Toxicological Sciences, Vol 52, 226-231, Copyright © 1999 by Society of Toxicology
B Said, MK Ross, AK Hamade, DC Matsumoto and RC Shank
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.
ARTICLES
DNA-damaging effects of genotoxins in mixture: nonadditive effects of aflatoxin B1 and N-acetylaminofluorene on their mutagenicity in Salmonella typhimurium
Department of Community and Environmental Medicine, College of Medicine, University of California at Irvine, 92697-1820, USA.
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