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Beyond two-stage models for lung carcinogenesis in the Mayak workers: implications for plutonium risk.

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.
AuthorsSascha Zöllner, Mikhail E Sokolnikov, Markus Eidemüller
JournalPloS one (PLoS One) Vol. 10 Issue 5 Pg. e0126238 ( 2015) ISSN: 1932-6203 [Electronic] United States
PMID26000637 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Plutonium
Topics
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Dose-Response Relationship, Radiation
  • Humans
  • Lung Neoplasms (diagnosis, etiology, mortality)
  • Middle Aged
  • Models, Theoretical
  • Neoplasms, Radiation-Induced (diagnosis, mortality)
  • Occupational Exposure (adverse effects)
  • Plutonium (toxicity)
  • Risk Factors
  • Young Adult

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