high- and low-exposure demonstrated multiple neuropsychological changes, including self-reports of memory problems, distractibility, irritability, and fatigue, and objective changes in verbal conceptualization skills, mnestic organization, and psychomotor activity. On the Trail-Making Test, which measures visual exploration speed, deficits correlated with TCDD tissue levels. Combined high-and low-exposure groups, however, deviated only slightly from published norms, with no significant differences. The limitations of this study include the small number of subjects (N = 19), the lack of an external control group, and the low estimated amount of exposure. Moreover, there may have been a selection bias in the sample. In consequence, the significance of these findings to the topic of cognitive and neuropsychiatric dysfunction is uncertain.

Decoufle et al. (1992) studied a large sample of Vietnam veterans whose exposure to herbicides was determined by subject reports without confirmation. Reports of psychological dysfunction including posttraumatic stress disorder correlated with self-reports of combat exposure and level of herbicide exposure. The shortcomings of this study are reported in the discussion below on peripheral neuropathy.

Zober et al. (1994) reported the health outcomes in 158 men exposed to TCDD in a factory accident in Germany. Illness episodes handled by hospitalization or outpatient care related to "mental disorders" correlated with severity of chloracne, but not with TCDD blood levels. It is not known whether chloracne documentation close to the time of exposure or TCDD levels many years after exposure represents the better index of actual TCDD exposure. Therefore, it is difficult to draw specific conclusions concerning the relationship between TCDD exposure and mental disorders based on these disparate findings.

In a large mortality study of Vietnam-era veterans in Michigan, proportional mortality ratios were significantly lower for veterans who served in Vietnam than for veterans serving elsewhere for the disease categories of "mental disorders" (not specifically defined) and disorders of "nervous system and sense organs" (Visintainer et al., 1995). The authors did not attempt to separate subjects exposed to herbicides, and they acknowledged that no conclusions could be made in regarding to the specific toxicity of TCDD or Agent Orange. Although some additional publications have appeared on the effect of military service in Vietnam on psychological health outcomes, including PTSD, these reports did not assess the effects of herbicide exposure (Goldberg et al., 1992; Bullman and Kang, 1994).

Conclusions

Strength of Evidence in Epidemiologic Studies

There is inadequate or insufficient evidence of an association between exposure to the herbicides considered in this report and cognitive or neuropsychiatric



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--> high- and low-exposure demonstrated multiple neuropsychological changes, including self-reports of memory problems, distractibility, irritability, and fatigue, and objective changes in verbal conceptualization skills, mnestic organization, and psychomotor activity. On the Trail-Making Test, which measures visual exploration speed, deficits correlated with TCDD tissue levels. Combined high-and low-exposure groups, however, deviated only slightly from published norms, with no significant differences. The limitations of this study include the small number of subjects (N = 19), the lack of an external control group, and the low estimated amount of exposure. Moreover, there may have been a selection bias in the sample. In consequence, the significance of these findings to the topic of cognitive and neuropsychiatric dysfunction is uncertain. Decoufle et al. (1992) studied a large sample of Vietnam veterans whose exposure to herbicides was determined by subject reports without confirmation. Reports of psychological dysfunction including posttraumatic stress disorder correlated with self-reports of combat exposure and level of herbicide exposure. The shortcomings of this study are reported in the discussion below on peripheral neuropathy. Zober et al. (1994) reported the health outcomes in 158 men exposed to TCDD in a factory accident in Germany. Illness episodes handled by hospitalization or outpatient care related to "mental disorders" correlated with severity of chloracne, but not with TCDD blood levels. It is not known whether chloracne documentation close to the time of exposure or TCDD levels many years after exposure represents the better index of actual TCDD exposure. Therefore, it is difficult to draw specific conclusions concerning the relationship between TCDD exposure and mental disorders based on these disparate findings. In a large mortality study of Vietnam-era veterans in Michigan, proportional mortality ratios were significantly lower for veterans who served in Vietnam than for veterans serving elsewhere for the disease categories of "mental disorders" (not specifically defined) and disorders of "nervous system and sense organs" (Visintainer et al., 1995). The authors did not attempt to separate subjects exposed to herbicides, and they acknowledged that no conclusions could be made in regarding to the specific toxicity of TCDD or Agent Orange. Although some additional publications have appeared on the effect of military service in Vietnam on psychological health outcomes, including PTSD, these reports did not assess the effects of herbicide exposure (Goldberg et al., 1992; Bullman and Kang, 1994). Conclusions Strength of Evidence in Epidemiologic Studies There is inadequate or insufficient evidence of an association between exposure to the herbicides considered in this report and cognitive or neuropsychiatric

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--> disorders. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Motor/Coordination Dysfunction Summary of VAO In VAO, the committee was concluded that there are no definitive studies to determine whether exposure to dioxin or related herbicides is associated with CNS motor/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. It was determined that longitudinal assessments of motor and coordination problems are warranted in exposed subjects, especially those with high exposure, such as the National Institute for Occupational Safety and Health cohort studied by Fingerhut et al. (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 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 accepted scales for movement disorders have been developed, and these scales should be used in future studies of such problems. In addition to assessments that capture the disability related to any objective findings, VAO also stressed that in the past decade an increasing concern—unrelated specifically to the question of TCDD and the CNS—has developed scientifically over the possible link between Parkinson's disease and chemicals used as herbicides and pesticides (Semchuk et al., 1992). It was suggested that as Vietnam veterans move into the decades when Parkinson's disease becomes more prevalent, attention to the frequency and character of new cases in exposed versus nonexposed individuals may be highly useful in assessing whether dioxin exposure is a risk factor for eventual Parkinson's disease. Update of the Scientific Literature No new data directly addressing this topic have been published since VAO. There is, however, a persisting concern about the role of herbicides and pesticides in the pathogenesis of parkinsonism (Semchuk et al., 1993; Butterfield et al., 1993; Golbe, 1993). Using multivariate statistical methods, occupational herbicide use was the third highest predictor of eventual Parkinson's disease risk in the study by Semchuk et al. (1993). Butterfield et al. (1993) examined occupational and environmental factors associated with disease risk in patients with early-onset Parkinson's disease, comparing the findings to a control group. Parkinson's

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--> disease was positively associated with herbicide exposure, insecticide exposure, previous residence in a fumigated house, and residence in a rural area at the time of diagnosis. The authors did not specify the type of herbicide or pesticide, so direct extrapolation to the agents used in Vietnam is not possible. Cases of early-onset parkinsonism are particularly important to testing the hypothesis that the disease relates to a toxic exposure. Patients in this category would presumably have received a heavier dose of toxin than those who developed the disorder at a more typical age in later life. For this reason, the systematic and prospective examination of Vietnam veterans for the development of early-onset parkinsonism assumes particular medical and scientific importance. Conclusions Strength of Evidence in Epidemiologic Studies There is inadequate or insufficient evidence of an association between exposure to the herbicides considered in this report and motor/coordination dysfunction. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Chronic Persistent Peripheral Neuropathy Summary of VAO Although some of the case reports reviewed in VAO suggested that an acute or subacute peripheral neuropathy can develop with exposure to TCDD and related products, other reports with comparison groups did not offer clear evidence that TCDD exposure is associated with chronic peripheral neuropathy. The most rigorously conducted studies argued against a relationship between TCDD or herbicides and chronic persistent 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 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 based on assessments made only a short time after exposure. It was concluded that careful definition of neuropathy and standardization of protocols will be essential to future evaluations. Update of the Scientific Literature Several articles on this topic have appeared since VAO. Decoufle et al.

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--> (1992) compared the self-reported health of 7,924 Vietnam veterans in 1985-86 with their perceived exposure to herbicides and combat in Vietnam. When a subset of subjects was examined neurologically, there was no correlation between the herbicide exposure index used and the occurrence of peripheral neuropathy. The exposure index depended entirely on the subjects' reports and no confirmatory documentation or blood levels of TCDD were obtained. In light of prior studies (CDC, 1988, 1989) that documented no relationship between this self-reported herbicide exposure index and a biological marker of actual dioxin exposure among Vietnam veterans, this study neither confirmed nor refuted a relationship between neuropathy and dioxin exposure among Vietnam veterans. The authors, however, suggested that emotional stress could account for the excessive self-reported symptoms, since complaints were widespread across many body systems, were often vague in quality, and involved many more subjects than were estimated to have been actually exposed to high levels of dioxin. In the study by Zober et al. (1994), the data were originally thought to suggest an increase in prevalence of disorders of the peripheral nervous system and sense organs. However, reanalysis demonstrated that there was only one case of peripheral neuropathy in the severe chloracne subgroup, and this patient was diabetic, which is a condition also associated with peripheral neuropathy. Their findings are consistent with others who found no evidence of increased occurrence of chronic persistent peripheral neuropathy after TCDD exposure. Conclusions Strength of Evidence in Epidemiologic Studies There is inadequate or insufficient evidence of an association between exposure to the herbicides considered in this report and chronic persistent peripheral neuropathy. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Acute And Subacute Transient Peripheral Neuropathy The methodology used to establish associations between putative causal agents and persistent chronic neurological deficits relies heavily on epidemiological studies with adequate control or comparison populations. Such methodology can rarely be set in motion with sufficient speed to assess relationships between unexpected chemical exposure and the development of acute or subacute transient neurological disturbance. Because of the very transient nature of the conditions, documenting signs and symptoms in association with documented exposures can be difficult to accomplish in a systematic manner. In such instances,

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--> greater reliance must be placed on isolated case histories and less well controlled studies. This section reviews the data from such sources regarding occupational, environmental, and Vietnam herbicide exposure. Because this disorder is of special interest to the DVA, this discussion integrates the studies reviewed in VAO with those published more recently. Review of the Scientific Literature Occupational Studies A 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; Goldstein et al., 1959; Todd, 1962; Berkley and Magee, 1963; Poland et al., 1971; Jirasek et al., 1974). However, only a very limited number of studies on the PNS provide any control or comparison group data. Since peripheral neuropathies can be induced by such common medical and environmental conditions 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, although especially important in the analysis of peripheral neuropathies, are not available for the topic of acute and subacute neuropathies. The studies cited below provide suggestive but limited evidence of the concept that acute or subacute peripheral neuropathy can develop after exposure to dioxin or related compounds. Todd (1962) reported a sprayer of 2,4-D weedkiller who developed a gastrointestinal disturbance and, within days, a severe sensory/motor polyneuropathy after contact with the chemical. Recovery occurred gradually over the ensuing months. Berkley and Magee (1963) reported another patient who developed a polyneuropathy four days after exposure to a liquid solution of 2,4-D, which was being sprayed in a cornfield. The neuropathy was purely sensory in type. His symptoms gradually resolved over months. Goldstein et al. (1959) described three patients who had sensory/motor polyneuropathies that developed over several days and progressed over several weeks after exposure to 2,4-D. All had incomplete recovery after several years. Although these patients were not examined neurologically before their exposure, the temporal relationship between the development of their clinical problem and the herbicide exposure was clearly documented. Nonetheless, the possibility that their occurrence was unrelated to the herbicide exposure and represented examples of other disorders, such as idiopathic Guillain-Barre syndrome, cannot be entirely excluded. Environmental Studies After the Seveso, Italy, chemical explosion, inhabitants from the high exposure zone were evaluated for signs and symptoms of peripheral nerve disease and compared with inhabitants of a lower exposure zone. No information is available on acute transient neuropathic effects, since the first

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--> reports documented findings in patients evaluated more than six months after the disaster. Boeri et al. (1978) conducted clinical and neurophysiological examination of the peripheral nerves 7 to 11 months after the explosion and reported descriptive differences between 470 volunteer subjects in Zone A (high exposure group) and 152 volunteer residents of Zone R (low-exposure group). Peripheral nerve problems were frequent in both groups, suggesting to the authors that undefined neuropathic factors predating the explosion may well have been responsible for their findings. Although cranial and peripheral nerve problems were generally more prevalent among the highly exposed group, no statistical analyses were performed on the prevalence data. The electrophysiological studies failed to show any significant abnormalities in either group. As a complement to the above screening in the first year after exposure, Pocchiari et al. (1979) echoed the observation that neuropathic symptoms were more prevalent in the high exposure group. No new data were provided. Reporting on symptoms and signs in patients examined eight or more months after the accident, Filippini et al. (1981) compared 308 Seveso residents with 305 nonexposed residents from nearby towns. They examined patients clinically and electrophysiologically, using strict physiological criteria for defining peripheral neuropathy. The authors found no increased risk of "acute" 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 other risk factors for peripheral neuropathy (alcoholism, diabetes, and inflammatory diseases), an elevated risk ratio was also observed (2.6, CI = 1.2-5.6). The authors argued that heavy exposure to dioxin was associated with mild peripheral neuropathy in this two year follow-up report. Subsequent follow-up studies suggested that there was no increased prevalence of peripheral neuropathy several years after the accident among the high-risk Seveso group (Barbieri et al., 1988; Assennato et al., 1989). Vietnam Veterans Studies The committee has identified no data on acute or subacute neuropathies related to herbicide exposure in Vietnam. All published data concern chronic effects. Summary of Acute and Subacute Transient Peripheral Neuropathy There is some evidence to suggest that neuropathy of acute or subacute onset may be associated with herbicide exposure. This is based primarily on case histories from occupational exposure and the descriptive reports following the Seveso accident. The trend to recovery in the individual cases reported and the negative findings of many long-term follow-up studies of peripheral neuropathy