Experimental human exposure to toluene

Summary The relationship between the individual toluene uptake and the urinary hippuric acid excretion was studied under experimental conditions. Six healthy male subjects were exposed to various concentrations in inspired air (50, 100, 125, 150, and 200 ppm) at rest or under different levels of physical effort.The hippuric acid excretion near the end of the exposure appeared under all circumstances directly proportional to the time-weighted uptake rate of toluene. The correlation between respiratory uptake rate and the rate of metabolite excretion near the end of the exposure period proved not to be systematically influenced by personal factors such as body weight, amount of body fat, urine flow rate and urinary pH. The relatively pronounced differences in background excretion of hippuric acid and, perhaps, distribution phenomena of toluene between different tissues under heavy workload conditions, can partly explain the greater variability in metabolite excretions as compared to the individual uptake rates.The correlation between the individual uptake rate of toluene and the hippuric acid excretion proved substantially better when using the end exposure excretion rate as exposure parameter as compared with the end exposure hippuric acid concentration, even after correcting the latter for urine density.Reasonable biological limit values complying to an acceptable time-weighted toluene dose were found to be 3000–3500 mg/l and 2.0–2.5 mg/min, resp. for average hippuric acid concentrations and excretion rates in spot samples during the second half of a complete work shift.     

Respiratory retention,uptake and excretion of organic solvents in man

Summary Mechanisms of respiratory retention of organic solvents are discussed. Respiratory retention, uptake and excretion were estimated separately in 66 men and women volunteer students exposed to benzene, toluene, n-hexane, trichloroethylene, acetone, ethyl acetate and ethyl alcohol.After 2 hrs exposure, respiratory retention reached constant levels; these differed for each of the 7 organic solvents tested. No sex difference in retention was observed. Respiratory excretion values differed as 100 × concentration in expired air immediately following breathing of solvent free air/concentration of solvent in air breathed during exposure. Men excreted more toluene and trichloroethylene than did women. Uptake varied 27–60%.These results were presented in part before the 16th International Congress on Occupational Health, September 25th, 1969, Tokyo.     

Experimental human exposure to n-hexane

Summary The respiratory uptake rate of n-hexane showed considerable differences in six healthy male persons, exposed at rest to 360 mg/m³ and 720 mg/m³ of n-hexane in inspired air and to 360 mg/m³ under different levels of physical exercise. These differences could partly be explained by a positive correlation with the amount of body fat. At rest also a strong influence of the respiratory minute volume and respiratory frequency on the uptake rate could be proven. The average uptake rate remained virtually constant over a range of 20 to 60 W of continuous external physical load, indicating that under these circumstances the inspired n-hexane concentration alone predominantly determines the uptake rate.The respiratory elimination during the first hours after an exposure was also subject to important inter- and intraindividual fluctuations. The pulmonary ventilation rate at the moment of breath sampling had a pronounced influence on the measured exhaled concentration. On the other hand, there was no apparent effect of the amount of body fat. Generally, the correlation between the amount of n-hexane taken up and breath concentrations at different time intervals was rather poor.n-Hexane concentrations in peripheral venous blood reacted rapidly to changes in exposure conditions, but not in the same proportion as the uptake rate. The blood concentration proved more closely related to respiratory n-hexane retention than to the uptake rate, reflecting the state of saturation of different body tissues. At rest this parameter was clearly influenced by the amount of body fat. A decrease in relative blood perfusion of fatty tissue could explain why such relation was not found during exposure combined with physical effort.     

Coexposure to toluene and p-xylene in man: uptake and elimination.

Eight male subjects were experimentally exposed to toluene, p-xylene, and a combination of toluene and p-xylene in order to study the influence of coexposure and exposure to different levels of each solvent on their uptake and elimination. The exposures were performed for four hours at exposure levels equivalent to or lower than the Swedish threshold limit value for toluene, 300 mg/m3 (3.2 mmol/m3). During and after the exposure, solvent concentrations were measured in blood and in expired air. In addition, the pulmonary ventilation rate was measured during the exposure. Decreases in the blood/end exhaled air concentration ratio were found for both toluene and p-xylene when given in combination compared with separate exposure. The total solvent uptake relative to the exposure level was decreased after exposure to the higher solvent concentrations, and the apparent clearance was also decreased after exposure to the higher concentrations of solvent. Finally, the blood solvent concentrations were lower at the end of the exposure compared with the maximal concentration during each exposure condition. In the kinetics of toluene and p-xylene the total amount of toluene or p-xylene, or both, seems to be of major importance. The change in blood/end exhaled air concentration ratio may indicate an effect of coexposure.     

Coexposure to toluene and p-xylene in man: uptake and elimination

Eight male subjects were experimentally exposed to toluene, p-xylene, and a combination of toluene and p-xylene in order to study the influence of coexposure and exposure to different levels of each solvent on their uptake and elimination. The exposures were performed for four hours at exposure levels equivalent to or lower than the Swedish threshold limit value for toluene, 300 mg/m3 (3.2 mmol/m3). During and after the exposure, solvent concentrations were measured in blood and in expired air. In addition, the pulmonary ventilation rate was measured during the exposure. Decreases in the blood/end exhaled air concentration ratio were found for both toluene and p-xylene when given in combination compared with separate exposure. The total solvent uptake relative to the exposure level was decreased after exposure to the higher solvent concentrations, and the apparent clearance was also decreased after exposure to the higher concentrations of solvent. Finally, the blood solvent concentrations were lower at the end of the exposure compared with the maximal concentration during each exposure condition. In the kinetics of toluene and p-xylene the total amount of toluene or p-xylene, or both, seems to be of major importance. The change in blood/end exhaled air concentration ratio may indicate an effect of coexposure.     

Kinetics of tetrachloroethylene in volunteers; influence of exposure concentration and work load

Summary Six male volunteers were exposed for 4 h to 72 ppm tetrachloroethylene (PERC) at rest, to 144 ppm PERC at rest, and to 142 ppm PERC at rest combined with work load (2 times 30 min, 100 W). Minute volume and concentrations in exhaled air were measured to estimate the uptake. Concentrations of PERC and trichloroacetic acid (TCA) were determined in blood. Exhaled air was analysed for PERC; urine for TCA.The uptake/min decreased in the course of the exposure to 60 % of the initial uptake. The total uptake was influenced more by (lean) body mass than by respiratory minute volume or adipose tissue. During work load the uptake and minute volume increased to 3 fold the value at rest. In the post exposure period the quotient of the bloodconcentrations and exhaled air concentrations of PERC remained nearly constant at 23. Following exposure about 80–100 % of the uptake was excreted unchanged by the lungs, whereas till 70 h after exposure the amount of TCA excreted in urine represented about 1 % of the uptake.     

Duration of increased pulmonary function sensitivity to an initial ozone exposure

The metabolic and pulmonary function effects were investigated in six non-smoking young adults who were exposed for 2 hours (22 degrees C WBGT) to: filtered air (FA) 0.45 ppm ozone (DAY1); and two days later to a second exposure to 0.45 ppm ozone (DAY2). The subjects alternated 20-minute periods of rest and 20-minute periods of bicycle ergometer exercise at a workload predetermined to elicit a ventilatory minute volume (VE) of 27 L/min (BTPS). Functional residual capacity (FRC) was determined pre- and post-exposure. Forced vital capacity (FVC) was determined before and after exposure, as well as 5 minutes after each exercise period. Heart rate was monitored throughout the exposure, and VE, oxygen uptake (VO2), respiratory rate (fR), and tidal volume (VT) were measured during the last 2 minutes of each exercise period. There were no changes in any variable consequent to FA exposure. Both ozone exposures induced significant (P less than 0.05) decrements in FVC; FEV1.0 (forced expiratory volume in 1 second); FEV3.0 (forced expiratory volume in 3 seconds); FEF25-75% (average flow rate between 25% and 75% of FVC); and total lung capacity (TLC). The decrements following the DAY2 ozone exposure were significantly greater than following DAY1, and averaged 7.2 percentage points greater than those following the DAY1 exposure.     

Toluene in alveolar air during controlled exposure to constant and to varying concentrations

Summary The concentratiuon of toluene in the alveolar air was measured in 20 males and 17 females exposed for 7 h either to a constant exposure to 100 ppm toluene or to a varying exposure with the same time-weighted average, but with peaks of 300 ppm every 30 min. Both exposure schedules included 50 to 100 W exercise in three 15-min periods. Repetitive measurements of the toluene concentrations in the alveolar air were made in two 30-min periods, one at rest and one including work. At rest the alveolar concentration increased rapidly in response to an increase in the inspiratory air concentration, while exercise delayed this increase by about 2 min, probably due to an altered distribution of toluene in the body. The average alveolar concentration was 16.5 ± 6.8 ppm (mean ±SD) at rest and 19.5 ± 5.3 ppm in the period including exercise while there was no difference between constant and varying exposure. The alveolar toluene concentration tended to be higher in females than in males both at rest and during exercise. Subjects exercising with an intensity of 100 W had 25% higher values at rest than those exercising at 75 W. The excretion of the metabolites hippuric acid and orthocresol in the last 3 h of exposure was correlated to the alveolar toluene concentration at rest but not during work. Besides this, body height and weight influenced the excretion rates, still leaving a large unexplained interindividual variation.     

Effect of various exposure scenarios on the biological monitoring of organic solvents in alveolar air

Summary The present study was undertaken to investigate the influence of different exposure scenarios on the elimination of toluene and m-xylene in alveolar air and other biological fluids in human volunteers. The study was also aimed at establishing the effectiveness of physiologically based toxicokinetic models in predicting the value of biological monitoring data after exposure to toluene and m-xylene. Two adult male and two adult female white volunteers were exposed by inhalation, in a dynamic, controlled-environment exposure chamber, to various concentrations of toluene (21–66 ppm) or mxylene (25–50 ppm) in order to establish the influence of exposure concentration, duration of exposure, variation of concentration within day, and work load on respective biological exposure indices. The concentrations of unchanged solvents in end-exhaled air and in blood as well as the urinary excretion of hippuric acid and m-methylhippuric acid were determined. The results show that doubling the exposure concentration for both solvents led to a proportional increase in the concentrations of unchanged solvents in alveolar air and blood at the end of a 7-h exposure period. Cumulative urinary excretion of the respective metabolites exhibited a nearly proportional increase. Adjustment of exposure concentration to account for a prolongation of the duration of exposure resulted in essentially identical cumulative urinary excretion of the metabolites. Induced within-day variations in the exposure concentration led to corresponding but not proportional changes in alveolar concentration for both solvents, depending on whether or not sampling preceded or followed peak exposure to solvent. At the end of repeated 10-min periods of physical exercise at 50 W, alveolar air concentrations of both solvents were increased by 40%. Experimental data collected during the present study were adequately simulated by physiologically based toxicokinetic modeling. These results suggest that alveolar air solvent concentration is a reliable index of exposure to both toluene and m-xylene under various experimental exposure scenarios. For clinical situations likely to be encountered in the workplace, physiologically based toxicokinetic modeling appears to be a useful tool both for developing strategies of biological monitoring of exposure to volatile organic solvents and for predicting alveolar air concentrations under a given set of exposure conditions.     

Differences in kinetics of pure and soil-adsorbed toluene in orally exposed male rats

Assessment of health risk following exposure to chemically contaminated soil has primarily utilized results from studies conducted with pure chemicals. However, complex interactions with soil may alter the way in which a chemical subsequently interacts with the body. This study was conducted to determine if adsorption to either of two New Jersey soils qualitatively or quantitatively altered the way in which toluene is absorbed, distributed, metabolized or excreted by the body following oral exposure.Adult, male rats were gavaged with an aqueous suspension of¹⁴C-toluene in the presence or absence of either an Atsion (sandy soil) or a Keyport soil (clay soil). Both soils reduced the peak plasma concentration of radioactivity, while sandy soil also reduced the time to reach peak vs toluene alone. Clay soil produced a statistically significant decrease in the half-life (t_1/2) of elimination of radioactivity from plasma vs toluene alone. However, neither soil altered the area under the plasma radioactivity-time curve (AUC) vs toluene alone.Three-h post administration, stomach and fat contained the highest concentrations of radioactivity. No differences were detected in the tissue concentrations of radioactivity between the treatment groups.Urine was the primary excretion route of radioactivity in all treatment groups with lesser amounts excreted in expired air and negligible amounts in feces during the 48 h following exposure. Unmetabolized toluene represented >98.8% of radioactivity in expired air of all treatment groups. Clay soil produced a statistically significant decrease in the excretion of radioactivity in expired air at the 0–1, 0–12, 0–24 and 0–48 h periods vs toluene alone. While the excretion of radioactivity in expired air during the 0–12 h period was similar for toluene in the presence or absence of sandy soil, sandy soil did significantly reduce excretion during the 0–1 and 2–6 h periods and significantly increase excretion during the 1–2 h period vs toluene alone. Hippuric acid was the major metabolite detected in the urine of all treatment     

Toluene in alveolar air during controlled exposure to constant and to varying concentrations

The concentration of toluene in the alveolar air was measured in 20 males and 17 females exposed for 7 h either to a constant exposure to 100 ppm toluene or to a varying exposure with the same time-weighted average, but with peaks of 300 ppm every 30 min. Both exposure schedules included 50 to 100 W exercise in three 15-min periods. Repetitive measurements of the toluene concentrations in the alveolar air were made in two 30-min periods, one at rest and one including work. At rest the alveolar concentration increased rapidly in response to an increase in the inspiratory air concentration, while exercise delayed this increase by about 2 min, probably due to an altered distribution of toluene in the body. The average alveolar concentration was 16.5 +/- 6.8 ppm (mean +/- SD) at rest and 19.5 +/- 5.3 ppm in the period including exercise while there was no difference between constant and varying exposure. The alveolar toluene concentration tended to be higher in females than in males both at rest and during exercise. Subjects exercising with an intensity of 100 W had 25% higher values at rest than those exercising at 75 W. The excretion of the metabolites hippuric acid and orthocresol in the last 3 h of exposure was correlated to the alveolar toluene concentration at rest but not during work. Besides this, body height and weight influenced the excretion rates, still leaving a large unexplained interindividual variation.     

Experimental human exposure to carbon disulfide

Six human volunteers were exposed to 10 and 20 ppm carbon disulfide at rest and to 3 and 10 ppm carbon disulfide under a 50 W level of physical exercise during four consecutive periods of 50 min. Every 5 min a sample was taken from the mixed exhaled air in which the concentration of carbon disulfide was determined. It was established that only an apparent steady state was reached during this exposure period. The retention values were established as 0.374 (SD = 0.106; n = 239) for exposure to 10 ppm carbon disulfide at rest and as 0.410 (SD = 0.103; n = 239) for exposure to 20 ppm carbon disulfide at rest. During exposure to 10 ppm and 3 ppm carbon disulfide, combined with a 50 W level of physical exercise, the retention values decreased to 0.286 (SD = 0.083; n = 239) and 0.277 (SD = 0.049; n = 239) respectively. Thereby, the measured individual retention values of carbon disulfide show considerable interindividual differences. The respiratory uptake of carbon disulfide (mg CS2) proved significantly influenced by the amount of body fat estimated from skinfold thickness measurements. The respiratory elimination of carbon disulfide in the exhaled air can be described by means of a two-exponential decay.     

Monitoring of workers exposed to a mixture of toluene,styrene and methanol vapours by means of diffusive air sampling,blood analysis and urinalysis

Summary Exposure of 34 male workers to combined toluene, styrene and methanol was monitored by personal diffusive sampling of solvent vapours in breathing zone air, analysis of shift-end blood for the 3 solvents and analysis of shift-end urine for hippuric, mandelic and phenylglyoxylic acids and methanol. The exposure of most of the workers was below current occupational exposure limits. Regression analysis showed that a linear correlation exists for each of the 3 solvents between any pairs of the concentrations in air, blood and urine. Namely, toluene, styrene and methanol concentrations in blood obtained at the end of a shift are linearly related to the time-weighted average intensity of exposure to corresponding solvents, and also hippuric, mandelic and phenylglyoxylic acids as well as methanol in shift-end urine. The concentrations of hippuric, mandelic and phenylglyoxylic acids as well as methanol in urine correlated with the respiratory exposure intensity. Comparison of the present results with the exposure — excretion relationship after occupational exposure to the individual solvent showed that no modification in metabolism is induced by the combined exposure when exposure is low, as in the present case.     

Kinetics of 1,1,1-trichloroethane in volunteers; Influence of exposure concentration and work load

Summary Six male volunteers were exposed for 4 h to 70 ppm 1,1,1-trichloroethane (methylchloroform, MC) at rest, to 145 ppm. MC at rest, and to 142 ppm MC at rest combined with work load (2 times 30 min, 100 W). Minute volume and concentration in exhaled air were measured to estimate the uptake. MC and its metabolites trichloroethanol (TCE) and trichloroacetic acid (TCA) were determined as far as present in blood, exhaled air and urine. The uptake/min decreased in the course of exposure to 30 % of the initial uptake. The total uptake was more influenced by minute volume than by body weight or amount of adipose tissue. During work load the uptake increased to 2.3 fold and the minute volume to 3 fold the value at rest. In the post exposure period the quotients of the concentrations in blood and in exhaled air for MC and TCE remained nearly constant at 8.2 and 14,000, respectively. Following exposure about 60–80% of the amount taken up was excreted unchanged by the lungs, while until 70 h after exposure the amount of TCE and TCA excreted in urine represented about 2% and 0.5% of the uptake.     

Toxicokinetics of toluene and urinary excretion of hippuric acid after human exposure to 2H8-toluene.

Nine male volunteers were exposed to 2H8-toluene (200 mg/m3 for two hours during a workload of 50 W) via inspiratory air with the aid of a breathing valve and mouthpiece. Labelled toluene was used to differentiate between hippuric acid originating from exposure to toluene and hippuric acid normally excreted in urine. The total uptake of toluene was 2.2 (standard deviation (SD) 0.2) mmol, or 50% of the amount inhaled. Four hours after the end of exposure 1.4 (SD 0.3) mmol or 65% of the total uptake had been excreted in urine as 2H-hippuric acid and 20 hours after the end of exposure the cumulative excretion of 2H-hippuric acid was 1.8 (SD 0.3) mmol, or 78% of the total uptake. By contrast the cumulative excretion of labelled plus unlabelled hippuric acid exceeded the total uptake of toluene already after four hours. The excretion rate of 2H-hippuric acid was highest, about 5 mumol/min, during exposure and the SD between the subjects was low. The background concentrations of unlabelled hippuric acid in urine were high, however, and there were large differences between subjects. These findings confirm earlier indications that for low exposure, urinary hippuric acid concentration cannot be used for biological monitoring of exposure to toluene.     

Human respiratory uptake of chloroform and haloketones during showering

Inhalation is an important exposure route for volatile water contaminants, including disinfection by-products (DBPs). A controlled human study was conducted on six subjects to determine the respiratory uptake of haloketones (HKs) and chloroform, a reference compound, during showering. Breath and air concentrations of the DBPs were measured using gas chromatography and electron capture detector during and following the inhalation exposures. A lower percentage of the HKs (10%) is released from shower water to air than that of chloroform (56%) under the experiment conditions due to the lower volatility of the HKs. Breath concentrations of the DBPs were elevated during the inhalation exposure, while breath concentrations decreased rapidly after the exposure. Approximately 85-90% of the inhaled HKs were absorbed, whereas only 70% of the inhaled chloroform was absorbed for the experiment conditions used. The respiratory uptake of the DBPs was estimated using a linear one-compartment model coupled with a plug flow stream model for the shower system. The internal dose of chloroform normalized to its water concentration was approximately four times that of the HKs after a 30-min inhalation exposure. Approximately 0.3-0.4% of the absorbed HKs and 2-9% of the absorbed chloroform were expired through lung excretion after the 30-min exposure. The inhalation exposure from a typical 10-15 min shower contributes significantly to the total dose for chloroform in chlorinated drinking water but only to a moderate extent for HKs.     

Gas inertia and ventilatory measurements under pressure: methodological considerations

A bag-in-box apparatus with a spirometer was used to measure the ventilatory minute volume in subjects exercising at air pressures up to 6.8 atm. During rest there was good agreement between minute volumes derived from the expired gas in the bag and the sum of tidal volumes from the spirometer, whereas during exercise the bag volume exceeded the spirometer volume by up to 20%. This was found to be due to the inertia of high density gas in the breathing hoses. Given sufficient flow rate the gas would continue to flow from the box to the bag following end expiration and end inspiration. The spirometer would not record this because it only responds to changes in the sum of box and bag volumes, whereas emptying the bag through a gas meter records the volume of gas actually moved. A model was constructed to investigate the phenomenon. It was concluded that many different conventional setups for respiratory measurements may be subject to this type of error. Solutions to the problem include a collapsible tube section downstream from the subject, pneumotachometers, chest-mounted magnetometers, or inductive plethysmographs.     

Pulmonary function responses of older men and women to NO2

The pulmonary function of eight men and eight women (51 to 76 years of age), all non-smokers, was measured before and after 2-hr exposures to filtered air (FA) and 0.60 ppm nitrogen dioxide (NO2). The subjects alternated 20-min periods of rest and 20-min periods of cycle ergometer exercise at a work load predetermined to elicit a ventilatory minute volume (VE) of approximately 25 liter/min. Functional residual capacity was determined pre- and postexposure. Forced vital capacity was determined preexposure and 5 min after each exercise period. VE was measured during the last 2 min of each exercise period, and heart rate was monitored throughout each exposure. The pulmonary function data were evaluated as the percentage change from pre- to postexposure to partially remove the effect of differences between men and women in absolute lung volume. There were no statistically significant (P greater than 0.05) differences between the responses of men and women to FA or NO2 exposure. There were no significant (P greater than 0.05) changes in any variable consequent to FA or NO2 exposure. Our older subjects had responses to NO2 exposure similar to those of young adults, suggesting that, at least for healthy people, exposure to 0.60 ppm NO2 has little effect.     

Breath analysis by API/MS—human exposure to volatile organic solvents

Summary The expired breath of subjects, exposed for periods of ca. 90 min to atmospheres artificially contaminated with low levels of methanol, (ca. 100 ppm) toluene (ca. 50 ppm) or tetrachloroethylene, (ca. 50 ppm) was monitored during and after the exposure period using an atmospheric pressure ionization mass spectrometer, fitted with a direct breath analysis system. The retention of solvent by the subjects, estimated from steady state levels in the expired breath, averaged 82% of the inspired level for methanol, 83% for toluene and 87% for tetrachloroethylene. The elimination of unchanged solvent via respiration during the post exposure period followed first order kinetics with mean half life values of 24 min for methanol, 27 min for toluene and 79 min for tetrachloroethylene.     

模拟36.5m氮氧饱和潜水26昼夜对人体肺通气量和摄氧量的影响

本文报道了7名受试者饱和暴露于36.5m氮氧条件下26昼夜及60-75m空气巡潜时肺通气量和摄氧量的变化。结果表明:1.高压条件下,影响人体肺通气功能最重要的因素是气体密度升高所致的呼吸阻力变大,因此,最大呼气、吸气流速、最大通气量和时间肺活量均有显著的下降。2.在高压暴露时,由于体力负荷的通气量有显著减少,所以呼吸困难指数有明显的增加。3.高压暴露期间的静息摄氧量和二氧化碳产生量与海平对照值接近,而体力负荷的摄氧量有增加的趋势,体力负荷后第3分钟的摄氧量有显著增加。这表明体力负荷时的氧债量增加了。