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Biomedical subjects

G Johanson

Publications and source records attributed to G Johanson.

At least 19 recordsLinked to original sources
PubMed2002

Are women more sensitive than men to 2-propanol and m-xylene vapours?

AIMS: To evaluate possible differences between men and women in acute health effects after controlled short term chamber exposure to vapours of two common organic solvents. METHODS: Fifty six healthy volunteers (28 per sex) were exposed to 150 ppm 2-propanol, 50 ppm m-xylene, and clean air for two hours at rest. The subjects rated symptoms on a visual analogue scale before, during, and after the exposure. Blinking frequency was measured continuously during exposure. Pulmonary function, nasal swelling, inflammatory markers (lysozyme, eosinophilic cationic protein, myeloperoxidase, albumin) in nasal lavage and colour vision (Lanthony D-15 desaturated panel) were measured before and at 0 and 3 hours after the exposure. RESULTS: There were no significant sex differences in response to solvent exposure with respect to blinking frequency, lung diffusing capacity, nasal area and volume, inflammatory markers in nasal lavage, and colour vision. Increased symptoms were rated by both sexes for nearly all 10 questions during exposure to 2-propanol or m-xylene, most increases being significant at one time point at least. The rating of "discomfort in the throat or airways" increased more in women during exposure to 2-propanol or m-xylene. During exposure to 2-propanol the rating of "fatigue" was more increased in men after one hour, but more increased in women after two hours of exposure. With regard to pulmonary function, women had small but significant decreases in FVC, FEV(1)/FVC, and FEF(75) three hours after exposure to m-xylene, but only the decrease in FVC was significantly different from that in men. CONCLUSION: Our results suggest that women are slightly more sensitive than men to the acute irritative effects of 2-propanol and m-xylene vapours.

2-Propanol↗
PubMed2001

A Bayesian analysis of the influence of GSTT1 polymorphism on the cancer risk estimate for dichloromethane.

The carcinogenicity of dichloromethane (DCM) is related to metabolic activation mediated by glutathione transferase theta 1 (GSTT1), whereas oxidation serves as a detoxification pathway. The aim of this study was to calculate the excess cancer risk from DCM, using Bayesian statistics. In a first step, a previously developed population physiologically based pharmacokinetic (PBPK) model for DCM was simultaneously fitted to extensive human toxicokinetic data from 27 male volunteers exposed to 250-1000 ppm DCM (Astrand et al. Scand. J. Work Environ. Health 1, 78-94, 1975; Engström and Bjurström, Scand. J. Work Environ. Health 7, 215-224, 1977) using Markov chain Monte Carlo simulation. Improved population estimates were obtained for the PBPK model parameters. In a second step, excess cancer risk was calculated for lifelong exposure to 1-1000 ppm DCM by Monte Carlo simulation. Data on GSTT1 gene frequencies in the Swedish population were used, including all three genotypes. Estimated mean and median excess risks were in general agreement with those previously derived (El-Masri et al. Toxicol. Appl. Pharmacol. 158, 221-230, 1999). However, we estimate higher excess risks at the upper confidence limits. Furthermore, our simulations suggest that 1% of the Swedish population is not covered by a factor 4.2-7.1 away from the mean target dose. The majority of the fraction of the population not covered was classified as GSTT1 homozygote. This indicates that a higher uncertainty factor than the commonly used 3.16 should be considered in noncancer risk assessment for substances with polymorphic bioactivation.

Administration, Inhalation↗
PubMed2001

Bayesian estimation of variability in adipose tissue blood flow in man by physiologically based pharmacokinetic modeling of inhalation exposure to toluene.

Due to the lipophilicity of many xenobiotics, the perfusion of fat tissue is of special interest in physiologically based pharmacokinetic (PBPK) modeling. In order to estimate inter- and intra-individual variability in fat tissue blood flow with exercise, a population PBPK model for toluene was fitted to experimental data from subjects exposed to toluene vapors (Carlsson, A., 1982. Exposure to toluene: uptake, distribution and elimination in man. Scand. J. Work Environ. Health 8, 43-55). Six male volunteers were exposed to 80 ppm toluene for two hours during rest and moderate to heavy exercise (50-150 W). Extensive data collection was made, including sampling of arterial blood, exhaled breath and subcutaneous fat tissue. The model was simultaneously fitted to the time courses of toluene in arterial blood, exhaled breath, and subcutaneous fat in the six individuals by Markov chain Monte Carlo (MCMC) simulation. In order to describe the experimental observations in subcutaneous fat accurately, the fat compartment was split in two. According to the analysis, the increased perfusion of perirenal fat associated with physical workload was best described if it was set to the same, elevated, level during all exercise levels, rather than scaled directly to the increase in oxygen uptake. No increase in subcutaneous fat perfusion could be detected at these exposure conditions.

Adipose Tissue↗
PubMed2001

Procedures for health risk assessment in Europe.

This report compares cancer classification systems, health risk assessment approaches, and procedures used for establishing occupational exposure limits (OELs), in various European countries and scientific organizations. The objectives were to highlight and compare key aspects of these processes and to identify the basis for differences in cancer classifications and OELs between various scientific organizations and countries. Differences in cancer classification exist in part due to differences in the ultimate purpose of classification and to the relative importance of different types of data (i.e., animal vs human data, mechanistic data, and data from benign vs malignant tumors). In general, the groups surveyed tend to agree on classification of chemicals with good evidence of carcinogenicity in humans, and agree less on classification of chemicals with positive evidence in animals and inadequate or limited evidence in humans. Most entities surveyed distinguish between genotoxic and nongenotoxic chemicals when conducting risk assessments. Although the risk assessment approach used for nongenotoxic chemicals is fairly similar among groups, risk assessment approaches for genotoxic carcinogens vary widely. In addition to risk assessment approaches, other factors which can affect OELs include selection of the critical effect, use of health-based vs technology-based exposure limits, and consideration of technological feasibility and socioeconomic factors.

Animals↗
PubMed2001

Assessing the reliability of PBPK models using data from methyl chloride-exposed, non-conjugating human subjects.

Physiologically based pharmacokinetic (PBPK) models are often optimized by adjusting metabolic parameters so as to fit experimental toxicokinetic data. The estimates of the metabolic parameters are then conditional on the assumed values for all other parameters. Meanwhile, the reliability of other parameters, or the structural model, is usually not questioned. Inhalation exposures with human volunteers in our laboratory show that non-conjugators lack metabolic capacity for methyl chloride entirely, and that elimination in these subjects takes place via exhalation only. Therefore, data from these methyl chloride exposures provide an excellent opportunity to assess the general reliability of standard inhalation PBPK models for humans. A hierarchical population PBPK model for methyl chloride was developed. The model was fit to the experimental data in a Bayesian framework using Markov chain Monte Carlo (MCMC) simulation. In a Bayesian analysis, it is possible to merge a priori knowledge of the physiological, anatomical and physicochemical parameters with the information embedded in the experimental toxicokinetic data obtained in vivo. The resulting estimates are both statistically and physiologically plausible. Model deviations suggest that a pulmonary sub-compartment may be needed in order to describe the inhalation and exhalation of volatile adequately. The results also indicate that there may be significant intra-individual variability in the model parameters. To our knowledge, this is the first time that the toxicokinetics of a non-metabolized chemical is used to assess population PBPK parameters. This approach holds promise for more elaborate experiments in order to assess the reliability of PBPK models in general.

Adult↗
PubMed2001

Acute health effects common during graffiti removal.

OBJECTIVE: The aim of this study was to identify possible health effects caused by different cleaning agents used in graffiti removal. METHODS: In 38 graffiti removers working 8-h shifts in the Stockholm underground system, the exposure to organic solvents was assessed by active air sampling, biological monitoring, and by interviews and a questionnaire. Health effects were registered, by physical examinations, porta7ble spirometers and self-administered questionnaires. The prevalence of symptoms was compared with 49 controls working at the underground depots, and with 177 population controls. RESULTS: The 8-h time-weighted average exposures (TWA) were low, below 20% of the Swedish permissible exposure limit value (PEL) for all solvents. The short-term exposures occasionally exceeded the Swedish short-term exposure limit values (STEL), especially during work in poorly ventilated spaces, e.g. in elevators. The graffiti removers reported significantly higher prevalence of tiredness and upper airway symptoms compared with the depot controls, and significantly more tiredness, headaches and symptoms affecting airways, eyes and skin than the population controls. Among the graffiti removers, some of the symptoms increased during the working day. On a group basis, the lung function registrations showed normal values. However, seven workers displayed a clear reduction of peak expiratory flow (PEF) over the working shift. CONCLUSIONS: Though their average exposure to organic solvents was low, the graffiti removers reported significantly higher prevalence of unspecific symptoms such as fatigue and headache as well as irritative symptoms from the eyes and respiratory tract, compared with the controls. To prevent adverse health effects it is important to inform the workers about the health risks, and to restrict use of the most hazardous chemicals. Furthermore, it is important to develop good working practices and to encourage the use of personal protective equipment.

Adult↗
PubMed2001

Physiologically based pharmacokinetic modeling of inhalation exposure of humans to dichloromethane during moderate to heavy exercise.

Dichloromethane (methylene chloride, DCM) is metabolized via two pathways in humans: mixed-function oxidases (MFO) and glutathione-S:-transferase (GST). Most likely, the carcinogenicity for DCM is related to metabolic activation of DCM via the GST pathway. However, as the two pathways are competing, the metabolic capacity for the MFO pathway in vivo is also of interest in risk assessment for DCM. Past estimates of MFO metabolism are based on the in vitro activity of tissue samples. The aim of the present study was to develop a population model for DCM in order to gain more knowledge on the variability of DCM inhalation toxicokinetics in humans, with main emphasis on the MFO metabolic pathway. This was done by merging published in vitro data on DCM metabolism and partitioning with inhalation toxicokinetic data (Astrand et al., 1975, Scand. J. Work.Environ. Health 1, 78-94) from five human volunteers, using the MCMC technique within a population PBPK model. Our results indicate that the metabolic capacity for the MFO pathway in humans is slightly larger than previously estimated from four human liver samples. Furthermore, the interindividual variability of the MFO pathway in vivo is smaller among our five subjects than indicated by the in vitro samples. We also derive a Bayesian estimate of the population distribution of the MFO metabolism (median maximum metabolic rate 28, 95% confidence interval 12-66 micromol/min) that is a compromise between the information from the in vitro data and the toxicokinetic information present in the experimental data.

Carcinogens↗
PubMed2000

Styrene oxide in blood, hemoglobin adducts, and urinary metabolites in human volunteers exposed to (13)C(8)-styrene vapors.

Styrene is used in the manufacture of plastics and polymers and in the boat-building industry. The major metabolic route for styrene in rats, mice, and humans involves conversion to styrene-7,8-oxide (SO). The purpose of this study was to evaluate blood SO, SO-hemoglobin (SO-Hb) adducts, and urinary metabolites in styrene-exposed human volunteers and to compare these results with data previously obtained for rodents. Four healthy male volunteers were exposed for 2 h during light physical exercise to 50 ppm (13)C(8)-styrene vapor via a face mask. Levels and time profiles of styrene in exhaled air, blood, and urine (analyzed by GC) and urinary excretion patterns of mandelic acid and phenylglyoxylic acid in urine (analyzed by HPLC) were comparable to previously published volunteer studies. Maximum levels of SO in blood (measured by GC-MS) of 2.5-12.2 (average 6.7) nM were seen after 2 h, i.e., in the first sample collected after exposure had ended. The styrene blood level in humans was about 1.5 to 2 times higher than in rats and 4 times higher than in mice for equivalent styrene exposures. In contrast the SO levels in human blood was approximately fourfold lower than in mice. The level of hydroxyphenethylvaline (determined by GC-MS-MS) in pooled blood collected after exposure was estimated as 0.3 pmol/g globin corresponding to a SO-Hb adduct increment of about 0.003 pmol/g and ppmh. NMR analyses of urine showed that a major portion (> 95%) of the excreted (13)C-derived metabolites was derived from hydrolysis of SO, while only a small percentage of the excreted metabolites (< 5%) was derived from metabolism via phenylacetaldehyde. Signals consistent with metabolites derived from other pathways of styrene metabolism in rodents (such as glutathione conjugation with SO or ring epoxidation) were not detected.

Carbon Isotopes↗
PubMed2000

Air and biological monitoring of solvent exposure during graffiti removal.

OBJECTIVE: The principal aim of the study was to estimate the level of exposure to organic solvents of graffiti removers, and to identify the chemicals used in different cleaning agents. A secondary objective was to inform about the toxicity of various products and to optimise working procedures. METHODS: Exposure to organic solvents was determined by active air sampling and biological monitoring among 38 graffiti removers during an 8-h work shift in the Stockholm underground system. The air samples and biological samples were analysed by gas chromatography. Exposure to organic solvents was also assessed by a questionnaire and interviews. RESULTS: Solvents identified were N-methylpyrrolidone (NMP), dipropylene glycol monomethyl ether (DPGME), propylene glycol monomethyl ether (PGME), diethylene glycol monoethyl ether (DEGEE), toluene, xylene, pseudocumene, hemimellitine, mesitylene, ethylbenzene, limonene, nonane, decane, undecane, hexandecane and gamma-butyrolactone. The 8-h average exposures [time-weighted average (TWA)] were below 20% of the Swedish permissible exposure limit value (PEL) for all solvents identified. In poorly ventilated spaces, e.g. in elevators etc., the short-term exposures exceeded occasionally the Swedish short-term exposure limit values (STEL). The blood and urine concentrations of NMP and its metabolites were low. Glycol ethers and their metabolites (2-methoxypropionic acid (MPA), ethoxy acetic acid (EAA), butoxy acetic acid (BAA), and 2-(2-methoxyethoxy) acetic acid (MEAA)) were found in low concentrations in urine. There were significant correlation between the concentrations of NMP in air and levels of NMP and its metabolites in blood and urine. The use of personal protective equipment, i.e. gloves and respirators, was generally high. CONCLUSIONS: Many different cleaning agents were used. The average exposure to solvents was low, but some working tasks included relatively high short-term exposure. To prevent adverse health effects, it is important to inform workers about the health risks and to restrict the use of the most toxic chemicals. Furthermore, it is important to develop good working procedures and to encourage the use of personal protection equipment.

Adult↗
PubMed2000

Toxicity review of ethylene glycol monomethyl ether and its acetate ester.

Ethylene glycol monomethyl ether (EGME) and its acetate ester (EGMEA) are highly flammable, colorless, moderately volatile liquids with very good solubility properties. They are used in paints, lacquers, stains, inks and surface coatings, silk-screen printing, photographic and photo lithographic processes, for example, in the semiconductor industry, textile and leather finishing, production of food-contact plastics, and as an antiicing additive in hydraulic fluids and jet fuel. EGME and EGMEA are efficiently absorbed by inhalation as well as via dermal penetration. Dermal absorption may contribute substantially to the total uptake following skin contact with liquids or vapours containing EGME or EGMEA. EGMEA is rapidly converted to EGME in the body and the two substances are equally toxic in animals. Therefore, the two substances should be considered as equally hazardous to man. Effects on peripheral blood, testes, and sperm have been reported at occupational exposure levels ranging between 0.4 and 10 ppm EGME in air, and with additional, possibly substantial, dermal exposure. Severe malformations and disturbed hematopoiesis have been linked with exposure to EGME and EGMEA at unknown, probably high, levels. Embryonic deaths in monkeys and impaired spermatogenesis in rabbits have been reported after daily oral doses of 12 and 25 mg per kg body weight, respectively. In several studies, increased frequency of spontaneous abortions, disturbed menstrual cycle, and subfertility have been demonstrated in women working in the semiconductor industry. The contribution of EGME in relation to other exposure factors in the semiconductor industry is unclear.

Animals↗
PubMed2000

Glutathione transferase T1 phenotype affects the toxicokinetics of inhaled methyl chloride in human volunteers.

The aim of the present study was to investigate how the genetic polymorphism in glutathione transferase T1 (GSTT1) affects the metabolism and disposition of methyl chloride in humans in vivo. The 24 volunteers (13 males and 11 females) who participated in the study were recruited from a group of 208 individuals previously phenotyped for GSTT1 by measuring the glutathione transferase activity with methyl chloride in lysed erythrocytes ex vivo. Eight individuals with high (+/+), eight with medium (+/0) and eight with no (0/0) GSTT1 activity were exposed to methyl chloride gas (10 p.p.m.) in an exposure chamber for 2 h. Uptake and disposition was studied by measuring the concentration of methyl chloride in inhaled air, exhaled air and blood. A two-compartment model with two elimination pathways corresponding to exhalation and metabolism was fitted to experimental data. The average net respiratory uptake of methyl chloride was 243, 158, and 44 micromol in individuals with high, intermediate and no GSTT1 activity, respectively. Metabolic clearance was high (4.6 l/min) in the +/+ group, intermediate (2.4 l/min) in the +/0 group, and close to zero in 0/0 individuals, while the exhalation clearance was similar in the three groups. No exposure related increase in urinary S-methyl cysteine was detected. However, gender and the GSTTl phenotype seemed to affect the background levels. In conclusion, GSTT1 appears to be the sole determinant of methyl chloride metabolism in humans. Thus, individuals with nonfunctional GSTT1 entirely lack the capacity to metabolize methyl chloride.

Administration, Inhalation↗
PubMed1999

Physiologically based modeling of 1,2,4-trimethylbenzene inhalation toxicokinetics.

A physiologically based toxicokinetic model was developed for inhalation exposure of 1,2,4-trimethylbenzene (TMB) in man. The model consists of six compartments for TMB and one compartment for the metabolite 3,4-dimethylhippuric acid (DMHA). Based on previous experimental findings from human exposures to TMB, liver metabolism was divided in two pathways, one of the first order and one of the Michaelis-Menten type. Muscle tissue was split in two compartments to account for working and resting muscle tissues during bicycle exercise. The model was used to investigate how various factors influence potential biomarkers of exposure, i.e., TMB in blood and exhaled air and DMHA in urine. Increasing the work load from rest to moderate exercise (100 W) more than doubled all biomarker levels end of shift. The effect on next morning levels was even more pronounced, illustrated by a fivefold increase in the DMHA excretion rate. Simulations of five daily 8-h exposures suggest that biomarker levels end of shift remain fairly constant whereas the levels prior to shift increase gradually during the week. This suggests that end of shift levels reflect the exposure of the same day whereas levels Friday morning reflect exposure during the entire working week. Simulations with randomly generated exposures show that the variability due to fluctuating exposure is lower next morning than end of shift. End of shift exhalation rate of TMB is more sensitive to fluctuation than TMB in venous blood and DMHA in urine. Biomarker levels for 25 ppm exposure at different sampling times are given.

Administration, Inhalation↗
PubMed1999

A compartmental model for the kinetics of mercury vapor in humans.

In an earlier study, we exposed nine healthy volunteers to known concentrations of mercury (Hg) vapor in air (median 399; range 365-430 micrograms/m3) for 15 min during light physical exercise (50 W) (Sandborgh-Englund, G., et al., Toxicol. Appl. Pharmacol. 150, 146-153, 1998). Exhaled air, urine, and plasma samples were collected. In the present study, the experimental observations from eight of these volunteers were subjected to an analysis with the aid of the software NONMEM. A four-compartment model, including two depot compartments to account for retention in lungs and kidneys, respectively, gave the best fit to the data. The fraction of dose excreted from the central compartment directly into urine was found to be positively correlated with the preexposure excretion rate of Hg via urine. The median half time in the respiratory depot compartment was estimated to 1.81 days (range 1.60-1.92). The median half time in the excretion depot was estimated to 63.2 days (range 12.8-98.9). The model was tested by simulating two experiments found in the literature and agreed well with these older data sets. Further simulations indicated that the excretion of Hg via urine would not reach a plateau until several months postexposure for most subjects.

Adult↗
PubMed1999

13C(2)-Labeled methyl tert-butyl ether: toxicokinetics and characterization of urinary metabolites in humans.

After exposure to methyl tert-butyl ether (MTBE), a gasoline additive, only one metabolite [tert-butyl alcohol (TBA), <1% of dose] has been identified in human urine [Nihlén, A., et al. (1998) Toxicol. Appl. Pharmacol. 148, 274-280]. In the study presented here, metabolites of MTBE were characterized by (1)H-decoupled (13)C NMR spectroscopy in urine obtained from four volunteers experimentally exposed to 50 ppm (13)C-labeled MTBE ([1,2-(13)C(2)]MTBE) vapor (facemask) for 2 h during a light physical work load (50 W). Chemical shifts for the two adjacent (13)C-labeled carbons in [1, 2-(13)C(2)]MTBE-derived metabolites were consistent with the shifts obtained for spiked standards of alpha-hydroxyisobutyric acid (HBA) and 2-methyl-1,2-propanediol (MPD). NMR signals were not detected for labeled MTBE, TBA, or possible MTBE-derived conjugates. Quantification of HBA and MPD was performed by NMR for two urine samples (collected 20 h after exposure). One subject had 11% HBA and 1% MPD, and the other individual had 3% HBA and 1% MPD in the urine, expressed as a percentage of MTBE uptake. This indicates that HBA and MPD occur at significantly higher levels in the urine (detected by NMR) than MTBE and TBA (detected by GC). To our knowledge, this is the first characterization of MTBE metabolites, other than TBA, in humans. Further urine, blood, and expired air were collected up to 22 h after exposure, and the toxicokinetics of MTBE, TBA, and acetone were determined by GC. Low relative uptake (39%), a low level of postexposure exhalation of MTBE (17%), and low recovery of TBA in the urine (<1%) were observed. The same subjects had previously been exposed to unlabeled MTBE in a whole-body exposure study [Nihlén, A., et al. (1998) Toxicol. Appl. Pharmacol. 148, 274-280], and the toxicokinetics of MTBE and TBA in this facemask exposure did not differ from the previous whole-body chamber exposure.

Adult↗
PubMed1999

Toxicokinetic interactions between orally ingested chlorzoxazone and inhaled acetone or toluene in male volunteers.

The aim of this study was to examine if the drug chlorzoxazone has any influence on the toxicokinetics of acetone and toluene. Chlorzoxazone is mainly metabolized by the same enzyme (Cytochrome P450 2E1) as ethanol and many other organic solvents. Ten male volunteers were exposed to solvent vapor (2 h, 50 watt) in an exposure chamber. Each subject was exposed to acetone only (250 ppm), acetone + chlorzoxazone, toluene (50 ppm) only, toluene + chlorzoxazone, and chlorzoxazone only. Chlorzoxazone (500 mg) was taken as two tablets 1 h prior to solvent exposure. Samples of blood, urine and exhaled air were collected before, during and until 20 h post exposure. The samples were analyzed by head-space gas chromatography (acetone and toluene) and high-performance liquid chromatography (chlorzoxazone, 6-hydroxychlorzoxazone and hippuric acid). The time-concentration curves of acetone and toluene in blood were fitted to one- and four-compartment toxicokinetic models, respectively. Intake of chlorzoxazone was associated with slight but significant increases in the area under the blood concentration-time curve (AUC) and steady state concentration of acetone in blood, along with non significant tendencies to an increased half time in blood and an increased AUC in urine. Except for a delayed excretion of hippuric acid in urine, no effects on the toluene toxicokinetics were seen after chlorzoxazone treatment. Small increases in chlorzoxazone plasma levels were seen after exposure compared to chlorzoxazone alone. These interactions, although statistically significant, seem to be small compared to the interindividual variability on metabolism and toxicokinetics.

Acetone↗
PubMed1999

Physiologically based toxicokinetic modeling of inhaled ethyl tertiary-butyl ether in humans.

A physiologically based toxicokinetic (PBTK) model was developed for evaluation of inhalation exposure in humans to the gasoline additive, ethyl tertiary-butyl ether (ETBE). PBTK models are useful tools to relate external exposure to internal doses and biological markers of exposure in humans. To describe the kinetics of ETBE, the following compartments were used: lungs (including arterial blood), liver, fat, rapidly perfused tissues, resting muscles, and working muscles. The same set of compartments and, in addition, a urinary excretion compartment were used for the metabolite tertiary-butyl alcohol (TBA). First order metabolism was assumed in the model, since linear kinetics has been shown experimentally in humans after inhalation exposure up to 50 ppm ETBE. Organ volumes and blood flows were calculated from individual body composition based on published equations, and tissue/blood partition coefficients were calculated from liquid/air partition coefficients and tissue composition. Estimates of individual metabolite parameters of 8 subjects were obtained by fitting the PBTK model to experimental data from humans (5, 25, 50 ppm ETBE, 2-h exposure; Nihlén et al., Toxicol. Sci., 1998; 46, 1-10). The PBTK model was then used to predict levels of the biomarkers ETBE and TBA in blood, urine, and exhaled air after various scenarios, such as prolonged exposure, fluctuating exposure, and exposure during physical activity. In addition, the interindividual variability in biomarker levels was predicted, in the eight experimentally exposed subjects after a working week. According to the model, raising the work load from rest to heavy exercise increases all biomarker levels by approximately 2-fold at the end of the work shift, and by 3-fold the next morning. A small accumulation of all biomarkers was seen during one week of simulated exposure. Further predictions suggested that the interindividual variability in biomarker levels would be higher the next morning than at the end of the work shift, and higher for TBA than for ETBE. Monte Carlo simulations were used to describe fluctuating exposure scenarios. These simulations suggest that ETBE levels in blood and exhaled air at the end of the working day are highly sensitive to exposure fluctuations, whereas ETBE levels the next morning and TBA in urine and blood are less sensitive. Considering these simulations, data from the previous toxicokinetic study and practical issues, we suggest that TBA in urine is a suitable biomarker for exposure to ETBE and gasoline vapor.

Biomarkers↗
PubMed1998

Experimental exposure to methyl tertiary-butyl ether. I. Toxicokinetics in humans.

Methyl tertiary-butyl ether (MTBE) is widely used in gasoline as an oxygenate and octane enhancer. The aim of this study was to evaluate the uptake, distribution, metabolism, and elimination of MTBE in humans. Ten healthy male volunteers were exposed to MTBE vapor (5, 25, and 50 ppm) on three different occasions during 2 h of light physical exercise (50 W). MTBE and the metabolite tertiary-butyl alcohol (TBA) were monitored in exhaled air, blood, and urine. Blood and urine were collected at selected time intervals, during and up to 3 days after the exposure, and analyzed by head space gas chromatography. MTBE in exhaled air was collected with sorbent sample tubes and subsequently analyzed by gas chromatography. The respiratory uptake of MTBE was rather low (42-49%), and the respiratory exhalation was high (32-47%). A relatively low metabolic blood clearance (0.34-0.52 L/h/kg) was seen compared to many other solvents. The kinetic profile of MTBE in blood could be described by four phases, and the average half-lives were 1 min, 10 min, 1.5 h, and 19 h. The post-exposure decay curve of MTBE in urine was separated into two linear phases, with average half-lives of 20 min and 3 h. The average post-exposure half-lives of TBA in blood and urine were 10 and 8.2 h, respectively. The urinary excretion of MTBE and TBA was less than 1% of the absorbed dose, indicating further metabolism of TBA, other routes of metabolism, or excretion. The kinetics of MTBE and TBA were linear up to the highest exposure level of 50 ppm. We suggest that TBA in blood or urine is a more appropriate biological exposure marker for MTBE than the parent ether itself.

Adult↗