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Thyroid cancer of papillary histology (PTC) is the dominant type in radio-epidemiological cohorts established after nuclear accidents or warfare. Studies on post-Chernobyl PTC and on thyroid cancer in the life span study (LSS) of Japanese a-bomb survivors consistently revealed high radiation risk after exposure during childhood and adolescence. For post-Chernobyl risk assessment overexpression of the CLIP2 gene was proposed as molecular biomarker to separate radiogenic from sporadic PTC. Based on such binary marker a biologically-based risk model of PTC carcinogenesis has been developed for observational Chernobyl data. The model featured two independent molecular pathways of disease development, of which one was associated with radiation exposure. To gain credibility the concept for a mechanistic risk model must be based on general biological features which transcend findings in a single cohort. The purpose of the present study is therefore to demonstrate portability of the model concept by application to PTC incidence data in the LSS. By exploiting the molecular two-path concept we improve the determination of the probability of radiation causing cancer (POC). The current analysis uses thyroid cancer incidence data of the LSS with thyroid cancer diagnoses and papillary histology (n = 292) from the follow-up period between 1958 and 2005. Risk analysis was performed with both descriptive and biologically-based models. Judged by goodness-of-fit all applied models described the data almost equally well. They yielded similar risk estimates in cohorts post-Chernobyl and LSS. The preferred mechanistic model was selected by biological plausibility. It reflected important features of an imperfect radiation marker which are not easily addressed by descriptive models. Precise model predictions of marker prevalence in strata of epidemiological covariables can be tested by molecular measurements. Application of the radiation-related molecular pathway from our preferred model in retrospective risk assessment decreases the threshold dose for 50% POC from 0.33 (95% confidence interval (CI) 0.18; 0.64) Gy to 0.04 (95% CI 0.01; 0.19) Gy for females and from 0.43 (95% CI 0.17; 1.84) Gy to 0.19 (95% CI 0.05; 1.00) Gy for males. These improvements are still not sufficient to separate radiation-induced from sporadic PTC cases at very low doses <0.015 Gy typical for the Fukushima accident. Successful application of our preferred mechanistic model to LSS incidence data confirms and improves the biological two-path concept of radiation-induced PTC. Model predictions suggest further molecular validation studies to consolidate the basis of biologically-based risk estimation. [ABSTRACT FROM AUTHOR]

Keywords: Biologically based models of cancer risk; radiation epidemiology; molecular biology; integrative modeling; adverse outcome pathways EN Biologically based models of cancer risk radiation epidemiology molecular biology integrative modeling adverse outcome pathways 2 11 10 01/18/21 20210101 NES 210101 Introduction Increasing grasp of disease processes leading to cancer and concomitantly the establishment of observational data sets for the general population prompted the development of biologically based models of cancer risk (BBCR models) (Armitage and Doll [4]; Moolgavkar et al. [64]; Moolgavkar and Knudson [65]). In radiation epidemiology the first deployment of BBCR models occurred with the Life Span Study (LSS) of Japanese a-bomb survivors decades after their application to observational cancer data (Little et al. [55]; Little [54]; Heidenreich et al. [37]; Kai et al. [42]). Early pioneering studies of radiation risk in the LSS were based on descriptive models which linked excess rates of cancer incidence and mortality to radiation exposure by statistical association (Wakabayashi et al. [85]; Thompson et al. [82]). Persistent radiation effects and radiation-associated inflammation Radiation can modulate cancer initiation, progression, and transformation in multiple ways thereby leading to multiple cancer types. [Extracted from the article]

Purpose: Biologically-based mechanistic models that are used in combining current understanding of human carcinogenesis with epidemiological studies were reviewed. Assessment was made of how well they fit the data, whether they account for non-linear radiobiological low-dose effects, and whether they suggest any implications for the dose response at low doses and dose rates. However, the present paper does not make an attempt to provide a complete review of the existing literature on biologically-based models and their application to epidemiological data. Conclusion: In most studies the two-stage clonal expansion (TSCE) model of carcinogenesis was used. The model provided robust estimates of identifiable parameters and radiation risk. While relatively simple, it is flexible, so that more stages can easily be added, and tests made of various types of radiation action. In general, the model performed similarly or better than descriptive excess absolute and excess relative risk models, in terms of quality of fit and number of parameters. Only very rarely the shape of dose-response predicted by the models was investigated. For some tumors, when more detailed biological information was known, additional pathways were included in the model. The future development of these models will benefit from growing knowledge on carcinogenesis processes, and in particular from use of biobank tissue samples and advances in omics technologies. Their use appears a promising approach to investigate the radiation risk at low doses and low dose rates. However, the uncertainties involved are still considerable, and the models provide only a simplified description of the underlying complexity of carcinogenesis. Current assumptions in radiation protection including the linearnon-threshold (LNT) model are not in contradiction to what is presently known on the process of cancer development. [ABSTRACT FROM AUTHOR]