Veterans and Agent Orange Update 2004 (2005) / Chapter Skim
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8 Neurologic Disorders
8 Neurologic Disorders
Pages 404-435
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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)
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This chapter reviews the association between exposure to 2,4-dichlorophenoxyacetic acid (2,4-D) , 2,4,5-trichlorophenoxyacetic acid (2,4,5-T)
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The AFHS study design and methods of exposure assessment, respectively, are discussed in Chapters 4 and 5 of this report. The studies reviewed in VAO (IOM, 1994)
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Although this was a well-designed study, capitalizing on the opportunity to evaluate potential associations between objective measures of exposure and psychological functioning using validated test instruments, the conclusions are limited by the possibility of misclassification of exposure, selection bias, and uncontrolled confounding (by subjects' educational achievement)
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indicated significant correlations between TCDD concentrations and cognitive-test results (see Update 2002) , test scores were higher at the follow-up examination and the correlations were no longer significant when the cognitive tests were repeated in 2001 (Peclova et al., 2002)
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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 doseresponse relationships, also prevent those studies from supporting an association between the exposures of interest and neurobehavioral disorders.
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Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 Based on growing concerns about a possible link between PD and pesticide exposures, the original committee suggested that attention be paid to the pattern
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Update of the Scientific Literature Since Update 2002 (IOM, 2002) , three reports have examined the possible association between PD and pesticide exposures: one (Baldi et al., 2003a)
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412 8 at exam exam nurse year Society criteria records Bank 10 PD neurologic trained Neurologic Dysfunction Self-report and follow-ups UK Brain clinical Neurologic Medical and exam Neurologic by pesticides pesticides (1.04.2) work 0.8 CI)
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413 exam exam exam exam continues 332 PD ICD-9 First-time hospitalization for Neurologic Neurologic Neurologic Neurologic for ratio (0.98.7)
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414 exam exam criteria history criteria history criteria history by by by PD PD PD Neurologic Dysfunction Standard of Neurologic Neurologic Standard of Standard of herbicides insecticides pesticides (1.24.4) herbicides trait or CI)
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(1.14.9) Herbicides no 2.2 Paraquat PMR pesticide horticultural farm and products Neighborhood herbicide 1.7 Regional herbicide 1.7 Pesticides Pesticides 2.3 Pesticide + + + + or = with positive exposure and to herbicides exposure use used to by application pesticide exposure of frequently Interview -- occupational exposures pesticides Occupational Interview -- dose-years years weighted Survey -- exposure if Interview -- occupation probable Interview -- direct indirect pesticides 240 755 2,070 245 148 of with years)
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416 exam exam criteria history criteria history criteria history by by by PD PD PD Neurologic Dysfunction Standard of Neurologic Standard of Neurologic Standard of onset (1.04.1)
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417 exam exam exam exam criteria history continues by PD Standard of Neurologic Neurologic Neurologic Neurologic more use onset onset used cases pesticides pesticide by or orchards or pesticide in pesticides (0.21.7)
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418 exam exam Neurologic Dysfunction Neurologic Neurologic 1.00 0.54 1.29 and CI) % growing growing growing (95 (1.012.9)
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, numerous historical exposures were compared for case subjects with PD and spouse controls. Relevant to the committee's charge was the assessment of pesticide exposure; however, no data are presented on herbicides in general or specifically for any of the compounds of interest.
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Table 8-2 summarizes research on the possible association between ALS and pesticide exposures. The research has covered heavy metal exposure (McGuire et al., 1997; Roelofs-Iverson et al., 1984)
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421 by of state 1990 Motor Register western certificates diagnosed Society ALS in reviewed Neurologic Dysfunction Diagnosis Death Scottish Neuron ALS America Newly with 1994 Washington Cases neurologists dose trend for CI) relationship (0.63.1)
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Update of the Scientific Literature No relevant epidemiologic studies have been published since Update 2002. Synthesis As with PD, epidemiologic studies of ALS have pursued a variety of environmental exposures as potential risk factors.
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NEUROLOGIC DISORDERS 423 PERIPHERAL NEUROPATHY Peripheral neuropathy consists of disorders of the PNS. Manifestations of this syndrome can include a combination of sensory changes, motor weakness, or autonomic instability.
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424 VETERANS AND AGENT ORANGE: UPDATE 2004 report, however, the terms "acute" (brief) and "chronic" (prolonged or protracted)
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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)
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Update of the Scientific Literature Peripheral neuropathy was one outcome considered in the study of Korean Vietnam veterans (Kim et al., 2003; see the section on neurobehavioral disorders and Chapter 4 for a description of the study)
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NEUROLOGIC DISORDERS 427 Although the study groups differed in terms of known risk factors for neuropathy, including age, alcohol use, and diabetes, the authors controlled for possible confounding by including age and alcohol use in the statistical analysis. It is not clear how diabetes was handled, but the report distinguishes between "peripheral neuropathy," for which there was a significant difference between groups, and "neuropathy with diabetes," which was not significantly different between the groups.
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428 VETERANS AND AGENT ORANGE: UPDATE 2004 the effects of diabetes is a technical challenge because there is evidence for 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.
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The evidence is drawn from epidemiologic studies of Vietnam veterans, from occupational studies, and from other studies in which subjects were exposed to at least one compound of interest. Biologic Plausibility This section summarizes the biologic plausibility of a connection between exposure to the compounds of interest and various neurologic disorders, on the basis of data from experimental studies (see Chapter 3 for a more detailed discussion)
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Experiments with TCDD in whole animals demonstrate specific effects on the PNS at doses that do not cause general systemic illness. As discussed in Chapter 3, extrapolation of those observations 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.
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2001. Mortality in chemical workers potentially exposed to 2,4 dichlorophenoxyacetic acid (2,4-D)
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1998. Genetic and environmental risk factors for Parkinson's disease in a Chinese population.
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1990. Parkinson's disease: a casecontrol study of occupational and environmental risk factors.
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2000. Parkinson's disease mortality and pesticide exposure in California 19841994.
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1991. Environmental risk factors in siblings with Parkinson's disease.
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