Carcinogenicity of Benzo[a]pyrene and Thirteen of Its Derivatives in C3H/fCum Mice 2 3

Benzo[a]pyrene (BP) and 13 of its derivatives were tested for their ability to induce fibrosarcomas in inbred male C3H/fCum mice after a single sc injection. A 0.9-μmol dose of BP in 0.05 ml dimethyl sulfoxide or 0.1 ml trioctanoin produced a 63 or 83% tumor incidence, respectively. At the same dose, benzo[a]pyrene-7,8-oxide had very weak tumorigenic activity whereas the benzo[a]pyrene-4,5-, 9,10-, and 11,12-oxides had no tumorigenic activity. When administered in dimethyl sulfoxide, (±)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-dihydrodiol) had tumorigenic activity comparable to BP. However, the tumorigenicity of this dihydrodiol was lost when it was injected in trioctanoin. The poor activity of BP-7,8-dihydrodiol relative to BP in trioctanoin may be due, in part, to the polarity of this metabolite because the 7,8-diacetate derivative of BP-7,8-dihydrodiol was 10–15 times more tumorigenic than the dihydrodiol. The lack of tumorigenicity of 7,8-dihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene, a compound lacking the double bond in the 9,10-position but otherwise identical to BP-7,8-dihydrodiol, suggested that the carcinogenicity of the dihydrodiol is mediated by a 7,8-diol-9,10-epoxide of BP. The potent tumorigenicity of 7,8-dihydrobenzo[a]pyrene, compared to that of 9,10-dihydrobenzo[a]pyrene, provided additional evidence for the importance of an intact 9,10-double bond for the metabolic activation of BP. (±)-7β,8α-Dihydroxy-9β,10β-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene had no tumorigenic activity, and its more stable diastereomer, (±)-7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, induced a fibrosarcoma in only 1 of 18 mice at risk. 2-Hydroxybenzo[a]pyrene, a potent carcinogen on mouse skin and in the newborn mouse, was only 10% as active as BP after sc injection in the mouse.