Purpose: Recent studies suggest ultra-high dose rate (FLASH) irradiation can spare normal tissues from radiotoxicity, while efficiently controlling the tumor, and this is known as the FLASH effect. This study performed theoretical analyses about the impact of radiolytic oxygen depletion (ROD) on the cellular responses after FLASH irradiation. Methods: Monte Carlo simulation was used to model the ROD process, determine the DNA damage, and calculate the amount of oxygen depleted (LROD) during FLASH exposure. A mathematical model was applied to analyze oxygen tension (pO2) distribution in human tissues and the recovery of 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 source particles on ROD and subsequent cellular responses were systematically evaluated. Results: The simulated electron LROD range was 0.38-0.43 {mu}M/Gy when pO2 ranged from 7.5-160 mmHg. The calculated DNA damage and SFs show that radioprotective effect is only evident in cells with a lower pO2. Different irradiation setups alter the cellular responses by modifying the pO2. Single pulse delivery or multi-pulse delivery with pulse intervals shorter than 10-50 ms resulted in fewer DNA damages and higher SFs. Source particles with a low radiation quality have a higher capacity to deplete oxygen, and thus, lead to a more conspicuous radioprotective effect. Conclusions: The FLASH radioprotective effect due to ROD may only be observed in cells with a low pO2. Single pulse delivery or multi-pulse delivery with short pulse intervals are suggested for FLASH irradiation to avoid oxygen tension recovery during pulse intervals. Source particles with low radiation quality are preferred for their conspicuous radioprotective effects.
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