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Summary T he 1990-1991 Persian Gulf War was considered a military success, with few injuries or deaths. However, a number of veterans began ex- periencing symptoms—such as fatigue, cognitive difficulties, and sleep disturbances—after their return home. In response to growing concern about possible exposure to a biologic, chemical, or physical agent as the cause of the symptoms, Congress passed two laws in 1998: PL 105-277, the Persian Gulf War Veterans Act, and PL 105-368, the Veterans Programs Enhancement Act. Under the legislation, the Department of Veterans Affairs (VA) was directed to ask the Institute of Medicine (IOM) to evaluate the scientific literature regarding associations between illness and exposure to specific toxic agents, environmental or wartime hazards, or preventive medicines or vaccines related to Gulf War service. In 1998, IOM began a program to examine health risks posed by specific agents and hazards to which Gulf War veterans might have been exposed dur- ing their deployment. Five reports have examined health outcomes related to depleted uranium, pyridostigmine bromide, sarin, and vaccines; insecticides and solvents; fuels, combustion products, and propellants; infectious diseases; and physiologic, psychologic, and psychosocial effects of deployment-related stress. A sixth IOM report examined the current health status of Gulf War–deployed vet- erans compared with their nondeployed counterparts. The present report updates the review of depleted uranium presented in the 2000 IOM report, Gulf War and Health, Volume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines (hereafter referred to as Volume 1). 

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 updated literature review of depleted uranium The Gulf War marked the first time that depleted-uranium munitions and armor were extensively used by the US military. Depleted uranium is used by the US military for both offensive and defensive purposes. Heavy-armor tanks have a layer of depleted-uranium armor to increase protection. Offensively, depleted ura- nium is used in kinetic-energy cartridges and ammunition rounds. The Army used an estimated 9,500 depleted-uranium tank rounds during the Gulf War. Ammuni- tion containing depleted uranium was used in Bosnia-Herzegovina in 1994-1995 and in Kosovo in 1999; about 10,800 depleted-uranium rounds were fired in Bosnia-Herzegovina, and about 30,000 in Kosovo. Depleted-uranium–containing weapons also have been used in Operation Iraqi Freedom (OIF), which began in 2003. Because depleted uranium continues to be used by the military, the charge to IOM has been expanded to include not only veterans of the Gulf War but vet- erans returning home from OIF. Military personnel have been exposed to depleted uranium as a result of friendly-fire incidents, cleanup and salvage operations, and proximity to burning depleted-uranium–containing tanks and ammunition. During the Gulf War, an estimated 134-164 people experienced “level I” exposure (the highest of three exposure categories as classified by the US Department of Defense) through wounds caused by depleted-uranium fragments, inhalation of airborne depleted- uranium particles, ingestion of depleted-uranium residues, or wound contami- nation by depleted-uranium residues. Hundreds or thousands more may have been exposed to lower exposure through inhalation of dust containing depleted- uranium particles and residue or ingestion from hand-to-mouth contact or con- tamination of clothing. Ten US military personnel who served in OIF had con- firmed depleted uranium detected in their urine; all 10 had depleted-uranium embedded fragments or fragment injuries. Summary of Findings in Volume 1 When Volume 1 was published in 2000, few studies of health outcomes of exposure to depleted uranium had been conducted. Therefore, the committee stud- ied the health outcomes of exposure to natural and processed uranium in workers at plants that processed uranium ore for use in weapons and nuclear reactors. After evaluating the literature, the committee concluded that there was inadequate or insufficient evidence to determine whether an association exists between uranium exposure and 14 health outcomes—lymphatic cancer, bone cancer, ner- vous system disease, reproductive or developmental dysfunction, nonmalignant respiratory disease, gastrointestinal disease, immune-mediated disease, effects on hematologic measures, genotoxic effects, cardiovascular effects, hepatic disease, dermal effects, ocular effects, and musculoskeletal effects. It also concluded that there was limited or suggestive evidence of no association between uranium and clinically significant renal dysfunction and between uranium and lung cancer at cumulative internal doses lower than 200 mSv.

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SUMMARY  Charge to the Committee Since Volume 1 was published in 2000, a number of studies of health out- comes of exposure to natural and depleted uranium have been published. For that reason and because depleted uranium continues to be used by the military, VA asked IOM to update the 2000 report and to take into consideration information published since Volume 1. In response, IOM entered into a contract with VA to conduct the following study: An IOM committee will review, evaluate, and summarize the scientific literature regarding the association between exposure to depleted uranium and long-term human health outcomes. The study committee will incorporate literature pub- lished since the 2000 IOM report Gulf War and Health, Volume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines was written. The committee will make determinations on the strength of the evidence of associations between exposure to depleted uranium and human health outcomes. The Committee’s Approach to Its Charge The committee began its evaluation by presuming neither the existence nor the absence of adverse health outcomes associated with exposure to depleted uranium. It sought to characterize and weigh the strengths and limitations of the available evidence. The committee did not concern itself with policy issues, such as decisions regarding disability, potential costs of compensation, or any broad policy implications of its findings. An extensive search of the scientific literature generated about 3,500 titles and abstracts. After examination of the titles and abstracts to identify articles that appeared to be relevant to the committee’s task (that is, articles on health out- comes of exposure to uranium), about 1,000 articles—including epidemiologic, toxicologic, and exposure-assessment studies—remained in the committee’s ref- erence database. Additional information was obtained from invited experts and the public during a meeting held on June 28, 2007, in Washington, DC. After securing the full text of the articles mentioned above, the committee had to determine which ones would be included in the review. For an epidemiologic study to be included in the committee’s review, it had to be published in a peer-reviewed journal or to have undergone an equally rigor- ous process. A study also needed to be judged as methodologically sound, on the basis of inclusion of details of its methods, use of appropriate control or reference groups, statistical adjustment to control for confounders and minimize selection bias, and appropriate assessment of uranium exposure in the study population. It needed to examine long-term health outcomes and had to have a followup time sufficient to detect a relevant clinical effect. Finally, it had to include a relevant study population, that is, uranium-exposed workers, military personnel deployed to the Gulf War, or people who lived near a uranium-processing facility (uranium

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 updated literature review of depleted uranium exposure in such residents may be similar to low-level exposures of military personnel). Studies in uranium miners were not included in the committee’s evaluation because several issues related to confounding substantially limited the usefulness of those studies. The committee used the evidence in the scientific literature to draw con- clusions about associations between exposure to depleted uranium and spe- cific adverse health outcomes. Those conclusions are presented as categories of strength of association. The categories have been used in many previous IOM studies, and they have gained wide acceptance by Congress, government agen- cies, researchers, and veteran groups. The categories are summarized below. • Sufficient evidence of a causal relationship. Evidence is sufficient to conclude that a causal relationship exists between the exposure to uranium and a specific health outcome in humans. The evidence fulfills the criteria for sufficient evidence of an association (below) and satisfies several of the criteria used to assess causality: strength of association, dose-response relationship, consistency of association, temporal relationship, specificity of association, and biological plausibility. • Sufficient evidence of an association. Evidence is sufficient to conclude that there is an association. That is, a consistent association unlikely to be due to sampling variability has been observed between exposure to uranium and a specific health outcome in human studies that were free of severe bias and that controlled for confounding. • Limited/suggestive evidence of an association. Evidence is suggestive of an association between exposure to uranium and a specific health outcome, but the body of evidence is limited by insufficient avoidance of bias, insufficient control for confounding, or large sampling variability. • Inadequate/insufficient evidence to determine whether an association exists. Evidence is of insufficient quantity, quality, or consistency to permit a con- clusion regarding the existence of an association between exposure to uranium and a specific health outcome in humans. • Limited/suggestive evidence of no association. Evidence is consistent in not showing an association between exposure to uranium of any magnitude and a specific health outcome. A conclusion of no association is inevitably limited to the conditions, magnitudes of exposure, and length of observation in the available studies. Conclusions The committee drew on information from the many studies published since 2000 and from Volume 1 and reached its conclusions by interpreting the new evidence in the context of the entire body of literature. Most of the evidence on health effects of exposure to uranium came from studies of workers in ­uranium-

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SUMMARY  processing mills and other facilities, and the committee relied heavily on those studies in developing its conclusions. Also taken into consideration in the evalu- ation were studies of Gulf War veterans exposed to depleted uranium and of residential exposure to uranium. All those studies were valuable in drawing conclusions, but they also had limitations. For example, the number of exposed people in many of the studies was relatively small, and this decreased the sta- tistical power to detect a small excess risk of disease. The period of followup in several studies might have been too short to detect some diseases that are typi- cally characterized by long latency; this limitation is of particular concern with respect to studies of cancer outcomes. And assessment of exposure to uranium was inadequate in many of the studies reviewed by the committee. On the basis of the available literature, the committee concluded that there is inadequate/insufficient evidence to determine whether an association exists between exposure to uranium and all the health outcomes examined: lung cancer, leukemia, lymphoma (Hodgkin lymphoma and non-Hodgkin lymphoma), bone cancer, renal cancer, bladder cancer, brain and other nervous system cancers, stomach cancer, prostatic cancer, testicular cancer, nonmalignant renal disease, nonmalignant respiratory disease, neurologic effects, reproductive and devel- opmental effects, and several other health outcomes (cardiovascular effects, genotoxicity, hematologic effects, immunologic effects, and skeletal effects). The committee’s conclusions on lung cancer and nonmalignant renal disease differ from those in Volume 1 (see “Summary of Findings in Volume 1” above). With respect to lung cancer, the committee decided not to place quantitative limits on the dose, primarily because of the wide variety of exposure-assessment methods used in the studies reviewed and the uncertainty in measurement of uranium exposure. With respect to nonmalignant renal disease, the committee decided that it could not rule out the occurrence of a renal effect “after exposure of any magnitude,” as required to meet the definition of limited/suggestive evidence of no association. In summary, the committee assigned the category inadequate/insufficient evidence to determine whether an association exists to each health outcome described above for one or more of the following reasons: • Well-conducted studies showed equivocal results. • The magnitude or frequency of a health outcome may be so low that it cannot be reliably detected given the sizes of the study populations. • The available studies had limitations (such as inadequate exposure assess- ment or followup that was too short) that made it impossible to reach clear con- clusions about health outcomes.

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