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CAN WE DISCARD THE OXYGEN DEPLETION HYPOTHESIS?
Abstract
Background and Aims
Radiochemical oxygen depletion (ROD) rates in pure water and radical scavenger containing solutions are too low to support the oxygen depletion hypothesis as a FLASH sparing mechanism. Dose rate dependency of ROD in living tissues has not been investigated. We performed in vitro and in vivo ROD measurements with two aims: 1) to investigate possible amplification of ROD rates in the presence of self-propagating chain reactions, and 2) to evaluate the dependency of radiation-induced transient oxygen depletion in living tissues on temporal beam characteristics.
Methods
We used phosphatidylcholine liposomes loaded with linoleic acid to model peroxidation chain reactions induced by irradiation of biological membranes. ROD rates in liposome samples were measured as a function of a) phospholipid concentration, and b) dose rate and dose per pulse. Next, we recorded changes in oxygen tension in mouse skin and brain irradiated at different dose rates. We determined the maximum drop in oxygen as a function of dose rate and compared it to the published dose rate dependencies of FLASH healthy tissue sparing. Quenching of phosphorescence was used to monitor oxygen in all cases.
Results
Upon CONV irradiation, oxygen consumption in liposomes was more than 10 fold higher than in pure water. On contrary, ROD rates upon FLASH irradiation were minimally affected, showing only 20% increase at the highest lipid concentration. In vivo measurements established the dependency of transient oxygen depletion on dose rate. This dependency is tissue specific and dominated by the rate of oxygen re-supply.
Conclusions
Weak impact of lipids on FLASH ROD rates indicates enhanced radical recombination and discards the assumption of increased ROD by chain reactions involving biological macromolecules. Poor match between dose rate dependencies of ROD induced drop in tissue oxygenation and FLASH healthy tissue sparing represents strong evidence against the oxygen depletion hypothesis.