Metabolism and mutagenicity of halogenated olefins--a comparison of structure and activity

Chlorinated ethylenes are metabolized in mammals, as a first step, to epoxides. The fate of these electrophilic intermediates may be reaction with nucleophiles (alkylation), hydrolysis, or intramolecular rearrangement. The latter reaction has been studied in the whole series of chlorinated epoxiethanes. The rearrangement products found were: acyl chlorides (tetrachloro-, trichloro-, and 1,1-dichloroethylenes), or chlorinated aldehydes (1,2-dichloroethylenes, cis- and trans-, vinyl chloride). The metabolities found in vivo are identical with, or further derivatives of these rearrangment products, with one important exception: trichloroethylene. With this compound, in vivo rearrangement yields chloral exclusively. The mechanism of the different rearrangement has been identified as a Lewis acid catalysis. All chlorinated ethylenes have been investigated in a tissue-mediated mutagenicity testing system. The prominent molecular feature of those with mutagenic effects (trichloro-, 1,1-dichloro-, and monochloroethylene) is unsymmetric chlorine substitution which renders the epoxides unstable, whereas symmetric substitution confers relative stability and nonmutagenic property.