Purpose: Ultra-high dose rate irradiation has demonstrated to improve sparing of normal tissues while maintaining an equivalent tumor response (the FLASH effect). Although the biological mechanism of the FLASH effect is still not understood, oxygen depletion seems to be one of the plausible hypotheses. However, current mechanistic studies rely on pure liquid water calculations. We implemented two models of water radiolysis with chemical reactions of oxygen and molecules of biological importance, which might help evaluate the FLASH effect in tissue in a more reliable way.
Methods: We extended TOPAS-nBio to allow delivering pulses of radiation and reactions with oxygen in two different scenarios: including reactions between free radicals and DNA (Model 1); and additional reactions with RNA, proteins, amino acids and free nucleotides (Model 2). Those molecules were implemented as scavengers with reaction rates and concentrations obtained from the literature. Our simulations were carried out using microsecond-width pulses of 1 MeV electrons uniformly irradiating a water phantom cube of 1 µm side. The oxygen depletion without replenishing was compared for a conventional dose rate ( 0.29Gy/s) and FLASH irradiation conditions (… Gy/s) for 21% oxygen concentration.
Results: At the end of the electron pulse, and for all irradiation settings, both models predict that FLASH irradiation depletes 2.7 times more oxygen than conventional irradiation for the same absolute dose. This is caused by the intertrack and interpulse reactions between reactive species. The oxygen consumption varied by 16.7% between the two Models, which results from introducing competing scavengers that react with free radicals.
Conclusion: The proposed models under pulsed irradiation allowed us to quantify the time course of oxygen depletion under more realistic biological conditions than pure liquid water. Further work is performed under even more realistic conditions mimicking the cell environment and will be validated by experimental studies.