The balance between initiation and promotion in radiation-induced murine carcinogenesis

Studies of radiation carcinogenesis in animals allow detailed investigation of how the risk depends on age at exposure and time since exposure and of the mechanisms that determine this risk, e.g., induction of new pre-malignant cells (initiation) and enhanced proliferation of already existing pre-malignant cells (promotion). To assist the interpretation of these patterns, we apply a newly developed biologically based mathematical model to data on several types of solid tumors induced by acute whole-body radiation in mice. The model includes both initiation and promotion and analyzes pre-malignant cell dynamics on two different time scales: comparatively short-term during irradiation and long-term during the entire life span. Our results suggest general mechanistic similarities between radiation carcinogenesis in mice and in human atomic bomb survivors. The excess relative risk (ERR) in mice decreases with age at exposure up to an exposure age of 1 year, which corresponds to mid-adulthood in humans; the pattern for older ages at exposure, for which there is some evidence of increasing ERRs in atomic bomb survivors, cannot be evaluated using the data set analyzed here. Also similar to findings in humans, initiation dominates the ERR at young ages in mice, when there are few background pre-malignant cells, and promotion becomes important at older ages.