Document 10G19kv65e1Q2w0jqyzDmXmLa

INSTITUTE OF C H ILD HEALTH U n iv e h st y o f L o n d o n M H C T O m N U m L D m O K U O R o r C H tiO HKALTM. V AUAHMONCMW. r.s.c^ .. r.n.c.o^.. j.r. * *. A. - o v u t y d im c t o r i, ; , _ .N O R M A R K .A X . .O i , OCA* . A. H, N IW N 1 >4 ' * *c**vit*Sr>^-Vw'-^'''\ Wh, A . R 1 0 9 0 M . A ^ C t i A ' : w` a THE H O SPITA L FOR: SIC K C H IL D R B K k GREAT ORMOND S T R E ^ ; - L O N D O N . W .C -1 : ^ V-;i T iL iP H o u n * '- H O L B O R N 2 ! * ft I X * " : .5 *' September 24-th, 1964. DeaS? B r . Kehoe, :/ : Manjl thanks for your further letter, and I hare- alee seen what you wrote to Dap.Clayton* <- " . . : - -.' < -1..I 'ha also grateful;to you for^the Harhen/ ;Leo%urea,*J-:-;c Curiously enough I ha^ce already been 'roanedrpt-^opy hy the Royal Institute, of Public Health"|hecause I gave the |Adtm?ee far 1963 : and"thhy kindly sent me y o ^ .Lectures to see the sort ^..ner al styla - ,t .Jt Yours s x-i-- .,1.: $ Sir Alan Moncrie . x- -V- ,V%'.'> - - sa 7v ' .; i jrS 1. *" -.T-- \*> ."V \ / Dr. Robert A*.Kehoe, University of Cincinnati^ Department of Preventive'Medicine and Industrial Health, The Kettering Laboratory\ College of Medicine, r Eden Avenue, Cinoizmati T9, OHIO,U.S.A. & lira o i 040 '# ' '^ v .;i/.; Ehre*; TL "2. - m m /.:v S ;, v x - v-"' /-j *,. v., ..::-;:':i\.:vi,vv^'''*i'Ks:f/;:.Vv,Kf..j-,j&fr*,'i?\.i...U4y `..:-vy & # !v/ *^ ^ > '; ' ^ &L* l 'l'{:\. ,. . t; v >.. ... &;... . \,V| '. I '..,' * -, ;:i.'H ', 1"k*'vOv/'jye. * ?M - ,?Mff1. \ \'K~ ''Ul /* ;g :O' y*t /i ' -''-V-'- " :" " - '*' '' ffi `r&t*a&4i .V* , .4 *vy' AlBJMfcA, 'uf: O;'- v: *;;*; X) i' /> il = `i S O s L ? " if- - S ! A ? w f c ''A - ' f e W ^ S ? . a | s . ^ i$f%'!ii`.l!g'. st.I" . pii; ; in.* 1$ iff V\; r : i^ i^ rr itodiflati 19, OHI, .S*A. --* 1 .. . rJfS.'jl. .- (, , 1--I------------- -- ~~1 am* odUna: ^T O ^_ O ES \y 'i,'-J',:-V*':'N "v- . A s i V -'-K ' V .1 ;. . .. " .?} 1V? '-VJ-.:<#> }.*>'iv; Vj W .!:'S-!* I ->' . , ' , 1 * , fr vV , -r : *-j *'.. * K t f i>, -j INSTmJTE CHILD HEALTH, GREAT RMOND STREET. LONDON, W.C.l. vi. AN AIR LETTER SHOULD NOT CONTAIN ANY ENCLOSURE: IF IT DOES IT WILL BE SURCHARGED OR SENT BY ORDINARY MAIL ,j'l* ":i 'i/? - ><.' ;:; ': ' ..'"V""'+t*^-e Form approved by the Postmaster General, No. 71995'/2E I MPERIAL AMR MAIL A I MO a MA M M i i *iredo o; September 4, 1964 Barbara K. Clayton, M.D., Chemical Pathologist The Hospital for Sick Children Great Ormond Street London, W.C. 1, England Dear Doctor Clayton: I am pleased to have your letter of August 25, and X hasten to deal with the point of special concern as to the "levels of lead"(in the blood and tissues, associated with) "clinical evidence of toxicity." This is a matter that has continued to give rise to misunderstanding of the specific significance of the analytical findings in the urine, blood, spinal fluid, or other body fluids or tissues,Including those obtained at necropsy. The fact, quite clearly, is that the concentration of lead in tissues or body fluids is not indicative of the existence of intoxication, but rather of the general level of the absorption of lead. These findings measure hazard but not illness, in as much as illness never Ca& so far observed) occurs unless the concentration of lead in the body has reached a certain level, but it does not necessarily occur hen the potentially dangerous range has been reached. For one example, we have never seen a case of lead poisoning, at the onset of the illness, in a person whose blood contained less than 80 micrograms of lead per 100 grams (whole blood). On the other hand, we have seen persons without symptoms whose blood contained ten times this concentration. It is evident, from these facts, that there is some mechanism, presently unknown and not capable of being even postulated, whereby lead in the tissues (in the gross sense) in an essentially inert fora is activated. I think of this as being chesUcally bound (un-lonlzed) and then coming into an ionized state, but there is no evidence that such is the case, and the matter may be quite complex. The phenomena of chelation fall, so far as I am concerned, to shed any very clear light on the problem. From the point of view of diagnosis, therefore, the analytical results contribute only the conclusion that the lead content of the blood (or indirectly, the soft tissues) is either compatible or incompatible with the diagnosis of plumbism, In practice, it can be said, under appropriate conditions, that this is definitely not lead poisoning, or that it is compatible with the diagnosis of lead poisoning. The tendency of modern physicians and, of course, the non-physicians who are Involved in diagnostic problems, is to employ the laboratory to furnish "scientific" proof of the nature of disease. This is at least one example of the fallacy of this type of thinking, for the diagnosis of lead poisoning is made on clinical grounds within the limits of the situation defined by the analytical findings. This is hard for many modern physicians to accept, but in your country, in which clinical medicine has been practiced for so long and so 01042 Barbara E. Clayton, M.D. - (2) - September 4, 1964 skillfully by so many keen observers, this should not pose too much of a problem. You will note of course, that there is no difference between your definition of the "normal range" of the findings in the blood, urine or tissues. It is likely, however, that this range, as so defined, differs quantitatively in England and the U.S.A. Ve know fairly well the con tribution made by various environmental factors in the U.S.A., and we have Some, but not nearly enough, information about your environment, with respect to food, water and air. It is my tentative opinion that your environment differs significantly from ours, but there may not be enough difference to be of any practical consequence. So long, however, as it does not approach the level of danger, it makes very little difference clinically. I do not suppose, for a moment, that the physiological differences in the human population, will cut much of a figure in the out come. (I am, of course, unable to appraise the nutritional situation within your juvenile population, and I am by no means certain of the facts within the varied economic levels of this population in the U.S.A. I would consider it likely, however, that this factor may play some part in the incidence of lead poisoning among children.) One other feature of your letter seems to call for some emphasis in my reply. You may not have meant to do so, but your reference to the "possibility of lead poisoning........... in industry" seems to minimize, somewhat, the significance of this matter. It appears (on somewhat unsatisfactory statistical evidence) that lead poisoning is the most frequent type of intoxication that occurs in American industry. In any case, my experience of nearly forty years in relation to a broad spectrum of the lead trades in the U.S.A., enables me to have a fair idea of the situation. The most significant advance in preventive medicine in this series of industries during the past several decades has been the establishment of the threshold of the danger of lead intoxication in terms of the lead con tent of the blood and (somewhat less effectively) the urine. Itiis this point which I had wished to emphasize in my letter to Sir Alan, since there is no question as to the fact that there is a sharp threshold. This is the precise reason that I objected to the statement, in the article, that the significajice of the level of lead concentration in the blood is uncertain. There is, of course, the mathematical uncertainty, as between 80 micrograms of lead per 100 grams of whole blood and the analytical error of the analytical method which may be as little as 4 0.01 mlcrogram, or as much as 0.05 microgram, dependent upon the specific method (among the good methods) employed by a competent analyst. However, there is no doubt as to the physiological fact that there is a well-defined threshold. (There may be, of course, highly unusual persons who do not fit the common pattern, but our thousands of observations over many years, under highly varied condltons, have established, as fact, the essential stability of the metabolism of lead in the human organism.) I must get on with the mountain of work which has accumulated on my desk during a vacation which has ended Just now. This brings me to terminate this discussion. Uy interest in your efforts, which will be evident to you, ^ 0 01 043 Barbar* B. Clayton - (3) - September 4, 1964 derive, in considerable part, from my hope that you and your associates will extend your work on this dread disease of childhood, so as to visualize clearly the environmental factors which affect it in Great Britain, and the means by which these factors can be brought under adequate control. Sincerely yours, R.1K: vr Robert A. Kehoe, M.D. 01044 THE HOSPITAL FOR SICK CHILDREN G R E A T O R M O N D S T R E E T . L O N D O N . W.C.1 C h a ir m a n > C L A U D E A. L U C A S . KftQ . t o . m a f .c . a H o u s e GOVIRNOR * SfCRITARY O - J . P I L L E R . r H A. Te l irhonc . HOLBORN 9 2 0 0 T il ig r a p h ic A d d r e ss : GREAT. HOLB. LONDON 2t>th August, 194 Jear Jr. ivehoe, On ny return irea holiday Bir Alan Boacrieff has passed your iaterestiag letter to me. It may be that we have aot made our poiat clear, jy t h e :,normal raa0e of lead ia olood'1 we meaia the levels we fouad ia a series of childrea exposed to the eaviroameatal lead of a city lime London but who have aot beea chewiag at all sorts of objects. I would fully appreciate your coaclusioas about the levels of lead at which cliaical evideace of toxicity defiaitely is a ^ a r e a t . to my miad, much work remaias to be doae to determine whether there is aay evideace of damage as a result of the iataice of lead so that the level ia the blood lies betweea that aormally fouad and the higaer levels giving cliaical toxicity. These boruerliae cases may be of 0reat significance ia the aetiology of mental retardation. I am of course familiar with your worm and already possess reprints of your narbea Lectures. These were mindly given to me by*Jr. damps. They have, of course, been a great source of interest. I agree with you chat the possibility of lead poisoning is an extremely important one ia industry and it is certainly of growing importance ia paediatrics. I strongly agree that our aim must be no prevent the possibility of children receiving increased internes of lead. ihaax you very much for the interest you have taxen. lours sincere i.y, Barbara J.Jlaytoa, J . , L.P.d.P. , rh.D., Jhemical patholo0ist. dopy to Prof. Jir Alan Moncrieff. Jr. -t.A.Aehoe, university of Jincinnati, Jollege of Jenicine, _dea Avenue, Jincinnati 19, Ohio. 0104 5 September 3, 1964 Professor Sir Alan Moncrleff Institute of Child Health The Hospital for Sick Children Great Ormond Street London, W.C. 1, England Dear Sir Alan: Please accept my thanks for your reply to my letter of some weeks ago, concerning lead poisoning. I have had a letter recently from Dr. Barbara Clayton, to which I have replied at some length, because of my obvious interest in the matter. I trust that she will bring this to your attention, for it concerns itself, among other matters, with issues that are strictly clinical. This, incidentally, aside from general physiological considerations, has been my role in our work, not so much in the detailed performance of clinical practice (which I have engaged in in the past) but rather in the application of preventive medicine to the clinical and toxicological problems of industry. There is much more to this than meets the eye of the analytical chemist or the biochemist. This is why I consider that you depreciate your contribution by suggesting that you are "only the clinician." I believe you will find the Harben Lectures (1960), of which I am sending a bound copy, to be a combination of physiological infor mation and its direct application to hygiene and clinical problems. I trust that I have some understanding and appreciation of academic life, since I have been in this environment most of my life. However, for a physician, with a physician's view of life, it is far from being the protected life in the ivory tower, or a retirement from the world into the realms of pure science. I do not scorn the latter, but it has never been my cup of tea. Sincerely yours, RAK:vr Robert A. Kehoe, M.D Enel. - Harben Lectures of 1960 ECU / INSTITUTE OF C H ILD HEALTH U n iv e r s it y o f L o n d o n O lM C T O K ft N U F F IE L D M O ^ r i l O M O P C H IL D H EALTH . A L A N M O N C R I C r r . C.ft.C.. M.O.. P.A .C .P .. F.W .C .O ... J.P . Oepoty d im c t o r : A. P. N O PM A N . M .B.E.. M .D.. P.ft.C .P. DEAN i O . H. N I W N S , M.D.. P.ft.C .P. SBCftWTAWY ? D. A. R E D I T O N ft.A.. P.C.A THE H O SPITAL FO R SIC K C H ILD R EN GREAT ORMOND STREET. LONDO N. W .C.l. T lL IP H O N n I H O L B O M X I XIXX July 29th, 1964. Dear Dr. Kehoe, Thank you for your very interesting letter about lead poisoning. I am afraid that I am only the clinician in the team and my colleague, Dr. Barbara Clayton who is head of our Biochemistry Department, is on leave until the end of August. I will certainly have your letter waiting for her on return. I am sure that we should find your Harben Lectures most interesting, although I was shown them briefly a little while ago when I was asked to give the Lectures for 1963 and wanted to get some idea of the length and style. It was very kind of you indeed to take all the trouble to write to us in so much detail. Yours sincerely,,. Professor Sir Alan Moncrieff Dr.R.A. Kehoe, University of Cincinnati, Department of Preventive Medicine and Industrial Health, The Kettering Laboratory, College of Medicine - Bden Avenue, Cincinnati 19, Ohio. I / y<Ky-: ir ''H'.fy.':'I'-' (par AVION,' i ^AI1|l LF.TT'^yr 1 ` ' jlROORAMME H ','jj \ `' K;' " v -'.'i Dr. R . . K e h b e , +' -`Vi r,, - 'A 1 - o. r';f ' University of Cincinnati, DpAitiljent of Preventive Modicinr and -ind-ae-trini-~^ei.th , 'V*)* +&' n ___________ 'V- 5 v i 4 ;v' ' VCblXofce ) ''tW Bden Avenue, Cincinnati 19. v,% 4M fcorndTuldhtlf^ B 10 j-- U-S A*' v<` Srbdtr'i anni od xMmmi * A)) CO o V---- CD ES & * ' S -ijr-, INSTITUTE OF CHILD HEALTH, GREAT ORMOND STREET, LONDON, W.C.l. A' !AN AIJR'L,E,TTER SHOULD NOT CONTAIN ANY ENCLOSURE: ", IF IT DOES IT WILL BE SURCHARGED . 1 OR SENT BY ORDINARY MAIL. I Form approved by the Ponrnaster General, No. 7199V2E /.t- IL U ' - V-o IMFBMIAL AIM MAIL AIROORAMMli u q jno na<!o o f July 18, 1864 A. A. Soncrieff OipartMUt of Chemical Pathology The Hospital for Sick Children,aud ths Institute of Child Health Orest Ormond Street London, England Dear Sir: My unfamlliarlty with Paediatrics and Paediatricians in your country denies me the privilege of addressing you with a proper salutation, for which^I trust, I any be forgiven. The occasion for this communication is an article by yourself and your associates in British Archives of Disease in Childhood, 1964, 39, 1. This otherwise splendid article has in it one highly significant conclusion shiah I believe to be incorrect, and since the point involved la crucial in relation to diagnosis, and even wore so in relation to industrial hygiene, I cannot refrain from commenting on it. X have considered it wiser, as well as more courteous, to write to you directly, rather than through a letter to the editor, for ay purpose is not to raise an objection ae a matter of record, but to invite your comments and apre particularly,^your search for evidence in support of your expressed view or mine. X shall not subtract ;anything from ay emphasis an this cam point, by coastsnting on any of the other M p f s t i of the physiological and clinical information assembled la this excellent paper. X should say, however, that it la necessary to examine, skeptically, the statements of a number of American authors, with respect to the significance of the analytical findings in the urine, blood and solid tissues, for exactly the same reason that I give in criticising your interpretation of the same data. There la no substitute for direct experience in these matters, and there are very few persona in the United States or elsewhere, who have had such experience. My point of departure from your position, which is also that of Byers and others cited in the very beginning of your article, relates to (1) the "normal" range of lead in the blood (of both adults and children), and (3) the variability of the levels of the concentration of lead in the blood which are indicative of lead poisoning. The first of $hsse requires little comment, perhaps, although the environmental background of the term "normal" in our day, as in former times, ia of more than a little significance, considering the natural opportunities for the absorption of lead, and the ubiquity and variety of the artificial factors in the environment. Concerning the second point, it seems evident that the variables? Id the concentration of lead in the blood of both adults and children have so Impressed themselves upon most of the interpreters of these phenomena as to have obscured almost utterly the facts A i o h emerge when the variability is examined critically In relation to the clinical entity of lead poisoning, snd the factor of time. X shall explain in some detail what ia meant by the latter part of the last sentence. There can be no doubt, whatever, that there is a high degree of variability 01 049 A. A. Moncrieff - (2) - July 15, 1964 in the concentration of lead in the blood. There is also, as the counter part of this variability, a high degree of variability in the rate of the absorption of lead by persons in our society. These relationships have been investigated in some detail in this Laboratory over the period of many years, and it is important to recognize, in this connection, an extremely important matter. The analytical data so obtained have been furnished by the same persons, employing the same two methods of analysis, in parallel, which have been in use essentially unchanged since 1938. The error associated with the application of each of these two methods has been well defined, so that the data can be given essentially absolute significance in positive and negative terms. The importance of this fact, in relation to the concentration of lead in the blood, is fundamental to the consideration of many of the analyt ical data which have found their way into the literature from certain other sources, especially those concexaed with case reports. Several practical facts have been established by these means. 1. It is entirely certain that there is no level of lead in the blood which is indicative of lead poisoning. Persons with very high levels up to approximately 1000 mlcrograas of lead per 100 grams of whole blood, may be wholly free of symptoms (not necessarily free of certain biochemical deviations from the apparently normal range). 2. Conversely, there Is a range of concentration, which is wholly incompatible with the onset of illness due to lead. In our experience with adults this is utterly incontestable at this time. No case of lead intoxication in industry has ever been found to occur (at the onset), in our experience, except in association with the concentration of lead In the blood equivalent to or in excess of 80 micrograms per 100 grams. (The exact point, if there is a point rather than a narrow range, is difficult to establish, for the reason that there is, inevitably, a small unknown area within the range of the variability of analytical precision. Thus a single finding of 80 micrograms may be 75 to 85 micrograms, at best, or 70 to 90 micrograms, at worst, in terms of analytical error. Only occasionally, however, is this a matter of practical importance, and then it can usually be settled by Multiple analyses.) 3. Our observations of "normal" and sick children, made over the period of more than twenty years, in collaboration with our colleagues in the Department of Paediatrics of this Medical Center, have indicated, beyond reasonable doubt, that the relationships of the concentration of lead in the blood to clinical plumbism in childhood are essentially the same as those in adult life. Children with high levels of concentration of lead in their blood (above the theshold) are not necessarily ill. There seems to be somewhat greater threat of the "triggering" of intoxication in the child than in the adult, but there may well be such a simple explanation of this as that the exposure of the child is shorter and more severe, in quantitative terms of absorption, and is thiis more difficult to handle^, than is that of the adult in the industrial environment. (The fact is, of course, that we do not understand the mechanism by which an excessive quantity of lead in the body initiates intoxication.) Q 01050 A. A. Moncrieff - (3) - July 15, 1964 V* bay never found an exception to the rule that, at the onBat of load intoxication, tb blood of the child contain 80 or more micrograms of load par 100 grains. It is trua that certain avidances of pluabiam persist (in sufficient intensity to Justify the diagnosis on historical grounds), after the concentration in the blood has subsided. It is also true that there are often residual findings Induced by organic injury, especially to the central nervous systea, which, on the historical basis (and on the fairly unique character of certain neuro-muscular lesions), can be diagnosed as the effects of the absorption of lead in excessive amount. Moreover, certain unpredictable (or so it seems to me) vagaries of the relationships between the concentration of lead in the blood and tbe "body burden" have resulted from the institution of chelation therapy. All of the foregoing factors, plum variability in analytical precision in various hands, have entered into reports in the literature in recent years. I have yet to encounter a systematic investigation, in the bands of competent persons whose analytical facilities are above criticism, which has brought out data that are in essential disagreement with any of the statements I have made in the several paragraphs above. Tou may suspect, at this point, that I have gone to extravagant lengths in presenting this issue to you. And so I have, if I were concerned only with the problem of diagnosis of lead poisoning. There is, however, a good reason for ay concern and this relates to the importance of the concentration of lead in the blood, from the aspect of preventive medicine, in industry, particularly, but alao in the general field of environmental medicine and hygiene. If you have examined the data, and the thests in preventive medicine that emerges irom the Harden Lectures on "The Mstsbolism of Lead in Health and Disease, ' you say realize that this is a very crucial point in the recognition of the danger of plumbism, before any illness or disability appears. The adoption and implementation of this principle in industrial hygiene has served to eliminate,utterly, the occurrence of cases of lead poisoning in a number of industries. Its-general application would clean up the "lead trades" in this country. This 1 nave been undertaking to bring about in an appropriate professional manner for many years. At this time considerable progress is being made. This progress could be brought to a standstill, or nearly so, If tne principle, itself, were to be regarded, in certain circles as Invalid. The application of this principle is costly, initially, in a badly managed (from tbe aapect of industrial hygiene) Industry. It is also troublesome, medically, because it requires understanding, attention to detail, and a thoroughgoing development of professional responsibility, on the part of persons who "do" industrial medicine with their left hands in their "spare time." (I should not like to be quoted in this vein, for reasons which will be evident to you, I believe, and it is for this reason, among others, that I write to you rather than to the editor of the Archives.) I trust that what I have taken the trouble to say will be of some Interest to you and your colleagues in their further investigation of this important and preventable (wltl* some difficulty to be sure) disease of childhood. A. A. Moncrieff - (4) - July 15, 1964 Incidentally, If you or others of your associates would like to have bound copies of the reprints of the Harben Lectures referred to above (and In your article), I shall be pleased to supply them. Cordially yours, RAK:vr cc - Dr. P. S. I. Barry Robert A. Kehoe, II.D. ^ E 01052