Abstract
We present a new approach to model dose rate effects on cell killing after photon radiation based on the spatio-temporal clustering of DNA double strand breaks (DSBs) within higher order chromatin structures of approximately 1–2 Mbp size, so called giant loops. The main concept of this approach consists of a distinction of two classes of lesions, isolated and clustered DSBs, characterized by the number of double strand breaks induced in a giant loop. We assume a low lethality and fast component of repair for isolated DSBs and a high lethality and slow component of repair for clustered DSBs. With appropriate rates, the temporal transition between the different lesion classes is expressed in terms of five differential equations. These allow formulating the dynamics involved in the competition of damage induction and repair for arbitrary dose rates and fractionation schemes. Final cell survival probabilities are computable with a cell line specific set of three parameters: The lethality for isolated DSBs, the lethality for clustered DSBs and the half-life time of isolated DSBs.By comparison with larger sets of published experimental data it is demonstrated that the model describes the cell line dependent response to treatments using either continuous irradiation at a constant dose rate or to split dose irradiation well. Furthermore, an analytic investigation of the formulation concerning single fraction treatments with constant dose rates in the limiting cases of extremely high or low dose rates is presented. The approach is consistent with the Linear-Quadratic model extended by the Lea-Catcheside factor up to the second moment in dose. Finally, it is shown that the model correctly predicts empirical findings about the dose rate dependence of incidence probabilities for deterministic radiation effects like pneumonitis and the bone marrow syndrome. These findings further support the general concepts on which the approach is based.
Highlights
Understanding the dose and dose rate dependence of the cellular response to radiation is of key interest for risk estimations after occupational or accidental radiation exposure as well as for medical applications in radiation oncology
In order to validate the concept of the kinetic extension of the Giant LOop Binary LEsion model (GLOBLE), we first assessed the quality of the model in the description of larger sets of experimental data for the two cases of irradiation with constant dose rate and of split dose experiments
In the data provided by Ruiz et al and Stephens et al [39,37] it clearly can be seen that the survival probability for a specific cell line after the application of a certain dose increases if the dose rate is lowered
Summary
Understanding the dose and dose rate dependence of the cellular response to radiation is of key interest for risk estimations after occupational or accidental radiation exposure as well as for medical applications in radiation oncology. Typical dose rates cover a broad range from mGy/year, that are relevant for everyday radiation risk, up to several Gy/min, which are of interest for effects as a consequence of medical applications or severe radiation accidents. Induction of DNA damage, in particular double strand breaks (DSBs), has been identified as the key initial event causing observable radiation effects like e.g. cell killing. Intriguingly the mere number of DSBs is not sufficient to characterize the extent of the effects, since cells in general are able to process and to repair large fractions of the initially induced DNA damage [9,10,11,12,13]. It is of utmost interest to characterize the type(s) or subset(s) of damage that are less susceptible to repair and lead to an observable effect with higher probability
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