Social Causes of Sick Absence

Eleven human subjects were experimentally exposed to methyl chloroform (1,1,1-trichloroethane) vapor, 500 ppm, for periods of 6.5 to 7 hours/day for five days. The subjective untoward responses reported were mild, inconsistently present, and of doubtful clinical significance. The only adverse, objective response was an abnormal modified Romberg’s test observed in two of the subjects during exposure. No clinical laboratory test performed during or following the vapor exposures revealed any abnormality of organ function.

Analysis of the exhaled breath of the subjects by infrared or gas chromatographic techniques provided a means with which to establish unequivocally a diagnosis of exposure. Serial measurements of the solvent present in the breath in the postexposure period provided the data from which to construct a family of breath excretion curves useful in estimating the magnitude of exposure to methyl chloroform.     

Experimental Human Exposure to Trichloroethylene

Ten experimental human exposures to frichloro-ethylene vapor, 100 and 200 ppm, for periods of one hour to a five-day work week were conducted. At 200 ppm, untoward subjective responses were mild, inconsistently present, and of doubtful clinical significance. The only troublesome response was a sensation of mild fatigue and sleepiness in five subjects during their fourth and fifth consecutive days of exposure to 200 ppm.

Analysis of expired breath of humans by infrared or gas chromatographic techniques provided a means by which to unequivocally establish a diagnosis of exposure. Serial measurements of the solvent present breath in the postexposure period provided the data from which to construct a family of breath excretion curves useful in estimating the magnitude of exposure.

Measurement of urinary metabolites of trichloroethylene proved to be an unsatisfactory index of exposure.     

Nutrition and Infection Field Study in Guatemalan Villages, 1959–1964

Triehloroethylene (TCE) postexposure breath decay curves were obtained from ten male and ten female volunteers who were exposed daily in a controlled-environment chamber to TCE vapor, 20, 100, or 200 ppm for one, three, or 71/2 hours. Alveolar breath samples were collected in glass pipettes for TCE analysis by gas chromatography.

The series of TCE breath decay curves obtained was highly reproducible and the narrow range of TCE in the breath at a specific time in the early postexposure period of persons identically exposed indicated that breath analysis could be used as a rapid method with which to estimate the magnitude of recent TCE exposure.

The TCE breath concentration in the immediate postexposure period accurately reflected the vapor concentration to which the subject had been most recently exposed. Breath samples collected eight to 24 hours following exposure were accurate indicators of the time-weighted average vapor exposure experienced by the subject on the previous day.     

Human Exposure to Styrene Vapor

Human volunteers were exposed to styrene vapor at approximately 50, 100, 200, and 375 ppm for periods of one to seven hours. Only at 375 ppm did the subjects experience significant subjective symptoms and show objective signs of transient neurological impairment. A small portion of the absorbed styrene was rapidly and exponentially excreted from the lungs in the postexposure period. A measurement of the amount of styrene present in the breath in the early postexposure period provided a means for making an estimation of magnitude of exposure. The determination of urinary hippuric acid proved to be insensitive as an indicator of exposure to this compound at these vapor concentrations.     

Trichloroethene levels in human blood and exhaled breath from controlled inhalation exposure.

The organic constituents of exhaled human breath are representative of bloodborne concentrations through gas exchange in the blood/breath interface in the lungs. The presence of specific compounds can be an indicator of recent exposure or represent a biological response of the subject. For volatile organic compounds, sampling and analysis of breath is preferred to direct measurement from blood samples because breath collection is noninvasive, potentially infectious waste is avoided, the sample supply is essentially limitless, and the measurement of gas-phase analytes is much simpler in a gas matrix rather than in a complex biological tissue such as blood. However, to assess the distribution of a contaminant in the body requires a reasonable estimate of the blood level. We have investigated the use of noninvasive breath measurements as a surrogate for blood measurements for (high) occupational levels of trichloroethene in a controlled exposure experiment. Subjects were placed in an exposure chamber for 24 hr; they were exposed to 100 parts per million by volume trichloroethene for the initial 4 hr and to purified air for the remaining 20 hr. Matched breath and blood samples were collected periodically during the experiment. We modeled the resulting concentration data with respect to their time course and assessed the blood/breath relationship during the exposure (uptake) period and during the postexposure (elimination) period. Estimates for peak blood levels, compartmental distribution, and time constants were calculated from breath data and compared to direct blood measurements to assess the validity of the breath measurement methodology. Blood/breath partition coefficients were studied during both uptake and elimination. At equilibrium conditions at the end of the exposure, we could predict actual blood levels using breath elimination curve calculations and a literature value partition coefficient with a mean ratio of calculated:measured of 0.98 and standard error (SE) = 0.12 across all subjects. blood/breath comparisons at equilibrium resulted in calculated in vivo partition coefficients with a mean of 10.8 and SE = 0.60 across all subjects and experiments and 9.69 with SE = 0.93 for elimination-only experiments. We found that about 78% of trichloroethene entering the body during inhalation exposure is metabolized, stored, or excreted through routes other than exhalation.     

Toxicokinetics of human exposure to methyl tertiary-butyl ether (MTBE) following short-term controlled exposures.

Methyl tertiary-butyl ether (MTBE) is an oxygenated compound added to gasoline to improve air quality as part of the US Federal Clean Air Act. Due to the increasing and widespread use of MTBE and suspected health effects, a controlled, short-term MTBE inhalation exposure kinetics study was conducted using breath and blood analyses to evaluate the metabolic kinetics of MTBE and its metabolite, tertiary-butyl alcohol (TBA), in the human body. In order to simulate common exposure situations such as gasoline pumping, subjects were exposed to vapors from MTBE in gasoline rather than pure MTBE. Six subjects (three females, three males) were exposed to 1.7 ppm of MTBE generated by vaporizing 15 LV% MTBE gasoline mixture for 15 min. The mean percentage of MTBE absorbed was 65.8 +/- 5.6% following exposures to MTBE. The mean accumulated percentages expired through inhalation for 1 and 8 h after exposure for all subjects were 40.1% and 69.4%, respectively. The three elimination half-lives of the triphasic exponential breath decay curves for the first compartment was 1-4 min, for the second compartment 9-53 min, and for the third compartment 2-8 h. The half-lives data set for the breath second and blood first compartments suggested that the second breath compartment rather than the first breath compartment is associated with a blood compartment. Possible locations for the very short breath half-life observed are in the lungs or mucous membranes. The third compartment calculated for the blood data represent the vessel poor tissues or adipose tissues. A strong correlation between blood MTBE and breath MTBE was found with mean blood-to-breath ratio of 23.5. The peak blood TBA levels occurred after the MTBE peak concentration and reached the highest levels around 2-4 h after exposures. Following the exposures, immediate increases in MTBE urinary excretion rates were observed with lags in the TBA excretion rate. The TBA concentrations reached their highest levels around 6-8 h, and then gradually returned to background levels around 20 h after exposure. Approximately 0.7-1.5% of the inhaled MTBE dose was excreted as unchange urinary MTBE, and 1-3% was excreted as unconjugated urinary TBA within 24 h after exposure.     

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.     

Experimental PVC material challenge in subjects with occupational PVC exposure

BACKGROUND: Polyvinyl chloride (PVC) materials have been linked to asthma in several epidemiologic studies, but the possible causal factors remain unknown. PARTICIPANTS: We challenged 10 subjects experimentally to degraded PVC products under controlled conditions. All of the subjects had previously experienced respiratory symptoms suspected to be caused by this kind of exposure in their work place. Five subjects had doctor-diagnosed asthma. METHODS: The subjects were exposed to degraded PVC material in an exposure chamber ; a challenge with ceramic tile was used as the control test. We followed exhaled nitric oxide, nasal NO, lung functions, cytokines [tumor necrosis factor-alpha (TNF-alpha) , interleukin-4 (IL-4) , IL-6, and IL-12] and NO in nasal lavage fluid (NAL) during and after the exposures. We also measured 2-ethylhexanol in exhaled breath samples and NAL. RESULTS: On the morning after the PVC exposure, subjects reported respiratory tract symptoms significantly more often than they did after the control test (50% vs. 0%, respectively ; p = 0.029 ; n = 10) . We did not detect any changes in lung functions or levels of exhaled NO, nasal NO, or NO in NAL after PVC challenge compared with the control test. Cytokine levels increased after both exposures, with no statistically significant difference between situations. All of the exhaled breath samples collected during the PVC exposure contained 2-ethylhexanol. CONCLUSIONS: PVC flooring challenge can evoke respiratory tract symptoms in exposed subjects. Our results do not support the hypothesis that PVC materials themselves evoke immediate asthmatic reactions. The chamber test used is well suited to this type of exposure study.     

Integration in human eye irritation

 Today it is widely known and accepted that indoor air pollution can affect health. To ensure a healthy indoor climate through source control it is necessary to be able to predict how much of a source can be introduced into a building without unacceptable health and comfort effects. This paper describes a study of human eye irritation, which is part of a research program aimed at developing the use of sensory reference scaling in source characterization. In reference scaling the sensory eye irritation caused by exposure to polluted air is measured in terms of a concentration of a reference gas causing equivalent eye irritation intensity. The purpose of this study, therefore, was to estimate a possible difference in the magnitude of perceived sensory irritation between unilateral and bilateral exposure of human eyes. In each of four runs ten subjects were exposed to five progressive concentrations of CO₂. In two of the runs the subjects were exposed unilaterally and in the other two runs the subjects were exposed bilaterally. In an analysis of variance no significant difference was found between unilateral and bilateral exposures. As expected, the intensity of the perceived irritation increased significantly with increasing exposure level. The sensitivity decreased slightly but significantly following previous exposures. These results enable us to develop a model for source characterization in which sensory eye irritation is measured by reference scaling. The use of reference scaling has the advantage that an otherwise subjective response (perceived irritation intensity) becomes less biased. Received: 5 February 1996/Accepted: 2 May 1996     

Airborne emissions at skin surfaces: a potential biological exposure index

 Dermal exposures of methanol were administered in a clinical study designed to compare several biological indicators. Four subjects were exposed in five exposure sessions of varying length. In each session, a sequence of measurements of methanol concentrations in blood, breath, and headspace samples of air at exposed and unexposed skin were collected before and after dermal exposures. Skin headspace samples, collected in gas sampling bags, were designed to reflect equilibrium skin: air partitioning. At exposed skin, headspace samples were highly elevated for at least 8 h following exposure, indicating the presence of a methanol reservoir in skin. After exposure, methanol concentrations at exposed skin showed a rapid initial decline, then a slower first-order decrease. Methanol concentrations were clearly detectable in headspace samples at unexposed skin. Substantial transfer from exposed skin occurred due to mechanical contact and washing. When transfer was restricted, surface concentrations at unexposed skin were similar to levels in breath and were strongly correlated to methanol concentrations in blood. While results are preliminary due to the small sample sizes and several unresolved experimental issues, the simple, rapid, and noninvasive skin headspace measurements appear useful as a biological exposure indicator that clearly shows the presence and site of a dermal exposure, and measurements at unexposed skin reflect concentrations in blood. Received: 14 March 1995/Accepted: 3 November 1995     

Breath, urine, and blood measurements as biological exposure indices of short-term inhalation exposure to methanol

Due to their transient nature, short-term exposures can be difficult to detect and quantify using conventional monitoring techniques. Biological monitoring may be capable of registering such exposures and may also be used to estimate important toxicological parameters. This paper investigates relationships between methanol concentrations in the blood, urine, and breath of volunteers exposed to methanol vapor at 800 ppm for periods of 0.5, 1, 2, and 8 h. The results indicate factors that must be considered for interpretation of the results of biological monitoring. For methanol, concentrations are not proportional to the exposure duration due to metabolic and other elimination processes that occur concurrently with the exposure. First-order clearance models can be used with blood, breath, or urine concentrations to estimate exposures if the time that has elapsed since the exposure and the model parameters are known. The 0.5 to 2-h periods of exposure were used to estimate the half-life of methanol. Blood data gave a half-life of 1.44±0.33 h. Comparable but slightly more variable results were obtained using urine data corrected for voiding time (1.55±0.67 h) and breath data corrected for mucous membrane desorption (1.40±0.38 h). Methanol concentrations in blood lagged some 15–30 min behind the termination of exposure, and concentrations in urine were further delayed. Although breath sampling may be convenient, breath concentrations reflect end-expired or alveolar air only if subjects are in a methanol-free environment for 30 min or more after the exposure. At earlier times, breath concentrations included contributions from airway desorption or diffusion processes. As based on multicompartmental models, the desorption processes have half-lives ranging between 0.6 and 5 min. Preliminary estimates of the mucous membrane reservoir indicate contributions of under 10% for a 0.5-h exposure and smaller effects for longer periods of exposure. Received: 1 August 1996 / Accepted: 24 January 1998     

Human inhalation pharmacokinetics of 1,1,2-trichloro-1,2,2-trifluoroethane (FC113)

Summary Seven male volunteers were exposed to atmospheric concentrations of either 1980, 4100 or 7630mg m⁻³ 1,1,2-trichloro-1,2,2-trifluoroethane (FC113) for 4 h. Blood and expired air samples were collected during the exposure period and for several days subsequently and analysed for FC113. Blood and breath concentrations of FC113 were related to the administered dose with some variation between individuals. The low blood/breath ratios measured are consistent with the low solubility of FC113 in blood. The absorption and elimination of FC113 can be described by a three-compartment model and the average half-lives of elimination of FC113 in breath were 0.22, 2.3 and 29 h. A pulmonary retention during the exposure period of 14% was measured but only 2.6 to 4.3% of the dose was recovered unchanged in breath after the exposure period, suggesting that FC113 could be metabolised following inhalation exposure. It is concluded that a practical method for biological monitoring during occupational exposure would be to measure end-tidal breath concentrations of FC113 in samples taken the morning after exposure. The predictive value of such a measurement can be improved if the results are normalised to the body fat content of individual workers which can be estimated from height and weight measurements.     

Dermal uptake of chloroform and haloketones during bathing

Dermal contact with some organic disinfection by-products (DBPs) such as trihalomethanes in chlorinated drinking water has been established to be an important exposure route. We evaluated dermal absorption of two haloketones (1,1-dichloropropanone and 1,1,1-trichloropropanone) and chloroform while bathing, by collecting and analyzing time profiles of expired breath samples of six human subjects during and following a 30-min bath. The DBP concentrations in breath increased towards a maximum concentration during bathing. The maximum haloketone breath concentration during dermal exposure ranged from 0.1 to 0.9 microg / m(3), which was approximately two orders of magnitude lower than the maximum chloroform breath concentration during exposure. Based on a one-compartment model, the in vivo permeability of chloroform, 1,1-dichloropropanone, and 1,1,1-trichloropropanone were approximated to be 0.015, 7.5 x 10(- 4), and 4.5 x 10(- 4) cm / h, respectively. Thus, haloketones are much less permeable across human skin under normal bathing conditions than is chloroform. These findings will be useful for future assessment of total human exposure and consequent health risk of these DBPs.     

Value of the simultaneous determination of PCO2 in monitoring exposure to 1,1,1-trichloroethane by breath analysis.

Eight volunteers were exposed for eight hours to about 200 ppm of 1,1,1-trichloroethane. On the next morning five series of five alveolar samples were collected for the simultaneous determination of PCO2 and 1,1,1-trichloroethane concentration. Three different methods of sampling were used: voluntary hyperventilation, 10-s breathholding, and "standard." A linear relationship between the alveolar concentrations of both gases was observed in all subjects. Expired air was also collected in two subjects and an analogous relationship was observed. Also the Bohr dead space was found to be of similar size for CO2 and for 1,1,1-trichloroethane. In the monitoring of solvent exposure by breath analysis it is suggested that the results should be corrected for hyperventilation or hypoventilation and for dilution of alveolar air with dead space air by a proportional adjustment of the solvent concentration at the mean normal adveolar PCO2 or by disregarding the samples with a PCO2 outside normal range. The PCO2 determination in 40 unselected workers has shown that in more than a third of them, to monitor exposure by breath analysis would have been of little meaning without such an adjustment or rejection criteria.     

Acute sensory irritation from exposure to isopropanol (2-propanol) at TLV in workers and controls: objective versus subjective effects

OBJECTIVES: Phlebotomists occupationally exposed to isopropanol (IPA) (2-propanol) and na?ve controls (n = 12 per group) were exposed to the time-weighted average threshold limit value of 400 p.p.m. IPA for 4 h in an environmental chamber to investigate: (i) acute effects of sensory irritation using subjective health symptom reports and objective, physiological end-points; and (ii) differences in measured effects in relation to exposure history. METHODS: Before, during and after exposure subjects gave self-reports of health complaints. During exposure subjects rated the intensity of the odor, sensory irritation and annoyance. Objective end-points of ocular hyperemia, nasal congestion, nasal secretion and respiration were obtained at various times before, during and after exposure. Results were compared with exposure to phenylethyl alcohol (PEA), a negative control for irritation, and to clean air (CA), a negative control for odor and irritation, using a within-subjects design. RESULTS: Significantly higher intensity ratings of odor, irritation and annoyance were reported during the exposure to IPA, when compared with exposure to CA or PEA. Nevertheless, the overall level of reported sensory irritation to IPA was low and perceived as 'weak' on average. Health symptom ratings were not significantly elevated for IPA as compared with PEA or CA exposure. The only physiological end-point that showed a change exclusively in the IPA condition was respiration frequency: relative to baseline, respiration frequency increased in response to IPA in both groups. No differences were encountered between the occupationally exposed and the control groups. CONCLUSIONS: The increase in respiration frequency in response to IPA may reflect either a reflexive change due to sensory irritation (an autonomic event) or a voluntary change in breathing in response to perception of an unpleasant, solvent-like odor (a physiological event caused by cognitive mediation). Our findings on objective end-points, including nasal and ocular sensory irritation, did not confirm subjective irritation reports. Irritation reports and odor intensity decreased, rather than increased, over time, lending credence to the cognitive argument and suggesting that the elevated subjective responses to IPA may be mediated by responses to its odor.     

Elimination of volatile organic compounds in breath after exposure to occupational and environmental microenvironments.

Breath measurements offer the potential for a direct and noninvasive evaluation of human exposure to volatile organic compounds (VOCs) in the environments in which people live and work. This research study was conducted to further evaluate and develop the potential of this exposure assessment methodology. Several people were exposed to the atmosphere in six microenvironments for several hours. Air concentrations of VOCs were measured during these exposures and breath samples were collected and analyzed at multiple time points after the exposure to evaluate elimination kinetics for 21 VOCs. A new alveolar breath collection technique was applied. Elimination half-lives were estimated using a mono- and bi-exponential model. The alveolar breath collection and analysis methodology proved to be very useful for collecting many samples in short time intervals and this capability was very important for more accurately describing the initial phase of the decay curves. Breath decay curves were generated from samples collected over a four hour period after exposure for 21 of 24 target VOCs. A biexponential function generally provided a better fit for the decay data than did the monoexponential function, supporting a multi-compartment uptake and elimination model for the human body.     

Human physiologic factors in respiratory uptake of 1,3-butadiene.

1,3-Butadiene (BD), a suspected human carcinogen, is used as the raw material in industries to make synthetic butyl rubber and plastics. Simulation models using experimental animal data have shown that physiologic factors play an important role in the kinetic behavior of BD. However, human data are limited. The aim of this inhalation study was to identify influential human physiologic factors in the respiratory uptake of BD. We recruited 133 healthy volunteers in Boston, Massachusetts, into this study and tested them under an approved human subjects protocol. Each subject was exposed to 2 ppm (4.42 mg/m3) BD for 20 min, followed by purified air for another 40 min. Five exhaled breath samples collected during exposure were used to determine the respiratory uptake of BD, which was defined as absorbed BD (micrograms) per kilogram of body weight during exposure. Although subjects were given identical administered doses (40 ppm x min), there was a wide range of uptake, 0.6-4.9 microg/kg. Of the studied physiologic factors, the blood:air partition coefficient and alveolar ventilation were most significant in determining the respiratory uptake (p < 0.001 for each). In addition, in the multiple regression analysis, females had significantly higher respiratory uptake of BD than males on a weight basis. For all subjects, increasing age and cigarette smoking led to significantly decreased respiratory uptake of BD. The results of this human study are consistent with previous kinetic simulations and animal studies. The findings also suggest that interindividual variation in human physiologic factors that affect the exposure-internal dose relationship should be considered while also exploring exposure-disease associations in future epidemiologic research.     

Human inhalation pharmacokinetics of 1,1,2-trichloro-1,2,2-trifluoroethane (FC113)

Seven male volunteers were exposed to atmospheric concentrations of either 1980, 4100 or 7630 mg m-3 1,1,2-trichloro-1,2,2-trifluoroethane (FC113) for 4 h. Blood and expired air samples were collected during the exposure period and for several days subsequently and analysed for FC113. Blood and breath concentrations of FC113 were related to the administered dose with some variation between individuals. The low blood/breath ratios measured are consistent with the low solubility of FC113 in blood. The absorption and elimination of FC113 can be described by a three-compartment model and the average half-lives of elimination of FC113 in breath were 0.22, 2.3 and 29 h. A pulmonary retention during the exposure period of 14% was measured but only 2.6 to 4.3% of the dose was recovered unchanged in breath after the exposure period, suggesting that FC113 could be metabolised following inhalation exposure. It is concluded that a practical method for biological monitoring during occupational exposure would be to measure end-tidal breath concentrations of FC113 in samples taken the morning after exposure. The predictive value of such a measurement can be improved if the results are normalised to the body fat content of individual workers which can be estimated from height and weight measurements.     

Cytological changes and conjunctival hyperemia in relation to sensory eye irritation

In general, irritation is a physiological response to a chemical or physical stimulus involving objective changes (e.g., local redness and edema) and subjective sensations (e.g., pruritus and pain). The perception of an irritating stimulus in the eyes and the upper airways is called sensory irritation. Sensory irritation is a prevalent symptom in relation to complaints about indoor air quality. The intensity of perceived sensory irritation in humans has mainly been evaluated using psychophysical methods. However, perceived sensory irritation is dependent on the subject expressing the symptoms; that is, it is a subjective measure. This is a problem in assessment of irritation effects from air pollution or other factors, since the expression of the irritation symptoms may be biased by, for example, interaction with other people and odors. The subjectivity of the measures is an important complication in several studies dealing with problems regarding indoor air quality. The bias problems make it important to complement the psychophysical measurements of sensory irritation with objective assessments of irritation. In addition, only little is known about the association between sensory irritation and possible physiological/pathological changes in the mucosal membranes in relation to studies of indoor air. Two studies (study 1 and study 2) were conducted to investigate changes in conjunctival hyperemia and conjunctival fluid cytology for subjects exposed to volatile organic compounds (VOCs) in their eyes only. Eight subjects participated in study 1. Each subject was exposed to three different mixtures of VOCs. A total of 16 subjects participated in study 2. Half of the subjects were exposed to 1-octene and the other half, to n-butanol. In both studies, photographs of bulbar conjunctiva were taken and conjunctival fluid was sampled before and after exposure. Moreover, the perceived irritation intensities were registered continuously during exposure. Overall, perceived irritation intensity and conjunctival hyperemia increased with increasing exposure concentrations, whereas cytological changes in the conjunctival fluid samples did not seem to be related to exposure concentration, perceived irritation, or changes in conjunctival hyperemia. Received: 4 April 1997 / Accepted: 25 September 1997     

Alveolar sampling and fast kinetics of tetrachloroethene in man. II. Fast kinetics.

Fast kinetic phenomena were studied in human subjects exposed to tetrachloroethene (perchloroethylene, PER). The duration of exposure ranged from one to 60 minutes and the concentration of PER in inhaled air ranged from 0.02 to 0.40 mmol/m3. The PER concentration in mixed venous blood (pulmonary artery) was estimated by alveolar concentration (CAlv) measured after a residence time of 10 s. During exposure, stoppage of intake (breath holding up to 50 s) caused a decrease of CAlv down to about 60% of the CAlv at a residence time of 10 s. At the end of exposure, stoppage of intake (breathing fresh air) caused a decrease of CAlv with t1/2 = 15-25 s; after two to four minutes, the decrease slowed down abruptly and the concentration remained more or less constant for about one to three minutes. After this stationary level, the decrease of CAlv continued but at a slower rate. During and after exposure, the decrease of CAlv seems to be caused by large differences in the circulation times of blood flowing through rapid, well perfused tissues and slower, well perfused tissues which may explain the stationary level. From this point of view, the vessel rich group in a compartment model must be split up in order to predict tissue and organ concentrations during peak environmental concentrations.