8

Neurobehavioral Disorders

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

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



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Veterans and Agent Orange: Update 2002 8 Neurobehavioral Disorders Neurologic problems in clinical medicine cover a wide variety of disorders. The nervous system actually consists anatomically and functionally of the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS includes the brain and spinal cord, and CNS dysfunction can be divided into two general categories: neurobehavioral dysfunction and motor or sensory dysfunction. Neurobehavioral difficulties involve cognitive decline, including memory problems and dementia; and neuropsychiatric disorders, including neurasthenia (a collection of such symptoms as difficulty in concentrating, headache, insomnia, and fatigue), depression, posttraumatic stress disorder (PTSD), and suicide. Motor dysfunction is characterized by such problems as weakness, tremors, involuntary movements, incoordination, and walking abnormalities; these are usually associated with subcortical or cerebellar disorders. The anatomic elements of the PNS include the spinal rootlets that leave the spinal cord, the brachial and lumbar plexus, and the peripheral nerves that innervate muscles. PNS dysfunctions, involving either the somatic nerves or the autonomic system, are known as peripheral neuropathies. Neurologic dysfunction can be further classified, on the basis of anatomic distribution as either global or focal; on the basis of temporal onset as acute, subacute, or chronic; or on the basis of temporal course as transient or persistent. For example, global cerebral dysfunction may lead to altered levels of consciousness, whereas focal lesions may cause isolated signs of cortical dysfunction, such as aphasia. Acute onset of motor or coordination disturbances leads to symptoms that develop over minutes or hours, whereas subacute onset occurs over days or weeks, and chronic onset over months or years. Transient peripheral neuropathies

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Veterans and Agent Orange: Update 2002 resolve spontaneously, whereas persistent ones may lead to chronic deficits. In the original VAO report, attention was deliberately focused on persistent neurobehavioral dysfunction. Later reports, including this one, review all new data pertinent to clinical neurobehavioral dysfunction and peripheral neuropathy. Case identification in neurology is often difficult. Despite advances in neuro-imaging, many types of neurologic alterations are biochemical and show no abnormalities on scanning tests. The nervous system is not usually accessible for biopsy, so pathologic confirmation is not feasible for many neurologic disorders. Behavioral and neurophysiologic changes can be partly or largely subjective and, even when objectively documented, are often reversible. Timing is important in assessing the effect of chemical exposure on neurologic function. Some symptoms of neurologic importance appear acutely but are short-lived, whereas others appear slowly and are detectable for extended periods. These caveats must be considered in the design and critique of epidemiologic studies aimed at evaluating an association between exposure to a chemical agent and neurologic or neurobehavioral dysfunction. Many reports have addressed the possible contribution of herbicides and pesticides to nervous system dysfunction, and reported abnormalities have ranged from mild and transient to severe and persistent. Those assessments have been conducted in three general settings: in relation to occupational, environmental, and Vietnam-veteran exposures. This chapter reviews reports of the following neurologic alterations associated with human exposure to the chemicals of interest (2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), 4-amino-3,5,6-trichloropicolinic acid (picloram), and cacodylic acid (dimenthylarsenic acid, DMA): cognitive and neuropsychiatric effects, motor or coordination dysfunction, chronic persistent peripheral neuropathy, and acute and subacute transient peripheral neuropathy. The potential neurotoxicity of those chemicals in recent animal studies is discussed in Chapter 3. The categories of association and the committee's approach to categorizing the health outcomes are discussed in Chapters 1 and 2. COGNITIVE AND NEUROPSYCHIATRIC EFFECTS Summary of VAO, Update 1996, Update 1998, and Update 2000 On the basis of the data available at the time, it was concluded in Veterans and Agent Orange (hereafter referred to as VAO; IOM, 1994), Veterans and Agent Orange: Update 1996 (hereafter, Update 1996; IOM, 1996), and Veterans and Agent Orange: Update 1998 (hereafter, Update 1998; IOM, 1999) that there was inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and cognitive or neuropsychiatric disorders. The majority of the data that formed the basis for those conclusions

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Veterans and Agent Orange: Update 2002 came from the Air Force Health Studies (AFHS, 1991, 1995). The 1987 AFHS (AFHS, 1991), originally reviewed in VAO, found no association between serum TCDD (both baseline and current concentrations) and such variables as anxiety, depression, and hostility on the Symptom Checklist-90–Revised (SCL-90-R) or between TCDD and the presence of sleep problems. In contrast, some scales on the Millon Clinical Multiaxial Inventory (MCMI) had significant associations with TCDD in a variety of analyses. The belief that the findings from the SCL-90-R and the MCMI and the reported medical information were inconsistent led to the conclusion of inadequate or insufficient evidence of an association between exposure and cognitive or neuropsychiatric disorders (IOM, 1994). In the 1992 AFHS (AFHS, 1995) some checklist variables (anxiety, hostility, obsessive–compulsive behavior, paranoid ideation, somatization, global severity index, and other neuroses) were significantly increased across all occupations in Ranch Hands, but the association was not significant for some after adjustment for covariates. In a later follow-up examination, the 1997 AFHS (AFHS, 2000), described in Update 2000 (IOM, 2001), a repeat psychologic assessment was performed with SCL-90-R and reported psychologic disorders verified through medical record review. The verified psychologic disorders were combined with those obtained on previous examinations—baseline, 1985, 1987, and 1992. Of the five psychologic diagnoses—psychoses, alcohol dependence, drug dependence, anxiety, and other neuroses—a dose–response pattern was found only for 1987 TCDD concentrations and prevalence of “other neuroses” in the enlisted ground crew. When the relationship between the 1987 lipid-adjusted serum TCDD concentrations from all Ranch Hands and the psychologic end points were examined, however, no significant results were found. The checklist results were not different across Ranch Hand occupational groups and were not associated with TCDD exposure. Both VAO and Update 2000 (IOM, 2001) had noted inconsistencies in the methods used to establish psychologic diagnoses in the 1987 and 1997 AFHS examinations (AFHS, 1991, 2000). Therefore, the conclusion of inadequate or insufficient evidence of an association between exposure and cognitive or neuropsychiatric disorders remained unchanged (IOM, 2001). Update of the Scientific Literature Since Update 2000 (IOM, 2001), three relevant studies of cognitive and neuropsychiatric effects have been published: an update of the AFHS (Barrett et al., 2001), an occupational study in Czechoslovakia (Pazderova-Vejlupkova et al., 1981), and a study of Alzeimer's disease after environmental exposure to herbicides and insecticides (Gauthier et al., 2001). Results of cognitive functioning from the AFHS examination in 1982 were published (Barrett et al., 2001). Neuropsychologic performance was measured in 937 Ranch Hand veterans (388 exposed to TCDD at background concentrations, 274 at low concentrations, and 275 at high concentrations) and 1,052 comparison

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Veterans and Agent Orange: Update 2002 veterans who served in Southeast Asia but were not involved in spraying herbicides (all of whom had a serum TCDD concentration below 10 ppt). Cognitive functioning was assessed with the Halsted Reitan (HR) neuropsychologic test battery (16 measures), the Wechsler Adult Intelligence Scale-Revised (WAIS-R) (11 measures), the Wechsler Memory Scale Form 1 (WMS) (five measures), and the reading subtest of the Wide Range Achievement Test (WRAT). Comparison veterans had been matched to Ranch Hand veterans on age, race, and military occupation. For all tests of cognitive functioning, mean scores for the three TCDD-exposed veteran groups were contrasted with the comparison group after adjustment for military occupation, age, race, drinking history, marital status, combat-exposure quartile, four psychiatric-diagnosis indicators (see Update 2000, page 442, for detailed description), and a psychotropic-medication use indicator. Finger tapping (HR) with the dominant and nondominant hands was significantly lower (poorer) in the Ranch Hand low-TCDD group than in the comparison group. Nondominant grip strength (HR) was significantly lower (weaker) in the Ranch Hand background-TCDD group than in the comparison group. Veterans in the Ranch Hand low-TCDD group were 3 times as likely to be rated severely impaired on the HR impairment index as all other veterans. When Vietnam veterans were separated into quintiles on the basis of TCDD concentration, and the second, third, fourth, and fifth TCDD-concentration quintiles were contrasted with veterans in the first quintile, the mean dominant-hand grip strength for veterans in the fourth quintile and the mean nondominant-hand grip strength for veterans in the third and fourth quintiles were significantly increased. WAIS-R information score was significantly decreased for veterans in the third quintile, and WAIS-R similarities score was significantly increased (better) for veterans in the fourth quintile. Contrasts between the fifth and first quintiles were not significant for any of the subtests on the WAIS-R and HR. The Ranch Hand veterans had significantly lower mean scores in immediate and delayed recall of Logical Memory (WMS) than the comparison veterans. Also, veterans in the fifth quintile had significantly lower Logical Memory scores than veterans in the first quintile. Enlisted Ranch Hand personnel who reported greater skin exposure than enlisted comparison veterans had significant decrements in immediate and delayed recall WMS Logical Memory and HR Tactual Memory. Associate Learning (VMS), another test of verbal memory, had no meaningful change in any Ranch Hand TCDD category. VAO reviewed a 10-year follow-up study of 55 men in Czechoslovakia with TCDD exposure during the production of 2,4,5-T (Pazderova-Vejlupkova et al., 1981). Initially, 7% of the workers had features of encephalopathy, and 75% had neurasthenia. Over time, the number of workers with neurasthenia decreased. VAO concluded that there were methodologic problems, including use of self-reported symptoms, lack of an objective measure of exposure, and selection bias. In a 30-year follow-up (Pelclova et al., 2001), 13 of the workers were re-examined. They had a mean plasma TCDD concentration of 256 ± 139 pg/g of lipid-

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Veterans and Agent Orange: Update 2002 (range = 14–760 pg/g of lipid) that was extrapolated to an estimated concentration of 5,000 pg/g of plasma fat at the time of initial exposure. All subjects had chloracne on the earlier examinations; two workers with TCDD of 760 and 420 pg/g of fat still had the condition. TCDD was correlated significantly with the memory quotient from WMS, the verbal IQ from WAIS-R, and the Benton test of visual memory. Age-corrected norms were used to determine abnormal performance. Surprisingly, education did not affect the results, but no demographic data on education were presented. Ten of 13 subjects drank alcohol every day, but this was not taken into account in the analyses. The low-voltage electroencephalogram with increased beta activity (seven subjects) could be related to the daily alcohol consumption. It is not possible to determine the relationship between TCDD and cognitive functioning without attention to confounding. The age-corrected norms used for test interpretation were not generated in a population similar to those workers. In the 1970s, five of the 13 subjects had abnormal tibial nerve studies compared to one in 1996. Because no data are presented, the underlying pathologic condition cannot be evaluated. As a general rule, toxic neuropathies are expected to improve once exposure has ceased or diminished, but because of selection bias of subjects the association of neuropathy with TCDD exposure cannot be determined. Gauthier et al. (2001) found that long-term exposure to herbicides and insecticides was not significantly related to the development of Alzheimer's disease (AD). Sixty-seven cases diagnosed with NINCDS-ADRDA criteria of probable and possible AD were matched for age and sex with nondemented controls. Exposure data on each municipality were examined to establish the area sprayed with herbicides and insecticides in 1971, 1976, 1981, 1986, and 1991. The results were combined with the subjects' residential histories to establish potential environmental pesticide exposure. Logistic regression with adjustment for confounders found that long-term exposure to herbicides and insecticides did not have a significant effect on the development of AD. Occupational exposure to neurotoxic substances, including pesticides, was also not significantly related to AD. Synthesis Cognitive functioning in the Ranch Hand veterans evaluated with about 33 measures from HR, WAIS-R, WMS, and WRAT found eight significant group differences that did not support a dose-effect relationship with TCDD, that is, worse performance was seen in the background or low-TCDD groups. Ranch Hand veterans with the highest TCDD exposure had significantly lower scores on Logical Memory (WMS). That finding could be attributed to chance alone and was not in agreement with other administered tests of verbal memory—Associate Learning (WMS) and Information and Vocabulary (WAIS-R). Each test of verbal memory measures memory in a different way. When performance on one test of verbal memory is mildly depressed and performance on other tests of verbal

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Veterans and Agent Orange: Update 2002 memory is normal, the conclusion that verbal memory is reduced is not warranted. Military occupation served as the surrogate for education and training. A better indicator than occupation or formal years of education is the WRAT-R Reading Test, it is a measure of educational achievement and educational experience that is believed to assess premorbid intelligence. Reading tests are considered to be “hold” tests—in other words, resistant to change—when cognitive functioning declines, whether because of neurotoxic exposure or age. WRAT-R was administered in this study but was not used as a measure of educational achievement; it would have been a more robust covariate for education than military occupation and might have accounted for the significant findings with Logical Memory. As noted by Barrett et al. (2001), “differences [on Logical Memory] were relatively small and of uncertain clinical significance.” As discussed in VAO, inconsistencies in the methods used to establish psychologic diagnoses in the 1987 AFHS (1991) examination brought the diagnoses into question; and an association between TCDD exposure and numerous dissimilar neuropsychiatric diagnoses is improbable (IOM, 2001). Therefore, the use of that information as covariates does not appear justified. It is also unclear how marital status and combat exposure 20 years after cessation are related to neuropsychologic test performance. Overall, the weaknesses in the study design, analyses, and interpretation of the results in the examination of serum TCDD and cognitive functioning in the Ranch Hand veterans prevent establishment of an association between exposure and neuropsychologic performance. Conclusion On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is still inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and cognitive or neuropsychiatric disorders. MOTOR OR COORDINATION DYSFUNCTION This section summarizes the data from previous Veterans and Agent Orange reports and updates the scientific literature on Parkinson's disease and on amyotrophic lateral sclerosis.

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Veterans and Agent Orange: Update 2002 Parkinson's Disease and Parkinsonism Summary of VAO, Update 1996, Update 1998, and Update 2000 Because of the increasing concern about a possible link between Parkinson 's disease (PD) and various chemicals used as herbicides and pesticides, VAO, Update 1996, Update 1998, and Update 2000 suggested that attention be paid to the frequency and character of new cases in exposed versus nonexposed persons as Vietnam veterans age and are in the decades when PD is more prevalent. Table 8-1 summarizes studies (reviewed in Update 1996, Update 1998, Update 2000, and this report) from numerous countries that examine the association between PD and pesticide (herbicide and insecticide) exposure. In those studies, cases of PD were identified with strict guidelines, either neurologic examination or review of medical data that required the presence of signs of PD (resting tremor, bradykinesia, cogwheel rigidity, and postural reflex impairment). Routine clinical diagnosis of PD has an accuracy of 75% by neuropathologic criteria that can be improved to 80–90% when stricter diagnostic criteria are applied (Langston, 1998). Clinical features were not verified in the large population studies that relied on death certificates or hospital admission diagnoses (Chaturvedi et al., 1995; Ritz and Yu, 2000; Schulte et al., 1996; Tuschen and Jensen, 2000). Exclusion criteria included the presence of atypical features— such as cerebellar involvement, gaze impairment, or pronounced autonomic dysfunction—or on all other causes of secondary parkinsonism, such as drugs, infections, or toxins. In the studies reviewed, for subjects to be included in the study pesticide exposure was usually required to occur before disease onset, but knowledge of when it occurred in relation to disease onset was not presented. In Update 1998, emphasis on the detection of early-onset parkinsonism was considered vital to test the hypothesis that the disease is related to a toxic exposure because aging is currently the only known definitive risk factor for PD. PD becomes clinically apparent when about 60–70% of the neurons in the substantia nigra have deteriorated. One possible reason for the early onset of PD is that neuronal loss is accelerated in people with pesticide exposure and causes expression of the disease at an earlier age than is usual in the general population (see Weiss, 2000 for review). In Update 2000, of the 30 epidemiologic studies of pesticide exposure and PD summarized in Table 8-1, only eight provided an estimate of relative risk posed by herbicides; of these studies, five had a positive significant association (Butterfield et al., 1993; Gorrell et al., 1998; Liou et al., 1997; Seidler et al., 1996; Semchuk et al., 1992), one had no association (Taylor et al., 1999), and the remaining two had a negative association (Kuopio et al., 1999; Stern et al., 1991). When a specific herbicide, paraquat, was examined in Taiwan (Liou et al., 1997), the OR was 3.2 (2.4– 4.3).

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Veterans and Agent Orange: Update 2002 TABLE 8-1 Epidemiologic Studies of Pesticide Exposure and Parkinson's Diseasea Reference and Country Study Group Comparison Group Exposure Assessment Significant Association with Pesticides OR (95% CI) Neurologic Dysfunction Diagnosis Butterfield et al., 1993; USb,c 63 young onset, (age < 50 years) 68 Questionnaire—pesticide or insecticide use 10 times in any year + Insecticides 5.8 Herbicides 3.2 (2.5–4.1) Past dwelling fumigated 5.3 Standard criteria of PD by history Chan et al., 1998; Hong Kongc 215 313 Interview—exposure to pesticides during farming (years) + Pesticides in women 6.8 (1.9–24.7) Pesticides in men 0.7 (0.3–1.8) Neurologic examination Chaturvedi et al., 1995; Canadac 87 (age > 64 years) 2,070 Survey—exposure positive if frequently used   Pesticides 1.8 (0.9–3.4) History of PD Engel et al., 2001; US 238 72 Self-administered questionnaire for occupational exposure + Pesticides 0.8 (0.5–1.2) Herbicide 0.9 (0.6–1.3) Highest tertile pesticide 2.0 (1.0–4.2) Neurologic examination by trained nurse Fall et al., 1999; Swedenc 113 263 Questionnaire—any job handling pesticides   Pesticides 2.8 (0.9–8.7) Neurologic examination Golbe et al., 1990; USb,c 106 106 Telephone survey— sprayed pesticides or insect spray once a year for a total of 5 years + Sprayed pesticide 7.0 (5.8–8.5) Neurologic examination

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Veterans and Agent Orange: Update 2002 Gorrell et al., 1998; USc 144 (age > 50 years) 464 Interview— herbicide and insecticide use while working on a farm or gardening + Occupational herbicides 4.1 (1.4–12.2) Occupational insecticides 3.6 (1.8–7.2) Standard criteria of PD by history Hertzman et al., 1990; Canada 57 122 Questionnaire—ever worked in an orchard + Working in orchards 3.7 (1.3–10.3) Neurologic examination Hertzman et al., 1994; Canadac 127 245 Interview—occupation with probable pesticide exposure + Pesticides in men 2.3 (l.1–4.9) Neurologic examination Ho et al., 1989; Hong Kongc 35 (age >60 years) 105 Interview—use of insecticides or herbicides (Y/N), farming, eating raw vegetables + Herbicides and pesticides 3.6 (1.0–12.9) Neurologic examination Hubble et al., 1993; USc 63 76 Questionnaire—pesticide or herbicide use 20 days per year for >5 years + Pesticide or herbicide 3.4 (1.3–7.3) Neurologic examination Hubble et al., 1998; US 43 PD with dementia 51 PD without dementia Interviews—pesticide exposure >20 days in any year and presence of allele for poor drug metabolism + Pesticide exposure and genetic trait 3.17 (1.1–9.1) Neurologic examination Jimenez-Jimenez et al., 1992; Spainc 128 256 Interview—exposure: applied pesticides, or lived and ate vegetables where pesticides used   Pesticide 1.3 (0.9–2.1) Standard criteria of PD by history

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Veterans and Agent Orange: Update 2002 Reference and Country Study Group Comparison Group Exposure Assessment Significant Association with Pesticides OR (95% CI) Neurologic Dysfunction Diagnosis Koller et al., 1990; USc 150 150 Interview—acre-years= acres multiplied by years of herbicide or pesticide use   Herbicide or pesticide use 1.1 (0.9–1.3) Neurologic examination Kuopio et al., 1999; Finland 123 (onset of PD before 1984) 279 Interview—pesticides or herbicides regularly or occasionally used   Regular use herbicides of 0.7 (0.3-1.3) Neurologic examination Liou et al., 1997; Taiwanb,c 120 240 Interview—occupational exposures to herbicides or pesticides + Herbicides or pesticides, no paraquat 2.2 (0.9–5.6) Paraquat use 3.2 (2.4–4.3) Neurologic examination McCann et al., 1998; Australiac 224 310 Questionnaire—daily or weekly exposure to industrial herbicides and pesticides >6 months   Herbicides or pesticides 1.2 (0.8–1.5) Neurologic examination Menegon et al., 1998; Australia 96 95 Interview—pesticide exposure more than once weekly for >6 months before onset of PD + Pesticide 2.3 (1.2–4.4) Standard criteria of PD by history

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Veterans and Agent Orange: Update 2002 Morano et al., 1994; Spainc 74 148 Interview—direct and indirect—exposure to pesticides   Pesticide 1.73 (1.0–3.0) Neurologic examination Petrovitch et al., 2002; US 2,623 5,363 Total years plantation work and years of pesticide exposure + Plantation work >20 years 1.9 (1.0–3.5) Medical records and neurologic examination Ritz and Yu, 2000; US 7,516 (PD cause of death 1984–1994) 498,461 (ischemic heart disease cause of death 1984–1994) Counties ranked by pesticide use from pesticide registry and agricultural census data + Prevalence OR: Moderate pesticide 1.36 (1.3–1.5) High insecticide 1.45 (1.3– 1.6) ICD-9 332 Schulte et al., 1996; USb 43,425 PD cause of death in 27 states 1982– 1991   Occupational exposure + PMR excess in male pesticide appliers, horticultural farmers, farm workers, and graders and sorters of agricultural products ICD-9 332 Seidler et al., 1996; Germanyb,c 380 (<66 years with PD after 1987) 755 Interview—dose-years = years of application weighted by use + Neighborhood controls for herbicide 1.7 (1.0–2.7) Regional controls for herbicide 1.7 (1.0–2.6) Neurologic examination Semchuk et al., 1992; Canadab,c 130 260 Interview— occupational exposure for each job held >1 month + Pesticide 2.25 (1.3–4.0) Herbicide 3.06 (1.3–7.0) Insecticide 2.05 (1.0–4.1) Neurologic examination

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Veterans and Agent Orange: Update 2002 peripheral nerve status was not remarkable (AFHS, 1991). In 1992, the neurologic assessment was comparable between the two groups, and there was no consistent evidence of a dose–response relationship for either estimated initial TCDD or current TCDD. In 1997 (AFHS, 2000), the peripheral nerve examination was based on physical examinations and verified vibrotactile measurement. The percentage of participants with a confirmed polyneuropathy index was consistently higher in Ranch Hands than in the comparison group. After adjustment for the covariates, the results of TCDD exposure were marginally significant for the enlisted ground crew. The development of neuropathy 30 years after exposure is highly unusual and not compatible with TCDD exposure. It was concluded that evidence of an association between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and chronic persistent peripheral neuropathy was still inadequate or insufficient. Update of the Scientific Literature A publication relating serum TCDD and peripheral neuropathy from the 1982, 1985, 1987, 1992, and 1997 examinations of the Ranch Hand study (Michalek et al., 2001) found significantly increased risk of peripheral neuropathy among Ranch Hand veterans in the high-exposure category in 1997. Exposure categories and numbers of veterans in the “comparison,” “background,” “low,” and “high” categories are described in Chapter 5. As part of the protocol, veterans received the diagnosis of “diabetic” if diagnosed by a physician as noted in the medical record or if a 2-hour postprandial glucose-tolerance test result was over 200 mg/dL. A neurologic examination recorded tremor, cranial nerve function, sensation, motor strength and coordination, and reflexes. In 1982, nerve-conduction studies of ulnar, peroneal, and sural nerves were performed. In 1992 and 1997, vibrotactile thresholds of the great toe were measured. The diagnosis of possible peripheral neuropathy required one of three physical signs: absent ankle jerk, abnormal vibration at the ankle, or abnormal pinprick in the foot bilaterally. For probable peripheral neuropathy, at least two of the three abnormalities had to be present. For a diagnosis of peripheral neuropathy, a diagnosis of probable peripheral neuropathy and bilateral abnormal vibrotactile measures were required. Nerve-conduction studies (1982) and vibrotactile abnormalities (1992 and 1997) did not support any peripheral nerve differences between low and high exposure to TCDD. In the high-TCDD category in 1997, the odds of possible peripheral neuropathy (OR = 1.8, 95% CI 1.2 –2.7) or probable peripheral neuropathy (OR = 5.0, 95% CI 2.2–11.2) were significantly increased with a significant trend with increasing exposure (p < 0.001). To determine whether the OR was different in veterans with and without diabetes, the groups were analyzed separately. In nondiabetic veterans, the odds of probable peripheral neuropathy were significantly increased (OR = 8.7, 95% CI 1.9–39.3); and in diabetic veter-

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Veterans and Agent Orange: Update 2002 ans, the odds were also significantly increased (OR = 3.5, 95% CI 1.3–9.4). In the 1992 examination, six veterans in the high-TCDD category had diagnosed neuropathy (OR = 4.9, 95% CI 1.5–15.3). In 1997, three of the six veterans had diagnosed neuropathy, one had normal measurements, one had missing data, and one did not attend. The number of nondiabetic veterans with diagnosed neuropathy in 1997 was too small for analysis, but the risk of diagnosed peripheral neuropathy in diabetic veterans in the high-TCDD category was significantly increased (OR = 5.8, 95% CI 1.6–20.3). When a secondary analysis was attempted and veterans were excluded if they had disease, disorders, exposures, or medications known to produce symptoms suggestive of neuropathy or had neurologic diseases unrelated to TCDD, the numbers were too small for analysis. In 1997, nine of the 14 veterans with probable peripheral neuropathy in the high-TCDD category had diabetes, and four veterans had preclinical diabetes. In the low-TCDD category, eight veterans had probable neuropathy, and seven were diabetic. Of the eight veterans with diagnosed peripheral neuropathy in the high-TCDD category, seven had diabetes, and one had preclinical diabetes. Of the five veterans with diagnosed peripheral neuropathy in the low-TCDD category, four had diabetes. That suggests a major problem in the interpretation of TCDD effects on the peripheral nerves in light of the presence of diabetes and preclinical diabetes, a major risk factor for peripheral neuropathy. That these cases of probable and possible peripheral neuropathy were identified for the first time in 1992 and 1997, when prior examinations were normal, weakens the ability to implicate TCDD exposure as the etiologic agent given that the peripheral nerve is known to repair itself after cessation of exposure or after diminution of the body burden of the responsible toxicant. Synthesis One of the classic features of a toxic neuropathy is improvement in peripheral nerve function after removal from exposure. The degree of recovery depends on the severity of the initial injury. A toxic neuropathy can begin days to weeks after high exposure or not until months or a few years after low exposure. Ranch Hand veterans exposed to Agent Orange 26–36 years previously showed no evidence of peripheral neuropathy associated with TCDD exposure at the time of the first examination in 1982. The finding of no association persisted in repeat examinations in 1985 and 1987. Only in 1992 and 1997, 10–15 years after the initial examination and 36–51 years after TCDD exposure, were odds ratios for the diagnosed neuropathy in the high-TCDD category significant. It is not plausible that peripheral nerve function was affected by TCDD in 1992 and 1997 if during the previous examinations when serum TCDD concentrations were higher no association with TCDD was found. The case definitions of probable and diagnosed neuropathy are confusing when results are closely examined. A toxic neuropathy usually begins distally (in

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Veterans and Agent Orange: Update 2002 the toes) and moves proximally (to the ankle). That is the basis of the term dying-back neuropathy. In 1997, some veterans with probable neuropathy had abnormal vibration at the ankle while vibrotactile measurements at the big toe were intact, the reverse of what the dying-back process would predict. Abnormal vibration at the ankle is found only after the neuropathy that began in the toes has progressed to the ankle. Therefore, vibrotactile score at the big toe should have been abnormal in the nine veterans with a probable neuropathy if vibration at the ankle was truly abnormal. The difficulty with agreement between different measures of peripheral nerve function may be an issue of sensitivity and specificity. Peripheral neuropathy was associated with TCDD exposure only after vibrotactile measures were added to the protocol in 1992, but odds of an abnormal vibrotactile score were not increased in the high-TCDD group. The small number of cases is also a problem, especially when some cases have normal results in examination at follow-up or for various reasons are not re-examined. A greater problem was the confounding created by the high prevalence of diabetes or preclinical diabetes in veterans with probable or diagnosed neuropathy in the high-TCDD category. Diabetic neuropathy is the most common cause of peripheral neuropathy, occurring in about 50% of people with type 2 non-insulin-dependent diabetes over time but present in less than 10% when the diagnosis of diabetes is first made (Pirart, 1978). A study of outpatients with type 2 diabetes (mean age, 70.6 years; mean duration, 11.7 years) found polyneuropathy in 49% of them according to the criteria of lower-limb sensory and motor nerve-conduction velocity or latency more than 2 standard deviations above or below the age-matched controls (de Wytt et al., 1999). When a case definition of neuropathy in a diabetic population included symptoms, signs, electrodiagnostic studies, quantitative sensory testing, and autonomic testing, the prevalence increased to 66% (Dyck et al., 1993). In contrast, prevalence of a diabetic neuropathy was 28.5% in a large multicenter United Kingdom study (Young et al., 1993). Differences in case definitions of diabetic neuropathy probably account for the large range in its prevalence. As duration of diabetes progresses, the prevalence of peripheral neuropathy increases (Simmons and Feldman, 2002). In mild diabetic neuropathy, a median mononeuropathy was found in 23% of patients at a time when the lower extremities did not differ significantly from controls in electrodiagnostic studies (Albers et al., 1996) The common neuropathy associated with type 2 diabetes is a distal symmetric sensorimotor polyneuropathy that affects primarily the sensory nerves. Type 2 diabetes can also affect other parts of the peripheral nervous system and produce autonomic neuropathy, polyradiculopathy, cranial mononeuropathies, limb mononeuropathy, and mononeuropathy multiplex. Intensive glycemic control (careful attention to blood sugar concentration) appears to slow the progression of diabetic polyneuropathy. Persistent glycemia indirectly leads to increased release of free radicals and oxidative damage to the

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Veterans and Agent Orange: Update 2002 nervous system. Those oxidative stressors are believed to lead to mitochondrial dysfunction and programmed cell death. That theory is supported by the finding that administration of antioxidants prevents the neuropathy (Feldman et al., 1999). Vascular factors in diabetes also account for damage to peripheral nerve fibers because of ischemic changes in the endoneurial capillaries (Simmons and Feldman, 2002). A diabetic neuropathy may be difficult to differentiate clinically from neuropathy secondary to toxic exposure except by the presence of other features in the clinical history and presentation, such as gastrointestinal symptoms after lead or arsenic exposure or alopecia after thallium exposure. In addition, if caused by a toxic exposure, the neuropathy should improve after cessation of exposure, but diabetic neuropathy will usually progress unless a dramatic change is made in glycemic control. Complaints of peripheral nerve disorders, however, often occur in isolation and are monotonously similar. In the clinical setting, about 30% of cases of peripheral neuropathy are left with no etiology after a complete evaluation (McLeod, 1995). Examination of family members for evidence of mild or subclinical neuropathy can provide a hereditary etiology for a subset of this group (Dyck et al., 1981). Also, the PNS undergoes constant age-related changes that may increase its susceptibility to other metabolic and toxic exposures. Conclusion On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that the evidence of an association between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and chronic persistent peripheral neuropathy remains inadequate or insufficient. It should be noted, however, that the committee categorizes diabetes as having limited or suggestive evidence of an association. ACUTE AND SUBACUTE TRANSIENT PERIPHERAL NEUROPATHY Update of the Scientific Literature The committee is aware of no new publications that investigate the association between exposure to the compounds of interest and acute and subacute transient peripheral neuropathy. If TCDD were associated with the development of transient acute and subacute peripheral neuropathy, the disorder would become evident shortly after exposure. The committee knows of no evidence that new cases of acute or subacute transient peripheral neuropathy that develop long after service in Vietnam are associated with herbicide exposure.

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Veterans and Agent Orange: Update 2002 SUMMARY Strength of Evidence from Epidemiologic Studies As in the earlier reports, on the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and disorders involving cognitive and neuropsychiatric dysfunction, motor or coordination deficits, or chronic persistent peripheral neuropathy. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components, as reviewed in previous reports. In Update 1996, the committee found that there was limited or suggestive evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and acute or subacute transient peripheral neuropathy. The evidence regarding association was drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Information available to the committees responsible for Update 1998, Update 2000, and this report continues to support the conclusion. Biologic Plausibility This section summarizes the biologic plausibility of a connection between exposure to TCDD or herbicides and various neurobehavioral disorders on the basis of data from animal and cellular studies. Chapter 3 presents the details of the committee's evaluation of recent data from animal and cellular studies. Some of the preceding discussions of neurobehavioral outcomes include references to papers relevant to specific neurobehavioral effects. Some information exists on the development of neurobehavioral disorders and TCDD exposure in laboratory animals. In vivo experiments have demonstrated that TCDD can affect biochemical processes, including having effects on calcium uptake and neurotransmission. Acute doses of TCDD administered to rats affect the metabolism of serotonin, a brain neurotransmitter that is able to modulate food intake. The biochemical change is consistent with observations of progressive weight loss and anorexia in experimental animals exposed to TCDD. A study in adult male Wistar rats suggests that a single low-dose intraperitoneal injection of TCDD could cause a toxic polyneuropathy (Grahmann et al., 1993; Grehl et al., 1993); no other studies in animals have reported such an effect. TCDD treatment has also been demonstrated to affect learning and memory in rats.

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Veterans and Agent Orange: Update 2002 The mechanism by which TCDD could exert neurotoxic effects is not established. TCDD has a wide array of effects on growth regulation, hormone systems, and other factors associated with the regulation of activities in normal cells; these effects could in turn influence nerve cells. Furthermore, animal studies and in vitro mechanistic studies continue to emphasize the importance of alterations in neurotransmitter systems as underlying mechanisms of TCDD-induced behavioral dysfunction. Most studies are consistent with the hypothesis that the effects of TCDD are mediated by the aryl hydrocarbon receptor (AhR), a protein in animal and human cells to which TCDD can bind. The TCDD–AhR complex is known to bind DNA and to lead to changes in transcription (that is, genes are differentially regulated). Modulation of genes could cause altered cell function. Although structural differences in the AhR have been identified among different species, it operates in a similar manner in animals and humans. Therefore, a common mechanism is likely to underlie the neurotoxic effects of TCDD in humans and animals, and data in animals can support a biologic basis of TCDD's neurotoxicity. Because of the many species and strain differences in TCDD responses, however, controversy remains regarding the magnitude of TCDD exposure that is neurotoxic. Little information is available on neurotoxic effects of exposure to the herbicides discussed in this report. At the cellular level, 2,4-D inhibited neurite extension. That effect was accompanied by a decrease in intracellular microtubules, inhibition of the polymerization of tubulin, disorganization of the Golgi apparatus, and inhibition of ganglioside synthesis. Studies in rats indicate an impairment of motor function, CNS depression, and inhibition of myelination in the brain. Behavioral alterations have also been seen after treatment of rats with 2,4-D. Results of in vitro mechanistic studies suggest that 2,4,5-T may acutely affect neuronal and muscular function by altering cellular metabolism and cholinergic transmission. There is evidence that other chemicals can induce a Parkinson-like syndrome in humans, possibly by generating free radicals in the target tissue. Such results might be biologically relevant in that it is suspected that TCDD and some of the herbicides used in Vietnam could indirectly generate free radicals or sensitize cells to free-radical injury; the exact relevance, however, has not been established. The foregoing evidence suggests that a connection between TCDD exposure and human neurotoxic effects is, in general, biologically plausible. However, definitive conclusions about the presence or absence of a mechanism of induction of neurotoxicity by TCDD in humans are complicated by differences in sensitivity and susceptibility among individual animals, strains, and species; the lack of strong evidence of organ-specific effects across species; and differences in route, dose, duration, and timing of exposure. Experiments with 2,4-D and 2,4,5-T indicate that they can have effects on brain cells at the subcellular level that could

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Veterans and Agent Orange: Update 2002 provide a biologically plausible mechanism of neurotoxicity if such toxicity is seen in animals or humans, but alone they do not provide a basis for concluding that they are neurotoxic. The observation of behavioral alterations in rats after exposure to 2,4-D also would support the neurotoxicity of this compound, but the species, strain, and dose specificities of the effects remain unknown. Considerable uncertainty remains about how to apply this information to the evaluation of potential health effects of herbicides or TCDD exposure in Vietnam veterans. Scientists disagree over the extent to which information derived from animals and cellular studies predicts human health outcomes and the extent to which the health effects resulting from high-dose exposure are comparable with those resulting from low-dose exposure. Investigating the biologic mechanisms underlying TCDD's toxic effects continues to be the subject of active research, and future updates of this report might have more and better information on which to base conclusions, at least for this compound. Increased Risk of Disease Among Vietnam Veterans The most recent Air Force Health Study publications (Michalek et al., 2001; Barrett et al., 2001) reported differences in prevalence of chronic peripheral neuropathy and verbal memory performance between the Ranch Hand and comparison groups, but the clinical relevance is not clear. The available data do not support the notion that the differences are associated with exposure to herbicides or TCDD. REFERENCES AFHS (Air Force Health Study). 1984. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Baseline Morbidity Study Results Brooks AFB, TX: USAF School of Aerospace Medicine. NTIS AD-A138 340. AFHS. 1987. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. First Followup Examination Results Brooks AFB, TX: USAF School of Aerospace Medicine. USAFSAM-TR-87-27. AFHS. 1991. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Serum Dioxin Analysis of 1987 Examination Results. Brooks AFB, TX: USAF School of Aerospace Medicine. AFHS. 1995. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1992 Followup Examination Results Brooks AFB, TX: Epidemiologic Research Division. Armstrong Laboratory. AFHS. 2000. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1997 Follow-up examination and results. Reston, VA: Science Application International Corporation. F41624–96–C1012. Albers JW, Brown MB, Sima AAF, Greene DA. 1996. Frequency of median mononeuropathy in patients with mild diabetic neuropathy in the early diabetes intervention trial (EDIT). Muscle and Nerve 19:140–146. Barrett DH, Morris RD, Akhtar FZ, Michalek JE. 2001. Serum dioxin and cognitive functioning among veterans of operation ranch hand. Neurotoxicology 22:491–502.

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Veterans and Agent Orange: Update 2002 Breland AE, Currier RD. 1967. Multiple Sclerosis and amyotrophic lateral sclerosis in Mississippi Neurology 17:1011–1016. Brooks BR. 1996. Clinical epidemiology of amyotrophic lateral sclerosis. Neurological Clinics 14(2):399–420. Burns CJ, Beard KK, Cartmill JB. 2001. Mortality in chemical workers potentially exposed to 2,4-dichlorophenoxyacetic acid (2,4-D) 1945–94: An update. Occupational and Environmental Medicine 58:24–30. Butterfield PG, Valanis BG, Spencer PS, Lindeman CA, Nutt JG. 1993. Environmental antecedents of young-onset Parkinson's disease. Neurology 43:1150–1158. Chan DK, Woo J, Ho SC, Pang CP, Law LK, Ng PW, Hung WT, Kwok T, Hui E, Orr K, Leung MF, Kay R. 1998. Genetic and environmental risk factors for Parkinson's disease in a Chinese population. Journal of Neurology, Neurosurgery, and Psychiatry 65(5):781–784. Chancellor AM, Slattery JM, Fraser H. 1993. Risk factors for motor neuron disease: A case–control study based on patients from the Scottish motor neuron disease register. Journal of Neurology, Neurosurgery, and Psychiatry 56:1200–1206. Chaturvedi S, Ostbye T, Stoessl AJ, Merskey H, Hachinski V. 1995. Environmental exposures in elderly Canadians with Parkinson's disease. Canadian Journal of Neurological Sciences 22:232– 234. Deapen DM, Henderson BE. 1986. A case-control study of amyotrophic lateral sclerosis. American Journal of Epidemiology 123:790–799. De Wytt CN, Jackson RV, Hockings GI, Joyner JM, Strakosch CR. 1999. Polyneuropathy in Australian outpatients with type II diabetes mellitus Journal of Diabetes and Its Complications 13:74– 78. Dyck PJ, Oviatt KF, Lambert EH. 1981. Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Annals of Neurology 10:222–226. Dyck PJ, Kratz KM, Karnes JL, 1993. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester diabetic study group. Neurology 43:817–824. Engel LS, Checkoway H, Keifer MC, Seixas NS, Longstreth WT, Scott KC, Hudnell K, Anger WK, Camicioli R. 2001. Parkinsonism and occupational exposure to pesticides. Occupational and Environmental Medicine 58:582–589. Fall PA, Fredrikson M, Axelson O, Granerus AK. 1999. Nutritional and occupational factors influencing the risk of Parkinson 's disease: a case-control study in southern Sweden. Movement Disorders 4:28–37. Feldman EL, Russell JW, Sullivan KA, Golovoy D. 1999. New insights into the pathogenesis of diabetic neuropathy. Current Opinion in Neurology 12:553–563. Gallagher JP, Sander M. 1987. Trauma and amyotrophic lateral sclerosis: A report of 78 patients Acta Neurologica Scandinavia 75:1041–1043. Gao H-M, Hong J-S, Zhang W, Liu B. 2002. Distinct role of microglia in rotenone-induced degeneration of dopaminergic neurons. The Journal of Neurosciences 22:782–790. Gauthier E, Fortier I, Courchesne F, Pepin P, Mortimer J, Gauvreau D. 2001. Environmental pesticide exposure as a risk factor for Alzheimer's disease: A case–control study. Environmental Research Section A 86:37–45. Golbe LI, Farrell TM, Davis PH. 1990. Follow-up study of early-life protective and risk factors in Parkinson 's disease. Movement Disorders 5:66–70. Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Richardson RJ. 1998. The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living. Neurology 50:1346– 1350. Grahmann F, Claus D, Grehl H, Neundoerfer B. 1993. Electrophysiologic evidence for a toxic polyneuropathy in rats after exposure to 2,3,7,8-tertachlorodibenzo-p-dioxin (TCDD). Journal of Neurological Sciences 115(1):71–75.

OCR for page 447
Veterans and Agent Orange: Update 2002 Greenamyre JT. 2001. The rotenone model of Parkinson's disease: In vivo and in vitro studies. Abstracts/Neurotoxicology 22:878. Grehl H, Grahmann F, Claus D, Neundorfer B. 1993. Histologic evidence for a toxic polyneuropathy due to exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats. Acta Neurologica Scandinavica 88(5):354–357. Gunnarsson LG, Lindberg G, Soderfeldt B, Axelson O. 1991. Amyotrophic lateral sclerosis in Sweden in relation to occupation Acta Neurologica Scandinavica 83(6)394–398. Hanisch R, Dworsky RL, Henderson BE. 1976. A search for clues to the cause of amyotrophic lateral sclerosis. Archives of Neurology 33:456–457. Hertzman C, Wiens M, Bowering D, Snow B, Calne D. 1990. Parkinson's disease: a case–control study of occupational and environmental risk factors. American Journal of Industrial Medicine 17:349–355. Hertzman C, Wiens M, Snow B, Kelly S, Calne D. 1994. A case–control study of Parkinson's disease in a horticultural region of British Columbia. Movement Disorders 9:69–75. Ho SC, Woo J, Lee CM. 1989. Epidemiologic study of Parkinson's disease in Hong Kong. Neurology 39:1314–1318. Hubble JP, Cao T, Hassanein RE, Neuberger JS, Koller WC. 1993. Risk factors for Parkinson's disease. Neurology 43:1693–1697. Hubble JP, Kurth JH, Glatt SL, Kurth MC, Schellenberg GD, Hassanein RE, Lieberman A, Koller WC 1998. Gene–toxin interaction as a putative risk factor for Parkinson's disease with dementia. Neuroepidemiology 17:96–104. IOM (Institute of Medicine). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam Washington, DC: National Academy Press. IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. IOM. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: National Academy Press. Jimenez-Jimenez FJ, Mateo D, Gimenez-Roldan S. 1992. Exposure to well water and pesticides in Parkinson's disease: a case-control study in the Madrid area. Movement Disorders 7:149–152. Koller W, Vetere-Overfield B, Gray C, Alexander C, Chin T, Dolezal J, Hassanein R, Tanner C. 1990. Environmental risk factors in Parkinson's disease. Neurology 40:1218–1221. Kuopio A, Marttila RJ, Helenius H, Rinne UK. 1999. Environmental risk factors in Parkinson's disease. Movement Disorders 14:928–939. Kurtzke JF, Beebe GW. 1980. Epidemiology of amyotrophic lateral sclerosis: 1. A case–control comparison based on ALS deaths. Neurology 30:453–462. Langston, JW. 1998. Epidemiology versus genetics in Parkinson's disease: Progress in resolving an age-old debate. Annals of Neurology 44(Suppl 1):S45–S52. Le Couteur DG, McLean AJ, Taylor MC, Woodham BL, Board PG. 1999. Pesticides and Parkinson's disease. Biomedicine and Pharmacotherapy 53:122–130. 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. McCann SJ, LeCouteur DG, Green AC Brayne C, Johnson AG, Chan D, McManus ME, Pond SM. 1998. The epidemiology of Parkinson's disease in an Australian population. Neuroepidemiology 17:310–317. McGuire V, Longstreth WT, Nelson LM, Koepsell TD, Checkoway H, Morgan MS, van Belle G. 1997. Occupational exposure and amyotrophic lateral sclerosis: A population-based case–control study. American Journal of Epidemiology 145:1076–1088. McLeod JG. 1995. Investigation of peripheral neuropathy. Journal of Neurology, Neurosurgery and Psychiatry 58:274–283. Menegon A, Board PG, Blackburn AC, Mellick GD, LeCouteur DG. 1998. Parkinson's disease, pesticides, and glutathione transferase polymorphisms. Lancet 352:1344–1346. Michalek JE, Akhtar FZ, Arezzo JC, Garabrant DH, Albers JW. 2001. Serum dioxin and peripheral neuropathy in veterans of Operation Ranch Hand. Neurotoxicology 22:479–490.

OCR for page 447
Veterans and Agent Orange: Update 2002 Morano A, Jimenez-Jimenez FJ, Molina JA, Antolin MA. 1994. Risk-factors for Parkinson's disease: case–control study in the province of Caceres, Spain. Acta Neurologica Scandinavica 89(3):164–170. Pazderova-Vejlupkova J, Nemcova M, Pickova J, Jirasek L. 1981. The development and prognosis of chronic intoxication by tetrachlorodibenzo-p-dioxin in men. Archives of Environmental Health 36:5–11. Pelclova D, Fenclova Z, Dlaskova Z, Urban P, Lukas E, Prochazka B, Rappe C. 2001. Biochemical, neuropsychological, and neurological abnormalities following 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. Archives of Environmental Health 56:493–500. Petrovich H, Ross GW, Abbott RD, Sanderson WT, Sharp DS, Tanner, CM, Masaki KH, Blanchette PL, Popper JS, Foley D, Launer L, White LR. 2002. Plantation work and risk of Parkinson's disease in a population-based longitudinal study. Archives of Neurology 59(11):1787–1792. Pirart J. 1978. Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973. Diabetes Care 1:168–188. Priyadarshi A, Khuder SA, Schaub EA, Shrivastava S. 2000. A meta-analysis of Parkinson's disease and exposure to pesticides. NeuroToxicology 21(4):435–440. Ritz B, Yu F. 2000. Parkinson's disease mortality and pesticide exposure in California 1984–1994. International Journal of Epidemiology 29:323–329. Roelofs-Iverson RA, Mulder DW, Elverback LR, Kurland LT, Craig AM. 1984. ALS and heavy metals: A pilot case-control study. Neurology 34:393–395. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O'Regan JP, Deng HX, Rahmani Z, Krizus A, McKenna-Yasek D, Cayabyab A, Gaston S, Tanzi R, Halperin JJ, Herzfeldt B, Van den Berg R, Hung WY, Bird T, Deng G, Mulder DW, Smith C, Laing NG, Soriano E, Pericak-Vance MA, Haines J, Rouleau GA, Gusella J, Horvitz HR, Brown RH. 1993. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362(6415):59–62. Rowland LP. 1998. Diagnosis of amyotrophic lateral sclerosis. Journal Neurological Science 160(Suppl 1):S6–S24. Rowland LP, Shneider NA. 2001. Amyotrophic lateral sclerosis. The New England Journal of Medicine 344:1688–1699. Savettieri G, Salemi G, Arcara A, Cassata M, Castiglione MG, Fierro B. 1991. A case–control study of amyotrophic lateral sclerosis. Neuroepidemiology 10:242–245. 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. Simmons Z, Feldman EL. 2002. Update on diabetic neuropathy. Current Opinion in Neurology 15:595–603. Smargiassi A, Mutti A, DeRosa A, DePalma G, Negrotti A, Calzetti S. 1998. A case-control study of occupational and environment risk factors for Parkinson's disease in the Emilia-Romagna region of Italy. NeuroToxicology 19:709–712. Stern M, Dulaney E, Gruber SB, Golbe L, Bergen M, Hurtig H, Gollomp S, Stolley P. 1991. The epidemiology of Parkinson's disease. A case-control study of young-onset and old-onset patients Archives of Neurology 48:903–907. Tanner CM, Chen B, Wang W, Peng M, Liu Z, Liang X, Kao LC, Gilley DW, Goetz CG, Schoenberg BS. 1989. Environmental factors and Parkinson's disease: a case-control study in China. Neurology 39:660–664.

OCR for page 447
Veterans and Agent Orange: Update 2002 Taylor CA, Saint-Hilaire MH, Cupples LA, Thomas CA, Burchard AE, Feldman RG,Myers RH. 1999. Environmental, medical, and family history risk factors for Parkinson 's disease: a New England-based case control study. American Journal of Medical Genetics (Neuropsychiatric Genetics) 88:742–749. Tuchsen F, Jensen AA. 2000. Agricultural work and the risk of Parkinson's disease in Denmark, 1981–1993. Scandinavian Journal of Work, Environment, and Health 26:359–362. Wechsler LS, Checkoway H, Franklin GM, Costa LG. 1991. A pilot study of occupational and environment risk factors for Parkinson 's disease. NeuroToxicology 12:387–392. Weiss B. 2000. Vulnerability to pesticide neurotoxicity is a lifetime issue. Neurotoxicology 21(1– 2) :67–73. Wong GF, Gray CS, Hassanein RS, Koller WC. 1991. Environmental risk factors in siblings with Parkinson's disease. Archives of Neurology 48:287–289. Young MJ, Boulton AJ, Macleod AF, Williams DR, Sonksen PH. 1993. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia 36(2):150–154.