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Purpose: Recent studies suggest ultra-high dose rate (FLASH) irradiation canspare normal tissues from radiotoxicity, while efficiently controlling thetumor, and this is known as the FLASH effect. This study performed theoreticalanalyses about the impact of radiolytic oxygen depletion (ROD) on the cellularresponses after FLASH irradiation. Methods: Monte Carlo simulation was used tomodel the ROD process, determine the DNA damage, and calculate the amount ofoxygen depleted (LROD) during FLASH exposure. A mathematical model was appliedto analyze oxygen tension (pO2) distribution in human tissues and the recoveryof pO2 after FLASH irradiation. DNA damage and cell survival fractions (SFs)after FLASH irradiation were calculated. The impact of initial cellular pO2,FLASH pulse number, pulse interval, and radiation quality of the sourceparticles on ROD and subsequent cellular responses were systematicallyevaluated. Results: The simulated electron LROD range was 0.38-0.43 {\mu}M/Gywhen pO2 ranged from 7.5-160 mmHg. The calculated DNA damage and SFs show thatradioprotective effect is only evident in cells with a lower pO2. Differentirradiation setups alter the cellular responses by modifying the pO2. Singlepulse delivery or multi-pulse delivery with pulse intervals shorter than 10-50ms resulted in fewer DNA damages and higher SFs. Source particles with a lowradiation quality have a higher capacity to deplete oxygen, and thus, lead to amore conspicuous radioprotective effect. Conclusions: The FLASH radioprotectiveeffect due to ROD may only be observed in cells with a low pO2. Single pulsedelivery or multi-pulse delivery with short pulse intervals are suggested forFLASH irradiation to avoid oxygen tension recovery during pulse intervals.Source particles with low radiation quality are preferred for their conspicuousradioprotective effects.

Modeling of cellular response after FLASH irradiation: a quantitative analysis based on the radiolytic oxygen depletion hypothesis