8
OTHER HEALTH OUTCOMES

This chapter will review the epidemiologic literature on possible associations between exposure to fuels and combustion products and a variety of health outcomes: posttraumatic stress disorder, neurologic outcomes, multiple chemical sensitivity, dermatologic outcomes, and sarcoidosis. The outcomes discussed in this chapter do not necessarily have a large literature base, but they are reviewed here because there might be veterans who have an interest in them.

NEUROLOGIC OUTCOMES

The committee reviewed the epidemiologic literature on neurologic effects of exposure to fuels and combustion products, focusing on studies that examined long-term effects. Most studies were of occupational exposure.

The committee selected for detailed evaluation only the studies that met its inclusion criteria, which are listed below and discussed in Chapter 2. The first three criteria apply uniformly across all study outcomes; the fourth is reserved for outcomes that are reversible, that is, gradually abating over days or months after cessation of exposure.

  • Methodologic rigor. The report of the study had to be a published in a peer-reviewed journal and had to include details of methodology; the study had to include a control or reference group, had to have the statistical power to detect effects, and had to include reasonable adjustment for confounders. Case studies and case series were generally excluded from the committee’s consideration.

  • Identification of class or agent. The study had to identify fuels or combustion products relevant to the committee’s charge (for example, fuels might include gasoline, kerosene, diesel and jet fuel). If agents were not identified, the study may have been included if it was a study of an occupation that entailed a fuel or combustion-product exposure similar to presumed veterans’ exposures in the Persian Gulf.

  • Specificity of outcome. The study had to specify a distinct outcome rather than a nonspecific group of health outcomes. Lack of specificity occurs primarily in mortality studies that examine all-cause mortality (such as deaths from all nervous system diseases) as opposed to cause-specific mortality (such as deaths from Parkinson’s disease). All-cause mortality studies were excluded unless they analyzed specific health outcomes separately.



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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 8 OTHER HEALTH OUTCOMES This chapter will review the epidemiologic literature on possible associations between exposure to fuels and combustion products and a variety of health outcomes: posttraumatic stress disorder, neurologic outcomes, multiple chemical sensitivity, dermatologic outcomes, and sarcoidosis. The outcomes discussed in this chapter do not necessarily have a large literature base, but they are reviewed here because there might be veterans who have an interest in them. NEUROLOGIC OUTCOMES The committee reviewed the epidemiologic literature on neurologic effects of exposure to fuels and combustion products, focusing on studies that examined long-term effects. Most studies were of occupational exposure. The committee selected for detailed evaluation only the studies that met its inclusion criteria, which are listed below and discussed in Chapter 2. The first three criteria apply uniformly across all study outcomes; the fourth is reserved for outcomes that are reversible, that is, gradually abating over days or months after cessation of exposure. Methodologic rigor. The report of the study had to be a published in a peer-reviewed journal and had to include details of methodology; the study had to include a control or reference group, had to have the statistical power to detect effects, and had to include reasonable adjustment for confounders. Case studies and case series were generally excluded from the committee’s consideration. Identification of class or agent. The study had to identify fuels or combustion products relevant to the committee’s charge (for example, fuels might include gasoline, kerosene, diesel and jet fuel). If agents were not identified, the study may have been included if it was a study of an occupation that entailed a fuel or combustion-product exposure similar to presumed veterans’ exposures in the Persian Gulf. Specificity of outcome. The study had to specify a distinct outcome rather than a nonspecific group of health outcomes. Lack of specificity occurs primarily in mortality studies that examine all-cause mortality (such as deaths from all nervous system diseases) as opposed to cause-specific mortality (such as deaths from Parkinson’s disease). All-cause mortality studies were excluded unless they analyzed specific health outcomes separately.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Exposure-free period for reversible neurologic effects. To be relevant to Gulf War veterans, the study had to examine long-term rather than short-term effects. Some neurologic outcomes can be determined only after an exposure-free period of weeks or months before evaluation of study subjects. The committee required an exposure-free period period specifically for effects that might be reversible (such as headache, light-headedness, poor coordination, and difficulty in concentrating), but not for irreversible effects (such as neurologic disease and peripheral neuropathy). The rationale for this criterion is described below. The committee evaluated long-term effects because they are most relevant to the veterans’ situation: exposure to fuels and combustion products during the Gulf War but symptoms that persist for years after the exposure. Long-term or very high exposure to fuels produce well-known short-term effects, including headache, light-headedness, poor coordination, difficulty in concentrating, tremors, myoclonus, and seizures (ATSDR 1995). The short-term effects are reversible and do not persist beyond hours or days after cessation of exposure. Long-term effects are often less well studied than short-term effects. Occupational or other epidemiologic studies of neurologic effects often do not permit distinction between short-term effects (hours or weeks) and long-term effects (months or years), because many studies examine workers who have both past and current exposure. Consequently, if a study finds a neurologic effect (for instance, headache or fatigue), it is difficult to determine whether the effect will persist after cessation of the exposure unless an exposure-free period of weeks or months has passed before the effect is measured. Many of the available studies were not designed to determine whether an effect was a long-term or a short-term effect. The challenge of distinguishing long-term and short-term effects is greater in the case of neurobehavioral effects than neurologic diseases for reasons related to onset, reversibility, and availability of objective testing. Neurobehavioral effects (such as symptoms of memory loss and fatigue) can be short-term effects, long-term effects, or both; they can appear within hours of exposure or later; and they can persist or disappear after cessation of exposure. Neurobehavioral effects cannot usually be verified with pathologic or biochemical tests, although objective and validated neurobehavioral tests of memory, attention, and other functions can be used in addition to symptom reporting (IOM 2003). Conversely, neurologic diseases are generally believed to be irreversible after a confirmed diagnosis and are associated with abnormal results of pathology or biochemistry tests. Thus, in evaluating the body of evidence, the committee required that there had been an exposure-free period of weeks or months before testing for a potentially reversible effect. For studies of peripheral neuropathy and neurologic diseases, the committee did not require an exposure-free period, because these effects are almost always long-lasting (although some degree of recovery or lack of progression is possible). Fuels This section covers fuel exposure and two neurologic effects: peripheral neuropathy and neurobehavioral effects. Some studies of neurologic effects, whether of those particular outcomes or others, were excluded by the committee for lack of methodologic rigor, nonspecific outcomes (Christie et al. 1987; Dagg et al. 1992; Hanis et al. 1985; Miller et al. 1986; Tsai et al. 1992; Wen et al. 1984), or lack of an exposure-free period in the case of reversible outcomes (Hakkola et al. 1997; Kilburn and Warshaw 1995; Kumar et al. 1988; Odkvist et al. 1987; Struwe et al. 1983).

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Peripheral Neuropathy The committee defined peripheral neuropathy as requiring a diagnosis with a thorough neurologic examination confirmed by quantitative laboratory testing, preferably using nerve-conduction studies and electromyography. Because peripheral neuropathy is often irreversible, the committee did not require a study to meet its criterion for an exposure-free period. Nevertheless, if the study reported other outcomes that were reversible (such as, symptoms or neurobehavioral effects), those findings were not evaluated in the absence of an exposure-free period. Knave et al. (1976, 1978) studied peripheral neuropathy through symptom reporting, neurologic examination, and nerve-conduction studies among 29 aircraft-factory workers. Other neurologic symptoms or outcomes were not considered by the committee, because of the lack of an exposure-free interval period. The 1976 study had two jet-fuel exposure groups: heavily and less heavily exposed. No internal controls that lacked a history of exposure were included, but external controls in four other industries were used as the comparison group. The jet fuel was a mixture of gasoline and kerosene that included the aromatic hydrocarbons benzene, toluene, xylene, and trimethylbenzene. Neurologists evaluated symptoms of polyneuropathy: pain, temperature, touch, discriminative sensitivity, joint kinesthesia, and paresis. Symptoms of “restless legs” (62% vs 19%), pain (31% vs 13%) and paresthesias (77% vs 25%) were more frequent in the heavily exposed group than in the less heavily exposed group. Symptoms of polyneuropathy were more prevalent in the heavily than in the less heavily exposed (pain 30% vs 6%; temperature 69% vs 43%; discriminative sensitivity 15% vs 6%). No other symptoms were increased in the heavily exposed group. Remarkably, 19% of the less heavily exposed compared and none of the heavily exposed had diminished reflexes. If the neuropathy symptoms are grouped, the heavily exposed workers had a higher frequency of those symptoms than did the less heavily exposed. The less heavily exposed had a higher frequency of symptoms than did four external control groups. An age-stratified analysis was attempted but the samples were too small. For most vibration-sensation measurements and conduction velocities, differences from one external control group were not noteworthy, except that there was a marked difference in hand-vibration threshold between the less heavily exposed group and one control group. In the 1978 study, the same exposed jet-fuel workers were compared with internal controls that had no jet-fuel exposure (matched for age, employment duration, and education) (Knave et al. 1978). The electroneurographic studies included conduction velocities and action potentials of four major peripheral nerves. The results were conflicting because, although the exposed group displayed lower nerve action potentials in the sural nerve, the nonexposed group displayed slower ulnar and median conduction velocities. The differences were statistically significant. There were higher peripheral vibration thresholds in the exposed group, but differences were nonsignificant. The overall results of those two studies indicated that although symptomatic differences are related to exposure, there were no objective measures to support a relationship between jet-fuel exposure and neuropathy. The limitations of the studies include small samples and the lack of an internal nonexposed group of controls. The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to fuels and peripheral neuropathy.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Neurobehavioral Effects A team of Australian researchers (Maruff et al. 1998) studied neurologic and cognitive abnormalities in young adults engaged in chronic petrol-sniffing, a form of substance abuse relatively common in tribal groups, including aborigines. The study was of 33 current sniffers (over 6 months), 30 ex-sniffers (abstained for at least 6 months), and 34 nonsniffers in two remote aboriginal communities. Petrol-sniffing involves inhaling petrol directly from a 375-mL soft-drink can whose top has been removed and whose contents have been replaced with about 200 mL of leaded petrol. Petrol-sniffing induces euphoria, relaxation, and slurred speech. A total of 112 men were recruited for the study, but subjects were excluded if they had a history of any hospitalization for acute toxic encephalopathy from petrol-sniffing. Current petrol sniffers were required to abstain from sniffing for at least 12 hours before testing because acute effects of petrol-sniffing can last up to 6 hours. Exposure was based on blood lead and hydrocarbon concentrations and a semistructured interview (with medical-record comparison). Neurobehavioral outcomes were measured with neurologic examination and 10 neurobehavioral tests in the Cambridge Neuropsychological Test Automated Battery. Conventional neuropsychologic tests of attention, memory, and learning were not suitable, because subjects were in remote communities where English was not the primary language. The Cambridge test battery is considered appropriate for cross-cultural use with an indigenous group for whom English is not the primary language. Subjects were recruited with the aid of local community health workers, and paid research assistants were recruited from the same communities. On entry into the study, all subjects were interviewed about petrol-sniffing behavior, history of alcohol and other drug use, school attendance, and employment. Petrol-sniffing history was verified with three different methods: local community health-clinic records, assessment by local community health worker, and assessment by research assistants who spoke the same language. Current sniffers, ex-sniffers, and nonsniffers were similar in age (20 years), education, alcohol use, and cannabis use. The only significant difference among the three groups was that nonsniffers were more likely to be in full-time school or employment. Ex-sniffers had abstained for an average of 2.4 years. Current sniffers and ex-sniffers were similar in age at which petrol-sniffing began, number of 375-mL cans per week, years of sniffing (6.2–7.5 years). Current sniffers and ex-sniffers met or had met, respectively, Diagnostic and Statistical Manual of Mental Disorders-IV criteria for inhalant abuse. Current sniffers had significantly increased blood lead (in log micromoles per liter) compared with ex-sniffers and nonsniffers. Lead concentrations in gasoline in Australia are 0.4 and 0.8 g/L. The physician who conducted the neurologic examination and the neuropsychologist who performed the cognitive-test battery were blinded to subjects’ petrol-sniffing status. Ex-sniffers (the group with an exposure-free period of at least 6 months) displayed higher rates of abnormal tandem gait and bilateral palmomental reflexes than did nonsniffers. Ex-sniffers also displayed cognitive deficits in two areas of the test battery: visual-recognition memory and pattern-location paired-associates learning. Current sniffers had the highest rates of abnormal neurologic signs and cognitive deficits. Blood lead and length of time of sniffing correlated significantly with the magnitude of both neurologic and cognitive deficits, whereas blood hydrocarbon concentrations did not. Hydrocarbons or their metabolites, however, are quickly cleared from the blood and then excreted or stored in lipid-rich tissues. Although hydrocarbons cannot be excluded as a contributor, lead is the most likely component of jet fuels that produces the observed long-term effects. The study found a

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 correlation between blood lead and neurobehavioral outcomes and a lack of correlation between blood toluene or benzene and outcomes. Chronic lead exposure, accumulated over a lifetime, has been found within the last several years to be associated with cognitive deficits in adults (Muldoon et al. 1996; Payton et al. 1998). In the petrol-sniffers study by Maruff et al. (1998), relatively high tetraethyl lead exposure occurred, as indicated by the blood lead concentrations of 1.08 and 1.58 μmol/L in ex-sniffers and current sniffers, respectively. Those concentrations are likely to be much higher and of much longer duration than the ones possibly sustained by Gulf War veterans. No published studies of Gulf War veterans assayed for bone or blood lead, most likely because environmental lead concentrations during the Gulf War did not implicate lead as a health concern. The US Army Environmental Hygiene Agency, which collected more than 4,000 samples in its comprehensive air-monitoring program during the Gulf War’s oil-well fires, found ambient lead (mean concentration 0.675 μg/m3) which were orders of magnitude below US occupational standards and below the concentrations found in ambient air in most US cities (Rostker, 2000). Tent heaters were another possible source of lead exposure of US troops, but heaters typically burned kerosene and jet diesel fuel, neither of which contains lead as an additive. Lead is an additive only to gasoline. A study of tent-heater emissions with kerosene and jet fuels found lead in ambient air to be negligible, less than 0.1 ppm (Zhou and Cheng 2000). Several population-based Gulf War studies found a relationship between veterans’ self-reported fuel exposure and their self-reported neuropsychologic or cognitive symptoms or nonspecific symptoms (Iowa Persian Gulf Study Group 1997; Kang et al. 2000; Spencer et al. 2001; Suadicani et al. 1999; Unwin et al. 1999). However, because of recall bias, the committee considered them as providing weak evidence of a relationship (Boyd et al. 2003). In conclusion, the study by Maruff et al. (1998) was well designed, but the neurobehavioral effects that it found among former petrol-sniffers are most likely related to lead in petrol rather than to petrol itself. The studies from the Gulf War provide weak evidence of a relationship between fuel exposure and neurobehavioral effects. The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to fuels and neurobehavioral effects. Combustion Products To identify long-term neurologic effects of combustion products, the committee evaluated numerous epidemiologic studies, virtually all of which covered three general types of neurologic effects: posttraumatic stress disorder (PTSD), neurobehavioral effects (assessed with symptom reporting or performance on validated neurobehavioral tests or batteries), and some neurologic diseases. Several studies were selected for detailed evaluation because they met the committee’s inclusion criteria for neurologic effects (described above). Studies were excluded for lack of methodologic rigor, nonspecific outcomes, or, most commonly, lack of an exposure-free period in the case of reversible outcomes (Arnold et al. 1985; Camerino et al. 1993; Hakkola et al. 1996, 1997; Sram et al. 1996; Strauss et al. 1992). The remainder of this section reviews the studies that met the committee’s inclusion criteria.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Posttraumatic Stress Disorder PTSD is a commonly studied neurologic effect in firefighters, one of the occupations of interest to this committee. It is a highly disabling anxiety disorder that affects 3–4% of the US population (US DHHS 1999), and that can occur after exposure to an extreme traumatic event, such as death or the threat of death. Its hallmark symptoms are frequent replaying of the traumatic event, avoidance of stimuli associated with the trauma, numbing of general responsiveness, and increased arousal. PTSD qualifies as a long-term, rather than a short-term, effect because of its persistence: it persists more than 12 months in about half the cases (APA 1994). Numerous studies have found increased rates of PTSD diagnosis or symptoms after exposure to such catastrophic events as war, terrorism, sexual or physical abuse, natural disasters, and serious injury (Kessler 2000). Trauma appears to have a dose-response relationship with PTSD: the greater the intensity or frequency of traumatic exposure, the greater the likelihood of developing PTSD or other serious mental-health outcomes (Kang et al. 2003). In many, especially Vietnam veterans, PTSD has lasted for years or decades (Bremner et al. 1996). Studies of firefighters in at least three countries met the committee’s criteria for inclusion. Overall, the prevalence of PTSD symptoms across firefighter samples was 15–40%. A study in Kuwait that used the Impact of Events Scale (IES) found the prevalence of PTSD symptoms in firefighters to be 18.5% (al-Naser and Everly 1999). A study in Germany of 402 firefighters engaged in different work functions found the prevalence of PTSD symptoms to be 18.2% (Wagner et al. 1998). A study comparing Canadian and US firefighters that used the IES found a similar prevalence of PTSD symptoms: 17 and 22%, respectively (Corneil et al. 1999). Although not explicitly a study of PTSD, another US study of firefighters found that 33–41% reported significant distress on the General Health Questionnaire and other measures of psychologic well-being (Boxer and Wild 1993). In a related study, firefighters reported that the most stressful aspect of their job was catastrophic injury to themselves or others (Beaton et al. 1998). None of the studies cited above used diagnostic interviews. Symptom scales are generally for screening purposes, so they probably overestimate the prevalence of a PTSD diagnosis, which can be determined only with an interview. Firefighters are exposed to both traumatic events and combustion products. Although PTSD in firefighters theoretically might be a toxic effect of exposure to combustion products, no studies of firefighters have examined PTSD as such an effect. The most plausible explanation is that PTSD is an emotional and physiologic response to the psychologic trauma of fighting fires. First, many studies have documented that trauma is a nonspecific cause of PTSD in numerous highly exposed populations (Kessler 2000). Second, the prevalence of PTSD symptoms in firefighters is well within the range found in other occupational groups that have high trauma exposure. Police and other rescue workers (Asukai et al. 2002; Weiss et al. 1995) and Vietnam and Gulf War veterans (Kang et al. 2003; Kulka et al. 1990) experience rates of PTSD symptoms comparable with those of firefighters. Third, no other occupational groups exposed to combustion products have been studied for PTSD as an outcome measure. Taken together, the evidence suggests that PTSD symptoms in firefighters are a response to traumatic events rather than toxic effects of combustion-product exposure. Few Gulf War studies examined whether self-reported combustion-product exposure was related to PTSD as an outcome measure, and none found a relationship (Proctor et al. 1998; Unwin et al. 1999). None of the studies with objectively measured oil-well fire smoke examined PTSD as an outcome measure. In studies that did not include combustion products as an exposure, PTSD symptoms or diagnoses were more likely in Gulf War veterans with combat

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 exposure or injury (Baker et al. 1997; Kang et al. 2003; Labbate et al. 1998; Wolfe et al. 1998), in women (Wolfe et al. 1993), in veterans who had been exposed to missile attack (Perconte et al. 1993), and in those with grave-registration duties (Sutker et al. 1994). The prevalence of PTSD increases with increasing combat exposure (Kang et al. 2003). The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to combustion products and posttraumatic stress disorder as a toxicologic effect. Neurobehavioral Effects Choi (1983) studied delayed neurologic sequelae in 65 of 2,360 victims of acute carbon monoxide intoxication (549 of whom were admitted to a South Korea hospital) in 1976–1981. The intoxication occurred at home, where coal, the main domestic fuel, is used for cooking and heating (under the floor). Symptoms most frequently appeared 15–30 days after exposure. Signs and symptoms were noted, and computed-tomographic (CT) scans were performed. The vast majority of the 65 had been unconscious for up to a day. The most common symptoms of delayed neurologic sequelae included “mental deterioration”, urinary or fecal incontinence, gait disturbance, and mutism. The most common signs were masked face, Glabella sign, and grasp reflex. CT scans performed on 17 of the 65 subjects revealed five with low density of both basal ganglia, two with decreased density of white matter in the cerebral cortex, and the rest normal. About 75% of patients recovered within a year. Kilburn (1999) studied the effects of diesel exhaust in 10 railroad workers and six electricians. The author did not indicate how the workers were selected except to say that their selection was “not random”. The railroad workers were either train crewmen or diesel-engine repairmen. They continued to be exposed to diesel exhaust, so findings could be confounded by continuing exposure. The electricians, however, were examined 9 months after having been exposed to diesel exhaust in an underground tunnel for 7–18 months. The author investigated symptoms, including the Profile of Mood States, and used 26 neurobehavioral tests. The results were compared with those in general population controls who had no chemical exposure and whose names were drawn from voter-registration rolls. The two groups of workers were found to be impaired in all neurobehavioral functions. The results were not stratified according to past vs continuing exposure, and no environmental-exposure monitoring was conducted. The results of the study are difficult to interpret primarily because the study sample was small and included people whose selection was nonrandom and who had continuing exposure. Several Gulf War studies included analysis of combustion-product exposure and neurobehavioral effects. They found positive relationships between self-reported exposure and self-reported neuropsychologic, cognitive, or mood symptoms or multiple unexplained symptoms (Iowa Persian Gulf Study Group 1997; Kang et al. 2000; Proctor et al. 1998; Spencer et al. 2001; Unwin et al. 1999; White et al. 2001; Wolfe et al. 2002). Because combustion-product exposure in those studies was self-reported and not confirmed by independent exposure assessment, the committee deemed the studies to provide weak evidence of an effect. The two studies with objectively measured combustion-product exposure are methodologically weak. The Choi study (1983) was a case series without a control group. The Kilburn study (1999) had serious limitations, especially in subject selection. Those studies, taken

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 together with Gulf War studies, all of which had self-reported exposure, provide only weak evidence of a relationship. The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to combustion products and neurobehavioral effects. Neurologic Diseases Rotorua, New Zealand, is above a geothermally active area with substantial hydrogen sulfide (H2S) exposure. About one-fourth of the population of 40,000 is regularly exposed to H2S at over 200 μg/m3 (143 ppb). A series of studies by Bates et al. investigated morbidity and mortality from peripheral nervous system (ONS) and central nervous system (CNS) diseases (Bates et al. 1997, 1998, 2002). The impetus for the studies was a 1981 World Health Organization report which recommended research expressly in Rotorua to take advantage of the natural conditions to study the health effects of H2S. Using census data, Bates et al. (1997) compared deaths in Rotorua with deaths in the rest of New Zealand (1981–1990). First examining diseases of the nervous system and sense organs as a whole (International Classification of Diseases [ICD] codes 320–398), they found the standardized mortality ratio (SMR) to be nonsignificant (SMR 1.07; 95% confidence interval [CI] 0.82–1.36). They also found nonsignificant SMRs for groupings of nervous-system diseases with more than four deaths: inflammatory diseases of the CNS (ICD codes 320–326), hereditary and degenerative diseases of the CNS (ICD codes 330–337), other disorders of the CNS (ICD 340–349), and disorders of the PNS (ICD codes 350–359). Although the study concluded that there were no indications of excess mortality, the authors noted that they were unable to adjust for ethnicity differences. Rotorua has a higher density of Maori residents than do other areas of New Zealand. The authors noted the potential for underreporting of Maori mortality statistics because ethnicity on death certificates is based on funeral directors’ impressions. In a second study, Bates et al. (1998) used hospital-discharge data over a decade (1981–1990) to calculate standardized incidence ratios (SIRs) for neurologic, respiratory, and cardiovascular diseases (and subgroupings) for Rotorua residents. No exposure groups were assigned. Significant findings were found for diseases of the nervous system and sense organs (SIR 1.11, 95% CI 1.07–1.15), and for these nervous-system disease subgroupings: other disorders of the CNS (ICD codes 340–349, SIR 1.22, 95% CI 1.11–1.33), disorders of the PNS (ICD codes 350–359, SIR 1.35, 95% CI 1.21–1.51), and disorders of the eye and adnexa (ICD codes 360–379, SIR 1.12, 95% CI 1.05–1.19). In addition, the following individual discharge diagnoses were statistically significant: migraine (ICD code 346, SIR 1.40, 95% CI 1.12–1.72), other conditions of the brain (ICD code 348, SIR 2.5, 95% CI 1.89–3.26), mononeuritis of the upper limb and mononeuritis multiplex (code 354, SIR 1.47, 95% CI 1.29–1.67), mononeuritis of the lower limb (ICD code 355, SIR 2.06, 95% CI 1.46–2.81), cataract (ICD code 366, SIR 1.26, 95% CI 1.14–1.38), disorders of the conjunctiva (ICD code 372, SIR 2.09, 95% CI 1.66–2.59), disorders of the orbit (ICD code 376, SIR 1.69, 95% CI 1.12–2.44). In a separate report, Bates et al. (2002) studied exposure to H2S in relation to hospital-discharge data (1993–1996). Exposures were continuing and so might be excluded from consideration, but the committee does not require an exposure-free period for studies of peripheral and nervous system diseases inasmuch as that they are most likely irreversible (as opposed to, for example, to neurobehavioral symptoms). Exposures were assigned as high, and

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 low on the basis of area of residence where H2S was mapped with passive sampling. Exposure-response trends were found for diseases of the nervous system and sense organs (p for trend <0.0001) as a whole. Significant exposure-response trends were also found for some neurologic-disease subgroupings: other disorders of the CNS (ICD codes 340–349: p for trend <0.0001) and disorders of the PNS (ICD codes 350–359: p for trend=0.027), disorders of the eye and adnexa (ICD codes 360–379: p for trend <0.0001) and disorders of the ear and mastoid process (ICD codes 380–389: p for trend <0.0001). In each of those cases, the SIRs for high exposure ranged from 2.0 to 2.68. SIRs for medium and low exposure were smaller but also significant. The major limitation of this study is the method of exposure assessment, which was based on residential location at the time of diagnosis. The authors acknowledge that such residential exposure assignment neglected to take into account residential histories or individual variation regarding daily mobility for work or study. They noted that subjects with low-exposure assignment based on residence probably work in the main business district of Rotorua, which is in a high-exposure area. Thus, there is a potential for exposure misclassification. Additionally, the Bates studies were the only epidemiologic studies of H2S found by the committee that examined long-term health outcomes. Due to the paucity of literature, the committee did not make a separate conclusion on H2S. Norman et al. (1983) performed a case-control study to determine risk factors for multiple sclerosis (ICD code 340), one of the diseases included in the Bates et al. nervous-system subgroupings (ICD codes 340–349). They studied 4,371 case-control pairs of World War II and Korea veterans to determine whether climatic factors, including air pollution, or latitude influenced risk. Air pollution was measured according to mean annual days of exposure to smog. Although air pollution and other factors were found to significantly influence the risk of multiple sclerosis when analyzed separately, their effects were found to be nonsignificant after adjustment for latitude. In summary, the three studies of H2S exposure of Bates et al. were evaluated, as was a separate study of multiple sclerosis. However, the committee excluded overbroad ICD codes and nonspecific health outcomes and focused on individual neurologic diseases or subgroupings of nervous-system diseases. Of the three studies of Bates et al., only one examined nervous-system subgroupings in relation to exposure. It found exposure-response relationships with nervous-system subgroupings in a hospital-discharge survey (Bates et al. 2002). The limitation of that study was assignment of exposure (residence only) and potential for exposure misclassification. The case-control study of Norman et al. (1983) did not find a relationship between combustion product exposure and multiple sclerosis, which was one of the ICD codes covered by Bates et al. No other studies of nervous-system subgroupings or the individual diseases met the committee’s criteria for inclusion. The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence of an association between exposure to combustion products and nervous-system disease subgroupings or individual nervous-system diseases. MULTIPLE CHEMICAL SENSITIVITY Multiple chemical sensitivity (MCS), also known as idiopathic environmental intolerance; it is a controversial, highly disabling set of symptoms evoked by low-level chemical

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 exposures. MCS is not formally recognized as a diagnosis in the 10th revision of ICD. Major medical associations question the existence of MCS as a unique clinical entity (AAAAI 1999; AMA 1992; American College of Physicians 1989). In the absence of an established diagnosis, epidemiologists and other researchers have developed case definitions by using a combination of self-reported symptoms. Therefore, the committee evaluated the evidence of a relationship between relevant exposures during the Gulf War and case definitions of MCS. Case definitions of MCS specify an array of symptoms (for example, fatigue, cognitive impairment, respiratory inflammation, and headache) elicited by exposure to relatively low levels of chemicals that have diverse structures and mechanisms of action (Cullen 1987; Simon et al. 1993). Symptomatic persons often report the belief that their symptoms are caused or later triggered by pesticides, fuels, combustion products, perfumes, and other chemical agents (Caress et al. 2002; Fiedler and Kipen 2001). Numerous studies of people who met an epidemiologic definition of MCS, including Gulf War veterans (Black et al. 1999), reported inability to work and significantly reduced quality of life (Fiedler et al. 1996; Jason et al. 2000). Background: Epidemiology of MCS Symptoms in Veteran and Civilian Populations The epidemiology of MCS has been examined in seven large or population-based studies of Gulf War veterans and in three population-based studies of US civilians. The Gulf War studies found that the prevalence of MCS—according to various case definitions based on symptom self-reporting—ranged from 2 to 6%. Each study found the prevalence in Gulf War veterans to be significantly higher than that in nondeployed veterans (Proctor 2000). The prevalence in Gulf War veterans is similar to that found in the general US population (Table 8.1). TABLE 8.1 Prevalence of MCS Symptoms in Gulf War and US Population-Based Samples Gulf War Sample MCS Symptoms or Related Condition Prevalence in Gulf War-Deployed vs Nondeployed Veterans Reid et al. 2001, n=3,531 UK Gulf War veterans MCSa 1.3% vs 0.2–0.3% in two non-Gulf War-deployed groups Reid et al. 2002, n=3,531 UK Gulf War veterans Sensitivity to at least one of 11 Gulf War chemicals 27.7% vs 12.7–14.2% in two non-Gulf War-deployed groups Black et al. 2000, n=3,695 Gulf War veterans MCS/IEIb 5.4% vs 2.6% Goss Gilroy 1998, n=3,113 Gulf War veterans MCS symptomsc 2.8% vs 0.5% Gray et al. 2002, n=11,868 Gulf War veterans Self-reported physician-diagnosed MCS 1.6% vs 0.4% Proctor et al. 2001, n=180 Gulf War veterans Presumptive MCSd 2.9% vs 0% Fukuda et al. 1998, n=3,723 Gulf War veterans Chemical sensitivitye 5.0% vs 2.0%

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 US Population-Based Sample Condition Prevalence Kreutzer et al. 1999, n=4,046 Self-reported doctor-diagnosed illness (“environmental illness” or MCS) 6.3% doctor-diagnosed illness; 11.9% reported sensitivity to more than one type of chemical Meggs et al. 1996, n=1,027 Chemical sensitivityf 4.1% Caress et al. 2002, n=1,579 Self-reported physician-diagnosed MCS or self-reported a hypersensitivityg 3.1% doctor-diagnosed MCS, 12.6% hypersensitivity aCriteria of Simon et al. 1993. bOperational case definition based on expert consensus and review of literature. cPositive responses to two sets of eight systemic symptoms produced by normal or routine exposures to at least two substances (set by a panel of physician experts in allergy, immunology, occupational health, environmental health, clinical epidemiology, and psychiatry). dCullen criteria (1987). eSingle item on symptom questionnaire. fReported becoming sick after smelling chemical odors almost daily. gAffirmative response to question “Compared to others, do you have an unusual sensitivity to common chemical products?” Hypotheses About MCS Etiology The etiology of MCS is unknown, but it has been hypothesized to involve CNS sensitization of mesolimbic pathways after exposure to chemicals or biologic stressors (Graveling et al. 1999). Studies of similar symptom clusters (for example, fibromyalgia and chronic fatigue syndrome, CFS) implicate a multifactorial process of exposure to biologic stressors followed by sensory amplification, reduced hypothalamic-pituitary function, lability of the autonomic nervous system, and psychosocial factors (Clauw 2001). Several researchers believe that the initial step in onset of MCS symptoms requires high exposure and/or repeated fluctuating moderate exposure, after which symptoms can be triggered by lower exposure (Bell et al. 2001; Clauw 2001). Animal studies have shown that the amygdala is vulnerable to sensitization, in which repeated exposure to a specific agent leads to increased response at doses lower than those normally expected to yield a response (Graveling et al. 1999). Altered hypothalamic-pituitary functioning has been identified in rodents sensitized to a chemical (Sorg et al. 1996, 1998, 2001). Evaluation of the Evidence: Inclusion Criteria For the purposes of this report, the committee evaluated studies of MCS in populations exposed to fuels or combustion products. The committee’s inclusion criteria required methodologic rigor, including criteria for a case definition, and a reasonably representative sample. Another inclusion criterion is the evaluation of subjects after an exposure-free period (free of the fuel or combustion product) to ensure the identification of long-term, rather than short-term, effects. Nine studies met the committee’s inclusion criteria: six of Gulf War veterans and three of occupational or general populations. Although two of the nine studies had verified exposure, most had self-reported exposure and self-reported health outcomes via questionnaire. Studies

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 study found higher rates of skin sensitization to D. pteronyssinus or mixed threshings among those with the combination exposure (OR 1.78, 95% CI 1.06–2.97) than among those who used only biomass. It also found increases in self-reported eczema in the preceding year (OR 2.82, 95% CI 1.61–4.96). More specifically, it found that kerosene use, but not gas or electricity use, was significantly associated with eczema (OR 3.20, 95% CI 1.62–6.32). Findings were similar to those in an earlier publication of the same investigators when they compared location of residence (urban site of Jimma with several nearby rural sites) as a proxy for type of heating-fuel use (Yemaneberhan et al. 1997). One study limitation is that pollutant concentrations in the home were not measured. The authors concluded that an increased risk of allergy is associated with the use of cleaner fuels, but their findings could not distinguish the contribution of direct contact with the cleaner fuels or of indoor air pollution from combustion products. In a cross-sectional study of male farmers in Iowa (n=382) and the wives of farmers (n=256), risk factors for farm-related dermatitis were examined (Park et al. 2001). The men and women were identified through the Iowa Farm Family Health and Hazard Survey that inquires about the prevalence of health conditions and injuries among farmers. A followup survey asked about demographics, farm characteristics, work practices, health-related behaviors, skin problems, and exposure to specific chemicals or substances. Nationally representative samples of US male farmers and wives of farmers who identified themselves as farmers and had completed an occupational-health supplement regarding problems with their skin were found through the National Health Interview Survey. A significantly higher risk of dermatitis was seen among farmers’ wives who reported being exposed to petroleum products (OR 2.51, 95% CI 1.05–6.05), than those who did not report that exposure. However, no increase was seen among the male farmers (OR 0.39, 95% CI 0.09–1.76). Specific petroleum products or exposures were not delineated, and the study is further limited by the relatively low response rate (39%), which may imply selection bias. No data on length of exposure were provided. Brender et al. (2003) studied the prevalence of rashes in 214 black people living near a former creosote wood-treatment facility contaminated with polycyclic aromatic hydrocarbons (PAHs). Increased PAHs were found in soil and in groundwater and led to classification of the site on the US Environmental Protection Agency’s National Priorities List. In comparison with residents of a nearby community largely of blacks, those living near the wood-treatment facility had higher rates of rashes (relative risk 5.7, 95% CI 3.0–10.9). Most of the rashes were not documented by a physician or an interviewer. The prevalence of rashes was significantly higher among members of the community exposed to higher soil concentrations of anthracene (over 1,000 μg/kg). Anthracene is a solid PAH and is used in wood preservatives. Rashes are frequently reported by Gulf War veterans, but only one study of Gulf War veterans searched for relationships between dermatitis and self-reported exposure during the Gulf War (Proctor et al. 1998). No exposure to combustion products or fuels or any other self-reported exposure was related to dermatitis, defined as rashes, eczema, or skin allergies. Many fuels (for example, gasoline and kerosene) are generally acknowledged skin irritants, as indicated by the studies discussed above. Irritant contact dermatitis is evident soon after exposure but usually disappears soon after removal of the irritant. There are few epidemiologic studies, however, of exposure to fuels and irritant and allergic contact dermatitis. The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to fuels and combustion products and chronic irritant and allergic contact dermatitis after cessation of exposure.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 SARCOIDOSIS Sarcoidosis is an inflammatory disorder that features accumulation of T lymphocytes and mononuclear phagocytes. The lungs are most frequently affected and undergo inflammatory changes, fibrosis, and other abnormalities; but skin, eyes, and lymph nodes may also be affected. Its etiology is unknown, but it is thought to be triggered by a hypersensitive response to exogenous or endogenous antigens. The prevalence of sarcoidosis in the United States is 10–40 per 100,000. Its frequency is higher in nonwhite and women, but it is also common in whites and men in the United States and throughout the world. Three epidemiologic studies examined the relationship between occupational or residential exposure to fires and sarcoidosis (Table 8.4). Kajdasz et al. (2001) conducted a case-control study of 44 people who had sarcoidosis. The study was designed to determine whether rural exposure, including the use of residential fireplaces and wood stoves, is related to onset. Cases were recruited from the Medical University of South Carolina Ambulatory Care System and were compared with controls (age-, race-, and sex-matched) recruited through random-digit dialing. A total of 49 people were recruited, but there is little information on how. Of the 49, 44 met the inclusion/exclusion criteria; one person was excluded because of active treatment for tuberculosis, and four declined to participate. Cases were required to have biopsy-confirmed sarcoidosis or, when the biopsy was inconclusive, clinical signs and symptoms of sarcoidosis combined with radiographic findings. The authors noted that “all diagnoses were confirmed by pulmonologists, dermatologists, or ophthalmologists with prior experience in diagnosing and treating sarcoidosis.” Trained interviewers administered a questionnaire, which covered exposure history, including magnitude of exposure, from birth through disease development. The questionnaire also covered employment history, smoking, and other factors. Six exposures were included, including home use of a coal stove, wood stove, or fireplace; use of insecticides (other than for home extermination); use of well or spring water; and living or working on a farm. No other details about the types of exposure were asked for other than frequency of use. In multivariate models, which controlled for demographic and geographic influences, the use of wood stoves (OR 3.1, 95% CI 1.2–7.9) and fireplaces (OR 5.7, 95% CI 1.8–18.4) was significantly related to the occurrence of sarcoidosis, and the use of coal stoves and insecticides/herbicides was not. Exposure-response relationships between number of times used per week as an ordinal variable and the risk of sarcoidosis were evaluated. Wood-stove use had an adjusted OR of 1.4, 95% CI 1.1–1.8, and fireplace use an adjusted OR of 1.8, 95% CI 1.3–2.6.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 TABLE 8.4 Case-Control Studies of Sarcoidosis and Combustion Product Exposure Reference, Country Cases Controls Exposure Determination Exposure Adjusted OR (95% CI or p) Comments Kajdasz et al. 2001 44 patients with sarcoidosis recruited from Medical University of South Carolina ambulatory-care system 88 persons recruited with random-digit dialing, matched for race, sex, age Questionnaire administered face to face by trained interviewers covering exposures from birth to onset, employment, smoking, and other factors Use of wood stove: never or none, less than weekly, weekly, several times per week, daily In multivariable, multiple-risk-factor conditional logistic-regression model with pairwise interaction terms, increasing woodstove use (adjusted OR 1.4, 95% CI 1.1–1.8) and increased fireplace use (adjusted OR 1.8, 95% CI 1.3–2.6) Dose-response gradient for woodstoves and fireplaces (reported as marginally significant) Prezant et al. 1999, New York City, US All New York City firefighters 1985–1998 All EMS health-care workers in fire department 1995–1998 Biopsy-proven sarcoidosis, pulmonary function (FVC, FEV, diffusing capacity for CO), airway hyperreactivity, maximal oxygen consumption Occupational 25 cases in firefighters (21 new, four prior), one prior case in health-care worker controls; average annual incidence 12.9/100,000 in firefighters (1985–1998) vs 0 in controls (1995–1998); pulmonary function normal in 68% of firefighters with sarcoidosis; all cases remained at work  

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Reference, Country Cases Controls Exposure Determination Exposure Adjusted OR (95% CI or p) Comments Kern et al. 1993, US 46 Providence, RI, firefighters class of 1979 53 firefighters classes of 1974, 1980; 50 police officers classes of 1973–1981 Questionnaire, chest radiographs, neopterin, IL-2, chlamydia serology Occupational Four sarcoidosis cases in firefighter index group, no cases in two control groups; serum neopterin significantly increased in 20% of index firefighter cohort, 22% of firefighter controls, 4% of police officers; via logistic regression firefighting found to be only significant determinant of neopterin increase (OR 5.8, 95% CI 1.3–26.9)   NOTE: CI=confidence interval; CO=carbon monoxide; FEV=forced expiratory volume; FVC=forced vital capacity; OR=odds ratio.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 The study had numerous limitations, such as inadequate description of how the cases without biopsy confirmation were diagnosed and the lack of control for employment history (besides farming), recall bias, and lack of measurement of pollutant concentrations. The authors noted that sarcoidosis could be associated with a component of wood-burning or wood-handling, namely contact with smoke, ash, wood particles, or wood molds. Researchers with the New York City Fire Department (Prezant et al. 1999) studied a cohort of more than 11,000 firefighters to determine incidence, prevalence, and severity of sarcoidosis over a 13-year period (1985–1998). The research grew out of a pulmonary surveillance program that began in 1985. In 1995, the program added a control group of emergency medical service (EMS) prehospital health-care workers (about 2,700). Cases of sarcoidosis were defined by biopsy that showed evidence of noncaseating granulomas. The methods of case ascertainment were the same in the two groups, except for the timeframe: chart reviews of all currently employed to identify those with pre-existing sarcoidosis, referral to a pulmonary specialist of workers who had signs or symptoms of pulmonary disease, routine chest radiography during wellness medical evaluations, review of all disability leave and retirement applications, and disclosure of study goals to health and safety personnel in employee unions. Cases were studied with physiologic measures of flow rates, diffusing capacity for carbon monoxide, lung volumes, airway hyperreactivity, and maximal oxygen consumption. The overwhelming majority of firefighters (94%) were white men, compared with 44 % of the controls. Nearly 15.9% of the controls were black men and 15.3% were Hispanic men. The program uncovered 25 cases of sarcoidosis in firefighters (1985–1998). Of the 25 cases, 24 were in white firefighters and one case was found in a black firefighter. One pre-existing case was found in the controls. The average annual incidence of sarcoidosis was 12.9 per 100,000 in firefighters and 0% in the controls. The point prevalence in 1998 was 222 per 100,000 in firefighters and 35 per 100,000 in the controls. Pulmonary function was normal in 68% of the firefighter cases, and maximal oxygen consumption was normal in 59%. Firefighter cases showed minimal impairment, and all were working in the fire department. A strength of the study is the systematic screening program, which probably resulted in fairly complete ascertainment of incident cases. Limitations include the lack of specific exposure assessment and of analysis of duration or frequency of exposure to combustion products. There was no control for potential confounders, such as race or familial aggregation of sarcoidosis (for example, if firefighters are more likely than EMS workers to have siblings enter the job). In addition, there is no way to determine the role of combustion products or exposure to other toxicants, allergens, or infectious agents. Kern et al. (1993) were the first to study the relationship between firefighting and sarcoidosis. The study stemmed from a cluster of three cases among 10 white firefighters who had trained together as apprentices in 1979. Sarcoidosis appeared 6–8 years later. When the cluster came to light, the investigators hypothesized that a factor intrinsic to firefighting, such as recurrent smoke exposure, might act synergistically with an infectious agent. One agent implicated at the time in sarcoidosis was Chlamydia pneumoniae. The investigators conducted a case-finding survey with a questionnaire sent to 1,282 active and retired male firefighters and police officers who had worked or were working in Providence, Rhode Island. They later set up a cohort study comparing the class of 1979 firefighters (n=46) with two control groups: one was the classes of 1974 and 1980 firefighters (n=53), and the other was of police officers (classes of 1973–1981, n=50). They had winnowed questionnaire responders down to those still employed as firefighters or police officers, believing that current occupation was a key to interpreting

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 laboratory results. Investigators compared medical history, exposures, chest radiographs, and seromarkers of T-lymphocyte activation; serum neopterin and interleukin-2 receptors, which are surrogate markers of lymphocytic alveolitis, were used because subjects were not willing to undergo bronchoalveolar lavage. Radiographs were read by specialists who were blinded to occupational group. A total of four sarcoidosis cases were found in the firefighter index group (including the three original cases), and no cases were found in the two control groups. Although the three groups did not differ by Chlamydia serology or interleukin-2 concentrations, serum neopterin was significantly increased in 20% of the index firefighter cohort, 22% of the firefighter controls, and 4% of the police officers. By logistic regression, firefighting was found to be the only significant determinant of neopterin increse (OR 5.8, 95% CI 1.3–26.9). The authors concluded that Chlamydia was not likely to be related to cases of sarcoidosis, but that firefighting was. They recommended more studies on neopterin and more studies of firefighters. The limitations of the study are the small sample, the low statistical power (sarcoidosis is a relatively rare disease), the lack of a risk estimate for firefighters vs police officers, the lack of exposure assessment for combustion products, and the lack of assessment of coexposures to other chemicals in the workplace. The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to combustion products and sarcoidosis. REFERENCES AAAAI (American Academy of Allergy, Asthma and Immunology). 1999. Idiopathic environmental intolerances. American Academy of Allergy, Asthma and Immunology (AAAAI) Board of Directors. Journal of Allergy and Clinical Immunology 103(1 Pt 1):36–40. al-Naser F, Everly GS Jr. 1999. Prevalence of posttraumatic stress disorder among Kuwaiti firefighters. International Journal of Emergency Mental Health 1(2):99–101. AMA (American Medical Association). 1992. Clinical ecology. Council on Scientific Affairs, American Medical Association. JAMA 268(24):3465–3467. American College of Physicians. 1989. Clinical ecology. American College of Physicians. Annals of Internal Medicine 111(2):168–178. APA (American Psychiatric Association). 1994. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. 4th ed. Washington, DC: APA. Arnold IM, Dufresne RM, Alleyne BC, Stuart PJ. 1985. Health implication of occupational exposures to hydrogen sulfide. Journal of Occupational Medicine 27(5):373–376. Asukai N, Kato H, Kawamura N, Kim Y, Yamamoto K, Kishimoto J, Miyake Y, Nishizono-Maher A. 2002. Reliability and validity of the Japanese-language version of the impact of event scale-revised (IES-R-J): Four studies of different traumatic events. Journal of Nervous and Mental Disease 190(3):175–182. ATSDR (Agency for Toxic Substances and Disease Registry). 1995. Toxicological Profile for Fuel Oils. Atlanta, GA: US Department of Health and Human Services, Public Health Service, ATSDR. Baker DG, Mendenhall CL, Simbartl LA, Magan LK, Steinberg JL. 1997. Relationship between posttraumatic stress disorder and self-reported physical symptoms in Persian Gulf War veterans. Archives of Internal Medicine 157(18):2076–2078. Bates MN, Garrett N, Graham B, Read D. 1997. Air pollution and mortality in the Rotorua geothermal area. Australian and New Zealand Journal of Public Health 21(6):581–586.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Bates MN, Garrett N, Graham B, Read D. 1998. Cancer incidence, morbidity and geothermal air pollution in Rotorua, New Zealand. International Journal of Epidemiology 27(1):10–14. Bates MN, Garrett N, Shoemack P. 2002. Investigation of health effects of hydrogen sulfide from a geothermal source. Archives of Environmental Health 57(5):405–411. Beaton R, Murphy S, Johnson C, Pike K, Corneil W. 1998. Exposure to duty-related incident stressors in urban firefighters and paramedics. Journal of Traumatic Stress 11(4):821–828. Bell IR, Baldwin CM, Schwartz GE. 1998. Illness from low levels of environmental chemicals: Relevance to chronic fatigue syndrome and fibromyalgia. American Journal of Medicine 105(3A):74S–82S. Bell IR, Baldwin CM, Schwartz GE. 2001. Sensitization studies in chemically intolerant individuals: Implications for individual difference research. Annals of the New York Academy of Sciences 933:38–47. Black DW, Doebbeling BN, Voelker MD, Clarke WR, Woolson RF, Barrett DH, Schwartz DA. 1999. Quality of life and health-services utilization in a population-based sample of military personnel reporting multiple chemical sensitivities. Journal of Occupational and Environmental Medicine 41(10):928–933. Black DW, Doebbeling BN, Voelker MD, Clarke WR, Woolson RF, Barrett DH, Schwartz DA. 2000. Multiple chemical sensitivity syndrome: Symptom prevalence and risk factors in a military population. Archives of Internal Medicine 160(8):1169–1176. Boxer PA, Wild D. 1993. Psychological distress and alcohol use among fire fighters. Scandinavian Journal of Work, Environment & Health 19(2):121–125. Boyd KC, Hallman WK, Wartenberg D, Fiedler N, Brewer NT, Kipen HM. 2003. Reported exposures, stressors, and life events among Gulf War Registry veterans. Journal of Occupational and Environmental Medicine 45(12):1247–1256. Bremner J, Southwick S, Darnell A, Charney D. 1996. Chronic PTSD in Vietnam combat veterans: Course of illness and substance abuse. The American Journal of Psychiatry 153(3):369–375. Brender JD, Pichette JL, Suarez L, Hendricks KA, Holt M. 2003. Health risks of residential exposure to polycyclic aromatic hydrocarbons. Archives of Environmental Health 58(2):111–118. Camerino D, Cassitto MG, Gilioli R. 1993. Prevalence of abnormal neurobehavioral scores in populations exposed to different industrial chemicals. Environmental Research 61(2):251–257. Caress SM, Steinemann AC. 2003. A review of a two-phase population study of multiple chemical sensitivities. Environmental Health Perspectives 111(12):1490–1497. Caress SM, Steinemann AC, Waddick C. 2002. Symptomatology and etiology of multiple chemical sensitivities in the Southeastern United States. Archives of Environmental Health 57(5):429–436. Choi IS. 1983. Delayed neurologic sequelae in carbon monoxide intoxication. Archives of Neurology 40(7):433–435. Christie D, Robinson K, Gordon I, Webley C, Bisby J. 1987. Current mortality in the Australian petroleum industry: The healthy-worker effect and the influence of life-style factors. Medical Journal of Australia 147(5):222, 224–225. Clauw DJ. 2001. Potential mechanisms in chemical intolerance and related conditions. Annals of the New York Academy of Sciences 933:235–253. Corneil W, Beaton R, Murphy S, Johnson C, Pike K. 1999. Exposure to traumatic incidents and prevalence of posttraumatic stress symptomatology in urban firefighters in two countries. Journal of Occupational Health Psychology 4(2):131–141. Cullen MR. 1987. The worker with multiple chemical sensitivities: An overview. Occupational Medicine 2(4):665–661. Dagg TG, Satin KP, Bailey WJ, Wong O, Harmon LL, Swencicki RE. 1992. An updated cause specific mortality study of petroleum refinery workers. British Journal of Industrial Medicine 49(3):203–212. Davidoff AL, Keyl PM. 1996. Symptoms and health status in individuals with multiple chemical sensitivities syndrome from four reported sensitizing exposures and a general population comparison group. Archives of Environmental Health 51(3):201–213.

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