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© 1982 Oxford University Press

research-article

Comparative genotoxicity studies of ethyl carbamate and related chemicals: further support for vinyl carbamate as a proximate carcinogenic metabolite

J.W. Allen 1, R. Langenbach 1, S. Nesnow 1, K. Sasseville 1, S. Leavitt 1, J. Campbell 2, K. Brock 2 and Y. Sharief 2

1Mutagenesis and Cellular Toxicology, Carcinogenesis and Metabolism Branches, Genetic Toxicology Division, Health Effects Research Laboratory, U.S. Environmental Protection Agency Research Triangle Park, NC 27711
2Northrop Services, Incorporated Research Triangle Park, NC 27709, USA

In vivo and/or in vitro mammalian cell systems were used to evaluate sister chromatid exchange (SCE) induction and gene mutagenesis effects following exposure to ethyl carbamate (urethane), vinyl carbamate, ethyl N-hydroxycarbamate, and 2-hydroxyethyl carbamate. Although ethyl carbamate caused dose-dependent increases in SCE when injected into mice, it was ineffective for inducing SCE and gene mutation (6-thioguanine resistance) in Chinese hamster V-79 cells cultured with or without the addition of S9 enzyme mix during treatment. Chemical-specific patterns of genotoxicity were evident for the known or suspect metabolites under test: only vinyl carbamate consistently (in vivo and in vitro) revealed strong activity for the genetic endpoints. SCE induction levels of 5–8 times baseline were observed after animal or cell culture exposures to vinyl carbamate. Doses required to produce this effect in V-79 cells in the presence of S9 mix were ~100 times lower than those needed when S9 was absent. The extensive gene mutagenesis (approaching 600 mutants/106 survivors) noted was completely dependent upon the presence of S9 mix. These observations are consistent with current theory holding that vinyl carbamate is a metabolic intermediate of ethyl carbamate, and is converted to the ultimately reactive species (presumably, vinyl carbamate epoxide) which is responsible for ethyl carbamate carcinogenesis.


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