11


Neurologic Disorders

Chapter Overview

Based on new evidence and a review of prior studies, the committee for Update 2012 did not find any new significant associations between the relevant exposures and neurological disorders. Current evidence supports the findings of earlier studies that

•    No adverse cardiovascular or metabolic outcome has sufficient evidence of an association with the chemicals of interest.

•    There is limited or suggestive evidence of an association between the chemicals of interest and Parkinson disease.

•    There is inadequate or insufficient evidence to determine whether there is an association between the chemicals of interest and for all other adverse neurologic outcomes.

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 central nervous system (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 for the purpose of this review they are distinguished from psychiatric conditions—such as posttraumatic stress disorder, depression, and anxiety—and from systemic conditions of uncertain cause, such as chronic fatigue syndrome, although either type of condition may actually have some



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11 Neurologic Disorders Chapter Overview Based on new evidence and a review of prior studies, the committee for Update 2012 did not find any new significant associations between the relevant exposures and neurological disorders. Current evidence supports the findings of earlier studies that • No adverse cardiovascular or metabolic outcome has sufficient evidence of an association with the chemicals of interest. • There is limited or suggestive evidence of an association between the chemicals of interest and Parkinson disease. • There is inadequate or insufficient evidence to determine whether there is an association between the chemicals of interest and for all other adverse neurologic outcomes. Immediate effects of toxicants may involve all aspects of the nervous sys- tem, whereas delayed effects are likely to produce more focal problems. Diffuse damage to the central nervous system (CNS) may cause alterations in thinking, consciousness, or attention, often in combination with abnormalities in move- ment. Focal dysfunction can cause myriad syndromes, depending on which area is damaged. Neurologic disorders can cause problems with thinking and emo- tional dysregulation, but for the purpose of this review they are distinguished from psychiatric conditions—such as posttraumatic stress disorder, depression, and anxiety—and from systemic conditions of uncertain cause, such as chronic fatigue syndrome, although either type of condition may actually have some 773

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774 VETERANS AND AGENT ORANGE: UPDATE 2012 neurophysiologic contributing factors. 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), spino- cerebellar degeneration, and amyotrophic lateral sclerosis (ALS); these diseases can occur in the absence of any toxicant exposure, but all may be triggered by aspects of the environment, including toxicant exposure. Disorders of the peripheral nervous system (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 af- fected. 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 found limited or suggestive evidence that dioxin exposure caused such short-term effects. 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 evaluated in Appendix B. The overall focus of this chapter is on delayed adverse effects on the PNS and the CNS. Timing is important in assessing the effects of chemical exposure on neuro- logic function and must be considered in the design and critique of epidemiologic 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 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), Update 2008 (IOM, 2009), and Up- date 2010 (IOM, 2012). 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

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NEUROLOGIC DISORDERS 775 exposures to neurologic disorders, but the committee’s focus is on the health effects of a particular set of chemicals: four herbicides—2,4-dichlorophen- oxyacetic 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 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a contaminant of 2,4,5-T. The committee also considers studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like chemicals to be informative if their results were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of specific congeners. Although all studies reporting TEQs based on PCBs were reviewed, studies that reported TEQs based only on mono-ortho PCBs (which are PCBs 105, 114, 118, 123, 156, 157, 167, and 189) were given very limited consideration because mono-ortho PCBs typically contribute less than 10% to total TEQs, based on the World Health Organization revised toxicity equivalency factors of 2005 (La Rocca et al., 2008; van den Berg et al., 2006). The specific- ity 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 (COIs) and neurobehavioral disorders, neurodegenerative disorders, and chronic peripheral system disorders. 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 Chapters 1 and 2. For citations new to this update that revisit previously studied populations, design information can be found in Chapter 5. BIOLOGIC PLAUSIBILITY Experimental data regarding the biologic plausibility of a connection be- tween exposure to the COIs and various neurologic disorders continue to accrue. This section summarizes in a general way some of the information reviewed in the current update and, for completeness, includes information from prior updates. Several studies have dealt with mechanisms of neurotoxicity that might be ascribed to the COIs, notably 2,4-D and TCDD. Molecular effects of the COIs are described in detail in Chapter 4. Some aspects of the biochemical activity they induce suggest pathways by which there could be effects on the neural systems. A number of the studies suggest that the COIs, primarily 2,4-D, have neurologic effects, both neurochemical and behavioral, 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 de- velopmental exposure of rodents to a 2,4-D–2,4,5-T mixture (Mohammad and St. Omer, 1986; St. Omer and Mohammad, 1987). Perinatal exposures to TCDD and coplanar, dioxin-like PCBs have reportedly caused deficits in learning behavior in rats (Curran et al., 2011; Haijima et al., 2010; Hojo et al., 2008). However,

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776 VETERANS AND AGENT ORANGE: UPDATE 2012 caution in interpreting the significance of those studies is warranted because the developing 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 COIs. Some studies further support suggestions that the concentration of reactive oxygen species could alter the functions of specific signaling cascades and be involved in neurodegeneration (Drechsel and Patel, 2008). Such studies do not specifically concern the COIs but are potentially relevant to these chemicals inasmuch as TCDD and herbicides have been reported to elicit oxidative 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 so 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 indicated that 2,4-D affected aspects of mitochondrial energetics and mitochondrial calcium flux (Palmeira et al., 1994a,b, 1995a,b); if these effects can also occur in nervous- system cell mitochondria, which is feasible, the energy balance and pathways of cells in the nervous system could be affected, and there could be later damage to nervous-system function. Those mechanistic studies, although they did not produce convincing evidence of specific effects of the COIs in the neurologic outcomes of concern, suggest possible avenues to pursue to determine linkages between the COIs 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 among 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. And 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-

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NEUROLOGIC DISORDERS 777 ceptibility among animals, strains, and species; by the lack of strong evidence of organ-specific effects occurring consistently across species; and by differences in route, dose, duration, and timing of chemical exposures. Thus, although the toxicologic observations themselves cannot establish a conclusion that the COIs produced neurotoxic effects in humans, they do suggest the biologic plausibility of an association and point to potential mechanisms that might have come into play. 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 past 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, Up- date 2006, Update 2008, and Update 2010 concluded that there was inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and neurobehavioral disorders. Many of the data that in- formed that conclusion came from the Air Force Health Study (AFHS; AFHS, 1991, 1995, 2000; Barrett et al., 2001, 2003). 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, but this study did not address delayed effects. For other studies (Kamel et al., 2007a; Solomon et al., 2007), no relationship was found with diverse neurologic outcomes and exposure to unspecified herbicides. Many of the studies reviewed were found to be methodologically flawed (Dahlgren et al., 2003; Pazderova-Vejlupkova et al., 1981; Pelclová et al., 2001, 2002) or uninformative (ADVA, 2005c; Decoufle et al., 1992; Park et al., 2005; Visintainer et al., 1995). VAO and the updates offer more complete discussions of the studies considered. Update of the Epidemiologic Literature One environmental study explored the association between pesticides and rapid-eye-movement (REM) sleep disorder. Postuma et al. (2012) conducted a case-control study of REM sleep disorder in 347 cases and 347 age- and sex- matched controls. Data on occupation and occupational exposures were captured by questionnaire. Significantly increased odds ratios (ORs) for REM sleep be- havior disorder (RBD) were found in farmers and in those reporting occupational exposure to herbicides (OR = 2.54, 95% confidence interval [CI] 1.05–6.16) but not nonoccupational herbicide exposure (OR = 1.30, 95% CI 0.56–2.99).

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778 VETERANS AND AGENT ORANGE: UPDATE 2012 Baldi et al. (2011) examined French vineyard workers’ performance on nine neurobehavioral tests. The adjusted odds of scoring in the worst 25% were higher in exposed than unexposed workers on all tests, and the differences were signifi- cant on all but one. Exposure was determined from job and task histories, but it was exposure only to the general category of “pesticides” and so did not satisfy the committee’s criteria for adequate exposure specificity. Biologic Plausibility Some animal studies have suggested possible involvement of the COIs in the occurrence of neurobehavioral effects. Akahoshi et al. (2009) produced a mouse neuroblastoma cell line that overexpressed the AHR, which is important in d ­ opamine synthesis. Treating the line with TCDD increased tyrosine hydroxylase activity and led to increased dopamine expression. The implication of that finding is not clear, but changes in dopamine regulation have been implicated in a number of neurobehavioral syndromes. In vitro exposure of human CD34+ cells to TCDD induced modulation in gene expression involving the GABAergic pathway, which may be associated with altered synaptic transmission, visual perception, and other neurologic conditions (Fracchiolla et al., 2011). Other recent studies have focused on neurobehavioral outcomes following perinatal exposure, which is of concern for the offspring of Vietnam veterans as discussed in Chapter 10. Haijima et al. (2010) found that perinatal exposure to TCDD impaired memory in male offspring. Mitsui et al. (2006) reported that hip- pocampus-dependent learning could be impaired in male rats exposed to TCDD in utero and that impairment could affect fear conditioning. Curran et al. (2011) assessed the effect of CYP1A2 and the AHR genotype on altered learning and memory in mice exposed to an environmentally relevant mixture of dioxin-like (coplanar) and non-dioxin-like PCBs in utero and during lactation. They observed the most significant deficits in response to PCB treatment in Ahrb1_Cyp1a2(–/–) mice, including impaired novel-object recognition and increased failure rate in the Morris water maze. Lensu et al. (2006) examined areas in the hypothalamus for possible involvement in TCDD effects on food consumption, potentially re- lated 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 and 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 summary of the biologic plausibility of neurologic effects arising from exposure to the COIs is presented at the beginning of this chapter.

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NEUROLOGIC DISORDERS 779 Synthesis There is not consistent epidemiologic evidence of an association between exposure to the COIs and neurobehavioral (cognitive or neuropsychiatric) disor- ders. More research on the COIs and RBD is warranted. 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 COIs and neurobehavioral (cognitive or neuropsychiatric) disorders. 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 past 2 years into the evidence database. Also, a section on AD has been added in this update. 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 nonmotor manifestations of PD have been described, and they can be the presenting symp- toms of the disease. They include cognitive dysfunction that often progresses to frank dementia, sleep disturbances, hallucinations, psychosis, mood disorders, fatigue, and autonomic dysfunction (Langston, 2006). In the almost two centuries since the initial description, much has been learned about the genetic predisposition and pathophysiology of the disease, but its etiology 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 neurode- generative diseases, such as atrophy of multiple systems, that 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.

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780 VETERANS AND AGENT ORANGE: UPDATE 2012 Estimates of 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 persons. It affects about 1% of all persons more than 60 years old and up to 5 million people world- wide. PD is the second-most common 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 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 a-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 The committees responsible for VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 concluded that there was inadequate or insufficient information to determine whether there was an associa- tion between exposure to the COIs and PD. Several studies of PD were reviewed by those committees and are described briefly here. In addition to two new case-control studies examining association specifi- cally with chlorophenoxy acid or esters (Brighina et al., 2008; Hancock et al., 2008), the committee responsible for Update 2008 considered five earlier case- control studies that examined the association between exposure to the COIs and PD. Two of these did not find associations with herbicide exposure (Stern et al., 1991; Taylor et al., 1999), but they may have been limited by little actual herbicide exposure, particularly occupational exposure. Three found significant associations with herbicide exposure (Butterfield et al., 1993; Gorell et al., 1998; Semchuk et al., 1992), and two found increased ORs specifically with chloro- phenoxy acid or esters (Brighina et al., 2008; Hancock et al., 2008). In the new case-control studies, the doubling in risk observed by Hancock et al. (2008) did not achieve statistical significance (OR = 2.07, 95% CI 0.69–6.23), while the increase for chlorophenoxy acids or esters chemical class noted by Brighina et al. (2008) was significant only in the quartile of cases who were youngest at diagno- sis (OR = 1.52, 95% CI 1.04–2.22). In the prospective Agricultural Health Study (AHS), incident PD was related in a dose–response manner to increasing days of pesticide use (Kamel et al., 2007b). On the basis of the evidence summarized

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NEUROLOGIC DISORDERS 781 above, Update 2008 concluded that there was limited/suggestive evidence relat- ing exposure to the COIs and PD. Update 2010 reviewed four more epidemiologic studies related to PD risk and the COIs. Two did not find associations with 2,4-D and other phenoxy herbi- cides (Dhillon et al., 2008; Firestone et al., 2010). Two others did find significant associations. In an analysis of 519 cases and 511 controls, Tanner et al. (2009) found an OR of 2.59 (95% CI 1.03–6.48) for 2,4-D exposure. Elbaz et al. (2009) conducted extensive job or task history evaluations among 224 PD cases and 557 controls, all of whom were agricultural workers in France, and found a suggestive increase in odds of PD (OR = 1.8, 95% CI 0.9–3.3) associated with the use of phenoxy herbicides, and this result was statistically significant when the analyses were restricted to people more than 65 years old (OR = 2.9, 95% CI 1.1–7.3), in contrast to the significant increase reported by Brighina et al. (2008) only in the youngest subjects. The analysis of phenoxy herbicides, however, was not adjusted for use of other types of pesticides. Another study found no association between herbicide exposure and progressive supranuclear palsy (Vidal et al., 2009), which is a distinct disease that has many similar symptoms. The committee responsible for Update 2010 affirmed the conclusion of the previous committee. Those findings are summarized in Table 11-1. Update of the Epidemiologic Literature Vietnam-Veteran and Case-Control Studies  No Vietnam-veteran studies or case-control studies addressing exposure to the COIs and PD have been published since Update 2010. Occupational Studies  Since the previous update, Kenborg et al. (2012) com- pared hospitalization for PD among 3,124 male members of the Danish Union of Gardeners with that among the general Danish population. With more than 68,323 person-years of followup, 28 gardeners were hospitalized for PD, which did not differ significantly from the rate in the general population (standardized hospitalization ratio [SHR] = 1.14, 95% CI 0.76–1.65). Year of birth was used as a surrogate for intensity of exposure, and high exposure was assumed for those born before 1915 (11 cases, SHR = 1.55, 95% CI 0.77–2.77), intermediate ex- posure for those born in 1915–1934 (16 cases, SHR = 1.15, 95% CI 0.66–1.87), and low exposure for those born in 1935 or later (1 case, SHR = 0.28, 95% CI 0.00–1.58). Although the specific pesticides to which individuals were exposed are not known, Danish gardeners have been found to have much higher exposures to pesticides—primarily herbicides, including phenoxy herbicides—than the gen- eral Danish population (Hansen et al., 1992, 2007). Two other occupational studies were published since the previous update, but the exposure assessments lacked specificity for the COIs. One study of agri- cultural workers in France considered only type of farming (Moisan et al., 2011),

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TABLE 11-1  Epidemiologic Studies of Herbicidea Exposure and Parkinson Disease (Shaded Entries Are New Information 782 for This Update) Reference Cases in Comparison Diagnosis of Neurologic and Country Study Group Group Exposure Assessment Exposure(s):a n OR (95% CI) Dysfunction Kenborg et 28 PD cases Incidence of Hospital diagnosis of PD, Pesticides (including Hospitalization: Not specified al., 2012; from male PD in general 1977–2008 phenoxy herbicides) 28 1.1 (0.8–1.7) Denmark members of population of Born before Danish Union Denmark 1915: of Gardeners 11 1.6 (0.8–2.8) (n = 3,124) Born 1915–1934: 16 1.2 (0.7–1.9) Born 1935 or later: 1 0.3 (0.0–1.6) Rugbjerg et 403 PD 405 matched Initial screening phone Herbicides 33 1.8 (0.97–3.4) Parkinsonian tremor, al., 2011; cases from controls interview followed by Neurotoxic pesticides 35 1.8 (0.95–3.3) rigidity, bradykinesia, Canada pharmacy an in-person physical (including 2,4-D, 2,4,5-T) masked facies, database assessment employing a micrographia, or postural checklist and record of imbalance symptoms, reviewed by a neurologist specializing in movement disorders Firestone Enrolled 526 unrelated Structured face-to-face 2,4-D 8 0.8 (0.3–2.0) ≥ 2 of 4 cardinal signs; et al., 2010 cases controls interviews; demographic must have bradykinesia (updates increased information collected, or resting tremor, may and expands from 250 job descriptions (if held have cogwheel rigidity, Firestone et (in original for more than 6 months) or postural reflex al. [2005]); study) to 404 and workplace exposures impairment Washington, to various industrial United toxicants identified from States a checklist were recorded

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Dhillon et 100 PD cases 84 controls Professionally- Ever personally used/ PD diagnosed by al., 2008; recruited without PD administered mixed or applied: neurologist specializing United from a recruited questionnaire used to Herbicide use—home or 34 0.8 (0.4–1.4) in movement disorders States medical from the determine military history agricultural using standard clinical/ (University center’s same medical (including spraying 2,4-D 17 1.2 (0.6–2.8) lab diagnostic criteria of Texas) neurological center herbicides/pesticides), 2,4,5-T 4 0.5 (0.1–1.6) institute in personal use/mixing Silvex or other 2,4,5-TP 1 0.3 (0.0–2.7) East Texas and average duration of products exposure to herbicides and specific pesticides, among other exposures Elbaz et 224 PD cases 557 controls Initial self-assessment, Phenoxy herbicides na 1.8 (0.9–3.3) ≥ 2 cardinal signs (resting al., 2009; plus individual interview Age of onset > 65 yrs na 2.9 (1.1–7.3) tremor, bradykinesia, France with occupational rigidity, impaired postural specialist reflexes) Tanner et 519 cases; 521 controls Telephone interviewers 2,4-D 16 2.6 (1.0–6.5) Enrolling investigator al., 2009; consecutively frequency collected information determined diagnosis and United eligible matched about exposures before type of Parkinsonism, States subjects to cases by the reference age; Unified Parkinson between July age, sex, and employment history— Disease Rating Scale 1, 2004, and location industry, location, score, and clinical May 31, processes, materials, features 2007 and job tasks. Toxicant exposure collected for some jobs. 783 continued

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NEUROLOGIC DISORDERS 803 in men than in women (NCHS, 1994). The most common forms of hearing im- pairment in adults are presbycusis and tinnitus. Heritable factors may influence susceptibility to hearing loss, but external agents can also contribute. Aspirin at high doses can cause reversible tinnitus, and permanent hearing loss may be in- duced by pharmaceuticals (particularly antibiotics and antineoplastic drugs) and by some environmental and industrial chemicals (primarily solvents and metals). In occupational medicine, hearing loss is most often considered as being noise- induced. Cochlear development has been found to be impaired by hypothyroidism induced by endocrine disruptors (Howdeshell, 2002), but such a gestational effect would not pertain to Vietnam veterans exposed to herbicides as adults. Summary from VAO and Previous Updates Epidemiologic results on hearing loss in relation to service in Vietnam or to herbicide exposure more generally were first discussed in Update 2010; the literature searches for that report found two citations that addressed this health outcome. O’Toole et al. (2009) reexamined the health status of a cohort of Aus- tralian Vietnam veterans; as for almost every health endpoint surveyed in that group, the incidences of self-reported complete or partial deafness and of tinnitus showed statistically significant increases compared to the general population, and the committee for Update 2010 had serious concerns that the results reported in O’Toole et al. (2009) were compromised by recall bias and other methodologic problems. Excesses in self-reported hearing loss were also found among licensed pesticide applicators in the AHS at the time of the 5-year followup interview (Crawford et al., 2008), but this effect was associated with insecticide exposure, not with herbicide use. Update of the Epidemiologic Literature No epidemiologic studies addressing herbicide exposure and hearing loss have been published since Update 2010. Biologic Plausibility Although no studies of hearing loss in adult animals directly exposed to the COIs were found, Crofton and Rice (1999) reported that perinatal mater- nal PCB126 exposure resulted in low-frequency hearing deficits in offspring of exposed maternal rats. Increased auditory thresholds occurred in the group treated at 1.0 μg/kg/day for 0.5- and 1-kHz tones, but higher frequencies were not significantly affected. The frequency-specific deficit was hypothesized to be caused by postnatal hypothyroxinemia that occurred during a sensitive period for development of the low-frequency regions of the cochlea. It was consistent with that hypothesis that pups from the study were found to have decreased serum

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804 VETERANS AND AGENT ORANGE: UPDATE 2012 T4 concentrations on postnatal day 21. It is important to note that PCB126 is a potent dioxin-like compound, having one-tenth the toxic potency of TCDD (see Chapter 4). A summary of the biologic plausibility of neurologic effects arising from exposure to the COIs is presented at the end of this chapter. Synthesis Two prior studies observed increased risk of hearing loss in Vietnam veter- ans and pesticide applicators, but neither was able to examine the specific COIs for the committee or to confirm hearing loss clinically. Furthermore, the report from the AHS (Crawford et al., 2008) observed an association only in insecticide applicators, not in herbicide applicators. The O’Toole et al. (2009) study evalu- ated Vietnam veterans, but it used a comparison group that was limited to the general population, not veterans from the same era who were not deployed to Vietnam, so it 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. In the absence of new studies, the synthesis remains unchanged since 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 COIs and hearing loss. 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. 1991. An Epidemiological Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Serum Dioxin Analysis of 1987 Examination Results. Brooks AFB, TX: USAF School of Aerospace Medicine. AFHS. 1995. An Epidemiological Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1992 Follow-Up Examination Results. Brooks AFB, TX: Epidemiologi- cal Research Division. Armstrong Laboratory. 1  Throughout this report, the same alphabetic indicator after year of publication is used consistently for a given reference when there are multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicators in order of citation in a given chapter is not followed.

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