Evaluation of acute sensory--motor effects and test sensitivity using termiticide workers exposed to chlorpyrifos.

Sensory and motor testing was performed on a group of termiticide workers primarily using chlorpyrifos-containing products to evaluate both the acute effects from current exposure and sensitivity of the measures to detect effects. The study group comprised 106 applicators and 52 nonexposed participants. Current exposure was measured by urinary concentrations of 3,5,6-trichloro-2-pyridinol (TCP) collected the morning of testing. The mean TCP value for the 106 applicators was 200 microg/g creatinine. Participants received 4--5 h of testing and were evaluated using a sensory--motor test battery recommended by a National Institute for Occupational Safety and Health (NIOSH)-sponsored advisory panel to be appropriate for testing effects from pesticide exposures. Measurements testing olfactory dysfunction, visual acuity, contrast sensitivity, color vision, vibrotactile sensitivity, tremor, manual dexterity, eye--hand coordination, and postural stability were analyzed. Study results indicated limited acute effects from exposure to chlorpyrifos using urinary TCP as a measure of current exposure. The effects occurred primarily on measures of postural sway in the eyes closed and soft-surface conditions, which suggests a possible subclinical effect involving the proprioceptive and vestibular systems. Several other tests of motor and sensory functions did not show any evidence of acute exposure effects, although statistically significant effects of urinary TCP on the Lanthony color vision test scores and one contrast sensitivity test score were found. The visual measures, however, were not significant when a step-down Bonferroni correction was applied. Information also is presented on the sensitivity of the measures to detect effects in an occupationally exposed population using standard error of the parameter estimates.

Neurologic function among termiticide applicators exposed to chlorpyrifos.

Chlorpyrifos is a moderately toxic organophosphate pesticide. Houses and lawns in the United States receive a total of approximately 20 million annual chlorpyrifos treatments, and 82% of U.S. adults have detectable levels of a chlorpyrifos metabolite (3,5, 6-trichloro-2-pyridinol; TCP) in the urine. The U.S. Environmental Protection Agency has estimated that there are 5,000 yearly reported cases of accidental chlorpyrifos poisoning, and approximately one-fourth of these cases exhibit symptoms. Organophosphates affect the nervous system, but there are few epidemiologic data on chlorpyrifos neurotoxicity. We studied neurologic function in 191 current and former termiticide applicators who had an average of 2.4 years applying chlorpyrifos and 2.5 years applying other pesticides, and we compared them to 189 nonexposed controls. The average urinary TCP level for 65 recently exposed applicators was 629.5 microg/L, as compared to 4.5 microg/L for the general U.S. population. The exposed group did not differ significantly from the nonexposed group for any test in the clinical examination. Few significant differences were found in nerve conduction velocity, arm/hand tremor, vibrotactile sensitivity, vision, smell, visual/motor skills, or neurobehavioral skills. The exposed group did not perform as well as the nonexposed group in pegboard turning tests and some postural sway tests. The exposed subjects also reported significantly more symptoms, including memory problems, emotional states, fatigue, and loss of muscle strength; our more quantitative tests may not have been adequate to detect these symptoms. Eight men who reported past chlorpyrifos poisoning had a pattern of low performance on a number of tests, which is consistent with prior reports of chronic effects of organophosphate poisoning. Overall, the lack of exposure effects on the clinical examination was reassuring. The findings for self-reported symptoms raise some concern, as does the finding of low performance for those reporting prior poisoning. Although this was a relatively large study based on a well-defined target population, the workers we studied may not be representative of all exposed workers, and caution should be exercised in generalizing our results.

Evaluation of postural stability in workers exposed to lead at a secondary lead smelter.

Postural sway testing was carried out on a group of 145 workers exposed to lead in a secondary lead smelter and 84 workers not exposed to lead in a hinge manufacturing plant. All workers were measured for blood lead levels (BLL) and erythrocyte zinc protoporphyrin (ZPP) concentrations at the time of testing and both a total cumulative and a time-weighted average BLL value was constructed for the lead exposed workers. The lead exposed workers mean BLL at the time of testing was 38.9 microg/dl and the non-exposed workers mean was 2.3 microg/dl. ZPP levels averaged 55.2 microg/dl for exposed workers and 18.9 microg/dl for non-exposed workers. Total cumulative BLL averaged 83476 microg/dl days for the exposed workers, with a mean time-weighted average BLL of 35.1 microg/dl. Six tests of postural stability, four two leg conditions and two single leg conditions were administered to all subjects using a force platform to produce measurements of sway for comparison purposes. The two leg conditions also manipulated the visual and proprioceptive systems. A statistically significant association was observed for sway measurements and the current BLL for all workers, but not with the current BLL of only the lead exposed workers. No statistically significant associations were present with the cumulative measures of long-term exposure. Of the six tests of sway, only the single leg conditions showed significant exposure effects. The results suggest effects of lead exposure among those with average BLL near 40.0 microg/dl, but only in the most challenging one leg conditions.

Chemicals in the workplace: incorporating human neurobehavioral testing into the regulatory process.

In February 1996, the United Kingdom Health and Safety Executive sponsored a workshop on the role of human neurobehavioral tests in the regulation of chemical exposures in the workplace. This paper presents the review of neurobehavioral testing that was initially prepared for the workshop but has been expanded and updated for publication. Information sources for the review were drawn from "preamble to the regulation," in the 1989 air contaminants project, an attempt by the Occupational Safety and Health Administration to update the 1968 regulatory limits of workplace exposures. The scientific citations listed in the preamble provide a chemical database to review for evidence of neurobehavioral testing to support limit setting. Several conclusions emerged: 1) A wide range of nervous system effects were reported in the scientific citations for the 172 chemicals identified with effects on the nervous system; 2) Citations of studies with human neurobehavioral test results are used to support limit setting, but many are old studies primarily of acute effects; 3) There is frequently a delay of several years after publication before studies with neurobehavioral testing are cited in regulatory forums; 4) With the 1989 proposed regulatory limits never legally adopted, there has not been an update for most of the substances affecting the nervous system since 1971; 5) Investigators should be more aware of the regulatory process and submit studies reporting neurobehavioral test results to organizations that regulate and recommend workplace exposure limits; 6) Issuances in the Federal Register by the U.S. Environmental Protection Agency provide a framework for assessing neurotoxic risks that can be used by investigators to help identify and report nervous system effects using neurobehavioral testing in a more uniform fashion.

Evaluation of tremor in aluminum production workers.

A cross-sectional study of 63 current and former aluminum potroom workers and 37 comparison workers was conducted to evaluate for evidence of neurological dysfunction, including tremor from long-term exposures to aluminum using sensitive quantitative measures of arm/hand and leg tremor. Signs of upper extremity tremor were also evaluated by neurological examination and compared with the quantitative measures of arm/hand tremor. Both arm/hand and leg tremor were measured using fatiguing test conditions, but no statistically significant differences due to exposure to aluminum were present between the potroom workers and the comparison workers. The neurological examination also showed no statistically significant differences between the groups on the evaluation of signs of tremor. These results do not support the findings of Best-Pettersen et al., who reported evidence of increased tremor in aluminum workers using the static steadiness test in the Halstead-Reitan battery. Differences between the studies that may have contributed to the contrasting results are discussed. In addition, techniques are presented for using microcomputer-controlled devices to evaluate tremor in both the visible (1-6 Hz) and nonvisible (7-18 Hz) frequencies of the tremor spectrum.

Neurobehavioral effects from acute exposures to methyl isobutyl ketone and methyl ethyl ketone.

Subjects were tested for neurobehavioral performance in an environmental chamber to detect the presence of subclinical central nervous system effects from 4-hr exposures to methyl isobutyl ketone (MIBK) at 100 ppm, methyl ethyl ketone (MEK) at 200 ppm, MIBK at 50 ppm with MEK at 100 ppm, or a placebo (i.e., a 5-min presentation of 25 ppm MEK-MIBK at each exposure period outset). Subjects were 68 males and 75 females recruited from local universities; ages ranged from 18 to 32 years. Ethanol by ingestion (95%-0.84 ml/kg) was used as a positive control. Five psychomotor tests (choice reaction time [CRT], simple reaction time [SRT], visual vigilance, dual task [auditory tone discrimination and tracking], memory scanning), one sensorimotor test (postural sway), and a test of mood (profile of mood states) were used to measure neurobehavioral effects. Additionally, chemical measurements (blood and breath) and reports of sensory and irritant effects were measured. The chemical exposures produced statistically significant performance effects on only 4 of 32 measures (% correct responses-visual vigilance, movement time-CRT, SRT, % incorrect responses-dual task). These effects, however, were not substantial and could not be attributed directly to the chemical exposures. Alcohol ingestion, however, produced significant decrements on every performance test except memory scanning and mood. An interaction occurred between gender and alcohol ingestion, such that more statistically significant performance decrements were found for females than for males. Significant odor sensations and irritant effects were reported by the subjects during the chemical exposures. The MEK results agree with earlier MEK experiments at comparable exposure conditions, and the MIBK results are consistent with a recent Swedish study that used MIBK exposures and showed no significant behavioral performance decrements from single MIBK exposures at 50 ppm with 50 W exercise. Additionally, the MIBK-MEK combination exposure showed no evidence of any interaction effects on either the behavioral or chemical measurements. The principal effects resulting from exposures to MEK and MIBK at the durations and concentrations used in the study are limited to sensory and irritant effects.

Use of a computerized postural sway measurement system for neurobehavioral toxicology.

The study of standing posture has been associated with nervous system functioning for over a hundred years. Measures of human standing ability have attracted some attention as indicators of neurotoxic insult. The use of postural sway measures as subclinical indicators of toxicity has not been regularly incorporated into most neurobehavioral test batteries, but the development of microcomputer-controlled systems offers new possibilities. The mechanisms involved in controlling postural sway are discussed, as well as the various measurement techniques. In addition, studies involving the effects of some neurotoxic agents are cited. A postural sway measurement system that is noninvasive, has 1-2-minute test periods, provides immediate test results, and is relatively free of practice and motivation effects is described. Results present the normative characteristics of the sway parameters, a comparison of three data transformation techniques, and the effects of height and weight on the sway parameters. Power calculations were also performed to estimate the number of subjects needed to detect effects at both the 80% and 90% power levels.

Neurobehavioural effects of short duration exposures to acetone and methyl ethyl ketone.

A total of 137 volunteers were recruited and tested for neurobehavioural performance before, during, and after a short duration (4 h) exposure to acetone at 250 ppm, methyl ethyl ketone (MEK) at 200 ppm, acetone at 125 ppm with MEK at 100 ppm, or a placebo. Ethanol (95%-0.84 ml/kg) was used as a positive control. Performance testing was computer controlled and took place in an environmental chamber with four test stations. The total test regimen before, during, and after exposure covered 10 hours and 32 measures were collected. The measurements were extracted from two biochemical (venous blood and alveolar breath) tests, four psychomotor (choice reaction time, visual vigilance, dual task (auditory tone discrimination and tracking), memory scanning) tests, one sensorimotor (postural sway) test, and one psychological (profile of mood states (POMS] test. The exposure to 250 ppm acetone produced small but statistically significant changes in performance from controls in two measures of the auditory tone discrimination task and on the anger hostility scale (men only) of the POMS test. Neither MEK nor the combined acetone/MEK exposures produced statistically significant interpretable results. The combination exposure provides some indication that there was no potentiation of the acetone effects with the coexposure to MEK or vice versa. More pronounced performance decrements occurred with ethanol at 0.07-0.08% BAC. Significant (less than 0.05) differences were evident on both the auditory tone and tracking tests in the dual task and there was partial significance on the visual vigilance test (0.05-0.06) and some postural sway measures (less than 0.09). These findings agree with an earlier Japanese study in showing some mild decrements on behavioural performance tests with exposures to acetone at 250 ppm.

Effects of short duration exposures to acetone and methyl ethyl ketone.

Workers are commonly exposed to mixtures or combinations of chemical agents, and these mixtures often consist of solvents. One group of solvents that has been extensively studied for its neurotoxic properties has been the ketones. However, previous research has focused on neuropathies produced by extended exposures and not on the simple pharmacokinetics or the reversible central nervous system (CNS) effects from short-duration exposures. In this research, 137 volunteers were recruited and tested for neurobehavioral performance changes and biochemical indicators during and after a short-duration (4-h) exposure to either acetone at 250 ppm, methyl ethyl ketone (MEK) at 200 ppm, acetone at 125 ppm with MEK at 100 ppm, or a chemical-placebo. Ethanol (95%, 0.84 ml/kg) was used as a positive control. Testing took place in an environmental chamber with four test stations. The computer-controlled test regimen took 10 h, and several measures were collected: (1) biochemical measurements of venous blood and alveolar breath; (2) psychomotor tests of choice reaction time, visual vigilance, dual task (auditory tone discrimination and tracking), and memory scanning; (3) one sensorimotor (postural sway) test; and (4) one psychological (Profile of Mood States [POMS]) test. Blood and breath concentrations during and after exposure did not demonstrate any interaction between the two solvents, nor were statistically significant sex differences present during uptake or elimination. The 250-ppm acetone exposure produced small but statistically significant differences from controls in two measures of the auditory tone discrimination task, and on the anger-hostility scale (males only) of the POMS test. The other chemical exposure conditions, MEK at 200 ppm and combination MEK with acetone, produced no consistent statistically significant results, which suggests there was no potentiation of the acetone effects with the co-exposure to MEK or vice versa under these test conditions. Ethanol at 0.07-0.08% blood alcohol concentration (BAC) caused significant decrements on both the auditory tone and tracking tests in the dual task.

Short duration exposures to organic solvents: the relationship between neurobehavioral test results and other indicators.

Short duration exposure to solvents at even low concentrations can induce signs of mild toxicity such as mucous membrane irritation, tearing, nasal irritation, headache, and nausea. These irritant effects are often used as warning properties for potential solvent toxicities and have frequently been classified in the literature as pre-narcotic effects. With higher exposures the toxic effects are more pronounced and can include intoxication, incoordination, exhilaration, sleepiness, stupor, and the beginning stages of anesthesia. Collectively these effects are taken as indicators of narcosis. Offering recommendations for safe exposure limits for these shorter term exposures is made difficult because, (1) the mild toxic effects are often reported subjectively and tolerance usually develops, (2) the solvent concentration(s) cannot be documented in all cases, and (3) the effects are reversible when individuals are removed from exposure. Laboratory experiments involving controlled exposures to solvents using neurobehavioral performance tests represent one form of investigation that can provide meaningful information in this instance. The results can be viewed in two ways with reference to issues of safe exposure limits. One is to ensure that performance functions that can compromise safety are not affected by the exposure limits prescribed. The second is to consider performance changes due to short-term exposures as possible precursors of similar but more severe effects given longer term exposures. Thus, setting exposure limits to protect against these performance changes could possibly prevent the development of more serious cases of chronic solvent neurotoxicity. This paper compares solvent concentrations from short-duration exposure studies using neurobehavioral tests with the concentrations producing irritant and narcotic effects, as documented by the two main standards recommending bodies, the National Institute for Occupational Safety and Health and the American Conference of Governmental Industrial Hygienists. Comparisons are also made with the regulatory exposure limits established by the Occupational Safety and Health Administration. In general, the neurobehavioral changes which occur following short-duration exposures are reported at concentrations between those which produce irritant effects and narcosis. For the chemicals which have been tested, the performance changes measured by the present day neurobehavioral tests in use rarely occur at or below those limits recommended by the standards recommending bodies.

Body burden profiles of single and mixed solvent exposures.

The dynamics of inhaled solvents have not been studied extensively for exposure conditions involving combinations of chemical agents. An ongoing laboratory study examining psychomotor performance effects on human volunteers exposed to spray paint agents offered an opportunity to gather data on the body burden profiles produced by the inhalation of two solvents alone and in combination. Breath and blood samples were collected from 70 male and female subjects who were randomly assigned to four treatment conditions: chemical placebo, 250 ppm acetone, 200 ppm methyl ethyl ketone, or 125 ppm acetone/100 ppm methyl ethyl ketone. The exposures lasted for four hours. No interaction between the two solvents affecting uptake or elimination was noted. There were no significant differences between the uptake and elimination in males and females. The results are discussed in relation to physiological simulation modeling of the exposure.

Effects of acute exposure of toluene and methyl ethyl ketone on psychomotor performance.

Organic solvents are used frequently in industry and workers are often exposed to various combinations of these chemicals. Several are CNS depressants, and the purpose of this experiment was to assess the behavioral effects of 4-hour inhalation exposures to two solvents, toluene and methyl ethyl ketone (MEK) alone and combined. Ethanol at 0.08% blood levels was used as a positive control. A total of 144 paid volunteers were randomly assigned to one of eight treatment combinations in a series of four two-group between subjects studies. Testing was carried out in an exposure chamber, and participants were tested before, during, and after the treatment or control condition on three performance tasks. The tasks measured alertness and psychomotor function and produced a total of 28 measures on each individual over the approximate 8 h of testing. Results indicated that toluene at 100 ppm produced a small but significant impairment on one measure of a visual-vigilance task by lowering the percentage of correct hits. MEK at 200 ppm produced no interpretable significant effects on any of these measures. Additivity was not evident when individuals were exposed to MEK (100 ppm) and toluene (50 ppm) in combination, as no significant performance differences were noted. Ethanol, at 0.08%, affected both the visual-vigilance and a choice-reaction time task at statistically significant levels on two measures, confirming the sensitivity of these two tasks to CNS depressants.