title: Characterization by two-endpoint comparisons of the genetic toxicity profiles of vinyl chloride and related etheno-adduct forming carcinogens in Drosophila.
abstract: The genetic toxicity profiles of vinyl chloride (VCl), vinyl bromide (VBr), ethyl carbamate (EC), vinyl carbamate (VC) and some structurally related chemicals were investigated in both somatic and germ cells of Drosophila melanogaster. In the white/white+ eye mosaic assay, a screening system measuring predominantly homologous recombination in somatic cells, only marginal genotoxic activities were observed for acetyl chloride (ACl), glycolaldehyde (GCA), 2,2'-dichlorodiethyl ether (DDE) and methyl carbamate (MC), whereas VCl, 2-chloroacetaldehyde (CAA), VBr, 2-bromoacetaldehyde (BAA) and EC were clearly recombinogenic in the assay. Those chemicals proven to be recombinogenic in somatic cells were investigated further in postmeiotic male germ cells, utilizing as descriptors of their genotoxicity I(CL/RL) and M(exr-)/M(exr+) indices. The I(CL/RL) index is the rate of induced chromosome loss (CL), a clastogenic event, divided by the forward mutation rate, measured as recessive lethal (RL) mutations in 700 loci of the X-chromosome. The M(exr-)/M(exr+) mutation enhancement ratio is obtained by determining RL under excision repair deficient versus repair proficient conditions. With I(CL/RL) values (2.7-6.9) similar to those obtained for cross-linking agents, vinyl chloride, vinyl bromide, ethyl carbamate and vinyl carbamate are all efficient clastogenic agents in Drosophila germ cells. In the absence of excision repair, however, neither CEO nor CAA gave a hypermutability response (M(exr-)/M(exr+) approximately 1). By contrast, VCl, VBr, EC and VC showed clearly enhanced M(exr-)/M(exr+) ratios, suggesting that these compounds produce some repairable DNA modification(s) that are not generated by their epoxides. This unexpected finding points to the formation of other, yet unknown, metabolites of vinyl chloride, vinyl bromide, ethyl carbamate and vinyl carbamate. Our results support the concept that the epoxides chloroethylene oxide (CEO), bromoethylene oxide (BEO) and vinyl carbamate epoxide (VCO) are the most essential mutagenic intermediates. Compared to chloroethylene oxide (CEO), 2-chloroacetaldehyde (CAA) was approximately 50 times less effective in the induction of RL, whereas BAA was inactive as a mutagen. These findings are consistent with the general view that CAA and BAA play no major role in the genotoxic action of vinyl halides.
authors.affiliation: Medical Genetic Centre South-West Netherlands, Leiden, The Netherlands.
authors.forename: L A
authors.initials: LA
authors.lastname: Ballering
authors.forename: M J
authors.initials: MJ
authors.lastname: Nivard
authors.forename: E W
authors.initials: EW
authors.lastname: Vogel
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D003432:Cross-Linking Reagents / Q000633:toxicity; D004331:Drosophila melanogaster; D005027:Ethylene Oxide / Q000031:analogs & derivatives / Q000633:toxicity; D008297:Male; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D013329:Structure-Activity Relationship; D014752:Vinyl Chloride / Q000633:toxicity*
chemical_list: D002273:Carcinogens; D003432:Cross-Linking Reagents; D009153:Mutagens; C015061:chloroethylene oxide; D005027:Ethylene Oxide; D014752:Vinyl Chloride