Physicochemical modeling of electron FLASH to identify the roles of oxygen, aqueous electrons and causal radical recombination effects underlying them.

Background: Ultra high dose rate (UHDR) irradiation reduces normal tissue toxicity as compared conventional dose rate (CDR) irradiation-known as the FLASH effect, yet the underlying radiochemical mechanisms remain poorly understood. Direct measurements rely upon longer lived water radiolysis species such as aqueous electrons (eaq-) and oxygen, to infer behaviors of toxic species leading to tissue damage. This study uses kinetic modeling to identify which chemical pathways exhibit dose rate dependent behavior and can be used to correlate experiments. Methods: A comprehensive physicochemical model of water radiolysis was developed, incorporating 17 molecular species and 56 coupled reaction rate equations, with pulsed beam structures matched to published UHDR electron irradiation experiments. Simulations were performed across a range of oxygen tensions (0.1-10% O₂) and dose rate conditions (0.3-300 Gy/s). Model predictions were validated against experimental measurements of eaq- transients,and oxygen consumption in vitro and in vivo. They also were compared to prior computational models. Results: Modeled lifetimes of eaq- matched experiments across O2 concentrations and showed that >90% of scavenging occurs via O2 and reactions with proteins, with radical-radical recombination contributing <5% even at 300 Gy/s. The lifetimes of OH• radicals were similarly dominated by protein scavenging, with recombination pathways remaining minor (<5%) with UHDR. Modeled oxygen consumption matched the magnitude and dose rate dependence observed in published experiments. The results indicated a primary dose rate sensitive pathway, the reaction between hydroperoxyl radical (HO₂•) and superoxide (O₂•⁻). Peroxyl radical formation decreased at UHDR within oxygen tensions (≈5-20 mmHg) corresponding to the experimentally observed FLASH oxygen window. Conclusion: This work identifies specific radiochemical pathways that exhibit true dose rate sensitivity and clarifies which proposed FLASH mechanisms are unsupported by homogeneous phase radical kinetics. Radical-radical recombination contributes too little (<5%) to account for known FLASH sparing at UHDR, whereas peroxyl radical and HO₂•/O₂•⁻ chemistry shows dose rate dependent behavior within physiologic oxygen tensions associated with FLASH. Although constrained by simplified aqueous conditions lacking scavengers and tissue heterogeneity, the model provides mechanistic insight into the radiochemical regimes dominating the homogeneous phase chemistry.&#xD.