The short term/limited bioassays for the detection of chemical carcinogens, tumor initiators and tumor promoters have been recognized as important components to the determination of the carcinogenic hazard of environmental chemicals and complex mixtures. These bioassays are useful for the determination 1) of whether a substance is carcinogenic, 2) of dose-response relationships and 3) of mechanism i.e., tumor initiator and/or promoter. Many of the chemicals that have been positive in the long-term carcinogenesis bioassay, were active in mouse liver. The objectives of this project are to determine whether the 15 day old mouse liver initiation-promotion bioassay can be used to distinguish carcinogens from non-carcinogens and then to develop the bioassay so that it can be used to determine their mechanism of action. C3H and B6C3F1 male mice shall be used because 1) we have determined them to be sensitive strains and sex; 2) the B6C3F1 mouse is used in the NTP long-term bioassay; and 3) the opposing effect of phenobarbital on diethylnitrosamine (DENA)- initiated hepatocarcinogenesis (promotion in B6C3F1 and inhibition in C3H). In phase 1, the relative sensitivity of the two strains of mice to different chemical classes and the effect of phenobarbital will be determined. Briefly, the protocol will consist of 1) administering the test substance to male mice at day 15 of age, 2) starting at weaning and continuing until sacrifice, to administer 500 ppm sodium phenobarbital in the drinking water, 3) sacrificing the mice at 180 days of age and 4) evaluation of the liver for neoplastic lesions. Once the protocol for the 15 day old mouse initiation-promotion bioassay has been developed, phase 2 will evaluate the ability of the assay 1) to determine dose- response and structure-activity relationships, and 2) to distinguish tumor initiators and promoters.
