Dichloroacetate (DCA) is a product of water chlorination and metabolism of various industrial solvents and pharmaceuticals. The presence of DCA in 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 are usually exposed. In contrast, DCA is an investigational drug for several acquired and congenital diseases, but therapeutic doses are approximately 10,000 times greater than environmental levels. This competitive renewal application combines patient-oriented and laboratory research to address three Specific aims: 1) Investigate the kinetics of single and repeat DCA dosing in healthy adults. These studies will test the hypotheses that DCA kinetics and metabolism are dose-dependent but are independent of gender. DCA will be administered orally and intravenously at doses equal to or exceeding environmentally relevant levels. The in vivo fate of [13C1, 2] DCA will be quantified by GC/MS and LC/MS. 2) Investigate the kinetics, metabolism and developmental toxicology of DCA in infants and children with congenital lactic acidosis who are exposed to daily, oral administration for at least one year.
This aim will address the postulate that altered plasma clearance of DCA following repeat administration is independent of age and that DCA exerts no significant toxicity in children. 3) Determine the potential in vivo genotoxicity of DCA using freshly isolated peripheral blood cells and urine from pediatric and adult subjects. Experiments will test the hypotheses that this xenobiotic exerts dose-dependent, but not gender-dependent, adverse DNA and chromosomal effects.
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