What's New

Nuclear proliferation, terrorist activity, and the distribution of nuclear and radioactive materials through underground networks make incidents involving radiation injuries increasingly likely. As explained in a recent Report to Congress, Al-Qa'ida is known to have ambitious plans to acquire or develop nuclear weapons and is receptive to outside nuclear assistance.

That group has attempted to purchase enriched uranium. Nuclear fuel-cycle and weapons-related technologies have spread to the point that additional groups may be able to obtain or produce sufficient fissile material to build radiological weapons. In view of the increasing likelihood of radiation exposure and bioterrorism, the development of fieldable radiation countermeasures is a high priority for the Department of Defense and other government agencies.

Photo: D. Morse (AFRRI)

Dr. Whitnall processes blood samples to analyze changes in white blood cells caused by ionizing radiation and an anti-radiation drug. Radiation injures a body’s infection-fighting white blood cells.

Military personnel, first responders, and civilians risk having their immune systems damaged from exposure to radiation resulting from combat, terrorist attack, or nuclear accidents. Many wouldn't know their health had been compromised until screened with radiation detection devices—or until symptoms of radiation sickness surface.

"At low doses, exposure to ionizing radiation increases the risk of cancer. At higher doses, ionizing radiation injures bone marrow, causing decreases in numbers of blood cells and platelets," says Armed Forces Radiobiology Research Institute (AFRRI) scientist Mark Whitnall. The drop in white blood cells, he adds, means the immune system cannot fight off infections that normally would be harmless.

Efforts to develop pharmacological compounds that will bolster the body's immune system focus on providing a safe, cost-effective, easily stored means of ameliorating radiation injuries for large populations. Scientists are researching drugs and dietary supplements that could be given either before or after exposure.

As the leader of AFRRI's Radiation Casualty Management Team, Dr. Whitnall emphasizes there won't be a one-pill-to-cure-all solution for diverse tissue and systemic damage resulting from varying doses of radiation exposure. "A useful radiation countermeasure must be extremely safe to be used for large numbers of radiation victims or potential victims. Some of the drug candidates that have been proposed in the past have shown unacceptable toxicity."

Dr. Whitnall explains that the current treatment of choice, other than basic clinical support including antibiotics, is the off-label use of bone marrow growth factors.

"These factors have been approved by the FDA for use in chemotherapy patients to stimulate blood-forming tissue, but not yet for use as radiation countermeasures," he said. "They need to be administered under the supervision of a physician. One goal at AFRRI is to develop countermeasures that have a safety and ease-of-administration profile that would make them suitable for use without direct involvement of physicians."

Research collaboration
In pursuit of such goals, AFRRI in January launched a research collaboration with the F. Edward Hébert School of Medicine of the Uniformed Services University of the Health Sciences (USUHS), Bethesda, MD, and Humanetics Corporation of Minneapolis, MN. The collaboration aims to develop oral agents to support immune function while exploring the potential benefits for military personnel.

Photo: D. Morse (AFRRI)

Vilmar Villa, of AFRRI's Radiation Casualty Management Team, centrifuges blood samples in preparation for analysis on a flow cytometer, which identifies cell types using fluorescent labels on the cell surface.

In addition to serving as a radioprotectant, such oral agents may increase the readiness and performance of troops by improving their response to a variety of challenges to their immune system. They include exposure to novel microorganisms, stress from environmental and psychological factors, military training, rapid transit through many times zones, and combat.

"The collaboration with Humanetics will allow us to explore a number of new compounds with possible nonprescription and prescription applications," explains AFRRI’s director, U.S. Army Colonel David Jarrett, M.D. "This program will expand our evaluation and possible development of radiation countermeasure candidates suitable for use in large numbers of people, with an emphasis on safety."

Humanetics, a privately held corporation, currently has several oral agents that have shown beneficial effects on the immune system. In pre-clinical research, some have shown promise as ways to counter some of the debilitating effects of radiation exposure. "We entered into a Cooperative Research and Development Agreement with Humanetics to partner our expertise in radiobiology with their background in developing oral agents with rigorous scientific testing of efficacy and safety in humans," says Colonel Jarrett.

Because hundreds or thousands of civilians living in any of the nation's large metropolitan areas could become radiation victims from a single terrorist attack, countermeasures developed by the AFRRI-USUHS-Humanetics collaboration have potential application beyond military uses. Still, Dr. Whitnall advises caution regarding hopes for finding a single cure-all for the diverse effects of ionizing radiation.

"Other agents that may be used for radiation victims, like potassium iodide (KI), chelators like Prussian blue, calcium-diethylenetriaminepentaacetate (Ca-DTPA), and zinc DTPA, are very useful in certain situations. However, they address the ingestion of specific radioactive isotopes—not the general injury caused by external exposure to ionizing radiation. For example, KI is used to prevent thyroid cancers caused by internalization of radioactive iodine. There is a pressing need to develop countermeasures to ionizing radiation that will have a general beneficial effect on blood-forming tissues and immune competence."

Dr. Whitnall explains that, at this stage, AFRRI's most advanced radiation countermeasure candidate is 5-androstenediol (5-AED). It is being developed for FDA approval as a drug under a Cooperative Research and Development Agreement with Hollis-Eden Pharmaceuticals. Also known as HE-2100 or NEUMUNE™, 5-AED has all the characteristics of a desirable countermeasure: extremely low toxicity, enhancement of survival, and stimulation of resistance to infection. It has shown extremely promising results in pre-clinical investigations, and now has entered Phase I clinical trials. An application for Investigational New Drug (IND) status will be filed in the first half of 2005.

The safety and efficacy profile of 5-AED is such that it could be used as a single therapy in a mass casualty scenario without the need for physician or medical support. This is an important consideration, because in mass casualty scenarios medical resources would be overwhelmed, leaving most victims without access to physicians or hospitals.

The countermeasures in AFRRI's research program will be developed to work in conjunction with other measures, such as antibiotics, marrow growth factors, and KI and chelators where appropriate. A combination of dietary supplements and injectable or oral prescription drugs may be used, depending on the results of ongoing research and the nature of the disaster scenario. The time required for FDA approval of any specific countermeasure is unpredictable, Dr. Whitnall adds, because of the nature of research and the drug development process.