11

Neurologic Disorders

Chapter Overview

The Department of Veterans Affairs (VA) gave the committee for Update 2014 the special task to address whether various diagnoses with Parkinsonian symptoms should be included in the presumptive service related category for Parkinson disease (PD). Because diagnostic specificity is improbable in both the studies upon which the conclusion of limited or suggestive association with exposure to military herbicides were based and in the documentation for the claims submitted to VA by Vietnam veterans, the committee clarifies that the finding for PD should be interpreted by VA to include all diseases with Parkinson-like symptoms unless those symptoms can be definitively attributed to be secondary to an external agent other than the herbicides sprayed in Vietnam.

Based on new evidence and a review of prior studies, the committee for Update 2014 did not find any new significant associations between the relevant exposures and neurological disorders. Current evidence supports the findings of earlier studies that:

• There is limited or suggestive evidence of an association between the chemicals of interest and PD and diseases that present with Parkinson-like symptoms.
• There is inadequate or insufficient evidence to determine whether there is an association between the chemicals of interest and any of the other adverse neurologic outcomes.

The immediate effects of toxicants may involve all regions of the nervous system, whereas delayed effects are likely related to focal deficits. Diffuse damage to the central nervous system (CNS) may cause alterations in thinking, consciousness, or attention, sometimes in combination with abnormalities of movement, while focal dysfunction can cause myriad syndromes, depending on which area of the brain is involved and the extent and severity of damage. For the purposes of this review, neurologic deficits associated with Vietnam service are distinguished from psychiatric/psychologic conditions—such as posttraumatic stress disorder (PTSD), depression, and anxiety—and from chronic fatigue syndrome. While the increased risks of these conditions among veterans of all US conflicts are of scientific and public health concern, this committee, like previous Veterans and Agent Orange (VAO) committees, believes that two major underlying principles justify their exclusion from systematic review and evaluation:

• First, military service alone, including deployment and service in Vietnam, confers a range of potentially traumatic psychological exposures that may be expected to increase the risk of developing PTSD and related psychological comorbidities. To illustrate this point, compelling evidence has established that the prevalence of PTSD is more than twice as high for operational infantry units exposed to direct combat than in the general population (Kok et al., 2012). Given the known relationship between combat exposure and an increased risk of mental health conditions, a synthesis of the literature would not provide the opportunity to disentangle any potential adverse effects from exposure to the chemicals of interest (COIs) on mental health outcomes that may occur independently of effects (psychological) accrued through military service.
• Second, a review of the vast toxicology literature that relates to the COIs reveals that there is a dearth of reports that address the potential associations and mechanistic explanations relating to how exposure to the COIs experienced during military service in Vietnam may influence the risk of developing mental health conditions. This applies specifically to an overall absence of published evidence as to how dioxin/2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure could be etiologically implicated in the development of PTSD and related psychological comorbidities.

This chapter will consider possible diffuse CNS effects of toxic exposure to the COIs and specific clinical conditions associated with focal dysfunctions. Examples of diseases that result from the degeneration of specific brain areas are PD, Alzheimer disease (AD), spinocerebellar degeneration, and amyotrophic lateral sclerosis (ALS). These diseases may occur in the absence of any toxicant exposure, but all may be triggered by environmental factors, including toxicant exposure (Bronstein et al., 2009; Chin-Chan et al., 2015; de la Monte and Ming, 2014; Kang H et al., 2014; Tanner et al., 2014; Wang et al., 2014).

Disorders of the peripheral nervous system (PNS) are generally referred to as neuropathies. Neuropathies can be purely motor, presenting as deficits in strength, but most often present with involvement of both motor and sensory fibers. Neuropathies are often symmetric and start with symptoms related to dysfunction of fibers that travel the greatest distance to their target organ. For that reason, the symptoms of neuropathy often start in the digits and travel toward the torso. Many 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 (i.e., acute) damage to peripheral nerves, and previous updates found limited or suggestive evidence that dioxin exposure can cause such short-term effects. Evidence related to the rapid onset of these conditions is summarized in Appendix B. However, the overall focus of this chapter is on delayed adverse effects on both 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 Vietnam¹ 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 name change of this chapter to “Neurologic Disorders” in Update 2004 (IOM, 2005), which was carried forward in Update 2006 (IOM, 2007), Update 2008 (IOM, 2009), Update 2010 (IOM, 2012), and Update 2012 (IOM, 2014). 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 result only in molecular or biochemical effects, so even the most advanced imaging techniques can miss abnormalities. Because the nervous system is not readily accessible for biopsy, pathologic confirmation is usually 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 COIs that constitute the committee’s focus are 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 TCDD, a contaminant of 2,4,5-T. The committee also considered

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¹Despite loose usage of “Agent Orange” by many people, in numerous publications, and even in the title of this series, this committee uses “herbicides” to refer to the full range of herbicide exposures experienced in Vietnam, while “Agent Orange” is reserved for a specific one of the mixtures sprayed in Vietnam.

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. While all studies reporting TEQs based on PCBs were reviewed, those studies that reported TEQs based only on mono-ortho PCBs (PCBs 105, 114, 118, 123, 156, 157, 167, and 189) were given limited consideration because mono-ortho PCBs typically contribute less than 10 percent to total TEQs, based on the World Health Organization (WHO) revised toxicity equivalent factors (TEFs) of 2005 (La Rocca et al., 2008; van den Berg et al., 2006). 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 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, relevant details on experimental design can be found in Chapter 6.

BIOLOGIC PLAUSIBILITY

Experimental data regarding the biologic plausibility of a connection between 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 pertinent 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 of the COIs suggest pathways by which there could be effects on the neural systems. A number of 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; Stürtz et al., 2008); older references described the behavioral effects of a developmental 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 to 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, 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 to the COIs by adults, as was the case for Vietnam veterans.

Some studies further support suggestions that the concentration of reactive oxygen species (ROS) 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; Kumar et al., 2014c; Shen et al., 2005; Wan et al., 2014). 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 HG et al., 2007). TCDD has also been shown to affect signaling pathways that regulate nitric oxide synthesis in neural and glial cells, leading to neurotoxicity and cell death (Jiang et al., 2014; Li Y et al., 2013). Cytochrome P450 1A1, the aryl hydrocarbon receptor (AHR), and the AHR nuclear transporter occur in the brain, so TCDD may exert effects in the brain (Huang et al., 2000). In addition, earlier studies in hepatocytes indicated that 2,4-D affects aspects of mitochondrial energetics and mitochondrial calcium flux (Palmeira et al., 1994a,b, 1995a,b); such that, if these effects occur in mitochondria of nervous-system cells, the energy balance and pathways of cells in the nervous system could be affected to later disrupt nervous-system function.

Basic scientific studies have emphasized the importance of alterations in neurotransmitter systems as potential mechanisms underlying TCDD-induced neurobehavioral disorders (Jiang et al., 2014; Xie et al., 2013). 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 (Rosso et al., 2000a,b). Those mechanisms are important for maintaining the connections between nerve cells, which are necessary for neuronal function and are involved in axon regeneration and recovery from peripheral neuropathy. Early animal experiments have demonstrated that TCDD treatments affect the fundamental molecular events that underlie neurotransmission initiated by calcium uptake (Hong et al., 1998). Mechanistic studies have demonstrated that 2,4,5-T can alter cellular metabolism and the cholinergic transmission necessary for neuromuscular transmission (Sastry et al., 1997).

TCDD treatment of rats at doses that do not cause general systemic illness or wasting produces electric changes in peripheral nerves associated with altered functions and pathologic findings that are characteristic of toxicant-induced axonal peripheral neuropathy (Grahmann et al., 1993; Grehl et al., 1993).

As discussed in Chapter 4, extrapolating 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 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 establish biologic plausibility 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 neurobehavioral 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, Update 2006, Update 2008, Update 2010, and Update 2012 concluded that there was inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and neurobehavioral disorders. The data that informed that conclusion were mostly from the Air Force Health Study (AFHS, 1991a,b, 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. In 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., 2003a; 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).

Update of the Epidemiologic Literature

Vietnam-Veteran and Case-Control Studies

Since Update 2012, no new Vietnam-veteran, occupational, or case-control studies have been published concerning cognitive or neuropsychiatric disorders and exposure to the COIs.

Environmental Studies

Since the previous update, Bouchard et al. (2014) examined the cross-sectional association between serum PCB concentrations and cognitive function in 708 adults ranging in age from 60 to 84 who participated in the 1999–2000 or 2001–2002 iterations of the National Health and Nutrition Examination Survey (NHANES). Analyses were limited to the 12 of the 23 PCB congeners measured that were detected in at least 75 percent of the subjects; among these, the dioxin-like compounds (DLCs) were two of the mono-ortho PCBs 118 and 156 and the relatively less potent non-ortho PCBs 126 and 169. Cognitive function was

assessed, in a limited fashion, with the Digit-Symbol Coding Test (Wechsler, 1997). Neither dioxin-like nor non–dioxin-like PCB concentrations were associated with cognitive scores of concern (p = 0.4 and 0.7, respectively). The authors observed a significant interaction between age and serum concentrations of dioxin-like PCB congeners in the older group (70–84 years of age), for whom a 100 ng/g increase in serum concentration of dioxin-like PCBs was associated with a 2.65 point lower cognitive score (p = 0.04).

Krieg (2013) performed a limited assessment of cognition in 700 adults, aged 20–59 years, participating in NHANES III. Twelve pesticide metabolites were measured in the urine, including two chemicals found in the urine after 2,4-D exposure: unmetabolized 2,4-D and 2,4-dichlorophenol (2,4-DCP) (Sauerhoff et al., 1977). A limited battery of three neurobehavioral tests was administered (simple reaction time, symbol–digit substitution, and serial digit learning). The authors found that urine levels of 2,4-D itself, which is the main form of elimination, were not associated with detrimental effects in any of the neurobehavioral tests. In contrast, increased urine levels of the trace metabolite 2,4-DCP were associated with an improved performance on the serial digit learning test (p = 0.0002).

Other Recent Literature

Sapbamrer and Nata (2014) studied neurobehavioral symptoms (headache, dizziness, epilepsy, balance problem, fatigue) in 182 rice farmers and 122 non-farmers in northern Thailand. None of the endpoints measured differed in frequency between the two groups. Of the rice farmers, 63.2 percent reported exposure to herbicides, but exposure specificity for the comparisons was insufficient for the results to be regarded as fully informative for VAO purposes.

Biologic Plausibility

Some toxicologic studies have suggested a 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, a TCDD-induced protein hypothesized to be important in the synthesis of dopamine, whose perturbation has been implicated in a number of neurobehavioral syndromes. Elevated expression of AHR in these cells was associated with increased production of neurotransmitters and augmented dopamine expression, but the implication of that finding is not clear. In vitro exposure of human CD34+ cells to TCDD has been associated with modulation of gene expression of the GABAergic pathway, which may be associated with altered synaptic transmission, visual perception, and other neurologic conditions (Fracchiolla et al., 2011). Lensu et al. (2006) gavaged rats with 50 µg/kg TCDD or with leptin, whose effect on food consumption is recognized. When the hypothalamuses of the two groups were compared

24 hours later, the results were not consistent with a primary role for the hypothalamus in TCDD-induced wasting syndrome.

Other studies have focused on neurobehavioral outcomes following perinatal exposure, which as discussed in Chapter 10, is of relevance in understanding possible consequences in the offspring of Vietnam veterans, particularly women. Haijima et al. (2010) found that gavage treatment of pregnant mice with 3 µ/kg TCDD on gestation day 12.5 (resulting in in utero and lactational exposure of the offspring) impaired memory in male offspring. Mitsui et al. (2006) reported that hippocampus-dependent learning could be impaired in male rats exposed to TCDD in utero and that the impairment could affect fear conditioning. Curran et al. (2011) assessed the effect of CYP1A2 and 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. Studies in week-old rodents have also detected molecular effects of TCDD in cerebellar granule cells and neuroblasts, which may be relevant to motor function and cognitive processes (Kim and Yang, 2005; Williamson et al., 2005). Stürtz et al. (2008) found alterations in how female rats fed on postpartum days 1–7 with diets containing 15, 25, or 50 mg/kg 2,4-D interacted with their pups. The specific relevance of the scientific evidence to neurobehavioral effects in humans exposed as adults is unclear.

A general summary of the biologic plausibility of neurologic effects arising from exposure to the COIs is presented at the beginning of this chapter.

Synthesis

There is not consistent epidemiologic evidence of an association between exposure to the COIs and neurobehavioral (cognitive or neuropsychiatric) disorders. More research on the COIs and these endpoints, particularly in the offspring of exposed parents, is warranted given findings in studies that address biologic plausibility.

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 on neurodegenerative diseases—specifically PD, ALS, and AD—discussed in previous VAO reports.

Previous VAO reports have not identified epidemiologic results for multiple sclerosis (MS) in relation to exposure to the COIs, so this committee notes that two studies new to this update reported on MS without providing enough substance to justify developing a section for this health outcome. MS is already eligible for service-connected consideration for all veterans who experienced symptoms while in the military or within 7 years of honorable discharge. In addition to reporting on the deaths from PD and ALS in the female Vietnam-era veterans, Kang HK et al. (2014) found an elevated risk of death from MS, although its confidence interval (CI) was wide due to a small number of cases, but no suggestion of increased risk of death from “other nervous system diseases.” In addition to reporting on the prevalence of PD, ALS, and AD, Yi et al. (2014a) found no association with herbicide exposure for the prevalence of MS, but the substantial power of this very large study did identify associations for a number of neurological conditions (paroxysmal disorders, nerve/plexus disorders, and paralytic syndromes), which are considerably more specific than the outcomes evaluated in previous VAO updates.

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. These signs were first described as a single entity in 1817 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 that often progresses to frank dementia, sleep disturbances, hallucinations, psychosis, mood disorders, fatigue, and autonomic dysfunction (Langston, 2006).

In the nearly two centuries since its initial description, much has been learned about the genetic predisposition and pathophysiology of PD, but its etiology in most patients and specific environmental risk factors remain largely unknown. The diagnosis of PD is based primarily on clinical examination, although in recent years, magnetic resonance imaging and functional brain imaging have become increasingly useful. PD is difficult to distinguish from a variety of Parkinsonian syndromes, including drug-induced Parkinsonism, and neurodegenerative diseases, such as atrophy of multiple systems, that present with Parkinsonian features combined with other abnormalities. Ultimately, a diagnosis of PD can be confirmed with postmortem pathology examination of brain tissue for the characteristic loss of neurons from the substantia nigra and telltale Lewy body intracellular inclusions. Pathology findings in other forms of Parkinsonism show different patterns of brain injury.

The incidence of PD is estimated to range from 2 to 22 per 100,000 person-years, while its prevalence ranges from 18 to 182 per 100,000 persons. It affects

about 1 percent of all persons over 60 years old and up to 5 million people worldwide. PD is the second-most common neurodegenerative disease (after AD).

Research on the genetic, epigenetic, and environmental causes of PD suggests that it has multiple risk factors, including aging, environmental exposure, and genetic predisposition (Gao and Hong, 2011; Kwok, 2010). The peak incidence and prevalence of PD 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 1methyl4phenyl1,2,4,6-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. Further evidence of environmental exposures playing a role in the development of PD has continued to accrue (Chin-Chan et al., 2015; Tanner et al., 2014).

Heredity has long been suspected of being an important risk factor for PD; as many as 25 percent 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

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 is an association between exposure to the COIs and PD. Five case-control studies reviewed by those committees had investigated association between PD and “herbicide” exposure without providing further specificity. Two of these did not find associations with herbicide exposure (Stern et al., 1991; Taylor et al., 1999), but they were limited because their subjects had experienced little actual herbicide exposure. Three found significant associations with herbicide exposure (Butterfield et al., 1993; Gorell et al., 1998; Semchuk et al., 1992).

Two new studies reviewed by the committee responsible for Update 2008 examined association specifically with chlorophenoxy acid and the esters and found increased odds ratios (ORs) (Brighina et al., 2008; Hancock et al., 2008). 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 increases for the chemical class of chlorophenoxy acids or esters noted by Brighina et al. (2008) reached statistical significance only in the quartile of cases who were youngest at diagnosis (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 above, Update 2008 concluded that there was limited/suggestive evidence associating exposure to the COIs with PD. Additional studies considered by the committees responsible for Update 2010 and Update 2012 led them to affirm this conclusion.

The findings of the literature reviewed are summarized in Table 11-1.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies Since the previous update, Kang HK et al. (2014) performed a retrospective study of mortality through 2010 in three cohorts of Vietnam-era military women—4,734 deployed to the theater of the war, 2,062 who served in countries near Vietnam, and 5,313 who were not deployed and served primarily in the United States. PD mortality, adjusted for age, race, duration of military service, officer status, and nursing status was not elevated in those deployed to Vietnam versus the non-deployed cohort (relative risk [RR] = 1.25, 95% CI = 0.34–4.59), and there was no suggestion of an increase when this comparison was made for the subsets of only nurses (RR = 0.78, 95% CI 0.17–3.50).

In the Korean Veterans Health Study (Yi et al., 2014b), 180,639 Korean veterans were followed up for vital statistics and cause of death. An Exposure Opportunity Index (EOI) score was assigned to each veteran based on the proximity of his unit to herbicide-sprayed areas. No association was found between PD (International Classification of Diseases, Revision 10 [ICD-10] G20-G21) mortality and the individual EOI scores (HR = 1.01, 95% CI 0.83–1.22) or when the high-exposure group was compared to the low-exposure group (HR = 0.88, 95% CI 0.40–1.95).

When Yi et al. (2014a) compared the high and low-exposure groups with respect to the prevalence data for primary PD (ICD-10 G20) and secondary Parkinsonism (ICD-10 G21), the results for both adjusted for age, rank, smoking, drinking, physical activity, domestic use of herbicides, education, income, and body mass index (BMI) were less suggestive of an association with herbicide exposure (OR = 1.18, 95% CI 0.99–1.42 and OR = 1.26, 95% CI 0.93–1.69, respectively) than were the unadjusted results (p = 0.002 and p = 0.014, respectively).

Occupational Studies No occupational studies addressing exposure to the COIs and PD have been published since Update 2012.

Environmental Studies Blood samples were drawn from 40,221 individuals between 1968 and 1972 in the course of the Finnish Mobile Clinic Health Examination Survey. From among those who were 20 to 79 years of age and had not been diagnosed with PD or psychosis at the time of sampling, Weisskopf et al. (2012) identified 196 individuals certified before 1994 to receive medication for PD from the national reimbursement program; hospital records were obtained

TABLE 11-1 Epidemiologic Studies of Herbicide^a Exposure and Parkinson Disease and Parkinson-Like Conditions (Shaded entries are new information for this update)

NOTE: 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; AHS, Agricultural Health Study; AO, Agent Orange; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; JEM, job–exposure matrix; HR, hazard ratio; na, not applicable; NCHS, National Center for Health Statistics; OR, odds ratio; PCB, polychlorinated biphenyl; PD, Parkinson disease; RDD, random-digit dialing; VA, US Department of Veterans Affairs; VV, Vietnam veteran.

^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.

for 126 of these cases, and from this information neurologists confirmed the PD diagnosis for all but 25. The 101 established PD cases were matched to controls without PD by age, sex, municipality, and vital status. The serum samples were analyzed in 2005–2007 for 55 PCB congeners, including the dioxin-like PCBs 105, 118, 156, 157, 167, 189. This set of dioxin-like PCBs consists only of mono-ortho congeners, which have considerably lower TEFs than the four non-ortho dioxin-like congeners, which were not covered in the serum analyses. In addition to analyses on total PCBs and three common non–dioxin-like congeners, results were reported individually for the common PCB 118 and for the measured set of dioxin-like PCBs. Concentrations (ng/g serum) for each congener group were partitioned into quintiles. With adjustments for smoking, occupation, BMI, triglycerides, cholesterol, and serum dieldrin concentration, the number of PD cases in the highest quintile was compared to the number in the lowest quintile, and a trend test was performed. Reduced ORs for PD in the highest quintile and the suggestion of an inverse relationship with increasing concentration were reported for both PCB 118 (OR = 0.37, 95% CI 0.37–0.95; p = 0.10) and for total dioxin-like PCBs (OR = 0.34, 95% CI 0.13–0.90; p = 0.05). These findings are not supportive of an association between dioxin-like activity and PD, but the committee does not attribute much weight to evidence based only on these mono-ortho PCBs whose dioxin-like activity is weak. Furthermore, the association that has been noted for the COIs is based primarily on exposure to the phenoxy herbicides themselves, rather than the dioxin-like activity of the contaminated mixtures sprayed in Vietnam.

Case-Control Studies van der Mark et al. (2014) identified PD cases newly diagnosed in 2006–2011 at five hospitals in the Netherlands. For each case, two controls matched on age and sex were identified from among patients without neurodegenerative symptoms who had been seen in the respective neurology department in that period. Of the 1,001 PD cases identified, 993 were alive and had current addresses. Of those, 45 percent completed computer-assisted telephone interviews addressing occupational histories with especially detailed information gathered on farming and gardening jobs. Of the matched controls, 35 percent completed the interview, giving a final sample for analysis of 444 cases and 876 controls. The responses were processed by a job–exposure matrix (JEM) and by an algorithm from the AHS to derive cumulative exposure to herbicides (as well as to insecticides or to fungicides); the exposure estimates were partitioned into three groups for comparison to those with no reported exposure. A crop-based method was used to estimate exposures to particular pesticides, with 2,4-D being one of the four herbicides assessed in this fashion; these estimates were partitioned into high and low groups for comparison to the never-exposed group. The analyses were adjusted for smoking, coffee consumption, occupational skill, and estimated endotoxin exposure (the other risk factor investigated in this study). For the overall herbicide exposure estimates, the medium and high groups

consistently showed non-significantly elevated risks: medium (OR = 1.30, 95% CI 0.70–2.39) and high (OR = 1.25, 95% CI 0.62–2.53) JEM groups; medium (OR = 1.21, 95% CI 0.62–2.33) and high (OR = 1.52, 95% CI 0.78–2.97) AHS-algorithm groups. However, only the product-specific results of the crop-based exposure estimation model provided findings fully informative for the VAO task; the two exposure groups for 2,4-D versus the neverexposed group had findings similar to those for herbicides overall: low (OR = 1.13, 95% CI 0.49–2.364) and high (OR = 1.68, 95% CI 0.81–3.49) groups. The only statistically significant finding was for the group with high exposure to the fungicide benomyl.

Biologic Plausibility

McDowell and Chesselet (2012) recently reviewed the literature on the ability of both toxicant-induced (6hydroxydopamine, MPTP, rotenone, cycad) and genetically based animal models to reproduce the nonmotor symptoms of PD. The very clear PD-like toxicity resulting from human exposure to MPTP has indicated that select chemicals can result in the same type of damage to dopaminergic neurons as occurs in classical PD, 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, but not one that was used in Vietnam), but structurally unrelated to any of this report’s COIs. Pesticides shown to produce PD-like toxicity in animal models include Paraquat, rotenone, maneb, and dieldrin. Substantial research has gone into understanding the molecular mechanisms responsible for the toxicity, especially in connection with Paraquat and rotenone (Blandini and Armentero, 2012; Di Monte et al., 2002; Drechsel and Patel, 2008; Duty and Jenner, 2011; Hatcher et al., 2008; Moretto and Colosio, 2013; Nunomura et al., 2007; Sherer et al., 2002; Yadav et al., 2012). The damage done to dopaminergic neurons in PD is probably caused by oxidative stress and inflammation and may well also involve damage to mitochondria in the target cells (Anderson and Maes, 2014: Janda et al., 2012; Liang et al., 2007; Littleljohn et al., 2011; Sarnico et al., 2008).

The COIs to this committee are known to be distributed to the CNS. Bongiovanni et al. (2007) found that rat cerebellar granule cells in culture (an in vitro model using cells not involved in PD pathology) produce increased concentrations of ROSs when exposed to 2,4-D. The COIs have not been investigated, however, in experimental systems such as those that have shown that compounds, such as Paraquat, cause inflammation and oxidative stress, so it is not known whether any of the COIs could produce these responses.

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). The injection of 2,4-D directly into the rat brain yields toxicity in the basal ganglia (Bortolozzi et al., 2001), but this route of administration is highly artificial. Postpartum dietary exposure of females to 2,4-D results in adverse alterations in maternal behavior and neurochemical changes, including increases in dopamine and its metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid (Stürtz et al., 2008). Such an increase in dopamine is the reverse of what is seen in PD, in which a 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, causes fibrillation of α-synuclein in vitro, but the study used purified protein and reported only a generalized result rather than data on 2,4-D (Uversky et al., 2002), so little confidence can be placed in it. Because most 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 do not support a role for the COIs in the etiology of PD.

A general summary of the biologic plausibility of neurologic effects arising from exposure to the COIs is presented at the beginning of this chapter.

Synthesis

The committee responsible for Update 2014 reviewed two new epidemiologic studies that examined herbicide exposure and PD mortality in Vietnam veterans that did not find an association (Kang HK et al., 2014; Yi et al., 2014b). When investigating the prevalence of PD among the Korean Vietnam veterans, however, Yi et al. (2014a) found indications of an elevation. While the Finnish study of environmental exposures was not particularly informative for the committee, its findings on exposure to herbicides, and 2,4-D in particular, are consistent with the conclusion that exposure to the phenoxy herbicides sprayed in Vietnam may be associated with the development of PD. A biologic mechanism by which the COIs may cause PD has not been demonstrated. Nevertheless, the overall epidemiologic evidence continues to support an association between herbicide exposure and PD and to be consistent with an association with exposure to the phenoxy herbicides specifically.

For this update, VA added a special task to the committee’s charge to evaluate the evidence of any association between neurodegenerative diseases with Parkinson-like symptoms and herbicide exposure. Strictly speaking, “genuine” or primary PD is a diagnosis of exclusion, and a patient with Parkinson-like symptoms would be diagnosed as having “Secondary Parkinsonism” if his condition were known to have been caused by exposure to herbicides, as indicated by the

TABLE 11-2 Correspondence of ICD-9 and ICD-10 Codes for Parkinson Disease and Other Extrapyramidal Disease and Abnormal Movement Disorders

NOTE: ICD, International Classification of Diseases; NOS, not otherwise specified; PD, Parkinson disease.
SOURCE: Excerpted from CDC’s ICD-10-CM (http://www.cdc.gov/nchs/icd/icd9cm.htm; http://www.cdc.gov/nchs/icd/icd10cm.htm#icd2016, accessed November 11, 2015).

description of ICD-9 332.1 in Table 11-2. For some patients with Parkinson-like symptoms, the details of their medical records may establish that their condition is definitively attributable to a specific genetic syndrome or to some identified external agent (other than possible exposure to herbicides in Vietnam). Contemporary sophisticated techniques and a thorough knowledge of a patient’s history may permit making distinctions among conditions having characteristics of PD with some degree of confidence, but in practice clinicians would not be expected to uniformly settle on the same diagnostic code for a given patient. Such variations in diagnostic specificity are factors that extend to the epidemiology studies supporting the conclusion of prior VAO committees that there is limited or suggestive evidence of association between PD and exposure to the herbicides sprayed in Vietnam.

In the ICD coding system, several codes are allocated to conditions with constellations of symptoms that are Parkinson-like, but their assignments differ somewhat between the ICD-9 and the ICD-10 classifications, as shown in Table 11-2. The revised coding system has progressed by providing individual codes for specific types of secondary Parkinsonism, which should facilitate VA’s processing of claims submitted since the ICD-10 codes became effective on October 1, 2015. Because the veteran is to be given the benefit of the doubt in the claims process, the current committee does not judge it reasonable to exclude from coverage for this presumptively service-related condition any Vietnam veterans with Parkinsonian symptoms unless VA can definitively establish, on a

case-by-case basis, that those symptoms are secondary to an external agent other than the herbicides sprayed in Vietnam or to a specific genetic condition.

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 COIs and PD, including Parkinson-like conditions such as Parkinsonism, in the setting of dementia, multiple system atrophy, and progressive supranuclear palsy.

Amyotrophic Lateral Sclerosis

ALS is a progressive, adult-onset, motor neuron disease that presents with muscle atrophy, weakness, and fasciculations and with signs that indicate the involvement of motor neuron pathways in the CNS. 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 performed by experienced neurologists (Rowland, 1998; Rowland and Shneider, 2001).

The cause of most cases of ALS is unknown, but about 5–10 percent of cases are recognized as resulting from inheritance of autosomal dominant or recessive genes (Wood, 2014). One-fifth of familial-ALS patients have mutations in the gene that encodes superoxide dismutase1 (Rosen et al., 1993). Many other possible etiologic factors have been investigated (Breland and Currier, 1967; Gallagher and Sander, 1987; Hanisch et al., 1976; Kang H et al., 2014; Kurtzke and Beebe, 1980; Mitchell and Borasio, 2007; Roelofs-Iverson et al., 1984; Sutedja et al., 2009a,b; Wang et al., 2014), including military service (Weisskopf et al., 2005), but they have not found conclusive evidence of association with any of the environmental exposures addressed.

Summary of Previous Updates

ALS was first evaluated as a disease that might be associated with the COIs by the committee for Update 2002.

Pesticide or herbicide exposure has been associated with an increased risk of ALS, including a doubling of the risk after long-term occupational exposure to pesticides (Deapen and Henderson, 1986) and a tripling after exposure to agricultural chemical products (Savettieri et al., 1991) and herbicides (McGuire et al., 1997), but 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 OR of 2.4 and a trend with duration of exposure that were both statistically significant (McGuire

TABLE 11-3 Epidemiologic Studies of Pesticide^a Exposure and Amyotrophic Lateral Sclerosis (Shaded entries are new information for this update)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AHS, Agricultural Health Study; ALS, amyotrophic lateral sclerosis; AO, Agent Orange; CI, confidence interval; EOI, Exposure Opportunity Index; HR, hazard ratio; nr, not reported.

^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.

et al., 1997). A mortality study of Dow Chemical Company employees exposed to 2,4-D found three deaths from ALS with a significant positive association (RR = 3.45, 95% CI 1.10–11.11) (Burns et al., 2001). Morahan and Pamphlett (2006) published an Australian case-control study 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 COIs were not identified make the results of this study difficult to interpret. Weisskopf et al. (2005) followed the vital status of 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, this large study indirectly suggests the lack of a strong effect of herbicide exposure on ALS risk. 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. Weisskopf et al. (2009) found no association between self-reported pesticide or herbicide exposure in the American Cancer Society's Cancer Prevention Study II, but the lack of exposure specificity and the possibility of exposure estimation error limit the weight of this evidence.

Table 11-3 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies Too few cases of ALS mortality were observed by Kang HK et al. (2014) in the study of female Vietnam-era veterans for a calculation of the relative risks comparing the deployed and non-deployed women.

In the Korean Veterans Health study, Yi et al. (2014b) determined the vital status and cause of death through 2005 for 180,639 Korean veterans who were alive in 1992. Individual EOI scores were derived based on the proximity of the veteran’s unit to given areas when herbicides were sprayed, which were partitioned into high and low-exposure groups. No association was found between spinal muscular atrophy [ICD-10 G12] and the EOI scores (HR = 0.94, 95% CI 0.74–1.18) and when the high-exposure group was contrasted with the low-exposure group (HR = 0.80, 95% CI 0.29–2.15).

In the study of disease prevalence among the Korean Vietnam veterans, after adjusting for age, rank, smoking, drinking, physical activity, domestic use of herbicides, education, income, and BMI, Yi et al. (2014a) found the risk for spinal muscular atrophy showed signs of slight elevation in both the analysis of the scores as a continuous variable (OR = 1.06, 95% CI 1.00–1.12) and for the two-group comparison (OR = 1.27, 95% CI 1.00–1.61). The more specific diagnosis of motor neuron disease [ICD-10 G12.2], which includes ALS, had nearly

the same risk estimate, but because these cases represented only about one-third of those in the entire G12 grouping, the CIs were wider for the scores (OR = 1.04, 95% CI 0.94–1.14) and for the comparison of the high and low-exposure groups (OR = 1.24, 95% CI 0.83–1.85).

Occupational Studies Since the last update, Malek et al. (2014) compared 66 ALS patients to 66 controls, administering a questionnaire on occupational, vocational, and avocational exposures. Self-reported pesticide exposure was associated with ALS (OR = 3.17, 95% CI 1.27–7.93). This association was more robust after controlling for smoking and education in a multivariate model (OR = 6.50, 95% CI 1.78–23.77). Additional analyses conducted on occupational exposure to insecticides, to herbicides, or to fungicides and fumigants, individually, found no associations with ALS, but the sample sizes were very small. None of the results is based on sufficiently specific exposure metrics to be fully informative for VAO purposes.

Environmental or Case-Control Studies Since Update 2012, no new environmental or case-control studies have been published concerning ALS and exposure to the COIs.

Biologic Plausibility

Several studies have addressed mechanisms of neurotoxicity that might be ascribed to COIs, notably 2,4-D and TCDD. The molecular effects of the COIs are described in Chapter 4. Some of those effects suggest possible pathways by which the COIs could disrupt neuronal systems. A number of the studies suggest that the COIs have had neurologic effects in animal models when exposure occurred during development. There also are studies that suggest ROS could alter specific signaling cascades and be involved in neurodegeneration. Although they do not specifically concern the COIs, such studies are potentially relevant inasmuch as TCDD and herbicides have been reported to elicit oxidative stress (Celik et al., 2006; Shen et al., 2005). The mechanistic studies suggest avenues that might be pursued to determine linkages between the COIs and neurologic outcomes that could result in adult humans. No toxicology studies concerning exposure to the COIs and ALS have been published since Update 2006.

A general summary of the biologic plausibility of neurologic effects of exposure to the COIs is presented at the beginning of this chapter.

Synthesis

Although there is overall limited evidence of an association between pesticides and ALS in broad terms, the published studies to date have had low power to detect associations, which has resulted in numerous studies with wide CIs and

non-significant ORs for exposure to the COIs. Four studies have been published since Update 2012, but these do not indicate a consistent association between herbicides as a class, or specifically 2,4-D or 2,4,5-T, and ALS.

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 COIs and ALS remains inadequate or insufficient.

Alzheimer Disease

Alzheimer disease is a progressive, neurodegenerative form of dementia that is characterized by memory loss, confusion, mood changes, social withdrawal, and deteriorating judgment. The course of the disease is divided into four stages—pre-dementia, early, moderate, and advanced—depending on the level of cognitive and functional impairment. Diagnosis typically occurs in people over 60 years old as symptoms develop, although pre-dementia and early AD are occasionally seen in people as young as 30 years old. AD is the sixth-leading cause of death in the United States and the fifth-leading cause of death in people over 65 years old (Singh et al., 2012). In 2012, an estimated 5.4 million Americans were living with the diagnosis. Mean life expectancy is 7 years after an AD diagnosis; about 3 percent of people who receive the diagnosis live 14 years or more (Alzheimer’s Association, 2012). Although the etiology of the disease remains elusive, suspected risk factors for AD include diet, exposure to aluminum or solvents, and genetics (Chi-nChan et al., 2015; de la Monte and Ming, 2014; Tanner et al., 2014).

Summary of Previous Updates

Update 2012 was the first VAO update to address AD directly. Until that time literature searches had not identified epidemiologic studies that assessed the possible association of AD with exposure to the specific COIs. However, an association with exposure to the broad classification of “pesticides” had been investigated. Because AD is a condition of considerable interest to aging Vietnam veterans, for that update the committee members thought it appropriate to present the small amount of peripherally related available information. In doing so, they revisited two publications that include inadequately specific exposure characterizations that were mentioned briefly in Update 2002 (Gauthier et al., 2001) and Update 2004 (Baldi et al., 2003). Gauthier et al. (2001) found that long-term exposure to herbicides and insecticides was not significantly related to the development of AD. In a study by Baldi et al. (2003), pesticide exposure (including herbicides, insecticides, and fungicides together) was defined on the,

basis of job histories. A significant association between pesticide exposure and AD was found in men (RR = 2.39, 95% CI 1.02–5.63), but not in women (RR = 0.89, 95% CI 0.49–1.62). On the basis of the evidence reviewed in Update 2012, the committee concluded that there was inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and AD.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies Since the last update, the Korean Veterans Health Study (Yi et al., 2014b) was published. In this study, 180,639 Korean veterans were followed for vital status and cause of death. The EOI scores were based on the temporal proximity of the veteran’s unit to herbicide-sprayed areas. There was no association between AD [ICD-10 G30] and the EOI scores analyzed as a continuous variable (HR = 0.87, 95% CI 0.60–1.25) or between the high and low-exposure groups (HR = 0.86, 95% CI 0.17–4.31).

In the study of disease prevalence among the Korean Vietnam veterans, after adjustiing for age, rank, smoking, drinking, physical activity, domestic use of herbicides, education, income, and BMI, Yi et al. (2014a) found the risk for AD to be elevated in both the analysis of the scores as a continuous variable (OR = 1.12, 95% CI 1.02–1.23) and the two-group comparison (OR = 1.64, 95% CI 1.12–2.41).

Environmental Studies The Canadian Study of Health and Aging has been monitoring more than 10,000 Canadian men and women who were at least 65 years old when this random sample was assembled in 1991. Clinical examinations were conducted on a portion of the full sample in 1991–1992 (n = 2,914), 1996–1997 (n = 2,914), and 2001–2002 (n = 2,914), with blood samples being drawn from a subset of these groups (422, 1,312, and 385, respectively). The study population addressed by Medehouenou et al. (2014) consisted of the 2,023 subjects for whom blood was available and who had a firm diagnosis of having dementia (n = 574, of which 399 were specifically diagnosed with AD) or not (n = 1,449). Among the 10 PCB congeners measured in the serum analyses were the mono-ortho PCBs 105, 118, and 156, which exhibit dioxin-like activity only to a modest extent. Two models were applied to the data; the first adjusted for time of age, sex, education, blood draw, total plasma lipids, and ApoE4, and the second additionally adjusted for BMI, alcohol and tobacco use, rural or urban residence, and a vascular score. Of the 10 PCBs analyzed, only PCBs 105 and 118 showed an inverse association with dementia overall in the first model (OR = 0.87, 95% CI 0.77–0.99; OR = 0.86, 95% CI 0.74–0.99, respectively), but adjustment for additional confounders in the second model eliminated the effect (OR = 0.90, 95% CI 0.79–1.02; OR = 0.88, 95% CI 0.76–1.02, respectively). Thus, no relationship with AD specifically was seen for any of the PCBs using either model.

Occupational and Case-Control Studies No occupational or case-control studies addressing exposure to the COIs and AD have been published since Update 2012.

Biologic Plausibility

There has been little toxicologic investigation of adult exposure to the COIs and endpoints relevant to AD.

A general summary of the biologic plausibility of neurologic effects of exposure to the COIs is presented at the beginning of this chapter.

Synthesis

The findings in the Korean Vietnam Veterans Study (Yi et al., 2014a,b) are the first in which the risk of AD has been investigated in association with a fully relevant exposure, but its findings for prevalence and mortality are not entirely consistent. The only relevant findings in Medehouenou et al. (2014) are for the mono-ortho PCBs 105, 118, and 156, which have only weak dioxin-like activity. The preliminary results of a “protective” effect against dementia in general for PCBs 105 and 118 vanished with an adjustment for additional possible confounders, so this study contributes little to deciding whether AD is associated with the COIs.

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 AD.

CHRONIC PERIPHERAL SYSTEM DISORDERS

The peripheral neuropathies are an array 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, 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 only later affect the hands. 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 or the axons, giving rise to changes in the amplitude of a nerve’s response to an electric stimulus.

The clinical mainfestations of most symmetric axonal neuropathies are similar except for variation in the rates of progression and in whether pain is prominent. No specific signature distinguishes a toxicant-related neuropathy from one induced by other causes. As many as 30 percent 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 percent. Thus, it is important to include an 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 early-onset (immediate) peripheral neuropathy or delayed-onset peripheral neuropathy, which occurs years after the external exposure has ended. For classification purposed, the committee considers a neuropathy early onset if abnormalities appear within 1 year after external exposure ends and delayed-onset if abnormalities appear more than 1 year after external exposure ends. A review of the data supporting the association of exposure with early-onset peripheral neuropathy is presented in Appendix B and will not be repeated here. Because the exposures of interest for Vietnam veterans are long past, the immediate effects of the COIs are no longer pertinent for this cohort. The focus of this section will be on data related to delayed-onset peripheral neuropathy.

Summary from VAO and Previous Updates

The committee for Update 2010 decided to move health outcomes that are manifested shortly after exposure to the COIs (TCDD in particular) to an appendix because they are no longer of interest for Vietnam veterans whose exposure occurred decades ago. Early-onset peripheral neuropathy was in this group with chloracne and porphyria cutanea tarda (PCT). That committee, however, noted that early-onset peripheral neuropathy is not necessarily a transient condition, as had been the previous judgment. This means that early-onset peripheral neuropathy may become a chronic condition that should be distinguished from delayed-onset peripheral neuropathy.

Henceforth, this section will address only studies of delayed-onset peripheral neuropathy.

A study by the Centers for Disease Control (now the Centers for Disease Control and Prevention [CDC]); (CDC, 1988b) reported a slight excess in the signs or symptoms of peripheral neuropathy among deployed versus non-deployed

Vietnam-era veterans. Decoufle et al. (1992) reported no association between self-reported exposure to herbicides in Vietnam and peripheral neuropathy.

There was no indication of an increased incidence of peripheral neuropathy in the first examination, which established the baseline for Ranch Hand veterans (AFHS, 1984a). A peer-reviewed article described the peripheral-neuropathy data on the AFHS cohort (Michalek et al., 2001c). In a primary analysis, the investigators had included diabetes as a potential confounder in the statistical model. In a secondary analysis, the subjects who had conditions that were known to be associated with neuropathy were excluded, and the 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 COIs and peripheral neuropathy in the absence of any effect of diabetes. The large veteran studies are limited by the confounding nature of concurrent diabetes and alcohol exposure, both of which are also related to neuropathy.

Lee et al. (2008) evaluated the association of exposure to a variety of toxicants to the presence of neuropathy in subjects who had either frank diabetes or impaired glucose tolerance. Concentrations of dioxin-like PCBs were ranked, and those subjects who had 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 relationship that suggested a concentration-dependent risk of neuropathy. Given the underlying risk of neuropathy inherent in patients who have diabetes, the lack of information regarding the duration of diabetes and the small numbers of subjects render this study difficult to evaluate.

Update of the Scientific Literature

Vietnam-Veteran Studies

In the study of disease prevalence among the Korean Vietnam veterans, after adjusting for age, rank, smoking, drinking, physical activity, domestic use of herbicides, education, income, and BMI, Yi et al. (2014a) found that the risk for polyneuropathies of the PNS [ICD-10 G60–G64] to be slightly elevated in both the analysis of the scores as a continuous variable (OR = 1.02, 95% CI = 1.01–1.03) and the two-group comparison (OR = 1.09, 95% CI = 1.04–1.13).

Occupational, Environmental, and Case-Control Studies

No occupational, environmental, or case-control studies addressing exposure to the COIs and chronic peripheral neuropathy have been published since Update 2012.

Biologic Plausibility

No new toxicity studies directly pertinent to the COIs and 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). The normal activity of those target processes is 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 observation of, respectively, electrophysiologic and pathologic abnormalities 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. These results constitute evidence of biologic plausibility for an association between exposure to the COIs and peripheral neuropathy.

A general summary of the biologic plausibility of neurologic effects arising from exposure to the COIs is presented at the beginning of this chapter.

Synthesis

The committee concludes that the evidence reviewed here does not support an association between exposure to COIs and the development of delayed-onset chronic neuropathy. The findings of the large study of Korean Vietnam veterans were small and non-compelling.

Conclusions

The committee for Update 2010 concluded that, in addition to evidence supporting an association for transient early-onset peripheral neuropathy, there is limited or suggestive evidence of an association between exposure to the COIs and early-onset peripheral neuropathy that may be persistent.

On the basis of the evidence reviewed to date, however, the present committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and delayed-onset chronic neuropathy.

HEARING LOSS

Hearing loss increases markedly with age, and about one-fourth of people over 70 years old are affected (NCHS, 2010). Its prevalence is somewhat higher in men than in women (NCHS, 1994). The most common forms of hearing impairment in adults are presbycusis and tinnitus. Heritable factors may influence the susceptibility to hearing loss, but external agents can also contribute. Aspirin at high doses can cause reversible tinnitus, and permanent hearing loss may be induced 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 regarded as noise-induced. Cochlear development may be impaired by the hypothyroidism associated with exposures to 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 Australian 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. 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 5year follow-up 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 2012.

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 maternal PCB 126 exposure resulted in low-frequency hearing deficits in the offspring of exposed maternal rats. Increased auditory thresholds occurred in the group treated at 1.0 µg/kg/day for 0.5 and 1kHz tones, but higher frequencies were

not significantly affected. The frequency-specific deficit was hypothesized to be secondary to postnatal hypothyroxinemia that occurred during a sensitive period for development of the low-frequency regions of the cochlea. This conclusion was consistent with that hypothesis that pups from the study were found to have decreased serum T4 concentrations on postnatal day 21. It is important to note that PCB 126 is a potent dioxin-like compound, having one-tenth the toxic potency of TCDD (see Chapter 4).

A general summary of the biologic plausibility of neurologic effects arising from exposure to the COIs is presented at the beginning of this chapter.

Synthesis

Two prior studies observed increased prevalence of hearing loss in Vietnam veterans and pesticide applicators, but neither was able to examine exposure specifically to the COIs 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 study evaluated Vietnam veterans, but it used the general population as a comparison group, 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 association between exposure to the COIs and hearing loss.

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