Executive Summary

On August 2, 1990, Iraqi armed forces invaded Kuwait; within 5 days, the United States began to deploy troops to Operation Desert Shield. Intense air attacks against the Iraqi armed forces began on January 16, 1991, and opened a phase of the conflict known as Operation Desert Storm. Oil-well fires became visible by satellite images as early as February 9, 1991; the ground war began on February 24, and by February 28, 1991, the war was over. The oil fires were extinguished by November 1991. The last troops to participate in the ground war returned home on June 13, 1991. In all, approximately 697,000 U.S. troops had been deployed to the Persian Gulf area during the conflict.

Although considered an extraordinarily successful military operation with few battle casualties and deaths, veterans soon began reporting health problems that they attributed to their participation in the Gulf War. Although the majority of men and women who served in the Gulf returned to normal activities, a large number of veterans have had a range of unexplained illnesses including chronic fatigue, muscle and joint pain, loss of concentration, forgetfulness, headache, and rash.

The men and women who served in the Gulf War theater were potentially exposed to a wide range of biological and chemical agents including sand, smoke from oil-well fires, paints, solvents, insecticides, petroleum fuels and their combustion products, organophosphate nerve agents, pyridostigmine bromide (PB), depleted uranium (DU), anthrax and botulinum toxoid vaccinations, and infectious diseases, in addition to psychological and other physiological stress. Veterans have become increasingly concerned that their ill health may be related to exposure to these agents and circumstances.



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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Executive Summary On August 2, 1990, Iraqi armed forces invaded Kuwait; within 5 days, the United States began to deploy troops to Operation Desert Shield. Intense air attacks against the Iraqi armed forces began on January 16, 1991, and opened a phase of the conflict known as Operation Desert Storm. Oil-well fires became visible by satellite images as early as February 9, 1991; the ground war began on February 24, and by February 28, 1991, the war was over. The oil fires were extinguished by November 1991. The last troops to participate in the ground war returned home on June 13, 1991. In all, approximately 697,000 U.S. troops had been deployed to the Persian Gulf area during the conflict. Although considered an extraordinarily successful military operation with few battle casualties and deaths, veterans soon began reporting health problems that they attributed to their participation in the Gulf War. Although the majority of men and women who served in the Gulf returned to normal activities, a large number of veterans have had a range of unexplained illnesses including chronic fatigue, muscle and joint pain, loss of concentration, forgetfulness, headache, and rash. The men and women who served in the Gulf War theater were potentially exposed to a wide range of biological and chemical agents including sand, smoke from oil-well fires, paints, solvents, insecticides, petroleum fuels and their combustion products, organophosphate nerve agents, pyridostigmine bromide (PB), depleted uranium (DU), anthrax and botulinum toxoid vaccinations, and infectious diseases, in addition to psychological and other physiological stress. Veterans have become increasingly concerned that their ill health may be related to exposure to these agents and circumstances.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines In response to these concerns, the Department of Veterans Affairs (VA) approached the National Academy of Sciences and requested that the Institute of Medicine (IOM) conduct a study to evaluate the published scientific literature concerning the association between the agents to which the Gulf War veterans may have been exposed and adverse health effects. To carry out the VA charge, the IOM formed the Committee on Health Effects Associated with Exposures During the Gulf War. The committee began its deliberations in January 1999 by choosing the initial group of compounds for study. The committee decided to select the compounds of most concern to the veterans. Following meetings with representatives of different veterans’ organizations, the committee decided to study the following compounds: depleted uranium, chemical warfare agents (sarin and cyclosarin), pyridostigmine bromide, and vaccines (anthrax and botulinum toxoid). Additional IOM studies will examine the remaining agents. The committee met with veterans and leaders of veterans’ organizations many times throughout the course of the study. These meetings were invaluable for the committee in providing an important perspective on the veterans’ experiences and concerns. Further, ongoing discussions with and written input from veterans became an integral part of the manner in which the committee conducted the study and greatly enhanced its process. Subsequent to the VA–IOM contract, two public laws were passed: the Veterans Programs Enhancement Act of 1998 (Public Law 105-368) and the Persian Gulf War Veterans Act of 1998 (Public Law 105-277). Each law mandated studies similar to the study already agreed upon by the VA and IOM. These laws detail several comprehensive studies on veterans’ health and specify many biological and chemical hazards that may potentially be associated with the health of Gulf War veterans. The charge to the IOM committee was relatively narrow: to assess the scientific literature regarding potential health effects of chemical and biological agents present in the Gulf War. The committee was not asked to determine whether a unique Gulf War syndrome exists, nor was it to make judgments regarding the veterans’ levels of exposure to the putative agents. In addition, the committee’s charge was not to focus on broader issues, such as the potential costs of compensation for veterans or policy regarding such compensation. These decisions remain the responsibility of the Secretary of Veterans Affairs. This report provides an assessment of the scientific evidence regarding health effects that may be associated with exposures to specific agents that were present in the Gulf. The Secretary may consider these health effects as the VA develops a compensation program for Gulf War veterans. METHODOLOGY The committee’s charge was to conduct a review of the scientific literature on the possible health effects of agents to which Gulf War veterans may have been exposed. The breadth of this review included all relevant toxicological, animal, and human studies. Because only a few studies describe the veterans’ exposures,

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines the committee reviewed studies of any human populations—including veterans—that had been exposed to the agent of concern at any dose. These studies come primarily from occupational, clinical, and healthy volunteer settings. The committee began its task by talking with representatives of veterans’ organizations, as an understanding of the veterans’ experiences and perspectives is an important point of departure for a credible scientific review. The committee opened several of its meetings to veterans and other interested individuals. The committee held a scientific workshop and two public meetings. It also received information in written form from veteran organizations, veterans, and other interested persons who made the committee aware of their experiences or their health status and provided information about research. This process provided valuable information about the Gulf War experience and helped the committee to identify the health issues of concern. The committee and staff reviewed more than 10,000 abstracts of scientific and medical articles related to the agents selected for study and then carefully examined the full text of over 1,000 peer-reviewed journal articles, many of which are described in this report. For each agent, the committee determined—to the extent that available published scientific data permitted meaningful determinations—the strength of the evidence for associations between exposure to the agent and adverse health effects. Because of the general lack of exposure measurements in veterans (with some exceptions), the committee reviewed studies of other populations known to be exposed to the agents of interest. These include uranium-processing workers, individuals who may have been exposed to sarin as a result of terrorist activity (e.g., the sarin attacks in Japan), healthy volunteers (including military populations), and clinical populations (e.g., patients with myasthenia gravis treated with PB). By studying health effects in these populations, the committee could decide, in some cases, whether the putative agents could be associated with adverse health outcomes. The committee’s judgments have both quantitative and qualitative aspects, and reflect the evidence and the approach taken to evaluate that evidence. The committee’s methodology draws from the work of previous IOM committees and their reports on vaccine safety (IOM, 1991, 1994a), herbicides used in Vietnam (IOM, 1994b, 1996, 1999), and indoor pollutants related to asthma (IOM, 2000). The committee adopted a policy of using only peer-reviewed published literature to form its conclusions. It did not collect original data or perform any secondary data analysis. Although the process of peer review by fellow professionals—which is one of the hallmarks of modern science—is the best assurance that a study has reached valid conclusions, peer review does not guarantee the validity or generalizability of a study. Accordingly, committee members read each research article critically. The committee used only peer-reviewed publications in forming its conclusions about the degree of association between exposure to a particular agent and adverse health effects. However, this report describes some non-peer-reviewed publications, which provided background information for the committee and raised issues that will require further research. In their evaluation of individual research articles, committee members

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines considered several important issues, including the quality of the study; its relevance; issues of error, bias, and confounding; the diverse nature of the evidence; and the study population. The committee classified the evidence for association between exposure to a specific agent and a health outcome into one of five previously established categories. The categories closely resemble those used by several IOM committees that evaluated vaccine safety (IOM, 1991, 1994a), herbicides used in Vietnam (IOM, 1994b, 1996, 1999), and indoor pollutants related to asthma (IOM, 2000). Although the categories imply a statistical association, the committee had sufficient epidemiologic evidence to examine statistical associations for only one of the agents under study (i.e., depleted uranium); the epidemiologic evidence for the other agents examined (i.e., sarin, pyridostigmine bromide, and anthrax and botulinum toxoid vaccines) was very limited. Thus, the committee based its conclusions on the strength and the coherence of the data in the available studies. In many cases, these data distinguished differences between transient and long-term health outcomes related to the dose of the agent. Based on the literature, it became incumbent on the committee to similarly specify the differences between dose levels and the nature of the health outcomes. This approach led the committee to reach conclusions about long- and short-term health effects, as well as health outcomes related to the dose of the putative agents. The final conclusions represent the committee’s collective judgment. The committee endeavored to express its judgments as clearly and precisely as the available data allowed. The committee used the established categories of association from previous IOM studies, because they have gained wide acceptance for more than a decade by Congress, government agencies, researchers, and veteran groups. Sufficient Evidence of a Causal Relationship. Evidence is sufficient to conclude that a causal relationship exists between the exposure to a specific agent and a 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,1 consistency of association, temporal relationship, specificity of association, and biological plausibility. Sufficient Evidence of an Association. Evidence is sufficient to conclude that there is a positive association. That is, a positive association has been observed between an exposure to a specific agent and a health outcome in human studies in which chance, bias, and confounding could be ruled out with reasonable confidence. Limited/Suggestive Evidence of an Association. Evidence is suggestive of an association between exposure to a specific agent and a health outcome in 1   A dose–response relationship refers to the finding of a greater health effect (response) with higher doses of an agent.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines humans, but is limited because chance, bias, and confounding could not be ruled out with confidence. Inadequate/Insufficient Evidence to Determine Whether an Association Does or Does Not Exist. The available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association between an exposure to a specific agent and a health outcome in humans. Limited/Suggestive Evidence of No Association. There are several adequate studies covering the full range of levels of exposure that humans are known to encounter that are mutually consistent in not showing a positive association between exposure to a specific agent and a health outcome at any level of exposure. A conclusion of no association is inevitably limited to the conditions, levels of exposure, and length of observation covered by the available studies. In addition, the possibility of a very small elevation in risk at the levels of exposure studied can never be excluded. These five categories describe different strengths of association, with the highest level being sufficient evidence of a causal relationship between exposure to a specific agent and a health outcome. The criteria for each category sound a recurring theme: An association is more likely to be valid to the extent that the authors reduced common sources of error in making inferences—chance variation, bias in forming a study cohort, and confounding. Accordingly, the criteria for each category express varying degrees of confidence based upon the extent to which it has been possible to exclude these sources of error. To infer a causal relationship from a body of observational evidence, the committee relied on long-accepted criteria for assessing causation in epidemiology (Hill, 1971; Evans, 1976). The following sections provide a discussion and conclusions regarding the putative agents (DU, PB, sarin, and vaccines). DEPLETED URANIUM Depleted uranium is a by-product of the enrichment process used to make reactor-grade uranium. Natural uranium is considered a low-level radioactive element. Because of the different percentages of uranium isotopes, the specific activity (a measure of radioactivity) of depleted uranium (14.8 mBq/μg) is 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, the chemical properties of depleted uranium are the same as those of the enriched and naturally occurring forms. The U.S. military used depleted uranium in the Gulf War for offensive and defensive purposes (OSAGWI, 1998). Heavy armor tanks had a layer of depleted uranium armor to increase protection. Depleted uranium was also used in kinetic energy cartridges and ammunition rounds. U.S. personnel were exposed to depleted uranium as the result of friendly fire incidents, cleanup operations, and

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines accidents (including fires). DU-containing projectiles struck 21 Army combat vehicles (OSAGWI, 1998). After the war, assessment teams and cleanup and recovery personnel may have had contact with DU-contaminated vehicles or DU munitions. In June 1991, a large fire, which occurred in Camp Doha near Kuwait City, led to a series of blasts and fires that destroyed combat-ready vehicles and DU munitions. Nearby troops and cleanup crews may have been exposed to DU-containing dust or residue. Other troops may have been exposed through contact with damaged vehicles or inhalation of DU-containing dust (Fahey, 2000). 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 retained in the body depends on the solubility of the uranium compounds to which the individual is exposed. Inhaled insoluble uranium concentrations may remain within the pulmonary tissues, especially the lymph nodes, for several years. Ingested uranium is poorly absorbed from the intestinal tract. Conclusions on the Health Effects of Depleted Uranium Although depleted uranium is the form of uranium that was present in the Gulf War, there are only a few studies of its health effects. Therefore, the committee studied the health effects of natural and processed uranium in workers at plants that processed uranium ore for use in weapons and nuclear reactors. The literature on uranium miners and on populations exposed to external radiation is largely not relevant to the study of uranium because the primary exposures of these populations were to other sources of radiation (e.g., radon progeny or gamma radiation). While studies of uranium processing workers are useful, these studies have several shortcomings. Although several studies involved tens of thousands of workers, even these studies were not large enough to identify small increases in the risk of uncommon cancers. Few studies had access to consistent, accurate information about individual exposure levels. Further, 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. 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. Lung cancer mortality

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines was not increased among occupationally exposed persons in most of these cohorts. 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. In a large study of employees at Oak Ridge, Tennessee, uranium processing and research facilities (Frome et al., 1990), the entire group experienced a small increase in lung cancer mortality. Despite its shortcoming in measuring radiation exposure, the committee felt the Frome 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. The study by Dupree and colleagues (1995) 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. This 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. 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. 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. Renal Function Although uranium is a heavy metal that can cause transient renal dysfunction, the preponderance of evidence indicates little or no clinically important renal effects of exposure to uranium. A few studies have shown functional 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 who had been exposed to high levels of

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines soluble uranium compounds 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). The committee concludes that there is limited/suggestive evidence of no association between exposure to uranium and clinically significant renal dysfunction. Other Health Outcomes The information on other health outcomes in humans comes from epidemiologic studies of uranium processing workers and case reports of workers or other individuals accidentally exposed to large doses of uranium compounds. While the studies did not suggest that uranium has adverse health effects, the studies were of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association in humans. 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: lymphatic cancer; bone cancer; nervous system disease; nonmalignant respiratory disease; or other health outcomes (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). SARIN Sarin is a highly toxic nerve agent produced for chemical warfare. It was synthesized in 1937 in Germany in a quest for improved insecticides (Somani, 1992). Although its battlefield potential was soon recognized, Germany refrained from using its stockpiles during World War II. Sarin’s first military use did not occur until the Iran–Iraq conflict in the 1980s (Brown and Brix, 1998). High-level exposures to sarin can be fatal within minutes to hours. In vapor or liquid form, sarin can be inhaled or absorbed, respectively, across the skin, eyes, or mucous membranes (Stewart and Sullivan, 1992). Because of its extreme potency, “high” sarin exposure for humans is quite low: Exposure to as little as 100 mg across the skin, or 50–100 mg/min/m3 by inhalation, is lethal to 50 percent of exposed individuals (Somani, 1992). Sarin, or isopropyl methylphosphonofluoridate, is a member of a class of chemicals known as organophosphorus esters (or organophosphates). A few highly toxic members of this large class are chemical warfare agents, but most are insecticides (Lotti, 2000). The drug pyridostigmine bromide is pharmacologically

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines similar to sarin and other organophosphates, but it is a member of a different chemical class, the carbamates. Both PB and sarin exert their effects by binding to and inactivating the enzyme acetylcholinesterase (AChE).2 The binding of sarin to AChE is irreversible, whereas the binding of PB to AChE is reversible. In March 1991, during the cease-fire period, troops from the U.S. 37th and 307th Engineering Battalions destroyed enemy munitions throughout the occupied areas of southern Iraq (PAC, 1996). One of the sites destroyed was a large storage complex at Khamisiyah, Iraq, consisting of more than 100 bunkers, which contained stacks of 122-mm rockets loaded with sarin and cyclosarin3 (Committee on Veterans’ Affairs, 1998). U.S. troops performing demolitions were unaware of the presence of nerve agents. In October 1991, inspectors from the United Nations Special Commission on Iraq (UNSCOM) first confirmed the presence of a mixture of sarin and cyclosarin (Committee on Veterans’ Affairs, 1998). At the time of the demolition, there were no medical reports by the U.S. Army Medical Corps of military personnel with signs and symptoms of acute exposure to sarin (PAC, 1996). Further, a 1997 survey mailed by the Department of Defense (DoD) to 20,000 troops within a 50-mile radius of Khamisiyah found that more than 99 percent of respondents (n = 7,400) reported no acute cholinergic effects (CIA–DoD, 1997). Nevertheless, low-level exposure could have occurred without producing acute cholinergic effects. Conclusions on the Health Effects of Sarin The committee reached the following conclusions after reviewing the literature on sarin. The committee was unable to formulate any conclusions about cyclosarin because of the paucity of toxicological and human studies. The committee concludes that there is sufficient evidence of a causal relationship between exposure to sarin and a dose-dependent acute cholinergic syndrome that is evident seconds to hours subsequent to sarin exposure and resolves in days to months. In humans, exposure to high doses of sarin produces a well-characterized acute cholinergic syndrome. This syndrome, as evidenced by acute cholinergic signs and symptoms, is evident seconds to hours after exposure and usually resolve in days to months. The syndrome is produced by sarin’s irreversible inhi- 2   AChE is an enzyme necessary to remove acetylcholine (ACh). ACh transmits nerve signals at the cholinergic neuromuscular junction or synapses in the central nervous system. Anticholinesterase agents inhibit (inactivate) AChE, resulting in an accumulation of acetylcholine. The accumulation repetitively activates the ACh receptors, resulting in exaggerated responses of the organ (e.g., excess salivation). 3   Cyclosarin is an organophosphate nerve agent. The committee examined the literature on this agent but found a very limited amount of information available on the health effects of this compound.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines bition of AChE. Inactivation of this enzyme, which normally breaks down the neurotransmitter acetylcholine, leads to the accumulation of acetylcholine at cholinergic synapses. Excess quantities of acetylcholine result in widespread overstimulation of muscles and nerves. At high doses, convulsions and death can occur. The committee concludes that there is limited/suggestive evidence of an association between exposure to sarin at doses sufficient to cause acute cholinergic signs and symptoms and subsequent long-term health effects. After sarin exposure, many health effects are reported to persist (e.g., fatigue; headache; visual disturbances such as asthenopia, blurred vision, and narrowing of the visual field; asthenia; shoulder stiffness; symptoms of posttraumatic stress disorder; and abnormal test results, of unknown clinical significance, on the digit symbol test of psychomotor performance, electroencephalogram records of sleep, event-related potential, visual evoked potential, and computerized posturography). These conclusions are based on retrospective controlled studies of three different exposed populations who experienced acute cholinergic signs and symptoms after exposure to sarin. One population consisted of industrial workers accidentally exposed to sarin in the United States; the other two populations were civilians exposed during terrorism episodes in Japan. The health effects listed above were documented at least 6 months after sarin exposure, and some persisted up to a maximum of 3 years, depending on the study. Whether the health effects noted above persist beyond the 3 years has not been studied. The committee concludes that there is inadequate/insufficient evidence to determine whether an association does or does not exist between exposure to sarin at low doses insufficient to cause acute cholinergic signs and symptoms and subsequent long-term adverse health effects. On the basis of positive findings in a study of nonhuman primates and studies of humans exposed to organophosphate insecticides, it is reasonable to hypothesize that long-term adverse health effects can occur after exposure to low levels of sarin. Studies of industrial workers exposed to low levels of organophosphate insecticides consistently show a higher prevalence of neurological and/or psychiatric symptom reporting. However, there are no well-controlled studies of long-term health effects in humans exposed to sarin at doses that do not produce acute signs and symptoms.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines PYRIDOSTIGMINE BROMIDE Pyridostigmine bromide was used during the Gulf War as a pretreatment for exposure to nerve agents. It has been used for more than 40 years in the routine treatment of myasthenia gravis and may be used following surgery in the reversal of neuromuscular blockade (Williams, 1984). PB, a reversible cholinesterase inhibitor, was synthesized in 1945 by Hoffman-La Roche Laboratories in Switzerland and is sold under the trade name Mestinon bromide (Williams, 1984). PB is one of the quaternary ammonium anticholinesterase compounds, which generally do not penetrate cell membranes. Compounds in this category are poorly absorbed from the gastrointestinal tract and are excluded by the blood–brain barrier (Williams, 1984; Goodman et al., 1996). Mestinon was approved by the Food and Drug Administration (FDA) in 1955 as safe for the treatment of myasthenia gravis. The FDA also approved an injectable form known as Regenol for reversing the effects of some anesthetic formulations (Rettig, 1999). In the treatment of myasthenia gravis, the average oral dose is 120–600 mg per day (in divided doses); however, the size and frequency of the dose must be adjusted to the needs of the individual patient (Physicians’ Desk Reference, 2000). The drug is poorly absorbed after oral administration, and peak plasma levels occur 2 to 3 hours after oral dosing. The drug is eliminated almost exclusively via the kidneys in the urine (Williams, 1984). Side effects of PB are generally related to the large doses given to myasthenics; in surgical patients, adverse reactions are controlled by simultaneous administration of atropine (Williams, 1984). The acute cholinergic side effects of PB are due to stimulation of muscarinic or nicotinic receptors by increased acetylcholine (ACh). Muscarinic reactions include nausea, vomiting, diarrhea, abdominal cramps, increased peristalsis, increased salivation, increased bronchial secretions, miosis, and heavy perspiration. Nicotinic effects are chiefly muscle cramps, fasciculations, and weakness (Williams, 1984). PB binds reversibly to AChE and prevents the enzyme from binding irreversibly with nerve agents. PB pretreatment is used by the military to obtain 10–20 percent inhibition of whole-blood AChE (Hubert and Lison, 1995). PB is not an antidote and has no value when administered after nerve agent exposure. It is not a substitute for atropine or 2-pralidoxime chloride; rather, it enhances their efficacy (Madsen, 1998). The DoD reported that 5,328,710 doses of PB were fielded and estimated that approximately 250,000 personnel took PB during the Gulf War. It was supplied as a 21-tablet blister pack; the dosage prescribed was one 30-mg tablet every 8 hours. Variation in use occurred, however, because it was self-administered and was to be taken only when ordered by the unit commander (PAC, 1996). Thus, veterans’ actual exposure to PB is not known, and there are few examples of documentation in either individual health records or unit records (PAC, 1996).

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines alum) had mild reactions. However, studies of the anthrax vaccine have not used active surveillance to systematically evaluate long-term health outcomes. Unfortunately, this situation is typical for all but a few vaccines. The committee concludes that there is sufficient evidence of an association between anthrax vaccination and transient acute local and systemic effects (e.g., redness, swelling, fever) typically associated with vaccination. The committee concludes that there is inadequate/insufficient evidence to determine whether an association does or does not exist between anthrax vaccination and long-term adverse health effects. Botulinum Toxoid Botulinum toxins, known primarily for causing cases of foodborne botulism, are produced by the anaerobic bacterium Clostridium botulinum. Different strains of the bacillus produce seven distinct botulinum toxins (A–G). These toxins are among the most toxic compounds per body weight of agent, with an LD50 of 0.001 μg/kg in mice (USAMRIID, 1996). Work on modifying the botulinum toxin to the nontoxic form of a toxoid began in 1924. A bivalent toxoid (for serotypes A and B) was developed in the United States in the 1940s. Further research led to a pentavalent toxoid (serotypes A–E) first produced in large lots by Parke, Davis, and Company in 1958 under contract to the U.S. Army (Anderson and Lewis, 1981). The current botulinum toxoid vaccine, a pentavalent toxoid (serotypes A–E), is in Investigational New Drug status. The toxoid has been administered to volunteers for testing purposes and to occupationally at-risk workers. The schedule for the pentavalent toxoid calls for subcutaneous injections at 0, 2, and 12 weeks, followed by annual boosters. Recent advances in molecular cloning techniques and new knowledge about the molecular mechanisms of action of the toxins have opened up avenues for new botulinum vaccine development (Middlebrook, 1995). Conclusions on the Health Effects of Botulinum Toxoid Early studies of the initial univalent botulinum toxoids in the 1940s reported a significant number of local and systemic reactions (Middlebrook and Brown, 1995). Several studies that primarily focused on the efficacy of the botulinum toxoid vaccine (Fiock et al., 1962, 1963) noted moderate local or systemic reactions. Studies of the botulinum toxoid vaccine have not used active surveillance to systematically evaluate long-term health outcomes. This situation is unfortunately typical for all but a few vaccines.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines The committee concludes that there is sufficient evidence of an association between botulinum toxoid vaccination and transient acute local and systemic effects (e.g., redness, swelling, fever) typically associated with vaccination. The committee concludes that there is inadequate/insufficient evidence to determine whether an association does or does not exist between botulinum toxoid vaccination and long-term adverse health effects. Multiple Vaccinations Military personnel often receive several vaccinations as they prepare for service in an environment with many endemic diseases. People have expressed concerns that multiple vaccinations prior to and during Gulf War service may have caused adverse health effects. Conclusions on the Health Effects of Multiple Vaccinations Certain multiple vaccination regimens can lead to suboptimal antibody responses, but there is little evidence, largely because of a lack of active monitoring, of adverse clinical or laboratory consequences beyond the transient local and systemic effects seen frequently with any vaccination. A group of 99 employees at Fort Detrick, Maryland, who received many vaccinations related to occupational requirements, were followed for up to 25 years to investigate the potential subclinical effects of intensive vaccination. The participants underwent physical examinations and laboratory testing in 1956, 1962, and 1971 (Peeler et al., 1958, 1965; White et al., 1974). No clinical sequelae attributable to intense long-term immunization could be identified in this cohort. None of the subjects suffered unexplained clinical symptoms requiring them to take sick leave that could be attributed to the vaccination program. There was some evidence of a chronic inflammatory response, as characterized by certain laboratory test abnormalities. However, these changes cannot necessarily be attributed to the vaccinations, because the workers studied were occupationally exposed to a number of virulent microbes. This series of longitudinal clinical studies had several shortcomings. However, the studies were valuable because careful monitoring did not disclose any evidence of serious unexplained illness in a cohort that received a series of intense vaccination protocols over many years. Several studies of U.K. Gulf War veterans provide some limited evidence of an association between multiple vaccinations and long-term multisymptom outcomes, particularly for vaccinations given during deployment (Unwin et al., 1999; Hotopf et al., 2000). There are some limitations and confounding factors in these studies, and further research is needed.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines The committee concludes that there is inadequate/insufficient evidence to determine whether an association does or does not exist between multiple vaccinations and long-term adverse health effects. COMMENTS ON INCREASED RISK OF ADVERSE HEALTH OUTCOMES AMONG GULF WAR VETERANS The committee reviewed the available scientific evidence in the peer-reviewed literature in order to draw conclusions about associations between the agents of interest and adverse health effects in all populations (see Table 1). The committee placed its conclusions in categories that reflect the strength of the evidence for an association between exposure to the agent and health outcomes. The committee could not measure the likelihood that Gulf War veterans’ health problems are associated with or caused by these agents. To address this issue, the committee would need to compare the rates of health effects in Gulf War veterans exposed to the putative agents with the rates of those who were not exposed, which would require information about the agents to which individual veterans were exposed and their doses. However, as discussed throughout this report, there is a paucity of data regarding the actual agents and doses to which individual Gulf War veterans were exposed. Further, to answer questions about increased risk of illnesses in Gulf War veterans, it would also be important to know the degree to which any other differences between exposed and unexposed veterans could influence the rates of health outcomes. This information is also lacking for the Gulf War veteran population. Indeed most of the evidence that the committee used to form its conclusions about the association of the putative agents and health effects comes from studies of populations exposed to these agents in occupational and clinical settings, rather than from studies of Gulf War veterans. Due to the lack of exposure data on veterans, the committee could not extrapolate from the level of exposure in the studies that it reviewed to the level of exposure in Gulf War veterans. Thus, the committee could not determine the TABLE 1 Summary of Findings Sufficient Evidence of a Causal Relationship Evidence is sufficient to conclude that a causal relationship exists between the exposure to a specific agent and a 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.   Exposure to sarin and a dose-dependent acute cholinergic syndrome that is evident seconds to hours subsequent to sarin exposure and resolves in days to months.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Sufficient Evidence of an Association Evidence is sufficient to conclude that there is a positive association. That is, a positive association has been observed between an exposure to a specific agent and a health outcome in human studies in which chance, bias, and confounding could be ruled out with reasonable confidence.   Pyridostigmine bromide and transient acute cholinergic effects in doses normally used in treatment and for diagnostic purposes. Anthrax vaccination and transient acute local and systemic effects. Botulinum toxoid vaccination and transient acute local and systemic effects. Limited/Suggestive Evidence of an Association Evidence is suggestive of an association between exposure to a specific agent and a health outcome in humans, but is limited because chance, bias, and confounding could not be ruled out with confidence.   Exposure to sarin at doses sufficient to cause acute cholinergic signs and symptoms and subsequent long-term health effects. Inadequate/Insufficient Evidence to Determine Whether an Association Does or Does Not Exist The available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association between an exposure to a specific agent and a health outcome in humans.   Exposure to uranium and lung cancer at higher levels of cumulative exposure (>200 mSv or 25 cGy). Exposure to uranium and lymphatic cancer; bone cancer; nervous system disease; nonmalignant respiratory disease; or other health outcomes (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). Pyridostigmine bromide and long-term adverse health effects. Exposure to sarin at low doses insufficient to cause acute cholinergic signs and symptoms and subsequent long-term adverse health effects. Anthrax vaccination and long-term adverse health effects. Botulinum toxoid vaccination and long-term adverse health effects. Multiple vaccinations and long-term adverse health effects. Limited/Suggestive Evidence of No Association There are several adequate studies covering the full range of levels of exposure that humans are known to encounter, that are mutually consistent in not showing a positive association between exposure to a specific agent and a health outcome at any level of exposure. A conclusion of no association is inevitably limited to the conditions, levels of exposure, and length of observation covered by the available studies. In addition, the possibility of a very small elevation in risk at the levels of exposure studied can never be excluded.   Exposure to uranium and lung cancer at cumulative internal dose levels lower than 200 mSv or 25 cGy. Exposure to uranium and clinically significant renal dysfunction.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines likelihood of increased risk of adverse health outcomes among Gulf War veterans due to exposure to the agents examined in this report. RESEARCH RECOMMENDATIONS The committee’s charge was to review the scientific literature on the potential health effects of agents to which Gulf War veterans may have been exposed. Of the many stressors and biological and chemical agents in the Gulf War theater, this report has reviewed the literature on the agents that were of most concern to the veterans and their representatives. Subsequent IOM studies will examine the literature on other Gulf War-related agents. The committee considered the evidence for each of the agents in turn, as if each one were the only risk factor for adverse health effects. It did so because committee members sought to learn how each agent, in the absence of all of the others, might affect human health. The committee realized through the course of this study, however, that there may also be a need to examine the impact of the total experience of deployment and war on veterans’ health. Such an approach may help elucidate the nature of the illnesses in Gulf War veterans in a way that is not possible by examining single agents. Unfortunately, most of the studies conducted to date focus only on single agents. Yet integrating the various stressors, biological and chemical exposures, the complexities faced by military personnel during all phases of deployment, and the issues surrounding war may provide a more realistic approach toward understanding veterans’ health issues and may provide insights for preventing illnesses in future deployments. The committee has developed the recommendations in Table 2 for future research, based on its review of the literature on each of the putative agents. These recommendations highlight areas of scientific uncertainty and, if implemented, will help to resolve important questions about the effect of the Gulf War on the health of the veterans. Finally, this report takes its place alongside several other recent IOM reports on the health of Gulf War veterans. Although the conclusions and recommendations presented here will not end the controversy surrounding Gulf War veterans’ illnesses, this report will provide a scientific basis for consideration by the Department of Veterans Affairs as they develop a compensation program for veterans. The committee hopes that its deliberations, along with the work of many others, will add to the body of accumulating knowledge about the health of Gulf War veterans.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines TABLE 2 Research Recommendations Biological, Chemical, and Psychological Interactions   Research on the interactions among the multiple agents and stressors to which military personnel were exposed as a result of the Gulf War conflict. Depleted Uranium   Continued follow-up of the Baltimore cohort of Gulf War veterans with DU exposure. Long-term studies of the health of other Gulf War veterans at high risk for DU exposure (e.g., cleanup or radiation control units). Continued follow-up of the cohorts of uranium processing workers. Additional studies of the effects of DU in animals. Sarin   Long-term follow-up of populations exposed to sarin in the Matsumoto and Tokyo terrorist attacks. Studies in experimental animals to investigate the long-term effects of an acute, short-term exposure to sarin at doses that do not cause overt cholinergic effects and minimal acetylcholinesterase inhibition. Research on genetic factors that may alter susceptibility to sarin toxicity. Pyridostigmine Bromide   Research on chemical interactions between PB and other agents such as stress, and certain insecticides. Research on genetic factors (e.g., genetic polymorphisms of butyrylcholinesterase, paraoxonase) that may alter susceptibility to the effects of PB. Epidemiologic studies on the possible long-term health effects of PB. Vaccines   Long-term longitudinal studies of participants in the Anthrax Vaccine Immunization Program that would actively monitor and systematically collect and analyze data about symptoms, functional status, and disease status. Long-term systematic research to examine potential adverse effects of anthrax and botulinum toxoid vaccination in multiple species and strains of animals. Careful study of current symptoms, functional status, and disease status in cohorts of Gulf War veterans and Gulf War-era veterans for whom vaccination records exist. REFERENCES Anderson JH Jr, Lewis GE Jr. 1981. Clinical evaluation of botulinum toxoids. In: Lewis GH Jr, ed. Biomedical Aspects of Botulism. New York: Academic Press. Bellone J, Ghigo E, Mazza E, Boffano GM, Valente F, Imperiale E, Arvat E, Procopio M, Nicolosi M, Valetto MR, D’Antona G, Rizzi G, Camanni F. 1992. Combined administration of pyridostigmine and growth hormone releasing hormone in the diagnosis of pituitary growth hormone deficiency. Acta Medica Auxologica 24(1):31–37.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Brachman PS, Gold H, Plotkin S, Fekety FR, Werrin M, Ingraham NR. 1962. Field evaluation of a human anthrax vaccine. Am J Public Health 52:632–645. Brown MA, Brix KA. 1998. Review of health consequences from high-, intermediate-and low-level exposure to organophosphorous nerve agents. J Appl Toxicol 18(6): 393–408. Christopher GW, Cieslak TJ, Pavlin JA, Eitzen EM Jr. 1997. Biological warfare. A historical perspective. JAMA 278(5):412–417. CIA–DoD (Central Intelligence Agency and Department of Defense). 1997. Modeling the Chemical Warfare Agent Release at the Khamisiyah Pit. Washington, DC: CIA– DoD. Coiro V, Volpi R, Marchesi C, DeFerri A, Capretti L, Caffarri G, Colla R, Chiodera P. 1998. Different effects of pyridostigmine on the thyrotropin response to thyrotropin-releasing hormone in endogenous depression and subclinical thyrotoxicosis. Metabolism 47(1):50–53. Committee on Veterans’ Affairs, U.S. Senate. 1998. Report of the Special Investigation Unit on Gulf War Illnesses. 105th Congress, 2nd session. S.PRT 105-39. Washington, DC: U.S. Government Printing Office. Cordido F, Penalva A, Peino R, Casanueva FF, Dieguez C. 1995. Effect of combined administration of growth hormone (GH)-releasing hormone, GH-releasing peptide-6, and pyridostigmine in normal and obese subjects. Metabolism 44(6):745–748. Dupree EA, Watkins JP, Ingle JN, Wallace PW, West CM, Tankersley WG. 1995. Uranium dust exposure and lung cancer risk in four uranium processing operations. Epidemiology 6(4):370–375. Ellenberg SS. 1999. Statement at the July 21, 1999, hearing of the Subcommittee on National Security, Veterans Affairs, and International Relations, Committee on Government Reform, U.S. House of Representatives. Rockville, MD: Food and Drug Administration. Evans AS. 1976. Causation and disease: The Henle–Koch postulates revisited. Yale J Biol Med 49(2):175–195. Fahey D. 2000. Don’t Look, Don’t Find: Gulf War Veterans, the U.S. Government and Depleted Uranium. Lewiston, ME: Military Toxics Project. Fiock MA, Devine LF, Gearinger NF, Duff JT, Wright GG, Kadull PJ. 1962. Studies on immunity to toxins of Clostridium botulinum. VIII. Immunological response of man to purified bivalent AB botulinum toxoid. J Immunol 88:277–283. Fiock MA, Cardella MA, Gearinger NF. 1963. Studies on immunity to toxins of Clostridium botulinum. X. Immunologic response of man to purified pentavalent ABCDE botulinum toxoid. J Immunol 90:697–702. Frome EL, Cragle DL, McLain RW. 1990. Poisson regression analysis of the mortality among a cohort of World War II nuclear industry workers. Radiat Res 123(2):138–152. GAO (U.S. General Accounting Office). 1999. Medical Readiness: Safety and Efficacy of the Anthrax Vaccine . Statement of Kwai-Cheung Chan, Director, Special Studies and Evaluations, National Security and International Affairs Division, before the Subcommittee on National Security, Veterans’ Affairs, and International Relations, Committee on Government Reform, House of Representatives. GAO/T-NSIAD-99-148. Washington, DC: GAO. Ghigo E, Arvat E, Mazza E, Mondardini A, Cappa M, Muller EE, Cammani F. 1990a. Failure of pyridostigmine to increase both basal and GHRH-induced GH secretion in the night. Acta Endocrinol (Copenh) 122(1):37–40.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Ghigo E, Bellone J, Imperiale E, Arvat E, Mazza E, Valetto MR, Boffano GM, Cappa M, Loche S, De Sanctis C, et al. 1990b. Pyridostigmine potentiates L-dopa- but not arginine- and galanin-induced growth hormone secretion in children. Neuroendocrinology 52(1):42–45. Ghigo E, Imperiale E, Boffano GM, Mazza E, Bellone J, Arvat E, Procopio M, Goffi S, Barreca A, Chiabotto P, et al. 1990c. A new test for the diagnosis of growth hormone deficiency due to primary pituitary impairment: Combined administration of pyridostigmine and growth hormone-releasing hormone. J Endocrinol Invest 13(4): 307–316. Ghigo E, Aimaretti G, Gianotti L, Bellone J, Arvat E, Camanni F. 1996a. New approach to the diagnosis of growth hormone deficiency in adults. Eur J Endocrinol 134(3): 352–356. Ghigo E, Bellone J, Aimaretti G, Bellone S, Loche S, Cappa M, Bartolotta E, Dammacco F, Camanni F. 1996b. Reliability of provocative tests to assess growth hormone secretory status. Study in 472 normally growing children. J Clin Endocrinol Metab 81(9):3323–3327. Giustina A, Bodini C, Bossoni S, Doga M, Girelli A, Pizzocolo G, Wehrenberg WB. 1990. Effects of calcitonin on GH response to pyridostigmine in combination with hGHRH (1–29)NH2 in normal adult subjects. Clin Endocrinol (Oxf) 33(3):375–380. Giustina A, Bossoni S, Bodini C, Doga M, Girelli A, Buffoli MG, Schettino M, Wehrenberg WB. 1991. The role of cholinergic tone in modulating the growth hormone response to growth hormone-releasing hormone in normal man. Metabolism 40(5): 519–523. Goodman LS, Gilman A, Hardman JG, Limbird LE. 1996. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 9th edition. New York: McGraw-Hill. Haley RW, Kurt TL. 1997. Self-reported exposure to neurotoxic chemical combinations in the Gulf War. A cross-sectional epidemiologic study. JAMA 277(3):231–237. Harley NH, Foulkes EC, Hiborne LH, Hudson A, Anthony CR. 1999. Depleted Uranium: A Review of the Scientific Literature as It Pertains to Gulf War Illnesses. Santa Monica, CA: RAND. Hill AB. 1971. Principles of Medical Statistics. New York: Oxford University Press. Hotopf M, David A, Hull L, Ismail K, Unwin C, Wessely S. 2000. Role of vaccinations as risk factors for ill health in veterans of the Gulf War: Cross-sectional study. BMJ 320:1363–1367. Hubert M, Lison D. 1995. Study of muscular effects of short-term pyridostigmine treatment in resting and exercising rats. Hum Exp Toxicol 14(1):49–54. IOM (Institute of Medicine). 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: National Academy Press. IOM (Institute of Medicine). 1994a. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: National Academy Press. IOM (Institute of Medicine). 1994b. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press. IOM (Institute of Medicine). 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. IOM (Institute of Medicine). 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. IOM (Institute of Medicine). 2000. Clearing the Air: Asthma and Indoor Air Exposures. Washington, DC: National Academy Press.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Lotti M. 2000. Organophosphorous compounds. In: Spencer P, Schaumburg H, Ludolph A, eds. Experimental and Clinical Neurotoxicology. 2nd edition. New York: Oxford University Press. Pp. 897–925. Lu S, Zhao F-Y. 1990. Nephrotoxic limit and annual limit of intake for natural uranium. Health Phys 58(5):619–623. Madsen JM. 1998. Clinical Considerations in the Use of Pyridostigmine Bromide as Pretreatment for Nerve-Agent Exposure. Aberdeen Proving Ground, MD: Army Medical Research Institute of Chemical Defense. (Available from the National Technical Information Service: NTIS/AD-A353931.) McDiarmid MA, Keogh JP, Hooper FJ, McPhaul K, Squibb K, Kane R, DiPino R, Kabat M, Kaup B, Anderson L, Hoover D, Brown L, Hamilton M, Jacobson-Kram D, Burrows B, Walsh M. 2000. Health effects of depleted uranium on exposed Gulf War veterans. Environ Res 82(2):168–180. Middlebrook JL. 1995. Protection strategies against botulinum toxin. Adv Exp Med Biol 383:93–98. Middlebrook JL, Brown JE. 1995. Immunodiagnosis and immunotherapy of tetanus and botulinum neurotoxins. Curr Top Microbiol Immunol 195:89–122. Murialdo G, Zerbi F, Filippi U, Tosca P, Fonzi S, Di Paolo E, Costelli P, Porro S, Polleri A, Savoldi F. 1991. Cholinergic modulation of growth hormone-releasing hormone effects on growth hormone secretion in dementia. Neuropsychobiology 24(3):129–134. Murialdo G, Fonzi S, Torre F, Costelli P, Solinas G, Tosca P, Di Paolo E, Porro S, Zerbi F, Polleri A. 1993. Effects of pyridostigmine, corticotropin-releasing hormone and growth hormone-releasing hormone on the pituitary–adrenal axis and on growth hormone secretion in dementia. Neuropsychobiology 28(4):177–183. O’Keane V, O’Flynn K, Lucey J, Dinan TG. 1992. Pyridostigmine-induced growth hormone responses in healthy and depressed subjects: Evidence for cholinergic supersensitivity in depression. Psychol Med 22(1):55–60. O’Keane V, Abel K, Murray RM. 1994. Growth hormone responses to pyridostigmine in schizophrenia: Evidence for cholinergic dysfunction. Biol Psychiatry 36(9):582–588. OSAGWI (Office of the Special Assistant for Gulf War Illnesses). 1998. Depleted Uranium in the Gulf. Washington, DC: U.S. Department of Defense. OSAGWI (Office of the Special Assistant for Gulf War Illnesses). 1999. Military Medical Recordkeeping During and After the Gulf War: Interim Report. Washington, DC: U.S. Department of Defense. PAC (Presidential Advisory Committee on Gulf War Veterans’ Illnesses). 1996. Presidential Advisory Committee on Gulf War Veterans’ Illnesses: Final Report. Washington, DC: U.S. Government Printing Office. Peeler RN, Cluff LE, Trever RW. 1958. Hyperimmunization of man. Bulletin of the Johns Hopkins Hospital 103:183–198. Peeler RN, Kadull P, Cluff L. 1965. Intensive immunization of man: Evaluation of possible adverse consequences. Ann Intern Med 63(1):44–57. Physicians’ Desk Reference. 2000. 54th ed. Montvale, NJ: Medical Economics Company, Inc. Pile JC, Malone JD, Eitzen EM, Friedlander AM. 1998. Anthrax as a potential biological warfare agent. Arch Intern Med 158(5):429–434. Rettig RA. 1999. Military Use of Drugs Not Yet Approved by the FDA for CW/BW Defense. Santa Monica, CA: RAND.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Ritz B. 1999. Radiation exposure and cancer mortality in uranium processing workers. Epidemiology 10(5):531–538. Ross RJ, Tsagarakis S, Grossman A, Nhagafoong L, Touzel RJ, Rees LH, Besser GM. 1987. GH feedback occurs through modulation of hypothalamic somatostatin under cholinergic control: Studies with pyridostigmine and GHRH. Clin Endocrinol (Oxf) 27(6):727–733. Somani SM. 1992. Chemical Warfare Agents. New York: Academic Press. Stewart CE, Sullivan J Jr. 1992. Military munitions and antipersonnel agents. In: Sullivan JB Jr, Krieger G, eds. Hazardous Materials Toxicology: Clinical Principles of Environmental Health. Baltimore: Williams & Wilkins. Pp. 986–1014. Unwin C, Blatchley N, Coker W, Ferry S, Hotopf M, Hull L, Ismail K, Palmer I, David A, Wessely S. 1999. Health of UK servicemen who served in Persian Gulf War. Lancet 353(9148):169–178. USAMRIID (U.S. Army Medical Research Institute of Infectious Diseases). 1996. Medical Management of Biological Casualties: Handbook. 2nd edition. Fort Detrick, MD: USAMRIID. White CS, Adler WH, McGann VG. 1974. Repeated immunization: Possible adverse effects. Ann Intern Med 81(5):594–600. Williams, JI. 1984. Human Response to Pyridostigmine Bromide. Fairborn, OH: Macaulay-Brown, Inc. (Available from the National Technical Information Service: NTIS/ AD-A140960.) Yang I, Woo J, Kim S, Kim J, Kim Y, Choi Y. 1995. Combined pyridostigmine–thyrotrophin-releasing hormone test for the evaluation of hypothalamic somatostatinergic activity in healthy normal men. Eur J Endocrinol 133(4):457–462. Zamora ML, Tracy BL, Zielinski JM, Meyerhof DP, Moss MA. 1998. Chronic ingestion of uranium in drinking water: A study of kidney bioeffects in humans. Toxicol Sci 43(1):68–77.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines CONTENTS      ADDRESSING GULF WAR HEALTH ISSUES   28      Past and Current Efforts,   28      Complexities in Resolving Gulf War Health Issues,   29      Multiple Exposures and Chemical Interactions,   29      Limitations of Exposure Information,   31      Individual Variability,   31      Unexplained Symptoms,   32      THE GULF WAR SETTING   32      Deployment,   32      Living Conditions,   33      Environmental and Chemical Exposures,   33      Threat of Chemical and Biological Warfare,   34      SCOPE OF THE REPORT   35      ORGANIZATION OF THE REPORT   36      REFERENCES   36