Effect of FLASH dose-rate and oxygen concentration in the production of HOin cellular-like media versus water: a Monte Carlo track-structure study.

To study the effect of dose-rate in the time evolution of chemical yields produced in pure water versus a cellular-like environment for FLASH radiotherapy research. A version of TOPAS-nBio with Tau-Leaping algorithm was used to simulate the homogenous chemistry stage of water radiolysis using three chemical models: 1) liquid water model that considered scavenging of eaq-, H● by dissolved oxygen; 2) Michaels & Hunt model that considered scavenging of ●OH, eaq-, and H● by biomolecules existing in cellular environment; 3) Wardman model that considered model 2) and the chemical repair enzyme glutathione (GHS). H2O2 concentrations at conventional and FLASH dose-rates were compared with published measurements. Model 3) was used to estimate DNA single-strand break (SSB) yields and compared with published data. SSBs were estimated from simulated yields of DNA hydrogen abstraction and attenuation factors to account for the scavenging capacity of the medium. The simulation setup consisted of monoenergetic protons (100 MeV) delivered in pulses at conventional (0.2857Gy s⁻¹) and FLASH (500Gy s⁻¹) dose rates. Dose varied from 5-20Gy, and oxygen concentration from 10µM-1mM. At the steady state, for model 1), H2O2 concentration differed by 81.5%±4.0% between FLASH and conventional dose-rates. For models 2) and 3) the differences were within 8.0%±4.8%, and calculated SSB yields agreed with published data within 3.8%±1.2%. A maximum oxygen concentration difference of 60% and 50% for models 2) and 3) between conventional and FLASH dose-rates was found between 2106 and 91013 ps for 20 Gy of absorbed dose. The findings highlight the importance of developing more advanced cellular models to account for both the chemical and biological factors that comprise the FLASH effect. It was found that differences between pure water and cellular environment models were significant and extrapolating results between the two should be avoided. Observed differences call for further experimental investigation.