Radiolysis Simulations Used to Evaluate Radical Recombination Effects and Oxygen Limitations In Flash Radiotherapy
Abstract
Purpose
The FLASH radiotherapy effect is the reduction of radiation-induced normal tissue damage with Ultra-High Dose Rate (UHDR) irradiation, relative to Conventional Dose Rates (CDR), while preserving tumor tissue damage. However, the underlying mechanism remains unknown. Leading hypotheses, including radical recombination and oxygen depletion, have not yet provided a clear explanation of the FLASH effect. By modeling the radiolysis process, the fundamental reactions responsible for mechanisms such as DNA damage can be probed to clarify these theories.
Methods
Beam parameters were derived from those used by the IntraOp Mobetron for UHDR and CDR delivery, and numerical simulations were used to propagate 56 radiolysis rate equations, matching parameters for a protein solution, involving 16 transient molecular species under a range of dose rates and oxygen tensions. Oxygen related differences, radical recombination, and protein-specific interactions were primarily analyzed. Model validation was performed by comparison with experimentally derived oxygen consumption and aqueous electron lifetime measurements under different oxygen and dose rate conditions.
Results
Short-lived reactive species such as aqueous electrons and hydroxyl radicals exhibited recombination rates of less than 5% at the highest dose rate of 300 Gy/s (10 Gy delivered in a 4-µs pulse). A primary finding was that the reaction pathway leading to reduced oxygen consumption at UHDR compared to CDR was from combination of hydroperoxyl and superoxide radicals, which replenishes molecular oxygen in the system. The primary radiolysis pathways that varied with oxygen tension were protein-mediated, showing reduced peroxyl radical production when both UHDR and low oxygen tension were present.
Conclusion
This study predicted a lack of significant radical recombination in protein solutions under UHDR conditions. Consistent with in vitro and in vivo observations, initial oxygenation was found to be crucial for UHDR-induced changes in key DNA-damaging radicals.