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Veterans and Agent Orange: Update 2002 (2003)

Chapter: 8. Neurobehavioral Disorders

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Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

8

Neurobehavioral Disorders

Neurologic problems in clinical medicine cover a wide variety of disorders. The nervous system actually consists anatomically and functionally of the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS includes the brain and spinal cord, and CNS dysfunction can be divided into two general categories: neurobehavioral dysfunction and motor or sensory dysfunction. Neurobehavioral difficulties involve cognitive decline, including memory problems and dementia; and neuropsychiatric disorders, including neurasthenia (a collection of such symptoms as difficulty in concentrating, headache, insomnia, and fatigue), depression, posttraumatic stress disorder (PTSD), and suicide. Motor dysfunction is characterized by such problems as weakness, tremors, involuntary movements, incoordination, and walking abnormalities; these are usually associated with subcortical or cerebellar disorders. The anatomic elements of the PNS include the spinal rootlets that leave the spinal cord, the brachial and lumbar plexus, and the peripheral nerves that innervate muscles. PNS dysfunctions, involving either the somatic nerves or the autonomic system, are known as peripheral neuropathies.

Neurologic dysfunction can be further classified, on the basis of anatomic distribution as either global or focal; on the basis of temporal onset as acute, subacute, or chronic; or on the basis of temporal course as transient or persistent. For example, global cerebral dysfunction may lead to altered levels of consciousness, whereas focal lesions may cause isolated signs of cortical dysfunction, such as aphasia. Acute onset of motor or coordination disturbances leads to symptoms that develop over minutes or hours, whereas subacute onset occurs over days or weeks, and chronic onset over months or years. Transient peripheral neuropathies

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

resolve spontaneously, whereas persistent ones may lead to chronic deficits. In the original VAO report, attention was deliberately focused on persistent neurobehavioral dysfunction. Later reports, including this one, review all new data pertinent to clinical neurobehavioral dysfunction and peripheral neuropathy.

Case identification in neurology is often difficult. Despite advances in neuro-imaging, many types of neurologic alterations are biochemical and show no abnormalities on scanning tests. The nervous system is not usually accessible for biopsy, so pathologic confirmation is not feasible for many neurologic disorders. Behavioral and neurophysiologic changes can be partly or largely subjective and, even when objectively documented, are often reversible. Timing is important in assessing the effect of chemical exposure on neurologic function. Some symptoms of neurologic importance appear acutely but are short-lived, whereas others appear slowly and are detectable for extended periods. These caveats must be considered in the design and critique of epidemiologic studies aimed at evaluating an association between exposure to a chemical agent and neurologic or neurobehavioral dysfunction.

Many reports have addressed the possible contribution of herbicides and pesticides to nervous system dysfunction, and reported abnormalities have ranged from mild and transient to severe and persistent. Those assessments have been conducted in three general settings: in relation to occupational, environmental, and Vietnam-veteran exposures. This chapter reviews reports of the following neurologic alterations associated with human exposure to the chemicals of interest (2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), 4-amino-3,5,6-trichloropicolinic acid (picloram), and cacodylic acid (dimenthylarsenic acid, DMA): cognitive and neuropsychiatric effects, motor or coordination dysfunction, chronic persistent peripheral neuropathy, and acute and subacute transient peripheral neuropathy. The potential neurotoxicity of those chemicals in recent animal studies is discussed in Chapter 3. The categories of association and the committee's approach to categorizing the health outcomes are discussed in Chapters 1 and 2.

COGNITIVE AND NEUROPSYCHIATRIC EFFECTS

Summary of VAO, Update 1996, Update 1998, and Update 2000

On the basis of the data available at the time, it was concluded in Veterans and Agent Orange (hereafter referred to as VAO; IOM, 1994), Veterans and Agent Orange: Update 1996 (hereafter, Update 1996; IOM, 1996), and Veterans and Agent Orange: Update 1998 (hereafter, Update 1998; IOM, 1999) that there was inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and cognitive or neuropsychiatric disorders. The majority of the data that formed the basis for those conclusions

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

came from the Air Force Health Studies (AFHS, 1991, 1995). The 1987 AFHS (AFHS, 1991), originally reviewed in VAO, found no association between serum TCDD (both baseline and current concentrations) and such variables as anxiety, depression, and hostility on the Symptom Checklist-90–Revised (SCL-90-R) or between TCDD and the presence of sleep problems. In contrast, some scales on the Millon Clinical Multiaxial Inventory (MCMI) had significant associations with TCDD in a variety of analyses. The belief that the findings from the SCL-90-R and the MCMI and the reported medical information were inconsistent led to the conclusion of inadequate or insufficient evidence of an association between exposure and cognitive or neuropsychiatric disorders (IOM, 1994).

In the 1992 AFHS (AFHS, 1995) some checklist variables (anxiety, hostility, obsessive–compulsive behavior, paranoid ideation, somatization, global severity index, and other neuroses) were significantly increased across all occupations in Ranch Hands, but the association was not significant for some after adjustment for covariates. In a later follow-up examination, the 1997 AFHS (AFHS, 2000), described in Update 2000 (IOM, 2001), a repeat psychologic assessment was performed with SCL-90-R and reported psychologic disorders verified through medical record review. The verified psychologic disorders were combined with those obtained on previous examinations—baseline, 1985, 1987, and 1992. Of the five psychologic diagnoses—psychoses, alcohol dependence, drug dependence, anxiety, and other neuroses—a dose–response pattern was found only for 1987 TCDD concentrations and prevalence of “other neuroses” in the enlisted ground crew. When the relationship between the 1987 lipid-adjusted serum TCDD concentrations from all Ranch Hands and the psychologic end points were examined, however, no significant results were found. The checklist results were not different across Ranch Hand occupational groups and were not associated with TCDD exposure. Both VAO and Update 2000 (IOM, 2001) had noted inconsistencies in the methods used to establish psychologic diagnoses in the 1987 and 1997 AFHS examinations (AFHS, 1991, 2000). Therefore, the conclusion of inadequate or insufficient evidence of an association between exposure and cognitive or neuropsychiatric disorders remained unchanged (IOM, 2001).

Update of the Scientific Literature

Since Update 2000 (IOM, 2001), three relevant studies of cognitive and neuropsychiatric effects have been published: an update of the AFHS (Barrett et al., 2001), an occupational study in Czechoslovakia (Pazderova-Vejlupkova et al., 1981), and a study of Alzeimer's disease after environmental exposure to herbicides and insecticides (Gauthier et al., 2001).

Results of cognitive functioning from the AFHS examination in 1982 were published (Barrett et al., 2001). Neuropsychologic performance was measured in 937 Ranch Hand veterans (388 exposed to TCDD at background concentrations, 274 at low concentrations, and 275 at high concentrations) and 1,052 comparison

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

veterans who served in Southeast Asia but were not involved in spraying herbicides (all of whom had a serum TCDD concentration below 10 ppt). Cognitive functioning was assessed with the Halsted Reitan (HR) neuropsychologic test battery (16 measures), the Wechsler Adult Intelligence Scale-Revised (WAIS-R) (11 measures), the Wechsler Memory Scale Form 1 (WMS) (five measures), and the reading subtest of the Wide Range Achievement Test (WRAT). Comparison veterans had been matched to Ranch Hand veterans on age, race, and military occupation. For all tests of cognitive functioning, mean scores for the three TCDD-exposed veteran groups were contrasted with the comparison group after adjustment for military occupation, age, race, drinking history, marital status, combat-exposure quartile, four psychiatric-diagnosis indicators (see Update 2000, page 442, for detailed description), and a psychotropic-medication use indicator. Finger tapping (HR) with the dominant and nondominant hands was significantly lower (poorer) in the Ranch Hand low-TCDD group than in the comparison group. Nondominant grip strength (HR) was significantly lower (weaker) in the Ranch Hand background-TCDD group than in the comparison group. Veterans in the Ranch Hand low-TCDD group were 3 times as likely to be rated severely impaired on the HR impairment index as all other veterans.

When Vietnam veterans were separated into quintiles on the basis of TCDD concentration, and the second, third, fourth, and fifth TCDD-concentration quintiles were contrasted with veterans in the first quintile, the mean dominant-hand grip strength for veterans in the fourth quintile and the mean nondominant-hand grip strength for veterans in the third and fourth quintiles were significantly increased. WAIS-R information score was significantly decreased for veterans in the third quintile, and WAIS-R similarities score was significantly increased (better) for veterans in the fourth quintile. Contrasts between the fifth and first quintiles were not significant for any of the subtests on the WAIS-R and HR. The Ranch Hand veterans had significantly lower mean scores in immediate and delayed recall of Logical Memory (WMS) than the comparison veterans. Also, veterans in the fifth quintile had significantly lower Logical Memory scores than veterans in the first quintile. Enlisted Ranch Hand personnel who reported greater skin exposure than enlisted comparison veterans had significant decrements in immediate and delayed recall WMS Logical Memory and HR Tactual Memory. Associate Learning (VMS), another test of verbal memory, had no meaningful change in any Ranch Hand TCDD category.

VAO reviewed a 10-year follow-up study of 55 men in Czechoslovakia with TCDD exposure during the production of 2,4,5-T (Pazderova-Vejlupkova et al., 1981). Initially, 7% of the workers had features of encephalopathy, and 75% had neurasthenia. Over time, the number of workers with neurasthenia decreased. VAO concluded that there were methodologic problems, including use of self-reported symptoms, lack of an objective measure of exposure, and selection bias. In a 30-year follow-up (Pelclova et al., 2001), 13 of the workers were re-examined. They had a mean plasma TCDD concentration of 256 ± 139 pg/g of lipid-

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

(range = 14–760 pg/g of lipid) that was extrapolated to an estimated concentration of 5,000 pg/g of plasma fat at the time of initial exposure. All subjects had chloracne on the earlier examinations; two workers with TCDD of 760 and 420 pg/g of fat still had the condition. TCDD was correlated significantly with the memory quotient from WMS, the verbal IQ from WAIS-R, and the Benton test of visual memory. Age-corrected norms were used to determine abnormal performance. Surprisingly, education did not affect the results, but no demographic data on education were presented. Ten of 13 subjects drank alcohol every day, but this was not taken into account in the analyses. The low-voltage electroencephalogram with increased beta activity (seven subjects) could be related to the daily alcohol consumption. It is not possible to determine the relationship between TCDD and cognitive functioning without attention to confounding. The age-corrected norms used for test interpretation were not generated in a population similar to those workers. In the 1970s, five of the 13 subjects had abnormal tibial nerve studies compared to one in 1996. Because no data are presented, the underlying pathologic condition cannot be evaluated. As a general rule, toxic neuropathies are expected to improve once exposure has ceased or diminished, but because of selection bias of subjects the association of neuropathy with TCDD exposure cannot be determined.

Gauthier et al. (2001) found that long-term exposure to herbicides and insecticides was not significantly related to the development of Alzheimer's disease (AD). Sixty-seven cases diagnosed with NINCDS-ADRDA criteria of probable and possible AD were matched for age and sex with nondemented controls. Exposure data on each municipality were examined to establish the area sprayed with herbicides and insecticides in 1971, 1976, 1981, 1986, and 1991. The results were combined with the subjects' residential histories to establish potential environmental pesticide exposure. Logistic regression with adjustment for confounders found that long-term exposure to herbicides and insecticides did not have a significant effect on the development of AD. Occupational exposure to neurotoxic substances, including pesticides, was also not significantly related to AD.

Synthesis

Cognitive functioning in the Ranch Hand veterans evaluated with about 33 measures from HR, WAIS-R, WMS, and WRAT found eight significant group differences that did not support a dose-effect relationship with TCDD, that is, worse performance was seen in the background or low-TCDD groups. Ranch Hand veterans with the highest TCDD exposure had significantly lower scores on Logical Memory (WMS). That finding could be attributed to chance alone and was not in agreement with other administered tests of verbal memory—Associate Learning (WMS) and Information and Vocabulary (WAIS-R). Each test of verbal memory measures memory in a different way. When performance on one test of verbal memory is mildly depressed and performance on other tests of verbal

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

memory is normal, the conclusion that verbal memory is reduced is not warranted.

Military occupation served as the surrogate for education and training. A better indicator than occupation or formal years of education is the WRAT-R Reading Test, it is a measure of educational achievement and educational experience that is believed to assess premorbid intelligence. Reading tests are considered to be “hold” tests—in other words, resistant to change—when cognitive functioning declines, whether because of neurotoxic exposure or age. WRAT-R was administered in this study but was not used as a measure of educational achievement; it would have been a more robust covariate for education than military occupation and might have accounted for the significant findings with Logical Memory. As noted by Barrett et al. (2001), “differences [on Logical Memory] were relatively small and of uncertain clinical significance.”

As discussed in VAO, inconsistencies in the methods used to establish psychologic diagnoses in the 1987 AFHS (1991) examination brought the diagnoses into question; and an association between TCDD exposure and numerous dissimilar neuropsychiatric diagnoses is improbable (IOM, 2001). Therefore, the use of that information as covariates does not appear justified. It is also unclear how marital status and combat exposure 20 years after cessation are related to neuropsychologic test performance.

Overall, the weaknesses in the study design, analyses, and interpretation of the results in the examination of serum TCDD and cognitive functioning in the Ranch Hand veterans prevent establishment of an association between exposure and neuropsychologic performance.

Conclusion

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is still inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and cognitive or neuropsychiatric disorders.

MOTOR OR COORDINATION DYSFUNCTION

This section summarizes the data from previous Veterans and Agent Orange reports and updates the scientific literature on Parkinson's disease and on amyotrophic lateral sclerosis.

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
Parkinson's Disease and Parkinsonism
Summary of VAO, Update 1996, Update 1998, and Update 2000

Because of the increasing concern about a possible link between Parkinson 's disease (PD) and various chemicals used as herbicides and pesticides, VAO, Update 1996, Update 1998, and Update 2000 suggested that attention be paid to the frequency and character of new cases in exposed versus nonexposed persons as Vietnam veterans age and are in the decades when PD is more prevalent.

Table 8-1 summarizes studies (reviewed in Update 1996, Update 1998, Update 2000, and this report) from numerous countries that examine the association between PD and pesticide (herbicide and insecticide) exposure. In those studies, cases of PD were identified with strict guidelines, either neurologic examination or review of medical data that required the presence of signs of PD (resting tremor, bradykinesia, cogwheel rigidity, and postural reflex impairment). Routine clinical diagnosis of PD has an accuracy of 75% by neuropathologic criteria that can be improved to 80–90% when stricter diagnostic criteria are applied (Langston, 1998). Clinical features were not verified in the large population studies that relied on death certificates or hospital admission diagnoses (Chaturvedi et al., 1995; Ritz and Yu, 2000; Schulte et al., 1996; Tuschen and Jensen, 2000). Exclusion criteria included the presence of atypical features— such as cerebellar involvement, gaze impairment, or pronounced autonomic dysfunction—or on all other causes of secondary parkinsonism, such as drugs, infections, or toxins. In the studies reviewed, for subjects to be included in the study pesticide exposure was usually required to occur before disease onset, but knowledge of when it occurred in relation to disease onset was not presented.

In Update 1998, emphasis on the detection of early-onset parkinsonism was considered vital to test the hypothesis that the disease is related to a toxic exposure because aging is currently the only known definitive risk factor for PD. PD becomes clinically apparent when about 60–70% of the neurons in the substantia nigra have deteriorated. One possible reason for the early onset of PD is that neuronal loss is accelerated in people with pesticide exposure and causes expression of the disease at an earlier age than is usual in the general population (see Weiss, 2000 for review).

In Update 2000, of the 30 epidemiologic studies of pesticide exposure and PD summarized in Table 8-1, only eight provided an estimate of relative risk posed by herbicides; of these studies, five had a positive significant association (Butterfield et al., 1993; Gorrell et al., 1998; Liou et al., 1997; Seidler et al., 1996; Semchuk et al., 1992), one had no association (Taylor et al., 1999), and the remaining two had a negative association (Kuopio et al., 1999; Stern et al., 1991). When a specific herbicide, paraquat, was examined in Taiwan (Liou et al., 1997), the OR was 3.2 (2.4– 4.3).

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 8-1 Epidemiologic Studies of Pesticide Exposure and Parkinson's Diseasea

Reference and Country

Study Group

Comparison Group

Exposure Assessment

Significant Association with Pesticides

OR (95% CI)

Neurologic Dysfunction Diagnosis

Butterfield et al., 1993; USb,c

63 young onset, (age < 50 years)

68

Questionnaire—pesticide or insecticide use 10 times in any year

+

Insecticides 5.8

Herbicides 3.2 (2.5–4.1)

Past dwelling fumigated 5.3

Standard criteria of PD by history

Chan et al., 1998; Hong Kongc

215

313

Interview—exposure to pesticides during farming (years)

+

Pesticides in women 6.8 (1.9–24.7)

Pesticides in men 0.7 (0.3–1.8)

Neurologic examination

Chaturvedi et al., 1995; Canadac

87 (age > 64 years)

2,070

Survey—exposure positive if frequently used

 

Pesticides 1.8 (0.9–3.4)

History of PD

Engel et al., 2001; US

238

72

Self-administered questionnaire for occupational exposure

+

Pesticides 0.8 (0.5–1.2)

Herbicide 0.9 (0.6–1.3)

Highest tertile pesticide 2.0 (1.0–4.2)

Neurologic examination by trained nurse

Fall et al., 1999; Swedenc

113

263

Questionnaire—any job handling pesticides

 

Pesticides 2.8 (0.9–8.7)

Neurologic examination

Golbe et al., 1990; USb,c

106

106

Telephone survey— sprayed pesticides or insect spray once a year for a total of 5 years

+

Sprayed pesticide 7.0 (5.8–8.5)

Neurologic examination

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Gorrell et al., 1998; USc

144 (age > 50 years)

464

Interview— herbicide and insecticide use while working on a farm or gardening

+

Occupational herbicides 4.1 (1.4–12.2)

Occupational insecticides 3.6 (1.8–7.2)

Standard criteria of PD by history

Hertzman et al., 1990; Canada

57

122

Questionnaire—ever worked in an orchard

+

Working in orchards 3.7 (1.3–10.3)

Neurologic examination

Hertzman et al., 1994; Canadac

127

245

Interview—occupation with probable pesticide exposure

+

Pesticides in men 2.3 (l.1–4.9)

Neurologic examination

Ho et al., 1989; Hong Kongc

35 (age >60 years)

105

Interview—use of insecticides or herbicides (Y/N), farming, eating raw vegetables

+

Herbicides and pesticides 3.6 (1.0–12.9)

Neurologic examination

Hubble et al., 1993; USc

63

76

Questionnaire—pesticide or herbicide use 20 days per year for >5 years

+

Pesticide or herbicide 3.4 (1.3–7.3)

Neurologic examination

Hubble et al., 1998; US

43

PD with dementia

51

PD without dementia

Interviews—pesticide exposure >20 days in any year and presence of allele for poor drug metabolism

+

Pesticide exposure and genetic trait 3.17 (1.1–9.1)

Neurologic examination

Jimenez-Jimenez et al., 1992; Spainc

128

256

Interview—exposure: applied pesticides, or lived and ate vegetables where pesticides used

 

Pesticide 1.3 (0.9–2.1)

Standard criteria of PD by history

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference and Country

Study Group

Comparison Group

Exposure Assessment

Significant Association with Pesticides

OR (95% CI)

Neurologic Dysfunction Diagnosis

Koller et al., 1990; USc

150

150

Interview—acre-years= acres multiplied by years of herbicide or pesticide use

 

Herbicide or pesticide use 1.1 (0.9–1.3)

Neurologic examination

Kuopio et al., 1999; Finland

123 (onset of PD before 1984)

279

Interview—pesticides or herbicides regularly or occasionally used

 

Regular use herbicides of 0.7 (0.3-1.3)

Neurologic examination

Liou et al., 1997; Taiwanb,c

120

240

Interview—occupational exposures to herbicides or pesticides

+

Herbicides or pesticides, no paraquat 2.2 (0.9–5.6)

Paraquat use 3.2 (2.4–4.3)

Neurologic examination

McCann et al., 1998; Australiac

224

310

Questionnaire—daily or weekly exposure to industrial herbicides and pesticides >6 months

 

Herbicides or pesticides 1.2 (0.8–1.5)

Neurologic examination

Menegon et al., 1998; Australia

96

95

Interview—pesticide exposure more than once weekly for >6 months before onset of PD

+

Pesticide 2.3 (1.2–4.4)

Standard criteria of PD by history

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Morano et al., 1994; Spainc

74

148

Interview—direct and indirect—exposure to pesticides

 

Pesticide 1.73 (1.0–3.0)

Neurologic examination

Petrovitch et al., 2002; US

2,623

5,363

Total years plantation work and years of pesticide exposure

+

Plantation work >20 years 1.9 (1.0–3.5)

Medical records and neurologic examination

Ritz and Yu, 2000; US

7,516 (PD cause of death 1984–1994)

498,461 (ischemic heart disease cause of death 1984–1994)

Counties ranked by pesticide use from pesticide registry and agricultural census data

+

Prevalence OR:

Moderate pesticide 1.36 (1.3–1.5)

High insecticide 1.45 (1.3– 1.6)

ICD-9 332

Schulte et al., 1996; USb

43,425 PD cause of death in 27 states 1982– 1991

 

Occupational exposure

+

PMR excess in male pesticide appliers, horticultural farmers, farm workers, and graders and sorters of agricultural products

ICD-9 332

Seidler et al., 1996; Germanyb,c

380 (<66 years with PD after 1987)

755

Interview—dose-years = years of application weighted by use

+

Neighborhood controls for herbicide 1.7 (1.0–2.7)

Regional controls for herbicide 1.7 (1.0–2.6)

Neurologic examination

Semchuk et al., 1992; Canadab,c

130

260

Interview— occupational exposure for each job held >1 month

+

Pesticide 2.25 (1.3–4.0)

Herbicide 3.06 (1.3–7.0)

Insecticide 2.05 (1.0–4.1)

Neurologic examination

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference and Country

Study Group

Comparison Group

Exposure Assessment

Significant Association with Pesticides

OR (95% CI)

Neurologic Dysfunction Diagnosis

Stern et al., 1991; USc

69 (onset before age 40 years)

80 (onset after age 59 years)

149

Interview—insecticides and pesticides measured by self-report of home or garden use

 

Herbicide—young onset 0.9 (0.5–1.7)

Herbicide—old onset 1.3 (0.7–2.4)

Insecticide—old onset 0.8 (0.3–2.1)

Insecticide—young onset 0.6 (0.2–1.7)

Standard criteria of PDby history

Smargiassi et al., 1998; Italyc

86

86

Interview—occupational exposure for at least 10 consecutive years

 

Pesticides or herbicides 1.15 (0.6–2.4)

Standard criteria of PD by history

Tanner et al., 1989; China

100

200

Interview—exposure for at least 1 year before onset of PD

 

Fruit growing 1.00 (1.0–1.0)

Corn growing 0.54 (0.3–1.1)

Rice growing 1.29 (0.7–2.3)

Neurologic examination

Taylor et al., 1999; US

140

147

Interview—exposure recorded as total days for lifetime

 

Pesticide 1.02 (0.9–1.2)

Herbicide 1.06 (0.7–1.7)

Neurologic examination

Tuchsen and Jensen, 2000; Denmark

134

128,935 expected cases 101.5

Occupations in farming, horticulture, and landscape expected to have exposure to pesticides

+

Age-standardized hospitalization ratio for all men in agriculture and horticulture 134 (109–162)

First-time hospitalization for PD

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Wechsler et al., 1991; US

34 (age >39 years)

22

Questionnaire—duration of occupational and home pesticide use

 

Home pesticides used more frequently by cases

Standard criteria of PD by history

Wong et al., 1991; USc

38 (19 sibling pairs with PD)

38 age and sex matched and 19 sibling pairs with essential tremor

Interview—acre-years = number of years exposed multiplied by number of acres applied herbicides or pesticides

 

Herbicides or pesticides 1.0 (0.7–1.4)

Neurologic examination

aModified from Le Couteur et al. (1999). bPreviously quoted in Update 1996 or Update 1998. cStudies used in meta-analysis (Priyadarshi et al., 2000).

ABBREVIATIONS: PMR, proportionate mortality ratio.

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

As described in Update 2000, a meta-analysis of 19 of the studies (see Table 8-1) examined the association between PD and exposure to pesticides (Priyadarshi et al., 2000). All were case–control studies, so the parameter calculated to estimate relative risk is an OR. Of the 19 studies, 17 had a positive association between PD and exposure to pesticide and eight had an estimated OR that was significant. Of the remaining two studies, one showed a negative association (Stern et al., 1991) and the other no association (Wong et al., 1991) between PD and exposure to pesticides. Heterogeneity was significant among the studies (p < 0.001); the random-effect model used generated a combined estimate for the 19 studies of 1.9 (1.5–2.5). The combined estimates for those studies by geographic location were as follows: United States, 2.1 (1.1–4.1); Asia, 2.5 (1.6–4.1); Europe, 1.8 (1.4–2.2); and Canada, 1.9 (1.4–2.8). In six studies, no increased incidence of PD was found with increasing dose as measured by duration of exposure (Chan et al., 1998; Gorell et al., 1998; Morano et al., 1994; Seidler et al., 1996; Semchuk et al., 1992; Smargiassi et al., 1998). Only one (Gorrell et al., 1998) showed an increased risk of PD with longer exposure to pesticide (>10 years), with an OR of 5.8 (2.0–17.0).

Update of the Scientific Literature

In a recent study (Engel et al., 2001), 238 subjects exposed to pesticides in an occupational setting and 72 nonexposed controls were examined for the presence of parkinsonism by a trained nurse using the Unified Parkinson's Disease Rating Scale (UPDRS). The signs rated for parkinsonism were rest tremor, rigidity, bradykinesia, and impairment of postural reflexes. A self-administered questionnaire on use of pesticides included detailed information on the use of specific insecticides, herbicides, and fungicides. Information on the category of chlorophenoxy herbicides or specific compounds in this category was not included in the exposure assessment. Pesticide exposure occurred in the setting of orchardists, professional pesticide appliers, pesticide-formulation plant workers, and other farm or agricultural workers. Parkinsonism was more prevalent with more years of exposure but was similar between the nonexposed and the most-exposed group. Prevalence ratio (PR) (95% CI) for parkinsonism, adjusted for age and pack-years of smoking, for any exposure to pesticides was 0.8 (0.5–1.2) and for any exposure to herbicides was 0.9 (0.6–1.3). General exposure to pesticides analyzed by tertile of years of exposure found a significantly increased adjusted PR (95% CI) for the highest tertile (2.0, 1.0–4.2). With different cut scores for rigidity on the UPDRS, only the highest tertile of years of exposure to herbicides was significantly associated with parkinsonism; the adjusted PR was 2.5 (95% CI 1.0–6.0). The overall results are similar to those of many other studies reviewed in Update 2000 in which an association with many years of occupational exposure is associated with parkinsonism but no association is found with any individual pesticide or class of pesticides.

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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Petrovich et al. (2002) conducted a prospective cohort study with 30 years of follow-up on 7,986 Japanese-American men (Honolulu Heart Program) who worked on sugar cane or pineapple plantations in Hawaii to determine whether working on a plantation or exposure to pesticides is associated with an increased risk of PD. Before 1991, incident cases of PD were identified through hospital records, death certificates, and medical records from offices of local neurologists. The entire cohort was re-examined in 1991 and 1993, and those with PD or parkinsonism were referred to a neurologist who used the UPDRS. After 1993, cases were added through record review. Exposure analysis used total plantation work, plantation type, and exposure to pesticides. Years of pesticide exposure summed days of exposure per year across years worked. Covariates adjusted for in the analyses included age, pack-years of cigarette-smoking, and caffeine intake. During the 30-year follow-up, 116 incident cases of PD were identified. As duration of work increased, pesticide exposure increased significantly. Even though age-adjusted incidence of PD increased with increasing pesticide exposure, the trend was not significant (p = 0.101). Those with over 20 years of plantation work had twice the risk of PD (10.3/10,000 vs 5.8/10,000 person-years) of those with no plantation work. With 10 years of plantation work or less, there was no increase in risk of PD, but a significant trend (p = 0.006) of increased risk occurred with further years of exposure.

Although the results are intriguing, an association of PD with exposure to 2,4-D, 2,4,5-T, or TCDD is not reported in any of the studies.

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with adult onset that presents with muscle atrophy, weaknesses, and fasciculations. Most cases of ALS are sporadic; only 5–10% are familial in origin. The annual incidence of sporadic ALS is 1–2 per 100,000 person-years and the incidence of ALS peaks between the ages of 55 and 75 (Brooks, 1996). Of familial-ALS patients, 20% have mutations in the gene encoding superoxide dismutase 1 (Rosen et al., 1993); the remaining patients with familial ALS have mutations in other genes. A specific diagnostic test does not exist, but it is believed that clinical diagnosis has a high degree of accuracy (Rowland, 1998; Rowland and Shneider et al., 2001). For the sporadic cases of ALS, interest in the role of occupational or environmental exposure originated in cases of motor neuron disease associated with exposure to heavy metals (Roelofs-Iverson et al., 1984, McGuire et al., 1997), chemical plants (Deapen and Henderson, 1986; McGuire et al., 1997), animal carcasses (Hanisch et al., 1976), heavy manual labor (Breland and Currier, 1967), work with electricity (Deapen and Henderson, 1986; Savettieri et al., 1991), pneumatic tools (Gallagher and Sanders, 1987; Savettieri et al., 1991), work in the plastic industry (Deapen and Henderson, 1986), and work as a

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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truck driver (Kurtzke and Beebe, 1980). During the period 1970–1983 in Sweden all 1961 cases of ALS were examined for association with occupations. The male cases of ALS were associated with a variety of occupations, including some that were protective. One county had a cluster of 25 male cases in agricultural work, 3 times the incidence expected (OR 3.4, 95% CI 1.2–9.3); but no specific exposures were examined (Gunnarsson et al., 1991).

Table 8-2 summarizes epidemiologic studies that examine the association of pesticide exposure and ALS.

A case–control study of 518 ALS cases (65% male) and 518 matched controls from all over the United States examined roles of physical trauma, prior neurologic diseases, or infection (Deapen and Henderson, 1986). Part of the exposure history included long-term occupational exposure to a variety of metals, plastic manufacturing, pesticides, and animal hides. The association between pesticides and ALS was not statistically significant but was positive (OR 2.0, 95% CI 0.8–5.4).

A case–control study of ALS in Palermo, Italy, that included 46 patients (25 men and 21 women) and 92 matched controls examined numerous risk factors— trauma, exposure to domestic animals, agricultural chemicals, organic solvents, and electric shock (Savettieri et al., 1991). No statistically significant associations were found between ALS and those exposures, although there was a positive association between ALS and agricultural chemicals (OR 3.0, 95% CI 0.4– 20.3).

A case–control study in Scotland of 103 ALS cases (61 men) from a Scottish motor neuron disease register and 103 age- and sex-matched controls identified risk factors for development of the disease (Chancellor et al., 1993). Significant differences with increased exposure in cases were found for occupational exposure to lead (OR = 5.7, 95% CI 1.6–30) and “solvent/chemicals” (OR = 3.3, 95% CI 1.3–10). Occupational pesticide exposure was not significantly different but did have a positive association (OR = 1.4, 95% CI 0.6 –3.1).

The results of a mortality study of male employees of the Dow Chemical Company who worked in the manufacturing or formulation of 2,4-D in 1945– 1994 (Burns et al., 2001) are discussed in Chapter 6. In this cohort, death-certificate examination of the six employees in the ICDA-8 category “Diseases of the Nervous and Sensory Organs ” revealed three with ALS. Analyses of their deaths found a significantly increased RR of death due to ALS (RR 3.45, 95% CI 1.1– 11.1). All three died more than 20 years after their first exposure; duration of employment was 1.3, 1.8, and 12.5 years.

McGuire et al. (1997) conducted a population-based case–control study to examine the relationship between ALS and occupational exposures to metals, solvents, and agricultural chemicals. Cases (95 men and 79 women) were newly diagnosed in 1990–1994, and two controls for each case matched for sex and age were obtained from the same geographic area. Cumulative exposure index was

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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TABLE 8-2 Epidemiologic Studies of Pesticide Exposure and Amyotrophic Lateral Sclerosis

Reference; Country

Study Group

Comparison Group

Exposure Assessment

Significant Association Pesticides

OR with (95% CI)

Neurologic Dysfunction Diagnosis

Burns et al., 2001; US

1,567

40,600

Industrial hygienist ranked job exposure. Cumulative exposure, years, or each job times weighted exposure

+

3.45 (1.1–11.1)

Death certificates

Chancellor et al., 1993; Scotland

103

103

Required regular occupational exposure to pesticides for 12 months or more

 

1.4 (0.6–3.1)

Scottish Motor Neuron Register

Deapen and Henderson, 1986; US

518

518

Ever worked in presence of pesticides

 

2.0 (0.8–5.4)

ALS Society of America

McGuire et al., 1997; US

174

348

Self-reported lifetime job history and workplace exposure reviewed by panel of four industrial hygienists

+

2.4 (1.2–4.8); significant trend analysis for dose-effect relationship p = 0.03

Newly diagnosed with ALS 1990– 1994 in western Washington state

Savettieri et al., 1991; Italy

46

92

Continual exposure to agricultural chemicals

 

3.0 (0.4–20.3)

Cases reviewed by neurologists

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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created by lifetime job history and workplace exposure to specific chemical agents collected by self-report and by a panel of four industrial hygienists blinded to the disease status of the participants. Exposure 10 years before diagnosis was not included. Exposure to metals and solvents was not associated with ALS. Association between exposure to agricultural chemicals and ALS was observed in men (OR = 2.4, 95% CI 1.2–4.8); the OR for low exposure compared with no exposure was 1.5 (95% CI 0.4–5.3) and for high exposure 2.8 (95% CI 1.3–6.1) (p trend = 0.03). The same trend was found with less than 3 years of exposure to agricultural chemicals (OR 1.2, 95% CI 0.3–4.1) compared with exposure greater than 3 years (OR 2.7, 95% CI 1.3–5.5 ) (p for trend = 0.03). Exposure to specific agricultural chemicals, such as herbicides, did not pose a significantly increased risk of ALS (OR 3.0, CI 95% 0.9–9.6). Excess exposure to agricultural chemicals from accidents or spills was associated with ALS (OR = 4.4, 95% CI 1.1–17.7), but this accounted for six cases and only three controls.

Synthesis

Epidemiologic studies continue to support an increased risk of PD with pesticide exposure, but specific pesticides or specific classes are lacking. As studies in the future collect exposure data that more closely reflect the dose at the critical receptor level and as underlying genetic susceptibilities to PD are identified, the relationship of PD and herbicide exposure may be clarified.

Continuing support for the biologic plausibility of PD and pesticide exposure is found in new studies of the rotenone model of PD that used in vivo and in vitro approaches to demonstrate how this pesticide produces a systemic defect in mitochondrial complex I, resulting in nigrostriatal dopaminergic degeneration that is expressed as hypokinesia and rigidity, features of parkinsonism (Greenamyre, 2001). Cytoplasmic inclusions that resemble Lewy bodies (abnormal protein collections) contained ubiquitin and α-synuclein. With chronic exposure to rotenone, oxidative damage to proteins and DNA was measured. Mitochondrial depolarization was observed with release of cytochrome c and activation of caspase-3. The rotenone model of PD reproduces many of the pathologic features of PD related to oxidative mechanisms.

Another in vitro study examined brain cell cultures (neurons and glia) from the rat mesencephalon after 2 days of 20 nM and 8 days of 1 nM rotenone and found significant neurodegeneration (Gao et al., 2002). The changes not present in the neuron-enriched cultures were attributed to rotenone's ability to stimulate release of superoxide from microglia. The neurotoxicity of rotenone was significantly diminished by blocking the release of superoxide from microglia. This study helps to explain the mechanism by which pesticides are associated with PD.

According to the results of epidemiologic studies, the association between pesticide exposure and PD is much stronger than the association between pesticide exposure and ALS. Known risk factors for ALS are age and a family history

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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of ALS. The careful attention to exposure assessment in the study by McGuire et al. (1997) makes the association between agricultural chemicals and ALS intriguing, but there are few exposed subjects, and further studies are needed.

Conclusions

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there remains inadequate or insufficient evidence of an association between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and motor or coordination dysfunction or Parkinson's disease. In the future, as diagnostic accuracy for PD improves, herbicide exposure assessment is quantified with specific biomarkers, and further research confirms the gene–toxicant interaction in larger prospective studies of PD, the evidence of an association may change; this underscores the importance of a prospective study of Vietnam veterans for the development of PD.

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is inadequate or insufficient evidence of an association between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and motor neuron disease or amyotrophic lateral sclerosis. More epidemiologic studies in the future might clarify the realtionship between exposure to herbicides and ALS. As with PD, prospective studies of Vietnam veterans for the development of ALS should be conducted.

CHRONIC PERSISTENT PERIPHERAL NEUROPATHY

Summary of VAO, Update 1996, Update 1998, and Update 2000

On the basis of data available at the time, it was concluded in VAO, Update 1996, Update 1998, and Update 2000 that there was inadequate or insufficient evidence of an association between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and chronic persistent peripheral neuropathy. Data from the Air Force Health Studies constituted a large part of the basis of the conclusions. In 1982, a baseline study of 1,208 Air Force Ranch Hands and a comparison group of 1,238 Air Force personnel found no differences between the groups in measures of peripheral nerve function, including neurologic symptom evaluation, physical examination, and nerve-conduction velocity tests (AFHS, 1984). A follow-up study conducted in 1985 used the same protocol except that nerve-conduction velocity was not assessed; once again, no differences were seen between groups (AFHS, 1987). In a 1987 follow-up, Ranch Hands had significantly more hereditary and degenerative diseases, such as benign essential tremor (not found to be associated with TCDD), but their

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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peripheral nerve status was not remarkable (AFHS, 1991). In 1992, the neurologic assessment was comparable between the two groups, and there was no consistent evidence of a dose–response relationship for either estimated initial TCDD or current TCDD. In 1997 (AFHS, 2000), the peripheral nerve examination was based on physical examinations and verified vibrotactile measurement. The percentage of participants with a confirmed polyneuropathy index was consistently higher in Ranch Hands than in the comparison group. After adjustment for the covariates, the results of TCDD exposure were marginally significant for the enlisted ground crew. The development of neuropathy 30 years after exposure is highly unusual and not compatible with TCDD exposure. It was concluded that evidence of an association between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and chronic persistent peripheral neuropathy was still inadequate or insufficient.

Update of the Scientific Literature

A publication relating serum TCDD and peripheral neuropathy from the 1982, 1985, 1987, 1992, and 1997 examinations of the Ranch Hand study (Michalek et al., 2001) found significantly increased risk of peripheral neuropathy among Ranch Hand veterans in the high-exposure category in 1997. Exposure categories and numbers of veterans in the “comparison,” “background,” “low,” and “high” categories are described in Chapter 5. As part of the protocol, veterans received the diagnosis of “diabetic” if diagnosed by a physician as noted in the medical record or if a 2-hour postprandial glucose-tolerance test result was over 200 mg/dL. A neurologic examination recorded tremor, cranial nerve function, sensation, motor strength and coordination, and reflexes. In 1982, nerve-conduction studies of ulnar, peroneal, and sural nerves were performed. In 1992 and 1997, vibrotactile thresholds of the great toe were measured. The diagnosis of possible peripheral neuropathy required one of three physical signs: absent ankle jerk, abnormal vibration at the ankle, or abnormal pinprick in the foot bilaterally. For probable peripheral neuropathy, at least two of the three abnormalities had to be present. For a diagnosis of peripheral neuropathy, a diagnosis of probable peripheral neuropathy and bilateral abnormal vibrotactile measures were required.

Nerve-conduction studies (1982) and vibrotactile abnormalities (1992 and 1997) did not support any peripheral nerve differences between low and high exposure to TCDD. In the high-TCDD category in 1997, the odds of possible peripheral neuropathy (OR = 1.8, 95% CI 1.2 –2.7) or probable peripheral neuropathy (OR = 5.0, 95% CI 2.2–11.2) were significantly increased with a significant trend with increasing exposure (p < 0.001). To determine whether the OR was different in veterans with and without diabetes, the groups were analyzed separately. In nondiabetic veterans, the odds of probable peripheral neuropathy were significantly increased (OR = 8.7, 95% CI 1.9–39.3); and in diabetic veter-

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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ans, the odds were also significantly increased (OR = 3.5, 95% CI 1.3–9.4). In the 1992 examination, six veterans in the high-TCDD category had diagnosed neuropathy (OR = 4.9, 95% CI 1.5–15.3). In 1997, three of the six veterans had diagnosed neuropathy, one had normal measurements, one had missing data, and one did not attend. The number of nondiabetic veterans with diagnosed neuropathy in 1997 was too small for analysis, but the risk of diagnosed peripheral neuropathy in diabetic veterans in the high-TCDD category was significantly increased (OR = 5.8, 95% CI 1.6–20.3). When a secondary analysis was attempted and veterans were excluded if they had disease, disorders, exposures, or medications known to produce symptoms suggestive of neuropathy or had neurologic diseases unrelated to TCDD, the numbers were too small for analysis. In 1997, nine of the 14 veterans with probable peripheral neuropathy in the high-TCDD category had diabetes, and four veterans had preclinical diabetes. In the low-TCDD category, eight veterans had probable neuropathy, and seven were diabetic. Of the eight veterans with diagnosed peripheral neuropathy in the high-TCDD category, seven had diabetes, and one had preclinical diabetes. Of the five veterans with diagnosed peripheral neuropathy in the low-TCDD category, four had diabetes. That suggests a major problem in the interpretation of TCDD effects on the peripheral nerves in light of the presence of diabetes and preclinical diabetes, a major risk factor for peripheral neuropathy. That these cases of probable and possible peripheral neuropathy were identified for the first time in 1992 and 1997, when prior examinations were normal, weakens the ability to implicate TCDD exposure as the etiologic agent given that the peripheral nerve is known to repair itself after cessation of exposure or after diminution of the body burden of the responsible toxicant.

Synthesis

One of the classic features of a toxic neuropathy is improvement in peripheral nerve function after removal from exposure. The degree of recovery depends on the severity of the initial injury. A toxic neuropathy can begin days to weeks after high exposure or not until months or a few years after low exposure. Ranch Hand veterans exposed to Agent Orange 26–36 years previously showed no evidence of peripheral neuropathy associated with TCDD exposure at the time of the first examination in 1982. The finding of no association persisted in repeat examinations in 1985 and 1987. Only in 1992 and 1997, 10–15 years after the initial examination and 36–51 years after TCDD exposure, were odds ratios for the diagnosed neuropathy in the high-TCDD category significant. It is not plausible that peripheral nerve function was affected by TCDD in 1992 and 1997 if during the previous examinations when serum TCDD concentrations were higher no association with TCDD was found.

The case definitions of probable and diagnosed neuropathy are confusing when results are closely examined. A toxic neuropathy usually begins distally (in

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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the toes) and moves proximally (to the ankle). That is the basis of the term dying-back neuropathy. In 1997, some veterans with probable neuropathy had abnormal vibration at the ankle while vibrotactile measurements at the big toe were intact, the reverse of what the dying-back process would predict. Abnormal vibration at the ankle is found only after the neuropathy that began in the toes has progressed to the ankle. Therefore, vibrotactile score at the big toe should have been abnormal in the nine veterans with a probable neuropathy if vibration at the ankle was truly abnormal. The difficulty with agreement between different measures of peripheral nerve function may be an issue of sensitivity and specificity. Peripheral neuropathy was associated with TCDD exposure only after vibrotactile measures were added to the protocol in 1992, but odds of an abnormal vibrotactile score were not increased in the high-TCDD group. The small number of cases is also a problem, especially when some cases have normal results in examination at follow-up or for various reasons are not re-examined.

A greater problem was the confounding created by the high prevalence of diabetes or preclinical diabetes in veterans with probable or diagnosed neuropathy in the high-TCDD category. Diabetic neuropathy is the most common cause of peripheral neuropathy, occurring in about 50% of people with type 2 non-insulin-dependent diabetes over time but present in less than 10% when the diagnosis of diabetes is first made (Pirart, 1978). A study of outpatients with type 2 diabetes (mean age, 70.6 years; mean duration, 11.7 years) found polyneuropathy in 49% of them according to the criteria of lower-limb sensory and motor nerve-conduction velocity or latency more than 2 standard deviations above or below the age-matched controls (de Wytt et al., 1999). When a case definition of neuropathy in a diabetic population included symptoms, signs, electrodiagnostic studies, quantitative sensory testing, and autonomic testing, the prevalence increased to 66% (Dyck et al., 1993). In contrast, prevalence of a diabetic neuropathy was 28.5% in a large multicenter United Kingdom study (Young et al., 1993). Differences in case definitions of diabetic neuropathy probably account for the large range in its prevalence. As duration of diabetes progresses, the prevalence of peripheral neuropathy increases (Simmons and Feldman, 2002). In mild diabetic neuropathy, a median mononeuropathy was found in 23% of patients at a time when the lower extremities did not differ significantly from controls in electrodiagnostic studies (Albers et al., 1996)

The common neuropathy associated with type 2 diabetes is a distal symmetric sensorimotor polyneuropathy that affects primarily the sensory nerves. Type 2 diabetes can also affect other parts of the peripheral nervous system and produce autonomic neuropathy, polyradiculopathy, cranial mononeuropathies, limb mononeuropathy, and mononeuropathy multiplex.

Intensive glycemic control (careful attention to blood sugar concentration) appears to slow the progression of diabetic polyneuropathy. Persistent glycemia indirectly leads to increased release of free radicals and oxidative damage to the

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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nervous system. Those oxidative stressors are believed to lead to mitochondrial dysfunction and programmed cell death. That theory is supported by the finding that administration of antioxidants prevents the neuropathy (Feldman et al., 1999). Vascular factors in diabetes also account for damage to peripheral nerve fibers because of ischemic changes in the endoneurial capillaries (Simmons and Feldman, 2002).

A diabetic neuropathy may be difficult to differentiate clinically from neuropathy secondary to toxic exposure except by the presence of other features in the clinical history and presentation, such as gastrointestinal symptoms after lead or arsenic exposure or alopecia after thallium exposure. In addition, if caused by a toxic exposure, the neuropathy should improve after cessation of exposure, but diabetic neuropathy will usually progress unless a dramatic change is made in glycemic control. Complaints of peripheral nerve disorders, however, often occur in isolation and are monotonously similar. In the clinical setting, about 30% of cases of peripheral neuropathy are left with no etiology after a complete evaluation (McLeod, 1995). Examination of family members for evidence of mild or subclinical neuropathy can provide a hereditary etiology for a subset of this group (Dyck et al., 1981). Also, the PNS undergoes constant age-related changes that may increase its susceptibility to other metabolic and toxic exposures.

Conclusion

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that the evidence of an association between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and chronic persistent peripheral neuropathy remains inadequate or insufficient. It should be noted, however, that the committee categorizes diabetes as having limited or suggestive evidence of an association.

ACUTE AND SUBACUTE TRANSIENT PERIPHERAL NEUROPATHY

Update of the Scientific Literature

The committee is aware of no new publications that investigate the association between exposure to the compounds of interest and acute and subacute transient peripheral neuropathy. If TCDD were associated with the development of transient acute and subacute peripheral neuropathy, the disorder would become evident shortly after exposure. The committee knows of no evidence that new cases of acute or subacute transient peripheral neuropathy that develop long after service in Vietnam are associated with herbicide exposure.

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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SUMMARY

Strength of Evidence from Epidemiologic Studies

As in the earlier reports, on the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and disorders involving cognitive and neuropsychiatric dysfunction, motor or coordination deficits, or chronic persistent peripheral neuropathy. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components, as reviewed in previous reports.

In Update 1996, the committee found that there was limited or suggestive evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and acute or subacute transient peripheral neuropathy. The evidence regarding association was drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Information available to the committees responsible for Update 1998, Update 2000, and this report continues to support the conclusion.

Biologic Plausibility

This section summarizes the biologic plausibility of a connection between exposure to TCDD or herbicides and various neurobehavioral disorders on the basis of data from animal and cellular studies. Chapter 3 presents the details of the committee's evaluation of recent data from animal and cellular studies. Some of the preceding discussions of neurobehavioral outcomes include references to papers relevant to specific neurobehavioral effects.

Some information exists on the development of neurobehavioral disorders and TCDD exposure in laboratory animals. In vivo experiments have demonstrated that TCDD can affect biochemical processes, including having effects on calcium uptake and neurotransmission. Acute doses of TCDD administered to rats affect the metabolism of serotonin, a brain neurotransmitter that is able to modulate food intake. The biochemical change is consistent with observations of progressive weight loss and anorexia in experimental animals exposed to TCDD. A study in adult male Wistar rats suggests that a single low-dose intraperitoneal injection of TCDD could cause a toxic polyneuropathy (Grahmann et al., 1993; Grehl et al., 1993); no other studies in animals have reported such an effect. TCDD treatment has also been demonstrated to affect learning and memory in rats.

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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The mechanism by which TCDD could exert neurotoxic effects is not established. TCDD has a wide array of effects on growth regulation, hormone systems, and other factors associated with the regulation of activities in normal cells; these effects could in turn influence nerve cells. Furthermore, animal studies and in vitro mechanistic studies continue to emphasize the importance of alterations in neurotransmitter systems as underlying mechanisms of TCDD-induced behavioral dysfunction.

Most studies are consistent with the hypothesis that the effects of TCDD are mediated by the aryl hydrocarbon receptor (AhR), a protein in animal and human cells to which TCDD can bind. The TCDD–AhR complex is known to bind DNA and to lead to changes in transcription (that is, genes are differentially regulated). Modulation of genes could cause altered cell function.

Although structural differences in the AhR have been identified among different species, it operates in a similar manner in animals and humans. Therefore, a common mechanism is likely to underlie the neurotoxic effects of TCDD in humans and animals, and data in animals can support a biologic basis of TCDD's neurotoxicity. Because of the many species and strain differences in TCDD responses, however, controversy remains regarding the magnitude of TCDD exposure that is neurotoxic.

Little information is available on neurotoxic effects of exposure to the herbicides discussed in this report. At the cellular level, 2,4-D inhibited neurite extension. That effect was accompanied by a decrease in intracellular microtubules, inhibition of the polymerization of tubulin, disorganization of the Golgi apparatus, and inhibition of ganglioside synthesis. Studies in rats indicate an impairment of motor function, CNS depression, and inhibition of myelination in the brain. Behavioral alterations have also been seen after treatment of rats with 2,4-D. Results of in vitro mechanistic studies suggest that 2,4,5-T may acutely affect neuronal and muscular function by altering cellular metabolism and cholinergic transmission.

There is evidence that other chemicals can induce a Parkinson-like syndrome in humans, possibly by generating free radicals in the target tissue. Such results might be biologically relevant in that it is suspected that TCDD and some of the herbicides used in Vietnam could indirectly generate free radicals or sensitize cells to free-radical injury; the exact relevance, however, has not been established.

The foregoing evidence suggests that a connection between TCDD exposure and human neurotoxic effects is, in general, biologically plausible. However, definitive conclusions about the presence or absence of a mechanism of induction of neurotoxicity by TCDD in humans are complicated by differences in sensitivity and susceptibility among individual animals, strains, and species; the lack of strong evidence of organ-specific effects across species; and differences in route, dose, duration, and timing of exposure. Experiments with 2,4-D and 2,4,5-T indicate that they can have effects on brain cells at the subcellular level that could

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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provide a biologically plausible mechanism of neurotoxicity if such toxicity is seen in animals or humans, but alone they do not provide a basis for concluding that they are neurotoxic. The observation of behavioral alterations in rats after exposure to 2,4-D also would support the neurotoxicity of this compound, but the species, strain, and dose specificities of the effects remain unknown.

Considerable uncertainty remains about how to apply this information to the evaluation of potential health effects of herbicides or TCDD exposure in Vietnam veterans. Scientists disagree over the extent to which information derived from animals and cellular studies predicts human health outcomes and the extent to which the health effects resulting from high-dose exposure are comparable with those resulting from low-dose exposure. Investigating the biologic mechanisms underlying TCDD's toxic effects continues to be the subject of active research, and future updates of this report might have more and better information on which to base conclusions, at least for this compound.

Increased Risk of Disease Among Vietnam Veterans

The most recent Air Force Health Study publications (Michalek et al., 2001; Barrett et al., 2001) reported differences in prevalence of chronic peripheral neuropathy and verbal memory performance between the Ranch Hand and comparison groups, but the clinical relevance is not clear. The available data do not support the notion that the differences are associated with exposure to herbicides or TCDD.

REFERENCES

AFHS (Air Force Health Study). 1984. An Epidemiologic 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 Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. First Followup Examination Results Brooks AFB, TX: USAF School of Aerospace Medicine. USAFSAM-TR-87-27.

AFHS. 1991. An Epidemiologic 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 Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1992 Followup Examination Results Brooks AFB, TX: Epidemiologic Research Division. Armstrong Laboratory.

AFHS. 2000. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1997 Follow-up examination and results. Reston, VA: Science Application International Corporation. F41624–96–C1012.

Albers JW, Brown MB, Sima AAF, Greene DA. 1996. Frequency of median mononeuropathy in patients with mild diabetic neuropathy in the early diabetes intervention trial (EDIT). Muscle and Nerve 19:140–146.

Barrett DH, Morris RD, Akhtar FZ, Michalek JE. 2001. Serum dioxin and cognitive functioning among veterans of operation ranch hand. Neurotoxicology 22:491–502.

Suggested Citation:"8. Neurobehavioral Disorders." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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This book updates and evaluates the available scientific evidence regarding statistical associations between diseases and exposure to dioxin and other chemical compounds in herbicides used in Vietnam, focusing on new scientific studies and literature.

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