Pharmacokinetics and Metabolism of Dichloroacetic Acid and Trichloroacetic Acid Administered in Drinking Water in Rats and Mice

摘要

As by-products of water chlorination, dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are ubiquitous contaminants of drinking water supplies. They are also major metabolites of several heavily used industrial solvents. DCA is a complete hepatocarcinogen and a tumor promoter in B6C3Fl mice. TCA is a tumorigen in mice and affects cardiac development in Sprague- Dawley rat fetuses. To describe the pharmacokinetics of orally ingested DCA and TCA, male Fischer 344 rats and B6C3Fl mice were given DCA in drinking water at 3 different dose levels (rat - 0.1, 0.5 and 2.0 g/l; mice - 0.08, 0.8, and 2.0 g/l) for 3 or 14 days. Blood and liver samples were collected at selected time points up to 8 hr after removal from treated drinking water. Cytosol was prepared from the remaining rat and mouse livers for investigation of metabolic competency. At the end of 14 days of treatment the blood DCA concentrations for mice and rats were 18.5 and 73.3 ug/ml, respectively, at the 2.0 g/l dose level. Liver concentrations at the same time point and dose level for mice and rats were 8.3 and 11.6 ug/ml, respectively. At the 0.08 and 0.8 g/l DCA dose level DCA was not measured in mouse blood or liver. Peak blood concentrations of TCA were 4.3, 30.6 and 93.6 ug/ml in rats drinking 0.1, 0.5 and 2.0 g/l of TCA, respectively, and 10.3, 72.9 and 79.9 ug/ml in mice drinking 0.08, 0.8 and 2.0 g/l of TCA, respectively. A group of mice and rats that received DCA treated drinking water were intravenously dosed with DCA after removal of the treated drinking water to determine inhibition of DCA metabolism. Alteration of metabolic degradation of DCA was substantial at the 0.8 and 2.0 g/l drinking water dose levels in both rats and mice.