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Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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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-

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

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.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

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

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

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).

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

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-

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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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-

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

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

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

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).

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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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-

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

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,

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

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).

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×
Carcinogenic and Genotoxic Effects

Filippova and colleagues (1978) studied the carcinogenic effects of intratracheal injection with 90 percent enriched 235U as tetravalent uranium (0.57–18.7 mg U/kg body weight) or hexavalent uranium (0.55–5.32 mg U/kg body weight) in the rat. A variety of cancers developed in both groups of uranium-injected rats (osteosarcoma, carcinoma of the lungs and kidneys, reticulolymphosarcoma of the lung, and leukemia) at a rate that was statistically significantly different from controls (24 percent with tetravalent uranium, 24 percent with pentavalent uranium, and 12 percent in controls). Cross and colleagues (1981a) measured the effects of inhalation exposure on tumor development in golden Syrian hamsters. Animals inhaled uranium ore dust at a concentration of 19 mg U/m3 for 16 months. The authors reported no apparent increase in the number of tumors in several tissues (liver, kidney, spleen, trachea, lungs, and heart) compared to unexposed animals.

In a chronic inhalation study, Leach and colleagues (1973) reported that uranium dioxide exposure (5 mg U/m3) led to pulmonary lymphatic neoplasm development and atypical epithelial proliferation in 30–46 percent of exposed beagle dogs. Although the rate of tumor development was 50–100 times higher than the expected spontaneous incidence in this species, the authors cautioned against extrapolating these findings to humans, given the infrequent occurrence of these types of lymphatic neoplasms in humans. Long-term feeding studies found no evidence of cancer in several animal species that were exposed to high levels of uranium (Maynard and Hodge, 1949; ATSDR, 1999b). The committee did not locate studies on the tumorigenic effects of uranium following dermal exposure.

A recent report is the first to suggest that, at least in vitro, DU can cause human cell transformation to a neoplastic phenotype, an effect that is comparable to other biologically reactive and carcinogenic heavy-metal compounds, such as nickel (Miller et al., 1998a). DU uranyl chloride-transformed cells displayed anchorage-independent growth, tumor formation in nude mice, expression of high levels of the k-ras oncogene, reduced production of the Rb tumor-suppressor protein, and elevated levels of sister chromatid exchanges per cell; all are associated with carcinogenic processes.

To assess the potential mutagenic effects of long-term exposure to internalized depleted uranium, Sprague-Dawley rats received 20 pellets of either tantalum or DU in various combinations (low DU: 4 DU and 16 tantalum pellets; medium DU: 10 DU and 10 tantalum pellets; high DU: 16 DU and 4 tantalum pellets) (Miller et al., 1998b). The rats excreted significant concentrations of uranium in urine throughout the 18 months of the study (224 ± 32 μg U/L urine in the low-dose rats and 1010 ± 87 μg U/L urine in the high-dose rats at 12 months). Investigators assessed the mutagenic potential of uranium at 0 days, 6 months, 12 months, and 18 months after implantation. Urine from animals implanted with DU pellets at each of the assessed time points enhanced mutagenic activity in Salmonella typhimurium strain TA98 and the Ames II mixed strains (TA7001–7006). Urine samples from animals implanted with tantalum alone

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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(and in the absence of detectable uranium levels in the urine) did not enhance mutagenic activity in these strains. In DU-implanted animals, urine mutagenicity increased in a dose- and time-dependent manner, demonstrating a strong positive correlation with urine uranium levels. In contrast to urine samples, the sera of animals implanted with either DU or tantalum pellets did not enhance mutagenicity in any bacterial strain. This study indicates that the mutagenic potential of uranium increases as its urinary concentration increases. Given that serum samples did not contain increased levels of uranium or show mutagenic activity in the same tests, it is possible that the strong positive relationship between urinary uranium and mutagenicity is causally related to the presence of uranium in the urine. The authors have speculated that uranium, possibly complexed with various ligands found in urine (carbonates, proteins, minerals, phospholipids), caused the increased mutagenic potential (Miller et al., 1998b).

Nonmalignant Renal Effects

In animal studies, uranium has been shown to have low-level metallotoxic effects on the renal system (reviewed in Stopps and Todd, 1982; Gilman et al., 1998a,b,c; ATSDR, 1999b). Other heavy metals (e.g., lead, arsenic, mercury) are much more toxic at the same dose level (ATSDR, 1999b). In general, renal injury occurs within days of exposure and manifests itself as a change in the proximal convoluted tubules, resulting in increased urinary enzyme excretion (alkaline phosphatase, lactate dehydrogenase, and leucine aminopeptidase). Hyaline casts, or casts containing necrotic cells shed from the tubular epithelium, are present at all levels of the tubular system (Berlin and Rudell, 1986). Parallel with tubular damage, glomerular changes also occur, principally in the basement membranes of glomerular capillaries. The corresponding functional changes in the kidney are proteinuria, impaired p-aminohippurate (PAH) clearance, increased clearance of amino acids and glucose, and decreased sodium reabsorption. After severe damage, renal inulin and creatinine clearance decreases (Stopps and Todd, 1982). Generally, if the uranium dose is sublethal, regeneration of the damaged epithelium commences within 2–3 days or when exposure ceases (Stopps and Todd, 1982; Berlin and Rudell, 1986; Gilman et al., 1998b; ATSDR, 1999b). Tolerance to uranium has also been observed after exposure to sublethal doses. In a 5-year study in dogs and monkeys of inhaled dust containing insoluble uranium dioxide, kidney injury did not occur at exposure levels of 5 mg U/m3 (Leach et al., 1970). Following a 91-day exposure to uranyl nitrate hexahydrate in drinking water (0.96, 4.8, 24, 120, or 600 mg/L), histopathological lesions were observed in the kidneys of male and female New Zealand white rabbits in all groups including the lowest-exposure groups (Gilman et al., 1998c). Pathological changes included lesions of tubular epithelial cells (apical nuclear displacement and vesiculation, cytoplasmic vacuolation, and dilation), glomeruli (capsular sclerosis), and renal interstitium (reticulin sclerosis and lymphoid cuffing). Studies of dermal and ocular absorption of UO3

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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in rabbits indicate that uranium was sufficiently well absorbed to cause kidney damage and even death from renal failure (Voegtlin and Hodge, 1949).

Several mechanisms may account for uranium-induced kidney damage. A mechanism involving bicarbonate activity in the kidney has been postulated. Uranium combines with bicarbonate, citrate, or plasma proteins in blood. At low pH, the bicarbonate–uranyl, and citrate–uranyl, complexes split (Bassett et al., 1948), and the resulting uranyl ion may combine with proteins on the tubular wall to cause renal damage. A second possible mechanism suggests that uranium compounds inhibit both sodium-dependent and sodium-independent adenosine triphosphate (ATP) utilization and mitochondrial oxidative phosphorylation in renal tubules (Brady et al., 1989).

Nonmalignant Neurological Effects

Neurological effects following inhalation of uranium occur in cats and dogs. In a 30-day inhalation study, dogs exposed to 0.5–18 mg U/m3 (as UF6 gas) exhibited muscular weakness and instability of gait on day 13 at the highest concentration tested (Dygert et al., 1949). Cats exposed by inhalation to 18 mg U/m3 (as UF6 gas) had similar symptoms, beginning on day 7 (Dygert et al., 1949). Exposure to high concentrations of uranium (9.5 mg U/m3 as uranyl nitrate hexahydrate for 30 days) has been associated with anorexia in dogs (Roberts, 1949). A similar effect was noted at the highest concentration tested in both dogs and cats exposed to uranyl fluoride (0.15–9.2 mg U/m3; 5 weeks) (Dygert et al., 1949). Acute cholinergic toxicity of uranium in rats occurred after a single oral dose of uranyl acetate dihydrate (11–717 mg U/kg) (Domingo et al., 1987). Exposure-related signs of neurotoxicity were not apparent in rats exposed to uranyl nitrate hexahydrate for 91 days at levels up to 600 mg/L drinking water, which is equivalent to a time-weighted average equivalent dose of 37 and 54 mg U/kg body weight per day for male and female rats, respectively (Gilman et al., 1998a).

There is limited evidence that large doses of uranium can cause changes in the central nervous system of animals. Purjesz and colleagues (1930) and Verne (1931) detailed epithelial degeneration of the choroid plexi in the CNS of dogs and rabbits exposed to toxic doses of soluble uranium salts. Verne (1931) described CNS changes that appeared relatively late (just prior to death) after very large injections of uranium. CNS changes were noted primarily in the cerebral and cerebellar cortices, and in the latter they were confined to pyramidal and Purkinje cells. Purjesz and colleagues (1930) studied the effects of uranium nitrate in dogs. After repeated delivery of the compound (1–4 g), the animals generally lived for only a few days. In each case, morphological changes were apparent in the choroid plexus. As the doses in these studies are orders of magnitude greater than human exposure to uranium, it is difficult to determine the relevance of these findings to humans.

The chronic long-term health consequences of exposure to DU fragments have been addressed by Pellmar and colleagues (1999a). As described earlier,

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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rats were surgically implanted with sterilized DU and/or tantalum pellets within the gastrocnemius muscle (low dose DU: 4 DU and 16 tantalum pellets; medium dose: 10 DU and 10 tantalum pellets; high dose: 16 DU and 4 tantalum pellets). The purpose of these experiments was to establish an animal model that would provide insight into the injuries sustained by Gulf War veterans from embedded DU fragments and would make it possible to evaluate the biological effects of intramuscularly embedded DU fragments. Many of these DU fragments were not removed from the veterans because the surgical procedure would have produced extensive tissue damage.

As early as 1 month after pellet implantation and at subsequent sample times (6 months), brain concentrations of uranium were statistically elevated in DU-implanted rats compared to controls implanted with tantalum (the high-dose group received 20 DU pellets). At 18 months, several brain areas were independently assessed. Uranium levels increased in a dose-dependent manner with the number of DU pellets implanted. The levels of uranium were not uniform throughout the brain; uranium levels in the motor cortex, frontal cortex, mid-brain, and vermis were elevated in DU-implanted rats compared to tantalum-implanted controls for both the medium- and the high-dose groups. The animals were not perfused prior to sacrifice, and the authors did not account for the uranium bound to red blood cells. Nonetheless, given the relatively low serum levels of uranium in the same animals (8.09 ng [nanograms] U/ml serum in the high-dose animals at 18 months), blood trapped within blood vessels does not account for the reported brain levels of uranium (~125 ng U/g for the same group). This study is the first to suggest that in the rat animal model, uranium can accumulate within the central nervous system. The mechanism of uranium transport into the CNS is unknown.

A follow-up study by the same group (Pellmar et al., 1999b) assessed the potential for electrophysiological changes in the hippocampus of rats implanted with DU fragments. At 12 months, the amplitudes of synaptic potentials were significantly greater in tissues derived from high-dose (20 pellets) DU-implanted rats compared with controls (tantalum implanted). In the same animal model, uranium did not affect locomotor activity, discrimination learning, or the results of a battery of general functional measures (Pellmar et al., 1997). The abnormal electrophysiological measurements were not apparent 18 months after exposure to 20 pellets of DU (high dose). The authors suggest that by 18 months the effects of aging and DU exposure converge, thereby obscuring the effects of the metal. The lack of an effect of DU on locomotor activity, discrimination learning, and a general functional observation battery makes it difficult to interpret the significance of uranium accumulation in the brain. It is possible that the behavioral measures of performance in learning tasks may have been insufficiently sensitive to detect the effects of brain uranium. No nephrotoxicity occurred in these animals (at urinary uranium concentrations of 1,009 ± 87 ng/ml 12 months after exposure to uranium). The study suggests that retained embedded DU fragments are associated with increased brain uranium concentrations.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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Gastrointestinal Effects

No gastrointestinal effects occurred in animals administered unenriched uranium nitrate orally in doses as high as 664 mg/kg per day for up to 2 years (Maynard and Hodge, 1949). A study of rats exposed to uranyl nitrate hexahydrate in drinking water (up to 40 mg/kg per day) for 28 days found no treatment-related histopathological changes (Gilman et al., 1998a). No gastrointestinal effects occurred in rabbits exposed for 91 days to uranyl nitrate hexahydrate in drinking water (0.96, 4.8, 24, 120, or 600 mg/L) (Gilman et al., 1998b,c).

Hepatotoxicity

Uranium-induced hepatotoxicity has not been a prominent finding in most animal studies (ATSDR, 1999b). No changes occurred in the liver of dogs administered insoluble uranium acetate dihydrate for 30 days at doses as high as 7,859 mg U/kg per day (Maynard and Hodge, 1949). Inhalation exposure to 17 mg U3O8/m3 for 26 days or to 22 mg UO2/m3 for 30 days had no hepatic effects (Dygert et al., 1949). Similarly, animals exposed to 10 mg UO3/m3 by inhalation for up to 2 years showed no changes in hepatic function (Stokinger et al., 1953).

Reproductive and Developmental Effects

A small number of studies addressed the effects of uranium on fertility, general reproductive parameters, or offspring survival. Llobet and colleagues (1991) evaluated the fertility of uranium-treated Swiss mice. Male mice received high doses of uranyl acetate dihydrate (10, 20, 40, and 80 mg/kg per day) in drinking water for 64 days and were then mated with untreated females. There was a significant but non-dose-related decrease in the pregnancy rate of these animals. Body weights were significantly depressed only in the group of adult male mice treated with 80 mg/kg per day. Testicular function and spermatogenesis were not affected by uranium at any dose, as evidenced by normal testes and epididymis weights and normal spermatogenesis. Vacuolization of Leydig cells was seen in the high-dose (80 mg/kg per day) group. These data indicate that normal dietary intake of uranium does not cause any adverse effect on testicular function in mice, with a safety factor of more than 1,000.

Paternain and colleagues (1989) studied the effect of uranyl acetate dihydrate on reproduction, gestation, and postnatal survival in Swiss mice. Male mice received oral uranyl acetate dihydrate (5, 10, and 25 mg/kg per day) for 60 days prior to mating with female mice treated orally (at the same doses) for 14 days prior to mating. Oral administration of the uranium compound to the female mice continued throughout mating, gestation, parturition, and nursing of the litters. Lethal effects on the embryo occurred only in the high-dose (25 mg/kg per day) group. The number of dead young per litter increased significantly at birth and at day 4 of lactation in that group. The growth rate in offspring was always significantly lower for uranium-treated animals. However,

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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uranium failed to cause any adverse effects on fertility, general reproductive parameters, or offspring survival (ATSDR, 1999b). No studies have reported chemical or radiological effects of uranium on fetal development after inhalation or dermal exposure to uranium compounds for any duration.

Other Health Effects

Cardiovascular effects. Animal studies report no adverse effects on cardiovascular function subsequent to oral or inhalation exposure to uranium (Dygert et al., 1949; Maynard and Hodge, 1949). Filippova and colleagues (1978) instilled 90 percent 235U-enriched soluble tetravalent and uranyl nitrate hexahydrate salts into the trachea of rats and found blood vessel dystrophy and enlargement of the heart. Rabbits exposed for 91 days to uranyl nitrate in drinking water (0.96, 4.8, 24, 120, or 600 mg/L) did not suffer cardiovascular effects (Gilman et al., 1998b,c). Cardiovascular effects also did not occur in rats exposed to 0.2 mg U/m3 as uranium hexafluoride for 1 year (Stokinger et al., 1953) or in rats, mice, guinea pigs, and rabbits exposed to 4.8 mg U/m3 triuranium octaoxide for 26 days (Dygert et al., 1949).

Dermal effects. Inhalation and oral exposures to uranium compounds have not led to dermal effects in animals (Spiegl, 1949). Dermal application of uranium compounds was associated with mild skin irritation, severe dermal ulcers, or superficial coagulation necrosis and inflammation of the epidermis in rabbits (Orcutt, 1949). An applied dose of 237 mg U/kg as uranyl nitrate hexahydrate on the skin of rats resulted in swollen and vacuolated epidermal cells and damage to hair follicles and sebaceous glands (de Rey et al., 1983). In rats exposed to U3O8 (0.012 g per day) in 30 daily topical applications, the epidermis was thinner than in control animals, and skin permeability was higher (Ubios et al., 1997).

Ocular effects. In animals, encrusted eyes and conjunctivitis occurred after inhalation of 13 mg U/m3 (UF6) for 30 days (Spiegl, 1949) as well as with uranium tetrachloride (Dygert et al., 1949). The ocular effects were caused by direct contact of the eye with uranium aerosol or vapor.

Musculoskeletal effects. The effects of inhaled uranium on the musculoskeletal system of animals have not been examined. There were no histopathologic findings in rat or rabbit muscles after exposure to orally administered uranyl nitrate in drinking water (up to 40 mg U/kg per day for 28 day, or up to 53 mg U/kg per day for 91 days in Sprague-Dawley rats; or up to 53 mg U/kg per day for 91 days in rabbits). However, acute uranium intoxication (2 mg/kg of body weight) with [238U]uranyl nitrate has been shown to inhibit bone formation, an effect believed to be due to the direct action of uranium on bone-forming cells or their precursors (Gugliemotti et al., 1985; Ubios et al., 1998).

Hematological effects. Inhalation exposure to ammonium diurnate ([NH4]2U2O7) dust (6.8 mg U/m3, 6 hours per day, 30 days) caused a decrease in red blood cell count and hemoglobin concentration in rats (Dygert et al., 1949). Inhalation exposure to uranyl nitrate hexahydrate (9.5 mg U/m3, 8 hours per day,

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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30 exposure days) caused a reduction in erythrocyte numbers and hemoglobin levels (Roberts, 1949). Significant increases in myeloblasts and lymphoid cells of the bone marrow occurred after inhalation exposure to uranium peroxide or uranium trioxide (15.4 mg U/m3, 5 hours per day, 23 days, and 16 mg U/m3, 6 hours per day, 24 days, respectively) (Dygert et al., 1949). However, a series of intermediate-duration inhalation studies showed no adverse effects of uranium on the blood (ATSDR, 1999b). Similarly, the majority of animal studies show no adverse effects of orally administered uranium compounds on blood. For example, in New Zealand white rabbits exposed for 91 days to uranium (uranyl nitrate hexahydrate) in drinking water (0.96, 4.8, 24, 120, or 600 mg U/L), hematological and biochemical parameters did not change (Gilman et al., 1998a,b,c).

EPIDEMIOLOGIC STUDIES: DESCRIPTION OF THE STUDIES

General Considerations

This section contains descriptions of epidemiologic studies of the human health effects of exposure to uranium. The section begins with an overview of the studies of uranium miners. The studies in this cohort have limited relevance to the depleted uranium exposures of Gulf War veterans because, as described below, the primary disease-causing exposures for the miners were not to uranium, but to radon. The remainder of the section provides detailed descriptions of studies on workers occupationally exposed to uranium in uranium-processing plants. The results of these studies appear in the next section of the chapter.

Although depleted uranium is the form of uranium that was present in the Gulf War theater, there are only a few studies of its health effects. Therefore, the committee relied on studies of the health effects of natural and processed uranium. As noted earlier in the chapter, the chemical characteristics of an element are independent of its isotopic form. As a result, DU has the same chemical effects as naturally occurring or enriched uranium. Given the same dose by the same route, the health effects that are due to the chemical characteristics of uranium should be identical from natural, enriched, or depleted uranium exposures. Thus, studies of the chemical effects of natural and processed uranium will provide a good indication of what studies of DU would show.

The literature examining the health effects of exposure to ionizing radiation is extensive. Recent reports including those by the NRC (National Research Council) and ATSDR (NRC, 1988, 1990, 1999; ATSDR 1999a) summarize this work. High-dose human and animal studies have shown that radiation is carcinogenic and that the incidence of cancer increases with the dose of radiation (ATSDR, 1999a). The principal isotope in natural and depleted uranium, 238U, has a long half life (4.5 billion years) and primarily decays by alpha particle emission. Alpha particles have a very short range and little penetrating power. They are therefore a hazard to humans only in close proximity to human tissue.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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For these reasons, natural uranium is considered a low-level internal radiation hazard. Thus, the focus of the discussion on radiation in this chapter is on the effects of radiation from uranium in the body, rather than from external radiation. Since the specific activity (a measure of radioactivity) of depleted uranium is 40 percent lower than that of natural uranium (and much lower than enriched uranium), any health effects that are a consequence of the radioactive nature of uranium would be expected to be less prevalent in people exposed to DU than in people exposed by the same route to the same amount by weight of natural or enriched uranium.

Studies of Uranium Miners

The committee examined studies of health effects in uranium miners, but concluded that these studies have limited relevance because the primary disease-causing exposures were not to uranium but to radon decay products. The principal form of radiation exposure of uranium miners in underground mines has been to inhalation of alpha particles emitted by radon decay products in poorly ventilated mines (NRC, 1999). Radon progeny are known to increase the risk of lung cancer (NRC, 1999). In addition, miners were exposed to other possibly toxic dusts and, potentially, to diesel gas fumes, which might cause cancer and other diseases of the lung (NRC, 1999). Another serious limitation of most studies of uranium miners is the lack of information on cigarette smoking. The experience of uranium miners with diseases other than those of the respiratory tract could inform our knowledge of the consequences of uranium mining in organ systems other than lung. However, the literature on uranium miners has focused largely on lung and other cancers, and most publications have used mortality rather than morbidity as the outcome measure.

Radon is a radioactive decay product of uranium. In a confined, poorly ventilated area, such as a mine shaft, radon gas diffuses from the surrounding uranium-containing rock and accumulates in the atmosphere within the mine shaft, where miners inhale it. Radon progeny (polonium-218, lead-214, bismuth-214, and polonium-214) decay rapidly (with half-lives of 30 minutes or less) by emitting alpha particles. These isotopes attach to dust particles, are inhaled and deposited on the bronchial epithelium, and decay before natural clearance mechanisms can remove them. However, in relatively well-ventilated work spaces, such as uranium mills or uranium fabricating plants, radon gas is present in low concentrations. Furthermore, some uranium refining processes remove radium, the immediate parent of radon in the uranium decay series. Exposure to radon decay products is known to be associated with increased risk of lung cancer (NRC, 1999).

The Committee on the Biological Effects of Ionizing Radiation (BEIR) of the National Research Council has extensively studied the published literature on the health effects of radon and other internally deposited alpha-particle emitters such as uranium (NRC, 1988, 1990, 1999). The following section briefly summarizes some of the literature on health effects in uranium mine workers.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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A series of studies describes the mortality experiences of uranium miners in the Colorado Plateau states (Colorado, Utah, New Mexico, and Arizona) of the United States (Lundin et al., 1969; Saccomanno et al., 1971, 1976, 1986; Archer et al., 1973b, 1976; Auerbach et al., 1978; Band et al., 1980; Whittemore and McMillan, 1983; Hornung and Meinhardt, 1987; Roscoe, 1997). In an early report in the series, Lundin and colleagues (1969) examined mortality among 3,414 white underground uranium miners from 1950 to 1967. Total mortality increased approximately 50 percent above the rates expected for white males of the same geographic area; this excess was largely accounted for by violent deaths and cancers of the respiratory system. Most of the excess respiratory cancer deaths occurred 10 or more years after the individual’s first uranium mining experience. Overall, the risk of respiratory cancer increased with cumulative estimated exposure to radon progeny during mining. Apart from the increases in respiratory cancer and violent deaths, the only other statistically significant finding was a reduced risk of death from major cardiovascular–renal disease among uranium miners, consistent with the expected healthy-worker effect (see later discussion). Many other publications in this series have focused on lung cancer or its premalignant precursors.

A recent update of the mortality of this cohort examined vital status through December 31, 1990 (Roscoe, 1997). The study found increased mortality risks in this cohort of 3,238 white male uranium miners for lung cancer (SMR = 580, 95% confidence interval [95% CI] 520–640). The study found a significant exposure–response trend for lung cancer with increased exposure to radon progeny and for duration of employment in uranium mining. Deaths from chronic nephritis were not significantly elevated in this update.

A case-control analysis of the Colorado Plateau miners examined lung cancer cases in a population of 9,817 miners during a 20-year period from 1960 to 1980 (Saccomanno et al., 1986). The study matched 489 cases of death from lung cancer with 992 non-cases to control for age and smoking history. There was a strong positive association between uranium mining and risk of lung cancer; the relative risk for those with 11 or more years of underground mining work was 8.5. Mining and cigarette smoking interacted multiplicatively in the multivariate model of the predictors of lung cancer.

Several studies have focused specifical1y on uranium mining and risk of lung cancer among Navajo men (Gottlieb and Husen, 1982; Samet et al., 1984). Samet and colleagues conducted a population-based case-control study using the New Mexico tumor registry to identify 32 cases of lung cancer occurring among Navajo men between 1969 and 1982. The authors identified two controls for each case. Of the 32 Navajo men with lung cancer, 72 percent (23) had been employed as uranium miners, whereas none of the controls had been miners. Another study followed the vital status from 1960 to 1990 of a cohort of 757 Navajo uranium miners who worked in the Colorado Plateau (Roscoe et al., 1995). Elevated SMRs were found for lung cancer (330, 95% CI 230–460), tuberculosis (260), and chronic lung disease (260). SMRs were reduced for heart disease, circulatory

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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disease, and liver cirrhosis. The SMR for lymphatic or hematopoietic disease was 80 (3 observed cases compared with 3.7 expected cases).

The relation between lung cancer mortality and uranium mining was also the subject of several reports from Canada (Muller et al., 1985; Nair et al., 1985; Howe et al., 1986; Kusiak et al., 1993). In a cohort of 8,487 workers employed between 1948 and 1980 in a uranium mine in Saskatchewan, a total of 65 lung cancer deaths occurred (Howe et al., 1986). There was a highly significant linear relationship between the estimated level of exposure to radiation from radon daughters and risk of lung cancer. Nair and colleagues (1985) provided additional data on other causes of death in this population. In addition to lung cancer, there were significant excess death rates for trauma, which in part reflected the safety hazards of mining. They also provided mortality data for 2,332 miners who worked in the Port Radium facility in the Northwest Territories. As with the Saskatchewan miners, mortality rates for lung cancer and trauma were significantly increased. For bone cancer, there were no cases, compared with 0.60 expected; there were 17 cases of lymphoma compared with 15.7 expected.

A study by Muller and colleagues (1985) examined the mortality experience of many types of miners (e.g., nickel, copper, gold, uranium) in Ontario between 1955 and 1986. In the cohort of uranium miners, 121 lung cancer deaths were identified; 70.54 were expected based on the general male population of Ontario. Risk increased with exposure to radiation from radon daughters, and the risk was greatest at an interval between 5 and 14 years after exposure. This study also provided data for other causes of death in this population. Deaths from silicosis and chronic interstitial pneumonia were significantly increased (11 versus 2.14 expected) as were traumatic deaths. There were 26 deaths from lymphatic and hematopoietic malignancies versus 27.4 expected; there were 2 deaths from bone cancer compared with 1.38 expected deaths.

Studies of uranium miners in Czechoslovakia provide further information on mortality from cancers other than lung cancer and from other diseases (Tomasek et al., 1993, 1994). The area near the Czech and German border has been a site for mining for many centuries, and lung disease has been a disproportionate cause of death since the sixteenth century (Tomasek et al., 1994). Tomasek and colleagues (1993, 1994) followed the mortality experience of 4,320 male mine workers from 1948–1959 to the end of 1990. Lung cancer mortality was greatly elevated in this population (SMR = 508, 95% CI 471–547), but mortality from all other cancers combined was not (SMR = 111, 95% CI 98–124) (Tomasek et al., 1993). Other than lung cancer, significant increases in cancer mortality were seen only for liver cancer (SMR = 167) and cancer of the gallbladder and extrahepatic bile ducts (SMR = 226). They found only 2 deaths from bone cancer (SMR = 69) and 11 deaths from lymphoma (SMR = 109). Despite exposures to high levels of radon, arsenic, and dust, mortality from chronic respiratory disease was only slightly and nonsignificantly elevated (SMR = 121). The observed deaths from urinary diseases in this cohort were lower than expected (SMR = 77). In addition to lung cancer, mortality was greater than expected for accidents, homicide, mental disorders, cirrhosis, and nonrheumatic circulatory disease (Tomasek et al., 1994).

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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In summary, the studies of uranium miners consistently show a large increase in deaths from lung cancer. However, these studies are of limited relevance to veterans of the Gulf War because the miners were exposed to high concentrations of radon gas as a consequence of working underground in poorly ventilated confined spaces. Radon decays into short-lived alpha-particle-emitting isotopes that have been found to increase the risk of lung cancer (NRC, 1999). Although long-lived isotopes of uranium, plutonium, and thorium are also present in lung tissue and thoracic lymph nodes of uranium miners (Singh et al., 1983, 1986, 1987, 1989), it has not been possible to distinguish their contribution to disease from that of radon progeny.

Studies of Uranium Processing Workers

The most important sources of evidence about the human health effects of exposure to uranium are studies of people who worked in plants whose purpose was to process and refine raw uranium ore into 235U-enriched uranium metal for use in weapons and nuclear reactors (Table 4.3). Their exposure history differs from that of uranium miners because they worked in an environment that had little radon gas, an exposure that confounds any attempt to link uranium exposure in mine workers to effects on the lung, an important potential site for disease caused by uranium. The principal exposure of uranium processing workers is to uranium oxides and derivative uranium compounds produced during the uranium refinement process. It is important to note, however, that uranium is not the sole potential hazard in the industrial settings described below. Studies vary in the nature of the work being conducted and the extent to which workers were exposed to enriched uranium, soluble and insoluble uranium compounds, other radioactive elements (e.g., radium, thorium), and other potentially hazardous industrial chemicals (e.g., sulfuric acid, fluorocarbons).

Occupational studies involve exposure that occurred in the course of day-to-day tasks, rather than as a single large exposure. The exposure was greatest in the early days of the uranium processing and machining industry; as the industry adopted improved safety measures, the degree of exposure decreased. The principal route of entry for uranium in occupational exposures was inhalation of dusts to which uranium compounds were attached. In this sense, the exposure was similar in character, albeit far more prolonged, to that of Gulf War veterans involved in cleanup actions after friendly fire incidents. The exposure in the case of uranium processing plant workers occurred over a period of months to many years, in contrast to the much shorter period of exposure in veterans involved in cleanup actions.

This section is a study-by-study description of the epidemiologic studies of uranium-processing workers and includes information on the exposure measures (where available) and the analytic methods used in each study. This section does not contain any results. Results appear in the following section, which is a disease-by-disease analysis of the strength of the evidence for associations between health outcomes and exposure to uranium.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×
Uranium Mill Workers on the Colorado Plateau (Wagoner et al., 1964; Archer et al., 1973a; Waxweiler et al., 1983)

In addition to the many studies of Colorado Plateau uranium miners, the mortality experience of uranium mill workers in the Colorado Plateau states has been a focus of study. The process of enriching uranium ore during the milling process leads to the exposure of workers to many substances, except during the final stage of purification. Airborne dust in the mills can contain vanadium, thorium, and radium isotopes in addition to the primary compound, uranium. Additionally, in the early years, substantial silica levels were present in uranium mills (Waxweiler et al., 1983).

The earliest study by the U.S. Public Health Service (Wagoner et al., 1964) examined cancer mortality in a prospectively identified cohort of uranium miners and millers. One subcohort of 611 white male millers had no reported mining exposure. The men volunteered for at least one physical examination. The authors ascertained vital status as of December 31, 1962, and compared mortality rates with the male population of the Colorado Plateau states.

A study by Archer and colleagues (1973a) continued the follow-up of the mill worker cohort with some additions through 1967. The study examined 662 white men who worked in uranium mills in 1950–1953 and were available for medical examinations in 1950, 1951, and 1953. Investigators obtained a thorough occupational history of this prospectively defined cohort. Social Security Administration (SSA) records and many other sources were used to trace the vital status of all but 1 percent of the cohort. Comparisons were made to the mortality experience of all white men who lived in the Colorado Plateau states.

The third study was a retrospective cohort analysis examining the mortality through 1977 of uranium mill workers on the Colorado Plateau (Waxweiler et al., 1983). The study identified 2,002 men who worked at least 1 year in a mill before 1972 and who had not worked in uranium mines; the study cohort may have overlapped with that of the previous two studies, but the extent of overlap is unclear. Deaths between 1940 and 1977 were identified using Social Security records; expected deaths were based on rates in the entire U.S. population.

Nuclear Fuels Fabrication Plant Workers (Hadjimichael et al., 1983)

United Nuclear Corporation fabricated nuclear fuels from enriched uranium in a plant in Connecticut. The company asked the Yale University Department of Epidemiology and Public Health to investigate possible effects of low-level exposure to radiation and other industrial nonradiation exposures in the manufacturing plant (Hadjimichael et al., 1983). Manufacturing processes involved receiving enriched uranium, machining the uranium into appropriate shapes, encapsulating it with a metal covering, and assembling the product into larger components for use as reactor fuel. The report states that approximately one-fifth of the employees had received occupational whole-body exposure to

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

TABLE 4.3 Epidemiologic Studies of Uranium Processing Workers

Reference

Study Design

Description

Radiation Dose in Exposed Subjects

Study Group (n)

Wagoner et al., 1964

Cohort

Prospective cohort study of mortality experience of white male uranium millers and miners in the Colorado Plateau states

Not known

611 millers

Archer et al., 1973a

Cohort

Prospective cohort study of mortality experience of white male uranium millers in the Colorado Plateau states

Not known

662

Polednak and Frome, 1981

Cohort

Mortality experience of white male employees (1943–1947) at a uranium conversion and enrichment plant in Oak Ridge, TN

Not known

18,869

Hadjimichael et al., 1983

Cohort

Mortality and cancer incidence experience of employees (1956–1978) in a nuclear fuel fabrication plant in Connecticut

0.5% had ≥ 10 rem cumulative dosea

4,106

Waxweiler et al., 1983

Cohort

Mortality experience of male uranium millers in the Colorado Plateau states

Not known

2,002

Stayner et al., 1985

Cohort

Mortality experience of workers at a phosphate fertilizer production facility in Florida

Not known

3,199

Brown and Bloom, 1987

Cohort

Mortality experience of white male uranium enrichment workers in Ohio

Not known

5,773

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

Dupree et al., 1987

Cohort

Mortality experience of white male employees of a uranium processing facility in Buffalo, NY

37.9% had >10 rem/year estimated dose of internal radiation to the lungb

995

Checkoway et al., 1988

Cohort

Mortality experience of white male employees (1947–1979) at a nuclear materials fabrication plant, in Oak Ridge, TN

29% had ≥ 10 rem cumulative internal radiation dosec

6,781

Frome et al., 1990

Cohort

Mortality experience of white male workers at Oak Ridge uranium enrichment and laboratory facilities

Not known

28,008

Dupree et al., 1995

Case control

Cases of lung cancer at four uranium processing operations

5% of cases had ≥ 0.5 cGy cumulative internal radiation dose

787

Ritz, 1999

Cohort

Mortality experience of white male employees at a uranium processing plant in Ohio

8.2% had ≥ 10 rem internal radiation doseb

4,014

aPercentage of those with known exposure (of the total cohort of 4,106 individuals, exposure was known for 786 individuals; 4 individuals had ≥ 10 rem).

bData in the study were given in units of millisieverts and have been converted to rems.

cPercentage of those with known exposure (of the total cohort of 6,781 individuals, exposure was known for 3,490).

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

gamma and x-ray radiation, and approximately 10 percent were at risk of internal alpha-particle exposure through inhalation or possibly ingestion.

The study cohort of 4,106 included all employees who worked at the plant for at least 6 months between 1956 and 1978. The authors constructed a list of 16 groups of job titles based on the similarity of the industrial radiation exposure within each group. Two groups had little exposure. Employment records had sufficient detail to permit the authors to assign each patient to the job category in which he or she had worked the longest. Thus, the data on each employee included one job category and the length of time in this category. SSA records and mortality records of the Connecticut Department of Health Services provided the vital status of each employee. Death certificates were available for 93.1 percent of the deceased. The vital status of 5.7 percent of the employees was unknown at the end of the study in 1978. By matching employee names to names in the Connecticut Tumor Registry, the authors measured the incidence of cancer.

Film badges, worn by all employees who worked in areas with exposure to radiation, provided a measure of cumulative external radiation. The plant monitored internal radiation by measuring urinary uranium excretion. Starting in 1969, employees with high urine uranium levels also received in vivo counting of lung radioactivity. Therefore, information on internal exposure levels was not complete for all employees. The basis of comparison of death rates was the Connecticut population. The authors determined each person’s years at risk by dividing the time from entering employment to the end of the study into 5-year intervals and summing the risk of disease in each interval over all intervals. They also performed a multivariate analysis with death from a disease as the dependent variable and year of employment, smoking, cumulative radiation exposure, previous occupational radiation exposure, and whether the person was an industrial worker or an office worker as independent variables.

Phosphate Fertilizer Production Workers (Stayner et al., 1985)

Stayner and colleagues (1985) conducted a retrospective cohort mortality study of 3,199 workers at a phosphate fertilizer production facility located in Polk County, Florida. The mining and processing of phosphate ore may result in exposure to uranium and the decay products of uranium, radon daughters, and thorium. The plant commenced operations in 1953 and was still in operation at the time of publication of the report. The plant became the subject of study after reports of several cases of lung cancer. The National Institute for Occupational Safety and Health (NIOSH) selected this plant for its cohort study because it had good personnel records, had many employees, and had been in operation continuously for several decades. An industrial hygiene survey by NIOSH found that the environmental samples for uranium were below applicable exposure standards.

Employee records had limited information beyond basic demographic data but did indicate the first and last day of employment and the job assignment on those days. To obtain vital status, the authors used employees’ Social Security number to link to SSA files and also to Internal Revenue Service (IRS) files and

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

to the files of the Florida Department of Motor Vehicles. The follow-up period (person-years at risk) lasted from the date of hire to December 31, 1979, or the date of death. To obtain the number of expected deaths, the authors grouped employees by age, sex, and race and into 5-year calendar groups according to date of hire. They calculated the expected deaths based on statistics for the entire United States. The study examined overall mortality as well as sex- and race-specific mortality rates, but did not categorize workers by job classification as a proxy for radiation exposures.

Portsmouth Uranium Enrichment Facility Workers (Brown and Bloom, 1987)

At the request of a labor union, NIOSH analyzed the causes of death in a cohort of uranium enrichment workers at the Portsmouth Uranium Enrichment Facility in Pike County, Ohio (Brown and Bloom, 1987). This plant used gaseous diffusion to enrich the uranium up to 98 percent 235U. In this facility the principal compounds of concern were uranyl fluoride (formed when uranium hexafluoride comes in contact with water vapor), technetium-99 compounds, and hydrogen fluoride. Because uranyl fluoride is highly soluble in water, the principal hazard from inhalation is renal damage, in contrast to the situation in plants that create finished metal products containing uranium in the form of insoluble oxides that may deposit in the lung and regional lymph nodes. As a result, the plant performed routine periodic assays of urine to determine the level of exposure of individual workers. However, because the body excretes uranium very quickly, an individual’s urine uranium level is not an accurate guide to the person’s usual or cumulative exposure. Therefore, the authors of the NIOSH study used the records of urinary uranium levels to classify jobs according to the relative level of exposure.

The authors used company employment records to identify all workers at the plant from its opening in 1954 and to document their work histories. It was possible to ascertain the time that each worker spent in each job. The cohort was made up of 5,773 white male employees who worked for at least a week. Two subcohorts were formed based on the company’s urinalysis data. Although the company’s urinalysis data were deemed inadequate for assigning exposure levels to individuals, the authors used the data to rank the company’s departments by relative degree of potential exposure. Based on the frequency of measuring urinary uranium values, the authors identified 57 departments as having some risk of exposure (100 or more urinalysis reports). The 4,876 workers in those departments made up one of the subcohorts. They then ranked the 57 departments according to the proportion of urinalyses in which the uranium concentration exceeded 50 μg/L. The second subcohort consisted of the 3,545 workers ever employed in a department that was ranked in the top 50 percentile of the 57 departments. Thus, there was an opportunity to evaluate a dose–response relationship. The authors determined vital status by searching the records of the SSA, the IRS, the U.S. Post Office, the Ohio Bureau of Motor Vehicles, and company records from 1954 to 1982. The authors determined the person-years at

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

risk starting with the time the person first worked in one of the at-risk departments of the plant and ending at death or in 1982. Death rates of U.S white males and Ohio state mortality rates served as comparisons. The level of exposure in this cohort was relatively low: 94 percent of reported values were below the limits of detection, 5.1 percent were between 10 and 50 μg/L, and 0.6 percent were greater than 50 μg/L. Only 50 percent worked at the plant more than 5 years, and the turnover of employees was 15–25 percent per 5 years.

Uranium Processing Workers—Linde Air Products Company (Dupree et al., 1987)

A study by Dupree and colleagues (1987) examined mortality among workers at the Linde Air Products Company Ceramics Plant in Buffalo, New York. The plant converted uranium ore to uranium tetrafluoride from 1943 to 1949. The intermediate products in the conversion process were insoluble uranium oxides. Workers also had exposure to other toxic chemicals, including sulfuric acid. Uranium ores with high content of radium-226, an external gamma radiation hazard, were present in the plant for 18 months. Workers were allowed to work for only 2 hours a day with these ores.

The study cohort (n = 995) consisted of white males who had worked at the plant for at least 30 days. The authors created an employment roster from company records and cross-checked it against IRS records (93–95 percent concordance). Worker’s individual job histories were reconstructed from security records, medical examination records, and earnings records. The authors tracked the vital status of the members of the cohort through the SSA and other sources. They obtained death certificates from the Department of Energy’s Death Certificate Retrieval Office and coded the cause of death. Vital status was ascertained for 94.3 percent of the workers, and death certificates were obtained for 94.6 percent of the deceased. The authors compared the death rates of the cohort with death rates for all U.S. white males and for white males in Erie and Niagara counties of New York, the counties in which the workers lived. The period during which a worker was at risk of death began at the date of hire and ended at death or on December 31, 1979, the close of the study.

The authors estimated the dose ranges for each job in the plant using information on airborne radon and uranium monitoring, surface contamination, and urine uranium levels and created a model that assumed a distribution of inhaled particle size. The jobs were grouped into three categories with estimated annual lung doses of <10 mSv, 10–100 mSv, and 100–1,000 mSv. For reference, the occupational limit for lung dose is 150 mSv/year. The authors classified jobs by external radiation dose, using film badge records. The estimated external dose during the 18 months in which radium-226 was present (<20 mSv/year) was considerably less than the allowable whole-body dose limit (50 mSv/year). Therefore, they classified workers only according to internal uranium exposure.

The cohort was relatively young, with 64 percent aged 16–35 years at the date of hire. The vast majority began work from 1943 to 1945, and 56 percent

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

worked less than a year. Of this cohort, 38 percent had an annual internal exposure that exceeded 100 mSv.

Fernald Feed Materials Production Center Workers (Ritz, 1999)

The Fernald Feed Materials Production Center (FFMPC) processed uranium from ore concentrate or low-grade enriched uranium into fabricated uranium metal products (Ritz, 1999). The primary radiation exposure was to 235U (varying from slightly enriched to depleted uranium); thorium was present in small amounts. The author of this recent report had access to the data set from the Comprehensive Epidemiology Data Resource (CEDR) of the Department of Energy. Although the Fernald cohort was relatively small (n = 4,014), it is one of the largest cohorts that received both internal and external exposure monitoring. Furthermore, the cohort had a long follow-up period (mean, 30.9 years), which allowed for many events to occur after the 10-year lag period assumed between exposure and radiation-related solid tumors. These factors enabled the author to evaluate the data for the combined effects of internal and external exposure over a long period. Lung cancer cases in the Fernald cohort were included in an analysis (described later in this section) by Dupree and colleagues (1995).

The cohort comprised white male workers with an estimated average age at employment of 30.1 years. The cohort was employed between the opening of the plant in 1951 and when operations stopped in 1989. The author used SSA files and the National Death Index to ascertain vital status. There were 1,064 deaths, and death certificates were available for 99 percent of the deceased. Workers’ salaries provided an index of socioeconomic status. Film badges were the source of external radiation exposure measurements. Individual urine bioassays and environmental sampling of uranium dust provided estimates of internal exposure, expressed as annual lung doses. The annual lung dose was part of the CEDR data set, which provided no information about the model used to calculate it from measures of urinary uranium excretion. Thus, the author acknowledged that the annual lung dose estimates were “no more than crude indicators of relative levels of exposure among Fernald workers.” The author also corrected for exposure to trichloroethylene and cutting fluids, potentially carcinogenic chemicals used in uranium processing.

The author’s analysis contained several unusual features. To have sufficient mortality data for a thorough dose–response analysis, the author focused on all cancers, lung cancer, and two groups of cancers thought to be radiation-associated (NRC, 1990). One group consisted of lymphopoietic and hematopoietic malignancies. The second group combined all radiation-associated solid cancers including lung, colon, esophagus, stomach, urinary tract, and brain cancers.3 For the dose–response analysis, the author used a case-control analysis nested in a cohort design in which she matched each death with one person who

3  

Lung cancers were considered separately and also as a subset of the second group.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

was still alive at the time of the index subject’s death and, when possible, the index subject’s age. To allow for a period of latency to correspond to the latent period before an exposure can cause a cancer, the author limited cumulative radiation dose to that experienced 0, 10, and 15 years before the index death (“lagging exposure”). The logistic regression analysis adjusted deaths for pay category (as a proxy for socioeconomic status), time since first monitored for radiation exposure, and internal and external radiation dose.

Oak Ridge Uranium Processing Workers

Uranium processing and energy research operations have been conducted at a number of facilities in Oak Ridge, Tennessee, since 1943. A total of about 45,000 persons worked at Tennessee Eastman Corporation’s Oak Ridge uranium processing plant during 1943–1947. In 1947, management of the Oak Ridge facility was transferred to Union Carbide Corporation, and work shifted to the fabrication of weapons parts and research and development (Checkoway et al., 1988). At the same time, the work force underwent a nearly complete turnover. These cohorts have been particularly informative because of the large number of employees; exposure at the beginning of the nuclear industry, which therefore provides long follow-up; and the availability of data on exposure to uranium for specific departments at the plant and, later, for individuals.

Because of the importance of this resource, a series of articles provides progressively longer follow-up and more sophisticated statistical analyses. There is overlap between several of the study cohorts. Thus, the results of the Oak Ridge studies are not necessarily independent. Two of the studies (Checkoway et al., 1988; Dupree et al., 1995) had measures of internal radiation, and there is overlap in the lung cancer cases in these studies. Other studies on the Oak Ridge workers that have focused on external radiation exposures in the research laboratory or other settings include Checkoway et al., 1985; Carpenter et al., 1988; Gilbert et al., 1993; and Cardis et al., 1995.

Uranium processing workers (1943–1947) (Polednak and Frome, 1981). Of the 45,000 persons who worked at the Y-12 Oak Ridge uranium processing plant from 1943 to 1947, complete work histories based on payrolls were available for approximately 38,000 who did not remain at the plant when ownership was transferred in 1947 (Polednak and Frome, 1981). Although about half of the employees were women, this analysis was limited to men because the method used to assess mortality using computer linkage with the Social Security Administration was less complete for women. After excluding men who worked for less than 2 days or had missing information for key data, 18,869 white males were included in the cohort for analysis. The authors do not give the reason for excluding minority groups, but the number of excluded workers was apparently small.

Uranium handled at the Y-12 Oak Ridge plant was received as UO3 from Mallinckrodt Chemical Works in Missouri until late 1945, when the plant began to receive uranium shipments in the form of UF6 gas. Thus, the main radiation hazard

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

was from the inhalation of uranium compounds, rather than from external gamma radiation. The process used to enrich the 235U content of uranium involved a mass spectrographic unit, with two enrichment stages that exposed workers to uranium dust. The first step enriched the 235U content to about 15 percent. Records indicate that many workers had high levels of exposure to uranium dust even by standards at that time (150 μg/m3 of ambient air). Air samples from the area involving the first enrichment stage included many readings higher than the standard; in the chemistry process area of the first stage, average levels were 250–500 μg/m3, whereas levels averaged 25–50 μg/m3 in the first-stage mass spectrographic area and in the second-stage area. After 1945, the high levels in the first-stage processing were reduced when UF6 began to be used as the starting material. Although UF6 is a gas and more soluble, it was immediately converted to less soluble oxides (UO4 and UO3) or to UF4. Although data on particle size are limited, the air contained small particles (<1 μm in diameter) that can be inhaled deeply into the alveoli of the lung and transported to other organs. According to the authors, probably only a few workers used respirators. Data on urinary uranium levels were too few to provide individual exposure estimates. However, about one-third of the workers had urinary uranium levels greater than 0.05 μg/ml, which corresponds approximately to the level expected at the maximum permissible concentration of uranium dust in the air. Thus, many employees, especially those involved in the early steps of uranium processing, were heavily exposed to uranium dust.

This study addressed the hypothesis that working up to several years in areas with high average levels of uranium dust was associated with increased mortality over a period 25–30 years after employment. The authors defined subgroups of workers by the department in which an individual worked and the average levels of uranium dust in these departments. The authors used an internal comparison group of employees with minimal exposure to uranium dust (e.g., workers in buildings where uranium was not processed) and an external comparison group of all U.S. white males. As noted above, deaths (reported by 1974) were ascertained through the SSA by record linkage; the authors estimated that they identified 94 percent of the deaths by this method. The authors used total and cause-specific death rates for U.S. white males, specific for age and calendar year, to compute expected numbers of deaths for the calculation of SMRs for subgroups of employees.

Oak Ridge nuclear materials fabrication workers (1948–1974) (Checkoway et al., 1988). This analysis by Checkoway and colleagues (1988) was based on a retrospective follow-up of 6,781 white men employed in the Oak Ridge nuclear materials fabrication plant (the Y-12 plant) between 1947 and 1979. The individuals included in this study cohort were hired after 1947, and therefore the cohort does not overlap with the workers studied by Polednak and Frome (1981).

Mortality follow-up was conducted primarily using SSA records, supplemented with other sources; vital status was determined for 96 percent of workers. In this facility, exposure to uranium was primarily as airborne dust resulting

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

from the reduction of uranium tetrafluoride to metal, casting of the metal, wet chemistry recycling of the uranium, and extraction of the UF4. Only men hired after 1947 and before 1974 were included, thus ensuring at least 5 years of follow-up for each person.

Compared to most earlier studies of uranium mill workers, considerable data were available on individual exposures to radiation. External radiation exposure was assessed using film badges and thermoluminescent dosimeters. Internal doses were estimated using a combination of urinalyses and in vivo counting of internally deposited uranium. Doses were low compared to those of uranium miners. For workers with known doses, 69 percent experienced less than 1 rem of external (gamma) radiation, 30.6 percent experienced 1.0–9.99 rem, and only 0.4 percent experienced greater than 10 rem. Similarly, for internal (alpha) radiation, the cumulative dose was less than 1 rem for 21 percent, 1.0–9.99 for 50 percent, and greater than 10 rem for 29 percent of the workers. Information on smoking was not available.

The authors followed 85 percent of the cohort for at least 10 years and ascertained 862 deaths. The cause of death was obtained from death certificates, and SMRs were calculated by comparison with death rates among U.S. white males and Tennessee white males. The dose–response analyses assumed both 0-and 10-year latency.

Oak Ridge uranium processing and laboratory workers (Frome et al., 1990). This study examined the mortality experience of a cohort of 28,008 white males who were employed for at least 1 month at one of three Oak Ridge facilities (two uranium enrichment facilities [Y-12 or K-25] or the research and development laboratory) from 1943 to 1947. The men were not employed at the plant at any other time after 1947. Thus, most men in the Polednak and Frome (1981) cohort were included, with the addition of other workers from the K-25 site and the research laboratory. Follow-up for mortality was from 1950 to 1980.

Occupational exposures varied in the three facilities. The laboratory produced plutonium, among other activities, and monitored workers with pocket ionization chambers and later with film badges for external radiation. There were no direct measures of internal radiation. The uranium enrichment process included exposure to enriched uranium, insoluble uranium oxides, and a variety of chemicals including fluorocarbons. Because detailed individual radiation exposure data were not available, workers were classified by the likelihood of exposure (yes, no); facility in which they worked (Y-12 uranium processing facility, X-10 research facility, and K-25 gaseous diffusion facility); and duration of employment. Other variables included socioeconomic status (unskilled, skilled, professional), decade of follow-up, and birth year (before 1910 and 1910 or later). Vital status was determined through the SSA, state records, and the Health Care Financing Administration. Death certificates were obtained to determine cause of death. The authors used three main analytic approaches: (1) standard SMR analysis, (2) evaluation of trends in SMRs over the 30-year follow-up (percentage change per year), and (3) multivariate analyses to assess the independent effects of radiation exposure and the other covariates noted above.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×
Four Uranium Processing Operations (Dupree et al., 1995)

Dupree and colleagues (1995) conducted a retrospectively assembled case-control study of lung cancer among employees in four uranium processing operations. Two of the groups were employed at the uranium processing plant at the Oak Ridge facility during nonoverlapping time periods and have been previously described in the studies by Polednak and Frome (1981) and by Checkoway and colleagues (1988). The third operation was the Mallinckrodt Chemical Works Uranium Division in Missouri, and the fourth was the Feed Materials Production Center in Fernald, Ohio (described in the study by Ritz, 1999). The primary exposure in common among these facilities was to alpha radiation from airborne dust containing insoluble natural uranium compounds. Enriched uranium was present at the Oak Ridge facility from 1943 to 1946, and exposure to radium and radon daughters was also possible at the Mallinckrodt facility. All operations, except the Oak Ridge facility from 1943 to 1947, also processed thorium.

The authors identified eligible cases of lung cancer (n = 787) by mortality follow-up of the employee cohorts through the end of 1982, which provided at least 30 years of follow-up for each cohort. One control was selected for each case, matching on race, gender, and birth and hire dates within 3 years. The authors required both cases and controls to have been employed for at least 6 months. By focusing on a limited number of cases and controls rather than the entire cohort, they were able to re-create each person’s work history in detail to provide a quantitative individual estimate of exposure to radiation.

Using employment and occupational radiation monitoring records, data was collected, as available, on smoking history (limited to never or ever smoked because further details were not routinely available), socioeconomic status (as first pay code), and complete work history. Smoking data were obtained for 48 percent of the cases and 39 percent of the controls, with 91 percent of the cases and 75 percent of the controls identified as smokers. Using the available individual and environmental data (including air monitoring data), health physicists estimated annual radiation lung doses from deposited uranium for each person.

As discussed throughout this section there is overlap between some of the cohorts of uranium-processing workers. Table 4.4 points out the extent of overlap.

HUMAN HEALTH EFFECTS OF URANIUM

This section discusses the scientific literature on the potential associations between human health effects and exposure to uranium. The committee has reorganized the results of the population studies (described in the previous section) and other research into disease-specific subsections that discuss the results and the strengths and limitations of current knowledge. The focus of the discussion is on the organs and organ systems that are the principal sites of uranium deposition following exposure. Malignant and nonmalignant diseases of the lung are impor-

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

TABLE 4.4 Studies with Overlapping Cohorts

 

Facility (dates of operation)

 

Oak Ridge

St. Louis, Mallinckrodt (1942–1966)

Ohio, Fernald (1951–1989)

Reference

TEC (1943–1947)

Y-12 (after 1947)

K-25

R&DX-10

Checkoway et al., 1988

 

+

 

Frome et al., 1990

+

 

+

+

 

 

Polednak and Frome, 1981

+

 

Dupree et al., 1995

+

+

 

 

+

+

Ritz, 1999*

 

+

NOTE: The Tennessee Eastman Company (TEC) operated the Y-12 plant in Oak Ridge as a uranium enrichment facility from 1943 to 1947. The plant (referred to here as Y-12) reopened with a largely new workforce and performed materials processing and fabrication from 1947 through at least 1982.

*Ritz performed follow-up seven years after Dupree and colleagues and identified additional lung cancer cases (raising the total from 51 to 112) in the cohort.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

tant because, as noted earlier, inhaled insoluble uranium oxides lodge in the lung and the hilar lymph nodes, where they may remain for an estimated several hundred days. Cancer of the lymphoid system is another focus of attention for the same reason. Bone is one of the principal sites for the deposition of soluble forms of uranium, either after ingestion or after clearance from the lung and its lymph nodes, and uranium remains in bone for a long time. The kidney is the major site at which uranium acts as a toxic heavy metal. Effects on the nervous system are discussed, despite the dearth of evidence, because of their possible interest in relation to illnesses in Gulf War veterans. The committee discusses other organ systems only briefly due to the paucity of research in these areas.

Assessing the Evidence: Factors Influencing the Quality of Studies

The following discussion highlights several issues that the committee considered in its evaluation of the epidemiologic studies on uranium processing workers. The committee followed the principle of giving more weight to high quality studies and considered a number of factors including methodological issues (as discussed in Chapter 3), measures of exposure, comparison groups, and duration of follow-up.

Measurement of Exposure

The most convincing way to demonstrate an association between an agent and disease is to show that the incidence of the disease increases as the level of the exposure increases. This approach requires an internal unexposed comparison group, which increases the likelihood that the comparison group is otherwise similar to the exposed group. Studies of occupational exposure on which the committee relied to evaluate the effect of uranium on disease used several methods for measuring exposure. Some of the methods discussed below have serious flaws that the committee considered in the evaluation of the study. Table 4.5 categorizes the occupational studies according to the method used to measure exposure to radiation.

Direct measurement in individual workers. The preferred method for an occupational study is to measure the level of exposure directly in each worker. Radiation film badges give a measure of cumulative exposure but measure only external radiation, which is a greater concern for exposure to enriched uranium than for exposure to natural or depleted uranium. Measuring the internal dose of radiation is more difficult. The best method is mathematical modeling to infer the lung dose of uranium from measurements of uranium in the urine and/or ambient dust.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

TABLE 4.5 Methods of Radiation Exposure Measurement

Direct measurement in individual workers

Ritz, 1999

Dupree et al., 1995a

Checkoway et al., 1988

Using work history to model cumulative exposure

Dupree et al., 1995a

Hadjimichael et al., 1983b

Classifying workers by maximum exposure

Frome et al., 1990

Brown and Bloom, 1987

Dupree et al., 1987

Polednak and Frome, 1981

No measurement of exposure

Stayner et al., 1985

Waxweiler et al., 1983

Archer et al., 1973a

aDupree used direct measures of exposure at one site and modeled cumulative dose by job site at two other sites.

bHadjimichael assigned each worker to the job site with the highest exposure but then calculated the cumulative exposure in that site (instead of simply making an ordinal classification of workers by work site).

However, this approach requires that the company monitored workers for radiation exposure and kept thorough records. In many of the occupational retrospective cohort studies the authors found that measurements of exposure in individual workers were not available or were unreliable. In some cases, records were incomplete, so that measurements were lacking for many workers. In other cases, the only measurements were of urinary uranium excretion. Since the body rapidly excretes uranium, urinary uranium is a measure only of exposure in the preceding several days.

Using work history to model cumulative exposure. Several authors approximated individual exposure by modeling cumulative exposure using a worker’s job history within the plant and the level of exposure in each work site. They measured the level of uranium exposure in various work sites within the processing plant, using measures of urinary uranium or uranium in ambient dust. This information was used to model the cumulative lung dose per unit time in the work site. They then used plant employment records to determine the amount of time each worker spent in each job. By totaling each worker’s cumulative exposure in each work site over the course of the worker’s period of employment, they estimated the worker’s total exposure.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

The modeling approach in effect assigns to each worker the average exposure in each work site. As compared with direct measurement, this approach loses information, since workers in a given site may vary in their exposure. Any approach that blurs the distinction between individual workers’ exposure levels while maintaining the distinction between workers’ health outcomes will reduce the variation in the sample. This biases the study toward failing to detect an association between exposure and health outcomes.

Classifying workers by maximum exposure. This approach measures average exposure in each work site, as described in the preceding section, and combines work sites into a relatively small number of groups according to the level of exposure. In one study, the authors did not make measurements of exposure but simply used the judgment of experts to classify work sites by the extent of exposure. However, instead of estimating cumulative exposure over all work sites, this method simply assigns a worker to the work site that has the highest exposure of all the sites in which the employee worked for a minimum period of time (usually one month).

This approach is a cruder form of exposure modeling since it reduces the variation among workers’ exposure levels in two ways. First, it assumes that a employee spent his or her entire period of employment in one group of work sites, when in fact the worker may have spent time in sites that varied considerably in exposure levels. Secondly, it combines sites that may vary considerably in their level of exposure. For these reasons, this approach is especially prone to false-negative results (i.e., failing to detect a dose-response relationship). However, the actual impact of the shortcomings of this approach is unknown as none of the studies estimated the probability of false-negative results.

No measurements of exposure. A study that does not classify workers according to exposure cannot use workers with low exposure as a control when estimating the health effects of high exposure. These studies must use the U.S. population, or the population of the region in which the plant is sited, as the control group. With this approach, the healthy worker effect is more likely to distort estimates of the effect of exposure on health outcomes.

Comparison Group Issues

Many of the cohort studies of occupationally-exposed workers described in this chapter compared death rates in workers to death rates in the U.S. population (or the population of the counties or states in which uranium workers lived). These studies used the standardized mortality ratio (SMR) because it is the principal means used in occupational studies to express the death rate in workers relative to individuals not exposed to the agent being studied. An increased SMR (greater than 100 with 95% confidence intervals that do not include 100) indicates the possibility of an association between an exposure and a disease. Whether an association truly exists depends on the strength of the evidence.

However, interpretation of the SMR in studies of occupational cohorts is not straightforward because of a phenomenon known as the “healthy-worker

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

effect” (see Chapter 3). The healthy-worker effect is a finding that workers in many industries experience a lower mortality rate than the general population, which includes people who are not employed. Presumably, this effect is the result of selecting healthy people for employment and of the need to stay healthy in order to stay employed. Thus, when comparing uranium-processing workers to the U.S. population, the SMRs for many diseases, such as cardiovascular diseases, are less than 100, indicating that the nuclear industry workers were more fit than the U.S. population. Howe and colleagues (1988) studied the healthy-worker effect and concluded that its cause was differential selection for employment and for continued employment. The healthy-worker effect appears to be smaller for cancer than for other diseases (Howe et al., 1988).

The best way to avoid the healthy-worker bias is to use an internal comparison group. However, even internal comparison groups can be subject to this bias, to the extent that less healthy workers may not stay in more physically demanding jobs or jobs (such as uranium milling) that may involve greater exposure to chemical agents. Although studies that use an internal comparison group are more valuable than those using the U.S. population or the population of a region as the comparison group, some internal comparison groups are more useful than others. It may be difficult to draw conclusions on studies that directly compare the SMRs of groups of workers who experienced different levels of radiation exposure (e.g., Polednak and Frome, 1981; Brown and Bloom, 1987; Dupree et al., 1987) because the values of confounding variables may differ between the groups.

To address these limitations, researchers use a standardized rate ratio (SRR) to assess and compare groups who experience different levels of exposure; this measure is preferable when expressing a dose–response relationship (Breslow and Day, 1987). Standardized rate ratios used in multivariate analyses adjust for inter-group differences in the value of confounding variables and provide the best means of comparing mortality rates in groups exposed to different doses of radiation. This preferred method was used in the studies by Ritz (1999), Hadjimichael et al. (1983), Dupree et al. (1995), Frome et al. (1990), and Checkoway et al. (1988). Table 4.6 outlines the different methods of internal comparisons that have been used in the studies of uranium processing workers.

Adequate Follow-Up Period

To strengthen the evidence for a true association (particularly for some health outcomes, such as most cancers), the follow-up period should allow for sufficient time after exposure for the health outcome to occur in the population of concern. There are several time-related factors. Biological latency of cancer is a factor in the delay between exposure to the putative carcinogen and the appearance of cancer. For most cancers, the lag period between exposure and diagnosis is at least 10 years, however, there are exceptions, e.g., leukemia. Eliminating study participants who died from cancer that occurred within 10 years of exposure should increase the SMR if there is a true association between expo-

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

sure to the agent and the cancer. Conversely, the case for an association is much weaker when the death rate relative to the U.S. population is the same whether or not the authors considered the early cancer deaths.

TABLE 4.6 Methods of Comparing Heavily Exposed Workers with Less Exposed Workers

Reference

Method of Comparing Heavily Exposed with Less Exposed Workers (internal comparison)

Ritz, 1999

Cohort study using risk set analysis and standardized rate ratios and adjusting for pay code (salaried vs. hourly), time since first monitoring, internal and external radiation dose.

Dupree et al., 1995

Case-control study (matching for race, gender, age, and hire date, facility) using conditional logistic regression to predict lung cancer mortality. The predictor variables were smoking status, pay code (a surrogate for socioeconomic status), exposure to thorium, exposure to radon.

Checkoway et al., 1988

Poisson rate regression analysis to obtain maximum likelihood ratios for causes of death classified according to cumulative radiation exposure. The internal referent group was that with the lowest cumulative dose.

Hadjimichael et al., 1983

Log-linear models to predict all-cancer mortality using year of employment, smoking, cumulative radiation exposure, previous work exposure, job type as predictor variables.

Frome et al., 1990

Poisson regression analysis to describe the joint effects, using a multiplicative main effects model, of the predictor variables (duration of employment, socioeconomic status, radiation exposure, facility, birth year, and length of follow-up) on lung cancer mortality.

Brown and Bloom, 1987

Qualitative comparison of SMRs for workers in sites with high exposure with SMRs for the entire cohort.

Dupree et al., 1987

Qualitative comparison of SMRs for workers in jobs with high exposure with SMRs for the entire cohort.

Polednak and Frome, 1981

Qualitative comparison of SMRs for workers in sites with high ambient air uranium levels with the entire group, which included workers with jobs involving no exposure.

Stayner et al., 1985

None

Waxweiler et al., 1983

None

Archer et al., 1973a

None

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×

Furthermore, the incidence of most cancers increases with age. Two-thirds of all cases of cancer are in individuals over age 65 (Longo, 1998). Lung cancer is largely a disease of men and women past the age of 55, with the peak incidence occurring between ages 55 and 65 (Minna, 1998).

In order to accumulate enough cases to avoid false-negative conclusions, it is important for the study to have adequate statistical power, which is a function of both the follow-up time and the size of the population. Longer follow-up time will allow an examination of a range of latency periods between the exposure and the diagnosis of disease.

Table 4.7 provides information on the follow-up periods of the uranium worker studies examined in this chapter. Otherwise well-designed studies such as those of Checkoway et al. (1988) and Hadjimichael et al. (1983) suffer from a relatively short period of follow-up. The studies of Ritz (1999), Dupree et al. (1995), Frome et al. (1990), and Polednak and Frome (1981) have 25 to 30 years of follow-up.

All Cancer Deaths

Collectively, the occupational cohorts of workers exposed to uranium, both to relatively insoluble oxides and to more soluble forms, provide a substantial body of evidence to judge the effects of exposure to uranium on cancer risk. Many of these workers may have had high levels of exposure during the early years of the nuclear industry and have now been followed for more than 30 years.

There is strong evidence that the levels of exposure in these occupational settings have not increased overall cancer mortality (Table 4.8). The SMRs are all close to or less than 100, indicating that cancer mortality in uranium workers was similar to the comparison group, which was either the entire U.S. male population or the population of the region near the work site. However, cancer is very heterogeneous, and organs and organ systems vary in their cumulative exposure to inhaled or ingested uranium and probably also in their susceptibility to carcinogenesis. Thus, the committee looked carefully at those cancers that were most likely to be related to internal exposure to uranium. However, we cannot exclude the possibility that exposure to uranium increases the risk of some relatively uncommon cancers.

Lung Cancer

Lung cancer has received the greatest attention in past studies of uranium exposure, and it is the disease about which the committee can make its most extensive analysis of the relationship between uranium exposure and disease. The reason for attention to lung cancer is due to the long residence of inhaled uranium dust in lung tissue and regional lymph nodes. In addition, lung cancer is a common disease and the number of cases is often sufficient to permit analysis

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

TABLE 4.7 Follow-up in Studies of Exposure to Uranium

Reference

Dates of Employment of Workers Who Are Eligible for Study

Date of Close of Mortality Follow-Up

Mean Follow-Up (years)

No. of Lung Cancer Deaths

Ritz, 1999

1951–1989

1990

30.9

112

Dupree et al., 1995

a

1983

26b

787

Checkoway et al., 1988

1947–1974

1979

20.6

89

Hadjimichael et al., 1983

1956–1978

1979

N/A

18c

Frome et al., 1990

1943–1947

1980

>33

850

Brown and Bloom, 1987

1954–1982

1982

N/A

48

Dupree et al., 1987

1943–1949

1979

30

21

Polednak and Frome 1981

1943–1947

1974

27

324

Stayner et al., 1985

1953–1977

1977

N/A

10

Waxweiler et al., 1983

1940–1972

1977

N/A

26

Archer et al., 1973a

1950–1953

1967

14

4

aDupree used four different populations: two Y12 cohorts (1943–1947 cohort and 1947– cohort), Malinckrodt (1942–1966), and Fernald (1951–1989). Dupree’s population and Frome’s have several hundred individuals in common (the exact number is not known to the committee).

bMean follow-up applies to the cases in this case-control study.

cThere were 14 lung cancer deaths in male workers in industrial jobs (the category that is used in Table 4.9).

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

of subgroups that received different doses. The results of epidemiologic studies examining lung cancer mortality (Table 4.9) are discussed below.

Uranium Mill Workers on the Colorado Plateau (Archer et al., 1973a;Waxweiler et al., 1983)

The study by Archer and colleagues (1973a) was one of the first to examine cancer mortality as a result of exposure to uranium in a setting other than the enclosed, poorly ventilated spaces in an underground mine. There were 104 deaths during the 17-year period (1950–1967) of follow-up of uranium mill workers. The number of lung cancer deaths was 4 (4.26 expected) for an SMR of 94. The small cohort, short period of follow-up (maximum of 17 years), and small number of cancer patients limit this study’s power to detect an increase in lung cancer deaths. In a somewhat larger cohort with up to 37 years of follow-up, Waxweiler and colleagues (1983) found fewer lung cancer deaths than expected (SMR = 83).

Phosphate Fertilizer Production Workers (Stayner et al., 1985)

The SMR for lung cancer in this study was 113 (90% CI 61–192). There was no trend to higher SMRs for lung cancer with increasing duration of employment (a proxy for dose of radiation) or length of follow-up. A trend toward higher SMRs with increasing duration of follow-up would be consistent with a biological effect of exposure because a longer period of follow-up reduces the influence of cancers detected during the first 10 years after employment. Most cancers detected in the first 10 years after exposure are not likely to be causally related to the exposure. The single exception was a trend for higher SMRs in black male employees who had been employed more than 20 years and followed over 20 years. There were only two cases of cancer in this category.

The study had several shortcomings. For most employees, the period of potential exposure was relatively brief. Fifty-four percent of the employees worked less than 6 months at the plant. Most employees were young, with 61 percent being between 18 and 28 years at the date of hire. There was no information on cigarette smoking status. The length of follow-up was too brief and the cohort still too young to accumulate enough deaths to draw any firm conclusions about the association between exposure and lung cancer. Additionally, the authors did not have precise information about job assignments and had no information about the level of radiation exposure. Therefore, workers could not be classified by the extent of their exposure. Further, the workers may have been exposed to other potentially hazardous compounds including radon daughters.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

TABLE 4.8 Mortality from All Forms of Cancer

Reference

Study Site

Study Group (n)

No. of Observed Deaths

No. of Expected Deaths

SMR (95% CI)

Wagoner et al., 1964

Uranium mills and mines, Colorado Plateau

611a

6

8

75 (4–146)b

Archer et al., 1973a

Uranium mills, Colorado Plateau

662

20

18.11

110 (63–157)b

Polednak and Frome, 1981

Y-12 uranium processing plant, Oak Ridge, TN

18,869

886

1,042

85 (79–91)b

Waxweiler et al., 1983

Uranium mills, Colorado Plateau

2,002

82

109.8

75 (59–93)

Hadjimichael et al., 1983

Nuclear fuel fabrication plant, Connecticut

2,613c

40

44.5

88 (62–120)

Stayner et al., 1985

Phosphate fertilizer production facility, Florida

3,199

22

28.99

76 (51–108)d

Brown and Bloom, 1987

Uranium enrichment plant, Portsmouth, OH

5,773

125

146.2

85 (71–102)

Dupree et al., 1987

Uranium processing plant, Buffalo, NY

995

74

70.1

106 (83–132)

Checkoway et al., 1988

Y-12 uranium materials fabrication plant, Oak Ridge, TN

6,781

196

193.4

101 (88–117)

Frome et al., 1990

Y-12 and K-25 uranium enrichment facilities and research laboratory, Oak Ridge, TN

28,008

2,207

2,108

105 (101–109)b

Ritz, 1999

Uranium processing plant, Ohio

4,014

332

303.6

109 (98–122)

aStudy Group comprised of white millers.

bThe confidence interval was calculated by the committee; it was not stated in the study.

cStudy Group comprised of males in industrial jobs.

d90% CI. 131

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×

TABLE 4.9 Lung Cancer Mortality

Reference

Study Site

Study Group (n)

No. of Observed Deaths

No. of Expected Deaths

SMR (95% CI)

Gradient of Risk with Increased Radiationa

Disease Classification

Wagoner et al., 1964

Uranium mills and mines, Colorado Plateau

611b

0

1.9

0

Not stated

International Lists, 6th Revision: 160–164

Archer et al., 1973a

Uranium mills, Colorado Plateau

662

4

4.26

94 (−3 to 191)

Not stated

International Lists, 6th Revision: 160–164

Polednak and Frome, 1981

Y-12 uranium processing plant, Oak Ridge, TN

18,869

324

296.47

109 (97–121)c

No gradient of risk

Lung cancer

Hadjimichael et al., 1983

Nuclear fuel fabricating plant, Connecticut

2,613d

14

14.7

95 (52–160)

No gradient of risk

ICDA-8:160–163

Waxweiler et al., 1983

Uranium mills, Colorado Plateau

2,002

26

31.4

83 (54–121)

Not stated

ICD-7:162–163

Stayner et al., 1985

Phosphate fertilizer production plant, Florida

3,199

10

8.85

113 (61–192)e

Not stated

Trachea, bronchus, lung

Brown and Bloom, 1987

Uranium enrichment plant, Portsmouth, OH

5,773

48

54.6

88 (65–117)

No gradient of risk

ICD-7:160–164

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×

Dupree et al., 1987

Uranium processing plant, Buffalo, NY

995

21

21.7

97 (60–148)

Not stated

ICDA-8:162–163

Checkoway et al., 1988

Y-12 uranium materials fabrication plant, Oak Ridge, TN

6,781

89

65.4f

136 (109–167)

Yes, if zero latency is assumed No, if 10-year latency is assumed

ICD-8:162–163

Frome et al., 1990

Y-12 and K-25 uranium enrichment facilities and research laboratory, Oak Ridge, TN

28,008

850

667.99

127 (120–135)c

Not stated

ICDA-8:162–163

Ritz, 1999

Uranium processing plant, Ohio

4,014

112

111.03

101 (83–121)

Yes

ICDA-8:162

NOTE: ICD = International Classification of Diseases; ICDA = International Classification of Diseases, Adapted.

aThe committee examined study results to see if there was a gradient of increased risk with increased levels of radiation.

bStudy Group comprised of white millers.

cThe CI was calculated by the committee; it was not stated in the study.

dStudy Group comprised of males in industrial jobs.

e90% CI.

fThe number of expected deaths was calculated by the committee; it was not stated in the study.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×
Portsmouth Uranium Enrichment Workers (Brown and Bloom, 1987)

This study found an SMR for lung cancer of 88 (48 observed, 54.6 expected; 95% CI 65–117). Additionally, the mortality for the two subcohorts who had higher exposure to uranium based on job categorization (as categorized by urine uranium levels) showed similar SMRs. The SMR was lower in the heavily exposed subcohorts than in the entire cohort, which is evidence against a meaningful association. There was no pattern of increasing cancer mortality with longer employment or when assuming a 15-year latency period.

The level of exposure of this cohort was relatively low. Only 50 percent worked at the plant more than 5 years, and the turnover of employees was 15–25 percent every 5 years. Further, the study did not have the power to detect small differences in increased risk of lung cancer for several reasons: the period of follow-up was relatively short (a maximum of 28 years and only 17 years for 40 percent of the cohort); according to the urinary uranium levels, relatively few workers had high levels of exposure to uranium; and members of the cohort were relatively young at the end of the follow-up period.

Uranium Processing Workers—Linde Air Products Company (Dupree et al., 1987)

There was no increase in lung cancer deaths in this cohort (21 observed, 21.7 expected; SMR 97, 95% CI 60–148). Results for lung cancer deaths were similar when the standard of comparison was white male residents of Erie and Niagara counties. Of the employees studied, 38 percent had an annual internal exposure that exceeded 100 mSv (10 rem) per year. The cohort of 995 workers was relatively young, with 64 percent aged 16–35 years at the date of hire. The vast majority of employees began work from 1943 to 1945, and 56 percent worked less than a year. A weakness of the study is the small number of workers, which means that the comparison of heavily exposed workers to less exposed workers lacked the power to detect small differences between the two groups.

Oak Ridge Workers (Polednak and Frome, 1981)

This study of workers at the Oak Ridge uranium processing plant from 1943 to 1947 found an SMR for lung cancer of 109 (95% CI 97–121). These numbers changed only slightly after corrections for incomplete ascertainment of deaths. For the 2,051 men who worked in the areas most highly exposed to uranium dust (first stage chemistry areas), the SMR was 97 for lung cancer. Lung cancer results were similar when analyses were restricted to men who had worked in heavily exposed areas for a year or more; based on 66 observed cases, the SMR was 106. Results were also similar when unexposed workers at Oak Ridge were used as the comparison group. The only suggestion of an increased risk of lung cancer was seen when men working in the heavily exposed areas were subdivided

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

by age at first employment. For those who were 45 years of age or more at hire the relative risk was 151 (95% CI 101–231), but for those younger than age 25 at hire the relative risk was 29 (95% CI 1–82) compared to nonexposed workers.

Because of the large size of this study and the high exposures experienced by many of the men, the lack of evidence for an increase in cancer risk is informative. However, the authors were not able to control for potentially important risk factors such as cigarette smoking, and they did not specifically test to see if cancer rates increased with longer periods of time after exposure. Further studies have evaluated this cohort (see below).

Fernald Feed Materials Production Center Workers (Ritz, 1999)

The author did not observe an increase in lung cancer deaths in this study; there were 112 observed and 111 expected deaths (SMR 101, 95% CI 83–121). However, the author made several new observations about the dose–response relationship and the possible interrelationship of external and internal radiation exposure, as shown in Table 4.10.

The author found that an external radiation dose greater than 100 mSv increased cancer mortality for all cancers, lung cancer, and radiation-associated cancers. External radiation dose increased mortality for all cancers and for lung cancer in several analyses in which the models were adjusted for exposure to cutting oil and trichlorethylene, and focused on workers whose exposure occurred after age 40, or when radiation doses were lagged by more than 10 years. Internal dose also affected cancer mortality. Internal doses of ≥200 mSv lagged by 15 years nearly doubled respiratory tract cancer mortality compared to the referent category of <10 mSv internal exposure. There were slight increases in bladder and kidney cancer deaths with increasing internal exposures, but there was no indication of an effect of increased internal radiation on hematopoietic or lymphoid cancers or colon cancer. Finally, the author combined internal and external radiation doses and showed an increase in lung cancer mortality when the internal dose exceeded 200 mSv at the same time that external dose exceeded 50 mSv.

Several aspects of this study raise concern about its interpretation. First, relatively few workers experienced high levels of external radiation exposure, with no one receiving more than 300 mSv, only 2.6 percent of the workers receiving more than 100 mSv, and 69 percent receiving less than 10 mSv. Thus, the number of cases associated with substantial external radiation exposure was small. Only 12 cancer deaths occurred in workers with greater than 100-mSv external radiation exposure. Only 18 deaths from cancer occurred in those with greater than 100-mSv internal radiation exposure. Second, a doubling of the death rate was associated with an internal radiation dose increment of 100 mSv per year, a surprisingly strong effect from a very small change in radiation exposure. Third, with internal radiation dose, there was no increase in risk of respiratory cancer after taking account of the lag period. Fourth, the highest

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×

TABLE 4.10 Combined Effects of External and Internal Radiation Dose on Lung Cancer Mortality

 

Internal Dose

 

<100 mSv

≥100 and <200 mSv

≥200 mSv

External Dose (mSv)

No. of Deaths

RR (95% CI)

No. of Deaths

RR (95% CI)

No. of Deaths

RR (95% CI)

<50

 

0-year lag

84a

1.0

6

0.72 (0.31–1.67)

0

 

15-year lag

90a

1.0

6

1.24 (0.53–2.89)

0

 

50–99

 

0-year lag

8

1.36 (0.65–2.83)

5

1.36 (0.54–3.40)

1

7.68 (1.06–55.7)

15-year lag

9

2.03 (1.0–4.14)

2

1.28 (0.31–5.32)

2

18.0 (4.32–74.9)

≥100

 

0-year lag

3

2.28 (0.71–7.31)

3

1.42 (0.44–4.54)

2

5.87 (1.42–24.2)

15-year lag

1

1.53 (0.21–1.17)

1

2.01 (0.28–14.7)

1

17.7 (2.36–133)

NOTE: RR = relative risk.

aThe referent comparison group for calculating the relative risk in the other groups.

SOURCE: Ritz, 1999.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

SRRs, in workers with high levels of both external and internal radiation, occurred with one or two deaths per category (albeit with 95% CI that did not overlap 1). Nevertheless, the data, based on well-characterized exposure levels in this study, do suggest that after controlling for external dose, internal doses up to 200 mSv are not associated with excess risk of lung cancer.

The strengths of the Fernald cohort study include direct measures of individuals’ radiation exposure, a sound method of analysis, and the use of internal controls. Analysis of the Fernald cohort suggests that high-level exposure to ionizing radiation increases the rate of lung cancer. However, a very small number of deceased workers received the relatively high doses of radiation (>200 mSv of internal exposure) that were the basis of the possible relationship between radiation dose and lung cancer death. Mortality ratios based on one or two deaths are statistically weak; therefore, the study’s suggestive findings require replication in a larger cohort.

Oak Ridge Nuclear Materials Fabrication Workers (Checkoway et al., 1988)

This study of Oak Ridge workers from 1947–1979 found an SMR of 136 (95% CI 109–167) for lung cancer when compared with death rates in U.S. white men during 1947 to 1979. Alternate analyses assumed 0- and 10-year latencies between exposure and mortality. Internal dose–response analyses for lung cancer mortality were based on a small number of cases in each category, so that the confidence intervals were wide. When the authors assumed no latency, there were nonsignificant increases in lung cancer risk at higher exposures. When the authors assumed a 10-year latency, there was no dose–response relationship. The study did show a dose–response gradient for gamma radiation for workers who received ≥ 5 rem of alpha radiation.

This study does not provide evidence of increased cancer risks for exposure to low levels of radiation. The borderline significant increased risk of lung cancer occurred with an assumed short latency period between radiation exposure and diagnosis. Radiation-induced cancer typically shows a minimum latency of 10 years between exposure and increased incidence, and in this analysis there was no increased risk with 10 years’ latency, which suggests that the modest elevation in lung cancer deaths is due to chance or to other factors. Although the radiation exposure data are a major strength of this study, the interpretation of findings for lung cancer risk is limited by the lack of data on smoking and other potential risk factors.

Oak Ridge Uranium Processing and Laboratory Workers (Frome et al., 1990)

This study of uranium enrichment facility and energy research laboratory workers found an SMR for lung cancer of 127, based on 850 observed deaths

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

and 667.99 expected deaths. The cohort had elevated rates of lung cancer deaths after 5 years of follow-up, and the trend increased throughout the follow-up period at a rate of 1.44 percent per year. This study did not have detailed exposure data on individual workers and measured individual exposure (yes/no) by whether or not the individual worked at least 30 days in a job or department that had contact with radioactive materials. In the multivariate analysis, the strongest predictor of lung cancer mortality was socioeconomic status; professional workers had a substantially lower rate of lung cancer mortality. Mortality due to lung cancer was not significantly associated with the exposure measure (whether or not there was exposure to radiation for 30 days or more), and the risk decreased with increasing duration of employment (this trend was significant for all cancers but not significant for lung cancer). However, the exposure measure was of limited validity since it reduced variation in workers’ exposure by classifying them according to exposure in one site rather than their entire work history. Detecting an effect of an agent is more difficult when anything reduces variation in individuals’ exposure.

The multivariate analysis suggests that exposure to radiation was not the explanation for the increase in lung cancer mortality since the coefficient for exposure to radiation was not significantly different from 1. Furthermore, the analysis suggests that other factors related to socioeconomic status (SES) may account for the association with lung cancer deaths. In particular, being a professional worker rather than an unskilled worker reduced the likelihood of dying from lung cancer, because this predictor variable had a large negative coefficient that was three times its standard deviation. There are a number of factors that could account for the differences in the socioeconomic variable including different rates of smoking or jobs with higher levels of exposure in lower SES individuals.

Four Uranium Processing Operations (Dupree et al., 1995)

The salient feature of this case-control study was a thorough dose–response analysis (Table 4.11). Overall, there was no apparent relationship between internal radiation dose, lagged for 10 years, and lung cancer mortality. The only suggestion of an increased risk was for a cumulative internal dose of 25 cGy or more; the relative risk was 2.05, but this figure had extremely wide confidence intervals (0.20–20.70) owing to the very small number of cases in this group. Notably, in the next highest category of exposure, 5 to <25 cGy, the relative risk was 0.64 (CI 0.37–1.12). Because smoking data were not available for all persons, it was not possible to adjust for smoking when examining the relation between exposure at 25 cGy or more and lung cancer risk. There was also no overall relationship between external radiation exposure and lung cancer deaths except when the data were restricted to the small number of persons hired at 45 years of age or older (n = 64 pairs). Even then, the confidence interval was very wide (95% CI 31–1,411), and there was no suggestion of any trend with increasing dose.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

TABLE 4.11 Dose–Response Relationship for Lung Cancer and Radiation Exposure

Internal Radiation Lung Dose (cGy)

Relative Risk of Lung Cancer (95% CI)

0.05−

0.25−

0.5−

2.5−

5.0−

25+

Unadjusted (787 pairs)

1.03

(0.73–1.45)

0.57

(0.38–0.85)

0.85

(0.58–1.14)

0.82

(0.52–1.30)

0.64

(0.37–1.12)

2.05

(0.20–20.70)

Adjusted for smoking (166 pairs)

0.47

(0.19–1.18)

0.46

(0.16–1.28)

0.64

(0.12–1.02)

0.34

(0.12–1.02)

0.36

(0.09–1.38)

 

 

SOURCE: Dupree et al., 1995.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

This study population overlaps considerably with the studies by Ritz (1999), Checkoway and colleagues (1988), and Frome and colleagues (1990) (Table 4.4). The overlap with the Ritz study is relatively minor. Only 51 of Dupree’s 787 cases of death from lung cancer were first employed at Fernald, the site of the Ritz study. On the other hand, the overlap with the study by Frome and colleagues is substantial. Five hundred and sixty-seven of Dupree’s 787 cases were first employed at TEC. Frome’s study population had 850 cases of lung cancer and derived 54 percent of its study population from TEC.

This study has several important strengths including its thorough dose–response analysis, large number of lung cancer cases, and thorough approach to estimating individual exposures, which are based on a variety of sources. The data provide strong evidence that lung cancer risk does not increase up to 25-cGy cumulative internal radiation exposure (primarily uranium dust in these operations). The data do not allow an informative examination of cumulative exposures greater than 25 cGy.

Conclusions on Lung Cancer

Lung cancer mortality has been the focus of attention in many cohort studies of workers employed in the uranium processing industry. Many of these studies were large and had a long period of follow-up. As shown in Table 4.9, lung cancer mortality was not increased among occupationally exposed persons in most of these cohorts, although several cohorts do show a small increase in lung cancer mortality. Because of the large number of cases of lung cancer, the committee closely analyzed the strengths and weaknesses of the studies and focused on the best quality studies in trying to form its conclusions about the effect of radiation exposure on lung cancer.

Several studies played little role in forming the committee’s conclusions due to poor exposure measures or other methodologic issues. The studies by Stayner and colleagues (1985) and Archer and colleagues (1973a) did not measure exposure to radiation and had very short periods of follow-up. The study by Polednak and Frome (1981) had the largest cohort and is useful for placing an upper bound on the possible effect of radiation on relatively uncommon cancers such as bone cancer and lymphatic cancer. However, for purposes of forming a highly exposed comparison group, this study classified workers according to the job in which they had the highest exposure rather than measuring the cumulative radiation exposure of individual workers, either directly or by modeling it from the worker’s job history. This approach tends to bias the study towards failing to see an effect of radiation. The studies by Hadjimichael and colleagues (1983) and Checkoway and colleagues (1988) used good methods but had relatively few cases, no doubt in part due to the relatively short period of follow-up.

The strongest studies used internal controls, used multivariate analysis to adjust for possible confounders, had at least 30 years of follow-up, and measured the cumulative radiation exposure of individual workers (with the exception of the study by Frome and colleagues [1990], which classified workers’

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

radiation exposure by the job that had the highest exposure). Thus, the committee placed the greatest weight on the studies of Ritz (1999), Dupree et al. (1995), and Frome et al. (1990).

In the large study of Oak Ridge employees by Frome and colleagues (1990), the entire group experienced a small increase in lung cancer mortality. Despite its shortcoming in measuring radiation exposure, the committee felt this study was important because of its large size and multivariate analysis. The analysis showed that radiation exposure was not associated with lung cancer mortality. It also demonstrated the relative importance of several confounders. Socioeconomic status strongly predicted lung cancer risk. Further, the large number of lung cancer cases (850) minimized the chance of a false-negative conclusion. Its study population does overlap with that of Dupree and colleagues (1995).

The study by Dupree and colleagues (1995) was important because it combined data from four separate studies and utilized quantitative estimates of individual cumulative exposures to uranium to form a dose–response analysis. The large number of cases of deaths from lung cancer (787) made it possible for Dupree and colleagues to perform a detailed dose–response analysis, while adjusting for confounders. The large number of lung cancer deaths also reduced the chance of a false-negative conclusion. The study population overlapped with the study populations in the studies by Ritz (1999) and Frome and colleagues (1990) (Table 4.4). The committee did not give these studies equal independent weight in forming its conclusions. The Dupree study found that the dose–response analysis did not suggest any increase in lung cancer risk up to 25 cGy. Above this level, there were too few cases to draw any conclusions.

The strongest suggestion of an association with lung cancer appeared in the recent report by Ritz (1999), in which large and statistically significant increases in lung cancer mortality occurred in the small group of workers with a cumulative internal dose of 200 mSv or more. The committee viewed this finding with caution because the subgroup with the elevated risk had only three cases of lung cancer and because the author could not adjust for cigarette smoking, which had been an important factor in the Dupree study. Further, workers in this study may also have been exposed to other sources of radiation (e.g., radium and thorium). Nevertheless, the data based on the well-characterized exposure levels in this study do suggest that after controlling for external dose, internal doses up to 200 mSv are not associated with excess risk of lung cancer.

Although studies of uranium miners have shown increased lung cancer mortality, the effect of uranium is difficult to interpret because the miners were simultaneously exposed to radon progeny, a known cause of lung cancer (NRC, 1999).

The lack of direct information on individual workers’ exposure to cigarette smoke is an important shortcoming of these studies, since cigarette smoking is generally a predictor of lung cancer. However, the apparent lack of a clear association between increased uranium exposure and increased rates of lung cancer lessens the burden of this shortcoming. If there had been an apparent positive association, it would be important to understand the relative contribution of ura-

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

nium and cigarette smoking and the impact of exposure to other sources of radiation or other potential hazards.

The committee concludes that there is limited/suggestive evidence of no association between exposure to uranium and lung cancer at cumulative internal dose levels lower than 200 mSv or 25 cGy. However, there is inadequate/insufficient evidence to determine whether an association does or does not exist between exposure to uranium and lung cancer at higher levels of cumulative exposure.

Lymphatic Cancer

The lymphatic system is an important potential target for uranium radiation because inhaled insoluble uranium oxides can remain up to several years in the hilar lymph nodes of the lungs. Studying the effect of uranium exposure on lymphatic cancer is more difficult than studying lung cancer because lymphatic cancer is much less common. Thus, the small number of cases magnifies the effects of all of the methodological concerns cited in the foregoing discussion of lung cancer data. The small number of expected cases means wide confidence intervals for SMRs and far too few cases for the subgroup analyses that are necessary to establish useful dose–response relationships.

Lymphomas are neoplastic transformations of cells that reside principally in lymph nodes. In view of the localization of inhaled uranium oxides in lung lymph nodes, uranium should be associated with malignant lymphomas if it is associated with any lymphoid malignancy. Table 4.12 shows the results of the epidemiologic studies that provide information on the relationship between uranium exposure and lymphoid malignancy. Some studies provided results on specific types of lymphoid malignancies while others grouped the data.

Studies of mill workers on the Colorado Plateau found an increase in lymphoid cancer deaths. The Archer et al. (1973a) study found an SMR of 392 in a small sample of uranium millers (4 cases observed versus 1.02 expected). The four cases were in millers who had not worked in the furnace area with the highest levels of exposure to uranium and vanadium. The Waxweiler et al. (1983) study with a larger cohort of millers found 5 observed and 4.2 expected deaths (SMR = 119, 95% CI 21–217) due to lymphosarcoma, reticulosarcoma, or Hodgkin’s disease. However, four of the deaths due to lymphatic cancers were of employees with less than 5 years of employment, and the increase in the SMR was not statistically significant. Further, other potential exposures including vanadium and thorium could have caused the increased cases of lymphoid malignancy. In most of the studies listed in Table 4.12, the number of deaths due to lymphatic cancer has been small and the deviations from the expected number of deaths have been consistent with random variation. The Fernald cohort (Ritz, 1999) showed an increased SMR (129), but the confidence interval (91–177) included 100. By far the largest study was the Polednak and Frome (1981) report of the Oak Ridge experience, which included the period early in the nuclear industry in which workers were exposed to

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

relatively high amounts of inhaled uranium. In that study there were 37 deaths compared to 61 expected (SMR = 61).

Conclusions on Lymphatic Cancer

The number of cases is too small and the confidence intervals for SMRs are too wide to draw any conclusions about the association between uranium exposure and lymphoid malignancy. In particular, it is not possible to do subgroup analyses linking different levels of uranium exposure to the death rate from lymphoid malignancy. In this instance, where the evidence is all epidemiological in nature, concluding that an association may not exist would require some evidence that the incidence of lymphoid malignancy remains the same as the level of exposure increases.

The committee concludes that there is inadequate/insufficient evidence to determine whether an association does or does not exist between exposure to uranium and lymphatic cancer.

Bone Cancer

Like the lymphatic system, bone is an important potential target for the effects of uranium because uranium is distributed to the bone, replaces calcium in bone matrix, and may remain in the bone for several years. Studying the effects of uranium exposure on bone cancer is even more difficult than studying lymphoid malignancy because bone cancer is rarer, which means wide confidence intervals for the SMRs and far too few cases to establish useful dose–response relationships. The studies of bone cancer are listed in Table 4.13. According to the BEIR IV report (NRC, 1988), if there were carcinogenic effects in humans from exposure to uranium it would most likely result in increased risk of bone sarcoma (i.e., there is biological plausibility due to the deposition of uranium in bone). However, studies to date have not found an increase in bone cancers.

Conclusions on Bone Cancer

Bone cancer is rare; thus, the number of cases in all studies is small. For this reason, there is insufficient evidence to determine whether an association exists between acute or chronic exposure to uranium and bone cancer. Nevertheless, the large size of the Oak Ridge cohort (Polednak and Frome, 1981) does provide some evidence that exposure to uranium is not associated with a large excess risk of bone cancer (e.g., a relative risk of 3.0 or greater).

The committee concludes that there is inadequate/insufficient evidence to determine whether an association does or does not exist between exposure to uranium and bone cancer.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

TABLE 4.12 Lymphatic Cancer Mortality

Reference

Study Site

Study Group (n)

No. of Observed Deaths

No. of Expected Deaths

SMR (95% CI)

Disease Classification

Archer et al., 1973a

Uranium mills, Colorado Plateau

662

4

1.02

392 (194–590)a

International Lists, 6th Revision: 200–203, 205

Polednak and Frome, 1981

Y-12 uranium processing plant, Oak Ridge, TN

18,869

37

61

61 (35–86)a

Lymphosarcoma, reticulum cell sarcoma, Hodgkin’s, other lymphatic

Hadjimichael et al., 1983

Nuclear fuel fabricating plant, Connecticut

2,613 males in industrial jobs

2

3.1

65 (7–234)

ICDA-8:200–203

Waxweiler et al., 1983

Uranium mills, Colorado Plateau

2,002

5

4.2

119 (21–217)a

ICD-7:200–201

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

Brown and Bloom, 1987

Uranium enrichment plant, Portsmouth, OH

5,773

12

7.7

156 (84–228)a

ICD-7:200–201

Dupree et al., 1987

Uranium processing plant, Buffalo, NY

995

6

6.8

89 (32–193)

ICDA-8:200–209

Checkoway et al., 1988

Y-12 uranium materials fabrication plant, Oak Ridge, TN

6,781

15

13.1

114 (59–169)

ICD-8:200–203, 208b

Frome et al., 1990

Y-12 and K-25 uranium enrichment facilities and research laboratory, Oak Ridge, TN

28,008

40

48.23

83 (54–112)a

ICDA-8:202–203, 208

Ritz, 1999

Uranium processing plant, Ohio

4,014

38

29.5

129 (91–177)

ICDA-8:200–208

NOTE: ICD = International Classification of Diseases; ICDA = International Classification of Diseases, Adapted.

aThe confidence interval was calculated by the committee; it was not stated in the study.

bThe causes of death included were lymphosarcoma, reticulosarcoma, Hodgkin’s disease, and other lymphatic cancers.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

TABLE 4.13 Bone Cancer Mortality

Reference

Study Site

Study Group (n)

No. of Observed Deaths

No. of Expected Deaths

SMR (95% CI)

Disease Classification

Polednak and Frome, 1981

Y-12 uranium processing plant, Oak Ridge, TN

18,869

6

6.68

90 (13–167)a

Bone cancer

Hadjimichael et al., 1983

Nuclear fuel fabricating plant, Connecticut

2,613 males in industrial jobs

1

0.5

206 (3–1140)

ICDA-8:170–171

Frome et al., 1990

Y-12 and K-25 uranium enrichment facilities and research laboratory, Oak Ridge, TN

28,008

11

10.35

106 (44–168)a

ICDA-8:170

Ritz, 1999

Uranium processing plant, Ohio

4,014

0

0.99

0

ICDA-8:170

NOTE: ICDA = International Classification of Diseases, Adapted.

aThe confidence interval was calculated by the committee; it was not stated in the study.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

Nonmalignant Renal Disease

Mortality Risk

Studies of mortality rates from nonmalignant renal disease in occupational cohorts exposed to uranium appear in Table 4.14. In the seven cohort studies of occupational exposure and mortality from renal disease, only one study shows an excess mortality from renal disease. In that study (Waxweiler et al., 1983), all of the cases were in short-term workers, and four of the six deaths occurred within 8 years of initial employment at the uranium mill, which implies that the apparent excess mortality is not related to the extent of exposure to uranium. In most of these studies, the authors measured death rates from all genitourinary causes instead of focusing on diseases of the kidney, the part of the genitourinary tract in which uranium accumulates. The largest study (Frome et al., 1990) had 52 deaths from chronic nephritis, compared with 52.65 expected deaths (SMR = 99).

Morbidity Studies

The potential effect of uranium exposure on kidney function in humans has been examined in studies with varying doses and with different routes of exposure. This information includes case reports and studies with small numbers of subjects.

Intravenous injections. Hodge and colleagues (1973) described six patients with normal kidney function who were injected with uranyl nitrate (6.3–109 μg/kg over a 1- to 2-day period). Transient proteinuria and catalasuria occurred 4–6 days after the injection in the two patients who received the highest dose (>42 μg/kg). The authors used these observations to estimate the uranium dosage that is associated with minimal tubular kidney damage.

Bernard (1958) administered 4–50 mg of uranium compounds intravenously to eight terminally ill patients with brain tumors. Transient proteinuria and catalasuria occurred in patients receiving uranium doses >70.9 μg/kg. There was no evidence at autopsy of acute damage to the renal tubules. Based on these observations, the author estimated that the minimal uranium dose that will produce catalasuria and albuminuria is about 0.1 mg/kg.

Oral exposure. There are a few case studies with limited information about the effects of orally administered uranium compounds. Oral ingestion of uranyl nitrate at dosages as high as 925 mg, three times per day, did not cause abnormalities on routine urinalysis (Morrow et al., 1980). A volunteer who orally ingested 1 g of uranyl nitrate (0.47 g uranium) experienced vomiting, diarrhea, and slight albuminuria (Stopps and Todd, 1982). In the only other reported oral ingestion of uranium salts with follow-up measurements, 10.8 mg of uranyl nitrate had no effects on kidney function in four patients (Stopps and Todd, 1982).

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

TABLE 4.14 Nonmalignant Renal Disease Mortality

Reference

Study Site

Study Group (n)

No. of Observed Deaths

No. of Expected Deaths

SMR (95% CI)

Disease Classification

Polednak and Frome, 1981

Y-12 uranium processing plant, Oak Ridge, TN

18,869

30

39.14

77 (45–109)a

Chronic nephritis

Waxweiler et al., 1983

Uranium mills, Colorado Plateau

2,002

6

3.6

167 (60–353)

ICD-7:592–594

Stayner et al., 1985

Phosphate fertilizer production plant, Florida

3,199

2

2.27

88 (16–277)b

Diseases of the genitourinary system

Brown and Bloom, 1987

Uranium enrichment plant, Portsmouth, OH

5,773

3

5.6

54 (11–156)

ICD-7:590–594, 600, 602, 604, 610-637, 650–652

Checkoway et al., 1988

Y-12 uranium materials fabrication plant, Oak Ridge, TN

6,781

8

11.1

72 (31–142)

ICD-8:580–629

Frome et al., 1990

Y-12 and K-25 uranium enrichment facilities and research laboratory, Oak Ridge, TN

28,008

52

52.65

99 (71–126)a

ICDA-8:582

Ritz, 1999

Uranium processing plant, Ohio

4,014

3

14.25

21 (4–129)

ICDA-8:580–629

NOTE: ICD = International Classification of Diseases; ICDA = International Classification of Diseases, Adapted.

aThe confidence interval was calculated by the committee; it was not stated in the study.

b90% CI.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

Occupational uranium exposure. Thun and colleagues (1985) compared kidney function in uranium mill workers (39 subjects) and a control group consisting of cement plant workers (36 subjects matched for sex, race, and age). In 115 of 535 (21 percent) of urinary uranium assays, mill workers had levels >30 μg/L (<1 μg U/g kidney weight). Uranium workers excreted more beta 2-microglobulin and five amino acids than the control group. The amount of proteinuria was small. The clearance of beta2-microglobulin, relative to that of creatinine, increased with increasing length of time that the uranium workers had spent in the yellowcake drying and packaging area, the work area with the highest exposures to soluble uranium. The age of the workers did not account for this relationship. Serum beta2-microglobulin was significantly higher in the uranium workers, an effect that was not due to reduced glomerular function, since glomerular function (serum creatinine and creatinine clearance) was the same in uranium workers and controls. The aminoaciduria was due to increased excretion of dicarboxylic amino acids and methionine by the uranium workers. The data suggest a reduction in renal proximal tubular reabsorption of amino acids and low-molecular-weight proteins, which is consistent with uranium nephrotoxicity.

The U.S. Uranium Registry reevaluated the intake and deposition of uranium in three men 38 years after they had been accidentally exposed to soluble uranium compounds in an explosion in 1944 (Kathren and Moore, 1986). The initial deposition of uranium in the lungs was approximately 40–50 mg, based on incomplete urinary excretion data that were obtained shortly after the accident (Eisenbud and Quigley, 1956). Two of the workers had extensive medical and health physics examinations 38 years after the accident. There was no detectable uranium, and the workers had no physical findings or renal function abnormalities that could be attributed to uranium exposure.

Lu and Zhao (1990) reported on renal function in a male worker 64 days after a 5-minute accidental exposure to uranium tetrafluoride powder (an estimated radioactivity of 6,905 Bq/m3). The worker showed a significant increase in urinary protein, nonprotein nitrogen, amino acid nitrogen and creatinine, and phenolsulfonphthalein. These abnormal levels were present up to 3 years later but gradually returned to normal values.

Boback (1975) describes uranium excretion and clinical urinalysis in accidental exposures to an estimated 100–200 μg/kg of soluble forms of uranium. Despite an initial urine uranium excretion of 7–14 mg per day, there was no renal injury as measured by urinary protein, sugar, pH, specific gravity, or excretion of formed elements such as red blood cells or tubular casts.

Drinking water exposure. Zamora and colleagues (1998) compared the effects of uranium on kidney function in two communities, one of which had private wells supplied by underground water with a uranium content higher than the Canadian drinking water guideline. The authors divided the subjects into two groups: a low-exposure group (n = 20), whose drinking water contained <1 μg U/L, and a high-exposure group (n = 30), whose drinking water contained uranium levels from 2 to 781 μg U/L. In the low-exposure group, time of residence

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

in a locale with uranium-contaminated drinking water varied from 1 to 33 years, and in the high-exposure group, it varied from 3 to 59 years. The indicators of kidney function included urinary excretion of glucose, creatinine, protein, and beta2-microglobulin (BMG). The markers for cell toxicity were alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), lactate dehydrogenase (LDH), and N-acetyl-beta-D-glucosaminidase (NAG). For males and females, the urinary glucose levels differed in the high- and low-exposure groups, and the amount increased with increasing uranium intake. Increases in ALP and BMG also correlated positively with increasing uranium intake. In contrast, there was no evidence for glomerular injury, as measured by normal serum creatinine concentration and no proteinuria. The authors suggest that intakes of uranium between 0.004 μg/kg and 9 mg/kg body weight are associated with altered kidney function but that the proximal tubule, rather than the glomerulus, is the site of this effect.

Fragments of depleted uranium. Uranium concentrations in the urine of Gulf War veterans have been found at higher levels in those with retained DU shrapnel than in those without when measured at 2, 4, and 7 years after first exposure (Hooper et al., 1999; McDiarmid et al., 2000). A recent study found that levels of urinary uranium ranged from 0.01 to 30.74 μg/g creatinine4 in veterans with retained shrapnel fragments (McDiarmid et al., 2000). The concentration of uranium in the urine of nonexposed veterans ranged from 0.01 to 0.047 μg/g creatinine. Despite much higher levels of urinary uranium in the veterans with retained fragments of DU, renal function parameters (serum creatinine, BMG, and retinol-binding and urine proteins) were the same in the two groups, strongly suggesting that years of exposure to uranium does not damage the kidneys (McDiarmid et al., 2000).

Conclusions on Nonmalignant Renal Disease

Although uranium is a heavy metal that causes transient renal dysfunction, the preponderance of evidence indicates little or no clinically important renal effects of exposure to uranium. A few studies have shown changes in renal function (Lu and Zhao, 1990; Zamora et al., 1998), but the number of cases has been quite small. Perhaps the strongest evidence is the absence of kidney damage in workers that had been exposed to high levels of soluble uranium compounds (Kathren and Moore, 1986) and in veterans exposed to DU from embedded shrapnel. Kidney function was normal in Gulf War veterans with embedded DU fragments, years after exposure, despite urinary uranium concentrations up to 30.74 μg/g creatinine (McDiarmid et al., 2000).

4  

The unit of measurement for urinary uranium is expressed as micrograms per gram creatinine.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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The committee concludes that there is limited/suggestive evidence of no association between exposure to uranium and clinically significant renal dysfunction.

Nonmalignant Neurological Disease

The committee carefully examined the studies on neurological outcomes as these outcomes are of interest in the study of Gulf War-related illnesses. Uranium has been shown in several animal studies to enter the brain of animals exposed through either inhalation or implantation of fragments of depleted uranium (see toxicology section). The mortality experiences of uranium processing workers (Table 4.15) generally show no excess neurologic disease mortality risks, with the exception of one study in which workers at a nuclear fuels fabrication plant had an SMR of 346 (95% CI 126–753) for death from diseases of the nervous system (Hadjimichael et al., 1983). There were 6 deaths from diseases of the central and peripheral nervous system and only 1.7 expected deaths. However, the number of cases was small, and the 95% CI was very wide. It is important to note that mortality is not a good measure for neurologic outcomes as they may not be the cause of death noted on the death certificate.

Several case studies have examined neurological outcomes or symptoms. Moore and Kathren (1985) studied three individuals 38 years after they were exposed to high concentrations of uranium (estimates of initial lung deposition of 40–50 mg of uranium) after an industrial accident. Shortly after the accident an examination found “mental status changes believed in excess of what which would be caused by fear reaction.” No other details were provided. Examination of two of these individuals 38 years after the accident revealed no clinical findings attributable to uranium exposure (Moore and Kathren, 1985; Kathren and Moore, 1986). Neurological symptoms were also absent in an examination of a male worker 6 days after he had a 5-minute accidental exposure to uranium tetrafluoride powder (an estimated radioactivity of 197 nCi/m3; 6,905.6 Bq/m3) (Lu and Zhao, 1990).

A case report described a 44-year-old man who developed foot cramps, leg pain, a gait disorder, and a tendency to fall backward (Goasguen et al., 1982). The symptoms progressed and he developed an extrapyramidal syndrome with ataxia, nystagmus, and peripheral neuropathy. Although the authors claimed that the etiology of his illness was related to a bar of metallic uranium that he handled frequently during the first 3 years of his illness, they presented no estimates of the level of exposure of this patient to uranium and did not make a convincing argument for its causal role in his illness.

The committee found no studies of neurological symptoms after human exposure to uranium by either the oral or the dermal route.

McDiarmid and colleagues (2000) studied a cohort of Gulf War veterans who had fragments of depleted uranium in their soft tissues. As noted in the preceding section, the veterans excreted substantial amounts of uranium, presuma-

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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TABLE 4.15 Nonmalignant Neurologic Disease Mortality

Reference

Study Site

Study Group (n)

No. of Observed Deaths

No. of Expected Deaths

SMR (95% CI)

Disease Classification

Polednak and Frome, 1981

Y-12 uranium processing plant, Oak Ridge, TN

18,869

38

49.3

77 (49–105)a

Diseases of the nervous system

Hadjimichael et al., 1983

Nuclear fuels fabricating plant, Connecticut

2,613 males in industrial jobs

6

1.7

346 (126–753)

ICDA-8:340–359

Stayner et al., 1985

Phosphate fertilizer production facility, Florida

3,199

3

8.73

34 (9–89)b

Diseases of the nervous system

Brown and Bloom, 1987

Uranium enrichment plant, Portsmouth, OH

5,773

13

32.7

40 (21–68)

ICD-7:330–334, 345

Frome et al., 1990

Y-12 and K-25 uranium enrichment facilities and research laboratory, Oak Ridge, TN

28,008

76

81.76

93 (71–115)a

ICDA-8:320–389

NOTE: ICD = International Classification of Diseases; ICDA = International Classification of Diseases, Adapted.

aThe confidence interval was calculated by the committee; it was not stated in the study.

b90% CI.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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bly as a result of gradual dissolution of DU fragments. Results from a battery of computer-based neurocognitive tests suggest a statistical relationship between elevated urinary uranium levels and “problematic performance on automated tests assessing performance efficiency and accuracy” (McDiarmid et al., 2000). Traditional tests of neurocognitive function (pen-and-pencil tests) did not show any statistical differences in performance between the veteran cohort and a control group.

The committee found several methodological issues that make it difficult to draw firm conclusions from this study. The authors did not adequately define their neurocognitive testing methods or the method for deciding the expected level of performance. The procedures involved calculating two “impairment indexes” for each test subject—one for the automated and one for the traditional neurocognitive measures. They calculated the impairment indexes for the neurocognitive tests by dividing the total number of scores that were below the expected score by the total number of scores obtained from each test battery. However, the investigators did not indicate how they chose the cutoff value that defined “expected” performance, nor did they explain how they chose the decision cut points.

As acknowledged by the authors, the number of individuals with high uranium levels in urine was small, “and it appeared that a few veterans with complex histories may have contributed appreciably to the observed variance.” Further studies may help explain the lack of correlation between the computer-based tests, which showed abnormalities, and the standard written tests, on which the subjects performed normally. Continued follow-up of this cohort will provide insight into any potential neurocognitive effects of depleted uranium.

In summary, the evidence regarding exposure to uranium and diseases of the nervous system is not strong enough to form a firm conclusion. In studies on Gulf War veterans, the search for evidence of neurological effects will require careful neurocognitive measurements, correlation of these with clinical dysfunction, and comparison of exposed veterans to control groups chosen to illuminate various facets of the complex exposure history of Gulf War veterans.

Conclusion on Nonmalignant Neurological Disease

The committee concludes that there is inadequate/insufficient evidence to determine whether an association does or does not exist between exposure to uranium and diseases of the nervous system.

Nonmalignant Respiratory Disease

Nonmalignant respiratory effects from inhaled uranium aerosols will depend in part on where in the lung the inhaled particles come to rest. Deposition depends primarily on particle size and solubility. Particle clearance mechanisms will remove a portion of deposited particles primarily by mucociliary action, which operates in the upper respiratory tract to sweep particles up to the pharynx

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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where they are swallowed. Particles in the lower respiratory tract may dissolve or be ingested by macrophages. In general, more soluble uranium compounds pass into the bloodstream, while less soluble forms remain in the lung or in lymph nodes for months to years. Uranium processing workers are exposed to the more soluble forms of uranium such as uranyl fluoride and uranium tetrachloride, as well as insoluble oxides. Conversely, uranium miners are exposed principally to less soluble compounds, such as UO3, UO2, and U3O8, that remain in the lung for years before fully dissolving, being taken up by the circulation, and then excreted in the urine.

Epidemiologic studies of the respiratory effects of uranium particles are difficult to interpret because of exposures to other respiratory toxicants along with uranium. Workers in uranium processing plants may have concomitant exposure to chlorine; oxides of nitrogen; nickel; or hydrofluoric, sulfuric, or nitric acids.

Studies of mortality in occupational cohorts (Table 4.16) are of limited value for assessing nonmalignant respiratory disease for many reasons. Death certificate coding for nonmalignant respiratory disease is relatively inaccurate. Most studies used only the immediate cause of death as the outcome measure of exposure, rather than also reporting the prevalence of co-morbid, nonfatal illnesses. The studies grouped multiple diseases together which decreases the ability of a study to observe an association with one disease. Additionally, most retrospective cohort studies had no direct information about cigarette smoking, which is an important cause of several common respiratory diseases and would be an important confounding variable in interpreting the effect of uranium exposure on lung disease. Further, as noted above, many of the workers were exposed to multiple agents, many of which (e.g., silica) also cause lung disease. For nonmalignant respiratory disease it is important, but often more difficult, to also examine morbidity data.

Alpha radiation from chronically inhaled uranium dust could cause lung fibrosis that could plausibly increase the incidence and mortality from chronic respiratory disease. However, studies of workers in uranium mills and uranium miners do not indicate any substantial elevation in risk of death from nonmalignant respiratory disease. Several epidemiologic studies of uranium miners have reported excess nonmalignant respiratory disease mortality, but the authors attributed these effects to dust exposure and cigarette smoking (Archer et al., 1976b; Roscoe et al., 1995), although they were observed among nonsmoking miners (Roscoe et al., 1989). Despite potential additional exposures, the SMRs for nonmalignant lung disease were close to 100 in the miner cohorts reported by Muller and colleagues (1985), Nair and colleagues (1985), and Tomasek and colleagues (1994). A report of lung pathology in 22 cases of diffuse interstitial fibrosis among uranium miners found silicosis or anthrasilicosis in six cases. The authors attributed the fibrotic changes to radiation from radon progeny alpha particles in the remaining cases (Archer et al., 1998), but they could not exclude effects of other exposures (e.g., diesel particles, other dusts) as the cause of the fibrotic findings.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
×

TABLE 4.16 Nonmalignant Respiratory Disease Mortality

Reference

Study Site

Study Group (n)

No. of Observed Deaths

No. of Expected Deaths

SMR (95% CI)

Disease Classification

Polednak and Frome, 1981

Y-12 uranium processing plant, Oak Ridge, TN

18,869

340

310.11

110 (98–121)a

Diseases of the respiratory system

Hadjimichael et al., 1983

Nuclear fuels fabrication plant, Connecticut

2,613b

6

2

303 (111–659)

ICD-8:490–493

Stayner et al., 1985

Phosphate fertilizer production facility, Florida

3,199

5

7.93

63 (25–133)c

Diseases of the respiratory system

Brown and Bloom, 1987

Uranium enrichment plant, Portsmouth, OH

5,773

14

33.5

42 (23–70)

ICD-7:470–527

Dupree et al., 1987

Uranium processing plant, Buffalo, NY

995

32

21.1

152 (104–214)

ICD-8:46–519

Checkoway et al., 1988

Y-12 uranium materials fabrication plant, Oak Ridge, TN

6,781

37

48.9

76 (53–104)

ICD-8:460–519

Frome et al., 1990

Y-12 and K-25 uranium enrichment facilities and research laboratory, Oak Ridge, TN

28,008

792

634.11

125 (117–133)a

ICDA-8:460–519

Ritz, 1999

Uranium processing plant, Ohio

4,014

53

79.78

66 (50–87)

ICD-8:460–519

NOTE: ICD = International Classification of Diseases; ICDA = International Classification of Diseases, Adapted.

aThe confidence interval was calculated by the committee; it was not stated in the study.

bMales in industrial jobs.

c90% CI.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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The study of Dupree and colleagues (1987) found a significant excess risk of nonmalignant respiratory disease based on 32 deaths; Frome and colleagues (1990) also observed a significantly increased risk of nonmalignant lung disease. However, the other reports, including the larger studies of Checkoway and colleagues (1988), Polednak and Frome (1981), and Ritz (1999), which showed SMRs of less than or close to 100, do not confirm those findings. Polednak and Frome (1981) showed a small but statistically significant risk (SMR = 110), but the study is important principally because it provides important evidence against a large excess risk of nonmalignant lung disease. In this cohort, exposure was probably relatively intense because it occurred during the World War II era when the control of uranium dust was less stringent. In addition, the period of follow-up was long, and the number of expected deaths was large. None of the studies were able to control for smoking, a major causal factor in chronic respiratory disease, or other occupational exposures, which limits the interpretation of the findings.

Conclusion on Nonmalignant Respiratory Disease

The committee concludes that there is inadequate/insufficient evidence to determine whether an association does or does not exist between exposure to uranium and nonmalignant respiratory disease.

Other Health Outcomes

The information on other health outcomes in humans comes primarily from case reports of workers or other individuals accidentally exposed to large doses of uranium compounds. These health outcomes have not been examined in detail in human studies.

Gastrointestinal Effects

Accidental inhalation exposure of one individual to high levels of uranium produced transient gastrointestinal distress, characterized by loss of appetite, abdominal pain, diarrhea, and pus and blood in the stool (Lu and Zhao, 1990). A case of accidental dermal exposure to uranium (Lu and Zhao, 1990) had no reported gastrointestinal effects.

Immunotoxic Effects

The human literature lacks documentation on adverse immunological or lymphoreticular effects of uranium. The detection of systemic lupus erythematosus (SLE)-typical antibodies in quartz dust-exposed uranium miners indicates a potentially higher risk for the development of systemic autoimmune disease (Conrad et al., 1996, 1998). The authors of one report detected the 16/6 idiotype,

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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a major cross-reactive idiotype of anti-DNA antibodies involved in the pathogenesis of experimental lupus, in every member of a cohort of uranium miners who had been exposed to quartz dust (Conrad et al., 1998). Another author reported that uranium miners were more likely to develop systemic sclerosis (scleroderma), a connective tissue disease with a wide range of clinical manifestations (Baur et al., 1996). It is important to note that exposure to silica in quartz dust may be associated with both SLE and scleroderma.

Reproductive or Developmental Effects

Only a few studies have examined the effects of uranium on human reproduction and development. A greater than predicted number of female offspring was reported in male uranium miners (Muller et al., 1967). One author reported gonadal endocrine system dysfunction, with significant reduction in testosterone levels in uranium miners (Zaire et al., 1997).

In a subgroup of Gulf War veterans with embedded DU fragments in soft tissues and muscles, semen ejaculates contained uranium (McDiarmid et al., 2000). However, the semen characteristics (volume, concentration, morphology, and functional parameters of motility) were the same in Gulf War veterans with high urinary uranium excretion as in veterans with low excretion. The study also evaluated reproductive endocrinological function in Gulf War veterans with DU fragments by measuring blood levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and prolactin (PL). The high (>0.10 μg/g creatinine) and low (<0.10 μg/g creatinine) uranium excretion groups had the same levels of LH, FSH, PL, and testosterone (McDiarmid et al., 2000). The authors performed an unusual secondary analysis in which they found higher urinary uranium excretion in men with prolactin levels above the median than in men with PL levels below the median. The committee felt that the unconventional method of analysis was of questionable validity; the primary conventional analysis showed no significant association and the post hoc analysis, which did show a difference, included only 14 men. In addition, the authors did not measure serum cortisol, a mediator of PL plasma levels, nor did they account for moment-to-moment daily variations in prolactin. Therefore, the correlation of PL levels with the uranium dose is a hypothesis-generating observation that requires further study before any conclusions can be reached about the effect of uranium on prolactin.

Hematologic Parameters

In the study by McDiarmid and colleagues (2000) of Gulf War veterans with retained fragments of DU, hematological parameters were the same when compared with nonexposed Gulf War veterans. The parameters were also the same in veterans with retained DU fragments with either high or low urinary uranium excretion. Retained DU fragments and the ensuing increased urinary

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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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.

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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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,

Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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  • nervous system disease,

  • nonmalignant respiratory disease, or

  • other health outcomes (gastrointestinal disease, immune-mediated disease, effects on hematological parameters, reproductive or development dysfunction, genotoxic effects, cardiovascular effects, hepatic disease, dermal effects, ocular effects, or musculoskeletal effects).

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Suggested Citation:"4 Depleted Uranium." Institute of Medicine. 2000. Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/9953.
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