Halogenated acetates are produced in the disinfection of drinking water by chlorine, chloramine or ozone. In waters containing low bromide concentrations, chlorinated derivatives predominate. However, trace amounts of bromide in the water will result in a predominance of brominated analogs. Recent studies have shown that dichloroacetate (DCA) is a potent hepatotoxin and hepatocarcinogen in B6C3Fl mice and F344 rats. On the other hand, trichloroacetate (TCA) is a potent, but species specific hepatocarcinogen for mice and does not induce the hepatotoxic effects observed with DCA. Thus, there seems to be some ability to differentiate between processes that are involved in inducing hepatotoxic and hepatocarcinogenic effects of these compounds. Acutely, DCA is a more potent inducer of lipid peroxidation, whereas TCA appears more active chronically as a peroxisome proliferator. Pretreatments with DCA exacerbate the lipid peroxidation resulting from an acute dose of DCA, while pretreatment with TCA inhibits formation of thiobarbituric acid reactive substances (TBARS) following an acute dose of TCA. Pretreatment with another peroxisome proliferator, clofibrate, blocks TBARS formation following an acute dose of either DCA or TCA. These results are at odds with the greater accumulation of lipofuscin seen with chronic treatments with TCA in mice. The present project examines the relative ability of DCA, TCA and two monobrominated analogs, bromochloroacetate (BCA) and bromodichloroacetate (BDCA), to induce lipid peroxidation, peroxisome proliferation, 8-OH-guanine formation in hepatic DNA and RNA, cell proliferative responses and to protect against chemically-induced lipid peroxidation in mice, rats and guinea pigs. The studies will specifically examine how modification of cytochrome P450 and aldehyde dehydrogenase expression might account for the differing effects of these chemicals in mice (a susceptible species), rats (a selectively sensitive species) and guinea pigs (a species predicted to be non-susceptible to TCA and other peroxisome proliferators). These experiments should provide some important insights into how sensitive humans might be to these by-products of drinking water disinfection.
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