Hepatic tumor-promoting ability of 3,3',4,4',5,5'-hexabromobiphenyl: the interrelationship between toxicity, induction of hepatic microsomal drug metabolizing enzymes, and tumor-promoting ability.

Female Sprague-Dawley rats were fed diets containing 0, 0.01, 0.1, or 1.0 mg/kg 3,3',4,4',5,5'-hexabromobiphenyl (345-HBB) for 140 days after a 70% partial hepatectomy and diethylnitrosamine administration (10 mg/kg body weight) to determine if 345-HBB had tumor-promoting ability in a two-stage hepatocarcinogenesis assay. Tumor-promoting ability was assessed by measuring enzyme-altered foci exhibiting gamma-glutamyl transpeptidase activity. Enhancement of enzyme-altered foci occurred only at a dietary concentration of 345-HBB (1.0 mg/kg) that was toxic. The toxic effects were decreased body weight gain, involution of the thymus, increased liver weight, histologic and ultrastructural alterations of the liver, and elevated serum concentrations of aspartate aminotransferase. 345-HBB is a strict 3-methylcholanthrene (MC) type of hepatic microsomal drug metabolizing enzyme inducer and caused a dose-related increase of cytochrome P-450. 345-HBB, at a dietary concentration of 0.1 mg/kg, caused a physiologic response in rats as determined by induction of hepatic microsomal drug metabolizing enzymes, but there was minimal evidence of toxicity and no evidence of tumor-promoting ability. Results indicate that there can be induction of MC type of hepatic microsomal drug-metabolizing enzymes without toxicity or tumor-promoting ability and that the tumor-promoting ability of 345-HBB was most likely the result of hepatic degeneration and necrosis. This finding is in contrast to previous studies in which a closely related congener, 2,2',4,4',5,5'-hexabromobiphenyl, enhanced the development of enzyme-altered foci at dietary concentrations that were not hepatotoxic.