Comparative genotoxicity studies of ethyl carbamate and related chemicals: further support for vinyl carbamate as a proximate carcinogenic metabolite.
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-thio-guanine 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 approximately 100 times lower than those needed when S9 was absent. The extensive gene mutagenesis (approaching 600 mutants/10(6) 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.
D000818:Animals; D001711:Biotransformation; D001854:Bone Marrow Cells; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D005796:Genes / Q000187:drug effects; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D012854:Sister Chromatid Exchange / Q000187:drug effects; D013723:Teratogens; D014520:Urethane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*
D013723:Teratogens; D014520:Urethane; C017963:vinyl carbamate