Dosimetry modeling of inhaled formaldehyde: the human respiratory tract.

Formaldehyde (HCHO), which has been shown to be a nasal carcinogen in rats and mice, is used widely and extensively in various manufacturing processes. Studies in rhesus monkeys suggest that the lower respiratory tract may be at risk and some epidemiologic studies have reported an increase in lung cancer associated with HCHO; other studies have not. Thus, an assessment of possible human risk to HCHO exposure based on dosimetry information throughout the respiratory tract (RT) is desirable. To obtain dosimetry estimates for a risk assessment, two types of models were used. The first model (which is the subject of another investigation) used computational fluid dynamics (CFD) to estimate local fluxes in a 3-dimensional model of the nasal region. The subject of the present investigation (the second model) applied a 1-dimensional equation of mass transport to each generation of an adult human symmetric, bifurcating Weibel-type RT anatomical model, augmented by an upper respiratory tract. The two types of modeling approaches were made consistent by requiring that the 1-dimensional version of the nasal passages have the same inspiratory air-flow rate and uptake during inspiration as the CFD simulations for 4 daily human activity levels. Results obtained include the following: (1) More than 95% of the inhaled HCHO is predicted to be retained by the RT. (2) The CFD predictions for inspiration, modified to account for the difference in inspiration and complete breath times, are a good approximation to uptake in the nasal airways during a single breath. (3) In the lower respiratory tract, flux is predicted to increase for several generations and then decrease rapidly. (4) Compared to first pulmonary region generation fluxes, the first few tracheobronchial generations fluxes are over 1000 times larger. Further, there is essentially no flux in the alveolar sacs. (5) Predicted fluxes based on the 1-dimensional model are presented that can be used in a biologically based dose-response model for human carcinogenesis. Use of these fluxes will reduce uncertainty in a risk assessment for formaldehyde carcinogenicity.     

Model for the deposition of aerosol particles in the respiratory tract of the rat. I. Nonhygroscopic particle deposition

Rats are used to test the toxicological and pharmacological effects of aerosol particles on the organism. For estimates of the delivered aerosol dose, lung deposition models provide a valuable tool. Here a previously developed deposition model for nonhygroscopic and hygroscopic aerosol particles in the lungs of man (Ferron et al., J. Aerosol Sci. 1988, 19:611) is adapted to the rat by implementing a lung structure for the rat combined with empirical equations for particle deposition due to impaction/sedimentation in the extrathoracic region and in bifurcations. To account for the effect of body weight (BW) on the physiological parameters (lung size, respiration frequency) we present BW-scaling laws with an estimated accuracy of about 16%. The present model shows good agreement with the measured total deposition (per breath) and other models from the literature to within the variability of the experimental data (20% absolute). Our calculations show that the variability of the experimental data is consistent with the combined effects from realistic variations in particle properties (mainly density) and physiological parameters (mainly activity level). For the alveolar region, which is of particular significance for pharmacological and health studies, we show that although the activity level may change the deposited dose by up to a factor of 2.2 for particles between 0.05 and 2.0 microm in diameter, the alveolar dose is almost independent (to within 10%) of activity level for particles between 0.5 and 1 microm, which makes this size range advantageous for pharmacological and toxicological experiments. The present model allows estimates of the total and regional particle dose deposited in the lungs of rats, which are consistent with experimental data. The advantage of the present model is that hygroscopic growth can be included in the calculations.     

A semi-empirical model of aerosol deposition in the human respiratory tract for mouth inhalation

A mathematical model for regional deposition of aerosols following inhalation via mouth has been developed. The model is in the form of algebraic equations which make it particularly efficient for computation of deposition of polydisperse aerosols. The parameters of the model were derived from average experimental data for‘head’ and tracheobronchial deposition which were supplemented by results of previous theoretical calculations and mass balance considerations. An example is presented to illustrate an application of the model to a problem in formulation of inhalation aerosols. To make the calculations more reliable for particular patho-physiological groups of patients, some modifications of the parameters used in the model are necessary. The model may be suitable, e.g. for testing the changes in regional deposition which would be likely to result from modification of particle size and related formulation properties of inhalation aerosols.     

Multicomponent aerosol particle deposition in a realistic cast of the human upper respiratory tract

Inhalation of aerosols generated by electronic cigarettes leads to deposition of multiple chemical compounds in the human airways. In this work, an experimental method to determine regional deposition of multicomponent aerosols in an in vitro segmented, realistic human lung geometry was developed and applied to two aerosols, i.e. a monodisperse glycerol aerosol and a multicomponent aerosol. The method comprised the following steps: (1) lung cast model preparation, (2) aerosol generation and exposure, (3) extraction of deposited mass, (4) chemical quantification and (5) data processing. The method showed good agreement with literature data for the deposition efficiency when using a monodisperse glycerol aerosol, with a mass median aerodynamic diameter (MMAD) of 2.3?μm and a constant flow rate of 15?L/min. The highest deposition surface density rate was observed in the bifurcation segments, indicating inertial impaction deposition. The experimental method was also applied to the deposition of a nebulized multicomponent aerosol with a MMAD of 0.50?μm and a constant flow rate of 15?L/min. The deposited amounts of glycerol, propylene glycol and nicotine were quantified. The three analyzed compounds showed similar deposition patterns and fractions as for the monodisperse glycerol aerosol, indicating that the compounds most likely deposited as parts of the same droplets. The developed method can be used to determine regional deposition for multicomponent aerosols, provided that the compounds are of low volatility. The generated data can be used to validate aerosol deposition simulations and to gain insight in deposition of electronic cigarette aerosols in human airways.     

Influence of airborne particulates on respiratory tract deposition of inhaled toluene and naphthalene in the rat

Objective: Most studies report that inhaled volatile and semivolatile organic compounds (VOCs/SVOCs) tend to deposit in the upper respiratory tract, while ultrafine (or near ultrafine) particulate matter (PM) (～100?nm) reaches the lower airways. The objective of this study was to determine whether carbon particle co-exposure carries VOCs/SVOCs deeper into the lungs where they are deposited.

Materials and methods: Male Sprague–Dawley rats were exposed by inhalation (nose-only) to radiolabeled toluene (20?ppm) or naphthalene (20?ppm) on a single occasion for 1?h, with or without concurrent carbon particle exposure (～5?mg/m³). The distribution of radiolabel deposited within the respiratory tract of each animal was determined after sacrifice. The extent of adsorption of toluene and naphthalene to airborne carbon particles under the exposure conditions of the study was also assessed.

Results: We found that in the absence of particles, the highest deposition of both naphthalene and toluene was observed in the upper respiratory tract. Co-exposure with carbon particles tended to increase naphthalene deposition slightly throughout the respiratory tract, whereas slight decreases in toluene deposition were observed. Few differences were statistically significant. Naphthalene showed greater adsorption to the particles compared to toluene, but overall the particle-adsorbed concentration of each of these compounds was a small fraction of the total inspired concentration.

Conclusions: These studies imply that at the concentrations used for the exposures in this study, inhaled carbon particles do not substantially alter the deposition of naphthalene and toluene within the respiratory tract.     

Assessment of toxicity using dehydrogenases activity and mathematical modeling

Dehydrogenase activity is frequently used to assess the general condition of microorganisms in soil and activated sludge. Many studies have investigated the inhibition of dehydrogenase activity by various compounds, including heavy metal ions. However, the time after which the measurements are carried out is often chosen arbitrarily. Thus, it can be difficult to estimate how the toxic effects of compounds vary during the reaction and when the maximum of the effect would be reached. Hence, the aim of this study was to create simple and useful mathematical model describing changes in dehydrogenase activity during exposure to substances that inactivate enzymes. Our model is based on the Lagergrens pseudo-first-order equation, the rate of chemical reactions, enzyme activity, and inactivation and was created to describe short-term changes in dehydrogenase activity. The main assumption of our model is that toxic substances cause irreversible inactivation of enzyme units. The model is able to predict the maximum direct toxic effect (MDTE) and the time to reach this maximum (T_MDTE). In order to validate our model, we present two examples: inactivation of dehydrogenase in microorganisms in soil and activated sludge. The model was applied successfully for cadmium and copper ions. Our results indicate that the predicted MDTE and T_MDTE are more appropriate than EC₅₀ and IC₅₀ for toxicity assessments, except for long exposure times.     

Characterization of regional and local deposition of inhaled aerosol drugs in the respiratory system by computational fluid and particle dynamics methods.

The present work describes the local deposition patterns of therapeutic aerosols in the oropharyngeal airways, healthy and diseased bronchi and alveoli using computational fluid and particle dynamics techniques. A user-enhanced computational fluid dynamics commercial finite- volume software package was used to compute airflow fields, deposition efficiencies, and deposition patterns of therapeutic aerosols along the airways. Adequate numerical meshes, generated in different airway sections, enabled us to more precisely define trajectories and local deposition patterns of inhaled particles than before. Deposition patterns show a high degree of heterogeneity of deposition along the airways, being more uniform for nanoparticles compared to micro-particles in the whole respiratory system at all inspiratory flow rates. Extrathoracic and tracheobronchial deposition fractions of nanoparticles decrease with increasing flow rates. However, vice versa happens to the micron-size particles, that is, the deposition fraction is higher at high flow rates. Both airway constrictions and the presence of tumors significantly increased the deposition efficiencies compared to the deposition efficiencies in healthy airways by a factor ranging from 1.2 to 4.4. In alveoli, the deposition patterns are strongly influenced by particle size and direction of gravity. This study demonstrated that numerical modeling can be a powerful tool in the aerosol drug delivery optimization. Present results may be integrated in future aerosol drug therapy protocols.     

Upper respiratory tract deposition of inspired acetaldehyde.

Inhalation exposure of rodents to high concentrations of acetaldehyde produces lesions in the upper respiratory tract (URT, all regions of the respiratory tract anterior to and including the larynx). Information on the inhalation dosimetric relationships for this vapor are needed for a comprehensive understanding of its inhalation toxicity. Toward this end, uptake of acetaldehyde was measured in the surgically isolated URT of the urethane-anesthetized male F344 rat under unidirectional (50, 100, 200, or 300 ml/min) and cyclic (100 ml/min) flow conditions at inspired concentrations of 1, 10, 100, or 1000 ppm. Under all flow conditions URT deposition efficiency was strongly dependent on inspired concentration. URT deposition efficiency (under cyclic flow) averaged 76, 48, 41, and 26% at 1, 10, 100, and 1000 ppm, respectively. Nasal acetaldehyde dehydrogenase activity averaged 1.2 micrograms/min. Absolute acetaldehyde deposition rates (micrograms/min) at 100 and 1000 ppm exceeded this activity by 5- to 100-fold, suggesting a possible mechanism for the reduced deposition efficiency at high concentrations. URT deposition under unidirectional flow was strongly dependent on the inspiratory flow rate. The effect of flow rate on deposition was reasonably predicted by the mass-transfer model of Aharonson et al. (J. Appl. Physiol. 37, 654-657, 1974). The uptake coefficients determined from the unidirectional flow studies were used to predict uptake under cyclic flow by integration of the model. The predicted cyclic deposition efficiencies differed from the observed efficiencies by 2.3 +/- 4.3% (mean +/- SEM), suggesting this model might provide a reasonable first approximation for acetaldehyde uptake under cyclic breathing conditions.     

3D in silico modeling of the human respiratory system for inhaled drug delivery and imaging analysis

The efficacies of inhaled pharmacologic drugs could be improved if drugs could be targeted to appropriate sites within the human respiratory system. The spatial deposition patterns of particles can now be detected with a high degree of resolution using advanced techniques of imaging (e.g., SPECT). However, the effectiveness of such laboratory regimens has been limited by the inability to clearly identify airway composition within images. Therefore, we have developed a theoretical protocol to map airways within human lungs that is designed to be used in a complementary manner with laboratory investigations. The in silico model has two components: a mathematical model based on concepts of topology; and, a computer algorithm which tracks the millions of constituent lung airways. The in silico model produces 3D lung structures that are anatomically correct and can be customized to each patient. We have applied the protocol to a SPECT study where the interiors of lungs were partitioned into a series of ten nested shells. Airway composition in the respective shells provides a heretofore unavailable quantification of scintigraphy images. The protocol can be employed in a practical manner in the medical arena to aid in the interpretation of SPECT images, and to provide a platform for the design of human subject tests.     

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

Abstract

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.     

Physiologically based pharmacokinetic modeling of inhaled 2-butoxyethanol in man

The arterial blood concentration of 2-butoxyethanol (ethylene glycol monobutyl ether) was simulated in a physiologically based pharmacokinetic model developed for a 70-kg man. Elimination data (Vmax and Km) were extrapolated from the perfused rat liver, while flows and volumes were from the literature. Simulated inhalation exposure to 2-butoxyethanol at 20 ppm (0.8 mmol/m3) and physical exercise at 50 W agrees well with the results from experimental exposure of human volunteers under identical conditions. In further simulations, the marked effects of physical exercise and co-exposure to ethanol are illustrated. The relatively rapid decay of 2-butoxyethanol in all compartments indicates that the parent compound is not likely to accumulate in the body. Further, linear kinetics may be expected at occupational inhalation exposure to 2-butoxyethanol. The study serves as an example of how a physiologically based pharmacokinetic model may be used to illustrate some aspects of occupational solvent exposure.     

Effect of the new spacer-device on the deposition of the inhaled metered dose aerosol

The effect of the new spacer-device on the in vitro and in vivo deposition of inhaled drug particles was studied. The in vitro deposition of beclomethasone dipropionate 250 micrograms/dose aerosol administered either through the conventional aerosol actuator with the short plastic mouthpiece or through the new pear-shaped spacer-device was evaluated with the modified cascade impactor method. For the in vivo study the disodium cromoglycate particles were labelled with a pure gamma-radiator 99mTc using a coprecipitation technique based on spray drying. The deposition of the inhaled disodium cromoglycate particles in the human respiratory tract after administration of the drug doses from the devices tested was determined by means of a gamma camera. The new spacer-device increased both in the in vitro and in vivo tests the fraction of the drug dose deposited into the therapeutically significant regions of the respiratory tract. In addition, the therapeutically insignificant fraction deposited in the upper airways and mouth clearly decreased. Thus using the new spacer-device evaluated in this study the local side effects would be decreased.     

A comparison of planar scintigraphy and SPECT measurement of total lung deposition of inhaled aerosol.

Planar gamma camera imaging of inhaled aerosol deposition is extensively used to assess the total deposition in the lung. However, validation of the measurements is not straightforward, as gold standard measurements of lung activity against which to compare are not readily available. Quantitative SPECT imaging provides an alternative method for comparison. Four different methods for planar image quantification are compared. Two attenuation correction techniques, thickness measurement and transmission measurement, have been combined with two scatter correction techniques, reduced attenuation coefficient and line-source scatter function convolution subtraction. Each technique has been applied to 10 studies of aerosol deposition of a fine aerosol (mass median aerodynamic diameter 1.8 microm) and 10 studies using a coarse aerosol (mass median aerodynamic diameter 6.5 microm). The total activity in the right lung for each measurement has been compared to the value determined from SPECT imaging on the same subjects. When the thickness measurement and transmission techniques were applied with scatter compensation using a reduced attenuation coefficient, activity was systematically overestimated by 5% in both cases. The corresponding random errors (coefficient of variation) were 8.6% and 6.6%. Separate scatter correction reduced these systemic errors significantly to -1.5% and 2.7%, respectively. The random errors were not affected. All techniques provided assessment of total lung activity with an accuracy and precision that differed by less than 10% compared to the SPECT values. Planar gamma camera imaging provides a good method of assessing total lung deposition of inhaled aerosol.     

Deposition of biomass combustion aerosol particles in the human respiratory tract

Smoke from biomass combustion has been identified as a major environmental risk factor associated with adverse health effects globally. Deposition of the smoke particles in the lungs is a crucial factor for toxicological effects, but has not previously been studied experimentally. We investigated the size-dependent respiratory-tract deposition of aerosol particles from wood combustion in humans. Two combustion conditions were studied in a wood pellet burner: efficient ("complete") combustion and low-temperature (incomplete) combustion simulating "wood smoke." The size-dependent deposition fraction of 15-to 680-nm particles was measured for 10 healthy subjects with a novel setup. Both aerosols were extensively characterized with regard to chemical and physical particle properties. The deposition was additionally estimated with the ICRP model, modified for the determined aerosol properties, in order to validate the experiments and allow a generalization of the results. The measured total deposited fraction of particles from both efficient combustion and low-temperature combustion was 0.21-0.24 by number, surface, and mass. The deposition behavior can be explained by the size distributions of the particles and by their ability to grow by water uptake in the lungs, where the relative humidity is close to saturation. The experiments were in basic agreement with the model calculations. Our findings illustrate: (1) that particles from biomass combustion obtain a size in the respiratory tract at which the deposition probability is close to its minimum, (2) that particle water absorption has substantial impact on deposition, and (3) that deposition is markedly influenced by individual factors.     

Recent advances in predictive understanding of respiratory tract deposition

Accurate prediction of respiratory tract deposition is important in gauging the health risks of ambient bioaerosols and environmental aerosols, as well as in developing pharmaceutical aerosols for drug delivery. The present article highlights recent advances in the prediction of total, extrathoracic, and lung deposition fractions of inhaled aerosols over a broad range of parameters for both oral and nasal breathing. These advances build on recent data from in vivo and in vitro studies that have benefited from recent improvements in high-resolution imaging, rapid prototyping, and computational simulation abilities that have significantly enhanced the current understanding of respiratory tract deposition. It is anticipated that the relatively simple equations for predicting total or whole lung deposition that follow from the recent work discussed herein will allow for improved correlation between respiratory tract deposition and a wide range of health outcomes.     

Aerosol deposition in the human respiratory tract breathing air and 80:20 heliox.

Aerosol mixing resulting from turbulent flows is thought to be an important mechanism of deposition in the upper respiratory tract (URT). Since turbulence levels are a function of gas density, the use of a low density carrier gas would be expected to reduce deposition in the URT. We measured aerosol deposition in the respiratory tract of 8 healthy subjects using both air and heliox, a low density gas mixture containing 80% helium and 20% oxygen, as the carrier gas. The subjects breathed 0.5, 1, and 2 microm-diameter monodisperse polystyrene latex particles from a reservoir at a constant flow rate (approximately 450 mL/sec) and tidal volume (approximately 900 mL). Aerosol concentration and flow rate were measured at the mouth using a photometer and a pneumotachograph, respectively. Deposition was 17.0%, 20.3%, and 38.9% in air and 16.8%, 18.5%, and 36.9% in heliox for 0.5; 1, and 2 microm-diameter particles, respectively. There was a small but statistically significant decrease in deposition when using heliox compared to air for 1 and 2 microm-diameter particles (p < 0.05). While it could not be directly measured from these data, it is likely that when breathing heliox instead of air, deposition is reduced in the URT and increased in the small airways and alveoli.