CIIT Centers for Health Research, 6 Davis Drive, Research Triangle Park, North Carolina 27709-2137
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ABSTRACT |
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Key Words: aerosol; deposition; inhalability; Long-Evans rats; mathematical modeling.
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INTRODUCTION |
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To exert harmful effects, inhaled particles must deposit in lung airways and translocate to various sites and organs in the body to yield response. Thus the fate of inhaled particles in the respiratory tract, as the initial port of entry in the body, is a critical first step toward realistic risk assessment for exposure to airborne particles. Due to ethical obligations or legal restrictions, studies in humans are limited. There is a wealth of information in the literature on exposure studies using rodents to study and model deposition, translocation, and response. However, weak links exist in the process of extrapolation of animal results to humans. For example, there are uncertainties regarding the selection of a relevant dose-metric between humans and animals. The uncertainties arise from differences in airway morphology, biological sensitivities, and breathing parameters. Equivalent rather than identical exposure scenarios are required to yield an equal dose in animals and humans since particles completely inhalable by humans may be only partially inhalable by rodents. In addition, nasal filtration, which controls the number of particles that reach the deep lung and are available for deposition, may vary considerably between humans and rodents. Thus, information on particle inhalability and regional deposition in rodents is critical in studying the adverse health effects posed to humans from exposure to airborne particles and to performing appropriate risk analyses. Regional deposition fractions can be found from direct measurements, and information on particle inhalability can be obtained from particle deposition studies in control studies. Particle inhalability is found by comparing particle deposition fractions between scenarios where particles are all inhalable and a fraction of particles are inhalable.
The lack of inhalability information on airborne particles could increase the variability of the deposition data as well as introduce errors in interspecies dosimetric comparisons. For nasal breathing, particle inhalability is essentially the sampling or aspiration efficiency of the nasal opening and generally limits the number of particles entering the respiratory tract (Vincent, 2002). Inhalability, therefore, depends in part on the size and orientation of the nasal opening and is different between humans and animals. Particles that are completely inhalable by people may be only partially inhalable by animals. Realistic extrapolation of deposition data from animals to humans should include an inhalability adjustment. There is considerable information on the inhalability (or aspiration efficiency) in humans (Aitken et al., 1999
; Breyesse and Swift, 1990
; Erdal and Esmen, 1995
; Hsu and Swift, 1999
; Kennedy and Hinds, 2002
; Ogden and Birkett, 1977
; Vincent and Armbruster, 1981
; Vincent et al., 1990
). However, additional studies are necessary to correlate inhalability, since particle aerodynamic properties and subject breathing parameters are both important in determining inhalability.
The database on particle inhalability in animals is inadequate. No experimental study has been designed specifically for determining inhalability. The study by Menache et al.(1995a) is the only study to date that offers inhalability adjustment curves, which were based on the particle deposition data of Raabe et al.(1988)
for various laboratory animal species. Since particles larger than 3.5 µm showed a decrease in total deposition, Menache et al.(1995a)
assumed that these particles deposited completely in the lung and that the ratio of the internal dose to inhaled mass represented particle inhalability. Due to the lack of sufficient data across particle size, the data of various rodents were combined to calculate a single inhalability curve.
Due to experimental difficulties associated with measurement of particle deposition, few studies have addressed both the deposition of fine and coarse inhalable particles in rats. Chen et al.(1989) measured regional, lobar, and total deposition of cigarette smoke in Fischer-344 rats, exposed nose-only, for 25 min a day for 5 days. Dahlbäck and Eirefelt (1994)
and Dahlbäck et al.(1989)
exposed male Sprague-Dawley rats to particles in a nose-only tower for 10 min and measured total deposition fraction and distribution in the lung. Raabe et al.(1977
, 1988)
studied deposition of various sized particles in different regions of the respiratory tracts of common laboratory species, including Long-Evans rats. These carefully conducted studies did not measure minute ventilation of the test animals (Raabe et al., 1988
), which is essential for a precise assessment of deposition. For large particles, deposition in the head region is largely by impaction. This means that losses mainly depend on the particle Stokes number, which, in turn, depends directly on the animals ventilatory parameters. Raabe et al.(1977
, 1988)
used allometric equations to determine breathing rates rather than measuring the animals ventilatory parameters. In addition, since particle clearance in most nasal regions is rapid, particle deposition studies have to be of short duration. This requires a generation system that produces a high concentration of monodisperse particles (106/cm3) to give measurable deposition during this period. In the aforementioned studies, some of these points were not addressed fully, thereby increasing variability of the results.
A number of studies have been published on modeling particle deposition in the rat lung. These models are semiempirical (Menache et al., 1995b), stochastic (Koblinger et al., 1995
), or deterministic (Schum and Yeh, 1980
; Yu and Xu, 1986
). Deterministic models are most often typical-path, and are therefore based on symmetric lung structures. Typical-path deposition models cannot address variation of dose among different airways at a given generation. Anjilvel and Asgharian (1995)
introduced a new generation of the mathematical model of particle deposition in the lung. They calculated particle deposition using a multiple-path analogy operative for any lung geometry structure. This model gave a more realistic prediction of deposition, since variations of deposition among different airways of the lung were innately calculated. The deposition model calculated particle deposition in every airway of the lower respiratory tract (LRT) from the information on breathing rate, lung parameters (e.g., airway length and diameter, branching angle), and deposition efficiencies per airway. Site-specific, lobar, regional, and total deposition fractions were calculated by adding deposition fractions of the individual airways.
Realistic PM deposition and clearance models for animals that incorporate physical phenomena require accurate lung geometries as input. Although one of the most commonly used laboratory animals is the rat, a set of structural data comprising the entire respiratory tract for any strain of rat is currently not available. Different strains of rats have been used for measurements of structure in different regions of the respiratory tract. For example, a detailed reconstruction of nasal geometry was developed for the Fischer 344 rat (Kimbell et al., 1993), while numerous anatomical measurements of the conducting airways of a Long-Evans rat were made by Raabe et al.(1976)
. In addition, the acinar region, for which structural data are extremely difficult to obtain, has been reconstructed for Sprague-Dawley and CD-1 rats (Mercer and Crapo, 1988
).
Despite progress on particle deposition in the lungs of rats, a significant data gap remains to be filled. A unified dataset on lung structure in a given strain of rat is desirable. Particle deposition in various regions of the lung, as well as inhalability fraction, must be established. This article details a study conducted to measure deposition and inhalability of particles in the respiratory tract of the Long-Evans rat, which was selected for this study because of the availability of anatomical data for its conducting airways and because this data set was used in a mathematical dosimetry model to calculate particle deposition in the rat lung (Anjilvel and Asgharian, 1995). Particle deposition fraction in the nasal passages and in various lobes and regions of the Long-Evans rat lung was measured following a nose-only exposure to radiolabeled monodisperse particles. Rat inhalability fraction was obtained by comparing lung deposition measurements with predictions.
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MATERIALS AND METHODS |
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Aerosol generation and characterization.
A condensation monodisperse aerosol generator (CMAG) (Model 3475; TSI Inc., St. Paul, MN) was used that produced monodisperse, radiolabeled aerosols with aerodynamic diameters ranging from 0.9 to 4.2 µm (0.9, 1.3, 1.9, 2, 2.3, 2.6, 2.7, 3.1, 3.4, 3.6, and 4.2 µm). Aerosol diameters had an average geometric standard deviation (g) of 1.12 (all values of
g were less than 1.18), reflecting monodisperse aerosols. Radiolabeled particles were formed in the CMAG by heterogeneous condensation of triphenyl phosphate (TPP) with a density of 0.95 g/cm3 (Tomaides et al., 1971
) onto radioactive iron chloride seed particles. Iron chloride solution with gamma-emitting 59Fe of 44.6 days half-life and a specific activity of about 2030 mCi/mg was purchased from Perkin Elmer Life Sciences, Inc. (Boston, MA) as iron chloride in 0.5 M hydrochloric acid.
The 59Fe solution was transferred to an atomizer inside the CMAG and diluted with distilled water to a concentration of 12 to 16 mg/l. Compressed air was delivered to the atomizer using a setting of 60 psi. The resulting aerosol was diffusion-dried and then bubbled through a temperature-controlled saturator containing heated TPP. The mixture of dry 59Fe seed aerosol and TPP vapor leaving the saturator entered a condensation chimney where TPP condensed into particles with a radioactive 59Fe core. Monodisperse aerosol was sampled from the condensation chimney and delivered to the exposure system. Desired particle sizes were achieved by controlling the concentration of TPP vapor and 59Fe seed aerosol in the condensation chimney. Particle size was monitored during animal exposures with an aerodynamic particle sizer (APS) (Model 3320; TSI Inc., St. Paul, MN).
Exposure system.
A schematic diagram of the exposure apparatus is shown in Figure 1. Aerosol, pumped from the CMAG by a peristaltic pump (Masterflex® Model No. 7565, Cole Parmer Instrument Co, Chicago, IL), was combined with filtered air generated with a house air source and delivered at a constant flow rate using a mass flow controller (MKS Instruments, Model 246B, Andover, MA). A fraction of this flow was diverted to an APS; the remaining flow, approximately 4.5 l/min, was delivered to a 52-port, Cannon nose-only tower (Lab Products, Maywood, NJ). Seven ports of the tower were used for experimental purposes (5 for animal exposure, one for a filter sample, and one for a pressure gauge); the unused ports were plugged. Therefore approximately 640 ml/min of aerosol flow was delivered to each port.
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Five female Long-Evans rats were loaded into nose-only tubes (Skornik Plethysmograph, CH Technologies Inc., Westwood, NJ) 1015 min prior to an exposure event. An exposure event involved exposing 5 rats to a single size of monodisperse, radiolabeled aerosols for a given period of time. A total of 11 exposure events were conducted. The length of exposure ranged from 10 to 17.5 min, with an average of 12 min. Exposures times were chosen to enable depositing sufficient radioactivity for detection in airway tissues while minimizing the time for nasal and TB clearance. Immediately following cessation of exposure, animals were killed by CO2 asphyxiation, and relevant tissues (i.e., nasal passage, larynx, esophagus, trachea, lung lobes, stomach, and duodenum) were dissected. The dissection involved isolating an entire lobe or region of the respiratory or digestive tract, not just a representative sample; total activity in a lobe or region was counted and used to estimate deposition.
Breathing measurements.
Animal respiratory parameters were monitored for a 5-min period prior to aerosol exposure and continuously during exposure. Each animal was placed in a nose-only tube with an opening through a screen pneumotachograph in the back end of the tube. The animals nose was led through a latex collar placed near the nose-only tube entrance, creating an airtight seal (Fig. 2). During breathing, contraction and expansion of the animals thorax forced air into and out of the chamber through the pneumotachograph, thereby causing periodic changes in chamber pressure. Measurements of respiration were made using a conventional data acquisition system (Buxco Electronics, Sharon, CT) by monitoring fluctuations in chamber pressure and calibrating pressure fluctuations to volume displacements.
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Each dissected tissue was placed in a single sample tube except for the nasopharynx and stomach. Since these tissues were each too large to fit into a single sample tube, the nasopharynx and stomach tissues were split into two tubes. Tools used to divide these tissues were wiped onto the respective tissue to minimize the potential loss of deposited activity. Cross-contamination of tissue samples was avoided by sanitizing the tools between tissue dissections.
Deposition fraction of inhaled material per breath of animal is a unique quantity as long as breathing parameters and lung geometry remain the same. Deposition fraction is defined as the amount of material deposited in the tissue divided by the amount of the material inhaled. Deposition fraction depends on particle aerodynamic properties, lung geometry, and breathing parameters of each animal and varies among different regions of the lung. Deposition fraction is determined by dividing the activity counted in each tissue sample by the activity counted on the filter sample that collected aerosol from the exposure atmosphere. The following formula, which accounts for differences in sampling rate of the animals and filter sample, was used to calculate the deposition fraction:
![]() | 1 |
where DFi is the deposition fraction in the ith airway, Ai the activity in the ith airway, Afs the activity on the filter sample, Qfs the filter sample flow rate, MV the animal minute volume, tfs the filter sampling time, and texp the exposure time.
The exposure time, filter sampling time, and flow rate were set during each exposure event. These values plus the measurements of Ai, Afs, and animal breathing parameters were used in Equation (1) to determine the deposition fraction in each animal per exposure event.
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RESULTS AND DISCUSSION |
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The mean and standard deviation of the head and lung deposition fractions in Long-Evans rats were plotted against particle diameter (Fig. 4). Head deposition fractions showed an increase followed by a decrease with particle size. Variability in the data prevented identifying the particle size at which maximum head deposition fraction was achieved. Most deposition occurred in the nasal passages. Due to strong filtering in the head and inertial losses in the upper airways of the LRT, particle deposition in the lung appeared to remain relatively constant. The lung deposition fraction was below 10% for most particle sizes. Considerable variation in deposition results was observed, since each animal had different breathing parameters and head orientation in the nose-only tube, which would alter particle inhalability.
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Inhaled particle concentration may be less than that in the exposure air for fine and coarse particles. Particle inhalability depends on particle size as well as on breathing parameters and is calculated using the following equation,
![]() | 2 |
where DF and are the measured and theoretical (100% inhalable) lung regional or total deposition fractions (see Appendix for derivation). Values for
can be found from studies where 100% of particles are inhalable or, alternatively, from experimentally validated mathematical models.
Anjilvel and Asgharian (1995) introduced a mathematical model of particle deposition in the lungs of rats based on the morphometric lung measurements of Long-Evans rats (Raabe et al., 1976
). The model was used here to calculate
based on the measured breathing parameters of the animals in the study. Inhalability was calculated from Equation 2
and plotted against the inertial parameter
d2Q in Figure 6
, where
is particle density, d is particle diameter, and Q is inhalation flow rate. The parameter
d2Q combines particle diameter and breathing parameters and is a measure of particle inertia. Due to experimental variability, a number of calculated inhalability values were higher than 100%. These values were not included here. The calculated inhalability fractions showed variability with
d2Q, but there was a decline in inhalability with increasing
d2Q. A predictive model of inhalability in Long-Evans rats was found by fitting a function of the form similar to that given by Menache et al.(1995a)
to the data.
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![]() | 3 |
Equation 3 has the same functional form as that of Menache et al.(1995a)
, with the difference of dependence on
d2Q in place of particle diameter. Fitting Equation 3
to the measurements yielded
= 19.87 and ß = 0.7466 with r2 = 0.46. This equation has the right behavior by approaching 1 for small particles and 0 for large particles. While some studies in humans suggested that inhalability reached a plateau for sufficiently large particles (Aitken et al., 1999
; Chung and Dunn-Rankin, 1992
; Erdal and Esmen, 1995
), this equation showed that inhalability became negligible around 50 µm.
The inhalability fraction computed by Equation 3 was compared with the results of Menache et al.(1995a)
in Figure 7
for various particle sizes. Equation 3
was plotted for slow, normal, and fast breathing, corresponding to a minute ventilation of 3.33 cm3/s, 7.14 cm3/s, and 14 cm3/s respectively. The inhalability prediction of Menache et al.(1995a)
gave a higher prediction of inhalability, because their expression was based on the deposition data of Raabe et al.(1988)
, which overestimated deposition (Fig. 4
). Raabe et al.(1988)
also used a different exposure system for which particle inhalability could have been different, depending on the orientation of incoming exposure air with respect to the nose of the animals.
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Summary
Deposition of radiolabeled monodisperse particles in the lungs of Long-Evans rats was measured following a short exposure to particles ranging in size from 0.9 to 4.2 µm in a Cannon nose-only exposure system. The breathing rates for all the animals were measured during the exposure and were used to calculate the lobar and regional deposition fractions. Deposition patterns were found to be similar among the various lobes, giving a maximum deposition for particles near 3.5 µm. The caudal and accessory lobes gave the highest and lowest deposition of particles in the right lung, while the medial and cranial had similar deposition falling between the two limits. Our deposition fractions agreed with the literature values for particles smaller than 3 µm but fell short of those for larger particles, because the breathing parameters used to calculate deposition were low and resulted in overestimation of deposition values. The particle deposition fraction decreased with particle size because of an inhalability limitation that increased with particle size. A new expression based on the deposition results was introduced for inhalability fraction prediction. This expression predicted smaller inhalability of particles than the previously used results of Menache et al.(1995a). The difference in inhalability results was attributed to the difference in deposition datasets used to construct the inhalability curves.
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APPENDIX |
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![]() | A1 |
Particles enter the head airways at Ci and exit at C1, enter the lung and exit at concentration C2, and enter the head region again before exiting the respiratory tract at a concentration Ce. Since Ca is larger than Ci, measured deposition fraction, DF, is smaller than theoretical deposition fraction when a fraction of the airborne particles enters the respiratory tract. Deposition fractions for the entire respiratory tract are calculated as below:
![]() | A2 |
![]() | A3 |
where subscript t denotes total deposition fraction. Taking the ratio of equations A2 and A3 and replacing Ci/Ca with IF from equation 1
gives
![]() | A4 |
The theoretical and measured deposition fractions in the lung compartment are
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![]() | A6 |
Taking the ratio and inserting the definition of inhalability fraction yields
![]() | A7 |
Similarly, the inhalability fraction using the head compartment deposition fractions can be shown to be
![]() | A8 |
The measurements for regional and total deposition fraction, along with the predicted deposition fractions for 100% particle inhalability, were used in equations A4, A7
, and A8
to calculate inhalability fractions.
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ACKNOWLEDGMENTS |
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NOTES |
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This study was supported in part by the U.S. Environmental Protection Agency. It has not been subjected to any review by the Agency. It does not necessarily reflect the views of the U.S. EPA, and no official endorsement should be inferred.
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