9

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, which 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 such internal events as changes in blood pressure or temperature and 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 in combination with abnormalities in movement. Focal dysfunction can cause myriad syndromes, depending on which area is damaged. Neurologic disorders can cause problems with thinking and emotional dysregulation, but 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 disease (PD), Alzheimer disease (AD), spinocerebellar degeneration, and amyotrophic lateral sclerosis (ALS); all these diseases occur in



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9 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, which 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 such internal events as changes in blood pressure or temperature and 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 ef - fects 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 in combina - tion with abnormalities in movement. Focal dysfunction can cause myriad syn- dromes, depending on which area is damaged. Neurologic disorders can cause problems with thinking and emotional dysregulation, but it is important to dis - tinguish 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 disease (PD), Alzheimer disease (AD), spinocerebellar degeneration, and amyotrophic lateral sclerosis (ALS); all these diseases occur in 611

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612 VETERANS AND AGENT ORANGE: UPDATE 2010 the absence of any toxicant exposure 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, however, 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 generally 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. Toxicant exposure can induce immediate damage to peripheral nerves, and previous updates have found limited or suggestive evidence that dioxin exposure caused such short-term ef - fects. Evidence related to rapid onset of these conditions is presented in Appendix B, which deals with short-term adverse health effects. Previously undistilled information concerning persistence of symptoms after early effects is also evalu - ated in Appendix B. The overall focus of this chapter is delayed adverse effects on the PNS and the CNS. Timing is important in assessing the effects of chemical exposure on neu- rologic function and must be considered in the design and critique of epide - miologic studies. In the original Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 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) and Update 2008 (IOM, 2009). The present chapter 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)—and a contaminant of 2,4,5-T, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Thus,

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613 NEUROLOGIC DISORDERS the specificity of exposure assessment is an important consideration 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 chronic peripheral system disorders. The scientific evidence supporting biologic plau - sibility 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 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 committees responsible for VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 concluded that there was inadequate or insuf- ficient evidence to determine whether there is an association between exposure to the chemicals of interest and neurobehavioral disorders. Many of the data that informed that conclusion 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

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614 VETERANS AND AGENT ORANGE: UPDATE 2010 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. Update 2002 reviewed three studies. Neuropsychologic tests of cognitive 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 mem- ory test in one subgroup of subjects suggested a chance finding ( Barrett et al., 2001). Gauthier et al. (2001) did not find a relationship between AD and expo - sure to herbicides and insecticides. The poorly documented results of Pelclová et al. (2001) from a 30-year follow-up of 13 of 55 workers in 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 Vietnam, 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 chemicals 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. Update 2008 considered data on subjects who participated in the Agricultural Health Study (Kamel et al., 2007a) and found no relationship between a constel - lation of neurobehavioral complaints and herbicide exposure. Another large study of rural residents of England failed to demonstrate a clear relationship between herbicide exposure and a variety of neurologic and neurobehavioral symptoms (Solomon et al., 2007). In contrast, the study of Urban et al. (2007) confirmed that acute neurologic symptoms experienced shortly after an acute exposure to TCDD could be sustained more than 30 years after the exposure; this study did not address delayed effects, because the subjects evaluated all had evidence of acute toxicity.

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615 NEUROLOGIC DISORDERS Update of the Epidemiologic Literature No Vietnam-veteran, occupational, or environmental studies of exposure to the chemicals of interest and neurobehavioral conditions have been published since Update 2008. Biologic Plausibility Some animal studies have suggested possible involvement of the chemicals of interest in the occurrence of neurobehavioral effects. Akahoshi et al. (2009) produced a mouse neuroblastoma cell line that overexpressed the aryl hydrocar- bon receptor, which is important in dopamine synthesis. Treating the line with TCDD increased tyrosine hydroxylase activity and led to increased dopamine expression. The implication of that finding is not clear, although changes in dopa- mine regulation have been implicated in a number of neurobehavioral syndromes. Other recent studies have focused on perinatal exposure. Haijima et al. (2010) found that perinatal exposure to TCDD impaired memory in male offspring. Mitsui et al. (2006) reported that hippocampus-dependent learning could be impaired in male rats exposed in utero to TCDD and that impairment could have affected fear conditioning. Lensu et al. (2006) examined areas in the hypothala - mus 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 cerebellar granule cells or neuroblasts, which are involved in cognitive and motor 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 between Agent Orange exposure and neurobehavioral (cognitive or neuropsychiatric) disorders. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and neurobehavioral (cognitive or neuropsychiatric) disorders.

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616 VETERANS AND AGENT ORANGE: UPDATE 2010 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 2 years into the evidence database. Parkinson 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 nonmo - tor manifestations of PD have been described, and 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 about genetic predisposition and the pathophysiology of the disease. However, 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, 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, and neurodegenerative diseases, such as multiple systems atrophy, which have par- kinsonian 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 com- mon neurodegenerative disease (after AD). Age is a risk factor for PD; the peak incidence and prevalence are 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 associ- ated 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,

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617 NEUROLOGIC DISORDERS 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 In Update 2008, both new and previous studies referring to specific herbi- cide exposures and risk of PD were reviewed. Stern et al. (1991) performed a case–control study of 69 cases in people who developed symptoms before the age of 40 years (early onset) and 80 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, the study is limited in that the design specifi - cally 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 cases as compared to 260 controls from Calgary, Alberta, Canada; a statistically significant crude OR of 3.06 (95% confidence interval [CI] 1.34–7.00) was found for herbicide exposure; 7 of the 17 cases reporting herbi - cide use were able to specify the particular product—1 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 as- sociation 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 asso- ciation 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 = 5.8, 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 associa- tion 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 bias. Update 2008 reviewed several new epidemiological studies related to PD risk and compounds of interest. Kamel et al. (2007b) studied the large cohort col- lected 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. 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 =

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618 VETERANS AND AGENT ORANGE: UPDATE 2010 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). Brighina et al. (2008) performed a large case–control study of 844 case–control pairs, and found that exposure to chlorophenoxy acid or esters chemical class was associated with increased risk of PD in younger subjects (OR = 1.52, 95% CI 1.04–2.22; p = 0.004); 2,4-D was the most commonly reported of the phenoxy herbicides. Another study reported in this Update was that of Hancock et al. (2008), who 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). Exposure to chlorophenoxy 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). On the basis of the preponderance of evidence summarized above, Update 2008 concluded that there was limited/suggestive evidence relating exposure to the compounds of interest and PD. These findings are summarized in Table 9-1. Update of the Epidemiologic Literature Since the previous update, a number of new epidemiologic studies have been published. Dhillon et al. (2008) evaluated a variety of risk factors in an East Texas cohort of 800 PD patients seen at a local medical center’s neurological institute. For the analysis, 100 cases and 87 controls were recruited; no details on the re - cruitment algorithm were provided. During a structured interview, study partici - pants were queried about their herbicide use in general and about their personal use, mixture, or application of individual products, including 2,4-D, 2,4,5-T, Silvex, or other 2,4,5-TP products. An equal number of cases (34) and controls (34) reported having used herbicides for home or agricultural purposes (OR = 0.8, 95% CI 0.4–1.4). No significant relationship was found between exposure to 2,4-D (OR = 1.2, 95% CI 0,6–2.8), 2,4,5-T (OR = 0.5 (0.1–1.6) or Silvex or other 2,4,5-TP products (OR = 0.3, 95% CI 0.03–2.7) and a diagnosis of PD. Firestone et al. (2010) extended a population based case–control study of incident PD cases in Washington State by adding cases newly diagnosed 2003–2006 to those diagnosed 1992–2002 and analyzed in Firestone et al. (2005). The total of enrolled PD cases increased from 250 to 404, who were compared to 526 un - related controls. The prevalence of exposure to compounds of interest was low; 8 cases reported exposure to 2,4-D, and there was no suggestion of a difference in exposure between cases and controls (OR = 0.8, 95% CI 0.3–2.0). In contrast, Tanner et al. (2009) performed a case–control study recruit- ing consecutive subjects from eight large movement disorders clinics in North America; 519 cases and 521 cases were recruited. Subjects whose occupation included frequent pesticide use had an increased risk of PD (OR = 1.90, 95% CI

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TABLE 9-1 Epidemiologic Studies of Herbicidea Exposure and Parkinson Disease Diagnosis of Reference and Cases in Study Comparison Neurologic Country Group Group Exposure Assessment Exposure(s)a n OR (95% CI) Dysfunction Firestone Enrolled cases 526 unrelated Structured face-to-face 2,4-D 8 0.8 (0.3–2.0) ≥ 2 of 4 cardinal et al., 2010 increased from controls interviews; demographic signs; must have (updates 250 (in original information collected, bradykinesia or and expands study) to 404 job descriptions (if held resting tremor, Firestone for more than 6 months) may have et al., 2005); and workplace exposures cogwheel rigidity, Washington, to various industrial or postural reflex US toxicants identified from a impairment checklist were recorded Dhillon et al., 100 PD cases 84 controls Professionally Ever personally used/mixed or applied: PD diagnosed 2009; US recruited from a without PD administered Herbicide use-home or 34 0.8 (0.4–1.4) by neurologist (University of medical center’s recruited questionnaire used to agricultural specializing Texas) neurological from the same determine military history 2,4-D 17 1.2 (0.6–2.8) in movement institute in East medical center (including spraying 2,4,5-T 4 0.5 (0.1–1.6) disorders using Texas herbicides/pesticides), Silvex or other 2,4,5- 1 0.3 (0.0–2.7) standard clinical/ personal use/mixing TP products lab diagnostic and average duration of criteria exposure to herbicides and specific pesticides, among other exposures Elbaz et al., 224 PD cases 557 controls Initial self-assessment, Phenoxy herbicides na 1.8 (0.9–3.3) ≥ 2 cardinal signs 2009; France plus individual interview na 2.9 (1.1–7.3) (rest tremor, Age of onset > 65 yrs with occupational bradykinesia, specialist rigidity, impaired postural reflexes) 619 continued

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TABLE 9-1 Epidemiologic Studies of Herbicidea Exposure and Parkinson Disease, continued 620 Diagnosis of Reference and Cases in Study Comparison Neurologic Country Group Group Exposure Assessment Exposure(s)a n OR (95% CI) Dysfunction Tanner et al., 519 cases; 521 controls Telephone interviewers 2,4-D 16 2.6 (1.0–6.5) Enrolling 2009; US consecutively frequency collected information investigator eligible subjects matched about exposures before determined between July 1, to cases by the reference age; diagnosis and type 2004, and May age, sex, and employment history— of parkinsonism, 31, 2007 location industry, location, Unified Parkinson processes, materials, Disease Rating and job tasks. Toxicant Scale score, and exposure collected for clinical features some jobs Brighina 833 PD sequential 472 unaffected Self-report down to For youngest quartile at diagnosis: PD diagnosed et al., 2008; cases from clinic; siblings and specific herbicides; 2,4-D Pesticides (ever): 87 1.8 (1.1–2.9) by movement US (Mayo median age = 67.7 361 unrelated said to be most prevalent Herbicides (ever): 2.5 (1.3–4.5) disorder specialist Clinic) controls in cases, but published Phenoxy herbicides 1.5 (1.0–2.2) yr, 208 cases ≤ 59.8 yr analysis 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 referent Pesticide application: 200 1.6 (1.1–2.3) et al., 2008; relatives and to those who never Insecticides: 1.8 (1.2–2.8) US (Duke) others applied any pesticide Botanical: 7 5.9 (0.6–56) 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)

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Kamel et al., 83 prevalent cases 79,557 Self-report of individual For incident cases: 2007b; US at enrollment; without PD at herbicides (2,4-D; 2,4-D: 49 1.0 (0.5–2.1) (Agricultural 78 incident cases enrollment; 2,4,5-T; 2,4,5-TP) on 2,4,5-T: 24 1.8 (1.0–3.3) Health Study) during follow-up 55,931 without detailed self-administered 2,4,5-TP: 7 0.9 (0.4–1.8) among private PD followed up questionnaires at Dicamba: 32 1.5 (0.8–2.8) [Updates applicators and enrollment or telephone Paraquat: 11 1.0 (0.5–1.9) Kamel et al., spouses interview for follow-up Trifuralin: 32 1.7 (1.0–3.2) 2005] Cyanazine 26 1.0 (0.5–1.8) 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 250 (156 men) 388 (241 men) Interview determining Occupational, men only Controlled for et al., 2005; newly diagnosed occupational and home- Pesticides: 19 1.0 (0.5–1.9) age, sex, smoking Washington, 1992–2002 at based pesticide exposure Insecticides: 15 0.9 (0.4–1.8) US Group Health characterized by chemical Fungicides: 2 0.4 (0.1–3.9) Cooperative name or brand, duration, Herbicides: 9 1.4 (0.5–3.9) and frequency Paraquat: 2 1.7 (0.2–12.8) Home use, all subjects 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, 377 matched Structured interview McNemar chi-square: p = 0.010 2001; India 76 women) for age (± 3 yr), Herbicides: but not sex 621 continued

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635 NEUROLOGIC DISORDERS to the general population, Vietnam veterans had an increased prevalence of dis - eases of the ear and mastoid (SMR = 1.93, 95% CI 1.81–2.05; SMR = 5.96, 95% CI 5.36–6.57) for complete or partial deafness and tinnitus, respectively. The committee had serious concerns that the results reported in O’Toole et al. (2009) were compromised by recall bias and other methodologic problems. Crawford et al. (2008) examined hearing loss among licensed pesticide ap - plicators in the Agricultural Health Study (see Chapter 5). Self-reported hearing loss was reported in the AHS 5-year follow-up interview. In this nested case– control study of the 14,229 white male applicators, 4,926 reported hearing loss (35%) not resulting from a congenital condition or infection (as determined from additional survey questions). Several variables related to pesticide accidents or high-exposure events were related to self-reported hearing loss. For example, compared to those who had not received pesticide-related medical care or who did not experience a high pesticide exposure event, risk of self-reported hearing loss was increased (OR = 1.81, 95% CI 1.25–2.62; OR = 1.38, 95% CI 1.24–1.53), for having been treated for a pesticide-related medical condition or ever having a high pesticide exposure event, respectively. Similarly, ever having a diagnosis of pesticide poisoning was associated with hearing loss (OR = 1.75, 95% CI 1.36–2.26). Analyses by pesticide class did not show strong associations with hearing loss. Compared to no reported days of insecticide use, applicators in the exposure category (greater than 175 days of insecticide use) was associated with self-reported hearing loss (OR = 1.19, 95% CI 1.04–1.35). In contrast, applicators reporting more than 651 lifetime days of herbicide use did not have a higher risk of self-reported hearing loss (OR = 1.04, 95% CI 0.91–1.20). Biologic Plausibility Toxicologic studies of hearing impairment in conjunction with the chemicals of interest have not been found in the published literature. Synthesis While two studies observed increased risk of hearing loss among Vietnam veterans and among pesticide applicators, neither study was able to examine the specific chemicals of interest to the committee and neither was able to clinically confirm hearing loss. Further, the report from the AHS (Crawford et al., 2008) only observed an association among insecticide applicators and not herbicide ap - plicators. While the O’Toole study evaluated Vietnam veterans, the comparison group was limited to the general population and not veterans from the same era not deployed to Vietnam and therefore could not distinguish between hearing loss that may be associated with noise-related to military service and hearing loss potentially associated with exposures to toxic chemicals.

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636 VETERANS AND AGENT ORANGE: UPDATE 2010 Conclusion On the basis of the evidence reviewed here, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an as - sociation between exposure to the chemicals of interest and hearing loss. 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 - 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 oxida - tive stress (Byers et al., 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 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

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637 NEUROLOGIC DISORDERS 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. 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 as - sociation between exposure to the chemicals of interest (2,4-D, 2,4,5-T, TCDD, picloram, and cacodylic acid) and neurobehavioral disorders (cognitive or neuro- psychiatric) or ALS.

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638 VETERANS AND AGENT ORANGE: UPDATE 2010 Previous VAO reports had concluded that there was inadequate or insuf- ficient evidence of an association between exposure to the chemicals of interest and PD. The committee for Update 2008 reviewed 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 of PD is posed by herbicide expo- sure in general. That impression was strengthened by newer studies that reported a specific risk related to the chemicals of interest, so the committee for Update 2008 concluded that there is limited or suggestive evidence of an association between exposure to the chemicals of interest and PD. The additional relevant information published since Update 2008 is consistent with that finding. The committee for Update 2004 exhaustively reviewed the data on peripheral neuropathy and concluded that there was limited or suggestive evidence of an as- sociation 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 neu- ropathy. The committees responsible for Update 2006 and Update 2008 concurred with that conclusion. The current committee scrutinized the available follow-up findings on individuals experiencing peripheral neuropathy shortly after exposure and wishes to clarify that early-onset peripheral neuropathy is not necessarily tran- sient. Consequently, the distinction to be made concerning the type of peripheral neuropathy for which there is limited or suggestive evidence of association with herbicide exposure is based on time of onset rather than chronicity. In summary, aside from noting limited or suggestive evidence of an associa - tion for persistent, as well as transient, peripheral neuropathy, on the basis of its review of new data and a re-evaluation of older studies, the present committee concurs with the conclusions of previous committees concerning neurologic outcomes. REFERENCES1 ADVA (Australian Department of Veteran’s Affairs). 2005c. Australian National Service Vietnam Veterans Mortality and Cancer Incidence Study. Canberra, Australia: Department of Veterans’ Affairs. AFHS (Air Force Health Study). 1984. An Epidemiological Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Baseline Morbidity Study Results. Brooks AFB, TX: USAF School of Aerospace Medicine. NTIS AD-A138 340. AFHS. 1987. An Epidemiological Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. First Follow-up Examination Results. Brooks AFB, TX: USAF School of Aerospace Medicine. USAFSAM-TR-87-27. 1 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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