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COMPARATIVE MUTAGENICITY OF HALOMETHANES AND HALONITROMETHANES IN SALMONELLA TA100: STRUCTURE-ACTIVITY ANALYSIS AND MUTATION SPECTRA
Citation:
Kundu, B., S. D. Richardson, C. A. Granville, D. T. Shaughnessy, N. M. Hanley, P. D. Swartz, A M. Richard, AND D M. DeMarini. COMPARATIVE MUTAGENICITY OF HALOMETHANES AND HALONITROMETHANES IN SALMONELLA TA100: STRUCTURE-ACTIVITY ANALYSIS AND MUTATION SPECTRA. MUTATION RESEARCH 554(1-2):335-350, (2004).
Impact/Purpose:
To compare the mutagenic potencies of halonitromethanes to those of their halomethane homologues
Description:
Halonitromethanes (HNMs) are a recently identified class of disinfection by-products (DPBs) in drinking water that are mutagenic in Salmonella and potent inducers of DNA strand breaks in mammalian cells. Here we compared the mutagenic potencies of the HNMs to those of their halomethane (HM) homologues by testing all 9 HNMs and 7 of the 9 HMs (minus bromomethane and chloromethane) under the same conditions (the pre-incubation assay) in Salmonella TA100 +/- S9. We also determined the mutation spectra for several DBPs. In the
presence of S9, all 9 HNMs, but only 3 HMs, dibromomethane (DBM), dichloromethane (DCM), and bromochloromethane (BCM) were mutagenic. Only 2 DBPs of each class were mutagenic in the absence of S9. The HNMs were generally more potent mutagens than their HM homologues, and the brominated forms of both classes of DBPs were more mutagenic and cytotoxic than their chlorinated homologues. The HNMs were at least 10 times more cytotoxic than the HMs, and the estimated cytotoxicity rankings in the presence of S9 were similar for the HNMs and the HMs. The addition of a nitro-group to BCM did not change the mutation spectra significantly, with both homologues inducing primarily (55-58%) GC -- AT transitions. The greater cytotoxic and mutagenic activities of the HNMs relative to the HMs are likely due to the greater intrinsic reactivity conferred by the nitro-group. Energy calculations predicted increased reactivity with increasing bromination and greater reactivity of the HNMs vs. the HMs (Elumo values were ~20 kcal/mol lower for the HNMs compared to their HM homologues). Given that the HNMs are potent genotoxins in mammalian cells (Environ. Sci. Technol., in press) and are more mutagenic and lOX more cytotoxic in Salmonella than the HMs, whose levels are regulated in drinking water, further study of their occurrence and potential health effects is warranted.