Importance of Dichloroacetate and Trichloroacetate to the Hepatocarcinogenic Response to Trichloroeylene in B6C3F1 Mice
Final rept. 15 Sep 1986-14 Sep 1989
WASHINGTON STATE UNIV PULLMAN COLL OF PHARMACY
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Trichloroethylene TCE is one of the most ubiquitous environmental contaminants. Its widespread commercial use in degreasing operations and as a solvent has lead, through improper disposal, to its being the most common synthetic organic chemical contaminant of groundwater. This project was aimed at determining the extent ot which the metabolism of trichloroethylene TCE to trichloroacetate TCA and dichloroacetate DCA was responsible for its hepatotoxic and hepatocarcinogenic effects in B6C3F1 mice. These effects were observed consistently only at high doses and were transitory, suggesting the modification to be non-specific. The project shifted to determining whether DCA and TCA could account for the hepatotoxic and hepatocarcinogenic effects of TCE in quantitative terms. It was established that both DCA and TCA were capable of inducing tumors at much lower doses with a shorter latency than TCE. DCA was very hepatotoxic, and tumorigenic response appeared to be dependent upon these effects. The tumorigenic effects of TCA were closely associated with the accumulation of lipofuscin and the induction of single strand breaks in hepatic DNA in vivo. Evidence suggests that DCA acts primarily by increasing growth of hyperplastic nodules whereas TCA appears to accelerate progression of tumors. Data suggest that TCA probably primarily was responsible for the hepatocarcinogenic effects of TCE. The cytotoxic effects of DCA-treatment may well contribute significantly to carcinogenic responses at very high doses of TCE. Keywords Trichloroethylene Trichloroacetate Dichloroacetate Hepatotoxicity Carcinogenicity B6C3F1 mice.
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