Document 9Q42x6OeBG321bqYnNXx7G3p

First Draft - Stepps THE RESULTS OP EPIDEMIOLOGICAL STUDIES OF THE BIOLOGICAL EFFECTS OF LEAD INFORMATION ... ........ ......' ....... - ' ------------------ ------ ---------------- K, JP PUBLICATION OR * p u b l ic a t io n REFERENCES In studying diseases due to a single environmental agent such as lead, three main stages in man's state of knowledge may he distinguished. The first is the recogni tion of the diseased state but without appreciating the nature of the causative agent. It is at this stage of man's knowledge that Paul ofAegina and Avicenna describe patients suffering from "colicky affections" accompanied by paralysis which may well represent descriptions of lead poisoning, but it is not until the 2nd century B.C. that man enters the second stage of his knowledge of the bio logical effects of lead when there is unequivocal evidence linking the disease to the causative agent - lead. At that time Nikander wrote his "Alexipharmaca" describing both colic and paralysis as the result of ingesting litharge (lead oxide). The third stage in our increasing knowledge of the biological action of an agent such as lead comes with the demonstration that the severity of the effect produced is directly related to the amount absorbed. This third stage of knowledge is often late in coming because only severe disease produced by massive doses is recognized at first and more subtle effects are missed. Such situations are illustrated by the sporadic and usually accidental lead exposures reported after 1500, at about which time the develop ment of printing made the dissemination of such reports easier and their preservation more certain. N40682 unap. j r Page 2 In 1572 an epidemic of lead poisoning occurred in * the French province of Poitou due to drinking wine adulter. ated with litharge (lead oxide) and from that time on repeated epidemics of lead poisoning due to intentional or accidental adulteration of cider, ^ rum, ^ food^' or caused by drinking water conveyed in lead pipes,^ ^ were reported, in the more recent past there have been outbreaks of lead poisoning presumably due to airborne lead, particulate derived from the burning of old automobile batteries to provide domestic heat ing. (I1) It is with the beginning of the Industrial Revolution with the splitting up of the manufacturing process into dis crete operations performed by separate groups of men with dif fering degrees of lead exposure that it becomes possible to study sickness rates and relate these to the level of lead in the men's environment. One of the first studies to clearly show such a relation ship between the level of the lead exposure andthe amount and severity of thd sickness produced was that of G. E. Puckering in 1908.(10a) As a result of his measurements of the amount of lead In the air breathed by workmen in a number of British factories and his records of the number of men showing signs of lead intoxication, Legge and.Goadby suggested in 1912 that "if the amount of lead present in the air breathed contains less than 5 milligrammes per 10 cubic metres of air, cases of j DUP050055970  Page 3 encephalopathy and paralysis would never, and cases of colic very rarely occur* And this figure is a quite practical one in any process amenable to locally-applied exhaust ventilation. Somewhere about 2 milligrammes, or 0,002 gramme, of.lead we regard as the lowest daily dose which, inhaled as fume or dust in the air, may in the course of years set up chronic plumbism. With the demonstration that exposure to a certain amount of lead caused a certain biological response and that as the dose of absorbed lead diminished the clinical response became less, the prevention of the disease depended increasingly upon the ability of the engineer to control the level of lead in the workman's environment, This ability to control lead poi soning by a combined medical and engineering approach backed by government regulations is illustrated by the figures for notified cases of lead poisoning in Great Britain which fell . from 1,058 in 190O to 239 in 1928.^10c^ Similar studies were carried out in the United States and confirmed that . the number of cases of plumbism was positively correlated with the' level of lead in the air as shorn in Table I taken from Reference 14, TABLE I CASES OF PLUMBISM AMONGST BATTERY WORKERS . IN AREAS HAVING DIFFERENT LEAD EXPOSURES Atmospheric Lead Concentration . (Mgm Pb per 10 m3 air) 0 - 0.74 0.75 - 1.4 1.5 - 2.9 Over 3 Men Exposed 97 84 168 125 Men with early plumbism 4 6 50 67 Percent affected 4.1 7,1 29.8 53*6 DUP050055971 Page 4 Because the major route of entry for lead in the industrial worker is through the lungs, information from the study of industrial populations commonly relates the clinical or bio chemical findings to the level of lead in the air, but similar relationships between the amount of lead absorbed and the bio logical effect produced has been found for ingested lead^^ and for lead injected intravenously as a therapeutic agent. It has also been found from such studies that the level of lead exposure is reflected in the level of lead in the blood and the amount of lead excreted in the urine of the exposed person. Such relationships may show a considerable degree of variation when the values from individual persons are considered, but this variation is much less when the average or median values for groups of persons are studied. (Table II) The values in Table II should be used only to show a general tendency for increasing levels of exposure to be reflected in increased blood lead con centrations since the lead exposure is not completely described in terms of particle size and this is known to play an Important part in the deposition and absorption of lead In the lung. Another factor tending to reduce the degree of correlation in this study betv/een the blood lead and the level of lead in the air is the medical control exerted by the physicians in charge of the battery workers. This control removed many of the men in the high exposure group and placed them in areas of lesser exposure where they appear in Table II under the heading "Exposure changed." A more recent studythat illustrates the relationship between lead exposure and urine and blood lead levels provides the data,for Table III. DUP050055972 Average and median blood le a d co n te n t /(d ith iz o n e method) in mg. p e r 100 gm. o f b lo o d . S to ra g e -b a tte ry w orkers c la s s ifie d by exposure and by d u ra tio n o f employment. CO u o uCD o co c m*vo3o' oion o c m oomm*mooo o CCMOCr0~f C-3pF . oo oo m com 4Oo*o0 $ COm Cn c m; . o CM CO 00 O H CO O CMVQ oM>-m i cot>- (O 4" oii' cno-4* muw coo mo mo O m .o o* o o H o fO *o o 9o Oo o UCD o p rh id O <i> 1 VO MO O co mo =t moo ' O t>-M0 t-i m H H CO ri O-^t c m h~<n coo co COO -=to COO 3* O o O S 9 ' O o , O O O O O o O P O it h- o 9 ri OCOCO COOO 00 ^ co co o H C0 CM ri h-CO CM 0YH 0\CM . HO 1 O . CM O O r-1 O O* CM O O O O O O oO O .O O wWC$oD d&*<D4 WxQi&co3 CHM lCOCooO*O*OoO^ v^o oomt^vooot CCMM--coo==*ott ot(o>O- VCOM o0moCM4omo* Page > hPWO nCd1D r,(Qdi XPi-OP vi vCoM cooCmoM* -ooc=Mt OcoooCCinVOJ CcoOOo mcOmooovoCooO t*- CrOOiOCOOM . 0) h IprQ\ V P< X CD <0 cM CD ri to U CM CD a> ^ fao g a) to ra & Pi -h g d> ts 3 > q) .SS^S .9 Q> u &od <d <0 <o fit Pi *H g <D'd 3 > <D t 9 d) P<D< tco3 cco & Pr-H g <u ,d 3 !> o> S .9 99 91 9 9 e' en I *1 om 9 9 H :1 O H CD QS4 gg P0)t -H p > < 50)! + m T-i N DUP050055973 Chap, 5 F Page 6 Departmental means arid standard errors of eight- hoar lead-in-air concentrations and blood and urine, lead concentrations for workers working in an electric storage battery plant. JOB n Machine pasting Hand pasting Forming Casting Plastics Dept. A Plastics Dept. B 6 8 9 6 <. 5 5 TABLE III (Ref, 18) Pb-in-Air (mg/m3) Mean S.E. 0.218 0.025 0.150 0.029 0.134 0.013 0.052 0.003 0.012 0.0008 0.009 0.0008 BL UL (ug./lOO ml.)1 (ug./l.) Mean S.E. Mean S.E. 74.2 4*7 163.8 21.2 63.2 9.2 111.3 .14.1 63.0 2.7 114.0 7.2 - - 87.9 6.8 27.2 1.4 34.5 3.2 29.I 1.6 34.8 2.0 In this study by Williams although the number^of men observed (39) was not large, the use of personal air samplers and. the number of observations 'made gives the results a more than usual value. Prom this data Williams calculated correlation coefficients (y) and regression equations XY of the biochemical value (Y) with the mean 8-hour lead-in-air concentration,(X). These results are shown below: Y Blood lead. r 0.90 Y30.1 + 201 X X - 0.0975 + 0.00399 Y Urine lead 0.82 < 45.5 + 486 X - 0.0277 + 0.00138 Y DUP050055974 Page 7 Experimental exposures of human beings to known concentrations of airborne or ingested lead have provided graphic ... * /` data describing the relationship between the exposure level, and the blood and urine lead concentrations.^^ All of the information so far discussed' deals with occupa tional or experimental exposure but.' ' ' at levels of lead found similar in the urban environment a ^correlation between the .concentration of lead in the air and lead in the blood has ^e^ound.^^^wlth regard to lead as a community air pollutant, there have been no cases of characteristic lead poisoning due to lead as a community air pollutant.' Therefore from this point on, attention will be centered on those studies concerned with health effects of lead other than classical lead poisoning. Three main epidemiological approaches have been used in seeking such health effects. The first has.been to compare the health of occupational groups with documented lead exposures with the health of groups not so exposed. The second approach has been to study persons V with a certain disease and compare their tissue levels of lead with persons who are otherwise similar but do not suffer from the disease. The third method is to study the geographical distribu tion of a disease and compare it with the geographical distribu tion of a type of lead exposure. DUP050055975 Chap. 5 F . Page 8 The first method, if properly carried out, probably offers the chance of the greatest precision but suffers from certain limitations which are inherent in the nature of an employed population such as being restricted to a certain age range and initial state of health. In the case of the lead industries it is also likely to be predominately a male group. There have been very few epidemiological studies of groups occupationally exposed to lead in which a large number of factors were documented and the results in different exposure groups com pared . r* One of the earliest of such studies to use modern epi demiological methods was of persons exposed to lead arsenate as a result of the use of this compound as an insecticide. In common with most epidemiological studies which may be looked upon as naturally occurring experiments in which the investigator has little or no control over the experimental design this study of the orchardists in the Wenatchee area of the state of Washington was complicated for the purposes of this discussion by dealing with an exposure to lead arsenate. This raises the compared with the question as to the relative importance of the lead j arsenical portion of the lead arsenate molecule in the overall toxicity of the compound. An attempt to answer this was made by special studies in animals. DUP050055976 Ctiap. p -f Page 9 these It was found in/animal studies that the more toxic portion of the molecule of lead arsenate is to be attributed to the f arsenical radical rather than to the lead or a synergistic \ action of the lead and arsenic. l TABLE IV 1 TJRINE LEAD VALUES OF PERSONS IN. WENATCHEE STUDY CLASSIFIED BY SEVERITY OF EXPOSURE ' Low exposure group .. (Ref. 22) Urinary Lead. mg Pb ;per liter No. of Aver Analyses age SD Men- 146 0.035 0.021 Women 123 0.028 0,019 Intermediate exposure group Men Women 102 25 0.043 0.027 0.301 0,014 High exposure group Men Women 386 0.09 0.060 61 0.05 0.024 Children under 15 Boys Girls 8l 0.05 0.039 45 0.05 0.405 DUP050055977 Chap. 5 F Page .10 While the lead values shown in Table IV are not as high as those sometimes seen in other industrial exposures, they are of particular importance for this reason since the urine lead slightly more than are concentrations range from those/commonly found in urban com munities to those found in moderate lead exposures in industry. Among the factors studied in assessing the health of the orchardists were weight, blood pressure, diseases of the cardiovascular system, skin disorders, eye irritation, chronic nervous diseases, blood dyscrasias, kidney disease, pulmonary tuberculosis, visual acuity, syphilis, neoplastic disease and fertility. Each factor was studied to find out whether it had been modified by Head arsenate exposure. Insofar as compara tive data for other populations were available, no evidence was found that any of these factors was altered by the lead arsenate exposure. Special attention was given to medical examination of children because, in the Wenatchee area where orchards surrounded the communities or the houses in which they lived, there were unusual opportunities for children to be exposed to lead arsenate insecticide sprays and spray residues on branches, leaves and grass in addition to lead . arsenate spray residues they ingested on apples. There was only one respect in which these children-differed from chil dren in other districts their urinary lead and urinary arsenic values were nearly twice as high as the corresponding values for a group of 18 children taken at the same time in Washing- DUP050055978 . - Chap. 5 F Sage 11 ton, D. .0. (who had a wean urine load level 0.026 mgm/Pb/ liter S.D. 0.0128.) There was no indication of adverse the Wenatchee chil- effects of lead arsenate exposure on the health of ' dren children.. While this study of persons exposed to lead arsenate has many deficiencies when used as a source of information on the possible biological effects of lead as an urban air pollutant it is particularly important for two reasons. Firstly, it is one of the few modern studies con taining an appreciable number of women of childbearing age; and, secondly, it is one of the few studies having children, with a lead exposure other .than flaking lead paint. A study of storage-battery workers previously ` referred to (l4) and who showed the range of blood lead eon- centrations shorn in Table ill was also studied for the pos sible effect of the lead exposure upon the incidence of diseases other than plumbism. Seventy-five percent of the 766 men studied had been employed in electric storage-battery plants for more than five years and about 12 percent for 20 -r years or more. In this study the incidence of disease in the high-exposure group (exposed to more than .15 mg Pb per m3) incidence in the . was compared with the/low-exposure group (exposed to less than 0.1$ mg Pb per M^). The prevalence of arteriosclerotie- -hypertensive heart disease did not increase with increasing atmospheric lead concentration. In the age range 4$ - $4 DUP050055979 Chap, 5 P Page 12 which covers the period when degenerative' cardiovascular disease is making its appearance, 53 workers were exposed . to atmospheric lead concentrations below 0.15 mg Pb.per and 32 percent were found to have arteriosclerotic hyper tensive heart disease as defined in the study. In the 66 workers in the same age range exposed to concentrations in excess of 0.15 mg Pb per Pr also had a 32 percent incidence of this type of heart disease. Another statistical treatment, shown in detail in Table V, is to use the population exposed to less than 0.15 mg per 1 m^ as a basis for predicting the number of cases that would be expected if the same rates of incidence pre vailed in all age groups of the more heavily^exposed popula tions. Thus, if this assumption were correct, one could expect to find 35 cases of heart diseases of the arterio sclerotic-hypertensive group in 263 workers between 25 and 65 years of age exposed to atmospheric lead concentrations in excess of 0.15 mg per 1 nrl, Making allowance for the differences in age distribution,. . actually, 37 cases were found, a number that agrees closely with the expected value. The agreement is even closer for the 102 workers who changed jobs within 5 years of the time of study, the expected value of 13*7 checking the observed number of cases, 1^. Thus, it may be concluded that an increase in lead exposure was not accom panied by any increase in the prevalence .of this group of diseases of the cardiovascular system. DUP050055980 - 13 Chap. 5 F Page 13 Com putation sheet, showing th e number o f cases o f a rte rio s c le ro tic -h y p e rte n s iv e h e a rt diseases th a t could be expected in r e la tiv e ly h e a v ily exposed w orkers1 supposing th e age in c id e n c e to be th e same as in r e la t iv e ly l i g h t l y exposed w orkers d 0 to U 00 r o -=t tn in -=t CM 0 cd to o ri dP 0 d o 0 to -OP 0CO 0pi Ocd 60 M d U0 0 60 P* .0 cd p 8 5s; 60 60 *00 CO >k C0O U0 Pi 00 cod O CMm o tn rl CM N* oo r*1 oo CM ri OO 00 CM H 00 tn ri CO CM Is- PO ri IIIIIIIII 0ts0- d in <0p t0o o co rH 0 cd 0 X d W & P aU0ds &ok ffclcd)Opp, %, lo 0 p d0 0O40O3 0 <H PH cd d o 00 =t CM* O H VO CM zt VO QO oo VO o\ rH CM * oo ri VO OO in CM rH OO OO ft to 00 Pi CO cd o ri oo vo ri 2 in ri d3Pd .3U0gQ 0m0 foPPni ,Q ri c OO H tn on tn Q\ rH 525-rt ,60 0 t0o a 06p cd it =t -=t oo , *t- tn VO Ii i1 m tn tn tn CM 0to0 tn tn 00 IIIlII!IIiIIiIIItIr iii tiii i( ti tiii 4BO> H H cd cd oo 00 00 .e e oo H rH fn SH 00 Pi Pi .Q .0 PH PH W hp in in ri ri P p 0 CO u CO o. 0 BH oO p *P dd 00 w CO oG ri CM DUP050055981 Chap. 5 F Page 14 * - 14 - When lead"affected workers are compared An the same way as before with workers exposed to less than 0.15 mg o Pb per 1 nr of air one would expect to find 27.3 case's of arteriosclerotic-hypertensive heart disease in the 169lead-affected workers between the ages of 25 and 65. Act ually, there were 34 cases but, considering the standard deviation (4.78) that attaches to such an estimate, the difference is not statistically significant. Application of a chi-square test confirms this conclusion. Response to a standard exercise test was as good in men exposed to lead concentrations in excess of 1.5 mg Pb 3 per 10 nr as it was in men of comparable age exposed to lower concentrations. Men who had changed jobs during the preceding 5 years also, as a class, had equally satisfactory returns to preexercise pulse rates and systolic and diastolic blood pressure values. In two age groups of storage-battery workers, 35-44and 45-54, the differences between preexercise values and the values prevailing 3-minutes after exercise were in close agree ment. Application of a probability test indi cated that the differences were in all cases.not significant. DUP050055982  *./* Chap, 5 F Page 15 Blood pressure values, measured with the mercury syphgmomanometer, agree closely with the average values for 6,667 industrial workers in 9 other industries studied-by'the Public Health Service. ^2^ As an additional check, a tabulation was made of men with preexercise blood pressures in excess of 150 mm. Hg. The number and percentage with higher systolic pressures, here designated as cases of hypertension, appear in table 68 for storage-battery workers and for other industrial workers.^2 The percentage values agree closely, showing that hypertension of this degree is no more prevalent in the storage-battery industry than in other industries. * This information on the status of the cardiovascular system has been given in some detail because this system has been the thought to be affected by lead by many earlier writers but after reviewing these authors Aub concludes "Although the general clinical opinion holds that arteriosclerosis is a result of chronic plumbism, this idea is based entirely on the occurrence of this condition in many postmortum examina tions. That arteriosclerosis is much more frequent in those . exposed to lead than in other individuals of the same age, however, needs much more statistical proof before it can be accepted.2Cantarow and Trumper in their book on lead poisoning are inclined to believe that lead at high concentra- DUP050055983 Chap. 5 F Page 16 tions such that lead poisoning has occurred or is likely to occur may be associated'with degenerative vascular disease. at high levels Support for the view that lead^ay be linked' to degenerative vascular disease found in a British study of battery workers in which three exposure grades were defined Grade A - no exposure, Grade B - negligible exposure and Grade C exposure represented for the last 20 years by a mean lead in urine values between*100 and1250 mg/liter(but in the past these have not infrequently exceeded-250 mg/liter.) The mean exposure period for the pensioners in Grades B and C was 35*3 and 32.3 years respectively, while for. men dying whilst employed, the mean exposure for Grade B exposures was 26.8 years and that for Grade C 21.8 years. In studying the number of deaths from all causes amongst ' the pensioners there was found to be a significant excess in Grade C but not in either of the other Grades. 'When the deaths attributed to vascular lesions are studied in this series a highly significant excess of deaths due to cerebro vascular catastrophies was found amongst Grade G pensioners. As can be seen in Table VI while the deaths of pensioners prior to 1950 showed an excess of those observed over those expected in both Grade B and C, after 1950 only Grade C Shows an excess of deaths. This, suggests that improvements DUP050055984 d 0 0mu B o [v0Po 0 f LTV 0HN oo in . O CO rl CIVII 04 X *L CM CO ON ON VO LTV Page 17 Id 0> u x0a oo oo ioo VO 00 TABLE V I 04 CVJ H # . O oo OO CO op i d<1) fc 0CO Q VO vo 00 B m n& d<D 4(OD> N* 04 > ON CVJ u8` o o- OO uo uM V$ 0 Oin vHo ON ON HI . Ht VcOvi Hin H VO HOlN VO 04 H VO ON rl VO >0* P0 OHN Oi N W OHN ON r*l OOr-i ' \) P(P . do B V" CrOl P 0 r-l Pi 1<P * DUP050055985 in hygienic standards with a consequent decrease in the lead exposure may have resulted in the observed improve ment in mortality experience. It is unfortunate that this Study which was initiated to study the incidence of cancer amongst battery workers did not contain more Information on the physiologic status of the men. For instance it would have been most interesting to have known the incidence of hypertension in the various exposure groups. The apparent difference in the experience of European and North American investigators studying the effect of lead on the blood vessels is thought by Lane^^) to be probably a reflection of differing working conditions on the two sides of the Atlantic a3though he points out that the study of Dreesen(' l41' contained only 12 percent of men with more than 20 years' exposure and that no adequate study has been con ducted of workers in the United States exposed to high levels of lead for one or two decades. Support for the view that lead workers in carefully supervised plants do not, even after long exposure have an increased risk of hypertension compared (*11) with nonlead workers comes from the study of Cramer. J ' Three-hundred and sixty-four workers were studied, 82 of whom had been employed for more than 20 years, and 265 for more than 10 years. The incidence rates of hypertension in the various age and exposure groups were then studied and compared not only within groups but against data gathered in an exten sive Norwegian study of nonlead-exposed men. In none of these DUP050055986 Chap-. 5 F ` Page 19 comparisons was there any evidence of an effect of lead exposure either in duration or in severity upon the inci dence of hypertension. ' The same confusion of claims and counter claims for the effects of lead surround the subject of kidney disease and high blood pressure. Views on these topics appear to depend as they do with arteriosclerosis on the character istics of the lead exposure of the workers studied. The earlier observers who saw many more cases of heavy pro longed exposure to lead than is possible today were con vinced that chronic kidney disease and high blood pressure were direct although delayed consequences of exposure to lead. The extensive literature on this matter has been reviewed by Radosev.^2) It is pointed out by Browning(30) that no actual rise in blood pressure of workers in the electric storage battery industry has been demonstrated by Belknap Dreesen, or Lane, and that this absence of significant change shows that their exposure had not reached a dangerous level and that the disappearance of chronic renal disease in lead workers is probably due to the improvement of conditions in modern lead industries. Therefore looking at these controversial matters from this point in time it would appear that the modern lead worker, although still showing a higher lead absorption than the nonlead vrorker, does not run the risk Of arteriosclerosis, hypertension or kidney disease due to his lead exposure. This conclusion would be supported by the Wenatchee study(22) rr'$ with is generally moderate level of lead exposure and the A DUP050055987 ' Chap. 5 F Page 20 studies of Baader^) and Vigliani. uhe epidemiological experience with groups of persons exposed to lead and other materials in consuming illicitly distilled alcohol is dealt with elsewhere in this publication, but in general it may be said that the kidney disease seen in such groups is asso ciated with high lead absorption.(33) In concluding this review of information from epidemio logical studies of lead workers, it is important to raise the question of whether certain groups of workers are more sus ceptible than others to the effect of lead. As must be repeatedly emphasized, it is not sufficient to consider this question alone, but as with every consideration of the bio- the level of the exposure logical effects of lead/must always be considered. It might be that differences in susceptibility would be shown under conditions of severe lead exposure that would not be found at lead levels commonly found in the general population while it is also possible that some persons would be found to be unusually susceptible even at "normal" levels of lead exposure. On balance the evidence available at this time would favor the former rather than the latter situation. There are two main groups that have been the subject of concern, controversy and legislation with regard to their exposure to lead. These groups are women and children and the controversy over whether or not they are more susceptible than adult men to lead poi soning contains many.of the same problems that were touched DUP050055988 Chap. 5 F Page 21 on in discussing the relationship of lead to kidney disease. One. additional factor in the case of women and children that makes resolution of the controversy difficult is the banning of both groups from the lead trades in most western countries for the past 50- 70 years* Thus,, the only occupational data comes down to us from a time when severe and prolonged expo sure to lead was common and the criterion of a lead effect was clinical lead poisoning. Oliversaid in 1902, "So far as occupational exposure to lead is concerned, my opinion is' (1) that women are more susceptible than man; (2) that while female liability is greatest between the ages of 18 and 23 years, that of men is later; and (3) that while females rapidly break down in health under the influence of lead, men can work a longer time in the factory without suffering, their resistance apparently being greater.11 On the other hand, the Germans at this same period felt that the apparent suscepti bility of women to lead poisoning is explained not by their sex, but by the fact that they are usually more poverty- stricken than the men, are undernourished, and obliged to do work for their families in addition to their factory work. Then, also, a women's skirt and hair collect the lead dust so that she carries it home with her after work. Support for this view is presented by Hamiltonfor the U. S. battery industry around the beginning of the century. In those areas where there were strong unions to which the men belonged, the men enjoyed good pay and living conditions while the nonunionized women were underpaid, poorly housed, poorly fed and subject to the worry and strain of supporting depend ents on low wages. Under these conditions.a much larger pro DUP050055989 Chap. 5 F Page 22 portion of women than of men were found suffering from lead poisoning while in the nonunionized pottery fields where both men and women were both making low wages and economic conditions were poor.for both men and women, the' rate of lead poisoning was slightly greater among men.. Information supporting the greater susceptibility of women to lead is given by Lane quoting a British departmental committee report on the dangers attendant on the use of lead in the manufacture of eafthenware and china. This report makes it possible to compare the incidence of lead poisoning in men and women engaged on the same work - ware cleaners, dippers and dipping assistants. The female incidence rate was shown to be from two to three times that of the male. . Of course ft f'rP factors such as work habits, labor turnover,^general health might influence these statistics but the committee making the report was sufficiently impressed with the data before them to express their belief that women are more susceptible to lead poisoning than men* While the statistics available on the relative sus ceptibility of men and women leave much to be desired, there is even less information 'on whether lead poisoning shows a significantly different* clinical picture in men when compared with women. In one of the few such comparisons undertaken there is a suggestion that there may be such a difference. Prendergast found the following'incidence rates for DUP050055990 Chap. 5 F Page 23 various expressions of lead poisoning among 640 eases of plumb!sm in the Staffordshire potteries. 4 Colic Paralysis Convulsions Blindness (total) Blindnes s (partial) Men 77-6 57.0 15.0 2.3 3.5 Worn* 69.8 30.0 34.9 7.7 10.2 Prom this* admittedly sketchy data there is a suggestion that when there has been a sufficient exposure to lead to - cause clinical poisoning women are more likely to show cen tral nervous system manifestations and men, peripheral nervous system involvement. This latter finding might be related to the fact that men are more likely to be engaged in heavy work and the amount and type of physical effort has been thought to affect the incidence and location of the muscular paralysis. . Hi discussing the possibility of women being more sensitive than men to the same dose of lead, there are related topics which it is also necessary to consider. These are the of lead effect/on fertility, gestation and neonatal health. In the study of the earthenware and china workers previously referred to the committee found that the incidence of miscarriage per hundred mothers was almost th^ee times as DUP050055991 Chap. 5 F Page 24 great among those who continued on lead work after their marriage compared with women not occupationally exposed to lead. In a review of the effect of lead on reproductive capacity Lund^$0 concludes from studies conducted prior to 1920 that "even when the mortality of that time is taken into account, the number of "productive" pregnancies is abnormally small" (in mothers occupationally exposed to lead). The earlier writers, Hamilton, Oliver, Legge, Cantarow and Trumper are unanimous in their view that lead in high con centrations affects the reproductive capacity of women and that having regard to the poor hygienic conditions in the lead trades at that time women should not work in these trades. As a result of these views, there was enactment of legislation in many countries barring women from occupations where they would be exposed to lead. Therefore, there is almost no data on the effect of the generally much lower concentrations of lead now prevailing in these industries upon reproductive capacity. The Wenatchee study&%) remains as the only evidence and in that study no effect on fertility was found. In summarizing their study of the fertility of men and women in the Wenatchee study the authors conclude "The instances reported in the literature of an effect of lead on human fertility appear to be limited to men and women who were far more heavily and much more regularly exposed to lead than the residents of Wenatchee. It would appear that a clinical state approaching that of'.frank lead poisoning DUP050055992 Chap, 5 F Page 25 is necessary before the fertility of men or women is affected." The other large .group of particular interest with regard to the possibility of specially sensitivity to lead is children and here again despite the voluminous literature on childhood lead poisoning, there is little data bearing directly on the problem. Since childhood lead poisoning is dealt with in detail elsewhere in this publication, this matter will not be discussed further beyond the following quotation from Chisholm. "The more frequent occurrence of encephalopathy in children as compared with adults may depend in part upon their more intense exposure rather than upon any inherent biologic differences between child and adult." The majority of the early writers on the health of'lead workers C have remarked on the individual variability shown by persons V. exposed to high levels of lead. Some men becoming intoxicated within a few weeks, whereas others can work for years in the same surroundings without apparent harm. Undoubtedly some of this variation in response was due to differences in working habits and even today similar variations can be found although now it is more likely to be confined to a difference in the amount of lead absorbed rather than to variations in overt toxicity. There is a good correlation between blood lead * .< .levels and air lead.,levels. - Vith relatively little variation from man to man when the ma.j or portion of the lead exposure is from the air but when the work involves jobs such '' . \ ft DUP050055993 Chap. 5 F Page 26 as hand pasting of battery plates'with a much greater chance of "local" lead contamination the variability of lead absorp tion between men increases as much as four-fold.- There fore, it is probable that at least some .of the apparent individual resistance to lead poisoning seen by the earlier writers reflects variations in working habits and therefore of lead absorption. There remains however a likelihood that persons respond differently to the same dose of lead, but whether this difference would be of any practical importance at the levels of lead exposure now found in the general popula tion seems unlikely* lyut merits further study. Such studies should first consider persons known to already have biochemical defects in systems of the body known to be affected by lead in adequate amounts. Examples of such defects would be sickle cell anemia, glucose-6-phosphate deficiency, the porphyrias and gout. . At the beginning of this section on the epidemiology of lead three main avenues for using epidemiological informa tion to throw light on the effects of single environmental agents were outlined. After devoting most of the available space to studies of occupationally exposed populations because in this type of study the factors under study are usually now easier to document consideration must/be given to the remaining ,(D two areas of study. Although/studying the tissue levels of lead in various diseases and/ioiking for a congruence between disease distribution and some measure of lead exposure are attractive concepts,, when the results are positive, the investigator is faced with a formidable task in dealing with DUP050055994 page 27 the question of - Did lead cause the disease under study? This problem of deciding whether two variables are merely associated or whether one bears a causal relationship to the other is dealt with by Sir Bradford Hill in his presi dential address to the section of occupational medicine of the Royal Society of Medicine.Among the aspects to be considered in deciding for or against a causal relation ship between the two variables. Professor Hill suggests: Strength of association, consistency, specificity, temporal relationship of the association, dose response curve, plausability from the biological standpoint, coherence with generally known facts, experimental evidence and judgement by analogy. Two diseases other than .classical lead poisoning have been studied for tissue levels of lead. These are renal disease in Queensland, Australia and multiple sclerosis in England. The Queensland study of bone lead levels in renal disease showed that in 866 autopsies there were 160 * cases of Bright's disease (chronic renal disease). If those aged 20 - 49 years of age at the time of their death are studied, 6.3 percent have no known cause for their renal disease and the remainder suffered from diseases recognized to involve the kidney. The bone lead levels of those persons with kidney disease of known causation were significantly lower than those having kidney disease of unknown causation, thus lending support to the belief (dealt with elsewhere in m this publication) that long-standing absorption of lead in sufficient quantity can cause chronic kidney disease. The source of the. lead in the Australian cases was childhood DUP050055995 ingestion of lead derived from exterior house paint. The authors of this study suggest that surveys of the lead content of tissues taken .from persons dying of kidney disease of unknown cause might be.useful in providing diagnostic clues at to the cause. This work derived from autopsy material has more recently been supported by ( A'a ) Emersonv ' who was able to show that in a group of Aus tralian patients with renal disease of undetermined origin, the mobilization of lead from'the bone by a standardized Infusion of Calcium EDTA gave evidence of a significant past exposure to high levels of lead in 12 out of 16 cases, thus suggesting that lead might have played a part in the causation of the renal disease. The other example of high tissue levels of lead being correlated with a particular disease in a population was that of Campbell who reported that teeth from patients with multiple sclerosis contained on the average significantly higher concentrations of lead than was present in the teeth of normal healthy people. This observation was followed up by Butler who observes that physiological changes accompanying chronic diseases may promote the deposition of metals in the skeleton as illustrated by the increased deposition of zinc in the teeth in tuberculosis. Butler then goes on to analyze the lead content of the urine, blood cerebrospinal fluid, and DUP050055996 Page 29 and bone in 31 cases of multiple sclerosis and in 5-4 cases of neurological disease other than multiple sclerosis. When the lead levels in the two series were compared one with the other and with commonly accepted normal values no significant differences were found. An examination of the lead levels in necropsy tissue including brain and spinal cord from patients in whom the diagnosis of multiple sclerosis was confirmed histologically did not show significantly elevated levels, Butler concludes that his study does not support the view that lead plays a part in the etiology of multiple 'sclerosis. The final epidemiological relationship to be explored is. that of the geographical distribution of a disease and the relationship of this distribution to some index of lead exposure. .- Two diseases have been looked at in this particular manner in their relationship to lead. The first is multiple sclerosis and the second is cancer, Warren has dram attention to the great variation in the incidence of multiple sclerosis in different geographical areas of Norway, Scotland, Sweden, England aid Canada while in some of those areas having a high incidence of the disease there are lead-bearing rocks . There are many reasons for not accepting this association to be a causal relationship at this time. The first is the difficulty of obtaining adequate' st0atistics on the true DUP050055997 Page 30 incidence of a disease whose prevalence is normally between 30 to 60 per 100,000 population and if deaths are the basis of the reporting, then death rates may vary from zero to 4 per 100,000. In the areas reported as having a high incidence such as the Orkney and Shetland Islands of Scotland with a total population of.around 36,000, the addition of a single case in a disease that is particularly difficult to diagnose with certainty can increase the overall prevalence rate by as much as 25 percent. Additional impediments to accepting a causal relationshipare the strong North-South gradient in prevalence rates,the lack of recognition of multiple sclerosis as a sequela to industrial lead exposure the failure to shoxy elevated lead levels in the brain, blood or urine of multiple sclerosis patients,('47 V1 and the evidence that multiple sclerosis is probably an auto-immune disease possibly related (48) to .an earlier viral infection.' Warren points out that if variations in cancer death rates are plotted on a geographic basis, striking differences appear in certain circumscribed areas. Allen-Price(51) ^ a BUrvey in Devon in England claims that there is a higher incidence of cancer in persons living on the highly mineralized Devonian geological formation than on the adjoining carboniferous and granite formations. Warren then goes on to state that in some cases rocks containing more than 1000 ppm lead can be correlated with some of the high cancer areas encountered by Alien-Price but this was not a uniform finding. Warren mentions two other examples of the same rather tenuous nature and suggests that further studies should be carried out. Apart from the difficulties mentioned earlier of obtaining reliable mortality statistics for small DUP050055998 UUM]/ I M Page 31 geographical areas the even larger problem of the reliability of the information upon which the cause of death is based is a well-recognized epidemiological problem. Although it is well recognized that lead at levels of one percent or more in the diet cause cancer of the kidney in rats, there is no evidence that this happens in other species including man. The study by Lane^1-^ referred to earlier among lead workers was undertaken to examine the incidence of cancer and no increase in cancer incidence was found. Although many.human diseases have been alleged to have been caused by lead. 'Cancer is one disease that even in the days of heavy *` & * and prolonged exposure sufficient to cause renal -disease was not thought by clinicians to be linked to the causation of cancer. As Hammond says, "It is comforting to see'evidence suggesting that something is not the cause of cancer*" (insert'from page 3) The epidemiological evidence that lead can cause cancer in man is mentioned more because of the seriousness of the disease than because of the strength of the evidence. G. J. 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"A study of the effect of lead arsenate exposure on orchardists and consumers of sprayed fruit," Public Health/Bulletin No. 267, 1941 .< Service DUP050056001 References (Cont'd.) 3 Stopps - Chap. 5 Page 34 23* Fairhall, L.T., and Miller, <T.W. . "The relative toxicity of the molecular components of lead arsenate." U.S. Public Health Reports 56, 1610-25, 1941. 24. Britten, R.H. and Thompson, L.R. "A health study' of ten thousand male industrial workers." Statistical analysis of surveys in ten industries," Public Health Bulletin No. 162, Washington Govt. Printing Office^1926. ` 25* Aub, J.C., Fairhall, L.T., Minot, A.S.. and Rejjnikoff, P. Lead Poisoning,yThe Williams & Wilkins Co., Baltimore* 1926. Medicine Monographs Yol. VII. __________ _ ... 26. Cantarow, A. and Trumper, M. Lead Poisoning, The Williams ' & Wilkins Co., Baltimore, 1944. 27. Dingwal 1 -Fordyce. I. and Lane, R.E. "A follow-up study of lead workers, Brit. J. Industr. Med. 20, 313, 1963 2.8. Oliver, T. 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Weyl'.s Handbuch derHygiene 8, 88, I897 Quoted in Women in the Lead Industries, Hamilton,* A. ,t Washington, d ?S?A 1919* kabor,/Bureau Bulletin of of Labor Statistics, the U.S. No. 253, 37. Hamilton, A. "Lead poisoning in potteries tile workers and porcelain enameled sanitary ware factories," U.S. Bureau of Labor Statistics, Bull. No. 104, pp.56-58. 38. Prendergast, W. D, "The classification of the symptoms of lead poisoning,'' ., Brit. Med. J. 1, 1164, 1910. ' 39* Lund, C. "The effect of chronic lead poisoning on repro ductive capacity," Norilsk Hygienisk Tidskrift 18, 12-20, 1936. ^ 4o; Chisholm, J.J.Jr. and Harrison. H.E. "Exposure of children to lead, Pediatrics 18, 943-957, 1956. . ... 41. Hill, A.B. "The environment and disease: association t or causation?" Proc. Royal See. Med. 58, 295-299, 1965. 42. Henderson, D.A. and Tnglis, J.A. "The lead content of bone - in chronic Bright1s disease," Australasian' Annals of Medicine 6, 145-154, 1957- 43. Emmerson, B.T. "Chronic lead nephropathy," AustralAsian Annals of Medicine 12, 310-324, 1963. "L'aspect clinique de 1.'intoxication saturnine professionnelle," 44. Baader, E.W. /Marco Medical 37, 409-4l5, 1958. 45. Vigliani, E. "Recenti studi sul satumismo in Italia," Med. de/. Lavoro 4l, 105-112, 1950, 46. Cambell, A.M.G., Herdan, G., Tattow, W.F.T. and Whittle, E.G., Brain 73, 52-71, 1950. 47. Butler, E.J. "Chronic neurological disease as a possible form of lead poisoning," Neurol. Neurosurg. Psychiat. 15, 119, 1952, ; 48. j 49. Warren, H. V. "Trace elements and epidemiology," J. College of General Practitioners 6, 517, 1963* Kurland, L. T, "Geographical and Climatic aspects of multiple sclerosis," Am. J. Pub. Health and The Nation's Health 54, 588-597, 1964. 50. Sibley, W.A. and Foley, J.M. "Infection and Immunization in multiple sclerosis," Ann. N.Y. Acad. Sciences 122, 457r468, 1965* DUP050056003 References (Cont'd.) $ Stopps - Chap. 5 Page 36 51* Alien-Price. E.D. "Uneven distribution of cancer in West Devon/' Lancet l, 1235-1238, i960. 52. Hammond, P. B. "Lead poisoning, an old problem with a nev? dimension," Essays in Toxicology, edited by . F. R. Blood, Academic Press' '1969 . 53 Aring,,C. D. and Trufaut, S.A. "Effects of heavy metals on the central nervous system," Metabolic and Toxic Diseases of the Nervous System. Proceedings of the Association for Research in Nervous and Mental Disease, Research Publications 32, Editor H. Houston Merrittand Clarena C. Hare, The Williams & Wilkins.Co., Baltimore, 1953. i\ i \ :> DUP050056004