Cell proliferation and carcinogenesis models: general principles with illustrations from the rodent liver system

Rates of cell proliferation, cell death, and cell differentiation affect the risk of cancer profoundly. An increase in cell proliferation rates 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 this paper I briefly discuss some of the consequences of incorporating cell proliferation kinetics into quantitative models of cancer risk assessment. Consideration of cell kinetics can shed light on apparently paradoxical observations, such as the observation that the administration of two different promoters may lead to the same volume fraction in the rodent liver, with one promoter giving rise to a large number of small foci and the other to a small number of large foci. Another observation that can be illuminated by a consideration of cellular proliferation kinetics is the phenomenon of the inverse dose-rate effect. It has been observed with exposure to high LET radiation and to certain chemicals that fractionation of a given total dose of the agent leads to an increased life-time probability of tumor. A biological explanation of this finding can be given in terms of the effect of the agent on cell proliferation kinetics.