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Issues in Risk Assessment The Two-Stage Model of Carcinogenesis INTRODUCTION In recent years, it has become clear that carcinogenesis is a multistep process that requires deregulation of cellular growth. Cell growth and differentiation are normally under genetic regulation, so it may be assumed that the critical events in carcinogenesis involve genetic damage and inappropriate genetic expression (Weinberg, 1988; 1989). Mathematical models based on those biologic considerations can be simple or complex depending on assumptions about the number and nature of the events required to transform normal cells into cancer cells and about the sequence of events. The simplest model judged to be consistent with the data available—a model that assumes two critical stages—was selected for evaluation by the Committee on Risk Assessment Methodology (CRAM). The two-stage model has been proposed as an improvement over currently used models for estimating carcinogenic risks to health, because it incorporates biologic considerations, notably cell population kinetics. The principal purposes of this CRAM study were to assess the scientific basis of the two-stage model of carcinogenesis and to evaluate the possible applications of the two-stage model to health risk assessment. As part of the information-gathering process, the committee held a workshop on November 8, 1990, with presentations by the originators and proponents of the two-stage model and by invited discussants. A