title: 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.
abstract: 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.
authors.affiliation: *University of Maryland School of Medicine, Baltimore, MD, 21201; †Duke University Medical Center, Durham, NC 27710; ‡Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA; §Indiana University School of Medicine, Indianapolis, IN; **Baylor University College of Medicine, Houston, TX.
authors.forename: Isabel L
authors.initials: IL
authors.lastname: Jackson
authors.forename: Pu-Ting
authors.initials: PT
authors.lastname: Xu
authors.forename: Giao
authors.initials: G
authors.lastname: Nguyen
authors.forename: Julian D
authors.initials: JD
authors.lastname: Down
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Johnson
authors.forename: Barry P
authors.initials: BP
authors.lastname: Katz
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Hadley
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Vujaskovic
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008168:Lung / Q000473:pathology / Q000528:radiation effects*; D051379:Mice; D010996:Pleural Effusion / Q000150:complications; D011833:Radiation Injuries, Experimental / Q000150:complications / Q000209:etiology / Q000473:pathology; D017564:Radiation Pneumonitis / Q000150:complications / Q000209:etiology / Q000473:pathology; D013045:Species Specificity; D013909:Thorax / Q000528:radiation effects