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

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

Previous Malignancy as a Risk Factor for the Second Solid Cancer in a Cohort of Nuclear Workers

This paper describes the results of epidemiological analysis of a cohort of nuclear workers hired at the main facilities of “Mayak” Production Association located in the city of Ozyorsk in Southern Urals of the Russian Federation. Previous malignancy as a risk factor for second cancer in a cohort of 22,373 workers occupationally exposed to ionizing radiation has been analyzed in a retrospective study with more than 60 years of follow-up. Information on main radiation and non-radiation risk factors (attained age, sex, tobacco smoking), as well as the dose of exposure to occupational ionizing radiation has been obtained for the analysis using the data from cancer register as well as other main population registries created in Epidemiological Laboratory of Southern Urals Biophysics Institute. Poisson’s regression realized in the “Amfit” module of “Epicure” statistical package has been applied for risk analysis. Excess relative risk per 1 Gy of absorbed dose of external gamma radiation and internal alpha radiation has been calculated using linear model. Among the 2,471 cancer cases accumulated in the study cohort to the end of follow-up 6.4% of second cancer cases have been diagnosed among workers occupationally exposed to protracted external gamma- and internal alpha radiation. The relative risk of second cancer (except for non-melanoma skin cancer) among nuclear workers with previously diagnosed cancer was about 4 times higher after a decade compared with those cancer patients who had single cancer only. The results showed that previous malignancy along with main non-radiation factors is statistically significant carcinogenic risk factor among nuclear workers exposed to protracted occupational radiation.   Doi: 10.28991/SciMedJ-2021-0301-2 Full Text: PD

Key parameter estimates for the two-stage model, including 95%-level uncertainties.

<p>For definitions and interpretation of the parameters used, see text. (Note that only certain rate combinations can be determined from the hazard.)</p

Same as Table 3, but for the parameters of the best three-stage models.

<p>Same as <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126238#pone.0126238.t003" target="_blank">Table 3</a>, but for the parameters of the best three-stage models.</p

Schematic structure of a <i>k</i>-stage model (top) and the two-path model studied in this paper (below).

<p>Here, <i>X</i>_<i>j</i> denotes the stochastic number of cells at stage <i>j</i>, with arrows indicating transitions at rates <i>μ</i>_<i>j</i>, etc. (see text). Cancer is assumed to occur once the first malignant cell appears, with latency period <i>t</i>_lag ∼ 5 years.</p