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Explore the debate surrounding the identification of potential human carcinogens and the relevance of precursor changes. This discussion includes analysis of dose, metabolism, kinetics, and mode of action, as well as evaluations of DNA reactivity, estrogenicity, immunosuppression, and urinary bladder hyperplasia.
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Is It A Human Carcinogen? Samuel M. Cohen, M.D., Ph.D. Professor and Chair, Pathology and Microbiology Havlik-Wall Professor of Oncology University of Nebraska Medical Center 983135 Nebraska Medical Center Omaha, NE 68198-3135 Debate at March, 2005 SOT Meeting
2 Year Bioassay – Gold Standard • In past 40 years we have identified precursor changes of carcinogenesis.
Present Paradigm: • 4 and 13 week assays 2 year bioassay tumors evaluate dose, metabolism, kinetics, MOA New Approach: • 4 and 13 week assays, DNA reactivity, estrogenicity, immunosuppression precursor changes detailed evaluation of dose, metabolism, kinetics, MOA evaluate relevance to humans.
MOA – Key Events A B C D Cancer Focus on precursor key events! Detailed analysis – dose, metabolism, kinetics, MOA. Is it relevant to humans?
Urinary Bladder DNA Reactivity Yes No Bladder Hyperplasia Bladder Hyperplasia SEM Changes BrdU LI - urothelium No Yes Likely BladderCarcinogen Not Likely a Bladder Carcinogen Possible Bladder Carcinogen Not a Bladder Carcinogen Evaluate Fresh Void Urine Urinary Solids Urinary Composition? Reactive Chemical and/or metabolite