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Veterans and Agent Orange: Update 2008 (2009)

Chapter: 8 Neurologic Disorders

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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- 510

NEUROLOGIC DISORDERS 511 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

512 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.

NEUROLOGIC DISORDERS 513 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

514 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

NEUROLOGIC DISORDERS 515 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

516 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

NEUROLOGIC DISORDERS 517 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

TABLE 8-1  Epidemiologic Studies of Herbicidea Exposure and Parkinson’s Disease 518 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 ≤ 59.8 yr but published analysis Phenoxy herbicides 1.5 (1.0–2.2) 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)

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) age (± 3 yr), but Herbicides p = 0.010 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] 519 continued

TABLE 8-1  Continued 520 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 sex, age (± 2 yr), or herbicides Occasional use: 26 1.2 (0.7–2.0) exam 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 (age > 50 years) and insecticide use contributing exposure to: criteria of PD 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 for age (± 2 yr) exposures to Paraquat use: 4.7 (2.0–12) 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 (age < 66 years (379 neighborhood, years = years of Herbicides—high dose: 2.4 (1.0–6.0) exam 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

controls Insecticides—high dose: 2.1 (0.9–4.8) over-matched) Dose trend vs neighbor controls p = 0.12 vs regional controls p < 0.001 Hertzman et al., 127 (71 men and 245 (121 with Interview— vs voters—among men Neurologic 1994; Canada 56 women) cardiac disease; occupation with Pesticides: 2.3 (1.1–4.9) exam 124 voters) probable pesticide Herbicides: 1.2 (0.6–2.5) exposure Chlorophenoxys: 1.2 (0.6–2.4) Paraquat: 1.3 (0.3–4.6) Insecticides: 0.3 (0.1–0.9) Fungicides: 0.5 (0.2–1.1) Butterfield 63 young 68 Questionnaire— Herbicides: 3.2 p = 0.033 Standard et al., 1993; US onset cases pesticide or Insecticides: 5.8 p < 0.001 criteria of PD (age < 50 years) insecticide use 10 Dwelling fumigated: 5.3 p = 0.45 by history times in any year Semchuk et al., 130 living cases 260 community Interview—self-report Pesticides: 32 2.3 (1.3–4.0) Neurologic 1992; Calgary, from register of controls matched of exposure for each Herbicides: 17 3.1 (1.3–7.0) exam Alberta, Calgary residents for age (± 2.5 yr) job held > 1 month  Exposed during age confirming Canada (population-based) and sex, identified interval: idiopathic by RDD 16–25 yr 1.4 (0.5–4.3) PD without 26–35 yr 4.8 (1.5–15.0) dementia 36–45 yr 3.8 (1.2–13.0) (average 7.8 yr 46–55 yr 4.9 (1.3–19.0) from diagnosis) Insecticides: 17 2.1 (1.0–4.1) Fungicides: 16 1.6 (0.8–3.3) 521 continued

TABLE 8-1  Continued 522 Diagnosis of Reference and Cases in Study Neurologic Country Group Comparison Group Exposure Assessment Exposure(s):a  n OR (95 % CI) Dysfunction Stern et al., 69—all young 149 nominated by Interview—self- Insecticides: 0.7 (0.3–1.4) Review of 1991; NJ & onset cases each case or picked report of insecticide Onset < 40 years: 0.6 (0.2–1.7) medical records, PA, US identified (age from hospital; and pesticide use by Onset > 59 years: 0.8 (0.3–2.1) responsive to < 40 years); 80— matched by age self or others in home Herbicides: 1.1 (0.7–1.7) PD medication random selection (± 6 yr), sex, and or garden Onset < 40 years: 0.9 (0.5–1.7) (under of old onset cases race Onset > 59 years: 1.3 (0.7–2.4) treatment (age > 59 years) Adjusted for smoking, head injury, rural residence: average of 8.2 Insecticides: 0.5 (0.2–1.1) yr), without Herbicides: 0.9 (0.6–1.5) Hertzman et al., 57 prevalent PD 122 aged 50–79 Questionnaire—ever Work in orchards: 3.7 (1.3–10.3) Neurologic 1990; British patients (age < 79 who responded worked in an orchard Paraquat: 4/57 (p = 0.01) exam confirmed Columbia, years) [50–54 had from electoral rolls diagnostic Canada confirmed PD, not criteria in 55 clear exactly how of 69 cases many] identified by asking physicians in area ABBREVIATIONS: CI, confidence interval; OR, odds ratio; PD, Parkinson’s disease; RDD, random-digit dialing. aFor the objective of this Veterans and Agent Orange review series, only associations with herbicides are of possible relevance; only the phenoxy herbicides, cacodylic acid, and picloram are of specific interest.

NEUROLOGIC DISORDERS 523 use; there was some reporting of paraquat use, but for the chemicals of interest it is generally unclear how many subjects were exposed. Update of the Epidemiologic Literature Since Update 2006, several relevant studies have been reported. There are still no data on Vietnam veterans and PD, but in addition to the several population- based studies that suggest a relationship between herbicide exposure and PD, a number of studies have identified exposure to specific chemicals of interest as a potential risk factor. Kamel et al. (2007b) studied the large cohort collected by the prospective AHS; this cohort was established from 1993 to 1997 and included 84,738 people of whom 57,259 were reached again 5 years later. During the enrollment telephone contact, in addition to extensive demographic information, a detailed pesticide- exposure history (including information about use of protective techniques) was collected. Subjects who reported a doctor’s diagnosis of PD at enrollment were classified as prevalent cases, and those who reported a diagnosis of PD that oc- curred in the 5 years before the second contact were classified as incident cases. Among prevalent cases, there was not a positive relationship between reported use of any pesticide and PD (OR = 0.5, 95% CI 0.2–1.1). Among incident cases, there was a trend toward increased risk of PD in subjects exposed to pesticides (OR = 1.3, 95% CI 0.5–3.3); although the overall relationship did not reach statistical significance, there was a dose effect over the quartiles (p = 0.009), with subjects with the highest number of days of pesticide use showing the greatest risk (OR = 2.3, 95% CI 1.2–4.5). This study obtained information about specific compounds of exposure and reported on 47 individual pesticides. Although risks were not presented in association with overall use of the 18 reported herbicides, individual results were given for three phenoxy herbicides (2,4-D, 2,4,5-T, and 2,4,5-TP) and the structurally similar benzoic herbicide, dicamba. With the statistics for those four chemicals of interest, findings on paraquat and the only two other pesticides with significant findings, trifluralin and cyanazine (which are also herbicides), have been transcribed into Table 8-1 for comparison. For prevalent cases, the risk of PD was significantly increased after exposure to cyanazine and barely significantly increased after exposure to paraquat. For incident cases, a modest just-significant increase in risk was found after exposure to 2,4,5-T (OR = 1.8, 95% CI 1.0–3.3) and triflualin (OR = 1.7, 95% CI 1.0–3.2) and a nonsignificant increase after exposure to dicamba (OR = 1.5, 95% CI 0.8–2.8). That study is provocative but raises questions. The findings on prevalent and incident cases do not reinforce each other, but in this prospective design, prevalent cases were associated with considerably less reliable data than incident cases in several ways. Selection bias could have been operational in connection with the PD cases already diagnosed at the time of enrollment; those already having PD may have self-selected themselves out of agricultural occupations

524 VETERANS AND AGENT ORANGE: UPDATE 2008 and hence disproportionately made themselves ineligible for enrollment in the AHS. Prevalent cases would also have been susceptible to recall bias when they provided their exposure profiles at enrollment; this would be consistent with the prevalent cases’ having a higher risk after exposure to paraquat (whose structural relationship to a chemical known to cause PD had been discussed in the public media at the time of enrollment), whereas its risk estimate was neutral in the incident PD cases. Another study (Brighina et al., 2008) investigated PD and pesticide exposure in light of new genetic insights. Mutations in the α-synuclein gene have been reported in families that have familial PD. That finding has led to the hypothesis that aggregation and formation of α-synuclein fibrils may lead to PD in sporadic disease. Brighina et al. (2008) tested the hypothesis that pesticide exposure might increase the aggregation and fibrillation of α-synuclein and thus lead to PD. A large case–control study was conducted, with 833 pairs; the REP1 genotype for α-synuclein was overrepresented in PD cases (OR = .18, 95% CI 1.02–1.37; p = 0.03). In this study, overall pesticide use was not associated with increased risk of PD (OR = 1.11, 95% CI 0.89–1.38; p = 0.37), but there was a trend toward increased risk in younger subjects. When herbicide, insecticide, and fungicide use was segregated, only herbicide use in younger subjects was associated with increased risk. Of the herbicides reported, those in the chlorophenoxy acid or esters chemical class was associated with the greatest risk (OR = 1.52, 95% CI 1.04–2.22; p = 0.004); 2,4-D was most commonly reported in this group. There was no clear interaction between specific haplotypes for α-synuclein and expo- sure in modifying the risk of PD. Although the lack of interaction between specific haplotype and exposure may raise questions about the mechanism by which herbicides might increase the risk of PD, the relationship between chlorophenoxy-herbicide exposure and PD risk in younger subjects is an important finding. Environmental modifiers of neurodegenerative diseases often alter the onset of symptoms; the increased risk in younger subjects may be a clue in that regard. Finally, Hancock et al. (2008) evaluated specific pesticide exposure and risk of PD by using a family-based case–control series of 319 PD patients and 296 controls. Overall pesticide use was significantly associated with PD (OR = 1.61, 95% CI 1.13–2.29). Organochlorine and organophosphorus compounds were associated with the greatest statistically significant risks. Exposure to chlorophe- noxy acid or esters, including chemicals of interest in this review, were associated with increased ORs but the relationship was not statistically significant (OR = 2.07, 95% CI 0.69–6.23). Biologic Plausibility Several reviews of the literature have addressed the possible involvement of environmental chemicals in the etiology of PD. The very clear PD-like toxic-

NEUROLOGIC DISORDERS 525 ity resulting from human MPTP exposure has indicated that select compounds can result in the same type of damage to dopaminergic neurons as PD does, and MPTP has become an important toxicant in studies that use animal and in vitro models. It is notable that MPTP’s bioactive metabolite, MPP+, is similar in chemical structure to paraquat (a commonly used herbicide although not one used in Vietnam); but it is different from the chemicals of interest in this report. Pesti- cides that have been shown to produce PD-like toxicity in animal models include paraquat, rotenone, maneb, and dieldrin, and substantial research has gone into understanding the molecular mechanisms responsible for the toxicity, especially in connection with paraquat and rotenone, as reviewed recently by Drechsel and Patel (2008), Hatcher et al. (2008), and Nunomura et al. (2007) and by others in the past, including DiMonte et al. (2002) and Sherer et al. (2002a). The damage done to dopaminergic neurons in PD is probably from oxidative stress and prob- ably also involves damage to mitochondria in the target cells (Liang et al., 2007; Sarnico et al., 2008). The chemicals of interest to this committee are known to be distributed to the CNS, but they have not been investigated in similar experi- mental systems, so there is no evidence that they could cause inflammation or oxidative stress similar to that caused by the compounds, such as paraquat, that have been investigated. Research on the neurotoxicity of 2,4-D has been going on for a number of years, but most of it has focused on its effects on the developing rodent nervous s­ystem. The studies have often used high doses of 2,4-D that have re- sulted in adverse changes in the developing nervous system, both neurochemical (such as changes in D2 receptors, tyrosine hydroxylase and dopamine beta- h ­ ydroxylase) and behavioral (for example, Bortolozzi et al., 1999, 2002, 2003, 2004; ­Duffard et al., 1996; Evangelista de Duffard et al., 1990, 1995; Garcia et al., 2004, 2006; Rosso et al., 2000a,b). Injection of 2,4-D directly into the rat brain yielded ­ toxicity in the basal ganglia (Bortolozzi et al., 2001), but this route of administration is highly ­artificial. Recent studies showed that postpartum dietary e ­ xposure of females to 2,4-D ­resulted in adverse alterations in maternal behavior and neuro­chemical changes including increases in dopamine and its metabolites 3,4-­dihydroxyphenylacetic acid and homovanillic acid (Sturtz et al., 2008). Such an increase in dopamine is the reverse of what is seen in PD, in which degradation of the dopaminergic system occurs. In addition, a study of mice and 2,4-D yielded no evidence of neurochemical damage to the dopaminergic system (Thiffault et al., 2001). One study indicated that 2,4-D, among a variety of pesticides and metals, caused fibrillation of α-synuclein in vitro, but it used purified protein and did not report data on 2,4-D but only a generalized result (Uversky et al., 2002), so little confidence can be placed in it. Because the majority of the studies were on the de- veloping nervous system, not the mature nervous system, and some studies yielded evidence of a lack of a role of 2,4-D in the development of PD, the existing studies are of little use in addressing the question of the etiology of PD. A summary of biologic plausibility related to general mechanisms pertinent

526 VETERANS AND AGENT ORANGE: UPDATE 2008 to neurologic effects, including PD, arising from exposure to the herbicides used in Vietnam is presented at the end of this chapter. Synthesis Many studies have found associations of PD with pesticides, but most of them have not determined what specific entities are responsible for generating these positive findings. Increasingly, an association between herbicide exposure and PD has been reported, and several studies since 2006 have suggested a spe- cific relationship between exposure to the chemicals of interest and PD. However, the newer studies are not completely consistent with each other; Kamel et al. (2007b) found an increased risk in incident cases in farm workers exposed to 2,4,5-T but not 2,4-D, and Brighina et al. (2008) found that subjects exposed to phenoxyacetate esters most often reported exposure to 2,4-D. The study of Han- cock et al. (2008) reported increased risks after exposure to multiple pesticides and herbicides, and the increased risk after exposure to chlorophenoxy acid or esters was not statistically significant. Given the broad spectrum of environmental exposures that epidemiologic studies have found to be associated with PD, it has been hypothesized that in- teractions may play a prominent role in its etiology. That would be compatible with PD’s arising from the interaction between herbicides and other substances to which people are exposed during service in Vietnam, such as insecticides. The charge of this committee, however, is limited to the herbicides sprayed in Vietnam; an extension to consideration and evaluation of the limitless universe of interactions is not feasible for a single health outcome, much less for the full array of adverse outcomes that the committee is responsible for examining. Data strengthening the concept of inflammation, oxidative stress, and the involvement of mitochondria in the etiology of PD have been generated recently but not on the herbicides sprayed by the military in Vietnam. Research with 2,4-D in rats, although relatively extensive, has been either on the developing nervous system or on maternal behavior and neurochemistry, and the results do not sup- port a definitive role of 2,4-D in the etiology of PD. Studies reported before 2006 produced a preponderance of data suggesting that exposure to herbicides in general may be related to increased risk of PD. The studies reported since Update 2006 support and extend those earlier observations. The lack of preclinical data on a specific mechanism by which herbicides in gen- eral or specific chemicals of interest may produce PD does not argue against such a relationship but should be a stimulus for further research. Similarly, the lack of data on Vietnam War veterans themselves does not suggest that the relationship does not exist but only that appropriate studies have not been performed. The lack of data relating PD incidence to exposure in the Vietnam-veteran population is of concern to the committee, and we recommend strongly that studies to produce such data be performed. We are also concerned that a bio- logic mechanism by which the chemicals of interest may cause PD has not been

NEUROLOGIC DISORDERS 527 demonstrated. Nevertheless, the preponderance of epidemiologic evidence now supports an association between herbicide exposure and PD and specifically implicates the chemicals of interest. 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 association between exposure to the chemicals of interest and PD. Amyotrophic Lateral Sclerosis ALS is a progressive, adult-onset, motor neuron disease that presents with muscle atrophy, weakness, and fasciculations and with signs that implicate in- volvement of motor pathways in the CNS. The cause of most cases of ALS is unknown, but about 10% of cases report an autosomal dominant pattern of inheritance. One-fifth of familial-ALS patients have mutations in the gene that encodes superoxide dismutase-1 (Rosen et al., 1993). The incidence of sporadic ALS is 1–2 per 100,000 person-years, and the incidence of ALS peaks at the ages of 55–75 years (Brooks, 1996). The diagnosis of ALS is made through clinical examination and electrodiagnostic testing and has a high degree of ac- curacy when made by experienced neurologists (Rowland, 1998; Rowland and Shneider, 2001). Summary of Previous Updates ALS was first considered by the committee for Update 2002. Although multiple potential etiologic factors have been investigated (Breland and Currier, 1967; Deapen and Henderson, 1986; Gallagher and Sander, 1987; Hanisch et al., 1976; Kurtzke and Beebe, 1980; McGuire et al., 1997; Roelofs-Iverson et al., 1984; Savettieri et al., 1991), associations have not been consistently identified. Pesticide or herbicide exposure has been associated with increased risk of ALS, including a doubling of the risk after long-term occupational exposure to pesticides (Deapen and Henderson, 1986) and a tripling of the risk after expo- sure to agricultural chemical products (Savettieri et al., 1991) and after exposure to herbicides (McGuire et al., 1997), although none of the risk estimates was statistically significant. A population-based case–control study demonstrated as- sociations between exposure to agricultural chemical products and ALS in men, with an odds ratio of 2.4 and a trend with duration of exposure that were both statistically significant (McGuire et al., 1997). A mortality study of Dow Chemi- cal Company employees exposed to 2,4-D included three deaths from ALS, with a significant positive association (relative risk, 3.45, 95% CI 1.10–11.11) (Burns et al., 2001).

528 VETERANS AND AGENT ORANGE: UPDATE 2008 In Update 2006, three additional studies were reviewed. Morahan and Pamphlett (2006) published a case–control study from Australia in which the cases were self-reported and the controls chosen in nonrandom fashion. The authors found an increased risk of ALS after exposure to pesticides or herbi- cides, but the lack of appropriate case and control ascertainment and the fact that specific chemicals of interest were not asked about make this study difficult to interpret. Weisskopf et al. (2005) followed vital status of subjects in the American Cancer Society’s cohort for the Cancer Prevention Study II and demonstrated an increased risk of ALS in those who served in any of the armed services during times of conflict. They adjusted for a variety of confounding variables in their model, including exposure to herbicides, and found that none of them signifi- cantly altered their conclusions. Thus, in an indirect way, this large study suggests the lack of a strong effect of herbicide exposure on ALS. Finally, a case–control study of Australian Vietnam veterans reported an association between deploy- ment in Vietnam and ALS (ADVA, 2005c) but did not specifically study exposure to pesticides or herbicides. Table 8-2 summarizes the results of the relevant studies. Update of the Epidemiologic Literature No studies concerning exposure to the chemicals of interest and ALS have been published since Update 2006. Biologic Plausibility No studies concerning the chemicals of interest specifically relevant to ALS have been published since Update 2006. A summary of biologic plausibility of neurologic effects arising from exposure to the chemicals of interest is presented at the end of this chapter. Synthesis Epidemiologic studies of ALS have pursued a variety of occupational expo- sures as potential risk factors; pesticide and herbicide exposures are among those receiving the most attention. Although it has rarely been possible to isolate the effects of selected chemicals of interest, a study of a cohort of 2,4-D production workers did identify significantly increased risk (Burns et al., 2001); however, this result is considered unstable, given the low number of cases and the wide CI. Case–control studies of occupational exposures to pesticides and herbicides have identified significantly increased risks (McGuire et al., 1997; Morahan and Pamphlett, 2006), but they did not weigh heavily, because of imprecise exposure assessments and other design limitations. Although recent prospective (Weisskopf et al., 2005) and retrospective (ADVA, 2005b) studies have identified increased

TABLE 8-2  Epidemiologic Studies of Pesticidea Exposure and Amyotrophic Lateral Sclerosis Significant Association Study Comparison with Neurologic Reference; Country Group Group Exposure Assessment Pesticidesa Estimated Relative Risk (95% CI) Dysfunction Morahan and Pamphlett, 179 179 Questionnaire—exposure to Herbicide, pesticide exposure: 1.6 Self-reported 2006; Australia environmental toxicants (1.0–2.4); industrial exposure: 5.6 (2.1–15.1) ADVA, 2005c; Australia nr nr Deployment to Vietnam 4.7 (1.0–22.8) Weisskopf et al., 2005; nr nr Self-administered 1.5 (1.1–2.1); p = 0.007 Self-reported military Australia questionnaire services, death certificates Burns et al., 2001; US 1,567 40,600 Industrial hygienist ranked + 3.45 (1.1–11.1) Death certificates jobs for exposure to 2,4-D to derive of years exposure and cumulative exposure McGuire et al., 1997; 174 348 Self-reported lifetime job + Herbicide exposure: 2.4 (1.2–4.8); New diagnosis of ALS US history, workplace exposures significant trend analysis for 1990–1994 in western reviewed by panel of four dose–effect relationship with Washington state industrial hygienists agricultural chemicals: p = 0.03 Chancellor et al., 1993; 103 103 Required regular occupational 1.4 (0.6–3.1) Scottish Motor Neuron Scotland exposure to pesticides for 12 Register months or more Savettieri et al., 1991; 46 92 Continual exposure to 3.0 (0.4–20.3) Cases reviewed by Italy agricultural chemicals neurologists Deapen and Henderson, 518 518 Ever worked in presence of 2.0 (0.8–5.4) ALS Society of 1986; US pesticides America ABBREVIATIONS: ALS, amyotrophic lateral sclerosis; CI, confidence interval; nr, not reported; OR, odds ratio. aFor the objective of the VAO review series, only associations with herbicides are of possible relevance; only phenoxy herbicides, cacodylic acid, and picloram 529 are of specific interest.

530 VETERANS AND AGENT ORANGE: UPDATE 2008 risk in veterans who served in Vietnam, they tend to implicate military service itself rather than exposure to the specific chemicals of interest. Conclusions On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that the evidence of an association between exposure to the chemicals of interest and ALS remains inadequate or insufficient. PERIPHERAL NEUROPATHY Peripheral neuropathies comprise a spectrum of disorders caused by damage to nerve fibers (axonal neuropathies) or to the myelin sheath that surrounds many fibers (demyelinating neuropathies). Manifestations of neuropathy can include a combination of sensory changes, motor weakness, and autonomic instability. Clinically, various forms of peripheral neuropathy can be characterized by the distribution of nerve abnormalities and their patterns of progression. Peripheral neuropathy resulting from toxic exposure usually affects nerve fibers in a symmetric pattern, beginning distally in the longest fibers (in the toes) and moving proximally (toward the spine). This kind of neuropathy is called sym- metric axonal sensorimotor polyneuropathy. Sensory deficits begin at the toes, progress above the ankles, and affect the hands only later. Motor symptoms show the same general pattern. Physiologically, various forms of peripheral neuropa- thy can be characterized by results of electrodiagnostic testing to indicate which neural structures are affected. Most toxicant-induced neuropathies involve injury to the nerve-cell bodies (neurons) or nerve fibers (axons) that produces changes in the amplitude of a nerve’s response to an electric stimulus. The clinical appearances of most symmetric axonal neuropathies are quite similar except for variation in rates of progression and in whether pain is a promi- nent symptom. There is no specific signature that distinguishes a toxicant-related neuropathy from one induced by other causes. As many as 30% of neuropathies are “idiopathic”; that is, no etiology is determined despite exhaustive clinical evaluation. The most common toxicant-induced neuropathy occurs as a result of chronic alcohol exposure. Peripheral neuropathy also occurs commonly as a complica- tion of diabetes: its reported prevalence in people who have chronic diabetes is up to 50%. It is important to include assessment of alcohol use and diabetes as covariates in epidemiologic studies because the neuropathies that are related to these conditions are clinically and physiologically indistinguishable from other toxicant-induced neuropathies. Clinically, in cases of toxicant-induced peripheral neuropathy, stabilization or improvement is the rule after exposure ends. Recovery may not be complete, however, and the degree of recovery can depend on the severity of the initial deficits and the particular exposure. Furthermore, there is a possibility of “sub-

NEUROLOGIC DISORDERS 531 clinical” effects, and a person might be unaware of symptoms although evidence of nerve dysfunction can be found through detailed neurologic examination or electrodiagnostic testing. In VAO, peripheral neuropathy was considered a single category of disease. Before revising the conclusion regarding neuropathies, the committee for Update 1996 divided them into “acute and subacute” and “chronic” classifications (on the basis of when an outcome occurs relative to exposure). In this section of the present report, however, the terms acute (brief) and chronic (prolonged or pro- tracted) describe the time course of toxicant exposure. Early onset and delayed onset are used to describe the time course of the neuropathy. The distinction between transient and persistent is not always clear, because recovery may be protracted and incomplete. The committee considers a neuropathy to be of early onset and transient if abnormalities appear and resolve within 2 years after ces- sation of external exposure. Conclusions from VAO and Previous Updates VAO and the previous updates noted that the literature on peripheral neuropa- thy had been difficult to integrate because it was characterized by variable meth- ods that lacked uniform operational definitions. The techniques used to identify affected persons, to define comparison populations, and to assess exposures differ considerably among studies. Many of the studies are limited by nonrandom se- lection, which raises a concern about bias, and by the relatively small number of participants, which decreases confidence in risk estimates and limits the power to detect a true association. Results have been variable; some studies demonstrated abnormalities of peripheral nerve function, and others did not. In the first update, the committee for Update 1996 partitioned the new infor- mation and that which had been addressed in VAO between “chronic persistent peripheral neuropathy” and “acute and subacute transient peripheral neuropathy.” With this information, that committee reached a conclusion of limited or sug- gestive evidence of association with exposure to the chemicals of interest and the “acute or subchronic” form. (To be more precise, the committee for Update 2004 applied the designation “early-onset transient peripheral neuropathy” to this outcome, which will be used henceforth in this discussion.) As reported in VAO, many occupational studies give an indication of early- onset transient peripheral neuropathy in conjunction with herbicide production. In a study of workers from Nitro, West Virginia, that did have a comparison group, Moses et al. (1984) demonstrated this among the workers with chloracne. This outcome was also established shortly after the Seveso accident (Boeri at al., 1978; Filippini et al., 1981; Gilioli et al., 1979), but the effect abated with time (Assennato et al., 1989; Barbieri et al., 1988). Findings were less clear among residents around contamination sites in Missouri (Hoffman et al., 1986; Stehr et al., 1986; Webb et al., 1987). In addition, the committee responsible for Update 1996 reviewed case re-

532 VETERANS AND AGENT ORANGE: UPDATE 2008 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 animal models (Grahmann et al., 1993; Grehl et al., 1993; see “Biologic Plau- sibility” 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. In subsequent updates, there has not been substantively more information found on this type of peripheral neuropathy and the committees have maintained the conclusion of limited evidence of an association for this outcome. New cases of this condition would not be expected among veterans who received their exposure during the Vietnam era. In addition to the short-term assessment done by Moses et al. (1984), the committee responsible for VAO reviewed results of three other occupational- cohort studies of workers who had been exposed to the chemicals of interest. Singer et al. (1982) reported decreased nerve conduction velocities (NCVs) in 2,4-D and 2,4,5-T production workers who were examined 2 months after expo- sures were reduced. In former 2,4,5-T production workers who had a history of chloracne (10 years after last exposure), Moses et al. (1984) found diminished pin-prick sensation, but Suskind and Hertzberg (1984) did not find differences in NCVs. Similarly, Sweeney et al. (1993) reported decreased pin-prick sensation but no differences in NCVs in former herbicide-production workers (evaluated 15 years or more after their last exposure). VAO also reviewed epidemiologic studies of populations potentially exposed to TCDD in the environment. A series of studies in Italy evaluated peripheral neu- ropathy in the Seveso population after the industrial accident on July 10, 1976. Boeri et al. (1978) reported more frequent symptoms and signs of neuropathy in a cohort of residents living in the contaminated area than in a comparison group last examined 7–10 months after the explosion; there was no statistical difference in conduction velocity between groups. Gilioli et al. (1979) noted electrodiag- nostic abnormalities in laboratory technicians potentially exposed to TCDD from analytic samples; however, the technicians were also exposed to solvents used in the analytic process. Filippini et al. (1981) reported an increased prevalence of peripheral neuropathy in Seveso residents with evidence of high exposure to TCDD (chloracne or liver enzyme abnormalities) who were last examined 21 months after the accident. Barbieri et al. (1988) reported a higher rate of abnor- malities on neurologic examination and electrodiagnostic testing in subjects who had a history of chloracne and 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

NEUROLOGIC DISORDERS 533 evaluation of that group 9 years after the accident; no differences were observed in NCVs or neuropathy as defined by WHO criteria. Other environmental stud- ies 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 semiecologic study design was not suited to causal inference. Some of the data from epidemiologic studies of environmental exposures have suggested an increased risk of peripheral nerve abnormalities, but evidence of an association between exposure to the chemicals of interest and peripheral neuropathy is inconsistent. Studies of Vietnam veterans were also reviewed in VAO (AFHS, 1984, 1987, 1991; CDC, 1988). A study by the Centers for Disease Control (now the Centers for Disease Control and Prevention) (CDC, 1988) focused on service in Vietnam, not on exposure to the chemicals of interest, and therefore provided no evidence of the possible effects of specific exposures. There was no indication of increased risk of peripheral neuropathy in the first reports on Ranch Hand veterans (AFHS, 1984, 1987, 1991). Studies reviewed in VAO did not indicate an association be- tween exposure and peripheral neuropathy in Vietnam veterans. Update 1996 reviewed two new epidemiologic studies. Using an administra- tive database, Zober et al. (1994) found no evidence of increased use of medical services 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 pos- sible relationship between exposure and 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 in that the commit- tee issued a special report a year later that concluded that there was limited or suggestive evidence of an association between exposure to Agent Orange and diabetes. Update 2000 reviewed what was then the most recent report on Ranch Hand veterans (AFHS, 2000), which combined signs of peripheral neuropathy to pro- duce increasingly specific, graded indexes of neuropathy—a common approach in epidemiologic studies. Ranch Hand veterans were significantly more likely than comparison subjects to have abnormalities in the indexes, and the preva- lence 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 con-

534 VETERANS AND AGENT ORANGE: UPDATE 2008 founders in their statistical analysis. However, the effect of diabetes could not be eliminated in the most specific neuropathy index, because there were not enough nondiabetic 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 pri- mary analysis, the investigators had included diabetes as a potential confounder in the statistical model. In a secondary analysis, subjects who had conditions that were known to be associated with neuropathy were excluded, and subjects who had diabetes were enumerated. In both analyses, there were strong and significant associations between dioxin concentrations and possible and probable neuropa- thy, and significant trends were found with increasing concentrations of dioxin. However, there were too few nondiabetic subjects to produce useful estimates of risk in the absence of the contribution of diabetes. Thus, questions remained about the specific association between exposure to the chemicals of interest and peripheral neuropathy in the absence of any effect of diabetes. Update 2004 considered one peer-reviewed article (Kim et al., 2003), which reported an association between Korean veterans’ service in Vietnam and periph- eral neuropathy. Methodologic limitations, such as a concern about recall bias and residual confounding due to diabetes, and issues related to TCDD dose estimation prevented a strong inference. Update 2006 (IOM, 2005) uncovered no reports dealing with peripheral neu- ropathy as a diagnosis. Kamel et al. (2005) queried the large AHS cohort about a battery of 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 rely on nonspecific clinical findings. Update of the Scientific Literature Since Update 2006, only a single study reported on outcomes related to peripheral neuropathy. Urban et al. (2007) evaluated the neurologic status of 15 subjects surviving since experiencing significant exposure to TCDD during 1965–1968. The subjects on the average still had grossly increased toxicant concentrations in blood and body fat, suggesting ongoing internal exposure since their occupational exposure. Clinical examination suggested neuropathy in nine subjects; however, nerve-conduction studies were abnormal in only three. Alcohol exposure was significant in the subjects, and the presence or absence of diabetes was not mentioned, so any etiologic relationship between neuropathy and TCDD exposure must be regarded as speculative. Biologic Plausibility No new studies directly pertinent to peripheral neuropathy were identified in the present update. However, it is worth reiterating findings from earlier updates.

NEUROLOGIC DISORDERS 535 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

536 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-

NEUROLOGIC DISORDERS 537 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.

538 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. REFERENCES ADVA (Australian Department of Veterans’ Affairs). 2005b. The Third Australian Vietnam Veterans Mortality Study. Canberra, Australia: Department of Veterans’ Affairs.   Throughout 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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From 1962 to 1971, the U.S. military sprayed herbicides over Vietnam to strip the thick jungle canopy that could conceal opposition forces, to destroy crops that those forces might depend on, and to clear tall grasses and bushes from the perimeters of U.S. base camps and outlying fire-support bases.

In response to concerns and continuing uncertainty about the long-term health effects of the sprayed herbicides on Vietnam veterans, Veterans and Agent Orange provides a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange and other herbicides used in Vietnam. The 2008 report is the eighth volume in this series of biennial updates. It will be of interest to policy makers and physicians in the federal government, veterans and their families, veterans' organizations, researchers, and health professionals.

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