* CIIT Centers for Health Research, P.O. Box 12137, 6 Davis Drive, Research Triangle Park, North Carolina 27709; and
Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
Received March 26, 2001; accepted August 4, 2001
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ABSTRACT |
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Key Words: formaldehyde; nasal passages; nasal airflow; nasal uptake; F344 rat; rhesus monkey; human; regional dosimetry; local dosimetry; computational fluid dynamics.
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INTRODUCTION |
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Uncertainty from interspecies extrapolation of target tissue dose in formaldehyde risk assessments to date arises primarily from an inability to account for both the site- and species-specific patterns of nasal lesions induced by formaldehyde in rats and monkeys. Lesion locations have been correlated with high levels of formaldehyde-induced DNAprotein cross-links (DPX; Casanova et al., 1991,1994
) and with local inspiratory airflow patterns in both species (Morgan et al., 1991
). Lesions in rats were confined to the nasal passages but were found as far down in the respiratory tract of monkeys as the carina (Monticello et al., 1989
,1991
). These studies imply that local formaldehyde dose plays a major role in determining formaldehyde-induced lesion distributions.
Various metrics have been used to define formaldehyde dose. In the earliest quantitative risk assessments of formaldehyde carcinogenicity, dose was based on exposure concentration in ppm or µg/m3 (Health and Welfare Canada, 1987; U.S. EPA, 1987
). To decrease the uncertainty associated with interspecies extrapolation of dose, a subsequent risk assessment was based on DPX as a dose metric in pmol/mg DNA (U.S. EPA, 1991
). To express the net transport of formaldehyde from inspired air to the air-liquid interface of the nasal walls, wall mass flux in units of mass/(area-time) may be used such as was done for the uptake of inhaled ozone (Overton and Miller, 1988
). Formaldehyde wall mass flux as a measure of transport prior to disposition within the body is critical to determining the link between administered doses such as exposure concentrations and target tissue doses or markers of exposure such as DPX. Knowledge of local formaldehyde wall mass flux patterns can also be used to better understand the relative roles that dose and tissue susceptibility play in the disposition of formaldehyde in tissue and responses such as enhanced cell proliferation and tumors.
Unlike rats, monkeys and humans are oronasal breathers. During oronasal and oral breathing, the scrubbing efficiency of the nasal passages is reduced. Breathing route has a significant effect on human pulmonary response from exposure to the highly water soluble gas sulfur dioxide (Adams et al., 1989; Kirkpatrick et al., 1982
) and varies during different levels of physical exertion (Niinimaa et al., 1981
). Since formaldehyde is water soluble and formaldehyde-induced lesions were observed as far down the respiratory tract as the first bifurcation of the lungs in exposed monkeys, the entire human respiratory tract should be considered for various activity states when studying potential effects of formaldehyde inhalation.
To better understand the roles of anatomy, airflow patterns, and local dose in species-specific nasal toxicity, 3-dimensional, anatomically accurate (i.e., reconstructed from actual cross sections) computer models of airflow and gas transport in the nasal passages of the F344 rat (Kimbell et al., 1993,1997a
), rhesus monkey (Kepler et al., 1998
), and human (Subramaniam et al., 1998
) were previously developed using computational fluid dynamics (CFD). The rat and monkey CFD models were created to test the hypothesis that species-specific inspiratory airflow patterns drive formaldehyde uptake in the nasal passages and could account for different distribution patterns of nasal lesions in formaldehyde-exposed rats and monkeys. Therefore factors other than anatomy, breathing rates, the diffusivity of formaldehyde in air, and the high solubility and reactivity of formaldehyde in the liquid lining layer were not included in the models. Predictions of local DPX using the CFD models in conjunction with models for the tissue disposition of formaldehyde were in good agreement with experimental measurements in rats (Cohen Hubal et al., 1997; Conolly et al., 2000
) and monkeys (Conolly et al., 2000
). These results suggest that the exclusion of other factors potentially affecting formaldehyde uptake from inhaled air, such as the presence of other inhaled contaminants, the presence of water vapor, the nasal cycle, and the relative lengths of inspiration and expiration times, did not contribute substantial error to CFD uptake predictions. Local uptake of inhaled formaldehyde estimated by the rat and monkey CFD models correlated with formaldehyde-induced nasal lesion distributions in both species (Kepler et al., 1998
; Kimbell et al., 1993
,1997b
), providing support for the hypothesis that species-specific airflow patterns play a major role in driving local formaldehyde-induced toxicity.
Recently, CFD simulations of formaldehyde uptake were updated to incorporate improved estimates of uptake conditions at the interface between air and tissue that differentiate between mucus-coated and nonmucus-coated tissue (Kimbell et al., 2001). The updated simulations were used to estimate flux in sites where DPX and cell proliferation rates were measured in formaldehyde-exposed rats and monkeys and to make interspecies comparisons of predicted regional flux such as maximum values and flux in lesion sites (Conolly et al., 2000
; Kimbell et al., 2001
).
The CFD models can be used to predict formaldehyde flux throughout the entire nasal passages of the rat, monkey, and human at varying airflow rates. At specific sites where DPX formation and formaldehyde-induced cytotoxicity were measured, relationships between flux and these responses can be estimated. These relationships and flux predictions throughout the nose thus allow an interpolation of DPX and cytotoxicity from measurement sites to the rest of the nasal passages in the rat and monkey, and provide a means for estimating these responses locally in the human nasal passages. When coupled with a model for uptake in the human lung, formaldehyde flux and subsequently DPX formation and potential formaldehyde-induced cytotoxicity could be estimated throughout the human respiratory tract for various activity patterns. This information is critical to biologically based modeling of formaldehyde carcinogenicity that can be used to generate human health risk estimates. However, a strategy for incorporating this information into cancer models while retaining local, species-specific variations in these values is needed.
To address this need, the nasal CFD models described by Kimbell et al. (2001) were used to partition the surface of the rat, monkey, and human nasal passages into flux bins to obtain quantitative descriptions of species-specific uptake patterns. An individual flux bin is the portion or portions of the tissue surface that receives flux within a specific range of flux values. An average value of flux over each bin surface area is associated with each bin. In addition, the human nasal CFD model was linked to a 1-dimensional (typical-path) dosimetry model of the human respiratory tract to provide a description of local dosimetry and corresponding flux bins throughout the entire respiratory tract for 4 activity states (Overton et al., 2001). Nasal flux predictions in humans were therefore obtained for inspiratory airflow rates that correspond to these activity states.
From correlations of rat nasal flux with formaldehyde-induced cell proliferation and DPX measured in specific sites in the rat, cell proliferation and DPX can be estimated for each flux bin throughout the rat nasal passages and human respiratory tract at a variety of airflow rates. These estimates allow cell birth and death processes in cancer cell clonal growth modeling to be parametrized for each flux bin in each species, and to capture human activity patterns as well. Aggregating risk for each flux bin would then produce an overall estimate of cancer risk that incorporates species-specific dosimetry patterns.
This article presents flux bins for the rat, monkey, and human nasal passages as zones that, taken together, describe a partitioning of the surface area of the nasal passages of the rat, monkey, and human based on formaldehyde flux. Tables of nasal surface areas and associated flux values are presented for use in incorporating local, species-specific flux variation into formaldehyde risk assessments. Nasal flux for the human is extended from the work described by Kimbell et al. (2001) for resting breathing to flow rates corresponding to other activity states including light and heavy exercise.
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METHODS |
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Model structure.
The rat and monkey CFD models were constructed from tracings of airway perimeters of the right nasal passages from the nostril to the nasopharynx from serial-step sections of embedded tissue specimens as described by Kimbell et al. (1993) and Kepler et al. (1995). Symmetry between the right and left sides of the rat and monkey nasal passages was assumed. All surface area estimates from the rat and monkey CFD models were therefore doubled to account for both sides of the nasal passages. The human model was constructed from airway tracings of both sides of the nasal passages from the nostril through the nasopharynx from magnetic resonance image scans as described by Subramaniam et al. (1998). Since the human CFD model included both sides, a surface area adjustment was not needed for results from this model.
In-house software (Godo et al., 1995) and the finite element mesh preprocessor of the CFD software package FIDAP (Fluent Inc., Lebanon, NH) were used to generate 3-dimensional computational meshes for each nasal geometry (Kepler et al., 1998
; Kimbell et al., 1997a
; Subramaniam et al., 1998
). All meshes were designed to have elements as uniform in shape and size as anatomy allowed. Steady-state, inspiratory airflow was simulated by solving the Navier-Stokes equations of motion numerically using FIDAP and the nasal meshes. Steady-state airflow was assumed to approximate cyclic breathing patterns based on calculation of the Strouhal number, or frequency parameter (Subramaniam et al., 1998
). Briefly, unsteady effects may be considered insignificant when the frequency parameter is less than 1 (Pedley, 1977
). The Strouhal number, S =
L/u, where
, L, and u are the breathing frequency, axial length of the nasal airway, and the average velocity, respectively, is 0.02 in the human, using
= 0.25 Hz, L = 11 cm, and u = 144 cm/s, corresponding to a flow rate of 26 l/min and a cross-sectional area of 3 cm2 (Subramaniam et al., 1998
).
Inspiratory rates for steady-state airflow were derived by dividing the amount of inspired air (tidal volume, VT) by the estimated time involved in inhalation (half the time a breath takes, or (1/2)(1/[breathing frequency, f]). Thus, an inspiratory flow rate was calculated to be 2 VT f, or twice the minute volume. Minute volumes for the rat and monkey used in this study were estimated to be 0.288 and 2.4 l/min, respectively. Rat and monkey simulations were therefore carried out at 0.576 and 4.8 l/min, respectively (Kimbell et al., 2001), and at various flow rates using the human mesh as described in detail below. Airflow simulation results, consisting of the magnitude and direction of flow predicted at each mesh point, were subsequently used as inputs to the convective-diffusion equation (Bird et al., 1960
) representing formaldehyde transport within the nasal passages.
The areas in which formaldehyde-induced nasal squamous cell carcinomas arise in F344 rats are normally lined by respiratory or transitional epithelium (Morgan et al., 1986). These epithelial types frequently respond to injury by transforming to a squamous epithelial type. The readiness with which the squamous epithelial phenotype is induced by injury to the respiratory and transitional epithelia of the nasal airways may account for squamous cell carcinomas arising from them following a carcinogenic insult. In the current study, attention was focused on formaldehyde uptake predicted in regions that are not normally lined by squamous epithelium. Formaldehyde gas is miscible with water and reacts readily with a number of components of nasal mucus (Bogdanffy et al., 1987
). Absorption rates of inhaled formaldehyde by the nasal lining were therefore assumed to depend on where the epithelial lining is coated by mucus and where it is not.
The approximate locations of nonsquamous and mucus- and nonmucus-coated epithelia were mapped onto the meshes, and separate conditions for mucus- and nonmucus-coated regions were imposed on the transport rate (flux) of formaldehyde at the interface between air and the airway lining as described by Kimbell et al. (2001). Briefly, formaldehyde flux to the nasal surface was assumed to be directly proportional to the air phase concentration of formaldehyde near the wall, with knm and km denoting the constants of proportionality or tissue-phase mass transfer coefficients for nonmucus- and mucus-coated epithelium, respectively. The uptake of inhaled formaldehyde by nonmucus-coated squamous epithelium located in the nasal vestibule of all 3 species was assumed to be similar to uptake determined by Lodén (1986) in experiments measuring formaldehyde transport through human epidermal tissue. An analysis of these measurements provided a mass transfer coefficient of knm = 0.41 cm/s for nonmucus-coated epithelium (Kimbell et al., 2001). A value of 4.7 cm/s for km was obtained for all mucus-coated epithelium in all 3 species by fitting the total percentage of nasal uptake predicted by the rat CFD model to 97% as measured by Patterson et al. (1986).
Simulations for human activity patterns.
Additional simulations were needed to model human activity patterns. Activity patterns consist of various activity states and time durations. The activity states modeled here consisted of sleeping, sitting, and light and heavy exercise and corresponded to cyclic breathing at minute volumes of 7.5, 9, 25, and 50 l/min, respectively (ICRP66, 1994). Nasal airflow patterns during the inspiratory phase of cyclic breathing were approximated by steady-state inspiratory airflow at flow rates equal to twice the cyclic minute volume except at 50 l/min. At 50 l/min, oronasal breathing occurs for most people with approximately 46% of airflow passing through the nasal passages (ICRP66, 1994
; Miller et al., 1988
). Thus cyclic rates of 7.5, 9, 25, and 50 l/min corresponded to 15, 18, 50, and 46 l/min steady-state, nasal inspiratory flow rates, respectively, in the human CFD model.
CFD airflow and formaldehyde uptake simulations were conducted at 15 and 18 l/min. Airflow simulations at 46 and 50 l/min could not be done since the highest flow rate for which convergence of the flow equations solver could be obtained in this human mesh was 37 l/min. Thus additional simulations were conducted at 7.4, 25.8, and 31.8 l/min and formaldehyde uptake was extrapolated from these results to 46 and 50 l/min (see section below on Nasal Flux Bins).
As described by Kimbell et al. (2001), mass balance errors for air (100 x [amount of air entering nostril amount exiting the distal outlet]/[amount entering nostril]) and inhaled formaldehyde (100 x [amount entering nostril amount absorbed by airway surfaces amount exiting distal outlet]/[amount entering nostril]) were calculated. Flux was calculated as the rate of mass transport in the direction perpendicular to the nasal surface per square millimeter of the surface and had units of pmol/(mm2-h-ppm).
Because airflow and formaldehyde uptake were simulated separately, or uncoupled, errors in mass balance arose separately from these calculations. Errors in mass balance of air were less than 0.4% in all airflow simulations. Mass balance errors associated with simulated formaldehyde uptake from air into tissue ranged from less than 14% for the rat and monkey and for the human at 7.4 and 15 l/min to approximately 27% at the highest human inspiratory flow rates of 31.8 and 37 l/min. In all the CFD simulations, the calculated amount entering the nostrils minus the calculated amount exiting the outlet was greater than the calculated amount absorbed by airway surfaces. As described by Kimbell et al. (2001), most of this error occurred when calculating formaldehyde flux to nasal airway surfaces element by element in the finite-element mesh. Flux estimation in directions perpendicular to airway surfaces evidently contributed error to flux calculations for each element of an airway surface region. This error was largest for element-by-element calculation of flux over large, complex nasal surfaces and less for smaller or flatter surfaces such as the nostrils and outlet.
Because the faces of the CFD mesh elements on the nasal airway surface were roughly uniform in shape and size, simulation results were corrected for mass balance errors by evenly distributing the lost mass over the entire nasal surface and adjusting flux values accordingly. For example, in the 15 l/min case where the mass balance error was 13.5%, this correction was calculated as follows:
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Since formaldehyde is highly water soluble and reactive, absorption was assumed to occur only during inspiration. Thus for each breath, flux into nasal passage walls was assumed to be 0 during exhalation. Simulations of formaldehyde uptake in the entire human respiratory tract using a typical-path model during cyclic breathing conditions (Overton et al., 2001) provided further evidence supporting this assumption. In this article, flux values represent an average over the breathing cycle; therefore flux values presented here were derived by halving estimates made using the steady-state inspiratory CFD models, assuming that inspiratory and expiratory phases of the breathing cycle take equal amounts of time.
Linking human nasal CFD and a typical-path lung model.
A linkage between formaldehyde uptake simulations using the human nasal CFD model and a typical-path lung model was necessary to provide formaldehyde uptake estimates throughout the human respiratory tract (Overton et al., 2001). To provide this link, the uptake efficiency of the nasal passage compartment of the typical-path model was required to equal that of the nasal CFD model at each of the 4 flow rates. The uptake efficiency of the nasal CFD model was calculated as 100% x (mass of formaldehyde entering nostril - mass exiting outlet)/(mass entering nostril). Uptake efficiencies at 46 and 50 l/min were extrapolated from efficiencies at 7.4, 15, 18, 25.8, 31.8, and 37.0 l/min by empirically fitting a curve to these efficiencies. A good fit was obtained using a curve of the form
![]() | ((2)) |
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To address these issues, the portion of the nasal surface of each species that is not normally lined by squamous epithelium was contoured or partitioned by formaldehyde flux into several levels for flux values evenly spaced between 0 and the maximum predicted flux value. A flux bin was defined as the nasal surface area of 1 of these contour levels (Fig. 2). Epithelia that is not normally of the squamous phenotype was identified as the region at risk from formaldehyde-induced carcinogenesis so the region near the nostrils lined by normal squamous epithelium was excluded from this partitioning in all 3 species. As an example, when 3 levels were used to contour flux at 15 l/min in the human (Fig. 2
), the first bin contained the amount of nasal surface area where regional flux values fell between 0 and 694 pmol/(mm2-h-ppm) or 1/3 of the maximum flux of 2082 pmol/(mm2-h-ppm), the second bin contained the nasal surface area where flux fell between 694 and 1388 pmol/(mm2-h-ppm), and the third bin contained the surface area where flux fell between 1388 and 2082 pmol/(mm2-h-ppm). Each bin was then associated with an average flux value calculated over the surface area of the region defined by that contour level. Average flux values of 307.9, 1004.5, and 1519.0 pmol/(mm2-h-ppm) and surface areas of 12901.2, 7374.4, and 1089.1 mm2 were associated with the flux bins in the 3-bin example (Fig. 2
).
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Airflow and formaldehyde uptake simulations in the human nasal airways at inspiratory flow rates associated with moderate and heavy exercise exceeded current capabilities for direct computation. To provide flux distribution estimates for these higher flow rates, average flux per bin was extrapolated to the inspiratory nasal airflow rates of 46 and 50 l/min by fitting curves to plots of the average flux per bin versus inspiratory nasal airflow rate for each bin at flow rates of 7.4, 15.0, 18.0, 25.8, 31.8, and 37.0 l/min. Specifically, average flux was assumed to be a function of inspiratory nasal airflow rate. Either a power function of the form
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Two methods were used to compute average human nasal airway surface flux for comparison with results for the nasal compartment of the typical-path model of Overton et al. (2001). At 15 and 18 l/min, the simulations themselves were used to calculate flux averaged in an area-weighted manner over the entire nasal surface. At 46 and 50 l/min, flow rates for which there were no simulations to provide direct calculations, total mass estimated to enter the nostrils was multiplied by the total nasal uptake efficiency estimated for each flow rate to get an estimate of the total mass absorbed at each flow rate. This mass was then divided by the surface area of the entire nasal passages to estimate average nasal airway surface flux.
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RESULTS |
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DISCUSSION |
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Uncertainty in risk estimates based on the use of models such as those presented here arises primarily from the assumptions made about model structures and parameter values used. In many cases, the justification for the assumption or parameter value lowers its contribution to uncertainty; in other cases, sensitivity analyses are necessary to understand effects of the assumption or parameter value on risk estimates. The development and use of CFD models for respiratory tract formaldehyde uptake required a number of assumptions to be made regarding simulation, parameter estimation, and anatomical factors (Kimbell et al., 2001). Model results may be sensitive to several of these factors. The relative contribution to uncertainty of these particular factors is discussed below.
Sources of uncertainty for which sensitivity analyses are appropriate include the use of individual rat, primate, and human nasal anatomies as representative of the general population, the estimation of the distributions of nonsquamous epithelia and mucus- and nonmucus-coated nasal regions in the human, and the number of flux bins used. Quantification of anatomical sources of uncertainty involves determining the extent to which normal variation in these model inputs affects flux estimates. To include variation in nasal anatomy, new models based on a variety of individuals need to be developed and effects on regional flux studied. To determine the location, surface area, and thickness of human nasal epithelial types, detailed mapping using light microscopy on step-sectioned human specimens could be conducted. Analyses to determine the sensitivity of flux resolution to the number of bins used are needed. The methods described here are not limited to a specific number of bins and could be used to conduct these analyses.
The values of mass transfer coefficients used in the boundary conditions for simulations of formaldehyde uptake were based on a single estimate of the thickness of the squamous epithelium. Since this thickness is likely to vary among species, simulations using the monkey CFD model were conducted with a 3-fold higher estimate of squamous epithelial thickness. Local fluxes in mucus-coated regions changed by less than 5% (Kimbell et al., 2001). Thus contributions to uncertainty from a lack of knowledge of squamous epithelial thickness in humans are assumed to be low.
Differences between human nasal airways fluxes extrapolated to 46 and 50 l/min from lower flow rates and nasal fluxes actually attained in reality at 46 and 50 l/min could arise from variations in nasal airflow patterns, particularly the onset of turbulence (Subramaniam et al., 1998). The transition to turbulence could alter the relationship between uptake and flow rate predicted here. That no such alteration takes place is 1 of the assumptions made in the extrapolations of uptake efficiency and average flux per flux bin from lower to higher flow rates. More research on the effects of turbulence on inhaled gas uptake is needed to address this issue.
Interspecies extrapolation of dose and response has been a significant source of uncertainty in all formaldehyde cancer risk assessments to date. Site-specific nasal lesions observed in species-specific patterns suggest that significant local, species-specific variations in formaldehyde uptake exist. Preliminary studies using 2-stage clonal growth models showed that cancer risk estimates in the rat were sensitive to the predicted local distribution of formaldehyde flux (Kimbell, 1998).
The research described here responds to the general recognition that human health risk assessments should account for interspecies differences in local dosimetry. A number of recent studies have used regional nasal airflow and flux predictions in tissue disposition modeling to strengthen extrapolations of dose and response across species (Andersen et al., 1999; Bogdanffy et al., 1999
; Bush et al., 1998
; Frederick et al., 1998
). The use of the flux-binning approach described here to incorporate local flux predictions into risk assessments captures the role of anatomy and inspiratory airflow patterns in determining site-specific flux from air into tissue. Since flux predicted by the CFD models is a linear function of inhaled concentration (Kimbell et al., 1997b
), and since cytotoxicity and DPX are nonlinear with respect to inhaled concentration (Casanova and Heck, 1987
; Casanova et al., 1989
,1991
,1994
; Monticello et al., 1996
), the relationships between flux and responses such as cytotoxicity and DPX formation are nonlinear. Therefore, local variations in flux due to nasal anatomy can lead to large variations in local predictions of potentially adverse effects. Formaldehyde risk models that incorporate flux binning derived from anatomically realistic CFD models will be significantly more accurate, (i.e., less uncertain) than risk estimates based on default methods that do not specifically consider interspecies differences in airway anatomy.
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ACKNOWLEDGMENTS |
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NOTES |
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Portions of this data were presented at the annual meeting of the Society for Risk Analysis, December, 1997, Washington, D.C., and at the 37th and 39th annual meetings of the Society of Toxicology, March 1998 and March 2000, Seattle, WA, and Philadelphia, PA.
1 To whom correspondence should be addressed. Fax: (919) 558-1300. E-mail: kimbell{at}ciit.org.
2 Present address: U.S. Environmental Protection Agency, Washington, D.C.
3 Present address: GlaxoSmithKlein Inc., Research Triangle Park, NC.
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