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8 Neurologic Disorders The nervous system is a complex organ system that allows human beings to interact with both the internal environment and the external environment. For convenience, we divide the nervous system into the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS comprises the brain and spinal cord, and the PNS includes sensory and motor nerves that enter or leave the spinal cord and are responsible for our ability to sense the outside world and to move within it, and autonomic nerve fibers, which sense internal events such as changes in blood pressure or temperature, and which act to control these and other aspects of our internal environment. Neurologic disorders due to toxicant exposure may result in either immediate or delayed dysfunction of any component of the nervous system; immediate effects of toxicants may involve all aspects of the nervous system, whereas delayed effects are likely to produce more focal problems. Diffuse damage to the CNS may cause alterations in thinking, consciousness, or attention, often combined with abnormalities in movement. Focal dysfunction can cause myriad syndromes, depending on which area is damaged. Although neurologic disorders can cause problems with thinking and emotional dysregu- lation, it is important to distinguish them from psychiatric conditions—such as posttraumatic stress disorder, depression, and anxiety—and from systemic conditions of uncertain cause, such as chronic fatigue syndrome. In this chapter, we will consider possible diffuse CNS effects of toxic exposure and specific clinical conditions that result from focal dysfunction. Examples of diseases that result from degeneration of specific brain areas are Parkinson’s disease (PD), Alzheimer’s disease (AD), spinocerebellar degeneration, and amyotrophic lateral sclerosis (ALS). All those diseases occur in the absence of any toxicant expo- 10

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11 NEUROLOGIC DISORDERS sure; but all may be triggered by aspects of the environment, including toxicant exposure. Disorders of the PNS are generally referred to as neuropathies. Neuropathies may be purely motor and affect only movement or purely sensory; most often, both motor and sensory fibers are affected. Neuropathies usually are symmetric and start with symptoms related to dysfunction of fibers that travel the greatest distance to their target organ. For that reason, symptoms of neuropathy gener- ally start in the digits and travel toward the torso. Most neuropathies also affect autonomic fibers and thus can result in changes in blood pressure and heart rate and in symptoms related to the control of digestion. Neurologic disorders related to toxicant exposure may be acute or delayed and may produce temporary or long-lasting problems. 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. That focus was maintained in Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), and Update 2002 (IOM, 2003). A slight change in emphasis toward chronic neurodegenerative disorders was reflected in the change in the name of this chapter to “Neurologic Disorders” in Update 2004 (IOM, 2005), which was carried forward in Update 2006 (IOM, 2007). This present report reviews data pertinent to persistent neurologic disorders of all types. 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. However, identifiable neurologic disorders always result in objective abnormali- ties that are reflected in anatomic or functional tests or discovered via clinical examination. 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), picloram (4-amino- 3,5,6-trichloropicolinic acid), and cacodylic acid (dimethyl arsenic 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 consider- ation in weighing evidence relevant to the committee’s charge. This chapter reviews the association between exposure to the chemicals of interest and neurobehavioral disorders, neurodegenerative disorders, and periph- eral neuropathy. The scientific evidence supporting biologic plausibility is also reviewed here. More complete discussions of the categories of association and of this committee’s approach to categorizing health outcomes are presented in

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12 VETERANS AND AGENT ORANGE: UPDATE 2008 Chapters 1 and 2. For citations new to this update that revisit previously studied populations, design information can be found in Chapter 5. 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 evidence database. Conclusions from VAO and Previous Updates On the basis of the data available at the time, the committee responsible for VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 concluded that there was inadequate or insufficient evidence to determine the existence of an association between exposure to the chemicals of interest and neurobehavioral disorders. Many of the data that informed that con- clusion came from the Air Force Health Study (AFHS, 1991, 1995, 2000; Barrett et al., 2001, 2003). VAO and the updates offer more complete discussions of the results. The AFHS studies (AFHS, 1991, 1995) reviewed in VAO revealed no association between serum TCDD concentration and reported sleep disturbance or variables on the Symptom Checklist-90-Revised (SCL-90); in contrast, serum TCDD was significantly associated with responses on some scales of the Millon Clinical Multiaxial Inventory. Observations on 55 highly exposed Czech 2,4,5- T production workers (Pazderova-Vejlupkova et al., 1981) were found to suffer from methodologic problems. Update 1996 reviewed two not particularly informative studies of Vietnam veterans (Decoufle et al., 1992; Visintainer et al., 1995) and a study of highly exposed German workers (Zober et al., 1994), which found a relationship be- tween “mental disorders” and severity of chloracne, but not with blood TCDD concentrations. Update 1998 considered a report on mental health problems in Australian Vietnam veterans, but not in the context of herbicide exposure (O’Toole et al., 1996). In Update 2000, results from the AFHS (AFHS, 2000) indicated that al- though the frequency of several self-reported neuropsychiatric symptoms differed between exposure groups, the associations were not significant after adjustment for covariates. In addition, a repeat psychologic assessment with the SCL-90 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.

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1 NEUROLOGIC DISORDERS Update 2002 reviewed three studies. Neuropsychologic tests of cogni- tive functioning indicated significant group differences on some scales in the AFHS cohort during the 1982 examination, 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 (Barrett et al., 2001). Gauthier et al. (2001) did not find a relationship between AD and exposure to herbicides and insecticides. The results of Pelclová et al. (2001) on a Czech 2,4,5-T-production cohort were not given much credence. Update 2004 reviewed five new studies. Among them was a report on the AFHS cohort (Barrett et al., 2003) in which the authors concluded that there were “few consistent differences in psychological functioning” between groups cat- egorized by serum-dioxin concentrations. Kim et al. (2003) described increased prevalence of posttraumatic stress disorder in Korean military who served in Viet- nam, but there was no association with estimated exposure to Agent Orange. The remaining three studies (Baldi et al., 2003; Dahlgren et al., 2003; Pelclová et al., 2002) were found to be uninformative because of methodologic limitations. Update 2006 considered two new studies of limited relevance. Park et al. (2005) analyzed cause of death as a function of subjects’ “usual occupation” on 2.8 million death certificates, but the significantly increased odds ratio (OR) for presenile dementia and “pest control” was not sufficiently specific for the toxicants of interest. The increase in mortality from “mental disorders” reported in Australian Vietnam veterans (ADVA, 2005c) was based on such a broad di- agnostic category that it was impossible to conclude whether subjects who were investigated had neurologic symptoms or signs. Prior committees have maintained the conclusion that there has been inad- equate or insufficient evidence of an association between exposure to the chemi- cals of interest and neurobehavioral disorders (cognitive or neuropsychiatric). Update of the Epidemiologic Literature No Vietnam-veteran or environmental studies concerning exposure to the chemicals of interest and neurobehavioral conditions have been published since Update 2006. Occupational Studies Since Update 2006, few studies relevant to the chemicals of interest and neurobehavioral disorders have been published. Kamel et al. (2007a) evaluated subjects participating in the Agricultural Health Study (AHS) and questionnaire responses from more than 18,000 subjects who listed a variety of neurologic symptoms, including memory and concentration. There was clear evidence of a dose-dependent relationship between pesticide use and neurologic symptoms but

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14 VETERANS AND AGENT ORANGE: UPDATE 2008 no increase in symptoms from herbicide exposure. Symptoms were considered as a group, so there was no evaluation of behavioral symptoms separated from the other neurologic complaints. Solomon et al. (2007) received responses (43%) to a mailed questionnaire dealing with pesticide exposure and a variety of neurologic symptoms includ- ing neuropsychiatric ones from 9,844 men born in 1933–1977 identified in the 1991 census of three rural areas of England and Wales. There was an increased incidence of symptoms reported by those with the highest frequency of exposure to a variety of pesticides; neuropsychiatric symptoms clustered with other neu- rologic symptoms and correlated strongly with a tendency toward somatization as assessed with a separate instrument. The authors concluded that there was a relationship between pesticide use and symptoms but considered psychologic factors, as opposed to a toxic effect, to be a likely cause. Those who had reported herbicide use constituted 40% of the subjects in the “other pesticides” category and about 80% of those who had used sheep dip and those who had used insec- ticides; comparisons of these three groups did not show clear differences. In any case, there was no separate evaluation of herbicide use in general or specifically of the chemicals of interest in this volume. In contrast with the large cohort studies described above, Urban et al. (2007) were able to gather follow-up information on 15 of the subjects who had became acutely ill after chronic exposure to TCDD in 1965–1968 at the Czech chemical plant, considered previously in methodologically limited studies (Pazderova- Vejlupkova et al., 1981; Pelclova et al., 2001, 2002). When examined in 2004, the mean plasma TCDD concentration was 128 ppt. The majority had abnormalities on neuropsychologic testing or single-photon emission computed tomography (SPECT) imaging. This study supports the idea that exposure to large amounts of TCDD over a period of years can produce neurologic abnormalities shortly after or during exposure that can continue for more than 30 years. However, it is not clear how the 15 subjects in this report were contacted or the extent to which this small sample was biased toward increased symptoms, and there was no compari- son group. SPECT scans are nonspecific studies, and many other environmental or age-related factors could have affected the results. Biologic Plausibility Some animal studies have suggested possible involvement of the chemicals of interest in the occurrence of neurobehavioral effects For example, Mitsui et al. (2006) reported that hippocampus-dependent learning could be impaired in male rats exposed in utero to TCDD and the impairment could have affected fear con- ditioning. Lensu et al. (2006) examined areas in the hypothalamus for possible involvement in TCDD effects on food consumption, potentially related to wasting syndrome, and suggested that their results were not consistent with a primary role of the hypothalamus. Studies in rodents have also detected molecular effects in

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1 NEUROLOGIC DISORDERS cerebellar granule cells or neuroblasts, which are involved in cognitive and mo - tor processes (Kim and Yang, 2005; Williamson et al., 2005). Sturtz et al. (2008) found that 2,4-D affected rat maternal behavior. The specific relevance of those studies and studies cited in earlier updates to neurobehavioral effects is unclear. 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. Synthesis There is not consistent epidemiologic evidence of an association be- tween Agent Orange exposure and neurobehavioral disorders (cognitive or neuropsychiatric). Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is still inadequate or insufficient evidence to determine the existence of an association between exposure to the chemicals of interest and neurobehavioral disorders (cognitive or neuropsychiatric). NEURODEGENERATIVE DISEASES This section summarizes the findings of previous VAO reports on neurode- generative diseases—specifically PD and ALS—and incorporates information published in the last two years into the evidence 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. In recent years, many nonmotor manifesta- tions of PD have been described, and in some cases they can be the presenting symptoms of the disease. These include cognitive dysfunction often progressing to frank dementia, sleep disturbances, hallucinations, psychosis, mood disorders, fatigue, and autonomic dysfunction (Langston, 2006). In the nearly 2 centuries since the initial description, much has been learned regarding genetic predisposition and the pathophysiology of the disease. How- ever, the etiology of PD in most patients is unknown, and specific environmental risk factors remain largely unproved. The diagnosis of PD is based primarily on clinical examination; in recent years, however, magnetic resonance imaging and functional brain imaging have been increasingly useful. PD must be distinguished from a variety of parkinsonian syndromes, including drug-induced parkinsonism

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16 VETERANS AND AGENT ORANGE: UPDATE 2008 and neurodegenerative diseases, such as multiple systems atrophy, which have parkinsonian features combined with other abnormalities. 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. 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. It affects about 1% of all persons over 60 years old, and up to 5 million people worldwide. That makes PD the second-most common neurodegenerative disease (after AD). Age is a risk factor for PD, with peak inci- dence and prevalence consistently found in people 60–80 years old. A consensus statement from a 2007 meeting of PD experts (Bronstein et al., 2009) concluded that, in addition to firm evidence that the toxicant 1-methyl-4-phenyl-1,2,4,6- tetrahydropyridine (MPTP) can induce PD, there is substantial evidence that men are at greater risk and that smoking and coffee consumption are associated with reduced risk. Heredity has long been suspected of being an important risk factor for PD; as many as 25% of all PD patients have at least one first-degree relative who has PD. At least 13 gene mutations have been identified in autosomal dominant PD, including mutations in parkin and α-synuclein (Klein and Lohmann-Hedrich, 2007). Mutations associated with an autosomal recessive inheritance pattern have also been described. Complex genetics may be found to account for an increasing number of PD cases in coming years, but environmental risk factors clearly are also important. Conclusions from VAO and Previous 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 chemicals of interest. That recommendation has been echoed in each update; however, no study has systematically evaluated cur- rent or changing prevalence in the Vietnam-veteran population. Thus, all previous updates have reviewed epidemiologic studies from other populations potentially exposed to the chemicals of interest. Previously reviewed studies were found to be inconclusive because levels of exposure were not systematically evaluated and sufficiently specific exposures were not defined. Many studies have evaluated the risks posed by pesticides in general; although a relationship to risk of PD has often been found, dose dependence was either not investigated or not present if investigated. For this update, we selectively re-reviewed all epidemiologic studies that specifically assessed herbicide exposures (none had evaluated exposures to the

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1 NEUROLOGIC DISORDERS specific herbicides of interest in the VAO series) and reviewed in detail the stud - ies published since Update 2006. The results are presented in Table 8-1. To gain a better insight into what specific exposures may underlie the many reports of association with pesticide exposure in general that have dominated the epide- miologic results for PD, estimated risks posed by other classes of pesticides are presented for comparison with those for herbicides. To provide perspective on the new results for phenoxy herbicides, findings on other specific herbicides are presented, particularly for paraquat, which has been a target of study because of its similarity in chemical structure to a drug contaminant found to induce a par- kinsonian syndrome (see the discussion of MPTP below in the section “Biologic Plausibility”). Stern et al. (1991) performed a case–control study of 69 cases that developed symptoms before the age of 40 years (early onset) and 80 cases whose symptoms began after the age of 60 years (late onset). Herbicide exposure (classified as “any” or “none”) was not more prevalent in either early-onset or late-onset cases. However, this study is limited in that the design specifically eliminated cases in the age ranges in which PD is most often diagnosed. In contrast, Semchuk et al. (1992) used a conditional logistic regression model to assess risk in 130 PD subjects in Canada; a statistically significant crude OR of 3.06 (95% confidence interval [CI], 1.34–7.00) was found for herbicide exposure; seven of the 17 cases reporting herbicide use were able to specify the particular product—one reported paraquat use, and the rest reported exclusive use of chlorophenoxy and thiocarbamate compounds. Butterfield et al. (1993), in another case–control study, also found a significant association between herbicide exposure and PD (OR = 3.22; p = 0.033). In a larger population-based case–control study, Gorell et al. (1998) found a significant association between PD and herbicide exposure, which increased after controlling for other confounding factors (OR = 4.10, p < 0.012). PD and control subjects were equally likely to report residential herbicide exposure, which presumably occurs at a lower level than occupational exposure, whereas risk of PD was increased in subjects who reported 10 years or more of occupational herbicide exposure (OR = 5.81, 95% CI 1.99–16.97). In contrast, Taylor et al. (1999) performed a case–control study of 140 cases at Boston City Hospital that showed no association between herbicide use and PD (OR = 1.1, 95% CI 0.7–1.7); this was probably a primarily urban sample, and there is no mention of how many cases or controls reported herbicide use. In addition, controls were identified by PD subjects and contacted by the subjects themselves—an unconventional way of accruing control subjects that may be subject to unknown bias. Taken as a group, those studies suggest that there is a relationship between herbicide exposure and risk of PD. Evidence defined simply as herbicide ex- posure, however, lacks the level of exposure specificity the committee requires for contributing fully relevant evidence toward a finding of association. All the studies used case–control methods and thus depended on the rigor of matching between cases and controls. Most of the studies did not record specific herbicide

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TABLE 8-1 Epidemiologic Studies of Herbicidea Exposure and Parkinson’s Disease 18 Diagnosis of Reference and Cases in Study Neurologic Country Group Comparison Group Exposure Assessment Exposure(s):a n OR (95 % CI) Dysfunction Brighina 833 PD sequential 472 unaffected Self-report down to For youngest quartile at PD diagnosed et al., 2008; US cases from clinic; siblings and specific herbicides; diagnosis: by movement (Mayo Clinic) median age = 361 unrelated 2,4-D said to most Pesticides (ever): 87 1.8 (1.1–2.9) disorder 67.7 yr, 208 cases controls prevalent in cases, Herbicides (ever): 2.5 (1.3–4.5) specialist but published analysis Phenoxy herbicides 1.5 (1.0–2.2) ≤ 59.8 yr not that detailed Insecticides (ever): 1.0 (0.6–1.7) Fungicides (ever): 1.0 (0.3–3.2) Hancock 319 cases 296 unaffected All comparisons Pesticide application: 200 1.6 (1.1–2.3) et al., 2008; US relatives and others referent to those who Insecticides: 1.8 (1.2–2.8) (Duke) never applied any Botanical: 7 5.9 (0.6–56) pesticide Organophosphate: 53 1.9 (1.1–3.6) Herbicides: 1.6 (1.0–2.5) Chlorophenoxy: 15 2.1 (0.7–6.2) Phosophonoglycine: 57 1.5 (0.9–2.5) Triazine: 5 1.1 (0.3–3.6) Kamel et al., 83 prevalent cases 79,557 without PD Self-report of For incident cases: Self-reported 2007b; at enrollment; at enrollment; individual herbicides 2,4-D: 49 1.0 (0.5–2.1) PD US 78 incident cases 55,931without PD (2,4-D; 2,4,5-T; 2,4,5-T: 24 1.8 (1.0–3.3) (Agricultural during follow-up followed up 2,4,5-TP) on detailed 2,4,5-TP: 7 0.9 (0.4–1.8) Health Study) among private self-administered Dicamba: 32 1.5 (0.8–2.8) applicators and questionnaires Paraquat: 11 1.0 (0.5–1.9) [supersedes spouses at enrollment or Trifuralin: 32 1.7 (1.0–3.2) Kamel et al., telephone interview Cyanazine: 26 1.0 (0.5–1.8) 2005] for follow-up For prevalent cases: 2,4-D: 47 0.9 (0.5–1.8) 2,4,5-T: 16 0.9 (0.5–1.7) 2,4,5-TP: 4 0.8 (0.3–1.9)

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Dicamba: 26 0.9 (0.5–1.6) Paraquat: 14 1.8 (1.0–3.4) Trifuralin: 31 0.9 (0.5–1.6) Cyanazine: 30 2.6 (1.4–4.9) Firestone et al., 250 (156 men) 388 (241 men) Interview determining Occupational, men only Controlled 2005; newly diagnosed occupational Pesticides: 19 1.0 (0.5–1.9) for age, sex, Washington, 1992–2002 at and home-based Insecticides: 15 0.9 (0.4–1.8) smoking USA Group Health pesticide exposure Fungicides: 2 0.4 (0.1–3.9) Cooperative characterized by Herbicides: 9 1.4 (0.5–3.9) chemical name or Paraquat: 2 1.7 (0.2–12.8) brand, duration, and Home use, all subjects frequency Pesticides: 178 1.0 (0.7–1.4) Insecticides: 141 0.8 (0.6–1.1) Fungicides: 14 0.6 (0.3–1.1) Herbicides: 116 1.1 (0.8–1.5) Behari et al., 377 (301 men, 76 377 matched for Structured interview McNemar chi-square: 2001; India women) Herbicides p = 0.010 age (± 3 yr), but not sex (protective effect—not confirmed by multivariate analysis) Insecticide: p = 0.169 Rodenticide: p = 0.662 Engel 238 72 Self-administered [prevalence ratios] Neurologic et al., 2001; questionnaire Any pesticide: 0.8 (0.5–1.2) exam by trained US [cross- for occupational Herbicides: 0.8 (0.5–1.2) nurse sectional, but exposure Insecticides: 0.9 (0.6–1.5) otherwise fairly Fungicides: 0.8 (0.6–1.3) high-quality design] 19 continued

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TABLE 8-1 Continued 20 Diagnosis of Reference and Cases in Study Neurologic Country Group Comparison Group Exposure Assessment Exposure(s):a n OR (95 % CI) Dysfunction Kuopio et al., 123 (onset of PD 246 matched on Interview—pesticides Pesticide use: 39 1.0 (0.6–1.7) Neurologic 1999; Finland before 1984; 63 or herbicides Occasional use: 26 1.2 (0.7–2.0) exam sex, age (± 2 yr), men, 60 women) and urban/rural regularly or Regular use: 13 0.7 (0.3–1.3) occasionally used Herbicide use: 33 1.4 (0.8–2.5) Occasional use: 20 1.7 (0.9–3.2) Regular use: 13 0.8 (0.4–1.7) Taylor et al., 140 147 controls Interview—exposure Logistic analysis adjusted for age, sex, family Neurologic 1999; Boston referred by cases recorded as total days history, education, smoking, water source, head exam Medical Center for lifetime injury, depression. Pesticides: 1.0 (0.9–1.2) Herbicides: 1.1 (0.7–1.7) Gorell et al., 144 464 Interview—herbicide All occupations Standard 1998; US and insecticide use contributing exposure to: criteria of PD (age > 50 years) while working on a Herbicides: 4.1 (1.4–12.2) by history farm or gardening Insecticides: 3.6 (1.8–7.2) Fungicides: 1.6 (0.5–5.5) Liou et al., 120 240 hospital Interview— Pesticides vs no pesticides: 2.9 (2.3–3.7) Neurologic 1997; Taiwan controls matched occupational But no paraquat use: 2.2 (0.9–5.6) exam exposures to Paraquat use: 4.7 (2.0–12) for age (± 2 yr) and sex herbicides or Paraquat use vs no pesticides paraquat: 3.2 (2.4–4.3) Seidler et al., 380 755 Interview—dose- Pesticides: 2.1 (1.6–2.6) Neurologic 1996; Germany (379 neighborhood, years = years of Herbicides—high dose: 2.4 (1.0–6.0) exam (age < 66 years with PD after 376 regional; application weighted Dose trend 1987) Dick suggests by use vs neighbor controls p = 0.06 neighborhood vs regional controls p < 0.001

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 NEUROLOGIC DISORDERS Neuronal cell cultures treated with 2,4-D showed decreased neurite extension associated with intracellular changes, including a decrease in microtubules, in- hibition of the polymerization of tubulin, disorganization of the Golgi apparatus, and inhibition of ganglioside synthesis (Rosso et al., 2000a,b). Those mechanisms are important for maintaining synaptic 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 the observations of electrophysiologic and pathologic abnormalities, respectively, in the peripheral nerves of rats treated with TCDD. When the animals were sacri- ficed 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 biologic plausibility of an association between exposure to the chemicals of interest and peripheral neuropathy. A summary of the biologic plausibility of neurologic effects arising from exposure to the chemi- cals of interest is presented at the end of this chapter. Synthesis Over the last 50 years, a body of literature has accumulated that suggests an association between the chemicals of interest and peripheral neuropathy. Past committees have concluded that there is evidence of an association between exposure to at least one chemical of interest and “acute and subacute transient” peripheral neuropathy (Update 1996). However, there remained questions about whether evidence supported an association with persistent neuropathy. Human case reports have documented peripheral neuropathy, as shown by neurologic examination and electrodiagnostic testing, after acute exposure to large amounts of 2,4-D. 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 chemicals 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 con- sistent associations between exposure to the chemicals of interest and 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

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6 VETERANS AND AGENT ORANGE: UPDATE 2008 a known cause of neuropathy. Controlling for the effects of diabetes is a tech - nical challenge because there is evidence of an association between exposure to at least one of the chemicals of interest and diabetes (IOM, 2003); in many cases, diabetes could be in the causal pathway that links exposure and peripheral neuropathy. Conclusions On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an as- sociation between exposure to the chemicals of interest and early-onset transient peripheral neuropathy. On the basis of the evidence reviewed here and previous VAO reports, the committee concludes that there is inadequate or insufficient evidence of an as- sociation between exposure to the chemicals 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 chemicals of interest and various neurologic disorders. This section summarizes in a general way some of the information reviewed in the current update and, to make the summary complete, includes information from prior updates. Several studies have dealt with mechanisms of neurotoxicity that might be ascribed to the chemicals of concern, notably 2,4-D and TCDD. Molecular effects of the chemicals of concern are described in detail in Chapter 4. Some of the effects suggest possible pathways by which there could be effects on the neural systems. A number of the studies suggest that there are neurologic ef- fects, both neurochemical and behavioral, of the chemicals of interest, primarily 2,4-D, in animal models if exposure occurs during development or in cultured nerve cells (Konjuh et al., 2008; Rosso et al., 2000a,b; Sturtz et al., 2008); older references described behavioral effects of developmental exposure of rodents to a 2,4-D–2,4,5-T mixture (Mohammad and St. Omer, 1986; St. Omer and Mohammad, 1987). TCDD has caused deficits in learning behavior in the rat after exposure during development (Hojo et al., 2008). However, caution against overinterpreting the significance of these studies is urged because the develop- ing nervous system is different from the mature nervous system and may not be an appropriate model for the possible consequences of exposure of adults to the chemicals of interest. Some studies further support suggestions that the level of reactive oxygen species could alter the functions of specific signaling cascades and may be in-

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 NEUROLOGIC DISORDERS volved in neurodegeneration (Drechsel and Patel, 2008). Such studies do not specifically concern the chemicals of interest but are potentially relevant to these chemicals inasmuch as TCDD and herbicides have been reported to elicit oxidative stress (Byers, 2006; Celik et al., 2006; Shen et al., 2005). In addition, TCDD has been shown to affect phosphokinase C biochemistry in nerve cells and therefore could affect the integrity and physiology of nerve cells (Kim et al., 2007; Lee HG et al., 2007). Cytochrome P450 1A1, the aryl hydrocarbon receptor (AHR), and the AHR nuclear transporter occur in the brain, so TCDD might be likely to exert effects in the brain (Huang et al., 2000). In addition, although they dealt with hepatocytes and not cells of the nervous system, earlier studies have indicated that 2,4-D affected aspects of mitochondrial energetics and mitochon- drial calcium flux (Palmeira et al., 1994a,b, 1995a,b); if these effects can also occur with nervous system cell mitochondria, which is feasible, then the energy balance and pathways of cells in the nervous system could be affected, with later damage to nervous system function. Those mechanistic studies, although they did not produce convincing evidence of specific effects of the chemicals of interest in the neurologic outcomes of concern, suggest possible avenues to pursue to de- termine linkages between the chemicals of interest and the neurologic outcomes that could occur 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 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 the 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 4, extrapolation of observations of cells in culture or animal models to humans is complicated by differences in sensitivity and sus- ceptibility among animals, strains, and species; by the lack of strong evidence of organ-specific effects among species; and by differences in route, dose, duration, and timing of chemical exposures. Thus, although the observations themselves cannot support a conclusion that the chemicals of interest produced neurotoxic effects in humans, they do suggest the biologic plausibility of an association and describe potential mechanisms that might have come into play.

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8 VETERANS AND AGENT ORANGE: UPDATE 2008 Conclusions On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence of an association between exposure to the chemicals of interest (2,4-D, 2,4,5-T, TCDD, picloram, and cacodylic acid) and neurobehavioral disorders (cognitive or neu- ropsychiatric) or ALS. Previous VAO reports have concluded that there was inadequate or insuf- ficient evidence of an association between exposure to the chemicals of interest and PD. In this report, we review both new data published after Update 2006 and older studies investigating the relationship between herbicide exposure and PD risk. Although a compelling biologic mechanism has not been identified, the bulk of evidence suggests a risk posed by herbicide exposure in general with regard to PD. That impression is strengthened by recent studies that report a specific risk related to the chemicals of interest. The committee now concludes that there is limited or suggestive evidence of an association between exposure to the chemi- cals of interest and PD. The committee responsible for Update 1996 concluded that there was limited or suggestive evidence of an association between exposure to at least one of the chemicals 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. The committee for Update 2004 exhaus- tively 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 insufficient to support an association between exposure to the chemicals of interest and “delayed or persistent” peripheral neuropathy. The committees responsible for Update 2006 concurred and the current committee concurs with that conclusion. In summary, the present committee, on the basis of its review of new data and a re-evaluation of older studies, has left the conclusions of previous commit- tees concerning neurologic outcomes unchanged. REFERENCES1 ADVA (Australian Department of Veterans’ Affairs). 2005b. The Third Australian Vietnam Veterans Mortality Study. Canberra, Australia: Department of Veterans’ Affairs. 1Throughout the report the same alphabetic indicator following year of publication is used con- sistently for the same article when there were multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicator in order of citation in a given chapter is not followed.

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