Establishing a murine model of the hematopoietic syndrome of the acute radiation syndrome.

We have developed a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS) for efficacy testing of medical countermeasures (MCM) against radiation according to the FDA Animal Rule. Ten to 12 week old male and female C57BL/6 mice were exposed to the LD50/30-LD70/30 dose of total body irradiation (TBI, 137Cs, 0.62-0.67 Gy min-1) in the morning hours when mice were determined to be most radiosensitive, and assessed for 30 day survival and mean survival time (MST). Antibiotics were delivered in the drinking water on days 4-30 post-TBI at a concentration based on the amount of water that lethally-irradiated mice were found to consume. The fluoroquinolones, ciprofloxacin and levofloxacin, and the tetracycline doxycycline and aminoglycoside neomycin, all significantly increased MST of decedent mice, while ciprofloxacin (p=0.061) and doxycycline + neomycin (p=0.005) showed at least some efficacy to increase 30 day survival. Blood sampling (30uL/mouse every 5th day) was found to negatively impact 30 day survival. Histopathology of tissues harvested from non-moribund mice showed expected effects of lethal irradiation, while moribund mice were largely septicemic with a preponderance of enteric organisms. Kinetics of loss and recovery of peripheral blood cells in untreated mice and those treated with two MCM, granulocyte-colony stimulating factor and Amifostine, further characterized and validated our model for use in screening studies and pivotal efficacy studies of candidate MCM for licensure to treat irradiated individuals suffering from H-ARS.