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Gulf War and Health: Volume 2: Insecticides and Solvents (2003)

Chapter: 7. Neurologic Effects

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Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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,

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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).

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

In a later study (Haley et al., 1997b), the investigators identified the 23 veterans who had the highest scores for syndromes 1–3. The 23 veterans were matched by age, sex, and educational level with 10 controls selected from 70 veterans who had been deployed to the Persian Gulf and had reported no serious health problems. An additional 10 matched controls were selected from veterans who had not been deployed to the Persian Gulf. Cases and controls were invited for further investigations that included a clinical neurologic examination. Five subjects received nerve-conduction studies after “initial review of the study results that suggested the presence of peripheral neuropathy.” Six neurologists, blinded to case or control status, reviewed all clinical findings and attempted to arrive at a consensus diagnosis. The relationship to insecticide or solvent exposures was not addressed in the report of this study. Of the 22 veterans identified in the initial study as suffering from syndrome 3, only five were included in this followup clinical study. Three of the five had at least one abnormality on neurologic examination (a similar proportion of controls had at least one abnormality). Only three of the syndrome 3 veterans had nerve-conduction studies; all three had abnormal tests of cool and vibratory sensation in the upper or lower extremities, and two had borderline abnormal motor-nerve conduction velocity in the lower extremities. The blinded neurologists concluded that the findings were nonspecific and insufficient to diagnose any known syndrome in any subgroup of subjects.

Proctor and colleagues (1998) tested the hypothesis that symptoms in Gulf War veterans were related to a number of specific agents, including exposure to pesticides, by using a random sample of two cohorts of US veterans who were identified at the time of demobilization immediately after the Gulf War. One of the cohorts was from Massachusetts (Fort Devens), the other from New Orleans. The two cohorts were compared with veterans deployed to Germany during the same era. The sample was stratified to oversample women and to give equal representation to veterans who had reported higher and lower prevalence of symptoms in prior surveys. Exposure to various agents during the Gulf War were assessed with a questionnaire that addressed eight exposures on a scale of 0–2 (0=no exposure; 1=exposed; 2=exposed and felt sick at the time). None of the questions addressed relevant solvent exposures. One question addressed exposure to “pesticides.”

Symptoms were reported on a 52-item checklist, from which the analysis grouped three or four related symptoms into nine symptom groups referring to body systems. Four judges who specialized in neuropsychology, and environmental and occupational health made the assignment of symptoms to a particular group independently. Two of the symptom groups bore some resemblance to symptoms of peripheral neuropathy. The neurologic group incorporated three symptoms: headache, numbness in arms or legs, and dizziness or lightheadedness. The musculoskeletal group also incorporated three symptoms: joint pains, backache, and neck ache or stiffness.

A series of multiple regressions explored associations between self-reported exposure to various agents and symptoms related to symptom groups. The analysis controlled for age, sex, education, the presence of anxiety disorder, posttraumatic stress disorder (PTSD), and the score on a 34-item expanded combat-exposure scale (designed to assess the presence and frequency of a variety of prominent war-zone stressors). Standardized regression coefficients and p values were reported for all associations reaching p<0.05. According to that significance criterion, exposure to pesticides was associated with the neurologic symptom group (p=0.007) and the musculoskeletal symptom group (p=0.001). Pesticide exposure was not related to the neuropsychologic symptom group

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

(difficulties in learning new material, difficulty in concentrating, and confusion) or the psychologic symptom group (depression and frequent periods of anxiety or nervousness). Correction for depression scores did not change the associations.

Summary and Conclusion

Most of the Gulf War studies of peripheral neuropathy-like symptom-exposure relationships did not conduct clinical examinations or nerve-conduction studies. Instead, studies relied on analysis of symptom self-reports. Therefore, it is not clear that veterans identified with some type of symptom-defined peripheral neuropathy actually had clinically diagnosable peripheral neuropathy, as defined by the committee.

The results of the studies were mixed. In one large, representative sample of UK veterans (Cherry et al., 2001a), associations were found between Gulf War pesticide exposure and self-reports of neuropathy-like symptoms. A study (Haley and Kurt, 1997) of a single US military unit-identified symptom cluster (labeled syndrome 3 by the investigators) found associations with government-issued insect repellent but not with brand-name repellents; moreover, a panel of six neurologists who examined a subset of five syndrome 3 subjects was unable to arrive at any neurologic diagnosis. In another study (Proctor et al., 1998), the investigators created groups of symptoms from responses to questionnaires. Their musculoskeletal and neurologic symptom groups, which were defined as having some peripheral neuropathy-like symptoms, were both associated with self-reported exposure to “pesticides,” but there was no more specificity about the type of pesticide or the degree of exposure. None of the studies found a relationship between solvent exposures and peripheral neuropathy, but very few asked about solvent exposures on the exposure questionnaire.

The committee was unable to draw particular conclusions from these studies, because of their limitations, both study-specific and more general. The committee did combine findings from the Gulf War veterans’ studies with those from other populations as they drew conclusions from the entire body of evidence.

OP Insecticides and Peripheral Neuropathy

Over 30 years ago, researchers began to report subtle yet persistent effects on the PNS from OP compounds (Roberts, 1976). This subtle type of peripheral neuropathy is pathologically and behaviorally distinct from organophosphate-induced delayed neuropathy (OPIDN), a more serious and disabling syndrome caused by high exposure to some OP compounds (Chapter 3).

Case reports, case series, and animal studies have been used to conclude that high dose exposure to OP insecticides may result in OPIDN through an irreversible inhibition of the enzyme NTE (Chapter 3). The committee did not examine studies of OPIDN as an end point after OP insecticide exposure because the human evidentiary base consists only of case studies and case series and because OPIDN is pathologically and behaviorally distinct from the more subtle type of peripheral nephropathy that is addressed in controlled studies of Gulf War veterans and occupational studies. As background, it is important to note that only two of the OP insecticides considered in this report, chlorpyrifos and dichlorvos, inhibit NTE—yet only at doses that are sufficient to cause lethal cholinergic poisoning. There were no reports of poisoning in military personnel in the Gulf War.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

As noted earlier, the committee defined peripheral neuropathy, for purposes of evaluation, as requiring a diagnosis by a thorough neurologic examination and confirmatory findings from quantitative laboratory testing. For confirmatory neurophysiologic testing, the committee favored nerve-conduction studies and electromyography (Appendix F). The committee viewed vibrotactile testing by itself as too limited a neurophysiologic measure to confirm the diagnosis of peripheral neuropathy. The committee excluded studies that did not have careful neurologic examinations.

Postural sway, which could be an indication of either a PNS or a CNS effect, is reported in this section because of its inclusion in several studies of peripheral neuropathy. Some of the studies on peripheral neuropathy evaluated here are also evaluated in the section on neurobehavioral effects because they contained measures of both neurologic outcomes.

Limitations of Studies of Peripheral Neuropathy

The major limitations of peripheral neuropathy studies include exposure to many types of pesticides or solvents and poor documentation of specific exposure. Other problems are misclassification of measurement and confounding.

Misclassification of measurement can occur with neurophysiologic testing to support the diagnosis of peripheral neuropathy. Nerve conduction can be slowed by the ambient temperature and by the height of the person. It is important to consider those variables in the interpretation of results. For the most part, it is less likely that test conditions and height will differ according to exposure group (such as exposed vs nonexposed). It is more likely that inattention to those variables would result in an underestimation of associations between outcome and exposure. Such diseases as diabetes and hypothyroidism, and alcohol use and nutritional deficiency can cause peripheral neuropathy, so it is important to assess their prevalence in the exposure groups; if the prevalence is different between groups, the difference must be taken into account in the analysis.

Confounders are factors that are related to both outcome and exposure. These extraneous variables may be true risk factors for the outcome but differ in distribution between exposure groups. For example, age is often a confounder because it is a risk factor for a number of diseases and may be associated with exposure. If not considered in the analysis, observed differences in likelihood of the outcome between two exposure groups may be attributed in whole or in part to the difference in age distribution between exposure groups. Confounding may be addressed in study design through restriction or matching or be adjusted for in the analysis. It is important to note that inadequate control for confounding variables can result in overestimation or underestimation of effect.

Another confounder, particularly in cross-sectional studies of long-term effects, is the inclusion of workers with current exposure. What is reported as a long-term effect may in fact be a short-term effect of current (or recent) exposure. That is less of a problem for peripheral neuropathy than for neurobehavioral effects. Peripheral neuropathy, based on clinical examination and confirmed by electrophysiologic alterations (such as decreased conduction velocity or pathologic evidence of denervation), usually takes several weeks to develop, can be tested objectively, and generally is not totally reversible when exposure to the agent is removed (Aminoff, 1987). Neurobehavioral effects, in contrast, may or may not persist once exposure ceases. The committee considers peripheral neuropathy to be a long-term effect that persists for months or years.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×
Epidemiologic Studies of Exposure to Insecticides

The body of epidemiologic evidence of an association between OP insecticides and peripheral neuropathy consists of numerous studies, but most were found by the committee to have methodologic limitations, as discussed below and in Table 7.2. The committee excluded several studies from consideration because of design flaws or lack of a thorough clinical examination for the diagnosis of peripheral neuropathy (Ames et al., 1995; Engel et al., 1998; London et al., 1998; Steenland et al., 1994). In two of the studies, the clinical examination was used only to exclude other causes of peripheral neuropathy rather than to diagnose it (Ames et al., 1995; Steenland et al., 1994); these studies were nevertheless evaluated in the next section, on neurobehavioral effects, because their methods were stronger for that set of outcomes. Two of the best-designed studies (Savage et al., 1988; Steenland et al., 2000) evaluated by the committee did not find evidence of peripheral neuropathy.

The committee reports its findings in one section combining studies of OP-exposed people with and without a history of OP poisoning. The reason for combining them is that, findings of both types of studies are negative. The combination approach contrasts with the next section, on neurobehavioral effects, in which the committee separates studies of previously poisoned people with those who have been exposed to pesticides but were not poisoned.

Savage and colleagues (1988) studied a group of 100 agricultural workers in Colorado and Texas with documented past OP poisoning (from rosters of documented pesticide poisoning in Colorado and Texas) and 100 matched controls. The last poisoning occurred an average of 9 years before testing, but there is no information about the extent of chronic OP exposure after the poisoning. The study excluded workers reporting exposure within 3 months of evaluation, so recent exposure cannot account for effects. Because most of the testing was with a comprehensive neurobehavioral battery, the study is described more extensively in a later section. The clinical neurologic examination consisted of 50 separate tests, including tests of cranial nerve function, motor-system function, and sensory-system function. The only difference between poisoned and nonpoisoned groups was an abnormality on one of 23 motor-reflex tests in the poisoned group.

Steenland and colleagues (2000) studied 191 former or current termiticide applicators exposed primarily to chlorpyrifos. Since the banning of chlordane in 1988, chlorpyrifos has been the main termiticide used. The mean time of exposure was 2.4 years for chlorpyrifos and 2.5 years for chlordane. Two-thirds of the exposed group were current applicators in a 12-county area of North Carolina. The study was population-based, using a list of all pesticide control applicators in North Carolina; of 688 licensed operators with more than 1 year of exposure, investigators were able to contact 200 for study.

For exposure assessment, questionnaire response and job history were supplemented with measurements of a urinary metabolite of chlorpyrifos (34% had very recent exposure). Eight applicators had been previously poisoned, according to self-reports. The exposed group was compared with a nonexposed group of 189 people (106 friends of exposed subjects and 83 state blue-collar municipal workers). Both the exposed subjects (36%) and the comparison group (up to 52%) also had a history of occupational solvent exposure.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

TABLE 7.2 Peripheral Neuropathy and Organophosphorous Insecticide Exposures

Reference

Population

Insecticide

Health Outcome or Test Type

Adjustment

Results

Limitations

Savage et al., 1988

100 OP-poisoned workers (Colorado, Texas registries, 1950–1976) vs 100 nonpoisoned workers 7–11 years after last OP poisoning

OPs; methyl parathion, parathion account for 96 of 100 OP poisonings

Neurologic examination, 50 tests

Pair matching on age, sex, level of education, social class, occupational class, ethnic background (Hispanic)

No difference on neurologic exam except for one test of motor reflex; motor summary score nonsignificant

 

Steenland et al., 2000

191 termiticide applicators from North Carolina registry (including 105 current applicators and eight formerly poisoned) vs 189 nonexposed controls (106 friends of exposed and 83 state employees);

Median 1.8 years of exposure (1987–1997)

Chlorpyrifos, some chlordane (1987–1988)

Neurologic examination; nerve-conduction velocity; vibrotactile sensitivity of finger, toe via automated device; postural sway; arm, hand tremor via device

Regression: age, race, education, current smoking, body-mass index

Nerve-conduction velocity, tremor, vibration sensitivity nonsignificant; worse performance on postural sway

Possible selection bias due to inability to locate majority of exposed population; occupational solvent exposure a potential confounder for exposed, controls

Jamal et al., 2001

16 OP-poisoned sheep dippers in UK vs 16 sheep dippers with chronic low OP exposure and 16 controls; exposed for 4 years or more; 4 months since last exposure

Diazinon, propetamphos, clorfenvinphos

Clinical examination (scores for symptoms, tendon reflexes); nerve-conduction studies; needle EMG; thermal threshold; vibration threshold; central evoked potentials

Controls matched for age, sex

Significant differences between all groups in all end points except central evoked potentials; OP-poisoned performed significantly worse than OP chronic low-level, which performed worse than controls; increases in vibration, cold threshold

Selection bias in two exposed groups

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference

Population

Insecticide

Health Outcome or Test Type

Adjustment

Results

Limitations

Stokes et al., 1995

90 male pesticide applicators vs 68 population-based controls; New York state; 20 years of exposure

Azinphos-methyl (mean, 14 years), chlorpyrifos (mean, 4 years), diazinon (mean, 1 year)

Vibration sensitivity (Vibratron II); clinical examination, detailed electrophysiologic studies in subset (n=9) with over 20 years of exposure (Horowitz et al., 1999)

Controls matched for sex, age, county of residence, but not height; controlled for recent exposure by testing during off-season

Vibration threshold higher in dominant, nondominant hands of pesticide applicators, but not in feet; scores for vibration threshold higher among applicators; in four of nine subjects with over 20 years of exposure, reduced sensation in lower extremities or slowed F-wave latency (Horowitz et al., 1999)

Low response rate (90 of 554); no indication of blinded testing

Amr, 1999

300 pesticide applicators vs 300 community controls; Egypt

OPs (including malathion, dichlorvos); pyrethroids (type 1: sumithrin, d-allethrin; type 2: cypermethrin, deltamethrin, tetramethrin); carbamate (propoxpur)

Clinical examination, EMG, EEG

Controls matched for age, education, socioeconomic status

Sensory hypoesthesia; muscle weakness; static tremor; abnormal deep-tendon reflexes; EMG not significant; EEG significantly higher frequency

Sparse on methods

Otto et al., 1990

229 pesticide workers vs 180 fertilizer workers exposed to lead, sulfuric acid and 167 textile workers; 1–26 years of exposure for most pesticide workers (range, 1–46 years); Egypt

OPs (including diazinon, malathion)

Neurologic examination, vibration threshold of index finger of nondominant hand via Optacon voltage

Controlled for age, education, but not alcohol consumption

Bilateral involuntary tremors on examination in pesticide, fertilizer workers (1985–1986); bilateral abnormal vibration sensitivity on examination in pesticide fertilizer workers (1985–1986); increased vibration threshold in pesticide workers

Automated tremor device not used; vibration device used to test only fingers, not toes

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference

Population

Insecticide

Health Outcome or Test Type

Adjustment

Results

Limitations

Cole et al., 1998

144 pesticide applicators vs 30 nonexposed farm workers and 72 nonexposed local controls; 9–17 years of past and current exposure; 28% of applicators report past OP or carbamate poisoning; Ecuador

OP (metamidophos); carbamate insecticides; dithiocarbamate fungicides

Neurologic examination; symptom questionnaire; vibration threshold

Controls matched for age, sex, level of education

Applicators report more peripheral nerve symptoms, more signs of poor coordination, reduced power, abnormal deep-tendon reflexes; applicators had significantly higher vibration thresholds in toe

No nerve-conduction velocity; EMG testing; mixed nature of insecticide exposures

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Testing included clinical examination, vibration sensitivity, tremor (through an automated device), nerve-conduction studies (peroneal, sural, and ulnar nerves), neurobehavioral batteries, and postural sway using platform posturography. There were no differences between exposed and nonexposed groups on clinical neurologic examination. Among the few abnormal findings were that exposed subjects had lower ulnar amplitudes than did the 83 state employees. There was no significant association between the presence of a susceptible genotype (paraoxonase polymorphism) and a history of poisoning (Chapter 3). Currently exposed workers had significantly lower ulnar nerve amplitudes, but they also had higher sural nerve conduction velocities. There was no relationship between nerve-conduction findings and duration of exposure. In other tests of peripheral neuropathy, there was no association between exposure and tremor or vibration sensitivity. The exposed group had greater length of sway on some of the 12 tests of postural sway, which were conducted under various conditions with eyes open and eyes closed. The abnormal sway findings were not associated with urinary OP metabolite concentrations.

The major strength of the study was that it was population-based. Its major limitation was possible selection bias due to inability to locate the majority of the exposed target population. The nature of the selection bias, however, was unclear. Workers more affected by exposure to insecticides may have been more likely to participate, or those more affected may have been harder to find. Another limitation was the history of occupational solvent exposure among exposed and controls.

Jamal and colleagues (2001) performed a small study with the most detailed clinical and neurophysiologic assessment of peripheral neuropathy. The goal was to compare the pattern of deficits occurring in sheep dippers of the UK who had previous OP poisoning with sheep dippers who had chronic, lower OP exposure and no history of poisoning. Sheep farmers in the UK were, until recent years, required to periodically dip their flocks in OP insecticides for sheep scab and other parasites. The two groups of exposed farmers (16 per group) were compared with age- and sex-matched subjects (16, mostly office workers) who had not been exposed to OP insecticides. Both exposed groups had been exposed for at least 4 years and had not been exposed within 4 months of the study.

The identification of farmers with past OP poisoning and those with chronic exposure was done by two methods, which may have introduced different types of selection bias. Those with OP poisoning were chosen at random from a list of 200 sheep farmers compiled by a voluntary organization. The list consisted of people who claimed to have developed chronic neurologic problems after their poisoning. That might have led to an overrepresentation of exposed subjects with the outcome of interest. The OP farmers with chronic exposure, but no poisoning, were selected at random from a telephone directory listing of almost 2000 farms in a 16-mile radius of Glasgow, Scotland. They recalled no history of symptoms or acute poisoning. That method is less likely to introduce selection bias, but there were difficulties during the recruitment phase and screening process during which the 39 sheep farmers identified were reduced to a total of 16. The investigators did not state their methods of exclusion of all other causes of peripheral neuropathy and did not take an exposure history. Even though the investigators found peripheral neuropathy by using detailed clinical and electrophysiologic measures, the results are compromised by selection bias in the exposed cohorts.

Stokes and colleagues (1995) studied 90 male pesticide applicators identified through a New York state registry and compared them with 68 population-based controls.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

The mean duration of OP exposure was 20 years. Testing during the offseason precluded detection of short-term effects. The authors found vibration threshold to be higher in the dominant and nondominant hands of pesticide applicators but not in their feet. The finding of no significant differences in foot-vibration thresholds may be attributable to lack of control for height. One weakness of the study was the lack of peripheral-neuropathy tests beyond vibration thresholds for nonpoisoned subjects. Another weakness of the study was the low response rate (90 of 554 licensed applicators), but this may have biased the findings in either direction. A followup study of nine of the subjects with increased vibration threshold and more than 20 years of exposure found reduced sensation in lower extremities or slowed F-wave latency (Appendix F), but there was no comparison group (Horowitz et al., 1999).

A study in Ecuador by Cole and colleagues (1998) examined peripheral nerve function in 144 pesticide applicators exposed for 9–17 years to a combination of OPs and carbamates (insecticides and fungicides). The applicators also had current exposure, as evidenced by their occupation and by slightly decreased red-cell AChE. Some 28% of the applicators had at least one past poisoning. The subjects were compared with two groups of controls (farm workers and nonfarm workers, such as housewives, students, and laborers) matched for age, sex, and education. Pesticide exposures among applicators were estimated from farm records and interviews concerning their total years of past and current use. Many applicators had engaged in practices likely to increase exposure, such as mixing pesticides with hands and a stick, using leaking backpack sprayers, and using little personal protective equipment. All subjects and controls completed a neurologic-symptom questionnaire and had clinical neurologic examinations. Vibration sensation was measured with the Vibratron II device (Appendix F).

The applicators reported significantly more peripheral nerve symptoms, had more signs of poor coordination, and were significantly more likely to have abnormal deep-tendon reflexes and reduced muscle power. Vibration thresholds in the toe were significantly higher among applicators and among those reporting previous pesticide poisoning (by OP compounds or carbamates). The researchers did not perform nerve-conduction velocity tests or EMG to confirm clinical findings. Another limitation was the mixed nature of the pesticide exposures, including fungicides (which are not being examined in this report). The symptom findings were excluded from the committee’s consideration in that they could represent short-term, rather than long-term, effects.

Amr (1999) reported on 300 male pesticide formulators (age, 20–55 years) randomly selected from two pesticide-formulating plants in Egypt. The workers were exposed to a combination of pesticides, including OP compounds (such as malathion and dichlorvos), carbamates (propoxpur), pyrethroids, and DDT. Exposure duration was 5–25 years (mean, 13.9 years). All pesticides formulated by the workers were detectable in air samples at 2–5 times the permissible exposure limits. None of the workers reported prior OP poisoning, but there was no attempt at verification with medical records. The exposed workers were compared with 300 community subjects (nonexposed) who had no history of occupational exposure to pesticides and were matched for age, sex, educational level, and socioeconomic status. Tests included blood-chemistry profiles, electroencephalography (EEG), and EMG (of the anterior tibial and flexor digiti minimi muscles); and the subjects had clinical examinations. Testing of the formulators revealed increases in clinical symptoms and signs of peripheral neuropathy, including sensory hypoesthesia, muscle weakness, static tremor,

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

and abnormal deep-tendon reflexes. (The findings are from both pesticide formulators and applicators, without clear identification of occupational group.) The neurologic findings were more prominent in older workers with longer duration of exposure (over 20 years). EEG studies showed that exposed workers had significantly higher frequencies than nonexposed; this is of unknown clinical significance. EMG findings were not significantly different. However, studies were missing crucial information with which to interpret the results. Studies did not report whether the testers were blinded, the selection criteria for subject inclusion or exclusion, and specific test equipment and methods of EMG and EEG analysis. AChE activity, which was assayed at only one of the plants (n=159), was decreased in about 70% of workers and was about 60–65% lower in them than in community subjects. That indicates recent OP or carbamate exposure. It was unclear whether cholinesterase activity was measured in plasma, red cells, or both.

Otto and colleagues (1990) conducted a study of 229 Egyptian production workers at a pesticide-formulation plant. The study was of current workers (who had significantly reduced serum cholinesterase). Neurologic examinations were performed 2 years in a row (1985–1986). The committee evaluated only study findings regarding peripheral neuropathy; it excluded study findings regarding neurobehavioral effects because the study was of current workers who had both current and past exposure (such findings may reflect short-term rather than long-term effects, whereas peripheral neuropathy is more likely a long-term effect). For neurologic examinations, workers were compared with 180 fertilizer workers exposed to other neurotoxicants but not to OP compounds. Neurologic findings from a separate comparison group of textile workers were not used in the analysis, because the clinician performing the examination was not blinded to exposure status. When age and education were controlled for, bilateral involuntary tremors and increased vibration threshold were found on examination in 1985 and 1986. An automated tremor device was not used, and the vibration device was used to test only fingers, not toes. The findings applied to both pesticide and fertilizer workers. About half the pesticide workers had 12–46 years of employment at the plant, and a slightly higher percentage of fertilizer workers had similarly long employment. However, there is scanty information about the nature of job exposure. There was also no measurement of nerve-conduction velocity.

Summary and Conclusion

The two stronger studies covered in this section did not find peripheral neuropathy associated with occupational exposure to OP insecticides (Savage et al., 1988 and Steenland et al., 2000). The other studies of peripheral neuropathy evaluated here had some positive findings, but all had design limitations that weakened the validity of their findings.

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 organophosphorous insecticides under review and peripheral neuropathy.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

SOLVENTS AND PERIPHERAL NEUROPATHY

It is well established that some solvents that were not sent to the Gulf War—n-hexane (found in glues), carbon disulfide, and methyl n-butylketone—cause peripheral neuropathy (Graham et al., 1995). With subchronic or chronic exposures to these solvents, symptoms appear insidiously over weeks or months. The clinical features include sensory loss, distal weakness, and areflexia with motor-nerve conduction slowing. Nerve biopsy shows axonal degeneration with axonal swelling. Symptoms can progress for months after termination of exposure (Huang et al., 1989). In mild cases, symptoms eventually resolve; in more severe cases, residual disability persists for a long time (Arlien-Søborg, 1992; Feldman, 1999). On the basis of onset and clinical course, peripheral neuropathy caused by solvent exposure (or, as discussed earlier, by insecticide exposure) is a long-term effect.

Peripheral neuropathy caused by the three solvents mentioned above was initially recognized in humans exposed in the occupational setting and later verified in experimental animals. N-hexane and methyl n-butyl ketone were found to be neurotoxic after bioactivation to a common toxic metabolite, 2,5-hexanedione. In contrast, carbon disulfide does not require bioactivation. The three solvents produce identical pathologic and clinical changes. Whether solvents sent to the Gulf War are associated with peripheral neuropathy remains controversial. Stoddard solvent, one of the solvents sent to the Gulf War, has some formulations with n-hexane, but the concentration is not expected to pose a risk of peripheral neuropathy. Peripheral neuropathy has not been observed in experimental animals exposed to Stoddard solvent (Pryor and Rebert, 1992).

Epidemiologic Studies of Exposure to Solvents

The committee evaluated five studies (Table 7.3) to address the relationship between relevant solvents and peripheral neuropathy (Buiatti et al., 1978; Fagius and Gronqvist, 1978; Gregersen et al., 1984; Mutti et al., 1982; Nasterlack et al., 1999). The studies included workers in the steel industry (Fagius and Gronqvist, 1978), shoe and leather workers (Buiatti et al., 1978; Mutti et al., 1982), painters (Nasterlack et al., 1999), and workers in a variety of jobs with solvent exposure (Gregersen et al., 1984).

Exposure-assessment methods were variable and focused mostly on current exposure, with years of work at the current job used as a proxy for past exposure. The studies used various outcome measures, but all incorporated a clinical examination. Several studies added symptom questionnaires to the clinical examination. Four included nerve-conduction velocity, one used EMG, and two used vibration-perception threshold.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

TABLE 7.3 Peripheral Neuropathy and Solvent Exposure

Reference

Exposed Population

Nonexposed Population

Health Outcomes or Test Type

Solvent

Adjustment

Results

Limitations

Buiatti et al., 1978

Italy

Italian shoe leather workers, perhaps 340; exclusion of workers with history of contact with neurotoxic compounds other than solvents [n not given]

“Normal subjects examined in the neurological department during neurological screening of the normal population” [n not given]

Objective signs of PNS involvement (muscle tone, tendon reflexes, muscle wasting, sensory disorders), subjective symptoms; EMG; maximal motor-conduction velocity, abnormal if lower than 5% fiducial limits in normal population; no detail of when tests were performed relative to last exposure or under what conditions

Mixture of solvents in glues; no details of timing of exposure

Age only

“Polyneuropathic” vs normal; prevalence of polyneuropathy higher in exposed (29% vs 17%; p<0.05); polyneuropathy more frequent with age: 38% over age 40, 18% younger (p<0.005); association between age, maximal motor-conduction velocity in exposed and nonexposed; correlation found between duration of exposure, MCV (r=−0.21; no p value given)

Unclear how many subjects included; study included n-hexane, solvent not sent to Gulf War and a known cause of peripheral neuropathy

Fagius and Gronqvist, 1978

Sweden

42 plastic-coated sheet production workers at steelworks

42 workers in other sections of steelworks

Clinical examination; questionnaire with information on history, exposure, tobacco, alcohol, symptoms (muscle cramping, pain in arms or legs, pins and needles, numbness, reduced sensation, loss of muscle power, diminished muscle volume); vibration sense; MCV, SCV, laboratory tests

Variety of organic solvents; methyl isobutyl ketone, methyl ethyl ketone; duration of employment 6 months–8 years; individual exposure mapped through estimation of mean daily exposure, each subject given exposure coefficient (product of duration in years and mean exposure in minutes per day)

Exposed, referents matched on age, sex, duration of employment

No overt polyneuropathy; one case of possible polyneuropathy in exposed as defined by symptoms; MCV, two cases of suspected polyneuropathy; two reference subjects had high vibration perception; reference subjects showed longer terminal latency in median nerve when all subjects were assessed and when only those with high exposure in preceding 6 months considered. Vibration perception worse in total group of exposed subjects but not retained when only higher exposure considered; considering only exposure in preceding 6 months, higher vibration threshold of forefinger of exposed than of referents (p<0.05), of styloid process of right radius

Authors conclude “some evidence that exposure to organic solvents has a noxious effect on the peripheral nerve function, but the evidence is weak and no definite conclusions can be drawn”

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference

Exposed Population

Nonexposed Population

Health Outcomes or Test Type

Solvent

Adjustment

Results

Limitations

Gregersen et al., 1984

Denmark

65 workers exposed to organic solvents

33 workers not exposed to organic solvents

Testing took place after an exposure free interval of over 40 h and after work; questionnaire for symptoms; neurologic examination; scores developed to quantify impairment

Variety of organic solvents (white spirits, perchloroethylene, styrene, toluene); job information collected in questionnaire; exposure index computed from occupational history, environmental data; other neurotoxic exposure scored

Age, alcohol consumption, brain trauma

No differences between exposure groups- so they were grouped; acute work-related symptoms significantly more common in exposed (no p value given); no symptoms or signs of sensory, motor peripheral neuropathy; VPT of exposed group higher than that of nonexposed group but not significant; significant correlation between exposure index, motor symptoms, signs of peripheral neuropathy (r=0.2 1, p<0.1)

 

Mutti et al., 1982

Italy

95 shoe factory workers; exposure duration 1–25 years

52 nonexposed from same factory

MCV; examination by physician

Hydrocarbon mixtures; main source of exposure was evaporation from glued surfaces and open cans containing solvents; environmental concentrations measured for 2 years; overall exposure score calculated

None

Acute symptoms more common among exposed workers; significantly more sleepiness and dizziness; chronic symptoms (weakness, paresthesia, hypoesthesia) more common in exposed; headache, muscle cramps, neurasthenic syndrome, sleep disturbances no different; motor action potentials reduced in median, ulnar nerves; MCV decreased in median, peroneal nerves (p<0.05); MAP duration increased only for ulnar nerve; exposure score, MCV highly correlated (r=0.455; p< 0.01

 

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference

Exposed Population

Nonexposed Population

Health Outcomes or Test Type

Solvent

Adjustment

Results

Limitations

Nasterlack et al., 1999

Germany

401 painters; at least 10 years of work experience

209 construction workers; at least 10 years of work experience

Nerve-conduction velocity; EMG; EEG; symptom questionnaires (Swedish 16-item survey, neurotoxic symptom score, Bf-Sa)

Questionnaire to assess occupational history separately for preceding 12 months and the time before; recent and cumulative solvent exposure score, recorded

 

Clinical signs of neuropathy in painters: vibration threshold in big toe, lateral ankle, patella; no difference in tendon reflexes or loss of sensitivity; higher frequency of clinically overt polyneuropathy in control subjects than in exposed eight (but not significant); age-adjusted nerve-conduction velocity almost identical in painters and controls;

EMG worse in controls than painters; painters had significantly more symptoms than controls; correlation with cumulative exposure index of 0.27 (p<0.001)

 

a.Befindlichkeitsskala (Bf-S) is a symptom questionnaire aimed at nonspecific health complaints indicative of somatization.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Buiatti and colleagues (1978) studied more than 300 Italian shoe and leather workers. The workers were exposed to glues that contained various solvents, including n-hexane, ethyl acetate, and traces (below 1%) of benzene, toluol (toluene), and xylol (xylene); all those except n-hexane were sent to the Gulf War. Their exposure was measured as amount of glues used per worker per day (in kilograms) and on the basis of air volume per worker and years of exposure to solvents. The outcomes were identified by clinical examination, subjective symptom reporting, and tests of maximal motor-nerve conduction velocity (MCV) (in the extensor digitorum brevis and abductor pollicis brevis muscles). The study did not report the conditions under which the tests were conducted. The investigators examined the relationship between peripheral neuropathy and sex and age but performed no adjustments. They reported a prevalence of peripheral neuropathy of 29% in exposed workers and 17% in the nonexposed group. They also reported that the prevalence increased with increasing exposure but that finding was not evident from the table in the publication. The investigators found that MCV decreased with age, more in workers than in the normal population, and even more in those with peripheral neuropathy. Years of exposure were positively associated with reduced MCV, but this finding was confounded by age. When the subjects were stratified by age, only a slight difference in the slope of the curve of MCV vs years of exposure was observed in those with peripheral neuropathy compared with normal workers. Finally, any findings of peripheral neuropathy in this study might be the result of exposure to n-hexane, which is a known cause of peripheral neuropathy.

Fagius and Gronqvist (1978) studied 42 solvent-exposed Swedish steel workers and workers in other parts of the plant. The exposures were primarily to methyl ethyl ketone and trichloroethylene used at the plant for coating the steel with plastic. The duration of employment ranged from 6 months to 8 years. The authors computed exposure in two ways. The first was by calculating an exposure coefficient based on the product of the duration of exposure (in years) and mean exposure per day (in minutes). The other was by calculating daily exposure in the last 6 months. The measures were clinical examination, symptom questionnaire, and nerve-conduction velocity. The clinical examination evaluated muscle power, occurrence of arthropathies, deep tendon reflexes, and senses of touch, temperature, and pain. Loss of function was quantified bilaterally with a score of 0 for normal function, 1 for slight impairment confined to the feet, 2 for more proximal involvement of the legs or involvement of the hands, and 3 for more severe impairment. Unilateral involvement was scored one unit lower. The investigators found a single case of “plausible” peripheral neuropathy and two cases of “suspected’ peripheral neuropathy in the 42 exposed workers, although no case definition was presented. None of the reference subjects showed any signs of peripheral neuropathy. Two reference subjects had a high vibration perception threshold (VPT) in the foot, but neither was believed to have sufficient functional impairment to indicate peripheral neuropathy. Overall, the VPT of the group of exposed subjects was significantly different in the forefinger (p<0.001), but the difference disappeared when the groups were analyzed according to increasing exposure.

Gregersen and colleagues (1984) studied 65 workers in Denmark who were exposed to a variety of organic solvents (white spirits, perchloroethylene [tetrachloroethylene], styrene, and toluene). They computed an exposure index that included years of exposure, evaporation, ventilation, frequency of work (percentage of day) with the solvent, skin absorption, frequency of mask use, and danger of the solvent. They were the only investigators who tested study subjects both more than 40 hours after work-related exposure

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

and just after work. They performed clinical examination, tested VPT, and administered a questionnaire. During the examination, they computed a sensory score and a motor score of 1 (no signs or symptoms of peripheral neuropathy) to 8 (symptoms and signs involving more than hands and feet for the sensory score or objective paresis of the extremities with muscular atrophy and tendon hyporeflexia or areflexia for the motor score). A combined index was calculated as the average of the sensory and motor scores. The investigators did not find a case of peripheral neuropathy on clinical examination, but they did report a small correlation between the exposure index and a computed combined index for peripheral neuropathy (r=0.21, p<0.1). They found that the VPT of the exposed group was higher than that of the nonexposed group in five of six fields of measurement, but the differences were not statistically significant.

Mutti and co-workers (1982) studied 95 shoe-factory workers who were exposed to various solvents and 52 nonexposed workers in the same factory. Their duration of exposure ranged from 1 to 25 years. The exposed workers were exposed to hydrocarbon mixtures consisting of n-hexane, cyclohexane, methyl ethyl ketone, and ethyl acetate; most of the constituents are known to cause peripheral neuropathy. Factory environmental conditions had been measured regularly over the 2 years before the study. An exposure score was computed as the product of number of years in the job and median hygienic effect (the ratio of the measured concentration of the compound and its threshold limit value). The study included clinical examination, a symptom questionnaire, and tests of nerve-conduction velocity. Symptoms present during work hours—sleepiness, dizziness, and headache—were classified as acute; and weakness, paresthesia, hypoesthesia, muscular cramps, neurasthenic syndrome, and sleep disturbances were classified as chronic. Nerve-conduction velocities were tested with workers in an air-conditioned temperature-controlled room at 24°C. On clinical examination, the investigators did not report any cases of peripheral neuropathy among the exposed workers, although they found a higher prevalence of self-reported acute symptoms during work (sleepiness and dizziness) and chronic symptoms—such as weakness in limbs, paresthesia and hypoesthesia—but not cramps, neurasthenic syndrome, or sleep disturbances. The median nerve-conduction velocity was decreased in the exposed subjects (54 mm/s vs 57 mm/s, p<0.01), as was the amplitude (7.69 mV vs 10.83 mV, p<0.01). For the ulnar nerve, both the amplitude (6.17 mV vs 8.08 mV, p<0.01; and duration (13.89 ms vs 12.63 ms, p<0.01) were significantly decreased. An association was also found between exposure score and median nerve-conduction velocity (r=0.455, p<0.01); surprisingly, no association was found between MCV and age. Adjustment for confounding variables was not mentioned.

Nasterlack and co-workers (1999) studied 401 painters with 10 years or more of work experience in Germany. The painters were compared with 209 construction workers. Indexes of exposure were computed for recent exposure (within the last 12 months) and exposure before that time. Painters were classified as being highly exposed if their exposure coefficient was at or above the upper 20th percentile. A clinical evaluation was performed with additional tools: two symptom questionnaires (the Swedish 16-item survey for chronic neurotoxicity and the neurotoxic-symptoms score), neurobehavioral tests, nerve-conduction velocity measurement, EEG, and EMG. This is the only solvent study that used EMG; the results of EMG were classified as normal, borderline, or pathologic. The publication states that subjects were tested “under temperature controlled conditions,” but no further details of the test conditions were reported. The authors found a higher, but nonsignificant, frequency

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

of overt peripheral neuropathy in the nonexposed subjects than in the painters (2.7% vs 1.7%). However, the subjective symptoms from the 16-item symptom questionnaire were significantly more frequent in the painters than in the nonexposed subjects. There was also a small but statistically significant correlation between symptoms reported on the 16-item survey and the coefficient of exposure (r=0.27, p<0.001). Almost identical age-adjusted nerve-conduction velocities were found. However, the prevalence of low velocity (bottom 20th percentile) in at least two nerves was significantly more common among the painters. The authors found that 86% of painters and 62% of construction workers classified as having normal electromyograms; the statistical significance of this result was not reported.

Summary and Conclusion

None of the five studies described above was appropriately designed to determine whether peripheral neuropathy is a long-term effect of exposure to solvents sent to the Gulf War. The studies were beset by a small range of outcome measures or by insufficient documentation of exposure or design. Furthermore, the findings from the five studies are inconsistent. No particular outcome was repeatedly associated with exposure to solvents. In three of the studies, the authors themselves commented on the paucity of findings. Gregersen and co-workers (1984) reported that the observed neurotoxic signs were only mildly correlated with exposure levels in the exposed group. Nasterlack and co-workers (1999) reported no overall effects of exposure on nerve-conduction velocities, and they were unable to come to a conclusion on either the time course or reversibility of the signs and symptoms. Only Fagius and Gronqvist (1978) found a weak association between exposure to solvents and some abnormal findings.

In contrast, two studies of shoe and leather workers reported more significant findings, including statistically significant slowing of nerve conduction (Buiatti et al., 1978; Mutti et al., 1982). Indeed, Buiatti and co-workers found that more than one-fourth of workers had peripheral neuropathy, but the study had design limitations. Neither study made adjustments for known confounders.

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 peripheral neuropathy.

NEUROBEHAVIORAL EFFECTS

Neurobehavioral (NB) effects are broadly defined to include changes in cognition, mood, and behavior that are mediated by the central nervous system. NB effects are measured via symptom questionnaires or validated tests. NB tests and the functional domains they measure are described in Appendix F. NB effects of exposure to sarin, an OP nerve agent, were evaluated in an earlier IOM committee report (IOM, 2000). This section evaluates the accumulated evidence from studies of Gulf War veterans and workers exposed to OP insecticides and solvents.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Studies of Gulf War Veterans and Neurobehavioral Effects

The body of Gulf War studies that examined NB effects of insecticide or solvent exposures is for the most part cross-sectional with respect to exposures and outcomes and frequently based on self-reports. Because of the unexplained nature of veterans’ symptoms, many of which are neurobehavioral, investigators strove to define new syndromes or to establish variants of existing syndromes (Appendix A). The methods of measuring and analyzing NB effects in veterans varied greatly, sometimes including a battery of validated NB tests and more frequently including a host of symptom checklists. Investigators grouped or clustered symptoms into particular NB functional domains in different ways (for example, by factor analysis or a priori symptom grouping). Furthermore, insecticides and solvents typically constituted only a small subset of the potential agents to which Gulf War veterans may have been exposed. The exposure classification was general, such as “pesticides,” and the level of exposure was rarely assessed.

This subsection describes several studies, beginning with the few that used NB tests, before proceeding to studies of symptom groupings covering what has been termed chronic multisymptom illness, symptoms of impaired memory and concentration, and finally symptoms of dizziness and impaired balance. The committee selected those general categories for ease of comparison with the occupational studies of insecticides and solvents. We concentrate here on Gulf War studies that examined exposure-symptom relationships, and we evaluate findings only for relevant pesticides or solvents. The studies covered here are presented in Table 7.4 and are categorized according to whether they were population-based or military-unit-based.

Studies with NB Testing

Two studies of veterans used NB testing to address possible effects of insecticide exposure during the Gulf War. The study with the stronger methods found an association between pesticide exposure and abnormal scores on the subscales of the Profile of Mood States (POMS) but found no associations with abnormalities on other components of a comprehensive NB test battery (White et al., 2001). The other study showed no associations between pesticide exposure and handgrip strength (Kaiser, 2000). Neither study specifically asked about veterans’ exposures to relevant solvents. Two followup studies by Haley and colleagues included NB testing but did not evaluate associations between pesticide or solvent exposure and test abnormalities (Haley et al., 1997b; Horn et al., 1997).

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

TABLE 7.4 Gulf War Studies and Neurobehavioral Effects

Reference

Population

Self-Reported Exposure to Relevant Pesticides or Solvents

Health Outcome or Test Type

Results

Limitations

Population-Based Studies

Unwin et al., 1999

UK

2735 UK veterans deployed to Gulf War vs 2393 deployed to Bosnia vs 2422 deployed elsewhere

Four of 29 related to pesticides or solvents: “personal pesticides,” “other paints or solvents,” “handled prisoners of war,” “pesticides on clothing or bedding”

Symptom questionnaires, exposure questionnaire

All solvent or pesticide exposures associated with chronic multisymptom syndrome, posttraumatic stress reaction; physical functioning in all three cohorts “Concentration” factor not associated with any relevant pesticide or solvent exposure in multivariate regression analysis; “neurologic” factor associated with pesticide handling in multivariate regression analysis (p< 0.001), but no clear dose-response relation; “neurologic” factor not associated with other pesticide, solvent exposures in multivariate analysis

Self-reported symptoms and exposures; lack of adjustment for interrelationships between multiple exposures; use of p value of 0.05 despite multiple comparisons

Cherry et al, 2001a

UK

(see also Table 7.1)

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: “days exposed to handling pesticides,” “days living in quarters sprayed with insecticides,” “days respraying vehicles,” “days applying insecticide to skin”

Symptom questionnaire, exposure questionnaire; surveys completed 7 years or more after war

Self-reported symptoms and exposures

Iowa Persian Gulf Study Group, 1997

US

1896 deployed veterans from Iowa as home of record vs 1799 nondeployed veterans from Iowa as home of record

Two of over 20 items related to solvents or pesticides: “solvents/petrochemicals,” “pesticides”

Symptom questionnaires, exposure questionnaire

Symptoms of cognitive dysfunction associated with higher prevalence of exposure to “solvents/petrochemicals” (prevalence difference of 6.6%, p<0.001), “pesticides” (prevalence difference of 14.2%, p<0.001)

Self-reported symptoms and exposures; low proportion of minority-group subjects; internal validation of responses not assessed; no adjustment for multiple comparisons; multiple associations between variety of exposures and variety of outcomes

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference

Population

Self-Reported Exposure to Relevant Pesticides or Solvents

Health Outcome or Test Type

Results

Limitations

Goss Gilroy Inc., 1998

Canada

3113 Canadian veterans deployed to Gulf War vs 3439 deployed elsewhere

Over 30 exposures divided into six categories; one category labeled “CNS factors” includes five relevant solvent or pesticide exposures (of eight total): “other paints and solvents,” “food contaminated with…other chemicals,” “personal pesticides,” “flea collars,” “pesticides on bedding or clothing”

Symptom questionnaires, exposure questionnaire

Exposure to “CNS factors” associated with cognitive dysfunction (OR=1.45, 95% CI=1.19–1.76)

Self-reported symptoms and exposures; subset of Canadian veterans not exposed to many agents (because they were based at sea) reported symptoms as frequently as did land-based veterans; no adjustment for multiple comparisons; multiple associations between various exposures and various outcomes; not clear which pesticide or solvent exposures were related to outcome

Kang et al., 2002

11441 US veterans deployed to Gulf War vs 9476 Non-Gulf deployed Nested case-control

Five of 23 exposures related to solvents: “personal pesticides, including creams, sprays and flea collars,” “contact with prisoners of war,” “food contaminated with smoke, oil, or other chemicals,” “other paint or solvent or petrochemicals substances,” “chemical agent resistant compound paint.”

Factor analysis, symptom questionnaires; exposure questionnaire

Exposure to CARC paint and one other solvent-related exposure at least 3 times more common in 277 Gulf-War deployed veterans than in controls who met case definition with all these symptoms: loss of balance or dizziness, speech difficulty, sudden loss of strength, tremors or shaking

Self-reported symptoms and exposures; no analysis for dose-response

Military-Unit-Based-Studies

White et al., 2001

US

(same cohort as Proctor et al., 1998)

273 US deployed veterans from Massachusetts (Fort Devens) and New Orleans vs 50 Germany-deployed veterans

One of eight environmental exposures related to pesticides or solvents: “pesticides”

15 NB tests: WAIS-R, tests of attention, executive function, motor-psychomotor, visuospatial, memory, mood (POMS), motivation; exposure questionnaires; diagnostic interviews for PTSD

Exposure to “pesticides” associated with significant differences on all five POMS subscales

Self-reported exposures; limited representativeness of entire Gulf War cohort

Kaiser, 2000

US

(same cohort as Gray et al., 1999)

527 active-duty Seabees formerly deployed to Gulf War vs 969 nondeployed veterans from same Seabee commands

Two exposures related to pesticides or solvents: “insecticide spray,” “burning insecticide coils”

Handgrip strength

Handgrip strength not associated with exposure to insecticide spray, burning of insecticide coils, or use of pyridostigmine bromide

Moderate to low response rate; exclusion of veterans no longer in active service; self-reported exposures; limited representativeness of entire Gulf War cohort

Nisenbaum et al., 2000

US

1002 veterans from four Air Force units; nested case-control survey of 459 Gulf

One of six environmental exposures related to pesticides or solvents:

Symptom questionnaires, exposure questionnaire

Severe and mild-moderate cases of chronic multisymptom illness

Self-reported symptoms and exposures; no reporting on exact time of exposure; exclusion of Gulf War veterans no longer in

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference

Population

Self-Reported Exposure to Relevant Pesticides or Solvents

Health Outcome or Test Type

Results

Limitations

(followup to Fukuda et al., 1998)

War veteran cases of chronic multisymptom illness vs 543 controls without chronic multisymptom illness

“regular use of insect repellent”

 

associated with “regular use of insect repellent” (OR=2.4, 95% CI 1.3–4.5)

active service; no adjustment of p value despite multiple comparisons; limited representativeness of entire Gulf War cohort

Haley and Kurt, 1997

US

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

Among 20 veterans with this syndrome, wearing flea collars more common (RR=8.7, 95% CI=3.0–24.7)

Self-reported symptoms and exposures; no control group in original cohort; limited representativeness of entire Gulf War cohort

Gray et al., 1999

US

527 active-duty Seabees formerly deployed to Gulf War vs 969 nondeployed veterans from same Seabee commands

Four of 30 exposures related to pesticides or solvents: “insecticide spray,” “direct contact with prisoners of war,” “burning insecticide,” “wore a flea collar for more than one day”

Symptom questionnaire, exposure questionnaire; clinical examination; handgrip strength; pulmonary function; serum collection

“Contact with POWs;” only pesticide or solvent exposure common enough to be analyzed with 10 other exposures for exposure-symptom relationships; “Contact with POWs” significantly associated with forgetfulness (RR=2.8) and confusion (RR=5.0)

Self-reported symptoms and exposures; Potential recall bias in symptom reporting; moderate to low response rate; exclusion of veterans no longer in active service; exclusion of several potentially important exposures from analysis; limited representativeness 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 end points other than peripheral neuropathy

Exposure to “pesticides” associated with neurologic symptom group (headaches, numbness in arms or legs, dizziness) (p=0.007), musculoskeletal symptom group (p=0.001); “pesticide” exposure not significantly related to neuropsychologic group (such as difficulty in concentrating, confusion) or psychologic symptoms (such as inability to fall asleep, anxiety, depression)

Self-reported symptoms and exposures; moderate to low response rate; limited representativeness of entire Gulf War cohort

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

White and colleagues (2001) reported NB findings from a larger study of the Ft. Devens and New Orleans cohorts described earlier (Proctor et al., 1998). Exposure during the Gulf War was assessed with a questionnaire that addressed eight different agents, one of which was to “pesticides.” Veterans completed a 2-hour NB test battery designed to assess all major functional domains of general intelligence, attention and executive function, motor ability, visuospatial processing, verbal and visual memory, mood, and motivation (Appendix F). Specific tests included subsets of the Wechsler Adult Intelligence Scale (WAIS) and the Wechsler Memory Scale, the POMS, the Purdue pegboard test, and tests of attention and reaction time (digit-span, trail-making, and continuous-performance tests), serial arithmetic, card-sorting, finger-tapping, and block design. All results were corrected for the presence of posttraumatic stress disorder, or PTSD (via the Clinician Administered PTSD Scale) and depression (via the Structured Clinician Interview for DSM-IV) because both have been shown to influence NB test performance in veterans. The study found that self-reported exposure to pesticides was associated with abnormal scores on all the POMS subscales but was not associated with abnormalities in any of the other NB tests.

Kaiser (2000) examined the association between self-reported exposure and results of a battery of questionnaires, clinical measurements, and handgrip strength. The study examined a sample of active-duty Seabees still serving in 1994. Gulf War veterans with more severe symptoms were likely to have been excluded because they were no longer on active-duty status. Handgrip strength was not associated with exposure to insecticide spraying, burning of insecticide coils, or use of pyridostigmine bromide (PB), which was used as prophylaxis for nerve-agent exposure. The actual focus of the study was PB, a carbamate.6 Multivariate models showed no interaction between PB and insecticide spraying or burning of insecticide coils.

Haley and colleagues published several articles comparing a subset of the veterans they identified as having one of their three syndromes with unaffected veterans from the same battalion. The three syndromes they had previously identified were categorized as “impaired cognition,” “confusion-ataxia,” and “arthro-myo-neuropathy” (Haley et al., 1997a). The general methods of identifying the syndromes are discussed earlier in this chapter and in Appendix A.

Two publications by Haley and colleagues (1997a,b) included NB testing. Both compared 23 veterans with the highest scores on the first three of their syndromes with 10 unaffected controls—matched by age, sex, and educational level—who were selected from 70 veterans who had been deployed to the Gulf War and had reported no serious health problems in the prior study. An additional 10 unaffected, matched controls were selected from veterans who had not been deployed to the Gulf War. Veterans with one of the three syndromes had more abnormal scores on global measures of brain dysfunction, tests of audiovestibular function, and somatosensory, visual, and brainstem auditory evoked potentials (Haley et al., 1997a,b). In a separate paper on what appears to be the same set of veterans, Horn and colleagues (1997) found “a generalized pattern of neuropsychological deficit” among the veterans with one of the three syndromes, as measured by a number of tests, including the Halstead Impairment Index and three subscales of the WAIS. Neither of the articles reported on pesticide or solvent exposures of the affected veterans. Thus, although Haley’s previous report had shown associations between the three syndromes and some pesticide exposure during the Gulf War (Haley and Kurt, 1997), the analysis in these

6  

PB was studied by the previous IOM Gulf War and Health committee (IOM, 2000).

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

two other studies did not address associations between NB test abnormalities and Gulf War exposures.

Summary and Conclusion

In summary, only one of the studies that performed NB tests was sufficiently large and well designed to examine NB test performance in relation to pesticide or solvent exposure in the Gulf War (White et al., 2001). Although the study contained an array of NB test measures, it examined only one relevant exposure—namely, to “pesticides.” That study found that self-reported exposure to pesticides was associated with mood symptoms as assessed by the POMS but not with any other NB tests. Nevertheless, it lacked specificity about the nature or degree of pesticide exposure, and the sample was military-unit-based, rather than population-based, so the findings are not necessarily representative of the entire Gulf War cohort. The other studies had more serious design limitations—for example, there were too few outcome measures, or the relationship between outcome and exposure of interest was not measured. The committee was not able to draw particular conclusions from these studies.

“Chronic Multisymptom Illness”

One of the first studies that endeavored to classify Gulf War veterans’ symptoms into a new syndrome created a case definition for “chronic multisymptom illness.” The case definition, which was based on factor analysis and other methods, required at least two of these three categories of symptoms to have been present for at least 6 months: fatigue, mood-cognition symptoms (such as feeling depressed and having difficulty in remembering or concentrating), and musculoskeletal symptoms (joint pain, joint stiffness, or muscle pain) (Fukuda et al., 1998). Conducted by the Centers for Disease Control and Prevention (CDC), the study focused on active-duty Air Force National Guard and three other Air Force units, two of which (from Florida) had not been deployed to the Persian Gulf. Because a sizable percentage of the nondeployed veterans also met the case definition, the study concluded that the case definition could not uniquely characterize veterans’ unexplained illnesses (Appendix A). Nevertheless, the case definition has been used since then because multisymptom illnesses are more prevalent among Gulf War veterans than among nondeployed veterans.

Two studies of Gulf War veterans searched for associations between chronic multisymptom illness and pesticide or solvent exposure (Nisenbaum et al., 2000; Unwin et al., 1999). Nisenbaum and colleagues (2000) performed a nested case-control study using the same cohort studied by Fukuda and colleagues (1998). They examined the association between chronic multisymptom illness and six environmental exposures, only one of which was relevant to the committee (“used insect repellent on a regular basis”). The sample, as noted above, was drawn from a military population still active in 1994. Cases of chronic multisymptom illness were classified as severe if each case-defining symptom was rated by veterans as severe; if not, the case was rated as mild-moderate. The study compared 459 Gulf War veterans with chronic multisymptom illness and 543 without the illness. In univariate analyses, all exposures were associated with mild-moderate or severe cases. In multivariate analysis that adjusted for all other exposures—and for age, sex, smoking, rank, and military unit—the association with regular use of insect repellent (and two other

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

environmental exposures) remained significant (p<0.05). The adjusted ORs were 2.4 (95% CI=1.3–4.5) for severe cases and 1.7 (95% CI=1.2–2.3) for mild-moderate cases of multisymptom illness. The interaction of insect repellent and pyridostigmine bromide was found not to be significant.

Unwin and colleagues (1999) studied three randomly selected samples of UK military personnel deployed to the Gulf War. The first was chosen from male and female veterans deployed from September 1, 1990 to June 30, 1991. They were compared with two comparison cohorts serving elsewhere during the same period: one in Bosnia and one in the armed forces but not deployed to the Gulf War. All three samples received a questionnaire by mail. The questionnaire included 29 items concerning possible agents to which Gulf War veterans may have been exposed; four of the agents were related to insecticides and solvents (Table 7.4). Analyses were restricted to responses from men, and the level of significance was set at 0.05 although multiple comparisons were performed. All four relevant agents were associated with chronic multisymptom illness regardless of deployment status. The ORs comparing exposed and nonexposed for each cohort of Gulf War-deployed and non-Gulf War-deployed veterans were weak to moderate (1.7–2.2).

Summary and Conclusion

In summary, two studies of Gulf War veterans using the same empirically derived case definition for chronic multisymptom illness found some associations with pesticide exposure. The possibility of a type I (false-positive) error exists for both studies, in that both made multiple comparisons without adjustment for the number of comparisons. Also, recall bias is a possibility inasmuch as both studies used self-reports of exposure. One study (Unwin et al., 1999) used rigorous methods and a random sample of UK Gulf War veterans; it found an association between chronic multisymptom illness and each of the relevant pesticide or solvent exposures, but a similar association was found with all but one of the other exposures. Therefore, the association found in this study might have been due to confounding by some other exposure that was correlated with the pesticide and solvent exposures. The second study (Nisenbaum et al., 2000) used a less representative sample that was likely to have excluded people with the highest levels of disability, and it used the same sample whose clinical findings were initially used to define cases of chronic multisymptom illness. An association between chronic multisymptom illness and pesticide exposure persisted after adjustment for the presence of other exposures. Still, no definitive conclusions can be drawn from these studies.

Symptoms Related to Memory and Concentration

Six studies of Gulf War veterans that used widely varied methods were reviewed by the committee for relationships between pesticides or solvents and symptoms related to memory and concentration. Two of the studies used factor analysis to group symptoms, the others clustered symptoms by using a priori categories.

Cherry and colleagues (2001a) studied illnesses and exposures in a population-based study of all UK veterans deployed to the Persian Gulf. (Study details were described in the discussion of peripheral neuropathy earlier in this chapter.) The study derived symptom groups by a factor analysis of symptoms from two random samples of all UK veterans stratified by age, sex, and rank. One of the seven factors derived from factor analysis and

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

labeled as “concentration” clustered 10 symptoms: difficulty in concentrating, poor memory, needing to make notes to remember things, needing to check on things already done, clumsiness, slurring words, other people noting a poor memory, difficulty in grasping meanings, difficulty in making decisions, and difficulty in saying what was intended (Cherry et al., 2001b). The “concentration” factor was not found to have an association with any pesticide or solvent exposure in the multivariate regression analysis.

Haley and Kurt (1997) linked one of their factor-analysis-derived syndromes to wearing of flea collars that contained insect repellent. Of the six new syndromes identified by factor analysis, syndrome 1 (“impaired cognition”) consisted of nine symptoms: distractibility, short-term and long-term memory problems, depression, fatigue, slurring of speech, confusion, insomnia, and headache (Haley et al., 1997a). Syndrome 1 was about 9 times more common among those who reported wearing flea collars than among those who never wore them (RR=8.7, 95% CI=3.0–24.7). A dose-response trend was also found in the syndrome 1 case group: 3% (seven of 229) of those who reported never wearing flea collars were found to have the syndrome, compared with 18% (three of 17) of those who wore them but not next to their skin, and 67% (two of three) who reported sometimes wearing flea collars next to their skin. No association was found between syndrome 1 and the three other pesticide exposures or the one solvent exposure relevant to the committee.

Gray and colleagues (1999) examined symptoms and exposures in active-duty Seabees who were still serving in 1994; Gulf War veterans with more severe symptoms were likely to have been excluded. The exposure questionnaire asked about 30 different exposures, but the authors chose to limit further analyses to the subset of 11 exposures that had an OR greater than 3 (Gulf War-deployed vs nondeployed veterans) and that were reported by more than 5% of Gulf War veterans. Because of those restrictions, associations between symptoms and three relevant pesticide exposures were not examined. The only pesticide-related exposure analyzed was “direct contact with prisoners of war” (POWs). The handling of POWs included delousing with pesticides, so veterans exposed to POWs may have had some pesticide exposure. Direct contact with POWs was significantly associated with only four symptoms in the univariate analysis. Two of the four were forgetfulness (RR =2.8) and confusion (RR=5.0), both of which were reported as having confidence intervals that excluded 1.7 (The other two symptoms were roving joint pain and sore throat.) The same investigators also performed a factor analysis of symptoms that was published separately (Knoke et al., 2000). They noted that one of the five factors they identified bore a close resemblance to syndrome 1 (as identified by Haley and Kurt, described earlier), but they did not examine relationships between symptom factors and exposures.

Proctor and colleagues (1998) studied veterans from Massachusetts and New Orleans in a study described earlier. In their multiple-regression analysis, which controlled for associations between self-reported exposures and for other factors (listed above) and set p at 0.05, the “neuropsychologic” group of symptoms was not significantly associated with exposure to “pesticides.” The “neuropsychologic” group was composed of three symptoms: difficulty in learning new material, difficulty in concentrating, and confusion.

The “Iowa study” (1997) was a large population-based study of US Gulf War veterans. It surveyed a representative sample of 4886 military personnel who had active service during the Gulf War and who listed Iowa as their home of record at the time of enlistment (Iowa Persian Gulf Study Group, 1997). The study examined the health of military

7  

Actual confidence intervals not reported, except that they excluded one.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

personnel from all branches of service who were still serving or had left service. The sample was randomly selected from and therefore representative of about 29,000 military personnel and was stratified by age, sex, race, rank, and range of military service. Among other findings (see Appendix A), the two groups of Gulf War veterans reported roughly twice the prevalence of symptoms suggestive of cognitive dysfunction compared with nondeployed veterans.8 That was the largest prevalence difference among all study findings. Researchers had grouped sets of symptoms from their telephone-administered symptom checklists into a priori categories of diseases or disorders. The Iowa study assessed exposure-symptom relationships by asking veterans to report on more than 20 agents, two of which were relevant to the committee: “solvents/petrochemicals” and “pesticides.” Researchers found that deployed veterans with symptoms of cognitive dysfunction had a higher prevalence of reporting solvent or petrochemical exposure than nondeployed veterans (exposure-prevalence difference, 6.6%; p<0.001). They also found them to have a higher prevalence of reporting exposure to pesticides (difference, 14.2%; p<0.001).

A study of all Canadian Gulf War veterans (1994) compared them with a large sample of Canadian forces serving elsewhere at the time of the Gulf War (Goss Gilroy Inc., 1998). Respondents filled out a long questionnaire. The authors defined the outcome of “cognitive dysfunction” as requiring at least one of the following symptoms or combinations of symptoms and severity: amnesia or severe memory loss (no severity scale); confusion or disorientation (“moderately” or more); any two of eight cognitive symptoms with a severity of “moderately” or more, or one of the eight with a severity of “quite a bit” or “extremely.” A severity greater than “moderately” for confusion and disorientation occurring alone qualified a person as cognitively impaired, as did the presence of amnesia or severe memory loss alone. The authors did not report on associations with single pesticide or solvent exposures but grouped a number of pesticide and solvent exposures as “CNS factors.” They reported an association between “CNS factors” and cognitive dysfunction, with an OR of 1.45 (95% CI=1.19–1.76).

Summary and Conclusion

In summary, difficulties with memory and concentration have been consistently shown to be more prevalent among Gulf War veterans than among comparison groups. However, the evidence of an association with pesticide or solvent exposure is inconsistent. For example, the strongest study, a population-based study of UK veterans (Cherry et al., 2001a), failed to show an association. Another study (Haley and Kurt, 1997) found an association only with the use of flea collars but failed to demonstrate an association with three other pesticide exposures or with a solvent exposure. A study by Proctor and colleagues (1998) using a multivariate analysis correcting for exposure to other agents also failed to demonstrate an association. Two population-based studies (Goss Gilroy Inc., 1998; Iowa Persian Gulf Study Group, 1997) showed an association between memory or concentration symptoms and pesticide exposure, broadly defined; both used univariate analyses but did not take into account the number of comparisons made between various

8  

Precise symptoms constituting cognitive dysfunction were not reported. After a veteran identified himself or herself as having the requisite set of symptoms, researchers analyzing responses considered the veteran to have symptoms “suggestive” of or consistent with a particular disorder but not to have a formal diagnosis of the disorder.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

exposures and various outcomes, which may have produced type I errors (false-positive results). No definitive conclusions can be drawn from these studies.

Symptoms Related to Dizziness and Balance

Cherry and colleagues (2001a,b) found that one of their factors identified by factor analysis, which included dizziness and balance, was associated with pesticide exposure. They studied illnesses and exposure in a population-based sample of all UK veterans deployed to the Persian Gulf. (Study details were described earlier.) One of the seven factors, “neurologic,” clustered 13 symptoms, including problems in buttoning, difficulty in rising from a chair, fainting, feeling too weak to complete tasks, losing balance, difficulty in bringing objects down from above the head, double vision, shortness of breath when walking, unsteadiness when walking, and feeling dizzy (Cherry et al., 2001b). Pesticide handling was significantly related to the neurologic factor in the multivariate regression analysis. No clear dose-response association was found with days of exposure to pesticide handling. Personal use of insect repellent and other pesticide and solvent exposures were not statistically significant associated with the neurologic factor.

Kang and colleagues (2002), in a population-based study of US veterans, found that one of their factors identified by factor analysis, which included dizziness and balance, was associated with solvent exposure. The study was the largest and most representative of US veterans (11,441 deployed and 9476 nondeployed veterans). The factor analysis of 47 symptoms identified six factors, only one of which contained a cluster of symptoms that did not load on any factors in the nondeployed Gulf War veterans. The symptoms in the cluster were: loss of balance-dizziness, speech difficulty, blurred vision, and tremors-shaking. A group of 277 deployed veterans (2.4%) and 43 nondeployed veterans (0.45%) met a case definition subsuming all four symptoms. A nested case-control analysis was performed to determine which of 23 self-reported exposures were more common among Gulf War veterans who met the case definition than among Gulf War veterans who lacked any of the symptoms. Of the nine exposures that were at least three times higher among cases, two were solvent-related: CARC paint (51.2% in cases vs 16.3% in controls) and food contaminated with oil smoke (73.4% in cases vs 20.6% in controls). No pesticide-related exposures were reported three or more times more frequently in cases versus controls. A dose-response relationship was not studied, because of the nature of the dataset regarding self-reported exposure. NB testing was not performed, but is likely to be in the final phase of this study.

Two other less representative US studies using factor analysis did not identify a factor related to dizziness and balance. The CDC study (Fukuda et al., 1998), which attempted to define a chronic multisymptom illness, included only a single question that addressed “dizziness or trouble maintaining balance.” No corresponding dizziness or balance-related factor was extracted in the factor analysis by Knoke and colleagues (2000). Haley’s “syndrome 1” (Haley et al., 1997a) contains one symptom (slurred speech) that could overlap with dizziness and balance problems, but the syndrome consists mainly of attention, reasoning, and memory problems that were grouped in a separate “concentration” cluster in the Cherry study (2001b, see above). Haley’s “syndrome 2” (“confusion-ataxia”) also has several symptoms of balance and coordination problems, but none of the pesticide or solvent exposures was related to this particular syndrome. A separate publication by Haley and colleagues (Roland et al., 2000), using audiovestibular testing, reported on the

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

vestibular complaints of 23 veterans with syndromes 1–3 compared with 20 unaffected controls; the study did not relate vestibular dysfunction to exposures.

In addition to the study by Cherry and colleagues, one study (Proctor et al., 1998) examined associations between pesticide exposure and individual symptoms of dizziness and balance problems. The neurologic group of symptoms included headache, numbness in arms or legs, and dizziness or lightheadedness and thus bore some similarity to Cherry and colleagues’ neurologic factor and peripheral factor. Exposure to “pesticides” in the Proctor et al. study was associated with their neurologic symptom group (p=0.007).

Summary and Conclusion

In summary, two population-based studies did identify a dizziness or balance factor among deployed veterans. In the study by Cherry and colleagues (2001a), some pesticide exposures were associated with the symptom factor related to dizziness and balance; the study did not find a dose-response relationship, and found no relationship to solvent exposure. In the study by Kang and colleagues (2002), a small subset of veterans who met a case definition including dizziness and balance problems were far more likely to report solvent exposures. The symptom-exposure findings from those two studies were considered by the committee in its evaluation of the entire body of studies on NB effects of pesticide and solvent exposure (see next sections). Dizziness and balance symptoms were not found in two other, yet less representative, factor-analysis studies of Gulf War veterans (Fukuda et al., 1998; Knoke et al., 2000), but these studies excluded veterans who had left the service. Because dizziness and balance symptoms are potentially quite disabling, a study using only Gulf War veterans who remained in active service could have missed the presence of this factor. One study reported some dizziness and balance symptoms in one of its factor-analysis syndromes, but the syndrome was not associated with pesticide or solvent exposure. No definitive conclusions can be drawn from these studies, but two of the studies (Cherry et al., 2001a; Kang et al., 2002) are incorporated into the committee’s conclusions in the next sections of this chapter.

OP INSECTICIDES AND NEUROBEHAVIORAL EFFECTS

This section contains the committee’s evaluation of two major types of studies on OP insecticides and neurobehavioral effects: studies of workers with past OP poisoning who had been hospitalized and treated for the acute cholinergic syndrome and studies of workers with chronic exposure to OP insecticides but no documented episode of past OP poisoning.

Limitations of Studies of Insecticides and Neurobehavioral Effects

The studies evaluated here are mostly cross-sectional studies. Various limitations apply to cross-sectional studies in general and to the particular types of studies of OP-poisoned workers or workers with chronic exposure without past poisoning.

A general limitation of occupational cross-sectional studies is that the study population frequently includes workers that are “healthier” and therefore are able to continue working (the “healthy-worker effect,” see Chapter 2). Workers who become ill leave the workforce and are not usually included in a cross-sectional study population.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Another potential limitation is related to bias in the selection of the groups. Different demographic characteristics of the control group (such as education and language) and the exposed group can lead to differences in performance on NB testing.

In several of the studies of past OP poisoning, a group is identified through registries of workers with a history of having been poisoned (e.g., Savage et al., 1988; Steenland et al., 1994). One potential limitation of this type of study is selection bias. Frequently, only about half of poisoned workers are locatable and available to participate. That raises the possibility that those with the most symptoms are more eager to participate. In addition, many of the poisoned subjects have had years of chronic exposure, and that makes it difficult to distinguish whether adverse effects are attributable to the poisoning or to years of chronic, lower-level exposure. Although details of the specific exposure are not always available, exposure misclassification of workers poisoned with OP insecticides or carbamates is unlikely because they were medically evaluated and treated for acute cholinergic signs and symptoms while spraying insecticides.

The committee’s charge to examine long-term effects created another type of limitation. Most studies in the occupational literature are of workers with both past and current insecticide exposure. The observed NB findings may be long-term effects of past exposure or short-term effects of current exposure (which might resolve once exposure ceases). The only way to separate out long-term from short-term effects is to examine workers with only past exposure. Therefore, the committee selected for its evaluation only studies of workers after an exposure-free interval (e.g., Rosenstock et al., 1991) or studies that used workers’ AChE concentrations to exclude those with current (or recent) exposure. For example, Savage and colleagues (1988) studied long-term effects by confirming that AChE in exposed and referent subjects did not indicate recent exposure.

OP Exposure and Neurobehavioral Effects With a History of Past OP Poisoning

Four studies examined populations of workers (mostly Hispanic males) previously treated for acute OP-insecticide poisoning (Reidy et al., 1992; Rosenstock et al., 1991; Savage et al., 1988; Steenland et al., 1994). OP poisoning results in symptoms or signs of the acute cholinergic syndrome (Chapter 3), which, because of its life-threatening nature, typically requires hospitalization. Two of the four studies documented AChE concentrations to confirm past poisoning or the absence of recent exposure (Savage et al., 1988; Steenland et al., 1994). In addition to acute poisoning, most of the workers in these studies had years of chronic exposure. Evaluations were conducted within 2 years of the last poisoning in one study (Reidy et al., 1992) and 1–11 years after poisoning in the other studies. Comparison subjects (not OP-poisoned) were selected from friends of the poisoned group in three of the four studies. Comparison subjects frequently also had a history of insecticide exposures or agricultural jobs even if they had no history of treatment for OP poisoning. For assessment of outcome measures, all the studies used standardized NB test batteries (sometimes in Spanish) covering an array of NB domains (language, attention and executive functioning, memory, visuomotor and visuospatial ability, and motor skills). Various questionnaires on CNS symptoms, including mood, were also incorporated into the design and analysis. Overall, OP-poisoned subjects performed worse on NB tests and reported more symptoms than comparison subjects. The studies, their strengths, and their limitations are described below in Table 7.5.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

TABLE 7.5 Neurobehavioral Effects with History of Past OP Poisoning

Reference

Population: Exposed

Population: Control

Health Outcomes or Test Type

OP Insecticide Exposure

Adjustment

Results

Limitations

Savage et al., 1988

100 male workers from Colorado and Texas registry of OP-insecticide poisonings

100 matched controls recruited from study-subject referrals, businesses, public agencies, investigators

>30 NB tests, including: WAIS, Halstead-Reitan, MMPI-mood, questionnaires; average impairment rating; 9 years after poisoning

History of 10 OPs reported as primary cause of poisoning; methyl parathion, parathion in at least half of poisoned workers; AChE of both groups within normal limits

Paired matching on age, sex, level of education, social class, occupational class, ethnic background (Mexican)

Poisoned workers worse average impairment rating; worse on 18 of 36 NB tests; some impairment of fine motor movements; more anxiety symptoms

No information on past or current exposure of controls; no correction for multiple testing

Steenland et al., 1994

128 people from CA registry of OP-insecticide poisoning; 28% hospitalized for one night

90 friends of poisoned workers “not currently working with pesticides,” 19% in agriculture

Eight NB tests from NES2 in English and Spanish, including mood scales; 1–9 years after poisoning

History of OP use; 83 also found to have significant decrease in AChE at time of poisoning; specific OPs named but limited insecticide-specific analyses because of small numbers

Poisoned workers, controls similar in mean grade level, race, preferred language, percentage of drinkers; regression to adjust for confounding

Hospitalized OP-poisoned workers significantly worse on two of 10 NB tests (continuous-performance test and digit-symbol); for all poisoned workers together, even worse performance in those with more severe poisonings; mood scales worse for tension and confusion

No information on past OP exposure of controls; no formal correction for multiple comparison

Rosenstock et al., 1991

36 men hospitalized and treated for OP poisoning in Nicaragua

25 male friends of study subjects with no prior OP poisoning; 69% with prior OP-pesticide exposure

Six of seven NB subtests from WHO battery, including BSI, CNS symptoms; Spanish-translated tests; 1–3 years after poisoning

History of OP hospitalization; no pesticide use within 3 months before testing

Matching on age, sex; testers blinded to exposure status; analysis and adjustment for premorbid intellectual functional difference in vocabulary scores

Exposed group had worse performance on five or six NB domains, more CNS symptoms (7.2 vs 4.7, p<.01); no difference in mood symptoms from BSI

Association strengthened by controls having prior OP pesticide exposure

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Savage and colleagues (1988) used the most comprehensive NB testing and studied a large group of agricultural workers (100 poisoned and 100 matched comparison subjects). Poisoned subjects were obtained from registries of pesticide poisonings in Colorado (1950–1976) and Texas (1960–1976). Workers were reported to have been poisoned with 10 types of OP compounds, one of which, malathion, is reviewed in this report (n=6). Some of the poisonings involved more than one OP insecticide. Each OP-poisoned worker was individually matched to a comparison subject for age, sex, level of education, occupational class, socioeconomic status, race, and, in the case of Mexican Americans, ethnic background. Comparison subjects were recruited from multiple sources, including referrals from study subjects, employee rosters, and investigator solicitations. The mean elapsed time from the last poisoning to the time of testing was 9 years. No specific information on jobs or exposures at the time of testing was provided, but red-cell and plasma cholinesterase tests were performed at the time of evaluation of all subjects. Both the OP-poisoned and comparison groups were found to be well within the limits of normal red-cell and plasma AChE, so recent exposure to OP compounds was unlikely. Residue analyses were also performed for organochlorine pesticides. Although OP-poisoned workers had significantly higher mean serum concentrations of organochlorines, the analysis of covariance failed to show any significant association with organochlorine-pesticide residues or summary scores on the NB battery.

NB testing was extensive; subjects took more than 30 individual NB tests or subtests (individual tests in a test battery). Batteries included the WAIS and the expanded Halstead-Reitan battery. An average impairment rating assigned to each subject was the average of ratings (0=better than average; 5=severely impaired) on 11 of the Halstead-Reitan battery subtests and one WAIS subtest. The Halstead-Reitan battery included measures of intelligence, attention, cognitive functions, motor proficiency, sensory perceptual functions, aphasia and related disorders, and learning and memory. The subjects were also given the Minnesota Multiphasic Personality Inventory (MMPI). In addition, each study participant and a close relative independently completed questionnaires rating the participant’s functioning regarding memory, communication, academic skills, sensory and motor abilities, various cognitive and intellectual abilities, and emotional status. Subjects also underwent a clinical neurologic examination, audiometric tests, ophthalmic tests, and electroencephalography. Examiners were blinded as to subjects’ exposure status.

The poisoned subjects performed significantly worse than referents on four of five summary measures and on 18 of 34 individual tests. The differences occurred on tests of intellectual functioning, academic skills, abstraction, flexibility of thinking, and simple motor skills (speed and coordination). Of the OP-poisoned workers, 24% had Halstead-Reitan battery summary scores in the range characteristic of cerebral damage or dysfunction, compared with 12% of comparison subjects. The poisoned subjects’ assessments of their own functioning found statistically significant differences in 10 of 32 aspects of language and communication, memory, cognitive functioning and perceptual functions. OP-poisoned subjects reported more difficulties in understanding speech of others (p=0.014), recognizing printed or written words (p=0.008), thinking of names of things (p=0.037), calculating (p=0.009), following instructions (p=0.004), solving problems (p=0.036), following directions (p=0.044), performing tasks with the right hand (p=0.01), and vision (p=0.019). Relatives’ assessment of subjects’ functioning found the poisoned cohort to have more significant problems than the comparison group in four of 31 items in those same

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

functions and four of 22 personality-scale items (depression, irritability, confusion, and social withdrawal). The mean scores on the MMPI were within normal limits for both groups of subjects but were significantly different on four of 13 scales that were indicative of slightly greater social anxiety and tendencies toward suspiciousness and sensitivity to social stresses. Although those results were consistent across a variety of tests, the OP-poisoned workers may have started out with somewhat lower functioning than the referents, given the group mean difference in tests of vocabulary (which is thought to be more resistant to toxic effects and to be an indicator of pre-exposure functioning). Nevertheless, paired matching and analysis were applied to a variety of factors between poisoned subjects and referents to ensure reasonable comparability and control of confounding. No correction was made for multiple testing.

The other large study (Steenland et al., 1994) evaluated 128 men listed in a California registry for pesticide poisoning and compared them with friends not currently working with pesticides. NB testing involved eight tests from the computer-administered Neurobehavioral Evaluation System (NES2). All poisoned workers had significantly worse performance on the continuous-performance test (a test measuring sustained visual attention and reaction time) and on two of five mood scales (those of tension and confusion). The more severely poisoned (hospitalized patients) performed even worse than referents on the continuous-performance test and the digit-symbol test but not on the mood scales. There was also a significant trend of worse performance on five of 10 NB tests in those who took more days off from work after poisoning. Variables related to current employment with potential pesticide exposure and years of self-reported past pesticide exposure were not found to be associated with outcomes. Insecticide-specific analyses were limited by small numbers of subjects.

Two smaller studies had similar results. Rosenstock and colleagues (1991) studied 36 men hospitalized and treated for work-related OP poisoning in a teaching hospital in Nicaragua (1986–1988). The comparison group consisted of male friends or siblings from the same community who were matched by age and had never been treated for OP poisoning. The examinations were performed in 1989 before the onset of the spraying season to reduce confounding by recent insecticide exposure. NB testing consisted of six of seven domains of the World Health Organization (WHO) core test battery. Symptoms were studied via the Brief Symptom Inventory (BSI) for mood and a 16-item CNS-symptom questionnaire covering memory, concentration, headache, and fatigue. Many of the standardized NB tests were translated into Spanish specifically for this study. The OP-poisoned workers performed significantly worse than the referents on five domains: attention, memory, visuomotor, motor, and symptoms. Individual NB tests on which performance was worse included digit vigilance (attention), digit symbol, Trails A, block design, pursuit aiming, and Santa Ana (Appendix F). There were a higher number of positive responses to the 16-item CNS-symptom questionnaire (7.2 vs 4.7, p<0.01), but no other information was provided about which symptoms were affected. The poisoned workers did not differ from controls in mood symptoms on the BSI. A potential limitation of this study was the use of a comparison group in which 69% had prior exposure to insecticides. That group did not have a history of OP poisoning, but their prior exposure potentially makes it more difficult to find differences between groups. That the investigators found a difference in NB-test performance strengthens the association.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

The smallest study involved 21 Spanish-speaking men with a history of two prior OP poisonings who were referred for NB testing by attorneys who were pursuing worker-compensation claims (Reidy et al., 1992); this population is therefore a specially selected population of poisoned workers and has substantial selection bias. The committee gave little weight to this study in reaching a conclusion.

Summary and Conclusion

In summary, the strongest and largest of the studies demonstrate more NB impairment in OP-poisoned than in comparison workers (Savage et al., 1988; Steenland et al., 1994). A smaller study by Rosenstock and colleagues (1991) reported consistent findings. Results of one test used in all the studies reviewed here—digit-symbol, a test of visuomotor coordination—were shown to be abnormal in OP-poisoned workers. Most of these studies show some effects on mood (such as increased anxiety) and an increase in self-reported CNS symptoms.

Those epidemiologic studies examined the most severely exposed persons. With previously poisoned persons, there is less chance of misclassification in the exposed group. However, exposure misclassification is more likely in the comparison groups because they had substantial past insecticide exposure. That might make it harder to detect differences between exposed and comparison groups. Despite those and other limitations discussed above, there is a consistent pattern of worse performance on NB testing with past OP poisoning. What is not clear is whether long-term effects on NB function are attributable solely to the OP poisoning event or to chronic exposure, inasmuch as the poisoned workers most likely had chronic exposure as well.

The committee concludes, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between exposure to the organophosphorous insecticides under review at doses sufficient to cause poisoning (the acute cholinergic syndrome) and long-term neurobehavioral effects assessed with neurobehavioral testing and symptom reporting. The affected neurobehavioral domains include visuomotor, attention/executive functioning, motor functioning and mood symptoms.

OP Exposure and Neurobehavioral Effects Without a History of Past OP Poisoning

This section evaluates nine studies of NB effects of OP exposure without a history of past OP poisoning (Table 7.6). In most of the studies, workers were exposed for many years and so had chronic exposure. However, exposure details are sometimes sparse, and there is little information about methods of application, environmental conditions, and use of personal protective equipment or clothing.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

TABLE 7.6 Neurobehavioral Effects Without Past History of OP Poisoning

Reference

Population: Exposed

Population: Control

Health Outcomes or Test Type

OP Insecticide Exposure

Adjustment

Results

Limitations

Ames et al., 1995

45 male pesticide applicators involved in California cholinesterase-monitoring program found to have 70% decrease in red-cell AChE or 60% decrease in serum AChE from baseline in records from 1985, 1988, 1989, but with no evidence of frank poisoning

90 male friends who had no history of past pesticide poisoning, past cholinesterase inhibition, or current pesticide exposure; no information on other past OP exposure, but 19% in agriculture

Eight computerized NB tests from NES: mood scales, finger tapping, sustained attention, hand-eye coordination, simple-reaction time, digit-symbol, pattern memory, serial-digit learning; noncomputerized Santa Ana dexterity test, pursuit aiming; regression coefficients to compare controls, exposed provided from regression models

History of use of OP insecticidnes; no information on specifics, but significant enough to lower AChE enough to cause removal from work

Used multiple linear-regression models to adjust for age, grade level, language of test (Spanish or English) for NB testing

For motor coordination tests, models involving ethnicity, age, grade level, height, weight used; no difference in alcoholic drinks, cups of coffee, hours of sleep before testing

No significant differences between referents and exposed on NB tests (except serial-digit performance, in which exposed performed better than referents)

Authors state that workers expected not to have current exposure, but basis for expectation not clear; possible misclassification error because referent group may have had significant OP exposure

Stephens et al., 1995

146 sheep farmers exposed to OP in course of sheep dipping; no dipping; in prior 2 months; contact by random-number selection; 69% response rate

143 nonexposed rural quarry workers from same area, response rate 35%

Eight computer-administered NB tests, General Health Questionnaire, Subjective Memory Questionnaire

Retrospective exposure questionnaire; dose index (average number sheep× number dips/year× number of years using OP insecticides); urine sample for dialkylphosphates to confirm lack of exposure during previuos 48 hours

Age, lifetime alcohol, smoking, computer familiarity, educational level, time of day of testing, first language; key ones included as covariates in multivariate analysis

Farmers significantly worse in tests of motor, visuomotor skills, cognition (simple-reaction time, digit-symbol, syntactic reasoning); dose-effect relationship for syntactic reasoning; farmers more symptomatic on General Health

Specific symptoms not reported; number of years of chronic exposure not reported

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference

Population: Exposed

Population: Control

Health Outcomes or Test Type

OP Insecticide Exposure

Adjustment

Results

Limitations

Fiedler et al., 1997

57 white male New Jersey fruit-tree farmers (pesticide applicators); initial response rate, 39%; no history of pesticide poisoning

23 volunteer blueberry-cranberry growers expected to have little or no exposure to pesticides (but other growers do have OP exposure); initial response rate, 14%); 20 male volunteer hardware-store owners; initial response rate, 8%

15 NB tests, including WRAT-R to estimate premorbid intellectual ability, MMPI-2

Detailed exposure interview to construct lifetime exposure metric; red-cell AchE; potentially low exposures over long time because farmers were owners and family members

Covariance analysis to adjust for confounders; referent group significantly more years of education, better reading test (WRAT); reading-test score used as covariate in analyses of each NB variable

All red-cell AChE normal (but not compared with subjects’ baseline, so acute OP effects less likely); simple-reaction time significantly longer in exposed than in referent and in high than low exposure; in regression analysis, exposure not correlated with reaction time

May have been some misclassification error because OP-pesticide exposure may have occurred in referent group of blueberry-cranberry growers; potential selection bias (farmers with pesticide problems did not want to volunteer)

Bazylewicz-Walczak et al., 1999

26 women performing planting jobs in greenhouses and using OPs but without history of earlier poisoning

25 women not exposed to neurotoxins; employed in kitchens, administrative jobs

Six NB tests (Polish adaptation of WHO NCTB), two symptom questionnaires (POMS, FSSQ); performed before, after pesticide application

OPs include dichlorvos, metamidophos, methidathion, pirimiphos-methyl; some carbamates, synthetic pyrethroids, dithiocarbamates; predominantly OPs measured on clothing, skin washes, air sampling during application midseason; dose “low,” or below 0.010 % of toxic dose; also carbamates, synthetic pyrethroids, dithiocarbamates

Groups similar in sex, age, education, residence, comparison of group characteristics (by ANOVA and chi-square tests) did not reveal significant differences between exposed, control groups

No significant changes over spraying season except increased errors in aiming test; long-term effects of exposure (“group factor”); OP-exposed had slower simple reaction and lower hand-movement efficiency (aiming), more mood (anxiety, depression, fatigue), more CNS symptoms than referents

Limited number of NB tests, sparse detail on some aspects of methods

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference

Population: Exposed

Population: Control

Health Outcomes or Test Type

OP Insecticide Exposure

Adjustment

Results

Limitations

Steenland et al., 2000

191 termiticide applicators from North Carolina registry, including 105 current applicators and eight formerly poisoned; median exposure, 1.8 years (1987–1997)

189 nonexposed referents (106 friends of exposed, 83 state employees)

Nine NB tests: seven from NES, Trails A and B; 24-item symptom questionnaire

Chlorpyrifos, some chlordane (1987–1988)

Regression: age, race, education, current smoking, body-mass index

Past exposure only group: one NB test significant (grooved pegboard for dominant hand); 12 of 24 symptoms more prevalent than in referents

Possible selection bias due to inability to locate majority of exposed population; exposed, referents had occupational history of solvent exposure

London et al., 1997

163 (from original pool of 231) spray men selected from deciduous fruit farms in South Africa

84 nonspraying male laborers from farms, matched on age, educational status

Five NB tests based on WHO NCTB without POMS, FSSQ; other information-processing tests for populations with little education

Long-term exposure calculated with job-exposure matrix; recent exposure assessed with history, plasma cholinesterase within 10 days of NB testing

Multiple linear, logistic regression used for long-term outcomes, exposure, factors of age, education, past history of pesticide poisoning, recent OP exposure, residential exposure, number of years of exposure

Multiple regression models showed small yet significant correlation between lifetime occupational OP exposure and pursuit aiming, Santa Ana Test, one of 21 tests of information processing

NB data present on all subjects, not cases and controls separately; current exposure; cannot separate long-term from short-term effects; no clear comparison of referents or exposed; high alcohol use in all

Gomes et al., 1998

226 migrant farm workers who had worked for at least 2 years in United Arab Emirates; 92 unmatched new farm workers who had worked in farming in another country for at least 2 years

226 referents never occupationally exposed to pesticides, never handled pesticides for domestic use; employed as domestic workers or in shops, offices, or industry

Two NB tests: digit-symbol, aiming; questionnaire: 30-day-recall symptom checklist

Farm workers lived on farms, did tilling, pesticide spraying, harvesting; red-cell AChE measure (timing related to spraying not known); data on duration of exposure collected but not run in regression analysis

Referents matched by age, nationality

Farm workers had statistically more symptoms of dizziness, headache, restlessness, sleeplessness than referents and did worse on digit-symbol test, aiming test; on regression analysis, type of job was significant predictor of symptoms; farm work also predicted low scores on symbol test and aiming test, lower AChE activity; AChE predicted blurred vision

Current exposure; cannot separate long-term from short-term effects

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference

Population: Exposed

Population: Control

Health Outcomes or Test Type

OP Insecticide Exposure

Adjustment

Results

Limitations

Daniell et al., 1992

49 volunteer male apple orchard pesticide applicators from Washington State; three had previous episodes of pesticide poisoning

40 volunteer male slaughterhouse workers; 68% currently nonexposed referent subjects had prior work picking or trimming crops, 27% used pesticides in past

Five NB tests from NES in English, Spanish; computer-administered.

OP pesticides, particularly azinphos-methyl; AChE measured

Stratified by language preference because of differences in educational level, other factors

No important differences between applicators and referents were found on preseason NB tests (when language preference considered); across-season changes resulted in no differences except decrease in digit-symbol test (in Spanish-preference group); no correlation of any NB results with AChE

No vocabulary or other tests to establish baseline CNS functioning; small comparison groups could contribute to difficulties in finding differences

Rodnitsky et al., 1975

23 exposed men: 12 farmers who personally apply OP to crops or animals, 11 commercial pesticide applicators; no information on how selected, must have used an OP compound within 2 weeks of testing date

23 farmers, matched for age, educational background; tested before spraying season or not involved in pesticide handling during spraying season

Five tests: memory tested by verbal-recall task, vigilance by simple-reaction time, signal-processing time, sentence-repetition subtest of Multilingual Aphasia Examination, proprioception (use of spring-loaded button, forefinger)

Regular use of OP insecticides, but many used other types as well (not described) Red-cell and plasma AChE measured, but timing not reported; no comparison with baseline; comparison of group means

Referents matched for age, educational level

Exposed subjects performed as well as referent subjects on five tests; mean plasma ChE of exposed group lower than that of referent group but not below “normal”

Study of acute effects of pesticide exposure, particularly given relative inhibition of AChE in exposed group; no information or adjustment for other possible differences between referent and exposed, such as language or intelligence level

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

One epidemiologic study selected its exposed population on the basis of a past finding of a decrease in AChE during 3 different years. Ames and colleagues (1995) studied 45 pesticide applicators that had participated in the California medical-surveillance program for OP insecticides. All had been found to have substantial declines in AChE, requiring removal from work, even though they had no evidence of frank poisoning (the acute cholinergic syndrome). California law requires removal of a worker when cholinesterase values have fallen 30% or more for red blood cell cholinesterase or 40% or more for plasma cholinesterase from pre-exposure baseline values. The decreases in AChE were noted in medical supervision records for 1985, 1988, and 1989. Duration of exposure was not reported, but workers’ records covered a 4-year period, which implied chronic, if intermittent, exposure. The study stated that none of the subjects was expected to have current cholinesterase inhibition.

The study was part of a larger study of poisoned subjects and had the same comparison group as a previously reported study (Steenland et al., 1994). Each exposed subject was asked to select a friend of comparable age (a “comparison subject;” n=90) not currently exposed to pesticides and without a history of OP-pesticide poisoning or a past decrease in AChE. Little information, however, was provided about the previous jobs or exposures of the comparison subjects, although 19% were reported to have had “current employment in agriculture.” Outcome measures consisted of results of eight NB tests from the computer-administered NES2 (Ames et al., 1995) mood scales, finger-tapping, sustained attention (continuous-performance tests), hand-eye coordination, simple reaction time, digit-symbol, pattern memory, and serial-digit learning. There were also two noncomputerized tests: the Santa Ana dexterity test and the pursuit aiming test (Appendix F).

The AChE-inhibited subjects on the average were older than the comparison group and had lower educational achievement (which may have decreased test performance) and had slightly higher body-mass index, were less likely to be current smokers or drinkers, and drank alcohol less often before testing (which could have improved test performance). Those factors were included in multiple linear-regression models to determine whether the exposed differed from the comparison population with respect to neurologic measures. When the values of the adjusted regression coefficients were examined, the AChE-inhibited subjects were not found to have worse performance on any of the NB measures than the comparison group. The AChE-inhibited group performed statistically better than the comparison group on serial-digit performance. The study did not administer a symptom questionnaire, but it did include a “mood scale” as part of the NES battery. No significant differences were found.

In summary, Ames and colleagues (1995) found no evidence of an association between moderate OP insecticide or n-methyl carbamate exposure, as reflected by prior blood AChE inhibition and effects on NB tests, including mood scales, in the absence of frank poisoning. However, the identification of statistical differences between exposed and comparison groups was rendered more difficult by the fact that almost one-fifth of the comparison group worked in agriculture and thus might have been misclassified.

In other studies of workers handling OP insecticides, discussed below, the exposed groups were made up largely of people who applied pesticides to plants or farm animals. In some studies, the evaluations occurred while the workers were still using pesticides. That made it more difficult to discern short- and long-term effects. Many of the studies used

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

comparison groups with past exposure to farming or pesticides (Cole et al., 1997; Daniell et al., 1992; Fiedler et al., 1997; London et al., 1997; Rodnitzky et al., 1975), which made it more difficult to find differences between the exposed and control groups. All the studies administered NB tests. None assessed the clinical significance of an effect, namely, whether the effect was associated with significantly lower functional activity. Studies also did not attempt to correlate NB test results and symptom findings.

A large study (Stephens et al., 1995) evaluated 146 sheep farmers who were exposed to OP insecticides in the course of sheep dipping and, for comparison, 143 rural quarry workers. The farmers were recruited from registration lists of the Wool Marketing Board for three regions of England and Wales, and the response rate was 69%. The study indicated that the farmers’ OP exposure was chronic, but it did not specify the number of years of exposure. The effects of recent insecticide exposure were eliminated or reduced by using sheep farmers who had not performed sheep dipping for 2 months before testing. Farmers also provided urine samples to test for metabolite (dialkylphosphates) to confirm further the lack of exposure to OPs during the previous 48 hours. Those exclusions were designed to focus on long-term, rather than short-term, effects. Study participants completed the General Health Questionnaire (30-item version) to screen for “vulnerability to psychiatric disorder,” the Subjective Memory Questionnaire (43 items) to measure subjects’ own assessment of memory, a retrospective exposure questionnaire, and eight computer-administered NB tests. The farmers scored significantly worse in three tests of motor skills (that is, simple reaction time, visuomotor skills, digit-symbol substitution), and cognition (that is, syntactic reasoning). The authors note that these effects “are subtle in nature, and…unlikely to be manifest as clinical symptoms.” On the basis of the self-reported exposure data, five dose groups were constructed, and a significant effect of dose group was observed for the syntactic reasoning test (F=5.54, p<0.0001) with ANCOVA. The adjusted mean scores on the Subjective Memory Questionnaire were not significantly different between the groups. The OR calculated from the General Health Questionnaire (in which “caseness” was defined as a report of at least five symptoms) was 1.5 (95% CI=1.31–1.69), indicating that the odds that farmers would report at least five psychiatric symptoms were 50% greater than those of comparison subjects. Further details on types of symptoms are not provided, and symptom findings were not dose-related. The authors reported being unable to rule out the role of social and economic factors in development of psychiatric symptoms.

In another study, Fiedler and co-workers (1997) studied 57 self-employed fruit-tree farmers who applied pesticides; the comparison group consisted of 23 blueberry-cranberry growers thought to have little or no exposure and 20 hardware-store owners. Researchers had found the applicators on a list of New Jersey-licensed pesticide applicators and contacted them by mail. Subjects were given 15 NB tests and the MMPI-2 to assess psychiatric and emotional states. Testing was conducted during the nonspraying season. Red-cell concentrations of AChE were within “normal laboratory ranges” in both exposed and nonexposed, but baseline (pre-exposure) concentrations were not available. Although OP-insecticide exposure might have occurred at the time of evaluation, the normal AChE readings suggest that large, recent OP exposure was unlikely. Simple-reaction time was found to be significantly longer in the exposed than in the comparison group and in the high-exposure than in the low-exposure group. However, the calculated exposure metric was not correlated with reaction time, so no dose-response relationship was shown. The study was relatively small, and the lack of significance on more of the NB tests may be related to that.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

There also may have been some misclassification error: pesticide exposure may have occurred in the comparison group of blueberry-cranberry growers, who may also have used insecticides. The authors speculated that the detection of simple-reaction time as the only abnormal finding might have been a chance positive result of multiple testing.

Bazylewicz-Walczak and co-workers (1999) studied 26 women who performed planting jobs in greenhouses. They used OP insecticides and other pesticides (mostly OPs, but also carbamates, synthetic pyrethroids, and dithiocarbamates) but had no history of past poisoning. The greenhouse workers were compared with 25 women who were employed in kitchens and administrative jobs and had no exposure to insecticides or solvents. Subjects were tested before the spraying season (probably a no-exposure period) and 1 month after the 3-month spraying season. Outcome measures included results of six tests from the WHO Neurobehavioral Core Test Battery (NCTB) and two symptom questionnaires (POMS and the Finnish Subjective Symptoms Questionnaire, FSSQ). Environmental sampling at peak OP-insecticide use estimated that the typical exposure was “low” or below 0.01% of WHO’s toxic dose. Investigators found little change associated with recent exposure during the spraying season except for a significant increase in errors on the aiming test (visuomotor coordination). Analysis of preseason data for what was termed the group effect (comparing exposed and control groups with ANCOVA) indicated possible long-term effects of exposure: a significantly longer simple-reaction time and slower hand-movement efficiency on the aiming test. The exposed group, before the spraying season, also reported significantly more anxiety, depression, and fatigue or inertia on the POMS and more complaints of “absent-mindedness” (p=0.10) and neurologic symptoms (p=0.10) than did referents. Neurologic symptoms were not specified. The limitations of this study were small sample size, limited number of NB tests, and sparse detail on some aspects of methodology.

Steenland and colleagues (2000) conducted a cross-sectional survey of 191 current or former termiticide applicators exposed predominantly to chlorpyrifos and 189 nonexposed controls. The applicators that agreed to participate amounted to fewer than half the eligible applicators. One-third were former applicators; they had not worked with pesticides in the current year (1998). Exposure assessment was based on questionnaire response and job history and was supplemented with measurements of a urinary metabolite of chlorpyrifos. Regression analyses adjusted for age, race, education, and current smoking. Applicators had worked a median of 1.8 years in applying termiticides. (Further details of the study were given earlier in this chapter in the section on peripheral neuropathy.) The investigators tested workers on the NES and two NB tests of eye-hand coordination. The former applicators (n=63) performed significantly worse on the grooved-pegboard test for the dominant hand (a test of motor skills) but not on other NB tests. Formerly exposed applicators also had significantly increased prevalence of 12 of 24 symptoms, but the report does not specify which ones. A major weakness in the study was the potential for selection bias due to nonparticipation during recruitment. Another limitation was potential confounding by occupational exposure to solvents in exposed and comparison groups.

Two other studies demonstrated small positive findings on NB testing but faced challenges in performing assessments in populations with low literacy. London and colleagues (1997) evaluated 163 men who used pesticides on fruit farms in South Africa and 84 nonspraying laborers who also worked on the farms and were matched for age and educational status. The study used the WHO NCTB screening subtests (except for POMS and the Subjective Symptoms Questionnaire, which were excluded because previous studies

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

established poorer performance in workers who had little education). The researchers also used other information-processing tests, which were deemed more appropriate for testing people who had little education. Long-term exposure was calculated with a job-exposure matrix. According to a multiple-regression model, cumulative lifetime occupational exposure was significantly associated with a reduction in the number of correct trials on pursuit aiming and on the Santa Ana test of the nondominant arm. Because workers had current exposure, this study could not distinguish between short-term and long-term effects of OP insecticides.

Gomes and co-workers (1998) compared 226 farm workers in the United Arab Emirates with 226 referents employed in shops and offices, in industry, or as domestic helpers. The comparison subjects were matched for age and nationality and had never been occupationally exposed to pesticides or handled pesticides for domestic use. Outcome measures included the results of a 30-day symptom-recall checklist and two NB tests, the digit-symbol and pursuit aiming. Red-cell AChE was measured at the time of NB testing. The exposed group continued farm work and handling of pesticides during the evaluations. Farm workers had significantly more symptoms of dizziness, headache, restlessness, and sleeplessness than referents, and did significantly worse on the digit-symbol and aiming tests. On regression analysis, farm work was a significant predictor of weakness, abdominal pain, blurred vision, muscular pain, restlessness, and, to a smaller extent, sleeplessness. Farm work was also predictive of low scores on digit-symbol and aiming tests and of low AChE. AChE decrease also significantly predicted weakness and blurred vision, known symptoms of cholinergic excess. Although data on duration of exposure (“period of service”) were collected, that was not reported as a factor in the regression analysis. Given that subjects were continually working and exposed during the study period and that the findings were correlated with a decrease in AChE, it is highly probable that the abnormal NB and symptom findings were related to recent exposure to OP insecticides. It is therefore difficult to separate long-term effects from short-term effects.

Studies by Daniell and co-workers (1992) and Rodnitsky and colleagues (1975) found no NB abnormalities. Daniell and co-workers studied 49 male orchard pesticide applicators in Washington State. They were compared with 40 male slaughterhouse workers (68% had worked in picking or trimming crops, and 27% had used pesticides in the past). The applicators used OP pesticides, mostly azinphos-methyl. NB testing consisted of five computer-administered tests from the NES delivered in English or Spanish. Evaluations were performed before and after spraying season. It was necessary to stratify the analyses by language preference because of differences in educational level between Spanish-speaking and English-speaking subjects. There were no statistically significant differences between pesticide applicators and referents on the preseason NB-test results, which would have reflected long-term exposures.

The study by Rodnitsky and colleagues (1975) was also small, comparing 23 men who applied pesticides with 23 farmers who were not handling pesticides during the time of the evaluation. The exposed population had used an OP insecticide within 2 weeks of the evaluation. Five NB tests were performed. Referents were matched for age and educational level. Red-cell AChE and plasma AChE were measured, but no information was provided as to the timing of the measurement, nor was there comparison with individual baseline values. Group AChE means were compared, and the plasma AChE of the exposed group was lower than that of the comparison group but not below normal. There were no significant

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

differences between exposed and comparison subjects in results of five NB tests. Given that OP-insecticide exposure occurred at least within 2 weeks of testing, this study was focused on detecting effects of recent than of past OP exposure. Small samples, potential pesticide exposure among the referents, and the use of relatively few NB tests may have compromised the ability of these two studies to detect significant NB effects of OP pesticides.

Kilburn (1999) studied people exposed to chlorpyrifos in the indoor setting who had been referred to a testing center. The study included people with past but no current exposures, but the study results are difficult to interpret because they represent a highly selected clinic sample or case series compared with historical referents.

Summary and Conclusion

In summary, four studies were evaluated to draw conclusions about long-term NB effects in persons handling OP insecticides but with no history of earlier OP poisoning. One found no adverse NB effects on the basis of test results in an exposed group with the best documentation of exposure to OP insecticides (Ames et al., 1995). However, the comparison was with friends of the exposed subjects, on whom little exposure history is available and 19% of whom had worked in agriculture, and the possibility of past insecticide or other exposures in the comparison group may have diminished the chances of finding significant differences between exposed people and referents. Another study compared an exposed group of sheep dippers with a large, objectively chosen comparison group that had no pesticide or chemical exposure (Stephens et al., 1995). With control of confounding factors, the study found significant performance decrements in three NB tests of visuomotor (digit-symbol), motor (simple-reaction time), and cognitive (syntactic reasoning) functioning and a dose-response relationship for the latter. The clinical impact of these findings was described by the study authors as subtle and unlikely to be manifest as symptoms. The exposed group was more likely to report psychiatric symptoms, but the authors could not rule out the impact of social and economic factors on symptom reporting.

Several other studies had some positive findings, but also limitations. The study by Fiedler and colleagues (1997) found that the exposed group had significantly worse performance on a single test (simple-reaction time), but there was no dose-response relationship, and there was potential misclassification error in the comparison group; the authors speculated that the positive finding was by chance. Bazylewicz-Walczak and colleagues (1999) found abnormalities on simple-reaction time and on the aiming test, but measured performance on only six NB tests and was sparse on some aspects of methodology. A population-based study of Gulf War veterans (discussed earlier in this chapter) found dizziness and balance symptoms related to pesticide handling, but there was no dose-response relationship or NB testing (Cherry et al., 2001a).

Some committee members believed that the evidence for long-term neurobehavioral effects reached the level of limited/suggestive because they viewed the study by Stephens and colleagues (1995) as a high-quality study with positive findings consistent with findings from two smaller studies of lesser quality (Fiedler and colleagues, 1997; Bazylewicz-Walczak et al, 1999). Other committee members believed that the evidence was inadequate/insufficient as the neurobehavioral test findings were too subtle to reach the level of clinical significance, and only one of the NB test findings (i.e., syntactic reasoning, a test of cognition) showed a dose-response relationship. The nature of the symptom findings from a separate questionnaire were not reported. The findings from the two smaller studies

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

were not sufficiently robust to reinforce those from Stephens and colleagues. Therefore, the committee was unable to reach consensus on a conclusion regarding exposure to organophosphorous insecticides under review at doses insufficient to cause poisoning (the acute cholinergic syndrome) and long-term neurobehavioral effects.

SOLVENTS AND NEUROBEHAVIORAL EFFECTS

Exposure to high concentrations of solvents is known to produce short-term NB effects (Chapter 4), including fatigue and impairment of memory and concentration (Spencer et al., 2000). The question relevant to Gulf War veterans is whether exposure to relevant solvents is associated with long-term NB effects that persist after exposure ceases.9

This section evaluates the evidence of long-term NB effects—as measured by symptom reporting or NB test performance—as a result of exposure to the solvents of interest to the committee. The committee had previously established three inclusion criteria for its evaluation of the occupational insecticide and solvent literature regarding NB effects discussed earlier in the chapter. It is important to remember that one of the criteria noted that the study must include an exposure-free interval of weeks to months before testing of study subjects or a subset of subjects (that is, workers with only past exposure). The purpose of that criterion is to distinguish between long-term (persistent) and short-term effects of solvent exposure. The criterion turned out to be very restrictive as the vast majority of the more than 300 solvent studies in the peer-reviewed literature focus on workers with both current and past exposure. For reasons explained earlier, studies examining current and past exposures together are not able to discriminate between short-term and long-term effects. Applying the three inclusion criteria resulted in the committee’s evaluating seven occupational studies of NB effects.

As background, it is important to acknowledge that the solvent literature refers to a solvent-induced condition termed “chronic toxic encephalopathy,” often described as impairment of cognitive performance. One of the earliest studies of this putative condition linked it to premature retirement of solvent-exposed workers in Scandinavia (Mikkelsen, 1980). The committee evaluated studies of chronic toxic encephalopathy (and similarly named syndromes) if they reported results on its constituent symptoms or NB test performance (for comparability with other studies) and met the committee’s inclusion criteria. One of those studies (Mikkelsen et al., 1988) figured prominently in the committee’s conclusions of limited/suggestive evidence of an NB effect. The committee did not evaluate the evidence of chronic toxic encephalopathy or similar clinical syndromes, because of the lack of uniform application of diagnostic criteria (Rom, 1998; Spencer et al., 2000; van der Hoek et al., 2000). The committee’s approach—to break down putative syndromes into constituent symptoms and effects on performance—is analogous to that taken by Gulf War researchers investigating NB impairment in the absence of a clearly defined syndrome (Appendix A).

9  

The effects of prolonged toluene abuse or intoxication (extremely high exposure over the course of 1 year) persist after exposure ceases (according to case studies; also see Chapter 4).

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Epidemiologic Studies of Exposure to Solvents

There are seven studies discussed in this section (Table 7.7). Mikkelsen and colleagues (1988) conducted comprehensive clinical evaluations of 85 house painters and 85 bricklayers.10 Subjects were recruited by random sampling from local union memberships; a supplementary sample was obtained by random stratified sampling based on symptom reporting in a prerecruitment questionnaire. Participation rates were moderately high (61–75% of those approached). The painters had been in their trade for at least 5 years (mean, 32 years). Half the painters (49%) reported no solvent exposure for at least a year, and only eight reported exposure within 2 days of evaluation. The study included clinical evaluations, 14 NB tests, and a symptom questionnaire. Because it did not separately list or describe the findings from the symptom questionnaire, such results were not included in the committee’s evaluation. A solvent-exposure index was devised by the investigators to reflect the number of years in a particular occupation (house painter, ship painter, industrial painter, and silk-screen painter) weighted by the average daily use of solvents. The adjusted analyses of the relation between solvent exposure and NB tests used age, alcohol use, educational achievement, verbal IQ, the presence of atherosclerosis, and history of neurologic disease as covariates. The results showed that painters had a significantly lower score than bricklayers on two NB tests: the digit-symbol and the block design (time per design, as opposed to correct number, which was nonsignificant). Performance on the digit-symbol test was significantly related to exposure: the most highly exposed performed worst. There was a marginally significant exposure-related trend (p=0.066) for a summary measure based on nine of 14 NB tests. A separate analysis of current vs formerly exposed workers was not conducted, but the overwhelming majority of the workers did not report exposure within 2 days of the evaluation, and 49% had not been exposed for a year or more. In summary, the study found that solvent exposure adversely affected tests of visuomotor and visuospatial skills. The findings for visuomotor and overall NB function were dose-dependent.

One of the major aims of the Mikkelsen et al. (1988) study was to relate solvent exposure to a diagnostic category that the authors termed dementia. A psychologist scored each subject’s degree of dementia. The authors acknowledge that there were no a priori criteria for this category, and it was based on the psychologist’s clinical assessment. Nevertheless, it is important to point out that an appendix to the study described an analysis to isolate the determinants of the psychologist’s dementia score. It found that the clinical assessment of dementia was influenced primarily by NB test performance (85% of the variance) and secondarily by symptom reporting and other clinical information. In addition, the study found that subjects with “suspected,” “mild,” or “more than mild” dementia reported significantly more symptoms of “mental impairment” and performed significantly less well on NB tests than subjects judged to have no dementia and with adjustment for age and verbal ability. The risk of dementia was found to increase with cumulative exposure and was not associated with recent exposure (during the preceding week, month, or 3 months). The study also attempted to assign functional significance to the dementia score. When differences in age and verbal ability were adjusted for, people with greater degrees of dementia were less likely to be employed (the OR for not being professionally active was 1.2 for “suspected dementia,” 2.04 for “mild dementia,” and 21 for “more than mild dementia”).

10  

Bricklayers are not likely to have been exposed to solvents.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

TABLE 7.7 Neurobehavioral Effects and Solvent Exposure

Reference

Exposed Population

Control Population

Health Outcomes or Test Type

Solvent Exposure

Adjustments

Results

Limitations

Mikkelsen et al., 1988

85 painters

85 bricklayers

14 NB tests, neurologic examination, symptom questionnaire

Paint, solvents; exposure index

Age, alcohol, education, verbal IQ, atherosclerosis, neurologic disease, word blindness

Decrease in performance in block design, symbol digit; latter related to degree of exposure

Symptom results not reported separately; clinical assessment not specified

Hannien et al., 1991

21 members of group of monozygotic twins; exposed twins

21 members of group of monozygotic twins; nonexposed twins

13 NB tests, including WAIS, POMS, personality test

Solvents, glues by work history; exposure index

Exposure index

Exposure associated with poorer performance on associative learning, digit span, block design, POMS symptom of absentmindedness

Of exposed twins, 13 of 21 with only prior exposure; only one comparison between current and past exposures on many NB tests

Parkinson et al., 1990

567 female microelectronics workers at plant in Pennsylvania

Different categories of exposure in same plant

Nine “neurologic” symptoms, Hopkins symptom checklist for depression, eight “somatic” symptoms, five NB tests

Solvent exposure in five categories, including two with only past exposure

Seven risk factors, including age, smoking, alcohol intake, obesity, medical disease

Groups with only past exposure had significantly more headaches, weakness or fatigue, rashes, abdominal pain; no difference on NB tests

 

Stollery, 1996

Two groups of women: eight accidentally exposed to toluene, other aliphatic hydrocarbons, 10 with past chronic exposure in same factory

10 workers in the factory, but in packing department

Four NB tests

Toluene, other aliphatic hydrocarbons in acute spill and with past chronic exposure; study 3 years after initial study (Stollery and Flindt, 1988)

Age, duration of employment

Syntactic, semantic reasoning worse in those with acute intoxication

 

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference

Exposed Population

Control Population

Health Outcomes or Test Type

Solvent Exposure

Adjustments

Results

Limitations

Daniell et al., 1993

100 car body repair workers: 29 with past exposure, 71 currently exposed

24 never-exposed car body repair workers

11 tests from NES, symptom questionnaire, after-the-fact outlier score

Paints, solvents; exposure in four groups

Age, education, vocabulary score, alcohol use

Past-exposure group had more symptoms, including lightheadedness, tiredness, irritability, lack of coordination; NES findings nonsignificant

 

Lundberg et al., 1995

135 house painters born 1925–1945, in local unions

71 carpenters born 1925–1945, in local unions

12 NB tests, neurologic and psychiatric symptoms

Paint, solvents; exposure index

Age, alcohol, reading and writing abilities, vocational training, handedness

Only block design was worse in painters than carpenters and was dose-dependent; subset with only past exposure not significantly different from currently exposed

Limited analysis of past-only exposure subset

Daniell et al., 1999

89 retired solvent-exposed workers 62–74 years old: 67 painters, 22 aerospace workers.

127 retired carpenters

21 NB tests, 25 symptoms, Beck depression inventory, psychiatric interview, after-the-fact outlier score

Paints, solvents; weighted by exposure level

Age, education, race, vocabulary score, alcohol

Painters significantly worse on motor score; subgroup of moderately to highly exposed aerospace workers significantly worse on visuomotor speed, motor; painters had significantly higher symptom scores, including fatigue, difficulty in concentrating; painters had more depression symptoms but not diagnoses; painters had higher rates of alcohol use; painters, aerospace workers with medium or high exposure had higher outlier scores, indicating clinical significance

 

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Hanninen and co-workers (1991) investigated previous exposure to organic solvents and NB-test performance in 21 twins discordant for solvent exposure during adult life. The authors used the Finnish Twin Registry that had information on 4300 monozygotic twins. They identified 30 pairs with discordant exposures, but interviews indicated that only 21 twin pairs were truly discordant. An exposure index was constructed from work history; the most common occupations were in painting or gluing (the most commonly used solvents were reported to be aliphatic hydrocarbon mixtures, toluene, and xylene). The median duration of exposure was 13 years, but the degree of exposure during that time was only one-third of the Swedish standard, and this led the investigators to conclude that the overall exposure was low to medium. An additional 28 pairs of twins were included as reference pairs. Of the 28 pairs, 21 were discordant for exposure and 13 of the 21 (62%) had been exposed only in the past. The NB testing battery consisted of 13 tests, including the POMS and personality. The analysis was adjusted for the degree of exposure in the discordant twin. The study found that exposure to solvents was associated with poorer performance on the associative-learning, digit-span, and block-design tests. Absentmindedness was the only symptom on the POMS that was significantly more common among exposed twins. Only one analysis compared formerly exposed with currently exposed twins: using a composite measure of nine NB tests, it was found that previously exposed twins performed somewhat better than currently exposed twins, but the difference did not reach statistical significance, and performance was still poorer than that of the reference twins. There was, however, no direct statistical comparison between the formerly exposed and the reference twins, but only between the formerly and currently exposed twins. The overall conclusion of the study was that solvent exposure affected primarily measures of attention and concentration and of visuospatial relations.

Lundberg and colleagues (1995) investigated 135 house painters and 71 carpenters born in 1925–1945.11 Both groups were affiliated with local trade unions, and most subjects were retired or had left active employment because of disability. The painters had a history of long-term exposure to organic solvents and thus constituted the exposed group. About half the painters (66) had no exposure within a year of evaluation, and this indicates an exposure-free interval. The investigators administered 12 NB tests and a symptom questionnaire. The analysis was adjusted for age, alcohol use, reading and writing abilities, vocational training, and handedness. Because the analysis of symptom questionnaires was not stratified by past vs current exposure, the results were not evaluated by the committee. Of the NB-test results, only block-design performance was worse in painters than in carpenters. The finding was dose-dependent, with larger effects at higher cumulative exposure. However, it is not clear from the publication whether the authors conducted a direct comparison of formerly exposed and reference workers (carpenters). The overall study conclusion was that chronic exposure to solvents was associated with poorer performance on a visuomotor task.

Parkinson and colleagues (1990) studied 567 female microelectronics workers in a Pennsylvania plant. Exposures at the plant included alcohol, acetone, xylene, trichloroethylene, trichloroethane, tetrachloroethylene, benzene, and dichlorobenzene. None of the workers used a respirator. The cohort was divided into five exposure groups the basis of analysis of self-report questionnaires, structured interviews, and a plant tour. Two of the

11  

Another study of the same cohort by Michelsen and Lundberg (1996) is not included here, because there was no analysis of the subset of workers with only past exposure.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

five groups had only past exposures: not exposed in the preceding year (n=173) and exposed in the preceding year but not within 2 weeks of interview (n=60). The mean tenure in the current job was 2.5 years for the entire cohort. The two groups with only past exposure were significantly more likely than the never-exposed plant workers (n=73) to report headaches (OR=2.6), weakness or fatigue (OR=2.97), rashes (OR=2.56), and abdominal pain (OR=2.59). The results were adjusted for seven risk factors as indicted in Table 7.7.

Stollery (1996) investigated the long-term effects of exposure to organic solvents in a followup study of women working in a tennis-ball factory who were exposed to high concentrations of toluene and other aliphatic hydrocarbons as a result of a ventilation accident; atmospheric monitoring was not conducted at the time of the accident, but solvents then used were toluene and SPB-7, a proprietary solvent containing hexane, heptane, octane, and nonane. Solvent exposure occurred over a 3-day period apparently because of failure of the ventilation system. The most severely exposed workers lost consciousness, experienced headaches, felt intoxicated, and had occasional vomiting. Following the problem with the ventilation, the factory underwent major renovations to control workplace contaminants, including the discontinuation of toluene use and its replacement with a water-soluble adhesive. A study, conducted 8 months after the accident, compared seven of the 12 most severely affected women with eight women who had prior chronic exposure in the same factory and to the same solvents but were not near the accident site (Stollery and Flindt, 1988). A group of 10 women who worked in the packing department of the factory were included as a second comparison group because they were not exposed to organic solvents. All three groups were matched on age and duration of employment (9 years). The acute-exposure group also had chronic exposure before the accident. No environmental monitoring was available before or during the accident. After 2–8 months, the acutely exposed women performed worse on paired associates, a word-list learning task, and the Brown-Peterson task of word recall than their peers who regularly worked with the solvents and the nonexposed workers. Three years later, the same investigators evaluated the women and included a few who had not been originally studied (Stollery, 1996). Only syntactic and semantic reasoning differed between the group with previous acute exposure and two other groups (chronic exposure and nonexposed). The earlier study showed diminished performance in memory tasks, but the long-term effects observed in the later study (3 years after the accident) were characterized as a slowing in verbal reasoning with no loss of accuracy. The three groups of women were similar in memory performance. The researchers concluded that slowed verbal reasoning was a long-term effect of the acute intoxication.

Daniell and colleagues (1993) studied 124 car-body repair workers who were exposed to solvents through spray painting or a combination of spray painting and body repair. The sample was divided into four groups: never painted (n=24), past exposure (n=29, over 5.6 years average duration), and two groups with current exposure—medium exposure (n=32) and high exposure (n=39). Study subjects were given 11 tests from the NES and a symptom questionnaire that included nervous-system symptoms. The study also developed a measure to assess the relative functional significance of NB effects. The findings presented here focus only on the outcomes in the previously exposed painters. They reported more symptoms (both at work and in general) than did the never-exposed, although their symptom reporting was somewhat less than that of the currently exposed. Symptoms with the greatest differences between past-exposed or currently exposed and never-exposed

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

were lightheadedness, tiredness, irritability, and lack of coordination. There were no significant differences in NES test results between the past-exposed and the never-exposed. The functional significance of the study-specific measures of NB dysfunction was determined in a novel way; there are no established normative data on clinical relevance of the NES test battery. Performance on each of nine representative NB test measures was categorized as an “outlier” or not on the basis of dichotomization at the worst fifth percentile of scores in the entire study sample (after adjustment for age, education level, alcohol use, and verbal ability). The number of outliers was summed to create a total outlier score. About 15% of subjects were found to have total outlier scores of 2 or more (maximum possible, 9); this score was selected after the fact for dichotomization of the outlier score. Formerly exposed subjects had a distribution of outlier scores that was nearly identical with that of those who had never worked as painters. Thus, the study found no evidence of cognitive impairment persisting after the end of exposure.

Finally, Daniell and co-workers (1999), in a separate study, focused exclusively on retired workers with prior chronic solvent exposure. The study is distinguished by its sole focus on prior occupational exposure, its array of outcome measures, and its method of assessing the clinical significance of the NB effects. The investigators examined NB effects in two formerly exposed groups: 67 retired painters and 22 retired aerospace manufacturing painters and fuel-cell sealers. Each group was compared with 126 retired carpenters who had no previous substantial occupational solvent exposure. Participation rates were relatively low (25–31% of those approached) but did not differ substantially among the three groups. The painters and aerospace workers had worked in solvent-exposed jobs for at least 9 years (mean, over 30 years), and all subjects had been retired for at least 6 months (mean, 6 years). The outcome measures were the results of 21 NB tests, symptom questionnaires (including the Beck depression inventory), psychiatric diagnoses, and outlier scores (which provide an indication of functional significance).

Solvent exposure among the painters was weighted by duration of exposure and intensity derived from a detailed interview. The painters and the aerospace workers had similar cumulative exposure to solvents. Age, alcohol use, educational achievement, race, and vocabulary score were included in the multivariate analysis with exposure level. The 21 NB tests covered six domains, with at least three tests for each domain: language, reasoning, attention, memory, visuomotor speed, and motor. The results reported here emphasize overall scores for a domain rather than individual NB-test results. The painters performed significantly worse than carpenters on overall motor score (three NB test results—finger tapping, grooved pegboard, and simple-reaction time—combined). The painters also showed a dose-response relationship for cumulative exposure and performance on a single test, the block design. Overall motor score was marginally significant (p=0.06) for cumulative exposure. Aerospace workers with medium or high cumulative exposures (n=8) performed significantly worse on overall scores for visuomotor speed—trails A, digit-symbol from WAIS-R, and d2 test (accuracy score)—and motor function. Aerospace workers with low cumulative exposure did not differ from the carpenters on NB tests. With regard to symptoms and diagnoses, the painters were more than twice as likely as carpenters to report three or more symptoms (OR=2.6, 95% CI=1.3–5.1), including fatigue, memory problems, and difficulty concentrating. Painters also had a significantly higher score on the Beck depression inventory, which indicates that they had more depression symptoms, but their overall scores were below the range for a diagnosis of depression. Depression scores

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

were unrelated to alcohol use. Painters were more likely to have clinically diagnosable alcohol dependence or overuse but had no more evidence of NB effects than did aerospace workers. The aerospace workers were no more likely than the carpenters to have higher symptom reporting, except for getting a “high” from chemicals. An outlier test score provided an indication of the functional significance of the NB effects. The outlier score used 17 representative NB-test measures and a threshold based on the worst 10th percentile of adjusted test performance among the carpenters. Most subjects, including 77% of the carpenters, had no more than two outliers (maximum possible, 17). The painters were more likely than the carpenters to have a total outlier score of at least 3 (OR=3.1, 95% CI=1.5–6.2). A higher risk of having an outlier was also seen among the aerospace workers with medium or high cumulative solvent exposure (OR=5.6, 95% CI=1.0–3.8). The painters, in contrast, showed no differential in risk associated with cumulative exposure. The study noted that 85% of the test outliers were 1 or more standard-deviation units below the outlier threshold; this indicates that the outliers at least represented a substantial departure from average test performance. Neither this study nor the 1993 study (Daniell et al., 1993) examined the possible relationship between outlier score and reported symptoms. The authors interpreted their findings, including the dose-dependent effects, as indicating residual CNS dysfunction after the cessation of long-term exposure.

One study evaluated by the committee (Rasmussen and Sabroe, 1986) was difficult to interpret because its analysis excluded about one-fourth of the subjects without explanation. Finally, two studies of Dutch painters by Hooisma and colleagues (1993, 1994) included workers (retired painters) with an exposure-free interval, but the authors did not perform a separate analysis comparing them with currently exposed workers or to a nonexposed group.

Summary and Conclusion

Using strict inclusion criteria, the committee evaluated several studies of chronic occupational solvent exposure and NB effects. The studies, of workers with years-long or career-long exposure, were selected by the committee on the basis of an exposure-free interval to ensure that the effects were long-term rather than short-term. Most studies found a variety of decrements in NB-test performance and greater symptom reporting. The sole study with exclusive focus on formerly exposed workers found poorer performance on motor and visuomotor types of NB tests (Daniell et al., 1999). Many of the abnormal findings displayed a dose-response relationship. Both solvent-exposed groups were more likely to have significantly greater outlier scores for NB performance, an indication of clinical significance. The affected domains and the dose-response relationship were similar to those found by Mikkelsen and colleagues (1988). That well-designed study found a dose-dependent visuomotor deficit and a visuospatial deficit. Daniell and co-workers (1999) also found greater symptom reporting in one exposed group, especially for fatigue, difficulty in concentrating, and depression. Supportive evidence came from a well-designed study by Stollery (1996). This study tracked highly exposed female workers for 3 years after a solvent accident. Before the accident, the workers had chronic exposures. At the 3-year mark, the workers involved in the accident had NB-performance decrements on syntactic and semantic reasoning in comparison with a group that had similar chronic exposure but no exposure during the accident. Finally, the occupational findings reported in this section are consistent with a population-based study of Gulf War veterans (Kang et al., 2002). That study found a

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

cluster of neurologic symptoms related to solvent exposure, although there was no dose-response analysis and no NB testing.

The types of symptoms reported after chronic exposure varied to some degree, as might be expected given the inherently subjective nature of NB symptoms. The most commonly reported symptoms are fatigue, headaches, difficulty in concentrating, in coordination, and mood symptoms. The study of Gulf War veterans found a cluster of symptoms related to dizziness and balance (Kang et al., 2002).

The clinical significance of the NB effects reported here is supported by the study of Daniell and colleagues (1999). It is also consistent with the body of case-control and retrospective cohort studies of chronic occupational solvent exposure, which found an excess of assorted psychiatric or neurologic diagnoses.12 The committee also evaluated that body of evidence. Most of the studies reported some degree of excess risk for clinically significant morbidity associated with a variety of neuropsychiatric diagnoses. Although the body of studies cannot be used to support a single diagnostic entity, because of variable and vague classifications, it is consistent in supporting the overall clinical significance of the NB effects described and evaluated in this section.

The committee concludes, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between past chronic exposure to at least one of the solvents under review, in occupational studies, and neurobehavioral effects. The most consistently affected neurobehavioral domains are visuomotor and motor functioning. The most consistently reported symptoms in occupational solvent studies are fatigue, headache, and difficulty in concentrating, in coordination and mood symptoms.

INSECTICIDES AND NEUROLOGIC DISEASES

This section examines the relationship between exposure to insecticides and neurologic diseases: Parkinson’s disease, amyotrophic lateral sclerosis, and Alzheimer’s disease. Studying the relationship between exposure and neurologic diseases poses methodologic challenges, including diagnostic uncertainty, presumed long latency, and concern about the reliability of self-reporting of past exposure, especially in patients with cognitive impairment or difficulty in communicating. The committee considered only studies that specifically examined exposure to insecticides, as opposed to the broader category of pesticides, because the latter includes herbicides and fungicides. Most studies were concerned with occupational exposure rather than with residential or leisure exposure. The committee found no case-control or cohort studies that specifically examined the relationship between insecticide exposure and multiple sclerosis.

12  

Axelson et al. (1976), Brackbill et al. (1990), Cherry et al. (1992), Labreche et al. (1992), Lindstrom et al. (1984), Mikkelsen (1980), Nelson et al. (1994), Olsen and Sabroe (1980), Palmer et al. (1998), Rasmussen et al. (1985), Riise and Moen (1990), Riise et al. (1995), van Vliet et al. (1989, 1990).

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Parkinson’s Disease and Insecticide Exposure: Background and Epidemiologic Studies

Parkinson’s disease (PD) is a chronic, progressive neurologic disease that affects about 40,0000–60,0000 people in the United States. The disease generally afflicts people over 45 years old. As the population ages, the prevalence of PD in the United States is projected to increase to 1.3 million by the year 2040 (Muir and Zegarac, 2001).

PD is characterized by clinical manifestations that include tremor, bradykinesia, rigidity, and postural instability. When those manifestations occur without a progressive course or other manifestations, such as dementia or ataxia, they are more broadly denoted as parkinsonism. Some neurotoxicants can cause a Parkinsonian-like syndrome, such as manganese, carbon monoxide, and the contaminant in synthetic heroin, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Manganese damages a different part of the CNS than does MPTP. Furthermore, MPTP neurotoxicity is called Parkinsonian-like, rather than Parkinson’s Disease in most of the literature.

The discovery of MPTP-induced parkinsonism in 1982 stimulated a new line of investigation into pesticides in the etiology of PD. Driving that line of investigation is the structural similarity between the biologically active form of MPTP, 1-methyl-4-phenylpyridinium ion, MPP+13 and the herbicide paraquat, widely used for the control of weeds.

The etiology of PD is not well understood. The body of epidemiologic evidence relating pesticides to PD comes from case-control and ecologic studies. In a recent ecologic study, Ritz and Yu (2000) showed a 19–47% higher mortality from PD than from ischemic heart disease in California counties where pesticide exposure was reported. Genetic factors are also thought to play a role in the onset of PD, but their contribution appears to decrease after the age of 50 years (Tanner et al., 1999). Genetic factors may contribute to susceptibility by influencing the toxic effect of pesticides on the CNS. A complex, multifactorial etiology of PD is suggested by Hubble and colleagues (1993), who found that the combination of pesticide exposure, family history of neurologic disorders (including PD, Alzheimer’s disease, tremor, or palsy), and depression results in an extremely high probability of developing PD. In the absence of those combined factors, the probability of developing PD was significantly lower.

Many epidemiologic studies have attempted to ascertain environmental risk factors for the development of PD. Respondents in epidemiologic studies often have difficulty in remembering specific agricultural exposures, so many investigators have simply asked generic questions about exposure to “pesticides.” Much of the literature deals with pesticide exposures that may include exposure to herbicides as well as to the insecticides of interest to the committee. In its evaluation, therefore, to ensure that the study groups were as homogeneous as possible, the committee included only studies of insecticides, rather than of the umbrella category of pesticides; studies with case-control or cohort designs; and studies

13  

Since its discovery, much insight has been gained into the mechanism of MPTP toxicity. Understanding this mechanism may shed light on a possible relationship between other exogenous exposures and parkinsonism. MPTP enters astrocytes, where it is converted to the active form, MPP+, by monoamine oxidase B. MPP+ enters the dopaminergic neurons of the nigrostriatal system through the reuptake mechanism. In the neuron, MPP+ blocks mitochondrial respiration at the complex I ubiquinone binding site, a blockade that results in cell death (Cleeter et al., 1992). Loss of neurons in the nigrostriatal system is the primary pathologic finding in PD.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

of PD rather than of the more general diagnosis of parkinsonism.14 The committee excluded studies that listed “farming” as an occupation if they did not specify the nature of the exposure.

Numerous case-control studies addressed the relationship between pesticide exposure and PD. Those studies evaluated patients for exposure via interview or questionnaire and then compared the prevalence of exposure among cases with that among a group of nondiseased controls. Of the case-control studies, the committee identified six as meeting its inclusion criteria. The six studies (Table 7.8) typically obtained information about past exposures from cases and controls and then developed a job-exposure matrix. Because exposure data rely for the most part on self-reports, there is the possibility of misclassification bias, a common limitation of case-control studies. In addition, the fact that people with PD may be more motivated to remember exposures that they perceive as being responsible for their disease can result in recall bias.

Butterfield and colleagues (1993) studied 63 patients from Oregon or Washington with early onset PD and 68 controls diagnosed with rheumatoid arthritis. They found PD to be positively associated with insecticide exposure over 10 times per year (adjusted OR=5.75, p=0.001). The study used good diagnostic criteria, but exposure was defined as having occurred at any time before diagnosis (as long as it was at least 10 times per year). That might have led to inclusion of exposure that occurred after the onset of PD, which would bias the estimate of effect. Another limitation was that only 69% of eligible cases and only 41% of controls participated. If a decision to participate was related in some way to the exposure, the estimate of effect could be biased. Finally, no information on dose-response relations was reported, and this limits the interpretation of the results.

The work of Gorell and colleagues (1998) was judged by the committee as the most methodologically rigorous study of the relationship between insecticides and PD. This study of a Detroit primary-care population in a single health system found a strong positive association between occupational insecticide exposure and PD (adjusted OR=3.55, 95% CI =1.75–7.18). The subset of people with occupational exposures of over 10 years had higher odds ratios than the subset with less than 10 years. Advantages of the study were explicit diagnostic criteria and inclusion of subjects who had at least one visit to a primary-care specialist within 5 years before enrollment (this ensures matching of cases and controls with respect to access to care). Two other advantages were its exclusion of cases and controls with a low score on the Mini-Mental Status Examination to reduce inclusion of cognitively impaired study subjects and its exclusion of controls who had symptoms that might be early signs of PD. One limitation was inclusion of all exposures until the time of diagnosis, which would include post-onset exposure. In addition, the risk-factor questionnaire focused on occupational exposure, which could have alerted subjects to the objective of the study. The authors were unable to assess the independent effects of herbicides and insecticides, because samples were small.

14  

The inclusion of parkinsonism studies in the evaluation might have attenuated any possible associations between insecticides and Parkinson’s disease. The committee separately evaluated two studies of insecticide exposure and parkinsonism. Both were case-control studies, and both found no association in subgroups with insecticide exposure (Engel et al., 2001, Herishanu et al., 1998).

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

TABLE 7.8 Case-Control Studies of Parkinson’s Disease and Insecticide Exposure

Reference, Country

Cases

Controls

Exposure Determination

Insecticide Exposure

OR (95% CI or p)

Adjusted OR (95% CI or p)

Comments

Butterfield et al., 1993

63 patients with early-onset PD; diagnosed before age 51 years; referred by physicians or other patients;

68 persons diagnosed with rheumatoid arthritis; frequency-matched for sex, birth year, year of diagnosis;

Self-report questionnaire;

Ever lived in fumigated house

3.29 (p=0.068)

5.25 (p=0.045)

Adjusted for age, age at diagnosis, race, sex, educational level, family history of PD;

US

Reconstruction of employment, exposure history

Ever lived within 1/4 mile of agricultural spraying

1.99 (p=0.106)

1.99 (p=0.099)

 

Mean duration of disease 9 years from diagnosis;

41% response

 

Insecticide exposure over 10 times per year

4.04 (p=0.002)

5.75 (p=0.001)

7.24 (2.29–22.92)

also adjusted for smoking;

 

69% response

 

4.30 (1.35–13.67)

also adjusted for eating seeds and nuts, rural residency, and past residence in fumigated house;

 

Participation very low in cases, controls

Gorell et al., 1998

144 PD patients receiving primary medical care from single health system; diagnostic criteria used;

MMSE result under 24 excluded;

464 controls frequency-matched for age, race, sex; controls reporting symptoms of potentially undiagnosed PD excluded;

MMSE result under 24 excluded

Questionnaire administered face to face by trained interviewers;

Residential insecticide spraying

1.02 (0.62–1.65)

1.03 (0.63–1.7)

Adjusted for race, age, sex, smoking status;

US

Gardening insecticide exposure

0.88 (0.58–1.36)

0.90 (0.58–1.38)

Questionnaire distinguished insecticide from herbicide, fungicide exposures;

Lifetime-exposure measure calculated from responses;

Farm residence insecticide exposure

1.4 (0.76–2.59)

1.28 (0.69–2.4)

Mean duration of disease 2.4 years from diagnosis

Exposure up to time of diagnosis

Occupational insecticide exposure:

 

 

Only four patients, 11 controls could identify one or more subclasses of insecticides they were exposed to

Overall

3.11 (1.56–6.15)

3.55 (1.75–7.18)

<10 years

2.39 (0.89–6.4)

>10 years

5.80 (1.99–16.97)

Adjusted for farming

3.15 (1.54–6.49)

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference, Country

Cases

Controls

Exposure Determination

Insecticide Exposure

OR (95% CI or p)

Adjusted OR (95% CI or p)

Comments

Hertzman et al., 1994

127 PD patients identified by their physicians, examined by neurologist to confirm diagnosis;

121 patients with cardiac disease identified by their physicians (79% participation rate); 124 randomly selected from list of voters (61% participation rate)

Trained interviewers blinded to study hypothesis;

Ever exposed to insecticides:

 

Pesticides associated with fruit-tree industry; cue cards with details on 79 specific pesticides presented to respondents;

men

Canada

vs cardiac controls

0.62 (0.28–1.38)

 

Exposure before date of onset

vs voter controls

0.33 (0.12–0.90)

 

Mean duration of disease 7 years from onset

women

 

 

Results also presented for OPs, OCs, carbamates (none significant);

vs cardiac controls

0.65 (0.27–1.57)

 

vs voter controls

0.41 (0.19–0.88)

 

 

Protective findings; inconsistent with all other studies

Seidler et al., 1996

380 PD patients from nine neurology clinics staffed by neurologists with special interest in PD;

379 control subjects matched by age, sex; recruited from same neighborhood with random route method;

Experienced interviewers blinded to hypothesis;

Insecticide Use:

 

 

Adjusted for smoking and education;

vs neighborhood controls:

Germany

Complete residential history with detailed pesticide exposure, including names of agents where possible;

never

 

1.0

“Dose-years” calculated by assigning a 1–3 frequency-of-usage weight to each year of exposure;

1–40 dose-years

 

1.4 (0.9–2.1)

Patients 65 years old or less at diagnosis;

376 controls recruited from elsewhere in same region

41–80 dose-years

 

1.5 (0.9–2.5)

>80 dose-years

 

1.6 (0.7–3.4)

 

 

 

p-trend=0.12

Mean duration of disease: 5.6 years from onset, 3.7 years from diagnosis

vs regional controls:

 

 

No mention of results of using job-exposure matrix

never

 

1.0

Job-exposure matrix to assess occupational exposures

40 dose-years

 

1.8 (1.1–2.7)

41–80 dose-years

 

2.5 (1.4–4.5)

80 dose-years

 

2.1 (0.9–4.8)

 

 

p-trend=0.001

Organochlorines ever:

 

 

vs neighborhood controls

 

1.6 (0.4–6.2)

vs regional controls

 

5.8 (1.1–30.4)

Alkylated phosphates and carbamates ever:

 

 

vs neighborhood controls

 

1.8 (0.9–3.3)

vs regional controls

 

2.5 (1.3–4.6)

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference, Country

Cases

Controls

Exposure Determination

Insecticide Exposure

OR (95% CI or p)

Adjusted OR (95% CI or p)

Comments

Semchuk et al., 1992

130 patients selected from population-based register of neurologist-confirmed PD cases;

260 age- and sex-matched community controls selected by random- digit dialing

Lifetime occupational history with details about dates of chemical exposure on each job, exposures after age 15, jobs held over 1 month;

Occupational insecticide use

2.05 (1.03–4.07)

1.48 (0.68–3.24)

Adjustment for herbicide use;

Canada

Occupational use of insecticides between ages 46–55 years

3.50 (1.03–11.96)

 

ORs consistently higher for herbicide than insecticide exposure; only herbicide use consistently associated in linear-regression models;

Demented excluded (on basis of clinical assessment);

 

Mean duration of disease: 7.8 years from diagnosis, 10 years from onset

 

Interviewers, subjects blinded to study hypotheses

No association with duration of pesticide exposure

Stern et al., 1991

69 patients with PD; onset before age of 40 years; identified from neurology departments at two university hospitals;

149 age- and sex-matched, randomly selected from nonfamily acquaintances; nominated by cases

Structured interview, including lifetime residential histories;

Exposure to insecticides in home, yard, garden, neighborhood by members of household or professionals ever

0.7 (0.3–1.4)

0.5 (0.2–1.1)

Adjustment for smoking, prior head injury, previous rural residence;

US

Apparently, no data on occupational exposures collected

 

Very broad exposure measure; 89% of respondents reported insecticide exposure;

80 with PD onset after age 60 years, randomly chosen from patients at one institution

Among young subset, exposure to any insecticide

0.6 (0.2–1.7)

 

Among older subset, exposure to any insecticide

0.8 (0.3–2.1)

 

Choice of controls based on nomination by cases may have resulted in too-similar control group

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Hertzman and colleagues (1994) studied 127 Canadian PD patients identified by their physicians and compared them with cardiac-disease controls and with controls selected from electoral lists. The study made the most aggressive attempt to assess exposure to specific agents. It was conducted in a region with a high prevalence of orchard chemicals and an agricultural office, which provided records of specific pesticides and dates of marketing. From that information, the investigators created cue cards with full descriptions of 79 agricultural chemicals to aid subjects’ memories. Analysis was performed for pesticides in general, insecticides in general, and specific insecticide classes. The study found a positive association between pesticide exposure and PD. But the opposite—a protective effect—was found specifically for insecticide exposure: the confidence intervals for PD were entirely below 1 for both men and women with past insecticide exposure compared with electoral-list controls. No positive associations were found for exposures to OPs, organochlorines, or carbamates. The study was limited by differential ascertainment between cases and controls. One control group was restricted to voters, but cases were not restricted in this manner. That might be important if cases included migrant workers or other noncitizens working in orchards; such inclusions would tend to increase the likelihood of exposure in the cases. The finding of a protective effect of insecticides is inconsistent with findings from other studies discussed in this part of the chapter.

Seidler and colleagues (1996) studied 380 PD patients from nine neurology clinics in Germany. The authors did not find positive associations between insecticide exposure and PD when they used neighborhood controls, but they did when they used regional controls (although not at the highest dose). They also found a positive association with exposure to organochlorine and alkylated phosphates or carbamates. The study’s advantages were large size, good diagnostic criteria, blinding of interviewers to the study hypothesis, and categorization of pesticide exposures by a toxicologist. Its limitations were recruitment of cases from clinics with a “special interest in PD,” which might result in inclusion of unusual cases. Regional (but not neighborhood) controls were recruited by random selection from electoral rolls. If there were demographic differences between cases and controls, they may be related to exposure, thereby increasing the likelihood of observing a positive association. Another problem was that cases were asked about exposure that occurred at any time before diagnosis, but controls were asked about exposure only one year prior to interview. Thus, cases were asked to remember exposure over a longer period, which might have attenuated effects. Another limitation was that the results from analyzing exposure with a job-exposure matrix were not reported.

Semchuk and colleagues (1992) studied Canadian patients from a population-based registry and community controls. They found a positive association with insecticides, but the association disappeared after adjustment for occupational herbicides. The study had the advantages of being population-based, of excluding people with dementia, and of restricting analysis to exposures with long latency. One limitation was having the primary author review occupational history, which introduced the possibility of bias. Another was the long disease duration in cases (mean duration from onset to evaluation, 7.8 years), which introduced the problems associated with patients’ recall of predisease risk factors and the potential for survival bias.

Stern and colleagues (1991) studied patients with early-onset and late-onset PD. They found no positive association with insecticide use in the home, yard, or garden, but

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

their findings were limited by lack of occupational-exposure information and by the separation of exposure into “any exposure” and “none.”

Summary and Conclusion

The six studies reviewed here offer conflicting results about the relationship between insecticides and PD. Three of the studies found no association (Seidler et al., 1996; Semchuk et al., 1992; Stern et al., 1991), one found a protective effect (Hertzman et al., 1994), and two found a positive association between insecticides and PD. Of the two positive studies, Butterfield and colleagues (1993) reported the highest odds ratios but was limited by low participation rates, which were considerably different between cases and controls. The best-designed study, Gorell and colleagues (1998), was hampered by its consideration of all exposures until the time of diagnosis, which could have included post-onset exposure.

The studies varied widely in reliability of their estimates of exposure. Investigators in some of the studies took more-detailed residential or occupational exposure histories and attempted to determine whether higher exposure led to increased risk of PD. Results, again, were mixed: two studies showed higher odds ratios at higher exposures (Butterfield et al., 1993; Gorell et al., 1998), and two found no association with duration of exposure to insecticides (Hertzman et al., 1994; Semchuk et al., 1992). Overall, because of the potential for bias, including confounding, these studies do not provide good evidence of an association between insecticide exposure and PD.

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 insecticides under review and Parkinson’s disease.

Amyotrophic Lateral Sclerosis and Insecticide Exposure: Background and Epidemiologic Studies

Amyotrophic lateral sclerosis (ALS) is a rapidly fatal neurologic disorder characterized by progressive muscle weakness, muscle atrophy, and fasciculations. The disease is associated with degeneration of motor neurons in the spinal cord. Because ALS affects only motor neurons, the disease does not impair a person’s mind, personality, intelligence, or memory. Nor does it affect a person’s senses. About 20,000 people living in the United States are afflicted with ALS, and an estimated 5000 people are diagnosed each year. ALS is most commonly diagnosed in people 40–60 years old, but younger people can also develop it. Men are affected slightly more often than women. Of all ALS cases, 90–95% are sporadic with no known risk factors and 5–10% are inherited. Although the etiology of ALS is unknown, some epidemiologic studies have suggested a relationship between lead exposure and ALS, because toxic lead concentrations can produce symptoms similar to those of ALS (Kamel et al., 2002). In North America, investigators generally use the term ALS in reference to three motor neuron diseases: ALS (the most common), progressive bulbar palsy (PBP), and progressive muscular atrophy (PMA). In Europe, investigators refer to ALS and classify the two other diagnoses as subtypes of the more generic term motor neuron disease (MND). PBP has the most rapidly fatal course, and PMA the most benign (Verma and Bradley, 2001). If the three diseases have different etiologies, differing case mixes within studies would render comparisons across studies difficult. To

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

date, there is no evidence that the etiologies differ, although no studies have addressed this specific issue.

The committee identified five case-control studies that examined the association between ALS and exposure to agricultural chemicals. Four did not specifically address exposure to insecticides but used broader categories, such as “pesticides” or “agricultural chemicals,” in their characterization of exposure; and they did not report positive associations (Chancellor et al., 1993; Deapen and Henderson, 1986; Granieri et al., 1981; Savettieri et al., 1991).

The fifth study did specifically address exposures to insecticides. McGuire and colleagues (1997) identified all newly diagnosed ALS patients in a three-county region in western Washington State using a surveillance system. Two controls were matched to each case with one of two techniques: random-digit dialing for cases under 65 years old and Medicare eligibility lists for older cases. The participants were 174 patients with ALS and 348 controls. Exposure information was obtained with a detailed interview that gathered information on all jobs held for at least a year since the age of 15 years. Job information included detailed descriptions of tasks performed and hours worked per week. Subjects also reported on exposures to 28 specific chemical agents, use of protective equipment, and exposure to any accident, spill, or explosion. Information about home activities and hobbies was also gathered. A panel of four industrial hygienists, blinded to the patient’s disease status and self-reported assessment of exposure, rated workplace exposure. ALS was found to be moderately associated with the hygienist panel’s assessment of insecticide exposure (OR=2.1, 95% CI=1.1–4.1) but not with the patients’ self-reports (OR=1.0, 95% CI=0.5–1.8). A dose-response gradient with insecticide exposure was found only for men. In a conditional logistic-regression analysis adjusting for age and education and using the hygienists’ assessments of exposure, the OR for low exposure was 2.0 (95% CI=0.5–7.7), and it rose to 2.8 with high exposure (95% CI=1.1–6.8). The study, however, had several limitations. Cases were less educated than controls, possibly creating a disparity that may have led to a selection bias in the direction of overestimating an effect. There was a higher refusal rate in controls than in cases, which might have resulted in a selection bias of unknown direction. The authors themselves comment that their findings are exploratory.

None of the reports about Gulf War veterans published in peer-reviewed journals specifically addressed ALS. However, a large government-funded epidemiologic study provides preliminary evidence that veterans who served in the Gulf War are nearly twice as likely as their nondeployed counterparts to develop ALS (Feussner, 2002). The committee was unable to obtain preliminary copies of the report for review and therefore could not evaluate its findings in reaching conclusions about insecticide exposure and ALS.

Summary and Conclusion

Only one peer-reviewed study (McGuire et al., 1997) expressly examined the relationship between insecticides and ALS. That study provided evidence of a relationship, but the possibility of selection bias resulting in an overestimation of effect cannot be excluded. There were no other studies with which to compare results.

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 insecticides under review and Amyotrophic Lateral Sclerosis.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Alzheimer’s Disease and Insecticide Exposure: Background and Epidemiologic Studies

Alzheimer’s disease (AD) is a neurodegenerative disease marked by progressive impairment in cognition and memory. It is the most common form of dementia in older people, with a prevalence of about 5% over the age of 65 years. AD is more common in women than in men. A variety of risk factors have been studied, but only age, family history, head trauma, fewer years of formal education, and presence of the apolipoprotein 4 allele show consistent results (CSHA, 1994; Hendrie, 1998). Nonsteroidal anti-inflammatory drugs and estrogen have been reported to be protective in a few studies (Paganini-Hill and Henderson, 1994; Wolfson et al., 2002). There is no evidence of a geographic gradient in incidence or prevalence. Because of the cognitive deficit in those suffering from AD, epidemiologic studies require the use of proxy respondents to obtain information on past exposure and lifestyle factors (Weiss et al., 1996).

In reviewing the evidence of insecticide exposure as a risk factor for AD, it is worth noting that one particular OP insecticide, metrifonate, has been investigated in the clinical setting as a potential treatment for AD. Because its mechanism of action involves the depletion of acetylcholine (Ormrod and Spencer, 2000), metrifonate was proposed to raise acetylcholine through its action as an irreversible acetylcholinesterase inhibitor with relatively low potency (Spencer et al., 2000). Metrifonate (under the insecticide name trichlorfon) had been tested in clinical trials, but the manufacturer withdrew its application to the Food and Drug Administration in 2000, when the trials uncovered a small number of cases of respiratory paralysis. Metrifonate has been used outside the United States since the 1960s by the World Health Organization to treat schistosomiasis.

The committee identified two studies that focused specifically on the relationship between insecticides and AD. Several other epidemiologic studies examined the relationship between the disease and pesticides but not insecticides (CSHA, 1994; French et al., 1985). Two other studies used occupational classes (such as farming) as proxies for exposure and so were too general for the committee’s consideration (Amaducci et al., 1986; Schulte et al., 1996).

Gauthier and colleagues (2001) studied environmental risk factors in a randomly selected group of 1924 older residents of Quebec, Canada. Of this group, 68 cases were compared with nondemented controls through structured questionnaires of subjects and proxy respondents. The investigators also used residential histories and agriculture census histories for herbicide and insecticide spraying (1970–1991). The study found no association between past insecticide (or herbicide) exposure and AD.

Gun and colleagues (1997) examined past occupational risk factors in 170 patients with AD and 170 medical-practice-based controls (matched for age and sex). Occupational exposures included “organophosphates” and “hydrocarbon solvents.” Occupational histories were gathered from informants (proxies) for both patients and controls, and exposure was assessed by a panel of occupational hygienists (blinded to case or control status). The study found no association between OP insecticides and AD.

Summary and Conclusion

The two case-control studies reviewed found no associations between insecticides and Alzheimer’s disease (Gauthier et al., 2001; Gun et al., 1997). Other studies did not

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

specifically examine insecticide exposure but focused on the broader category of “pesticides.” The occupational studies reviewed used occupations as surrogates for exposure, but the committee was unable to determine whether exposure relevant to the Gulf War had occurred.

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 insecticides under review and Alzheimer’s disease.

SOLVENTS AND NEUROLOGIC DISEASES

This section addresses the association between exposure to solvents and four neurologic diseases: Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and Alzheimer’s disease. Those diseases have distinct sex and age distributions and pose numerous challenges to epidemiologic research, such as diagnostic uncertainty, presumed long latency, and concern about the reliability of self-reported exposure information from patients with cognitive impairment or inability to communicate. The committee evaluated the body of evidence on solvent exposure and neurologic disorders almost exclusively from case-control studies. The design of the studies is inherently subject to a number of potential biases, some of which cannot be avoided. Those limitations are described in the context of each study that the committee evaluated.

Parkinson’s Disease and Solvent Exposure: Epidemiologic Studies

PD is described earlier in this chapter. The committee evaluated studies only with PD as the outcome measure rather than the more generic diagnosis of parkinsonism, as explained earlier. Only two studies were found to be sufficiently rigorous in design to be useful in providing evidence on the relationship between solvent exposure and PD (Hertzman et al., 1994; Seidler et al., 1996). One of them (Hertzman et al., 1994) focused on pesticides and presented little pertaining to solvent exposure. Both were case-control studies that used prevalent cases (Table 7.9).

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

TABLE 7.9 Parkinson’s Disease and Solvent Exposure

Reference, Country

Cases

Controls

Exposure Determination

Solvent Exposure

OR (95% CI)

Adjusted OR (95% CI)

Comments

Hertzman et al., 1994

127 PD patients identified by their physicians, examined by neurologist to confirm diagnosis;

121 patients with cardiac disease identified by their physicians;

Trained interviewers blinded to study hypothesis;

Ever exposed to solvents in occupation:

 

 

Electoral list would have to be citizens but no such exclusion for cases;

men:

Canada

vs cardiac controls

1.80 (0.91–3.58)

vs voter controls

2.16 (1.07–4.37)

124 randomly selected from list of voters

Exposure before onset

Primary focus on pesticides

Mean duration of disease 7 years from date of onset

women:

vs cardiac controls

1.34 (0.42–4.25)

vs voter controls

1.20 (0.48–3.01)

Seidler et al., 1996

380 PD patients from nine neurology clinics staffed by neurologists with special interest in PD;

379 control subjects matched by age, sex recruited from same neighborhood with random-route method;

Experienced interviewers blinded to hypothesis;

Solvents:

 

Adjusted for smoking and education;

vs neighborhood controls:

Germany

never

1.0

in free time

2.6(1.2−5.4)

No associations found when job-exposure matrix used as measure of exposure

Complete residential history with detailed exposure, including names of agents where possible;

at work

1.6(1.1−2.4)

Patients 65 years old or less at time of diagnosis;

376 controls recruited from elsewhere in same region with same methods

vs regional controls:

never

1.0

in free time

3.4(1.5–7.5)

 

71% participation rate;

at work

1.8 (1.2–2.7)

Mean duration of disease: 5.6 years from onset, 3.7 years from diagnosis

 

 

 

Job-exposure matrix to assess occupational exposures

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Hertzman and colleagues (1994) studied 127 Canadian PD patients identified by their physicians and compared them with cardiac-disease controls and healthy controls drawn from electoral rolls. The latter control group was chosen to reduce the impact of potential recall bias. Exposure was ascertained in face-to-face interviews. The main focus of the study was on pesticides, but there was one exposure question about occupational exposure to solvents. Exposure was defined only as ever or never exposed before reported onset of disease. When cases were compared with controls from the electoral rolls, a moderate association between occupational exposure to any solvents before disease onset was found for men (OR=2.16, 95% CI=1.07–4.37). No association was found for men in comparison with the cardiac-disease controls or for women in comparison with either control group. The validity of the association—men with PD compared with electoral-list controls—is limited for three reasons. The first is a difference in findings depending on the control group; the association only with the electoral-list controls suggests that the finding is a result of recall bias from underreporting of exposure by this group of controls. The second is the use of the electoral list as the source of the healthy control group. Noncitizens were excluded, and this exclusion was not applied to the case group. If citizenship status is related in some way to the probability of being exposed to solvents, the comparison between cases (including noncitizens) and controls (excluding noncitizens) may be biased. It is difficult, however, to predict the direction of the bias in terms of either underestimating or overestimating the effect of solvents on PD occurrence. The third is that the focus of this study was the relationship between pesticides and PD, not solvents and PD. As a result, the method describing solvent-exposure assessment is only briefly presented, and the analysis is limited.

Seidler and colleagues (1996) studied 380 PD patients from nine neurology clinics in Germany. The UK PD Society Brain Bank clinical diagnostic criteria were used to screen subjects for eligibility. Potential cases with dementia or secondary parkinsonian syndromes were excluded. Cases were compared with two control groups that were population-based and were recruited with the random-route procedure in which the interviewer contacts every second household, starting with the patients. In addition to the natural matching on residence, the controls were matched on sex and age ±3 years. The investigators elicited information on exposure to “solvents”-never, in free time, or at work. Controls were asked to report exposure at any time at least a year before interview, but cases reported exposure at any time before diagnosis. Because the cases had average illness duration of 3.7 years, that discrepancy meant that controls did not have to remember as far back. A detailed occupational history was also collected from each study subject, from which a panel of experts constructed a job-exposure matrix. Conditional logistic regression was used to analyze results, and smoking and education status were included as covariates in the model.

Seidler and colleagues (1996) reported positive associations regardless of whether the self-reported exposure was to solvents at work or in free time. Contrary to expectations, free-time exposure resulted in higher odds ratios than did work exposure. When the exposure assessment using the job-exposure matrix was used, no association was found. It is generally accepted that although a job-exposure matrix is itself based on information obtained from self-reports, it provides a more accurate measure of occupational exposure. The discrepancy in findings between the two types of exposure variables (self-report vs job-exposure matrix) suggests recall bias through possible underreporting of exposure in

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

controls relative to cases. Other study limitations are discussed in the section above on insecticides and PD.

Summary and Conclusion

Two studies found an association between past exposure to solvents and PD, but both studies were likely to have been subject to recall bias. It should be noted that little attention has been focused on solvent exposure as a risk factor for the occurrence of PD.

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 Parkinson’s disease.

Amyotrophic Lateral Sclerosis and Solvent Exposure: Epidemiologic Studies

This section addresses the association between solvent exposure and ALS. Four case-control studies (Table 7.10) were evaluated by the committee (Chio et al., 1991; Gunnarsson et al., 1992; McGuire et al., 1997; Strickland et al., 1996). One was a pilot study of only 25 cases and 50 controls (Strickland et al., 1996). Mortality studies using only death certificates (Hawkes et al., 1989; Neilson et al., 1994) and a study of the occupational distribution of ALS cases in Greece (Kalfakis et al., 1991) were excluded because the committee could not ascertain the nature of the exposure in those studies.

Gunnarsson and colleagues (1992) studied cases and controls in a nine-county region of Sweden. Cases, which were recruited from all departments of neurology and internal medicine, had any one of the three diagnoses subsumed under “motor neuron disease.” A self-administered questionnaire was mailed to study subjects to gather information on current and past occupational, physical, and chemical exposure. Exposure of controls occurring within 5 years before the date of completion of the questionnaire was excluded, as were case exposures occurring within 1 year of symptom onset. Additional potential confounders were contact with animals, physical trauma, use of aluminum utensils, and lack of exercise. Exposure to solvents was reported to be rare in women. For men, none of the occupational solvent-exposure categories (including the umbrella category of “any solvent” exposure) yielded positive associations. A strong association was found for the combination of male sex, any occupational exposure to solvents, and heritability (a family history of neurodegenerative disease or thyroid disease) (OR=15.6, 95% CI=2.8–87.0). Because that combination occurred in seven cases and three controls, the result, if valid, is unlikely to be responsible for a large proportion of cases in the population.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

TABLE 7.10 Amyotrophic Lateral Sclerosis (Motor Neuron Disease) and Solvents

Reference, Country

Cases

Controls

Exposure Determination

Solvent Exposure

OR (95% CI or p)

Adjusted OR (95% CI)

Comments

Gunnarsson et al., 1992

112 cases of MND, age 45–79 years; from departments of neurology and internal medicine in nine counties;

496 controls randomly selected from national population registry

Excluded exposure occurring less than 5 years before 1990;

Men: any occupational solvent (three diagnoses);

 

1.3 (0.7–2.5)

Exposure to solvents might be confounder with regard to physical trauma

Sweden

 

for cases, considered only exposure in last year before onset of MND;

Combination of male with MND, any solvent exposure, heritability (family history of AD, PD, ALS, thyroid disease);

15.6 (2.8–87.0)

 

ALS: lower motor neuron symptoms in at least two regions; symptoms of upper motor neuron involvement within 3 years after onset;

 

 

Self-administered questionnaire on current and past jobs;

Both sexes combined: any occupational solvent, PMA alone with no trauma

2.5 (1.0–6.5)

PBP: bulbar paresis as dominating symptom but no evidence of upper neuron involvement;

Also asked physical and chemical exposure, other factors, including diet, family history;

 

PMA: only lower motor neuron involvement during first 3 years;

Most solvents were aromatic hydrocarbons, mixed volatile hydrocarbons, petroleum

 

Mean duration of MND 5 years;

 

Prevalent cases

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference, Country

Cases

Controls

Exposure Determination

Solvent Exposure

OR (95% CI or p)

Adjusted OR (95% CI)

Comments

Strickland et al., 1996

25 cases from University of Minnesota ALS clinic; cases selected from “active” clinic; patients living in area;

50 controls from two sources:

Mailed set of interview forms to prepare for inclinic interview;

Occupational exposures:

 

 

 

paint or pigment manufacture

1.9 (0.5–7.4)

US

25 community controls from random-digit dialing, matched on age ±5 years and sex;

Questions on work history, times, job description

organic solvents

1.2 (0.4–3.7)

excluded if physical incapacity in mobility or communication;

Shown cards listing industries, chemicals; “organic solvents” on card

paint thinners

1.2 (0.3–4.6)

Time since diagnosis 1 month-7 years (mean, 118 weeks);

25 clinic controls with other neuromuscular diseases, matched on clinic enrollment date; mostly patients with myopathies; matched on sex, age ±5 years, residence; same exclusion for physical incapacity

 

 

 

Prevalent cases

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference, Country

Cases

Controls

Exposure Determination

Solvent Exposure

OR (95% CI or p)

Adjusted OR (95% CI)

Comments

McGuire et al., 1997

174 cases of ALS, PBP, PMAa in Washington State (1990–1994);

348 controls (two for each case); matched on sex, age ±5 years, in one of two ways: by random-digit dialing if less than 65 years old, Medicare list if over 65 years old

Interviewers, not blinded to case or control status, conducted detailed interview of jobs held from age 15 years to reference date;

Both sexes combined:

 

 

Cases had less formal education;

self-report,

1.6 (1.1–2.5)

panel assessment

1.2 (0.8–1.9)

US

Matching on age, sex, respondent type (self, proxy for cases; matched controls, if case died before interview)

Incident cases

Men:

 

self-report,

1.1 (0.6–2.1)

panel assessment

1.3 (0.7–2.3)

Panel of four industrial hygienists rated workplace exposure to 28 agents, depending on job history from interview; blinded to disease status, self-reported exposure;

Women:

self-report,

2.4 (1.3–4.3)

 

panel assessment

1.1 (0.6–2.2)

 

Specific solvents: cleaning solvents, degreasers;

Excluded exposure during 10 years before diagnosis

self-report,

1.8 (1.2–2.8)

panel assessment

1.9 (1.1–3.3)

Chio et al., 1991

512 cases of MND seen at author’s hospital 1960–1982;

512 controls admitted to same hospital for neurologic diagnoses matched on date of admission sex, age, province of residence

Occupational history collected from patient’s clinical record; occupation, marital status also collected from municipal records

Occupational exposure:

 

No direct reporting of occupation;

house painter

2.8 (1.6–3.9)

Italy

No information on duration of employment; types of solvents exposed to;

Diagnostic criteria included electromyography;

Prevalent cases

 

Use of hospitalized controls might be problem if it prevented them from working in some occupations

a MND=motor neuron disease; ALS=amyotrophic lateral sclerosis; PBP=progressive bulbar palsy; PMA=progressive muscular atrophy.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Strickland and colleagues (1996), in a pilot study, investigated the occupational history of patients diagnosed with ALS at the University of Minnesota. Cases were compared with two control groups, one obtained through random-digit dialing and the other from the same clinic but having other neuromuscular diseases (as a means of adjusting for the potential problem of recall bias). Investigators mailed a job-history questionnaire to subjects before an exposure interview to permit them and their proxies to prepare. At the interview, participants were shown cards listing industries with possible exposure to organic solvents. The authors noted that the information they collected “antedated the development of ALS symptoms,” but no further detail was provided on the timing of exposure. No associations between ALS and occupational history of solvent exposure were found. The small sample in this study is an important limitation but, even so, the point estimate for solvent exposure is small (1.2), and the confidence intervals include values as small as 0.4. In addition, the use of clinic controls with other neuromuscular diseases may have resulted in a biased estimate of the association, particularly if the control diseases share etiologic factors with the cases.

McGuire and colleagues (1997) used a surveillance system to identify all 174 newly diagnosed ALS patients in a three-county region in western Washington State. Two controls were matched to each case with one of two techniques: random-digit dialing for cases under 65 years old and Medicare eligibility lists for older cases. Exposure, as summarized previously in this chapter, was assessed according to self-reported information and by a panel of four industrial hygienists that rated workplace exposure. Self-reports and panel assessments were also used to determine exposure to 28 specific agents, including 13 solvents. The study found different associations depending on the method of exposure assessment. After adjustment for age and education, a positive association was found between any self-reported exposure to solvents in both men and women (OR=1.6, 95% CI =1.1–2.5)—a finding due largely to the association in women (OR=2.4, 95% CI=1.3–4.3). Both associations disappeared when exposure was assessed by a panel of industrial hygienists. Of the 28 specific agents, investigators found a single positive association between ALS and exposure to “cleaning solvents or degreasers” according to both self-report (OR=1.8, 95% CI=1.2–2.8) and panel assessment (OR=1.9, 95% CI=1.1–3.3). Stratified by sex, the association remained for women but not for men, and there was no dose-response relationship. No positive associations were found with 12 other solvents, including those relevant to the committee’s mandate: “benzene, toluene, or xylene,” “paint, varnish, or stain,” and “alcohols or ketones.” The limitations in interpreting this study include the discrepancies in findings depending on the type of exposure information (more positive associations based on self-reports than on hygienists’ assessments). Finally, there was a higher refusal rate in controls than in cases, which might have resulted in a selection bias of unknown direction. The authors themselves comment that their findings are exploratory, not confirmatory.

Chio and colleagues (1991) conducted a case-control study in Italy. Cases were included if they met specific clinical and electromyographic criteria outlined in a prior study (Chio et al., 1987). Controls were recruited from the same hospital as the cases. The controls were matched on age, date of admission, sex, and province of residence. Occupational data were collected from patients’ clinical records and municipal records. Taking into account the matching of the controls to the cases, the authors used a McNemar test for paired data. The authors state that they did not adjust for any other variables, because “previous studies did not unequivocally identify any risk factor.” Thus, only crude odds ratios are presented.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Considering specific occupations, the authors report a moderate association for only one occupation relevant to the committee: house painting (OR=2.8, 95% CI=1.6–3.9). The results of this study must be considered in light of the absence of direct reporting of occupation and of duration of employment. A further limitation is the use of hospital controls; this might have been problematic if the reason for their hospitalization was in some way associated with the likelihood of exposure—for instance, if controls were suffering from conditions that would prevent them from working in some occupations—and may have resulted in an underestimation of exposure in this group relative to the cases.

Summary and Conclusion

All studies used prevalent cases. Two used only self-reports of exposure to solvents (dichotomized as ever or never) (Gunnarsson et al., 1992; Strickland et al., 1996), and a third relied on occupational information drawn from hospital charts and municipal records (Chio et al., 1991). In the only study with a more sophisticated assessment of exposure by a panel of industrial hygienists, only one of the positive associations for self-reported occupational solvent exposure was maintained (exposure to cleaning solvents and degreasers); the data did not, however, show an increased risk at higher exposure. Overall, these findings do not support an association between solvent exposure and ALS.

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 amyotrophic lateral sclerosis.

Multiple Sclerosis and Solvent Exposure: Background and Epidemiologic Studies

Multiple sclerosis (MS) is a chronic and disabling neurologic disorder whose pathologic hallmark is immune-system-mediated destruction of myelin. The disorder has a marked geographic distribution. Its prevalence and incidence have been found to increase with increasing distance from the equator. The disease has a female:male ratio of about 2:1, with peak incidence between the ages of 25 and 35 years (IOM, 2001). The epidemiologic evidence points to the importance of susceptibility in adolescence and a long latency (Wolfson and Wolfson, 1993). There is some evidence, albeit weaker, that in addition to risk factors acting during the susceptibility period, there may be environmental triggers that act closer to the time of disease onset. Although the precise etiology of MS is unknown, the most widely accepted hypothesis is that early exposure to one or more viruses may initiate it (Granieri et al., 2001). More recently, smoking has been shown to be associated with an increased risk of MS (Hernan et al., 2001).

The committee reviewed four primary research articles, and it excluded results of reviews or meta-analyses of organic solvents and MS (Landtblom, 1997; Landtblom et al., 1996). An additional study was excluded (Amaducci et al., 1982) because the ascertainment of exposure to solvents was based only on occupational information obtained from census data (not from subjects themselves) and related only to the time of the census. Another study, from Denmark (Mortensen et al., 1998), was excluded because it was based on

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

registry data and occupation was used as a proxy for exposure to solvents. In other words, the two studies were both excluded for lack of specificity about solvent exposure.

The remaining studies used a case-control design. Two were carried out in Sweden (Flodin et al., 1988; Landtblom et al., 1993), one in Norway (Gronning et al., 1993), and one, a twin study, in Finland (Juntunen et al., 1989) (Table 7.11). Three of the studies used the diagnostic criteria of Schumacher to identify clinically definite MS (Schumacher et al., 1965), whereas the study by Gronning and colleagues (1993) used the Bauer diagnostic criteria (Bauer, 1980). All four studies included prevalent cases.

Juntunen and colleagues (1989) studied 19 twins with MS drawn from the Finnish Twin Cohort and cross-referenced with the country’s Hospital Discharge Registry. The controls were the unaffected twins, except that two of the 19 twin pairs were concordant for MS, and they were excluded from the study. The authors report collecting a “detailed history” of exposure at work, chemical compounds used, work tasks completed, working conditions, ventilation, and protective equipment used; but they give only sparse details in the publication. A “rough” classification of exposure to chemicals (including solvents) was determined as follows: 0=no exposure, 1=occasional exposure, and 2=slight exposure. The precise timing of the exposure relative to disease onset is not stated. The use of only same-sex twin pairs obviated consideration of the confounding effect of age and sex, but the possible confounding effect of other exposures also was not considered. In only one twin pair had the affected twin been exposed to solvents and the unaffected not, this resulted in an OR of 0.4. In short, no association was found.

Gronning and colleagues (1993) studied 155 cases, 93% with clinical onset in Hordaland, an area of western Norway. The publication does not specify the source of cases (such as hospital records and an MS registry). The 164 controls were recruited from hospital patients with a diagnosis of traumatic fractures, traumatic rupture of ligaments, sciatica, minor plastic surgical procedures, or benign gynecologic disorders. Both cases and controls had been participants in a larger case-control study who reported ever having been active workers. The investigators assessed occupational exposure to solvents in a questionnaire about the types of exposure, frequency and duration, symptoms of intoxication, and use of protective equipment. It is not clear from the article whether the questionnaire was self-administered or interview-based. For cases, exposure occurring before the onset of MS was used for the analysis. For controls, exposure before the mean year of onset in the cases was used. In addition, exposures were quantified with an exposure index. Gronning and colleagues found no evidence to support an association between exposure to organic solvents and the occurrence of MS. Compared with no exposure, occupational exposure to solvents for 1–5 years and more than 5 years yielded ORs of 1.23 (95% CI=0.55–2.76) and 1.97 (95% CI=0.87–4.48), respectively. No significant associations were found with use of protective equipment, exposure to the combination of organic solvents and welding, or exposure to organic solvents and other chemical compounds.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

TABLE 7.11 Multiple Sclerosis and Solvent Exposure

Reference, Country

Cases

Controls

Exposure Determination

Solvent Exposure

OR

Adjusted OR (95% CI or p)

Comments

Juntunen et al., 1989

19 twins from Finnish twin cohort (all adult, same sex); linked to hospital discharge register;

17 unaffected twins; examined carefully; two twins found to have MS

Information collected by specialist in occupational medicine;

Occupational solvent exposure

0.4 (p>0.1)

 

Sparse on exposure methodology;

Finland

 

 

Five control twins had occupational solvent exposure, but not cases

 

work tasks, working conditions, equipment used;

Twin study

 

Prevalent cases (1972–1985);

0=no exposure,

Schumacher diagnostic criteria; checked all diagnoses

1=occasional exposure,

2=slight exposure

Gronning et al., 1993

155 cases with onset from 1976–1986; diagnosed by 1986;

164 hospital patients with other diagnoses; matched on age, sex, residence

Questionnaire with specific questions on occupational exposure to solvents;

Occupational solvent exposure

1.55 (0.83–2.90)

Logistic regression controlled for sex, age, area of residence

Norway

Unweighted duration:

 

Bauer criteria;

 

1–5 years

1.23 (0.55–2.76)

Subset of larger

Only exposures before onset;

over 5 years

1.97 (0.87–4.48)

case-control

Living in Hordaland;

 

study of MS

Exposure index:

 

Prevalent cases

Exposure information: type, frequency, duration, symptoms of toxicity;

less than 2.5

1.44 (0.69–3.00

over 2.5

1.74 (0.72–4.25)

 

Ravnskov method used to develop exposure index

 

 

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference, Country

Cases

Controls

Exposure Determination

Solvent Exposure

OR

Adjusted OR (95% CI or p)

Comments

Flodin et al., 1988

83 cases from two hospitals, diagnosed 1981–1985; sample overlaps that of Landtblom et al. (1993)

467 controls from cancer study; randomly drawn from population registers of hospital catchment area

Questionnaire, 10 of 17 questions on occupational exposure; minimum of 1 year of exposure required; discarded exposure information within 5 years of onset

Men: occupational solvent

 

 

Use of Miettinen confounder score (age, sex, other exposures); also stratification by sex

middle-to-high (2,3,4) vs low-to-none (0,1);

3.1 (1.4–6.8)

Sweden

Men and women: occupational solvent

Diagnostic criteria, definite per Schumacher criteria, probable-possible per Rose criteria

 

2 vs 0, 1

1.7 (0.7–4.0)

 

3 vs 0, 1

3.6 (1.2–11)

4 vs 0, 1

0.7 (0.05–9)

Ravnskov method for exposure index:

Solvent only

2.0 (0.9–4)

0=not exposed;

4=highest, as defined by occupation

Solvent and welding exposure

13.2 (3.4–51)

Landtblom et al., 1993

91 cases from two hospitals, diagnosed 1983–1988; sample overlaps that of Flodin et al. (1988)

348 controls from population registers of hospital catchment area

same as Flodin et al. (above)

Men: occupational solvent

3.4 (1.2–9.4)

Use of Miettinen confounder score (age, sex, other exposures); also stratification by sex

middle-to-high (2,3,4) vs low-to-none (0,1);

Sweden

 

 

Women: occupational solvent

Diagnostic criteria Same as Flodin et al. (above)

middle-to-high (2,3,4) vs low-to-none (0,1);

2.8 (0.9–8.0)

Occupational solvent; logistic regression

men and women

2.8 (1.3–5.5)

men

3.3 (1.1–9.5)

women

1.9 (0.6–5.7)

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Two studies from Sweden by the same team of investigators were of largely overlapping patient populations. They recruited cases from patient files of neurology clinics and departments (Flodin et al., 1988; Landtblom et al., 1993). The major differences between the studies were the years over which cases were recruited and the method of recruiting controls. For the earlier study (Flodin et al., 1988), controls were selected from previous participants in a cancer case-control study. The controls had been randomly selected from the population registries of the counties of interest, corresponding to the catchment areas of the hospitals with the MS cases. In the later study (Landtblom et al., 1993), the population registries of the catchment areas of the hospitals were used directly. The two studies used similar methods to ascertain exposure. Questionnaires were mailed to cases and controls. More than half the questions were related to occupational exposure. Some of the questions required more-detailed responses with respect to frequency, intensity, and duration of exposure. A minimum of 1 year of exposure was required, as was a 5-year latency period (that is, exposure that took place less than 5 years before disease onset was excluded). The 5-year latency period was selected to avoid inclusion of exposures that may have been a consequence of the disease itself, such as a diagnostic x-ray exposure. Exposure to ionizing radiation was also a risk factor considered in the case-control studies. A quantitative classification was developed to describe five levels of increasing exposure based strictly on occupational category (0=not exposed and 4=highest intensity of exposure).

The results of the 1988 Swedish study by Flodin and colleagues indicated a strong association between occupational exposure of men to solvents and MS (OR=3.1, 95% CI=1.4–6.8). There was an even stronger odds ratio for leisure-time exposure to solvents and MS (OR=16.2, 95% CI=2.8–92), but there were only four cases and two controls, and thus a very wide confidence interval. In another analysis, the combination of occupational exposure to solvents and welding resulted in a strong association (OR=13.2, 95% CI=3.4–51), but no association was observed for occupational exposure to solvents alone. No significant associations were observed in women. In the second Swedish study (Landtblom et al., 1993), solvent exposure (middle to high vs low to none) resulted in a moderate association in men and women combined (OR=2.8, 95% CI=1.3–5.5). In women only, there was no positive association. In men only, occupational solvent exposure was associated with MS, as was exposure specifically to kerosene. The authors speculated that solvents might contribute to MS by enhancing viral entry across the blood-brain barrier into the CNS.

Summary and Conclusion

Two case-control studies found no association between occupational solvent exposure and MS (Groning et al., 1993; Juntenen et al., 1989). The two studies conducted in Sweden found some positive associations with exposure to solvents, particularly in men. Those two studies were conducted with similar methods by the same group of investigators. The exposure classification was based on occupational category without the benefit of an occupational hygienist’s evaluation. No stated adjustment was performed for alcohol exposure or smoking. In addition, the timing of the exposure relative to the onset of MS is unknown, apart from its being more than 5 years before onset. Those studies raise suspicion, but they do not meet the committee’s criteria for “limited/suggestive” evidence, because of the potential for bias, including confounding.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

The committee concludes, from its review of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to the solvents under review and multiple sclerosis.

Alzheimer’s Disease and Solvent Exposure: Epidemiologic Studies

Alzheimer’s disease (AD), a neurodegenerative disease marked by progressive impairment in cognition and memory, is described earlier in this chapter. The committee evaluated five studies: three from the United States (Graves et al., 1998; Kukull et al., 1995 and Shalat et al., 1988), one from Canada (CSHA, 1994), and one from Australia (Gun et al., 1997) (Table 7.12).

All studies, which were case-control, included cases based on the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria for the diagnosis of AD (McKhann et al., 1984). This diagnostic scheme distinguishes between possible, probable, and definite AD. Definite AD can be diagnosed only pathologically through biopsy or at autopsy. Three of the studies included only probable AD, one included possible AD (Gun et al., 1997), and one (Shalat et al., 1988) did not state whether subjects with possible AD were included. Cases for four studies were recruited from medical-care settings; the other study (CSHA, 1994) recruited cases with recent onset (within 3 years) previously identified in a population-based prevalence study.

Two studies were based on the AD registry of Group Health Cooperative, a large health maintenance organization in Seattle, Washington. The first was by Kukull and colleagues (1995), and the later study (Graves et al., 1998) was restricted to a subset of cases from the Kukull et al. (1995) study for whom a spouse was available to serve as a proxy informant. That strategy was adopted to enhance the accuracy of job information. The controls in both studies were a random sample of patients from the same Group Health Cooperative from which the AD registry recruited cases. Controls were frequency-matched on age and sex, and they were included if they achieved a score of more than 28 of a possible 30 on the Mini-Mental Status Examination, a test of cognitive function. Job-history information was obtained at interview about exposure to five classes of solvents: aromatic hydrocarbons, chlorinated solvents, ketones, fuels, and alcohols.

Kukull and colleagues (1995) reported an association between occupational solvent exposure and AD in men. When exposure was defined as “exposure to any solvent” in one of the five classes, the study found, in men only, an adjusted OR of 6.3 (95% CI=2.2–18.1). The adjusted odds ratio for both sexes was not significant. The authors speculate that underreporting by controls may have resulted in the findings of the higher association in men. When solvent exposure was defined differently, through job descriptions of four solvent-related occupations, the adjusted OR for the association between what was termed probable solvent exposure and AD was 1.8 (95% CI=1.1–3.1).

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

TABLE 7.12 Alzheimer’s Disease and Solvent Exposure

Reference, Country

Cases

Controls

Exposure Determination

Exposure

Adjusted OR (95% CI)

Comments

Kukull et al., 1995

193 cases of probable or definite (if deceased) AD from Group Health Cooperative AD registry;

243 controls randomly sampled from same Group Health Cooperative;

frequency-matched on age, sex

Interview with proxy about all jobs over 1 year since age 16 years;

Both sexes: ever (vs never) occupationally exposed to any solvent class

2.3 (1.1–4.7)

Adjusted for age, sex, child proxy, greater than high-school education

US

Considered exposure to five specific classes of solvents (aromatic hydrocarbons, chlorinated solvents, ketones, fuels, alcohol);

Men only: exposure to any solvent class

6.0 (2.1–17.3)

Authors comment that underreporting by controls may have accounted for higher association in men;

Required proxy for interview

Women only: exposure to any solvent class

0.7 (0.2–2.1)

15–20 years elapsed between last exposure and onset of AD

Also asked about “probable” solvent exposure based on job descriptions of occupations (printing, asphalt-related, oils, glues, rubber production);

Reference year was 1 year before onset of first symptom

Graves et al., 1998

89 cases of probable AD from Group Health Cooperative AD registry;

subset of Kukull et al. (1995)

89 controls randomly sampled from same Group Health Cooperative;

frequency-matched on age, sex;

Interview with spouse proxy about all jobs over 1 year since age 16 years;

Ever (vs never) occupationally exposed to any solvent class:

1.77 (0.8–3.9)

Participation by only 89 of 130 eligible cases and 89 of 166 eligible controls;

US

Industrial hygienist blind to case-control status rated each job for exposure to solvents; five classes of solvents (aromatic hydrocarbons, chlorinated solvents, ketones, fuels, alcohol);

Duration exposure:

Dose-response findings divergent

1–17 years

1.10 (0.43–2.82)

18 or more years

2.62 (1.07–7.43)

Required spouse informant for interview

Spouses both interviewed

p-trend=0.03

Age at half cumulative exposure:

1.20 (0.48–3.00)

1–33 years

2.67 (1.03–6.94)

Rreference year was 1 year before onset of first symptom

34 or more years

p-trend>0.05

 

Low intensity×duration

1.57 (0.62–3.96)

High intensity×duration

2.00 (0.79–5.10)

Low intensity

2.46 (0.92–6.57)

Moderate-high intensity

1.37 (0.60–3.36)

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference, Country

Cases

Controls

Exposure Determination

Exposure

Adjusted OR (95% CI)

Comments

Gun et al., 1997

170 from Sydney hospitals; possible or probable AD admitted 1986–1988;

170 controls recruited from same or neighboring practice; matched on age, sex; interviewed 1986–1989

Interview (blind to case-control status) of informant; complete job-history details of all jobs over 6 months; employer name, type of activity, substances handled

Aromatic hydrocarbons

1.33 (0.79–2.24)

Simulation to assess impact of information bias on exposure to aromatic hydrocarbons gave OR=1.90 (1.23–2.96)

Australia

Chlorinated hydrocarbons

1.86 (0.75–4.92)

Not clear whether cases are incident or prevalent cases

Any hydrocarbons

1.31 (0.83–2.07)

Job-exposure matrix developed, given to panel of industrial hygienists, which estimated probability of exposure to specific chemicals by reviewing matrix, informant responses

Also looked at control-proxy agreement, estimated sensitivity with control as standard; sensitivity 0.33–0.67; proxy underestimated exposure

Timing of exposure not specified, but mention of subanalyses “exposure before 1980 and before 1970”

 

CSHA, 1994

258 population-based, recent-onset prevalent AD, probable only;

535 controls from prevalence study found cognitively normal on clinical examination; matched on age, study center

Self-administered risk-factor questionnaire;

Occupational solvent

0.76 (0.38–1.54)

Adjusted for age, sex, residence (community vs institution);

Canada

Occupational glue

2.16 (1.25–3.70)

Proxies for cases, controls;

also adjusted for education

1.80 (0.99–3.27)

Symptoms present not more than 3 years before study diagnosis

Subjects older than in most other studies;

Asked about exposures since leaving school or in adulthood

Reliability of occupational-exposure information by proxy low; kappa=0.38

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference, Country

Cases

Controls

Exposure Determination

Exposure

Adjusted OR (95% CI)

Comments

Shalat et al., 1988

98 male cases from Massachusetts veterans hospital; iagnosed 1975–1985;

162 controls from voter-registration list; matched on sex, birth year, town of residence

Mail questionnaire on previous occupation to spouse or next of kin;

Solvent exposure:

 

Adjusted for education;

ever

1.0 (0.05–1.9)

over 10 years

0.8 (0.4–1.9)

US

Exposure to organic solvents;

Organic-solvent exposure index

0.9 (0.4–2.2)

Unknown whether possible AD also included

Detailed occupation history (18 industry categories) assessed by panel of industrial hygienists blind to hypothesis;

Not clear how findings are related to each method of exposure assessment

Ttiming of exposure not specified

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

The later analysis by Graves and colleagues (1998) used a subset of the Kukull study subjects for whom spouses served as proxy informants. It diverged from the earlier study by having an industrial hygienist rate the exposure information gathered from spouse proxies (for cases and controls). The study reported that the hygienist-assessed exposure to any solvent was not associated with AD. The study examined dose-response relationships in four ways. It found a moderate association in those with 18 years or more of occupational solvent exposure (OR=2.62, 95% CI=1.07–7.4) and a moderate association with being 34 years old or older at half-cumulative lifetime exposure (OR=2.67, 95% CI=1.03–6.94). Total intensity of exposure (years on the job multiplied by intensity ratings) was not associated with AD, and intensity ratings alone resulted in a paradoxic relationship: low intensity carried higher (albeit nonsignificant) odds ratios (OR=2.46, 95% CI=0.92–6.57) than did moderate to high intensity (OR=1.37, 95% CI=0.60–3.36). On the basis of the conflicting dose-response relationships, the authors concluded that lifetime occupational exposure to solvents was not likely to be an important risk factor for AD.

Gun and colleagues (1997) compared 170 cases of possible or probable AD with controls who were recruited from the same or neighboring general practices as the cases (recruited from Sydney, Australia, hospitals) and matched on age and sex. Informants (proxies) were interviewed by trained lay interviewers and were asked to provide a complete job history. Investigators used that information to construct a job-exposure matrix. The matrix was given to a panel of occupational hygienists to generate lifetime cumulative exposure. After adjusting for family history of AD, the study did not report any significant associations between AD and occupational solvent exposure. The relevant solvent exposures listed in the study were to aromatic hydrocarbons, chlorinated hydrocarbons, and any hydrocarbons. A special analysis, however, found that the occupational-exposure information supplied by proxies underestimated exposure of controls; this suggested to the authors that the odds ratio was biased toward unity.

The Canadian Study of Health and Aging (CSHA, 1994) was a major population-based study of risk factors for AD. Cases (n=258) were identified from subjects who were found to be suffering from AD in a national study of dementia in Canada. Controls (n=535) were drawn at random from subjects who were found not to be cognitively impaired during the diagnostic clinical examination. Proxies for both cases and controls were asked about exposure, including occupational and environmental, in a risk-factor questionnaire. The study adjusted for age, sex, education, and residence in the community or institution. There was no observed association with occupational exposure to solvents. For occupational exposure to glues, in particular, the analysis found a significant association when adjusting for age, sex, and residence but the association became nonsignificant (OR=1.8, 95% CI=0.99–3.27) when the adjustment also included education, because lower education was a strong, independent risk factor for AD (OR=4.00, 95% CI=2.49–6.43). The authors report, however, that the reliability of occupational-exposure information was questionable: the kappa coefficient for the agreement between the control report and the control-proxy report of exposure to glues was only 0.38, indicating poor agreement.

Shalat and colleagues (1988) drew male cases of AD from a Massachusetts veterans hospital and compared them with controls from voter-registration lists (matched on sex, birth year, and town of residence). The investigators mailed a questionnaire to spouses or next of kin to obtain job histories and had a panel of industrial hygienists rate the degree of

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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.

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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

Suggested Citation:"7. Neurologic Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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.

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Gulf War and Health, Volume 2, is the second in a series of congressionally-mandated studies by the Institute of Medicine that provides a comprehensive assessment of the available scientific literature on potential health effects of exposure to certain biological, chemical, and environmental agents associated with the Gulf War. In this second study, the committee evaluated the published, peer-reviewed literature on exposure to insecticides and solvents thought to have been present during the 1990-1991 war.

Because little information exists on actual exposure levels – a critical factor when assessing health effects – the committee could not draw specific conclusions about the health problems of Gulf War veterans. However, the study found some evidence, although usually limited, to link specific long-term health outcomes with exposure to certain insecticides and solvents.

The next phase of the series will examine the literature on potential health effects associated with exposure to selected environmental pollutants and particulates, such as oil-well fires and jet fuels.

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