Dose-specific production of chlorinated quinone and semiquinone adducts inrodent livers following administration of pentachlorophenol

Production of chlorinated quinoid metabolites was investigated in the liver s of Sprague-Dawley rats and B6C3F(1) mice following single oral administra tion of pentachlorophenol (PCP) (0-40 mg/kg body weight) and in male Fische r 344 rats, following chronic ingestion of PCP at 1,000 ppm in the diet for 6 months (equivalent to 60 mg PCP/kg body weight/day). Analyses of the rat es of adduction in the livers of Sprague-Dawley rats and B6C3F(1) mice sugg ested that the production of tetrachloro-1,2-benzosemiquinone (Cl-4-1,2-SQ) adducts was proportionally greater at low doses of PCP (less than 4-10 mg/ kg body weight) and was 40-fold greater in rats than in mice. Production of tetrachloro-1,4-benzoquinone (Cl-4-1,4-BQ) adducts, on the other hand, was proportionally greater at high doses of PCP [greater than 60-230 mg/kg bod y weight] and was 2- to 11-fold greater in mice than in rats over the entir e range of dosages. A mathematical model employed these data to predict the rates of daily adduct production and steady state levels of PCP-derived qu inone and semiquinone adducts in rats and mice. To evaluate predictions of the model, levels of PCP-derived adducts at steady state were investigated in the livers of male Fischer 344 rats chronically ingesting 60 mg PCP/kg b ody weight/day. Levels of total Cl-4-1,4-BQ-derived adducts in liver cytoso lic proteins (Cp) (22.0 nmol/g) and in liver nuclear proteins (Np) (3.07 nm ol/g) were comparable to those of model predictions (15.0 and 3.02 nmol/g f or Cp and Np, respectively). Overall, these results suggest that species di fferences in the metabolism of PCP to semiquinones and quinones were, in pa rt, responsible for the production of liver tumors in mice but not rats in chronic bioassays.