Biological effects of conventional and ultra high dose rate radiation in human cells

FLASH radiotherapy (FLASH-RT) that uses an ultra-high dose rate (UHDR) radiation is emerging as an effective cancer treatment modality but the biological effects of UHDR are not fully understood. In this study, biological effects induced by conventional dose rate (CDR; 1 Gy/min) and UHDR (600 Gy/s) were evaluated in human peripheral blood lymphocytes of 10 donors at two different radiation doses (3 Gy and 8 Gy) of 9 MeV electrons. Cytogenetic analysis revealed that the unstable chromosome aberrations (dicentrics, rings and fragments) were reduced by 1.5–twofold after UHDR exposure (600 Gy/s) relative to CDR (1 Gy/min) at both radiation doses (3 Gy and 8 Gy). A similar trend was observed for the stable chromosome aberrations (insertions, balanced and unbalanced translocations) detected by fluorescence in situ hybridization (FISH) using a cocktail of DNA probes for chromosomes 1, 2 and 4. Pooled data indicated that the translocations (color junctions) were reduced by 40–50% in 600 Gy/s irradiated lymphocytes at both 3 Gy and 8 Gy doses relative to CDR. In corroboration, genome wide analysis of translocations by the multicolor FISH technique revealed reduced yields of chromosome exchange events after UHDR compared to CDR of electrons. In agreement with inter-chromosomal aberrations, intra-chromosomal aberrations detected by multicolor BAND analysis of chromosome 1 also showed reduced yields of different aberrations (inversions, insertions, and p- and q arm translocations) after UHDR exposure relative to CDR. Quantitative modeling of dicentrics and translocations, utilizing the linear-quadratic formalism with polynomial regression (inverse-variance weighting) and quantile regression, revealed significant dose response reductions at 600 Gy/s versus 1 Gy/min. In agreement with the reduced yields of unstable and stable chromosome aberrations, UHDR of electrons resulted in a modest increase in leukocyte viability and reduced BAX protein expression. Further molecular studies using well defined human cell model systems are required for gaining insight into the cellular DNA repair mechanisms for UHDR radiation.