wh iil uh Sia trace | — | 0.27 | — —_— —_— — BIE 8 Le dent ie dink vn Ra trace | — 0 0 ee — re administered. According to Behrens and Baumann, the heaviest deposits occur in the glandular epithelial cells, an observation which suggests that the high lead content of the intestines is related to its excretory function. However, obviously, observations made after introduction of lead into the alimentary tract must be interpreted with caution because under such circumstances processes of absorption and excretion in the intestines are proceeding simultaneously. This is true also following parenteral adminis- tration, because of the possibility of reabsorption of lead by the intestines after its excretion in the bile. Skin and Appendages. There have been several reports of the presence ABSORPTION, TRANSPORTATION, EXCRETIEN OF LEAD 29 of significant quantities of lead in the skin (Meillére?; Erlenmeyer?; Schiitz and Bernhardt; Aub, Fairhall, Minot and Reznikoff). After feeding lead to rabbits, Kisskalt and Friedmann found 2.48 mg. in 100 gm. of skin and TABLE 6 Distribution of Lead in Human Tissues (After Badham and Taylor) Normal Painter Lacquerer mg. % mg. % mg. % Long Bones. cus sia vasvnsns es —_— 0.72 ee SUOTIIIIL, /o v vite 1x » esinninssio s 3 0.04 1.48 0.08 Brain... nn a re 0.00 0.27 0.10 EE A AIA Ss ee A 0.09 0.08 0.11 LADIES i foils iis ow ni diminivs 0.00 0.05 0.06 HAVEL... ovoid vis Bas sninsvri sd 0.07 0.34 0.26 Heart ov. overt bos bases — _ 0.13 BVIIREI0 Lo. via foe min Sack roe 0.05 — TABLE 7 Distribution of Lead in Animals (After Flury) Author Animal Route Plumbism | Liver Li Bone Muse GUsSSeroOw... 0s vd iss rabbit | intestinal acute +3 | +3 | +4 | +2 and sub- acute Danckwortt and Jurgens.| dog intestinal chronic | +2 | 43 | +4 | +1 Buchler...«:.... ..ohv0n rabbit | intestinal chronic — | — | +4 | — Weyraueh..............u rabbit | intestinal chronic | +3 | +3 | +4 | +1 V. Lehmann.............| rabbit | subcutaneous| acute +1 | +3 | +3 | +1 Aub and Minot { cat subcutaneous acute +2 | 41 | +4 | — SRE cat subcutaneous| chronic | +1 | £ | +4 | * Weyraueh......... .. 0 rabbit | subcutaneous| acute +3 +3| 43] +1 Behrens and Baumann...| mouse | intravenous | after 1 +4 | +4 | +2 | — hour Kehoe and Thamann....| rabbit | intravenous | acute +4 | +3 | +1 | + Behrens................. cat intravenous | after 5 +4 | +1 | +1 | — hours Weyraueh......... 00 rabbit | intravenous | acute +4 | +143] 0 hair. Lead was also found in hair by Meillere! and in the toe nails of in- fants by Zangger and Baader. In a careful study of this problem, Behrens and Baumann were unable to demonstrate evidence of storage of lead in 30 LEAD POISONING the skin and could find it in the hair only near the site of injection. Similar findings were obtained by Melnick and Cowgill, who believe that the presence of lead in the hair depended upon external contamination. They suggest that the lead content of hair may serve as a measure of the degree of exposure and of the efficiency of devices used and measures taken to reduce the concentration of lead in the air of industrial plants. Lead has been found in the milk of women with no unusual exposure to lead, in concentrations of 0.00-0.05 mg. per liter (Kehoe, Thamann and Cholak) and has been demonstrated in the milk of rats with experimental “._plumbism (Calvery; Morris, Laug, Morris and Grant). ” Nervous System. There are wide discrepancies in the reports of thelead content of nervous tissue in subjects with lead poisoning. Variable amounts have been found by several observers (Oliver?; Heuble; Kisskalt and Friedmann; Danckwortt and Jiirgens; Schiitz and Bernhardt; Gusse- row; Aub et al.; Kehoe; Badham and Taylor; Lomholt?). Kisskalt and Friedmann found more in the brain than in other organs after intravenous injection. Many recent observers have been unable to demonstrate lead in the central nervous system (Legge and Goadby; Teleky’; Weyrauch?). As stated by Flury?, it seems apparent that the presence of lead in the nervous system is influenced by the quantity administered, the duration of exposure, the time elapsing since the last exposure, and the nature of the lead compound administered. V. Lehmann! injecting lead salts subcu- taneously, found only small amounts in the brain after a single injection and relatively large quantities after frequently repeated injections. Simi- lar observations were reported by Oppenheimer. As has been indicated elsewhere (p. 19), localization in the central nervous system is much more pronounced following exposure to volatile organic lead compounds, such as tetraethyl lead, than in the case of inorganic lead compounds (Kehoe and Thamann). According to Ehrenberg, this is even more true of phenyl lead than of ethyl lead preparations. Several authors have pointed out the striking discrepancy between the frequently marked manifestations of severe central nervous system dysfunction, such as encephalopathy, and the relatively small content and indeed at times complete absence of lead from the brain. Many early observers were unable to find lead in the cerebrospinal fluid (literature reviewed by Seiser and Litzner). Recent studies indicate, how- ever, that it may be present in this fluid even under normal conditions. According to Schmitt and Basse, normal cerebrospinal fluid may contain 0.015 to 0.038 mg. of lead per 100 cc. Values as high as 0.493 mg. per 100 cc. have been observed in patients and experimental animals with severe lead intoxication (Schmitt and Basse; Rabinowitch et al.; Duensing; Aub, Fairhall, Minot and Reznikoff). It is significant that the concentra- ABSORPTION, TRANSPORTATION, EXCRETION OF LEAD 31 tion of lead in the cerebrospinal fluid in lead intoxication bears no consistent relationship to the severity or nature of the clinical manifestations nor to the concentration of lead in the blood. EXCRETION OF LEAD Lead is eliminated in the body largely in the feces and urine. It has also been found in milk and may possibly be excreted to a slight extent by the skin. Excretion by the Gastrointestinal Tract. As stated by Aub and his asso- ciates, the fact that lead is eliminated in the feces has been well-established ever since the time of Tanquerel des Planches and data that have accumu- lated during the past century have led to the general belief that the entire alimentary tract excretes as well as absorbs lead. In animals and patients with plumbism it has been found in practically all portions of the gastro- intestinal tract and in its secretions, including the salivary glands and saliva (Blum; Renon; Pouchet'; Meillere?). The frequent complaint by patients with plumbism of a sweet “lead” taste is often cited as a suggestive indication of the excretion of lead into the mouth. However, as pointed out by Flury?, this may possibly be due to hypersensitivity of these specific taste buds (p. 102). It has also been claimed that the lead line in the gums and cheek is dependent upon excretion of lead by the gingival and buccal mucosa (Blum; Almkvist; Santesson). This subject has been considered in detail elsewhere (p. 77). Claims by early observers of significant ex- cretion of lead by the salivary glands appear to be discredited by recent observations with more satisfactory experimental methods (p. 79). In a careful study of 30 cases of lead intoxication, J. Schmidt was unable to find significant amounts of lead in the saliva in a single instance. Flury? believes that at the present time it is justifiable to assume that lead may be excreted in the saliva and the mouth secretions but probably only in insig- nificant quantity. In view of the important part played by the liver in the distribution of lead throughout the organism, particularly after absorption from the intestines, interest has naturally centered in the bile as a medium of excre- tion of this substance. Since the time of the early studies of Annuschat, practically all investigators of this problem have found lead in the bile, particularly in acute plumbism (V. Lehmann?; Harnack; Bricker; Legge and Goadby; Oliver’; Meillere'; Aub, Fairhall, Minot and Reznikoff; Brady). According to Harnack, the proportion of lead eliminated in the bile is greater following absorption by the gastrointestinal tract than by other routes, an observation which is in conformity with the fact, noted elsewhere, that under such circumstances the liver removes from the blood stream and retains relatively large quantities of lead. Data obtained by 32 LEAD POISONING Brady by direct cannulation of the bile ducts (rabbits) and the parenteral and oral administration of a large single dose of lead, indicate clearly an independent excretion of lead in the bile and in the secretions of thestomach, small intestine and cqlon. Following the intravenous administration of 69-130 mg. of lead or the oral administration of 546-1000 mg., the average hourly excretion of lead in the bile ranged from 0.03 to 1.00 mg. per hour, the average for all animals being 0.23 mg. per hour. As pointed out by Aub and his associates, this figure is considerably higher than would be expected in more chronic poisoning, an observation which was made in the early experiments of Annuschat. It has been found that there is no consistent quantitative relationship between the lead content of the liver and bile. V.Lehmann?, in animals with chronic lead poisoning, found more in the bile than in the liver and Annuschat found that at times no lead was excreted in the bile although significant quantities were present in the liver. Following injection of radio-active lead in rats with mild exposure, Behrens and Baumann observed its appearance in the bile after six minutes, the highest concentration being obtained at about fourteen minutes and then remaining constant for about one hour. There can be no doubt that lead is excreted in the bile even when absorbed through channels other than the gastrointestinal tract. Excretion of lead by the pancreas was demonstrated by Bricker, who found it in the pancreatic juice of dogs with pancreatic fistulae ten to nineteen days following its introduction into the body. Comparatively little accurate information is available regarding the quantitative excretion of lead by different segments of the intestine. Aliavdin and Peregood reported the interesting observation that the concentration of lead in the duodenal juice may be 10 to 30 times as high as in the urine. In one-third of their cases the duodenal juice contained 0.18 to 0.2 mg. per 100 cc. with none in the urine, in one-third, the former contained 10 times as much as the latter, while occasionally lead was present in the urine and not in the duodenal juice. Behrens and Baumann, studying the distribution of radio-active lead in the tissues of rats and mice, found the highest concentrations in the intestinal tract in the duodenum and particularly in the epithelial cells of the mucosal glands. However, after diverting the bile by means of a cannula, they found that this segment contained no more lead than did the remainder of the small intestine. It was therefore concluded that the higher lead content of the duodenum is attributable to the presence of bile and is probably dependent to a large extent upon absorption of lead previously excreted into its lumen in the bile. Excluding the liver, the large intestine apparently plays the greatest role in the excretion of lead by the gastrointestinal tract, as in the case of other heavy metals. Behrens and Baumann found that the lead in the ABSORPTION, TRANSPORTATION, EXCRETION OF LEAD 33 intestinal wall was concentrated particularly in the glandular epithelium, with only a small portion in the serosa. The observations of Huppert suggest that excretion occurs largely in the ileocecal region. Obviously, unless the possibility of entrance of lead into the alimentary canal can be rigidly excluded, the fecal lead may consist in part of that which has been absorbed and reexcreted into the bowel and in part of that which has passed through the gastrointestinal tract without having been absorbed (Oliver®; Legge and Goadby; et al.). Vigliani and Debernardi found that 84 per cent of the amount of lead ingested was excreted in the feces unabsorbed. Since the magnitude of this fraction must vary con- siderably under different conditions, it is apparent that the quantity of lead in the feces under conditions of exposure commonly encountered clinically cannot be regarded as an index of the amount of lead entering the body. Reported values for fecal lead in normal subjects without apparent undue exposure are presented in Table 8. TABLE 8 Normal Fecal Lead Author Lead in Feces mg. per 24 hours Kehoe, Thamann and Cholak...... .. 0.02-0.39 (av. 0.13) (occasionally to 1.0) Tompsett and Anderson........... .. 0.22-0.4 Fretwurst and Hertz.............. OH Davidson ob al. L000 oa di band .. 0.0-1.75 It should be stated in this connection that values above 0.4 mg. in 24 hours should be regarded with suspicion of excessive exposure, since the average normal daily intake of lead has been estimated as 0.2 to 0.4 mg. (Minot; Monier-Williams). It seems justifiable to regard a daily fecal excretion greater than 0.6 mg. as abnormal (Kehoe?). The observations of Aub and his associates indicate that even after subcutaneous admin- istration the rate of excretion of lead by the gastrointestinal tract is usually greater than by the kidneys. Studies by these authors in patients with chronic plumbism some time after removal from exposure to lead revealed that the average excretion of lead in the feces was 2.5 times as great as in the urine. On the basis of their findings, these authors conclude that the quantity of lead which the kidneys can eliminate is small, while that which the gastrointestinal tract can eliminate is unlimited and, consequently, the greater the total output of lead the greater becomes the disproportion between the quantities eliminated in the feces and urine. Excretion of Lead by the Kidneys. Obviously, the excretion of lead in 34 LEAD POISONING the urine implies its circulation in the blood and consequently its absorption into the organism. Most of the early quantitative data must be discarded because of the unreliability of the methods employed. With the demon- stration of its rather consistent occurrence in subjects with acute and chronic plumbism, the presence of lead in the urine was, until comparatively recently, regarded by most authorities as an indication of lead poisoning. However, in 1926, Kehoe and his associates demonstrated the presence of measurable quantities of lead in the urine of persons without a history of industrial exposure to lead, and it has been shown adequately since then that some degree of lead absorption and excretion must be regarded as TABLE 9 Normal Urine Lead Author Lead in Urine nn TAC ES pda Bh es I nT LTT 0.004-0.01 mg. in 24 hours Ross and Ta0a8. Ju 1 cou nsiminins vv lame «ex 8 0.05 0.06 mg. in 24 hours IMB cnt ns ine a sw sapien 46 PF 0.085 mg. in 24 hours Fh A i SRE er SLE A 0.04 -0.05 mg. in 24 hours Badham and Taylor... seria ais be sudan dion 0.03 -0.15 mg. in 24 hours Litzneriand Weyraueh. co... colo viugiis'vnn don 0.00 0.06 mg. in 24 hours Kehoe, Thamann and Cholak....... epi sae s He 0.05 -0.1 mg. in 24 hours Keith and van: Dijk... i ioe svn aiiodumens os 0.008-0.059 mg. in 24 hours Pretwurst and Hertz... .. o.oo heii inmnnsn sas 0.001-0.05 mg. per liter a or nh en a ee wh + A Renae 0.005-0.078 mg. per liter Koith and van Dijk..." oo... fo o0al fa vena 0.005-0.055 mg. per liter BCI crs shy «it tain 200 sen brimiiecchiohs oan whe Ronis ap 0.00 -0.2 mg. per liter Kehoe, Thamann and Cholak.................... 0.02 -0.08 mg. per liter British Ethyl Petrol Committee. ................ 0.00 0.108 mg. per liter Cooksey ahdaWalton. ...5 0h. ve avven d's 3s imimmaint 0.02 -0.05 mg. per liter Schmidt and-Weyrauch.................cov0ioen. 0.02 mg. per liter normal. Because of this fact, normal limits for urinary lead excretion must be carefully established before this factor can be regarded as significant in the diagnosis of lead poisoning. The values for normal urinary lead excre- tion reported by different observers are presented in Table 9. In a study of the lead content of the urine of subjects living under primi- tive conditions in Mexico, Kehoe, Thamann and Sanders found values of 0.00 to 0.009 mg. per liter in 45 per cent of cases, and 0.01 to 0.019 mg. per liter in 32 per cent, while values of 0.02 to 0.129 mg. per liter were obtained in isolated instances. The following values were reported by the British Committee on ethyl petrol in subjects without history of unusual exposure to lead: medical students, 0.03 to 0.04 mg. per liter; physicians, 0.073 to 0.092 mg.; laborers 0.025 to 0.033 mg.; waiters 0.018 mg. ; school ABSORPTION, TRANSPORTATION, EXCRETION OF LEAD 35 boy 0.15 mg.; decorator 0.085 mg.; the average value for country dwellers was 0.023 mg. per liter and that for city dwellers 0.049 mg. Although Shiels reported as much as 0.2 mg. per liter in the urine of appar- ently normal subjects, the general consensus is that 0.08 mg. per liter should be regarded as the upper limit of normal. Values above this level may be regarded as evidence of abnormal exposure to and absorption of lead but normal figures may be obtained even in the presence of mani- festations of lead intoxication (p. 163). Webster has demonstrated a rather marked diurnal variation of urinary lead excretion in a group of subjects probably exposed to abnormal quantities of lead (workers in orchards in which a lead arsenate spray had been employed, and consumers of the fruit from these orchards). The greatest variation in a single day was 0.017-0.060 mg. per liter for a consumer and 0.025-0.101 mg. for an orchardist. High and low points on the diurnal curve of excretion tended to occur at approximately the same time of day, the peak excretion occur- ring between 4 p.m. and midnight (average 7 p.m.) in 959%, of instances. It was also found that there was an inverse correspondence between the lead concentrations and the urinary pH values, the highest degree of acidity occurring at times of maximal lead concentrations. The total daily urinary lead output was remarkably constant for any one individual. This normal excretion of lead in the urine prevents its accumulation in the body in abnormal amounts. After a period of normal exposure to lead an equilibrium is reached, the concentration in the tissues remaining essentially constant and the lead output becoming approximately equal to the intake. The question of what constitutes normal exposure to lead is considered elsewhere (p. 167), but it should be noted here that recognition of the existence of such exposure is of the utmost importance in the inter- pretation of the significance of the lead content of the body fluids and tissues in any given case. Although the urine lead does not rise above about 0.08 mg. per liter when the concentration of lead in the blood is less than 0.08 mg. per 100 cc., it has been found that when the blood lead concentration rises to abnormal levels there is no consistent relationship between the amounts in the blood and in the urine (Litzner and Weyrauch=?; Tompsett and Anderson’; Flury?). More definite information regarding the nature of the physiologic relationship between these two factors must await the acquisition of more exact data regarding the concentration of lead in the circulating plasma and the form in which it is present. Aub and his associates found that the caloric intake, salt intake and the volume of urine have little or no influence upon the quantity of lead excreted in the urine. However, this is obviously. influenced by such factors as may influence the formation of urine and the concentrating ability of the kidneys (renal disease, dehydration, edema, 36 1 LEAD POISONING diarrhea, vomiting, etc.). Although urinary excretion of excessive quan- tities of lead constitutes one of the earliest and surest indices of excessive exposure to lead or of lead intoxication, it does not occur regularly in chronic plumbism. There may be transitory periods in which little or no lead can be found in the urine, particularly in the presence of renal func- tional impairment or of deposition of inactive deposits in the tissues, particularly in the skeleton. These and other factors mentioned above probably account for the commonly observed and marked quantitative variation in urinary lead as compared with the relative constancy of its concentration in the blood. The observations of Kehoe and Thamann indicate that excretion of lead in the urine proceeds gradually. Following administration of lead to rabbits, they found that about three-quarters of the quantity given was excreted within thirty days, about one-half during the first week. Of this amount, about 25-33 per cent was eliminated in the urine. They attributed the primary decrease in elimination to disappearance of lead from the blood, and the final decreased excretion to alteration in the dis- tribution of lead in the tissues and to the decrease in the total amount of lead in the organism. After ingesting about 800 mg. of lead, L. Schmidt found excessive quantities in the urine and feces as long as five weeks after the ingestion had been discontinued. It is of interest in this connection that Behrens and Baumann found no consistent relationship between the quantity of lead in the kidney at any time and its concentration in the urine. According to Newman, a single dose of 50 mg. of colloidal lead injected intravenously into patients with carcinoma was excreted over a period of ten weeks. As has been indicated previously, the portal of entry plays an important part in determining the relative proportion of lead eliminated in the urine and in the feces, the urinary fraction being relatively greater when lead enters by the respiratory or the parenteral route. The great variation in urinary lead excretion in clinical lead poisoning is illustrated by data presented in Table 10. According to the report of the British ethyl petrol committee, the urine of workers in lead industries may contain 0.007 to 0.58 mg. of lead per liter, depending on the nature of their work and the conditions of exposure. Kehoe, Thamann and Cholak' found an average of 0.24 mg. per liter of urine in workers in white lead factories, lower values being obtained in workers in other industries, including tetra- ethyl lead. They state that the lead hazard is not serious if the excretion is not greater than 0.15 mg. per liter of urine or 0.6 mg. daily in the feces. Values of 0.21 mg. per liter of urine or more and more than 1.1 mg. daily in the feces were regarded as dangerous. However, as indicated previously, the experience of most observers is that there is no consistent relationship ABSORPTION, TRANSPORTATION, EXCRETION OF LEAD 37 between the quantity of lead excreted in the urine or feces and the develop- ment of manifestations of lead intoxication. Further data regarding uri- nary lead excretion in subjects exposed to abnormal amounts of lead, with and without manifestations of intoxication, are presented elsewhere (p. 158). : Aub and his associates state that after absorption has ceased the rate of excretion of lead depends chiefly upon the rate of its mobilization from skeletal deposits. The urinary excretion of lead is increased by factors which favor mobilization from the bones, several of which have been enumerated elsewhere (p. 25). Among the most important of these are factors which also increase the mobilization of calcium from the skeleton, TABLE 10 Lead Excretion in Urine and Feces in Clinical Lead Poisoning (After Aub, Fairhall, Minot and Reznikoff) Case Urine Feces Urine ces mg. per 3-day period mg. per 3-day period 1 0.12 0.51 1:4.0 2 0.15 0.06 1:0.4 3 0.23 1.11 1:4.8 4 0.23 0.39 1:11.77 5 0.26 0.42 1:1.6 6 0.28 1.10 1:4.0 Y 0.29 0.85 1:3.0 8 0.30 0.78 1:2.6 9 0.43 1.15 1:2.7 10 0.45 0.17 1:0.4 11 0.46 0.97 1:2.1 12 0.58 1.86 1:3.2 13 0.72 1.56 1:24 14 0.78 0.96 1:1.2 including (a) acidosis, spontaneous or induced, (b) lactation, (¢) adminis- tration of parathyroid hormone, (d) hyperthyroidism, (¢) massive doses of vitamin D, (f) dihydrotachysterol (A. T. 10), low calcium and phosphorus intake (Aub, Fairhall, Minot and Reznikoff; Schmitt and Taeger; Hunter; Aub; Flinn and Smith; Grant et al.; Minot). In addition, increased mobi- lization and, consequently, increased urinary excretion of lead may result from the administration of large doses of alkali (p. 39) and may also occur during the course of infection and starvation, probably because of the accumulation of excessive quantities of organic acids locally in the tissue fluids. According to Roche-Lynch and Weyrauch, postoperative shock, starvation, alcoholism, acute infections, and changes in diet may tend to 38 LEAD POISONING mobilize lead from the skeleton. Epstein observed the development of symptoms of lead poisoning in two subjects during administration of bismuth for treatment of syphilis. He suggests that the deposition of bismuth in the bones may result in liberation of stored lead. The mode of action of certain of these agents and conditions is fairly well understood, but that of certain other agents is not. Among the most important of the latter are potassium iodide and other iodine preparations, which have been used empirically for some time for the purpose of increasing the elimination of lead. Parkes, in 1853, found lead in the urine after administration of potassium iodide. Contradictory observations by many observers since then have caused condiderable controversy over the use- fulness of this agent in the treatment of lead poisoning (Annuschat; Pouchet?; V. Lehmann?; Mann; Scremin; Wolf-Eisner; Aub, Fairhall, Minot and Reznikoff; Flury?). Hanzlik and Presho found that it had a beneficial effect upon lead poisoning in dogs. According to Schachnow- skaja, potassium iodide causes only partial liberation of lead from deposits in the tissues, the effect being most marked early and diminishing with continued administration. There has been a great deal of speculation regarding the probable mode of action of iodine and its salts in this connec- tion. Some believe that it is dependent upon the formation of lead iodide, but, on the basis of experimental observations, Scremin concluded that iodine does not react chemically with lead compounds present in the tissues. Similar findings were reported by Ludwig. Wolf-Eisner believed that lead compounds in the tissues (carbonate or phosphate) react with iodides to form compounds which pass into solution in a highly dispersed state, their diffusibility being increased, their absorption inhibited and their excretion enhanced. According to Hesse, iodides stimulate certain chemical proc- esses in the body, perhaps through the medium of thyroid activity, and thus alter metabolism and stimulate excretory processes. However, no definite statement can be made at the present time regarding the mode of action of iodine and its compounds in promoting lead excretion. Their influence has been conclusively demonstrated by Aub and his associates and by Schmitt and Taeger, the increased excretion of lead being apparently less marked than following the administration of acids, acid-forming salts or alkalies. According to Flury and to Sollmann, the increase in lead excretion following the adminstration of iodides is pro- portionately greater in the feces than in the urine. Although the sig- nificance of fecal lead from this standpoint may be questioned (p. 164), the observation is significant that iodides cause the reappearance of lead in the feces from which it had previously been absent (Sollmann?). It has been suggested by some that the chemical and physical characteristics of the lead salts and preparations absorbed may influence the quantity of lead excreted in the urine (Millet, Newman; Kehoe, Thamann and Cholak). ABSORPTION, TRANSPORTATION, EXCRETION OF LEAD 39 According to Holmes, Campbell and Amberg, the administration of relatively large doses of ascorbic acid is followed by a distinct diminution in the urinary excretion of lead. They suggest that lead compounds in the tissue fluids may react with ascorbic acid to form a poorly ionized salt (perhaps possibly lead ascorbate) or a complex salt which yields a very low concentration of lead ions. They believe that this compound may be preferentially excreted by the liver in the bile rather than stored in the skeleton or other tissues. Subsequent studies by other observers have failed to confirm these observations regarding the influence of ascorbic acid on the metabolism of lead (Evans, Norwood, Kehoe and Machle). Kety and Letonoff reported that the administration of sodium citrate was followed by distinct amelioration of manifestations of plumbism, a sharp fall in the concentration of lead in the blood and usually an increase in the urinary excretion of lead. Similar results were obtained in rats. These effects were attributed to the profound solvent effect of sodium citrate in dilute solution on tertiary lead phosphate and to the fact, as expressed by the authors, that citrate removes lead ion from solution by the formation of a soluble complex of extremely low dissociation. Sulphur, hydrogen sulphide and other sulphides have been used to promote excretion of lead since the days of Tanquerel des Planches. Al- though good results were reported by Hanzlik and Presho and by Danck- wortt and Ude in dogs, no effect was observed by Almkvist and the majority of investigators of this problem. The same may be said for sodium thio- sulphate. Whereas some beneficial effect was observed in clinical lead poisoning by a few investigators (McBride and Dennie; Hegler), the majority of reports in clinical and experimental plumbism indicates that this agent is of little or no value in this regard (Curtis and Young; Sabba- tani and Linguerri). The influence upon lead excretion of agents which affect the deposition and mobilization of calcium and phosphorus in the organism (administration of calcium and phosphate, parathyroid hormone, vitamin D) is considered elsewhere (p. 25). Administration of acidifying and alkalinizing agents has also been found to increase the urinary excretion of lead under certain circumstances. Among the substances most commonly employed are dilute hydrochloric acid, ammonium chloride, sodium acid phosphate and sodium bicarbonate. All of these have been found effective in man and experi- mental animals (Fairhall and Shaw; Litzner, Weyrauch and Barth; Schachnowskaja; Behrens and Baumann; Tscharny and Israilewitsch; Aub et al.). This rather paradoxical fact is explained by Fairhall and Shaw on the basis that lead phosphate is only slightly soluble at the normal pH of the tissues and tissue fluids and that its solubility is increased by a change in pH toward either the acid or alkaline side. Accordingly, Schach- nowskja found that the increased lead excretion induced by administration 40 LEAD POISONING of acidifying agents is inhibited by the subsequent administration of alkali, and vice versa. In general, alkalies have been found to be somewhat less effective than acidifying agents in promoting mobilization and excretion of lead (Aub, Fairhall, Minot and Reznikoff; Litzner, Weyrauch and Barth). Many laxative agents, particularly magnesium sulphate, have been found useful in the treatment of clinical lead intoxication. These do not act by increasing lead elimination in the urine but perhaps by diminishing its absorption from the bowel (p. 193). The effect of certain physical agents, particularly light, has been studiéd. Pincussen found that, in the rat and mouse, lead excretion was increased by exposure to heat and visible light rays but that ultra violet rays were ineffective. Flury believes that the influence of physical stimuli may be exerted through the medium of their effect upon metabolic processes in general. Excretion by the Respiratory Tract. It is improbable that significant quantities of lead are excreted by the lungs and the tracheobronchial tree. No definite observations are available. However, Flury? believes that lead may be present in the secretions of the mucous membranes, especially of the bronchi. This may be increased in the presence of inflammatory processes in the mucosa, as in chronic bronchitis, which is apparently rather common in lead workers. Excretion of Lead by the Skin. The observation of early investigators which suggested that lead is excreted by the skin may be regarded as of purely historic interest. Oliver is among the few modern authorities who has reported the presence of lead in the perspiration. The majority regard this as improbable and are inclined to attribute such findings to contam- ination of the surface of the skin with lead, the possibility of which can scarcely be eliminated in lead workers (Legge and Goadby; Aub et al.) (see also p. 31). Excretion in the milk does occur, however, a fact which may be of importance in connection with the development of lead intoxi- cation in nursing infants (Flury?; Morris et al.). It has been found in the milk of women with no unusual exposure to lead, in concentrations of 0.00-0.05 mg. per liter (Kehoe, Thamann and Cholak) and in the milk of rats with experimental lead poisoning (Calvery; Morris, Laug, Morris and Grant). It has also been observed in the milk of cattle, the quantity and quality of which appears to be affected under such circumstances (Stumpf; Baum and Seliger). CrAPTER II PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY INTRODUCTION One of the striking features of lead poisoning is the remarkable lack of correlation between the clinical manifestations and the demonstrable mor- phologic changes (Aub, Fairhall, Minot and Reznikoff). Many contra- dictory conclusions which have been reached regarding the effects of lead upon various tissues, based entirely upon post-mortem observations, have caused considerable confusion. Much of this confusion has resulted from the fact that it is obviously impossible to control clinical material adequate- ly and to eliminate the possibility of the coincident presence of morphologic changes due to factors other than lead. The uncertainty of postmortem evidence in plumbism and the difficulties encountered in demonstrating lead to be the immediate cause of death in such cases has been apparent for some time (Alcock). Improvements in analytic methods and in experi- mental technic in recent years have served to emphasize the importance of the physiological and biochemical approach in the investigation of lead intoxication. Aub and his associates summarize the lesions which have been attributed to lead as follows: A. Lesions found constantly, due to lead. 1. Blue line on gums. 2. Anemia and stippling. B. Lesions found frequently, due to lead. . Degeneration of anterior horn cells. . Peripheral neuritis. . Chronic muscular atrophy and fibrous myositis . Degenerative changes in male gonads. . Hyperplasia of bone marrow. . Productive meningitis. . Bluish pigmentation in mucosa, in large and lower small intestines. . Optic atrophy. C. Lesions seen frequently in people with evidence of lead absorption. 1. Arteriosclerosis. 2. Gastric and duodenal ulcer. 3. Contraction of small intestine. 4. Nephritis. 5. Hemorrhages and exudate in retina and neuroretinitis. 41 00 NO Ot WN 42 LEAD POISONING D. Lesions which have been reported occasionally in subjects with evidences of lead absorption or lesions possibly due to lead. . Vascular hemorrhages. . Cardiac hypertrophy, hemorrhages, brown atrophy. . Degeneration of unstriated muscle of vessels. . Perivenule hemorrhages. . Arteritis. . Gangrene of extremities. . Acute and chronic enterocolitis. . Hypertrophy or sclerosis of sympathetic ganglia. . Parotitis. 10. Hepatocellular degeneration and cirrhosis of the liver. 11. Hematogenous pigmentation of liver and spleen. 12. Splenomegaly or atrophy of the spleen. 13. Encephalitis. 14. Hyperplasia of neuroglia. 15. Lymphocytic infiltration of the brain and spinal cord. 16. Hemorrhagic myositis and fatty degeneration of muscle. 17. Gelatinous degeneration and increased pigmentation of the bone marrow. 18. Acute and chronic bronchitis. 19. Gouty deposits and necrosis of bone. 20. Hypertrophy of the suprarenal cortex. 21. Hemorrhagic and sero-fibrinous polyserositis. 22. Calcification at site of injection of lead salts. © ONO WN As stated by Aub and his associates, Examination of this pathological picture of lead poisonng indicates quite clearly that definite information about the action of lead can hardly be obtained from such a study. The effect of lead might be considered too subtle to yield to this type of in- vestigation. Certainly, many biological effects are evident which produce no ap- parent gross or microscopic lesions. The conclusion must be drawn, therefore, that further knowledge of the action of lead on the organism can only be reached by physiological and chemical methods which deal with living rather than postmortem conditions. CHANGES IN THE BLOOD AND HEMATOPOIETIC FUNCTION Changes in the blood and evidences of altered hematopoietic function are among the most important and most constant manifestations of lead intoxication. Certain of the most characteristic of these phenomena will be discussed individually in order that their pathogenesis may be more clearly understood. Stippling, Polychromasia, and Reticulocytes This phenomenon has received a variety of designations, including stippling, punctate basophilia, basophilic granulation and basophilic degeneration. It occurs, although less consistently and less strikingly than in plumbism, in a variety of conditions, including pneumonia, severe PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 43 anemia, leukemia, advanced malignancy, following the administration of certain poisons (mercury, arsenic, anilin, nitrobenzol, carbon disulphide etc.), and in the blood of embryos of certain species (Aub, Fairhall, Minot and Reznikoff). As stated by Aub, this suggests that stippling represents a general pathological reaction of the cell rather than a specific phenomenon . attributable to the action of lead. Its essential nature and significance have been discussed comprehensibly by Pappenheim, Naegeli?, Key? Grawitz?, P. Schmidt? Miinz, and Aub and his associates, and need not be con- sidered in detail here. However, because of the importance universally attached to this phenomenon in the diagnosis of lead poisoning, present views regarding its pathogenesis and significance will be reviewed briefly. Although some observers believed that the basophilic granules are de- rived from the nuclei of red blood cells (Naegeli?, Schmidt), the view maintained by Ehrlich that they are of cytoplasmic origin was quite con- clusively proven by Grawitz? (Key?). Moreover, Key? has demonstrated the intimate relationship between stippling and the diffusely distributed basophilic substance which may be present in the cytoplasm of red blood cells. Not only do both react similarly to the same fixatives and stains and appear to have similar chemical composition, but all transitions be- tween polychromatophilic, stippled polychromatic and stippled ortho- chromatic cells may be observed in a single preparation (Key?). There has been considerable controversy regarding the question as to whether stippling represents a regenerative (Naegeli®) or a degenerative (Key?) process. The bulk of evidence available at present seems to justify the conclusion, concurred in by Key? and Aub and his associates, that stippling is a granular degeneration or coagulation of basophilic substance in the cytoplasm of the red blood cells. This view is supported by the fact that the same phenomenon may occur in a variety of pathologic processes, frequently in the absence of other evidence of blood regeneration. Another argument advanced in the support of the degenerative hypothesis is that stippling does not occur in the bone marrow (Key®; Aub et al.; Grawitz?; Pappenheim). However, Young and Osgood reported the presence of stippled cells in the bone marrow in animals and they regard this phenomenon as evidence of blood regeneration. This observation has been confirmed by the careful and comprehensive studies of Klima and Seyfried who, however, do not attempt to attribute to it any conclusive significance in determining the regenerative or degenerative origin of punctate basophilia. The still controversial nature of this subject is evidenced by the recent statement by Biondi that punctate basophilia is an indication of disturbed regeneration, if not of an embryonic or pathological reaction of the blood forming tissues, rather than the result of degenerative changes in the red blood cells due to the action of a toxic agent. According 44 LEAD POISONING to Whitby and Britton, polychromasia and stippling are manifestations of the phenomenon of reticulation. They believe that the polychromatic cells from blood films stained with Leishmann stain and the reticulocytes of vitally stained smears are identical and normal, stippling being the same chromatic substance slightly altered by lead or some other poison. Me- Cord, Holden and Johnston believe that polychromasia, punctate baso- philia and reticulation are all manifestations of a single phenomenon, namely, the presence of basophilic substance. Because of the frequent occurrence and intensity of the stippling process in lead poisoning, interest has naturally been focused on the mechanism of production of this phenomenon by lead. It is interesting and perhaps significant that it cannot be produced by exposure of red blood cells to lead in vitro and that, while it occurs rather consistently in certain species (man, guinea-pig, rabbit, rat) it has not been observed in others (cat, chicken, pigeon, amphibia) (Aub et al.; Key!-?; Hanzlik; K. B. Lehmann? +4; Schmidt-Kehl). The majority of observers regard basophilia (polychromasia) and stip- pling as important early manifestations of lead poisoning (P. Schmidt? 4; K. B. Lehmann?; Flury?). In the first 4-6 hours after intravenous injec- tion of lead salts, Giinther, Anton, and Dawidson observed the appearance in the blood of intensely ‘“‘blue-staining’’ cells, which diminished in number in the course of 12-24 hours. These were probably reticulocytes, since they could be stained only by vital stains. It has frequently been noted that the number of reticulocytes in the circulating blood increases before anemia develgps, these cells constituting frequently 20 per cent and rarely more than 30 per cent of the total circulating erythrocytes. The phe- nomenon of stippling may occur in both mature and immature red blood cells. At times it has been found to constitute the earliest manifestation of lead intoxication in man and experimental animals (Bell; Key; Schon- feld; Sohler; Weisbach; Miinz). It has been observed as early as three hours after the intravenous administration of lead in experimental animals and within forty-eight hours in man. This increase in stippled cells and reticulocytes in lead poisoning may be transitory, particularly in severe cases. They have frequently been found to disappear from the blood shortly before death in experimental animals, due presumably to severe injury to the blood-forming organs (p. 50). Moreover, there may be a rather marked degree of diurnal variation which renders single estimations of little value, especially if they are negative (Weindel; Sohler; Fuchs- berger). Stippled cells and reticulocytes usually disappear from the blood in two to four weeks after cessation of exposure to lead, but they may occasionally persist for a few months (Baader; Teleky?). The work of Key! has thrown considerable light upon this problem. PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 45 His observations lead to the following conclusions: (a) stippling is a clump- ing of basophilic material and not precipitated lead; (b) it appears in the blood of anemic (following bleeding) and normal animals (rabbits) within 24 hours after administration of lead and persists for 10 days to three weeks or more; (¢) the number of stippled cells varies directly with the number of young cells in the circulating blood, being greater in the anemic than in the normal animal; (d) stippled cells are apparently young red blood cells that have been exposed to lead and the granules are probably aggrega- tions of the basophilic substance into discreet masses. A similar view is expressed by Klima and Seyfried in explanation of their observations of stippled erythrocytes and erythroblasts in the bone marrow of animals with lead poisoning. They present evidence that the primary hemolytic effect of lead is followed promptly by increased erythropoetic activity in the bone marrow and suggest that this state of relative immaturity of the marrow increases the susceptibility of these cells as well as of those young forms thrown out into the blood stream as a result of the toxic action of lead. They point out in this connection that it has long been known that immature and rapidly growing cells exhibit a relatively high degree of susceptibility to lead. Thus, the presence of stippled cells in the bone marrow in lead poisoning does not necessarily support the hypothesis that the stippling process is a manifestation of regeneration rather than de- generation. Anemia Anemia is recognized as one of the important consequences of the toxic action of lead. Two hypotheses have been advanced in explanation of its pathogenesis: (1) that it is due to degeneration or functional depression of the bone marrow resulting in diminished erythropoietic activity and (2) that is is due to a hemolytic action of lead resulting in peripheral destruction of red blood cells (in the circulating blood). The evidence advanced in support of the first hypothesis is chiefly of historic interest and need not be reviewed here. Recent observations indicate clearly that, although in late stages of lead intoxication the bone marrow may undergo degenerative changes, the primary changes demonstrable in the marrow following the administration of lead are those which are commonly regarded as charac- teristic of increased activity of this tissue. These changes will be con- sidered elsewhere (p. 49). Suffice it to state here that pnenomena demon- strable in the peripheral blood as well as in the marrow indicate that the administration of lead is followed by stimulation rather than depression of hematopoiesis. The degree of anemia varies considerably with the species, experimental conditions and the severity and duration of exposure. With certain ex- 46 LEAD POISONING ceptions (mice), the degree of anemia is usually regarded as an index of the ° severity of poisoning in experimental animals. Although some believe this to be true also in man (Gelman?), the majority of observers have found no parallelism between this factor and the severity of lead intoxication. In clinical plumbism, even if severe, the hemoglobin seldom falls below 60 per cent (Naegeli?; Kost; Meyer; Seitz; Kretschmer; Legge and Goadby), although values as low as 35 per cent have been encountered in extreme cases (Legge and Goadby; Matussewitsch). Although not invariably the case, the decrease in the number of red blood cells is not usually as great as that in hemoglobin. In clinical lead intoxication the erythrocyte count is seldom below 4,000,000 per cubic millimeter, occasionally 2,500,000 and rarely 1,000,000. Accordingly, the color index is usually less than 1.0, although exceptions to this statement are occasionally observed. It has been found that at first the hemoglobin and red blood cells may fall propor- tionately and that subsequently the hemoglobin may continue to diminish while the red blood cells remain stationary or increase in number (Schmidt- Kehl; Schmidt). A slight to moderate increase in red blood cells and hemoglobin has been reported occasionally in the very early stages of clinical plumbism and shortly after the administration of small doses of lead to experimental animals (Kost; P. Schmidt*:7; Kogan and Smirnova). P. Schmidt*'” believes that this may result from primary stimulation of the bone marrow by lead and Naegeli suggests that it may also constitute a “reparative polycythemia,” resulting from stimulation of the marrow due to peripheral destruction of red blood cells. If the anemia is severe, ani- socytosis and poikilocytosis may occur. According to some observers, microcytosis may develop before polychromasia (Flury?). In addition to reticulocytes, mentioned above, other young forms of red blood cells may be found in the circulating blood, including normoblasts and erythroblasts. There have been occasional reports of the occurrence of megaloblasts (Grawitz?; Hamel) but this is doubted by others (Naegeli?; Kost). The present consensus is that lead causes increased hemolysis of circu- lating red blood cells, the consequent anemia in turn resulting in stimula- tion of bone marrow activity. Some authors believe that other factors are involved. According to Duesberg, the anemia of lead poisoning may be of three varieties: (I) anemia with evidence of increased regenerative activity, as indicated by reticulocytosis; (2) anemia accompanied by some perversion of hema- topoiesis, an indicated by increased porphyrin excretion and diminution in reticulocytes (also Kark and Meiklejohn); (3) aplastic anemia, accom- panied by and dependent upon aplasia of the bone-marrow. The occurrence of increased hemolysis is evidenced also by an increase in serum bilirubin concentration, an increase in the bilirubin content of the PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 47 bile, increased urobilinuria, deposition of hemosiderin in tissues throughout the body and abnormal excretion of porphyrin in the urine and feces (p. 51). The mechanism of production of this hemolytic effect has been greatly clarified by the experimental observations of Aub, Reznikoff and Smith, and has been discussed in detail by Aub, Fairhall, Minot and Reznikoff. Their observations may be summarized as follows: 1. When exposed to lead, the red cells first swell slightly and then shrink, the surface becoming crenated. Crenation gradually disappears and the cell outline becomes smooth and refractile. Similar changes were noted by Maurel, Orskov, and Henriques and Orskov. The latter (Orskov; Henriques and Orskov) found that under optimum conditions (bicarbonate concentration 0.007 N and pH 6.3-6.6), cells exposed to concentrations of lead as low as 1 to 25 million lost about 40 per cent of their volume within ten minutes. A similar decrease in the volume of the red blood cells was observed following the administration of lead to rabbits but not to cats or goats. 2. These changes are followed or accompanied by a significant increase in the resistance of these red cells to hemolysis in hypotonic sodium chloride solution. Cells that have been exposed to solutions of lead of concen- trations as high as 1 part per 100,000 did not hemolyze completely in 0.1 per cent saline, whereas normal cells are usually completely hemolyzed by 0.25 per cent saline solution. 3. Although their resistance to hemolysis by hypotonic salt solution is increased, the cells are in reality more fragile than normal. This is evi- denced by their diminished resistance to mechanical trauma and by the fact that an abnormally large number undergo hemolysis within a few hours when allowed to stand in Ringer’s solution. In other words, as stated by Aub and his associates, the action of lead upon the red blood cells is there- fore a double one: (a) the “leaded” cells withstand greater change in osmotic tension, but (b) they break up more readily than normal cells. This double action was also observed by Fici. According to Minot, the red blood cells lose their ability to swell, and are more rigid and brittle and less resilient and durable than normal cells. 4. After exposure to lead, the agglutination of red cells by heterologous sera is slowed and may be completely inhibited. There is also some evidence that the surface of these cells is less sticky than normally. 5. All of these phenomena are probably manifestations of surface altera- tion. Orskov found that the red blood corpuscles exposed to very low concentrations of lead under optimum conditions lost 80-90 per cent of their potassium content into the surrounding medium within 10 minutes, indi- cating a marked increase in the permeability of these cells to potassium. Loss of water from these cells is indicated by the decrease in size and by the 48 LEAD POISONING fact that their specific gravity is distinctly higher than normal (Aub et al.). Following this initial decrease in volume and increase in density, their range of swelling and shrinking in solutions of different varying tonicity is much less than that of normal cells under similar conditions. Aub and his associates interpret this as evidence of a restricted exchange of sub- stances across the cell membrane, i.e., decreased permeability to water. 6. It was shown that when the red blood cells are exposed to lead which has been previously mixed with serum the effects described above no longer occur. The effectiveness of serum in this respect is indicated by the obser- vation that 0.2 cc. can completely inactivate 0.01 mg. of lead so far as con- cerns the effect of the latter upon the red blood cells. The experimental evidence indicates that the “inactivating” substance in the serum is probab- ly inorganic phosphate (Aub and Reznikoff; Orskov). As stated by Minot, it might be expected on this basis that, in vitro, the red blood cells would be protected by the inorganic phosphate of the plasma. She points out, however, that lead absorbed into the circulation comes into contact with cells and plasma simultaneously and reacts with both. Aub and Reznikoff proposed the hypothesis that lead combines with the inorganic phosphate of cells and plasma as follows: 3PbCl; + 2B,HPO, — Pb;(PO4): + 4 BCl + 2 HCl The essential feature of this reaction consists in the transformation of soluble salts of lead to the very insoluble and inactive tri-lead phosphate, with the simultaneous liberation of free acid. These authors attribute the injury to the red blood cells to an increased acidity at the cell mem- brane resulting from this reaction. As was indicated elsewhere (p. 10), this hypothesis has been challenged by Maxwell and Bischoff, who observed similar changes in red blood cells following exposure to lead compounds which did not cause the liberation of free acid. They believe that the injury may be due to the formation of the diglycerophosphate of lead, which is much more active than the tertiary phosphate. As stated by Minot!, whatever the mechanism may be, exposure to lead results in a shortening of the life of the red blood cells in the circulation. As a result of their increased brittleness and diminished elasticity, the “leaded” cells are less able to stand the trauma of normal circulation and are destroyed more rapidly than are normal cells. Key was actually able to demonstrate hemoglobin containing fragments and debris in the livers and spleens of animals with lead poisoning, and he believes that these cells undergo disintegration as a result of fragmentation rather than hemolysis. Changes in Bone Marrow Studies of changes in the bone marrow induced by the administration of lead have aided materially in elucidating certain of the changes which PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 49 occur in the circulating blood (Duesberg; Seiffert and Arnold; Klima and Seyfried). Despite certain discordant observations (Rauch and Michaelis; Koch; Fleckel, Tschernow and Turgel), the carefully controlled and thor- ough studies of Klima and Seyfried and of Speransky and Sklianskaja appear to justify the following conclusions: 1. The development of anemia following administration of lead to ex- perimental animals is accompanied or followed by the appearance of mani- festations of increased hematopoietic activity in the bone marrow (bone- marrow puncture and biopsy). During the first week of lead intoxication there is a 100-200 per cent increase in the number of nucleated red blood cells, this increase consisting at first largely of typical normoblasts. As the condition progresses, the increase in red blood cells continues, with a progressive tendency toward a relatively large proportion of younger forms, such as macroblasts, erythroblasts and normoblasts. A maximum increase was observed usually between the third and ninth weeks, following which the number of cellular elements steadily diminished, with a relatively large proportion of immature forms (early erythroblasts and macroblasts). 2. These changes are accompanied by a corresponding increase and subsequent decrease in the percentage of reticulocytes and of cells showing punctate basophilia, the peak of the latter two phenomena occurring be- tween the second and fourth weeks. 3. Similar changes were observed simultaneously in the peripheral blood. There was an immediate increase in the number of reticulocytes, followed in order within a few days by increases in cells showing polychromatophilia and punctate basophilia and, finally, by a progressive increase in normo- blasts and erythroblasts. These changes reached a peak during the second week of lead administration and were maintained at approximately the same level for at least one week subsequently. 4. A phase of apparent exhaustion of bone marrow function begins after the ninth or tenth week, with an absolute decrease in the number of cellular elements and a relative increase in the proportion of immature erythro- blasts. This cellular depletion continues until eventually the marrow becomes fatty or gelatinous. This is ascribed to either exhaustion following prolonged overstimulation of erythropoietic function or to an actual process of degeneration of the marrow. : 5. The reaction of the bone marrow in lead poisoning is regarded as primarily one of hyperactivity induced by the development of a hemolytic type of anemia. The increase in the number of nucleated red blood cells and reticulocytes in the peripheral circulation has been noted by others (Key; Aub, Fairhall, Minot and Reznikoff). It is interesting to note in this connection, as pointed out by Aub and his associates, that there seems to be a definite relationship between the several effects of lead upon the blood. This is evidenced by the fact that anemia, punctate basophilia and increased 50 LEAD POISONING resistance to hypotonic sodium chloride solution all occur in certain animal species and are completely absent in others, suggesting that these phenom- ena may depend upon a single cause. It is important to note that Klima and Seyfried found that in the late stages of chronic lead poisoning the number of stippled cells in the blood and bone marrow decreases consider- ably and in some cases they may disappear. This phenomenon may be dependent upon a decrease in the number of new and relatively immature red blood cells in the peripheral blood and bone marrow, consequent upon exhaustion of the erythropoietic function. Therefore, the number of stippled cells and reticulocytes cannot be regarded as an invariable index of the severity of the condition. The hypothesis that stimulation of hematopoietic activity in the bone marrow in lead poisoning is due to excessive hemolysis in the peripheral blood has not gone unchallenged. Schmidt found lead in the bone-marrow within two hours after its subcutaneous injection and he believes that this may stimulate bone-marrow activity directly. This view is also main- tained by other observers (Schnitter; Trautmann; Seiffert and Arnold; Flury?). In an elaborate series of experiments in guinea pigs, P. Schmidt and Barth were unable to find evidence that anemia per se (bleeding or phenylhydrazine), hemoglobinemia, or the presence of the spleen are in themselves responsible for the production of the characteristic changes in the circulating blood and the bone-marrow. They concluded that these must be dependent upon direct action of lead on the marrow. Flury? states that there can be no doubt that lead exerts a primary stimulating effect upon the bone-marrow, the result depending upon individual dif- ferences in capacity for stimulation, the concentration of lead and the duration of the stimulation. It seems reasonable to assume, with P. Schmidt and Weyrauch, that the stimulus may be of a dual nature: (a) direct action of lead on the bone-marrow and (b) anoxemia due to peripheral hemolysis. As has been indicated, by far the most striking changes in the bone- marrow occur in the erythropoietic function. Relatively few changes occur in the myeloid elements. The number of neutrophiles is usually diminished and there is generally an increase in the number of myeloblasts, promyelocytes and myelocytes (Flury?). According to Seiffert and Arnold, the eosinophiles and basophiles are also increased. Alteration in Pigment Formation, Excretion and Deposition The essentially hemolytic nature of lead anemia is further suggested by certain changes in the metabolism of derivatives of hemoglobin. Among the most important of these are (a) excessive deposition of hemosiderin in the tissues, (b) hyperbilirubinemia and increased excretion of bilirubin in PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 51 the bile and urine, (¢) excessive urobilinuria and (d) increased excretion of porphyrins. Excessive deposition of hemosiderin in certain tissues has long been regarded as one of the consequences of excessive red-cell destruction, although it can occur in the absence of other evidences of the latter, notably in the case of hemochromatosis. Abnormal deposition of hemo- siderin has been observed in the liver, spleen, and bone marrow in lead poisoning (Jores; Aub et al.; Klima and Seyfried; Nagao; Seiffert and Arnold). Klima and Seyfried also observed evidence of increased erythro- phagocytosis in the spleen, which they regard as a further proof of excessive blood destruction. Visible jaundice is not observed commonly in lead poisoning. This of course does not preclude the possibility of the much more common oc- currence of relatively, slight degrees of hyperbilirubinemia. Tanquerel des Planches saw only 51 cases of true jaundice in 1217 cases of lead/colic. He believes that it might be due to (1) “extravasation of bile from its usual resevoir”’ or (2) “direct change of the blood by lead.” According to Legge and Goadby, in acute plumbism there is frequently a distinctly yellowish appearance of the sclera, “due to the pigmentation of that tissue by broken down blood pigment.” Rolleston and McNee state that jaundice in lead poisoning, in the absence of any other satisfactory cause, might be due to spasm of the bile ducts. They cite a case of recurrent attacks of painful jaundice in lead workers in the apparent absence of biliary calculi. In our experience, hyperbilirubinemia is not uncommon in subjects with acute lead intoxication, the serum bilirubin concentration frequently ranging from 1.0 to 2.3 mg. per 100 cc., often, although not always, with a negative direct van den Bergh reaction (Cantarow?). A purely hemolytic form of icterus has seldom been observed (C. Lewin!). An increased serum bili- rubin concentration has been reported by other observers (Klima and Seyfried; Schmidt-Kehl; Vigliani and Angeleri; Heubel) and an increase has also been observed in the quantity of bile pigment in the urine and bile in experimental and clinical plumbism (Heubel; Brady; Jones; Klima and Seyfried). Excessive urobilinuria has also been observed rather con- sistently (Cantarow!; Schmidt-Kehl; Flury?). According to Hamilton!, Deriode and LeCompt were the first to report the occurrence of prophyrinuria in lead poisoning, an observation which they made in 12 of 13 cases. Flury states that it was first noted by Stockvis “and Binnendijk in 1893 and was produced experimentally by Stockvis in rabbits in 1896. Since then, this finding has been reported by a number of observers (Teleky!; Lageder; Vigliani and Angeleri; Schreus; Van den Bergh; P. Schmidt’; Klima and Seyfried; Gerbis; Curschman; Watson! ?3; Lemberg; Kammerer; Fischer and Duesberg; Grotepass). Other workers 52 LEAD POISONING have been unable to demonstrate its occurrence consistently enough to permit any significant conclusions to be drawn (p. 153). Liebig found that the oral or intraperitoneal administration of lead carbonate in experimental animals was followed by increased excretion of porphyrin. This was not influenced by the administration of hemoglobin, hematin, bilirubin nor by reticuloendothelial block or removal of the spleen. It occurs before the development of anemia and basophilia and disappears in the course of a few days, bearing no relation to the severity of the manifestations of lead poisoning. Porphyrin was also found in the bone-marrow but not in the liver, spleen, intestines or blood serum. Ac- cording to Hirschhorn and Robitschek, there is a quantitative relationship between the porphyrin and the iron content of urine in lead poisoning, suggesting that both result from a similar disturbance. Several observers have pointed out the relationship between porphyrinuria and the develop- ment of other manifestations of plumbism, such as severe digestive-tract disturbances, particularly colic, and encephalopathy (Gelman; Schuman; H. Fischer'). Gelman believes that these symptoms may be related in some way to the occurrence of a fundamental disturbance of pigment metabolism, as in idiopathic hematoporphyrinuria. Recent studies have thrown considerable light upon the significance of increased porphyrinuria but knowledge in this field is still limited. Increase in porphyrinuria in a number of conditions has long been recognized (fever, infections, hepatic disease, pernicious anemia, pellagra, alcoholism, con- gestive heart failure, following sulphonal administration, etc.), but its exact significance is not clearly understood because of difficulties en- countered in its isolation and chemical identification. The work of H. Fischer! 2 and, subsequently, of other workers, has established the fact that porphyrins of two isomeric series occur in nature. Porphyrin I, which is present in small amounts in normal urine (Fink) and the origin of which is not clearly understood, has no apparent relation to the forma- tion or destruction of hemoglobin (Lemberg). Porphyrin III is related to hemoglobin, and its increased excretion has therefore come to be re- garded as related in some way to an aberration of hemoglobin formation or destruction. Lemberg believes that porphyrins are not normal inter- mediates in hemoglobin destruction but that they may be intermediates in blood-pigment formation. This view is supported by the observation that porphyrin is present in the embryo and in erythroblasts (Borst and Konigsdorffer; Burmester; Watson and Clarke; Miiller-Nef), that the porphyrin content of reticulocytes is larger than that of erythrocytes, and that porphyrin excretion is increased with increased hematopoietic activity of the bone marrow (Lemberg). It has recently been demonstrated that coproporphyrin III is present in the urine in experimental and clinical PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 53 lead poisoning (Grotepass; Fischer and Duesberg; Lemberg; Watson). This may be due to some disturbance in the combination of porphyrin III with iron or to an aberration of the normal hemoglobin-breakdown process, resulting in the formation of porphyrin instead of bilirubin (Carrié; Schreus and Carrié; Lemberg). Thus Klima and Seyfried suggest that this phenomenon in lead poisoning may result from the development of a relatively immature type of bone marrow with an associated embryonic type of porphyrin synthesis. Such an hypothesis is in accord with the view of Emminger and Battistini, who believe that macroblasts and immature erythroblasts constitute the site of formation of porphyrin. According to Kark and Meiklejohn, porphyrinuria in lead poisoning is due probably to arrested maturation of hemoglobin rather than to excessive hemolysis, and is intimately related to the metabolic disturbance that causes stippling of the red blood cells. They regard this phenomenon as evidence that the anemia in plumbism is chiefly of dyshematopoietic rather than hemolytic origin. In spite of these many interesting observations, no final statement can be made at such time regarding the true nature and significance of porphyrinuria in lead poisoning. Changes in Leukocytes No constant change in the total white cell count has been observed in lead poisoning, mild leucocytosis having been reported in some cases and leucopenia in others (Smith, Rathmell and Marcil; Gould, Kullman and Sheket). Aub and his associates state that the total white blood cell count is usually normal in lead poisoning. Leucocytosis is frequently reported in acute lead poisoning in experimental animals and in the late stages of chronic poisoning (Sohler; Grawitz?). Legge and Goadby believe it to be one of the early manifestations of plumbism. In the majority of clinical reports there is either a mild increase in white blood cells, to about 15,000 per cubic millimeter, or a decrease, not infrequently to 4,000 per cubic millimeter (Kost). There have been several reports of alterations in the monocytes, lympho- cytes and granulocytes: (a) Increase in monocytes (Lenzi; Brookfield; Shiels; Petrov; Gould, Kullman and Shecket; Biondi). (b) Increase in lymphocytes (Seitz; Petrov; Miiller; Ferguson and Ferguson; Shiels). (¢) Eosinophilia has been reported by some (Selig; Seiffert and Arnold; Biondi) and its absence has been noted by others (Gould, Kullman and Shecket). There have been reports of an increase in the relative number of young granulocytes, even myelocytes at times, with the consequent in- crease in the Schilling index (shift to left), frequently with the appearance of toxic granules in the cytoplasm of the neutrophiles (Gould, Kullman and Shecket; Kasahara and Nagahama; Smith, Rathmell and Marcil). Ac- 54 LEAD POISONING cording to Ferguson and Ferguson, the left shift in the neutrophiles in acute plumbism changes to a right shift in more chronic lead poisoning. Carles demonstrated the presence of lead in the nuclei of leucocytes. The question of its possible influence upon the functional activity of leucocytes is raised by the observations of Fine, who showed that exposure of these cells to varying concentrations of lead chloride resulted in a signifi- cant reduction in their phagocytic power. This is interpreted as indicating injury of the leucocytes, but the mechanism involved is not clear. Blood Platelets There are not many observations regarding alteration in the number of blood platelets in the lead poisoning. If any change does occur, it is usually a decrease, as has been noted following administration of other metals (Brookfield; Smith, Rathmell and Marcil; Jones; Weil and Brousser; Seitz; Fabroni). Lymphatics Few data are available regarding the effects of lead upon the lymphatic system (Flury?). However, there have been isolated reports of dilatation of the lymph passages in the region of subcutaneous deposits of lead, storage of lead by cells in lymphoid tissues, and the occurrence of a relative lympho- cytosis in the circulating blood (p. 152), suggesting that lead exerts some effect upon this system (Flury?). According to Paroni? following the sub- cutaneous injection of colloidal lead, granules of this substance may be found in the adjacent lymph passages and lymph nodes. METABOLISM Growth and Enzyme Activity Certain more or less isolated observations suggest that lead affects cellular metabolism and nutrition and that its effect upon various tissues may be produced through this mechanism. Flury? states that lead salts do not have a marked bactericidal action and that they cannot be very toxic for plants, as the latter flourish in the presence of small quantities of lead. According to Gleisberg, lead, and also other heavy metals, in certain concentration has a stimulating effect on enzyme activity, cell growth, and respiration and oxidation processes in plants. A similar observation has been made by Murback. Lead has been found to exert little or no effect upon spirochaetes (Levaditi; Flury?) or trypanosomes (Krauss and Collier). In a review of this subject, Flury? concludes that small amounts of lead may at times increase and larger amounts usually inhibit growth and enzyme activity in plants and lower forms of animal life. PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 55 Calvery observed significant retardation of growth of male rats at relatively low levels of lead in the diet (3.53 parts per million) and of most males and females at higher levels. It is interesting that a significant effect was noted at very low levels of intake while relatively little change was observed when enormous doses of lead were administered. A similar observation was made by Sollmann!, who reported that very small quanti- ties of lead seemed to have a greater effect on growth than larger quanti- ties. The reason for this is not apparent. On the other hand, Horwitt and Cowgill found that diets containing 100 mg. of lead per kilogram had no effect on the growth of rats or dogs, whereas inhibition of the growth of rats was observed with 200 mg. of lead per kilogram of food. Lead has been found to retard the growth rate of roots (Hammett) and chick em- bryo (Hammett and Wallace), and to inhibit the germination of frog spawn (Dilling). According to Hammett the most pronounced effect is noted in areas of most rapid growth and cell division. He believes that this retardation of growth is due to suppression of cell proliferation, mitotic nuclei apparently evidencing the greatest affinity for lead, which, however, was also found in the nuclei and walls of other cells. The studies of this author led him to conclude that lead enters into combination with an organic sulphydryl compound analagous to if not glutathione itself. This predilection of lead for embryonic and rapidly growing tissues constitutes the basis for its use in the treatment of cancer, but experience has demon- strated that malignant tissues have little or no specific affinity for lead (Minott). Studies of the effects of lead on the processes of oxidation, dehydrogena- tion and glycolysis in liver, kidney, brain and testis have yielded interesting results (Dolowitz, Frazekas and Himwich). Marked decrease in oxygen consumption was observed in all tissues following exposure to very small quantities of lead. Inhibition of glycolysis and almost complete abolition of hydrogen transfer was observed in brain tissue. There authors believe that the profound metabolic changes which occur in tissues exposed to lead are the results of its effect on enzyme systems, and they suggest that this may be the underlying cause of the varied manifestations of plumbism. According to Corran and Lewis, administration of lead is followed by an increase in the lipolytic activity of the blood serum, while it has been found to delay lactic acid fermentation (Chassevant and Richet) and the action of trypsin (Bell). It has been reported that the urinary nitrogen increases in animals given non-toxic doses of lead and in human subjects with lead poi- soning (Preti?; Tscherkess). This phenomenon was regarded as indicative of an action of lead upon intracellular enzymes. Preti? found that small quantities of lead increased and larger quantities decreased liver autolysis. 56 LEAD POISONING Protein Metabolism Studies of the effect of lead upon protein metabolism have yielded con- tradictory findings. In many instances the circumstances of the experi- ment and the doses employed created conditions which were not comparable to those encountered in clinical lead intoxication. According to Tscher- kess?, when small doses of lead are administered changes in protein metab- olism may be divided characteristically into two stages: (I) a primary stage of increased protein katabolism, with increased excretion of nitrogen and negative nitrogen balance; (2) a secondary stage of decreased protein katabolism, accompanied by a variety of other metabolic disturbances, including acidosis, increased ammonia excretion in the urine and creatin- uria. The latter (creatinuria) may be dependent upon functional distur- bances in the muscles during this period (p. 62). In fatal cases a third period was observed, with increased protein katabolism and negative ni- trogen balance. Somewhat similar findings were reported by Pavlov in dogs, cats and rabbits. During a primary period of increased protein kat- abolism, the urinary excretion of nitrogen and creatin was increased and the blood nitrogen concentration decreased, these changes disappearing during the second period of diminished protein katabolism. According to Tscharny, the administration of lead is followed by a period of negative nitrogen balance with increased creatinuria. The concentration of non- protein nitrogen in the blood increased and, at the height of lead intoxica- tion, the residual nitrogen of the blood was diminished. Simultaneously with the latter there is a marked decrease in the urinary excretion of urea and ammonia, which was regarded as indicative of hepatic damage and disturbance of deamination. Calvery found that the administration of lead to rats resulted in a decrease in the concentration of liver arginase. "Since this enzyme is involved in intermediary protein metabolism, specifi- cally in the formation of urea, he regarded this finding as evidence of a lowered rate of protein katabolism. A similar observation was made in the livers of sucklings whose mothers were given food containing lead, indicating the passage of this substance into the milk. The effect of lead upon nucleoprotein metabolism is of particular interest in view of the occurrence of manifestations of gout in clinical lead intoxica- tion (p. 140). Several observers have reported an increase in blood uric acid and a decrease in uric acid in the urine of subjects with lead poisoning (Folin and Denis; Biondi). Garrod appears to have been the first to des- cribe the increase in uric acid. This has also been reported in clinical lead poisoning by Goetze, Brugsch, and Schittenhelm, Bucco and Preti. Val- ues as high as 14 mg. per 100 cc. of blood have been reported and it is inter- esting that increased concentrations have been found in both acute and PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 57 chronic lead poisoning in man, particularly during episodes of lead colic. Observations on experimental animals are difficult to evaluate because of the difference in purine metabolism in different species. Brugsch and Schit- tenhelm have observed increased excretion of uric acid in occasional cases of lead colic in man while in dogs lead poisoning was accompanied by de- creased excretion of uric acid with a relatively high elimination of purine bases (Liithje!). Rambousek found a consistent increase in the concentra- tion of uric acid in the blood but an increase in the urinary excretion only in the early stages. Increased excretion of allantoin was reported in rabbits by Pohl and by Stransky. Carbohydrate Metabolism There is no substantial evidence that lead exerts a direct effect upon car- bohydrate metabolism. Taubmann found that rabbits with lead poisoning react to insulin in a manner identical with that observed in normal animals. Ottinger, in 1858, observed glycosuria in patients with lead poisoning and since then these findings have been reported frequently, (literature re- viewed by Seiser and Litzner). Although this glycosuria appears to have been usually of the so-called “alimentary” type, transitory hyperglycemia has been reported occasionally, usually during acute episodes (Pavlov; Petroff). In the majority of instances no alteration in blood sugar has been observed in lead poisoning, and it is possible that abnormalities in carbo- hydrate metabolism, when they do occur, may be dependent upon distur- bance of liver function rather than upon a direct action of lead on carbohydrate metabolism. The occurrence of hemochromatosis has been reported occasionally in lead workers, but there is no evidence that this relationship is other than purely accidental. Fat Metabolism There have been relatively few studies of the state of fat metabolism in lead poisoning. Considerable loss of weight is commonly observed clini- cally and Flury states that chronic lead poisoning is accompanied by defec- tive deposition of fat in man and in experimental animals. In chronic lead poisoning in rabbits, Caccuri reported an increase in all blood lipids while in acute poisoning there was a decrease in both free and ester cholesterol and an increase in phosphatase. Other observers have reported normal, increased and decreased values for blood lipids in all stages of lead intoxica- tion in man and in experimental animals (Cresoli; Kretschmer and Frieder; Kuhn; Gelman'; Petroff). The lack of consistency in these findings sug- gests that changes in fat and lipid metabolism may be produced through the medium of injury of certain organs, notably the liver and kidneys or may be related to the development and severity of anemia. 58 LEAD POISONING Mineral Metabolism In view of the parallelism between the deposition and storage of lead and of calcium and phosphorus, it is natural that the metabolism of the latter elements in lead poisoning should have received particular attention. There is evidence that suggests that in the process of its deposition as a relatively insoluble phosphate in the bone, lead displaces calcium (Aub, Fairhall, Minot and Reznikoff; Bischoff and Maxwell; Brooks; Jowett). According to Tscharny and Israelewitsch, the serum calcium concentration is increased in dogs with experimental lead poisoning. In our experience, which is in accord with that of the majority of investigators in this problem, no significant change can be detected in the calcium concentration of the blood serum. Schmitt and Taeger believe that the calcium content of the erythrocytes is markedly diminished, due perhaps, as they suggest to dis- placement by lead. However, in view of the generally accepted fact that the calcium content of the red blood cells is extremely low, and since it appears probable that lead does not penetrate to the interior of the cell, this observation appears to be of little consequence. No significant alteration in calcium balance has been demonstrated in subjects with lead poisoning although Tscharny and Israelewitsch reported increased excretion of cal- cium in the urine and feces of dogs in the early stages of lead intoxication. Evidences of disturbance of phosphorus metabolism have been reported, related perhaps in part to the direct effect of lead and in part to the develop- ment of acidosis due to renal functional impairment (Flury?). Tscharny made the following observations upon dogs with lead poisoning: in the first few days the lipid phosphorus increased to about 26 mg. per 100 cc.; after about one week the organic acid-soluble phosphorus fell to about 19 mg. per 100 cc. of blood; after about one month the serum inorganic phos- phorus concentration increased from 4.8 to 8.0 mg. per 100 cc.; the phos- phate in the urine fell to about 25 per cent of its normal value. These complex changes are not readily explained. We have been unable to de- monstrate significant alterations in the serum phosphate concentration in clinical lead poisoning in the absence of complicating factors such as renal functional impairment. According to Peregud a decrease occurs in a majority of cases except during periods of colic, at which time an increase is observed. Disturbance of iron metabolism, when it occurs, is related in part to the direct effect of lead upon hematopoiesis in the bone-marrow and in part to excessive peripheral destruction of red blood cells, with consequent deposi- tion of iron-containing pigment in various organs (p. 50). Increase in the chloride concentration of whole blood has been reported (Dauwe; Goetze), but this is perhaps due to the presence of anemia with a relative increase in plasma volume; we have not found significant alterations in plasma chloride PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 59 concentration in clinical lead poisoning in the absence of complicating fac- tors. An increase in blood potassium was reported by Celcov in cases of lead intoxication. Following the intravenous or oral administration of lead to rabbits, Henriques and Orskov found a decrease in the potassium content of the erythrocytes (as much as 75%) and a simultaneous decrease in their volume. The permeability of the cells to sodium appeared to be increased simultaneously. Decrease in the alkali reserve and the pH of the blood has been reported by several observers in man and experimental animals (Gar- rod?; Prisco; Omeljanowitsch-Pavlenko; Tscharny). In dogs, Tscharny found a decrease of about 20 to 25% in the alkali reserve. According to Flury?, this may be dependent upon disturbance in enzyme reactions and oxidation processes, with impairment of the buffer mechanisms of the blood and other body ffuids. It has been suggested by Minot! ? that acids are liberated at the surface membrane of cells in consequence of the reaction whereby lead phosphate is formed (p. 48). ENDOCRINE GLANDS The effect of lead on the gonads have been considered elsewhere (p. 84). Little information is available regarding its effect upon other endocrine glands. Adrenal cortical hypertrophy with degenerative and fatty changes (Gouchet; Bianchi) and an increase in the lipid content of the adrenal (Pen- netti; Peisachowitsch) have been reported. According to Petroff, lead workers are particularly susceptible to the development of hyperthyroid- ism. On the other hand, Porritt believes that the cumulative effect of small doses of lead results in functional injury to the thyroid, which may become atrophied. SKIN AND APPENDAGES The skin may be pale or ashy-gray, with a shiny or “leaden” hue and occasionally with an icteric tint. These variations in color are due to one or more of several factors, including anemia, vasospasm and hyperbilirubin- emia. The skin may be dry, scaly or atrophied, perhaps as a result or trophic disturbances or loss of subcutaneous fat (Flury?). Cutaneous eruptions resembling eczema and decubitus ulcers have occurred in experi- mental animals. © In clinical plumbism the hair may be coarse; dryness of the wool has been reported in sheep, ruffling of the feathers in birds and loss of the gloss of the fur in other animals with lead intoxication. Flury? be- lieves that the sebaceous and sweat glands may be injured, but little infor- mation is available in this regard. EFFECT ON SKELETAL MUSCLE The effect of lead upon skeletal muscle has attracted considerable atten- tion because of its possible relation to lead paralysis, one of the most strik- 60 LEAD POISONING ing and important manifestations of lead poisoning. There is still considerable difference of opinion as to the relative significance of primary muscular as against primary nervous system damage in this connection. In the past, the majority of pathologists inclined toward the view that the primary lesion of lead paralysis is in the nervous system, the evidence favor- ing this view being presented elsewhere (p. 65ff.). However, recent physio- logical and chemical studies support the opinion that lead palsy is probably dependent fundamentally upon a direct effect of lead on the muscle. Practically all of the early studies were of a morphologic or clinical nature. Several histologic changes have been described by various authors; fatty degeneration (Legge and Goadby); scattered, minute hemorrhages (Legge and Goadby); degenerative myositis with replacement fibrosis (Friedléin- der) ; nuclear proliferation and granular degeneration (Eisenlohr; Gombault; Aub, Fairhall, Minot and Reznikoff) ; atrophy (Harnack; Friedlinder; Kost; Meillere?; Hyslop and Krauss; Laslett and Warrington; Eisenlohr). Ac- cording to Uliverdi, subcutaneous injection of lead acetate in rabbits and guinea-pigs is followed by nuclear pyknosis, vacuolation and necrosis of muscle cells, loss of striation and proliferation of connective tissue. Flury? states that chronic lead poisoning in animals is accompanied by varying degrees of muscular atrophy, fatty degeneration, exudative phenomena, myositis, increase in the number of muscle cells and a decrease in the size of the fibers and a loss of striation. The picture is essentially one of degenera- tion, followed by reactive proliferation of cells and connective tissue, often accompanied by hemorrhagic phenomena. Similar findings have been de- scribed in clinical lead poisoning. Messing regarded the lesion as essentially a chronic, degenerative, paren- chymatous myositis, with replacement fibrosis and atrophy, caused by the direct action of lead upon the muscle fibers. This opinion is based upon the observation that the changes in the muscle were more pronounced than in the nerves and that there was evidence of an inflammatory process, as con- trasted with the type of simple atrophy that might follow a primary nerve lesion with interruption of trophic fibers (Messing; Friedlinder; Kost). Tt was believed by some observers that these changes in the muscles are due to a primary action of lead on the blood vessels, the walls of which were believed to be injured, with consequent rupture during muscular activity (Legge and Goadby; Hitzig). However, there is no substantial evidence to support this view. It has long been recognized that lead paralysis ap- pears earliest in muscles that are most used and, therefore, most readily fatigued (Meyer; Moebius?; Edinger; Teleky). As stated by Aub and his associates, through the work of Edinger, which was subsequently strength- ened by evidence presented by Teleky’, this observation constitutes the most important single clinical contribution to the explanation of lead palsy. PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 61 It is now generally accepted by most authorities (Oliver?; Legge and Goadby; Aub, Fairhall, Minot and Reznikoff). Until recently, however, no cause had been satisfactorily demonstrated for this rather selective in- volvement of fatigued muscles. It was suggested by Hitzig that as a result of the greatly increased circulation in these muscles they were exposed to disproportionately large quantities of lead. However, as stated by Aub, this does not explain the mechanism of action of lead on the muscles. Some early investigators of this problem found that muscle exposed to lead rap- idly became fatigued and inexcitable (Gusserow; Harnack; Mellon) and that its relaxation time was prolonged (Cash). That this effect was due to some change in the contractile elements in the cells was suggested by the fact that it occurred on direct stimulation of the muscle. This view is also supported by the observation by Reznikoff and Aub that action potentials could be obtained from the nerve but not from the muscle of a nerve-muscle preparation exposed to lead. The studies of Reznikoff and Aub on isolated muscle showed that exposure to lead results in more rapid fatigue and greater difficulty in recovery. They concluded that lead interferes markedly with the function of isolated muscle. These authors made the interesting and important observation that after exposure to lead there was a marked increase in the rate of diffusion of inorganic phosphate from the muscle, a phenomenon which they attributed to alteration of the surface membrane with increase in its permeability. They believed that this in- creased permeability is accomplished in much the same way as in the case of the red blood cells, being due essentially to precipitation of insoluble lead phosphate at the surface of the cell with liberation of free acid. According to this hypothesis, excessively large quantities of lactic acid, which diffuse from fatigued muscle cells in regions of muscular activity, convert the cir- culating lead phosphate into lead lactate. The soluble lead lactate comes in contact with inorganic phosphate at the surface of the muscle cell, lead being reprecipitated as the insoluble tertiary phosphate with the liberation of free lactic acid. Subsequent observations regarding the physiology of muscular contrac- tion necessitated reinterpretation of these findings. The following are of significance in this connection: (a) the discovery of phosphocreatine and the demonstration that inorganic phosphate constituted only 15-20 per cent of the total acid-soluble phosphorus of the muscle (Fiske and Sub- barow; Eggleton and Eggleton); (b) the demonstration of the fact that energy for muscular contraction is supplied by the breakdown of phospho- creatine into creatine and inorganic phosphate (Lundsgaard); (c) the observation that phosphocreatine cannot diffuse through the muscle mem- brane whereas creatine and phosphate are freely diffusible (Eggleton). In view of the fact that the inorganic phosphate content of muscle is now 62 LEAD POISONING known to be only 20-25 mg. per cent, and in view of the observation (Stella) that the diffusibility of inorganic phosphate is the same for resting and fatigued muscle, Steiman raised the question as to whether the great in- crease in the diffusion of phosphate from “leaded” muscle might not be due to hydrolysis of phosphocreatine with consequent increase in the concentra- tion of inorganic phosphate in the muscle. He found that the resting level of phosphocreatine in the muscles of animals exposed to lead was much lower than normal, while the inorganic phosphate was greatly increased. Whereas in normal muscle the phosphocreatine hydrolyzed during a two- minute tetanus was completely resynthesized after a half-hour recovery period, practically no resynthesis occurred in lead poisoned muscle. The loss of inorganic phosphate from the latter was shown to be due to the in- creased amount of inorganic phosphate resulting from phosphocreatine hydrolysis (Steiman). Since there is a direct correlation between the presence of phosphocreatine and the ability of the muscle to contract (Fiske and Subbarow), the poisoned muscles with a low phosphocreatine content have a diminished capacity for contraction. Since the force of contraction is proportional to the breakdown of phosphocreatine (Lundsgaard), the poisoned muscles cannot develop and maintain normal tension. Since resynthesis of the hydrolyzed phosphocreatine is essential for the restoration of muscle excitability, the poisoned muscle is readily rendered inexcitable. Thus, as stated by Steiman, the low level of phosphocreatine and the marked interference with its resynthesis can readily explain the muscular weakness, fatigability, and paralysis resulting from exposure to lead. These observations lend new support to the view that the fundamental physiological lesion of lead palsy is in the muscle (Aub, Fairhall, Minot and Reznikoff). It is interesting in this connection that the development of lead intoxication has been found to be accompanied by an increase in the urinary excretion of creatine (Cantarow!). The impairment of phospho- creatine resynthesis in the muscle may be dependent upon a direct action of lead on intracellular enzyme systems (p. 55). EFFECT ON NERVOUS SYSTEM The frequent occurrence of striking manifestations suggestive of involve- ment of the nervous system (paralysis, peripheral neuritis, and encephalo- pathy) has led to intensive investigation of morphologic changes in the brain, spinal cord, peripheral nerves and meninges in clinical and experimental lead intoxication. Many of these studies were undertaken primarily for the purpose of determining the possible basis for the develop- ment of lead paralysis, and, until recently, the opinion of the majority of pathologists was that changes in the nervous system rather than in the mus- cles constituted the fundamental basis for the development of this phenom- PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 63 enon. As indicated above, the recent demonstration of the effect of lead upon the physiology of muscular contraction renders such a view highly improbable. However, there can be no doubt that lead intoxication may be accompanied by morphologic changes in practically all portions of the nervous system, which may unquestionably contribute to the clinical mani- festations of this condition. Brain The dramatic character of acute cerebral manifestations (lead encephalo- pathy), especially in children, has naturally focused attention upon changes in the brain. The following lesions have been observed: gross hemorrhage, edema, hyperemia, or pallor, with either swelling or shrinking of the brain and atrophy or flattening of the convolutions (Tanquerel; Meillere’; von Monakow; Seifert; Oliver’; Blackman; Akelaitis; Freifeld; Staemmler). Swelling and hyperemia apparently occur more frequently in acute than in chronic lead poisoning. Changes observed in the blood vessels include arteriosclerosis, arteritis, capillary lesions, and microscopic and gross hemor- rhage (Hutton; Timme; Westphal; Oppenheim; Courtney; Freifeld; Cad- walder; Winkelman and Eckel; Rhea). The variability of changes in the circulation of the brain is indicated by the frequent observation of both hy- peremia (Blackman?) and anemia (Meillere?; Ménétrier; Rosenstein; Black- man?). Diffusely distributed punctate hemorrhages have been reported, dependent apparently upon changes in arterioles, venules, or capillaries (Legge and Goadby; Freifeld; Courtney; Tuthill; Blackman?®; Mott). Staemmler describes nodular proliferation of glial cells in the white matter, usually grouped about small blood vessels. This phenomenon was also observed occasionally in the gray matter. The olive showed evidence of injury and there was a decrease in the number of Purkinje cells in the cere- bellum. On the other hand, Lehmann, Spatz and Wisbaum-Neuberger state that there are no typical vascular changes in the brain in lead poison- ing. They group the anatomical changes in this organ under three head- ings: (1) Exudative changes, (2) fatty changes, and (3) regressive changes in nerve and glial cells. The most striking abnormality in experimental plumbism in cats was severe damage to the ganglion cells, which showed varying degrees of vacuolation, nuclear pyknosis and karyorrhexis. Simi- lar changes were described by Spielmeyer. Blackman? described changes in the arterial capillaries similar to those found in acute or subacute inflammatory process. The capillaries were found to be dilated, particularly in acute cases, or narrowed, some of the lining cells undergoing degeneration, nuclear pyknosis and fragmentation, some of the capillary loops being thrombosed and necrotic. Many of these damaged blood vessels were surrounded by an abundance of exudate, usu- 64 LEAD POISONING ally of a serous nature and, in older areas, inspissated, taking a basophilic stain and giving staining reactions for calcium and iron. New formation of capillaries was described by Hassin and by Winkelman and Eckel. Black- man? found that this widespread exudative process resulted in serious dis- tortion of the architecture of the brain, areas in both gray and white matter being stretched and torn. These areas contained torn and necrotic glial and nerve cells, the latter frequently surrounded by glial neurophagocytes. There were scattered perivascular hemorrhages and small focal areas of necrosis throughout the brain, usually associated with necrotic capillary segments or capillary thrombi. Similar lesions were observed in the cere- bellum and, less frequently, in the basal nuclei, brain stem, pons and medulla. Blackman? believes that most of the injury to the nervous tissues is dependent on the accumulation of exudate. Mott reported hyper- plasia of the neuroglia cells. According to Hassin, the chief lesion in lead encephalopathy is marked proliferation of fibrous tissue and blood vessels in the pia-arachnoid, with relatively slight change in the parenchyma. These consist chiefly of proliferation of the glial cells, which frequently in- vade the ganglion cells, the latter usually being well-preserved, except for occasional vacuolization and chromatolysis. Other observers have re- ported focal lesions in various parts of the brain, consisting of degenerated or destroyed nerve cells, especially marked in the case of Purkinje cells in the cerebellum, some of which were completely replaced by neuroglia, with the consequent formation of glial rosettes (Freifeld; Tuthill; Winkelman and Eckel; Blackman?). Meninges In recent years attention has been directed toward changes in the menin- ges in lead encephalopathy. Examination of spinal fluid has yielded evi- dence of meningeal irritation. The significant changes include increased cerebrospinal fluid pressure, hyperproteinemia and pleocytosis, the cells being usually lymphocytes (Norton; Boveri; Troisier; Mass; Suzuki and Kaneko; Thomas and Blackfan; Mosny and Malloizell). Hassin found that the most constant and most marked changes in lead encephalopathy were in the meninges, which showed evidence of a proliferative inflamma- tory process (also Akelaitis), especially in the pia-arachnoid, and, in acute cases, round-cell infiltration. The experimental observation of Camus suggest that the manifestations of lead encephalopathy may be related to meningeal irritation due to the presence of lead in the cerebrospinal fluid. Lead has been demonstrated in this fluid both in normal subjects and in those with lead poisoning (Schmitt and Basse; Rabinowitch, Dingwall and Mackay; Duensing; Taeger; Aub, Fairhall, Minot and Reznikoff). It would appear that, contrary to the usual belief, the choroid plexus is nor- PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 65 mally permeable to this substance; however, in view of the fact that in lead poisoning the concentration in the cerebrospinal fluid bears no apparent relation to that in the blood, it seems probable that the permeability of the hemato-encephalic barrier is altered under such circumstances. On the basis of these observations, Aub and his associates concluded that the cere- bral manifestations of lead intoxication are probably dependent upon pri- mary involvement of the meninges, and that the condition is a meningo- pathy rather than an encephalopathy. This conclusion was reached before the appearance of reports of the careful studies by Blackman, Freifeld, Tut- hill, Winkelman and Eckel and others referred to above. Spinal Cord There are numerous reports of changes in the meninges, the blood vessels, and the gray and white matter of the cord in poisioning. According to Hyslop and Kraus, the commonest pathologic changes in the cord occur in the blood vessels and the gray matter. The vascular changes include con- gestion and capillary hemorrhages (E. D. Fisher; Stieglitz, Kussmaul and Maier; Legge and Goadby), arteritis and periarterial lymphocytic infiltra- tion (Hitzig; Mott). One of the most constantly observed lesions is degen- eration of the anterior horn cells, a point which has been regarded as of particular significance in its relation to the pathogenesis of muscular atrophy in lead poisoning. This phenomenon is characterized usually by chromatolysis, vacuolation, fatty change and degeneration of these cells (Spiller; Mott; Meillere?; McCarthy; Stieglitz; Laslett and Warrington; Bernard and Salomon; Claude and Loyez; Philippe and Gothard). Changes have been observed also in the white matter of the cord (E. D. Fisher; Baker), including extensive demyelinization and sclerosis of the posterior and lateral columns. Thickening of the meninges, particularly the pia-arachnoid, has been described (E. D. Fisher; Hassin). Nerve Roots and Peripheral Nerves Degenerative changes have been reported in the anterior roots (HE. D. Fisher; Laslett and Warrington; Philippe and Gothard) and in the posterior roots and ganglia (Spiller; Stieglitz). There are numerous reports of changes in the peripheral nerves, including diffuse hemorrhages (Goadby and Goodbody) and Wallerian degeneration (Westphal; Oppenheim and Siemerling; Dejerine-Klumpke; Meillere’; Gombault). According to Flury, the peripheral nerves may show degeneration, swelling of the axis cylinders and atrophy of the end apparatus. Spatz found rela- tively little involvement of the medulla and the cranial nerve nuclei, but Straub and Erlenmeyer observed severe damage in the medulla and the nuclei of the glossopharyngeal, acoustic and hypoglossal nerves of cats with 66 LEAD POISONING lead poisoning. De Villaverde believes that lead inhibits regeneration of nerves. Changes have been reported in the sympathetic nervous system, consisting chiefly of diffuse degeneration of the cells in the superior and in- ferior ganglion and celiac plexus (Griinberg; Omaru). Sclerosis of the celiac ganglia has been described (Kussmaul and Maier) as well as marked changes in the ganglia of the submucous and myenteric plexus (Masse). A number of observers believe that lead exerts its effect upon that part of the neurone which is temporarily most vulnerable because of its functional condition (Raymond; Gordon; Putnam?; E. D. Fisher; Spiller; Wilson; Goodwin). In a review of the literature on this subject, Hyslop and Kraus conclude that the entire lower motor neurone is involved rather than only its peri- pheral parts, and that the condition is essentially a true neuronitis. Obviously, the literature dealing with the effects of lead upon the nervous system is in a rather confused state. The extremely variable and indeed contradictory findings have caused considerable difference of opinion re- garding the relation of the nervous system changes to the clinical mani- festations of encephalopathy and paralysis, the two outstanding features of lead poisoning which might presumably be dependent upon such lesions. As stated by Aub and his associates, lead encephalopathy has been attri- buted to (a) cerebral vascular change (Timme; Hutton), (b) cerebral anemia (Meillere?; Rosenstein; Ménétrier), (¢) diffuse punctate hemorrhages sec- ondary to capillary lesions (Legge and Goadby), (d) an associated state of uremia secondary to renal damage caused by lead, (¢) changes in the corti- cal cells due to the direct action of lead, and (f) meningeal lesions (Norton; Hassin; Troisier; Boveri; Mosny). The majority of these hypotheses can be readily eliminated from consideration. Aub, Fairhall, Minot and Rez- nikoff concluded that so-called lead encephalopathy is really a meningoen- cephalopathy, and that the meninges are the structures primarily involved. More recently, McKhann and Vogt suggested that the clinical manifesta- tions might be dependent on increased intracranial pressure due to cerebral edema (Weller and Christiansen). According to Lehmann, Spatz and Wisbaum-Neubiirger, the important cerebral lesions are degenerative in nature (nerve cells and fibers, blood vessels and ganglia). On the basis of very careful pathological studies in 22 cases of lead encephalopathy, Black- man? concludes that the clinical manifestations are dependent upon con- sistently occurring lesions in the brain, resulting primarily from vascular damage and exudation. These lesions have been reviewed above. He states, however, that the precise relation between lead in the tissues and the pathogenesis of the vascular phenomena is not clear. It was suggested that factors which cause vasodilatation such as fever and hot weather, may be of importance in precipitating the brain lesions by increasing the per- meability of the blood vessels and thus rendering the brain tissue PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 67 more susceptible to the action of lead. Blackman? found no primary changes suggestive of meningopathy other than those in the blood vessels, which were similar to the vascular lesions in the brain tissue. It is difficult to reconcile these very striking and consistent morphologic changes with the statement made by some recent observers that no definite information is available regarding the characteristic nervous system lesions of lead poisoning nor of their relation to the development of signs and symptoms referable to this system (Aub, Fairhall, Minot and Reznikoff; Baker; Taeger). It seems significant that some observers have found little or no morphologic alterations or only cerebral edema with few histologic changes (Barron and Habein; Taeger). It may be that metabolic rather than mor- phologic abnormalities are of fundamental importance in the pathogenesis of these cerebral manifestations. It will be recalled in this connection (p. 55) that Dolowitz, Fazekas and Himwich found that brain tissue ex- posed to lead showed decreased glycolysis and inhibition of dehydrogena- tion. The authors suggested that these phenomena may constitute the basis for the symptomatic manifestations of plumbism, similar changes being found also in other tissues (kidney, liver, testis). Numerous attempts have naturally been made to establish a relationship between the morphologic changes in the cord and peripheral nerves and the pathogenesis of lead paralysis. The primary lesion has been regarded by some to be in the spinal cord (anterior horn cells and lateral columns), and by others in the peripheral nerves. Belief in the primarily peripheral location of the lesion is based on the fact that typical lead paralysis usually resembles so-called peripheral neuritis and upon the observation of changes in the peripheral nerves other than those which may be attributed to pe- ripheral degeneration following a central lesion. It has also been remarked as significant that the most pronounced changes are present in the muscles and peripheral parts of the nerves, becoming less marked centrally (Legge and Goadby; Remak). It has been suggested that the primary lesions occur in the most vulnerable portion of the neurones and then spread either centrally or peripherally. The possibility of ascending changes in the nerves has been questioned and no exact information is available re- garding the mechanism whereby a peripheral injury may produce central lesions (Aub, Fairhall, Minot and Reznikoff). Objections to the hypothesis that lead palsy is dependent primarily upon changes in the peripheral nerves have been summarized by Hyslop, and Kraus. It has long been recognized that the muscle groups involved in lead palsy are usually those which are functionally correlated rather than those constituting the zone of peripheral distribution of single nerves (Remak; von Monakow; Déjérine). As stated by Hyslop and Kraus, it would be difficult, on the basis of primary involvement of the peripheral 68 LEAD POISONING nerves, to explain the occurrence of paralysis of several muscles innervated by the musculospiral nerve and the absence of involvement of other muscles - supplied by branches of the same nerve. The observation has frequently been made that lead paralysis appears to affect preferentially muscles supplied by certain segments of the cord rather than those supplied by a particular nerve or nerves. It is difficult to understand how a lesion can ascend from the distal portion of a nerve, such as the musculospiral, to the cord without involving all of the roots of that nerve. Moreover, the not infrequent occurrence of clinical pictures suggesting amyotrophic lateral sclerosis points to the presence of cord involvement, as do the several re- ports indicative of changes in the meninges and cerebrospinal fluid. It would be difficult to explain the latter on the basis of primary changes in the peripheral nerves. On the other hand, it is equally difficult to explain on the basis of primary cord changes the reports of absence of such changes in several instances, and in others the relatively limited extent of involvement of the cord as compared to the peripheral nerves and muscles. Hyslop and Kraus discount early reports of the absence of changes in the anterior horn cells on the basis of inadequate study, but the recent report by Goodwin seems to be rather conclusive in this regard. The former believed that the available evidence favors the concept that the entire neurone is involved from the onset of symptoms and that lead paralysis should properly be regarded as neuronitis (Spiller; Remak; Hyslop and Kraus). As pointed out by Aub and his associates, it is impossible to explain all of the phenomena associated with lead palsy on the basis of morphologic changes in the nervous system. Recent chronaximetric studies indicate that lead poisoning or prolonged exposure to lead is accompanied by diminu- tion in nerve-muscle irritability, which may never return to normal even after years of freedom from exposure (Lewy; Schuetz). However, this observation does not aid in localizing the point of primary damage. As was stated elsewhere (p. 59ff.), recent physiological and chemical studies suggest that the fundamental lesion of lead paralysis is in the muscle and that the primary abnormality is one of muscle physiology rather than morphology. Nevertheless, subsequent changes in the brain, spinal cord, meninges and peripheral nerves may contribute significantly to the develop- ment of clinical manifestations of lead intoxication. Sense Organs A variety of disturbances in the function of all sense organs may occur in lead poisoning. However, anatomic bases for these disturbances are usually lacking except in the case of the eye and, occasionally, the ear. Serous exudate in the labyrinth, sclerosis of the tympanic membrane and injury of the acoustic and cochlear nerves have been reported (Flury?). PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 69 Interest centers particularly in changes in the visual apparatus because of the relative frequency of occurrence of the disturbances of vision in lead poisoning (p. 124). There may be no detectable change in the eye in acute lead poisoning with the exception of the occasional observation of retinal artery spasm, particularly during periods of colic or encephalopathy (p. 110). In chronic poisoning, changes have been observed in the ex- trinsic eye muscles similar to those reported in other muscles. There have been many reports of paralysis of muscles supplied by the oculomotor and abducens nerves and, less commonly, the trochlear nerve. Complete ophthalmoplegia may occur. Degenerative changes have been described in the visual center and in the optic nerve nuclei, leading to so-called ‘“hemi- anopsia saturnina.” Keratitis has also been reported. The most im- portant changes include acute neuroretinitis, papilledema, optic atrophy and all of the manifestations of hypertensive retinitis. The retina may show spasm, narrowing and tortuosity of the arteries, dilatation of the veins, edema, exudate, hemorrhages and pigmentation. The choroid is often damaged extensively. With the exception of occasional instances of pri- mary optic neuritis, the majority of these changes in the eye are dependent upon alterations resulting from vascular injury. This may be due to the direct action of lead upon the retinal blood vessels or may represent a true hypertensive retinitis (Lewin and Guillery). EFFECT ON SMOOTH MUSCLE The importance of colic as a clinical manifestation of plumbism naturally led to intensive investigation of the effect of lead on the musculature of the gastrointestinal tract. As stated by Aub, it is generally agreed that colic is due to marked constriction of the small intestine, but the mechanism whereby lead produces this effect is not clearly understood. Postmortem observations in acute clinical and experimental lead intoxication have revealed irregular constriction of the small intestine, so intense in some regions as to produce complete occlusion of the lumen in segments three or four inches in length (Oliver?; Legge and Goadby). By means of the X-ray, Wassermann demonstrated primary hypermotility and spasm of the small intestine with evidence of subsequent atonicity, with increased peristalsis and contraction rings in the large bowel causing delayed emptying of its contents. Similar observations were made in a patient with lead colic by Aub and his associates, who found also increased peristalsis and hypertonic- ity of the stomach and enormous dilatation of the cecum and ascending colon due apparently to spasm at the hepatic flexure. Evidence of the production of increased peristalsis by lead has also been obtained by direct observation in rabbits (Hirschfelder) and by kymograph records following the introduction of a balloon into the crop of the duck (Hanzlik). Ex- 70 LEAD POISONING posure of isolated intestinal muscle to lead has been found to result in in- creased tonicity and simultaneous inhibition of spontaneous contraction (Siceardi; Siccardi and Dozzi; Aub and Smith). According to Aub and his associates, these two phenomena are independent of each other. Similar findings have been reported by Dilling and Griinberg. Other types of smooth muscle appear to respond to lead in much the same manner as the intestinal muscle. There are several postmortem reports of marked constriction of cerebral arteries in experimental and clinical lead intoxication (Heubel; Rosenstein; Meillere?; Oliver?). Spasm of the retinal arterioles has been observed during attacks of lead colic (Blum; Elschnig; Labadie-Lagrave and Laubry). According to Tscher- kess, exposure to very dilute solutions of lead nitrate caused vasoconstric- tion, and Beckmann found that the administration of lead to rabbits resulted in increased arteriolar and capillary blood pressure, suggesting constriction of the capillaries or venules (see also p. 75). By direct capillaroscopy, Otto and Hahn found constriction of the arterial ends of the capillaries in 75 per cent of a group of lead workers. Similar findings were obtained in experimental lead intoxication in rats. Isolated strips of blood- vessel muscle have also been found to contract under the influence of lead (Siccardi and Dozzi). Similar findings have been obtained in the case of other types of smooth muscle, such as that of the ureter and the pregnant and non-pregnant uterus (Dilling; Griinberg; Siccardi and Dozzi). Although there is general agreement regarding the ultimate effect of lead upon smooth muscle, as indicated above, there is no unanimity of opinion regarding the mechanism underlying the production of this effect. As stated by Aub and his associates in connection with lead colic, intestinal spasm must result from one of three causes: (a) direct stimulation of the muscle fibers; (b) stimulation of the vagus, through its center in the medulla, the nerve cells, or their endings; (¢) inhibition of some portion of the sym- pathetic supply to the intestines. It has been proposed that the funda- mental cause of lead colic may reside in the peritoneum, the abdominal and the diaphragmatic plexus, the mesentery, inflammatory changes in the intestines, increase in intestinal pressure and spasm of splanchic vessels (Frank; Riegel). Evidence has been advanced in support of each of these possibilities. The hypothesis that lead exerts its effect by direct action on the muscle fibers is based upon the following observations: (a) the effect on intestinal muscle strips containing no ganglion cells is essentially the same as on strips containing nerve cells (Aub and Smith); (b) the effects on isolated muscle strips is not abolished or prevented by atropine, epinephrin or nicotine (Dilling; Siccardi; Siccardi and Dozzi; Hanzlik); (¢) increased intestinal peristalsis induced by lead is not influenced by atropine or epinephrin but is inhibited promptly by chelidonin, which is PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 71 believed to depress smooth muscle fibers directly (Hanzlik). On the other hand, Hirschfelder and his associates found that the increased intestinal peristalsis disappeared following administration of atropine or nicotine, but not following section of the spinal cord or vagus, and concluded that the effect of lead is exerted through the medium of preganglionic nerve fibers. Inhibition of sympathetic nerve impulses has been attributed to sclerosis and other changes in the sympathetic ganglia (Mosse; Wassermann) the celiac ganglion (Tanquerel des Planches), and the submucous and myenteric ganglion cells (Maier). Stimulation of the vagus center in the medulla has been suggested (Mason). In a clinical review of the subject, with particular reference to lead colic, Aub and his associates conclude that whereas no definite statement is justified on the basis of available data at the present time, lead does not appear to exercise a selective action on any of the nervous structures of the gastrointestinal tract. They believe that the action of lead is exerted directly on the smooth-muscle fibers. It must be admitted that the weight of evidence favors this view. It must be remembered, however, that the experimental approach to this problem necessitates the establish- ment of conditions which are not at all comparable to those encountered in clinical states of lead intoxication and that few if any of the observations reviewed above may be regarded as entirely free from criticism. This is particularly true of in vitro experiments with muscle strips. Moreover, the more recent, careful work of Griinberg upon various types of smooth muscle strongly suggests that the autonomic nervous system is involved in the production of the lead effects. Contraction occurred in some cases and inhibition in others, the effect closely resembling in each instance that produced by adrenalin or sympathetic stimulation. Introduction of lead into the systemic circulation resulted in intestinal constriction which was prevented by section of the vagi in the neck. Grinberg believes that lead produces its effect on the intestines, at least, through a dual mechanism: (1) it acts locally to inhibit intestinal movements by stimulating the sympathetic nerve endings in the muscle and (2) it acts centrally to cause muscular contraction by stimulating the vagus. Unfortunately, no chemi- cal studies have been made similar to those which have improved our understanding of the effect of lead upon skeletal muscle (p. 59ff.). As stated by Minot, it would be interesting to know whether exposure to lead is accompanied by increased permeability of the muscle cells to certain inorganic ions and to changes in electrolyte equilibrium; such changes “might well be an essential factor in the functional disturbance of smooth muscle in view of the marked influence which inorganic ions are known to have on both smooth muscle and autonomic nerve activity.” CuAPTER III PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY (Continued) HEART, BLOOD VESSELS AND BLOOD PRESSURE There has long been a great deal of controversy regarding the effects of lead upon the circulatory system. It is believed by many that hyperten- sion occurs rather commonly in lead poisoning, due perhaps primarily to arteriolar spasm and subsequently to development of arteriosclerosis and, at times, nephrosclerosis. The evidence in favor of this view is by no means entirely conclusive. On the basis of the observation (p. 69ff.) that lead may cause contraction and spasm of smooth muscle, including that of the arterioles, it would appear justified to assume that exposure to this agent may result in elevation of blood pressure. There have been several reports of moderate to marked hypertension during acute episodes of lead intoxi- cation, such as colic and encephalopathy (Riegel; Vaquez; Frank; Pal; Traube; Fishberg; Legge and Goadby). According to Teleky, the blood pressure may rise for a few days during periods of exacerbation in the early stages of lead colic, may remain elevated for a short time and then fall with the subsidence of symptoms. He believes that the blood pressure varies in different stages of acute lead intoxication. On the other hand, Oliver? found the blood pressure to be often low during lead colic. He also found that the intravenous injection of lead salts in experimental animals usually resulted in a fall in blood pressure, due probably to a direct effect on the heart and vasomotor center. The significance of this observation is doubtful because of the relatively large doses of lead employed. Fall in blood pressure in acute lead poisoning may be a manifestation of collapse (shock syndrome). Observations upon experimental animals have yielded variable results. Tscherkess found that the injection of lead in rabbits was followed by a decrease in the blood pressure. Dilling found that the intravenous administration of colloidal lead to cats resulted in a brief rise in blood pressure followed by a fall. According to Petroff, three different phases may be demonstrated (dog and rabbit), the duration of which varies with different animals and in different species: (1) No change in blood pressure, (2) increased blood pressure, (3) falling blood pressure. Ruhl found that whereas injection of lead acetate in rabbits resulted in no alteration in blood pressure, the administration of an emulsion of white lead was followed by an increase which persisted in some instances for as long as one month. Inasmuch as no morphological change could be demon- strated in the vessels, it was believed that this hypertension was due to 72 PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 73 vasospasm, which in some cases resulted in aortic enlargement and cardiac hypertrophy. In evaluating the significance of the observation of an increase in blood pressure during episodes of acute colic, the effect of pain in the production of this response must not be disregarded. In our own experience, acute lead intoxication is frequently but by no means consistently accompanied by a significant rise in blood pressure. This is in accord with the experience of Teleky®. One exception may be made to this statement, namely lead encephalopathy, in which condition hypertension is almost invariably present unless counteracted by such factors as shock or left ventricular failure. It is generally believed that long-continued exposure to lead may cause a significant increase in blood pressure. This belief is based upon the clinical observation that hypertension appears to be unusually common in chronic lead poisoning and lead workers (Allbutt; Harris; Feil and Balsac; Fishberg; Teleky®; Legge and Goadby; Oliver’). On the other hand, Lasius states that if one excludes cases of nephritis, the blood pressure is not increased in lead workers even after 30 to 40 years of exposure, and Engel found normal blood pressures in 80 per cent of lead workers. Several other recent authors are of the opinion that hypertension cannot be regarded as a common manifestation of clinical lead intoxication (Pfeil; Schnitter). In the majority of instances these conclusions were not based upon suffi- ciently critical analysis of the blood-pressure findings in comparison with properly selected control groups to permit a satisfactory evaluation of the data from a statistical standpoint. In a careful analysis of data obtained in 81 cases with heavy exposure to lead over a period of years (58%, 5 years, 179%, 10-20 years), Belknap concluded that there is no significant difference in blood-pressure in workers with lead and in non-workers in the same age group. However, the majority of the subjects of this study were not exposed to lead for sufficiently long periods of time to justify the conclusion that lead is incapable of producing hypertension. Vigodortchik studied the blood pressure in 1437 lead workers and 1332 non-workers, the data being analyzed statistically according to age groups, duration of exposure, and other factors. It was found that the average blood-pressure was higher and the percentage of subjects showing moderate or marked hypertension greater in each age group of lead workers than of non-workers, and it was concluded that prolonged exposure to lead is accompanied by a tendency toward an increase in blood pressure. This view is maintained by Teleky® and by the majority of workers in this field. Dreessen and his associates made an exhaustive survey of 766 men employed in 6 lead storage battery factories, 759%, of whom had been employed for 5 years or more and about 129, for 20 years or more. These men were classified according to age 74 LEAD POISONING groups and the concentration of lead in the air to which they were exposed. Statistical analysis of their data revealed the following: (1) exposure to hazardous concentrations of lead was not accompanied by a significant increase in the prevalence of manifestations of arteriosclerotic or hyper- tensive cardiovascular disease; (2) arteriosclerosis, as indicated by thicken- ing, beading or tortuosity of the radial and brachial arteries, or by tortuosity of the retinal arterioles, was no more frequent in heavily exposed than in lightly exposed or non-exposed workers; (3) hypertension (systolic pressure above 150 mm. Hg) was no more prevalent in workers in the storage battery industry than in a group of 9540 workers in other industries involving no abnormal exposure to lead. These findings would have more weight if the data were treated with regard to the duration of employment in addition to the other methods of statistical analysis, since the duration of exposure is more important than the severity of exposure in connection with the devel- opment of changes in the cardiovascular system. Several early observers believed that the primary morphological lesions of lead poisoning are in the blood vessels (Heubel; Maier; Rosenstein). There are numberous reports of the occurrence of periarteritis, arteritis, and endarteritis, even to the point of obliteration, particularly in the nerv- ous system (p. 63ff.) but also in other parts of the body (Hitzig; Uhthoff; Pfleuger; Oeller; Pal; Timme; Kazda). Capillary hemorrhages and hemorrhages in the pericardium, pleura and peritoneum have been observed clinically and in experimental animals (Legge and Goadby; Seiser and Litzner; Teleky”). Weller? reported gangrene of the ear of guinea-pigs with experimental plumbism and Jores found occlusion of the arterioles of the stomach and the intestines, with necrosis and ulceration in the region of these vessels. Endarteritis and thrombosis of the mesenteric vessels was described by Knapp. The vascular lesions reported most commonly include arteriosclerosis, degenerative and fatty changes in the intima, thickening of the intima and media and proliferation of the perivascular connective tissue (Flury?). Clinical observations stress involvement of the intima of the arterioles and all arteries, including the coronary arteries (Kockel; Timm; Badham and Taylor). In their studies of clinical and experimental lead poisoning, Legge and Goadby concluded that the fundamental action of lead is exerted on blood vessels, particularly the small ones, and also on the arterial and venule sides of the capillaries. Minute hemorrhages were found in all organs (brain, muscle, liver, intestines, spinal cord, peripheral nerves, kidneys), the chief lesions being capillary hemorrhage. Many of these observations are difficult to interpret because of the use of exceptionally high concentra- tions of lead in the production of experimental plumbism. However, there are many observations that lead causes vasoconstriction, perhaps through PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 75 direct action upon the vascular musculature (Tscherkess and Philippowa; Sasaki). On the other hand, Ariola reported vasodilatation after the subcutaneous injection of metallic lead and Taubmann pointed out dif- ferences in results obtained in isolated organ experiments and in the intact animal. However, constriction of cerebral arteries has been found in experimental and clinical lead poisoning (Heubel; Rosenstein; Maier; Oliver) and spasm of the retinal arterioles has been observed during episodes of lead colic (Blum; Elschnig; Labadie-Lagrave and Laubry). Moreover, certain disturbances of vision, described elsewhere (p. 124), are probably dependent upon temporary vascular spasm (transitory amaurosis, amblyopia, ete.), either caused by the direct action of lead upon the vessels or constituting a manifestation of systemic hypertension. Pallor of the skin, which occurs commonly in acute lead intoxication, is regarded as the result of vasoconstriction of the skin vessels, and spasm of the splanch- nic vessels has been implicated by some in the pathogenesis of lead colic (p. 80). Complete spastic occlusion of arteries, a rare condition, has been reported, but its relationship to lead poisoning must be regarded as ques- tionable except under unusual circumstances. This is true also of occa- sional instances of mild forms of the Raynaud syndrome reported in asso- ciation with lead poisoning. This association is probably usually coincidental (Flury?). The opinion is prevalent among clinicians that chronic plumbism may cause arteriosclerosis. As stated by Aub and his associates, this idea is based entirely on post-mortem findings, the statistical significance of which is still doubtful. According to Flury, arteriosclerosis is not rare following prolonged exposure to lead and Biondi states that changes in the vessels are regarded by the majority of observers as a late manifestation of chronic plumbism. Observations in experimental animals of the presence (Gouget; Elschnig; Legge and Goadby; Hoffa) or the absence (Jores; Eger) of vascu- lar damage induced by lead can scarcely be regarded as significant in this connection because of the great difference between experimental and clinical conditions of lead poisoning. The possible effect of lead upon the blood vessels of the kidney is of particular interest because of the impor- tance of interference with the renal circulation in the pathogenesis of hyper- tension (p. 90ff.). Hoffa reported the following changes in the renal vessels of guinea pigs with experimental lead intoxication: swelling of the endo- thelium of the larger vessels, occasionally to the point of obliteration of their lumen, with degeneration of the.walls and occasionally rupture and hemorrhage. He regarded these as the primary changes in the kidney, leading to subsequent parenchymal damage. The general opinion among early observers was that the primary renal lesion consisted in endarteritis of the small vessels (Legge and Goadby), a view which is maintained also 76 LEAD POISONING by modern authorities (Fahr; Fishberg). According to Vigodortchik, nephrosclerosis is about three times as common in lead workers as in non- workers in the same age group, and Fahr believes that lead may produce changes in the kidneys identical with these found in malignant hyper- tension. According to Fishberg, the rénal lesions of chronic plumbism are essentially those of arteriosclerosis. He states that in some cases there is striking hypertrophy of the media of the small renal arteries (also Brog- sitter and Wodarz), that endarteritis occurs frequently and sometimes arteriolonecrosis, as in malignant hypertension. The effects of lead upon the kidneys are discussed in detail elsewhere (p. 89ff.). On the basis of clinical evidence, however, it is difficult to escape the conclusion expressed by Fishberg that nephrosclerosis, with its associated changes in the renal vessels, may occur as a result of prolonged exposure to lead and may contribute to the development of hypertension under such circumstances. The important matter of the effect of lead upon blood vessels may be summarized as follows (Flury?): There is no universal agreement regarding the mechanism and the fundamental nature of the damaging effect of lead upon the blood vessels. However, if the premise that lead causes vascular damage is accepted, a basis is furnished for the pathogenesis of many of the morphologic and functional manifestations of lead poisoning. For example, lead circulating in the blood and coming in contact with the intima of the vessels produces a reaction in the vessel walls leading to stimulation and spasm of the vascular muscle. This is followed by morphologic damage which occurs first in capillaries and arterioles. The intima of the medium- sized and small arteries is involved later and eventually all layers of the vessel wall may be affected. The subsequent changes include cell infiltra- tion, nuclear proliferation, degeneration, fatty change, calcification, sclero- sis, thrombosis and fraying of the elastic lamina. The veins become wid- ened or thrombosed. Capillary damage occurs chiefly on the venous side, with increased permeability or actual rupture leading to profuse hemor- rhage. These changes may occur in a variety of organs, perhaps the most important of which is the kidney, since the changes in that organ resulting from disturbance of its circulation may have far-reaching effects upon the organism as a whole (p. 89ff.). Lead is not believed to exert a significant primary effect upon the myo- cardium. Legge and Goadby reported the occurrence of myocardial degeneration following hemorrhagic phenomena in the heart muscle, but the most commonly observed change is hypertrophy and dilatation, attributable to chronic hypertension, the pathogenesis of which has been discussed above (also p. 89ff.). It is possible that changes in the myo- cardium may result from functional and organic disturbances of coronary circulation (Flury?). There is evidence that lead may produce contraction PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY v7 of the coronary arteries (Meyer and Gottlieb) and varying degrees of coro- nary artery occlusion have been observed not infrequently in clinical lead poisoning (Hirschfeld; Seiser and Litzner; Badham and Taylor!). How- ever, the majority of authorities agree that if the effects of hypertension are excluded the heart suffers less than other vital organs in lead poisoning. ALIMENTARY TRACT Lead Line The development of a line or band of blue or blue-black discoloration in the mucous membrane of the gums, lips or cheek, the so called “lead line,” is of importance from the standpoint of diagnosis of lead poisoning. Ob- served under a hand lens, the discoloration is found to be due to the pres- ence of a large number of minute granules which are believed to be pre- cipitated particles of lead sulphide. According to Aub and his associates, microscopic examination reveals that these amorphous granules are entirely subepithelial in position and occur within the lumen and in the walls of blood vessels, in fixed cells of the connective tissue, in macrophages and particularly in the papillae of connective tissue which run to the base of the epithelium (Fagge). Several hypotheses have been advanced in ex- planation of the pathogenesis of this phenomenon, all of which concur in the assumption that the lead sulphide results from the interaction of other lead salts with hydrogen sulphide. It has also been suggested that the source of the sulphur which participates in this reaction may be the potassium sulphocyanate of the saliva rather than hydrogen sulphide (Oliver). As stated by Aub, questions which naturally arise are (a) how hydrogen sulphide is formed in this situation, (b) how the lead is brought to the region in which it is precipitated and (c) how the lead and hydrogen sulphide come in contact. There seems little doubt that the hydrogen sulphide forms as a result of decomposition of protein food that has accumulated about the edges of the teeth and in the interdental spaces and, to some extent perhaps, from tissue decomposition in gingival ulcers. This explains the common clinical observation that the lead line usually fails to develop if the teeth, gums and mouth are cleaned regularly and that it is usually absent in endentulous subjects. It is also significant in this connection that this phenomenon usually does not occur in herbivorous animals exposed to lead, although it is frequently observed in carnivora (cats) (Aub, Fairhall, Minot and Reznikoff). However, Teleky” believes that a lead line may be found in the presence of good dental hygiene and healthy gums. : There is much less agreement regarding the route of entrance of lead into the tissues in which it is deposited. Some have maintained that it is absorbed from the mucosal surface, consisting largely of lead which has 78 LEAD POISONING entered the mouth from the outside. The possibility of direct absorption by the oral mucosa has been demonstrated by Blumgart. Paul observed the development of a lead line following the application of lead acetate to the gums in a human subject but not in animals. Becker rubbed white lead into the gums of cats, after 5-10 days noticed the appearance of a lead line in portions of the gums where no lead had been applied. Legge and Goadby, emphasizing the association of the deposition of lead sulphide with the presence in those situations of inflammation, infection and ulceration, believe that the most important source of the precipitated lead is that present in the mouth. In support of this contention, they state that a lead line does not occur in experimental animals (cat and dog) except in the presence of inflammation or infection of the buccal, labial or gingival mucous membranes, a statement which is contradicted by the observations of Aub and his associates. Several other observers emphasize the im- portance of gingivitis and pyorrhea, which are regarded by some as mani- festations of lead stomatitis, in predisposing to the local formation of HS and to the development of the lead line (K. B. Lehmann?; Alles). Considerable importance has also been attached to lead excreted in the saliva as a source from which absorption may occur into the mucous mem- branes (Pouchet; P. Schmidt’; Rénon and Latron; Blum). However, although lead has been found in the salivary glands and in the saliva in clinical and experimental plumbism (Pouchet!; Oliver®; Aub), there is little satisfactory evidence of significant excretion of lead by the salivary glands. If the lead line results from direct absorption from the mouth, it seems most logical to assume that the most important source of the lead is from without. The observations of Aub, Fairhall, Minot and Reznikoff suggest that although lead may reach the gums directly by absorption from the mouth this is not the usual mechanism of production of the so-called “blue line.” They advanced the following argument in support of the contention that lead is brought to the site of deposition in the blood. The deposition of lead sulphide occurred in cats following subcutaneous injection, under which circumstances the only possible mode of access of lead to the interior of the mouth would be through its problematic excretion in significant quantities in the saliva. Furthermore, the granules of lead sulphide were never found to be scattered throughout the mucous membranes as would be expected if the lead had been absorbed through the mucosa, but were al- ways subepithelial in position, suggesting strongly that the lead was brought to the tissues by the circulation. This view received added support from ' the observation by Oliver of the development of a typical blue line with frank clinical manifestations of lead intoxication following the administra- tion of potassium iodide to a subject who had previously had no lead line and who had not been recently exposed to lead. There is clinical and PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 79 experimental evidence of local areas of hyperemia in the mucous membranes before the deposits of lead sulphide become visible (Stephens; Aub et al.). As mentioned previously, Legge and Goadby believe that these changes facilitate the direct absorption of lead from the mouth and Stephens be- lieves that they predispose to the deposition of lead in the areas of vascular engorgement. However, as stated by Aub, it seems more probable that these changes represent an inflammatory reaction to the precipitation of lead sulphide, particularly since this substance can be detected chemically before it becomes visibly apparent. The discoloration becomes evident only when large quantities of lead sulphide have been deposited. Micro- scopically, there is evidence in these areas of acute inflammation, with numerous phagocytic cells containing particles of lead sulphide. This probably represents a process of removal of these particles from this region rather than, as believed by Meillére?, one of transportation of lead to the gums for elimination. Salivary Glands It is frequently stated that chronic parotitis is a manifestation of lead poisoning (Meillere?; Biondi). There may be increased secretion, inflam- mation, hypertrophy and damage of the ducts of the salivary glands, particularly the parotid and submaxillary glands (Flury?). According to Thielemann, parotitis due to lead was present in 24 per cent of a series of 50 cases of lead poisoning. Evidence of the presence of lead in the saliva, as in the salivary glands, has been advanced in support of the view that inflammation of the parotid gland is dependent upon the presence of lead (Rénon; Rénon and Latron; P. Schmidt’; K. B. Lehmann?; Pouchet!; Blum; Almkvist; Santesson). The evidence of significant excretion of lead in the saliva is certainly not striking, and that present in the salivary glands in experimental lead intoxication may represent merely the natural tissue distribution shortly after absorption (Aub et al). Legge and Goadby state that chronic parotitis does not occur frequently in lead workers, and it seems likely that when it does occur it is dependent upon infection asso- ciated with poor mouth hygiene rather than upon the action of lead upon the salivary gland tissues. J. Schmidt was unable to find lead in the saliva in more than thirty cases of lead poisoning and, as suggested by Allevi, it is possible that inflammatory changes in the salivary glands may occur as a consequence of lesions in the mouth and poor dental and gingival hygiene. Teeth It has been remarked frequently that the teeth of lead workers are in notoriously poor condition. This may, of course, be due to poor dental hygiene. However, there are certain indications that it may be dependent 80 LEAD POISONING upon some direct effect of the lead upon the teeth themselves. As pointed out elsewhere, (Table 2, p. 14) even under normal conditions lead accumu- lates in the teeth, usually in higher concentrations even than in the bone (Pfrieme; Maulbetsch and Rutishauser). Values as high as 7.9 mg. per 100 gm. of ash have been obtained in normal subjects and over twice that concentration in patients with lead poisoning. According to Maulbetsch and Rutishauser, this accumulation of lead occurs chiefly in the dentine of the roots. These observations may be of significance in this connection although a direct relationship between the deposition of lead and the de- velopment of caries has not been demonstrated. As stated by Aub and his associates, this relationship is suggested by the rapid occurrence of caries in cats exposed to lead in view of the fact that this species invariably has perfect teeth under normal conditions. Severe ulcerative gingivitis and stomatitis have also been observed in lead poisoning (Koelsch!). Stomach and Intestines It is generally agreed that lead produces increased tonicity of the circular muscle of the intestines and, simultaneously, inhibition of spontaneous contraction (Aub and Smith). The evidence bearing on this point is re- viewed elsewhere (p. 69ff.). Postmortem observations in experimental lead intoxication have revealed intense constriction of the bowel (Oliver?). It appears reasonable to assume that these phenomena are responsible for the development of constipation and colic, which play such an important part in the clinical picture of lead poisoning. However, according to Walko, the intestinal muscle may be atonic in lead colic, which has been attributed by other investigators to spasm of the mesenteric vessels (Vaquez; Riegel; Harnack). It is conceivable that intestinal spasm may result from this cause. Several observers have reported morphologic changes in the gastrointes- tinal tract, which they believe may be responsible for the spasm and pain of lead colic. Legge and Goadby found degeneration of the muscle layers. with infiltration and minute hemorrhages throughout the small intestine accompanied by atrophy of the intestinal wall. Diffuse gastritis has been reported, simulating that caused by arsenic, with thickening of the sub- mucosa of the stomach and intestines. Inflammatory changes have been observed in the small intestine and colon (enteritis), accompanied by evidence of endarteritis and atrophy of the mucosal glands (Legge and Goadby). According to Hutton, lead may cause enterocolitis in acute fatal cases, while in chronic plumbism there may be chronic gastroenteritis with atrophy of the glands of the stomach and small intestine. Necrosis of the gastric epithelium and ulcerations in the stomach and intestines have followed the administration of lead to experimental animals (Jores; Mec- PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 81 Junkin). Administration of large doses of lead salts experimentally has been followed also by fatty degeneration and atrophy of gland cells and follicles of Lieberkiihn with evidence of mucosal degeneration, venous stasis and hemorrhage, and sclerotic changes in the submucous myenteric gang- lion cells in the intestines as well as in the celiac ganglion (Kussmaul and Maier; Maier; Masse). In view of the large doses employed, these changes may have been due to a purely local action of the ingested lead. Walko reported diminished secretion of acid and enzymes in the gastric juice in acute lead intoxication. According to Flury? in acute lead poisoning, the corrosive action of lead may result in swelling and redness of the gastric mucosa. In chronic lead poisoning, the primary stage of stimulation of gastric motility and secretion may be followed by hypoacidity, anacidity and even achylia, the morphologic changes consisting chiefly in chronic inflammation of the mucosa, atrophy of the glands, thickening of the sub- mucosa, vascular injury and muscosal hemorrhages. The picture is essen- tially that of chronic catarrhal or hypertrophic gastritis (Seiser and Litzner; Legge and Goadby; Flury?; Masse). A blue-gray or blue-black pigmentation may occur in the intestines in clinical and experimental lead poisoning (Oliver?; Legge and Goadby). This may occur in any portion of the bowel but is most common and most marked in the ileum and colon and particularly in the region of the cecum. The vessels of the omentum and mesentery may be engorged and the lymph nodes in this region enlarged. As is the case with the pig- mented areas in the mouth and gums, this pigmentation of the bowel is due to the deposition of particles of lead sulphide, formed by the interaction of lead salts circulating in the intestinal mucosa and hydrogen sulphide absorbed from the lumen of the bowel. According to Legge and Goadby, these deposits are found not only in the interstitial tissue but actually within the cells of the intestinal mucosa. These authors regard the usual localization of the pigmentation in the large bowel as evidence that lead, in common with other heavy metals, is absorbed in the upper intestine and excreted in the lower. However, such a conclusion is scarcely warranted on the basis of this observation alone, as was indicated in discussing the pathogenesis of the lead line in the gums. BONES AND JOINTS Under normal conditions as well as in clinical and experimental lead poisoning, a large proportion of the lead retained in the body is localized in the skeleton (see pages 21-26 and Tables 2-7). The following values were reported by Tompsett in 19 cases of plumbism: rib, 4-17.5 mg. of lead per kilogram of fresh bone; vertebra, 3.4-16.5 mg.; femur, 18.2-108.3 mg; tibia, 15.3-96.5 mg. Both the actual quantity and the percentage of the 82 LEAD POISONING total body lead present in the skeleton are greater following prolonged than after brief exposure and, if examined some time after cessation of exposure, practically all of the lead will be found to be localized in the bone (Aub, Fairhall, Minot and Reznikoff). Skeletal deposits of lead are con- fined practically entirely to the solid portions of the bones, particularly in the trabeculae (Aub, Robb and Rossmeisl; Behrens and Baumann?) and, according to Aub and his associates, histologic study has demonstrated that the lead is usually deposited in the endosteum and occasionally near capil- lary walls. These observers found that the bone marrow contains only traces comparable to the quantity present in other soft tissues, the absence of significant retention by the marrow being suggested also by the presence of high concentrations of lead in the pneumatic bones of the wings of hens exposed to lead. As indicated elsewhere, the bones of young subjects during the period of growth retain more lead than do those of adults and these lead deposits are more stable in young than in mature animals (Shields, Mitchell and Kieth; Kasahara and Nasu). It has also been found that rachitic bones store much less lead than non-rachitic (Calvery). In children and in young experimental animals, x-ray examination reveals interesting evidence of the selective deposition of lead in the growing ends of bones. In the ends of long bones and at the margins of flat bones, zones of increased density appear as a series of transverse lines in the diaphysis immediately below the epiphysis and as linear rings of density in the ossification centers of the epiphyseal cartilages and carpal bones, similar to findings obtained in healing rickets (Vogt; Caffey; Park, Jackson and Kajdi; McKhann and Vogt). Slowly growing portions of the bones appear normal and the bands of increased density are most conspicuous where growth is most rapid, e.g., at the anterior ends of the middle six ribs, the lower ends of the femur, the upper end of the humerus, the lower ends of the radius and ulna, and both ends of the tibia and fibula (Park, Jackson and Kajdi). According to Vogt!?, the concentration of lead is four times as great in the epiphyseal zones as in the mid-cortex. Histologic studies reveal that in the zones of increased density contiguous to the proliferating cartilage the trabeculae are more numerous and more compact than in normal bones. The observations of Vogt indicate that lead may be repeatedly mobilized from these areas and be subsequently redeposited along the epiphyseal lines of growth. Occasionally, an inflammatory or ulcerating lesion of the gums may lead to a rarefying osteitis of the adjacent bone. However, although E. Leivy was of the opinion that lead could cause necrosis of bone, the bulk of evidence is against this view and indicates that the deposition of lead in the bones has no significant effect upon their structure or function. Despite the very common complaint of arthralgia in subjects with lead poisoning, careful examination has revealed no evidence of significant PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 83 morphologic abnormality in the joints that can be attributed to the action of lead. Of particular interest in this connection is the relationship between chronic lead poisoning and the development of gout (p. 140). This rela- tionship is so widely recognized that it has led to the common employment of the designation “saturnine gout” (Legge and Goadby; Oliver?; Hubner; Brouardel; Magnus-Levy; Liithje?; Tompson). Liithje? who believed that lead can cause true gout, stated that the distinguishing features are the youth of the subject, the rapid spread of the process, the involvement of unusual joints and the great tendency to form tophi, the clinical aspects being more malignant, more extensive and more rapidly progressive than in ordinary gout. The concentration of uric acid in the blood increases as in idiopathic gout (Peters and Van Slyke; Biondi). According to von Jakseh, chronic plumbism is invariably accompanied by evidence of in- creased breakdown of nucleoprotein, caused, he believes, by diminished oxidation, with consequent retention of uric acid and urates. Liithje? believes that lead increases the production of uric acid but has no influence on its excretion. Some observers have found that the urinary excretion of purine bases is increased (Preti!) and others that it is decreased (Biondi). Rambousek reported increased excretion of purines early in the course of experimental lead poisoning, followed by a decrease with the supervention of renal injury. RESPIRATORY TRACT It is generally believed that diseases of the respiratory tract are unusually prevalent among lead workers. The important question has frequently been raised as to the possible relation of exposure to lead to the develop- ment, of pulmonary tuberculosis. Although, as stated by Flury? one can readily understand how the inhalation of lead dust may cause non-specific injury to the lungs, the bulk of evidence suggests, as stated by Oliver?, that lead causes no typical pathological changes in these organs. E. Lewy believed that exposure to lead may be followed by degeneration, inflamma- tion and necrosis of the bronchial mucosa, with the subsequent development of chronic bronchitis. According to Legge and Goadby, the lungs may be emphysematous and, if exposure to lead dust is prolonged, broncho- pneumonia may develop, with particles of lead in the alveolar cells and interstitial tissues. Flury? states that in lead workers there is a high incidence of diseases of the respiratory passages, such as pharyngitis, bronchitis, emphysema, ‘‘asthma,” and pulmonary infection, the pneu- monic foci being at times impregnated with lead particles. In experimental animals and, less frequently, in man, laryngeal disturbances and injury to the muscles of respiration (p. 142) may result in hoarseness and dyspnea (Flury?) and, occasionally, in death from asphyxia. Greven reported 84 LEAD POISONING endarteritis in the lungs of rabbits exposed to lead and Aub and his asso- ciates reported the occurrence of pulmonary congestion, broncho-pneu- ‘monia and hemorrhagic areas in the lungs of cats to whom lead was administered by the respiratory route. The lungs of such animals at times showed polymorphonuclear leukocytes and mononuclear phagocytic cells containing lead, probably in process of absorption (Fine). The following changes have been described in the lungs of animals exposed to lead dust: hyperemia, congestion, exudation, stasis, sclerosis of vessels, endarteritis, degeneration, fibrosis, emphysema and broncho-pneumonia. However, as stated by Flury? in chronic experiments of this nature one must take into consideration the possibility of complicating infection. GONADS AND REPRODUCTION Lead is frequently referred to as a race poison, because of the fact that its effects are not confined to the individuals exposed but are passed on to their offspring (Hamilton!). The frequency of occurrence of sterility and abortion, especially if the mothers have been exposed to lead, will be re- ferred to in detail elsewhere (p. 142). Suffice it to state here that there can be no doubt as to the influence of lead in this connection although there may be still some question as to whether lead poisoning in the father can exert a deleterious influence upon the fetus. Female Gonads and Uterus Disturbances of menstruation occur commonly in women with lead poisoning, including irregularity of the menses, amenorrhea, dysmenorrhea and menorrhagia. There may be transitory periods of sterility with the subsequent occurrence of normal pregnancy after withdrawal from ex- posure; this important fact has been demonstrated in man and in experi- mental animals indicating that lead injures only. the germ cells which are formed during the period of intoxication and that the damage to the gonads is not permanent (Paul; Flury?). The exact nature of the injury resulting in failure to conceive is not known since no significant morphologic changes have been demonstrated in the ovaries (Aub, Fairhall, Minot and Reznikoff). It may be that the injury is primarily functional in nature, as in the case of skeletal muscle and erythrocytes. Direct application of small amounts of lead to the fertilized eggs of various species has been found to exert an unfavorable influence upon their development (Oliver!; Loeb; Bell; Breton and Marie). Buschke and Beerman reported cessation of the sexual cycle in mice exposed to lead, while Forster, using very small doses, could observe no change in the vaginal cycle in mice and rats. Calvery, also, found that the administration of lead seemed to have no effect on the fertility or fe- cundity of rats. According to Tanquerel, hens exposed to lead did not PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 85 lay and cows gave no milk, sterility being also observed in sheep, goats, and cattle. It is generally agreed that if pregnancy does occur it is frequently charac- terized by miscarriage, intrauterine death of the fetus, premature birth and, if living children are born, they are usually smaller, weaker, slower in de- velopment and have a higher infant mortality (Hamilton!; Meillere?; Legge and Goadby; Bell; Flury?; Biondi; Glibert; Cole and Bachhuber; Weller; Bischoff and Maxwell?; Aub, Fairhall, Minot and Reznikoff; Lewin?; Teleky, Gerbis and Schmidt). These observations have been made in a variety of animal species, including man, dogs, cats, rabbits, guinea pigs, and fowl. These phenomena have been attributed to various causes, among which are (a) placental injury and hemorrhage, (b) degenerative changes in the chorionic epithelium, (¢) spasm of the uterine muscle and (d) direct action of lead on the fetal tissues. Legge and Goadby believe that hemorrhage from placental vessels con- stitutes an important cause of intrauterine death and abortion in women with lead poisoning, but this phenomenon has not been observed frequently. Bell and Annett found that injection of colloidal lead preparations caused abortion in pregnant rabbits without the development of other manifesta- tions of lead intoxication. They observed thrombosis of the maternal ves- sels but no placental hemorrhages, the chief lesion according to them being degeneration of the chorionic epithelium, which Bell believes to be a specific effect of lead administration. This view is questioned by Bischoff and Maxwell? and is contradicted by the observations of Behrens and Baumann! regarding the distribution of radioactive lead in pregnant rats. This was found to pass into the fetal tissues in a relatively few hours and, although some was present in the uterine mucosa, there was no indication of its localization in the placental structures. Moreover, Bischoff and Maxwell? observed no change in the placenta of pregnant rabbits and histologic dam- age in the chorionic epithelium only in one case. It seems obvious that abortion may be dependent in part upon the effect of lead in producing spasm of the uterine musculature, as of other smooth muscle fibers (Oliver®; Aub et al.). Observations on isolated strips of uterine muscle are contradictory. According to Dilling, lead inhibits the contraction of pregnant and non-pregnant uterine muscle strips. How- ever, as stated by Griinberg, it is well known that the pregnant uterus acts differently from the non-pregnant and that the response of the uterine muscle varies in different periods of pregnancy. According to Griinberg, whereas the non-pregnant uterus responds to lead, as to adrenalin, by relax- ation and cessation of contraction, the pregnant uterus exhibits increased contraction when exposed to lead. Clinical observations and experimental studies indicate that lead produces increased excitability of the uterine 86 LEAD POISONING musculature, which may possibly contribute to intrauterine death of the fetus and to abortion (Key and Wright!). The passage of lead from the maternal circulation to the fetus has been demonstrated repeatedly (Porak; Meillere?; Ganiayre; L. Lewin'; Morris et al.; Flury?; Bell and Annett; Kehoe; Thamann and Cholak!; Behrens and Baumann!). Lead has been found in all of the organs of the fetus and also occasionally in the placenta (Hall; Ganiayre), but recent work contra- dicts the view that there is any significant localization of lead in the latter situation. Judging from the observations of Behrens and Baumann! re- garding the extremely rapid appearance of radioactive lead in the fetal tissues following its injection into pregnant rats, it would appear that the placenta does not constitute a significant barrier to the passage of lead from the maternal to the fetal circulation. The fetal lead was deposited chiefly in the zones of provisional calcification in the bone, although small amounts were found in the liver and traces in the kidneys and intestinal wall. No definite statement can be made at the present time as to whether intrauterine death and abortion are contributed to by the direct toxic action of lead on fetal tissues. According to Bell and to others (p. 55), embryonal and other growing cells are particularly susceptible to the toxic action of lead, their growth being inhibited. This increased susceptibility to injury by lead has been attributed to the relatively large amounts of phosphatides in these cells (Bell). The validity of this hypothesis is open to question. However, that living children born of mothers with lead poisoning may be subsequently affected by their intrauterine exposure to lead is evidenced by the facts that they develop more slowly than normal and have a higher mortality during the first year of life, and that according to Meillere?, they may even show evidence of lead poisoning, particularly muscular spasms and nervous disturbances. Male Gonads Much less definite information is available regarding the influence of lead poisoning in the male upon his fertility and upon the production of ab- normalities in fetal development or in the course of pregnancy should con- ception occur. The literature dealing with this subject has been reviewed by Petri. Some observers have reported disturbances of potency in males exposed to lead (Meillere?; Baader!). According to Weller! ?, guinea pigs (males) exposed to lead were not sterile but the young fathered by them were weak and underdeveloped and their subsequent development was slow. Similar observations were reported by Cole and Bachhuber in rab- bits and fowl. Lead has been found in the testes in cases of lead poisoning and it has also been observed that spermatozoa are damaged by exposure to solutions of lead salts in rather high concentration (Giinther). Others PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 87 have reported atrophy of the seminiferous tubules and damage to the parenchyma resulting in inhibition of spermatogenesis and division of spermatocytes with gradual disappearance of spermatozoa (Bell; Weller! 2; Fraenkel; Peisachowitsch; Pennetti). On the other hand, negative results were reported by Stieve. Statistics show that an unusually large proportion of children of fathers exposed to lead were still-born, but the evidence is by no means conclusive (Hamilton). The difference of opinion among authorities in this regard is evidenced by the statement by Biondi that it is well known that lead injures the generative organs and functions in both man and woman and the doubt expressed by Teleky of the validity of clinical or experimental evi- dence of damage exerted upon the fetus or the course of pregnancy by lead poisoning in the male. LIVER Attention has been directed towards changes in the liver chiefly for three reasons: (1) this organ contains lead in relatively high concentration, partic- ularly in acute poisoning; (2) it lies directly in the path of absorption of lead from the intestines and is therefore exposed to larger quantities than are other organs during the process of absorption; (3) it serves as an important avenue of elimination of lead. There is considerable difference of opinion regarding the effect of lead upon this organ, reports in the early literature generally tending to minimize and those in the recent literature to empha- size the frequency of hepatic damage in lead poisoning. According to Flury?, disturbances of liver function probably precede actual morphologic changes in the liver cells. These are evidenced by such phenomena as excessive urobilinuria, hyperbilirubinemia, porphyrinuria, and disturbances in the intermediary metabolism of carbohydrates, fats and proteins (p. 56ff.). However, caution must be exercised in attributing the manifestations of abnormal formation, transformation and decomposition of various pigments (urobilinogen, bilirubin, porphyrin) entirely to dis- turbance of hepatic function, since they may be dependent in large part upon abnormality of hematopoietic function and excessive blood destruc- tion. This is particularly true of excessive excretion of urobilinogen and porphyrin. On the other hand, it is probable that hyperbilirubinemia is dependent in part at least upon hepatic functional impairment, since it may occur in the absence of evidence of increased blood destruction of a degree sufficient to permit its explanation on this basis alone. In this connection, Lewin states that jaundice is seldom of purely hemolytic origin in lead poisoning. According to Zadek, the toxic effect of lead on the liver in many instances is first evidenced by decreased resistance to infection, perhaps related to diminished storage of hepatic glycogen. 88 LEAD POISONING All forms and degrees of liver damage have been described, ranging from mild degeneration to acute yellow atrophy (Koelsch!; Seiser and Litzner; C. Lewin!). According to Pennetti, in acute plumbism the liver suffers more damage than any organ except the kidney; certainly the evidence indicates that in the majority of cases of both acute and chronic lead poi- soning morphologic changes in the liver are not as common nor as severe as in the kidney. The changes reported include fatty degeneration or in- filtration, hepatic cell degeneration with nuclear changes, varying degrees of proliferation of intercellular and interlobar fibrous tissue, and focal or extensive hepatic cell necrosis, with lobular atrophy and cirrhosis (Oliver?; Pennetti; Meillere®; Hutton; Alcock; Glibert). Increased deposition of hematogenous pigment, chiefly hemosiderin, is a rather common finding and is regarded as due to excessive destruction of hemoglobin. Lobular atrophy and cirrhosis have been found in new-born infants of parents working with lead, lead being found in the liver (Seeligmiiller; Oliver?). Legge and Goadby describe small scattered areas of hemorrhage and exudation. In a study of 21 cases of acute lead intoxication in children, Blackman! reported hepatocellular degeneration and occasionally necrosis in some cases and, in the majority, evidence of destruction of a few periportal hepat- ic cells with slight chronic inflammatory reaction and scarring in the portal areas. In some cases there was proliferation of the small bile ducts and usually an increase in fat. Of particular interest in these cases was the observation of nuclear inclusion bodies in the liver cells, which were inter- preted as probably representing an accumulation, in the damaged cells, of acidophilic material which is present in smaller quantity in normal cells. These inclusion bodies, which varied in size and shape, were similar to those seen in virus diseases, and were present more consistently and in larger numbers in the kidneys than in the liver. Some observers believe that lead may exert a direct effect upon the portal vessels (Kussmaul and Meillere?) and Rolleston and McNee state that jaundice in lead poisoning may at times be due to spasm of the bile ducts. Glibert found liver damage consistently in guinea-pigs with chronic lead poisoning, with hemorrhage, interstitial inflammatory reaction, lobular atrophy, fatty degeneration of the liver cells and areas of focal necrosis. These findings could not be confirmed by Ophiils, who observed nosignificant lesions other than areas of focal necrosis with consequent liver-cell atrophy. Following administration of rather large doses of lead acetate, Mallory observed basophilic hyaline changes in the hepatic cells, with necrosis and phagocytosis of these cells and evidence of active regeneration (mitotic figures). Despite the fact that hepatocellular damage does not occur consistently in clinical or experimental lead poisoning, there seems to be little doubt that PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 89 under certain conditions lead is at least able to contribute to the develop- ment of such damage which, if protracted, may eventuate in cirrhosis of the liver. This effect of lead is furthered by simultaneous exposure to some other hepatotoxic agent, such as alcohol. The observation has frequently been made clinically that so-called alcoholic cirrhosis may be accelerated and aggravated by exposure to lead (Flury?; Mallory; Meillere?). SPLEEN There is no substantial evidence that lead exerts a direct effect upon the spleen, but many changes have been observed in that organ apparently dependent largely if not entirely upon abnormal hematopoiesis and ex- cessive red blood cell destruction. Varying degrees of splenomegaly may occur, particularly in the presence of severe grades of anemia (Bianchi; Klima and Seyfried; Legge and Goadby). On the other hand, atrophy has been reported (Galvini). The most consistently reported abnormality in clinical and experimental lead poisoning is increased deposition of hemo- siderin, due to excessive hemoglobin destruction (Bianchi; Flury?; Jores; Greven; Klima and Seyfried). Seiffert and Arnold have reported myeloid metaplasia, Glibert leukocytic infiltration of the pulp and Duesberg the occurrence in rabbits of numerous foci of normoblasts and erythroblasts in active mitosis, these elements crowding out the usual pulp cells. According to Bianchi, in experimental animals (dogs, rabbits, guinea- pigs), the primary congestive splenomegaly may be followed by degenera- tive changes, fatty infiltration and atrophy. The observations of Fontana and Sante Stanzi suggest that the spleen may act in the capacity of a defense mechanism, since the toxic effects of lead, including hepatocellular damage, were much more marked in splenectomized than in intact animals. Fol- lowing the administration of radioactive lead to rats and mice, Behrens and Baumann? found relatively large quantities in the splenic pulp but none in the follicles. KIDNEYS The effect of lead upon the kidneys has been investigated intensively. By far the majority of investigators of this subject agree that lead is ca- pable of producing functional and morphologic abnormalities in this organ, but there is still considerable controversy regarding the exact nature and pathogenesis of these changes. In view of the marked differences in the findings reported in animals with experimental lead poisoning and in clinical lead poisoning in man, it seems advisable to consider these two groups of observations separately. Experimental Observations. Although there have been occasional re- ports of the absence of significant renal damage in animal experiments 90 LEAD POISONING (Heubel; Rosenstein), the great majority of investigators report changes which fall into one or other of two groups, (a) marked vascular damage with relatively slight change in the tubular epithelium and (b) marked tubular damage with little or no change in the vessels. Vascular changes have been reported by almost all observers. These are usually noted first in the smaller arteries, which show thickening of the muscular layer and of the intima, with progressive decrease in the diameter of the lumen, lead- ing at times to complete obliteration. According to Gayler, one of the earliest manifestations is obliterating endarteritis of the smallest vessels. Many regard intimal thickening as the primary change, alteration in the media occurring later. Hoffa observed these changes regularly in guinea- pigs, even in the larger renal vessels, the walls of which showed varying degrees of degeneration and thickening, leading at times to occlusion and at times to rupture with consequent hemorrhage into the interstitial tissue. Hemorrage occurred frequently into the glomerular capsule, with com- pression of the glomerular tufts, and the tubules showed little damage. Ophiils found a great number of changes in both the parenchyma and the vessels of the kidneys of guinea-pigs, but since a great majority of these were observed also in control animals he concluded that the only constant lesion caused by lead is a rather limited degree of degeneration and fibrosis of the glomeruli. Others have reported hyaline degeneration of the vessel walls and glomerulitis (Coen and d’Ajutolo; Pennetti). The surface of the kidneys may present a finely granular appearance but, according to many observers, this granulation and contraction of the kidneys occur only to a slight degree if at all in experimental animals (Jores; Ophiils; Hoffa; Fasioli). Dilling reported chronic interstitial fibrosis in dogs and rabbits (also Coen and d’Ajutolo). Fouts and Page observed no significant in- crease in the arterial blood pressure of two dogs receiving large doses of lead over a period of 160 weeks, but an increase was observed in rats by Griffith. Jores observed no significant vascular change in rabbits, the only ab- normality being a mild degree of granular and hyaline degeneration of the tubular epithelium which was not regarded as particularly significant. Petroff reported slight changes in the vessels and extensive degeneration of the tubular epithelium, with leukocytic infiltration, proliferation of interstitial tissue and hemorrhage into the glomeruli and many tubules. According to Riihl, the kidneys of rabbits with mild chronic lead poisoning showed marked fatty change in the tubular epithelium and interstitial tissue and also, sporadically, fatty change in the endothelium of the small and medium-sized arteries, but no definite degenerative or proliferative phenomena in the vessels. Deposits of pigment, probably hemosiderin, have frequently been observed in the renal epithelium and interstitial tissue. Peculiar concrements have been found occasionally in the tubules PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 91 and the interstitial tissues (Prevost and Binet; Ophiils; Glibert; Jores; Eger). Their pathogenesis is not clearly understood, but they have been variously regarded as deposits of uric acid, urates, and calcium or as cal- cium infarcts. The observations of Eger are of interest in this connection. According to this investigator, the kidneys of rats in lead poisoning fre- quently showed primary enlargement with subsequent contraction if the period of exposure was more than three months. No change was observed in the vessels or glomeruli, the damage occurring practically entirely in the tubular epithelium, which showed varying degrees of granular and hyaline degeneration with nuclear pyknosis and karyorrhexis. Concretions were seen in the tubules, apparently consisting primarily of deposits of lead salts, occasionally later encrusted with calcium and at times causing obstruction and distention of the tubules. Scars were often noted in relation to these concretions, consisting of collapsed uriniferous tubules with remnants of epithelial cells, proliferated endothelial cells and fibroblasts and a few lymphocytes. Well-preserved glomeruli could often be demonstrated in these areas of fibrosis, which, if immediately beneath the capsule, resulted in fine granulation of the surface of the kidney. Eger regards this patho- logical picture as the result of the combined effects of nephrosis and the local mechanical action of the concretions. As stated by Flury?, much of the discrepancy in observations reported in animals may be attributed largely to differences in experimental methods and conditions. Although lead may cause a varying degree of tubular damage similar to that caused by other heavy metals, the fact that the majority of investigators have observed distinct changes in the renal vessels appears to be significant. According to Flury?, the lesions which occur in the kidneys of experimental animals, including interstitial changes and exudative processes, apparently represent the possible basis for the ultimate development of fibrosis. Observations in Man. There is a great difference of opinion as to whether lead causes serious renal damage in man and as to the nature and patho- genesis of the kidney lesions if they do occur. There are many reports in the literature of evidence of mild renal damage in lead workers, manifested chiefly by oliguria, albuminuria and ecylindruria (Legge and Goadby; Oliver?; Teleky®; Beintker; Flury?). Occasionally, red blood cells also may appear in the urine during the course of acute plumbism, especially during episodes of colic, but manifestations of severe acute injury are seldom seen in man although isolated cases have been reported (Chajes). These phenomena are generally attributed to a condition of more or less acute nephrosis, similar to that caused by several metallic poisons, which may be transitory, leaving no permanent damage (Beintker). Following the in- travenous injection of colloidal lead preparations, Bell and Cunningham 92 LEAD POISONING observed oliguria, albuminuria and edema, with marked degenerative changes in the renal tubular epithelium. Nuclear inclusion bodies similar to those seen in virus diseases were found by Blackman! in 21 children with lead encephalopathy. Some of the affected tubular cells were enlarged, others flattened and basophilic, some contained fat and some were necrotic. Some of the tubules were atrophied and there was evidence of mild chronic inflammation and fibrosis. Active regeneration of tubular epithelium was evidenced by the presence of mitotic figures and by flattening and baso- philia and newly formed epithelial cells. According to Flury? in fatal cases of acute lead intoxication the tubules are often enlarged with fatty degeneration and cloudy swelling of the epithelium of the convoluted tu- bules, thickening of Bowman’s capsules, interstitial hemorrhage, thickening of the small vessels, and leukocytic infiltration. Oliver? states that, in addition to tubular damage, there may be atrophy of the glomeruli and hyaline degeneration. Flury? regards these nephrotic manifestations as due to a non-specific effect of lead similar to that exerted by other heavy metals, and inclines towards the view that these changes bear little if any relation to those which are believed to represent the result of prolonged chronic lead poisoning. According to most authorities, the characteristic effects of lead on the kidneys are seen only in chronic lead poisoning and are characterized by the slow development of a contracted kidney practically indistinguishable from that resulting from arteriosclerosis due to causes other than lead poisoning (nephrosclerosis). Almost all observers describe vascular lesions in the kidneys in clinical as in experimental lead poisoning, these lesions being generally regarded as the probable basis for subsequent parenchymal damage. According to Volhard, there first occurs spasm of the small renal vessels, followed by hyperplastic changes in the intima and media and, eventually, by endarteritis, with parenchymal fibrosis and contraction. Interstitial nephritis may result from exudation from the damaged vessels, the smaller arterioles particularly showing evidence of inflammatory reac- tion, with degenerative changes in the intima, fraying of the elastica and hypertrophy of the media (Flury?; Brogsitter and Wodarz). Other changes which have been described include renal arteriosclerosis (Teleky®), glomer- ular atrophy and hyaline degeneration of the vessels (Hutton) and, occa- sionally, glomerulitis (Oliver?). Fasoli believed that renal fibrosis is unusual in clinical lead poisoning and Legge and Goadby regarded the renal changes as due to some factor other than lead, perhaps alcohol. Aub and his associates state that, as in the case of arteriosclerosis, the accepted clinical opinion that lead can cause chronic interstitial nephritis is far from convincing. It is admittedly hazardous to attribute clinical evidence of renal damage and post-mortem ; PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 93 observations in human subjects with lead poisoning to the action of lead. One encounters here all of the difficulties inherent in the interpretation of uncontrolled clinical material. However, the few available statistical analyses indicate a relatively high incidence of Bright’s disease in subjects exposed to lead (Machwitz and Rosenberg; Nye; Murray; Badham and Taylor!) (p. 115). Moreover, the weight of authoritative opinion on this subject cannot be disregarded. Oliver® states that chronic interstitial nephritis, with small contracted kidneys and thickened renal arterioles, is a frequent finding in chronic lead poisoning. Fishberg states that the renal lesions in chronic plumbism are those of the arteriosclerotic kidney, often with endarteritis and sometimes with arteriolonecrosis, as in malignant hypertension. Fahr regards lead as capable of producing changes in the arteries and of reproducing the typical picture of malignant nephrosclerosis. The literature on this subject has been reviewed by Koelsch!. The nega- tive findings of Dreessen and his associates regarding the incidence of evi- dences of arteriosclerosis and hypertension in a large group of workers in the storage battery industry have been referred to elsewhere (p. 73ff.). In the opinion of most observers, lead usually exerts a relatively slight direct effect on the kidneys, at least under conditions encountered clinically, and it is highly questionable whether such nephrotic lesions, even if severe, play a significant role in the development of the contracted kidneys of chronic lead poisoning. Some investigators failed to find evidence of vascular damage in experimental animals. Among these is Eger, who, however, believes that the contracted kidney seen in clinical chronic lead poisoning results from vascular damage. Flury? believes that although tubular damage may occur in acute and subacute lead poisoning, arterio- sclerosis probably forms the basis for the contracted kidney of chronic lead poisoning. This may cause or may aggravate existing hypertension and, occasionally, may be accompanied by renal functional impairment. Some authors go so far as to attribute certain of the nervous manifestations of lead poisoning, such as encephalopathy, convulsions, ete., to uremia, a hypothesis which does not appear to be well founded in fact. It must be borne in mind that impairment of kidney function in such cases may interfere with the urinary elimination of lead, under which circumstances the determination of the lead content of the urine is of little value and may actually be misleading. Under such circumstances, normal urine lead values may be obtained in the presence of increased concentrations in the blood. According to Flury, the lead content of the kidneys may also be increased significantly in the presence of renal functional impairment with consequent inadequate excretion of lead in the urine. Certain abnormal urinary findings have already been mentioned. Oli- guria, albuminuria, cylindruria and hematuria, with increased numbers of | 94 LEAD POISONING white blood cells and epithelial cells, have been observed in animals and in man with acute and, acute exacerbations of chronic lead intoxication (Petroff; Flury?; Chajes; Legge and Goadby; Oliver?; Teleky®; Beintker; Bell and Cunningham). These abnormalities may disappear entirely after subsidence of the acute incident. In a study of 766 workmen in the storage battery industry, Dreessen and his associates found that albumin- uria occurred twice as frequently in lead-affected workers (24.39) as in nonaffected workers (12.29). It was present in 149, of those exposed to atmospheric lead concentrations below 1.5 mg. per 10 cubic meters (limit of safety), in 20.89%, of those exposed to 1.5-2.9 mg. per 10 cubic meters and in 24.09, of those exposed to more than 3 mg. per 10 cubic meters. Both the incidence and degree of albuminuria were highest in those employed more than 15 years, the incidence within this group increasing from 209%, for men exposed to less than 1.5 mg. of lead per 10 cubic meters of air to 89.19, for men exposed to more than 3 mg. per 10 cubic meters. The urinary changes in chronic plumbism, if any, are those of nephrosclerosis, varying considerably depending upon the supervention of congestive heart failure or renal insufficiency. There may be an initial diuresis followed by oliguria, particularly if the latter complications occur. In addition to changes indicative of renal abnormality, the urine may contain substances indicative of metabolic abnormalities, particularly of disturbed pigment metabolism (porphyrin, urobilinogen, bilirubin) (p. 50ff.). Urinary sup- pression has been observed during attacks of lead colic. TOXIC DOSE OF LEAD The quantity of lead capable of producing manifestations of intoxication varies within wide limits, depending upon, among other factors, (1) the path of absorption, (2) the facility of absorption of the particular compound in question, (3) the duration of exposure, (4) age, (5) race, (6) sex, (7) in- dividual predisposition or sensitivity, (8) habituation and (9) the influence of complicating conditions, such as infections, post-operative acidosis, alcoholism, trauma, renal and hepatic disease and factors influencing the storage or mobilization of lead in the organism. There is also a rather . marked species difference in susceptibility to the general toxic effects of lead, dogs and cattle being most susceptible, cats and rabbits moderately so, guinea-pigs, sheep and goats slightly susceptible and rats, mice and birds most resistant. This, however, does not hold for the effects upon single systems, particularly the blood and nervous system, which may exhibit considerable variation from the above order (Flury?). Relatively little accurate information is available regarding the quantity necessary to produce acute lead poisoning in man. According to Bell, Williams and Cunningham, the minimum toxic dose of colloidal lead, PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 95 given intravenously, is 40 mg. for females and 100 mg. for males. Ad- ministration of 200 mg. was followed by manifestations of severe plumbism (colic, nephritis, encephalopathy). The fatal dose of lead acetate, by mouth, has been variously stated to be from 20 to over 50 gm. (Kobert; Giirtner; Flury?) and of lead carbonate 25 to 40 gm. (Legge and Goadby; Giirtner). According to Flury?, the smallest oral dose of lead capable of causing acute lead poisoning is 5 mg. per kilogram of body weight. How- ever, it is important to note that much larger quantities may not cause intoxication, probably because of failure of absorption from the intestine. Much smaller quantities are toxic when taken into the body through the lungs (p. 6ff.). Because of the several factors enumerated above, it is impossible to state with any degree of certainty the quantity of lead, particularly when taken in by the gastrointestinal route, that will cause chronic lead poisoning. Sollmann! estimated that the ingestion of 0.2-0.4 mg. per kilogram (10-20 mg.) daily by the average adult will result in clinical plumbism in several weeks, but he believed that smaller quantities are probably harmful. Teleky’ states that 1 mg. daily over a period of several months may cause symptoms, while 10 mg. daily may produce symptoms of acute intoxication in one week. According to Wright, Sappington and Rantoul, poisoning was caused by the daily ingestion of 0.1 mg. over a period of about 8 years. P. Schmidt? cites the case of a patient who drank daily 2500 cc. of water containing 2.9 mg. of lead per liter, i.e., 7.25 mg. lead daily, and first de- veloped symptoms after 2 years, with frank plumbism after 2; years. The following figures are given by other observers: Brouardel, 1 mg. daily; Starkenstein, 5-10 mg. daily may produce death in 3-4 weeks; Weiss, 90 mg. daily for one month; Neimann, 127 mg. daily for 3-4 weeks; Flury?, 50 mg. of white lead daily for 20 days, about 0.5 mg. per kilogram producing anemia and mild plumbism within 5 months. Dangerous concentrations of lead in drinking water have been reported as follows: Flury?, 0.36 mg. per liter; Steiner, 0.7 mg. per liter; Giirtner, 1 mg. per liter; White, 1.4 mg. per liter; Lewin, 0.35-0.75 mg. per liter; Kruse and Fischer, 2 mg. per liter. Legge and Goadby state that inhalation of 2 mg. daily will lead to lead poisoning in the course of several years, but Teleky” believes that much smaller amounts are dangerous by this route. Ten mg. of lead, in the form of lead carbonate, blown into the mouth and nose daily for 30 days have caused pallor and anorexia. The careful studies of Russell, Jones Bloomfield, Britten and Thompson, and of Dreessen indicate rather con- clusively that, under conditions of industrial exposure, a concentration of 1.5 mg. of lead per 10 cubic meters of atmospheric air constitutes the threshold of safety, and that concentrations above this level are distinctly hazardous. 96 LEAD POISONING It is commonly believed that children are more susceptible than adults, females more than males and negroes more than whites, but the validity of this belief is open to question. There can be little doubt that mani- festations of lead poisoning are usually more severe in children than in adults, encephalopathy particularly being much more common. However, as pointed out by Hamilton!, it is difficult to evaluate this apparent dif- ference accurately because of difficulty in estimating the incidence, duration and extent of exposure in infants and children. Obviously, merely on the basis of surface area or body weight, much smaller quantities are required to produce toxic effects than in the case of adults. Moreover, lead poison- ing in children is usually due to accidental exposure to rather large quanti- ties of lead, as from lead nipple shields (Wilcox and Caffey), face powder containing lead (Kato; Fukushima and Matsumoto) and paint on cribs, toys, woodwork and furniture. The incidence is highest at the time of eruption of the teeth, when there is a great tendency to put such things in the mouth. On the other hand, there is evidence that lead is stored more actively in the bones of growing animals than in those of adults (p. 23), and the possibly greater lability of these stores and an increased capacity for their mobilization under a variety of conditions may contribute to the apparently unusual susceptibility of children to lead poisoning and to the severity of its manifestations. According to many observers, the incidence of lead poisoning is higher in women than in men workers in lead industries (Hamilton!; Oliver?; Newman, McConnell, Spencer and Phillips). This subject has received particular attention because of the influence of lead upon fertility and the course of pregnancy (p. 84ff.). Oliver? stated that the liability of women to develop lead poisoning was greatest between the ages of 18 and 23 years, earlier than in men, and with shorter periods of exposure than the latter. This observation was also made by Newman and his associates, reported data indicating that the incidence is approximately twice as high in women as in men workers in the same industry, apparently working under similar conditions of exposure. However, as stated by Hamilton!, many of these studies are not conclusive because of failure to take into consideration cer- tain essential differences in the nature of the work and conditions of ex- posure within the same industry. There seems to be little question of the higher incidence of manifestations of encephalopathy, including visual disturbances, in women with lead intoxication, and the lower incidence of paralysis and colic (Hamilton!; Prendergast) (pp. 118, 126). Similar find- ings have been reported in studies of negro and white subjects exposed to lead, the former being apparently more susceptible to the development of lead poisoning and encephalopathic manifestations. According to Hamil- ton?, the widespread belief in this increased susceptibility is not supported PATHOLOGY AND PATHOLOGICAL PHYSIOLOGY 97 by adequate data and, asin the case of supposed variations in different white racial groups, much may depend upon extrinsic factors, such as diet, alcoholism, renal and hepatic functional abnormalities, cleanliness, infec- tions, ete. (Legge and Goadby). It has often been noted in mass experiments that in spite of identical conditions of exposure only a relatively small proportion of subjects may be affected, and similar findings have been obtained in studies in lead industries. Hirt stated that, in a hazardous industry, about 35-40% of workers develop lead poisoning quickly, 35-409, slowly and 20-30% are unaffected. However, Hamilton! found that if recent employees are excluded from consideration, the incidence of plumbism is 40-529, and only 10-129, are resistant for as long as 8 years. Working under identical conditions in the same room, some develop lead poisoning within a few months and others only after several years. In some instances men are able to work under conditions of heavy exposure for 25-35 years while some in the same room die of lead poisoning in a few months, symptoms having developed in a few weeks (also Legge and Goadby; Oliver; Flury?). Moreover, subjects reacting within the same period of time may present symptoms of extremely variable severity and referable to different systems. Thus, some develop encephalopathy, others palsy and others colic; in some the kidneys are particularly affected, in others the nervous system and in others the vascular system (Hamilton!). Legge and Goadby state that persons with fair complexions and red hair are more susceptible than dark complected subjects. Although a similarly wide difference in individual susceptibility exists in uniform groups of experimental animals, it is im- portant that, as pointed out by Minot!, there is a consistent quantitative relationship between the amount of lead and the intensity of its effect upon single tissues, such as blood cells, muscle, intestinal strips, etc., no such variability of response being observed as occurs when the intact organism is exposed to lead. As she suggests, the individual difference in suscepti- bility to lead poisoning is therefore probably due largely to variations in factors which influence the amount of lead to which the tissues are exposed rather than to variations in the degree of resistance of the tissues. These include factors influencing absorption, storage, mobilization and excretion (diet, alcohol, constipation, malnutrition, acute and chronic infections, trauma, renal, vascular and hepatic disease, vitamin deficiencies, drugs, such as iodides, and acid-forming substances and alkalies). Thus, acute symptoms of plumbism may follow injury (Shufflebotham), pneumonia or influenza (Shie), alcoholism (Oliver?; Legge and Goadby), renal disease (Edsall; Oliver®), etc. As stated by Aub and his associates, immunity is always relative and may be broken down by several factors which influence the general physical condition. Then, too, local tissue damage may render 08 LEAD POISONING those tissues more susceptible to the toxic action of lead, e.g., renal, vascu- lar or hepatic disease and anemia (hematopoietic organs). There has been some discussion of the question of acquired tolerance to lead. Legge and Goadby state that it is the experience of all students of this subject that workers in lead industries, even if they show evidences of mild plumbism early, gradually acquire a resistance to lead, the number of attacks of poisoning diminishing in proportion to the number of years of employment. They attribute this phenomenon to a hypothetical aug- mentation of the defensive forces of the body. On the other hand, Oliver? states that one attack usually predisposes to another and that long contact does not necessarily confer immunity. Aub and his associates, too, state that once an attack occurs, others follow with increasing ease, colic tending to recur and weakened muscles usually suffering first after re-exposure. However, subsequent attacks may be entirely different from the preceding (Aub et al.). Employing epileptiform seizures as fhe criterion of intoxica- tion in guinea-pigs fed increasing doses of lead, Weller? found that some animals exposed for long periods required 4 times the original convulsive dose to produce epileptiform seizures and that some animals after pro- longed exposure could withstand four times the dose that was originally convulsive in 1009, of animals. He hesitated to apply these observations to the matter of acquisition of tolerance in man, however, because of the possibility of a marked degree of individual variation in susceptibility to lead in the experimental animals. The consensus at present is that there is little substantial evidence that tolerance to lead may be acquired by prolonged exposure. CHAPTER IV CLINICAL MANIFESTATIONS INTRODUCTION Lead poisoning may be acute or chronic, the latter being the form most frequently encountered clinically. Acute plumbism may occur following sudden accidental exposure to and absorption of a large quantity of lead or of relatively small quantities by unusually susceptible subjects; it is also encountered, rarely, after ingestion of lead compounds with suicidal intent or for the induction of abortion. Particularly when the lead enters by way of the gastrointestinal tract, the initial symptoms are an ashen pallor, and a sweet, metallic, astringent taste, followed shortly by a sensation of burning in the mouth, pharynx, substernal and epigastric regions and, with- in a few minutes to several hours, vomiting, nausea, abdominal pain, which is often colicky, and constipation or diarrhea, the stools being at times bloody and at times black (lead sulphide). In severe cases, there may be collapse into a state of shock, with hypothermia and, at times, bradycardia and hypotension. Prolonged vomiting and diarrhea may lead to profound dehydration. Instances have been reported of acute hemolytic anemia and of acute renal irritation, with albuminuria, oliguria and hematuria. Coma, with and without convulsions, has been observed, as well as other mani- festations of encephalopathy, including visual disturbances, hyperirrita- bility, emotional disturbances and mental aberrations. Death may occur during acute plumbism, usually as a result of shock, but the great majority of cases recover within a few days. Subsequent relapses have been known to occur without additional exposure to lead, suggesting the possibility of the development of subacute or chronic lead poisoning following a single heavy exposure. This is extremely unusual, however. The acute mani- festations referable to the central nervous system in subjects exposed to toxic amounts of tetra-ethyl lead are probably not due entirely to lead (see p. 137). Acute manifestations of lead intoxication frequently occur during the course of chronic poisoning, constituting an important and rather charac- teristic part of the clinical picture of the latter condition, but, for obvious reasons, a sharp distinction must be drawn between these phenomena and true acute plumbism, as between, for example, acute and chronic glo- merulonephritis. The clinical manifestations of chronic lead poisoning are discussed in detail below. It is perhaps well to emphasize here the fact that the accurate definition and diagnosis of early chronic plumbism 99 100 LEAD POISONING TABLE 11 Common Signs and Symptoms in Cases of Excessive Absorption of Lead and Lead Intoxication (After Jones) Suggestive Evidence of ead Absorption Suggestive Evidence of Incipient Intoxication Suggestive Evidence of Definite Intoxication A. General Appearance Restive, moody, easily excited, emotional. Lead line. Pallor Lead line Jaundice Anemia Lead Line Jaundice Emaciation “Premature aging”’ B. Digestive System Persistent metallic taste Slight anorexia Slight constipation Metallic taste Definite anorexia Slight colic Constipation Metallic taste Increasing anorexia Nausea and vomiting Marked colic Rigid abdomen Marked constipation Blood in stool C. Nervous System Irritability Uncooperativeness Slight headache Insomnia Slight dizziness Palpitation Increased irritability Increased reflexes Severe headache Increased insomnia Increased dizziness (ataxia) Confusion Marked reflex changes Tremor Fibrillary twitching Neuritis Visual disturbances Encephalopathy (halluci- nations, convulsions, coma) Paralysis D. Miscellaneous Muscle soreness Easily fatigued General weakness Arthralgia Hypertension E. Urine Examination Abnormal lead content Abnormal lead content Albumin Casts Abnormal lead content Albumin; casts Porphyrinuria Hematuria- CLINICAL MANIFESTATIONE TABLE 11—Continued Suggestive Evidence of Lead Absorption Suggestive Evidence of Incipient Intoxication Suggestive Evidence of Definite Intoxication F. Blood Changes Polycythemia Normal red cell count and | Decrease in hemoglobin Polychromatophilia hemoglobin Decrease in RBC Increased platelets Further reticulocytosis Increase in cells showing Reticulocytosis 50-100 stippled cells per basophilia Abnormal blood lead 100,000 RBC Anisocytosis and poikilo- Abnormal blood lead cytosis Nucleated RBC Reticulocytosis Decreased platelets Increase in blood lead TABLE 12 Complaints of Ill Health at Time of Examination of Workers in Storage Battery Plants (Dreessen et al.) Per Cent of Workers with Symptom Who Were Diagnosed as— Symptom Adfected by Eatly Not Affected BOLEXIN oi se Das es una nm ine 11.5 1.9 Muscle pain or eramp...........¢c.0nuennn.. 11.5 3.4 Qonstipation...... oo. 0 lah edi ld 10.3 7.4 Abdominal pain... cc ivainci dain n 9.2 3.0 JOIMUAOMN. foc itt E00 Sh its ww sibin Sibi aide & 8.0 2.6 Metallic taste... ... conicesii ie ivamnwive es 7.5 3.6 (eS a Re RS SMR Ri ET 6.9 2.0 Headaches... 0055 ey, dt ad 5.7 7.0 DEPRES a aa he 2.3 0.8 Eases. ah i She dae + wel 1.7 1.0 is extremely difficult and necessitates clear differentiation between absorp- tion, tissue damage and intoxication (Aub et al.). The matter of diagnosis of this condition most often arises in subjects who have been admittedly exposed to abnormal amounts of lead by reason of their occupation; in such subjects, as indeed in any, evidences of abnormal exposure to lead are not in themselves indicative of the existence of lead intoxication (lead line in the gums; basophilia; reticulocytosis; abnormal lead content of urine or blood). Moreover, physical or functional abnormalities in such subjects, particu- larly in the cardiovascular system, blood and kidneys, may or may not be due to the absorption of excessive quantities of lead and do not necessarily, even in conjunction with the former phenomena, constitute certain evidence 1 MRT eal “. LEAD POISONING of lead poisoning. This diagnosis must rest upon the occurrence, at some time, of clinical signs and symptoms of the disease, as considered below, together with the demonstration of evidence of abnormal absorption of lead into the organism. Some of the most common of these manifestations are listed in Table 11 (Jones) and Table 12 (Dreessen). ALIMENTARY TRACT Symptoms referable to the alimentary tract are among the most common manifestations of lead poisoning and gastrointestinal complaints are proba- bly the most common presenting symptoms in subjects with chronic plumb- ism. Early evidence of deranged gastric function may be dependent upon abnormality of secretion and motility. There is also loss of appetite, particularly in the morning, a foul or metallic taste, more marked in sub- jects with poor dental and oral hygiene, accompanied by a fetid odor of the breath. The anorexia may be so marked as to result in varying degrees of undernutrition. The metallic taste in the mouth is frequently very disagreeable and is sometimes described as sweet. This has been at- tributed by some to abnormality of the nervous mechanism for taste per- ception (p. 31), and by others to the presence of lead in the saliva (p. 31). Many complain of a sense of heaviness, distention and discomfort in the epigastric region, especially after meals, accompanied by “indigestion” and eructation of gas. Nausea or vomiting or both occur in 30-40 per cent of cases, independently of colic. Although diarrhea may occur in a small proportion of cases (159%), constipation, at times obstinate, is the rule, particularly before attacks of colic. In cases with acute gastrointestinal irritation accompanied by diarrhea, the stools may contain blood, but this is unusual except after the ingestion of relatively large amounts of irritating lead compounds. During the period of constipation the patient may frequently experience a desire to defecate but is usually unable to pass anything except a small amount of mucus (Aub et al.). There may be alternating periods of diarrhea and constipation, resembling those which occur in patients with spastic colon, or ulcerative colitis. These abnor- malities of gastrointestinal function are commonly accompanied by dull pains in various portions of the abdomen, at times in the umbilical region, lower abdomen, epigastrium, or in the region of the splenic or hepatic flexures of the colon. These symptoms may occur independently of epi- sodes of colic, but frequently increase in severity and culminate in the latter. Spasm of the descending or ascending colon may be demonstrated by palpation, as may in some instances distention of the cecum and evi- dence of increased intestinal peristalsis (auscultation). A sensation of generalized abdominal discomfort may exist for weeks or months prior to CLINICAL MANIFESTATIONS 103 or following an attack of acute colic, often with intervals of freedom from pain of one to two weeks. Acute plumbism, due to the absorption of large amounts of lead over a relatively short period of time, may be accompanied by severe gastro- intestinal disturbance, particularly if the lead has been ingested. This condition may be produced readily in experimental animals but is rarely seen clinically except occasionally as a result of severe accidental exposure, or after the ingestion of lead compounds with suicidal intent or as an aborti- facient. There may be marked salivation, with metallic or burning taste in the mouth, acute epigastric pain, hiccough, retching and vomiting, colicky abdominal pain and diarrhea. The character and severity of these manifestations depend in large measure upon the irritating properties of the particular lead compound ingested. Similar manifestations may occur, although rarely, during acute episodes in chronic lead poisoning (Hamil- ton!). Parotitis. Painful swelling and inflammation of the parotid gland, chronic parotitis, has been frequently observed in patients with lead poison- ing (Meillere®; Biondi). Thielmann reported its occurence in 24 per cent of a series of 50 cases. Involvement of the other salivary glands is less common, the submaxillary being affected more frequently than the sub- lingual glands (Flury?). It appears likely that this phenomenon, when it occurs, is dependent not upon the presence of lead in these glands nor its excretion in the saliva, as has been suggested by several authors, but rather upon oral and gingival infection with extension into the ducts of the salivary glands (p. 79). The Lead Line. The so-called “lead line” or Burtonian line, occurring in the gums and buccal mucous membrane, is of diagnostic significance. It appears to have been reported first by Grisolle in 1835, and subsequently was described in detail by Tanquerel and by Burton. The nature and pathogenesis of this phenomenon have been discussed in detail elsewhere (p. 77). Inits typical form this line, which consists of minute particles of lead sulfide, is usually blue-black or light gray-blue in color, extends along the margin of the gums close to the dental border, is usually most pro- nounced in the interdental processes of the gum and is about 1 mm. or less in width. It occurs more frequently in the lower than in the upper gum, especially about the incisors and canines, and is almost invariably absent where teeth have been removed (Aub et al.). In some instances the entire gingival mucosa may be involved, from the margin of the teeth to the buccal sulcus; such extensive involvement almost never occurs except in the presence of marked gingival infection, with soft edematous gums and fre- quently loose teeth (Legge and Goadby). Similar pigmentation is oc- 104 LEAD POISONING casionally observed in the mucous membrane of the cheek or lips, usually near dirty or decayed teeth. The discoloration varies considerably in intensity, and is at times so faint that it may be detected only by careful examination with a hand lens after removing any peculiar exudate or other detritus that may have accumu- lated about the teeth and gums. There has been considerable discussion regarding the relation of gingival infection and dental caries to the develop- ment of the lead line. Some observers believe that this phenomenon does not occur if the teeth are clean and free from coating and if the gums are closely adherent to the teeth, clean and free from infection (Legge and Goadby). Moreover, the observation has frequently been made that the discoloration may be absent in lead workers who brush their teeth and gums and rinse their mouths before leaving the factory, and also in edentulous and otherwise healthy portions of the gums. There can be little doubt that poor oral and dental hygiene, dental caries, stomatitis and gingivitis markedly increase the rate of development and intensity of the discolora- tion. On the other hand, there is abundant evidence that a perfectly typical lead line can develop in the presence of good oral and dental hy- giene, healthy gums, and sound teeth (K. B. Lehmann?; Teleky’; Aub et al). These deposits within the gum must be differentiated from dark deposits on the surface of the tooth behind the gum. This may be done readily by inserting the edge of a piece of white paper between the gum and the teeth and examining with a hand lens, under which circumstance the localization of the pigmentation in the gingival substance and its punctate character can be demonstrated. The discoloration due to lead may also be simulated by a bluish appearance of the edges of the gums in the presence of pyorrhea, by a bluish line due to mercury, a black line due to bismuth, a dark green line on the teeth of workers with copper, and carbon deposits in coal miners and resulting from the use of charcoal as a tooth powder. Similar pig- mentation may also be due to silver. Care must be exercised in excluding normal pigment deposits in the gums, particularly in dark-skinned subjects. Discoloration (melanin) resembling a lead line has been observed in a large percentage of Javanese and Madurese, the deposits being located chiefly on the buccal or labial side of the gums, chiefly along the incisors, both upper and lower, and never occurring on the lingual side or in the tongue (Breyer). A lead line, as is true of the presence of lead in any of the body tissues or fluids, is indicative only of the absorption of abnormal quantities of lead and not of the presence of lead poisoning. However, since it is frequently found in patients with even mild lead intoxication, it is of diagnostic sig- nificance. Many regard the intensity and extent of this discoloration as a CLINICAL MANIFESTATIONS 105 rough index of the severity and duration of exposure, but the enormous influence of such factors as poor oral and dental hygiene and gingival infection makes this observation extremely unreliable in this connection. The absence of the lead line does not eliminate lead poisoning, particularly in edentulous subjects or in those with healthy gums and teeth, but careful examination may reveal some evidence of discoloration in subjects with lead poisoning and poor oral hygiene. In some cases the lead line may ap- pear in normal gums after brief exposure while in others it develops only after periods of prolonged and heavy exposure. It usually persists for several months after exposure has ceased (Aub, 7 months; Teleky?, 11 months). The recurrence of discoloration after it has disappeared during treatment is rare, but it has been observed to develop during acute lead intoxication during a period of hospitalization without medication (Aub et al.). The appearance of a typical lead line has also been noted in subjects with no previous discoloration and no recent exposure to lead following the administration of potassium iodide, with the consequent development of manifestations of lead intoxication as a result of mobiliza- tion of lead from deposits resulting from previous exposure (Aub et al.; Fagge). According to Biondi, a lead line is present in about 709, of cases of clinical lead intoxication and in about 20-409, of cases of abnormal exposure to lead. Teleky states that it may be lacking in 209, and Oliver in 259%, of instances of plumbism. Xoelsch observed this phenomenon in 129, of 5000 painters and Oliver? in 509, of lead workers without other manifesta- tions of lead poisoning. Colic. Intestinal colic is perhaps the most striking and the most common of the acute manifestations of chronic lead poisoning. It occurred in 819, of 1493 cases reviewed by Tanquerel and constitutes the symptom for which relief is first sought in the great majority of cases. Because it is so frequently the first acute episode in subjects with chronic lead intoxication, it is of great value in the diagnosis of this condition. Colic may appear in rare instances of acute accidental lead poisoning following exposure to a single large dose, and in particularly susceptible subjects it may develop occasionally in industrial poisoning after exposure of only a few days. In the majority of instances, however, colic appears only after weeks, months or even years of industrial exposure, and may be precipitated by factors which suddently increase the mobilization of lead from its storage depots or interfere in some way with its elimination (alcoholic debauch, acute or chronic infection, renal functional impairment, dietary indiscretion, in- gestion of acids, alkalis, potassium iodide, magnesium sulfate, etc.). The acute fulminating manifestations may have a very sudden onset with little or no warning, but they are usually preceded by two to three days of 106 LEAD POISONING such vague symptoms as epigastric discomfort, indigestion, anorexia, and unpleasant taste in the mouth, nausea, indefinite abdominal pain, languor and constipation. In rare instances diarrhea may occur, or alternating diarrhea and constipation (Legge and Goadby), but in the great majority of cases acute lead colic is preceded by several days of obstinate constipa- tion. During this preliminary period, as well as during the attack itself, the patient experiences a frequent desire to defecate but is usually unable to pass more than a small amount of mucus (Aub et al.). The acute attack may come on abruptly, frequently during the night. Hamilton! cites a case in which pain appeared so suddenly that the patient thought someone had struck him in the abdomen. The pain varies considerably in intensity, and is of a colicky, griping or tearing character, at times severe enough to cause collapse and even delirium. It usually occurs intermittently, at intervals of a few minutes to several hours, a sense of pressure within the abdomen frequently persisting between the acute attacks. The pain is generally in the lower portion of the abdomen, but may shift from one region to another and may be localized in the right iliac fossa, the upper right quadrant or, at times, the epigastrium. These unusual localizations may cause some difficulty in diagnosis. In severe cases the patient may scream or writhe about the bed or floor in agony. The body is usually flexed at the hips, the legs being brought up towards the abdomen, and there may be convulsive movements of the limbs. The face is drawn and anxious, with an expression of pain, the eyes are staring, and the skin is pale, cold, and usually covered with sweat, although there may be a striking absence of perspiration even during periods of intense pain (Hamilton!). Some observers attach considerable diagnostic signifi- cance to the fact that relief is often obtained by making firm pressure upon the abdomen; the patient may seek temporary relief by leaning over a pillow placed on the back of a chair or the edge of the bed (Legge and Goadby), but abdominal tenderness is sometimes present. As stated previously, there is usually a constant desire to defecate but only a little mucus and occasionally blood is passed. Nausea is common and the patient frequently complains of intense thirst. Vomiting occurs frequently at the onset and may either subside or persist throughout the attack. The vomitus usually contains a considerable amount of tenacious mucus and frothy green bile; there may be retching with little or no vomitus. Intestinal colic is at times accompanied by evidences of spasm in other situations, including the bladder, uterus and vagina, scrotal muscles and ureters, pain due to the latter frequently being referred to the scrotum and penis and simulating the pain of renal colic. The abdomen is rarely distended, the abdominal walls being usually retracted and held rigid, at times with fibrillary twitchings and migrating CLINICAL MANIFESTATIONS 107 areas of hyperesthesia. Increased peristalsis may or may not be demon- strable. In cases in which the abdominal wall is sufficiently relaxed, shift- ing intestinal spasm may be demonstrable by palpation. Rectal palpation may reveal alternating violent contraction and relaxation (Hamilton'; Aub et al.). In intervals between the spasmodic attacks, there may be a sensation of doughy resistance in the abdomen and, a point of considerable importance in differential diagnosis, there is no true spasm or rigidity of the abdominal wall. The pulse rate often drops, frequently to 40-45 per minute and occasionally even to 20. The pulse is small and hard and the blood pressure is usually elevated during the paroxysm (p. 110). Respira- tions may be rapid and labored. The temperature is usually slightly sub- normal, falling at times as low as 96°F., but occasionally there may be a slight fever, rarely over 100°F., at the onset of the attack. The urine vol- ume may be markedly decreased during an attack of colic; this may result from diminished intake of fluids, vomiting or sweating, actual suppression of urine formation or interference with excretion due to spasm of the bladder. The first urine passed after an attack may contain albumin, casts, porphyrin and excessive amounts of urobilinogen (Hamilton). In rare instances death may occur during the paroxysm of lead colic, due to cardiac failure. The duration of each paroxysm varies considerably, from a few seconds or minutes to a few hours, usually recurring at intervals of a few minutes to several hours for periods ranging from a few days to many weeks in untreated cases. Between attacks the patient is usually restless and complains of a sense of weight or pressure in the abdomen. In 31 untreated cases referred to by Tanquerel, the duration of attacks of colic was as follows: More than 12 days in 15 cases; 8-12 days in 11 cases; 7 days in 1 case; 4 days in one case. According to Brouardel, colic usually yields to treatment in 8 days, but, if untreated, may continue from 2 to 6 weeks; Legge and Goadby cite one instance of 8 weeks duration. The response to active treatment is usually prompt, with complete relief within 2 days in the great majority of cases (Aub et al.). If exposure to lead continues, the attacks may continue, usually with diminished intensity, over periods of many months punctuated by rather acute episodes at in- tervals of one to two weeks. It should be emphasized that mobilization of stored lead (p.25ff.) may result in typical lead colic as well as other mani- festations of lead intoxication, such as encephalopathy, many months or even many years after exposure to lead has ceased. Miscellaneous. Constipation occurs in about 85% of cases, particularly before attacks of colic, and diarrhea occurs occasionally (15%). Alter- nating diarrhea and constipation, with the passage of blood and mucus, is observed at times in rare cases, usually fatal, with ulcerative enteritis and colitis. Severe ulcerative gingivitis and stomatitis, similar to that seen 108 LEAD POISONING in mercury poisoning, have also been observed in lead intoxication (Koelsch'). Various manifestations of protein and fat indigestion may develop as a result of chronic gastritis, with achlorhydria or hypochlor- hydria and decreased enzyme secretion, and of subacute or chronic hepatic disease (p. 88). Visible jaundice is not observed commonly in chronic lead poisoning. Tanquerel saw only 51 cases in 1217 patients with lead colic, but Legge and Goadby say that there may be a yellowish appearance of the skin in many cases of acute plumbism. Rolleston and McNee cite occasional recurring attacks of jaundice in lead workers in the apparent absence of biliary calculi, due apparently to spasm of the bile ducts. In our experience, although visible jaundice is unusual, hyperbilirubinemia is not uncommon in acute lead intoxication, the serum bilirubin concentra- tion ranging from 1.0 to 2.3 mg. per 100 cc., often although not always with a negative direct van den Bergh reaction (Cantarow!). An increased serum bilirubin concentration has been reported by other observers (Klima and Seyfried; Schmidt-Kehl; Vigliani and Angeleri; Heubel). This hyper- bilirubinemia is probably due in part to increased destruction of hemo- globin and in part to impaired hepatocellular function, and is accompanied in many instances by bilirubinuria, excessive urobilinuria and increased excretion of bile pigment in the bile (p. 87). Vomiting, very sudden in onset and projectile in nature, resembling that of brain tumor, may occur as a manifestation of lead encephalopathy (p. 120). CARDIOVASCULAR SYSTEM It is difficult to evaluate properly the significance of clinical manifesta- tions of abnormalities of the cardiovascular system in lead poisoning. As indicated elsewhere (p. 72ff.), there is still a great deal of controversy re- garding the effects of lead upon the circulatory apparatus. Opinions on this subject vary, from denial that lead produces significant deleterious effects upon the blood vessels to a firm belief that vascular damage caused by lead constitutes the basis for many of the morphologic and functional manifestations of lead poisoning. However, critical appraisal of the available evidence indicates that, in experimental animals at least, lead is capable of producing damage to the blood vessels, although the mechanism and fundamental basis of its effects in this connection are open to question. These changes have been discussed in detail (p.72ff.) but may be summarized briefly here as follows (Flury?): The primary reaction to lead is probably a spasm of the vascular musculature, followed by morphologic damage, first in arterioles and capillaries. The intima of the medium-sized and small arteries is involved later and eventually all layers of the vessel wall may be affected. The subsequent changes include cell infiltration, nuclear proliferation, degeneration, fatty change, calcification, sclerosis, thrombosis, CLINICAL MANIFESTATIONS 109 and fraying of the elastic lamina. The veins become widened or throm- bosed. Capillary damage occurs chiefly on the venous side, with increased permeability or actual rupture, leading to profuse hemorrhage. These changes may occur in a variety of organs, perhaps the most important of which is the kidney, since the changes in that organ resulting from disturb- ances of its circulation may have far-reaching effects upon the organism as a whole. It is admittedly hazardous to attempt to apply to clinical lead poisoning observations made upon animals with experimental lead intoxication. However, there are many post-mortem observations in clinical lead poison- ing that are in conformity with those made in experimental animals (p. 74ff.). Here too, caution must be exercised in attributing such lesions to lead poisoning, because of the frequency with which similar vascular changes occur in the population as a whole, particularly in the older age groups. Until comparatively recently, the data had not been subjected to critical statistical analysis from this standpoint, and as yet the volume of material studied in this manner is too small to permit a definite statement to be made on this basis. Nevertheless, it is difficult to escape the conclusion that clinical lead intoxication may produce changes in the cardiovascular system. A peculiar shiny, ashen pallor of the skin and mucous membranes is one of the earliest and most constant manifestations of chronic lead poison- ing (Teleky®; P. Schmidt*; Aub et al.; Legge and Goadby; Oliver?). This shiny, grayish pallor cannot be explained in all cases on the basis of anemia alone, and has been attributed, in part at least, to superficial vasocon- striction (Koelsch?; Flury?). Otto and Hahn studied the superficial capil- laries by direct capillary microscopy in subjects exposed to lead but with- out. evidence of lead poisoning, in patients with clinical manifestations of lead poisoning and in animals with experimental lead intoxication. Va- rious regions were examined including the margin of the fingernails, the skin of the chest, above the aureolae of the nipples, the inner margin of the lips, the upper arm, the thighs and the wrists. A variety of capillary abnormalities were observed in subjects with prolonged exposure and vary- ing degrees of lead intoxication. These included atypical forms of the terminal loops with abnormal elongation and convolution, constriction of the arterial branches, producing in severe cases ischemia of the correspond- ing fields of distribution, and variations in the rate of flow of blood through the capillaries. Similar changes were observed in experimental animals. On the basis of these studies it was concluded that the abnormalities of the capillary system are dependent primarily upon spasm of the arterial branches and are particularly prone to occur in subjects whose vasomotor mechanism is constitutionally unusually labile. With prolonged exposure to lead the originally reversible process in the capillaries tends to become 110 LEAD POISONING irreversible resulting in-a condition of arteriocapillary fibrosis and per- manent vascular damage (Otto and Hahn). Constriction of cerebral arteries has been found in experimental and clinical lead poisoning (Heubel; Rosenstein; Maier; Oliver?) and spasm of the retinal arteries has been ob- served during episodes of lead colic (Blum; Elschnig; Labadie-Lagrave and Laubry). This is perhaps responsible for the occasional occurrence of certain disturbances of vision, such as amblyopia and transitory amauro- sis (p. 124). Complete spastic occlusion of arteries, a rare condition, has been reported as have occasional instances of mild forms of the Ray- naud syndrome, but the association of these conditions with lead poisoning is probably purely coincidental (Flury?). The question of the relation of lead poisoning to the development of hypertension is of great practical significance, particularly from the medico- legal standpoint. Variable findings may be obtained during acute episodes of lead intoxication, and many observers have reported moderate to marked hypertension in association with manifestations of colic and encephalopathy (Riegel; Vaquez; Frank; Pal; Traube; Fishberg; Legge and Goadby). Except in the presence of such complications as shock, left ventricular failure and coronary occlusion, encephalopathy is almost invariably ac- companied by elevation of arterial blood pressure, at times of extreme degree. The blood pressure may be normal, low or high in patients with lead colic. Oliver? found that it was often low, but our own experience, which coincides with that of Teleky®, is that a significant rise occurs fre- quently but by no means consistently. In the evaluation of the significance of this rise, however, the effect of pain must not be disregarded, but the occasional persistence of hypertension after the subsidence of the attack of colic suggests the operation of a more fundamental mechanism. Ac- cording to Teleky, who believes that the blood pressure varies in different stages of acute lead intoxication, a rise may occur for a few days during periods of exacerbation. In the early stages of lead colic, it may persist for a short time and then disappear with a subsidence of symptoms. It is probable that, apart from the operation of such factors as shock, left ventricular failure, and coronary occlusion, which tend to lower blood pressure, the presence or absence of hypertension during acute episodes of lead intoxication may be dependent upon constitutional variations in the responsiveness of the arterioles to contractile stimuli. It is generally believed that prolonged exposure to lead may cause a significant increase in blood pressure. This belief is based upon the clinical observation that hypertension is apparently unusually common in lead workers and in subjects with chronic lead poisoning (Allbutt; Harris; Feil and Balsac; Teleky®; Legge and Goadby; Oliver?). This view has met with some opposition in recent years. Lasius states that, excluding CLINICAL MANIFESTATIONS 111 , cases of nephritis, the blood pressure is not increased in lead workers after 30 to 40 years of exposure, and Engel found the blood pressure to be normal in 80 per cent of lead workers. Several other recent authors are of the opinion that hypertension cannot be regarded as a common manifestation of clinical lead intoxication (Pfeil; Schnitter). The great majority of reports bearing on this point may be criticized on the ground that the con- clusions were not based upon sufficiently critical analysis of the blood pressure findings in comparison with properly selected control groups to permit the satisfactory evaluation of the data from a statistical standpoint. In an analysis of data in 81 cases exposed to lead over a period of years (589, 5 years, 179%, 10-20 years), Belknap®3 concluded that there is no significant difference in blood pressure in workers with lead and non-workers in the same age group. However, the majority of the subjects in this study were not exposed to lead for sufficiently long periods of time to justify the conclusion that lead is incapable of producing hypertension. The same statement applies to the data reported by Dreessen and his associates, who found no significant deviation from the normal in blood pressure or the incidence of arteriosclerosis in a group of 766 workers in the storage battery industry. Vigodortchik studied the blood pressure of 1437 lead workers and 1332 non-workers, analyzed statistically according to age groups, duration of exposure, and other factors. It was found that the average blood pressure was higher and the percentage of subjects showing moderate or marked hypertension greater in each group of lead workers than of non-workers, and it was concluded that prolonged exposure to lead is accompanied by an increase in blood pressure. This view is maintained by Teleky and by a majority of workers in this field. The exact nature of the hypertension due to lead poisoning is open to question. The evidence at hand is not clear as to whether it is dependent primarily upon diffuse arterial disease or upon changes in the renal arteries and arterioles (pp. 72, 90ft.). Naturally, the patient with chronic lead poisoning may present any of the symptoms commonly caused by hypertension or its consequences, including hypertensive encephalopathy, hypertensive retinitis, cerebral vascular accidents, coronary artery disease, left ventricular failure, pro- gressive heart failure, arteriosclerosis, arteriolosclerosis, etc. Bradycardia may occur in patients with encephalopathy (increased intracranial pres- sure). Heart failure in patients with lead poisoning, if related at all to the effects of lead, is practically always secondary to hypertension or to coro- nary artery spasm or organic occlusion (p. 76). Sudden death due to sudden left ventricular failure has been reported during acute attacks of lead colic, being perhaps dependent upon coronary artery disease in the great majority of instances. The problem of the relation of lead to the 112 LEAD POISONING development of arteriosclerosis is intimately related to the question of its effect upon blood pressure and has been considered in detail elsewhere (p. 72ff.). Suffice it to state that although the prevalent clinical opinion that chronic plumbism may cause arteriosclerosis is based almost entirely on post-mortem findings, and is thus open to question (Aub et al.), the bulk of both experimental and clinical evidence appears to support this view. Manifestations of chronic lead poisoning may therefore include symptoms referable to any organ in which arteriosclerosis is prone to occur, notably in the brain, kidneys, heart and aorta. URINARY TRACT It is difficult to evaluate properly the significance of evidence of renal disease in patients with lead poisoning. The problem of the possible role of lead in the production of renal damage is intimately related to the question of the influence of this agent upon the development of vascular damage and hypertension and its solution presents difficulties similar to those discussed in connection with the latter problem (p. 72ff.). The clinical manifestations of renal damage due to lead may be broadly classified under two headings: (a) those occurring during acute episodes of plumbism, probably dependent upon the production of a nephrotic lesion similar to that caused by other heavy metals; (b) those occurring in advanced stages of chronic lead intoxication, dependent upon the development of nephro- sclerosis as a result of damage to the renal vessels (p. 92ff.). The former condition, which is regarded as non-specific in nature, being produced by a variety of metallic poisons, is transitory and leaves no significant residual damage (Beintker), while the latter is regarded as a specific effect of lead and is permanent and progressive in nature. Polyuria, albuminuria and cylindruria may occur at times during the course of chronic lead poisoning, particularly during periods of acute exacer- bation in association with colic or encephalopathy (Legge and Goadby; Oliver?; Teleky®; Beintker; Flury?). Under such circumstances red-blood cells may occasionally appear in the urine, but manifestations of severe renal damage are seldom seen in clinical plumbism although isolated cases have been reported (Chajes). Except in the presence of congestive heart failure, edema is not commonly observed in the acute episodes, or, if it does occur it is not of severe degree, as is the case also in the nephrosis due to mercury poisoning. Dreessen and his associates found albuminuria twice as frequently in lead workers with other evidence of intoxication as in nonaffected workers or workers in other industries, the incidence and sever- ity of albuminuria increasing with duration of exposure and increasing concentrations of lead in the air to which the subjects were exposed (p. 94) (Fig. 1). These authors suggest that the test for albumin in the urine CLINICAL MANIFESTATIONS 113 should be used in conjunction with hematologic tests for the detection of early changes in workers exposed to lead, which is in accord with our ob- servations. Polyuria, albuminuria, and edema have been observed in human subjects following intravenous injection of colloidal lead preparations (Bell and Cunningham). There is usually no associated significant impairment of renal function in uncomplicated cases and hypertension, if it occurs, is, like the urinary manifestations, almost invariably transitory and disappears upon termination of these episodes. The consensus is that the renal lesions responsible for these clincial findings, even if severe, probably do not Fic. 1. Per cent of each of 16 groups of storage battery workers found to have more than a trace of albumin in their urine. (Dreessen et al., U. S. Public Health Bulletin No. 262.) contribute significantly to the development of the characteristic nephro- sclerosis of chronic lead poisoning. The clinical picture resulting from chronic renal damage due to lead is essentially that of nephrosclerosis and demonstration of the possible etiologic réle of lead in any given case must be based upon a history of exposure to this agent, the presence of more specific manifestations of lead exposure or lead poisoning, such as a lead line, colic, encephalopathy and palsy, or the demonstration of abnormally large amounts of lead in the blood, urine, or other body fluids. As in nephrosclerosis due to other causes, the condition may be asymptomatic for many years and may be detected accidentally by the observation of mild hypertension or slight albuminuria in the course of examination for life insurance or incidental 114 LEAD POISONING illness. Over a period of many years there may be headache of varying severity, numbness and tingling of the hands and feet, muscular cramps, insomnia, palpitation of the heart, and dyspnea on exertion, i.e., symptoms associated with and dependent upon hypertension and vascular spasm. In these early stages the urine may be normal, but as the renal lesion progresses there may develop albuminuria, some increase in the number of hyaline casts and, perhaps, polyuria and nocturia. In later stages the clinical picture may be dominated by symptoms due to hypertension, cardiac hypertrophy and dilatation, left ventricular or congestive heart failure and arteriosclerosis in various situations, particularly in the cerebral and coronary arteries. Edema practically never occurs except in the presence of congestive heart failure and in association with manifestations of pulmonary, hepatic and other visceral congestion. Under such circum- stances the urine may contain large quantities of albumin, hyaline casts, and occasionally red-blood cells, with a diminution in the twenty-four hour output. There may be varying grades of dyspnea of different types, paroxysmal, nocturnal or occurring after exertion, depending upon the nature of the underlying mechanism, i.e., left or right-sided heart failure. As in the case of nephrosclerosis due to other causes, renal failure with clini- cal manifestations of uremia occurs in a relatively small proportion of cases (probably less than 109), except in certain instances of so-called malig- nant nephrosclerosis or, occasionally, when precipitated by extreme oliguria resulting from congestive heart failure and generalized edema. Investigations of the renal function over a period of several years may reveal a steady decrease in urea clearance values and in the maximum specific gravity of the urine as indicated by one of the ordinary concentra- tion tests. The blood urea and non-protein nitrogen concentrations re- main within normal limits except in the presence of renal failure. The severity of the renal lesion is usually reflected clinically in the condition of the eye-grounds, which may show any or all of the changes characteristic of hypertensive retinitis. One of the important practical consequences of the impairment of the renal function which may occur as a result of this condition is a diminution in the concentration and total quantity of lead in the urine, a fact which may obscure the diagnosis in some cases. We have observed several instances of essentially normal values for urinary lead in the presence of high blood lead concentrations. It is of interest that complete supression of urination may occur at times during attacks of lead colic; rarely, this may represent true urinary supression resulting from acute severe nephrosis (p. 91ff.) or, more commonly, it may result from spasm of the ureteral or bladder musculature with consequent ob- struction to the flow of urine. Uremia has been regarded by some as the CLINICAL MANIFESTATIONS 115 basis for the clinical manifestations of lead encephalopathy, but there is no evidence of the validity of this hypothesis. It is extremely difficult to obtain accurate information regarding the incidence of renal disease due to lead poisoning. Even data gathered in studies of large numbers of workers in lead industries, carefully controlled as regards age grouping and otherwise satisfactory from a statistical standpoint, may be actually misleading because of the fact that the majority of lead workers who have suffered renal damage and have developed symp- toms referable to this condition have probably left their positions in such industries and are therefore not included in these studies. As stated else- where (p. 92ff.), the consensus of opinion among most pathologists and clinicians is that the incidence of renal disease is relatively high in subjects exposed to lead over long periods of time. It is probable that more definite information on this point may be obtained from studies that have ap- proached the problem from a different standpoint, namely, investigating the previous history with regard to exposure to lead in large series of cases showing definite evidence of nephrosclerosis. A few such reports are avail- able, such as that of Volhard, who found that four of thirty-six patients with chronic Bright’s disease had been lead workers, and that of Machwitz and Rosenberg, who found that nine of thirty-six cases of malignant nephro- sclerosis had been exposed to lead. Of particular interest in this connection are the studies by Nye and by Murray of the relation of lead poisoning to the development of chronic renal disease in children and young adults in Queensland, Australia. Investigations by these and other observers (Croll; Cilento) indicated that chronic renal disease was unusually frequent in persons under forty years of age in Queensland, and that the high in- cidence of this condition was apparently related to the occurrence of lead poisoning in infancy and early childhood, the source of these poisons having been the paint on the veranda railings of the homes. Children with this condition presented a rather characteristic appearance, with pale, wizened features, dry undernourished skin and stunted physical development. Hypertension and hypertentive retinitis were invariably present and, in the late stages, there were a variable degree of cardiac hypertrophy, left or right-sided heart failure, and frequently, renal failure. Older subjects presented the typical clinical picture of nephrosclerosis, the renal lesion being initiated in early childhood and progressing after exposure to lead has ceased. Including only those cases in which the etiologic role of lead could be demonstrated definitely, plumbism could be regarded as probably involved in the pathogenesis of the renal lesion in 189, of Nye’s cases, 159, of Murray’s and 309, of Cilento’s. Viewing the problem from another angle, it was found by Nye that of 34 patients who had had severe 116 LEAD POISONING lead intoxication during childhood, 29 had well-established renal insuf- ficiency at the time of study, with hypertension, nitrogen retention and low urinary concentrating ability. Evidence of kidney damage was observed in about 809, of children with lead poisoning, and it was concluded that every child who has had lead poisoning is a potential subject of chronic renal disease in later life (Nye). It was also believed that, particularly in children, once nephrosclerosis is established, its progress is constant and relentless. The likelihood of exposure to toxic amounts of lead in infancy and early childhood is not very great, except in isolated instances or under unusual circumstances (p. 199). However, the above-mentioned studies serve to emphasize the high incidence of renal disease as a late manifestation of lead poisoning and the possibility that a relatively brief period of exposure may initiate a nephrosclerotic lesion which may progress even to a fatal termination over a period of many years after such exposure has ceased. CHAPTER V CLINICAL MANIFESTATIONS (Continued) NEUROMUSCULAR SYSTEM Signs and symptoms referable to the neuromuscular system constitute perhaps the most disabling and important manifestations of lead intox- ication. They may mimic a great variety of diseases of the brain, spinal cord and peripheral nerves and other clinical evidences of lead poison- ing may be overlooked if the possibility of lead poisoning is not considered. The most important of these are grouped under the designations (a) lead encephalopathy and (b) lead palsy, but other manifestations occur fre- quently, including disturbances of sensation and of special sense organs, muscular tremors and twitchings, psychic and emotional disturbances and nervous system manifestations due to or associated with hypertension and renal failure. Encephalopathy The term encephalopathia was applied by Tanquerel des Planches to all manifestations of cerebral involvement in lead poisoning. Grisolle had classified these manifestations under three headings, (a) convulsive, (b) delirious and (c) comatose, to which Tanquerel added a fourth, (d) a com- bination of one or more of these forms. Westphal divided cases of lead encephalopathy into two groups, (a) those with evidence of general cerebral involvement and (b) those with evidence of focal lesions. Under the former he included, in addition to the phenomena mentioned above, manifestations suggestive of multiple sclerosis, hysteria and progressive general paralysis. Under the latter he included such manifestations as are indicative of isolated lesions in the brain, such as bulbar paralysis, and involvement of one or more cranial nerves. Analysis, so far as is possible, of several cases re- ported in the early literature, suggests that manifestations attributed to lead poisoning in certain instances may have been dependent rather upon renal failure, hypertension, syphilis of the central nervous system or some other complicating condition. Eliminating these from consideration, there remains a group presenting manifestations which may still be classified under the aforementioned heading. The pathogenesis of these forms of true lead encephalopathy is not clearly understood, as is indicated by the number and variety of hypotheses advanced in explanation of this phenom- enon. However, in the light of present knowledge, it appears probable that despite the many reports of morphologic abnormalities in the brain 117 118 LEAD POISONING and meninges, none of which have been found to be present consistently, many if not indeed the majority of the clinical manifestations of lead encephalopathy are dependent upon or associated with hypertension, which some authorities believe to be invariably present in this condition (Vacquez; Traube; Fishberg). Fishberg regards these cerebral manifestations of lead poisoning as one form of hypertensive encephalopathy, dependent perhaps upon cerebral vasoconstriction, cerebral anemia and sometimes cerebral edema. Modern improvements in hygienic conditions in lead industries have resulted in a marked decrease in the incidence of this most serious mani- festation of lead intoxication. It seems probable, however, that many instances of lead encephalopathy are not recognized, particularly when occurring as a result of accidental exposure. Evidence of cerebral involve- ment was present in 5.9% of 1217 cases of industrial lead poisoning gathered by Tanquerel in 1839, whereas encephalopathy was stated to be present in only 0.56% of 6762 cases of lead poisoning reported in Great Britain during the years 1900-1909 inclusive. However, the accuracy of the latter statement is open to question inasmuch as, according to Legge and Goadby, there were 38 instances of encephalopathy (14.4%) in fatal cases of lead poisoning occurring during the same ten-year period. The comparative rarity of this condition in industrial poisoning in the United States is in- dicated by the fact that Hamilton! was able to collect histories of only 132 cases during a fourteen-year period. Sex, race and age appear to have a decided influence upon the incidence of lead encephalopathy. In a survey of the pottery industry in 1911, Hamilton found the incidence of encephalopathy to be about four times as high in women (1:4.5) as in men (1:17). In a study of 640 cases of lead poisoning, Prendergast found the incidence of convulsions to be 15% in men and 34.9% in women and that of total or partial blindness 5.8% in men and 17.9% in women. Encephalopathy apparently occurs more frequently in negro than in white subjects with lead poisoning. Of nine cases of encephalopathy occurring during a period of six months in workers engaged in making white lead, four were negroes, who constituted only 15% of the total number of employees (Hamilton?). In a survey of the lead smelting industry, it was found that the incidence of this condition was 1.3 per 100 white employees per year and 6.8 per 100 negroes employed per year. In one plant the incidence was 4.7 per 100 whites employed and 20 per 100 negro employees per year (Hamilton®). The fact that clinical manifesta- tions of lead intoxication are frequently much more severe in children than in adults is reflected in the relatively high incidence of encephalopathy in the lower age groups. This may be dependent upon the relatively large amounts of lead absorbed per kilogram of body weight rather than to an CLINICAL MANIFESTATIONS 119 increased susceptibility of the tissues to lead and to the fact that, at the present time at least, lead poisoning in children is usually of accidental rather than industrial origin. Manifestations of encephalopathy were present in 45 of 77 cases of lead poisoning observed in infants’ and chil- drens’ hospitals in Boston during the years 1924-1933 (McKhann and Vogt). Blackman? reported 22 cases in children, 17 of whom were negroes. He points out the curious fact that 19 of the 22 cases occurred between the months of June and October; the tendency of lead encephalopathy to appear during the summer and early fall was also remarked by Suzuki and Kaneko and by Fukushima and Matsumato. Blackman? suggests that this may be due in part to precipitation of brain lesions by factors which cause vasodi- latation, such as fever and the heat of the summer and early fall months. Rapoport and Rubin observed the onset of manifestations of lead encephalo- pathy between the months of May and September in 24 of 30 children. They believe that the important factor in this connection is not heat and vasodilatation, but rather the fact that the antirachitic effect of solar radia- tion is greatest during this period (in Philadelphia), resulting in increased absorption of lead from intestine. They also suggest that sensitization by sunlight of increased amounts of porphyrin in plumbism may contribute to the seasonal incidence of lead encephalopathy. Because of the important relation of hypertension to the development of certain of the manifestations of lead encephalopathy, the existence of hypertension or of conditions which predispose to its development increases the likelihood of occurrence of en- cephalopathy in subjects with lead poisoning (‘“‘essential” hypertension, glomerulonephritis, chronic pyelonephritis, etc.). In general, with allow- ance for variations due to factors such as age, sex, and race, encephalopathy tends to occur most commonly in subjects exposed to relatively high con- centrations of lead, especially in the dusty trades in which large quantities are absorbed through the respiratory route. Nevertheless, as is true of all manifestations of lead intoxication, no generalization can be made in this regard because of the remarkably wide range of individual variation due probably largely to differences in absorption, storage, and excretion and to complicating conditions. The clinical manifestations of lead encephalopathy closely resemble those of the ordinary forms of hypertensive encephalopathy, a fact which, to- gether with the almost invariable existence of elevation of the blood pres- sure, has led many to believe that this manifestation of lead poisoning is in reality merely a form of hypertensive encephalopathy. It is probable that many if indeed not the majority of the phenomena which are commonly included under this designation are due to this cause, particularly the very striking convulsive manifestations and the subjective and objective ocular abnormalities. However, in many instances certain of the symptoms are 120 LEAD POISONING . undoubtedly due to one or more of the great variety of lesions of the brain and meninges reported by several observers. The classification of different forms of lead encephalopathy merely on the basis of differences in the most prominent clinical manifestations is therefore unwarranted and, indeed, misleading. Obviously, this term should not be applied to cerebral mani- festations of uremia, arteriosclerosis, cerebral hemorrhage or thrombosis, but should be used only in reference to phenomena directly dependent upon or associated with hypertension due to lead or those due to the direct action of lead upon the brain or meninges. Severe manifestations of encephalopathy, such as convulsions, delirium, mania, partial or complete blindness, transitory aphasia, paralyses, etc., may come on very suddenly, without warning, or they may be preceded by a variety of premonitory symptoms of variable duration. The sudden type of onset occurs particularly in children and under unusual circum- stances of heavy exposure in adults, notably in those exposed to large amounts of tetraethyl lead. In the usual type of industrial lead poisoning encephalopathy is generally preceded by some other manifestations of plumbism and by some alteration in mental attitude which may be so slight as to be overlooked entirely (Aub et al.). The most common of these are general sluggishness and dulness of mentality, bad dreams, restlessness, irritability, loss of ability to concentrate, loss of memory, and disturbed sleep or insomnia. These often become more marked prior to the onset of generalized convulsions, which may also be preceded by mental depression, vertigo, paresthesias, muscular tremors and twitching, mild and localized paralysis, visual disturbances, hallucinations, and headache (Grisolle; Tanquerel; Hamilton). The latter is particularly important because of the frequency of its occurrence and because its intensity and duration are of prognostic significance insofar as the subsequent development of convul- sions is concerned. Headache may be extremely severe, comparable to that occurring in migraine and in brain tumor. It is usually localized chiefly to the occipital or temporal regions, but is occasionally most marked in the frontal regions and vertex. Localization of the pain in the petrous portion of the temporal bone may suggest disease of the ear or mastoid, but this is not common. The pain may be persistent or spasmodic, the former type being especially serious since it often increases progressively in inten- sity and may terminate in a fatal form of encephalopathy. The patient often states that his head feels as though it were being crushed in a vice and, immediately before the onset of convulsions or coma, the pain may resemble that of a sharp blow on the head or “as if a nail had been driven in” or “as if something had blown up inside my brain” (Hamilton!). There may be remissions and exacerbations of the headache, resembling intestinal colic in CLINICAL MANIFESTATIONS 121 this respect. It may be accompanied by dizziness, faintness, emotional and nervous excitement or dullness, and, particularly if persistent, loss of mental acuity, visual disturbances, vomiting, delirium and mania. These severe manifestations usually culminate in convulsions or coma or both. A great variety of mental symptoms may precede, accompany or follow an attack of lead encephalopathy. In some cases they constitute the chief and, occasionally, the only manifestations of this condition. The oceur- rence of such phenomena as prodromal manifestations of lead encephalo- pathy has been referred to above. Charcot! cited instances presenting the characteristic picture of hysteria, with hemianesthesia, partial blindness, loss of sense of taste and smell and other stigmata, accompanying outbursts of emotional excitement and convulsions. This condition occurs especially in predisposed young women and perhaps is not directly dependent upon the action of lead upon the brain. There may be terrifying hallucinations’ and delusions, resembling delirium tremens, with complete mental disorien- tation and delusions of persecution (Goodhart; Robertson; Smith; Margarot and Blanchard). The acute psychotic manifestations of lead poisoning are identical with those of other types of psychosis, the etiological signifi- cance of lead being indicated by certain characteristic associated phenom- ena, such as epileptiform seizures (hypertension), which constitute the most distinctive feature of lead encephalopathy, and manifestations of lead poi- soning referable to other systems. According to Quensel, acute lead psycho- sis may be manifested by confusion, clouded mentality, fleeting, dis- connected, irrational ideas, hallucinations, rapidly changeable emotional moods with intermittent periods of excessive motor excitation alternating with periods of inhibition and interrupted by sudden lapses into stupor (Hamilton). He distinguishes three forms of this condition: (1) lead mania, (2) hallucinatory delirium, and (3) a syndrome resembling delirium tremens and perhaps due to the combined effects of lead and alcohol. Quensel and others have described a chronic condition resembling dementia paralytica, in which lead poisoning may be purely coincidental but to which it may contribute certain distinctive features, such as epileptiform convul- sions, palsy, colic, etc. According to Oliver? this condition of “pseudo- general paralysis” due to lead is characterized by the suddenness of its onset, the acuteness of its symptoms, the rapidity of its course and the tend- ency to improve. One of the significant features of the psychotic mani- festations of lead encephalopathy is the abruptness with which violent symptoms may appear. They may be very brief in duration, but delirium commonly lasts for several days or weeks, and in some cases may result in permanent insanity. In such cases there may be a background of advanced organic vascular disease of the brain. Occasionally, acute episodes of en- 122 LEAD POISONING cephalopathy may be followed by marked mental weakness or even ad- vanced grades of mental deterioration, tremors and paralyses, constituting a clinical picture resembling that of paresis. Convulsions constitute the most characteristic feature of lead encephalo- pathy and, as stated by Fishberg, the symptomatology of severe attacks is identical with that of eclampsia and other forms of hypertensive encephalo- pathy, such as those occurring in patients with essential hypertension and glomerulonephritis. In its classical form, this condition closely resembles an epileptic seizure, often with prodromal manifestations referred to pre- viously, followed by clonic and tonic spasms, with or without coma during and after the convulsion. According to Tanquerel, partial preservation of consciousness is a distinctive feature of lead “epilepsy,” but this is certainly not invariably the case. The observation has been made that genuine epilepsy may be precipitated by lead poisoning in the absence of true en- cephalopathy, a circumstance which may give rise to certain difficulties in differential diagnosis (Putnam!; White; Robertson). The seizures may come on without warning, but there is frequently a period of prodromal symptoms, the most common of which are severe headache, pallor and mental or emotional disturbances (Oliver). There is no true aura such as occurs in genuine epilepsy (Westphal?). As in hypertensive encephalopathy due to other causes, the seizures may assume a variety of forms. They may vary in severity from tonic or clonic spasms of isolated muscle groups to generalized convulsions. The clinical picture may resemble that of brain tumor or Jacksonian epilepsy in the localized nature of the convulsions at the onset. Differentiation from brain tumor may be difficult in some cases because of the simultaneous occurrence of severe headache, hypertension, vomiting, convulsions, coma, edema of the optic disc (choked disc) and marked increase in cerebrospinal fluid pressure. In extremely severe cases in children there may be sepa- ration of the cranial sutures. Fever may or may not be present, occurring more commonly in children than in adults. There may be a preliminary cry as in true epilepsy. The attack may begin with twitching of one side of the face, spreading to include the arm and leg of the same side and then becoming generalized, with or without loss of consciousness, partial or com- plete. Coma may occur without accompanying convulsions. In severe attacks there may be a primary period of generalized tonic spasm, with opisthotonos, cessation of respiration and interference with venous return, producing a picture of asphyxia, followed by a period of clonic convulsions as indicated above. According to Quensel, convulsions are usually partial but may be generalized, and they are frequently followed by rigidity of the limbs and trunk and a state of coma, with open and staring eyes. There CLINICAL MANIFESTATIONS 123 may be frothing at the mouth and nose and loss of sphincter control, with involuntary evacuation of urine and feces. The breathing may be ster- torous and occasionally the tongue may be bitten or other injury occur, as in idiopathic epilepsy. As stated previously, the convulsive seizures may be preceded, accom- panied or followed by any or all of the other manifestations of encephalo- pathy, variability in the latter phenomena being largely responsible for the diversified clinical picture of lead encephalopathy in different individuals or at different, times in the same individual. Death may occur during a con- vulsive seizure or the subject may pass into coma which persists until death. On the other hand, the seizure may only last a few minutes, followed by rapid and complete recovery, usually with temporary headache and slight TABLE 13 Data on Lead Poisoning in Infants and Children (McKhann and Vogt) "Fotal number ‘of cases of PlumbISIM. cou. vunilin dit sana is dh dmv ve Lol sieve 98 Number with latent or minimal symptoms. .............covviiiiinniinnernnnn, 12 Number with frank lead IntoZIeatION. ..ccvv vt vvivisn vnnn sess s saivmnss ss ss iene 77 Neuritis without encephalopathy.................c.ccciiiiniiiinnnennn. 4 RCE a OR RY rr di cd a a tiditeaie soaks Winn tile, oa sien ssa tips Ra AS 45 Peiths ab dA ne ed mR Dh cl SR aR 11 Complalo FRCOVOITE. «nics «1s» kv awd oh v3 Weise ins Fale sion Hoe verity 22 Permanent Sequellan.. ... cco. « cusmmnii vos dale imsiibis foo dn slips 12 CONVIISIONS....: conniriy ois» nmoins te 3 4 $550 ems S35 Rahs 4 Cerebral ALTODHY . ovis + + sh amamtan vs ss 2s mame shave amine 4 ITI cn LR or a a le 2 Mental retardationt... vo... bis isi sie bho dosnt cme pe 6 Muscular WenRness... .. cx ali s ois 5 cilia of vt siakinth 2 BANANeEE 1. civ ih iran na tiem tthe pci sa pee 3 Speech dolonh.. ooonily oo ruisins an pn fy vias + ad «phe 1 mental dulness. Following cessation of convulsions there may be a variable period of delirium, mania, depression, headache, tremors, paralyses, loss of memory, and partial or complete blindness, any or all of which are usually transitory but may be permanent. These convulsive seizures may recur at frequent intervals for periods of several hours or several days, during which the subject may be in a state of partial or complete coma. In chil- dren who survive severe lead encephalopathy there frequently remain sequellae indicating permanent cerebral damage. Cerebral atrophy or degeneration may become manifest in cerebral palsy, epileptiform seizures or mental deficiency (McKhann and Vogt). The incidence of such sequellae is presented in Table 13. 124 LEAD POISONING Visual Disturbances There is considerable difference of opinion regarding the frequency with which subjective and objective manifestations referable to the visual appa- ratus occur in lead poisoning. Tanquerel regarded visual disturbances as unusual, observing them in only 12 of 1217 cases of lead poisoning. Elsch- nig reviewed 88 cases of lead blindness reported up to 1898 and Lewin and Gueillery were able to find only 142 authentic cases in literature in 1905. During the period 1900-1909, 24 instances of optic neuritis were reported in 6762 cases of lead poisoning in Great Britain. On the other hand, Pren- dergast, in a series of 640 cases of lead poisoning in a pottery region in Eng- land, found partial blindness in 3.59%, of men and 10.29, of the women and total blindness in 2.39%, of the men and 7.79, of the women. Gibson, too, believed that ocular manifestations were not rare, having seen 45 instances of optic neuritis in children with lead poisoning during a period of 15 years. In the light of present understanding of the hypertensive basis of many if not the majority of these visual disturbances, it is probable that routine ophthalmoscopic examination in cases of lead encephalopathy would dis- close evidence of abnormality in a great majority of patients presenting no subjective disturbances of vision. Reference has already been made to the observation of retinal artery spasm during attacks of lead colic. Symptoms dependent upon disorders of the extrinsic or intrinsic muscles of the eye are considered elsewhere. There may be paralysis or spasm of single or several muscles of the eye. Particularly in children, strabismus and nystagmus may occur in association with convulsive manifestations of encephalopathy (Blackman?). According to Legge and Goadby, the exter- nal rectus is the muscle most frequently paralyzed, but others may be af- fected simultaneously. In some instances all of the orbital muscles are involved, with the usual exception of the superior oblique, and there may be ptosis of the upper lid. In general, the prognosis in paralysis of the ex- trinsic eye muscles is poor so far as complete recovery is concerned. Pupil- lary abnormalities and disturbances of accommodation may occur, but are rare. Blindness is the most striking and most important of the subjective mani- festations. It may come on suddenly and be complete in a few minutes or hours and may disappear as rapidly. On the other hand, it may occur gradually, the subject at first being unable to distinguish letters at a dis- tance, with steady progression to complete loss of vision and subsequent gradual improvement to complete recovery. One or both eyes may be affected and blindness may be transitory or permanent, partial or complete. Permanent complete blindness is not common when the onset is sudden, except in children with associated encephalopathy (Gibson; McKhann and Vogt). Rare instances have been recorded of bilateral temporal hemianop- CLINICAL MANIFESTATIONS 125 sia (Elschnig) and homonymous hemianopsia (Posey and Farr; Lewin and Gueillery; Westphal?). There may be scotomata for color and form, color flashes, visual hallucinations and narrowing of the visual field. Care must be exercised in eliminating hysteria as a cause for blindness, disturbances of color vision, temporary hemianopsia and concentric narrowing of the visual fields under such circumstances (Charcot?). The important objective ocular manifestations, in addition to those men- tioned previously, are principally those of hypertensive retinitis (spasm and sclerosis of the retinal arteries, dilation of the veins, edema of the retina and dise, exudative phenomena, retinal hemorrhage), optic neuritis or neuro- retinitis and optic atrophy. Corneal opacity has been observed (L. Lewin'). De Schweinitz described five varieties of visual disturbances in lead poisoning: (1) transient, without demonstrable ophthalmoscopic changes, perhaps due to an anesthetic effect of lead upon the retina and optic nerve, and at times followed by terminal optic neuritis; (2) permanent visual disturbance with slight or no demonstrable objective manifestations, dependent upon retrobulbar neuritis or neuroretinitis; (3) optic nerve atrophy, primary or secondary; (4) optic neuritis or neuroretinitis; (5) va- rious forms of retinitis. The consensus is that transient visual disturb- ances are due probably to ischemia resulting from spasm of the retinal arteries and that permanent disturbances are dependent upon irrevers- ible changes in the vessels, optic nerve or retina or, in rare instances of hemianopsia, possibly to a lesion in the posterior portion of the internal “capsule (Posey and Farr). Gibson saw 45 cases of optic neuritis in lead poisoning in 15 years and, of 64 cases analyzed by the ophthalmologist, de Schweinitz, 13 had optic neuritis, 4 neuroretinitis and 17 optic atrophy. During the years 1900-1909, 24 instances of optic neuritis were reported in 6762 cases of plumbism in Great Britain. Edema or choking of the disc may be of extreme grade, with or without loss of vision (Gibson) and this phenomenon, occurring in conjunction with headache, vomiting, vertigo, convulsions and disturbances of speech and mentality, may cause difficulty in differential diagnosis from brain tumor (Elschnig). Hemorrhages have been observed in the conjunctivae (Legge and Goadby). Temporary blind- ness or temporary scotomata may also result from retinal hemorrhages, which may be resorbed with subsequent restoration of vision. The same is true of mild grades of optic neuritis, neuroretinitis and atrophy. The prognosis with regard to restoration of vision in cases of blindness naturally depends upon the nature of the underlying or associated morpho- logic changes. The extreme variability of the subjective and objective manifestations, as indicated above, renders impossible any generalization in this regard. The outlook is better, of course, in cases without ophthal- moscopic changes than in those with demonstrable damage, but, even in 126 LEAD POISONING the former, permanent blindness may result from progressively increasing retrobulbar neuritis, optic neuritis or optic atrophy, which may not be detect- able in the early stages of these conditions. There is no consistent rela- tionship between the rapidity of onset or the original extent of the disturb- ance of vision and the course which it takes subsequently. However, Gibson states that total blindness usually occurred eventually in children with a very acute onset of edema of the optic dise, particularly in those cases which also showed paralysis of the extrinsic muscles of the eye. The prog- nosis is poor as regards complete recovery in cases of external ocular palsy. Paralysis Paralysis (palsy) is one of the most important as well as the most definite of the objective manifestations of chronic lead poisoning. Although the clinical features of lead paralysis may vary considerably, in the majority of instances it presents certain peculiarities which are of considerable impor- tance from the standpoint of diagnosis. This condition was recognized by the ancients and was described in 1656 by Stockhusen and subsequently by several other observers (Aub et al.). Perhaps the earliest thorough clinical description is that presented in the treatise by Tanquerel. The incidence of lead palsy has varied considerably in different reported series of cases. Tanquerel encountered 112 instances in 1493 cases of lead poisoning (7.5%). Paralysis was present in 21.19, of 6762 cases of lead poisoning reported in Great Britain during the years 1900-1909. Hamilton! suggests that this excessively high incidence may be due to the long duration of paralysis in many patients, resulting in the reporting of the same case several times. Teleky" ® encountered 40 instances (53 attacks) in 1336 cases of lead poison- ing during the years 1905 to 1909 (3.97%). Prendergast reported the oc- currence of palsy in 579%, of men and 309%, of women in a group of 640 cases of lead poisoning in a pottery district in Great Britain, and Thomas reported 30 instances in a group of 54 patients with plumbism seen at the Johns Hopkins Hospital. Chyzer saw 114 instances of paralysis in a series of 996 cases of lead poisoning encountered among pottery workers in Hungarian homes (11.49). Fortunately, the incidence of this serious disabling com- plication has decreased considerably in recent years as a result of improve- ment in working conditions in lead industries. It is noteworthy that, in striking contrast to the relative incidence of encephalopathy (p. 118), lead palsy occurs much less frequently in young children than in adults and is more common and usually more severe in men than in women. Certain other factors, such as alcoholism and the relative degree of physical exertion or muscular work, may be of importance in re- lation to this variation in age and sex incidence. The absence of a close, consistent relationship between the development of palsy and the duration CLINICAL MANIFESTATIONS 127 of exposure to lead has been well illustrated by data reported by Tanquerel. In his series, paralysis developed during the first month of exposure in 9 cases, after 1 to 12 years in 24, after 12 to 20 years in 20 and after more than 20 years in 8 instances. If one includes weakness of certain muscle groups as evidence of the same lead effect which, in more advanced degree, pro- duces paralysis, the incidence of this manifestation of lead intoxication is increased considerably, For example, Teleky? found decrease of power in the extensor muscles of the hand in 17.49, of 711 lead workers without ob- vious subjective symptoms and in 529, of 26 patients with frank lead poi- soning. Although palsy may occur as the only manifestation of lead intoxication, it is usually preceded or accompanied by other evidences of this condition; for example, colic had been or was present at the time in 629, of the cases studied by Tanquerel. As has been pointed out in the discussion of the pathologic physiology of lead palsy, one of the important if not indeed the most fundamental effect of lead in this connection is to interfere with the process of resynthesis of | phosphocreatine. On this basis, it would be suspected that muscular fa- tigue should play an important part in predisposing to the development of weakness and paralysis in subjects with lead poisoning. There is abundant clinical evidence that this is the case and that, as will be indicated below, one of the characteristic peculiarities of lead palsy is the preferential in- volvement of muscle groups subjected to the greatest strain in the particu- lar occupation engaged in each instance. Although lead paralysis can occur in the absence of unusual muscular exertion, fatigue appears to be the most important factor in determining the occurrence and localization of this phenomenon. Other important predisposing factors are alcoholism and vitamin B; (thiamin) deficiency, which may of themselves produce a pe- ripheral neuropathy and thus enhance the toxic effect of lead upon the neu- romuscular apparatus. The fact that lead paralysis occurs more commonly in adults than in children and in males than in females, differing in this respect from certain other manifestations of lead intoxication, notably en- cephalopathy, may possibly be related to the aforementioned factors of muscular fatigue and alcoholism. In rare instances the sudden appearance of evidences of paralysis following injury suggests that trauma may act as a predisposing factor (Windscheid; Schlapp). There may be no premonitory symptoms, but in the great majority of instances the onset of palsy is preceded, for varying periods of time, by evidences of abnormality in the region involved subsequently. Usually the earliest and most common of these is weakness of the affected muscles, which become fatigued readily and prematurely. Tanquerel described a sensation of heaviness in the limbs, which seem cold and stiff, especially in the morning. There are at times painful cramps in the affected muscles 128 LEAD POISONING and fine or coarse tremors, which may be of the intention type, i.e., aggra- vated by voluntary movement of the affected muscle groups. Pain and tenderness of the muscles are occasionally observed, the former being at times of an arthralgic or neuralgic nature; however, there is practically never tenderness over the nerve trunks and pain is not referred to the dis- tribution of specific nerves, being usually related rather to periarticular structures and muscles (Legge and Goadby). There are sometimes dis- turbances of sensation over the affected areas, including numbness, tingling, formication, anesthesia, analgesia, and rarely, hyperesthesia. The latter is practically never observed except in association with cerebral manifesta- tions. Chronaximetric studies have been employed in an attempt to ob- tain early objective evidence of lead upon the neuromuscular mechanism. Chronacxie is a measure of the irritability of a conduetive tissue in terms of time of reaction, when currents of known intensity are employed. By this procedure, prolongation of the reaction time is interpreted as indicative of diminished neuromuscular irritability. According to L. Lewy, such changes occur only after some months of exposure and do not return to normal, even after periods of years of freedom from exposure to lead. These observa- tions, as well as those of Schuetz, suggest that chronaximetric measure- ments are of value in the diagnosis of neuromuscular damage due to lead. However, the consensus appears to be that this procedure is not very use- ful in the detection of impending damage. Moreover, abnormal findings, when obtained in subjects exposed to lead, must be evaluated in the light of other manifestations of lead intoxication or abnormal lead exposure (urine and blood lead concentrations, hematological findings, ete.). Paralysis may occur in acute lead poisoning but it is typically a feature of chronic plumbism. It may occur suddenly, i.e., spontaneously or fol- lowing coma, but usually develops gradually. It varies in severity from slight weakness, noticeable only during muscular exertion or demonstrable by objective measurements, to total loss of power. Although single or several muscle groups on one side of the body are usually affected primarily, those on the other side are almost invariably involved eventually, although frequently to a lesser degree. Weakness or paralysis beginning in one mus- cle group may remain localized in this situation or may extend to involve eventually almost the entire body. This is rare, however, and the muscles of the head and neck almost invariably are not affected. One of the char- acteristic features of lead palsy is the preferential involvement of certain muscle groups. Of 112 cases reviewed by Tanquerel, the upper extremities were involved in 97 cases and the lower in 15; loss of power in the legs with- out palsy of muscles in the upper extremities occurred in only 5 instances. The distribution of the paralysis was as follows: generalized in the upper extremities, 5 cases; shoulders 7; arm 1; arm, forearm, wrist, fingers 4; fore- CLINICAL MANIFESTATIONS 129 arms, wrists, fingers 26; wrists 10; legs 5; fingers 30; intercostals 2; dorsal muscles, pectorals, sternocleidomastoids 1; abdominal muscles 5; vocal cords 16; legs and arms 10; legs 5. According to Legge, in 781 cases re- ported in Great Britain during the years 1904 to 1909, both forearms were involved in 63%, of instances, the right forearm in 139, the left forearm in 4.59, fingers in 4.5%, arms and legs in 99, and the legs alone in 49. In 606 cases of paralysis or weakness reported in Great Britain during the years 1910 to 1914, the distribution was as follows (Biondi): both forearms, 519; right forearm, 129; arms and legs, 8%; left forearm, 6%; legs, 5%; fingers, 4%. Chyzer observed involvement of the lower extremities one- tenth as frequently as the upper, and his series, as pointed out by Hamilton, is practically confined to potters, whose work includes turning a wheel by foot-pressure. In 30 cases reported by Thomas, both arms were involved in 18, the right arm alone in 7, the left arm alone in 1, and arms and legs in 4 instances. In 22 cases of lead palsy observed by Hamilton in 1910, the wrists were involved in 5, wrists and ankles in 13 and the legs alone in 4 instances. As she points out, it is important to note, in connection with the relatively high incidence of involvement of the lower extremities in this series, that these subjects were unskilled laborers whose work involved such processes as lifting, shoveling, trucking and dumping. The tendency toward localization of lead palsy in overused and fatigued muscle was noted by several early clinicians (Meyer; Weill; Vierordt; Moe- bius!). The fact was also noted that the distribution of palsy was related to the functional grouping of muscles rather than to their nerve sup- ply (Remak). As stated by Aub and his associates, through the work of Edinger, the observation regarding the occurrence of paralysis in fatigued muscles is the most important single clinical contribution to the understand- ing of the pathogenesis of lead palsy. His theory of exhaustion of overused muscles, based largely upon observations of paralysis in painters, was soon substantiated by Teleky’, who, in an analysis of atypically localized palsies in subjects engaged in a variety of occupations, made a careful study of the relation of the muscular movements required by the occupation to the mus- cles involved in the paralytic processes. The observations and conclusions of these authors may be summarized as follows (Hamilton!): work which requires exactness makes unusual func- tional demands upon the long extensor muscles of the fingers and extensors of the wrist and the small muscles of the fingers and the thumbs. The powerful flexor and supinator muscles of the arms are admirably constructed for the performance of heavy work, such as lifting, pulling and carrying, whereas the extensors of the fingers and wrists, which participate to only a slight extent in the performance of heavy work, are correspondingly weak and slender. However, it is the latter muscles that are called upon largely 130 ' LEAD POISONING in the performance of fine work in which workers in the majority of lead industries or in occupations entailing exposure to lead are engaged for con- siderable periods of time (painters, printers, plumbers, potterers, molders, ete.). To quote Hamilton: Throughout the ages man has had to perform chiefly coarse, heavy work, such as lifting, carrying, pulling and heaving, and his muscular system is adapted to this. Such work calls upon the long finger flexors of the arm and supinators, in grasping, while the extensors have little to do. In fine work, on the other hand, the extensors are in continual use to offset the flexors and to adjust the finger movements, and they, with the small muscles of the hand, have only about one-quarter of the bulk of the flexors. The intrinsic muscles suffer less than the extensors from overuse, because, being shorter, their physical relation to their points of attachment is much more favorable. Old people have their fingers in flexion, but this is not true of the old in the leisure class or in the class of skilled workers. In typical lead palsy, therefore, the involvement of the long wrist and finger extensors is explained by their relative slenderness, their intrinsic weakness, and their relative overuse, while escape of the supinator, innervated by the same radial nerve, is explained by its bulk and strength and the fact that functionally it belongs with the flexors and is not over-used in fine work. The escape of the small muscles of the hand or their late involvement is ex- plained on the ground of their favorable position with reference to their attachments and by the fact that they work partly in conjunction with the powerful flexors. The long flexor of the thumb is bulky and is not affected. The extensor, although it is feeble, is little if at all affected because it is helped by the powerful abductor, while the thenar muscles are affected by fine work because such work calls upon the op- ponens and the short flexor and short abductor The extensors of the fingers suffer much more than those of the wrist, but the index is not involved as much as the other fingers unless it has had to work harder than they, for it is stronger. The little finger, especially on the left hand, is also less affected, not because it is stronger but because it is so little used. In all advanced cases of this form of lead palsy the right thumb is involved less often than the left. Atrophy of the interossei is rare and usually involves only the first interossous space. There are numerous observations of atypical localization of lead paraly- sis in cases in which an unusual strain is placed upon certain groups of mus- cles. Teleky! pointed out the fact that in painters the shoulder muscles are frequently affected if the conditions of employment involve the necessity of raising the arms above the head to an unusual extent. Thomas reported an instance of palsy of the right leg alone in a painter who had worked all day in a squatting position. Hamilton! remarked that whenever the nature of the work is less precise and more varied the paralysis is more widespread in distribution. If the work requires much lifting, as in lifting pottery, paralysis of the shoulder muscles occurs more frequently than in the wrists. She also quotes the superintendent of a lead works as stating that he had observed that “men who worked with their hands developed wrist drop, those who carried loads on their shoulders developed palsy of the shoulders and those who did an unusual amount of walking developed ankle drop.” CLINICAL MANIFESTATIONS 131 Moebius was the first to point out the peculiar localization of paralysis in file makers in the thumb and finger muscles of the left hand, which is the one in which the chisel is grasped firmly in the process of file cutting. Teleky! reported an instance in which palsy was confined chiefly to the index finger in a type-finisher who held the type between the index finger and the thumb while filing them smooth, and other observers have reported instances of pure ulnar nerve paralysis in type-polishers who drew the type over the file in a motion always toward the ulnar side. Oli- ver? found that only the muscles of pronation of the right hand were affected in a street-lamp lighter with lead palsy. Chyzer found an unusually high incidence of paralysis of the lower extremities in potters who turned the potters-wheel by foot pressure. It has been observed frequently that in children with lead palsy the lower extremities are involved much more fre- quently than in adults and, indeed, more frequently than the upper extrem- ities. This is explained as due to the relatively greater strain on the legs than on the arms in childhood. Manouvrier reported an instance of iso- lated palsy of the fourth and fifth fingers in a man who pressed lead cap- sules over the tops of bottles, always making the final pressure with these two fingers. These and large numbers of similar observation substantiate the view that overuse and fatigue are perhaps the most important factors in determining the localization of lead paralysis. The several distributional varieties of lead paralysis are commonly clas- sified into several groups, according to the function of different muscles rather than to their anatomical relationship or nerve supply. The classi- fication suggested by Dejerine-Klumpke, in 1889, is the most generally recognized at the present time: (7) antibrachial type (Dejerine-Klumpke; Remak), the most common variety, with the characteristic ‘“wrist-drop” due to paralysis of the extensor muscles of the wrist and fingers; (2) the brachial type (Remak), in which the muscles affected are those of the Du- chenne-Erb group, i.e., the deltoid, biceps, brachialis anticus and supinator longus and, occasionally, others; (3) the Aran-Duchenne type, in which the muscles of the thenar and hypothenar eminences and the interossei are affected; (4) the peroneal type, with involvement particularly of the per- oneal muscles and the extensors of the toes; (4) paralysis of the muscles of special sense organs, particularly the larynx. These varieties are stated in order of the frequency of their occurrence in collected series of cases of lead poisoning but, as indicated above, the incidence of each type varies con- siderably in different occupations in accordance with the nature of the mus- cular effort entailed in each instance. Moreover, these types may, of course, be present simultaneously. Many cases have been observed that do not conform to any of these classical types, and many bizarre forms of paralysis have been reported in patients with lead poisoning. 132 LEAD POISONING Antibrachial Type. In its typical form, this produces the so called “wrist- drop,” with ventral flexion of the wrists as the result of paralysis of the extensor muscles and unopposed action of the flexors, the fingers being also somewhat flexed as a result of paralysis of their long extensor muscles. The extensor communis digitorum is usually the first muscle affected, resulting in dropping or flexion of the middle and ring fingers while the index and fourth fingers may still be extended because of the presence of separate extensor muscles to those digits. In this stage, dorsiflexion (extension) of the wrists cannot be accomplished while the fingers are extended, and attempts to doso result in flexion of the first phalanges of the fingers, particularly the middle and ring fingers. The same phenomenon follows attempts at passive flexion when the hand is supported (Hamilton). A very early stage of paralysis of the long extensors of the fingers may be revealed by this test (Hamilton). However, if the fingers are flexed, partially or completely, the wrists can be extended. In more advanced stages the latter is impossible because of involvement of the extensors of the wrists. The palsy may be limited to the extensor communis digitorum, but it usually progresses, the sequence of involvement being generally as follows: the extensors of the index and fourth fingers, the long extensor of the thumb and the extensors of the wrist. Later, the interossei may become affected and, at times, the long abductor of the thumb. In a typical case of advanced paralysis of this variety the hand is in a position of semi-pronation and, when it hangs down, forms a right angle with the forearm, the fingers being slightly flexed, with the thumb directed toward the palm and the hand deflected to the ulnar side, being unable to pass the median line in the other direction (Legge and Goadby.) Although the long abductor of the thumb is rarely involved early, instances have been reported in lead-capsule polishers in which this muscle was the only one affected. A feature of great importance is the almost invariable absence of involvement of the supinator longus, which has the same nerve supply as the affected muscles. The condition is almost always bilateral, although it may begin at first on one side and appear on the other after a few days or weeks. The paralyzed muscles undergo progressive atrophy and there is reduction or loss of response to faradic and, to a lesser extent, to galvanic stimulation. In advanced cases there is the characteristic reaction of degeneration. Atrophy, twitching and tremor of the affected muscles occur frequently. Brachial Type of Paralysis. This type of palsy affects the muscles of the so called “Duchenne-Erb” group, including the deltoid, biceps, brachialis anticus and supinator longus, usually also the supra- and infraspinatus muscles and rarely the pectoralis major. The deltoid is usually most mark- edly involved and is at times the only muscle affected. This variety of lead paralysis is usually seen in conjunction with other forms but may be CLINICAL MANIFESTATIONS “133 present alone. It occurs particularly in occupations which involve heavy lifting or raising the arms above the shoulders. In an advanced case of this type, which is essentially a deltoid-biceps-supinator palsy, the arm hangs by the side with the forearm in a position of semi-pronation, the arm cannot be abducted, the elbow cannot be flexed and supination is impossible. If the supra- and infraspinatus muscles are involved, rotation of the shoulders is affected. Atrophy, twitchings and tremors and abnormal electrical reactions occur as in the case of the antibrachial type of palsy. Aran-Duchenne Type of Paralysis. This consists in atrophy, with weak- ness or paralysis of the thenar and hypothenar eminences, the interossei and the other small muscles of the hands. The atrophy is usually extensive, producing the so-called “simian” hand. This variety may occur alone, as has been reported particularly in file cutters (Moebius! 2), but is usually seen in association with antibrachial paralysis. Peroneal Type of Paralysis. Paralysis of the lower extremities occurs infrequently in adults except when-the conditions of occupation place an unusual strain upon these muscles, as mentioned previously. In the great majority of instances the upper extremities are also involved and, as in the case of the latter, the condition is usually bilateral. In children, on the other hand, paralysis of the lower extremities occurs much more commonly than in adults and, frequently, in the absence of involvement of other muscles. The muscles most commonly affected are the lateral peroneal muscles, the common extensor of the toes and the extensor of the great toe, i.e., muscles analagous to those involved in the antibrachial type of palsy. Rarely, the tibialis anticus and the gastrocnemii are involved alone or in association with the muscles mentioned above; this occurs more frequently in children than in adults. Occasionally, the small muscles of the feet and, rarely, the thigh muscles are included in the process. In an advanced form of this type of lead palsy, the patient walks on the lateral borders of his feet, cannot stand on his toes and has difficulty in climbing stairs. The gait is uncertain and the toes drag on the ground in walking so that the foot has to be swung around at each step and the medial borders lifted by action of the tibialis anticus. Dorsal flexion of the foot, abduction of the foot and extension of the basal phalanges of the toes cannot be accomplished. Walking is difficult and, if it is continued, the toes drag more and more and a characteristic stepping gait is assumed by bringing into action the muscles of the thigh (Legge and Goadby). The patellar reflex may be increased, normal, diminished or absent. Localized paralysis may occur occasionally in other situations. Laryn- geal paralysis has been observed, the muscles most commonly affected being the abductors, with consequent aphonia, less frequently the abductors, with inspiratory dyspnea and, rarely, the transverse and oblique arytenoid 134 LEAD POISONING muscles. The extrinsic muscles of the eyeball may be affected, the external rectus most commonly, but cases have been reported of complete ophthal- moplegia with the exception of the superior oblique. There may be com- plete or partial paralysis of the ciliary muscles, with inequality of the pupils and loss of accommodation. Localized involvement of cranial nerves has also affected the optic, abducens and facial nerves. Such involvement, however, is usually accompanied by manifestations of encephalopathy. Occasional instances have been observed of rapid or gradual extension of the paralysis from its primary peripheral localization to eventual involve- ment of the muscles of the back and limbs, the intercostal muscles and even the diaphragm. Deaths have been reported from asphyxia resulting from paralysis of the muscles of respiration. As a rule, the muscles of the head and neck appear to escape involvement even in extreme cases in which the subject may be unable to rise or even to eat. In the acute form, complete palsy of one or more limbs may develop within a few days, but such cases are rare. Cases have been reported that resemble polyneuritis, with severe pain and tenderness, rapid wasting of muscles, fibrillary twitching and tremors and paralysis (Oliver?). Collier quotes Gowers as stating that a condition resembling progressive muscular atrophy may be caused by lead, differing from that condition, however, in that the process does not progress after removal from exposure to lead. There may be nervous manifestations of cerebral vascular accidents (thrombosis, hemorrhage) resulting from or associated with hypertension and arteriosclerosis, including transitory or permanent monoplegia, hemi- plegia or paraplegia. Oliver? refers to cases which simulate vascular cere- brospinal syphilis, frequently with unilateral manifestations such as paralysis of one hand, one foot, or the external muscles of one eye-ball or limited loss of power of one or more extremities. Instances have been re- ported in patients with apparent lead poisoning of symptoms indicative of involvement of various portions of the spinal cord. Various authors have observed the clinical picture of diffuse anterior poliomyelitis (Dejerine- Klumpke; Putnam! ?), spastic paraplegia (Bechtold; Eichhorst), amyo- trophic lateral sclerosis (Putnam!' 2; Mitchell; Oliver®), postero-lateral sclerosis or tabes (Putnam!: 2; Thomas) and cerebellar ataxia (Kraffczyk). Other instances of generalized cord involvement have been reported by Shattuck. Hamilton! cites a fatal case simulating ascending paralysis, with progressive involvement of the forearm, tongue, pharynx and larynx and with clouded mentality. The reflexes have been described as increased, decreased and absent, and Babinski’s sign, ankle clonus and patellar clonus have been observed in certain of these cases. Cone, Russel and Harwood reported several cases of apparent multiple sclerosis in which lead was incriminated as the etiologic agent because of the finding of lead in the CLINICAL MANIFESTATIONS 135 cerebrospinal fluid. However, no quantitative estimations were made and the etiological significance of lead in these cases seems to be highly questionable. In fact, as stated by Aub and his associates, in most of the reported cases in which the clinical picture suggested the presence of a generalized cord lesion there is far from sufficient evidence that these changes were due to lead poisoning. Nevertheless, the possibility cannot be denied that manifestations of spinal cord damage may be dependent upon lead poisoning in view of the abundant evidence of a great variety of lesions in the central nervous system in clinical and experimental plumbism. There may be evidences of disturbance in the sympathetic system, particu- larly the vasomotor mechanism, such as unusual pallor of the skin and, frequently, cyanosis of the skin of paralyzed extremities. Sensory Disturbances. Hyperesthesia over the subsequently affected area may precede paralysis. Schmidt-Kehl, in his observations on self-induced lead poisoning, noted paresthesia at times before the development of manifest nervous disturbances of other types. There may be patches of anesthesia and analgesia over the paralyzed areas, particularly over the inner and pos- terior aspects of the forearm and legs (Oliver®), and corneal anesthesia has been observed (Flury?). There are occasionally complaints of a sensation of heaviness in the limbs and pain in the muscles and joints, tenderness being at times elicited in the muscles but rarely along the nerve trunk. Muscular pains may precede the paralysis but usually do not remain severe after the latter has occurred, except in cases of paralysis of the lower extremities (Oliver?). Loss of sense of taste, smell and hearing has been reported, but this occurs rarely if ever in the absence of generalized paralysis or of evi- dence of lead encephalopathy. The latter may be accompanied by hemi- anesthesia, and in such cases great care must be exercised in eliminating the possibility of hysteria as a causative factor. Course and Prognosis. The temperature is usually normal in uncompli- cated cases of lead paralysis, except in those unusual instances of rapidly progressive, generalized palsy, in which the frequent occurrence of fever may cause considerable difficulty in differential diagnosis from anterior poliomyelitis. As stated previously, any type of change in reflexes may be observed. According to Jones, the reflexes are usually increased during the first attack of lead palsy and are usually decreased during relapses or subsequent attacks. Exaggerated tendon reflexes may be due to changes in the upper motor neurone but may be due also to weakness of the muscles that normally oppose contraction of the stimulated muscles. This is particularly true in the case of the patellar reflex inasmuch as the quadriceps group is seldom involved in lead paralysis. The extreme variability of the course of lead palsy has already been 136 LEAD POISONING indicated. In general, the condition tends to improve, even to the point of complete recovery, following removal from exposure to lead and the institution of proper therapeutic methods. Complete recovery from total palsy has been observed to occur within less than two weeks; on the other hand, weakness may persist for years. In the average case, the prognosis appears to be related to the duration, extent and intensity of the paralysis and the associated atrophy. In fresh cases improvement usually begins within a few weeks and progresses to complete or almost complete recovery in a few months. If further absorption of lead is prevented as soon as paralysis develops, complete recovery usually occurs, although the rapidity of improvement varies considerably (Aub et al.). In cases of long standing, improvement is usually slow; if the palsy is severe, complete recovery is not common and in some cases there may be little or no tendency toward improvement. Nevertheless, complete restoration of function has been observed even in cases of paralysis of long standing. It is interesting that, as a rule, the muscles first affected are the last to recover (Aub). The capacity for voluntary contraction generally begins to return before the normal reactions to electrical stimulation reappear (Legge and Goadby). The outlook is bad in cases in which atrophy persists and there is progres- sive decrease or loss of response to electrical stimulation. In protracted paralysis with extensive atrophy, contractures often develop as a result of the action of unaffected opposing groups of muscles. As is true of other manifestations of lead intoxication, relapses may occur without further exposure to lead. The development of lead palsy has been observed as long as 17 years after the last known exposure to lead (Oliver?; Tanquerel; Thompson; Larzell; Hamilton!). In such cases the condition may be precipitated by factors which enhance the mobilization of stored lead, such as acute and chronic infections, post-operative acidosis, alcoholism, fractures, administration of iodides, ete. Death has occurred in occasional cases of lead palsy, usually of the acute, rapidly progressive and spreading variety, due to intercurrent infection or to respiratory dif- ficulty resulting from paralysis of the larynx, diaphragm and other muscles of respiration. In cases with extensive.cord involvement there may be paralysis of the bladder and rectum, with subsequent urinary tract in- fection. Cerebrospinal Fluid Changes have been found in the cerebrospinal fluid in some cases of lead encephalopathy that have led to the view that this condition may be in reality a meningoencephalopathy or perhaps a true meningitis rather than an encephalopathy (Aub, Fairhall, Minot and Reznikoff). The most constant finding has been an increase in pressure, at times to as high as 600 CLINICAL MANIFESTATIONS 137 to 700 mm, of water, lymphocytic pleocytosis and an increase in proteins (Mosny and Malloizell': 2; Norton; Boveri; Troisier; Mass; Strong; Suzuki and Kaneko; Thomas and Blackfan; Blackman?; McKhann and Vogt). The fluid is clear and colorless and, whereas Mosny and Malloizell found the average cell count to be 100 per cu.mm., the highest count reported by Blackman? was 60 and the experience of the majority of observers indicates that pleocytosis occurs only occasionally and is usually of slight degree. Mass cited a case of so-called ‘“‘serous meningitis” due to lead poisoning in which the enormous increase in the quantity of cerebrospinal fluid resulted in a marked degree of hydrocephalus. The available evidence appears to indicate that the increased quantity of protein and increased number of cells are derived from perivascular exudate in the meninges rather than from a diffuse inflammatory reaction. Data regarding the concentration of lead in the cerebrospinal fluid are presented elsewhere (p. 165). Tetraethyl Lead The clinical manifestations of acute poisoning with tetraethyl lead are referable chiefly to the central nervous system. This substance is widely employed to eliminate the knock or detonation in internal combustion engines, being marketed in the form of “ethyl fluid”, a mixture of 60— 759 of tetraethyl lead with a solvent. This fluid is usually added to gasoline in a proportion of 1-1260 to 1-4000. The present consensus is that lead poisoning will not result from the use of leaded gasoline as it is usually handled commercially (Machle?, Sayers et al.; Leake; Kehoe and Thamann?; Kehoe, Thamann and Cholak??). As stated by Machle?, there have been numerous reports of lead poisoning caused by handling motor fuel containing tetraethyl lead, but careful investigation has established the fact that plumbism was not a factor in the production of illness in any instance. The hazard in connection with this agent is limited to the manufacture of tetraethyl lead and the anti-knock mixtures, the mixing of these substances with gasoline and the cleaning of tanks in which leaded gasoline has been stored (Machle?). In view of certain rather peculiar features of poisoning with the agent, it seems advisable to consider it separately from other forms of lead poisoning. Eldridge was able to produce acute intoxication in dogs by the applica- tion of tetraethyl lead to the skin of the abdomen and concluded that this substance is comparatively stable, highly lipoid-soluble and capable of penetrating the intact skin, being probably the only compound which, absorbed through the skin, causes lead poisoning. Symptoms in the dog include acute intestinal colic, followed by diarrhea, with abdominal tender- ness and rigidity, then depression, weakness of the legs, tremors, con- vulsions, coma and death. Inhalation of tetraethyl lead by mice resulted 138 LEAD POISONING in excitement, followed by depression, collapse, tremors, convulsions and death. The neurologic effects appear to be due to (I) stimulation of the central nervous system, particularly the medulla and higher centers and (2) stimulation of the central motor nerve mechanism. There also occur an extreme fall in blood-pressure, apparently of central origin, slowing of the pulse, increased intestinal peristalsis, and changes in the respiration, which is first slowed and later accelerated and deepened (Hamilton). Autopsies on dogs dying in acute poisoning showed acute inflammation of the small and large intestines, with numerous clean, punched-out ulcers, chiefly in the region of Peyer’s patches. There was mild congestion of the kidneys. Lead was present in the urine, feces, skeleton, liver, lungs and intestines, by far the largest amounts being present in the skeleton (Eldridge). The following findings were obtained in four fatal human cases (Norris and Gettler): yellowish discoloration of the skin; hemorrhagic foci in the bone- marrow; intense pulmonary congestion with scattered areas of pneumonia; generalized visceral congestion, with the exception of the liver; cerebral congestion and thrombosis; lead was found in the brain in non-volatile form. All of the organs, including the blood, contained lead, the brain (15.84-28.19 mg.), liver (30.53-61.47 mg.) and lungs (2.25-6.71 mg.) unusually large quantities and the skeleton relatively small amounts as compared with the findings in the usual forms of lead poisoning. The high content in the brain is attributed to a specific attraction of the brain tissue for this form of lead. Clinical poisoning occurs as a result of inhalation of tetraethyl lead or its absorption through the skin. As stated by Kehoe, Thamann and Cholak?*?, the symptoms of this condition differ from those of the great majority of cases of ordinary lead poisoning because this compound is extremely rapidly absorbed and, being readily soluble in fats, becomes concentrated in the central nervous system and the liver (Kehoe and Thamann?®). Very acute, fatal cases present the following picture (Thompson and Schoenleber): Marked hypothermia; bradycardia; manifestations of nervous system stimu- lation, including persistent insomnia, marked restlessness, talkativeness, delusions and ataxia, followed by exaggerated muscular movements and violent, destructive mania, all of these symptoms being apparently ac- centuated by morphine; death usually ensues in exhaustion, occasionally with marked pre-agonal rise in temperature. Eldridge reported the follow- ing symptoms, in order of incidence, in a series of 28 cases of tetraethyl lead poisoning: insomnia (28), hypotension (20), hypothermia (19), anorexia and nausea (18), weakness (16), abdominal cramps (12), unaccustomed and annoying dreams (11), vertigo and morning vomiting (11), headache and loss of weight (7), and, occasionally, tremors, metallic taste in the mouth, lead line in the gums and pruritis. In cases with slight and brief CLINICAL MANIFESTATIONS 139 exposure, there are usually insomnia, anorexia, mild hypotension and hypothermia, basophilia and, occasionally, leukocytosis and a lead line in the gums (Kehoe et al.??). With longer and more severe exposure, the symptoms occur in the following order (Kehoe et al.2:3): Insomnia, with restlessness and excited dreams; anorexia, nausea and vomiting, especially in the early morning, with a sickening taste which increases; aversion to breakfast; vertigo and headache; muscular weakness. The physical signs include marked pallor, out of proportion to the degree of anemia, hypo- tension, with a relatively low diastolic pressure, hypothermia, particularly marked in the early morning, loss of weight, coarse tremors, exaggerated reflexes and muscular hyperirritability, muscle twitchings, bradycardia and increased respiratory rate (Kehoe and Thamann®). In one fatal case there was a marked alteration in the red blood cells, with a loss of coagula- bility of the blood, which had a cherry-red color similar to that of carboxy- hemoglobin. Convalescence from severe attacks is usually slow, lasting several weeks or months, and there may be residual central nervous system damage. Chronic poisoning with tetraethyl lead can occur, and may present manifestations identical with those of chronic plumbism due to other lead compounds. This is unusual, however, and it must be emphasized that in acute or subacute poisoning with this agent many of the characteristic manifestations of lead poisoning may be absent, such as intestinal colic, constipation, lead line in the gums, anemia, basophilia and reticulocytes, and albuminuria. The diagnosis must be based on (a) the history of ex- posure to tetraethyl lead, (b) the symptoms and signs outlined above and (c) the presence of lead in abnormal quantity in the urine and blood (Kehoe). CHAPTER VI CLINICAL MANIFESTATIONS (Continued) BONES AND JOINTS Tanquerel noted the frequent occurrence of arthralgia in patients with lead poisoning, the pain being apparently in the muscles and joints. He stated also that no gross abnormality of the joints could be detected that might be responsible for this complaint. The majority of authorities are in agreement regarding both the frequency of “rheumatic” or arthralgic pains in subjects with chronic plumbism and the lack of definite informa- tion as to their cause. There is no substantial evidence that they are due to neuritis or arthritis or to other demonstrable morphologic bone changes. Legge and Goadby believed that these pains may be due to minute hemor- rhages in the muscles, but this lesion has not been demonstrated con- sistently and it appears more probable that they are dependent upon or associated with the existing functional abnormality in the muscle resulting from the effects of lead upon the chemical phenomena of muscular con- traction. According to Legge and Goadby, these pains are present in about 10.5% of subjects with lead poisoning. Wright states that indefinite pains in the muscles are common and calls attention to the usually early occurrence of pain in the joints, especially the knees and elbows. Ac- cording to this author, bursitis is a rather frequent complication of lead poisoning. The well-established fact that the skeleton constitutes the most important site of storage of lead in the body has led to careful investiga- tion of the possible effect of the stored lead upon the structure and function of the bones. Although there are isolated observations of the extension of inflammation or ulceration of the gums to the adjacent bones, leading to a rarefying osteitis (Legge and Goadby), and an occasional suggestion that lead can cause necrosis of bone (Leivy), the bulk of evidence indicates overwhelmingly that the deposition of lead in the bones causes no signifi- cant change in their structure and that the stored lead, as long as it remains in this situation, is harmless (Aub, Fairhall, Minot and Reznikoff). The relation of chronic lead poisoning to the development of gout is of particular interest. This relationship was so generally recognized by early authorities that it led to the employment of the designation “saturnine” gout (Legge and Goadby; Oliver; Hubner; Brouardel; Magnus-Levy; Luthje? ; Thomp- son). According to Garrod!, gout is common in painters, but Goadby believed that the etiologic significance of lead in this connection is question- able inasmuch as the incidence of gout is much lower in other occupations 140 CLINICAL MANIFESTATIONS 141 equally as hazardous as that of painting. Hubner described typical gout involving the big toe and other joints and stated that this complication is not uncommon in older subjects and that it occurs even in young men with lead poisoning. Brouardel cited six instances of gout in lead workers, Thompson five cases in 64 subjects with lead poisoning and Magnus-Levy reported 36 cases of gout, 13 of whom had definite lead poisoning while six others were painters with an unusual exposure to lead. Luthje believed that lead can cause true gout, differing from idiopathic gout chiefly in the youth of the subject, the rapidity of its spread, the wider distribution of joint involvement, the greater tendency to form tophi and the generally more malignant clinical picture. The increase in blood uric acid and the alteration in excretion of uric acid are the same as in idiopathic gout (p. 000). In the experience of more recent observers, this complication of lead poison- ing is not nearly as common as it appears to have been formerly (Aub, Fairhall, Minot and Reznikoff). We have seen only one case in which lead could be definitely incriminated as an etiologic factor. The selective deposition of lead in the growing ends of bones (p. 000), is of importance because the demonstration of this deposit by X-ray ex- amination aids greatly in the diagnosis of lead poisoning in children. In the ends of long bones and at the margins of flat bones, zones of increased density appear as a series of transverse lines in the diaphysis immediately below the epiphysis and as linear rings of density in the ossification centers of the epiphyseal cartilages and carpal bones, resembling the changes ob- served in healing rickets (Vogt!?; Caffey; Park, Jackson and Kajdi; McKhann and Vogt). Slowly growing portions of the bones appear normal and the bands of increased density are most conspicuous where growth is most rapid, e.g., at the anterior end of the middle sixth rib, the lower end of the femur, the upper end of the humerus, the lower end of the radius and ulna, and both ends of the tibia and fibula (Park, Jackson and Kajdi). According to Vogt! 2, the intensity and breadth of the bands on the roent- genogram depend on several factors, including the age and size of the child, the duration of exposure to lead and the quantity absorbed. Smaller amounts of lead are more readily demonstrable in the small bones of an infant than in those of a larger child, because the lead, which is very opaque to the x-ray, is concentrated in a smaller area. Since deposition of the lead occurs chiefly along the line of growth, the width of the bands is directly related to the duration of the period of absorption and storage (Vogt! 2). These bands are not specifically diagnostic of lead deposition; a similar x-ray picture may be produced by healing rickets, recalcification following severe demineralization due to nutritional disturbance, storage of other opaque metals, such as bismuth, and the rare condition of “marble bones” (Vogt! 2; Pirie; Phemister). 142 LEAD POISONING RESPIRATORY TRACT Workers in lead industries appear to have a relatively high incidence of diseases of the respiratory tract, particularly chronic bronchitis, emphy- sema, ‘‘asthma’” and, according to some, bronchopneumonia (Flury?; Biondi). Lewy believes that acute paroxysms of asthma may result from inflammation and necrosis of the bronchial mucosa, eventuating in chronic bronchitis. However there is no substantial evidence that lead is capable of causing specific lesions in the tracheobronchial tree or lungs; it is pos- sible that such manifestations, when they occur, are due rather to a non- specific irritating effect of the inhalation of lead or other dusts. Such irritation may lower the resistance of the mucous membrane of the respira- tory passages to infection. Many authors have stated that exposure to lead predisposes to the development of pulmonary tuberculosis (Biondi), but there is no evidence that this relationship is in any way specific. It appears more likely that the development of tuberculosis in lead workers is dependent rather upon the influence of special environmental conditions operating perhaps in conjunction with non-specific irritation of the respira- tory passages by dusts. Paralysis of the vocal cords and of the diaphragm, intercostal muscles and other muscles of respiration occurs occasionally, with the development of severe dyspnea and, occasionally, death from asphyxia (p. 83). GENITAL SYSTEM It has long been known that lead is an active abortifacient, and the frequency of miscarriages, stillbirths and premature births in women lead workers has been recognized since the time of Tanquerel. The literature dealing with this subject has been reviewed by Teleky, Gerbis and Schmidt. Fortunately, this effect of lead is of relatively little practical importance at the present time because of the institution of legislation regarding the employment of women in occupations involving a lead hazard. Menstrual disturbances, such as amenorrhea, dysmenorrhea and menor- rhagia may occur in women exposed to lead (Legge and Goadby). How- ever, the influence upon reproduction is much more striking and important. In a group of 134 pregnancies reported by Deneufbourg, 17% resulted in abortion or stillbirths and, of the live births, 26.19, died within the first year of life. Ganiayre reported only 2 children surviving more than one year out of 19 pregnancies in 4 women with lead poisoning, and Tardieu stated that in France, in 1905, 608 of 1000 pregnancies in lead workers terminated in abortion. Legge cites the following data obtained in 1897 from 77 women lead workers: 15 never became pregnant and 15 conceived but bore no living children; the other 47 women had 21 stillbirths, 90 mis- carriages and 101 living children at birth, 40 of whom died in early infancy. CLINICAL MANIFESTATIONS 143 Thus, 212 pregnancies in this group resulted in 61 living children. Accord- ing to Reid, in 100 mothers exposed to lead there had been 135 miscarriages and stillbirths and 271 deaths under one year per 1000 born; corresponding figures for 100 mothers working in mills with no lead exposure were 47.6% miscarriages and stillbirths and 214 deaths under one year per 1000 born. It has frequently been observed that a woman who has several miscarriages and stillbirths during a period of exposure to lead may subsequently have normal pregnancies after cessation of exposure (Paul). According to Biondi, if a woman is removed from contact with lead at about the third month of pregnancy, the course of the pregnancy may be entirely normal These observations suggest that lead injures only those germ cells which are formed during the period of exposure to this agent (p. 84). There is also some evidence that lead may cause a certain degree of uterine inertia with prolonged and difficult labor (Hall). The passage of lead through the placenta into the fetal tissues has been referred to elsewhere (p. 86), and, if born alive, the child frequently shows evidence of the deleterious effects of lead exerted during the period of intrauterine development. It is often weak and undersized, and there is a high incidence of epilepsy, muscular spasms, convulsions and other nervous disturbances, idiocy and imbecility (Biondi; Meillere?; Prendergast). Hall reported that dentition was delayed in 809, of the offspring of Indian women living in a smelter village. Ac- cording to Rennert, in a village where pottery glazing was done in the homes, a large proportion of children had convulsions and a peculiar form of macrocephaly, with a square-shaped head which developed slowly; this condition was not accompanied by imbecility. About 71% of a group of 79 such children in this village had either macrocephaly or convulsions or both, and the mortality was 50%. In this instance the possibility of absorption of lead after birth must be considered, particularly since signifi- cant quantities of lead may be present in the mother’s milk (p. 40). It is interesting in this condition that Hall found that 22% of the native women in the smelter village mentioned above were unable to nurse their infants because of insufficient lactation, although no difficulty had been experienced before they were exposed to lead. There can be little doubt that exposure of mothers to lead has a damaging effect upon fertility, the course of pregnancy and the development of the fetus. Of much greater practical importance, however, is the question as to whether exposure of the fathers to lead can exert a serious influence in this connection. Whereas data in the German, Italian and English litera- ture appear to indicate that the incidence of miscarriage and stillbirths is excessively high in wives of men working in lead industries, there is a great deal of contradictory evidence, particularly in the American literature. Some observers have reported diminished sperm motility, testicular atrophy 144 LEAD POISONING and diminished spermatogenesis in lead workers (Meillere?; Baader!; Aub et al.; Fraenkel; Pennetti; Peisachowitsch), while others have reported negative findings (Stieve). Paul reported 32 pregnancies in 7 wives of lead workers, only 2 children surviving a few years after birth; there were 12 mis- carriages and stillbirths and, of 20 children born alive, 8 died in the first year, 4 in the second, 5 in the third and 1 after the third year of life. Deneufbourg analyzed a series of 442 pregnancies in the wives of men ex- posed to lead. There were 66 abortions and 47 stillbirths (25.5%) and only 246 survived the first year of life (44.39%, of the total number of preg- nancies). Although statistics such as these appear to be rather striking, many modern authorities doubt the validity of the evidence either of sterility of male lead workers or of damage transmitted through them to the fetus (Teleky®; Hamilton). HEMATOPOIETIC SYSTEM A great deal of attention has been directed toward the study of changes in the blood in lead poisoning. These include anemia, anisocytosis and poikiloeytosis, polychromatophilia, punctate basophilia (stippling), reticulo- cytosis, the appearance of early forms of red-blood cells in the peripheral blood, alteration in the white-blood cell picture and abnormalities of pig- ment metabolism (hyperbilirubinemia, urobilinuria, porphyrinuria). The pathogenesis of these abnormalities has been discussed elsewhere (p. 42ff.). Anemia Laennec was apparently the first to describe an unusual pallor of the tissues and the “thin” blood in autopsied subjects with lead poisoning while, according to Aub and his associates, Andral and Gavarret were the first to record a low red-blood cell count in this condition. Since then, the occurrence of this phenomenon has become generally recognized. Occa- sionally, especially in the very early stages of exposure to toxic amounts of lead, there may be a condition of mild polycythemia, with an increase in both hemoglobin and red-blood cells (Flury?; Kost!; P. Schmidt* 7; Kogan and Smirnowa; Naegeli?; Jones). In one case reported by Kost!, the hemoglobin was 115%, and the red-blood cells were 7,000,000 per cu. mm. P. Schmidt*” believes that this may be due to toxic stimulation of the bone-marrow, while Naegeli? suggested that it may represent a condition of reparative polycythemia (following peripheral destruction of red-blood cells) in addition to primary regenerative stimulation of the marrow. The incidence of anemia in lead workers without clinical manifestations of lead poisoning varies considerably in differently reported series. In a study of 381 such subjects, Mayers recorded the presence of anemia in 719%, aniso- cytosis in 44%, poikilocytosis in 23%, and nucleated red-blood cells in 8%. CLINICAL MANIFESTATIONS 145 The opposite extreme is reporesented by the study of Shie, who, in an investigation of 900 lead workers, found that the great majority had hemoglobin values ranging from 809%, to 100%. In our experience, hemo- globin values below 759%, and red-blood cell counts below 4,000,000 per cu. mm. are rarely encountered in lead workers without clinical lead intoxi- cation in the absence of complicating conditions. The anemia of lead poisoning is practically invariably of the hypochromic variety, the color index being usually below 1.0 and at times as low as 0.59 (Kost!). Biondi states that the hematologic picture of pernicious anemia (macrocytic anemia) is never seen in this condition. Although a drop in hemoglobin is usually accompanied by a parallel decrease in the number of red-blood cells, the former usually precedes the latter and usually slightly exceeds it. However, this parallelism is by no means constant. Schmidt-Kehl, in self-induced lead poisoning, observed a parallel decrease in hemoglobin and red-blood cells at first, while later the red- blood cell count increased during a period of continued fall in hemoglobin. A similar observation was reported by P. Schmidt*”. There have been occasional reports of extreme grades of anemia in patients with lead poison- ing, with hemoglobin values as low as 359%, and red-cell counts less than 1,000,000 per cu. mm. (Legge and Goadby; Matussewitch). Legge and Goadby remarked that the capacity for work is not significantly affected even in the presence of extremely severe anemia. However, the majority of observers believe that marked anemia is rare in clinical lead intoxication; even when severe, hemoglobin values below 709, are seldom encountered (Naegeli?; Kost!; Meyer; Seitz; Kretschmar; Flury?; Shie; Trumper and Cantarow). In the average case of chronic lead poisoning, the hemoglobin ranges between 75 and 809, with the red-blood cells about 4,000,000 per cu. mm.; occasionally the hemoglobin falls to 609, and rarely to 509%. The red-blood cells occasionally fall to 3,000,000 and rarely to 2,500,000 per cu. mm. In cases with more than slight anemia there may be anisocytosis, poikilo- cytosis or microcytosis. Cabot’s ring bodies and Howell-Jolly bodies have been reported (Biondi). According to Jones, in about 59%, of cases the anemia is severe enough to be accompanied by nucleated red-blood cells in the peripheral blood, and Cadwallader reported 26 normoblasts and 23 megaloblasts per 100 white-blood cells in one case with an erythrocyte count of about 3,700,000 per cu. mm. The presence of megaloblasts in the peripheral circulation has been reported (Grawitz!; Hamel) but the validity of this observation is questioned by some observers (Naegeli?; Kost!). Flury? states that all young forms of red-blood cells may be found in clinical lead poisoning. Some believe that a decreased hemoglobin may be the first sign of lead 146 LEAD POISONING poisoning (Legge and Goadby; Matussewitch) and that the degree of anemia is roughly proportional to the severity of the intoxication (Gel- man?). There is very little evidence to support these views and an over- whelming majority of observers maintain a contrary opinion. According to Flury?, evaluation of the significance of anemia in lead poisoning is rendered difficult because it may be only transitory, the hemoglobin and red-blood cells increasing subsequently in spite of the continued action of lead. He suggests that this may be due to diminished stimulation of hematopoiesis or, perhaps, to increased tolerance of this system to the poison. Although in experimental studies the degree of anemia has been regarded as an index of the severity of the poisoning no such regular paral- lelism exists in clinical plumbism (Flury?). As a rule, however, a fall in hemoglobin and red-blood cells of some degree is usually encountered in patients with active chronic lead poisoning. Polychromasia, Punctate Basophilia, Reticulocytosis There is considerable evidence that these phenomena, at least as they occur in lead poisoning, are closely related to one another (Whitby and Britton; McCord, Holden and Johnston), and that they are an index of stimulation of erythropoietic activity in the bonemarrow. Grawitz! and Hamel, who were among the first to report the occurrence of punctate basophilia in lead poisoning, believed it to be a reliable diagnostic feature of that condition. However, as indicated elsewhere, this phenomenon is in no way specifically due to the action of lead, being present in a great number of other conditions, and the large literature which has grown up in connection with its occurrence in lead poisoning deals largely with its diagnostic significance. There has been considerable controversy also re- garding the relative importance of polychromasia, punctate basophilia (stippling) and an increase in reticulocytes in this connection. Then, too, various modifications of staining methods for the demonstration of the basophilic substance have been proposed in an endeavor to render the enumeration of these cells more accurate. Perhaps the most widely em- ployed of these precedures is the so called ‘basophilic aggregation” test of McCord, Minster and Rehm. In this precedure, the red-blood cells in one-half of the blood smear are hemolyzed by covering that portion of the blood with distilled water or a hypotonic salt solution, and brilliant cresyl blue or some other vital stain is added subsequently. Because of the hemolysis, the basophilic material, which includes the reticulum of reticulo- cytes, is more easily stained, and the number of cells which originally con- tained this material is computed on the basis of the number of cells in the non-hemolyzed portion of the smear occupying the same area. There is considerable difference of opinion regarding the number of these CLINICAL MANIFESTATIONS 147 cells that should be regarded as significant in subjects exposed to lead. Most of this difference of opinion is in relation to the normal number of stippled cells, since the normal values for reticulocytes (0.2 to 3.09%) and basophilic aggregation (up to 1-1.59%, of the total red-blood cells) have been fairly well established. The following values have been set by differ- ent observers as indicative of a toxic effect of lead in subjects exposed to this agent: Schonfeld, 70 per million red cells suspicious; Schmidt, 100 per million suspicious; K. B. Lehmann! +4, 200 per million; Trautmann, 300 per million; Naegeli' 2, 500 per million; Sellers, 1,000 per million; Schmidt and Weyrauch, over 500 per million suspicious and over 1,000 important evi- dence; Flury?, 100 per million; Belknap? 1,000 per million; Johnson, 2,000 per million. Kehoe! states that 69, of several thousand normal subjects had over 1,000 stippled cells per million red-blood cells, the mean value being 339.18 == 9.72 per million in 784 subjects. According to McCord, Holden and Johnston, values for basophilic aggregation are rarely over 19, in normal subjects, figures between 1 and 1.59, being of doubtful signifi- cance. It has also been found that here may be a considerable degree of diurnal variation in the number of stippled cells in the peripheral circulation (Weindel; Sohler; Fuchsberger). Many believe that single estimations, particularly if within normal limits, are of little or no significance in elimi- nating the possibility of lead intoxication. It has been stated by some that stippling may be the first manifestation of plumbism in lead workers (Schonfeld; Weisbach), but there is little evi- dence to support this contention. Opinion regarding the significance of this phenomenon has been modified considerably since Grawitz first stated his belief in the absolute diagnostic value of stippling in lead poisoning. Trautmann found it to be present in 56.29, of lead workers and 709, of painters undergoing periodic examination. 20.69, of lead workers and 33.39, of painters showed more than 100 stippled cells per million red- blood cells and 11.29%, of lead workers and 21.79, of painters more than 200 per million. Moritz reported the occurrence of stippling after only eight days’ exposure to lead. According to P. Schmidt! +, counts of over 100 stippled cells per million red-blood cells were found in 9.2%, of 546 lead workers in only 1.89, of 110 controls. This author, as well as K. B. Lehmann, believes that polychromasia and stippling are important early manifestations of plumbism. Mathew reported observations made upon smelters who showed suggestive evidence of lead intoxication. Varying degrees of stippling were observed in 63.89, of 715 examinations, values significantly above normal being obtained in about 25-309 of cases. There was no consistent relationship between the number of stippled cells and the duration of exposure to lead, and in some instances persistence of this phenomenon was observed for several months after removal from exposure. 148 LEAD POISONING Extensive stippling was generally found in the presence of severe symptoms and signs (pallor, wasting, weakness, colic, anemia, lead line, headache, tenderness along peripheral nerves). When such symptoms and signs were slight or absent there was usually little or no excessive stippling. A con- siderable degree of variation was noted from day to day and week to week, even during periods of continued exposure. Mathew believes that the presence of punctate basophilia is a definite indication of lead absorption and that the extent, type and degree of permanency of the stippling phe- nomenon afford some indication as to the extent and degree of permanency of damage to the organism. Schnitter? believes that excessive stippling is present in all cases of clinical lead poisoning. He has seen it as early as two days after exposure to white lead and states that in a series of 294 hospitalized patients with plumbism only 59%, had fewer than 500 stippled cells per million red-blood cells. According to Biondi, punctate basophilia, in the absence of other manifestations, should be regarded as evidence of latent plumbism. Some authorities state this phenomenon is absent in 50 to 809, of cases (Linenthal; Harris), while Teleky” says that it is absent in 259%, Russell in 279%, Lutolawski in 179%, Oliver® in 609%, and Smith, Rathmell and Marcil in 709, of cases of lead poisoning. Belknap? states that a lead line usually appears when the stippled cells exceed 1,000 to 2,000 per million red-blood cells. He believes that the presence of 500 to 1,000 stippled cells per million red-blood cells does not necessarily indicate anything more than absorption of lead and that such counts may continue for years without the development of manifestations of lead poisoning. However, Belknap? believed that if a steady increase occurs from day to day, from 2,000 to 5,000 to 10,000 or more per million red-blood cells, an acute episode of lead intoxication is impending. This author believes that whereas single counts may be of little value, the establishment of a curve by counts made every 1-2 days to once a week may be of considerable value, inasmuch as a gradual rise usually occurs for several weeks before the onset of acute symptoms, such as colic. In a series of 169 cases of lead poisoning, Naegeli? found a significant increase in the number of stippled cells in 44.59%, of mild cases, 76.8% of the moderately severe cases and 78%, of severe cases. He regarded the presence of stippling as of value, but not conclusive, in the diagnosis of plumbism. He found that it may be absent in unquestionable cases of lead poisoning and stated that the number of cells is proportional not to the severity but to the duration of the poisoning. Henning and Keilhack found that the number of stippled cells was greater in the sternal marrow (puncture) than in the peripheral blood in 9 of 11 subjects with lead poisoning. Many observers believe that the basophilic aggregation test is preferable to the ordinary method of enumeration of stippled cells. McCord, Holden CLINICAL MANIFESTATIONS 149 and Johnston state that values of 1.5-29%, or more are suggestive of lead absorption in lead workers and of the possibility of approaching clinical plumbism. They state that two weeks exposure to lead is adequate to cause an increase in basophilic aggregation and that the chief value of this procedure lies in the detection of lead absorption and early lead poisoning, its value diminishing as lead poisoning progresses to a state of prolonged chronic intoxication. Hyler and Bradley applied the basophilic aggrega- tion test to 390 male lead workers and found it to be positive in all cases in which appreciable amounts of lead were being absorbed. There was no precise correlation between basophilic aggregation and the number of stip- pled cells in these cases nor was any consistent correlation observed be- tween these values and the severity of lead poisoning. The basophilic aggregation values tended to decrease as clinical manifestations of plumb- ism disappeared but high values were not seen regularly in prolonged chronic poisoning. These authors believe that the basophilic aggregation test is to be preferred to the simple enumeration of stippled cells from the standpoint of time, economy and accuracy. McCord, Walworth, Johnston and Fisher found high basophilic aggregation values in storage-battery workers exposed to excessively high concentrations of lead in the atmos- phere. Some observers believe that reticulocyte counts are preferable to the determination of basophilic aggregation or the number of stippled cells. According to Fleckel and his associates, reticulocytosis and polychromasia, both of which precede the appearance of punctate basophilia, constitute the earliest and most consistent change in the blood following exposure to lead. Fleckel and Tschernow described a method of classifying the degree of exposure to lead according to the percentage of reticulocytes, a procedure also thought to be useful by Bottrich. Whitby and Britton found that there was a close relationship between the percentage of reticulocytes and the sum of the percentages of polychromatic cells and stippled cells, but that the latter appeared later than the former in induced lead poisoning. A maximum rise in reticulocytes, to about 309, was observed on the fourth day, while the stippled cells rose to a maximum of only about 8%, on the sixth day (following intravenous injection of lead salts). Following a second administration of lead, two weeks later, there was an immediate rise in reticulocytes while the stippled cells remained practically constant. These observers showed that the stippled cells appeared in waves, an in- crease occurring at the expense of the diffusely polychromatic cells. Drees- sen found that the number of reticulocytes, stippled cells and polychromato- philic cells increased with increasing duration of exposure to lead. In a group of patients with cancer receiving lead therapy, Gould, Kullman and Shecket found that the basophilic aggregation test was unreliable; it 150 LEAD POISONING yielded values higher than the percentage of stippled cells in only 25%, of instances and was invariably lower than the reticulocyte count. Jones found that the increase of reticulocytes was always greater than that of stippled cells (Table 14). According to Pearlman and Limarzi, the reticu- locyte count exceeds the basophilic aggregation in 809, of cases. It would appear that, in lead poisoning, increase in polychromatic and stippled cells and in reticulocytes are manifestations of the same phenome- non. The evidence seems to indicate, however, that determination of the number of reticulocytes or possibly, of basophilic aggregation, is of greater value than the estimation of the number of stippled cells. According to Gant, the chief value of these studies is that if positive results are obtained TABLE 14 (Jones) Ratio of Number of Reticulocytes Found in Stippled Cells per 100,000 RBC Workers Suspected of Plumbism to Number Found in Non-exposed Subjects less than 6 2.00 6-9 3.31 10-62 4.18 63-159 5.34 160-399 8.78 400-999 13.73 1000-1599 22.71 1600-2499 27.90 2500-3999 38.61 toxic amounts of lead may be present, negative results being of no signifi- cance. It has often been observed that an increase in these cells is transi- tory, especially in cases of severe poisoning or shortly before death (Flury?). They diminish in number after cessation of exposure, usually disappearing in 2-4 weeks, but occasionally persist for a few months (Flury?; Baader?; Teleky?; Kretchmar). Smith, Rathmell and Marcil found that the rise in reticulocytes usually precedes that in stippled cells but that it occurs in about the same time as suggestive symptoms of lead intoxication. They agree with other observers (Krafka; Haemisch) that the quantitative estimation of reticulocytes, stippled cells, polychromatic cells and normo- blasts and of basophilic aggregation is of little value in prognosis, low counts being obtained at times during periods of active lead poisoning, even in the presence of severe manifestations. Kehoe! states that in the presence of hazardous exposure to lead, an abundant and progressive increase in the number of reticulocytes, stippled and polychromatic cells is strongly sug- gestive of increased lead absorption but is not necessarily indicative of the CLINICAL MANIFESTATIONS 151 existence or imminence of clinical lead poisoning. Such findings should, however, be regarded as a warning signal. On the other hand, he believes that with the exception of unusual cases of acute overwhelming toxemia from a single or brief massive exposure, the absence of these phenomena in a case of suspected lead poisoning during a period of active intoxication is very nearly conclusive evidence that the condition is not due to lead. We cannot subscribe to this view without reservation, for, as mentioned pre- viously, these hematologic manifestations may be absent in cases of un- doubted severe lead intoxication, even during terminal stages. Jones described cases of severe lead poisoning with marked anemia and few basophilic cells until the subjects were removed from exposure to lead and a “deleading” procedure was begun. However, high values are the rule in acute exacerbations, although frequently large numbers of these cells may be found in subjects with few or no clinical symptoms (Jones; Badham; H. Lehmann?; Willcocks; Gaul; Kehoe, Thamann, and Cholak?). Johnson states that clinical evidence of lead poisoning is usually present when the reticulocyte count is above 49, and the stippled cells above 0.2%. How- ever, many cases of lead exposure were seen by him with much higher counts without clinical symptoms, and some workers with heavy exposure showed no increase in these cells. Jones states that he has seen men with more than 3000 stippled cells per million red-blood cells without symptoms who later developed disturbances of sufficient severity to require compen- sation for disability, at which time the stippled cells numbered only 50 60 per million red-blood cells. The point has been emphasized by several workers that lead poisoning differs from other conditions which may be accompanied by comparable basophilic changes in the erythrocytes in that, in the former, these phenomena are often seen in the absence of even moderate grades of anemia, while in the latter they usually follow the development of severe anemia (Cabot; Jones; Flury?). As stated by Jones, whereas stippled cells are found in other conditions accompanied by anemia, in no other disease are stippled cells found in such numbers in the absence of other major blood changes. Leucocytes and Platelets In the experience of the majority of observers, there is little significant or consistent alteration in the leucocytes in clinical lead poisoning. Ac- cording to Minot!, the total count is usually within normal limits; in most instances, counts have been recorded ranging from about 5000 to 50,000, with a few above and below these figures. Kost! reported a count of 3000 per cubic millimeter. In clinical plumbism the leucocyte count is usually towards the upper rather than the lower limits of normal and many authors believe that in uncomplicated cases lead has no influence upon the number 152 LEAD POISONING or distribution of white blood cells in the circulation (Baader?; Gelman?). Reports by other observers are as follows: Cabot, a leucocytosis of 10,000 to 22,400 in 10 of 15 cases, with an average of 12,922; Boston, 4000-25,500, with an average of 12,600 in 24 cases of acute lead poisoning, the counts being over 10,000 in all but 3 instances; Cadwallader, 4700-12,550, averag- ing 7568, in 37 cases; Hamilton!, 3800-21,000 in 63 cases, averaging 9900, with counts over 15,000 in 6, over 10,000 in 30 and under 10,000 in 27, the highest counts being observed in cases with severe anemia. Legge and Goadby believed that an increase in leucocytes is one of the first signs of lead intoxication and Grawitz? observed a marked increase in some cases. Gould, Kullman and Shecket found a usually marked leucocytosis about 31 weeks after beginning administration of lead salts in patients with malignancy, myelocytes being present in the peripheral blood in 9 of 22 cases. Leucocytosis occurs most commonly in younger age groups and particularly during acute episodes, such as colic and encephalopathy, and is likely to be particularly marked in the presence of fever. Ina series of 29 fatal cases of lead encephalopathy in children ranging from 13 months to seven years of age, Blackman? reported leucocyte counts of 8200 to 58,500, the counts being above 12,000 in 17 and above 20,000 in 12 in- stances. The temperature was elevated in the great majority of these cases. Some authors have stressed the importance of lymphocytosis (Flury?; Legge and Goadby; Baader?; Seitz; Stickl; Petrov; Lenzi). Ferguson and also Shields emphasized the value of the ratio of large lymphocytes and monocytes to small lymphocytes in persons exposed to lead. According to these observers, this ratio increases during the early stages of exposure and later exhibits a marked fall when symptoms of plumbism develop. They believe that a gradual fall in this ratio in exposed subjects serves as a valuable premonitory indication of the imminence of clinical lead intoxi- cation. Some authors report an increase in monocytes (Petrov; Brook- field; Lenzi; Legge and Goadby; Shie). According to Flury?, the mono- cytes often show morphologic changes, particularly degeneration of the nucleus. A shift to the left in the granulocytes (Schilling) has been re- ported, particularly during acute episodes, with and without the presence of toxic granules in these cells (Ferguson and Ferguson; Flury?; Petroff; Gould, Kullman and Shecket; Kasahara and Nagahama). Seelig has re- ported eosinophilia as high as 70%, and others have recorded an increase in these cells up to 56% (Legge and Goadby; Seiffert; Biondi). The great majority of observations contradict these specific effects of lead upon the relative proportions of the white blood cells in the peripheral circulation in uncomplicated cases. Little mention is made of the platelet count in subjects with clinical lead poisoning (p. 54). Thrombopenia has been reported by Seitz. According CLINICAL MANIFESTATIONS 153 to Jones, an increase in platelets may occur during the early stages in some instances simultaneously with the occurrence of polycythemia. A de- crease may occur at times in advanced cases. In 42 moderately severe cases of lead poisoning studied by Jones the average platelet count was 130,000 per cu. mm. as compared to a range of 250,000-700,000 in control subjects. The decrease in platelets was not associated with a demon- strable hemmorrhagic tendency. PIGMENT METABOLISM ' Many observations of abnormalities in pigment metabolism have been interpreted as evidence of disturbances in hematopoietic function (p. 501t.). An increase in serum bilirubin concentration, rarely above 2.5 mg. per 100 cc., has been reported by several observers (Klima and Seyfried; Schmidt-Kehl; Vigliani and Angeleri; Heubel; Cantarow!). This type of bilirubinemia, which may be due in part to excessive hemolysis and in part to impaired liver function, may be accompanied by bilirubinuria, excessive urobilinuria and increased excretion of pigment in the bile (p. 51). Ab- normal excretion of urobilin in the urine occurs quite frequently, particu- larly in the presence of acute symptoms, and may be a rather constant finding immediately after episodes of lead colic (Hamilton!). Visible jaundice is not observed commonly but has been reported by Tanquerel, Legge and Goadby and Rolleston and McNee (p. 51). Considerable attention has been devoted to the occurrence of porphyri- nuria in clinical lead poisoning; the pathogenesis and significance of this phenomenon is discussed elsewhere (p. 51ff.). Much more emphasis has been placed on the clinical importance of this phenomenon by European than by American observers (p. 52ff.) and only a few of the more significant observations will be mentioned here. The earliest references to the occur- rence of porphyrinuria in lead poisoning were made by Stockvis and Bin- nendyk, Garrod and Deroide and Le Compt, the latter observing it in 12 of 13 lead workers. Hamilton! states that it occurs most commonly in patients with excessive red-cell destruction. Froboese believes that excre- tion of more than 0.33 mg. of porphyrin per liter is significant and reported the presence of 1.71-3.98 mg. per liter in a group of lead workers. Recent studies emphasize the importance of qualitative as well as quantitative determinations of urinary porphyrin. Grotepass found 8 mg. of copro- porphyrin III in a 24 hour urine excretion but no evidence of the presence of uroporphyrin. Watson?®, too, found coproporphrin III in the urine of subjects with lead poisoning, and also found coproporphyrin I in the feces in one case. The importance of this observation lies in the belief that coproporphyrin III is probably a side product of disturbed hemoglobin metabolism rather than being indicative of destroyed hemoglobin (Dues- 154 LEAD POISONING berg). It has been found in a few conditions other than lead poisoning, such as rare cases of congenital porphyrinuria, a few cases of cirrhosis of the liver and, occasionally, following administration of arsphenamine. Franke and Litzner emphasize the importance of porphyrinuria in the early diagnosis of lead poisoning. They believe that, in the absence of severe hepatic disturbance or acute porphyria, a daily excretion of more than 500 micrograms or concentrations in the urine of more than 50 micrograms per 100 ce. indicate impairment of bone-marrow function by lead. They made the interesting observation that considerably higher values for urinary porphyrin are obtained in healthy than in unhealthy lead workers. Van Embden and Kleerekoper found porphyrin in the urine in lead poison- ing so consistently in about 1000 observations that they believe this phenomenon to be a valuable aid in diagnosis. Porphyrinuria in lead poisoning appears to be evidence of a fundamental disturbance of hemo- globin breakdown and synthesis. It often makes its appearance with the onset of colic and may persist for several days after the latter has subsided (Gelman?; Schumm; Fischer). Some authors believe that although an increase in urinary porphyrin is in no way specific for lead poisoning and may indeed be absent, it is nevertheless an important feature of the general picture of that condition (P. Schmidt’; Schwarz; Teleky*). The majority of observers in this country agree with Flury? that the clinical significance of porphyrinuria in lead poisoning is limited, as are indeed all other labo- ratory manifestations with the exception of the quantitative estimation of lead in the tissues and body fluids. CrAPTER VII LEAD IN BLOOD, BODY FLUIDS AND EXCRETIONS The demonstration of excessively high concentrations of lead in the body fluids or the tissues is perhaps the most important single factor in establishing the etiologic significance of lead in the production of symptoms and signs suggestive of poisoning by this agent. The lead content of vari- ous body fluids, tissues and excretions is discussed in detail elsewhere (pp. 8-40). Itis necessary here only to review the significance of this factor in lead intoxication. LEAD CONTENT OF BLOOD As stated elsewhere (p. 8), although values as high as 0.13 mg. per 100 ce. of blood are reported in apparently normal subjects (Kehoe, Thamann and Cholak?), we believe that concentrations above 0.08 mg. per 100 cc. should be regarded as abnormal, values of 0.05 mg. or less being obtained in about 75% of normal subjects and of 0.06 mg. or less in about 859%. Several observers have attempted to establish concentrations of blood lead above which clinical manifestations of lead poisoning make their appearance. This so-called “critical limiting value” has been variously set at 0.06 mg. per cent (Litzner and Weyrauch?®) and 0.10 mg. per cent (Blumberg and Scott; Teissinger; Taeger and Schmitt; Tompsett and Anderson?). According to Litzner and Weyrauch?, symptoms were ob- served occasionally with blood lead concentrations of about 0.04 mg., but this is contrary to the findings of the majority of investigators. The maximum blood lead concentration observed in occupational lead poisoning by Bass was 0.47 mg. per 100 cc., by Smith, Rathmell and Marcil 0.64 mg. and by Litzner and Weyrauch?® 0.5 mg., but Magnuson and Raulston re- ported an instance of lead poisoning in a roofer with a whole-blood lead concentration of 1.0 mg. per 100 cc. and Smith, Rathmell and Marcil observed a concentration of 1.06 mg. per 100 cc. in a patient with carcinoma receiving active lead therapy. The existence of a close relationship be- tween the quantity of lead in the blood and the development of clinical manifestations of intoxication has been emphasized by several authors (Litzner and Weyrauch?®; Bass; Schmitt and Taeger; Blumberg and Scott; McMillen and Scott). McMillen and Scott state that they have never observed clinical manifestations of lead poisoning in the presence of blood- lead concentrations lower than 0.1 mg. per 100 cc., while values above 0.2 mg. were obtained in cases of severe poisoning. Kaplan and Mec- 155 156 LEAD POISONING Donald obtained values of 0.1-0.6 mg. per cent in children with clinical plumbism. As indicated elsewhere (p. 8ff.), the bulk of available evidence suggests that by far the greater part of the blood lead is contained within the red- blood cells. According to Behrens and Pachur, the distribution of lead depends to a certain extent upon the amount present, the percentage of the total contained in the serum or plasma increasing as the total quantity in the blood increases. Smith, Rathmell and Marcil state that if the blood is defibrinated, all under normal conditions should be contained in the cells and fibrin and none in the serum (maximum normal values: cells and fibrin 0.110 mg. per cent; whole blood 0.060 mg. per cent; serum 0.000 mg. per cent). They believe, as do Wexler and Sobel, that clinical symptoms of lead poisoning are related more directly to the quantity of lead in the serum or plasma than to that in whole blood, particularly since the lead in the cells appears to be in comparatively firm combination and would not be expected to pass into the tissue fluids and to exert its toxic effect on the tissue cells (Blumberg and Scott). In 18 cases of inactive lead poisoning, four months or longer after the disappearance of symptoms, they found whole-blood lead values of 0.07-0.64 mg. per cent with no lead, however, in the serum. In 35 cases of active plumbism, occupational or induced, with mild or moderately severe symptoms, the lead content of the serum ranged from 0.01-0.04 mg., with concentrations in the whole blood ranging from 0.02-0.83 mg. per cent. In 41 cases with severe symptoms the serum lead concentration ranged from 0.02 to 0.15 mg. per cent and the whole- blood lead from 0.05 to 0.41. In 5 fatal cases the whole-blood lead varied from 0.05 to 0.26 mg. per cent and the serum lead from 0.04 to 0.2 mg. per cent. Smith and his associates believe that as lead intoxication ap- proaches a fatal termination there is a tendency for the lead to become equally distributed between the cells and the serum, whereas during an acute exacerbation of lead intoxication the serum fraction increases, usually but not invariably with a simultaneous but not necessarily proportional increase in the whole-blood lead concentration. According to Blumberg and Scott, more than 509%, of the lead of normal blood is in the red-blood cells while in clinical lead poisoning these cells contain about 909 of the total lead. Although, as stated above, it is logical to assume that clinical manifestations of lead intoxication should be more directly related to the concentration of lead in the circulating plasma than that in the red-blood cells, we feel that difficulties inherent in the methods of separation of cells and plasma or serum preclude the possibility of securing exact information regarding the distribution of lead in the circulating blood. It is obvious that a portion of the blood lead must be contained in the circulating plasma under both normal and abnormal conditions, for its presence in the other LEAD IN BLOOD, BODY FLUIDS AND EXCRETIONS 157 body fluids and tissues and its excretion in the urine can be explained only on this basis. The data reviewed above indicate that the concentration of lead in the blood bears no consistent relationship to the appearance or severity of clinical manifestations of lead poisoning. The latter may be absent at high levels of blood lead and may be present at low levels. The diagnosis of lead poisoning must depend on the presence of clinical manifestations of that condition and the demonstration of lead as the etiologic agent. In the presence of such symptoms, the demonstration of an abnormally high con- centration of lead in the blood is of course of inestimable value in establish- ing this diagnosis, but it must be emphasized that normal blood lead values may be obtained in cases of active lead intoxication and that the latter may be absent in subjects with high concentrations of lead in the blood. The presence of abnormally large amounts of lead in the blood results either from absorption from the outside or mobilization from deposits previously stored in the tissues. In either case, the abnormally high concentration of lead in the blood may be interpreted as evidence of exposure, past or present, to excessively large amounts of this substance. Active mobili- zation from the bones, with the development of acute episodes of lead intoxication, may occur many months or even years after unusual exposure to lead has ceased (p. 26). This may occur either spontaneously or as a result of the action of one or more of several factors which favor the mobili- zation of lead (p. 37ff.). This fact is of importance from a medico-legal standpoint. In a study of 766 men working in storage battery plants, Dreessen found that almost all who worked at atmospheric lead concentrations below 0.75 mg. per 100 cubic meters of air had blood lead values below 0.04 mg. per cent, but as the atmospheric lead concentration increased, the frequency of higher blood values increased, although only 11 showed concentrations above 0.1 mg. per 100 ce. As would be expected, workers exposed to the same range of atmospheric lead concentration differed considerably among themselves in their blood lead concentrations. However, as pointed out by Kehoet, considerable variation may occur in exposure to and absorption of lead with relatively little alteration in the blood lead concentration, which does not reflect such changes in exposure nearly as strikingly as does the urinary lead concentration. In an analysis of about 1000 samples of blood, Sawyer, Wagoner and Erickson state that there was some correlation be- tween the average blood lead content and the occupational exposure, the concentration in samples from painters, for example, being almost double that in white collar workers. They also stress the fact that a single obser- vation of a high concentration of lead in the blood cannot be regarded as diagnostic of lead poisoning, although it may be suggestive. They found 158 LEAD POISONING abnormally high concentrations in 7 apparently normal persons and average normal concentrations in 2 cases of lead poisoning. Ehrhardt states that the level of blood lead is not always related to the severity of lead poisoning and that this diagnosis cannot be made on the basis of the blood lead con- centration alone. According to Taeger and Schmitt, whereas the blood lead concentration is usually above 0.1 mg. per 100 cc. in the presence of unmistakable manifestations of clinical lead poisoning, it is usually within normal limits in subjects exposed to lead with only slight or questionable symptoms of intoxication. They believe that in doubtful cases, single estimations of blood lead concentration are of little value and that a single, slightly increased value cannot be considered as decisive in establishing the diagnosis. Whereas the validity of this conclusion cannot be questioned, it should be added that the absence of abnormally high lead concentrations is not conclusive evidence against the diagnosis of lead poisoning. LEAD IN URINE Inasmuch as the presence of abnormal amounts of lead in the urine implies the presence in the organism, and particularly in the circulating blood plasma, of abnormally large amounts of this substance, this finding is universally regarded as of the utmost importance in the diagnosis of lead poisoning. As pointed out elsewhere (p. 155), the upper limit of normal urinary lead excretion is probably 0.08 mg. per liter, although the average excretion of normal subjects is considerably below this figure. It must be emphasized that an increase in the quantity of lead in the urine, as in the blood (p. 157), is indicative of the absorption of excessive quantities into the body and not necessarily of the presence of lead poisoning. The existence of the latter must be manifested by clinical signs or symptoms resulting from the toxic effect of lead upon the tissues. Kehoe states that an increase in urinary lead is the first demonstrable response to increased absorption of this substance and that the quantity excreted is in direct relation to the magnitude of its absorption. As stated by this author, changes in urine lead concentration occur more promptly and are more marked than those in the blood and reflect more readily than the latter the existing conditions of exposure to lead. He therefore regards it as of greater value than the blood lead concentration in revealing the extent of danger of lead intoxication in occupations in which a lead hazard exists. Increase in urine lead concentration under conditions of increased lead exposure was beautifully demonstrated by an extensive study by Neal and his associates of a group of orchard workers exposed to lead arsenate which was used as an insecticide. The average lead excretion ranged from 0.068 mg. per liter in January to 0.1225 mg. in July, the highest concentration observed being 0.419 mg. per liter. The peak of urine lead concentration LEAD IN BLOOD, BODY FLUIDS AND EXCRETIONS 159 in the late summer and early autumn coincided with the period of maximum exposure to the lead arsenate spray. Fretwurst and Hertz found that lead workers with no symptoms of lead intoxication had urine lead concen- trations of 0.03-0.06 mg. per liter, whereas those with symptoms showed concentrations of 0.07-0.2 mg. per liter. According to Kehoe, values up to 0.14 mg. per liter are compatible with safe occupational exposure, a rather large group of lead workers having been maintained for years below the threshold of lead intoxication with values of 0.02-0.22 mg. per liter. He states that values above 0.2 mg. per liter cannot occur in the absence of definitely abnormal exposure to lead, that concentrations above 0.3 mg Fic. 2. Average urinary lead excretion, in milligrams per liter, of 16 groups of storage battery workers, classified by atmospheric lead concentration and years of lead exposure. (Dreessen et al., U. S. Public Health Bulletin No. 262). per liter are associated with grossly dangerous conditions of lead exposure and absorption and that values above 0.5 mg. per liter are observed only rarely, although figures as high as 1.0 mg. or more per liter have been reported. Gant states that values of 0.08 mg. to 0.14 mg. per liter are indicative either of mild exposure or of recovery following heavier ex- posure, that 0.15-0.28 mg. per liter usually indicate lead intoxication and that values over 0.28 constitute a sure sign of severe exposure and a reliable indication of intoxication. According to this author, the range of values in patients with chronic lead intoxication is 0.08-0.76 mg. per liter and occasionally higher. There is a wide range of variation in urinary lead excretion in individuals working under identical conditions of exposure to this agent. In a group 160 LEAD POISONING TABLE 15 Lead Excretion in Urine of Lead Workers Urine Lead Author No Lead Poisoning mg. per liter 0.03 Seiser and Litzner 0.059-0.36 British Ethyl Petrol Committee <0.21 Kehoe, Thamann and Cholak <0.20 Badham and Taylor 0.01-0.05 Fretwurst and Hertz 0.01-0.26 Trumper and Cantarow Lead Poisoning 0.15 Seiser and Litzner 0.23 Brown 0.07-0.09 Litzner, Weyrauch and Barth 0.1 -0.2 Bradham and Taylor 0.00-0.13 Fretwurst and Hertz 0.01-0.42 Trumper and Cantarow TABLE 16 Urine Lead in Subjects with Occupational Exposure (After Kehoe?) Borderline Dangerous Exposure Urine Lead Safe Exposure Dangerous Exposure Urine Lead % mg. per liter % % mg. per liter 0.00 -0.019 2 — 0.00-0.07 9 0.02 0.039 23 4 0.08-0.15 39 0.04 0.059 47 20 0.16-0.23 23 0.06 -0.079 20 23 0.24-0.31 13 0.08 -0.099 4 14 0.32-0.39 3 0.10 -0.119 0.4 12 0.40-0.47 4 0.12 -0.139 0.8 8 0.48-0.55 2 0.14 -0.159 0.6 12 0.56-0.63 2 0.16 -0.200 — 5 0.64-0.71 1 0.200-0.220 — 1 0.72-0.79 0.5 0.220 — 1 0.80-0.87 1 0.88-0.95 0.5 0.96 2 of 356 subjects exposed to tetraethyl lead, Kehoe, Thamann and Cholak? found that 25%, excreted 0.0-0.03 mg. per liter and 389, 0.04-0.07 mg. per liter, the remainder excreting larger quantities. We have obtained LEAD IN BLOOD, BODY FLUIDS AND EXCRETIONS 161 values of 0.01 to 0.26 mg. per liter in subjects without clinical manifesta- tions of lead poisoning working under practically identical conditions of exposure to lead. This marked variation, which has been observed by many investigators, naturally must be due to variations in absorption, TABLE 17 Urine Lead in Lead Miners and Smelters (After Tannahill) All Lead Miners Urine Lead Incidence mg. per liter % 0.00-0.05 36 0.06-0.09 1 0.10-0.19 29 0.20-0.29 14 0.30-0.39 6 0.40-0.49 4 Lead Miners with Intermittent Exposure Total Period Mining Work Lead Excretion in Urine ' mg. per liter 1 year or less 0.00-0.17 1-5 years 0.01-0.44 6-10 years 0.02-0.25 11-20 years 0.00-0.27 over 20 years 0.17-0.32 Continuous Exposure Urine Lead Period of Exposure Miners Smelters mg. per liter mg. per liter Less than 1 year <0.02-0.49 0.07-1.04 1 year or more <0.02-0.39 0.06-0.62 storage or excretion of this substance. It is apparent that although, as shown by Dreessen, the average concentration of lead in the urine and blood increases with increasing concentrations in the working atmosphere, certain individuals, i.e., those with poor absorption and ready excretion and storage, may be free from symptoms with relatively heavy exposure. Ac- cording to the report of the British Ethyl Petrol Committee, the urine of 162 LEAD POISONING workers in lead industries contained 0.007-0.58 mg. of lead per liter, a variation which they believed depended upon the nature of the work and the conditions of exposure, but which may obviously be due, in some meas- ure at least, to the factors mentioned above. It has also been shown that there is a rather marked variation in lead concentration in urine samples selected at random from the same individual and that determinations made upon large samples or 24-hour specimens afford a more exact indication of the true condition of lead excretion (Kehoe*; Webster) (see p. 35). The influence on urinary lead excretion of the route of absorption and of factors that influence the storage of absorbed lead and mobilization of lead from these deposits has been considered elsewhere (p. 37ff.), and need not be reviewed in detail here. In a study of workers in lead mines, Tannahill found that the duration of exposure had little influence upon the urinary lead concentration, which was almost invariably over 0.1 mg. per liter and ranged from 0.02 to 0.49 mg. per liter in subjects with continued exposure over periods up to five years. The values were less consistently elevated, although of approximately the same range of magnitude (0.02-0.44 mg. per liter) in subjects with intermittent exposure. Values as high as 1.04 mg. per liter were obtained in smelters. Shiels also states that there is no definite relationship between urine lead concentration and the period of exposure. Kehoe? states that immediately after cessation of exposure to excessive quantities of lead, the concentration in the urine rarely exceeds 0.3 mg. per liter and diminishes rapidly, so that it seldom exceeds 0.15 mg. per liter if examined some time after absorption has ceased. This is true, however, only under conditions of normal storage of lead and in the absence of factors which increase the mobilization and liberation of lead from stored deposits in the bones, such as infection, trauma, alcoholism, administration of such agents as acids, alkalies, iodides, citrates, etc., and conditions ac- companied by a state of negative calcium and phosphorus balance, as in- duced by parathyroid hormone or excessive quantities of vitamin D or inadequate calcium and phosphorus intake, or as present in conditions accompanied by active demineralization, such as hyperthyroidism, hyper- parathyroidism and prolonged periods of immobilization of various bones (p. 37ff.). When such factors are operative, an increase in urinary lead concentration may occur years after the last exposure to abnormal quanti- ties of lead, being derived from mobilization of deposits in the skeleton, stored during previous periods of exposure. The concentration‘ of lead in the urine is influenced by factors which influence the concentration of other solid constituents of the urine. It is increased in the presence of conditions accompanied by decrease in the volume of urine, providing that renal function is not impaired, (dehydra- tion, edema, diarrhea, vomiting, etc.), and is decreased in the presence of LEAD IN BLOOD, BODY FLUIDS AND EXCRETIONS 163 conditions of renal functional impairment (glomerulonephritis, nephro- sclerosis, etc.), and under conditions of large urine volume. As has been mentioned elsewhere, there is no consistent relationship between the con- centrations of lead in the urine and the blood, the former, under ordinary conditions, exhibiting considerably more variation than the latter, espe- cially during periods of increasing or decreasing exposure to or mobilization of lead. Abnormally high urine lead values may be obtained in subjects with normal concentrations of lead in the blood and extremely high urine values may be present in subjects with only moderate elevations in the blood. Dreessen reported values of 0.12-0.66 mg. per liter of urine in cases with blood lead concentrations of 0.03-0.07 mg. per 100 cc. A urine lead concentration of 0.93 mg. per liter was observed in one subject with a blood lead concentration of only 0.14 mg. per 100 cc. Litzner and Wey- rauch?:? state that if the blood contains 0.01-0.03 mg. per 100 cc., the 24-hour urine excretion is about 0.06 mg. (0.04 mg. per liter). When the blood lead concentration increases to 0.06 mg. per 100 cc., the daily urine excretion of lead is about 0.1 mg., but this varies considerably. These authors also point out that the urinary excretion of lead may be normal in subjects with severe lead poisoning and a high blood lead concentration. We have observed urinary lead values as low as 0.06 mg. per liter (daily excretion 0.085 mg.) in a subject with a blood lead concentration of 0.28 mg. per 100 cc. Findings such as these, i.e., normal urine values with high blood values, occur particularly in patients with renal functional impair- ment, due usually to glomerulonephritis or nephrosclerosis, during periods of excessive exposure to or mobilization of lead. This factor is of the utmost importance in limiting the clinical significance of urinary lead values and the state of renal function must always be ascertained in interpreting such findings. In determining the significance of the quantity of lead excreted in the urine, the fact must be re-emphasized that the concentration of lead in this, as in other body fluids, is indicative, at best, of the condition of exposure to lead or of the quantity of mobilizable lead in the organism and does not at all indicate the presence of clinical lead intoxication (see Table 15). Tompsett and Anderson believe that lead poisoning is probably present if the blood lead concentration is over 0.1 mg. per cent and the urinary excretion is more than 0.1 mg. daily. Several observers state that only concentrations above 0.2 mg. per liter of urine can be accepted as evidence of plumbism (Shields; Grignaschi; Labat; Kehoe!). On the basis of what has been stated previously, it is evident that such statements cannot be accepted unequivocally. Litzner and Weyrauch state that there is no constant relationship between lead excretion in the urine and clinical - symptoms and signs of lead poisoning. There can be no doubt that there 164 LEAD POISONING may be a considerable increase in urinary lead in the absence of clinical manifestations of lead poisoning (Taeger and Schmitt; Kehoe?+#; Dreessen; Trumper and Cantarow). Dreessen obtained values as high as 0.93 mg. per liter in storage-battery workers with clinical manifestations of only incipient lead intoxication. Conversely, but less frequently, the urinary lead excretion may be normal in subjects with chronic lead poisoning, usually, as noted above, in the presence of renal functional impairment. In the presence of normal renal function, abnormally high excretion of lead in the urine is almost invariably present in subjects with acute lead poison- ing or during acute episodes in chronic poisoning (colic, encephalopathy, paralysis, etc.). In chronic lead poisoning, the urine frequently contains increased amounts of lead but not invariably and not constantly, there being considerable variation in the quantity eliminated from time to time. There may be transitory periods during the course of chronic lead poisoning in which the lead content of the urine is normal, e.g., during periods of impaired renal function or deposition of inactive deposits in the skeleton. On the other hand, relatively large quantities may be excreted in the urine in the total absence of evidence of lead poisoning (Table 15, p. 160). For example, Craik reported a daily excretion as high as 0.7 mg. in the urine in healthy lead workers. Monier-Williams believes that a high degree of tolerance to lead can be developed by lead workers, who may, he states, while apparently in normal health, constantly excrete lead in quantities which would almost invariably indicate severe poisoning in the ordinary individual. It is questionable whether such failure to react to relatively large quantities of lead can be justifiably ascribed to the development of an increased tolerance to this agent (p. 98). It is of interest in this con- nection that lead has been found in 21 urinary calculi (the only ones re- ported in which its presence has been investigated) (Trumper and Gordy; Wood). In one of these it constituted 3% of the calculus, the subject having been exposed to abnormal quantities of lead (Trumper and Gordy). It seems probable that lead, being a constituent of the majority of urine specimens, may be found in any urinary calculus containing phosphate. LEAD IN FECES It is obvious that under ordinary conditions of occupational exposure to lead, a variable quantity enters the gastrointestinal tract. Inasmuch as the fecal lead consists in part of that which has been absorbed and re- excreted into the intestine, and in part of that which has passed through the intestine without having been absorbed (p. 33), determination of the quantity excreted in the feces is of little practical value. Since the average normal daily intake of lead has been estimated as less than 0.5 mg. (Monier- Williams), excretion in the feces of quantities greater than this figure should LEAD IN BLOOD, BODY FLUIDS AND EXCRETIONS 165 be regarded with suspicion of excessive exposure. According to Kehoe, values above 0.6 mg. should be regarded as definitely abnormal. This author states also that whereas values of 1 mg. or more are occasionally obtained in healthy adults, the fecal excretion of quantities of this magni- tude are the rule in lead poisoning. Legge and Goadby state that lead workers may occasionally excrete as much as 8-10 mg. in the feces and that the excretion of 2 mg. daily is not necessarily accompanied by clinical manifestations of lead intoxication. As might be expected, the quantity of lead in the urine bears no consistent relation to that in the feces (Tanna- hill; Aub et al.). The absence of such relationship is indicated by data presented in Table 10 (p. 37). Tompsett and Anderson! reported cases of clinical lead poisoning with blood lead concentrations of 0.1-0.4 mg. per 100 cc. with no abnormality of lead excretion in the urine or feces. It has been estimated by Vigliani and Debernardi that approximately 849 of the amount of lead ingested is excreted in the feces unabsorbed and it seems justifiable, as suggested by Gant, to regard the fecal excretion of lead as indicating rather the amount ingested during the preceding 24-36 hours than as indicative in any way of the quantity present in or absorbed into the organism. LEAD IN CEREBROSPINAL FLUID Until comparatively recently, it was believed that lead is not: present in the cerebrospinal fluid of normal subjects (literature reviewed by Seiser and Litzner) and the demonstration of its presence in this fluid was re- garded by some as indicating the etiologic significance of lead in certain diseases of the central nervous system. With the development of more accurate quantitative methods, however, lead has been found in the cerebrospinal fluid of normal subjects with no unusual exposure to lead. Values of 0.015-0.038 mg. per 100 cc. have been reported by Schmitt and Basse, and we have observed concentrations ranging from 0.001-0.040 mg. per 100 cc. in hospital patients with no demonstrable disease of the meninges or central nervous system and no history or evidence of abnormal exposure to lead. It has been found in the cerebrospinal fluid of infants by Tada and by Kasahara and Arimichi. Aub and his associates found a concen- tration of 0.1 mg. per 100 cc. in a patient with lead encephalopathy and Duensing reported values of 0.22 mg. and 0.493 mg. per 100 cc. in two cases of lead poisoning with neurologic manifestations. We have observed concentrations as high as 0.35 mg. per 100 cc. in subjects with lead poisoning with no nervous manifestations, indicating that the lead in the cerebrospinal fluid does not necessarily exert a toxic influence, at least to the point of producing symptoms, in the concentrations observed, upon the meninges or tissues of the nervous system with which it comes in direct contact. 166 LEAD POISONING Moreover, as might be anticipated on the basis of knowledge regarding the circulation and formation of the cerebrospinal fluid, there is no consistent parallelism between its content of lead and that of the blood. For ex- ample, in the cases reported by Duensing, with cerebrospinal fluid lead concentrations of 0.022 and 0.49 mg. per 100 cc., the concentrations in the blood were 0.072 and 0.129 mg. per 100 cc. respectively. We have ob- tained values below 0.04 mg. per 100 cc. in the presence of blood lead concentrations above 0.15 mg. per 100 cc. and in one case without nervous system symptoms the cerebrospinal fluid lead concentration was 0.20 mg. per 100 cc. in the presence of a blood lead concentration of 0.28 mg. per 100 cc. CrAPTER VIII NORMAL INTAKE OF LEAD Although lead may not be properly regarded as a normal constituent of the body, the fact that it is present in the tissues, body fluids and excre- tions of individuals known not to be exposed to unusual quantities of lead indicates that it must enter the body under conditions of ordinary existence, at least in civilized communities. Having established rather definite limits for the “normal” concentration of lead in the blood and urine, it is important to determine, insofar as is possible, the source of this lead and the magnitude of exposure which may be regarded as compatible with health and within the range that might be considered unavoidable under average living conditions. Practically all of this “normal” lead enters the body in food and drink, and a small quantity, perhaps, by the respira- tory tract. As stated by Monier-Williams, “we need not look far to discover the sources of this lead. Many tons of lead paint are used annually on ex- terior and interior painting, much of which in course of time becomes weathered into dust; nearly all coal dust contains traces of lead, as do most soils; lead pipes are used for the conveyance of water, and although hard water is not as a rule markedly plumbo-solvent, it usually takes up traces of lead; lead solder is used to close the seams of cans in which food is packed, and thus comes into contact with, and is slightly dissolved by, many kinds of food; lead alloys are sometimes used for taps, fittings and plating of cooking appliances and food vessels; lead insecticides, used on fruit and vegetables, are not always completely removed before sale; food is cooked or allowed to stand in earthenware vessels glazed with lead silicate; tea is packed in cases lined with lead foil; citric, tartaric and phosphoric acids, artificial colors and other materials used in foods may contain appre- ciable amounts of lead derived from the materials or plant used in their manufacture.” Lead is present in the dust of city streets and on the earth’s surface (Selby Smelter Commission Report), the average amount inhaled by town dwellers in the form of dust being about 0.08 mg. daily (Departmental Committee on Ethyl Petrol). According to Kehoe and Thamann, lead is present in the carcasses of experimental animals so com- monly as to suggest that meat-producing animals also have a significant amount in their tissues. The literature dealing with the lead content of foods has been reviewed by Pope and by Monier-Williams, and only a few of the more significant 167 168 LEAD POISONING observations need be summarized here, some of the data accumulated by the Laboratory of the Ministry of Health (Monier-Williams) being pre- sented in Table 18. Canned foods may contain appreciable amounts of lead derived from the solder used to close the seams of the cans, the tin- plate used to coat the cans or the “tin” coating of the cheaper cooking utensils used in the preparation of the foods. Canned sardines may con- tain relatively large quantities of lead due to the fact that the fish may be cooked, before canning, on the grills coated with an alloy of tin and lead. Substances packed in tin-foil (cheese) or in lead-lined chests (tea) may become contaminated from this source. Fruits and vegetables may con- tain large amounts of lead as a result of the common use of lead arsenate spray as an insecticide, and wines may contain lead if made from grapes subjected to this treatment. Lead has been found in a variety of fresh fish, shell-fish and crustaceans, derived presumably from contamination of the water in which they had lived (Chapman and Linden). The use of lead chromate as a coloring matter in foods (confectionery, egg-powder, pepper, etc.) is fortunately rare at the present time, being prohibited by law, but this source of contamination is not entirely eradicated, lead chromate having been found in several samples of turmeric, one of the ingredients of curry powder (Monier-Williams). Lead has been found also in a number of other materials employed for coloring foods (ferric oxide, ultramarine, Rhodamine B, Damson Blue, etc.). In past years, appreciable quantities of lead have been found in tartaric and citric acids, cream of tartar, acid calcium phosphate baking powders and self-raising flours, the source being apparently the pans or other vessels in which these substances are prepared. Lead may also contaminate foods cooked in earthenware vessels coated with lead glaze. Pewter vessels, some of which contained large proportions of lead, were formerly a source of potential danger in this connection. Lead has been found in beer, in some samples in concentrations of 0.3 to 3.0 mg. per liter and occasionally as much as 9-13 mg. per liter. Con- centrations of 3-60 mg. per liter have been reported in cider. This has been due chiefly to contamination from lead pipes used for conveying these liquors from the casks to the bar, the pipes often being coated internally with a thin film of tin, which affords little if any protection from the cor- rosive action of cider. Aub and his associates found 0.6-52.7 mg. per liter in distilled liquors and 0.00-75.4 mg. per liter in wines, only 2 of 18 samples of the latter being free from contamination. In the case of distilled liquors, the source is apparently the lead worms which are used as condensers. In the case of wines, the fruit acids, chiefly tartaric, are excellent solvents for the majority of lead compounds which are readily dissolved from crocks glazed with lead glaze, metal vessels containing solder and copper vessels NORMAL INTAKE OF LEAD Lead Content of Foods and Beverages (in milligrams per 1000 grams) Fruits: Strawberries (stalks re- moved)... . LV... ceaia ll Cherries (stones removed)... Gooseberries................ Red currants (stalks re- IOYOMI, vith vo 0 vin sivimns v4 Black currants.............. Black grapes................ Peaches. F003. dite BOONE... ov eisiv ve nniinnn s Vegetables: Tomato puree............... Tomato juice. .............. Canned peas (imported)... .. Canned peas (domestic). .... Runner beans............... OIRO... 4. vis oi no wininms da Coen Pag... coiiss ii vans onl Dried poag........00iuneens Tomato soup (canned)...... Fish Foods: Salmon and shrimp paste... . Sardine'paste............... Bloater paste............... Brisling (aluminum con- BONORY, . dh ad ok Bk ais Shrimps (aluminum con- BRINELY. iii sod six ass nate Silds (aluminum container).. Silds (tinned can)........... Creamed crab (canned)...... Herring roes............:.... Canned and Bottled Fruits: PEATE oi vn ek sie as Apritots....... 0... a Pineapple....... 0c. ied TABLE 18 (Monier-Williams) Dried and Crystallized Fruits: Basing. or. co tit ans fie Nil PIER is vi iid Dd oo tae Nil Apple Rings................ 0.2 Prunes. 2h pA ae 0.6 Cereals: Cake mixture A............. Nil Cake mixture B............. 0.5 Oatmeal... iv oviid inns, Vile Nil Corn flakes. ......... v.05 Nil White bread................. 0.2 R100. ..0ucinniioys mines sie 0.4 Self-raising flour............ 2.4 Condiments: Black pepper................ 2.0 WHIte Pepper... ..... «veh 1.0 Curry powder A............. 1.8 Curry powder B............. 21.6 Mustard... .....ccconve seid Nil Ground ginger.............. 0.4 Mixed spice................. 1.6 Nutmeg........ Lo. conn 8 0.2 Cloves. >. ul. Joo malig 4.0 Dried gravy A........ cis 2.0 Dried gravy B.............. 4.4 Dried SoUD. ise bruins dh 08 1.4 Milk Foods: Malted milk. .... iii suiia 0.4 5 Chocolate milk.............. 1.2 Coffee and milk preparation.. Nil Condensed milk............. Nil Butter... ... cv 00 HL J SINY Soft wrapped cheese......... Nil Beverages: BOE... ota id odie a A Nil China tea (loose)............ 1.9 China tea (lead foil)........ 4.4-6. Indian tea (loose)........... 10.2 Ground coffee.............., 0.4 Coffee essence............... 0.3 Aerated water............... .Nil-20.0 Beer (at bar, as served)..... 0.3-13.0 Cider (as served)............ 60.0 169 170 LEAD POISONING TABLE 18—Continued Miscellaneous: Meat Foods: Turmeric root A............ 282.5 Beef paste... cody cre cov rivils Nil Turmeric root B............ 10.0 Corned beef (canned)....... Nil Damson Blue paste (food Chicken and ham paste. .... Nil BOLOLY. i cls, Lenin Liens 337.0 Tongue and ham paste...... Nil Apple Green paste (food Beal PONG ..cuvniss ss sinininnis 6.8 GOIOEY. Lis «51 wpa Fpoit 85.0 Moat extract............c... 1.6 Apricot Yellow paste (food Meat extract cubes.......... 2.0-2.4 GOLOPI NL hs onda len viva 0 ee 54 44.0 Liquid Saffron color......... 5.2 Baking powder (alum and phosphate)........ + .rve0e 7.1 Baking powder (tartrate)... 1.1 Margaring.. o.com cons innas 0.3 Gelatin od. ..codeis ses serine 2.0 Table jelly. .......4«0 inns 0.3 Blanc Mange powder........ 1.0 Custard powder B........... 1.2 Custard powder A........... Nil New laid eggs............... Nil HG NR Nil Currant jam... ... . -.owsdty Nil Plum iam... csc snrunvsess Nil tinned with an inferior tin-lead alloy. Carbonated water, dispensed from soda fountains with soldered fittings, has been found to contain as much as 20 mg. per liter, 409, of one series of samples containing 0.7-15 mg. per liter (Henderson). The important question of the lead content of drinking water has re- ceived careful attention. The largest tolerated amount per liter has been variously stated to be 0.7 mg. (Steiner), 1 mg. (Gartner), 1.4-1.5 mg. (White) and 0.35-0.75 mg. (Lewin). Teleky’ states that 0.72-2 mg. daily “may be tolerated, and P. Schmidt! cites a case in which there was a daily intake of about 2.6 liters of water containing 2.9 mg. of lead per liter, manifestations of lead poisoning developing in about two years. On the basis of an investigation of a number of representative samples of domestic water (British), Ingleson estimated the average daily intake of lead in drinking water to be about 0.2 mg., due largely to the use of lead or lead- containing pipes or fittings. In a survey of this problem, he states that the general opinion is that 0.3 mg. per liter is a safe concentration, that 0.5 mg. is permissible and that 0.7 mg. per liter is likely to cause chronic lead poisoning. Many believe that the maximum safe concentration is con- siderably lower than 0.3 mg. per liter, and the American Public Health NORMAL INTAKE OF LEAD 171 Association has set 0.1 mg. per liter as the maximum concentration allowed in potable water used by interstate carriers. : Kehoe! states that the average American adult ingests (food and drink) daily quantities of lead varying from 0.05 mg., rarely, to somewhat more than 2.0 mg., occasionally, the mean quantity over a period of months being approximately 0.33 mg. To this must be added about 0.08-0.1 mg. taken by inhalation. According to Monier-Williams, the average amount of lead entering the body of a normal individual in ordinary circumstances is about 0.5 mg. daily (0.22 mg. in food, 0.20 mg. in water, 0.08 mg. in inspired air). Under normal conditions, with an intake of this magnitude, the greater part of the ingested lead is not absorbed, passing through the gastrointestinal tract to be eliminated in the feces. Under such circum- stances, although minute amounts may be deposited in the skeleton (p.21ff.), the individual is in a state of approximately perfect balance with regard to lead, the quantity excreted being equal to that taken in. However, in view of the marked variation in the lead content of foods and beverages, and because of the ever-present possibility of exposure to additional quanti- ties of lead from other sources, the so-called “normal” lead in foods, water and air cannot be dismissed as harmless. This is particularly true because of the existing state of uncertainty as to the maximum intake of lead compafible with perfect health, a subject which is discussed elsewhere (p. 94ff.). As stated by Monier-Williams, It cannot be emphasized too strongly that in discussing the amount of lead which may be considered as negligible in food, consideration of the toxic limits, so far as these are defined by the appearance of symptoms of poisoning, is beside the point, and tends to obscure the real question. What we want to know is not so much the toxic limit as the safe limit, if indeed any limit, however small, for a cumulative poi- - son can be regarded as safe. We cannot assume that there is a sharp dividing line between what is obviously toxic, giving rise to lead colic or other symptoms, and what is completely harmless. In all probability there is a range of lead intake between these two extremes in which some effects, however slight, are produced upon metab- olism, effects which, clinically, may be difficult or impossible to detect or to ascribe to their real cause. . . . It is clear that no general limit for lead applicable to all foods would be satisfactory. The presence of lead in any particular food must be regarded not only as a danger in itself, but as a contribution, more or less serious, to the total daily intake of lead from all sources. CHAPTER IX TREATMENT OF LEAD POISONING Three major problems are involved in the treatment of lead poisoning: (1) prevention, (2) curative measures and (3) symptomatic treatment during acute toxic episodes (Aub, Fairhall, Minot and Reznikoff). INDUSTRIAL CONTROL OF LEAD POISONING* By May R. Mayers, M.D. The prevention of lead poisoning is a subject of considerable magnitude since, in the last analysis, it is a matter which requires the technical evalua~ tion of each plant and process where lead is being handled for the purpose of making concrete decisions specifically applicable to that particular situation. Each plant has its own special problems depending upon the type of building, size and number of workrooms, the number of employees, the chemical and physical properties of the lead handled, and the special machinery or procedures employed for processing it. Current information with reference to the amount of lead in the air and current medical data as to the extent of lead absorption by workers in the several lead depart- ments of a plant are only examples of the type of technical evaluation required for successful control of the lead hazard in a given plant. However, there are a certain number of problems common to all of the lead industries. The melting and casting of metallic lead, for example, is apt to be done in very much the same way regardless of the end product to be manufactured. It is the purpose of this section, therefore, to stress particularly the prevention of lead poisoning in certain basic lead processes; only occasionally selecting for more detailed discussion typical problems in specific industries. In general, the amount of lead in the air of a workroom should be kept below 1.5 mg. per 10 cubic meters of air for continuous exposure. Housing and Building Construction It is of prime importance that lead industries be housed in modern buildings. Old factory buildings that have grown up with the industry * A more detailed presentation of this subject will be found in Special Bulletin No. 195, New York State Department of Labor, Division of Industrial Hygiene, by M. R. Mayers, M.D., and M. M. McMahon, 1938. 172 TREATMENT OF LEAD POISONING 173 offer every opportunity for the accumulation of dust. It is literally im- possible to keep them clean. The older the building the more difficult it becomes to keep it free from lead dust, especially so in old converted buildings. Workrooms where lead is handled should be spacious and planned with care. The design should be simple and the materials used in their construction both durable and readily cleaned. Attention should be directed toward keeping the room from getting cluttered up. Excess equipment, such as workbenches and receptacles, when not in use, should be removed whenever practicable to storage rooms, which preferably should adjoin the workroom or be readily accessible. This will facilitate good housekeeping and reduce the dust exposure. Air Space per Worker. In every workroom where metallic lead is being heated or melted there should be at least 500 cubic feet of air space for each person employed therein. Where other lead processes are carried on there should be 250 cubic feet of air space for each person employed therein, with some exceptions. In computing the air space, no height over 12 feet should be taken into account. These workrooms should have a sufficient number of windows to provide adequate light and natural ventilation, unless there is an adequate air-conditioning system in opera- tion. Where lead workers work in rows along workbenches, as those who do pasting in storage battery plants, solderers or those engaged in file- cutting by hand, the distance between the center of the working position of any two workers should be not less than 5 feet. Floors. The floors should be graded for drainage and impervious to water and should also be smooth so that no lead dust can accumulate. Thus, the floor immediately around mills, mixers, grinders or open vats, or where dry lead compounds are packed or manipulated, where pasting is done in the storage battery industry, where there is enameling, dipping or glazing in the manufacture of pottery, where cooperage of old casks or barrels which have previously contained lead compounds is carried on, should be of smooth, impervious material and should be kept damp at all times. Floor grids are of great practical value in preventing the stir- ring up of accumulation of lead dust on the floor. In the printing industry, racks for type cases should be either built flush with the floor of the composing room so that no lead dust or lead serap will accumulate underneath, or at a sufficient height above the floor so as to permit ready cleaning of the floor beneath them. No material, other than ingots or pigs of lead, should be deposited or allowed to remain in any part of the workroom. Walls and Ceilings. In every workroom in which a lead process is carried on, the walls should have a smooth surface, should be kept in good repair and should be washable. Walls and ceilings, or such parts as are 174 LEAD POISONING painted with oil paint, should be repainted once a year. Oil-painted walls that are varnished should be revarnished every other year. Walls and ceilings, or such parts thereof as are not painted with oil paint, varnished or made of glazed brick, should be white-washed at least once every six months. Workbenches and Tools. All workbenches where lead materials are being handled should have a smooth surface, impervious to water, and should be kept in good repair at all times. The workbenches used for pasting or handling of raw oxides of lead in storage battery plants, for example, should also be provided with raised edges or a hopper for catching excess paste so that it does not fall to the floor. In addition, such work- benches and materials should be kept constantly moist while pasting is being done. All workbenches should be kept free from all material not required for, or produced in, that particular process. In electrotyping, in the process of backing plates, no lead should be permitted to splash on the floor. A narrow triangular gutter, running along the “backing” table is useful for catching lead scrap, instead of allowing it to fall to the floor and subsequently be ground into dust. All workbenches at which lead materials, capable of giving off lead dust, are being handled should be provided with proper means for removing this dust at its source. In one storage battery plant, the value of the lead dust that was recovered more than paid for the cost of the installation and maintenance of the down-draft ventilation system. This has since been confirmed in other storage battery plants and other lead industries. Shelves, Window-Sills and Furnishings. These should have a smooth, washable, surface and should be kept in good repair and free from lead dust. The cleaning should be done at the end of the workday by means of a damp cloth or, preferably, with an efficient vacuum cleaner. Housekeeping Good housekeeping is perhaps the most effective single means of re- ducing lead exposure. Indeed, it is an absolute essential, quite regardless of whatever other measures are taken for the control of lead poisoning. Good housekeeping involves the daily removal of all lead dust generated in the course of each day’s work. This is best done by vacuum cleaner— using either a portable, or preferably, a built-in system. Filters used in connection with portable vacuum cleaners should be frequently checked. Unless kept in good condition, the dust collected by portable vacuum cleaners may be returned to the air of the workroom causing serious air contamination. Blowing off of lead dust from workbenches or equipment by the use of a compressed air hose and dry sweeping of floors should never be per- TREATMENT OF LEAD POISONING 175 mitted. Wet saw-dust is an aid to hand sweeping operations. How- ever, any and all cleaning operations, which unavoidably tend to scatter dust and so contaminate the air of the workroom, should be conducted only at the end of the day, after all workers have departed excepting those doing the cleaning. Workers who are given the responsibility for the cleaning operations should be instructed in the importance of their work, and the hazards involved, and should be provided with suitable respiratory protection. Good housekeeping, however, implies even more than daily washing or vacuum cleaning of floors, workbenches, tools, equipment and other items where lead dust may accumulate in the course of the day’s work. It includes such matters as providing special storage rooms for stocks of lead so that they will be kept off the floor of the workroom; providing a sufficient number of covered waste receptacles along workbenches and elsewhere to receive waste scraps of lead, so that they do not find their way to the floor of the workroom; separation of workrooms in which lead materials are handled from adjoining rooms so as to confine the lead to limited parts of the plant where control measures can be concentrated. Lead and lead dust which is permitted to remain on workbenches, day after day, will fall on the floor, be ground under foot and will be an ever- present, source of significant amounts of lead in the air breathed. The same is true of lead dust on shelves, ledges or other parts of the room, lead on hand tools, utensils, ete., all of which should at all times be kept scrupulously clean. No amount of expensive ventilation will make up for fundamental deficiencies in good housekeeping. Illumination Adequate illumination of the workroom is essential not only to good eyesight, but to good housekeeping. Dark corners are difficult to keep clean. Good housekeeping in relation to bulbs and lighting fixtures is frequently overlooked even in plants where considerable attention is given to dust control. Lighting fixtures may appear to be clean on the under surface, but if one takes the trouble to remove accumulations of dust from the upper surfaces, candle power will be conserved and workers will have the benefit of the total illumination provided. Exposure to Metallic Dust and Fumes Metallic lead is handled extensively in industry, usually as pig lead or in the form of lead castings. The latter may be polished, filed, trimmed, or cut off. Little danger is involved in handling cold, metallic lead, in any of these forms. Where castings are filed or polished, however, creating 176 LEAD POISONING lead dust, or where small pieces of metallic lead are permitted to fall to the floor and be trampled upon, a serious dust hazard may be created. The finer and lighter the particles of lead, the more readily are they in- haled and the more dangerous do they become. In plants where file cutting is done by hand, the files are cut on a lead bed, which produces considerable dust that should be removed. The Printing Industry. The printing industry is unique in that lead exposure is practically confined to metallic lead in the form of dust or fumes. It will, therefore, be discussed in some detail with a view to em- phasizing certain general principles, many of which are applicable to other industries involving a similar type of exposure. Lead dust is to be found in abundance in the composing rooms of many printing establishments. The dust arises in various ways. It may accumulate in the drawers of type cabinets from the rubbing together of pieces of type metal. A considerable amount of lead may accumulate on the floor from the spilling of molten lead or from the dropping of lead fragments on the floor. This is true especially of such processes as the backing of plates in electrotyping and in stereotyping. Furthermore, in the cleaning of type-cases and linotype plungers, considerable lead dust is discharged into the air. Some of this dust may be inspired directly by the worker and the remainder ultimately settles on the floors and upon everyone and everything in the room. Unless a vacuum cleaner is used, floors should be sprinkled with wet saw-dust before sweeping is done at the end of the shift, so that lead dust will not be disseminated throughout the workroom. Lead Pots. The dangers arising from molten lead are not appreciated sufficiently, probably because the fumes are not visible. The heating and melting of lead in pots is a process common to many industries, in- cluding that of printing. Only in those pots that are heated by electricity and are controlled thermostatically has it been demonstrated that the molten lead seldom reaches a temperature sufficiently high to volatilize it. Under all other conditions where lead is apt to approach or exceed a temperature of 1000°C, local exhaust ventilation is necessary. Molten lead, near or above the boiling point (1629°C.) gives rise to highly danger- ous concentrations of lead in the air. Lead pots require adequate enclosures and adequate local exhaust ventilation. Working openings should be as small as practicable. The ventilating system should not only provide for removal of lead fumes but also for the removal of carbon monoxide or other products of combustion generated by the fuel used to heat the pots. Particularly during the summer months, when there is maximum TREATMENT OF LEAD POISONING 177 natural ventilation, one may develop a false sense of security. During the winter months when doors and windows are closed, workers may be subjected to toxic concentrations of lead unless proper ventilation is provided. Occasionally when dependence is placed only upon natural ventilation, workers have been poisoned because they inhaled the dust before it was vented. “Drossing Off.” In the printing and some other industries, it is custom- ary to throw dirty pig lead together with scrap metal into the lead pots. The type metal contains some antimony and tin. These are melted to- gether for the purpose of recovering the metal. As the lead assumes a molten form, a scum forms on the surface of the metal. Any dust, dirt or grease that had adhered to the scrap metal when it was thrown into the melting pot, adds considerably to the quantity of floating scum or dross. The grayish color of the dross is due to the fine, flaky particles of gray lead oxide which, because of their light weight, are discharged into the air when the molten metal is stirred or agitated. The skimming process or ‘“drossing off’ introduces the fluffy oxide of lead into the air. In addi- tion to this, fumes of lead will be given off if the metal pots become suffi- ciently hot, as is frequently the case when not controlled thermostatically. Since lead fumes and the very light oxide of lead (dross) reach the alveoli of the lungs more readily than other forms of lead dust, their presence in the atmosphere of the workroom must be reduced to a mini- mum. Agitation of the molten lead in the process of ‘“‘drossing off’ is the principle factor in liberating the fine flakes of lead oxide into the air. This operation should, therefore, be done with the greatest caution, not merely for the safety of those who work in the room, but especially for the man engaged in ‘“drossing.” Too frequently, the operator opens the door of the furnace, or raises the hood over the lead pot, and skims off the surface of the molten lead with a long-handled ladle or other implement. This scum-like material is deposited in an open tray or some other re- ceptacle, which the operator carries with him. When the dross-container is full, its contents are apt to be poured back into the lead pot with a flux and remelted for future use. It is of interest that even in some metropolitan newspaper plants, where linotype pots are heated electrically, controlled thermostatically and fed automatically, and where the most modern stereotype machines are in use, there has been little advance over the old-fashioned method of “drossing off’’ by means of the hand ladle and open tray. The hazard has increased because of the larger quantities of oxidized metal handled by the individual worker assigned to this task. In view of the many ingenious engineering contributions to industry in recent years, and 178 LEAD POISONING considering the large number of industries in which lead pots are used, it is surprising that some automatic device for ‘“‘drossing off’’ these pots has not been perfected. It is essential that all workers engaged in ‘“‘drossing off” operations wear suitable respirators. This work should be done at the end of the workshift if adequate local exhaust ventilation is not available. Every appliance in which considerable lead is heated should be pro- vided with a suitable closed receptacle for deposition of the dross. Lead Casting. In all lead casting operations, hand-pouring should be replaced by machine processes wherever possible. Pouring may be done automatically by machinery or it may be accomplished by means of a pump and spout operated by hand. Either method is a distinct improve- ment over the old hand-ladle pouring methods. Heat-Treating of Metals. In the tempering of metals, special attention to ventilation must be directed to the following operations: 1. Melting of the lead. 2. Brushing of lead oxides from metal objects which have been tempered, in the lead bath, as in the manufacture of cutlery, files, tools of various sorts, ete. A layer of charcoal spread over the surface of a lead bath will control dispersion of lead fumes from the bath. Exposure to Lead Dust or Fumes from Lead Compounds Exposure to lead dust or fumes from the various compounds of lead are to be found especially in the manufacture of storage batteries; in the manufacture of white lead, red lead and other compounds of lead; in paint making; in the manufacture of colors and inks; and in the manu- facture of pottery, tiles, glazed sanitary ware and porcelain. Lead processes involving the handling of lead materials capable of giving off dust include dumping and mixing operations; the placing of such materials in hoppers or chutes; the packing of such materials into cases, carts or other containers for conveyance to a furnace, or from one place to another in the workroom. Any and all such manipulations of these lead materials should be carried on in one or another of the fol- lowing ways: 1. In a wet state 2. In mechanically closed air-tight compartments 3. Provision shall be made for the removal of dust at its source 4. Isolated from other plant operations When mechanical processes are impracticable or unavailable and hand operations are employed, openings should be kept as few and as small as possible and provided with lateral exhaust ventilation carrying the dust away from the worker through horizontal slot openings. TREATMENT OF LEAD POISONING 179 Lead Smelting. In all lead processes carried on in connection with the smelting of lead ore or zine, containing more than 5 per cent lead, for example, proper provision should be made to have all dust and fumes generated promptly and effectively removed at their source unless the lead materials are handled in a wet state or in mechanically enclosed apparatus. This is applicable specifically to such processes as the following: 1. Crushing, sifting, dumping or mixing of lead ore with other in- gredients. 2. Heating lead materials, including scrap lead. 3. Charging furnaces or retorts with lead materials. 4. Manipulating lead materials in any furnace or retort including lead testing or sampling. 5. Removing lead materials from any furnace or retort. 6. Depositing lead materials, or transferring them into vessels, carts or other receptacles by any means whatever (including hoppers, - chutes, barrel packers, etc.). 7. Conveying lead materials from one part of the plant to another, unless this is done in an enclosed system. 8. Handling or treating of lead materials by means of pulverizers, chasers, corrosion grids, or in dry pans or other apparatus for drying pulp lead, unless these are entirely enclosed or dust tight. Potteries. In potteries, all lead glaze which is used in the manufacture of pottery, utility, sanitary ware and tiles, should be fritted and should contain no lead compounds which have not been vitrified by fusion. All these processes which are productive of lead dust should be provided with adequate ventilation. Examples of such processes are the following: 1. Shovelling, mixing, weighing and carrying of lead materials for the making of glaze, and the grinding of frit. 2. Charging and emptying fritting ovens. 3. Dipping and sponging biscuit ware. 4. Stacking glazed ware on boards or trays, and transferring them to the kilns. 5. Scraping, finishing or fettling of glazed ware. 6. Brushing, in connection with decorating. 7. Color making. The processes in connection with glaze-making which require special attention from the standpoint of ventilation, are the following: 1. The hand mixing and weighing of materials which are to be con- verted into frit or glaze. 2. Mixing (mill). 3. Firing. 4. Sagger and frit breaking. 180 LEAD POISONING . Glaze crushing. . Frit grinding (chaser). . Frit screening. . Hand mixing and weighing of frit. Storage Battery Manufacture. In storage battery manufacture, special provisions for dust removal must be considered especially in connection with: 1. Melting of lead or materials containing lead. 2. Handling of raw oxides unless done in an enclosed apparatus to pre- . vent the escape of dust into the workroom. 3. Pasting, unless the method insures that the paste and the machine are kept constantly wet. 4. Trimming, brushing, filing, or any other abrading or cutting of pasted plates, giving rise to dust. 5. Group burning. 6. Plate stacking. Recent developments in mechanization of processes in storage battery plants—especially those involving the manufacture of lead oxide paste and the application of this paste to the grids—is of great interest in point- ing the way to the possibilities for the prevention of lead poisoning in this hazardous industry. In the preparation of the paste, the lead oxide powder is dumped onto the floor into ventilated, enclosed and isolated hoppers which feed the dry powder into completely enclosed chaser mills operating under neg- ative pressure. The necessary sulfuric acid used in making the paste is supplied to the mills. Only one man is required to dump these kegs of lead oxide powder into the hoppers; he is the only worker on that floor, and since the hoppers are provided with good lateral exhaust ventilation, he is in general well protected. However, where exposure to lead dust is believed to be high, despite these precautions, respiratory protection need be provided for only the one man. In pasting of the grids, machines have been developed and are now in use which eliminate all hand pasting operations and the hazardous ex- posure to lead dust which always accompanies these hand operations. Manufacture of Dry Colors. In the manufacture of dry colors, where “breathers” have been installed as dust collectors in connection with grinding or mixing mills, they should be enclosed in dust-tight metal boxes and connected to a separator which discharges directly out-of-doors. Such a system should have the discharge properly filtered. Where sepa- rators or vents from separators do not discharge directly out-of-doors, special ventilation should be provided for dust removal. In color manufacturing, lead is dumped by hand from bags into solu- 0 JC TREATMENT OF LEAD POISONING 181 tions which are sometimes hot. There is dumping and shovelling of dry lead compounds from trucks, their removal from the drying ovens into wheel barrows, and often on to the floors near the grinding mills. The dry materials are either shovelled from the floor into the mills or dumped down a chute into the mills from an open barrel. In the mills they are ground and pulverized in a dry state. These are extremely dusty opera- tions, and adequate ventilation should be provided. The packing of finished colors—all in pulverized form—into barrels also creates consider- able dust. The problem here is rather difficult as the dust is not a by- product of the process but the primary material, and there is no desire to waste it. Similarly, in paint manufacturing, it is customary for various ingredients such as chrome colors and lead oxides to be lined up in sacks and barrels in the workroom. The worker then goes from one to the other with a scoop, taking out the amount of material required and transporting it by hand to a mixing machine. The extent to which dry lead compounds are still scooped up in this primitive way is inexcusable. It is by no means confined to paint manufacturing, but may be seen in a great many of the smaller lead industries. Manufacture of Lead Oxides. In the manufacture of lead oxides, cer- tain batches of litharge or red lead are made for special uses. After weighing, the special “batches,” as they are called, are often dumped from the furnaces into batch carts, and dumped through a grating into a storage hopper below. From this hopper, the lead is then mechanically conveyed upstairs to the mills and screens. This dumping into the batch cart is usually done under an exhaust hood but is a hazard nevertheless. This is easily the most dangerous operation in such a plant. In view of our efficiency in industry, it is indeed strange to observe the paradoxes to be found in some industries. There are plants, for example, where rows of costly dust-tight mills and grinders of various sorts, connected to efficient exhaust systems, have been installed so that during the mixing and grinding operations there is no visible dust of any kind. Even the machines may be charged by means of enclosed hoppers. And then in the same plant one finds that the only method employed for discharging a batch of dusty lead material is that of dumping it into an open cart or shovelling it out by hand—thereby covering not only the man doing this work, but much of the floor about him. Exposure to lead in open barrels, and the shovelling of lead is by no means confined to the industries or processes above mentioned. Wherever possible these hand processes should be mechanized so that lead materials may be handled and conveyed without exposing workers to lead dust unnecessarily. Where dust cannot be sufficiently eliminated at a par- 182 LEAD POISONING ticular spot, means should be provided for its prompt removal, so that it may not contaminate the air of the workroom. Workers engaged in these hazardous processes should be provided with, and required to wear approved respirators. Every machine or apparatus which, in its operation, produces waste material containing lead or any of its compounds, should be provided with one or more suitable receptacles capable of receiving all such waste materials, so that none can be deposited on the floor or elsewhere in the workroom. All such receptacles should be provided with well fitting covers and should be kept covered when not in use. No lead materials that may give off dust should be deposited or stored in any open receptacle where such dust may get into the atmosphere of a plant where there are workers. White Lead Processes. In the Old Dutch Process of white lead manu- facture, there are specific hazards which should be considered. Each bucket into which corrosion pots are emptied, or into which empty corro- sion pots are dumped, should be provided with a cover and the method for dust removal should be flexible and movable with the bucket. This should be at all times in operation during the dumping process, as it is the most dangerous operation in lead corrosion. Each buckle-beater should be provided with the means for prompt removal of the dust that is generated and should always be in operation when the corroded buckles are being dumped therein. The process of wetting down corrosions prior to, and subsequent to, their discharge from cylinders should be carried out with a minimum dissemination of dust, otherwise lead poisoning will develop. Drying ovens should be entirely enclosed, and there should be no hand raking of lead materials during the drying process. Such raking should be accomplished by mechanical means. The following is an example of one of the more efficient methods of drying: The lead pulp, thoroughly mixed and ground in the various wet processes, is pumped up to a tank in the oven room, forced from this tank through steel rollers on to a wire mesh conveyor belt. The wire mesh, coated with pulp, then passes into the drying oven where it is carried slowly up and down over rollers—in what are called festoons—meanwhile travelling horizontally through the long drying oven. The festoons are met at the end of the oven by a rapidly moving iron paddle or beater which beats the dry lead off the wire mesh very much as one would beat dust from a rug hanging on a line. The dry lead falls into a hopper and is carried down to storage bins and then conveyed to dry packing machines. The man in charge of the oven wears a respirator at all times. TREATMENT OF LEAD POISONING 183 In another special process of white lead manufacture, the lead has to be tested from time to time. The worker in charge opens a small door in the cylinder and scoops out a sample. He should be required to wear a respirator. Semi-Wet Processes. In general, the grinding or smoothing out of lead materials even in a semi-wet state by means of stone mills, water mills or other methods should be carried out under conditions which will not permit the dust generated to become disseminated into the air of the workroom. The water tends to evaporate and leaves a dusty sediment which can be blown into the air. All such mills should, therefore, be provided with means for the prompt removal of all dust. This applies to all industries using a semi-wet process. Exposure to Lead in Cleaning and Repair of Equipment It is a common experience in visiting plants to find that workers like the general helper who “drosses off” the pots, or the skilled mechanic from another department who is called in to repair some equipment does not take the necessary precautions to avoid inhaling lead fumes or dust. Often the maintenance man or pinch hitter, whenever there is trouble, is the first to show symptoms of poisoning. As a matter of experience, the number of cases of poisoning is disproportionately large in the case of these men in maintenance work. No person should be permitted to enter any furnace, melting pot, retort, condensing chamber or flue until it has been reasonably cooled and well ventilated. No person should be permitted to work in any furnace flue (unless damp) or condensing chamber for more than three hours in any one work- ing day. No person should be permitted to repair or clean any machinery which has been used for lead materials except when such materials are damp. Re-coopering or heading of barrels which have been, or are being used for lead materials should be provided with means for the prompt removal of any dust that may be given off. Much of this kind of work has to be done in the manufacture of white lead, red lead or litharge. Even the heading of newly filled barrels gives rise to considerable dust. Similarly, in lead smelting operations the sacks in which lead materials have been packed should be cleaned in a closed apparatus. In the cleaning and repair of workrooms and machinery, attention should be directed to the following: 1. The cleaning of the interior structure of the workroom such as floors, walls, ceiling, workbenches, window-sills, etc., and also the cleaning of 184 LEAD POISONING shelves, furniture, furnishings, or hand tools or apparatus in which lead materials are being handled should be done by a wet process and workers should be required to wear respirators. 2. The floor of every workroom should be washed once a day by means of a hose after being sprayed with water. This should be done when no other workers are in the room. 3. In storage battery plants the racks or shelves of the drying room should be cleansed daily, after being thoroughly dampened unless an efficient vacuum apparatus is used for this purpose. 4. All workbenches should be washed daily after being dampened. 5. All machines and apparatus in which lead materials are handled or manipulated should be kept free from lead dust on the outside by wash- ing and cleaned daily on the outside. It is not an uncommon experience in visiting plants where paint is being mixed in machines, to find that not only are the outsides of these machines heavily coated with a thick layer of lead dust, but even the floors, the rafters and pipes. In one plant where white lead paint was being mixed, the interior of the room, including the beams, rafters, walls, window-sills, machines and floor were covered with a thick compact layer of white dust (containing lead). Special Cleaning Problems in Printing Plants. In the printing industry, as in other industries, perhaps the greatest exposure to lead dust occurs in the processes of cleaning machines, utensils and general equipment. Special precautions are required in these operations. Since exposure to metallic dust in cleaning operations is perhaps more common in the print- ing industry than elsewhere, special recommendations are suggested. The general principles are applicable to any industry where similar ex- posure occurs. The casting mechanism of linotype machines, also the molds of stereo- type machines, melting pots, pumps and connections should be cleaned at a time when no other work is being done in the room, and adequate ventilation is provided. Any worker engaged in this cleaning job should wear an approved respirator. Linotype plungers are usually cleaned once a day, and in some plants more frequently. In the small plant, with but a few machines, the plungers are cleaned by the linotype operators; but in the larger plants, one man (usually the assistant mechanic) does all the plunger cleaning. In large newspaper plants, one worker may clean 40 to 50 plungers at least once a day. In many plants plunger cleaning is done crudely. The plungers are carried one by one to the dross barrel and brushed vigorously. In some instances the plungers are brushed off out on the fire escape. Me- TREATMENT OF LEAD POISONING 185 chanical means for cleaning plungers are now available. When still done by hand the worker should wear an approved type of respirator. Cleaning and Repair of Leaded-Gasoline Tanks. Tetra-ethyl lead pre- sents a special problem in prevention because it is the only lead substance which is readily absorbed through the skin. In the cleaning out of tanks which had contained leaded gasoline, several fatalities have occurred—but only when such tanks were cleaned without the use of proper safeguards. The potential hazard to health in these operations arises from exposure to volatile organic lead compounds in the sludge and also to these compounds in the scale. A further danger exists from the inorganic lead compounds in the water bottoms and the sludge resulting from treating operations other than tetra-ethyl lead. In cleaning or repair of these tanks, therefore, whether above or under- ground the following precautions should be strictly followed :* (1) A blower-type or positive-pressure airline hosemask should be worn by any person who enters a leaded gasoline tank that has not been thoroughly cleaned. This applies not only to tank cleaners but to all others who go into the tank for any purpose. (2) Hoselines for airmasks must be kept clean. If a workman notices any odor, as of gasoline, while wearing his mask, he must leave the tank at once and find the cause or get a new hoseline. (3) All workmen must wear clean clothing from the skin out; also acid-proof gloves and rubber boots of good quality and in perfect condition. (4) Clothing must be changed and laundered and a bath must be taken every day, either at the end of the day’s work or when the job is finished. If at any time clothing gets soaked with gasoline or sludge, the workman must bathe at once and put on clean clothes. At the end of each day, and after the job is completed, respirators, boots, gloves and tools must be cleaned. (5) Sludge is dangerous even after it has been taken out of the tank. It should be kept wet and buried at once, in a place where it will not be uncovered later. Repairmen engaged in any type of work in tanks that have not been thoroughly cleaned must follow the instructions given above. If possible, all cold work should be done only after the tanks have been thoroughly cleaned. Welding and other hot work should never be done until the tanks have been cleaned and all areas that may get hot are down to clean metal. The hazard of lead poisoning is present whenever men are called upon to enter any tank which has contained leaded gasoline. Tetra-ethyl lead is toxic when it enters the body, and it may do so through inhalation, skin absorption, or by way of the digestive tract. The entering of a tank is usually dictated by the need for cleaning, repair or inspec- tion. Normally the interior inspection of both steel and concrete tanks need be made only when cleaning of the tank is required. Finish leaded gasolines have been held in storage for as long as three years without deteriorating below specifications, ex- cept in color. The interval between tank cleanings is, therefore, customarily a * Recommended by the Ethyl Corporation. 186 LEAD POISONING matter of years. Normally, the character of the settlings taken from the tank’s sump through the draw-off, determines the need for tank cleaning. If the tank is leaking to a degree that it is unwise to continue the tank in operation, it may be neces- sary to empty it, in order to make repairs. The special hazards in connection with the cleaning of tanks are briefly sum- marized: a. The Ethyl fluid may be trapped in the bottom sediment of leaded gasoline storage tanks, and the agitation or sludge, when cleaning tanks, allows it to vaporize. This vapor may be present, even though the tank has been gas freed, as determined by the combustible-gas indicator. This condition will exist until the tank has been thoroughly cleaned. b. Future changes in the composition of high octane gasoline will tend to increase toxic hazards. ¢. The hazards of fire, explosion, and asphyxiation are present, in addition to the hazard of lead poisoning. The American Petroleum Institute, New York City, has issued an ex- cellent and comprehensive pamphlet of instructions on the cleaning of petroleum storage tanks, with special emphasis on all the hazards. General Safe Practice Measures Ventilation. The amount of lead in the air of any workroom should never be permitted to exceed 1.5 mg. per 10 cubic meters of air, for con- tinuous exposure. Where the concentration of lead in the air tends to be in excess of this amount, all processes giving off lead dust or fumes should be carefully studied with the view of preventing further contamination. Each plant presents a technical problem for which only specialists in the field of industrial hygiene or toxicology can provide a solution. Precise ap- praisal of the lead hazard in a given situation and the steps necessary for its elimination require consultation with ventilating engineers, chemists, and physicians who have had special training and experience in this field. Local exhaust ventilation is the ventilation of choice for lead opera- tions. In general, vertical exhaust hoods are applicable only to the removal of lead fumes, as from lead pots, soldering and lead burning operations. For lead dust, which is heavy, lateral down-draft ventilation through horizontal slot openings will carry the dust away from the worker’s face giving him maximum protection. A ventilating system must not only be properly designed to begin with, but must be properly installed and properly maintained at all times. Failure to keep a ventilating system clean and in good repair negates the whole purpose of the installation. It is a mistake to make major changes in ventilating systems during work hours, In one large storage battery plant, the electrician had to hurry to connect up a large exhaust fan with the result that it worked in TREATMENT OF LEAD POISONING 187 reverse and many workers were unnecessarily exposed to a thick fog of lead dust which had long accumulated in the flue or chimney. Personal respiratory protection for the worker may be necessary at specific points where local ventilation is inapplicable for a variety of reasons. However, respiratory equipment is never to be regarded as a substitute for ventilation. Demolition operations, where it is necessary to burn through heavily painted steel girders, is a classic example of a situation where the respirator provides the only means of giving necessary protection to the worker. A considerable amount of this type of work has recently been done in the removal of elevated structures in New York City. The exposure to lead fumes and dust is very great and ventilation is obviously inapplicable. An air-line respirator is difficult to use at great heights and in the many precarious situations in which a worker finds himself on the elevated structure. Special respirators have been required which not only provide protection against lead fumes but which also filter out the lead dust. Flue-Connected Equipment. Where a flue alone is relied upon to secure exhaust ventilation, such flues should be installed in accordance with the following general principles: 1. Every flue-connected appliance should be equipped with an effective draft hood. It should, when practicable, be placed in a vertical position adjacent to the appliance. 2. Before making a flue-connection, the chimney or flue should be examined to ascertain that it is properly constructed and clean; and that it will normally conduct the products of combustion to the outer air. 3. The area of the flue and vent pipe or connection should be ample to remove all flue gases. 4. Where the appliance has more than one vent, the area of the vent pipe should equal the combined areas of the vents for which it acts as a connection to the flue. 5. Horizontal vent connections should be made as short as possible and the appliance installed as near the chimney or flue as practicable. 6. Whenever possible the vent pipe should be so designed as to avoid sharp turns or other features which would create excessive resistance to the flow of the gaseous products. 7. The vent pipe should maintain a pitch or rise from the appliance to the flue of the chimney. (For long runs it is desirable to maintain a pitch or rise of at least 1 inch to the foot—horizontal length.) 8. In entering the flue or chimney the connection should be above the extreme bottom to avoid stoppage by falling substances. Where more than one vent pipe is connected to a chimney flue, the connections should be at different levels. Means should be employed which will prevent 188 LEAD POISONING the vent pipe from entering so far as to restrict unduly the space between its end and the opposite wall of the flue. 9. The material used for the vent pipe should be such as to resist the corrosive action of the flue gases and the condensate. 10. The chimney flues should be of corrosion-resisting material and the points should be tight with the male spigot or crimped end pointing down. Enclosed Mechanized Processes. Progress in the mechanization of lead processes has made great strides in recent years and has contributed tre- mendously to the reduction in the incidence of lead poisoning—especially in its acute manifestations. It could readily, however, be further de- veloped to cover any number of additional operations and processes. The possibilities, for example, of the use of covered carts or containers, with chutes to fit into discharge hoppers, so as to prevent hand shovelling and dumping of lead batches from furnaces, have not yet been adequately exploited. It would seem reasonable to believe that partial or complete mechanization of all dusty lead processes is both practical and necessary. Safe Machine Construction. Any machine which creates lead dust should be constructed or enclosed in non-breakable glass so that no dust can escape into the breathing atmosphere of the workroom. Such equip- ment should be opened only after the dust has settled or the machinery has had time to cool down. There is need for enclosing dusty machine operations, especially smaller units, in non-breakable glass. Segregation of Lead Processes. Any workroom, or workplace, in which lead materials may give off dust should be so separated from adjoining rooms as to prevent effectively the escape of lead dust into adjoining rooms. This is especially important where dusty workrooms are in the vicinity of the plant cafeteria or rest rooms. General Hygienic Measures Clothing and Respirators. Lead workers should be provided with, and required to wear approved overalls and head coverings while engaged in any lead process. All lead workers should be required to remove their work clothes before leaving the factory premises. All working clothes should, when removed, be deposited in lockers separate from their street clothes. Overalls and head coverings should be washed or renewed weekly, but in one of the processes of white lead manufacture, i.e., stripping of stacks, uniforms should be washed or renewed daily. Respirator filters should be renewed daily or more often if necessary. Cartridges, for protection against lead fumes, should be checked fre- quently, removed when saturated, and new ones supplied as frequently TREATMENT OF LEAD POISONING 189 as required. Each worker should have his own respirator which bears his name or number. Respirators should never be permitted to be stored in the workroom. Frequently a worker will allow his respirator to hang around his neck while in a dusty atmosphere. This is a bad practice for lead dust is trapped therein and will be inhaled when he wears his respirator. It is the duty of the foreman or employer to see that the men wear their respirators in processes where exposure to lead dust or fumes cannot be prevented by local exhaust ventilation or other safe practice measures. One way to insure this is for the foreman not only to require this, but for him to continue to wear a respirator for the same length of time the workers are asked to wear them. This will demonstrate the reasonable- ness of the request. . Dressing Room and Lockers. These rooms should be equipped with double lockers for each worker, one for work clothes and the other for street clothes. Ample wash and shower rooms are essential. Lunch Rooms. In all factories in which lead materials are handled or where any lead process is carried on, a suitable lunchroom should be pro- vided and all lead workers should be required to eat their meals in such lunchrooms. The lunchroom should not communicate directly with any workroom in which a lead process is carried on nor be located near a highly dusty area of the plant. Suitable provision should be made in the lunchroom for the temporary storage of food brought by the workers. No food should be permitted to be kept elsewhere in the factory. An abundant supply of drinking water should be maintained by the use of angle jet fountains. If these fountains are not provided, water should be supplied outside of the workrooms with individual drinking cups. Personal Cleanliness. There should be one wash-basin or its equivalent for every ten employees. Each basin should be equipped with running hot and cold water with an adequate supply of soap and nail brushes. One shower bath with running hot and cold water for every five lead workers should be provided. All washing and bathing facilities should be kept clean and in good repair. Individual paper towels should be furnished. Large paper bath towels with good tensile strength are avail- able and desirable. Each and every lead worker should take a complete bath at least twice a week. An ideal arrangement is for the shower room to separate the two locker rooms (one for street clothes on one side and one for work clothes on the other). Thus the workers cannot get their street clothes without passing through the showers. To encourage cleanliness 10 minutes of factory time should be allowed and devoted to washing up under factory supervision. This will more than pay for itself in good health, good will and production. 190 LEAD POISONING No lead worker should be permitted to partake of food or leave the premises of the factory without washing up in accordance with the afore- mentioned rules. Poster for Workrooms. It is suggested that the following placard be posted in a conspicuous place in every workroom in which lead materials are handled or any lead process carried on. Instructions to Lead Workers. 1. All workers exposed to lead dust, lead fumes, lead solutions and lead compounds may be poisoned. These poisons get into the body through the nose while breathing, or through the mouth when chewing or swallowing or wetting the lips. Therefore to protect your health follow these rules. 2. Do all you can to keep down the dust in your workroom. When sweeping or cleaning, always dampen with water, oil or preferably wet awdust. Do not shake the dust out of your uniforms into the air of the workroom or in the locker room. 3. Where dust cannot be kept down, wear a respirator and keep it clean. 4. Eat breakfast before going to work. Eat wholesome nutritious food. Drink milk at meals and if possible once between meals. Do not eat in the workroom. 5. Keep your fingers out of your mouth. Be sure to wash your hands and face with warm water and soap before eating, as well as at quitting time. 6. A mustache if worn must be kept short. Keep your finger-nails clean and cut them short. 7. Do not smoke or chew tobacco or gum while at work. 8. Alcohol promotes lead poisoning. 9. Do not wear your street clothes while at work so that you can go home in clean clothes and not bring lead dust home to your family. 10. Some people get lead poisoning much more easily than do others.’ If you know some worker who never gets sick even though he does not obey these rules, don’t follow his example. You may get lead poisoning more easily than he does. Take no chances. 11. Be sure that you get a physical examination before starting to work in a lead plant. If you are suffering from chronic constipation, anemia, heart or kidney trouble, high blood pressure or some nervous trouble, do not work with lead, except upon the approval of a physician. Get some other kind of a job. 12. Report to your foreman if you notice (1) loss of appetite, (2) poor sleep, (3) indigestion, (4) continued constipation, (5) vomiting, (6) stomach pains, (7) dizziness, (8) frequent headache, or (9) weakness in arms, limbs or body. TREATMENT OF LEAD POISONING 191 13. You should be examined every month by the doctor to see how you are getting along. He knows how to keep you well. Cooperate with him. 14. Get a copy of Instructions on Prevention of Lead Poisoning issued by the U. S. Department of Labor, Washington, D. C., or by the National Institute of Health, Bethesda, 14, Maryland, or your own State Depart- ment of Labor or Health. It tells you many things about the dangers and how to avoid exposure to lead as well as how to keep well. Read it from time to time for guidance. MEDICAL SUPERVISION OF LEAD WORKERS Prevention is the ultimate aim in the control of lead poisoning in in- dustries involving a lead hazard. This consists primarily in the institu- tion of measures designed to prevent absorption by the workers of toxic amounts of lead (p. 173ff.). Despite enormous advances in this direction, ideal conditions are difficult and in some instances virtually impossible to attain because of increasing demands for mass production and the necessity for frequent changes in operation methods (Belknap). Conse- quently, careful medical supervision of workers in such industries is essen- tial if lead poisoning is to be prevented, even though efficient mechanical protective devices are in use and presumably safe working conditions are secured. The final test of the efficiency of such devices is the absence of manifestations of undue lead absorption and of lead intoxication in the worker. Medical supervision consists in (a) pre-employment examina- tion, (b) periodic examination during employment and, (¢) prompt treat- ment if manifestations of lead poisoning develop. Pre-employment Examination. Prospective workers in a hazardous industry should be questioned carefully regarding previous exposure to lead. Those with symptoms of lead poisoning or with a history of previous lead intoxication, especially attacks of encephalopathy, palsy or severe colic, should not be employed in such occupations. Those with a history of previous exposure without significant manifestations of poisoning should be studied carefully for evidence of latent plumbism or of abnormal amounts of lead in the body (see periodic examination during employ- ment, p. 192). Such studies should include physical examination, hemo- globin determination and red blood cell count, determination of stippled cells, reticulocytes or basophilic aggregation, routine urine examination and determination of the lead content of blood or urine or both. If evi- dence is obtained of the presence of abnormal amounts of lead or of ab- normalities that might have been due to previous exposure to lead, employment should be deferred. Subjects with anemia, hypertension, 192 LEAD POISONING diabetes, arteriosclerosis, renal or hepatic disease, alcoholism, hyper- thyroidism or chronic infections (tuberculosis, syphilis, undulant fever, etc.) should not be exposed to abnormal quantities of lead. Periodic Examination during Employment. From the medical stand- point, this constitutes the most important means of preventing the de- velopment of severe lead poisoning. The frequency of examination of workers depends primarily upon the severity of the lead exposure, which may vary considerably in different occupations within a single industry. Consequently, there should be available to the physician an accurate survey of the extent of the hazard in every portion of the plant, and he should receive prompt notification and accurate records of shifts in per- sonnel to different conditions of exposure and of significant changes in operating procedure. It has been found advisable to make routine examinations at intervals of two weeks to three months, depending upon the severity of the exposure. A written record should be kept of such examinations, with specific mention of the presence or absence of symptoms, signs or laboratory findings suggestive of undue lead absorption or poisoning (Tables 11 and 12, p. 100). These should include a statement of the weight, presence or absence of a lead line, strength of the extensors of the wrists (p. 132), blood count, reticulocyte or stippled cell count or basophilic aggregation and urinalysis. The urinary lead excretion should be determined at least every 6 months and, if feasible, the concentration of lead in the blood. Great care must be exercised in the collection of specimens to avoid contamination and 24-hour urine specimens are preferable to random specimens. The significance of symptoms, signs and laboratory findings is discussed else- where in detail and need not be repeated here. It should be emphasized, however, that such objective findings as a lead line, excessive basophilia or reticulocytosis or an abnormal amount of lead in the blood or urine indicate absorption of abnormal amounts of lead but not necessarily the presence of lead poisoning. Although the latter may often be impending or present when the urine lead exceeds 0.2 mg. per liter, the blood lead 0.1 mg. per 100 cc. and the basophilic aggregation 2%, or when the reticu- locytes exceed 5%, and the stippled cells 500-1000 per 1,000,000 red blood cells, this is by no means always the case. Clinical lead intoxication may exist in the presence of lower values for these factors and may be absent at higher levels. However, when findings of these magnitudes are ob- tained, the subject should be examined at intervals of 1-3 days and at least the number of stippled cells or reticulocytes determined. A steadily increasing count often presages the development of symptoms of lead poisoning. From a practical standpoint, removal from exposure to lead is indicated TREATMENT OF LEAD POISONING 193 (1) when symptoms suggestive of lead intoxication make their appearance, until or unless proven to be due to some other cause, (2) when, even in the absence of symptoms, there is a progressive increase in basophilic cells (above 500-1,000 stippled cells per 1,000,000 erythrocytes; more than 5%, reticulocytes; basophilic aggregation over 2%), (3) when the urine lead exceeds 0.2 mg. per liter and the blood lead 0.1 mg. per 100 cc. and (4) when albumin appears in previously normal urine. Moreover, all workers should report for examination and more frequent re-examination during the course of acute infections, such as. rhinitis, pharyngitis, tonsillitis, sinusitis, bronchitis, etc., because of the possibility of rapid mobilization of stored lead during such periods. Removal from exposure should be followed by active treatment (p. 194) if symptoms of lead poisoning are: present. Strict adherence to principles such as outlined above is essential if the incidence of lead poisoning is to be diminished materially in hazardous industries. Specific Curative Measures. The so-called specific treatment of lead poisoning may be considered under three headings: (1) measures designed to limit the absorption of lead from the intestine; (2) measures designed to diminish the quantity of lead in the blood stream and tissue fluids by facilitating its deposition and storage in the skeleton; (3) after subsidence of manifestations of acute plumbism, measures designed to effect gradual mobilization of the lead deposits and elimination of the liberated lead from the body. The rationale of the first two phases of treatment has been well established and the procedures fairly well standardized; there has been considerable controversy regarding the advisability of the last of these therapeutic procedures (mobilization of lead deposits) and there is no unanimity of opinion on this score. In view of the low solubility of lead sulfate, the administration of sodium or magnesium sulfate has long been regarded as perhaps the most effective means of limiting absorption of lead from the intestine. In the relatively rare cases of acute lead poisoning, if there is reason to believe that lead is still present in the stomach, gastric lavage should be performed, em- ploying a solution of sodium or magnesium sulfate and allowing the equivalent of 15-30 gm. of these salts to remain in the stomach after the lavage has been completed. Similar doses of magnesium sulfate should be given frequently in order to secure free purgation. In an emergency, if the sulfates are not available, egg albumin or milk may be used for gastric lavage. In the presence of colic, with intense intestinal spasm, purgation may be facilitated by preliminary administration of morphine, atropine or pilocarpine and by the use of large enemas of magnesium sulfate or oil. These procedures, with the exception of gastric lavage, are also useful in the treatment of acute episodes during the course of chronic 194 LEAD POISONING lead poisoning, in order to diminish reabsorption of lead excreted into the bowel (p. 40). There is some evidence that the beneficial effects of calcium therapy are due, in part at least, to diminished absorption of lead from the intestine (p. 5). The use of sulfur and sulfides, which are of questionable value, is also based perhaps upon the possibility of forma- tion of poorly soluble lead sulfide in the bowel. Aub, Fairhall, Minot and Reznikoff advanced the hypothesis that the metabolism of lead resembles that of calcium in that storage and mobiliza- tion of the former are influenced by the same factors which influence storage and mobilization of the latter. This subject is discussed in detail elsewhere (p. 23ff.) and need not be reviewed here. Although there is some difference of opinion regarding the validity of certain assumptions in con- nection with this hypothesis (p. 24), a few general principles have been well established and the beneficial effects of their practical application are ‘unquestionable. In the presence of acute manifestations of intoxication, the main objective is to bring about a decrease in the quantity of circulating lead by hastening its storage in harmless deposits in the skeleton. Despite contradictory findings in experimental animals (Calvery, Laug and Morris; Lederer and Bing; Sobel, Yuska, Peters and Kramer), reviewed elsewhere (p. 24), clinical experience indicates that this is perhaps best accomplished by a high calcium and phosphorus intake (Aub, Fairhall, Minot and Rez- nikoff; Hunter and Aub; Lomholt!; Behrens and Baumann?; Badham and Taylor?; Belknap!; Wiegeldt; Leschke; Goodman and Gilman; Cantarow?!). The diet should also contain an adequate amount of vitamin D. The addition of 3-4 pints of milk to the daily diet usually suffices to cause disappearance of manifestations of intoxication in mild cases within a few days. In cases with severe symptoms (colic, encephalopathy, palsy), calcium may also be administered intramuscularly (calcium glucogalacto- gluconate, 209, 10 cc. twice daily) or intravenously (chloride, 109%, gluconate, 109, glucogalactogluconate, 209, 10 cec., every 6-8 hours, if necessary). Intravenous calcium therapy almost invariably causes prompt relief from the pain of lead colic, which often subsides before the injection is completed. This dramatic response is probably due to a non- specific antispasmodic action of calcium rather than to “fixation” of the circulating lead. Advantage should be taken of the period of relief from pain to secure purgation by the use of magnesium sulfate (Bauer, Salter and Aub). Gant advocates the use of di-basic sodium phosphate, 1-2 gm. three times daily. Calcium gluconate or lactate may be given orally in doses of 4 gm., 3-4 times daily. Colic usually responds promptly, muscular weakness and palsy more slowly and encephalopathy rather poorly to this form of therapy. We have observed no ill effects, but Gray and Greenfield reported several TREATMENT OF LEAD POISONING 195 instances of permanent damage of the peripheral nervous system by lead, which they believed was related to the use of continuous high calcium therapy. Kety and Letonoff noted rapid subsidence of acute symptoms of plumbism, with a prompt decrease in the concentration of lead in the blood and an increase in its elimination in the urine (p. 39), following administration of sodium citrate (2-4 gm. three times daily in adults, and 1-2 gm. three times daily in children). We have made similar observa- tions and, in our experience, the most satisfactory results are obtained by the use of sodium citrate in addition to the high calcium and phos- phorus intake, as outlined above. Holmes, Campbell and Amberg recom- mend the addition of 100-200 mg. of ascorbic acid daily to the diet, stating that it was usually accompanied by improvement in the general condition of persons exposed to a lead hazard and by gradual disappearance of manifestations of chronic intoxication (p. 39). We have been unable to confirm these observations (also Evans, Norwood, Kehoe and Machle). After acute symptoms have subsided, the question arises as to whether the increased amounts of lead stored in the bones should be permitted to remain or whether an attempt should be made to mobilize the lead de- posits and to remove this potentially dangerous substance from the body. Opinion on this point is divided. Aub has stated the problem as follows: Lead stored in the bones in relatively large quantities may be readily mobilized by therapeutic measures or spontaneously (infections, alco- holism, strenuous exercise, severe trauma, prolonged immobilization, hyperthyroidism, metabolic disorders accompanied by acidosis or alkalosis, administration of acids, alkalies, iodides, ete.). If the precipitating factor is a serious illness, such as pneumonia, the superimposition of acute plumbism may impair the chances of recovery. Moreover, lead liberated in this manner may not be excreted, but may circulate and be redeposited in the skeleton. In favor of the principle of “deleading” is the possibility of reducing, under controlled conditions, the lead stores in the bones; against “deleading” is the consideration that it may be desirable to avoid the liberation of lead, which can be kept stored in harmless deposits in the bones during periods of good health. Aub feels that from a theo- retical standpoint it seems advantageous to remove the lead in order to obviate the possibility of its sudden liberation during periods of metabolic stress, while from a practical standpoint the decision must be made as to what procedure will result in most prompt recovery of health in each case. Kehoe and Thamann advise against administration of agents which promote rapid liberation of lead from the tissue deposits, and call atten- tion to the possibility of storage of the mobilized lead in the central nervous system. McKhann and Vogt stated that efforts at “deleading” children after recovery from attacks of lead encephalopathy resulted at times in 196 LEAD POISONING recurrence of cerebral symptoms and that, although in the absence of such therapy the danger of recurrence of symptoms persists for some time, it gradually subsides because of spontaneous elimination of the stored lead. Kehoe states that the “deleading’’ procedure is unwarranted, inas- much as he has found that after heavy exposure spontaneous elimination restores the lead content of the tissues to an essentially normal level within 12-18 months. Experimental data bearing on this point are con- tradictory. However, reports of the occurrence of acute episodes of lead poisoning years after cessation of exposure (p. 107) suggest that, in some cases at least, dangerous amounts of mobilizable lead may remain in the bones for prolonged periods of time. Aub states that, in his experience, a vigorous course of mobilization of lead is usually followed by prompt recovery to normal health, without the precipitation of manifestations of acute intoxication during the course of therapy. In patients with palsy, he feels that thorough “deleading” diminishes the period of disability by approximately one-half. We have observed no evidence of recurrence of symptoms of plumbism in adult subjects in whom this procedure has been employed, but have not utilized it extensively in children. If active “deleading” is to be attempted, the subject should be in good physical condition, with no clinical or laboratory evidence of acute intoxication and should preferably be hospitalized. According to Belknap? the hemo- globin should be over 809%, the red blood cell count over 4,000,000 per cubic millimeter, the stippled cell count less than 5,000 per 1,000,000 red blood cells and the urinary lead excretion less than 0.15 mg. daily. Modi- fied procedures may be carried out in ambulatory patients. Mobilization of lead from the bones is accomplished by administration of a low calcium, relatively high phosphorus diet (Ca/P ratio approxi- mately 1:4), with acids, acid-producing salts, alkalies, iodides, or, occa- ionally, parathyroid hormone. The diet recommended by Aub and his associated consists of meat, liver, potato, rice, tomatoes, canned corn, bananas, peeled apples, tea, coffee (no milk), butter fat, bread (prepared without milk), sugar, salt, pepper. The mobilization and urinary excre- tion of lead induced by the substances mentioned above is considerably greater when such a diet is employed simultaneously than when the intake of calcium is unrestricted (Aub, Fairhall, Minot and Reznikoff). Phos- phoric acid (dilute) may be given in doses of 5 ce. every hour for 12 hours each day and N/10 hydrochloric acid in doses of 140 cc. daily. Ammonium chloride or ammonium nitrate may be administered, preferably in enteric coated tablets, 1 gm. every hour, for 8-10 hours daily. Sodium bicar- . bonate, in quantities up to 40 gm. daily, usually causes a distinct increase in the urinary excretion of lead, but is not as effective as acid therapy and is not influenced so strikingly by the low calcium intake (Flury?). Sodium TREATMENT OF LEAD POISONING 197 or potassium iodide, 1 gm., 2-3 times daily, may be effective, particularly in the early stages of the “deleading” procedure, but the effect of iodide is not as marked nor as sustained as is that of either acid-forming agents or alkalies. The most pronounced effect is probably obtained by the use of parathyroid hormone, in doses of 40-80 units, once daily (intramuscu- larly). If this is employed, the patient should be under close observation, preferably in a hospital, and the serum calcium concentration should be determined frequently to obviate the possibility of development of hyper- calcemia. The duration of the period of lead mobilization varies considerably in different cases, and depends in part upon the quantity of mobilizable lead stored in the tissues and the response in each instance. The quantity of lead excreted in the urine should be determined frequently, and active therapy should be discontinued when the daily excretion falls to a normal level. In the average case, this may occur within 2-3 weeks. If abnor- mally large amounts are still excreted at the end of 3-4 weeks, or if any symptom or laboratory evidence of acute plumbism should develop at any time, therapy should be discontinued for a period of 2-4 weeks and then be resumed, if desired. We have not observed manifestations of lead intoxication in patients subjected to this therapeutic procedure; if they do occur, they should be treated in the manner outlined in discussing the treatment of acute plumbism, preferably by the use of sodium citrate and a high calcium, high phosphorus diet, purgation with magnesium sulfate and, in the presence of colic, calcium salts intravenously. It should be pointed out that “deleading’ procedures are attended with some danger in subjects with impairment of renal function. In such cases, active mobilization of lead that cannot be excreted promptly may precipitate symptoms of acute intoxication. Moreover, as suggested by Aub, Fairhall, Minot and Reznikoff, since patients with kidney damage do not tolerate inorganic salts well, particularly potassium iodide and acid-producing salts, sodium bicarbonate is usually the safest agent to use if mobilization of lead is desired. SYMPTOMATIC TREATMENT In addition to the measures designed to favor storage and to diminish absorption of lead during episodes of acute plumbism, symptomatic treatment is often required for the control of many of the manifestations of acute intoxication. As stated previously, colic is usually promptly relieved by intravenous administration of calcium salts, but occasionally other antispasmodic agents may be useful, such as atropine, nitrites (nitroglycerine, amyl nitrite), papaverine and pilocarpine. The bowels should be kept open by magnesium sulfate in adequate dosage and by 198 LEAD POISONING enemas (magnesium sulfate or oil). Rarely, morphine or other opiates may be required to relieve pain, but they should be used only as a last resort, because of their constipating effect. Brief inhalations of ether or chloroform have been employed at the height of otherwise uncontrollable attacks. Firm pressure on the abdomen and warm applications are often comforting, and water should be given freely in the absence of severe vomiting. The treatment of encephalopathy is generally unsatisfactory. Aub and his associates observed prompt recovery following the use of the “specific” storage measures outlined previously, i.e., large quantities of milk, calcium salts and sodium bicarbonate in small doses. However, MecKhann and Vogt feel that the treatment of children with lead en- cephalopathy is disappointing. The intense cerebral edema present in many cases appears to be resistant to ordinary methods of combating this phenomenon, the effects of intravenously administered magnesium sulfate and hypertonic solutions of dextrose or sodium chloride being only tempo- rary. In their experience, convulsions may be controlled by such agents as magnesium sulfate, paraldehyde, phenobarbital, pentobarbital and amytal, but the eventual outcome is not affected and the unfortunate sequellae of encephalopathy are not prevented. Good results have been reported following the relief of increased intracranial pressure by surgical decompression (McKhann?; Bucy and Buchanan; Haverfield, Bucy and Elonen). Haverfield and his associates state that subtemporal or sub- occipital decompression should be performed, according to the indication in each instance. They believe that the acute manifestations of lead encephalopathy can be relieved in this manner with sparing of vision and preservation of life and that such sequellae as mental retardation, tremor and paralysis may be prevented. Lumbar puncture may be helpful in some cases. Chloral, hyoscine, bromides and hot packs may prove useful in controlling convulsions and delirium. Care must be exercised to pre- vent, insofar as is possible, the severe exhaustion that commonly follows periods of mania and convulsions. Anemia, neuritis and other neuromuscular manifestations and symp- toms referable to changes in the cardiovascular and renal systems, the joints and other organs and structures are treated in the same manner as similar manifestations due to causes other than lead. CHAPTER X OCCURRENCE OF CHRONIC LEAD POISONING At the present time, lead poisoning is almost exclusively an occupational disease, instances of aeeidebtol or non-industrial plumbism being encoun- tered but occasionally in this country. It is important to remember, ‘how- ever, that such cases do occur, especially in infants and young children, and that recognition of the true nature of the condition depends primarily upon keeping in mind the possibility of its presence. Among the common causes of lead poisoning referred to in the early lit- erature of this subject were the addition of lead compounds to wine to pro- mote fermentation, contamination of drinking water piped through lead pipes and of cider and beer conveyed through lead pipes and fittings from the casks to the bar counter, and the extensive use of pewter and lead-lined cooking vessels. Some of these sources of poisoning are not entirely a thing of the past, as indicated by the occasional occurrence of cases of plumbism as a result of home fermenting and distilling of wines, beer and cider in uten- sils glazed with lead compounds, the acidity of these beverages liberating lead from the glaze (Willcox; Duy; Wright, Sappington and Rantoul). Cases due to contamination of drinking water have also been reported in recent years (Quan and Klein; Kruse and Fischer; Beaumont and Wyburn- Mason; Wright, Sappington and Rantoul; University of Aberdeen Report), but are unusual under modern plumbing conditions. In a study by Wright, Sappington and Rantoul of 102 lead-conducted water supplies, it was found that the lead content of the water was related to its CO, content and not to the length of pipe in the system. This relationship has been noted in the case of other beverages. The contamination of beverages and foods by lead is considered elsewhere in detail (p. 167). The tin coating of tin-plated food-containers contains variable amounts of lead, usually up to 0.1%, but is still an occasional cause of lead poisoning (Candy), although fortunately not as commonly as when the lead content was as high as 30-409, (Wolffhiigel). Plumbism has also occurred as a re- sult of the use of snuff wrapped in lead foil (Utall; Bauer and Ropes), and handling dyed furs (Koelsch and Ilzhéfer). Other unusual causes of lead intoxication include contamination of flour by lead used to counterbalance a grinding wheel in a flour mill (Studeny and Rosegger), and lead dust and fumes produced by burning storage-battery casings as fuel (Williams, Schulze, Rothschild, Brown and Smith; Crutcher). Lead poisoning has occurred in roofers, apparently as a result of holding galvanized nails in 199 200 LEAD POISONING their mouths (Magnuson and Raulston). Wilcox reported cases of severe poisoning among alcohol addicts who made a practice of drinking “canned heat,” due presumably to contamination of the contents by lead from the containers. Biondi cites the following rare sources of lead poisoning: pack- ing lead figures covered with lacquer; handling of lead seals by a customs house officer; polishing precious stones; handling amber; cigar-making on a lead table (also Jordans et al.); marble polishing using a mixture of wax, sulfur, alum and metallic lead; asbestos weaving, using lead threads. Ny- feldt reported the occurrence of lead poisoning in a police bureau employee engaged in examination of articles for finger prints, the procedure consisting in dusting each article with large amounts of finely pulverized white lead and then brushing the powder away. The possibility of lead poisoning re- sulting from the inhalation and ingestion of lead dust arising from the use of colored blackboard crayons is rather remote. Ruf and Fluck analyzed 27 samples and found lead only in various shades of yellow, orange and green, the maximum lead content being 129, by weight. A source of in- dustrial poisoning not sufficiently appreciated is the volatilization of lead paints from steel during the process of cutting the metal with an acetylene flame (Batta, Firket and Leclerc). The most common cause in children is ingestion of lead from paint on cribs, toys, porch-railings and steps, furniture, window sills, lead-contain- ing rubber nipples, lead incorporated in the glass of nursing bottles, etc., gnawing or eating lead toys and, perhaps, inhalation of lead as a result of drying and weathering of paints on porches and window sills (McKhann and Vogt). The highest incidence of poisoning from these sources is be- tween 1 and 3 years of age, during the period of eruption of teeth, when there is a tendency to put such things in the mouth. The possibility has also been suggested that this may be a cause of early development of arter- iolosclerosis and nephrosclerosis (Nye; Murray). Sources of acute lead intoxication in infants include rubber nipples containing lead, lead nipple shields (Lewin; Wilcox and Caffey; Rapoport and Kenney; Bass and Blu- menthal), lead ointments on the breasts of nursing mothers and the use, by mothers, of cosmetics and hair dyes containing lead (Dufour-Labastide; Hirai; Suzuki and Kaneko; Fukushima and Matsumoto; Kato). There can be little doubt that lead poisoning is the most serious occupa- tional hazard at the present time. It has been estimated that there are about 900 specific occupations involving a potential exposure to lead, a general classification of which is presented in Table 19. In a survey of 16,803 industrial plants, employing 1,487,224 workers in 15 states, it was found that approximately 800,000 (54%) persons were handling lead and its compounds (U. S. Public Health Bulletin No. 259, 1940). It was felt that the sample was sufficiently accurate and representative of industrial OCCURRENCE OF CHRONIC LEAD POISONING 201 TABLE 19 Occupations Involving Potential Lead Exposure Acid finishers (glass) Amber workers Art-glass workers Artificial-flower makers Babbitters Battery (dry) makers Bench molders (foundry) Blacksmiths Blooders (tannery) Bookbinders Bottle-cap makers Brass founders Brass polishers Braziers Brick burners Brick makers Bronzers Browners (gun barrels) Brush makers Buffers (rubber) Burners (enameling) Burners (welding) Cable makers Cable splicers Calico printers Canners Cartridge makers Chargers (zine smelting) Chippers Colorers (white) of shoes Color makers Compositors Compounders (rubber) Concentrating-mill workers (lead and zine) Copper refiners Cut-glass workers Cutlery makers Cutters (oxyacetylene and other gases) Decorators (pottery) Dental workers Diamond polishers Dye makers Dyers Electroplaters Electrotypers Embroidery workers Emery-wheel makers Enamelers Enamel makers Farmers File cutters Filers Filling-station workers Floor molders (foundry) Galvanizers Garage workers Gardeners Gasoline blenders Gasoline tank cleaners Glass finishers Glass mixers Glass polishers Glass dippers (pottery) Glaze mixers (pottery) Glost-kiln workers Gold refiners Grinders (metals) Grinders (rubber) Heater boys (riveters) Imitation-pearl makers Incandescent-lamp makers Insecticide makers Japan makers Japanners Jewelers Junk-metal refiners Labelers (paint cans) Lacquerers Lacquer makers Lead burners Lead-foil makers Lead miners Lead-pipe makers Lead-salts makers Lead smelters Linoleum makers Linotypers Linseed-oil boilers Lithographers Lithotransfer workers Match-factory workers Mirror silverers Mixers (rubber) 202 LEAD POISONING TABLE 19—Continued Monotypers Musical-instrument makers Nitro-acid workers Nitroglycerin makers Painters Paint makers Paint removers Paper hangers Patent-leather makers Petroleum refiners Photograph retouchers Pipe fitters Plumbers Polishers Pottery workers Printers Putty makers Putty polishers (glass) Pyroxylin-plastics workers Reeclaimers (rubber) Red-lead workers Refiners (metals) Riveters Roofers Rubber workers Sagger makers Sandpapers (enameling and painting auto bodies, ete.) Screen workers (lead and zine smelting) Sheet-metal workers Shellackers Shellac makers Shot makers Slip makers (pottery) Slushers (porcelain enameling) Solderers Solder makers Stainers (shoes) Steel engravers Stereotypers Storage-battery makers Sulfuric-acid workers Table-turners (enameling) Tackers (welder’s) Tannery workers Temperers Tetraethyl lead makers Tile makers Tin-foil makers Tinners Toy makers Transfer workers (pottery) Tree sprayers Type founders Typesetters Varnishers Varnish makers Wall-paper printers Welders White-lead workers Wood stainers Zine miners Zinc smelters conditions in this country to warrant considering the data applicable to all industrial establishments of the type studied in the United States. When one recalls that, according to the last Federal Census, approximately 49,- 000,000 persons were gainfully employed in this country, the magnitude of the potential lead hazard becomes apparent. Obviously, all workers with lead are not necessarily exposed to the possibility of developing lead poison- ing. The quantity and type of lead compounds used, the manner in which they are used, the equipment in which they are processed and the health protection afforded are all important from the industrial standpoint in de- termining whether a given occupation is actually or merely potentially hazardous. OCCURRENCE OF CHRONIC LEAD POISONING 203 It is practically impossible to estimate the incidence of chronic lead poi- soning in industry with any degree of accuracy. This is due chiefly to failure to recognize and report mild forms of the disease and to the greatly varying conditions of industrial exposure resulting from frequent changes in technical methods. The only available statistical data of even presump- tive value in this connection deal largely with mortality and not morbidity and even these are not entirely reliable because of common errors in diagno- sis. Enumeration of such data here is therefore of little value. Frey and Biondi have covered in detail the industrial statistics and legislation of lead hazards and poisoning throughout the world up to 1934. Some of the most hazardous occupations are indicated in the sections on the industrial uses Fic. 3. The percentages of storage battery workers in each of 16 exposure groups diagnosed as cases of early plumbism, classified according to extent and duration of exposure. Thus, of the group exposed more than 15 years to atmospheric lead con- centrations in excess of 3 mg. Pb per 10 meters of air, 61%, were found to have early plumbism. (Dreessen et al., U.S. Public Health Bull. No. 262.) of lead (p. 205) and the prevention of lead poisoning (p. 173). Some indi- cation of the actual incidence in hazardous industries is afforded by the studies of Dreessen in six storage-battery plants. A diagnosis of early plumbism was made in 177 (23%) of 766 workers examined (Fig. 3). The diagnostic difficulties encountered in such cases is emphasized by the fact that in only nine instances did a diagnosis of incipient plumbism seem war- ranted on the basis of clinical and hematological findings, without the aid of blood and urine lead determinations. In some departments (group burners, oxide mixing, salvage, pasting), the incidence of plumbism was 35-45%, the distribution between the various departments within this single industry correlating well with the departmental exposure to lead. 204 LEAD POISONING The problem of lead poisoning has occupied the attention of physicians and industry for centuries. Lead is becoming more widely used throughout all civilized countries with the development of new industrial processesand new materials for consumption. As stated by Lanza, lead poisoning may be regarded as a counterpart of syphilis, not only in the variety of its effects, but in the manner in which it may be dormant and unsuspected for years, until some exciting factor precipitates manifestations of serious disturbance, the underlying cause of which may not be readily apparent. CHAPTER XI LEAD PRODUCTS IN INDUSTRY Lead is one of the six prehistoric ancient metals and is mentioned in the Bible. It is the softest and heaviest of the common metals, melts at 327°C. (621°F.), and boils at about 1613° C. While many lead-containing minerals are found in various parts of the earth, the only ore of commercial import- ance is galena, lead sulfide (PbS). Lead carbonate and cerussite (PbCOj), as well as other oxidized ores, are found at the surface of lead deposits, and they have nearly all been used up in developing such deposits, so that the deeper ore deposits consist mainly of a mixture of various sulfides in which lead, zinc and iron predominate in varying degree. I. PRIMARY PRODUCTION OF LEAD Concentrating. After the ore is mined, it is crushed and separated from the waste rock or gangue. This may be done by gravity methods or by . flotation. To concentrate the ore by the latter method, the finely crushed ore is diluted with several volumes of water containing a small percentage of pine oil and other organic agents and is agitated violently in a large tank with air. The soapy liquid forms a froth of air bubbles which carries the heavier sulfide particles to the top where they are floated off, and the value- less gangue, which is “wetted” by the solution, sinks to the bottom for sub- sequent removal. Unless the ore is high grade galena, the lead sulfide must be further separated from the other sulfides, principally zine, and this is done by a similar process called selective flotation, in which certain agents are added to the suspension which selectively ‘“wet’ one of the sulfide min- erals and enable a separation to be made. Concentrates of two portions result, one of which is often as high as 909%, lead sulfide and the other 90%, zinc sulfide. The process of flotation has made possible the commercial development of many heretofore unprofitable low grade complex sulfide ores. Roasting. The lead concentrates are roasted to remove the greater part of the sulfur and at the same time prepare the ore for the smelter. In re- cent years the concentrates are roasted on Dwight-Lloyd sintering machines, abandoning the former hand-rabbled or mechanically-rabbled reverberatory furnaces. This is a distinct gain in safety as well as efficiency since the Dwight-Lloyd machine employs a down draft and a moistened charge, thus lessening the dust hazard. 205 206 LEAD POISONING To the lead concentrates is added the proper amount of sand and granu- lated slag from previous smelting operations, as well as pyrite FeS; and re- covered flue dust or other waste products containing metal values. This charge is then moistened and ignited by a flame as it travels along the slowly moving grate of the machine until most of the sulfur is driven off and sinter- ing takes place, which means that the surfaces of the particles in the charge just reach a liquid phase and cement together in a porous mass. Smelting. The finished sinter is now prepared for the blast furnace by mixing it with the required amount of coke, limestone, scrap iron or waste and charging it into the top of the furnace. This furnace is a large shaft with a line of air blasts along its lower portion below which the molten lead and slag are tapped off. The air blast is controlled to reduce the now oxidized charge and the molten lead is tapped off, as well as the slag and matte, the latter an intermediate product of the blast furnace con- taining more of the copper and iron and any nickle or cobalt present. The crude lead may contain gold and silver, in addition to small amounts of copper, antimony and bismuth. Nearly all the lead today is smelted in the blast furnace. Refining. The refining operation depends on the source of the galena and the grade of lead to be produced. There are three principal grades of lead and the following specifications of the American Society for Testing Materi- als may be of value: Grade I. Corroding Lead Grade II. Chemical Lead Grade III. Common Lead I 2% III . min. — 0.00: 0 — Blvbr:... co 0 dl Aa mins. 0.0015% 0.020 0.002% OODPEL. + 5 hi stdin mats node eit In oo di ik max. .0015 .08 .0025 Arsenic, Tin, Antimony....... max. .0110 .002 .015 Bismaath. on dows dies ne max. .05 .005 15 IE hs ha vob a a tid a a max. .0015 .001 to .002 ROI chin i eh ara pri iaia 4 max. .002 .0015 .002 al a min. 99.94 99.90 99.85 Lead must usually be desilverized because of its precious metal value, and the Parkes process is universally used for this purpose. This is conducted in large steel kettles by the addition of zinc to the molten metal; and the crusts which form contain the silver and gold. These are skimmed off and treated for recovery of precious metal as well as zinc, which is reused. The lead then gets a final heating in which traces of remaining impurities are driven off, after which it is cast into pigs. There is one grade of lead famous for the remarkable purity of its ore supply, which contains so little silver LEAD PRODUCTS IN INDUSTRY 207 that it is not desilverized. This is the Southeast Missouri grade known as chemical lead, which contains a eutectic amount of copper (0.06%) together with very small amounts of silver and nickel, and is remarkably free from zine, arsenic, antimony or bismuth. This lead is preferred where corrosion resistance to acids is required. The principal danger of lead poisoning in all these operations is the occa- sional clean-out job. General room air in the concentrator and smelter can be controlled to a large extent by proper draft ventilation. Proper flues and hoods are provided wherever possible and dust is dampened. The walls of the furnace must be periodically scraped. In some smelters this is accomplished by setting off small dynamite bombs in the furnace, after first barring the top. This process frees the furnace of accretions. Fine dust is recovered in bags in a bag house where the cotton or woolen bags are mechanically shaken to recover the dust, which is moistened and reused as part of the charge to the sintering machines or roasting furnace. When an occasional clean-out job cannot be avoided, men who must do such work should wear approved respirators and work for short periods only. Secondary Smelting and Refining. Secondary smelters used for recover- ing scrap lead and its alloys are similar in principle to the primary blast fur- naces, or they may be reverberatory furnaces. They more often produce antimonial lead. Many scrap alloys such as solder stock for instance, need only to be refined. This is done by several different methods, in steel ket- tles provided with stirrers and hoods or covers, somewhat similar to the equipment used in the Parkes process. While this phase of the lead indus- try needs more space, the hazards are no different from those of the primary refining processes, provided the usual precautions are taken as to hoods and ventilation. ; II. MANUFACTURE AND USE OF LEAD PRODUCTS A. Consumption Lead consumed in a normal year averages about as shown in the following table, which is arranged for convenience in a manner differing but slightly from the U.S. Government tables from which it was taken: Lead Compounds: Couient Storage Battery litharge...............ooiiiiiiiiiiiininneee, 65,000 Storage Battery red lead. ...............cooiiiiiiiiiiiiiiienn 20,000 Chemical Industry litharge (Insecticides, Petroleum, Ceramics, AE 0 RP ABU a A lL 45,000 Red Lead pigment. .........oovueeunreriresneenenasnannnsness 20,000 White Lead in oil pastes. ............ocooininnneiniiiiiinenn, 30,000 White, Lead, dry..... be Ge his sini hiss § Seti iv Rr 25,000 Misc., other Lead Compounds (Basic Sulfate, Silicate Frit, etc.). 25,000 Total, Compounds. ........covnerrnerenreierinarnnasannss 230,000 208 LEAD POISONING Metal: BI LOPAEE BAbbOIY «it civ 1 1iiis wins oie WE 5 Tow elise Alo brat Halu’ +50 100,000 Cable SNAG. viv vee eee so bos aete HE Sin isa Sars a 100,000 DINER BIER. i, «cree 335 Berwin 0 Eg dA ate an kde 58,000 T4 eL Eo S S IA I c Ti SA S 55,000 OMB a i I a a Fate a Br lhe bX eds 25,000 BOIL ht ts Ce sd hs RA i RE a RNR Ba 23,000 CaulEnE Load. oli. 0h ods be by smth % aie a + aires delim 19,000 Be Metal. vi. vies i ie aan x ras iden Sani be sid DR 16,000 Bearing Metal, Tetra Ethyl Lead, Collapsible tubes and mise.... 90,000 otal, METALL. co cui s 100 Fantilisins + £856 3 Gaiaio Bd a sins 5 aries 486,000 This amounts to a combined total of about 700,000 tons of lead annually. U. S. Minerals Yearbook figures include Antimony and are therefore some- what higher. It will be noted that the storage battery is the largest single user of lead products, consuming about 200,000 tons annually. In the lead industry, a few large basic manufacturers make the principal compounds and metal products. These in turn are sold to numerous inter- mediate and secondary manufacturers, large and small, who make the prod- ucts used by the ultimate consumers, such as storage batteries, paints, insecticides, telephone and power cables, plumbing supplies, bearings, type, glass, ceramic objects, shot and many other products. At the present time, the U. S. Government is a large consumer of lead. PrincipaL Uses FOr LEAD As Metal: “chemical,” for process industries and general acid resistance, ete. Sheet Lead foil for wrappings for tobacco, electrical goods, ete. Cold rolled |impression leads for reproductions. hard lead, antimonial for chemical industry, roofing, ete. Pipe, Warm | plumbing, traps, bends, etc. Extruded |wire and caulking wool. grid metal, antimony, for storage battery grids. solder, lead-tin, lead-cadmium, lead-silver. castings—die and ordinary castings. Alloys cable sheathing, telephone and power cables. bearing metals, antimony-lead, calcium-lead, copper-lead type metals, tin, antimony, for printing industry. shrapnel and shot, antimony and arsenic. powdered lead, manufacturing uses and powder. metallurgy. Special lead-coated steel or copper, pipe, sheet, valves, pumps, for acid Uses resistance. leaded steel and leaded brass or bronze, for better machinability. quenching baths for steel; pure lead. LEAD PRODUCTS IN INDUSTRY 209 As Compounds (principal ones, only): Storage battery oxides; negative, litharge, (PbO) ; positive, lith- arge and sometimes red lead, (Pb;04), litharge, (PbO), for mak- ing other lead compounds, oil refining, rubber, varnish, ceram- ics, steel treating. Red lead (Pb;O.) for metal priming paints, glass, ete. Peroxide (PbO,) for electrical use. White lead (2PbCO;-Pb(OH);) pigment for white and tinted paints. Basic lead sulfate (PbSO4-PbO) pigment for white and tinted paints, other compounds for special uses. Silicate frit (PbSiOs) for ceramic glazes, glass, enamels. Basie chromate (PbCrOs-PbO) for metal priming paints, colors. Arsenate (PbAsOy) for insecticides. Azide (PbNj) explosive uses, special primers. Acetate (Pb(CH3;COOH),) chemical use. The most important compounds of lead are the oxides, litharge and red lead, and white lead. B. Manufacture of Important Lead Compounds Litharge (PbO). Lead monoxide, called “massicot’” in the old terminol- ogy, exists in two forms. The red modification (not to be confused with red lead), is of tetragonal crystalline form and stable only at temperatures be- low about 488°C. All processes making litharge from molten lead operat- ing above this temperature produce the common yellow variety, of ortho- rhombic form. Litharge is usually made by heating pig lead in furnaces of the low arched reverberatory type by what may be termed a drossing operation. Iron rabbles periodically rake off the litharge, exposing fresh surfaces of metal to facilitate oxidation. The products of combustion and some fumes escape through a hood and the oxide is removed in iron cars for packing, or for wet grinding if a fine grade is desired. Litharge may also be made by the Barton process, in which the metal is heated in iron pots or pans, stirred, and subjected to a steam blast which blows the fine oxide through a heated flue into condensing chambers, where it is cooled and removed. Some litharge is also made by cupellation at high temperatures. Another process is that in which lumps of lead are used in a ball mill, gradually mak- ing a fine powdered mixture of lead and lead oxide. This litharge mixture is used in storage batteries. Red Lead (PbsO4). This higher oxide of lead, called ““minium” in the older literature, has been fairly well established as a definite compound of 2PbO- PbO,. It is made by heating litharge under careful control at a tempera- ture over 488°C. in a furnace similar to that used for making litharge. 210 : : LEAD POISONING When the proper amount of coloring has taken place, the red lead is removed and classified as to fineness or water ground. High grade “painters red lead” contains about 979%, true red lead and only a small amount of litharge, while lower grades are used in storage batteries. Small amounts of a variety of red lead known as “orange mineral’’ are made by heating white lead at the lower coloring temperatures, to produce a product with a brilliant orange tone. A very dark red lead is made by fuming at higher temperatures. White Lead, Basic Carbonate, hydrated (2PbCOs-Pb(OH),). While it has been contended recently that another basic carbonate does exist, white lead made by the Dutch or Carter processes of corroding approximates the above composition. In the Dutch process, thin buckles of cast lead are placed in small pots with dilute acetic acid and surrounded with moistened tan bark. Whole tiers are built up to form a high stack. The slow fermentation of the tan bark produces carbon dioxide and heat, which, together with the corrosion of the lead by the acid, converts it to the basic carbonate. Normally this takes considerable time and the stacks are usually left untouched for about 100 days, after which they are broken down and the white lead carefully removed. It is then put through a series of steps involving washing, clas- sifying, and then either drying or wet pulping with linseed oil in which the oil displaces the water. In the Carter process, the chemistry is very similar but the operation looks quite different. Molten lead is atomized by blowing it with air or steam, the fine powder is charged into a large slowly revolving wooden cyl- inder and sprayed with water containing dilute acetic acid, and carbon dioxide gas is introduced through a pipe. This continues with automatic regularity for from 6 to 10 days, after which the charge is removed and the agglomerated mass of white lead broken up, washed, screened and pulped with linseed oil. The Carter process is less hazardous from the toxicologi- cal viewpoint when produced as a paste in oil. However the mixed paint manufacturers who blend a number of ingredients require dry pigments. By the precipitation process, lead or litharge is dissolved in dilute acetic acid and carbon dioxide gas passed into the solution precipitates the basic carbonate. In the so-called electrolytic process, lead acetate is produced by the electrolysis of a lead anode in acetic acid solution and thence is simi- lar to the precipitation process. Recently a process described as treating a suspension of litharge in water in a large tank, introducing carbon dioxide gas, was reported. A small amount of acetic acid facilitates the formation of a basic carbonate of a high quality. This process appears to be most hygienic in that it is under LEAD PRODUCTS IN INDUSTRY 211 control at all times, and is completely mechanized with no hazard except that in making the litharge used as a starting material. Lead Sulfates (PbO-PbSO, and PbSO;). White basic lead sulfate is commonly made by subliming galena in an oxidizing atmosphere in a suitable furnace. The sulfate is collected in a number of bags. Recently a precipitation process has come into use which produces acicu- lar or long needlelike crystals with superior paint-making properties. This product is made by adding sulfuric acid to a suspension of litharge in water, stirring and then continuing the addition of acid until a mixture of the nor- mal sulfate and basic sulfate is obtained, which has more desirable pigment properties. A small amount of blue basic lead sulfate, a less pure product, is occasionally made by subliming galena in open hearth furnaces. Leaded zine oxides are similarly produced and collected in a baghouse. Lead Chromale and Basic Lead Chromate (PbCrO, and PbO-PbCroy). These compounds are usually made by wet processes in which a soluble chromate is mixed with lead acetate or litharge suspensions, then filtered, washed and dried. C. Manufacture of Storage Balleries (Fig. 4) This industry will be given separate consideration because it is the larg- est user of lead and is at the same time, the most important from the stand- point of hazards of lead absorption. We shall endeavor to describe the various operations from the viewpoint of good practice. Each plant will of necessity have its own modifications which differ to some extent from those of other plants. The essential unit of the storage battery is the plate containing a conduc- tive framework or grid which serves to hold the active lead material. The negative plate in the finished battery consists of metallic lead in a porous or sponge form, while the positive plate is lead peroxide which is the more noble product. The E.M.F. between these two poles is about 2.2 volts or more and the amperage is built up by placing a number of plates in par- allel. The auto-type battery has about 15 or 17 plates and an amperage of about 120. The Metallic Grid. Manufacturers vary in their exact specifications for grid metal but the usual grid for both negative and positive plates has about the following composition: TIOt isch itlo or votes © Riel 13. € 5 Pn wed mnt ov ol ets 88.0 to 93.09% AIEUINOIY iid Dore 5s 5 mining sw 0% 5m edna 4.5 94 adblain 7.0 to 12.0% a In RS SR ha el Sn sel 0.3 to 0.4% Small amounts of arsenic and copper (under 0.05%) add strength to the grid while all other impurities are held to a minumum. The balance is lead. maT 4 OFFICE 1 RECEIVING SHOPS 1 10.9% | 0.6 4.5%, Ree sr ee. i et. ip. id LEAD MAINTENANCE STORAGE LABORATORY 14 0 %e 0.2 9%, 1.7 ®% Se SMELTER CASTING OXIDE MFG 1.8 10.3%, 1.4 °/ I | Noe I PASTING OXIDE MIXING ONLY ONE FORMING 9.5 °/ 1.2 %e OPERATION IS USED ON ANY ONE UNIT DRYING PLATE PLATE FORMING FINISHING 1.4 °, 1,2 %% UP MBLY le GRO ASSE BATTERY BATTERY REPAIR Ii. ASSEMBLY 0.9 ° 14.2 ° EJ ¥ 1 I — da ria el de ICASE FORMING ME INAL CHARGE | 3.3%, | AVERAGE ATMOSPHERIC Lo 3.0% = ob de SHIPPING 6.0% LEGEND CASE MFG 2.9% [TSEPARATOR | MAKE & TREAT | 3.2 %e J LEAD CONCENTRATION | over amc B PER 10 M3 1.5-3 MG PER 10 M3 LESS THAN 1.5 MG PER 10 M3 Fic. 4. Flow sheet of operations in storage battery manufacture, indicating the average exposure to lead in various departments. The most common movement of materials is shown by heavy arrows and the less common by light or broken arrows. (Dreessen et al., U. S. Public Health Bulletin No. 262.) 212 LEAD PRODUCTS IN INDUSTRY 213. Certain special batteries, such as those used in submarines, for instance, which are very large and pasted by hand, are not considered here. The description which follows applies to automobile batteries and would also serve for airplane batteries. The first operation consists in casting the grids. The grid metal alloy may either be purchased from the large producers or made at the battery plant. In either case the metal is melted in a pot which must constantly be kept clean of skimmings and is either ladled out and poured by hand or cast by automatic casting machines. In this operation in a modern plant, hoods are used and the temperature is kept well below any significant vapor pressure of lead, but the dross is usually cast aside hurriedly and may be- come a source of dust after it dries and cools. The grids are inspected for rejects (returned for future melting) and are passed along to be pasted either by hand or by pasting machines. In the meantime, the paste has been prepared. This begins in the mixing depart- ment, which is likely to be one of the most hazardous parts of the storage battery plant. Here the litharge is dumped and mixed either with expander material for the negative plate mix or possibly with red lead for the positive plate mix. These mixing operations can be largely eliminated by purchas- ing ready mixed oxides from the large producers who are able to do these operations more expertly with full mechanical control. The negative mix consists of litharge to which is added a small amount of material known to the trade as expanders. Lamp black, barium sulfate, and organic material are commonly used in an amount of about 1% of the weight of the litharge. These expanders avoid excessive shrinkage in the finished plate and impart greater capacity to the finished battery. The positive plate mix often contains about 25%, red lead, the balance being litharge. The object of adding some red lead to the positive mix is primarily to control the proper rate of “forming” which will be described later. The oxide mix is moistened with the proper amount of sulfuric acid and water to form a plastic paste. If pasting machines are used the paste is applied to the slowly moving grids mechanically, giving them a final wipe at the end. After this they are automatically suspended in a vertical posi- tion on conveyers, close together but not touching. From here they pass to the drying tunnels or ovens. If pasting is done by hand, the operator pastes one side of a number of plates, placing each plate on a piece of paper, one on top of the other, and then turns them over and pastes the other side of each plate. They are then racked closely together or piled up in stacks. The principal danger in the pasting operation is the drying out of the paste which may be left lying around and become a hazard. It is believed that except for the paper used in hand pasting, this process is no more dangerous 214 LEAD POISONING than machine pasting, where large amounts of paste may fall on the floor and dry, thereby constituting a dust hazard. In pasting rooms good ex- haust ventilation is essential. Since the paste tends to set quickly, the time between the mixing of the acid and the water to the dry oxide and the past- ing operation is usually limited to about fifteen minutes. The plates are dried in long tunnels or large drying chambers for periods of from 12 to 36 hours, depending on the temperature. In cases where room temperature is depended upon, the longer periods will prevail, while if heated air is applied, careful control of the humidity is necessary to pre- vent cracking of the plates. After they receive a full brushing, they are ready for “forming” in acid. In the forming operation, they are connected in their proper negative and positive positions in a large tank containing weak sulfuric acid, held apart by spacers, and the negative sponge lead and the positive lead peroxide are formed by transmission of electric current. After this operation the plates are again dried and passed on to the finishing operation and their assembly into the battery case. Sometimes the plates are formed after the battery is assembled, using weak acid which is re- placed by a stronger acid after “forming” is completed. The grids which were originally cast double are now separated, trimmed, and inspected and made ready for assembly. All of these operations should be done under efficient exhaust hoods. The plates are assembled in their desired groups, burned together, placed in their cells, lugs burned to connector strips, tops sealed into place and the acid poured in. At times they are shipped without acid. They are usually given a low rate charge until fully charged. While the general room air in a battery plant may show a definite amount of lead dust, this may be kept low by proper ventilation except in the dump- ing and mixing departments or in the pasting department where paste is allowed to dry out before being removed. Here special additional sanitary precautions should be taken by providing the men with air-line respirators. In the modern plants, physicians inspect periodically all workers, detecting the first signs of lead absorption. D. Fabrication of Metal Products The sheet-lead and pipe industry is another important user of lead. Sheet and Pipe. Lead is cold-rolled by passing a cast slug through rolls until it is reduced to a sheet of the desired thickness. It is then stored and cut on order in the various weights carried in stock. Sheet lead is used principally in the various chemical industries handling sulfuric acid, as well as other acids, plating baths, and tanks for chemical processing. Pipes, traps, and bends are extruded in a warm, solid state. The molten metal is poured into a chamber and a stream of warm metal is passed around LEAD PRODUCTS IN INDUSTRY 215 a core through dies of proper size. Lead is used for service pipes, waste plumbing, and chemical plumbing. On account of its plastic nature, the lead can easily be bent and shaped to fit various needs. For the same rea- son it has been preferred as a service connection between water mains and houses to withstand ground movements in the street. Lead pipe is seldom used now for potable water. In the past, considerable literature has ap- peared on the subject of solvent action of certain natural waters on lead. It is faily well established that a protective film of the basic carbonate quickly forms on the inside of pipes when the water is sufficiently hard, and this hardness is usually considered sufficient when it is at least 50 in terms of total hardness. Wherever a soft water is present, or where the source of the water is of organic, peaty origin, or in the case of certain more highly carbonated waters, or where the water contains relatively large amounts of the chlorides of calcium or magnesium, lead pipe is not to be recommended. The United States Public Health Service maximum for drinking water is 0.1 part of lead per million of water. In ordinary plumbing installations, the various parts are usually soldered. On large tank installations, however, the seams of the sheet are welded to- gether by lead burners. In soldering, there should be no serious hazards, while in lead burning a temperature is reached which may volatilize small amounts of lead. Lead burners are usually trained in their work and they must be protected by respirators, since large installations can usually be made only at the place of their use. Collapsible tubes are either lead or a mixture of lead and tin made from extruded disks of the laminated sheets cut from rolled metal. These are used for cosmetics, tooth pastes, shaving cream and various other similar materials. No ill effects have resulted from the use of such containers, since only the tin comes in contact with the contained material. Cable Sheathing. Lead cable sheathing is extruded in a warm state under hydraulic pressure similar to pipe, except that the cable itself acts as the core in going through the center of the die around which the lead flows. It is believed that its fabrication should involve little or no danger. Alloys. The alloys of lead which are used in industry are numerous and varied. Those in common use contain either a small amount of antimony or calcium, the balance being lead. Usually serious trouble is encountered only when unnecessarily high temperatures are used in melting the alloys. They are used principally as grid metal, solder, bearing metals, and type metals. Grid metal is commonly cast at temperatures somewhat above the melt- ing point of the eutectic antimonial lead used in order to insure proper fluidity. A temperature of about 450°C. is about average, but in some cases it is allowed to reach much higher levels, and may volatilize lead as 216 LEAD POISONING well as antimony. Needless to say, excessive temperatures must be avoided and hoods should be installed over the melting pots and casting machines to provide efficient ventilation. This question has already been discussed under storage batteries. Solder baths are normally covered with a flux and kept at low tempera- tures to avoid drossing tin, which is more valuable than the lead. At such temperatures there is little vapor pressure of lead. One of the large uses for solder is in the manufacture of automobile bodies and radiators. A number of articles are dip-soldered by passing through a layer of flux on top of the molten solder and withdrawn. Because of the present world war, several substitute solders are coming into use which have slightly higher melting points than the standard tin solders. Whenever there is a substi- tution of metals or a change from a hand process to one of machine produc- tion or vice versa, the toxicological questions should be reexamined. Linings for bearings are frequently made of lead-base alloys. In this connection, because of the strategic nature of tin, the use of lead for bearings will undoubtedly increase. Lead-base bearing metals vary considerably in composition, containing about 809, to 989, lead. Copper-lead bearings are produced at higher temperatures, being practically an emulsion of lead in copper, and care is required in the technique of their production. More perfect distribution of lead in copper is claimed by powder metallurgy, where the metal powders are compressed under great pressure below their melting points, but this method, while practically hazardless, is more costly. Powder metallurgy is coming into greater use particularly where metals non-readily miscible are concerned. Shot is made in towers by dropping molten lead into water. Small amounts of antimony and arsenic are added to insure that the globules re- main spherical. They are then sized and packed automatically. The larger sizes are cast in multiple molds, as is shrapnel, which is an antimonial lead usually containing about 21%, antimony. Bullet metal cores for small arms ammunition are fabricated antimonial lead wire, which is made by extrusion under hydraulic pressure through dies of proper diameter. The alloy usually contains about 21%, antimony. Terne plate ordinarily consists of thin sheet steel covered with an alloy of about 209, tin and 809 lead instead of 1009; tin. It is used for roofing and for cans containing products other than food, such as lubricating oil. Pewter is an alloy of tin containing about 15 to 209, lead. At the present time very little pewter is made and the Britannia type alloy has entirely supplanted the latter (pewter) metal. Britannia contains no lead, being an alloy of tin with about 3 to 79, antimony and a small amount of copper. LEAD PRODUCTS IN INDUSTRY 217 Lead powder may be made in a number of ways, but it is often made by spraying molten lead through an atomizing nozzle containing very small holes. It may also be made by a steam blast on a pot of molten metal, or by the attrition of lumps of lead in the ball mill. Powder is col- lected and stored to avoid oxidation as much as possible. Other lead products which may be mentioned in passing are caulking wool, the 10%, sodium-lead alloy used in the manufacture of tetraethyl lead for gasoline, which incidentally is consumed by the same manufacturer in a process which is operated under strict control as regards safety measures, and many other small products. Lead is also used as an addition agent to improve machineability. In the case of its addition to brass or bronze, its use is attended with only slight hazard because lead is readily miscible in small amounts and may be added in the form of metal to the melting pot. In the case of its addi- tion to molten steel however, the temperature is such as to vaporize the lead almost immediately and it is necessary to exercise considerable care in introducing the lead or lead compound below the surface of the steel. Fortunately, great care is exercised in this operation, not only on account of its danger, but also to insure the fact that the lead will stay in the steel in sufficient amounts. Recent toxicological studies of this process may well serve as a model for other investigations. Leaded-steel can be machined and cut with much greater speed than ordinary steel. While the process is comparatively new, its sponsors are taking excellent toxicological precautions. We have touched briefly on the more important metallic lead products, their manufacture and use. It is essential to maintain the temperatures involved in the various operations consistently below the significant vapor phase of lead. Wherever this cannot be done, for example in the melting of large quantities of metal and prolonged pouring, efficient hoods and ventilation must be provided. It is always desirable to have a continuous record of the temperature made. The following data on Vapor Pressure of Lead and the Eutectics of the metal are included for reference purposes: Vapor Pressure (calculated) Temp.°C. Pressure mm. Mercury 482 0.000002 Lead Melting Point 327.4°C. 727 .017 1000 1.91 1200 19.1 Boiling Point 1400 110.5 (visible bubbling) 1700°C. 1700 760. 218 LEAD POISONING Eutectics of Lead Melting point of lead with other metals: Other Metals % by weight Temp. °C. Temp.°F. Silver (Ag) 2.5 304 579 Arsenic (As) 2.5 202 557 Gold (Au) 15. 215 419 Barium (Ba) 4.5 290 554 Bismuth (Bi) 58. 125 257 Cadmium (Cd) 17.4 249 480 Magnesium (Mg) 3. 250 482 Palladium (Pd) 5. 265 509 Platinum (Pt) 5. 290 554 Antimony (Sb) 12.5 250 476 Tin (Sn) 63. 183 361 Zine (Zn) .49 318 604 Copper (Cu) .06 326 619 E. Lead Products in the Ceramic Industry Glazes. Earthenware, pottery, and sometimes porcelain are glazed with enamel compositions which often contain lead, on account of the ad- vantage gained thereby in lowering the melting point of the glaze. In the past, litharge or white lead have been used for this purpose. These products are somewhat dusty to handle. More recently, lead silicate has been introduced which has the advantage of being less dusty. The materi- als comprising the glaze are mixed in the dry state and then usually fritted by fluxing in a suitable furnace. The resulting silicates are now ground in water and applied wet to the object to be glazed, which is then baked or fired in a furnace. Glass. Red lead has long been preferred for introduction into molten glass pots requiring lead on account of its tendency to aid in oxidizing impurities and preventing reduction to metallic lead. Litharge has also been used to some extent; both products must be free from impurities but need not be as fine as painters’ products. The litharge used for this purpose has been chiefly ‘flake’ litharge, which is made by the exfoliation of lumps of fused molten litharge. Lead silicate frit has supplanted other products to a considerable extent for use in glass because it forms less dust and goes into solution more readily at a lower temperature. Since the lead is combined with silica in approximately eutectic proportions, it has the lowest possible melting point for that combination. Lead is used in the better grades of glass and such glass mixes are usually made in pot furnaces. These are large circular, brick, low-arched furnaces, approxi- mately 20 feet in diameter, with a tapered chimney. The hazard exists in the more or less dusty mixing and grinding operations which precede charging of the furnace. CHAPTER XII PROCEDURES FOR DETERMINATION OF LEAD \ By Morris B. Jacobs, Ph.D. There are numerous methods for the determination of lead. It would be best if one could pick one of these methods and use it for all samples. Unfortunately this is not practical for a number of reasons. Thus some methods are better than others for larger quantities of lead. Conversely some methods are better than others for small quantities of lead. The instruments required for certain methods may not be available in a given laboratory and therefore such methods cannot be used in that laboratory. For the purposes of this chapter, it will be adequate to describe in de- tail two qualitative: methods, a method using s-diphenylcarbazide, a dithizone colorimetric method, a dithizone photometric method and a polarographic method. It has been shown by several investigators that these methods are approximately equal in sensitivity and precision. SAMPLING In order to obtain some idea of environmental exposure, it is necessary to sample the air in which a worker or subject is exposed. The samples should be taken at positions which make them representative of the general conditions of the workroom or of the air breathed by the worker. If a dithizone method is to be used, the lead content of the sample should not exceed 0.1 mg. of lead. Since the lead content of the blood and urine is increased in lead-affected workers, it is necessary to take samples of these fluids to assist in making a diagnosis. At times the cerebrospinal fluid may have to be sampled. A more extensive investigation of the source of lead intake may make it necessary to analyze the food that is eaten, the lead content of the materials with which the worker comes in contact and the product being manufactured or processed. In an attempt to get a more complete picture of the lead excreted, it may be necessary to analyze the feces of a subject and in post-mortem examinations various organs such as the liver, kidneys, spleen and bone may have to be analyzed. It is clear then that a variety of materials may have to be sampled and analyzed in the course of a lead investigation. Agr. Standard methods for the sampling of air are discussed by M. B. Jacobs!. In sampling lead-bearing dust and fume, the use of (7) the Greenburg-Smith impinger, (2) the midget impinger, (3) an electrostatic 219 220 LEAD POISONING precipitator, and (4) a filter paper device are common. Each of these has its advantages and disadvantages. The large impinger requires power, the electrostatic precipitator requires an alternating electric current, while the midget impinger is a hand-power device. The electric precipitator is considered by many preferable for the col- lection of lead fume samples. However, Buxell and others find that there is little difference in the efficiency of impingers and the precipitator in respect to collecting fumes formed in operations such as the melting and pouring of lead alloys. For the collection of lead fumes by the electric precipitator, the air should be sampled at a rate of 3 cubic feet per minute for 23% minutes. This is equivalent to a total sample of 2 cubic meters and thus simplifies calculations. The general procedure using the all-glass Greenburg-Smith impinger is to trap the lead dust in 250 ml. of lead-free water. Some lead compounds require collection in a dilute nitric acid solution. In this case 10 ml. of nitric acid, sp. gr. 1.42, in 250 ml. of water is adequate. If modified im- pingers of this type are used which require less absorbing solution, the amount of acid added should be known for it is important when the dithi- zone method is used. It is necessary to keep the sampling rate of the Greenburg-Smith impinger slightly below 1 cubic foot per minute; therefore, in order to obtain a sample of 1 cubic meter, from 30 to 40 minutes should be allotted for the sampling. It may be necessary to sample as much as 60 to 90 cubic feet or as little as 10 cubic feet depending entirely on the lead content of the air being sampled. Filtration devices are also used for fumes and dusts. Fairhall, et al. describe devices for the collection of samples on filter paper. Urine. Collect a 24-hour sample of urine in an acid-washed heat-re- sistant glass container using toluene as a preservative. When not con- venient to collect the larger specimen 100 to 200 ml. samples of urine may be collected. Great care must be taken in the collection of this sample. It should not be taken in working areas and preferably not while the subject is wearing work clothes. These precautions are necessary to avoid contamination of the sample with extraneous material. Generally 100-ml. aliquots are used for the analysis. However, proportionally smaller ali- quots should be taken if the volume of urine passed is less than normal. (Letonoff and Reinhold). h Blood. Tt is preferable to use all-stainless steel needles and Pyrex glass syringes which have been sterilized in all-glass vessels to avoid contamina- tion in the collection of blood samples. Cholak and Bambach found that the principal source of contamination could be traced to the use of the generally available needles made by pressing a steel tube into a hub of screw-cutting brass. The friction of the stylet against the opening in the PROCEDURES FOR DETERMINATION OF LEAD 221 hub frequently released minute particles of brass which were carried into the container by the blood. About 12 ml. of blood should be drawn for the sample since 10 ml. is required for the analysis. Hot saturated sodium oxalate can be used as an anticoagulant. If serum lead is required, then the blood must be collected without an anticoagulant and allowed to clot. Other Materials. Cerebrospinal fluid should be sampled in the usual manner (Todd and Sanford). As in the case of blood, 10 ml. may be used for the analysis. Feces, sampled in the usual manner, should be mixed well, dried and ground. A weighed portion should be taken for the analysis. Procedures for the sampling of food are detailed in the Methods of the A. O. A. C. and by M. H. Jacobs2. QUALITATIVE TESTS Microscopic Test. The microscopic test (Zhitkova, Kaplun and Ficklen) based on the identification of potassium copper lead hexanitrite is often used as a qualitative means of ascertaining if lead is present. The lead is precipitated as the sulfide in the presence of ammonium sulfate and copper acetate, the copper acting as a collector. After careful washing of the filtered precipitate, the lead sulfide is dissolved in a few drops of con- centrated nitric acid. A drop of this solution is evaporated to dryness on a microscope slide. Minute quantities of sodium acetate, acetic acid and a small crystal of potassium nitrite are added. Lead, if present, crystallizes out as characteristic brown squares and cubes of potassium copper lead hexanitrite, K;CuPb(NO,)s. Lead Sulfide Method. The following method based on the precipitation of lead as the sulfide is a comparatively simple method and is easily adapt- able to all types of sampling. It is limited, however, to those instances where most of the other metals of the insoluble sulfide group are absent or are present in negligible amounts. It can also be used as a quantitative method. If the lead-bearing dust is caught on filters, paper or cellulose materials, place these lead bearing substances in a silica dish and ash at 500°C. Other samples should be evaporated, if necessary, dried and then ashed at the same temperature. Dissolve the ash in 10 ml. of water and 1 ml. of nitric acid. Filter, add a drop of phosphoric acid and make the colorless filtrate alkaline with ammonia. The phosphate precipitate will contain practically all of the lead and the copper, if any is present, will remain in the filtrate as the complex ammonia compound. Filter, wash well, and dissolve the precipitate in 5 ml. of dilute acetic acid. Make up to 50 ml. in a Nessler tube. Add 5 ml. of hydrogen sulfide solution and, if desired, match the color with that of standard lead solutions treated the same way. The lead sulfide precipitate may be stabilized by the use of solutions of arabic or 222 LEAD POISONING ghatti gum by adding 1 ml. of a 5 per cent solution of the gum to the solution in the Nessler tube before it is made to volume. The standards are treated the same way. The quantity of lead present is taken to be that of the closest standard. QUANTITATIVE METHODS It is clear that in making analyses for micro quantities of lead it is essential that all the equipment, glassware and reagents be as free of lead as possible. This will reduce possible sources of contamination and mini- mize the blank. The water used in the analyses must be distilled water, preferably redistilled or treated so as to be lead-free. The glassware should be of the Pyrex or similar type glass. New silica dishes should be ignited and treated with hot hydrochloric acid before use. Reagents such as hydrochloric acid, nitric acid, ammonium hydroxide, and chloroform should be redistilled and stored in Pyrex glassware. Filter papers should be soaked over night in nitric acid (1:100) and then washed free from lead and acid, using large volumes of water with the aid of a Biichner funnel and suction. The papers may be dried in a vacuum desiccator over sulfuric acid to avoid the brittleness induced by drying in an oven. It is good practice in the dithizone method to give the glassware used an additional washing with a mixture of 50 ml. of nitric acid (1:1000), 10 ml. of ammonia- cyanide mixture and a few ml. of dithizone in chloroform solution (see p. 000). Then rinse thoroughly with lead-free water. In other methods, in addition to the usual treatment with cleaning solution, washing, etc., the glassware should be rinsed thoroughly with tap water, distilled water and lead-free water. s-Diphenylcarbazide Method In the Fairhall? method, the sample is ashed and the ash is dissolved. The lead is precipitated as the sulfide. If further separation from other metal sulfides is necessary, the sulfides are dissolved, separated in the usual manner, and the lead is reprecipitated as the sulfide. It is redissolved and reprecipitated as the chromate. This lead chromate precipitate is dissolved in hydrochloric acid and the amount of lead present is ascertained by iodo- metric estimation with the addition of potassium iodide and titration with standard sodium thiosulfate solution, or it may be determined colori- metrically with s-diphenylcarbazide. The titration method is preferable for larger quantities of lead and the colorimetric procedure for smaller quantities. The details of the titration method are given elsewhere (M. B. Jacobs). In the modification of Letonoff and Reinhold, after ashing the material sampled, the lead is precipitated as the complex lead potassium chromate, PROCEDURES FOR DETERMINATION OF LEAD 223 PbK;(CrOs)s, by the addition of potassium chromate to a solution of the ash containing chloride, citrate, acetate and ammonium ions at pH 6.6 to 7.4. The double chromate is precipitated in a centrifuge tube and is separated and washed by centrifuging. After dissolving in hydrochloric acid, the lead is estimated colorimetrically by means of the red color formed by diphenylcarbazide with chromate. Reagents. s-Diphenylcarbazide, 0.02 per cent solution: Transfer 0.100 gram of pulverized s-diphenylcarbazide to a liter beaker. Add 500 ml. of ammonia-free distilled water, cover with a watch glass and dissolve com- pletely by boiling several minutes and stirring. Cool, dilute to 500 ml. and store in a brown bottle. This solution will keep at room temperature for 2 months. Ferric chloride ash-aid: Dissolve 10 grams of ferric chloride, FeCl; - 6H,0O in a liter of distilled water. Add 34 ml. of ammonium hydroxide solution with stirring, allow the precipitate to settle, decant, collect the precipitate on a Biichner funnel, wash with about 3 liters of distilled water and twice with lead-free water. Do not allow the precipitate to dry before the washing is completed. Remove the precipitate from the filter paper, dry at 105°C. and powder in a mortar. Dissolve 0.1 gram in 10 ml. of 20 per cent hydrochloric acid by warming and make up to 250 ml. with lead-free water. Potassium chromate, 30 per cent solution: Dissolve 60 grams of potas- sium chromate, KoCrOy, in distilled water and make up to 200 ml. Allow to stand for 14 days, if possible, before filtering through Whatman No. 44 paper which has been washed with chromate solution just before use. Potassium chromate solutions filtered before this period should be re- filtered after 14 days. Standard lead acetate solution: Dissolve 0.183 gram of lead acetate, Pb(CyH30,)s-3H:0, in 1 per cent acetic acid, transfer to a 100-ml. volu- metric flask and dilute to volume. One ml. of this solution contains 1 mg. of lead. Dilute 1 ml. of this solution to 100 ml. with 1 per cent acetic acid. One ml. of this solution is equivalent to 0.01 mg. of lead. Standard lead chromate solution: Dissolve 39 mg. of lead chromate in 10 per cent hydrochloric acid. Transfer to a 100-ml. flask and dilute to volume. One ml. of this solution is equivalent to 0.25 mg. of lead. It is stable for 3 months or longer if stored in a refrigerator. Working standards may be made by diluting 2 and 4 ml. respectively to 50 ml. with 10 per cent hydrochloric acid thus obtaining solutions equivalent to 0.01 and 0.02 mg. of lead in 1 ml. Procedure. Transfer 10 ml. of blood after thoroughly suspending any precipitated oxalate, if hot saturated sodium oxalate solution was used as the anticoagulant, or 10 ml. of serum to a 30-ml. lipped silica dish containing 224 LEAD POISONING 5 ml. of lead-free water for whole blood or 5 ml. of ferric chloride ash-aid for serum. Evaporate to dryness on a hot plate. Transfer the dish to an electric muffle oven, heat at low temperature until the material is charred, raise the temperature to 450-500°C. and continue heating until ashing is complete. Remove the dish from the oven, allow to cool and wash down the sides of the dish with 1-2 ml. concentrated nitric acid. Evaporate carefully to dryness, replace the dish in the oven and continue heating until any remaining carbon is consumed. This generally requires 30 minutes. Remove the dish from the muffle again, allow to cool and wash down the sides of the dish with 5 ml. of 20 per cent hydrochloric acid. Evaporate cautiously to about one-third the volume on an asbestos-covered hot plate, cool, add 2 ml. of 20 per cent sodium citrate solution, 1 drop of phenol red indicator solution and while stirring with a Pyrex rod add concentrated ammonium hydroxide until the indicator turns just pink. Filter through a 4.25-cm. Whatman No. 44 filter paper washed with lead-free water into a 15-ml. centrifuge tube which has been designed to retain precipitates. Wash the dish and filter paper four times with 1 ml. of 0.1 N ammonium hydroxide. Add sufficient, generally 1 to 3 drops, 25 per cent acetic acid to change the indicator to orange-yellow. Add precisely 1 ml. of standard lead acetate solution containing 0.01 mg. of lead with the aid of a calibrated pipette and wash down the walls of the tube with 1 ml. of 40 per cent ammonium acetate solution. Add 1 ml. of 30 per cent potassium chromate solution and mix completely by stirring but avoid scratching or rubbing sides of the tube. Cover and allow to stand over night. Remove the stirring rod and wash any adherent material into the tube with about 3 ml. of 0.4 per cent ammonium acetate solution. Centrifuge 10 minutes at about 2400 r.p.m., decant supernatant liquid, invert tube and allow to drain for 5 minutes. Wipe the remaining liquid from the mouth of the tube. Wash with 10 ml. of 0.4 per cent ammonium acetate solution taking care to wash the walls of the tube. Suspend the precipitate by stirring gently and wash stirring rod as before. Centrifuge for 10 minutes, decant and allow to drain for 5 minutes. Repeat the washing with another 10-ml. portion of ammonium acetate solution. Centrifuge again and after allow- ing to drain for 5 minutes, wipe the mouth of the tube, replace the stirring rod and add 3 ml. of 10 per cent hydrochloric acid so that it washes the walls of the tube and the stirring rod. Stir until the precipitate dissolves, add 10 ml. of s-diphenylcarbazide solution, remove the stirring rod, stopper and mix by inversion. Allow 10 minutes for color development. Measure color in a photoelectric colorimeter using a green filter with maximum transmission at 540 mg, or compare in a colorimeter with standard lead chromate solution treated with s-diphenylcarbazide solution. Transfer 3 ml. of each of the lead chromate solution standards into test PROCEDURES FOR DETERMINATION OF LEAD 225 tubes with the aid of calibrated pipettes, add 10 ml. of diphenylcarbazide solution, mix, and allow to stand for 10 minutes for color development. The color is stable for an hour or more. S Mg. of lead per 100 ml. = 12 X 0.03 X 05] — Blank S = reading of standard. U = reading of unknown. 0.03 represents concentration of lead in standard. It is replaced by 0.06 when more concentrated standard is used. Blank includes added lead (0.01 mg.) plus any lead present in reagents. Blank and Control. To determine the blank, place 5 ml. of lead-free water and the actual amount of anticoagulant used in the blood aliquot taken, or 5 ml. of ferric chloride ash-aid into a silica dish. Evaporate to dryness and proceed with the method as detailed. After average values for blanks have been determined, controls containing the added lead may be substituted. To prepare such a control, transfer 5 ml. of lead-free water to a 15-ml. centrifuge tube, add 1 drop of phenol red indicator solution, 2 ml. of 20 per cent sodium citrate solution, 1 drop of 25 per cent acetic acid, exactly 1 ml. of standard lead acetate solution, 1 ml. of 40 per cent ammonium acetate solution and 1 ml. of 30 per cent potassium chromate solution. Proceed as outlined above. To the result which represents 0.01 mg. of lead plus the lead in the reagents mentioned, add the average lead found in the blank less 0.01 mg. of added lead. Subtract this value from the total amount of lead found in the sample and reagents. Citric acid should replace sodium citrate when the former is required in the analytical procedure. Neutralization with ammonia is necessary if it is used. Other Materials. An aliquot of the urine collected in a 24-hour period is evaporated to dryness and the method is followed but 2 ml. of 50 per cent citric acid is substituted for 2 ml. of sodium citrate solution. A 0.2-gram portion of dried, pulverized feces is analyzed in an analogous manner again substituting citric acid for sodium citrate. Ten ml. of cerebrospinal fluid and 0.1 to 0.3-gram portions of minced tissues may be analyzed by the procedure described for blood. In the case of bone, a 0.1-gram portion is used and citric acid is substituted for sodium citrate solution. Dithizone Method: General With the introduction by Fischer of the dithizone method for the deter- mination of lead, numerous variations of this method have appeared (H. Fischer; Wichmann, Murray, Harris, Clifford, and Vorhes; Vorhes and Clifford; Winter, Robinson, and Miller; Wilkins, Willoughby and Kraemer; Willoughby, Wilkins and Kraemer; Clifford and Wichmann; Hubbard; 226 LEAD POISONING Fischer and Leopoldi; Kozelka and Kluchesky). These methods have the ability of detecting very small quantities of lead and are based on the formation of a red precipitate of a lead-dithizone complex which is soluble in chloroform or carbon tetrachloride, when an ammoniacal cyanide solu- tion of dithizone is added to a solution containing lead. 2 Dithizone is the short name for diphenylthiocarbazone. It is the type of reagent which is best used for the estimation of low concentrations. It forms green colored solutions in chloroform. The lead complex has a red color and is soluble in chloroform but is praciteally insoluble in dilute ammonia, whereas dithizone itself is soluble in this solvent. Upon these factors, the various methods for the isolation and subsequent determination of lead depend. The nature of the reaction which takes place between dithizone and a metallic salt, and the structure of the resulting compound are not definitely known. Purification. Commercial diphenylthiocarbazone generally must be purified before use. Dissolve about 1 gram of the commercial reagent in 50 to 75 ml. of chloroform and filter if insoluble material remains. Shake out in a Jacobs-Singer separatory flask (M. B. Jacobs! ?), an apparatus designed to permit multiple extractions with a lighter specific gravity solvent layer, with four 100-ml. portions of metal-free, redistilled am- monium hydroxide solution (1:99). Dithizone passes into the aqueous layer to give an orange colored solution. Filter the aqueous extracts into a large separatory funnel through a pledget of cotton inserted in the stem of the funnel. Acidify slightly with dilute hydrochloric acid and extract the precipitated dithizone with two or three 20-ml. portions of chloroform. Combine the extracts in a Jacobs-Singer separatory flask and wash 2 or 3 times with water. Pour off into a beaker and evaporate the chloroform with gentle heat on the steam bath, avoiding spattering as the solution goes to dryness. Remove the last traces of moisture by heating for an hour at not over 50°C. in vacuo. Store the dry reagent in the dark in a tightly stoppered bottle. Make up the reagent solutions for extraction to contain approximately 100, 50, and 10 mg. per liter in redistilled chloro- form. A stock solution of dithizone in chloroform containing 1 mg. per ml. will keep a long time and is convenient for use in making dilutions. Interferences. Dithizone is not a specific reagent for lead for it will form colored compounds with 14 other metals. Even in the presence of excess potassium cyanide, stannous tin, bismuth and thallium interfere. Tin and bismuth are likely to occur in biological specimens but the occurrence of thallium is unlikely. Both thallous thallium and stannous tin are converted to the stannic and thallic states by oxidation during evaporation with nitric acid. This reduces the possibility of their extraction by the dithizone. Bismuth is eliminated as an interference by an extra dithizone PROCEDURES FOR DETERMINATION OF LEAD 227 extraction from the lead solution before its final estimation by extracting a nitric acid solution of the two metals, which has been adjusted to a pH of 3.5, with a chloroform solution of dithizone. Dithizone Method: One Color (Harrold, Meek and Holden) In this method the lead is extracted with a small excess of dithizone in chloroform solution and the excess dithizone is removed from the combined extracts by washing with dilute ammonia-potassium cyanide solution. The amount of lead in the extract is then estimated colori- metrically by a comparison of the red color of the lead-dithizone complex. Preparation of Reagents. 1. Prepare a 5 per cent solution of ammonium citrate from citric acid by the addition of ammonium hydroxide until just alkaline to litmus paper. 92. Lead extractive solution: Mix 15 ml. of 10 per cent potassium cyanide solution, 10 grams of potassium cyanide dissolved in water and made up to 100 ml., and 20 ml. of ammonium citrate solution with 53 ml. of concen- trated ammonium hydroxide, sp. gr. 0.9 and then add 450 ml. of water. This solution is used to neutralize the excess nitric acid and provide the proper pH of from 9.5 to 10. 3. Dithizone extractive solution: Dilute 5 ml. of 10 per cent potassium cyanide solution and 15 ml. of concentrated ammonium hydroxide to 500 ml. with water. 4. Standard lead solution: Dissolve 1.598 grams of recrystallized lead nitrate in 0.1 per cent nitric acid and make up to 1 liter with this solvent. One ml. of this solution contains 1 mg. of lead. Dilute 10 ml. of this solu- tion to 1 liter One ml. of this dilution equals 0.01 mg. of lead. Procedure. Collect the sample either with 10 ml. of nitric acid or in water as explained on page 220. If collected in water, add the same quanti- ty, that is, exactly 10 ml. of concentrated nitric acid, or the additional amount of acid if a lesser quantity was used in the collector, after collection. Boil the sample in the original sampling vessel until the volume is less than 90 ml. After cooling, transfer to a 100-ml. volumetric flask. Wash the sampling flask with two 5-ml. portions of water and add this wash water to the volumetric flask. Then dilute to the mark with water. Remove a 5-ml. aliquot portion, which volume will contain approximately 0.5 ml. of concentrated nitric acid. It is important to add exactly 10 ml. of nitric acid and nomore. Too little acid will cause the destruction of the dithizone reagent. Too great an amount will lower the pH below 9.7 which is the alkalinity to which the lead extractive solution has been adjusted. This has been shown to be the optimum pH by Clifford and Wichmann. The reagents have been adjusted to care for all the commonly interfering metal- lic ions, but the procedure must nevertheless be closely followed. 228 LEAD POISONING Suitable modifications of the above procedure must be made for samples other than air samples. Place 15 ml. of the lead extractive solution containing the potassium cyanide, ammonium citrate, ammonium hydroxide and water into a pear- shaped separatory funnel. Add the 5-ml. aliquot of the unknown with the aid of a standard pipette. Add dithizone solution, 25 mg. per liter of chloroform, from a semi-micro burette in 0.3-ml. portions, shaking the separatory funnel after each addition until a slight purple tinge is noticed in the chloroform layer This purple tinge shows that uncombined dithi- zone is now present. The dithizone in the chloroform layer turns a bright cherry red when shaken with solutions containing lead. Add chloroform from a burette in sufficient quantity so that the total of dithizone-chloro- form solution and chloroform is equal to exactly 10 ml. Shake for not over 10 seconds. Allow the layers to separate. Drain the chloroform layer into another Squibb separatory funnel containing 20 ml. of the dithizone extractive solution, consisting of potassium cyanide and ammonium hydroxide. Shake the chloroform layer with the 20 cc. of dithizone ex- tractive solution, if too great an excess of dithizone has been added. Re- peat if necessary to remove the excess dithizone. It has been shown that two extractions are usually sufficient to remove any excess. The color of the resulting chloroform solution should be a bright, clear cherry red. The drop at the top of the aqueous layer may be brought down to the rest of the chloroform by repeatedly tapping and shaking with a slight rocking motion. Transfer the chloroform layer into a test tube or comparator tube, first wiping the inside of the stem of the separatory funnel with a cotton swab or pipe cleaner to remove moisture. The test tube or comparator tube should then be stoppered. Three standard solutions containing 0.005 mg., 0.01 mg., and 0.015 mg. of lead respectively are made at the same time that the unknown is prepared for analysis. These standards, after the lead extraction and the removal of excess dithizone, are placed in tubes similar to those used for the unknown. By placing the unknown sample between the two standards that are nearest the unknown in shade and holding up in front of a standard source of white light, one is able to determine the lead content within 0.001 mg. This does not hold when more than 0.1 mg. of lead is present in the sample taken for analysis. Best results are obtained when the aliquot taken contains less than 0.04 mg. of lead. To prepare the 0.005 mg. standard, add 5 ml. of the dilute lead nitrate standard solution to 40 ml. of water and 5 ml. of concentrated nitric acid. After this solution has been thoroughly mixed, take a 5-ml. aliquot and treat it exactly as has been described for the unknown. To make up other stand- PROCEDURES FOR DETERMINATION OF LEAD 229 ards use proportionately larger amounts of the dilute lead standard solution. For comparison standards containing 0.045 mg. or more of lead, use the concentrated lead nitrate solution containing 1.0 mg. of lead per ml. Thus, for making a 0.07 mg. standard, add 0.7 ml. of the concentrated lead nitrate standard solution to 5 ml. of nitric acid and dilute to 50 ml. with water. Take 5 ml. of this as an aliquot for analysis. The resultant pH is between 9.5-10 under conditions as stated. When large amounts of iron (Harrold, Meek and Holden?) are present in samples analyzed for lead by the colorimetric dithizone method, fading will occur unless a small amount of hydroxylamine hydrochloride is present as an inhibitor. Add 2-4 drops of a saturated aqueous solution of hy- droxylamine hydrochloride to each sample and standard prior to the addi- tion of dithizone. When 200-300 times as much iron as lead is present, extract the lead with an excess quantity of very strong dithizone solution, approximately 100 mg. per liter, and then strip the excess with the dithizone extractive solution. The final color is developed after adding 2 drops of hydroxylamine hydrochloride to the solution which is brought to a pH of 9.5-10.0 by the addition of a known quantity of standard dithizone solution as in the procedure outlined above. Dithizone Method: Titrimetric (Horwitt and Cowgill; Moskowitz and Burke) In this method, the lead is separated from a given solution by means of dithizone and the resulting lead-dithizone complex is then isolated. The latter is freed of lead by washing with acid. The chloroform solution of dithizone remaining is mixed with some dilute cyanide solution which re- moves most of the dithizone from the chloroform imparting a brown color to the aqueous layer. A lead solution is added from a burette to this mixture until all the dithizone has been converted to lead dithizonate as indicated by (1) the disappearance of the brown color in the aqueous layer and (2) the absence of a red color when the aqueous layer is mixed with chloroform and additional lead solution. As the final titration is carried out directly with a known standard lead solution, it eliminates the necessity for special precautions in the handling of the dithizone. For details see the original articles or Jacobs. Dithizone Method: Mixed Color Photometric In this method the lead is also extracted with an excess of dithizone in chloroform solution but the excess is allowed to partition between the aqueous and chloroform phases and so modify the color of the extract ac- cording to the relative amounts of lead and dithizone. According to this proportion, a series of colors from red to green may be arranged with inter- mediate crimsons, purples and blues, consequently Clifford and Wichmann 230 LEAD POISONING termed this procedure mixed color. If the extraction is made under definite conditions of volume and strength of dithizone solution and volume and strength and pH of aqueous fraction, the mixed color obtained is definite and reproducible and, provided excess dithizone is present, depends only upon the amount of lead present. The transmission spectra of the two eomponents in the dithizone extract, namely, lead dithizonate and free dithizone, show a marked difference in their ability to absorb light of wave length 510 mg, for the red lead com- plex absorbs strongly and the free dithizone transmits freely. Consequent- ly when the absorption of light of this wave length by the individuals of a standard color series, measured through suitable cell length, is determined photometrically, a practically linear relation is observed between the amounts of lead and the absorption coefficient. Preparation of Reagents. 1. Ammonia-cyanide solution: Add 75 ml. of concentrated ammonium hydroxide solution, sp. gr. 0.9, to 100 ml. of 10 per cent potassium cyanide solution and make up to 500 ml. with distilled water. 2. Standard dithizone solution: Dissolve 0.125 gram of purified dithizone (see p. 226) in chloroform in a 250-ml. volumetric flask, and complete to volume with chloroform. Fach ml. is equivalent to 0.5 mg. dithizone. The standard solutions listed in Table 20 may be prepared from this solu- tion. 3. Standard lead solutions: Solution A: Weigh out accurately 1.598 gram of recrystallized lead nitrate, Pb(NOs), and transfer to a liter volu- metric flask. Add 10 ml. of concentrated nitric acid and a few ml. of redistilled water to dissolve the salt. Make to volume with water and mix. This solution contains 1 mg. lead per ml. It is stable and should be used as the standard lead stock solution. It should be discarded if any cloud or sediment appears. Solution B: Dilute 100 ml. of solution A to 1 liter with water and then dilute 50 ml. of this to 500 ml. with nitric acid (1:1000). One ml. of this solution contains 0.01 mg. lead. This solution may be used for standardiz- ing the dithizone in the 0-100 and 0-200 microgram lead ranges. Solution C: Dilute 50 ml. of solution B to 500 ml. with nitric acid (1:1000). This solution may be used for standardizing the dithizone for the 0-5, 0-10, 0-20, and 0-50 microgram lead ranges. Prepare solutions B and C as needed. Standardization of Dithizone Solutions. The appropriate volumes and concentrations of solutions specified for the various ranges of lead content and the cell length are given in Table 20. Transfer with the aid of pipettes the required volumes of standard lead solution, 1 ml. of which equals some simple fraction or multiple of PROCEDURES FOR DETERMINATION OF LEAD 231 1 microgram of lead to a series of separatory funnels. Add sufficient nitric acid (1:1000) to bring the volume to 50 ml. For so-called zero lead, use 50 ml. of nitric acid (1:1000). Saturate each mixture with chloroform by shaking with 2 ml. Allow to stand for a few minutes, swirling the funnel to carry down any globules of chloroform clinging to the side and draw off the chloroform layer completely, being careful not to draw off any of the aqueous layer. Remove any chloroform in the stem with a pledget of cotton, or use filter paper. Add 10 ml. of the ammonia-cyanide mixture and mix. Immediately add the appropriate volume of dithizone solution as given in the table and shake for 1 minute. Allow to stand for 2 minutes and then filter the chloroform extract through lead-free filter paper (see p. 222) inserted gently into the neck of a dry 50-ml. Pyrex Florence or similar flask in order to avoid loss of chloroform by evaporation. Rinse the proper absorption cell with a small volume of the dithizone extract and then fill the cell almost to the top of the vent with the extract. Set TABLE 20 Dithizone Concentrations and Cell Lengths for Various Lead Ranges Lead Ranges Dithizone Concentration Volume Cell Length micrograms mg. per liter ml. inches 0-5 4 5 2 0-10 4 10 2 0-20 8 10 i 0-50 8 25 1 0-100 10 30 3 0-200 20 30 3 the cell in the trough of the photometer. Take the average of 5 or 10 readings which seldom vary more than 2 mm. Plot scale readings against micrograms of lead on a large scale graph. Procedure (Gant). Measure the volume of blood in the syringe with which it was drawn and expel it into a silica dish, if convenient to do so. Otherwise, place the sample in a blood bottle containing oxalate and pipette an aliquot into the silica dish. The lead content of the anticoagu- lant must be known. Evaporate to dryness on a steam bath or hot plate. Transfer the dish to an electric muffle oven and gradually raise the tempera- ture to 500°C. Ash over night at this temperature. Remove the dish, cool, wash down the sides with 2 ml. of concentrated nitric acid and evaporate to dryness as before. Replace in the muffle furnace and heat for about 30 minutes or until a white ash is obtained. Remove the dish, cool, add 10 ml. of concentrated hydrochloric acid and evaporate to dryness on a steam bath or hot plate. Add another 10 ml. portion of concentrated hydro- 232 LEAD POISONING chloric acid and again evaporate to dryness. Remove the dish and while it is still hot add 2 ml. of hydrochloric acid and about 20 ml. of hot water to dissolve the ash completely. Transfer to a 250-ml. separatory funnel. Add 10 ml. of 50 per cent citric acid solution to the dish, add a small quantity of hot water, swirl gently and add to the separatory funnel. Rinse the dish three times with hot water and add the washings to the funnel. Mix the contents of the separatory funnel and add 2-3 drops of metacresol purple indicator solution. Adjust the pH to 8.5 with concen- trated ammonium hydroxide with the aid of a burette and cool. Generally 7-8 ml. is needed. Add 5 ml. of 10 per cent potassium cyanide solution to the dish, rinse into the separatory funnel with water and mix. The total volume should be about 100-125 ml. Add 5-ml. portions of the dithi- zone solution, 20 mg. dithizone per liter of chloroform, shaking between additions until the chloroform extract assumes a purple color. Allow to stand for a few minutes and swirl to shake down the chloroform globules. Draw off the chloroform phase into a 125-ml. separatory funnel containing 50 ml. of nitric acid (1:1000) but permit a drop or two of chloroform to remain in the first funnel. Repeat the extraction of the aqueous phase with 20 ml. of the dithizone solution and combine the chloroform extracts. Shake for one minute to strip the lead from the dithizone complex. Dis- card all but 2-3 ml. of the dithizone solution, dilute with 2-3 ml. of chloro- form and shake for two minutes. If the dithizone retains its original green color, bismuth is absent. A trace of bismuth will give the dithizone solution a dirty purple or iridescent blue color, a larger amount of this metal yields a yellowish brown. If bismuth is present, extract repeatedly with excess dithizone shaking for two minutes between extractions until the dithizone retains its original color. Discard the dithizone layer and wash the aqueous portion with successive 2-3-ml. portions of chloroform until free from dithizone. Shake down globules of chloroform and allow to stand for a few minutes. Draw off the chloroform layer completely be- ing careful not to draw off any of the aqueous layer. Add 10 ml. of the ammonia-cyanide mixture and mix. Add the ap- propriate volume of standardized dithizone solution (see Table 20) and shake for 1 minute. Allow to stand for two minutes and filter through specially prepared filter papers inserted directly into the neck of a 50-ml. Pyrex Florence or similar flask. The lead-free filter papers are prepared by soaking over night in nitric acid (1:100) and then washing with large volumes of water (distilled in pyrex) with the aid of a Biichner funnel until free of acid. Rinse out the proper cell with a small amount of the filtered extract and fill it almost to the top. Determine the absorption coefficient using the standardized dithizone with the same cell used in making the PROCEDURES FOR DETERMINATION OF LEAD 233 standard curve and read the amount of lead from the curve or calculate from the factor of the dithizone solution as detailed by the A. O. A. C. The above method can be used for urine, food, bone and soft tissues with but slight modification. Transfer 100 ml. of urine to an evaporating dish, evaporate to dryness and proceed with the method. In the case of liver, kidney and other organs Gant suggests stripping off adhering fat, cutting off several cross-sections, mincing finely and using 20 grams weighed to the nearest 0.1 gram for the analytical specimen. For bone, strip clean of adhering tissue, cut several cross sections with a chisel and hammer and weigh accurately 5 grams for the analytical sample. Simple color matching may be made without the use of a photometer by making a series of 10 standards as detailed on page 230 but drawing off the dithizone layers into a series of tubes, vials or Nessler tubes. The unknown is treated in a similar way and drawn off into a similar tube or vial. View longitudinally for ranges up to 20 micrograms in the flat- bottomed vials and transversely for higher ranges in Nessler tubes. If the range is exceeded, use a smaller aliquot, or re-extract with nitric acid reagent and make standards covering a higher range. Electrolytic Method The Wichmann-Clifford method is based on the electrolytic separation of lead as the peroxide and its titration by iodometric means. The lead is deposited on the anodic, positive pole by the use of a low electric current. Tin, antimony, bismuth and manganese interfere with the deposition and must, therefore, be removed. Samples are ashed, if necessary, and pre- cipitated with hydrogen sulfide, using copper as a collector for the lead. The sulfides are filtered, washed with hot polysulfide solution, and finally with sodium sulfate solution. The lead and copper sulfides remaining are then dissolved in hot nitric acid, neutralized with ammonium hydroxide, and made up to 2 per cent acid with nitric acid. Potassium dichromate solution is added, the mixture is heated, electrolyzed and the lead deposited as the peroxide, PbO,. It is then washed thoroughly, and removed from the anode, with a sodium acetate acidic solution. Potassium iodide is added and the liberated iodine titrated with 0.001 N sodium thiosulfate solution, using starch as an indicator. For the exact details of the method, which is the preferred method for lead, if serious interference from tin and bismuth exists, consult the references cited. Polarographic Method The lead present in atmospheric dust and fumes or in biological materials may be determined by the following polarographic method which follows 234 LEAD POISONING closely the procedure detailed by Feicht, Schrenk and Brown. The reader is referred to other recent articles and discussions for greater detail (Kolthoff and Lingane; Barnes and Speicher; Kolthoff and Laitinen). Apparatus. The essential parts of the dropping-mercury electrode are: Cell for holding the solution that contains the component to be estimated; dropping-mercury electrode which is ordinarily used as a cathode but may be used as an anode in determining electro-oxidizable components; electrode consisting of a pool of mercury on the bottom of the cell; battery for supply- ing electromotive force; potentiometer for varying the potential across the cell; and galvanometer for measuring current that results from the dif- fusion of ions of the substance to be estimated to the dropping electrode. Various types of cells are available to accomodate different volumes of solution and for special purposes. The dropping electrode consists of a reservoir of mercury usually con- nected by pressure rubber tubing to a glass capillary, 0.03-0.04 mm. in diamter, from which small drops of mercury, about 0.5 mm. in diameter, issue at intervals of about 3 to 4 seconds or 15 to 20 drops per minute. The second electrode may be a quiet mercury electrode, greater than 1 em.?, in the bottom of the cell, or an external calomel, Hg,Cls, electrode connected to the cell by a low-resistance salt bridge. Any battery such as a lead storage battery or dry cells capable of pro- ~ viding potentials up to 3 volts is suitable. Ordinarily the current passing through the solution is less than 50 microamperes. Slide-wire or potentiometer-type radio rheostats are used for varying and measuring the potentials applied to the electrolytic cell. Sensitive galvanometers of the D’Arsonval or reflecting type are em- ployed to measure the current. The maximum sensitivity of the galvanom- eter, with suitable shunts in the circuit, should be at least 0.1 micro- ampere per mm. and preferably 0.01 per mm. Indicating and recording type dropping-mercury electrodes are available. In the indicating type, the voltage regulator is operated by hand and the current is indicated by the galvanometer, whereas in the recording type, the voltage is regulated automatically and the current at various voltages is recorded photographically or by other means. Both types give equally reliable results. The indicating type is less expensive and is generally as satisfactory as the recording type for most purposes. Use in Analysis. The qualitative features of the method depend on the characteristic values of the half-wave potentials at the half values of the currents resulting from the diffusion of the ions of the pertinent component to the dropping electrode and the quantitative features upon the final or limiting value of the diffusion current. Consideration of a particular PROCEDURES FOR DETERMINATION OF LEAD 235 determination is helpful in understanding the principles involved. A current-voltage curve for lead is shown in Figure 5. Air must be removed from the solution to be tested as oxygen is reduced readily at the dropping-mercury cathode and consequently interferes with the determination of other components. It can be removed by passing some inert gas, such as nitrogen or hydrogen, through the solution for several minutes before the determination but not during the determination 80 iti en iting current 1.6 70 14 £0 7) z 12 & bs w i 50 : $ 5 § 103 5 9 S & 40 £ Diffusion 3 Ss 2 & current ’ = Z 30 8 « < ° 6 5 & 3 3 20 a 10 2 Residual current 0 0 Decomposition potential Half - potential -2 i 2 4 6 8 1.0 APPLIED E.M.F., VOLT Fie. 5. Current-voltage characteristics of air-free lead nitrate solution 0.0003 molar with respect to lead and about 0.1 molar with respect to potassium chloride. (From F. L. Feicht, H. H. Schrenk, and C. E. Brown, Rept. Investigations No. 3639 (1942), U. S. Bureau Mines.) because the stirring produced would disturb the dropping of the mercury and cause abnormal current fluctuations. Commercial nitrogen or hydro- gen may be used, but these gases should not contain more than a fraction of a per cent of oxygen. Excess oxygen may be removed from the nitrogen or hydrogen by passing the gas through a Pyrex or quartz tube containing copper turnings heated to about 450°C. As the applied potential is increased to a certain value, a small, steadily increasing residual current flows. This current results from the building 236 LEAD POISONING up of a charge on the constantly changing dropping-mercury surface cor- responding to the applied potential and by acquisition of electrons by any substance reducible in this range of potentials. Continuous electrolysis, that is, passage of current other than the residual current through the solution, begins when the applied potential reaches the decomposition value. The reduction of lead and its combination with the dropping mercury to form a very dilute amalgam begin at the dropping cathode, and the loss of electrons or dissolution of a corresponding amount of mercury from the anode and the combination of these mercury ions with the chloride ions to form insoluble mercurous chloride, Hg:Cl,, begin at the anode. These reactions may be illustrated by the following equa- tions: Pbtt + 2¢ — Pb(Hg) at the dropping cathode 2Hg — 2¢ — 2Hg* + 2Cl- — HgCl; at the anode As the applied potential is increased above the decomposition value, reduction at the dropping cathode increases and causes the concentration of the lead ions in the immediate vicinity to decrease; this decrease in turn causes the diffusion of the lead ions from the solution to the cathode. The migration portion of the current, attributed to the travel of ions to this cathode under the influence of electrical forces, is eliminated by the transport of virtually all the charges through the solution by the relatively large number of ions of the “indifferent salt” potassium or ammonium chloride, which does not participate in the reaction at the cathode. Thus, the resulting current is purely a diffusion current. The value of the residual current must be deducted from that of the observed diffusion or limiting current to obtain the value of the actual diffusion current. The basis of the quantitative aspect of this method of analysis is the relation that when all other factors are constant, the diffusion current is proportional to the concentration; that is: ta = KC However, this relationship holds only when the dropping time is equal to or more than 3 seconds per drop. The diffusion coefficient of the component being determined and the amount of mercury issuing from the cathode per second are affected by the temperature; consequently the temperature should be controlled to at least 0.5°C. to keep variations attributed to this factor within 1 per cent in the measurement of the diffusion current. The temperature can be readily controlled within this range by means of a large beaker of water. Instead of rising only to the limiting value, as shown in Figure 5 the cur- rent may increase almost directly with the applied potential to a so-called PROCEDURES FOR DETERMINATION OF LEAD 237 maximum before falling more or less suddenly to the limiting value. These maxima usually can be prevented by the use of a solution of gelatin, or a mixture of methyl red and bromocresol green. The relatively large, quiet pool of mercury ordinarily used as the second electrode, having an area larger than 1 cm.?, is depolarized completely and has a constant potential when present in solutions containing halide or other ions that form insoluble salts with mercury. In solutions containing chloride ions the potential of the electrode is about the same as that of a calomel electrode at the same chloride-ion activity. The potential of the dropping electrode is the difference between the observed potential and the potential of this quiet electrode. , Although characteristic of the electro-reducible or electro-oxidizable component present, the decomposition potential of a solution depends part- ly upon the concentration of the pertinerit component. The half-wave potential is constant and independent of the concentration of the reducible metal ions, the particular capillary used, and the dropping time of the capillary, provided the temperature and composition of the solution are constant with respect to substances other than the reducible one. This characteristic nature of the half-wave potential is the basis of the qualitative aspects of this method of analysis. Ordinarily the half-wave potentials must differ by at least 0.2 volt to permit the formation of suitable curves for the determination of more than one component in the same solution. Polarographic Method: Dropping-Mercury Electrode At least three methods of using the dropping-mercury electrode for quantitative analysis are available. General Method. The dropping-mercury electrode is calibrated against known concentrations of the substance to be estimated under the same conditions planned for the actual analysis. These resulting data are plotted to give a calibration curve. : Standard-Addition’ Method. A current-voltage curve for the unknown amount of a standard solution of the pertinent substance is determined in the regular manner, and then a known amount is added and a second curve is obtained. The original concentration of the substance to be estimated is then calculated from the values of the diffusion currents in- dicated by the two curves after a correction has been applied for the change in volume. : Pilot-Ion or Internal-Standard Method. The relationship between the diffusion current of the substance to be estimated and that of another substance used as the internal standard in the solution, having the same kind and concentration of indifferent salt or supporting electrolyte and the same temperature as the solution to be used in the actual analysis, is ob- 238 LEAD POISONING tained from actual determination. The ratio of the diffusion current of the pertinent substance to that of the internal standard may then be plotted against the concentration of the substance being determined to give a calibration curve; the concentration of the pertinent substance may be determined from the diffusion current of this and of the internal standard in the actual solution. Results obtained by this procedure are inde- pendent of the particular capillary and, within certain small limits, temper- ature changes in the solution. The need for only the internal-standard solution rather than for a separate one for each substance being deter- TABLE 21 Accuracy and Precision of the Dropping-M ercury-Electrode Procedure for Lead Lead Precision Found A 4 Added a (Found/ Bs Determination ded) Ave.) Average 1 2 3 4 5 mg. per mg. per mg. per mg. per mg. per mg. per % 50 mil. 50 ml. 50 ml. 50 ml. 50 ml. 50 mi. 0 0.10 0.13 0.16 — — —_ 0.2 —_— — .25 .29 .26 0.22 0.26 0.27 .26 1.04 15 .25 .25 27 — —_ — .26 1.04 4 .35 .38 .40 “37 .42 —_ .39 1.11 8 .35 .34 .36 some —— —_— .35 1.00 3 .50 .56 .51 47 as — 51 1.02 10 .50 .50 .49 — — —_ .495 .99 1 .65 .65 .65 —_ — — .65 1.00 0 .80 .80 79 st so — .795 .99 1 1.00 98 .93 98 an ot 96 96 3 AVOTREOL. vityssis is nwt tr dea diab hve alanis oals es Waid 1.02 5 mined, as in the standard-addition method, is one of the important ad- vantages of this procedure. After the complete current-voltage curve has been determined for a particular substance the concentration of the same substance in similar solutions under the same conditions may be obtained from the difference between the current found at a potential slightly below the point at which the current increase begins and that found at a potential slightly above the point at which the current increase ends. Procedure. Collect samples from the atmosphere by electric precipita- tion. Wash the collected material using a rubber policeman from the glass tube, central electrode, or aluminum foil, according to the type of electric PROCEDURES FOR DETERMINATION OF LEAD 239 precipitator used, with the smallest practical amount of nitric acid (5:95) and distilled water into a Pyrex beaker. Transfer a small weighed portion of other samples of source material of the atmospheric-particulate matter or of settled particulate matter to a beaker and dissolve in nitric acid or some other suitable solvent. Evaporate the liquid to 1 or 2 ml. to reduce the volume and remove excess acid and dilute to 25 or 50 ml., depending upon the weight of the sample. Place 1 or 5 ml. of the diluted solution in the electrolytic cell of the dropping-mercury electrode. Add 1 ml. of a solution 0.7 N with respect to potassium chloride containing 2.5 ml. per liter of a “maxima suppressor” solution, 3 parts of a 0.2 per cent alcoholic solution of methyl red and 2 parts of a 0.2 per cent alcoholic solution of bromocresol green. If zinc or cadmium is known to be absent, add 0.5 mg. of the absent metal from a nitrate solution containing 0.5 mg. per ml. to serve as the internal standard. Dilute the solution to about 7 ml. with distilled water and acidify to about pH 3, as indicated by an indicator paper and the methyl red and bromocresol green indicator solution with dilute nitric acid and potassium hydroxide or sodium hydroxide solution. Bubble nitrogen, shown by analysis to contain less than 0.25 per cent oxygen, through the solution for at least 10 minutes. Seal the electrolytic cell to the dropping-mercury electrode with a rubber connection to prevent the reentry of oxygen. Adjust the dropping time to maintain a rate of 6 to 7 seconds per drop. Use of the internal-standard procedure at room temperature eliminates the necessity for exact temperature control. Ash biological material at 500°C. as described on page 223. Dissolve the ash by the addition of nitric acid and distilled water and rinse into glass- stoppered Pyrex cylinders or volumetric flasks, adjusting the volumes with water as dictated by experience. An aliquot or the entire sample, con- sisting of 5 to 20 grams of blood or solid tissue, 100 to 250 ml. of urine, 0.1 to 0.15 gram of the ash of feces, or 3% of a day’s mixed food is extracted with dithizone solution, 0.03 gram in 1 liter of chloroform, preferably in the pres- ence of citrate and cyanide (Cholak and Bambach?). Wash the dithizone extract with 50 ml. of water. Shake out the lead with 20 to 40 ml. of nitric acid (1:100). If the lead content is sufficiently high, the acid washing of the extract may be polarized as described above. If the lead content is low evaporate to a small volume, 3 to 5 ml., and proceed with the method. To obtain information on the accuracy and precision of the dropping- mercury-electrode procedure for lead, analyses were made by one chemist on solutions prepared by another. Table 21 gives the results of these determinations. The 0.01 mg. of lead in 5 ml. of the most dilute solution was not accurate, but the 0.025 mg. in 5 ml. of the next weakest solution was. Thus the smallest amount of lead that can be determined reliably by the above procedure is probably less than 0.025 mg. (25 gamma) and more than 0.01 mg. BIBLIOGRAPHY AkELAITIS, A. J.: J. Nervous and Mental Dis. 93:313, 1941. ArLsutr, C.: Diseases of the Arteries, London, 1:166, 1915. Avrcock, S. K.: Brit., Med. J. 1:1371, 1905. AL1avDIN, N. AND PEREGOOD, E.: J. Ind. Hyg. and Toxicol. 18:139, 1936. Aries, L.: Diss. Wiirzburg, 1931. AvLevi, G.: Parotide saturnina, Florence, 1913. Armkvist: Dermatol. Ztschr. 19:949, 962, 1912. ANNUSCHAT, A.: Arch. f. exper. path. 7:45, 1877; 10:267, 1879. Arrora, G.: Arch. di farmacol. sper. 32:75, 1921. American Public Health Association Report (Water Examination), N. Y., 1933. Anton, G. AND Dawipson, L.: Ztschr. f. d. ges. exper. Med. 89:622, 1933. ANDRAL AND GAVARRET: cited by Aub, Fairhall, Minot and Reznikoff, 1. c. ArLipGE, C.: Hygiene, Disease and Mortality of Occupations, London, 1892. Association Official Agricultural Chemists. Official and Tentative Methods, Wash- ington, D. C., 1940. Aus, J.C.: J. A. M. A. 104:87, 1935. Aus, J. C., FaraaLy, L., Minot, A. AND REzNIKOFF, P.: Lead Poisoning, Medicine 4:1, 1025. Aus, J. C. ano Ruznikorr, P.: J. Exper. Med. 40:189, 1924. Aus, J. C., RezNikoFF, P. AND Smite, D. E.: J. Exper. Med. 40: 151, 173, 1924. Aus, J. C., Ross, G. P. AND Rossmeist, E.: Am. J. Pub. Health 22:825, 1932. Aus, J. C. AnD Smith, D. E.: cited by Aub et al., Medicine, 1. c., p. 171. AvuersAcH, F. AnD Pick, H.: Arb. a. d. k. Gsudhtsamte 45:113, 166, 1913. BaAADER, E. W.: (1) Ztschr. drztl. Fortbild. 25:205, 1928. (2) Gewerbekrankheiten, Urban and Schwarzenberg, 1931. (3) Weisbaden Kong. f. inn. Med. 45:318, 1933. Bapuawm, C.: Med. J. Australia 2:816, 1933. BapuAM, C. AND TAYLOR, H. B.: (1) Rep. Div. Pub. Health, New So. Wales, 1925 and 1927. (2) Rep. of Director-General of Public Health, New So. Wales, 1926. Baconr, K. N., GancuLy, H. D. anp S1rpor, J. M.: Indian J. Med. Res. 26:935, 1939. BAKER, A. B.: Arch. Path. 19:213, 1935. Am. J. Path. 10:637, 1934. Barron, M. axnp Hosan, H. C.: Am. J. Med. Sci. 162:833, 1921. BarnEs, E. C. AND Spercuer, H. W.: J. Ind. Hyg. and Tox. 23:397, 1941. Barth, E.: Virch. Arch. 281:146, 1931. Bass, E.: Deutsch. med. Wehnschr. 59:1665, 1933. Bass, M. H. AnD BLumenTHAL, S.: J. Pediat. 15:724, 1939. Barra, G., FirkeT, J. AND LecLErc, E.: Chimie u. Industrie 43:637, 1940. Bauer, W., Sauter, W. T. AND Aus, J. C.: J. A. M. A. 96:1216, 1931. BAUER, W. AND Ropes, M. W.: J. A. M. A. 90:757, 1928. Baum AND SELIGER: Arch. Tierheilk. 21:297, 1895. Beaumont, G. E. AND WyBURN-MasonN, R.: Brit. Med. J. 1:150, 1939. BecaroLp, C.: Miinch. med. Wehnschr. 51:1648, 1904. 240 BIBLIOGRAPHY 241 Beck, K. AND StEIGMULLER, P.: Arb. a. d. k. Gsundhtsamte 34:446, 1910. BECKER, E.: Diss. Wiirzburg, 1925. Beckmann, K.: Deutsch. Arch. f. klin. Med. 149:177, 1925. BeHREND: cited by Aub et al., Medicine, 1. c. Benrens, B.: (1) Arch. f. exper. Path. 109:332, 345, 353, 1925. (2) Deutsch. med. Wehnschr. 60:890, 1934. BEHRENS, B. AND BAUMANN, A.: (1) Arch. f. Gyniik. 153:584, 1933. (2) Ztschr. f. exper. Med. 92:16, 241, 251, 296, 1933. BEHRENS, B. AND GUNTHER, A.: Arch. f. exper. Path. 137:305, 1928. BeHrENS, B. AND PACHUR, R.: Arch. f. exper. Path. 122:319, 1927. Benrens, B. AND Taraer, H.: Ztschr. f. d. ges. exper. Med. 96:282, 1935. BrINTKER, K.: Med. Welt 3:1292, 1929. BeLkNap, E. L.: (1) Wisconsin Med. J. 28:346, 1929. (2) Indust. Med. 9:505, 1940. J. A. M. A. 104:205, 1935. (3) J. Ind. Hyg. and Toxicol. 18:380, 1936. Ber, W. B.: Lancet 1:206, 267, 1924. BeLL, W. B. AND ANNETT: J. Obstet. Brit. Emp. 32:1, 1923. BeLr, W. B., WiLLrams, W. R. aNp CunningHAM, L.: Lancet 2:793, 1925. BERNARD AND Sarnomon: Rev. Neurol. 11:722, 1903. BERTRAND, G. AND C1UREA, V.: Compt. rend. Acad. Sci. Paris, 192:990, 1931. Bianchi, C.: (1) Il Lavoro 7:38, 1914. (2) 11 Lavoro 7:326, 1914. Biscuorr, F. AND MaxweLL, L. C.: (1) J. Biol. Chem. 79:5, 1928. (2) J. Pharmacol. and Exper. Therap. 34:98, 1928. Bronoi, C.: Occupation and Health, International Labour Office, Geneva, 1934. Brackman, 8. S.: (1) Bull. Johns Hopk. Hosp. 58:384, 1936. (2) ibid. 61:1, 1937. Brum, F.: Deutsch. med. Wchnschr. 38:645, 1912. BruMBERG, H. AND ScorT, T. F. McN.: Bull. Johns Hopk. Hosp. 56:32, 276, 311, 1935. Brumearr, H. L.: J. Indust. Hyg. 5:153, 1923. BonmuOFF, F.: Beitr. z. klin. Chir. 126:324, 1922. Borst, M. AND KoN1GSDORFFER, H.: Untersuchungen iiber Porphyrin, S. Hirzel, Leipzig, 1929. Boston, L. N.: Phila. Med. J. 10:441, 1902. Borrrich, H.: Ztschr. f. Gewerbehyg. 9:3, 1932. Boucuarp, P.: Compt. rend. Soc. biol. de Paris, 5:358, 1873. Boveri, P.: Riforma med. 29:844, 1913. Brapy, J. W. S.: cited by Aub et al., Medicine, 1. c. BreTON AND MARIE: Compt. rend. Soc. biol. de Paris, 62:734, 1907. Brever, H. B. G.: Beitr. z. path. anat. u. allgem. Path. 102:397, 1939. BreziNg, E. AND ExGrING, M.: Wien. Arb. a. d. Geb. d. soz. Med. 5:29, 1912. Bricker, E.: Arch. f. exper. Path. 119:129, 1928. BroGsITTER, L. AND WoDARz, L.: Deutsch. arch. f. klin. Med. 139:129, 1922. BronviN, pE S.: Union méd., Paris 3:89, 1867. BrookrieLp, R. W.: J. Path. and Bact. 31:277, 1928. Brooks, J.: Biochem. J. 21:766, 1927. BrouarpEL, P.: (1) Ann. d. hyg. pub. 1:132, 1904. (2) Med. mod. 15:25, 1904. (3) Les Intoxications, Paris, 1914. 242 LEAD POISONING Broun, G. O.: J. Exper. Med. 36:481, 1922. BRrUGSCH AND ScHITTENHELM: Ztschr. f. exper. Pharm. u. Ther. 4:480, 495, 1907. Bucco, M.: cited by Flury, ibid. Bucy, P. C. anp Bucaanan, D. N.: J. A. M. A. 105:244, 1935. BucHLER, D.: Diss. Wiirzburg, 1929. BurMESTER, B. R.: Folia Haematol. 56:312, 1936. Burton, H.: Gaz. méd. de Paris 8: 470, 1840. BuscHKE, A. AND BERMAN, L.: Klin. Wehnschr. 6:2428, 1927. BuxgeLy, J.: J. Ind. Hyg. and Toxicol. 25:35, 1943. Caso, R. C.: Clinical Examination of the Blood, N. Y., Ed. 5, 1904. Caccurr, S.: Fol. med. Napoli 16:48, 1930. CapwALLADER, W. B.: (1) Bull. Ayer Lab. Penna. Hosp. 3:44, 1906. (2) J. Nerv. and Mental Dis. 39:153, 1912. CarFEY, J.: Radiology 17:905, 957, 1931. CaLMETTES, E.: Le Saturnisme, Paris, 1910. CALVERY, H. O.: J. A. M. A. 111:1722, 1938. CaLvERY, H. O., Lava, E. P. AN» Morris, H. J.: J. Pharmacol. and Exper. Therap. 64:364, 1938. Camus, J.: Compt. rend. Soc. biol. de Paris, 72:861, 1912. CanpY, R. H.: Indian Med. Gaz. 68:136, 1933. CaNTAROW, A.: (1) Unpublished data. (2) Calcium Metabolism and Calcium Therapy, Lea and Febiger, Philadelphia, Ed. 2, 1933. CARLES, J.: Folia Haematol. 7:34, 1909. CARLSON, A. J. AND WoELFEL, A.: J. A. M. A. 61:181, 1913. Am. J. Pub. Health 3:755, 1913. J. Pharmacol. and Exper. Therap. 5:549, 1913- 1914. Carrif, C.: Die Porphyrine, G. Thieme, Leipzig, 1936. CasH, J. T.: cited by Aub et al., Medicine, 1. c. Cercov: Zentralbl. f. Hyg. 17:297, 1928. CuAJES, B.: Med. Klin. 66:848, 885, 1928. CHAPMAN, A. C. AND LinpeN, H.: Analyst 51:563, 1926. Crarcor, J. P.: (1) quoted by Meillére, 1. c. (2) cited by Hamilton, 1. c. CHASSEVANT AND RicaeT: Compt. rend. Acad. Sci. de Paris, 117:675, 1893. CHisToNI, A. AND MrLaNEsI, E.: Arch. Farmacol. sper. 46:147, 1929. CHOLAK, J. AND Bamsach, K.: (1) J. Ind. Hyg. and Toxicol. 25:47, 1943. (2) Ind. Eng. Chem., Anal. Ed. 13:583, 1941. CHRISTIANSEN, HEVESY AND Lomuovrt: Compt. rend. Acad. Sci. d Paris, 179:291, 1925. Cento, R. W.: Commonwealth of Australia, Interim Report of an Official In- Inquiry into the Chronic Nephritis of Queensland with Spceial Reference to Plumbism in Children, 1932. CHYZER, A.:'Les intoxications par le plomb se presentant dans la ceramique en Hongrie, Schmidt, Budapest, 1908. Cracue, T. M. ano WaTson, A. J.: Brit. Med. J. 2:757, 1917. Craupg, H. anp Loyez: Encéphale, 9:30, 1914. CLirrorDp, P. A. AND WicamaN, H. J.: J. Assoc. Off. Agr. Chem. 19:130, 1936. CoEN AND D’AsuToLo: Ziegler’s Beitr. 3:18, 449, 1888. Coie, L. J. AND BacuuBgr, W.: Proc. Soc. Exper. Biol. and Med. 12:24, 1914. BIBLIOGRAPHY 243 Covuier, J.: The Oxford Medicine, London, 6:333, 1921. Committee on Ethyl Petrol Report, Ministry of Health, London, 1930. Cong, W., Russer, C. AND HArwoop, R. U.: Arch. Neur. and Psychiat. 31:236, 1934. Cooksey, T. AND WALTON, S. G.: Analyst 54:97, 1929. CorraN, R. F. ano Lewis, W. C. M.: Biochem. J. 22:451, 1928. CourTNEY, J. W.: Bost. Med. and Surg. J. 142:136, 1900. CraIg, R.: Brit. Med. J. 1:888, 1937. Cresorr: Clin. med. ital. 55:99, 1924. Croirr, D. G.: Med. J. Australia 2:144, 1929. CRUTCHER, J. S. Jr.: J. Tenn. Med. Assn. 26:20, 1933. CurscaMAN: cited by Teleky, 1919, ibid. Curtis, A. C. AND YOUNG, A. G.: J. Lab. and Clin. Med. 13:628, 1928. DaCosta, J.: Lead Poisoning, Phila., 1912. Dankworrt, P. W. AND JURGENS, E.: Arch. d. Pharm. 266:492, 1928. DaNkworTT, P. W. AND Upg, W.: Arch. d. Pharm. 264:712, 1926. Dave, C.: Arch. Internat. Pharmacodynamie 17:387, 1901. Davipson, L. S. P., FuLLerron, H. W., Rag, H. J. AND HENDERSON, A.: Lancet 2:374, 1933. DfisfiriNg-KLuMPKE, A.: Des polynévrites, Paris, 1889. DENEUFBOURG, H.: Thése de Paris, 1905. Dzeroipe AND Le Compr: Compt. rend. Soc. de Biol., Paris, 10:396, 1898. De Scaweinitz, G. E.: Text-Book of Ophthalmology, Phila., Ed. 9, 1921, p. 539. Toxic Amblyopias, Alvarenga Prize Essay, College of Physicians of Philadelphia, 1894. De ViLLAvERDE, J. M.: Trav. lab. Biol., Madrid, 27:227, 1931. Diruing, W. J.: Brit. Med. J. 2:924, 1926. J. Pharmacol. 35:449, 1929. Divring, W. J. AND HaworTH, E. F.: J. Path. and Bact. 32:753, 1929. DrersseN, W. C.: Proceedings of Industrial Hygiene Section, Natl. Battery Manu- facturers Assn., 1939, p. 19. J. Ind. Hyg. and Toxicol. 25:60, 1943. Dressen, W. C., Epwarps, T. I., ReinaarT, W. H., Page, R. T., WEBSTER, S. H., ARMSTRONG, D. W. AND SAvYERS, R. R.: U. 8. Public Health Bull. No. 262, 1941. DuckEerinGg, E.: Lead Poisoning, Boston, 1910. Duensing, F.: Deutsch. Ztschr. f. Nervenheilk. 143:297, 1937. DuEsBERG, R.: Arch. f. exper. Path. 162:249, 1931. Durour-LABAsTIDE, A.: Thése de Paris, 1902. Duy, J.: Wien. klin. Wchnschr. 48:1413, 1935. Dovowirz, D.; Fazekas, J. F. ANp Hivwice, H. E.: J. Ind. Hyg. 19:93, 1937. EpINGER, L.: Anteil der Funktion an der Entstehung von Nervenkrankheiten, Bergmann, Wiesbaden, 1908. Epsarr, D. L.: (1) Chronic Lead Poisoning, N. Y., 1907. (2) Lead Poisoning, in Osler and McCrae’s Modern Medicine, D. Appleton Co., N. Y., 2:356, 358, 1914. Eger, W.: Arch. f. exper. Path. 299: 654, 1937. EgaeLETON, P.: J. Physiol. 70:294, 1930. EcGLETON, P. AND EcGLETON, G. P.: J. Physiol. 63:155, 1927. EHRENBERG, R.: Biochem. Ztschr. 161:337, 1925. EnraArDT, W.: Ztschr. f. drztl. Fortbild. 34:436, 1937. EHRISMANN, O.: Arch. f. Hyg. 114:224, 1932. Enrich, P.: Charité-Annalen 10:136, 1885. 244 LEAD POISONING EicarorsT, H.: Med. Klin. 9:201, 1913. E1seNLoHR, C.: Arch. f. klin. Med. 26:543, 1880. Eipripae, W. A.: Report No. 29, Chemical Warfare Service, 1921. Error, W. E.: Preface to Monier-Williams, ibid. EvscaniG, A.: Wien. med. Wehnschr. 48:1305, 1898. EMMINGER, E. AND BarTisTINI, G.: Arch. f. path. Anat. 290:492, 1933. ENGEL, S.: Reichsgesdh. 13:209, 1927. EpsTEIN, E.: Arch. Dermatol. and Syphilol. 41:38, 1940. Esser, A.: Deutsch. Ztschr. f. d. ges. Gerichtliche Med. 26:430, 1936. Ers, W.: Arch. f. Psychiat. 5:445, 1874. ERLENMEYER, E.: Miinch. med. Wehnschr. 60:1114, 1913. Diss. Wiirzburg, 1913. Evans, E. E., Norwoop, W. D., Kenog, R. A. ANp MacaLE, W.: J. A.M. A. 121:501, 1943. FaBroni, G.: Atti. Accad. Fisiocritici Siena 17:207, 1926. Facag, C. H.: Medico-chirurgical Trans., London, 59:327, 1876. Fang, T.: in Handbuch von Henke-Lubarsch 6:425, 1925. Famruarn, L. T.: (1) J. Biol. Chem. 40:481, 1924. (2) J. Indust. Hyg. 4:9, 1922-1923. FairuALL, L. T. AnD Savers, R. R.: U. S. Pub. Health Bull. No. 253, 1940. FamreALL, L. T. AND Saw, C. P.: J. Ind. Hyg. 6:159, 1924. Fegs, E.: Arch. exper. Path. 165:583, 1932. Feicur, F. L., Scarenk, H. H. axp Brown, C. E.: U. S. Bureau Mines Reports, Invest. No. 3639, 1942. FERRARO, A. AND HERNANDEZ, R.: The Psychiatric Quart. 6:121, 1932. FerGUsON, A. E. AND FErcuson, T.: J. Ind. Hyg. 34:295, 1934. Ficr, V.: Folia med., Napoli, 6:587, 1920; 7:82, 201, 1921. Fing, J.: J. Ind. Hyg. 5:138, 1923. FiscHER, H.: (1) Ztschr. f. physiol. Chem. 132:18, 1924. (2) Die Naturwissenschaften 18:1026, 1930. Verhandl. d. deutsch. Gesellsch. f. inn. Med. 1933, p. 7. (3) Angew. Chem. 42:1025, 1929. FiscHER, H. AND DUESBERG, R.: Arch. f. exper. Path. 166:95, 1932. Fiscuir, H. AND LeoroLpi, G.: Ztschr. anal. Chem. 119:161, 1940. FisaBERG, A. M.: Hypertension and Nephritis, Lea and Febiger, Phila. Ed. 4, 1939. FisHER, E. D.: Am. J. med. Sci. 104:51, 1892. Fiske, C. H. AnD SusBarOow, Y.: Science 65:1686, 1927. J. Biol. Chem. 81:629, 1929. FLeECKEL, I. M. AND TscuerNow, I. G.: Zentralbl. f. Gewerbehyg. 7:65, 1930. FLeckeL, I. M., Tscaernow, I. G. anp Turcer, K. I.: Zentralbl. f. Gewerbehyg. 11:34, 1934. Fuinn, F. B.: J. Ind. Hyg. 8:51, 1926. Frinn, F. B. AnD Smith, A. R.: J. Ind. Hyg. 15:156, 1933. Frury, F.: (1) in Zernick’s Toxicology, 1931. (2) Blei. in Handbuch der experimentellen Pharmakologie, Heffter, A. and Heubner, W., vol. 3, part 3, 1934, p. 1575, Julius Springer, Berlin. Foun, O. anp Denis, W.: J. Biol. Chem. 13:14, 1913. FoNTANA, A. AND Stazz1, S.: Gior. di clin. med. 14:251, 1933. ForsTER, A.: Endocrinol. 4:260, 1929. Fours, P. J. AND PacE, I. H.: Am. Heart. J. 24:329, 1942. BIBLIOGRAPHY 245 Fraenker, E.: Mitt. d. Staatskrankenh., Hamburg, 5:14, 1905. FrANK, A.: Deutsch. Arch. f. klin. Med. 16:423, 1875. FrankE, K. AND LITZNER, S.: Ztschr. f. klin. Med. 129:115, 1935. Frerrerp, H.: Virch. Arch. 268:456, 1928. FreTrwurst, F. AND HERTZ, A.: Arch. f. Hyg. 104:215, 1930. Frey, G.: Lead. in Occupation and Health, International Labour Office, Geneva, 1934, vol. 2, p. 99. FRIEDLANDER, C.: Arch. f. path. Anat. 75:24, 1879. FroBoEesE, V.: Reichsgesundh. 57 Festband, 1926. FucasBERGER: Diss. Wiirzburg, 1925. FukusaiMa, M. AND MaTsumoTo, H.: Orient. J. Dis. Child. 3:27, 1928. Fusira, N.: Acta dermatol. Kioto 9:48, 1927. GARTNER, A.: cited by Flury. Garvin: cited by Legge and Goadby. GANIAYRE, R.: Thése de Paris, 1900. Gant, V. A.: Lead Poisoning, Chicago, 1939, Ind. Health Book Co. Gaur, L. E. anp Staup, A. H.: J. Nerv. and Ment. Dis. 81:265, 1935. GARrOD, A.: (1) quoted by Legge and Goadby. (2) Lancet 2:82, 1854. GAYLER, J.: Diss. Tiibingen, 1887. GELMAN, I.: (1) Arch. f. Hyg. 96:301, 1926. (2) Deutsch. Arch. f. klin. Med. 163:1, 1929. Gerais, H.: Schrift. a. d. Gesamtgebiet d. Gewerbehyg. 5:30, 1919. GiBsoN, L. J.: Brit. Med. J. 2:1488; 1908. Optic Neuritis Due to Lead, Australasian Medical Publishing Co. Ltd., Sydney, 1922. GiNaNnDES, G. J.: J. Mt. Sinai Hosp. 2:74, 1935. GLeIsBERG, W.: Honcamp’s Handbuch der Pflanzenihrung 2:633, 1931. GuiBERT, D. J.: Le Saturnisme Expérimental, Brussels, 1907. Goapsy, K. W.: J. Hyg. 9:122, 1909. Goapsy, K. W. AND Goopsopny, A.: Lancet 2:988, 1909. Goetze, R.: Diss. Wiirzburg, 1892. GomBavuLt, M.: (1) Arch. de Physiol. 5:592, 1873. (2) Arch. de Neurol. 1:11, 177, 1880. GoopmaN, L. anp Gruman, A.: The Pharmacological Basis of Therapeutics, The Macmillan Co., N. Y., 1941. Goopwin, T. C.: Bull. Johns Hopk. Hosp. 55:347, 1934. Gorpon, A.: Am. Med. 9:700, 1905. Gouwp, S. E., Kuruman, H. J. AnD SaeckeT, H. A.: Am. J. Med. Sci. 194:304, 1937. GRANT, R. L., CALVERY, O., LAouG E. P. AND MoRgris, H. J.: J. Pharmacol. and Exper. Therap. 64:446, 1938. GrawiTz, E.: (1) Deutsch. med. Wehnschr. 25:585, 1899. (2) Klinische Pathologie des Blutes, Ed. 3, 1906, Leipzig. Gray, I. AND GREENFIELD, I.: Ind. Med. 8:507, 1939. GreveN, H.: Diss. Bonn, 1900. GRIFFITH, J. Q. AND LINDAUER, M. A.: Proc. Physiol. Soc. Phila., 18:11, 1943. GriaNascHI, S.: J. Med., Bordeaux, 114:41, 1937. GRISOLLE, A.: (1) These de Paris, 1835. (2) Au Bureau du Journal Hebdomadaire, Paris, 1836. (3) quoted by Meillére. GrorePAss, W.: Ztschr. f. physiol. Chem. 205:193, 1932. 246 LEAD POISONING GRUNBERG, F.: (1) Ztschr. f. d. ges. exper. Med. 62:649, 1928. (2) Virch. Arch. 27:372, 1930. GUNTHER, G.: Pfliiger’s Arch. 118:561, 1907. Gusserow, A.: Arch. f. path. Anat. 21:443, 1861. HaeMmisa, G. F.: Fortschr. Geb. Rontgenstrahlen 53:484, 1936. Harn, H. C.: Texas State Med. J.: 10:308, 1914. Hamer, C.: (1) Deutsch. Arch. f. klin. Med. 67:357, 1900. (2) Zentralbl. f. Gewerbehyg. 5:264, 1928. HaminTon, A.: (1) Industrial Poisons in the United States, Macmillan Co., N. Y., No © 1925. (2) U. 8S. Bureau of Labor, Statistical Bull. No. 95, 1911; No. 104, Gtr hn 1912; No. 141, 1914. (3) in Occupation and Health, International Labour Office, Geneva, ; 2:1021, 1934. Hammer, F. S.: Protoplasma 4:187, 1928; 5:135, 187, 535, 547, 1929. HammerT, F. S. AND WALLACE, V. L.: J. Exper. Med. 48:659, 1928. HansMmANN, G. H. AND Perry, M. C.: Arch. Path. 30:226, 1940. Hanzuk, P. J.: Arch. f. exper. Path. 97:183, 1923. Hanzuik, P. J. AND PrEsHo, E.: J. Pharmacol. and Exper. Therap. 21:131, 1923. HARrNACK, E.: (1) Arch. f. exper. Path. 9:152, 1878. (2) Deutsch. med. Wchnschr. 23:8, 1897. Harris, L. I.: Arch. Int. Med. 22:129, 1918. Harrorp, G. C., MEEK, S. F. aAnp Houpen, F. R.: (1) J. Ind. Hyg. 18:725, 1936. (2) J. Indust. Hyg. and Toxi- col. 20:589, 1938. Hassin, G. B.: Arch. Neur. and Psychiat. 6:268, 1921. Haverrierp, W. T., Bucy, P. C. AND ELoNEN, A. S.: J. A. M. A. 114:2432, 1940. HEeGLER, G.: Deutsch. med. Wehnschr. 59:570, 1933. HeNDERSON, J. B.: Report of Government Analyst for Queensland, 1927. Henning, N. anp Keruaack, H.: Deutsch. med. Wehnschr. 66:323, 1940. HeNRrIQUES, V. AND Orskov, S. L.: Scand. Arch. Physiol. 74:78, 1936. Hesse, E.: Arch. f. exper. Path. 102:63, 1924; 117:265, 1926; 122:354, 1927. Heusew, E.: Pathogenese und Symptome der chronischen Bleivergiftung, Berlin, 1871. HisMAN, A. J.: Far East Assn. Trop. Med., Trans. 9th Congress 1:373, 1934. HierLE: Report of British Ethyl Petrol Committee, 1930. Hirai, I.: Arch. Pediat. 44:137, 1927. HirscareLD, E.: Ztschr. f. klin. Med. 104:698, 1926. HIRSCHFELDER, A. D., ARNsoN, J. H. Er AL.: Proc. Soc. Exper. Biol. and Med. 12:215, 1914. HirscHHORN, S. AND RoBirscHEK, W.: Ztschr. f. klin. Med. 106:664, 1927. Hirt, L.: Die Krankheiten der Arbeiter, Breslau, 2:36, 1938. Hirzig, E.: Studieren iiber Bleivergiftung, Berlin, 1868. Horra: Inaugural Diss., Freiburg, 1883. Houmes, H. N., CampBELL, K. AND AMBERG, E. J.: J. Lab. and Clin. Med. 24:1119, 1939. Horwirr, M. K. anp Cowairn, G. R.: (1) J. Biol. Chem. 119:553, 1937. (2) J. Pharmacol. and Exper. Therap. 61:300, 1937; 66:289, 1939. HussARrDp, D. M.: Ind. Eng. Chem., Anal. Ed. 9:493, 1937. Husner, H.: Diss. Berlin, 1904. BIBLIOGRAPHY 247 HuNTER, D. AND AUB, J. C.: Quart. J. Med. 20:123, 1926-1927. Huppert, E.: Diss. Wiirzburg, 1925. Hurron, R. M.: (1) Lead Poisoning. Provincial Board of Health of Ontario, Toronto, 1923. (2) quoted by Aub et al. Hyrer, M. C. anp Bravrey, W. R.: Ind. Med. 7:185, 1938. Hysrop, G. H. axp Kraus, W. M.: Arch. Neur. and Psychiat. 10:444, 1923. IncLEsON, H.: Analyst 63:546, 1938. Department of Scientific and Industrial Research. Water Pollution Research, Technical Paper No. 4, 1934. Jacoss, M. B.: (1) Analytical Chemistry of Industrial Poisons, Hazards and Sol- vents, Interscience Pub. Co., N. Y., 1941. 4% (2) Chemical Analysis of Foods and Food Products, Van Nostrand, N.Y. 1938. : tar Jacoss, M. H.: Am. J. Physicl. 51:321, 1920; 53:457, 1920. ¢ Jarre, H. D., Bopansky, A. AND Brair, J. E.: Arch. Path. 12:715, 1931. Jonnson, T. A.: Penna. Med. J. 40:741, 1937. Jones, C.: cited by Aub et al. Jones, R. R.: (1) J. A. M. A. 104:195, 1935. ' (2) U.S. Public Health Reports 48:1011, 1933. Discussion of paper by Belknap, J. A. M. A. 104:211, 1935. Jorpans, G. H. W., Zuyumans, A. anp Broos, J.: Nederlandsch. Tijdschr. voor Geneeskunde 80:304, 1936. Jores, L.: Ziegler’s Beitr. 31:183, 1902. JowerTt, M.: Biochem. J. 26:6, 2103, 1932. KaemMeRER: Verhandl. d. deutsch. Gesellsch. f. inn. Med. Kong. 45:28, 1933. Karran, E. ANp McDonarp, J. M.: J. Pharmacol. and Exper. Therap. 63:P17, 1938. KARK, R. AND MEIKLEJOHN, A. P.: J. Clin. Invest. 21:91, 1942. KasaHARA, M. AND Armvicur, K.: (1) Ztschr. f. exper. Med. 81:696, 1932. (2) ibid. 92:629, 1934. KAsAHARA, M. AnD Naganama, M.: Folia haematol. 53:37, 1934. KasaHARA, M. AND Nasu, S. J.: Arch. exper. Path. u. Pharmakol. 177:272, 1935. Kato, K.: Am. J. Dis. Child. 44:569, 1932. Kazpa, F.: Wien. klin. Wehnschr. 36:694, 1923. KenoE, R. A.: (1) Am. J. Clin. Path. 5:13, 1935. (2) J. A. M. A. 104:211, 1935. (8) Proc. Ind. Hyg. Sect., Natl. Battery. Mfgrs. Assn. 2:19, 51, 1939. KeHOE, R. A. AND CHOLAK, J.: J. Ind. Hyg. 15:257, 273, 318, 1933. KeHOE, R. A., EDGAR, G., THAMANN, F. AND SANDERS, L.: J. A. M. A. 87:2081, 1926. KenoE, R. A. AND TuAMANN, F.: (1) Am. J. Pub. Health 18:55, 1928. (2) J. A. M. A. 92:1418, 1929. (3) Am. J. Hyg. 13:478, 1931. KeHOE, R. A., THAMANN, F. AND CHOLAK, J.: (1) J. Ind. Hyg. 15:257, 273, 290, 301, 306, 320, 1933. (2) J. Ind. Hyg. 16:100, 1934. (3) J. Ind. Hyg. 18:42, 1936. (4) J. A. M. A. 104:90, 1935. Kety, S. 8. ANp LeToNOFF, T. V.: Proc. Soc. Exper. Biol. and Med. 46:476, 1941. Key, J. A.: Arch. Int. Med. 28:511, 1921. Am. J. Physiol. 70:86, 1924. 248 LEAD POISONING Key, J. A. ANpD WricHT, W.: Bost. Med. and Surg. J. 187:328, 1922. Kissgavr, K. AND FRIEDMANN: Ztschr. f. Hyg. 78:500, 1914. Kuma, R. anp Seyrriep, H.: Folia Haematol. 17:283, 1937. Knapp, H.: Diss. Bonn, 1906. Koserrt: cited by Flury. Koch, E. W.: Arch. f. exper. Path. 252:253, 1924. Kocker, H.: Virch. Arch. 277:856, 1930. Kogrusch, F.: (1) Jahresk. f. dirztl. Fortbild. 9:35, 1917. (2) ibid. 10:15, 1919. (3) Die meldepflichtigen Berufskrankheiten, Miinchen, 1926. Korwusch, F. an Inzaorer, H.: Minch. med. Wehnschr. 72:1466, 1925. Kogan, B. AND SMirNowaA, L.: J. Ind. Hyg. 9:435, 1927. Kost, E.: Arch. Gewerbepath. 4: 42, 1932. . Kovraorr, I. M. AND Laitinen, H. A.: pH and Electrotitrations, Wiley, N. Y., 1941. Kovrnorr, I. M. ABp LINGANE, J. J.: Polarography, Interscience, N. Y., 1941. Kozerka, F. L. AND Krucaesky, E. F.: Ind. Eng. Chem., Anal. Ed. 13:492, 1941. Krarrczyk, H.: Deutsch. Ztschr. f. Nervenheilk. 80:184, 1923. KRraAFka, J., Jr.: J. Ind. Hyg. 17:13, 1935. Krauss, F. ANp Conner, W. A.: Arch. f. exper. Path. 162:452, 1931. Krerscamer: Deutsch. med. Wehnschr. 50:1404, 1924. KrETscHMER AND FRIEDER: Biochem. Ztschr. 164:44, 1925. Kruse AND Fiscuer, M.: Deutsch. med. Wehnschr. 56:1814, 1930. Kuan, E.: Zentralbl. f. Gewerbehyg. 4:117, 1927. Kussmaur, A. AND MAIER, R.: Deutsch. Arch. f. klin. Med. 9:283, 1872. LABADIE-LAGRAVE AND LAUBRY: Tribune méd. 38: 437, 1906. Lasar, J. A.: J. Med. Bordeaux 114:41, 1937. Laennec, R. T. H.: Traité d’auscultation, Paris, 1831. Laceper, K.: Arch. Verdauungskrank. 56:237, 1934. Lanza, A. J.: J. A. M. A. 104:85, 1935. Larzern, E. W.: Colorado Med. 7: 348, 1910. Lasrtus, O. J.: Arch. f. Gewerbepath. 1:574, 1930. Lasvert, E. E. AND WARRINGTON, W. B.: Brain 21:224, 1898. Leaks, C. P.: U. S. Public Health Bull. No. 163, 1926. LepERER, L. G. AND Bing, F. C.: J. A. M. A. 114:2457, 1940. Legge, T. M.: J. Hyg. 1:96, 1901. Legare, T. M. AND GoapBy, K. W.: Lead Poisoning and Lead Absorption, London, 1912. Lerman, H.: (1) Die Frithdiagnose der Bleivergiftung, Habil. Schrift, 1928. (2) Die Bekiimpfung der Bleigefahr in der Industrie, Jena, 1908. (3) Arch. f. Hyg. 111:49, 1933. Lenmann, K. B.: (1) Lehrbuch der Arbeits- und Gewerbehygiene, Leipzig, 1919. (2) Arch. f. Hyg. 94:1, 26, 30, 1924. (3) Die Deutsche Bleifarbenindustrie vom Standpunkt der Hy- giene, Berlin, Julius Springer, 1925. (4) Minch. med. Wchnschr. 33:1373, 1926. Lenmann, K. B., Sarro, Y. aNp Grrori, W.: Arch. f. Hyg. 75:134, 152, 160, 1912. Lenmann, K. B., Sparz, H. AND WisBaAuM-NEUBURGER, K.: Ztschr. f. d. ges. Neur. u. Psychiat. 103:323, 1926. Leamann, V.: Ztschr. f. physiol. Chem. 6:528, 1882. LeMBERG, R.: Ann. Rev. Biochem. 7:421, 1938. BIBLIOGRAPHY 249 Lenzi, L.: Arch. ital. di anat. istol. pat. 5:891, 1934. Lescake, E.: Miinch. med. Wehnschr. 78:1657, 1931. Leronorr, T. V. AND REINHOLD, J. G.: Ind. Eng. Chem., Anal. Ed. 12:280, 1940. | Lewin, C.: (1) Med. Klin. 23:848, 858, 1928. (2) Ergeb. inn. Med. 35:286, 1929. (3) Deutsch. med. Wehnschr. 54:1450, 1928. Lewin, L.: (1) Arch. f. klin. Chir. 94:937, 1910-1911. « (2) Med. Klin. 12:31, 1916. © (3) Die Fruchtabtreibung durch Gifte, Berlin, 1925. ~ (4) Gifte und Vergiftungen, Berlin, 1929, Ed. 4. _ Levapir, C.: Compt. rend. Soc. Biol. Paris, 97:167, 1927. Lewin AND GuiLLeERY: quoted by Williams, C.: Arch. Ophth. 20:719, 1911. Lewy, E.: Oesterreich. Ztschr. f. prakt. Heilk. 16:96, 1870. Lewy, F. H.: Arch. Gewerbehyg. 6:63, 1935. Ligeia, H.: Arch. f. exper. Path. 125:15, 1927. LiNGUERRI, R.: Arch. internat. de pharmacodyn. 46:268, 1933. LinenTHAL, H.: in Diseases and Occupation, Kober and Hanson, Phila., 1916. Lirzner, S. T. AND WEYRAUCH, F.: (1) Arch. Gewerbepath. 4:1, 1932. (2) Med. Klin. 29:13, 381, 1933. (3) Arch. Gewerbepath. 4:74, 1932. LitznNER, S. T., WeyraucH, F. AND Barta, E.: Arch. Gewerbepath. 2:330, 1931. Logs, J.: Am. J. Physiol. 6:411, 1902. LoepPER, M. AND VERPY, G.: Progress Med. 32:81, 1916. Lomuort, S.: (1) Biochem. J. 18:693, 1924. (2) J. Pharmacol. 40:235, 1930. Lupwia, H.: Biochem. Ztschr. 210:353, 1929. Litruie, H.: (1) Diss. Berlin, 1895. (2) Ztschr. f. klin. Med. 29:266, 1896. Lunpsaaarp, E.: Biochem. Ztschr. 217:162, 1930. LurorLawskr: cited by Biondi. MacHLE, W.: J. A. M. A. 115:1536, 1940; 117:1965, 1941. Macawirz, H. AND RosENBERG, M.: Deutsch. med. Wehnschr. 42:1188, 1916. Maanus-LEvy, A.: Ztschr. f. klin. Med. 36:353, 1899. Maanuson, H. J. AnD RavrsTon, B. O.: J. A. M. A. 114:1528, 1940. Maier, R.: Virch. Arch. 90:455, 1882. MaLLory, F. B.: cited by Aub et al. MANN, D.: Brit. Med. J. 2:401, 1893. MANOUVRIER, A.: Thése de Paris, 1874. MARGAROT, J. AND BLANCHARD, A.: Montpel. Med. 37:106, 1913. MarTINI, P.: Vortrag. Kongressbl. inn. Med. Wiesbaden, 1933. Mason, E. C.: J. Pharmacol. and Exper. Therap. 17:340, 1921. Mass, O.: Monatschr. f. Psychiat. u. Neurol. 30:207, 1911. Masse, M.: Ztschr. f. klin. Med. 1:62, 1903. MaraEw, R. Y.: Med. J. Australia 1:208, 1929. MarussewrrscH, I. S.: Wien. klin. Wehnschr. 41:849, 1928. MAULBETSCH, A. AND RUTISHAUSER, E.: Arch. int. Pharmacodyn. 53:55, 1936. Maurer, E.: Compt. rend. Soc. Biol. de Paris, 73:550, 1912. Mayers, M. R.: J. Ind. Hyg. 8:222, 1926. Mayers, M. R. AND McManoON, M. M.: Special Bulletin No. 195, N. Y. State De- partment of Labor, Division of Industrial Hygiene, 1938. 250 LEAD POISONING MaxweLr, L. C. anp BiscHoFF, F.: J. Pharmacol. and Experimental Therap. 36:279, 1929; 37:413, 1929. McCartrY, D. J.: U. of Penna. Med. Bull. 14:398, 1902. McCorp, C. P., HoLpEN, F. R. AND JOHNSTON, J.: Ind. Med. 4:180, 1935. . Am. J. Pub. Health 25:1089, 1935. McCorp, C. P., MinsTER, D. K. AND REHM, M.: J. A. M. A. 24:1795, 1924. McCorp, C. P., WaLworTH, H. T., JoansTON, J. AND FosHER, P. E.: Ind. Med. 6: 357, 1937. McKuanN, C. F.: (1) Am. J. Dis. Child. 32:386, 1926. (2) Arch. Neur. and Psychiat. 27:294, 1932. McKHANN, C. F. ano Voar, E. C.: J. A. M. A. 101:1131, 1933. McMiLLEN, J. H. AND ScorT, T. F. McN.: Proc. Soc. Exper. Biol. and Med. 35:364, 1937. MeiLLirE, G.: (1) Compt. rend. Soc. Biol. de Paris 54:1134, 1902. (2) ibid. 55:517, 1903. (3) Le Saturnisme, Paris, 1903. Merron, R. R.: Arch. Int. Med. 12:399, 1913. MEeLNICcK, J. L. AND CowaiLr, G. R.: Proc. Soc. Exper. Biol. and Med. 38:899, 1938. MENBTRIER, P.: Bull. et mem. Soc. med. d. hop. de Paris, 31:141, 1904. MEesSING, Z.: Neuroglia Polska 3:596, 1913. Meyer, H. H. AND GorrrIEB, R.: Experimentelle Pharmakologie, Ed. 2, p. 300, 1926. Meyer, M.: Elektrizitit in ihrer Anwendung auf praktische Medizin, 1854, Berlin, quoted by Weill, ibid. MEYER, S.: J. Ind. Hyg. 10:29, 1928. MiLLerT, H.: J. Biol. Chem. 83:265, 1929. Minor, A.: (1) Physiol. Rev. 18:554, 1938. (2) J. Ind. Hyg. 6:137, 1924. Minor, A. AND Aus, J. C.: J. Ind. Hyg. 6:149, 1924. MircaeLL, J. K.: J. Nerv. and Mental Dis. 37: 296, 1910. Mivasaxki, S.: Arch. f. exper. Path. 150:39, 1930. Mogsius, P. J.: (1) Zentralbl. f. Nervenheilk. 1:6, 1886. (2) cited by Aub et al. Moni1er-WiLriams, G. W.: Public Health Reports, Ministry of Health, London, No. 88, 1938. Moritz, O.: Deutsch. med. Wchnschr. 27:68, 1901. Morris, H. P., Lava, E. P., Morris, H. J. AND Grant, R. L.: J. Pharmacol. and Exper. Therap. 64:420, 1938. Moskowitz, S. AND Burke, W. J.: N. Y. State Ind. Bull. 17:492, 1938. J. Ind. Hyg. and Tox. 20:457, 1938. Mosny, E. AND HarvIER, P.: Trib. méd. 40:101, 1908. Mosny, E. AND MaALLOIZELL, L.: (1) Trib. méd. 87:277, 1905. (2) Rev. de méd. 27:505, 1905. Morr, F. W.: Arch. Neur. and Psychiat. 4:117, 1909. MvutLLER, A. H.: Klin. Wchnschr. 17:1183, 1938. MutLLER-NEF, H.: Folia Haematol. 56:18, 1936. Minz, L.: Diss. Wiirzburg, 1922. Murray, R. E.: Plumbism and Chronic Nephritis in Young People in Queensland 1939, Pub. No. 2, Dept. of Health, Commonwealth of Australia. BIBLIOGRAPHY : 251 Mryrsick, H.: Ztschr. f. physiol. Chem. 158:160, 1926. NagkgeL1, O.: (1) Folia Haematol. 24:86, 1919. (2) Blutkrankheiten und Blutdiagnostik, Berlin, 1931. Nagao, K.: Mitt. med. Gesellsch., Tokyo, 48 2074, 1934. NEAL, P. A.: U. 8S. Public Health Bull. No. 267, 1941. Newman, B. J., McConnEgLL, W. J., SPENCER, O. M. AND PHiLuies, F. M.: Public Health. Bull. No. 116, 1921. NewMAN, R. K.: Med. J. Australia 1:170, 1930. NiemANN: cited by Flury. Norris, C. AND GETTLER, A. O.: cited by Hamilton (1). Norton, N. R.: Internat. Clin. 32:231, 1922. Nyg, L. J. J.: Chronic Nephritis and Lead Poisoning, 1933, Sydney, Angus and Robertson. Nyrerpr, A.: Ugesk. f. Laeger, 99:283, 1937. OELLER, J. N.: Zur Pathologischen Anatomie der Bleilihmung, Miinchen, 1883. OrriNger, R.: Wien. med. Wehnschr. 7:1, 1858. OnMURA, T.: Ztschr. f. d. ges. exper. Med. 98:769, 1936. OxUBO, A. AND TANAKA, H.: J. Pediat. Tokyo, 3:1325, 1925. Ouiver, T.: (1) Brit. Med. J. 1:1096, 1911. (2) Brit. Med. J. 2:1891, 1905. $ in Allbutt, C. and Rolleston, H. D., System of Medicine, London, 2:1053, 1912. (3) Diseases of Occupation, London, 1914. OMARU, J.: Fukuoka Ikawat. Zasshi. 24:7, 1931. OMELIANOWITSCH-PAVLENKO, M. J.: Ztschr. f. Hyg. 110:348, 1929. OprtiLs, W.: Am. J. Med. Sci. 150:518, 1915. Proc. Soc. Exper. Biol. and Med. 9:43, 1912. OrpeNHEIM, C.: Diss. Berlin, 1899. OrppENHEIM, H.: Arch. f. Psychiat. u. Neurol. 16:476, 1885. OpPENHEIM, H. AND S1EMERLING, E.: Arch. f. Path. 18:487, 1887. ORBAN, R.: Deutsch. med. Wehnschr. 38:2079, 1912. OresrtaNoO, G.: Boll. d. Soc. ital. di biol. sper. 5:273, 1930. Orskov, S.: Biochem. Ztschr. 279:250, 1935. Otro, H. AND ZAEBN, G.: Ztschr. f. klin. Med. 136:61, 1939. Paw, J.: Gefiisskrisen, Leipzig, 1905. ParrENHEIM, A.: Folia Haematol. 24:86, 1919. Parg, E. A., Jackson, D., Goopwin, T. C. AND Kaspr, L.: J. Pediat. 3:265, 1933. Pagrk, E. A, Jackson, D. ano Kaspr, L.: Am. J. Dis. Child. 41 :485, 1931. Parkes, E. A.: cited by Flury. Paroni, G.: Arch. Inst. biochim. ital. 1:227, 1929. Boll. Soc. med. chir. Pavia 43:821, 1924. Pauw, C.: Arch. gén. de méd. 1:15, 513, 1860. Pawrow, N.: Compt. rend. Soc. biol. de Paris 97:361, 430, 1927. PEARLMAN, M. D. AnD LiMarz1, L. R.: Am. J. Clin. Path. 8:608, 1938. PearsE, H. E.: Arch. Int. Med. 37:715, 1926. Prisacaowrrsch, T.: Virch. Arch. 273:276, 1929. PeNNETTI, G.: Arch. internat. Pharmacodyn. 30:254, 1925. PERRIN, M.: Rev. med. de I’Est. 40:407, 1908. Peters, J. P. AND VAN SLYkE, D. D.: Quantitative Clinical Chemistry, Interpreta- tions, v. 1, Williams & Wilkins, Baltimore, 1931. : Perri, E.: Pathologische Anatomie und Histologie der Vergiftungen, Berlin, 1930. 252 LEAD POISONING Perrorr, D.: Diss. Wirzburg, 1905. PeTroFF, I. R.: Arch. f. exper. Path. 148:330, 1930. Gewerbehyg. und Unfallverhutung. 3:62, 1930. PreiL: Verhandl. Kong. inn. Med. Wiesbaden, 1933. Prrevcer: Die Bekimpfung der Bleifefahr in der Industrie, von Leymann, 1908, p- 21. PrrieMe, F.: Arch. f. Hyg. 111:232, 1934. PrEMISTER, D. E.: J. A. M. A. 70:1737, 1918. PuiLiPPE AND GoTHARD: Rev. Neurol. 11:117, 1903. PincusseN, L.: Klin. Wehnschr. 12:275, 1933. Pirie, H. A.: Am. J. Roentgenol. 24:147, 1930. PonL, J.: Biochem. Ztschr. 133:434, 1922. Porr, T. H.: Analyst 57:775, 1932. PorAK, M.: Arch. med. exper. et d’anat. path. 6:192, 1894. Porrrrr, N.: Brit. Med. J. 2:92, 1931. Posey, W. C. anp Farr, C. F.: U. of Penna. Med. Bull. 23:47, 1910. PoucHET, A. G.: (1) Compt. rend. Acad. de Sci. Paris 89:244, 1879. (2) Arch. Physiol. norm. et path. 11:74, 1880. PrENDERGAST, W. D.: Brit. Med. J. 1:1164, 1910. Preti, L.: (1) II Lavoro 6:217, 1913. (2) Ztschr. f. physiol. Chem. 58:539, 1908; 62:354, 1909. Biochem. Ztschr. 45:488, 1912; 21:551, 1909. Deutsch. Arch. f. klin. Med. 95:411, 1909. Prevost, G. L. ax Binet, P.: Rev. med. de la Suisse rom. 9:606, 669, 1889. Prisco, L.: Arch. Farmacol. sper. 55:123, 1933. Putnam, J. J.: (1) J. Nerv. and Ment. Dis. 10:466, 1883. (2) Bost. Med. and Surg. J. 117:73, 97, 1887. Quan, G. N. ano Kuen, A.: Am. J. Public Health 26: 778, 1936. QuenseL: Arch. f. Psychiat. 35:612, 1902. RapivowrrcH, I. M., DiNawALL, A. AND Mackay, F. H.: J. Biol. Chem. 103:707, 1933. RAIMONDI: Ann. univ. di med. e. chir. 251:52, 1880. RAMBOUSEK, J.: Ztschr. f. exper. Pharm. u. Ther. 7:686, 1910. Ranp, H. W.: U. 8. Bureau of Labor Statistics, Monthly Labor Revue, Feb., 1921, p. 135. RarororT, M. AND KENNEY, A. S.: J. A. M. A. 112:2040, 1939. RarororT, M. AND RUBIN, M. I.: Am. J. Dis. Child. 61:245, 1941. Raymond: Rev. gen. de clin. et de therap. 18:403, 1904. Rem: quoted by Oliver, T. ibid (1). Rerra, J. F. AnD van Duk, C. P.: Neitherl. Tijdschr. v. Geneesk. 83: 1584, 1939. RemAk, E.: Arch. f. Psychiat. 6:1, 1876. ReNNERT, O.: Arch. f. Gynik. 16:109, 1881. Rion, L.: Compt. rend. Soc. Biol. de Paris, 10:862, 1897. RENON, L. AND LATRON, L.: Bull. et mem. Soc. med. d. hop. de Paris, 17:800, 1900. REzZNIKOFF, P. AND AUB, J. C.: Arch. Neur. and Psychiat. 17:444, 1927. RuEeA, L. J.: Internat. Clin. 1:202, 1934. RieceL, F.: cited by Oliver, T. ibid (3). Deutsch. Arch. f. klin. Med. 21:1, 1878. ROBERTSON, A.: J. Ment. Sci. 32:217, 1886-1887. . Rocue-LyncH, G., SLATER, R. H. AND OsLER, T. G.: Analyst 59: 787, 1934. BIBLIOGRAPHY 253 RorresToN, H. D. AND McNEE, J. W.: Diseases of the Liver, Gall-bladder and Bile Ducts, Macmillan, 1929, Ed. 3, pp. 579, 793. RosENSTEIN, S.: Arch. f. path. Anat. 39:1, 174, 1867. Ross, J. R. anp Lucas, C. C.: J. Biol. Chem. 111:285, 1935. Rous, P. AND RoBerTsoN, O. H.: J. Exper. Med. 25:651, 1917. Rut, A.: Arch. f. exper. Path. 140:256, 269, 1929. Rur, H. W. anp Fruck, W. Z.: Am. J. Pub. Health 29:1149, 1939. RusseL, A. E., Jones, R. R., BLoomrIELD, J. J., Brirren, R. H. AND THOMPSON, L. R.: Public Health Bull. No. 205, 1933. RusseLy, J.: cited by Biondi. SantessoN, C. G.: Scand. Arch. Physiol. 67:177, 1934. Sasakr: Fol. jap. pharmacol. 6:602, 1925. SAwYER, R. A., WAGONER, R. W. AND ERICKSON, A. A.: Science 90:11, 1939. Sayers, R. R., FIELDNER, A. C., YanT, W. P. AND THOMAS, B. G. H.: U. S. Bureau of Mines. Experimental Studies on the Effect of Ethyl Gasoline and its Com- bustion Products, 1927. ScHACHNOWSKAJA, S.: Ztschr. f. exper. Med. 70:513, 1930. ScaicksaL: Die Bekimpfung der Bleigefahr in der Industrie, 1908, p. 38. Scararp, M.: Internat. Clin. 4:122, 1903. ScuiLLING, V.: Das Blutbild und seine Klinische Verwertung, Jena, S. Fischer, 1920. Scamipr, J.: Zentralbl. f. Gewerbehyg. 10:101, 1933. Scamp, L.: Habilit.-Schrift., Wiirzburg, 1927. ScamipT, P.: (1) Deutsch. Arch. f. klin. Med. 96:1042, 593, 1909. (2) Zentralbl. f. Gewerbehyg. 2:8, 1914. (3) Ergeb. Med. 13:321, 1929. (4) Die Bleivergiftung, Urban und Schwarzenberg, 1931. \ (5) Arch. f. Hyg. 63:1, 1907. (6) Experimentelle Beitriige zur Pathologie des Blutes, Jena, 1902. (7) Schr. a. d. Gesamtgeb. d. Gewerbehyg. 5:53, 1919. (8) Deutsch. med. Wehnschr. 35:2017, 1909. ScamipT, P. AND BarTH, E.: Arch. Schiffs-u. Tropenhyg. 29:326, 1925. Scamipt, P. AND WEYRAUCH, F.: Ueber die Diagnostik der Bleivergiftung im Lichte moderner Forschung, Jena, 1933. ScamipT-KeHL, L.: Arch. f. Hyg. 98:1, 1927. Scamrrt, F. AND Basse, W.: Klin. Wchnschr. 16:65, 1937. Scamirr, F. AND TAEGER, H.: Ztschr. f. d. ges. exper. Med. 101 21, 1937; 100:717, 1937. ScanrrreR: (1) Deutsch. Arch. f. klin. Med. 117:127, 1915. (2) Deutsch. med. Wehnschr. 45:711, 1919. ScHNITTER AND Paris: cited by Flury. ScHONFELD, J.: Med. Klin. 9:1, 1913. Scurrus, H. T.: Arch. exp. Path. 117:543, 1935. Scareus, H. T. ANp Carri, C.: Klin. Wehnschr. 13:121, 1670, 1934; 14:1717, 1935. Scaurrz, H. I.: Arch. f. Gewerbepath. 9:198, 1938. Scutirz, F. AND BernuaArDT, H.: Ztschr. f. Hyg. 104:441, 1925. Scaumm, O.: Ztschr. f. physiol. Chem. 126:1, 1923. ScawARz, L.: Ztschr. arztl. Fortbild. 20:20, 1923. ScremIN, L.: Arch. f. exper. Path. 99:96, 1923. SeewL1G, S.: Klin. Wchnschr. 3:583, 1924. SEELIGMULLER, A.: Deutsch. med. Wchnschr. 28:317, 1902. 254 LEAD POISONING SerreERT, A.: Berlin. klin. Wehnschr. 21:555, 1884. SerrreRT, G. AND ARNOLD, A.: Arch. f. Hyg. 99:272, 1928. SEISER, A. AND L1TzNER, S.: Ergeb. Med. 13:321, 1929. Sez, A.: (1) Minch. med. Wehnschr. 75:1544, 1928. (2) Arch. f. Hyg. 109:199, 1933. Klin. Wehnschr. 7:1234, 1928. Selby Smelter Commission Report, Bull. 98, Bureau of Mines, 1915. SeLLERs, A.: J. Ind. Hyg. 2:361, 1921. SuaTTUCK, F. C.: Bost. Med. and Surg. J. 158:223, 1908. SueLLING, D. H.: Proc. Soc. Exper. Biol. and Med. 30:248, 1932. Sure, M.: J. A. M. A. 76:835, 1921; 83:580, 1924. Su1eLps, J. B. AND MircueLL, H. H.: J. Nutrit. 21: 541, 1941. SureLps, J. B., MrrcaeLy, H, H. ano Kiera, W. A.: J. Ind. Hyg. and Tox. 21:7, 1939: SuieLs, D. O.: Med. J. Australia 1:847, 1936. ; SuurrLEBoTHAM, F.: Brit. Med. J. 1:672, 1915. Siccarpr, P. D.: Il Lavoro, Milano, 7:299, 1914. Siccarpi, P. D. ano Dozzi, L.: Clin. Med. Ital. 53:1, 1914. SILVERMAN, L. AND Egg, J. F., Jr.: J. Ind. Hyg. and Tox. 25:185, 1943. Simon, J.: Arch. Inst. biochim. ital. 1:13, 1929. Smite, F. L., RarameLs, T. K. AND Marcin, G. E.: Am. J. Clin. Path. 8:471, 1938. Smyrr, H. F.: J. Ind. Hyg. 24:5, 1923. SoBEL, A. E., Yuska, H., PETrRovsKY, D. D. AND KRAMER, B.: J. Biol. Chem. 128:96P, 1939; 132:239, 1940. SouLER: Diss. Wiirzburg, 1923. SortmAnN, T.: (1) J. Pharmacol. and Exper. Therap. 19:375, 1922. (2) A Manual of Pharmacology, Ed. 3, W. B. Saunders, Phila., 1928, p. 1049. Sparz, H.: cited by Flury. SPERANSKY, J. AND SKLIANSKAJA, R.: Folia Haematol. 36:289, 1928. SpieLMEYER, W.: Ztschr. Neurol. 99:756, 1925. SpiLLer, W. G.: J. Med. Res. 5:142, 1903. StaEMMLER, M.: Klin. Wchnschr. 8:1210, 1929. STARKENSTEIN: cited by Flury. STAUB AND ERLENMEYER: cited by Flury. STEIMAN, S. E.: Am. J. Physiol. 126:261, 1939. STEINBERG: Internat. Congress Ind. Hyg., Brussels, 1910. STEINER: cited by Flury. SteLLA, G.: J. Physiol. 66:19, 1928. StepHENS, G. A.: Brit. Med. J. 1:626, 1910. Stickn, O.: Arch. f. Hyg. 98:1926, 1928. Srtiearirz, L.: Arch. f. Psychiat. 24:1, 1892. Steve: Ztschr. mikrosk.-anat. Forschung. 1:491, 1924; 5:463, 1926. S1ocKMAN, R. AND CHARTERIS, F.: J. Path. and Bact. 9:202, 1904. Stockvis AND BINNENDLIK: cited by Flury. STRANSKY, E.: Biochem. Ztschr. 133:434, 1922. Straus, W.: Miinchen. med. Wehnschr. 61:5, 1914. StroNG, R. A.: Arch. Pediat. 37:532, 1920. STupENY, O. AND ROSSEGGER, F.: Wien. klin. Wehnschr. 45:586, 1932. Stumpy, M.: Deutsch. Arch. f. klin. Med. 30:201, 1883. StrssMANN, P. O.: Miinch. med. Wehnschr. 65:1407, 1918. Suzuki, T. ANp Kaneko, J.: J. Orient. Med. 2:55, 1924. BIBLIOGRAPHY 255 Tapa, K.: Orient. J. Dis. Infants 3:34, 1928. TarGER, H.: Sammlung von Vergiftungsfillen 9:23, 1938. TarceR, H. AND Scamrrr, F.: Ztschr. f. d. ges. exper. Med. 100: 717, 1937. TanNaHILL, R. W.: Med. J. Australia 1:201, 1929. / TANQUEREL DES PLANCHES, L.: Traites des maladies se plomb, ou saturnines, Paris, 1839. TarpiEU, A. A.: Poisons industrielles, Paris, 1905. TaAuBMANN, G.: Arch. f. exper. Path. 118:121, 1926. TEISINGER, J.: Biochem. Ztschr. 277:178, 1935. Ztschr. f. d. ges. exper. Med. 98:520, 1936. TeLEKY, L.: (1) Deutsch. Ztschr. f. Nervenheilk. 37:234, 1909. (2) Klin. Wchnschr. 2:861, 1923. (3) Deutsch. med. Wchnschr. 51:906, 1925. (4) Schrift. a. d. Gesamtgebiet der Gewerbehyg. 5:1, 1919. (5) Bleivergiftung. in Handbuch der sozialen Hygiene, von Gottstein- Schlossmann-Teleky, v. 2, Berlin, 1926. (6) J. Ind. Hyg. and Tox. 19:1, 1937. (7) cited by Flury. TeLexy, L., Gernis, H. aNp Scamipt, P.: Die Frithdiagnose der Bleivergiftung, Berlin, J. Springer, 1919. THIELEMANN: cited by Biondi. TroMmas, H. M.: Bull. Johns Hopk. Hosp. 15:209, 1904. Traomas, H. M. AND BrackFaN, K. D.: Am. J. Dis. Child. 8:377, 1914. TrompsoN, W. G.: The Occupational Diseases, N. Y., 1914. TaoMPsON, W. G. AND SCHONLEBER, A. W.: cited by Hamilton (1). Tum, F.: Zellmikrochemie der Schwermetallgifte, Habil.-Schrift. Leipzig, 1932. Time, W.: Lancet 2:162, 1916. Topp, A. T.: Chemotherapeutic Researches on Cancer, London, 1928. Topp, J. C. AND SANFORD, A. H.: Clinical Diagnosis by Laboratory Methods, W. B. Saunders, Phila., 1943. TompseTT, S. L.: Biochem. J. 30:345, 1936; 33:1237, 1939. TompseTT, S. L. AND ANDERSON, A. B.: (1) Biochem. J. 29:1851, 1935. (2) Lancet 1:559, 1939. TrauBE: Gesammelte Beitriige, Berlin, 3:416, 1878. TRAUTMANN, A.: Arch. f. Hyg. 94:298, 1924. TROISIER, J.: Trib. méd. 41:21, 1909. TruMPER, M. AND CANTAROW, A.: unpublished data. TruMPER, M. AND Gorpy, S. T.: J. A. M. A. 116:1389, 1941. TcHARNY, A.: Arch. Gewerbepath. 2:11, 42, 1931. TcHARNY, A. AND IsRATLEWITSCH, E.: Arch. Gewerbepath. 2:56, 1931. TscHERKESS, A.: (1) Arch. f. exper. Path. 108:220, 235, 1925. (2) Arch. f. exper. Path. 110:174, 1925. TscHERKESS, A.: AND PaILIPPOWA, E.: Arch. f. exper. Path. 108:365, 1925. TurHILL, R.: Bull. Buffalo Gen. Hosp. 7:15, 1929. Untaorr, W.: Handbuch der Aug, Lief, Leipzig, 1901. University of Aberdeen Report, Lancet, Dec., 1933. Urary, J.: J. A. M. A. 90:288, 1928. VAN DEN BErGH, A. A.: Deutsch. med. Wehnschr. 54:1244, 1928. VAN EMBDEN AND KLEEREKOPER: Trans. Internat. Congress. Ind. Hyg., Brussels, 1910. Vaquez, H.: Semaine méd. 23:385, 1904. 256 LEAD POISONING Vierorpt, K.: Arch. f. Psychiat. 18:48, 1887. VicLIiANI, E. AND ANGELERI, C.: Clin. med. ital. 66:5, 1935. Klin. Wchnschr. 15:700, 1936. VieLIANI, E. AND DEBERNARDI, G.: Rass. di Med. Applic. Lav. Indust. 5:409, 1934. VicoporrcHIK, N. A.: J. Ind. Hyg. and Tox. 17:1, 1935. Voar, E. C.: (1) Am. J. Roentgenol. 24:550, 1930. (2) J. A. M.. A. 98:125, 1932. VoruARrD, F. AND SUTER, F.: in Handbuch der innere Medizin, von Mohr und Stae- helm, v. 3, 1918. Von JakscH, R.: Die Vergiftungen, Vienna, 1910. Von LIEBERMANN, L. AND VON FILLINGER, F.: Deutsch. med. Wchnschr. 38:462, 1912. Von Monakow, C.: Arch. f. Psych. u. Nervenheilk. 10:495, 1879-1880. VoraEs, F. A. AND CLiFrorD, P. A.: J. Assoc. Official Agr. Chem. 17:130, 1934. WaLko, K.: Miinch. med. Wehnschr. 54:1728, 1907. WasseERMANN, F.: Arch. f. exper. Path. 79:383, 1916. Watson, C. J.: (1) J. Clin. Invest. 14:106, 110, 116, 1935. (2) ibid 15:327, 1936 (3) ibid 16:383, 1937. Watson, C. J. anp CLarkEe, W. O.: Proc. Soc. Exper. Biol. and Med. 36:65, 1937. WEBSTER, S. H.: Pub. Health Rep. 56:1834, 1941. Weir, P. E. AND BROUSSER, J.: Le Sang 6:825, 1932. WEILL, G.: Diss., Strassburg, 1892. WeinpeL: Diss. Wiirzburg, 1922. WeisBacH, W.: Deutsch. med. Wechnschr. 54:2154, 1928. Weiss: cited by Flury. WELLER, C. V.: (1) J. Med. Res. 3:271, 1915. Proc. Soc. Exper. Biol. and Med. 14:14, 1916. (2) Proc. Soc. Exper. Biol. and Med. 23:37, 1925. (3) Trans. Assn. Am. Physicians 41:34, 1926. Arch. Int. Med. 39:45, 1927. WELLER, C. V. AND CHRISTIANSEN, A. D.: Arch. Neur. and Psychiat. 14:327, 1925. WESTERGREN: cited by Flury. WESTPHAL, A.: (1) Arch. f. Psychiat. 4:776, 1874. (2) ibid. 19:620, 1888. WeXTER, I. B. AND SoBEL, A. E.: Proc. Soc. Exper. Biol. and Med. 32:719, 1935. WeyravucH, F.: (1) Ztschr. Hyg. u. Infektionskr. 111:162, 1930. (2) Ztschr. f. d. ges. exper. Med. 75:706, 1931. WeYRAUCH, F. AND L1TZNER, S.: Arch. f. Gewerbepath. 3:15, 1932. WeyraUucH, F. AND MULLER, H.: (1) Ztschr. f. Hyg. u. Infektionskr. 115:216, 1933. (2) Arch. f. Hyg. 114:46, 1935. WeyravcH, F., NECKE, A. AND MULLER, H.: Ztschr. Hyg. u. Infektionskr. 116:28, 1934. WaiTBY, L. E. H. AND BrITTON, C. J. C.: Lancet 1:1173, 1933. Waite: cited by Flury. WiceMAN, H. J. anp CLirrorD, P. A.: J. Assoc. Official Agr. Chem. 17:123, 1934. Wicaman, H. J., Murray, C. W., Harris, M., Cuirrorp, P. A., LovueHREY, J. H. AND Vorugs, F. A.: J. Assoc. Official Agr. Chem. 17:108, 1934. WipaL, F.: Rev. gén. de clin. et de thérap. 29: 422, 1915. WieceLpT: cited by Teleky, L.: Miinch. med. Wehnschr. 78:354, 1931. Wircox, H. B. anp Carrey, J. P.: J. A. M. A. 86:1514, 1926. BIBLIOGRAPHY 257 WiLkins, E. 8., WiLLouveaBY, C. E. AND KRAEMER, E. O.: Ind. Eng. Chem. Anal. Ed. 7:33, 1935. WiLLcocks, G. C.: Med. J. Australia 2:813, 1933. WiLLcox, R. L : Brit. Med. J. 2:222, 1931. Wirriams, H., Scavrze, W. H., Rorascuirp, H. B., BRown, A. S. AND Smit, F. R., Jr.: J. A. M. A. 100:1485, 1933. WiLLoveusy, C. E. AND WILKINS, E. 8., Jr.: J. Biol. Chem. 124: 639, 1938. WiLrouensy, C. E., WiLkiNs, E. S., Jr. AND KRAEMER, E. O.: Ind. Eng. Chem., Anal. Ed. 7:285, 1935. WiLson, S. A. K.: Rev. Neurol. and Psychiat. 5:441, 1907. WiINDscHEID: cited by Aub et al. WiNkELMAN, N. W. AND Ecker, J. L.: N.Y. State J. Med. 33:427, 1933. WinTER, O. B., RoBinsoN, H. M., Lams, F. W. AND MILLER, E. J.: Ind. Eng. Chem., Anal. Ed. 7: 265, 1935. Wovrr-E1sNER: Arch. f. exper. Path. 102:305, 1924. Wourr, A.: Klin. Wehnschr. 39:840, 1902. WovLrratGEL, G.: Arb. Gesundh., Berlin, 2:112, 1887. Woop, F. C.: J. A. M. A. 117:20, 1941. W=ricHT, W.: Bost. Med. and Surg. J. 187:328, 1927. WricaT, W., SAPPINGTON, C. O. AND RANTOUL, E.: J. Ind. Hyg. 10:234, 1928. Young, R. H. AND OsGoop, E. E.: Arch. Int. Med. 55:186, 1935. ZADEK, E.: Deutsch. med. Wehnschr. 55:1336, 1929. ZANGGER, H.: Wiesbaden Kongr. f. inn. Med. 45:304, 1933. Zurtrova, A. S., KapLuN, S. I. AnD FickLEN, J. B.: Some Methods for the Detection and Estimation of Poisonous Gases and Vapors in Air, Service to Industry, Hart- ford, 1936. ZUNKER, E.: Ztschr. f. klin. Med. 1:496, 1880. BRP! Vo A Bs INDEX Abdominal pain, 105-107 Abortion, 85, 142 Absorption, 1 alimentary, 2 cutaneous, 1 effect of laxatives on, 40 from mouth, 77 of tetraethyl lead, 19 respiratory, 6 subcutaneous, 2 Acid-base balance, 59 Acidity (see H-ion) Acids, and lead mobilization, 37, 39 in therapy, 196 Adrenals in lead poisoning, 59 Age, and encephalopathy, 118 and paralysis, 126 and susceptibility to lead, 94, 96 and tissue lead, 12, 82 Air, lead in, 95, 167 Albuminuria, 91, 93, 112 Alcohol, and lead excretion, 37 and lead mobilization, 37 and lead poisoning, 105, 126, 127, 192 Alimentary tract, absorption from, 1, 77 in lead poisoning, 77-81, 102-108 in tetraethyl lead poisoning, 137 lead in, 28 pigmentation of, 103 symptoms, 102-108, 137 Alkalinity (see H-ion) Alkalis, and lead excretion, 37, 39 and lead mobilization, 37, 39 in therapy, 196 Analgesia, 135 Anemia, 45, 144 Anesthesia, 128, 135 Anorexia, 102, 138 Arteriosclerosis, 72-76, 108-112 Arthralgia, 82, 140 Ascorbic acid, and lead excretion, 39 and lead mobilization, 39 therapy, 195 Basophilia, 42-45, 146-151 Beer, lead in, 168 Beverages, lead in, 168 Bilirubin, in blood, 51, 87, 153 in urine, 51, 87, 153 Bismuth, and lead mobilization, 38 Bladder spasm, 114 Blindness, 120, 123, 124 Blood, in feces, 102, 106, 107 in lead poisoning, 42-54, 144-154 in urine, 91, 93, 112 lead, 8-11, 155-158 relation of, to urine lead, 11, 35, 163 pressure, in colie, 107, 110 in lead poisoning, 72-77, 99, 110-112 in tetraethyl lead poisoning, 138 sugar, 57 vessels, 72-77, 108-112 Bones, lead in, 21-26, 81 mobilization from, 23, 25, 37-40 storage in, 21-26 effect of age on, 23 effect of H-ion concentration on, 25 symptoms, 140 x-ray visualization of lead in, 23, 82, 141 Bradycardia, 99, 107 Brain, (see also nervous system) in lead poisoning, 63 lead in, 15, 19, 138 Calcium, and lead deposition, 23-26 and lead excretion, 23, 37-39 and lead metabolism, 23-26, 37-39 and lead mobilization, 23-26, 37-39 metabolism in lead poisoning, 58 therapy, 194 Capillaries in lead poisoning, 74, 76, 109 Carbohydrate metabolism, 57 Cardiovascular symptoms, 108-112, 138 Ceramic industry, 218 Cerebral manifestations, 117-123, 138 (see also nervous system) Cerebrospinal fluid, in lead poisoning, 64, 136 lead in, 10, 30, 64, 165 Chloride metabolism, 58 Cider, lead in, 168 259 260 Citrate, effect of, on lead excretion, 39, 195 therapy, 195 Colic, 80, 99, 102, 105-107, 138 blood-pressure in, 107, 110 mechanism of, 80 treatment of, 193-195 Color vision, 125 Coma, 99, 117-123 Constipation, 99-101, 102, 106, 107 Convulsions, 99, 117-123 Creatine metabolism, 56, 62 Delirium, 117-123, 138 Delusions, 117-123, 138 Deposition of lead, 12-31 Determination of lead, 219-239 Diarrhea, 99, 101, 102, 106, 107 Diet in lead poisoning, 196 Dihydrotachysterol, effect of, on lead excretion, 37 on lead mobilization, 37 Distribution of lead in tissues, 12-31 influence of portal of entry on, 16-21 Dust, lead in, 167 Dyspnea, 83, 142 Ears in lead poisoning, 68 Encephalopathy, 117-123 treatment of, 198 Endocrine glands in lead poisoning, 59, 84 Enterohepatic circulation of lead, 5, 31, 32 Enteritis, 80, 99, 102, 138 Enzyme activity, 54 Excretion of lead, 31-40, 158-165 by alimentary tract, 31-33, 164 by kidneys, 33-40, 158-164 by liver, 31 by pancreas, 32 by respiratory tract, 40 by skin, 40 effect on, of acids, 37, 39 alcohol, 37 alkali intake, 37, 39 ascorbic acid, 39 bismuth, 38 calcium intake, 24, 25, 37 citrate, 39 dihydrotachysterol, 37 INDEX heat, 40 infection, 37 iodide, 38 laxatives, 40 light, 40 parathyroid hormone, 25, 37 phosphorus intake, 24, 25, 37 shock, 37 starvation, 37 sulfur, 39 thyroid, 37 vitamin D, 24, 25, 37 in bile, 31 in feces, 31-33, 164 in milk, 30, 40 in perspiration, 40 in saliva, 31, 78 in urine, 33-40, 158-164 Eyes in lead poisoning, 68, 124-126 Fat metabolism, 57 Fatigue, and paralysis, 127, 129 Feces, blood in, 102, 106, 107 lead in, 31-33, 164 Fertility, 85, 86, 142-144 Fetus, in lead poisoning, 85, 86, 142-144 lead in, 12, 85, 86 Food, lead in, 167-171 Fragility of blood cells, 47, 48 Gastritis, 80, 99, 102 Gastrointestinal (see alimentary) Gingivitis, 79, 103, 104, 107 Glycosuria, 57 Gonads in lead poisoning, 84-87, 142-144 Gout, 83, 140 Growth in lead poisoning, 54, 55 Gums in lead poisoning, 79, 103, 104, 107 H-ion concentration, effect of, on lead in bones, 25 on lead mobilization, 25, 37, 39, 40 Hair, in lead poisoning, 59 lead in, 29, 30 Hallucinations, 120, 121 Headache, 120, 122, 138 Heart, failure, 76, 110, 111 in lead poisoning, 74, 76, 77 lead in, 15, 28, 29 Heat, effect of, on lead excretion, 40 INDEX Hematopoiesis in lead poisoning, 42-54, 144-154 Hematuria, 91, 93, 112 Hemianopsia, 125 Hemolysis, 45-563, 153 Hemosiderin, 51 Hygiene, industrial, 172-191 Hyperbilirubinemia, 51, 87, 153 Hyperesthesia, 128, 135 Hyperglycemia, 57 Hypertension, 72-77, 99, 110-112, 138 Hyperthyroidism and lead poisoning, 59 Hysteria, 121 Illusions, 121 Industrial control of lead poisoning, 172- 191 Infant, effect of lead poisoning on, 84-87, 142- 144 mortality in lead poisoning, 85, 86, 142-144 Infection and lead poisoning, 105, 192, 193 effect of on lead excretion, 37 on lead mobilization, 37 Insomnia, 120, 138, 139 Intake of lead, normal, 167-170 Intestinal spasm, 69, 80, 107 Intestines (see alimentary tract) Iodide, effect of on lead mobilization, 38 Iron metabolism, 58 Jaundice, 51, 87, 153 Joint symptoms, 82, 83, 140, 141 Kidney excretion of lead by, 33-40, 158-164 effect of renal function on, 35, 93, 163 function in lead poisoning, 89, 93, 94, 114, 115 in lead poisoning, 89-94, 112-116 lead in, 12, 14-21, 27 Laxatives, and lead absorption, 40 and lead excretion, 40 Lead, determination of, 219-239 Lead in air, 95, 167 in beer, 168 in beverages, 168 261 in blood, 8-11, 155-158 in cerebrospinal fluid, 10, 30, 64, 165 in cider, 168 in dust, 167 in feces, 31-33, 164 in food, 167-171 in milk, 30, 40 in tissues, 12-31 in urine, 33-40, 93, 158-164 in water, 95, 170 in wine, 168 Lead intake, normal, 167-171 Lead line, 77-79, 103-105 Lead poisoning, acute, 99, 137 alimentary tract in, 77-81, 102-108 blood in, 42-54, 144-154 blood lead in, 8-11, 155-158 blood vessels in, 72-77, 108-112 bones in, 81-83, 140, 141 bone-marrow in, 48-50 cardiovascular symptoms in, 108-112, 138 causes of, 199-204 cerebrospinal fluid in, 64, 136 cerebrospinal fluid lead in, 10, 30, 64, 165 chronic, 99-166 clinical manifestations of, 99-166 creatinuria in, 56, 62 effect on fetus, 85, 86, 142-144 effect on skeletal muscle, 59-62 effect on smooth muscle, 69-71 effect on sympathetic system, 70, 71 endocrine glands in, 59, 84 encephalopathy in, 117-123 enzyme activity in, 54 feces lead in, 31-33, 164 gastrointestinal symptoms, 102-108, 137 genital tract symptoms, 142-144 gonads in, 84-87, 142-144 growth in, 54, 55 hair in, 59 heart in, 74, 76, 77, 110, 111 hematopoietic system symptoms in, 42-54, 144-154 incidence of, 203 industrial control of, 172-191 infant mortality in, 85, 86, 142-144 joints in, 82, 83, 140, 141 262 Lead poisoning—Continued kidneys in, 89-94, 112-116 liver in, 87-89 lymphatics in, 54 metabolism in, 54-59 nervous system in, 62-68 neurological symptoms in, 117-139 neuromuscular symptoms in, 117-139 non-industrial, 199-204 occurrence of, 199-204 pallor in, 99, 100, 106, 109, 139 paralysis in, 126-136 pathological physiology of, 41-98 pathology of, 41-98 pigment metabolism in, 50-53, 163, 154 placenta in, 85, 86 prevention of, 172-193 reproduction in, 84-87, 142-144 respiratory tract in, 83 respiratory tract symptoms in, 142 sense organs in, 68, 69 sensory disturbances in, 135 skin in, 59 spleen in, 89 temperature in, 99, 107, 122, 138, 139 treatment of, 191-198 ureters in, 106, 114 urinary tract symptoms in, 112-116 urine in, 51, 91, 93, 94, 99, 107 urine lead in, 33-40, 93, 158-164 uterus in, 85 visual disturbances in, 120, 123, 124- 126 Lead, production of, 205-207 Lead products, consumption of, 207-209 in industry, 205-218 manufacture of, 207-218 Lead, susceptibility to, 94-98 tests for, 219-239 tolerance to, 94-98 toxic dose of, 94-98 Lead workers, medical examination of, 191-193 Leukocytes in lead poisoning, 53, 151, 152 Light, effect of on lead excretion, 40 Lipid metabolism, 57 Liver, in lead poisoning, 87-89 lead in, 12-21, 26 Lungs (see also respiratory tract) absorption of lead from, 6-8 INDEX in lead poisoning, 83, 142 lead in, 12-21 Lymphatics in lead poisoning, 54 Magnesium sulfate, and lead absorption, 40 and lead excretion, 40 in treatment, 193 Mania in tetraethyl lead poisoning, 138 Medical supervision, 191-193 Meninges in lead poisoning, 64, 65, 136, 137 Menstrual disturbances, 84, 142 Mental symptoms, 117-123, 138 Metabolism in lead poisoning, 50-53, 54-59, 153, 154 calcium, 58 carbohydrate, 57 fat, 57 iron, 58 mineral, 58 phosphorus, 58 pigment, 50-53, 153, 1564 protein, 56 Metallic taste in lead poisoning, 31, 99, 102, 139 Milk, lead in, 30, 40 Miscarriages, 85-87, 142-144 Mobilization of lead, effect of acids on, 37, 39 alcohol on, 37 alkali on, 37, 39 ascorbic acid on, 39 bismuth on, 38 calcium on, 24, 25, 37 citrate on, 39 dihydrotachysterol on, 37 heat on, 40 infection on, 37 iodide on, 38 laxatives on, 40 light on, 40 parathyroid hormone on, 25, 37 pH on, 25, 37, 39, 40 phosphorus on, 24, 25, 37 shock on, 37 starvation on, 37 sulfur on, 39 thyroid on, 37 vitamin D on, 24, 25, 37 Mouth, excretion of lead by, 31, 78 INDEX Muscle, lead in, 15, 17, 27, 28 skeletal, in lead poisoning, 59-62 smooth, in lead poisoning, 69-71 Nasopharynx (see respiratory tract) Nausea, 99, 100, 101, 102, 106, 138, 139 Nephritis in lead poisoning, 89-94, 112- 116 Nephrosclerosis in lead poisoning, 89-94, 112-116 Nerves in lead poisoning, 65-68 Nervous system autonomic, in lead poisoning, 70, 71 in lead poisoning, 62-68 lead in, 10, 15, 19, 30, 64, 138, 165 symptoms, 117-139 Neuromuscular symptoms, 117-139 Nose (see respiratory tract) Nucleoprotein metabolism, 56, 57, 83, 141 Optic neuritis, 68, 124-126 Organic lead compounds (see also tetra- ethyl lead) distribution of, 1, 19, 137-139 Oxygen consumption in lead poisoning, 55 Pain, 99, 101, 103, 105-107, 120, 128, 135, 138 Pallor, 99, 100, 106, 109, 139 Palsy (see paralysis) Pancreas, excretion of lead by, 32 Paralysis, 126-136 treatment of, 193-198 Parathyroid hormone and lead deposition, 25, 37 and lead excretion, 25, 37 * and lead mobilization, 25, 37 therapy, 197 Parotitis, 79, 103 Pathological physiology of lead poison- ing, 41-98 Pathology of lead poisoning, 41-98 of tetraethyl lead poisoning, 137-139 Perspiration, lead in, 40 Phosphorus and lead metabolism, 23-25, 37 effect of, on lead excretion, 24, 25, 37 on lead mobilization, 24, 25, 37 metabolism in lead poisoning, 58 therapy, 194, 196 263 Pigment metabolism, 50-53, 153, 154 Placenta in lead poisoning, 85, 86 Platelets in lead poisoning, 54, 152, 153 Plumbism (see lead poisoning) Polychromasia (see basophilia) Porphyrinuria, 50-53, 153, 154 Pregnancy in lead poisoning, 84-87, 142- 144 Prevention of lead poisoning, 172-193 Psychosis, 121, 138 Race, and susceptibility to encephalop- athy, 118 to lead, 94, 96 Reproduction in lead poisoning, 84-87, 142-144 Respiratory tract, absorption of lead from, 6 in lead poisoning, 83 symptoms, 142 Reticulocytes in lead poisoning, 44, 149, 150 Reticuloendothelium and lead distribu- tion, 18, 19 Retinitis, 68, 124-126 Saliva, excretion of lead in, 31, 78 Salivary glands in lead poisoning, 79, 103 Sense organs in lead poisoning, 68, 69 Sensory disturbances, 135 Sex, and encephalopathy, 118 and paralysis, 126 and susceptibility to lead, 94, 96 Shock, and lead excretion, 37 and lead mobilization, 37 in lead poisoning, 72, 99 Skeleton (see bones) Skin, absorption of lead from, 1 excretion of lead by, 40 in lead poisoning, 59 lead in, 28 Spermatogenesis in lead poisoning, 86, 143, 144 Spinal cord in lead poisoning, 65 Spleen, in lead poisoning, 89 lead in, 15, 17, 18, 19, 21, 89 Starvation, effect of on lead excretion, 37 Sterility, 85, 86, 142-144 Stillbirths in lead poisoning, 84-87, 142- 144 Stippling (see basophilia) 264 Stomach (see also alimentary tract) secretion of, in lead poisoning, 81 Stomatitis, 78, 99, 103, 107, 108 Storage batteries, manufacture of, 180, 211-214 Storage of lead (see also mobilization), 12-30 in alimentary tract, 28 in bones, 21-26, 81 in fetus, 12, 85, 86 in heart, 15, 28, 29 in kidneys, 12, 14-21, 27 in liver, 12-21, 26 in nervous system, 10, 15, 19, 30, 64, 138, 165 in skin, 28 in spleen, 15-19, 21, 89 Subcutaneous tissues, absorption of lead from, 2 Sulfur and lead excretion, 39 Susceptibility to lead, 94-98 age and, 94, 96 factors influencing, 94-98 race and, 94, 96 sex and, 94, 96 Teeth, in lead poisoning, 79, 80 lead in, 14, 80 Temperature, in lead poisoning, 99, 107, 122, 138, 139 in tetraethyl lead poisoning, 138, 139 Testes in lead poisoning, 86, 143 Tests for lead, 219-239 Tetraethyl lead, absorption of, 19, 137 distribution of, 19, 138 poisoning, 137-139 Thiamin and paralysis, 127 Thiosulfate and lead excretion, 39 Thyroid, and lead excretion, 37 and lead mobilization, 37 Tissues, lead in, 12-31 Tolerance to lead, 94-98 Toxic dose of lead, 94-98 INDEX Transportation of lead, 8-11, 155-158 Treatment of lead poisoning, 172-198 preventive, 172-193 specific, 193-197 symptomatic, 197, 198 Tuberculosis and lead poisoning, 83, 142, 192 Uremia in lead poisoning, 93, 114, 115 Ureters in lead poisoning, 106, 114 ' Uric acid in lead poisoning, 56, 57, 83, 141 Urinary tract symptoms, 112-116 Urine, albumin in, 91, 93, 112 bilirubin in, 51, 87, 153 blood cells in, 91, 93, 112 casts in, 91, 93, 112 in lead poisoning, 51, 91, 93, 94, 99, 107 lead in, 33-40, 93, 158-164 and lead poisoning, 158-164 effect of renal function on, 35, 93, 163 relation of, to blood lead, 11, 35, 163 porphyrin in, 51-53, 153, 154 sugar in, 57 urobilin in, 50, 51, 107, 153 Urobilinuria, 50, 51, 107, 153 Uterus in lead poisoning, 85 Vasoconstriction in lead poisoning, 72, 74-77, 80, 108-110 Vision in lead poisoning, 120, 123, 124-126 Vitamin B (see thiamin) Vitamin C (see ascorbic acid) Vitamin D, and lead excretion, 24, 25, 37 and lead mobilization, 24, 25, 37 therapy, 194 Vomiting, 99, 100, 102, 106, 122, 138, 139 Water, lead in, 95, 170 Wine, lead in, 168 X-ray visualization of lead in bones, 23, 82, 141 C02941b2Yys