CELL-PROLIFERATION AND CARCINOGENESIS MODELS - GENERAL-PRINCIPLES WITH ILLUSTRATIONS FROM THE RODENT LIVER SYSTEM

Rates of cell proliferation, cell death, and cell differentiation affe ct the risk of cancer profoundly. An increase in cell proliferation ra tes leads to an increase in mutation rates per unit of time, which, in turn, leads to an increase in the risk of cancer. An increase in cell division rates relative to death or differentiation rates may lead to an increase in the population of critical target cells, which, again, leads to an increase in cancer risk. These fundamental principles are well illustrated by the rodent liver model for carcinogenesis. In thi s paper I briefly discuss some of the consequences of incorporating ce ll proliferation kinetics into quantitative models of cancer risk asse ssment. Consideration of cell kinetics can shed light on apparently pa radoxical observations, such as the observation that the administratio n of two different promoters may lead to the same volume fraction in t he rodent liver, with one promoter giving rise to a large number of sm all foci and the other to a small number of large foci. Another observ ation that can be illuminated by a consideration of cellular prolifera tion kinetics is the phenomenon of the inverse dose-rate effect. It ha s been observed with exposure to high LET radiation and to certain che micals that fractionation of a given total dose of the agent leads to an increased lifetime probability of tumor. A biological explanation o f this finding can be given in terms of the effect of the agent on cel l proliferation kinetics.