Evaluating the Carcinogenic Potency of Complex MixturesEPA Grant Number: R829360
Title: Evaluating the Carcinogenic Potency of Complex Mixtures
Investigators: Albert, Roy E. , Warshawsky, David
Institution: University of Cincinnati
EPA Project Officer: Hahn, Intaek
Project Period: October 1, 2001 through September 30, 2004 (Extended to September 30, 2005)
Project Amount: $733,943
RFA: Complex Chemical Mixtures (2000) RFA Text | Recipients Lists
Research Category: Hazardous Waste/Remediation , Land and Waste Management , Safer Chemicals
Complex mixtures of combustion and related products contain many carcinogens and anti-carcinogens of varying potency that interact in theoretically unpredictable ways. The conventional complete mouse skin tumor carcinogenesis assay is too time consuming and expensive to be of more than limited use. If based on tumor initiation alone, skin tumor assays are of uncertain accuracy in the prediction of cancer outcomes and also not rapid. We propose to evaluate a new and more rapid approach for assessing carcinogenic potency using cancer induction as the endpoint. This involves determining the potency of complex mixtures as tumor initiators and progressors. The method uses a dominant negative p53 mutant transgenic mouse skin model (Vp53) with the combined topical application of the test mixture and a strong promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). The co application of the test agent and TPA saturates the system with promoting action and provides a rapid display of the potency of the test material as the combination of initiation and progression. Preliminary data using the carcinogen benzo(a)pyrene (BaP) showed that the earliest cancer appeared at 4 weeks and a 50% carcinoma response occurred in only 12 weeks.
The central thrust of the proposed research is to determine whether the combined action of initiation & promotion is a useful and rapid predictor of the carcinogenicity of complex mixtures. This will be evaluated by determining whether the potencies of 3 complex mixtures in relation to benzo(a)pyrene (BaP) are the same with the proposed initiation-progression protocol as they are for the complete carcinogen protocol. The 3 complex mixtures include roofing tar, Nissan diesel engine exhaust particle extracts, and coke oven particle extracts. We also will determine whether the initiation-progression model is made even faster by the use of a cross between the Vp53 transgenic mouse and a heterozygous p53 knockout mouse.
By the end of the 3 year grant period, we anticipate that the model will be established as an important new tool for use in the carcinogen risk assessment of complex mixtures.