Document b5NMvQD7X5Z01kj9yoGMNypVo

FOR DU PONT USE ONLY HASKELL LABORATORY LEAD (ORGANiC AND INORGANIC) For more than fifty years it has been recognized that chronic exposure to lead can adversely affect the human reproductive system. However, most of these effects resulted from the heavy industrial exposures which were common in the early part of this time (7, 16. But see 15 for disagreement). EffectsofOiganolmdCompoundsoaRatEmbryonicandFetal Develop ment Mc Cl mn ,R- A.(1972).Tojrfco/.yf/ip/./,Aannoco. 21,265-274. Tetraethyl lead CTRL) and tetrafaethyl lead (TML) and tri- roethyl leadchloride (TriML), were found to be essentially iwntewtbgeflSc fa Sprague-Dawley rats. Oral doses ofTEL (73,15, of 30 rag/kg), TML (40, SO, 112, or 160 mg/kg) and TriML (13,30,or 38mg/kg) were admini* steredas 3divideddosesciurinj early orfano*enes5*(days9,10,and 11) pr late orsanoitenesis (days l2,13, and WX tbe day of positive sperm being day 1. In addition, TriML was admlnlstered iv at doses of 20,28,33, or 40 mg/kg on individuri gestatkm days S Uuough 15 inclusive. The highest dose of each compound fa each experfafentwas lethal to the maternal animal. Lower dot* levels produced typical slight to severe maternal erganofead toxicity, dependent upon desk Embryo or fetal toxicity was observed to accompany tbs administration of die organokad compounds and wa* characteriMd far growth retardation and delayed ossification of bone. Marked fetal effects were observed only fa maternal animals that exhibitedteffcrcorgaBoieadtoxicityandwere,thcrcforc,scvcrelydebilitated. Infusion studies with TriML revealed that the rate ofplacental transfer was minimal when bloodconcentrationswere bdowan apparent saturation of binding sites on maternal erythrocytes ami was greatly increased at maternal blood concentrations above this saturation point. When the maternal anfatal was by-passedby'directintra-amnioticinjectionsofTriML (10-100 pg/fetus) dose-related fetal lethality was observed. , Abstract Groups of pregnant albino mice and rata were treated by garage with dotes up to 714 mg lead acetats^kg or 10 mg tetracthyikad (TELVkg The compounds were administered daily during the period of rapid organogenesis {days 3-13 of pregnancy for mice and days 6-16 for rats). Maternal toxicity was observed and foetal resorption and general retardation of development were encountered at the higher dosage levels, blather lead compound caused any congenital .malformations. Foetuses derived from lead-exposed females were examined grossly and for internal structural and skeletal devel opment but so teratogenic response was evident, even at dose levels at which frank signs of maternal toxicity were observed. It is concluded that lead, as the acetate or as tetraethyllead, is not teratogenic to the mouse or rat. /3\ 6Z9 A National. Academy of Sciences review expresses the view that industrial lead exposure is also not a genetic hazard currently - because, of improved hygienic controls*. However, there is disagreement on this point; Haley urges (exclusion of pregnant women from lead-using industries, citing .recfent reports (Bourret and 24ehl) of increased spontaneous abortion rates among lead-exposed typographers. Ragucci agrees, noting that absorption of as little as 1-2 mg. lead/day can cause abortion, premature birth, and intrauterine death; ^ Part of the uncertainty concerning industrial"- lead effects on child-bearing females arises from a lack of epidemiological data (1, 8,15, 16) . Women have been excluded from most lead industries since about 1920**. Only one study of the type needed has been reported since that time; a survey of lead arsenate-exposed' orchardists and consumers of sprayed fruit (11). It concludes that "a clinical state approaching that of frank lead poisoning is necessary before the fertility of men or women is affected". A-second cause for confusion is the difficulty in diagnosing low-level lead poisoning. With the exception of motor palsy, the symptoms of plurabism are nonspecific (8), and it is possible -that fetal abnormalities due to chronic poisoning in the parent have not been identified as such. ' The most serious reproductive hazard from lead in this country is caused by pregnant women drinking lead- contaminated whiskey. . Auto radiators soldered with lead are used as moonshine .stills, resulting each year in cases of sterility, abortion, and fetal deformity. In 1966, 17,000 of these stills were seized in the Southeastern United States (13) * "The effect of lead pn human reproduction is primarily of historical importance". (1) **Reports of high fetal morbidity among female lead workers led to this exclusion. " .. References Attached Reference in C-1516 -2 . DUP0400112381 References 1. Airborne Lead in Perspective, Committee on Biological Infects of Atmospheric Pollutants, National Academy of 'Sciences, Washington, D., C. (1972), pages 117, 153 and >.154 enclosed. : 2, Anon. Food Cosroet, Toxicol, 7:255-60 {1969). "lead astray?" Enclosed, ^ 3, Baker, 3. B- E. Pharmacol. Rev. 12:37-90 (1960). Summary* attached; . 4. Butt, E, M, and D. G, Simonsen. Ain. 3- Clin. Bath. 20:716-23 . (1950). Summary enclosed. 5* Fahian, M. S'- et al. Science News 101:264' (April 1972). ,, Enclosed. 6.. Greenfield, I. N. Y. State J. Med. 57:4032-4 (1957). Summary enclosed, 7, Haley, T. 3. Clin, `Toxicol, 4:11-29 {1971), * - 8, Bafdy, H. L, Clin. Pharmacol, and Therapeut, 7s713-22 (1966). Summary enclosed. V ' 9, XdpRich, F. et al. Acad, Repub. Pop. Roja. Fil- Clnj,; Studii Cere. Stidufc 3(1-2) : 339-54 (1954). Stannary enclosed. 10. Larabin, P, Cahiers Med, Travail 4^:191-216 (Apr.-Jnly 1966). Summary enclosed, 1.1, Neal, P. A, et al. Public Health Bull. #267, Wash,, D. C, O.S.G.P.O. (1941), No copy enclosed. * - * 12. Nogaki, K. Igalu Kenkyu 27(6^1314-38 (1957). Summary enclosed. 13. PalMsano, P, A. Clean Air and Water News 2_(43) :3 (Oct. 1970). Enclosed. "14. Ragucci, N. Minerva Ginecolog. 21:1163-71 (Sept. 1969)Summary enclosed, 15, Scanlon, 3, Clin. Ped, 11:135-41 (Mar. 1972). Summary enclosed. *All summaries, unless otherwise noted, are taken from The Biological Aspects of Lead: An Annotated Bibliography, I, R, Campbell and E. G. Margard; Kettering Laboratory, Cincinnatti (1972), covering the 1950-64 literature, and The Kettering Abstracts on Lead, Lead industries, Inc. covering 1965-74. -3 - DUP040011239 16., Symposium on Air Quality Criteria J. Occ. Med. 10:437-567 (1968). Summary enclosed. 17. Valyi-Nagy, T. et al. Acta Physiol. Acad. Scien. Hunger. 5_:537-42 (1954), Summary enclosed. 18. Van Assen, F. J. J# Nederlands Tijdschrift Verloskunde Gyn. 58(3-4)s258-63 (1958). Summary enclosed. / 19. Verraande -Van Eck, G. J. and J. W. Meigs Fertil. and Steril, 11.S 223-34 {I960) , Summary enclosed. 20. Waldron, H, A* and D, Stofen Sub-clinical lead Poisoning, Academic Press, N. Y. (1974), Also .Enclosed.: ' j Chemcon printout of recent (1972 to present) references. Copies* of Haskell "Lead File" references on reproductive effects Basis Of, Effibryotoxic Classficafcion Historical - dates back to years ago in TEL areas of chandlers Works (See C-1516). Richard C. Graham:md May .25, 1978 DUP040011240 I Lead C'OiStQ Carcinogenicity? Although many human diseases have been correlated with lead exposure, cancer is not. one of them (1). Some salts of lead are known to be carcinogenic in animals (2) with the kidney the main target organ, but the equivalent dose level which would be needed to induce such tumors' in man is well above the maximum tolerated dose (3). Mutagenicitys There is no firm experimental evidence that lead can affect animal cell imitations at physiological concentrations (!). Teratogenicity? The fetal effects of chronic lead exposure were recently reviewed (4); a copy Is attached, . N ~nmi }1. Airborne Lead In Perspective, National Academy of Sciences, Wash.,D.C. ~~ Pp7l57 a5cl lY57 2, Lead acetate to rats and mice; lead subacetate and lead phosphate to rats; possibly lead arsenate and lead carbonate (see Ref. 1), 3. IARC Monographs on the Evaluation of Carcinckrenic Risk, Vol. I internatl. Agency for Res. on Cancer,Lyon (1972), p.: 48, 4, Letter, N, Hunt to B. W. Karrh 3/31/75. N, J.Hunt tnn E. X.Du Font de Nemours & Co, Haskell Laboratory 5/19/75 DUP040Q11241