Model for Human Carcinogenesis: Action of Environmental Agents

Abstract

Current statistical prescriptions for low-dosage extrapolation of carcinogenic risk make no distinction between exposure to initiators and exposure to promoters despite the abundant data that these two classes of carcinogens have different modes of action. One reason for this is the lack of an appropriate model. In this paper, a model for carcinogenesis is presented which provides a framework for understanding the roles of "spontaneous" events, hereditary factors, and environmental agents in human carcinogenesis and for interpreting experimental carcinogenesis. This model incorporates two features: transition of target stem cells into cancer cells via an intermediate stage in two irreversible steps and growth and differentiation of normal target and intermediate cells. Cast in mathematical terms, the model can be fitted to age-specific incidence data on human cancers of both children and adults and can illuminate the relative importance of agents that affect transition rates, tissue growth and tissue differentiation. Within the context of the model, initiators act by affecting the transition rates, whereas promoters influence the kinetics of growth, especially of initiated cells. The model provides a good quantitative description of the epidemiology of carcinomas of the breast and of the lung. The data are consistent with the notion that hormones and cigarette smoke act as promoting agents in carcinoma of the breast and of the lung, respectively.