  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 tissue
oxygenation has led to the assumption that oxygen "depletion" could be its
major driving force. 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. 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, and eventually a detrimental effect on the therapeutic window. 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.
