Mechanistic models of carcinogenesis: An application to lung-cancer risk in the Mayak nuclear workers

Mechanistic multi-stage models are used to analyze lung-cancer mortality after Plutonium exposure in the Mayak-workers cohort. Besides the established two-stage model with clonal expansion, models with three mutation stages as well as a model with two distinct pathways to cancer are studied. The results suggest that three-stage models offer an improved description of the data. The best-fitting models point to a mechanism where radiation increases the rate of clonal expansion. This is interpreted in terms of changes in cell-cycle control mediated by bystander signaling or repopulation following cell killing. To elucidate the implications of the different models for radiation risk, several exposure scenarios are studied. Models with a radiation effect at an early stage show a delayed response and a pronounced drop-off with older ages at exposure. Moreover, the dose-response relationship is strongly nonlinear, revealing a marked increase above a critical dose.