Dose rate-driven responses to ionizing radiation in CBA/Ca and C57BL/6N evaluated using benchmark dose (BMD) modeling

Dose rate is an important factor influencing the biological outcomes of environmental ionizing radiation exposure. This study aimed to investigate genotoxic and phenotypic effects of dose rate while keeping the total dose constant (3 Gy). Using the Figaro facility, CBA/CaOla and C57BL/6N mice were exposed to gamma radiation (⁶⁰Co) at low (2.5 mGy/h for 54d) and higher dose rates (10 mGy/h for 14d and 100 mGy/h for 30h). Cellular stress was assessed through micronuclei in reticulocytes, DNA damage (comet assay), mitochondrial DNA copy number variation and common deletions (digital droplet PCR), and protein carbonylation in plasma. Micronucleus formation in reticulocytes proved to be a highly sensitive and specific dose rate predictor, shown by a log-linear dose rate response (R² = 0.98). Mitochondrial DNA copy number increased in a strain- and dose rate-dependent manner, while no significant effects on common deletions or protein carbonylation were detected. Chronic low dose rate exposure led to an approximate 60 % reduction in testis weights, other phenotypic results were not evident. Benchmark dose analysis of liver transcriptomic data revealed shared radiation responses across functional categories and transcriptional points of departure for DNA damage-related pathways. The BMD analysis of MN-RETs demonstrated a BMDL far below the lowest dose, indicating that the MN-RET-assay is suitable for lower dose rates and total doses. Integrating adverse effect analysis with BMDL estimations improves dose rate-response characterization and contributes to more refined risk assessment, reducing reliance on high dose rate extrapolation.