  Background and purpose: Recent observations in animal models show that
ultra-high dose rate ("FLASH") radiation treatment significantly reduces normal
tissue toxicity maintaining an equivalent tumor control. The dependence of this
"FLASH" effect on target oxygenation has led to the assumption that oxygen
"depletion" could be its major driving force. Materials and Methods: In a
bottom-up approach starting from the chemical track evolution of 1 MeV
electrons in oxygenated water simulated with the TRAX-CHEM Monte Carlo code, we
determine the oxygen consumption and radiolytic reactive oxygen species
production following a short radiation pulse. Based on these values, the
effective dose weighted by oxygen enhancement ratio (OER) or the in vitro cell
survival under dynamic oxygen pressure is calculated and compared to that of
conventional exposures, at constant OER. Results: We find an excellent
agreement of our Monte Carlo predictions with the experimental value for
radiolytic oxygen removal from oxygenated water. However, the application of
the present model to published radiobiological experiment conditions shows that
oxygen depletion can only have a negligible impact on radiosensitivity through
oxygen enhancement, especially at typical experimental oxygenations where a
FLASH effect has been observed. Conclusion: We show that the magnitude and
dependence of the "oxygen depletion" hypothesis are not consistent with the
observed biological effects of FLASH irradiation. While oxygenation plays an
undoubted role in mediating the FLASH effect, we conclude that state-of-the-art
radiation chemistry models do not support oxygen depletion and
radiation-induced transient hypoxia as the main mechanism.
