Kinetic model of radiochemical oxygen depletion (ROD) in FLASH radiotherapy

The role of oxygen in "Ultra-High Dose Rate" (UHDR) radiotherapy is currently subject to active debate, due to its importance in the FLASH effect. Radiochemical oxygen depletion (ROD) is used to characterize the removal of oxygen by its interaction with the free radicals produced by the radiation. Currently, there is a need to understand why ROD depends on the radiation dose rate and the initial oxygen pressure.

Development of a kinetic model of ROD that explains its dependence on (i) radiation dose rate and (ii) initial oxygen pressure, $O_2$ .

The current work uses a variety of published ROD studies performed in vitro and in vivo in mice to evaluate the kinetic model prediction of ROD. The in vitro studies include evaluation of ROD in water, bovine serum albumin (BSA), and CELL medium consisting of HEPES ( $10\mathrm{mM}$ ), glycerol ( $1M$ ), glucose ( $5\mathrm{mM}$ ), and glutathione ( $5\mathrm{mM}$ ). Published in vivo studies were performed in C57BL/6 mice (male and female) and NU(Ico)-Foxn1nu mice (female Swiss nude) using proton FLASH and electron, respectively. Oxygen pressure measurements were performed with a variety of different probes such as (i) TROXSP5 sensors, (ii) Oxyphor PtG4, and (iii) Oxylite (NX-BF/OT/E). Two definitions of ROD were used in the current work to represent separately the ROD dependence in "time" ( $\mathrm{RO}{D}_{\mathrm{Time}}$ ) and "dose" ( $\mathrm{RO}{D}_{\mathrm{Dose}}$ ).

The kinetic model $\mathrm{RO}{D}_{\mathrm{Dose}}$ prediction agreed well with published measurements, yielding reduced ${\chi }^2$ values near the unity for water, BSA, and CELL medium, and comparably strong agreement for the animal-study datasets, within the reported or estimated uncertainties used in this work. The solvated electron G-value, $G_{e_{\mathrm{aq}}^{-}}$ , was shown to be dose rate, LET dependent and medium specific. For a medium with radical scavenging capacity (such as BSA and CELL), a higher value of $G_{e_{\mathrm{aq}}^{-}}$ was observed compared to water, which had a much lower radical scavenging capacity. The kinetic model $\mathrm{RO}{D}_{\mathrm{Dose}}$ dose rate predictions also achieved very good agreement, with the published in vitro in water and BSA medium. The $\mathrm{RO}{D}_{\mathrm{Dose}}$ kinetic model's dose-rate predictions for in vivo mice studies also showed excellent agreement once the raw oxygen consumption data were corrected for oxygen diffusion during radiation delivery.

A systematic review of all published ROD studies was performed and used as the basis for testing the novel kinetic model for ROD. The kinetic model prediction of ROD showed that the radiolysis products, $\mathrm{OH}•$ , $e_{\mathrm{aq}}^{•-}$ , $O_2^{•-}$ , ${\mathrm{HO}}_2^{•-}$ , play an important role in ROD and provide an explanation why ROD depends on (1) dose rate and (2) initial oxygen pressure.