A theory is presented t o explain the effect of radiation on cell survival. The theory is based on the assumption that a double strand break in the DXA helix is the critical damage. The theory is derived from the radiation induced molecular bond breaks in the DNA strands and parameters are included to take account of various repair processes which may occur between the radiation event and the biological result. Implications of the theory with respect to RBE, the oxygen effect and radiological protection are mentioned and a fit of the theoretically derived expression to experimental data for 250 kV, X-rays and 15 MeV neutrons is presented. An appendix contains data which show that the enzymatic repair of single strand breaks in DNA is in accordance with the theoretical analysis of protracted irradiations and that a coherent analysis of the variation of radiation sensitivity in the cell cycle is in strong support of the primary assumption that a double strand break in the DNA helix is the critical damage leading t o cell reproductive death.

No abstract

Three sets of data (population statistics in non-smokers, data from an investigation of the smoking habits of British doctors and a study of Colorado uranium miners) were used to analyse lung cancer in humans as a function of exposure to radon and smoking. One of the aims was to derive implications for radon risk estimates. The data were analysed using a two-mutation radiation carcinogenesis model and a stepwise determination of the model parameters. The basic model parameters for lung cancer were derived from the age dependence fit of the spontaneous lung cancer incidence in non-smokers. The effect of smoking was described by two additional parameters and, subsequently, the effect of radon by three other parameters; these five parameters define the dependence of the two mutation steps on smoking and exposure to radon. Using this approach, a consistent fit and comprehensive description of the three sets of data have been achieved, and the parameters could, at least partly, be related to cellular radiobiological data. The model results explain the different effect of radon on non-smokers and smokers as seen in epidemiological data. Although the analysis was only applied to a limited number of populations, lung cancer incidence as a result of radon exposure is estimated to be about ten times higher for people exposed at the age of about 15 than at about 50, although this effect is masked (especially for smokers) by the high lung cancer incidence from smoking. Using the model to calculate the lung cancer risks from lifetime exposure to radon, as is the case for indoor radon, higher risks were estimated than previously derived from epidemiological studies of the miners' data. The excess absolute risk per unit exposure of radon is about 1.7 times higher for smokers of 30 cigarettes per day than for non-smokers, even though, as a result of the low spontaneous tumour incidence in the non-smokers, the excess relative risk per unit exposure for the smokers is about 20 times lower than for the non-smokers. This prediction could have serious consequences for the transfer of risk estimates between populations. Although the solution of the model presented here is not unique but dependent on the model assumptions, the predictions and risk implications are sufficiently supported to justify a thorough investigation of the applicability of the model to other radon data sets.

An attempt is made to develop a model for radiation carcinogenesis linking DNA damage to malignancy. A modification of the two-stage model for carcinogenesis developed by Knudson and Moolgavkar (see J. Natl. Acad. Sci. (USA), vol. 68, p. 1037-52, 1981) is combined with a linear-quadratic dose response 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 and is used to fit data of lung tumours in mice and rats exposed to different radiation types. The satisfactory application of the combined model to animal data has led to an examination of the implications of the model, which may prove to be far-reaching for the extrapolation of risk to low doses, the effect of life exposures and other aspects of radiation risk assessment.

The recombination type of process, which has been proposed by Resnick to explain the rejoining of radiation-induced DNA double-strand breaks, is combined with the molecular theory of radiation action to provide a description of the formation of chromosomal rearrangments. It is shown that the majority of chromosomal aberration types found at the first mitosis after radiation can be explained on the basis of one radiation-induced DNA double-strand break in the backbone of the unineme chromatid, followed by the enzymatically controlled recombinational process for the rejoining of the double-strand break. The recombinogenic process for the repair of DNA double-strand breaks relies on the close association between the broken DNA double helix and homologous DNA. The homologous nature of repeated DNA base pair sequences is used, in this model, to explain the occurrence of chromosomal exchanges between non-homologous chromosomes. The important role which repetitive DNA plays in the formation of chromosomal rearrangements and in the distribution of 'break-points' found in radiation experiments is discussed.