title: Dichloroacetate (DCA) dosimetry: interpreting DCA-induced liver cancer dose response and the potential for DCA to contribute to trichloroethylene-induced liver cancer.
abstract: Pharmacokinetic studies with dichloroacetate (DCA) provide insights into the likelihood that trichloroethylene-induced liver cancers arise from formation of DCA as a metabolite and the mode of action by which DCA induces liver cancer. A simple physiologically based pharmacokinetic model was developed to analyze DCA blood concentration data from mice unexposed to or pre-treated with DCA. The large first pass metabolism of DCA in the liver is significantly reduced by DCA pretreatment. Because DCA inhibits its own metabolism, large increases in area under the blood concentration curve occur at lower doses than would be predicted from single-dose pharmacokinetic studies with naive mice. The dose metrics associated with the incidence of liver tumors in contrast to the multiplicity of tumors per animal may be different, suggesting potentially different roles in the cancer process for DCA versus its metabolites. By linking a model for trichloroethylene (TCE) pharmacokinetics with the DCA model, maximum levels of DCA potentially produced from TCE were estimated to be at or below the analytical chemistry detection limits. In addition, the predicted levels of DCA would be too small to produce the observed liver cancers following corn oil gavage exposure of mice to TCE.
authors.affiliation: The K.S. Crump Group, Inc., ICF Kaiser, Research Triangle Park, NC 27709, USA. habarton@aol.com
authors.forename: H A
authors.initials: HA
authors.lastname: Barton
authors.forename: R
authors.initials: R
authors.lastname: Bull
authors.forename: I
authors.initials: I
authors.lastname: Schultz
authors.forename: M E
authors.initials: ME
authors.lastname: Andersen
mesh_terms: D000818:Animals; D003999:Dichloroacetic Acid / Q000493:pharmacokinetics* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D051379:Mice; D014241:Trichloroethylene / Q000378:metabolism / Q000633:toxicity*
chemical_list: D014241:Trichloroethylene; D003999:Dichloroacetic Acid