A Passive Biomolecular Oxygen Diffusion Mechanism that Removes Oxygen from the Cell Nucleus as a Proposed Mechanism for the FLASH Effect by Radiochemical Oxygen Depletion and Transient Hypoxia of the Cell Nucleus

Many mechanisms have been proposed to explain the normal tissue-sparing effect observed with FLASH radiation therapy. However, a satisfactory explanation has not been found. While the hypothesis of transient hypoxia through radiochemical oxygen depletion (ROD) initially seemed promising, experimental evidence and simulations have led to this mechanism falling out of favor. In this work, we briefly review the oxygen diffusion theory of August Krogh and present an updated version that includes a more detailed mechanism of oxygen diffusion in tissues and within cells. Specifically, we show that oxygen is removed from the cell nucleus, a process named the Hoover® effect. This effect provides a basis for explaining the biphasic oxygen enhancement ratio phenomenon, which creates a volume-based enhancement to the FLASH sparing effect at low pO2 away from capillaries. Additionally, the differential depletion of oxygen inside and outside the cell nucleus may lead to Hoover-assisted radiochemical oxygen depletion and enhanced transient hypoxia of the cell nucleus. Thus, the Hoover effect is a passive biomolecular oxygen vacuum diffusion pump that reduces the concentration of oxygen in the cell nucleus and is hypothesized to provide a mechanism for radiochemical oxygen depletion as a primary cause of the FLASH effect.