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.
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.
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,
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
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
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 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
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 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
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.
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
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 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
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-
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.
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).
Conclusions on the Health Effects of Pyridostigmine Bromide
A large number of clinical studies have reported that PB causes acute transient cholinergic effects in normal volunteers, patients given PB as a diagnostic test of hypothalamic pituitary function, and myasthenia gravis patients treated with the drug for extended periods. When used as a diagnostic test, PB is generally administered as a single oral 30- to 180-mg dose, which produces acute transient cholinergic symptoms in a minority of patients and normal volunteers. Within several hours of ingesting PB, 25 percent of subjects experience abdominal symptoms (cramps, increased digestive sounds, pain, diarrhea, and nausea), and 10 percent have muscular symptoms (skeletal muscle and tongue fasciculations sometimes accompanied by dysarthria) that typically last 1–2 hours (see, for example, Ross et al., 1987; Ghigo et al., 1990a,b,c, 1996a,b; Giustina et al., 1990, 1991; Murialdo et al., 1991, 1993; Bellone et al., 1992; O’Keane et al., 1992, 1994; Cordido et al., 1995; Yang et al., 1995; Coiro et al., 1998). The symptoms are usually mild, transient, and tolerable; seldom require medical intervention; and are not accompanied by central nervous system symptoms. Although the studies summarized in this report did not show a relationship between increasing dose and more severe side effects, none was designed specifically to demonstrate a dose–response relationship. There is, however, a trend toward a greater rate of symptoms at higher PB doses among subjects given several different doses in the same study.
The main therapeutic use of PB is to control muscle weakness in myasthenic patients; the daily doses of PB usually range from 120 to 600 mg. About one-third of those who take PB have one or more side effects, which are usually mild. The most common symptoms are gastrointestinal in origin. A few patients experience other cholinergic symptoms such as hypersalivation, increased perspiration, urinary urgency, increased bronchial secretion, and blurred vision. Patients seldom stop taking the drug because of side effects.
During the Gulf War, acute accidental poisoning with PB in doses ranging from 390 to 900 mg resulted in mild-to-moderate cholinergic symptoms occurring within several minutes of ingestion and lasting up to 24 hours. Patients typically developed muscarinic effects (e.g., abdominal cramps, diarrhea, nausea, hypersalivation, vomiting), urinary incontinence, and transient muscle fasciculation and weakness. The effects were self-limited and were well tolerated.
The most extensive information available on the acute effects of PB comes from studies of its use for diagnosis of growth hormone deficiency and its therapeutic use for myasthenia gravis. The doses of PB in these applications are higher than those used for prophylaxis during the Gulf War, yet these studies consistently indicate that PB is safe and effective in clinical applications. Side effects are predominantly gastrointestinal and muscular, do not last long, and have no long-term residual effects.
Results from other human studies, in both clinical and healthy volunteer populations, report the same gastrointestinal and muscular side effects, which
are transient and characteristically mild. Idiosyncratic reactions occur at a much lower rate.
The committee concludes that there is sufficient evidence of an association between PB and transient acute cholinergic effects in doses normally used in treatment and for diagnostic purposes.
Since unexplained Gulf War-related illnesses have been chronic, possible long-term effects of PB are of great interest. There are no reports of chronic toxicity related to human PB exposure in clinical or military populations. Haley and Kurt (1997) suggested that unexplained Gulf War-related symptoms could be a unique manifestation of organophosphate-induced delayed neuropathy associated with PB exposure alone or in combination with other wartime exposures, in the absence of acute symptoms of organophosphate toxicity. There is evidence that some AChE inhibitors may be associated with chronic neurological changes. Haley and Kurt provide evidence that a small number of ill Gulf War veterans have neurological impairment compared to a small number of well veterans from the same unit. The committee felt that the validity of this association, and the possible causal relationship between PB and the neurological findings, are uncertain. Among the reasons for withholding judgment are the large potential for selection and information biases4 in this study population, the lack of a nondeployed comparison group, and the lack of clinical validity in the measures of neurological damage. Haley and Kurt’s hypothesis requires further investigation.
Haley and Kurt (1997) have also suggested that chronic neuropsychological syndromes derived from factor analysis are linked to acute responses to administration of PB. The evidence that they present has several shortcomings. The major limitation was the lack of comparable studies in a nondeployed group of veterans. There is uncertainty about how the authors selected, administered, and interpreted the neuropsychological tests. The study population consisted of self-selected individuals who replied to a survey (41 percent of the battalion). The data on exposure to PB were self-reports of events that had occurred many years before.
The epidemiologic data do not provide evidence of a link between PB and chronic illness in Gulf War veterans. Most epidemiologic studies of Gulf War veterans have focused on whether a unique Gulf War syndrome exists and defining its characteristics. Only two epidemiologic studies specifically investigated the possible association of PB use and chronic symptoms among Gulf War veterans (Haley and Kurt, 1997; Unwin et al., 1999). This summary has already noted the limitations of the small, selected population studied by Haley and colleagues. Based on factor analysis, they defined three syndromes associated with
Gulf War service. These factor-derived syndromes were not associated with taking PB or with the dose of PB. Haley and Kurt found an association between two of the three syndromes and self-reported symptoms that are consistent with adverse effects of PB. Because the study cohort was not assembled from a random sample of Gulf War veterans, this apparent association may be the result of inadvertent selection for veterans with both adverse health syndromes and adverse effects of PB. The evidence is not strong enough to conclude that an association exists between Gulf War illnesses and side effects of PB. In the second epidemiologic study (Unwin et al., 1999), all exposures studied (PB, diesel or petrochemical fumes, oil fire smoke, viewing dismembered bodies, etc.) showed an association of similar magnitude with adverse symptoms in U.K. servicemen. The lack of specificity of the association between the type of exposure and symptoms suggests that PB itself is not the cause of the symptoms. Recall bias and reporting bias5 may explain this finding. Thus, neither of these two studies provides good evidence for a specific association between PB and chronic adverse health effects.
The committee concludes that there is inadequate/insufficient evidence to determine whether an association does or does not exist between PB and long-term adverse health effects.
During the Gulf War, a number of different immunobiologics (e.g., cholera, meningitis, rabies, tetanus, and typhoid vaccines) were sent to the war theatre to protect military personnel against potential exposures to biological threats (Committee on Veterans’ Affairs, 1998). Concerns about Iraq’s offensive biological warfare capabilities led to the decision that available vaccines should be utilized as preventive measures against biological warfare agents. The military sent approximately 310,000 doses of FDA-licensed anthrax vaccine to the Gulf War theatre, and it is estimated that 150,000 U.S. troops received at least one anthrax vaccination (Christopher et al., 1997; Committee on Veterans’ Affairs, 1998). Approximately 137,850 doses of botulinum toxoid were sent to the Gulf, and it is estimated that 8,000 military personnel were vaccinated (Committee on Veterans’ Affairs, 1998). However, medical records from the Gulf War contain little or no information about who received these vaccines, how frequently the vaccines were administered, or the timing of vaccinations relative to other putative exposures (OSAGWI, 1999).
The primary use of the anthrax vaccine in humans was initially for the protection of occupationally exposed individuals (e.g., persons working with animal hair or hide, including goat hair mill workers, tannery workers, and veterinarians). Protective antigen, one of the three toxin proteins produced by the anthrax bacillus, is the immunogenic component of both the U.S. and the U.K. vaccines. The U.S. vaccine is an aluminum hydroxide-adsorbed cell-free culture filtrate of an unencapsulated anthrax strain (Pile et al., 1998). Product licensure for Anthrax Vaccine Adsorbed was granted on November 10, 1970. It is estimated that 68,000 doses of the U.S. anthrax vaccine were distributed from 1974 to 1989, 268,000 doses in 1990, and 1.2 million doses from 1991 to July 1999 (Ellenberg, 1999). The exact number of people who received the vaccine is not known. The current dosing schedule is 0.5 ml administered subcutaneously at 0, 2, and 4 weeks and 6, 12, and 18 months, followed by yearly boosters.
In December 1997, the Secretary of Defense announced that all U.S. military forces would receive anthrax vaccinations for protection against the threat of biological warfare. The Anthrax Vaccine Immunization Program began vaccinations in March 1998.
Conclusions on the Health Effects of the Anthrax Vaccine
There is a paucity of published peer-reviewed literature on the safety of the anthrax vaccine. Brachman and colleagues (1962) conducted the only randomized clinical trial of vaccination with a protective antigen anthrax vaccine.6 The clinical trial was conducted among eligible workers at four goat hair processing mills in which some raw materials were contaminated by anthrax bacilli. Participants were examined 24 and 48 hours following each vaccination to assess both local and systemic reactions to the vaccine. There were no reports of subsequent active or passive surveillance for possible adverse effects beyond 48 hours after each vaccination (however, there was further monitoring for the vaccine’s efficacy). The typical reaction is described as a ring of erythema (1–2 cm in diameter) at the injection site, with local tenderness that lasted 24–48 hours. Some subjects (a number was not given) reported more extensive edema, erythema (more than 5 cm in diameter), pruritus, induration, or small painless nodules at the injection site (lasting up to several weeks). Twenty-one individuals had moderate local edema that lasted up to 48 hours. The only systemic reactions were reported in two individuals (0.9 percent of the actively vaccinated subjects) who experienced “malaise” lasting 24 hours following vaccination. The study notes that three individuals who received the placebo (0.1 percent
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 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.
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.
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.
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.
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 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.
likelihood of increased risk of adverse health outcomes among Gulf War veterans due to exposure to the agents examined in this report.
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.
TABLE 2 Research Recommendations
Biological, Chemical, and Psychological Interactions
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