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Zollner S.,Helmholtz Center Munich | Sokolnikov M.E.,Southern Urals Biophysics Institute | Eidemuller M.,Helmholtz Center Munich
PLoS ONE | Year: 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. © 2015 Zöllner et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source


Jacob P.,Helmholtz Center Munich | Meckbach R.,Helmholtz Center Munich | Kaiser J.C.,Helmholtz Center Munich | Sokolnikov M.,Southern Urals Biophysics Institute
Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis | Year: 2010

Recent publications on the integration of radiobiological effects in the two-step clonal expansion (TSCE) model of carcinogenesis and applications to radioepidemiological data are reviewed and updated. First, a model version with radiation-induced genomic instability was shown to be a possible explanation for the age dependence of the radiation-induced cancer mortality in the Techa River Cohort. Second, it is demonstrated that inclusion of a bystander effect with a dose threshold allows an improved description of the lung cancer mortality risk for the Mayak workers cohort due to incorporation of plutonium. The threshold for the annual lung dose is estimated to 12 (90%CI: 4; 14). mGy/year. This threshold applies to the initiation of preneoplastic cells and to hyperplastic growth. There is, however, no evidence for a threshold for the effects of gamma radiation. Third, models with radiation-induced cell inactivation tend to predict lower cancer risks among the atomic bomb survivors with exposure at young age than conventionally used empirical models. Also, risks after exposures with doses in the order of 100. mGy are predicted to be higher in models with low-dose hypersensitivity than in models with conventional cell survival curves. In the reviewed literature, models of carcinogenesis tend to describe radioepidemiological data better than conventionally used empirical models. © 2010 Elsevier B.V. Source


Grant
Agency: Cordis | Branch: FP7 | Program: CSA-SA | Phase: Fission-2008-3.1.1 | Award Amount: 1.31M | Year: 2009

The sharing of data and biomaterials from publicly funded experimental radiation science adds enormous value to the original investment. Sharing will yield substantial scientific rewards through re-analysis and new investigations. The goal of STORE is to generate a platform that will allow the storage and retrieval of both data and the corresponding biological material from past, current and future radiobiological studies. The STORE project will perform four tasks: 1) Deliver a Data Warehouse that will also present a single portal to radiobiological information distributed over scientific centres throughout the world. 2) Provide a foundation for the creation of a virtual store of biological material. 3) Establish Standard Operating Procedures (SOPs) on how best to evaluate, store and use the biological material to ensure that the collection, archiving and storage of these non-renewable materials are state-of-the-art. 4) Assess potential financial models for long term support of a bioresource and Data Warehouse for radiobiology. STORE will thus provide a mechanism for ensuring the future survival of these invaluable and irreplaceable resources and provide a platform for the sharing of new data across the radiobiology community


Grant
Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: Fission-2009-3.1.2 | Award Amount: 9.07M | Year: 2010

This project aims to improve estimates of the risks of long-term health effects associated with protracted external and internal radiation exposures, through further studies of exposed populations in the Southern Urals (Russian Federation). Specific objectives of the project are as follows: 1. To develop improved modules for estimating external doses to exposed cohorts in the Southern Urals. It is anticipated that new dosimetry systems that come into use after the end of SOLO will incorporate these modules and support future epidemiological work. 2. To carry out epidemiological studies of morbidity and mortality from non-cancer diseases - specifically respiratory and circulatory diseases - and of cancer incidence among workers at Mayak Production Association, based on Mayak-Doses-2008. 3. To examine the feasibility of conducting a pooled epidemiological analysis of the Mayak and Sellafield plutonium worker cohorts. A common internal dosimetry protocol for assessing doses from plutonium exposures will be produced , with quantification of uncertainties. If judged feasible, doses will be calculated and an epidemiological analysis undertaken. 4. To analyse the feasibility of conducting a pooled analysis of cancer incidence and mortality following in utero irradiation among the offspring of Mayak female workers and of the Techa River female population, based on the estimation of doses to the embryo and fetus, and - if judged feasible - to undertake this analysis. The research will be coordinated with related research in the Southern Urals. The findings should provide a more robust scientific basis for underpinning radiation protection standards.


Recent epidemiological studies suggest that cancer risk after exposures with doses comparable to the dose limits for occupationally exposed workers may be larger than assumed by ICRP in the derivation of these limits. The value of cancer risk from such exposures and its dependence on tissue, radiation type and individual factors is largely unknown. The innovative approach proposed here combines epidemiology and radiobiology in order to quantify cancer risks after low-dose or low-dose-rate exposures to ionizing radiation. Key factors of radiation induced carcinogenesis such as genomic instability will be measured in cancer tissues and blood samples from members of the following radio-epidemiological cohorts: French Haemangioma Cohort, Mayak Worker Cohort and thyroid cancer cases after the Chernobyl accident. Inter-cellular communication after exposure to low-dose radiation exposure and its influence on apoptosis, cell proliferation, differentiation and genomic instability will be explored with 2D cell cultures and 3D tissue models. This includes research on stem cells, which will be isolated from healthy human breast tissue. The results of the radiobiological studies will be integrated in the development of models of carcinogenesis for evaluation of major epidemiological cohorts: Atomic Bomb Survivors, French-Swedish-Italian Thyroid Cancer Cohort, Mayak Worker Cohort, Swedish Haemangioma Cohort, UkrAm Cohort on thyroid cancer after the Chernobyl accident, and UK National Registry for Radiation Workers. Cancer risk will be determined for the breast, lung, thyroid and the digestive tract after low-dose-rate exposure to low-LET radiation (external gamma radiation and internal radiation from 131I) and to high-LET radiation (alpha-particles from incorporated plutonium). Lifetime cancer risks including individual risk factors will be calculated to establish a new basis for deriving dose limits and estimating cancer risks including those from medical diagnostic exposures.

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