TUMOR-INITIATING ACTIVITY AND CARCINOGENICITY OF DIBENZO[A,L]PYRENE VERSUS 7,12-DIMETHYLBENZ[A]ANTHRACENE AND BENZO[A]PYRENE AT LOW-DOSES IN MOUSE SKIN

Dibenzo[a,l]pyrene (DB[a,l]P) is an extremely potent carcinogen that m ay be present in environmental samples. Dose - response studies were c onducted at low doses in mouse skin by initiation-promotion and repeat ed application to compare its activity to that of 7,12-dimethylbenz[a] anthracene (DMBA), benzo[a]pyrene (B[a]P), DB[a,l]P-8,9-dihydrodiol an d DB[a,l]P-11,12-dihydrodiol. Female SENCAR mice were initiated with 1 or 0.25 nmol of DB[a,l]P, DMBA, B[a]P or DB[a,l]P-11,12-dihydrodiol a nd promoted with phorbol ester acetate. At q nmol, DB[a,l]P induced 2. 6 tumors/mouse, whereas DB[a,l]P-11,12-dihydrodiol and DMBA induced 0. 17 and 0.29 tumors/mouse respectively. At the low dose, DB[a,l]P induc ed 0.79 tumors/mouse, but the other two compounds were virtually inact ive. B[a]P, tested only at 1 nmol, was inactive. These three compounds , as well as DB[a,l]P-8,9-dihydrodiol, were tested by repeated applica tion twice weekly for 40 weeks at 1 and 4 nmol per dose. In addition, DB[a,l]P, DMBA and B[a]P were also tested at 8 nmol. At 8 and 4 nmol, DB[a,l]P induced malignant tumors in 91 and 70% of mice respectively. At 4 nmol DB[a,l]P-11,12-dihydrodiol elicited only benign tumors in 36 % of mice. At 4 nmol DMBA induced two carcinomas in one mouse and at 8 nmol it induced one papilloma and one sebaceous gland adenoma. B[a]P and DB[a,l]P-8,9-dihydrodiol were inactive at all doses tested. These results demonstrate that DB[a,l]P is a much more potent carcinogen tha n DMBA, the aromatic hydrocarbon previously considered to be the most potent. Combination of these results with previous comparisons of DB[a ,l]P, DB[a,l]P-11,12-dihydrodiol, DMBA and B[a]P at higher doses (E.L. Cavalieri et al. (1991) Carcinogenesis, 12, 1939-1944) shows clearly t he interference of toxicity with the tumorigenicity of DB[a,l]P and it s 11,12-dihydrodiol.