10
Neurobehavioral Disorders

BACKGROUND

The nervous system is made up of a central portion—the central nervous system (CNS)—that consists of the brain and spinal cord, and the peripheral nervous system (PNS), which includes the nerve roots, the brachial and lumbar plexuses, and the peripheral nerves that pass to the extremities. The peripheral nerves are responsible for innervating the muscles and also are made up of afferent fibers that convey sensory information to the CNS. In addition, they contain autonomic fibers that regulate the activity of the heart, blood vessels, sweat glands, bladder, and bowels.

Disturbances of the CNS may lead to neurobehavioral abnormalities such as cognitive changes and neuropsychiatric disorders. Other disturbances related to CNS dysfunction include abnormalities of sensation, weakness, tremors, incoordination, and the development of abnormal movements.

Disturbances of the PNS lead to peripheral neuropathy. Peripheral neuropathy is an imprecise term that includes the symmetric involvement of numerous nerves in the extremities (polyneuropathy) or the selective involvement of one or several individual peripheral nerves (mononeuropathy simplex or multiplex). It is sometimes used to refer to pathology affecting the nerve roots, which emerge from the spinal cord and have branches that ultimately form the nerves to the extremities. Chronic peripheral neuropathy may occur for many different reasons; it varies in its pathology and severity in different cases. It may be a feature of a number of common general medical disorders, especially diabetes mellitus.

Numerous publications have addressed the neurotoxicity of herbicides and pesticides. Such reports have been based on studies related to occupational, environmental, or Vietnam veteran exposure. In Veterans and Agent Orange: Health



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Veterans and Agent Orange: Update 1998 10 Neurobehavioral Disorders BACKGROUND The nervous system is made up of a central portion—the central nervous system (CNS)—that consists of the brain and spinal cord, and the peripheral nervous system (PNS), which includes the nerve roots, the brachial and lumbar plexuses, and the peripheral nerves that pass to the extremities. The peripheral nerves are responsible for innervating the muscles and also are made up of afferent fibers that convey sensory information to the CNS. In addition, they contain autonomic fibers that regulate the activity of the heart, blood vessels, sweat glands, bladder, and bowels. Disturbances of the CNS may lead to neurobehavioral abnormalities such as cognitive changes and neuropsychiatric disorders. Other disturbances related to CNS dysfunction include abnormalities of sensation, weakness, tremors, incoordination, and the development of abnormal movements. Disturbances of the PNS lead to peripheral neuropathy. Peripheral neuropathy is an imprecise term that includes the symmetric involvement of numerous nerves in the extremities (polyneuropathy) or the selective involvement of one or several individual peripheral nerves (mononeuropathy simplex or multiplex). It is sometimes used to refer to pathology affecting the nerve roots, which emerge from the spinal cord and have branches that ultimately form the nerves to the extremities. Chronic peripheral neuropathy may occur for many different reasons; it varies in its pathology and severity in different cases. It may be a feature of a number of common general medical disorders, especially diabetes mellitus. Numerous publications have addressed the neurotoxicity of herbicides and pesticides. Such reports have been based on studies related to occupational, environmental, or Vietnam veteran exposure. In Veterans and Agent Orange: Health

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Veterans and Agent Orange: Update 1998 TABLE 10-1 Selected Neurobehavioral Studies of Herbicide Exposure Reference Study Group Tests of Neurological Dysfunction Exposure Measures Comparison Group OCCUPATIONAL Zober et al., 1994 158 German BASF employees Medical record review Chloracne and TCDD levels 161 reference comparisons Berkley and Magee, 1963 1 farmer Neurological examination No None Todd, 1962 1 weed-sprayer Neurological examination No None Goldstein et al., 1959 2 farmers Neurological examination No None   1 book-keeper EMG     Baader and Bauer, 1951 10 pentachlorophenol plant workers Record review clinical evaluation No None ENVIRONMENTAL Peper et al., 1993 19 German residents exposed to 2,3,7,8-TCDD Neuropsychological battery and symptom questionnaires Serum TCDD None VIETNAM VETERANS Visintainer et al., 1995 151,377 Michigan veterans who served in Vietnam No: mortality data only No 225,651 Non-Vietnam veterans Decoufle et al., 1992 7,924 veterans Self-report with neurological examinations in a subset Self-report 7,364 Non-Vietnam veterans

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Veterans and Agent Orange: Update 1998 Effects of Herbicides Used in Vietnam (henceforth called VAO) (IOM, 1994), attention was focused particularly on persistent neurobehavioral dysfunction. In Veterans and Agent Orange: Update 1996 (henceforth called Update 1996) (IOM, 1996), attention was also directed at the occurrence of acute and subacute peripheral neuropathy, and earlier data relating to that aspect were reexamined. In the present report, at the specific request of the Department of Veteran Affairs, the possibility of chronic peripheral neuropathy developing in Vietnam veterans as a consequence of herbicide exposure has been reconsidered. COGNITIVE AND NEUROPSYCHIATRIC EFFECTS Summary of VAO and Update 1996 In VAO, the committee concluded that the literature was insufficient to determine whether an association existed between exposure to herbicides and related compounds and chronic cognitive or neuropsychiatric disorders. As suggested by Sharp et al. (1986), the delayed effects of such exposures 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 was no shortage of studies concerning this topic, methodologic problems made it difficult to reach definitive conclusions. Shortcomings in defining exposure included absent or poor exposure assessments; inconsistencies in identifying exposed individuals for study (i.e., some studies relied on the presence of chloracne for inclusion, whereas others assumed that all subjects had been exposed); and concomitant exposure to different chemicals, mixtures of chemicals, or concentrations of chemicals. 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. The committee noted that in order to maximally define the direct effects of dioxin on cognitive and neuropsychiatric function, future studies should focus primarily on occupationally exposed groups for whom levels of exposure are better known and should include neurobehavioral testing in relative proximity to the time of exposure. VAO also concluded that significantly exposed subjects should be followed for the development of neuropsychological dysfunction in middle and later life. It is possible that minor CNS changes acquired in early adulthood are too subtle to be detected by current neuropsychological testing methods, but they could manifest themselves later when compounded by ''normal age-related changes" of the CNS. Theoretically, exposure to neurotoxins could produce "accelerated aging" of the brain due to premature neuronal loss, which could then result in neurobehavioral deficits.

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Veterans and Agent Orange: Update 1998 In Update 1996, the committee reviewed the several publications that had appeared since the original report, concluding that there was still inadequate or insufficient evidence from occupational and other studies of any association between exposure to the herbicides under consideration and cognitive or neuropsychiatric disorders. Update of the Scientific Literature In a report from Australia, O'Toole et al. (1996) analyzed the self-reported psychiatric states of Vietnam veterans as determined 20-25 years after the war. It was found that the veterans had higher prevalences than the civilian population of alcohol abuse or dependence, posttraumatic stress disorder, and social and simple phobias. This related to combat rather than posting to a combat unit. No attempt was made in the report to relate these behavioral disorders to herbicide exposure. We are aware of no other new studies since the last report that have provided any further evidence of an association between herbicide exposure and cognitive or neuropsychiatric dysfunction. MOTOR/COORDINATION DYSFUNCTION Summary of VAO and Update 1996 In VAO, the committee concluded that there were no definitive studies to determine whether exposure to dioxin or related herbicides was associated with CNS motor/coordination problems. However, follow-up of veterans and, to a lesser extent, environmental observations suggested that motor and coordination difficulties should be assessed further in exposed subjects. It was determined that longitudinal assessments of motor and coordination problems were 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 (2,3,7,8-tetrachlorodibenzo-p-dioxin) 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

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Veterans and Agent Orange: Update 1998 versus nonexposed individuals may be highly useful in assessing whether dioxin exposure is a risk factor for eventual Parkinson's disease. In Update 1996 it was noted that no new data relating to this topic had been published. Nevertheless, it was pointed out that concern persisted about the role of herbicides and pesticides in the pathogenesis of parkinsonism. For example, Semchuk et al. (1993) had noted following multivariate statistical analysis that occupational herbicide use was the third highest predictor of eventual Parkinson's disease risk. Similarly, Butterfield et al. (1993) examined occupational and environmental factors associated with disease risk in patients with early-onset Parkinson's disease and found that the 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 committee emphasized the importance of cases of early-onset parkinsonism in testing the hypothesis that the disease relates to a toxic exposure, and pointed to the particular medical and scientific importance of a systematic and prospective study of Vietnam veterans for the development of early-onset parkinsonism. Update of the Scientific Literature As far as this committee is aware, no new studies relating directly to this aspect have been published. However, Schulte et al. (1996) examined the death certificates from 27 states in the National Occupational Mortality Surveillance System and calculated proportional mortality ratios by occupation for certain neurodegenerative disorders. They found an increase in proportionate mortality ratio for Parkinson's disease among male pesticide applicators, horticultural farmers, farm workers, and graders and sorters of agricultural products. Similarly, in Taiwan, an increased risk of Parkinson's disease has been found among those using paraquat and other herbicides and pesticides (Liou et al., 1997). This was a case-control study in which 120 patients with Parkinson's disease were age-and sex-matched with 240 controls, and data were then obtained on demographic and residential history and on potential exposure to occupational and environmental agents. In Germany significantly elevated odds ratios with pesticide exposure have been noted among patients with Parkinson's disease (Seidler et al., 1996). The implications of these studies for the health of Vietnam veterans are unclear. Such reports underscore the importance of a prospective study of Vietnam veterans for the development of parkinsonism. CHRONIC PERSISTENT PERIPHERAL NEUROPATHY Summary of VAO and Update 1996 Although some of the case reports reviewed in VAO suggested that an acute or subacute peripheral neuropathy can develop with exposure to TCDD and

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Veterans and Agent Orange: Update 1998 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 uniform 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. In Update 1996 it was noted that several new articles had appeared on this topic related to occupational and other studies. Careful analysis, however, showed there to be inadequate or insufficient evidence of any association between exposure to the herbicides under consideration and the development of chronic persistent peripheral neuropathy. Update of the Scientific Literature No new information has appeared in the intervening two years that alters this conclusion. It is important, however, to review the context in which this conclusion was reached. Synthesis There have been only a limited number of epidemiologic studies of chronic peripheral neuropathy, except for the neuropathy associated with diabetes. A recent study from Europe estimated that a chronic symmetric polyneuropathy occurs in about 8 percent of people over the age of 55 years with a severity that is sufficient to lead to symptoms of the disorder (Italian General Practitioner Study Group, 1995). Prevalence studies of peripheral neuropathy performed both in Asia and in Europe also suggest that peripheral neuropathy is common, occurring in between 2 and 7 percent of the population. In the United States, the most common cause of chronic peripheral neuropathy is diabetes. Several types of peripheral neuropathy are associated with diabetes, including a predominantly sensory polyneuropathy, an asymmetric proximal neuropathy, involvement of individual cranial or limb nerves, and an autonomic neuropathy. In one study it was found that approximately 4 percent of diabetic patients develop a neuropathy within 5 years of diagnosis and 15 percent do so within 20 years (Palumbo et al., 1978). More recent population studies or studies of clinical case

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Veterans and Agent Orange: Update 1998 series suggest that the prevalence of neuropathy is even higher among diabetic patients. Thus, in one study of insulin-dependent diabetic patients, the overall prevalence of distal polyneuropathy was 34 percent, and this increased to 58 percent in patients who were aged 30 years or more (Maser et al., 1989). In diabetics who are not dependent upon insulin, evidence of peripheral sensory loss has been found in 26 percent of instances (Franklin et al., 1990). A study from Finland in 1995 has indicated that among non-insulin-dependent diabetic subjects, 8 percent satisfied criteria for definite or probable neuropathy at the time of diagnosis; after a 10-year follow-up period, the prevalence of neuropathy had increased to 42 percent in the diabetic patients, compared to 6 percent in control subjects (Partanen et al., 1995). Among the factors that relate to the development of neuropathy in diabetics are the duration of the disease and the extent to which the blood glucose level is controlled (Orchard et al., 1990; DCCT Research Group, 1995). Further reference to diabetes can be found in Chapter 11. The peripheral nerves are vulnerable to a number of toxic substances including some of the heavy metals such as lead, arsenic, and thallium; certain organic solvents such as n-hexane and methyl n-butyl ketone; and various organophosphates. A neuropathy is also a common complication of chronic alcohol abuse and, in this circumstance, may relate to either a direct toxic effect of alcohol, a concomitant nutritional deficiency, or both. Other causes of chronic peripheral neuropathy include infection (such as leprosy), diverse metabolic disorders, and a number of general medical diseases. Some neuropathies have a hereditary basis, even though they may not become symptomatic until adulthood. It is often not possible to distinguish with confidence among various possible causes of neuropathy, except by the setting in which the neuropathy develops. Distinction depends on the results of a detailed family and general medical history, any associated clinical findings, the results of various investigations including electrophysiologic studies, and pathologic examination of nerve biopsy specimens. A neuropathy with acute onset suggests a metabolic or toxic cause or an infective or inflammatory disturbance. A toxic basis for a neuropathy is supported by the cessation of progression—and by subsequent clinical improvement—after discontinuation of exposure to the offending substance. A chronic peripheral neuropathy due to toxic exposure (such as might be attributed to herbicide exposure) would not be expected to develop years after exposure to that toxin ceases. Despite intensive investigation, a specific cause of a chronic peripheral neuropathy may not be found in between 20 and 50 percent of cases (Dyck et al., 1981; McLeod et al., 1984; Notermans et al., 1993; McLeod, 1995). It is not possible to ascribe such neuropathies to exposure to a possible neurotoxin when that exposure occurred years earlier and is not continuing.

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Veterans and Agent Orange: Update 1998 ACUTE AND SUBACUTE TRANSIENT PERIPHERAL NEUROPATHY Summary of VAO and Update 1996 In Update 1996 it was noted that the methodology used to establish associations between putative causal agents and persistent chronic neurological deficits relies heavily on epidemiologic 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, greater reliance must be placed on isolated case histories and less well controlled studies. Based on an analysis of the data from studies reviewed in VAO and Update 1996, as well as those published more recently regarding occupational, environmental, and Vietnam veteran exposure to herbicides and herbicide components, this committee agrees with the conclusion of the last committee that there is limited/suggestive evidence of an association between exposure to certain herbicides used in Vietnam and the development of an acute or subacute transient peripheral neuropathy. Acute peripheral neuropathies have been reported following acute occupational exposure to 2, 4-dichlorophenoxy-acetic acid (2,4-D) weedkiller by several authors (Goldstein et al., 1959; Todd, 1962; Berkley and Magee, 1963). Affected patients had not been examined prior to exposure, but the temporal relationship between clinical disturbance and herbicide exposure was well documented. It remains possible, however, that the neuropathy was unrelated to the herbicide exposure and related to other disorders, such as Guillain-Barré syndrome. Update of the Scientific Literature The committee is aware of no new publications that bear on this issue. If TCDD were associated with the development of transient acute and subacute peripheral neuropathy, the disorder would become evident shortly after exposure. The committee knows of no evidence that new cases developing long after service in Vietnam are associated with herbicide exposure. CONCLUSIONS FOR NEUROBEHAVIORAL DISORDERS Strength of Evidence in Epidemiologic Studies As in the earlier reports, this committee finds that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides used in Vietnam and disorders involving cognitive and

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Veterans and Agent Orange: Update 1998 neuropsychiatric dysfunction, motor/coordination deficits, 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, as reviewed in previous reports. No new evidence has appeared since those reports. In Update 1996, the committee indicated that there is limited/suggestive evidence of an association between exposure to the herbicides considered in this report and acute or subacute transient 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. This conclusion remains unchanged. Biologic Plausibility Chapter 3 details the committee's evaluation of data from animals and studies with cells regarding the biological plausibility of a connection between exposure to dioxin or herbicides and various neurobehavioral disorders. This section summarizes that evidence. Some of the preceding discussions of neurobehavioral outcomes include references to specific relevant papers. Little information exists on the development of neurobehavioral disorders and TCDD exposure in laboratory animals. Acute doses of TCDD administered to rats affect the metabolism of serotonin, a neurotransmitter in the brain able to modulate food intake. This biochemical change is consistent with observations of progressive weight loss and anorexia in experimental animals exposed to TCDD. In primary cultures of rat hippocampal neuronal cells, there is evidence that TCDD may increase the uptake of intracellular calcium. This concentration-dependent increase in calcium is associated with a decrease in mitochondrial membrane potentiation and activation of α-protein kinase C. An experimental study in rats suggested that a single low dose of TCDD could cause a toxic polyneuropathy. In general, TCDD has a wide range of effects on growth regulation, hormone systems, and other factors associated with the regulation of activities in normal cells. These effects may in turn influence nerve cells. Studies in animals indicate that some TCDD effects are mediated through the Ah receptor (AhR), a protein in animal and human cells to which TCDD can bind. It is hypothesized that TCDD, together with the AhR, can interact with sites on DNA and alter the information obtained from DNA in a way that transforms normal cells into abnormal cells. Although structural differences in the AhR have been identified, this receptor operates in a similar manner in animals and humans. Evidence has also begun to accumulate for non-AhR-mediated effects. Animal studies and in vitro mechanistic studies continue to emphasize the importance of alterations in neurotransmitter systems as underlying mechanisms of TCDD induced behavioral dysfunction.

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Veterans and Agent Orange: Update 1998 Limited information is available on health effects of exposure to the herbicides discussed in the report. Some studies have observed impairment of motor function in rats administered high single oral doses of 2,4-D. Another study showed that the toxic effects of 2,4-D in rats were observed within one-half hour after its oral administration and correlated with signs and symptoms of CNS depression. These data were interpreted to suggest that the toxic mechanism of 2,4-D is related to an action on the central nervous system. 2,4-D also renders the developing rat nervous system vulnerable by hindering the process of myelination in the brain. Evidence was recently presented suggesting that 2,4-D and 2,4,5-T access to the central nervous system is energy-dependent. Results from in vitro mechanistic studies suggest that 2,4,5-T may acutely affect neuronal and muscular function by altering cellular metabolism and cholinergic transmission. The herbicide 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) is known to produce parkinsonism in humans and experimentally in animals, including nonhuman primates. Paraquat, another herbicide, shares with MPTP the ability to increase free-radical load in target tissues and exposure to it has also been related to an increased incidence of parkinsonism. These results may be biologically relevant because it is suspected that TCDD and some of the herbicides used in Vietnam may indirectly generate free radicals or sensitize cells to free radical injury. The foregoing evidence suggests that a connection between TCDD or herbicide exposure and human health effects is, in general, biologically plausible. However, differences in sensitivity and susceptibility across individual animals, strains and species, lack of strong evidence of organ-specific effects across species, and differences in route, dose, duration and timing of exposure complicate any more definitive conclusions about the presence or absence of a mechanism for the induction of neurobehavioral effects. Considerable uncertainty remains over how to apply this information to the evaluation of potential health effects of herbicides or dioxin exposure in Vietnam veterans. Scientists disagree over the extent to which information derived from animals and cellular studies predicts human health outcomes, and the extent to which the health effects resulting from high-dose exposure are comparable to those resulting from low-dose exposure. Research on biological mechanisms is burgeoning and subsequent Veterans and Agent Orange updates may have more and better information on which to base conclusions. Increased Risk of Disease Among Vietnam Veterans Under the Agent Orange Act of 1991, the committee is asked to determine (to the extent that available scientific data permit meaningful determinations) the increased risk of the diseases it studies among those exposed to herbicides during their service in Vietnam. Chapter 1 presents the committee's general findings regarding this charge. Where more specific information about particular health

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Veterans and Agent Orange: Update 1998 outcomes is available, this information is related in the preceding discussions of those diseases. REFERENCES Baader EW, Bauer H. 1951. Industrial intoxication due to pentachlorophenol. Industrial Medicine and Surgery 20:286-290. Berkley MC, Magee KR. 1963. Neuropathy following exposure to a dimethylamine salt of 2,4-D. Archives of Internal Medicine 111:133-134. Butterfield PG, Valanis BG, Spencer PS, Lindeman CA, Nutt JG. 1993. Environmental antecedents of young-onset Parkinson's disease. Neurology 43:1150-1158. 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. Diabetes Control and Complications Trial (DCCT) Research Group. 1995. The effect of intensive diabetes therapy on the development and progression of neuropathy. Annals of Internal Medicine 122:561-568. Dyck PJ, Oviatt KF, Lambert EH. 1981. Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Annals of Neurology 10:222-226. 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. Franklin GM, Kahn LB. Baxter J, Marshall JA, Hamman RF. 1990. Sensory neuropathy in non-insulin-dependent diabetes mellitus. The San Luis Valley Diabetes Study. American Journal of Epidemiology 131:633-643. 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. Institute of Medicine (IOM). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press. Institute of Medicine. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. Italian General Practitioner Study Group. 1995. Chronic symmetric symptomatic polyneuropathy in the elderly: a field screening investigation in two Italian regions. I. Prevalence and general characteristics of the sample. Neurology 45:1832-1836. Liou HH, Tsai MC, Chen CJ, Jeng JS, Chang YC, Chen SY, Chen RC. 1997. Environmental risk factors and Parkinson's disease: a case-control study in Taiwan. Neurology 48:1583-1588. Maser RE, Steenkiste AR, Dorman JS, Nielsen VK, Bass EB, Manjoo Q, Drash AL, Becker D J, Kuller LH, Greene DA, et al. 1989. Epidemiological correlates of diabetic neuropathy. Report from Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes 38:1456-1461. McLeod JG, Tuck RR, Pollard JD, Cameron J, Walsh JC. 1984. Chronic polyneuropathy of undetermined cause. Journal of Neurology, Neurosurgery and Psychiatry 47:530-535. McLeod JG. 1995. Investigation of peripheral neuropathy. Journal of Neurology, Neurosurgery and Psychiatry 58:274-283. Notermans NC, Wokke JH, Franssen H, van der Graaf Y, Vermeulen M, van den Berg LH, Bar PR, Jennekens FG. 1993. Chronic idiopathic polyneuropathy presenting in middle or old age: a clinical and electrophysiological study of 75 patients . Journal of Neurology, Neurosurgery and Psychiatry 56:1066-1071. O'Toole BI, Marshall RP, Grayson DA, Schureck RJ, Dobson M, French M, Pulvertaft B, Meldrum L, Bolton J, Vennard J. 1996. The Australian Vietnam Veterans Health Study: III. Psychological health of Australian Vietnam veterans and its relationship to combat. International Journal of Epidemiology 25:331-340.

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Veterans and Agent Orange: Update 1998 Orchard TJ, Dorman JS, Maser RE, Becker DJ, Drash AL, Ellis D, LaPorte RE, Kuller LH. 1990. Prevalence of complications in IDDM by sex and duration. Pittsburgh Epidemiology of Diabetes Complications Study II. Diabetes 39:1116-1124. Palumbo PJ, Elvehack LR, Whisnant JP. 1978. Neurological complications of diabetes mellitus: transient ischaemic attack, stroke and periperal neuropathy. In: Schoenberg BS, ed. Neurological Epidemiology: Principles and Clinical Applications. New York: Raven Press. 593-601. Partanen J, Niskanen L, Lehtinen J, Mervaala E, Siitonen O, Uusitupa M. 1995. Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. New England Journal of Medicine 333:89-94. Peper M, Klett M, Frentzel-Beyme R, Heller WD. 1993. Neuropsychological effects of chronic exposure to environmental dioxins and furans. Environmental Research 60:124-135. Schulte PA, Burnett CA, Boeniger MF, Johnson J. 1996. Neurodegenerative diseases: occupational occurrence and potential risk factors, 1982 through 1991. American Journal of Public Health 86(9): 1281-1288. Seidler A, Hellenbrand W, Robra BP, Vieregge P, Nischan P, Joerg J, Oertel WH, Ulm G, Schneider E. 1996. Possible environmental, occupational, and other etiologic factors for Parkinson's disease: a case-control study in Germany. Neurology 46(5):1275-1284. Semchuk KM, Love EJ, Lee RG. 1992. Parkinson's disease and exposure to agricultural work and pesticide chemicals. Neurology 42:1328-1335. Semchuk KM, Love EJ, Lee RG. 1993. Parkinson's disease: a test of the multifactorial etiologic hypothesis. Neurology 43:1173-1180. Sharp DS, Eskenazi B, Harrison R, Callas P, Smith AH. 1986. Delayed health hazards of pesticide exposure. Annual Review of Public Health 7:441-471. Todd RL. 1962. A case of 2,4-D intoxication. Journal of the Iowa Medical Society 52:663-664. Visintainer PF, Barone M, McGee H, Peterson EL. 1995. Proportionate mortality study of Vietnamera veterans of Michigan. Journal of Occupational and Environmental Medicine 37:423-428. Zober A, Ott MG, Messerer P. 1994. Morbidity follow up study of BASF employees exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) after a 1953 chemical reactor incident. Occupational and Environmental Medicine 51:469-486.