TUMORIGENICITY STUDIES WITH DIOL-EPOXIDES OF BENZO(A)PYRENE WHICH INDICATE THAT (+/-)-TRANS-7 BETA,8 ALPHA-DIHYDROXY-9 ALPHA,10 ALPHA-EPOXY-7,8,9,10-TETRAHYDROBENZO(A)PYRENE IS AN ULTIMATE CARCINOGEN IN NEWBORN MICE

Abstract

The tumorigenic activities of benzo(a)pyrene (BP), (.+-.)-trans-7.beta.,8.alpha.-dihydroxy-9.beta.,10.beta.-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (diol-epoxide 1), (.+-.)-trans-7.beta.,8.alpha.-dihydroxy-9.alpha.,10.alpha.-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (diol-epoxide 2), (.+-.)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene (BP 7,8-dihydrodiol) and the tetraols derived from the hydrolysis of diol-epoxide 2 were evaluated in newborn mice. The mice were given injections sequentially of 4, 8 and 16 nmol of each compound on the 1st, 8th and 15th days of life, and the animals were killed when they were 28 wk old. Diol-epoxide 1 was toxic in newborn mice, and most of the animals treated with this compound died before weaning. Diol-epoxide 2 and BP 7,8-dihydrodiol were, respectively, about 40- and 15-fold more active than BP in causing pulmonary adenomas. Vehicle-treated control animals had an average of 0.13 lung adenoma/mouse, whereas animals treated with BP, BP 7,8-dihydrodiol, or diol-epoxide 2 had, respectively, 0.24, 1.77 and 4.42 pulmonary adenomas/mouse. Diol-epoxide 1 and the tetraols derived from diol-epoxide 2 did not induce pulmonary adenomas. The inactivity of diol-epoxide 1 under the conditions of this study should be interpreted with caution because of the high toxicity of this compound. The results provide evidence that BP 7,8-dihydrodiol is a proximate carcinogenic metabolite and diol-epoxide 2 is an ultimate carcinogenic metabolite of BP in the newborn mouse.