Chronic cell death may play a crucial role in mutagenesis and carcinogenesis due to radon exposure Balázs G. Madas, Imre Balásházy MTA Centre for Energy Research,, Hungary balazs.madas@energia.mta.hu Low dose radiation effects on the immune system: current knowledge and future research needs, Hungary November 5-7, 2013
2/16 Definition of low doses The DoReMi defines low doses as those of 100 mgy or less and medium doses as 0.1 Gy - 1 Gy for low LET radiations. Low and medium dose rates are defined as 0.1 Gy/h or less for low LET radiations. For high-let radiations, dose and dose-rates of interest are lower, e.g. for alpha radiation by an order of magnitude.
3/16 Spatial dose distribution In medium scale not subcellular nanodosimetry not whole body irradiation radiation protection weighting factors Are these low doses? Are these relevant?
4/16 Significance of radon progeny extremely inhomogeneous dose distribution in the bronchial airways responsible for half of the radiation burden of the public second most important cause of lung cancer
5/16 Objective What does it happen at the deposition hot spots in case of chronic exposures? effects on cell survival effect on cell division rate effects on mutation rate
6/16 Methods mathematical model of the bronchial epithelium based on experimental data (volumes, depth distributions) considering abundances of progenitor and non-progenitor cells microdosimetry model for α-particles in order to quantify cell nucleus hits and cellular doses model of biological response supposing exponential decrease of cell survival by cell nucleus hits equilibrium between cell death rate and cell division rate: α 1 1 β 1 N 1 = i β i N i that the number of mutations is proportional to the expected number of DNA DSBs at cell division considering DNA repair and spontaneous damages
α 1 1 β 1 Results surviving fractions significant cell death rate, especially for differentiated cells in the upper part N 1 = β i N i i possible response: increased cell division rate 7/16
α 1 1 β 1 Results cell division rate very high cell division rates even at moderate exposure rates tissue regeneration capacity may be exhausted N 1 = β i N i i possible response: number of progenitor cells increases hyperplasia 8/16
Results effect of hyperplasia plausible response of the tissue to cope with high dose rates for long term observed in the bronchial epithelium exposed to other irritants unique processes in radon induced carcinogenesis possible explanation for IERE 9/16
10/16 Classic way of radiation induced mutagenesis? Ionizing radiation causes DNA damages. Mutation induction rate is increased. The mechanism can be studied without a tissue context.
11/16 Another way of radiation induced mutagenesis Densely ionizing radiation effectively kills cells. Neighboring cells are forced to divide more frequently. Mutation induction rate is increased. The mechanism cannot be studied without a tissue context.
Results mutation induction cell death contributes to mutagenesis accelerated turnover due to cell death is the dominant mechanisms in vitro studies may underestimate mutation induction rate no differences in sporadic and RI cancers 12/16
13/16 One of the reasons
14/16 Summary spatially inhomogeneous dose distribution may be crucial in carcinogenesis further investigations are needed local hyperplasia is a plausible response of the tissue exposed chronically to high radon concentrations it provides an alternative explanation for inverse exposure rate effect unique processes may contribute to radon induced carcinogenesis, which are not characteristic of other exposures (e.g. local hyperplasia) accelerated cell turnover due to increased cell death rate may be crucial in some exposure scenarios kind of bystander, which is significant in whole dose range
15/16 Open questions Can radiation protection maintain such a universal system as the current one? different mechanisms in different exposure scenarios How spatial and temporal inhomogeneities can be taken into account in radiation protection? spatial and temporal distributions cannot be considered in the framework of LNT
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