Appendix

Organophosphorus Insecticides

Although there are not an abundant number of studies on the health effects of sarin and cyclosarin, a great deal of research, including much epidemiologic work, has been conducted on the health effects of other organophosphorus (OP) compounds that are used as insecticides. As discussed in Chapter 2, most of the effects of sarin are thought to be mediated by inhibition of acetylcholinesterase (AChE); that mechanism is common among OP compounds, as are some of the established health effects (such as the acute cholinergic syndrome). Because of the common mechanism of action, the health effects of those insecticides could provide some insight into potential health effects of sarin and cyclosarin. The committee responsible for Gulf War and Health, Volume 2 (GW2; IOM, 2003), reviewed the literature on OP compounds. This appendix summarizes that committee’s findings and reviews relevant epidemiology studies published since the preparation of that report.

GULF WAR AND HEALTH: VOLUME 2 CONCLUSIONS

The committee responsible for GW2, reviewed the epidemiologic literature and concluded that there was limited/suggestive evidence of an association between chronic exposure to OP insecticides and two cancers, non-Hodgkin’s lymphoma and adult leukemia. The committee also drew conclusions regarding the association between OP insecticides and a number of neurologic outcomes. This section summarizes that review and the conclusions of GW2 with respect to OP insecticides, focusing on outcomes for which the GW2 committee concluded that there was limited or suggestive evidence of an association, sufficient evidence of



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Gulf War and Health: Updated Literature Review of Sarin Appendix Organophosphorus Insecticides Although there are not an abundant number of studies on the health effects of sarin and cyclosarin, a great deal of research, including much epidemiologic work, has been conducted on the health effects of other organophosphorus (OP) compounds that are used as insecticides. As discussed in Chapter 2, most of the effects of sarin are thought to be mediated by inhibition of acetylcholinesterase (AChE); that mechanism is common among OP compounds, as are some of the established health effects (such as the acute cholinergic syndrome). Because of the common mechanism of action, the health effects of those insecticides could provide some insight into potential health effects of sarin and cyclosarin. The committee responsible for Gulf War and Health, Volume 2 (GW2; IOM, 2003), reviewed the literature on OP compounds. This appendix summarizes that committee’s findings and reviews relevant epidemiology studies published since the preparation of that report. GULF WAR AND HEALTH: VOLUME 2 CONCLUSIONS The committee responsible for GW2, reviewed the epidemiologic literature and concluded that there was limited/suggestive evidence of an association between chronic exposure to OP insecticides and two cancers, non-Hodgkin’s lymphoma and adult leukemia. The committee also drew conclusions regarding the association between OP insecticides and a number of neurologic outcomes. This section summarizes that review and the conclusions of GW2 with respect to OP insecticides, focusing on outcomes for which the GW2 committee concluded that there was limited or suggestive evidence of an association, sufficient evidence of

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Gulf War and Health: Updated Literature Review of Sarin an association, or sufficient evidence of a causal relationship between exposure to organophosphates and given health outcomes. It is important to remember, however, that not all health effects might be common and that dose and duration of exposure might play an important role in the occurrence of effects. Cancers Non-Hodgkin’s Lymphoma A number of well-conducted case–control studies show an increased risk of non-Hodgkin’s lymphoma (NHL) associated with exposure to specific OP and carbamate insecticides (see IOM, 2003 for discussion). By design, such studies assign specific exposures to individual subjects albeit without direct workplace or environmental measurements; in these studies, increased risks were observed with exposure to OP agents and carbamates in general and malathion, diazinon, lindane, and carbaryl in particular. However, there are too few studies with exposure measurements at the individual insecticide level to draw conclusions on any specific insecticide. The increase in risk estimates, especially those related to OP insecticides and carbamates, lends support to a possible association. The associations are consistently increased across various categories of type of use or source of exposure information (self-report or proxy respondent). In addition, the studies that have examined insecticide and pesticide use in general have shown increased NHL risks. The potential for downward bias resulting from a healthy-worker effect inherent in studies with occupationally exposed cases and population controls underscores the positive results. The GW2 committee concluded, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between chronic exposure to OP insecticides and non-Hodgkin’s lymphoma. Adult Leukemia Although specific and accurate exposure information on insecticide use is difficult to ascertain in epidemiologic studies, most populations studied involve workers who use insecticides on a regular basis over the course of many years. Most of the studies discussed above reported an increased risk of leukemia, especially among those exposed to OP insecticides. The studies on specific OP agents—such as diazinon, dichlorvos, and malathion—and on the broader category of insecticides provided additional support for a conclusion on exposure to OP compounds. Most of the findings were of sufficient statistical power to detect a precise estimate of risk. Given that most studies included all types of leukemia

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Gulf War and Health: Updated Literature Review of Sarin and that more specific cell types were identified in only a few of the studies, the committee focused its conclusion on adult leukemia broadly. The GW2 committee concluded, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between chronic exposure to OP insecticides and adult leukemia. Neurologic Effects The committee responsible for GW2 (IOM, 2003) reviewed the epidemiologic literature on neurologic effects of OP insecticide, focusing on studies that examined long-term effects. Four general types of neurologic effects were examined: peripheral neuropathy, neurobehavioral effects (assessed by symptom reporting or performance on validated neurobehavioral tests or batteries), neurologic diseases, and sensory effects. Almost all the studies of exposure to insecticides available to that committee focus on exposures to insecticides as a broad group, to insecticide mixtures, or to OP insecticides in particular. Peripheral Neuropathy 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 to the GW2 committee that veterans identified with some type of symptom-defined peripheral neuropathy actually had clinically diagnosable peripheral neuropathy, as defined by that committee. The results of the studies were mixed. In one large, representative sample of UK veterans (Cherry et al., 2001), 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 neurologists who examined a subset of five subjects who exhibited Syndrome 3 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. The committee was unable to draw particular conclusions from those 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.

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Gulf War and Health: Updated Literature Review of Sarin 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. The committee excluded several studies from consideration because of design flaws or lack of a thorough clinical examination for the diagnosis of peripheral neuropathy (Steenland et al., 1994; Ames et al., 1995; Engel et al., 1998; London and Myers, 1998). In two of the studies, the clinical examination was used only to exclude other causes of peripheral neuropathy rather than to diagnose it (Steenland et al., 1994; Ames et al., 1995); those studies were nevertheless evaluated for 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 did not find evidence of peripheral neuropathy. The other studies of peripheral neuropathy evaluated had some positive findings, but all had design limitations that weakened the validity of their findings. The GW2 committee concluded, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to OP insecticides and peripheral neuropathy. Neurobehavioral Effects Neurobehavioral (NB) effects were broadly defined to include changes in cognition, mood, and behavior that are mediated by the central nervous system (CNS). Studies on NB effects that were reviewed in GW2 are summarized in Table A-1. NB effects are measured via symptom questionnaires or validated tests. 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 those studies showed 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.

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Gulf War and Health: Updated Literature Review of Sarin The GW2 committee concluded, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between exposure to OP insecticides 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 and executive functioning, motor functioning, and mood symptoms. 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 those 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. A study by Fiedler et al. (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 et al. (1999) found abnormalities on simple-reaction time and on the aiming test, but their study measured performance on only six NB tests and was sparse on some aspects of methodology. A population-based study of Gulf War veterans found dizziness and balance symptoms related to pesticide handling, but there was no dose–response relationship or NB testing (Cherry et al., 2001). Some of the GW2 committee members believed that the evidence of long-term NB effects reached the level of “limited/suggestive” because they viewed the study by Stephens et al. (1995) as a high-quality study with positive findings consistent with findings from two smaller studies of less quality (Fiedler et al.,

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Gulf War and Health: Updated Literature Review of Sarin TABLE A-1 Epidemiologic Studies of Neurobehavioral Effects of OP Insecticides Without Past History of OP Poisoning Reference Population: Exposed Population: Control Health Outcomes or Test Type 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 Neurobehavioral Evaluation System (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 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

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Gulf War and Health: Updated Literature Review of Sarin OP Insecticide Exposure Adjustment Results Limitations History of use of OP insecticides; 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 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 previous 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 Questionnaire Specific symptoms not reported; number of years of chronic exposure not reported

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Gulf War and Health: Updated Literature Review of Sarin Reference Population: Exposed Population: Control Health Outcomes or Test Type 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 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 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

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Gulf War and Health: Updated Literature Review of Sarin OP Insecticide Exposure Adjustment Results Limitations 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) 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 slower 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 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

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Gulf War and Health: Updated Literature Review of Sarin Reference Population: Exposed Population: Control Health Outcomes or Test Type 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 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 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

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Gulf War and Health: Updated Literature Review of Sarin OP Insecticide Exposure Adjustment Results Limitations 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 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 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- No vocabulary or other tests to establish baseline CNS functioning; small comparison groups could contribute to difficulties in finding differences

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Gulf War and Health: Updated Literature Review of Sarin Reference Population: Exposed Population: Control Health Outcomes or Test Type Rodnitzky 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) 1997; Bazylewicz-Walczak et al., 1999). Other committee members believed that the evidence was inadequate/insufficient because the NB test findings were too subtle to reach the level of clinical significance, and only one of the NB test findings (syntactic reasoning, a test of cognition) showed a dose–response relationship. The nature of the symptom findings from a separate questionnaire was not reported. The findings from the two smaller studies were not sufficiently robust to reinforce those from Stephens et al. (1995). The GW2 committee was unable to reach consensus on a conclusion regarding exposure to OP insecticides at doses insufficient to cause poisoning (the acute cholinergic syndrome) and long-term neurobehavioral effects. Neurologic Diseases This section summarizes the review in GW2 on the relationship between exposure to insecticides and neurologic diseases: Parkinson’s disease (PD), amyo-

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Gulf War and Health: Updated Literature Review of Sarin OP Insecticide Exposure Adjustment Results Limitations     season changes resulted in no differences except decrease in digit-symbol test (in Spanish-preference group); no correlation of any NB results with AChE   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 AChE 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 trophic lateral sclerosis (ALS), and Alzheimer’s disease (AD). Studying the relationship between exposure and neurologic diseases posed 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 GW2 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 GW2 committee found no case–control or cohort studies that specifically examined the relationship between insecticide exposure and multiple sclerosis. Parkinson’s Disease The six studies reviewed offered conflicting results about the relationship between insecticides and PD. Three of the studies found no association (Stern et al., 1991; Semchuk et al., 1992; Seidler et al., 1996), one found a protective effect (Hertzman et al., 1994), and two found an association between insecticides and PD. Of the two positive studies, Butterfield et al. (1993)

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Gulf War and Health: Updated Literature Review of Sarin 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 et al. (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 (Semchuk et al., 1992; Hertzman et al., 1994). 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 GW2 committee concluded, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to OP insecticides and Parkinson’s disease. 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 5,000 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. There is no evidence that the etiologies differ, but 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

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Gulf War and Health: Updated Literature Review of Sarin “pesticides” or “agricultural chemicals”, in their characterization of exposure; and they did not report associations ( Granieri et al., 1981; Deapen and Henderson, 1986; Savettieri et al., 1991; Chancellor et al., 1993;). The fifth study did specifically address exposures to insecticides. 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 GW2 committee concluded, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to OP insecticides and amyotrophic lateral sclerosis. 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). 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 (French et al., 1985; CSHA, 1994). 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). The two case–control studies reviewed found no association between insecticides and Alzheimer’s disease (Gun et al., 1997; Gauthier et al., 2001). Other studies did not 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 GW2 committee concluded, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to OP insecticides and Alzheimer’s disease.

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Gulf War and Health: Updated Literature Review of Sarin RECENT EPIDEMIOLOGY STUDIES OF OP INSECTICIDES Since the release of GW2, further research on sheep farmers and dippers has been published. Buchanan et al. (2001) characterized the exposures to OP pesticides that occur in various jobs associated with sheep dipping. Those researchers found that handling of the sheep dip concentrate was the most important predictor of exposure to OP pesticides. The second phase of that study investigated whether the repeated exposure to the OP pesticides resulted in cumulative and irreversible damage to nerves (Pilkington et al., 2001). Of an initial 995 sheep farmers invited to participate, 611 agreed to participate, 50 were followed up, 335 were suitable for the survey, and 293 of suitable farmers took the survey. Neurological outcomes were assessed using a symptoms questionnaire and quantitative sensory tests. Symptoms were reported as autonomic symptoms, sensory symptoms, and muscle weakness. Sheep dippers reported symptoms more often (19%) than non-sheep dippers (11%). Looking at cumulative exposure, both as OP dips and total number of days of dipping, the odds ratio adjusted for age, the nonadjusted odds ratios were elevated (OR, 1.15; 95% CI, 1.04–1.26 and OR, 1.13; 95% CI, 1.03–1.24 for number of days and OP dips, respectively). When adjusted for age and country, positive linear effects were seen for symptoms but not for sensory tests. Handling of the OP concentrate was significantly associated (p = 0.005) with symptoms and vibration threshold. Those results, however, were highly dependent on data from two highly exposed individuals. REFERENCES Amaducci LA, Fratiglioni L, Rocca WA, Fieschi C, Livrea P, Pedone D, Bracco L, Lippi A, Gandolfo C, Bino G, et al. 1986. Risk factors for clinically diagnosed Alzheimer’s disease: A case-control study of an Italian population. Neurology 36(7):922–931. Ames RG, Steenland K, Jenkins B, Chrislip D, Russo J. 1995. Chronic neurologic sequelae to cholinesterase inhibition among agricultural pesticide applicators. Archives of Environmental Health 50(6):440–444. Bazylewicz-Walczak B, Majczakowa W, Szymczak M. 1999. Behavioral effects of occupational exposure to organophosphorous pesticides in female greenhouse planting workers. Neurotoxicology 20(5):819–826. Buchanan D, Pilkington A, Sewell C, Tannahill SN, Kidd MW, Cherrie B, Hurley JF. 2001. Estimation of cumulative exposure to organophosphate sheep dips in a study of chronic neurological health effects among United Kingdom sheep dippers. Occupational and Environmental Medicine 58(11):694–701. Butterfield PG, Valanis BG, Spencer PS, Lindeman CA, Nutt JG. 1993. Environmental antecedents of young-onset Parkinson’s disease. Neurology 43(6):1150–1158. Chancellor AM, Slattery JM, Fraser H, Warlow CP. 1993. Risk factors for motor neuron disease: A case-control study based on patients from the Scottish Motor Neuron Disease Register. Journal of Neurology, Neurosurgery, and Psychiatry 56(11):1200–1206. Cherry N, Creed F, Silman A, Dunn G, Baxter D, Smedley J, Taylor S, Macfarlane GJ. 2001. Health and exposures of United Kingdom Gulf war veterans. Part I: The pattern and extent of ill health [comment]. Occupational and Environmental Medicine 58(5):291–298.

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