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.

Acute effects of exposure to vapours of standard and dearomatized white spirits in humans. 2. Irritation and inflammation.

Low aromatic and dearomatized white spirits (deWS) are often considered less hazardous to health than 'standard' or aromatic white sprit (stdWS, 15-20% aromatics). However, data on health effects of deWS in humans are sparse and controlled exposure studies are lacking. The aim of this study was to compare deWS and stdWS with respect to irritation and inflammation. Six female and six male healthy volunteers were exposed on five occasions in balanced order to 100 or 300 mg m(-3) deWS (0.002% aromatics) or stdWS (19% aromatics), or to clean air, for 4 h at rest. Discomfort in the eyes, nose and throat and breathing difficulty were assessed by ratings on visual analogue scales. The only significant increases in ratings (compared to clean air) were seen for eye irritation at the high stdWS exposure and for solvent smell at all but the low deWS exposure. Excluding smell, all average ratings were at the lower end of the 0-100 mm scale, and did not exceed the verbal expression 'somewhat'. Ratings during stdWS exposure tended to be higher than during deWS exposure. No exposure-related effects on pulmonary function, nasal swelling, nasal airway resistance, breathing frequency, blinking frequency, plasma inflammatory markers (C-reactive protein, interleukin-6) or biochemical variables (sodium, potassium, amylase, creatine kinase, urate) were seen. In conclusion, stdWS appears to be slightly more irritating than deWS. This could, however, not be confirmed by objective measurements.

Acute effects of exposure to hexanal vapors in humans.

OBJECTIVE: n-Hexanal is a major component in emissions from stored wood pellets. The production and use of wood pellets has increased dramatically. Our aim was to evaluate acute health effects of n-hexanal vapors. METHODS: Twelve healthy volunteers were exposed to 0, 2, and 10 ppm n-hexanal for 2 hours at rest in a balanced order. RESULTS: Ratings of discomfort in the eyes and nose, solvent smell, and headache increased significantly with the level of exposure. Frequency of blinking was significantly increased at 10 ppm. No effects on pulmonary function and nasal swelling were detected, except a not-significant tendency to increased nasal obstruction at 10 ppm. No clear effects on plasma inflammatory markers (C-reactive protein and interleukin-6) were observed. CONCLUSIONS: Two hours of exposure to n-hexanal results in mild irritation at 10 ppm, with no apparent adversity at 2 ppm.

Acute effects of exposure to vapours of acetic acid in humans.

Acetic acid is used in plastics, chemical and pharmaceutical industries. Despite a widespread use, information of possible health effects is sparse. The aim of this study was to evaluate acute irritation during controlled exposure to vapours of acetic acid. Six female and six male healthy volunteers were exposed to 0 ppm (control exposure), 5 and 10 ppm acetic acid vapour for 2 h at rest in a balanced order. Subjective ratings of nasal irritation and smell increased significantly with exposure level. Except for smell, all average ratings at 10 ppm were at the lower end of the 0-100mm visual analogue scale, and did not exceed the verbal expression "somewhat" (26 mm). No effects on pulmonary function, nasal swelling, nasal airway resistance or plasma inflammatory markers (C-reactive protein, and interleukin-6), measured before and after exposure, were seen. There was a non-significant tendency to increased blinking frequency, as measured continuously during exposure, after exposure to 10 ppm acetic acid. In conclusion, our study suggests a mild irritative effect at 10 ppm acetic acid.

Low-level styrene exposure and color vision in Swedish styrene workers.

Styrene exposure and color vision for 108 workers (21-65 years) was studied at Swedish reinforced plastic plants. Acute exposure was measured at work. Data on past exposures and personal background data were collected by questionnaire. Current exposure varied between 0.3 and 96mg/m(3). Cumulative past exposures varied from 18 to 4455mg years/m(3), and an index of lifetime weighted average exposure (LWAE) varied from 5 to 129mg/m(3). Color vision was tested using the Lanthony D15 desaturated panel binocularly without prior training in conditions with ample light (1400lx). Color vision was slightly correlated to LWAE (r=0.188, p=0.052). Workers were divided into two exposure groups according to LWAE. Analyses of variance revealed effects on the Vingrys' color vision confusion index (F=6.04; p=0.016) and total error (F=6.296; p=0.014). This study thus indicates that styrene exposure even at levels below the current Swedish OEL of 20mg/m(3) may affect color vision negatively.

The nervous system effects of occupational exposure on workers in a South African manganese smelter.

Five hundred and nine production workers at a manganese (Mn) smelting works comprising eight production facilities and 67 external controls were studied cross-sectionally for Mn related neuroehavioural effects. Exposure measures from personal sampling included Mn in inhalable dust as cumulative exposure indices (CEI) and average intensity (INT). Biological exposure and biological effect measures included blood (MnB), urine (MnU) manganese and serum prolactin. Endpoints included items from the Swedish nervous system questionnaire (Q16), World Health Organisation neurobehavioural core test battery (WHO NCTB), Swedish performance evaluation system (SPES), Luria-Nebraska (LN), and Danish product development (DPD) test batteries, and a brief clinical examination. Potential confounders and effect modifiers included age, educational level, alcohol and tobacco consumption, neurotoxic exposures in previous work, past medical history, previous head injury and home language. Associations were evaluated by multiple linear and logistic regression modelling. Modelling assumptions were tested. Average exposure intensity across all jobs ranged from near 0 (0.06 microg/m3) for external controls to 5.08 mg/m3 for inhalable Mn, and was greater than the ACGIH TLV for 69% of subjects. Results from the large number of tests performed resolved into three groups. Group 1 shows differences between external unexposed referents and all the exposed and/or differences between internal low exposed referents and the rest of the exposed but no further exposure-response relationships. It includes the Santa Ana, Benton and digit-span tests from the WHO NCTB; the hand tapping and endurance tapping tests from the SPES; Luria-Nebraska item 2L; questionnaire items tired, depressed, irritated, having to take notes in order to remember things, and subjects' perception that they had sex less often than normal; a test of clinical abnormality; and increased sway under two conditions (eyes open without foot insulation, eyes open with foot insulation). Group 2 shows the presence of a more substantive exposure-response relationship. It consists of only two tests: and includes the WHO digit-symbol test (although the major impact is at low exposure and therefore counterintuitive, arguably placing this test in group 3) and the LN item 1R which has a step to a poorer score at high exposure. Group 3 contains the overwhelming majority of test results (almost all the questionnaire items, almost all the DPD tests including tremor, sway and diadochokinesia, and serum prolactin) which were either null or counterintuitive (did not make sense). The CEI was the strongest predictor of test abnormalities, except for the clinical test which was more strongly associated with blood manganese. Despite a comprehensive range of endpoints, and levels of exposure ranging from environmental to industrial, this large study of Mn workers found little convincing evidence for a continuum of effects, contributing further questions to current debates about the adequacy of the current ACGIH TLV.

EUROQUEST--a questionnaire for solvent related symptoms: factor structure, item analysis and predictive validity.

The study evaluates the factor structure and predictive validity of the symptom questionnaire EUROQUEST (EQ) that had been developed with the goal of simplifying the evaluation of health effects associated with long-term solvent exposure. The EQ was added to the normal evaluation procedures for 118 male patients with suspected solvent-induced toxic encephalopathy (TE) referred to seven Swedish clinics of occupational medicine during an 18-month period. EQ was also completed by 239 males from a random sample of 400 Swedish males aged 25-64 years selected from the general population and a sample of 559 occupationally active male spray painters aged 25-64 years. Factor and item analyses of EQ responses were performed. Ordinary least square regression analysis was used to evaluate sensitivity and correlation to evaluate the specificity of EQ and the separate components. Questions concerning memory and concentration symptoms alone showed better sensitivity than the other five EQ dimensions singly or combined for the entire EQ and for a subset of questions approximating Q16, a widely used organic solvent symptom screening questionnaire. However, the diagnosis of TE required information in addition to exposure and responses to EQ and Q16-like questions. The results indicate that the subset of EQ questions concerning memory and concentration might replace the more cumbersome EQ and less sensitive Q16 in screening for TE, although none of the screening instruments alone replaces current clinical diagnostic procedures.

Color vision and occupational chemical exposures: I. An overview of tests and effects.

The paper presents a summary of the literature published until December 2000 on effects from some industrial chemical exposures on color perception, as well as short descriptions of the tests applied. Several different tests have been used to study acquired alterations of color vision. These changes are frequently found in the blue-yellow axis. Many of the tests were originally designed to detect congenital alterations in the red-green axis, and thus have relatively low sensitivity when studying chemically induced deficits in color perception. At present, the Lanthony D15-desaturated panel seems most suitable for application in industrial settings, since it is clearly the most sensitive and easily administered test. Color vision seems to be a physiological function very sensitive to several chemicals. The potency of industrial chemicals to induce color vision deficiencies has often been investigated during the last two decades. The chemicals most frequently studied are different solvents and mercury. Pronounced effects on color perception have been reported following chronic exposure to organic solvents such as styrene, carbon disulphide, perchloroethylene, n-hexane and solvent mixtures, and to organic as well as inorganic mercury. The effect of occupational toluene exposure seems not as well established, since only slight effects and several negative studies have been reported. For some of these compounds the effect on color vision has been further established through the finding of clear dose-effect relationships. In a few cases, even acute exposure situations, e.g. exposure to toluene for a few hours or acute alcohol intake, seem to affect color perception. Follow-up studies are needed to investigate the possible reversibility of effects in relation to discontinued or reduced exposures.

Color vision and occupational chemical exposures. II. Visual functions in non-exposed subjects.

This paper presents data on visual functions (visual acuity, contrast sensitivity, and several tests of color vision), in a group of 199 non-exposed healthy subjects with an even distribution over the age range 18-65 years, and sex. Although subjects with obvious congenital color vision deficiencies were removed from the analyses (four males), females were superior to males on several of the color vision tests applied. Age influenced visual acuity and contrast sensitivity, while color discrimination was less affected. Correlations between functions of the right and the left eye in the individual subjects were rather low, ranging from 0.40 to 0.73. Correlations between visual acuity and contrast sensitivity on the one hand and color discrimination ability on the other hand were still lower (r < 0.20). These low correlations between functions in the two eyes support the need for testing each eye separately.