Comparative dose-response tumorigenicity studies of dibenzo[alpha,l]pyrene versus 7,12-dimethylbenz[alpha]anthracene, benzo[alpha]pyrene and two dibenzo[alpha,l]pyrene dihydrodiols in mouse skin and rat mammary gland

Comparative studies were conducted of the tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland of dibenzoa,l]pyrene (DBa,l]P) versus 7,12-dimethyl-benza]anthracene (DMBA), the most potent recognized carcinogenic polycyclic aromatic hydrocarbon (PAH); benzoa]pyrene (Ba]P), the most potent recognized carcinogenic environmental PAH; DBa,l]P 8,9-dihydrodiol, the K-region dihydrodiol; and DBa,l]P 11,12-dihydrodiol, precursor to the bay-region diolepoxide. The tumor-initiating activity of DBa,l]P and Ba]P was compared in the skin of female SENCAR mice at doses of 300, 100 and 33.3 nmol. The mice were promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA) twice-weekly for 13 weeks. DBa,l]P at all doses induced significantly more tumors than Ba]P at the corresponding dose, with a significantly shorter latency. Subsequently, the tumor-initiating activity of DBa,l]P was compared in the skin of female SENCAR mice to that of DMBA, Ba]P, DBa,l]P 8,9-dihydrodiol and DBa,l]P 11,12-dihydrodiol at doses of 100, 20 and 4 nmol. The mice were promoted with TPA twice-weekly for 24 weeks. In addition, groups of mice were initiated with 100 nmol of DBa,l]P, DMBA, Ba]P, DBa,l]P 8,9-dihydrodiol or DBa,l]P 11,12-dihydrodiol and kept without promotion. This experiment showed that in the mouse skin, DBa,l]P and DBa,l]P 11,12-dihydrodiol displayed similar tumor-initiating activity with a response inversely proportional to the dose, presumably due to the toxicity of the compounds. At the high dose they elicited tumors earlier than DMBA, though DMBA produced a much higher tumor multiplicity. At the low dose, DMBA, DBa,l]P and DBa,l]P 11,12-dihydrodiol exhibited similar tumorigenicities. DBa,l]P 8,9-dihydrodiol was a marginal tumor initiator. Once again, DBa,l]P was by far a much stronger tumor initiator than Ba]P. Female Sprague-Dawley rats were treated with 1.0 or 0.25 mumol of DBa,l]P, DMBA or Ba]P by intramammillary injection at eight teats. DBa,l]P at both doses was a more potent carcinogen than DMBA at the corresponding dose in the rat mammary gland. Ba]P was a marginal mammary carcinogen, eliciting only a few fibrosarcomas. Thus, these data suggest that DBa,l]P is the strongest PAH carcinogen ever tested.