Lung Cancer Mortality (1950–1999) among Eldorado Uranium Workers: A Comparison of Models of Carcinogenesis and Empirical Excess Risk Models

Eidemüller, Markus; Jacob, Peter; Lane, Rachel; Frost, Stanley E.; Zablotska, Lydia B.

doi:10.1371/journal.pone.0041431

Cited by 19 publications

(27 citation statements)

References 48 publications

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“…standard model is the two-stage clonal expansion (TSCE) model [15,16] that reduces the evolution towards cancer to two basic time-limiting steps, and this model has been applied with good success to many epidemiological data sets, e.g. [17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Breast cancer risk and possible mechanisms of radiation-induced genomic instability in the Swedish hemangioma cohort after reanalyzed dosimetry

Eidemüller

Holmberg

Jacob

et al. 2015

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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The cohort of 17,200 female Swedish hemangioma patients, who had been exposed to ionizing radiation because of skin hemangioma, was analyzed for breast cancer incidence with descriptive excess relative risk models and mechanistic models of carcinogenesis. The dosimetry system has recently been updated, leading to substantially reduced doses for the most highly exposed part of the Stockholm cohort. The follow-up includes persons until December 2009 with 877 breast cancer cases. All models agree on the risk estimates. The excess relative and excess absolute risk at the age of 50 years are 0.48 Gy(-1) (95% CI 0.28; 0.69) and 10.4 (10(4)PYR Gy)(-1) (95% CI 6.1; 14.4) (95% CI 6.1; 14.4), respectively. These risk estimates are about a factor of 2 higher than previous analyses of this cohort as a consequence of the re-evaluation of the dosimetry system. Explicit models incorporating effects of genomic instability were developed and applied to the hemangioma cohort. It was found that a radiation-induced transition towards genomic instability was highly significant. The models indicate that the main effect of radiation-induced genomic instability is to increase the rate of transition of non-initiated cells to initiated cells with a proliferative advantage. The magnitude of such an acceleration cannot be inferred from epidemiological data alone, but must be complemented by radiobiological measurements.

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Section: Introductionmentioning

confidence: 99%

Breast cancer risk and possible mechanisms of radiation-induced genomic instability in the Swedish hemangioma cohort after reanalyzed dosimetry

Eidemüller

Holmberg

Jacob

et al. 2015

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…For lung cancer, mechanistic modeling studies are abundant but have focused almost exclusively on the twostage model. These indicate that for the two main risk factors, smoking [20][21][22] and α-particle radiation (most relevant being Radon decay products) [23][24][25][26][27][28][29][30][31][32], the best description is afforded by an enhancement of the proliferation rate of premalignant cells. However, for radiation, this conclusion has been disputed [33] because it lacks a conclusive biological mechanism, in contrast to the accepted mutagenic effect of radiation.…”

Section: Introductionmentioning

confidence: 99%

Beyond Two-Stage Models for Lung Carcinogenesis in the Mayak Workers: Implications for Plutonium Risk

2015

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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.

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“…While the induction of hyperplasia diminishes the local tissue damage by alpha-particles, on one hand, it may increase the risk of stochastic effects, on the other hand. Some analyses of epidemiological data suggests that radon exposure is primarily a promoting agent for lung carcinogenesis (Luebeck et al 1999;Eidemüller et al 2012). It is expected that the induction of progenitor cell hyperplasia is accompanied by an increase in the number of preneoplastic progenitor cells, and so it may contribute to promotion.…”

Section: Hyperplasia Induced By Radon Exposure As a Radioadaptive Resmentioning

confidence: 99%

Radon induced hyperplasia: effective adaptation reducing the local doses in the bronchial epithelium

Madas¹

2016

J. Radiol. Prot.

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There is experimental and histological evidence that chronic irritation and cell death may cause hyperplasia in the exposed tissue. As the heterogeneous deposition of inhaled radon progeny results in high local doses at the peak of the bronchial bifurcations, it was proposed earlier that hyperplasia occurs in these deposition hot spots upon chronic radon exposure. The objective of the present study is to quantify how the induction of basal cell hyperplasia modulates the microdosimetric consequences of a given radon exposure. For this purpose, computational epithelium models were constructed with spherical cell nuclei of six different cell types based on histological data. Basal cell hyperplasia was modelled by epithelium models with additional basal cells and increased epithelium thickness. Microdosimetry for alpha-particles was performed by an own-developed Monte-Carlo code. Results show that the average tissue dose, and the average hit number and dose of basal cells decrease by the increase of the measure of hyperplasia. Hit and dose distribution reveal that the induction of hyperplasia may result in a basal cell pool which is shielded from alpha-radiation. It highlights that the exposure history affects the microdosimetric consequences of a present exposure, while the biological and health effects may also depend on previous exposures. The induction of hyperplasia can be considered as a radioadaptive response at the tissue level. Such an adaptation of the tissue challenges the validity of the application of the dose and dose rate effectiveness factor from a mechanistic point of view. As the location of radiosensitive target cells may change due to previous exposures, dosimetry models considering the tissue geometry characteristic of normal conditions may be inappropriate for dose estimation in case of protracted exposures. As internal exposures are frequently chronic, such changes in tissue geometry may be highly relevant for other incorporated radionuclides.

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Lung Cancer Mortality (1950–1999) among Eldorado Uranium Workers: A Comparison of Models of Carcinogenesis and Empirical Excess Risk Models

Cited by 19 publications

References 48 publications

Breast cancer risk and possible mechanisms of radiation-induced genomic instability in the Swedish hemangioma cohort after reanalyzed dosimetry

Breast cancer risk and possible mechanisms of radiation-induced genomic instability in the Swedish hemangioma cohort after reanalyzed dosimetry

Beyond Two-Stage Models for Lung Carcinogenesis in the Mayak Workers: Implications for Plutonium Risk

Radon induced hyperplasia: effective adaptation reducing the local doses in the bronchial epithelium

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