Ultra-High Dose-Rate Oxygen Depletion and Skin Response to Irradiation.

Background/Objectives: This study investigates the hypothesis that transient oxygen depletion is the mechanism of the skin sparing effect of ultra-high dose-rate irradiation, commonly referred to as FLASH irradiation. Methods: Two skin tattoo dots were placed approximately 1.0 cm apart on the thigh of FVB/N mice. The area overlapping the dots was irradiated with a single dose of 27 Gy protons delivered with either FLASH (~120 Gy/s) or 0.5 Gy/s conventional dose-rate (CDR) irradiation. Skin contraction was assessed by measuring the distance between the tattoo dots and complemented by histopathological skin analyses. Mice were placed in a 1.4 L chamber flushed with 5%, 7%, 20.9% or 100% oxygen (balance nitrogen, where applicable) prior to and during irradiation. Skin oxygenation was measured non-invasively using the phosphorescence quenching method. Results: Compared to air-breathing mice, skin contraction increases in mice breathing 100% oxygen and decreases when breathing 7% and 5% oxygen following CDR irradiation, showing that skin is neither fully oxygenated nor hypoxic. FLASH irradiation reduced skin contraction, epidermal thickening, and fibrosis in air-breathing mice compared to CDR irradiation. The difference between FLASH and CDR skin contraction decreases as the inspired gas oxygen content is reduced from 20.9% to 7%. Under 5% oxygen breathing conditions, the FLASH sparing effect is eliminated. Conclusions: Mean normal tissue pO2 does not reveal the presence of cells at low pO2 that could become susceptible to FLASH-induced radiobiological hypoxia at doses lower than would be predicted from the mean tissue pO2 value. In the absence of oxygen, FLASH skin sparing for the late normal tissue effect, skin contraction, is eliminated.