The Acute Gastrointestinal Subsyndrome of the Acute Radiation Syndrome

Abstract

The development of medical countermeasures against the acute gastrointestinal subsyndrome of the acute radiation syndrome in humans requires well characterized and validated animal models. These models must adhere to the criteria of the U.S. Food and Drug Administration's Animal Rule and consider the natural history and clinical context of the human radiation response and treatment in the nuclear terrorist scenario. The models must define the radiation dose- and time-dependent relationships for mortality and major signs of morbidity, including concurrent damage in other organs, such as the bone marrow, that may contribute to the overall mortality and morbidity. There are no such models of the gastrointestinal syndrome in response to total-body irradiation in the nonhuman primate. Herein, these parameters are defined for the rhesus macaque exposed to potentially lethal doses of radiation and administered medical management. Rhesus macaques (n = 69) were exposed bilaterally to 6 MV linear accelerator-derived photon total body irradiation to midline tissue (thorax) doses ranging from 10.0 to 14.0 Gy at 0.80 Gy min(-1). Following irradiation, all animals were administered supportive care consisting of fluids, anti-emetics, anti-diarrheal medication, antibiotics, blood transfusions, analgesics, and nutrition. The primary endpoint was survival at 15 d post-irradiation. Secondary endpoints included indices of dehydration, diarrhea, weight loss, hematological parameters, cellular histology of the small and large intestine, and mean survival time of decedents. Mortality within the 15-d in vivo study defined the acute gastrointestinal syndrome and provided an LD30/15 of 10.76 Gy, LD50/15 of 11.33 Gy, and an LD70/15 of 11.90 Gy. Intestinal crypt and villus loss were dose- and time-dependent with an apparent nadir 7 d post-irradiation and recovery noted thereafter. Severe myelosuppression and thrombocytopenia were noted in all animals, requiring the administration of antibiotics and blood transfusions. The model defines the dose response relationship and time course of acute gastrointestinal syndrome-induced morbidity and mortality in the rhesus macaque.

Gas Chromatography/Mass Spectrometry Metabolomics of Urine and Serum from Nonhuman Primates Exposed to Ionizing Radiation: Impacts on the Tricarboxylic Acid Cycle and Protein Metabolism

“…As previously mentioned, 16 7 day biomarkers are needed because individuals may need extended time for sample processing due to ensuing alarm and panic following potential mass radiation exposures. Additionally, NHP systems have the advantage of (1) clinical signs and mitigator effects from IR exposure being well documented, 28–31 (2) continually expanding knowledge on metabolomic signatures from IR exposure, 9,10,13,16,17,32,33 and (3) genetically closer to human studies than murine models. 18 We found several small carboxylic acids, amino acids, and tricarboxylic acid (TCA) cycle intermediates not previously identified by targeted and global metabolomic studies performed on LC–MS platforms.…”

Global Metabolomic Identification of Long-Term Dose-Dependent Urinary Biomarkers in Nonhuman Primates Exposed to Ionizing Radiation

“…NHP models are advantageous due to the closer genetic similarity to humans over other animal models (i.e., murine models), the ability to minimize exogenous variability (e.g., diet) and intraspecific genetic differences seen in human studies (8). In addition, a wealth of information has been collected on primary radiation exposure effects in NHP models, such as postirradiation hematopoiesis (21, 22), damage to the gastrointestinal (GI) tract (23–25) and kidney (26). The acute and prolonged GI syndromes have been described and categorized in detail in total- and partial-body-irradiated NHPs (23, 24).…”

“…In addition, a wealth of information has been collected on primary radiation exposure effects in NHP models, such as postirradiation hematopoiesis (21, 22), damage to the gastrointestinal (GI) tract (23–25) and kidney (26). The acute and prolonged GI syndromes have been described and categorized in detail in total- and partial-body-irradiated NHPs (23, 24). While NHP responses to radiation exposure have been well characterized, metabolomic data on NHP tissues and biofluids is lacking, since only a limited number of studies have analyzed NHP samples using high-throughput global metabolomics (7, 20).…”

A Mathematical Model of the Human Small Intestine Following Acute Radiation and Burn Exposures

“…For instance, non-human primates (NHPs) have been studied in the context of radiationinduced gut injuries (MacVittie et al, 2012b, MacVittie et al, 2012a, Wang et al, 2015. We can use this data to build an NHP model of radiation response in the small intestine.…”