Document 5De5Lx8o3qkKQ9Nm4xgr6opOD

toxicology and applied pharmacology 49, 15-2Y (1979) Risk of Angiosarcoma in Workers Exposed to Vinyl Chloride as Predicted from Studies in Rats P. J. Gehring, P. G. Watanabe, and C. N. Park Toxicology Research Laboratory, Health and Environmental Research, and Computations Research Laboratory, Dow Chemical U.S.A., Midland, Michigan 48640 Received June I, 1978; accepted December 2,1978 Risk, or Angiosarcoma in Workers Exposed to Vinyl Chloride as Predicted from Studies in Rats. Gehring, P. J., Watanabe, P. G., and Park, C. N. (1979), Toxicol. Appl. Phar macol. 49, 15-21. Dose-response data for the induction of angiosarcoma in rats exposed to various levels of vinyl chloride (VC) together with attendant biotransformation data were used to estimate the risk of developing angiosarcoma in persons exposed to VC. Since a biotransformation product of VC, not VC-per se, is responsible for the induction of angiosarcoma, the body surface area of people relative to rats was used to estimate the dose of the carcinogen biotransformed from VC by the former; Four models were used to extrapolate the data. Using a probit model, 10 hepatic angiosarcomas were pre dicted to occur in a recently reported epidemiological cohort of 9677 workers whereas five have occurred. Linear models and that based on the equation. Risk = 1 --er?*, where x se dose, do not appear as reliable. For an 8-hr day, 5 days/week, 35-year time-weighted- average exposure of 1 ppm, the predicted incidence of hepatic angiosarcoma using the probit model is 1.5 x 10'*. Exposure of rats (Maltoni and Lefemine, 1975) and humans (Creech and Johnson, 1974; Tabershaw and Gaffey, 1974; Makk et a!,, 1976; Fox and Collier, 1977) to vinyl chloride (VC) has been associated with the development of hepatic angiosarcoma. Nu merous studies in rats indicate that it is not VC per se which is responsible for production of angiosarcoma but rather a reactive meta bolite formed from it in the body (Bartsch etal., 1975; Barbin eta!., 1975; Kappus eta!., 1976; Malavielle et at., 1975; Bolt et al., 1975; Watanabe et al., 1978). Biotransfor mation of VC in rats is a nonlinear process occurring in accordance with MichaelisMenten kinetics; and maximum velocity, respectively, for the biotransformation of VC expressed as micro gram equivalents VC metabolized daily. S and K,, are the concentration of VC being inhaled and the Michaelis constant expressed as micrograms of VC per liter of air, res pectively. Utilizing the foregoing information, Gehring et al. (1978) revealed a good corre lation between the probit percentage inci dence of angiosarcoma in rats exposed to varying concentrations of VC, 4 hr daily, and the amount of vinyl chloride biotransformed, v, microgram equivalents VC metabolized per day. The probit equation is: Probit percentage incidence = v = VmS/(K,,, + S) (1) -- 1.625 4-1.543 Log v. (2) (Watanabe et al., 1976a,b,c; Bolt et al., Hypothesizing that the biotransformation 1976) . In this equation, v and Vm are velocity of VC is related directly to body surface area, O04l-OOKX/7`Z0roOU O7j0'00,0 Copyright 197} hy Academe rres$. tnc. AH fight? of reproduction in jny form rctr*ed. Printed tn Great ttriuin SL 101946