Document JrQQ5rd53qy67G5MDnVJbNRkB

12A2/75 Mr. F. F. Hoy: This is the last page of the Dow studyon metabolic pathways of VCM. Note the conclusion suggests that ^CM may have a threshold and can be detoxified by tne body at low concentrations per our recent tel phone conversation. R. S. BROOKMAN r , Toxicology 54 why SK&F-525-A causes a slight inhibition of me CH -CH, -CH----- (CH,)S------CC0H tabolism in rats exposed to approximately 1000 but not 65 ppm VCM. Also it may explain why mono- CH -S chloroacetic acid may be excreted by rats exposed CH. to 5000 ppm but pot 50 ppm VCM. In the former case, chloroacetaldehyde is produced by each of OH the hypothesized pathways which may result in a greater amount being oxidized to monochloroacetic acid than being conjugated with glutathione and/or cysteine. Inferences from the results of these studies about Although this postulated mechanism is highly sr,, ulative,--the rarity of'materials"'known'to prodii" untoward hepatic effects like those of VCM must I given some weight. the toxicodynamics of VCM are preliminary, but worth mentioning. First, the saturation of a primary metabolic pathway for VCM degradation and re direction through other pathways provides some -"hope tHaTa~ threshold concentration for the un told e--Ct f VCM mav exist- Metabolites "of VCM formed only via the alternate pathways may constitute the ultimate toxin and carcinogen. It has been reported that the administration of cysteine or glutathione provides protection against ACKNOWLEDGMENTS These studies were supported in part by a gra from The Manufacturing Chemists Associatio The technical advice of Dr. B. K. J. Leong1 designing the inhalation apparatus and the critic,: review of the manuscript by Dr. V. K. Rowe7gratefully acknowledged. the untoward effects of various aliphatic and aro matic mustards, triethylenemelamine. X-rays, and ionizing radiation12-51115. Conceivably, cysteine and glutathione may provide a natural defense against tumor-producing free radicals generated within the body, as well as synthetic or naturally REFERENCES occurring alkylating agents which are absorbed into 1. Ball, C. R. 1966. Biochem. Pharmacol. 15:809-816.. ,; the body. Therefore, reduction of the nonprotein 2. Calcutt, G., T. A. Connors, L. A. Elson and W. C. J. Ross sulfhydryl content of the liver in animals exposed to 1963. Biochem. Pharmacol. 12:833-837. VCM may constitute predisposition to toxicity and carcinogenicity mediated via other materials. 3. Carter, E. A. and K. J. Isselbacher. 1972. Lab, Inves 27:283-286. Finally, the speculated formation of chlo- 4. Dow Chemical Co. -- Unpublished data. roethylene oxide seems particularly pertinent inso 5. Goldenthal, E. I., M. U. Nadkami and P. K. Smith. 1959: far as postulation of the mechanism of car Rad. Res. 5:571-583. cinogenesis. This compound is undoubtedly a very active difunctional alkylating agent. It is most inter 6. Gonsalus, I, C. 1953. J. Cell. Comp. Physiol. 41 (suppt* 11:133. esting that inorganic arsenicals have been reported to cause untoward hepatic effects, portal cirrhosis 7. Heim, W. G., D. Applemanand H. T. Pvfrom. 1955. Science 122:693-694. and angiosarcoma, like those reported for VCM13. 8. Johnson, M. K. 1965. Biochem. Pharmacol. 14:1383. The mechanism of toxicity for arsenic has been 9. Johnson, M. K. 1967. Biochem. Pharmacol. 16:185-199. shown to occur via its reaction with 6, 8-dithiooctanoic acid (a-lipoic acid)s. In this reaction arsenic forms a stable bridge between the two sulfhydryl groups. If chloroethylene oxide were formed, it would readily react with a-lipoic acid, bridging the sulfhydryl groups like arsenic. 10. Maltoni, C.--to be published in Ann. N.Y. Acad. Sci. 11. Part. H. M. 1953. Physiol. Rev. 33:35-T6. 12. Popper, H. National Institute of Health. Bethesda. 'ID. Personal Communication- 13. Sedlak. I. and R. H. Lindsav. 1968. Anal. Biochem. 25:192-205 14 Soliman, M. R. [.. H. D. Johnson and A. E- W'ade. Ig.4. Drug Metab. and Disposition. 2:87-96. CH + CH,-- CH SH CH------ (CHi)4--------C00H SH 15. Stacev. K. A., M. Cobb. S. E. Consent .-.d P. Ale.under. 1958. Ann. N.Y. Acad. Sci. 68:657. 16. Wagner. E. R. and Muelder, W. W. in press. Ann. NAAcad. Sci. -19741. I/. Zicf, M. and C. H. Schramm. April IS, 1964. Cheat. Ind. 660-^01. OCC 07