Carcinogenic activity of benzo[a]pyrene and some of its synthetic derivatives by direct injection into the mouse fetus.

Abstract

We have studied the carcinogenic effects of direct injection of benzo[a]pyrene (BP) and 6-methylbenzo[a]pyrene (BP6M) into fetal Swiss mice at 15 days of intrauterine growth. To determine the sensitivity of mouse fetuses to the action of ultimate carcinogens, benzo[a]pyrene-4,5-oxide (BPO) and a racemic mixture of 7 beta,8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9, 10-tetrahydrobenzo[a]pyrene (BPDE), respectively, a proximal metabolite and an ultimate carcinogenic metabolite of BP, were also investigated in our system. The compounds were dissolved in acetone and trioctanoin (1:1) and injected at doses ranging from a minimum of 0.4 to a maximum of 19.8 nmol/fetus. Controls received 1 microliter/fetus of solvent. The experiment was terminated when the animals were 12-15 weeks old. On the basis of the percentages of lung adenomas and the average number of nodules/mouse, BPDE appears to be the most potent carcinogen of this group, causing 55% of tumors at a dose of 0.4 nmol and 73% at a dose of 4.0 nmol/fetus. At the dose of 0.4 nmol/fetus, neither BP nor BP6M induced tumors; injection of 4.0 or 19.8 nmol/fetus, caused incidences of 53% and 92%, respectively, in the case of BP6M and 24% and 39%, respectively, in the case of BP. BPO was not tumorigenic in this system, even at doses as high as 15.7 nmol/fetus. Eleven percent of the control animals had lung adenomas. The average number of nodules/mouse varied with the compound and the dose injected and closely followed the pattern of tumor incidence.