9
Neurobehavioral Disorders

INTRODUCTION

Neurologic problems in clinical medicine cover a wide variety of disorders. The nervous system is anatomically and functionally divided into central and peripheral subsystems. The central nervous system (CNS) includes the brain and spinal cord, and CNS dysfunction can be subdivided into two general categories: neurobehavioral and motor/sensory. Neurobehavioral difficulties involve two primary categories: cognitive decline, including memory problems and dementia; and neuropsychiatric disorders, including neurasthenia (a collection of symptoms including difficulty concentrating, headache, insomnia, and fatigue), depression, posttraumatic stress disorder (PTSD), and suicide. Other CNS problems can be associated with motor difficulties, characterized by problems such as weakness, tremors, involuntary movements, incoordination, and gait/walking abnormalities. These are usually associated with subcortical or cerebellar system dysfunction. The anatomic elements of the peripheral nervous system (PNS) include the spinal rootlets that exit the spinal cord, the brachial and lumbar plexus, and the peripheral nerves that innervate the muscles of the body. PNS dysfunctions, involving either the somatic nerves or the autonomic system, are known as neuropathies.

Neurologic dysfunction can be further classified, based on anatomic distribution, as either global or focal; temporal onset, as acute, subacute, or chronic; or temporal course, as transient or persistent. For example, global cerebral dysfunction may lead to altered levels of consciousness, whereas focal lesions cause isolated signs of cortical dysfunction, such as aphasia. Acute onset of motor/coordination disturbances leads to symptoms that develop over minutes or hours, whereas



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Veterans and Agent Orange: Update 2000 9 Neurobehavioral Disorders INTRODUCTION Neurologic problems in clinical medicine cover a wide variety of disorders. The nervous system is anatomically and functionally divided into central and peripheral subsystems. The central nervous system (CNS) includes the brain and spinal cord, and CNS dysfunction can be subdivided into two general categories: neurobehavioral and motor/sensory. Neurobehavioral difficulties involve two primary categories: cognitive decline, including memory problems and dementia; and neuropsychiatric disorders, including neurasthenia (a collection of symptoms including difficulty concentrating, headache, insomnia, and fatigue), depression, posttraumatic stress disorder (PTSD), and suicide. Other CNS problems can be associated with motor difficulties, characterized by problems such as weakness, tremors, involuntary movements, incoordination, and gait/walking abnormalities. These are usually associated with subcortical or cerebellar system dysfunction. The anatomic elements of the peripheral nervous system (PNS) include the spinal rootlets that exit the spinal cord, the brachial and lumbar plexus, and the peripheral nerves that innervate the muscles of the body. PNS dysfunctions, involving either the somatic nerves or the autonomic system, are known as neuropathies. Neurologic dysfunction can be further classified, based on anatomic distribution, as either global or focal; temporal onset, as acute, subacute, or chronic; or temporal course, as transient or persistent. For example, global cerebral dysfunction may lead to altered levels of consciousness, whereas focal lesions cause isolated signs of cortical dysfunction, such as aphasia. Acute onset of motor/coordination disturbances leads to symptoms that develop over minutes or hours, whereas

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Veterans and Agent Orange: Update 2000 subacute onset occurs over days or weeks and chronic onset over months or years. Finally, transient peripheral neuropathies resolve spontaneously, whereas persistent ones may lead to chronic deficits. In the original report, VAO, attention was deliberately focused on persistent neurobehavioral dysfunction. In later reports including the present one, all new data pertinent to clinical neurobehavioral dysfunction as well as transient acute and subacute peripheral neuropathy are reviewed. Case identification in neurology is often difficult. Despite advances in neuroimaging, many types of neurologic alterations are biochemical and show no abnormalities on scanning tests. The nervous system is not usually accessible for biopsy, so pathologic confirmation is not feasible for many neurologic disorders. Behavioral and neurophysiologic changes can be partly or largely subjective and, even when objectively documented, may often be reversible. Timing is important in assessing the effect of chemical exposures on neurologic function. Some symptoms of neurologic importance will appear acutely but be short-lived, whereas others will appear slowly and be detectable for extended periods. These caveats must be considered in the design and critique of epidemiologic studies evaluating an association between exposure to any chemical agent and neurologic or neurobehavioral dysfunction. Many reports have addressed the possible contribution of herbicides and pesticides to nervous system dysfunction, and reported abnormalities have ranged from mild and reversible to severe and long-standing. These assessments have been conducted in three general settings, related to occupational, environmental, and Vietnam veteran exposures. This chapter reviews reports of neurologic alterations associated with exposure to herbicides, TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), or other compounds used in herbicides in Vietnam. The potential neurotoxicity of TCDD and herbicides in animal studies is discussed in Chapter 3. COGNITIVE AND NEUROPSYCHIATRIC EFFECTS Update of the Scientific Literature On the basis of the data available at the time, it was concluded in Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred to as VAO; IOM, 1994), Veterans and Agent Orange: Update 1996 (hereafter, Update 1996; IOM, 1996), and Veterans and Agent Orange: Update 1998 (hereafter, Update 1998; IOM, 1999) that there was inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides 2, 4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxy-acetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); cacodylic acid, and picloram and cognitive or neuropsychiatric disorders. The majority of the data that formed the basis for these conclusions came from the Air Force Health Studies (AFHS, 1991, 1995). AFHS (1991), originally

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Veterans and Agent Orange: Update 2000 reviewed in VAO, found no association between serum TCDD concentrations (both baseline and current concentrations) and variables such as anxiety, depression, and hostility on a symptom checklist (the Symptom Checklist-90—Revised, SCL-90-R) and between TCDD concentrations and the presence of problems with sleep. By contrast some scales on the Millon Clinical Multiaxial Inventory (MCMI) had significant associations with TCDD across a variety of analyses. The findings from the SCL-90-R, the MCMI, and the reported medical information were thought to be inconsistent, leading to the conclusion of inadequate or insufficient evidence for an association between exposure and cognitive or neuropsychiatric disorders (IOM, 1994). Although in the follow-up study (AFHS, 1995), some checklist variables (anxiety, hostility, obsessive-compulsive behavior, paranoid ideation, somatization, and global severity index, along with other neuroses) were significantly elevated across all occupations in Ranch Hands, the association was not significant for some after adjustment for covariates. Therefore, the conclusion of inadequate or insufficient evidence of an association remained unchanged (IOM, 1996). Since Update 1998 (IOM, 1999), results of the AFHS 1997 follow-up examination have been published (AFHS, 2000). In that follow-up, 870 Ranch Hand veterans and 1,251 comparison subjects received a psychological assessment that consisted of the SCL-90-R and reported psychological disorders that were verified through a medical records review. The verified psychological disorders from the 1997 examination were combined with the verified psychological disorders obtained at baseline, and in 1985, 1987, and 1992. Comparisons were made between Ranch Hand veterans and the comparison group. Of five psychological diagnoses, only “other neuroses” (i.e., hysteria, phobic disorder, obsessive-compulsive disorder, somatization disorder, somatoform disorder, personality disorders, sexual deviations and disorders, nondependent abuse of drugs, acute reaction to stress, adjustment reaction, depressive disorder, sleep disorders, eating disorders, psychogenic pain, and tension headache) were significantly elevated in any of the Ranch Hand veterans, and even this end point was elevated only compared to corresponding controls in the enlisted ground crew (64.7 percent in ground crew; 57.1 percent in comparison group). The enlisted ground crew was the occupational classification with the highest dioxin concentrations. A dose-response pattern among 1987 dioxin concentrations and the prevalence of other neuroses was seen among low-, medium-, and high-dioxin categories (45.0, 53.5, and 64.9 percent, respectively). When the relationship between the 1987 lipid-adjusted dioxin levels from all Ranch Hands and the psychological end points was examined, however, no significant results were found. No differences were found for any of the scales for the checklist across Ranch Hand occupational groups and the comparison group. The 12 outcome variables from the checklist were also not associated with dioxin exposure.

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Veterans and Agent Orange: Update 2000 Synthesis When drawing conclusions about associations between exposures and diseases or disorders, the underlying reasonableness of such an association must be considered. The AFHS (2000) found an association between other neuroses and dioxin exposure, but the biological plausibility for such an association is lacking. It is improbable that herbicide or dioxin exposure could be associated with other neuroses, a category that includes more than 100 clinically dissimilar International Classification of Diseases, Ninth Edition, Clinical Modification (ICD•9-CM) codes. Furthermore, interpretation of the results for this end point is hindered because the percentage of diagnoses verified in the medical records and a frequency table listing the diagnoses included in other neuroses category are not provided in AFHS (2000). In addition, in cases where verified psychological diagnoses from AFHS (2000) were combined with verified psychological diagnoses from previous AFHS studies, it is not clear whether the past diagnoses were active at the time of follow-up (AFHS, 2000). Also, if these other neuroses were associated with dioxin exposure, the onset of symptoms of specific conditions would have occurred at a much earlier time, when they would be more closely related to actual exposure. Moreover, the lack of correlation of these other neuroses with the SCL-90-R—a standardized and validated questionnaire that includes scales for anxiety, depression, hostility, interpersonal sensitivity, obsessive-compulsive behavior, paranoid ideation, phobic anxiety, psychoticism, somatization, global severity index, positive symptom total and positive symptom, distress index—brings into question the criteria used for the psychological diagnoses. VAO identified that the SCL-90-R, MCMI and related medical outcomes information reported for an earlier AFHS (1991) examination were inconsistent. Because of the above-mentioned problems, such inconsistencies are also present in the 1997 examination results. Conclusion There is still inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides 2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram, and cognitive or neuropsychiatric disorders. MOTOR/COORDINATION DYSFUNCTION Update of the Scientific Literature Because of the increasing concern of a possible link between Parkinson’s disease (PD) and various chemicals used as herbicides and pesticides, VAO,

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Veterans and Agent Orange: Update 2000 Update 1996, and Update 1998 suggested that as Vietnam veterans move into the decades when PD is more prevalent, attention be paid to the frequency and character of new cases in exposed versus nonexposed individuals. Table 9-1 summarizes studies (some reviewed in Update 1996 and Update 1998) from numerous countries that examined the association between PD and pesticide (herbicide and insecticide) exposure. In these studies, cases of PD were identified using strict guidelines, either neurological examination or review of medical data that required the presence of signs of PD (resting tremor, bradykinesia, cogwheel rigidity, and postural reflex impairment). Routine clinical diagnosis of PD has an accuracy of 75 percent by neuropathological criteria that can be improved to 80–90 percent when more strict diagnostic criteria are applied (Langston, 1998). Clinical features were not verified in the large population studies that relied on death certificates or hospital admission diagnoses (Schulte et al., 1996; Chaturvedi et al., 1995; Ritz and Yu, 2000; Tuschen and Jensen, 2000). Exclusion criteria included the presence of atypical features such as cerebellar involvement, gaze impairment, pronounced autonomic dysfunction, or all other causes of secondary parkinsonism such as drugs, infections, or toxins. In the studies reviewed, pesticide exposure was usually required to occur prior to disease onset, but knowledge of when it occurred in relation to disease onset was not presented. In Update 1998, emphasis on the detection of early-onset parkinsonism was considered vital to test the hypothesis that the disease is related to a toxic exposure because, currently, aging is the only known definitive risk factor for PD. PD becomes clinically apparent when approximately 60 to 70 percent of the neurons in the substantia nigra have deteriorated. One possible reason for the early onset of PD is that neuronal loss is accelerated in individuals with pesticide exposure, causing expression of the disease at a younger age than usually found in the general population (see review in Weiss, 2000). When attempting to address the issue of early-onset PD, study populations with an onset prior to age 40 or 50 years have been investigated. Butterfield et al. (1993) studied 63 persons, mean age 41 years, diagnosed with PD on or before age 50. Sixty-eight controls were used from the same area with comparable age and diagnosis of rheumatoid arthritis. Standard diagnostic criteria for PD were verified with the treating neurologist. Exposure history for herbicides, obtained by questionnaire, was positive if exposure occurred more than 10 times in any year. Time of exposure ranged from 1 to 46 years before the diagnosis of PD. The adjusted odds ratio (OR) for herbicide exposure and PD was 3.22 (p<.034). No herbicides were identified. By contrast, a case-control study of young-onset and late-onset Parkinson’s disease found no association with pesticide exposure (Stern et al., 1991). In that study, cases with PD were divided into 69 young-onset individuals, with the first symptoms of PD before age 40, and 80 old-onset individuals, with the first symptoms after age 60. Cases were matched for age, sex, and race. Exposure to herbicides, obtained through interview, was a sum-

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Veterans and Agent Orange: Update 2000 mary variable for any exposure in the home, yard, or garden. Fifty-four percent of cases and fifty-two percent of controls were exposed to herbicides; the OR for herbicides was not significant (0.9; 95 percent confidence interval [95% CI] 0.6– 1.5). The relationship between herbicide exposure and PD, when comparing younger and older matched pairs, also showed no significant differences. As seen in Table 9-1, cases of early-onset Parkinson’s disease are included in the study groups of many other studies but are not analyzed as a separate subset. Although the presence of PD is carefully assessed in studies investigating an association between exposure to herbicides and PD, exposure assessment for herbicides (and TCDD) in these studies (see Table 9-1) is not well documented or quantified. Specific chemical agents or classes of compounds of interest are not identified, and virtually any pesticide exposure for any duration has been accepted for an individual to be classified as exposed. Even the use of the term pesticide changes between studies, from its general use to reflect both insecticides and herbicides, to its use only for insecticides. Some studies used occupations in agriculture as surrogates for pesticide exposure (Tanner et al., 1989; Hertzman et al., 1990; Schulte et al., 1996; Fall et al., 1999; Tuchsen and Jensen, 2000). Ritz and Yu (2000) performed a study of PD mortality and pesticide exposure in which the level of pesticide use by county in California was determined through a required pesticide registry and the amount of land in each county that was treated. They found a 2.5 fold increase in the risk of dying from Parkinson’s disease if more than 37 percent of the county land was treated. If 5–37 percent of the county’s land was treated, the risk of dying from PD was increased by 50 percent. In a case-control study conducted in Parma, Italy, 68 cases with PD fulfilling the criteria established the UK Parkinson’s Disease Society Brain Bank enrolled from the Institute of Neurology were compared for herbicide and pesticide exposure to 86 controls from other outpatient clinics (Smargiassi et al., 1998). Exposure required either occupational or residential contact for at least ten consecutive years prior to the onset of PD. Twenty five cases and 20 controls fulfilled this criteria for pesticide/herbicide exposure, giving an odds ratio of 1.2 (0.6–2.4). Liou et al. (1997) conducted a case-control study in Taiwan in which subjects identified specific herbicides and pesticides that they had used. When PD cases were compared to a referent group with no exposure, the use of paraquat with or without other herbicides or pesticides had an OR of 4.7 (2.0–11.5). When the cases were exposed to herbicides or pesticides other than paraquat, however, the OR was 2.2 (0.9–5.6). Paraquat is of interest to PD researchers because of its structural similarity to a neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), MPP+, that causes parkinsonism with similar pathology to idiopathic PD. Paraquat, however, is not structurally or mechanistically related to 2,4-D or 2,4,5-T and is not relevant to Agent Orange. In a study by Seidler et al. (1996), an effort was made to obtain specific names of products used, but in the final exposure assessment, exposure was

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Veterans and Agent Orange: Update 2000 categorized by use of herbicides, insecticides, organochlorines, alkylated phosphates, and carbamates; “inhibitors of cellular metabolism”; and “other.” Comparison of cases with regional controls for the alkylated phosphates and carbamates had an OR of 2.5 (1.3–4.6). The other analyses with use of specific classes of pesticides found no differences even though the broad categories of herbicide and insecticide use were significant. Herbicide use for 41–80 dose-years had an OR of 3.0 (1.5–6.0), and pesticide use for 41–80 dose-years had an OR of 2.5 (1.4– 4.5). In the occupational setting, Gorell et al. (1998) stratified by years of exposure and found that PD cases had more frequent use of herbicides and insecticides at work than the referent group (herbicide exposure OR, 4.1, 1.6–12.2; insecticide exposure OR, 3.6, 1.8–7.2). The association was stronger when insecticide exposure was 10 or more years (OR=5.8, 2.0–17.0). For individuals with more than 20 years of herbicide exposure, however, the OR (3.0, 0.6–15.4) was not statistically significant. Examination of these last two groups for age of onset of PD showed no difference from that of individuals with fewer years of occupational exposure. Koller et al. (1990) had access to pesticide questionnaire responses previously used in a study of lymphoma in Kansas. Herbicide or pesticide exposure included type of application (aerial, direct, sprayer), number of years exposed, number of acres to which herbicide was applied, type of crop (corn, wheat, sorghum, or pastureland), and type of herbicide/pesticide used. Examination of the differences between cases and controls found a weak association with herbicide or pesticide use on corn and PD. That association, however, was discounted for statistical reasons. The same exposure variables were collected by Wong et al. (1991) to examine the risk of PD from pesticide exposure in 19 families with two or more siblings who have PD and a matched comparison group, as well as a second comparison group of 19 sibling pairs with essential tremor. No differences in herbicide or pesticide use, farming, drinking of well water, or rural living were found between the PD group and the comparison group with essential tremor. The group with essential tremor, however, was significantly different from the control group for rural living and farming. A new approach to establish a link between pesticide exposure and PD is to determine whether the presence of mutant alleles that alter the enzymes needed to detoxify chemicals are more prevalent in PD. The prevalence of a cytochrome P450 CYP2D6 polymorphism, a gene involved with xenobiotic metabolism, was examined in 215 Chinese individuals with PD and 313 controls of similar age, sex, and locality (Chan et al., 1998). Of the 874 alleles examined, only three mutant alleles were found; two were control subjects and one PD. Although polymorphism of the CYP2D6 gene is common among Caucasians, it is rare in the Chinese people and did not contribute to PD. In the Chinese with PD, however, years of pesticide exposure while farming were significantly related to PD in women (OR=6.8, 1.9–24.7) but not in men (OR=0.7, 0.3–1.8).

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Veterans and Agent Orange: Update 2000 Another study that examined the interaction between pesticide exposure and altered genetic makeup in PD used cases of PD with dementia and, as the comparison group, cases of PD with no dementia (Hubble, 1998). One-fifth of patients with PD develop dementia. Researchers found that patients with PD, past pesticide exposure (>20 days per year in any year of life), and the presence of the CYP 2D6 29B+gene had 83 percent predicted probability of PD and dementia. Neither pesticide exposure nor the allele alone had predictive value, but the gene-toxicant interaction was significant (OR=3.2, 1.1–9.1). Menegon et al. (1998) investigated the presence of a glutathione s-transferase (GST) polymorphism in PD. This polymorphism was investigated because GST is necessary for the metabolism of pesticides. No association with GST polymorphism was found. In the group of PD and controls exposed to pesticides, however, the GSTP1 genotypes differed significantly. GSTP1 is involved in pesticide metabolism, and in humans, GSTP1-1 is located in the brain and blood-brain barrier. It was hypothesized that this could influence how neurotoxic pesticides are metabolized and therefore provide one explanation of why individuals with PD are more susceptible to the effects of pesticides. A recent meta-analysis of 19 studies (see Table 9-1) examined the association between PD and exposure to pesticides (Priydarshi et al., 2000). These are all case-control studies, and therefore, the parameter calculated to estimate relative risk is an odds ratio. Of the 19 studies, 17 had a positive association between PD and exposure to pesticides and 8 had an estimated odds ratio that was significant. Of the remaining two studies, one showed a negative association (Stern et al., 1991), and the other no association (Wong et al., 1991), between PD and exposure to pesticides. Heterogeneity was significant among the studies (p<.001), and therefore, the random-effect model used generated a combined estimate for the 19 studies of 1.9 (1.5–2.5). The combined estimates for these studies by geographic location was United States, 2.1 (1.1–4.1); Asia, 2.5 (1.6–4.1); Europe, 1.8 (1.4–2.2); and Canada, 1.9 (1.4–2.8). The presence of a dose-response relationship was examined in six studies in which duration of exposure was included (Smargiassi et al., 1998; Chan et al., 1998; Morano et al., 1994; Seidler et al., 1996; Gorell et al., 1998; Semchuk et al., 1992); no increased incidence of PD was found with increasing dose. Gorrell et al. (1998) showed an increased risk of PD with longer duration of exposure to pesticide (>10 years), with an OR of 5.8 (2.0–17.0). Although the results are intriguing, an association of PD with exposure to 2,4-D, 2,4,5-T, and its contaminant dioxin is not reported in any of these studies. Synthesis Of the 30 studies summarized in Table 9-1, only eight provide an estimate of relative risk for herbicides; of these studies, five had a significant association (Butterfield et al., 1993; Gorrell et al., 1998; Liou et al., 1997; Seidler et al., 1996;

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Veterans and Agent Orange: Update 2000 Semchuk et al., 1992), one had no association (Taylor et al., 1999), and the remaining two had a negative association (Kuopio et al., 1999; Stern, 1991). When a specific herbicide was examined in Taiwan (Liou, 1997) the OR for paraquat was 3.2 (2.4–4.3). Paraquat is of interest to PD researchers because of its structural similarity to the active metabolite of the neurotoxin MPTP, MPP+, that is known to produce pathology identical to PD. The biological plausibility for PD and pesticide exposure is further supported by a recent study of rats exposed to the lipophilic insecticide, rotenone, a known inhibitor of complex 1, a mitochondrial enzyme involved in oxidative phosphorylation. After receiving 2– 3 mg/kg of rotenone for 5 weeks, the rats developed features of parkinsonism with hypokinetic and unsteady movement and hunched posture. Neuropathological examination showed degeneration of dopaminergic neurons and cytoplasmic inclusions that possessed ultrastructural and chemical properties suggestive of Lewy bodies, a hallmark of PD in humans (Betarbet et al., 2000). It is believed that the underlying mechanism of PD in humans is related to oxidative damage from free radicals and mitochondrial impairment. Conclusions There remains inadequate or insufficient evidence of an association between exposure to the herbicides in this report and motor or coordination dysfunction or Parkinson’s disease. In the future, however, as diagnostic accuracy for Parkinson’s disease improves, herbicide exposure assessment is quantitated with specific biomarkers, and further research confirms the gene-toxicant interaction in larger prospective studies of PD, this evidence for association may change. This underscores the importance of a prospective study of Vietnam veterans for the development of PD.

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Veterans and Agent Orange: Update 2000 TABLE 9-1 Epidemiologic Studies of Pesticide Exposure and Parkinson’s Diseasea Reference and Country Study Group Comparison Group Exposure Assessment Significant Association with Pesticides OR (95 % CI) Neurological Dysfunction Butterfield et al., 1993; USAb,c 63 young onset, (age < 50 years) 68 Questionnaire—pesticide or insecticide use 10 times in any year + Insecticides 5.8, herbicides 3.2 (2.5–4.1), past dwelling fumigated 5.3 Standard criteria for PD by history Chan et al., 1998; Hong Kongc 215 313 Interview—exposure to pesticides during farming (years) + Pesticides in women 6.8 (1.9–24.7) Pesticides in men 0.7 (0.3–1.8) Neurological exam Chaturvedi et al., 1995; Canadac 87 (age > 64 years) 2,070 Survey—exposure positive if frequently used   Pesticides 1.8 (0.9–3.4) History of PD Fall et al., 1999; Swedenc 113 263 Questionnaire—any job handling pesticides Pesticides 2.8 (0.9–8.7) Neurological exam Golbe et al., 1990; USAb,c 106 106 Telephone survey— Sprayed pesticides or insect spray once a year for a total of 5 years + Sprayed pesticide 7.0 (5.8–8.5) Neurological exam Gorrell et al., 1998; USAc 144 (age > 50 years) 464 Interview— Herbicide and insecticide use while working on a farm or gardening + Occupational herbicides 4.1 (1.4–12.2) Occupational insecticides 3.6 (1.8–7.2) Standard criteria for PD by history Hertzman et al., 1990; Canada 57 122 Questionnaire—ever worked in an orchard + Working in orchards 3.7 (1.3–10.3) Neurological exam

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Veterans and Agent Orange: Update 2000 Reference and Country Study Group Comparison Group Exposure Assessment Significant Association with Pesticides OR (95 % CI) Neurological Dysfunction Hertzman et al., 1994; Canadac 127 245 Interview—occupation with probable pesticide exposure + Pesticides in men 2.3(1.1– 4.9) Neurological exam Ho et al., 1989; Hong Kongc 35 (age >60 years) 105 Interview—use of insecticides or herbicides (Y/N), farming, eating raw vegetables + Herbicides and pesticides 3.6 (1.0–12.9) Neurological exam Hubble et al., 1993; USAc 63 76 Questionnaire—pesticide or herbicide use 20 days per year for >5 years + Pesticide or herbicide 3.4 (1.3–7.3) Neurological exam Hubble et al., 1998; USA 43 PD with dementia 51 PD without dementia Interviews—pesticide exposure >20 days in any year and presence of allele for poor drug metabolism + Pesticide exposure and genetic trait 3.17 (1.1–9.1) Neurological exam Jimenez-Jimenez et al., 1992; Spainc 128 256 Interview—exposure: applied pesticides, or lived and ate vegetables where pesticides used   Pesticide 1.3 (0.9–2.1) Standard criteria for PD by history Koller et al., 1990; USAc 150 150 Interview—acre-years= acres multiplied by years of herbicide or pesticide used Herbicide or pesticide use 1.1 (0.9–1.3) Neurological exam

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Veterans and Agent Orange: Update 2000 Reference and Country Study Group Comparison Group Exposure Assessment Significant Association with Pesticides OR (95 % CI) Neurological Dysfunction Schulte et al., 1996; USAb 43,425 PD cause of death in 27 states 1982– 1991   Occupational exposure + PMR excess in male pesticide appliers, horticultural farmers, farm workers, and graders and sorters of agricultural products. ICD•9 332 Seidler et al., 1996; Germanyb,c 380 (age <66 years with PD after 1987) 755 Interview—dose-years (years of application weighted by usage.) + Neighborhood controls for herbicide 1.7 (1.0–2.7) Regional controls for herbicide 1.7 (1.0–2.6) Neurological exam Semchuk et al., 1992; Canadab,c 130 260 Interview — occupational exposure for each job held >1 month + Pesticide 2.25 (1.3–4.0) Herbicide 3.06 (1.3–7.0) Insecticide 2.05 (1.0–4.1) Neurological exam Stern et al., 1991; USAc 69 (onset before age 40 years) 80 (onset after age 59 years) 149 Interview—insecticides and pesticides measured by self-report of home or garden use   Herbicide—young onset 0.9 (0.5–1.7) Herbicide—old onset 1.3 (0.7–2.4) Insecticide—young onset 0.6 (0.2–1.7) Insecticide—old onset 0.8 (0.3–2.1) Standard criteria for PD by history

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Veterans and Agent Orange: Update 2000 Smargiassi et al., 1998; Italyc 86 86 Interview—occupational exposure for at least 10   Pesticides or herbicides 1.15 (0.6–2.4) Standard criteria for PD by history Tanner et al., 1989; China 100 200 consecutive years Interview—exposure for at least 1 year before onset of PD Fruit growing 1.00 (1.0–1.0) Com growing 0.54 (0.3–1.1) Rice growing 1.29 (0.7–2.3) Neurological exam Taylor et al., 1999; USA 140 147 Interview—exposure recorded as total days for lifetime Pesticide 1.02 (0.9–1.2) Herbicide 1.06 (0.7–1.7) Neurological exam Tuchsen and Jensen, 2000; Denmark 134 128,935 expected cases 101.5 Occupations in farming, horticulture, and landscape were expected to have exposure to pesticides + Age-standardized hospitalization ratio for all men in agriculture and horticulture 134 (109–162) First-time hospitalization for PD Wechsler et al., 1991; USA 34 (age >39 years) 22 Questionnaire—duration of occupational and home pesticide use   Home pesticides used more frequently by cases Standard criteria for PD by history Wong et al., 1991; USAc 38 (19 sibling pairs with PD) 38 age and sex matched and 19 sibling pairs with essential tremor Interview—acre-year (number of years exposed multiplied by the number of acres applied herbicides or pesticides) Herbicides or pesticides 1.0 (0.7–1.4) Neurological exam Note: PMR=proportionate mortality ratio. aModified from Le Couteur et al. (1999). bPreviously quoted in Update 1996 or Update 1998. cStudies used in meta-analysis (Priyadarshi et al., 2000).

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Veterans and Agent Orange: Update 2000 CHRONIC PERSISTENT PERIPHERAL NEUROPATHY Update of Scientific Literature On the basis of data available at the time, it was concluded in VAO, Update 1996, and Update 1998 that there was inadequate or insufficient evidence of an association between exposure to the herbicides considered in this report and chronic persistent peripheral neuropathy. Data from the Air Force Health Studies were a large part of the basis for these conclusions. In 1982 a baseline study of 1,208 Air Force Ranch Hands and a comparison group of 1,238 Air Force personnel found no differences between the groups in measures of peripheral nerve function, including neurological symptom evaluation, physical examination, and nerve conduction velocity tests (AFHS, 1984). A follow-up study was conducted in 1985 using the same protocol, except that nerve conduction velocity was not assessed, and once again no differences were seen between groups (AFHS, 1987). In a 1987 follow-up, Ranch Hands had significantly more hereditary and degenerative diseases, such as benign essential tremor (not found to be associated with dioxin), but the peripheral nerve status was not remarkable (AFHS, 1991). In 1992, the neurological assessment was comparable between the two groups and there was no consistent evidence of a dose-response relationship to either estimated initial dioxin levels or current dioxin levels. The most recent AFHS follow-up (AFHS, 2000) studied 870 Air Force Ranch Hand veterans and 1,251 Air Force personnel in the comparison group. The neurological examination was based on physical examinations and verified histories of neurological diseases. Vibrotactile measurement with the Vibratron II complemented the peripheral nerve examination. A history of peripheral nerve disorders was significantly associated with the covariates age, insecticide exposure, and diabetic class. The percentage of participants with a confirmed polyneuropathy index was consistently higher in Ranch Hands than in the comparison group. After adjustment for the covariates, the results with dioxin exposure were marginally significant for the enlisted ground crew. A decreased range of motion in the neck was found to be more prevalent in Ranch Hands than in the comparison group; this finding was associated with dioxin levels and a history of peripheral nerve disorders. Decreased range of motion in the neck is commonly a result of degenerative disease of the cervical vertebrae that can lead to cervical nerve root compression. Decreased range of motion in the neck is not caused by a peripheral neuropathy and is not an outcome related to any known toxic exposure. Synthesis The recent Air Force Health Study (2000) is the first time since the baseline examination in 1982 that a difference in measures of peripheral nerve function

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Veterans and Agent Orange: Update 2000 between the Ranch Hands and comparison group was found. In the Ranch Hand population, many risk factors for peripheral neuropathy, including age-related changes, diabetic class, alcohol use, occupation, and insecticide exposure, were significantly associated with measures of peripheral nerve function. Other uncontrolled confounders (related to life-style) also might have been involved in the increased incidence of peripheral neuropathy in the Ranch Hand ground crew. Five cases of peripheral neuropathy were seen in the Ranch Hand ground crew (1.4 percent of the crew). This prevalence is consistent with the expected prevalence for peripheral neuropathy in the general population (2–8 percent) and the prevalence increases with age. The development of a peripheral neuropathy associated with a toxic exposure begins when the exposure is occurring or shortly after cessation of exposure. Furthermore, the peripheral nervous system has the ability to repair itself when exposure ceases. Therefore, it is not biologically plausible that peripheral neuropathies found for the first time in the recent examination (AFHS, 2000) were caused by an exposure to dioxin or herbicides that occurred 30 years earlier. In addition, the clinical relevance of the peripheral neuropathy findings is questionable because the neurological examination and its analyses cannot be understood from the perspective of a clinical or preclinical peripheral neuropathy. The various indices of peripheral nerve function, as reported by AFHS (2000), do not correspond to clinical neuropathy. For example, the presence of a Romberg sign may be caused by lesions in the nervous system that are not necessarily peripheral nervous system effects. Also, in the clinical setting, the severity of sensory loss in a peripheral neuropathy is determined by examining the distribution of diminished perception of vibration, pin, and light touch, which should be more severe distally than proximally. The results of such an examination were not included in the results for peripheral neuropathy. Important measures of sensory loss described in the methods—vibration at the ankle and vibrotactile threshold at the great toe—were also not included in the results, even though these were two of the four variables used to classify an individual as having a confirmed peripheral neuropathy. Measuring vibrotactile threshold with a Vibratron II provides a quantitative value for a sensory test, allowing examination of sensory impairment on a continuous scale. Individuals with abnormal vibration at the ankle should have higher vibrotactile thresholds of the great toe. As with sensory loss in peripheral neuropathy, motor weakness and altered reflexes, when present, should also be more pronounced in the distal part of an extremity, and therefore, ankle reflexes are diminished compared to the corresponding knee reflexes in many peripheral neuropathies. The only diagnostic criterion for ankle reflex used in the AFHS (2000) evaluation of peripheral neuropathy was absence of reflex. However, this is a poor marker for anything other than an advanced neuropathy. A more clinically relevant criterion would have been based on a comparison of ankle jerk to knee jerk or an evaluation of diminished ankle jerk with relation to knee jerk.

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Veterans and Agent Orange: Update 2000 Diabetic neuropathy is a common cause of peripheral neuropathy, occurring in approximately 50 percent of individuals with Type 2 diabetes over time, and is present in less than 10 percent when the diagnosis is first made (Pirart, 1978). A recent study of non-insulin-dependent outpatients with Type 2 diabetes (mean age, 70.6 years; mean duration, 11.7 years) found polyneuropathy in 49 percent of the individuals when using the criteria of lower limb sensory and motor nerve conduction velocity or latency more than 2 standard deviations above or below the age-matched controls (de Wytt et al., 1999). In mild diabetic neuropathy, a median mononeuropathy was found in 23 percent of patients at a time when the lower extremities did not differ significantly from controls in electrodiagnostic studies (Albers et al., 1996). The common neuropathy associated with Type 2 diabetes is a distal symmetric sensorimotor polyneuropathy that primarily affects the sensory nerves. Type 2 diabetes can also affect other parts of the peripheral nervous system to produce an autonomic neuropathy, a polyradiculopathy, cranial mononeuropathies, limb mononeuropathy, and mononeuropathy multiplex. Intensive glycemic control (i.e., careful attention to blood sugar levels) appears to diminish the rate of progression of diabetic polyneuropathy. Persistent glycemia indirectly leads to an increased release of free radicals and oxidative damage to the nervous system. It is believed that these oxidative stressors lead to mitochondrial dysfunction and programmed cell death. This theory is supported by the fact that administration of antioxidants prevents the neuropathy (Feldman et al., 1999). The clinical presentation of a diabetic neuropathy versus a neuropathy secondary to toxic exposure may be difficult to differentiate except by the presence of other unique features in the clinical history and presentation, such as gastrointestinal symptoms with lead or arsenic exposure or alopecia with thallium exposure. In addition, if caused by a toxic exposure, over time the neuropathy should improve after cessation of exposure, but a diabetic neuropathy will usually progress unless a dramatic change is made in glycemic control. Complaints of peripheral nerve pathology, however, often occur in isolation and are monotonously similar. In the clinical setting, approximately 30 percent of peripheral neuropathies are left with no etiology after a complete evaluation (McLeod, 1995). Examination of family members for evidence of mild or subclinical neuropathy can provide a hereditary etiology for a subset of this group (Dyck et al., 1981). Also the peripheral nervous system undergoes constant age-related changes that may increase its susceptibility to other metabolic and toxic exposures. Conclusion There remains inadequate or insufficient evidence of an association between exposure to dioxin or the herbicides studied in this report and chronic persistent peripheral neuropathy.

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Veterans and Agent Orange: Update 2000 ACUTE AND SUBACUTE TRANSIENT PERIPHERAL NEUROPATHY Update of the Scientific Literature The committee is aware of no new publications that investigate the association between exposure to the compounds of interest and acute and subacute transient peripheral neuropathy. If TCDD were associated with the development of transient acute and subacute peripheral neuropathy, the disorder would become evident shortly after exposure. The committee knows of no evidence that new cases of acute or subacute transient peripheral neuropathy that develop long after service in Vietnam are associated with herbicide exposure. CONCLUSIONS FOR NEUROBEHAVIORAL DISORDERS Strength of Evidence in Epidemiologic Studies As in the earlier reports, this committee finds that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides used in Vietnam and disorders involving cognitive and neuropsychiatric dysfunction, motor or coordination deficits, and chronic persistent peripheral neuropathy. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components, as reviewed in previous reports. In Update 1996, the committee found that there was limited/suggestive evidence of an association between exposure to the herbicides considered in this report and acute or subacute transient peripheral neuropathy. The evidence regarding association was drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Information available to the committees responsible for Update 1998 and this report continues to support this conclusion. Biologic Plausibility This section summarizes the biologic plausibility of a connection between exposure to dioxin or herbicides and various neurobehavioral disorders on the basis of data from animal and cellular studies. The details of the committee’s evaluation of data from these studies are presented in Chapter 3. Some of the preceding discussions of neurobehavioral outcomes include references to papers relevant to specific neurobehavioral effects. Some information exists on the development of neurobehavioral disorders and TCDD exposure in laboratory animals. In vivo experiments have demonstrated that TCDD can affect biochemical processes, including having effects on calcium uptake and neurotransmission. Acute doses of TCDD administered to

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Veterans and Agent Orange: Update 2000 rats affect the metabolism of serotonin, a neurotransmitter in the brain that is able to modulate food intake. This biochemical change is consistent with observations of progressive weight loss and anorexia in experimental animals exposed to TCDD. A study in adult male Wistar rats suggests that a single low-dose intraperitoneal injection of TCDD could cause a toxic polyneuropathy (Grahmann et al., 1993; Grehl et al., 1993); no other studies in animals have reported such an effect. TCDD treatment has also been demonstrated to affect learning and memory in rats. The mechanism by which TCDD could exert neurotoxic effects is not established. TCDD has a wide range of effects on growth regulation, hormone systems, and other factors associated with the regulation of activities in normal cells; these effects could in turn influence nerve cells. Furthermore, animal studies and in vitro mechanistic studies continue to emphasize the importance of alterations in neurotransmitter systems as underlying mechanisms of TCDD-induced behavioral dysfunction. Most studies are consistent with the hypothesis that the effects of TCDD are mediated by the aryl hydrocarbon receptor (AhR), a protein in animal and human cells to which TCDD can bind. Following the binding of TCDD, the TCDD-AhR complex is known to bind DNA, leading to changes in transcription (i.e., genes are differentially regulated). Modulation of genes could cause altered cell function. Although structural differences in the AhR have been identified among different species, this receptor operates in a similar manner in animals and humans. Therefore, a common mechanism is likely to underlie the neurotoxic effects of TCDD in humans and animals, and data in animals can support a biologic basis for TCDD’s neurotoxicity. Because of the many species and strain differences in TCDD responses, however, controversy remains regarding the TCDD exposure level that is neurotoxic. Limited information is available on neurotoxic effects of exposure to the herbicides discussed in this report. At the cellular level, 2,4-D inhibited neurite extension. This effect was accompanied by a decrease in intracellular microtubules, inhibition of the polymerization of tubulin, disorganization of the Golgi apparatus, and inhibition of ganglioside synthesis. Studies in rats indicate an impairment of motor function, central nervous system depression, and inhibition of myelination in the brain. Behavioral alterations have also been seen following treatment of rats with 2,4-D. Results from in vitro mechanistic studies suggest that 2,4,5-T may acutely affect neuronal and muscular function by altering cellular metabolism and cholinergic transmission. There is evidence that other chemicals can induce a Parkinson-like syndrome in humans, possibly through the generation of free radicals in the target tissue. These results might be biologically relevant because it is suspected that TCDD and some of the herbicides used in Vietnam could indirectly generate free radi-

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Veterans and Agent Orange: Update 2000 cals or sensitize cells to free-radical injury; the exact relevance, however, has not been established. The foregoing evidence suggests that a connection between TCDD exposure and human neurotoxic effects is, in general, biologically plausible. However, differences in sensitivity and susceptibility across individual animals, strains, and species; the lack of strong evidence of organ-specific effects across species; and differences in route, dose, duration, and timing of exposure complicate any more definitive conclusions about the presence or absence of a mechanism for the induction of neurotoxicity by TCDD in humans. Experiments with 2,4-D and 2,4,5-T indicate these chemicals can have effects on brain cells at the subcellular level that could provide a biologically plausible mechanism for neurotoxicity, if such toxicity is seen in animals or humans, but alone do not provide a basis to conclude these compounds are neurotoxic. The observation of behavioral alterations in rats following exposure to 2,4-D also would support the neurotoxicity of this compound, but the species, strain, and dose specificities of these effects remain unknown. Considerable uncertainty remains about how to apply this information to the evaluation of potential health effects of herbicides or dioxin exposure in Vietnam veterans. Scientists disagree over the extent to which information derived from animal and cellular studies predicts human health outcomes and the extent to which the health effects resulting from high-dose exposure are comparable to those resulting from low-dose exposure. Investigating the biological mechanisms underlying TCDD’s toxic effects continues to be a very active area of research, and subsequent updates of this report might have more and better information on which to base conclusions, at least for this compound. Increased Risk of Disease Among Vietnam Veterans The most recent Air Force Health Study (AFHS, 2000) reported differences in prevelance of peripheral neuropathy between the Ranch Hand and comparison group, but the clinical relevance is not clear. However, data do not support the notion that these differences are associated with exposure to herbicides or dioxin. REFERENCES AFHS (Air Force Health Study). 1984. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Baseline Morbidity Study Results. Brooks AFB, TX: USAF School of Aerospace Medicine. NTIS AD-A138 340. 362 pp. AFHS. 1987. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. First Follow-up Examination Results. 2 vols. Brooks AFB, TX: USAF School of Aerospace Medicine. USAFSAM-TR-87–27. 629 pp. AFHS. 1991. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Serum Dioxin Analysis of 1987 Examination Results. 9 vols. Brooks AFB, TX: USAF School of Aerospace Medicine.

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