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A two-mutation model of carcinogenesis: Analysis of radiation induced lung tumours in animals and implications for risk evaluation

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Synopsis

In this paper an attempt is made to develop a model for radiation carcinogenesis essentially from first principles ; to demonstrate that the model can describe both the age and dose dependent induction of cancer in animals for widely differing exposure conditions ; and to outline the implications of the model for radiation biology and protection. The two-stage model for carcinogenesis developed by Knudson and Moolgavkar is modified and combined with the molecular model for cellular radiation effects to analyse radiation induced lung tumours in rodents for a variety of radiation types and conditions. The combined model provides the possibility of calculating the age dependent and dose dependent incidence of cancer simultaneously. The model is used to fit data of lung tumours in mice for acute exposures to X-rays, neutrons and to different dose-rates of gamma-rays, and of lung tumours in rats exposed for longer periods to radon. The satisfactory application of the combined model to animal data has led to an examination of the implications of the model, which prove to be far-reaching for the extrapolation of risk to low doses, the effect of life time exposures and other aspects of radiation risk assessment. The combined model predicts that the age dependent tumour incidence can follow either an absolute risk type of pattern when exposure occurs at an older age, or a relative risk type of pattern when exposure occurs at an early age. It also predicts that the radiation effect is intimately related to the spontaneous incidence and thus has implications for the transfer of risk across populations.

 

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