Document jykYK19OoeqM9wRj0QZr67em5

THE HARDEN LECTURES, 11960 THE METABOLISM OF LEAD IN MAN IN HEALTH AND DISEASE by ROBERT A. KEHOE, M.D. (From the Kettering Laboratory in the Department of Preventive Medicine and Industrial Health, College of Medicine, University of Cincinnati, Cincinnati, Ohio, U.S.A.) LECTURE III PRESENT HYGIENIC PROBLEMS RELATING TO THE ABSORPTION OF LEAD In the Chair: J. C. AINSWORTH-DAVIS, M.A., M.D., F.R.C.S. {Chairman of the Executive Committee of the Council) The natural environment of this planet is of 1 and 3 years with distressing frequency such that the occurrence of lead in the and regularity, in many North American tissues, body fluids and excreta of its human cities. inhabitants is inevitable. On the other From the broader aspect of the public hand, tlye artifacts introduced into the en- health, the contamination of the atmosvironment by the past and current activities phere with lead from a number of sources of mankind have provided numerous unan- . may increase under the influences of ticipated and often unrecognized opportu- modern technolog)', especially in industrial nities for human absorption of a- wide and urban centres, and therefore,, this variety of lead compounds. Most of these potential source of public exposure to lead contributions to the alimentary or respira- requires periodic investigation. More tory intake of lead are small, but sometimes importantly, the opportunities afforded for single or multiple factors produce danger- the contamination of food with lead, in a ous conditions. This occurs most frequently country in which the processing of food in connection with the occupations of materials is a complex industry of very individuals and groups. In the United large and widespread proportions, must be States of America, for example, occupa- kept under constant surveillance. The tional lead poisoning, although reduced in variety and volume of the beverages conseverity now, in comparison with .earlier sumed by the public must also be considerperiods, occurs more frequently, according ed in this relationship, and not even the to somewhat untrustworthy statistics, than drinking water of a nation can be ignored, any other occupational disease. The large despite the comparative ease with which proportion of cases of lead poisoning are the lead content of urban water supplies occupational in origin, but cases occur from can be controlled. The general exposure time to time in the adult population as the of the population to lead from these result of a variety of conditions in the combined sources must be kept within household. Moreover, permanently dis- apnropriate limits, and, therefore, no standabling and fatal cases of lead intoxication ard promulgated for the safety of the occur among children between the ages public, with respect to the concentration 55 of lead in individual items of food or beverages, or in the air, has independent validity. Of the many medical and hygienic prob lems that arise out of the matters mentioned above, as well as those which stem from other sources, four have been singled out for consideration on the background of the facts concerning the metabolism of lead, which have been the burden of the two preceding lectures. 1. THE DIAGNOSIS OF LEAD INTOXICATION. Lead poisoning, in a variety of forms, has been known to physicians for centuries, and like many another matter that is " common knowledge ", there have been many false ideas and many more hazy concepts of its nature and significance. This is neither the time nor the place to deal with the manifold facets of this situa tion, which has been further obscured and complicated by the socio-economic and legalistic aspects of workmen's compensa tion laws and procedures. Suffice it here to consider the contributions to the clarifi cation of these problems which derive from the establishment of sound physiological criteria by which the magnitude and significance of the absorption of lead by an individual patient can be appraised, not by hearsay, nor by the generally inade quate and quantitatively unreliable history of the patient's exposure to lead as re counted by himself, nor even by the appraisal of his environment, but by the determination of the lead content of his urine and blood, or that of his tissues (post-mortem). Systematic analyses of the lead in the atmosphere of industrial establishments over sufficient periods of time, in concert with clinical examinations and determina tions of the lead in the urine and blood of the populations at risk in lead-using indus tries, have yielded data which have reveal ed the relationships which exist (a) between exposure to lead and absorption of lead, and (b) between the absorption of lead and the incidence (and to a lesser extent, the severity) of lead poisoning. The extent of the absorption of lead by men in industry is clearly related to the severity and the duration of their occupational exposure to lead. Under the somewhat variable con ditions which exist in a specific industry or series of industries, this relationship, to be sure, is not as well defined, quanti tatively, as it has been shown to be in our well-controlled experiments in the labora tory. On the other hand, the greater range of severity in industrial exposure to lead generally, as compared with the modest range which is compatible with the com plete safety of experimental subjects in the laboratory, has yielded unmistakable evi dence of a correlation between exposure and absorption. This fact is illustrated in Tables 25 and 26, from the aspect of the absorption of lead, by the data obtained in the investigation of five industrial popu lations (selected more or less at random from many other corresponding series of data which cover the desired range of find ings without unnecessary replication). The environmental conditions under which these groups of men worked were such as clearly to differentiate them, in increasing order of severity from left: to right in Tables 25 and 26, on the basis both of periodic inspections, and analyses of the air at the breathing zone of the workmen. The gradation of the absorption of lead among the groups, as indicated by the ranges and the distribution of the frequencies of occurrence of various levels of the concen tration of lead in the urine (Table 25), requires little comment, despite the over lapping of the findings in the higher rubrics in the four columns to the right. The mean values show the order of severity' satisfac torily, except for the fact that the exposure associated with one of the occupations of the group listed under the sub-heading " Slight and Severe " was considerably greater and more difficult to control than that of the others. As we shall see later, certain individuals in this group (those em ployed in the job referred to above) were in danger, while the majority of the group was not. This situation exists in many in dustries. In the absence of quantitative measurements of the severity of the exposure associated with specific jobs or areas within an industrial plant, it has often produced unexpected cases of poisoning and has contributed greatly to the un warranted belief that the "susceptibility" 56 O A rn ~7 U / J on- TABLE 25 itry . to Comparison of VTarious Occupational Groups with Respect to the Concentration nti- of Lead in Their Urine, in Association with Varying Degrees of Severity of our Exposure to Lead Below and Above the Threshold of Danger. )ra- nge Lead in Urine | Frequencies in Ascending Order of Severity of Exposure to Lead--Left to Right sad ; | lest ;j Near Threshold j imthe mg. per litre | Slight and .---------------------- ,---------------------- , Very Severe Demonstrable ! Severe '> Safe Unsafe Very Dangerous i\*i- 0-00 -- 0-039 41 i 35 j _ 32 ure ; in 0-04 -- 0-079 0-08 -- 0-119 0-12-- 0-159 150 ! 9S : 11 7 2 9 56 \ 22 10 13 35 16 14 14 the 0-16 -- 0-199 27 ! 7 11 9 \ed puom 0-20 -- 0-239 0-24 -- 0-279 0-28 -- 0-319 0-32 -- and over --- I ---- j --- j --j 8 7i 2 2 4 3 j J 3 --- 39 46 3 o 5 19 of ndThe ich Total Number ... Mean ... S.D..................... 200 0-051* 0-014 i 273 0-102* 1 4-0-069 ; 63 : 0-130* | 4-0-059 57 0-152* 0-024 79 0-238 -0-151 as ing Calculated from a different arrangement of the frequencies. )les die the "he TABLE 26 mg ind Comparison of Various Occupational Groups with Respect to the Concentration of of Lead in Their Blood, in Association with Varying Degrees of Severity of en- Exposure to Lead Below and Above the (Thresholci of Danger. 25), / er- Lead in Blood Frequencies in Ascending Order of Severity of Exposure to Lead --Left to Right *ics an ac- mg. per 100 g. Demonstrable Slight and Severe Near Threshold Safe Unsafe Very Severe Very Dangerous ire of 0-00 to 0-019 __ --- ' _ 0-02 -- 0-039 ii So 4 1 ---- 0-04 -- 0-059 0-06 -- 0-079 24 122 1 50 30 18 oo 21 9' 12 ;an 0-08 -- 0-099 -- 7 5 6 17 er, m?re up inve 0-10 -- 0-119 0-12 -- 0-139 0-14 -- 0-159 0-16 -- 0-179 0-18 -- 0-199 0-20 -- 0-219 0-22 and over -- 616 _2-- -- -- -- -- 1 _ ____ -- ___ _ _ _ -. ---- -- 1 14 5 4 1- 1 2 10 he Total Number ... 36 272 62 54 75 or en Mean S.D................................. 0-042* 0-008 0-050 0-019 0-060 0-016 0`075 0-041 0-130* ` 0-091 g ;n- * Calculated from a different arrangement of the frequencies. V" of individuals to lead poisoning is highly variable. We shall return to Table 25 later, in con sidering the relationship between severity of exposure and degree of hazard. Table 26 deals with the analytical findings in the blood of the same individuals and groups (the groups are the same, but certain dis crepancies in the frequency of sampling are apparent) represented in Table 25. In keeping with the lesser degree of physio logical variability of the concentration of lead in the blood, versus that in the urine, as noted in experimental subjects, as well as with the relatively slighter dependence of the concentration of lead in the blood upon the daily or immediate rate of absorp tion of lead, the results in Table 26 are more indicative of the true status of these men, with respect to the extent of their body burden of lead at the time of samp ling, than are those in Table 25. The dis tribution of the results within and among the industrial groups is, therefore, more clearly indicative of the relative status of the individuals and groups. Here, there is no doubt as to the gradation of absorption from left to'right, except in the " Slight and Severe " group, in which certain individuals in [one occupation differ significantly from the main group. (The lack of a bi-modal distribution of the results is due to the small number of persons in this divergent sub group.) ' Alike, in Tables 25 and 26, the sub headings indicate the point at which safe levels of absorption are differentiated from those which are dangerous. The basis for this differentiation is the purely practical criterion of the non-occurrence or the occurrence of cases of lead poisoning within these populations. As the environmental conditions in the industrial plants in which these men were employed were appraised from time to time over periods of years, and as the employees were investigated periodically by clinical and analytical means, a definitive correlation between the levels of lead concentration in the urine and blood, and the non-occurrence or occurrence of lead intoxication, was estab lished. The data listed in these tables, as indicated, are recent examples of the sharp ness of the analytical criteria that may now be applied. Experience and the accumula tion of voluminous data have spoken for themselves, in proclaiming that cases of lead poisoning occur only when certain limits of concentration of lead in the urine or blood (or in both) have been exceeded. The critical concentration of lead in the blood of child or adult, below which, in our experience (during the period of ex posure, not weeks or months later), no case of even the mildest type of poisoning has been induced by the absorption of in organic compounds of lead*, is approxi mately 0.08 mg. (80 miicrograms) per 100 grams of whole blood. Due allowance must be made for an analytical error which rarely exceeds 0.01 mg. (10 micrograms) on either the positive or negative side, within the range of concentration of 0.01 to 0.10 mg. per 100 grams (somewhat greater in the higher range), as calculated from the results obtained by the analyses of 10 grams of whole blood. The qualifications, with respect to the known precision of the preparatory and analytical methods, are essential, since the methods and the facili ties used by highly competent analysts vary in the type and quality of the equip ment, reagents and manipulative pro cedures, to such an extent that the magnitude of the deviation, although it may be uniform within a specific labora tory, varies from laboratory to laboratory, almost without exception. Aside from carefully controlled procedures for the preparation of samples, two methods of analysis, one essentially chemical and colorimetric, the otherphvsieal and densitometric, have been employed in parallel in these investigations, and are applied, as a rule, to duplicate samples of blood, in order by their combined qualities to pro mote precision, sensitivity and specificity, and also to detect the fortuitous contam ination of a sample which occurs from time to time, inevitably. Parallel analyses are not readily applicable to the urine because of the difficulty of obtaining duplicate soecimens as tbe urine is being voided. The division of a specimen after single or * It teems wise to remind physicians and analysts thtt the determination of lead in the blood in an attempt to appraise the degree of absorption or tetraethyl lead, and. in all probability, other lead alkyls, is futile. Because of the metabolic behaviour of these compounds in the body, the concentration of lead in the blood bears little or no relationship to their absorption and distribution in the tissues. k# gr? n / >j mla: for s of .-tain irine ded. the i3 in ex case has inroxi- 100 ance hich 0 on ithin 0.10 1 the the ' 10 ions, , the are iciliiysts :uippro- the h it jora:ory, . rom the s of and sito-I in as a * in pro- city,.am. ;ime are lose cate ded. e or that pt tn and. esc of body. ->r no multiple voidings is fraught with gross possibilities for error, since, after even slight cooling, the sample, following the precipitation of the phosphates, is no longer homogeneous. The factor of physiological variability, however, renders imperative the analysis of multiple samples of the urine of an individual. The concentration of lead in the urine, or the output of lead in the urine per unit of time (on the part of individuals without renal damage or impairment of function) which corresponds to the threshold level in the blood, is a range rather than a single value, because of physiological factors (other than the rate of absorption or the body burden of lead) which result in a considerable %'ariability in the rate of the urinary excretion of lead. The value in the individual case may be as low as 0.15 mg. per litre and as high as 0.24 mg. per litre, dependent upon the num ber and volume of the urinary samples which have yielded an average result, and also upon the climatic conditions (prevail ing temperature) under which the samples were obtained. The objective of the in vestigation of the urine by analytical means is the determination of the current rate of the urinary excretion of lead. Attention has been directed repeatedly toward this matter in these discussions. Further em phasis on it is justified, however, for despite the absurdity of the performance, a single result obtained from a sample of urine,_collected without special precautions and analysed by a nondescript method, is often advanced as definitive diagnostic evi dence in case reports and in medico-legal reports and testimony. Such results are likely to be grossly misleading and should be discarded in favour of purely clinical evidence until and unless they have been confirmed conclusively. Unfortunately, their status as numbers, fortified by the semblance of technical precision, catches the poorly disciplined or ill-informed mind, and acquires an authority that can hardly be matched by the superior but nonquantitative judgment of the most com petent and experienced clinician. The significance of the data in Tables 25 and 26 goes beyond their diagnostic relevance, as we shall see later. They are presented in this relationship, however, for the sole purpose of defining the ranges of the concentration of lead in the blood, and urine which are associated with the occur rence of lead intoxication. No such range, in either instance, is indicative of the existence of intoxication. There is, how ever, a critical level of concentration of lead in the human body, at or above which, under suitable conditions, individuals may develop intoxication. Such a situation, as revealed by the excretion of lead in the urine, or as shown more precisely by the concentration of lead in the blood, when accompanied by symptoms and signs com patible with the known effects of lead, as revealed by clinical investigation of a patient, provides a sound basis for the diagnosis of lead intoxication. The actual existence of intoxication, however, is estab lished on clinical grounds alone, for there are no analytical findings which, of them selves, are indicative of illness. They merely denote the conditions in the back ground, without which the diagnosis of lead poisoning cannot be made or substantiated. It is difficult to establish this concept in the minds of physicians and laymen who are unduly impressed by the historic toxicity of lead compounds. The facts, however, are as crystal clear as present physiological knowledge and skill in clinical observation can make them. Lead occurs naturally in the human body; within cer tain limits of concentration therein, whether useful or not, it is harmless; above a welldefined, critical concentration it is capable of causing lead poisoning; the higher the concentration above the critical point, the more likely it is to cause poisoning in the individual person (higher incidence in groups); even the highest concentration yet found does not, of necessity, cause intoxi cation. or so it seems, and, therefore, there must be some conditioning, biochemical factor (release of lead ions from chemical bonds?) which initiates a toxic effect. It is obvious that further clinical and physiollogical investigation may identify toxic effects which are not now recognizable. A phenomenon which mav well belong in this category--one, which, in fact, we tend to regard as the first sign of lead intoxica- ry n f, -"X *7 Uh Z / tion, is the alteration wherein certain porphyrins, principally coproporphyrin III, occur in the urine in concentrations well above the normal range. This abnormality, as is well known, is not induced by lead alone, but when other causes can be ex cluded, it seems reasonable to regard it as an early sign of lead intoxication, in the absence of other clinical evidence of illness. The acceptance of this view does not alter the threshold values which are set forth in Tables 25 and 26, for abnormal concentra tions of porphyrins have not been found in the urine of men in the safe categories of occupational exposure to lead as defined therein. In practice, in the clinical investigation of alleged or suspected cases of lead poison ing, it is desirable and feasible to secure analytical data on both the urine and blood of the patient. If the interval of time be tween the examination of the patient and the termination of highly abnormal exposure to lead, whether occupational or non-occupational in origin, has been suffi cient to diminish the concentrations in the urine and blood below threshold levels, the analytical results will have little value. (It may be possible, in some instances, to fit the analytical findings into points on a curve which represents the diminishing rate of excretion of lead in the urine, and the corresponding decrease in the concentra tion of lead in the blood, with lapse of time after the termination of abnormal absorp tion, and so to determine the probable status of the individual in this regard at the termination of his exposure. However, this procedure will often involve fruitless speculations.) In such cases, only clinical judgment can yield a tenable diagnosis. When the physician in industry is presented with a diagnostic problem at the onset of the illness of regular workmen, the analy tical findings in the urine and blood at that time make their maximum contribution, on the background of results obtained pre viously at intervals on the same individual. Atypical symptoms or clinical signs lose their potential significance as " unusual " manifestations of lead intoxication, when considered in relation to insignificant ex posure as defined by analytical data, while plausible but non-specific symptoms or signs find a secure basis in concentrations of lead in urine and blood which denote harzardous absorption of lead. Bizarre clinical patterns of illness, in concurrence with dangerous levels of lead absorption, continue to pose diagnostic difficulties and medico-legal controversies, but it is per tinent commentary on the " protean " manifestations of lead intoxication, that they have come to be fewer in number and much more comprehensible, as exposure to lead and the resultant absorption have been given quantitative significance. This sim plification and clarification of the clinical pattern of lead poisoning is partially due, in all likelihood, to the fact that some of the more serious effects of this disease are sel dom seen in American industry. On the other hand, analytical evidence which is capable of demonstrating the probable in significance of the absorption of lead as a factor in an illness of obscure etiology, has had a salutary effect in divesting specula tive diagnoses' of their capacity to become presumptive and then definitive, through authoritarian medical and legal pronounce ments. It is obvious that one cannot, with out self-deceit or lack of perspicacity, employ the clinical syndrome , of lead poisoning as a criterion for defining the level or range of lead concentration in the blood which is required for the induction of illness, and then, simultaneously, use this range as the criterion for defining the clinical pattern of the disease. On the other hand, sound investigative procedure often calls for this very device, when, one after another, individual variables in such an association can be held constant while the manifestations of the others are being observed. Through such a device, proba bility increases to a point which approaches certainty. During the past twenty-odd years since the present methods of analysis came into use, thousands of observations have been made, and the correlation be tween analytical results and the clinical features of plumbism has been put on an unassailable basis. 60 <1 n '! rs Z / ry / ex- TABLE 27 hile or The Concentration of Lead in the Tissues of Children Fatally Poisoned by Lead, ions or Suspected of Having Been So Poisoned."0 lote urre Milligrams of Lead per 100 Grams of Fresh, Unfixed Tissue 'nee ion, Tissue ] Case Identification and Per th at and e to een Brain ... Liver ... Kidney Flat Bone Long Bone Blood ... A. j. 0-29 3-27 0-61 10-65 -- -- 1 S.j. I 0-58 1 4-00 1 0-88 i 26-80 ! 13-15 j D.S. 0-24 3-91 -- 17-00 -- v.w. 0-42 4-40 2-59 17-90 -- ~~ L.D. 0-50 2-96 1-74 -- -- " C.B. 0-09*** 1-80 1-10 9-80 5-60 0-46* D.E.M. 0-14**** 8-00 5-5 8-0 -- ;im- Obtained during life. .ical Illustrative data from case material so selected as to exclude results that , in may have been influenced by chelation therapy. the Not characteristic of encephalopathic plumbism. sel- ooeo Poliomyelitis. the i is The problem of post-mortem diagnosis is time over which such absorption occurred, in presented not infrequently, in connection whereas the concentration of lead in a soft is a with a belated or neglected history of tissue, such as the liver, reflects the sum has exposure to lead, when the cause of death, mation of the effect of the stream of lead ula- especially in an infant, is left in doubt, in being absorbed currently (shortly before ime the absence of definitive pathologic pro death) from the environment, with that of ugh cesses or in the presence of a non-specific the stream flowing from the skeleton, into lce- form of encephalopathy. The analytical which relatively large amounts had been ith- j evidence at such a time may exclude lead absorbed previously. When the lead con itv, as an etiological factor in the fatal illness, tent of the skeleton is found to be high ead or it may demonstrate not that lead was and that in the soft tissues is relatively low, the the cause of death, but that lead had, been the time involved in the absorptive process the absorbed- to an extent compatible with such was relatively long, while the rate of rion a diagnosis if, in afterthought, the type and absorption shortly before death was rela use the course of the terminal illness of the child was such as to justify it. tively low. Attention is called to the fact that the concentration of lead in the flat the An illustrative series of results obtained bone, in these cases, is higher than that in ure by the analysis of tissues taken from the the long bone, this relationship being the one bodies of children, post-mortem, are given reverse of that which obtains in the normal uch in Table 27. In all but one of these cases, skeleton (cf. Table 15, Lecture I). hile the diagnosis of lead poisoning had been ing arrived at before death occurred, and the In one case, that of L.D. in Table 27, no ba analytical findings' had demonstrated data relative to the skeleton are available. bes clearly that each child had absorbed grossly This is an example of the usefuless of even idd abnormal quantities of lead within a period scanty data. It is always desirable to have vsis not too far removed from that of his ter information concerning the skeleton, but ons be- minal illness. In scanning these data, it is skeletal tissues are not always obtained by enlightening to compare the levels of the the pathologist in the absence of a toxico ical an concentration of lead in the skeleton with logical consultant. In this instance, the those in the soft tissues, and to reflect that high concentrations of lead in the liver and the deposition of lead in the skeleton is the kidney are sufficient proof of a potentially product of the rate of absorption and the dangerous degree of absorption of lead, & U C\ A r-i p, U HZ/O while that in the brain is quite high, only currently, but the symptomatology cannot, one in the series being higher. be attributed solely to the effects of lead. The coincidence of the relatively high concentrations of lead in the brain, in five of the seven cases illustrated in Table 27, with the common encephalopathic charac ter of the clinical pattern of lead poisoning The use in Table 27 of data derived ex clusively from cases of lead poisoning in childhood should not be construed to indicate that the diagnostic significance of analytical results differs in any respect in in children, is not, it seems, fortuitous. It fatal cases of lead poisoning among adults. had been our experience, until the recent As it happens, however, fatal cases of lead appearance of the two exceptions recorded poisoning are seen but rarely among adults, in Table 27, that the concentration of lead and the facts could be illustrated much in the brain, in encephalopathy due to lead, more satisfactorily by the more numerous was always equivalent to, and usually cases that occur among children. These greater than, 0.20 mg. per 100 grams of data serve, moreover, to introduce the sub fresh brain tissue (there is a moderate ject of lead poisoning in early childhood, degree of variability in the concentration and to call attention to the frequently tragic in different areas of the brain). In case outcome of such cases. C. B. the finding of 0.09 mg. per 100 grams of brain was a surprise, for this represents 2. LEAD POISONING AMONG CHILDREN only twice the mean normal concentration and is barely beyond the normal range. This child, in life, was convulsing and otherwise dangerously ill, when first seen, and the concentration of 0.46 mg. per 100 grams of whole blood was indicative of a rapid and highly dangerous rate of absorp tion of lead. The relatively low concen trations of lead ranging from 0.20 to 0.60 tissue are evidence of the relative brevity of the child's severe exposure, and, there fore, it is reasonable to assume that the shortness of this period of absorption was responsible for the unusually low level of absorption into the brain. It is likely, we believe, that the symptoms were more intimately associated with circulatory dynamics than with the direct effects of lead in the brain. In any case, because of the frequency of the occurrence of concen trations of lead ranging from 0.20 to 0.60 mg. per 100 grams in the brains of children To those who are familiar with the his tory of lead poisoning among children in Queensland, Australia, in the first three decades of this century (1, 2), it may not be surprising that similar cases occur as the result of somewhat similar environ mental conditions in the United States. In Queensland, principally in Brisbane, large numbers of children were poisoned by the ingestion of lead in paint applied on the exterior surfaces of homes built of wood. The most commonly accessible painted sur faces were those of the side walls and rail ings of the verandas, from which, after the weathering which resulted rapidly in the tropical climate of this city, lead carbonate came off as a powder on the hands and fingers of small children who were con fined, for their greater physical safety, during their daily sojourn out of doors, on these verandas. that have died with encephalopathic In older sections of many North Ameri plumbism, we have come to consider this can cities, children of the same age group to be an important diagnostic criterion. In as those in Queensland (largely 1.5 to 3 one instance, that of the case designated as years), and characterized by some of the D. E.M., this criterion led us to suggest that same habits of eating, or putting fingers, the diagnosis of lead encephalopathy was thumbs and other objects in their mouths, in doubt, and that further investigation of ingest the crumbling and flaking paint from the case was indicated. A thorough exam surfaces that had been painted repeatedly ination of the brain resulted in the demon in earlier periods of better maintenance. stration of characteristic lesions of The interior paints of an earlier day con poliomyelitis. Certainly this child had tained much larger quantities of lead absorbed abnormal quantities of lead, and pigments than those which are marketed the two diseases may have developed con- and used at present, and this problem, 62 nu `.t4 o 7/ Qy therefore, while not entirely eliminated in variable numbers of that order of magni modern homes by changes in paint techno tude in the years since, culminating in 28 logy, is not increasing greatly in its scope cases in 1959, of which 6 were fatal. (Of with the further growth of cities. The 128 cases entered into the records of the circumstances of life conspire to make this Kettering Laboratory, mostly from Cincin a serious problem of public health, how nati, several from neighbouring cities, and ever, in that young children, in the poorer two from distant cities, in the period from areas or slums of our cities, live under un 1928 through 1955, there were 35 fatalities.) satisfactory conditions of housing, and in Sanitary inspectors in the Department of addition are likely to be left too much to Health of Cincinnati collaborated in the their own devices; some of them are un investigation of the homes from which wanted and unloved, while the mothers of these children had come, and an aroused others are compelled to leave them in the professional and official concern led to the care of children but little older than them enactment, in 1960, of local legislation, selves, while they (the mothers) engage in which, with appropriate official and legal employment outside the home. The action and the intelligent co-operation of children develop aberrant appetites, the manufacturers and distributors of interests and habit of eating (pica), and paints, can be expected to eliminate the tend to deviate psychologically in other large proportion of these cases in the not respects from those with more favourable too distant future among the children of social and physical environments. Cincinnati. The problem is widespread, however, within the country, as is attested In Cincinnati, in the period extending especially strikingly by the evidence ad from 1928 through 1949,. when interest in duced in Baltimore and New York. So long this subject, and the alertness of the house as present conditions, with respect to hous staffs of the two principal hospitals with ing and maintenance of the interiors of which we were associated, were relatively houses, persist in the poorer districts of undercultivated and somewhat intermit Cincinnati and other North American cities, tent, 45 cases- of lead poisoning among ' cases will continue to occur with tragic children, 12 of whom died, were brought to consequences. the attention of the Kettering Labt^atory. These were verified, with respect to the clinical significance of their absorption of lead, by analytical means, and confirmed by adequate clinical investigation in three local hospitals. They were also investi gated in a somewhat desultory manner, from the aspect of the social and environ mental conditions out of which they had arisen. Paint from toys, furniture, and the interior woodwork of houses, was impli cated as the source of lead in most of these cases; old storage battery casings, used for fuel, were responsible for several cases; toys of lead-containing alloys were involved in a few instances, one of which, in an infant, .was fatal; and a nipple shield made of lead was convicted in one case. A curious phenomenon, in connection with these cases, is their seasonal incidence. They occur sporadically, throughout the year, but, in the Eastern and North Central States, to the extent of the available records, almost all of the cases occur between the months of May and September in accord ance with an essentially Gaussian curve of frequencies. This fact Iras been responsi ble for much speculation concerning a seasonal factor (or factors), which may coincide with the presence of dangerous quantities of lead in the bodies of children, in the induction of.intoxication. There can be no doubt that the temperature (and humidity) of the summer months along or near the 39th parallel of the northern hemi sphere provides a significant factor of In 1950 and afterward, with an increasing stress, and the experiments of Baetjer (3)', ly intense and concerted diagnostic effort have demonstrated an effect of this factor, on the part of the staffs of two hospitals, the in association with lead poisoning. No recorded cases of lead poisoning among evidence has been found, however, of a pro children in Cincinnati increased in number. found disturbance in the metabolism of There were 12 in 1950, 18 in 1951 and lead in association with elevated ambient 63 rr . n A O r- H I- " + i. . u temperatures. On the contrary, it is clear that these children have been ingesting large quantities of lead up to the very day of the onset of their illness. Roentgenographic examination of the abdominal region of the sick child reveals, frequently, the presence of irregularly shaped, radio paque objects along the course of the ali mentary tract, and the feces, which often contain grossly demonstrable flakes of paint (sometimes painted splinters of wood) yield variable but large quantities of lead on analysis. By the latter means, the nature of the source of the ingested lead is often rendered apparent, and an investigation in the home, and an analysis of paint scraped from a tooth-marked wooden object--a win dow sill, the railing of a play-pen, the arm of a highchair, the orally accessible part of a toy--complete the record in this respect. It is not always so easy, however, for when no one has been caring for a child and observing its activities, there is no direct source of information, and often there is no physical clue to the source of the ingested lead. Under such circumstances a thorough search of the child's environment may call for numerous analyses, before the source of the absorbed lead shall have been disclosed. As a generalization, it may be said that no great mystery attaches to these cases. The exposure to lead, in immediate temporal relationship to their onset, has been readily demonstrable, and the extent of the absorption of lead has not been slight or dubious but of gross and obviously dangerous proportions. Two questions of major importance arise out of their occur rence.^ (a) What factor or factors operate to cause the absorption of lead by these children to reach a critical level in the summer months? (b) Why is it that ence phalopathy is so frequently the presenting form of lead poisoning in children up to four years of age? It is obvious of course, that the accumula tion of lead within the tissues of these children will usually have reached a dan gerous level some weeks or months before the onset of the convulsive seizure which so frequently is the alarming episode that brings the child to the hospital. Such an occurrence on a specific day, which, in terms of the quantity of lead in the body of the child, differed little from many a pre ceding day, had some exciting cause-- perhaps a fall, a blow on the head, an unusually hot day or succession of days, or some other added stress. The stage was set, and as is true of lead poisoning in the adult, some necessary ` trigger mechanism ' was all that was required to initiate a toxic response. Generally, however, the length of time involved in the period of abnormal absorption of lead is short in the case of the child, as compared to that of the adult whose exposure to lead is occupational in origin. It may be as brief as 30 days, or even less under unusual circumstances, al though it may continue, at a much lower rate of absorption, for six months or even a year. (We have seen two cases of lead poisoning in young adults, whose abnormal exposure to lead, by ingestion, was limited to 30 days, and we have also seen several children who continued, probably inter mittently, to absorb lead at rates which did not result in actually dangerous levels of accumulation in their bodies for periods of time somewhat shorter or longer than one year.) The usual brevity of the period of absorption, coupled with the unusually high rate of absorption which is common in childhood, means, however, that the child is especially vulnerable to the initia tion of the intoxication, for the danger of acute saturnism is the greater, the more rapid the absorption of lead, so long as the quantity absorbed is sufficient to raise the concentration of lead in the body to the necessary level. It means, also, in most instances, that the abnormal absorption began several months, at least, before the onset of illness. It is likely, therefore, that some feature in the lives of many of these children or in the character of their sur roundings, leads to a gross increase in their exposure to, and absorption of, lead during the first half of the year. An alternative explanation of the facts may lie in the fre quency with which some stimulus, asso ciated with the summer months, operates to bring about the onset of an intoxication for which the way had been prepared weeks or perhaps months previously. The frequency of the occurrence of encephalopathy in the child is an expres sion, we believe, of the rapid rate of the absorption of lead by these children. Saturnine encephalopathy, as we have ob served it occasionally in the adult who has been subjected to exposure to inorganic lead, may or may not occur in response to brief, as well as highly severe, exposure to lead, but it has not occurred except under the conditions of severe exposure. When such exposure has been brief, the adult patient with cerebral symptoms may recover promptly, even abruptly; when the exposure has been prolonged, and asso ciated with multiple episodes of minor severity, recovery is much less likely to follow promptly, and the outlook for even tual, complete recovery is relatively poor. In the case of the child, the facts with respect to the duration of the exposure are often in doubt, but the severity is always great, and, as the data in Table 27 have indicated, the quantity of lead absorbed by the children who die is large. Moreover, the concentration of lead in the brain, in encephalopathic plumbism, is greatly in creased over normal levels, and while this may, in a sense, be coincidental, the pro bability is high that it is an important factor in the character and the outcome of the disease. In view of the apparent similarity of the conditions of housing in the poorer districts of many cities in North America, and in consideration of the fact that the recorded incidence of lead poisoning among children varies greatly with the quality and accessi bility of the diagnostic facilities in these cities, or in any one of them in different periods, the conclusion is virtually unavoid able that the large proportion of such cases escape recognition. It is this fact which justifies this somewhat lengthy discussion, and points to the urgent need for special consideration of the requirements of differential diagnosis of lead poisoning in the small child. The strictly clinical aspects of this problem have been discussed fully in numerous publications, of which only two recent articles (4, 5) have been selected for citation because of their appraisals of certain recent methods of therapy. These and earlier articles demonstrate clearly that the careful application of non-specific clini cal methods will usually identify cases of lead poisoning in infants and children, and will differentiate them from other types of disease. The fact is, however, that the less serious forms of lead poisoning--colic for example--are rarely seen or recognized in the inarticulate and neglected child, and that it is the children with varying degrees of encephalopathic involvement, who are brought to the public clinic or to the pedia tric wards of the hospitals. Whether or not lead poisoning is regarded then and there to be a possibility, depends, to a very large extent, upon the clinical experience of the physician. Whether or not a definite diagnosis of lead poisoning is made promptly, and appropriate therapy initiated without delay, will depend, in no small measure, upon the availability of analytical facilities for the determination of the con centration of lead in the blood. Often, the differential diagnosis by other means can not be made promptly, and in some in stances, not at all, with certainty. Time after time, in our association with a completely competent and thoroughly indoctrinated pediatric staff, the prompt exclusion or conviction of lead as an etiological factor in a specific case has rested upon precise information as to the concentration of lead in the blood, ty is evident, therefore, that this analytical pro cedure, in and of itself; when properly carried out on satisfactory specimens of blood, is the most important clue to the existence of this disease in an infant or small child. Even more important, perhaps, is the fact that it is the best of all specific procedures for use in case-finding, or in the exploration of the effects of environmental conditions which pose the threat of lead poisoning to children. The emphasis on the determination of the concentration of lead in the blood for diagnostic purposes in the small child, in contradistinction to the application of this procedure to the urine, is entirely inten tional. It is not to be denied that satis factory results may be obtained in many instances by the analytical investigation of the urine. We relied upon it before we had gained sufficient experience with analy tical results on blood to be certain of their meaning. There are, however, altogether too many cases in which this cannot be done, and since lead poisoning is often a 65 fatal disease in the child, such exceptions should not be disregarded. It often hap pens that a satisfactory sample of urine cannot be obtained, or that obtaining such a sample is too difficult to be practicable, if there is a suitable alternative. The urine of a co-operative or even a semi-conscious male child can usually be obtained with out contamination, but this is not true in the case of the female child, for it is advisable to collect the urine from the patient in the container from which it is to be taken for analysis. Any intermediate container, and especially the use of a catheter, in-dwelling or otherwise, is a likely source of a contamination of a type and degree which is rarely appreciated or avoided by anyone who lacks quantitative chemical training or careful indoctrination and supervision. Urine voided by the female child is likely to undergo some degree of contact with the perineum, and if this occurs, the urine will usually have been contaminated appreciably and, some times, grossly. An even more serious diffi culty exists, however, in that the urine excreted by a very sick child may fail com pletely to contain lead in any significant relationship to the amounts available in the body. It is not unusual to find a low con centration of lead in the brine of a child that is very ill, at a time when the concen tration in the blood is very high. The corresponding situation in the adult is very rare--so rare, indeed, that it scarcely justi fies consideration in relation to diagnosis, although there are other reasons, as indicated previously, for obtaining addi tional information by the analysis of the blood. The nature of the presumed impair ment of the kidney that is responsible for this phenomenon has not been investigated, but it is reversible in many, if not most, instances, for, as the child recovers, the rate of the urinary excretion of lead mounts until it reaches its usual relationship (in terms of concentration or daily output) to that in the blood. Meanwhile, of course, the concentration in the blood will have diminished gradually, and the somewhat paradoxical relationship, for a time, will have been that of a progressively decreas ing concentration of lead in the blood in association with a progressively increasing concentration and output of lead in the urine. A further important fact, with reference to the blood, and one which is true also of the urine, with the exceptions noted above, is that the significance of the concentration of lead therein, in relation to the likelihood of the onset of intoxication, is no different in the child than in the adult. We have not seen a case of lead intoxication in an infant or child, at or within a few days of the time of the onset of illness, in whose blood the concentration of lead was lower than 0.08 mg. (80 micrograms) per 100 grams. The intoxication, once developed, tends to persist after the concentration of the lead in the blood has dropped well below the threshold level, but illness is not initiated at lower levels. This fact, added to the more frequent observation that ill ness is not always associated with high concentrations of lead in the blood, has misled some investigators into the belief that there is no relationship between illness and the qpncentration of lead in the blood. It is true that the discovery of significantly high concentrations of lead in the blood, is not, in itself, diagnostic of lead intoxication. On the other hand, there can be no doubt that there is a level of concentration in the blood, below which, lead poisoning does not occur in the child or in the adult. In the light of extensive experience this critical level is very little above or below 80 micrograms of lead per 100 grams of whole blood. The individual who has absorbed lead to that extent is in grave danger of developing lead intoxication, if and when the conditioning state or stimulus comes into being. 3. OCCUPATIONAL HYCIENE IN THE LEAD USING INDUSTRIES The danger, indicated in the preceding discussion, that intoxication by lead will occur, if the concentration of lead in the blood, or the rate of the excretion of lead in the urine, exceeds threshold levels as defined herein, constitutes one of the basic considerations in the prevention, by medi cal means, of occupational lead poisoning. The fact that such poisoning will not occur if these threshold levels are not reached or 66 w n * o O^ zO exceeded, provides the one additional feature of sound preventive medicine that is required to eliminate lead poisoning, as an occupational hazard, from even those industries in which serious obstacles are afforded to wholly and continuously suc cessful environmental control, or in which, from time to time, the hazard incurred by an individual workman or a small group of workmen may differ markedly from that associated with the usual operating condi tions. This is not to say that the fortuitous consequences of a highly unusual circum stance, such as a mechanical or human failure or other emergency, can always be avoided. It can be said, however, with full assurance based on many years of experi ence, that cases of lead poisoning, in con nection with all of the regular operations of a highly hazardous industry, can be eliminated utterly, through careful and per sistent application of this principle of preventive medicine. What is required is the will to do so, and the economic and administrative backing of managers who believe in the complete protection of their employees against the avoidable hazards of their work. There must also, of course, be a parallel and equally meticulous control of environmental conditions, as these are influenced by the processes and equipment employed in the operations, and by the associated procedures and equipment of environmental hygiene, together with satisfactory maintenance of all equipment, careful housekeeping, and attention to such supervision and indoctrination as may be ' required to insure against carelessness and disregard of instructions on the part of operating personnel. All of the appropriate armamentarium of industrial hygiene should be put to use for the control of the conditions of work, and for the protection of the workmen. The special virtue, how ever, of a medical regimen which includes determinations of lead in blood or urine (or both) and the interpretation of the results of such analyses, lies in its direct applicability to the individuals who com prise the industrial population, as well as to the specific groups of individuals who represent the several occupations in which the industrial population, as a whole, is engaged. A man can work in freedom from the risk of lead poisoning, so long as the concen tration of lead in his blood or the rate of the excretion of lead in his urine remains within the limits defined by the threshold values indicated above. If his work is potentially hazardous, as it may be, at times, under unusual circumstances or during operating stresses within the indus try, or if, under ordinary circumstances, his freedom from hazardous absorption of lead is difficult to maintain, he may approach or reach the threshold level. At such a time, he can be transferred to a job in which his exposure to lead is negligible or greatly reduced, and after a period of relative freedom from exposure, sufficient to lower the body burden of lead to the desired point, he may be returned to his former work. Such a man may be paired with another man whose work is substan tially free of hazard, and provision may be made thereby for a schedule of rotation which will insure the avoidance of signifi cant hazard by both men. Such procedures as those indicated above can be carried out satisfactorily, only if arrangements have been made in advance whereby all of the difficulties inherent in such an administrative and employment policy can be surmounted. Admittedly, certain industries are so constituted or organized that such arrangements are extremely difficult to effect; policies and agreements, with respect to wages, promo tions, grievances, seniority and similar features of labour relations, may operate as obstacles to such plans; or there may be no jobs which are sufficiently free of exposure to lead. Generally, however, the imple mentation of such a programme, developed in advance of casualties, and designed in the strictly professional terms of industrial hygiene, will be found to be acceptable to both employers and employees. If the circumstances are such that the regimen of medical supervision cannot be made to in clude the temporary removal of workmen from hazardous exposure, there remains but one alternative--the operations of the industry must then be so designed as to eliminate truly hazardous conditions, and so to avoid the necessity for such a pro cedure. This alternative may be the 67 _ (? i 0 4 2 3 4 method of choice in the large proportion of industries in which the hazards of exposure to lead may be controlled by conventional engineering methods at moderate cost, and it is recommended highly as the best and often the most economical manner of deal ing with the problem. There are, however, a number of extremely useful products, such as for example, electric storage bat teries, in the manufacture of which, large quantities of metallic lead and of lead com pounds are so handled as to become signifi cant sources of human exposure. Not all of the plants in which such batteries are made are of the best design, from the aspect of industrial hygiene, and not all of them are operated so as to achieve the best results obtainable by the application of appropriate methods of industrial hygiene. Even the best of them have certain hazar dous operations, and the maintenance of safe working conditions for the employees engaged in these operations requires intelli gently designed and constantly applied technical and medical measures of indus trial hygiene. It is in the medical super vision of such employees that a properly planned programme for the analysis of the blood and urine of employees can have its most effective and salutary application. Indeed, the question may properly be raised as to whether a wholly satisfactory regimen of medical supervision can be maintained in actually hazardous industries without resort to such a programme. Cer tainly the current status of industrial health in many of the plants engaged in the manu facture of electric storage batteries in the United States is evidence of the need for the consistent application of sounder, more specific, and more stringent standards, with respect to the permissible limits of the absorption of lead. It may be useful to view the present position of industrial hygiene, generally, in the lead-using industries of the United States, and to consider how this situation has come about. As stated previously, the more severe forms of occupational lead poisoning are encountered infrequently, but the frequency of occurrence of the less severe cases demonstrates clearly that occupational exposure to lead has not been controlled adequately. On the one hand, there are young industries in the more recently industrialized areas of the coun try, in which knowledge and experience are lacking, and there are old, well established industries, in which the ideas and practices of the past are entrenched; in neither of these has the science and art of industrial hygiene been developed. On the other hand, some industries have pioneered or shared in the development of measures both of environmental control and of medical supervision, and have eliminated lead poisoning from among their occupational hazards and liabilities. As examples of what to avoid and of what to strive for, these opposite extremes of the present situ ation are not unimportant, but the more general state of affairs is the more deserving of attention, especially from the aspect of preventive medicine. As one takes stock of this matter, the striking fact is that the role played by the physician has diminished greatly in importance, while that played by the engineer has enlarged. As a corollary to this, the principal techniques of indus trial hygiene in the lead-using industries in recent years have been those of analy tical chemistry and engineering, yand not those of medicine. The abdication of medicine has been nearly complete in many instances, having often reduced itself to the level of the nominal supervision of a laboratory technician who, at arbitrary intervals, examines a series of blood films for " stippling." and of making sober inter pretations of these non-specific, nonquantitative and often irrelevant findings, in lieu of the critical observations of en vironmental conditions and work-a-dav practices, and the periodic examinations of the personnel, that would give meaning to medical supervision. In consequence, conditions of work which fall short of adequacy are condoned, and some degree of impairment of the health and well-being of workmen is accepted as the natural consequence of employment in a dangerous occupation. Under such conditions, some workmen have occasional episodes of minor or incipient intoxication or continue in a state often referred to, ambiguously, as " lead absorption," which, apparently, while not being clinical " lead poisoning " is the nearest approximation that can be sustained by the individual without complaint or disability. From time to time, inevitably, these conditions give rise to frank cases of occupational lead poisoning among " un usually susceptible " persons who are often, if not usually, relatively new employees. This is the state of the science and art of industrial hygiene in the United States, in its medical aspects, that yields an unneces sary incidence of occupational lead poison ing. Clearly it is in need of an infusion of methods of preventive medicine that are in accord with physiologic and toxicologic facts. The medical procedures of an earlier day in the lead trades have been plagued by gross inadequacies based upon their non-specificity, on the one hand, and their lack of quantitative significance, on the other. They have made a poor showing, indeed, in comparison with the specific and quantitatively precise methods of the in dustrial hygiene engineer. Preventive medicine, in the strict sense of the word, was ineffectual in practice, prior to the development and application of specific and precise methods for determining the magnitude of the absorption and excretion of lead by exposed workmen. Instead, the control of the environment according to specifications was the method of choice, find despite the fact that the adequacy of the specification depended basically upon competent and persistent medical interpre tation of the hygienic status of the exposed personnel, the latter, being relatively un satisfactory and difficult of attainment, was characterized more by default than by its application in the specific instance. The principle of environmental control is, of course, basic in industrial'hygiene. As it was first expressed in relation to occu pational exposure to lead by Sir Thomas Legge (6) as the result of his clinical observations and the analytical work of his associate Duckering, it was' a profoundly significant contribution to the armamen tarium of industrial hygiene. It is a prin ciple, however, which is difficult to apply to many industrial operations, and even in its best application, it leaves something to be desired, in so far as the safety of certain individual workmen is concerned. More over, it has not been extended, by the conjoined efforts of the engineer and the physician, so as to apply broadly to the variety of the compounds of lead or to the various physical forms of these compounds dispersed in the air. It is, in fact, an approximate expression of good practice for the lead-using industries, which, when employed in co-ordination with a sound programme of medical supervision, can be expected to yield a satisfactory control of hazards due to lead. With the develop ment of sound methods for the interpreta tion of the status of the individual workman, the physician may now resume his former position of professional responsi bility, and find security and satisfaction in the precision and efficacy of technical pro cedures that lie within his own domain. Some objection has been raised to the technical difficulties and also the expense of establishing and maintaining a medical regimen which includes a programme for the sampling and analysis of the urine or. blood (or both urine and blood) of work men. The difficulties, while real, are far from insurmountable, being more formid able in anticipation than in their vanquishment. The laboratory in which such analyses are carried out must be specially designed, properly equipped, and capably manned; the containers for samples must be selected for the purpose and prepared with an eye to the avoidance of even the most minute contamination with lead; and the procedures for the collection of samples must be carried out by properly trained or carefully supervised persons. Even so, samples will be contaminated with lead occasionally. Attention to minute details, therefore, is mandatory; everyone con cerned must know what he is doing and why he is doing it, and the technique must be essentially faultless, for lead is everywhere in the environment, and unless it is excluded by satisfactory technical means, it finds its way into samples in the process of their collection and while they are being analysed. The minuteness of the quantities of lead which are to be determined, and the facilities and techniques required to collect satisfactory samples and to carry out such determinations with adequate pre cision, contribute to the cost of the entire activity, but they do not render it pro hibitively expensive, if reasonable judg- 69 n d or uT> ment is exercised in the economical employment of the analytical regimen. One may be inclined to ask how it is that a medical procedure which is so important to the safety of many men should be so carefully weighed in economic terms. What is a reasonable cost in such a situa tion? An acceptable answer would be, that if it is essential it must be borne, but that it should be used only to the extent of its essentiality. A further question is often raised in this relationship, to which atten tion is given here because it relates to the frequency with which workmen in the lead trades are to be examined in this or in any other manner, whether the periodicity is determined by official or legislative regu lation, or as a matter of policy or design within an industrial organization. Nothing is more frustrating to a wise and com petent industrial physician, or to a responsi ble and prudent management, than to find that the procedure in such a matter is dictated bv a statute or by an official authority, and that their own knowledge and judgment may not be exercised. It is hard to resist the impulse to condemn utterly, as senseless, the regulation of such matters by official or legislative fiat, for such regulation cannot create the know ledge and judgment without which, the task cannot be done; it can only hope or imply that these exist, on the one hand, or interfere with their application, on the other. The point is, that the periodicity of the application of any specific medical measure_of industrial hygiene, if it is to be effective, must be determined by the nature and the degree of the hazard that is being guarded against. With specific reference to the proper utilization of medical inform ation obtained by the analysis of the urine or blood for their content of lead, fre quently repeated observations are wholly unnecessary and wasteful of effort and money, unless the hazard of a specific man or group of men in a specific operation or area are such as to result in a rapid increase in' their absorntion of lead. In some indus tries in which lead or its compounds are employed, the environmental conditions, with respect to exposure to lead, are stable, uniform and well controlled, and the men are well-trained and indoctrinated in appropriate performance. In others some processes and areas are much more difficult to control than others. In still others, all or most of the processes are potentially hazardous, and uniformity of both human exposure and performance are difficult of attainment. Periodic medical surveys of the personnel, in co-ordination with careful observation of the conditions under which men work and of their manner of working, will disclose the degrees of hazard to which men are subjected, and will show clearly how the medical pro cedures must be scheduled so as to provide the necessary information at the proper time. It may be that the status of the workmen in a specific industrial establish ment can be determined by the analytical investigation of a representative group of employees once per year or even once in two years. Or it may be that every man in an occupational group will have to be sampled at intervals of one month, if the risk is large and unpredictable. Within these extremes of scheduling, a programme can be adapted to the requirements of safety within an industry. When so designed, it can be counted on to reveal the sites of hazard that require the application of more satisfactory measures of environ mental control, and to demonstrate faulty operations, faulty performance on the part of the men, or faulty maintenance of operating equipment or of housekeeping. Inasmuch as the extent of the analytical effort and of its cost will depend upon the severity of the hazard of lead absorption, it can be expected, automatically, to indicate the need for better environmental control, which, if achieved, will reduce the need for analytical information and lower its cost. It is not likely, however, after once having been instituted as a part of the medical regimen, of a lead-using indus try, that this regimen will ever be aban doned. The security of mind which is afforded to all who are involved in responsibility for the safety of workmen, and the satisfaction of the workmen with a regimen that protects them, are assets which are not lightly to be regarded. With respect to the attitude of the work men, it has been our experience that, once their natural resistance to inconvenience or 70 p. ^ o r, U * + zl u / to their initial dread of venipuncture have A second and alternate method of col been overcome, as these so easily are over lecting the urine, and one that has the come by the ministrations of doctor or tidvantage of being accomplished under nurse, they will offer vigorous resistance to the eye of the examiner, is that of obtaining any reduction in the established schedule a single voiding of somewhat more or less of sampling and analysis. This is a con than 100 ml., in a small container. This sideration of sufficient importance to justify can be obtained when the workman has some caution in fitting the scope and fre presented himself, after bathing, for an quency of these observations to the actual examination (as a normal part of the pro needs of the situation in the beginning. cedure of examination along with the collection of blood, if desired) or it can be The sampling of the urine has been obtained at the bathing and clothes-changsomething of a problem under certain ing quarters, at the end of the work of the circumstances. There are two general day (or shift), or at its beginning. By such methods which can be employed satisfac torily, in our experience. Other investiga tors or industrial physicians have employed other procedures with success. Workmen can be instructed verbally and also in writing, as to the means of avoiding con tamination of specimens of urine with lead, means, contamination of these samples can be avoided, and a further advantage can be gained by the judicious use of the bathing facilities, in that the samples will have a uniform relationship to the day's work and its exposure to lead. These samples of small volume will be somewhat and in the collection of physiologically less satisfactory than those of large volume, representative samples of large volume. A container with a capacity of four litres can be so prepared as to be chemically clean, sealed in a paper or plastic bag, and given to a workman, after he has bathed and changed his clothing, to take home with him (or, if need be, the container can be delivered to his home). There, he is to keep it in a place which is reasonably secure because of the factor of physiological variability, but this disadvantage can be overcome by the numbers of samples which represent the group or by increasing the frequency of the sampling in the "individual instance. The statistical array of data ^representative of a group of men engaged in comparable work will be entirely satis factory in portraying the status of the against accident or tampering, and to void directly into it at intervals until a suitable volume (2 to 3 litres, up to a mark) has been obtained. He is not to group, while individuals at either extreme of the statistical array can be checked by the collection and analysis of additional samples. Moreover, when an individual collect unusually dilute or unduly concen trated voidings (such as would be associated with the convivial drinking of unusual quantities of beer, ale, or other beverages, or with a period of restricted consumption of liquids), but to obtain a composite sample representative of his ordinary man ner of living. This type of sample is likely to be a very good representation of the general rate of the urinary excretion of who has been exposed to the inorganic compounds of lead is found to be in a dubious state, the necessary facts can be established by an analysis of his blood. The latter procedure, as has been indicated pre viously, is always desirable when, as in private or medico-legal practice, the patient may not be available later for re examination. lead, as the latter is expressed in terms of The foregoing details of procedure may the concentration of lead therein, rather appear to be wholly redundant, in a broad than on the basis of time. (As ample data presentation of the physiological principles have demonstrated, this is as satisfactory and facts with which we are here engaged. a means of expression, for comparative Experience has shown, however, that atten purposes, as is that based on time, and it tion to these details, which is so necessary obviates the necessity for the collection of in order to obtain valid information, is the time-honoured, but not always prac honoured frequently in the breach. There ticable, twenty-four or forty-eight-hour fore, at some risk of wearying or even specimen.) offending those to whom the facts are well- 71 known, it seems wise to speak of them for ments in the techniques of sampling and the benefit of those who, otherwise, now analysis (which have reduced the opportu or later, may waste valuable time and effort nities for contamination of samples at our in learning, as we have done, by trial and hands), we should be justified in concluding error. that the over-all exposure to lead, on the 4. EXPOSURE TO LEAD IX THE REALM OF THE PUBLIC HEALTH The facts concerning the metabolism of lead are of paramount importance in the development of criteria for public safety. Modern technological developments pose certain problems with respect to the com posite ex'posure of men, generally, to lead in the food and beverages which they con sume, and in the air which they breathe. No standard of safety in relation to any one of these general sources of exposure has validity, in itself, but each may achieve validity, in practice, when considered in part of the " average " adult citizen of the United States, has decreased in the past decade. The food and beverages of the country represent the largest source of lead intake, under the ordinary conditions of life, and they are most open to opportunities for artificial contamination. It appears that this source has undergone some decrease in recent years. The data obtained by the analysis of the feces of 453 persons (Table 9, Lecture I) involved in a field survey in 1955 yielded the somewhat surprising mean lead content of 0.23 mg. per sample. relation to the others. (The relationship of these data to the lead It is fair to say that, at the present time, in food and beverages has been demon in the United States, the absorption of lead strated in Lecture I.) The mean value of on the part of the public, generally, from a corresponding series of results obtained all sources, is attended by no hazard. This is not to say thaU there may not be situa-.. in 1934 in the investigation of a group of 307 persons of comparable type from the tions productive of danger and of actual same general area of the country (7) was cases of lead poisoning within the popula tion. Attention has been called emphati cally, herein, to lead poisoning among 0.32 milligram. The difference between these two values is barely significant, statistically, and so is not to be taken too children. Cases of lead poisoning also seriously, but the frequency with which occur among adults, as the result of the the mean lead content of the food and contamination of food and drinking water, feces of various large and small groups of and even of the air in the home (e.g., from persons had been found to exceed 0.3 mg. the use of battery cases scavenged from per day (8) in the period prior to the year dumps or heaps of refuse, as fuel). On the 1950, and the more recent and fairly regu whole, however, the food and beverages of lar finding of mean quantities appreciably the nation contain but little more lead than less than 0.3 mg. per day have not gone that which occurs naturally in them, while unnoticed. (Note the mean lead content the ambient air, even in the more heavily of the food and feces of the experimental contaminated areas of our cities, is con subjects listed in Table 12, Lecture I; the taminated with lead only to the extent three subjects, E.B., I.F., and S.W., were of a few micrograms per cubic metre. The under study prior to 1945, while the investi facts in these matters, as they now obtain, gations concerned with the last six subjects have been given in a fairly representative began in 1950; the last three subjects are manner in Lecture I, in which, also, the now under observation and will continue normal metabolism of lead, as we have so through 1961.) These and other similar chosen to speak of it. has been described. results provide only the proof of the varia We have found no reason to believe or to bility of individuals, in this respect, but suspect that the quantities of lead involved the coincidental factor of time is, at least, in this normal metabolism of lead have in suggestive. It seems reasonably certain creased within the past twenty-odd years. that if any change has occurred it has not Indeed, if we were to rely upon the avail been in the direction of an increase. able evidence, without some reservation of The lead content of drinking and culinary judgment based upon recognized improve water, as supplied to town and city 72 dwellers from a common source, is not a The answer to the first of these questions problem in the United States, with the is based in part on the observation (Lecture exception of certain of the older communi II) that the oral administration of 0.3 mg. ties in the New England area, in which, of lead (as lead acetate, in solution) per even now, lead pipes are said to be in use. Throughout the greater part of the country, the methods employed in the treatment, if any, and in the distribution, of water sup plies, are such that the concentration of lead therein rarely exceeds 0.03 mg. per litre. There is no present reason, there fore, for the persistence of the standard of 0.10 mg. per litre which was adopted by the United States Public Health Service many years ago, but was reduced to 0.05 mg. per litre in 1960. Obviously, oppor tunities for the ingestion and absorption of lead from this source should be as few and as insignificant as possible, in view of the day (in addition to that contained in the food and beverages, thus bringing the total quantity ingested per day up to approxi mately 0.6 mg.) to experimental subject S.W., for a period somewhat longer than a full year, resulted in a barely detectable increase in the rate of the excretion of lead in the urine, but in no demonstrable in crease in the concentration of lead in the blood. This is as near as one might expect to get to the least incremental increase in the oral dosage of lead that would yield a detectable response. On the background of the evidence provided by other similar ease with which this can be accomplished experiments, in which larger dosages of when the general water supply of a com lead were administered orally, the conclu munity is subject to control. On the other sion is fully justified that the quantity of hand, there is no reason for concern, when, lead which accumulated in the body of in emergency, the water supply of an entire subject S.W. was slight indeed, and that community, or a sizeable segment of it, such a rate of accumulation could continue contains lead in a concentration approach for many years, probably for an entire life ing 0.10 mg. per litre, for a few weeks or time, without any likelihood of reaching a months. This, to our knowledge, has potentially dangerous level. On thq other occurred in times of severe drought, when hand, the ingestion of approximately twice/ water had to be transported in highway this quantity of lead daily (1.3 mg. per day, and rail tanks that had not been made by subject M.R., Lecture II) gave rise to a chemically clean. The quality of the water progressive increase in the rate of the ex made available under such circumstances cretion of lead in the urine and in the should be known, however, from this and content of lead in the blood and other other aspects, in order that proper steps tissues of the body. The retention of lead may be taken to protect the public. in the body of subject M.R., continuing Two related questions arise concerning the ingestion of lead, both of which can be answered in straightforward terms, on the basis of the experimental observations that have been described in Lectures I and II. One of these is concerned with the matter of the average quantity of lead which may be ingested daily, without risk, over the span of life, in the food and beverages including water, if it be assumed that the quantity absorbed from the air remains essentially unchanged or undergoes no significant increase. The other question involves the opposite side of the same coin, namely, the quantity of lead which, when over the period of four years, at an essen tially constant rate, resulted in the accumu lation of 120 mgs. therein, at the average rate of approximately 30 mgs. per year. One cannot be certain that such a rate of accumulation would continue indefinitely, but since there was no evidence of a gradual diminution in the rate within four years, there are no grounds for the assump tion that it would not. As it will be shown later, there is reason to believe that this would be dangerous if it were to continue unabated. It is unlikely that the ingestion of 0.6 mg. of lead daily for many years would be a source of danger to an adult. ingested, will result in a dangerous degree The accumulation of lead in the body, of absorption within a definite period of under these conditions, appeared to be of time. the approximate order of 8 mgs. per 73 year, at which rate it would be insignificant for many years and probably for a lifetime. At any rate it may be said, with reasonable assurance, that the quantities of lead in the food and beverages available to a population should be such that individuals may choose what they will in quality and quantity, without running the risk of ingest ing more than 0.6 mg. of lead per day, on the average, over any prolonged period (years) of time. In considering the problem of public health involved in the possible contamina tion of food and beverages with lead, from the aspect of any type of regulatory action, the conclusion arrived at above would seem at first to be wholly academic and impractical. And so it would be, were it not for the feasibility of ascertaining the facts, as they apply to persons or groups in the population, by the application of methods of investigation that have been described herein. There are, of course, other approaches to the more specific hazards presented by the discovery of the contamination of certain items of food or drink, which occupy established and quan titatively ascertainable places in the dietary habitude of the population. Tolerances may be, and indeed have been/ applied to these in accordance with their importance in specific instances. These represent special situations, however, and even they need to be fitted into a general or allinclusive standard. The second question raised above, con cerning the risk of lead poisoning in rela tion to the degree of contamination of food with lead, can now be answered with reasonable accuracy. Various statements have been made in the literature concern ing the dose of lead which, when ingested, i.e., taken by mouth, daily, can be expected to cause lead poisoning. These estimates have been based on indirect evidence, and they have varied so widely as to have dubious worth. No doubt the conditions out of which they came, as interpretations, were variable and subject to a large margin of error. The carefullv controlled conditions of the experiments relating to the ingestion of lead in solution have provided oppor tunity for much more precise estimates of the relationship between time and dosage, on the one hand, and a toxic effect, on the other. This is made possible by the estab lishment of the association between the concentration of lead in the blood (also the rate of the urinary excretion of lead) and the induction of lead intoxication. The fact that this association, in the quantitative sense, has a statistical, rather than a strictly individual basis makes it the more appli cable as a general, rather than an indivi dual, human experience. There is a high degree of probability, therefore, that if the experiments involving the ingestion of lead by our experimental subjects could have been continued until the threshold concen tration of 0.08 mg. of lead per 100 grams of whole blood had been reached, we should have observed the early clinical evidence of a dangerous degree of absorp tion of lead, at least to the extent of an abnormal degree of elevation of copropor phyrin III in the urine. Fortunately it is unnecessary to go to such an extreme of experimental* zeal, even if it were feasible, since it is possible to extend the curves in which the concentration of lead in the blood has been plotted against time (cf. Fig. 3 and Fig. 10, Lecture II) so as to establish approximately the length of time required to reach the threshold concentra tion in the blood. The result of this extra polation, in the case of subject M.R., whose average daily intake of lead in food and beverages, together with that taken in solution, was 1.27 mgs., came to somewhat more than 7.5 and somewhat less than nine years (while the mathematical treatment of the extrapolation would yield a more precise value, such a value, without qualifi cation, would be misleading); the corres ponding result in the case of subject E.B., who ingested 2.35 mgs. daily, was approxi mately four years, while that of subject I.F., who ingested the average quantity of 3.27 mgs. daily, approximately eight months. Whether or not these subjects, or their counterparts in the population, would develop episodes of lead intoxication at or near the time indicated in each instance, is, of course, open to question, but that they would incur such danger is reasonably certain. With respect to the factor of time in association with still larger oral dosages taken regularly, we have had the oppor- HP r? O * o o -1 U ri z_ >' i tunitv recently of investigating the illness lead in the blood of subject S.W. (total daily of two young adults, whose ingestion of oral dose of 0.6 mg. of lead) did not unusual quantities of lead began at the increase demonstrably during the experi- same time and terminated in the nearly mental period, but apparently he added simultaneous onset of acute intoxication, approximately 8 mgs. per year to his The entire period of exposure was limited body burden, under the conditions of the to about one month, during which the dos- experiment. On the reasonable and modest age of lead, while variable from day to day assumption that his body, prior to the and from one to the other person, is experimental ingestion of lead, contained believ ed (on the basis of simulated experi- a quantity of lead of the order of 100 mgs., ence) to have averaged between 5 and 10 a period of 1.2.5 years of continuing inges- mgs. per day. It is interesting in this con- tion at the same rate would be required to nection to consider the problem of suscepti- double, and 25 years, to triple, his body bility, and that of the exciting or enabling burden. His assumption of risk in so feature of lead intoxication to which doing must certainly be considered to be reference has been made. As these matters negligible, in view of the fact that the body have been viewed critically over the years, burden of lead of ordinary (normal) indivi- human susceptibility to lead poisoning has duals in the general population is found, diminished steadily in importance, in favour from time to time, to be of that order of of the influence of the variability of human magnitude (See Table 15, Lecture I). experience whereby the quantities of lead being absorbed bv 'individuals were signifi- As judged by similar means, subjects cantlv different. ' Likewise, and as some- M.R., E.B., and IF. might be expected to thing of a corollary observation, the have added quantities of lead of the order variability in the time of onset of intoxica- of 279> 2;50- iind 110 mgs. respectively to tion among individuals, under seemingly their initial body burden, if each had con- similar environmental conditions, has tinued on his experimental regimen until tended to be greater when the exposure to he had reached the threshold level in his lead has been fairlv uniform at a moderate blood (Le-> in 9' 4 and 064 years> resPec* level of severitv. 'it seems that the onset tively). It will be noted that the total body of intoxication' often coincides with the burden, at the time the blood reaches its occurrence of a shorn increase in the rate of critical level, tends to be greater as the the absorption of lead by an individual. daily rate f intake and absorption dimin- This observation has led us to suspect that ishes, whereas the time factor involved in the "trigger mechanism" of lead intoxica- reaching the critical concentration in the tion is that of overburdening the tissues blood, under these circumstances, is dis- with unbound or ionic lead, whether proportionately large. This is in keeping through an undulv rapid rate of absorption with the relative inaccessibility of the lead or through the loosening, under appropriate which moves slowly into the relatively but presently unknown conditions, of more dense and less vascular areas of the chemical bonds within the tissues. skeleton. Evidently it is not the body burden of lead, per se, which is the primary It is of further interest to consider the factor in providing the conditions in the order of magnitude of the contribution body that arc necessary to induce lead made to the body burden of lead in subjects intoxication, but, rather, the manner in S.W., M.R., E.B., and I.F., at the time which the lead is distributed, with specific when each of them, by extrapolation, reference to its immediate metabolic would have reached the concentration of accessibility, is the important factor. That 0.08 mg. of lead per 100 grams in his blood, is to say that the concentration of lead This can be arrived at by extending the must be sufficiently high at the point or upward sloping curves of Figure 11 r>oints of vulnerability, if intoxication is to (Lecture II), for these subjects, for the be induced. lengths of time required in each instance Notwithstanding the importance of the to bring the concentration of lead in the lead in human food and beverages, as the blood to that point. The concentration of principal ^source of that which enters into 75 the " normal " metabolism of the popula tion of the United States, generally, the finely divided lead in the ambient atmo sphere cannot be ignored, as the observa tions noted in Lectures I and II have indicated. In so far as the quantities in the air are dispersed as particles less than 1 micron in diameter (as the large proportion of these appear, on somewhat scanty evi dence, to be, under prevalent atmospheric conditions); and to the extent that the particles are retained within the lungs, rather than deposited in the nasopharynx, trachea and bronchi, or returned to the atmosphere in the expired air (the results of the respiratory experiments indicate that such retention ranges from 35 to 45 per cent); and, further, to the degree that the highly dispersed compounds of lead in the atmosphere are capable of being absorbed (as most of the lead in the general atmo sphere seems to be); the air-borne lead in the general human environment has greater significance in the human economy, quan tity for quantity, than that in the food and beverages. Whereas less than 10 per cent of the lead which occurs commonly in the food and beverages is absorbed (the absorption is proportionately greater when the quantities (concentrations) of compara bly soluble compounds of lead are large), virtually all of that retained in the lungs is absorbed. Therefore, a given quantity of lead drawn into the respiratory tract in inspiration, if it meets the necessary' speci fications as to particulate dimensions and some degree of solubility, may contribute three to four times as much absorbed lead to the tissues of the body as would the same quantity of lead taken in with food and beverages. Likewise, a given quantity of lead actually retained in the lungs may yield ten to twelve times as much absorbed lead as would an equivalent quantity which enters the alimentary tract. On the other hand, it must not be forgotten that when the particles of lead compounds in the atmosphere exceed 1 micron in diameter, few of them reach the finer air passages of the lungs. Most of the particles between 2 and 5 microns in diameter will be cap tured in the upper respiratory tract and will eventually be deposited in the naso pharynx, to be swallowed or expectorated, and so absorbed to a much lesser extent than if they had been retained in the respiratory tract. It seems advisable, in passing, to refer briefly to a potential source of inhaled lead to which undue speculative significance has been ascribed recently. The occurrence of lead in tobacco (along with arsenic and certain other mineral constituents) has given rise to calculations of the amounts of lead that might be absorbed in the respira tory tract, from this source. The calcula tions have failed to take into account three factors which are highly pertinent, namely: (a) the extent to which the lead in tobacco appears in the smoke which enters the mouth, as differentiated from that which remains in the ash of the burning cigarette, cigar or pipe tobacco; (b) the degree to which the smoker draws the smoke into his lungs; and (c) the actual length of the time, per day, involved in smoking. While the latter two factors cannot be ignored in any strictly quantitative appraisal qf the absorption of lead from the smoke, there is no urgent need for their investigation, for the Reason that only a small proportion of the (available lead is found in the smoke; much the,, larger proportion of it remains in the ash. When this matter was brought somewhat forcibly to our attention by per sistent questions, we were taken aback by the realization that we had no direct in formation on the subject. It was plain to be seen that there was no such difference between smokers and non-smokers, within the groups of persons whom we had investi gated, as to justify the suspicion that this was a significant factor in the absorption of lead. The explanation was supplied by an associate (Cholak) in the Kettering Labora tory, who determined the quantities of lead removed from the smoke of each of several cigarettes by millioore filters, the quantities of lead in the residual ash of each cigarette, and the quantities of lead in individual cigarettes (ashed in the manner of the usual preparatory procedure for analysis, rather than bv smoking). The average weight of each of several cigarettes was approxi mately 1 gram, of which the weight of the ash (obtained bv the usual preparatory method) averaged approximately 150 mgs., and the lead content of the ash of the 76 md REFERENCES 7. Kehoe, R. A., Thamann, F. and Cholak, J.: ial, ira- ab to 1. Xye, L. J. J.: Chronic Nephritis and Lead Poisoning. Angus and Robertson, Ltd., Sydney, Australia, 1933, pp. 47-62. An appraisal of the lead hazards associated with the distribution and use of gasoline containing tetraethyl lead. II. The occupa tional lead exposure of filling station atten iiy ry. 2. Murray, R. E.: Plumhism and Chronic Nephritis in Young People in Queensland. dants and garage mechanics. J. Ind. Ihjg. Toxicol 18: 42-68, 1936. ion School of Public Health and Tropical Medi ad cine (University of Sydney), Commonwealth 8. Kehoe, R. A., Cholak, J., Hubbard, D. M , ith Health Department, Glebe, N.S.W., Publ. Bambach, K., McNary, R. R., and Story, R. nd No. 2, 1939, pp. 32-34. V.: Experimental studies on the ingestion of an lead compounds. ]. Ind. Ihjg. Toxicol. 22: ict 3. Baetjer, A. M., Joardar, S. N. D. and 381-400, 1940. ive McQuary, W. A.: Effect of environmental ad temperature and humidity on lead poisoning. 9. Utall, J.: Chronic lead poisoning from snuff; xi- Arch. Environmental Health 1: 463-77, 1960. report of 3 cases. }. Am. Med. Assoc. 90: all 288-90, 1928. ri- 4. Chisolm, J. J. and Harrison, II. E.: The 'se treatment of acute lead encephalopathy in 10. Cholak, J., Schafer, L, J. and Sterling, T. D. : :ai children. Pediatrics 19: 2-20, 1957. The lead content of the atmosphere. J. Air Pollution Control Assoc. 11: 281-88, 303, 5. Smith, H. D.: Lead poisoning in children 1961. and its therapy with EDTA. Ind. Med. and nt Surg. 28: 148-51, 1959. 11. Kehoe, R. A., Thamann, F. and Cholak, J.: nd An appraisal of the lead hazards associated Id 6. Legge, T. M. and Goadby, K. \V.: Lead with the distribution and use of gasoline ./e, Poisoning and Lead Absorption. Edward containing tetraethyl lead. Part I }. Ind. *s- Arnold, London, 1912. " Ihjg. Toxicol. 16: ' 100-28, 1934. iO, as le ) -;y `V Id >o lr :s. \r- [y iO I i)t n s e s c r 81