Automated bidirectional coupling of multiscale models of aerosol dosimetry: validation with subject-specific deposition data.

Assessing the toxicity of airborne particulate matter or the efficacy of inhaled drug depends upon accurate estimates of deposited fraction of inhaled materials. In silico approaches can provide important insights into site- or airway-specific deposition of inhaled aerosols in the respiratory system. In this study, we improved on our recently developed 3D/1D model that simulate aerosol transport and deposition in the whole lung over multiple breath cycles (J. Aerosol Sci 151:105647). A subject-specific multiscale lung model of a healthy male subject using computational fluid-particle dynamics (CFPD) in a 3D model of the oral cavity through the large bronchial airways entering each lobe was bidirectionally coupled with a recently improved Multiple Path Particle Dosimetry (MPPD) model to predict aerosol deposition over the entire respiratory tract over multiple breaths for four conditions matching experimental aerosol exposures in the same subject from which the model was developed. These include two particle sizes (1 and 2.9 µm) and two subject-specific breathing rates of ~300 ml/s (slow breathing) and ~750 ml/s (fast breathing) at a target tidal volume of 1 L. In silico predictions of retained fraction were 0.31 and 0.29 for 1 µm and 0.66 and 0.62 for 2.9 µm during slow and fast breathing, respectively, and compared well with experimental data (1 µm: 0.31±0.01 (slow) and 0.27±0.01 (fast), 2.9 µm: 0.63±0.03 (slow) and 0.68±0.02 (fast)). These results provide a great deal of confidence in the validity and reliability of our approach.

Influence of alveolar mixing and multiple breaths of aerosol intake on particle deposition in the human lungs.

Predictive dosimetry models play an important role in assessing health effect of inhaled particulate matter and in optimizing delivery of inhaled pharmaceutical aerosols. In this study, the commonly used 1D Multiple-Path Particle Dosimetry model (MPPD) was improved by including a mechanistically based model component for alveolar mixing of particles and by extending the model capabilities to account for multiple breaths of aerosol intake. These modifications increased the retained fraction of particles and consequently particle deposition predictions in the deep lung during tidal breathing. Comparison with an existing dataset (J. Aerosol Sci., 99:27-39, 2016) obtained under two breathing conditions referred to as slow and fast breathing showed significant differences in 1 µm particle deposition between predictions based on subject-specific breathing patterns and lung volume (slow: 30 ± 1%, fast: 21 ± 1%, (average ± standard deviation), N = 7) and measurements (slow: 43 ± 9%, fast: 30 ± 5%) when the prior version of MPPD (single breath and no mixing, J. Aerosol Sci., 151:105647, 2021) was used. Adding a mixing model and multiple breaths moved the predictions (slow: 34 ± 2%, fast:25 ± 2%) closer to the range of deposition measurements. For 2.9 µm particles, predictions from both the original (slow: 70 ± 2%, fast: 57 ± 2%) and the revised MPPD model (slow: 71 ± 2%, fast: 59 ± 3%) compared well with experiments (slow: 67 ± 8%, fast: 58 ± 10%). This was expected as suspended fraction of 2.9 µm particles was small and thus the addition of alveolar mixing and multi breath capability only slightly increased the retained fraction for particles of this size and greater. The revised 1D model improves dose predictions in the deep lung and support human risk assessment from exposure to airborne particles.

Efficient bi-directional coupling of 3D Computational Fluid-Particle Dynamics and 1D Multiple Path Particle Dosimetry lung models for multiscale modeling of aerosol dosimetry.

The development of predictive aerosol dosimetry models has been a major focus of environmental toxicology and pharmaceutical health research for decades. One-dimensional (1D) models successfully predict overall deposition averages but fail to accurately predict local deposition. Computational fluid-particle dynamics (CFPD) models provide site-specific predictions but at a computational cost that prohibits whole lung predictions. Thus, there is a need for developing multiscale strategies to provide a realistic subject-specific picture of the fate of inhaled aerosol in the lungs. CT-based 3D/CFPD models of the large airways were bidirectionally coupled with individualized 1D Navier-Stokes airflow and particle transport based upon the widely used Multiple Path Particle Dosimetry Model (MPPD). Distribution of airflows among lobes was adjusted by measured lobar volume changes observed in CT images between FRC and FRC + 1.5 L. As a test of the effectiveness of the coupling procedures, deposition modeling of previous 1 µm aerosol exposure studies was performed. The complete coupled model was run for 3 breaths, with the computation-intense portion being the 3D CFPD Lagrangian particle tracking calculation. The average deposition per breath was 11% in the combined multiscale model with site-specific doses available in the CFPD portion of the model and airway- or region-specific deposition available for the MPPD portion. In conclusion, the key methods developed in this study enable predictions of ventilation heterogeneities and aerosol deposition across the lungs that are not captured by 3D or 1D models alone. These methods can be used as the foundation for multi-scale modeling of the full respiratory system.

Computational modeling of nanoscale and microscale particle deposition, retention and dosimetry in the mouse respiratory tract.

Comparing effects of inhaled particles across rodent test systems and between rodent test systems and humans is a key obstacle to the interpretation of common toxicological test systems for human risk assessment. These comparisons, correlation with effects and prediction of effects, are best conducted using measures of tissue dose in the respiratory tract. Differences in lung geometry, physiology and the characteristics of ventilation can give rise to differences in the regional deposition of particles in the lung in these species. Differences in regional lung tissue doses cannot currently be measured experimentally. Regional lung tissue dosimetry can however be predicted using models developed for rats, monkeys, and humans. A computational model of particle respiratory tract deposition and clearance was developed for BALB/c and B6C3F1 mice, creating a cross-species suite of available models for particle dosimetry in the lung. Airflow and particle transport equations were solved throughout the respiratory tract of these mice strains to obtain temporal and spatial concentration of inhaled particles from which deposition fractions were determined. Particle inhalability (Inhalable fraction, IF) and upper respiratory tract (URT) deposition were directly related to particle diffusive and inertial properties. Measurements of the retained mass at several post-exposure times following exposure to iron oxide nanoparticles, micro- and nanoscale C60 fullerene, and nanoscale silver particles were used to calibrate and verify model predictions of total lung dose. Interstrain (mice) and interspecies (mouse, rat and human) differences in particle inhalability, fractional deposition and tissue dosimetry are described for ultrafine, fine and coarse particles.

A lung dosimetry model of vapor uptake and tissue disposition.

Inhaled vapors may be absorbed at the alveolar-capillary membrane and enter arterial blood flow to be carried to other organs of the body. Thus, the biological effects of inhaled vapors depend on vapor uptake in the lung and distribution to the rest of the body. A mechanistic model of vapor uptake in the human lung and surrounding tissues was developed for soluble and reactive vapors during a single breath. Lung uptake and tissue disposition of inhaled formaldehyde, acrolein, and acetaldehyde were simulated for different solubilities and reactivities. Formaldehyde, a highly reactive and soluble vapor, was estimated to be taken up by the tissues in the upper tracheobronchial airways with shallow penetration into the lung. Vapors with moderate solubility such as acrolein and acetaldehyde were estimated to penetrate deeper into the lung, reaching the alveolar region where absorbed vapors had a much higher probability of passing through the thin alveolar-capillary membrane to reach the blood. For all vapors, tissue concentration reached its maximum at the end of inhalation at the air-tissue interface. The depth of peak concentration moved within the tissue layer due to vapor desorption during exhalation. The proposed vapor uptake model offers a mechanistic approach for calculations of lung vapor uptake, air:tissue flux, and tissue concentration profiles within the respiratory tract that can be correlated to local biological response in the lung. In addition, the uptake model provides the necessary input for pharmacokinetic models of inhaled chemicals in the body, thus reducing the need for estimating requisite parameters.

Derivation of mass transfer coefficients for transient uptake and tissue disposition of soluble and reactive vapors in lung airways.

Evaluation of vapor uptake by lung airways and subsequent dose to lung tissues provides the bridge connecting exposure episode to biological response. Respiratory vapor absorption depends on chemical properties of the inhaled material, including solubility, diffusivity, and metabolism/reactivity in lung tissues. Inter-dependent losses in the air and tissue phases require simultaneous calculation of vapor concentration in both phases. Previous models of lung vapor uptake assumed steady state, one-way transport into tissues with first-order clearance. A new approach to calculating lung dosimetry is proposed in which an overall mass transfer coefficient for vapor transport across the air-tissue interface is derived using air-phase mass transfer coefficients and analytical expressions for tissue-phase mass transfer coefficients describing unsteady transport by diffusion, first-order, and saturable pathways. Feasibility of the use of mass transfer coefficients was shown by calculating transient concentration levels of inhaled formaldehyde in the human tracheal airway and surrounding tissue. Formaldehyde tracheal air concentration and wall-flux declined throughout the breathing cycle. After the inhalation period, peak tissue concentration moved from the air-tissue interface into the tissue due to desorption into the air and continued diffusional transport across the tissue layer. While model predictions were performed for formaldehyde, which serves as a model of physiologically relevant, highly reactive vapors, the model is equally applicable to other soluble and reactive compounds.

Airflow distribution in the human lung and its influence on particle deposition.

Realistic descriptions of lung geometry and physiology are the primary determinants of accurate predictions of inhaled particle deposition and distribution in the human lung. While there have been considerable efforts devoted to geometry reconstruction, little attention has been given to lung ventilation as applied to particle deposition applications. Models of lung ventilation based on pressure differential between extrathoracic airways and the pleural cavity were developed and used to calculate lobar and regional deposition of particles in the human lung. Local airflow in the lung varied in accordance with regional physiological properties. Calculations showed that airflow rate entering each lobe was different for compliant and noncompliant lung models and similar for uniform and nonuniform lung expansions. Regional particle deposition predictions were almost identical between the two compliance models. However, differences in lobar depositions were observed. The coupled lung ventilation and deposition models can be used in site-specific deposition predictions of inhaled particles in the human lungs.

Influence of exhaled air on inhalation exposure delivered through a directed-flow nose-only exposure system.

In order to conserve material that is available in limited quantities, "directed-flow" nose-only exposure systems have at times been run at flow rates close to the minute ventilation of the animal. Such low-flow-rate conditions can contribute to a decrease of test substance concentration in inhaled air; near the animal nose, exhaled air and the directed flow of exposure air move in opposite directions. With a Cannon "directed-flow" nose-only exposure system (Lab Products, Maywood, NJ), we investigated the extent to which exposure air plus exhaled air can be inhaled by an animal. A mathematical model and a mechanical simulation of respiration were adopted to predict for a male Fischer 344 rat the concentration of test substance in inhaled air. The mathematical model was based on the assumption of instantaneous mixing. The mechanical simulation of respiration used a Harvard respirator. When the system was operated at an exposure air flow rate greater than 2.5 times the minute ventilation of the animal, the concentration of test substance in the inhaled air was reduced by less than 10%. Under these conditions, the circular jet of air exiting the exposure air delivery tube tended to reach the animal's nose with little dispersion. For exposure air flow rates less than 2 times the minute ventilation, we predict that the interaction of exhaled air and exposure air can be minimized by proportionally reducing the delivery tube diameter. These findings should be applicable to similar "directed-flow" nose-only exposure systems.

Modeling age-related particle deposition in humans.

Inhalation of airborne material poses a potential health risk to various subpopulations one of which is children. Little is known about the fate of particles in the respiratory tracts of children. Modeling efforts have been limited due largely to the lack of adequate information on lung geometry during growth. Lung morphometry measurements in children and adults between 3 months and 21 years of age were used to create 5-lobe lung geometries. Each lobe had a dichotomous, symmetric branching structure and was structurally different from the other lobes. The lung geometries were used in a multiple-path particle deposition model to calculate particle deposition fractions in different regions, lobes and airway generations of the lungs. Simulated breathing patterns were representative of resting breathing. Age-dependent, semi-empirical expressions of particles losses in the nasal airways, which were based on fits to the available experimental measurements, showed larger nasal deposition in adults than in children. Predicted tracheobronchial deposition patterns were similar among different ages for a given particle size. In the alveolar region, the predicted deposition fraction varied with age such that a clear trend could not be identified. Deposition fraction in a lobe was proportional to the volume of air going to that lobe. Deposition fractions in the lower left and right lobes were similar but higher than those in the other lobes for a given particle diameter. Lobar deposition fraction adjusted for lobar lung volume or lung deposition fraction adjusted for lung volume was found to be a unique property for an individual and presented a means for age-dependent deposition comparisons. The adjusted tracheobronchial and pulmonary deposition fractions were greatest for infants and decreased with age. A similar trend was also observed for deposition fraction per unit area as a function of airway generation. The distribution of particle deposition fraction per unit surface area varied with particle size for an individual, with ultrafine particles being more uniformly distributed throughout the lungs and coarse particles depositing primarily in the first few tracheobronchial airways. The trend of particle deposition with age indicates that children, particularly infants, may be at a greater health risk from exposure to airborne particulate matter and noxious materials all other conditions being equal. The age-dependent predicted deposition fraction pattern per unit area of different size particles has implications in the calculation of inhaled reference concentrations as well as site-specific delivery of drugs and other therapeutic compounds to the lungs of patients.

Prospective study of the ability of histamine, serotonin or serum chromogranin A levels to identify gastric carcinoids in patients with gastrinomas.

BACKGROUND: Chronic hypergastrinaemia causes gastric enterochromaffin cell proliferation and carcinoid tumours. The only reliable means to diagnose enterochromaffin cell changes/carcinoids is by biopsy. AIM: To assess whether serum histamine, chromogranin A or serotonin and urinary N-methylimidazoleacetic acid or 5-hydroxyindoleacetic acid correlate with advanced enterochromaffin cell changes or gastric carcinoids in patients with gastrinomas. METHODS: Consecutive patients (n=145) had the above assays and endoscopy with gastric biopsies. RESULTS: Lower N-methylimidazoleacetic acid and chromogranin A levels (P < 0.0001) occurred in disease-free patients. In patients with active disease, the fasting serum gastrin levels correlated (P < 0.0001) with both chromogranin A and N-methylimidazoleacetic acid levels. Chromogranin A (P=0.005), but not N-methylimidazoleacetic acid, serotonin, 5-hydroxyindoleacetic acid or histamine levels, correlated with the enterochromaffin cell index. Carcinoids, but not advanced enterochromaffin cell changes only, were associated with higher chromogranin A and N-methylimidazoleacetic acid levels. CONCLUSIONS: Serum chromogranin A levels and urinary N-methylimidazoleacetic acid levels, but not serum histamine or serotonin or urinary 5-hydroxyindoleacetic acid, correlate with the presence of gastric carcinoids. However, no assay identified patients with advanced enterochromaffin cell changes only with high sensitivity/specificity. Thus, N-methylimidazoleacetic acid and chromogranin A levels are unable to identify patients with advanced changes in enterochromaffin cells and therefore neither can replace routine gastric biopsies.

In vivo measurement of fine and coarse aerosol deposition in the nasal airways of female Long-Evans rats.

Experimental data on fine and coarse aerosol deposition in the nasal airways of animals are essential in appropriately using toxicological studies to assess the potential risk to human health from exposure to airborne pollutants. However, such data are scarce. The objective of this study was to determine aerosol deposition efficiencies for the nasal airways in Long-Evans rats for particles with diameters ranging from 0.5 to 4 microm. Polystyrene latex (PSL) microspheres in steady-state and pulsatile flows were passed through the nasal airways for simulated inspiratory and expiratory scenarios. Average flow rates ranged from 220 to 640 ml/min. Deposition increased sharply with increasing particle inertia for all exposure scenarios. Expiratory deposition efficiency appeared to be somewhat higher than inspiratory deposition efficiency for both steady-state and pulsatile flow conditions. Pulsatile flow yielded significantly higher deposition than steady-state flow. This result emphasizes the importance of considering fluid accelerations inherent in normal breathing when determining aerosol deposition that is dominated by inertial impaction. Variability in the data, which was suspected to result primarily from the difficult surgical procedure, was in excess of expected intersubject variability. The results of this study will be incorporated into extrapolation-modeling and risk-assessment activities for inhaled pollutants.

Deposition of fine and coarse aerosols in a rat nasal mold.

The objective of this study was to investigate the deposition characteristics of large, inhalable particles in rat nasal passages by determining the deposition efficiencies of these particles in a nasal mold of an F344 rat for steady-state and pulsating flow conditions. Particles with geometric diameters ranging from 0.5 to 4 microm and flow rates ranging from 100 to 900 ml/min were employed for simulated inspiratory and expiratory flow situations. The optically clear acrylic mold was fabricated from a life-size metal cast that comprised the nares, nasal cavity, pharynx, and larynx. Deposition efficiencies were calculated for each flow situation and plotted as functions of particle inertia. Inspiratory and expiratory deposition efficiencies were similar for a given flow condition. Deposition efficiencies for the cases of pulsating flows were markedly higher than those of steady flows. The results for pulsating flows indicated higher deposition efficiencies than were found in previous studies performed with live rats. These differences may be due to uncertainties in particle inhalability, clearance, and flow rate in the previous studies, as well as differences between the nasal geometries of live rats and the geometry of the nasal mold made from a postmortem cast. The results suggest that the pulsating nature of breathing is an important consideration when determining the deposition of fine and coarse particles.

The effect of heterogeneity of lung structure on particle deposition in the rat lung.

Differences in particle deposition patterns between human and rat lungs may be attributed primarily to their differences in breathing patterns and airway morphology. Heterogeneity of lung structure is expected to impact acinar particle deposition in the rat. Two different morphometric models of the rat lung were used to compute particle deposition in the acinar airways: the multiple-path lung (MPL) model (Anjilvel and Asgharian, 1995, Fundam. Appl. Toxicol. 28, 41-50) with a fixed airway geometry, and the stochastic lung (SL) model (Koblinger and Hofmann, 1988, Anat. Rec. 221, 533-539) with a randomly selected branching structure. In the MPL model, identical acini with a symmetric subtree (Yeh et aL, 1979, Anat. Rec. 195, 483-492) were attached to each terminal bronchiole, while the respiratory airways in the SL model are represented by an asymmetric stochastic subtree derived from morphometric data on the Sprague-Dawley rat (Koblinger et al., 1995, J. Aerosol. Med. 8, 7-19). In addition to the original MPL and SL models, a hybrid lung model was also used, based on the MPL bronchial tree and the SL acinar structure. Total and regional deposition was calculated for a wide range of particle sizes under quiet and heavy breathing conditions. While mean total bronchial and acinar deposition fractions were similar for the three models, the SL and hybrid models predicted a substantial variation in particle deposition among different acini. The variances of acinar deposition in the MPL model were consistently much smaller than those for the SL and the hybrid lung model. The similarity of acinar deposition variations in the two latter models and their independence on the breathing pattern suggests that the heterogeneity of the acinar airway structure is primarily responsible for the heterogeneity of acinar particle deposition.

Protein Carbonyls in Bronchoalveolar Lavage Fluid in Mice, Rats and Hamsters Following Inhalation of Pigmentary Titanium Dioxide Particles.

Elevation of protein carbonyls has been implicated in the clinical setting as a result of oxidant damage associated with a number of disease states in both humans and laboratory animals. Protein carbonyls, the product of oxidative modification of amino acid residues, may result from macrophage and neutrophil inflammatory responses to inhaled particles. We hypothesized that increased levels of protein carbonyl groups in the bronchoalveolar lavage fluid (BALF) may serve as a biomarker of oxidative stress in rodents exposed to extremely high airborne concentrations of poorly soluble particles (PSP) of low toxicity. The objective of the present study was to compare the BALF protein carbonyl levels in three rodent species following a subchronic PSP exposure known to result in pulmonary pathology in chronically exposed rats under similar conditions. Female Fischer 344 rats, B6C3F1 mice, and Syrian golden hamsters were identically exposed by whole-body inhalation to concentrations of aerosolized pigmentary titanium dioxide (TiO2)(MMAD and GSD, 1.42 and 1.3 µm, respectively) for 6 h/day and 5 days/wk for 13 wk. Groups of animals were exposed to 0, 10, 50, or 250 mg/m(3) of pigmentary TiO2. Levels of protein carbonyl groups in BALF were measured at the termination of the 13-wk exposure with an ELISA assay utilizing a 2,4-dinitrophenylhydrazine fluorescent probe. Protein carbonyl levels were elevated in rats at both the mid and high dose (50 and 250 mg/m(3)), while in mice and hamster the levels were elevated only at the high dose (250 mg/m(3)). The elevations in protein carbonyl levels paralleled changes in BALF-associated cytologic and biochemical inflammatory indices, including total protein levels and neutrophil counts. Inflammatory changes in all three species were limited to animals exposed to the highest concentrations of particles. Rats were the only species tested that had coincidental elevation of both protein carbonyls and a high inflammatory response measured in BALF following the 50-mg/m(3) exposure. These results suggest that the measurement of protein carbonyl groups in BALF may be a useful biomarker of particle-induced oxidant change, although this endpoint should be used in conjunction with other oxidative endpoints as a total assessment of oxidant stress.

Comparison of Selected Pulmonary Responses of Rats, Mice, and Syrian Golden Hamsters to Inhaled Pigmentary Titanium Dioxide.

We present a preliminary report of a bioassay designed to compare and contrast selected pulmonary responses of female B6C3F1 mice, Fischer 344 rats, and Syrian golden hamsters to inhaled pigmentary titanium dioxide (TiO2). Animals were administered 10, 50, or 250 mg/m(3) TiO2 for 6 h/day and 5 days/wk, for 13 wk. Recovery groups were held for an additional 4-, 13-, or 26-wk period. Following exposure and at each recovery time, TiO2 burdens in the lung and lung-associated lymph nodes were determined. A separate group of animals was used at each time point to assess the inflammatory response of the lung by assaying total protein in bronchoalveolar lavage fluid (BALF) and cytologic examination of cells recovered in BALF. Burdens (mg/mg dry weight) of TiO2 in the lung following exposure to 10, 50, or 250 mg/m(3) TiO2 were 5.2, 53.5, and 170.2 for the mouse; 7.1, 45.1, and 120.4 for the rat; and 2.6, 14.9, and 120.3 for the hamster. With time after exposure, lung burdens of TiO2 particles were decreased and lymph-node burdens increased. Changes in the hamsters' burdens were more rapid than those in mice and rats. Increases in BALF cell numbers (macrophages and neutrophils) and in total protein were observed in all 3 species following exposure to 50 and 250 mg/m(3) TiO2, with the magnitude of response being the grea test in the rat. These responses remained elevated relative to control levels at 26 wk postexposure. Histopathologic examination of lungs showed a concentration-dependent retention pattern of particles that varied by species. Hypertrophy and hyperplasia of alveolar epithelium along with alveolar metaplastic and fibrotic changes were observed in rats exposed to 250 mg/m(3) TiO2. Alveolar epithelial proliferative changes were associated with inflammation in mice and hamsters, but the metaplastic and fibrotic changes noted in rats were not present in similarly exposed mice or hamsters. These data suggest that rats exposed subchronically to extremely high concentrations of pigmentary TiO2 differ from mice and hamsters in their cellular responses in the lung as well as in the way they clear and sequester particles. These differences may partly explain the differential outcome of pulmonary responses in various rodent species following chronic inhalation exposure to poorly soluble particles.

Influence of gender and acetone pretreatment on benzene metabolism in mice exposed by nose-only inhalation.

Benzene (BZ) requires oxidative metabolism catalyzed by cytochrome P-450 2E1 (CYP 2E1) to exert its hematotoxic and genotoxic effects. We previously reported that male mice have a two-fold higher maximum rate of BZ oxidation compared with female mice; this correlates with the greater sensitivity of males to the genotoxic effects of BZ as measured by micronuclei induction and sister chromatid exchanges. The aim of this study was to quantitate levels of BZ metabolites in urine and tissues, and to determine whether the higher maximum rate of BZ oxidation in male mice would be reflected in higher levels of hydroxylated BZ metabolites in tissues and water-soluble metabolites in urine. Male and female B6C3F, mice were exposed to 100 or 600 ppm 14C-BZ by nose-only inhalation for 6 h. An additional group of male mice was pretreated with 1% acetone in drinking water for 8 d prior to exposure to 600 ppm BZ; this group was used to evaluate the effect of induction of CYP 2E1 on urine and tissue levels of BZ and its hydroxylated metabolites. BZ, phenol (PHE), and hydroquinone (HQ) were quantified in blood, liver, and bone marrow during exposure and postexposure, and water-soluble metabolites were analyzed in urine in the 48 h after exposure. Male mice exhibited a higher flux of BZ metabolism through the HQ pathway compared with females after exposure to either 100 ppm BZ (32.0 2.03 vs. 19.8 2.7%) or 600 ppm BZ (14.7 1.42 vs. 7.94 + 0.76%). Acetone pretreatment to induce CYP 2E1 resulted in a significant increase in both the percent and mass of urinary HQ glucuronide and muconic acid in male mice exposed to 600 ppm BZ. This increase was paralleled by three- to fourfold higher steady-state concentrations of PHE and HQ in blood and bone marrow of acetone-pretreated mice compared with untreated mice. These results indicate that the higher maximum rate of BZ metabolism in male mice is paralleled by a greater proportion of the total flux of BZ through the pathway for HQ formation, suggesting that the metabolites formed along this pathway may be responsible for the genotoxicity observed following BZ exposure.

A multiple-path model of fiber deposition in the rat lung.

An asymmetric multiple-path model of particle deposition in the lung airways developed previously (S. Anjilvel and B. Asgharian, 1995, Fundam. Appl. Toxicol. 28, 41-50), was extended to calculate deposition of fibers in the rat lung by replacing the deposition efficiency expressions for particles with those of fibers. The effects of various parameters such as breathing parameters or fiber dimensions on deposition were studied. Fiber deposition fraction for one single breath was calculated per acini, lobe, and region of interest in the lung. The results were compared with one other model prediction and with data available in the literature. Good agreement between the model predictions and other studies was found.

Ethylene oxide dosimetry in the mouse.

Ethylene oxide (EO) is a direct-acting mutagen and animal carcinogen used as an industrial intermediate and sterilant with a high potential for human exposure. Understanding the exposure-dose relationship for EO in rodents is critical for developing human EO exposure-dose models. The study reported here examined the dosimetry of EO in male B6C3F1 mice by direct determination of blood EO concentrations. Steady-state blood EO concentrations were measured during a single 4-h nose-only inhalation exposure (0, 50, 100, 200, 300, or 400 ppm EO). In addition, glutathione (GSH) concentrations were measured in liver, lung, kidney, and testis to assess the role of the GSH depletion in the saturable metabolism previously observed in mice (Brown et al., Toxicol. Appl. Pharmacol. 136, 8-19, 1996). Blood EO concentrations were found to increase linearly with exposure concentration up to 200 ppm. Markedly sublinear blood dosimetry was observed at exposure concentrations exceeding 200 ppm. An EO exposure concentration-dependent reduction in tissue GSH levels was observed, with both liver and lung GSH levels significantly depressed at EO exposure concentrations of 100 ppm or greater. Our results also indicate that depletion of GSH is likely responsible for nonlinear dosimetry of EO in mice and that GSH depletion corresponds with reports of dose-rate effects in mice exposed to EO.

Evaluation of the metabolism and hepatotoxicity of styrene in F344 rats, B6C3F1 mice, and CD-1 mice following single and repeated inhalation exposures.

Styrene is used for the manufacture of plastics and polymers. The metabolism and hepatotoxicity (mice only) of styrene was compared in male B6C3F1 mice, CD-1 mice, and F344 rats to evaluate biochemical mechanisms of toxicity. Rats and mice were exposed to 250 ppm styrene for 6 h/day for 1 to 5 days, and liver (mice only) and blood were collected following each day of exposure. Mortality and increased serum alanine aminotransferase (ALT) activity were observed in mice but not in rats. Hepatotoxicity in B6C3F1 mice was characterized by severe centrilobular congestion after one exposure followed by acute centrilobular necrosis. Hepatotoxicity was delayed by 1 day in CD-1 mice, and the increase in ALT and degree of necrosis was less than observed for B6C3F1 mice. Following exposure to unlabeled styrene for 0, 2, or 4 days, rats and mice were exposed to [7-14C]-styrene (60 microCi/mmol) for 6 h. Urine, feces, and expired air were collected for up to 48 h. Most styrene-derived radioactivity was excreted in urine. The time-course of urinary excretion indicates that rats and CD-1 mice eliminated radioactivity at a faster rate than B6C3F1 mice following a single 250 ppm exposure, consistent with a greater extent of liver injury for B6C3F1 mice. The elimination rate following 3 or 5 days of exposure was similar for rats and both mouse strains. Following three exposures, the total radioactivity eliminated in excreta was elevated over that measured for one exposure for both mouse strains. An increased excretion of metabolites on multiple exposure is consistent with the absence of ongoing acute necrosis following 4 to 5 daily exposures. These data indicate that an induction in styrene metabolism occurs after multiple exposures, resulting in an increased uptake and/or clearance for styrene.

A comparison of physiologically based pharmacokinetic model predictions and experimental data for inhaled ethanol in male and female B6C3F1 mice, F344 rats, and humans.

Ethanol is added to unleaded gasoline as an oxygenate to decrease carbon monoxide automobile emissions. This introduces inhalation as a new possible route of environmental exposure to humans. Knowledge of the pharmacokinetics of inhaled ethanol is critical for adequately assessing the dosimetry of this chemical in humans. The purpose of this study was to characterize the pharmacokinetics of inhaled ethanol in male and female B6C3F1 mice and F344 rats and to develop a physiologically based pharmacokinetic (PBPK) model for inhaled ethanol in mice, rats, and humans. During exposure to 600 ppm for 6 hr, steady-state blood ethanol concentrations (BEC) were reached within 30 min in rats and within 5 min in mice. Maximum BEC ranged from 71 microM in rats to 105 microM in mice. Exposure to 200 ppm ethanol for 30 min resulted in peak BEC of approximately 25 microM in mice and approximately 15 microM in rats. Peak BEC of about 10 microM were measured following exposure to 50 ppm in female rats and male and female mice, while blood ethanol was undetectable in male rats. No sex-dependent differences in peak BEC at any exposure level were observed. Species-dependent differences were found following exposure to 200 and 600 ppm. A blood flow limited PBPK model for ethanol inhalation was developed in mice, rats, and humans which accounted for a fractional absorption of ethanol. Compartments for the model included the pulmonary blood and air, brain, liver, fat, and rapidly perfused and slowly perfused tissues. The PBPK model accurately simulated BEC in rats and mice at all exposure levels, as well as BEC reported in human males in previously published studies. Simulated peak BEC in human males following exposure to 50 and 600 ppm ranged from 7 to 23 microM and 86 and 293 microM, respectively. These results illustrate that inhalation of ethanol at or above the concentrations expected to occur upon refueling results in minimal BEC and are unlikely to result in toxicity.