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Biomedical subjects

G Johanson

Publications and source records attributed to G Johanson.

At least 37 records · Page 2Linked to original sources
PubMed1998

Experimental exposure to methyl tertiary-butyl ether. II. Acute effects in humans.

Methyl tertiary-butyl ether (MTBE) is widely used in gasoline as an oxygenate and octane enhancer. Acute effects, such as headache, nausea, and nasal and ocular irritation, have been associated with the exposure to gasoline containing MTBE. The aim of this study was to assess acute health effects up to the Swedish occupational exposure limit value, both with objective methods and a questionnaire. Ten healthy male volunteers were exposed to MTBE vapor for 2 h at three levels (5, 25, and 50 ppm), during light physical work (50 W). All subjects rated the degree of irritative symptoms, discomfort, and CNS effects before, during, and after all three exposure occasions using a questionnaire. Answers were given on a 100-mm visual analog scale, graded from "not at all" to "almost unbearable." Ocular (redness, tear film break-up time, self-reported tear film break-up time, conjunctival epithelial damage, and blinking frequency) and nasal (mouth and nasal peak expiratory flow, acoustic rhinometry, biochemical inflammatory markers, and cells in nasal lavage) measurements were performed mainly at the highest exposure level. The ratings of solvent smell increased dramatically (ratings up to 50% of the scale) as the volunteers entered the chamber and declined slowly with time (p < 0.05, repeated-measures ANOVA). All other questions were rated from "not at all" to "hardly at all" (0-10% of the scale) with no significant relation to exposure. The eye measurements showed no effects of MTBE exposure. Blockage index, a measure of nasal airway resistance calculated from the peak expiratory flows, increased significantly after exposure; however, the effect was not related to exposure level. In addition, a nonsignificant tendency of decreased nasal volume was seen in the acoustic rhinometry measurements, but with no clear dose-effect relationship. In conclusion, our study suggests no or minimal acute effects of MTBE vapor upon short-term exposure at relatively high levels.

Adult↗
PubMed1998

The absorption, blood levels, and excretion of mercury after a single dose of mercury vapor in humans.

Nine healthy volunteers without amalgam fillings were exposed to 400 micrograms/m3 mercury vapor (Hg0) for 15 min, corresponding to 5.5 nmol Hg0/kg body wt (median range: 4.4-7.2). Frequent sampling of blood, urine, and exhaled air was performed for 30 days after exposure. The median retention of Hg0 was 69% of the inhaled dose. During the first 3 days after exposure 7.5-12% of the absorbed dose was lost by exhalation, with the median half time of Hg0 in expired breath being 2.0 days. In blood and plasma, a rapid absorption phase of Hg was seen, followed by a biexponential decline of the curves in both media. A substantial interindividual variation was observed in the area under the concentration-time curves of Hg in blood and plasma. In plasma the median half time of the second phase was 10 days. About 1.0% of the absorbed Hg was excreted via urine during the first 3 days after exposure, whereas the estimated amount excreted during 30 days ranged from 8 to 40%. In order to evaluate the chronic exposure to mercury from dental amalgam in the general population, the daily Hg dose from the fillings were estimated based on the plasma Hg levels found in subjects with amalgam fillings and on the plasma Hg clearance obtained in the present study. The daily Hg dose was estimated to 5-9 micrograms/day in subjects with an ordinary number of amalgam fillings.

Absorption↗
PubMed1998

Controlled ethyl tert-butyl ether (ETBE) exposure of male volunteers. I. Toxicokinetics.

Ethyl tert-butyl ether (ETBE) might replace methyl tert-butyl ether (MTBE), a widely used additive in unleaded gasoline. The aim of this study was to evaluate uptake and disposition of ETBE, and eight healthy male volunteers were exposed to ETBE vapor (0, 5, 25, and 50 ppm) during 2 h of light physical exercise. ETBE and the proposed metabolites tert-butyl alcohol (TBA) and acetone were analyzed in exhaled air, blood, and urine. Compared to a previous MTBE study (A. Nihlen et al., 1998b, Toxicol. Appl. Pharmacol. 148, 274-280) lower respiratory uptake of ETBE (32-34%) was seen as well as a slightly higher respiratory exhalation (45-50% of absorbed ETBE). The kinetic profile of ETBE could be described by four phases in blood (average half-times of 2 min, 18 min, 1.7 h, and 28 h) and two phases in urine (8 min and 8.6 h). Postexposure half-times of TBA in blood and urine were on average 12 and 8 h, respectively. The 48-h pulmonary excretion of TBA accounted for 1.4-3.8% of the absorbed ETBE, on an equimolar basis. Urinary excretion of ETBE and TBA was low, below 1% of the ETBE uptake, indicating further metabolism of TBA or other routes of metabolism and elimination. The kinetics of ETBE and TBA were linear up to 50 ppm. Based upon blood profile, levels in blood and urine, and kinetic profile we suggest that TBA is a more appropriate biomarker for ETBE than the parent ether itself. The acetone level in blood was higher after ETBE exposures compared to control exposure, and acetone is probably partly formed from ETBE.

Acetone↗
PubMed1998

Controlled ethyl tert-butyl ether (ETBE) exposure of male volunteers. II. Acute effects.

The aim of this study was to evaluate acute effects of ethyl tert-butyl ether (ETBE) in man after short-term exposure. ETBE may in the future replace methyl tert-butyl ether, a widely used oxygenate in unleaded gasoline. Eight healthy male volunteers were exposed to ETBE vapor for 2 h at four levels (0, 5, 25, and 50 ppm) during light physical exercise. The subjects rated irritative symptoms, discomfort, and central nervous system effects in a questionnaire. Ocular (eye redness, tear film break-up time, conjunctival epithelial damage, and blinking frequency), nasal (acoustic rhinometry and analysis of inflammatory markers and cells in nasal lavage fluid), and pulmonary (peak expiratory flow, forced expiratory volume in 1 s, forced vital capacity, vital capacity, and transfer factor) measurements were performed. Significantly increased ratings of solvent smell (p = 0.001, repeated-measures ANOVA) were seen during exposures and correlated to exposure levels. Furthermore, significantly elevated ratings of discomfort in throat and airways were seen during and after 50 ppm compared to the control exposure (p = 0.02). Increased nasal swelling (p = 0.001) and blinking frequency (p = 0.01) were noted at all exposure levels, but their magnitudes were not related to exposure levels. A slightly impaired pulmonary function was seen at 25 and 50 ppm, since forced vital capacity (p = 0.02) and vital capacity (p = 0.04) differed significantly from the clean air exposure. Although the impairments seemed to fall within normal inter- and intraindividual variation and have no clinical relevance as such, it cannot be excluded that other individuals may react more severely than eight healthy male volunteers in this study.

Administration, Inhalation↗
PubMed1998

Toxicokinetics of organic solvents: a review of modifying factors.

This article reviews, with an emphasis on human experimental data, factors known or suspected to cause changes in the toxicokinetics of organic solvents. Such changes in the toxicokinetic pattern alters the relation between external exposure and target dose and thus may explain some of the observed individual variability in susceptibility to toxic effects. Factors shown to modify the uptake, distribution, biotransformation, or excretion of solvent include physical activity (work load), body composition, age, sex, genetic polymorphism of the biotransformation, ethnicity, diet, smoking, drug treatment, and coexposure to ethanol and other solvents. A better understanding of modifying factors is needed for several reasons. First, it may help in identifying important potential confounders and eliminating negligible ones. Second, the risk assessment process may be improved if different sources of variability between external exposures and target doses can be quantitatively assessed. Third, biological exposure monitoring may be also improved for the same reason.

Age Factors↗
PubMed1998

Pulmonary reactions after exposure to 3-methylfuran vapour, a fungal metabolite.

A case of obstructive pulmonary reaction with flu-like symptoms after exposure to 3-methylfuran is described. This compound is produced by fungi, and can be found in buildings with mould growth. Previous studies have shown that exposure to the substance might increase the prevalence of respiratory symptoms, and is pneumotoxic to animals at high concentrations.

Air Pollutants↗
PubMed1997

Inhalation toxicokinetics of 1,2,4-trimethylbenzene in volunteers: comparison between exposure to white spirit and 1,2,4-trimethylbenzene alone.

The objective of this study was to compare the toxicokinetics of inhaled 1,2,4-trimethylbenzene (1,2,4-TMB) in man after exposure to white spirit with that observed after exposure to 1,2,4-TMB alone. TMBs occur mainly in petroleum products and the TMBs or their metabolites have been suggested as suitable biomarkers of exposure to white spirit and other distillation products. The toxicokinetics were studied in 9 male, healthy volunteers exposed to solvent vapours in an exposure chamber for 2 h during a work load of 50 W. The subjects were exposed to 11 mg/m3 of 1,2,4-TMB on two occasions; during exposure to 1,2,4-TMB vapour alone and during exposure to 300 mg/m3 of white spirit. The 1,2,4-TMB isomer was analyzed in blood and exhaled air by gas chromatography. In addition, a major urinary metabolite of 1,2,4-TMB, 3,4-dimethylhippuric acid (3,4-DMHA), was analyzed by high performance liquid chromatography. Further the occurrence of acute effects was studied by means of a questionnaire. Irritation and central nervous system symptoms were recorded by ratings on a 100-mm visual analogue scale. Blood levels of 1,2,4-TMB and excretion rates of 3,4-DMHA in urine were markedly elevated both during and after exposure to white spirit as compared to exposure to TMB alone. Thus, it appears that components in white spirit inhibit the metabolic elimination of 1,2,4-TMB. This should be considered in biological exposure monitoring as well as in risk assessment. No irritation or central nervous system effects were reported at these conditions.

Administration, Inhalation↗
PubMed1997

Urinary excretion of dimethylhippuric acids in humans after exposure to trimethylbenzenes.

The aim of this study was to determine the urinary excretion of dimethylhippuric acids (DMHAs) in humans after experimental chamber exposure to trimethylbenzene (TMB) vapor. The DMHAs have been put forward as suitable biomarkers of exposure to products containing TMBs such as white spirit and petrol. Ten healthy male volunteers were exposed to TMB vapor in an exposure chamber for 2 h at a work load of 50 W. The subjects were exposed on four occasions, to 25 ppm of 1,2,4-TMB, 1,2,3-TMB, and 1,3,5-TMB, respectively, and 2 ppm of 1,2,4-TMB. Urine was collected from the onset of exposure until the following morning. All six possible DMHA isomers were analyzed by high-performance liquid chromatography. About 22% of the inhaled amount of 1,2,4-TMB was excreted as DMHAs within 24 h, mainly as 3,4-DMHA. The 24-h recovery of 1,2,3-TMB as DMHAs was 11%. Only 3% of the absorbed amount of 1,3,5-TMB was excreted as 3,5,-DMHA. The half-times of the different DMHA isomers ranged from 4 to 16 h. In addition to analysis of DMHAs, the excretion of unconjugated dimethylbenzoic acids in urine was estimated to account for approximately 3% of the dose of all TMBs. In conclusion, the urinary excretion of DMHA isomers may serve as a good indicator of TMB exposure. In this controlled short-term-exposure study the sum of excretion rate of several DMHA isomers reflected exposure more closely than did the excretion rate of any single DMHA.

Adult↗
PubMed1996

PBPK model for butadiene metabolism to epoxides: quantitative species differences in metabolism.

We have developed a physiologically based pharmacokinetic (PBPK) model for 1,3-butadiene (BD) and its first reactive metabolite 1,2-epoxybutene-3 (EB). This model contrasts with other published ones, in that it incorporates three important features: (I) reduced alveolar ventilation, based on experimental observations on a number of vapors and gases; (II) intrahepatic first-pass hydrolysis of EB, based on experimental observations with BD-EB, ethylene-ethylene oxide, and styrene-styrene oxide; (III) a two-substrate Michealis-Menten kinetic description of EB conjugation with GSH. We believe these features are essential for a correct toxicokinetic description of BD. The model was validated against a number of published experimental observations on BD, EB, and liver glutathione (GSH), kinetics made in vivo with rats and mice, including EB exhalation upon BD exposure and liver GSH depletion at high exposure levels of BD. According to our model, the relative internal doses of EB (expressed as the relation between steady-state concentrations or AUCs in mixed venous blood) are: mouse 1.6, rat 1.0, man 0.3. In the mouse, GSH depletion occurs after 6-9 h exposure at high concentrations resulting in a shift of the relative internal dose from 1.6 to between 2 and 3. The clear but relatively small mouse-rat difference in internal EB doses can only partly explain the marked species difference in cancer response between mice and rats exposed to BD.

Animals↗
PubMed1996

Toxicokinetics of inhaled trimethylbenzenes in man.

The objective of this study was to determine the uptake and disposition of inhaled trimethylbenzenes (TMBs) in man. The toxicokinetics were studied in 10 male, healthy volunteers exposed to TMB vapor in an exposure chamber for 2 hr during a work load of 50 W. The subjects were exposed on four occasions to 25 ppm of 1,2,4-TMB, 1,2,3-TMB, and 1,3,5-TMB, and to 2 ppm of 1,2,4-TMB. The TMB isomers were analyzed in blood, urine, and exhaled air by gas chromatography. The relative respiratory uptake was in the range 56-64%. The elimination of TMBs was moderate compared to other aromatic solvents, with a total blood clearance of 0.6-1.0 liter hr(-1) kg(-1). Large volumes of distribution (30-39 liters/kg) and long terminal half-lives of the TMBs in blood (78-120 hr) imply extensive accumulation in adipose tissue. Exhalation during and postexposure accounted for 20-37% of the absorbed amount, whereas the urinary excretion of unchanged TMBs was low (< or = 0.002%). The kinetics of 1,2,4-TMB seemed linear up to 25 ppm. In addition, the occurrence of symptoms of acute effects was studied by means of a questionnaire. The subjects rated the degree of irritation and central nervous system symptoms on a 100-mm visual analog scale. No discomfort was reported at these exposure conditions.

Administration, Inhalation↗
PubMed1995

Toxicokinetics and acute effects of MTBE and ETBE in male volunteers.

Methyl tertiary butyl ether (MTBE) is widely used in gasoline as an oxygenator and octane enhancer. There is also an interest in using the ethyl tertiary butyl (ETBE) and methyl tertiary amyl (TAME) ethers. We measured the blood, water, and olive oil/air partition coefficients in vitro of MTBE, ETBE, TAME and tertiary butyl alcohol (TBA), a metabolite of MTBE and ETBE. The results indicate similar uptake and distribution behavior for the three ethers and a slight affinity for fatty tissues. The partition coefficients of TBA indicate that this metabolite is not excreted via the lungs to any great extent and that it is preferentially distributed in body water. Further, we exposed 10 healthy male volunteers to MTBE vapor at 5, 25 and 50 ppm for 2 h during light physical exercise. Uptake and disposition were studied by measuring MTBE and TBA in inhaled and exhaled air, blood and urine. Low uptake, high post-exposure exhalation, and low blood clearance indicate slow metabolism of MTBE relative to many other solvents. A low recovery of TBA in urine (below 1% of uptake) indicates further metabolism of TBA. The concentration of MTBE and TBA in blood was proportional to exposure level suggesting linear kinetics up to 50 ppm. The half life of 7-10 h in blood and urine indicates that TBA would be more suitable than the parent compound as a biomarker for MTBE exposure. Subjective ratings (discomfort, irritative symptoms, CNS effects) and eye (redness, tear film break-up time, conjunctival damage, blinking frequency) and nose (peak expiratory flow, acoustic rhinometry, inflammatory markers in nasal lavage) measurements indicated no or minimal effects of MTBE.

Adult↗
PubMed1994

Inhalation toxicokinetics of butoxyethanol and its metabolite butoxyacetic acid in the male Sprague-Dawley rat.

A total of 16 male Sprague-Dawley rats were continuously exposed to 20 ppm or 100 ppm butoxyethanol (BE) vapor for 1, 2, 3, 4, 6, 8, 10, or 12 days. Urine was collected in 24-h intervals and stored at -70 degrees C. At the end of the exposure the animals were euthanized by decapitation and tissue samples of blood, muscle, liver and were rapidly collected and frozen to -70 degrees C. The samples were later derivatized and analyzed for BE and its major metabolite butoxyacetic acid (BAA) by electron capture gas chromatography. BE and BAA were rapidly distributed to the tissues examined. The concentration of BE in blood was slightly higher, and that of BAA markedly higher than in other tissues, indicating weak (BE) and pronounced (BAA) blood protein binding, respectively. BE was efficiently metabolized and the blood clearance averaged 2.6 l/h per kg, corresponding to a hepatic extraction ratio of about 0.75. The renal clearance of BAA (average 0.53 l/h per kg) corresponded to approximately 15% of the renal blood flow. The kinetics of BE and BAA were linear up to 100 ppm. There were no clear indications of changes in the toxicokinetics, such as metabolic induction or inhibition of metabolism or excretion, during the course of the exposure. The recovery of BAA in urine was 64% of the calculated inhaled amount of BE, on an equimolar basis.

Adaptation, Physiological↗
PubMed1993

A physiologically based pharmacokinetic model for butadiene and its metabolite butadiene monoxide in rat and mouse and its significance for risk extrapolation.

The gas 1,3-butadiene (BU) is an important industrial chemical and an environmental air pollutant. BU has been shown to be a weak carcinogen in the rat but a potent carcinogen in the B6C3F1 mouse. This species difference makes risk extrapolation to humans difficult and the underlying mechanism should be clarified before meaningful risk extrapolation to humans can be made. One possible explanation for the species differences in cancer response is that there are quantitative species differences in the formation of genotoxic epoxides. To investigate this possibility a physiologically based pharmacokinetic (pbpk) model for BU together with its first reactive metabolite 1,2-epoxybutene-3 (butadiene monoxide, BMO) was developed. Previously reported values on hepatic glutathione (GSH) turnover, depletion of hepatic GSH in rodents exposed to BU, and in vitro metabolic data of BU and BMO were included in the model, which incorporates intrahepatic first-pass hydrolysis of BMO and the ordered sequential, ping-pong mechanism to describe the enzyme kinetics of BMO-GSH conjugation. In vitro studies were carried out to obtain tissue: air partition coefficients of BU and BMO in rat tissue homogenates. The simulated pharmacokinetics of BU, BMO, and GSH agreed with previously published experimental observations in rat and mouse obtained in closed and open chamber experiments. According to the model, the internal dose of BMO (expressed either as the concentration in mixed venous blood or as the area under the concentration-time curve) is approximately 1.6 times higher in the mouse than in the rat for exposure to BU below 1000 ppm. At higher exposure levels, GSH depletion occurs in the mouse, but not in the rat, after about 6-9 h. This GSH depletion results in up to 2-3 times higher internal doses in the mouse than in the rat. The clear but relatively small species differences in body burdens of BMO indicated from our model can only partly explain the marked species difference in cancer response between mice and rats exposed to BU.

Animals↗
PubMed1993

Exposure dependent increase in DNA single strand breaks in leucocytes from workers exposed to low concentrations of styrene.

Single strand breaks in DNA were monitored in leucocytes from 17 men occupationally exposed to styrene. Personal air monitoring was carried out during one workday with two diffusion samplers and a portable photoionisation detector placed in the breathing zone. Exposure to styrene was also monitored by analysing styrene in blood and urine and mandelic acid in urine. Single strand breaks were measured in leucocytes by the alkaline elution technique. The biological samples were collected before a shift, at the end of a shift, and the next morning, before the next shift. An exposure dependent increase in single strand breaks was seen at the end of a shift but not before a shift or the next morning. Linear regression analysis indicated that the amount of DNA damage was roughly doubled after eight hours of exposure to 18 ppm styrene or at a urine concentration of 240 mg mandelic acid/g creatinine compared with the damage in non-exposed men. This study indicates that monitoring of single strand breaks with the alkaline elution technique may be a sensitive marker of genotoxic effects. To our knowledge, this is the first time that such a marker has been shown to correlate with exposure to less than 20 ppm styrene.

Adult↗
PubMed1993

Increase in neuropsychiatric symptoms after occupational exposure to low levels of styrene.

The results of this study suggest that exposure to styrene below the current Swedish permissible exposure limit of 20 ppm induces neurotoxic effects expressed as an increased number of neuropsychiatric symptoms. Twenty men exposed to styrene at a plastics factory participated. The reference group included 20 non-exposed men matched for age, working schedule, and physical work load. Exposure to styrene during one workday was assessed by personal air monitoring and biological monitoring. To evaluate the physical work load the pulse(heart) rate was measured. One week before the study each man completed a neuropsychiatric symptom questionnaire containing 16 items. Also 17 questions regarding acute symptoms of local irritation and symptoms of the central nervous system were presented after the psychometric tests were performed. The tests were simple reaction time, colour word vigilance, and symbol digit. A follow up with regard to the symptoms among the exposed men was done after their summer vacation, about two to five weeks after their last exposure. The mean eight hour time weighted average (TWA) concentration of styrene in air, measured by passive dosimetry was 8.6 ppm (range 0.04-50.4 ppm). The exposed men had significantly more symptoms than the referents although there were no significant differences for the psychometric tests. At the follow up the exposed men reported fewer symptoms. This study indicates that symptoms are earlier indicators of adverse effects than complex tests and underlines the importance of regular follow up of people exposed to styrene (and probably organic solvents in general).

Acute Disease↗