Proton FLASH effects on mouse skin at different oxygen tensions.

Objective . Irradiation at FLASH dose rates (>40 Gy s -1 ) has received great attention due to its reported normal tissue sparing effect. The FLASH effect was originally observed in electron irradiations but has since been shown to also occur with both photon and proton beams. Several mechanisms have been proposed to explain the tissue sparing at high dose rates, including effects involving oxygen, such as depletion of oxygen within the irradiated cells. In this study, we investigated the protective role of FLASH proton irradiation on the skin when varying the oxygen concentration. Approach . Our double scattering proton system provided a 1.2 × 1.6 cm 2 elliptical field at a dose rate of ∼130 Gy s -1 . The conventional dose rate was ∼0.4 Gy s -1 . The legs of the FVB/N mice were marked with two tattooed dots and fixed in a holder for exposure. To alter the skin oxygen concentration, the mice were breathing pure oxygen or had their legs tied to restrict blood flow. The distance between the two dots was measured to analyze skin contraction over time. Main results . FLASH irradiation mitigated skin contraction by 15% compared to conventional dose rate irradiation. The epidermis thickness and collagen deposition at 75 d following 25 to 30 Gy exposure suggested a long-term protective function in the skin from FLASH irradiation. Providing the mice with oxygen or reducing the skin oxygen concentration removed the dose-rate-dependent difference in response. Significanc e. FLASH proton irradiation decreased skin contraction, epidermis thickness and collagen deposition compared to standard dose rate irradiations. The observed oxygen-dependence of the FLASH effect is consistent with, but not conclusive of, fast oxygen depletion during the exposure.