1. 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
Nebraska Medical Center
Omaha, NE
Debate at March, 2005 SOT Meeting

2. 2 Year Bioassay – Gold Standard
In past 40 years we have identified precursor changes of carcinogenesis.

3. Present Paradigm:
4 and 13 week assays 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.

4. MOA – Key Events A B C D Cancer Focus on precursor key events!
Detailed analysis – dose, metabolism, kinetics, MOA.
Is it relevant to humans?

6. Bladder Hyperplasia SEM Changes BrdU LI - urothelium
Urinary Bladder
DNA Reactivity
Yes No
Bladder Hyperplasia
Bladder Hyperplasia SEM Changes
BrdU LI - urothelium
Yes No
Likely Bladder Carcinogen
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

7. Is It A Human Carcinogen?