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11 Neurologic Disorders
Pages 773-813

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From page 773...
... • There is limited or suggestive evidence of an association between the chemicals of interest and Parkinson disease. • There is inadequate or insufficient evidence to determine whether there is an association between the chemicals of interest and for all other adverse neurologic outcomes.
From page 774...
... , spinocerebellar degeneration, and amyotrophic lateral sclerosis (ALS) ; these diseases can occur in the absence of any toxicant exposure, but all may be triggered by aspects of the environment, including toxicant exposure.
From page 775...
... A number of the studies suggest that the COIs, primarily 2,4-D, have neurologic effects, both neurochemical and behavioral, 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.
From page 776...
... Those mechanisms are important for maintaining the connections among nerve cells that are necessary for neuronal function and that are involved in axon regeneration and recovery from peripheral neuropathy. Animal experiments have demonstrated that TCDD treatments affect the fundamental molecular events that underlie neurotransmission initiated by calcium uptake.
From page 777...
... Conclusions from VAO and Previous Updates On the basis of the data available at the time, the committees responsible for VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, and Update 2010 concluded that there was inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and neurobehavioral disorders. Many of the data that informed that conclusion came from the Air Force Health Study (AFHS; AFHS, 1991, 1995, 2000; Barrett et al., 2001, 2003)
From page 778...
... The specific relevance of those studies and studies cited in earlier updates to neurobehavioral effects is unclear. A summary of the biologic plausibility of neurologic effects arising from exposure to the COIs is presented at the beginning of this chapter.
From page 779...
... . In the almost two centuries since the initial description, much has been learned about the genetic predisposition and pathophysiology of the disease, but its etiology in most patients is unknown, and specific environmental risk factors remain largely unproved.
From page 780...
... 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 The committees responsible for VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 concluded that there was inadequate or insufficient information to determine whether there was an association between exposure to the COIs and PD.
From page 781...
... The analysis of phenoxy herbicides, however, was not adjusted for use of other types of pesticides. Another study found no association between herbicide exposure and progressive supranuclear palsy (Vidal et al., 2009)
From page 782...
... :a n OR (95% CI) Dysfunction Kenborg et 28 PD cases Incidence of Hospital diagnosis of PD, Pesticides (including Hospitalization: Not specified al., 2012; from male PD in general 1977–2008 phenoxy herbicides)
From page 783...
... East Texas and average duration of products exposure to herbicides and specific pesticides, among other exposures Elbaz et 224 PD cases 557 controls Initial self-assessment, Phenoxy herbicides na 1.8 (0.9–3.3) ≥ 2 cardinal signs (resting al., 2009; plus individual interview Age of onset > 65 yrs na 2.9 (1.1–7.3)
From page 784...
... : 2.5 (1.3–4.5) specialist States clinic; 361 unrelated prevalent in cases, but Phenoxy herbicides 1.5 (1.0–2.2)
From page 785...
... smoking Washington, diagnosed based pesticide exposure Insecticides: 15 0.9 (0.4–1.8) United 1992–2002 at characterized by chemical Fungicides: 2 0.4 (0.1–3.9)
From page 786...
... Neurologic exam 1997; controls exposures to herbicides or But no Paraquat use: 2.2 (0.9–5.6) Taiwan matched for pesticides Paraquat use: 4.7 (2.0–12)
From page 787...
... Semchuk et 130 living 260 Interview -- self-report Pesticides: 32 2.3 (1.3–4.0) Neurologic exam al., 1992; cases from community of exposure for each job Herbicides: 17 3.1 (1.3–7.0)
From page 788...
... propionic acid or Silvex; CI, confidence interval; OR, odds ratio; PD, Parkinson disease; RDD, random-digit dialing. aFor the objective of the VAO review series, only associations with herbicides are of possible relevance; only the phenoxy herbicides, cacodylic acid, and picloram are of specific interest.
From page 789...
... . In addition, an ecologic study in Spain examined prevalence of PD by areas of high and low pesticide use, but the use of pesticides was dominated by nonherbicide pesticides, so whether the analysis contrast reflects herbicide exposure differences is unclear (Parron et al., 2011)
From page 790...
... (2007) found that rat cerebellar granule cells in culture B produce increased concentrations of reactive oxygen species when exposed to 2,4-D.
From page 791...
... A summary of the biologic plausibility of neurologic effects arising from exposure to the COIs is presented at the end of this chapter. Synthesis The committee responsible for Update 2012 reviewed epidemiologic studies published since Update 2010 that examined the association between herbicides -- possibly including the COIs -- and PD, but they lacked the exposure specificity of earlier studies.
From page 792...
... , associations have not been consistently identified. Pesticide or herbicide exposure has been associated with increased risk of ALS, including a doubling of the risk after long-term occupational exposure to pesticides (Deapen and Henderson, 1986)
From page 793...
... cohort for the Cancer Prevention Study II and demonstrated an increased risk of ALS in those who served in any of the armed services during times of conflict. They adjusted for a variety of confounding variables in their model, including exposure to herbicides, and found that none of them significantly altered their conclusions; thus, this large study indirectly suggests the lack of a strong effect of herbicide exposure on ALS risk.
From page 794...
... ; Self-reported military services, questionnaire p = 0.007 death certificates Burns et al., 2001; 1,567 40,600 Industrial hygienist ranked + 3.45 (1.1–11.1) Death certificates United States jobs for exposure to 2,4-D to derive years of exposure and cumulative exposure
From page 795...
... ALS Society of America Henderson, 1986; pesticides United States NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; ADVA, Australian Department of Veterans Affairs; AHS, Agricultural Health Study; ALS, amyotrophic lateral sclerosis; CI, confidence interval; nr, not reported. 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.
From page 796...
... There also are some studies that further support suggestions that the concentrations of reactive oxygen species could alter the functions of specific signaling cascades and may be involved in neurodegeneration. Although they do not specifically concern the COIs, such studies are potentially relevant to them inasmuch as TCDD and herbicides have been reported to elicit oxidative stress (Celik et al., 2006; Shen et al., 2005)
From page 797...
... Summary of Previous Updates This is the first VAO update to address AD directly. Although literature searches have not identified epidemiologic studies of possible association of AD with exposure to the specific COIs, association with exposure to the broad classification of "pesticides" has been investigated.
From page 798...
... for AD was significantly higher in the high-pesticide-use areas (PR = 1.65, 95% CI 1.52–1.80) , but this pesticide use was dominated by nonherbicide pesticides, so whether the analysis contrast reflects herbicide exposure differences is unclear.
From page 799...
... (2011) reported that in vitro exposure of rat cerebellar granule cell cultures to 2,4-D produced a drastic decrease in cell viability, in association with an increased incidence of necrosis and apoptosis, and an increased concentration of reactive oxygen species, a decrease in glutathione content, and an abnormal activity of some enzymes relative to that in the control group.
From page 800...
... Because the exposures of interest for Vietnam veterans are long past, immediate effects of the COIs are no longer pertinent for this cohort. The focus of this section will be on data related to delayed-onset peripheral neuropathy.
From page 801...
... Biologic Plausibility No new studies directly pertinent to peripheral neuropathy were identified in the present update. However, it is worth reiterating findings from earlier updates.
From page 802...
... A summary of the biologic plausibility of neurologic effects arising from exposure to the COIs is presented at the end of this chapter. Synthesis The epidemiologic studies relating industrial or individual exposure to acute neuropathy were judged by the committee for Update 1996 and later updates to constitute limited or suggestive evidence of an association between exposure to the COIs and early-onset transient peripheral neuropathy.
From page 803...
... Update of the Epidemiologic Literature No epidemiologic studies addressing herbicide exposure and hearing loss have been published since Update 2010. Biologic Plausibility Although no studies of hearing loss in adult animals directly exposed to the COIs were found, Crofton and Rice (1999)
From page 804...
... Synthesis Two prior studies observed increased risk of hearing loss in Vietnam veterans and pesticide applicators, but neither was able to examine the specific COIs for the committee or to confirm hearing loss clinically. Furthermore, the report from the AHS (Crawford et al., 2008)
From page 805...
... 2010. Exposure to pesticides and risk of amyotrophic lateral sclerosis: A population-based case-control study.
From page 806...
... 2012. Familial, environmental, and occuational risk factors in development of amyotrophic lateral sclerosis.
From page 807...
... 1987. Trauma and amyotrophic lateral sclerosis: A report of 78 patients.
From page 808...
... 1976. A search for clues to the cause of amyotrophic lateral sclerosis.
From page 809...
... 2012. Pesticide exposure and amyotrophic lateral sclerosis.
From page 810...
... 1997. Occupational exposure and amyotrophic lateral sclerosis: A population-based case-control study.
From page 811...
... 1991. A case-control study of amyotrophic lateral sclerosis.
From page 812...
... Amyotrophic Lateral Sclerosis 10:295–301. Sutedja NA, Fischer K, Veldink JH, van der Heijdem GJ, Kromhout H, Heederik D, Huisman MH, Wokke JJ, van den Berg LH.
From page 813...
... 2009. Prospective study of chemical exposures and amyotrophic lateral sclerosis.


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