Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 566
Veterans and Agent Orange: Update 2006 8 Neurologic Disorders Neurologic disorders include a wide variety of medical conditions. The nervous system can be divided anatomically and functionally into the central nervous system (CNS) and the peripheral nervous system (PNS). Distinguishing between CNS dysfunction and PNS dysfunction is a useful starting point for understanding and evaluating neurologic disorders. The CNS consists of the brain and the spinal cord. CNS disorders can be broadly divided into neurobehavioral disorders and movement disorders. Neurobehavioral disorders can involve cognitive syndromes, including memory problems, dementia, and Alzheimer’s disease; and neuropsychiatric problems, including neurasthenia (a collection of such symptoms as difficulty in concentrating, headache, insomnia, and fatigue), posttraumatic stress disorder, anxiety disorder, depression, and suicide. Those disorders result from problems in the cerebral cortex or limbic system. Movement disorders, such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), involve weakness, tremors, involuntary movements, incoordination, or gait abnormalities. Those disorders result from problems in the basal ganglia, cerebellum, or spinal cord. The PNS includes the spinal nerve roots that leave the spinal cord through the vertebral column, traverse the brachial and lumbar plexuses, and end in the peripheral nerves that connect with muscles, skin, and internal organs. PNS disorders are classified as various types of peripheral neuropathy, which can involve sensory changes, motor weakness, or autonomic instability. Those disorders result from problems in somatic or autonomic nerves or both. Neurologic disorders can also be classified on the basis of anatomic distribution as global or focal, on the basis of timing relative to exposure to a causative agent, as early or of delayed onset, or on the basis of duration as transient or
OCR for page 567
Veterans and Agent Orange: Update 2006 persistent. For example, global CNS dysfunction can lead to a general abnormality, such as an altered level of consciousness, whereas focal CNS dysfunction might lead to an isolated abnormality, such as difficulty with language function (aphasia). Early-onset disorders are seen within days or weeks of exposure; delayed onset may occur after months or years. Transient disorders are short-lived; persistent disorders produce lasting deficits. Timing is important in assessing the effects of chemical exposure on neurologic function and must be considered in the design and critique of epidemiologic studies. In the original Veterans and Agent Orange report, hereafter referred to as VAO (IOM, 1994), attention was deliberately focused on persistent neurobehavioral disorders. Veterans and Agent Orange: Update 1996, or Update 1996 (IOM, 1996); Veterans and Agent Orange: Update 1998, or Update 1998 (IOM, 1999); Veterans and Agent Orange: Update 2000, or Update 2000 (IOM, 2001); Veterans and Agent Orange: Update 2002, or Update 2002 (IOM, 2003); Veterans and Agent Orange: Update 2004, or Update 2004 (IOM, 2005); and this report review data pertinent to all neurologic disorders. Case identification in neurologic disorders is often difficult because there are few disorders for which there are specific diagnostic tests. Many disorders involve cellular or molecular biochemical effects, so even the most advanced imaging techniques can miss an abnormality. Because the nervous system is not readily accessible for biopsy, pathologic confirmation usually is not feasible. Furthermore, neurologic disorders are by their nature largely subjective, so there often is no objective evidence with which to confirm a diagnosis. Many studies have addressed the possible contribution of various chemical exposures to neurologic disorders, but the committee’s focus is on the health effects of a particular set of chemicals: four herbicides (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 [dimethyl arsinic acid or DMA]) and a contaminant of 2,4,5-T, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Thus, the specificity of exposure assessment is an important consideration in weighing evidence relevant to the committee’s charge, as described earlier (Chapters 2 and 5). This chapter reviews the association between exposure to the compounds of interest and neurobehavioral disorders, movement disorders, and peripheral neuropathy. The scientific evidence supporting biologic plausibility also is reviewed briefly here; a more thorough discussion of updated toxicologic studies is in Chapter 3. More complete discussions of the categories of association and of this committee’s approach to categorizing health outcomes are presented in Chapters 1 and 2. If a study new to this update reports only a single neurologic outcome and is not revisiting a previously studied population, its design information is summarized with its results; design information on other new studies is in Chapter 4.
OCR for page 568
Veterans and Agent Orange: Update 2006 NEUROBEHAVIORAL (COGNITIVE OR NEUROPSYCHIATRIC) DISORDERS This section summarizes the findings of VAO and previous updates on neurobehavioral disorders and incorporates information published in the last 2 years into the evidentiary database. Conclusions from VAO and Updates On the basis of the data available at the time, it was concluded in VAO, Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 that there was inadequate or insufficient evidence to determine the existence of an association between exposure to the compounds of interest and neurobehavioral disorders. Many of the data that informed that conclusion came from the Air Force Health Study (AFHS, 1984, 1987, 1990, 1991, 1995, 2000, 2005). VAO and the updates offer more complete discussions of the results. The AFHS study design and methods of exposure assessment are discussed in Chapters 4 and 5, respectively. The studies reviewed in VAO (IOM, 1994) revealed no association between serum TCDD concentration and reported sleep disturbance or variables on the Symptom Checklist-90-Revised (SCL-90-R). In contrast, serum TCDD was significantly associated with responses on some scales of the Millon Clinical Multiaxial Inventory. In Update 2000 (IOM, 2001), results from the AFHS indicated that although the frequency of several self-reported neuropsychiatric symptoms differed between exposure groups, the associations were not significant after adjustment for covariates. In addition, a repeat psychologic assessment with the SCL-90-R in conjunction with self-reported psychologic disorders verified through medicalrecord review showed that among five diagnostic categories (psychosis, alcohol dependence, drug dependence, anxiety, and other neurosis), a dose–response pattern with serum TCDD concentration was found only for “other neuroses” in the enlisted ground crew. When the entire cohort was evaluated, there were no significant associations between serum TCDD and various psychologic diagnoses. Update 2002 (IOM, 2003) reviewed three studies. Neuropsychologic tests of cognitive functioning indicated significant group differences on some scales, but the findings did not support a dose–response relationship with serum TCDD: poorer performance was seen in groups with background or low exposure, and the lower performance on only one memory test for one subgroup of subjects suggested a chance finding. Update 2004 (IOM, 2005) reviewed five new studies. Among them was a report on the AFHS cohort (Barrett et al., 2003) in which the authors conclude that there were “few consistent differences in psychological functioning” between groups categorized by serum dioxin concentrations. Another report
OCR for page 569
Veterans and Agent Orange: Update 2006 described increased prevalence of PTSD among Korean military who served in Vietnam, although there was no association with estimated exposure to Agent Orange. The remaining three studies were uninformative because of methodologic limitations. Prior committees have maintained the conclusion that there has been inadequate or insufficient evidence of an association between exposure to the compounds of interest and neurobehavioral disorders (cognitive or neuropsychiatric). Update of the Epidemiologic Literature Since Update 2004, Park et al. (2005) investigated the association between occupational factors and mortality from neurodegenerative diseases, including Alzheimer’s disease and presenile dementia (PSD), PD, and motor neuron disease (see also the section on PD and parkinsonism below). The authors examined data from 1992–1998 death certificates for over 2.6 million deaths in 22 states. They report mortality odds ratios associated with subjects’ “usual occupation” and with a subgroup of “pesticide-exposed” occupations. Subjects who had worked in “pest control” had significantly increased risk for PSD (odds ratio [OR] = 2.96). However, the exposure assessment was too imprecise for the results to inform the present committee’s conclusions. A study of Australian Vietnam veterans reported an association between deployment in Vietnam and “mental disorders” (ADVA, 2005c). The authors state that “there was a borderline significant elevation in mortality from mental disorders, with a relative rate of 2.75 (95% confidence interval [CI] 0.98–8.83). The number of deaths for this group of diseases was small enough for an examination to be made for the 19 deaths involved. All of the deaths were due to conditions associated with alcohol or drug misuse.” Therefore, that report did not inform the committee’s conclusions regarding the possible association between neurobehavioral disorders and exposure to herbicides in Vietnam. Biologic Plausibility A few animal studies suggesting possible involvement of chemicals of interest in neurobehavioral effects were identified in this review. Mitsui et al. (2006) suggested that hippocampus-dependent learning could be impaired in male rats exposed in utero to TCDD producing effects on fear conditioning, via hippocampus effects, in adult male rats exposed to TCDD while in utero. Lensu et al. (2006) examined areas in the hypothalamus for possible involvement in TCDD effects on food consumption, potentially related to wasting syndrome caused by TCDD, and suggest that their results are not consistent with a primary role for the hypothalamus. Although this study does not address cognitive or neuropsychiatric disorders, it involves behavior (food consumption). There also were studies in rodents that detected molecular effects in cerebellar granule cells or
OCR for page 570
Veterans and Agent Orange: Update 2006 neuroblasts, which are involved in cognitive and motor processes (Kim and Yang, 2005; Williamson et al., 2005) A general summary of the biologic plausibility of neurologic effects of exposure to the herbicides used in Vietnam is presented at the end of this chapter, and detailed discussion is in Chapter 3. Synthesis There is not consistent epidemiologic evidence of an association between neurobehavioral disorders (cognitive or neuropsychiatric) and Agent Orange exposure. Difficulties in case identification and diagnosis, misclassification of exposures because of a lack of contemporaneous measures, subject ascertainment and selection bias, and uncontrolled confounding from many comorbid conditions are common weaknesses in the studies reviewed. The variability of the test results over time, the weak and inconsistent associations, and a lack of consistent dose–response relationships also detract from evidence of an association between the exposures of interest and neurobehavioral disorders. Conclusion On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is still inadequate or insufficient evidence to determine the existence of an association between exposure to the compounds of interest and neurobehavioral disorders (cognitive or neuropsychiatric). MOVEMENT DISORDERS This section summarizes the findings of previous VAO reports on movement disorders, including PD and ALS, and incorporates information published in the last 2 years into the evidentiary database. Parkinson’s Disease and Parkinsonism PD is a progressive neurodegenerative disorder that affects millions of people worldwide. Its primary clinical manifestations are bradykinesia, resting tremor, cogwheel rigidity, and gait instability. Those signs were first described in 1817 as a single entity by James Parkinson, who believed that severe fright from a traumatic experience was a probable cause. Despite nearly 2 centuries of investigation, the true causes of the disease remain enigmatic, and the diagnosis still relies on a characteristic constellation of signs found in a clinical neurologic examination. However, the signs are not pathognomonic; they are seen in other disorders, including parkinsonism resulting from syndromes that are virtually indistinguishable from PD. Ultimately, a diagnosis of PD can be confirmed with
OCR for page 571
Veterans and Agent Orange: Update 2006 postmortem pathologic examination of brain tissue for the characteristic loss of neurons from the substantia nigra and telltale Lewy body intracellular inclusions. Pathologic findings in other causes of parkinsonism show different patterns of brain injury. Estimates of population-based incidence of PD range from 2 to 22 per 100,000 person-years, and estimates of prevalence range from 18 to 182 per 100,000 person-years. That makes PD the second-most common neurodegenerative disease (after Alzheimer’s disease). Age is the only definite risk factor for PD; peak incidence and prevalence are consistently found in the seventh and eighth decades of life. Heredity has long been suspected as a primary risk factor for PD, and identification of evidence of genetic transmission—marked by the determination of specific mutations in two genes, Parkin and α-synuclein—has accumulated over the last decade. However, it has become clear that simple Mendelian transmission can account only for some rare forms of familial and early-onset PD. Conclusions from VAO and Updates On the basis of growing concerns about a possible link between PD and pesticide exposures, the original VAO committee suggested that attention be paid to the pattern of new cases in Vietnam veterans as they enter the decades when PD is most prevalent to determine whether there is evidence of an association between PD and exposure to the compounds of interest. That recommendation has been echoed in each update. Prior studies have identified PD on the basis of clinical signs or diagnostic coding (ICD-9 332) from death certificates or hospital admission records. Although exposure would be relevant to causation if it occurred before disease onset, the specific timing of exposure and disease onset is often unknown. The Update 1996 and Update 1998 committees considered the detection of early-onset cases to be vital to test the hypothesis that cases are related to a toxic exposure. The Update 2000 committee noted that most studies had grouped cases of all ages; studies that separated early-onset cases have yielded inconsistent results (Butterfield et al., 1993; Stern et al., 1991). Estimates of relative risk have also been inconsistent: five studies demonstrate positive associations (Butterfield et al., 1993; Gorell et al., 1998; Liou et al., 1997; Seidler et al., 1996; Semchuk et al., 1992), two demonstrate negative associations (Kuopio, 1999; Stern et al., 1991), and one shows no association (Taylor et al., 1999). A meta-analysis indicated significant heterogeneity in the published work (Priydarshi et al., 2000). Evidence supporting a dose–response relationship was limited to one study (Gorell et al., 1998), which demonstrated an increased incidence of PD with increasing dose as measured by duration of exposure. Update 2002 reviewed reports of two cohort studies (Engel et al., 2001;
OCR for page 572
Veterans and Agent Orange: Update 2006 Petrovich et al., 2002), whose results were similar to those of the many other studies reviewed for earlier updates. Long duration of agricultural work was associated with parkinsonism in many reports, but the results did not show consistent dose–response trends, and no association with any specific compound of interest was identified. Update 2004 reviewed reports of three epidemiologic studies: a cohort study (Baldi et al., 2003a) and a nested case–control study (Baldi et al., 2003b) in France and a case–control study in Belgium (Pals et al., 2003). None showed significant associations with the compounds of interest. None of the studies has described specific exposures to the compounds of interest. Table 8-1 summarizes the relevant studies. Update of the Epidemiologic Literature Since Update 2004, several reports have examined the possible associations between PD and pesticide exposures, but none has addressed exposure to herbicides in particular or specifically to the chemicals of interest for this series of reviews. One was a mortality study described in the section on neurobehavioral disorders (Park et al., 2005), another was a prospective cohort study (Ascherio et al., 2006), and one was derived from the AHS cohort (Kamel et al., 2005). Ascherio et al. (2006) investigated the relationship between PD and exposures self-reported in 1992 among the 143,325 participants in the Cancer Prevention Study II Nutrition Cohort who responded to the 2001 health status survey. Medical records were obtained for 677 of the 840 reported cases of PD, permitting a movement disorder specialist to confirm 588 cases (413 diagnosed after 1992). After adjusting for age, sex, and smoking, the risk for PD was higher among the 5.7 percent of the participants (n = 7,864) reporting exposure to pesticides or herbicides compared to those not reporting such exposure (RR = 1.7, 95% CI 1.2–2.3, p = 0.002); this risk remained unchanged whether occupation was a farmer or not. The statistical significance of the findings for “pesticides/herbicides” in this large prospective study with information on some possible confounders is worthy of note in light of the absence of association with the other 11 exposures studied, but again any elevation in the risk of PD cannot be attributed specifically to the chemicals of interest in this report with any certainty. The design of the mortality study by Park et al. (2005) was not as strong. Information from death certificates was used to identify subjects with PD and their usual occupations. A primary limitation of the study is that “exposure to pesticides” was inferred on the basis of a retrospective job–exposure matrix that was not constructed to account for specific compounds; thus, although the authors indicated that exposure to pesticides was associated with mortality from PD, exposure to specific compounds of interest was not assessed. From the baseline (cross-sectional) data collected in the Agricultural Health Study, exposure to various herbicides was more common in subjects who reported
OCR for page 573
Veterans and Agent Orange: Update 2006 TABLE 8-1 Epidemiologic Studies of Pesticidea Exposure and Parkinson’s Diseaseb Reference and Country Cases in Study Group Comparison Group Exposure Assessment Significant Association with Pesticidesa OR (95 % CI) Neurologic Dysfunction Ascherio et al., 2006; US 413 confirmed cases of PD diagnosed after 1992 142,485 respondents to 2001 survey without self- report of PD 1992 baseline self-report of exposure to pesticides + 1.7 (1.2–2.3) 2001 follow-up of health outcomes; confirmation of PD self-report with medical records Kamel et al., 2005; US Questionnaire—self-reported pesticide use by number of days per year Symptoms that might be indicative of Parkinson’s disease, but no formal diagnosis Park et al.,2005; US 33,678 cases of PD, during 1992 to 1998 Death certificates—any mention of PD along with an occupation associated with probable pesticide exposure + Farming 1.2 (1.1–1.2) Death certificates from 22 states with any mention of PD Baldi et al., 2003a; France 585 men (age > 70 years) Questionnaire—detailed occupational histories + Occupational pesticides (mostly fungicides) 5.6 (1.5–21.6) Self-report at 8 and 10 year follow-ups Baldi et al., 2003b; France 84 (age > 70 years) 252 (age > 70 years) Interview–Occupational history coded by experts–Residential history + Occupational pesticides (mostly fungicides) 2.2 (1.1–3.4) UK PD Society Brain Bank clinical criteria
OCR for page 574
Veterans and Agent Orange: Update 2006 Reference and Country Cases in Study Group Comparison Group Exposure Assessment Significant Association with Pesticidesa OR (95 % CI) Neurologic Dysfunction Palset al., 2003; Belgium 423 205 Questionnaire—occupational history not interpreted with respect to pesticide use Neurologic exam 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 exam Engel et al., 2001; US 238 72 Self-administered questionnaire for occupational exposure + Pesticides 0.8 (0.5–1.2) Highest tertile pesticide 2.0 (1.0–4.2) Herbicide 0.9 (0.6–1.3) Neurologic exam by trained nurse 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) ICD-9 332 Tuchsenand Jensen, 2000; Denmark 134 128,935 expected cases 101.5 Occupations in farming, horticulture, and landscape expected to have exposure to pesticides + Age-standardized hospitalization ratio for all men in agriculture and horticulture 1.34 (1.09–1.62) First-time hospitalization for PD Fallet al., 1999; Swedenc 113 263 Questionnaire—any job handling pesticides Pesticides 2.8 (0.9–8.7) Neurologic exam
OCR for page 575
Veterans and Agent Orange: Update 2006 Kuopio et al., 1999; Finland 123 (onset of PD before 1984) 279 Interview—pesticides or herbicides regularly or occasionally used Regular use of herbicides 0.7 (0.3–1.3) Neurologic exam Taylor et al., 1999; US 140 147 Interview—exposure recorded as total days for lifetime Pesticides 1.02 (0.9–1.2) Herbicides 1.06 (0.7–1.7) Neurologic exam 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 exam 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) Standard criteria of PD by history Hubble et al., 1998; US 3 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 exam 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 exam Menegon et al., 1998; Australia 96 95 Interview—pesticide exposure more than once weekly for >6 months before onset of PD + Pesticides 2.3 (1.2–4.4) Standard criteria of PD by history Smargiassi et al., 1998; Italyc 86 86 Interview—occupational exposure for at least 10 consecutive years Pesticides or herbicides 1.15 (0.6–2.4) Standard criteria of PD by history
OCR for page 576
Veterans and Agent Orange: Update 2006 Reference and Country Cases in Study Group Comparison Group Exposure Assessment Significant Association with Pesticidesa OR (95 % CI) Neurologic Dysfunction Liou et al., 1997; Taiwanc,d 120 240 Interview—Occupational exposures to herbicides orpesticides + Herbicides or pesticides, no paraquat 2.2 (0.9–5.6) Paraquat use 3.2 (2.4–4.3) Neurologic exam Schulte et al., 1996; USd 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; Germanyc,d 380 (age < 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 exam 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 Hertzman et al., 1994; Canadac 127 245 Interview—occupation with probable pesticide exposure + Pesticides in men 2.3 (1.1–4.9) Neurologic exam Morano et al., 1994; Spainc 74 148 Interview—direct and indirect exposure to pesticides Pesticides 1.73 (1.0–3.0) Neurologic exam
OCR for page 588
Veterans and Agent Orange: Update 2006 TCDD at a BASF plant. Decoufle et al. (1992) reported no association between self-reported exposure to herbicides in Vietnam and peripheral neuropathy. The limitations of those studies were such that they did not confirm or refute a possible relationship between exposure and neuropathy. In addition, the committee responsible for Update 1996 reviewed case reports that described peripheral neuropathy after exposures to the compounds of interest (Berkley and Magee, 1963; Goldstein et al., 1959; Todd, 1962). In each instance, the peripheral neuropathy improved gradually but had not resolved completely even after several months or years. The possibility cannot be entirely excluded that the five cases reported in those publications were unrelated to herbicide exposure and were examples of other disorders, such as idiopathic Guillain-Barré syndrome. The committee also considered several supportive animal models (Grahmann et al., 1993; Grehl et al., 1993; see “Biologic Plausibility” below). The committee concluded that there was limited or suggestive evidence of an association between exposure to the compounds of interest and early-onset transient peripheral neuropathy. Update 1998 reviewed no new studies. The context for the issue of peripheral neuropathy, its relationship with toxic exposures, and the occurrence of diabetes mellitus was discussed. In particular, it was noted that neuropathy is a common consequence of diabetes. That was particularly relevant because the committee issued a special report a year later that concluded that there was limited or suggestive evidence of an association between diabetes and exposure to Agent Orange. Update 2000 reviewed what was then the most recent report on RH veterans (AFHS, 2000), which combined signs of peripheral neuropathy to produce increasingly specific, graded indexes of neuropathy—a common approach in epidemiologic studies. RH veterans were significantly more likely than were comparison subjects to have abnormalities in the indexes, and the prevalence of abnormalities increased with dioxin concentration. Although the clinical relevance of epidemiologic indexes of neuropathy is never certain, the strong associations described between the indexes and the conditions known to produce peripheral neuropathy, such as diabetes and alcohol use, supported their validity in this study. The AFHS investigators included those conditions as potential confounders in the statistical analysis. However, the effect of diabetes could not be eliminated in the most specific neuropathy index, because there were not enough non-diabetic subjects. It therefore was impossible, lacking any effect of diabetes, to estimate the association between dioxin exposure and neuropathy. Update 2002 considered one peer-reviewed article that described the peripheral-neuropathy data on the AFHS cohort (Michalek et al., 2001). In a primary analysis, the investigators had included diabetes as a potential confounder in the statistical model. In a secondary analysis, subjects with conditions that were known to be associated with neuropathy were excluded, and subjects with diabetes were enumerated. In both analyses, there were strong and significant associa-
OCR for page 589
Veterans and Agent Orange: Update 2006 tions between possible and probable neuropathy and dioxin concentration, and significant trends were found with increasing concentrations of dioxin. However, there were too few non-diabetic subjects to produce meaningful estimates of risk in the absence of the contribution of diabetes. Thus, questions remained about the specific association between exposure to the compounds of interest and peripheral neuropathy in the absence of any effect of diabetes. Update 2004 also considered one peer-reviewed article (Kim et al., 2003), which reported an association between Korean veterans’ service in Vietnam and peripheral neuropathy. Methodologic limitations, such as a concern about recall bias and residual confounding due to diabetes, and issues related to the TCDD dose estimation prevented a strong inference. Update of the Scientific Literature Since Update 2004 (IOM, 2005), no reports dealing with peripheral neuropathy as a diagnosis have been published, although a cohort report (Kamel et al., 2005) assessed neurologic symptoms, some of which could arise from peripheral neuropathy. As mentioned in the section on PD, it is not clear how to interpret studies that simply rely on nonspecific clinical findings. Furthermore, it is not possible to rule out bias or residual confounding. There is no compelling new evidence that supports an association between peripheral neuropathy and exposure to the compounds of interest. Biologic Plausibility No new studies directly pertinent to peripheral neuropathy were identified in this update. However, it is worth reiterating findings from earlier updates. Neuronal cell cultures treated with 2,4-D showed decreased neurite extension associated with intracellular changes, including a decrease in microtubules, inhibition of the polymerization of tubulin, disorganization of the Golgi apparatus, and inhibition of ganglioside synthesis. Those mechanisms are important for maintaining synaptic connections between nerve cells and supporting the mechanisms involved in axon regeneration during recovery from peripheral neuropathy. Grahmann et al. (1993) and Grehl et al. (1993) reported on abnormalities in electrophysiology and pathology, respectively, observed in the peripheral nerves of rats treated with TCDD. When the animals were sacrificed 8 months after exposure, there was pathologic evidence of persistent axonal nerve damage and histologic findings typical of toxicant-induced injury. Those results constitute evidence of the biologic plausibility of an association between peripheral neuropathy and exposure to the compounds of interest. A summary of biological plausibility of neurologic effects arising from exposure to the compounds of interest is presented at the end of this chapter and more detailed discussion appears in Chapter 3.
OCR for page 590
Veterans and Agent Orange: Update 2006 Synthesis Over the last 50 years, a body of literature has accumulated that suggests an association between the compounds of interest and peripheral neuropathy. Past committees have concluded that there is evidence of an association between “acute and subacute transient” peripheral neuropathy and exposure to at least one compound of interest (Update 1996). However, there remained questions about whether evidence supported an association with persistent neuropathy. Human case reports have documented peripheral neuropathy after acute exposure to large amounts of 2,4-D as shown by neurologic examination and electrodiagnostic testing. Reports have indicated eventual symptom stabilization and improvement, but sensory and motor deficits have persisted in some people for months or years after exposure ended. Several epidemiologic studies have reported increased risk of peripheral neuropathy in populations exposed to the compounds of interest in a variety of occupational and environmental settings. However, the literature is inconsistent and suffers from methodologic limitations. The most dramatic exposures have involved industrial accidents that caused environmental contamination, such as the one in Seveso, Italy, in 1976. Studies of residents in that region have shown early-onset neuropathy, and subclinical abnormalities in some subjects have been demonstrated with electrodiagnostic testing. Epidemiologic studies that used appropriate comparison groups and standard techniques for diagnosis and assessment of exposure have not demonstrated consistent associations between exposure to the compounds of interest and the development of peripheral neuropathy. Several reports have shown no significant association, and in the reports that did indicate an association, chance, bias, or confounding could not be ruled out with confidence. In particular, diabetes might confound the results, inasmuch as many of the subjects with neuropathy also had diabetes, which is a known cause of neuropathy. Controlling for the effects of diabetes is a technical challenge because there is evidence of an association between diabetes and exposure to at least one of the compounds of interest (IOM, 2003); in many cases, diabetes could be in the causal pathway that links exposure and peripheral neuropathy. Conclusions On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to the compounds of interest and early-onset transient peripheral neuropathy. On the basis of its evaluation of the evidence reviewed here and previous VAO reports, the committee concludes that there is inadequate or insufficient
OCR for page 591
Veterans and Agent Orange: Update 2006 evidence of an association between exposure to the compounds of interest and delayed or persistent peripheral neuropathy. SUMMARY Biologic Plausibility Experimental data continue to accrue regarding the biologic plausibility of a connection between exposure to the compounds of interest and various neurologic disorders. This section summarizes in a more general way some of this information reviewed in the current update, as well as information from the prior update, for a more complete summary. A more detailed discussion of the newer research can be found in Chapter 3. The effects of TCDD are mediated by interaction with the AhR, a protein found in animal and human cells. The AhR complex is known to bind DNA and produce changes in transcription, thereby influencing genetic function. The AhR complex can produce an array of molecular effects that influence cell growth, hormone regulation, and normal cellular metabolism. Although some structural differences have been identified in the AhRs of different species, the AhR is functionally similar among species. Therefore, data from animal studies can be used to support the biologic plausibility of human neurotoxicity. Several studies have been published since Update 2004 that deal with mechanisms of neurotoxicity that might be ascribed to chemicals of concern, notably 2,4-D and TCDD. Molecular effects of the chemicals of concern are described in detail in Chapter 3. Some of those effects suggest possible pathways by which there could be effects on the neural systems involved in this outcome. A number of the studies suggest that there are neurological effects of chemicals of interest in animal models when exposure is during development. There also are some studies that further support suggestions that the level of reactive oxygen species could alter the functions of specific signaling cascades and may be involved in neurodegeneration. Although not specifically concerning the chemicals of interest, such studies are potentially relevant to the chemicals of concern, as TCDD and herbicides have been reported to elicit oxidative stress. The mechanistic studies suggest possible avenues to pursue to determine linkages between the chemicals of concern and the neurological outcomes that could result in adult humans. Basic scientific studies have emphasized the importance of alterations in neurotransmitter systems as potential mechanisms that underlie TCDD-induced neurobehavioral disorders. Neuronal cultures treated with 2,4-D exhibited decreased neurite extension associated with intracellular changes, including a decrease in microtubules, inhibition of the polymerization of tubulin, disorganization of the Golgi apparatus, and inhibition of ganglioside synthesis. Those mechanisms are important for maintaining the connections between nerve cells that are necessary for neuronal function and that are involved in axon regeneration and recovery
OCR for page 592
Veterans and Agent Orange: Update 2006 from peripheral neuropathy. Animal experiments have demonstrated that TCDD treatments affect the fundamental molecular events that underlie neurotransmission initiated by calcium uptake. Mechanistic studies have demonstrated that 2,4,5-T can alter cellular metabolism and cholinergic transmission necessary for neuromuscular transmission. TCDD treatment of rats at doses that do not cause general systemic illness or wasting disease produces electrodiagnostic changes in peripheral nerve function and pathologic findings that are characteristic of toxicant-induced axonal peripheral neuropathy. As discussed in Chapter 3, extrapolation of observations of cells in culture or animal models to humans is complicated by differences in sensitivity and susceptibility among animals, strains, and species; by the lack of strong evidence of organ-specific effects across species; and by differences in route, dose, duration, and timing of chemical exposures. Thus, although the observations in themselves cannot support a conclusion that Agent Orange produces neurotoxic effects in humans, the studies provide evidence of the biologic plausibility of an association. Conclusions On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence of an association between exposure to the compounds of interest (2,4-D, 2,4,5-T, TCDD, picloram, and cacodylic acid) and neurobehavioral disorders (cognitive or neuropsychiatric), PD, or ALS. In Update 1996, the committee concluded that there was limited or suggestive evidence of an association between exposure to at least one of the compounds of interest and “acute and subacute transient” peripheral neuropathy. The evidence 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 Update 2002 supported that conclusion. The committee for Update 2004 exhaustively reviewed the data on peripheral neuropathy and concluded that there was limited or suggestive evidence of an association between exposure and “early onset, transient” peripheral neuropathy, but that the evidence was inadequate or insufficient to support an association between exposure to the compounds of interest and “delayed or persistent” peripheral neuropathy. The present committee did not review new evidence that would modify the conclusions of prior VAO committees concerning possible associations between exposure to the chemicals sprayed in Vietnam and adverse neurologic health outcomes.
OCR for page 593
Veterans and Agent Orange: Update 2006 REFERENCES1 ADVA (Australian Department of Veteran’s Affairs). 2005b. The Third Australian Vietnam Veterans Mortality Study. Canberra, Australia: Department of Veterans’ Affairs. ADVA (Australian Department of Veteran’s Affairs). 2005c. Australian National Service Vietnam Veterans Mortality and Cancer Incidence Study. Canberra, Australia: Department of Veterans’ Affairs. AFHS (Air Force Health Study). 1984. An Epidemiological 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 Epidemiological Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. First Follow-up Examination Results. Brooks AFB, TX: USAF School of Aerospace Medicine. USAFSAM-TR-87-27. AFHS. 1990. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Brooks AFB, TX: USAF School of Aerospace Medicine. USAFSAM-TR-90-2. AFHS. 1991. An Epidemiological 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 Epidemiological Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1992 Follow-up Examination Results. Brooks AFB, TX: Epidemiological Research Division. Armstrong Laboratory. AFHS. 2000. An Epidemiological 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. Ascherio A, Chen H, Weisskopf MG, O’Reilly E, McCullough ML, Calle EE, Schwarzschild MA, Thun MJ. 2006. Pesticide exposure and risk for Parkinson’s disease. Annals of Neurology 60(2):197–203. Assennato G, Cervino D, Emmett E, Longo G, Merlo F. 1989. Follow-up of subjects who developed chloracne following TCDD exposure at Seveso. American Journal of Industrial Medicine 16:119–125. Baldi I, Lebailly P, Mohammed-Brahim B, Letenneur L, Dartigues J-F, Brochard P. 2003a. Neurodegenerative diseases and exposure to pesticides in the elderly. American Journal of Epidemiology 157(5):409–414. Baldi I, Cantagrel A, Lebailly P, Tison F, Dubroca B, Chrysostome V, Dartigues J-F, Brochard P. 2003b. Association between Parkinson’s disease and exposure to pesticides in southwestern France. Neuroepidemiology 22:305–310. Barbieri S, Pirovano C, Scarlato G, Tarchini P, Zappa A, Maranzana M. 1988. Long-term effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the peripheral nervous system. Clinical and neurophysiological controlled study on subjects with chloracne from the Seveso area. Neuroepidemiology 7:29–37. Barrett DH, Morris RD, Jackson WG Jr, Stat M, Michalek JE. 2003. Serum dioxin and psychological functioning in US Air Force veterans of the Vietnam War. Military Medicine 168:153–159. Berkley MC, Magee KR. 1963. Neuropathy following exposure to a dimethylamine salt of 2,4-D. Archives of Internal Medicine 111:133–134. 1 Throughout the report the same alphabetic indicator following year of publication is used consistently for the same article when there were multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicator in order of citation in a given chapter is not followed.
OCR for page 594
Veterans and Agent Orange: Update 2006 Boeri R, Bordo B, Crenna P, Filippini G, Massetto M, Zecchini A. 1978. Preliminary results of a neurological investigation of the population exposed to TCDD in the Seveso region. Rivista di Patologia Nervosa e Mentale 99:111–128. 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. CDC (Centers for Disease Control and Prevention). 1988. Health status of Vietnam veterans. II. Physical health. Journal of the American Medical Association 259:2708–2714. Celik I, Tuluce Y, Isik I. 2006. Influence of subacute treatment of some plant growth regulators on serum marker enzymes and erythrocyte and tissue antioxidant defense and lipid peroxidation in rats. Journal of Biochemical and Molecular Toxicology 20(4):174–182. 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. Decoufle P, Holmgreen P, Boyle CA, Stroup NE. 1992. Self-reported health status of Vietnam veterans in relation to perceived exposed to herbicides and combat. American Journal of Epidemiology 135:312–323. Elbaz A, Levecque C, Clavel J, Vidal J-S, Richard F, Amouyel P, Alpérovitch A, Chartier-Harlin M-C, Tzourio C. 2004. CYP2D6 Polymorphism, pesticide exposure, and Parkinson’s disease. Annals of Neurology 55:430–434. 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. Filippini G, Bordo B, Crenna P, Massetto N, Musicco M, Boeri R. 1981. Relationship between clinical and electrophysiological findings and indicators of heavy exposure to 2,3,7,8-tetrachlorodibenzodioxin. Scandinavian Journal of Work, Environment and Health 7:257–262. Gallagher JP, Sander M. 1987. Trauma and amyotrophic lateral sclerosis: A report of 78 patients. Acta Neurologica Scandinavia 75:1041–1043. Gilioli R, Cotroneo L, Bulgheroni C, Genta PA, Rota E, Cannatelli P, Fereari E. 1979. Neurological monitoring of workers exposed to TCDD: Preliminary neurophysiological results. Activitas Nervosa Superior 21:288–290. 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.
OCR for page 595
Veterans and Agent Orange: Update 2006 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. 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-tetrachlorodibenzo-p-dioxin (TCDD). Journal of Neurological Sciences 115(1):71–75. 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. 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. Epidemiological study of Parkinson’s disease in Hong Kong. Neurology 39:1314–1318. Hoffman RE, Stehr-Green PA, Webb KB, Evans RG, Knutsen AP, Schramm WF, Staake JL, Gibson BB, Steinberg KK. 1986. Health effects of long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of the American Medical Association 255:2031–2038. 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. IOM. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. IOM. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. IOM. 2006. Amyotrophic Lateral Sclerosis in Veterans: Review of the Scientific Literature. Washington, DC: The National Academies 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. Kamel F, Engel LS, Gladen BC, Hoppin JA, Alavanja MC, Sandler DP. 2005. Neurologic symptoms in licensed private pesticide applicators in the Agricultural Health Study. Environmental Health Perspectives 113(7):877–882. Kim JS, Lim HS, Cho SI, Cheong HK, Lim MK. 2003. Impact of Agent Orange exposure among Korean Vietnam veterans. Industrial Health 41(3):149–157. Kim SY, Yang JH. 2005. Neurotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in cerebellar granule cells. Experimental and Molecular Medicine 37:58–64. 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.
OCR for page 596
Veterans and Agent Orange: Update 2006 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. Le Couteur DG, McLean AJ, Taylor MC, Woodham BL, Board PG. 1999. Pesticides and Parkinson’s disease. Biomedicine and Pharmacotherapy 53:122–130. Lensu S, Miettinen R, Pohjanvirta R, Lindén J, Tuomisto J. 2006. Assessment by c-Fos immunostaining of changes in brain neural activity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and leptin in rats. Basic and Clinical Pharmacology and Toxicology 98:363–371. 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. 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. Mitsui T, Sugiyama N, Maeda S, Tohyama C, Arita J. 2006. Perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin suppresses contextual fear conditioning-accompanied activation of cyclic AMP response element-binding protein in the hippocampal CA1 region of male rats. Neuroscience Letters 398(3):206–210. Morahan JM, Pamphlett R. 2006. Amyotrophic lateral sclerosis and exposure to environmental toxins: An Australian case–control study. Neuroepidemiology 27(3):130–135. 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. Moses M, Lilis R, Crow KD, Thornton J, Fischbein A, Anderson HA, Selikoff IJ. 1984. Health status of workers with past exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in the manufacture of 2,4,5-trichlorophenoxyacetic acid: comparison of findings with and without chloracne. American Journal of Industrial Medicine 5:161–182. Pals P, Van Everbroeck B, Grubben B, Viaene MK, Dom R, van der Linden C, Santens P, Martin JJ, Cras P. 2003. Case–control study of environmental risk factors for Parkinson’s disease in Belgium. European Journal of Epidemiology 18(12):1133–1142. Park RM, Schulte PA, Bowman JD, Walker JT, Bondy SC, Yost MG, Touchstone JA, Dosemeci M. 2005. Potential occupational risks for neurodegenerative diseases. American Journal of Industrial Medicine 48(1):63–77. 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. Priyadarshi A, Khuder SA, Schaub EA, Shrivastava S. 2000. A meta-analysis of Parkison’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.
OCR for page 597
Veterans and Agent Orange: Update 2006 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 of the Neurological Sciences 160(Suppl 1):S6–S24. Rowland LP, Shneider NA. 2001. Amyotrophic lateral sclerosis. New England Journal of Medicine 344(22):1688–1700. 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. Shen D, Dalton TP, Nebert DW, Shertzer HG. 2005. Glutathione redox state regulates mitochondrial reactive oxygen production. Journal of Biological Chemistry 280(27):25305–25312. Singer R, Moses M, Valciukas J, Lilis R, Selikoff IJ. 1982. Nerve conduction velocity studies of workers employed in the manufacture of phenoxy herbicides. Environmental Research 29(2):297–311. 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. Stehr PA, Stein G, Webb K, Schramm W, Gedney WB, Donnell HD, Ayres S, Falk H, Sampson E, Smith SJ. 1986. A pilot epidemiologic study of possible health effects associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin contaminations in Missouri. Archives of Environmental Health 41:16–22. 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. Suskind RR, Hertzberg VS. 1984. Human health effects of 2,4,5-T and its toxic contaminants. Journal of the American Medical Association 251(18):2372–2380. Sweeney, MH, Fingerhut MA, Arezzo JC, Hornung RW, Connally LB. 1993. Peripheral neuropathy after occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). American Journal of Industrial Medicine 23(6):845–858. 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. 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. Todd RL. 1962. A case of 2,4-D intoxication. Journal of the Iowa Medical Society 52:663–664. 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.
OCR for page 598
Veterans and Agent Orange: Update 2006 Webb KB, Evans RG, Stehr P, Ayres SM. 1987. Pilot study on health effects of environmental 2,3,7,8-TCDD in Missouri. American Journal of Industrial Medicine 11:685–691. 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. Weisskopf MG, O’Reilly EJ, McCullough ML, Calle EE, Thun MJ, Cudkowicz M, Ascherio A. 2005. Prospective study of military service and mortality from ALS. Neurology 64(1):32–37. Williamson MA, Gasiewicz TA, Opanashuk LA. 2005. Aryl hydrocarbon receptor expression and activity in cerebellar granule neuroblasts: implications for development and dioxin neurotoxicity. Toxicological Sciences 83:340–348. Wong GF, Gray CS, Hassanein RS, Koller WC. 1991. Environmental risk factors in siblings with Parkinson’s disease. Archives of Neurology 48:287–289. 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 51:479–486.