Possible estuary-associated syndrome: symptoms, vision, and treatment.

The human illness designated as possible estuarine-associated syndrome (PEAS) by the Centers for Disease Control and Prevention (CDC) has been associated with exposure to estuaries inhabited by toxin-forming dinoflagellates, including members of the fish-killing toxic Pfiesteria complex (TPC), Pfiesteria piscicida and Pfiesteria shumwayae. Humans may be exposed through direct contact with estuarine water or by inhalation of aerosolized or volatilized toxin(s). The five cases reported here demonstrate the full spectrum of symptoms experienced during acute and chronic stages of this suspected neurotoxin-mediated illness. The nonspecific symptoms most commonly reported are cough, secretory diarrhea, headache, fatigue, memory impairment, rash, difficulty in concentrating, light sensitivity, burning skin upon water contact, muscle ache, and abdominal pain. Less frequently encountered symptoms are upper airway obstruction, shortness of breath, confusion, red or tearing eyes, weakness, and vertigo. Some patients experience as few as four of these symptoms. The discovery that an indicator of visual pattern-detection ability, visual contrast sensitivity (VCS), is sharply reduced in affected individuals has provided an objective indicator that is useful in diagnosing and monitoring PEAS. VCS deficits are present in both acute and chronic PEAS, and VCS recovers during cholestyramine treatment coincident with symptom abatement. Although PEAS cannot yet be definitively associated with TPC exposure, resolution with cholestyramine treatment suggests a neurotoxin-mediated illness.

Human visual function in the North Carolina clinical study on possible estuary-associated syndrome.

The U.S. Environmental Protection Agency assisted the North Carolina Department of Health and Human Services in conducting a study to investigate the potential for an association between fish kills in the North Carolina estuary system and the risk for persistent health effects. Impetus for the study was recent evidence suggesting that estuarine dinoflagellates, including members of the toxic Pfiesteria complex (TPC), P. piscicida and P. schumwayae, may release a toxin(s) that kills fish and adversely affects human health. This report describes one component of the study in which visual system function was assessed. Participants working primarily in estuaries inhabited by TPC or in off-shore waters thought not to contain TPC were studied. The potentially exposed estuary (n = 22) and unexposed offshore (n = 20) workers were matched for age, gender, and education. Visual acuity did not differ significantly between the cohorts, but visual contrast sensitivity (VCS), an indicator of visual pattern-detection ability for stimuli of various sizes, was significantly reduced by about 30% in the estuary relative to the offshore cohort. A further analysis that excluded participants having a history possibly predictive of neuropsychological impairment showed a similar VCS reduction. Additional analyses indicated that differences between the cohorts in age, education, smoking, alcohol consumption, and total time spent on any water did not account for the difference in VCS. Exploratory analyses suggested a possible association between the magnitude of VCS reduction and hours spent in contact with a fish kill. The profile of VCS deficit across stimulus sizes resembled that seen in organic solvent-exposed workers, but an assessment of occupational solvent, and other neurotoxicant, exposures did not indicate differences between the cohorts. These results suggest that factor(s) associated with the North Carolina estuaries, including the possibility of exposure to TPC toxin(s), may impair visual system function.

Effects from environmental Mn exposures: a review of the evidence from non-occupational exposure studies.

OBJECTIVE: The risk posed to human health by environmental manganese exposure is unknown. Occupational-exposure outcomes may not extrapolate to environmental exposures due to the healthy worker effect and differences in dosage parameters which may affect the biological response. This paper attempts to combine the existing literature on non-occupational Mn exposures with results from our current study in SW Quebec on environmental Mn exposure (Mergler et al., this issue) within the framework of a biologically-based, dose-response (BBDR) model. BBDR MODEL: The basic BBDR model consists of seven stages relating exposure to health effects. The stages are: 1) sources, 2) applied dose, 3) absorbed dose, 4) target-site dose, 5) toxic event, 6) measurable change, and 7) health outcome. RESULTS: Several air monitoring programs, such as the PTEAM study (Riverside, CA, 1990, mean PM10 Mn outdoor-airborne 24 h average = 0.045 microgram/m3), provided data relevant to the estimation of Mn applied dose, but did not include measures of body burden. Data from the SW Quebec study showed a mean total-particulate airborne Mn concentration of 0.022 microgram/m3 with a range of 0.009 to 0.035 microgram/m3 across four sampling sites, whereas the EPA reference concentration (RfC) is 0.05 microgram/m3. EPA has considered tap water levels to be safe below 200 micrograms/l Mn, and mean Mn tap-water (MnW) level in the participants' homes was 6.38 +/- 11.95 micrograms/l with a range from 0.1 to 158.9 micrograms/l Mn. A previous study of MnW exposure in Greece reported Mn levels in areas with low, medium and high MnW ranging from 4 to 2,300 micrograms/l and a significant association with Mn in hair but not Mn in blood (MnB). The mean absorbed dose of the SW Quebec study participants, as indicated by MnB, was 7.5 +/- 2.3 micrograms/l with a range of 2.5 to 15.9 micrograms/l. Our study and others on environmental Mn exposure did not provide an estimate of target-site dose. However, a significant correlation (r = 0.65) between MnB and signal intensity in T1-weighted MRI images has been reported in liver-disease patients with Parkinson-like signs who had MnB levels as low as 6.6 micrograms/l. Only animal and in vitro studies have provided evidence on the mechanisms of toxicity caused by Mn in the CNS. Several studies reported measurable changes in endpoints suggestive of a Parkinson-like syndrome in subjects with MnB levels ranging from 7.5 to 25.0 micrograms/l. Among other effects on neurobehavioral function observed in the current study was a significant relationship between MnB and the direction and speed of body-sway in men. The effects observed in these participants are sub-clinical and no health outcomes have been diagnosed. However, the Parkinson's disease incidence in the study area was previously reported to be 2-5 times higher than in the rest of Quebec, and several studies indicate that 25-35% of idiopathic Parkinson disease diagnoses are incorrect. Our study, the Greek study, and some clinical studies suggest that the risk of a Parkinson-like syndrome diagnosis may increase with continued Mn exposure and aging. CONCLUSION: The limited data available for the BBDR model point to the need for evidence, particularly on relationships between Mn species, exposure route, MnB with chronic environmental exposure, ageing, and susceptibility factors, to improve human-health risk assessments for chronic, environmental Mn exposure.

Time course of sensory eye irritation in humans exposed to N-butanol and 1-octene.

In this study, we investigated the time course effect of sensory eye irritation in 16 subjects exposed (i.e., eye only) to n-butanol and 1-octene. Half the subjects were exposed to n-butanol, and the remaining subjects were exposed to 1-octene. Each subject was studied on 5 different days; during each day each subject was exposed in three runs (i.e., run 1, run 2, and run 3) to a constant concentration of either n-butanol or 1-octene. We performed run 1 and run 3, both of which lasted 15 min each, to evaluate persistence in "sensitization." We performed run 2, which lasted 60 min, to study the time course of sensory irritation. Ratings of ocular irritation intensity were obtained continuously during all three runs. The exposure concentrations for n-butanol were 0 mg/m3, 300 mg/m3, 900 mg/m3, and 3 000 mg/m3, and the exposure concentrations for 1-octene were 0 mg/m3, 6 000 mg/m3, 10 400 mg/m3, and 18 000 mg/m3. During run 2, we observed a slight increase in perceived eye irritation intensity for the lower concentrations of 1-octene and for all exposure concentrations of n-butanol. However, the threshold for irritation was clearly exceeded for only the 1-octene 10 400-mg/m3 and 18 000-mg/m3 exposures. During these two exposures, the response increased 10-fold following 20-40 min of exposure during run 2, after which the response remained constant. We investigated the existence of persistence in "sensitization" by comparing intensity of responses between run 1 and run 3. Persistence in "sensitization" was apparent for only the 1-octene exposure.

Critical issues in the use and analysis of the Lanthony Desaturate Color Vision test.

The Lanthony Desaturate Color Vision test (D-15d) has been used to demonstrate the incidence of acquired color vision defects resulting from toxic exposure. The D-15d is a sensitive test designed to grade color deficiencies, but results can be difficult to interpret beyond the qualitative level, and the high incidence of errors reported for controls in some toxicology studies raises questions about how to effectively use this test. This article reviews standard administration of the test, physical determinants of performance, classification of acquired color vision defects, and methods of analysis that have been used to quantify results. The basis for a new method of analysis is discussed, illustrating the source of some characteristic errors, and recommendations are made for test protocols to attempt to more closely identify the type of color vision loss with the goal of identifying the site of toxicological insult.

Agonistic sensory effects of airborne chemicals in mixtures: odor, nasal pungency, and eye irritation.

Thresholds responses of odor, nasal pungency (irritation), and eye irritation were measured for single chemicals (1-propanol, 1-hexanol, ethyl acetate, heptyl acetate, 2-pentanone, 2-heptanone, toluene, ethyl benzene, and propyl benzene) and mixtures of them (two three-component mixtures, two six-component mixtures, and one nine-component mixture). Nasal pungency was measured in subjects lacking a functional sense of smell (i.e., anosmics) to avoid interference from olfaction. Various degrees of stimulus agonism (additive effects) were observed for each of the three sensory channels when testing mixtures. As the number of components and the lipophilicity of such components in the mixtures decreased, so did the degree of agonism. Synergistic stimulus agonism characterized the eye-irritation response for the most complex (the nine-component) and the most lipophilic (one of the six-component) mixtures. Physicochemical properties play a large role in the determination of sensitivity to airborne chemicals, particularly to their ability to evoke irritation. While this has revealed itself previously with respect to single chemicals, it seems to have relevance to mixtures as well.

Visual contrast sensitivity deficits in Bohemian children.

Visual contrast sensitivity (VCS) tests have been used successfully in medical diagnosis and subclinical neurotoxicity detection. This paper reports VCS measurements in three studies of children in the Czech Republic. Study 1 compared children in standard schools and schools for the learning disabled. Studies 2 and 3 compared children in Teplice, an area in which soft-brown coal combustion produced high levels of pollutants (e.g. Hg, As, SO2, NOx, and aromatic hydrocarbons), with children in areas of low air pollution, Znojmo and/or Prachatice. It was hypothesized that in utero exposure to the combustion products disrupted neurological development (Sram, 1991). The VCS test (Stereo Optical Co.) consisted of circular fields containing sinusoidal gratings at 5 spatial frequencies (1.5-18 cycles/degree) and various levels of contrast. Subjects indicated orientation of the gratings by pointing left, up, or right. Visual acuity and VCS were measured in each eye of 74 children in Study 1,327 second-grade children in Study 2, and 426 fourth-grade children in Study 3. Hair samples were collected in Studies 2 and 3 analyzed for Hg and As content. Children attending schools for the learning disabled scored significantly lower than controls on VCS, whereas visual acuity was normal. The deficit was greatest at mid- to high spatial frequency. In Study 2, significant VCS deficits were seen in exposed second-grade children at low to mid-spatial frequency, even though visual acuity was slightly above control level. Regression analyses showed that VCS had no relationship to As, but a significant negative correlation with hair Hg was observed in the exposed district. However, current Hg levels were higher in Prachatice. VCS deficits were not observed in the fourth-grade students of Teplice in Study 3. The results of Study 1 indicated that behavioral VCS testing in field studies is practical in young, non-English speaking children, and suggested that vision may be compromised in learning-disabled children. Studies 2 and 3 indicated that at these levels, current Hg body-burdens are poor predictors of VCS. If the VCS deficits seen in Study 2 were related to prenatal exposures, the results of Study 3 suggest that they represent a developmental delay. A longitudinal-study design is needed to address this issue.

The influence of vision on computerized neurobehavioral test scores: a proposal for improving test protocols.

Computerized tests of neurobehavioral function are frequently administered in neurotoxicological studies with little attention given to the optical properties of test stimuli or to the vision of subjects. Yet many test stimuli are small or briefly presented, and test endpoints often involve short reaction times. Stimulus detection and reaction time are known to be strongly dependent upon stimulus luminance, contrast, and size, as well as on the subject's visual abilities. The current study assessed the influence of visual contrast sensitivity on Neurobehavioral Evaluation System 2 (NES2) test results in three data sets. Analyses indicated that vision was associated with up to 24% of the variance (Hand Eye Coordination test) in NES2 scores, even when visual acuity was normal, and that vision often influenced the significance of group differences. It is suggested that researchers measure the luminance, contrast, and size of test stimuli, the distance from the subject's eyes to the monitor, and the subject's visual contrast sensitivity. The measurement and control of stimulus parameters and the inclusion of visual function scores in analysis models could reduce the variability among computerized test scores both within and between studies. Models that assess the influence of vision on computerized test results may help to identify the CNS domains and specialized functions adversely affected by neurotoxicant exposures.

Feasibility and validity of three computer-assisted neurobehavioral tests in 7-year-old children.

Three tests from the computerized Neurobehavioral Examination System (NES) were administered to a group of 917 Faroese children at approximately 7 years of age. The NES Continuous Performance Test (CPT) was modified to use animal silhouettes as stimuli instead of letters. Almost all children completed Finger Tapping (FT), the modified CPT, and Hand-Eye Coordination (HE). However, 18% of the children missed at least 25% of the stimuli on the CPT (full test period), and 37% of the children did not improve their HE performance by at least 10%, as compared to the first trial. Boys obtained better results than girls, and older children performed better than younger ones. However, both factors were confounded by acquaintance with computer games. Children who used glasses, who had strabismus, or who had decreased contrast sensitivity obtained less satisfactory scores, especially on CPT and HE. The NES performance was significantly associated with functional neurological performance, including catching a ball, diadochokinesia, and finger agnosia. Slight, though statistically significant, decrements were seen with increased levels of prenatal exposure to neurotoxicants, as indicated by the mercury concentrations in cord blood obtained at the time of birth. In conclusion, the tests were feasible in this age group after slight modifications, and the test results showed meaningful associations with major predictors, thus supporting the validity of the data.

Neurobehavioral Evaluation System (NES): comparative performance of 2nd-, 4th-, and 8th-grade Czech children.

The Neurobehavioral Evaluation System was designed for field studies of workers, but many NES tests can be performed satisfactorily by children as young as 7 or 8 years old and a few tests, such as simple reaction time, can be performed by preschool children. However, little comparative data from children of different ages or grade levels are available. Studies of school children in the Czech Republic indicate that 2nd-grade children could perform the following NES tests satisfactorily: Finger Tapping, Visual Digit Span. Continuous Performance, Symbol-Digit Substitution, Pattern Comparison, and simpler conditions of Switching Attention. Comparative scores of boys and girls from the 2nd, 4th, and 8th grades and power analyses to estimate appropriate sample size were presented. Performance varied systematically with grade level and gender. Larger samples were needed with younger children to achieve comparable levels of statistical power. Gender comparisons indicated that boys responded faster, but made more errors than girls.

Frequency-domain measurement of vibrotactile driving responses in first-order afferent populations.

Surface recordings made at the wrist during moderate vibrotactile stimulation of a digit display rhythmic activity at the frequency of the driving stimulus. This activity is abolished by local anesthesia of the stimulated digit and by substitution of the corresponding digit of the opposite hand with the recording geometry and the load on the stimulator unchanged. Several additional features of the response are similarly incompatible with an artifactual origin in properties of the stimulus motion or the associated electromagnetic field, but consistent with previous neurophysiological observations. The frequency-domain analysis extends readily to the single-trial level, making the technique potentially useful for a variety of basic research and clinical purposes.

Work-site clinical and neurobehavioral assessment of solvent-exposed microelectronics workers.

Twenty-five workers, five currently and 20 formerly involved in the manufacture of hybrid microcircuits, underwent clinical evaluations at the request of a management-union committee concerned about chronic solvent exposures in a research and development laboratory. A battery of neurobehavioral tests was administered to compare the solvent-exposed group with 32 age-, gender-, ethnicity-, and education-matched controls. The tests included: MMPI-I, hand grip strength, tactile sensitivity, dexterity, color discrimination, visual acuity and contrast sensitivity, and tests selected from the computerized Neurobehavioral Evaluation System (NES2). Clinical narratives and retrospective exposure assessments in the study group suggested chronic low-level exposure to solvents, with intermittent acute excursions. Work-related diagnoses included upper respiratory mucosal irritation and sinusitis (44%), lower respiratory reactive airway disease (12%), and dermatitis (5%). Three workers (12%) had findings consistent with a solvent-induced encephalopathy. Significant differences (after Bonferroni correction) were found between the two groups on 5 of 11 NES subtests: symptom scale, mood scale, finger tapping, simple reaction time, and symbol-digit substitution. Differences also reached significance for overall vibration sensitivity thresholds, visual contrast sensitivity, and grip strength. The MMPI average clinical scale elevation was significantly higher in the exposed group than controls. These results support an association between chronic low-dose solvent exposure and measurable neurobehavioral changes.

The use of visual and chemosensory evoked potentials in environmental and occupational health.

The application of visual (VEP) and chemosensory evoked potentials (CSEP) in occupational and environmental health is briefly reviewed. VEPs have been used extensively in experimental neurotoxicity and play an increasingly important role in human neurotoxicity testing. The similarity of VEP waveforms in different species renders them useful for cross-species extrapolation. CSEPs, used in conjunction with traditional psychophysical tests and rating scales, offer a promising new approach to the study of indoor air pollution.

Exposure of humans to a volatile organic mixture. I. Behavioral assessment.

Exposure to a low-level mixture of volatile organic compounds, typical of those found in new buildings, has been reported to impair neurobehavioral function in persons who have experienced sick building syndrome (SBS). Sixty-six healthy young males who had no history of chemical sensitivity were exposed for 2.75 h to a complex mixture of volatile organic compounds at 0 and 25 mg/m3. Even though subjects reported more fatigue and more mental confusion following exposure to volatile organic compounds than to clean air, performance on 13 neurobehavioral tests was not affected. Practice or learning effects were observed if administration of many behavioral tests were repeated. Further studies are needed to clarify the relationship of exposure to volatile organic chemicals, neurobehavioral performance, and subject characteristics, e.g., age, gender, and chemical sensitivity.

Exposure of humans to a volatile organic mixture. II. Sensory.

Time-course functions for symptoms of the sick building syndrome were derived from 66 healthy males who, during separate sessions, were exposed to clean air and to a volatile organic compound (VOC) mixture. The mixture contained 22 VOCs (25 mg/m3 total concentration) commonly found airborne in new or recently renovated buildings. Subjects rated the intensity of perceived irritation, odor, and other variables before, and twice during, 2.75-h exposure periods. Eye and throat irritation, headache, and drowsiness increased or showed no evidence of adaptation during exposure, whereas odor intensity decreased by 30%. These results indicate that irritation intensity and other symptoms are not related in any simple way to odor intensity, which suggests that the symptoms may not be a psychosomatic response to the detection of an aversive odor. Instead, subthreshold levels of VOCs may interact additively or hyperadditively and stimulate trigeminal nerve receptors. Also, air quality ratings improved by 18% during exposure, which suggests that both odor and irritation intensity may influence assessments of air quality.

The comparability of rat and human visual-evoked potentials.

A series of experiments addressed the issue of comparability among neurological processes in pigmented rat and human visual systems. In the first set of experiments, transient visual-evoked potentials (VEPs) were elicited by the onset of sine-wave gratings of various spatial frequencies. The spatial frequency-response profiles of the first positive and immediately succeeding negative components differed from one another, but were similar in the two species. In addition, amplitude of the negative, but not the positive, component was strongly attenuated in both species following stationary pattern adaptation. In the second set of experiments, steady-state VEPs were elicited by the onset and offset of the gratings. The spatial frequency profiles of the 1F (response amplitude at the frequency of stimulus onset-offset) and 2F response components differed from one another, but were similar in both species. The final set of experiments indicated that diazepam, a GABA agonist, reduced amplitude of 2F, but not 1F, in both species. These results suggested that at least some functional subsystems mediating spatial vision in humans may have qualitatively similar counterparts in rats.

Quantitative methods for cross-species mapping (CSM).

Cross-species extrapolation will be defined as prediction from one species to another without empirical vetification. Cross-species mapping (CSM) is the same except empirical vetification is performed. CSM may be viewed as validation of methods for extrapolation. Algorithms for CSM may originate from theory, from empirical observations or a combination of the two. Regardless of their origins, CSM algorithms must be explicated and confidence intervals given around their predictions. This paper offers a quantitative method for constructing CSM equations which is useful in evaluation of the CSM and as an aid in the design of new experiments in CSM and extrapolation. The method requires fitting mathematical models for the physiological or behavioral phenomena to be mapped across species. A CSM equation can then be derived from the models in each species and approximate confidence limits may be obtained for predictions from the equation. The method is useful even when the models in the two species differ in form, implying differences in physiology or behavioral principles between species. The method proposed has a number of remaining uncertainties and possible problems.

Neurobehavioral and sensory irritant effects of controlled exposure to a complex mixture of volatile organic compounds.

Subjective reactions of discomfort, impaired air quality, irritation of mucosal membranes, and impaired memory have been reported in chemically sensitive subjects during exposure to volatile organic compounds (VOCs) found in new buildings. Sixty-six normal healthy male subjects aged 18-39 were exposed for 2.75 hr to a complex VOC mixture at 0 and 25 mg/m3. Each subject completed control and exposure sessions at one-week intervals in counterbalanced order. Measurements included comfort ratings of eye, nose and throat irritation, symptom questionnaire and computerized behavioral tests. Subjects found the odor of VOCs unpleasantly strong and reported that VOC exposure degraded air quality, increased headache and produced general discomfort. VOC exposure did not affect performance on any behavioral tests.

Rat and human visual-evoked potentials recorded under comparable conditions: a preliminary analysis to address the issue of predicting human neurotoxic effects from rat data.

Pattern-onset visual-evoked potentials (VEPs) were recorded from rats and humans in order to perform cross-species comparison of neuronal functional properties reflected by the early VEP components. The spatial frequency of a sinusoidal test grating was varied in Experiment 1. For both species, amplitude of the first positive VEP component was larger at low spatial frequency and decreased as spatial frequency increased. The immediately succeeding negative component was small at low spatial frequency and was of maximal amplitude at moderate spatial frequency. The effects of stationary pattern adaptation on these components were investigated in Experiment 2. Subjects viewed either a blank field or the test grating prior to recording VEPs. For both species, adaptation had no effect on the positive component but strongly attenuated the negative component. Experiment 3, in which only humans were tested, indicated that the negative component was of cortical origin. Only cortical neurons are known to be orientation selective, and the effect of adaptation diminished as the orientation difference between the adaptation and test gratings increased. These results suggest that the early positive and negative components arise from parallel visual pathways, and that the rat components may reflect visual processes qualitatively similar to those of humans.