7
NEUROLOGIC EFFECTS

Neurologic effects are difficult to diagnose because of variability in signs and symptoms, difficulty in interpreting neurologic test results, and lack of biologic markers of many symptoms related to the nervous system. The nonspecificity of symptoms often makes it difficult to draw etiologic conclusions on the basis of a single test or measure of nervous system function. That is true especially of chronic environmental exposures (Grandjean et al., 1991), and it presents challenges for the clinician in making neurologic diagnoses (Juntunen, 1982).

The nervous system is functionally and anatomically divided into the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the brain and the spinal cord. The PNS includes nerve roots, the brachial and lumbar plexuses, and the peripheral nerves that pass to the extremities. The peripheral nerves innervate muscles, convey sensory information to the CNS, and contain autonomic fibers that regulate the activity of the heart, blood vessels, sweat glands, bladder, and intestines. Environmental assaults on the CNS can lead to neurobehavioral abnormalities, such as cognitive and neuropsychiatric disorders, and to disturbances related to attention, memory, perception, anxiety, mood, sensation, weakness, tremors, reaction time, and abnormal movement. Assaults on the PNS can lead to peripheral neuropathy also known as polyneuropathies; however, neuropathies can be a feature of many common medical disorders, such as the neuropathy associated with diabetes.

The senses (such as vision, hearing, balance, taste, and smell) depend on neural pathways that originate in peripheral receptors and terminate in the cerebral cortex, brainstem, or spinal cord. Chemical agents that affect the senses often interfere with peripheral sensory receptors (Spencer et al., 2000). And many diseases of the nervous system might have environmental etiologies, such as Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease. All of the studies evaluated in this chapter examine the relationship between insecticide or solvent exposure and neurologic effects.

Clinicians diagnose neurologic diseases and disorders by administering neurologic tests. Numerous tests of neurologic function are discussed in this chapter. The neurologic examination comprises comprehensive social and medical histories, clinical tests of nervous system function, detailed neurobehavioral test batteries (Appendix F), laboratory examinations, and other ancillary tests. The results need to be integrated and analyzed critically to ensure a valid assessment. Performance on neurologic tests and neurobehavioral test batteries may be influenced by a host of confounding factors, including medications,



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Gulf War and Health: Insecticides and Solvents, Volume 2 7 NEUROLOGIC EFFECTS Neurologic effects are difficult to diagnose because of variability in signs and symptoms, difficulty in interpreting neurologic test results, and lack of biologic markers of many symptoms related to the nervous system. The nonspecificity of symptoms often makes it difficult to draw etiologic conclusions on the basis of a single test or measure of nervous system function. That is true especially of chronic environmental exposures (Grandjean et al., 1991), and it presents challenges for the clinician in making neurologic diagnoses (Juntunen, 1982). The nervous system is functionally and anatomically divided into the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the brain and the spinal cord. The PNS includes nerve roots, the brachial and lumbar plexuses, and the peripheral nerves that pass to the extremities. The peripheral nerves innervate muscles, convey sensory information to the CNS, and contain autonomic fibers that regulate the activity of the heart, blood vessels, sweat glands, bladder, and intestines. Environmental assaults on the CNS can lead to neurobehavioral abnormalities, such as cognitive and neuropsychiatric disorders, and to disturbances related to attention, memory, perception, anxiety, mood, sensation, weakness, tremors, reaction time, and abnormal movement. Assaults on the PNS can lead to peripheral neuropathy also known as polyneuropathies; however, neuropathies can be a feature of many common medical disorders, such as the neuropathy associated with diabetes. The senses (such as vision, hearing, balance, taste, and smell) depend on neural pathways that originate in peripheral receptors and terminate in the cerebral cortex, brainstem, or spinal cord. Chemical agents that affect the senses often interfere with peripheral sensory receptors (Spencer et al., 2000). And many diseases of the nervous system might have environmental etiologies, such as Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease. All of the studies evaluated in this chapter examine the relationship between insecticide or solvent exposure and neurologic effects. Clinicians diagnose neurologic diseases and disorders by administering neurologic tests. Numerous tests of neurologic function are discussed in this chapter. The neurologic examination comprises comprehensive social and medical histories, clinical tests of nervous system function, detailed neurobehavioral test batteries (Appendix F), laboratory examinations, and other ancillary tests. The results need to be integrated and analyzed critically to ensure a valid assessment. Performance on neurologic tests and neurobehavioral test batteries may be influenced by a host of confounding factors, including medications,

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Gulf War and Health: Insecticides and Solvents, Volume 2 alcohol, age, education, motivation and culture, and the presence of comorbid conditions (such as diabetes, depression, and cardiovascular disease). The committee reviewed the epidemiologic literature on neurologic effects of insecticide and solvent exposure, focusing on studies that examined long-term effects. Four general types of neurologic effects are examined in this chapter: peripheral neuropathy, neurobehavioral effects (assessed by symptom reporting or performance on validated neurobehavioral tests or batteries), neurologic diseases, and sensory effects. For each, the chapter covers studies of Gulf War veterans, when available, and studies of occupational exposure to insecticides and to solvents. Almost all the available studies of exposure to insecticides focus on exposures to insecticides as a broad group, to insecticide mixtures, or to organophosphorous (OP) insecticides in particular. Similarly, studies of exposure to solvents often examined solvents as a broad group, solvent mixtures, or workers in occupations that were exposed to the solvents of interest (Chapter 2). The committee was unable to identify epidemiologic studies of sufficient quality to permit a separate evaluation of the long-term neurologic effects of pyrethrins, carbamates, organochlorines, or the insect repellent N,N-diethyl-3-methylbenzamide (DEET). The evidence base for many of those pesticides and neurologic effects generally consisted of case reports and case series—study designs that do not carry the methodologic rigor of cross-sectional, cohort, or case-control studies. Several of the OP-insecticide studies evaluated in this chapter, where noted, did include mixed exposures to OPs and carbamates but not of carbamates alone. The committee was not able to draw conclusions about long-term effects of pesticides other than OP insecticides, because of the lack of methodologically rigorous studies. The effects of pesticides are covered in greater detail in Chapter 3. The committee reviewed hundreds of peer-reviewed and published studies of neurologic effects of insecticides and solvents, and it selected for detailed evaluation only the studies that met its inclusion criteria, which are listed below.1 The study had to be a published in a peer-reviewed journal and had to have methodologic rigor, including a control or reference group, and reasonable control for confounders. Case studies and case series were generally excluded from the committee’s consideration. The study had to identify insecticides and solvents relevant to the committee’s charge (Chapters 1 and 2). If solvents were not identified, for example, the study may have been included if it examined occupations with presumed exposure to many of the solvents sent to the Gulf War. For example, studies of painters, workers in paint manufacturing, printers, dry cleaners, or workers in boot or shoe manufacturing and repair were included in the committee’s assessment. For some neurologic effects, the committee only considered studies that examined long-term rather than short-term effects. That was accomplished typically by examining studies that analyzed only past exposure—by requiring an exposure-free interval of 1   Additional criteria, specific for particular neurologic effects, are listed in the appropriate sections of the chapter.

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Gulf War and Health: Insecticides and Solvents, Volume 2 weeks to months before testing of study subjects. (The next section describes the rationale for this criterion.) As the committee reviewed the body of evidence, it was apparent that some studies of multiple outcomes could provide strong evidence for one of the outcomes and only weak evidence for another. For example, a study that was well-designed for assessing a neurobehavioral effect might not have been as well-designed for assessing peripheral neuropathy. Short-Term vs Long-Term Effects The committee evaluated long-term effects because they are most relevant to veterans whose exposures occurred during the Gulf War but whose symptoms persisted for months or years after cessation of exposure (Appendix A). Long-term effects of a given exposure can be distinct from short-term effects. For example, OP-insecticide exposure produces a well-defined short-term effect, the acute cholinergic syndrome (Chapter 3); this life-threatening syndrome is quite different in characteristics and severity from the long-term effects considered in this chapter. Occupational studies of neurologic effects often do not permit the distinction between long-term effects (months or years) and short-term effects (hours to weeks), because many studies examine workers with both past and current (ongoing) exposure. Consequently, if a study finds a neurologic effect, it is difficult to determine whether the observed effect will persist or disappear on cessation of the exposure unless an exposure-free interval of weeks or months has passed before the effect is measured. Many of the studies reviewed by the committee were not designed to determine whether an effect was a long-term or short-term one. The challenge of distinguishing long-term and short-term effects is greater for examining 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. Conversely, neurologic diseases are generally believed to be irreversible after a confirmed diagnosis and are associated with abnormal results of pathologic or biochemical tests. Thus, in evaluating the body of evidence specifically on long-term neurobehavioral effects, the committee required that an exposure-free interval of weeks to months elapse before testing. The committee also held sensory effects to that standard because sensory effects can also be reversible. For studies of peripheral neuropathy and neurologic diseases, the committee did not require an exposure-free interval, because these neurologic effects are almost always long-term effects (although some degree of recovery or lack of progression is possible). Short-Term vs Long-Term Effects of Organophosphorous (OP) Compounds The most immediate short-term effect of high OP exposure is known as the acute cholinergic syndrome. Its signs and symptoms are recognizable within minutes to hours and include pinpoint pupils, salivation, severe nausea, vomiting, and diarrhea. The acute cholinergic syndrome, which is highly dose-dependent, requires emergency care to prevent

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Gulf War and Health: Insecticides and Solvents, Volume 2 respiratory failure and death (Chapter 3). About 10–20% of people who survive an acute poisoning episode are at risk for the intermediate syndrome, which can appear within 16–20 hours after exposure to the insecticide (Shailesh et al., 1994) or 7–75 hours after the onset of acute poisoning (He et al., 1998). Marked by weakness of neck flexors and proximal limb muscles, the intermediate syndrome is also life-threatening and requires hospitalization (Chapter 3), but it resolves after 30–40 days and so cannot be characterized as a long-term effect (Lotti, 2001). High OP-insecticide exposure is presumed to have occurred if a person displays the acute cholinergic syndrome. High and low OP-insecticide exposure can be confirmed by assessment of the biomarker acetylcholinesterase (AChE). The degree of AChE inhibition is both an effect of recent OP-pesticide exposure and a measure of the magnitude of the exposure. The degree of AChE inhibition is best interpreted by comparing a person’s postexposure and pre-exposure (baseline) red-cell AChE concentrations. A reduction of 20–30% is considered an objective indication of recent OP exposure, and a reduction of 50–70% generally confirms clinical OP poisoning. If a person’s baseline value is unavailable, other methods can be used. One is to compare the person’s value with a population mean; however, because of population variability, this comparison is less reliable. Another is to compare the increase in AChE several months after recovery from poisoning; this indirect method measures how much a person’s AChE was depressed at the time of acute poisoning (Coye et al., 1986). Serum cholinesterase (such as butyrylcholinesterase) values have less utility because their functional significance is unknown, and there is a wider range of normal values. GULF WAR VETERANS STUDIES A number of studies have shown that Gulf War veterans have much higher rates of fatigue, headache, pain, and cognitive symptoms than nondeployed military personnel in several countries, including the United States (Iowa Persian Gulf Study Group, 1997; Kang et al., 2000), United Kingdom (Cherry et al., 2001a; Unwin et al., 1999), and Canada (Goss Gilroy Inc., 1998). Veterans’ symptoms are discussed in this chapter because they are most closely related to nervous system function, yet they are characterized as “unexplained illnesses” because they do not fit established diagnoses (IOM, 2000). The committee reviewed epidemiologic studies of Gulf War veterans (Appendix A). For the purposes of this chapter, the committee sought to answer these questions: What are the nature and quality of the evidence that specifically links solvent or insecticide exposures during the Gulf War to long-term neurologic effects?2 Is the evidence strong enough to justify particular conclusions regarding Gulf War veterans, or can it be marshaled to support the committee’s conclusions drawn from other populations, mostly workers with occupational exposure to relevant pesticides or solvents? To answer those questions, the committee focused its evaluation on the subset of well-designed studies of Gulf War veterans that contained analyses of neurologic effects in relation to pesticide or solvent exposures. Tables 7.1 and 7.4 summarize information about each study’s population, including exposure to relevant pesticides and solvents, findings, and limitations. The only 2   Neurologic effects is a broad term loosely defined to encompass many of the unexplained symptoms—such as headache, pain, and fatigue reported by Gulf War veterans.

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Gulf War and Health: Insecticides and Solvents, Volume 2 findings reported in those tables are related to symptom-exposure relationships. The limitations listed are those identified by the study authors or by the committee. The studies are divided into two general types: population-based and military-unit-based. Population-based studies are methodologically the most robust type of epidemiologic study because they include study subjects representative of a population of interest, which in this case is Gulf War veterans. A cohort may include all personnel from a given country who were deployed to the Persian Gulf (Goss Gilroy Inc., 1998) or a randomly selected sample of those deployed (Unwin et al., 1999). Population-based studies attempt to sample an entire cohort by contacting people where they live, in contrast with studies that include only veterans who seek treatment or who remain in military service (for example, on a particular base or in a particular branch, such as the Air Force). Studies of military units or other military subgroups are less representative of the broader Gulf War veteran population than are population-based studies (IOM, 2000). The largest and most representative population-based study of US Gulf War veterans (Kang et al., 2000) is not included in the body of evidence evaluated by the committee, because the study, by design, examined only symptom or syndrome prevalence, not symptom-exposure relationships. Most studies of Gulf War veterans were designed to detect the nature and prevalence of veterans’ symptoms and illnesses and whether they constituted a new syndrome rather than specifically to assess the effects of exposure to insecticides or solvents. When the effects of exposure to various agents were assessed, numerous potential agents were evaluated in the same study. For example, in one key population-based study (Cherry et al., 2001a), only four of 14 potential exposure categories were related to insecticides or solvents. When insecticide or solvent exposures were assessed, few investigators attempted to quantify exposures to specific agents. Questions asked were very general—for example “Did you handle pesticides?” “Did you bathe in or drink contaminated water?” Most of the studies were cross-sectional, with outcomes and exposure to various agents measured simultaneously after the Gulf War had ended. Cross-sectional studies limit opportunities to learn about symptom duration and latency of onset (IOM, 2000). They are especially subject to recall bias: veterans who develop symptoms may be more likely than asymptomatic veterans to recall particular exposures. Symptoms reported in cross-sectional studies do not necessarily accurately represent the total symptom experience after an exposure. Many cross-sectional studies of Gulf War veterans were also limited by being conducted years after the war. Only one cohort was studied soon after the war and then longitudinally (Proctor et al., 1998). Furthermore, studies may not have examined outcomes in relation to insecticide and solvent exposures. The veteran population and sampling strategies used varied widely from study to study. Two studies attempted to include all the Gulf War veterans from a particular country (Goss Gilroy Inc., 1998; Suadicani et al., 1999). Others used a random sample of veterans from a country (Cherry et al., 2001a; Unwin et al., 1999) or from a region of a country (Iowa Persian Gulf Study Group, 1997). Still others used veterans who demobilized at a given base in the country (Proctor et al., 1998) or members of a specific military unit (Gray et al., 1999; Haley and Kurt, 1997). Most studies used active-duty veterans, reserve veterans, or veterans who left military service; but some (Gray et al., 1999; Nisenbaum et al., 2000) used only veterans who had remained in active service for many years after the war. Using only active-duty veterans creates selection bias by potentially excluding those who had suffered the most disabling symptoms and had left the military. One study included mainly veterans who

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Gulf War and Health: Insecticides and Solvents, Volume 2 had served in the Persian Gulf as peacekeepers after the war; the majority had served many years after hostilities ended (Suadicani et al., 1999). All Gulf War studies relied on self-reports of insecticide or solvent exposure. In most cases, the self-reports were made years after the end of the war. Most studies did not identify specific insecticides or solvents. Some broke down potential exposure into broad categories (for example, use of personal pesticides, pesticide handling, and spraying of quarters), but others simply asked about exposure to “pesticides” or “solvents.” Because the studies all used self-reported data generally gathered years after the events in question, there is a strong possibility of recall bias—that is, veterans with symptoms would be more likely than those without symptoms to recall exposure. Most of the studies relied on symptom self-reports elicited via questionnaire or structured interview. Several approaches were taken to combine the reported symptoms into outcome variables. One approach was to use a statistical method called factor analysis to uncover an underlying structure in reported symptoms (Cherry et al., 2001a; Fukuda et al., 1998; Haley and Kurt, 1997).3 A second approach attempted to match symptoms in some way to previously defined syndromes or illnesses (Iowa Persian Gulf Study Group, 1997; Nisenbaum et al., 2000; Unwin et al., 1999). In some cases, previously validated instruments were used. In others, symptoms were assembled into established syndromes on the basis of criteria devised by the investigators; subjects who did not meet established syndromes or diagnoses were said to have unexplained symptoms that could be related to a Gulf War exposure. Other studies did not attempt a synthesis of any sort but searched for associations between exposures to various agents during the Gulf War and individual symptoms. Another limitation of Gulf War studies was the problem of multiple comparisons between exposure to numerous agents and health outcomes. When investigators examine a large number of exposure-symptom associations, the chances of reporting a spurious association as statistically significant (a type I error) are increased. Gulf War studies took a wide variety of statistical approaches to adjust for the problem of multiple comparisons. However, many did not account for that problem and reported as statistically significant any association with a p value of 0.05 or less. In some of those studies, the investigator did not adjust for multiple comparisons because of the exploratory nature of the study, and their desire to reduce the probability of not finding a true association (a type II error). Other investigators were more conservative and set a more stringent significance level to reduce the probability of a type I error (Cherry et al., 2001a; Haley and Kurt, 1997; White et al., 2001). Many studies noted that many different agents were associated with the outcomes they measured, but only one attempted to examine the association between specific agents and found them to be strongly correlated (Cherry et al., 2001a), however, the interrelationships might reflect information bias and might be an important limitation of the study. The limitations described above precluded the committee from drawing specific conclusions solely from studies of Gulf War veterans. The committee therefore combined its evaluation of the evidence from Gulf War studies with the evidence from other populations (mostly in occupational studies). The committee then drew conclusions from the entire body of evidence. That combined approach was undertaken for only two neurologic effects—peripheral neuropathy and neurobehavioral effects—because there were no peer-reviewed 3   The studies are not reported in Table 7.1 if they did not address symptom-exposure relationships.

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Gulf War and Health: Insecticides and Solvents, Volume 2 published studies of Gulf War veterans for other neurologic effects covered in this chapter. (The committee did not evaluate a study of amyotrophic lateral sclerosis, because it has not yet been peer-reviewed or published.) INSECTICIDES AND PERIPHERAL NEUROPATHY Peripheral neuropathy is a general term referring to any abnormality, inflammation, or disease of a peripheral nerve. The most common causes of peripheral neuropathy are diabetes and alcoholism (Poncelet, 1998). The symptoms of peripheral neuropathy include numbness, tingling, and weakness, but the nature and pattern of symptoms can vary greatly, depending on the etiology. With the exception of the Gulf War veteran studies, the committee defined peripheral neuropathy, for purposes of its evaluation, as requiring a diagnosis by a thorough neurologic examination and confirmatory findings from quantitative laboratory tests, such as nerve-conduction studies and electromyography (see Appendix F). The question posed is whether peripheral neuropathy is associated with exposure to the insecticides and solvents of interest to the committee. In the subsection below, the committee evaluates the body of evidence from studies of Gulf War veterans and from occupational studies of exposure to OP insecticides and relevant solvents (those identified as having been present in the Persian Gulf). Gulf War Veterans and Peripheral Neuropathy Three studies of Gulf War veterans assessed the relationship between insecticide or solvent exposures in the Persian Gulf and peripheral neuropathy (Table 7.1). The general limitations of Gulf War studies have been described in the previous section, and a description of the entire body of Gulf War studies, regardless of whether they examine insecticide or solvent exposure, is in Appendix A. Each of the studies evaluated in this section, like most Gulf War studies, used questionnaires to assess exposure to various agents and symptoms. Peripheral neuropathy was defined in the studies in various ways through symptom reporting, but few included a neurologic examination or confirmatory electrophysiologic tests. In the Gulf War studies, peripheral neuropathy and symptoms suggesting peripheral neuropathy were typically among a broad array of outcomes examined. Likewise, insecticide or solvent exposure was among a host of agents being examined. None of the studies of Gulf War veterans, however, focused exclusively on the question of whether insecticide or solvent exposure in the Persian Gulf was associated with the development of peripheral neuropathy.

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Gulf War and Health: Insecticides and Solvents, Volume 2 TABLE 7.1 Gulf War Studies and Peripheral Neuropathy Reference Population Self-Reported Exposure to Relevant Pesticides or Solvents Health Outcome or Test Type Results Limitations Military-Unit-Based Studies Haley & Kurt, 1997 US 249 deployed veterans from Navy reserve battalion (Seabees); Nested case-control study of 23 veterans with up to three newly defined syndromes (derived from factor analysis) vs 229 veterans without newly defined syndromes Five of 18 related to pesticides or solvents: “DEET-containing insect repellent,” “environmental pesticides,” “pesticides in uniforms,” “pesticides in flea collars,” “CARC paint on vehicles” Symptom questionnaire Exposure questionnaire Amount of insect repellent (DEET) applied to skin was associated with arthro-myo-neuropathy syndrome (RR=1.6, 95% CI=0.5–5.5 for lowest exposure; and RR=7.8, 95% CI=2.4–24.7 for greatest exposure); association held only for veterans using government-issued insect repellent, not commercial insect repellent. Self-reported symptoms and exposure to various agents; lack of neurologic examination and electrophysiologic testing; small sample size; low participation rate   In a separate clinical study (Haley et al., 1997b), subset of five veterans with arthro-myoneuropathy syndrome was evaluated by blinded neurologists, who concluded that clinical and electrophysiologic findings were insufficient to diagnose any known syndrome Lack of control group in original cohort; limited representation of entire Gulf War cohort Proctor et al., 1998 US 300 US deployed veterans from Massachusetts (Fort Devens) and New Orleans vs 48 Germany-deployed veterans One of eight environmental exposures related to pesticides or solvents: “pesticides” Symptom questionnaires; Exposure questionnaires (Clinical evaluations used for other end points but not for peripheral neuropathy) Exposure to “pesticides” associated with neurologic symptom group (headache, numbness in arms or legs, dizziness) (p=0.007), musculoskeletal symptom group (p=0.001) “Pesticide” exposure not significantly related to neuropsychologic symptom group (difficulty in learning and concentrating, confusion) or psychologic symptom group (inability to fall asleep, anxiety, depression) Self-reported symptoms and exposure to various agents; moderate to low response rate; limited representation of entire Gulf War cohort

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Gulf War and Health: Insecticides and Solvents, Volume 2 Reference Population Self-Reported Exposure to Relevant Pesticides or Solvents Health Outcome or Test Type Results Limitations Population-Based Study Cherry et al., 2001a UK 4795 UK veterans deployed to Gulf War (and validation cohort of 4750) vs 4793 UK veterans not deployed to Gulf War Four of 14 related to pesticides or solvents: “using insect repellent on the skin,” “handling of pesticides,” “quarters sprayed with insecticides,” and “respraying of vehicle” Symptom questionnaire, which directly asked about symptoms but also contained two mannequin diagrams for shading areas indicating numbness and tingling to indicate peripheral neuropathy; Exposure questionnaire; Surveys completed 7 or more years after war Handling of pesticides was associated with “peripheral symptom factor;” using insect repellent was associated with “peripheral symptom factor” in dose-dependent manner; handling of pesticides was associated with peripheral neuropathy, indicated by shading areas of numbness and tingling on two mannequin diagrams (OR=1.26, p<0.001) Self-reported symptoms and exposure to various agents; lack of neurologic examination and electrophysiologic testing

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Gulf War and Health: Insecticides and Solvents, Volume 2 Cherry and colleagues (2001b) conducted the only population-based study that included assessment of peripheral neuropathy. They collected symptom and exposure data from UK veterans 7 years or more after the Gulf War. The veterans in this study consisted of two random samples of all UK troops deployed to the Gulf War stratified by age, sex, and rank. One sample was designated the main cohort (n=4795), the second a validation cohort (n=4793). (The cohorts did not overlap with the UK cohort studied by Unwin and colleagues [1999].) A questionnaire was used to gather data on 95 symptoms on visual analogue scales. The questionnaire also included diagrams of two mannequins on which respondents were asked to shade areas where they were experiencing pain or numbness and tingling. A second questionnaire, completed concurrently, asked for the dates when the respondent had been sent to each location in the Persian Gulf and the types of exposures experienced there. Four of 14 exposure categories were insecticide- or solvent-related: “using insect repellent on the skin,” “handling of pesticides,” “quarters sprayed with insecticides,” and “respraying of vehicles.” Multiple regression—controlling for officer status; service in army, navy, or air force; current service status; age; sex; and marital status—was used to determine the relationship between self-reported exposure and seven symptom factors extracted by factor analysis from the symptom questionnaire. Analyses were carried out separately for the two cohorts, and results were reported only when they reached a significance level of 0.001 in the combined cohorts and 0.01 in each of the two cohorts. Through symptom reporting, the investigators defined peripheral neuropathy in two ways: a “peripheral” symptom factor (one of the seven symptom factors), which included such symptoms as painful tingling or loss of sensation in hands and feet, feeling stiff, muscle cramps, tingling under the skin, cold hands and feet, watery eyes, acne and rashes, and itchy skin; and areas of numbness or tingling that veterans shaded on the pictures of mannequins (Cherry et al., 2001b). Pesticide handling and using insect repellent were associated with the peripheral symptom factor. Trends in the dose-response relationship were explored by relating days of exposure to the symptom score. There was a clear dose-response trend across three of the four exposure categories for insect-repellent use; however, the trend was less apparent for handling of pesticides, although those exposed for more than 63 days had higher symptom scores than those exposed for shorter periods. Veterans’ shading of areas of numbness and tingling on the mannequin diagrams was not included in the factor analysis but was analyzed separately. In a logistic-regression analysis that controlled for other types of exposures, pesticide handling (but not using insect repellent) was associated with shading on the mannequins. There was a dose-response gradient. Almost 35% of Gulf War veterans who reported handling pesticides for more than a month indicated numbness or tingling on the mannequin diagrams, compared with 13.6% of veterans who did not report handling pesticides. This study was well designed and reveals a dose-response relationship, but it is limited by potential recall bias and lack of clinical evaluations or nerve-conduction studies. Haley and Kurt (1997) examined pesticide, solvent, and other agents in relation to three of six new syndromes4 that they had defined by factor analysis in a companion publication (Haley et al., 1997a). Their hypothesis was that the new syndromes were related 4   Numerous other factor analyses of more-representative populations have not supported the existence of a new syndrome (see Appendix A).

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Gulf War and Health: Insecticides and Solvents, Volume 2 to exposure to OP insecticides and other cholinesterase-inhibiting insecticides used in the Gulf War. Veterans in the study were members of a single naval reserve construction battalion (Seabees) known to have a high prevalence of postwar illness. Efforts were made to include veterans who had left the service and those still serving; a total of 249 veterans (41% of 606 battalion members) participated. An exposure questionnaire contained five of 18 exposures that were relevant to the committee’s mandate: “DEET-containing insect repellent,” “environmental pesticides,” “pesticides in uniforms,” “pesticides in flea collars,” and “CARC (Chemical Agent Resistant Coating) paint on vehicles.” When veterans reported exposure to any agent, additional questions were asked to address such issues as the duration and dose of exposure and the anatomic areas exposed. For insect-repellent use, the questionnaire addressed the brand of insect repellent, typical frequency of repellent application, and the amount typically applied each time; this allowed the authors to construct a six-point scale to quantify the exposure. A complex approach was used to address clusters of symptoms experienced by the veterans. A survey booklet was used to elicit reports of the major symptoms commonly associated with the Gulf War on the basis of reporting to Department of Defense (DOD) and Department of Veterans Affairs (VA) registries (see Appendix A). The booklet directed veterans who responded affirmatively to one of the symptoms, to answer an additional set of four to 20 followup questions designed to differentiate characteristics of the symptom. A two-stage factor analysis was used to develop symptom scales from each set of followup items and then to organize the symptom scales into six factors. Six “syndromes” were defined from the factors by dichotomizing each factor and using a cutoff designed to label at least nine veterans as “cases” for each syndrome (Haley et al., 1997a). Logistic regression was then used to explore possible associations between agents each of the six syndromes (Haley and Kurt, 1997). Syndrome 3 (labeled “arthro-myo-neuropathy” by the investigators) was the only one of the six to include peripheral neuropathy-like symptoms, including joint pains in hips and extremities or neck and shoulders; generalized muscle weakness; fatigue; myalgia in arms, neck, shoulders, legs, buttocks, or back; and tingling in the extremities. This syndrome was associated with the use of DEET-containing insect repellent. A dose-response trend was found (p<0.001); the syndrome was more prevalent in those who used greater amounts of repellent or used it more frequently (relative risk [RR]=1.6–7.8 with increasing reported use; Table 7.1). In a multiple logistic regression, the association held only in veterans who used government-issued repellent (adjusted odds ratio [OR] 1.54; confidence interval [CI] 95%,=1.17–2.03), but not in those using personally acquired brand-name repellent OFF! (adjusted OR=1.08, 95% CI=0.79–1.46) or Skin-So-Soft (adjusted OR=0.87, 95% CI=0.64–1.18).5 No associations were found between syndrome 3 and three other pesticide exposures—environmental pesticides, pesticides in uniforms, and pesticides in flea collars—or the single solvent exposure CARC paint on vehicles. The significance level was set at 0.005 because of the large number of comparisons. The authors provided a detailed discussion of possible biologic mechanisms to support the association of syndrome 3 with the use of DEET but did not provide any explanation of the lack of association with other pesticide exposure. 5   Haley and Kurt (1997) report that most government-issued insect repellent contained 33% DEET, but some contained 75% DEET; Off! contained 31% or less DEET, and Skin-So-Soft contains no DEET.

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Gulf War and Health: Insecticides and Solvents, Volume 2 exposure. No associations were found between solvent exposure and AD after adjustment for education. Summary and Conclusion The evidence of an association between exposure to solvents and AD is weak. However, the very nature of the disease—late onset and dementia, leading to the need for proxy respondents—makes it extremely difficult to study the association. For the most part, the methodologic limitations in the studies (such as use of proxy respondents, lack of description of latent period, and crude measurements of exposure) most likely led to nondifferential misclassification that resulted in attenuation of odds ratios. Indeed, in some of the studies, the authors compared self-reported exposure classifications of controls with those reported by their proxies and found that the proxies generally underestimated exposure. If such findings can be generalized to proxies for cases, it would lead to underestimation of odds ratios. Several authors comment that occupational solvent exposure is most likely to occur in men, but a male-only study by Shalat and colleagues (1988) did not find a relationship, and the positive results in men were discounted by Kukull and colleagues (1995). Furthermore, population-based studies indicate that women are at greater risk for AD. In addition, the prevalence of solvent exposure in the studies evaluated here is generally low; even if there is a relationship between solvent exposure and AD, exposure is not likely to be a major contributor to the population burden of AD. 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 the solvents under review and Alzheimer’s disease. SOLVENTS AND SENSORY EFFECTS Color Discrimination Numerous studies have assessed color vision in workers exposed to solvents in a wide variety of occupational settings (Gobba and Cavalleri, 2000). The exposures included toluene, ethanol, perchloroethylene (tetrachloroethylene), and several solvents not relevant to the committee’s mandate. Studies used the Lanthony D15 desaturated color discrimination test (Lanthony, 1978; see Appendix F for background on this test). Several of the studies found subclinical impairments in color discrimination (clinically overt color-vision loss is known as dyschromatopsia), but the occupational exposures were both current and past. The combined nature of the exposure makes it difficult to distinguish whether the effect was short-term or long-term. The elapsed time between the most recent exposure and color-vision testing ranged from unstated (Baird et al., 1994; Mergler et al., 1988; Semple et al., 2000; Valic et al., 1997) through about 16 hours (Blain et al., 1985; Cavalleri et al., 1994, 2000; Gonzalez et al., 1998; Mergler and Blain, 1987; Mergler et al., 1987; Muttray et al., 1997, 1999; Zavalić et al., 1996, 1998a,b,c) to about 60 hours (Muttray et al., 1995). These cross-sectional studies were thus not designed to examine whether effects on color discrimination were long-term or short-term.

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Gulf War and Health: Insecticides and Solvents, Volume 2 A longitudinal study of dry-cleaning workers exposed to perchloroethylene (tetrachloroethylene) found that over a 2-year period color-vision discrimination worsened with increased exposure and did not decline in workers whose exposure was reduced (Gobba et al., 1998). However, because the study did not have an exposure-free interval before vision testing, its results do not bear on the question of whether tetrachloroethylene’s effects were short-term or long-term. The only studies with an exposure-free interval were of styrene, a solvent not reported to have been sent to the Gulf War. After an exposure-free interval of 1 month, styrene’s effects on color discrimination were mixed: one study showed a positive result, and the other showed recovery (Gobba and Cavalleri, 2000). Thus, none of the published studies shed light on the question of whether exposure to relevant solvents is associated with long-term effects on color vision. 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 the solvents under review and a long-term reduction in color discrimination. Hearing Loss Occupational noise is the most common cause of noise-induced hearing loss (Sataloff and Sataloff, 1993). In about 40% of the 28 million people in the United States with hearing loss, the loss is partly attributable to exposure to loud sounds. Noise-induced hearing loss can be severe and permanent, but it is entirely preventable. Two types of hearing loss can occur—conductive and sensorineural—depending on which parts of the ear and nerve pathways are affected. Conductive hearing loss is caused when the conduction of sound from the outer to the inner ear is blocked. The causes include middle ear infections, collection of fluid or wax in the ear, damage to the eardrum by infection or trauma, otosclerosis, and, rarely, rheumatoid arthritis that affects the joints between the ossicles (Sataloff and Sataloff, 1993). Sensorineural hearing loss involves damage to the pathway for sound impulses from the cochlea to the auditory nerve and the brain. The causes include age; damage to the cochlea caused by loud noise; viral infection; Meniere’s disease (abnormal pressure in the inner ear); some drugs, such as aspirin, quinine, and some antibiotics, which can affect the hair cells; acoustic neuroma; meningitis; encephalitis; multiple sclerosis; brain tumors; and strokes (Sataloff and Sataloff, 1993). In 1986, a longitudinal study reported a higher prevalence of hearing disability in workers with both solvent and noise exposure than in workers at the same facility exposed only to noise (Bergström and Nyström, 1986). Several studies have since examined the relationship between simultaneous exposure to solvents and noise and the occurrence of hearing impairment. Morata and colleagues (1993, 1997a,b) performed audiometry (see Appendix F) in three studies of current workers exposed to noise and mixed solvents, including toluene. Two studies (Morata et al., 1993, 1997b) found mild hearing loss with mixed solvent exposure (but it is not clear whether the population was the same for both studies). In one of those studies, Morata et al. (1993) also found that the risks were greater with combined noise and toluene exposure than with noise alone or mixed solvents alone. The other of the three studies (Morata et al., 1997a) found hearing loss in petroleum-refinery

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Gulf War and Health: Insecticides and Solvents, Volume 2 workers in South America, but the study did not make adjustments for alcohol use or smoking and had much more limited exposure information. Despite the positive findings in those studies, it is not known whether the hearing loss was short-term or long-term, because none of the studies included an exposure-free interval before testing. The short-term nature of the effect is suggested by two lines of evidence from the studies themselves: the correlation between hearing loss and the concentrations of urine biomarkers for solvent exposure (Morata et al, 1997b) and the lack of an association with employment duration in two of the studies (Morata et al., 1993, 1997b). The committee did not identify any epidemiologic studies of relevant solvent exposure and hearing loss with an exposure-free interval. 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 the solvents under review and long-term hearing loss. Olfactory Function Schwartz and co-workers (1990) reported a strong association between current solvent exposures at two paint-manufacturing plants and impaired olfactory function as measured by the University of Pennsylvania Smell Identification Test. A cross-sectional study of current painters, however, found no association with impaired olfactory function on the test (Sandmark et al., 1989); the authors suggested that because some painters had had much greater exposures in the past, any solvent effect on olfactory function is likely to be reversible. A third cross-sectional study of workers exposed primarily to toluene (Hotz et al., 1992) also reported associations with self-reported smell and taste problems that appeared to be temporary and reversible. The committee did not identify any studies with an exposure-free interval. The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposures to the solvents under review and long-term reduction in olfactory function. REFERENCES Amaducci L, Arfaioli C, Inzitari D, Marchi M. 1982. Multiple sclerosis among shoe and leather workers: An epidemiological survey in Florence. Acta Neurologica Scandinavica 65(2):94–103. Amaducci LA, Fratiglioni L, Rocca WA, Fieschi C, Livrea P, Pedone D, Bracco L, Lippi A, Gandolfo C, Bino G, Prencipe M, Bonatti ML, Girotti F, Carella F, Tavolato B, Ferla S, Lenzi GL, Carolei A, Gambi A, Grigoletto F, Schoenberg BS. 1986. Risk factors for clinically diagnosed Alzheimer’s disease: A case-control study of an Italian population. Neurology 36(7):922–931. Ames RG, Steenland K, Jenkins B, Chrislip D, Russo J. 1995. Chronic neurologic sequelae to cholinesterase inhibition among agricultural pesticide applicators. Archives of Environmental Health 50(6):440–444. Aminoff MJ. 1987. Electromyography in Clinical Practice: Electrodiagnostic Aspects of Neuromuscular Disease. 2nd ed. New York: Churchill Livingstone. Amr MM. 1999. Pesticide monitoring and its health problems in Egypt, a Third World country. Toxicology Letters 107(1–3):1–13. Arlien-Søborg P. 1992. Solvent Neurotoxicity. Boca Raton, FL: CRC Press.

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Gulf War and Health: Insecticides and Solvents, Volume 2 Daniell WE, Claypoole KH, Checkoway H, Smith-Weller T, Dager SR, Townes BD, Rosenstock L. 1999. Neuropsychological function in retired workers with previous long-term occupational exposure to solvents. Occupational and Environmental Medicine 56(2):93–105. Deapen DM, Henderson BE. 1986. A case-control study of amyotrophic lateral sclerosis. American Journal of Epidemiology 123(5):790–799. Engel LS, Keifer MC, Checkoway H, Robinson LR, Vaughan TL. 1998. Neurophysiological function in farm workers exposed to organophosphate pesticides. Archives of Environmental Health 53(1):7–14. Engel LS, Checkoway H, Keifer MC, Seixas NS, Longstreth WT Jr, Scott KC, Hudnell K, Anger WK, Camicioli R. 2001 Parkinsonism and occupational exposure to pesticides. Occupational and Environmental Medicine 58(9):582–589. Fagius J, Gronqvist B. 1978. Function of peripheral nerves and signs of polyneuropathy in solvent-exposed workers at a Swedish steelworks. Acta Neurologica Scandinavica 57(4):305–316. Feldman RG. 1999. Occupational and Environmental Neurotoxicology. Philadelphia: Lippincott-Raven. Feussner, JR, Chief Research and Development Officer Veterans Health Administration Department of Veterans Affairs. 2002. Research and Treatment of Gulf War Veterans’ Illnesses. Statement on January 24, 2002 before the National Security, Veterans Affairs and International Relations Subcommittee Committeee on Government Reform, US House of Representatives. [Online]. Available: http://www.va.gov/OCA/testimony/24ja02JF_USA.htm [accessed September 30, 2002]. Fiedler N, Kipen H, Kelly-McNeil K, Fenske R. 1997. Long-term use of organophosphates and neuropsychological performance. American Journal of Industrial Medicine 32(5):487–496. Flodin U, Soderfeldt B, Noorlind-Brage H, Frederiksson M, Axelson O. 1988. Multiple sclerosis, solvents, and pets. A case-referent study. Archives of Neurology 45(6):620–623. French LR, Schuman LM, Mortimer JA, Hutton JT, Boatman RA, Christians B. 1985. A case-control study of dementia of the Alzheimer type. American Journal of Epidemiology 121(3):414–421. Fukuda K, Nisenbaum R, Stewart G, Thompson WW, Robin L, Washko RM, Noah DL, Barrett DH, Randall B, Herwaldt BL, Mawle AC, Reeves WC. 1998. Chronic multisymptom illness affecting Air Force veterans of the Gulf War. Journal of the American Medical Association 280(11):981–988. Gauthier E, Fortier I, Courchesne F, Pepin P, Mortimer J, Gauvreau D. 2001. Environmental pesticide exposure as a risk factor for Alzheimer’s disease: A case-control study. Environmental Research 86(1):37–45. Gobba F, Cavalleri A. 2000. Evolution of color vision loss induced by occupational exposure to chemicals. Neurotoxicology 21(5):777–782. Gobba F, Righi E, Fantuzzi G, Predieri G, Cavazzuti L, Aggazzotti G. 1998. Two-year evolution of perchloroethylene-induced color-vision loss. Archives of Environmental Health 53(3):196–198. Gomes J, Lloyd O, Revitt MD, Basha M. 1998. Morbidity among farm workers in a desert country in relation to long-term exposure to pesticides. Scandinavian Journal of Work, Environment and Health 24(3):213–219. Gonzalez M, Velten M, Cantineau A. 1998. Increased acquired dyschromatopsia among solvent-exposed workers: An epidemiology study on 249 employees of an aluminum-foil printing factory. International Archives of Occupational and Environmental Health 71(5):317–324. Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Richardson RJ. 1998. The risk of Parkinson’s disease with exposure to pesticides, farming, well water, and rural living. Neurology 50(5):1346–1350. Goss Gilroy Inc. 1998. Health Study of Canadian Forces Personnel Involved in the 1991 Conflict in the Persian Gulf, Volume 1. Ottawa, Canada: Goss Gilroy Inc. Department of National Defence. Grandjean P, Sandoe SH, Kimbrough RD. 1991. Nonspecificity of clinical signs and sypmptoms caused by environmental chemicals. Human Experimental Toxicology 10:167–173. Graham DG, Amarnath V, Valentine WM, Pyle SJ, Anthony DC. 1995. Pathogenetic studies of hexane and carbon disulfide neurotoxicity. Critical Reviews in Toxicology 25(2):91–112. Granieri E, Rosati G, Tola R, Pinna L, Paolino E, D’Agostini G. 1981. Amyotrophic lateral sclerosis frequency in Italy. Incidence and prevalence in the province of Ferrara. Acta Neurologica 3(4):549–557. Granieri E, Casetta I, Tola MR, Ferrante P. 2001. Multiple sclerosis: Infectious hypothesis. Neurological Sciences 22(2):179–185. Graves AB, Rosner D, Echeverria D, Mortimer JA, Larson EB. 1998. Occupational exposures to solvents and aluminium and estimated risk of Alzheimer’s disease. Occupational and Environmental Medicine 55(9):627–633.

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Gulf War and Health: Insecticides and Solvents, Volume 2 Gray GC, Kaiser KS, Hawksworth AW, Hall FW, Barrett-Connor E. 1999. Increased postwar symptoms and psychological morbidity among U.S. Navy Gulf War veterans. American Journal of Tropical Medicine and Hygiene 60(5):758–766. Gregersen P, Angelso B, Nielsen TE, Norgaard B, Uldal C. 1984. Neurotoxic effects of organic solvents in exposed workers: An occupational, neuropsychological, and neurological investigation. American Journal of Industrial Medicine 5(3):201–225. Gronning M, Albrektsen G, Kvale G, Moen B, Aarli JA, Nyland H. 1993. Organic solvents and multiple sclerosis: A case-control study. Acta Neurologica Scandinavica 88(4):247–250. Gun RT, Korten AE, Jorm AF, Henderson AS, Broe GA, Creasey H, McCusker E, Mylvaganam A. 1997. Occupational risk factors for Alzheimer disease: A case-control study. Alzheimer Disease and Associated Disorders 11(1):21–27. Gunnarsson LG, Bodin L, Soderfeldt B, Axelson O. 1992. A case-control study of motor neurone disease: Its relation to heritability, and occupational exposures, particularly to solvents. British Journal of Industrial Medicine 49(11):791–798. Haley RW, Kurt TL. 1997. Self-reported exposure to neurotoxic chemical combinations in the Gulf War. A cross-sectional epidemiologic study. Journal of the American Medical Association 277(3):231–237. Haley RW, Kurt TL, Horn J. 1997a. Is there a Gulf War syndrome? Searching for syndromes by factor analysis of symptoms. Journal of the American Medical Association 277(3):215–222. Haley RW, Horn J, Roland PS, Bryan WW, Van Ness PC, Bonte FJ, Devous MDS, Mathews D, Fleckenstein JL, Wians FH Jr, Wolfe GI, Kurt TL. 1997b. Evaluation of neurologic function in Gulf War veterans. A blinded case-control study. Journal of the American Medical Association 277(3):223–230. Hanninen H, Antti-Poika M, Juntunen J, Koskenvuo M. 1991. Exposure to organic solvents and neuropsychological dysfunction: A study on monozygotic twins. British Journal of Industrial Medicine 48(1):18–25. Hawkes CH, Cavanagh JB, Fox AJ. 1989. Motoneuron disease: A disorder secondary to solvent exposure? Lancet 1(8629):73–76. He F, Xu H, Qin F, Xu L, Huang J, He X. 1998. Intermediate myasthenia syndrome following acute organophosphates poisoning—an analysis of 21 cases. Human and Experimental Toxicology 17(1):40–45. Hendrie HC. 1998. Epidemiology of dementia and Alzheimer’s disease. American Journal of Geriatric Psychiatry 6(2 Suppl 1):S3–S18. Herishanu YO, Kordysh E, Goldsmith JR. 1998. A case-referent study of extrapyramidal signs (preparkinsonism) in rural communities of Israel. Canadian Journal of Neurological Sciences 25(2):127–133. Hernan MA, Oleky MJ, Ascherio A. 2001. Cigarette smoking and incidence of multiple sclerosis. American Journal of Epidemiology 154(1):69–74. Hertzman C, Wiens M, Snow B, Kelly S, Calne D. 1994. A case-control study of Parkinson’s disease in a horticultural region of British Columbia. Movement Disorders 9(1):69–75. Horn J, Haley RW, Kurt TL. 1997. Neuropsychological correlates of Gulf War syndrome. Archives of Clinical Neuropsycholo 12(6):531–544. Hooisma J, Hanninen H, Emmen HH, Kulig BM. 1993. Behavioral effects of exposure to organic solvents in Dutch painters. Neurotoxicology and Teratology 15(6):397–406. Hooisma J, Hanninen H, Emmen HH, Kulig BM. 1994. Symptoms indicative of the effects of organic solvent exposure in Dutch painters. Neurotoxicology and Teratology 16(6):613–622. Horowitz SH, Stark A, Marshall E, Mauer MP. 1999. A multi-modality assessment of peripheral nerve function in organophosphate-pesticide applicators. Journal of Occupational and Environmental Medicine 41(5):405–408. Hotz P, Tschopp A, Soderstrom D, Holtz J, Boillat M-A, Gutzwiller F. 1992. Smell or taste disturbances, neurological symptoms, and hydrocarbon exposure. International Archives of Occupational and Environmental Health 63(8):525–530. Huang CC, Chu NS, Cheng SY, Shin TS. 1989. Biphasic recovery in n-hexane polyneuropathy. A clinical and electrophysiological study. Acta Neurologica Scandinavica 80(6):610–615. Hubble JP, Cao T, Hassanein RES, Neuberger JS, Koller WC. 1993. Risk factors for Parkinson’s disease. Neurology 43(9):1693–1697. IOM (Institute of Medicine). 2000. Gulf War and Health. Volume 1, Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines. Washington DC: National Academy Press.

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