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Biological Disposition of Airborne Particles: Basic Principles en cl Application to Vehicular ~ - ~mlsslons RICHARD B. SCHLESINGER New York University Medical Center Structure of the Respiratory Tract / 240 Upper Respiratory Tract / 240 Tracheobronchial Tree / 241 Pulmonary Region / 244 Research Recommendations / 246 Ventilation / 246 Ventilatory Parameters / 246 Comparative Aspects of Ventilation / 248 Airflow Patterns / 248 Research Recommendations / 249 Deposition of Inhaled Particles in the Respiratory Tract / 250 Deposition Mechanisms and Controlling Factors / 250 Measurement of Deposition / 253 Factors Modifying Deposition / 258 Localized Patterns of Deposition / 259 Mathematical Modeling / 260 Research Recommendations / 262 Retention of Deposited Particles / 263 Clearance Mechanisms: Basic Structure and Function / 263 Clearance Kinetics / 266 Factors Modifying Clearance / 272 Research Recommendations / 273 Disposition of Vehicular Particulate Emissions / 275 Diesel Exhaust Particles / 275 Metals / 276 Sulfates / 280 Research Recommendations / 281 Summary 1 283 Summary of Research Recommendations: Discussion / 284 Summary of Research Recommendations: Priorities / 285 Air Pollution, the Automobile, and Public Health. @) 1988 by the Health Effects Institute. National Academy Press, Washington, D.C. 239

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240 Biological Disposition of Airborne Particles The primary route of exposure to motor vehicle emissions is inhalation. The respi- ratory tract has a large internal surface area that is directly and continually exposed to 10,000 to 20,000 liters of ambient air in- haled daily, making it a potential target site for exhaust products. In addition, because the barrier between inhaled air and the pulmonary bloodstream is very thin, the respiratory tract is also an efficient portal of entry into the general circulation. A large fraction of emissions is either directly released in particulate form or be- comes adsorbed onto the surface of other ambient particles. The disposition of in- haled particles, and any adsorbed constitu- ents, determines the dose delivered to tar- get tissues. However, their ultimate fate and any potential hazard depend upon various interacting parameters: the physicochemical characteristics of the particles, the amount that actually deposits in the respiratory tract, and the rates and routes by which deposited material is cleared from the respiratory tract or translocated to other organs. Particles derived from motor vehicles do not have unique properties that influence their deposition or clearance. Thus, their dis- position can be assessed in general terms. This chapter is a review of the biological dis- position of inhaled particulate matter in terms of the factors that influence and control its deposition, clearance, translocation, and ultimate retention. The fate of specific non- organic particles found in automobile ex- haust will be assessed as examples of the dis- position of toxicologically relevant material. Some of the information presented is based on studies with humans, but much is derived from experiments with laboratory animals. Since human experimentation is precluded in many instances and often yields only limited data, surrogate animal models are needed. However, extrapola- tion from animal studies requires informa- tion on similarities and differences between species that may influence the disposition of inhaled materials. Thus, an attempt has been made to interrelate and integrate hu- man data with that obtained with experi- mental animals and, in some cases, even . . . Wlt 1 in vitro systems. The chapter is divided into five major sections. The first describes the anatomy of . . . t :le respiratory tract, since airway structure is a major determinant of particle disposi- tion. The second section discusses the as- pects of ventilation important in exposure assessment, including scaling for different ~1 . ~ - ~ . - ~ 1 ~ species. l he third section describes the physical mechanisms by which inhaled par- tlcles deposit in the respiratory tract, their controlling influences and modifying fac- tors. It critically reviews the available data for total and regional deposition in humans and experimental animals and provides a comparative analysis of interspecies depo- sition patterns. The fourth section discusses the structure, physiology, kinetics, and modifiers of the mechanisms by which deposited particles are cleared from, or translocated and retained within, the respi- ratory tract. The fifth section discusses the fate of specific nonorganic particles of rel- evance to automobile exhaust toxicology, that is, diesel particles, metals, and sulfates. In all five sections, knowledge gaps are highlighted and recommendations for re- search to fill these gaps are presented. Structure of the Respiratory Tract The respiratory tract is divided into two . . . . sections accorc lug to tunctlon: one IS con- cerned with transporting air from the ex- ternal environment to the sites of gas exchange and consists of the upper respira- tory tract and the tracheobronchial tree; the other, the pulmonary region, is involved in gas exchange. Upper Respiratory Tract This region originates at the nostrils and mouth and extends through the larynx; a diagram of the human upper respiratory tract is shown in figure 1. Air entering the nostrils passes first through the vestibule, the narrowest cross-section in the entire nasal region, before entering the main nasal passages. These consist of two airways separated almost symmetrically by the na- sal septum. They are convoluted (due to

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Richard B. Schlesinger Vestibule ..... t\ \\ \ ~ \_Trachea Figure 1. Diagram of the human upper respiratory tract. the folds of the nasal turbinates), down- ward-curving shelf-like structures, result- ing in a large surface area and a relatively narrow distance between opposing airway walls. Here, exchange of heat and moisture modify the temperature and humidity of the inhaled air. The nasopharynx begins at the posterior end of the turbinates, where the septum ends and the nasal passage narrows and turns downward. Although the basic structure of the nasal airways is similar in humans and most other mam- mals, there are considerable interspecies differences in the relative position, shape, and size of individual components, as shown in figure 2. For example, the naso- pharynx in the rat encompasses a greater percentage of the total length of the nasal passages than in the human, whereas that in rabbits and dogs is intermediate between rats and humans. The oral passages begin at the mouth and are characterized by much greater inter- and intraindividual variation in shape and cross-section than the nasal passages. At the posterior of the mouth, inhaled air enters the oropharynx. The oro- and nasopharynx join to form the hypopharynx, an airway that extends to the entrance of the larynx. The latter extends to the trachea and has a variable cross-section depending upon the rate of airflow through it. 241 r _Hypopharynx Figure 2. Silicone rubber replica casts of the naso ) pharyngeal region of different species: (A) human; (B) _~:arunx rabbit; (C) rat; (D) guinea pig; (E) hamster; (F) ba boon; scale in cm. (Adapted with permission from Patra 1986, and from Hemisphere Publishing Corporation.) Tracheabronchial Tree The tracheobronchial tree consists of air- ways from the trachea through the terminal bronchioles. The trachea divides into two main bronchi which then enter the lungs at the hilar region. These main bronchi fur- ther subdivide into smaller airways. Sup- port for the trachea and bronchi are derived from cartilagenous rings or plates. As the bronchial tree proceeds distally, the carti- lage eventually disappears, and these air- ways the bronchioles are supported by smooth muscle. In humans, the transition from bronchi to bronchioles occurs in air- ways of~1-mm diameter. Simplistically, the tracheobronchial tree can be considered to be a system of tubes connected at specific division points. In most cases, division is by dichotomy, whereby a single branch (the parent) gives .% j ,,, A B BEAN\ ;7 Ok (,/ Figure 3. Schematic diagram of tracheobronchial tree branching patterns: (A) human lung; (B) mono- podial system common in experimental animals.

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242 Biological Disposition of Airborne Particles rise to two branches (the daughters). To describe this structure, the position of an individual airway is usually assigned a code number. There are two basic coding sys- tems: the numbering of divisions up from distal end branches or, alternatively, down from the trachea. For example, in the of- ten-used Weibel ordering system (Weibel 1963), each branching division is known as a generation; the trachea is generation 0, and each distal division increases by one number. In a dichotomous branching system, the pattern can vary in terms of the degree of symmetry (figure 3~. If both daughters have the same diameter and length, and branch from the parent at the same angle, the mode of division is known as regular or symmetrical. If the two daughters differ from each other in one or more dimen- sions, the mode of branching is termed irregular or asymmetrical, the extreme case of which is monopody. In a monopodial branching system, the larger-diameter daughter (major daughter) may not be eas- ily distinguishable from the parent since the change in diameter and direction from the parent may be negligible. A major difference in respiratory tract anatomy between humans and most other mammals commonly used in inhalation studies is in the pattern of bronchial airway branching. Figure 4 shows casts of the upper bronchial tree in humans and in a number of other species, and figure 5 pre- sents a quantitative analysis that allows characterization of branching patterns. In a regular dichotomous branching system, the ratio of daughter diameters is 1, whereas in a perfect monopodial branching system, the ratio of major daughter diameter to Figure 4. Silicone rubber replica casts of the tra- cheobronchial tree of different species. (A) human; (B) baboon; (C) dog; (D) rhesus monkey; (E) rabbit; (F) guinea pig; (G) rat; (H) hamster; (I) mouse. Both photos are reproduced here at the same scale, given in inches at the bottom. (Adapted with permission from Patra 1986, and from Hemisphere Publishing Corpo- ration. ) parent diameter is 1. The human bronchial tree, at least for the first six generations, exhibits the most symmetrical branching of all of the species shown, whereas the dog's bronchial tree is almost ideally monopodal. The other species exhibit various degrees of irregularity. Recent qualitative observa- tions on the tracheobronchial trees of two nonhuman primates-the rhesus monkey and the baboon suggest a branching pat- tern that is more irregular than that of humans, but not to the extent of the exper- imental animal species shown in figure 5 (Patra 1986~. But although there may be striking interspecies differences in the upper bronchial tree, the branching patterns in most mammals tend to approach more regular symmetry in distal conducting air- ways. An important difference between regu

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Richard B. Schlesinger A ~ Major/minor Major/parent Minor/parent c', 3.0 o Go 2.c LU LU ~ 1.0 - c`' 3.0 o ~ 2.0 I; 1.0 6 n 90: u, at, 60 Al ~ 30 an At: 90 Hamster B Major ~ Minor Human Hamster ~ 60 _ / L9U ~ , 30 ~ l: 0 1 2 3 4 5 6 Herman AIRWAY GENERATION Human _: Rabbit Dog Rat l l l l l l 1 2 3 4 5 6 Dog - iV: I' Rat 1~ ~ 1 2 3 4 5 6 1 2 3 4 5 6 AIRWAY GENERATION Figure 5. Morphometric relationships for the bronchial trees of different species. Each panel is derived from measurements of a single silicone rubber cast. (A) Ratios of airway diameters as a function of branching generation; (B) ratios of branching angles as a function of generation. (Adapted with permission from Schlesinger and McFadden 1981 .) lar and irregular dichotomous branching modes concerns the number of airways between the trachea and the terminal bron- chioles. In a regular dichotomous branch- ing system, the number of divisions and, 243 therefore, the path length, between the trachea and the most distal conducting air- ways is the same along any pathway. In addition, all airways at any branch level have exactly the same dimensions. In an

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244 Biological Disposition of Airborne Particles Table 1. Airway Path Lengths Number of Airway Divisions (Generations)a Mean Range of Means Species (for entire lung) (for individual lobes) Reference Human 17 Weibel (1963) Human 15 1017 Schum et al. (1976) Rat 15 11-19 Raabe et al. (1977) Hamster 14 10-18 Raabe et al. (1977) Dog (beagle) 18 15-21 Schum et al. (1976) a From trachea through terminal bronchioles. SOURCE: Adapted with permission from Schlesinger and McFadden 1981. irregular dichotomous system, the number of branch divisions from the trachea to each distal bronchiole is not the same along every pathway, and not all airways at a given branch level have the same dimen- sions. Table 1 presents the average number of branching generations from the trachea through the terminal bronchioles for vari- ous species. Humans have the narrowest range of branching generations, a reflection of the greater symmetry of their lungs. Because of the complexity of airway branching structure, the geometry of the tracheobronchial tree has been represented by models; these are idealizations derived from experimental data, usually from mea- surements performed on castings prepared from actual lungs. One of the most widely used human structural models is the sym- metrically dichotomous Weibel Model A (Weibel 1963~. This is a 23-generation sys- tem, with generations (}16 representing conducting airways. Although the assump- tion of regular dichotomy simplifies the treatment of morphometric data, the actual bronchial tree is asymmetrical, and a num- ber of models of human airways that ac- count for asymmetry have been described (Horsfield and Cumming 1968; Olson et al. 1970; Horsfield et al. 1971; Parker et al. 1971~. In addition, Phalen and coworkers (1978) and Yeh and Schum (1980) devel- oped structural models of the human lung which consist of"typical pathways," based on mean dimensions, for each lobe within the lung. Although the models were devel- oped with symmetrical branching within each lobe, they do account for the asym- metry, and resultant variable path length, between different lobes. Most of the tra cheobronchial models have been based upon measurements made in only one lung. The very limited data base suggests that there is significant variability in airway dimensions between individuals (Nikiforov and Schlesinger 1985), but the only model that accounts for this is a statistical descrip- tion of the tracheobronchial tree based upon the Weibel geometry (Soon" et al. 1979~. Structural models of the bronchial tree have also been developed for experimental animals. These include symmetrical dichot- omous models for the rabbit (Kliment 1974), the rat (Kliment 1973), and the guinea pig (Kliment et al. 1972) and typical pathway models for the dog, the rat, and the hamster (Yeh 1980~. Pulmonary Region The pulmonary region extends from the respiratory bronchioles through the alveoli and contains airways involved in gas ex- change between the air and blood (figure 6a). In the human lung, the final generation of airways that merely conduct air the terminal bronchioles branch into several generations of respiratory bronchioles, which are characterized by the presence of alveoli. The degree of alveolarization in- creases toward the lung periphery; when the airway becomes totally alveolarized, it is termed an alveolar duct. This may branch into other ducts, or into blind- ended alveolar sacs. The adult human lung contains ~ 375 million alveoli, the number varying with body size, and the average alveolar diameter is 25(}300 ,um. This re- sults in a total alveolar surface area on the order of 150-180 m2 (Weibel 1980~.

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Richard B. Schlesinger A \' ''''": 245 B ~Type I alveolar cell -~~ Surface-active layer (surfactant) (~7 \~1 Terminal bronchioles Respiratory bronchioles Alveoli Alveolus pair space) <~: ~ Type It alveolal$y :( ~ Intern 4~\ Figure 6. (A) Diagram of the human airways in the pulmonary region; (B) diagram of the cellular makeup and surrounding structures of the alveolus. There are large interspecies differences in the gross structure of the pulmonary region (Gehr et al. 1981; Tyler 1983~. The number of branching generations of respiratory bronchioles and alveolar ducts varies, and some species appear to have no respiratory bronchioles. The degree of alveolarization of the respiratory bronchioles also differs, as does alveolar size and total alveolar sur- face area, the latter increasing in direct proportion to body mass. The alveolar surface is lined with a con- tinuous layer of two distinct cell types (figure 6b). About 9~95 percent is covered by type I cells, which are characterized by a central nucleus surrounded by cytoplasm stretching out in thin winglike processes to form part of the alveolar wall. The remain- ing surface is covered by cuboidal-shaped type II cells, which are actually more numer- ous than the type I cells. The relative num- bers of these cell types, as well as the percent- age of the alveolar surface covered by each, are similar in humans and most other mam- mals (Crapo et al. 1983; Gehr 1984~. The alveoli are supported by a frame- work of connective tissue termed the inter- stitium. Capillary endothelial cells are joined through the interstitium to alveolar epithelial cells, to form the "alveolo-cap- illary membrane." This membrane is about 2 ,um thick in humans, but appears to be thinner in most experimental animals (Meessen 1960; Crapo et al. 1983; Gehr 1984~. The interstitium and associated structures form the part of the lung known as the parenchyma. This region also in- cludes the pulmonary lymphatic vessels. The lungs contain two lymphatic net- works. One set (superficial or pleural net- work) is located within the connective tis- sue layer of the visceral pleura, whereas the other (deep or peribronchovascular net- work) consists of interconnecting vessels within the connective tissue surrounding both the airways (to the level of the respi- ratory bronchioles) and the pulmonary vas- cular system. A plexus of vessels connects the two sets. In both systems, the network begins as blind-ended capillaries and fluid flows toward the hilar region of the lung. Many larger lymphatic vessels are inter- spersed with nodes (encapsulated aggre- gates of lymphoid tissue); the most prom- inent of these are located along the trachea and main bronchi, and at branching sites between these airways. More diffuse lym- phoid aggregates occur near the branching regions of smaller bronchi and bronchioles. Eventually, the entire pulmonary lym

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246 Biological Disposition of Airborne Particles phatic system drains into the general ve . . nous c~rcu anon. Research Recommendations Quantitative anatomy or morphome- try of the respiratory tract is essential for understanding the dosimetry of inhaled particles. The structure of the various com- ponents of the respiratory tract influences the airflow and, thus, the resultant pattern of particle deposition and the distribution of sites of potential damage. Morphometry must be assessed in humans as well as experimental animals, the latter so as to assist in the extrapolation of toxicologic data to humans. Data are available for normal adult humans and some other spe . . . . cles, rut cntlca gaps remain. Recommendation 1. Variability in morphometry of the tracheobronchial and pulmonary regions in normal humans as well as experimental animals (including dif- ferent strains) should be studied. Better statistical descriptions of interindividual variation at all levels of the respiratory tract are needed to validate conclusions drawn from current theoretical or empirical dep- osition models, which are generally based upon a single morphometric model. Recommendation 2. Lung morphom- etry should be assessed in potentially "sus- ceptible" subsegments of the human pop- ulation: children, the elderly, and people with respiratory disease. Although data are becoming available on the morphometry of children's lungs at different ages, these are not yet sufficient to develop a compre- hensive morphometric model describing growth of the tracheobronchial tree. No information exists at all for assessment of morphometric changes due to aging or disease. Recommendation 3. Comparative morphometry of human and animal upper respiratory tracts should be assessed. Be- cause of large interspecies differences in the nasopharyngeal region, more quantitative information is needed to allow better com- parison with that in humans. For example, rodents have essentially a straight pathway from the nostrils to the trachea, a situation radically different from that in humaps and nonhuman primates. In humans, more de- tailed information on dimensions of the oral passages under different ventilatory conditions is also needed to assess particle removal by the upper respiratory tract. ~ Recommendation 4. Comparative structure and physiology of human and animal pulmonary lymphatic systems should be studied. This knowledge is needed for better comparisons of particle clearance by this route in humans and ex- perimental animals. Ventilation Ventilatory Parameters Ventilation is the movement of air in and out of the respiratory tract and is a factor in determining the amount of an exposure atmosphere that is actually inhaled. Venti- latory parameters also affect the deposition of particles once inhaled. The amount of air inspired (or expired) during a normal breath is the tidal volume ~ VT); it averages 450-600 ml in resting healthy males and slightly less for females. The fraction of the VT that does not reach the alveolated airways about 150-200 ml in resting males and 120-160 ml in females is termed the anatomic dead space volume ( VDanac) Not all of the inspired air reaching the pulmonary region is equally effective in oxygenating the blood, since air may enter alveoli that are ventilated but poorly per- fused. The portion of VT that does not equilibrate with gas pressure in the pulmo- nary capillary blood is the alveolar dead space volume (ED, ). The total volume of inhaled air that does not participate in gas exchange, VDanac + VDa,v, is termed the total or ph,vs~olog~cal dead space ~ ED ~ During expiration, air within the tra- cheobronchial tree largely from the pre- vious inspiration is expelled along with some alveolar air which is a mixture from a number of inspirations. Particles inhaled

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Richard B. Schlesinger 247 into the pulmonary region can therefore be exhaled over a number of breaths. Thus, the time available to deposit inhaled parti- cles in the conducting airways is fairly short (a few seconds), whereas the residence time in pulmonary air may be longer (about a minute). Total ventilation ~ VE), or minute volume (MV), is defined as the volume of air expired each minute and is equal to VT times the breathing frequency by. The av- erage f during normal quiet breathing in adults is 11-17 breaths/min, and the rest- ~ng VE averages ~10 liters/mint The VE consists of anatomic dead space ventilation (VD~nat) and total alveolar ventilation (VA), the latter being the amount of air entering the pulmonary region each minute. The effective portion of VA that participates in gas exchange is equal tOf(VT- VDIO'). Ventilation is affected by numerous ex- ogenous factors such as altitude, ambient temperature, and smoking, as well as endogenous factors such as body size. Two of the major modifiers in any particular individual are physical activity and age. Physical Activity. Healthy humans at rest normally breath through the nose, but when respiratory demand increases above a certain level there is a shift to oronasal (combined nose and mouth) breathing. Maximum inspiratory nasal airflow occurs at a VE of 30 40 liters/min (Swift and Proctor 1977; Niinimaa et al. 1980), at which point ~40 60 percent of total air- flow occurs through the nose. As respi- ratory demand increases further, the pro- portion of air entering the mouth increases, but even at high demand the oral path- way accounts for no more than 60 per- cent of the inhaled air (Swift and Proctor 1987~. With mounting respiratory demand, VT and f increase, and the maximum volume of air that can be inhaled per minute, or the maximum voluntary ventilation, may rise to more than 10 times the resting ventilatory level. As breathing frequency increases, expiratory time diminishes, but inspiratory time remains relatively con- stant. Furthermore, respiratory pauses, the gaps between expiration and inspiration which can occupy 25 percent of the breath- ing cycle in resting individuals, become shorter with increasing level of activity. Growth and Aging. The volume of air in the lungs and the ventilatory capacity de- pend on body and lung size and, thus, increase with growth from childhood. In addition, the contribution of VT and f to total ventilation also changes; VT increases while f decreases until maturity is reached (Mauderly 1979~. Ventilatory function reaches a peak be- tween the ages of 20 and 35 and then begins to decline. Although various models have been proposed to describe these changes, they differ in their assumptions about the rate of functional decline (Buist 1982~. Fur- thermore, most of the reported data for age-related changes in lung function are derived from cross-sectional population studies and may not reflect the true aging process, especially since these studies may be measuring the heartiest survivors. The best way to avoid possible bias is to exam- ine true aging patterns in longitudinal stud- ies in which the same people are tested over a number of years. Such analyses are scarce, and those that do exist have measured only a few parameters (Fowler 1985~. Changes in lung function with aging are the result of deterioration of the lung tissue itself, a decrease in the strength of the respiratory muscles, and an increase in the stiffness of the thoracic cage. The time course varies from individual to individual and may be aggravated by chronic pollut- ant exposure. Some ventilatory indices are affected by age, whereas others are not. Figure 7 shows a diagram of the various divisions into which the volume of air in the lungs may be separated. With age, functional residual capacity (FRC) and re- sidual volume (RV) increase, whereas vital capacity (VC), inspiratory capacity (IC), and expiratory reserve volume (ERV) de- crease. Anatomic dead space ~ VD ~ in- creases w~th age because of a decrease ~n lung elasticity and a resultant increase in lung volume at the same pressure differen- tials. Aging is associated with regional in- equalities in the distribution of ventilation

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248 Biological Disposition of Airborne Particles ~I AN I Figure 7. Diagram of subdivisions of lung volumes as measured with a spirometer. A typical spirometer tracing is shown on the right. TLC = total lung capacity, VC = vital capacity, RV = residual volume, FRC = functional residual capacity, IRV = inspira- tory reserve volume, ERV = expiratory reserve vol- ume, VT = tidal volume, and IC = inspiratory capacity. and a decrease in the uniformity of perfu- sion (Holland et al. 1968~. Nonuniform mixing of inspired air may result when sections of the lungs communicate poorly with others and, because of this, some alve- olar regions may not be continuously venti- lated during normal tidal breathing. Non- uniform perfusion results in an increase in VD} which, together with the increase In VD, results In an ag~ng-related rise in VD . Although this does not affect rest- ing levels of BE, which show no major change with aging, the ability of the lungs to respond to increased activity is altered, and maximum voluntary ventilation de- clines by about 30 percent between ages 30 and 70. Comparative Aspects of Ventilation Since much of the toxicologic work with inhaled particles involves experimental an- imals, it is essential that their respiratory mechanics be quantitated. Various animal data exist (see, for example, Guyton 1947; Spell 1969), but the methods used to obtain them were not standardized, so there is much variability, even for similarly sized animals of the same species. "Repre- sentative" ventilatory values for a particu- lar species are therefore difficult to snecifv. so generalized values based on scaling pro cedures are used. Scaling is based on the principle that respiratory mechanical prop- erties may be related to body size or mass in some consistent fashion, even though there may be interspecies differences in the mech- anisms that determine these properties. This allows quantitative comparisons of function between animals of different sizes, within or between species. Scaling makes use of dimensional or dimensionless pa- rameters that either remain constant with body size or can be related to body size by some proportionality factor (Leith 1983~. For example, VE is proportional to body mass (M) raised to the 3/4 power, whereas lung volumes, such as VT, tend to vary with M to the first power. Similarly, breathing frequency is proportional to M-~/4, whereas the ratio of VD to VT is Independent of body size. Stahl (1967), after an extensive literature search, developed predictive equations re- lating respiratory variables in mammals to body weight. These equations can be used to scale values between animals of different species as well as between individuals of different body weights within one species, as long as the animals are in comparable physiological states. Scaling is not a precise technique, however, and is only as good as the values upon which the exponents and proportionality factors are based. For ex- ample, many of these values have been obtained in anesthetized animals, in which actual lung volumes and ventilation may be less than normal (Sweeney et al. 1983~. Airflow Patterns Patterns of airflow in the conducting air- ways are a major determinant of particle deposition sites. Basic principles of airflow are presented by Ultman (this volume). Aspects of airflow critical to particle depo- sition are addressed below. Within straight tubes, two main types of flow may occur: laminar and turbulent. In laminar flow, gas molecules move in par- allel as a smooth stream, with the highest velocity occurring at the center of this stream. The flow can be imagined as con- centric layers of air sliding or telescoping lengthwise along each other, with no trans

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Richard B. Schlesinger 249 verse mixing between layers. In turbulent flow, gas molecules are in an agitated state, and there is erratic mixing of concentric layers. Random secondary flows (eddies) are superimposed on the average longitudi- nal motion of flow velocity. Flow that is partially laminar and partially turbulent is termed transitional. The type of flow that occurs depends upon the strength of the inertial forces in the moving air in relation to the frictional and viscous forces acting on it. For exam- ple, turbulence occurs when the former exceed the latter. Airflow may thus be described in terms of the ratio of inertial forces to viscous and frictional forces, which is expressed as the dimensionless Reynolds number (Re). The Reynolds number depends on the geometry of the conduit through which the air passes and the velocity of airflow, and flow character- istics change as Re passes certain critical values. Thus, for steady flow in a straight, smooth-walled, circular tube, flow will be laminar when Re is less than 2100, transi- tional when Re is between 2100 and 4000, and fully turbulent when it exceeds 4000 (Hinds 1982~. Within the respiratory tract, bends, bi- furcations, constrictions, surface roughness and convolutions, and other features of airway shape that add inertial forces may lead to turbulent flow at a velocity lower than that at which turbulence would be initiated in a smooth, straight, obstacle-free tube having the same cross-section. Thus, flow instability and turbulence may occur in the upper respiratory tract and upper tracheobronchial tree at Reynolds numbers well below 2100 (West and Hugh-Jones 1959; Dekker 1961; Sekihara et al. 1968; Olson et al. 1973; Swift and Proctor 1977~. Turbulence is also produced by the contin- uous acceleration and deceleration of air during the breathing cycle (Lakin and Fox 1974~. But although turbulent flow gener- ated in the upper airways upon inspiration may be propagated into a few generations of downstream bronchi, air velocity de- creases with depth into the lung, and in the smaller conducting airways, flow is always laminar. Because of structural differences between the tracheobronchial trees of humans and most other mammals, one would expect differences in resultant flow patterns. For example, the trachea of most mammals is much longer relative to its diameter than is the human trachea. Thus, any turbulence introduced by flow through the larynx is much less likely to persist into the down- stream bronchi of nonhuman mammals. Unfortunately, there are few data on air- flow patterns in the airways of most com- monly used experimental animals (see, for example, Snyder and Jaeger 1983~. Research Recommendations Ventilatory patterns and airflow dynamics are critical determinants of dose to the respiratory tract from inhaled particles. The following important gaps In our knowledge of ventilation in humans and in experimental animals should be filled. ~ Recommendation 5. Patterns and dis- tribution of airflow in the tracheobronchial tree of healthy adult experimental animals and humans should be determined. This information is important for the develop- ment of deposition models and for the extrapolation of results of toxicologic stud- ies to humans. Recommendation 6. Effects of aging on ventilation in humans and experimental animals should be determined by use of longitudinal studies of humans and experi- mental animals involving numerous venti- latory parameters. In animals, a cross-cor- relation of age equivalencies between species should be performed, so that pa- rameters of toxicologic studies may be bet- ter related to lung function in humans. Recommendation 7. Ventilatory me- chanics and airflow in children should be analyzed. Although data are available for some stages of growth, there is a gap between birth and ~9 years of age. ~ Recommendation 8. Flow patterns in the upper respiratory tracts of experimental animals and humans should be studied. Most experimental animals are obligate na

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