4
Depleted Uranium

Uranium is a naturally occurring element that is present in soil (with an average concentration of 3 parts per million), rocks, surface and underground water, air, plants, and animals (ATSDR, 1999b). As a result, it occurs in trace amounts in many foods and in drinking water. An individual’s daily intake of uranium is estimated to be 1–2 micrograms (μg) in food and 1.5 μg in each liter of water consumed (ATSDR, 1999b). The International Commission on Radiological Protection (ICRP) has reported that the average uranium content of the human body is 90 μg, with 69 μg in the skeleton and 7 μg in the kidneys (ICRP, 1975). A range in total body content of uranium of 2–62 μg has been noted in human postmortem studies (NRC, 1988). The primary civilian use of uranium is as fuel for nuclear power plants. Additionally, minute amounts are used in the production of ceramic glazes, light bulbs, and photographic chemicals (ATSDR, 1999b).

Natural uranium is a radioactive element with three principal isotopes: 234U, 235U, and 238U. These isotopes are alpha particle emitters. Alpha particles are positively charged ions composed of two protons and two neutrons. Due to their size and charge, alpha particles lose their kinetic energy quickly and have little penetrating power. The range of an alpha particle is approximately 4 cm in air and considerably less (25–80 μm) in tissue (ATSDR, 1999a). As a result, pure uranium is principally an internal radiation hazard. Uranium isotopes decay to other radioactive elements that eventually decay to stable isotopes of lead (ATSDR, 1999b). In the decay process, beta and gamma radiation1 are emitted.

1  

Beta particles are high-energy electrons; the path length of a beta particle averages 0–15 m in air and 0–1 cm in solids. Gamma radiation is an external radiation hazard be-



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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines 4 Depleted Uranium Uranium is a naturally occurring element that is present in soil (with an average concentration of 3 parts per million), rocks, surface and underground water, air, plants, and animals (ATSDR, 1999b). As a result, it occurs in trace amounts in many foods and in drinking water. An individual’s daily intake of uranium is estimated to be 1–2 micrograms (μg) in food and 1.5 μg in each liter of water consumed (ATSDR, 1999b). The International Commission on Radiological Protection (ICRP) has reported that the average uranium content of the human body is 90 μg, with 69 μg in the skeleton and 7 μg in the kidneys (ICRP, 1975). A range in total body content of uranium of 2–62 μg has been noted in human postmortem studies (NRC, 1988). The primary civilian use of uranium is as fuel for nuclear power plants. Additionally, minute amounts are used in the production of ceramic glazes, light bulbs, and photographic chemicals (ATSDR, 1999b). Natural uranium is a radioactive element with three principal isotopes: 234U, 235U, and 238U. These isotopes are alpha particle emitters. Alpha particles are positively charged ions composed of two protons and two neutrons. Due to their size and charge, alpha particles lose their kinetic energy quickly and have little penetrating power. The range of an alpha particle is approximately 4 cm in air and considerably less (25–80 μm) in tissue (ATSDR, 1999a). As a result, pure uranium is principally an internal radiation hazard. Uranium isotopes decay to other radioactive elements that eventually decay to stable isotopes of lead (ATSDR, 1999b). In the decay process, beta and gamma radiation1 are emitted. 1   Beta particles are high-energy electrons; the path length of a beta particle averages 0–15 m in air and 0–1 cm in solids. Gamma radiation is an external radiation hazard be-

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines The isotopes of uranium have the same chemical properties because they all have the same number of protons, 92. However, variation in the number of neutrons gives the isotopes different radiological properties. The radioactivity of isotopes can be compared using specific activity, a measurement of the number of nuclear transformations (disintegrations) per second per unit mass (Box 4.1). The most abundant naturally occurring uranium isotope, 238U, has the lowest specific activity (0.33 microcuries per gram [μCi/g]) (U.S. AEPI, 1995). The high specific activity of 234U (6,200 μCi/g) contributes to more than half of the radioactivity of natural uranium even though by weight its percentage is extremely small (Table 4.1). Enriched uranium is quantified by its percentage of 235U (specific activity 2.2 μCi/g) which can range from 2 percent to more than 90 percent (U.S. AEPI, 1995). Because of the high percentage of 238U in natural uranium (Table 4.1) and that isotope’s low specific activity, natural uranium is considered a low-level radioactive element. Uranium is also categorized as a heavy metal (i.e., any metal with a specific gravity of 5.0 or greater). The chemical toxicity of a uranium compound varies depending on the nature of the compound, its solubility, and its route of exposure. There are a number of radiological protection regulations and guidelines. The U.S. Nuclear Regulatory Commission’s (U.S. NRC’s) regulations for occupational dose to individual adults state an annual limit of the total effective dose equivalent of 5 rem per year (50 millisieverts [mSv] per year) (10 CFR 20). For members of the general public, the U.S. NRC’s regulations require that the total effective dose equivalent to individual members of the general public not exceed 0.1 rem in a year (1 mSv), exclusive of the dose contributions of background radiation (10 CFR 20). Depleted uranium (DU) is a by-product of the enrichment process used to make reactor-grade uranium. Because of the different percentages of uranium isotopes in depleted uranium (Table 4.1), its specific activity (14.8 mBq/μg) is TABLE 4.1 Percentage of Uranium Isotopes by Weight Isotope Natural Uranium Depleted Uraniuma 238U 99.2745 99.745 235U 0.7200 0.250 234U 0.0055 0.005 aDepleted uranium may have trace amounts of 236U (U.S. AEPI, 1995). SOURCES: Durakovic, 1999; Lide, 1999.     cause it is highly penetrating. Gamma radiation (high-energy photons) is the energy released due to the change in the energy state of the nucleus.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines BOX 4.1 Units of Measurement Specific Activity The curie (Ci) is the traditional unit of measure of nuclear transformations (disintegrations) per second of unit mass. It is a concentration defined as the ratio of the amount of radioactivity divided by the mass or volume of radioactive substance. The International System unit for specific activity is the becquerel (Bq). Absorbed Dose The gray (Gy), formerly the rad, is the unit that describes the magnitude of absorbed radiation in terms of energy deposited on a tissue. However, the amount of energy deposited in tissue does not account for differences in the biological effects of different radiation types. Dose Equivalent The rem (Roentgen-equivalent-man) is the traditional unit of measure that incorporates the relative biological damage caused by different radiation types and deposition mechanisms. The International System unit for the biologically effective dose, dose equivalent, is the sievert, (Sv).   Specific Activity Absorbed Dose Biologically Effective Dose Units curie (Ci) becquerel (Bq) gray (Gy) rad (old standard unit) rem sievert (Sv) Conversion 1 Bq = 1 transformation or disintegration per second = 2.7 × 10−11 Ci 1 Gy = 100 rad 1 mSv = 0.001 Sv 1 Sv = 100 rem   SOURCE: ATSDR, 1999a,b. approximately 40 percent lower than that of naturally occurring uranium (25.4 mBq/μg) and considerably lower than that of enriched uranium (approximately 1,750 mBq/μg) (Harley et al., 1999). However as discussed above, the chemical properties of depleted uranium are the same as those of the enriched and natural forms. The chemical and physical properties of depleted uranium are ideal for many military and commercial uses. It is 65 percent more dense than lead (with a density of 18.9 g/cm3), has a high melting point (2070°F, 1132°C), is highly pyrophoric (it ignites when it fragments), has a tensile strength comparable to most steels, and is chemically highly reactive (Kirk, 1981). The density of DU and its ability to self-sharpen are properties that attracted the attention of the Department of Defense (DoD) beginning in the late 1950s, as the military

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines sought to increase the armor penetration of munitions (OSAGWI, 1998). In addition, depleted uranium is useful as a ballast or counterweight in aircraft and gyroscopes because it lends itself to casting into small but dense weights. Additional uses of depleted uranium include as radiation shielding and as a chemical catalyst (it is a strong reducing agent) (Kirk, 1981; Lide, 1999). The process of converting uranium ore into enriched uranium, with depleted uranium as a by-product, begins with the mining of uranium-containing ore (work previously conducted in deep underground mines but now mostly in surface mines). Sites of significant uranium deposits include the western United States, Canada, southern Africa, and Australia. The milling process crushes the ore and then leaches uranium from the ore with sulfuric acid or alkaline carbonates (du Preez, 1989). The dissolved uranium precipitates as triuranium octaoxide, U3O8 (termed “yellowcake”); this process does not alter the ratio of radioisotopes of uranium (U.S. AEPI, 1995). The enrichment process converts uranium to its hexafluoride (UF6) form, which is a gas, and separates the various isotopes using gaseous diffusion or centrifuge technology, thereby increasing the percentage of 235U in UF6. The remainder of the UF6 (depleted UF6) has a smaller proportion of both 235U and 234U relative to the enriched UF6. The final steps of the milling process are the reduction of depleted UF6 to uranium tetrafluoride (“green salt”) which is further reduced to depleted uranium metal. The Nuclear Regulatory Commission defines depleted uranium as uranium with less than 0.711 percent 235U by weight (10 CFR 40.4). Department of Defense specifications state that depleted uranium used by DoD must have a 235U concentration of less than 0.3 percent (U.S. AEPI, 1995). In the Gulf War, weapons systems utilized depleted uranium (frequently alloyed three-fourths of 1 percent with titanium by weight to reduce oxidation) for offensive and defensive purposes (Parkhurst et al., 1995; OSAGWI, 1998). Heavy armor tanks had a layer of DU armor to increase protection. Offensively, depleted uranium increases the penetration effectiveness of the kinetic energy cartridges and ammunition rounds used by the Army (105- and 120-mm tank ammunition), Air Force (armor piercing munitions for the Gatling gun mounted on the A-10 aircraft), Marine Corps (Harrier aircraft and tank munitions), and Navy (rounds for the Phalanx Close-in Weapon System)2 (OSAGWI, 1998). The Army used an estimated 9,500 depleted uranium tank rounds during the Gulf War, many as training and practice rounds (OSAGWI, 1998). Known exposure of U.S. personnel to depleted uranium during the Gulf War occurred as the result of friendly fire incidents, cleanup operations, and accidents (including fires). DU-containing projectiles struck 21 Army combat vehicles (15 Bradley Fighting Vehicles and 6 Abrams tanks) (U.S. AEPI, 1995). Additionally, U.S. forces used DU rounds to destroy three unoccupied Abrams tanks in order to prevent them from being captured by the enemy, and five 2   The only firings reported during the Gulf War of this weapon system were test firings and an accidental discharge. The Navy is transitioning to tungsten rounds (OSAGWI, 1998).

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Abrams tanks became contaminated when DU rounds were involved in onboard fires (U.S. AEPI, 1995). After the war, assessment teams and cleanup and recovery personnel (including Explosive Ordnance Disposal, Battle Damage Assessment, and Radiation Control teams and salvage personnel) may have had contact with DU-contaminated vehicles or depleted uranium munitions. In July 1991, a large fire occurred in Camp Doha near Kuwait City. This site housed a number of combat-ready vehicles, and the series of blasts and fires damaged or destroyed vehicles and munitions including M1A1 tanks and depleted uranium munitions. Troops at the scene and those involved in cleanup efforts may have been exposed to DU residue. Other troops may have been exposed through contact with vehicles or inhalation of DU-containing dust (Fahey, 2000). In estimating the number of U.S. personnel exposed to depleted uranium and the extent of this exposure, the DoD Office of the Special Assistant for Gulf War Illnesses (OSAGWI) categorized potential DU exposure scenarios into three levels (OSAGWI, 1998). Level I exposure, the highest level, occurred in or near combat vehicles when they were struck by DU rounds or when soldiers entered vehicles soon after the impact. An estimated 143–173 people may have experienced Level I exposure through wounds caused by DU fragments, inhalation of airborne DU particles, ingestion of DU residues, or wound contamination by DU residues. Some Gulf War veterans, including those with internal DU fragments, are participating in the Depleted Uranium Follow-up Program, a medical surveillance follow-up study, at the Baltimore VA Medical Center (McDiarmid et al., 2000). There are ongoing efforts to expand this program to include additional veterans. Level II, the intermediate exposure level, occurred when soldiers and civilian employees worked on DU-contaminated vehicles or were involved in cleanup efforts from the Camp Doha fire. More than 700 individuals may have had Level II exposure through inhalation of dust containing DU particles and residue, or ingestion from hand-to-mouth contact or contamination of clothing. Level III, the lowest level of exposure, occurred when troops were downwind from burning DU ammunition, DU-contaminated vehicles, or the Camp Doha fire or when personnel entered DU-contaminated Iraqi tanks. These Level III exposures could have occurred though inhalation or ingestion. Hundreds of people are thought to have experienced potential Level III exposure, but there is little to substantiate these estimates (OSAGWI, 1998). Since the Gulf War, there has been extensive modeling and testing of potential depleted uranium exposure, including evaluation of radiological and chemical hazards and characterization of DU aerosols (Parkhurst et al., 1991, 1995; Parkhurst and Scherpelz, 1994; GAO, 2000). It has been estimated that the exposure (Level I) of individuals (excluding those with embedded DU fragments), who were inside an Abrams M1A1 tank when a single DU penetrator entered the crew compartment, would be approximately 0.48 rem for a 15-minute exposure (OSAGWI, 1998). The U.S. Army Center for Health Promotion and Preventive Medicine (CHPPM) is in the process of completing a com-

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines prehensive exposure assessment that includes quantitative risk assessments for selected health end points. This chapter examines the published scientific literature on potential health effects of uranium and depleted uranium. The chapter begins with an overview of the toxicology and animal studies and then examines the scientific literature on human health effects, most of which comes from epidemiologic studies of workers exposed to uranium and from human case reports. In summarizing the scientific research on the toxicology of uranium, the committee frequently references the Agency for Toxic Substances and Disease Registry’s (ATSDR’s) Toxicological Profile for Uranium (ATSDR, 1999b). ATSDR’s extensive report is a review and assessment of the peer-reviewed literature on the toxicological end points. The ATSDR report was reviewed by a nongovernmental panel and by scientists from federal agencies. TOXICOLOGY As discussed above, uranium is both a heavy metal and a low-specific-activity radioactive element. Studies on the toxicity of uranium have examined both its chemical and its radiological effects. The primary routes of exposure to uranium for humans are through ingestion or inhalation; the effects of dermal exposure and embedded fragments have also been studied. The amount of uranium that the body absorbs depends largely on the route of exposure and the solubility of the uranium compounds to which the individual is exposed. Insoluble uranium compounds may remain within the pulmonary tissues, especially the pulmonary lymph nodes, for a long time and thus constitute a localized radiological hazard. As a general rule, uranium is less readily absorbed from the intestinal tract than from the respiratory tract, resulting in lower doses per unit intake. Chemical toxicity, characterized predominantly by renal dysfunction as a consequence of exposure to soluble uranium, and lung injury potentially caused by the ionizing radiation from uranium decay isotopes are the best-characterized consequences of exposure to uranium compounds. However, the chemical and radiological properties of uranium could act cooperatively to cause tissue damage, and therefore, it cannot be assumed that excess cancers would be due solely to the radiological effects of uranium or that organ damage is exclusively due to its heavy-metal properties. Pharmacokinetics and Toxicokinetics Absorption Inhalation exposure. The site of deposition of uranium particles in the respiratory tract is the result of a combination of physical forces that govern particle behavior in an air stream, as well as the anatomy of the respiratory tract (Gordon and Amdur, 1991). The site of deposition affects the degree of ura-

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines TABLE 4.2 Dissolution Types of Uranium Compounds Type F (fast) Type M (medium) Type S (slow) Uranium hexafluoride (UF6) Uranium tetrafluoride (UF4) Uranium dioxide (UO2) Uranium tetrachloride (UCl4) Uranium trioxide (UO3) Triuranium octaoxide (U3O8) Uranyl fluoride (UO2F2)     Uranyl nitrate hexahydrate [UO2(NO3)2·6H20]     nium absorption, the clearance mechanisms that are available to remove uranium particles, and the severity of the consequences of tissue damage to the respiratory system. Inhaled uranium dust particle deposition in the various regions of the respiratory tract and lung (extrathoracic, tracheobronchial, and deep pulmonary or alveolar) depends on the particle’s aerodynamic diameter. An aerodynamic diameter is typically assigned to particles that are nonspherical in shape and incorporates both the density and the diameter of the particle, as well as its aerodynamic drag. It represents the particle as the diameter of a unit-density sphere having the same terminal velocity as the particle, whatever its size, shape, or density (Gordon and Amdur, 1991). Larger particles are deposited in the tracheobronchial region; mucociliary action then transports the particles to the pharynx where they are swallowed. Smaller particles reach the terminal bronchioles and the alveoli. The ICRP has developed extensive models of the dosimetry of inhaled radioactive materials (ICRP, 1994). At the alveolar level, the more soluble uranium compounds (categorized as Type F for fast dissolution [e.g., UF6 and uranyl nitrate hexahydrate]) are taken up within days by the systemic circulation (Table 4.2). The less soluble uranium compounds (Type M for medium dissolution [e.g., uranium tetrafluoride, UF4, and uranium trioxide, UO3]) are more likely to remain for weeks in the pulmonary tissue and associated lymph nodes. The relatively insoluble compounds (categorized as Type S for slow dissolution [e.g., uranium dioxide, UO2, and triuranium octaoxide U3O8]) are least likely to enter the systemic circulation and may remain for up to several years within the lung and tracheobronchial lymph nodes (ATSDR, 1999b). The lungs and the tracheobronchial lymph nodes are the two major sites of accumulation for Type S uranium compounds (administered as UO2) in dogs, monkeys, and rats, accounting for greater than 90 percent of the total body burden of uranium after inhalation of those compounds (Leach et al., 1970). Given their high density, most occupationally inhaled uranium particle-containing dusts have an aerodynamic diameter that does not permit them to be carried to the peripheral part of the lung (Berlin and Rudell, 1986; Morris et al., 1992). Estimates based on measurements in uranium processing plants (Davies, 1961), suggest that only between 1 and 5 percent of uranium particle-containing

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines dusts will penetrate the lungs. The rest will deposit in the upper respiratory tract and eventually will be swallowed and go through the gastrointestinal tract. Oral exposure. The absorption of uranium across the gastrointestinal tract generally increases with increasing solubility of the compound. Absorption is greatest for the relatively soluble uranium compounds. Notably, even with the soluble compounds, only a small fraction of uranium is absorbed across the gastrointestinal epithelium. Humans ingesting uranyl nitrate hexahydrate or uranyl nitrate absorb only 0.5–5 percent of the ingested dose (Hursh et al., 1969; Karpas et al., 1998). Adult hamsters that received actinide preparations of uranyl nitrate and uranium dioxide through an intragastric tube absorbed 0.77 and 0.11 percent of the total doses, respectively (Harrison and Stather, 1981). After administering UO2 to rats by the same route, other investigators could not detect any uranium in liver, kidney, muscle, bone, brain, blood, and urine (Lang and Raunemaa, 1991). Dermal absorption. Dermal absorption of uranium compounds in humans has not been characterized (ATSDR, 1999b). In animals, the soluble uranium compounds uranyl nitrate hexahydrate (0.5–7 g/kg body weight) and ammonium uranyl tricarbonate (7 g/kg body weight) penetrated the skin of experimental rats within 15 minutes of application (de Rey et al., 1983). Forty-eight hours after exposure, uranium was no longer present on the skin, and the rats had experienced severe toxic signs ranging from weight loss to death, indicating absorption of uranium into the systemic circulation. No penetration of uranium through the skin occurred after applying the more insoluble compound uranium dioxide (de Rey et al., 1983). Other uranium compounds, such as uranium tetrafluoride, uranium tetrachloride, and uranium trioxide, are absorbed through the skin of mice, rats, and guinea pigs (Orcutt, 1949). Although the absorption rate was relatively low (0.1 percent of uranium applied to the skin), the amount of absorbed uranium was sufficiently high to cause toxicity (Orcutt, 1949). These animal studies show that percutaneous absorption is an effective route for soluble uranium compounds to enter the systemic circulation. However, the application of these findings to human dermal exposure is unclear because the concentrations of uranium that were applied to the skin were extremely high. Transport and Biotransformation Once absorbed, uranium forms soluble complexes with bicarbonate, citrate, or proteins in the plasma (Dounce and Flagg, 1949; Stevens et al., 1980; Cooper et al., 1982). Approximately 47 percent of blood uranium forms a complex with bicarbonate in plasma, 32 percent of uranium binds to plasma proteins, and 20 percent binds to erythrocytes (Chevari and Likhner, 1968).

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Distribution Inhalation of less soluble uranium compounds (Type M and Type S) is associated with retention of uranium in bronchial lymph nodes as well as lung tissue itself (Leach et al., 1970), from which it passes slowly into the systemic circulation. Of the total uranium absorbed into the circulation, 85 percent deposits in the bone (Donoghue et al., 1972). Of the remaining uranium (15 percent), greater than 90 percent is distributed to the kidneys; detectable amounts are also present in the liver. In bone, uranium replaces calcium in the hydroxyapatite complex. The half-life of uranium in bone is approximately 300 days (Harley et al., 1999). In the kidney, uranium accumulates primarily in the proximal tubule. Excretion and Retention Systemic clearance. The stability of the bicarbonate complex of uranium depends on the pH of the solution and differs in various bodily compartments (Berlin and Rudell, 1986). The low-molecular-weight bicarbonate complex passes through the renal glomerulus and is excreted in the urine at a rate that depends on urinary pH. At high pH, small amounts of uranium are retained within the walls of the tubular lumen of the kidney. At low pH, bicarbonate– uranyl (and citrate–uranyl) complexes dissociate (Bassett et al., 1948). The uranyl ion forms complexes with proteins on the surface of cells lining the tubule, a process that may account for uranium-induced tubular dysfunction (see below). In contrast to the low-molecular-weight uranyl–bicarbonate complex, uranium that is protein bound is more likely to remain in blood since little protein passes through the glomerulus. In humans, approximately two-thirds of an intravenous injection of uranium is eliminated from the plasma within 6 minutes, and 99 percent of the uranium is eliminated from the plasma 20 hours after injection (Struxness et al., 1956; Luessenhop et al., 1958). The kidneys excrete more than 90 percent of hexavalent soluble uranium salt injected intravenously, and less than 1 percent is excreted in the feces. Approximately 70 percent of the dose is excreted within the first 24 hours, followed by a slower phase with a half-time exceeding several months (Bassett et al., 1948). Inhalation exposure. The rate of deposition and clearance of uranium-containing particles from the lung depends on their chemical form and particle size. As discussed above, mucociliary action transports most of the larger particles from the respiratory system to the pharynx, where they are swallowed and then eliminated in the feces. The clearance of the smaller particles that are deposited in the lungs depends on the solubility of the compounds. Particles that contain the more soluble forms of uranium are more rapidly absorbed into the bloodstream and excreted in urine. For example, in studies of rat lung retention of uranium administered as an aerosol powder (commercial yellowcake) with median aerosol concentrations from 0.04 to 0.34 μg U/L (micrograms of ura-

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines nium per liter) (Damon et al., 1984), the half-time for Type F uranium compounds was between 1 and 5 days. The body retains Type S compounds for much longer. The half-time of uranium deposited in the lungs of dogs, rats, and monkeys exposed up to 5 years to uranium dioxide dust (5.1 mg U/m3) was approximately 15 months (Leach et al., 1973). Reports from human subjects occupationally exposed to insoluble uranium compounds suggest a two-phase clearance process, consisting of a short phase with a biological half-time between 11 and 100 days and a slow phase of clearance with a biological half-time between 120 and 1,500 days (Hursh and Spoor, 1973). The biological half-time of uranium dioxide in the lungs of occupationally exposed workers was estimated to be 109 days in one study (Schieferdecker et al., 1985). The aerosol by-products of exploded DU munitions are primarily the uranium oxides—uranium trioxide, triuranium octaoxide, and uranium dioxide (OSAGWI, 1998). Uranium trioxide behaves more like a soluble uranyl salt than the insoluble oxides (U3O8 and UO2) and is rapidly removed from the lung (half-time, 4.7 days). More than 20 percent of the exposure burden of UO3 passes into the systemic circulation, and approximately 20 percent of the excreted uranium appears in the urine (Morrow et al., 1972). Conversion of UO3 to uranyl hydroxide hydrate followed by cation exchange with structural hydroxyl groups is a possible mechanism for the high solubility of UO3 in biological fluids (Stuart et al., 1979). Uranium dioxide and triuranium octaoxide have slow dissolution rates (Type S dissolution), and the mechanical processes (mucociliary transport) and particle size determine their pulmonary clearance rates. Oral exposure. The low rate of gastrointestinal absorption of uranium in humans results in approximately 95 percent of ingested uranium being eliminated in feces without being absorbed; the remainder is excreted in urine (Wrenn et al., 1985; Spencer et al., 1990). The average gastrointestinal uptake of uranium in adult humans is estimated at 1.0–1.5 percent (Leggett and Harrison, 1995). Although differences in uranium uptake with age have not been reported, more definitive information is needed for children (Leggett and Harrison, 1995). Animal studies indicate that uranium absorption through the gastrointestinal tract depends strongly on its chemical form when ingested and the length of time between the last meal and the ingestion of uranium. Both rats and rabbits absorb about 0.06 percent of ingested uranium in the gastrointestinal tract (Tracy et al., 1992). The distribution and retention of uranium in the skeleton and kidneys of rats are comparable to parameters reported for humans. Studies with rats indicate that the majority of ingested uranium (99 percent) is eliminated in the feces without being cycled through the bile. Most of the uranium absorbed through the gastrointestinal tract is excreted within a few days in urine, with a half-time of 2–6 days (Durbin and Wrenn, 1975). Depleted uranium fragments. Pellmar and colleagues (1999a) studied the organ distribution of uranium dissolved from DU fragments. The study examined rats that had DU and/or tantalum pellets surgically implanted within the gastrocnemius muscle. Tantalum, an inert metal that is widely used in prosthetic devices,

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines was used as a control. Tissue samples were collected at day 1, and at 6, 12, and 18 months after implantation. Bone and kidney were the primary reservoir for the uranium that had dissolved from embedded DU fragments. Dissolved uranium also localized within the central nervous system (CNS), lymph nodes, testes, and spleen (Pellmar et al., 1999a). Low levels of uranium were noted in the serum at all time points. The size of the pellets diminished with time. Animal and In Vitro Studies The following section summarizes and highlights a number of key animal and in vitro studies of the toxic effects of uranium. Researchers have examined the health effects of exposure to uranium via the inhalation, oral, and dermal routes; there are also studies on the effects of injected uranium and embedded DU fragments. A more thorough description of these studies and others can be found in the recent ATSDR (1999b) review. Nonmalignant Respiratory Effects Acute exposure to uranium (UF6; 10-minute exposure at 637 mg U/m3) resulted in gasping and severe irritation of the nasal passages in rats and mice (Spiegl, 1949); nasal hemorrhage occurred in rats after 5-minute exposure to 54,503 mg/m3 (Leach et al., 1984). These effects were most likely due to the hydrolysis of UF6 to hydrofluoric acid, a potent toxicant to respiratory tract epithelium (Spiegl, 1949; Leach et al., 1984). Rats, mice, and guinea pigs exposed to uranium hexafluoride for an intermediate duration (6 hours a day for 30 days at 13 mg U/m3) showed pulmonary edema, hemorrhage, emphysema, and inflammation of the bronchi and alveoli (Spiegl, 1949). Cats and dogs exposed for 30 days to 18 mg U/m3 as uranium tetrafluoride or 5 weeks exposure to 9.2 mg U/m3 as uranyl fluoride exhibited rhinitis (Dygert et al., 1949). Notably, uranium dioxide and triuranium octaoxide, insoluble uranium compounds, did not lead to pulmonary toxicity. Hemorrhagic lungs were noted in dogs exposed to carnotite uranium ore, likely reflecting deeper penetration of this material into the dogs’ respiratory tract compared to guinea pigs and mice, which remained asymptomatic in similar exposure studies. Rats, rabbits, guinea pigs, and dogs exposed to aerosols containing 0.05–10 mg U/m3 of various uranium compounds for 7–13 months did not suffer uranium-related histological damage to the lungs (Cross et al., 1981a,b). In a comprehensive study by Leach and colleagues (1970), lung damage did not occur in rats and dogs exposed to 5 mg U/m3 as uranium dioxide dust for 1–5 years (5.4 hours a day, 5 days a week). Occasional patchy hyaline fibrosis was evident in the tracheobronchial lymph nodes of dogs and monkeys exposed for a minimum of 3 years to the same concentrations of uranium (Leach et al., 1970).

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines uranium excretion did not affect hematocrit, hemoglobin, or the number of platelets, lymphocytes, neutrophils, basophils, eosinophils, and monocytes. Genotoxicity Background frequencies of chromosomal aberrations and sister chromatid exchanges in peripheral blood lymphocytes collected and cultured from DU-exposed veterans were identical to those of nonexposed Gulf War veterans and similar to those noted in other control populations (McDiarmid et al., 2000). Cardiovascular Effects SMRs for cardiovascular disease in uranium workers have been consistently less than 100, implying no important effect of uranium on cardiovascular disease. The lower than expected mortality rates are probably due to the healthy-worker effect. In addition, no cardiovascular effects occurred after one intense accidental inhalational exposure in which neither blood pressure nor pulse rate increased in a man exposed to powdered uranium tetrafluoride for 5 minutes (Lu and Zhao, 1990). Although the authors did not measure the concentration and mean particle size of the inhaled aerosol, electrocardiograms and chest x-rays were normal shortly after the accident and over a 7.5-year follow-up period. Hepatotoxicity In a 3-year follow-up of an individual accidentally exposed to uranium tetrafluoride, serum hepatic enzyme levels and liver function tests were within normal limits (Lu and Zhao, 1990). Dermal, Ocular, and Musculoskeletal Effects Dermal, ocular, and musculoskeletal effects of uranium have not been reported in the literature. Conclusion on Other Health Outcomes The committee concludes that there is inadequate/insufficient evidence to determine whether an association does or does not exist between exposure to uranium and gastrointestinal disease, immune-mediated disease, effects on hematological parameters, reproductive or developmental dysfunction, genotoxic effects, cardiovascular effects, hepatic disease, dermal effects, ocular effects, or musculoskeletal effects.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines CONCLUSIONS In general, animal studies have provided invaluable information on the pharmacokinetics of uranium, as well as qualitative insight into the toxicology of uranium. As discussed in this chapter, the majority of the evidence on the human health effects of exposure to uranium is from studies of workers in uranium processing mills and other facilities. Few studies of Gulf War veterans have specifically focused on the effects of uranium. Additionally, the literature on uranium miners is largely not relevant to the study of uranium per se because the primary exposure of this population was to radon progeny, which are known lung carcinogens. Although the studies of uranium processing workers are useful for drawing conclusions, the study settings have inherent weaknesses. First, even studies that involved tens of thousands of workers are not large enough to identify small increases in the relative risk of uncommon cancers. Second, few studies had accurate information about individual exposure levels. Some authors estimated the cumulative dose by following an employee’s path through various jobs whose average radiation exposure was known. Third, in these industrial settings, the populations could have been exposed to other radioisotopes (e.g., radium ore, thorium) and to a number of industrial chemicals that may confound health outcomes. Finally, no studies had reliable information about cigarette smoking, which may also confound outcomes of lung cancer. However, these cohorts of uranium processing workers are an important resource, and the committee encourages further studies that will provide progressively longer follow-up, improvements in exposure estimation, and more sophisticated statistical analyses. The committee makes recommendations in Chapter 8 related to research on depleted uranium. The following is a summary of the chapter’s conclusions: The committee concludes that there is limited/suggestive evidence of no association between exposure to uranium and the following health outcomes: lung cancer at cumulative internal dose levels lower than 200 mSv or 25 cGy, or clinically significant renal dysfunction. The committee concludes that there is inadequate/insufficient evidence to determine whether an association does or does not exist between exposure to uranium and the following health outcomes: lung cancer at higher levels of cumulative exposure (> 200 mSv or 25 cGy), lymphatic cancer, bone cancer,

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Dupree EA, Cragle DL, McLain RW, Crawford-Brown DJ, Teta MJ. 1987. Mortality among workers at a uranium processing facility, the Linde Air Products Company Ceramics Plant, 1943–1949. Scand J Work Environ Health 13(2):100–107. Dupree EA, Watkins JP, Ingle JN, Wallace PW, West CM, Tankersley WG. 1995. Uranium dust exposure and lung cancer risk in four uranium processing operations. Epidemiology 6(4):370–375. du Preez JGH. 1989. A review of the industrial processes involving uranium: From the ore to the reactor. Radiat Protection Dosimetry 26:7–13. Durakovic A. 1999. Medical effects of internal contamination with uranium. Croat Med J 40(1):49–66. Durbin PW, Wrenn ME. 1975. Metabolism and effect of uranium in animals. In: Wrenn ME, ed. Conference on Occupational Health Experience with Uranium. Washington, DC: U.S. Energy Research and Development Administration. ERDA-93. Pp. 67–129. Dygert HP, LaBelle CW, Laskin S, Pozzani UC, Roberts E, Rothermel JJ, Rothstein A, Spiegl CJ, Sprague GF Jr, Stokinger HE. 1949. Toxicity following inhalation. In: Voegtlin C, Hodge HC, eds. Pharmacology and Toxicology of Uranium Compounds. New York: McGraw-Hill. Pp. 423–700. Eisenbud M, Quigley JA. 1956. Industrial hygiene of uranium processing. AMA Archives of Industrial Health 14:12–22. Fahey D. 2000. Don’t Look, Don’t Find: Gulf War Veterans, the U.S. Government and Depleted Uranium. Lewiston, ME: Military Toxics Project. Filippova LG, Nifatov AP, Liubchanskii ER. 1978. [Some of the long-term sequelae of giving rats enriched uranium]. Radiobiologiia 18(3):400–405. Frome EL, Cragle DL, McLain RW. 1990. Poisson regression analysis of the mortality among a cohort of World War II nuclear industry workers. Radiat Res 123(2):138–152. GAO (General Accounting Office). 2000. Gulf War Illnesses: Understanding of Health Effects from Depleted Uranium Evolving but Safety Training Needed. Washington, DC: GAO. GAO/NSIAD-00-70. Gilbert ES, Cragle DL, Wiggs LD. 1993. Updated analyses of combined mortality data for workers at the Hanford site, Oak Ridge National Laboratory, and Rocky Flats Weapons Plant. Radiat Res 136:408–421. Gilman AP, Villeneuve DC, Secours VE, Yagminas AP, Tracy BL, Quinn JM, Valli VE, Willes RJ, Moss MA. 1998a. Uranyl nitrate: 28-day and 91-day toxicity studies in the Sprague-Dawley rat. Toxicol Sci 41:117–128. Gilman AP, Moss MA, Villeneuve DC, Secours VE, Yagminas AP, Tracy BL, Quinn JM, Long G, Valli VE. 1998b. Uranyl nitrate: 91-day exposure and recovery studies in the male New Zealand white rabbit. Toxicol Sci 41(1):138–151. Gilman AP, Villeneuve DC, Secours VE, Yagminas AP, Tracy BL, Quinn JM, Valli VE, Moss MA. 1998c. Uranyl nitrate: 91-day toxicity studies in the New Zealand white rabbits. Toxicol Sci 41:129–137. Goasguen J, Lapresle J, Ribot C, Rocquet G. 1982. [Chronic neurological syndrome resulting from intoxication with metallic uranium]. Nouv Presse Med 11:119–121. Gordon T, Amdur MO. 1991. Responses of the respiratory system to toxic agents. In: Amdur MO, Doull J, Klaassen CD, eds. Toxicology: The Basic Sciences of Poisons. New York: Pergamon Press. Pp. 383–406. Gottlieb LS, Husen LA. 1982. Lung cancer among Navajo uranium miners. Chest 81(4): 449–452.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines CONTENTS      ACUTE CHOLINERGIC SYNDROME   170      POSSIBLE U.S. TROOP EXPOSURE   172      SARIN TOXICOLOGY   174      Mechanisms of Acute Toxicity,   174      Inhibition of Acetylcholinesterase,   174      Noncholinergic Mechanisms,   175      Toxicokinetics,   176      Absorption and Metabolism,   176      Distribution and Elimination,   177      Biomarkers of Exposure,   178      Animal Studies,   178      Acute Toxicity,   179      Neurotoxicity,   180      Genotoxicity,   183      Sub-Chronic Toxicity,   183      Reproductive or Developmental Toxicity,   186      CYCLOSARIN TOXICOLOGY   186      SUMMARY OF TOXICOLOGY   187      HUMAN STUDIES   187      Studies of Military Volunteers,   189      U.S. Military Studies,   189      U.K. Military Study,   190      Accidental Exposure of Industrial Workers,   191      Matsumoto, Japan, Terrorist Attack,   191      Tokyo, Japan, Terrorist Attack,   193      Gulf War Veterans,   196      Genetic Susceptibility to Sarin Toxicity,   197      CONCLUSIONS   198      REFERENCES   199