Ann. occup. Hyg. Vol. 19, pp. 1-12. Pergnmon Press 1976. Printed in Great Britain
MASS-TRANSFER COEFFICIENT FOR SULPHUR DIOXIDE AND NITROGEN DIOXIDE REMOVAL IN CAT UPPER RESPIRATORY TRACT* CORN, N.
KOTSKO and
D.
STANTON
Abstract—A new technique is described for measuring absorption in the cat respiratory tract of pollutant gases in air at ppm concentrations. A retrograde catheter was surgically inserted in lightly anaesthetized animals ventilated by a Harvard breathing pump. A gas sampling system actuated by the pump permitted withdrawal of gas samples during inhalation or exhalation through a tracheal cannula and the retrograde catheter. The effects of pollutant concentration and breathing volume and frequencies on uptake were studied with SOi- and NO2-in-air. Postmortem techniques were used to quantitate the transfer surface available in each experiment. Results are expressed by a mass-transfer coefficient, KG, expressed as moles transferred per square centimeter of tissue per second per mm mercury (partial pressure of pollutant gas). Kc for SOj in these studies varied from 6.77 x 10" 7 mol/cm2 s mmHg at an SOi concentration of 5.2 ± 0.8 ppm to 1.77 x 10" 6 mol/cm2 s mmHg at 1.8 ± 0.4 ppm SO2 in air. The value of KG increased slightly as the partial pressure of SO2 in air increased. There was little, if any, increase in Kc, as the frequency of breathing increased from lOcycles/min to 30 cycles/min and as the depth of breathing increased from 75 ml to 100 ml per stroke. Kg for NOj varied from 1.80 x 10~6 mol/cm2 s mmHg at an NO a concentration of 5.5 ± 0.7 ppm to 1.55 x 10" 6 mol/cm2 s mmHg at an NOj concentration of 2.2 ± 0.4 ppm. Thus, there was no change in A^ with change of concentration. Kc did not vary with frequency or depth of breathing. The values of KG reported here may be utilized with models of the human lung to predict local doses of adsorbed pollutants following inhalation. INTRODUCTION THE ESTABLISHMENT of air quality standards for specific pollutants in the air of U.S. cities (ENVIRONMENTAL PROTECTION AGENCY, 1973) requires that consideration be
given to dosage-response data for the inhaled pollutants, either alone or preferably in combination (HATCH, 1968). Sources of these data are epidemiologicalfieldstudies or laboratory investigations using animal species or human subjects. The former studies yield a practical dosage-response curve, as do the laboratory exposures of human subjects. The dosage to the critical body organ, in this case the lung, can best be estimated by studies with laboratory animals. There are guidelines for estimation of the amount of particulate matter deposited at different sites in the respiratory tract following inhalation by man (TASK GROUP ON LUNG DYNAMICS, 1966). A model to estimate uptake of inhaled gases by the respiratory tract is not as well developed as those for losses following inhalation of a disperse phase. We describe investigations to develop a direct method for measuring uptake by * Supported by Grant No. 5 RO1 ESOO5O1-O3, National Institute of Environmental Health Sciences.
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M.
Department of Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pennsylvania, U.S.A.
2
M. CORN, N. KOTSKO and D. STANTON
gen (COSBY et al, 1962).
Animal studies have involved more complicated techniques. GADASKINA (1946) measured SO2 in the upper respiratory tract of tracheotomized and non-tracheotomized rabbits. DALHAMN and STRANDBERG (1961) and STRANDBERG (1964) measured the difference between the concentration of SO 2 in inhaled and exhaled air; sampling was from the trachea and was precisely controlled by a pressure signal actuated by animal inspiration and expiration cycles. KAJLAND and STRANDBERG (1962) described a technique for sampling via tracheal cannula in rabbits during maximum inspiration and expiration, respectively; labelled S 35 O 2 was used. Endotracheal catheter was used to obtain upper and lower respiratory tract samples to determine aldehyde retention in the dog (EGLE, 1972). S 3 5 O 2 was utilized by BALCHUM et al. (1959) to study gas uptake in different body organs of the dog and by FRANK et al. (1969) to determine SO2 absorption in surgically isolated upper airways of anaesthetized dogs. A chronically implanted Teflon catheter in awake, unrestrained cats facilitated continuous intratracheal sampling of respiratory gases at end-expiration (SCOTTO and NATTOVE, 1970). Implanted catheters in the aorta and the vena cava of awake, unrestrained cats yielded blood gas values of selected gases (HERBERT and MITCHELL, 1971). Results of gas uptake experiments have been expressed as percentage penetration or removal (efficiency) in the nose, naso-pharyngeal chamber, upper or lower respiratory tract, a well established procedure (HENDERSON and HAGGARD, 1943). BRAIN (1970) offered a general discussion of nasal uptake of inhaled gases. DuBois and ROGERS (1968) presented a systematic theoretical analysis of the respiratory factors which influence the intensity of exposure at the site of tissue damage following inhalation of a toxic gas. The solubility and diffusion coeflicient of the inhaled gas must be known, as well as the respiratory factors of bronchial dimensions, minute volume and frequency of respiration, pulmonary, arterial and bronchial blood flows. We have measured SO 2 and NO 2 uptake to calculate an overall mass transfer coeflicient for the cat upper respiratory tract under varying conditions of pollutant concentration in air, and depth and frequency of breathing. Thus, we liken the scrubbing eflBciency of the upper respiratory tract to that of an industrial scrubbing tower. If the analogy is valid, with this methodology it is now possible to calculate dosage of inhaled pollutant gas to local areas of the respiratory tract.
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the cat respiratory tract of pollutant gases introduced via the naso-pharyngeal chamber or the trachea. The basis for development of our techniques was the retrograde catheter, previously successfully used to measure static pressures in conducting airways of excised dog lungs (MACKLEM and MEAD, 1957) and to evaluate the effect of pharmacological agents on peripheral airway resistance (BATTISTA et al., 1973). BATTISTA and GOYER (1974) utilized a technique similar to that described here to measure absorption of acetaldehyde vapour in the dog lung. Many previous studies of uptake of inhaled gas in the respiratory tract of human subjects utilized inspired and expired air analysis (WEST and DOLLERY, 1962; WEST et al., 1962). SPETZER and FRANK (1966) sampled inspired and expired air from a closefitting hard plastic mask fitted over the mouth and nose. Others have sampled tracheal air at different phases of the respiratory cycle; interpretation of results relates tracheal air to air deeper in the respiratory tract at any phase of the respiratory cycle (WEST, 1961). In another approach, arterial blood gas tension has been measured with electrodes, as has alveolar air, a method restricted to selected gases, particularly oxy-
SOj and NOj removal in catrespiratorytract
3
EXPERIMENTAL METHODS
FIG. 1. Schematic diagram of pollutant generation system for SOa in air. A—Medical grade breathing air; B—Valve; C—'Catch all' air cleaner; D—Silica gel; E—Milliporc HA filter; F—Orifice; G— Pressure gauge; H—Permeation oven with pollutant permeation tubes; J—Pollutant gas reservoir; K—Extra dry nitrogen.
Pollutant gas sampling and analysis Figure 2 is a schematic diagram of the system used for simultaneous sampling SO2 in air from the tracheal cannula and the retrograde catheter. Pollutant was sampled during the inspiratory stroke of the pump. A microswitch was activated during the 1
AID Model 303.
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Preparation of pollutant mixtures Mixtures of SO2 in air for animal exposures were produced using FEP Teflon SO2 permeation tubes (NELSON, 1971) 15 cm long and 0.030 cm wall thickness. The tubes were placed in a 3-tube capacity glass permeation chamber in a gas mixing oven.* Medical-grade compressed breathing air was passed through activated carbon, silica gel, membrane filter and was metered with calibrated orifice meters prior to entering the oven with permeation tubes. The gas exited from the permeation oven and entered a glass reservoir, where it was either exhausted or withdrawn by a Harvard breathing pump for delivery to the animal undergoing exposure. Figure 1 is a schematic diagram of the pollutant generation system for SO2 in air. Because of changes which occur in NO2 permeation tubes with exposure to air containing water vapour, it was necessary to provide continuous flushing of the NO2 permeation tubes with nitrogen. Pollutant gas concentration was varied by changing the temperature of the permeation oven. All components of the system, with the exception of the reservoir, were of stainless steel, rigid plastic or Teflon (CORN et al., 1972). Room air or pollutant in air entered the Harvard pump through a three-way valve at the pump entry. Pump stroke and frequency was adjustable. The inspiratory stroke of the pump was at positive pressure relative to room air pressure; the animal expired passively.
M.
CORN, N. KOTSKO and
D. STANTON K
2 = partial pressure of pollutant gas at exit (mmHg), pe — partial pressure of pollutant gas in mucus (mmHg (unknown)), d = diffusivity of pollutant gas in air (cm2/s), p = pollutant gas density (g/cm3), w = pollutant gas mass flow rate (g/s), and L = length of wetted airway path (cm). The mass diffusivity constants for SO2 and NO 2 in air were computed to be 0.143 cm 2 /s and 0.138 cm 2 /s (BIRD et al, 1960). After calculating (pe— p j), KG could be determined from equation (6). NA =
or Ka = where terms in equations (6) and (7) are defined as above. In order to transform experimental data into measured values of KG for different conditions of breathing (frequency, volume) and pollutant concentrations, the following computational procedures were followed. 1. From pollutant concentrations determined from samples obtained at tracheal cannula and retrograde catheter sampling ports, the moles of pollutant absorbed between sampling points was calculated. 2. The integrated time of sampling, as measured by an electric timer in the sampling circuit, was used as the measure of gas transfer time associated with absorption of gas in (1).
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where NA = gas transferred, mol/s cm , kG = gas transfer coefficient, mol/s cm mmHg, KG = overall mass-transfer coefficient, mol/s cm 2 mmHg, -Pso^o = Partial pressure of SO 2 in gas phase, mmHg, -Pso2(1) = partial pressure of SO 2 at interface, mmHg, PSOl* = partial pressure of SO2 in gas phase corresponding to concentration of SO2 in liquid phase (a fictitious partial pressure), mmHg, APso2iOAy = overall partial pressure difference. The concept of mass-transfer coefficient is potentially a powerful one for utilization with a model of the human respiratory tract, where estimates are available for transfer surface area and time of residence of air volumes in airway generations. Experimental data for changes in axial concentrations of the pollutant gas from tracheal or mouth entry to the implanted catheter were transformed into concentration differences along the axis of diffusion by using the Graetz equation (equation (5)) to calculate (j>t —
ttp://annhyg.oxfordjournals.org/ at University of California, Santa Barbara on June 28, 2015
TABLE 2. CALCULATED MASS-TRANSFER COEFFICIENTS FOR SULPHUR DIOXIDE ABSORPTION IN CAT RESPIRATORY TRACT
Harvard pump settings (ml/cycle) (cycles/min) 75 75 75 75 75 75 75 75 75 100 100 100 100 100 100
10 10 10 20 20 20 30 30 30 10 10 20 20 30 30
SO2 concentration in air (ppm) Range Mean ± s.d. 1.0- 3.0 3.1- 6.0 8.0-14.0 1.0- 3.0 3.1- 6.0 9.0-12.0 1.0- 3.0 3.1- 6.0 8.0-11.0 1.0- 3.0 3.1- 6.0 1.0- 3.0 3.1- 6.0 1.0- 3.0 3.1- 6.0
2.0 ± 0.8 3.1 ± 0.4
11.4 ±3.9 1.7 ±0.6 3.3 ± 0.6 10.0 ± 1.5 1.4 ±0.4 3.3 ± 0.6 10.1 ± 1.5 1.4 ±0.3 5.2 ± 0.8 1.3 ±0.6 5.5 ± 0.8 1.8 ±0.4 5.7 ± 0.7
Number of measurements
Number of animals
37 6 17 29 20 45 30 19 20 19 13 20 14 16 13
5 1 2 4 2 3 4 2 2 2 2 2 2 2 2
KG, overall mass-transfer coefficient (mol/cm 2 ;> mmHg) Mean ± s.d. Range 4.64 7.38 1.05 8.73 1.43 9.62 1.15 1.27 2.33 9.10 6.77 1.66 1.10 1.77 1.23
x 10" 7 ± x I0" 7 x 10"* x 10- 7 ± x 10"7 x 10"7 ± x 10"* ± x 10"* x 10"* x 10"7 x 10"7 x 10"* x 10"* X 10"* x 10"*
0.75 2.75 1.61 0.22
4.06- 5.93 x lO"7 8.98-12.2 5.73-11.9 7.48-21.2 7.77-10.7 8.90-13.6 9.20-16.2 1.36- 3.29 8.54- 9.65 4.65- 8.88 1.54- 1.77 7.64-14.4 1.74- 1.80 8.60-15.9
x 10- 7 X lO"7 x lO"7 x 10"7 X 10"7 X 10"7 x 10-* X 10"7 x 10- 7 X 10-* X 10"7 x 10-* X 10"7
s 9 z *-* 3
g 5 CL
hi
w >
z
p://annhyg.oxfordjournals.org/ at University of California, Santa Barbara on June 28, 2015
TABLE 3. CALCULATED MASS-TRANSFER COEFFICIENTS FOR NITROGEN DIOXIDE ABSORPTION IN CAT RESPIRATORY TRACT
Harvard pump settings (ml/cycle) (cycles/min) 75 75 75
75 75 100 100 100 100 100 100 100 100 100 100 100
10
10 20 20 30 10 10 10 10 20 20 20 30 30 30 30
NO2 concentration in air (PPm) Range Mean ± s.d. 3.0-4.0 4.1-5.0 2.0-3.0 4.0-5.0 4.0-5.0 1.0-3.0 3.1^t.O 4.1-5.0 5.1-6.0 1.0-3.0 3.1-1.0 4.1-5.0 1.0-3.0 3.1-1.0 4.1-5.0 5.1-6.0
3.8 ± 4.1 ± 2.9 ± 4.5 ± 4.6 ± 2.4 ± 3.4 ± 4.4 ± 5.3 ± 2.2 ± 3.7 ± 4.4 ± 2.5 ± 3.5 ± 4.4 ± 5.5 ±
0.4 0.6 0.2 0.4 0.5 0.5 0.4 0.4 1.0 0.4 0.4 0.4 0.5 0.3 0.9 0.7
Number of measurements
Number of animals
14 7 6 21 25 14 34 41 6 21 50 38 30 40 28 14
2 1 1 3 4 2 5 6 1 3 7 6 4 6 4 2
Kc, overall mass-transfer coefficient (mol/cm2 s mmHg) Range Mean ± s.d.
1.59 1.50 1.99 2.01 1.80
x x x x x x x x x x
10-77 lO" 10-76 10" 10"66 10"6 1010"76 1010-66
x 10" X 10"6 x 10- 6 x 10"6 x 10- 6
O CD
aa.
2.63- 5.93 x 10"7
4.28 X 10- 7
6.95 9.32 8.82 1.06 1.48 1.80 1.10 8.73 1.55 1.56
VI
±0.25 ±0.23 ±0.94 ± 0.41 ±0.58 ±0.34
±0.47 ±0.39 ±0.64 ± 0.43
5.98-10.8 7.43-12.8 1.34- 1.61 8.49-33.5 4.29-15.8
x lO"7 x 10"7 x 10"6 x 10"7 X lO"7
1.12- 2.21 1.13- 2.00 9.82-21.5 8.70-18.0 1.35- 3.01 1.55- 2.5 1.42- 2.18
x x x x x x x
10-* lO"6 10"7 10"7 lO"6 10-* 10- 6
O | o
i.5' 8 •S a T'
to O
3 n
10
M. CORN, N. KOTSKO and D. STANTON
REFERENCES ADRIAN, R. W. (1964) Am. J. vet. Res. 25, 1724-1733. BALCHUM, O. J., DYBICKI, J. and MENEELY, G. R. (1959) Am. J. Physiol. 197,1317-1321. BAT-TOTA, S. P. and GOYER, M. M. (1974) Fed. Proc. 33 (3), 569. BATITSTA, S. P., STEBER, W. D., GREEN, M. and KENSLER, C. J. (1973) Archs emir. Hlth 27, 334-339. BIRD, R. B., STEWART, W. E. and LIGHTFOOT, E. N. (1960) Transport Phenomena, p. 512, Wiley, New
York. BRAIN, J. D. (1970) Ann. Otol. Rhinol. LOT. 79, 529-539. CORN, M. and BELL, W. (1963) Am. ind. Hyg. Ass. J. 24, 502. CORN, M., KOTSKO, N., STANTON, D., BELL, W. and THOMAS, A. P. (1972) Archs emir. Hlth 24,
248-256. COSBY, R. S., STOWELL, E. C , MORRISON, D. M., MAYO, M., RUYMANN, F. B. and BERNARD, B.
(1962) J. appl. Physiol. 17, 1. DALHAMN, T. and STRANDBERO, L. (1961) Int. J. Air. Water Pollut. 4,154. DUBOB, A B. and ROGERS, R. M. (1968) Resp. Physiol. 5, 34-52. EGLE, J. L. (1972) Archs emir. Hlth 25, 119-124. ENVIRONMENTAL PROTECTION AGENCY (1973) Fed. Reg. 36, (21).
FRANK, N. R., YODER, R. E., BRAIN, J. D. and YOKOYAMA, E. (1969) Archs emir. Hlth 18, 315-322.
GADASKINA, I. D. (1946) Farmakol. Toksik 9, 51-33. HATCH, T. F. (1968) Archs emir. Hlth 16, 571.
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3. ADRIAN'S (1964) classification of the segmental anatomy of the cat lung, together with a cylindrical airway model, was used to estimate the surface area of the airways to which pollutant gas was exposed proximal to the retrograde catheter. Table 2 summarizes KG values for sulphur dioxide absorption in the cat respiratory tract. Data for frequency and depth of breathing, pollutant gas concentration and the number of animals and independent measurements contributing to the calculation of Ka are presented. Table 3 contains similar results for NO2 absorption in the cat respiratory tract. The overall mass-transfer coefficient for SO2 varied from 6.77 x 10"7 mol/cm2 s mmHg at an SO2 concentration of 5.2 ± 0.8 ppm to 1.77 x 10"6 mol/cm2 s mmHg at 1.8 ± 0.4 ppm SO2 in air. The value of KG increased slightly as the partial pressure of SO2 in air increased. There was little, if any, increase in KG as the frequency of breathing increased from 75 ml to 100 ml per stroke. An important observation in this investigation was that KQ values were not significantly different during 30 min of exposure to the pollutant gas when experimental variables (depth and frequency of breathing, gas concentration) remained constant. This suggests that an equilibrium condition is rapidly attained. The value of Ko for NO 2 varied from 1.80 x 10"6 mol/cm2 s mmHg at an NO2 concentration of 5.5 ± 0.7 ppm to 1.55 x 10" 6 mol/cm2 s mmHg at an NO2 concentration of 2.2 ± 0.4 ppm. Thus, there was no change in KG with change of concentration. Ka did not vary with frequency or depth of breathing. Because airflow in the cat respiratory tract and in the human respiratory tract are in the streamline flow regime, except during extraordinary exertions by man where turbulence can occur in the trachea, values of KG derived from these experiments should be applicable to estimation of pollutant gas absorption after inhalation by man. Estimation of area of airways available for uptake of gas can be obtained from WEIBEL'S (1963) morphometric models of the human lung. Using values of KG reported here, it is now possible to predict local dosage of SO2 following inhalation by man. Extension of these results to calculations of SO2 and NO2 absorption in the human respiratory tract is currently under way.
SO2 and NO 2 removal in cat respiratory tract
11
HENDERSON, Y. and HAGGARD, H. W. (1943) Noxious Gases and the Principles of Respiration Influencing Their Action. Reinhold, New York. HERBERT, D. A. and MITCHELL, R. A. (1971) J. appl. Physiol. 30, 434-^36. INTERSOOETY COMMITTEE (1972) Methods of Air Sampling and Analysis, p. 447. Washington, D.C. KAJLAND, A. and STRANDBERG, L. (1962) Nord. hyg. Tidskr. 43, 21. LJNCH, A. L. and CORN, M. (1965) Am. ind. Hyg. Ass. J. 26, 601.
MACKLEM, P. T. and MEAD, J. (1967) / . appl. Physiol. 22, 395-401. NELSON, G. O. (1971) Controlled Test Atmospheres, p. 134. Ann Arbor Science Pub., Mich., U.S.A. PATE, J. B., AMMONS, B. E., SWANSON, G. A. et al. (1965) Analyt. Chem. 37, 942-945.
SCOTTO, P. and NATTOVE, A. (1970) / . appl. Physiol. 28, 714-715. SPEEZER, F. E. and FRANK, N. R. (1966) Archs envir. Hlth 12, 725-728. STRANDBERG, L. G. (1964) Archs emir. Hlth 9, 160-166. WEIBEL, E. R. (1963) Morphometry of the Human Lung. Springer, Berlin. WEST, J. B. (1961) Inhaled Particles and Vapours (edited by DA VIES, C. N.). pp. 3-7. Pergamon Press, Oxford. WEST, J. B. and DOLLERY, C. T. (1962) / . appl. Physiol. 17, 9. WEST, J. B., HOLLAND, R. A. B., DOLLERY, C. T. and MATTHEWS, C. M. E. (1962) / . appl. Physiol. 17,
14. WEST, P. W. and GAEKE, G. C. (1956) Analyt. Chem. 28,1816-1819.
DISCUSSION M. KUSCHNER: IS the diffusion coefficient dependent on the character of the mucus? Some years ago Francis Roe pointed out that the cat was particularly unsuited to experiments with irritant gases. He stated that the bronchial glands of the cat (which contain no PAS-positive material) produce large quantities of watery serous fluid in which the cat often drowns on irritant exposure. DR CORN: The diffusion coefficient used in this approach is the gaseous diffusion coefficient. There would have to be a rejection mechanism at the mucus surface if what you say is true; I cannot reply to that. If the gas reached the mucus and was for one reason or another rejected, your point is well taken. Cats were used in these experiments because of prior experience with the species; I felt comfortable working with them. Their mechanisms of control of airway calibre are closer to those of the human than those of other animals. C. N. DAVIES : Inherent in the use of the diffusion equation quoted is the condition that rate of transfer is controlled in the gas phase. In fact, some vapours (e.g. phosgene) produce a resistance to absorption in the mucous film; in such cases, the assumption of steady state diffusions all along the length of bronchial pathway is not valid. Absorptions in the nose may also be important with soluble gases which do not set up a saturation check at the mucus surface. DR CORN : I do not disagree with your comments. However, I use a modified form of the diffusion equation and insert an experimental value of the coefficient which should cover all cases, gas or liquid controlled diffusion. When calculations using this coefficient for SO2 are used to predict penetration, they show SO2 penetrating to the alveolar ducts in man. The literature abounds with evidence that SO2 should all be scrubbed out higher up. This is disconcerting, to say the least. Dr Robert Frank, at the University of Washington in Seattle, is modelling gas penetration in the respiratory tract in a similar way. He finds the same kind of deep penetration. Also, please note that the manner in which I have expressed the transfer coefficient is a distortion of the traditional chemical engineering coefficient. This is a first attempt at this type of calculation. M. F. SUDLOW : I am worried by your extrapolation from large airways in the cat to small airways in man. Experiments in models and casts have shown complex flow regimes at nominal laminar Reynolds numbers. These would influence mixing characteristics at the airway and the thickness at boundary layers, which, in turn, should influence mass transfer from the airways. I cannot see how your theory accounts for this. Would you comment? D R CORN : The dependence of Ka on boundary layer changes in the streamline flow regime is assumed not to be that sensitive. We are, indeed, in the streamline flow regime and that was the basis for my going ahead with calculations extended to man using the Weibel model of the human respiratory tract. You will note the conspicuous absence of calculations for man from the paper. The calculations for extrapolation to man are being advanced here in a preliminary manner to solicit comments. M. LIPPMANN : An important factor in particle deposition within the lungs is the degree of mixing between reserve and tidal air within the conductive airways. Such mixing indicates that there will be turbulent diffusion as well as molecular diffusion for the gases. As Dr Sudlow just indicated, the flow
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TASK GROUP ON LUNG DYNAMICS (1966) Hlth Phys. 12,173.
12
M. CORN, N. KOTSKO and D. STANTON
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regime in the smaller airways will be very different from that in the first four airway generations. Thus, the transfer coefficient determined from the partial pressure changes observed for the first four generations will probably not be accurate for the more distal airways where only molecular diffusion will occur. DR CORN: I agree. For this first effort I have assumed complete mixing all the way down the respiratory tract. The partial pressure is uniform at any cross section of the gas stream as it penetrates the respiratory tract. The magnitude of error associated with this assumption must and will be determined. D. B. YEATES: The second peak would be lower and more symmetrical if the asymmetric model of Horsfield et al. were used for the airways rather than Weibel's symmetric model. DR CORN: Calculations have not been performed with models other than that of Weibel. D. L. SWIFT: The model which you used to calculate gas transport assumed that all the resistance to mass transfer resides in the liquid side of the interface. Recent work at Johns Hopkins in which transport of acetone to the nasal mucosa was measured indicates that this assumption is not valid for all flow rates. Would you please comment? DR CORN: YOU comment is valid. My illustration of how we must extrapolate these coefficients to the human respiratory tract was aimed at highlighting the necessary assumptions. It is my hope that this illustration will stimulate critics of the approach to produce refinements of my broad, sweeping assumptions. I have taken a first, coarse cut at the problem of calculating localized dosages in the human respiratory tract. It was quite a difficult step for us. It demands refinement.
MASS-TRANSFER COEFFICIENT FOR SULPHUR DIOXIDE AND NITROGEN DIOXIDE REMOVAL IN CAT UPPER RESPIRATORY TRACT* CORN, N.
KOTSKO and
D.
STANTON
Abstract—A new technique is described for measuring absorption in the cat respiratory tract of pollutant gases in air at ppm concentrations. A retrograde catheter was surgically inserted in lightly anaesthetized animals ventilated by a Harvard breathing pump. A gas sampling system actuated by the pump permitted withdrawal of gas samples during inhalation or exhalation through a tracheal cannula and the retrograde catheter. The effects of pollutant concentration and breathing volume and frequencies on uptake were studied with SOi- and NO2-in-air. Postmortem techniques were used to quantitate the transfer surface available in each experiment. Results are expressed by a mass-transfer coefficient, KG, expressed as moles transferred per square centimeter of tissue per second per mm mercury (partial pressure of pollutant gas). Kc for SOj in these studies varied from 6.77 x 10" 7 mol/cm2 s mmHg at an SOi concentration of 5.2 ± 0.8 ppm to 1.77 x 10" 6 mol/cm2 s mmHg at 1.8 ± 0.4 ppm SO2 in air. The value of KG increased slightly as the partial pressure of SO2 in air increased. There was little, if any, increase in Kc, as the frequency of breathing increased from lOcycles/min to 30 cycles/min and as the depth of breathing increased from 75 ml to 100 ml per stroke. Kg for NOj varied from 1.80 x 10~6 mol/cm2 s mmHg at an NO a concentration of 5.5 ± 0.7 ppm to 1.55 x 10" 6 mol/cm2 s mmHg at an NOj concentration of 2.2 ± 0.4 ppm. Thus, there was no change in A^ with change of concentration. Kc did not vary with frequency or depth of breathing. The values of KG reported here may be utilized with models of the human lung to predict local doses of adsorbed pollutants following inhalation. INTRODUCTION THE ESTABLISHMENT of air quality standards for specific pollutants in the air of U.S. cities (ENVIRONMENTAL PROTECTION AGENCY, 1973) requires that consideration be
given to dosage-response data for the inhaled pollutants, either alone or preferably in combination (HATCH, 1968). Sources of these data are epidemiologicalfieldstudies or laboratory investigations using animal species or human subjects. The former studies yield a practical dosage-response curve, as do the laboratory exposures of human subjects. The dosage to the critical body organ, in this case the lung, can best be estimated by studies with laboratory animals. There are guidelines for estimation of the amount of particulate matter deposited at different sites in the respiratory tract following inhalation by man (TASK GROUP ON LUNG DYNAMICS, 1966). A model to estimate uptake of inhaled gases by the respiratory tract is not as well developed as those for losses following inhalation of a disperse phase. We describe investigations to develop a direct method for measuring uptake by * Supported by Grant No. 5 RO1 ESOO5O1-O3, National Institute of Environmental Health Sciences.
Downloaded from http://annhyg.oxfordjournals.org/ at University of California, Santa Barbara on June 28, 2015
M.
Department of Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pennsylvania, U.S.A.
2
M. CORN, N. KOTSKO and D. STANTON
gen (COSBY et al, 1962).
Animal studies have involved more complicated techniques. GADASKINA (1946) measured SO2 in the upper respiratory tract of tracheotomized and non-tracheotomized rabbits. DALHAMN and STRANDBERG (1961) and STRANDBERG (1964) measured the difference between the concentration of SO 2 in inhaled and exhaled air; sampling was from the trachea and was precisely controlled by a pressure signal actuated by animal inspiration and expiration cycles. KAJLAND and STRANDBERG (1962) described a technique for sampling via tracheal cannula in rabbits during maximum inspiration and expiration, respectively; labelled S 35 O 2 was used. Endotracheal catheter was used to obtain upper and lower respiratory tract samples to determine aldehyde retention in the dog (EGLE, 1972). S 3 5 O 2 was utilized by BALCHUM et al. (1959) to study gas uptake in different body organs of the dog and by FRANK et al. (1969) to determine SO2 absorption in surgically isolated upper airways of anaesthetized dogs. A chronically implanted Teflon catheter in awake, unrestrained cats facilitated continuous intratracheal sampling of respiratory gases at end-expiration (SCOTTO and NATTOVE, 1970). Implanted catheters in the aorta and the vena cava of awake, unrestrained cats yielded blood gas values of selected gases (HERBERT and MITCHELL, 1971). Results of gas uptake experiments have been expressed as percentage penetration or removal (efficiency) in the nose, naso-pharyngeal chamber, upper or lower respiratory tract, a well established procedure (HENDERSON and HAGGARD, 1943). BRAIN (1970) offered a general discussion of nasal uptake of inhaled gases. DuBois and ROGERS (1968) presented a systematic theoretical analysis of the respiratory factors which influence the intensity of exposure at the site of tissue damage following inhalation of a toxic gas. The solubility and diffusion coeflicient of the inhaled gas must be known, as well as the respiratory factors of bronchial dimensions, minute volume and frequency of respiration, pulmonary, arterial and bronchial blood flows. We have measured SO 2 and NO 2 uptake to calculate an overall mass transfer coeflicient for the cat upper respiratory tract under varying conditions of pollutant concentration in air, and depth and frequency of breathing. Thus, we liken the scrubbing eflBciency of the upper respiratory tract to that of an industrial scrubbing tower. If the analogy is valid, with this methodology it is now possible to calculate dosage of inhaled pollutant gas to local areas of the respiratory tract.
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the cat respiratory tract of pollutant gases introduced via the naso-pharyngeal chamber or the trachea. The basis for development of our techniques was the retrograde catheter, previously successfully used to measure static pressures in conducting airways of excised dog lungs (MACKLEM and MEAD, 1957) and to evaluate the effect of pharmacological agents on peripheral airway resistance (BATTISTA et al., 1973). BATTISTA and GOYER (1974) utilized a technique similar to that described here to measure absorption of acetaldehyde vapour in the dog lung. Many previous studies of uptake of inhaled gas in the respiratory tract of human subjects utilized inspired and expired air analysis (WEST and DOLLERY, 1962; WEST et al., 1962). SPETZER and FRANK (1966) sampled inspired and expired air from a closefitting hard plastic mask fitted over the mouth and nose. Others have sampled tracheal air at different phases of the respiratory cycle; interpretation of results relates tracheal air to air deeper in the respiratory tract at any phase of the respiratory cycle (WEST, 1961). In another approach, arterial blood gas tension has been measured with electrodes, as has alveolar air, a method restricted to selected gases, particularly oxy-
SOj and NOj removal in catrespiratorytract
3
EXPERIMENTAL METHODS
FIG. 1. Schematic diagram of pollutant generation system for SOa in air. A—Medical grade breathing air; B—Valve; C—'Catch all' air cleaner; D—Silica gel; E—Milliporc HA filter; F—Orifice; G— Pressure gauge; H—Permeation oven with pollutant permeation tubes; J—Pollutant gas reservoir; K—Extra dry nitrogen.
Pollutant gas sampling and analysis Figure 2 is a schematic diagram of the system used for simultaneous sampling SO2 in air from the tracheal cannula and the retrograde catheter. Pollutant was sampled during the inspiratory stroke of the pump. A microswitch was activated during the 1
AID Model 303.
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Preparation of pollutant mixtures Mixtures of SO2 in air for animal exposures were produced using FEP Teflon SO2 permeation tubes (NELSON, 1971) 15 cm long and 0.030 cm wall thickness. The tubes were placed in a 3-tube capacity glass permeation chamber in a gas mixing oven.* Medical-grade compressed breathing air was passed through activated carbon, silica gel, membrane filter and was metered with calibrated orifice meters prior to entering the oven with permeation tubes. The gas exited from the permeation oven and entered a glass reservoir, where it was either exhausted or withdrawn by a Harvard breathing pump for delivery to the animal undergoing exposure. Figure 1 is a schematic diagram of the pollutant generation system for SO2 in air. Because of changes which occur in NO2 permeation tubes with exposure to air containing water vapour, it was necessary to provide continuous flushing of the NO2 permeation tubes with nitrogen. Pollutant gas concentration was varied by changing the temperature of the permeation oven. All components of the system, with the exception of the reservoir, were of stainless steel, rigid plastic or Teflon (CORN et al., 1972). Room air or pollutant in air entered the Harvard pump through a three-way valve at the pump entry. Pump stroke and frequency was adjustable. The inspiratory stroke of the pump was at positive pressure relative to room air pressure; the animal expired passively.
M.
CORN, N. KOTSKO and
D. STANTON K
2 = partial pressure of pollutant gas at exit (mmHg), pe — partial pressure of pollutant gas in mucus (mmHg (unknown)), d = diffusivity of pollutant gas in air (cm2/s), p = pollutant gas density (g/cm3), w = pollutant gas mass flow rate (g/s), and L = length of wetted airway path (cm). The mass diffusivity constants for SO2 and NO 2 in air were computed to be 0.143 cm 2 /s and 0.138 cm 2 /s (BIRD et al, 1960). After calculating (pe— p j), KG could be determined from equation (6). NA =
or Ka = where terms in equations (6) and (7) are defined as above. In order to transform experimental data into measured values of KG for different conditions of breathing (frequency, volume) and pollutant concentrations, the following computational procedures were followed. 1. From pollutant concentrations determined from samples obtained at tracheal cannula and retrograde catheter sampling ports, the moles of pollutant absorbed between sampling points was calculated. 2. The integrated time of sampling, as measured by an electric timer in the sampling circuit, was used as the measure of gas transfer time associated with absorption of gas in (1).
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where NA = gas transferred, mol/s cm , kG = gas transfer coefficient, mol/s cm mmHg, KG = overall mass-transfer coefficient, mol/s cm 2 mmHg, -Pso^o = Partial pressure of SO 2 in gas phase, mmHg, -Pso2(1) = partial pressure of SO 2 at interface, mmHg, PSOl* = partial pressure of SO2 in gas phase corresponding to concentration of SO2 in liquid phase (a fictitious partial pressure), mmHg, APso2iOAy = overall partial pressure difference. The concept of mass-transfer coefficient is potentially a powerful one for utilization with a model of the human respiratory tract, where estimates are available for transfer surface area and time of residence of air volumes in airway generations. Experimental data for changes in axial concentrations of the pollutant gas from tracheal or mouth entry to the implanted catheter were transformed into concentration differences along the axis of diffusion by using the Graetz equation (equation (5)) to calculate (j>t —
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TABLE 2. CALCULATED MASS-TRANSFER COEFFICIENTS FOR SULPHUR DIOXIDE ABSORPTION IN CAT RESPIRATORY TRACT
Harvard pump settings (ml/cycle) (cycles/min) 75 75 75 75 75 75 75 75 75 100 100 100 100 100 100
10 10 10 20 20 20 30 30 30 10 10 20 20 30 30
SO2 concentration in air (ppm) Range Mean ± s.d. 1.0- 3.0 3.1- 6.0 8.0-14.0 1.0- 3.0 3.1- 6.0 9.0-12.0 1.0- 3.0 3.1- 6.0 8.0-11.0 1.0- 3.0 3.1- 6.0 1.0- 3.0 3.1- 6.0 1.0- 3.0 3.1- 6.0
2.0 ± 0.8 3.1 ± 0.4
11.4 ±3.9 1.7 ±0.6 3.3 ± 0.6 10.0 ± 1.5 1.4 ±0.4 3.3 ± 0.6 10.1 ± 1.5 1.4 ±0.3 5.2 ± 0.8 1.3 ±0.6 5.5 ± 0.8 1.8 ±0.4 5.7 ± 0.7
Number of measurements
Number of animals
37 6 17 29 20 45 30 19 20 19 13 20 14 16 13
5 1 2 4 2 3 4 2 2 2 2 2 2 2 2
KG, overall mass-transfer coefficient (mol/cm 2 ;> mmHg) Mean ± s.d. Range 4.64 7.38 1.05 8.73 1.43 9.62 1.15 1.27 2.33 9.10 6.77 1.66 1.10 1.77 1.23
x 10" 7 ± x I0" 7 x 10"* x 10- 7 ± x 10"7 x 10"7 ± x 10"* ± x 10"* x 10"* x 10"7 x 10"7 x 10"* x 10"* X 10"* x 10"*
0.75 2.75 1.61 0.22
4.06- 5.93 x lO"7 8.98-12.2 5.73-11.9 7.48-21.2 7.77-10.7 8.90-13.6 9.20-16.2 1.36- 3.29 8.54- 9.65 4.65- 8.88 1.54- 1.77 7.64-14.4 1.74- 1.80 8.60-15.9
x 10- 7 X lO"7 x lO"7 x 10"7 X 10"7 X 10"7 x 10-* X 10"7 x 10- 7 X 10-* X 10"7 x 10-* X 10"7
s 9 z *-* 3
g 5 CL
hi
w >
z
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TABLE 3. CALCULATED MASS-TRANSFER COEFFICIENTS FOR NITROGEN DIOXIDE ABSORPTION IN CAT RESPIRATORY TRACT
Harvard pump settings (ml/cycle) (cycles/min) 75 75 75
75 75 100 100 100 100 100 100 100 100 100 100 100
10
10 20 20 30 10 10 10 10 20 20 20 30 30 30 30
NO2 concentration in air (PPm) Range Mean ± s.d. 3.0-4.0 4.1-5.0 2.0-3.0 4.0-5.0 4.0-5.0 1.0-3.0 3.1^t.O 4.1-5.0 5.1-6.0 1.0-3.0 3.1-1.0 4.1-5.0 1.0-3.0 3.1-1.0 4.1-5.0 5.1-6.0
3.8 ± 4.1 ± 2.9 ± 4.5 ± 4.6 ± 2.4 ± 3.4 ± 4.4 ± 5.3 ± 2.2 ± 3.7 ± 4.4 ± 2.5 ± 3.5 ± 4.4 ± 5.5 ±
0.4 0.6 0.2 0.4 0.5 0.5 0.4 0.4 1.0 0.4 0.4 0.4 0.5 0.3 0.9 0.7
Number of measurements
Number of animals
14 7 6 21 25 14 34 41 6 21 50 38 30 40 28 14
2 1 1 3 4 2 5 6 1 3 7 6 4 6 4 2
Kc, overall mass-transfer coefficient (mol/cm2 s mmHg) Range Mean ± s.d.
1.59 1.50 1.99 2.01 1.80
x x x x x x x x x x
10-77 lO" 10-76 10" 10"66 10"6 1010"76 1010-66
x 10" X 10"6 x 10- 6 x 10"6 x 10- 6
O CD
aa.
2.63- 5.93 x 10"7
4.28 X 10- 7
6.95 9.32 8.82 1.06 1.48 1.80 1.10 8.73 1.55 1.56
VI
±0.25 ±0.23 ±0.94 ± 0.41 ±0.58 ±0.34
±0.47 ±0.39 ±0.64 ± 0.43
5.98-10.8 7.43-12.8 1.34- 1.61 8.49-33.5 4.29-15.8
x lO"7 x 10"7 x 10"6 x 10"7 X lO"7
1.12- 2.21 1.13- 2.00 9.82-21.5 8.70-18.0 1.35- 3.01 1.55- 2.5 1.42- 2.18
x x x x x x x
10-* lO"6 10"7 10"7 lO"6 10-* 10- 6
O | o
i.5' 8 •S a T'
to O
3 n
10
M. CORN, N. KOTSKO and D. STANTON
REFERENCES ADRIAN, R. W. (1964) Am. J. vet. Res. 25, 1724-1733. BALCHUM, O. J., DYBICKI, J. and MENEELY, G. R. (1959) Am. J. Physiol. 197,1317-1321. BAT-TOTA, S. P. and GOYER, M. M. (1974) Fed. Proc. 33 (3), 569. BATITSTA, S. P., STEBER, W. D., GREEN, M. and KENSLER, C. J. (1973) Archs emir. Hlth 27, 334-339. BIRD, R. B., STEWART, W. E. and LIGHTFOOT, E. N. (1960) Transport Phenomena, p. 512, Wiley, New
York. BRAIN, J. D. (1970) Ann. Otol. Rhinol. LOT. 79, 529-539. CORN, M. and BELL, W. (1963) Am. ind. Hyg. Ass. J. 24, 502. CORN, M., KOTSKO, N., STANTON, D., BELL, W. and THOMAS, A. P. (1972) Archs emir. Hlth 24,
248-256. COSBY, R. S., STOWELL, E. C , MORRISON, D. M., MAYO, M., RUYMANN, F. B. and BERNARD, B.
(1962) J. appl. Physiol. 17, 1. DALHAMN, T. and STRANDBERO, L. (1961) Int. J. Air. Water Pollut. 4,154. DUBOB, A B. and ROGERS, R. M. (1968) Resp. Physiol. 5, 34-52. EGLE, J. L. (1972) Archs emir. Hlth 25, 119-124. ENVIRONMENTAL PROTECTION AGENCY (1973) Fed. Reg. 36, (21).
FRANK, N. R., YODER, R. E., BRAIN, J. D. and YOKOYAMA, E. (1969) Archs emir. Hlth 18, 315-322.
GADASKINA, I. D. (1946) Farmakol. Toksik 9, 51-33. HATCH, T. F. (1968) Archs emir. Hlth 16, 571.
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3. ADRIAN'S (1964) classification of the segmental anatomy of the cat lung, together with a cylindrical airway model, was used to estimate the surface area of the airways to which pollutant gas was exposed proximal to the retrograde catheter. Table 2 summarizes KG values for sulphur dioxide absorption in the cat respiratory tract. Data for frequency and depth of breathing, pollutant gas concentration and the number of animals and independent measurements contributing to the calculation of Ka are presented. Table 3 contains similar results for NO2 absorption in the cat respiratory tract. The overall mass-transfer coefficient for SO2 varied from 6.77 x 10"7 mol/cm2 s mmHg at an SO2 concentration of 5.2 ± 0.8 ppm to 1.77 x 10"6 mol/cm2 s mmHg at 1.8 ± 0.4 ppm SO2 in air. The value of KG increased slightly as the partial pressure of SO2 in air increased. There was little, if any, increase in KG as the frequency of breathing increased from 75 ml to 100 ml per stroke. An important observation in this investigation was that KQ values were not significantly different during 30 min of exposure to the pollutant gas when experimental variables (depth and frequency of breathing, gas concentration) remained constant. This suggests that an equilibrium condition is rapidly attained. The value of Ko for NO 2 varied from 1.80 x 10"6 mol/cm2 s mmHg at an NO2 concentration of 5.5 ± 0.7 ppm to 1.55 x 10" 6 mol/cm2 s mmHg at an NO2 concentration of 2.2 ± 0.4 ppm. Thus, there was no change in KG with change of concentration. Ka did not vary with frequency or depth of breathing. Because airflow in the cat respiratory tract and in the human respiratory tract are in the streamline flow regime, except during extraordinary exertions by man where turbulence can occur in the trachea, values of KG derived from these experiments should be applicable to estimation of pollutant gas absorption after inhalation by man. Estimation of area of airways available for uptake of gas can be obtained from WEIBEL'S (1963) morphometric models of the human lung. Using values of KG reported here, it is now possible to predict local dosage of SO2 following inhalation by man. Extension of these results to calculations of SO2 and NO2 absorption in the human respiratory tract is currently under way.
SO2 and NO 2 removal in cat respiratory tract
11
HENDERSON, Y. and HAGGARD, H. W. (1943) Noxious Gases and the Principles of Respiration Influencing Their Action. Reinhold, New York. HERBERT, D. A. and MITCHELL, R. A. (1971) J. appl. Physiol. 30, 434-^36. INTERSOOETY COMMITTEE (1972) Methods of Air Sampling and Analysis, p. 447. Washington, D.C. KAJLAND, A. and STRANDBERG, L. (1962) Nord. hyg. Tidskr. 43, 21. LJNCH, A. L. and CORN, M. (1965) Am. ind. Hyg. Ass. J. 26, 601.
MACKLEM, P. T. and MEAD, J. (1967) / . appl. Physiol. 22, 395-401. NELSON, G. O. (1971) Controlled Test Atmospheres, p. 134. Ann Arbor Science Pub., Mich., U.S.A. PATE, J. B., AMMONS, B. E., SWANSON, G. A. et al. (1965) Analyt. Chem. 37, 942-945.
SCOTTO, P. and NATTOVE, A. (1970) / . appl. Physiol. 28, 714-715. SPEEZER, F. E. and FRANK, N. R. (1966) Archs envir. Hlth 12, 725-728. STRANDBERG, L. G. (1964) Archs emir. Hlth 9, 160-166. WEIBEL, E. R. (1963) Morphometry of the Human Lung. Springer, Berlin. WEST, J. B. (1961) Inhaled Particles and Vapours (edited by DA VIES, C. N.). pp. 3-7. Pergamon Press, Oxford. WEST, J. B. and DOLLERY, C. T. (1962) / . appl. Physiol. 17, 9. WEST, J. B., HOLLAND, R. A. B., DOLLERY, C. T. and MATTHEWS, C. M. E. (1962) / . appl. Physiol. 17,
14. WEST, P. W. and GAEKE, G. C. (1956) Analyt. Chem. 28,1816-1819.
DISCUSSION M. KUSCHNER: IS the diffusion coefficient dependent on the character of the mucus? Some years ago Francis Roe pointed out that the cat was particularly unsuited to experiments with irritant gases. He stated that the bronchial glands of the cat (which contain no PAS-positive material) produce large quantities of watery serous fluid in which the cat often drowns on irritant exposure. DR CORN: The diffusion coefficient used in this approach is the gaseous diffusion coefficient. There would have to be a rejection mechanism at the mucus surface if what you say is true; I cannot reply to that. If the gas reached the mucus and was for one reason or another rejected, your point is well taken. Cats were used in these experiments because of prior experience with the species; I felt comfortable working with them. Their mechanisms of control of airway calibre are closer to those of the human than those of other animals. C. N. DAVIES : Inherent in the use of the diffusion equation quoted is the condition that rate of transfer is controlled in the gas phase. In fact, some vapours (e.g. phosgene) produce a resistance to absorption in the mucous film; in such cases, the assumption of steady state diffusions all along the length of bronchial pathway is not valid. Absorptions in the nose may also be important with soluble gases which do not set up a saturation check at the mucus surface. DR CORN : I do not disagree with your comments. However, I use a modified form of the diffusion equation and insert an experimental value of the coefficient which should cover all cases, gas or liquid controlled diffusion. When calculations using this coefficient for SO2 are used to predict penetration, they show SO2 penetrating to the alveolar ducts in man. The literature abounds with evidence that SO2 should all be scrubbed out higher up. This is disconcerting, to say the least. Dr Robert Frank, at the University of Washington in Seattle, is modelling gas penetration in the respiratory tract in a similar way. He finds the same kind of deep penetration. Also, please note that the manner in which I have expressed the transfer coefficient is a distortion of the traditional chemical engineering coefficient. This is a first attempt at this type of calculation. M. F. SUDLOW : I am worried by your extrapolation from large airways in the cat to small airways in man. Experiments in models and casts have shown complex flow regimes at nominal laminar Reynolds numbers. These would influence mixing characteristics at the airway and the thickness at boundary layers, which, in turn, should influence mass transfer from the airways. I cannot see how your theory accounts for this. Would you comment? D R CORN : The dependence of Ka on boundary layer changes in the streamline flow regime is assumed not to be that sensitive. We are, indeed, in the streamline flow regime and that was the basis for my going ahead with calculations extended to man using the Weibel model of the human respiratory tract. You will note the conspicuous absence of calculations for man from the paper. The calculations for extrapolation to man are being advanced here in a preliminary manner to solicit comments. M. LIPPMANN : An important factor in particle deposition within the lungs is the degree of mixing between reserve and tidal air within the conductive airways. Such mixing indicates that there will be turbulent diffusion as well as molecular diffusion for the gases. As Dr Sudlow just indicated, the flow
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TASK GROUP ON LUNG DYNAMICS (1966) Hlth Phys. 12,173.
12
M. CORN, N. KOTSKO and D. STANTON
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regime in the smaller airways will be very different from that in the first four airway generations. Thus, the transfer coefficient determined from the partial pressure changes observed for the first four generations will probably not be accurate for the more distal airways where only molecular diffusion will occur. DR CORN: I agree. For this first effort I have assumed complete mixing all the way down the respiratory tract. The partial pressure is uniform at any cross section of the gas stream as it penetrates the respiratory tract. The magnitude of error associated with this assumption must and will be determined. D. B. YEATES: The second peak would be lower and more symmetrical if the asymmetric model of Horsfield et al. were used for the airways rather than Weibel's symmetric model. DR CORN: Calculations have not been performed with models other than that of Weibel. D. L. SWIFT: The model which you used to calculate gas transport assumed that all the resistance to mass transfer resides in the liquid side of the interface. Recent work at Johns Hopkins in which transport of acetone to the nasal mucosa was measured indicates that this assumption is not valid for all flow rates. Would you please comment? DR CORN: YOU comment is valid. My illustration of how we must extrapolate these coefficients to the human respiratory tract was aimed at highlighting the necessary assumptions. It is my hope that this illustration will stimulate critics of the approach to produce refinements of my broad, sweeping assumptions. I have taken a first, coarse cut at the problem of calculating localized dosages in the human respiratory tract. It was quite a difficult step for us. It demands refinement.
