Beyond two-stage models for lung carcinogenesis in the Mayak workers: Implications for Plutonium risk

TL;DR

This study uses advanced multi-stage models to analyze lung cancer risk from Plutonium exposure in Mayak workers, revealing that three-stage models better fit the data and suggest radiation influences clonal expansion, with nonlinear dose-response relationships.

Contribution

It introduces and compares multi-stage models with three mutation stages and dual pathways, showing improved data fit and insights into radiation effects on carcinogenesis.

Findings

Three-stage models better fit the data than two-stage models.

Radiation increases the rate of clonal expansion in lung cells.

Dose-response relationship is strongly nonlinear, with a critical dose threshold.

Abstract

Mechanistic multi-stage models are used to analyze lung-cancer mortality after Plutonium exposure in the Mayak-workers cohort, with follow-up until 2008. 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. No statistical evidence for a two-pathway model is found. 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 for all three-stage models, revealing a marked increase above a critical dose.