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 dysfunction and PNS dysfunction is a useful starting point for understanding and evaluating neurologic disorders.

The CNS consists of the brain and the 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), posttraumatic 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 leave 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 can also be classified on the basis of anatomic distribution as global or focal, on the basis of timing relative to exposure to a causative agent, as early or of delayed onset, or on the basis of duration as transient or



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8 Neurologic Disorders Neurologic disorders include a wide variety of medical conditions. The ner- vous system can be divided anatomically and functionally into the central nervous system (CNS) and the peripheral nervous system (PNS). Distinguishing between CNS dysfunction and PNS dysfunction is a useful starting point for understanding and evaluating neurologic disorders. The CNS consists of the brain and the 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 concen- trating, headache, insomnia, and fatigue), posttraumatic 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 dis- ease (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 leave 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 dis- orders 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 can also be classified on the basis of anatomic distribu- tion as global or focal, on the basis of timing relative to exposure to a causative agent, as early or of delayed onset, or on the basis of duration as transient or 566

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567 NEUROLOGIC DISORDERS persistent. For example, global CNS dysfunction can lead to a general abnormal- ity, 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 of exposure; de- layed 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 neurologic function and must be considered in the design and critique of epidemiologic studies. In the original Veterans and Agent Orange report, hereafter referred to as VAO (IOM, 1994), attention was deliberately focused on persistent neurobehavioral disorders. Veterans and Agent Orange: Update 1996, or Update 1996 (IOM, 1996); Veterans and Agent Orange: Update 1998, or Update 1998 (IOM, 1999); Veterans and Agent Orange: Update 2000, or Update 2000 (IOM, 2001); Veterans and Agent Orange: Update 2002, or Update 2002 (IOM, 2003); Veterans and Agent Orange: Update 2004, or Update 2004 (IOM, 2005); 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. Furthermore, neurologic disorders are by their nature largely subjective, so there often is no objective evidence with which to confirm a diagnosis. Many studies have addressed the possible contribution of various chemical exposures to neurologic disorders, but the committee’s focus is on the health ef- fects of a particular set of chemicals: four herbicides (2,4-dichlorophenoxyacetic acid [2,4-D], 2,4,5-trichlorophenoxyacetic acid [2,4,5-T], 4-amino-3,5,6-trichlo- ropicolinic acid [picloram], and cacodylic acid [dimethyl arsinic acid or DMA]) and a contaminant of 2,4,5-T, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Thus, the specificity of exposure assessment is an important consideration in weigh- ing evidence relevant to the committee’s charge, as described earlier (Chapters 2 and 5). This chapter reviews the association between exposure to the compounds of interest and neurobehavioral disorders, movement disorders, and peripheral neuropathy. The scientific evidence supporting biologic plausibility also is re- viewed briefly here; a more thorough discussion of updated toxicologic studies is in Chapter 3. More complete discussions of the categories of association and of this committee’s approach to categorizing health outcomes are presented in Chapters 1 and 2. If a study new to this update reports only a single neurologic outcome and is not revisiting a previously studied population, its design informa- tion is summarized with its results; design information on other new studies is in Chapter 4.

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568 VETERANS AND AGENT ORANGE: UPDATE 2006 NEUROBEHAVIORAL (COGNITIVE OR NEUROPSYCHIATRIC) DISORDERS This section summarizes the findings of VAO and previous updates on neu- robehavioral disorders and incorporates information published in the last 2 years into the evidentiary database. Conclusions from VAO and Updates On the basis of the data available at the time, it was concluded in VAO, Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 that there was inadequate or insufficient evidence to determine the existence of an association between exposure to the compounds of interest and neurobehavioral disorders. Many of the data that informed that conclusion came from the Air Force Health Study (AFHS, 1984, 1987, 1990, 1991, 1995, 2000, 2005). VAO and the updates offer more complete discussions of the results. The AFHS study design and methods of exposure assessment are discussed in Chapters 4 and 5, respectively. The studies reviewed in VAO (IOM, 1994) revealed no association between serum TCDD concentration and reported sleep disturbance or variables on the Symptom Checklist-90-Revised (SCL-90-R). In contrast, serum TCDD was sig- nificantly associated with responses on some scales of the Millon Clinical Multi- axial Inventory. In Update 2000 (IOM, 2001), results from the AFHS indicated that although the frequency of several self-reported neuropsychiatric symptoms differed be- tween exposure groups, the associations were not significant after adjustment for covariates. In addition, a repeat psychologic assessment with the SCL-90-R in conjunction with self-reported psychologic disorders verified through medical- record review showed that among five diagnostic categories (psychosis, alcohol dependence, drug dependence, anxiety, and other neurosis), a dose–response pat- tern with serum TCDD concentration was found only for “other neuroses” in the enlisted ground crew. When the entire cohort was evaluated, there were no sig- nificant associations between serum TCDD and various psychologic diagnoses. Update 2002 (IOM, 2003) reviewed three studies. Neuropsychologic tests of cognitive functioning indicated significant group differences on some scales, but 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. Update 2004 (IOM, 2005) reviewed five new studies. Among them was a report on the AFHS cohort (Barrett et al., 2003) in which the authors con- clude that there were “few consistent differences in psychological functioning” between groups categorized by serum dioxin concentrations. Another report

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569 NEUROLOGIC DISORDERS described increased prevalence of PTSD among Korean military who served in Vietnam, although there was no association with estimated exposure to Agent Orange. The remaining three studies were uninformative because of methodo- logic limitations. Prior committees have maintained the conclusion that there has been inade- quate or insufficient evidence of an association between exposure to the compounds of interest and neurobehavioral disorders (cognitive or neuropsychiatric). Update of the Epidemiologic Literature Since Update 2004, Park et al. (2005) investigated the association between occupational factors and mortality from neurodegenerative diseases, including Alzheimer’s disease and presenile dementia (PSD), PD, and motor neuron disease (see also the section on PD and parkinsonism below). The authors examined data from 1992–1998 death certificates for over 2.6 million deaths in 22 states. They report mortality odds ratios associated with subjects’ “usual occupation” and with a subgroup of “pesticide-exposed” occupations. Subjects who had worked in “pest control” had significantly increased risk for PSD (odds ratio [OR] 2.96). However, the exposure assessment was too imprecise for the results to inform the present committee’s conclusions. A study of Australian Vietnam veterans reported an association between deployment in Vietnam and “mental disorders” (ADVA, 2005c). The authors state that “there was a borderline significant elevation in mortality from mental disorders, with a relative rate of 2.75 (95% confidence interval [CI] 0.98–8.83). The number of deaths for this group of diseases was small enough for an ex- amination to be made for the 19 deaths involved. All of the deaths were due to conditions associated with alcohol or drug misuse.” Therefore, that report did not inform the committee’s conclusions regarding the possible association between neurobehavioral disorders and exposure to herbicides in Vietnam. Biologic Plausibility A few animal studies suggesting possible involvement of chemicals of inter- est in neurobehavioral effects were identified in this review. Mitsui et al. (2006) suggested that hippocampus-dependent learning could be impaired in male rats exposed in utero to TCDD producing effects on fear conditioning, via hippo- campus effects, in adult male rats exposed to TCDD while in utero. Lensu et al. (2006) examined areas in the hypothalamus for possible involvement in TCDD effects on food consumption, potentially related to wasting syndrome caused by TCDD, and suggest that their results are not consistent with a primary role for the hypothalamus. Although this study does not address cognitive or neuro- psychiatric disorders, it involves behavior (food consumption). There also were studies in rodents that detected molecular effects in cerebellar granule cells or

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570 VETERANS AND AGENT ORANGE: UPDATE 2006 neuroblasts, which are involved in cognitive and motor processes (Kim and Yang, 2005; Williamson et al., 2005) A general summary of the biologic plausibility of neurologic effects of exposure to the herbicides used in Vietnam is presented at the end of this chapter, and detailed discussion is in Chapter 3. Synthesis There is not consistent epidemiologic evidence of an 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 condi- tions 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 detract from evidence of an association between the exposures of interest and neurobehavioral disorders. Conclusion On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is still inadequate or insuf- ficient evidence to determine the existence of an association between expo- sure to the compounds of interest and neurobehavioral disorders (cognitive or neuropsychiatric). MOVEMENT DISORDERS This section summarizes the findings of previous VAO reports on movement disorders, including PD and ALS, and incorporates information published in the last 2 years into the evidentiary database. 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. Those 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 2 centuries of investigation, the true causes of the disease remain enigmatic, and the diagnosis still relies on a characteristic constellation of signs found in a clinical neurologic examination. However, 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

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571 NEUROLOGIC DISORDERS postmortem pathologic examination of brain tissue for the characteristic loss of neurons from the substantia nigra and telltale Lewy body intracellular inclusions. Pathologic findings in other causes of parkinsonism show different patterns of brain injury. Estimates of population-based incidence of 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. That makes PD the second-most common neu- rodegenerative disease (after Alzheimer’s disease). Age is the only definite risk factor for PD; peak incidence and prevalence are consistently found in the seventh and eighth decades of life. Heredity has long been suspected as a primary risk factor for PD, and iden- tification of evidence of genetic transmission—marked by the determination of specific mutations in two genes, Parkin and -synuclein—has accumulated over the last decade. However, it has become clear that simple Mendelian transmission can account only for some rare forms of familial and early-onset PD. Conclusions from VAO and Updates On the basis of growing concerns about a possible link between PD and pesticide exposures, the original VAO committee suggested that attention be paid to the pattern of new cases in Vietnam veterans as they enter the decades when PD is most prevalent to determine whether there is evidence of an association between PD and exposure to the compounds of interest. That recommendation has been echoed in each update. Prior studies have identified PD on the basis of clinical signs or diagnos- tic coding (ICD-9 332) from death certificates or hospital admission records. Although exposure would be relevant to causation if it occurred before disease onset, the specific timing of exposure and disease onset is often unknown. 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 had grouped cases of all ages; studies that separated early-onset cases have yielded inconsistent results (Butterfield et al., 1993; Stern et al., 1991). Estimates of relative risk have also been 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 in the published work (Priydarshi et al., 2000). Evidence supporting a dose–response relationship was limited to one study (Gorell et al., 1998), which 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;

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572 VETERANS AND AGENT ORANGE: UPDATE 2006 Petrovich et al., 2002), whose results were similar to those of the many other studies reviewed for earlier updates. Long duration of agricultural work was associated with parkinsonism in many reports, but the results did not show con- sistent dose–response trends, and no association with any specific compound of interest was identified. Update 2004 reviewed reports of three epidemiologic studies: a cohort study (Baldi et al., 2003a) and a nested case–control study (Baldi et al., 2003b) in France and a case–control study in Belgium (Pals et al., 2003). None showed significant associations with the compounds of interest. None of the studies has described specific exposures to the compounds of interest. Table 8-1 summarizes the relevant studies. Update of the Epidemiologic Literature Since Update 2004, several reports have examined the possible associations between PD and pesticide exposures, but none has addressed exposure to her- bicides in particular or specifically to the chemicals of interest for this series of reviews. One was a mortality study described in the section on neurobehavioral disorders (Park et al., 2005), another was a prospective cohort study (Ascherio et al., 2006), and one was derived from the AHS cohort (Kamel et al., 2005). Ascherio et al. (2006) investigated the relationship between PD and ex- posures self-reported in 1992 among the 143,325 participants in the Cancer Prevention Study II Nutrition Cohort who responded to the 2001 health status survey. Medical records were obtained for 677 of the 840 reported cases of PD, permitting a movement disorder specialist to confirm 588 cases (413 diagnosed after 1992). After adjusting for age, sex, and smoking, the risk for PD was higher among the 5.7 percent of the participants (n 7,864) reporting exposure to pes- ticides or herbicides compared to those not reporting such exposure (RR 1.7, 95% CI 1.2–2.3, p 0.002); this risk remained unchanged whether occupation was a farmer or not. The statistical significance of the findings for “pesticides/ herbicides” in this large prospective study with information on some possible confounders is worthy of note in light of the absence of association with the other 11 exposures studied, but again any elevation in the risk of PD cannot be attrib- uted specifically to the chemicals of interest in this report with any certainty. The design of the mortality study by Park et al. (2005) was not as strong. Information from death certificates was used to identify subjects with PD and their usual occupations. A primary limitation of the study is that “exposure to pesticides” was inferred on the basis of a retrospective job–exposure matrix that was not constructed to account for specific compounds; thus, although the authors indicated that exposure to pesticides was associated with mortality from PD, exposure to specific compounds of interest was not assessed. From the baseline (cross-sectional) data collected in the Agricultural Health Study, exposure to various herbicides was more common in subjects who reported

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TABLE 8-1 Epidemiologic Studies of Pesticidea Exposure and Parkinson’s Diseaseb Reference Significant and Cases in Comparison Association Neurologic Country Study Group Group Exposure Assessment with Pesticidesa OR (95 % CI) Dysfunction Ascherio 413 142,485 1992 baseline self-report of 1.7 (1.2−2.3) 2001 follow-up of et al., confirmed respondents to exposure to pesticides health outcomes; 2006; US cases of PD 2001 survey confirmation of PD diagnosed without self- self-report with after 1992 report of PD medical records Kamel Questionnaire—self-reported Symptoms that et al., pesticide use by number of might be indicative 2005; US days per year of Parkinson’s disease, but no formal diagnosis Park et al., 33,678 cases Death certificates—any Farming Death certificates 2005; US of PD, during mention of PD along with an 1.2 (1.1−1.2) from 22 states with 1992 to 1998 occupation associated with any mention of PD probable pesticide exposure Baldi 585 men (age Questionnaire—detailed Occupational pesticides Self-report at 8 and et al., 70 years) occupational histories (mostly fungicides) 10 year follow-ups 2003a; 5.6 (1.5–21.6) France Baldi 84 (age 70 252 (age 70 Interview Occupational pesticides UK PD Society et al., years) years) –Occupational history coded (mostly fungicides) Brain Bank clinical 2003b; by experts 2.2 (1.1–3.4) criteria France –Residential history 573 continued

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TABLE 8-1 Continued 574 Reference Significant and Cases in Comparison Association Neurologic Country Study Group Group Exposure Assessment with Pesticidesa OR (95 % CI) Dysfunction Pals 423 205 Questionnaire—occupational Neurologic exam et al., 2003; history not interpreted with Belgium respect to pesticide use Petrovitch 2,623 5,363 Total years plantation work Plantation work 20 years Medical records et al., and years of pesticide 1.9 (1.0–3.5) and neurologic 2002; US exposure exam Engel 238 72 Self-administered Pesticides Neurologic exam et al., questionnaire for occupational 0.8 (0.5–1.2) by trained nurse 2001; US exposure Highest tertile pesticide 2.0 (1.0–4.2) Herbicide 0.9 (0.6–1.3) Ritz and 7,516 498,461 Counties ranked by pesticide Prevalence OR: ICD-9 332 Yu, 2000; (PD cause (ischemic use from pesticide registry Moderate pesticide US of death heart disease and agricultural census data 1.36 (1.3–1.5) 1984–1994) cause of death 1984–1994) Tuchsen 134 128,935 Occupations in farming, Age-standardized First-time and Jensen, expected cases horticulture, and landscape hospitalization ratio for hospitalization 2000; 101.5 expected to have exposure to all men in agriculture and for PD Denmark pesticides horticulture 1.34 (1.09–1.62) Fall 113 263 Questionnaire—any job Pesticides Neurologic exam et al., 1999; handling pesticides 2.8 (0.9–8.7) Swedenc

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Kuopio 123 279 Interview—pesticides or Regular use of herbicides Neurologic exam et al., 1999; (onset of PD herbicides regularly or 0.7 (0.3–1.3) Finland before 1984) occasionally used Taylor 140 147 Interview—exposure recorded Pesticides Neurologic exam et al., as total days for lifetime 1.02 (0.9–1.2) 1999; US Herbicides 1.06 (0.7–1.7) Chan et al., 215 313 Interview—exposure to Pesticides in women Neurologic exam 1998; Hong pesticides during farming 6.8 (1.9–24.7) Kongc (years) Pesticides in men 0.7 (0.3–1.8) Gorrell 144 (age 50 464 Interview—herbicide and Occupational herbicides Standard criteria of et al., years) insecticide use while working 4.1 (1.4–12.2) PD by history 1998; USc on a farm or gardening Hubble 3 PD with 51 PD without Interviews—pesticide Pesticide exposure and Neurologic exam et al., dementia dementia exposure 20 days in any year genetic trait 1998; US and presence of allele for poor 3.17 (1.1–9.1) drug metabolism McCann 224 310 Questionnaire—daily or Herbicides or pesticides Neurologic exam et al., 1998; weekly exposure to industrial 1.2 (0.8–1.5) Australiac herbicides and pesticides 6 months Menegon 96 95 Interview—pesticide exposure Pesticides Standard criteria of et al., 1998; more than once weekly for 6 2.3 (1.2–4.4) PD by history Australia months before onset of PD Smargiassi 86 86 Interview—occupational Pesticides or herbicides Standard criteria of et al., exposure for at least 10 1.15 (0.6–2.4) PD by history 1998; Italyc consecutive years 575 continued

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TABLE 8-1 Continued 576 Reference Significant and Cases in Comparison Association Neurologic Country Study Group Group Exposure Assessment with Pesticidesa OR (95 % CI) Dysfunction Liou 120 240 Interview—Occupational Herbicides or pesticides, no Neurologic exam et al., 1997; exposures to herbicides or paraquat Taiwanc,d pesticides 2.2 (0.9–5.6) Paraquat use 3.2 (2.4–4.3) Schulte 43,425 PD Occupational exposure PMR excess in male ICD-9 332 et al., cause of pesticide appliers, 1996; USd death in horticultural farmers, farm 27 states workers, and graders and 1982–1991 sorters of agricultural products Seidler 380 755 Interview—dose-years Neighborhood controls for Neurologic exam et al., 1996; (age 66 years of application weighted herbicide Germanyc,d years with by use 1.7 (1.0–2.7) PD after Regional controls for 1987) herbicide 1.7 (1.0–2.6) Chaturvedi 87 2,070 Survey—exposure positive if Pesticides History of PD et al., 1995; (age 64 frequently used 1.8 (0.9–3.4) Canadac years) Hertzman 127 245 Interview—occupation with Pesticides in men Neurologic exam et al., 1994; probable pesticide exposure 2.3 (1.1–4.9) Canadac Morano 74 148 Interview—direct and indirect Pesticides Neurologic exam et al., 1994; exposure to pesticides 1.73 (1.0–3.0) Spainc

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588 VETERANS AND AGENT ORANGE: UPDATE 2006 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 pos- sible relationship between exposure and neuropathy. In addition, the committee responsible for Update 1996 reviewed case re- ports 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 en- tirely excluded that the five cases reported in those publications were unrelated to herbicide exposure and were examples of other disorders, such as idiopathic Guillain-Barré syndrome. The committee also considered several supportive ani- mal models (Grahmann et al., 1993; Grehl et al., 1993; see “Biologic Plausibility” below). 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 neuropathy, its relationship with toxic exposures, and the occurrence of diabetes mellitus was discussed. In particular, it was noted that neuropathy is a common consequence of diabetes. That was particularly relevant because the commit- tee issued a special report a year later that concluded that there was limited or suggestive evidence of an association between diabetes and exposure to Agent Orange. Update 2000 reviewed what was then the most recent report on RH veter- ans (AFHS, 2000), which combined signs of peripheral neuropathy to produce increasingly specific, graded indexes of neuropathy—a common approach in epidemiologic studies. RH veterans 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 rel- evance of epidemiologic indexes of neuropathy is never certain, the strong as- sociations 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 con- founders 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, lacking any effect of diabetes, to estimate the association between dioxin exposure and neuropathy. Update 2002 considered one peer-reviewed article that described the peripheral- neuropathy data on the AFHS cohort (Michalek et al., 2001). In a 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 diabe- tes were enumerated. In both analyses, there were strong and significant associa-

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589 NEUROLOGIC DISORDERS tions 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 in the absence of the contribution of diabetes. Thus, questions remained about the specific association between exposure to the compounds of interest and peripheral neuropathy in the absence of any effect of diabetes. Update 2004 also considered one peer-reviewed article (Kim et al., 2003), which reported an association between Korean veterans’ service in Vietnam and peripheral neuropathy. Methodologic limitations, such as a concern about recall bias and residual confounding due to diabetes, and issues related to the TCDD dose estimation prevented a strong inference. Update of the Scientific Literature Since Update 2004 (IOM, 2005), no reports dealing with peripheral neuropa- thy as a diagnosis have been published, although a cohort report (Kamel et al., 2005) assessed neurologic symptoms, some of which could arise from peripheral neuropathy. As mentioned in the section on PD, it is not clear how to interpret studies that simply rely on nonspecific clinical findings. Furthermore, it is not possible to rule out bias or residual confounding. There is no compelling new evidence that supports an association between peripheral neuropathy and exposure to the compounds of interest. Biologic Plausibility No new studies directly pertinent to peripheral neuropathy were identified in this update. However, it is worth reiterating findings from earlier updates. Neuro- nal 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 synap- tic connections between nerve cells and supporting the mechanisms involved in axon regeneration during recovery from peripheral neuropathy. Grahmann et al. (1993) and Grehl et al. (1993) reported on abnormalities in electrophysiology and pathology, respectively, observed in the peripheral nerves of rats treated with TCDD. When the animals were sacrificed 8 months after exposure, there was pathologic evidence of persistent axonal nerve damage and histologic findings typical of toxicant-induced injury. Those results constitute evidence of the bio- logic plausibility of an association between peripheral neuropathy and exposure to the compounds of interest. A summary of biological plausibility of neurologic effects arising from exposure to the compounds of interest is presented at the end of this chapter and more detailed discussion appears in Chapter 3.

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590 VETERANS AND AGENT ORANGE: UPDATE 2006 Synthesis Over the last 50 years, a body of literature has accumulated that suggests an association between the compounds of interest and peripheral neuropathy. Past committees have concluded that there is evidence of 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 evidence supported 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 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 suffers from methodologic 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 with electrodiagnostic testing. Epidemiologic studies that used 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 in the reports that did indicate an association, chance, bias, or confounding could not be ruled out with confidence. In particular, diabetes might confound the results, inasmuch as many of the subjects with neuropathy also had diabetes, which is a known cause of neuropathy. Controlling for the effects of diabetes is a technical challenge because there is evidence of 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 On the basis of its evaluation of the 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. On the basis of its evaluation of the evidence reviewed here and previous VAO reports, the committee concludes that there is inadequate or insufficient

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591 NEUROLOGIC DISORDERS evidence of an association between exposure to the compounds of interest and delayed or persistent peripheral neuropathy. SUMMARY Biologic Plausibility Experimental data continue to accrue regarding the biologic plausibility of a connection between exposure to the compounds of interest and various neu- rologic disorders. This section summarizes in a more general way some of this information reviewed in the current update, as well as information from the prior update, for a more complete summary. A more detailed discussion of the newer research can be found in Chapter 3. The effects of TCDD are mediated by interaction with the AhR, a protein 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 among species. Therefore, data from animal studies can be used to support the biologic plausibility of human neurotoxicity. Several studies have been published since Update 2004 that deal with mecha- nisms of neurotoxicity that might be ascribed to chemicals of concern, notably 2,4-D and TCDD. Molecular effects of the chemicals of concern are described in detail in Chapter 3. Some of those effects suggest possible pathways by which there could be effects on the neural systems involved in this outcome. A number of the studies suggest that there are neurological effects of chemicals of interest in animal models when exposure is during development. There also are some studies that further support suggestions that the level of reactive oxygen species could alter the functions of specific signaling cascades and may be involved in neu- rodegeneration. Although not specifically concerning the chemicals of interest, such studies are potentially relevant to the chemicals of concern, as TCDD and herbicides have been reported to elicit oxidative stress. The mechanistic studies suggest possible avenues to pursue to determine linkages between the chemicals of concern and the neurological outcomes that could result in adult humans. Basic scientific studies have emphasized the importance of alterations in neu- rotransmitter systems as potential mechanisms that underlie TCDD-induced neu- robehavioral 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

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592 VETERANS AND AGENT ORANGE: UPDATE 2006 from peripheral neuropathy. Animal experiments have demonstrated that TCDD treatments affect the fundamental molecular events that underlie neurotransmis- sion 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 of rats at doses that do not cause general systemic illness or wasting disease produces electrodiagnostic changes in peripheral nerve func- tion and pathologic findings that are characteristic of toxicant-induced axonal peripheral neuropathy. As discussed in Chapter 3, extrapolation of observations of cells in culture or animal models to humans is complicated by differences in sensitivity and susceptibility among animals, strains, and species; by the lack of strong evi- dence 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 of the biologic plausibility of an association. Conclusions On the basis of its evaluation of the evidence reviewed here and in previ- ous VAO reports, the committee concludes that there is inadequate or insuffi- cient evidence of an association between exposure to the compounds of interest (2,4-D, 2,4,5-T, TCDD, picloram, and cacodylic acid) and neurobehavioral dis- orders (cognitive or neuropsychiatric), PD, or ALS. In Update 1996, the committee concluded that there was limited or sug- gestive evidence of an association between exposure to at least one of the com- pounds 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 avail- able to the committees responsible for Update 1998, Update 2000, and Update 2002 supported that conclusion. The committee for Update 2004 exhaustively reviewed the data on peripheral neuropathy and concluded that there was limited or suggestive evidence of an association between exposure and “early onset, transient” peripheral neuropathy, but that the evidence was inadequate or insuf- ficient to support an association between exposure to the compounds of interest and “delayed or persistent” peripheral neuropathy. The present committee did not review new evidence that would modify the conclusions of prior VAO committees concerning possible associations between exposure to the chemicals sprayed in Vietnam and adverse neurologic health outcomes.

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