Presidential Advisory Committee on Gulf War Veterans' Illnesses
U.S. service members potentially were exposed to a broad range of risk factors during the Gulf War. The Committee evaluated the potential health effects of several suspected risk factors, which were selected based on our charter, previous reports on Gulf War veterans' illnesses, and expert and stakeholder testimony at meetings held nationwide. We also have attempted to analyze the extent and likelihood of exposure to these risk factors during the Gulf War. In most instances, however, exposure data have been difficult to obtain or nonexistent. This chapter reports the Committee's findings on the following risk factors:
The chapter first reports what is known currently about possible U.S. troop exposure to each risk factor. Following this analysis, we discuss health effects known to date, and we present our findings and recommendations in the final section of this chapter.
EXPOSURE TO RISK FACTORS IN THE GULF
As described in the Committee's Interim Report, few exposure data exist on many key Gulf War risk factors. In fact, for most of the risk factors we analyzed, the only exposure information available today is anecdotal recollections of Gulf War veterans. As a consequence, it will be difficult to link, in a scientifically valid manner, any adverse health outcomes detected by ongoing research to specific exposures or risk factors. As noted in chapter 2, the Committee has concluded that DOD's Persian Gulf Registry of Unit Locations will be of little use for investigating questions about Gulf War veterans' health issues and is certainly an inadequate substitute for missing exposure data.
Exposure to Pesticides
Precise records exist for pesticides DOD shipped to the Gulf region (table 4-1). All pesticides shipped were approved by EPA or FDA for general use in the United States at the time of the Gulf War. U.S. consumers can purchase these at grocery, gardening, and other stores in products such as: OFF® and Cutters® (DEET), Raid® Ant and Roach Killer Spray and Raid® Yard Guard (permethrin), Black Flag® Insect Spray (Baygon), permethrin spray for treating clothes, and a variety of Ortho® brand and other name brands of gardening products containing carbaryl, diazinon, malathion, chlorpyrifos, and permethrin.
While DOD can document what pesticides were shipped-and how much-there are virtually no records available today on how these pesticides were used in the Gulf region. DOD made no provisions for collecting or keeping distribution or use records of U.S.-shipped and approved products. Reports from a few veterans about the use of other, locally obtained, unapproved pesticides are impossible for the Committee to followup.
Assuming DOD adhered to its policies on pesticide use, its programs closely parallel those established by EPA and FDA regulations for domestic pesticide use. According to DOD policy, the majority of U.S. service members had access to two pesticides: permethrin in a spray can (for treating uniforms) and DEET liquid or stick as a personal mosquito and fly repellent. DOD reports about 2.2 spray-cans of permethrin and 2.0 tubes of DEET (33 percent formulation) were shipped to the Gulf for each U.S. service member. According to DOD, U.S. troops were not provided with permethrin pretreated uniforms. All other pesticides shipped to the Gulf region were to be used only by specifically trained individuals or for special applications. For example, lindane apparently was used nearly exclusively on Iraqi prisoners of war as a delousing agent.
Exposure to Chemical Warfare Agents
DOD has fully acknowledged one case of CW agent exposure. U.S. Army Sergeant Fisher was exposed to a small amount of mustard agent while patrolling an Iraqi bunker during the war. Diagnosis was made on the basis of small chemical burns on his arms consistent with mustard exposure.52 DOD also has confirmed nerve agent detections by Czech units, but has identified neither sources nor potentially exposed U.S. troops.13,119 DOD has confirmed release of nerve agent at Khamisiyah in March 1991, and the Committee has concluded that troops near the demolition activity should be presumed to have been exposed to some level of nerve agent (see chapter 2). The Committee does not presume, however, that this implies long-term health effects in those exposed. DOD continues to investigate other reported CW agent detections.
Except for the Fisher incident, DOD reports in-theater medical surveillance observed no immediate or characteristic poisoning symptoms from any exposure to CW agents. According to representatives from the U.S. Army Medical Corps, which was responsible for training medical personnel to be alert during the war for signs and symptoms of CW agent exposures, characteristic poisoning from nerve agents such as sarin and soman were not seen by medical personnel during the Gulf War.52 At least one other DOD medical repre
sentative, however, posits that a presumption of low-level exposure to OP nerve agents should be made when evaluating unexplained medical problems reported by some Gulf War veterans.13
Exposure to Biological Warfare Agents
Based on classified and public information currently available, the Committee has concluded there is no persuasive evidence that U.S. troops were exposed to BW agents during the Gulf War.35,51,52,119,148,274 We note our determination is based on imperfect information. For instance, the United Nations cannot verify the quantities and weaponization status of Iraqi BW products because Iraq claims it unilaterally destroyed all its biological weapons. Additionally, the United States did not deploy a real-time BW agent detection system during the war.
Two salient factors, however, led to the Committee's conclusion. First, there were no verified detections of anthrax or botulinum toxin during the war. Second, stateside examination of soil samples and enzyme assays did not reveal the presence of BW agents. The Committee's review of U.S. Army hospital admissions records identified one admission for anthrax (a disease indigenous to the Gulf region) and none for botulinum poisoning.342,343 DOD has investigated reports of dead animals that might have succumbed to biological agents, and we concur with the finding that the evidence does not implicate BW agents. Finally, UNSCOM reported to the Committee that Iraqi officials have denied any use of biological weapons during the war and that its own assessment supports this claim.
Exposure to Vaccines
DOD estimates approximately 150,000 U.S. military personnel received at least one anthrax vaccination, and about 8,000 service members received at least one dose of BT vaccine during the Gulf War. As noted in the Interim Report, however, medical recordkeeping on these and other matters was woefully inadequate.
Exposure to Pyridostigmine Bromide
All U.S. troops received blister packs containing PB pills during the Gulf War. The pills were intended to be self-administered upon a unit commander's order. DOD estimates approximately 250,000personnel took at least some PB during the Gulf War.118 As noted in the Interim Report, accurate assessment of PB exposure of U.S. troops is not possible today because no records were kept of self-administered medications.
Exposure to Infectious Diseases
Infectious diseases endemic to the Gulf region include shigellosis, malaria, sandfly fever, and cutaneous leishmaniasis.6,65,90,187 Along with
these infectious diseases, DOD medical personnel also monitored troops for dengue, Sindbis, West Nile fever, Rift Valley fever, and Congo-Crimean hemorrhagic fever.90,293
According to DOD, no cases of sandfly fever were reported during Operations Desert Shield/Desert Storm. Medical personnel saw seven individuals with malaria, one with West Nile fever, and none with rickettsial or other arthropod-borne viral illnesses; arthropod-borne viral diseases endemic to the Gulf are not known to cause chronic infection or disease. The documented low rates of infection among U.S. troops suggest exposures were minimal and/or preventive measures were effective.
Exposure to Depleted Uranium
According to the Office of the Army Surgeon General, 36 U.S. service members are known to have been exposed to DU when wounded in "friendly fire" incidents involving DU munitions.112,267 VA reports it believes about two dozen of these individuals retain embedded DU shrapnel in their bodies.
In addition to exposure through "friendly fire" incidents, a review by the U.S. General Accounting Office concluded that several dozen service members were exposed to DU while retrieving or servicing vehicles damaged by DU munitions.267,306 This number comprises about two dozen Army National Guard soldiers from the 144th Service and Supply Company who have reported they were unknowingly exposed to DU-contaminated debris while working with combat vehicles hit by DU munitions. Another two dozen soldiers from the 24th Infantry Division have reported they were unknowingly exposed to such debris in the course of vehicle recovery and maintenance operations.96,97,267,306
Although DOD had appropriate procedures for protecting personnel who worked with DU contaminated vehicles during the Gulf War, apparently few U.S. service personnel were adequately trained in these procedures. U.S. service personnel also could have been exposed to DU if they inhaled DU dust particles during incidental contact with vehicles destroyed by DU munitions, or if they lived or worked in areas contaminated with DU dust from accidental munitions fires. Thus, unnecessary exposure of many individuals could have occurred.15,18,20,27,42 44,57,141,142,161,186,191,203,226,260,267,306
With the exception of individuals who retain embedded DU munitions fragments, it is not possible to use in vivo monitoring today to develop accurate assessments of DU exposure in the Gulf. Whole-body counting to detect photons of x-ray or gamma radiation cannot be used to test for DU: The equipment is not designed to detect the low energy photons associated with DU decay.87 Moreover, the time that has elapsed since the Gulf War is long compared to the body's retention rate of uranium-i.e., it would be difficult to detect DU even with more sophisticated equipment performing specialized tests such as lung counts.87,259
Exposure to Oil-well Fire Smoke
In contrast to other risk factors, exposure to oil-well fire smoke is better characterized. Many U.S. service members who remained in the Gulf after the oil well fires started could have been exposed to oil-well fire smoke. The burning wells were located in eastern Kuwait, with the majority to the south of Kuwait City. Smoke plumes rose and combined in a "superplume" that could be seen for hundreds of kilometers and sometimes even partially blocked out the sun. Occasionally, smoke plumes touched down to the ground, sometimes enveloping nearby troops. Exact exposure levels for individual soldiers are not certain, but local and regional exposure information is available for oil well fires.
Multiple U.S. and international agencies performed extensive air monitoring during the fires and did not find pollutant levels likely to cause long-term health effects:
The data indicate that, despite the dramatic appearance of the oil plumes, pollutant levels were surprisingly low. All groups found that levels of nitrogen oxides, carbon monoxide, sulfur dioxide, hydrogen sulfide, other pollutant gases, and polycyclic aromatic hydrocarbons (PAHs) were lower than anticipated and did not exceed those seen in urban air in a typical U.S. industrial city.89,289,302,339
High levels of airborne particulate matter (sand and soot), however, were observed frequently at several monitoring sites. Analysis of samples suggested particles were mostly sand-based materials; high levels of airborne sand particulates are typical for this region of the world. Within the samples of particulate matter, levels of PAHs and toxic metals were low.84,265
Samples were collected during at least one instance when the smoke plume had touched down, providing "worst case" exposure data. Although airborne contaminants were detectable, they were surprisingly low compared to current U.S. occupational standards for these contaminants-even within the plume touchdown.84,265,266
Various biological samples also were collected from troops or other personnel working in Kuwait while the fires burned. One CDC study found blood levels of volatile organic compounds (VOCs) in firefighters were significantly higher than those in a U.S. reference population,55 but individuals in Kuwait City, about 20 km from oil fires, had VOC levels approximately that of the reference group. These data are limited by small sample size and the short half-life of VOCs in service members' blood, but they suggest oil-well fire smoke did not significantly increase VOC exposures in troops in the Kuwait City area when most of the fires were active.
Blood and urine samples collected from a group of U.S. service members before, during, and after their 1991 deployment to Kuwait were analyzed for VOCs, PAH-DNA adducts, metals, and sister chromatid exchange (SCE) frequency in lymphocytes.265 Pulmonary function tests and questionnaires also were administered. Levels of metals, VOCs, and PAH-DNA adducts showed no changes or showed decreases in troops living in Kuwait compared to troops living in Germany, with few exceptions. Lead levels in blood were not statistically significantly altered during deployment to the Gulf region.*
Exposure to Petroleum Products
Few specific data exist about possible exposures of U.S. service members to petroleum fuels or their combustion products. Operating the vehicles and machinery used in the Gulf War involved exposure to petroleum-based material. Petroleum fuels also were used for burning wastes and trash, dust suppression, and fueling stoves and tent heaters; none of these uses is unique to the Gulf War. Such uses, however, probably led to increased petroleum vapor and combustion product exposures. Thus, some U.S. service members were exposed to petroleum materials, including benzene, toluene, xylene, ethyl benzene, and combustion products including carbon monoxide, sulfur dioxide, nitrogen dioxide, particulates, lead, and other pollutants.
The U.S. Army's air monitoring (and blood monitoring done by CDC in a small study) found no evidence of elevated exposure to VOCs (including petroleum materials).55,265 Still, some service members clearly experienced short-term, elevated exposures to petroleum fuels. For example, diesel was sprayed on the ground to suppress dust from the fine sand found in the Gulf region. A U.S. Central Command document lists crude oil/waste oil as the least desirable option for dust suppression, but does not mention diesel fuel.280 One U.S. Army sanitary engineer testified to the NIH Technology Assessment Panel in 1994 that units used water or diesel fuel for dust suppression during the war.100 He described one brigade dumping 30,000 gallons of diesel fuel on the roads daily, and said U.S. service members living in tents near the roads-and particularly truck drivers carrying out the spraying-complained of nausea from breathing the resulting fumes. As a result, the preventive medicine person to whom they complained obtained respirators for the drivers' use.101 Another occupational group that could have experienced some risk of elevated exposures to petroleum products during the Gulf War were those who worked at military "Petroleum, Oils, and Lubricants" points where these materials were distributed.
The fuel used most widely during the war for both vehicles and equipment was Jet A-1, an internationally used kerosene-based aviation fuel provided at no cost by the Saudi Arabian government. Of the 1.8 billion gallons of fuel used during Operations Desert Shield/Desert Storm, roughly 75 percent was jet fuel (mostly Jet A-1), 24 percent was diesel fuel, and 1 percent was gasoline.248 The gasoline used during Operations Desert Shield/Desert Storm was commercial leaded gasoline refined to Saudi Arabia's national standard.135
Combustion products from heaters used in poorly ventilated areas also are a general exposure concern for Gulf War participants. Burning leaded fuels indoors without proper ventilation-e.g., heaters in tents-could have caused increased lead exposure. Kerosene heaters, widely used in the United States, also could have been significant sources of exposure to nitric oxides, sulfur dioxide, inorganic combustion gases, carbon monoxide, and particles when used with inadequate ventilation.165 During the war, four hospitalizations in U.S. Army field hospitals occurred because of asphyxiation from carbon monoxide.342,343
Exposure to Psychological and Physiological Stress
U.S. service members encountered many stressors during the Gulf War, including short deployment notice, uncertainty about length of deployment, isolation and separation from family, a polluted environment, poor living conditions with little privacy or social outlets, prolonged work hours, decreased income and worry about job retention, fear of SCUD missile and chemical and biological weapon attacks, anticipation of high casualty rates and torture, frequent CW agent alarms that often required a defensive posture and full chemical gear, and dealing with casualties and dead bodies.
Even when the war was over, many veterans experienced postdeployment stress on their return from the Gulf. These included financial and employment difficulties, unresolved military pay issues, the revelation of cases of leishmaniasis and the consequent temporary ban on blood donations, increasing numbers of health complaints and "unexplained illnesses," and media accounts of apparent increased numbers of birth defects and cancer.
HEALTH EFFECTS OF GULF WAR RISK FACTORS
The Committee undertook a comprehensive analysis of the health effects of the ten Gulf War risk factors for which we examined possible exposures. Our analysis of possible health effects was performed independently of whether exposures were undocumented, imprecise, or known. That is, we considered the possible health consequences of a range of scenarios from high-level to low-level exposure and from single to multiple event and chronic or continuing exposure. The Committee also considered short-term and long-term health effects, including symptoms that might have appeared while service members were still in the KTO and symptoms that might not have appeared until sometime after the service members left the Gulf. The Committee's search for possible health effects extended to all organ systems and to cancer and noncancer outcomes.
Our examination of health effects drew on three types of sources: scientific literature; briefings and workshops with recognized experts; and information presented at Committee meetings. The Committee reviewed human exposure (mostly occupational) data and laboratory animal data. We found extensive scientific literature describing the human health effects for all the risk factors investigated, including CW agents, for which we initially had anticipated would have significant data gaps. The breadth and depth of information generally were sufficient** to make conclusions about the short- and long-term health effects that would be anticipated for U.S. service members exposed to a particular risk factor during the Gulf War.The information available in these sources, however, represents the boundaries of the Committee's investigation. We conducted no primary research and elected not to base our findings on research not yet subjected to peer review.
Finally, the Committee drew conclusions about the role of each risk factor in Gulf War veterans' illnesses based on comparison of the known health effects of the risk factor to the symptoms reported by Gulf War veterans. Symptoms reported by Gulf War veterans used in these comparisons were based on DOD's CCEP and VA's Persian Gulf Health Registry (see table 3-2).
As noted earlier in this chapter, pesticides DOD shipped for use during the Gulf War fell into five major categories: OP pesticides, methyl carbamate pesticides, organochlorine pesticides (lindane), pyrethroid pesticides (chiefly permethrin), and DEET.
Organophosphorus pesticides. Several OP pesticides were used during the Gulf War, including chlorpyrifos, diazinon, dichlorvos, and malathion. When administered in high doses, OP pesticides cause irreversible inhibition of acetylcholinesterase, an enzyme crucial to normal nerve and nerve/muscle function. Inhibiting acetylcholinesterase leads to unique and highly characteristic poisoning symptoms. Immediate symptoms of OP poisoning in humans usually develop within four hours of exposure and include narrowing of the pupil of the eye (miosis), headache, nausea, dizziness, anxiety, and restlessness. Severe and rapid onset poisoning symptoms include muscle twitching, weakness, tremor, incoordination, vomiting, abdominal cramps, diarrhea, sweating, salivation, tearing, runny nose, and production of phlegm. Life-threatening symptoms include unconsciousness, incontinence, convulsions, and depression of breathing function. According to DOD, its medical monitoring and surveillance efforts reported no cases of immediate and severe OP poisoning symptoms in U.S. military personnel during the Gulf War.
Some individuals who recover from immediate and severe OP poisoning show long-term (lasting more than a year), subtle, neuropsychological abnormalities that can be detected using a battery of standardized neuropsychological tests. In an epidemiologic study of such long-term effects, severely poisoned individuals showed clear but subtle differences in intellectual functioning, academic skills, abstraction and flexibility of thinking, and simple motor skills. For example, about a five point difference in IQ was measured in severely poisoned versus control subjects.
Neurophysiologic effects were less apparent; abnormalities were found only in measurements of memory, abstraction, and mood and on one test of motor reflexes.221 These effects could not be detected, however, in a subset of the same worker population that had been exposed to doses of OP pesticides that were too low to cause the symptoms of immediate and severe poisoning.241 Other studies of low-level occupational exposures reinforce the finding that these types of long-term effects present solely in the aftermath of severe and immediate OP agent poisoning.4,241
Some OP pesticides that are no longer sold in the United States have been associated with human cases of a second type of delayed toxic effect called organophosphate-induced delayed neurotoxicity (OPIDN, sometimes referred to as delayed neuropathy). Initial symptoms are muscular incoordination progressing to numbness, tingling, fatigue or a cramp-like pain in the calf muscles, and even moderate to severe muscular weakness and paralysis.7,117 Typically, effects occur 7 to 14 days following recovery from immediate and severe poisoning by the OP pesticide and involve neuropathologic lesions and degeneration of the nerve axon and myelin nerve sheath in both the central and peripheral nervous systems;117 these effects are easy to measure in a clinical setting. In general, OPIDN caused by OP pesticide poisoning is associated with immediate poisoning symptoms.
All OP pesticides sold in the United States today are routinely screened for OPIDN toxicity with a standardized hen assay used by EPA; the hen is a laboratory animal especially sensitive to OPIDN effects. For some OP agents, these effects only can be observed by giving the hen extremely high doses that would rapidly lead to death, but then keeping the hen alive through the use of protective drugs such as atropine. Many investigators conclude any OP agent theoretically could cause this effect at sufficiently high doses, but that, in fact, immediate toxic effects cause death before delayed effects can be seen.117 None of the pesticides DOD shipped to the Gulf War test positive for OPIDN in standard EPA screens.
Methyl carbamate pesticides. Methyl carbamate insecticides shipped for use during the Gulf War included propxur (Baygon®), carbaryl (Sevin®), and methomyl (Lannate®). These insecticides reversibly inhibit acetylcholinesterase, which leads to poisoning effects similar to OP poisoning. Poisoning with methyl carbamates tends to be of much shorter duration-with a greater margin of safety between symptom-producing and lethal doses-compared to OP pesticides, which bind permanently with acetylcholinesterase.
Pyrethroid pesticides. DOD shipped the pyrethroid insecticide permethrin to the Gulf for use as an insect repellent. Permethrin is used widely in the United States as the active ingredient in personal care products, such as shampoos and lotions, and for treating clothes to make them insect repellent. There are few reported poisonings of humans by permethrin, most likely because such a large dose is required to cause poisoning. Humans rapidly detoxify and excrete permethrin. Clinical signs of immediate permethrin poisoning following large oral doses become evident within two hours and include incoordination, ataxia, hyperactivity, and convulsions, followed by prostration, paralysis, and death.171 Unlike OP pesticides, the Committee found no reports of long-term effects from permethrin poisoning in humans.
A National Research Council (NRC) subcommittee that reviewed possible health problems for military personnel wearing permethrin-treated military clothing concluded it is unlikely that soldiers using such uniforms would experience adverse health effects at the suggested exposure levels. The subcommittee concluded, "the weight of evidence shows that permethrin is unlikely to be a skin irritant or skin sensitizer for military personnel who are exposed to it dermally from wearing permethrin impregnated [uniforms]." The estimated "no observable adverse effect level" for immediate neurotoxic effects in humans from daily exposure is 200 milligram (mg)/kilogram, which is approximately three million times greater than estimated dermal exposure from permethrin treated uniforms.171 NRC's worst-case estimate of lifetime carcinogenicity risk for humans wearing permethrin treated uniforms was less than 2 in 1,000,000.
In laboratory animal studies, dermal absorption of permethrin is low, although scientists observe neurotoxic effects if the substance is injected.171,301 Most, but not all, studies have reported permethrin does not cause damage to genetic material in a wide variety of standard measurement systems. Permethrin is neurotoxic to laboratory animals at high oral doses. Rats fed permethrin at 6,000 mg/kg for 14 days showed fragmented and swollen sciatic nerve axons and myelin degeneration. However, nerve conduction studies in 23 permethrin workers showed no evidence of nerve impairment associated with permethrin exposure.171 Rodent bioassays of chronic exposure to permethrin showed carcinogenic effects, such as liver and lung adenomas and lung carcinomas in mice, but data on human carcinogenicity of permethrin are lacking.
Organochlorine pesticides. DOD shipped one organochlorine pesticide, lindane, to the Gulf region. Lindane, once widely used as an agricultural insecticide in the United States, is still available as a lotion to treat head and body lice and scabies.283,301 Lindane is dermally absorbed, stored in body fat, and only slowly leaves the body. Reports document that a few people who have used large amounts of lindane on their skin have had blood disorders and even seizures. Under conditions of extremely high exposure, lindane can cause liver and kidney disease.
Some pregnant laboratory animals orally treated with the maximum tolerated dose (the dose just below that causing immediate and severe toxicity) showed a statistical increase in the number of fetuses with extra limbs, indicating that lindane is a teratogen for this laboratory animal strain. Lindane has not been shown to be a human carcinogen, although long-term oral exposure of lindane to certain species and strains of laboratory rodents has been reported to cause liver cancer.283 Hence, DHHS has determined that lindane should be viewed as a human carcinogen.
DEET. DEET, first introduced in 1955, continues to be a widely used liquid insect repellent in the United States, and DOD shipped approximately two 2-oz tubes per U.S. service member during the Gulf War. According to EPA, 50 to 100 million Americans use DEET-containing insect repellents annually. Relative to most pesticides, DEET has notably low immediate toxicity.190,301 Although generally well tolerated when used as an insect repellent applied to human skin, about five to nine percent is absorbed through skin, and reports exist of tingling, mild irritation, and occasional skin peeling following repeated application.301 Topically applied DEET is rapidly eliminated, mostly in the urine. In the past 35 years a few reports in the medical literature suggest rare neurotoxic effects.190 In adult humans, ingestion of enormous doses of DEET has been associated with immediate toxic effects, including tremors, generalized seizures, and coma, although no long-term effects of poisoning have been reported.320 (For possible synergistic effects, see section on PB later in this chapter.)
Rats continuously fed DEET up to the maximum tolerated dose over three generations showed a slight increase in the high-dose animals in a single neurological abnormality-a slight increase in exploratory locomotor activity-and no histopathologic central nervous and peripheral nervous system changes of significance.190 Other reports indicate that rats fed the maximum tolerated dose of DEET can show severe and often fatal prostration accompanied by a brain myelinopathy.320
What do we conclude about the risks of pesticides to Gulf War veterans? According to DOD, after-action reports from in-theater medical personnel did not reveal any U.S. troops reporting symptoms that would indicate pesticide poisoning. Evidence from studies of humans poisoned by OP pesticides suggests that low-level exposures that do not cause signs and symptoms of immediate and severe poisoning will not result in long-term health effects. Thus, the Committee concludes it is unlikely that health effects and symptoms reported today by Gulf War veterans are the result of exposure to pesticides during the Gulf War. Lindane is an animal liver carcinogen, but it is too early to see an elevated liver cancer rate in Gulf War veterans.
Chemical Warfare Agents
At the time of the Gulf War, the U.S. military believed Iraq had weapons that could deliver OP nerve agents, including sarin, soman, and VX, and mustard (blister) agents. Hence, U.S. forces were supplied with protective gear, detectors, and prophylactic drugs to protect against the known consequences of exposure.
Immediate signs and symptoms of nerve agent poisoning. OP nerve agents are designed to incapacitate and kill humans. Inhalation exposure to these agents leads to immediate effects, including miosis, runny nose, and increased salivation. Immediate effects following skin exposure include local sweating and muscle twitching. Eye exposure rapidly produces miosis, which often is associated with eye pain, headache, and blurred vision.264 In fact, miosis is the most sensitive and specific immediate response to acute poisoning in humans, and this reaction has served as the basis for establishing allowable occupational concentrations for CW nerve agents. Higher doses of these agents cause more severe effects, including convulsions, neuromuscular blockage, profuse airway obstruction and apnea-developing within one to two minutes of exposure.77 Death occurs due to respiratory paralysis. The effects of nerve agent poisoning (figure 4-1) are virtually identical to those of severe OP-pesticide poisoning.
Data on human effects of CW nerve agent poisoning derive largely from human experiments carried out by the U.S. Army from the 1940s to the 1960s. Table 4-2 illustrates the type of information on immediate poisoning effects from low-level exposures to the OP nerve agent sarin.
Immediate signs and symptoms of mustard agent poisoning. With mustard agents, poisoning symptoms are severe irritation and tissue damage to eyes, skin, and respiratory and gastrointestinal (GI) tracts. Usually the onset of symptoms is delayed for some hours after exposure.
One report of Iraqi use of mustard agent against Iranian troops in 1984 documented health effects in more than 5,000 Iranian casualties. Affected individuals had first to third degree burns over 20 to 70 percent of the total skin surface. Eye exposure caused tearing, severe conjunctivitis, and temporary loss of vision. Corneal abrasion was nearly always present, and photophobia and blurred vision developed in some cases. Upper airway involvement due to chemical burning of the throat led to pharyngitis and tracheobronchitis. These effects were quite severe, and this group suffered approximately 15 percent mortality. Those who survived the initial symptoms later experienced various GI complaints, including nausea, vomiting, and diarrhea. After five to seven days, hematologic problems were the greatest health threat to survivors.105
Long-term health effects of exposure to CW nerve agents. Two NRC reports addressed possible long-term morbidity and mortality in about 1,400 servicemen intentionally exposed to CW nerve agents in experiments conducted over a 20-year period ending in 1975. The possibilities of excess cancer risk and adverse mental, neurologic, hepatic, and reproductive effects were reviewed. Both NRC analyses concluded that no evidence exists that CW nerve agents cause long-term, adverse human health effects at the doses tested. The doses were nonlethal, but were high enough to cause clinical effects (such as miosis). NRC reported that both analyses had the power to detect any major health effects had they been present. A statistically significant increase in admissions to VA hospitals for malignant neoplasms was detected, with the caveat that admission numbers were small, showed no dose relationship, and no clustering of specific chemicals in relation to tumor site.174,175
Numerous studies in humans and animals report that survival from severe, immediate poisoning by OP nerve agents (including OP pesticides) can be associated with measurable, long-term neurological effects. One study of 77 industrial workers exposed to levels of sarin that caused immediate toxicity showed slight alterations in electroencephalograms (EEGs) one year after exposure. The study also reported, however, that trained experts could not distinguish an individual EEG from an exposed individual from an EEG of a person who had not been exposed, and that no clear relationship existed between alterations in EEG frequency spectrum and alterations in brain function.22 A 1975 review by Lohs of the effects of CW agents in humans similarly reported long-lasting effects following severe, immediate OP pesticide and CW agent poisoning.140
CW nerve agents do not show OPIDN toxicity as measured in EPA's standardized hen bioassay for evaluating OP pesticides, except with extremely high doses (10 to 100 times the lethal dose) where immediate and severe toxic effects, including death, are seen.117 Because OP CW nerve agents are chemically similar to OP pesticides and affect the same enzyme system in the body, similar long-term health effects would likely occur in the aftermath of immediate, severe poisoning with sarin, soman, or VX-i.e., the subtle, but measurable, neurophysiological and neuropsychological effects described earlier in this chapter. Again, these health effects did not occur in populations that had been exposed to subclinical amounts of OP pesticides. Current scientific evidence suggests that subclinical exposure to OP CW nerve agents does not result in long-term neurophysiological and neuropsychological health effects. Ongoing research at the Boston and Portland Environmental Hazards Research Centers is investigating the possibility of such effects in Gulf War veterans.
Long-term health effects of exposure to mustard agents. Based on epidemiologic research, humans exposed to mustard agent are at increased risk for lung cancer.98,287 Several other reviews of human exposure to mustard agent during World War I (WWI) and other wars also indicate veterans exposed to mustard agents during the Gulf War could experience other respiratory problems as well.98,287
During World War II (WWII), more than 60,000 U.S. service members were used as human test subjects and exposed to mustard agents, including at least 4,000 individuals exposed to high concentrations of these agents.98 An Institute of Medicine (IOM) review concluded that several specific chronic diseases are causally associated with mustard agent exposure. These include various respiratory cancers, skin cancer, chronic skin ulceration and scar formation, chronic respiratory disease including asthma, chronic bronchitis, emphysema, chronic eye diseases, and various psychological disorders including PTSD. IOM also found suggestive evidence (weaker than the associations for the conditions just mentioned) that exposure to mustard agent was associated with leukemia. Finally, IOM also analyzed two studies that examined the link between mustard and reproductive dysfunction, but determined that the database could not be used to make conclusions about human reproductive health effects.98
What do we conclude about the risks of CW agents to Gulf War veterans? Current scientific literature indicates that when exposure to OP CW agents results in immediate and severe poisoning, long-term, subtle neuropsychological and neurophysiological effects could occur. Available scientific evidence does not indicate that such long-term effects occur in humans following low-level exposures, but the amount of data from either human or animal research on low-level exposures is minimal. Long-term effects in humans exposed to mustard agents include an elevated risk of lung cancer beginning decades after exposure. Based on available data, it is unlikely the health effects reported by Gulf War veterans today are the result of exposure to OP or mustard CW agents during the Gulf War. Ongoing or planned federally-funded studies focused specifically on low-level exposures and delayed neurotoxicity of CW agents should elucidate gaps in knowledge and eliminate uncertainty and/or identify new directions for research.
Biological Warfare Agents
The U.S. military prepared for the possibility that Iraq might use two BW agents-anthrax and botulinum toxin-against U.S. service members during the Gulf War. After the war, new data revealed Iraq had also weaponized aflatoxin. The Committee evaluated the potential health effects of these three BW agents on the long-term health of Gulf War veterans.
Anthrax. Anthrax is a bacterial disease most often found in cattle and sheep. Human infection can occur by contact with infected animals or by inhalation of spores from infected animal products (e.g., as hides or wool). Left untreated the disease usually is fatal. After exposure, the anthrax bacteria travel to the intestines and other areas where they cause severe tissue damage. Initial symptoms include nonspecific malaise, low grade fever, and nonproductive cough. Initially, anthrax can be difficult to diagnose because symptoms, although severe, are not specific.103 As the disease progresses, symptoms include high fever, labored breathing, choking cough, and vomiting; death usually occurs within four days.276 Terminal symptoms include abrupt onset of shortness of breath, harsh breathing, skin turning blue, excessively rapid heartbeat, and rapid progression to shock and death. Cases of pulmonary anthrax caused by inhalation of aerosolized spores (which would be the case in a military use) are almost invariably fatal if not treated immediately with antibiotics. Exposure to small numbers of infecting spores can increase the incubation time of the disease from a few days to several weeks, but if infection occurs, the disease progresses toward death in the same manner as for high-level exposure.103,276 No long-term effects have been reported in persons successfully treated for anthrax.
Botulinum toxin. Botulinum toxin is a group of related, highly poisonous protein agents isolated from fermentation of the bacterium Clostridium botulinum, which naturally occurs in soil and can grow in many meats and vegetables. Botulinum toxin is fast-acting, usually producing symptoms within 18 to 36 hours after ingestion. Death occurs in 80 percent of an exposed population after one to three days.276 Botulinum toxin blocks neuromuscular conduction by binding to receptor sites on motor nerve terminals and by inhibiting the release of acetylcholine. Symptoms at high exposure levels can include respiratory distress and respiratory paralysis, which may persist for six to eight months.117 Disability progresses from difficulty in walking and swallowing and impaired vision and speech to convulsions. Ultimately, symptoms include paralysis of the respiratory muscles, suffocation, and death-all within a few hours or days, depending on the amount of toxin ingested.276 In cases of accidental exposure in the general population, the fatality rate is 35 to 65 percent and is fatal in three to ten days.117 Botulism antitoxin can be effective if administered within days of exposure.276 The Committee found no scientific literature suggesting adverse long-term health effects from low-level exposure to botulinum toxin.
In fact, botulinum toxin has conventional medical therapeutic uses. Botox® is an FDA-approved, purified, type A botulinum toxin, and injecting it into the muscle of patients causes a localized, temporary denervation and muscle paralysis. Such an effect is therapeutically useful for treating a number of conditions, including blepharospasm (an involuntary recurrent spasm of both eyelids) and for use in certain types of eye surgery. Studies on thousands of adults treated with Botox® have shown only mild side effects-e.g., a diffuse skin rash lasting several days-as a result of the localized muscle paralysis effects of the toxin. The only long-term effect reported is a slight reduction in the effectiveness of Botox® due to a person's natural immune responses.
Aflatoxin. Aflatoxin is a naturally occurring toxic metabolite from certain fungi that sometimes occur on grains, peanuts, and other foods stored under certain conditions.117 Aflatoxin ingestion can result in immediate, toxic effects in many different species, and death results from acute liver toxicity.29,117 Aflatoxicosis in humans has been reported following ingestion of aflatoxin contaminated food, and symptoms include vomiting, abdominal pain, pulmonary edema, gastrointestinal hemorrhage, convulsions, coma, and death.29 Several epidemiologic studies suggest aflatoxin causes liver cancer in humans. The only documented health effect that could be expected from low-level exposure to aflatoxin would be an increased prevalence of liver cancer years to decades after exposure.
What do we conclude about the risks of BW agents to Gulf War veterans? In cases where an individual survives exposure to anthrax or botulinum toxin, no known, long-term health consequences exist. The Committee concludes it is unlikely the health effects reported today by Gulf War veterans are the result of exposures to BW agents. Aflatoxin, however, is a liver carcinogen, and increased rates of liver cancer could result decades following low-level exposure, although available evidence reviewed by the Committee does not indicate such exposures occurred during the Gulf War (see chapter 2).
Anthrax and Botulinum Toxoid Vaccines
Before U.S. troops deployed to the Gulf region, they received a standard series of inoculations against infectious diseases-e.g., cholera, typhoid, tetanus, diphtheria, polio, and measles-that might be given to any U.S. citizen traveling to these regions. After arriving in the Gulf War region, some U.S. service members received two additional vaccines for protection against the BW agents anthrax and botulinum toxin.
Anthrax vaccine. In 1970, FDA licensed anthrax vaccine to protect civilian workers against possible infection by anthrax bacteria. Since 1967 and before the Gulf War, more than 20,000 inoculations had been routinely administered to at-risk populations, including laboratory personnel who work with the bacteria that causes anthrax, persons in industries that work with animal hides and wool (which can be a source of anthrax infection), and veterinarians who come in contact with anthrax-infected animals.
Although active long-term safety surveillance is not generally part of the FDA vaccine licensing process, the FDA encourages U.S. health care providers and the law requires manufacturers to report serious adverse reactions for all licensed vaccines.305 FDA has not received data that raise concerns about the safety of the anthrax vaccine.
Historical data for short-term health effects of the anthrax vaccine indicate up to six percent of recipients experience mild discomfort, including tenderness, redness, swelling or itching at the inoculation site for up to 72 hours. Fewer than one percent experience a more severe local reaction that potentially limits the use of the arm for one to two days. Systemic reactions, e.g., fever, malaise, are uncommon (about 0.1 percent).102,103
According to DOD, medical monitoring and surveillance conducted during the Gulf War found the expected short-term side effects of anthrax vaccines occurring at approximately the historical rates.53 A single hospitalization for a vaccination site infection was reported. DOD points out that precise information about all possible short-term side effects is unknown, however, because of difficulties in collecting such data during and after the Gulf War.
Botulinum toxoid vaccine. Botulinum toxoid (BT) vaccine has been used for more than 25 years to protect industry and laboratory workers from occupational exposure to the extremely poisonous botulinum toxins. All civilian vaccinations have been administered under an investigational new drug (IND) application sponsored by CDC. For both civilian and military use, BT vaccine remains in "investigational" status-i.e., not yet licensed by FDA.
Since 1970, as part of the IND evaluation, FDA has reviewed information from CDC about the cumulative safety record for BT vaccine. Records of more than 10,000 administered vaccine doses (including approximately 2,200 in the five years before the Gulf War) indicate that treated individuals experience only local side effects often associated with many types of vaccinations. These effects, primarily at the injection site, include local pain, tenderness, swelling, redness, and itching. Systemic reactions such as temporary fever, tiredness, headache, or muscle pain also can occur. Rarely, reactions include soreness of the arm sufficient to leave individuals unable to perform duties for a day or two or development of a lump at the injection site that generally resolves within several weeks. Such adverse reactions also are observed with other licensed toxoid vaccines, such as diphtheria and tetanus toxoids.53,102
The U.S. Army examined the frequency of side effects of BT vaccinations seen in some U.S. service members. In one report of 237 Gulf War veterans who had received BT vaccine, 2.5 percent had systemic reactions. This rate parallels that recorded by the U.S. Army and CDC prior to the Gulf War.127
Precautions against contaminants. The Committee examined the hypothesis that Gulf War veterans' illnesses could be the result of contamination of anthrax vaccine lots by Mycoplasma incognitus.182 Discussions with staff of FDA, Walter Reed Army Medical Center, U.S. Army Medical Research and Materiel Command, academic experts, and the manufacturer of the vaccines indicate that Mycoplasma could not survive in the anthrax and BT vaccines.136,138,168,303 Mycoplasma is difficult to grow, and the culture media used to produce Anthrax and BT vaccines do not contain serum, an essential ingredient for Mycoplasma growth. In addition, the vaccines are preserved and/or processed with other products that create a hostile environment for Mycoplasma, including:
The Committee concludes it is unlikely that Mycoplasma organisms contaminated anthrax vaccine or BT vaccine.
Health effects of multiple vaccines. The human immune system has evolved the capability to deal with thousands of foreign substances, to sort them out, and to regulate immune response. Humans live among a vast population of hostile microorganisms, and vaccinations-even multiple, contemporaneous vaccinations-are a small part of total immune stimulation. Individual vaccines can cause adverse effects, but several studies of the effects of giving multiple vaccinations at one time have found no adverse effects associated with the practice. Research on this issue continues, but based on available evidence, the Committee believes it is unlikely that multiple vaccines are responsible for illnesses reported today by Gulf War veterans.202,219,268
What do we conclude about the risks of vaccines to Gulf War veterans? The Committee concludes it is unlikely that health effects reported by Gulf War veterans today are the result of exposures to the BT or anthrax vaccines, used alone or in combination.
PB is a pretreatment drug used to protect against the CW nerve agent soman. By itself PB is not protective against CW nerve agent poisoning. Used as a pretreatment, however, PB might enhance the antidote effects of the standard atropine and 2-PAM treatments used by the U.S. military for nerve agent poisoning.269
Since 1955, FDA has approved PB for use by persons suffering from myasthenia gravis. No long-term health problems thought to be associated with PB have been reported for persons with myasthenia gravis who regularly take PB over many years or decades.196,220 DOD filed a New Drug Application in May 1996, but PB currently has the status of an IND for nerve gas pretreatment use.
According to FDA, its conclusion that PB was safe for use by U.S. service members during the Gulf War was based largely on the extensive cumulative experience with this drug in patients with myasthenia gravis. Typically these patients are treated with PB doses of up to 1,500 mg per day for many years, compared to the prescribed dose of 90 mg per day for a maximum of seven days use during the Gulf War. Reported side effects of PB include increased salivation, increased tearing, urinary urgency and frequency, nausea, vomiting, muscle weakness, abdominal cramps and diarrhea.167 These effects disappear when individuals stop taking PB.
Data from one DOD retrospective study on 30 medical support officers of the 18th Airborne Corps reveal a similar range of short-term health effects from PB. The 18th Airborne Corps instructed 1,650 soldiers (6.5 percent women) to take PB tablets at the onset of Operation Desert Storm in January 1991. Half those surveyed reported gastrointestinal symptoms, 5 to 30 percent reported increased urinary urgency and frequency, and fewer than 5 percent reported headaches and tingling of extremities. The need for a medical visit was reported by less than 1 percent, and the decision to discontinue use based on medical advice was reported by less than 0.1 percent. As with myasthenia patients, DOD reported that side effects ceased when PB use was discontinued.110 Other retrospective studies found similar results.32,270
A survey of 213 Israeli soldiers asked about possible symptoms of PB and their severity. The most frequent health complaints reported were generally mild and nonspecific, including dry mouth, general malaise, fatigue, and weakness, which appeared about 1.6 hours after taking the medication and recurred after each intake. For this group the typical side effects associated with PB, such as nausea, abdominal pain, frequent urination and runny nose, were infrequent.228
DOD recently completed a study begun in November 1994 that looked at differential tolerances to PB between women and men.128,296 Ninety subjects, equally divided by gender and in three weight classes, took 30 mg of PB every 8 hours for 21 days (plus one dose). PB was found to be safe and well-tolerated. All side effects were mild and resolved with no intervention. Headaches, dizziness, nausea, rash, and hair loss were reported in both drug and placebo groups. Diarrhea and abdominal pain were reported in the PB group only (four study participants). Overall, the occurrence of adverse effects did not differ between active and placebo subjects, nor were differences observed among gender or weight groups. Results from a 1-year followup, indicated no long-term effects except possibly a skin rash that resolved with treatment.128
DOD continues to seek FDA approval to use PB for the protection of U.S. troops against CW agents. To support this approval process, DOD has sponsored various research efforts since 1984 to gather information on the effects of PB pretreatment on healthy individuals. To date, DOD reports no serious or long-term reactions from this research.
Genetic predisposition to PB sensitivity. Some scientists suggest that persons who are genetically unable to produce the plasma enzyme butyryl cholinesterase (BuChE) could be more sensitive to PB's known side effects, and at least one apparent case has been reported.139 The estimated frequency in the general population of persons unable to produce BuChE is about 0.03 percent. Exposure to PB (or similar compounds) could causeimmediate and marked health effects in these individuals. Based on studies of PB-related compounds in BuChE deficient individuals, however, symptoms vanish when exposure to PB is removed. Limited population genetic data indicate that about four percent of all people have slightly reduced ability to produce functional BuChE. It is unclear whether these individuals could be more susceptible to temporary PB side effects. 1,67,68,71,139,192,193,224,269
Synergistic effects. Concern has been raised about the possibility of increased health problems from PB when it is combined with other risk factors. Some researchers have hypothesized that PB in combination with stress may create central nervous system effects.59,170,228 The insect repellent DEET and the insecticide permethrin are most often mentioned as cofactors with PB for Gulf War illnesses.
After the Gulf War, one U.S. Department of Agriculture researcher conducted a study on synergistic effects of various chemicals, including DEET and PB, on cockroaches. DEET showed a four-fold increase on the lethality of PB-i.e., it took one fourth as much PB to kill cockroaches in the presence of a sublethal dose of DEET.314 In 1996, another researcher reported that PB given at near lethal levels to chickens could increase the toxicity of DEET and permethrin.1 Under these conditions, nervous system damage to the chickens was reported. A 1995 DOD study with rats reported that PB caused a slight increase in lethality of DEET and permethrin when compared to expected additive values.263
These three studies report enhanced toxic effects from PB, DEET, and permethrin in combination. However, doses used in the laboratory experiments were far greater than exposures U.S. service members could have experienced during the Gulf War. Moreover, for DEET and permethrin, the routes of administration were not comparable to that used by U.S. service members in the Gulf War. For example, in the chicken model, DEET and permethrin were injected underneath the skin and, in the rat study, they were administered orally. During the war, DEET should have been applied to the skin, and permethrin should have been applied to the uniform.
These studies did not address the effect PB, DEET, and permethrin-individually or in combination-would have on morbidity in humans and what illnesses might be induced by such use. Neither did the studies answer whether there would have been detectable harmful effects in humans in-theater under the likely operational use by U.S. troops.
Some researchers suggest the immediate toxicity of the OP pesticides available to Gulf War veterans could have been increased from coexposure to PB,1,150,151 leading to the well-characterized, long-term signs and symptoms of immediate and severe poisoning described earlier in this chapter. As previously mentioned, however, DOD reports that on-site medical personnel did not observe any immediate and severe effects of OP poisoning among U.S. service members, and the current scientific knowledge base indicates that long-term health effects do not occur in the absence of immediate poisoning.
In setting priorities for new research projects on Gulf War veterans' health issues, a subcommittee of the RWG of the Coordinating Board gave priority to toxicology studies on subtoxic exposures to PB and pesticides, either alone or in combination. Several federally funded studies now underway are assessing combined exposure to PB and other chemical risk factors.
What do we conclude about the risks of PB to Gulf War veterans? Given the extensive cumulative experience with the use of PB in patients with myasthenia gravis and data collected from military personnel, the Committee concludes it is unlikely that health effects reported today by Gulf War veterans are the result of exposure simply to PB. Ongoing federally funded studies should help the scientific community draw conclusions about the synergistic effects of PB and other risk factors.
Endemic Infectious Diseases
During WWII, British military units were stationed in the Gulf region and based on this experience documented the nature of endemic infectious diseases. Thus, the U.S. command was concerned about diseases, including shigellosis, malaria, sandfly fever, and cutaneous leishmaniasis.6,65,90,187 For example, cutaneous leishmaniasis, known locally as the Baghdad boil, is endemic to that area; 80 to 90 percent of people in some parts of Southwest Asia have scars from previous attacks.187 During WWII, rates of sandfly fever were 3 to 10 percent of all troops in the Middle East, and in some units it exceeded 50 percent.187 Infectious diseases during the Gulf War, however, were not a major cause of sickness or lost work time.90 During the Gulf War, only one death due to infectious disease (meningococcal meningitis) was reported.342,343
Experts attribute the lack of a problem with infectious diseases during the Gulf War to a comprehensive infrastructure of medical care and preventive medicine efforts.90,185,271,273,293 DOD took measures to minimize infectious disease risk, including strict monitoring of drinking water purity, inspecting food sources and supplies, maintaining field camp sanitation, and instituting an insect vector control program. U.S. service members received booster doses of routine vaccinations, including typhoid, meningococcus and, during the fall, influenza. Immune gamma globulin was used to prevent Hepatitis A, and the small number of troops who entered Iraq near the Euphrates River valley received drug prophylaxis for malaria.
Most of the combat troops were isolated in barren desert locations, distant from rivers, oases, and urban areas. Additionally, maximum troop deployment occurred during the cooler winter months, which provided the least favorable conditions for the transmission of insect-borne diseases.90,185 Indeed, the majority of the 12 individuals who developed viscerotropic leishmaniasis had been deployed to urban areas.145
Diagnosis of infectious diseases in-theater. Short-term diarrhea was a common symptom among troops in-theater. Most cases were mild, traveler's-type diarrhea that resolved spontaneously without antibiotics after a few days.64,90 Gastroenteritis among outpatients decreased from four percent per week early in the deployment to less than 0.5 percent per week after U.S. medical command tightened control of food sources-especially imposing a ban on locally-grown fresh fruits and vegetables. The most common organisms identified in service members with diarrhea severe enough to warrant cultures were Shigella sonnei and Escherichia coli. DOD reports no confirmed cases in-theater of food-borne, diarrheal diseases, such as cholera, typhoid fever, or giardiasis.90
DOD medical personnel evaluated U.S. service members for several diseases transmitted by insects, including leishmaniasis, sandfly fever, malaria, dengue, Sindbis, West Nile fever, Rift Valley fever, and Congo-Crimean hemorrhagic fever.90,293 As noted, sandfly fever had been a major concern, but no cases were seen during the Gulf War. DOD reports detecting seven cases of malaria and one case of West Nile fever, a mosquito-borne viral illness. No rickettsial illnesses and no cases of other arthropod-borne viral illnesses were identified.
Viscerotropic leishmaniasis (VL) and cutaneous leishmaniasis (CL) are the only endemic infectious diseases demonstrated to cause chronic morbidity among a number of Gulf War service members. These diseases are transmitted through the bites of sand flies; person-to-person infection does not occur. Thirty-two cases of leishmaniasis were diagnosed among U.S. troops, consisting of 12 cases of VL and 20 cases of CL.145,277 CL causes a characteristic ulcerative or nodular skin rash that can persist for more than a year without treatment. And, while VL can be difficult to confirm, it is not considered to be a cause of widespread illness in Gulf War veterans. All veterans diagnosed with VL, except one, have experienced the signs characteristic of the disease.90,146,293
It is unlikely that veterans in the Registry or CCEP who have unexplained illnesses are suffering from VL. The incidence of VL during the Gulf War and the five years since has been low (12 of 697,000), and other sandfly-borne infectious diseases in the troops have been absent.90,278 Additionally, individuals with unexplained illnesses also lack signs and symptoms characteristic of VL. VL can sometimes occur following a prolonged incubation period (more than 18 to 24 months); there is also a risk of activation of latent infections in immunosuppressed persons.65,90,146 To date, DOD and VA report that delayed onset of VL has not occurred.
From August 1990 through July 1991, the U.S. Army deployed approximately 347,000 individuals to the Gulf region. Based on information from U.S. Army field hospitals, the only infectious diseases that caused 30 or more each of approximately 14,000 admissions were pneumonia, intestinal infections, inflammation of the testes and/or epididymus, chicken pox, and kidney infections.342,343
What do we conclude about the risks of infectious diseases to Gulf War veterans? Based on a review of the rates and types of the diseases diagnosed during and after the Gulf War, the Committee concludes it is unlikely that infectious diseases endemic to the Gulf region are responsible for long term health effects in Gulf War veterans, except in a small, known number of individuals.
Uranium is a naturally occurring, chemically toxic, and radioactive element composed of three isotopes. Relative to other radionuclides, natural uranium is only slightly radioactive because of its low specific activity.288 When the uranium isotope used for nuclear reactors and weapons is extracted from natural uranium, DU is the byproduct.
DU is nearly twice as dense as lead-a property used to improve the performance of both armor and armor penetrating munitions. During the Gulf War, some U.S. tanks and U.S. aircraft fired DU munitions, which produced shrapnel and an aerosolized dust on impact with armor or on ignition in accidental munitions fires. DU retains natural uranium's toxicological properties and approximately half its radiological activity.267 Most of DU's radiation cannot penetrate skin, and DU poses little threat to human health while it is external to the body.288
Because it is slightly radioactive, natural uranium is considered to be a potential carcinogen-albeit with a small cancer risk relative to other radionuclides.288 Taken together, human and animal studies do not indicate conclusively that natural uranium causes cancer in humans. Epidemiologic studies of uranium miners experiencing extremely high, lifetime, occupational exposures to uranium show an increase in mortality due to lung cancer, but such cancers are thought to be caused by miners' concurrent exposures to radioactive radon gas and its decay products, tobacco smoke, silica and other dusts, or exhaust fumes from diesel engines.172,321 Animal studies conclude that exposure to uranium for long periods of time does not result in increased incidence of cancer, except in the case of one study. This study found prolonged (more than five years) inhalation of high levels of uranium dioxide led to lung neoplasms in dogs.130,131
The chemical toxicity of uranium as a heavy metal is well characterized. In fact, the kidney is the most sensitive organ affected by exposure to uranium and is the critical target organ for risk assessment.133,218,322,341 For this reason, uranium exposure is regulated based on its chemicaltoxicity and not its radiological properties.129,156 Even so, more than 50 years of occupational health data from uranium miners reveal little epidemiologic evidence of excess kidney disease among workers exposed for years or decades.322
The health risks of internalized uranium or DU particles depend on dose, exposure pathway, and solubility of the ingested particle. Ingestion of insoluble uranium compounds poses little health hazard because they pass rapidly through the body and are eliminated in the feces. However, animal studies have shown that ingestion of large doses of relatively soluble uranium compounds are associated with kidney toxicity.129,288 Inhaled uranium particles that are nonrespirable are cleared from the respiratory tract and either expelled from the body (cough) or swallowed and passed to the GI tract. Respirable and relatively soluble particles are cleared to blood and can affect kidney toxicity.14,129 Less soluble particles can remain in the lung longer and in theory could pose a radiological hazard. The U.S. Army has conducted tests to characterize aerosols associated with DU munitions impacts with armor and with accidental DU munitions fires; it concluded a service member's risk exceeds civilian safety standards only when he or she is inside a vehicle when it is penetrated by DU munitions.39,96,97 The adequacy of the research supporting this conclusion has been questioned by some reviewers.229,267
No studies of long-term human health effects of uranium metal implanted in tissue exist. Nevertheless, toxic effects are likely to be similar to the kidney toxicity observed from inhaled or ingested uranium. To date, VA has reported no kidney toxicity among soldiers wounded by DU fragments in friendly fire episodes.112 VA currently monitors the health of approximately 30 veterans suspected of retaining embedded DU fragments, and the U.S. Army Medical Research and Materiel Command is funding animals studies to investigate the health hazards associated with short- and long-term exposure to DU metal fragments.296
What do we conclude about the risks of DU to Gulf War veterans? The Committee concludes it is unlikely that health effects reported by Gulf War veterans today are the result of exposure to DU during the Gulf War. Since uranium is a potential carcinogen, it is possible that exposure to DU during the Gulf War could lead to a slight increase in the risk for lung cancer after decades following the end of the war.
Oil-well Fire Smoke
At the end of the Gulf War, more than 600 Kuwaiti oil wells and several pools of spilled oil were left burning after being ignited by retreating Iraqi troops. Huge, dramatic plumes of billowing smoke from these fires rose high into the atmosphere. Occasionally the smoke remained low to the ground, in some cases enveloping U.S. military personnel.
Some chemicals contained in oil-well fire smoke, such as benzene and PAHs, are human carcinogens. As described earlier in this chapter, the amounts of these pollutants in the air were low. Hence, their contribution to excess cancer risk would be expected to be small and increased rates of cancers likely would not result. The U.S. Army used EPA's standardized methodology to estimate cancer and noncancer risks from the oil-well fire smoke.265 It concluded "the potential for significant long-term adverse health effects for the exposed DOD troop or civilian employee populations is minimal." Risks from cancers were estimated not to exceed two excess cancers per one million people exposed, a value well within EPA's acceptable range.
Noncancer risks from smoke exposure were calculated as Hazard Indices (HI). When the HI exceeds 1.0, there can be concern about potential noncarcinogenic health effects. In Saudi Arabia, the HI ranged from 0.6 to 2.0, while in Kuwait it ranged from 2.0 to 5.0. Most of this noncancer risk was contributed by inhalation of VOCs, particularly benzene. The U.S. Army concluded that risk of noncarcinogenic health effects among the U.S. service members was low since HIs are based on EPA toxicity values that are set far below levels thought to cause health effects and that also account for sensitive subpopulations such as children and the elderly. A congressional Office of Technology Assessment analysis of the U.S. Army's risk assessment methods and findings concluded "the risks to health from exposure to the smoke and the background air contaminants in the Persian Gulf are likely to be extremely small."275
Oil-well fire smoke appears not to have caused observable changes in lung tissue. Researchers at the Armed Forces Institute of Pathology found no significant differences when they compared lung tissue from autopsies of 33 U.S. service members who died after the start of the oil well fires to lung tissue from autopsies of soldiers who died before the fires.164
Information has been gathered from 110 firefighters working for private companies in the Kuwaiti oil fields in 1991. Individuals were deployed for 28-day periods, working daily at the well heads without breathing-protection equipment. Most were over 30 years old and had 10 or more years experience fighting similar well fires, many of them in Kuwait and elsewhere in Southwest Asia. No cases of illnesses resembling those reported by Gulf War veterans were reported, nor have such complaints been observed among thousands of oil-well firefighters who have spent years experiencing similar exposures.60,61
Known immediate health effects from inhaling large amounts of smoke and particulates are primarily respiratory, including coughing, wheezing, increased airway resistance, and respiratory infections. Toxic gases that can be found in oil-well fire smoke-such as hydrogen sulfide and sulfur dioxide-can cause eye and nose irritation, decreased pulmonary function, and increased airway reactivity.312,315 Nevertheless, these toxic gases were not detected at high levels during the fires.89,289,302,339 High levels of airborne particulates, which sometimes occurred in the Gulf region, are associated with increased rates of asthma and can exacerbate other chronic respiratory conditions. With chronic (months or years) exposure to particulates, there is increased risk of some loss in lung function or chronic bronchitis, especially in cigarette smokers.
What do we conclude about the risks of oil-well fires to Gulf War veterans? Based on research on human and animal health effects of exposure to air pollutants and on currently available exposure data, the Committee concludes it is unlikely exposure to oil-well fire smoke is responsible for symptoms reported today by Gulf War veterans. Although smoke from the oil-well fires did not include levels of carcinogens that would be expected to increase cancer rates among Gulf War participants, VA mortality studies will include cancer surveillance.
Diesel, kerosene, gasoline, jet fuel, and other petroleum-based fuels were widely used during the Gulf War for dust suppression, waste incineration, and for fueling vehicles, stoves, heaters and generators. U.S. service members in certain jobs were occupationally exposed to petroleum fuel vapors and combustion products, such as toluene, xylene, benzene, ethyl benzene, carbon monoxide, sulfur dioxide, nitrogen dioxide, particulates, lead, and other pollutants. Additionally, in some areas near the Kuwaiti oil-well fires, unburned crude oil drizzled down, covering the ground and troops below.242
Petroleum fuels are a complex mixture of aliphatic hydrocarbons and aromatic hydrocarbons such as benzene and PAHs. These fuels also commonly contain various additives, like lead. When burned, petroleum fuels produce a variety of potentially hazardous combustion products. High-level, short-term exposures to fuel solvents can cause immediate effects. In most cases, however, complete recovery occurs when the exposure ceases.5,286
U.S. service members could have been exposed to petroleum fuels by inhalation, ingesting contaminated water or dust, and skin contact. Inhalation exposure could depress the central nervous system (CNS). Symptoms include short-term effects ranging from fatigue, headache, nausea, blurred vision, and dizziness, to convulsions, paralysis, and loss of consciousness depending on the dose.282,312 Again, exposure to high, nonlethal levels usually is followed by complete recovery, although rare cases of permanent brain damage after massive exposure have been reported.117,205,282
Prolonged breathing of diesel fuel vapors can damage kidneys or lower blood clotting ability.284 Studies of workers occupationally exposed to certain hydrocarbon solvents in petroleum fuels suggest that long-term high-dose exposure over 12 to 14 years can lead to neurotoxic effects.117,285 For example, psychomotor disturbances, visual memory and perception, and visuomotor learning ability were significantly affected in exposed gasoline-pump workers compared to matched controls, particularly workers exposed for more than a year.125 Some studies suggest there are neurotoxic effects from long-term exposure, including decrements in memory, cognitive functioning, and sometimes neuromotor functions.117 Other researchers, however, have challenged the existence of what is sometimes referred to as "chronic toxic encephalopathy," and uncertainty exists about CNS effects from long-term, low-level exposures to solvents.69
Benzene makes up about one percent of U.S. gasoline and up to five percent of European formulations. It is a known human carcinogen that is associated with certain types of leukemia. Nevertheless, more than 55 published epidemiologic studies of workers exposed occupationally to hydrocarbons such as gasoline generally do not replicate the carcinogenic effects reported for experimental animals.157,282 Recent studies of refinery workers also do not reveal a clear association between gasoline production and leukemia.88,282 Still, based on the limited evidence from animal studies and the presence of benzene in gasoline, the International Agency for Research on Cancer (IARC) concluded that gasoline is possibly carcinogenic to humans. It is not known if other petroleum products cause cancer in humans. IARC believes there are insufficient data to assess whether light fuel oils or light diesel fuels cause cancer in humans. However, IARC has determined that occupational exposure to fuel oils during petroleum refining is probably carcinogenic to humans.284
Although ingesting small amounts of fuel oils is unlikely to cause significant symptoms, ingesting fuel oils in larger quantities can cause vomiting, diarrhea, swelling of the stomach, stomach cramps, coughing, drowsiness, restlessness, irritability, and unconsciousness.284 Ingestion of fuel oils can be accompanied (during vomiting) by aspiration of some of the material into the lungs, which can produce a chemical pneumonitis.
Skin exposure to large amounts of oil can physically clog pores and hair follicles, compromising body heat loss. Long-term exposure can cause acne and other skin problems. With high concentration or extended exposure, lighter components of crude oil or other fuel oils can defat the skin, leading to redness and itching or dermatitis.284,312
Exposure to the normal combustion products of petroleum fuels is also a health concern. Limited epidemiologic evidence indicates daily use of kerosene stoves for cooking or heating does not cause breathing problems for most people.284 If insufficiently vented, however, carbon monoxide generated from fuel oil combustion can build up, causing drowsiness, nausea, and even asphyxiation. Individuals exposed to unvented combustion of fuels containing lead could experience health effects ranging from subtle biochemical changes in blood to severe CNS effects at high doses. Occupational exposure to inorganic lead is associated with subjective signs of neurotoxicity such as forgetfulness, lethargy, and weakness. These neurological signs and symptoms occur at about the same blood lead levels as other overt signs of lead intoxication, such as gastrointestinal complaints like abdominal pain, nausea, and vomiting.286
What do we conclude about the risks of petroleum products to Gulf War veterans? While certain subsets of Gulf War service members could have experienced occupational exposures to petroleum products that would entail increased risks of health effects, it is unlikely that health effects reported today by Gulf War veterans are due to exposure to petroleum products during the war.
Psychological and Physiological Stress
Virtually all Gulf War participants were exposed to a wide range of stressors associated with the war. Throughout human history, observers have noted a correlation between the horrors of war and "mysterious" illnesses in soldiers and veterans.91 Only recently, however, have the broad range of symptoms for such illnesses been recognized as serious, physiological effects of stress.
Unexplained illnesses in soldiers were widely interpreted as a form of malingering until the 1940s. When WWII veterans experienced many of the same symptoms seen in WWI, Charles Samuel Dyers coined the term "shell shock." He began to study and write about what actually happened to the minds and bodies of soldiers on and off the battlefield. Physicians began to describe psychosomatic symptoms-physical disorders caused or influenced by a psychological state-as the normal and expected consequences of experiencing fear and fright, and recognized the relationship between intense emotion and bodily changes.
During this period, a telling example came to light that illustrated how traumatic experience can lead to a decline in physical health. A group of merchant marines in Norway during WWII were preselected for their excellent physical and mental health. Yet after exposure to extraordinary stress, they showed a sharp decline in their health. Many had symptoms of chronic fatigue, chronic pain, impotence, and irritability.
Today, scientists are beginning to unravel the physiological connection between the brain and various other parts of the human body. Recent animal and human studies reveal numerous pathways connecting the brain to the rest of the body, through which psychological stress can be physically expressed.31 Animal studies demonstrate that stress can have measurable effects on the brain, immune system, cardiovascular system, and various hormonal responses. Although the human body can adapt to normal stresses, if the stress lasts longer it can be expressed in a variety of physical illness symptoms.155 Some researchers suspect that the inadequate production of stress hormones and stress response occurs in some (not all) humans with CFS and PTSD.31
Based on this understanding and supported by decades of clinical observations, physicians recognize that many physical, as well as psychological, diagnoses are the consequences of stress. This connection is not limited to soldiers only. Experts now know that conventional stressors, such as bereavement, family problems, financial and job problems, domestic or other violence, can cause significant and long-term physical health effects.76,184
Physicians and scientists also note substantial variability in the human response to stress. One individual's reaction to trauma could be hypertension; in another individual, the reaction to similar trauma might be severe anxiety. A number of medical diagnoses are linked with stress, including somatoform disorders, CFS and FM. These conditions share many overlapping features, and each diagnosis depends on meeting specific case definitions. Significant evidence supports the likelihood of a physiological, stress-related origin for many of these ailments.
What do we conclude about the risks of stress to Gulf War veterans? The Committee concludes that stress does not cause a unique illness or set of symptoms. Stress can contribute to a broad range of physiological and psychological illnesses. Stress is likely to be an important contributing factor to the broad range of illnesses currently being reported by Gulf War veterans.
The Committee has examined exposure and, independently, expected health effects for ten Gulf War risk factors: pesticides, CW agents, BW agents, vaccines, PB, infectious disease, DU, oil-well fire smoke, petroleum products, and psychological and physiological stress. In our evaluation, we used the substantial amount of relevant scientific information available in published peer reviewed literature, interviews with experts, invited testimony, public comment, and discussions with scientific experts in academic and government agencies. For most of the risk factors evaluated, the Committee has determined-even in the absence of exposure data-they are unlikely to be associated with the health problems currently reported by Gulf War veterans. Based on its review, the Committee makes the following findings and recommendations.
*As noted, individuals in this group also were assessed for SCEs, which were found to increase with deployment to Kuwait and remain elevated even after the return to Germany.154 SCEs are a sensitive measure of DNA damage and repair and occur at a background rate in normal cells, but increase with exposures to DNA damaging agents. It is not clear what exposures in Kuwait could have led to the observed increases, since elevated SCEs are a nonspecific measure that can reflect exposure to infections and vaccinations, or to dietary, occupational, or environmental mutagens.
**In chapter 2, we identify those areas for which we believe new research data could fill in current gaps in knowledge.