A nonhuman primate model of the hematopoietic acute radiation syndrome plus medical management

Abstract

The development of medical countermeasures against the hematopoietic subsyndrome of the acute radiation syndrome requires well characterized and validated animal models. The model must define the radiation dose- and time-dependent relationships for mortality and major signs of morbidity to include other organ damage that may contribute to morbidity and mortality. Herein, the authors define these parameters for a nonhuman primate exposed to total body radiation and administered medical management. A blinded, randomized study (n = 48 rhesus macaques) determined the lethal dose-response relationship using bilateral 6 MV linear accelerator photon radiation to doses in the range of 7.20 to 8.90 Gy at 0.80 Gy min(-1). Following irradiation, animals were monitored for complete bloodcounts, body weight, temperature, diarrhea, and hydration status for 60 d. Animals were administered medical management consisting of intravenous fluids, prophylactic antibiotics, blood transfusions, anti-diarrheals, analgesics, and nutrition. The primary endpoint was survival at 60 d post-irradiation; secondary endpoints included hematopoietic-related parameters, number of transfusions, incidence of documented infection, febrile neutropenia, severity of diarrhea, mean survival time of decedents, and tissue histology. The study defined an LD30/60 of 7.06 Gy, LD50/60 of 7.52 Gy, and an LD70/60 of 7.99 Gy with a relatively steep slope of 1.13 probits per linear dose. This study establishes a rhesus macaque model of the hematopoietic acute radiation syndrome and shows the marked effect of medical management on increased survival and overall mean survival time for decedents. Furthermore, following a nuclear terrorist event, medical management may be the only treatment administered at its optimal schedule.

Figure 1. Dose response relationship for total-body irradiated (tbi) rhesus macaques

The 60 day mortality dose response relationship (DRR) for the hematopoietic sub-syndrome of the ARS in rhesus macaques, presented as probit percent mortality vs TBI dose (Gy) (on a linear scale). The graph contains two historical data sets showing the DRR and calculated LD50/30 values [95% CI] of rhesus macaques exposed to TBI from Co-60 γ-radiation or 2 MeV x-radiation (Eltringham 1967, Dalrymple 1969). These cohorts were not administered supportive care. The current study used TBI with 6MV LINAC-derived photons at a dose rate of 0.80 Gy/min with administration of supportive. The in-life phase was 60 days post TBI.

Figure 2. Mean absolute neutrophil counts in rhesus macaques following total-body irradiation

Animals were exposed to total body irradiation (TBI) with 6MV LINAC-derived photons at a dose rate of 0.80 Gy/min and administered supportive care. Shown are the decrease in the absolute neutrophil count (ANC) in the peripheral blood of rhesus macaques (n=8/radiation dose) as a function of time post TBI and dose (Gy). The respective dose of TBI and survivors/total NHP are: 7.20Gy 5/8, 7.55Gy 4/8, 8.05Gy 3/8. The radiation doses shown approximate the LD30, LD50, and LD70/60 estimated from the resultant data set.

Figure 3. Mean platelet counts in rhesus macaques following total-body irradiation

Animals were exposed to total body irradiation (TBI) from LINAC-derived photons at a dose rate of 0.80 Gy/min with administration of supportive care as defined in the material and Methods. Shown are the changes in the platelet count (PLT) × 10³ μL⁻¹ in the peripheral blood of rhesus macaques (n=8/radiation dose) as a function of time post TBI and dose (Gy). The respective dose of TBI and survivors/total NHPs are: 7.20Gy 5/8, 7.55Gy 4/8, 8.05Gy 3/8. TBI, of 6 MV LINAC-derived photons was administered at 0.80Gy min⁻¹. The radiation doses shown approximate the LD30, LD50, and LD70/60 estimated from the resultant data set.