Throughout life, every person is constantly exposed to different types of ionising radiation, without even noticing the exposure. The mean radiation exposure for people living in Germany amounts to approximately 4 mSv per year and encompasses the exposure from natural and man-made sources. The risks associated with exposure to low doses of radiation are still the subject of intense and highly controversial discussions, emphasizing the social relevance of studies investigating the effects of low radiation doses. Molecular studies could provide new insights into the radiation response of cells and organisms, thus contributing to a better understanding of radiation effects and improving current risk assessment models. One approach focuses on the diverse damages induced by ionising radiation in cells of the organism which are the underlying cause for radiation effects. In this thesis, DNA double-strand breaks (DSBs) were analyzed within three projects covering different aspects. DSBs are among the most hazardous DNA lesions induced by ionizing radiation, because this type of damage can easily lead to the loss of genetic information. Consequently, the DSB presents a high risk for the genetic integrity of the cell.

In the first project, extensive results uncovered the track structure of charged particles in a biological model tissue. This provided the first biological data that could be used for comparison with data that were measured or predicted using theoretical physical dosimetry methods and mathematical simulations. Charged particles contribute significantly to the natural radiation exposure and are used increasingly in cancer radiotherapy because they are more efficient in tumor cell killing than X- or gamma-rays. The difference in the biological effects of high energy charged particles compared with X- or gamma-rays is largely determined by the spatial distribution of their energy deposition and the track structure inducing a three-dimensional damage pattern in living cells. This damage pattern consists of cells directly hit by the particle receiving a high dose and neighboring cells not directly hit by primary particles but exposed to far-reaching secondary electrons (delta-electrons). These cells receive a much lower dose deposition in the order of a few mGy. The radial dose distribution of single particle tracks was assessed with sub-µm resolution by utilizing the unique morphology of the retina as a model tissue. The analysis revealed a 1/r2 dependency of the dose deposition by delta-electrons, which was hitherto only determined with physical approaches in inorganic material. Moreover, the biological measurements indicate the presence of a background dose at larger distances from primary particles, which arises as a result of additive dose contributions from several independent particles. In conclusion, this interdisciplinary project put emphasis on the transition between the physical and the biological radiation effects and provided extensive data for the biological verification of physical measurements and models. Some of these models are used for the planning of tumor treatment with charged particles.

The second project built upon previously obtained data and focused on the investigation of the DSB repair efficiency of cells irradiated with low doses. For this project, radiation doses were selected that are comparable to the doses, which are routinely used during diagnostic medical examinations. While a linear induction of DSBs with the applied dose was detected in human fibroblasts, these cells fail to repair DSBs efficiently after very low doses of X-rays. However, the repair efficiency was increased in cells pre-treated with low concentrations of hydrogen peroxide, suggesting that this induces a response, which is required for the repair of radiation-induced DSBs after exposure to low radiation doses (Grudzenski et al., 2010, PNAS 107:14205-10). One interpretation of this finding is that a certain cellular radical level is required to efficiently activate the repair machinery. To test this hypothesis, we asked if the DSB repair capacity at low doses can be further diminished when cells are treated with a radical scavenger prior to irradiation. Indeed, a decreased DSB repair capacity in cells pre-treated with the radical scavenger N-Acetylcystein was observed. Appropriate in vivo experiments with mice confirmed the physiological relevance of our cellular studies and suggests that the cellular radical level is critical for efficient DSB repair after low doses.

In the third project, the inhomogeneous distribution of radon within the body of the mouse was investigated using a biological approach for the first time. To determine the distribution of radon, the DSBs induced by the decay of radon and its daughter nucleotides were quantified in several tissues. Radon is a naturally occurring noble gas, which can be found all over the world in different concentrations and contributes significantly to the natural radiation exposure of the population. Although the exposure to radon is a well-characterized risk factor for the development of lung cancer, radon is a popular remedy for the treatment of patients suffering from painful inflammatory diseases. Since conditions for the animal experiments were comparable to radon therapy sessions, the experimentally detected doses in the organs reflect their therapy-associated radiation exposure. Knowledge of the inhomogeneous radon distribution within the body and its resulting biological effects will help to shed light on the underlying mechanism that results in the therapeutic effect during the treatment of inflammatory diseases. The extensive biological data obtained here generally provides the unique possibility to verify and optimise mathematical models for risk assessment of radon exposures.

Collectively, the three projects of this thesis investigated consequences of the exposure to low radiation doses. The controversy surrounding the effects of low doses is still standing and the presented results support the view that every exposure leads to non-negligible biological effects. Therefore, detailed knowledge of radiation effects is essential for the therapeutic application as well as for radiation protection.