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Purpose: Simulation of indirect damage originating from the attack of free radical species produced by ionizing radiation on biological molecules based on the independent pair approximation is investigated in this work. In addition, a new approach, relying on the independent pair approximation that is at the origin of the independent reaction time (IRT) method, is proposed in the chemical stage of Geant4‐DNA. Methods: This new approach has been designed to respect the current Geant4‐DNA chemistry framework while proposing a variant IRT method. Based on the synchronous algorithm, this implementation allows us to access the information concerning the position of radicals and may make it more convenient for biological damage simulations. Estimates of the evolution of free species as well as biological hits in a segment of DNA chromatin fiber in Geant4‐DNA were compared for the dynamic time step approach of the step‐by‐step (SBS) method, currently used in Geant4‐DNA, and this newly implemented IRT. Results: Results show a gain in computation time of a factor of 30 for high LET particle tracks with a better than 10% agreement on the number of DNA hits between the value obtained with the IRT method as implemented in this work and the SBS method currently available in Geant4‐DNA. Conclusion: Offering in Geant4‐DNA more efficient methods for the chemical step based on the IRT method is a task in progress. For the calculation of biological damage, information on the position of chemical species is a crucial point. This can be achieved using the method presented in this paper. [ABSTRACT FROM AUTHOR]

Purpose: The simulation of individual particle tracks and the chemical stage following water radiolysis in biological tissue is an effective means of improving our knowledge of the physico‐chemical contribution to the biological effect of ionizing radiation. However, the step‐by‐step simulation of the reaction kinetics of radiolytic species is the most time‐consuming task in Monte Carlo track‐structure simulations, with long simulation times that are an impediment to research. In this work, we present the implementation of the independent reaction times (IRT) method in Geant4‐DNA Monte Carlo toolkit to improve the computational efficiency of calculating G‐values, defined as the number of chemical species created or lost per 100 eV of deposited energy. Methods: The computational efficiency of IRT, as implemented, is compared to that from available Geant4‐DNA step‐by‐step simulations for electrons, protons and alpha particles covering a wide range of linear energy transfer (LET). The accuracy of both methods is verified using published measured data from fast electron irradiations for •OH and eaq‐ for time‐dependent G‐values. For IRT, simulations in the presence of scavengers irradiated by cobalt‐60 γ‐ray and 2 MeV protons are compared with measured data for different scavenging capacities. In addition, a qualitative assessment comparing measured LET‐dependent G‐values with Geant4‐DNA calculations in pure liquid water is presented. Results: The IRT improved the computational efficiency by three orders of magnitude relative to the step‐by‐step method while differences in G‐values by 3.9% at 1 μs were found. At 7 ps, •OH and eaq‐ yields calculated with IRT differed from recent published measured data by 5% ± 4% and 2% ± 4%, respectively. At 1 μs, differences were 9% ± 5% and 6% ± 7% for •OH and eaq‐, respectively. Uncertainties are one standard deviation. Finally, G‐values at different scavenging capacities and LET‐dependent G‐values reproduced the behavior of measurements for all radiation qualities. Conclusion: The comprehensive validation of the Geant4‐DNA capabilities to accurately simulate the chemistry following water radiolysis is an ongoing work. The implementation presented in this work is a necessary step to facilitate performing such a task. [ABSTRACT FROM AUTHOR]

Purpose: Indirect biological damage due to reactive species produced in water radiolysis reactions is responsible for the majority of biological effect for low linear energy transfer (LET) radiation. Modeling water radiolysis and the subsequent interactions of reactive species, as well as track structures, is essential to model radiobiology on the microscale. Recently, chemistry models have been developed for Geant4‐DNA to be used in combination with the comprehensive existing physics models. In the current work, the first detailed, independent, in silico validation of all species yields with published experimental observations and comparison with other radiobiological simulations is presented. Additionally, the effect of LET of protons and heavier ions on reactive species yield in the model was examined, as well as the completeness of the chemical reactions following the radiolysis within the time after physical interactions simulated in the model. Methods: Yields over time of reactive species were simulated for water radiolysis by incident electrons, protons, alpha particles, and ions with various LETs using Geant4 and RITRACKS simulation tools. Water dissociation and recombination was simulated using Geant4 to determine the completeness of chemical reactions at the end of the simulation. Yield validation was performed by comparing yields simulated using Geant4 with experimental observations and other simulations. Validation was performed for all species for low LET radiation and the solvated electron and hydroxyl radical for high LET ions. Results: It was found that the Geant4‐DNA chemistry yields were generally in good agreement with experimental observations and other simulations. However, the Geant4‐DNA yields for the hydroxyl radical and hydrogen peroxide at the end of the chemistry stage were found to be respectively considerably higher and lower than the experimentally observed yields. Increasing the LET of incident hadrons increased the yield of secondary species and decreased the yield of primary species. The effect of LET on the yield of the hydroxyl radical at 100 ns simulated with Geant4 was in good agreement with experimental measurements. Additionally, by the end of the simulation only 40% of dissociated water molecules had been recombined and the rate of recombination was slowing. Conclusions: The yields simulated using Geant4 are within reasonable agreement with experimental observations. Higher LET radiation corresponds with increased yields of secondary species and decreased yields of primary species. These trends combined with the LET having similar effects on the 100 ns hydroxyl radical yield for Geant4 and experimental measurements indicate that Geant4 accurately models the effect of LET on radiolysis yields. The limited recombination within the modeled chemistry stage and the slowing rate of recombination at the end of the stage indicate potential long‐range indirect biological damage. [ABSTRACT FROM AUTHOR]

The objective of this work was to study the differences in terms of early biological effects that might exist between different X-rays energies by using a mechanistic approach. To this end, radiobiological experiments exposing cell monolayers to three X-ray energies were performed in order to assess the yields of early DNA damage, in particular of double-strand breaks (DSBs). The simulation of these irradiations was set in order to understand the differences in the obtained experimental results. Hence, simulated results in terms of microdosimetric spectra and early DSB induction were analyzed and compared to the experimental data. Human umbilical vein endothelial cells (HUVECs) were irradiated with 40, 220 kVp, and 4 MV X-rays. The Geant4 Monte Carlo simulation toolkit and its extension Geant4-DNA were used for the simulations. Microdosimetric calculations aiming to determine possible differences in the variability of the energy absorbed by the irradiated cell population for those photon spectra were performed on 10,000 endothelial cell nuclei representing a cell monolayer. Nanodosimetric simulations were also carried out using a computation chain that allowed the simulation of physical, physico-chemical, and chemical stages on a single realistic endothelial cell nucleus model including both heterochromatin and euchromatin. DNA damage was scored in terms of yields of prompt DSBs per Gray (Gy) and per giga (109) base pair (Gbp) and DSB complexity was derived in order to be compared to experimental data expressed as numbers of histone variant H2AX (γ-H2AX) foci per cell. The calculated microdosimetric spread in the irradiated cell population was similar when comparing between 40 and 220 kVp X-rays and higher when comparing with 4 MV X-rays. Simulated yields of induced DSB/Gy/Gbp were found to be equivalent to those for 40 and 220 kVp but larger than those for 4 MV, resulting in a relative biological effectiveness (RBE) of 1.3. Additionally, DSB complexity was similar between the considered photon spectra. Simulated results were in good agreement with experimental data obtained by IRSN (Institut de radioprotection et de sûreté nucléaire) radiobiologists. Despite differences in photon energy, few differences were observed when comparing between 40 and 220 kVp X-rays in microdosimetric and nanodosimetric calculations. Nevertheless, variations were observed when comparing between 40/220 kVp and 4 MV X-rays. Thanks to the simulation results, these variations were able to be explained by the differences in the production of secondary electrons with energies below 10 keV. [ABSTRACT FROM AUTHOR]