National Academies Press: OpenBook
« Previous: 9 Reproductive Effects
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

10
Neurobehavioral Disorders

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

Neurologic dysfunction can be further classified as either global or focal. For example, in neurobehavioral disorders, global dysfunction can involve altered levels of consciousness or agitated behavior, whereas focal changes give rise to isolated signs of cortical dysfunction such as aphasia or apraxia. Likewise, global neuropathies could affect all peripheral nerves of the body, whereas a focal lesion would damage only a single nerve.

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

The usual evaluation of neurologic function involves the clinical neurologic examination in conjunction with several testing procedures. The neurologic examination is a five-part battery of tests performed by a physician that systematically evaluates cerebral (mental status), cranial nerve, motor, sensory, and cerebellar/gait functions. Special ancillary tests that can be performed by additional professionals (physicians, neuropsychologists, or technicians) may include detailed neuropsychological evaluations with standardized and validated test protocols, electromyography (EMG) and nerve conduction studies for PNS function, neuroimaging for identifying CNS anatomic lesions, and neurophysiology tests such as electroencephalography (EEG) for the assessment of epilepsy and metabolic disorders.

The neuropsychologic battery of tests chosen depends on the age of the patient and the type of behavioral alterations being evaluated. Although there are literally hundreds of standardized tests available for neuropsychological assessment, a few of the most commonly used are the Wechsler Adult Intelligence Scales (WAIS) and its revised version (WAIS-R), the Minnesota Multiphasic Personality Inventory (MMPI), and the Self-Report Symptom Inventory (known as SCL-90). The WAIS and WAIS-R assess general intelligence as well as verbal and nonverbal cognitive abilities using 11 different subtests. The MMPI, a standardized 566-item questionnaire, provides objective assessment of personality characteristics and psychopathology (Green, 1980). The MMPI consists of three validity scales and ten clinical scales; test norms are based on scores of a sample of Minnesota men who took the test before World War II. The SCL-90 is a 90-question, self-administered checklist that examines various personality characteristics, psychiatric disorders, health-related concerns, anxiety, and depression.

Although the neurologic examination and the specialty tests described above are widely available, they are not all uniformly standardized and their results can be affected by a number of factors. They are often able to detect neurologic dysfunction but cannot always distinguish it from the effects of abnormal emotional states or diseases outside the nervous system that can alter a patient's function. For example, body temperature can modify EMG data, examiner style and native intelligence can affect patient performance on neuropsychologic tests, and fatigue or medications can profoundly affect EEG patterns. For these reasons, rigorous methodology and maximally matched control or comparison populations are especially important for the scientific study of the causes of neurologic and behavioral alterations.

Case identification in neurology is also often difficult. Despite the advances in neuroimaging, many types of neurologic alternations are biochemical and show no abnormalities on scanning tests. The nervous system is not usually accessible for biopsy, so pathologic confirmation is not feasible

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

for many neurologic disorders. Behavioral and neurophysiologic changes can be partly or largely subjective and, even when objectively documented, may often be reversible. Timing is important in assessing the effect of chemical exposures on neurologic function. Some symptoms of neurologic importance will appear acutely but be short-lived, whereas others will appear slowly and be detectable for extended periods. These caveats must be considered in the design and critique of epidemiologic studies evaluating an association between exposure to any 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 reversible to severe and long-standing. These assessments have been conducted in three general settings, related to occupational, environmental, and Vietnam veteran exposures (see Table 10-1). Several case reports of patients ingesting 2,4-dichlorophenoxyacetic acid (2,4-D) are mentioned under environmental exposures. This chapter reviews reports of neurologic alterations associated with exposure to herbicides, TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), or other compounds used in herbicides in Vietnam and focuses on chronic effects of neurotoxicity. It emphasizes the small number of cross-sectional studies with comparison samples in which both exposed and unexposed were neurologically assessed by systematic physical examinations and/or ancillary tests such as neuropsychological evaluations or EMG measurements.

In approaching this study of the health effects of herbicide exposure, the committee discussed meta-analysis for certain health outcomes with consideration of sample size, measurement of exposure as well as outcome, selection of controls, period of observation, and other methodologic factors. For neurobehavioral disorders, however, a sufficient number of studies of neurological disorders with similar exposure classifications and disease outcome diagnostic groups were not available for this type of analysis.

The potential neurotoxicity of TCDD and herbicides in animal studies has not been thoroughly investigated. A large number of acute and subchronic toxicity studies have been conducted with TCDD but the majority of these studies was not designed specifically to investigate neurotoxicity. Available data imply that CNS alterations or changes in the responsiveness of neurochemical processes in the CNS may be associated with lethal or near lethal dose levels of TCDD in some animal species, however, the changes observed may also be regulatory responses occurring secondary to changes induced in other organ systems (see Chapter 4). TCDD concentrations in the brain after systemic exposure are low, and quite similar among rodent species. Relatively little work has been done to quantify the concentration of Ah receptors in the central or peripheral nervous systems.

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

TABLE 10-1 Neurobehavioral Studies of Herbicide Exposure

Reference

Study Group, N

Tests of Neurological Dysfunction

Exposure Measures

Comparison Group, N

Occupational

Alavanja et al., 1989

1,411 forest/soil conservationists

No: mortality data only

No

None

Alderfer et al., 1992

281 TCP or 2,4,5-T production workers

Psychological evaluation, Becks, SCL-90-R

Serum TCDD

260 community matched referents

Bashirov, 1969

292 2,4-D production workers

No: interviews

No

None

Bond et al., 1987

322 Dow chemical workers (with chloracne)

No: mortality data only

Chloracne

2,026 workers without chloracne

Bond et al., 1989

2,072 Dow chemical workers (with chloracne)

No: mortality data only

Job classification

Internal comparison

Coggon et al., 1986

5,754 MCPA production and spraying workers

No: mortality data only

Occupational records

British national population

Green, 1991

1,222 forestry workers

No; mortality data only

Job classification

Ontario male population

Klawans, 1987

45 railroad workers

Neuropsychological evaluation

No

None

Moses et al., 1984

117 2,4,5-T production workers

Neurologic examination,

Self-reports, chloracne

109 workers without chloracne

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Group, N

Tests of Neurological Dysfunction

Exposure Measures

Comparison Group, N

Manz et al., 1991

1,184 production workers

No: mortality data only

Job classification

a) 3,120 workers at gas supply company

b) German population

Pazderova-Vejlupkova et al., 1981

55 2,4,5-T production workers

Neurologic examination, EMG

No

None

Poland et al., 1971

73 2,4-D and 2,4,5-T production workers

Neurologic examination, MMPI

Job classification

Internal comparison

Singer et al., 1982

56 2,4-D and 2,4,5-T production workers

EMG, nerve conduction

No

25 nonexposed referents

Suskind and Hertzberg, 1984

204 2,4,5-T production workers

Neurologic examination, EMG

Job classification

163 nonexposed workers

Sweeney et al., in press

281 TCP and 2,4,5-T production workers

EMG

Serum TCDD

260 community-matched referents

Thomas, 1987

1,412 fragrance and flavor plant workers

No: mortality data only

Job classification

U.S. male population

Environmental

Assennato et al., 1989

Seveso residents, 152—1st follow-up (FU);

142—2nd FU;

141—3rd FU

EMG

Chloracne

Unexposed subjects from nearby towns

123—1st FU

196—2nd FU

167—3rd FU

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Barbieri et al., 1988

152 Seveso residents of TCDD contaminated area

Neurologic examination, EMG

Chloracne

123 residents from nearby towns

Bertazzi et al., 1989

Seveso residents, 556 zone A; 3,920 zone B; 26,227 zone R

No: mortality data only

Residence in contaminated area

167,391 nonexposed residents of surrounding area

Boeri et al., 1978

470 zone A Seveso residents

Interview, neurologic exam, EMG

Residence in zone A

152 zone R residents

Filippini et al., 1981

308 Seveso residents

EMG, neurologic examination

Chloracne, abnormal hepatic enzymes

305 nearby nonexposed residents

Gilioli et al., 1979

35 lab technicians in Seveso

EMG

No

35 subjects from more distant areas

Pocchiari et al., 1979

446 Seveso residents

Neurologic examination

Residence in zone A

255 inhabitants from low exposure area (zones B and R)

Stehr et al., 1986

68 Missouri residents of TCDD contaminated area

Neurologic examination

Self-reports

36 individuals with little or no TCDD exposure

Hoffman et al., 1986 Stehr-Green et al., 1987

154 Missouri residents, Quail Run

Neurologic examination, neuropsychologic battery

Residence in contaminated area 6+ months

155 unexposed residents

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Group, N

Tests of Neurological Dysfunction

Exposure Measures

Comparison Group, N

Webb et al., 1987

68 Missouri residents of TCDD contaminated area

Neurologic examination

Soil measurements

36 individuals with little or no TCDD exposure

Vietnam Veterans

AHFS, 1984

1,208 Air Force Ranch Hands

Neurologic examination

Exposure index

1,238 Air Force veterans who did not participate in Ranch Hand

AFHS, 1987

1,016 Air Force Ranch Hands

Neurologic examination

Exposure index

1,293 Air Force veterans who did not participate in Ranch Hand

AFHS, 1990

995 Air Force Ranch Hands

Neurologic examination

Exposure index

939 Air Force veterans who did not participate in Ranch Hand

AFHS, 1991

888 Air Force Ranch Hands

Neurologic examination, questionnaire

Serum TCDD

856 Air Force veterans who did not participate in Ranch Hand

Boyle et al., 1987

9,324 Vietnam veterans

No: mortality data only

Vietnam service

8,989 Vietnam era veterans

Breslin et al., 1988

24,235 Army and Marine Vietnam veterans

No: mortality data only

Vietnam service

26,685 Vietnam era veterans

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Bullman et al., 1991

374 Vietnam veterans with PTSD

No

Vietnam service

373 Vietnam veterans without PTSD

CDC, 1987

9,324 veterans, Vietnam Experience Study

No: mortality data only

Vietnam service

8,989 Vietnam era veterans

CDC, 1988

2,490 veterans, Vietnam Experience Study

Neuropsychiatric test, EMG, hearing test

Vietnam service

1,972 Vietnam era veterans

Decoufle et al., 1992

7,924 Vietnam veterans

Questionnaire data

Self-reported exposure

7,364 Vietnam era veterans

Eisen et al., 1991

2,260 Vietnam veteran twin pairs

Self-reported symptoms

Service in SEA

Twin siblings who did not serve in SEA

Fett et al., 1987

19,205 Australian Vietnam veterans

No: mortality data only

No

25,677 Vietnam era veterans

Fiedler and Gochfeld, 1992

10 New Jersey Vietnam veterans

Neuropsychiatric test, WAIS-R

Serum TCDD

10 nonexposed Vietnam veterans; 7 Vietnam era veterans

Goldberg et al., 1990

2,092 Vietnam veteran twin pairs

Questionnaire data

No

Twin siblings who did not serve in Vietnam

Kogan and Clapp, 1985

840 Massachusetts Vietnam veterans

No: mortality data only

Vietnam service

Massachusetts population and 2,515 Vietnam era veterans

Lawrence et al., 1985

555 New York State Vietnam veterans

No: mortality data only

Vietnam service

941 Vietnam era veterans

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Reference

Study Group, N

Tests of Neurological Dysfunction

Exposure Measures

Comparison Group, N

Levy, 1988

6 Massachusetts Vietnam veterans with chloracne

Standardized interview for PTSD, WAIS-R

Chloracne

25 Vietnam veterans without chloracne

Rellahan, 1985

232 Vietnam veterans, Hawaii residents

Self-reported symptoms

Vietnam service, combat

186 Vietnam era veterans

Snow et al., 1988

2,858 Vietnam veterans

Self-reported symptoms

Vietnam service, combat

Internal comparison

True et al., 1988

775 Vietnam veterans

Self-reported symptoms

Vietnam service, combat

1,012 Vietnam era veterans

Wendt, 1985

10,846 Iowa Vietnam veterans

Questionnaire data

Service in SEA

None

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

COGNITIVE AND NEUROPSYCHIATRIC EFFECTS

Epidemiologic Studies of Cognitive and Neuropsychiatric Effects

Occupational Studies

Numerous occupational studies of neurobehavioral effects of herbicides have been conducted, but most are limited by methodologic problems. In 1971, Poland and colleagues (1971) reported on personality changes in 73 male workers involved in manufacturing of the herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Physical neurologic examination detected no abnormalities in these workers. Mean MMPI scores for 28 production workers (with potentially higher exposures) and 20 administrative staff (with potentially lower exposures) each differed significantly from published norms. Production workers differed on 9 of 13, and administrative staff on 6 of 13, clinical scales. Chloracne was found in a total of 13 workers, but there was no significant correlation between job location within the plant and chloracne. The subgroup of workers with chloracne had significantly higher mean mania scores when compared to workers with less severe acne (p < .05). The authors note, however, that the workers are not comparable to the population on which the test norms are based. The overall results of this study did not show a strong association between exposure to 2,4-D and 2,4,5-T and significant personality change.

A 10 year follow-up study examined 55 men in Czechoslovakia who were exposed to TCDD during the production of 2,4,5-T and who developed signs of illness during the study period (Pazderova-Vejlupkova et al., 1981). During the initial evaluation at onset of illness, 7 percent of the workers demonstrated encephalopathy, and 75 percent neurasthenia. The severity of symptoms was unrelated to length of exposure, job classification, or age. Over time (i.e., mean of 9.3 years), the number of patients with neurasthenia decreased, and the accompanying anxiety and depression disappeared completely. The authors proposed two possible mechanisms for these results. First, psychiatric symptoms could have been caused directly by the neurotoxicant and gradually resolved. Alternatively, these symptoms could be related to a severe somatic condition that developed as a result of fears and changes in daily activities, both at home and at work. In this case, adaptation and new coping mechanisms resulted in a diminution of symptoms over time. Methodologic problems in this study included the use of self-reported symptoms, no objective measure of exposure (all workers were considered exposed), and selection bias (i.e., only sick workers were studied).

The results of a study of 45 railroad workers exposed to TCDD in early

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

1979 were reported by Klawans (1987). The workers were exposed to TCDD during cleanup of a chemical spill from damage to a tank car that contained polychlorinated phenols. The concentration of TCDD found in the tank car was approximately 45-46 parts per billion (ppb). Initial complaints of the workers were fatigue (91 percent), muscle ache (51 percent), and distal paresthesia (93 percent). The results of a neuropsychological evaluation given two years later revealed cognitive impairment in 49 percent of the workers (i.e., decreased attention/concentration as assessed by the Mental Control and Digit Span subtest of the Wechsler Memory Scales and Reaction Time task). Some degree of depression as measured by Beck's Depression Inventory was found in 69 percent of the workers. The same percentage of workers was found to be depressed at the six year follow-up examination. Although this study performed detailed psychometric evaluations of the CNS, only exposed workers were examined. No control group of workers was included for comparison, and no direct or indirect measures of TCDD exposure were employed.

Self-reports of sleep difficulties (Bashirov, 1969), headaches (Bashirov, 1969), fatigue (Kimmig and Schulz, 1957; Goldman, 1973), and other subjective neurologic complaints have appeared frequently in case studies and some cohort reports, but studies with comparison populations have not regularly suggested CNS problems. In a cohort mortality study of 1,222 male Canadian forestry workers at an electrical utility presumed to have been exposed to 2,4-D and 2,4,5-T (Green, 1991), a significant excess in the number of suicides was observed for the cohort as a whole compared to the total male population of Ontario (SMR = 2.1, CI 1.1-3.8). However, the overall mortality rate was lower in the forestry workers than in the general population, and fewer deaths from diseases of the nervous system occurred than were expected. Although the author of this study speculated that CNS toxicity from phenoxy herbicides might be the cause of the increased rate of suicides, the rationale for this is not stated. Because of the nature of the workers' routine job duties at the utility, length of employment was used as a surrogate measure of exposure. The study was limited by the young age of the cohort (the mean age at the end of the last follow-up was 43 years), no mention of whether protective equipment was used, and no control for potential confounders (age, education, general health). The limitations imposed by the ''healthy worker effect" and the use of death certificates to ascertain the cause of death are described in Chapter 5.

Of all studies assessing neurobehavioral outcomes after occupational exposure to dioxin, the National Institute for Occupational Safety and Health (NIOSH) study stands out as particularly rigorous (Alderfer et al., 1992). A group of 281 workers who manufactured trichlorophenol (TCP) or 2,4,5-T was compared with an unexposed referent group (N = 260) recruited from the same communities as the workers and matched on age, race, and sex. A

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

comprehensive medical and psychological evaluation was administered over a three day period in 1987 or 1988. Depressed mood was assessed using the Beck Depression Inventory and the depression subscale of the Self-Report Symptom Inventory-Revised-90 (SCL-90-R). These depression scales are well standardized and validated. The authors noted that the study had statistical power of 85 percent to detect a twofold increase in the prevalence of depressive symptoms. Separate multiple regression models were used to evaluate the relationships between two measures of TCDD exposure, current serum TCDD level and status as a worker or referent, and each of the two outcome measures of depression. Considered in the analysis were the following covariates: age, race, income, education, family history of psychiatric disorders, current treatment for psychiatric disorders, current treatment with neurotoxic drugs or drugs that can produce depression as a side effect, history of head injury, history of low vertebral disk herniation, history of chronic medical disorders, self-reported occupational exposure to neurotoxicants, self-reported exposure to Agent Orange during military service in Vietnam, smoking history, and lifetime alcohol use.

Workers had a mean serum TCDD level of 220 parts per trillion (ppt) and the referents had a mean TCDD level of 6 ppt (p = .0001). Neither serum level nor group membership was significantly associated with scores on the Beck Depression Inventory or the SCL-90 in either the unadjusted or the adjusted analyses. These results suggested that current TCDD level was not associated with current depression in this group of highly exposed workers. The authors warned that since this study was conducted many years after TCDD exposure, depression may have been present following exposure but resolved prior to data collection. Additional analyses showed self-reported Agent Orange exposure during the Vietnam war to be a significant covariate in the model for the Beck depression score. However, only seven referents and one worker reported Agent Orange exposure; the mean serum TCDD level in these eight participants was 43 ppt compared to a mean level of 116 ppt in participants reporting no Agent Orange exposure (p < .10).

Environmental Studies

The largest environmental accident, in which TCDD contaminated about 2,000 hectares, occurred in 1976 at Seveso, Italy. Pocchiari and colleagues (1979) reported preliminary clinical findings on 446 inhabitants living in the most highly contaminated area (zone A), closest to the plant where the explosion occurred, and 255 inhabitants who lived a distance from the plant (zones B and R) who were thought to be less exposed. TCDD was found in environmental soil samples from areas next to the factory at levels as high as 15,000 ppb. An initial neurologic evaluation was done in 1977; a second evaluation was completed in 1978 on about one-half of the individuals from

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

zone A who were screened in 1977. Idiopathic clinical neurologic damage (not specifically defined) was found in 6.7 percent of zone A residents, compared to 1.2 percent of zone B and R residents; subclinical damage was found in 3.1 percent and 1.2 percent of residents of the respective zones (no statistical analysis provided). Two years later, 11.7 percent of 205 exposed residents had evidence of neurologic dysfunction (no data for comparison group).

Bertazzi and colleagues (1989) examined the mortality of adults (aged 20-74 years) residing in zones A, B, and R for the period from July 1976 to December 1986. A referent cohort of subjects who lived in the immediate surrounding area was also examined. Men who ever lived in a TCDD contaminated zone demonstrated excess mortality from chronic ischemic heart disease in the first five years following the accident compared to the male reference population. The authors proposed that both the psychosocial stress caused by the accident (e.g., relocation, loss of jobs, loss of property) and the TCDD toxicity may have contributed independently or interactively to increased cardiovascular morbidity. No long-term effects on the CNS were reported.

In 1971, sludge waste containing TCDD was sprayed for dust control purposes on residential, recreational, and commercial areas of eastern Missouri (Stehr-Green et al., 1987). TCDD levels were measured in composite soil samples from this area at levels between 39 and 1,100 ppb. In 1984, comprehensive examinations of 154 exposed residents (defined as residing in the contaminated area for six months or more) and 155 unexposed persons (defined as residents for six months or longer of sites with no potential exposure to TCDD) were performed to assess possible acute and subacute health effects. Results of the neurobehavioral tests showed no significant differences on tests of cognitive functioning, with the exception of the Vocabulary subtest from the WAIS. This subtest is a good estimate of premorbid level of verbal intelligence, which significantly influences performance on neurobehavioral tests (Bolla-Wilson and Bleeker, 1986). Group differences on the Vocabulary subtest indicate that the control and exposed groups were not comparable on this confounding variable, and no statistical adjustments were used to control for the possible confounding effects. Higher scores were found for the exposed group relative to the unexposed group for a number of scales on the Profile of Mood States (tension/anxiety, anger/hostility, depression/dejection, and fatigue/inertia). An implicit confounder in all neurobehavioral research related to environmental disasters is the inability to separate confidently symptoms related to stress from the disaster itself from those related to the putative neurotoxicant. Because the differences cited above could reasonably be attributed to the stress associated with environmental disasters (exaggerated media coverage, relocation, or inability to relocate due to limited financial resources), no specific effect could be identified for exposure to TCDD.

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Neurobehavioral effects were described in two case reports of ingestion of 2,4-D. Severe CNS depression was reported in a 61 year old woman who intentionally consumed dandelion killer (Friesen et al., 1990). Initial serum 2,4-D concentration after hospitalization was 392 mg/liter. Clinically, the woman was comatose, and showed depressed respiration, pinpoint pupils, and no deep tendon reflexes. As her 2,4-D concentrations decreased, her mental status improved. At discharge, she showed no neurologic or other systemic effects from the 2,4-D overdose. In a case of fatal 2,4-D ingestion described by Dudley and Thapar (1972), a 76 year old man with senile dementia ingested a large amount of 2,4-D. The patient was comatose when admitted to the hospital, with minimal response to deep pain and hyperactive deep tendon reflexes. Three days after hospitalization the patient died from a trial fibrillation. Autopsy revealed tissue concentrations of 2,4-D in the following organs: liver, 408 parts per million (ppm); brain, 93 ppm; and blood, 58 ppm. In the brain, plaques of perivascular demyelination similar to those found in multiple sclerosis or after arsenic and carbon monoxide poisoning were found. These two case studies demonstrate a positive association between ingestion of extremely high doses of an herbicide and CNS depression. However, it is not possible to determine whether the CNS depression may have been related to chemical components in the herbicides other than 2,4-D. In the second case, where dementia was already present, the relationship between histologic changes and 2,4-D exposure remains unclear.

Vietnam Veterans Studies

As with environmental disasters, neurotoxicant studies conducted on war victims are confounded by the stress of the war experience. For many centuries it has been well recognized that catastrophes, personal tragedies, and armed conflict lead to a variety of somatic and psychologic symptoms. The American Civil War resulted in descriptions of palpitations, chest pains, and other cardiac disturbances, which were called "soldier's heart." Many World War I soldiers developed a syndrome called "shell shock" or war gas syndrome. During and after World War II and the Korean War, there was further experience with these symptoms, particularly because large numbers of civilians were exposed to physical catastrophe. Thus, the concentration camp syndrome/prisoner syndrome and the traumatic neurosis of war were recognized as ramifications of this pattern of response.

In the 1950s, psychiatrists developed a diagnosis called posttraumatic distress disorder (PTSD) and established specific criteria for this diagnostic category. PTSD is described in the Diagnostic and Statistical Manual of Mental Disorders—third edition, revised (American Psychiatric Association, 1987) as a disabling complex of memories, behaviors, and affective

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

states occurring in the aftermath of an extraordinarily stressful experience. The salient features of the disorder are recurrent reexperiencing of the traumatic event (e.g., repetitive dreams or intrusive memories), hyperarousal (e.g., exaggerated startle response or insomnia), avoidance of stimuli reminiscent of the traumatic event, and diminished emotional responsiveness. Symptoms of anxiety and depression are common and may be severe. There may also be symptoms of organic mental disorder (i.e., failing memory, difficulty concentrating, emotional lability, headache, and vertigo).

It has been estimated that 10 to 20 percent of veterans who served in Vietnam reported that they had at one time suffered from psychological disturbances (neurasthenia) or PTSD (Hall and Macphee, 1985; CDC, 1988). The prevalence of similar psychiatric disorders in the general population is between 10 and 20 percent, with severe disturbances found in 3 percent (Andrews et al., 1981; Hall and Macphee, 1985). Therefore, although Vietnam veterans show higher rates of psychiatric disturbance than veterans who did not serve in Vietnam, they appear to be no more likely than the general population to develop these difficulties. However, it should be noted that Vietnam veterans are predominantly young and male, and the prevalence of these psychological conditions may be different than for the general population. Some investigators have found that service in Vietnam was associated with increased mortality due to trauma, such as suicide, motor vehicle accidents, and "accidental poisonings" (Lawrence et al., 1985; Fett et al., 1987; Breslin et al., 1988). In some cases, psychiatric difficulties are reported as direct manifestations of the neurotoxicity of Agent Orange (Barr, 1982; Levy, 1988). A suggestion that Agent Orange causes neuropsychiatric disorders by producing metabolic disturbance or temporal lobe seizures (Barr, 1982) has not been tested with empirical research.

Other studies employing different methodologies failed to find these same associations. A body of evidence has shown that the development of PTSD is likely to be related to being wounded (Bullman et al., 1991), high intensity of combat experience (Blum et al., 1984; Hall and Macphee, 1985; Hall, 1986; Snow et al., 1988; True et al., 1988; Goldberg et al., 1990; Decoufle et al., 1992) young age, low level of education, and race (True et al., 1988).

Levy (1988) compared 6 Vietnam veterans with chloracne to a matched control group of 25 Vietnam veterans without chloracne on a battery of neuropsychological tests and interviewed them for PTSD. Active cases of chloracne were used to estimate Agent Orange exposure. The groups were matched on age, education, and period of Vietnam service. In order to control for the effects of combat stress, control subjects had to report a similar number of contacts with the enemy. The exposed group scored significantly lower on six of the nine neuropsychological tests. One of the largest group differences was on the WAIS-R Vocabulary subtest, which is a good estimate of verbal intelligence. In general, the lower the score on this

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

test, the poorer is the performance on other neurobehavioral tests. These data suggest that the exposed group was not comparable to the referent group on intellectual level, and therefore, the evidence for organic psychological deficits (reported group differences on the neuropsychological tests) is questionable. Exposed Vietnam veterans reported a significantly higher rate of PTSD-related symptoms, although the study involved only a small number of Vietnam veterans, was conducted nearly 20 years after potential exposure in Vietnam, and did not control for confounding variables.

The National Vietnam Veterans Readjustment Study (Kulka et al., 1988) examined current and lifetime prevalence of PTSD and other psychological disorders (e.g., depression, anxiety reaction, obsessive compulsive disorder, alcohol abuse or dependence) in both men and women Vietnam theater veterans. The lifetime prevalence of PTSD (disorder occurred at sometime during their lives) was 30.6 percent in the male veterans and 26.9 percent among female veterans. Exposure to war zone stress in Vietnam was positively associated with higher rates of all the psychiatric disorders. These disorders all tended to be chronic rather than acute. It was hypothesized that the development of PTSD in an individual was related to a variety of risk factors, which included individual vulnerability (biological, psychological, and sociodemographic factors) and war zone stressors that were independent of other risk factors. Exposure to herbicides in Vietnam was not examined as a potential risk factor in this large-scale study.

Boyle and colleagues (1987) examined the postservice mortality of a cohort of 9,324 Army Vietnam veterans compared to 8,989 Vietnam era Army veterans who did not serve in Vietnam. In the first five years after discharge, Vietnam veterans had a 17 percent higher mortality rate than Vietnam era veterans and most deaths were from external causes (e.g., motor vehicle accidents, drug and alcohol use). The authors suggested that the excess of traumatic deaths among Vietnam veterans was probably related to unusual stresses the veterans endured while stationed in a war zone. On the other hand, drug-related deaths were felt to be linked to intensity of combat experience, rather than the "Vietnam experience" per se. Unfortunately, it is extremely difficult to separate effects of herbicide exposure and combat since it is possible that those who were the most heavily exposed to herbicides were also most likely to be in combat zones. The results of the Wisconsin Vietnam Veteran Mortality Study (Anderson et al., 1986) revealed that alcohol consumption was related to such demographic characteristics as region of residence, age, income, and marital status rather than to veteran status. This suggests that differences in alcohol consumption between veterans and nonveterans were related to demographic differences between the two groups rather than veteran status.

Farberow and colleagues (1990) examined potential risk factors for suicide among 38 Vietnam veterans compared to 46 Vietnam veterans who

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

died from motor vehicle accidents. Veterans combat exposure was assessed using information from military personnel records on military occupational specialty code (MOSC) and from psychological autopsy. Suicide was not associated with specific combat experiences or military occupation, however symptoms related to PTSD were observed more frequently among suicide cases than accident cases.

Several other studies of Vietnam veterans have evaluated suicide as an outcome (Lawrence et al., 1985; CDC, 1987; Fett et al., 1987). However, because of methodologic problems with these studies, including variability and lack of information on herbicide exposure, and inadequate consideration of potential confounding variables in the veterans' studies, such as combat experience, it was not possible to determine whether there is an increased suicide risk associated with herbicide or TCDD exposure.

There are few studies that directly assess the cognitive effects of herbicide exposure by using standardized neuropsychological tests. In two studies that have been completed—the Vietnam Experience Study conducted by the CDC (1988) and the New Jersey Pointman study (Fiedler and Gochfeld, 1992)—neither found consistent associations between exposure and decrements in performance. One explanation for this could be the length of time that elapsed between exposure and evaluation. If herbicide exposure was associated with cognitive effects at the time of exposure, it is likely that these effects would have disappeared or been compensated for in the time since exposure ceased. A poor measure of herbicide exposure could also lead to a lack of apparent differences; problems with self-reported exposures and the use of current serum TCDD levels to estimate prior dioxin exposure are discussed in Chapter 6.

Serum TCDD concentrations from 888 participants in Operation Ranch Hand were compared to those of 856 Air Force veterans who did not participate in Ranch Hand (AFHS, 1991). The highest levels were found among the ground crew, but the variation in individual TCDD scores was considerable. In the Ranch Hands, no associations were found between body burden of TCDD (current serum levels) and reports of sleep disturbances or SCL-90 variables (e.g., anxiety, depression, somatization). Although significant results were found between serum TCDD and certain elements of the self-administered Millon Chemical Multiaxial Inventory test, which assesses basic personality patterns, pathological personality disorders, and clinical symptom syndromes, these findings were not consistent with similar variables on the SCL-90-R and other reported information.

Summary of Cognitive and Neuropsychiatric Effects

The existing literature on neurobehavioral effects of occupational, environmental, and Vietnam veterans' exposure to herbicides and related compounds

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

is insufficient to determine whether an association exists between herbicide exposure and chronic cognitive or neuropsychiatric disorders. As suggested by Sharp and colleagues (1986), the delayed effects of pesticides on human health are difficult to detect, and the health risks may be sufficiently small that they are below the power of present epidemiologic studies to detect.

Although there are no shortages of studies concerning this topic, methodologic problems make it difficult to reach definitive conclusions. Shortcomings in defining exposure include absent or poor exposure assessments; inconsistencies in identifying exposed individuals for study (i.e., some studies rely upon the presence of chloracne for inclusion, others assumed all subjects were exposed); and concomitant exposure to different chemicals, mixtures of chemicals, or concentrations. Studies of cognitive or neuropsychiatric disorders are also weakened by the small numbers of subjects; poor selection, or absence of, comparison groups; confounding of the possible effects of herbicides with the effects of stress; and inadequate statistical analyses. Self-reports of exposure and symptoms may not be verified independently. To maximally define the direct effects of herbicides and dioxin on cognitive and neuropsychiatric function, future studies should focus primarily on occupationally exposed groups for whom levels of exposure are better known and neurobehavioral testing can be conducted in relative proximity to the time of exposure.

Based on past findings, if herbicide or TCDD exposure is associated with neurobehavioral disorders, these are in all likelihood subtle. Since the central nervous system can compensate for minor damage, the chances of finding subtle effects 20 years after exposure are small given the assessment tools currently available. However, it is also possible that subtle CNS changes acquired in early adulthood could manifest themselves in later adult life when compounded by "normal age-related changes" of the CNS. That is, exposure to neurotoxins could produce "accelerated aging" of the brain due to premature neuronal loss, which could then result in neurobehavioral deficits. Therefore, a prospective study of individuals with documented significant exposure, after they reach the age of 60 years, would be of interest in investigating the interactive effects of exposure to herbicides and dioxins with age on neurobehavioral functioning.

Conclusions for Cognitive and Neuropsychiatric Effects

Strength of Evidence in Epidemiologic Studies

There is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides* (2,4-D; 2,4,5-T and its contaminant TCDD; cacodylic acid; and picloram) and cognitive or neuropsychiatric disorders.

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Biologic Plausibility

Studies in laboratory animals do not support an association between exposure to TCDD or herbicides and cognitive or neuropsychiatric disorders.

Increased Risk of Disease Among Vietnam Veterans

Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the studies that have been reviewed and inadequate control for important confounders, it is not possible for the committee to quantify the degree of risk likely to be experienced by Vietnam veterans because of their exposure to herbicides in Vietnam.

MOTOR/COORDINATION DYSFUNCTION

Epidemiologic Studies of Motor/Coordination Dysfunction

Occupational Studies

Tremor and dystonia were described in a series of exposed railroad workers (Klawans, 1987), but no comparison group was studied. The high prevalence of the findings (53 percent with dystonia and 78 percent with tremor), detected specifically by a movement disorder specialist, suggests that movement disorders may be subtle but present in many subjects if specifically sought. Other reports of occupational exposure have not confirmed these findings, and thus a strong association between herbicides and motor/sensory CNS dysfunction cannot be established.

Mortality studies that have included evaluations of strokes or vascular lesions of the CNS as a cause of death have not reported a significant increase in risk from occupational exposure to TCDD (Thomas, 1987; Alavanja et al., 1989; Bond et al., 1989). Using chloracne as a clinical measure of TCDD exposure, one study found that strokes occurred more frequently than expected in chloracne subjects compared to nonchloracne subjects (RR = 3.8, CI 1.8-12.1; Bond, 1987). This risk estimate, however, was based on only four cases, and multiple chemical exposures were likely.

Environmental Studies

Nonbehavioral CNS effects that included increased tendon jerks, ataxia, and extrapyramidal signs occurred in 37 of 470 patients in the high-exposure Seveso group compared to 8 of 152 in the comparison group, but no statistical analysis was presented (Boeri et al., 1978). Mortality studies

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

based on combined Seveso exposure zones (A, B and R) showed no increased risk for death from strokes (RR = 1.0, CI 0.8-1.3; Bertazzi et al., 1989). However, in the highest exposure group, five subjects died from cerebrovascular disease, resulting in increased relative risk values for zone A. The small number of strokes in the entire group limits the impact of the observation. Other environmental reports did not focus on CNS effects.

Effects seen in fatal intoxication cases have included depressed levels of consciousness, increased reflexes, altered pupillary signs, and other neurologic deficits, but it is not clear whether these signs were direct toxic manifestations of herbicide exposure or nonspecific effects of cardiopulmonary collapse (Nielsen et al., 1965; Dudley and Thapar, 1972). One patient received 2,4-D as therapy for a life-threatening fungal infection, disseminated coccidioidomycosis (Seabury, 1963). After 2,000 mg of 2,4-D delivered intravenously had no neurologic effects, he received 3,600 mg over two hours. The patient became semistuperous, developed fibrillary movements about his mouth and upper extremities, and showed hyporeflexia on neurologic examination. Within 48 hours after cessation of treatment, these signs reversed. Although the patient died 17 days after this treatment, autopsy examination showed no signs to suggest a specific lesion from the 2,4-D treatment.

Vietnam Veterans Studies

Several of the Vietnam veteran studies have examined other CNS functions besides behavior. In the 1982 baseline examination for the Ranch Hand study (AFHS, 1984), an increased frequency of abnormal Babinski signs was reported in Ranch Hands compared to the control group, but this finding did not reoccur in the 1985 examination (AFHS, 1987). In the 1987 follow-up examination, coordination difficulty and postural tremor reportedly occurred more frequently in Ranch Hands (AFHS, 1990). This clinical finding was reinforced in the serum TCDD analysis of the 1987 examination data; Ranch Hands with elevated serum TCDD levels experienced more coordination difficulties than the comparison group (AFHS, 1991). Serum TCDD was also shown to be positively and significantly associated with the CNS index, a composite score based on coordination, gait, and tremor. Although the Ranch Hand studies are difficult to interpret (see Appendix C), these findings recall the CNS observations of tremor and dystonic postures in the series of railroad cleanup workers reported by Klawans (1987).

A final neurologic effect reported with greater frequency for Vietnam veterans than Vietnam era veterans was hearing loss (CDC, 1988). This observation was interpreted as consistent with exposure to high levels of noise during military service in Vietnam and not specifically related to

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

herbicide exposure, because the study population was not selected to assess toxic exposure but rather for the Vietnam experience.

Questionnaires on perceived neurologic problems in Vietnam veterans showed more tiredness, headaches, dizziness, ringing in the ears, and complaints of hearing loss compared to a control group of Vietnam era veterans (Rellahan, 1985; Eisen et al., 1991; Decoufle et al., 1992). A survey of 10,846 Vietnam veterans in Iowa (Wendt, 1985) showed that chronic headaches and ''nerve/brain" problems were more frequent after Vietnam service than before military experience, but no statistical analysis was performed. This assessment, like the other questionnaire studies discussed in this report, focused on Vietnam experience as opposed to herbicide exposure. None of these cited surveys included neurologic examinations.

In mortality studies, the only neurologic disorder commonly investigated is stroke or vascular disease of the CNS. In the mortality study of Massachusetts veterans (Kogan and Clapp, 1985), the mortality risk for cerebrovascular disease was significantly higher for Vietnam veterans than for non-Vietnam veterans. The 19 Vietnam veteran deaths observed between 1978 and 1983 resulted in a proportionate mortality ratio of 1.6, adjusted for age, (p = .02) when compared with the mortality experience of non-Vietnam veterans. The study was limited to those veterans who applied for a state military service bonus. Information on potential confounders, such as smoking and alcohol use, was not available for study, and herbicide or TCDD exposure was not specifically addressed.

A final area of focus has been the neurologic function of Vietnam veterans' offspring. One study found that children whose fathers reported exposure to Agent Orange in Vietnam scored significantly worse on a variety of sensory integrative function tests. Because of the small number of subjects and the lack of distinction between Vietnam service and specific TCDD exposure, it is not possible to determine whether herbicide exposure was associated with the test scores (Becker, 1982).

Summary of Motor/Coordination Dysfunction

There are no definitive studies to determine whether exposure to dioxin or related herbicides is associated with CNS motor/sensory/coordination problems. However, follow-up of veterans, and, to a lesser extent, environmental observations suggest that motor and coordination difficulties should be assessed further in exposed subjects. Additional longitudinal assessments of motor and coordination problems are warranted in exposed subjects, especially those with high exposure as in the NIOSH cohort studied by Fingerhut and colleagues (1991). Vietnam veterans represent the most systematically evaluated group with chronic TCDD exposure, and the findings in this group suggest that CNS disorders may focus on the subtle

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

clinical area of coordination and abnormal involuntary movement disorders. Since this area is a specific subspecialty of neurology, future evaluations should involve specialists in this field. Internationally respected scales for movement disorders have been developed and should be used in future studies of such problems, as well as assessments that capture the disability related to any objective findings.

In the past decade—and unrelated specifically to the question of TCDD and the CNS—an increasing concern has developed scientifically over the possible link between parkinsonism and chemicals used as herbicides and pesticides (Semchuk et al., 1992). The most dramatic and well-studied chemical is MPTP, which is a narcotic derivative with a chemical composition resembling paraquat. It has been reported that laboratory workers exposed to the compound have developed parkinsonism (Langston and Ballard, 1983). Parkinsonian syndromes have also been described in association with the fungicide manganous ethylene bisdithiocarbamate (Ferraz et al., 1988) and the grain fumigant consisting of 80 percent carbon tetrachloride and 20 percent carbon disulfide (Peters et al., 1988). Paraquat has been shown to be associated with pathologic damage to the substantia nigra (Grcevic et al., 1977). These data support the concept that some herbicides and pesticides could possibly be associated with parkinsonism. Furthermore, since the laboratory workers had insidious onset of parkinsonism, chronic exposure could be associated with the problem, without a massive accident or evidence of acute intoxication (Langston and Ballard, 1983).

As Vietnam veterans move into the decades when Parkinson's disease becomes more prevalent, attention to the frequency and character of new cases of parkinsonism in exposed versus nonexposed individuals may be highly useful in assessing whether dioxin or herbicide exposure is a risk factor for eventual Parkinson's disease.

Conclusions for Motor/Coordination Dysfunction

Strength of Evidence in Epidemiologic Studies

There is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides* (2,4-D; 2,4,5-T and its contaminant TCDD; cacodylic acid; and picloram) and motor/coordination dysfunction.

Biologic Plausibility

Studies in laboratory animals do not support an association between exposure to TCDD and motor/coordination dysfunction. However, the herbicide MPTP, which does not share strong structural similarities to TCDD, has been associated with the onset of parkinsonism in animals and in humans.

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Increased Risk of Disease Among Vietnam Veterans

Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the studies that have been reviewed and inadequate control for important confounders, it is not possible for the committee to quantify the degree of risk likely to be experienced by Vietnam veterans because of their exposure to herbicides in Vietnam.

PERIPHERAL NERVOUS SYSTEM DISORDERS

Epidemiologic Studies of Peripheral Nervous System Disorders

Occupational Studies

A large number of reports have suggested that acute or subacute peripheral neuropathies can be associated with occupational exposure to herbicides (Ashe and Suskind, 1950; Baader and Bauer, 1951; Kimmig and Schulz, 1957; Goldstein et al., 1959; Todd, 1962; Berkley and Magee, 1963; Poland et al., 1971; Jirasek et al., 1974; Oliver, 1975; Pazderova-Vejlupkova et al., 1981). Only a very limited number of studies on the PNS provide any control or comparison group data. Since peripheral neuropathies can be induced by common medical and environmental disorders such as diabetes and poor nutrition, especially in alcoholics, the presence of neuropathy in an herbicide-exposed population cannot be attributed necessarily to the herbicide without consideration of these other factors. Rigorously defined and examined comparison groups are therefore especially important in the analysis of peripheral neuropathies. The studies cited below have at least provided some form of comparison group.

Moses and colleagues (1984) studied 226 men identified by union records as occupationally exposed to 2,4,5-T in Nitro, West Virginia. A cohort of 117 subjects with either current evidence or a history of chloracne over the previous 30 years defined the exposed group. The comparison group consisted of 109 factory workers from the same occupational environment, but without chloracne. A neurologic evaluation of a smaller group of 90 volunteers was not specifically described, but the workers with chloracne experienced significantly more symptoms of muscle pains, decreased libido, and erection/ejaculation difficulties than the nonchloracne subjects. Furthermore, 18.3 percent of chloracne subjects, compared to none of the controls, had decreased pin sensation (p < .01). The authors did not indicate how many workers had skin lesions at the time of neurologic examination or whether the decreased sensation was in the same distribution as the skin rash and could be explained by hypertrophic skin. This study is further compromised because the analytical and clinical methods were vaguely described,

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

no EMG examinations were performed, and the groups were not necessarily comparable for other factors known to be associated with peripheral neuropathy, such as alcoholism and diabetes mellitus (which were considered for the study's assessments of liver function). Finally, participation was voluntary, and it is not clear what proportions of the total chloracne and nonchloracne group were represented.

When Suskind and Hertzberg (1984) examined nerve conduction velocities among a larger number of exposed (N = 204) and nonexposed workers (N = 163) from the same West Virginia plant, they found no differences between the two groups. This second study was a long-term follow-up assessment, 30 years after the time of exposure. Exposure to 2,4,5-T during the manufacturing process was determined from occupational histories.

Singer and colleagues (1982) examined 56 plant workers from Arkansas who were exposed to 2,4,5-T and 2,4-D and who had no history of diabetes or neurologic disease. They compared these men to 25 unexposed subjects from completely different work environments—a group of laboratory personnel and a group of brake workers. Alcohol consumption of more than four drinks per day was exclusionary for controls, but not subjects, and it is not clear whether the groups were of comparable ages. EMG was performed to detect peripheral neuropathy, and nerve conduction velocities were found to be significantly slowed in exposed subjects compared to controls.

Sweeney and colleagues (in press) performed the most rigorous evaluation of peripheral chronic neuropathy in a study of chemical workers exposed 15 years earlier to TCDD during the production of TCDD-contaminated chemicals. A referent group of randomly selected unexposed neighborhood comparison subjects, matched on age, sex, and race, was also studied. Serum TCDD levels were assessed and documented to be different in the exposed workers (median = 220 ppt, N = 281) than in the comparison group of unexposed referents (median = 7 ppt, N = 260). Peripheral nerve function was assessed by nerve conduction tests, thermal thresholds, and physical examinations, with strict definitions applied to the term peripheral neuropathy. There were no significant differences in the prevalence of peripheral neuropathy between the two groups. Serum TCDD levels were not associated with the incidence of peripheral neuropathy.

Environmental Studies

Major environmental disasters in Seveso, Italy, and Missouri have served as sources for study of the neurologic effects of TCDD exposure. Boeri and colleagues (1978) conducted peripheral nerve examinations seven months after the accidental explosion in Seveso and reported descriptive differences between 470 volunteer subjects in zone A (high-exposure group) and 152

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

volunteer residents from the town of Bovisio in zone R (low-exposure group). Cranial and peripheral nerve symptoms and signs were generally more prevalent among the highly exposed group. No statistical analyses were performed, except on EMG examinations, and these data showed no significant differences.

As a follow-up to the above screening, Filippini and colleagues (1981) compared 308 Seveso residents with 305 nonexposed residents from nearby towns. The authors found no increased risk of peripheral neuropathy among the exposed residents. However, within the subgroup of exposed subjects who showed clinical signs of significant exposure (chloracne or elevated hepatic enzymes) the risk ratio was 2.8 (CI 1.2-6.5). Similarly, for Seveso residents with known risk factors for peripheral neuropathy (alcoholism, diabetes, and inflammatory diseases) an elevated risk ratio was observed (2.6, CI 1.2-5.6).

The above-mentioned assessments of subacute morbidity have been complemented by reports of chronic follow-up. Twenty months after the explosion, Gilioli and colleagues (1979) examined 35 laboratory technicians working in the area of heavy TCDD contamination and 35 controls matched for age and sex. Electromyographic examinations resulted in statistically significant differences in some variables; the values for the exposed cases, however, were always within the range of published norms.

Focusing specifically on a subgroup of 193 subjects (88 percent were under 15 years of age) with chloracne, Assennato and colleagues (1989) performed follow-up electrophysiologic examinations in 1982-1983, 1983-1984, and 1985. The comparison group (individually matched by age and sex) was randomly selected from a nearby unexposed town. They did not observe an increased prevalence of abnormal findings in the exposed group at any point in the follow-up study, suggesting that whatever effects might have been seen after the Seveso accident were no longer distinctive between the two groups. Similarly, Barbieri and colleagues (1988) found that six years after the Seveso accident, there was no increased prevalence of peripheral neuropathy among 152 residents with chloracne or a history of lesions, compared to 123 age- and sex-matched unexposed control subjects.

The other major environmental study involved a self-selected group of Missouri residents living in areas sprayed with TCDD (Stehr et al., 1986; Webb et al., 1987). Exposure was based on TCDD soil measurements. A pilot study examined 68 subjects at high risk of exposure with potential exposure to 20-100 ppb of TCDD for at least two years, or levels greater than 100 ppb for at least six months. The low-risk comparison group was formed of 36 volunteers with little or no reported history of exposure to TCDD. No statistically significant differences in neurologic dysfunction were documented in the high-exposure patients, although the percentage of patients with abnormalities was higher in every neurologic test for that

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

group. Hoffman and colleagues (1986) found no clinical evidence for PNS damage in their study of 154 residents of the Quail Run mobile home park, one of the Missouri sites with extremely high TCDD levels. A group of 155 individuals residing for at least six months in another mobile home park with no TCDD contaminants in the soil formed the comparison group.

Vietnam Veterans Studies

The Air Force Health Study (1984) compared 1,208 Air Force Ranch Hands to a group of 1,238 Air Force personnel assigned to cargo missions in Southeast Asia. The groups were matched for age, race, and occupational codes. Assessments included neurologic symptom evaluation, physical examination, and nerve conduction velocity tests. No neurological differences were observed at follow-up between Ranch Hands and the comparison population when controlling for diabetes and alcohol consumption (AFHS, 1984; 1987). Peripheral and cranial nerve dysfunction was strongly correlated with alcohol consumption and serum glucose levels. There was no interaction between the records-based exposure index and peripheral nerve deficits in the earlier reports. The serum TCDD analysis did not produce evidence of an association between peripheral neuropathy and TCDD exposure (AFHS, 1991). The assessments, however, were restricted to questionnaires and physical examination data, and no electrophysiologic evaluations were performed.

To assess whether Vietnam service per se increased the risk of chronic peripheral neuropathy, the CDC (1988) evaluated 2,490 male Vietnam veterans serving one term of enlistment with a minimum of 16 weeks of active Vietnam duty and 1,972 non-Vietnam veterans. Symptom history, neurologic examination, nerve conduction velocity, thermal sensitivity, hearing acuity, and visual acuity were monitored. There were more symptoms of peripheral neuropathy reported among Vietnam veterans than among non-Vietnam veterans, but there was no increased objective evidence of peripheral neuropathy (CDC, 1988).

Summary of Peripheral Nervous System Disorders

Although many case reports suggest that an acute or subacute peripheral neuropathy can develop with exposure to TCDD and related chemicals, reports with comparison groups do not offer clear evidence that TCDD exposure is associated with chronic peripheral neuropathy. The most rigorously conducted studies argue against a relationship between TCDD or herbicides and chronic neuropathy.

As a group, the studies concerning peripheral neuropathy have been conducted with highly varying methodologies and have lacked uniformity of operational definitions of neuropathy. They have not applied consistent

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

methods to define a comparison population or to determine exposure or clinical deficits. Timing of follow-up may be important since many, but not all, reports that find neuropathy were short-term assessments (months after exposure). Careful definition of neuropathy and standardization of protocols will be essential to future evaluations.

Conclusions for Peripheral Nervous System Disorders

Strength of Evidence in Epidemiologic Studies

There is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides* (2,4-D; 2,4,5-T and its contaminant TCDD; cacodylic acid; and picloram) and disorders of the peripheral nervous system.

Biologic Plausibility

Studies in laboratory animals do not support an association between exposure to TCDD or herbicides and disorders of the peripheral nervous system.

Increased Risk of Disease Among Vietnam Veterans

Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the studies that have been reviewed and inadequate control for important confounders, it is not possible for the committee to quantify the degree of risk likely to be experienced by Vietnam veterans because of their exposure to herbicides in Vietnam.

NOTE

*  

The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components.

REFERENCES

Air Force Health Study (AFHS). 1984. Air Force Health Study (Project Ranch Hand II). 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-A138340. 362 pp.

Air Force Health Study. 1987. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. First Follow-Up Examination Results. Summary Report. Brooks AFB, TX: USAF School of Aerospace Medicine. USAFSAM-TR-87-36. NTIS PC A03/MF A01. 47 pp.

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Air Force Health Study. 1990. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 2 vols. Brooks AFB, TX: USAF School of Aerospace Medicine. USAFSAM-TR-90-2.

Air Force Health Study. 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. Vol. 3.

Alavanja MC, Merkle S, Teske J, Eaton B, Reed B. 1989. Mortality among forest and soil conservationists. Archives of Environmental Health 44:94-101.

Alderfer R, Sweeney M, Fingerhut M, Hornung R, Wille K, Fidler A. 1992. Measures of depressed mood in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Chemosphere 25:247-250.

American Psychiatric Association. 1987. Diagnostic and Statistical Manual of Mental Disorders (DSM-IIIR). 3rd ed. rev. Washington, DC: American Psychiatric Association.

Anderson HA, Hanrahan LP, Jensen M, Laurin D, Yick W-Y, Wiegman P. 1986. Wisconsin Vietnam Veteran Mortality Study: Proportionate Mortality Ratio Study Results. Madison, WI: Wisconsin Division of Health.

Andrews G, Tennant C, Brodaty H. 1981. The need for psychiatric care. Medical Journal of Australia 1:593-594.

Ashe WF, Suskind RR. 1950. Reports on Chloracne Cases. Nitro, WV: Monsanto Chemical Co.

Assennato G, Cervino D, Emmett EA, 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.

Baader EW, Bauer H. 1951. Industrial intoxication due to pentachlorophenol. Industrial Medicine and Surgery 20:286-290.

Barbeau A, Roy M, Langston JW. 1985. Neurological consequence of industrial exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (letter). Lancet 1(8431):747.

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.

Barr M. 1982. Neuropschiatric effects of herbicides. Australian and New Zealand Journal of Psychiatry 16:88-90.

Bashirov AA. 1969. The health of workers involved in the production of amine and butyl 2,4-D herbicides. Vrachebnoye Delo 10:92-95.

Becker MS. 1982. Level of sensory integrative functioning in children of Vietnam veterans exposed to Agent Orange. Occupational Therapy Journal of Research 2:234-244.

Berkley MC, Magee KR. 1963. Neuropathy following exposure to a dimethylamine salt of 2,4-D. Archives of Internal Medicine 111:133-134.

Bertazzi PA. 1991. Long-term effects of chemical disasters. Lessons and results from Seveso. Science of the Total Environment 106:5-20.

Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. 1989. Mortality in an area contaminated by TCDD following an industrial incident. Medicina Del Lavoro 80:316-329.

Blackburn AB. 1983. Review of the effects of Agent Orange: a psychiatric perspective on the controversy. Military Medicine 148:333-340.

Blum MD, Kelly EM, Meyer M, Carlson CR, Hodson WL. 1984. An assessment of the treatment needs of Vietnam-era veterans. Hospital and Community Psychiatry 35:691-696.

Boeri R, Bordo B, Crenna P, Filippini G, Massetto M, Zecchini A. 1978. Preliminary results of a neurological investigation of the population exposed to TCDD in the Seveso region. Rivista di Patologia Nervosa e Mentale 99:111-128.

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Bolla-Wilson K, Bleeker ML. 1986. The influence of verbal intelligence, gender, age, and education on the Rey Auditory Verbal Learning Test. Developmental Neuropsychology 2:203-211.

Bond GG, Cook RR, Brenner FE, McLaren EA. 1987. Evaluation of mortality patterns among chemical workers with chloracne. Chemosphere 16:2117-2121.

Bond GG, McLaren EA, Lipps TE, Cook RR. 1989. Update of mortality among chemical workers with potential exposure to the higher chlorinated dioxins. Journal of Occupational Medicine 31:121-123.

Boyle C, Decoufle P, Delaney RJ, DeStefano F, Flock ML, Hunter MI, Joesoef MR, Karon JM, Kirk ML, Layde PM, McGee DL, Moyer LA, Pollock DA, Rhodes P, Scally MJ, Worth RM. 1987. Postservice Mortality Among Vietnam Veterans. Atlanta: Centers for Disease Control. 143 pp. CEH 86-0076.

Breslin P, Kang H, Lee Y, Burt V, Shepard BM. 1988. Proportionate mortality study of U.S. Army and U.S. Marine Corps veterans of the Vietnam War. Journal of Occupational Medicine 30:412-419.

Bullman TA, Kang H, Thomas TL. 1991. Posttraumatic stress disorder among Vietnam veterans on the Agent Orange Registry: a case-control analysis. Annals of Epidemiology 1:505-512.

Centers for Disease Control (CDC). 1987. Postservice mortality among Vietnam veterans. Journal of the American Medical Association 257:790-795.

Centers for Disease Control. 1988. Health status of Vietnam veterans. II. Physical health. Journal of the American Medical Association 259:2708-2714.

Centers for Disease Control. 1989a. Comparison of Serum Levels of 2,3,7,8-Tetrachlorodibenzo-p-dioxin with Indirect Estimates of Agent Orange Exposure among Vietnam Veterans: Final Report. Atlanta: U.S. Department of Health and Human Services.

Centers for Disease Control. 1989b. Health Status of Vietnam Veterans. Vietnam Experience Study. Atlanta: U.S. Department of Health and Human Services. Vols. I-V, Supplements A-C.

Coggon D, Pannett B, Winter PD, Acheson ED, Bonsall J. 1986. Mortality of workers exposed to 2 methyl-4-chlorophenoxyacetic acid. Scandinavian Journal of Work, Environment, and Health 12:448-454.

Coggon D, Pannett B, Winter P. 1991. Mortality and incidence of cancer at four factories making phenoxy herbicides. British Journal of Industrial Medicine 48:173-178.


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

Dudley AW, Thapar NT. 1972. Fatal human ingestion of 2,4-D, a common herbicide. Archives of Pathology 94:270-275.


Eisen S, Goldberg J, True WR, Henderson WG. 1991. A co-twin control study of the effects of the Vietnam war on the self-reported physical health of veterans. American Journal of Epidemiology 134:49-58.

Evatt P. 1985. Royal Commission on the Use and Effect of Chemical Agents on Australian Personnel in Vietnam, Final Report. Canberra: Australian Government Publishing Service. 9 vols.


Farberow N, Kang H, Bullman T. 1990. Combat Experience and Postservice Psychosoical Status as Predictors of Suicide in Vietnam Veterans. The Journal of Nervous and Mental Disease 178(1):32-37.

Ferraz HB, Bertolucci PHF, Periera JS, Lima JG, Andrade LA. 1988. Chronic exposure to the fungicide maneb may produce symptoms and signs of CNS manganese intoxication. Neurology 38:550-553.

Fett MJ, Nairn JR, Cobbin DM, Adena MA. 1987. Mortality among Australian conscripts of

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

the Vietnam conflict era . II. Causes of death. American Journal of Epidemiology 125:878-884.

Fiedler N, Gochfeld M. 1992. Neurobehavioral Correlates of Herbicide Exposure in Vietnam Veterans. New Jersey Agent Orange Commission, Pointman Project.

Filippini G, Bordo B, Crenna P, Massetto N, Musicco M, Boeri R. 1981. Relationship between clinical and electrophysiological findings and indicators of heavy exposure to 2,3,7,8-tetrachlorodibenzodioxin. Scandinavian Journal of Work, Environment, and Health 7:257-262.

Fingerhut MA, Halperin WE, Marlow DA, Piacitelli LA, Honchar PA, Sweeney MH, Greife AL, Dill PA, Steenland K, Suruda AJ. 1991. Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. New England Journal of Medicine 324:212-218.

Friesen EG, Jones GR, Vaughan D. 1990. Clinical presentation and management of acute 2,4-D oral ingestion. Drug Safety 5:155-159.

Gilioli R, Cotroneo L, Bulgheroni C, Genta PA, Rota E, Cannatelli P, Fereari E. 1979. Neurological monitoring of workers exposed to TCDD: preliminary neurophysiological results. Activitas Nervosa Superior 21:288-290.

Goldberg J, True WR, Eisen SA, Henderson WG. 1990. A twin study of the effects of the Vietnam war on posttraumatic stress disorder. Journal of the American Medical Association 263:1227-1232.

Goldman PJ. 1973. Most severe acute chloracne, a mass intoxication caused by 2,3,6,7-tetrachlorodibenzodioxin. Hautarzt 24:149-152.

Goldstein NP, Jones PH, Brown JR. 1959. Peripheral neuropathy after exposure to an ester of dichlorophenoxyacetic acid. Journal of the American Medical Association 171:1306-1309.

Grcevic N, Jadro-Santel J, Jukic S. 1977. Cerebral changes in paraquat poisoning. In: Roizin L, Shiraki H, Grcevic N, eds. Neurotoxicology. New York: Raven Press. 469-484.

Green LM. 1987. Suicide and exposure to phenoxy acid herbicides. Scandinavian Journal of Work, Environment, and Health 13:460.

Green LM. 1991. A cohort mortality study of forestry workers exposed to phenoxy acid herbicides. British Journal of Industrial Medicine 48:234-238.

Green RL. 1980. The MMPI: An Interpretive Manual. Orlando: Grune and Stratton.


Hall W. 1986. The Agent Orange controversy after the Evatt Royal Commission. Medical Journal of Australia 145:219-225.

Hall W, Macphee D. 1985. Do Vietnam veterans suffer from toxic neurasthenia? Australian and New Zealand Journal of Psychiatry 19:19-29.

Ho SC, Woo J, Lee CM. 1989. Epidemiologic study of Parkinson's disease in Hong Kong. Neurology 39:1314-1318.

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 255:2031-2038.


Jimenez-Jimenez FJ, Mateo D, Gimenez-Rolan S. 1992. Exposure to well water and pesticides in Parkinson's disease: a case-control study in the Madrid area. Movement Disorders 7:149-152.

Jirasek L, Kalensky K, Kubec K, Pazderova J, Lukas E. 1974. Chronic poisoning by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Ceskoslovenska Dermatologie 49:145-157.


Kimmig J, Schulz KH. 1957. Occupational chloracne caused by aromatic cyclic ethers. Dermatologica 115:540-546.

Klawans HL. 1987. Dystonia and tremor following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Movement Disorders 2:255-261.

Kogan MD, Clapp RW. 1985. Mortality Among Vietnam Veterans in Massachusetts, 1972-1983. Massachusetts Office of the Commissioner of Veterans Services, Agent Orange Program.

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Kulka RA, Schlenger WE, Fairbank JA, Hough RL, Jordan BK, Marmar CR, Weiss DS. 1988. Contractual Report of Findings from the National Vietnam Veterans Readjustment Study. Research Triangle Park, NC: Research Triangle Institute. Conducted for the Veterans Administration under contract number V101(93)P-1040.

Langston JW, Ballard PA. 1983. Parkinson's disease in a chemist working with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (letter). New England Journal of Medicine 309:310.

Langston JW, Ballard PA, Tetrud JW, Irwin I. 1983. Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979-980.

Lawrence CE, Reilly AA, Quickenton P, Greenwald P, Page WF, Kuntz AJ. 1985. Mortality patterns of New York State Vietnam veterans. American Journal of Public Health 75:277-279.

Levy CJ. 1988. Agent Orange exposure and posttraumatic stress disorder. Journal of Nervous and Mental Disorders 176:242-245.


Manz A, Berger J, Dwyer JH, Flesch-Janys D, Nagel S, Waltsgott H. 1991. Cancer mortality among workers in chemical plant contaminated with dioxin. Lancet 338:959-964.

Moses M, Lilis R, Crow KD, Thornton J, Fischbein A, Anderson HA, Selikoff IJ. 1984. Health status of workers with past exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in the manufacture of 2,4,5-trichlorophenoxyacetic acid: comparison of findings with and without chloracne. American Journal of Industrial Medicine 5:161-182.


Nielsen K, Kaempe B, Jensen-Holm J. 1965. Fatal poisoning in man by 2,4-D. Acta Pharmacologica et Toxicologica 22:224-234.

Oliver RM. 1975. Toxic effects of 2,3,7,8 tetrachlorodibenzo 1,4-dioxin in laboratory workers. British Journal of Industrial Medicine 32:49-53.


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.

Peters HA, Levine RL, Matthews CG, Chapman LJ. 1988. Extrapyramidal and other neurologic manifestations associated with carbon disulfide fumigant exposure . Archives of Neurology 45:5376-5380.

Pocchiari F, Silano V, Zampieri A. 1979. Human health effects from accidental release of tetrachlorodibenzo-p-dioxin (TCDD) at Seveso, Italy. Annals of the New York Academy of Sciences 320:311-320.

Poland AP, Smith D, Metter G, Possick P. 1971. A health survey of workers in a 2,4-D and 2,4,5-T plant. Archives of Environmental Health 22:316-327.


Rellahan W. 1985. Aspects of the Health of Hawaii's Vietnam-Era Veterans. Honolulu: Hawaii State Department of Health, Research and Statistics Office.


Seabury JH. 1963. Toxicity of 2,4-dichlorophenoxyacetic acid. Archives of Environmental Health 7:202-209.

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

Sharp DS, Eskenazi B, Harrison R, Callas P, Smith AH. 1986. Delayed health hazards of pesticide exposure . Annual Reviews of Public Health 7:441-471.

Singer R, Moses M, Valciukas J, Lilis R, Selikoff IJ. 1982. Nerve conduction velocity studies of workers employed in the manufacture of phenoxy herbicides. Environmental Research 29:297-311.

Snow BR, Stellman JM, Stellman SD, Sommer JF. 1988. Posttraumatic stress disorder among American Legionnaires in relation to combat experience in Vietnam: associated and contributing factors. Environmental Research 47:175-192.

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 41:16-22.

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Stehr-Green PA, Hoffman R, Webb K, Evans RG, Knutsen A, Schramm W, Staake J, Gibson B, Steinberg K. 1987. Health effects of long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Chemosphere 16:2089-2094.

Suskind RR, Hertzberg VS. 1984. Human health effects of 2,4,5-T and its toxic contaminants. Journal of the American Medical Association 251:2372-2380.

Sweeney MH, Fingerhut MA, Arezzo JC, Hornung RW, Connally LB. In press. Peripheral neuropathy after occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Tanner CM. 1989. The role of environmental toxins in the etiology of Parkinson's disease. Trends in Neuroscience 12:49-54.

Thomas TL. 1987. Mortality among flavor and fragrance chemical plant workers in the United States. British Journal of Industrial Medicine 44:733-737.

Todd RL. 1962. A case of 2,4-D intoxication. Journal of the Iowa Medical Society 52:663-664.

True WR, Goldberg J, Eisen SA. 1988. Stress symptomatology among Vietnam veterans. Analysis of the Veterans Administration Survey of Veterans II. American Journal of Epidemiology 128:85-92.


Vyner HM. 1988. The psychological dimensions of health care for patients exposed to radiation and other invisible environmental contaminants. Social Science and Medicine 27:1097-1103.


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 11:685-691.

Webb KB, Evans RG, Knutsen AP, Roodman ST, Roberts DW, Schramm WF, Gibson BB, Andrews JS Jr, Needham LL, Patterson DG. 1989. Medical evaluation of subjects with known body levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of Toxicology and Environmental Health 28:183-193.

Wendt AS. 1985. Iowa Agent Orange Survey of Vietnam Veterans. Iowa State Department of Health.

Wolfe WH, Lathrop GD, Albanese RA, Moynahan PM. 1985. An epidemiologic investigation of health effects in Air Force personnel following exposure to herbicides and associated dioxins. Chemosphere 14:707-716.

Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 640
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 641
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 642
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 643
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 644
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 645
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 646
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 647
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 648
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 649
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 650
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 651
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 652
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 653
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 654
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 655
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 656
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 657
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 658
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 659
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 660
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 661
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 662
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 663
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 664
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 665
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 666
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 667
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 668
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 669
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 670
Suggested Citation:"10 Neurobehavioral Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×
Page 671
Next: 11 Other Health Effects »
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam Get This Book
×
Buy Paperback | $225.00
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

Have U.S. military personnel experienced health problems from being exposed to Agent Orange, its dioxin contaminants, and other herbicides used in Vietnam? This definitive volume summarizes the strength of the evidence associating exposure during Vietnam service with cancer and other health effects and presents conclusions from an expert panel.

Veterans and Agent Orange provides a historical review of the issue, examines studies of populations, in addition to Vietnam veterans, environmentally and occupationally exposed to herbicides and dioxin, and discusses problems in study methodology. The core of the book presents

  • What is known about the toxicology of the herbicides used in greatest quantities in Vietnam.
  • What is known about assessing exposure to herbicides and dioxin.
  • What can be determined from the wide range of epidemiological studies conducted by different authorities.
  • What is known about the relationship between exposure to herbicides and dioxin, and cancer, reproductive effects, neurobehavioral disorders, and other health effects.

The book describes research areas of continuing concern and offers recommendations for further research on the health effects of Agent Orange exposure among Vietnam veterans.

This volume will be critically important to both policymakers and physicians in the federal government, Vietnam veterans and their families, veterans organizations, researchers, and health professionals.

  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!