Radiation-Induced Carcinogenesis: Mechanistically Based Differences between Gamma-Rays and Neutrons, and Interactions with DMBA

Center for Radiological Research, Columbia University Medical Center, New York, New York, United States of America.
PLoS ONE (Impact Factor: 3.23). 12/2011; 6(12):e28559. DOI: 10.1371/journal.pone.0028559
Source: PubMed


Different types of ionizing radiation produce different dependences of cancer risk on radiation dose/dose rate. Sparsely ionizing radiation (e.g. γ-rays) generally produces linear or upwardly curving dose responses at low doses, and the risk decreases when the dose rate is reduced (direct dose rate effect). Densely ionizing radiation (e.g. neutrons) often produces downwardly curving dose responses, where the risk initially grows with dose, but eventually stabilizes or decreases. When the dose rate is reduced, the risk increases (inverse dose rate effect). These qualitative differences suggest qualitative differences in carcinogenesis mechanisms. We hypothesize that the dominant mechanism for induction of many solid cancers by sparsely ionizing radiation is initiation of stem cells to a pre-malignant state, but for densely ionizing radiation the dominant mechanism is radiation-bystander-effect mediated promotion of already pre-malignant cell clone growth. Here we present a mathematical model based on these assumptions and test it using data on the incidence of dysplastic growths and tumors in the mammary glands of mice exposed to high or low dose rates of γ-rays and neutrons, either with or without pre-treatment with the chemical carcinogen 7,12-dimethylbenz-alpha-anthracene (DMBA). The model provides a mechanistic and quantitative explanation which is consistent with the data and may provide useful insight into human carcinogenesis.

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    • "The shape of the dose-response curve is uncertain for cancer effects. Neutron ionizing radiation often produces downwardly curving dose-responses, where the risk initially grows with dose, but eventually stabilizes or decreases (inverse dose-rate effect) [32]. In contrast with an inverse dose-rate effect with neutron exposure, γ-rays in the same mouse strain produce a relatively linear dose-response. "
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