A modified lethal–potentially lethal model for oxygen‐mediated FLASH sparing in stem cell niches

BACKGROUND: Ultra-high dose rate (FLASH) irradiation can reduce normal-tissue toxicity while preserving tumor control, but a mechanistic explanation consistent with classical radiobiology remains incomplete. In particular, oxygen-depletion arguments based solely on bulk tissue oxygenation can appear inconsistent with clinically relevant fraction sizes, motivating a DNA-target-level oxygen formulation. PURPOSE: To develop a theory-based mechanistic extension of the Lethal and Potentially Lethal (LPL) model that explains oxygen-mediated FLASH trends without prescribing dose rate-dependent radiosensitivity, and to identify the baseline nuclear oxygen window in which sparing is expected to be largest. METHODS: , which decreases via radiolytic depletion during irradiation and recovers toward a baseline via reduced-order reoxygenation kinetics. To address the oxygen paradox, we distinguish bulk vascular oxygenation from a lower effective DNA target-level oxygenation that may arise in regulated stem-cell niches because of niche hypoxia and intracellular oxygen consumption. Oxygen modulation is implemented through a mechanistic exponential OER formulation parameterized by an oxygen-fixation rate constant, while retaining classical LPL behavior in the conventional low-dose-rate limit. RESULTS: = 30 mmHg). Sensitivity analyses preserve this intermediate oxygen window while shifting the magnitude and threshold of the effect. CONCLUSIONS: By explicitly resolving Precursor Lesion fixation kinetics and by treating niche-to-nucleus oxygenation as an effective target-level variable, this mechanistic LPL framework predicts that oxygen-mediated FLASH sparing is most likely when baseline oxygenation lies within an intermediate physiologic-hypoxia window. The model should therefore be viewed as a mechanistic, testable framework rather than as a universal explanation of all FLASH responses.