Veterans and Agent Orange Update 2006 (2007) / Chapter Skim
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8 Neurologic Disorders
8 Neurologic Disorders
Pages 566-598
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From page 566... ...
and amyotrophic lateral sclerosis (ALS) , involve weakness, tremors, involuntary movements, incoordination, or gait abnormalities.
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From page 567... ...
Many studies have addressed the possible contribution of various chemical exposures to neurologic disorders, but the committee's focus is on the health effects of a particular set of chemicals: four herbicides (2,4-dichlorophenoxyacetic acid [2,4-D] , 2,4,5-trichlorophenoxyacetic acid [2,4,5-T]
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From page 568... ...
Conclusions from VAO and Updates On the basis of the data available at the time, it was concluded in VAO, Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 that there was inadequate or insufficient evidence to determine the existence of an association between exposure to the compounds of interest and neurobehavioral disorders. Many of the data that informed that conclusion came from the Air Force Health Study (AFHS, 1984, 1987, 1990, 1991, 1995, 2000, 2005)
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All of the deaths were due to conditions associated with alcohol or drug misuse." Therefore, that report did not inform the committee's conclusions regarding the possible association between neurobehavioral disorders and exposure to herbicides in Vietnam. Biologic Plausibility A few animal studies suggesting possible involvement of chemicals of interest in neurobehavioral effects were identified in this review.
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. MOVEMENT DISORDERS This section summarizes the findings of previous VAO reports on movement disorders, including PD and ALS, and incorporates information published in the last 2 years into the evidentiary database.
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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.
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From page 572... ...
Update of the Epidemiologic Literature Since Update 2004, several reports have examined the possible associations between PD and pesticide exposures, but none has addressed exposure to herbicides in particular or specifically to the chemicals of interest for this series of reviews. One was a mortality study described in the section on neurobehavioral disorders (Park et al., 2005)
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From page 573... ...
2001 follow-up of et al., confirmed respondents to exposure to pesticides health outcomes; 2006; US cases of PD 2001 survey confirmation of PD diagnosed without self- self-report with after 1992 report of PD medical records Kamel Questionnaire -- self-reported Symptoms that et al., pesticide use by number of might be indicative 2005; US days per year of Parkinson's disease, but no formal diagnosis Park et al., 33,678 cases Death certificates -- any Farming Death certificates 2005; US of PD, during mention of PD along with an 1.2 (1.1−1.2) from 22 states with 1992 to 1998 occupation associated with any mention of PD probable pesticide exposure Baldi 585 men (age Questionnaire -- detailed Occupational pesticides Self-report at 8 and et al., 70 years)
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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 (1.09–1.62) Fall 113 263 Questionnaire -- any job Pesticides Neurologic exam et al., 1999; handling pesticides 2.8 (0.9–8.7)
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From page 575... ...
drug metabolism McCann 224 310 Questionnaire -- daily or Herbicides or pesticides Neurologic exam et al., 1998; weekly exposure to industrial 1.2 (0.8–1.5) Australiac herbicides and pesticides 6 months Menegon 96 95 Interview -- pesticide exposure Pesticides Standard criteria of et al., 1998; more than once weekly for 6 2.3 (1.2–4.4)
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Hertzman 127 245 Interview -- occupation with Pesticides in men Neurologic exam et al., 1994; probable pesticide exposure 2.3 (1.1–4.9) Canadac Morano 74 148 Interview -- direct and indirect Pesticides Neurologic exam et al., 1994; exposure to pesticides 1.73 (1.0–3.0)
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Hubble 63 76 Questionnaire -- pesticide or Pesticides or herbicides Neurologic exam et al., herbicide use 20 days per year 3.4 (1.3–7.3) 1993; USc for 5 years Jimenez- 128 256 Interview -- exposure: applied Pesticides Standard criteria of Jimenez pesticides, or lived and ate 1.3 (0.9–2.1)
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From page 578... ...
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 specific interest. b Modified from Le Couteur et al.
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A summary of biologic plausibility of neurologic effects arising from exposure 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 potential risk factors for PD; pesticide use is among those receiving the most attention, but it has rarely been possible to isolate the effects of selected chemical
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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 5–10 percent of cases are familial.
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Thus the means of identifying subjects raises concerns about possible selection bias. The findings were also limited by the imprecise exposure assessment.
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2005c Weisskopf Self-administered 1.5 (1.1–2.1) Self-reported et al., 2005 questionnaire p 0.007 military services and death certificates Burns 1,567 40,600 Industrial hygienist ranked 3.45 (1.1–11.1)
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From page 583... ...
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 specific interest.
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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 exposures as potential risk factors; pesticide and herbicide exposures are among those receiving the most attention.
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From page 585... ...
studies have identified increased risk in veterans who served in Vietnam, they tend to implicate military service itself rather than exposure to the specific compounds of interest. Conclusions On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that the evidence of an association between exposure to the compounds of interest and ALS remains inadequate or insufficient.
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Furthermore, there is a possibility of "subclinical" 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.
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From page 587... ...
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 compounds 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 588... ...
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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Neuronal cell cultures treated with 2,4-D showed decreased neurite extension associated with intracellular changes, including a decrease in microtubules, inhibition of the polymerization of tubulin, disorganization of the Golgi apparatus, and inhibition of ganglioside synthesis. Those mechanisms are important for maintaining synaptic connections between nerve cells and supporting the mechanisms involved in axon regeneration during recovery from peripheral neuropathy.
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From page 590... ...
; 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.
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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 592... ...
Conclusions On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence of an association between exposure to the compounds of interest (2,4-D, 2,4,5-T, TCDD, picloram, and cacodylic acid) and neurobehavioral disorders (cognitive or neuropsychiatric)
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Serum Dioxin Analysis of 1987 Examination Results. Brooks AFB, TX: USAF School of Aerospace Medicine.
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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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1976. A search for clues to the cause of amyotrophic lateral sclerosis.
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1997. Occupational exposure and amyotrophic lateral sclerosis: A population-based case–control study.
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1996. Neurodegenerative diseases: Occupational occurrence and potential risk factors, 1982 through 1991.
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1991. Environmental risk factors in siblings with Parkinson's disease.
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