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Beyond two-stage models for lung carcinogenesis in the Mayak workers: Implications for Plutonium risk.
PLoS ONE 10:e0126238 (2015)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Clonal Expansion Model; Induced Cell Inactivation; Biologically-based Model; Colon-cancer Data; Genomic Instability; Multistage Carcinogenesis; 2-mutation Model; Incidence Curves; Initiated Cells; Hazard Function
ISSN (print) / ISBN
1932-6203
Journal
PLoS ONE
Quellenangaben
Volume: 10,
Issue: 5,
Article Number: e0126238
Publisher
Public Library of Science (PLoS)
Publishing Place
Lawrence, Kan.
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Radiation Protection (ISS)