Tài liệu Ncrp report no 125 deposition, retention, and dosimetry of inhaled radioactive substances

NCRP REPORT No. 125 DEPOSITION, RETENTION AND DOSIMETRY OF INHALED RADIOACTIVE SUBSTANCES Recommendations of the NATIONAL COUNCIL ON RADIATION PRO'TEC'TION AND MEASUREMENTS Issued February 14, 1997 National Council on Radiation Protection and Measurements 7910 Woodmont Avenue I Bethesda, MD 20814-3095 LEGAL NOTICE This report was prepared by t h e National Council on Radiation Protection and Measurements (NCRP).The Council strives to provide accurate, complete and useful information in its reports. However, neither the NCRP, the members of NCRP, other persons contributing to or assisting in the preparation of this report, nor any person acting on the behalf of any of these parties: (a) makes any warranty or representation, express or implied, with respect to the accuracy, completeness or usefulness of the information contained in this report, or that the use of any information, method or process disclosed in this report may not infringe on privately owned rights; or (b) assumes any liability with respect to the use of, or for damages resulting from the use of any information, method or process disclosed in this report, under the Civil Rights Act of 1964, Section 701 et seq. as amended 42 U.S.C. Section 2000e et seq. Z) (Title V Z or any other statutory or common law theory governing liability. Library of Congress Cataloging-in-Publication Data National Council on Radiation Protection and Measurements. Deposition, retention, and dosimetry of inhaled radioactive substances : recommendations of the National Council on Radiation Protection & Measurements. p. cm. - (NCRP report ; no. 125) "Issued February 1997 Includes bibliographical references and index. ISBN 0-929600-541 1. Aerosols, Radioactive-Toxicology. 2. Radiation dosimetry. I. Title. 11. Series. RA1231.R2N28 1997 96-37944 CIP 612'.01448-dc21 Copyright Q National Council on Radiation Protection and Measurements 1997 All rights reserved. This publication is protected by copyright. No part of this publication may be reproduced in any form or by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotation in critical articles or reviews. Preface The development of a respiratory tract model which accurately reflects reality is a difficult and complicated effort. This stems largely from the variety of airway shapes, airflow patterns, and cell types having different radiosensitivities. Anatomic and physiologic alterations in smokers or those exposed to chemicals, among others, further complicate modeling. In spite of the inherent difficulties, the continuing pursuit of a model that mimics actual conditions has been considered to be important by those involved in radiation protection. Recently, the International Commission on Radiation Protection published a report on the respiratory tract, ICRP Publication 66 (ICRP, 1994). While the ICRP model arrives a t similar results t o the NCRP model in most instances, quite different results are obtained for certain radionuclides. Given the considerableuncertainties involved in the calculations for both models and in order to avoid confhsion in the radiation protection community as to which model to use, the NCRP recommends the adoption of ICRP Publication 66 (ICRP, 1994)for calculating exposures for radiation workers and the public, e.g., for computing annual reference levels of intake and derived reference air concentrations for workers, and arriving at values of dose per unit intake for workers and members of the public. However, given the considerable uncertainties involved in modeling the respiratory tract, the NCRP believes that the present alternate model is a significant contribution to the radiation protection field and will be useful to many. This Eeport was prepared by Scientific Committee 57-2 on Respiratory Tract Dosimetry Modeling. Serving on Scientific Committee 57-2 were: Richard G. Cuddihy, Chairman Albuquerque, New Mexico Members Gerald L. Fisher Wyeth-Ayerst Research Princeton, New Jersey Robert F. Phalen University of California Irvine, California iv 1 PREFACE George M. Kanapilly* Inhalation Toxicology Research Institute Albuquerque, New Mexico Richard B. Schlesinger New York University Medical Center New York, New York Owen R. Moss Chemical Industry Institute of Toxicology Research Triangle Park, North Carolina David L. Swift Johns Hopkins School of Hygiene and Public Health Baltimore, Maryland Hsu-Chi Yeh Inhalation Toxicology Research Institute Albuquerque, New Mexico Consultants I-Yiin Chang Inhalation Toxicology Research Institute Albuquerque, New Mexico Morton Lippmann New York University New York, New York Keith F. Eckerman Oak Ridge National Laboratory Oak Ridge, Tennessee Fritz A. Seiler International Technology Corporation Albuquerque, New Mexico William C. Griffith Inhalation Toxicology Research Institute Albuquerque, New Mexico Samuel E. Walker Raton, New Mexico NCRP Secretariat Thomas M. Koval, Senior Staff Scientist (1993-1997) E. Ivan White, Senior Staff Scientist (1982-1993) Cindy L. O'Brien, Editorial Assistant The Council wishes to express its appreciation to the Committee members for the time and effort devoted to the preparation of this Report. Charles B. Meinhold President, NCRP Contents Preface ....................................................................................... iii 1 Introduction ........................................................................ 1 11 Purpose ............................................................................. 2 . 2 12 Scope ................................................................................ . 13 Description of this Report ............................................... 3 . 2 Anatomy and Morphometry of the Human Respiratory Tract ............................................................... 21 Anatomy of the Respiratory Tract ................................. . 2 1 1 Naso-Oro-Pharyngo-LaryngealRegion ............... .. 212 Tracheobronchial Region ..................................... .. 2 1 3 Pulmonary Region ................................................ .. 214 Thoracic Lymphatic System ................................ .. 215 Innervation of the Respiratory System .............. .. 216 Cells a t Risk ......................................................... .. 2 2 Morphometry of Respiratory Tract Airways ................. . 221 Naso-Oro-Pharyngo-Laryngeal Region ............... .. 222 Tracheobronchial Region ..................................... .. 223 Pulmonary Region ................................................ .. 3 Physiology of the Respiratory Tract ............................. 31 Ventilation ....................................................................... . 311 Normal Parameters .............................................. .. 3 1 2 Changes i Ventilation with Physical Activity ..... .. n 313 Effects of Aging .................................................... .. 314 Other Factors ........................................................ .. 32 Clearance ........................... . . . ....................................... 321 Naso-Oro-Pharyngo-Laryngeal .. Region ............... 322 Tracheobronchial Region ..................................... .. 323 Pulmonary Region ................................................ .. 4 Factors Affecting Normal Respiratory Tract Structure and Function .................................................... 41 Tobacco Smoke and Other Irritants .............................. . 42 Disease ............................................................................ . 4 3 Miscellaneous Factors ..................................................... . 44 Modeling Assumptions .................................................... . 5 Deposition of Inhaled Substances ................................. 51 Particles ........................................................................... . 511 Particle Size Definitions ...................................... .. . . . . . vi / CONTENTS Particle Inhalability ........................................... Deposition Mechanisms ...................................... Inhaled Particle Deposition Models ............. ... Naso-Oro-Pharyngo-Laryngeal Deposition ......... Tracheobronchial and Pulmonary Deposition .... Regional Deposition of Inhaled Particles ........... 5.2 Gases and Vapors ............................................................ 5.2.1 Gas-Phase Transport Mechanisms ..................... 5.2.2 Gas-Phase Transport and Conditions a t the Phase Boundary ............................................................... 5.2.3 Gas Transport on the Liquid Side ofthe Interface 5.2.4 Gas Deposition . in the Naso-Oro-PharyngoLaryngeal Region ................................................. 5.2.5 Gas Deposition in the Tracheobronchial and Pulmonary Regions .............................................. 5.2.6 Predicted Deposition of Specific Radioactive Gases .................................................................... 6 Respiratory Tract Clearance ........................................... 6.1 Concepts of Respiratory Tract Clearance ...................... 6.2 Mechanical Clearance of Particles ................................. 6.2.1 Particle Clearance in the Naso-Oro-PharyngoLaryngeal Airways ............................................... 6.2.2 Particle Clearance in Tracheobronchial Airways ... 6.2.3 Particle Clearance in the Pulmonary Region ...... 6.2.4 Particle Clearance to Pulmonary Lymph Nodes ... 6.3 Absorption into the Blood ............................................... 6.4 Comparison of Clearance Model Projections with Experimental Measurements ......................................... 7 Lung Model for Exposure to Radioactive Particles ..... 7.1 Deposition ........................................................................ 7.1.1 Naso-Oro-Pharyngo-Laryngeal Airways ............. 7.1.2 Tracheobronchial Tree and Pulmonary Region .... 7.2 Clearance ......................................................................... 7.2.1 Model Characteristics .......................................... 7.2.2 Clearance Functions M(t) and A(t) ..................... 7.2.3 System of Differential Equations ........................ 7.3 Dose Calculations ............................................................. 7.3.1 Absorbed Dose from Photons, Electrons and Alphas ................................................................... 7.3.1.1 Estimating Dose from Photon-Emitting Radiation ................................................. 7.3.1.2 Estimating Dose from Alpha Radiation ... 7.3.1.3 Estimating Dose from Beta Radiation .... 7.3.2. Sample Calculations of Dose .............................. 5.1.2 5.1.3 5.1.4 5.1.5 5.1.6 5.1.7 . . .... CONTENTS 1 ~ i i 733 Modifying Factors .................................................. 140 .. 7331 Influence of Age ...................................... 140 ... 7332 Effect of Tobacco Smoking ..................... 142 ... 7333 Effect of Disease States .......................... 142 ... 8 Consideration for Nonradioactive Substances ........... 143 81 Deposition of Inhaled Chemical Toxicants .................... 143 . 82 Respiratory Tract Clearance of Chemical Toxicants .... 144 . 83 Chemical Dose to Cells at Risk ..................................... 146 . 9 Summary .............................. . ............................................ 150 91 Anatomy and Morphometry of the Respiratory Tract ..... 150 . 9 2 Cells at Risk from Inhaled Radioactive Aerosols .......... 152 . 93 Physiological Factors Related to Deposition and . . . Clearance ......................................................................... 153 94 Regional Deposition of Inhaled Particles ...................... 154 . 95 Regional Solubility of Inhaled Gases and Vapors ........ 155 . 96 Respiratory Tract Clearance of Particles ...................... 156 . 97 Calculation of Dose from Inhaled Radionuclides .......... 158 . 98 Chemically Toxic Inhaled Substances .......................... 159 . Appendix A Clearance Data ................................................ 161 A1 Manganese ...................................................................... 162 k 2 Cobalt .............................................................................. 164 A 3 Yttrium ......................................................................... 166 A 4 Niobium ........................................................................... 167 A 5 Ruthenium ..................................................................... 170 A 6 Cesium ............................................................................. 172 A 7 Barium ............................................................................. 175 A 8 Lanthanum ..................................................................... 178 A 9 Cerium ........................................................................ 180 A10 Polonium .................................................................... 182 A l Uranium .......................................................................183 l A12 Plutonium ...................................................................... 186 A13 Americium ..................................................................... 188 A14 Curium ......................................................................... 190 Glossary ..................................................................................... 192 References ............................................................................ 200 The NCRP ............................................................................... 226 NCRP Publications ................................................................. 234 Index ......................................................................................... 246 Introduction The respiratory tract is a complex system characterized by a number of unique features related to airway shapes and airflow patterns with a variety of cell types with differing radiosensitivities. In addition, there are anatomic and physiologic alterations in individuals who smoke or are exposed to chemical irritants, or have other special attributes. Therefore, the prediction of regional deposition and retention of inhaled radioactive particles, gases and vapors in the human respiratory system, the dosimetry involved, and the determination of the impact are far from straightforward. It follows, then, that the development of a realistic respiratory tract model is a difficult and extremely complicated task. Both the National Council on Radiation Protection and Measurements (NCRP) and the International Commission on Radiological Protection (ICRP) have been able to take advantage of work in this area that is at the forefront of studies concerned with the respiratory tract. The recently published ICRP report on this topic, ICRP Publication 66 (ICRP, 1994), and the present NCRP report have arrived at remarkably similar mathematical assessments, in general, although detailed calculations for specific radionuclides can be quite different in terms of the way they are handled. For example, the ICRP principally uses the model of Egan et al. (1989), whereas the NCRP uses the model of Yeh and Schum (1980) for deposition, and the ICRP and NCRP use quite different models for respiratory clearance. The ICRP and NCRP models are both applicable for simulation of exposure cases for individuals and populations. In order to ensure a uniform course of action providing a coherent and consistent international approach to radiation protection, the NCRP adopts the recommendations of ICRP Publication 66 on the human respiratory tract (ICRP, 1994) for calculating exposures for radiation workers and the public, e.g., for computing annual reference levels of intake and derived reference air concentrations for workers, and arriving at values of dose per unit intake for workers and members of the public. The present NCRP report does not specifically address these issues, but rather focuses on fundamental considerations of human respiratory tract structure and function in deriving an alternate mathematical model to describe the deposition, clearance and dosimetry of inhaled radioactive substances. For 2 / 1. INTRODUCTION example, this Report incorporates a multigenerational airway approach to modeling the lung while the ICRP publication uses a multicompartment model for clearance and dosimetry. The ICRP model also incorporates a slow clearance component for material deposited in the bronchial and bronchiolar regions while the NCRP will await further verification of this phenomenon before incorporating it. Considering the degree of uncertainty associated with modeling the respiratory system, the NCRP believes that such an alternate presentation a t this time can present a significant contribution to the development of the field of radiation protection and supplements the ICRP publication by enhancing the confidence in the results of calculating doses from t.he intake of airborne radionuclides. 1.1 Purpose This Report provides a summary of scientific information and mathematical models that describe respiratory tract deposition, retention and dosimetry for radioactive substances inhaled by people. The treatment of deposition and retention is applicable, as well, to nonradioactive substances. The result of this review is an integrated mathematical model of deposition and clearance that is suitable for calculating doses to the respiratory tract. The Report provides a framework for interpreting human exposures and related bioassay measurements. 12 Scope . This Report describes the deposition, clearance and dosimetry of inhaled substances in the respiratory tract. It can be used by scientists, and others concerned with the effects of inhaled radioactive and chemically toxic substances, to calculate approximate doses to the cells and tissues at risk. Mathematical models described in this Report are designed to predict the most likely mean values of deposition and clearance in various regions of the respiratory tract, and variations in these patterns to be expected for individuals who may differ in size, state of health, and mode of breathing. An important characteristic of these models is that they provide information on particle deposition and clearance on an airway generation-bygeneration basis. This allows a user to pinpoint an airway for the purposes of estimating initial particle deposition, or dose, at any time after deposition. 1.3 DESCRIPTION OF THIS REPORT / 3 Most of the experimental data used in this Report are derived from studies with radioactive substances, but the deposition and retention models also apply to nonradioactive materials. However, dosimetry concerns for chemically toxic agents may differ from those involving radiation. The most frequently calculated radiation dose parameters are the time-integrated total energy deposition and energy deposition rate in tissue. For inhaled chemicals, it may be important to know peak exposure concentration, duration of exposure, cytotoxicity, potential metabolic products and, possibly, other factors. Three mathematical models describing the deposition and retention ofinhaled radioactive particles have been developed by the ICRP for calculating doses from the inhalation of radionuclides. The first was described in ICRP Publication 2, Report of Committee I1 on Permissible Dose for Internal Radiation (ICRP, 19591, and it was used to calculate maximum permissible concentrations of radionuclides in air. The second was published in 1966 by an ICRP Task Group on Lung Dynamics EGLDACRP (1966)1, but it was not officially used for developing radiation protection guidelines until 1979 when it formed the basis for calculated annual limits on intakes of inhaled radionuclides by workers (ICRP, 1979a; 197913). The TGLD model has been widely used by the scientific community during the last 30 y. During this period, no major deficiencies have been noted with respect to its intended use in formulating radiation protection guidelines for workers. A third ICRP human respiratory tract model for radiological protection of workers and the public has been published (ICRP, 1994). Following the successful use of the 1966 ICRP model this Report extends its application by including people other than the healthy male worker, by incorporating the results of recent scientific investigations on inhaled aerosols and by use of improved deposition and retention modeling techniques. Additional scientific information is now available to improve respiratory tract dosimetry models for assessment of exposures over a broad range of applications. For those cases in which detailed studies of deposition and retention are not available, default parameters may be used. This Report includes information and calculations appropriate to individuals in heterogeneous populations, including males and females of different ages, smokers and people with compromised respiratory tract defenses. 1.3 Description of this Report This Report is divided into nine sections. Section 1is the Introduction. Section 2 contains a description of the anatomy of the 4 1 1. INTRODUCTION respiratory tract airways as needed for radiation dose calculations. A discussion of cell populations that may be a t risk from inhaled radioactive aerosols is also included. Section 3 contains respiratory physiology information which is used in combination with respiratory tract morphometry to predict regional deposition of inhaled particles, gases and vapors. Anatomic and physiologic alterations of the respiratory tract that may occur in smoking, certain disease states, and exposure to chemical irritants are discussed in Section 4. Section 5 contains a description of mathematical models that can be used to predict regional deposition of particles, gases and vapors in the human respiratory tract. Calculations for individuals of various body sizes and for particles of various sizes, densities, shapes, electric charge states, and hygroscopicities are also discussed. Section 6 describes a mathematical model that can be used to predict clearance rates for materials deposited in the several regions of the respiratory tract. The clearance model is designed to be consistent with known clearance pathways and is not restricted to compartments having first-order kinetic relationships. Section 7 contains a description of dosimetry models that can be used to calculate radiation dose to the epithelium of the naso-oro-pharyngo-laryngeal (NOPL)region, the tracheobronchial (TB)airways region, the pulmoregion, and the TB lymph nodes (LN). This Section also nary (P) contains pertinent dose-modifjmg factors related to age, smoking status and selected disease states. The parameters that have to be entered into the model are specificallyidentified and sample calculations are provided. Section 8 is a discussion relating to the use of the deposition, retention and dosimetry calculations for nonradioactive substances. Section 9 provides a summary of the Report. Appendix A of this Report contains information on clearance pathways, clearance rates and dosimetric data for individual radionuclides. This information can be revised and expanded to include additional radionuclides as new data become available. Lacking specific radionuclide data, the NCRP recommends the use of information pertaining to respiratory tract clearance categories as described in ICRP Publications 30 and 56 (ICRP, 1979a; 1990). 2. Anatomy and NIorphometry of the Human Respiratory Tract The following discussion is a brief review of the anatomy and morphometry of the respiratory tract beginning a t the nose or mouth and leading to the gas exchange units, the alveoli. While the respiratory tract may be looked upon as a n integrated system, working as one functional unit, it is convenient to divide the respiratory tract into subunits that are primarily responsible for conditioning of air, subdividing airflow and gas exchange. This approach follows the general descriptive scheme used by the TGLDIICRP (1966), which divides the respiratory tract into the nasopharyngeal, TB and P regions. However, in this Report, the definition of the nasopharyngeal region is changed to the NOPL region to emphasize the differences between nasal and oral modes of breathing. The TB and P regions remain essentially a s defined by the earlier ICRP Task Group. Additionally, the thoracic lymphatic system is included as a separate region because of its important role in pulmonary clearance and defense against inhaled insoluble toxicants. Unless otherwise specified, the information provided in this Section applies to healthy adults. 2.1 Anatomy of the Respiratory Tract 2.1.1 Naso-Oro-Phatyngo-Laryngeal Region Because of the historical lack of agreement among experts on the terms nasopharyngeal region, extrathoracic region and upper airways, it is appropriate to be precise about the structures first encountered by inhaled particles and gases. There are many unique features ofthese airways related to their shapes and airflow patterns. It is important to recognize that a person may choose to breathe through his or her nose, mouth or both. While most people breathe nasally a t rest, mild exercise, conversation and other conditions lead 6 1 2. ANATOMY AND MORPHOMETRY to oronasal breathing (Camner and Bakke, 1980; Swift and Proctor, 1977). Additional respiratory loading changes the ratio of oral to nasal flow in favor of greater oral flow. The nasal airways begin at the external nose with a pair of elliptical nostrils [less than three percent have circular nostrils (Farkas et al., 198311 that lead inward through the narrowing vestibule to the nasal valves (Figure 2.1). These valves have the smallest crosssectional area along the respiratory tract through which the entire airflow must pass. The vestibular area contains many nasal hairs protruding from the walls into the airstream. They are assumed to have filtering and sensory functions. The walls of the nasal vestibule consist of squamous epithelium, but this changes to columnar ciliated mucus-secreting epithelium just posterior to the valves. Air entering the nasal vestibule travels upward, then undergoes a change of direction beyond the valve so that it travels horizontally through the main nasal passages. This region of the nasal airways Fig. 2.1. Adopted terminology for the upper airways. The term oropharynx or oropharyngeal should be confined to the airway from lips to pharynx during mouth breathing. 2.1 ANATOMY OF THE RESPIRATORY TRACT 1 7 consists of two similar passages separated by a septum. These passages are bounded on their outer walls by three shelf-like folds, the nasal turbinates, which provide for a large surface area with narrow distances between airway walls. A mucus-secreting ciliated epithelium covers the surfaces of the main nasal passages except for the olfactory regions at the top of the passages. The cilia normally function to move mucus and deposited substances back to the nasopharynx where they are swept off the posterior wall and swallowed. The septum ends at the entrance to the nasopharynx which narrows to a nearly circular cross section. The surface cells gradually change to a squamous epithe!ium which lines the airways down to the trachea, except for some lymphoid tissue in the nasopharynx and oropharynx. Observations of the nasal passages under a variety of environmental conditions indicate that they vary considerably in cross-sectional opening; this is especially true for the main nasal passages. Presumably, this change in cross section provides a means of controlling the degree of air conditioning, removing irritants and preventing excessive dehydration of the mucosa. The oral airway has even greater variability in cross section. It is used to some degree for respiration during conversation, but is involved in respirationto a much greater extent, along with the nasal airway, during exercise and nasal blockage (oronasalbreathing). Air enters the mouth through the parted lips and teeth and passes between the tongue and hard palate. The cross section of this airway depends on the position of the jaw and tongue. The distance between the tongue and hard palate has been observed using x-ray fluorography to be as narrow as 1cm during speaking and singing (Roctor and Swift, 1971).Aidow changes direction at the back of the mouth where it enters the oropharynx and encounters the soft palate. The position of the soft palate determines the nature of airflow in the posterior nasopharynx and oropharynx. The soft palate can be positioned by muscular action either against the posterior nasopharyngeal wall or in the center of the oropharynx, allowing air to flow in both the oral and nasal airways. The naso- and oropharynx join beyond the soft palate to form the hypopharynx. This airway is bounded by the posterior pharyngeal wall and the epiglottis, which is the entrance to the larynx. The air stream is vertical at this point, and it passes slightly anterior to enter the larynx. Here, the airway changes from being circular in cross section to a modest constriction of the false vocal cords and then to the variable constriction of the true vocal cords. This musclecontrolled region is constricted when producing sounds, but is partially relaxed during normal breathing. However, it is always 8 1 2. ANATOMY AND MORPHOMETRY sufficiently constricted to produce an aij e t in the downstream direction. The larynx is maintained in a patent state by a series of muscles and the complete circular cricoid cartilage. The cricoid cartilage is the upper boundary of the trachea, which is the first airway of the next major region of the respiratory tract. All airways above the trachea constitute the NOPL region. 2.1.2 Tracheobronchial Region The TB region (Figure 2.2) begins at the top of the trachea, a roughly circular airway approximately 2 cm in diameter and 10 cm in length. The posterior wall of the trachea is adjacent to the esophagus and the anterior wall is supported by a series of c-shaped cartilages. The tracheal mucosa contains bands of smooth muscle. Their state of contraction and the pressure imposed by the surrounding TER Fig. 2.2. Replica cast of the human lungs with dissected TB tree. This cast, made in situ, was subjected to the morphometric measurements that were used to generate the typical path model (Phalen et al., 1978). 2.1 ANATOMY OF THE RESPIRATORY TRACT 1 9 tissues influence the tracheal airway cross section. The upper half of the trachea is extrathoracic while the lower half is in the thoracic cavity and is subjected to intrathoracic (or pleural) pressure. If this intrathoracic pressure significantly exceeds the intratracheal pressure, the posterior wall of the trachea moves inward forming a narrow c-shaped airway in the extreme. The tracheal epithelium primarily consists of ciliated cells interspersed with mucus-secreting goblet cells and ducts that lead to mucus-secreting glands. These cilia are like the nasal cilia and normally beat in synchrony to propel mucus and deposited matter toward the larynx to be swallowed. The trachea subdivides at the canna to form the leR and right main bronchi leading to their respective lungs. These airways are like the trachea in that they are supported by cartilage, encircled by smooth muscle, lined with ciliated epithelium, and coated by secretions from mucus glands and goblet cells. The two main bronchi subdivide further to supply the lobes of each lung through their respective airway segments. Each subdivision typically leads to smaller diameter airways. The supporting cartilage changes in shape from rings to plates as the bronchial subdivision continues. This is accompanied by a decrease in the number of mucus-secreting structures and cilia. As the bronchi become smaller, the plates cover smaller areas, providing less rigid walls and giving the smooth muscle a larger role in determining airway length and patency. The smallest airways of the TB region are collectively called the bronchioles, which have no cartilage plates but are supported by smooth muscle. Their surfaces have patches of ciliated cells that clear secretory fluids toward the epiglottis in the TB airways. 213 .. Pulmonary Region The most proximal airways that contain alveoli for gas exchange are called respiratory bronchioles; the acinus branch from terminal bronchioles (Figure 2.3). These airways have ciliated epithelium and secreting cells between alveoli. The alveolar pouches are roughly polyhedral in shape with an average equivalent spherical diameter of approximately 250 p,m in adults. The cells are of several types and include flat (Type I) cells through which gases move readily, cells that produce surfactant (Type 11) and mobile alveolar macrophages that are responsible for defenses. Endothelial blood capillary cells are separated from the epithelial cells by a thin membrane that permits rapid gas transport from the alveoli to blood and vice versa. The alveoli are surrounded by elastic fibers that play a role in airway patency in concert with pulmonary surfactant. 10 / 2 ANATOMY AND MORPHOMETRY . Fig. 2.3. The P region includes all of the airways of the acinus of the lung (CIBA Pharmaceutical Company, 197911980). Respiratory bronchioles subdivide into succeeding airways that contain more alveolar coverage. Eventually, the alveolar sacs branch from alveolar ducts and are organized somewhat in the fashion of a bunch of grapes. The average adult human lung has about 3 x loB alveoli and a total fluid surface area of about 40 m2. 2.1.4 Thoracic Lymphatic System Many laboratory studies of animals and autopsy studies of people have shown that some inhaled particles are transported from the P region to specific sites in the lymphatic system serving these tissues (Morrow,1972;Snipes et al., 1983a;Thomas, 1968).It is appropriate, 2.1 ANATOMY OF THE RESPIRATORY TRACT 1 11 therefore, to discuss the anatomic features of the lymphatic system that provide an important mode of pulmonary clearance. This clearance may bring deposited material to LN where it is brought into contact with lymphoid cells and may be stored for long periods of time. Interstitial spaces around alveoli are served by lymphatic channels that are similar to blood capillaries, but larger in diameter. The channels join to form successively larger drainage vessels whose walls become progressively less permeable to high molecular weight substances and particles. These vessels are described by Morrow (1972) as being similar to veins, in that they have a basement membrane, smooth muscle sheath, anaconnective tissue elements. Fluid flow in these vessels is primarily in the central direction along the bronchi and pulmonary arteries toward the hilar area. However, there is also evidence for some lymphatic drainage toward the pleura. Near the smaller branches of the bronchial airways, larger lymphaticvessels join and there are aggregates of lymphoid tissue. These are not sufficiently well-organized to be recognized as LN. Further up the bronchial tree, the vessels empty into LN; the most prominent of these are the bronchial and TI3 nodes surrounding the bifurcations. The LN are important collection points for a variety of materials, including insoluble particles, bacteria and cellular debris. They consist of organized aggregates of lymphoid tissue. They have fibrous capsules with afferent and efferent vessels carrying lymph through sinusoids lined by phagocytic cells. Efferent flow from the nodes serving the P region of humans moves primarily through the right lymphatic duct into the venous circulation. 2.1.5 Innervation of the Respiratory System The nervous system receives, generates, conveys, stores and processes information. Portions of the nervous system, found in nearly every tissue of the body, including the respiratory tract, play an important part in the voluntary and involuntary control and coordination of muscles, organs, glands and their subunits, tissues and cells. In the respiratory system, nerves are responsible for (1) control of muscles for breathing, adjustment of the size of bronchial airways, and control .of the cough, sneeze and gag reflexes, (2) the initiation and control of protective breathing patterns, (3) the control of secretions, (4) adjustment of the distribution of blood flow, and (5) provision of sensory information on odor, irritancy and the composition of lung tissue fluids and blood. As for the body in general, much 12 / 2. ANATOMY AND MORPHOMETRY of the information that is carried by the nervous systems of the respiratory tract is not noticed at the conscious level. Especially important in toxicologic considerations are nerves that trigger the cough reflex, nerves that lead from pressure, stretch, and chemical receptors, and nerves involved in bronchial muscle constriction, protective breathing patterns and mucus gland secretion. It is clear that the innervation of the respiratory tract is extensive and, in fact, present in nearly every region from the nose down to the alveoli. 216 .. Cls at R s el ik The respiratory tract appears to contain more than 40 distinct cell types, each with unique and important functions (Breeze and 93. Wheeldon, 1977;Evans, 1982; Jeffery, 1983; Spicer et al., 1 8 ) It is not yet possible to present a concise description of these cell populations because a variety of techniques have been used to distinguish cell types, and the scientific literature includes studies with several different animal species. Some cell types have been identified by their morphologic characteristics, whereas others have been characterized by their histochemical properties, functions or kinetics. Thus, it is likely that some overlap exists among the cell types discussed in various reports under different names. Several types of secretory cells have been described in respiratory tract epithelium. Goblet, glandular mucus, serous, Clara and Type I1 cells. Goblet and serous cells are most common in the upper airways, whereas Clara cells are found mainly in the bronchioles and Type I1 cells in alveoli. Goblet and glandular mucus cells secrete mucus; serous and Clara cells secrete thinner periciliary liquid that flows beneath the mucus. Type I1 alveolar cells secrete surfactant. Overall, ciliated cells are the most common cell type in the airway epithelium. They extend into the respiratory bronchioles and their main functions are to propel mucus toward the pharynx and transport fluids across the epithelial barrier. The basal, intermediate and secretory cells of the airway epithelium provide for growth and repair of injury. Basal cells are found in the epithelium as far as the bronchioles, but they are more numerous in the trachea and bronchi. They form along the basement membrane and are responsible for the pseudostratified appearance of the epithelium. Intermediate cells form a poorly defined layer just above the basal cells. They are spindle shaped and extend toward the surface with a nucleus that is large and oval with abundant mitochondria profiles of roughsurfaced endoplasmic reticulum. 2.1 ANATOMY OF THE RESPIRATORY TRACT 1 13 Other types of cells in the epithelium include brush cells, K cells, squamous cells, oncocytes, lymphocytes,leukocytes and neuroepithelial bodies. The functions of these cells have not been clearly defined, although the lymphocytes and leukocytes probably contribute to pulmonary defense mechanisms. Brush cells have been identified in rodents, but their presence in human airway epithelium is still under debate. Beneath the basement membrane of the airway epithelium is the lamina propria. The loose connective tissue of the lamina propria coritains mucus-secreting apparatus, mast cells, lymphocytes and lymphoid tissue. The mucus-secreting apparatus are gland-like structures that connect to the airway lumen through ducts. They are lined with mucus and serous cells that secrete mucus and periciliary fluids that cover the airway surfaces. Mucus-secreting glands are found in the airways of humans down to the small bronchi. Beginning at the respiratory bronchioles, there is a transition from columnar airway epithelium to thin, flattened epithelium that covers air spaces responsible for gas exchange. Ciliated, mucus and basal cells are not present and alveoli are covered with large squamous Type I cells and cuboidal Type I1cells (Evans, 1982).An intermediate cell type may also be present and may differentiate into a Type I cell or synthesize lamellar bodies and become a Type I1 cell. The most numerous cells in the peripheral portions of the lung are interstitial and endothelial cells. Together they account for about 70 percent of all noncirculating lung cells (Bowden, 1983; Crapo et al., 1983). The interstitial cells are a mixture of fibroblasts, pericytes, monocytes, lymphocytes and plasma cells.Their turnover is normally slow, but can be stimulated by deposition of large amounts of inhaled particles. Endothelial cells line pulmonary blood and lymphatic vessels. Their turnover rate is also slow, about one percent per day, but this increases markedly in response to injury. Damage to endothelial cells may occur from toxic substances entering either the pulmonary airways or the blood circulation. When considering damage to cells of the respiratory tract caused by radiation, several factors should be taken into account. Inhaled radioactive substances may selectively irradiate cells in the NOPL, TB or P regions, depending upon their pattern of deposition and clearance as determined by aerosol characteristics and breathing pattern. For large doses of low-LET penetrating radiation (i.e., beta or gamma rays) delivered at highdose rates, acute injuries result from widespread killing of all types of respiratory tract cells. If the exposures are to high-LET radiation with low penetration (e.g.,alpha particles), only those cells within 20 pm or as much as 200 pm of the source of the alpha particles are irradiated.