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Summary Depleted uranium (DU) is a weakly radioactive, chemically toxic heavy metal derived from natural uranium and is used by the U.S. military for muni- tions and for armor on some tanks. DU is well suited as a munition because of its high density and “self-sharpening” nature, both of which help it to penetrate armor. Its high density also makes DU an effective shield. DU has been used by all branches of the U.S. military since the 1980s, and it has been used on the battlefield in the Persian Gulf War, the Balkans, and the Iraq War. Concern about the adverse health effects on survivors of combat exposure to DU arose in response to “friendly-fire” incidents in which U.S. vehicles were accidentally struck with DU rounds. In the Gulf War, about 115 U.S. soldiers in or on six Abrams tanks and 14 Bradley fighting vehicles were caught in friendly-fire events that involved the use of large-caliber munitions containing DU penetrators. Some of the soldiers were injured by DU shrapnel. Most of the large metal embedded fragments in the surviving 104 soldiers were removed during treatment for their injuries. However, many small fragments remain em- bedded in their muscle tissue because their removal might lead to other health complications. When used as an antitank armor-piercing munition, a DU penetrator can create an airborne spray of uranium with particles of various sizes that can be inhaled by the tank crew or escape into the environment. Soldiers may ingest DU oxide dust by hand-to-mouth contact or when inhaled dust is coughed up and swallowed. Exposure may also occur when DU oxide dust is absorbed through open wounds, burns, or other breaks in the skin. Some think that DU may be responsible for illnesses noted in veterans involved in the conflicts and civilians living near the battlefields. Because of the concern about health effects, the U.S. Army commissioned a report, Depleted Uranium Aerosol Doses and Risks: Summary of U.S. Assessments, referred to as the Capstone Report, that evaluates the health risks associated with exposure to DU aerosols and asked the National Research Council’s Committee on Toxicology in collaboration with the 1

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2 Risks to Military Personnel from Exposure to Depleted Uranium Nuclear and Radiation Studies Board to review it independently. As a result of the Army’s request, the National Research Council convened the Committee on Toxicologic and Radiologic Effects from Exposure to Depleted Uranium During and After Combat, which prepared the present report. The committee’s task was to review the toxicologic, radiologic, epidemi- ologic, and toxicokinetic data on DU and to assess the Capstone Report on toxi- cologic and radiologic risks to soldiers posed by exposure to DU. It was to con- sider health-hazard and environmental reports prepared by such organizations as the World Health Organization, the UN Environment Programme (for the post- conflict Balkans), the International Atomic Energy Agency, the Agency for Toxic Substances and Disease Registry, and the UK Royal Society. The com- mittee was also to identify relevant data deficiencies and offer recommendations for future research. CAPSTONE REPORT Exposure Assessment The Capstone Report considered three kinds of scenarios of exposure to DU in combat and postcombat settings. Level I exposure involved soldiers who were in vehicles at the time of perforation with DU munitions or first responders who entered the struck vehicles shortly thereafter to rescue the injured. Five scenarios were considered for level I exposure: crew exiting a struck vehicle within 1 min, 5 min, 60 min, or 120 min or first responders entering a vehicle within 5 min to rescue injured crew members and exiting within 10 min. Level II exposure involved workers who were in or around vehicles containing DU fragments and particles at times after the event but were not in the vehicles at the time of impact and did not immediately enter vehicles after they were struck. Level III exposure was brief or incidental and was considered negligible. The Army conducted an aerosol study to characterize the DU exposures that were likely to have occurred in combat situations. The study involved shooting DU munitions into stripped-down Abrams tanks and a Bradley fighting vehicle and collecting samples to estimate time-integrated concentrations of DU in the air in the vehicles. Intakes of DU were estimated, and biokinetic models were used to predict the chemical and radiologic doses to body tissues. Overall, the committee found the methods and results of the Capstone ex- posure assessment to be appropriate and well done. To verify the exposure- assessment results, the committee made its own estimates on the basis of data developed largely outside the Capstone program. Using older datasets on the aerosol characteristics of the dusts and fumes produced when a DU penetrator strikes a hard target, the committee found that its estimated intakes in level I exposures were within a factor of 2 of the Capstone results. For levels II and III exposures, the committee calculated exposure rates resulting from surface con- tamination resuspended in the air and from incidental ingestion by using stan-

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3 Summary dard exposure-assessment values. The committee’s rates were again similar to those in the Capstone Report. The committee concluded that the Capstone expo- sure results are reasonable and appropriate for use in the human health risk analysis of DU. Health Risk Assessment Noncancer Effects In the Capstone Report, renal effects are used as the most sensitive end point for evaluating noncancer risks to soldiers. To evaluate that choice, the committee reviewed the literature on DU and uranium and their effects on vari- ous organ systems, such as the immune, cardiovascular, gastrointestinal, hema- tologic, reproductive, nervous, hepatic, and renal systems. On the basis of its review, the committee concurred with the Capstone Report that the kidneys are the most sensitive targets of uranium toxicity. Other toxic effects reported in the literature either were observed at uranium exposure concentrations unlikely to be encountered by military personnel in combat or postcombat scenarios or that required prolonged exposure. Furthermore, renal effects were consistently ob- served whenever other effects were observed. The primary targets in the kidneys are the proximal tubules, but glomeru- lar effects may also occur. Early evidence of the effects can be found by measur- ing markers of biochemical changes in the body. Biomarkers of tubular effects include increased urinary excretion of low-molecular-weight proteins, amino acids, and glucose. Biomarkers of glomerular effects include urinary excretion of high-molecular-weight proteins. Glucosuria (increased urinary concentration of glucose) is the most persistent biomarker of tubular effects observed after acute exposure of animals and humans. Biomarker measurements can be used in biokinetic models to estimate renal uranium concentration, which is considered the best estimate of exposure. The Capstone Report developed a categorization scheme, termed the Re- nal-Effects Group, that correlates renal uranium concentrations, renal effects, and likely health outcomes (see Table S-1). The scheme is based on observa- tions from human acute-exposure studies and estimates of renal uranium con- centrations derived from biokinetic modeling. The committee encountered sev- eral difficulties in verifying the upper bound of the REG-0 value (2.2 µg/g) calculated by the Army. The difficulties included questions about the interpreta- tion of some studies used to derive the REG values, uncertainties about the attri- bution of effects solely to uranium exposure, questions about the models that were used to estimate renal concentrations, and questions about the relevance of exposure scenarios in some studies to those encountered in military combat and postcombat settings. The renal uranium concentrations found in some cases after acute expo- sure suggest that minimal, transient effects (such as proteinuria and albuminuria)

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4 Risks to Military Personnel from Exposure to Depleted Uranium TABLE S-1 REG Predictions of Chemical Risk to Kidneys in the Army’s Capstone Report Renal Uranium Renal-Effects Concentration (µg/g of renal tissue) Acute Renal Effect Predicted Outcome Group No detectable effects No detectable effectsa 0 <2.2 1 >2.2 to <6.4 Possible transient Not likely to become illb indicators of renal dysfunction May become illc 2 >6.4 to <18 Possible protracted indicators of renal dysfunction Likely to become illd 3 >18 Possible severe clinical symptoms of renal dysfunction a The committee interprets no detectable effects to mean no low-level transient renal ef- fects and no clinical symptoms. b The committee interprets not likely to become ill to mean may exhibit low-level, tran- sient renal effects. c The committee interprets may become ill to mean may experience clinical symptoms of renal dysfunction and require medical attention. d The committee interprets likely to become ill to mean likely to experience clinical symp- toms of renal dysfunction and require medical attention. Source: Guilmette, R.A., M.A. Parkhurst, G. Miller, E.F. Hahn, L.E. Roszell, E.G. Daxon, T.T. Little, J.J. Whicker, Y.S. Cheng, R.J. Traub, G.M. Lodde, F. Szrom, D.E. Bihl, K.L. Creek, and C.B. McKee. 2005. Human Health Risk Assessment of Capstone Depleted Uranium Aerosols. Attachment 3 of Depleted Uranium Aerosol Doses and Risks: Summary of U.S. Assessments. Columbus, Ohio: Battelle Press. Reprinted with permission; copyright 2005, Battelle Press. may occur at concentrations as low as 1 µg/g. Similar effects have been reported at renal concentrations around 1 µg/g in workers with chronic occupational ex- posure to uranium and in Gulf War veterans with embedded DU fragments. The Royal Society has noted transient renal effects at renal concentrations of 1 µg/g and noted further that the trend in chronic exposure is toward greater renal ef- fects with lower renal concentrations, possibly as low as 0.1 µg/g. Thus, the REG-0 kidney concentration for uranium may need to be redefined, and any revision of the upper-bound REG-0 value would also require that the REG-1 range be redefined. If the REG-0 value is lowered, some soldiers may have to be reclassified. The committee found REG 2 and 3 to be appropriately defined in the Capstone Report. Cancer Effects Evidence on the risk of cancer or other chronic diseases after exposure to DU in Gulf War soldiers is inadequate. Epidemiologic evidence indicates a very

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5 Summary low risk of cancer in people exposed to uranium. However, the possibility of a radiation-induced cancer caused by inhalation of insoluble DU particles cannot be ruled out, given that alpha particles are emitted by DU. The latent period as- sociated with radiation-induced lung cancer is at least 10 y and might be much longer. In animals, insoluble forms of uranium have been found to be weakly car- cinogenic; lung cancer is the primary cancer that occurs after chronic inhalation exposure. Powdered or solid implants of uranium in the muscles of laboratory animals have shown evidence of carcinogenicity, and sarcomas have been ob- served in the vicinity of embedded uranium metal. Chromosomal assessments of exposed human populations (such as ura- nium production workers, uranium miners, and Gulf War DU-exposed veterans) have given mixed results regarding the genotoxic effects of uranium and DU in humans. Uranium has been shown to cause mutations, cell transformation, and DNA strand breaks in both in vitro and in vivo studies. Proposed mechanisms of the genotoxicity of uranium include both chemical and radiologic effects. The Capstone Report’s cancer risk assessment for DU exposure is based on the radioactive properties of DU. The concern that DU may increase the risk of cancer is based on knowledge that radiation doses can be delivered to various organs from inhaled DU and that radiation is a known carcinogen. Because no cancer risk factors are specifically related to DU, estimation of the risk of devel- oping cancer in the Capstone Report is based on the radiation risks posed by alpha-emitters. For level I exposure, the Capstone Report calculated radiation dose esti- mates for the five exposure scenarios. To assess the Army’s calculations, the committee performed its own calculations for selected scenarios (ventilated and unventilated Abrams tank and Bradley fighting vehicle with conventional ar- mor) and found the Capstone estimates to be reasonable; the Capstone estimates agree to within a factor of about 2 (Table S-2). Those estimates are within U.S. radiation standards for occupational exposure (for example, the U.S. annual limit for routine occupational exposure is 5 rem). The doses accrue over 50 y instead of a single year and do not directly correspond to annual doses. Further- more, the Capstone-estimated median exposure is below the U.S. Nuclear Regu- latory Commission annual dose limit of 10 rem for occupational workers with planned exposure. Radiologic cancer risks were calculated in the Capstone Report on the ba- sis of the sum of individual organ risks rather than whole-body effective dose. Biokinetic models were used to calculate organ doses, which were then used with established organ-specific cancer risk factors for alpha-emitters to deter- mine the individual organ risks. The committee found that approach to assessing cancer risks to be appropriate because it allows for the lack of uniformity in dose distribution among organs. Lifetime cancer mortality risks were calculated with a linear dose-response model (see Table S-3), which the Capstone Report ac- knowledges might overestimate risks at the low doses predicted for the exposure scenarios.

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6 Risks to Military Personnel from Exposure to Depleted Uranium The decision to use median lifetime cancer-mortality risk estimates means that the inherent variability in the exposure estimates is not considered. At the 10th- and 90th-percentile estimates of exposure, the lifetime cancer-mortality estimates for some exposure scenarios could be lower by as much as a factor of 6 or higher by about a factor of 3, respectively. For the 90th-percentile exposure scenarios, the estimated lifetime cancer-mortality risks approach 0.6%; if a vehicle is struck twice with a DU penetrator, the lifetime cancer mortality would be expected to roughly double. That would result in median and 90th-percentile estimated lifetime cancer risks of 0.9% and less than 1.2%, respectively. However, at those levels of risk, it would not be possible to distinguish between increased cancer mortality from DU exposure and background lung-cancer rates. The Capstone Report does not provide estimates of radiologic-cancer risks for levels II and III personnel. The committee finds that to be a deficiency in the TABLE S-2 Committee and Capstone Estimates of Effective Lifetime Committed Radiation Dose Equivalents from DU in Air for Selected Level I Exposure Scenarios, rem (Sv) ABRAMS Unventilated Ventilated Scenario Committee Capstone Committee Capstone A: Exit 1 min 0.94 2.0 0.61 0.09 (0.0094) (0.020) (0.0061) (0.0009) B: Exit 5 min 3.1 3.7 1.0 0.44 (0.031) (0.037) (0.010) (0.0044) C: Exit 60 min 6.5 4.8 1.0 1.02 (0.065) (0.048) (0.010) (0.0102) D: Exit 120 min 6.5 5.0 1.0 1.20 (0.065) (0.050) (0.010) (0.0120) E: First responder 2.3 0.92 0.02 0.41 (0.023) (0.0092) (0.0002) (0.0041) BRADLEY Unventilated Ventilated Scenario Committee Capstone Committee A: Exit 1 min 0.91 0.59 0.64 (0.0091) (0.0059) (0.0064) B: Exit 5 min 2.7 1.7 1.1 (0.027) (0.017) (0.011) C: Exit 60 min 4.2 2.1 1.2 (0.042) (0.021) (0.012) D: Exit 120 min 4.2 2.4 1.2 (0.042) (0.024) (0.012) E: First responder 1.3 0.89 0.04 (0.013) (0.0089 (0.0004)

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7 Summary TABLE S-3 Capstone Summary of Median (10th-, 90th-Percentile) Estimates of Increased Lifetime Risk of Fatal Lung Cancer (Expressed as %) from Inhalation Exposures of DU for Level I Personnel from Single Perforation of Vehicle Abrams Tank: Abrams Tank: Abrams Tank: Bradley Vehicle: Regular Armor, DU Armor, DU Armor, Regular Armor, Exposure No Ventilation No Ventilation Ventilation No Ventilation Exit in 1 min 0.11 0.12 0.0049 0.034 (0.07, 0.14) (0.08, 0.24) (NA) (0.009, 0.059) Exit in 5 min 0.20 0.32 0.025 0.099 (0.17, 0.40) (0.24, 0.52) (NA) (0.019, 0.180) First responder 0.05 0.10 0.023 0.052 (0.03, 0.11) (0.06, 0.16) (NA) (0.016, 0.077) Exit in 60 min 0.27 0.44 0.057 0.12 (0.17, 0.44) (0.32, 0.64) (NA) (0.06, 0.40) Exit in 120 min 0.28 0.45 0.065 0.14 (0.16, 0.44) (0.33, 0.65) (NA) (0.07, 0.41) NA = not available. Source: Parkhurst, M.A., E.G. Daxon, G.M. Lodde, F. Szrom, R.A. Guilmette, L.E. Roszell, G.A. Falo, and C.B. McKee. 2005. Depleted Uranium Aerosol Doses and Risks: Summary of U.S. Assessments (Capstone Summary Report). Columbus, Ohio: Battelle Press. Reprinted with permission; copyright 2005, Battelle Press. report. On the basis of estimated exposure of levels II and III unprotected per- sonnel working in or around a perforated vehicle 2 h or more after a single DU- munition perforation, the 50-y whole-body dose (inhalation + ingestion) is up to 0.079 rem/h of exposure, and the 50-y lung dose via inhalation is up to 0.56 rem/h of exposure. The estimated dose would be higher for extended exposure in a vehicle with multiple perforations. The Capstone Report also does not include cancer risk estimates for sol- diers who have embedded DU fragments. That was an intentional omission that perhaps is being addressed separately. However, its exclusion from the Capstone Report leads to an underestimation of risk due to increased, prolonged systemic exposure to DU in this cohort of soldiers and risk of developing sarcomas in the vicinity of the embedded fragments. RECOMMENDATIONS On the basis of its independent review of the Capstone Report and the toxicologic and epidemiologic literature concerning uranium, the committee offers the following recommendations. (Additional, more specific recommenda- tions are listed at the ends of individual chapters.) • The committee recommends that the Army review the accuracy of the acute-exposure data presented in the Capstone Report in support of its REG-0 and REG-1 values by verifying that uranium intakes were estimated appropri-

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8 Risks to Military Personnel from Exposure to Depleted Uranium ately from the original data, by verifying that peak renal uranium concentrations were estimated appropriately with the same model, by re-evaluating its interpre- tation of some studies, and by re-evaluating the dataset by considering the rele- vance of route of exposure and chemical form to those in the military-exposure scenarios. Depending on the outcome of that review and later calculations, the upper bound of the REG-0 range might need to be revised and the lower bound of the REG-1 range modified accordingly. Because of the uncertainties associ- ated with such estimates, the Army should avoid setting REG values that sug- gest a great deal of precision, particularly for renal concentrations below 3 µg/g. • Cancer risk estimates should be calculated for levels II and III exposure to determine whether decontamination of vehicles perforated by DU munitions should be conducted to reduce the risk of fatal cancer from exposure of unpro- tected people. • For level II personnel working in vehicles perforated by DU munitions, the number of hours should be limited, and protective equipment, particularly respirators, should be used to reduce potentially important cumulative DU expo- sure. • If Gulf War level II personnel who had several hours of unprotected exposure to DU in perforated vehicles can be identified, they should receive health monitoring.