title: DNA-damaging effects of genotoxins in mixture: nonadditive effects of aflatoxin B1 and N-acetylaminofluorene on their mutagenicity in Salmonella typhimurium.
abstract: Most animal genotoxicity studies have used exposures to single chemicals; humans, however, are potentially exposed to mixtures of genotoxins. Cancer and developmental toxicity risks associated with genotoxins in mixture are generally estimated by assuming additivity of the components. Two or more genotoxins acting sequentially or simultaneously may present a greater or lesser hazard than that predicted by simple addition of their potencies. Previously, we studied the effect of one genotoxin on the binding of a second genotoxin to DNA in an in vitro system and demonstrated that consecutive binding of the two toxins was not additive. In the present study, the effect of one genotoxin on the mutagenicity of another was evaluated for two well-known genotoxins using the Salmonella assay. Pretreatment of frameshift strains TA98 and TA1538 with AFB1-8,9-epoxide (17.3 ng/plate) enhanced the mutagenicity induced by subsequent exposure to N-acetoxy-acetylaminofluorene (N-AcO-AAF) approximately 2-3 times above theoretical values for additivity. Pretreatment of base-substitution strain TA100 with N-AcO-AAF (0.1 microg/plate) inhibited the mutagenicity following subsequent exposure to AFB1-8,9-epoxide by 3 times below the theoretical additive value. Concentration-response relationships for these enhancing or inhibitory effects were demonstrated using increasing concentrations of the first genotoxin during pretreatment. These results demonstrate effects, other than additive, of sequential exposures to two genotoxins on the induction of mutations in a bacterial system.
authors.affiliation: Department of Community and Environmental Medicine, College of Medicine, University of California at Irvine, 92697-1820, USA.
authors.forename: B
authors.initials: B
authors.lastname: Said
authors.forename: M K
authors.initials: MK
authors.lastname: Ross
authors.forename: A K
authors.initials: AK
authors.lastname: Hamade
authors.forename: D C
authors.initials: DC
authors.lastname: Matsumoto
authors.forename: R C
authors.initials: RC
authors.lastname: Shank
mesh_terms: D015073:2-Acetylaminofluorene / Q000633:toxicity*; D000099:Acetoxyacetylaminofluorene / Q000633:toxicity; D016604:Aflatoxin B1 / Q000031:analogs & derivatives / Q000633:toxicity*; D000483:Alleles; D004249:DNA Damage / Q000187:drug effects*; D016368:Frameshift Mutation / Q000187:drug effects; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics*
chemical_list: D009153:Mutagens; C006426:aflatoxin B1-2,3-oxide; D000099:Acetoxyacetylaminofluorene; D015073:2-Acetylaminofluorene; D016604:Aflatoxin B1