Tumorigenicity of fjord region diol epoxides of polycyclic aromatic hydrocarbons

(+/-)-anti-Benzo[c]phenanthrene-3,4-diol-1,2-epoxide (BcPDE), (+/-)-anti-benzo[g]-chrysene-1 1,12-diol-13, 14-epoxide (BgCDE), and (+/-)-anti-dibenzo[a,l]pyrene-11,12-diol-13,14-epoxide (DB[a,l]PDE) were synthesized for use in biological assays. To compare mammary carcinogenicity, BcPDE and (+/-)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE) were tested by direct application to the mammary glands of female CD rats at a total dose of 12.2 mu mol per animal. 6-Nitrochrysene (6-NC) at the same dose was used as a positive control. BcPDE was found to be a potent mammary tumorigen and carcinogen, inducing significantly more fibroadenomas and adenocarcinomas than the other two compounds. In a second bioassay, BcPDE, BgCDE, and DB[a,l]PDE at a total dose of 1.2 mu mol were compared. All three diol epoxides were potent mammary carcinogens and based on the collective results to date, the relative carcinogenic activities of the diol epoxides can be approximated as DB[a,l]PDE > BcPDE > BgCDE > BPDE. To determine tumorigenic potencies in newborn mice, BPDE was compared with BgCDE, DB[a,l]PDE, and BcPDE at a total dose of 25 nmol per mouse, administered on days 1, 7, and 15 of life. BgCDE and BcPDE had similar potency in inducing lung tumors. BgCDE induced more liver tumors in male mice than BcPDE. Both compounds were more tumorigenic than BPDE. DB[a.l]PDE was highly toxic at 25 nmol and all animals died within one week after the first dose. DB[a,l]PDE was also tested at total intended doses of 5 nmol and 1 nmol. Due to high toxicity, only the first dose of the intended 5 nmol was given. This dose as well as the 1 nnol total dose caused significant incidence and multiplicity of lung tumors. These results support the hypothesis that sterically hindered fjord region diol epoxides are potent mammary carcinogens in CD rats and strong lung tumorigens in newborn mice.