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FLASH radiotherapy is a novel irradiation modality that employs ultra-high mean dose rates exceeding 40–150 Gy/s, far surpassing the typical ~0.03 Gy/s used in conventional radiotherapy. This advanced technology delivers high doses of radiation within milliseconds, effectively targeting tumors while minimizing damage to the surrounding healthy tissues. However, the precise mechanism that differentiates responses between tumor and normal tissues is not yet understood. This study primarily examines the ROD hypothesis, which posits that oxygen undergoes transient radiolytic depletion following a radiation pulse. We developed a computational model to investigate the effects of dose rate on radiolysis in an aqueous environment that mimics a confined cellular space subjected to instantaneous pulses of energetic protons. This study employed the multi-track chemistry Monte Carlo simulation code, IONLYS-IRT, which has been optimized to model this radiolysis in a homogeneous and aerated medium. This medium is composed primarily of water, alongside carbon-based biological molecules (RH), radiation-induced bio-radicals (R^●), glutathione (GSH), ascorbate (AH⁻), nitric oxide (^●NO), and α-tocopherol (TOH). Our model closely monitors the temporal variations in these components, specifically focusing on oxygen consumption, from the initial picoseconds to one second after exposure. Simulations reveal that cellular oxygen is transiently depleted primarily through its reaction with R^● radicals, consistent with prior research, but also with glutathione disulfide radical anions (GSSG^●−) in roughly equal proportions. Notably, we show that, contrary to some reports, the peroxyl radicals (ROO^●) formed are not neutralized by recombination reactions. Instead, these radicals are rapidly neutralized by antioxidants present in irradiated cells, with AH⁻ and ^●NO proving to be the most effective in preventing the propagation of harmful peroxidation chain reactions. Moreover, our model identifies a critical dose rate threshold below which the FLASH effect, as predicted by the ROD hypothesis, cannot fully manifest. By comparing our findings with existing experimental data, we determine that the ROD hypothesis alone cannot entirely explain the observed FLASH effect. Our findings indicate that antioxidants might significantly contribute to the FLASH effect by mitigating radiation-induced cellular damage and, in turn, enhancing cellular radioprotection. Additionally, our model lends support to the hypothesis that transient oxygen depletion may partially contribute to the FLASH effect observed in radiotherapy. However, our findings indicate that this mechanism alone is insufficient to fully explain the phenomenon, suggesting the involvement of additional mechanisms or factors and warranting further investigation. Full article

This study conducts a comparative analysis of cystamine (RSSR), a disulfide, and cysteamine (RSH), its thiol monomer, to evaluate their efficacy as radioprotectors and antioxidants under high linear energy transfer (LET) and high-dose-rate irradiation conditions. It examines their interactions with reactive primary species produced during the radiolysis of the aqueous ferrous sulfate (Fricke) dosimeter, offering insights into the mechanisms of radioprotection and highlighting their potential to enhance the therapeutic index of radiation therapy, particularly in advanced techniques like FLASH radiotherapy. Using Monte Carlo multi-track chemical modeling to simulate the radiolytic oxidation of ferrous to ferric ions in Fricke-cystamine and Fricke-cysteamine solutions, this study assesses the radioprotective and antioxidant properties of these compounds across a variety of irradiation conditions. Concentrations were varied in both aerated (oxygen-rich) and deaerated (hypoxic) environments, simulating conditions akin to healthy tissue and tumors. Both cystamine and cysteamine demonstrate radioprotective and strong antioxidant properties. However, their effectiveness varies significantly depending on the concentration employed, the conditions of irradiation, and whether or not environmental oxygen is present. Specifically, excluding potential in vivo toxicity, cysteamine substantially reduces the adverse effects of ionizing radiation under aerated, low-LET conditions at concentrations above ~1 mM. However, its efficacy is minimal in hypoxic environments, irrespective of the concentration used. Conversely, cystamine consistently offers robust protective effects in both oxygen-rich and oxygen-poor conditions. The distinct protective capacities of cysteamine and cystamine underscore cysteamine’s enhanced potential in radiotherapeutic settings aimed at safeguarding healthy tissues from radiation-induced damage while effectively targeting tumor tissues. This differential effectiveness emphasizes the need for personalized radioprotective strategies, tailored to the specific environmental conditions of the tissue involved. Implementing such approaches is crucial for optimizing therapeutic outcomes and minimizing collateral damage in cancer treatment. Full article

(1) Background: Water radiolysis leads to the formation of hydronium ions H₃O⁺ in less than 50 fs, resulting in the formation of transient acidic pH spikes in the irradiated water. The purpose of this study is to examine the time evolution of these spikes of acidity under irradiation conditions combining both high absorbed dose rate and high-LET radiation. (2) Methods: The early space–time history of the distributions of the various reactive species was obtained using our Monte Carlo multitrack chemistry simulation code IONLYS-IRT. To simulate different LETs, we used incident protons of varying energies as radiation sources. The “instantaneous pulse” (or Dirac) model was used to investigate the effect of dose rate. (3) Results: One major finding is that the combination of high dose rates and high LETs is clearly additive, with a very significant impact on the pH of the solution. For example, at 1 ns and for a dose rate of ~10⁷ Gy/s, the pH drops from ~4.7 to 2.7 as the LET increases from ~0.3 to 60 keV/μm. (4) Conclusions: Confirming previous work, this purely radiation chemical study raises the question of the possible importance and role of these spikes of acidity in underpinning the physical chemistry and biology of the “FLASH effect”. Full article