Document e51okQrpx0wMkL95039xOZbv9

n (CORRESPONDENCE) February 23, 1966 J. Julian Chisolm, Jr., M.D. Associate Professor of Pediatrics Johns Hopkins University School of Medicine Baltimore City Hospitals 4340 Eastern Avenue Baltimore, Maryland. 21224 Peaph&peior Chisolm.: There are certain statements in the article which you sent me with which I am not in agreement, certain others of which I am in doubt, and certain others about which I wish to raise questions. These are not of earthshaking: importance, and I shall refer to them later. The principal matters come first and I should like to state my viewpoints on them and the reasons behind them. First let me say that, in jthe course of preparing a monograph on lead, 1 have set myself the task of reviewing carefully the literature of this subject the older and newer clinical reports, and the later interpretations that have come out of recent analytical and biochemical work. I have not had an opportunity, yet, to do sol I cannot comment on work 1 am not familiar with, and therefore I may be a bit behind in ray awareness of the evidence. We are now in a period in which this is a bit hazardous, considering the work that is being done, and it is no time tjo be dogmatic. However, I shall state my views and. to the extent that they are erroneous or incomplete, I shall be prepared to retract or expand them on suitable evidence. Of first importance to me is the attempt to find means of visualizing the distribution of lead in the intact (living) person, whether he is ill or apparently well. In my experience, the best of all ways to set the stage for doing this is to make sure that the distribution of lead in the body is disturbed as little as possible, during a period in which the intake and absorption of lead are kept under control, preferably at the usual (otherwise spoken of as normal, in the sense of arising out of the general prevalent environment); that is, the patient has been removed, entirely, from his abnormal source of exposuire/^s not treated in any way until samples of blood and urine have been obtained. This, of course, does not mean that therapy need be or should be delayed, if if seems urgently required, but certainly blood can be obtained for analysis^ and a spot specimen of urine can usually be obtained. (I shall say something about this vis-a-vis the 24-hour specimen later, but what one wishes jto determine is whether the urinary concentration of lepd is in general keeping with the concentration in the blood, in evidence of the functional integrity! of the excretory apparatus. I do pot consider the "propktive test" with a chelating agent to be appropriate, for tie simple reason that it distorts the distribution of lead in the body, and renders it impossible to determine its pattern. 1 do not believe that anyohe Can interpret the meaning of such a test, for despite the fact that the response is usually related) to the dosage of the chelating agent, it has no 0018015 !i G ' ' J. Julian Chisolm, Jr., M.D. Page 2 February 23, 1968 V^ frV^iW eV evjiSvA meaning as to the source^of the lead that is chelated. With the exception of '.he period that follows shortly after the resm'al of much of the lead from feyUthe soft tissues, something like 5 to percent of the lead in the body k. in the soft tissues. This amounts in the average "normal" adult to .-iiliarams. One is not likely to get this entire amount out of the body in any one course of chelation therapy. The quantity will be several times thus ..mount in the person with even a moderately elevated body burden, and, the quantitative sense, the body burden will be revealed more definitively^ by the concentration of lead in the blood than by the amount removed from the oody in the urine. The latter, in our experience is much too variable to be interpreted with a reasonable degree of precision. I think we are being deceived here by an empirical "rule pf >thuiab" that has no' physiological meaning. Now it is possible that there is something in the mechanisms of chelation that i understand much less completely than some of my colleagues, but I have beer; totally unable to find any rationale in this procedui'e, and I have no faith in it whatever. (p The icco. behind your use of B.A.L. (or some other agent that releases the lead from the erythrocytes), ,in concert with disodium-calcium edathamil, is an entirely reasonable one. So ;far as I know, B.A.L. is the only agent that does this effectively, (how about ipenacillamfne?) and it is entirely possible that the brevity of its action (atjout 8 hours following a single injection of B.A.L.) can be combatted in some manlier that' will .maintain the effect for a longer period. I have not thought much of- the usefulne ss of B.A.L., alone, for this purpose^ because of the slender quantitative effect. The removal of a few .milligrams of lead from the bjody, when there are several hundred milligrams to be removed, does not strike me as being very significant - unless, of course, one canj remove it from som yital site. Is there any evidence that such can bs done? Incidentally, I had hoped that a thiol; of lesser toxicity than B.A.L.,, might bq made available to usj, so that a more prolonged effect could be achieved through repetitive dosage. If one could release the lead in the blood, remove it from the body, allow the blood to pick up mor lead from the tissues land remove it again aiid again, we might accomplish theI"deleading" much more rapidly and effectively. .'.oturaii)g to the consideration of the blood as a soft tissue that reveals the general order of magnitude of the lead content of the body, because it partakes in the distribution <j>f lead according to a pattern which appears to be very characteristic (unless it is disturbed by chelation), I believe we shall b^ able, through the careful study of our metabolic data^ to write a formula jin which the time factor, (the length of the abnormal exposure, and the actual time of its beginning and ending in relation to the time of analysing the blood), is given its proper weight, and the body j burden can then be ealoiilated. I believe this, because, in our experience, tfe metabolism of lead in the body is remarkably stable in its pattern. In- tliis connection you have considered the relative abundance of the erythrocytes, as indicated by the hematocrit, to be an important factor in the concentrateon of lead in the blood. I cannot say flatljy that this is not the case, but I'd like very mucp to see the evidence jfor it. I doubt the truth of the statement, for the reason that the erythrocytes have a very large capacity for binding lead. Tpere must, of course, jbe some kind of equilibrium betwe<sen the erythrocytes and the plasma, bjut the avidity of thfe erythrocytijc binding of lead is great that the concentration of lead in the plasma is always very low, so in fact, that it is difficult to find differences in the KE 0015016 J. Julian Chisolm, Jr., M.D, Page 3 February 23, 1966 concentration of load in the plasma between samples of blood that are very high in lead and those that are very low. That is, the total range of the quantities of lean .in the plasma are within the r*.nge of the analytical deviation. (Some more recent methods of analysis may overcome this hurdle. .It least, I hope they will.) here also - that is, as to analytical precision - something needs to be said. You seem to have been impressed by the significance of the findings referred co by Moncrieff and his associates. I have no doubt as to the clinical abilities of this group, but I think they' went far beyond their competence in interpreting the.tr analytical results. Their ideas are naive and their analytical procedures leave something to be desired. I have corresponded with cheia, but without any meeting of the minds. There is no depth of understanding, and no appreciation of quantitative relationships in their approach. Or so it seems to me. It is necessary to bring a severe analytical critique to bear on results within the range of values with 'which they dealt. I do not take#'' too seriously^' from that source, the suggestion that clinical lead poisoning occurs or recurs in association with levels of lead concentration in the blood of 0.05 mg. (50 micrograms) per 100 grams of blood. It is true that evidences of lead poisoning continue to be found in persons whose blood lead concentration has subsided, but 1 have never seep the onset of symptoms at a level under 80 fiierograms, and I have never seen symptoms recur after they and the hematological signs have disappeared completely, when the blood has fallen to and remains at such low level as 50, 00 or 70 micrograms (checked for accuracy.) per 100 grams of blood, I shall, of course, be convinced if and when, we obtain such findings,, or if there are such results from experienced and reliable analysts (who know the limitations of the methods which they use), Most of our clinical colleagues do not know that the error of the dthizone method at best is of the order of tlO micrograms in the normal range of findings. x now return to the question which I raised with you in my earlier letter. You have stated in this article that significant amounts of lead are (or may be) by, or as you have put it, in association with, acute, infections in children. 1 have never seen this phenomenon in the adult, oven under the influence of' serious infections and intoxication, and while this need not apply to the [child, I'd like to see the evidence that it does not. Is it possible that you are assuming that this is the case because of clinical rather than analytical findings? Please do not think that I am denying, by implication, the truth off your statement. My question is, rather, a straight forward one. In ne with this question, you have also said that the rate of turnover of bone i children differs from that in the adult. This seems probable, and if so it may suit in differences ia the "mobilization" of lead - I should say in the metai lism of bone, generally, and in most of its constituents - but here ag I'd like to be better informed as to the evidence, and as to the extent of the difference. With respect to the means of determining the averag-e or general rate of the urinary excretion of lead. I should like to take exception to the idea that the collection and analysis of a 24-hour specimen is the answer to this problem. I don't think Byers is any authority on this matter. The variability of the process is considerable and several days of observation are necessary for this purpose, if one wishes to be precise. Some compromise or approximation is necessary,I and I should prefer, for very practical reasons. ^ 0015017 J. Julian Chisolm, Jr., M.D. Page 4 February 23, I960 to have several spot samples, collected directly into a satisfactory container under direct observation, to ensure that no contamination occurs. The latter is the chief obstacle to precision, especially in the case of the child, for the use of catheters, or other special equipment, is fraught with the very great likelihood of contamination. The.problem is not insurmountable but extremely difficult, and. only a few people are aware of the difficulties. This is the principal reason for turning to the blood for trustworthy results. As to the renal damage associated with acute intoxication by lead in the child, we have observed the phenomenon, not infrequently, of a very sick child with a high concentration of lead in the blood, and a very low concentration and output of lead in the urine; if and when such a child survives and begins to recover, we have seen the urinary excretion of lead increase and eventually reach a level compatible with tho concentration in the blood:. This fits the tubular injury that has been described at times. What disturbs me is that this type of functional effect la' the only type I have seen. I distrust the alleged evidence of fibrotio and vascular renal damage that has been attributed to lead, oven an the Queensland children. This has been in controversy for a long time, and the evidence is not convincing to me or to many others, including some of the excellent clinicians there. The controversy occupied a lot of space in the Australian Medical Journal, and was not. resolved satisfactorily. Hare again, I am being a bit stubborn perhaps, but, while I respect the views of my colleagues, I am unconvinced. There one point in your article, a minor.one in most minds, but a significant one tlo ipe since we are sow concerned about the total Incidental exposure to lead of i the general population. The dietary intake of lead of the "normal" person in our population, is not 0.5 to 1.0 mg. per day, but is considerably less, fcije mean value, for a large .hummer of individuals, being of the order of 0.30 jmg;.' per day. (It may j.foe as low as 0.12 mg. per day in a person who eats sparingly.) The difference i$ important, since somewhere near 0.5 is just about the maximum that would tie safe, under present conditions with respect to airbojne lead;while an intake 'of 1 mg. per day is. potentially dangerous, if our interpretation of our balance experiments is correct. At this level of daily intake, tho body burden vjfould probably reach a dangerous level in from 8 to 10 years (for under these conditions, . accumulation occurs in the body at a steady rate, indefinitely). You may Relieve that I am: finding a great deal to criticise in your paper. But this is not the case". It is an excellent and thought-provoking paper. What I atjj doing is deliberately picking out ail or almost all points that can be questioned, as I would if we- were to sit down together and exchange ideas with complete frankness. The Written word always sounds more severe in its implications because there is not the opportunity for exchange. I hope you will reply both to my criticisms and my questions in the same spirit. With best: regards. i Sincerely, RAX: wp Dictated but not read Robert A. Kehoe, M.D. He 0015018