Parkinsonism and occupational exposure to pesticides.

OBJECTIVE: To examine the risk of parkinsonism related to lifetime occupational exposure to pesticides among a cohort of men, mostly orchardists, in Washington State. METHODS: All 310 subjects in this study had previously participated in a cohort study of men occupationally exposed to pesticides. Subjects were given a structured neurological examination and completed a self administered questionnaire which elicited detailed information on pesticide (insecticide, herbicide, and fungicide) use throughout their working careers. Demographic characteristics were also sought. Subjects had a mean age of 69.6 years (range 49-96, SD 8.1). There were 238 (76.8%) subjects who reported some occupational exposure to pesticides, whereas 72 (23.2%) reported none. Parkinsonism was defined by the presence of two or more of rest tremor, rigidity, bradykinesia, and impairment of postural reflexes in subjects not on antiparkinsonian medication, or the presence of at least one sign if they were on such medication. Parkinson's disease was not studied explicitly because of the difficulty in distinguishing it from other parkinsonian syndromes. A generalised linear model was used to estimate prevalence ratios (PRs) for parkinsonism relative to history of farming, pesticide use, and use of well water. RESULTS: A PR of 2.0 (95% confidence interval (95% CI) 1.0 to 4.2) was found for subjects in the highest tertile of years of exposure to pesticides; a similarly increased, non-significant, PR was found for the middle tertile (1.9 (95% CI 0.9 to 4.0)), although a trend test did not show a significant exposure-response relation. No increased risks were found associated with specific pesticides or pesticide classes, nor with a history of farming or use of well water. CONCLUSION: Parkinsonism may be associated with long term occupational exposure to pesticides, although no associations with specific pesticides could be detected. This finding is consistent with most of the publications on this topic.

Discriminating mild parkinsonism: methods for epidemiological research.

Methods for the efficient and accurate detection of parkinsonism are essential for epidemiological studies. We sought to determine whether parkinsonism could be detected by a neurologist from a videotaped assessment and whether neurobehavioral methods (motor, cognitive, and sensory) discriminated between patients with Parkinson's disease (PD) and controls. Fifteen patients with mild PD (Hoehn and Yahr I-III) were compared to 15 age-, sex-, and education- matched controls. Each participant underwent a videotaped neurological examination (based on the Unified Parkinson's Disease Rating Scale, UPDRS), administered by a trained technician, and reviewed by a neurologist, as well as a series of neurobehavioral tests. The neurologist identified PD patients with 86% sensitivity and 100% specificity. Among the neurobehavioral tests, finger tapping, combined with one or more among olfaction, visual contrast sensitivity, or Paired Associates Learning, correctly classified 90%, or more, of subjects. Individual psychological tests did not discriminate reliably between groups. We conclude that videotaped assessments of parkinsonism or objective tests of motor and sensory function can accurately detect patients with PD. Both approaches have potential for identifying PD cases, but the latter may be more efficient for screening.

Estuary-associated syndrome in North Carolina: an occupational prevalence study.

Atlantic coast estuaries recently have experienced fish kills and fish with lesions attributed to Pfiesteria piscicida and related dinoflagellates. Human health effects have been reported from laboratory exposure and from a 1997 Maryland fish kill. North Carolina has recorded Pfiesteria-related fish kill events over the past decade, but human health effects from environmental exposure have not been systematically investigated or documented here. At the request of the state health agency, comprehensive examinations were conducted in a cross-sectional prevalence study of watermen working where Pfiesteria exposure may occur: waters where diseased or stressed fish were reported from June to September 1997, and where Pfiesteria had been identified in the past. Controls worked on unaffected waterways. The study was conducted 3 months after the last documented Pfiesteria-related fish kill. The goal was to document any persistent health effects from recent or remote contact with fish kills, fish with lesions, or affected waterways, using the 1997 U.S. Centers for Disease Control and Prevention case description for estuary-associated syndrome (EAS). Examinations included comprehensive medical, occupational, and environmental history, general medical, dermatologic, and neurologic examinations, vision testing, and neuropsychologic evaluations. Seventeen of 22 watermen working in affected waters and 11 of 21 in unaffected waters reported exposure to a fish kill or to fish with lesions. We found no pattern of abnormalities on medical, neurologic, neuropsychologic, or NES-2 evaluation. By history, one subject in each group met the EAS criteria, neither of whom had significant neuropsychological impairment when examined. Watermen from affected waterways had a significant reduction in visual contrast sensitivity (VCS) at the midspatial frequencies, but we did not identify a specific factor or exposure associated with this reduction. The cohorts did not differ in reported occupational exposure to solvents (qualitative) or to other neurotoxicants; however, exposure history was not sufficiently detailed to measure or control for solvent exposure. This small prevalence study in watermen, conducted 3 months after the last documented fish kill related to Pfiesteria, did not identify an increased risk of estuary-associated syndrome in those working on affected waterways. A significant difference between the estuary and ocean watermen was found on VCS, which could not be attributed to any specific factor or exposure. VCS may be affected by chemicals, drugs, alcohol, and several developmental and degenerative conditions; it has not been validated as being affected by known exposure to dinoflagellate secretions. VCS should be considered for inclusion in further studies, together with documentation or quantification of its potential confounders, to assess whether it has utility in relationship to dinoflagellate exposure.

Manganese neurotoxicity, a continuum of dysfunction: results from a community based study.

Excessive manganese (Mn) has been associated with neurobehavioral deficits and neurological and/or neuropsychiatric illness, but the level at which this metal can cause adverse neurotoxic effects, particularly with long-term exposure, is still unknown. The objective of the present study was to assess nervous system functions in residents exposed to manganese from a variety of environmental sources. A random stratified sampling procedure was used to select participants; persons with a history of workplace exposure to Mn and other neurotoxic substances were excluded. A self-administered questionnaire provided data on socio-demographic variables. Blood samples were analyzed for total manganese (MnB), lead, mercury and serum iron. Nervous system assessment included computer and hand-administered neurobehavioral tests, computerized neuromotor tests, sensory evaluation and a neurological examination. The present analyses include 273 persons (151 women and 122 men); MnB range: 2.5 micrograms/L-15.9 micrograms/L (median: 7.3 micrograms/L). Multivariate analyses were used and neuro-outcomes were examined with respect to MnB, taking into account potential confounders and covariables. Results were grouped according to neurofunctional areas and MANOVA analyses revealed that higher MnB (7.5 micrograms/L) was significantly associated with changes in coordinated upper limb movements (Wilks' lambda = 0.92; p = 0.04) and poorer learning and recall (men: Wilks' lambda = 0.77; p = 0.002; women: Wilks' lambda = 0.86; p = 0.04). Further analyses revealed that with increasing log MnB (Simple regression: p < 0.05) performance on a pointing task was poorer, frequency dispersion of hand-arm tremor decreased, while harmonic index increased, and the velocity of a pronation/supination arm movement was slower. An Mn-age interaction was observed for certain motor tasks, with the poorest performance observed among those _50 y and in the higher MnB category. Differences between genders suggest that men may be at greater risk than women, although effects were also observed in women. These findings are consistent with the hypothesis that Mn neurotoxicity can be viewed on a continuum of dysfunction, with early, subtle changes at lower exposure levels.

Bioindicator and exposure data for a population based study of manganese.

Exposure data and bioindicators were obtained for a study whose objective was detection of early manifestations of manganese (Mn) neurotoxicity in a population with potential environmental exposure. The study included persons with no history of neurotoxic workplace exposure in Southwest Quebec, drawn from seven postal code regions, defining a set of geographically contiguous zones. Blood samples were analyzed for total Mn (MnB), lead (PbB), total mercury (HgT) and serum iron (FeS). Drinking water samples from participants' residences were analyzed for manganese (MnW). At 4 sites, limited 24-hour high volume air samples for total particulates (TP) and PM10, were analyzed for Mn and Pb. Sociodemographic and dietary information was obtained by self-administered questionnaire. The geometric mean (GM) for MnB values (n = 297) was 7.14 micrograms/L. Levels of MnB in women (n = 156; GM 7.50 micrograms/L) were significantly higher than in men (n = 141; GM 6.75 micrograms/L). No relationship was found between MnB and PbB or HgT. FeS was significantly higher in men (GM 18.38 mumol/L) than women (GM 15.0 mumol/L). For women, MnB was correlated to FeS, with a tendency to decrease with increasing age. For men, no relationship was found between MnB levels and either FeS or age, although FeS showed a strong inverse relationship with age. The 24-hour mean levels of MnTP at the 4 sites varied between 0.009 microgram/m3 and 0.035 microgram/m3; intersite differences were not significant. For Mn in PM10 (MnPM10), mean values ranged from 0.007 microgram/m3 to 0.019 microgram/m3; intersite differences were significant. A total of 278 MnW samples were obtained, 16 from residences served by wells. The GM for MnW was 4.11 micrograms/L (range: 0.50-71.1 micrograms/L, excluding wells; MnW for wells ranged from non-detectable to 158.9 micrograms/L. Individually, there was no relation between MnW and MnB. Geographic analysis of the MnB and MnW data by an algorithm grouping contiguous postal code zones, combined with air data, lead to definition of a geographic parameter, distinguishing two regions relative to a former manganese alloy plant, which contributed significantly to MnB. A multiple regression model was developed, explaining 6.7% of the variability in MnB (F = 5.12; p < 0.001); when controlling for gender, geographic region with higher levels of airborne manganese and the frequency of consumption of cereals and leaf vegetables contributed positively to MnB levels, while serum iron was negatively related.

Neuropsychiatric effects of manganese on mood.

Adverse mood effects of overexposure to Manganese (Mn) have been described in 15 studies which frequently report an association of Mn exposure with adverse effects in six dimensions of mood: 1) anxiety, nervousness, irritability; 2) psychotic experiences; 3) emotional disturbance; 4) fatigue, lack of vigor, sleep disturbance; 5) impulsive/compulsive behavior; 6) aggression hostility. Only 1:15 studies used a standardized psychological measure of mood, while the current study of environmental Mn exposure used two standardized mood scales in evaluating low levels of Mn exposure and mood sequelae. The Profile of Moods State (POMS) and Brief Symptom Inventory (BSI) were used, and results indicate that men who are older and have higher Mn levels show significant disturbances on four of the six mood dimensions. Increased scores were seen in the anxiety, nervousness, irritability; emotional disturbance; and aggression, hostility dimensions relative to those who had lower levels of Mn. The BSI and POMS are useful adjuncts in the assessment of mood/Mn effects.

Sensory eye irritation in humans exposed to mixtures of volatile organic compounds.

Eight subjects participated in a controlled eyes-only exposure study of human sensory irritation in ocular mucosal tissue. The authors investigated dose-response properties and the additive effects of three mixtures of volatile organic compounds. The dose-response relationships for these mixtures showed increases in response intensity as concentration increased. Replication of exposure did not result in significantly different dose- response relationships. Moreover, the result implied that components of the three mixtures interacted additively to produce ocular irritation, a result referred to as simple agonism. Finally, the authors addressed the comparability of two methods to measure sensory irritation intensity (visual analogue scale and a comparative scale). The results indicated that the two rating methods produced highly comparable results.

Preliminary evidence of neurotoxicity associated with eating fish from the Upper St. Lawrence River Lakes.

Pollution of hydrographic basins has affected the flora and fauna that thrive in these aquatic ecosystems, and fish, which constitute an important food resource, often contain a plethora of potentially toxic chemicals. In a major research project on early neurotoxic effects of environmental exposure to manganese among residents in Southwest Quebec, fish consumption from 2 lakes of the Upper St. Lawrence River System, was surveyed as a potential confounding factor. Participants were selected using a random, stratified sampling strategy from lists of the Quebec Health Plan. Following exclusions, 273 men and women between 20-69 years were retained for the present analysis. A total of 103 (37.7%) reported eating fish from the Upper St. Lawrence. Although fisheaters and non-fisheaters were similar for most socio-demographic variables, significantly more fisheaters (65.2%) reported consuming alcoholic beverages as compared to non-fisheaters (42.4%) (Chi Sq. <0.01). To eliminate this possible bias, fisheaters were matched to non-fisheaters for the variables sex, alcohol consumption (never or occasionally vs. regularly), age (+/-5y) and education (+/-2y). A total of 63 matched pairs were thus created. Paired analyses (t-test or Signed Rank) showed that fisheaters had higher levels of blood organic mercury and lead. Analysis of nervous system functions revealed that both groups performed similarly on tests of sensory function, visual memory and recognition, fine motor performance and some motor tests, but fisheaters performed significantly more poorly (p<0.05) on tests requiring cognitive flexibility, word naming, auditory recall, and more complex motor tasks. The profile of deficits is consistent with diminished capacity for information processing. These observations were made within a study that was not specifically designed to examine the effects of fish eating from these two lakes, and the characterization of fish dietary habits has many limitations. Nevertheless, the findings are sufficiently compelling to warrant further studies, since fish from the Upper St. Lawrence Lakes are known to contain multiple neurotoxic substances.

Neurogenic inflammation: with additional discussion of central and perceptual integration of nonneurogenic inflammation.

The Working Group on Neurogenic Inflammation proposed 11 testable hypotheses in the three domains of neurogenic inflammation, perceptual and central integration, and nonneurogenic inflammation. The working group selected the term people reporting chemical sensitivity (PRCS) to identify the primary subject group. In the domain of neurogenic inflammation, testable hypotheses included: PRCS have an increased density of c-fiber neurons in symptomatic tissues; PRCS produce greater quantities of neuropeptides and prostanoids than nonsensitive subjects in response to exposure to low-level capsaicin or irritant chemicals; PRCS have an increased and prolonged response to exogenously administered c-fiber activators such as capsaicin; PRCS demonstrate augmentation of central autonomic reflexes following exposure to agents that produce c-fiber stimulation; PRCS have decreased quantities of neutral endopeptidase in their mucosa; exogenous neuropeptide challenge reproduces symptoms of PRCS. In the domain of perceptual and central integration, testable hypotheses included: PRCS have alterations in adaptation, habituation, cortical representation, perception, cognition, and hedonics compared to controls; the qualitative and quantitative interactions between trigeminal and olfactory systems are altered in PRCS; higher integration of sensory inputs is altered in PRCS. In the domain of nonneurogenic inflammation, testable hypotheses included: increased inflammation is present in PRCS in symptomatic tissues and is associated with a heightened neurosensory response; PRCS show an augmented inflammatory response to chemical exposure. The working group recommended that studies be initiated in these areas.

Neurobehavioral test methods for environmental health studies of adults.

The Agency for Toxic Substances and Disease Registry convened a workshop in Atlanta, GA, that evaluated approaches and methods to ascertain whether there are neurobehavioral sequelae to children and adults exposed to hazardous substances in the environment. This article, developed from that Workshop, recommends testing methods [to identify neurotoxic insult] for immediate use in environmental health field studies of adults. A list of broad functional domains or modalities affected by chemicals was identified from the occupational and related literature (learning and memory, coding, sustained attention, higher intellectual function, strength, coordination, speed, vision, somatosensory, and affect). A core set of tests was selected that should assess those functions with the greatest demonstrated sensitivity to established neurotoxic chemicals, and a secondary set was selected to assess a broader group of functions. The core tests should be used in all investigations where neurotoxic effects would be targeted for identification; secondary tests would be used where suggested by questionnaire or symptom data or by knowledge of the effects of chemicals at the hazardous waste site.

Electrophysiological measures of visual and auditory function as indices of neurotoxicity.

The application of auditory and visual evoked potentials (VEP) to neurotoxicity testing of humans and animals is reviewed. VEPs elicited by flash, reversing-checkerboard patterns, and sine wave grating are described. The flask evoked potential in rats is altered by exposure to many heavy metals, pesticides and solvents. The brainstem auditory evoked potential also appears to be sensitive to neurotoxic chemicals, but the evidence available is limited. The homology of auditory and visual evoked potentials in rats and humans is useful for cross-species extrapolation in neurotoxicology research.

Adaptation of the binocular rivalry mechanism.

The completeness of binocular rivalry suppression was measured by recording the fraction of a trial during which targets were perceived as alternating in their entirety, rather than blending together into a composite. It was found that the completeness of rivalry declines with prolonged stimulation. A control condition in which subjects saw the same grating targets, but without rivalry, resulted in no decrement. The phenomenon was spatial-frequency specific. The results suggest that binocular rivalry suppression is mediated by a cooperative mechanism which is susceptible to adaptation.