Commentary: the oxygen effect as a possible contributing factor to the mechanism for FLASH protection of normal tissue.

Abstract

Purpose: Despite seven decades of research on radiation protection by thiols and radiation sensitization by oxygen, there is no universal agreement on their interaction in defining the overall radiation response of (mammalian) cells. Thus, even in modern textbooks, the 'Oxygen Effect' (greater radiation resistance at reduced oxygen levels) is typically described using the same equation derived by Howard-Flanders and Alper in 1957 for bacterial cells and yeasts, without consideration for the impact of thiols (unknown at that time). A major contributing factor to this lack of agreement involves the very low oxygen concentrations (µM range) required for radiation sensitization. This causes severe challenges to oxygen measurement and control, and is further complicated by the depletion of oxygen by radiation itself (radiation chemical oxygen depletion - ROD). Recently, an unexpected protection of normal (but not tumor) tissue was found for radiation delivered at >40 Gy/s (FLASH), compared with conventional (<1 Gy/s) dose rates. A possible mechanism for FLASH was suggested to involve ROD, leading to reduced tissue oxygenation and protection through the oxygen effect.

Conclusions: This commentary will review the discovery of the 'Oxygen Effect', discuss problems associated with original and alternative models, and summarize a radiation-chemistry-based model that is relevant to interest in dose-modification. The radiation chemistry background to this model shows directly how radiation depletes oxygen (and other molecules) and that while this depletion is a part of the oxygen effect, it does not define it. Finally, the impact of a shift in half-maximal resistance on radiation protection by FLASH will be illustrated.