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 may be present in environmental samples. Dose-response studies were conducted at low doses in mouse skin by initiation-promotion and repeated 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 and 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 and promoted with phorbol ester acetate. At 1 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 induced 0.79 tumors/mouse, but the other two compounds were virtually inactive. 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 application 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 than 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 the interference of toxicity with the tumorigenicity of DB[a,l]P and its 11,12-dihydrodiol.
Higginbotham
S
S
Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha 68198-6805.
RamaKrishna
N V
NV
Johansson
S L
SL
Rogan
E G
EG
Cavalieri
E L
EL
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000236:Adenoma / Q000139:chemically induced / Q000473:pathology; D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D001580:Benzopyrenes / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002277:Carcinoma / Q000139:chemically induced / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D010212:Papilloma / Q000139:chemically induced / Q000473:pathology; D012626:Sebaceous Gland Neoplasms / Q000139:chemically induced* / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000473:pathology; D013997:Time Factors
D001580:Benzopyrenes; D002273:Carcinogens; D001564:Benzo(a)pyrene; D015127:9,10-Dimethyl-1,2-benzanthracene; C041517:dibenzo(a,l)pyrene