National Academies Press: OpenBook

Veterans and Agent Orange: Update 2010 (2012)

Chapter: 9 Neurologic Disorders

« Previous: 8 Reproductive Effects and Impacts on Future Generations
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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,

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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.

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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.

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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,

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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 =

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 9-1 Epidemiologic Studies of Herbicidea Exposure and Parkinson Disease

Reference and Country Cases in Study Group Comparison Group Exposure Assessment Exposure(s)a n OR (95% CI) Diagnosis of Neurologic Dysfunction
Firestone el al., 2010 (updates and expands Firestone et al., 2005); Washington, US Enrolled cases increased from 250 (in original study) to 404 526 unrelated controls Structured face-to-face interviews; demographic information collected. job descriptions (if held for more than 6 months) and workplace exposures to various industrial toxicants identified from a checklist were recorded 2,4-D 8 0.8 (0.3–2.0) ≥ 2 of 4 cardinal signs: musl have bradykinesia or resting tremor, may have cogwheel rigidity, or postural reflex impairment
Dhillon el al.,2009; US (University of Texas) 100 PD cases recruited from a medical center's neurological institute in East Texas 84 controls without PD recruited from the same medical center Professionally administered questionnaire used to determine military history (including spraying herbicides/pesticides), personal use/mixing and average duration of exposure to herbicides and specific pesticides, among other exposures Ever personally used/mixed or applied: Herbicide use-home or agricultural 2,4-D
2,4,5-T
Silvex or other 2,4.5-
TP products
34
17
4
1
0.8(0.4-1.4)
1.2(0.6-2.8)
0.5(0.1-1.6)
0.3 (0.0-2.7)
PD diagnosed by neurologist specializing in movement disorders using standard clinical/ lab diagnostic criteria
Elbaz et al.. 2009; France 224 PD cases 557 controls Initial self-assessment, plus individual interview with occupational specialist Phenoxy herbicides Age of onsel > 65 yrs na
na
1.8(0.9-3.3)
2.9(1.1-7.3)
≥ 2 cardinal signs (rest tremor, bradykinesia, rigidity, impaired postural reflexes)
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference and Country Cases in Study Group Comparison Group Exposure Assessment Exposure(s)a n OR (95% CI) Diagnosis of Neurologic Dysfunction
Tanner et al.,2009; US 519 cases; consecutively eligible subjects between July 1, 2004, and May 31,2007 521 controls frequency matched to cases by age,sex. and location Telephone interviewers collected information about exposures before the reference age; employment history— industry, location, processes, materials, and job tasks. Toxicant exposure collected for some jobs 2,4-D 16 2.6(1.0-6.5) Enrolling investigator determined diagnosis and type of parkinsonism. Unified Parkinson Disease Rating Scale score, and clinical features
Brighina el al., 2008; US (Mayo Clinic) 833 PD sequenlial cases from clinic: median age = 67.7 yr, 208 cases ≤ 59.8 yr 472 unaffected siblings and 361 unrelated controls Self-report down to specific herbicides: 2,4-D said to be most prevalent in cases, but published analysis not that detailed For youngest quartile al diagnosis:
Pesticides (ever):
Herbicides (ever):
Phenoxy herbicides
Insecticides (ever):
Fungicides (ever):
87 1.8(1.1-2.9)
2.5(1.3-4.5)
1.5(1.0-2.2)
1.0(0.6-1.7)
1.0(0.3-3.2)
PD diagnosed by movemenl disorder specialist
Hancock el al., 2008; US (Duke) 319 cases 296 unaffected relatives and others All comparisons referent to those who never applied any pesticide Pesticide application: Insecticides: Botanical:
Organophosphate: Herbicides:
Chlorophenoxy:
Phosophonoglycine:
Triazine:
200

7
53

15
57
5
1.6(1.1-2.3)
1.8(1.2-2.8)
5.9 (0.6-56)
1.9(1.1-3.6)
1.6(1.0-2.5)
2.1(0.7-6.2)
1.5(0.9-2.5)
1.1 (0.3-3.6)
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference and Country Cases in Study Group Comparison Group Exposure Assessment Exposure(s)a n OR (95% CI) Diagnosis of Neurologic Dysfunction
Kamel el al., 2007b: US (Agricultural Health Study)[Updates Kamel et al.. 20051 83 prevalent cases al enrollment; 78 incident cases during follow-up among private applicators and spouses 79,557 without PD at enrollment; 55,931 without PD followed up Self-report of individual herbicides (2,4-D; 2,4,5-T; 2,4,5-TP) on detailed self-ad ministered questionnaires at enrollment or telephone interview for follow-up For incident cases:
2,4-D:
2,4,5-T:
2,4,5-TP:
Dicamba:
Paraquat:
Trifuralin:
Cyanazine
For prevalent cases:
2,4-D:
2,4,5-T:
2.4.5-TP:
Dicamba:
Paraquat:
Trifuralin:
Cyanazine

49
24
7
32
11
32
26

47
16
4
26
14
31
30
1.0(0.5-2.1)
1.8(1.0-3.3)
0.9(0.4-1.8)
1.5(0.8-2.8)
1.0(0.5-1.9)
1.7(1.0-3.2)
1.0(0.5-1.8)
0.9(0.5-1.8)
0.9(0.5-1.7)
0.8(0.3-1.9)
0.9(0.5-1.6)
1.8(1.0-3.4)
0.9(0.5-1.6)
2.6(1.4-4.9)
Firestone el al., 2005; Washington. US 250 (156 men) newly diagnosed 1992-2002 at Group Health Cooperative 388 (241 men) Interview determining occupational and home-based pesticide exposure characterized by chemical name or brand, duration, and frequency Occupational, men only
Pesticides:
Insecticides:
Fungicides:
Herbicides: Paraquat:
Home use, all subjects
Pesticides:
Insecticides:
Fungicides:
Herbicides:

19
15
2
9
2

178
141
14
116

1.0(0.5-1.9)
0.9(0.4-1.8)
0.4(0.1-3.9)
1.4(0.5-3.9)
1.7(0.2-12.8)
1.0(0.7-1.4)
0.8(0.6-1.1)
0.6(0.3-1.1)
1.1(0.8-1.5)
Controlled for age. sex, smoking
Behari el al., 2001; India 377(301 men, 76 women) 377 matched for age (± 3 yr), bul nol sex Structured interview McNemar chi-square: Herbicides: p = 0.010
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference and Country Cases in Study Group Comparison Group Exposure Assessment Exposure(s)a n OR (95% CI) Diagnosis of Neurologic Dysfunction
(protective effect—not confirmed
by multivariate analysis)
Insecticide:
Rodenticide:
p = 0.169
p = 0.662
Engel et al., 2001; US [cross-sectional, but otherwise fairly high-quality design] 238 72 Self-ad mi nisicred questionnaire for occupational exposure [prevalence ratios]
Any pcsiicide:
Herbicides:
Insecticides:
Fungicides:
0.8(0.5-1.2)
0.9(0.6-1.3)
0.9(0.6-1.5)
0.8(0.6-1.3)
Neurologic exam by trained nurse
Kuopio et al., 1999; Finland 123 (onset of PD before 1984; 63 men, 60 women) 246 matched on sex, age (± 2 yr). and urban/ rural Interview—pesticides or herbicides regularly or occasionally used Pesticide use:
Occasional use:
Regular use:
Herbicide use:
Occasional use:
Regular use:
39
26
13
33
20
13
1.0(0.6-1.7)
1.2(0.7-2.0)
0.7(0.3-1.3)
1.4 (0.8-2.5)
1.7 (0.9-3.2)
0.8(0.4-1.7)
Neurologic exam
Taylor el al., 1999; Boston Medical 140 147 controls referred by cases Interview—exposure recorded as lotal days for lifetime Logistic analysis adjusted for age, sex, family history, education, smoking, water source, head injury, depression Pesticides:
Herbicides:
1.0(0.9-1.2)
1.1 (0.7-1.7)
Neurologic exam
Gorell et al., 1998; US 144 (age > 50 yrs 464 Interview—herbicide and insecticide use while working on a farm or gardening All occupations contributing exposure to: Herbicides:
Insecticides:
Fungicides:
4.1 (1.4-12.2)
3.6(1.8-7.2)
1.6(0.5-5.5)
Standard criteria of PD by history
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference and Country Cases in Study Group Comparison Group Exposure Assessment Exposure(s)a n OR (95% CI) Diagnosis of Neurologic Dysfunction
Liouet aL,1997;Taiwan 120 240 hospital controls matched for age (± 2 yr) and sex Interview—occupational exposures to herbicides or pesticides Pesticides vs no pesticides:
But no paraquat use:
Paraquat use:
Paraquat use vs no paraquat:
2.9 (2.3-3.7)
2.2 (0.9-5.6)
4.7(2.0-12))
3.2 (2.4-4.3)
Neurologic exam
Seidler a al., 1996; Germany 380(age < 66 yrs with PD after 1987) 755 (379 neighborhood, 376 regional; neighborhood controls may be over-matched) Interview—dose-years = years of application weighted by use Pesticides: Herbicides—high dose:
Dose trend
vs neighbor controls
vs regional controls Insecticides—high dose:
Dose trend
vs neighbor controls
vs regional controls
2.1(1.6-2.6)
2.4(1.0-6.0)


p = 0.06
p < 0.001
2.1 (0.9-4.8)


p = 0.12
p < 0.001
Hertz man el ah, 1994; Canada 127 (71 men and 56 women) 245 (121 with cardiac disease; 124 voters) Interview—occupation with probable pesticide exposure Cases
vs volers—among men
Pesticides: Herbicides:
Chlorophenoxys: Paraquat:
Insecticides:
Fungicides:

23(1.1-4.9)
1.2(0.6-2.5)
1.2(0.6-2.4)
13 (0.3-4.6)
03(0.1-0.9)
Neurologic exam
Buiterlield et al., 1993; US 63 young onset cases (age < 50 years) 68 Questionnaire—pestiicide or insecticide use 10 limes in any year Herbicides:
Insecticides:
Dwelling fumigated:
3.2 p = 0.033
5.8 p < 0.00l
5.3 p = 0.45
Standard criteria of PD by history
Semchuk a al., 1992; Calgaiy, Alberta, Canada 130 living cases from register of Calgary residents (population-based) 260 community controls matched for age (± 2.5 yr) and sex, identified by RDD Interview—self-report of exposure for each job held > I month Pesticides:
Herbicides:
Exposed during age
interval:
16-25 yr
26-35 yr
36-45 yr
32
17
2.3(1.3-4.0)
3.1 (1.3-7.0)
1.4 (0.5-4.3)
4.8(1.5-15.0)
3.8(1.2-13.0)
Neurologic exam confirming idiopathic PD without dementia (average 7.8 yr from diagnosis)
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference and Country Cases in Study Group Comparison Group Exposure Assessment Exposure(s)a n OR (95% CI) Diagnosis of Neurologic Dysfunction
Stem et al., 1991; NJ and PA, US 69—all young onset cases identified (age < 40yrs); 80—random selection of old onset cases (age > 59 yrs) 149 nominated by each case or picked from hospital; matched by age (± 6 yr). sex, and race Interview—self-report of insecticide and pesticide use by self or others in home or garden 46-55 yr
Insecticides: Fungicides:
Insecticides:
Onset < 40 years:
Onset > 59 years:
Herbicides:
Onset < 40 years:
Onset > 59 years:
Adjusted for smoking, head injury, rural residence:
17
16
4.9(1.3-19.0)
2.1 (1.0-4.1)
1.6(0.8-3.3)
0.7(0.3-1.4)
0.6(0.2-1.7)
0.8(0.3-2.1)
1.1(0.7-1.7) 0.9(0.5-1.7)
1.3 (0.7-2.4)
0.5(0.2-1.1)
0.9(0.6-1.5)
Review of medical records, responsive to PD medication (under treatment average of 8.2 yr), without major cognitive impairment
Hertz man el al.. 1990; British Columbia, Canada 57 prevalent PI) patients (age < 79 yrs) (50-54 had confirmed PD, not clear exactly how many) 122 aged 50-79 who responded from electoral rolls Questionnaire—ever worked in an orchard Work in orchards: Paraquat: 4/57 3.7(1.3-10.3)
(p-0.01)
Neurologic exam confirmed diagnostic criteria in 55 of 69 cases identified by asking physicians in area

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.

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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.

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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.

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 9-2 Epidemiologic Studies of PesticideaExposure and Amyotrophic Lateral Sclerosis

Reference; Country Study Group Comparison Group Exposure Assessment Significant Association with Pesticidesa Exposure of Interest/ Estimated Risk (95% CI) Neurologic Dysfunction
Morahan and Pamphlett, 2006; Australia 179 179 Questionnaire—exposure to environmental toxicants Herbicides, pesticides/1.6 (1.0-2.4); industrial exposure: 5.6(2.1-15.1) Self-reported
ADVA, 2005c; Australia nr nr Deployment to Vietnam All COIs/4.7 (1.0-22.8)
Weisskopf et al., 2005 nr nr Self-administered questionnaire Military Service/1.5 (1.1-2.1); p = 0.007 Self-reported military services, death certificates
Bums et al., 2001; 1,567 40,600 Industrial hygienist ranked jobs for exposure to 2,4-D to derive years of exposure and cumulative exposure + 2,4-D/3.45(l.l-ll.l) Death certificates
McGuire et al., 1997; US 174 348 Self-reported lifetime job history, workplace exposures reviewed by panel of four industrial hygienists + Herbicides/2.4 (1.2-4.8); significant trend analysis for dose-effect relationship with agricultural chemicals; p = 0.03 New diagnosis of ALS 1990-1994 in western Washington state
Chancellor et al.. 1993; Scotland 103 103 Required regular occupational exposure to pesticides for 12 months or more Pesticides 1.4(0.6-3.1) Scottish Motor Neuron Register
Saveitieri et al., 1991; Italy 46 92 Continual exposure to agricultural chemicals Pesticides3.0(0.4-20.3) Cases reviewed by neurologists
Deapen and Henderson, 1986; US 518 518 Ever worked in presence of pesticides Pesticides 2.0 (0.8-5.4) ALS Society of America

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.

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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-

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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.

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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.

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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.

REFERENCES1

ADVA (Australian Department of Veteran’s Affairs). 2005c. Australian National Service Vietnam Veterans Mortality and Cancer Incidence Study. Canberra, Australia: Department of Veterans’ Affairs.

AFHS (Air Force Health Study). 1984. An Epidemiological Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Baseline Morbidity Study Results. Brooks AFB, TX: USAF School of Aerospace Medicine. NTIS AD-A138 340.

AFHS. 1987. An Epidemiological Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. First Follow-up Examination Results. Brooks AFB, TX: USAF School of Aerospace Medicine. USAFSAM-TR-87-27.

_____________________

1 Throughout the report the same alphabetic indicator following year of publication is used consistently for the same article when there were multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicator in order of citation in a given chapter is not followed.

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

AFHS. 1991. An Epidemiological Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Serum Dioxin Analysis of 1987 Examination Results. Brooks AFB, TX: USAF School of Aerospace Medicine.

AFHS. 1995. An Epidemiological Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1992 Follow-up Examination Results. Brooks AFB, TX: Epidemiologi-cal Research Division. Armstrong Laboratory.

AFHS. 2000. An Epidemiological Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1997 Follow-up Examination Results. Brooks AFB, TX: Epidemiologic Research Division, Armstrong Laboratory. AFRL-HE-BR-TR-2000-02.

Akahoshi E, Yoshimura S, Uruno S, Ishihara-Sugano M. 2009. Effect of dioxins on regulation of tyrosine hydroxylase gene expression by aryl hydrocarbon receptor: A neurotoxicology study. Environmental Health: A Global Access Science Source 8(1):24.

Assennato G, Cervino D, Emmett E, Longo G, Merlo F. 1989. Follow-up of subjects who developed chloracne following TCDD exposure at Seveso. American Journal of Industrial Medicine 16:119–125.

Baldi I, Lebailly P, Mohammed-Brahim B, Letenneur L, Dartigues J-F, Brochard P. 2003. Neurodegenerative diseases and exposure to pesticides in the elderly. American Journal of Epidemiology 157(5):409–414.

Barbieri S, Pirovano C, Scarlato G, Tarchini P, Zappa A, Maranzana M. 1988. Long-term effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the peripheral nervous system. Clinical and neurophysiological controlled study on subjects with chloracne from the Seveso area. Neuroepidemiology 7:29–37.

Barrett DH, Morriss RD, Akhtar FZ, Michalek JE. 2001. Serum dioxin and cognitive functioning among veterans of Operation Ranch Hand. NeuroToxicology 22:491–502.

Barrett DH, Morris RD, Jackson WG Jr, Stat M, Michalek JE. 2003. Serum dioxin and psychological functioning in US Air Force veterans of the Vietnam War. Military Medicine 168:153–159.

Behari M, Srivastava AK, Das RR, Pandey RM. 2001. Risk factors of Parkinson’s disease in Indian patients. Journal of Neurological Sciences 190(1-2):49–55.

Bongiovanni B, De Lorenzi P, Ferri A, Konjuh C, Rassetto M, Duffard AME, Cardinali DP, Duffard R. 2007. Melatonin decreases the oxidative stress produced by 2,4-dichlorophenoxyacetic acid in rat cerebellar granule cells. Neurotoxicity Research 11(2):93–99.

Bortolozzi AA, Duffard RO, Evangelista de Duffard AM. 1999. Behavioral alterations induced in rats by a pre- and postnatal exposure to 2,4-dichlorophenoxyacetic acid. Neurotoxicology and Teratology 21(4):451–465.

Bortolozzi A, de Duffard AME, Dajas F, Duffard R, Silveira R. 2001. Intracerebral administration of 2,4-dichlorophenoxyacetic acid induces behavioral and neurochemical alterations in the rat brain. NeuroToxicology 22(2):221–232.

Bortolozzi A, Duffard R, Antonelli M, Evangelista de Duffard AM. 2002. Increased sensitivity in dopamine D(2)-like brain receptors from 2,4-dichlorophenoxyacetic acid (2,4-D)-exposed and amphetamine-challenged rats. Annals of the New York Academy of Sciences 965:314–323.

Bortolozzi A, Duffard R, de Duffard AM. 2003. Asymmetrical development of the monoamine systems in 2,4-dichlorophenoxyacetic acid treated rats. NeuroToxicology 24(1):149–157.

Bortolozzi AA, Evangelista de Duffard AM, Duffard RO, Antonelli MC. 2004. Effects of 2,4-dichlorophenoxyacetic acid exposure on dopamine D2-like receptors in rat brain. Neurotoxicology and Teratology 26(4):599–605.

Breland AE, Currier RD. 1967. Multiple sclerosis and amyotrophic lateral sclerosis in Mississippi. Neurology 17:1011–1016.

Brighina L, Frigerio R, Schneider NK, Lesnick TG, de Andrade M, Cunningham JM, Farrer MJ, Lincoln SJ, Checkoway H, Rocca WA, Maraganore DM. 2008. Alpha-synuclein, pesticides, and Parkinson disease: A case–control study. Neurology 70(16 pt 2):1461–1469.

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Bronstein J, Carvey P, Chen H, Cory-Slechta DA, DiMonte D, Duda J, English PB, Goldman S, Grate S, Hansen J, Hoppin J, Jewell S, Kamel F, Koroshetz W, Langston J, Logroscino G, Nelson L, Ravina B, Rocca WA, Ross G, Schettler T, Schwarzschild M, Scott B, Seegal R, Singleton A, Steenland, K, Tanner C, Eeden, S, Weisskopf M. 2009. Meeting report: Consensus statement— Parkinson’s disease and the environment: Collaborative on Health and the Environment and Parkinson’s Action Network (CHE PAN) Conference 26–28 June 2007. Environmental Health Perspectives 117(1):117–121.

Brooks BR. 1996. Clinical epidemiology of amyotrophic lateral sclerosis. Neurological Clinics 14(2):399–420.

Burns CJ, Beard KK, Cartmill JB. 2001. Mortality in chemical workers potentially exposed to 2,4-dichlorophenoxyacetic acid (2,4-D) 1945–94: An update. Occupational and Environmental Medicine 58:24–30.

Butterfield PG, Valanis BG, Spencer PS, Lindeman CA, Nutt JG. 1993. Environmental antecedents of youngonset Parkinson’s disease. Neurology 43:1150–1158.

Byers JP, Masters K, Sarver JG, Hassoun EA. 2006. Association between the levels of biogenic amines and superoxide anion production in brain regions of rats after subchronic exposure to TCDD. Toxicology 228(2-3):291–298.

CDC (Centers for Disease Control and Prevention). 1988. Health status of Vietnam veterans. II. Physical health. Journal of the American Medical Association 259:2708–2714.

Celik I, Tuluce Y, Isik I. 2006. Influence of subacute treatment of some plant growth regulators on serum marker enzymes and erythrocyte and tissue antioxidant defense and lipid peroxidation in rats. Journal of Biochemical and Molecular Toxicology 20(4):174–182.

Chancellor AM, Slattery JM, Fraser H. 1993. Risk factors for motor neuron disease: A case–control study based on patients from the Scottish motor neuron disease register. Journal of Neurology, Neurosurgery, and Psychiatry 56:1200–1206.

Crawford JM, Hoppin JA, Alavanja MCR, Blair A, Sandler DP, Kamel F. 2008. Hearing loss among licensed pesticide applicators in the Agricultural Health Study. Journal of Occupational and Environmental Medicine 50(7):817–826.

Dahlgren J, Warshaw R, Horsak RD, Parker FM 3rd, Takhar H. 2003. Exposure assessment of residents living near a wood treatment plant. Environmental Research 92(2):99–109.

Deapen DM, Henderson BE. 1986. A case–control study of amyotrophic lateral sclerosis. American Journal of Epidemiology 123:790–799.

Decoufle P, Holmgreen P, Boyle CA, Stroup NE. 1992. Self-reported health status of Vietnam veterans in relation to perceived exposed to herbicides and combat. American Journal of Epidemiology 135:312–323.

Dhillon AS, Tarbutton GL, Levin JL, Plotkin GM, Lowry LK, Nalbone JT, Shepherd S. 2008. Pesticide/environmental exposures and Parkinson’s disease in East Texas. Journal of Agromedicine 13(1):37–48.

Di Monte D, Lavasani M, Manning-Bog A. 2002. Environmental factors in Parkinson’s disease. NeuroToxicology 23(4-5):487–502.

Drechsel DA, Patel M. 2008. Role of reactive oxygen species in the neurotoxicity of environmental agents implicated in Parkinson’s disease. Free Radical Biology and Medicine 44(11):1873–1886.

Duffard R, Garcia G, Rosso S, Bortolozzi A, Madariaga M, Di Paolo O, Evangelista De Duffard A. 1996. Central nervous system myelin deficit in rats exposed to 2,4-dichlorophenoxyacetic acid throughout lactation. Neurotoxicology and Teratology 18(6):691–696.

Elbaz A, Clavel J, Rathouz PJ, Moisan F, Galanaud JP, Delemotte B, Alperovitch A, Tzourio C. 2009. Professional exposure to pesticides and Parkinson disease. Annals of Neurology 66(4):494–504.

Engel LS, Checkoway H, Keifer MC, Seixas NS, Longstreth WT, Scott KC, Hudnell K, Anger WK, Camicioli R. 2001. Parkinsonism and occupational exposure to pesticides. Occupational and Environmental Medicine 58:582–589.

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Evangelista de Duffard AM, Orta C, Duffard RO. 1990. Behavioral changes in rats fed a diet containing 2,4-dichlorophenoxyacetic butyl ester. Neurotoxicology 11:563–572.

Evangelista de Duffard AM, Bortolozzi A, Duffard RO. 1995. Altered behavioral responses in 2,4-dichlorophenoxyacetic acid treated and amphetamine challenged rats. Neurotoxicology 16(3):479–488.

Firestone JA, Smith-Weller T, Franklin G, Swanson P, Longstreth WT Jr, Checkoway H. 2005. Pesticides and risk of Parkinson disease: A population-based case–control study. Archives of Neurology 62(1):91–95.

Firestone JA, Lundin JI, Powers KM, Smith-Weller T, Franklin GM, Swanson PD, Longstreth WT Jr, Checkoway H. 2010. Occupational factors and risk of Parkinson’s disease: A population-based case–control study. American Journal of Industrial Medicine 53(3):217–223.

Gallagher JP, Sander M. 1987. Trauma and amyotrophic lateral sclerosis: A report of 78 patients. Acta Neurologica Scandinavia 75:1041–1043.

Garcia C, Pascual JA, Mena E, Hernandez T. 2004. Influence of the stabilisation of organic materials on their biopesticide effect in soils. Bioresource Technology 95(2):215–221.

Garcia GB, Konjuh C, Duffard RO, de Duffard AME. 2006. Dopamine-beta-hydroxylase immunohistochemical study in the locus coeruleus of neonate rats exposed to 2,4-dichlorophenoxyacetic acid through mother’s milk. Drug and Chemical Toxicology 29(4):435–442.

Gauthier E, Fortier I, Courchcesne F, Pepin P, Mortimer J, Gauvreau D. 2001. Environmental pesticide exposure as a risk factor for Alzheimer’s disease: A case–control study. Environmental Research 86:37–45.

Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Richardson RJ. 1998. The risk of Parkinson’s disease with exposure to pesticides, farming, well water, and rural living. Neurology 50:1346–1350.

Grahmann F, Claus D, Grehl H, Neundoerfer B. 1993. Electrophysiologic evidence for a toxic polyneuropathy in rats after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Journal of Neurological Sciences 115(1):71–75.

Grehl H, Grahmann F, Claus D, Neundorfer B. 1993. Histologic evidence for a toxic polyneuropathy due to exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats. Acta Neurologica Scandinavica 88(5):354–357.

Haijima A, Endo T, Zhang Y, Miyazaki W, Kakeyama M, Tohyama C. 2010. In utero and lactational exposure to low doses of chlorinated and brominated dioxins induces deficits in the fear memory of male mice. NeuroToxicology 31(4):385–390.

Hancock DB, Martin ER, Mayhew GM, Stajich JM, Jewett R, Stacy MA, Scott BL, Vance JM, Scott WK. 2008. Pesticide exposure and risk of Parkinson’s disease: A family-based case–control study. BMC Neurology 8(6):1–12.

Hanisch R, Dworsky RL, Henderson BE. 1976. A search for clues to the cause of amyotrophic lateral sclerosis. Archives of Neurology 33:456–457.

Hatcher JM, Pennell KD, Miller GW. 2008. Parkinson’s disease and pesticides: A toxicological perspective. Trends in Pharmacological Sciences 29(6):322–329.

Hertzman C, Wiens M, Bowering D, Snow B, Calne D. 1990. Parkinson’s disease: A case–control study of occupational and environmental risk factors. American Journal of Industrial Medicine 17:349–355.

Hertzman C, Wiens M, Snow B, Kelly S, Calne D. 1994. A case–control study of occupational of Parkinson’s disease in a horticultural region of British Columbia. Movement Disorders 9:69–75.

Hoffman RE, Stehr-Green PA, Webb KB, Evans RG, Knutsen AP, Schramm WF, Staake JL, Gibson BB, Steinberg KK. 1986. Health effects of long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of the American Medical Association 255(15):2031–2038.

Hojo R, Kakeyama M, Kurokawa Y, Aoki Y, Yonemoto J, Tohyama C. 2008. Learning behavior in rat offspring after in utero and lactational exposure to either TCDD or PCB126. Environmental Health and Preventive Medicine 13(3):169–180.

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Howdeshell KL. 2002. A model of the development of the brain as a construct of the thyroid system. Environmental Health Perspectives 110(Suppl 3):337–348.

Huang P, Rannug A, Ahlbom E, Haakansson H, Ceccatelli S. 2000. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the expression of cytochrome P450 1A1, the aryl hydrocarbon receptor, and the aryl hydrocarbon receptor nuclear translocator in rat brain and pituitary. Toxicology and Applied Pharmacology 169(2):159–167.

IOM (Institute of Medicine). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press.

IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press.

IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press.

IOM. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: National Academy Press.

IOM. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press.

IOM. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press.

IOM. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press.

IOM. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press.

Kamel F, Engel LS, Gladen BC, Hoppin JA, Alavanja MC, Sandler DP. 2005. Neurologic symptoms in licensed private pesticide applicators in the Agricultural Health Study. Environmental Health Perspectives 113(7):877–882.

Kamel F, Engel LS, Gladen BC, Hoppin JA, Alavanja MC, Sandler DP. 2007a. Neurologic symptoms in licensed pesticide applicators in the Agricultural Health Study. Human and Experimental Toxicology 26(3):243–250.

Kamel F, Tanner C, Umbach D, Hoppin J, Alavanja M, Blair A, Comyns K, Goldman S, Korell M, Langston J, Ross G, Sandler D. 2007b. Pesticide exposure and self-reported Parkinson’s disease in the Agricultural Health Study. American Journal of Epidemiology 165(4):364–374.

Kim JS, Lim HS, Cho SI, Cheong HK, Lim MK. 2003. Impact of Agent Orange exposure among Korean Vietnam veterans. Industrial Health 41(3):149–157.

Kim SY, Yang JH. 2005. Neurotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in cerebellar granule cells. Experimental and Molecular Medicine 37:58–64.

Kim SY, Lee HG, Choi EJ, Park KY, Yang JH. 2007. TCDD alters PKC signaling pathways in developing neuronal cells in culture. Chemosphere 67(9):S421–S427.

Klein C, Lohmann-Hedrich K. 2007. Impact of recent genetic findings in Parkinson’s disease. Current Opinion in Neurology 20(4):453–464.

Konjuh C, Garcia G, Lopez L, de Duffard AME, Brusco A, Duffard R. 2008. Neonatal hypomyelination by the herbicide 2,4-dichlorophenoxyacetic acid. Chemical and ultrastructural studies in rats. Toxicological Sciences 104(2):332–340.

Kuopio A, Marttila RJ, Helenius H, Rinne UK. 1999. Environmental risk factors in Parkinson’s disease. Movement Disorders 14:928–939.

Kurtzke JF, Beebe GW. 1980. Epidemiology of amyotrophic lateral sclerosis: 1. A case–control comparison based on ALS deaths. Neurology 30:453–462.

Langston JW. 2006. The Parkinson’s complex: Parkinsonism is just the tip of the iceberg. Annals of Neurology 59(4):591–596.

Lee D-H, Jacobs DR Jr, Steffes M. 2008. Association of organochlorine pesticides with peripheral

neuropathy in patients with diabetes or impaired fasting glucose. Diabetes 57(11):3108–3111.

Lee HG, Kim SY, Choi EJ, Park KY, Yang JH. 2007. Translocation of PKC-betaII is mediated via RACK-1 in the neuronal cells following dioxin exposure. NeuroToxicology 28(2):408–414.

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Lensu S, Miettinen R, Pohjanvirta R, Lindén J, Tuomisto J. 2006. Assessment by c-Fos immunostaining of changes in brain neural activity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and leptin in rats. Basic and Clinical Pharmacology and Toxicology 98:363–371.

Liang CL, Wang TT, Luby-Phelps K, German DC. 2007. Mitochondria mass is low in mouse substantia nigra dopamine neurons: Implications for Parkinson’s disease. Experimental Neurology 203(2):370–380.

Liou HH, Tsai MC, Chen CJ, Jeng JS, Chang YC, Chen SY, Chen RC. 1997. Environmental risk factors and Parkinson’s disease: A case–control study in Taiwan. Neurology 48:1583–1588.

McGuire V, Longstreth WT, Nelson LM, Koepsell TD, Checkoway H, Morgan MS, van Belle G. 1997. Occupational exposure and amyotrophic lateral sclerosis: A population-based case– control study. American Journal of Epidemiology 145:1076–1088.

Michalek JE, Akhtar FZ, Arezzo JC, Garabrant DH, Albers JW. 2001. Serum dioxin and peripheral neuropathy in veterans of Operation Ranch Hand. Neurotoxicology 22:479–490.

Mitsui T, Sugiyama N, Maeda S, Tohyama C, Arita J. 2006. Perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin suppresses contextual fear conditioning-accompanied activation of cyclic AMP response element-binding protein in the hippocampal CA1 region of male rats. Neuroscience Letters 398(3):206–210.

Mohammad FK, St. Omer VE. 1986. Behavioral and developmental effects in rats following in utero exposure to 2,4-D/2,4,5-T mixture. Neurobehavioral Toxicology and Teratology 8(5):551–560.

Morahan JM, Pamphlett R. 2006. Amyotrophic lateral sclerosis and exposure to environmental toxins: An Australian case–control study. Neuroepidemiology 27(3):130–135.

NCHS (National Center for Health Statistics). 1994. Vital and Health Statistics: Prevalence and Characteristics of Persons with Hearing Trouble: United States, 1990–91. Series 10: Data from the National Health Survey, Number 188.

NCHS. 2010. Vision, hearing, balance, and sensory impairment in Americans aged 70 years and over: United States, 1999–2006. NCHS Data Brief, Number 31.

Nunomura A, Moreira PI, Lee HG, Zhu X, Castellani RJ, Smith MA, Perry G. 2007. Neuronal death and survival under oxidative stress in Alzheimer and Parkinson diseases. CNS and Neurological Disorders—Drug Targets 6(6):411–423.

O’Toole BI, Marshall RP, Grayson DA, Schureck RJ, Dobson M, Ffrench M, Pulvertaft B, Meldrum L, Bolton J, Vennard J. 1996. The Australian Vietnam Veterans Health Study: III. Psychological health of Australian Vietnam veterans and its relationship to combat. International Journal of Epidemiology 25(2):331–340.

O’Toole BI, Catts SV, Outram S, Pierse KR, Cockburn J. 2009. The physical and mental health of Australian Vietnam veterans 3 decades after the war and its relation to military service, combat, and post-traumatic stress disorder. American Journal of Epidemiology 170(3):318–330.

Palmeira CM, Moreno AJ, Madeira VM. 1994a. Interactions of herbicides 2,4-D and dinoseb with liver mitochondrial bioenergetics. Toxicology and Applied Pharmacology 127:50–57.

Palmeira CM, Moreno AJ, Madeira VMC. 1994b. Metabolic alterations in hepatocytes promoted by the herbicides paraquat, dinoseb and 2,4-D. Archives of Toxicology 68:24–31.

Palmeira CM, Moreno AJ, Madeira VM. 1995a. Effects of paraquat, dinoseb and 2,4-D on intracellular calcium and on vasopressin-induced calcium mobilization in isolated hepatocytes. Archives of Toxicology 69:460–466.

Palmeira CM, Moreno AJ, Madeira VM. 1995b. Thiols metabolism is altered by the herbicides paraquat, dinoseb and 2,4-D: A study in isolated hepatocytes. Toxicology Letters 81:115–123.

Park RM, Schulte PA, Bowman JD, Walker JT, Bondy SC, Yost MG, Touchstone JA, Dosemeci M. 2005. Potential occupational risks for neurodegenerative diseases. American Journal of Industrial Medicine 48(1):63–77.

Pazderova-Vejlupkova J, Lukas E, Nemcova M, Pickova J, Jirasek L. 1981. The development and prognosis of chronic intoxication by tetrachlorodibenzo-p-dioxin in men. Archives of Environmental Health 36:5–11.

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Pelclová D, Fenclová Z, Dlasková Z, Urban P, Lukás E, Procházka B, Rappe C, Preiss J, Kocan A, Vejlupková J. 2001. Biochemical, neuropsychological, and neurological abnormalities following 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. Archives of Environmental Health 56(6):493–500.

Pelclová D, Fenclová Z, Preiss J, Prochazka B, Spacil J, Dubska Z, Okrouhlik B, Lukás E, Urban P. 2002. Lipid metabolism and neuropsychological follow-up study of workers exposed to 2,3,7,8- tetrachlordibenzo-p-dioxin. International Archives of Occupational and Environmental Health 75:S60–S66.

Pelclová D, Fenclova Z, Urban P, Ridzon P, Preiss J, Kupka K, Malik J, Dubska Z, Navratil T. 2009. Chronic health impairment due to 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure. Neuroendocrinology Letters 30(Suppl 1):219–224.

Roelofs-Iverson RA, Mulder DW, Elverback LR, Kurland LT, Craig AM. 1984. ALS and heavy metals: A pilot case–control study. Neurology 34:393–395.

Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX, Rahmani Z, Krizus A, McKenna-Yasek D, Cayabyab A, Gaston S, Tanzi R, Halperin JJ, Herzfeldt B, Van den Berg R, Hung WY, Bird T, Deng G, Mulder DW, Smith C, Laing NG, Soriano E, Pericak-Vance MA, Haines J, Rouleau GA, Gusella J, Horvitz HR, Brown RH. 1993. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362(6415):59–62.

Rosso SB, Caceres AO, Evangelista de Duffard AM, Duffard RO, Quiroga S. 2000a. 2,4-dichlorophenoxyacetic acid disrupts the cytoskeleton and disorganizes the Golgi apparatus of cultured neurons. Toxicological Sciences 56:133–140.

Rosso SB, Garcia GB, Madariaga MJ, De Duffard AME, Duffard RO. 2000b. 2,4-dichlorophenoxyacetic acid in developing rats alters behaviour, myelination and regions brain gangliosides pattern. NeuroToxicology 21(1-2):155–164.

Rowland LP. 1998. Diagnosis of amyotrophic lateral sclerosis. Journal of the Neurological Sciences 160(Suppl 1):S6–S24.

Rowland LP, Shneider NA. 2001. Amyotrophic lateral sclerosis. The New England Journal of Medicine 344(22):1688–1700.

Sarnico I, Boroni F, Benarese M, Sigala S, Lanzillotta A, Battistin L, Spano P, Pizzi M. 2008. Activation of NF-kappaB p65/c-Rel dimer is associated with neuroprotection elicited by mGlu5 receptor agonists against MPP(+) toxicity in SK-N-SH cells. Journal of Neural Transmission 115(5):669–676.

Savettieri G, Salemi G, Arcara A, Cassata M, Castiglione MG, Fierro B. 1991. A case–control study of amyotrophic lateral sclerosis. Neuroepidemiology 10:242–245.

Seidler A, Hellenbrand W, Robra BP, Vieregge P, Nischan P, Joerg J, Oertel WH, Ulm G, Schneider E. 1996. Possible environmental, occupational, and other etiologic factors for Parkinson’s disease: A case–control study in Germany. Neurology 46:1275–1284.

Semchuk KM, Love EJ, Lee RG. 1992. Parkinson’s disease and exposure to agricultural work and pesticide chemicals. Neurology 42:1328–1335.

Shen D, Dalton TP, Nebert DW, Shertzer HG. 2005. Glutathione redox state regulates mitochondrial reactive oxygen production. Journal of Biological Chemistry 280(27):25305–25312.

Sherer T, Betarbet R, Stout A, Lund S, Baptista M, Panov A, Cookson M, Greenamyre J. 2002a. An in vitro model of Parkinson’s disease: Linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 22(16):7006–7015.

Solomon C, Poole J, Palmer KT, Peveler R, Coggon D. 2007. Neuropsychiatric symptoms in past users of sheep dip and other pesticides. Occupational and Environmental Medicine 64(4):259–266.

St. Omer VEV, Mohammad FF. 1987. Ontogeny of swimming behavior and brain catecholamine turnover in rats prenatally exposed to a mixture of 2,4-dichlorophenoxyacetic and 2,4,5-trichlorophenoxyacetic acids. Neuropharmacology 9:1351–1358.

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Stehr PA, Stein G, Webb K, Schramm W, Gedney WB, Donnell HD, Ayres S, Falk H, Sampson E, Smith SJ. 1986. A pilot epidemiologic study of possible health effects associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin contaminations in Missouri. Archives of Environmental Health 41(1):16–22.

Stern M, Dulaney E, Gruber SB, Golbe L, Bergen M, Hurtig H, Gollomp S, Stolley P. 1991. The epidemiology of Parkinson’s disease: A case–control study of young-onset and old-onset patients. Archives of Neurology 48:903–907.

Sturtz N, Deis RP, Jahn GA, Duffard R, Evangelista de Duffard AM. 2008. Effect of 2,4-dichlorophenoxyacetic acid on rat maternal behavior. Toxicology 247(2-3):73–79.

Tanner CM, Ross GW, Jewell SA, Hauser RA, Jankovic J, Factor SA, Bressman S, Deligtisch A, Marras C, Lyons KE, Bhudhikanok GS, Roucoux DF, Meng C, Abbott RD, Langston JW. 2009. Occupation and risk of Parkinsonism: A multicenter case–control study. Archives of Neurology 66(9):1106–1113.

Taylor CA, Saint-Hilaire MH, Cupples LA, Thomas CA, Burchard AE, Feldman RG, Myers RH. 1999. Environmental, medical, and family history risk factors for Parkinson’s disease: A New England-based case–control study. American Journal of Medical Genetics (Neuropsychiatric Genetics) 88:742–749.

Thiffault C, Langston WJ, Di Monte DA. 2001. Acute exposure to organochlorine pesticides does not affect striatal dopamine in mice. Neurotoxicity Research 3(6):537–543.

Urban P, Pelclova D, Lukas E, Kupka K, Preiss J, Fenclova Z, Smerhovsky Z. 2007. Neurological and neurophysiological examinations on workers with chronic poisoning by 2,3,7,8-TCDD: Follow-up 35 years after exposure. European Journal of Neurology 14(2):213–218.

Uversky V, Kiowa Bower JL, Fink AL. 2002. Synergistic effects of pesticides and metals on the fibrillation of α-synuclein: Implications for Parkinson’s disease. NeuroToxicology 23:527–536.

Vidal JS, Vidailhet P, Derkinderen P, Dubard de Gaillarbois T, Tzourio C, Alperovitch A. 2009. Risk factors for progressive supranuclear palsy: A case–control study in France. Journal of Neurology, Neurosurgery and Psychiatry 80:1271–1274.

Visintainer PF, Barone M, McGee H, Peterson EL. 1995. Proportionate mortality study of Vietnam-era veterans of Michigan. Journal of Occupational and Environmental Medicine 37:423–428.

Webb KB, Evans RG, Stehr P, Ayres SM. 1987. Pilot study on health effects of environmental 2,3,7,8-TCDD in Missouri. American Journal of Industrial Medicine 11(6):685–691.

Weisskopf MG, O’Reilly EJ, McCullough ML, Calle EE, Thun MJ, Cudkowicz M, Ascherio A. 2005. Prospective study of military service and mortality from ALS. Neurology 64(1):32–37.

Weisskopf MG, Morozova N, O’Reilly EJ, McCullough ML, Calle EE, Thun MJ, Ascherio A. 2009. Prospective study of chemical exposures and amyotrophic lateral sclerosis. Journal of Neurology, Neurosurgery and Psychiatry 80(5):558–561.

Williamson MA, Gasiewicz TA, Opanashuk LA. 2005. Aryl hydrocarbon receptor expression and activity in cerebellar granule neuroblasts: Implications for development and dioxin neurotoxicity. Toxicological Sciences 83:340–348.

Zober A, Ott MG, Messerer P. 1994. Morbidity follow-up study of BASF employees exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) after a 1953 chemical reactor incident. Occupational and Environmental Medicine 51:479–486.

Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 611
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 612
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 613
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 614
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 615
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 616
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 617
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 618
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 619
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 620
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 621
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 622
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 623
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 624
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 625
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 626
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 627
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 628
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 629
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 630
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 631
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 632
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 633
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 634
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 635
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 636
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 637
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 638
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 639
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 640
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 641
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 642
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 643
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 644
Suggested Citation:"9 Neurologic Disorders." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Page 645
Next: 10 Cardiovascular and Metabolic Effects »
Veterans and Agent Orange: Update 2010 Get This Book
×
Buy Hardback | $147.00 Buy Ebook | $119.99
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

Because of continuing uncertainty about the long-term health effects of the sprayed herbicides on Vietnam veterans, Congress passed the Agent Orange Act of 1991. The legislation directed the Secretary of Veterans Affairs (VA) to request the Institite of Medicine to perform a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange and other herbicides used in Vietnam to be followed by biennial updates. The 2010 update recommends further research of links between Vietnam service and specific health outcomes, most importantly COPD, tonsil cancer, melanoma, brain cancer, Alzheimer's disease, and paternally transmitted effects to offspring.

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    Switch between the Original Pages, where you can read the report as it appeared in print, and Text Pages for the web version, where you can highlight and search the text.

    « Back Next »
  6. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  7. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  8. ×

    View our suggested citation for this chapter.

    « Back Next »
  9. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!