Characterization of the dose response relationship for lung injury following acute radiation exposure in three well-established murine strains: developing an interspecies bridge to link animal models with human lung.

Approval of radiation countermeasures through the FDA Animal Rule requires pivotal efficacy screening in one or more species that are expected to react with a response similar to humans (21 C.F.R. § 314.610, drugs; § 601.91, biologics). Animal models used in screening studies should reflect the dose response relationship (DRR), clinical presentation, and pathogenesis of lung injury in humans. Over the past 5 y, the authors have characterized systematically the temporal onset, dose-response relationship (DRR), and pathologic outcomes associated with acute, high dose radiation exposure in three diverse mouse strains. In these studies, C57L/J, CBA/J, and C57BL/6J mice received wide field irradiation to the whole thorax with shielding of the head, abdomen, and forelimbs. Doses were delivered at a rate of 69 cGy min using an x-ray source operated at 320 kVp with half-value layer (HVL) of 1 mm Cu. For all strains, radiation dose was associated significantly with 180 d mortality (p < 0.0001). The lethal dose for 50% of animals within the first 180 d (LD50/180) was 11.35 Gy (95% CI 11.1-11.6 Gy) for C57L/J mice, 14.17 Gy (95% CI 13.9-14.5 Gy) for CBA/J mice, and 14.10 Gy (95% CI 12.2-16.4 Gy) for C57BL/6J mice. The LD50/180 in the C57L/J strain was most closely analogous to the DRR for clinical incidence of pneumonitis in non-human primates (10.28 Gy; 95% CI 9.9-10.7 Gy) and humans (10.60 Gy; 95% CI 9.9-12.1 Gy). Furthermore, in the C57L/J strain, there was no gender-specific difference in DRR (p = 0.5578). The reliability of the murine models is demonstrated by the reproducibility of the dose-response and consistency of disease presentation across studies.Health Phys. 106(1):000-000; 2014.