Veterans and Agent Orange Update 2010 (2012) / Chapter Skim
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9 Neurologic Disorders
9 Neurologic Disorders
Pages 611-645
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From page 611... ...
, Alzheimer disease (AD) , spinocerebellar degeneration, and amyotrophic lateral sclerosis (ALS)
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From page 612... ...
Many studies have addressed the possible contribution of various chemical exposures to neurologic disorders, but the committee's 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)
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From page 613... ...
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 614... ...
for presenile dementia and "pest control" was not sufficiently specific for the chemicals of interest. The increase in mortality from "mental disorders" reported in Australian Vietnam veterans (ADVA, 2005c)
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Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and neurobehavioral (cognitive or neuropsychiatric) disorders.
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However, the etiology of PD in most patients is unknown, and specific environmental risk factors remain largely unproved. The diagnosis of PD is based primarily on clinical examination; in recent years, magnetic resonance imaging and functional brain imaging have been increasingly useful.
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From page 617... ...
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 In Update 2008, both new and previous studies referring to specific herbicide exposures and risk of PD were reviewed.
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From page 618... ...
(2008) evaluated a variety of risk factors in an East Texas cohort of 800 PD patients seen at a local medical center's neurological institute.
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From page 619... ...
, Silvex or other 2,4,5- 1 0.3 (0.0–2.7) standard clinical/ personal use/mixing TP products lab diagnostic and average duration of criteria exposure to herbicides and specific pesticides, among other exposures Elbaz et al., 224 PD cases 557 controls Initial self-assessment, Phenoxy herbicides na 1.8 (0.9–3.3)
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controls in cases, but published Phenoxy herbicides 1.5 (1.0–2.2) yr, 208 cases ≤ 59.8 yr analysis not that detailed Insecticides (ever)
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on 2,4,5-T: 24 1.8 (1.0–3.3) Health Study)
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Neurologic exam US [cross- occupational exposure Herbicides: 0.9 (0.6–1.3) by trained nurse sectional, but Insecticides: 0.9 (0.6–1.5)
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Insecticides -- high dose: 2.1 (0.9–4.8) Dose trend vs neighbor controls p = 0.12 vs regional controls p < 0.001 Hertzman 127 245 Interview -- occupation Cases vs voters -- among men Neurologic exam et al., 1994; (71 men and 56 (121 with with probable pesticide Pesticides: Canada women)
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From page 624... ...
asking physicians in area ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid or Silvex; CI, confidence interval; OR, odds ratio; PD, Parkinson disease; RDD, random-digit dialing.
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From page 625... ...
(2007) found that rat cerebellar granule cells in culture produce increased levels of reactive oxygen specials when exposed to 2,4-D.
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From page 626... ...
A general summary of the biologic plausibility of neurologic effects of ex posure to the herbicides used in Vietnam is presented at the end of this chapter. Synthesis Update 2008 reviewed three recent epidemiological studies (Brighina et al., 2008; Hancock et al., 2008; Kamel et al., 2007)
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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 in volvement of motor pathways in the CNS. The cause of most cases of ALS is unknown, but about 10% of cases report an autosomal dominant pattern of inheritance.
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Finally, a case–control study of Australian Vietnam veterans reported an association between deployment in Vietnam and ALS (ADVA, 2005c) but did not specifically study exposure to pesticides or herbicides.
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ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; ALS, amyotrophic lateral sclerosis; CI, confidence interval; COI, chemical of interest; nr, not reported; OR, odds ratio. 629 aFor the objective of the VAO review series, only associations with herbicides are of possible relevance; only phenoxy herbicides, cacodylic acid, and picloram are of specific interest.
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From page 630... ...
Toxicant exposure can result in an immediate response of peripheral neu ropathy (early onset) or chronic peripheral neuropathy that occurs years after the external exposure has ended (delayed onset)
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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 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 632... ...
In summary, studies on Vietnam veterans originally did not demonstrate a relationship between service and symptoms of neuropathy; however, the more recent studies suggesting a relationship are not due to an increase in neuropathic symptoms but to a more sensitive measure of assaying symptom complexes (AFHS, 2000; Michalek et al., 2001)
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From page 633... ...
A summary of the biologic plausibility of neurologic effects arising from exposure to the chemicals of interest is presented at the end of this chapter. Synthesis The epidemiological studies relating industrial or individual exposure to acute neuropathy were judged by the committee for Update 1996 and subsequent updates to constitute limited or suggestive evidence of an association between exposure to the chemicals of interest and early-onset transient peripheral neu ropathy.
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In the original assessment, 641 Australian Vietnam veterans were randomly selected for participation from the list of Army veterans deemed eligible for previous studies of Agent Orange and 450 were included in the more recent assessment. Interviewers administered the Australian Bureau of Statistics National Health Survey that assessed physi cal health and associated risk factors, a 32-item combat index, an assessment for combat-related PTSD, and an assessment of general psychiatric status.
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Synthesis While two studies observed increased risk of hearing loss among Vietnam veterans and among pesticide applicators, neither study was able to examine the specific chemicals of interest to the committee and neither was able to clinically confirm hearing loss. Further, the report from the AHS (Crawford et al., 2008)
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From page 636... ...
A number of the studies suggest that there are neurologic ef fects, both neurochemical and behavioral, of the chemicals of interest, primarily 2,4-D, in animal models if exposure occurs during development or in cultured nerve cells (Konjuh et al., 2008; Rosso et al., 2000a,b; Sturtz et al., 2008) ; older references described behavioral effects of developmental exposure of rodents to a 2,4-D–2,4,5-T mixture (Mohammad and St.
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Thus, although the observations themselves cannot support a conclusion that the chemicals of interest produced neurotoxic effects in humans, they do suggest the biologic plausibility of an association and describe potential mechanisms that might have come into play. Conclusions On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence of an as sociation between exposure to the chemicals of interest (2,4-D, 2,4,5-T, TCDD, picloram, and cacodylic acid)
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From page 638... ...
Consequently, the distinction to be made concerning the type of peripheral neuropathy for which there is limited or suggestive evidence of association with herbicide exposure is based on time of onset rather than chronicity. In summary, aside from noting limited or suggestive evidence of an associa tion for persistent, as well as transient, peripheral neuropathy, on the basis of its review of new data and a re-evaluation of older studies, the present committee concurs with the conclusions of previous committees concerning neurologic outcomes.
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1967. Multiple sclerosis and amyotrophic lateral sclerosis in Mississippi.
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2008. Hearing loss among licensed pesticide applicators in the Agricultural Health Study.
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1976. A search for clues to the cause of amyotrophic lateral sclerosis.
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1980. Epidemiology of amyotrophic lateral sclerosis: 1.
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1996. The Australian Vietnam Veterans Health Study: III.
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1991. A case–control study of amyotrophic lateral sclerosis.
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2009. Prospective study of chemical exposures and amyotrophic lateral sclerosis.
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