Neurobehavioral performance in volunteers after inhalation of white spirits with high and low aromatic content.

The content of aromatic hydrocarbons in solvent mixtures, such as white spirits (WS), has been assumed a major contributor to the neurotoxic effects of these compounds. Hence, dearomatized WS have been introduced to the market rapidly in the last decade. Studies investigating other aromatic hydrocarbons (toluene) and animal models have supported the aforementioned assumption, but the current study is the first one to compare acute neurobehavioral effects of exposure to aromatic and dearomatized WS (aWS, daWS) content in human volunteers at current occupational exposure limit values. In a pseudo-randomized crossover design, six female and six male healthy volunteers were exposed to aWS and daWS at two concentrations (100 and 300 mg/m(3)) and to clean air for 4 h at rest. During each of the five exposure conditions, volunteers performed five neurobehavioral tasks that were selected following a multidisciplinary approach that accounted for findings from the cognitive neurosciences and mechanisms of solvent toxicity. Two of the tasks indicated performance changes during aromatic WS exposure, the working memory (WM) and the response shifting task, but both effects are difficult to interpret due to low mean accuracy in the WM task and due to a lack of dose-response relationship in the response shifting task. Healthy human volunteers showed weak and inconsistent neurobehavioral impairment after 4-h exposures to 100 and 300 mg/m(3) aromatic or dearomatized WS. Our multidisciplinary approach of selecting neurobehavioral test methods may guide the test selection strategies in future studies.

Behavioral toxicology: from historical background to future trends.

In the 1960's and 70's some investigators started to use behavioral tests in toxicology, realizing that classical toxicological methods were inadequate to describe the negative effects on workers health caused by workplace neurotoxic exposures. Among the first publications were those of Helena Hänninen, who reported on exposure to CS2 (24, 22). In clinical examinations, these workers presented severe functional changes to the central nervous system (CNS), although there were no observable signs of frank brain damage. In experimental studies of effects from acute exposures to various chemicals, methods from classical toxicology were definitely not useful. Such investigations were performed with exposure to carbon monoxide and to different solvents. Studies were carried out in the US, Sweden, and Germany, and reported by Richard Stewart (53), Francesco Gamberale (15, 16), and Gerhard Winneke (63). Rapid development followed. Scientists active in behavioral toxicology gathered at various meetings, and in 1982 an international symposium dedicated solely to the use and development of behavioral testing techniques in toxicology was organized by Renato Gilioli. He then used the Scientific Committee of Neurotoxicology and Psychophysiology of the International Commission on Occupational Health as a platform for a series of triennal symposia. The 9th meeting was held in Korea 2005, and the 10th will be organized in Costa Rica 2008. By providing a basis for the exchange of scientific knowledge and ideas, these symposia have been successful in further advancing the development and application of behavioral techniques in toxicology. This history is presented in some more detail, and a few possibilities for further development of the area will be discussed.

Acute effects of exposure to vapours of dioxane in humans.

Information on the acute effects associated with the handling of 1,4-dioxane is sparse. Our aim was to evaluate the acute effects of 1,4-dioxane vapours. In a screening study, six healthy volunteers rated symptoms on a visual analogue scale (VAS), while exposed to stepwise increasing levels of 1,4-dioxane, from 1 to 20 ppm. The initial study indicated no increased ratings at any of the exposure levels; we decided to use 20 ppm (72 mg/m3) as a tentative no observed adverse effect level (NOAEL). In the main study, six female and six male healthy volunteers were exposed to 0 (control exposure) and 20 ppm 1,4-dioxane vapour, for 2 hours at rest. The volunteers rated 10 symptoms on VAS before, during, and after the exposure. Blink frequency was monitored during exposure. Pulmonary function, and nasal swelling, was measured before, and at 0 and 3 hours after exposure. Inflammatory markers in plasma (C-reactive protein, and interleukin-6) were measured before and at 3 hours after exposure. In conclusion, exposure to 20 ppm 1,4-dioxane for 2 hours did not significantly affect symptom ratings, blink frequency, pulmonary function, nasal swelling, or inflammatory markers in the plasma of the 12 volunteers in our study.

Effects on the nervous system in different groups of workers exposed to aluminium.

OBJECTIVE: To investigate possible neurotoxic effects in groups of aluminium pot room and foundry workers, aluminium welders, and a small group of workers exposed to aluminium in the production of flake powder. METHODS: Exposure to aluminium was evaluated with aluminium concentrations in blood and urine as well as a questionnaire. The groups exposed to aluminium were compared with a group of mild steel welders. Neurotoxic effects were studied with mood and symptom questionnaires and several psychological and neurophysiological tests. RESULTS: The pot room and foundry workers showed very low aluminium uptake as their aluminium concentrations in blood and urine were close to normal, and no effects on the nervous system were detected. The group of workers exposed to flake powder had high concentrations of aluminium in blood and urine, even higher than those of the aluminium welders. However, aluminium could not be shown to affect the functioning of the nervous system in flake powder producers. Although significant effects could not be shown in the present analysis of the data on welders, the performance of the welders exposed to high concentrations of aluminium was affected according to the analyses in the original paper from this group. CONCLUSIONS: For the pot room and foundry workers no effects related to the exposure to aluminium could be found. For the group of flake powder producers exposed for a short term no effects on the nervous systems were evident despite high levels of exposure. Due to the high concentrations of aluminium in the biological samples of this group, measures to reduce the exposure to aluminium are recommended, as effects on the central nervous system might develop after protracted exposures. However, this assumption needs to be verified in further studies.

Manganese neurotoxicity in industrial exposures: proof of effects, critical exposure level, and sensitive tests.

Manganese neurotoxicity has been known for more than 150 years, since Couper (1837) described a syndrome, similar to Parkinson's disease, in Scottish workers exposed to high levels of dust while grinding "black oxide of manganese" at a chemical industry. Since then, the syndrome has been described in several groups of highly exposed miners and other workers. A thorough review of manganese neurotoxicity was provided by the WHO (1981) and a recent update was written by Mergler and Baldwin (1997). From these reviews it is evident that the critical effect from manganese exposure is damage to the central nervous system, and that the effects, once established, are generally irreversible. Therefore, the early detection of symptoms of manganese neurotoxicity in populations at risk is of the utmost importance. In spite of this fact, only about a dozen studies of manganese exposed groups of workers have been performed using psychological test methods. These studies are briefly presented, the preponderance of proof for Mn neurotoxicity even in present industrial settings is demonstrated, the critical exposure level is briefly discussed, the test methods are evaluated, and recommendations for a test battery useful for studies of manganese neurotoxicity, are presented.

SPES: a psychological test system to diagnose environmental hazards. Swedish Performance Evaluation System.

The effects of unfavorable work environmental conditions can be studied using psychological performance measures and subjective ratings of mood and symptoms. In the present article the rationale for such investigations is discussed, and the computerized performance evaluation system developed at the Swedish National Institute of Occupational Health is presented. The background and the research experience leading to the system's development are described, and references to the numerous empirical studies demonstrating its applicability to different research objectives are given. Also included is information regarding the technical requirements for running the SPES tests.

Lessons for neurotoxicology from selected model compounds: SGOMSEC joint report.

The ability to identify potential neurotoxicants depends upon the characteristics of our test instruments. The neurotoxic properties of lead, methylmercury, polychlorinated biphenyls, and organic solvents would all have been detected at some dose level by tests in current use, provided that the doses were high enough and administered at an appropriate time such as during gestation. The adequacy of animal studies, particularly rodent studies, to predict intake levels at which human health can be protected is disappointing, however. It is unlikely that the use of advanced behavioral methodology would alleviate the apparent lack of sensitivity of the rodent model for many agents.

Behavioral methods and organic solvents: questions and consequences.

This paper reviews some illustrative examples of studies of human neurobehavioral effects from experimental as well as long-term occupational organic-solvent exposure. My objective is to present a selection of neurobehavioral solvent studies with the educational aim that we may hopefully learn from the early experiences of others. Some of the methodological problems encountered in these studies are discussed, as well as some reasons for the relative success of the work performed by certain Scandinavian research teams.

Effects on the nervous system among welders exposed to aluminium and manganese.

OBJECTIVES: The purpose was to study the effects on the nervous system in welders exposed to aluminium and manganese. METHODS: The investigation included questionnaires on symptoms, psychological methods (simple reaction time, finger tapping speed and endurance, digit span, vocabulary, tracking, symbol digit, cylinders, olfactory threshold, Luria-Nebraska motor scale), neurophysiological methods (electroencephalography, event related auditory evoked potential (P-300), brainstem auditory evoked potential, and diadochokinesometry) and assessments of blood and urine concentrations of metals (aluminium, lead, and manganese). RESULTS: The welders exposed to aluminium (n = 38) reported more symptoms from the central nervous system than the control group (n = 39). They also had a decreased motor function in five tests. The effect was dose related in two of these five tests. The median exposure of aluminium welders was 7065 hours and they had about seven times higher concentrations of aluminium in urine than the controls. The welders exposed to manganese (n = 12) had a decreased motor function in five tests. An increased latency of event related auditory evoked potential was also found in this group. The median manganese exposure was 270 hours. These welders did not have higher concentrations of manganese in blood than the controls. CONCLUSIONS: The neurotoxic effects found in the groups of welders exposed to aluminium and manganese are probably caused by the aluminium and manganese exposure, respectively. These effects indicate a need for improvements in the work environments of these welders.

Neurobehavioral effects of manganese in workers from a ferroalloy plant after temporary cessation of exposure.

OBJECTIVES: The goal of this study was to assess long-term neurobehavioral effects associated with low airborne concentrations of manganese in a ferroalloy plant. METHODS: During a period of forced cessation of work (1 to 42 d) neurobehavioral performance on tests of simple reaction time, finger tapping, digit span, additions, symbol digit, and shapes comparison was evaluated for 58 workers exposed from 1 to 28 (mean 13, SD 7) years to manganese. Airborne manganese concentrations in total dust had been reduced in the last 10 years from 70-159 micrograms x m-3 (geometric means in different areas) to 27-270 micrograms x m-3. For each worker, manganese concentrations in blood and urine were measured, and a cumulative exposure index was also calculated. RESULTS: Blood manganese and urinary manganese ranged from 4 to 18 micrograms x 1-1 (0.07 to 0.03 mumol x 1-1) and from 0.7 to 7 micrograms x 1-1 (0.01 to 0.13 mumol x 1-1) respectively. Significant relationships were found between the blood manganese and urinary manganese levels and between these biological measures and the cumulative exposure index. Correlations were also found between the blood manganese level, the urinary manganese level, and the cumulative exposure index and the following tests: finger tapping, symbol digit, digit span, and additions. The correlation coefficients increased as the latency time after the cessation of exposure and work seniority increased. CONCLUSIONS: The results support the hypothesis that the neurobehavioral effects observed at exposure levels well below current occupational standards are related to manganese body burden, which is better reflected by the blood manganese level after the cessation of exposure.

Nervous system dysfunction among workers with long-term exposure to manganese.

Neurological disorders, bearing many similarities to Parkinson's disease, have been associated with environmental and occupational exposure to manganese (Mn). To document early nervous system dysfunction associated with long-term exposure to Mn, a battery of neurofunctional tests was administered to workers employed in Mn alloy production. Study participation was 95% (n = 115). A matched pair design was used; actively working men, with no history of workplace exposure to neurotoxins, were recruited from the region as referents. Matching was done on the variables: age (+/- 3 years), educational level (+/- 2 years), smoking status, and number of children. Stationary environmental sampling indicated that Mn levels varied widely (geometric means: Mn dust, 0.89 mg/m3; respirable Mn, 0.04 mg/m3). The alloy workers had significantly higher levels of whole blood Mn (geometric mean: 1.03 microgram/100 ml vs 0.68 microgram/100 ml); no differences were observed for urinary Mn. Univariate analysis (paired t test, Signed Rank and McNemar) and multivariate analysis of variance (Hotelling-Lawley statistic) revealed that the pairs differed on symptom reporting, emotional state, motor functions, cognitive flexibility, and olfactory perception threshold; verbal fluency, basic mathematics, reading capability, and attentional capacity were similar. These findings are consistent with current knowledge on brain Mn activity and suggest that manifestations of early manganism can be observed in well designed population studies, using sensitive testing methods.

Using psychological tests for the early detection of neurotoxic effects of low level manganese exposure.

The neurotoxic effects from chronic exposure to high concentrations of manganese dust are well known from studies of highly exposed miners, as well as from numerous clinical reports. The very first of these reports dates back to the early 19th century (Couper, 1837). A thorough review of the toxicity of manganese was provided by the WHO in 1981 (WHO, 1981). It is evident from these early reports that the critical effect from manganese exposure, i.e. the effect used in the establishment of environmental exposure criteria, is the effect on the central nervous system (CNS). Furthermore, impaired motor functions are clearly central to the manganese syndrome (WHO, 1981). It is also obvious from the clinical knowledge gathered over the years, that once the neurotoxic effects from manganese exposure are openly manifested at the clinical level, the damage to the CNS is essentially irreversible, and may, in some cases, be progressive. For this reason, detection of early signs of Mn exposure is fundamental to the prevention of chronic neurotoxic illness in manganese exposed populations. Very few investigations have been studying early signs of manganese toxicity by the use of behavioural methods in groups of active workers before the onset of clinically observable problems. To our knowledge, there are only four studies reported using behavioural measures to explore possible CNS effects from current industrial levels of manganese exposure in asymptomatic populations (Siegl and Bergert, 1982; Roels et al., 1987; Iregren, 1990; Roels et al., 1992).(ABSTRACT TRUNCATED AT 250 WORDS)

Irritation effects from experimental exposure to n-butyl acetate.

The irritation produced by acute exposure to n-butyl acetate in human subjects without any history of occupational solvent exposure was studied in three experiments. Exposure levels tested in the different experiments were 350, 700, 1,050, and 1,400 mg/m3 in 20 min sessions, 70 and 1,400 mg/m3 in 20 min sessions, and 70 and 700 mg/m3 in 4 h sessions. Rating scales, various measures of eye irritation, and pulmonary functions were used to evaluate the irritation produced by the exposures in different parts of the study. The results indicate only very slight irritation from the exposures as revealed by categorical ratings, magnitude estimation, and some of the clinical measures of eye irritation and pulmonary functions, such as eye redness, lipid layer thickness, and bronchial responsiveness. These essentially negative results indicate the need to explore and develop the utility of new/different methods of quantifying irritative effects of exposure to various substances.

Human experimental MIBK exposure: effects on heart rate, performance, and symptoms.

Heart rate, performance, and symptoms were studied in six female and six male volunteers, aged 19 to 47 years, during experimental 2-hr exposures to 10 and to 200 mg/m3 of methyl isobutyl ketone (MIBK). No effects from exposure on performance of a reaction time task or an arithmetic test could be demonstrated, and no consistent effects on heart rate were found. Subjects reported significantly more symptoms from the central nervous system, e.g., fatigue, due to the exposure. There was also an indication of an increase in ratings of irritation to the airways. A reduction of the threshold limit value (TLV) of 205 mg/m3 for MIBK exposure presently indicated by the American Conference of Governmental Industrial Hygienists, is therefore recommended.

Manganese exposure in steel smelters a health hazard to the nervous system.

In a study of the effects of low-level exposure to manganese (0.19-1.39 mg/m3 for 1-45 years) 30 men (aged 20-64 years) from two steel smelting works and 60 unexposed referents (aged 22-65 years) were examined with the use of a general health inquiry, electroencephalography, event-related auditory evoked potentials, brain-stem auditory evoked potentials, diadochokinesometry, simple and complex reaction time, finger tapping, digit span, mental arithmetic, vocabulary, a coding task, manual dexterity, symptoms, and mood scales, the diagnostic interview scheme, a dynamic rating scale for neurasthenic syndrome, and a comprehensive psychopathological rating scale. No group differences were found in the electroencephalography or the psychiatric examinations. However, there were increased frequencies of some symptoms, the diadochokinesis was slower, the P-300 latency and reaction time were increased, and finger-tapping and digit-span performance were impaired in the exposed group. These effects were interpreted as early (subclinical) signs of disturbances of the same type as parkinsonism.

Psychological test performance in foundry workers exposed to low levels of manganese.

A sample of 30 manganese-exposed foundry workers from two Swedish plants were examined with a partly computerized psychological test battery, comprised of 10 performance tests. Performance of the manganese-exposed workers was compared to that of a matched control group of 60 workers. Matching criteria were age, geographical area, type of work, and the results on a test of verbal comprehension. Performance of the exposed workers was inferior to that of the control group on tests of simple reaction time, digit span, and finger tapping. No correlations were found between performance and the present manganese exposure levels or the number of years employed in manganese work. The results seem to indicate that the present exposure standards for manganese, in Sweden 2.5 mg/m3 and in most other countries 5 mg/m3, are not sufficient to protect workers from negative effects on performance capacity.

Human behavioral toxicology. Central nervous effects of low-dose exposure to neurotoxic substances in the work environment.

The central nervous effects of low-dose exposure to the neurotoxic substances found in the work environment can manifest themselves both as adverse subjective reactions and as performance impairments and physiological changes. The acute manifestations of these effects can be studied under highly controlled conditions in laboratory experiments on volunteers or in quasi-experimental field studies on occupationally exposed workers. The effects of long-term occupational exposure are commonly studied with the use of epidemiologic techniques in cross-sectional investigations or cohort studies. In addition studies using data from clinical cases have been conducted to describe the chronic effects of exposure. Although these types of investigations can provide valuable information on the health hazards due to the neurotoxicity of different substances, their accomplishment encounters theoretical and practical problems, some of which are described and discussed in the present paper.

Exposure to methyl isobutyl ketone: toxicokinetics and occurrence of irritative and CNS symptoms in man.

The toxicokinetics as well as irritative effects and CNS symptoms of methyl isobutyl ketone (MIBK) were studied in human volunteers during inhalation exposure. The volunteers were exposed (2h, 50 W) in an exposure chamber on four different occasions to about 10, 100 and 200 mg/m3 MIBK and to a combination of about 100 mg/m3 MIBK and 150 mg/m3 toluene. The relative pulmonary uptake of MIBK was about 60% and the total uptake increased linearly with increasing exposure concentration. The concentration of MIBK in blood rose rapidly after the onset of exposure and no plateau level was reached during exposure. No tendency for saturation kinetics could be observed within the dose interval and the apparent blood clearance was 1.61/h/kg at all exposure levels. The concentration of unchanged MIBK in the urine after exposure was proportional with the total uptake. Only 0.04% of the total MIBK dose was eliminated unchanged via the kidneys within 3 h post exposure. The concentrations of the metabolites 4-hydroxy-4-methyl-2-pentanone and 4-methyl-2-pentanol were below the detection limit (5 nmol/l). Irritative and CNS symptoms occurred during exposure. The degree of both irritative and CNS symptoms increased during exposure to 100 and 200 mg/m3 compared with 10 mg/m3, but combination exposure with toluene exhibited the most pronounced effect. There were no significant effects from exposure on the performance of a simple reaction time task or a test of mental arithmetic.

Effects on human performance from acute and chronic exposure to organic solvents: a short review.

The present short review deals with investigations of CNS-effects from acute and chronic exposure to some organic solvents and solvent mixtures, as measured by human performance. Some of the methodological problems in experimental and epidemiological investigations of effects from solvent exposure are discussed. Problem areas where further research is needed are indicated, and some methodological suggestions for future studies are presented.

Subjective and objective signs of organic solvent toxicity among occupationally exposed workers. An experimental evaluation.

A questionnaire consisting of 55 items concerning acute and long-term symptoms associated with exposure to organic solvents, as well as questions about type and duration of exposure, was distributed to 225 male spray painters in the Stockholm region. From the 152 respondents, two extreme groups were selected on the basis of frequency of solvent-related symptoms. Subjects for the experimental study (N = 26) were chosen from these groups and matched with respect to age and number of years employed as a painter. The subjects were experimentally exposed for 4 h to 3.2 mmol/m3 (300 mg/m3) of toluene and a control condition in an exposure chamber. Effects on performance were assessed with a computerized battery of four tests. Ratings of acute symptoms were also studied, and toluene exposure was found to affect them. However, there were no indications of toluene effects on performance, nor was there any correlation between symptom frequencies and performance levels. The only difference found between the two groups was a higher frequency of symptoms of local irritation in the group which had reported high symptom frequencies on the questionnaire.