A computational fluid dynamics analysis of the effects of size and shape of anterior nasal septal perforations.

BACKGROUND: Nasal septal perforations (NSPs) often cause bleeding, crusting, obstruction, and/or whistling. The objective was to analyze the impact of anterior NSP size and shape on nasal physiology using computational fluid dynamics (CFD). METHODS: A 3-dimensional model of the nasal cavity was constructed from a radiologically normal CT scan using imaging software. Anterior NSPs (ovoid (ONSP): 0.5, 1, 2, and 3 cm long anterior-to-posteriorly and round (RNSP, 0.5 and 1 cm)) were virtually created in the model and divided into ventral, dorsal, anterior, and posterior regions. Steady-state inspiratory airflow, heat, and water vapor transport were simulated using Fluent CFD software. Air crossover through the perforation, wall shear, heat flux, water vapor flux, resistance, and humidification were analyzed. RESULTS: Air crossover and wall shear increased with perforation size. Regionally, wall shear and heat and water vapor flux were highest posteriorly and lowest anteriorly, generally increasing with size in those regions. RNSPs had greater heat and water vapor flux compared to corresponding size ONSPs. Resistance decreased by 10% or more from normal only in the 3 cm ONSP. Maximum water content was achieved more posteriorly in larger NSP nasal cavities. CONCLUSIONS: High wall shear and heat and water vapor flux in posterior perforation regions may explain the crusting most commonly noted on posterior NSP edges. This preliminary study suggests that larger NSPs have a greater effect on nasal resistance and water content. Decrease in resistance with larger NSP size may be implicated in reported symptomatic improvement following enlargement of NSPs for treatment.

A computational study of functional endoscopic sinus surgery and maxillary sinus drug delivery.

BACKGROUND: Topical medication is increasingly used following functional endoscopic sinus surgery (FESS). Information on particle sizes that maximise maxillary sinus (MS) delivery is conflicting, and the effect of antrostomy size on delivery is unclear. The purpose of this study was to estimate antrostomy and particle size effects on topical MS drug delivery. METHODOLOGY: Sinonasal reconstructions were created from a pre- and a post-FESS CT scan in each of four chronic rhinosinusitis patients. Additional models were created from each post-FESS reconstruction representing four alternative antrostomy sizes. Airflow and particle deposition were simulated in each reconstruction using computational fluid dynamics for nebulised and sprayed delivery. RESULTS: MS ventilation and drug delivery increased following FESS, the largest virtual antrostomy led to greatest delivery, and MS delivery was sensitive to particle size. Particles within a 5-18 µm and 5-20 µm size range led to peak MS deposition for nebulised and sprayed particles, respectively. Post-FESS increases in drug delivery varied across individuals and within individuals by the type of antrostomy created. CONCLUSION: Our findings suggest that FESS, particularly with larger antrostomies, improves topical drug delivery, and that certain particle sizes improve this delivery. Further research is needed to contextualise these findings with other post-surgical effects.

Changes in nasal airflow and heat transfer correlate with symptom improvement after surgery for nasal obstruction.

Surgeries to correct nasal airway obstruction (NAO) often have less than desirable outcomes, partly due to the absence of an objective tool to select the most appropriate surgical approach for each patient. Computational fluid dynamics (CFD) models can be used to investigate nasal airflow, but variables need to be identified that can detect surgical changes and correlate with patient symptoms. CFD models were constructed from pre- and post-surgery computed tomography scans for 10 NAO patients showing no evidence of nasal cycling. Steady-state inspiratory airflow, nasal resistance, wall shear stress, and heat flux were computed for the main nasal cavity from nostrils to posterior nasal septum both bilaterally and unilaterally. Paired t-tests indicated that all CFD variables were significantly changed by surgery when calculated on the most obstructed side, and that airflow, nasal resistance, and heat flux were significantly changed bilaterally as well. Moderate linear correlations with patient-reported symptoms were found for airflow, heat flux, unilateral allocation of airflow, and unilateral nasal resistance as a fraction of bilateral nasal resistance when calculated on the most obstructed nasal side, suggesting that these variables may be useful for evaluating the efficacy of nasal surgery objectively. Similarity in the strengths of these correlations suggests that patient-reported symptoms may represent a constellation of effects and that these variables should be tracked concurrently during future virtual surgery planning.

Deviated nasal septum hinders intranasal sprays: a computer simulation study.

BACKGROUND: This study investigates how deviated nasal septum affects the quantity and distribution of spray particles, and examines the effects of inspiratory airflow and head position on particle transport. METHODS: Deposition of spray particles was analysed using a three-dimensional computational fluid dynamics model created from a computed tomography scan of a human nose with leftward septal deviation and a right inferior turbinate hypertrophy. Five simulations were conducted using FluentTM software, with particle sizes ranging from 20-110 μm, a spray speed of 3 m/s, plume angle of 68(deg), and with steady state inspiratory airflow either present (15.7 L/min) or absent at varying head positions. RESULTS: With inspiratory airflow present, posterior deposition on the obstructed side was approximately four times less than the contralateral side, regardless of head position, and was statistically significant. When airflow was absent, predicted deposition beyond the nasal valve on the left and right sides were between 16% and 69% lower and positively influenced by a dependent head position. CONCLUSION: Simulations predicted that septal deviation significantly diminished drug delivery on the obstructed side. Furthermore, increased particle penetration was associated with presence of nasal airflow. Head position is an important factor in particle deposition patterns when inspiratory airflow is absent.

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.

Magnetic resonance imaging and computational fluid dynamics (CFD) simulations of rabbit nasal airflows for the development of hybrid CFD/PBPK models.

The percentages of total airflows over the nasal respiratory and olfactory epithelium of female rabbits were calculated from computational fluid dynamics (CFD) simulations of steady-state inhalation. These airflow calculations, along with nasal airway geometry determinations, are critical parameters for hybrid CFD/physiologically based pharmacokinetic models that describe the nasal dosimetry of water-soluble or reactive gases and vapors in rabbits. CFD simulations were based upon three-dimensional computational meshes derived from magnetic resonance images of three adult female New Zealand White (NZW) rabbits. In the anterior portion of the nose, the maxillary turbinates of rabbits are considerably more complex than comparable regions in rats, mice, monkeys, or humans. This leads to a greater surface area to volume ratio in this region and thus the potential for increased extraction of water soluble or reactive gases and vapors in the anterior portion of the nose compared to many other species. Although there was considerable interanimal variability in the fine structures of the nasal turbinates and airflows in the anterior portions of the nose, there was remarkable consistency between rabbits in the percentage of total inspired airflows that reached the ethmoid turbinate region (approximately 50%) that is presumably lined with olfactory epithelium. These latter results (airflows reaching the ethmoid turbinate region) were higher than previous published estimates for the male F344 rat (19%) and human (7%). These differences in regional airflows can have significant implications in interspecies extrapolations of nasal dosimetry.

Nasal dosimetry of inhaled gases and particles: where do inhaled agents go in the nose?

The anatomical structure of the nasal passages differs significantly among species, affecting airflow and the transport of inhaled gases and particles throughout the respiratory tract. Since direct measurement of local nasal dose is often difficult, 3-dimensional, anatomically accurate, computational models of the rat, monkey, and human nasal passages were developed to estimate regional transport and dosimetry of inhaled material. The computational models predicted that during resting breathing, a larger portion of inspired air passed through olfactory-lined regions in the rat than in the monkey or human. The models also predicted that maximum wall mass flux (mass per surface area per time) of inhaled formaldehyde in the nonsquamous epithelium was highest in monkeys (anterior middle turbinate) and similar in rats and humans (dorsal medial meatus in the rat and mid-septum in the human, near the squamous/nonsquamous epithelial boundary in both species). For particles that are 5 microm in aerodynamic diameter, preliminary simulations at minute volume flow rates predicted nasal deposition efficiencies of 92%, 11% and 25% in the rat, monkey, and human, respectively, with more vestibular deposition in the rat than in the monkey or human. Estimates such as these can be used to test hypotheses about mechanisms of toxicity and supply species-specific information for risk assessment, thus reducing uncertainty in extrapolating animal data to humans.

Dose response for formaldehyde-induced cytotoxicity in the human respiratory tract.

Human studies of the sensory irritant effects of formaldehyde are complicated by the subjective nature of some clinical endpoints. This limits the usefulness of such studies for quantitative noncancer risk assessment of airborne formaldehyde. Objective measures of the noncancer effects of formaldehyde, such as the rate of regenerative cellular proliferation (RCP) secondary to cytolethality, can be obtained from laboratory animals but present the challenge of interspecies extrapolation of the data. To the extent that uncertainties associated with this extrapolation can be reduced, however, dose-response data obtained in laboratory animals are a viable alternative to clinical studies. Here, we describe the extrapolation of dose-response data for RCP from F344 rats to humans. Rats inhaled formaldehyde (0, 0.7, 2.0, 6.0, 10, and 15 ppm) 6 h/day, 5 days/week for up to 2 years. The dose response for RCP was J-shaped, with the rates of RCP at 0.7 and 2.0 ppm below but not statistically different from control, while the rates at the higher concentrations were significantly greater than control. Both the raw J-shaped data and a hockey-stick-shaped curve fitted to the raw data were used for predicting the human dose response for RCP. Cells lining the nasal airways of F344 rats and rhesus monkeys are comparably sensitive to the cytolethal effects of inhaled formaldehyde, suggesting that the equivalent human cells are also likely to be comparably sensitive. Using this assumption, the challenge of rat-to-human extrapolation was reduced to accurate prediction of site-specific flux of formaldehyde from inhaled air into the tissue lining the human respiratory tract. A computational fluid dynamics model of air flow and gas transport in the human nasal airways was linked to a typical path model of the human lung to provide site-specific flux predictions throughout the respiratory tract. Since breathing rate affects formaldehyde dosimetry, cytotoxicity dose-response curves were predicted for three standard working levels. With the most vigorous working level, the lowest concentrations of formaldehyde predicted to exert any cytotoxic effects in humans were 1.0 and 0.6 ppm, for the J-shaped and hockey-stick-shaped RCP curves, respectively. The predicted levels of response at the lowest effect concentrations are smaller than can be measured clinically. Published literature showing that the cytotoxicity of inhaled formaldehyde is related to exposure level rather than to duration of exposure suggests that the present analysis is a reasonable basis for derivation of standards for continuous human exposure.

Dosimetry modeling of inhaled formaldehyde: comparisons of local flux predictions in the rat, monkey, and human nasal passages.

Formaldehyde-induced nasal squamous cell carcinomas in rats and squamous metaplasia in rats and rhesus monkeys occur in specific regions of the nose with species-specific distribution patterns. Experimental approaches addressing local differences in formaldehyde uptake patterns and dose are limited by the resolution of dissection techniques used to obtain tissue samples and the rapid metabolism of absorbed formaldehyde in the nasal mucosa. Anatomically accurate, 3-dimensional computational fluid dynamics models of F344 rat, rhesus monkey, and human nasal passages were used to estimate and compare regional inhaled formaldehyde uptake patterns predicted among these species. Maximum flux values, averaged over a breath, in nonsquamous epithelium were estimated to be 2620, 4492, and 2082 pmol/(mm(2)-h-ppm) in the rat, monkey, and human respectively. Flux values predicted in sites where cell proliferation rates were measured as similar in rats and monkeys were also similar, as were fluxes predicted in a region of high tumor incidence in the rat nose and the anterior portion of the human nose. Regional formaldehyde flux estimates are directly applicable to clonal growth modeling of formaldehyde carcinogenesis to help reduce uncertainty in human cancer risk estimates.

Dosimetry modeling of inhaled formaldehyde: binning nasal flux predictions for quantitative risk assessment.

Interspecies extrapolations of tissue dose and tumor response have been a significant source of uncertainty in formaldehyde cancer risk assessment. The ability to account for species-specific variation of dose within the nasal passages would reduce this uncertainty. Three-dimensional, anatomically realistic, computational fluid dynamics (CFD) models of nasal airflow and formaldehyde gas transport in the F344 rat, rhesus monkey, and human were used to predict local patterns of wall mass flux (pmol/[mm(2)-h-ppm]). The nasal surface of each species was partitioned by flux into smaller regions (flux bins), each characterized by surface area and an average flux value. Rat and monkey flux bins were predicted for steady-state inspiratory airflow rates corresponding to the estimated minute volume for each species. Human flux bins were predicted for steady-state inspiratory airflow at 7.4, 15, 18, 25.8, 31.8, and 37 l/min and were extrapolated to 46 and 50 l/min. Flux values higher than half the maximum flux value (flux median) were predicted for nearly 20% of human nasal surfaces at 15 l/min, whereas only 5% of rat and less than 1% of monkey nasal surfaces were associated with fluxes higher than flux medians at 0.576 l/min and 4.8 l/min, respectively. Human nasal flux patterns shifted distally and uptake percentage decreased as inspiratory flow rate increased. Flux binning captures anatomical effects on flux and is thereby a basis for describing the effects of anatomy and airflow on local tissue disposition and distributions of tissue response. Formaldehyde risk models that incorporate flux binning derived from anatomically realistic CFD models will have significantly reduced uncertainty compared with risk estimates based on default methods.

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.

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.

Use of computational fluid dynamics models for dosimetry of inhaled gases in the nasal passages.

Computational fluid dynamics (CFD) models of the nasal passages of a rat, monkey, and human are being used (1) to determine important factors affecting nasal uptake, (2) to make interspecies dosimetric comparisons, (3) to provide detailed anatomical information for the rat, monkey, and human nasal passages, and (4) to provide estimates of regional air-phase mass transport coefficients (a measure of the resistance to gas transport from inhaled air to airway walls) in the nasal passages of all three species. For many inhaled materials, lesion location in the nose follows patterns that are both site and species specific. For reactive, water-soluble (Category 1) gases, regional uptake can be a major factor in determining lesion location. Since direct measurement of airflow and uptake is experimentally difficult, CFD models are used here to predict uptake patterns quantitatively in three-dimensional reconstructions of the F344 rat, rhesus monkey, and human nasal passages. In formaldehyde uptake simulations, absorption processes were assumed to be as rapid as possible, and regional flux (transport rate) of inhaled formaldehyde to airway walls was calculated for rats, primates, and humans. For uptake of gases like vinyl acetate and acrylic acid vapors, physiologically based pharmacokinetic uptake models incorporating anatomical and physical information from the CFD models were developed to estimate nasal tissue dose in animals and humans. The use of biologically based models in risk assessment makes sources of uncertainty explicit and, in doing so, allows quantification of uncertainty through sensitivity analyses. Limited resources can then be focused on reduction of important sources of uncertainty to make risk estimates more accurate.

A hybrid computational fluid dynamics and physiologically based pharmacokinetic model for comparison of predicted tissue concentrations of acrylic acid and other vapors in the rat and human nasal cavities following inhalation exposure.

To assist in interspecies dosimetry comparisons for risk assessment of the nasal effects of organic acids, a hybrid computational fluid dynamics (CFD) and physiologically based pharmacokinetic (PBPK) dosimetry model was constructed to estimate the regional tissue dose of inhaled vapors in the rat and human nasal cavity. Application to a specific vapor would involve the incorporation of the chemical-specific reactivity, metabolism, partition coefficients, and diffusivity (in both air and tissue phases) of the vapor. This report describes the structure of the CFD-PBPK model and its application to a representative acidic vapor, acrylic acid, for interspecies tissue concentration comparisons to assist in risk assessment. By using the results from a series of short-term in vivo studies combined with computer modeling, regional nasal tissue dose estimates were developed and comparisons of tissue doses between species were conducted. To make these comparisons, the assumption was made that the susceptibilities of human and rat olfactory epithelium to the cytotoxic effects of organic acids were similar, based on similar histological structure and common mode of action considerations. Interspecies differences in response were therefore assumed to be driven primarily by differences in nasal tissue concentrations that result from regional differences in nasal air flow patterns relative to the species-specific distribution of olfactory epithelium in the nasal cavity. The results of simulations with the seven-compartment CFD-PBPK model suggested that the olfactory epithelium of the human nasal cavity would be exposed to tissue concentrations of acrylic acid similar to that of the rat nasal cavity when the exposure conditions are the same. Similar analysis of CFD data and CFD-PBPK model simulations with a simpler one-compartment model of the whole nasal cavities of rats and humans provides comparable results to averaging over the compartments of the seven-compartment model. These results indicate that the general structure of the hybrid CFD-PBPK model applied in this assessment would be useful for target tissue dosimetry and interspecies dose comparisons for a wide variety of vapors. Because of its flexibility, this CFD-PBPK model is envisioned to be a platform for the construction of case-specific inhalation dosimetry models to simulate in vivo exposures that do not involve significant histopathological damage to the nasal cavity.

Simulation modeling of the tissue disposition of formaldehyde to predict nasal DNA-protein cross-links in Fischer 344 rats, rhesus monkeys, and humans.

Formaldehyde inhalation causes formation of DNA-protein cross-links (DPX) in the nasal mucosa of Fischer 344 (F344) rats and rhesus monkeys. DPX are considered to be part of the mechanism by which cytotoxic and carcinogenic effects of formaldehyde in laboratory animals are exerted, and DPX data have been used as a measure of tissue dose in cancer risk assessments for formaldehyde. Accurate prediction of DPX concentrations in humans is therefore desirable. The goal of this work was to increase confidence in the prediction of human DPX by refining earlier models of formaldehyde disposition and DPX kinetics in the nasal mucosa. Anatomically accurate, computational fluid dynamics models of the nasal airways of F344 rats, rhesus monkeys, and humans were used to predict the regional flux of formaldehyde to the respiratory and olfactory mucosa. A previously developed model of the tissue disposition of formaldehyde and of DPX kinetics was implemented in the graphical simulation tool SIMULINK and linked to the regional flux predictions. Statistical optimization was used to identify parameter values, and good simulations of the data were obtained. The parameter estimates for rats and monkeys were used to guide allometric scale-up to the human case. The relative levels of nasal mucosal DPX in rats, rhesus monkeys, and humans for a given inhaled concentration of formaldehyde were predicted by the model to vary with concentration. This modeling approach reduces uncertainty in the prediction of human nasal mucosal DPX resulting from formaldehyde inhalation.

Dosimetric adjustment factors for methyl methacrylate derived from a steady-state analysis of a physiologically based clearance-extraction model.

Cells within the epithelial lining of the nasal cavity metabolize a variety of low-molecular-weight, volatile xenobiotics. In common with terminology developed for other metabolizing organs, the nose extracts these chemicals from the airstream, thereby clearing some portion of the total nasal airflow. In this article, a physiologically based clearance-extraction (PBCE) model of nasal metabolism is used to predict extraction for steady-state conditions. This model, developed by simplification of existing physiologically based pharmacokinetic (PBPK) nasal models, has three tissue regions in two flow paths. A dorsal flow stream sequentially passes over a small area of respiratory epithelium and then over the entire olfactory epithelial surface within the nose. A ventral airstream, consisting of most of the total flow, passes over the larger portion (>80%) of the respiratory epithelium. Each underlying tissue stack has a mucus layer, an epithelial tissue compartment, and a blood exchange region. Metabolism may occur in any of the subcompartments within the tissue stacks. The model, solved directly for a steady-state condition, specifies the volumetric airflow over each stack. Computational fluid dynamic (CFD) solutions for the rat and human for the case with no liquid-phase resistance provided a maximum value for regional extraction, E(max)'. Equivalent air-to-liquid phase permeation coefficients (also referred to as the air-phase mass transfer coefficient) were calculated based on these E(max)' values. The PBCE model was applied to assess expected species differences in nasal extraction and in localized tissue metabolism of methyl methacrylate (MMA) in rats and in humans. Model estimates of tissue dose of MMA metabolites (in micromol metabolized/h/ml tissue) in both species were used to evaluate the dosimetric adjustment factor (DAF) that should be applied in reference concentration (RfC) calculations for MMA. For human ventilation rates equivalent to light exercise, the DAF was estimated to be 3.02 at 28.4 ppm, the benchmark concentration for nasal lesions. Depending on specific assumptions about distribution of esterase activities in human tissues, the range of DAF values was 1.56-8.00. The DAF for heavy exercise with a ventilation rate of 42 L/min was still 2.98. Estimated DAFs were concentration dependent, varying between 2.4 and 4.76 in the inhaled concentration range from 1 and 400 ppm. Present default methods utilize a DAF of 0.145. These steady-state calculations with this PBCE model should be useful in risk assessment calculations for a variety of vapors and gases that are converted to toxic metabolites in cells in the respiratory tract.

Application of a hybrid computational fluid dynamics and physiologically based inhalation model for interspecies dosimetry extrapolation of acidic vapors in the upper airways.

This study provides a scientific basis for interspecies extrapolation of nasal olfactory irritants from rodents to humans. By using a series of short-term in vivo studies, in vitro studies with nasal explants, and computer modeling, regional nasal tissue dose estimates were made and comparisons of tissue doses between species were conducted. To make these comparisons, this study assumes that human and rodent olfactory epithelium have similar susceptibility to the cytotoxic effects of organic acids based on similar histological structure and common mode of action considerations. Interspecies differences in susceptibility to the toxic effects of acidic vapors are therefore assumed to be driven primarily by differences in nasal tissue concentrations that result from regional differences in nasal air flow patterns relative to the species-specific distribution of olfactory epithelium in the nasal cavity. The acute, subchronic, and in vitro studies have demonstrated that the nasal olfactory epithelium is the most sensitive tissue to the effects of inhalation exposure to organic acids and that the sustentacular cells are the most sensitive cell type of this epithelium. A hybrid computational fluid dynamics (CFD) and physiologically based pharmacokinetic (PBPK) dosimetry model was constructed to estimate the regional tissue dose of organic acids in the rodent and human nasal cavity. The CFD-PBPK model simulations indicate that the olfactory epithelium of the human nasal cavity is exposed to two- to threefold lower tissue concentrations of a representative inhaled organic acid vapor, acrylic acid, than the olfactory epithelium of the rodent nasal cavity when the exposure conditions are the same. The magnitude of this difference varies somewhat with the specific exposure scenario that is simulated. The increased olfactory tissue dose in rats relative to humans may be attributed to the large rodent olfactory surface area (greater than 50% of the nasal cavity) and its highly susceptible location (particularly, a projection of olfactory epithelium extending anteriorly in the dorsal meatus region). In contrast, human olfactory epithelium occupies a much smaller surface area (less than 5% of the nasal cavity), and it is in a much less accessible dorsal posterior location. In addition, CFD simulations indicate that human olfactory epithelium is poorly ventilated relative to rodent olfactory epithelium. These studies suggest that the human olfactory epithelium is protected from irritating acidic vapors significantly better than rat olfactory epithelium due to substantive differences in nasal anatomy and nasal air flow. Furthermore, the general structure of the hybrid CFD-PBPK model used for this study appears to be useful for target tissue dosimetry and interspecies dose comparisons for a wide range of inhaled vapors.

Computer simulation of inspiratory nasal airflow and inhaled gas uptake in a rhesus monkey.

There is increasing evidence that inspiratory airflow patterns play a major role in determining the location of nasal lesions induced in rats by reactive, water-soluble gases such as formaldehyde and chlorine. Characteristic lesion patterns have also been seen in inhalation toxicity studies conducted in rhesus monkeys, the nasal anatomy of which resembles that of humans. To examine the hypothesis that regions of high airflow-dependent uptake and lesions occur in similar nasal locations in the primate, airflow and gas uptake patterns were simulated in an anatomically accurate computer model of the right nasal airway of a rhesus monkey. The results of finite-element simulations of steady-state inspiratory nasal airflow for the full range of resting physiological flow rates are reported. Simulated airflow patterns agreed well with experimental observations, exhibiting secondary flows in the anterior nose and streamlined flow posteriorly. Simulated airflow results were used to predict gas transport to the nasal passage walls using formaldehyde as an example compound. Results from the uptake simulations were compared with published observations of formaldehyde-induced nasal lesions in rhesus monkeys and indicated a strong correspondence between airflow-dependent transport patterns and local lesion sites. This rhesus computer model will provide a means for confirming the extrapolation of toxicity data between species by extrapolating rat simulation results to monkeys and comparing these predictions with primate lesion data.

A CFD-PBPK hybrid model for simulating gas and vapor uptake in the rat nose.

In laboratory studies of rodents, the inhalation of organic vapors often results in preferential damage to olfactory epithelium. Such focal lesion formation may be due either wholly or in part to a corresponding nonuniformity in the spatial distribution of vapor uptake within the nasal cavities. As a tool for determining this dose distribution, a mathematical model based on a combination of computational fluid dynamics (CFD) and physiologically based pharmacokinetic (PBPK) modeling was developed for simulating toxicant vapor uptake in the rat nose. The nasal airways were subdivided into four distinct meatuses selected such that each contained a major air flow stream. Each meatus was further divided into four serial regions attached to separate tissue stacks containing mucus, epithelial, and subepithelial compartments. Values for the gas-phase mass transfer coefficients and gas flows in the 16 airway regions were determined by a solution of the Navier-Stokes and convection-diffusion equations using commercially available CFD software. These values were then input to a PBPK simulation of toxicant transport through the 16 tissue stacks. The model was validated by using overall uptake data from rodent inhalation studies for three "unreactive" vapors that were either completely inert (i.e., acetone), reversibly ionized in aqueous media (i.e., acrylic acid), or prevented from being metabolized by an enzyme inhibitor (i.e., isoamyl alcohol). A sensitivity analysis revealed that accurate values of the mass transfer coefficient were not necessary to simulate regional concentrations and uptake of unreactive vapors in the rat nose, but reliable estimates of diffusion coefficients in tissue were crucial for accurate simulations.