Toxicological Sciences, Vol 47, 126-133, Copyright © 1999 by Society of Toxicology
PH Lin, S Waidyanatha, GM Pollack, JA Swenberg and SM Rappaport
Production of chlorinated quinoid metabolites was investigated in the
livers of Sprague-Dawley rats and B6C3F1 mice following single oral
administration of pentachlorophenol (PCP) (0-40 mg/kg body weight) and in
male Fischer 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 rates of adduction in the livers of Sprague-Dawley rats and
B6C3F1 mice suggested that the production of
tetrachloro-1,2-benzosemiquinone (Cl4-1,2-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 (Cl4-1,4-BQ) adducts, on the other hand, was
proportionally greater at high doses of PCP [greater than 60-230 mg/kg body
weight] and was 2- to 11-fold greater in mice than in rats over the entire
range of dosages. A mathematical model employed these data to predict the
rates of daily adduct production and steady state levels of PCP-derived
quinone 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 body weight/day. Levels of total Cl4- 1,4-BQ-derived adducts
in liver cytosolic proteins (Cp) (22.0 nmol/g) and in liver nuclear
proteins (Np) (3.07 nmol/g) were comparable to those of model predictions
(15.0 and 3.02 nmol/g for Cp and Np, respectively). Overall, these results
suggest that species differences in the metabolism of PCP to semiquinones
and quinones were, in part, responsible for the production of liver tumors
in mice but not rats in chronic bioassays.
ARTICLES
Dose-specific production of chlorinated quinone and semiquinone adducts in rodent livers following administration of pentachlorophenol
Department of Environmental Sciences and Engineering, School of Pharmacy, University of North Carolina, Chapel Hill 27599, USA.
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