8
Neurologic Disorders

Neurologic disorders include a wide variety of medical conditions. The nervous system can be divided anatomically and functionally into the central nervous system (CNS) and the peripheral nervous system (PNS). Distinguishing between CNS and PNS dysfunction is a useful starting point for understanding and evaluating neurologic disorders.

The CNS includes the brain and spinal cord. CNS disorders can be broadly divided into neurobehavioral disorders and movement disorders. Neurobehavioral disorders can involve cognitive syndromes, including memory problems, dementia, and Alzheimer’s disease; and neuropsychiatric problems, including neurasthenia (a collection of such symptoms as difficulty in concentrating, headache, insomnia, and fatigue), post-traumatic stress disorder, anxiety disorder, depression, and suicide. Those disorders result from problems in the cerebral cortex or limbic system. Movement disorders, such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), involve weakness, tremors, involuntary movements, incoordination, or gait abnormalities. Those disorders result from problems in the basal ganglia, cerebellum, or spinal cord.

The PNS includes the spinal nerve roots that exit the spinal cord through the vertebral column, traverse the brachial and lumbar plexuses, and end in the peripheral nerves that connect with muscles, skin, and internal organs. PNS disorders are classified as various types of peripheral neuropathy, which can involve sensory changes, motor weakness, or autonomic instability. Those disorders result from problems in somatic or autonomic nerves or both.

Neurologic disorders also can be classified on the basis of anatomic distribution as either global or focal; on the basis of timing relative to exposure as early



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Veterans and Agent Orange: Update 2004 8 Neurologic Disorders Neurologic disorders include a wide variety of medical conditions. The nervous system can be divided anatomically and functionally into the central nervous system (CNS) and the peripheral nervous system (PNS). Distinguishing between CNS and PNS dysfunction is a useful starting point for understanding and evaluating neurologic disorders. The CNS includes the brain and spinal cord. CNS disorders can be broadly divided into neurobehavioral disorders and movement disorders. Neurobehavioral disorders can involve cognitive syndromes, including memory problems, dementia, and Alzheimer’s disease; and neuropsychiatric problems, including neurasthenia (a collection of such symptoms as difficulty in concentrating, headache, insomnia, and fatigue), post-traumatic stress disorder, anxiety disorder, depression, and suicide. Those disorders result from problems in the cerebral cortex or limbic system. Movement disorders, such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), involve weakness, tremors, involuntary movements, incoordination, or gait abnormalities. Those disorders result from problems in the basal ganglia, cerebellum, or spinal cord. The PNS includes the spinal nerve roots that exit the spinal cord through the vertebral column, traverse the brachial and lumbar plexuses, and end in the peripheral nerves that connect with muscles, skin, and internal organs. PNS disorders are classified as various types of peripheral neuropathy, which can involve sensory changes, motor weakness, or autonomic instability. Those disorders result from problems in somatic or autonomic nerves or both. Neurologic disorders also can be classified on the basis of anatomic distribution as either global or focal; on the basis of timing relative to exposure as early

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Veterans and Agent Orange: Update 2004 or delayed onset; or on the basis of duration as transient or persistent. For example, global CNS dysfunction can lead to a general abnormality, such as an altered level of consciousness, whereas focal CNS dysfunction might lead to an isolated abnormality, such as difficulty with language function (aphasia). Early onset disorders are seen within days or weeks or exposure; delayed onset may occur after months or years. Transient disorders are short-lived; persistent disorders produce lasting deficits. Timing is important in assessing the effects of chemical exposure on neurological function and must be considered in the design and critique of epidemiologic studies. In the original Veterans and Agent Orange (VAO) report (IOM, 1994), attention was deliberately focused on persistent neurobehavioral disorders. Later reports—Veterans and Agent Orange: Update 1996 (hereafter, Update 1996 [IOM, 1996]), Veterans and Agent Orange: Update 1998 (hereafter, Update 1998 [IOM, 1999]), Veterans and Agent Orange: Update 2000 (hereafter, Update 2000 [IOM, 2001]) and Veterans and Agent Orange: Update 2002 (hereafter, Update 2002 [IOM, 2003])—and this report review data pertinent to all neurologic disorders. Case identification in neurologic disorders is often difficult, because there are few disorders for which there are specific diagnostic tests. Many disorders involve cellular or molecular biochemical effects, so even the most advanced imaging techniques can miss an abnormality. Because the nervous system is not readily accessible for biopsy, pathologic confirmation usually is not feasible. Neurologic disorders are by their nature largely subjective; so there often is no objective evidence with which to confirm diagnosis. Many studies have addressed the possible contribution of herbicides and pesticides to neurologic disorders. Studies relevant to this report investigated exposures from one of three general settings: in the workplace, from the environment, or during military service in Vietnam. This chapter reviews the association between exposure to 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); 4-amino-3,5,6-trichloropicolinic acid (picloram); and cacodylic acid (dimethylarsenic acid or DMA) and neurobehavioral disorders, movement disorders, and peripheral neuropathy. The scientific evidence for biologic plausibility also is reviewed briefly. More complete discussions of the categories of association and this committee’s approach to categorizing health outcomes are presented in Chapters 1 and 2. A more thorough discussion of biologic plausibility is found in Chapter 3. For studies new to this update that report only a single neurological health outcome and that are not revisiting a previously studied population, their design information is summarized with their results; the design information for all other new studies can be found in Chapter 4.

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Veterans and Agent Orange: Update 2004 NEUROBEHAVIORAL DISORDERS (COGNITIVE OR NEUROPSYCHIATRIC) Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 On the basis of the data available at the time, it was concluded in VAO, Update 1996, Update 1998, Update 2000, and Update 2002 that there was inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and neurobehavioral disorders. Much of the data that informed that conclusion came from the Air Force Health Study (AFHS, 1984, 1987, 1990, 1991, 1995, 2000), an ongoing, longitudinal study of a cohort of Air Force veterans (Ranch Hands) whose duties involved spraying pesticides during their service in Vietnam. VAO and the Updates offer more complete discussions of the AFHS protocols and results; a brief summary is included here. The AFHS study design and methods of exposure assessment, respectively, are discussed in Chapters 4 and 5 of this report. The studies reviewed in VAO (IOM, 1994) revealed no association between serum TCDD concentration and reported sleep disturbance or variables from the Symptom Checklist-90-Revised (SCL-90-R). In contrast, serum TCDD was significantly associated with responses on some scales of the Millon Clinical Multiaxial Inventory (MCMI). In Update 2000 (IOM, 2001), results were reviewed from AFHS (2000). Some self-reported symptoms on a checklist (anxiety, hostility, obsessive–compulsive behavior, paranoid ideation, somatization, global severity index, other neuroses) were significantly more frequent in Ranch Hands, but associations for some of those variables were not significant after adjustment for covariates. In addition, a repeat psychological assessment was performed with SCL-90-R, and reported psychological disorders were verified through medical record review and combined with those obtained on previous examinations. Of the five categories of psychological diagnosis—psychosis, alcohol dependence, drug dependence, anxiety, and other neurosis—a dose–response pattern was found for serum TCDD concentration and “other neuroses” in the enlisted groundcrew. However, when the relationship between the serum TCDD and the psychological diagnoses was examined for all Ranch Hands, there were no significant results. Three new studies were reviewed in Update 2002 (IOM, 2003). Neuropsychological tests of cognitive functioning indicated significant group differences on some scales. However, the findings did not support a dose–response relationship with serum TCDD; poorer performance was seen in groups with background or low exposure, and the lower performance on only one memory test for one subgroup of subjects suggested a chance finding. Uncertainty in interpreting results from the AFHS relates to variations in diagnostic approach, variable findings within subgroups on similar tests, and the lack of dose–response relationships with objective measures of exposure. The

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Veterans and Agent Orange: Update 2004 committee has summarized data from many other studies; similar limitations have affected interpretation of those results, as described in Update 1998. Therefore, that committee maintained the conclusion that there has been inadequate or insufficient evidence of an association between exposure to the compounds of interest and neurobehavioral disorders (cognitive or neuropsychiatric). Update of the Scientific Literature Since Update 2002 (IOM, 2003), five reports have investigated associations between neurobehavioral disorders (cognitive or neuropsychiatric) and possible exposure to the compounds of interest: an update of the AFHS (Barrett et al., 2003), a cross-sectional study of a cohort of Korean veterans who served in Vietnam (Kim et al., 2003), an update of an occupational cohort from the Czech Republic (Pelclova et al., 2002), a cohort study from the Bordeaux region of France (Baldi et al., 2003a), and a semi-ecological study from a community adjacent to a wood treatment plant (Dahlgren et al., 2003). Psychological functioning was compared in Ranch Hand veterans and other Vietnam veterans (Barrett et al., 2003). The number of study participants changed depending on the year of examination, with a range of 921–953 Ranch Hands (roughly 75% participation rate) and 1,037–1,202 comparison subjects. Exposure was determined by serum dioxin measured in 1987 or 1992 and back-extrapolated to the final year of each subject’s tour of duty, assuming a constant half-life for dioxin of 8.7 years. Ranch Hands were placed in background-, low-, and high-exposure groups (with the mean serum concentration marking the cutoff between low and high). The characteristics of the study groups indicated that those with high exposure were more likely to be younger enlisted personnel; those with background or low exposure were older officers. Two standard psychological test instruments were administered: the Minnesota Multiphasic Personality Inventory (MMPI) in 1982 and 1985, and MCMI in 1987 and 1992. MMPI results were inconsistent over time and showed no clearly significant associations with exposure. There was no association between dioxin concentration and PTSD symptoms as measured on the MMPI. MCMI results were essentially identical for all groups for both years, with a single exception—1992 results showed significantly elevated personality scores in the background-exposure group. Although this was a well-designed study, capitalizing on the opportunity to evaluate potential associations between objective measures of exposure and psychological functioning using validated test instruments, the conclusions are limited by the possibility of misclassification of exposure, selection bias, and uncontrolled confounding (by subjects’ educational achievement). The authors quite reasonably conclude that there were “few consistent differences in psychological functioning” between groups based on serum dioxin concentrations. Pelclova et al. (2002) published an updated description of neuropsychological test results from 12 members of a group of workers at a 2,4,5-T production

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Veterans and Agent Orange: Update 2004 facility in the Czech Republic. Although a prior report (Pazderova-Vejlupka et al., 1981) indicated significant correlations between TCDD concentrations and cognitive-test results (see Update 2002), test scores were higher at the follow-up examination and the correlations were no longer significant when the cognitive tests were repeated in 2001 (Peclova et al., 2002). Previous publications from that group were reviewed in VAO and Update 2002, which identified significant methodologic problems in selection bias and lack of control for confounding by educational achievement, tobacco use, or alcohol use. An essential limitation is the lack of a comparison group, which precludes any causal inference. A cross-sectional study of Korean veterans who served in Vietnam described a variety of health outcomes (Kim et al., 2003). The subjects were recruited from a roster of the Korean Ministry of Patriots and Veterans Affairs, with participation rates for Vietnam veterans of 27.6% and for a comparison group of non-Vietnam-veteran pensioners of 5.7%. The demographic characteristics of the participating Vietnam veterans were significantly different both from the source population and from the comparison group. Participants were older and had served in Vietnam longer than had non-participants. Among the participants, Vietnam veterans were younger, less likely to be married, less likely to smoke tobacco or drink alcohol, and less likely to have advanced education than were non-Vietnam-veteran comparison subjects. Participants were assigned to one of four Agent Orange exposure categories, based on a combination of self-report of personal exposure and duty within specific geographic–military regions. Further details on the exposure assessment can be found in Chapter 5 of this report. Health outcomes were assessed by a group of four family practitioners, blinded to subjects’ exposure status, using a “standardized comprehensive clinical investigation.” Associations between exposure and health outcome were estimated using χ-square tests or multiple linear regression to control for potential confounders. There was a significantly higher prevalence of PTSD and mood disorder in Vietnam veterans than in the non-Vietnam-veteran comparison group; although the association was not significant after controlling for multiple potential confounders, and it did not differ by exposure in Vietnam veterans. The study is limited because of the possibility of selection bias. There is also a chance of residual confounding because of the demographic differences between groups, although the authors appropriately included potential confounders in their statistical models. The study does not provide evidence for a significant association between exposure to the compounds of interest and neurobehavioral disorders. The Bordeaux study (Baldi et al., 2003a) focused on a cohort of 2,792 persons over age 65, enrolled in 1987 for the purposes of studying normal and pathological cerebral aging and loss of independence in the elderly. By the time of the 5-, 8-, and 10-year follow-ups, the cohort had decreased to 1,507, 1,118, and 1,026 persons, respectively. Exposures were categorized into quartiles by the likelihood of occupational use of chemical pesticides on the basis of self-reports,

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Veterans and Agent Orange: Update 2004 which introduce the possibility of recall bias. The high drop-out rate raises concerns of selection bias. The authors also could not identify exposure to specific compounds, although fungicides were implicated as the most heavily used compounds in grape cultivation in Bordeaux. It is unlikely that those exposures were comparable to herbicide exposures in Vietnam, so the study offers no evidence that would implicate the compounds of interest. The final study used a semi-ecological design to assess the possibility that self-reported symptoms suggesting neurobehavioral disorders in a group of people from eastern Mississippi were related to residence near a creosote treatment plant (Dahlgren et al., 2003). The study suffers from design weaknesses, including selection and ascertainment bias, lack of objective exposure data, and lack of physician-confirmed diagnoses; its design is not suited to address the presence of an association. Synthesis There is no consistent evidence for any association between neurobehavioral disorders (cognitive or neuropsychiatric) and Agent Orange exposure. Difficulties in case identification and diagnosis, misclassification of exposures because of a lack of contemporaneous measures, subject ascertainment and selection bias, and uncontrolled confounding from many comorbid conditions are common weaknesses in the studies reviewed. The variability of the test results over time, the weak and inconsistent associations, and a lack of consistent dose–response relationships, also prevent those studies from supporting an association between the exposures of interest and neurobehavioral disorders. Conclusion Strength of Evidence from Epidemiologic Studies On the basis of its evaluation of the epidemiological evidence reviewed here and in previous VAO reports, the committee concludes that there is still inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and neurobehavioral disorders (cognitive or neuropsychiatric). Biologic Plausibility No new animal studies are relevant to the compounds of interest and neurobehavioral disorders (cognitive or neuropsychiatric). A summary of biologic plausibility is presented at the end of this chapter.

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Veterans and Agent Orange: Update 2004 Increased Risk of Disease Among Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and neurobehavioral disorders, including cognitive and neuropsychiatric, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk. MOVEMENT DISORDERS This section summarizes the data from previous VAO reports and updates the scientific literature on movement disorders, including PD and ALS. Parkinson’s Disease and Parkinsonism PD is a progressive neurodegenerative disorder that affects millions of people worldwide. Its primary clinical manifestations are bradykinesia, resting tremor, cogwheel rigidity, and gait instability. These signs were first described in 1817 as a single entity by James Parkinson, who believed that severe fright from a traumatic experience was a probable cause. Despite nearly two centuries of investigation, the true causes of the disease remain enigmatic, and the diagnosis still relies on a characteristic constellation of signs from clinical neurologic examination. Unfortunately, the signs are not pathognomonic; they are seen in other disorders, including parkinsonism resulting from syndromes that are virtually indistinguishable from PD. Ultimately, a diagnosis of PD can be confirmed with postmortem pathologic examination of brain tissue for the characteristic loss of neurons from the substantia nigra and telltale Lewy body intracellular inclusions. Pathology findings in other causes of parkinsonism show different patterns of brain injury. Estimates of population-based incidence for PD range from 2 to 22 per 100,000 person-years, and estimates of prevalence range from 18 to 182 per 100,000 person-years (both age adjusted to the 1970 US census). That makes PD the second most common neurodegenerative disease (after Alzheimer’s disease). Age is the only definite risk factor for PD; peak incidence and prevalence are consistently found in the seventh or eighth decades of life. Heredity has long been suspected as a primary risk factor for PD, and identification of the evidence for genetic transmission has accumulated over the past decade, marked by the determination of specific mutations in two genes, Parkin and α-synuclein. However, it has become clear that simple Mendelian transmission can account only for some rare forms of familial and young-onset PD. Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 Based on growing concerns about a possible link between PD and pesticide exposures, the original committee suggested that attention be paid to the pattern

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Veterans and Agent Orange: Update 2004 of new cases in exposed and non-exposed Vietnam veterans, especially as they entered the decades during which PD becomes more prevalent. That recommendation was echoed in each subsequent Update. It was noted that many published studies have used similar methodology, with diagnostic criteria based either on clinical signs of PD or on International Classification of Diseases, Ninth Edition (ICD-9) diagnostic coding from death certificates or hospital admission records. Usually, pesticide exposure was considered relevant only when it occurred before disease onset, although the specific timing relative to onset usually was not clear. The Update 1996 and Update 1998 committees considered the detection of early-onset cases to be vital to test the hypothesis that cases are related to a toxic exposure. The Update 2000 committee noted that most studies have grouped cases of all ages; those that have separated early-onset cases have yielded inconsistent results (Butterfield et al., 1993; Stern et al., 1991). Estimates of relative risk have been quite inconsistent: Five studies demonstrate positive associations (Butterfield et al., 1993; Gorell et al., 1998; Liou et al., 1997; Seidler et al., 1996; Semchuk et al., 1992), two demonstrate negative associations (Kuopio, 1999; Stern et al., 1991), and one shows no association (Taylor et al., 1999). A meta-analysis indicated significant heterogeneity among the published work (Priyadarshi et al., 2000). Evidence for a dose–response relationship was limited: only one study (Gorell et al., 1998) demonstrated an increased incidence of PD with increasing dose as measured by duration of exposure. Update 2002 reviewed reports of two cohort studies (Engel et al., 2001; Petrovich et al., 2002), the results of which were similar to those of the many other studies reviewed for earlier volumes. Lengthy agricultural occupation was associated with parkinsonism in many reports; however, the results did not show consistent dose–response trends, and no association was identified for any individual compound or class of pesticides. None of the studies has described specific exposures to the compounds of interest. Table 8-1 summarizes the relevant studies. Update of the Scientific Literature Since Update 2002 (IOM, 2002), three reports have examined the possible association between PD and pesticide exposures: one (Baldi et al., 2003a) was described above (see the section on neurobehavioral disorders); the second is a nested case–control study related to the Bordeaux cohort (Baldi et al., 2003b); the third comes from a Belgian case–control study that examined associations with a variety of environmental factors, including exposure to pesticides (Pals et al., 2003). In the Bordeaux cohort study (Baldi et al., 2003a), incident (new) cases at the 8- and 10-year follow-up were identified by self-report in response to the question, “Do you have Parkinson’s disease?” Prevalent (existing) cases of PD were excluded at the time of enrollment and after 5 years of follow-up; for those cases,

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Veterans and Agent Orange: Update 2004 TABLE 8-1 Epidemiologic Studies of Pesticide Exposure and Parkinson’s Diseasea Reference and Country Study Group Comparison Group Exposure Assessment Significant Association with Pesticides OR (95 % CI) Neurologic Dysfunction Baldi et al., 2003a; France 585 men (age > 70 years)   Questionnaire—detailed occupational histories + Occupational pesticides (mostly fungicides) 5.6 (1.5–21.6) Self-report at 8 and 10 year follow-ups Baldi et al., 2003b; France 84 (age > 70 years) 252 (age > 70 years) Interview –Occupational history coded by experts –Residential history + Occupational pesticides (mostly fungicides) 2.2 (1.1–3.4) UK PD Society Brain Bank clinical criteria Pals et al., 2003 423 205 Questionnaire–occupational history not interpreted with respect to pesticide use     Neurologic exam Petrovitch et al., 2002; US 2,623 5,363 Total years plantation work and years of pesticide exposure + Plantation work >20 years 1.9 (1.0–3.5) Medical records and neurologic exam Engel et al., 2001; US 238 72 Self-administered questionnaire for occupational exposure + Pesticides 0.8 (0.5–1.2) Herbicide 0.9 (0.6–1.3) Highest tertile pesticide 2.0 (1.0–4.2) Neurologic exam by trained nurse

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Veterans and Agent Orange: Update 2004 Ritz and Yu, 2000; US 7,516 (PD cause of death 1984–1994) 498,461 (ischemic heart disease cause of death 1984–1994) Counties ranked by pesticide use from pesticide registry and agricultural census data + Prevalence OR: Moderate pesticide 1.36 (1.3–1.5) High insecticide 1.45 (1.3–1.6) ICD-9 332 Tuchsen and Jensen, 2000; Denmark 134 128,935 expected cases 101.5 Occupations in farming, horticulture, and landscape expected to have exposure to pesticides + Age-standardized hospitalization ratio for all men in agriculture and horticulture 134 (109–162) First-time hospitalization for PD Fall et al., 1999; Swedenb 113 263 Questionnaire—any job handling pesticides   Pesticides 2.8 (0.9–8.7) Neurologic exam Kuopio et al., 1999; Finland 123 (onset of PD before 1984) 279 Interview—pesticides or herbicides regularly or occasionally used Regular use of herbicides 0.7 (0.3–1.3) Neurologic exam Taylor et al., 1999; US 140 147 Interview—exposure recorded as total days for lifetime Pesticide 1.02 (0.9–1.2) Herbicide 1.06 (0.7–1.7) Neurologic exam Chan et al., 1998; Hong Kongb 215 313 Interview—exposure to pesticides during farming (years) + Pesticides in women 6.8 (1.9–24.7) Pesticides in men 0.7 (0.3–1.8) Neurologic exam

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Veterans and Agent Orange: Update 2004 Reference and Country Study Group Comparison Group Exposure Assessment Significant Association with Pesticides OR (95 % CI) Neurologic Dysfunction Gorrell et al., 1998; USb 144 (age > 50 years) 464 Interview—herbicide and insecticide use while working on a farm or gardening + Occupational herbicides 4.1 (1.4–12.2) Occupational insecticides 3.6 (1.8–7.2) Standard criteria of PD by history Hubble et al., 1998; US 3 PD with dementia 51 PD without dementia Interviews—pesticide exposure >20 days in any year and presence of allele for poor drug metabolism + Pesticide exposure and genetic trait 3.17 (1.1–9.1) Neurologic exam McCann et al., 1998; Australiab 224 310 Questionnaire—daily or weekly exposure to industrial herbicides and pesticides >6 months   Herbicides or pesticides 1.2 (0.8–1.5) Neurologic exam Menegon et al., 1998; Australia 96 95 Interview—pesticide exposure more than once weekly for >6 months before onset of PD + Pesticide 2.3 (1.2–4.4) Standard criteria of PD by history Smargiassi et al., 1998; Italyb 86 86 Interview—occupational exposure for at least 10 consecutive years   Pesticides or herbicides 1.15 (0.6–2.4) Standard criteria of PD by history

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Veterans and Agent Orange: Update 2004 al. (1988) reported a higher rate of abnormalities on neurologic examination and electrodiagnostic testing in subjects with a history of chloracne who were examined 6 years after the accident, but there was no significant increase in peripheral neuropathy as defined by World Health Organization (WHO) criteria. Assennato et al. (1989) described electrodiagnostic evaluation of that group 9 years after the accident; no differences were observed in NCV or neuropathy as defined by WHO criteria. Other environmental studies reviewed in VAO were of Missouri residents potentially exposed to TCDD in the early 1970s when waste oil was sprayed to control dust (Hoffman et al., 1986; Stehr et al., 1986; Webb et al., 1987). Although more frequent sensory abnormalities were reported in potentially exposed subjects, the differences were not statistically significant, and the semi-ecological study design was not suited to causal inference. Some of the data from epidemiologic studies of environmental exposures have suggested increased risk of peripheral nerve abnormalities, but evidence of an association between exposure to the compounds of interest and peripheral neuropathy is inconsistent. Studies of Vietnam veterans were also reviewed in VAO (AFHS, 1984, 1987, 1991; CDC, 1988). A Centers for Disease Control and Prevention study (CDC, 1988) focused on service in Vietnam, not on exposure to the compounds of interest, and it therefore provided no evidence for the possible effects of exposures. There was no indication of increased risk of peripheral neuropathy from the first Ranch Hand reports (AFHS, 1984, 1987, 1991). No evidence of an association between exposure and peripheral neuropathy in Vietnam veterans was derived from the studies reviewed in VAO. Update 1996 reviewed two new epidemiologic studies. Using an administrative database, Zober et al. (1994) found no evidence of increased medical service utilization for diagnosis of peripheral neuropathy in workers previously exposed to TCDD at a BASF plant. Decoufle et al. (1992) reported no association between self-reported exposure to herbicides in Vietnam and peripheral neuropathy. The limitations of those studies were such that they did not confirm or refute a possible relationship between exposure and neuropathy. In addition, the committee responsible for Update 1996 reviewed case reports that described peripheral neuropathy after exposures to the compounds of interest (Berkley and Magee, 1963; Goldstein et al., 1959; Todd, 1962). In each instance, the peripheral neuropathy improved gradually, but had not resolved completely even after several months or years. The possibility cannot be entirely excluded that the five cases reported in these publications were unrelated to herbicide exposure and represented examples of other disorders, such as idiopathic Guillain-Barré syndrome. The committee also considered several supportive animal models (Grahmann et al., 1993; Grehl et al., 1993; see section on biological plausibility). The committee concluded that there was limited or suggestive evidence of an association between exposure to the compounds of interest and early-onset transient peripheral neuropathy. Update 1998 reviewed no new studies. The context for the issue of peripheral

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Veterans and Agent Orange: Update 2004 neuropathy, its relationship with toxic exposures, and the occurence of diabetes mellitus was discussed. In particular, it was noted that neuropathy is a common consequence of diabetes. That was particularly relevant, and the committee issued a special report a year later concluding that there was limited or suggestive evidence of an association between diabetes and exposure to Agent Orange. Update 2000 reviewed the most recent Ranch Hand report available at that time (AFHS, 2000), which combined signs of peripheral neuropathy to produce increasingly specific, graded indexes of neuropathy—a common approach in epidemiologic studies. Ranch Hand subjects were significantly more likely than were comparison subjects to have abnormalities in the indexes, and the prevalence of abnormalities increased with dioxin concentration. Although the clinical relevance of epidemiologic indexes of neuropathy is never certain, the strong associations described between the indexes and the conditions known to produce peripheral neuropathy, such as diabetes and alcohol use, supported their validity in this study. The AFHS investigators included those conditions as potential confounders in the statistical analysis. However, the effect of diabetes could not be eliminated in the most specific neuropathy index, because there were not enough non-diabetic subjects. It therefore was impossible to estimate the association between dioxin exposure and neuropathy, absent any effect of diabetes. The committee responsible for Update 2002 considered one peer-reviewed article that described the peripheral neuropathy data from the Ranch Hand cohort (Michalek et al., 2001). In primary analysis, the investigators had included diabetes as a potential confounder in the statistical model. In a secondary analysis, subjects with conditions that were known to be associated with neuropathy were excluded, and subjects with diabetes were enumerated. In both sets of analyses, there were strong and significant associations between possible and probable neuropathy and dioxin concentration, and significant trends were found with increasing concentrations of dioxin. However, there were too few non-diabetic subjects to produce meaningful estimates of risk, absent the contribution of diabetes. Thus, questions remained about the specific association between exposure to the compounds of interest and peripheral neuropathy absent any effect of diabetes. Update of the Scientific Literature Peripheral neuropathy was one outcome considered in the study of Korean Vietnam veterans (Kim et al., 2003; see the section on neurobehavioral disorders and Chapter 4 for a description of the study). It was significantly more common in Vietnam veterans than in non-Vietnam veterans, with a 2.4-fold risk (95% CI, 1.04–5.48) even after controlling for alcohol use and age, although there were no differences based on estimated TCDD exposure within subgroups of Vietnam veterans. Diabetes was also more common in Vietnam veterans. The authors concluded that there was an excess frequency of peripheral neuropathy in Vietnam veterans.

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Veterans and Agent Orange: Update 2004 Although the study groups differed in terms of known risk factors for neuropathy, including age, alcohol use, and diabetes, the authors controlled for possible confounding by including age and alcohol use in the statistical analysis. It is not clear how diabetes was handled, but the report distinguishes between “peripheral neuropathy,” for which there was a significant difference between groups, and “neuropathy with diabetes,” which was not significantly different between the groups. The possibility of selection bias is a concern—only 28% of eligible Vietnam veterans participated in the study and participation may have been related to health status. Therefore, the study provides some evidence of an association between service in Vietnam and peripheral neuropathy, although the weight of the results is limited because of the study’s limitations. The study does not provide evidence for an association between specific exposure to the compounds of interest and peripheral neuropathy. Synthesis Over the past 50 years, a body of literature has accumulated suggesting an association between the compounds of interest and peripheral neuropathy. Past committees have concluded that there is evidence for an association between “acute and subacute transient” peripheral neuropathy and exposure to at least one compound of interest (Update 1996). However, there remained questions about whether there was evidence for an association with persistent neuropathy. Human case reports have documented peripheral neuropathy after acute exposure to large amounts of 2,4-D as shown by neurologic examination and electrodiagnostic testing. Reports have indicated eventual symptom stabilization and improvement, but sensory and motor deficits have persisted in some people for months or years after the exposure ended. Several epidemiologic studies have reported increased risk of peripheral neuropathy in populations exposed to the compounds of interest in a variety of occupational and environmental settings. However, the literature is inconsistent and has suffered from methodological limitations. The most dramatic exposures have involved industrial accidents that caused environmental contamination, such as the one in Seveso, Italy, in 1976. Studies of residents in that region have shown early onset neuropathy and subclinical abnormalities in some subjects have been demonstrated using electrodiagnostic testing. Epidemiologic studies, using appropriate comparison groups and standard techniques for diagnosis and assessment of exposure, have not demonstrated consistent associations between exposure to the compounds of interest and the development of peripheral neuropathy. Several reports have shown no significant association, and for the reports that did indicate an association, chance, bias, or confounding could not be ruled out with confidence. In particular, it is possible that diabetes confounds the results, because many of the subjects with neuropathy also had diabetes, and diabetes is a known cause of neuropathy. Controlling for

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Veterans and Agent Orange: Update 2004 the effects of diabetes is a technical challenge because there is evidence for an association between diabetes and exposure to at least one of the compounds of interest (IOM, 2003); in many cases, diabetes could be in the causal pathway that links exposure and peripheral neuropathy. Conclusions Strength of Evidence from Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to the compounds of interest and early onset transient peripheral neuropathy. However, on the basis of its evaluation of the epidemiologic evidence reviewed here and previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and delayed or persistent peripheral neuropathy. Biologic Plausibility Toxicology experiments have demonstrated adverse effects of the compounds of interest on nerve cells at a molecular and cellular level; many common mechanisms of neurotoxicity are involved. Neuronal cell cultures treated with 2,4-D showed decreased neurite extension associated with intracellular changes, including a decrease in microtubules, inhibition of the polymerization of tubulin, disorganization of the Golgi apparatus, and inhibition of ganglioside synthesis. Those mechanisms are important for maintaining synaptic connections between nerve cells and supporting the mechanisms involved in axon regeneration during recovery from peripheral neuropathy. Whole-animal experiments have demonstrated that TCDD treatments affect the fundamental molecular events that underlie neurotransmission. Grahmann et al. (1993) and Grehl et al. (1993) reported on abnormalities in electrophysiology and pathology, respectively, observed in the peripheral nerves of a set of rats treated with TCDD. Those treatments did not produce a wasting syndrome, nor was there evidence of general organ system failure. When the animals were sacrificed 8 months after exposure, there was pathologic evidence for persistent axonal nerve damage and histologic findings typical of toxin-induced injury. Those results provide evidence for the biologic plausibility of an association between peripheral neuropathy and exposure to the compounds of interest. Replicating and extending these findings would strengthen the observation and could provide additional insight regarding pathophysiologic mechanisms.

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Veterans and Agent Orange: Update 2004 Increased Risk of Disease Among Vietnam Veterans The lack of data supporting an association between exposure to the chemicals of interest and peripheral neuropathy, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk. SUMMARY Strength of Evidence from Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest (2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid) and neurobehavioral disorders (cognitive or neuropsychiatric) or movement disorders (PD or ALS). The evidence regarding association is drawn from studies of Vietnam veterans and from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. In Update 1996, the committee stated that there was limited or suggestive evidence of an association between exposure to at least one of the compounds of interest and “acute and subacute transient” peripheral neuropathy. The evidence was drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Information available to the committees responsible for Update 1998, Update 2000, and Update 2002 supported that conclusion. In this report, the committee concludes that there is limited or suggestive evidence of an association between exposure and “early onset, transient” peripheral neuropathy. The committee also concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and “delayed or persistent” peripheral neuropathy. That conclusion is based on evaluation of the accumulated epidemiologic evidence described here, some of which was detailed in earlier VAO reports. The evidence is drawn from epidemiologic studies of Vietnam veterans, from occupational studies, and from other studies in which subjects were exposed to at least one compound of interest. Biologic Plausibility This section summarizes the biologic plausibility of a connection between exposure to the compounds of interest and various neurologic disorders, on the basis of data from experimental studies (see Chapter 3 for a more detailed discussion). The effects of TCDD are mediated by interaction with the AhR, a protein

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Veterans and Agent Orange: Update 2004 found in animal and human cells. The AhR complex is known to bind DNA and produce changes in transcription, thereby influencing genetic function. The AhR complex can produce an array of molecular effects that influence cell growth, hormone regulation, and normal cellular metabolism. Although some structural differences have been identified in the AhRs of different species, the AhR is functionally similar across species. Therefore, data from animal studies can be used to support the biologic plausibility of human neurotoxicity. Basic scientific studies have emphasized the importance of alterations in neurotransmitter systems as potential mechanisms that underlie TCDD-induced neurobehavioral disorders. Neuronal cultures treated with 2,4-D exhibited decreased neurite extension associated with intracellular changes, including a decrease in microtubules, inhibition of the polymerization of tubulin, disorganization of the Golgi apparatus, and inhibition of ganglioside synthesis. Those mechanisms are important for maintaining the connections between nerve cells that are necessary for neuronal function and that are involved in axon regeneration and recovery from peripheral neuropathy. Animal experiments have demonstrated that TCDD treatments affect the fundamental molecular events that underlie neurotransmission initiated by calcium uptake. Mechanistic studies have demonstrated that 2,4,5-T can alter cellular metabolism and cholinergic transmission necessary for neuromuscular transmission. TCDD treatment produces peripheral neuropathy in rats. Treatment at doses that do not cause general systemic illness or wasting disease produces electrodiagnostic changes in peripheral nerve function and pathologic findings that are characteristic of toxin-induced axonal peripheral neuropathy. The foregoing evidence demonstrates biologic plausibility for a connection between Agent Orange exposure and neurotoxic effects in humans. Experiments with 2,4-D, 2,4,5-T, and TCDD indicate toxic effects on nerve cells that are molecular and cellular, demonstrating evidence for common mechanisms of neurotoxicity. Experiments with TCDD in whole animals demonstrate specific effects on the PNS at doses that do not cause general systemic illness. As discussed in Chapter 3, extrapolation of those observations to humans is complicated by differences in sensitivity and susceptibility among animals, strains, and species; by the lack of strong evidence of organ-specific effects across species; and by differences in route, dose, duration, and timing of chemical exposures. Thus, although the observations in themselves cannot support a conclusion that Agent Orange produces neurotoxic effects in humans, the studies provide evidence for the biologic plausibility of an association. Increased Risk of Disease Among Vietnam Veterans The inadequacy of data supporting an association of neurological effects (other than early onset, transient peripheral neuropathy) with exposure to the

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