We have undertaken studies to characterize the biological effects of TCPOBOP [1,4-bis-(3,5-dichloropyridyloxy)benzene], a highly unusual chemical which is a potent tumor promoter, complete carcinogen and inducer of P450IIB1 in the mouse (3 mg/kg, one i.p. injection biweekly), while it is relatively ineffective as a promoter or inducer in the rat at even 10 times that dose (30 mg/kg, one i.p. injection biweekly). This compound is of particular interest, since despite the fact that it is a potent complete carcinogen, it appears that it is not mutagenic to Salmonella typhimurium tester strains. We have undertaken to examine the coordinate induction of a hepatic """"""""pleiotropic"""""""" response in various strains and species of rats and attempted to relate these results to tumor promotion. Various strains of rats responded similarly to 500 ppm phenobarbital, inducing various cytochromes P450 (IlBl, IIA1, IIIAI), glucuronyl transferases, and epoxide hydrolase. This similarity of induction by 500 ppm PB is apparently paralleled by the fact that tumor promotion is observed in all strains. In contrast to the clear-cut """"""""pleiotropic"""""""" effect observed in all strains of rats, PB and related compounds do not necessarily yield parallel responses in all animal species. Thus, in hamsters and cynomolgus monkeys, PB does not induce cytochrome P45OIlBl, while in mice, patas monkeys, and rabbits, the induced P450s show strikingly different substrate specificities than those observed in induced rats. Finally, we have expanded our studies on the relationship of IIB1 induction to tumor promotion/carcinogenesis to include a number of compounds of environmental importance, e.g., DDT, a-hexachlorocyclohexane and Aroclor-1254. These studies demonstrated that DDT and Aroclor-1254 have strong tumor promoting activities in D2B6Fl mice. However, we found that at lower doses of Aroclor-1254, which are most likely to be environmentally significant, only limited induction of P450IIBI is observed.
