Decoding the chemistry of the FLASH effect: a physicochemical model of dose-rate, pH and oxygen-dependent H₂O₂ production

<i>Objective.</i>To elucidate the initial chemical mechanisms that may underlie the FLASH effect by developing and validating a unified simulation framework for the radiolysis of pure water. The goal is to create a single model capable of reconciling conflicting experimental and simulation data regarding H₂O₂ production and explaining key radiobiological observations across conventional (CDRs) and ultra-high dose rates (UHDRs) under varied oxygenation levels.<i>Approach.</i>An ordinary differential equation-based model was developed to simulate the homogeneous chemistry phase of water radiolysis. The framework incorporates a detailed chemical reaction network and a novel description of acid-base equilibrium, allowing pH to evolve dynamically. A key innovation is the integration of an empirically derived, dose-rate dependent<i>G</i>-value coefficient (<i>G</i>_F(<i>D</i>_R)) that anchors the simulation to experimental data. The temporal evolution of key species (H₂O₂, O₂, H₃O⁺, OH^-) is tracked to investigate the impact of dose rate and oxygen concentration.<i>Main results.</i>The model reproduces two key experimental findings relevant to the FLASH effect-previously challenging for simulations: decreased net H₂O₂ production at UHDR under physioxic conditions. This reduction (vs CDR) aligns with normal tissue sparing, while hypoxic (tumour-like) conditions show comparable H₂O₂ production at UHDR and CDR, consistent with iso-tumour control. These results confirm that H₂O₂ radiochemistry is profoundly influenced by both dose rate and oxygen levels.<i>Significance.</i>This work resolves a key discrepancy between previously published simulations and experimental data on UHDR water radiolysis. The model provides a robust, mechanistic foundation linking the physical parameter of dose rate to the distinct chemical environments that likely drive the differential biological outcomes of the FLASH effect. It serves as a powerful new tool for investigating the complex interplay between dose rate, oxygenation, and radiolytic chemistry.