Radiological/Nuclear Preparedness
Written by TERRY C. PELLMAR, PH.D.
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WITH CURRENT COUNTERMEASURES LIMITED, A THOROUGH UNDERSTANDING AND PREPAREDNESS OF THE THREAT IS CRITICAL.
Recent terrorist activities and potential illegal trafficking of radioactive materials have raised alarms about the possibility of an attack with radiological or nuclear weapons. The prevailing view of the United States government is that it is a matter of when, not if, such an attack will take place. The nation needs to be prepared for this eventuality. Currently recommended countermeasures for radiation injury are based heavily on experiences with industrial radiation accidents, experiences that do not replicate exposure expected from terrorist events. Furthermore, few pharmaceuticals are FDA-approved to treat injuries expected from radiological or nuclear terrorist events, and they have limitations and logistical drawbacks for use with mass casualties.
THREAT SCENARIOS
Current strategic planning considers three scenarios: a) a radiation-dispersal device (RDD)—the so-called dirty bomb; b) radiation-emitting device (RED); or c) a 1-50 kiloton (KT) nuclear weapon. An RDD is considered to be the most likely exposure scenario because of the availability of explosives and radioactive materials from waste, hospital sources or test sources. One example of an RDD employs a radioactive material such as 137Cs combined with an explosive to disperse the isotope. Estimates of casualties from this kind of device range from a few to several hundred. Those injured are likely to receive burns and wounds from the explosion in addition to radiation exposure. Since a large variety of radioactive material could be used in such a weapon, the specifics of radiation exposure can vary. Given the simplicity of an RDD, it seems almost only a matter of time before it is used.
An RED placed in a heavily frequented area would be an effective way to expose the civilian population surreptitiously to radiation. Carefully disguised, an RED on a train or in a shopping mall could expose extremely large numbers of people to radiation before discovery.
Severe local injuries such as radiation burns may occur after exposure to an RED and, depending on the duration of exposure and the amount of radioactive material, doses could be high enough to cause lethality from acute radiation syndrome (ARS). Chechen rebels used this approach when they positioned a stolen radiation source under a Moscow park bench in 1995. Fortunately in this instance the source was found through an anonymous tip before any injuries occurred. Quick identification of an RED could be complicated by the fact that symptoms of exposure may not appear until well after leaving the site. Depending on the dose, nausea and vomiting might be delayed for minutes to hours, and skin lesions would require days or weeks. This is exemplified by the 1996 exposures on a Georgian military base that had been used as a Soviet radiological training camp. The Soviets left behind at least 10 radiation sources shallowly buried in the field. Within a few months, eleven soldiers developed symptoms of fevers and skin lesions. Radiation was not even suspected until more than a year later. Lethal consequences have resulted from misplaced and unrecognized industrial sources. For example, in Algeria a radiation source fell from a truck, was brought home by two children and placed on a kitchen shelf. It was a month before the source was identified and removed. By then, several family members had acute radiation syndrome and one subsequently died from the exposure.
While detonation of a nuclear weapon is considered less likely than use of an RDD or RED, it is the most devastating of the complex scenarios. A nuclear weapon in terrorist hands might range from a 1 kiloton (KT) device the size of a large backpack, readily carried by a suicide bomber, to a 10-20 KT device analogous in power to nuclear weapons used against Japan in World War II. Even though employing larger devices as terrorist weapons would be complex, we must assume that determined terrorists can obtain expertise to develop, place and detonate them. Blast, thermal and radiation injuries caused by these devices would be substantial (Table 1).
Detonation of a nuclear device would lead to prompt exposure to both gamma and neutron radiation. The ratio of neutrons to gamma photons would vary with weapon yield, distance from the blast and shielding. With a surface burst, soil and water would be vaporized by the heat of the explosion, activated by neutrons and dispersed as fallout. The distribution of the fallout would depend on the height of the burst and meteorological conditions. External radiation from fallout is predominantly gamma and beta. Doses from fallout would likely be at lower dose rates than the prompt dose and may be delayed because of the time required to reach downwind locations (Table 2). The expected casualties from the doses received in such a scenario are shown in Table 3. Hazards from internalization of radioactive material also exist. A nuclear device is likely to produce combined injuries, with about 40 percent of the injuries consisting of burns plus irradiation. Such combined injuries significantly increase mortality.
RADIATION INJURY
Acute radiation syndrome (ARS) occurs only when most of the body is exposed to radiation. Depending on total dose and dose rate, symptoms develop within few hours to days (prodromal phase). A transient recovery (latent phase) follows, but symptoms reappear after several days or weeks (manifest illness). ARS is a continuum of syndromes. At the lowest doses (less than 1 Gy) few symptoms are evident. Some people might have mild nausea within the first day and white cell counts may drop slightly, but survival is probable. Radiation doses over 1 Gy affect the bone marrow (hematopoietic syndrome) resulting in reduced neutrophil and platelet counts within a few weeks. Neutropenia increases susceptibility to infection, and loss of platelets leads to bleeding. Since the integrity of the gut wall is also impaired at these same doses, translocation of gut bacteria, which can lead to sepsis, becomes a concern as well. Hematopoietic and GI consequences are more severe with increasing doses. With partial body exposures, GI effects are evident because the sparing of bone marrow limits the hematopoietic symptoms. With whole body irradiation at doses greater than 8-12 Gy, GI consequences become the primary cause of death. Loss of intestinal crypts is severe and accompanied by extensive breakdown of the mucosal barrier. At doses greater than 10 Gy, death occurs relatively quickly from cardiovascular and nervous system effects.
Because radiation impairs the immune system’s response and compromises the body’s normal barriers to infection in the gut and the lung, an individual becomes more susceptible to infectious disease after radiation exposure. Animal studies have demonstrated that radiation in combination with exposure to pathogens causes significantly more morbidity and mortality than either the radiation or the pathogen alone. This is a serious concern since a nuclear event would adversely impact sewage disposal, availability of clean water and other factors that impact public health.
PREVENTION AND TREATMENT
The cytokine G-CSF (Neupogen) is the compound most likely to be recommended for hematopoietic reconstitution following radiation injury. Neupogen and the pegylated form of G-CSF (Neulasta) are currently FDA-approved for treatment of severe neutropenia that occurs with chemotherapy for cancer. Neupogen recently received investigational new drug (IND) status for treatment of radiation injury and can now be added to the strategic national stockpile (SNS) for use if an emergency waiver is authorized. Neupogen must be injected subcutaneously for several days (up to two weeks) starting as soon as possible after radiation exposure. The recommended dosage of Neulasta is a single subcutaneous injection. Both Neupogen and Neulasta can cause moderate bone pain.
Other drugs are in development. Neumune by Hollis-Eden is undergoing Phase I clinical trials under IND status. Several other agents are currently under investigation and, in preliminary and animal studies, show promise.
In the event of a radiological/nuclear terrorist attack, first responders, remediation workers and, given advanced warning, the resident population would benefit from a radioprotectant to mitigate radiation injury. For a radioprotectant to be safe and effective for large numbers of people, it would need to be long-lasting, be orally administered and have very low toxicity. Currently, nothing of the kind is available. Amifostine has been shown to be an effective radioprotectant in animals, and it is approved as a preventive measure for xerostomia with clinical radiation, but the side effects of hypotension and nausea and the requirement for an intravenous injection in a short time frame (30 minutes) prior to exposure limit its usefulness. Nutritional supplements such as vitamin E (alpha tocopherol) have been extensively tested because of their antioxidant properties and relative safety. Vitamin E has been shown to significantly reduce the lethality of radiation in mice. Other compounds such as the soy isoflavones also show some promise as safe and efficacious radioprotectants.
Because infections are a major cause of mortality, antibiotics will be a part of the therapeutic regimen for any radiation injury. Many antibiotics are readily available. In animal models, quinolones that preserve the anaerobic gut flora are an effective treatment for infection consequent to radiation. In contrast, however, use of an antibiotic strongly effective on both anaerobes and aerobes (e.g., metronidazole) can actually increase mortality in an irradiated animal.
RADIATION DOSE DETERMINATION
Medical management after a radiological or nuclear event would require biodosimetric assessment to triage those casualties who need immediate medical attention from those who do not. A dose estimate in addition would guide the therapeutic regimen for an individual. The best validated approach to biodosimetry is the measurement of chromosomal aberrations (specifically, dicentrics) in peripheral blood lymphocytes. This assay, however, is tedious and requires radiation cytogenetics expertise to manually score chromosome aberrations and three to five days to provide results. Furthermore, with higher doses of radiation, the number of cells that can be analyzed for chromosome aberrations is limited because of delays in mitosis and radiation-induced cell death. Efforts are underway to overcome these limitations. The rapid interphase chromosome aberration (RICA) assay provides one such approach, because it has an easily monitored fluorescent endpoint and works with non-dividing cells. Assays for biomarkers such as RNA expression and proteins that can be measured quickly by technicians without specialized training also are under development.
SUMMARY
Recent terrorist activities and potential illegal trafficking of radioactive materials have raised alarms about the possibility of an attack with radiological or nuclear weapons. Whole-body exposure to radiation elicits acute radiation syndrome (ARS). At approximately 3.5 Gy about half of a population will die without treatment. Countermeasures for ARS are currently limited but several are in the pipeline for development. ♦