Modeling the oxygen effect in DNA strand break induced by gamma-rays with TOPAS-nBio

<i>Objective.</i>To present and validate a method to simulate from first principles the effect of oxygen on radiation-induced double-strand breaks (DSBs) using the Monte Carlo Track-structure code TOPAS-nBio.<i>Approach.</i>Two chemical models based on the oxygen fixation hypothesis (OFH) were developed in TOPAS-nBio by considering an oxygen adduct state of DNA and creating a competition kinetic mechanism between oxygen and the radioprotective molecule WR-1065. We named these models 'simple' and 'detailed' due to the way they handle the hydrogen abstraction pathways. We used the simple model to obtain additional information for the •OH-DNA hydrogen abstraction pathway probability for the detailed model. These models were calibrated and compared with published experimental data of linear and supercoiling fractions obtained with R6K plasmids, suspended in dioxane as a hydroxyl scavenger, and irradiated with¹³⁷Cs gamma-rays. The reaction rates for WR-1065 and O₂with DNA were taken from experimental works. Single-Strand Breaks (SSBs) and DSBs as a function of the dose for a range of oxygen concentrations [O₂] (0.021%-21%) were obtained. Finally, the hypoxia reduction factor (HRF) was obtained from DSBs.<i>Main Results.</i>Validation results followed the trend of the experimental within 12% for the supercoiled and linear plasmid fractions for both models. The HRF agreed with measurements obtained with¹³⁷Cs and 200-280 kVp x-ray within experimental uncertainties. However, the HRF at an oxygen concentration of 2.1% overestimated experimental results by a factor of 1.7 ± 0.1. Increasing the concentration of WR-1065 from 1 mM to 10-100 mM resulted in a HRF difference of 0.01, within the 8% statistical uncertainty between TOPAS-nBio and experimental data. This highlights the possibility of using these chemical models to recreate experimental HRF results.<i>Significance.</i>Results support the OFH as a leading cause of oxygen radio-sensitization effects given a competition between oxygen and chemical DNA repair molecules like WR-1065.