Occupational chronic exposure to organic solvents XVI. Ambient and biological monitoring of workers exposed to toluene

Object Ambient air and biological monitoring of an occupational toluene exposure was carried out on a group of 33 workers. Method The biological monitoring of the workers was based on determination of the concentration of toluene in blood and on quantification of the urinary metabolites o-cresol and hippuric acid. All blood and urine samples were collected post-shift. Results The average toluene concentration in the workplace air was 65?ppm, ranging from 13 to 151?ppm. An average concentration of toluene in blood of 911?μg/l was found, corresponding to an average urinary concentration of 2.9?mg/l (2.3?mg/g creatinine) o-cresol and 2.4?g/l (1.9?g/g creatinine) hippuric acid. Both urinary metabolites can be correlated with the concentration of toluene in ambient air and blood, respectively. Conclusions The results of our study indicate that the determination of the urinary o-cresol excretion represents a diagnostically specific and sensitive parameter for the estimation of an individual toluene uptake. In contrast, monitoring of the concentration of hippuric acid in urine cannot be recommended for assessment of individual exposure. To set up a biological tolerance value (BAT) for o-cresol, a urinary concentration of 3?mg/l o-cresol should be in accordance with the current MAK value of 50?ppm toluene.     

Occupational chronic exposure to organic solvents

Summary Four female assistants using a mixture of xylenes and ethylbenzeneas solvent in a histology laboratory were examined according to the concentrations of solvents in blood and the excretion of phenolic compounds in urine during 24 h. The average concentrations of (m+p)-xylene and ethylbenzene in air were between 56 and 68 ppm and 34 and 41 ppm respectively. It is shown that about 1.1–1.4% of the retained ethylbenzene is metabolized to 2-ethyl-phenol. 2,4-Dimethylphenol as a metabolite of m-xylene could not be detected. It is supposed that a competitive reaction mechanism between xylenes and ethylbenzene takes place preventing m-xylene from oxidation at the aromatic nucleus. Possible carcinogenic properties of epoxides formed as intermediates must be considered.-The estimation of threshold values for the concentration of solvents in blood was attempted.     

Occupational chronic exposure to organic solvents XI. Alkylbenzene exposure of varnish workers: effects on hematopoetic system

Summary Thirty-five spraymen, who were varnishing vehicles with alkyd-, phenol- and polyestervarnishes, which were dissolved in solvent mixtures mainly containing o-, m-, p-xylene and ethylbenzene, have been investigated. The concentrations of these solvents in air were 2.1, 7.9, 2.8 and 4.0 ppm on average. The levels of alkylbenzenes in blood and those of their metabolites in urine have been determined. At two of the six working places the spraymen were additionally exposed to n-butanol, respectively 1,1,1-trichloroethane, and several C₉-aromatic hydrocarbons. Some of the lacquers contained lead pigments. Alterations of blood cell counts have been observed under the described conditions of exposure. On average the number of lymphocytes was higher than that of segmented granulocytes. Erythrocytes and hemoglobin level of the spraymen were lower than those of the controls.     

Symptoms and signs in workers exposed predominantly to xylenes

Summary Surveys were conducted in factories in China where workers were engaged in the production of rubber boots or plastic-coated wire or in printing work, and were exposed to xylene vapors. Based on the data on exposure as monitored by personal diffusive sampling, 175 xylene-exposed workers (107 men and 68 women) were selected as those (1) who underwent all examinations and (2) for whom the sum of the three xylene isomers accounted for 70% or more of the total exposure (on a ppm basis). The intensity of exposure was such that the sum of the three isomer concentrations was l4 ppm as a geometric mean and 21 ppm as an arithmetic mean. As controls, 241 nonexposed workers (116 men and 125 women) were recruited either from the same factories or from factories in the same regions. There was an increased prevalence of subjective symptoms in the exposed workers which were apparently related to the effects on the central nervous system and to the local effects on the eyes, the nose, and the throat, although dose-dependency of the symptoms was evident in only a limited number of cases, possibly because the intensity of exposure was rather low. It was further observed that the findings of hematology and serum biochemistry in respect of liver and kidney functions were generally negative, showing that xylenes are not toxic to the hematopoietic organs, the liver, or the kidney.     

Occupational chronic exposure to organic solvents

Summary A group of printing workers (n = 34) exposed to toluene was examined according to the concentrations of hippuric acid, phenol, o-cresol, and (m+p)-cresol in urine. The average concentration in the air of the workroom was 23 ppm. It is shown that, besides hippuric acid, small amounts of o-cresol. which is not a normal constituent of urine, were formed from toluene. The occurrence of o-cresol could be proved by mass spectrometry. On account of the small amounts of benzene present in industrially used toluene—in this case 0.025%—the average concentration of phenol in urine of the exposed group was significantly higher statistically than in urine from the controls .     

Occupational chronic exposure to organic solvents

Summary Seventeen persons (2 women and 15 men), who were exposed to glycolethers in a varnish production plant, were examined according to their external and internal solvent exposure. The workers in the production plant (n =12) were exposed to average concentrations of ethoxyethanol, ethoxyethyl acetate, butoxyethanol, 1-methoxypropanol-2, 2-methoxypropyl-1-acetate and xylene of 2.8; 2.7; 1.1; 7.0; 2.8 and 1.7 ppm. In the air of the store (n = 3) and in the laboratory (n = 2) only minor concentrations of xylene respectively xylene and ethoxyethyl acetate could be measured. Internal exposure was estimated by measuring butoxyethanol (BE) in blood as well as ethoxyacetic acid (EAA) and butoxyacetic acid (BAA) in urine samples. Urine samples were taken pre- and post-shift. As expected, the highest values were found in the varnish production. The average post shift concentrations of BE, EAA and BAA were 121.3 g/l; 167.8 and 10.5 mg/l. The relatively high concentrations of EAA and BAA in pre-shift samples can be explained by the long half-lives of these metabolites. According to our findings most of the glycolethers were taken up through the skin. Comparing our results with those reported in the literature we think that a future tolerable limit value for the concentration of ethoxyacetic acid in urine should be in the order of 100 to 200 mg/l.     

Occupational chronic exposure to organic solvents

Summary Two groups of workers occupationally exposed to glycol ethers in a varnish production plant or the ceramic industry were examined. For 19 persons the external and internal exposure was assessed on the Monday and Tuesday after an exposure-free weekend. In the varnish production area the concentrations of 2-ethoxy-ethanol (EE) 2-ethoxyethyl acetate (EEAc), and 2-butoxyethanol (BE) in air averaged 2.9, 0.5, and 0.5 ppm, respectively, on the Monday, and 2.1, 0.1, and 0.6 ppm, respectively, on the Tuesday. At the same workplaces the mean urinary 2-ethoxyacetic acid (EAA) and 2-butoxyacetic acid (BAA) concentrations were 53.2 and 0.2 mg/l on Monday preshift and 53.8 and 16.4 mg/l on Tuesday postshift. The results show that glycol ethers are very well absorbed through the skin. Therefore biological monitoring is indispensable. To study the kinetics of the toxic metabolite, 17 persons were examined for their excretion of EAA in urine during an exposure-free weekend. The median values of the calculated half-times were 57.4 and 63.4 h, respectively, which are longer than the values presented in literature until now. According to our calculations the limit value should not exceed 50 mg EAA per liter of urine, which is the current German biological tolerance value (BAT value) for EAA in urine. The maximum concentration value at the work place (MAK value) for EE and EEAc in air should be revised. Finally, the subjects from the varnish production plant as well as a group of reference persons were studied for cytogenetic effects of glycol ethers (sister chromatid exchange, micronucleus test). Such effects could not be detected.     

Occupational chronic exposure to organic solvents

Summary A study was carried out among 20 workers employed in a printing, office at three different work places (methanol concentration: 85, 101, and 134 ppm) to determine whether the concentration of formic acid in blood or urine and the methanol content of alveolar air permit the estimation of methanol exposure.For this purpose blood, urine, and end expiratory air were collected at the beginning and the end of the shift. For comparison formic acid concentrations were determined in the morning and in the afternoon in blood and urine of 36 and 15 control persons, respectively.The concentration of formic acid in blood increased significantly from 3.2 ± 2.4 mg/l before to 7.9 ± 3.2 mg/l after the shift in the exposed workers (mean increase 4.7 ± 3.8 mg/l). The corresponding concentrations in urine were 13.1 ± 3.9 mg/l and 20.2 ± 7 mg/l, respectively, with a mean increase of 7.1 ± 5.3 mg/l. This difference is also significant. On the contrary, in the control groups there was a small but significant decrease of formic acid concentration in blood from 5.6 ±4.5 mg/l in the morning to 4.9 ± 4.2 mg/l in the afternoon. In urine, the formic acid concentrations in the morning (11.9 ± 6.4 mg/l) and in the afternoon (11.7 ±5.6 mg/l) were not significantly different. The increase of formic acid concentration in blood during the shift is the most useful parameter for monitoring methanol exposed persons. In contrast determinations of methanol concentrations in the ambient air or in the exhaled air are only crude estimates.(Direktor: Prof. Dr. G. Lehnert)     

Occupational chronic exposure to organic solvents

Summary Twenty persons occupationally exposed to methanol were examined according to their methanol levels in blood and urine and their formic acid excretion. An 8-h exposure to a methanol concentration of 93 ml/m³ (geometric mean) in the air at the working area caused average methanol levels in blood and urine of (8.9 ± 14.7) mg/l and (21.8 ± 20.0) mg/l, respectively, and a mean formic acid excretion of (29.9 ± 28.6) mg/l. These average concentrations for the exposed group showed statistically significant increases compared to those of a control group. For the methanol workers we succeeded in] correlating their methanol levels in blood and urine. When considering the possible application of these parameters for biological monitoring, difficulties were encountered, especially for the individual case from the overlapping range in the concentrations of exposed and unexposed persons for each of the applied parameters. This range is minimum for the methanol concentration in urine. About 80% of the urinary levels from the methanol workers lies above the upper limit within the control group range. Based on our results a rough estimate shows the corresponding methanol content in urine to be about 40 mg/l for an 8-h exposure at 200 ml/m³ (German MAK value).     

Possible preferential metabolism of xylene isomers following occupational exposure to mixed xylenes

Objectives: Solvent exposures commonly involve mixtures of substances or mixtures of isomers of a single solvent. These may be metabolised through common pathways, resulting in the potential for metabolic interactions. These may then lead to accumulation of solvent or metabolic intermediates, some of which may be toxic. This paper describes a pilot study conducted to determine the correlation between airborne xylene isomers and the appearance of methylhippuric acid (MHA) isomers in urine of workers exposed mainly to xylene. The project also aimed to determine whether there is preferential metabolism of any isomer by comparison of the ratios of airborne isomers with the ratios of metabolite isomers appearing in urine. Subjects and methods: A total of 12 workers (11 male, 1 female) were recruited into this study, with 2 of the participants providing samples on more than one occasion. Workers included flooring contractors (5), printers (2), chemical manufacturers (2), histology technicians (2) and one householder using a xylene-based varnish. Subjects were aged between 24 and 48 years (37.6 ± 2.0 years; mean ± SEM). After giving informed consent, workers provided a prework and postwork urine sample on a midweek work day. Samples were stored frozen prior to analysis. Breathing-zone air samples were collected using personal air samplers at 50 ml/min. Solvents were trapped on activated-charcoal sampling tubes. Subjects wore pumps for 18–304 (178 ± 24) min on the same day on which urine samples were collected. Results: Xylene exposures ranged from 1.6 to over 7000 ppm. In all, 7 of 16 measurements exceeded the Australian TWA standard of 80 ppm. Two of the flooring contractors wore respiratory protective equipment (RPE) and the two histopathology technicians used workplace ventilation systems. Total urinary MHA output ranged from 10 to 8000 mmol/mol creatinine, with 6 of 16 samples exceeding the modified biological exposure index of 702 mmol/mol. Correlations between airborne concentrations of individual xylene isomers and their corresponding MHA isomers were poor but improved when workers using RPE were excluded from the analysis. Gradients of the regression lines (millimoles of MHA per mole of creatinine per parts per million of xylene) were 3.2 for o-isomers, 7.0 for p-isomers, and 14.4 for m-isomers. Comparisons of isomer ratios of xylene in air were made with the corresponding ratio of MHA isomers in urine. These revealed higher ratios of m-MHA to other MHA isomers than those of m-xylene to the other xylene isomers. The MHA isomer ratios were expected to be the same as the airborne xylene isomer ratios if there were no preferential elimination of any isomer. m-MHA appeared in urine in a greater proportion than would be predicted from the proportion of m-xylene detected in air. The time course of the appearance of MHA isomers in urine also suggests that interactions were taking place, with m-MHA appearing in high proportion in urine following several days of repeated heavy xylene exposure. On a single moderate exposure, m-MHA appeared initially in high proportion in the first few hours but was undetectable in urine after 18 h. p-MHA was detectable for up to 6 h after exposure, and o-MHA remained detectable after 18 h. Conclusions: This study suggests that excretion of m-MHA in urine is favoured over that of the other isomers following exposure to mixed xylenes. This is independent of airborne xylene isomer composition and suggests that the metabolism of m-xylene occurs preferentially to that of the other isomers. It is not clear at which step in the metabolism of xylene this preference occurs, although other work indicates that the initial oxidation of xylene to methylbenzyl alcohol by cytochrome P450 2E1 occurs at the same rate for each isomer. These findings suggest that there is potential for metabolic interactions between xylene isomers and that these may be the basis for xylene toxicity. Received: 11 May 1998 / Accepted: 15 October 1998     

Occupational chronic exposure to organic solvents XII. O-cresol excretion after toluene exposure

Summary Thirty-five printing workers were investigated according to their external and internal exposure to toluene. The concentration of toluene in the air of the working place was determined using stationary air sampling and gas chromatography. To determine the levels of toluene in blood as well as the concentrations of o-cresol, hippuric acid, and phenol in urine, biological specimens were collected at the end of exposure. The parameters were determined by gas chromatography and gas chromatography/mass spectrometry. According to our results, o-cresol concentrations higher than 5.3 mg per litre of post-shift urine might indicate an external exposure higher than the present MAK-value of 200 ppm.     

Ambient monitoring and biomonitoring of workers exposed to N-methyl-2-pyrrolidone in an industrial facility

Objectives: The exposure of seven workers and three on-site study examiners to N-methyl-2-pyrrolidone (NMP) was studied in an adhesive bonding compound and glue production facility. Methods: Airborne NMP was analysed by personal and stationary sampling on activated charcoal tubes. NMP and its main metabolites, 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI), were analysed in pre-shift and post-shift spot urine samples by gas chromatography-mass spectrometry. The workers were examined with respect to irritation of the eyes, the mucous membranes and the skin, and health complaints before and after the work-shift were recorded. Results: The time-weighted average concentration of NMP in most work areas varied between 0.2 and 3.0 mg/m³. During the manual cleaning of stirring vessels, valves and tools, 8-h TWA exposures of up to 15.5 mg/m³ and single peak exposures of up to 85 mg/m³ were observed. NMP and its metabolites were detected in two pre-shift urine specimens. NMP and 5-HNMP concentrations in post-shift urine samples of five workers and three on-site study examiners were below 125 μg/g creatinine and 15 mg/g creatinine, respectively, while two vessel-cleaning workers showed significantly higher urinary NMP concentrations of 472 and 711 μg/g creatinine and 5-HNMP concentrations of 33.5 and 124 mg/g creatinine. 2-HMSI was detectable in four post-shift samples (range: 1.6–14.7 mg/g creatinine). The vessel cleaner with the highest NMP exposure reported irritation of the eyes, the upper respiratory tract and headaches. Conclusions: The results of this study indicate a relatively low overall exposure to NMP in the facility. An increased uptake of NMP occurred only during extensive manual vessel cleaning. Health complaints associated with NMP exposure were recorded in one case and might be related to an excessive dermal exposure due to infrequent and inadequate use of personal protective equipment.     

Application of biological monitoring to the quantitative exposure assessment for neuropsychological effect by chronic exposure to organic solvents

Objective: Quantitative exposure assessment became more common as a result of attempts to reduce nondifferential exposure misclassification and to observe a steeper exposure-response relationship. Several exposure variables were compared in a demonstration of the exposure-response relationship between neuropsychological abnormality and long-term exposure to organic solvents in workers at one shipyard. Method: Environmental monitoring and biological monitoring were performed to evaluate the exposure of the workers to organic solvents. Cumulative exposure (CE) and lifetime-weighted average exposure variables were developed with both environmental and biological monitoring data. A neuropsychological questionnaire and a function test for confirmation of a disorder or dysfunction in attention, executive function, visuospatial, and constructional abilities, learning and memory, and psychomotor function were performed. Results: The abnormal rate in neuropsychological diagnosis was 9.3% in the exposed group, which was much higher than the 2.1% rate obtained in the nonexposed group (P < 0.01). The neuropsychological abnormal rate showed a significant dose-response association with CE created with biological monitoring data. The results also suggest that biological monitoring can provide impressive and effective information for quantitative exposure assessment, even in epidemiology studies. Received: 2 April 1998 / Accepted: 23 September 1998     

Urinary methylhippuric acid isomer levels after occupational exposure to a xylene mixture

Summary The quantitative relationship between exposure to xylene vapor and urinary excretion of methylhippuric acid (MHA) isomers were studied in the second half of a working week. The participants in the study were 121 male workers engaged in dip-coating of metal parts who were predominantly exposed to three xylene isomers. The intensity of exposure measured by diffusive sampling during an 8-h shift was such that the geometric mean vapor concentration was 3.8 ppm for xylenes (0.8 ppm for o-xylene, 2.1 ppm for m-xylene, and 0.9 ppm for p-xylene), 0.8 ppm for toluene, and 0.9 ppm for ethylbenzene. Urine samples were collected at the end of the shift and analyzed for metabolities by HPLC. The statistical analysis showed that there is a linear relationship between the intensity of exposure to xylenes and the concentration of MHA in urine, that the regression line passes very close to the origin, and that the increment in observed (i.e., noncorrected) MHA concentrations as a function of increasing xylene concentration was 17.8 mg × 1^–1 ppm^–1. Further examination on the basis on individual xylene isomers showed that the slopes of the regression lines for o- and m-isomers were similar (i.e., 17.1 and 16.6 mg l^–1 ppm^–1, respectively), whereas that for p-xylene was larger (21.3 mg l^–1 ppm^–1).     

Behavioural evaluation of workers exposed to mixtures of organic solvents.

Reports from Scandinavia have suggested behavioural impairment among long term workers exposed to solvents below regulatory standards. A cross sectional study of behavioural performance was conducted among printers and spray painters exposed to mixtures of organic solvents to replicate the Scandinavian studies and to examine dose-response relationships. Eligible subjects consisted of 640 hourly workers from four midwestern United States companies. Of these, 269 responded to requests to participate and 240 were selected for study based on restrictions for age, sex, education, and other potentially confounding variables. The subjects tested had been employed on average for six years. Each subject completed an occupational history, underwent a medical examination, and completed a battery of behavioural tests. These included the Fitts law psychomotor task, the Stroop colour-word test, the Sternberg short term memory scanning test, the short term memory span test, and the continuous recognition memory test. Solvent exposure for each subject was defined as an exposed or non-exposed category based on a plant industrial hygiene walk-through and the concentration of solvents based on an analysis of full shift personal air samples by gas chromatography. The first definition was used to maintain consistency with Scandinavian studies, but the second was considered to be more accurate. The average full shift solvent concentration was 302 ppm for the printing plant workers and 6-13 ppm for the workers at other plants. Isopropanol and hexane were the major components, compared with toluene in Scandinavian studies. Performance on behavioural tests was analysed using multiple linear regression with solvent concentration as an independent variable. Other relevant demographic variables were also considered for inclusion. No significant (p greater than 0.05) relation between solvent concentration and impairment on any of the 10 behavioural variables was observed after controlling for confounding variables. Exposed/non-exposed comparisons showed a significantly poorer digit span among those exposed, but this has not been generally reported in the Scandinavian studies. The medical examination showed no abnormalities of clinical significance. The inability to replicate the findings of the Scandinavian studies could have been due to the shortness of the duration of workers' exposure, the type of solvents in the mixtures, use of different behavioural tests, or to selection factors.     

Occupational medicine monitoring of workers exposed to benzene

Based on the present level of perception of the benzene biotransformation, the influence of reactive metabolites on the haematopoetic system - maintaining low MAK rates of 5 mg/m3 and below them - is presented. Consequences for the rate of the biological exposition test utilized at present result from this statement. The importance of a regular SCE determination in circulating lymphocytes, of the longtermed examination of possible damages of sperm and the differentiated analysis of individual kinds of lymphocytes, incl. of the cell-mediating immunity is emphasized besides the performance of a regular supervision of the external exposition, i.e. by means of personal dosimeters. To clarify the benzene influence, the research should be orientated on the damages of the cytoskeleton and the stroma cells within the haematopoetic system.     

Prenarcotic and neuraesthenic symptoms among Dutch workers exposed to organic solvents.

A population of 379 Dutch workers exposed to organic solvents was compared with a non-exposed population of 443 workers with regard to the prevalence of prenarcotic and neuraesthenic symptoms. Participants completed a questionnaire to collect information about their occupational history, exposure to organic solvents, and the occurrence of symptoms. The results of the study indicated that workers exposed to solvents have a higher reporting rate of prenarcotic symptoms than workers not exposed to solvents. The prevalence of chronic neurotoxic effects, however, in the form of neuraesthenic symptoms was only weakly associated with reported exposure to organic solvents. The influence of work stress in the development of these symptoms is perhaps more important than the role of exposure to organic solvents. It is concluded that the organic solvent syndrome type I, as defined by an international workshop, is not an important health hazard among Dutch painters.     

Excretion of methylhippuric acids in urine of workers exposed to a xylene mixture: comparison among three xylene isomers and toluene

Summary The correlation between exposure to three xylene isomers and resulting urinary excretion of corresponding methylhippuric acid (MHA) isomers was studied among 175 Chinese workers of both sexes who had been predominantly exposed to xylenes (exposure to xylenes accounting for 70% or more of the total exposure on a ppm basis). Nonexposed controls (281 men and women) were also studied to define the background level of MHAs in urine. The solvent exposure of xylene-exposed workers during their workshift was monitored by diffusive sampling of breathing zone air, and MHAs in shift-end urine were determined by high-performance liquid chromatography. Regression analysis showed that the concentration of each MHA isomer correlated significantly with the time-weighted average intensity of exposure to the corresponding xylene isomer, and therefore the correlation between the sum of three xylene isomers in air and that of three MHA isomers in urine was also significant; the slope of the regression line was essentially the same among the three isomers. The calculated regression line suggested that the urinary MHA level after hypothetical exposure to xylenes at 100 ppm will be somewhat less than the proposed biological exposure index and biological tolerance value. Two social habits of smoking and drinking in combination suppressed the conversion of xylenes to MHAs in male workers.     

Studies of transferrin in serum of workers exposed to organic solvents.

Earlier studies have shown that determination of the serum concentration of different forms of transferrin (isotransferrins) may be used to detect hepatic effects caused by alcohol abuse. The isotransferrin variant with an isoelectric point of 5.7 has been compared with the total amount of serum transferrin in order to study hepatic effects caused by occupational exposure to organic solvents. Eighteen workers from a paint industry were tested before and after their holiday and compared with two different groups, a total of 60 subjects. The solvent workers had significantly higher values both before and after their holiday. This suggests that the effects on the liver caused by organic solvents are similar to those caused by alcohol abuse and that this is a long term effect. The level of exposure to organic solvents was below the Swedish threshold limit values.