A multiscale radiation biophysical stochastic model describing the cell survival response at ultra-high dose rate under different oxygenations and radiation qualities

Background and purpose: While the advantages of ultra-high dose-rate (UHDR) irradiation have been well highlighted experimentally, the biological mechanism underlying the FLASH effect is still unclear and highly debated. The aim of this work is to reproduce the main in-vitro UHDR experiments and to try to explain the different in-vivo response between healthy tissues and tumors, developing a fully consistent radiation biophysical model for UHDR regime. Materials and methods: We developed the MultiScale Generalized Stochastic Microdosimetric Model (MS-GSM2), a multi-stage extension of the GSM2, which is a probabilistic model describing the time evolution of the lesions in an irradiated cell nucleus. We coupled the slow DNA damage evolution with the fast chemical reaction kinetics, including the impact of the redox environment. Results: The MS-GSM2 can investigate the combined effects of chemical species, DNA damage formation and time evolution. We demonstrate that the MS-GSM2 predictions are coherent with the in-vitro UHDR experimental results across various oxygenation levels, and radiation qualities. We analyze the role of the chemical environmental conditions of the irradiated medium, i.e. oxygenation, and scavengers concentration, discussing possible factors that can attenuate or level out the dose rate dependence of the cell survival, to understand the differential effect that occurs in-vivo between normal tissue and tumor. Conclusion: The MS-GSM2 can accurately describe multiple aspects of the FLASH effect and be consistent with the main evidence from the in-vitro experiments with different types of radiation and oxygenations. Our model proposes a consistent explanation for the differential outcomes observed in normal tissues and tumors, in-vivo and in-vitro.