Document wwLwgVZm7zE9rNJVMwjM8eXQ

( CORRESPONDENCE) r ID o o k N21139 Baltimore City Hospitals 4940 Eastern Avenue Baltimore, Maryland. 21224 pear Doctor 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 jfche course of preparing a monograph on lead, I 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 tp 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 ar 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 exposure,^s not treated in any way until samples of blood and urine have been obtained. Thip, of course, does not mean that therapy need be or should foe delayed, if it 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 to determine is whether the urinary concentration of lefd 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 "propltive test" with a chelating agent to be appropriate, for the simple reason that it distorts the distribution of lead in the body, and renders it impossible to determine its pattern. I do not believe that anyone 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 ice 0015015 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 of thumb" that has no physiological meaning, how 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. The idea 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 penaci11amine?) and it is antirely possible that the brevity-: of its action (at}out 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 usefulness of B.A.L., alone, for this purpose|, because of the slencjer quantitative effect. The removal of a few milligrams of lead from the body, 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 some vjital site. Is there any evidence! that such can bs done? Incidentally, I had! hoped that a thiol of lesser toxicity than B.-t.L.,, might be 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 tissuesand remove it again akd again, we might accomplish the! "deleading" much more rapidly and effectively. to the consideration of the blood as a soft tissue that reveals the gnral 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 able, through the careful study of our metabolic data^ to write a formula in 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 |burden can then be caloujlated. I believe this, because, in our experience, the metabolism of lead [in the body is remarkably stable in its pattern. In tljis connection you have considered the relative abundance of the erythrocytes, as indicated by the hematocrit, to be an in portant factor in the concentration of lead in tiie blood. I cannot say flat! y that this is not the case, but I'd like very much to see the evidence for it. I doubt the truth of the statement, for the reason that the erythr ocytes have a very large capacity for binding lead. There must, of course, be some kind of equilibrium between the erythrocytes and the plasma, but the avidity of th erythrocytifc: binding of lead is o great that the concentration of lead in the plasma is always very low, so low, in fact, that it is difficult to find differences in the S co by iionerieff 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' their analytical results. Their ideas are naive and their analytical procedures leave something to be desired. I have corresponded with them, 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 seirere analytical critique to bear on results within the range of values with which they dealt. I do not i-akejjf 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 continued to be found in persons whose blood lead concentration has subsided, but I have never seep the onset of symptoms at a level under DO raicrograras, 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, ox course, be convinced if and when, we obtain such findings, or ill 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 aithizone method at best is of the order of flO micrograms in the normal range of findings. . I 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) mobilized from the skeleton by, or as you have put it, in association with, acute, affections in children. I have never seen this phenomenon in the adult, even 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 of your statement. My question is, rather, a straight forward one. In line with this question, you have also said that the rate of turnover of bone in children differs from that in the adult. This seems probable, and if so it may result in differences in the "mobilization" of lead - I should say in the metabolism of bone, generally, and in most of its constituents - but here again, I'd like to be better informed as to the evidence, and as to the extent of the difference. i With respect to the means off determining the average or general rate of the urinary excretion of lead, jI 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,fand I should prefer, for very practical reasons, KE" 0015017 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 is the only type I have seen. I distrust the alleged evidence of fibrotio and vascular renal damage that has been attributed to lead, even in 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 ip one point in your article, a minor one in most minds, but a significant one tie ip since we are now concerned about the total Incidental exposure to lead p i \the general population. The dietary intake of lead of the "normal*' person in our population, is not 6.5 to 1.0 mg. per day, but is considerably less, tlj mean value, for a large humlber of individuals, being of the order of 6.30 rag. per day. {It may i.he as low as 0.12 mg. per day in a person who eats sparingly.);: The difference is important, since somewhere near 0.5 is just about:th| maximum that would lie safe, under present conditions with respect to airborne leadjwhile .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, the. body burden would probably reach a dangerous level in from 8 to 10 years (for under these conditions, .accumulation occurs in the body at a steady rate, inpefinitely). 1 You may Relieve that I am finding a great deal to criticize in your paper. But this is not the case". It is an excellent and thought-provoking paper. What I ar^j doing is deliberately picking out all or almost all points that can be questioned, as I would if we were to sit down together and exchange ideas with complete ifrankness. 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 beati regards, ; Sincerely, itili:wp Dictated but not read Robert A. Kehoe, M.D K 0015018