Performance of 181 chemicals in a Drosophila assay predominantly monitoring interchromosomal mitotic recombination.
An evaluation is presented of the effects of 181 chemicals in the (white/white+) (w/w+) eye mosaic assay, an in vivo short-term test measuring genetic damage in somatic cells of Drosophila after treatment of larvae. The genetic principle of this system is loss of heterozygosity for the wild-type reporter gene w+, an event predominantly resulting from homologous interchromosomal mitotic recombination between the two X chromosomes of female genotypes. The w/w+ eye mosaic test detects a broad spectrum of DNA modifications, since all distinct classes of genotoxins are monitored. Non-DNA-reactive chemicals are in principle not detected by this system. Occasional positive responses obtained for chemicals such as amitrole, ethionine and hexachloeroethane are probably not related to the mechanism responsible for their tumorigenicity. The principle outcome of this analysis is the necessity for classification of responses into three categories. (i) Positive, '++'. The 92 chemicals (Tables II and III) falling into this category were clearly recombinagenic in the assay, meaning that dose-response relations were obtained (or could have been established as was evident from the strong responses obtained at one or two exposure doses). Among the 92 chemicals were 49 promutagens including volatile chemicals such as vinyl bromide and vinyl chloride. (ii) Marginally positive, '+w'. The definition of a weakly positive response is the absence of a dose-response relationship due to the fact that a weak but reproducible effect, in most cases no more than a doubling of the spontaneous clone frequency, is inherently related to toxicity. The 40 chemicals (Tables IV and V) belonging to this category mainly represented four distinct types. (a) Procarcinogens, such as 2-acetylaminofluorene, dibenz[a,h]anthracene, p-dimethylaminoazobenzene, 2-naphthylamine and safrole, for which metabolic conversion was the apparent problem in the assay. (b) Electrophilic chemicals of high nucleophilic selectivity: acrolein, acrylamide, acrylonitrile, epichlorohydrin, chloroethylisocyanate, 1,2-epoxybutane, N-methyl-n-vinylacetamide, methyl vinylketone, 2-methyl-2-vinyloxirane and methyl vinylsulfone. These chemicals have a relatively low DNA reactivity. Chloroethylisocyanate was active only in the absence of excision repair, suggesting that efficient DNA repair is the cause for the weak genotoxic effectiveness of these genotoxins. (c) Spindle poisons (Table V) were active at rather low but toxic exposure levels. Irregularities in the structure of ommatidia were seen at dose levels producing no more than 2- to 3-fold increases in clone frequencies. (d) The fourth group consisted of chemicals generally regarded as non-genotoxic carcinogens: amitrole, ethionine, ethylurea, tetrachloroethylene and thiourea. Their weak responses were always accompanied by signs of toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)
Vogel
E W
EW
Department of Radiation Genetics and Chemical Mutagenesis, Leiden, Netherlands.
Nivard
M J
MJ
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002875:Chromosomes / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D005127:Eye Color / Q000235:genetics; D005260:Female; D006579:Heterozygote; D007814:Larva; D008938:Mitosis / Q000187:drug effects; D009030:Mosaicism / Q000235:genetics; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology; D011355:Prodrugs / Q000494:pharmacology; D011995:Recombination, Genetic / Q000187:drug effects; D008941:Spindle Apparatus / Q000187:drug effects; D013329:Structure-Activity Relationship
D000963:Antimetabolites; D002273:Carcinogens; D003432:Cross-Linking Reagents; D009153:Mutagens; D011355:Prodrugs