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PubMed2003

Metabolic distribution of radioactivity in Sprague-Dawley rats and B6C3F1 mice exposed to 1,3-[2,3-14C]-butadiene by whole body exposure.

The uptake of 1,3-[2,3-(14)C]-butadiene and its disposition, measured as radioactivity in urine, faeces, exhaled volatiles and CO(2) during and following 6 h whole body exposure to 20 ppm butadiene has been investigated in male Sprague-Dawley rats and B6C3F1 mice. Whilst there were similarities between the two species, the uptake and metabolic distribution of butadiene were somewhat different for rats and mice. The major differences observed were in the urinary excretion of radioactivity and in the exhalation of 14C-CO(2). After 42 h from the start of exposure, 51.1% of radioactivity was eliminated in rat urine compared with 39.5% for mouse urine. 34.9% of the recovered radioactivity was exhaled by rats as 14C-CO(2), compared with 48.7% by mice. Excretion of radioactivity in faeces was similar for both species (3.8% for rats and 3.4% for mice). The tissue concentrations of 14C-butadiene equivalents measured in liver, testes, lung and blood of exposed mice were 0.493, 0460, 0.457, and 1.626 nmol/g tissue, respectively. The values for the corresponding rat tissues were 0.869, 0.329, 0.457, and 1.626 nmol butadiene equivalents/g tissue, respectively. For rats, 6.2% of recovered radioactivity (0.288 nmol butadiene equivalents/g tissue) was retained in carcasses whereas for mice the amount was 3.6% (0.334 nmol butadiene equivalents/g tissue). There were also some significant differences between the metabolic conversion of 1,3-[2,3-(14)C]-butadiene and excretion by mice following the 20 ppm whole body exposure compared to previously reported data for nose-only exposure to 200 ppm butadiene [Richardson et al., Toxicol. Sci. 49 (1999) 186]. The main difference between the high- and low-exposure studies was in the exhalation of 14C-CO(2). At the 200 ppm exposure, 40% of the radioactivity was exhaled as 14C-CO(2) by rats whereas 6% was measured by this route for mice. The proportional conversion of butadiene to CO(2) by mice was significantly greater at the low exposure concentration compared with that reported for the higher concentration. This shift was not observed for rats. The difference between species could be caused by a saturation of metabolism in mice between 20 and 200 ppm for the pathways leading to CO(2). Restraint or error in collection of CO(2) in the 200 ppm study could also be factors.

Animals↗
PubMed2000

Effect of alveolar volume and sequential filling on the diffusing capacity of the lungs: I. theory.

The diffusing capacity, DL, is a critical physiological parameter of the lung used to assess gas exchange clinically. Most models developed to analyze experimental data from a single breath maneuver have assumed a well-mixed or uniform alveolar region, including the clinically accepted Jones-Meade method. In addition, all previous models have assumed a constant DL, which is independent of alveolar volume, VA. In contrast, experimental data provide evidence for a non-uniform alveolar region coupled with sequential filling of the lung. In addition, although the DL for carbon monoxide is a weak function of VA, the DL of nitric oxide depends strongly on VA. We have developed a new mathematical model of the single breath maneuver that considers both a variable degree of sequential filling and a variable DL. Our model predicts that the Jones-Meade method overestimates DL when the exhaled gas sample is collected late in the exhalation, but underestimates DL if the exhaled gas sample is collected early in the exhalation phase due to the effect of sequential filling. Utilizing a prolonged constant exhalation method, or a three-equation method, will also produce erroneous predictions of DL. We conclude that current methods may introduce significant error in the estimation of DL by ignoring the sequential filling of the lung, and the dependence of DL on VA.

Humans↗
PubMed1991

Physiological pharmacokinetic modeling of inhaled trichloroethylene in rats.

The pharmacokinetics of trichloroethylene (TCE) was characterized during and following inhalation exposures of male Sprague-Dawley rats. The blood and exhaled breath TCE time-course data were used to formulate and assess the accuracy of predictions of a physiologically based pharmacokinetic (PB-PK) model for TCE inhalation. Fifty or 500 ppm of TCE was inhaled by unanesthetized rats of 325-375 g for 2 hr through a miniaturized one-way breathing valve. Repetitive samples of the inhaled and exhaled breath streams, as well as arterial blood, were collected concurrently during and for 3 hr following the exposures and analyzed for TCE by headspace gas chromatography. Respiratory rates and volumes were continuously monitored and used in conjunction with the pharmacokinetic data to delineate uptake and elimination profiles. Levels of TCE in the exhaled breath attained near steady-state soon after the beginning of exposures, and were then directly proportional to the inhaled concentration. Exhaled breath levels of TCE in rats were similar in magnitude to values previously published for TCE inhalation exposures of humans. Levels of TCE in the blood of the 50 ppm-exposed animals also rapidly approached near steady-state, but blood levels in the 500 ppm-exposed animals rose progressively, reaching concentrations 25- to 30-fold higher than in the 50 ppm group during the second hour of exposure. The 10-fold increase in inhaled concentration resulted in an 8.7-fold increase in cumulative uptake, or total absorbed dose. These findings of nonlinearity indicate that metabolic saturation ensued during the 500 ppm exposure. The PB-PK model was characterized as blood flow-limited with TCE eliminated unchanged in the exhaled breath and by saturable liver metabolism. The uptake and elimination profiles were accurately simulated by the PB-PK model for both the 50 and 500 ppm TCE exposure levels. Such a model may be quite useful in risk assessments in predicting internal (i.e., systemically absorbed) doses of TCE and other volatile organics under a variety of exposure scenarios.

Administration, Inhalation↗
PubMed1997

Biological monitoring of exposure to benzene in the production of benzene and in a cokery.

The purpose of this study was to compare different biological methods in current use to assess benzene exposure. The methods involved in the study were: benzene in blood, urine and exhaled air, and the urinary metabolites t,t-muconic acid (MA) and S-phenylmercapturic acid (S-PMA). Blood, urine and exhaled air samples were collected from workers in a benzene plant (pure benzene exposure) and cokery (mixed exposure, e.g. polycyclic aromatic hydrocarbons--PAHs) in an Estonian shale oil petrochemical plant. The benzene in these samples was analysed with a head-space gas chromatograph, and the metabolites MA and S-PMA with a liquid chromatograph using methods developed from published procedures. Some of the values measured in the Estonian shale oil area were high in comparison with those published during the last few years, whereas the values measured in the control group did not show any exposure to benzene except in the smokers group. The highest median exposure was in the benzene factory, 0.9 cm3/m3 TWA (2.9 mg/m3) and the highest individual value was 15 cm3/m3 TWA (49 mg/m3). All biological measurements in this study gave the same assessment about exposure to benzene and correlated highly significantly with each other and with the air measurements (r = 0.8 or more). In the benzene factory the correlation was good even when calculated from samples with air concentration < 1 cm3/m3 (3.2 mg/m3) in the case of blood benzene and urinary MA. However, for S-PMA it was weak (r = 0.4) and for benzene in urine and exhaled air it did not exist any more. In the cokery, with mixed exposure, the correlation at low levels was weaker even for blood benzene and urinary MA (r = 0.6). According to the results in the benzene factory the exposure to pure benzene at the level 1 cm3/m3 (3.25 mg/m3) TWA gave: the blood benzene value about 110 nmol/l (8.6 micrograms/l), MA 23 mumol/l (3.3 micrograms/l) or 2.0 mg/g creatinine, S-PMA 58 micrograms/g creatinine or 0.4 mumol/l (95.7 micrograms/l), benzene in urine 499 nmol/l (39 micrograms/l), and benzene in the exhaled air 2.8 nmol/l (0.2 microgram/l). In general, the measurement of benzene in blood and in exhaled air, as well as benzene and its metabolites MA and S-PMA in urine, all gave similar results. However, at low exposure level (< 1 cm3/m3) the most reliable analyses were MA in urine and benzene in blood.

Acetylcysteine↗
PubMed2003

Variations of the ambient dose equivalent rate in the ground level air.

The ambient dose equivalent rate is caused by ionizing radiation of radionuclides in the atmosphere and on the ground surface as well as by cosmic radiation. Seasonal and diurnal variations of the ambient dose equivalent rate (ADER) in the ground level air are influenced by the concentration of 222Rn daughters. The 222Rn concentration in the ground level atmosphere, in turn, depends on the rate of the 222Rn exhalation from soil and turbulent air mixing. Its diurnal and seasonal variations depend on meteorological conditions. The aim of this study is to estimate the influence of variations of the rate of the 222Rn exhalation from soil and its concentrations in the ground level air on variations of ADER in the ground level air, as well as the dependence of these parameters on meteorological conditions. The 222Rn diffusion coefficient and its exhalation rate in undisturbed loamy soil have been determined. The 222Rn concentration in the soil air and its concentration in the ground level air correlate inversely (correlation coefficient is r = -0.62). The main factors determining the 222Rn exhalation from soil are: the soil temperature (r = 0.64), the difference in temperature of soil and air (r = 0.57), and the precipitation amount (r = 0.50). The intensity of gamma radiation in the ground level air is mostly related to the 222Rn concentration in the air (r = 0.62), while the effect of the exhalation rate from soil is relatively low (r = 0.36). It has been shown that ADER due to 222Rn progeny causes only 7-16% of the total ADER and influences its variation. The comparison of variations of ADER due to 222Rn progeny and the total ADER during several years shows that these parameters correlate positively.

Air Pollutants, Radioactive↗
PubMed1997

Impact of nitric oxide on blood pressure in hemodialysis patients.

Nitric oxide (NO) is a powerful vasoactive agent that contributes to the regulation of blood pressure (BP). However, the role of NO in uremic patients and during the course of hemodialysis is still debated. Blood L-arginine concentrations and exhaled NO concentrations were measured in 22 healthy controls and in 22 hemodialysis patients before and after dialysis. On the basis of their BP response during hemodialysis, the patients were divided into three groups: 6 of the 22 patients presented with a decrease in BP during dialysis (group 1), eight presented with a stable BP (group 2), and eight with an increase in BP (group 3). The exhaled NO concentration was higher in dialysis patients than in healthy controls (22.7 +/- 2.6 ppb in dialysis patients v 16.7 +/- 0.9 ppb in controls, mean +/- SEM, P = 0.044). The predialysis and postdialysis exhaled NO concentrations were inversely correlated with the change in BP during hemodialysis (r = -0.47, P = 0.013). Patients with a decrease in BP (group 1) had the highest NO concentrations; patients with an increase in BP (group 3) had the lowest values; and patients with a stable BP during the course of dialysis (group 2) had intermediary values (trend test, P = 0.0291). In addition, both the exhaled NO concentration and the blood L-arginine concentration decreased during dialysis in all patients (P = 0.005 and P = 0.001, respectively). These results provide several novel insights into NO metabolism and BP regulation during hemodialysis: (1) maintenance hemodialysis is associated with a chronic increase in NO concentrations; (2) changes in BP during hemodialysis are inversely correlated with exhaled NO concentrations, higher NO levels being associated with a decrease in BP and lower NO levels with an increase in BP during dialysis; (3) blood L-arginine levels decrease during hemodialysis, and this reduction may in turn influence NO production.

Adult↗
PubMed2002

Precise and real-time measurement of 3D tumor motion in lung due to breathing and heartbeat, measured during radiotherapy.

PURPOSE: In this work, three-dimensional (3D) motion of lung tumors during radiotherapy in real time was investigated. Understanding the behavior of tumor motion in lung tissue to model tumor movement is necessary for accurate (gated or breath-hold) radiotherapy or CT scanning. METHODS: Twenty patients were included in this study. Before treatment, a 2-mm gold marker was implanted in or near the tumor. A real-time tumor tracking system using two fluoroscopy image processor units was installed in the treatment room. The 3D position of the implanted gold marker was determined by using real-time pattern recognition and a calibrated projection geometry. The linear accelerator was triggered to irradiate the tumor only when the gold marker was located within a certain volume. The system provided the coordinates of the gold marker during beam-on and beam-off time in all directions simultaneously, at a sample rate of 30 images per second. The recorded tumor motion was analyzed in terms of the amplitude and curvature of the tumor motion in three directions, the differences in breathing level during treatment, hysteresis (the difference between the inhalation and exhalation trajectory of the tumor), and the amplitude of tumor motion induced by cardiac motion. RESULTS: The average amplitude of the tumor motion was greatest (12 +/- 2 mm [SD]) in the cranial-caudal direction for tumors situated in the lower lobes and not attached to rigid structures such as the chest wall or vertebrae. For the lateral and anterior-posterior directions, tumor motion was small both for upper- and lower-lobe tumors (2 +/- 1 mm). The time-averaged tumor position was closer to the exhale position, because the tumor spent more time in the exhalation than in the inhalation phase. The tumor motion was modeled as a sinusoidal movement with varying asymmetry. The tumor position in the exhale phase was more stable than the tumor position in the inhale phase during individual treatment fields. However, in many patients, shifts in the exhale tumor position were observed intra- and interfractionally. These shifts are the result of patient relaxation, gravity (posterior direction), setup errors, and/or patient movement.The 3D trajectory of the tumor showed hysteresis for 10 of the 21 tumors, which ranged from 1 to 5 mm. The extent of hysteresis and the amplitude of the tumor motion remained fairly constant during the entire treatment. Changes in shape of the trajectory of the tumor were observed between subsequent treatment days for only one patient. Fourier analysis revealed that for 7 of the 21 tumors, a measurable motion in the range 1-4 mm was caused by the cardiac beat. These tumors were located near the heart or attached to the aortic arch. The motion due to the heartbeat was greatest in the lateral direction. Tumor motion due to hysteresis and heartbeat can lower treatment efficiency in real-time tumor tracking-gated treatments or lead to a geographic miss in conventional or active breathing controlled treatments. CONCLUSION: The real-time tumor tracking system measured the tumor position in all three directions simultaneously, at a sampling rate that enabled detection of tumor motion due to heartbeat as well as hysteresis. Tumor motion and hysteresis could be modeled with an asymmetric function with varying asymmetry. Tumor motion due to breathing was greatest in the cranial-caudal direction for lower-lobe unfixed tumors.

Adenocarcinoma↗
PubMed1999

Non-invasive evaluation of lower airway inflammation in hyper-responsive elite cross-country skiers and asthmatics.

Asthma-like symptoms and bronchial hyper-responsiveness (BHR) to methacholine are prevalent in competitive cross-country skiers. Whether these symptoms (ski asthma) in these athletes are caused by asthma remains uncertain. Bronchial responsiveness to adenosine 5'-monophosphate (AMP) and nitric oxide (NO) concentration in exhaled air, both indirect markers of asthmatic airway inflammation, were investigated in two non-smoking study populations of skiers and asthmatics. Of 18 skiers with ski asthma, 15 non-steroid and 14 steroid-treated asthmatics, BHR to AMP was present in five (28%), six (40%) and 10 (71%) subjects respectively. Although the groups were not significantly different in responsiveness to methacholine, responsiveness to AMP increased in order of magnitude from ski asthma < non-steroid-treated < steroid-treated asthma. Exhaled NO in 44 (nine with ski asthma) skiers was not significantly different from 82 healthy non-atopic controls [median [interquartile range (IQR)] 6.5 (4.1-9.9) vs. 5.2 (4.2-6.5) ppb]. Exhaled NO in 29 subjects with mild intermittent asthma was three-fold greater [median (IQR) 19.2 (5.1-25.6) ppb, P < 0.01] than in skiers. Exhaled NO was two- and four-fold greater in atopic than non-atopic subjects in the skier (P < 0.001) and asthmatic (P < 0.01) groups, respectively, and was correlated to methacholine responsiveness in atopic asthmatics (n = 22, rho = 0.55, P < 0.01). Exhaled NO was not elevated in ski asthma and may be more useful as a marker of atopic status than inflammation in the lower airway in skiers. Few skiers were hyper-responsive to AMP, indicating that pre-activated mucosal mast cells are not a predominant feature in ski asthma.

Adenosine Monophosphate↗
PubMed1998

Increased production of endogenous nitric oxide in patients with bronchial asthma and chronic obstructive pulmonary disease.

BACKGROUND: Nitric oxide (NO) plays an important role as an inflammatory mediator in the airways. Though direct measurement of endogenous NO has been difficult in humans, we have recently found that measurement of NO derivatives in induced sputum may be useful for assessing airway inflammation in asthmatic patients. OBJECTIVE: This study was designed to determine the direct in vivo evidence of increased production of endogenous NO in patients with bronchial asthma and chronic obstructive pulmonary disease (COPD). METHODS: We have investigated simultaneous assessment of NO using two non-invasive methods, such as NO level in exhaled air and induced sputum, in these patients. We determined the concentration of stable end-products of NO (nitrite plus nitrate) in induced sputum and exhaled NO concentration using a chemiluminescence analyser in 10 normal controls, 10 asthmatic patients and 11 patients with COPD, and evaluated whether endogenous NO levels correlate with percentage of neutrophils and interleukin-8 (IL-8) level in induced sputum in patients with COPD. RESULTS: We found significantly higher concentrations of exhaled NO in patients with bronchial asthma (25.1 [5.1] p.p.b.) than in patients with COPD (12.1 [1.9] p.p.b.) and normal controls (5.2 [1.4] p.p.b.). However, higher concentrations of NO derivatives in induced sputum were found in patients with bronchial asthma (1190 [106] micromol/L) and COPD (950 [105] micromol/L) than in normal controls (514 [30] micromol/L). In patients with asthma, but not in those with COPD, concentrations of NO derivatives in induced sputum were significantly correlated with concentrations of exhaled NO (r = 0.64, P < 0.05). Moreover, in patients with COPD, concentrations of NO derivatives in induced sputum were significantly correlated with percentage of neutrophils (r = 0.71, P < 0.05) and IL-8 level (r = 0.80, P < 0.01). CONCLUSION: We conclude the increased production of endogenous NO in patients with asthma and COPD, and that NO derivatives in induced sputum are more valuable than exhaled NO in assessing airway inflammation in patients with COPD.

Adult↗
PubMed2000

Inhaled glucocorticosteroids decrease hydrogen peroxide level in expired air condensate in asthmatic patients.

H2O2 is elevated in the exhaled air condensate in several inflammatory disorders of the lung, including bronchial asthma, and thus may reflect inflammatory processes in the airways. Exhaled H2O2 may be used to guide the anti-inflammatory treatment of patients with asthma. Therefore in this study we analysed the effect of inhaled glucocorticosteroid beclomethasone for 4 weeks on H2O2 level in the exhaled air condensate. Seventeen asthmatics and 10 healthy subjects were included to the study. Eleven patients were given inhaled beclomethasone and six were given placebo (3M Health Care). In all patients pulmonary function tests were performed. H2O2 in the expired air condensate was measured spectrofluorimetically (homovanillic acid method). Inhaled beclomethasone significantly decreased H2O2 in the expired air condensate in the active-treatment group, with a fall from baseline on day 1 which remained on day 43 (follow-up) (P<0.05). Exhaled H2O2 in the active-treatment group was significantly lower than that in placebo group (P<0.05). A negative correlation between H2O2 and forced expiratory volume in 1 sec (FEV1) on day 29 was observed. The decrease in exhaled H2O2 in the active-treatment group was accompanied by an improvement in pulmonary function tests results. Inhaled glucocorticoids reduce the level of H2O2 in the expired air condensate of asthmatic patients over a 4-week period and this may reflect their anti-inflammatory activity in lung diseases.

Administration, Inhalation↗
PubMed1999

[Importance and perspectives of breath analysis].

Quantitative chemical analysis of volatile constituents in exhaled gas can provide useful insights into biochemical processes in the body. Relations between the chemical composition of human exhaled air and inflammatory processes, states of high oxidative activity, inhalation or ingestion of various noxious substances as well as diseases like ARDS, pneumonia or sleep apnea have been described. Clinical interpretation of these findings, however, remains difficult because definite marker substances for certain diseases could not yet be identified, substance concentrations in the exhaled air change under various conditions, and results vary in a wide range. Because of very low substance concentrations in the exhaled air sophisticated analytical techniques are necessary. Analyses are hampered by high water content and numerous contaminants in the samples. A clear distinction has to be made between substances originating from within the patient and those coming from outside of the body. Despite all these limitations there is no doubt that relations exist between the chemical composition of human exhaled air and clinical parameters. Upcoming new analytical techniques will allow more efficient extraction and preconcentration of substances in minute concentrations. Fast track bedside analyses will shortly become possible with the introduction of miniature gas chromatographic and mass spectrometric equipment. This will open a new area for clinical and basic research.

Air↗
PubMed2006

Use of a physiologically based pharmacokinetic model to identify exposures consistent with human biomonitoring data for chloroform.

Biomonitoring data provide evidence of human exposure to environmental chemicals by quantifying the chemical or its metabolite in a biological matrix. To better understand the correlation between biomonitoring data and environmental exposure, physiologically based pharmacokinetic (PBPK) modeling can be of use. The objective of this study was to use a combined PBPK model with an exposure model for showering to estimate the intake concentrations of chloroform based on measured blood and exhaled breath concentrations of chloroform. First, the predictive ability of the combined model was evaluated with three published studies describing exhaled breath and blood concentrations in people exposed to chloroform under controlled showering events. Following that, a plausible exposure regimen was defined combining inhalation, ingestion, and dermal exposures associated with residential use of water containing typical concentrations of chloroform to simulate blood and exhaled breath concentrations of chloroform. Simulation results showed that inhalation and dermal exposure could contribute substantially to total chloroform exposure. Next, sensitivity analysis and Monte Carlo analysis were performed to investigate the sources of variability in model output. The variability in exposure conditions (e.g., shower duration) was shown to contribute more than the variability in pharmacokinetics (e.g., body weight) to the predicted variability in blood and exhaled breath concentrations of chloroform. Lastly, the model was used in a reverse dosimetry approach to estimate distributions of exposure consistent with concentrations of chloroform measured in human blood and exhaled breath.

Chloroform↗
PubMed1998

Aerosol penetration behavior of respirator valves.

Exhalation and inhalation valves from half-facepiece negative pressure respirators were evaluated for leakage during an 8-hour cyclic breathing test period using two work rates (415 and 622 kg-m/min) and two particle sizes (0.3 and 0.8 micron). Three different models (manufacturers) of exhalation valves were tested, with two lots for each model. Exhalation valve leakage ranged from 0.0 to 0.03%; no failure of exhalation valves occurred. No differences in lot or manufacturer were found. Differences in particle size did not lead to differences in penetration at the lower work rate; at the higher work rate 0.3-micron particles were less penetrating than 0.8-micron particles (0.03 versus 0.06%). When tested for air leakage at a pressure of 2.54 cm H2O, following the National Institute for Occupational Safety and Health certification method, exhalation valves exhibited no leakage either before or after the experiments. Inhalation valves averaged 20% leakage for all experiments; 0.3-micron particles were again less penetrating (13%) than 0.8-micron particles (27%). No inhalation valve failure occurred. No differences in lot (within manufacturer) were found; there were, however, significant differences in particle penetration among the three manufacturers' inhalation valves. Airflow leakage through the inhalation valves did not change during the experimental period, but differed among the three manufacturers. Measurements using airflow leakage and particle penetration produced the same ranking for the three manufacturers' inhalation valves.

Aerosols↗
PubMed1998

Comparison of six respirator fit-test methods with an actual measurement of exposure in a simulated health care environment: Part I--Protocol development.

Quantitative fit tests (QNFT) have been assumed to be predictive of the protection respirators would provide to a wearer in the workplace. Workplace studies have consistently found no correlation between quantitative fit factors and workplace protection factors. This article is the first in a series of three describing a study designed to compare the fit factors from six QNFT methods against the actual dose of 1,1,2 trichloro-1,2,2 trifluoroethane (Freon-113) received under the same laboratory conditions. Five preliminary studies conducted to develop the protocol to assess the respirator wearer's dose through end-exhaled air analysis are described in this article: (1) chamber characterization, (2) end-exhaled air sampling, (3) skin absorption testing, (4) pharmacokinetic modeling, and (5) subject characterization. It was established that the concentration of corn oil aerosol and Freon-113 could be generated simultaneously in the chamber. It was ascertained that the optimum time to sample the exhaled breath was 30 minutes after the subject exited the chamber. It was also found that in a chamber concentration of 500 ppm, without any respiratory exposure, Freon-113 was still present in the end-exhaled air. This was attributed to skin absorption. The end-exhaled air of subjects exposed to 0.5, 3, 5, 25, 50, and 100 ppm (30 minute time-weighted average) of Freon-113 was evaluated at 30 minutes postexposure. This characterization was then used to predict the actual dose of Freon-113 received during the method comparison and validation testing to be described in subsequent articles.

Adult↗
PubMed2000

Physiologically based pharmacokinetic modeling of the temperature-dependent dermal absorption of chloroform by humans following bath water exposures.

The kinetics of chloroform in the exhaled breath of human volunteers exposed skin-only via bath water (concentrations < 100 ppb) were analyzed using a physiologically based pharmacokinetic (PBPK) model. Significant increases in exhaled chloroform (and thus bioavailability) were observed as exposure temperatures were increased from 30 to 40 degrees C. The blood flows to the skin and effective skin permeability coefficients (Kp) were both varied to reflect the temperature-dependent changes in physiology and exhalation kinetics. At 40 degrees C, no differences were observed between males and females. Therefore, Kps were determined (approximately 0.06 cm/hr) at a skin blood flow rate of 18% of the cardiac output. At 30 and 35 degrees C, males exhaled more chloroform than females, resulting in lower effective Kps calculated for females. At these lower temperatures, the blood flow to the skin was also reduced. Total amounts of chloroform absorbed averaged 41.9 and 43.6 microg for males and 11.5 and 39.9 microg for females exposed at 35 and 40 degrees C, respectively. At 30 degrees C, only 2/5 males and 1/5 females had detectable concentrations of chloroform in their exhaled breath. For perspective, the total intake of chloroform would have ranged from 79-194 microg if the volunteers had consumed 2 liters of water orally at the concentrations used in this study. Thus, the relative contribution of dermal uptake of chloroform to the total body burdens associated with bathing for 30 min and drinking 2 liters of water (ignoring contributions from inhalation exposures) was predicted to range from 1 to 28%, depending on the temperature of the bath.

Adult↗
PubMed2002

Use of real-time breath analysis and physiologically based pharmacokinetic modeling to evaluate dermal absorption of aqueous toluene in human volunteers.

Toluene is a ubiquitous chemical that is commonly used for its solvent properties in industry and manufacturing, and is a component of many paint products. Although human exposure to toluene is most likely to be through inhalation, toluene is also found in well and surface water. Therefore, an assessment of the dermal contribution to total toluene uptake is useful for understanding human exposures. To evaluate the significance of these exposures, the dermal absorption of toluene was assessed in human volunteers using a combination of real-time exhaled breath analysis and physiologically based pharmacokinetic (PBPK) modeling. Human volunteers wearing swimsuits were submerged in warm tap water to neck level in a stainless steel hydrotherapy tub containing an initial concentration of approximately 500-microg/l toluene. Volunteers were provided purified breathing air to eliminate inhalation exposures, and exhaled breath was continually analyzed before, during, and post exposure to track the absorption and subsequent elimination of the compound in real time. A PBPK model was used to estimate the dermal permeability coefficient (K(p)) to describe each set of exhaled breath data from 4-6 human volunteers. An average K(p) value of 0.012 +/- 0.007 cm/h was found to provide a good fit to all data sets. Volunteers also participated in a second study phase, in which the subject was allowed to breathe the room air during immersion, thus both dermal and inhalation exposures to toluene occurred. Exhaled breath analyses revealed that concurrent inhalation of volatilized toluene resulted in a transient increase in the peak exhaled-breath level by 100 ppb, or an approximate 50% increase over breath levels observed in dermal-only studies. For perspective, the total intake of toluene associated with oral consumption of 2 liters of water containing toluene at bath water concentrations were estimated to be more than 30 times greater than the dermal contribution due to bathing.

Administration, Cutaneous↗
PubMed2004

Repeated validation of parental self-reported smoking during pregnancy and infancy: a prospective cohort study of infants at high risk for allergy development.

Exposure to environmental tobacco smoke (ETS) during fetal life and infancy is closely related to the smoking habits of the parents. Estimates of exposure to ETS require valid and detailed information on changes in cigarette smoking over time. The objective was to test the validity of self-reported smoking among parents during pregnancy and early childhood in a cohort of children at high risk for allergy development by measurement of exhaled carbon monoxide (CO). The cohort comprised 117 families enrolled from the general population of pregnant women at admission to antenatal care. Data on parental tobacco smoking were obtained by interview and exhaled CO was measured (Micro-Smokerlyzer(R)) in parents twice during pregnancy and when the child was 6 and 18 months old. The median (range) exhaled CO levels were 3 (0-10) parts per million (ppm) for non-smokers and 15 (1-39) ppm for smokers (P < 0.0005). A receiver operating characteristic (ROC) analysis was performed at each examination. The areas under the ROC curve were high for both mothers (between 0.88 and 0.99) and fathers (between 0.87 and 0.89), indicating exhaled CO as a good diagnostic tool for determining smoking status. Comparing the ROC areas obtained for mothers from late pregnancy and during infancy with the area from early pregnancy showed no statistical differences (P = 0.21, 0.43 and 0.44 respectively) and the same was true for fathers during infancy (P = 0.81). The level of 8 ppm was used as the cut-off between smokers and non-smokers, based on data from a pilot study. Using CO as a diagnostic tool for smoker status showed very high specificity (between 97 and 100%), indicating that very few persons claiming to be non-smokers had CO levels higher than 8 ppm. In conclusion, the validity of interview-obtained self-reported smoking among parents during pregnancy and early childhood was high. Repeated interviews and CO measurements in a prospective study design did not change the validity, indicating a low risk of information bias. A structured interview combined with measurement of exhaled CO is a valid and reliable method for estimating ETS exposure to the fetus and young infant.

Breath Tests↗
PubMed2003

Automated generation of a four-dimensional model of the liver using warping and mutual information.

The use of mutual information (MI) based alignment to map changes in liver shape and position from exhale to inhale was investigated. Inhale and exhale CT scans were obtained with intravenous contrast for six patients. MI based alignment using thin-plate spine (TPS) warping was performed between each inhale and exhale image set. An expert radiation oncologist identified corresponding vessel bifurcations on the exhale and inhale CT image and the transformation for identified points was determined. This transformation was then used to determine the accuracy of the MI based alignment. The reproducibility of the vessel bifurcation identification was measured through repeat blinded vessel bifurcation identification. Reproducibility [standard deviation (SD)] in the L/R, A/P, and I/S directions was 0.11, 0.09, and 0.14 cm, respectively. The average absolute difference between the transformation obtained using MI based alignment and the vessel bifurcation in the L/R, A/P, and I/S directions was 0.13 cm (SD=0.10 cm), 0.15 cm (SD=0.12 cm), and 0.15 cm (SD-0.14 cm), respectively. These values are comparable to the reproducibility of bifurcation identification, indicating that MI based alignment using TPS warping is accurate to within measurement error and is a reliable tool to aid in describing deformation that the liver undergoes from the exhale to inhale state.

Algorithms↗