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Determination of the Number of Events Required for Mammary Carcinogenesis in the Sprague-Dawley Female Rat¹

Oncology Center and Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Female Sprague-Dawley rats were exposed to a single, graded dose of either of two highly effective mammary chemical carcinogens, 7,12-dimethylbenzanthracene (DMBA) or N-methylnitrosourea, in order to determine the number of mammary cancers per rat induced by a range of carcinogenic doses. These data were then used to separately construct dose-response curves characteristic for DMBA- and N-methylnitrosourea-induced mammary carcinogenesis. Analysis of these characteristic dose-response curves demonstrated that, following a single exposure to either DMBA or N-methylnitrosourea, the number of mammary cancers per rat increased not linearly but as the second power of dose of carcinogen used. These results are clearly incompatible with mammary carcinogenesis being a single step process in the female Sprague-Dawley rat. In direct contrast these results are entirely consistent with a malignant process requiring two transformation events. When female Sprague-Dawley animals are exposed multiple times to a suboptimal dose of DMBA, the number of mammary cancers induced per rat increases synergistically, not merely additively, as compared to a single dose exposure. Again this result is consistent only with mammary carcinogenesis requiring at least two transformation events.

¹ Supported by grants from the American Cancer Society (IN-11U) and Department of Health and Human Services (CA 06973).

Received 2/21/85. Revised 6/10/85. Accepted 6/19/85.