Analysis of hydrogen peroxide production in pure water: Ultrahigh versus conventional dose-rate irradiation and mechanistic insights.

BACKGROUND

Ultrahigh dose-rate radiation (UHDR) produces less hydrogen peroxide (HO) in pure water, as suggested by some experimental studies, and is used as an argument for the validity of the theory that FLASH spares the normal tissue due to less reactive oxygen species (ROS) production. In contrast, most Monte Carlo simulation studies suggest the opposite.

PURPOSE

We aim to unveil the effect of UHDR on HO production in pure water and its underlying mechanism, to serve as a benchmark for Monte Carlo simulation. We hypothesized that the reaction of solvated electrons ( ) removing hydroxyl radicals (•OH), the precursor of HO, is the reason why UHDR leads to a lower G-value (molecules/100 eV) for HO (G[HO]), because: 1, the third-order reaction between and •OH is more sensitive to increased instantaneous ROS concentration by UHDR than a two-order reaction of •OH self-reaction producing HO; 2, has two times higher diffusion coefficient and higher reaction rate constant than that of •OH, which means would dominate the competition for •OH and benefit more from the inter-track effect of UHDR. Meanwhile, we also experimentally verify the theory of long-lived radicals causing lower G(HO) in conventional irradiation, which is mentioned in some simulation studies.

METHODS AND MATERIALS

HO was measured by Amplex UltraRed assay. 430.1 MeV/u carbon ions (50 and 0.1 Gy/s), 9 MeV electrons (600 and 0.62 Gy/s), and 200 kV x-ray tube (10 and 0.1 Gy/s) were employed. For three kinds of water (real hypoxic: 1% O; hypoxic: 1% O and 5% CO; and normoxic: 21% O), unbubbled and bubbled samples with NO, the scavenger of , were irradiated by carbon ions and electrons with conventional and UHDR at different absolute dose levels. Normoxic water dissolved with sodium nitrate (NaNO), another scavenger of , and bubbled with NO was irradiated by x-ray to verify the results of low-LET electron beam.

RESULTS

UHDR leads to a lower G(HO) than conventional irradiation. O and CO can both increase G(HO). NO increases G(HO) of both UHDR and conventional irradiation and eliminates the difference between them for carbon ions. However, NO decreases G(HO) in electron conventional irradiation but increases G(HO) in the case of UHDR, ending up with no dose-rate dependency of G(HO). Three-spilled carbon UHDR does not have a lower G(HO) than one-spilled UHDR. However, the electron beam shows a lower G(HO) for three-spilled UHDR than for one-spilled UHDR. Normoxic water with NO or NaNO can both eliminate the dose rate dependency of HO production for x-ray.

CONCLUSIONS

UHDR has a lower G(HO) than the conventional irradiation for both high LET carbon and low LET electron and x-ray beams. Both scavengers for , NO and NaNO, eliminate the dose-rate dependency of G(HO), which suggests is the reason for decreased G(HO) for UHDR. Three-spilled UHDR versus one-spilled UHDR indicates that the assumption of residual radicals reducing G(HO) of conventional irradiation may only be valid for low LET electron beam.