A mechanistic consideration of oxygen enhancement ratio, oxygen transport and their relevancies for normal tissue sparing under FLASH irradiation

Our study investigated the role of oxygen in mediating the FLASH effect. This effect, which was first reported in vitro in the 1950s and in vivo in the 1970s, recently gained prominence with a number of publications showing differential sparing between normal tissues and tumors. Oxygen depletion (and subsequent induction of transient hypoxia) is the oldest and most prominent hypothesis to explain this effect. To better understand how the oxygen depletion hypothesis and oxygen enhancement ratio (OER) are relevant for interpreting FLASH benefits, an analytical model was proposed to estimate the sparing factor. The model incorporated factors such as OER, oxygen partial pressure (pO2), loco-regional oxygen diffusion/metabolism, total dose and dose rate. The sparing factor, was used to quantify the sparing of normal tissue (initially physoxic). The radiosensitivity parameters of two cell types (V79 Chinese hamster cells and T1 human kidney cells) were selected. Furthermore, the transient behavior of OER during finite time intervals was modeled, for both without and with the presence of oxygen transport using a diffusion model. For tissues with an oxygen consumption rate of 20 mmHg/s and a distance of 60 μm away from blood vessels, the sparing factor demonstrates an increase from 1.03/1.06 (V79/T1) at 2.5 Gy/s up to 1.28/1.72 (V79/T1) at 100 Gy/s (total dose: 10 Gy). For normal tissues of initial pO2 between 1.5 and 8 mmHg, the benefit from pushing the dose rate above 100 Gy/s is found to be marginal. Preliminary animal experiments have been conducted for validation. Overall, our study predicts that the dose rate associated with maximum normal tissue protection is between 50 Gy/s and 100 Gy/s. Other than the postulation of the hypoxic stem cell niches in normal tissues, we believe that a framework based upon the oxygen depletion hypothesis and OER is not able to efficiently interpret differential responses between normal and tumor tissue under FLASH irradiation.