Dichloroacetate (DCA) is a product of water chlorination and the metabolism of the industrial solvents tri-chloroethylene and perchlorethylene. The presence of DCA in the chlorinated ground water is considered to be a potential environmental hazard to humans, based on toxicological studies in animals at doses exceeding those to which humans may he exposed. Although the dechlorinated end products of DCA metabolism in rodents include CO2, oxalate and glycine, the mechanism of dechlorination of DCA is not known and the relevance of the rodent toxicology of DCA to its human toxicology is also obscure. The principal objectives of this project are to investigate (1) the metabolism of DCA in vivo in humans and rats and in vitro with subcellular fractions of human and rat tissue and (2) the developmental toxicology of DCA in infants and children with chronic lactic acidosis during long-term exposure. The following specific aims and methods address these objectives.
Specific aim 1 : Determine the influence of gender on the in vivo pharmacokinetics and metabolism of single and repeat doses of DCA (sodium salt) in healthy human adults, and quantitate the in vivo metabolites. These studies will test the hypotheses that DCA bioavailability, plasma clearance and routes of metabolism are dose- dependent but are independent of gender. (13C]-labeled DcA will be administered at a range of doses equal to or exceeding those levels that have been reported to exist in chlorinated ground water and be available for human consumption. DcA and metabolites will be quantitated using GC- MS and other analytical techniques.
Specific aim 2 : Determine the pharmacokinetics and metabolism of DCA in infants and children treated with daily, oral doses of 25 mg DCA/kg for at least l year.
This specific aim will address the postulate that the fate of DCA is independent of age in humans, and will provide information on the human developmental toxicology of DCA. Both [13C]- and unlabeled DcA will be administered to subjects aged 3 months to 18 years and its pharmacokinetics and metabolism will be correlated with detailed studies of its effects on biochemical, ophthalmological, reproductive, intellectual and neurological indices.
Specific aim 3 : Compare and contrast the human in vivo data with similar experiments performed in rats, and extend these studies to in vitro experiments aimed at elucidating the mechanism of dechlorination in humans and rats. These experiments will test the hypothesis that the routes of DCA metabolism between rats and humans are qualitatively similar, despite important quantitative differences in pharmacokinetic indices between species. The pathways of metabolism will be studied using subcellular fractions of rat and human liver tissues, purified enzymes, antibodies and inhibitors, [14C]- labeled DCA and several analytical techniques including Gc, HPLC, MS and NMR. This proposal, therefore, will provide the first detailed investigation of the kinetics, metabolic fate and toxicology of DCA, a putative environmental hazard, following acute and chronic exposure to children and adults, and the first comparative studies of the chemical in humans and rodents.
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