Comparative study of pathology of various organs of rhesus macaques exposed to two different doses of acute total-body radiation

Abstract Acute, whole-body exposure to ionizing radiation has the potential to induce widespread injury, compromising multiple organ systems and predisposing the individual to a variety of pathologies. For medical countermeasures to advance towards regulatory approval, the United States Food and Drug Administration Animal Rule requires the use of validated large animal models of acute radiation syndrome (ARS). The rhesus macaque (Macaca mulatta) serves as a primary model for therapeutic development due to its close genetic, anatomic, and physiological homology to humans. Characterizing the nature of ARS is critical prior to drug development as it provides detailed insights into the system-specific responses to radiation exposure. In this study, we assessed the effects of 5.8 and 6.5 Gy total-body irradiation (TBI) on multiple organ systems in male and female rhesus macaques through histological evaluations of various tissues, clinical parameters, complete blood counts, and serum biochemistry. A total of 31 nonhuman primates were used to investigate the injury cascade of ARS. Our results demonstrate that TBI induces consistent lung injury along with gastrointestinal and hematopoietic alterations. Of note, severe splenic depletion in non-surviving animals, alongside unexpected tissue-specific responses such as reversed trends in sternum cellularity, were observed. Hematopoietic suppression was dose-dependent, with profound leukopenia, neutropenia, and thrombocytopenia, while red blood cell parameters declined more gradually. Serum biochemistry further revealed dynamic changes in various renal, hepatic, and pancreatic markers. Comparisons between 5.8 and 6.5 Gy exposures, as well as between males and females, revealed differences in injury severity and recovery, underscoring the need to account for both dose and sex in ARS model characterization.