Do Pure Water-Radiolysis Experiments Truly Unlock the Secrets of the FLASH Effect? A Numerical Revelation

Background and Aims
Reduced production of Reactive Oxygen Species (ROS) offers a potential explanation for the FLASH effect observed at ultra-high dose rates (UHDR). Recent studies consistently demonstrate decreased hydrogen peroxide (H2O2) generation in pure water under UHDR conditions. Additionally, the nature of irradiating particles significantly influences this phenomenon. This research aims to investigate ROS formation and decay kinetics in both FLASH and conventional conditions, spanning various Linear Energy Transfer levels and particle types.

Methods
In this work, chemical concentrations are assessed by solving systems of Ordinary Differential Equations (ODEs). These ODEs are constructed based on (i) chemical reaction definitions and (ii) the production of radicals resulting from irradiation, as determined by radiolytic yields. Despite the simplification of modeling cells as homogeneous systems, this approach facilitates simulation of the temporal evolution of various ROS concentrations over an extended duration, spanning several minutes. Furthermore, this methodology enables insightful sensitivity analysis by selectively activating or deactivating components of the reaction schemes or adjusting the reaction rates of specific reactions, thereby highlighting their respective roles.

Results
This study elucidates the chemical mechanisms governing H2O2 generation and consumption. A comparative analysis of irradiation effects on pure water and cellular biochemistry is conducted. The results for pure water closely align with experimental literature, showing reduced H2O2 levels with increasing dose rates. In contrast, when turning on more complex cellular biochemistry, the dose rate dependence diminishes significantly due to cells' capacity to scavenge ROS.

Conclusions
A distinct correlation emerges between UHDR and decreased H2O2 levels in pure water, aligning with established experimental data. Nevertheless, the association wanes notably when enabling cellular systems, primarily due to the potent ROS scavenging abilities inherent to cells. The translational applicability of water radiolysis findings to biological contexts remains an open inquiry, carrying profound implications for our comprehension of the FLASH effect in radiotherapy.