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An Interlaboratory Validation of the Radiation Dose Response Relationship (DRR) for H-ARS in the Rhesus Macaque

Thrall, Karla D.*; Love, Ruschelle*; O'Donnell, Kyle C.; Farese, Ann M.; Manning, Ronald*; MacVittie, Thomas J.

doi: 10.1097/HP.0000000000000339

The Medical Countermeasures against Radiological Threats (MCART) consortium has established a dose response relationship for the hematopoietic acute radiation syndrome (HARS) in the rhesus macaque conducted under an individualized supportive care protocol, including blood transfusions. Application of this animal model as a platform for demonstrating efficacy of candidate medical countermeasures is significantly strengthened when the model is independently validated at multiple institutions. The study reported here describes implementation of standard operating procedures at an institute outside the consortium in order to evaluate the ability to establish an equivalent radiation dose response relationship in a selected species. Validation of the animal model is a significant component for consideration of the model protocol as an FDA-recommended drug development tool in the context of the “Animal Rule.” In the current study, 48 male rhesus macaques (4–8 kg) were exposed to total-body irradiation (TBI) using 6 MV photon energy at a dose rate of approximately 0.8 Gy min−1. Results show that onset and duration of the hematological response, including anemia, neutropenia, and thrombocytopenia, following TBI ranging from 6.25 to 8.75 Gy correlate well with previously reported findings. The lethality values at 60 d following TBI were estimated to be 6.88 Gy (LD30/60), 7.43 Gy (LD50/60), and 7.98 Gy (LD70/60). These values are equivalent to those published previously of 7.06 Gy (LD30/60), 7.52 Gy (LD50/60), and 7.99 Gy (LD70/60); the DRR slope (p = 0.68) and y-intercepts show agreement along the complete dose range for HARS. The ability to replicate the previously established institutional lethality profile (PROBIT) and model outcomes through careful implementation of defined procedures is a testament to the robustness of the model and highlights the need for consistency in procedures.

*SNBL USA Ltd, 6605 Merrill Creek Parkway, Everett, WA; †Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, MD.

The authors declare no conflicts of interest.

For correspondence, contact: K. Thrall, SNBL USA Ltd, 6605 Merrill Creek Parkway, Everett, WA, or email at.

(Manuscript accepted 16 June 2015)

© 2015 by the Health Physics Society