Sensitivity factors in perinatal carcinogenesis are studied through analysis of the roles of fetal and maternal metabolism of chemical carcinogens and of promotion later in life of tumors initiated during the perinatal period. In a pharmacogenetic investigation in mice of transplacental carcinogenesis by methylcholanthrene, genetic backcrosses of C57BL/6 and DBA/2 mice were employed to produce fetuses which were, in the same mother, either inducible or noninducible for the enzymes which metabolize this carcinogen. The mothers themselves were either inducible or noninducible. Induction-responsive offspring exhibited 2-3 times more lung and liver tumors than did nonresponsive littermates. Furthermore, offspring of nonresponsive mothers developed 3-4 times more lung and liver tumors than did those of responsive mothers. Thus, the numbers of lung and liver tumors were greatest when the fetus was inducible and the mother noninducible. Important roles for both fetal and maternal metabolism are thus confirmed. In an assay of the nitroso derivative of a common pharmaceutical, N-nitrosocimetidine, given transplacentally, during lactation, and chronically, treatment with this chemical was associated with an increase in size and malignancy of lung tumors but a reduction in numbers of mammary tumors. Studies of the effects of this chemical on tumor development are ongoing. In a test of the effect of polychlorinated biphenyls (PCBs) on the development of tumors initiated in infant mice by dimethylnitrosamine, it was found that treatment with the PCBs 4 days after the carcinogen resulted in a doubling in the numbers of lung tumors at 2 endpoints in time, an effect associated with retention in the bodies of the mice of 2 specific hexachlorobiphenyl congeners. Thus, PCBs may result in tumor promotion in an extrahepatic organ, and may do so after a single treatment with the chemical. There were also multiple significant effects on the liver, including a reduction in number but an increase in size of neoplasms. This finding is of particular interest in light of the tendency of PCBs to accumulate in milk.
