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8 Neurologic Disorders Neurologic disorders include a wide variety of medical conditions. The ner- vous 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 Alzheimerâs disease; and neuropsychiatric problems, including neurasthenia (a collection of such symptoms as difï¬culty in concen- trating, 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 Parkinsonâs dis- ease (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 dis- orders are classiï¬ed 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 classiï¬ed on the basis of anatomic distribu- tion 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 566
NEUROLOGIC DISORDERS 567 persistent. For example, global CNS dysfunction can lead to a general abnormal- ity, such as an altered level of consciousness, whereas focal CNS dysfunction might lead to an isolated abnormality, such as difï¬culty with language function (aphasia). Early-onset disorders are seen within days or weeks of exposure; de- layed onset may occur after months or years. Transient disorders are short-lived; persistent disorders produce lasting deï¬cits. 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 identiï¬cation in neurologic disorders is often difï¬cult because there are few disorders for which there are speciï¬c 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 conï¬rmation usually is not feasible. Furthermore, neurologic disorders are by their nature largely subjective, so there often is no objective evidence with which to conï¬rm a diagnosis. Many studies have addressed the possible contribution of various chemical exposures to neurologic disorders, but the committeeâs focus is on the health ef- fects 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-trichlo- ropicolinic 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 speciï¬city of exposure assessment is an important consideration in weigh- ing evidence relevant to the committeeâs 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 scientiï¬c evidence supporting biologic plausibility also is re- viewed brieï¬y here; a more thorough discussion of updated toxicologic studies is in Chapter 3. More complete discussions of the categories of association and of this committeeâs 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 informa- tion is summarized with its results; design information on other new studies is in Chapter 4.
568 VETERANS AND AGENT ORANGE: UPDATE 2006 NEUROBEHAVIORAL (COGNITIVE OR NEUROPSYCHIATRIC) DISORDERS This section summarizes the ï¬ndings of VAO and previous updates on neu- robehavioral 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 insufï¬cient 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 sig- niï¬cantly associated with responses on some scales of the Millon Clinical Multi- axial Inventory. In Update 2000 (IOM, 2001), results from the AFHS indicated that although the frequency of several self-reported neuropsychiatric symptoms differed be- tween exposure groups, the associations were not signiï¬cant after adjustment for covariates. In addition, a repeat psychologic assessment with the SCL-90-R in conjunction with self-reported psychologic disorders veriï¬ed through medical- record review showed that among ï¬ve diagnostic categories (psychosis, alcohol dependence, drug dependence, anxiety, and other neurosis), a doseâresponse pat- tern with serum TCDD concentration was found only for âother neurosesâ in the enlisted ground crew. When the entire cohort was evaluated, there were no sig- niï¬cant associations between serum TCDD and various psychologic diagnoses. Update 2002 (IOM, 2003) reviewed three studies. Neuropsychologic tests of cognitive functioning indicated signiï¬cant group differences on some scales, but the ï¬ndings did not support a doseâresponse 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 ï¬nding. Update 2004 (IOM, 2005) reviewed ï¬ve new studies. Among them was a report on the AFHS cohort (Barrett et al., 2003) in which the authors con- clude that there were âfew consistent differences in psychological functioningâ between groups categorized by serum dioxin concentrations. Another report
NEUROLOGIC DISORDERS 569 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 methodo- logic limitations. Prior committees have maintained the conclusion that there has been inade- quate or insufï¬cient 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 Alzheimerâs disease and presenile dementia (PSD), PD, and motor neuron disease (see also the section on PD and parkinsonism below). The authors examined data from 1992â1998 death certiï¬cates for over 2.6 million deaths in 22 states. They report mortality odds ratios associated with subjectsâ âusual occupationâ and with a subgroup of âpesticide-exposedâ occupations. Subjects who had worked in âpest controlâ had signiï¬cantly increased risk for PSD (odds ratio [OR] 2.96). However, the exposure assessment was too imprecise for the results to inform the present committeeâs conclusions. A study of Australian Vietnam veterans reported an association between deployment in Vietnam and âmental disordersâ (ADVA, 2005c). The authors state that âthere was a borderline signiï¬cant elevation in mortality from mental disorders, with a relative rate of 2.75 (95% conï¬dence interval [CI] 0.98â8.83). The number of deaths for this group of diseases was small enough for an ex- amination to be made for the 19 deaths involved. All of the deaths were due to conditions associated with alcohol or drug misuse.â Therefore, that report did not inform the committeeâs 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 inter- est in neurobehavioral effects were identiï¬ed 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 hippo- campus 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 neuro- psychiatric disorders, it involves behavior (food consumption). There also were studies in rodents that detected molecular effects in cerebellar granule cells or
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. Difï¬culties in case identiï¬cation and diagnosis, misclassiï¬cation of exposures because of a lack of contemporaneous measures, subject ascertainment and selection bias, and uncontrolled confounding from many comorbid condi- tions 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 doseâresponse 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 insuf- ï¬cient evidence to determine the existence of an association between expo- sure to the compounds of interest and neurobehavioral disorders (cognitive or neuropsychiatric). MOVEMENT DISORDERS This section summarizes the ï¬ndings of previous VAO reports on movement disorders, including PD and ALS, and incorporates information published in the last 2 years into the evidentiary database. Parkinsonâs 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 ï¬rst 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 conï¬rmed with
NEUROLOGIC DISORDERS 571 postmortem pathologic examination of brain tissue for the characteristic loss of neurons from the substantia nigra and telltale Lewy body intracellular inclusions. Pathologic ï¬ndings 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 neu- rodegenerative disease (after Alzheimerâs 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 iden- tiï¬cation of evidence of genetic transmissionâmarked by the determination of speciï¬c mutations in two genes, Parkin and -synucleinâhas 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 identiï¬ed PD on the basis of clinical signs or diagnos- tic coding (ICD-9 332) from death certiï¬cates or hospital admission records. Although exposure would be relevant to causation if it occurred before disease onset, the speciï¬c 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 (Butterï¬eld et al., 1993; Stern et al., 1991). Estimates of relative risk have also been inconsistent: ï¬ve studies demonstrate positive associations (Butterï¬eld 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 signiï¬cant heterogeneity in the published work (Priydarshi et al., 2000). Evidence supporting a doseâresponse 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;
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 con- sistent doseâresponse trends, and no association with any speciï¬c compound of interest was identiï¬ed. Update 2004 reviewed reports of three epidemiologic studies: a cohort study (Baldi et al., 2003a) and a nested caseâcontrol study (Baldi et al., 2003b) in France and a caseâcontrol study in Belgium (Pals et al., 2003). None showed signiï¬cant associations with the compounds of interest. None of the studies has described speciï¬c 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 her- bicides in particular or speciï¬cally 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 ex- posures 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 conï¬rm 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 pes- ticides or herbicides compared to those not reporting such exposure (RR 1.7, 95% CI 1.2â2.3, p 0.002); this risk remained unchanged whether occupation was a farmer or not. The statistical signiï¬cance of the ï¬ndings for âpesticides/ herbicidesâ 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 attrib- uted speciï¬cally 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 certiï¬cates was used to identify subjects with PD and their usual occupations. A primary limitation of the study is that âexposure to pesticidesâ was inferred on the basis of a retrospective jobâexposure matrix that was not constructed to account for speciï¬c compounds; thus, although the authors indicated that exposure to pesticides was associated with mortality from PD, exposure to speciï¬c 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
TABLE 8-1 Epidemiologic Studies of Pesticidea Exposure and Parkinsonâs Diseaseb Reference Signiï¬cant and Cases in Comparison Association Neurologic Country Study Group Group Exposure Assessment with Pesticidesa OR (95 % CI) Dysfunction Ascherio 413 142,485 1992 baseline self-report of 1.7 (1.2â2.3) 2001 follow-up of et al., conï¬rmed respondents to exposure to pesticides health outcomes; 2006; US cases of PD 2001 survey conï¬rmation of PD diagnosed without self- self-report with after 1992 report of PD medical records Kamel Questionnaireâself-reported Symptoms that et al., pesticide use by number of might be indicative 2005; US days per year of Parkinsonâs disease, but no formal diagnosis Park et al., 33,678 cases Death certiï¬catesâany Farming Death certiï¬cates 2005; US of PD, during mention of PD along with an 1.2 (1.1â1.2) from 22 states with 1992 to 1998 occupation associated with any mention of PD probable pesticide exposure Baldi 585 men (age Questionnaireâdetailed Occupational pesticides Self-report at 8 and et al., 70 years) occupational histories (mostly fungicides) 10 year follow-ups 2003a; 5.6 (1.5â21.6) France Baldi 84 (age 70 252 (age 70 Interview Occupational pesticides UK PD Society et al., years) years) âOccupational history coded (mostly fungicides) Brain Bank clinical 2003b; by experts 2.2 (1.1â3.4) criteria France âResidential history 573 continued
TABLE 8-1 Continued 574 Reference Signiï¬cant and Cases in Comparison Association Neurologic Country Study Group Group Exposure Assessment with Pesticidesa OR (95 % CI) Dysfunction Pals 423 205 Questionnaireâoccupational Neurologic exam et al., 2003; history not interpreted with Belgium respect to pesticide use Petrovitch 2,623 5,363 Total years plantation work Plantation work 20 years Medical records et al., and years of pesticide 1.9 (1.0â3.5) and neurologic 2002; US exposure exam Engel 238 72 Self-administered Pesticides Neurologic exam et al., questionnaire for occupational 0.8 (0.5â1.2) by trained nurse 2001; US exposure Highest tertile pesticide 2.0 (1.0â4.2) Herbicide 0.9 (0.6â1.3) Ritz and 7,516 498,461 Counties ranked by pesticide Prevalence OR: ICD-9 332 Yu, 2000; (PD cause (ischemic use from pesticide registry Moderate pesticide US of death heart disease and agricultural census data 1.36 (1.3â1.5) 1984â1994) cause of death 1984â1994) Tuchsen 134 128,935 Occupations in farming, Age-standardized First-time and Jensen, expected cases horticulture, and landscape hospitalization ratio for hospitalization 2000; 101.5 expected to have exposure to all men in agriculture and for PD Denmark pesticides horticulture 1.34 (1.09â1.62) Fall 113 263 Questionnaireâany job Pesticides Neurologic exam et al., 1999; handling pesticides 2.8 (0.9â8.7) Swedenc
Kuopio 123 279 Interviewâpesticides or Regular use of herbicides Neurologic exam et al., 1999; (onset of PD herbicides regularly or 0.7 (0.3â1.3) Finland before 1984) occasionally used Taylor 140 147 Interviewâexposure recorded Pesticides Neurologic exam et al., as total days for lifetime 1.02 (0.9â1.2) 1999; US Herbicides 1.06 (0.7â1.7) Chan et al., 215 313 Interviewâexposure to Pesticides in women Neurologic exam 1998; Hong pesticides during farming 6.8 (1.9â24.7) Kongc (years) Pesticides in men 0.7 (0.3â1.8) Gorrell 144 (age 50 464 Interviewâherbicide and Occupational herbicides Standard criteria of et al., years) insecticide use while working 4.1 (1.4â12.2) PD by history 1998; USc on a farm or gardening Hubble 3 PD with 51 PD without Interviewsâpesticide Pesticide exposure and Neurologic exam et al., dementia dementia exposure 20 days in any year genetic trait 1998; US and presence of allele for poor 3.17 (1.1â9.1) drug metabolism McCann 224 310 Questionnaireâdaily or Herbicides or pesticides Neurologic exam et al., 1998; weekly exposure to industrial 1.2 (0.8â1.5) Australiac herbicides and pesticides 6 months Menegon 96 95 Interviewâpesticide exposure Pesticides Standard criteria of et al., 1998; more than once weekly for 6 2.3 (1.2â4.4) PD by history Australia months before onset of PD Smargiassi 86 86 Interviewâoccupational Pesticides or herbicides Standard criteria of et al., exposure for at least 10 1.15 (0.6â2.4) PD by history 1998; Italyc consecutive years 575 continued
TABLE 8-1 Continued 576 Reference Signiï¬cant and Cases in Comparison Association Neurologic Country Study Group Group Exposure Assessment with Pesticidesa OR (95 % CI) Dysfunction Liou 120 240 InterviewâOccupational Herbicides or pesticides, no Neurologic exam et al., 1997; exposures to herbicides or paraquat Taiwanc,d pesticides 2.2 (0.9â5.6) Paraquat use 3.2 (2.4â4.3) Schulte 43,425 PD Occupational exposure PMR excess in male ICD-9 332 et al., cause of pesticide appliers, 1996; USd death in horticultural farmers, farm 27 states workers, and graders and 1982â1991 sorters of agricultural products Seidler 380 755 Interviewâdose-years Neighborhood controls for Neurologic exam et al., 1996; (age 66 years of application weighted herbicide Germanyc,d years with by use 1.7 (1.0â2.7) PD after Regional controls for 1987) herbicide 1.7 (1.0â2.6) Chaturvedi 87 2,070 Surveyâexposure positive if Pesticides History of PD et al., 1995; (age 64 frequently used 1.8 (0.9â3.4) Canadac years) Hertzman 127 245 Interviewâoccupation with Pesticides in men Neurologic exam et al., 1994; probable pesticide exposure 2.3 (1.1â4.9) Canadac Morano 74 148 Interviewâdirect and indirect Pesticides Neurologic exam et al., 1994; exposure to pesticides 1.73 (1.0â3.0) Spainc
Butterï¬eld 63 68 Questionnaireâpesticide or Insecticides Standard criteria of et al., (age 50 insecticide use 10 times in 5.8 PD by history 1993; USb,c years) any year Past dwelling fumigated 5.3 Herbicides 3.2 (2.5â4.1) Hubble 63 76 Questionnaireâpesticide or Pesticides or herbicides Neurologic exam et al., herbicide use 20 days per year 3.4 (1.3â7.3) 1993; USc for 5 years Jimenez- 128 256 Interviewâexposure: applied Pesticides Standard criteria of Jimenez pesticides, or lived and ate 1.3 (0.9â2.1) PD by history et al., 1992; vegetables where pesticides Spainc used Semchuk 130 260 Interviewâoccupational Pesticides Neurologic exam et al., 1992; exposure for each job held 1 2.25 (1.3â4.0) Canadac,d month Herbicides 3.06 (1.3â7.0) Stern et al., 69 (age 40 149 Interviewâinsecticides and Herbicidesâyoung onset Standard criteria of 1991; USc years) pesticides measured by self- 0.9 (0.5â1.7) PD by history 80 (age 59 report of home or garden use Herbicidesâold onset years) 1.3 (0.7â2.4) Wechsler 34 (age 39 22 Questionnaireâduration Home pesticides used more Standard criteria of et al., years) of occupational and home frequently by cases PD by history 1991; US pesticide use Wong 38 (19 sibling 38 (age and sex Interviewâacre-years Herbicides or pesticides Neurologic exam et al., pairs with matched and number of years exposed 1.0 (0.7â1.4) 1991; USc PD) 19 sibling pairs multiplied by number of with essential acres applied herbicides or tremor) pesticides 577 continued
TABLE 8-1 Continued 578 Reference Signiï¬cant and Cases in Comparison Association Neurologic Country Study Group Group Exposure Assessment with Pesticidesa OR (95 % CI) Dysfunction Golbe 106 106 Telephone surveyâsprayed Sprayed pesticide Neurologic exam et al., pesticides or insect spray once 7.0 (5.8â8.5) 1990; USb,d a year for a total of 5 years Hertzman 57 122 Questionnaireâever worked Working in orchards Neurologic exam et al., 1990; in an orchard 3.7 (1.3â10.3) Canada Koller 150 150 Interviewâacre-years Herbicide or pesticide use Neurologic exam et al., acres multiplied by years of 1.1 (0.9â1.3) 1990; USc herbicide or pesticide used Ho et al., 35 (age 60 105 Interviewâuse of insecticides Herbicides and pesticides Neurologic exam 1989; Hong years) or herbicides (Y/N), farming, 3.6 (1.0â12.9) Kongc eating raw vegetables Tanner 100 200 Interviewâexposure to what? Fruit growing 1.00 (1.0â1.0) Neurologic exam et al., 1989; for at least 1 year before onset Corn growing 0.54 (0.3â1.1) China of PD Rice growing 1.29 (0.7â2.3) ABBREVIATIONS: PMR, proportionate mortality ratio. a For the objective of this Veterans and Agent Orange review series, only associations with herbicides are of possible relevance; only the phenoxy herbicides, cacodylic acid, and picloram are of speciï¬c interest. b Modiï¬ed from Le Couteur et al. (1999). c Studies used in meta-analysis (Priyadarshi et al., 2000). d Reviewed in Update 1996 or Update 1998.
NEUROLOGIC DISORDERS 579 at least 10 neurologic symptoms than in those who reported fewer than 10 (Kamel et al., 2005). However, diagnosis of a neurologic condition, such as PD, generally relies on full clinical assessment that integrates symptoms and signs with other historical information; it is not at all clear how to interpret nonspeciï¬c symptom groupings. Biologic Plausibility Interest in possible environmental causes of PD was increased by the ob- servation that 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP) poisoning induces a movement disorder that recapitulates the classic features of PD. The effects of MPTP and its bioactive metabolite MPP have become well known, and MPTP toxicity has become the pre-eminent animal model for PD research. It is notable that MPP is similar in chemical structure to paraquat (a commonly used herbicide, although not one used in Vietnam), but it is different from the compounds of interest in this report. Studies detailed in Chapter 3 addressed a hypothesis that 2,4-D may cause signiï¬cant damage to dopaminergic terminals and contribute to nigrostriatal de- generation. The results did not support a link between acute exposure to 2,4-D and nigrostriatal injury in the mouse model. However, various studies have ad- dressed neurologic systems in animal models, and several studies support effects of 2,4-D on the developing brain in animal models. The etiology of PD remains unclear. Chemicals including chemicals of concern are known to be distributed to all organs including the CNS. Some chemicals have been associated with PD in the literature, including the herbicide paraquat, although that is not among the chemicals of concern here. Elbaz et al. (2004) reported results of a caseâcontrol study, indicating an association between speciï¬c alleles of cytochrome P450 2D6 (CYP2D6), unspeciï¬ed pesticide expo- sure, and the risk of PD. These results suggest that the lowered enzyme activity associated with some alleles of CYP2D6 may represent a susceptibility factor for response to exposure to certain neurotoxicants. This study is consistent with earlier reports suggesting some as yet undeï¬ned involvement of CYP2D6 in the etiology of PD. This supports an implication that chemicals may be involved in PD, although not speciï¬cally the chemicals of concern. A summary of biologic plausibility of neurologic effects arising from expo- sure to the herbicides used in Vietnam is presented at the end of this chapter, and in Chapter 3 there are detailed descriptions of the studies. Synthesis Epidemiologic studies have pursued various occupational exposures as po- tential risk factors for PD; pesticide use is among those receiving the most at- tention, but it has rarely been possible to isolate the effects of selected chemical
580 VETERANS AND AGENT ORANGE: UPDATE 2006 herbicides, because exposures often are mixed and assessments usually are ret- rospective, relying on such broad categories as âever exposed to any pesticide,â which, as noted above, is not considered informative for this report. In addi- tion, reported associations have been inconsistent, and only rarely has evidence supported doseâresponse relationships. Thus, the data are weakened for the committeeâs purposes by persistent methodologic limitations and by the lack of speciï¬city for the compounds of interest. Conclusions On the basis of its evaluation of the evidence reviewed here and in pre- vious VAO reports, the committee concludes that evidence of an association between exposure to the compounds of interest and PD remains inadequate or insufï¬cient. Amyotrophic Lateral Sclerosis ALS is a progressive, adult-onset, motor neuron disease that presents with muscle atrophy, weakness, and fasciculations. Most cases of ALS are sporadic; only 5â10 percent of cases are familial. One-ï¬fth of familial-ALS patients have mutations in the gene that encodes superoxide dismutase-1 (Rosen et al., 1993). The incidence of sporadic ALS is 1â2 per 100,000 person-years, and the inci- dence of ALS peaks between the ages of 55 and 75 years (Brooks, 1996). A speciï¬c diagnostic test does not exist, but clinical diagnosis has a high degree of accuracy (Rowland, 1998; Rowland and Shneider, 2001). Summary of Update 2002 and Update 2004 ALS was ï¬rst considered by the committee for Update 2002. Although mul- tiple potential etiologic factors have been investigated (Breland and Currier, 1967; Deapen and Henderson, 1986; Gallagher and Sander, 1987; Hanisch et al., 1976; Kurtzke and Beebe, 1980; McGuire et al., 1997; Roelofs-Iverson et al., 1984; Savettieri et al., 1991), associations have not been consistently identiï¬ed. Pesticide or herbicide exposure has been associated with increased risk of ALS, including a doubling of the risk from long-term occupational exposure to pesticides (Deapen et al., 1986) and a tripling of the risk from exposure to agricul- tural chemical products (Savettieri et al., 1991) and from exposure to herbicides (McGuire et al., 1997), although none of those risk estimates was statistically signiï¬cant. A population-based caseâcontrol study demonstrated associations be- tween exposure to agricultural chemical products and ALS in men, with a statisti- cally signiï¬cant 2.4-fold increased risk and a statistically signiï¬cant trend with duration of exposure (McGuire et al., 1997). A mortality study of Dow Chemical Company employees exposed to 2,4-D included three deaths from ALS, with
NEUROLOGIC DISORDERS 581 a signiï¬cant positive association (RR 3.45, 95% CI 1.10â11.11; Burns et al., 2001). Table 8-2 summarizes the results of the relevant studies. Update of the Epidemiologic Literature Since Update 2004, three studies relevant to the committeeâs charge have been identiï¬ed. One evaluated the possible association between ALS and occu- pational exposures to herbicides and pesticides, and two evaluated the possible association between ALS and military service in Vietnam. Morahan and Pamphlett (2006) published a caseâcontrol study from Australia (179 cases and 179 convenience controls matched by age, sex, and ethnicity) in which they analyzed possible associations between ALS and exposures to various environmental toxicants. Exposures were based on subjectsâ self-reports with a structured questionnaire. The authors report increased risk associated with expo- sure to herbicides or pesticides (OR 1.57, 95% CI 1.03â2.41). A doseâreponse was suggested by higher risk estimates for subjects reporting regular exposure (OR 4.65, 95% CI 1.82â11.87) and industrial exposure (OR 5.58, 95% CI 2.07â15.06); the relationship was apparent for use in hobby gardening, but not in farming. Those estimates remained signiï¬cantly increased after Bonferroni cor- rection for multiple comparisons, and this reduced the likelihood that the results were due to chance alone. Although materials from the casesâ neurologists were reviewed to conï¬rm a probable or deï¬nite ALS diagnosis by well-established clinical criteria, the cases in this study were self-referred members of Austra- lian ALS associations; similarly, the controls were a non-random collection of spouses, relatives, and acquaintances of the patients, and community volunteers. Thus the means of identifying subjects raises concerns about possible selection bias. The ï¬ndings were also limited by the imprecise exposure assessment. By following up the vital status of the American Cancer Societyâs cohort for the Cancer Prevention Study II, Weisskopf et al. (2005) conducted a prospective cohort study of the relationship between self-reported military service and death from ALS as coded on death certiï¬cates listed in the US National Death Index in 1989â1998. Among 408,288 men without self-reported âserious illnessâ at enrollment (1982) and alive at the beginning of 1989; 280 deaths from ALS were observed. With control for age and smoking history, the risk of dying from ALS was signiï¬cant (RR 1.58, 95% CI 1.14â2.19); further adjustment for several factors that have been suggested to contribute to the risk of ALS (education, alcohol intake, several occupations, and self-reported exposure to pesticides and herbicides) only slightly modiï¬ed by adjustment (RR 1.53, 95% CI 1.12â2.09). Risk estimates were similarly elevated for all branches of the military except the Marines and for service during the World War II, Korean War, and Vietnam War eras. Largely on the basis of that report, with supporting evidence from three other studies related to service in the Gulf War, the Institute of Medicine has recently concluded that the evidence linking ALS with military service is limited
582 TABLE 8-2 Epidemiologic Studies of Pesticidea Exposure and Amyotrophic Lateral Sclerosis Reference Signiï¬cant and Comparison Association Neurologic Country Study Group Group Exposure Assessment with Pesticidesa OR (95% CI) Dysfunction Morahan 179 179 Questionnaireâexposure to Herbicide or pesticide Self-reported and environmental toxicants exposure Pamphlett, 1.6 (1.0â2.4); 2006 Industrial exposure 5.6 (2.1â15.1) ADVA, Deployment to Vietnam 4.7 (1.0â22.8) 2005c Weisskopf Self-administered 1.5 (1.1â2.1) Self-reported et al., 2005 questionnaire p 0.007 military services and death certiï¬cates Burns 1,567 40,600 Industrial hygienist ranked 3.45 (1.1â11.1) Death certiï¬cates et al., job exposure: cumulative 2001; US exposure, years, or each job times weighted exposure 2,4-D
McGuire 174 348 Self-reported lifetime job Herbicide exposureâ Newly diagnosed et al., history and workplace 2.4 (1.2â4.8); signiï¬cant with ALS 1990â 1997; US exposures reviewed by panel trend analysis for dose- 1994 in western of four industrial hygienists effect relationship with Washington state agricultural chemicalsâ p 0.03 Chancellor 103 103 Required regular occupational 1.4 (0.6â3.1) Scottish Motor et al., 1993; exposure to pesticides for 12 Neuron Register Scotland months or more Savettieri 46 92 Continual exposure to 3.0 (0.4â20.3) Cases reviewed by et al., agricultural chemicals neurologists 1991; Italy Deapen 518 518 Ever worked in presence of 2.0 (0.8â5.4) ALS Society of et al., pesticides America 1986; US aFor the objective of this VAO review series, only associations with herbicides are of possible relevance; only the phenoxy herbicides, cacodylic acid, and picloram are of speciï¬c interest. 583
584 VETERANS AND AGENT ORANGE: UPDATE 2006 or suggestive (IOM, 2006). This VAO committee reviewed the ï¬ndings carefully and concluded that they are not directly relevant to its charge, however, because the reported association is with military service itself rather than with exposure to speciï¬c compounds of interest. The insensitivity of the ï¬ndings to adjustment for exposure to herbicides and pesticides (simultaneously with other factors) further reduces the support of these data for an association between ALS and the herbicides sprayed in Vietnam. The third study focused on Vietnam veterans from Australia and reporting an association between deployment in Vietnam and ALS (ADVA, 2005c). The study compared troops deployed in Vietnam with those who did not serve in Viet- nam and is described in more detail in Chapter 4. The authors identiï¬ed a large increase in relative risk of ALS that was of borderline statistical signiï¬cance (9 cases; RR 4.73, 95% CI 0.98â22.76). Biologic Plausibility Several studies have been published since Update 2004 that deal with mecha- nisms 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 speciï¬c signaling cascades and may be involved in neurodegeneration. Although not speciï¬cally concerning the chemicals of inter- est, such studies are potentially relevant to the chemicals of concern, as TCDD and herbicides have been reported to elicit oxidative stress (Celik et al., 2006; Shen et al., 2005). The mechanistic studies suggest possible avenues to pursue to determine linkages between the chemicals of concern and the neurological out- comes that could result in adult humans. A summary of biologic plausibility of neurologic effects arising from exposure to the compounds of interest is presented at the end of this chapter and in Chapter 3. Synthesis Epidemiologic studies of ALS have pursued a variety of occupational expo- sures as potential risk factors; pesticide and herbicide exposures are among those receiving the most attention. Although it has rarely been possible to isolate the effects of selected compounds of interest, a study of a cohort of 2,4-D production workers did identify signiï¬cantly increased risk (Burns et al., 2001); however, this result is considered unstable, given the low number of cases and the wide conï¬dence interval. Caseâcontrol studies of occupational exposures to pesti-
NEUROLOGIC DISORDERS 585 cides and herbicides have identiï¬ed signiï¬cantly increased risks (McGuire et al., 1997; Morahan and Pamphlett, 2006), but they did not weigh heavily, because of imprecise exposure assessments and other design limitations. Although recent prospective (Weisskopf et al., 2005) and retrospective (ADVA, 2005b) studies have identiï¬ed increased risk in veterans who served in Vietnam, they tend to implicate military service itself rather than exposure to the speciï¬c compounds of interest. Conclusions On the basis of its evaluation of the evidence reviewed here and in previ- ous VAO reports, the committee concludes that the evidence of an association between exposure to the compounds of interest and ALS remains inadequate or insufï¬cient. PERIPHERAL NEUROPATHY Peripheral neuropathy consists of disorders of the PNS. Manifestations of this syndrome can include a combination of sensory changes, motor weakness, and autonomic instability. Clinically, various forms of peripheral neuropathy can be characterized by the distribution of nerve abnormalities and their patterns of progression. For example, a peripheral neuropathy resulting from toxic exposure usually affects the limbs in a symmetric pattern, beginning distally (in the toes) and moving proximally (toward the spine) and providing the basis of the term âdying-back neuropathy,â now more rigorously referred to as âdistal axonopa- thy.â Thus, sensory deï¬cits at the ankle generally occur after deï¬cits in the toes. Physiologically, various forms of peripheral neuropathy can be characterized by results of electrodiagnostic testing to indicate which neural structures are af- fected. Most toxicant-induced neuropathies involve injury to the nerve cell bod- ies (neurons) or nerve ï¬bers (axons) that produces changes in the amplitude of a nerveâs response to an electric stimulus. In severe cases, there also can be slowing in the speed of nerve impulses. Those conditions contrast with the prominent slowing of nerve-conduction velocity (NCV) that results from injury to myelin, as seen in such inï¬ammatory conditions as Guillain-BarrÃ© syndrome. The clinical appearances of several peripheral neuropathies can be virtually identical, so it is often difï¬cult to determine whether a peripheral neuropathy is caused by a toxic exposure. Sometimes, clues in particular features of the clini- cal history and presentation suggest toxic exposure, but complaints of peripheral nerve disorders often occur in isolation and are monotonously similar, so etiologic determination can be difï¬cult. As many as 30 percent of cases are âidiopathicâ; that is, no etiology is determined despite exhaustive clinical evaluation. The most common toxicant-induced neuropathy occurs as a result of chronic alcohol exposure. Peripheral neuropathy also occurs commonly as a complica-
586 VETERANS AND AGENT ORANGE: UPDATE 2006 tion of diabetes: its reported prevalence in people with chronic diabetes is up to 50 percent. It is important to include assessment of alcohol use and diabetes as covariates in epidemiologic studies because the neuropathies that are related to these conditions are clinically and physiologically indistinguishable from other toxicant-induced neuropathies. Clinically, in cases of toxicant-induced peripheral neuropathy, stabilization or improvement is the rule after exposure ends. Recovery might not be complete, however, and the degree of recovery can depend on the severity of the initial deï¬cits. Furthermore, there is a possibility of âsubclinicalâ effects, and a person might be unaware of symptoms although evidence of nerve dysfunction can be found in a detailed neurologic examination or through electrodiagnostic testing. In VAO, peripheral neuropathy was considered a single category of disease. Before revising the conclusion regarding neuropathies, the committee for Update 1996 divided them into âacute and subacuteâ and âchronicâ classiï¬cations (on the basis of when an outcome occurs relative to exposure). In this section of this report, however, the terms âacuteâ (brief) and âchronicâ (prolonged or protracted) describe the time course of toxicant exposure. âEarlyâ and âdelayed onsetâ are used to describe the time course of the neuropathy. The distinction between âtran- sientâ and âpersistentâ is not always clear, because recovery may be protracted and incomplete. The committee considers a neuropathy to be of early onset and transient if abnormalities appear and resolve within 2 years after cessation of external exposure. Conclusions from VAO and Updates VAO and subsequent updates noted that the literature on peripheral neuropa- thy had been difï¬cult to integrate because it is characterized by variable methods that lack uniform operational deï¬nitions. The techniques used to identify affected persons, to deï¬ne comparison populations, and to assess exposures differ con- siderably among studies. Also, many of the studies are limited by nonrandom selection, which raises a concern about bias, and by the relatively small number of participants, which decreases conï¬dence in risk estimates and limits the power to detect a true association. There have been variable results, with some studies demonstrating abnormalities of peripheral nerve function and others not. In VAO, the committee reviewed results of four occupational-cohort studies of workers who had been exposed to the compounds of interest (Moses et al., 1984; Singer et al., 1982; Suskind and Hertzberg; 1984; Sweeney et al., 1993). Singer et al. (1982) reported decreased NCVs in 2,4-D and 2,4,5-T production workers who were examined 2 months after exposures were reduced. In former 2,4,5-T production workers with a history of chloracne (10 years after last ex- posure), Moses et al. (1984) found diminished pin-prick sensation, but Suskind and Hertzberg (1984) did not ï¬nd differences in NCVs. Similarly, Sweeney et al. (1993) reported decreased pin-prick sensation but no differences in NCVs in
NEUROLOGIC DISORDERS 587 former herbicide production workers (evaluated 15 years or more after their last exposure). VAO also reviewed epidemiologic studies of populations potentially exposed to TCDD in the environment. A series of studies in Italy evaluated peripheral neuropathy in the Seveso population after the industrial accident on July 10, 1976 (Assennato et al., 1989; Barbieri et al., 1988; Boeri et al., 1978; Filippini et al., 1981; Gilioli et al., 1979). Boeri et al. (1978) reported more frequent symptoms and signs of neuropathy in a cohort of residents living in the contaminated area than in a comparison group who were last examined 7â10 months after the explosion. There was no statistical difference in conduction velocity between groups. Gilioli et al. (1979) noted electrodiagnostic abnormalities in laboratory technicians potentially exposed to TCDD from analytic samples; however, the technicians were also exposed to solvents used in the analytic process. Fillipini et al. (1981) reported an increased prevalence of peripheral neuropathy in Seveso residents with evidence of high exposure to TCDD (chloracne or liver enzyme abnormalities) who were last examined 21 months after the accident. Barbieri et al. (1988) reported a higher rate of abnormalities on neurologic examination and electrodiagnostic testing in subjects with a history of chloracne who were examined 6 years after the accident, but there was no signiï¬cant increase in peripheral neuropathy as deï¬ned by World Health Organization (WHO) criteria. Assennato et al. (1989) described electrodiagnostic evaluation of that group 9 years after the accident; no differences were observed in NCV or neuropathy as deï¬ned by WHO criteria. Other environmental studies reviewed in VAO were of Missouri residents potentially exposed to TCDD in the early 1970s when waste oil was sprayed to control dust (Hoffman et al., 1986; Stehr et al., 1986; Webb et al., 1987). Although more frequent sensory abnormalities were reported in potentially exposed subjects, the differences were not statistically signiï¬cant, and the semi-ecologic study design was not suited to causal inference. Some of the data from epidemiologic studies of environmental exposures have suggested an increased risk of peripheral nerve abnormalities, but evidence of an associa- tion between exposure to the compounds of interest and peripheral neuropathy is inconsistent. Studies of Vietnam veterans were also reviewed in VAO (AFHS, 1984, 1987, 1991; CDC, 1988). A study by the Centers for Disease Control and Prevention (CDC, 1988) focused on service in Vietnam, not on exposure to the compounds of interest, and therefore provided no evidence of the possible effects of speciï¬c exposures. There was no indication of increased risk of peripheral neuropathy in the ï¬rst reports on Ranch Hand (RH) veterans (AFHS, 1984, 1987, 1991). Studies reviewed in VAO did not indicate an association between exposure and peripheral neuropathy in Vietnam veterans. Update 1996 reviewed two new epidemiologic studies. Using an administra- tive database, Zober et al. (1994) found no evidence of increased use of medical services for diagnosis of peripheral neuropathy in workers previously exposed to
588 VETERANS AND AGENT ORANGE: UPDATE 2006 TCDD at a BASF plant. Decouï¬e 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 conï¬rm or refute a pos- sible relationship between exposure and neuropathy. In addition, the committee responsible for Update 1996 reviewed case re- ports 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 en- tirely excluded that the ï¬ve cases reported in those publications were unrelated to herbicide exposure and were examples of other disorders, such as idiopathic Guillain-BarrÃ© syndrome. The committee also considered several supportive ani- mal models (Grahmann et al., 1993; Grehl et al., 1993; see âBiologic Plausibilityâ 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 commit- tee 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 veter- ans (AFHS, 2000), which combined signs of peripheral neuropathy to produce increasingly speciï¬c, graded indexes of neuropathyâa common approach in epidemiologic studies. RH veterans were signiï¬cantly more likely than were comparison subjects to have abnormalities in the indexes, and the prevalence of abnormalities increased with dioxin concentration. Although the clinical rel- evance of epidemiologic indexes of neuropathy is never certain, the strong as- sociations 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 con- founders in the statistical analysis. However, the effect of diabetes could not be eliminated in the most speciï¬c 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 diabe- tes were enumerated. In both analyses, there were strong and signiï¬cant associa-
NEUROLOGIC DISORDERS 589 tions between possible and probable neuropathy and dioxin concentration, and signiï¬cant 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 speciï¬c 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 veteransâ 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 Scientiï¬c Literature Since Update 2004 (IOM, 2005), no reports dealing with peripheral neuropa- thy 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 nonspeciï¬c clinical ï¬ndings. 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 identiï¬ed in this update. However, it is worth reiterating ï¬ndings from earlier updates. Neuro- nal 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 synap- tic 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 sacriï¬ced 8 months after exposure, there was pathologic evidence of persistent axonal nerve damage and histologic ï¬ndings typical of toxicant-induced injury. Those results constitute evidence of the bio- logic 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.
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 âacute and subacute transientâ 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 deï¬cits 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 signiï¬cant association, and in the reports that did indicate an association, chance, bias, or confounding could not be ruled out with conï¬dence. 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 insufï¬cient
NEUROLOGIC DISORDERS 591 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 neu- rologic 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 inï¬uencing genetic function. The AhR complex can produce an array of molecular effects that inï¬uence cell growth, hormone regulation, and normal cellular metabolism. Although some structural differences have been identiï¬ed 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 mecha- nisms 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 speciï¬c signaling cascades and may be involved in neu- rodegeneration. Although not speciï¬cally 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 scientiï¬c studies have emphasized the importance of alterations in neu- rotransmitter systems as potential mechanisms that underlie TCDD-induced neu- robehavioral 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
592 VETERANS AND AGENT ORANGE: UPDATE 2006 from peripheral neuropathy. Animal experiments have demonstrated that TCDD treatments affect the fundamental molecular events that underlie neurotransmis- sion 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 func- tion and pathologic ï¬ndings 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 evi- dence of organ-speciï¬c 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 previ- ous VAO reports, the committee concludes that there is inadequate or insufï¬- cient 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 dis- orders (cognitive or neuropsychiatric), PD, or ALS. In Update 1996, the committee concluded that there was limited or sug- gestive evidence of an association between exposure to at least one of the com- pounds of interest and âacute and subacute transientâ 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 avail- able 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 âearly onset, transientâ peripheral neuropathy, but that the evidence was inadequate or insuf- ï¬cient to support an association between exposure to the compounds of interest and âdelayed or persistentâ 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.
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