Document YrV8bzdyqD28j0bX5NgQNZoa0

March 18, 1966 Dr. M. K. Williams London School of Hygiene and Tropical Medicine Keppel Street London, W.C.I., England Dear Doctor Williams: I agree that It will be wise for us to wait for an opportunity to meet and talk about many of the aspects of clinical lead poisoning, and the Industrial hazard associated with excessive absorption of lead. My objection to the term "lead absorption" is a personal one in which my feelings are involved; the term has been used to describe persons who are not disabled or acutely 111, but are "leaded" and not really well. It has been a basis for inaction In some instances. I really have no objection to the term "excessive lead absorption" or Its equivalent, If it is used by a physician who does something to see that the exposure is reduced to a safe level - unfortunately, a goodly number of Industrial physicians of the old school, in this country, are resorting to chelation therapy, while these sen continue at work, in order to reduce their "body burden" rather than their exposure and rate of absorption. This I consider to be naive, irresponsible and immoral professional performance, while being also ineffectual. Incidentally, I expect to be in London for a week, or two (perhaps), prior to or after the Vienna Congress, and I'd like nothing better than to meet and talk with friends and colleagues in London and specifically in the London School of Hygiene. With kindest personal regards, Sincerely, RAK: wp Robert A. Kehoe, M.D. 00575 LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE INCORPORATING THE ROSS INSTITUTE (UNIVERSITY OF LONDON) Cables ffygoner London W .C.l KEPPEL STREET, ___ (GOWER STREET), LONDON, W.C.l. MKW/JD March 4th, 1966, Professor R.A. Kehoe, M.D., The Kettering Laboratory, University of Cincinnati, College of Medicine, Eden Ave, Cincinnati 43219. Dear Professor Kehoe, Thank you very nuch for your letter of January,'- 26th. I find it most interesting, but would like to make just one comment I do feel that when one is controlling lead absorption in industry it is useful to have a term to describe those men whose lead absorption is higher than is safe, but who are not yet suffering from lead poisoning. This I call excessive lead absorption which I do not feel is semantic hair-splitting; b+rt- it requires that action should be taken to reduce their lead absorption in sone way I would very- much like to discuss at length your other points with you, but perhaps this would be better kept for a in.eetine r,ather than a letter. Yours sincerely, K--.K--*- W--i.-.l.'il-ia--mi--s f rx n n t; / First iold here Professor R A Kehoe, M .D . , .. The Kettering Laboratory, University of Cincinnati, ..... College&-MeUi o-ine-,... Eden Ave, CINCINNATI 4^219, t H.S.A. ^ r - Second fold here --^ Sender*! name jnd jddiru: y\ Dr. H .K . Williams, Department of Occupational Health, London School of Hygiene ft Tropical Medicine, Keppel Street, (Gower Street), LONDON W.C.3. AN AIR I.ETTER SI IOULD NOT CONTAIN ANY ENCLOSURE: IF IT DOES II WILL BE SURCHARGED OR SENT BY ORDINARY MAIL E'orin jfijimvc'il by the Postmaste_*rr General, Nd;'71^95/2J IMPERIAL AIR MAIL AtROtHAMI r ijf iVai-k*' co*bU! tp.^rxirnAiirro h" *13JIIODado0 C\ t-O CD CD January 26, 1966 Dr. M. K. Williams London School of Hygiene and Tropical Medicine Keppel Street LONDON, W.C.l. Dear Doctor Williams: I am impelled to comment on certain of the further queries and views in your letter of January 7; I shall take them in the order oi their occurrence in your letter. First, with reference to the significance of the concentration of lead in the blood, I shall have to say that 1 cannot accept your statement that it is the best index of the exposure to lead(which I shall soeak of as the current level cl' exposure to lead). The rate of the urinary excretion from day to day is by far the best indication. The concentration in the blood, on the other hand, is the best available evidence of the extent of the absorption that has occurred - that is, of the body burden of lead, or the result of the exposure to ieuu over some considerable period of time. It .s clearly not indicative of tne existence of lead poisoning, which, as I have indicated previously, is manifested by a characteristic illness, or a specific interference with a specific interference with function - as, for example a lead-induced disturbance of the porphyrin-hemoglobin metabolism. I wonder why it is that you are loath to label the latter phenomenon as a feature of lead poisoning. I agree that it is not always possible to determine the cause of this phenomenon, or the cause of anemia. However, these are situations in which I would be quite willing, on the probabilities (without actual orooi), to ascribe one or the otner, or both of these, to the effects of lead. Under such circumstances, it is intoxication. Why split semantic hairs? 'excessive lead absorption" has no meaning in clinical medicine, except to indicate that the individual so involved, is in a state of risk. He is not, necessarily, in a state of illness. I abhor confusing words, and this phrase is not only obscure, but has been a shield to hide behind, mecically speaking. On the other hand, the man with lead-caused anemia or lead-induced porphyrinuria is ill. He may not be aware of it, but his physician may be. I think here you are bandying words when you say this is not clinical poisoning, because there is no awareness on the part of the patient, of exceeding the symptomatic threshold. You ire in error, in my experience, in saying that a little lead causes an Increase in porphyrinuria. If one determines the concentration of porphyrins in the urine (this, of course, requires the use of a good quantitative procedure), he will find a sharp cut-off between the results which occur under ordinary conditions and those which are associated with dangerous levels of lead absorption. This, in my view, when other causes of an abnormal concentration of coproporphyrins in the urine can be excluded, is the first clinical (in the sense of a functional disturbance) sign of lead poisoning, and one which should be heeded promptly, lest a more serious form of poisoning should appear. I am prescribing, here, of course, a conservative medical procedure in handling the workmen in a dangerous lead-using industry. This is a bit different, admittedly, from the making of a diagnosis for Dr. U. K. Williams Page 2 January 26, 1966 medico-legal purposes, on a basis that is acceptable, generally, among oadical men. However, this is the way a new diagnostic position is achieved, and this is something quite different from compensable disability due to lead poisoning. But so, for that matter, is the recognition of Impending danger because of a degree of absorption of lead - a danger which requires action on the part of a physician in removing a man from further exposure. We have no mechanism in this country for dealing in compensation law with such cases. Consequently, the employer will make every effort to find a Job for the workmen that is free of lead hazard. In any case, I see no reason for not expecting a knowledgeable physician from exercising Judgment in such cases, as to whether the probabilities are in favor of abnormal effect due to lead. I really don't care whether or not he labels the condition as "lead poisoning,"or "incipient lead poisoning," or "threatened lead poisoning," but I don't take kindly to the term, lead absorption (by itself or modified by an adjective) since this term relates to a general physiological process. It suggests that lead absorption implies some potentially harmful effect of lead, whereas this is basically untrue, and it is high time that we recognize this fact in our speech. One other point requires some clarification. (Please do not think I enjoy being a carping critic. I am merely trying to talk plainly.) You speak of the "release of lead from cells." That is not what I have in mind when I consider the release of lead from a firm or loose chemical bond. I think rather of its release within cells, and the induction of an effect thereby. There is no evidence for this, any more than there is evidence cf an elevation of the lead content of the plasma in acute infections, alcoholic bouts, and disturbances In the acia-base equilibrium of the tissues. But since there is no evidence of the latter group of factors (which you speak of as having been noted in the past), I cannot but suspect that some such subtle biochemical change occurs, without any representation of such change in the peripheral blood. You may be right, of course, about the occurrence of lead poisoning when the concentration of lead in the blood is low. If so its occurrence is rare, for I have never seen such a c^se. The erythrocytes have a very great capacity for taking up lead and virtually depriving the plasma of more than traces. Consequently, I cannot think it very likely that their reduction in number, within moderate limits, will have much effect upon their carriage of the lead that is available through the usual metabolic processes of the body. It is entirely possible that you will react unfavorably to ray comments, although I have found British physicians and scientists to be somewhat less reactive in such matters of discussion and controversy than many of my colleagues in this country. I am encouraged, therefore, to express divergent points of view, without fear of seeming to be excessively opinionated or discourteous. Believe me, I should like to talk with you in person. Cordially yours, RAK:wp Robert A. Kehoe, M.D. S 00579  S / LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE INCORPORATING THE ROSS INSTITUTE ( u n i v e r s i t y - or Lo n d o n ) Telephones Museum Lanqham 3706412/S5hlnineessj- Telearums Hvgower London WCl KEPPEL STREET. (GOWER S T R E E T ) LONDON, W. C-1 D ep artm en t of O ccupational H ealth and A pplied P h y sio lo g y Professor R .S .F Sch illincf. J a n u a ry 7"th 1 9 6 6 Professor R. A. Kehoe College of Medicine, University of Cincinnati, Eden Avenue, Cincinnati, Chio. Dear Professor Kehoe, Thank you so much for your very detailed and helpful letter? and for the reprints. I was glad to hear you are continuing experiments with lead inhalation. I am particularly interested in its estimation using personal samplers and would like to prove mathematically that blood lead, say, is the best index of exposure, but not necessarily of poisoning; whereas ALA say might be the best index of tendency to poisoning - but not of exposure, for example, some cases of clinical lead poisoning have blood leads of 110 ugryloo ml: whereas some workmen without poisoning have 400 ugm/lOO ml. (a 50^ increase). It would be nice to show that no-one with ALA less than x units has clinical poisoning, but everyone with x + 50`,-^has clinical poisoning. I wonder if workers in this field on the whole do not distinguish sufficiently between the use cf certain biological indices to estimate exposure, and the use of the same indices to estimate the tendency to poisoning. I wonder if you agree? I certainly agree with your point (page 2) that lead poisoning is diagnosed clinically and not by analytical means. That is why I am less happy when you say (page 5) that a reduction in haemoglobin due to lead is lead poisoning. For the reduction may only be detectable by analytical means, and not clinically - 30 I would prefer to call the case "excessive lead absorption" (and grossly excessive to be sure.') \tr 0 0 0 6 8 0 Professor R. A. Kehoe -2 - January 7th 1966 Admittedly, men with lowered haemoglobins, but no symptoms and denying "tiredness", when removed from leadlsajy later that they feel much better, and were tired before. But one would call this poisoning from the symptoms rather than from lowered haemoglobin. Similarly, 1 am not hap^y to call unusual quantities of coproporphyrin in the urine (analytical test), lead poisoning, in the absence of clinical symptoms and signs. A very little lead causes an increase in porphyrinuria where then can one draw the line and say this is an "unusual quantity" and therefore = lead poisoning? Increased porphyrin in urine is certainly a sign of interference with a physiological process, and an abnormal metabolite appears in the urine. But an abnormal metabolite appears in the urine after drinking a pint of beer - yet again we do not say this is a sign of alcoholic poisoning. I was very interested to hear your hypothesis that poisoning may be precipitated by the release of lead from cells. I too had imagined that possibly when the red cell becomes "poisoned", it may release some of the large amount of protein bound le id it holds; which in turn, as ionic lead, increases the plasma ionic lead concentration which initiates further stages of poisoning - a sort of trigger mechanism which could be fired earlier by illness, alcohol, dietary deficiency and other factors noted in the past. 'This incidentally might cause a lowering of the total blood lead, accounting for poisoning with "low blood lead" and non-poisoning with high - I would like to do .some animal experiments on that. I take your point about not adding to unproven hypotheses in the literature, and agree that normally this is a very undesirable approach. But 1 feel strongly that a lowered red cell volume must reduce the "leadcarrying power" of blood, and therefore there are good grounds for deducing a correction factor for "observed total blood lead" to get the "corrected blood lead" in cases of lowered haemoglobin. So I am publishing the suggestion in a subsidiary paragraph of a paper in Brit. Joum. Industr. iled. next April, very tentatively to stimulate thinking on this line - I hope this meets with your approval. The paper, incidentally, is on blood lead and haemoglobin and demonstrates (yet again.') that haemoglobin is not a good control - though better than nothing, which is why the legislation was introduced in this country. K, ` Again, very many thanks for your letter and reprints. I hope this letter isn't too long - it would be a great privilege to talk sometime insteadi I hope that may be possible someday. Yours sincerely, M. K. Williams. January 3, 1966 Dr. M. K. Williams London School of Hygiene and Tropical Medicine Xeppel Street London, W.C.l. Dear Doctor Williams: I am pleased to answer (somewhat tardily) your letter of December 9, 19G5. I have returned, only recently, from a mission of three months duration in Santiago, Chile, and my correspondence suffered appreciably during that time and since. I should let you know, further, that I have retired, as of July 1st, from the direction of the Kettering Laboratory and the Department of the .Medical College of which it is a part. Ity successor, Edward P. Radford, Jr., is now in charge, although;at this time, he is on leave fulfilling a commitment which he made before being appointed to this post. I shall continue here for a time with some experiments on the inhalation of lead compounds which have been carried on under my direct guidance for a number of years. I hope to find an understudy soon and to leave further experiments in good hands. With respect to the threshold values, relating to the danger of intoxication with' lead, whether of the urine or blood (the latter, for a number of physiological reasons is the more trustworthy of these two values), it should be said that these relate to the lowest level of concentration (in either fluid) at which lead poisoning has been found to occur within the somewhat selected populations of industry, that is, among male adults who are able to carry on their work. The question as to the precise numbers, excluding the margin of the analytical error, which is of the usual order of plus or minus 0.01 mg. (per liter of urine or per 100 grams of blood) for samples of the size usually obtained for analysis, is one of the sensitivity of the criterion to be satisfied. These which we have advocated depend upon the utter nonoccurrence of any symptom or sign that may be identified by a physician of competence and experience as due to lead. (Thus when, for example, any interference with the synthesis of hemoglobin can be discerned, as an expression of the effects of the absorption of lead, we regard this as intoxication.) For preventive purposes it is inadvisable to wait for the classical clinical signs of plumbism. In short, in our experience, no industrial workmen has developed ieid intoxication when hi9 blood level (confirmed by multiple analyses) has remained below 0.08 mg. per 100 grams, while at this level an occasional case is found, ana at levels progressively higher, the incidence of poisoning increases, as does also the severity of the poisoning. This is not equivalent to saying that intoxication occurs, necessarily, above the threshold value, for there is no level of the concentration of lead in the 005 Dr. M. K. Williams Page 2 January 3, 1966 urine, blood, or tissues, individually or collectively, that signifies illness. The diagnosis of lead poisoning is made clinically, and not by analytical means. Just what it is that converts "inert" lead to toxic lead, in the body, is not known. (We have some working hypotheses, and some opinions, but no conclusions. 1 suspect that some biochemical factor releases intracellular lead from its chemical bonds and permits ionic lead to exert toxic effects, but there is no real evidence that such is the case.) Incidentally, Cantarow and Trumper, combined, knew very little about these matters. They reviewed the literature, and in my view misinterpreted (or underinterpreted) much of it, through unfamiliarity with either the clinical problems or their physiologic-1 background. The application of the threshold value, as a principle, is made in industry, and occasionally in general medical practice - as a means of recognizing danger and of avoiding it before it has taken effect. Its value as a diagnostic procedure is limited to the determination of whether, in the individual case, (at the right time, du"tng or immediately after exposure) U that o f -demonstration has absorbed enough lead to be capable of inducing intoxication. Tnis level was derived in a purely pragmatic manner, as being the lowest level of concentration that has been found In association with any form of (recognizable) lead intoxication. If we should come across some type of intoxication due to lead which has not, previously, been recognized as such by our best and most thorough clinicians, we might have to change the threshold downward. I have spoken thus far of industrial exposure, but we have been able to extend this threshold to infants and young children. We have had a long and extensive experience in Cincinnati with lead poisoning in childhood. We have yet to see even one child with lean poisoning (at the onset of illness, i.e., in immediate temporal relationship to the actual exposure), whose blood has not contained at least 0.03 mg. cf lead for 100 grams. Most of them have had much higher levels of concentration, and most of them have had a very severe (and relatively brief) exposure. (This is why I have taken exception - in a letter to the authors - to the statements in the article by Moncrieff and Clayton which appeared fairly recently in one of the Britisn journals concerned with diseases of children - I shall not trouble to look it up and give the reference, since you nave seen or he..re. cf it no doubt. They have had neither the experience nor the analytical precision that would enable them to make some of their statements of fact without challenge.) You ask for evidence in support of my statements, I am sending certain reprints that deal with this point, but I call your attention to the data clteG on page 57 of the harden lectures and the discussion on pages 58 and 59. The discussion is brief, indeed, but it is quite to the point. (I am planning now that I have been freed fro.: :y responsibilities for directing the affairs of the .fettering Laboratory, to spend the next few years in assembling, studying and publishing (in a monograph) the data o.t various types that have been collected curing the past twelve or fifteen years.) as to the relationship of the analytical data (concerning urine, blood and tissues) to the hematological findings, both Histological ano chemical, I must insist that 1 00 583 Dr. M. K. Williams Page 3 January 3, 1966 the extent of the alterations in the blood depends upon c variety of factors other than the absorption of lead. One cannot say that any analytical finding correlates with any abnormality, or with any degree of severity in the abnormality, in the blood. The question always arises - is this person, with unusual quantities of lead in bis body, actually ill? If he has a reduction in his hemoglobin that can be attributed to the absorption of lead, he has lead poisoning. This is not a question of fact, but of degree. Moreover, if he has unusual quantities of porphyrins in his blood or urine, because of the presence of lead in his body, he has intoxication, since this, when due to lead, (not always easily determined, to be sure) is an interference with a physiological process. I am not splitting hairs; in my view, an interference with a physiological process is an expression of intoxication. For preventive purposes, I would not wait for colic, palsy or encephalopathy, but would get the endangered man out of exposure before he becomes ill. This is the meaning of the threshold point of danger. This is the means by which occupational plumbism is prevented. I stress the occupational situation, since here, ideally, we have the means of determining the status of the individual workman and the occupational group, whereas this is hardly ever possible in general medical practice. Your other point, that the incidence of poisoning is low among workmen exposed to lead under fairly constant conditions, in contrast with that of persons subjected to brief periods of severe exposure, is well taken. There is a wealth of evidence that this is true, and indeed I have come to believe that the triggering mechanism of occupational lead poisoning is often, if not usually, a sudden significant increase in exposure. The evidence for this viewpoint is not as clearly defined as I would like, but there are bases in both physiology and clinical medicine for this opinion. However, I have made a practice of not advancing hypotheses in published articles, except in the most tentative manner, fly reason for this is that the literature of lead poisoning is horribly cluttered with hypotheses which, because of their frequent repetition, have become cherished beliefs. When we began our investigations, in 1924, there was so much "authoritative opinion" and so little substance in the physiological approach to lead poisoning, that we began to look for facts, and to allow the explanations to cone only when the facts were overwhelmingly weighted in their direction. I am still wedded, is an investigator, tc this approach. When as a physician, I must accept responsibility for iCti^n, I put the facts together in the most favorable light in relation to hoiun safety, or to put the matter In the opposite form, in the mcst unfavorable light with respect to human risk. I*d like/very much, to gain some better insight into the actual mechanism of the toxic eft^cts of lead, but, for the present, I must be content with the description of effect and the conditions under which It occurs. In this respect, the study of lead intoxication resembles, in its resulta, many other phenomena of nature, in that the more one knows, the more difficult becomes the ultin.it'' interpretation of the facts. I hope my lenathy letter will have acted toward the answer to some of your questions, rather than h_ving adued to your uncertainties, as you are aware, there is much to be done and learned, and perhaps the ;r,cst useful posture is that of further openminded observation. RAK: wp Sincerely yours, P.f.: Robert A, Kehoe, M.D. I should -ppreciate it if, in conveying the Season's greetings to yourself, I might count on your passing them along to my friends in the London School. 00584 RAK k J LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE INCORPORATING THE ROSS INSTITUTE (U N IV ERSITY OF LONDON) Telephones Museum 30 41 14 tines) Langham 7 6 2 / .'5 lines/ Telegrams: H vgoiver London WCl KEPPEL STREET, (GOWER S T R E E T ) LO NDO N, W .C.l. D e p a rtm e n t o f O ccupational H ealth and A pplied P h y3ioloqy Professor R .S F S c h illin g - r f -1" Vrc1 i r I I % , v ' i c :'r '' ! c; ' ^ y i -p -- V* - r> p - - ^ . ' 1 p ri( 'ifF B 00585 s 1 -p- Professor ?..A. TIehce, ,T.P. Pecetriber 9th, Iff 5 '!y second pnjrt Is as followst m a oarer to be rublished in tbe -"ritish Journal ci` Industrial "edicire dr tprll 1966, I s''ov/ that in PC lea^ '.Yorkers t'^^re ?s no indication of anr fall *r* ^go'--'o.-.-t r'b"'n w 1"tb blood leads v'd'i.c'h or'" "^actoT*,r Tns^ectorate "edical Perartnent think- usually are associated "rith a werted ar._Lj_ j>- =a~o :lcMr. I rostuiate several byretheses to ;fC C '?V"t **f'T* rri"r p r'*1>10 0 % O f J vVp Qk | G TVCT* "0 P 0O V , * l 'r g 0 20 c o n ^ J* 0 C r P OT* ]_p tf ^ 13*;r OT*v''T 4 ^71 '' -> p -r* 11*1 q - 7 J_0 p r? y f _L'ipc; g **p r*r> q y-y '' rr**c* r> rl(vi cprn* r p p r*jt* o r . 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