Role of cell proliferation in regenerative and neoplastic disease

DNA replication does not have 100% fidelity. Consequently, a chemical can increase the risk of cancer either by directly damaging DNA (genotoxic) or by increasing the number of cell replications, or both. Increased cell proliferation can be produced by increasing cell births (by direct mitogenesis or regeneration following toxicity), or decreasing cell deaths (by inhibiting apoptosis or differentiation). Cell proliferation can affect the dose-response curve for genotoxic carcinogens and is the basis for carcinogenicity by nongenotoxic agents. Bladder carcinogens will be used to illustrate these mechanisms, and their implications with respect to human risk assessment will be presented.