Total-body irradiation (TBI) and partial-body irradiation (PBI) mouse models have been used for many years to develop safe and effective medical countermeasures (MCMs) against the acute radiation syndrome (ARS). ARS MCM development will benefit from a demonstration of the impact on survival from (a) the handling stress associated with repeat dose administrations, and (b) radiation beam quality with additional filtering of the orthovoltage X-ray beam, which we provide here. An open source "R" statistical tool is also provided to aid in generating dose response relationships (DRR) for establishing institutional lethality profiles. Compiled results from 27 TBI and 28 PBI studies in C57BL/6J male and female mice show the impact of the number of vehicle dose administrations and beam hardening on survival. For dose administration frequency, irradiated, non-dosed groups were compared with groups receiving increasing numbers of vehicle doses. Linear probit plots and lethality estimates were generated for the Thoraeus filter (tin, copper and aluminum) with and without 5 days of twice daily (5 × BID) dosing and for the aluminum filter without vehicle administration. A Wald test compared the slopes and intercepts of the probit estimates to assess differences in estimated lethality. Log-rank tests were used to determine the impact of vehicle administrations on observed lethality. A statistically significant reduction in survival was observed with increasing numbers of vehicle doses in the TBI model and for females in the PBI model using aluminum filtration. Repeated vehicle administrations (5× BID) also resulted in lower survival than in non-dosed males and females with the Thoraeus filter. Probit estimates of lethality when comparing non-dosed and 5× BID dosed groups indicate lower radiation doses were needed to achieve lethality in the 5× BID dosed groups, which were statistically significant in most log rank tests. When comparing the impact of filtration on survival, there was a statistically significant difference in intercepts for the estimated lethality values for each filter type, and the hardened Thoraeus-filtered beam required nearly 2 Gy of additional radiation dose to achieve the same survival as the aluminum filter. Lastly, our freely available "R" tool accurately generated probit estimates and confidence intervals (CI) when compared with estimates and CIs generated by a certified statistician using the STATA STS statistical package. Our results show that handling stress should be taken into consideration in designing ARS MCM development studies. Beam hardening with the removal of the low-energy photons and characteristic X rays resulted in a consistent shift in the DRRs for both males and females, with the "softer" aluminum beam resulting in greater mortality as compared to the Thoraeus-filtered beam. These findings will inform effective dose administration strategies in the design of ARS MCM development studies and aid in radiation dose harmonization efforts across the radiation community.
Beach et al. (Thu,) studied this question.