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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

International Agency for Research on Cancer, Unit of Chemical Carcinogenesis, 150 cours Albert-Thomas, 69372 Lyon Cédex 2 [A. B., C. M., L. T., H. B.]; Institut National de la Santé et de la Recherche Médicale, Unité de Physiologie Cellulaire, Institut du Radium, Faculté de Sciences, 91405 Orsay [F. Z.]; and Institut de Chimie des Substances Naturelles, Centre National de Recherche Scientifique, 91190 Gif-Sur-Yvette [A. C.], France

Repeated s.c. administration of chloroethylene oxide, 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 either bis(chloromethyl)ether or chloroethylene oxide, followed by 3-times-weekly applications of 12-O-n-tetradecanoylphorbol-13-acetate for 42 weeks, 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 three compounds was noted. Our results support the hypothesis that epoxidation of the ethylenic double bond in vinyl chloride yields an ultimate carcinogenic metabolite, chloroethylene oxide, a highly reactive compound which appears also to be largely responsible for the known genetic changes caused by the parent compound.

¹ Partially supported by National Cancer Institute Contract NO1-CP-55630 from the National Cancer Institute, NIH, Bethesda, Md.

² To whom requests for reprints should be addressed.

Received 7/30/79. Accepted 11/ 6/79.

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