Veterans and Agent Orange: Update 2010 (2012)

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

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 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 delayed adverse effects on the PNS and the CNS.

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: 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 abnormalities 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 effects 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,

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 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.

NEUROBEHAVIORAL (COGNITIVE OR NEUROPSYCHIATRIC) DISORDERS

This section summarizes the findings of VAO and previous updates on neurobehavioral 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 insufficient 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 between “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 although 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 pattern with serum TCDD concentration was found only for “other neuroses” in the enlisted ground crew. When the entire cohort was evaluated, there were no significant 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 memory 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 exposure 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 categorized 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 diagnostic 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 constellation 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.

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 hydrocarbon 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 dopamine 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 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 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.

NEURODEGENERATIVE DISEASES

This section summarizes the findings of previous VAO reports on neurodegenerative 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 nonmotor 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 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; 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 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 herbicide 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 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 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 herbicide 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 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 = 5.8, 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 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 bias.

Update 2008 reviewed several new epidemiological studies related to PD risk and compounds of interest. 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. 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). 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 recruitment algorithm were provided. During a structured interview, study participants 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 unrelated 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 recruiting 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

TABLE 9-1 Epidemiologic Studies of Herbicide^a Exposure and Parkinson Disease

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid or Silvex; CI, confidence interval; OR, odds ratio; PD, Parkinson disease; RDD, random-digit dialing.
^aFor the objective of the VAO review series, only associations with herbicides are of possible relevance; only the phenoxy herbicides, cacodylic acid, and picloram are of specific interest.

1.12–3.21), and exposure to 2,4-D also significantly increased risk (OR = 2.59, 95% CI 1.03–6.48). The strengths of this study were the multicenter recruitment strategy and the careful job ascertainment.

Another well-controlled study was performed investigating 224 PD cases and 557 controls drawn from an agricultural area in France with a high degree of pesticide/herbicide use (Elbaz et al., 2009). Occupational exposure was conducted with a two-stage process that included initial self-assessment followed by individual interviews with an occupational specialist. Farming as an occupation as well as professional pesticide use were significantly associated with an increased risk of PD. Exposure to phenoxy herbicides was associated with a trend toward higher risk of PD (OR = 1.8, 95% CI 0.9–3.3) which became statistically significant when age of onset was restricted to greater than 65 years (OR = 2.9, 95% CI 1.1–7.3).

Progressive Supranuclear Palsy (PSP) is a disorder that overlaps PD with respect to many symptoms. In a small case–control study of 79 patients with PSP and 79 controls, Vidal et al. (2009) found no relationship between risk of PSP and exposure to herbicides in general.

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 toxicity resulting from human exposure to MPTP 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. Pesticides 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 Di Monte et al. (2002) and Sherer et al. (2002a). The damage done to dopaminergic neurons in PD is probably from oxidative stress and probably also involves damage to mitochondria in the target cells (Liang et al., 2007; Sarnico et al., 2008). In this regard, Bongiovanni et al. (2007) found that rat cerebellar granule cells in culture produce increased levels of reactive oxygen specials when exposed to 2,4-D. The chemicals of interest to this committee are known to be distributed to the CNS, but they have not been investigated in similar experimental 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 resulted in adverse changes in the developing nervous system, both neurochemical (such as changes in D2 receptors, tyrosine hydroxylase and dopamine beta-hydroxylase) 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 exposure 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 developing 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 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

Update 2008 reviewed three recent epidemiological studies (Brighina et al., 2008; Hancock et al., 2008; Kamel et al., 2007) as well as reevaluated older studies that did not specifically investigate relationships between disease and the compounds of interest (COIs). Based on the preponderance of data, the committee concluded that there was limited or suggestive evidence of an association of COIs with PD. This conclusion was arrived at despite concern that no specific studies had been performed on veterans, as well as the fact that a clear biological mechanism underlying a relationship was not known. Since 2008, two well-designed epidemiological studies performed in the United States and France primarily on rural workers have also shown a relationship. There continues to be a dearth of investigation on veterans, and biological plausibility is still lacking. We continue to strongly urge the performance of studies relating PD incidence to exposure in the Vietnam-veteran population. We are also concerned that a biologic mechanism by which the chemicals of interest may cause PD has not been demonstrated. Nevertheless, the preponderance of epidemiologic evidence

continues to support 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 involvement 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 accuracy 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 exposure 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 associations 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 Chemical 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).

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 herbicides, 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 significantly 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 deployment in Vietnam and ALS (ADVA, 2005c) but did not specifically study exposure to pesticides or herbicides.

No additional studies concerning exposure to the chemicals of interest and ALS were found for review in Update 2008.

Table 9-2 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Since the last update, there has been one report evaluating the relationship between a variety of chemical exposures and death from ALS in more than 1 million participants of the American Cancer Prevention Study (Weiskopf et al., 2009). Among men, 617 deaths due to ALS were identified, and 539 deaths among women. Exposure to pesticides and herbicides were considered together, so the exposure characterization was not sufficiently specific to meet the committee’s criteria. Nonetheless, no evidence of a significant relationship of exposure to death from ALS was found.

Biologic Plausibility

No toxicology studies concerning exposure to the chemicals of interest and ALS have been published since Update 2008. 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

No well-designed studies have implicated a relationship between compounds of interest and the risk of developing ALS.

TABLE 9-2 Epidemiologic Studies of Pesticide^aExposure and Amyotrophic Lateral Sclerosis

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; ALS, amyotrophic lateral sclerosis; CI, confidence interval; COI, chemical of interest; 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 are of specific 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.

CHRONIC PERIPHERAL SYSTEM DISORDERS

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 symmetric 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 neuropathy 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 prominent 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 complication 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.

Toxicant exposure can result in an immediate response of peripheral neuropathy (early onset) or chronic peripheral neuropathy that occurs years after the external exposure has ended (delayed onset). The committee considers a neuropathy to be early onset if abnormalities appear within a year after external exposure ends or to be chronic if abnormalities appear more than a year after external exposure has ended. A review of the data supporting the association of

exposure with early-onset peripheral neuropathy is presented in Appendix B, and will not be recapitulated here. Because the exposures of interest for Vietnam veterans are long past, immediate effects of the chemicals of interest are no longer pertinent for this cohort. The focus of this section will be on data related to chronic peripheral neuropathy.

Summary from VAO and Previous Updates

VAO reviewed epidemiology studies of populations potentially exposed to TCDD in the environment. A series of studies in Italy evaluated peripheral neuropathy in the Seveso population. Barbieri et al. (1988) reported a higher rate of abnormalities 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 the World Health Organization criteria. Assennato et al. (1989) studied 193 exposed residents of the area 9 years after the accident and did not demonstrate neurophysiological abnormalities. Other environmental studies 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 between exposure and peripheral neuropathy in Vietnam veterans.

Update 1996 reviewed two new epidemiologic studies. Using an administrative 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 possible relationship between exposure and neuropathy.

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 prevalence 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 confounders 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 primary 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 neuropathy, 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.

In summary, studies on Vietnam veterans originally did not demonstrate a relationship between service and symptoms of neuropathy; however, the more recent studies suggesting a relationship are not due to an increase in neuropathic symptoms but to a more sensitive measure of assaying symptom complexes (AFHS, 2000; Michalek et al., 2001). All of the large veteran studies are limited by the confounding nature of concurrent diabetes and alcohol exposure, both of which also are related to neuropathy.

Update of the Scientific Literature

Since the last update, there has been one study evaluating the association of exposure to a variety of toxicants to the presence of neuropathy in subjects with either frank diabetes or impaired glucose tolerance (Lee et al., 2008). Concentrations of dioxin-like polychlorinated biphenyls (PCBs) were ranked, and subjects with hemoglobin A1C levels of greater or less than 7 were compared separately. In neither group was there evidence of an increased incidence of neuropathy or of a dose response that suggested a concentration dependent risk of neuropathy. Given the underlying risk of neuropathy inherent in patients with diabetes, the

lack of information regarding duration of diabetes as well as small subject numbers renders this study difficult to evaluate.

Also, Pelclová et al. (2009) updated a study of Czech workers (aged 64.4 ± 1.5 years) exposed to TCDD between 1965–1968, while working in a plant producing 2,4,5-T. Eleven out of the original group of approximately 80 workers were reevaluated for this update. Seven exposed workers were found to have mild polyneuropathy, as well as diabetes. The usefulness of this study is limited because of the small sample size, the lack of a well-defined comparison population, the lack of comparison data between the exposed and non-exposed populations, and the absence of information about the relationship between diabetes and neuropathy in these workers.

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. Neuronal cell cultures treated with 2,4-D showed decreased neurite extension associated with intracellular changes, including a decrease in microtubules, inhibition of the polymerization of tubulin, disorganization of the Golgi apparatus, and inhibition of ganglioside synthesis (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 sacrificed 8 months after exposure, there was pathologic evidence of persistent axonal nerve damage and histologic findings typical of toxicant-induced injury. Those results constitute evidence of the 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 chemicals of interest is presented at the end of this chapter.

Synthesis

The epidemiological studies relating industrial or individual exposure to acute neuropathy were judged by the committee for Update 1996 and subsequent updates to constitute limited or suggestive evidence of an association between exposure to the chemicals of interest and early-onset transient peripheral neuropathy. As summarized above, further studies of the long-term sequelae of these exposures also suggest persistence of symptoms either permanently or over years.

There are, however, no data that suggest that exposure to compounds of interest can lead to the development of delayed-onset chronic neuropathy many

years after termination of exposure among those who did not originally complain of early onset neuropathy.

Conclusions

The committee concludes that, in addition to evidence for transient early-onset peripheral neuropathy, there is limited or suggestive evidence of an association between exposure to the chemicals of interest and early-onset peripheral neuropathy that may be persistent.

On the basis of the evidence reviewed here and by previous committees, however, this committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and delayed-onset chronic neuropathy.

HEARING LOSS

Hearing loss increases markedly with age, with about one in four people over 70 years of age being affected and the prevalence being somewhat higher in men than women (NCHS, 1994, 2010). The most common forms of hearing impairment developing adults are presbycusis and tinnitus. Heritable factors may be influenced susceptibility to hearing loss, but external agents can also contribute. Aspirin at high doses can cause reversible tinnitus, while permanent hearing loss may be induced by pharmaceuticals (particularly antibiotics and anti-neoplastic 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 effects would not pertain to Vietnam veterans exposed to herbicides as adults.

Update of the Epidemiologic Literature

A cohort of Australian Vietnam veterans (O’Toole et al., 2009) was studied between 1990–1993 and reexamined in 2005–2006. In the original assessment, 641 Australian Vietnam veterans were randomly selected for participation from the list of Army veterans deemed eligible for previous studies of Agent Orange and 450 were included in the more recent assessment. Interviewers administered the Australian Bureau of Statistics National Health Survey that assessed physical health and associated risk factors, a 32-item combat index, an assessment for combat-related PTSD, and an assessment of general psychiatric status. The prevalences of a variety of self-reported health conditions were compared to the general population and standardized mortality ratios (SMRs) were calculated (standardized to the Australian male population in 5-year age groups). Compared

to the general population, Vietnam veterans had an increased prevalence of diseases 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 applicators 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 applicators. 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.

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 association 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 effects, 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 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 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 involved 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 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

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 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 determine 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 neurotransmitter systems as potential mechanisms that underlie TCDD-induced neurobehavioral 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 neurotransmission 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 function 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 susceptibility 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 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 neuro-psychiatric) or ALS.

Previous VAO reports had concluded that there was inadequate or insufficient 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 exposure 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 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 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 transient. 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 association 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.

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