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.



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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 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.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 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

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 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.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 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

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 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

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 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

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 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

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 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

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 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

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 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

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 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

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 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.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 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,

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 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

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 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

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 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

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 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.

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