Assessment of interaction among three carcinogens on rat mammary carcinogenesis in a factorially designed experiment

Female Sprague-Dawley rats were given by stomach tube 7,12-dimethylbenz[a]anthracene [(DMBA) CAS: 57-97-6] on the 77th day of age at the rate of 1.6 mg/100 g body weight, or procarbazine [(PCZ) CAS: 671-16-9] on the 84th day of age at the rate of 10 mg/100 g body weight, or 0.5 Gy of total-body x-rays on the 91st day of age, singly or in all possible combinations or no treatment. All rats were studied for mammary carcinogenesis for 370 days after the 84th day of age. Three measures of mammary carcinogenesis were studied. These were the incidence of rats with mammary adenocarcinomas, or mammary fibroadenomas, or mammary neoplasia of either type. Each of these measures was studied also for rats with 2 or more or 3 or more mammary neoplasms. Assessment of possible interaction among the three carcinogens with regard to the incidence of neoplasms was done by time-independent or time-dependent methods, both of which gave remarkably consistent results. For rats with 1 or more adenocarcinomas, 1 or more fibroadenomas, or 1 or more adenocarcinomas and/or fibroadenomas, both methods showed no interaction among the carcinogens, which can, therefore, be considered to have produced additive effects. An exception to this finding of additivity was an apparent synergistic interaction between DMBA and PCZ when the measures of rats with 2 or more, or 3 or more mammary neoplasms of either type, or 3 or more fibroadenomas were analyzed; these analyses, however, were based on relatively small numbers of rats with multiple tumors. Since no interactions were found for the usual measure of carcinogenesis, namely, incidence of rats with 1 or more neoplasms, the overall conclusion is that DMBA, PCZ, and x-ray act additively in the induction of mammary neoplasms in the female Sprague-Dawley rat.