title: 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.
authors.affiliation: Helmholtz Zentrum München, Institute of Radiation Protection, Neuherberg (Germany).
authors.forename: Sascha
authors.initials: S
authors.lastname: Zöllner
authors.affiliation: Southern Urals Biophysics Institute, Ozyorsk (Russia).
authors.forename: Mikhail E
authors.initials: ME
authors.lastname: Sokolnikov
authors.affiliation: Helmholtz Zentrum München, Institute of Radiation Protection, Neuherberg (Germany).
authors.forename: Markus
authors.initials: M
authors.lastname: Eidemüller
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000209:etiology / Q000401:mortality; D008875:Middle Aged; D008962:Models, Theoretical; D009381:Neoplasms, Radiation-Induced / Q000175:diagnosis* / Q000401:mortality; D016273:Occupational Exposure / Q000009:adverse effects*; D011005:Plutonium / Q000633:toxicity*; D012307:Risk Factors; D055815:Young Adult
chemical_list: D011005:Plutonium