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Mar 14, 2013 - Describe the 3 different subsyndromes of acute radiation syndrome. 4. Describe the indications for Prussian blue, potassium iodine, pentetate ...

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Nuclear and Radiological Terrorism : Continuing Education Article Peter D. Anderson and Gyula Bokor Journal of Pharmacy Practice published online 14 March 2013 DOI: 10.1177/0897190012474238 The online version of this article can be found at: http://jpp.sagepub.com/content/early/2013/03/12/0897190012474238

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New York State Council of Health-system Pharmacists

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Nuclear and Radiological Terrorism: Continuing Education Article

Journal of Pharmacy Practice 00(0) 1-12 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190012474238 http://jpp.sagepub.com

Peter D. Anderson, PharmD1 and Gyula Bokor, MD2 Abstract Terrorism involving radioactive materials includes improvised nuclear devices, radiation exposure devices, contamination of food sources, radiation dispersal devices, or an attack on a nuclear power plant or a facility/vehicle that houses radioactive materials. Ionizing radiation removes electrons from atoms and changes the valence of the electrons enabling chemical reactions with elements that normally do not occur. Ionizing radiation includes alpha rays, beta rays, gamma rays, and neutron radiation. The effects of radiation consist of stochastic and deterministic effects. Cancer is the typical example of a stochastic effect of radiation. Deterministic effects include acute radiation syndrome (ARS). The hallmarks of ARS are damage to the skin, gastrointestinal tract, hematopoietic tissue, and in severe cases the neurovascular structures. Radiation produces psychological effects in addition to physiological effects. Radioisotopes relevant to terrorism include titrium, americium 241, cesium 137, cobalt 60, iodine 131, plutonium 238, califormium 252, iridium 192, uranium 235, and strontium 90. Medications used for treating a radiation exposure include antiemetics, colony-stimulating factors, antibiotics, electrolytes, potassium iodine, and chelating agents. Keywords CBRNE, homeland security, radiation, emergency preparedness, toxicology Continuing Education Learning Objectives By the end of the article, the reader should be able to: 1. 2. 3. 4. 5.

Describe the 4 types of ionizing radiation. Distinguish between the stochastic and deterministic effects of ionizing radiation. Describe the 3 different subsyndromes of acute radiation syndrome. Describe the indications for Prussian blue, potassium iodine, pentetate calcium trisodium, and pentetate zinc trisodium. Name several radioactive isotopes that are concern to homeland security.

The United States has been on heightened alert for terrorism since the attacks on September 11, 2001. The anthrax letters that soon followed added to the concerns with terrorism. The Federal Bureau of Investigation defines terrorism as ‘‘the unlawful use of force and violence against persons or property to intimidate or coerce a government, the civilian population, or any segment thereof, in furtherance of political or social objectives.’’1 Amid these concerns are preparations by various government agencies and the private sector regarding potential attacks with chemical, biological, radiological, nuclear, and high-yield explosives (CBRNEs).2 Management of CBRNE events includes public safety, political, forensic, clinical, disaster response, and environmental issues to name a few. Chemical and biological weapons were discussed in previous issues of the Journal of Pharmacy Practice.3-5 This article discusses terrorism involving radioactivity or nuclear weapons.

The electrons are in orbits in the shells of the atom. The atomic number refers to the number of protons in an atom. The atomic number defines what element the substance is. For example hydrogen has 1 proton, helium has 2 protons, and lithium has 3 protons. The atomic weight refers to the total number of protons and neutrons. The chemical properties of an element are determined by the atomic number. The number of neutrons for a given element varies. An isotope contains the same number of protons but a different number of neutrons thus a different atomic weight. Regular hydrogen has 1 proton and no neutrons. Deuterium (hydrogen 2) is an isotope of hydrogen that contains 1 proton and 1 neutron. Tritium (hydrogen 3) is an isotope of hydrogen and has 1 proton and 2 neutrons. When an atom lacks

1 2

Review of Physics Atoms are primarily composed of protons, neutrons, and electrons. The protons and neutrons are in the nucleus of the atom.

Private Practice, Randolph, MA, USA Staff Psychiatrist Taunton State Hospital, Taunton, MA, USA

Corresponding Author: Peter D. Anderson, Private Practice, 5308 Avalon Drive, Randolph, MA 02368, USA Email: [email protected]

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Figure 1. A Geiger-Muller counter is device for detecting gamma and beta radiation.

the right balance of neutrons and protons it is radioactive. Nuclear fission occurs when the nucleus splits into smaller parts and releases particles and energy. Fission occurs artificially within a nuclear reactor or naturally from nuclear decay. A smaller nucleus is produced and the atom is converted to a new element. The new atoms produced by fission are called the daughters. Radiation is energy that travels from a source through material or space.6 Radiation can be described as ionizing and nonionizing radiation.7 Nonionizing radiation is radiation that possesses enough energy to cause the atoms to vibrate or move atoms within a molecule but not enough energy to remove electrons.7 Examples of nonionizing radiation are light, heat, ultraviolet, microwaves, and radio waves. Ionizing radiation removes electrons from atoms. This changes the valence of the electrons enabling chemical reactions with elements that normally do not occur. The 4 types of ionizing radiation are alpha radiation, beta radiation, gamma radiation, and neutron radiation. Alpha radiation consists of particles of 2 protons with 2 neutrons.8 This is equivalent to the nucleus of a helium atom. Alpha particles tend to be produced when the ratio of neutrons to protons in the nucleus is too low. Alpha radiation is not very penetrating and is stopped by a piece of paper or the skin. Exposure to external alpha radiation is only a low health risk. Alpha radiation is dangerous if alpha emitters are absorbed or inhaled by the body. Alpha emitters include americium 241, plutonium 236, uranium 238, thorium 232, radium 226, radon 222, and polonium 210. Beta radiation consists of electrons. Beta radiation has some penetration and can pass through the skin or thin clothing.9 Plastic typically stops beta radiation. Beta radiation is produced when the ratio of neutrons to protons is too high. One of the neutrons converts to a proton and electron. The electron is then

released from the nucleus as a beta particle.9 Higher doses of beta radiation cause damage to the basal layer of the skin. Examples of beta emitters include tritium, cobalt 60, strontium 90, technetium 99, iodine 129, iodine 131, and cesium 137. Gamma radiation is similar to x-rays.10 Gamma radiation is generated when the nucleus of the atom possesses too much energy. Gamma rays are released during nuclear fission. X-rays are produced by shifts in the electrons among their shells whereas gamma rays are produced from the nucleus. In the past, gamma rays and x-rays were distinguished by wavelength but an overlap exists within the range of x-rays and gamma rays. X-rays and gamma rays are now distinguished by their source in the atom. Gamma radiation is very penetrating and only dense material (eg, lead) stops gamma radiation. The release of a beta particle from the nucleus is often followed by a release of gamma rays. In other words, most but not all beta emitters are also gamma emitters. Examples of gamma emitters include cobalt 60, zinc 65, cesium 137, and radium 226. The Geiger Muller is used for detecting beta and gamma radiation (see Figure 1). Neutron radiation is also very penetrating and requires several feet of concrete to stop. Neutron radiation occurs mainly during nuclear fission and is rarely seen outside of the nuclear reactor. Nuclear radiation can be generated by bombarding beryllium with alpha particles. For example, mixing americium 241 with beryllium produces neutron radiation.11 Neutrons lack a charge and are not directly ionizing but still cause serious damage. As the neutrons move through material they collide with nuclei which possess a positive charge. The nuclei then move around and collide with molecules. The nuclei ionize the atoms of these molecules.12 Neutron radiation causes 2 to 20 times the tissue damage of gamma radiation. The physical half-life is the time interval for the radioactive material to decay to half its original value. The physical halflife is not to be confused with the pharmacokinetic or biological half-life. The effective half-life is the time interval required for the radioactivity of a certain amount of radioactive substance distributed in tissues and organs to decrease to half its original value due to radioactive decay and biological elimination. The determination of effective half-life considers both the physical half-life and the pharmacokinetic half-life of the material.

Units of Measurement for Radiation One Becquerel (Bq) is one disintegration per second. One curie is 3.7  1010 Bq. The radiation absorbed dose (RAD) is used to measure energy deposited in tissue by the radiation. The International System of Unit for absorbed dose is the gray (Gy). 1 Gy ¼ 100 rad; 10 milligray ðGYÞ ¼ 1 rad Different types of ionizing radiation may cause more tissue damage than others. This is adjusted for with a quality factor (QF). The QF converts RAD to roentgen equivalent man (rem). For example, alpha particles cause much more damage than beta particles. The QF for gamma and beta radiation is 1. The QF factor for alpha rays is 20. Neutron radiation QF factor ranges between 3 and 20 depending on the type of neutron

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radiation. For most practical applications the rad and rem are equivalent. The average natural radioactivity in the body is 40 millirems per year. The annual exposure to cosmic radiation if living at sea level is 24 millirems per year. A standard chest x-ray is 4 millirems.13 The exposure limits for the general public is 0.1 rem (100 millirems) per year.14 The occupational exposure limit is 5 rem per year.15 Emergency responders have a limit of 25 rem.16

Types of Threats Radiological related terrorism includes an attack on a nuclear power plant, a concealed radiation exposure device (RED), contamination of food sources, an attack on a facility or vehicle having radioisotopes, dispersal of radioisotopes in a concentrated population area, or the use of an improvised nuclear device. An improvised nuclear device would involve a nuclear reaction with a fission or fusion of atoms. A fission device is only practical for uranium 235, uranium 233, and plutonium 239.17 A fusion device utilizes deuterium and tritium to form heavier elements.17 Fortunately, numerous engineering hurdles need to be overcome to construct an improvised nuclear device. An improvised nuclear device creates thermal and blast injuries in addition to the radiation. The shock wave from a detonation can rupture of the eardrum or produce intrathoracic injuries. The blast winds result in flying debris physically striking individuals and causing a variety of trauma.17 A more likely scenario is the use of a radiological dispersal device (RDD).18 A common example of a RDD is a dirty bomb. A dirty bomb combines radionucleotides with conventional explosives. The idea behind a dirty bomb is creating an explosion that will spread the radioactive material.19 Many CBRNE experts consider a ‘‘dirty bomb’’ more of a ‘‘weapon of mass disruption’’ rather than a weapon of mass destruction.20 The damage from a dirty bomb will likely produce no more fatalities or injuries than a conventional bomb. The biggest danger is the fear created in the public. A radiation dispersal device is not limited to dirty bombs. A number of methods could be used to disperse radioisotopes such as a release from an airplane.20 A RDD is unlikely to cause massive fatalities. It would cause mass disruption (eg, environmental contamination, economic consequences, psychological reactions, etc) rather than mass destruction. Potential radioisotopes used in a RDD include americium 241, californium 252, cesium 137, cobalt 60, iridium 192, plutonium 238, polonium 210, radium 226, and strontium 90.19 A RED is a hidden sealed radiation source.21 The goal of a RED is to expose people to ionizing radiation without their knowledge.21 An example of a RED would be a brief case with radioactive material placed on a passenger train and left there. Another example is taping a radioactive source under a seat at a movie theater or a sports stadium.

Notable Radiological and Nuclear Incidents On August 6, 1945, the first atomic bomb, made from uranium 235, was dropped on Hiroshima, Japan.22 Approximately 90%

of the city was destroyed. An estimated 45 000 people died the first day out of a population of 250 000. Another 19 000 died over the following months.22 Three days later, a plutoniumbased bomb was dropped on Nagasaki.22 An estimated 22 000 people died out of a population of 174 000. In the next 4 months, another 17 000 people died. Most of the deaths resulted from the explosion rather than the radiation. A secondary source of radiation exposure may have been neutron bombardment reacting with iron producing radioactive iron.22 At least 400 people died from cancers over the next 30 years. Cesium 137 was found in the soil and farm products years after the attacks. The atomic bomb was a key factor leading to the end of World War II. On March 28, 1979, an accident happened at the Three Mile Island nuclear power plant.23 No injuries or deaths occurred, but is still the worst nuclear power accident in US history. The cooling system for the reactor malfunctioned resulting in the core overheating. Eventually the core of one of the reactors partially melted. Most of the radiation was contained but small amounts of radiation were released into the environment. An estimated 2 million people in the area were exposed to 1 millirem. 23 A typical chest x-ray delivers approximately 4 millirems of radiation. Several regulatory changes were made to the nuclear power industry as a result of the accident.23 In 1985, a private radiotherapy institute located in Goiania, Brazil moved to a new site. The organization left behind a cesium 137 teletherapy unit. The institute failed to notify the licensing authority as required by law. The building was partially demolished and left unsecured. Two individuals seeking valuable scrap metal removed the source assembly from the machine not knowing the material was radioactive.24 They took the device home and attempted to dismantle it and during the process the capsule containing the cesium 137 chloride was ruptured. The device and the cesium were sold to a junk dealer. The dealer noticed the material glowed in the dark and was fascinated. The dealer shared the cesium with family and friends and later the community. Over the next 5 days individuals started showing gastrointestinal (GI) symptoms from radiation exposure. One individual linked the symptoms to the material and alerted authorities. The material was identified as cesium 137. Several sites of significant contamination were identified and the residents evacuated. A stadium was set up as a triage area for identification of victims. Twenty victims required hospital treatment.24,25 Many of the patients were administered Prussian blue to enhance the excretion of the cesium 137.25 Colony-stimulating factors were used in some cases.25 Four individuals died within the first month. Autopsies revealed hemorrhagic and septic complications consistent with radiation exposure.25 Two of the fatalities were due to Klebsiella sepsis.25 The number of contaminated individuals was 249.24,25 However, 112 000 individuals eventually showed at the stadium for evaluation. In other words, over 111 000 people, who were not exposed, sought out an evaluation. Environmental contamination was a major issue and 85 homes were found to be contaminated with cesium 137. Over 700 workers participated in the response.24 The Goiania incident was the worst

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accident with radioactive material not involving a nuclear power plant or an atomic bomb. In 1986, an accident occurred at the Chernobyl nuclear power plant in the Ukraine.26,27 The root cause of the accident was a flawed design and inadequate training of workers. A power surge caused a steam explosion rupturing the reactor. Two workers died the night of the accident and another 28 people died within a few weeks from acute radiation syndrome (ARS). Another 134 people developed ARS but survived. The accident is the largest uncontrolled release of radiation by a civilian organization in the world. Large amounts of iodine 131, cesium 134, and cesium-137 were released from the plant. The radiological half-life of iodine 131 is 8 days, cesium 134 is 2 years, and cesium 137 is 30 years. Lighter radioactive material was carried by wind to Russia, Ukraine, and Belarus. Small amounts of radioactive material were found in Europe. Approximately 200 000 individuals were involved in the recovery and cleanup operations.27 In the years following the accident, approximately 220 000 people were resettled to less contaminated areas. The only documented long-term public health impact was an increase in the rates of thyroid cancer.26 However, an increase in cataracts may have occurred in individuals recovering from ARS.27 Alexander Litvinenko, a former KGB agent, was allegedly murdered with polonium 210 in 2006. 28,29 Polonium 210 is a rare earth metal and an alpha emitter.30 The most likely route of exposure for Litvinenko was oral administration.28 He first became ill on November 1, 2006 and was admitted to the hospital. Initial symptoms included nausea and vomiting. Thallium poisoning was suspected but later ruled out. He died on November 23, 2006 in the intensive care unit. The incident became a public health issue so the United Kingdom Health Protection Agency (HPA) became involved. Over 40 locations in London were considered potentially contaminated sites. Assessment reduced the sites to 11 locations which were evaluated by radiation specialists.29 Officials found detectable traces of polonium in the 2 hospitals were Litvinenko was treated, various business offices in London, nightclubs, coffee shops, a sports stadium, airplanes, cars, and 3 hotels. The number of individuals with exposure was 1029 in the United Kingdom.29 The HPA conducted biomonitoring by collecting urine samples on 787 individuals.29 The urine specimens identified 139 individuals with significant exposures. None of the individuals had ARS.29 A number of US citizens may have been exposed to polonium 210, so the Centers for Disease Control and Prevention (CDC) was involved.28 The CDC obtained urine specimens from 31 citizens.28 A number of Americans had testing through their private physicians rather than the CDC. A difficulty experienced by both CDC and HPA was the available laboratories that could rapidly use a validated method for analyzing clinical samples.28 The HPA had to establish a validated procedure for polonium as well as quality control procedures. A 9.0 magnitude earthquake struck Japan on March 11, 2011.31 The earthquake produced a tsunami which damaged 6 reactors at the Fukushima Diaichi nuclear power plant. The reactors were not directly damaged by the earthquake. The

cooling system was disabled by the flooding causing the reactors to overheat. Three of the reactors had a meltdown. The main radioactive isotope that was released was iodine 131. Cesium 134 and cesium 137 were also released.32 The population within the 20 km radius of the plant was evacuated. Evacuees under the age of 40 were advised to take stable iodine as a precaution against ingestion of radioactive iodine.32 No cases of ARS were reported.32

Biological Effects of Radiation Ionizing radiation causes atoms to lose electrons. These atoms then react with other atoms that would not normally occur. The ionized atoms react with sensitive areas of the cell such as the DNA. Ionizing radiation also acts indirectly by ionizing materials such as water. Free radicals are generated that interact with cell structures such as DNA.12 A mutation occurs in the DNA resulting in cell death or neoplasm.33 Cells that replicate most rapidly are the most sensitive to the effects of radiation.34 Sperm are the most sensitive cells to radiation and lymphocytes are second. Other cells that are affected by radiation, in descending order are erythroblasts, other hematopoietic cells, small intestine cells, epithelium, dermal cells, nerve cells, muscle, and then bone.34 The stochastic effects of radiation are the mutagenic and carcinogenic changes to individual cells.33 Stochastic effects are the long-term, low-level effects of radiation.35 Cancer is the typical example of disease resulting from stochastic effects.33 Radiation-induced teratogenic and genetic defects passed to offspring are also stochastic effects.35 Deterministic or nonstochastic effects are damage to cells resulting in cell death.33 With stochastic effects there is no clear cut threshold for effects. In contrast to deterministic effects, a specific threshold dose of radiation is generally required to produce toxicity.33 Deterministic effects are from high doses of radiation occurring acutely. This article focuses on the deterministic or nonstochastic effects. The radioactivity of an isotope does not affect its metabolism in the body. For example, the body processes cesium 137 in the same way it does for dietary nonradioactive cesium. The pharmacokinetics or toxicokinetics of a radioisotope does not differ from the nonradioactive isotope of the same element.

Exposure Versus Contamination Exposure results when the patient is exposed to a radiation source such as gamma rays. The person may or may not have tissue damage based on the dose. The patient does not become radioactive from the exposure. Health caregivers are not at risk of radiation exposure from treating the patient. Contamination means the person has radioactive isotopes on the skin or within the body. External contamination refers to the presence of radioisotopes on the skin, hair, or clothing. External contamination is treated by removal of clothing and washing the patient. Internal contamination involves the inhalation, absorption, or ingestion of radioisotopes. Internal

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contamination, depending on the element and the dose, may need to be treated with pharmaceuticals to increase the excretion of the material.

Acute Radiation Syndrome Pathophysiology The clinical presentation that appears after radiation exposure is termed ARS.34,36 This syndrome consists of hematopoietic, GI, and neurovascular subsyndromes. Each subsyndrome can be divided into 4 stages prodromal, latent, manifest illness, and recovery.34 ARS is most likely to be caused by gamma or neutron radiation.36 ARS will only be caused by beta particles or alpha particles if an emitter is absorbed or ingested by the body.34,36 A dose of 1 Gy of radiation in most individuals would produce ARS.36 A radiation dose of approximately 1 to 8 Gy of radiation would produce damage to the hematopoietic tissue in the bone barrow. The hematopoietic is seen within 2 weeks of significant exposure of 1.0 to 2.5 Gy. Prodromal symptoms include nausea, vomiting, anorexia, and diarrhea. The latent period lasted approximately 3 weeks where fatigue and weakness will be present. The manifest illness phase includes pancytopenia. Severe bleeding is a complication from platelet loss. Infections result from a loss in white blood cells. The lymphocytes are affected the earliest. The red blood cells are the last to be affected by radiation. Patients with coexisting burns or wounds have decreased wound healing and an increased chance of infection because of the myelosuppression.36 Patients receiving 2 to 6 Gy of radiation are the most responsive to treatment. The GI subsyndrome appears within a week or 2 after exposure to higher doses. The underlying pathology is the destruction of the crypt cells in the epithelial lining of the intestine.34 A radiation dose of 5 to 20 Gy would produce the GI subsyndrome in addition to the hematopoietic manifestations.36 The prodromal stage involves severe nausea, vomiting, watery diarrhea, and cramps occurring within hours after radiation exposure. A asymptomatic latent period of 5 to 7 days follows.34 Thereafter, the manifest illness begins with vomiting, severe diarrhea, and fever. Damage to the intestinal lining allows for entry of intestinal flora into the blood. Excessive fluid loss and imbalance of electrolytes follows. Complications from the GI subsyndrome include malnutrition, paralytic ileus, acute renal failure, cardiovascular collapse, sepsis, and anemia.34 Death often occurs from multiple organ failure.36 Higher doses of radiation are needed to produce the neurovascular subsyndrome, which consists of irreversible damage to the central nervous system (CNS).34 A radiation dose of 20 to 30 Gy produces the neurovascular subsyndrome. Cardiovascular shock occurs at such doses. The condition progresses to edema, increased intracranial pressure, and cerebral anoxia. A burning sensation appears almost immediately after exposure. The stages of the neurovascular subsyndrome are shorter than the other subsyndromes. Nausea and vomiting happen within an hour. The latent period lasts only a few hours. The manifest illness follows within 5 to 6 hours after exposure and

includes severe watery diarrhea, respiratory distress, and numerous CNS abnormalities. CNS signs include ataxia, confusion, and convulsions. Death can result within 2 days. The underlying pathology of the neurovascular subsyndrome is destruction of microcirculation. A massive release of histamine may also contribute to the pathology.34 Most individuals exposed to this degree of radiation from a nuclear blast would likely die from blast and thermal injuries.

Assessment and General Treatment Considerations Any life-threatening injuries are addressed first. The next consideration is whether the patient is contaminated or just exposed. A patient only exposed to radiation does not produce a risk to rescuers or clinicians. A patient contaminated with radionucleotides needs to be decontaminated after the necessary lifesaving procedures has been done. An ingestion or absorption of radionucleotides requires specific treatment to enhance the elimination of the radioisotope. The timing of the onset of nausea and vomiting needs to be considered because it is a rough estimate of the degree of radiation exposure. Nausea and vomiting within 1 to 2 hours after exposure indicates a massive radiation dose. A drop in lymphocyte count to one-half or one-third of baseline values within 24 hours indicates a life-threatening exposure. Ondansetron (Zofran1; GlaxoSmithKline, Research Triangle Park, North Carolina) and granisetron (Kytril1; Roche Pharmaceuticals, Nutley, New Jersey) are used to treat nausea and vomiting. Neutropenia occurs and an absolute neutrophil count below 100 is the greatest risk of infection. The current recommendations for neutropenic fever by the Infectious Disease Society of America should be followed. Colony-stimulating factors such as filgrastim (Neupogen1; Amgen, Thousand Oaks, California), a granulocyte colony-stimulating factor, and its longacting pegylated form can be used to aid in neutrophil recovery. Sargramostim (Leukine1; Genzyme, Cambridge, Massachusetts), a granulocyte-macrophage colony-stimulating factor can also be used to shorten the recovery time of neutropenia. Ideally, the start of colony-stimulating factors should be within 24 to 72 hours after exposure. Daily injections should be continued daily until the absolute neutrophil count is above 1000. Patients with ARS should be in isolation rooms. Avoid H2 blockers, antacids, and proton pump inhibitors to maintain gastric acidity. Sucralfate may be used. 36 Treatment includes administering platelets for bleeding complications. Fluid and electrolyte replacement is needed.36 Treatment of neurological complications is supportive (eg, anticonvulsants for seizures).

Internally Deposited Radioisotopes Internal contamination occurs when a radioisotope is swallowed, inhaled, or enters via a wound. Internal contamination could result from exposure to a radiation dispersal device or downwind from a nuclear power plant accident. Contamination of food or water sources can cause internal contamination. Treatment is aimed at reducing the absorption or enhancing the

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elimination of the radioisotope. Another technique is blocking uptake to the organ of interest. There are over 8000 radioactive isotopes. However, there are only about 13 important isotopes with regard to terrorism and industrial accidents including hydrogen 3 (tritium), phosphorous 32, carbon 14, cobalt 60, iodine 125, iodine 131, califormium 252, iridium 192, cesium 137, uranium 235, plutonium 239, strontium 90, and americium 241. Cobalt 60 and cesium 137 are considered the highest risk of terrorism.

Tritium Tritium was discovered in 1934.37 Tritium is a weak beta emitter.37 Tritium is produced naturally in the upper atmosphere when cosmic rays react with nitrogen. Tritium is also produced by nuclear weapons’ explosions. Tritium exists as a gas but readily reacts with oxygen to produce water. Water containing titrium is referred to as tritiated water. Thermonuclear weapons involving fusion use tritium. Tritium is also found in selfluminescent devices such as exit signs and some wristwatches. Human exposure occurs mainly with ingestion of tritiated water. Exposure may also occur by inhaling the gas. The titrium may replace regular hydrogen in water. The titrium also binds with organic molecules in the body. A single ingestion is unlikely to produce ill health effects. Treatment of a significant exposure includes increasing water intake but avoiding over hydration.38

Americium 241 Americium 241 is a man-made element produced from plutonium and not found in nature.39 Americium 241 is primarily an alpha emitter but also emits beta particles.39,40 The principal use of americium 241 is in residential and commercial smoke detectors. It is also used in medical diagnostic devices, thickness gauges, aircraft fuel gauges, and in research. Americium 241 is a potential agent that could be used in a radiation dispersal device. Amercium 241 is also a product from nuclear weapons detonation.39,40 It poses a significant health risk if swallowed or inhaled. The oral absorption is minimal but radiation can damage the GI tract. Americium 241 concentrates in the liver, bone, and muscle. The preferred treatment is chelation with diethylentriamine pentaacetate (DTPA) within 24 to 48 hours.40 An alternative treatment is with EDTA.40

Cesium 137 and Cesium 134 Cesium 137 is the most common radioactive isotope of cesium. Cesium 134 is another radioactive isotope of cesium.41,42 Cesium 137 is fission product of uranium and plutonium. It is a beta and gamma emitter.41,42 The radiological half-life is 30 years for cesium 137 and 2 years for cesium 134. Cesium 137 is used in medicine to treat cancer. A variety of industrial gauges employ cesium 137. Cesium is readily absorbed in the lungs and in the GI tract. Cesium 137 distributes throughout the

body. Metabolism of cesium is similar to potassium. Treatment is with Prussian blue.42

Cobalt 60 Cobalt is metal with a bluish tint.43 The most common radioactive isotope of cobalt is cobalt 60, a strong gamma emitter.43,44 Linear accelerations are used to manufacture cobalt 60 for commercial uses. Cobalt 60 is a source of radiotherapy in hospitals. Cobalt 60 is employed in the sterilization of food and some spices. Industrial uses include a variety of gauges and leveling devices and industrial radiography. Risks include inhalation of cobalt 60 in dust.44 It is also absorbed by ingesting contaminated food or water.43,44 Cobalt concentrates in the liver, kidneys, and bones.44 With oral exposure some cobalt is eliminated quickly in the feces. Absorbed cobalt is primarily renally eliminated. Cobalt, including nonradioactive cobalt, is a heavy metal poison.45,46 It produces multiple organ toxicity affecting the heart, lungs, endocrine, skin, and reproductive system.45,46 At the biochemical level, cobalt interferes with protein synthesis and the Krebs cycle.46 Treatment for exposures includes EDTA, succimer (Chemet1; Kremer Urban Pharmaceuticals, Seymour, Indiana), dimercaprol, and N-acetylcysteine.46

Radioactive Iodine Iodine is a nonmetallic solid substance. Radioactive versions of iodine include iodine 131, iodine 132, iodine 134, iodine 135, iodine 129, and iodine 124.47,48 Iodine 123, iodine 131, and iodine 124 are used in medical procedures. Iodine 131, iodine 132, iodine 134, and iodine 135 may be released into the environment in an accident or in an attack on a nuclear reactor. Radioactive iodine is primarily a beta emitter with some gamma radiation.47,48 Iodine 123 and iodine 124 are low risk in the environment because of their shot half-lives. The main risk of toxicity is damage to the thyroid gland. An elevated incidence of thyroid cancer was found after the Chernobyl accident. Iodine 129 and iodine 131 may also be released from the detonation of uranium- or plutonium-based nuclear weapons. If exposure is anticipated, oral administration of potassium iodine or sodium iodine will prevent uptake into the thyroid gland.47,48

Plutonium Plutonium 238 and plutonium 239 are fission products of uranium.49 Plutonium 239 is used in nuclear weapons. There are 13 other isotopes of plutonium.50 Plutonium is mainly an alpha emitter.49,50 Plutonium 238 is used as a heat source in satellites. External exposure to plutonium poses essentially no health risks. Plutonium is poorly absorbed in the GI tract but various salts of plutonium may be absorbed. Inhalation of plutonium is dangerous because of the alpha particles. After entering the lungs, plutonium travels through the blood stream to liver, bones, and spleen.50 Plutonium also produces heavy metal toxicity on the kidney. The treatment for exposures is DTPA.50

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Radium Radium is formed naturally in the environment by the decay of uranium and thorium. Purified radium and some radium compounds exhibit luminescence (ie, glows in the dark). Radium 226 is primarily an alpha emitter with some gamma radiation. Radium 228 is primarily a beta emitter.51 Radium 226 is not a federally regulated material.51 Radium decays to form radon gas. In the past, radium was used in a variety of dials and gauges because of the luminescence properties.51 Radium continued to be used in industrial radiography equipment. Combining radium 226 with beryllium produces neutron radiation. Treatment is with 200 mg to 1 g of calcium chloride 10% by slow intravenous (IV) push every 1 to 3 days. Treatment for oral exposure is aluminum hydroxide administered once followed by a regimen of calcium gluconate administered orally.52

Strontium 90 Strontium 90 is a direct fission product of uranium. Strontium 90 is a beta emitter and decays to yttrium 90.53 Strontium is a soft metal. Strontium is used as a radioactive tracer in medical and agricultural studies. Strontium 90 is used as a heat source for navigational beacons, weather stations, and space vehicles.53 Strontium acts chemically similar to calcium in the body. Therefore, strontium concentrates in the teeth and bones. Treatment is similar to radium.52

Uranium Isotopes The isotopes of uranium include uranium 238, uranium 235, and uranium 239.54,55 Uranium and its daughters are emitters of alpha, beta, and gamma radiations.54,55 Uranium is found naturally in low levels in soil and rocks. Refined uranium is a silvery white metal with low reactivity. The density of uranium is greater than lead.54 Uranium 235 is used for making nuclear weapons and used in nuclear power plants.17 Depleted uranium is almost pure uranium 238. Depleted uranium is not a radiological hazard. Depleted uranium is used in armor piercing munitions and armor for tanks. Very little of the uranium is absorbed orally because 99% is excreted in the feces.54,55 The majority of the absorbed dose is excreted by the kidneys. A small amount deposits in the bones where it can remain for years.54 Ingestion of uranium can lead to cancer of bone or liver.55 Uranium also damages the kidney chemically rather than radiologically.55 Internal ingestion is treated with sodium bicarbonate to alkalize the urine.52 Dialysis should also be considered.52

Iridium 192 Iridium is a silvery white matter. Iridium 192 is a beta and gamma emitter.56 Iridium 192 is used in industrial gauges to check welding seams. Iridium 192 is used in medicine to treat certain types of cancers. It is a silvery white metal.56 Another radioactive isotope is iridium 194 that releases more gamma

radiation.57 However, iridium 192 is less available thus considered a lower risk of terrorism than iridium 194.57 External exposure can produce ARS.56 Only 1% of iridium ingested orally is absorbed by the blood.57 The target organ for iridium is the liver.57 Treatment for exposure includes EDTA or DTPA.52

California 252 Californium is a man-made element not found in nature. It is silvery white or gray metal with a density greater than lead. Californium has 10 known isotopes and all are radioactive. Calfornium 252 is the only isotope with commercial applications.58 Californium 252 is an alpha emitter and a strong neutron emitter.58 It is used as a source of fission fragments for research. Another industrial use is to identify gold and silver ores. Californium 252 is employed in brachytherapy to treat cancer.59 Californium is poorly absorbed orally with an absorption rate of 0.05%.58 Inhalation of californium is also hazardous. Orally or inhaled californium travels through the blood. The main target organs are the bones (65%) and the liver (25%). Treatment is with DTPA.52

Radiopharmaceuticals A number of radioactive drugs (radiopharmaceuticals) are used in diagnostic imaging studies and less for the treatment of disease. Common radiopharmaceuticals are molybdenum 99, technetium 99, iodine 131, phosphorous 32, chromium 51, strontium 89, samarium 153, rhenium 186, and lutetium 172.60 Iodine 131 and phosphorous 32 are the only agents considered high on the risk of industrial accidents and terrorism. Most radiopharmaceuticals have relatively short physical half-lives and thus poor candidates for RDDs or REDs.

Other Clinical Aspects of Radiation Delayed and Chronic Effects of Radiation Radiation-induced leukemia has been reported for all types of leukemia except for chronic lymphocytic leukemia.61 Radiation is also known to cause cancer in the breast, thyroid, colon, 61 stomach, lung, and ovary. Cataracts are a well-documented complication of radiation exposure especially in the posterior pole of the lens.61 In utero exposure to radiation produces infant microcephaly, mental retardation, developmental delays, and impaired growth.61 Other noncancer delayed effects of radiation include hyperparathyroidism and a decrease in T-celland B-cell-mediated immunity.61 Exposure to at least 1 Gy per year for 3 years may produce chronic radiation syndrome.62 Clinical manifestations may include leucopenia, thrombocytopenia, and neuroregulatory disorders. More severe cases produce anemia, atrophy of the GI membranes, and encephalomyelitis.62

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Psychological Effects of Radiation Radiation produces a number of psychological effects that can persist decades after the index event.63 Any type of disaster produces psychological distress. Radiation is odorless and is invisible which contributes to the fear. The psychological effects impact victims, first responders, cleanup workers, and the general public.63 The psychological effects contribute to the worried well. Case in point, over 111 000 individuals who were not exposed to radiation sought out an evaluation during the Goiania incident.

Pharmacological Countermeasures Prussian Blue Prussian blue is also known as ferric hexacyanoferrate (II) and is commercially available as a pharmaceutical preparation, RadiogardaseTM (Heyltex Corporation, Katy, Texas) 0.5 g gelatin capsules. It has Food and Drug Administration (FDA) approval for treating radioactive cesium exposures. Radiogardase also has FDA approval for treating both radioactive thallium and nonradioactive thallium.64 Thallium is poisonous as a heavy metal.65,66 Nonradioactive cesium has minimal toxicity and rarely warrants treatment. Thallium 201 has a physical half-life of 3 days so it not considered a high-risk agent for terrorism. The oral absorption of Prussian blue is less than 1%. Prussian blue binds the cesium or the thallium in GI tract. Both thallium and cesium follow potassium in the body. Potassium is excreted in the intestine and reabsorbed into the blood. Potassium is then excreted in the bile and thus back into the gut. In other words, potassium undergoes enterohepatic circulation as does cesium and thallium. The Prussian blue binds the thallium and cesium after it is excreted into the gut.64,65 Prussian blue has been reported to reduce the effective halflife of cesium by 69% in adults, 46% in adolescents, and 43% in children. Ferric hexacyanoferrate reduces the biological half-life of thallium from 8 days to 3 days. The dose for adults is 3 g daily 3 times a day. The dose for children 2 to 12 years is 1 g orally 3 times a day. Administration with food is recommended to increase the release of bile and thus cesium and thallium. With cesium 137 exposure the Prussian blue should be continued for a minimum of 30 days.64,65 The patient should be reassessed for whole-body radioactivity. The duration of treatment for thallium is not well defined.65 Prussian blue is typically continued until the thallium concentrations fall below 0.5 mg/d.65 A common side effect of Prussian blue is constipation. Administration of laxatives such as fiber may be needed. Prussian blue binds with potassium so the hypokalemia may occur but is usually not clinically signficant.65 Monitoring the potassium levels is advised. Prussian blue contains iron so it binds with tetracycline reducing the absorption of tetracycline.65 The package insert for Prussian blue warns the coadministration with tetracycline but not ciprofloxacin.64 The binding of iron to ciprofloxacin is well documented.67 Prussian blue would also be expected to bind with ciprofloxacin and other

fluoroquinolones. The package insert for ciprofloxacin warns the coadministration of iron and ciprofloxacin.68 The manufacturer of ciprofloxacin recommends that oral ciprofloxacin be administered 2 hours before or 6 hours after iron products.68

Potassium Iodine Potassium iodine (KI) contains the nonradioactive isotope of iodine. The thyroid is the primary organ in the body that uses iodine. Radioactive iodine can damage the thyroid resulting in hypothyroidism or cancer. The uptake of iodine in the thyroid is a saturable process. The thyroid metabolizes radioactive and nonradioactive iodine similarly. Rapid administration of nonradioactive iodine saturates the thyroid so no radioactive iodine enters the thyroid.69 The protective effects of KI last 24 hours.70 The KI should be administered until the risk of inhaling or ingesting radioiodine no longer exists. Adults over 40 years of age do not need to take KI unless the expected dose is >500 mGy to the thyroid.70 Ideally the drug should be administered prior to or immediately after an exposure. However, benefits may still be seen from KI administration within 3 to 4 hours after exposure.70 The dose of KI for adults is 130 mg orally daily. Children between the ages of 3 and 18 take a dose of 65 mg. Children weighing 150 lbs or more should take the full adult dose. For infants between 1 and 3 years the dose is 32 mg. Newborns between 1 day and 1 month take a dose of 16 mg.70 Side effects include GI upset and rash. Hypothyroidism in infants can result from KI treatment so the thyroid function tests should be monitored. Allergic reactions also have been reported.70 A common misconception about KI is that it is a universal protector against radiation.71 When administered in a timely fashion it protects the thyroid from absorbing radioactive iodine. However, the radioactive iodine may still affect other parts of the body. Potassium iodine offers no protection against external radiation or other internal radioisotopes.

Ca-DTPA and Zn-DTPA In 2004, the FDA approved the chelating agents, pentetate calcium trisodium (Ca-DTPA) and penetetate zinc trisodium (ZnDTPA), for treating internal contamination of plutonium, americium, and curium.72 During the first 24 hours after exposure, Ca-DTPA is more effective than Zn-DTPA.73 After 24 hours postexposure, Ca-DTPA and Zn-DTPA are equally effective.73 On the first day of treatment, Ca-DTPA was administered. Zn-DTPA is administered for subsequent treatment. Ca-DTPA causes more depletion of essential nutrients including zinc, magnesium, and manganese than Zn-DTPA. CaDTPA produces more renal and hepatic vacuolization, higher mortality, and increased small bowel hemorrhagic lesions than Zn-DTPA. The drug can be administered either intravenously or using a nebulizer. With inhalation exposure the nebulizer treatment alone is effective. Ca-DTPA should be used cautiously in patients with hemochromatosis.73

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Table 1. Recommended Dosages for Cytokines.a Filgrastim (Neupogen): 2.5-5 mcg/kg per day or 100-200 mcg/m2 per day administered subcutaneously daily Sargramostim (Leukine): 5-10 mcg/kg per day or 200-400 mcg/m2 per day administered subcutaneously daily Pegfilgrastim (Neulasta): 6 mg once subcutaneously a

Source: Armed Forces Radiobiology Research Institute.36

The dose for Ca-DTPA is 1 g daily by IV push or infusion. If given by IV push, the drug is administered slowly over 3 to 4 minutes.74 An infusion may be given in 100 to 250 mL of normal saline or D5W. The dose for inhalation is 5 mL of the drug that is diluted 1:1 with either sterile water or normal saline. Monitoring includes complete blood count, blood urea nitrogen, creatinine, and radioactivity levels of the relevant isotope.74 The dose for Zn-DTPA is 1 g daily by IV push or infusion.75 If given by IV push the drug is administered slowly over 3 to 4 minutes. An infusion may be given in 100 to 250 mL of normal saline or D5W. The dose for inhalation is 5 mL of the drug that is diluted 1:1 with either sterile water or normal saline. Treatment may need to be continued for months to years especially if the radioisotope deposits in bones. Serum electrolytes and essential metals need to be monitored with Zn-DTPA.75 If Zn-DTPA is not available but Ca-DTPA is available then CaDTPA can be administered for ongoing therapy. Patients with asthma should be monitored for a precipitation of an asthma attack when either drug is administered by nebulizer.

radioprotectant for patients undergoing radiation treatment for cancer. Amifostine needs to be given intravenously. Numerous side effects of amifostine include hypotension, nausea, and vomiting. Amifostine is therefore not practical for pretreatment of emergency responders to a radiological incident. A potential agent for radiation protection is tempol which is an antioxidant that targets the mitochondria.79 Flexseed is a dietary supplement with antioxidative and anti-inflammatory properties. Flexseed improved survival in mice exposed to thoracic radiation.80 Alpha-tocopherol is also being explored as an antioxidant protector for radiation exposures.81,82 An oral version of DTPA is being developed. Oral medications are much easier to use when dealing with a mass casualty situation.

Role of the Pharmacists Pharmacists have important roles in responding to a CBRNE event, major accident, or natural disaster. Hospitals pharmacists can work with their Pharmacy and Therapeutics Committees to developing plans and stocking medications for a radiological emergency. Clinical pharmacists can assist physicians in treating patients with radiation exposure or contamination. Nuclear pharmacists can conduct radioactivity screenings in the event of a mass casualty. Infectious disease pharmacists would help in recommending and evaluating antibiotic for infections resulting from ARS. Community pharmacists can educate patients regarding the misconceptions of KI. Psychiatric pharmacists are needed to deal with the psychological consequences of the disaster.

Other Chelating Agents

Conclusions

Deferoxamine, dimercaprol, edentate calcium disodium, penicillamine, and succimer are chelating agents used for other radioactive heavy metal exposures.52

Radiological and nuclear terrorism is a real possibility. ARS affects the immune system, nervous system, GI system, and the skin. Numerous radioactive isotopes present an exposure and contamination risk. Certain radioisotopes such as cobalt 60 possess a radiological and chemical toxicity risk. Medications used to treat radiation casualties include colony-stimulating factors, antibiotics, chelating agents, and KI. In addition to the physical effects, radiation has psychological effects. Pharmacists serve in a variety of potential roles during a radiological or nuclear emergency.

Cytokines Filgrastim, sargramostim, and pegfilgrastim do not have FDA approval for treating ARS.76-78 Colony stimulating factors are recommended by the Armed Forces Radiobiology Research Institute and the CDC. See Table 1 for the recommended doses for cytokines.

Declaration of Conflicting Interests

Other Drugs Nausea and vomiting are treated with 5-HT3 antagonists such as ondansetron or granisetron. Fluids and electrolytes are needed in the GI subsyndrome. Antibiotics are required for secondary infections.

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Potential Future Therapies A number of agents are being explored to mitigate the radiation effects at the subcellular level. Many of these agents are antioxidants. Amifostine (Ethyol1; MedImmune, Bedford Laboratories, Bedford, Ohio) is FDA approved as a

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Continuing Education Credit The New York State Council of Health-system Pharmacists (NYSCHP) is pleased to provide you with the opportunity to obtain continuing education credit for this article online at HealthSystemCE.org (http://www.healthsystemce.org); login using your email address and HSCE password; then click the ‘‘Journal CE’’ tab. There is no charge to NYSCHP members. If you are not a member of NYSCHP, call 1-518-456-8819 to pay the $15 fee to access the quiz and obtain the password necessary to access the Journal’s CE article. In lieu of this fee, a completed membership application with your dues may be submitted. A grade of 70% or above is required to earn the CE credit. Repeat examinations will be permitted once for a grade below 70%. The NYSCHP is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This activity provides 1.3 contact hours (0.13 CEUs) of continuing education. The Universal Activity Number is 0134-0000-13001-H01-P. Submission of exam for CE credit expires February 28, 2016.

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