Oxygen Enhancement Ratio-Weighted Dose Quantitatively Describes Acute Skin Toxicity Variations in Mice After Pencil Beam Scanning Proton FLASH Irradiation With Changing Doses and Time Structures.

Purpose: The aim of this work was to investigate the ability of a biological oxygen enhancement ratio-weighted dose, D, to describe acute skin toxicity variations observed in mice after proton pencil beam scanning irradiations with changing doses and beam time structures.

Methods And Materials: In five independent experiments, the right hind leg of a total of 621 CDF1 mice was irradiated previously in the entrance plateau of a pencil beam scanning proton beam. The incidence of acute skin toxicity (of level 1.5-2.0-2.5-3.0-3.5) was scored for 47 different mouse groups that mapped toxicity as function of dose for conventional and FLASH dose rate, toxicity as function of field dose rate with and without repainting, and toxicity when splitting the treatment into 1 to 6 identical deliveries separated by 2 minutes. D was calculated for all mouse groups using a simple oxygen kinetics model to describe oxygen depletion. The three independent model parameters (oxygen-depletion rate, oxygen-recovery rate, oxygen level without irradiation) were fitted to the experimental data. The ability of D to describe the toxicity variations across all experiments was investigated by comparing D-response curves across the five independent experiments.

Results: After conversion from the independent variable tested in each experiment to D, all five experiments had similar MDD50 (D giving 50% toxicity incidence) with standard deviations of 0.45 - 1.6 Gy for the five toxicity levels. D could thus describe the observed toxicity variations across all experiments.

Conclusions: D described the varying FLASH-sparing effect observed for a wide range of conditions. Calculation of D for other irradiation conditions can quantitatively estimate the FLASH-sparing effect for arbitrary irradiations for the investigated murine model. With appropriate fitting parameters D also may be able to describe FLASH effect variations with dose and dose rate for other assays and endpoints.