CARCINOGENICITY OF CHLOROETHYLENE OXIDE, AN ULTIMATE REACTIVE METABOLITE OF VINYL-CHLORIDE, AND BIS-(CHLOROMETHYL)ETHER AFTER SUBCUTANEOUS ADMINISTRATION AND IN INITIATION-PROMOTION EXPERIMENTS IN MICE

Abstract

Repeated s.c. administration of chloroethylene oxidase, a reactive metabolite of the carcinogen vinyl chloride, induced local tumors in mice, with an incidence comparable to that of bis(chloromethyl)ether, a structurally related human and animal carcinogen, when both compounds were applied at maximum tolerated chronically toxic doses; no tumors distant from the injection site were produced. Bis(chloromethyl)ether, chloroethylene oxide and its rearrangement product chloroacetaldehyde, a highly toxic compound, were further tested in an initiation-promotion experiment. Application to the skin of a single dose of bis(chloromethyl)ether or chloroethylene oxide, followed by 3-times-weekly applications of 12-0-n-tetradecanoylphorbol-13-acetate for 42 wk, produced skin tumors in mice; chloroacetaldehyde under comparable conditions produced no increase in benign or malignant tumors. A good correlation between the chemical reactivity, on the basis of hydrolysis constants in aqueous media, and the carcinogenicity of the 3 compounds was noted. Apparently epoxidation of the ethylenic double bond in vinyl chloride yields an ultimate carcinogenic metabolite, chloroethylene oxide, a highly reactive compound which also appears to be largely responsible for the known genetic changes caused by the parent compound.