Document RjGZ4go3qYgGV0qN99oGrBVQk

March 3, 1960 David W. Fassett, M.D.S Director Laboratory of Industrial Medicine Eastman Kodak Company Kodak Park Works Rochester d, N.Y. Dear Dave: Herewith are the two copies of my contribution to the book. X hope the text will be to your liking. I could have done better if I had started sooner and taken more time, but 1 am fairly well pleased with the result. You (or Frank Patty) may think I have been a bit wordy in spots, or that there is some unnecessary repetition. This may be true, but I am not inclined to think so. Perhaps I wouldn't be sufficiently critical. I am convinced, however, that there have been some islands of confusion or lack of understanding in this general problem, and I've tried hard to eliminate them. Something might have been said on toxicity per se. In my view, the intrinsic toxicity (in the sense of lethel concentrations or dosages) of these compounds, even of lead arsenate, for example, which combine's two elements, is almost wholly irrelevant so far as occupational exposure and absorption are concerned, and therefore, 1 have simply omitted reference to toxicity. The only important question relates to the rate and duration of a relatively prolonged and not immediately dangerous absorption and this, after all, is not a question of relative toxicity but rather the characteristic behavior of lead in the body. I shall be glad to have any comments or criticisms which seem to you to be justified. I have edited the text most carefully, but I shall be surprised if you do not find some errors that have slipped past me. I believe the manuscript is fairly satisfactory in matters of form. Sincerely yours. Robert A. Kehoe, M. D, Enclosure (2 copies of manuscript) THE RISK ASSOCIATED WITH THE ABSORPTION OF LEAD BY THE GENERAL POPULATION IN THE UNITED STATES The Conditions Under Which the Ingestion of Lead is Hazardous by Robert A. Kehoe, M.D.* From the Kettering Laboratory in the Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45219 * Professor Emeritus of Occupational Medicine The discussions of this meeting are concerned with the degree of risk of lead poisoning, if any, to which persons in the general population of the United States of America are subjected through the occurrence of lead in their general environment. In examining this problem, it is necessary, first, to differentiate between general environmental conditions, and those which have long been known to be potentially hazardous in certain lead trades and lead-using industries. It is also necessary to recognize certain other situations in which lead poisoning occurs, when, through innocence, ignorance or irresponsibility the Ron-occupational environment of an individual, a family, or some other group may be rendered dangerous by personal behavior, or through the utilization of materials or equipment commonly known to bo dangorous. An oxamplc of unusual behavior is that of the infant, usually poorly cared for, who habitually, for weeks or months, eats dangerously large quantities of lead-containing paint from the surfaces of outer or inner walls, woodwork, furniture, or toys, in his home. Further examples are furnished by the owner of an isolated cabin or camp, or even a permanent home, who conveys water into his house from a spring or other source through a long stretch of lead pipe; or by the frugal collector of maple sap, who preserves hi3 wooden pails against disintegration by coating or them generously, inside and out, with a paint high in its lead content;^ by the art-conscious but technically incompetent potter who puts out a badly glazed 0003587 N9758.01 2 brand of tableware with which to beguile aesthetic housewives into feeding their families dangerously. The foregoing are but a few examples of serious dangers associated with the ingestion of lead compounds, as variants of a host of recorded and assembled (1, 2, 3} human experiences which, collectively, have been responsible for numerous and sometimes fatal cases of non-occupational lead intoxication incidents and epidemics v;hich have come and gone oyer the centuries, some of which have been investigated and elucidated in time3 past and present. But while some of these have been informative, with respect to the quantitative relationships between dosage and time in the induction of lead poisoning, it is only in those respects that they arc pertinent to the subject under discussion here. For the object of present concern is not the incident or the mischance that has yielded the unusual case of lead poisoning within the general population but is, rather, the prevalent, regular exposure to and absorption of lead, which are the- common lot of people who live in the environment of a modern technologies nation. The- question, as I choose to restate it for my purposes, is threefold. What are the facts with respect to the magnitude of the total exposure to lead to which citizens of the United States are being subjected? Is such exposure hazardous to a certain segment (or segments) of the population nov; or in the near future? If not, what margin of safety exists, or should exist? I am scheduled to speak only of the hazard of ingested lead, and I shall fulfill to thi3 mandate However, it must be evident to all of us, that this is but one facet of the matter at issue, and that it cannot bo dealt with, at this or any other time, in indcpondonco of the respiratory absorption of lead. Therefore, in order to determine the threshold value of the alimentary factor in relation to public safety, the reopiratory component mu3t be held constant, and vice versa. This, ^jf 0008588 for nil practical purposes, is what has been done in an experimental approach to this matter. The Total Magnitude of the Current Exposure of the General Population to Lead In the course of a series of investigations carried out in the Kettering Laboratory during the past forty years, but more specifically, those of the past twenty-eight years (because of the essential uniformity of the analytical method employed during that period), it has been possible to visualize, in a fairly comprehensive manner, the daily contribution made to the alimentary intake and absorption of lead by the food and beverages consumed generally in the United States (4,5). By indirect measurements, on the one hand (5) and by calculations based on physiological parameters on the other, a reasonably satisfactory approximation of the quantities of lead breathed in from the ambient atmosphere by adults in the population has also been arrived at. (The latter quantities vary from time to time and from place to place, and also, to some extent, from individual to individual, as do, also, the quantities ingested in food and drink. There is no present means, however, by which the respiratory intake can be measured, directly, so as to obtain a statistically valid array estimated of findings. Therefore, they must be expressed as a range of,values, for which, at present, there is little virtue in an average value. The range, however, is not extensive in the absolute sense, and there is little doubt that the order of magnitude cncompa33ed thereby is realistic.) The food and beverages consumed daily by an adult in the United- States contain lead in amounts which range from somewhat .less than 0.1 to 4.0 milligram (occasionally more). The lowermost and the highest values occur infrequently, the large proportion of the quantities grouping themselves regularly around the mean value- of approximately 0.3 mg. per day (this mean value is derived from 0006589 4- - a large number of results obtained from a sizeable group of adults; the mean values for individuals obtained by daily observations over periods of months or years, range from 0.12 to about 0.38 mg. per day, thoir variance being due to the differences in the gross quantities and the choices of food and beverages consume habitually, by different individuals of different size, occupation, and appetite. The quantities taken in daily with the inspired air may range from somov/hat less than 0,015 to 0.09 (15 to 90 micrograms) per day, (no doubt, being considerably closer,a3 the usual experience, to the lower than to the higher value), depending upon where and in what manner one resides and where and how he works; i.e., upon the quality of the air breathed during the 24 hours of each day, with respect to lead content, and upon the rate and depth of the respiration during sloop, work and recreation. The quantities of lead absorbed into the human body from the sources indicated above may he estimated with fair accuracy on experimental evidence which shows that somewhat less than 10 per cent of that ingested under ordinary circumstances is absorbed daily from the alimentary tract, while from 25 to 59 pc cent of that inhaled (5), dependent upon the size, shape and density of the particles inhaled, is retained and absorbed in the respiratory system. The average quantity absorbed daily in the alimentary tract of the uuult is of the order of 0.03 milligram (30 micrograms), while a reasonably satisfactory estimate of that absorbed in the respiratory system would not be far from 0.2 milligram or 20 micrograms (5,6). The Significance of the Current Exposure of the General Population to Load, from. the Aspect of Hazard If there is to be a satisfactory answer to the question as to whether the current trend In the absorption of lead by the general population is hazardous, tho answer must come, it sooras, from quantitative, physiological Information as ^g 0006500 -F to the fate of lead absorbed over long periods of time (extended, in the final sense, to the human lifetime), and from the facts of toxicology and clinical medicine, as to the conditions under which intoxication by lead occurs. First, with respect to the metabolism of load taken in and absorbed by typical representatives of the healthy, adult population, the facts, while seemingly not so comprehensive, in relation to a population of nearly two hundred million people distributed throughout the wide expanse of the United States, as to cover all of the possible environmental variations, arc so uniform, physiologically, as to be convincing. The results of experiments carried out under exacting conditions in the Laboratory, supported in breadth by entonsivo sampling of selected and random groups in the population, have demonstrated, (a) that the intahe of lead by typical, healthy, male adults is balanced for all practical purposes, by an equivalent output; (b) that there is no progressive a increase, over prolonged period of time, in the rate of the excretion of lead *\ from the body, nor in the concentration of lead in the blood; and (c) that any increase in the concentration of lead in the tissues of the body, including the skeleton, which may occur ovor the span of life, is too small to bo measured, being within the limits of the individual variability in the intake and output of lead (4,5). (The latter statement should not be misinterpreted to mean that the total quantity of lead found in the body does not increase with growth from childhood to adult life. The increase observed, however, is not accumulation, in the physiological sense, but is, rather, the maintenance of a balanced concentration of lead in individual tissues, that is to say, the maintenance of an equilibrium with the environment. Second, with rospect to whether the concentration of load in the tissues of poopio. Generally, in the population, and the quantities in tholr entire bodies and in the metabolic processes described above, constitute a risk - the risk of Ng 0008591 G intoxication by lead in any fora known to physicians, physiologists and pathologists - the answer is in tho negative. The tonic effects of lead upon tho human body, as expressed in tho more severe types of plumbism known classically, both before and since tho days of Tanquerel des Planches (7), have not been seer, frequently in recoat years, but they still occur from time to time, especially among children, to display tho immediate signs and symptoms and certain sequelae of the most damaging forms of plumbism. The milder types of lead poisoning are tho moro common manifestations of the disease in our time, in tho adult, and, because of this, much attention ha3 been focused upon biochemical evidences of disturbances in the rates- of destruction and replacement of tho erythrocytes and tho degradation and synthesis of hemoglobin. Those disturbances, while not confined to tho effects of lead, are among the earlier and more subtle changes induced by load, which may givo warning of moro serious symptomatic and organic effects to follow. Even these subtle chemical changes do not occur in association with the levels of tho concentration of lead that are prevalent in tho tissues, body fluids, and excreta of persons in the general population that have not been subjected to unusual types of exposure to lead. The evidence on this point is extonsivo and convincing (0,9,10,11), and from such evidence, obtained frex unusual incidents and accidents within the general population, including those involving infants and small children, and from a wealth of systematic observation of groups of persons engaged in occupations that yield cases of lead poisoning, as well as those that do not, has demonstrated that there is a critical concentration (or a narrow range of concentration) of lead in tho body (in the tissues, including the blood, and in the urine), below which none of the obvious or even suggestive manifestations of plumbism have been found. In the intact living body of man, the most readily available tissue for sampling is tho blood. This tissue is the most precise indicator, under certain necessary and appropriate 0003592 -7 - conditions, of tho lead content of tho entire living body, and, specifically, of the soft tissues of the body. (Tho measurement of the rate of the excretion of lead in the urine can often but not always be counted on to yield the same type of information, but the difficulties of sampling, and the physiological variability of the excretory process combine to make this measurement more difficult of interpretation than that of the concentration of lead in tho blood.) The Margin Between the Current Levels of tho Concentration of Load in the General Population and Those Associated with the Occurrence of Lead Poisoning Tho large proportion of cases of load poisoning aro associated with the absorption of relatively largo quantities of lead. The quantities found in individual organs, in tho blood, and in the urine, in typical lead poisoning, aro many times larger than those found in the corresponding organs, blood and urine of persons in tho general population. The skeleton, for example, may contain from ten to twenty times the usual levels found in persons in the general population. The liver, kidneys and brain, likewise, may contain eight to ten times tho usual quantities, while tho concentration of lead in the bleed is as a rule, similarly elevated, tho values rangingyfrom 0.1 to 0.8 mg. (150 to COO micrograms) per 100 grams of whole blood, as contrasted with the highest value, 0.05 (GO micrograms) per 100 grams, found among persons in the population who have been screened, carefully, to eliminate all occupational factors (5,8). Occasional cases of load poisoning are found, usually after an intervening period of freedom from exposure occasioned by a delay of somo weeks before tho blood has been sampled, in which the concentration of lead in the blood is at the level of 0.00 io.005 rag. (GO i'0 micrograms) per 100 grams. The latter is the lowest concentration that has occurred, in tho experience of the Kottoring laboratory'-, in association with the onset of load poisoning in a child or adult, i.e., without an interval of freedom from exposure of more than a few days. This value is not, as some ill-informed persons have believed, the critical level above which KP 0003593 one may properly conclude that the person concerned is suffering froni lead poisoning. It is, rather, as stated above, the level below; which no case of poisoning induced by inorganic load, however mild, ha3 been found in our nearly thirty years of extensive experience with all types of lead poisoning, during which the current, sensitive methods of analysis have been employed. It is not certain, in the absolute sense, that this is the actual threshold level between safety and danger, for it may be (and is believed by certain other investigators to be) slightly in error on the low side. It is also not beyond tuo bare possibility, in view of the extent of the reduction which may occur in the erythrocytic content of the bicod (to which the predominant portion of the lead in the blood is bound), that a bena fide case of lead poisoning cay be found at the onset of symptoms, at a slightly lower level. This lias not occurrc in our cnooracnc as yet, despite the fact that no correction of the analytic::. finding has ever been made for a lowered erythrocytic content. (Duo allowance must be made, here, for the analytical deviation, which is of the order of 0.001 ir.g. or 1 micrograia per 1 ' rams of whole blood; and for the calculation, which increases it by a factor of 10, in expressing the result in terms of 1GD grans cf blood.) This error can be and is partially counteracted, when the result obtained is near, above or below, the critical value, by multiple analyse by enlarging the sample of bleed, or by special manipulations. In tbo analytical sense, there is a small margin between the upper limit of the concentration of lead in the whole blood of persons in the general population (who have not sustained any unusual exposure to lead), that is 0.05 Eg. (GO raicrograins) of lead per 100 grans, and the lowermost limit of concentration which, occasionally, may bo associated with the onset of (mild) lead intoxication. In the physiological sense, however, if the accuracy of the analytical findings can bo substantiated, the difference is not slight, for many months of potentially hazardous occupational (or experimental) exposure to load 000(3394 9 >1 are required to clevato the concentration of lead in the blood by an increment f i of 0.02 mg. <[20 micrograras). Tho reason for this lies in the fact that most of the absorbed lead* in tho process of its distribution in the body, goes selectively into tho skeleton, leaving only a snail proportion (5 to C per cent) distributed within tho soft tissues, including the blood. Thus, a difference of 0.02 mg. (20 micrograms) per 100 grans of whole blood, as has been demonstrated (4), may be indicative of an increase of more than 1G0 milligrams in the body burden of lead. It is such physiological facts ns these, with their background in known analytical variance, that must bo understood before one can consider intelligently the quantitative relationships in this field of toxicology. Load Poisoning iron tho Ingesticn of Load Returning nor; to the assigned topic - namely, the conditions under which L-liO possible to describe such conditions in a fairly precise manner. They nay bo stated in principle, as follows; 1. Load poisoning nay be induced in a short period of tine by a high love', of regular, daily, oral dosage, and in a longer period of time by a relatively low level of daily, oral dosage. 2. Tho requirements arc that the dose of load taken regularly, so as to maintain an essentially constant rate of absorption of lead from the alimentary tract, shall bo largo enough to lead to a progressive accumulation of load of critical proportions within the lifetime of tho individual. o. Tho presence of critical quantities of lead in the intact, living body-- the potentially hazardous body burden - can bo identified by tho finding of a critical concentration of lead in tho fluid tissue, tho blood, and, with somewhat lessor precision, by tho finding of a critical elevation of the rate of tho excretion of lead in the urine. HE 0008395 V.. 10 - 4. The actual onset of lead poisoning cannot be predicted, nor can this specific illness to identified, with certainty, on the basis of any analytical finding in the tissues, body fluids or excreta.. Only the danger of lead poisoning can be recognized by such naans. It is a fact, however, that the likelihood cf the actual occurrence of lead poisoning in the individual case is greatly augmented if the concentration of lead in the tissues of the body increases rapidly in response to relatively high dosage. It appears, from, this fact, that if lead is absorbed slowly, some mechanism in the body (beyond the distribution of the major portion into the skeleton) inhibits its tonic effects, possibly by binding it as it is absorbed. The failure of such a mechanism is also indicated by the fact that persons with high body burdens arc* often precipitated into a bout of intoxication, by a sudden, brief increase in the rat< cf their absorption of lead. The foregoing principles can bo translated into quantitative terms on the basis of experiments carried out, within the .'.. . its of safety, in the bettering Laboratory, by means of human subjects, raid through certain clinical observations made under fortuitous circumstances. After varying periods of preliminary observation of the metabolism cf lead as displayed in a scries of young, healthy human subjects, lead was administered by mouth in soluble form, in three doses of equal sine, taken with the meals. jTheso experiments have been described in detail, so that only the pertinent facts need bo given here (4,5}j . One subject took 3 mg. of lead as the chloride, daily, for 10 weeks, in addition to that which occurred in his diet during that period. Another took 2 mg. (in addition to that in his diet), daily, for approximately 2 years; still another took 1 mg. daily for somewhat more than 4 years, while another took 0.3 mg. per day (plus the mean quantity of 0.32 mg. taken daily in the diet), ovor the period of CO weeks. There -v/as a progressive increase in the output and concentration of lead in K ? 0 0 0 8 o 9 6 11 the urine of the first three subjects, in the concentration of lead in their blood, and in the quantities of lead retained in their bodies (the cumulative difference between the intake of lead in the food and beverages plus that administered), and in the output of lead in their fecos and urine). With some daily seasonal and incidental variability, the accumulation progressed at essentially constant individual rates throughout the periods of administration, there being no indication of any decline in rate, even after 4 years in the cas of one subject. The output and concentration of lead in the urine of the fourth subject, whose mean daily ingestion of lead amounted to 0.G2 mg. (0.0 administered and O.CO taken with food and beverages), increased slightly (barely sign!ficantly in the statistical sense), and there was a difference of about 12 mg. on the si of intake, between the intake and output of lead, at the end of 15 months - a difference too slight to bo considered significant but for the consistency of the trend in this direction from month i. -nth. There can be little doubt that, the addition of 0.3 mg. of load nor day to that which occurred regularly i the diet of this subject was sufficient to bring about some slight accumulation load in his body. On the other hand, the rate of accumulation was insufficient to yield an elevation in the concentration of load in the blood in the course of 13 months. It is believed that this experiment has gone about as far in the achievement of a positive result as is possible, and it is clear that a Ion time would be required, probably longer than the ! fo expectation of this subjc to roach a potentially dangerous concentration of lead in the blood. It would saem, therefore, that the average intake of lead in the food and beverages of the nation should bo maintained, for tho safety of the public, to sene quantity short of. C.G mg. per day, so long as tho respiratory intake and absorption of load remains at or near its present level. In view of the experience of the past thirty years in tho United States, during which there has been no increase Kg' 0008597 * CO 10 ro o O o Ui 12 in the average oral intake, (there has been a slight trend toward a decrease), it should not be difficult to maintain a satisfactory margin of safety in this respect. The other levels of dosage, namely 3, 2 and 1 mg., daily, continued regularly, in addition to the quantity, approximately 0.3 mg. per day in each instance, taken in with food and beverages, can be counted on, at some time, to yield dangerous levels of the concentration of lead in the tissues, body fluids and excreta. The period of time required to reach the point of danger (not necessarily of illness, but the distinct threat of illness), in each instance, can be arrived at, with sufficient accuracy for present purposes, by extrapolating on the curves yielded by the values in the blood during the respective periods of observation, to the level of 0.00 mg. (80 micrograms) per 100 grams. Those periods turn out to bo of the order of 0 months, 4 3/ears and 0 years, under the turec conaations. The shortest period of time, approximately SO days, which, in our cxporicnc has intervened between the initiation of the ingestion of lead, regularly, and the onset of n typical bout of gastro-entoric plumbisn, was associated with an alimentary intake of 10 to 15 milligrams of lead per day. Of particular interes in this connection, were circumstances which fixed, conclusively, the duration of the period of the ingestion, and the quantities of leud taken daily by two adults, one male and one female, and the dates of the onset of intoxication in the two persons. The dosage and the temporal relationships of these two cases wore practically identical. A single oral dose, in sufficient quantity, of an inorganic (soluble} compound of lead, has been known to cause fatal poisoning within 24 hours. This fact, while of some general importance, especially because the resultant intoxication boars little roscmblanco to lead poisoning of any recognizable type, is irrelevant, otherwise, for the purposes of this discussion. The lethal dose, while very large (grams), in tho one instance in our experience, could not be ascertained. Oral dosages of several hundred milligrams are capable of inducing 13 acute but not fatal illness in the adult. 0008399 14 References 1. Kehoe, K. A., Tham.inn, F., and Choi ak, J.: On the normal ahsorntinn and excrcti on of load. 1TT. The .sources of normal load absor-'-tinn. J. in,lust. Hyg. 10:290-301), 1933. 2. Conway, N.: Read poisoning from unusual causes. Indust. fed. f; 3. Machle, T.r.: Lead absorption from bullets lodged in tissues: report of two cases. J. A. H. A. 115:1536-41, 1940. 4. Kehoe, R. A., Cholak, J., Hubbard, D.M., Bambach, K., McKary, IC. II., and Story, R.Y.: Experimental studies on the ingestion of lead compounds. J, Indust. ilyg. Toxicol. 22:3f'l-40o, 1940. 5. Kehoe, It. A.: The llarben Lectures, 1960. The metabolism of lead in nan in health and disease. Lecture 1. The normal metabolism of lead; Lecture 2..The metabolism of lead under abnormal conditions; lecture 3. Present hygienic problems relating to the absorption of lead. -J. Tnst,, Public Health 24:83-97; 101-20, 129-43; 177-203, 1961. 6. Kehoe, R.A.: Experimental studies on the inhalation of lead by human subjects. Pure Appl. Chcm. 3:129-44, 1931. 7. Tanqu or cl dcs blanches, I.,: lead Diseases, Uith Notes and Additions on 1 ho l!sc of load ih.no and Its Substitutes, by Samuel L. Lana. 3 ovrcll , Daniel Pirn-, 164f`, <9. Kehoe, R.A.: Lead poisoning. In Cecil, R.L., and I.oob, eds.: A Textbook of Medicine. 10th ed. Philadelphia., V,. H. Saunders. 1959, pn. 498-505. 9. Kehoe, R.A.: Industrial load poisoning. In Patty, F.A., ed.: Industrial Hygiene and Toxicology. 2nd rev. ed. Nov; lorn, Intc-rscrcr.co Publishers, 1963, Volume IT, Chapter XXII, pn. 941-85. 10. Kehoe, R.A., Thamann, F., and Cholak, J.: An appraisal of the load hazards as social ed with the distribution and use of gascj j r.o con1- aining tetraethyl lead. Part I. .T. Indust. Hyg. '16:100-28, 1934 II. The occupational lead exposure of filling station attendants and garage mechanics, J. Indus!. Hyg. 13:42-68, 3936. 11. Unpublished data of the Kettering Laboratory (being assemble-: for publication).