-edited) There is strong evidence for an association between breast cancer risk and environmental factors, but few specific exposures have been identified. Recently, associations have been found between breast cancer risk and organochlorine exposures as estimated from blood and tissue levels of residues. Therefore, organochlorine exposures may contribute to the high breast cancer rates in the U.S., where wide- spread exposure to agents such as DDT and PCBs have occurred for decades, in addition to a high prevalence of other environmental risk factors. Several organochlorines such as DDT, PCB mixtures, and several PCB congeners have considerable estrogenic activity. Endogenous estrogens are well established breast cancer risk factors, and timing and duration of exposure is critical. This application addresses the hypothesis that exposure to estrogenic organochlorines enhances breast cancer development. Possible enhancing effects on breast carcinogenesis of estrogenic organochlorine exposure may be most profound when endogenous estrogen production is low (before puberty or postmenopausal). To test this hypothesis, the MNU mammary carcinogenesis model system in the Sprague Dawley rat will be used to examine the influence on mammary cancer development of well controlled exposure during specific time periods to the estrogenic DDT isomer o,p-DDT and an estrogenic PCB mixture Aroclor 1221. Thus, it will be determined whether these organochlorines modify mammary cancer induction when administered at the following times: (1) from 2 weeks after the carcinogen (""""""""promotion"""""""" stage); (2) subsequent to surgically-induced menopause as surrogate for menopause in women (""""""""post-ovariectomy"""""""" stage); and (3) from weaning (3 weeks of age) until carcinogen injection (""""""""pre-initiation"""""""" stage). To achieve aim 3, it will be necessary to compensate for possible organochlorine-induced shifts in the timing of cell proliferation during puberty which is a critical element of the single carcinogen dose mammary carcinogenesis model in the rat. Therefore, changes in the time of occurrence of cell proliferation in the cellular target of carcinogens in the developing mammary gland (the terminal end-bud) will be determined with respect to organochlorine exposure during the pre- initiation and perinatal stages. The results of these studies will demonstrate the mammary carcinogenesis-enhancing potential of estrogenic organochlorines, and they will establish differential effects of exposure at critical times during development and aging in relation to environmental mammary carcinogenesis.
