Document ZnJyqE6KLNVgvVn8QBx5YOOp

yfe\ j. LEAD INDUSTRIES ASSOCIATION, INC. 11 MADlSOtt AVKNUI NCW VO**, H. Y. 10017 TTVC^HOMS - A.AC& CO fttft C MM Key 14, 1964 To 411 Keabars < f the Health and Srfuty Cccsdtteoi Attached for your mforaation, consents ani criticises# la a oop7 of a **>rk proposal bj Dr. Valles of the Harvard Nodical School. Aa you reneeber this vs* discussed brlofly at our Health and Safety Cceclttee Keetlr^ aa Agenda Itee Bo. 4. Will you plaaaa let aa have your thought# on tha suitability of thia type of research to aeet tha industry1 a needs and j whether you would like to sake changes and suggestions to Dr. Valles? 3 When we hare obtained your cccsenta we will ask Dr. Valise to write ua a proposal and develop a contract for research which will than be subeitted to you for an approval or disapproval. Tery truly yours* 'pTy^a^u^ is Den 0. fowler. Secretary Health and Safety Cccnltte# DGftad &M. . ua iliwiii <r*jgFwwa.!ry<v u - *yw*japv \ 1 '*U*' > "1% jSi>s--j1 m*- LI A115 30 -NjTM 1 ' '-Sty- A Biochenical Approach to Lend Toxicity Bart L. Vallee, M.D. Biophysics Research Laboratory Harvard Medical School ? i N 379.01 Li a 1153I Tho diagnosis of lead poisoning has depended both on the identification of this element in sacples of blood and urine and upon the clinical nanifestatlons observed subsequent to exposure. However, the analytical chcnis* try of lead as well as uncertainties surrounding Its retabolisn have resulted in r.ajor discrepancies of data obtained and of their interpretation. This has ccaplicated the recognition and nanagesent of tho disease. For the same reasons, the evaluation of the clinical state of industrial workers exposed to this occupational hazard have presented cocplcx probleas, both r.edical and legal. Efforts to clarify the basis for these uncertainties have not been satisfactory. This nay be attributed in large acasure to the circumstance that the metabolic role \ of eetals in general, and that of lead in particular, have been understood poorly. It has certainly not boon possible to reduce the clinical ranifestations to a meaningful set of blochenicai denominators. In recent years nuch has been learned about the lnteractlonof eetals with racromolecules in general and proteins In particular, especially those with cnzyeatic function. Lead, like rercury, cadnlur. or zinc,the elonents of the JIB group of the periodic systec, Interacts preferentially with sulfhydryl groups of both slnple and complex molecules. Since sulfur groups play a major role both in the stabilize* tlon and function of proteins and enzymes, aajor disorders ray be expected vhon excess quantities of metal are available for Interaction with and blocking of these groups* Thus, peripheral neuritis and encephalopathy which accompany ',"SS. LI A11532 *^-V ' -2lntoxication both with cercury and lead and, of course, othor elements has been attributed to the formation of such Bcrcaptidos. The therapeutic relief often obtained by neans of agents such as DAL is duo to their successful competition for the toxic eetal ion. However, not enough is understood currently to integrate the results of sporadic investigations that have been conducted. It seecs clear that a core rational diagnosis and therapy could ensue if systematic studies were to be conducted to localize the interaction of lead and to ascertain the stability of the conplexes formed and their functicnal or toxic import. A number of observations suggest that lead inter feres with hemoglobin synthesis and, in fact, at differ ent stages of the synthetic pathway of porphyrins. It has been shewn, for example, that lead ray inhibit the synthesis of 4-anino levulinic acid froa glycine and succinyl cocniycc*A, the synthesis of prophobilinogen fros 4-acino levulinic ocid; and the synthesis of heat fron protoporphyrin and iron. It is known, coreover, that patients with chronic lead intoxication excrete increased quantities of urinary coproporphyrln and uroporphyrin, presuaably as ' consequence of lntorferenco with the seat critical steps in the Mechanise of hone synthesis. Ve ourselves have shown that lead may displace the functionally essential tine atoms of various tine con taining eniyaes, resulting either in cocplete inactiva tion or in the alteration of the activities of a given 9 enxyae. It seecs cost likely that the actual concentre- LI A115 33 "" ' i /; -3tions of lead In serun and urine are but the resultant of the couple* interactions of lead with cany molecular species that uust be expected in a heterogenous environ* cont such as cellular and serun proteins constitute. Mo therefore propose to study critically the role of lead in hese synthesis and the resultant changes in sorun and urir.o lead concentrations of living eninals, employed as test systens for the codels that can be devised. Thus for instance, it would be of great in* terest to know whether or not lead Mocks the notal binding site of transferrin, the iron binding globulin of serua, -which is a critical intermediate in iron trans* port and hone synthesis. (Xir laboratory has a longstanding tradition of work in this general area and is fully eoulpped for analytical checical work by ecission spectroscopy, atonic absorption spectroscopy and sicrochcnicai analyses to deal with problcns posed either by isolated protein systens or those which cay be encountered in living aninals and can. K are sieilarly equipped for all phases of protein checlstry and enzynology. In the past, our studies have been concerned with the role of line, copper, agnesiun, arsenic, nickel, cadnlun and chronlun and our efforts in this regard are a natter of literature record. Vo feel certain that studies of the type here suggested would clearly advance the ales of the Institute and we would he pleased to nake specific suggestions for future studies if this should be desirable. \