Based on new evidence and a review of prior studies, the committee for Update 2012 did not find any new significant associations between the relevant exposures and neurological disorders. Current evidence supports the findings of earlier studies that
• No adverse cardiovascular or metabolic outcome has sufficient evidence of an association with the chemicals of interest.
• 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.
Immediate effects of toxicants may involve all aspects of the nervous system, whereas delayed effects are likely to produce more focal problems. Diffuse damage to the central nervous system (CNS) may cause alterations in thinking, consciousness, or attention, often in combination with abnormalities in movement. Focal dysfunction can cause myriad syndromes, depending on which area is damaged. Neurologic disorders can cause problems with thinking and emotional dysregulation, but for the purpose of this review they are distinguished from psychiatric conditions—such as posttraumatic stress disorder, depression, and anxiety—and from systemic conditions of uncertain cause, such as chronic fatigue syndrome, although either type of condition may actually have some
neurophysiologic contributing factors. In this chapter, we will consider possible diffuse CNS effects of toxic exposure and specific clinical conditions that result from focal dysfunction. Examples of diseases that result from degeneration of specific brain areas are Parkinson disease (PD), Alzheimer disease (AD), 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.
Disorders of the peripheral nervous system (PNS) are generally referred to as neuropathies. Neuropathies may be purely motor and affect only movement or purely sensory; most often, however, both motor and sensory fibers are affected. Neuropathies usually are symmetric and start with symptoms related to dysfunction of fibers that travel the greatest distance to their target organ. For that reason, symptoms of neuropathy generally start in the digits and travel toward the torso. Most neuropathies also affect autonomic fibers and thus can result in changes in blood pressure and heart rate and in symptoms related to the control of digestion. Toxicant exposure can induce immediate damage to peripheral nerves, and previous updates found limited or suggestive evidence that dioxin exposure caused such short-term effects. Evidence related to rapid onset of these conditions is presented in Appendix B, which deals with short-term adverse health effects. Previously undistilled information concerning persistence of symptoms after early effects is also evaluated in Appendix B. The overall focus of this chapter is on delayed adverse effects on the PNS and the CNS.
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. In the original Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam report, hereafter referred to as VAO (IOM, 1994), attention was focused on persistent neurobehavioral disorders. That focus was maintained in Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), and Update 2002 (IOM, 2003). A slight change in emphasis toward chronic neurodegenerative disorders was reflected in the change in the name of this chapter to “Neurologic Disorders” in Update 2004 (IOM, 2005), which was carried forward in Update 2006 (IOM, 2007), Update 2008 (IOM, 2009), and Update 2010 (IOM, 2012). The present chapter reviews data pertinent to persistent neurologic disorders of all types.
Case identification in neurologic disorders is often difficult because there are few disorders for which there are specific diagnostic tests. Many disorders involve cellular or molecular biochemical effects, so even the most advanced imaging techniques can miss an abnormality. Because the nervous system is not readily accessible for biopsy, pathologic confirmation usually is not feasible. However, identifiable neurologic disorders always result in objective abnormalities that are reflected in anatomic or functional tests or discovered via clinical examination.
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-dichlorophen-oxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram (4-amino-3,5,6-trichloropicolinic acid), and cacodylic acid (dimethyl arsenic acid)—and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a contaminant of 2,4,5-T. The committee also considers studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like chemicals to be informative if their results were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of specific congeners. Although all studies reporting TEQs based on PCBs were reviewed, studies that reported TEQs based only on mono-ortho PCBs (which are PCBs 105, 114, 118, 123, 156, 157, 167, and 189) were given very limited consideration because mono-ortho PCBs typically contribute less than 10% to total TEQs, based on the World Health Organization revised toxicity equivalency factors of 2005 (La Rocca et al., 2008; van den Berg et al., 2006). The specificity of exposure assessment is an important consideration in weighing evidence relevant to the committee’s charge.
This chapter reviews the association between exposure to the chemicals of interest (COIs) and neurobehavioral disorders, neurodegenerative disorders, and chronic peripheral system disorders. The scientific evidence supporting biologic plausibility is also reviewed here. More complete discussions of the categories of association and of this committee’s approach to categorizing health outcomes are presented in Chapters 1 and 2. For citations new to this update that revisit previously studied populations, design information can be found in Chapter 5.
Experimental data regarding the biologic plausibility of a connection between exposure to the COIs and various neurologic disorders continue to accrue. This section summarizes in a general way some of the information reviewed in the current update and, for completeness, includes information from prior updates.
Several studies have dealt with mechanisms of neurotoxicity that might be ascribed to the COIs, notably 2,4-D and TCDD. Molecular effects of the COIs are described in detail in Chapter 4. Some aspects of the biochemical activity they induce suggest pathways by which there could be effects on the neural systems. 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. Omer, 1986; St. Omer and Mohammad, 1987). Perinatal exposures to TCDD and coplanar, dioxin-like PCBs have reportedly caused deficits in learning behavior in rats (Curran et al., 2011; Haijima et al., 2010; Hojo et al., 2008). However,
caution in interpreting the significance of those studies is warranted because the developing nervous system is different from the mature nervous system and may not be an appropriate model for the possible consequences of exposure of adults to the COIs.
Some studies further support suggestions that the concentration of reactive oxygen species could alter the functions of specific signaling cascades and be involved in neurodegeneration (Drechsel and Patel, 2008). Such studies do not specifically concern the COIs but are potentially relevant to these chemicals inasmuch as TCDD and herbicides have been reported to elicit oxidative stress (Byers et al., 2006; Celik et al., 2006; Shen et al., 2005). In addition, TCDD has been shown to affect phosphokinase C biochemistry in nerve cells and so could affect the integrity and physiology of nerve cells (Kim et al., 2007; Lee et al., 2007). Cytochrome P450 1A1, the aryl hydrocarbon receptor (AHR), and the AHR nuclear transporter occur in the brain, so TCDD might be likely to exert effects in the brain (Huang et al., 2000). In addition, although they dealt with hepatocytes and not cells of the nervous system, earlier studies have indicated that 2,4-D affected aspects of mitochondrial energetics and mitochondrial calcium flux (Palmeira et al., 1994a,b, 1995a,b); if these effects can also occur in nervous-system cell mitochondria, which is feasible, the energy balance and pathways of cells in the nervous system could be affected, and there could be later damage to nervous-system function. Those mechanistic studies, although they did not produce convincing evidence of specific effects of the COIs in the neurologic outcomes of concern, suggest possible avenues to pursue to determine linkages between the COIs and the neurologic outcomes that could occur in adult humans.
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. 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. And mechanistic studies have demonstrated that 2,4,5-T can alter cellular metabolism and the cholinergic transmission necessary for neuromuscular transmission.
TCDD treatment of rats at doses that do not cause general systemic illness or wasting disease produces electrodiagnostic changes in peripheral nerve function and pathologic findings that are characteristic of toxicant-induced axonal peripheral neuropathy.
As discussed in Chapter 4, extrapolation of observations of cells in culture or animal models to humans is complicated by differences in sensitivity and sus-
ceptibility among animals, strains, and species; by the lack of strong evidence of organ-specific effects occurring consistently across species; and by differences in route, dose, duration, and timing of chemical exposures. Thus, although the toxicologic observations themselves cannot establish a conclusion that the COIs produced neurotoxic effects in humans, they do suggest the biologic plausibility of an association and point to potential mechanisms that might have come into play.
This section summarizes the findings of VAO and previous updates on neurobehavioral disorders and incorporates information published in the past 2 years 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, 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). Urban et al. (2007) confirmed that acute neurologic symptoms experienced shortly after an acute exposure to TCDD could be sustained more than 30 years after the exposure, but this study did not address delayed effects. For other studies (Kamel et al., 2007a; Solomon et al., 2007), no relationship was found with diverse neurologic outcomes and exposure to unspecified herbicides. Many of the studies reviewed were found to be methodologically flawed (Dahlgren et al., 2003; Pazderova-Vejlupkova et al., 1981; Pelclová et al., 2001, 2002) or uninformative (ADVA, 2005c; Decoufle et al., 1992; Park et al., 2005; Visintainer et al., 1995). VAO and the updates offer more complete discussions of the studies considered.
Update of the Epidemiologic Literature
One environmental study explored the association between pesticides and rapid-eye-movement (REM) sleep disorder. Postuma et al. (2012) conducted a case-control study of REM sleep disorder in 347 cases and 347 age- and sex- matched controls. Data on occupation and occupational exposures were captured by questionnaire. Significantly increased odds ratios (ORs) for REM sleep behavior disorder (RBD) were found in farmers and in those reporting occupational exposure to herbicides (OR = 2.54, 95% confidence interval [CI] 1.05–6.16) but not nonoccupational herbicide exposure (OR = 1.30, 95% CI 0.56–2.99).
Baldi et al. (2011) examined French vineyard workers’ performance on nine neurobehavioral tests. The adjusted odds of scoring in the worst 25% were higher in exposed than unexposed workers on all tests, and the differences were significant on all but one. Exposure was determined from job and task histories, but it was exposure only to the general category of “pesticides” and so did not satisfy the committee’s criteria for adequate exposure specificity.
Some animal studies have suggested possible involvement of the COIs in the occurrence of neurobehavioral effects. Akahoshi et al. (2009) produced a mouse neuroblastoma cell line that overexpressed the AHR, which is important in dopamine synthesis. Treating the line with TCDD increased tyrosine hydroxylase activity and led to increased dopamine expression. The implication of that finding is not clear, but changes in dopamine regulation have been implicated in a number of neurobehavioral syndromes. In vitro exposure of human CD34+ cells to TCDD induced modulation in gene expression involving the GABAergic pathway, which may be associated with altered synaptic transmission, visual perception, and other neurologic conditions (Fracchiolla et al., 2011).
Other recent studies have focused on neurobehavioral outcomes following perinatal exposure, which is of concern for the offspring of Vietnam veterans as discussed in Chapter 10. Haijima et al. (2010) found that perinatal exposure to TCDD impaired memory in male offspring. Mitsui et al. (2006) reported that hippocampus-dependent learning could be impaired in male rats exposed to TCDD in utero and that impairment could affect fear conditioning. Curran et al. (2011) assessed the effect of CYP1A2 and the AHR genotype on altered learning and memory in mice exposed to an environmentally relevant mixture of dioxin-like (coplanar) and non-dioxin-like PCBs in utero and during lactation. They observed the most significant deficits in response to PCB treatment in Ahrb1_Cyp1a2 (-/-) mice, including impaired novel-object recognition and increased failure rate in the Morris water maze. Lensu et al. (2006) examined areas in the hypothalamus for possible involvement in TCDD effects on food consumption, potentially related to wasting syndrome, and suggested that their results were not consistent with a primary role of the hypothalamus. Studies in rodents have also detected molecular effects in cerebellar granule cells and neuroblasts, which are involved in cognitive and motor processes (Kim and Yang, 2005; Williamson et al., 2005). Sturtz et al. (2008) found that 2,4-D affected rat maternal behavior. 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.
There is not consistent epidemiologic evidence of an association between exposure to the COIs and neurobehavioral (cognitive or neuropsychiatric) disorders. More research on the COIs and RBD is warranted.
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.
This section summarizes the findings of previous VAO reports on neurodegenerative diseases—specifically PD and ALS—and incorporates information published in the past 2 years into the evidence database. Also, a section on AD has been added in this update.
Parkinson Disease and Parkinsonism
PD is a progressive neurodegenerative disorder that affects millions of people worldwide. Its primary clinical manifestations are bradykinesia, resting tremor, cogwheel rigidity, and gait instability. Those signs were first described in 1817 as a single entity by James Parkinson. In recent years, many nonmotor manifestations of PD have been described, and they can be the presenting symptoms of the disease. They include cognitive dysfunction that often progresses to frank dementia, sleep disturbances, hallucinations, psychosis, mood disorders, fatigue, and autonomic dysfunction (Langston, 2006).
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. The diagnosis of PD is based primarily on clinical examination; in recent years, magnetic resonance imaging and functional brain imaging have been increasingly useful. PD must be distinguished from a variety of Parkinsonian syndromes, including drug-induced Parkinsonism, and neurodegenerative diseases, such as atrophy of multiple systems, that have Parkinsonian features combined with other abnormalities. Ultimately, a diagnosis of PD can be confirmed with postmortem pathologic examination of brain tissue for the characteristic loss of neurons from the substantia nigra and telltale Lewy body intracellular inclusions. Pathologic findings in other causes of Parkinsonism show different patterns of brain injury.
Estimates of incidence of PD range from 2 to 22 per 100,000 person-years, and estimates of prevalence range from 18 to 182 per 100,000 persons. It affects about 1% of all persons more than 60 years old and up to 5 million people worldwide. PD is the second-most common neurodegenerative disease (after AD). Age is a risk factor for PD; the peak incidence and prevalence are consistently found in people 60–80 years old. A consensus statement from a 2007 meeting of PD experts (Bronstein et al., 2009) concluded that, in addition to firm evidence that the toxicant 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP) can induce PD, there is substantial evidence that men are at greater risk and that smoking and coffee consumption are associated with reduced risk.
Heredity has long been suspected of being an important risk factor for PD; as many as 25% of all PD patients have at least one first-degree relative who has PD. At least 13 gene mutations have been identified in autosomal-dominant PD, including mutations in parkin and α-synuclein (Klein and Lohmann-Hedrich, 2007). Mutations associated with an autosomal recessive inheritance pattern have also been described. 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. Several studies of PD were reviewed by those committees and are described briefly here.
In addition to two new case-control studies examining association specifically with chlorophenoxy acid or esters (Brighina et al., 2008; Hancock et al., 2008), the committee responsible for Update 2008 considered five earlier case-control studies that examined the association between exposure to the COIs and PD. Two of these did not find associations with herbicide exposure (Stern et al., 1991; Taylor et al., 1999), but they may have been limited by little actual herbicide exposure, particularly occupational exposure. Three found significant associations with herbicide exposure (Butterfield et al., 1993; Gorell et al., 1998; Semchuk et al., 1992), and two found increased ORs specifically with chlorophenoxy acid or esters (Brighina et al., 2008; Hancock et al., 2008). In the new case-control studies, the doubling in risk observed by Hancock et al. (2008) did not achieve statistical significance (OR = 2.07, 95% CI 0.69–6.23), while the increase for chlorophenoxy acids or esters chemical class noted by Brighina et al. (2008) was significant only in the quartile of cases who were youngest at diagnosis (OR = 1.52, 95% CI 1.04–2.22). In the prospective Agricultural Health Study (AHS), incident PD was related in a dose–response manner to increasing days of pesticide use (Kamel et al., 2007b). On the basis of the evidence summarized
above, Update 2008 concluded that there was limited/suggestive evidence relating exposure to the COIs and PD.
Update 2010 reviewed four more epidemiologic studies related to PD risk and the COIs. Two did not find associations with 2,4-D and other phenoxy herbicides (Dhillon et al., 2008; Firestone et al., 2010). Two others did find significant associations. In an analysis of 519 cases and 511 controls, Tanner et al. (2009) found an OR of 2.59 (95% CI 1.03–6.48) for 2,4-D exposure. Elbaz et al. (2009) conducted extensive job or task history evaluations among 224 PD cases and 557 controls, all of whom were agricultural workers in France, and found a suggestive increase in odds of PD (OR = 1.8, 95% CI 0.9–3.3) associated with the use of phenoxy herbicides, and this result was statistically significant when the analyses were restricted to people more than 65 years old (OR = 2.9, 95% CI 1.1–7.3), in contrast to the significant increase reported by Brighina et al. (2008) only in the youngest subjects. 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), which is a distinct disease that has many similar symptoms. The committee responsible for Update 2010 affirmed the conclusion of the previous committee.
Those findings are summarized in Table 11-1.
Update of the Epidemiologic Literature
Vietnam-Veteran and Case-Control Studies No Vietnam-veteran studies or case-control studies addressing exposure to the COIs and PD have been published since Update 2010.
Occupational Studies Since the previous update, Kenborg et al. (2012) compared hospitalization for PD among 3,124 male members of the Danish Union of Gardeners with that among the general Danish population. With more than 68,323 person-years of followup, 28 gardeners were hospitalized for PD, which did not differ significantly from the rate in the general population (standardized hospitalization ratio [SHR] = 1.14, 95% CI 0.76–1.65). Year of birth was used as a surrogate for intensity of exposure, and high exposure was assumed for those born before 1915 (11 cases, SHR = 1.55, 95% CI 0.77–2.77), intermediate exposure for those born in 1915–1934 (16 cases, SHR = 1.15, 95% CI 0.66–1.87), and low exposure for those born in 1935 or later (1 case, SHR = 0.28, 95% CI 0.00–1.58). Although the specific pesticides to which individuals were exposed are not known, Danish gardeners have been found to have much higher exposures to pesticides—primarily herbicides, including phenoxy herbicides—than the general Danish population (Hansen et al., 1992, 2007).
Two other occupational studies were published since the previous update, but the exposure assessments lacked specificity for the COIs. One study of agricultural workers in France considered only type of farming (Moisan et al., 2011),
|Reference and Country||Cases in Study Group||Comparison Group||Exposure Assessment||Exposure(s):a||n||OR (95% CI)||Diagnosis of Neurologic Dysfunction|
|Kenborg et al., 2012; Denmark||28 PD cases from male members of Danish Union of Gardeners (n = 3,124)||Incidence of PD in general population of Denmark||Hospital diagnosis of PD, 1977–2008||Pesticides (including phenoxy herbicides)||Hospitalization:||Not specified|
|28||1.1 (0.8–1.7) Born before 1915:|
|11||1.6 (0.8–2.8) Born 1915–1934:|
|16||1.2 (0.7–1.9) Born 1935 or later:|
|Rugbjerg et al., 2011; Canada||403 PD cases from pharmacy database||405 matched controls||Initial screening phone interview followed by an in-person physical assessment employing a checklist and record of symptoms, reviewed by a neurologist specializing in movement disorders||Herbicides Neurotoxic pesticides (including 2,4-D, 2,4,5-T)||33||1.8 (0.97–3.4)||Parkinsonian tremor, rigidity, bradykinesia, masked facies, micrographia, or postural imbalance|
|Firestone et al., 2010 (updates and expands Firestone et al. ); Washington, United States||Enrolled cases increased from 250 (in original study) to 404||526 unrelated controls||Structured face-to-face interviews; demographic information collected, job descriptions (if held for more than 6 months) and workplace exposures to various industrial toxicants identified from a checklist were recorded||2,4-D||8||0.8 (0.3–2.0)||≥ 2 of 4 cardinal signs; must have bradykinesia or resting tremor, may have cogwheel rigidity, or postural reflex impairment|
|Dhillon et al., 2008; United States (University of Texas)||100 PD cases recruited from a medical center’s neurological institute in East Texas||84 controls without PD recruited from the same medical center||Professionally-administered questionnaire used to determine military history (including spraying herbicides/pesticides), personal use/mixing and average duration of exposure to herbicides and specific pesticides, among other exposures||Ever personally used/ mixed or applied:||PD diagnosed by neurologist specializing in movement disorders using standard clinical/ lab diagnostic criteria|
|Herbicide use—home or agricultural||34||0.8 (0.4–1.4)|
|Silvex or other 2,4,5-TP products||1||0.3 (0.0–2.7)|
|Elbaz et al., 2009; France||224 PD cases||557 controls||Initial self-assessment, plus individual interview with occupational specialist||Phenoxy herbicides Age of onset > 65 yrs||na
|≥ 2 cardinal signs (resting tremor, bradykinesia, rigidity, impaired postural reflexes)|
|Tanner et al., 2009; United States||519 cases; consecutively eligible subjects between July 1, 2004, and May 31, 2007||521 controls frequency matched to cases by age, sex, and location||Telephone interviewers collected information about exposures before the reference age; employment history—industry, location, processes, materials, and job tasks. Toxicant exposure collected for some jobs.||2,4-D||16||2.6 (1.0–6.5)||Enrolling investigator determined diagnosis and type of Parkinsonism, Unified Parkinson Disease Rating Scale score, and clinical features|
|Reference and Country||Cases in Study Group||Comparison Group||Exposure Assessment||Exposure(s):a||n||OR (95% CI)||Diagnosis of Neurologic Dysfunction|
|Brighina et al., 2008; United States (Mayo Clinic)||833 PD sequential cases from clinic; median age = 67.7 yrs, 208 cases ≤ 59.8 yrs||472 unaffected siblings and 361 unrelated controls||Self-report down to specific herbicides; 2,4-D said to be most prevalent in cases, but published analysis not that detailed||For youngest quartile at diagnosis:||PD diagnosed by movement disorder specialist|
|Pesticides (ever):||87||1.8 (1.1–2.9)|
|Herbicides (ever):||2.5 (1.3–4.5)|
|Phenoxy herbicides||1.5 (1.0–2.2)|
|Insecticides (ever):||1.0 (0.6–1.7)|
|Fungicides (ever):||1.0 (0.3–3.2)|
|Hancock et al., 2008; United States (Duke)||319 cases||296 unaffected relatives and others||All comparisons referent to those who never applied any pesticide||Pesticide application:||200||1.6 (1.1–2.3)|
|Kamel et al., 2007b; United States (Agricultural Health Study) (Updates Kamel et al., )||83 prevalent cases at enrollment; 78 incident cases during followup among private applicators and spouses||79,557 without PD at enrollment; 55,931 without PD followed up||Self-report of individual herbicides (2,4-D; 2,4,5-T; 2,4,5-TP) on detailed self-administered questionnaires at enrollment or telephone interview for followup||For incident cases:|
|For prevalent cases:|
|Firestone et al., 2005; Washington, United States (Updated by Firestone et al. )||250 (156 men) newly diagnosed 1992–2002 at Group Health Cooperative||388 (241 men)||Interview determining||Occupational, men only||Controlled for age, sex, smoking|
|occupational and home-||Pesticides:||19||1.0 (0.5–1.9)|
|based pesticide exposure||Insecticides:||15||0.9 (0.4–1.8)|
|characterized by chemical||Fungicides:||2||0.4 (0.1–3.9)|
|name or brand, duration,||Herbicides:||9||1.4 (0.5–3.9)|
|and frequency||Paraquat:||2||1.7 (0.2–12.8)|
|Home use, all subjects|
|Behari et al., 2001; India||377 (301 men, 76 women)||377 matched for age (± 3 yrs), but not sex||Structured interview||McNemar chi-square:|
|Herbicides:||p = 0.010|
|(protective effect—not confirmed by multivariate analysis)|
|Insecticide:||p = 0.169|
|Rodenticide:||p = 0.662|
|Engel et al., 2001; United States (cross-sectional, but otherwise fairly high-quality design)||238||72||Self-administered questionnaire for occupational exposure||[prevalence ratios]|
|Any pesticide:||0.8 (0.5–1.2)||Neurologic exam by trained nurse|
|Reference and Country||Cases in Study Group||Comparison Group||Exposure Assessment||Exposure(s):a||n||OR (95% CI)||Diagnosis of Neurologic Dysfunction|
|Kuopio et al., 1999; Finland||123 (onset of PD before 1984; 63 men, 60 women)||246 matched on sex, age (± 2 yrs), and urban/rural||Interview—pesticides or herbicides regularly or occasionally used||Pesticide use:||39||1.0 (0.6–1.7)||Neurologic exam|
|Occasional use:||26||1.2 (0.7–2.0)|
|Regular use:||13||0.7 (0.3–1.3)|
|Herbicide use:||33||1.4 (0.8–2.5)|
|Occasional use:||20||1.7 (0.9–3.2)|
|Regular use:||13||0.8 (0.4–1.7)|
|Taylor et al., 1999; Boston Medical Center||140||147 controls referred by cases||Interview—exposure recorded as total days for lifetime||Logistic analysis adjusted for age, sex, family history, education, smoking, water source, head injury, depression||Neurologic exam|
|Gorell et al., 1998; United States||144 (age > 50 yrs)||464||Interview—herbicide and insecticide use while working on a farm or gardening||All occupations contributing exposure to||Standard criteria of PD by history|
|Liou et al., 1997; Taiwan||120||240 hospital controls matched for age (± 2 yrs) and sex||Interview—occupational exposures to herbicides or pesticides||Pesticides vs no pesticides:||2.9 (2.3–3.7)||Neurologic exam|
|But no Paraquat use:||2.2 (0.9–5.6)|
|Paraquat use:||4.7 (2.0–12))|
|Paraquat use vs no||3.2 (2.4–4.3)|
|Seidler et al., 1996; Germany||380 (age < 66 yrs with PD after 1987)||755 (379 neighborhood, 376 regional; neighborhood controls may be overmatched)||Interview—dose-years = years of application weighted by use||Pesticides:||2.1 (1.6–2.6)||Neurologic exam|
|Herbicides—high dose:||2.4 (1.0–6.0)|
|vs neighbor controls||p = 0.06|
|vs regional controls||p < 0.001|
|Insecticides—high dose:||2.1 (0.9–4.8)|
|vs neighbor controls||p = 0.12|
|vs regional controls||p < 0.001|
|Hertzman et al., 1994; Canada||127 (71 men, 56 women)||245 (121 with cardiac disease; 124 voters)||Interview—occupation with probable pesticide exposure||Cases vs voters—among||Neurologic exam|
|Butterfield et al., 1993; United States||63 young||68||Questionnaire—pesticide or insecticide use 10 times in any year||Herbicides:||3.2 p = 0.033||Standard criteria of PD by history|
|onset cases||Insecticides:||5.8 p < 0.001|
|(age < 50||Dwelling fumigated:||5.3 p = 0.45|
|Semchuk et al., 1992; Calgary, Alberta, Canada||130 living cases from register of Calgary residents (population-based)||260 community controls matched for age (± 2.5 yrs) and sex, identified by RDD||Interview—self-report of exposure for each job held > 1 mo||Pesticides:||32||2.3 (1.3–4.0)||Neurologic exam confirming idiopathic PD without dementia (average 7.8 yrs from diagnosis)|
|Exposed during age interval:|
|16–25 yrs||1.4 (0.5–4.3)|
|26–35 yrs||4.8 (1.5–15.0)|
|36–45 yrs||3.8 (1.2–13.0)|
|46–55 yrs||4.9 (1.3–19.0)|
|Reference and Country||Cases in Study Group||Comparison Group||Exposure Assessment||Exposure(s):a||n||OR (95% CI)||Diagnosis of Neurologic Dysfunction|
|Stern et al., 1991; New Jersey and Pennsylvania, United States||69—all young-onset cases identified (age < 40 yrs); 80—random selection of old onset cases (age > 59 yrs)||149 nominated by each case or picked from hospital; matched by age (± 6 yrs), sex, and race||Interview—self-report of insecticide and pesticide use by self or others in home or garden||Insecticides:||0.7 (0.3–1.4)||Review of medical records, responsive to PD medication (under treatment average of 8.2 yrs), without major cognitive impairment|
|Onset < 40 yrs:||0.6 (0.2–1.7)|
|Onset > 59 yrs:||0.8 (0.3–2.1)|
|Onset < 40 yrs:||0.9 (0.5–1.7)|
|Onset > 59 yrs:||1.3 (0.7–2.4)|
|Adjusted for smoking, head injury, rural residence:|
|Hertzman et al., 1990; British Columbia, Canada||57 prevalent PD patients (age < 79 yrs) (50–54 had confirmed PD, not clear exactly how many)||122 age 50–79 who responded from electoral rolls||Questionnaire—ever worked in an orchard||Work in orchards:||3.7 (1.3–10.3)||Neurologic exam confirmed diagnostic criteria in 55 of 69 cases identified by asking physicians in area|
|Paraquat:||4/57||(p = 0.01)|
NOTE: 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.
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.
and another of pesticide users in Great Britain did not specify which pesticides were used (Frost et al., 2011).
The committee also noted the publication of Ruder and Yiin (2011), but that analysis examined mortality from all neurologic disorders together and so is unhelpful in light of the great heterogeneity of conditions in this rubric.
Environmental Studies Sanyal et al. (2010) conducted a case-control study of 175 PD cases at a movement-disorder clinic and 350 age- and sex-matched controls recruited from among relatives of patients attending the clinic. Whether they were relatives of the 175 PD patients was not made clear, nor were specifics of control recruitment, such as the participation rate. Participation among cases was reported as 100% of those still alive and who had not moved out of the area. Exposure was determined with a structured interview and questionnaire. Subjects who had at least 5 years of exposure to herbicides were considered to be exposed. Herbicide exposure was reported three times more frequently among cases than controls, but only six cases and four controls reported such exposure. In multivariate analysis, the authors did not find a significant association with exposure to herbicides, but an effect estimate was not reported so whether the lack of significance resulted from adjustments or small numbers cannot be determined. Thus, this study cannot be considered evidence either for or against an association with herbicides.
Rugbjerg et al. (2011) conducted a case-control study in British Columbia, Canada, for which 403 PD patients, 40–69 years old, were recruited from a pharmacy database that managed reimbursements for PD medications and 405 controls matched on birth-year, sex, and geography. Pesticide exposure was self-reported and based on job history, which was used by industrial hygienists to determine whether pesticide exposure was likely to have been greater than background. Self-reported exposure to herbicides (OR = 1.82, 95% CI 0.97–3.40) and to neurotoxic pesticides, including 2,4-D and 2,4,5-T (OR = 1.76, 95% CI 0.95–3.25), were increased, although both results were substantially reduced in analyses of exposures based on industrial hygienists’ review.
Several other papers examined the association between pesticides and PD, but the exposure assessments were not more detailed than “pesticide” exposure (Das et al., 2011; Kiyohara et al., 2010; Lin et al., 2011; Pereira and Garrett, 2010). 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).
Several reviews of the literature have addressed the possible involvement of environmental chemicals in the etiology of PD. Recently, van der Mark et al.
(2012) conducted a systematic review and meta-analysis of the epidemiologic literature published on PD and exposure to pesticides. The results suggest that exposure to pesticides, and to herbicides or insecticides in particular, increases the risk of developing PD. Most studies reviewed relied solely on self-report (yes or no), and none of the specific COIs was identified in the reviewed studies. McDowell and Chesselet (2012) recently reviewed the literature on the ability of both toxin-induced (6-hydroxydopamine, MPTP, rotenone, cycad) and genetically-based animal models to reproduce the nonmotor symptoms of PD. Gao and Hong (2011) and Kwok (2010) reviewed research on the genetic, epigenetic, and environmental causes of PD, which suggests that PD develops from multiple risk factors, including age, genetic predisposition, and environmental exposure. However, exposures to none of the COIs have been linked with development of PD.
The very clear PD-like toxicity resulting from human exposure to MPTP has indicated that select chemicals can result in the same type of damage to dopaminergic neurons as PD does, and MPTP has become an important toxicant in studies that use animal and in vitro models. It is notable that MPTP’s bioactive metabolite, MPP+, is similar in chemical structure to Paraquat (a commonly-used herbicide, but not one used in Vietnam), but different from the COIs in this report. Pesticides that have been shown to produce PD-like toxicity in animal models include Paraquat, rotenone, maneb, and dieldrin; and substantial research has gone into understanding the molecular mechanisms responsible for the toxicity, especially in connection with Paraquat and rotenone, as reviewed recently by Blandini and Armentero (2012) and Duty and Jenner (2011) and in the past by others, including Di Monte et al. (2002), Drechsel and Patel (2008), Hatcher et al. (2008), Nunomura et al. (2007), and Sherer et al. (2002a). The damage done to dopaminergic neurons in PD is probably caused by oxidative stress and inflammation and may well also involve damage to mitochondria in the target cells (Liang et al., 2007; Littlejohn et al., 2011; Sarnico et al., 2008). In that regard, Bongiovanni et al. (2007) found that rat cerebellar granule cells in culture produce increased concentrations of reactive oxygen species when exposed to 2,4-D. The COIs for this committee are known to be distributed to the CNS, but they have not been investigated in similar experimental systems, so there is no evidence that they could cause inflammation or oxidative stress similar to those caused by the compounds, such as Paraquat, that have been investigated.
Research on the neurotoxicity of 2,4-D has been going on for a number of years, but most of it has focused on its effects on the developing rodent nervous system. The studies have often used high doses of 2,4-D that have resulted in adverse changes in the developing nervous system—both neurochemical (such as changes in D2 receptors, tyrosine hydroxylase, and dopamine beta-hydroxylase) and behavioral (for example, Bortolozzi et al., 1999, 2002, 2003, 2004; Duffard et al., 1996; Evangelista de Duffard et al., 1990, 1995; Garcia et al., 2004, 2006; Rosso et al., 2000a,b). Injection of 2,4-D directly into the rat brain yielded tox-
icity in the basal ganglia (Bortolozzi et al., 2001), but this route of administration is highly artificial. Recent studies showed that postpartum dietary exposure of females to 2,4-D resulted in adverse alterations in maternal behavior and neurochemical changes, including increases in dopamine and its metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid (Sturtz et al., 2008). Such an increase in dopamine is the reverse of what is seen in PD, in which degradation of the dopaminergic system occurs. In addition, a study of mice and 2,4-D yielded no evidence of neurochemical damage to the dopaminergic system (Thiffault et al., 2001). One study indicated that 2,4-D, among a variety of pesticides and metals, caused fibrillation of α-synuclein in vitro, but it used purified protein and did not report data on 2,4-D but rather a generalized result (Uversky et al., 2002), so little confidence can be placed in it. Because most of the studies were on the developing nervous system, not the mature nervous system, and some studies yielded evidence of a lack of a role of 2,4-D in the development of PD, the existing studies are of little use in addressing the question of the etiology of PD.
A summary of the biologic plausibility of neurologic effects arising from exposure to the COIs is presented at the end of this chapter.
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. A new case-control study, by Rugbjerg et al. (2011) found a positive association between herbicide exposure and PD, although only when exposure was determined by questionnaire, not by industrial hygienist review of occupational history. The followup study by Kenborg et al. (2012) of Danish gardeners who had individually-uncharacterized pesticide exposures that were known to have been primarily to herbicides, including the phenoxys, was also consistent with an association. The committee also noted that the study by Postuma et al. (2012) described in the neurobehavioral disorders section above found a significant association between the COIs and REM sleep disorder, which may be an early symptom of PD, but the association between smoking and RBD was opposite to what is expected for PD. The committee reviewed several other studies that lacked exposure specificity adequate to be useful for this review. There continues to be a dearth of investigation of veterans, and biologic plausibility is still lacking. We continue to urge the performance of studies relating PD incidence to exposure in the Vietnam-veteran population. We are also concerned that a biologic mechanism by which the COIs may cause PD has not been demonstrated. Nevertheless, the epidemiologic evidence continues to support an association between herbicide exposure and PD and to be consistent with an association with exposure to the phenoxy herbicides (and perhaps to other specific herbicides).
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 COIs 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 imply involvement of motor pathways in the CNS. The cause of most cases of ALS is unknown, but about 10% of cases reportedly show an autosomal-dominant pattern of inheritance. Several environmental exposures, including military service, have been investigated as potential risk factors for ALS, but no studies have found conclusive evidence of an association. One-fifth of familial-ALS patients have mutations in the gene that encodes superoxide dismutase-1 (Rosen et al., 1993). The incidence of sporadic ALS is 1–2 per 100,000 person-years, and the incidence of ALS peaks at the ages of 55–75 years (Brooks, 1996). The diagnosis of ALS is made through clinical examination and electrodiagnostic testing and has a high degree of accuracy when performed by experienced neurologists (Rowland, 1998; Rowland and Shneider, 2001).
Summary of Previous Updates
ALS was first considered by the committee for Update 2002. Although multiple potential etiologic factors have been investigated (Breland and Currier, 1967; Deapen and Henderson, 1986; Gallagher and Sander, 1987; Hanisch et al., 1976; Kurtzke and Beebe, 1980; McGuire et al., 1997; Mitchell and Borasio, 2007; Roelofs-Iverson et al., 1984; Savettieri et al. 1991; Sutedja et al., 2009a,b), 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) and a tripling after exposure to agricultural chemical products (Savettieri et al., 1991) and after exposure to herbicides (McGuire et al., 1997), but none of the risk estimates was statistically significant. A population-based case-control study demonstrated associations between exposure to agricultural chemical products and ALS in men, with an OR of 2.4 and a trend with duration of exposure that were both statistically significant (McGuire et al., 1997). A mortality study of Dow Chemical Company employees exposed to 2,4-D found three deaths from ALS with a significant positive association (relative risk, 3.45, 95% CI 1.10–11.11) (Burns et al., 2001).
In Update 2006, three additional studies were reviewed. Morahan and Pamphlett (2006) published an Australian case-control study in which the cases
were self-reported and the controls chosen in nonrandom fashion. The authors found an increased risk of ALS after exposure to pesticides or herbicides, but the lack of appropriate case and control ascertainment and the fact that specific COIs were not asked about make the results of this study difficult to interpret. Weisskopf et al. (2005) followed vital status of subjects in the American Cancer Society’s (ACS’s) 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. 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.
No additional studies concerning exposure to the COIs and ALS were found for review in Update 2008, and Update 2010 considered one additional study (Weisskopf et al., 2009). No association was seen between self-reported pesticide or herbicide exposure in the ACS Cancer Prevention Study II, but the lack of exposure specificity and the possibility of exposure estimation error limit the weight of this evidence.
Table 11-2 summarizes the results of the relevant studies.
Update of the Epidemiologic Literature
Vietnam-Veteran or Case-Control Studies No Vietnam-veteran studies or case-control studies addressing exposure to the COIs and ALS have been published since Update 2010.
Occupational Studies Since Update 2010, Kamel et al. (2012) have evaluated the relationship between a variety of chemical exposures and death from ALS in the AHS. In the AHS, private pesticide applicators and their spouses in Iowa and North Carolina reported on their use of specific pesticides when enrolled in 1993–1997. Among 84,739 pesticide applicators and their spouses, 41 ALS deaths were identified via linkage with the National Death Index in followup through February 7, 2010. Exposure to herbicides—which included exposure to the COIs—had somewhat-increased odds of ALS (OR = 1.6, 95% CI 0.7–3.7) in analyses adjusted for age and sex. A weaker association was seen in analyses specifically of 2,4-D (OR = 1.00, 95% CI 0.5–2.1) and 2,4,5-T (OR = 1.3, 95% CI 0.5–3.2).
Frost et al. (2011) examined ALS mortality in pesticide users in Great Britain compared with the general population. The standard mortality ratio (SMR) for ALS was not increased, but details on what specific pesticides—or types—this
|Reference; Country||Study Group||Comparison Group||Exposure Assessment||Significant Association with Pesticidesa||Exposure of Interest/ Estimated Risk (95% CI)||Neurologic Dysfunction|
|Kamel et al., 2012; United States (AHS)||41||84,698||Self-administered questionnaire||Herbicides: 1.6 (0.7–3.7) 2,4-D: 1.0 (0.5–2.1) 2,4,5-T: 1.3 (0.5–3.2)||ALS cases identified via linkage with National Death Index|
|Pamphlett, 2012; Australia (followup to Morahan and Pamphlett )||614||778||Questionnaire||+||Herbicide/pesticide exposure: Men: 1.8 (1.3–2.4) Women: 1.4 (1.0–2.0)||Self-reported and fulfilled probable or definite revised El Escorial criteria|
|Morahan and Pamphlett, 2006; Australia||179||179||Questionnaire—exposure to environmental toxicants||+||Herbicide, pesticide exposure: 1.6 (1.0–2.4); industrial exposure: 5.6 (2.1–15.1)||Self-reported|
|ADVA, 2005c; Australia||nr||nr||Deployment to Vietnam||+||4.7 (1.0–22.8)|
|Weisskopf et al., 2005||nr||nr||Self-administered questionnaire||+||1.5 (1.1–2.1); p = 0.007||Self-reported military services, death certificates|
|Burns et al., 2001; United States||1,567||40,600||Industrial hygienist ranked jobs for exposure to 2,4-D to derive years of exposure and cumulative exposure||+||3.45 (1.1–11.1)||Death certificates|
|McGuire et al., 1997; United States||174||348||Self-reported lifetime job history, workplace exposures reviewed by panel of four industrial hygienists||+||Herbicide exposure: 2.4 (1.2–4.8); significant trend analysis for dose–effect relationship with agricultural chemicals: p = 0.03||New diagnosis of ALS 1990–1994 in western Washington state|
|Chancellor et al., 1993; Scotland||103||103||Required regular occupational exposure to pesticides for 12 months or more||1.4 (0.6–3.1)||Scottish Motor Neuron Register|
|Savettieri et al., 1991; Italy||46||92||Continual exposure to agricultural chemicals||3.0 (0.4–20.3)||Cases reviewed by neurologists|
|Deapen and Henderson, 1986; United States||518||518||Ever worked in presence of pesticides||2.0 (0.8–5.4)||ALS Society of America|
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.
group was exposed to were not known, so the results of the study do not contribute to the evidentiary database according to VAO criteria.
Environmental Studies Pamphlett (2012) followed up on the prior report in Australia (Morahan and Pamphlett , reviewed in Update 2006) and included additional cases and controls from the original report. Among 614 ALS cases and 778 controls, increased odds of ALS were found for herbicide or pesticide exposure in both men (OR = 1.77, 95% CI 1.30–2.39) and women (OR = 1.43, 95% CI 1.03–1.99). However, those results appear unadjusted, and the limitations described in Update 2006 persist in the newer report, limiting the interpretability of the results.
Two other environmental studies were published since Update 2010, each of which found a statistically-significantly-increased risk of ALS, but the exposures occurred in agricultural work or other pesticide-related professional activities (Bonvicini et al., 2010) or were self-reported pesticide or insecticide exposures (Das et al., 2012). Thus, the studies are of little use in assessing the association with the COIs.
Several studies have addressed mechanisms of neurotoxicity that might be ascribed to COIs, notably 2,4-D and TCDD. Molecular effects of the COIs are described in Chapter 4. Some of those effects suggest possible pathways by which there could be effects on the neural systems. A number of the studies suggest that the COIs have had neurologic effects in animal models when exposure occurred during development. 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). The mechanistic studies suggest avenues to pursue to determine linkages between the COIs and the neurologic outcomes that could result in adult humans. No toxicology studies concerning exposure to the COIs and ALS have been published since Update 2006.
A summary of the biologic plausibility of neurologic effects of exposure to the COIs is presented at the beginning of this chapter.
One well-designed study was published since Update 2010 (Kamel et al., 2012) that suggested an association between herbicides as a class, but not specifically 2,4-D or 2,4,5-T, and ALS.
On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that the evidence of an association between exposure to the COIs and ALS remains inadequate or insufficient.
AD (International Classification of Diseases, Ninth Revision 331.0) is a progressive, neurodegenerative form of dementia that is characterized by memory loss, confusion, mood changes, social withdrawal, and deteriorating speech and judgment. The course of the disease is divided into four stages—predementia, early, moderate, and advanced—depending on the level of cognitive and functional impairment. Diagnosis typically occurs in people more than 60 years old as symptoms develop, although predementia and early AD are occasionally seen in people as young as 30 years old. AD is the sixth-leading cause of death in the United States and the fifth-leading cause of death in people more than 65 years old (Singh et al., 2012). In 2012, an estimated 5.4 million Americans were living with the diagnosis. Mean life expectancy is 7 years after an AD diagnosis; about 3% of people who receive the diagnosis live 14 years or more (Alzheimer’s Association, 2012). Although the etiology of the disease remains elusive, suspected risk factors for AD include diet, exposure to aluminum or solvents, and genetics.
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. Because AD is a condition of considerable interest to aging Vietnam veterans, the committee for this update thought it appropriate to present the small amount of peripherally-related available information. In doing so, we revisit below two publications that include inadequately specific exposure characterization that were mentioned briefly in Update 2002 (Gauthier et al., 2001) and Update 2004 (Baldi et al., 2003).
Update of the Epidemiologic Literature
Vietnam-Veterans Studies No Vietnam-veteran studies addressing exposure to the COIs and AD have been published since Update 2010.
Occupational Studies Frost et al. (2011) studied 62,960 pesticide users (median age at start of followup was about 30, followed for 829,709 person-years) in Great Britain and found only three AD cases, all in men. There was no differ-
ence in SMR for AD between the pesticide users and the general male population (SMR = 0.95, 95% CI 0.31–2.94). However, all-cause mortality in men was significantly lower in pesticide users (SMR = 0.58, 95% CI 0.55–0.60). The specific pesticides that this group used were not stated, so these results cannot be regarded as sufficiently well characterized to contribute to the evidentiary database concerning the COIs and the occurrence of AD.
Environmental Studies In 1992, Baldi et al. (2003) sought out 2,792 people in France who had been 65 years old or older in 1987 when they participated in an earlier study. Of these, 1,507 were alive and agreed to participate at a 5-year followup point. From 1992 through 1998, 96 incident AD cases were identified, 25 of which were in men. Pesticide exposure (including herbicides, insecticides, and fungicides together) was determined on the basis of job histories. A significant association between pesticide exposure and AD was found in men (RR = 2.39, 95% CI 1.02–5.63) but not in women (RR = 0.89, 95% CI 0.49–1.62). Actual exposures are likely to be different between men and women because of differences in tasks performed that involve pesticide exposure.
An ecologic study in Spain examined prevalence of AD by high- and low- pesticide-use areas (Parron et al., 2011). The age- and sex-adjusted prevalence ratio (PR) 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.
Case-Control Studies Gauthier et al. (2001) found that long-term exposure to herbicides and insecticides was not significantly related to the development of AD. About 67 cases of probable and possible AD diagnosed according to criteria of the National Institute of Neurological and Communicative Disorders and Strokes and the Alzheimer’s Disease and Related Disorders Association (now the Alzheimer’s Association) were matched for age and sex with nondemented controls. Exposure data on each municipality were examined to establish the area sprayed with herbicides and insecticides in 1971, 1976, 1981, 1986, and 1991. The results were combined with the subjects’ residential histories to establish potential environmental pesticide exposure. Logistic regression with adjustment for confounders found that long-term exposure to herbicides and insecticides did not have a significant effect on the development of AD. Occupational exposure to neurotoxic substances, including pesticides, was also not significantly related to AD.
Some animal studies have suggested involvement of the COIs in the occurrence of neurobehavioral effects. Akahoshi et al. (2009) produced a mouse neuroblastoma cell line that overexpressed the AHR, which is important in dopamine
synthesis. Treating the line with TCDD increased tyrosine hydroxylase activity and led to increased dopamine expression. The implication of that finding is not clear, but changes in dopamine regulation have been implicated in a number of neurobehavioral syndromes. Other recent studies have focused on perinatal exposure. Haijima et al. (2010) found that perinatal exposure to TCDD impaired memory in male offspring. Mitsui et al. (2006) reported that hippocampus-dependent learning could be impaired in male rats exposed in utero to TCDD and that impairment could have affected fear conditioning. Lensu et al. (2006) examined areas in the hypothalamus for possible involvement in TCDD’s effects on food consumption, potentially related to wasting syndrome, and suggested that their results were not consistent with a primary role of the hypothalamus. Studies in rodents have also detected molecular effects in cerebellar granule cells or neuroblasts, which are involved in cognitive and motor processes (Kim and Yang, 2005; Williamson et al., 2005).
Bongiovanni et al. (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. Earlier, Sturtz et al. (2008) found that 2,4-D affected rat maternal behavior. The specific neurobehavioral relevance of those studies and studies cited in earlier updates is unclear.
A general summary of the biologic plausibility of neurologic effects of exposure to the COIs is presented at the beginning of this chapter.
There is no epidemiologic evidence on an association between exposure to the specific COIs and AD. Findings with respect to broader categories of pesticides are inconsistent. The data on AD are limited to exposure measures that are too nonspecific to implicate the COIs.
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 AD.
The peripheral neuropathies are an array of disorders caused by damage to nerve fibers (axonal neuropathies) or to the myelin sheath that surrounds many fibers (demyelinating neuropathies). Manifestations of neuropathy can include
a combination of sensory changes, motor weakness, and autonomic instability. 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) and moving proximally (toward the spine). This kind of neuropathy is called symmetric axonal sensorimotor polyneuropathy. Sensory deficits begin at the toes, progress above the ankles, and only later affect the hands. Motor symptoms show the same general pattern. Physiologically, various forms of peripheral neuropathy can be characterized by results of electrodiagnostic testing to indicate which neural structures are affected. Most toxicant-induced neuropathies involve injury to the nerve-cell bodies (neurons) or nerve fibers (axons) that produces changes in the amplitude of a nerve’s response to an electric stimulus.
The clinical appearances of most symmetric axonal neuropathies are similar except for variation in rates of progression and in whether pain is prominent. No specific signature distinguishes a toxicant-related neuropathy from one induced by other causes. As many as 30% of neuropathies are “idiopathic”; that is, no etiology is determined despite exhaustive clinical evaluation.
The most common toxicant-induced neuropathy occurs as a result of chronic alcohol exposure. Peripheral neuropathy also occurs commonly as a complication of diabetes; its reported prevalence in people who have chronic diabetes is up to 50%. It is important to include assessment of alcohol use and diabetes as covariates in epidemiologic studies, because the neuropathies that are related to these conditions are clinically and physiologically indistinguishable from other toxicant-induced neuropathies.
Toxicant exposure can result in early-onset (immediate) peripheral neuropathy or delayed-onset peripheral neuropathy that occurs years after the external exposure has ended. The committee considers a neuropathy to be of early onset if abnormalities appear within 1 year after external exposure ends and to be of delayed onset if abnormalities appear more than 1 year after external exposure ends. A review of the data supporting the association of exposure with early-onset peripheral neuropathy is presented in Appendix B, and will not be recapitulated here. 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.
Summary from VAO and Previous Updates
The committee for Update 2010 decided to move health outcomes that are manifested shortly after exposure to the COIs (TCDD in particular) to an appendix because they are no longer of interest for Vietnam veterans whose exposure occurred decades ago. Early-onset peripheral neuropathy was in this group with chloracne and porphyria cutanea tarda (PCT). That committee did, however, note
that early-onset peripheral neuropathy is not necessarily a transient condition, as had been the previous judgment.
Henceforth, this section will address only studies of delayed-onset peripheral neuropathy.
A study by the Centers for Disease Control (now the Centers for Disease Control and Prevention [CDC]) (CDC, 1988); focused on service in Vietnam, not on exposure to the COIs, and therefore provided no evidence of the possible effects of specific exposures. Decoufle et al. (1992) reported no association between self-reported exposure to herbicides in Vietnam and peripheral neuropathy.
There was no indication of an increased incidence of peripheral neuropathy in the first examination, which established the baseline for Operation Ranch Hand veterans (AFHS, 1984). A peer-reviewed article described the peripheral-neuropathy data on the AFHS cohort (Michalek et al., 2001). In a primary analysis, the investigators had included diabetes as a potential confounder in the statistical model. In a secondary analysis, subjects who had conditions that were known to be associated with neuropathy were excluded, and subjects who had diabetes were enumerated. In both analyses, there were strong and significant associations between dioxin concentrations and possible and probable neuropathy, and significant trends were found with increasing concentrations of dioxin. However, there were too few nondiabetic subjects to produce useful estimates of risk in the absence of the contribution of diabetes. Thus, questions remained about the specific association between exposure to the COIs and peripheral neuropathy in the absence of any effect of diabetes. The large veteran studies are limited by the confounding nature of concurrent diabetes and alcohol exposure, both of which also are related to neuropathy.
Lee et al. (2008) evaluated the association of exposure to a variety of toxicants to the presence of neuropathy in subjects who had either frank diabetes or impaired glucose tolerance. Concentrations of dioxin-like PCBs were ranked, and subjects who had hemoglobin A1C levels of greater or less than 7 were compared separately. In neither group was there evidence of an increased incidence of neuropathy or of a dose–response relationship that suggested a concentration-dependent risk of neuropathy. Given the underlying risk of neuropathy inherent in patients who have diabetes, the lack of information regarding duration of diabetes and the small subject numbers render this study difficult to evaluate.
Update of the Epidemiologic Literature
No new studies of exposure to the COIs and chronic peripheral neuropathy have been published since Update 2010.
No new studies directly pertinent to peripheral neuropathy were identified in the present update. However, it is worth reiterating findings from earlier updates.
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 (Rosso et al., 2000a,b). Normal activity of those target processes is important for maintaining synaptic connections between nerve cells and supporting the mechanisms involved in axon regeneration during recovery from peripheral neuropathy. Grahmann et al. (1993) and Grehl et al. (1993) reported observation of electrophysiologic and pathologic abnormalities, respectively, in the peripheral nerves of rats treated with TCDD. When the animals were sacrificed 8 months after exposure, there were pathologic evidence of persistent axonal nerve damage and histologic findings typical of toxicant-induced injury. Those results constitute evidence of the biologic plausibility of an association between exposure to the COIs and peripheral neuropathy.
A summary of the biologic plausibility of neurologic effects arising from exposure to the COIs is presented at the end of this chapter.
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. As summarized above, results of further studies of the long-term sequelae of the exposures also suggest persistence of symptoms either permanently or over years. However, no data suggest that exposure to COIs can lead to the development of delayed-onset chronic neuropathy many years after termination of exposure of those who did not originally complain of early-onset neuropathy.
The committee for Update 2010 concluded that, in addition to evidence supporting an association for transient early-onset peripheral neuropathy, there is limited or suggestive evidence of an association between exposure to the COIs and early-onset peripheral neuropathy that may be persistent.
On the basis of the evidence reviewed to date, however, the present committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and delayed-onset chronic neuropathy.
Hearing loss increases markedly with age; about one-fourth of people more than 70 years old are affected (NCHS, 2010). Its prevalence is somewhat higher
in men than in women (NCHS, 1994). The most common forms of hearing impairment in adults are presbycusis and tinnitus. Heritable factors may influence susceptibility to hearing loss, but external agents can also contribute. Aspirin at high doses can cause reversible tinnitus, and permanent hearing loss may be induced by pharmaceuticals (particularly antibiotics and antineoplastic drugs) and by some environmental and industrial chemicals (primarily solvents and metals). In occupational medicine, hearing loss is most often considered as being noise-induced. Cochlear development has been found to be impaired by hypothyroidism induced by endocrine disruptors (Howdeshell, 2002), but such a gestational effect would not pertain to Vietnam veterans exposed to herbicides as adults.
Summary from VAO and Previous Updates
Epidemiologic results on hearing loss in relation to service in Vietnam or to herbicide exposure more generally were first discussed in Update 2010; the literature searches for that report found two citations that addressed this health outcome. O'Toole et al. (2009) reexamined the health status of a cohort of Australian Vietnam veterans; as for almost every health endpoint surveyed in that group, the incidences of self-reported complete or partial deafness and of tinnitus showed statistically significant increases compared to the general population, and the committee for Update 2010 had serious concerns that the results reported in O'Toole et al. (2009) were compromised by recall bias and other methodologic problems. Excesses in self-reported hearing loss were also found among licensed pesticide applicators in the AHS at the time of the 5-year followup interview (Crawford et al., 2008), but this effect was associated with insecticide exposure, not with herbicide use.
Update of the Epidemiologic Literature
No epidemiologic studies addressing herbicide exposure and hearing loss have been published since Update 2010.
Although no studies of hearing loss in adult animals directly exposed to the COIs were found, Crofton and Rice (1999) reported that perinatal maternal PCB126 exposure resulted in low-frequency hearing deficits in offspring of exposed maternal rats. Increased auditory thresholds occurred in the group treated at 1.0 μg/kg/day for 0.5- and 1-kHz tones, but higher frequencies were not significantly affected. The frequency-specific deficit was hypothesized to be caused by postnatal hypothyroxinemia that occurred during a sensitive period for development of the low-frequency regions of the cochlea. It was consistent with that hypothesis that pups from the study were found to have decreased serum
T4 concentrations on postnatal day 21. It is important to note that PCB126 is a potent dioxin-like compound, having one-tenth the toxic potency of TCDD (see Chapter 4).
A summary of the biologic plausibility of neurologic effects arising from exposure to the COIs is presented at the end of this chapter.
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) observed an association only in insecticide applicators, not in herbicide applicators. The O'Toole et al. (2009) study evaluated Vietnam veterans, but it used a comparison group that was limited to the general population, not veterans from the same era who were not deployed to Vietnam, so it could not distinguish between hearing loss that may be associated with noise related to military service and hearing loss potentially associated with exposures to toxic chemicals. In the absence of new studies, the synthesis remains unchanged since Update 2010.
On the basis of the evidence reviewed here, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and hearing loss.
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