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Air Pollution, the Automobile, and Public Health (1988)

Chapter: Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions

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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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Suggested Citation:"Biological Disposition of Airborne Particles: Basic Principles and Application to Vehicular Emissions." National Research Council. 1988. Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press. doi: 10.17226/1033.
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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

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

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.

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

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

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~.

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

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

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

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

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

250 Biological Disposition of Airborne Particles sal breathers, so only their nasal passages need be studied. But in humans, analyses of the nature of flow in the oral passages through the oropharynx, including the ef- fects of speech and increased physical activ- ity, are also needed. Deposition of Inhalec! Particles in the Respiratory Tract The concentration of particles in ambient air does not by itself define the dose deliv- ered to the respiratory tract. To provide , . . . . ~ such quant~cat~on, it Is first necessary to determine deposition sites that is, regions where inhaled particles initially contact air- way surfaces. Deposition sites determine the subsequent pathways for removal or translocation and, as such, constitute a ma- jor contributor to the ultimate toxicologic response. Deposition Mechanisms and Controlling Factors SpeciJic Deposition Mechanisms. The size of inhaled particles is a critical factor affecting their deposition; thus, resultant biological effects are, to some extent, par- ticle-size dependent. Size may, however, be expressed in various ways. For spherical particles, actual measured diameter is un- ambiguous, but for nonspherical or irreg- ularly shaped particles some "effective" di- ameter is more appropriate. Such particles are often described in terms of equivalent spheres, on the basis of equal volume, mass, or aerodynamic drag. In order to compare deposition data ob- tained using particles of different materials, a diameter that accounts for the factors affecting deposition should be used; the most common of these is aerodynamic equivalent diameter (Dae). This term ac- counts for shape and density and is defined as the diameter of a spherical particle with unit density that has the same terminal settling velocity (see below) as the particle in question. Particles that have higher than unit density will have actual diameters smaller than their Dae. The significant mechanisms by which particles are deposited in the respiratory tract are impaction, sedimentation, Brown- ian diffusion, interception, and electrostatic precipitation (figure 8~. The relative contri- bution of each depends on characteristics of the particles as well as on ventilatory pat- terns and respiratory tract anatomy. Impaction onto an airway surface occurs when a particle's momentum prevents it from changing course in an area where there is a rapid change in the direction of bulk airflow. It is the main deposition mechanism for particles having Dae ' 0 5 ,um in the upper respiratory tract and at or near tracheobronchial tree branching points. The probability of impaction in- creases with increasing air velocity, rate of breathing, particle density, and size. Sedimentation is deposition due to grav- ity. When the gravitational force on a par- ticle is balanced by the total forces due to air buoyancy and air resistance, the inspired particle will fall out of the airstream at a interception // impaction // fusion ~ `: ~/- \', ~ Sedimentation / / ~ electrostatic / / S'` deposition Flow streamline ---Particle trajectory Figure 8. Mechanisms for particle deposition in the respiratory trace. (Adapted with permission from Lippmann and Schlesinger 1984.)

Richard B. Schlesinger 251 constant rate, known as its terminal settling velocity. The probability of sedimentation increases with increasing residence time in the airway, particle size, and density, but decreases with increasing breathing rate. Sedimentation is important for particles with Dae ' 0.5 ,um in medium to small airways where air velocity is relatively low. Submicrometer-size airborne particles, especially those with diameters '0.2 ,um, have imparted to them a random motion due to bombardment by surrounding air molecules: this motion mav then cause such surface of the airways by charged particles and/or from space/charge effects, whereby repulsion of similarly charged particles causes increased migration toward the air- way wall. The effect of charge on deposi- tion increases with decreasing particle size and airflow rate. Since most ambient parti- cles become neutralized naturally by air ions, electrostatic deposition is a minor contributor to particle collection by the respiratory tract. Factors Controlling Deposition. An un- derstanding of the extent and loci of par particles to come into contact with the ' ' ' airway wall. The displacement sustained by the particle is a function of the diffusion coefficient, which is inversely related to particle cross-sectional area. Brownian dif fusion is a major deposition mechanism in airways where bulk flow is low or no longer occurring, that is, in the bronchioli and alveoli. However, molecular-size par ticles may be deposited by diffusion in the upper respiratory tract, trachea, and larger bronchi. As mentioned, particles with Dae ' 0 5 ,um are subject to impaction and sedimen- tation, whereas the deposition of particles '0.2 ,um is diffusion dominated. Particles with diameters between these values are only minimally influenced by these mech- anisms and tend to have prolonged suspen- sion times in air. They may, thus, undergo little deposition, being carried out of the respiratory tract in the exhaled air. Interception is a significant deposition mechanism for elongated particles, such as fibers, and occurs when the edge of the particle contacts the airway wall. The aero- dynamic diameter of a fiber is related to its transverse diameter. Thus, fibers that are long (for example, 50-100 lam) but thin (for example, 0.5 lam) behave aerodynam- ically like small particles, penetrating into distal airways. Fiber shape is also impor- tant, since straight fibers penetrate more distally than do curly ones. Some freshly generated particles can be electrically charged and may exhibit depo- sition greater than that expected on the basis of size alone. Electrostatic deposition results from image charges induced on the tlcle deposition in tile respiratory tract requires an appreciation of various control- ling factors: characteristics of the inhaled particles, anatomy of the respiratory tract, and ventilation pattern. Characteristics of Inhaled Particles. The major particle characteristic that influences deposition is size. However, particles are inhaled not singly, but as constituents of aerosols, which are suspensions of liquid or solid particles in a gas. The components of the particulate phase may differ, but even if this consists of a single material, a spectrum of particle sizes is often present. In general, the size distribution of particles in com- monly encountered aerosols fits reasonably well with a lognormal distribution; that is, the logarithm of particle diameter is nor- mally distributed. Such a distribution can be described by a geometric mean size (which is also the median diameter) and by an index of dispersion the geometric stan- dard deviation fogs. This latter is the ratio of the diameter at 84.1 percent (or 15.9 percent) cumulative probability, that is +1 standard deviation (SD) of the normal curve, to the diameter corresponding to 50 percent cumulative probability (figure 9~. Depending upon the specific size parameter used to develop the distribution, the result- ant median diameter may be count median (CMD, using the physical diameter of the particles), mass median (MMD, using the particle mass distribution relative to diameter), or aerodynamic mass median (MMAD, using aerodynamic equivalent diameter). If not directly measured, the MMD and MMAD may be calculated from the measured CMD for spherical particles.

252 Biological Disposition of Airborne Particles ( 10.OI UJ N - C~ 1.0 _ J Or ~ . ~ (a) ,/ /b) (a) CMD = 1.5 ~m; a9 = 2.3 (b) CMD = 1.5 ~m; cry = 1.5 0.1 ~ ~ ~ ~ . ' o.o, 0.1 1 10 do e01~4,0,O 98 99.99 CUMULATIVE PERCENTAGE Figure 9. Cumulative frequency distribution plots of particle number for two polydisperse aerosols. Both aerosols have the same count median diameter (CMD) (50 percent probability), but they have dif- ferent geometric standard deviations (erg). Because of the different cog, the percentage of particles with diam- eters greater or less than the CMD differs substantially for the two aerosols. Radioactive or toxic aerosol size distribu- tions are often expressed as activity median aerodynamic diameter (AMAD). The deposition probability of particles with physical diameters ~ 0.5 ,um is gov- erned largely by particle aerodynamic di- ameter, whereas deposition probability of smaller ones is governed by actual physical diameter. Thus, use of the MMAD param- eter is appropriate only in describing aero- sols in which most particles are physically -0.5 ,um; the median size of aerosols con- taining particles with actual diameters less than this is usually expressed in terms of a diffusion diameter or actual physical size. Aerodynamic diameter is, therefore, the most appropriate unit for describing depo- sition by sedimentation and impaction, but not by diffusion. The size distribution of an aerosol, which largely depends on its method of produc- tion, is characterized as monodisperse or polydisperse (heterodisperse). A monodis- perse aerosol consists of particles of uni- form size. Since, in reality, perfect mono- dispersity does not exist, an aerosol is considered monodisperse if the IT_ is <1.2 (Fuchs and Sutugin 1966~. But use of this term in deposition analyses means that all of the particles are assumed to behave as if x they were exactly the same size, that is, the median size. In polydisperse aerosols, par- ticles of widely differing sizes may be pres- ent, and the Erg is 21.2. If the trg of a polydisperse aerosol is <2, its total respiratory tract deposition will probably not differ substantially from that for a monodisperse aerosol having the same median size (Morrow 1981; Din and Yu 1983~. However, size distribution is impor- tant in determining the spatial pattern of initial dose. This is because the effect of size dispersion on regional deposition depends upon the sequential "filtering" action of each component of the respiratory tract, which in turn depends upon particle size. For example, as erg increases for aerosols with median sizes between 0.01 and about 0.07 ,um, tracheobronchial deposition will likely increase, but pulmonary deposition will decrease because of less penetration into this region. On the other hand, as or increases for aerosols with median sizes of 0.07 to about 1 Am, bronchial as well as pulmonary deposition will increase (Diu and Yu 1983~. A particle characteristic that may dynam- ically alter its size is hygroscopicity. Hy- groscopic particles may grow substantially while they are still in transit in the respira- tory tract and will be deposited according to their hydrated, rather than their initial dry size. The deposition pattern of specific hydroscopic aerosols can generally be re- lated to their particle growth characteris- tics, if known. Respiratory Tract Anatomy. Respiratory tract geometry affects particle deposition in various ways. For example, airway diame- ter sets the displacement required for a particle to contact a surface, whereas cross- section determines the air velocity for a given flow rate. Differences in pathway lengths in different lung lobes affect regional deposition. Lobes with the shortest average path length between the trachea and terminal bronchioles may have the highest concentra- tion of deposited particles 21 ,um in the alveoli. Regional differences become less ob- vious for submicrometer particles, which tend to deposit evenly in all lobes regardless of path length but in proportion to relative ventilation (Raabe et al. 1977~. , . .

Richard B. Schlesinger 253 Although humans differ from most other mammals in various aspects of respiratory tract anatomy, the implications of this for particle deposition have not been ade- quately appreciated. For example, alveolar size differs among species; since particles with Dae ' 0.5 ,um that reach the alveoli will be deposited primarily by sedimenta- tion, and different-size alveoli have dif- ferent characteristics as sedimentation chambers, the net result will be that the pulmonary region of various species will have different deposition efficiencies. Dif- ferences in deposition patterns affect the dosimetry of inhaled particles and the abil- ity to use the results of toxicity tests in experimental animals for human risk as- sessments. In addition to interspecies dif- ferences, the data available indicate that size of tracheobronchial airways and alveoli vary considerably within species. Such variation is probably a major factor respon- sible for the observed differences in depo- sition efficiency among individuals of one species (Heyder et al. 1982~. Ventilatory Parameters and Mode of Inhala- tion. The pattern of respiration during particle exposure influences regional depo- sition sites and efficiencies. For example, high inhalation velocities enhance deposi- tion by impaction but decrease that due to sedimentation and diffusion. Thus, a rise in flow rate, such as during increased physical activity, may shift regional deposition, in- creasing collection in the upper respiratory tract and central bronchi and reducing it in more distal conducting airways and the pulmonary region (Valberg et al. 1982; Morgan et al. 1984; Bennett et al. 1985~. Increased flow velocities may also result in the development of turbulence, which tends to enhance particle deposition, the degree of potentiation depending on parti- cle size (Schlesinger et al. 1982~. Tidal volume affects deposition by deter- mining how deep into the lungs the in- spired air penetrates. At a constant breath- ing frequency, increasing tidal volume deepens penetration of inhaled particles, thus increasing deposition in the smaller conducting airways and pulmonary region. Alterations in tidal volume can also dra- matically affect total respiratory tract dep osition. For example, Schum and Yeh (1980) suggested that, in the rat, doubling tidal volume from 1.4 ml to 2.8 ml increases the deposition of a 1-,um (median Dae) aero- sol by seven times. Finally, the duration of respiratory pauses influences sedimentation or diffusion deposition by affecting particle residence time in relatively still air. A major ventilatory change that occurs in humans when activity level increases is a switch from nasal to oronasal breathing. Since the nasal passages remove inhaled particles more efficiently than the oral pas- sages, bypassing the nose increases the pen- etration of particles into the lungs. The actual magnitude of this increase is influ- enced by particle size, since larger particles are more effectively filtered in the nose than are smaller ones. Measurement of Deposition Measurement Techniques. Various tech- niques have been used to measure particle deposition in the respiratory tract of hu- mans and experimental animals (Valberg 1985~. Unfortunately, the use of different experimental methods and assumptions, especially In assessment of regional deposi- tion, has resulted in large variations in reported values, even within the same spe- c~es. Total respiratory tract deposition has of- ten been determined by a procedure that compares the concentration of test particles administered in inhaled air with that in collected exhaled air, the difference repre- senting the total amount deposited. If as- sumptions are made about mixing and dead space, estimates of regional deposition can be derived from measurements of particle concentration in different volume fractions of the expired air, but such assumptions cannot be validated. Specific particle characteristics may be used to measure deposition. Most com- monly, radioactively tagged tracer particles are used with various types of detector systems. Total deposition is estimated by monitoring the thoracic and head regions immediately after exposure, whereas re- gional deposition is usually defined func- tionally on the basis of subsequent clear

254 Biological Disposition of Airborne Particles ance. For example, it is often assumed that any particles remaining in the thorax 20 to 24 hr after exposure are in the pulmonary region, and particles that deposited in the tracheobronchial region were cleared from the lungs prior to this time. This is a reasonable assumption for healthy subjects but may not be for subjects with disease states where clearance is slower, and its use could result in an overestimation of pulmo- nary deposition and an underestimation of tracheobronchial deposition. Deposition in the upper respiratory tract is inferred from measurements on the head immediately after exposure. Since this re- gion clears rapidly to the stomach, even the first measurement may not accurately re- flect actual deposition; accordingly, some . . . . . . . investigators lncluc .e an lnltla . measure- ment of material in the gastrointestinal tract in their reported value for upper respiratory deposition. However, the upper respira- tory tract, as defined in various studies, may include any or all of the following . . anatomic regions: nasop narynx, oro- pharynx, larynx, or upper trachea. Another technique for deposition analy- sis in experimental animals is chemical and/ or radiological assay of tissues or whole organs removed by dissection after expo- sure. Obtaining accurate deposition values requires immediate sacrifice, and the as- sumption of no particle translocation (ex- cept to the gastrointestinal tract) prior to or during dissection. Experimental Deposition Assessment. The species of choice for deposition analy- ses is the human. However, experimenta- tion with human subjects is not always possible, and various animals are therefore used instead, with the ultimate goal of extrapolating the results to humans. If the results are to be valid, the extrapolation must take into account interspecies differ- ences in total and regional deposition. It is difficult to systematically compare deposition patterns obtained from reported studies in one species, and it is even harder to do this between species, because of vari- ations in experimental protocols, measure- ment techniques, definitions of specific res- piratory tract regions, and so on. For example, tests with humans are generally conducted under protocols that standardize tidal volume and breathing frequency (al- though the standardization parameters of- ten differ in different laboratories), whereas those using experimental animals involve a . . . . . W1C .er variation in respiratory exposure conditions (for example, spontaneous breathing versus controlled breathing as well as various degrees of sedation). Much of the variability in the reported data for individual species is due to the lack of . . . .. . norma. Ration tor specific respiratory pa rameters during exposure. In addition, experimental inhalation studies use different exposure techniques, such as nasal mask oral mask. oral tube or tracheal incubation. Regional deposition fractions are affected by the exposure route and delivery technique used (Wolfsdorf et al. 1969; Swift et al. 1977a). Even the specific size of the delivery device can affect inspired airflow rates, which influence the extent of deposition in the upper respira- tory tract and the degree of particle pene- tration into the lungs (Heyder et al. 1980b). Compilations of experimentally deter- mined deposition values in humans and those experimental animals commonly used in inhalation toxicology studies are shown in figure 10. Not all deposition studies reported in the literature were in- cluded in this survey, since the objective was to make the intercomparisons as valid as possible. Thus, only studies where re- gional deposition values as a fraction of the amount of particles inhaled were provided, or could be derived, were included. Most studies describe regional fractions as a per- centage of total deposition rather than in terms of amount of material inhaled and were, therefore, excluded. In addition, only studies using nonhygroscopic, nonvi- able, nonfibrous aerosols and reporting an aerodynamic or diffusion-related diameter were included. Most studies with humans used monodisperse aerosols, whereas many of those with experimental animals used polydisperse aerosols. Since some of these latter may have consisted of particles of widely different sizes, it is often difficult to evaluate deposition based upon the median size alone. However, it is necessary to

Richard B. Schlesinger 255 include some of these studies, since a sub- stantial amount of the existing data base is derived using such aerosols. Finally, al- though the tracer aerosols in some studies were not charge neutralized, data using these tracer aerosols were included. The presence of electrical charges could account for some of the variability between dif- ferent studies using the same species and . . . . . slm1 ar size partlc. .es. Total Respiratory Tract. Figure 10a shows total respiratory tract deposition. In humans, nasal inhalation results in somewhat greater total deposition than oral exposures for par- ticles with diameters >0.5 ,um because the nasal passages collect larger particles more efficiently than the oral passages. There is little difference in total deposition between nasal or oral breathing for particles from 0.02 to 0.5 ,um. With even smaller particles, total deposition should be greater with nose breathing than with mouth breathing, al- though the difference would be small, amounting to, for example, only about 5 percent for particles with diameters of 0.005 ,um (Schiller et al. 1987~. Dogs and guinea pigs exhibit greater total deposition of 0.1-1-,um particles than do nasal-breathing humans. However, for particles >1 ,um, deposition is less in dogs than in humans, but deposition in guinea pigs is similar to that in humans. On the other hand, both rats and hamsters gener- ally show less total deposition than nasal- breathing humans. In some cases, the data indicate that total deposition for the same size particle can be quite similar in experimental animals and humans. It therefore follows that deposi- tion efficiency is independent of body (or lung) size (McMahon et al. 1977; Brain and Mensah 1983~. However, different species exposed to the same size particles at the same exposure concentration will not re- ceive the same initial mass deposition. If the total amount of deposition is divided by body (or lung) weight, smaller animals would receive greater initial particle bur- dens per unit weight per unit exposure time than would larger ones. For example, for 1-,um (Dee) particles, it is predicted that the receive 3 times that of humans, if deposi tion was calculated on a per unit lung (or body) weight basis (Phalen et al. 1977~. Not all atmospheric particles to which an individual is exposed will be inhaled. The inspirable fraction is the portion of the ambient concentration that actually enters the upper respiratory tract. In humans, for example, the fraction for particles with Dae <10,um is greater than 80 percent, whereas that for particles ranging from 30 to 80 ,um is about 50 percent (Vincent and Arm bruster 1981~. The probability of particles being inhaled into the respiratory tract de pends upon particle size as well as the orientation of the individual to external air currents and the size of the entrance to the respiratory tract. Thus, inspirable fractions likely differ among species. An additional point concerns hygroscop icity. If figure 10a is examined, it is evident that total deposition of hydroscopic parti cles c 0.5 Em inhaled by humans would tend to decrease if particles grow no larger than 0.5 ,um, and deposition will only begin to increase if particle final diameter is >1 ,um. Furthermore, since particles > 5 ,um may grow minimally in one respira tory cycle, their deposition may not in crease at all compared to nonhygroscopic particles (Ferron et al. 1987~. On the other hand, deposition probability for 0.3 to 0.5-,um hydroscopic particles may change substantially. Upper Respiratory Tract. Figure 10b shows upper respiratory tract deposition. There is substantial variability between species as well as large differences between individuals of the same species. Most ex perimental animals are obligate nasal breathers, and a large part of the intraspe cies variability may be due to nasal geom etry variation (Brain and Valberg 1979) as well as to different breathing patterns dur ing exposure. Note the large intraspecies variability in deposition for particle sizes subject to impaction; this is probably re sponsible for a large portion of the intra species variation in total respiratory tract deposition (Stahlhofen et al. 1981a; Heyder et al. 1982~. rat would receive an initial deposit 5 to 10 In humans, nasal inhalation results in times that of humans, and the dog would enhanced deposition compared to oral in

256 8O 70 z 60 o ~ 50 o 40 30 2n 10 Biological Disposition of Airborne Particles A 100 - T^tal 90 80 70 60 50 40 30 20 lO ~ O GO' 0.' 1.0 10 10OI 90L 80r 70 0 ~ E 50 o 40 30 20 10 I ^^ , , , ,,,, ~ , , i li,,' I u D1 Q11.0 10 B 100 - Upper respiratory tract - 100 90 ~ Human (oral inhalation) - 90 80 · Human (nasal inhalation) ~ . 80 ] ~T · ' ~ ~ ~ 1 ~ ~ 1 o Ret · Mouse 0 Hamster o Guinea pig o Dog o on o 100 ii 80 ~ J ~ , ,,, ,,,1 , , ,,, ..,, , . , ... ,. O 0.1 1.0 10 PARTICLE DIAMETER (~m) 100 90 80 70 at 60 o <~' 50 o t~ 40 Cal 30 20 10 O _ O.01 - Upper respiratory tract o Ret 0 Hamster · Mouse Guinea pig 0 Dog ~ , , , IF,] , ~ , 9,+~] 0.1 1.0 PARTICLE DIAMETER (~m) Figure 10. Deposition efficiency (that is, percentage deposition of amount inhaled) as a function of particle size for (A) total respiratory tract, (B) upper respiratory tract, (C) tracheobronchial tree, and (D) pulmonary region. All values are means (with standard deviations when available). Deposition efficiencies for experimental animals are based on nasal breathing. Particle diameters are aerodynamic (MMAD or AMAD) for those 20.5 ,um and diffusion equivalent for those <0.5 ,um. Data were compiled from Altshuler et al. 1957, 1966; Chan and Lippmann 1980; Craig and Buschbom 1975; Cuddihy et al. 1973; Foord et al. 1977; George and Breslin 1967; Giacomelli- Maltoni et al. 1972; Gibb and Morrow 1962; Heyder and Rudolf 1977; Heyder et al. 1973, 1975, 1980b, 1982; halation. In all species shown, there is a rapid increase in deposition with increasing particle size about 1 Am, although the apparent "rate" of deposition increase with size is not the same. Thus, in humans, deposition appears to plateau somewhat for sizes >2 ,um, whereas in rodents, deposi- tion increases more rapidly. Upper respiratory deposition of particles > 1 ,u m is sometimes greater in nasal- breathing humans than in the experimental animals. This is not necessarily expected, since the nasal passages of animals are more intricate than are those in humans and should therefore be more efficient particle collectors. However, the actual observant lions may be a reflection of exposure con- ditions. Many of the experimental animals were sedated or anesthetized and therefore breathed slower than fully awake animals.

Richard B. Schlesinger C 60 - Tracheobronchial region an 10 _ 60 50 40 30 20 10 o 10 8J ' 6o1 sot ~ 40 o E 30 us o uJ 20 ~ . .... o 0~1 - Tracheobronchial region o Rat 0 Hamster · Mouse ~ Guinea pig o Dog 257 D ~^ rPulmonary region . . . ..... I . . . · .. ~ Of 1.0 rem 6C 5C z o ~ 3( - o ~ 2( rv 60 50 en 30 ~ 20 Q' l.0 ,0~ ,0 PARTICLE DIAMETER (,um) ~ u 170 ~ Human (oral inhalation) · Human (nasal inhalation) _ 60 50 _ 40 _ 30 _ 20 10 0.01 0.1 '^ - Pulmonary region o Ret 0 Hamster Guinea pig · Mouse 0 Dog O 0.01 Ti , tT, . PARTICLE DIAMETER (~m) 170 l6o I! 15° 4° 30 20 10 Figure 10 (continued). Hounam et al. 1969;Johnson and Zeimer 1971; Kanapilly et al. 1982; Landahl et al. 1951, 1952; Lippmann 1970, 1977; Lippmann and Albert 1969; Lippmann and Altshuler 1976; Martens end Jacob) 1974; McMahon et al. 1977; Moores et al. 1980; Muir and Davies 1967; Palm et al. 1956; Pattle 1961; Raabe et al. 1977, 1987; Schiller et al. 1987; Stahlhofen et al. 1981a,b; Swift et al. 1977b; Tu and Knutson 1984; Wilson et al. 1985; Wolffet al. 1981, 1982; Yeh et al. 1980. Since the dominant mechanism for deposi- tion of particles >1 ,um in the upper respi- ratory tract is impaction, low flow rates should reduce deposition efficiency. Inas- much as smaller particles can penetrate the upper respiratory tract at all flow rates, deposition for these is similar in all species. If deposition were plotted in a manner that would normalize for flow, which is not possible for most of the experimental ani- mal studies because of the lack of such data, the experimental animals would probably show greater deposition efficiency for larger particles than would humans at equivalent size/flow normalization param- eters. The extent of particle removal by the upper respiratory tract may vary depending upon whether an aerosol is mono- or poly- disperse. For example, Thomas and Raabe (1978) compared the deposition in hamsters of a monodisperse and a polydisperse aero- sol having similar median diameters (AMAD, 1.53 ,um vs. 1.87 film). The major difference was that the polydisperse aerosol deposited to a greater extent in the upper respiratory tract because of the presence of a certain percentage of larger particles that were effectively removed by impaction. Total respiratory tract deposition of the two aerosols, expressed as a percentage of inhaled amount, was the same. The less the

258 Biological Disposition of Airborne Particles deposition in the head, the greater is the amount available for removal in the lungs. Thus, the extent of removal in the upper respiratory tract may affect deposition pat- terns in distal regions. Tracheobronchial Tree. Figure 10c shows tracheobronchial deposition; the amount of data available is less than for other regions. The figure indicates that the percentage of inhaled aerosol that is removed is greater in the oral-breathing human than in the nasal- breathing dog, hamster, or rat, at least in the limited region where particle sizes over- lap. As mentioned above, a lower tracheo- bronchial deposition in experimental ani- mals may be a reflection of greater upper respiratory tract deposition. On the other hand, the differences in regional deposition may be due to differences in flow in the upper bronchial tree and/or in airway branching patterns. In all cases, especially in the experimental animals. there is no well-defined trend relating deposition to particle size, unlike the situation in the other respiratory tract regions; on the con- trary, fractional tracheobronchial deposi- tion is relatively constant over a wide par . . tlC. e size range. Pulmonary Region. . . . Deposition in the pulmonary region IS shown in figure fed. In general, deposition in humans breathing orally increases as particle size decreases, after a minimum deposition is reached at about 0.5 ,um. In nasal-breathing humans and experimental animals, deposition tends to decrease with increasing particle size. The removal of particles in more proxi- mal airways determines the shape of the pulmonary deposition curves. Increased upper respiratory and tracheobronchial deposition of particles >1 ,um results in a reduction of pulmonary deposition that oc- curs more sharply in smaller animals than in humans. This is due not to reduced efficiency of pulmonary deposition of larger particles, but to the fact that only a small fraction of these large particles reach the lower respiratory tract. Similarly, nasal breathing in humans results in less pulmo- nary penetration of larger particles; thus, there is a lesser fraction of deposition for entering aerosol than for oral inhalation. In oral-breathing humans, the peak for pul monary deposition shifts upward to a larg- er-size particle compared to nasal breathing humans, and is more pronounced. On the other hand, with nasal breathing, there is a relatively constant pulmonary deposi- tion over a wider size range, that is, 0.7-3 ,um. Pulmonary deposition is much less in hamsters and rats, which are similar to each other, than in dogs, guinea pigs, or hu- mans. However, deposition in nasal- breathing humans is less than in these other species when available data for comparable size ranges are compared. Patterns are sim- ilar for oral inhalation, although the particle size for peak deposition is greater in hu- mans than in guinea pigs or dogs. This is probably due to the more efficient removal; of larger particles in the upper respiratory tract and tracheobronchial airways of these experimental animals. Factors Modifying Deposition Various factors cause deposition patterns to differ from those in normal healthy adults, the greatest contributors to the human data base. These include exposure to airborne irritants, lung disease, growth, and aging, all of which can affect particle deposition by changing ventilation patterns and/or air- way geometry. Bronchoconstriction induced by inhaling . . . · · . . . Irritants Increases Impaction c .eposltlon In the upper airways. Thus, for example, cig- arette smokers with no clinical disease ex- hibit somewhat greater tracheobronchial deposition of tracer particles >1 ,um than do nonsmokers. As a consequence, smok- ers also exhibit a reduction in pulmonary region deposition compared to nonsmokers (Lippmann et al. 1972). There are some deposition data in disease states. In humans with chronic bronchitis, an obstructive airway disease, tracheobron- chial and upper respiratory tract deposition of particles- 1,um is quite variable, but greater than in healthy individuals (Thom- son and Short 1969; Lippmann et al. 1972). Airway obstruction associated with lung disease in humans reduces the peripheral deposition of particles and may even en- tirely eliminate deposition in some parts of

Richard B. Schlesinger 259 the lungs (Lourenco et al. 1972; Thomson and Pavia 1974~. Total deposition has been found to be lower in rodents with enzyme- induced emphysema than in normal con- trols (Hahn and Hobbs 1979; Damon et al. 1983~. This is probably due to an increase in alveolar size, resulting in greater dis- tances to deposit on a surface and a con- comitant reduction in pulmonary region deposition efficiency (Brain and Valberg 1979~. There are some data on the effects of fibrotic disease on deposition. Heppleston (1963) found that inhaled hematite particles deposited more distally in rats with coal- or silica-derived pneumoconiosis than in nor- mal animals. On the other hand, Love and coworkers (1971) found no difference in the total respiratory tract deposition of 1-,um particles in coal workers with simple pneu- moconiosis compared to normal people. Most particle deposition studies in hu- mans are performed with young to middle- aged adults, and few data are available on the growing lung. The available informa- tion is based on estimates of the influence of anatomic and ventilatory changes upon deposition during postnatal growth, ob- tained by using assumed respiratory pa- rameters and mathematical particle deposi- tion modeling techniques in conduction with actual child lung morphometric values or scaled versions of available adult mor- phometric models (see, for example, Crawford 1982; Hofmann 1982; Martonen 1985; Phalen and Oldham 1985; Phalen et al. 1985; Phalen 1987~. These studies sug- gest that the relative effectiveness of the major deposition mechanisms may differ at various times in the growth of the individ- ual and that this, in turn, may alter the pattern of regional particle deposition. Thus, all age groups may not have the same distribution of deposition after exposure to the same particles. Although the results of the modeling studies are not consistent in terms of which regions or specific age groups diner, they all suggest that deposi- tion efficiency, in at least some regions, is greater in children than adults. Taking into account the greater ventilation per unit body weight in children, the deposition fractions in certain regions could be well above those measured in adults. Since there are also regional differences in clearance rates, it follows that the dose to specific lung compartments will vary with age from newborn to adult. There are no systematic data that would allow an analysis of deposition in the ag- ing lung, that is, between adulthood and senescence. There are also few data on deposition differences according to gender. Available evidence indicates that under equivalent inspiratory conditions, total res- piratory tract and tracheobronchial deposi- tion of particles with Dae from 2.5 to 5 ,um, inhaled orally at rest, is similar in men and women (Pritchard et al. 1987~. However, women's smaller-diameter airways result in higher flow rates and, hence, more im . . . pactlon in t be upper respiratory tract, re- sulting in less deposition in the pulmonary region. This suggests that as particle size increases, women (and perhaps children) may be at less risk from material in pulmo- nary airways but at a greater risk from deposition in the upper respiratory tract and tracheobronchial tree. vocalized Patterns of Deposition Specific patterns of enhanced local deposi- tion within various regions of the respira- tory tract are important to consider, since tissue dose depends on the surface density of deposited particles. The occurrence of non- uniform deposition suggests that the initial dose delivered to specific sites may be greater than that occurring if a uniform density of surface deposit is assumed. This is especially important for inhaled particles, such as irri- tants, that affect tissues on contact. In the human upper respiratory tract, enhanced deposition may occur in the lar- ynx, oropharyngeal bend, and soft palate (Swift 1981~. Deposition is also nonuni- form in the nasal passages; varying relative amounts occur in the anterior and posterior regions, depending largely on particle size (Itoh et al. 1985; Swift and Proctor 1987~. The change in airflow direction at the ves- tibule in the nasal passages, together with the fact that it is an area of high velocity, produces locally enhanced deposition pos . . . . terror to thus region.

260 Studies in models and hollow casts of the human upper tracheobronchial tree have shown that deposition of aerosols > 1 ,um is not homogeneous. Entrance conditions produced by the larynx result in enhanced deposition in the upper trachea. At bron chial bifurcations, deposition is greatly en hanced relative to the rest of the airway length (Schlesinger et al. 1982; Cohen et al. 1987~. This occurs by impaction during inspiration, although deposition is also en hanced downstream of bifurcations during exhalation (Schlesinger et al. 1983a). En hanced deposition of submicrometric par ticles at bifurcations also occurs (Cohen et al. 1987~; since this size aerosol is not B subject to impaction, the effect is probably from turbulent diffusion. The experimental conditions used in the numerous microdistribution studies varied widely, yet the relative distribution of en hancement among the airways was quite similar. This suggests that within the larger bronchi, local patterns of deposition may be fairly insensitive to particle size and airflow rate. Measurements in hollow hu man airway casts have also shown that the proportional distribution of deposition in specific airways is relatively constant over a wide range of particle sizes and overall deposition efficiencies (Schlesinger and Lippmann 1978~. In addition, inhalation studies with rodents indicate that the dis tribution of deposition in the various lobes of the lungs is also relatively constant over a range of particle sizes and different total lung deposition efficiencies (Raabe et al. 1977~. There are few data on local deposition patterns for distal airways. Available infor mation is based on examination by micros copy of tissues after in viva exposures of experimental animals (Holma 1969; Brody and Roe 1983~. These studies indicate that bronchiolar and alveolar duct bifurcations are preferential sites for deposition of a wide range of particles small enough to reach these regions. Differences in the geometry of airways in humans and other species may result in differences in the microdistribution pat terns of particle deposition, a factor that should be accounted for in extrapolation Biological Disposition of Airborne Particles A ~-it< ~ /-~ '<I< ~// ~ Figure 11. Location and relative intensity of en- hanced tracheobronchial particle deposition for (A) inspiratory flow; and (B) expiratory flow, in humans (a) and nonprimate laboratory animals (b). (Adapted with permission from Lippmann and Schlesinger 1984.) modeling. For example, nasal turbinates of rodents are more complex than those of primates and, as a result, the bulk of im- paction-dominated deposition occurs more anteriorly in the nasal passages of rodents (Gooya and Patra 1986; Schreider 19861. Unfortunately, there are no other data to relate geometry to microdeposition. Spec- ulated differences in the site and extent of localized deposition in the tracheobronchial tree are depicted in figure 11. Mathematical Modeling Mathematical models are needed to predict deposition sites and efficiencies since it is not possible to study all conditions of ex- posure experimentally. A mathematical model relates the main factors that control deposition to various geometric parameters

Richard B. Schlesinger 261 and is used to predict the mean probability of particle deposition in the respiratory tract. Although most models have been designed for assessing deposition of spher- ical particles in humans, some have been developed for experimental animals (Kli- ment et al. 1972; Kliment 1973, 1974; Schreider and Hutchens 1979; Schum and Yeh 1980). The first mathematical treatment of re- gional particle deposition in humans was performed by Findeisen (1935~. This was later refined by others (Landahl et al. 1951, 1952; Beeckmans 1965; Task Group on Lung Dynamics 19661. Because of their very nature, . . . these analytical models adopted assumptions and idealizations of almost all aspects of the respiratory tract and of particle dynamics. This simplifica- tion resulted in the loss of some important characteristics of the real system and often limited their ultimate usefulness and reli- ability. When compared to results from human experiments, these early models tended to overestimate pulmonary and un- derestimate tracheobronchial deposition (Mercer 1975~. They were, however, very useful in quantitating the influence of vari- ous controlling parameters on deposition. One of the major components of any deposition model, and one subject to the greatest oversimplification, is the represen- tation of airway geometry. Most of the early predictive models made use of a very simple stylized lung structure. Recently, however, more realistic anatomic descrip- tions have become available, some devel- oped specifically for use in deposition anal- yses and others easily adapted for such applications. As discussed earlier, some of these are symmetrical, others asymmetri- cal. Since the actual human bronchial tree is asymmetrical, and because the amount of deposition depends upon the path length over which the inhaled aerosol passes, re- alistic computations require consideration of asymmetry. In order to assess the effect of anatomic structure, Yu and Din (1982) calculated . . . . . c .eposlt1on in humans, using venous sym- metrical and asymmetrical geometries, and compared results to experimental data. They found that predicted total deposition did not differ greatly from geometry to geometry, and all compared reasonably well with experimental values. However, predicted regional deposition was quite sensitive to the particular geometry used. Since the anatomic models are generally derived from examination of single casts, they reflect, to some extent, actual interin- dividual structural variability. These results may provide the reason for variations from individual to individual in deposition ex- periments, even under identical breathing conditions. The sensitivity of predicted deposition to the specific anatomic model has also been noted by others (Martonen and Gibby 1982~. Another drawback of analytical models is the oversimplification of airflow pattern, a necessity since there are no exact expres- sions for flow dynamics in noncylindrical, tapering tubes that undergo repeated branchings and often have asymmetrical, nonlaminar flow profiles. Analytical mod- els generally assume laminar flow, no dis- turbances produced by bifurcations, and uniform ventilation of airways. In addition, many assume a constant velocity of air . . . . . . c luring Inspiration anc . expiration. Any predictive model must also contain expressions for deposition probability. However, equations for deposition within a realistic geometry and flow pattern are not available. Thus, semiempirical expres- sions based upon analyses of simplified analogues of sections of the bronchial tree are often used. For example, impaction expressions are often obtained from the analytical solution to the equation of mo- tion of a particle in ideal flow in a bent tube; diffusion expressions are obtained from the analytical solution for flow in an infinitely long, horizontal tube with ideal flow; and sedimentation expressions are obtained from the solution for deposition along a long, horizontal tube. Recent mathematical deposition models have increased in sophistication and flexi- bility. Some allow for variations in air velocity, mode and pattern of breathing, polydispersity, hydroscopic growth, and even for changes in linear airway dimen- signs over the breathing cycle (see, for example, Taulbee and Yu 1975; Ferron

262 Biological Disposition of Airborne Particles 1977; Din and Yu 1983; Egan and Nixon 1985~. Some also include a more realistic treatment of the upper respiratory tract (Scott et al. 1978; Yu et al. 1981; Yu and Din 1982~. When predictions from these recent models are compared to experimental data, there is more often agreement for total than for regional deposition. However, given the complexity of the respiratory tract and inter- subject variability, this is not surprising. A relatively recent approach to modeling in humans is dimensional analysis, in which deposition is related to some dimensionless parameter. Heyder and coworkers (1980a) formulated a parameter that is a function solely of particle size and flow rate and upon which total deposition was dependent; single parameters for regional deposition have been reported by Rudolf et al. (1987~. Because of the importance of drawing conclusions about humans from experi- ments with animals, special attempts have been made to develop methods for direct interspecies extrapolation. Stauffer (1975) used dimensional analysis to develop scal- ing factors based on particle physics and the assumption of a geometric similarity among all mammalian lungs. He predicted that interspecies particle deposition proba- bilities would be similar for sedimentation but a function of body weight for diffusion. McMahon and coworkers (1977) attempted to scale the collection efficiency of the respi- ratory tract in different species, based on inhalation studies in mice, hamsters, rats, rabbits, and dogs. They concluded that the overall collection efficiency of the lung would be independent of body size (this is essentially what is observed in figure lOa). Research Recommendations There is a considerable body of data on the deposition of inhaled aerosols in humans and experimental animals. We also have a fairly good understanding of some of the factors that control deposition. But our knowledge in certain critical areas is still not adequate. · Recommendation 9. Particle removal in the human upper respiratory tract should be assessed experimentally for oral and nasal breathing as should the influence of breathing mode on deposition in other re- gions of the respiratory tract. Information on removal of particles in the upper tract will allow the prediction of appropriate starting concentrations for modeling parti- cle transport into the lungs, since particle removal in the upper respiratory tract de- termines the concentration penetrating to distal regions. It is still not well defined how the specific route of entry affects re- ~ional deposition in humans especially those with respiratory disease. No system- atic studies have been done in which oral geometry, flow, and deposition of particles have been measured during natural oral breathing, that is, without an inhalation tube or mouthpiece placed in the anterior oral passages. These types of studies will enable better interpretation of the large available data base on deposition in hu- mans, which was obtained with mouth- piece breathing. In addition, the effect of various degrees of oronasal breathing upon deposition should be assessed. Recommendation 10. Microdistribu- tion patterns of deposition should be stud- ied under a wide range of exposure condi- tions. The nonuniformity of deposition in both the tracheobronchial tree and the pul- monary region may be important factors in ultimate dose. Further assessment of mi- crodistribution is needed for incorporation of"enhancement functions" into deposi- tion models. · Recommendation 11. Regional depo- sition efficiencies should be determined for ultrafine (<0.1 Am) particles in the human respiratory tract. Much of the lack of such data is due to the difficulty in generating monodisperse aerosols in this size range, as well as in accurately detecting the generated particles. More studies are needed that eval- uate deposition in the upper respiratory tract where such small particles, if soluble, may be rapidly absorbed into the blood, as well as in the tracheobronchial tree, where increased deposition compared to larger submicrometer sizes may occur. The avail- able theoretical models appear to be incon- sistent in that predicted deposition for par- ticles in this size range depends very much on the particular model being used.

Richard B. Schlesinger 263 · Recommendation 12. The effects of anatomic variability on deposition should be analyzed systematically, and appropriate statistical descriptions developed for incor- poration into deposition models. Theoret- ical predictions and in vivo studies show a dependence of regional deposition upon morphometry, and there is interindividual variability in structural characteristics of the human lungs. Yet the significance of this variability in affecting deposition is not currently known. a Recommendation 13. Effects of spe- cific aspects of ventilation upon deposition should be determined. More data are needed with exercise breathing patterns, which may result in greater risk because of increased ventilation. More information is also needed on the relation of changes in tidal volume and breathing rate to the uniformity of deposition in the lungs. Studies should also be performed in exper- imental animals relating ventilation to dep- osition for use in extrapolation models. Recommendation 14. Deposition in sensitive subsegments of the human popu- lation, such as children, the aged, and peo- ple with chronic lung disease (for example, emphysema and bronchitis), should be ex- amined. Since children cannot be used in experimental studies, the development of deposition models based upon accurate ventilatory and morphometric information is critical. Although it is difficult to study deposition in individuals with lung disease, because of ventilatory and anatomic dys- function which result in a large variability in deposition, more studies performed us- ing well-controlled in viva testing proce- dures and/or hollow airway cast systems would provide a better basis for assessing deposition in the compromised lung. · Recommendation 15. The deposition of hydroscopic particles in the human res- piratory tract should be evaluated. Many important pollutant aerosols are hygro- scopic, and there may be substantially greater deposition during inhalation as well as exhalation compared to dry particles of the same initial size, making mathematical predictions of deposition based on nonhy groscopic particles difficult. Most calcula- tions of the growth of hydroscopic particles are based upon growth curves developed for sodium chloride or sulfate particles, and few data for other dynamic material exist. Studies of such deposition in the head, especially during nasal breathing, are needed. Recommendation 16. Intercompari- sons of regional deposition patterns among experimental animals (unsedated) and hu- mans should be made using comparable monodisperse particles over a wide size range and comparable experimental tech- niques. Most of the regional deposition data that allow any cross-species compar- ison are for particles > 1 ,um. In addition, there are no consistently applied methods for assessment of regional deposition in experimental animals and humans. "Cali- bration factors" need to be developed that may be used to relate results of toxicolo- gic studies in experimental animals to hu- man exposure assessment and health ef- fects. a Recommendation 17. Models that al- low calculation of deposition by airway generation should be expanded to other species. Coupled with data on ventilation and morphometry, this will allow better estimations of delivered dose in experimen- tal animals. Retention of Deposited Particles Retention refers to the amount of particles remaining in the respiratory tract at specific times after exposure, and is the net result of deposition and clearance. Clearance is the physical removal from the respiratory tract of particles deposited on its surfaces. Clearance Mechanisms: Basic Structure and Function Particles are cleared from the respiratory tract by several different processes, some of which are regionally distinct as shown in table 2.

264 Biological Disposition of Airborne Particles Table 2. Respiratory Tract Clearance Mechanisms Upper Respiratory Tract Tracheobronchial Tree Pulmonary Region Mucociliary transport Mucociliary transport Macrophage transport Sneezing Coughing Interstitial pathways Nose wiping and Dissolution (for soluble Dissolution (for soluble and "insoluble" blowing particles) particles) Dissolution (for soluble particles) Upper Respiratory Tract. The nasal pas- sages beyond the vestibular region are lined with a ciliated epithelium overlaid by mu- cus (see Overton and Miller, this volume, figure 1~. The mucus is produced by spe- cialized epithelial cells and submucosal glands and consists of two layers: a low- viscosity hypophase that surrounds the cilia and within which they move, and a high- viscosity epiphase lying on top of the cilia (Lucas and Douglas 1934~. The composi- tion and characteristics of mucus are de- scribed in detail by Overton and Miller (this volume). Material depositing on the mucus is cleared by movement of the epi- phase due to coordinated beating of the ., . cilia. The general flow of mucus in the ciliated nasal passages is toward the nasopharynx. In the region just distal to the Conciliated vestibule, however, mucous flow is for- ward, clearing deposited material to an area where sneezing, wiping, or blowing can occur. Soluble material deposited on the ciliated nasal epithelium will be accessible to underlying cells if diffusion through the mucus occurs at a rate faster than mucous flow. Since there is a rich vasculature in the nose, uptake into the blood can occur rap- idly. Insoluble particles deposited in the oral passages are cleared by swallowing into the gastrointestinal tract. Although there are no data on the clearance of soluble particles, oral tissue has the capacity for rapid sys- temic absorption (Swift and Proctor 1987~. In the larynx, mucus moving toward the head from the trachea passes into the hy- popharynx and is swallowed. Tracheabronchial Tree. Most of the sur- face of the tracheobronchial tree through the terminal bronchioles is lined with cili- ated epithelium overlaid by mucus, and insoluble particles are cleared primarily by the net movement of fluid toward the oro- pharynx. Some insoluble particles may tra- verse the tracheobronchial epithelium, en- tering the peribronchial region (Masse et al. 1974; Sorokin and Brain 1975), while sol- uble particles can be absorbed through the mucus into the circulation. The bronchial surfaces are not homoge- neous. For example, there are openings of daughter bronchi and islands of Conciliated squamous cells at bifurcations. Within these regions, the usual progress of mucous movement is interrupted (Hilding 1957), and clearance can be retarded. The eff~- ciency with which Conciliated obstacles are passed depends on the traction of the mu- cous layer. Pulmonary Region. A number of mech- anisms and pathways contribute to clear- ance from the pulmonary region, but their relative importance is uncertain and de- pends to some extent on the physicochem- ical properties and amount of material de- posited. The mechanisms involve either absorptive (dissolution) or nonabsorptive processes, which can occur simultaneously or at different times. Nonabsorptive clearance processes, which are outlined in figure 12, are medi- ated primarily by alveolar macrophages. These large, mononuclear cells (figure 13) . . . . Originate trom precursors In tone marrow, reach the lung as circulating monocytes, and mature in the pulmonary interstitium, from which they traverse the epithelium to reach the alveolar surface. As macrophages move freely on alveolar surfaces, they pha- gocytize, transport, and detoxify deposited

Richard B. Schlesinger Movement Within Alveolar Lumen .T Bronch~lar / Bronchial - _ Lumen Mucociliary Blanket Gl Tract Blood ad. | Deposited Particle | ~ ~ ~Passage Through Phagocytosis by Alveolar Macrophages ~Pulmonary Capillary Endothelium ~ ~ ~ t Passage Through / Phagocytos~ by Alveolar Epithelium / Inte~tRial Macrophages Interstitium //~ ~ -'1~ Lymphatic Channels 1 __ Lymph Nodes~~ , _ _ ~ - Figure 12. Flowchart of clearance pathways for particles depositing in the pulmonary region (dissolution is not included). material, which they contact by chance or by directed motion due to chemotactic factors. Macrophages normally comprise about 3 percent of total alveolar cells in healthy, Figure 13. (Top) Electron micrograph (12,000x) of an alveolar macrophage. (Bottom) Light micro- graph of an alveolar macrophage that has phagocy- tosed polystyrene latex particles. The dark area is the nucleus. 265 nonsmoking humans and in other mamma- lian species (Gehr 1984~. However, the actual count can be influenced by particle deposition. Few particles may not result in an increase in cell number. Above a certain loading, however, macrophage numbers increase in proportion to particle number until a saturation point is reached (Brain 1971; Adamson and Bowden 1981~. This increase is due to monocytic egress, prolif- eration of interstitial mononuclear cells, and/or to actual division of alveolar mac- rophages (Bowden and Adamson 1980; Blusse van Oud Alblas et al. 1983), and appears to be a generalized response that follows exposure to many types of parti- cles, although the extent differs for particles of different composition (Adamson and Bowden 1981~. Furthermore, the magni- tude of the increase is more closely related to the number of deposited particles than to the total dose by weight, so equal masses of an identical material will stimulate more macrophages if the material is delivered as many small particles rather than as fewer large ones. Particle-laden macrophages are cleared from the pulmonary region along a number of pathways. The primary route is by the mucociliary system, but the mechanisms by which cells reach it is not certain. One possibility is movement along the alveolar epithelium due to surface tension gradients between the alveoli and conducting air- ways; alternatively, locomotion could be

266 Biological Disposition of Airborne Particles directed along a density gradient, such as that produced by chemotactic factors re- leased by macrophages actively ingesting deposited material (Kilburn 1968; Sorokin and Brain 1975; Ferin 1976~. Another pos- sible route to the mucociliary system in- volves passage through the alveolar epithe- lial wall into the interstitium (Brundelet 1965; Green 1973; Corry et al. 1984; Harm- sen et al. 1985~. Macrophages could then reach the surface of ciliated airways, per- haps through small collections of lymphatic tissue that exist at the alveolar/bronchiolar junction (Macklin 1955~. Some of the cells that follow interstitial clearance pathways are probably resident interstitial macro- phages that have ingested particles trans- ported through the alveolar epithelium by endocytosis by type I pneumocytes (Brody et al. 1981; Bowden and Adamson 1984~. Particle-laden macrophages that do not clear by way of the bronchial tree may actively migrate within the interstitium to a nearby lymphatic channel or, along with uningested particles, be carried in the flow of interstitial fluid toward the lymphatic system. Passive entry into lymphatic ves- sels is fairly easy since endothelial cells are loosely connected with wide intercellular junctions (Lauweryns and Baert 1974~; lymphatic endothelium has also been ob- served to actively engulf particles from the surrounding interstitium (Leak 1980~. De- posited particles can then be translocated to the tracheobronchial lymph nodes, which often become reservoirs of retained mate- rial. Some particles subsequently appear in postnodal lymph, from which they enter the blood and may then translocate to extrapulmonary sites. Alternatively, unin- gested particles or macrophages in the in- terstitium may cross the alveolar capillary endothelium, entering the blood directly (Robertson 1980; Holt 1981; Raabe 1982~. Whatever the route to the systemic circula- tion, particle-laden macrophages as well as free particles have been found in various extrapulmonary organs (Hourihane 1965; Pooley 1974; Lee et al. 1981; LeFevre et al. 1982~. Free particles in macrophages within the interstitium can end up in perivenous or subpleural sites, where they then become trapped. The migration and grouping of particles and macrophages can lead to the redistribution of deposits into focal aggre- gates in the lungs (Heppleston 1953~. The specific clearance route for particles depositing in the pulmonary region may depend upon loading. Earlier reports have suggested that at low-exposure concentra- tions, most particles are removed within macrophages via the bronchial mucociliary system, whereas at higher exposure levels, a larger proportion of free particles are translocated by the lymphatic system (Ferin 1977~. More recently, however, researchers have found that the percentage of initial lung burden cleared by the lymphatic sys- tem a. fter exposure to a high particle level is the same as that after exposure to a lesser burden (Snipes and Clem 1981; Snipes et al. 1983; Lehnert et al. 1986~. Thus, some free particles are likely cleared by the lymphat- ics under most conditions of exposure. The most important mechanism for ab- sorptive clearance is dissolution. Free par- ticles that dissolve in the alveolar fluid can diffuse through the epithelium and intersti- tium into the lymph or blood, whereas particles initially translocated to and trapped in interstitial sites may undergo dissolution there. Dissolution is a major clearance route even for particles usually considered to be relatively insoluble (Mor- row et al. 1964; Mercer 1967~. The factors affecting the solubility of deposited parti- cles are poorly understood, although they are influenced by the particle's surface-to- volume ratio and other surface properties (Morrow 1973~. Some deposited material can dissolve af- ter phagocytic uptake by macrophages. For example, certain metals dissolve within the acidic milieu of phagosomes. It is, how- ever, not certain whether the dissolved material then leaves the cell. This is dis- cussed further in a subsequent section. Clearance Kinetics Kinetic data are essential for determining the dosimetry of inhaled particles. Al- though the lungs may clear deposited ma- serial completely, the time frame over which clearance occurs determines the dose

Richard B. Schlesinger 267 delivered to the lungs as well as to other organs. Tissue doses to the upper respira- tory tract and tracheobronchial tree are often limited by the rapid clearance from these regions and are thus proportional to concentration and exposure duration. On the other hand, doses from material depos- ited in the pulmonary region depend much more on the characteristics of both the particle matrix and any associated materi- als. Both the pulmonary region and the tra- cheobronchial clearance rates (that is, the fraction cleared per unit time) are well- defined functional characteristics of an in- dividual human or experimental animal when repeated tests are performed under the same conditions (Gibb and Morrow 1962; Schlesinger et al. 1978; Lippmann et al. 1980; Bohning et al. 1982~; but there is substantial interindividual variability. In addition, because of differences in experi- mental techniques and the fact that mea- sured rates are strongly influenced by the specific methodology, comparisons be- tween studies by different investigators are difficult to make. Measurement Techniques. Methods for measuring clearance have been reviewed recently by Schlesinger (1985~. Some of the techniques are identical to those used in assessing deposition, since the first mea- surement after aerosol inhalation is as- sumed to represent initial deposition. The velocity of mucous transport in the nasal passages, trachea, and main bronchi can be measured directly by monitoring inert marker particles placed on the epithe- lium, or by measuring the movement of a bolus of radioactive particles selectively de- posited within these airways or, in the case of the trachea and main bronchi, moving through them from more distal airways. The advantage of local velocity techniques is that they allow measurement in anatom- ically defined, albeit limited, airways. Be- cause of this specificity, there is no doubt about whether clearance rates altered by toxicant exposure resulted from actual al- terations in the mucociliary system or from a change in deposition pattern, a doubt not easily resolved when using whole-lung clearance assays, as discussed below. How- ever, local velocity techniques have a num- ber of disadvantages. Some marker tech . . . . . . niches are invasive, since particles may have to be selectively introduced into the airway of interest. Anesthesia, necessary in many cases, may affect the observed trans- port rates. Finally, the actual method of marker introduction can result in trauma to the airway. In a number of studies aimed at assessing the effects of inhaled toxicants upon muco- ciliary clearance, alteration in tracheal transport rate has been used as the sole end point because it is easier to measure than is whole-lung clearance. However, an overall effect cannot necessarily be inferred from a change in this index, since toxicant-induced changes in bronchial clearance are not al- ways associated with an alteration in tra- cheal transport rate. This could occur if the toxic particles are of a size too small to provide significant deposition within the trachea. The most common technique to measure whole-lung clearance uses inhalation of ra- diolabeled (nonleaching) tracer particles. The total amount of radioactivity remain- ing in the lungs at selected intervals is then measured by external detector systems. The decline in emission rate, corrected for radioactive decay, represents clearance. Various types and configurations of mobile and/or fixed-scintillation detector systems have been used, and each has its own advantages and disadvantages in terms of spatial resolution and sensitivity. One of the problems in using external monitors to assess tracheobronchial muco- ciliary clearance is that the observed clear- ance pattern depends on the initial deposi- tion of the tracer particles. This is because the techniques are indirect, and clearance rate is proportional to transit pathways. For example, an apparent increase in clearance rate after toxicant exposure could be due to a proximal shift in deposition of the tracer rather than to an effect on the clearance system itself. This presents a special prob- lem when different groups are being com- pared; for example, persons with chronic obstructive pulmonary disease tend to have greater central bronchial deposition than do

268 Biological Disposition of Airborne Particles healthy subjects for the same size tracer particles. There is, however, no basis tor any kinetic distinction between mucous transport rates measured using different particles, as long as the deposition sites are the same. The rate of mucous transport in the trachea has been found to be indepen- dent of the shape, size, or composition of the insoluble marker used to measure it (van Antweiler 1958; Man et al. 1980~. There is no a priori reason to assume that this does not hold true for transport in more distal airways as well, provided there is no toxic effect from the deposited material. Pulmonary region clearance is relatively slow, and therefore measurements should be performed over, perhaps, several months. When radioactively tagged tracer particles are used, a nuclide having a long half-life is required. In addition, since the total dose to the subject should be mini- mized, especially if humans are used, long counting times may be required to obtain statistically reliable data. Health risks may therefore rule out such long-term radioac- tive tracer clearance studies. A technique that avoids this problem is magnetopneumography (Cohen 1973~. In this procedure, the subject is exposed to magnetizable particles and, at various times, a magnetic field is applied externally to the thorax in order to magnetize the bulk of the deposited particles. After the external field is removed, a remanent field remains, which is measured with an appropriate sensor (Freedman et al. 1982~. Magneto- pneumographic techniques have some ad- vantages over radioaerosol techniques in terms of temporal and spatial resolution. Furthermore, certain information can be obtained using them that is not obtainable by other whole-animal in vivo techniques, for example, the assessment of in situ phagocytosis of tracer particles by macro- phages (Brain et al. 1987~. However, mag- netopneumography has some significant drawbacks: all sources of external magnetic contamination on the subject or on the measurement apparatus must be removed; critical positioning is required since the measurements are highly sensitive to dis- tance from the source; and there are diff~- culties in deducing actual particle distribu- tion in the lungs from the data. Fecal analysis is a technique for indirect monitoring of clearance using experimental animals that involves radioaerosols but not external monitoring. The radioactivity in feces collected at fixed intervals after expo- sure to tracer particles is measured. The fecal excretion activity curve presumably represents material cleared by the mucocil- iary system into the gastrointestinal tract and can thus be used to provide an index of tracheobronchial clearance. This technique assumes that all material cleared from the lungs is transported to the gastrointestinal tract and subsequently excreted in the feces. It is also very sensitive to feeding behavior of the animals; those that do not eat or do not excrete for a particular fraction of the sampling interval cannot be included in the analysis. Clearance of deposited particles can also be assessed in experimental animals by se- rial sacrifice at various intervals after expo- sure, followed by microscopic, chemical, or radiological analysis. Various parts of the respiratory tract or the lungs as a whole can be sampled. The measured burden plotted as a function of time provides an index of clearance. Although microscopy can provide only a qualitative assessment of particle distribution and clearance from various regions, other techniques alone or combined with microscopy allow quantita- tive determination of the material retained regionally, and without interference from material in adjacent areas. Sacrifice tech- niques have the advantage of being very sensitive, but major disadvantages are that a large number of animals is needed for statistical reliability, the intraindividual variability in clearance cannot be examined, and the effects of toxicants on the course of clearance in the same individual on different occasions or under different conditions can- not be assessed. Clearance Rates and Times. Upper Respi- ratory Tract. Nasal mucous flow rates are nonuniform. Regional velocities in the healthy adult human range from <2 to >20 mm/min (Proctor 1980), with the fastest flow in the midportion of the nasal pas- sages; average velocities for the nasal pas- sages as a whole range from 4 to 12 mm/ min (Bang et al. 1967; Phipps 1981~. The

Richard B. Schlesinger 269 resultant mean transport time for insoluble particles over the nasal passages is about 10 to 13 min (Rutland and Cole 1981; Majima et al. 1983; Stanley et al. 1985~. If soluble particles diffuse through the mucus within this time period, they become accessible to underlying epithelial cells. Particles deposited in the anterior, non- ciliated portion of the nasal passages can be cleared slowly by mucous movement; a flow rate of 1 to 2 mm/hr has been sug- gested for fluid moved by traction from more distal cilia (Hilding 1963~. Particles may take over 12 hr to be cleared by this mechanism and are usually more effectively removed by sneezing or wiping, in which case clearance may occur in under 30 min (Fry and Black 1973; Morrow 1977~. The velocity of mucous transport in the larynx has not been measured. However, it is probably about the same as that in the trachea (Swift and Proctor 1987~. Tracheobronchial Tree. Clearance of par- ticles deposited on tracheobronchial air- ways occurs by the parallel processes of mucous transport and absorption. The fraction of deposited material cleared by either of these pathways is a function of its physicochemical properties, but because of the short time frame for mucociliary clear- ance, relatively insoluble material will be cleared solely by this route. Mucous clearance occurs at different rates in different local regions; mucus moves fast- est in the trachea, and progressively slower in more distal airways. Measured rates in the human trachea range from 4 to 20 mm/min, depending upon the experimental technique used (Yeates et al. 1981a). Anesthesia and invasive procedures affect transport, result- ing in rates apparently slower than normal. Using noninvasive measurement procedures on unanesthetized, healthy nonsmokers, re- searchers have observed average tracheal mu- cous transport rates of 4.3 to 5.7 mm/min (Yeates et al. 1975, 1981b; Foster et al. 1980; Leikaufet al. 1981, 1984~. The mean mucous velocity in the human main bronchi has been found experimen- tally to be about 2.4 mm/min (Foster et al. 1980~. Although rates of mucous move- ment in smaller airways cannot be mea- sured directly, transport rates in human medium bronchi have been estimated at 0.2 loo 20 0 24-48 hr. TIME POSTEXPOSURE Figure 14. Schematic representation of tracheo- bronchial clearance after exposure to tracer particles. Particles remaining beyond 24 to 48 hr (shaded area) are assumed to have deposited in the pulmonary region. to 1.3 mm/min, and those in the most distal ciliated airways as low as 0.001 mm/ min (Morrow et al. 1967b; Yeates and Aspin 1978~. The total duration of bronchial clearance or some other time parameter is often used as an index of mucociliary function. In healthy, nonsmoking adult humans, 90 percent of insoluble particles depositing in the tracheobronchial tree will be cleared within 2.5 to 20 hr after deposition. The actual time depends on the individual sub- ject and the size of the tracer aerosol used, which affects the depth of deposition and subsequent pathway length for removal (Albert et al. 1973~. Clearance will be 99 percent completed by 48 hr after deposition (Bailey et al. 1985a). In humans, normal tracheobronchial mucociliary clearance exhibits a two-phase pattern (figure 14~: a short initial phase characterized by rapid clearance lasting a few hours, followed by a slower, second phase extending until 24 to 48 hr after exposure. These probably represent clear- ance of the tracer particles deposited in the "upper" and "lower" tracheobronchial tree, respectively. As the size of the tracer particles is reduced, resulting in more distal deposition, there is an increase in the frac- tion of total tracheobronchial clearance which is accounted for by the slower phase. Although some portion of the above clear- ance pattern may include rapid early clear- ance of material deposited in the pulmo- nary region, the contribution of this to the apparent bronchial clearance rate appears . . mlnlma .

270 Biological Disposition of Airborne Particles Studies in rodents have shown that a small fraction of insoluble material is re- tained for prolonged periods within the upper respiratory tract or tracheobronchial tree (Patrick and Stirling 1977; Watson and Brain 1979; Gore and Patrick 1982~. In humans, it has been estimated that the average residence time in bronchial tissue of insoluble particles derived from cigarette smoke is 3 to 5 months (Redford and Martell 1977~. Soluble material may also be retained in ciliated airways for long periods because of binding to cells or specific mac- romolecules (Boecker et al. 1983~. The mechanisms underlying the long- term retention of insoluble particles is un- known. It may involve endocytosis by epithelial cells with subsequent transloca- tion into deeper tissue or merely passive movement into the tissue (Sorokin and Brain 1975; Watson and Brain 1979; Gore and Patrick 1982~. In addition, long-term tracheobronchial retention patterns for in- soluble particles are not uniform. Enhanced retention occurs at bifurcation regions (Redford and Martell 1977; Henshaw and Fews 1984; Cohen et al. 1987), which may be the result of greater deposition as well as ineffective mucous clearance. Because of this nonuniformity, doses calculated using uniform surface retention density may be misleading. Pulmonary Region. Particles are cleared from the pulmonary region by a number of pathways and mechanisms. Their effective- ness depends on the nature of the particles, but just what this dependence is has not been completely resolved. Consequently, the kinetics of clearance from the pulmo- nary region are not definitively under- stood, although particles deposited there generally remain longer than do those de- posited in ciliated airways. Data on clear- ance rates in humans are limited, and those for experimental animals (and humans) vary widely because of different properties of the particles in the various studies. Many of these studies used high concentrations of particles, which may of itself have inter- fered with normal mechanisms, producing rates different from those that would occur at lower exposure levels. Pulmonary region clearance data appear to fit an exponential model, and each com- ponent is believed to represent removal by a different mechanism or pathway (Casarett 1972~. For example, an initial fast phase having a clearance half-time of about 2 to 6 weeks presumably represents rapid clear- ance by macrophages; an intermediate phase, with a half-time of months, may represent macrophage clearance by interstitial path- ways; and a phase of prolonged clearance with a half-time of months to years repre- sents removal by dissolution. Rates of re- moval by dissolution are extremely variable but likely dominate the long-term retention of relatively insoluble particles. Rates that correspond to the various clearance phases can only be obtained if clearance is measured until all the deposited particles are removed from the lungs. This is usually not possible, and many studies are terminated when the radioactivity levels of retained particles fall below detectable limits. Clearance of inert insoluble particles in healthy, nonsmoking humans has been observed experimentally to consist of two phases: the first has a half-time measured in days, and the second in hundreds of days (Bailey et al. 1982; Bohning et al. 1982; Philipson et al. 1985~. Table 3 summarizes data from numerous studies for the half- times of the longer, second phase of clear- ance. Wide variations in clearance times indicate a dependence upon the nature of the material being cleared. For example, when polydisperse aerosols are used, vari- ous size fractions clear by different routes and, thus, with varying rates (Snipes et al. 1984a,b). Different clearance rates have also been observed when using different-size particles (Morgan and Holmes 1980; Bailey et al. 1982~; but if dissolution is accounted for, mechanical removal to the gastrointes- tinal tract and lymph nodes is independent of particle size (Snipes et al. 19831. There is also considerable intersubject variation in the clearance rates of similar particles, which increases with time postexposure (Bailey et al. 1985a; Philipson et al. 19851. This large difference in pulmonary region clearance kinetics among different individ- uals suggests that equivalent exposures to insoluble particles will result in differences in respiratory tract burdens.

Richard B. Schlesinger 271 Table 3. Long-Term Particle Clearance from the Pulmonary Region in Human Nonsmokers Clearance Tracer Particle Half-Time Material Size (,um) (days) Reference Polystyrene latex 5 150-300 Booker et al. (1967) Polystyrene latex 5 140340 Newton et al. (1978) Polystyrene latex 0.5 33-602 Jammet et al. (1978) Polystyrene latex 3.6 296 Bohning et al. (1982) Teflon 4 200-2,500 Philipson et al. (1985) Aluminosilicate 1.2 330 Bailey et al. (1982) Aluminosilicate 3.9 420 Bailey et al. (1982) Iron oxide (Fe2O3) 0.8 62 Morrow et al. (1967a,b) Iron oxide (Fe2O3) 0.1 270 Waite and Ramsden (1971) Iron oxide (Fe304) 2.8 70 Cohen et al. (1979) a Half-time of clearance for the slowest phase observed. Even less is known about relative rates along specific pathways than about overall pulmonary region clearance kinetics. After deposition, the uptake of particles by alve- olar macrophages is very rapid, unless the particles are cytotoxic (Lehnert and Mor- row 1985; Naumann and Schlesinger 1986~. The actual rate of subsequent clearance of these cells is not certain; perhaps 5 percent or less of their total number is translocated from the lungs each day (Masse et al. 1974; Lehnert and Morrow 1985~. Uningested particles may penetrate into the interstitium within a few hours after deposition (Sorokin and Brain 1975; Ferin and Feldstein 1978; Brody et al. 1981~. The amount transported via transepithelial pas- sage seems to increase as particle loading increases, especially when loading sur- passes the level at which the number of macrophages saturate (Ferin 1977; Adam- son and Bowden 1981~. Similarly, a depres- sion of phagocytosis by toxic particles may increase the number of free particles in the alveoli, enhancing removal by other routes. Free particles or those within alveolar mac- rophages reach the lymph nodes within a few days after deposition (Harmsen et al. 1985; Lehnert et al. 1987~. However, most clearance by the lymphatic system is very slow (Sorokin and Brain 1975; Ferin 1976~. Soluble particles deposited in the pulmo- nary region are cleared rapidly by absoro- tion through the epithelial surface ~nto the blood, but there are few data on dissolu- tion and transfer rates in humans. The rate does depend upon the size of the particle, with smaller ones clearing faster than larger ones. Some dissolved material may be re- tained in lung tissue because of binding with cellular components, prevent~ng ~t from passing into the circulation (Cuddihy 1984~. Comparative Clearance Kinetics and Mod- eling. The retention of certain materials cannot be studied experimentally in hu- mans, so experimental animals must be used. Since dosimetry depends upon clearance rates and routes, adequate toxicologic assess- ment necessitates relating clearance kinetics in animals to that in humans. Although the basic mechanisms of respiratory tract clear- ance are similar in humans and most other mammals, regional clearance rates vary sub- stantially among species, even for similar particles deposited under comparable expo- sure conditions. It is likely that dissolution rates and rates of transfer of dissolved sub- stances into blood are related solely to the properties of the material being cleared and are essentially independent of species (Cud- dihy et al. 1979; Griffith et al. 1983; Bailey et al. 1985b). On the other hand, different rates of mechanical transport, such as mac- rophage clearance from the pulmonary re- gion (Bailey et al. 1985b) or mucociliary transport in conducting airways (Felicetti et al. 1981), are found, resulting in species dependent rate constants tor these c~earance pathways. Differences in regional (and per- haps total) clearance rates among species

272 Biological Disposition of Airborne Particles are probably due to these latter processes. Accordingly, respiratory tract clearance in humans can be predicted by using dissolu- tion rates in experimental animals and me- chanical clearance rates in humans, as long as lung damage or binding to lung mole- cules has not occurred (Bailey et al. 1985b). Another approach used to predict clear- ance in humans is mathematical modeling. Various theoretical and empirical models have been developed to predict regional as well as total respiratory tract clearance of particles. Most of these models have been used for dosimetry of inhaled radionuclides (see, for example, International Commis- sion on Radiological Protection 1959, 1972; Bailey and James 1979~. In these models, fractional allocations are made between mechanical clearance processes and dissolu- tion on the basis of properties of each specific material being assessed. Mathematical models have also been de- veloped that describe overall tracheobron- chial clearance patterns by calculating mu- cous transport rates in each generation (Yeates and Aspin 1978; Lee at al. 1979; Yu et al. 1983~. These models make various assumptions: for example, all mucus is produced in the terminal airways; no fluid reabsorption occurs; or the thickness of the mucous layer is constant in all airways. In addition, the overall clearance rates gener- ated by some of these models are very sensitive to the rates assumed in the small- est airways; this is because this region has the slowest rate and a large surface area, and the models assume transport rates to be inversely proportional to surface area or circumference. Only limited testing of the accuracy of these models is possible because actual transport rates are not known for distal airways. Thus, predicted results are often compared to actual observations for total time of tracheobronchial clearance and to values for mucous transport rates in the trachea. Internal adjustments are made so that the predicted time is the same as that observed experimentally. Factors Modifying Clearance A number of host and environmental fac- tors modify normal clearance patterns, af- fecting the dose delivered by exposure to inhaled particles. These factors include ag- ing, gender, work load, disease, and irri- tant inhalation exposure. In many cases, however, their exact role is not resolved. The evidence for aging-related effects on mucociliary function in healthy individuals is contradictory, with studies showing ei- ther no change or a slowing in clearance with age after maturity (Goodman et al. 1978; Yeates et al. 1981a). One problem is that it is difficult to determine whether an apparent decrement in function is due to aging alone, or to long-term, low-level ambient pollutant exposure (Wanner 1977~. There are no data for changes in overall pulmonary region clearance related to ag- ing. Functional differences have been found between alveolar macrophages from ma- ture and senescent mice (Esposito and Pen- nington 1983), although no age-related de- cline in human macrophage function has been seen (Gardner et al. 1981~. There are not sufficient data to assess changes in clearance in the growing lung. Nasal mucociliary clearance time in a group of children (average age 7 yr) has been found to be about 10 min (Passali and Ciampoli 1985), which is within the range for adults. There is one report of bronchial clearance in 12 yr olds, but this study was performed in hospitalized patients (Huh- nerbein et al. 1984~. In terms of gender, no difference in nasal mucociliary clearance has been observed between male and female children (Passali and Ciampoli 1985), nor in tracheal trans- port rates in adults (Yeates et al. 1975~. Slower bronchial clearance has been noted in male compared to female adults, but this was attributed to differences in lung size rather than inherent gender differen- ces in transport velocities (Gerrard et al. 1986~. The effect of increased physical activity on mucociliary clearance is also unresolved, with the available data indicating either no change or an increase with exercise (Wolff et al. 1977; Pavia 1984~. There are no data relating changes in pulmonary region clear- ance to increased activity levels, but Val- berg and coworkers (1985) found that CO2-stimulated hyperpnea had no effect on early pulmonary clearance and redistribu- tion of particles.

Richard B. Schlesinger 273 Various diseases are associated with al- tered clearance. Nasal mucociliary clear- ance is prolonged in humans with chronic sinusitis, bronchiectasis, or rhinitis (Ma- jima et al. 1983; Stanley et al. 1985), and with cystic fibrosis (Rutland and Cole 1981~. Bronchial mucous transport may be impaired in people with bronchial carci- noma (Matthys et al. 1983), chronic bron- chitis (Vastag et al. 1986), asthma (Pavia et al. 1985), and various acute respiratory infections (Lourenco et al. 1971b; Camner et al. 1979; Puchelle et al. 1980~. In some of these conditions, coughing may enhance mucous clearance but is generally effective only if excess secretions are present. Rates of pulmonary region particle clear- ance appear to be reduced in humans with chronic obstructive lung disease (Bohning et al. 1982), and the viability and functional activity of macrophages has been found to be impaired in human asthmatics (Godard et al. 1982~. Reduced clearance from the pulmonary region of experimental animals with viral infections has also been observed (Cresia et al. 1973~. On the other hand, Tryka and coworkers (1985) found in- creased pulmonary clearance in hamsters with interstitial fibrosis. Damon and co- workers (1983) observed no clearance dif- ference in rats with emphysema. Hahn and Hobbs (1979), however, found that the copresence of inflammation resulted in pro- longed retention. Inflammation may en- hance the penetration of free particles and macrophages through the alveolar epithe- lium into the interstitium by increasing the permeability of the epithelium and the lymphatic endothelium (sorry et al. 1984~. Cigarette smoking in humans is associ- ated with persistently slowed mucociliary clearance in both the nasal passages and the tracheobronchial tree (Lourenco et al. 1971a; Camner and Philipson 1972; Good- man et al. 1978; Stanley et al. 1984), and the extent of decline appears related to the amount of smoking (Vastag et al. 1986~. Smokers can also exhibit specific clearance abnormalities, including intermittent retro- grade mucous flow in the trachea and in- termittent periods of stasis that alternate with abrupt drops in particle retention in the bronchi (Albert et al. 1971, 1973~. The rate of particle clearance from the pulmo- nary region also appears to be reduced in heavy cigarette smokers (Cohen et al. 1979; Bohning et al. 1982~. In addition to cigarette smoke, other inhaled irritants have an effect on mucocil- iary clearance function in humans as well as experimental animals (Wolff 1986~. Single exposures to a particular material may in- crease or decrease the overall rate of tra- cheobronchial clearance, depending upon the exposure concentration. Although al- terations in clearance rate following single exposures to moderate concentrations of irritants are transient lasting <24 hr repeated exposures may persistently retard clearance. The effects of irritant exposure may be enhanced by exercise, or by coex- posure to other materials. Acute and chronic exposures to inhaled irritants can also alter clearance from the pulmonary region. For example, nitrogen dioxide (NO2), ozone (03), sulfuric acid (H2SO4), and some metals (for example, cadmium) have been shown to change the rate of tracer particle clearance (Ferin and Leach 1977; Oberdorster and Hochrainer 1980; Driscoll et al. 1986; Schlesinger and Gearhart 1986~. Clearance may be acceler- ated or depressed, depending upon the spe- cific material and/or length of exposure. Alterations in alveolar macrophage func- tion may underly some of the observed changes, since numerous irritants have been shown to impair the functional prop- erties of these cells (Gardner 1984~. Specific macrophage properties, which include phagocytosis and mobility, allow them to adequately perform their role in clearance. However, the relation between these characteristics and overall clearance is not certain. For example, in comparisons among a number of species, no positive correlation was found between macrophage mobility and clearance rate since slower movement was often associated with an ac- celeration in clearance (Metivier 1984; Nau- mann and Schlesinger 1986~. Research Recommendations ~ Recommendation 18. Interspecies com- parisons of short-term (mucociliary) and long-term (pulmonary) clearance kinetics

274 Biological Disposition of Airborne Particles . . should be made, with an emphasis on mechanical processes, using equivalent in- soluble particles and experimental tech- niques. These studies should assess the effects of exposure characteristics- for ex- ample, particle size and mass concentra- tion on retention patterns, and should ex- amine the effects of differences in lung anatomy. The use of equivalent experimen- tal conditions is essential to avoid differ- ences in the results due to lack of standard- ization in measurement techniques and particle characteristics. Newer, nonradio- active experimental techniques should be used to expand the data base on long-term pulmonary region clearance kinetics in hu- mans. Recommendation 19. The long-term fate of particles in conducting airways should be examined. To determine whether spe- cific cell types preferentially handle certain particles or to assess whether cells critical in clearance change during their normal activ- ity, these studies should include morpho- logical techniques to precisely locate sites of particle deposition and retention. Recommendation 20. Studies should be undertaken on the pathways and cir- cumstances by which macrophages and free particles are removed from alveoli to re- gions of potential long-term retention in the lung, such as peribronchial and peri- vascular sites, as well as lymph nodes. Effects of particle loading should be con- sidered, since it is not clear how this affects transport by various routes. Recommendation 21. Alveolar mac- rophages should be characterized. There is a need to study how alterations in cell functional properties are manifested in changes in overall clearance patterns, so as to determine whether or not specific func- tional changes induced by inhaled materials critically affect the cell's ability to partici- pate in lung defense. The effects of various characteristics of exposure (for example, mass loading), on phagocytosis, mobility, release of chemotactic factors for neutro- phils, or production of other mediators, requires further examination. In addition, since macrophages are not homogeneous, and different subsets exhibit functional dif- ferences, more work is needed to charac- terize the heterogeneity of macrophages recovered after particle exposures. Recommendation 22. In vitro effects on macrophages should be related to those produced in viva. Dose to cells is better defined in in vitro studies, but calibra- tion factors are needed to relate exposure concentration to actual target tissue dose in extrapolating in vitro to in viva results. Recommendation 23. The effects of ex- ogenous factors on retention should be deter- mined. For example, exercise may alter dep- osition pattern, but how clearance and ultimate retention are affected is not known. ~ Recommendation 24. Mucus should be characterized as to average and regional variations in thickness, physicochemical properties, and synthesis rates. Data are needed on humans as well as most experi- mental animals. ~ Recommendation 25. Fate of soluble particles in the tracheobronchial tree should be determined. There are uptake data for the nasal passages but not for other con . . c ~uctlng airways. Recommendation 26. Animal models that mimic human respiratory disease should be developed further. These models should be used to examine clearance and retention of potentially sensitive subseg- ments of the human population. Recommendation 27. Clearance ki- netics of the growing lung and the aging lung should be studied. Studies of muco- ciliary clearance and pulmonary region clearance are needed; when combined with deposition studies, a comprehensive picture of defense capabilities in the young and elderly segments of the population can be developed. Animal models can be used to some extent, since it is difficult in human populations to separate true aging effects from certain environmental influences, such as air pollution.

Richard B. Schlesinger 275 Recommendation 28. Gender-related differences in the disposition of inhaled particles in humans should be investigated. A comparison of the efficiency of defense mechanisms is needed to determine whether, as has been suggested, doses in males and females may indeed differ. Disposition of Vehicular Particulate Emissions This section addresses the fate of particles- specifically, carbon, metals, and sulfates- emitted in vehicular exhaust. Gasoline and diesel engines produce carbon, but much greater amounts are released by diesels. These particles contain adsorbed organic compounds, the fate of which is discussed by Sun, Bond, and Dahl (this volume). Metals present in fuel are released in the exhaust in amounts that differ with the type of fuel. Sulfates, primarily sulfuric acid, are produced by diesel and gasoline engines on approximately the same scale. Diesel Exhaust Particles Diesel exhaust particles have a diameter (MMD) of 0.2 to 0.3 ,um and a dense carbonaceous core. They usually contain adsorbed organic matter, but this section discusses the general fate of inhaled diesel particles without regard to specific ad- sorbed components. Available data are based largely on inhalation studies using rodents exposed to diluted diesel exhaust containing particles, usually at predeter- mined concentrations, as well as various gases. About 15 to 20 percent of diesel particles inhaled by rodents are initially deposited (Chan et al. 1981; Dziedzic 1981; Lee et al. 1983~; this value is quite close to that for total respiratory tract deposition of similar- sized particles in humans (figure lOa). Al- though there are no actual experimental studies in humans, diesel particle deposi- tion in different age groups under various gional deposition vary with age. For nasal breathing at rest, total and pulmonary dep- osition in infants and children are predicted to be greater than that in adults, with . . . maximum c reposition occurring at a tout two years of age. Because of its particle size, diesel particle deposition is predicted to be unaffected by the mode of inhalation or by the frequency of respiration but should increase with increasing tidal vol ume. The clearance routes for diesel particles depend on their regional deposition. The fraction deposited in the tracheobronchial tree, about 40 to 50 percent of the initial deposit, is rapidly cleared by mucociliary transport in about one to two days (Chan et al. 1981; Lee et al. 1983), although there is some evidence that diesel particles depress mucociliary clearance rates (Battigelli et al. 1966~. Most of the particles that reach the pulmonary region are phagocytized by macrophages (Barnhart et al. 1981; White and Garg 1981), and the numbers of these cells seem to increase in relation to the rate of particle entry into the lung rather than to the total cumulative exposure (Strom 1984; Mauderly et al. 1987~. Although diesel par ticle exposures to levels up to about 2 mg/m3 do not reduce viability of macro phages, phagocytic activity has been vari ously reported to be either depressed or unaltered (Chen et al. 1980a,b; Weller et al. 1980; Barnhart et al. 1981; Castranova et al. 1985~. Diesel particles can also be taken up by type I alveolar epithelial cells (Barnhart et al. 1981~. Enhanced uptake probably occurs if the macrophages are overloaded, since the number of type I cells containing par ticles increases as particle concentration and exposure duration increase. Following deposition, diesel particles are fairly evenly distributed throughout the pulmonary region. Gradually, within mac rophages, the particles are moved from peripheral lung regions toward the termi nus of the mucociliary transport system, from where they may be cleared via the tracheabronchial tree (White and Garg breathing conditions has been estimated~ 96-i J . Blusters of particle-laden macro using mathematical modeling (Xu and Yuphages are often found at the distal ends of 1985~. Results suggest that total and re-theterminalbronchiolesafterhigh-orlow

276 Biological Disposition of Airborne Particles level exposures (Barnhart et al. 1979; Puro 1980; Garg 1985~. Aggregates of free par- ticles have been observed in focal areas of the tracheobronchial tree, perhaps because of a general depression of mucociliary clearance, local accumulation in areas of inadequate transport, or longer-term reten- tion after uptake by or through the epithe- lium. Another clearance pathway from the pul- monary region is by the lymphatic system. Free diesel particles, as well as particle- laden macrophages, have been found in parenchymal lymphoid aggregates, lym- phatic vessels, and mediastinal lymph nodes (Vostal et al. 1979~. The amount cleared along this pathway increases with increasing duration and level of exposure (Chan et al. 1981; White and Garg 1981~. The kinetics of diesel particle clearance have been examined in rodents. However, exposure concentrations were generally high, and it is not known whether the kinetics are the same when exposure levels are lower. In rats, two phases of pulmonary clearance were observed, with half-times of 6 and 80 days, respectively (Lee et al. 1983~. The faster clearance was ascribed to the mucociliary transport of particles deposited in proximal respiratory bronchioles, whereas the slower phase was ascribed to other alveolar removal processes. The ki- netics were the same with exposure to either 7 mg diesel particulate/m3 for 45 min. or 2 mg/m3 for 140 min. Guinea pigs exposed to 7 mg/m3 for 45 min showed little clearance from days 10 to 432 after exposure, even though initial deposition percentages and mucociliary clearance times were the same as in the rat. On the other hand, the clearance was found to occur at the same rate in rats and mice chronically exposed to 0.35 to 7.0 mg diesel particulate/m (Henderson et al. 1982~. It has been suggested that the observed increase in macrophage numbers after ex- posure to diesel particles should increase the pulmonary clearance rate of this mate- rial relative to clearance in nonexposed controls (Lee 1981~. Experiments do not always support this hypothesis; diesel par- ticle exposure has been associated with depressed and accelerated clearance from the pulmonary region (table 4~. Lung bur- den appears to be a critical factor affecting the overall efficiency of pulmonary clear- ance, perhaps by altering relative amounts cleared by different pathways. Diesel parti- cles may be retained in the lungs for long periods of time after exposure, with the amount increasing with increasing deposi- tion (Chan et al. 1981; Rudd and Strom 1981; Henderson et al. 1982~. A long resi- dence time provides an extended period for elusion of adsorbed material. The development of dust clusters and their residence times probably depend on exposure concentration and duration (Moore et al. 1978~. Perhaps accumulation and persistence begin, or increase, when normal clearance processes are overloaded during chronic exposures; this could occur at exposure levels lower even than those used in most studies, but there are few data at realistic concentrations. Most of the data on diesel particle disposition were obtained from chronic studies in rodents using di- luted exhaust with diesel particulate levels -0.25 mg/m3. Furthermore, the observed rates and routes of clearance could have been affected by the various combustion products, many of which are irritants, found either in the gas phase of diesel exhaust or adsorbed on particle surfaces. Metals Many metals present in motor vehicle fuel are emitted in the exhaust (Lee and van Lehmden 1973~. They are distributed in the atmosphere as individual particles or ad- sorbed onto the surfaces of other particles. Particle sizes range from submicrometer to about 2 to 3 ,um, depending on the metal. Once deposited in the respiratory tract, the disposition of a metal varies with its valence state and the compound containing it. The solubility of metals and their com- pounds in biological fluids strongly influ- ences their biological availability, utiliza- tion, and toxicity. Insoluble forms of some metals can accumulate in the lungs over time because of continuous exposure and slow systemic absorption, whereas more soluble forms are rapidly absorbed into the blood and translocated to other organs. But

Richard B. Schlesinger Table 4. Elects of Diesel Particles on Respiratory Tract Clearance Exposure Parameters Species Particle Mass Conca (mglm3) 277 Duration Effect Reference Rat 0.2, 0.99, 4.1 7 hr/day, 5 ~ pulmonary region Griffins et al. days/week clearance at 4.1 ma/ (1983) for 18 weeks m3 Rat 0.35, 3.5, 7 7 hr/day, 5 ~ pulmonary region Mauderly et al. days/week clearance at 3.5 and (1987) for 30 months 7 mg/m3 Mouse 0.35, 3.5, 7 7 hr/day, 5 v pulmonary region Henderson et al. days/week clearance at 3.5 and (1982) for 18 months 7 mg/m3 Rat 0.25, 6 20 hr/day, 2 ~ pulmonary region Chan et al. (1984) days/week clearance when 7-112 days burden ~ 6.5 ma/ m3 Rat 8, 17 3040 hr at ~ tracheal clearance Battigelli et al. 6-fur sessions (1966) Rat 17 4 hr v tracheal clearance Battigelli et al. (1966) Sheep 0.00.5 0.5 hr NC tracheal clearance Abraham et al. (resuspended (1980) particles) Hamster 4.0 Rat 2 Rat 4 Rat 4.0 95 hr/week, for 19 months 95 hr/week for 19 months 7 hr/day, 5 days/week 6 months daily, 16 months Rat 0.35, 3.5, 7 7 hr/day, 5 days/week 30 months i, pulmonary region clearance v pulmonary region clearance pulmonary region clearance; NC bronchial clearance i, pulmonary region clearance NC tracheal clearance; ~ pulmonary region clearance at 3.5 and 7 mg/m3 Muhle et al. (1987) Muhle et al. (1987) Oberdorster et al. (1984) Heinrich et al. (1981) Wolff et al. (1987) a Concentration of particles in diluted exhaust. NOTE: NC = no change; ~ = significant acceleration of clearance; ~ = significant retardation of clearance. some soluble forms can actually undergo greater retention than insoluble ones be- cause of binding to protein in the lungs. Unfortunately, most ambient measure- ments determine the total concentration of the metal and do not discriminate among different compounds or valence states. Thus, for dosimetric purposes, it is usually assumed that all compounds, whatever their source, will dissociate to some degree after deposition in the respiratory tract, releasing metal ions that will be absorbed and redistributed in the body in a similar manner. The absorption efficiency for most met- als is about 50 to 80 percent from the pulmonary region, and 5 to 15 percent from the upper respiratory tract and tra- cheobronchial tree (Natusch et al. 1974~. This may reflect the more efficient extrac- tion of metals from the smaller particles that would preferentially deposit in the

278 Biological Disposition of Airborne Particles pulmonary region, and/or the shorter resi- dence time of particles depositing on the tracheobronchial tree. After absorption from the respiratory tract, these metals will be distributed rapidly to blood-rich organs and more slowly to other organs and to fat, and will very slowly equilibrate with poorly perfused tissues (Luckey and Venu- gopal 1977~. Metals that deposit in the pulmonary region have the greatest toxic potential because of the likelihood of extended resi- dence times. The more insoluble the metal, the more likely it is to be cleared from this area by movement to the tracheobronchial tree, followed by swallowing. Systemic absorption from the respiratory tract is minimal in the course of this movement. In general, metals are absorbed less effectively from the gastrointestinal tract than from the lungs, in part because of differences in residence times (Natusch et al. 1975; Luckey and Venugopal 1977~. Thus, mate- rial processed by the gastrointestinal tract often has less toxic impact, and may also be influenced by dietary factors. Dissolution is a major clearance mecha- nism for metal particles deposited in the pulmonary region, and it may be enhanced if the particles are first phagocytized by macrophages. When deposited particles are ingested and subsequently exposed to the acidic environment of the phagosome, metal ions can be released. Studies of rabbit and human alveolar macrophages exposed in vitro to submicrometer manganese diox- ide (MnO2) particles have shown that the cells of both species were able to dissolve two to three times more of the material than was dissolved in the culture media within the same time (Lundborg et al. 1984, 1985~. Dissolved metals can then leave the macrophage, and the lungs, at rates faster than their normal dissolution rate in lung fluid. The early clearance rate of a metal can therefore vary with the form in which it is inhaled. For example, MnO2, which is insoluble in lung fluid, dissolves in the macrophage, but soluble manganese chloride (MnCl2) probably dissolves extra- cellularly and is not ingested, so deposited Mn may clear at different initial rates de- pending upon its original state (Camper et al. 1985~. Furthermore, intracellular disso- lution, by enhancing the release of metals into the cellular milieux, can be a mecha- nism for the local cytotoxic action of some phagocytosed metal particles, for example, lead (Pb) (DeVries et al. 1983~. Intracellular dissolution must therefore be considered in models of the pulmonary clearance of par- ticles and in assessment of mechanisms of differential toxicity of metal compounds. Various characteristics of macrophages have been examined by performing bron- chopulmonary ravage after in viva expo- sure to metal particles or after direct in vitro exposures. Subchronic particle inha- lations may or may not produce a nonspe- cific increase in macrophage number, de- pending upon the metal particle. For example, macrophages in rats increased af- ter exposure to nickel oxide (NiO) but not nickel chloride (NiCl2) or lead chloride (PbCl2), whereas lead oxide (Pb203) expo- sure reduced the numbers of recovered cells (Bingham et al. 1972~. Exposures of rabbit alveolar macrophages to soluble chlorides of cadmium (Cd2+), Ni2+, Mn2+, and chro- mium (Cr3+) resulted in significantly re- duced viability, with Cd2+ being the most toxic (Waters et al. 1975~. Except for Cd, these metals produced cell lysis in a roughly concentration-dependent manner and with a relative potency similar to that which characterized the change in viability. It is conceivable that the mode of cell death affects subsequent clearance pathways for a metal. If the cell dies after phagocytosis but does not lyse, the particle-laden cell may be cleared by the mucociliary system. Alter- natively, phagocytosis-induced cell lysis would liberate particles for systemic ab- sorption or reengulfment. Examination of the viability of rabbit alveolar macrophages exposed in vitro to fly ash with adsorbed oxides of Pb, Ni, or Mn showed Pb to be the most cytotoxic, with Mn and Ni exhibiting somewhat lower toxicity (Aranyi et al. 1977~. At any specific particle concentration, the effect on viability decreased with increasing particle size over a 2- to 8-,um range, even though the percentage of metal in the ash was the same for all sizes. This finding was ascribed both to the fact that bigger particles were

Richard B. Schlesinger 279 ingested in fewer numbers than were smaller ones and that, once ingested, the larger particles presented less surface area to the phagosomal contents, resulting in less leaching of metal ions. Thus, the cytotox- icity of a metal at a specific concentration depends upon the size of its associated carrier particle and, conversely, the nature of the carrier particle influences the fate and effects of the compound it transports into the cell. The rate of phagocytosis for equivalent- sized particles depends upon the nature of the adsorbed surface coating. Rabbit alve- olar macrophages exposed to 5 ,um Teflon particles coated with various metals pha- gocytosed those with carbon or Cr to a greater degree than those coated with Pb, Mn, or silver (Ag) (Camper et al. 1973, 1974~. Direct in vitro exposure to Ni2+ Cd2+, vanadate (VO3-), Mn2+, or Cr3+ impaired the phagocytic ability of macro- phages (Graham et al. 1975; Waters et al. 1975; Castranova et al. 1980~; in vivo ex- posure to MnO2 also depressed phagocyto- sis (Bergstrom 1977~. The effect may de- pend upon the concentration of the metal. In rats exposed to cadmium chloride (CdCl2) at 1.5 or 5 mg/m3, the lower level stimulated phagocytosis whereas the higher level depressed it (Greenspan and Morrow 1984~. Reduced phagocytosis could result in increased lung burdens of the offending metal or of other deposited substances. The effects of metals on various cytologic end points may not be equal. For example, Ni2+ impaired phagocytosis at a concentra- tion much lower than that required to de- crease viability, whereas Cd2+ and Cr3+ de- pressed phagocytosis as well as viability at comparable concentrations (Waters et al. 1975~. Concentrations of VO3- that caused macrophage lysis did not reduce phagocyto- sis in the surviving cells (Graham et al. 1975~. Thus, examination of viability as the only toxic end point may not be appropriate. Other functions may be more sensitive and may also play a role in determining the ultimate disposition of deposited particles. Examples of the disposition of selected Lead. Until recently, Pb was the metal of greatest concern, but as the amount of Pb in gasoline has been gradually reduced, so has the concern. About 20 to 60 percent of inhaled Pb particles deposit in the adult human respiratory tract (Nozaki 1966; Moore et al. 1980; Morrow et al. 1980~. Most is rapidly cleared by absorption; lung retention half-times of 13 to 14 hr have been measured (Morrow et al. 1980~. Of the Pb cleared to the gastrointestinal tract, only about 5 to 15 percent is subsequently absorbed in adults (Kehoe 1961; Goyer and Chisolm 1972; Baksi 1982), with the rest excreted in the feces. Gastrointestinal ab- sorption is, however, greater in infants and children (Rabinowitz et al. 1976; Ziegler et al. 1978~. The total contribution of airborne Pb to total blood Pb levels is hard to determine, but the percentage of airborne Pb ulti- mately found in the blood is in the range of 7 to 40 percent (Patterson 1965; Ratinowitz et al. 1973, 1974; Manton 1977), and the biological half-time in blood is about 25 days (Baksi 1982~. Absorbed Pb is excreted primarily in urine but also in bile and by exfoliation of epithelial tissue. About 25 to 40 percent of inhaled Pb is retained in the body, almost all in bone, where it accumu- lates slowly with age and continued expo- sure (Goyer and Chisolm 1972; Barry 1975; Gross et al. 1975~. Cadmium. The solubility of Cd salts var- ies widely, and the relative rates of clear- ance by specific pathways probably depend on specific form. For example, whereas soluble CdCl2 and insoluble CdO2 have similar long-term clearance rates, with a retention half-time of ~67 days (Ober- dorster et al. 1979), a larger proportion of the oxide is cleared by an earlier fast phase, perhaps mediated by macrophages or mu- cociliary transport. Although Cd is absorbed from the respi- ratory tract, the relation between exposure and uptake in humans is not known. On the basis of experimental animal studies, up ~to 30 percent appears to be absorbed, de inhaled metals found in exhaust namely pending on the specific form of Cd (Friberg Pb, Cd, Cr. Mn, Ni, and vanadium (V) 1950~. Absorption from the gastrointestinal are discussed below. tract is quite poor less than 10 percent in

experimental animals and adult humans- but there is increased absorption in young individuals (Rahola et al. 1972; Fleischer et al. 1974). Once absorbed, Cd accumulates primar- ily in the liver and kidneys, which together account for about 50 percent of the total body burden (Fleischer et al. 1974~. The primary route of excretion of absorbed Cd is urine, and its biological half-time in the human body is estimated at 19 to 38 years (Friberg et al. 1974~. Chromium. After deposition, the water- soluble salts of Cr are rapidly absorbed from the respiratory tract into the circula- tion, but the less-soluble, and more-toxic, forms remain primarily in the respiratory tract, where their concentration increases with age (Baselt 1982~. Lesser amounts of Cr accumulate in skin, muscle, fat, and liver. There is low gastrointestinal absorption, only up to about 25 percent of the initial dose (Baselt 1982~. Of the Cr that is absorbed, at least 80 percent is excreted in urine. Manganese. The use of Mn additives as alternatives to Pb as antiknock ingredients in gasoline will probably result in an in- crease of Mn in exhaust emissions. A num- ber of studies have examined the clearance of deposited particulate Mn from the lungs of humans and experimental animals (Morrow et al. 1964, 1967a; Maigetter et al. 1976; Bergstrom 1977; Drown et al. 1986~. Unfortunately, the data are not directly comparable; residence times vary widely because of differences in particle size and resultant deposition, exposure duration, and concentration. However, like Cd, in- soluble and soluble forms may clear at similar long-term rates, but dissimilar short-term rates. Once it is absorbed, Mn is stored primar- ily in liver, kidneys, intestines, and pan- creas, but does not accumulate with age; it is excreted primarily in bile. Injected radio- labeled Mn has been found to disappear from the human body at two rates: about 70 percent is removed with a half-time of 39 days, and 30 percent with a half-time of 4 days (Mahoney and Small 1968~. . 280 Biological Disposition of Airborne Particles Nickel. Respiratory tract clearance mech- anisms for Ni are not very effective, and lung levels remain high for years after exposures have ended (Torjussen and An- derson 1979; Williams et al. 1980~. The passage of Ni across lung epithelium is slow, and studies in rodents show no sig- nificant removal by the lymphatic system (Williams et al. 1980~. Because of this slow removal, the concentration of Ni within the respiratory tract increases with age, even during chronic exposure to low levels. In addition, the lung actually sequesters significant amounts of Ni because of bind- ing to a variety of macromolecules; this may be an additional cause of Ni accumu- lation and toxicity. Of the Ni that reaches the gastrointestinal tract, more than 90 percent is excreted unabsorbed in the feces (Sunderman 1977~. Aside from lungs, ab- sorbed Ni tends to localize in connective tissue and kidney. Excretion of absorbed Ni is in the urine. Vanadium. Vanadium concentrates pri- marily in fat, which can account for 90 percent of the total body burden, but also in bones and teeth (Schroeder et al. 1963; Myron et al. 1978~. Of the other organs, the lungs contain the greatest concentra- t~on, but lung kinetics for V are not known. It is possible that insoluble forms may accumulate in the lungs with age, but this is also not known. Any V that reaches the gastrointestinal tract is excreted unab- sorbed. Sulfates Sulfates in exhaust, primarily sulfuric acid (H2SO4) and its neutralization products with atmospheric ammonia, occur in am- bient air as submicrometric aerosols. These particles are hydroscopic and their deposi- tion depends upon their effective diameter within the respiratory tract which, in turn, depends upon the rate of particle growth. In guinea pigs and rats, total respiratory tract deposition of H2SO4 aerosols ranging in size from 0. k1.2 ,um (MMAD) in- creased with increasing initial droplet size (Dahl and Griffith 1983~. Desposition mod

Richard B. Schlesinger 281 els developed for hydroscopic sulfate parti- cles (Martonen and Patel 1981) predict that total respiratory tract deposition efficiencies should be greater than those for nonhygro- scopic particles only if the sulfate originated from dry particles with diameters greater than about 0.3 ,um. Although the regional deposition of H2SO4 has not been studied experimentally in humans, predictive dep- osition models indicate that patterns of deposition for 0.5-1 ,um (final size) H2SO4 particles are similar, with deposition con- centrated in the distal conducting airways (Leikauf et al. 1984~. Sulfate is cleared from the lungs by dif- fusion (Charles et al. 1977), but the exact rate depends upon the inhaled concentra- tion and associated cations. Using radioac- tive 35S label, Dahl and coworkers (1983) studied the clearance of inhaled submicrom- eter H2SO4 from the lungs of experimental animals. For dogs, rats, and guinea pigs, they found that the half-time of sulfate clearance from all sites in the lungs ranged from 2 to 9 min. with smaller airways clearing faster than larger ones. The lungs cleared H2SO4 much faster than the nasal region, suggesting that clearance from the nose was not primarily by the blood. There were some interspecies differences; the dog cleared slower than the guinea pig, which cleared slower than the rat. In humans as well as experimental ani- mals, either acute or chronic H2SO4 expo- sure alters the bronchial mucociliary clear- ance rates of tracer particles. Acceleration or depression of clearance may occur, de- pending on the concentration and exposure regime. These effects, recently reviewed by Schlesinger (1986), are likely due to the deposition of hydrogen ion (H+), rather than sulfate (SO42-), on the airway sur- faces. Sulfuric acid exposures of experi- mental animals have also been associated with alterations in the rate of clearance of tracer particles from the pulmonary region (Phalen et al. 1980; Naumann and Schlesin- ger 1986; Schlesinger and Gearhart 1986) and with changes in macrophage function (Neumann and Schlesinger 1986; Schlesin- ger 1987~. Effects of H2SO4 on respiratory tract clearance are summarized in table 5. Research Recommendations Recommendation 29. Factors that control the bioavailability of material ad- sorbed onto particles should be examined. A major effort should be made to evaluate the effects of carrier particle characteristics, such as size, composition, surface area, and surface characteristics, on translocation and redistribution, intra- as well as extrapulmo- nary, of adsorbed nonorganic pollutants. Another aspect of this effort involves ex- amination of modifiers of toxic action. For example, macrophages dissolve metals, but there are no comprehensive data to deter- mine if this occurs for all metals of interest, or whether the extent varies significantly . among anlma species. Recommendation 30. Studies should be undertaken at low concentrations of diesel exhaust which simulate actual human exposure. There is a need to determine whether all aspects of diesel particle dispo- sition are the same for chronic exposures at low dose levels. In addition, studies of diesel particle retention beyond a 100-day postexposure observation time, to more completely assess long-term clearance, translocation, and body retention, should be performed. · Recommendation 31. Effects of partic- ulate as well as gas-phase components of diesel exhaust should be studied. Because diesel exhaust is a complex mixture of parti- cles and gases, it is essential that the effects of these components be separated to determine underlying toxicologic mechanisms. · Recommendation 32. In experimental animal systems, effects should be deter- mined of concurrent exposures to more than one specific material on clearance pathways, retention patterns, and extrapul- monary disposition. This could involve coexposures to diesel exhaust with other components of ambient air, including cig- arette smoke. ~ Recommendation 33. Effects of com- ponents of exhaust emissions on susceptible

282 Table 5. Effects of Sulfuric Acid on Respiratory Tract Clearance Exposure Parameters Mass Particle Conc Size (mg/m3) (~m) Rat Sheep Sheep 1-100 1 1-27 0.8-0.9 14 4 1 0.1-1.0 0.5 Donkey 0.2-1.4 0.4 6 hr 6 hr 0.1 0.1 0.5 0.3 hr 4 hr Duration Effect tracheal clearance at 1 day after 100 mg/m3 ,( tracheal clearance at 1 day after 1 mg/m3 NC tracheal clearance NC tracheal clearance 2.5 hr ~ bronchial clearance $, ~t bronchial clearance (concentration dependent), NC tracheal clearance 0.1-2.2 0.3 1 hr l, ~ bronchial clearance (concentration dependent) bronchial clearance (persistent in 2 of 4 animals), NC tracheal clearance NC bronchial clearance Mouse 1.5 0.6 Mouse 15 3.2 Rat 3.6 1.0 Donkey 0.1 0.5 Rabbit 0.25-0.5 0.3 Rabbit 1 0.3 Rabbit 0.25 0.3 Rabbit 0.5 0.3 Biological Disposition of Airborne Particles Reference Wolff (1986) Wolff (1986) 1 hr 1 hr 4 hr 4 hr J. bronchial clearance 4 hr NC bronchial clearance ~1, pulmonary region clearance 1 hr/day, 5 ,, bronchial clearance within 3 days/week months up to 6 months 1 hr/day, 5 days/week up to 4 weeks 1 hr it bronchial clearance within 1 week 1 hr/day, 5 days/week, up to 8 months 2 hr/day, 14 days Sackner et al. (1978) Sackner et al. (1978) Newhouse et al. (1978) Leikauf et al. (1981, 1984) Schlesinger et al. (1984) Schlesinger et al. (1978) Fairchild et al. (1975) Fairchild et al. (1975) Phalen et al. (1980) Schlesinger et al. (1979) Schlesinger et al. (1983b) pulmonary region clearance Naumann and Schlesinger (1986) Schlesinger and Gearhart (1986) pulmonary region clearance within 2 weeks pulmonary region clearance Schlesinger and Gearhart (1987) NOTE: NC = no change; ~ = significant acceleration of clearance; i, = significant retardation of clearance. populations, such as those with respiratory disease, should be examined. This can be performed with animal models of specific human diseases. There is a need to use these models, and to develop others, so as to be able to study effects of exhaust prod- ucts on specific sensitive individuals. Stud- ies are also needed to assess the disposition of pollutants in exercising adults, the young, and the elderly. In addition, the role

Richard B. Schlesinger 283 of concomitant stresses should be assessed in these individuals, as should the question of dose distribution in various extrapulmo- nary tissues as a function of age. · Recommendation 34. The effects of particulate emissions on clearance of other deposited particles should be examined. In addition to sulfates, other materials need investigation in this regard. Studies should assess underlying mechanisms of alteration; for example, changes in bronchial and al- veolar epithelial permeability may affect ultimate clearance rates. Summary A basic goal of risk assessment is to relate dose to exposure. The deposition of inhaled particles on the internal surfaces of the airways defines the delivery rate to the initial contact sites and is controlled by various physical mechanisms that are influ- enced by particle characteristics, airflow patterns and rates, and respiratory tract anatomy. Biological effects are often more directly related to the quantitative pattern of deposition within specific sites than to total respiratory tract deposition. This is because regional deposition patterns deter- mine the specific pathways and rates by which deposited particles are ultimately cleared and redistributed. There are numerous data on regional deposition of inert particles in humans, but the risk of inhaling hazardous aerosols or chronic exposure protocols requires the use of experimental animals and interspecies extrapolation of the results. To adequately apply these results to human risk assess- ment it is essential to consider differences in regional deposition patterns. But different species exposed to the same aerosol may not receive identical doses in comparable respiratory tract regions and, thus, the use of a particular species influences the esti- mated initial lung dose, the subsequent translocation sites, and the relation of ex- posure to potential human health effects. The toxic response from inhaled particles depends on both the amount of material deposited at target sites and the length of time this persists (that is, retention). Parti- cles are cleared from their deposition sites by various routes and interacting processes. The specific pathway depends on the re- gion of the respiratory tract where the material deposits, physicochemical proper- ties of the material, and, perhaps, exposure concentration and duration. The primary biological clearance mech- anisms for insoluble particles are mucocil- iary transport in the nasal passages and tracheobronchial tree, and removal by res- ident macrophages from the pulmonary region. Residence time depends on route. Material deposited on the conducting air- ways is cleared within two days, although some long-term retention can occur. Parti- cles deposited in the pulmonary region may remain for months to years or be retained indefinitely in various interstitial sites. Sol- uble particles, even those with relatively low solubility, can dissolve in the pulmo- nar`,r region. Solubilized components can be retained in the lungs or be redistributed in the body, where they may be retained in extrapulmonary tissues or excreted. In the conducting airways, solubilization occurs only if the rate of dissolution is faster than the rate of removal by mucous transport. Although clearance mechanisms are sim- ilar in humans and experimental animals, clearance rates may differ if mediated by biological processes, for example, mucous transport or macrophages. On the other hand, physical processes such as diffusion across epithelial barriers proceed at about the same rate in most species examined. In addition to reviewing the principles and mechanisms that influence the deposi- tion and clearance of particulate matter, the disposition of three classes of inorganic materials produced by vehicles were dis- cussed: diesel particles, metals, and sulfates. Diesel exhaust contains carbonaceous par- ticles onto which various, usually organic, materials are adsorbed. Only the fate of the matrix was discussed, although it is possi- ble that it is affected by any associated materials. Almost all reported studies have been conducted using high concentrations of particles at least 10 times that found in ambient air-and it is conceivable that dis

284 Biological Disposition of Airborne Particles position is not the same at lower levels of exposure. Inhaled diesel particles are cleared primarily by mucociliary transport and alveolar macrophages, but significant long-term retention in the lungs can occur. The fate of inhaled metals depends largely on the particular metal, as well as its valence state or inhaled form. Some metals are cytotoxic to macrophages, whereas others alter the function of these cells with- out affecting their viability. Some metals accumulate in the lungs or extrapulmonary tissues after continuous exposure, whereas other metals reach a steady-state concentra- tion unless exposure levels are very high. Sulfates primarily sulfuric acid pro- duce their main effect on the respiratory tract; response is probably related to the phi of the specific sulfate species. These mate- rials alter the rates of clearance processes, both in conducting airways and in the pulmonary region, thus compromising the lung's defense capabilities. Summary of Research Recommendations: Discussion Many of the recommendations presented are for highly goal-oriented studies needed to expand or refine the data base on factors that control the disposition of inhaled par- ticles. The precision of exposure assess- ment and risk analysis will improve from an enhanced understanding of these factors. In many cases, experimental animals should be used for studies that are not feasible in humans. In other cases, the use of physical models, such as airway casts, is appropriate. A major area of concern is the disposition of inhaled particles in sensitive subseg- ments of the human population, such as children, the aged, and people with chronic respiratory diseases. Predictive models sug- gest that particle deposition will be greater in children than in adults and that children may receive a disproportionately large res- piratory tract dose from inhaled toxicants in relation to their body mass. This is due largely to differences between children and adults in ventilation, general activity level, and lung morphometry, but such differ . . . ences are Ignored In exposure assessments. Since direct extrapolation from experimen- tal inhalation studies using adults may not be valid, studies aimed directly at children are, therefore, needed. It is also important to determine whether the distribution of dose to extrapulmonary sites diners during growth. Older individuals and people with chronic respiratory disease may also be more suscep- tible to effects of inhaled toxicants and/or may show differences in particle disposition compared to normal, healthy younger adults, the group upon which most of the current data are derived. Although some basic studies of particle deposition and clear- ance have been performed in people with chronic respiratory disease, results are diff~- cult to interpret because of the large inherent variability in these individuals caused by ventilatory and anatomic irregularities. Ex- panding the data base depends on additional, well-controlled studies. Finally, to examine aging-related changes in particle deposition and clearance, longitudinal tests could be performed in healthy humans as they age. The use of children in experimental stud- ies is generally precluded. Thus, particle deposition in children is generally modeled, using predictive deposition equations cou- pled with empirically derived morphomet- ric models. More data, therefore, are needed on growth-related morphometric and ventilatory changes in the lung. This information can be used to develop a better model of the growing lung which, in turn, will allow for more accurate predictions of . . . . party e c ~spos~t~on. To assess clearance and retention charac- teristics of specific vehicular pollutants as a function of growth in viva, animal models will be needed. For example, rodents rang- ing in age from newborn to adult could be exposed to particulate pollutants, and clear- ance or retention correlated with age. Along these same lines, animal models could be developed to assess how particle disposition in the aging or diseased lung compares to that in healthy young adult lungs. Since certain types of information on particle disposition must be obtained from experimental animals, extrapolation to hu- mans for use in risk estimates is necessary. However, each species has unique physio

Richard B. Schlesinger 285 logical and anatomic characteristics that serve to differentiate it from others, and these factors may play a role in determining species-specific responses to inhaled agents. Reliable interspecies comparisons can be per- formed only if appropriate data are available. Thus, some of the research recommenda- tions are aimed at providing additional infor . . , matron on respiratory tract structure and function in experimental animals. It is essen- tial that similarities and differences among these animals and humans be assessed. This information will allow selection of appropri- ate animal models that resemble humans for particular situations, or that have specific individual characteristics that are highly de- sirable for mechanistic studies. In addition, systematic studies of deposition and clearance in various experimental animal species and humans, wherein comparable techniques are used, are needed to provide cross-species calibration factors. Such studies will avoid the problems inherent when comparing data obtained from different laboratories and us- ing various methodologies. Another gap in the current data base on the disposition of vehicular-derived parti- cles relates to exposure conditions. Despite the inherent problems, chronic exposures to toxicologically relevant materials at re- alistic concentrations are necessary. The disposition of particles may be concentra- tion dependent and, thus, risk assessments based upon studies at high concentrations may not be appropriate for assessing haz- ards at ambient levels. In addition, chronic studies are needed, since acute exposures are not always predictive of effects from longer-term exposures. Currently, there is no sound basis to extrapolate the effects of vehicular-derived particles from high to low concentrations, in terms of their dis- position. Furthermore, the role of increased physical activity of exposed individuals in altering particle disposition needs to be determined, since enhanced ventilation may drastically alter dose. · . . . In ambient situations, exposures to more than one material occur. It is necessary to determine whether retention kinetics of particles of a single material are adequate representations of that associated with joint exposures. Concomitant irritant exposures affect airway size, ventilation, clearance rates, and distribution of cells in the air- ways. Studies are needed to see if such effects alter the ultimate fate of vehicular- derived materials. All of the research recommendations presented provide data that can be used as components of a dosimetric model; the more accurate the individual components of the model, the more reliable are the predictions. A complete model must in- clude accurate input for regional deposition and clearance, species variability in ventila- tion and anatomy, as well as relevant prop- erties of the inhaled particles. Summary of Research Recommendations: Priorities To meet the broad goals of a basic research initiative as discussed above, the following specific areas were proposed as requiring additional research. These are ranked in groups, depending upon . . . . . . . . t leer priority tor Improving rats ~ estimations. H I G H P R I O R I T Y These studies are essential in order to provide needed data for more accurate risk assessment. Recommendation 1 Interindividual variability of dimensions of the upper respiratory tract, tracheobronchial tree, and pulmonary region for adult hu mans and experimental animals (including strain differences) should be assessed to provide statistical descriptions of morphom etry at all levels of the respiratory tract.

286 Biological Disposition of Airborne Particles Recommendation 12 The effects of interspecies anatomic variability on deposition should be analyzed systematically. Recommendation 2 Morphometry of the human growing lung, the aging lung, and the diseased lung should be assessed. Recommendations Patterns and distribution of airflow in the nasal passages and 5, 6, 7 tracheobronchial tree of experimental animals and humans, and in the oral passages of humans, should be determined. This should include assessments in the growing, aging, and diseased lung. Recommendations Systematic study should be undertaken of regional deposition 11,16 using a full range of particle sizes with comparable exposure conditions in humans and experimental animals; especially needed are studies with ultrafine (<0.1 ,um) particles. Recommendation 18 Interspecies comparison of clearance kinetics should be made, using comparable methods and particles, for assessment of muco ciliary transport from conducting airways and mechanical transport from pulmonary airways. Recommendations Effects of modifying factors on particle deposition, clearance, 13, 14, 23, 26, 27, 28 and retention should be studied. This should include examina tion of growing;, acing;, and diseased lungs, as well as of differ ences due to physical activity and gender. The development and use of appropriate animal models for these studies should be pursued. Recommendation 29 The effects of carrier particle characteristics (for example, size, surface characteristics, mass concentration) on ultimate disposition of adsorbed material should be examined. Recommendation 30 Chronic exposures to diesel exhaust products at realistic levels should be undertaken. Recommendation 32 Coexposures to diesel exhaust products, or to diesel exhaust and other ambient pollutants, should be conducted. Recommendation 33 Pollutant exposures in animal models of sensitive populations, such as the young, elderly, or diseased, should be performed. MEDIUM PRIORITY These studies will provide data to refine risk assessment. Recommendlation3 Comparative morphometry of the upper respiratory tract in humans and experimental animals should be assessed. Recommendation 9 The effects of breathing mode and of particle removal in the upper respiratory tract on regional deposition in animals and humans should be assessed systematically.

Richard B. Schlesinger 287 Recommendlation 10 Nonuniform particle deposition (microdistribution) should be studied under a wide range of exposure conditions. Recommendation 17 Models that allow calculation of deposition by airway generation should be expanded to other species. Recommendation 19 Pathways and mechanisms of long-term retention in conducting airways (tracheobronchial tree and upper respiratory tract) should be examined and quantified. Recommendation 20 Pathways of clearance from the pulmonary region to sites of long-term retention in the parenchyma should be studied. Recommendations Regional deposition and ultimate fate of hydroscopic and soluble 15, 25 particles should be evaluated. Recommendation31 Ejects of individual paticulate and gas-phase components of diesel exhaust should be studied. Recommendation 34 Effect of vehicular particulate emissions on disposition of other inhaled particles should be examined. LOW PRIORITY These studies will provide information useful in fine tuning risk assessment, but are not critical to its development. Recommendation 21 The relationship of changes in macrophage functional character istics to particle clearance, including effects of exposure conditions, such as particle burden, should be characterized. Recommendlation 4 Comparative structure and physiology of human and laboratory animal pulmonary lymphatic systems should be studied. Recommendation 8 Flow patterns in experimental animal nasal passages and human oral passages should be studied during different levels and types of activity. Recommendlation 22 The relationship between effects on macrophages in viva and in vitro should be better defined. Recommendlation 24 The mucous layer should be characterized in various species. References Abraham, W., Kim, A., Januszkiewicz, M., Welker, M., Mingle, M., and Schreck, R. 1980. Effects of a Correspondence should be addressed to Richard B. Schlesinger, Institute of Environmental Medicine, New York University Medical Center, 550 First Av- enue, New York, NY 10016. brief low-level exposure to the particulate fraction of diesel exhaust on pulmonary function of con- scious sheep, Arch. Environ. Health 35:77-80. Adamson, I. Y. R., and Bowden, D. H. 1981. Dose response of the pulmonary macrophagic system to various particulates and its relationship to transepi- thelial passage of free particles, Exp. Lung Res. 2:165-175. Albert, R. E., Lippmann, M., and Peterson, H. T., Jr. 1971. The effects of cigarette smoking on the kinet

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"The combination of scientific and institutional integrity represented by this book is unusual. It should be a model for future endeavors to help quantify environmental risk as a basis for good decisionmaking." —William D. Ruckelshaus, from the foreword. This volume, prepared under the auspices of the Health Effects Institute, an independent research organization created and funded jointly by the Environmental Protection Agency and the automobile industry, brings together experts on atmospheric exposure and on the biological effects of toxic substances to examine what is known—and not known—about the human health risks of automotive emissions.

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