10
Neurobehavioral Disorders
BACKGROUND
The nervous system is made up of a central portion—the central nervous system (CNS)—that consists of the brain and spinal cord, and the peripheral nervous system (PNS), which includes the nerve roots, the brachial and lumbar plexuses, and the peripheral nerves that pass to the extremities. The peripheral nerves are responsible for innervating the muscles and also are made up of afferent fibers that convey sensory information to the CNS. In addition, they contain autonomic fibers that regulate the activity of the heart, blood vessels, sweat glands, bladder, and bowels.
Disturbances of the CNS may lead to neurobehavioral abnormalities such as cognitive changes and neuropsychiatric disorders. Other disturbances related to CNS dysfunction include abnormalities of sensation, weakness, tremors, incoordination, and the development of abnormal movements.
Disturbances of the PNS lead to peripheral neuropathy. Peripheral neuropathy is an imprecise term that includes the symmetric involvement of numerous nerves in the extremities (polyneuropathy) or the selective involvement of one or several individual peripheral nerves (mononeuropathy simplex or multiplex). It is sometimes used to refer to pathology affecting the nerve roots, which emerge from the spinal cord and have branches that ultimately form the nerves to the extremities. Chronic peripheral neuropathy may occur for many different reasons; it varies in its pathology and severity in different cases. It may be a feature of a number of common general medical disorders, especially diabetes mellitus.
Numerous publications have addressed the neurotoxicity of herbicides and pesticides. Such reports have been based on studies related to occupational, environmental, or Vietnam veteran exposure. In Veterans and Agent Orange: Health
TABLE 10-1 Selected Neurobehavioral Studies of Herbicide Exposure
Reference |
Study Group |
Tests of Neurological Dysfunction |
Exposure Measures |
Comparison Group |
OCCUPATIONAL |
||||
Zober et al., 1994 |
158 German BASF employees |
Medical record review |
Chloracne and TCDD levels |
161 reference comparisons |
Berkley and Magee, 1963 |
1 farmer |
Neurological examination |
No |
None |
Todd, 1962 |
1 weed-sprayer |
Neurological examination |
No |
None |
Goldstein et al., 1959 |
2 farmers |
Neurological examination |
No |
None |
|
1 book-keeper |
EMG |
|
|
Baader and Bauer, 1951 |
10 pentachlorophenol plant workers |
Record review clinical evaluation |
No |
None |
ENVIRONMENTAL |
||||
Peper et al., 1993 |
19 German residents exposed to 2,3,7,8-TCDD |
Neuropsychological battery and symptom questionnaires |
Serum TCDD |
None |
VIETNAM VETERANS |
||||
Visintainer et al., 1995 |
151,377 Michigan veterans who served in Vietnam |
No: mortality data only |
No |
225,651 Non-Vietnam veterans |
Decoufle et al., 1992 |
7,924 veterans |
Self-report with neurological examinations in a subset |
Self-report |
7,364 Non-Vietnam veterans |
Effects of Herbicides Used in Vietnam (henceforth called VAO) (IOM, 1994), attention was focused particularly on persistent neurobehavioral dysfunction. In Veterans and Agent Orange: Update 1996 (henceforth called Update 1996) (IOM, 1996), attention was also directed at the occurrence of acute and subacute peripheral neuropathy, and earlier data relating to that aspect were reexamined. In the present report, at the specific request of the Department of Veteran Affairs, the possibility of chronic peripheral neuropathy developing in Vietnam veterans as a consequence of herbicide exposure has been reconsidered.
COGNITIVE AND NEUROPSYCHIATRIC EFFECTS
Summary of VAO and Update 1996
In VAO, the committee concluded that the literature was insufficient to determine whether an association existed between exposure to herbicides and related compounds and chronic cognitive or neuropsychiatric disorders. As suggested by Sharp et al. (1986), the delayed effects of such exposures on human health are difficult to detect, and the health risks may be sufficiently small that they are below the power of present epidemiologic studies to detect.
Although there was no shortage of studies concerning this topic, methodologic problems made it difficult to reach definitive conclusions. Shortcomings in defining exposure included absent or poor exposure assessments; inconsistencies in identifying exposed individuals for study (i.e., some studies relied on the presence of chloracne for inclusion, whereas others assumed that all subjects had been exposed); and concomitant exposure to different chemicals, mixtures of chemicals, or concentrations of chemicals. Studies of cognitive or neuropsychiatric disorders are also weakened by the small numbers of subjects; poor selection or absence of comparison groups; confounding of the possible effects of herbicides with the effects of stress; and inadequate statistical analyses. Self-reports of exposure and symptoms may not be verified independently.
The committee noted that in order to maximally define the direct effects of dioxin on cognitive and neuropsychiatric function, future studies should focus primarily on occupationally exposed groups for whom levels of exposure are better known and should include neurobehavioral testing in relative proximity to the time of exposure.
VAO also concluded that significantly exposed subjects should be followed for the development of neuropsychological dysfunction in middle and later life. It is possible that minor CNS changes acquired in early adulthood are too subtle to be detected by current neuropsychological testing methods, but they could manifest themselves later when compounded by ''normal age-related changes" of the CNS. Theoretically, exposure to neurotoxins could produce "accelerated aging" of the brain due to premature neuronal loss, which could then result in neurobehavioral deficits.
In Update 1996, the committee reviewed the several publications that had appeared since the original report, concluding that there was still inadequate or insufficient evidence from occupational and other studies of any association between exposure to the herbicides under consideration and cognitive or neuropsychiatric disorders.
Update of the Scientific Literature
In a report from Australia, O'Toole et al. (1996) analyzed the self-reported psychiatric states of Vietnam veterans as determined 20-25 years after the war. It was found that the veterans had higher prevalences than the civilian population of alcohol abuse or dependence, posttraumatic stress disorder, and social and simple phobias. This related to combat rather than posting to a combat unit. No attempt was made in the report to relate these behavioral disorders to herbicide exposure. We are aware of no other new studies since the last report that have provided any further evidence of an association between herbicide exposure and cognitive or neuropsychiatric dysfunction.
MOTOR/COORDINATION DYSFUNCTION
Summary of VAO and Update 1996
In VAO, the committee concluded that there were no definitive studies to determine whether exposure to dioxin or related herbicides was associated with CNS motor/coordination problems. However, follow-up of veterans and, to a lesser extent, environmental observations suggested that motor and coordination difficulties should be assessed further in exposed subjects. It was determined that longitudinal assessments of motor and coordination problems were warranted in exposed subjects, especially those with high exposure, such as the National Institute for Occupational Safety and Health cohort studied by Fingerhut et al. (1991). Vietnam veterans represent the most systematically evaluated group with chronic TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) exposure, and the findings in this group suggest that CNS disorders may focus on the subtle clinical area of coordination and abnormal involuntary movement disorders. Since this area is a specific subspecialty of neurology, future evaluations should involve specialists in this field. Internationally accepted scales for movement disorders have been developed, and these scales should be used in future studies of such problems.
In addition to assessments that capture the disability related to any objective findings, VAO also stressed that in the past decade, an increasing concern—unrelated specifically to the question of TCDD and the CNS—has developed scientifically over the possible link between Parkinson's disease and chemicals used as herbicides and pesticides (Semchuk et al., 1992). It was suggested that as Vietnam veterans move into the decades when Parkinson's disease becomes more prevalent, attention to the frequency and character of new cases in exposed
versus nonexposed individuals may be highly useful in assessing whether dioxin exposure is a risk factor for eventual Parkinson's disease.
In Update 1996 it was noted that no new data relating to this topic had been published. Nevertheless, it was pointed out that concern persisted about the role of herbicides and pesticides in the pathogenesis of parkinsonism. For example, Semchuk et al. (1993) had noted following multivariate statistical analysis that occupational herbicide use was the third highest predictor of eventual Parkinson's disease risk. Similarly, Butterfield et al. (1993) examined occupational and environmental factors associated with disease risk in patients with early-onset Parkinson's disease and found that the disease was positively associated with herbicide exposure, insecticide exposure, previous residence in a fumigated house, and residence in a rural area at the time of diagnosis. The committee emphasized the importance of cases of early-onset parkinsonism in testing the hypothesis that the disease relates to a toxic exposure, and pointed to the particular medical and scientific importance of a systematic and prospective study of Vietnam veterans for the development of early-onset parkinsonism.
Update of the Scientific Literature
As far as this committee is aware, no new studies relating directly to this aspect have been published. However, Schulte et al. (1996) examined the death certificates from 27 states in the National Occupational Mortality Surveillance System and calculated proportional mortality ratios by occupation for certain neurodegenerative disorders. They found an increase in proportionate mortality ratio for Parkinson's disease among male pesticide applicators, horticultural farmers, farm workers, and graders and sorters of agricultural products. Similarly, in Taiwan, an increased risk of Parkinson's disease has been found among those using paraquat and other herbicides and pesticides (Liou et al., 1997). This was a case-control study in which 120 patients with Parkinson's disease were age-and sex-matched with 240 controls, and data were then obtained on demographic and residential history and on potential exposure to occupational and environmental agents. In Germany significantly elevated odds ratios with pesticide exposure have been noted among patients with Parkinson's disease (Seidler et al., 1996). The implications of these studies for the health of Vietnam veterans are unclear. Such reports underscore the importance of a prospective study of Vietnam veterans for the development of parkinsonism.
CHRONIC PERSISTENT PERIPHERAL NEUROPATHY
Summary of VAO and Update 1996
Although some of the case reports reviewed in VAO suggested that an acute or subacute peripheral neuropathy can develop with exposure to TCDD and
related products, other reports with comparison groups did not offer clear evidence that TCDD exposure is associated with chronic peripheral neuropathy. The most rigorously conducted studies argued against a relationship between TCDD or herbicides and chronic persistent neuropathy.
As a group, the studies concerning peripheral neuropathy have been conducted with highly varying methodologies and have lacked uniform operational definitions of neuropathy. They have not applied consistent methods to define a comparison population or to determine exposure or clinical deficits. Timing of follow-up may be important, since many, but not all, reports that find neuropathy were based on assessments made only a short time after exposure. It was concluded that careful definition of neuropathy and standardization of protocols will be essential to future evaluations.
In Update 1996 it was noted that several new articles had appeared on this topic related to occupational and other studies. Careful analysis, however, showed there to be inadequate or insufficient evidence of any association between exposure to the herbicides under consideration and the development of chronic persistent peripheral neuropathy.
Update of the Scientific Literature
No new information has appeared in the intervening two years that alters this conclusion. It is important, however, to review the context in which this conclusion was reached.
Synthesis
There have been only a limited number of epidemiologic studies of chronic peripheral neuropathy, except for the neuropathy associated with diabetes. A recent study from Europe estimated that a chronic symmetric polyneuropathy occurs in about 8 percent of people over the age of 55 years with a severity that is sufficient to lead to symptoms of the disorder (Italian General Practitioner Study Group, 1995). Prevalence studies of peripheral neuropathy performed both in Asia and in Europe also suggest that peripheral neuropathy is common, occurring in between 2 and 7 percent of the population. In the United States, the most common cause of chronic peripheral neuropathy is diabetes. Several types of peripheral neuropathy are associated with diabetes, including a predominantly sensory polyneuropathy, an asymmetric proximal neuropathy, involvement of individual cranial or limb nerves, and an autonomic neuropathy. In one study it was found that approximately 4 percent of diabetic patients develop a neuropathy within 5 years of diagnosis and 15 percent do so within 20 years (Palumbo et al., 1978). More recent population studies or studies of clinical case
series suggest that the prevalence of neuropathy is even higher among diabetic patients. Thus, in one study of insulin-dependent diabetic patients, the overall prevalence of distal polyneuropathy was 34 percent, and this increased to 58 percent in patients who were aged 30 years or more (Maser et al., 1989). In diabetics who are not dependent upon insulin, evidence of peripheral sensory loss has been found in 26 percent of instances (Franklin et al., 1990). A study from Finland in 1995 has indicated that among non-insulin-dependent diabetic subjects, 8 percent satisfied criteria for definite or probable neuropathy at the time of diagnosis; after a 10-year follow-up period, the prevalence of neuropathy had increased to 42 percent in the diabetic patients, compared to 6 percent in control subjects (Partanen et al., 1995). Among the factors that relate to the development of neuropathy in diabetics are the duration of the disease and the extent to which the blood glucose level is controlled (Orchard et al., 1990; DCCT Research Group, 1995). Further reference to diabetes can be found in Chapter 11.
The peripheral nerves are vulnerable to a number of toxic substances including some of the heavy metals such as lead, arsenic, and thallium; certain organic solvents such as n-hexane and methyl n-butyl ketone; and various organophosphates. A neuropathy is also a common complication of chronic alcohol abuse and, in this circumstance, may relate to either a direct toxic effect of alcohol, a concomitant nutritional deficiency, or both. Other causes of chronic peripheral neuropathy include infection (such as leprosy), diverse metabolic disorders, and a number of general medical diseases. Some neuropathies have a hereditary basis, even though they may not become symptomatic until adulthood.
It is often not possible to distinguish with confidence among various possible causes of neuropathy, except by the setting in which the neuropathy develops. Distinction depends on the results of a detailed family and general medical history, any associated clinical findings, the results of various investigations including electrophysiologic studies, and pathologic examination of nerve biopsy specimens. A neuropathy with acute onset suggests a metabolic or toxic cause or an infective or inflammatory disturbance. A toxic basis for a neuropathy is supported by the cessation of progression—and by subsequent clinical improvement—after discontinuation of exposure to the offending substance. A chronic peripheral neuropathy due to toxic exposure (such as might be attributed to herbicide exposure) would not be expected to develop years after exposure to that toxin ceases.
Despite intensive investigation, a specific cause of a chronic peripheral neuropathy may not be found in between 20 and 50 percent of cases (Dyck et al., 1981; McLeod et al., 1984; Notermans et al., 1993; McLeod, 1995). It is not possible to ascribe such neuropathies to exposure to a possible neurotoxin when that exposure occurred years earlier and is not continuing.
ACUTE AND SUBACUTE TRANSIENT PERIPHERAL NEUROPATHY
Summary of VAO and Update 1996
In Update 1996 it was noted that the methodology used to establish associations between putative causal agents and persistent chronic neurological deficits relies heavily on epidemiologic studies with adequate control or comparison populations. Such methodology can rarely be set in motion with sufficient speed to assess relationships between unexpected chemical exposure and the development of acute or subacute transient neurological disturbance. Because of the very transient nature of the conditions, documenting signs and symptoms in association with documented exposures can be difficult to accomplish in a systematic manner. In such instances, greater reliance must be placed on isolated case histories and less well controlled studies. Based on an analysis of the data from studies reviewed in VAO and Update 1996, as well as those published more recently regarding occupational, environmental, and Vietnam veteran exposure to herbicides and herbicide components, this committee agrees with the conclusion of the last committee that there is limited/suggestive evidence of an association between exposure to certain herbicides used in Vietnam and the development of an acute or subacute transient peripheral neuropathy. Acute peripheral neuropathies have been reported following acute occupational exposure to 2, 4-dichlorophenoxy-acetic acid (2,4-D) weedkiller by several authors (Goldstein et al., 1959; Todd, 1962; Berkley and Magee, 1963). Affected patients had not been examined prior to exposure, but the temporal relationship between clinical disturbance and herbicide exposure was well documented. It remains possible, however, that the neuropathy was unrelated to the herbicide exposure and related to other disorders, such as Guillain-Barré syndrome.
Update of the Scientific Literature
The committee is aware of no new publications that bear on this issue. 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 developing 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/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. No new evidence has appeared since those reports.
In Update 1996, the committee indicated that there is 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 is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. This conclusion remains unchanged.
Biologic Plausibility
Chapter 3 details the committee's evaluation of data from animals and studies with cells regarding the biological plausibility of a connection between exposure to dioxin or herbicides and various neurobehavioral disorders. This section summarizes that evidence. Some of the preceding discussions of neurobehavioral outcomes include references to specific relevant papers.
Little information exists on the development of neurobehavioral disorders and TCDD exposure in laboratory animals. Acute doses of TCDD administered to rats affect the metabolism of serotonin, a neurotransmitter in the brain able to modulate food intake. This biochemical change is consistent with observations of progressive weight loss and anorexia in experimental animals exposed to TCDD. In primary cultures of rat hippocampal neuronal cells, there is evidence that TCDD may increase the uptake of intracellular calcium. This concentration-dependent increase in calcium is associated with a decrease in mitochondrial membrane potentiation and activation of α-protein kinase C. An experimental study in rats suggested that a single low dose of TCDD could cause a toxic polyneuropathy.
In general, 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 may in turn influence nerve cells. Studies in animals indicate that some TCDD effects are mediated through the Ah receptor (AhR), a protein in animal and human cells to which TCDD can bind. It is hypothesized that TCDD, together with the AhR, can interact with sites on DNA and alter the information obtained from DNA in a way that transforms normal cells into abnormal cells. Although structural differences in the AhR have been identified, this receptor operates in a similar manner in animals and humans. Evidence has also begun to accumulate for non-AhR-mediated effects. 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.
Limited information is available on health effects of exposure to the herbicides discussed in the report. Some studies have observed impairment of motor function in rats administered high single oral doses of 2,4-D. Another study showed that the toxic effects of 2,4-D in rats were observed within one-half hour after its oral administration and correlated with signs and symptoms of CNS depression. These data were interpreted to suggest that the toxic mechanism of 2,4-D is related to an action on the central nervous system. 2,4-D also renders the developing rat nervous system vulnerable by hindering the process of myelination in the brain. Evidence was recently presented suggesting that 2,4-D and 2,4,5-T access to the central nervous system is energy-dependent. 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.
The herbicide 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) is known to produce parkinsonism in humans and experimentally in animals, including nonhuman primates. Paraquat, another herbicide, shares with MPTP the ability to increase free-radical load in target tissues and exposure to it has also been related to an increased incidence of parkinsonism. These results may be biologically relevant because it is suspected that TCDD and some of the herbicides used in Vietnam may indirectly generate free radicals or sensitize cells to free radical injury.
The foregoing evidence suggests that a connection between TCDD or herbicide exposure and human health effects is, in general, biologically plausible. However, differences in sensitivity and susceptibility across individual animals, strains and species, 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 neurobehavioral effects.
Considerable uncertainty remains over 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 animals 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. Research on biological mechanisms is burgeoning and subsequent Veterans and Agent Orange updates may have more and better information on which to base conclusions.
Increased Risk of Disease Among Vietnam Veterans
Under the Agent Orange Act of 1991, the committee is asked to determine (to the extent that available scientific data permit meaningful determinations) the increased risk of the diseases it studies among those exposed to herbicides during their service in Vietnam. Chapter 1 presents the committee's general findings regarding this charge. Where more specific information about particular health
outcomes is available, this information is related in the preceding discussions of those diseases.
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