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Peter A. Valberg, PhD Gradient Corporation September 5, 1991 The Respiratory Tract as a Route of Exposure I. Major surfaces of the body: skin, respiratory tract, gastrointestinal tract. A. Histology and thickness of skin B. Absorption of materials from the GI tract. C. Basic anatomy and histology of the respiratory tract. II. Review of Particulate Deposition A. Forces acting to deposit particles in the lungs: 1. Inertia. 2. Gravitation. 3. Diffusion. 4. Interception. B. Factors determining the effectiveness of these forces: 1. Aerosol characteristics. 2. Parameters of respiration. 3. Anatomy of the respiratory system. C. Predicting deposition of particles in the lungs. :QI. Lung Clearance Mechanisms A. Clearance from the ciliated regions of the lungs: mucus transport. 1. Frequency and quality of the ciliary beat. 2. Quantity and rheological properties of the mucus. B. Clearance of particles from the non-ciliated regions of the lungs. 1. Role of alveolar macrophages. 2. Lymphatic drainage. 3. Permanent stores. C. Uptake and distribution of inhaled gases. IV. Fate of Toxic Materials that Enter the Body A. The Circulation. 1. Anatomy and physiology. 2. Overall patterns. B. Elimination: transfer of materials back to the outer environment. 1. Via lungs. 2. Via gut. 3. Via kidney. C. Metabolic changes and detoxification mechanisms.

2 I. The Respiratory Tract Humarl lung surfaces, because of their primary function of gas exchange, are brought into intimate contzct with irritating gases and airborne particles. The mass of air we inhale each day far exceeds the mass of material entering into our GI tract. The same thinness and extensive area that qualify the air-blood barrier for the rapid exchange of oxygen and carbon dioxide reduce its effectiveness as a barrier to inhaled micro-organisms, allergens, carcinogens, toxic particles, and noxious gases. Inhala- tion of these agents can initiate or at least aggravate chronic obstructive lung disease. Particularly in the cases of cigarette smoking and occupational exposures, the health consequences of particle depo- sition and toxic gas uptake are increasingly being demonstrated. To assess adequately the risk of a particutar exposure, an understanding of the factors involved in the deposition and clearance of inhaled substances is needed. Therefore, the mechanisms which are pertinent to particle deposition and clearance will be described, and the relationship of these respiratory defense mechanisms to the pathogenesis of lung disease will be presented. II. Review of Deposition: A. Deposition is the process that determines what fraction of inspired particulates will be caught in the respiratory tract and thus fail to exit with the expired air. Several distinct processes following physical laws operate to move particles suspended in the inspired air toward the surface of the respiratory tract: inertial forces, sedimentation, Brownian diffusion, and interception. It is likely that all particles deposit upon touching a surface, and thus the site of initial deposition is the site of contact. 1. Inertia refers to the tendency of moving particles to resist changes in direction and speed. Repeated branching in the airways cause sudden changes in the direction of air-flow; however, because of inertia, particles tend to continue in their original direction, crossing air-flow streamlines and eventually impacting on the airway walls. 2. G7avity accelerates falling bodies downward, and terminal settling velocity is reached when viscous resistive forces are equal and opposite in direction to gravitational forces. Respirable particles reach this constant terminal or sedimentation velocity in less than 0.1 msec. Thus, particles are also removed as their terminal velocity causes them to strike the airway walls or alveolar surfaces. 3. Ae.rosol particles also undergo Brownian diffusion, a random motion caused by collisions of gas molecules with particles suspended in the air; this motion also causes the particles to cross streamlines and reach lung surfaces where they will deposit. B. The eif'ectiveness of these deposition mechanisms depends on: (1) the size distribution of aero- dynanuc diameters of the particles, (2) the pattern of breathing, and (3) the anatomy of the resp'r:ratory tract. These factors will determine not only the fraction of the inhaled particles that are deposited but also the site of deposition. 1. TP7e effective aerodynamic diameters of particles determine the magnitude of forces acting on diem. For example, while inertial and gravitational effects increase with increasing particle size, diffusion produces larger displacements as particle size decreases. Effective aerodynamic diameter is a function of particle size, shape, and density. In order to predict deposition pat- terns, it is essential to describe the distribution of aerodynamic diameters of particles in the aerosol. Two commonly-used parameters summarizing the size distribution are the mass rnedian aerodynamic diameter (MMAD) and the geometric standard deviation (GSD).

3 2. Another factor modulating site and amount of deposition is breathing pattern. Minute volume defines the average flow velocity of the aerosol-containing air in the lung and the total number of particulates to which the lung will be exposed. Increasing the velocity of gas flow enhances deposition by inertial impaction. Respiratory frequency will affect the residence time of aero- sols in the lungs and hence the probability of deposition by gravitational and diffusional forces. Changing lung volume will alter the dimensions of the airways and parenchyma. 3. The anatomy of the respiratory tract is important since it is necessary to know the diameters of the airways, the frequency and angles of branching, and the average distances to alveolar walls. For a given inspiratory or expiratory flow rate, airway anatomy determines local linear velocity of the air stream and the character of the flow. A significant change in the effective anatomy of the respiratory tract occurs when there is a switch between nose and mouth breathing. In addition to warming and humidifying the air, the nose prevents penetration of large particles and highly soluble gases to the remainder of the respiratory system. The nar- row cross section of the airway here results in high linear velocities. The sharp bends in direc- tion of airflow and the nasal hairs both promote impaction of aerosols. Particle deposition exhibits variability due to inter- and intra-species differences in lung morphometry; even within the same individual, the dimensions of the respiratory tract vary with changing lung volume, with aging, and with pathological processes. C. The ICRP lung model (See reference 5) provides some predictions for the percentage deposition of ,particles for an adult human breathing a 1,450 ml tidal volume, 15 times a minute. Deposition in the nasopharynx ranges from 50.2% of the inspired particles with 2.0 pm MMAD to 95.6% of 20 ym particles. Deposition in the tracheobronchial compartment decreases from 3.6 to 1.0% as the MMAD increases from 2.0 µm to 20 pm and finally, deposition in the pulmonary compartment det:neases from 21 to 2.6% as MMAD increases from 2.0,um to 20.0,4m. The predictions of the ICR]P lung model are summarized in the graph below: 100 90 so 70 so a °n Sa m O ~ 40 30 20 10 0.01 0.05 0.1 0 5 1.0 Mass Median Diameter, p 5 10 50 -Aerosol deposition in respiratory tract. Tidal volume is 1,450 mf: frequency, 15 breaths per minute. Variability introduced by change of sipma, geometric standard de- viation, from 1.2 to 4.5. Particle size equals diameter of mass median size. (Adapted from Tnsk Group on Lung Dynamics')

4 III. Lung ~Cearance Mechanisms: Clearance refers to the dynamic processes that physically expel particulates from the respiratory tract; it is the output of particulates previously deposited. Highly soluble particles dissolve rapidly and are absorbed into the blood from the respiratory tract. Their metabolism and excretion resemble that of an intravenously injected dose of the same material. A. C.i[iated Regions 1. Less soluble particles that are deposited on the mucus blanket covering pulmonary airways are moved toward the pharynx by the cilia. Also present in this moving carpet of mucus are cells and particles which have been transported from the non-ciliated alveoli to the ciliated airways. Similarly, particles deposited on the ciliated mucus membranes of the nose are propelled toward the pharynx. There, mucus, cells, and debris coming from the nasal cavities and the lungs meet, mix with salivary secretions, and enter the gastrointestinal tract after being swal- lowed. Since the particles are removed with half-times of minutes to hours, there is little time for solubilization of slowly dissolving materials. In contrast, particles deposited in the non- ciliated compartments have much longer residence times and hence, there, small differences in in vivo solubility can have great significance. 2. A number of factors can affect the speed of mucus flow. They may be divided into two categories: those affecting the cilia themselves and those affecting the properties of the mucus. The following aspects of ciliary action may be affected: the number of strokes per minute, the amplitude of each stroke, the time course and form of each stroke, the length of the cilia, the ratio of ciliated to non-ciliated areas, and the susceptibility of the cilia to intrinsic and extrinsic agents that modify their rate and quality of motion. The characteristics of the mucus may become critically important. The thickness of the mucus layer and its rheological properties may undergo wide variations. Typical mucus carpet flow rates in the major airways are 5-10 mm f min. B. Non• Ciliated Regions 1. Particles deposited in the non-ciliated portion of the lungs are either moved toward the ciliated region, primarily within alveolar macrophages, or they enter the alveolar wall and accumulate n1 connective tissue, especially lymph nodes. Particles remaining on the surface are cleared with a biological half-time estimated to be twenty-four hours in humans, while particles that have penetrated into "fixed" tissues are cleared with half-times ranging from a few days to thousands of days. Therefore, the probability of particle penetration is critical in determining the clearance of particles from the non-ciliated regions of the lungs. 2. Particles removed by alveolar macrophages show a variety of patterns and half-lives which are &-pendent upon particle number, size, shape and surface reactivity. However, generally alveo- lar macrophages act to decrease the probability of particle penetration, thereby aiding clear- ance. These free cells, ultimately derived from the hematopoietic system, play the primary re cle in removal of dust particles and potentially pathogenic micro-organisms from the alveoli. Most free cells containing the deposited particles eventually reach the ciliated region of the lungs and are eliminated into the pharynx and swallowed. 3. The digestive capacity of the pulmonary macrophage and its ample lysosomal endowment is reF`.lected in its high content of hydrolytic enzymes. Although this clearly constitutes an impor- tant aspect of the lung's defensive posture, when kept in a chronically activated state, this

5 digestive capacity may serve to damage pulmonary tissues. Release of lysosomal enzymes, particularly proteases, from activated macrophages and polymorphonuclear leukocytes may be involved in the development of emphysema. Release may occur as a consequence of cell death, cell injury, or exocytosis. Other mediators released from these cells may also be involved in fibrogenesis. Since increased particle deposition acts to recruit additional macro- phages and other cells, these untoward effects may be reinforced by increased dust deposition. IV. Retention and particle excretion. The actual amount of a substance in the respiratory tract at any time is called the retention. When the exposure is continuous, the equilibrium concentration (achieved when the clearance rate matches the deposition rate) is also the retention. Thus, the relative rate constants of deposition and clearan'ce determine the equilibrium levels; it is the equilibrium level, or retention integrated over time, and the properties of the particle that are presumably related to the probability of a pathological response. The pathological consequences of dust retention may be a result of its allergic, irritant, carcinogenic, infective, or other properties. Continuing research focusing on the deposition and clearance of dusts and -the significance of their retention is needed. On the figure below, an example of a model of particle excretion is shown (Ref. # S): (a) Blood (c) (e) 4- 4- D3 N-P (b) (1) (g) Lymph (h) Gastrointestinal Tract -Particle deposition sites and clearance processes based on 4CRP lung model. Symbols are as follows: (a), uptake of material from N-P region directly into bloodstream; (b), clearance of all particulate matter from N-P region by ciliary-mucous transport: (c), absorption of material deposited on T-8 surface into systemic circulation; (d), T-8 clear- ance by ciliary-mucous action. Particles thus cleared go quantitatively to gastrointestinal tract; (e), direct absorption of material from pulmonary region into blood; (f) relatively rapid clearance of P region (in reality, coupled to ciliary-mucous transport system); (g), relatively slow clearance process, also coupied to N-P ciliary-mucous mechanism; (h), removal of matter into lymph system; and (i), tiecondary pathway in which particles cleared by pathway h are Introduced into systemic blood. (Adapted from Task Group on Lung Dynamics') Table 1.-Clearance Constants for Use With Lung Mode)• Clearance Constsntst Com partment Pathway Class D Class W Ctass Y N-P (a) 4 min/0.50 4 min/0.10 4 min/0.01 (b) 4 min/0.50 4 min/0.90 4 min/0.99 T-8 (c) 10 min/0.50 10 min/0.t0 10 min/0.01 (d) 10 min/0.50 10 min/0.90 10 min/0.99 P (e) 30 min/0.ti0 90 days/0.15 360 days/0.05 (f) NA 24 hr/0.40 24 hr/0.40 (p) NA 90 days/0.40 360 days/0.40 (h) 30 min/0.20 90 days/0.05 360 days/0.15 L (I) 30 min/1.00 90 days/1.00 360 days/0.10 ° Adapted from Task Group on Lung Dynamics.' t First value ts biological haif-time: second, regiona) fraction. Lymphatic clearance for class Y compounds Indicates that 1Ve regional traction follows 360-day biologiui half•time. Ctemainin® 90•.% fs presumed to be permanently retained in nodes and subject only to radioa active decay.

6 B1BLI®GRAPHY I. Aerosol Deposition and Clearance in the Respiratory Tract 1. Bra:in, J.D., and P.A. Valberg. Models of lung retention based on the report of the ICRP Task Group. Arch. Environ. Health 28:1-11, 1974. 2. Davies, C.N. Deposition of particles in human lungs as a function of particle size and breathing pat- tern, an empirical model. In: Walton, W.H. (ed), Inhaled Particles V Oxford: Pergamon Press, pp. 119-135,1982. 3. Churg, A, and F.H.Y. Green, eds. Pathology o f Occupational Lung Disease Igaku-Shoin, New York, 19F~8. 4. Hatc±,T. F., and P. Gross. Pulrnonary Deposition and Retention of Inhaled Aemsols. Academic Press, NeN York. 1964. 5. Morrow, P. E., Chairman, Task Group on Lung Dynamics. Deposition and retention models for inter- nal dosimetry of the human respiratory tract. Health Phys. 12:173-207, 1966. 6. Lippmann, M., D. B. Yeates, and R E. Albert. 1980. Deposition, retention and clearance of inhaled pa:n:icles. Br. J. Ind Med 37:337-362. 7. Valb erg, P.A.. Determination of Retained Lung Dose Handbook of Experimental Phamzacology, YoZ 75, (H.P. Witschi and J.D. Brain, eds.) Springer-Verlag, Berlin, 1985, pp. 57-91. 8. Valberg, P.A., J.D. Brain, S.L. Sneddon, and S.R.LeMott. Breathing patterns influence aerosol deposi- tion sites in excised dog lungs. J. Appl, PhysioZ: Respir. Environ. Exercise PhysioZ 53:824-837, 1982. 9. Valbf,rg, P.A., RK. Wolff and J.L. Mauderly. Redistribution of retained particles: Effect of hyperpnea. Am. Rev. Respir. Dis. 131: 273-280, 1985. 10. Wo1f~ R K 1986. Effects of airborne pollutants on mucociliary clearance. Env. Health Persepc. 66:223- 237. II. Pulmonary Macrophages 11. Bowden, D. H. 1987. Macrophages, dust, and pulmonary diseases. Exp. LungRes. 12:89-107. 12. Brain, J. D. 1985. Physiology and pathophysiology of pulmonary macrophages. In: The Reticuloen- dothelial System. Reichard, S.M. and J. Filkins, editors. Plenum, New York. 315-337. 13. Brain, J. D., and G. C. Corkery. The effect of increased particles on the endocytosis of radiocolloids by pulmonary macrophages in vivo: competitive and toxic effects. In: Inhaled Particles and Vapours, N. W.H. Walton, Ed., Unwin Brothers, London. pp. 551-564, 1977. 14. Brain, J. D., J. J. Godleski, and S. P. Sorokin. Quantification, origin, and fate of pulmonary macro- phages. In: Respiratory Defense Mechanisms, YoZ 5. J.D. Brain, D.F. Proctor and L. Reid, Eds., Mar- cel I)ekker, New York. pp. 849-885, 1977. 15. Carr, I. The Macrophage: A Review of Utrastructure and Function. Academic Press, New York. 1973. 16. Fels, A. O. S., and Z. A. Cohn. 1986. The alveolar macrophage..I. App1. PhysioL 60:353-369. 17. Green., ~G. M. Lung defense mechanisms. Medical Clinics of 1Vorth America 57:547-562, 1973.

7 18. Hocking, W.G., and D.W. Golde. The pulmonary-alveolar macrophage I. New Eng. J. Med 301:580- 587, 1980. 19. Hocking, W.G., and D.W. Golde. The pulmonary-alveolar macrophage II. New Eng. J. Med 301:639- 645, 1'980. 20. Keller, H. U., M. W. Hess, and H. Cottier. Physiology of chemotaxis and random motility. Semincus in Hemaa'o1o$y 12:47-57, 1975. 21. Morrovt, P. E. 1988. Possible mechanisms to explain dust overloading of the lungs. Fund Appl. Tozicol 10:369 -384. 22. Sanders, C.L., Schneider, RP., Dagle, G.E., and Ragan, HA (eds.). Pulmonary macrophage and epithelial cells. Proceedings of the 16th Annual Hanford Biology Symposium Richland, Washington, September 27-29,1976. Washington: Technical Information Center, Energy Research and Develop- ment A,dministration. 23. Sanders, C.L., Cross, F.T., Dagle, G.E., Mahaffey, J.A. (eds.). Pulmonary toxicology of respirable parti- cles. Proceedings of the 19th Annual Hanford Biology Symposium Richland, Washington, October 22-24, 1979. .Washington: Technical Information Center, Energy Research and Development Administration. 24. Sorokin, S. P., and J. D. Brain. Pathways of clearance in mouse lungs exposed to iron oxide aerosols. Anaz Rec. 181:581-625, 1975. 25. Sorokin, &P. Phagocytes in the lungs: Incidence, general behavior, and phylogeny. In: Respiratory Defense Mechanisms, VoI. 5. J.D. Brain, D.F. Proctor, and L. Reid, Eds., Marcel Dekker, New York. pp. 71 j~-848, 1977. 26. Valberg, PA., Chen, B.H., and Brain, J.D. Endocytosis of colloidal gold by pulmonary macrophages. Expt. Ce'1 Res. 141: 1-14, 1982. 27. Valberg, PA. Magnetometry of ingested particles in pulmonary macrophages. Science 224: 513-516, 1984. 28. Valberg, P.AA and Albertini, D.F. Cytoplasmic Motions, Rheology, and Structure Probed by a Novel Magnetic-Particle Method. J. Cell Biol. 101: 130-140, 1985. 29. VanFurth, R, ed. Mononuclear Phagocytes (2 vols.). The Hague: Martinus Nijhoff Publishers, 1980. 30. VanFurth~ R., ed. Mononuclear Phagocytes in Immunity, Infection, and Pathology. Blackwell Scientific Publications, London. 1975.

8 III. Bacterjicidal Activity of the Lungs and Phagocytic Mechanisms 31. Badwey, J. A., and M. L Karnovsky. 1980. Active oxygen species and the functions of phagocytic leuko- cytes. Anrz Rev. Biochem. 49:695-726. 32. Goldstein, E. Hydrolytic enzymes of alveolar macrophages Reviews of Infectious Diseases. 5: 1078- 1092, 1983. 33. Green, G. M., and E. H. Kass. Role of alveolar macrophage in clearance of bacteria from the lung. J. Ezp.112'ed 119:617-622, 1964. 34. Kavet, R..I. and Brain, J.D. Methods to Quantify Endocytosis: A Review. ,T. Reticuloendothelial Soc. 21:201-221,1980. 35. Klebano:~ S. 11980. Oxygen metabolism and the toxic properties of phagocytes. Ann. Int Med 93:480-489. 36. Silversten, S.C., R.M. Steinman, and Z.A. Cohn. Endocytosis. Ann. Rev. Biochem. 46:669-722, 1977. 37. Steinman, RM., I.S. Mellman, W.A. Muller, and Z.A. Cohn. Endocytosis and the recycling of plasma membrme. J. Cell Bio. 96: 1-27, 1983. 38. Stossel, 7: P. Phagocytosis. New Eng. J. Med 290:717, 774, 833, 1974. 39. Winkelstein, J.A., and RH. Drachman. Phagocytosis: the normal process and its clinically significant abnonnalities. Pedtahics Clinics of NorthAmenca 21:551-565,1974. IV. General Sources 40. Beck, B.I:>., E.J. Clabrese, and P.D. Anderson. The use of toxicology in the regulatory process. Princi- ples and Methods of Toxicology, 2nd Edition. (A.W. Hayes, Editor), Raven Press Ltd., New York, pp. 1-28, 19E9. 41. Brain, J.D., D.F. Proctor, and L. Reid, Eds. Respiratory Defense Mechanisms, Yol 5. Marcel Dekker, New Y)rk. 1216 pages, 1977. 42. Cohen, A.B., and W.M. Gold. Defense mechanisms of the lungs. Annual Reviews of Physiology 37:325-3 50, 1975. 43. Lee, H.L. Fallc~ and S.D. Murphy (eds). Reactions to EnvimnmentalAgents. Section 9 of Handbook of Physiology (S.RGeiger, Executive Editor). American Physiological Society, Bethesda, Maryland, 1977. 44. West, J.E:..Respirafory Physiology. Baltimore: Williams and Wilkins, 1979.

Table 1 ANATOMY OF EPITHEL.IAL BARRIERS Interface with Environment Area (m2) Thickness from Environment-to Blood (fun) Organ Weight (kg) skin 1.8 100-1000 12 gastrointestinal 200 8-12 7 lungs 140 0.2-0.4 0.8 LUagVsszoz

Table 2 FUNCTION OF EPITHELIAL BARRIERS Interface with Environment Basal Blood Flow (liter/min) Cell 7°urnover (days) Basal Exposure Rate skin 0.5 12 variable gastrointestinal 1.4 3 2 kg/day lungs 5.8 28 24 kg air/day SU®9VSSz107