Cell proliferation in the evaluation of carcinogenic risk and the inadequacies of the initiation-promotion model

The classic model of multistage carcinogenesis of initiation-promotion- progression is model-dependent for the definition of individual stages, and it is inadequate for explaining much of the data regarding carcinogenesis in animal models and in humans. Nevertheless, such animal models can be useful in evaluating chemicals for potential carcinogenicity, especially for detecting nongenotoxic chemicals. Rather than focusing on such a model, identifying genotoxic and cell proliferative effects of various agents provides a paradigm that is more readily applicable to the multiple exposures characterized for the human population. For nongenotoxic agents, an identification of mechanism needs to ascertain whether the effects are due to increasing cell births, either by direct mitogenesis or cytotoxicity and regenerative hyperplasia, or decreasing cell deaths, either by inhibiting apoptosis or blocking differentiation. This guideline is a more realistic approach for assessing potential carcinogenic hazard for humans, whether in evaluating chemicals, physical agents, or infectious organisms.