A short-term inhalation study to assess the reversibility of sensory irritation in human volunteers.

Sensory irritation is an acute adverse effect caused by chemicals that stimulate chemoreceptors of the upper respiratory tract or the mucous membranes of the outer eye. The avoidance of this end point is of uttermost importance in regulatory toxicology. In this study, repeated exposures to ethyl acrylate were analyzed to investigate possible carryover effects from day to day for different markers of sensory irritation. Thirty healthy subjects were exposed for 4 h on five subsequent days to ethyl acrylate at concentrations permitted by the German occupational exposure limit at the time of study. Ratings of eye irritation as well as eye blinking frequencies indicate the elicitation of sensory irritation. These markers of sensory irritation showed a distinct time course on every single day. However, cumulative carryover effects could not be identified across the week for any marker. The rhinological and biochemical markers could not reveal hints for more pronounced sensory irritation. Neither increased markers of neurogenic inflammation nor markers of immune response could be identified. Furthermore, the performance on neurobehavioral tests was not affected by ethyl acrylate and despite the strong odor of ethyl acrylate the participants improved their performances from day to day. While the affected physiological marker, the increased eye blinking frequency stays roughly on the same level across the week, subjective markers like perception of eye irritation decrease slightly from day to day though the temporal pattern of, i.e., eye irritation perception stays the same on each day. A hypothetical model of eye irritation time course derived from PK/PD modeling of the rabbit eye could explain the within-day time course of eye irritation ratings repeatedly found in this study more precisely.

Does seasonal allergic rhinitis increase sensitivity to ammonia exposure?

Allergic inflammation in the upper airways represents a wide-spread health issue: Little is known about whether it increases sensitivity to airborne chemicals thereby challenging established exposure limits that neglect such differences in susceptibility. To investigate the role of pre-existing allergic inflammation, 19 subjects with seasonal allergic rhinitis (SAR) and 18 control subjects with low risk of sensitization were exposed for 4h to ammonia in two concentrations (cross-over design): 2.5ppm (odor threshold) and 0-40ppm (occupational exposure limit: 20ppm TWA). Prior to the whole-body exposure, it was confirmed that subjects with SAR showed persistent inflammation outside the pollen season as indicated by increased exhaled nitric oxide and total immunoglobulin E in serum compared to controls. Despite concentration-dependent increases in chemosensory perceptions and acute symptoms, SAR status did not modulate subjective effects of exposure. Moreover, SAR status did not affect the investigated physiological endpoints of sensory irritation: While eye-blink recordings confirmed weak ocular irritation properties of ammonia at 0-40ppm, this effect was not enhanced in SAR subjects compared to controls. Irrespective of SAR status, exposure to 0-40ppm ammonia did not result in a cortisol stress response, objective nasal obstruction as measured with anterior active rhinomanometry, or an inflammatory response as indexed by substance P, tumor-necrosis-factor α, and high-mobility-group protein 1 in nasal lavage fluid. At least for the malodorous compound ammonia, these results do not support the hypothesis that SAR enhances chemosensory effects in response to local irritants. Before generalizing this finding, more compounds as well as sensitization to perennial allergens need to be investigated.

Prediction of human sensory irritation due to ethyl acrylate: the appropriateness of time-weighted average concentration × time models for varying concentrations.

Human data about the potency of ethyl acrylate to evoke sensory irritation is currently not available. Therefore, we conducted an experimental exposure study and the magnitude of chemosensory effects in healthy human volunteers was mathematically modeled by combining the factors current concentration (c) and duration/time (t). In a repeated-measures design, 19 subjects were exposed for 4 h to constant and varying concentrations (including peaks of 5 and 10 ppm) of ethyl acrylate with either a 2.5 or 5 ppm time-weighted average (TWA) concentration. Clean air served as control condition. Nasal lavage fluid, eye blinking frequencies, and rhinomanometry were used as physiological measures of sensory irritation. Several subjective ratings assessed olfactory and trigeminal perceptions. The blinking frequency was significantly increased during the varying 5 ppm condition. Regardless of the TWA concentration, varying exposures caused stronger effects than constant exposures. Our mathematical modeling showed that olfactory perceptions generally decreased over time while ratings of eye irritation increased over time even under the constant 5 ppm condition. Including the current concentration in the mathematical modeling always increased the goodness of fit substantially. The results showed that the intensity of sensory irritation could be predicted best with a complex c × t model. During the 2.5 ppm conditions, only the current concentration predicted the ratings and time-dependent processes could not be observed. However, in both 5 ppm TWA conditions strong eye irritations and increased blinking frequency, only at the end of the 4-h exposures a dose-dependency of these adverse effects was clearly shown.

Interindividual differences in chemosensory perception: Toward a better understanding of perceptual ratings during chemical exposures.

Perceptions that arise from stimulation of olfactory and trigeminal receptors in the nasal cavity guide the evaluation of chemical environment in humans. Strong interindividual differences in these assessments may be attributed to nonsensory factors such as gender, anxiety, and chemical sensitivity. Knowledge regarding the influence of these factors originates mainly from basic odor research using short-term exposure scenarios. In situations with continuous chemical exposures-common in the working environment-their impact is less clear. To investigate their role during the exposure to workplace chemicals, 4-hour experimental exposure studies (total N = 105) using nine different airborne chemicals were summarized. In each study, subjects evaluated a single chemical in a controlled environment by rating five chemosensory perceptions, including odor intensity, disgust, annoyance, pungency, and burning, several times during occupational limit and low exposures. It was investigated whether the effects of trait-like modulators, such as anxiety and self-reported chemical sensitivity, depend on exposure-related factors and gender. Trait-like modulators markedly affected ratings by women, but not men. Highly anxious women reported more intense annoyance and disgust than less anxious women. Stronger self-reported chemical sensitivity was associated with increased ratings of pungency and burning in women exposed to occupational limit concentrations. This study demonstrates that a complex interplay of exposure-related factors, gender, and trait-like individual differences affects perceptual ratings during continuous chemical exposure. It seems necessary to incorporate the assessment of specific as well as general trait-like modulators into future experimental exposure studies.

Neurobehavioral effects of exposure to propionic acid revisited-Does psychosocial stress interfere with distractive effects in volunteers?

Local irritants stimulate the nervous system via chemosensory pathways that trigger cognitive distraction, subjective complaints about impaired health, and physiological defense reflexes (e.g. eye-blinks). At workplaces and in the environment chemical exposures often co-occur with psychosocial stress. This study investigated if stress modulates adverse effects of exposure to the local irritant and malodorant propionic acid (PA). Forty-eight participants were randomly assigned to an experimental (false negative feedback+salient surveillance) or control group. In a cross-over design, both groups were exposed for 4h to PA in concentrations of 0.3 and 0-20ppm (time-weighted average=10ppm). In the experimental group, the stress protocol induced moderate psychosocial stress as indicated by salivary cortisol and subjective responses. Despite concentration-dependent increases in chemosensory perceptions and symptoms, the level of exposure to PA had no impact upon the results of four out of six neurobehavioral tests. In the sustained attention test, there was a significant increase in error rates that corresponded to the exposure levels. However, a concentration-dependent impairment of spatial working memory and an adverse increase in eye-blink frequency were restricted to the control group. Stressed participants had shorter simple reaction times and high eye-blink frequency irrespective of exposure suggesting enhanced alertness. Psychosocial stress increased complaints, ocular irritation and unspecific symptoms at the end of the 0.3ppm exposure to a level that was comparable with that in the control group during exposure to 0-20ppm. Results indicate that the adverse effects of a local irritant and psychosocial stress are non-additive.

Multidimensional assessment of self-reported chemical intolerance and its impact on chemosensory effects during ammonia exposure.

PURPOSE: Healthy individuals differ in self-reported chemical intolerance (CI). It is unclear whether this inter-individual variability impacts well-being and performance in environmental and occupational settings with chemical exposures. So far, operational definitions and questionnaires of CI have either emphasized physical symptoms or affective/behavioral disruption. In contrast, this study focused on healthy individuals who reported strong CI which generalized to awareness, physiology, affect, and behavior. We investigated whether generalized self-reported CI is associated with hyper-reactivity and reduced cognitive functioning due to chemosensory-mediated distraction during ammonia exposure. METHODS: An online sample (N = 321) answered established CI questionnaires. Based on the convergent self-reports in these questionnaires, healthy women with generalized CI and healthy female control participants were selected (total N = 26). Baseline characterization was performed using implicit association, lung and olfactory function tests, health-related self-reports, plasma inflammatory and metabolic markers. Performance in neurobehavioral tasks, perceptual ratings, nasal inflammatory, neuroendocrine, and autonomic nervous system reactivity were examined by means of a 75-min whole-body challenge to ammonia (stepwise increase: 0-10 ppm). RESULTS: Correlational analyses confirmed the multidimensionality of CI. Participants with generalized self-reported CI exhibited better olfactory function and reported stronger pungency during the challenge than controls. Cognitive performance and physiological response to the challenge were comparable between the two groups. CONCLUSIONS: Self-reports of CI are complex and not easily assessed by unidimensional questionnaires. While generalized self-reported CI is associated with altered chemosensory processing, it seems unlikely that it modulates health effects and cognitive functioning during chemical exposure.

Stress lowers the detection threshold for foul-smelling 2-mercaptoethanol.

Previous studies have reported enhanced vigilance for threat-related information in response to acute stress. While it is known that acute stress modulates sensory systems in humans, its impact on olfaction and the olfactory detection of potential threats is less clear. Two psychophysical experiments examined, if acute stress lowers the detection threshold for foul-smelling 2-mercaptoethanol. Participants in Experiment 1 (N = 30) and Experiment 2 (N = 32) were randomly allocated to a control group or a stress group. Participants in the stress group underwent a purely psychosocial stressor (public mental arithmetic) in Experiment 1 and a stressor that combined a physically demanding task with social-evaluative threat in Experiment 2 (socially evaluated cold-pressor test). In both experiments, olfactory detection thresholds were repeatedly assessed by means of dynamic dilution olfactometry. Each threshold measurement consisted of three trials conducted using an ascending method of limits. Participants in the stress groups showed the expected changes in heart rate, salivary cortisol, and mood measures in response to stress. About 20 min after the stressor, participants in the stress groups could detect 2-mercaptoethanol at a lower concentration than participants in the corresponding control groups. Our results show that acute stress lowers the detection threshold for a malodor.

Meta-analysis on occupational exposure to pesticides--neurobehavioral impact and dose-response relationships.

While the health impact of high exposures to pesticides is acknowledged, the impact of chronic exposures in the absence of acute poisonings is controversial. A systematic analysis of dose-response relationships is still missing. Its absence may provoke alternative explanations for altered performances. Consequently, opportunities for health prevention in the occupational and environmental field may be missed. Objectives were (1) quantification of the neurotoxic impact of pesticides by an analysis of functional alterations in workers measured by neuropsychological performance tests, (2) estimates of dose-response relationships on the basis of exposure duration, and (3) exploration of susceptible subgroups. The meta-analysis employed a random effects model to obtain overall effects for individual performance tests. Twenty-two studies with a total of 1758 exposed and 1260 reference individuals met the inclusion criteria. At least three independent outcomes were available for twenty-six performance variables. Significant performance effects were shown in adults and referred to both cognitive and motor performances. Effect sizes ranging from dRE=-0.14 to dRE=-0.67 showed consistent outcomes for memory and attention. Relationships between effect sizes and exposure duration were indicated for individual performance variables and the total of measured performances. Studies on adolescents had to be analyzed separately due to numerous outliers. The large variation among outcomes hampered the analysis of the susceptibility in this group, while data on female workers was too scant for the analysis. Relationships exist between the impact of pesticides on performances and exposure duration. A change in test paradigms would help to decipher the impact more specifically. The use of biomarkers appropriate for lower exposures would allow a better prevention of neurotoxic effects due to occupational and environmental exposure. Intervention studies in adolescents seem warranted to specify their risk.

Toward better research practice--shortcomings decreasing the significance of epidemiological studies in the toxicological field.

Neurobehavioral studies do not always gain the impact they should have, neither in the scientific nor in the regulatory field of neurotoxicology. Among others, shortcomings and inconsistencies across epidemiological studies may contribute to this situation. Examples were compiled to increase awareness of obstacles for conclusions. Meta-analyses were exploited since they sometimes allow the detection of deficits that are not obvious from individual studies. Exposure assessment, performance measures, and confounding were scrutinized among 98 primary studies included in meta-analyses on mercury, solvents, manganese and pesticides. Inconsistent and hardly comparable markers of exposure were found; figures, units or sampling periods were not always provided. The contribution of test materials to differences in test outcomes across studies could sometimes not be evaluated due to the insufficient description of the employed tests. Hypotheses for the selection of performance variables often remained undisclosed. Matching procedures prevailed with respect to the confounder age; the comparability of groups with respect to intelligence and gender remained more elusive. 8% and 16% of the studies did not even mention confounding from intelligence and gender, respectively. Only one third of the studies provided adjusted means for group comparisons; the proportion was slightly larger for studies published 2000-2010. While 50% of the studies considered confounders for their dose-response assessment, only 29% reported results for the total of test variables. The outlined deficits impede, among others, the assessment of exposure-effect relationships and confounding across studies; thereby they limit the use of the studies for toxicological risk assessment and future prevention. Some shortcomings also impede a deeper insight into the mechanisms of toxicity: tests like the Digit Symbol show that something is affected, but not what is affected. Thorough description of measures employed is among the first consequences from the data. The consideration of mechanistic insights from research on animals and neurobiology may further help to increase the significance of epidemiological studies.

The neurobehavioral impact of manganese: results and challenges obtained by a meta-analysis of individual participant data.

Results from a meta-analysis of aggregated data provoked a new analysis using individual data on the neuropsychological performance of occupationally exposed workers. Data from eight studies examining 579 exposed and 433 reference participants were included, 28 performance variables analyzed. The performance scores were adjusted for well-known individual-level covariates; the influence of possible, but unknown study-level covariates was attenuated by means of a z-normalization. Associations between performance and exposure were estimated by ANOVAs and ANCOVAs, the latter representing multi-level models. Four cognitive and motor performance variables each indicated significantly lower performances of exposed individuals when confounding was considered; slowed motor performances and deficits in attention and short-term memory were found. Performance on a single test was significantly related to the biomarker manganese in blood. The outcomes on susceptibility were weak. The slowing of responses was the most distinct feature of performances of exposed workers. It remains unclear, whether this result is related to the employed tests or provides important information about early stages of the neurotoxic impairment. More specific cognitive tests need to be employed to answer this question. The lack of dose-response relationships was related to features of the biomarker: it does not reflect the Mn in brain responsible for changes in performances.

Neurobehavioral performance in human volunteers during inhalation exposure to the unpleasant local irritant cyclohexylamine.

Chemosensory active volatile organic compounds occur in the breathing air at many workplaces and it has been assumed that they are potent to impair workers' cognitive performance; however, the nature of this relationship is not understood. In the current study we investigated whether the combination of strong chemosensory potency and unpleasant odor valence is a sufficient predictor for the appearance of neurobehavioral impairment. Human volunteers were exposed to three workplace-relevant concentrations of the malodorant cyclohexylamine: 0.3 (odor control condition), 0-4 (varying condition), and 10 ppm (occupational exposure limit value, OEL, Sweden & Germany). The highest exposure evoked strong chemosensory sensations (annoyance), rather much olfactory related symptoms (bad air, stink), and increase in eye-blink frequency, which can be interpreted as indicator of trigeminal mediated adversity. Neurobehavioral performance measures (reaction times, accuracy) from three visual tasks requiring attention, motor inhibition and cognitive control did not show impairment in a consistent, dose-response related way and thus could not be related to cyclohexylamine exposure. Odorant characteristics of intensity and unpleasantness seem not sufficient to predict neurobehavioral impairment. Instead factors like participant selection bias, personality factors as well as effects related to the study design are discussed as contributing factors.

Statistical means to enhance the comparability of data within a pooled analysis of individual data in neurobehavioral toxicology.

Meta-analyses of individual participant data (IPD) provide important contributions to toxicological risk assessments. However, comparability of individual data cannot be taken for granted when information from different studies has to be summarized. By means of statistical standardization approaches the comparability of data might be increased. An analysis of individual data on the neurobehavioral impact of manganese (Mn) exemplifies challenges and effects of a multilevel statistical procedure. Confounding from individual-level and study-level covariates was shown by analyses of variance, but could be reduced by linear regressions and z-normalization using data of the respective control groups. Fixed models that were used to estimate the impact of the neurotoxic exposure, provided evidence that the employed procedures, especially the z-normalization, effectively reduced variance that was unrelated to the neurotoxic exposure. Even after this statistical treatment the fixed effect models revealed differences among studies that did not seem to be exhaustively explicable by concentration differences obvious from the Mn biomarker at hand. IPD studies using confounded endpoints as effects markers can be reasonably summarized when appropriate statistical operations are employed. For the data at hand the proposed normalization allowed new insights into exposure-effect relationships, in general it appears appropriate to investigate the effect of the independent variable more closely.

Odor thresholds and breathing changes of human volunteers as consequences of sulphur dioxide exposure considering individual factors.

OBJECTIVES: Though sulfur dioxide (SO(2)) is used widely at workplaces, itseffects on humans are not known. Thresholds are reported without reference to gender or age and occupational exposure limits are basedon effects on lung functioning,although localized effects in the upper airways can be expected.This study's aim is to determine thresholds with respect to age and gender and suggests a new approach to risk assessment using breathing reflexes presumably triggered by trigeminal receptors in the upper airways. METHODS: Odor thresholds were determined by the ascending method of limits in groups stratified by age and gender.Subjects rated intensities of different olfactory and trigeminal perceptions at different concentrations of SO(2). During the presentation of the concentrations, breathing movements were measured by respiratory inductive plethysmography. RESULTS: Neither age nor gender effects were observed for odor threshold. Only ratings of nasal irritation were influenced bygender. A benchmark dose analysis on relative respiratory depth revealed a 10%-deviation from baseline at about 25.27 mg/m(3). CONCLUSION: The proposed new approach to risk assessment appearsto be sustainable. We discuss whether a 10%-deviation of breathingdepth is relevant.

Sensory and pulmonary effects of acute exposure to sulfur dioxide (SO2).

BACKGROUND: Exposure to sulfur dioxide (SO(2)) affects large populations worldwide. Pulmonary effects have been reported at concentrations relevant in the general (<0.5 ppm) and working environment (>0.5 ppm). SO(2) is an irritant but the existing studies often emphasize only pulmonary effects and no clear dose-response relationship has yet been described. OBJECTIVES: Using a multi-level, multi-method approach, odor annoyance, sensory irritation and pulmonary effects of SO(2) were to be investigated in an experimental exposure study. METHODS: Eye blink frequency, rhinomanometry, spirometry and symptom ratings of acute health effects were assessed before, during, and after the exposures. Each session lasted 4h and concentrations of 0.5, 1, and 2 ppm were investigated and compared to a control condition using clean air. Sixteen human volunteers (8 females/8 males) participated and during exposure light physical exercise was simulated with bicycle ergometry. RESULTS: Eye blink frequency, nasal airflow, and lung function were not affected by the acute SO(2) exposure investigated. These physiological responses to moderate SO(2) exposures were not significantly affected by gender. Regarding subjectively measured chemosensory sensations, only odor annoyance ratings increased in a dose-dependent manner, but the average magnitudes were labeled weak to moderate. CONCLUSIONS: In healthy volunteers, without hyperresponsiveness to SO(2), no dose-dependent effects of acute SO(2) exposures up to 2 ppm could be measured. Due to olfactory perceptions subjects were aware of the different SO(2) exposures but the associated annoyance was relatively low.

Neurobehavioral effects during exposures to propionic acid--an indicator of chemosensory distraction?

The chemosensory effects of propionic acid (PA) in humans have not been conclusively studied and there is no established occupational exposure limit (OEL) in Germany. In addition to sensory irritation caused by PA, it was hypothesized that the annoying odor of PA might interfere with the performance results. There were 23 consenting healthy participants (12 female, 11 male) in the group studied. They were exposed for 4 h to PA in concentrations of 0.3, 5 and 10 ppm in a cross-over design. During these exposures, performance was recorded with four cognitive tests measuring response-inhibition, working memory, set-shifting, and divided attention. Odor annoyance, other chemosensory sensations, and acute symptoms were assessed before, during, and after exposure with standardized rating scales. Moderate odor annoyance and weak sensory irritation were reported during 5 and 10 ppm exposure conditions. The different levels of exposure to PA had no impact upon the results of three out of the four behavioral tests. The difficulties of the task were reflected in the results. However in the fourth, which was the response-inhibition task, there was significant increase in the error rates which corresponded to the exposure levels. Results from previous experiments suggested high odor annoyance at the investigated concentrations. Our findings showed that odor annoyance and reported sensory irritations were low. In conclusion, the hypothesis of a distractive effect due to the malodor of PA could not be confirmed. Only in concentrations as high as 10 ppm acute PA exposure affected the response accuracy of one of the four neurobehavioral task. For other more annoying substances, a neurobehavioral effect influenced by an indirect mechanism of resources competition is still conceivable.

Performance alterations associated with occupational exposure to manganese--a meta-analysis.

The review aimed at quantifying the evidence of performance effects resulting from occupational exposure to manganese. Epidemiological studies published between 1987 and 2008 were analyzed. The approach was based on the meta-analytical method of effect size estimates and sought to contribute to the following issues: (1) identification of the affected functions; (2) identification of sensitive neuropsychological tests; (3) analyses of exposure-effect relationships. Thirteen studies examining 958 exposed and 815 unexposed workers were included in the meta-analysis. Mean concentrations of inhalable manganese ranged from 0.05 to 1.59 mg/m(3), mean concentrations of manganese in whole blood ranged from 8.1 to 48.4 microg/L. Nineteen neuropsychological performance variables were analyzed as they were included in at least three of the identified studies. Apart from two outcomes, the overall effects displayed a negative impact of manganese on performance. Significant overall effects were obtained for six test variables; their size ranged from d=-0.23 to -0.36. Four of the variables measured motor speed and two of them speed of information processing. The analysis of exposure-effect relationships showed that larger effect sizes were more consistently associated with higher concentrations of inhalable manganese than with manganese in blood. The evidence of cognitive and motor performance effects is in accordance with the knowledge about accumulation of manganese in the basal ganglia and the effect of manganese on the neurotransmitter dopamine. Inconsistencies in the relationship between effect sizes and the biomarker manganese in blood were discussed in the context of results indicating that the biomarker might not be sufficiently meaningful for the neurobehavioral alterations. Simple motor performance tests with a distinct speed component seem to be highly recommendable for further studies, because they seem to be appropriate for measuring manganese-related changes, seem to provide homogenous results and their outcomes show consistent relations to exposure. The rigorous quantitative approach was especially appropriate for revealing exposure-effect relationships, but information about individual cumulative exposure would enhance the potential for risk assessment of manganese.

The effects of toluene plus noise on hearing thresholds: an evaluation based on repeated measurements in the German printing industry.

OBJECTIVES: The ototoxicity of occupational exposure to toluene plus noise was investigated in a longitudinal study in rotogravure printing and existing findings in the literature were evaluated. MATERIAL AND METHODS: The study comprised four repeated examinations during 5 years and started with 333 male workers. Lifetime weighted average exposures (LWAE) to toluene and noise were determined from individual work histories and historic recordings; recent individual exposures were measured 10 times during the study (toluene, active sampling; noise, stationary measurements). Auditory thresholds were measured with pure tone audiometry at 0.125, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12 kHz. RESULTS: Mean LWAE exposures to toluene and noise were 45+/-17 ppm plus 82+/-7 dB(A) for high toluene exposed and 10+/-7 ppm plus 82+/-4 dB(A) for low toluene exposed subjects, mean current exposures were 26+/-20 ppm plus 81+/-4 dB(A) and 3+/-3 ppm plus 82+/-4 dB(A). Mean exposure duration was 21.3+/-6.5 years for long exposed and 5.9+/-2.2 years for short exposed subjects. Repeated measurement analyses of variance did not reveal effects of toluene intensity, exposure duration and interactions between toluene intensity and noise intensity. Noise intensity [79+/-3 dB(A) vs. 84+/-1 dB(A)] was significant for auditory thresholds. A case concept utilising developments of individual auditory thresholds did not reveal significant toluene effects. Logistic models including age, exposure duration, toluene in ambient air, current noise and either hippuric acid or ortho-cresol (o-cresol) found only age to be significant for elevated OR of high frequency hearing loss. CONCLUSIONS: Due to missing toluene effects, it was concluded that the threshold level for developing hearing loss as a result of occupational exposure to toluene plus noise might be above the current limit of 50 ppm toluene.

Evaluation of ethyl acetate on three dimensions: investigation of behavioral, physiological and psychological indicators of adverse chemosensory effects.

A variety of national occupational exposure limits for ethyl acetate exist based on different studies, mostly relying on subjective evaluations of ethyl acetate as an irritant. Only one study also used physiological methods with inconsistent results in subjective and objective data. The present study was designed to investigate ethyl acetate on three different dimensions: behavioral, physiological and psychological indicators of adverse chemosensory effects were investigated during acute exposures to different concentrations of ethyl acetate. Twenty-four subjects were challenged with ethyl acetate in three exposure patterns (2 ppm, 400 ppm, 400 ppm including peaks of 800 ppm). While the odor intensity is rated "strong", trigeminal perceptions were rated less than "moderate". The absence of substantial trigeminal ratings was supported by physiological data. There was neither an effect of concentration on blinking frequency nor on nasal resistance which both are indicators of irritation. Furthermore, there are no effects of ethyl acetate concentration on behavioral measures indicating no olfactory or trigeminally mediated disturbance of cognitive processing. In conclusion, the results of this multilevel approach revealed no adverse chemosensory effects at ethyl acetate concentrations as recommended by the German MAK-value.

Odor annoyance of environmental chemicals: sensory and cognitive influences.

In low concentrations, environment pollutants like volatile organic compounds (VOCs) may be perceived via olfaction. Modulators of odor-mediated health effects include age, gender, or personality traits related to chemical sensitivity. Severe multi-organ symptoms in response to odors also characterize a syndrome referred to as idiopathic environmental intolerance (IEI). One prominent feature of IEI is self-reported odor hypersensitivity that is usually not accompanied by enhanced olfactory functioning. The impact of interindividual differences in olfactory functioning on chemosensory perceptions is sparsely investigated, and therefore this study addressed the influences of different types of modulators, including olfactory functioning. In a psychophysical scaling experiment, an age-stratified sample of 44 males and females was examined. After controlled application of nine concentrations of six chemicals by flow-olfactometry, the participants rated four olfactory and nine trigeminal perceptions. Weak effects were found for gender and age, as well as some modulating effects of self-reported chemical sensitivity and odor discrimination ability. For chemical sensitivity, the results were as expected: Subjects with higher sensitivity reported stronger perceptions. The individual odor threshold (n-butanol) exerted no influence on the subjects' ratings of olfactory and trigeminal perceptions. Surprisingly, above-average odor discrimination ability was associated with lower ratings of odor intensity and nausea. This particular aspect of olfactory functioning might be a reflection of a more objective odor evaluation model buffering emotional responses to environmental odors.

The impact of solvent mixtures on neurobehavioral performance: conclusions from epidemiological data.

The review of epidemiological studies investigating the neurobehavioral effects of occupational exposure to solvent mixtures sought to contribute to the following issues: (1) Identification of affected cognitive and motor functions. (2) Identification of sensitive neuropsychological tests. (3) Analysis of exposure-effect relationships. The approach was based on the meta-analytical method of effect size estimates. Fifty-three groups from occupational studies were included in the meta-analysis. Forty-eight neuropsychological performance variables could be analyzed as they were included in at least three studies. Seventeen articles provided detailed information on the constituents of mixtures, thereby enabling the computation of an exposure index that allowed the comparison of different mixtures. Significant negative effect sizes were obtained for 12 test variables measuring attention, memory, motor performance and constructional abilities. The greatest proportion of lower performance scores in the exposed groups was shown by different tests of attention: significant effect sizes between d=-0.16 and -0.46 were calculated. Tests of cognitive processing speed, response alternation and inhibition seemed to be sensitive tools for the detection of poorer performance. Exposure-effect relationships were mainly characterized by inconsistent patterns. Crude and inappropriately calculated exposure measures were blamed for this outcome. A healthy worker effect was suggested more consistently: studies examining groups with longer exposure duration obtained smaller effect sizes. Indications of confounding were observed; however, they did not seem sufficient to question consistent effect size patterns. Paying greater attention to the measurement of exposure and including measures of confounding is advisable for future studies and would enhance the explanatory power of cross-sectional studies and meta-analyses.