Veterans and Agent Orange Update 2008 (2009) / Chapter Skim
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8 Neurologic Disorders
8 Neurologic Disorders
Pages 510-545
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From page 510... ...
Focal dysfunction can cause myriad syndromes, depending on which area is damaged. Although neurologic disorders can cause problems with thinking and emotional dysregulation, it is important to distinguish them from psychiatric conditions -- such as posttraumatic stress disorder, depression, and anxiety -- and from systemic conditions of uncertain cause, such as chronic fatigue syndrome.
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From page 511... ...
Neurologic disorders related to toxicant exposure may be acute or delayed and may produce temporary or long-lasting problems. 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.
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From page 512... ...
Update 1998 considered a report on mental health problems in Australian Vietnam veterans, but not in the context of herbicide exposure (O'Toole et al., 1996)
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From page 513... ...
(2003) described increased prevalence of posttraumatic stress disorder in Korean military who served in Vietnam, but there was no association with estimated exposure to Agent Orange.
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From page 514... ...
to a mailed questionnaire dealing with pesticide exposure and a variety of neurologic symptoms including neuropsychiatric ones from 9,844 men born in 1933–1977 identified in the 1991 census of three rural areas of England and Wales. There was an increased incidence of symptoms reported by those with the highest frequency of exposure to a variety of pesticides; neuropsychiatric symptoms clustered with other neurologic symptoms and correlated strongly with a tendency toward somatization as assessed with a separate instrument.
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From page 515... ...
. NEURODEGENERATIVE DISEASES This section summarizes the findings of previous VAO reports on neurodegenerative diseases -- specifically PD and ALS -- and incorporates information published in the last two years into the evidence database.
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From page 516... ...
Complex genetics may be found to account for an increasing number of PD cases in coming years, but environmental risk factors clearly are also important. Conclusions from VAO and Previous 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 chemicals of interest.
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From page 517... ...
, 1.34–7.00) was found for herbicide exposure; seven of the 17 cases reporting herbicide use were able to specify the particular product -- one reported paraquat use, and the rest reported exclusive use of chlorophenoxy and thiocarbamate compounds.
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From page 518... ...
on detailed 2,4,5-TP: 7 0.9 (0.4–1.8) Health Study)
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From page 519... ...
for age, sex, Washington, 1992–2002 at and home-based Insecticides: 15 0.9 (0.4–1.8) smoking USA Group Health pesticide exposure Fungicides: 2 0.4 (0.1–3.9)
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From page 520... ...
TABLE 8-1 Continued 520 Diagnosis of Reference and Cases in Study Neurologic Country Group Comparison Group Exposure Assessment Exposure(s)
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From page 521... ...
controls Insecticides -- high dose: 2.1 (0.9–4.8) over-matched)
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From page 522... ...
identified by asking physicians in area ABBREVIATIONS: CI, confidence interval; OR, odds ratio; PD, Parkinson's disease; RDD, random-digit dialing. aFor 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 specific interest.
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From page 523... ...
There are still no data on Vietnam veterans and PD, but in addition to the several populationbased studies that suggest a relationship between herbicide exposure and PD, a number of studies have identified exposure to specific chemicals of interest as a potential risk factor. Kamel et al.
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Environmental modifiers of neurodegenerative diseases often alter the onset of symptoms; the increased risk in younger subjects may be a clue in that regard. Finally, Hancock et al.
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From page 525... ...
. The damage done to dopaminergic neurons in PD is probably from oxidative stress and probably also involves damage to mitochondria in the target cells (Liang et al., 2007; Sarnico et al., 2008)
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Research with 2,4-D in rats, although relatively extensive, has been either on the developing nervous system or on maternal behavior and neurochemistry, and the results do not support a definitive role of 2,4-D in the etiology of PD. Studies reported before 2006 produced a preponderance of data suggesting that exposure to herbicides in general may be related to increased risk of PD.
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From page 527... ...
Conclusions On the basis 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 chemicals of interest and PD. Amyotrophic Lateral Sclerosis ALS is a progressive, adult-onset, motor neuron disease that presents with muscle atrophy, weakness, and fasciculations and with signs that implicate involvement of motor pathways in the CNS.
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From page 528... ...
Synthesis Epidemiologic studies of ALS have pursued a variety of occupational exposures 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 chemicals of interest, a study of a cohort of 2,4-D production workers did identify significantly increased risk (Burns et al., 2001)
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From page 529... ...
ALS Society of 1986; US pesticides America ABBREVIATIONS: ALS, amyotrophic lateral sclerosis; CI, confidence interval; nr, not reported; OR, odds ratio. aFor the objective of the VAO review series, only associations with herbicides are of possible relevance; only phenoxy herbicides, cacodylic acid, and picloram 529 are of specific interest.
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From page 530... ...
PERIPHERAL NEUROPATHY Peripheral neuropathies comprise a spectrum of disorders caused by damage to nerve fibers (axonal neuropathies) or to the myelin sheath that surrounds many fibers (demyelinating neuropathies)
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From page 531... ...
Results have been variable; some studies demonstrated abnormalities of peripheral nerve function, and others did not. In the first update, the committee for Update 1996 partitioned the new information and that which had been addressed in VAO between "chronic persistent peripheral neuropathy" and "acute and subacute transient peripheral neuropathy." With this information, that committee reached a conclusion of limited or suggestive evidence of association with exposure to the chemicals of interest and the "acute or subchronic" form.
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From page 532... ...
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)
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From page 533... ...
Some of the data from epidemiologic studies of environmental exposures have suggested an increased risk of peripheral nerve abnormalities, but evidence of an association between exposure to the chemicals of interest and peripheral neuropathy is inconsistent. Studies of Vietnam veterans were also reviewed in VAO (AFHS, 1984, 1987, 1991; CDC, 1988)
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From page 534... ...
The subjects on the average still had grossly increased toxicant concentrations in blood and body fat, suggesting ongoing internal exposure since their occupational exposure. Clinical examination suggested neuropathy in nine subjects; however, nerve-conduction studies were abnormal in only three.
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From page 535... ...
Several epidemiologic studies have reported increased risk of peripheral neuropathy in populations exposed to the chemicals of interest in a variety of occupational and environmental settings. However, the literature is inconsistent and suffers from methodologic limitations.
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From page 536... ...
On the basis of the evidence reviewed here and previous VAO reports, the committee concludes that there is inadequate or insufficient evidence of an association between exposure to the chemicals 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 chemicals of interest and various neurologic disorders.
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From page 537... ...
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.
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From page 538... ...
or ALS. Previous VAO reports have concluded that there was inadequate or insufficient evidence of an association between exposure to the chemicals of interest and PD.
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From page 539... ...
2001. Serum dioxin and cognitive functioning among veterans of operation ranch hand.
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From page 540... ...
1993. Risk factors for motor neuron disease: A case–control study based on patients from the Scottish motor neuron disease register.
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From page 541... ...
1987. Trauma and amyotrophic lateral sclerosis: A report of 78 patients.
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1997. Occupational exposure and amyotrophic lateral sclerosis: A population-based case– control study.
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From page 543... ...
1996. The Australian Vietnam Veterans Health Study: III.
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From page 544... ...
1998. Diagnosis of amyotrophic lateral sclerosis.
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From page 545... ...
American Journal of Industrial Medicine 11:685–691. Weisskopf MG, O'Reilly EJ, McCullough ML, Calle EE, Thun MJ, Cudkowicz M, Ascherio A
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