Effects of PCBs and related compounds on hepatocarcinogenesis in rats and mice.

Commercial mixtures of polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs) can cause hepatocellular carcinoma in rats and mice. Present evidence indicates that these chemicals act as promoters and not initiators of hepatocarcinogenesis. Our results show that Firemaster BP-6 (FM) and its nontoxic major congener, 2,2', 4,4', 5,5'-hexabromobiphenyl (HBB), act as promoters in the two-stage model for hepatocarcinogenesis devised by Pitot and associates. A toxic congener, 3,3', 4,4', 5,5'-HBB, also was assessed for tumor-promoting activity. This congener, though not in FM, is similar to TCDD, in that both cause 3-methylcholanthrene (MC)-type induction of hepatic microsomal enzymes and produce similar toxic responses. FM contains several congeners which are mixed-type inducers in that they induce MC-type and phenobarbital (PB)-type enzymes. The toxicity of FM is most likely associated with its congeners which are mixed-type inducers and not to relatively nontoxic congeners such as 2,2', 4,4', 5,5'-HBB which are strictly PB-type inducers. Congener 3,3', 4,4', 5,5'-HBB acted as a tumor promoter only at a dose that was hepatotoxic. A synergistic effect on tumor promoting ability was produced by combining a nontoxic and nonpromoting dose of 3,3', 4,4', 5,5'-HBB with a promoting dose of 2,2', 4,4', 5,5'-HBB. Our results suggest that synergism between toxic and nontoxic congeners in FM may explain why mixtures such as FM have greater promoting ability than individual congeners. Our results also indicate that with PBB, toxicity and carcinogenicity are not necessarily related.