Radiation-Chemical Oxygen Depletion Depends on Chemical Environment and Dose Rate: Implications for the FLASH Effect

Purpose FLASH (dose rates >40 Gy/s) radiation therapy protects normal tissues from radiation damage, compared with conventional radiation therapy (∼Gy/m). Radiation-chemical oxygen depletion (ROD) occurs when oxygen reacts with radiation-induced free radicals, so a possible mechanism for FLASH involves radioprotection by the decreased oxygen as ROD occurs. High ROD rates would favor this mechanism, but prior studies have reported low ROD values (∼0.35 µM/Gy) in chemical environments such as water and protein/nutrient solutions. We proposed that intracellular ROD might be much larger, possibly promoted by its strongly reducing chemical environment. Methods and Materials ROD was measured, using precision polarographic sensors, from ∼100 µM to zero in solutions containing intracellular reducing agents ± glycerol (1M), to simulate intracellular reducing and hydroxyl-radical-scavenging capacity. Cs irradiators and a research proton beamline allowed dose rates from 0.0085 to 100 Gy/s. Results Reducing agents significantly altered ROD values. Most greatly increased ROD but some (eg, ascorbate) actually decreased ROD and additionally imposed an oxygen dependence of ROD at low oxygen concentrations. The highest values of ROD were found at low dose rates, but these montonically decreased with increasing dose rate. Conclusions ROD was greatly augmented by some intracellular reducing agents but others (eg, ascorbate) effectively reversed this effect. Ascorbate had its greatest effect at low oxygen concentrations. ROD decreased with increasing dose rate in most cases. FLASH (dose rates >40 Gy/s) radiation therapy protects normal tissues from radiation damage, compared with conventional radiation therapy (∼Gy/m). Radiation-chemical oxygen depletion (ROD) occurs when oxygen reacts with radiation-induced free radicals, so a possible mechanism for FLASH involves radioprotection by the decreased oxygen as ROD occurs. High ROD rates would favor this mechanism, but prior studies have reported low ROD values (∼0.35 µM/Gy) in chemical environments such as water and protein/nutrient solutions. We proposed that intracellular ROD might be much larger, possibly promoted by its strongly reducing chemical environment. ROD was measured, using precision polarographic sensors, from ∼100 µM to zero in solutions containing intracellular reducing agents ± glycerol (1M), to simulate intracellular reducing and hydroxyl-radical-scavenging capacity. Cs irradiators and a research proton beamline allowed dose rates from 0.0085 to 100 Gy/s. Reducing agents significantly altered ROD values. Most greatly increased ROD but some (eg, ascorbate) actually decreased ROD and additionally imposed an oxygen dependence of ROD at low oxygen concentrations. The highest values of ROD were found at low dose rates, but these montonically decreased with increasing dose rate. ROD was greatly augmented by some intracellular reducing agents but others (eg, ascorbate) effectively reversed this effect. Ascorbate had its greatest effect at low oxygen concentrations. ROD decreased with increasing dose rate in most cases.