Project Summary (1995-2000)

The principal objectives of this project are to investigate the in vivo and in vitro metabolism of dichloroacetate (DCA) in humans and rats as well as the developmental toxicology of DCA in infants and children with chronic lactic acidosis during long-term exposure. The pharmacokinetics and metabolism of DCA in infants and children treated with daily, oral doses of DCA for at least 1 year and the metabolism of DCA in infants and children exposed to doses of DCA present in chlorinated ground water are being studied. Comparison of the human in vivo data with similar experiments performed in rats is being performed. These studies are being extended to in vitro experiments aimed at elucidating the mechanism of dechlorination in humans and rats. The pathways of metabolism of DCA are also being studied in vitro using subcellular fractions of rat and human liver, purified enzymes, antibodies and inhibitors, and [¹⁴C]-labeled DCA. This research, therefore, provides the first detailed investigation of the kinetics, metabolic fate and toxicology of DCA, a putative environmental hazard, following acute and chronic exposure of children and the first comparative studies of the chemical in humans and rodents.