Veterans and Agent Orange Update 11 (2018) (2018) / Chapter Skim
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9 Neurologic Disorders
9 Neurologic Disorders
Pages 433-464
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This chapter considers the possible effects of toxic exposure to the her bicides used during the Vietnam War and specific clinical conditions associated with the central nervous system (CNS) and the peripheral nervous system (PNS)
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Toxicant exposure can induce immediate (i.e., acute) damage to peripheral nerves, and previous updates found limited or suggestive evidence that dioxin exposure can cause such short-term effects.
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However, identifiable neurologic disorders always result in objective abnormalities that are reflected in anatomic or functional tests or discovered via clinical examination. This chapter reviews the association between exposure to the COIs and neurobehavioral disorders, neurodegenerative disorders, and chronic PNS disorders.
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. Those mechanisms are important for maintaining the connections among nerve cells, which are necessary for neuronal function and are involved in axon regeneration and recovery from peripheral neuropathy.
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. TCDD treatment of rats at doses that do not cause general systemic illness or wasting produces electric changes in peripheral nerves that are associated with altered functions and pathologic findings that are characteristic of toxicant-induced axonal peripheral neuropathy (Grahmann et al., 1993; Grehl et al., 1993)
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; the authors do not list specific neurologic disorders of interest, and senility may have included both vascular and non-vascular or Alzheimer-like dementia. Overall, the results of this study for hospital admissions due to all causes combined showed a small increase in rates for Vietnam veterans compared with the population of New Zealand.
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NEUROBEHAVIORAL, COGNITIVE, AND NEUROPSYCHIATRIC DISORDERS This section summarizes the findings of VAO and previous updates on neuro behavioral disorders and incorporates information published since Update 2014 into the evidence database. Conclusions from VAO and Previous Updates On the basis of the data available at the time, the committees responsible for VAO and all subsequent updates through Update 2014 concluded that there was inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and neurobehavioral disorders.
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. Update of the Epidemiologic Literature Since Update 2014, no new studies of Vietnam veterans or case-control studies that examined neurobehavioral, cognitive, or neuropsychiatric outcomes in relation to exposure to the COIs have been published.
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, six nondioxin-like PCBs, and two metals (lead and cadmium) with cognitive impairment in adults aged 60–84 years as measured by the Digit Symbol Coding Test of the Wechsler Adult Intelligence Scale.
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Multiple linear regression models were used to assess the dose–response relationship between TCDD concentration and the outcomes of interest, with a squared term to assess consistency with a linear relationship; they also conducted further sensitivity analyses using semiparametric methods to make fewer assumptions about functional forms. The potential confounding variables included educational attainment, smoking, alcohol consumption, age at interview, age at explosion, menarche status at explosion, menopause status (pre versus post)
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Biologic Plausibility Some toxicologic studies have suggested a possible involvement of the COIs in the occurrence of neurobehavioral effects. Akahoshi et al.
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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 COIs and neurobehavioral (cognitive or neuropsychiatric) disorders.
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. Hospitalizations for PD do not occur until very late in the disease process, if at all, and thus even though the accuracy of hospital records in terms of diagnosis might be better than death certificates, they may miss the less severe cases.
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Clinical accuracy also is much higher if patients are diagnosed in specialty clinics of tertiary care facilities (by movement disorder specialists)
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Five case-control studies reviewed by those committees had investigated the association between PD and "herbicide" exposure without providing further specificity and had reported mixed findings. Two studies reviewed in Update 2008 examined the association specifically with chlorophenoxy acid and ester herbicides and found increased odds ratios
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. In the Korean Veterans Health Study, 180,639 Korean veterans were followed for vital status and cause of death (Yi et al., 2014b)
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Yang (2016) conducted an analysis of the effect of exposure to Agent Orange on Korean veterans who served in Vietnam and had been diagnosed with PD.
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produce increased concentrations of reactive oxygen species when exposed to 2,4-D. González-Barbosa et al.
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Synthesis Previously reviewed studies of PD in Vietnam veterans have not shown increased mortality or incidence of PD in U.S. or Korean Vietnam veterans.
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Wang et al., 2014) , including military service (Weisskopf et al., 2005)
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Update of the Epidemiologic Literature Two studies of ALS in Vietnam veterans and one case-control study of occupational exposures and environmental toxicants on the odds of developing ALS have been identified since Update 2014. Table 40, which can be found at www.
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. Overall, ALS was positively associated with an exposure to herbicides for military purposes, nasopharyngeal radium, personal pesticides, exhaust from heaters or generators, high-intensity radar waves, contaminated food, explosions within 1 mile, herbicides in the field, mixing and application of burning agents, burning agents in the field, and Agent Orange in the field.
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. Inverse probability weights were used to adjust for potential confounding and missing covariate data biases as well as to adjust for potential selection bias among a case group that included a disproportionate number of long-term survivors at enrollment.
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There also are studies that suggest reactive oxygen species could alter specific signaling cascades and be involved in neurodegeneration. Although they do not specifically concern the COIs, such studies are potentially relevant inasmuch as TCDD and herbicides have been reported to elicit oxidative stress (Celik et al., 2006; Shen et al., 2005)
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Clinical accuracy also is much higher if patients are diagnosed in specialty clinics of tertiary care facilities (by dementia specialists) , which are not common outside of urban areas.
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. However, a separate investigation of disease prevalence among the Korean Vietnam veterans found the risk for AD to be elevated in both the analysis of the scores as a continuous variable and the high- versus low-exposure comparison after adjusting for age, rank, smoking, drinking, physical activity, domestic use of herbicides, education, income, and BMI (Yi et al., 2014a)
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was quantified using high-resolution gas chromatography/mass spectrometry from stored serum samples collected at the time of entry into the PIVUS study, and these measure were normalized using individual lipid levels. The authors analyzed exposures using a compound summary score for the three organochlorine pesticides and the PCBs, grouping them according to the < 25th, 25th–75th, and > 75th percentile of exposure.
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Clinically, various forms of peripheral neuropathy can be characterized by the distribution of nerve abnormalities and their patterns of progression. Peripheral neuropathy resulting from toxic exposure usually affects nerve fibers in a symmetric pattern, beginning distally in the longest fibers (in the toes)
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Conclusions from VAO and Previous Updates Several studies of Vietnam veterans have examined peripheral neuropathy. A study by the Centers for Disease Control and Prevention (CDC, 1988b)
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Synthesis The epidemiologic studies relating industrial or individual exposure to acute neuropathy were judged by the committee for Update 1996 and later updates to provide limited or suggestive evidence of an association between exposure to the COIs and early onset transient peripheral neuropathy. Beginning with Update 2010, these acute outcomes were removed from this section to keep the focus on chronic and delayed-onset conditions.
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. These estimates are based on NHANES data and are likely to underestimate the true population prevalence of hearing loss because the NHANES sampling frame does not include people living in assisted care facilities, group homes, or nursing homes or those unable to come to the mobile examination center.
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Synthesis Two prior studies observed an increased prevalence of hearing loss in Vietnam veterans and pesticide applicators, but neither was able to examine exposure specifically to the COIs or to confirm hearing loss clinically. Furthermore, the report from the AHS (Crawford et al., 2008)
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