May oxygen depletion explain the FLASH effect? A chemical track structure analysis

TL;DR

This study uses chemical track structure simulations to investigate if oxygen depletion explains the FLASH effect, concluding that oxygen depletion alone cannot account for the observed biological effects.

Contribution

The paper provides a detailed Monte Carlo analysis showing that oxygen depletion is insufficient to explain the FLASH effect, challenging the oxygen depletion hypothesis.

Findings

Oxygen depletion has negligible impact on radiosensitivity at typical oxygen levels.

Simulation results agree with experimental oxygen removal data.

Oxygen depletion does not account for the FLASH effect's biological observations.

Abstract

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.