Model studies of the role of oxygen in the FLASH effect

Current radiotherapy facilities are standardized to deliver dose rates around 0.1-0.4 Gy/s in 2 Gy daily fractions, designed to deliver total accumulated doses to reach the tolerance limit of normal tissues undergoing irradiation. FLASH radiotherapy (FLASH-RT), on the other hand, relies on facilities capable of delivering ultrahigh dose rates in large doses in a single microsecond pulse, or in a few pulses given over a very short time sequence. For example, most studies to date have implemented 4-6 MeV electrons with intra-pulse dose rates in the range 106 -107  Gy/s. The proposed dependence of the FLASH effect on oxygen tension has stimulated several theoretical models based on three different hypotheses: (i) Radiation-induced transient oxygen depletion; (ii) cell-specific differences in the ability to detoxify and/or recover from injury caused by reactive oxygen species; (iii) self-annihilation of radicals by bimolecular recombination. This article focuses on the observations supporting or refuting these models in the frame of the chemical-biological bases of the impact of oxygen on the radiation response of cell free, in vitro and in vivo model systems.