NCRP report no 125 deposition, retention, and dosimetry of inhaled radioactive substances

Therefore, the prediction of regional deposition and reten- tion of inhaled radioactive particles, gases and vapors in the human respiratory system, the dosimetry involved, and the deter

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

791 0 Woodmont Avenue I Bethesda, MD 2081 4-3095

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 (Title VZZ) 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

612'.01448-dc21

96-37944 CIP

Copyright Q National Council on Radiation Protection and Measurements 1997

All rights reserved This publication is protected by copyright No part of this publica- tion 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 alter- ations in smokers or those exposed to chemicals, among others, fur- ther 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 considerable uncertain- ties 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 Respira- tory Tract Dosimetry Modeling Serving on Scientific Committee 57-2 were:

Albuquerque, New Mexico

Members

George M Kanapilly* Richard B Schlesinger

North Carolina

Hsu-Chi Yeh

Inhalation Toxicology Research Institute Albuquerque, New Mexico

Consultants

Albuquerque, New Mexico

Albuquerque, New Mexico

Research Institute

Albuquerque, New Mexico

NCRP Secretariat

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 1 Introduction

1.1 Purpose

1.2 Scope

1.3 Description of this Report

2 Anatomy and Morphometry of the Human Respiratory Tract

2.1 Anatomy of the Respiratory Tract

2.1.1 Naso-Oro-Pharyngo-Laryngeal Region

2.1.2 Tracheobronchial Region

2.1.3 Pulmonary Region

2.1.4 Thoracic Lymphatic System

2.1.5 Innervation of the Respiratory System

2.1.6 Cells a t Risk

2.2 Morphometry of Respiratory Tract Airways

2.2.1 Naso-Oro-Pharyngo-Laryngeal Region

2.2.2 Tracheobronchial Region

2.2.3 Pulmonary Region

3 Physiology of the Respiratory Tract

3.1 Ventilation

3.1.1 Normal Parameters

3.1.2 Changes in Ventilation with Physical Activity

3.1.3 Effects of Aging

3.1.4 Other Factors

3.2 Clearance

3.2.1 Naso-Oro-Pharyngo-Laryngeal Region

3.2.2 Tracheobronchial Region

3.2.3 Pulmonary Region

4 Factors Affecting Normal Respiratory Tract Structure and Function

4.1 Tobacco Smoke and Other Irritants

4.2 Disease

4.3 Miscellaneous Factors

4.4 Modeling Assumptions

5 Deposition of Inhaled Substances

5.1 Particles 5.1.1 Particle Size Definitions

iii

1

2

2

3

5.1.2 Particle Inhalability

5.1.3 Deposition Mechanisms

5.1.4 Inhaled Particle Deposition Models

5.1.5 Naso-Oro-Pharyngo-Laryngeal Deposition

5.1.6 Tracheobronchial and Pulmonary Deposition

5.1.7 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-Pharyngo- Laryngeal 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-Pharyngo- Laryngeal 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

CONTENTS 1 ~ i i

7.3.3 Modifying Factors 140

7.3.3.1 Influence of Age 140

7.3.3.2 Effect of Tobacco Smoking 142

7.3.3.3 Effect of Disease States 142

8 Consideration for Nonradioactive Substances 143

8.1 Deposition of Inhaled Chemical Toxicants 143

8.2 Respiratory Tract Clearance of Chemical Toxicants 144

8.3 Chemical Dose to Cells a t Risk 146

9 Summary 150

9.1 Anatomy and Morphometry of the Respiratory Tract 150

9.2 Cells at Risk from Inhaled Radioactive Aerosols 152

9.3 Physiological Factors Related to Deposition and Clearance 153

9.4 Regional Deposition of Inhaled Particles 154

9.5 Regional Solubility of Inhaled Gases and Vapors 155

9.6 Respiratory Tract Clearance of Particles 156

9.7 Calculation of Dose from Inhaled Radionuclides 158

9.8 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

All Uranium 183

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 num- ber of unique features related to airway shapes and airflow patterns with a variety of cell types with differing radiosensitivities In addi- tion, 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 reten- tion 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 Com- mission on Radiological Protection (ICRP) have been able to take advantage of work in this area that is a t 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 a t remarkably similar mathemat- ical assessments, in general, although detailed calculations for spe- cific 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 indi- viduals 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 refer- ence 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 spe- cifically 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 incorporat- ing it Considering the degree of uncertainty associated with model- ing 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

This Report provides a summary of scientific information and mathematical models that describe respiratory tract deposition, retention and dosimetry for radioactive substances inhaled by peo- ple The treatment of deposition and retention is applicable, as well,

to nonradioactive substances The result of this review is an inte- grated mathematical model of deposition and clearance that is suit- able for calculating doses to the respiratory tract The Report provides a framework for interpreting human exposures and related bioassay measurements

This Report describes the deposition, clearance and dosimetry of inhaled substances in the respiratory tract It can be used by scien- tists, 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 deposi- tion 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 a n airway generation-by- generation basis This allows a user to pinpoint an airway for the purposes of estimating initial particle deposition, or dose, at any time after deposition

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 expo- sure, cytotoxicity, potential metabolic products and, possibly, other factors

Three mathematical models describing the deposition and reten- tion 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 radio- nuclides in air The second was published in 1966 by an ICRP Task Group on Lung Dynamics EGLDACRP (1966)1, but it was not offi- cially 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 pub- lished (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 investi- gations 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 heteroge- neous populations, including males and females of different ages, smokers and people with compromised respiratory tract defenses

This Report is divided into nine sections Section 1 is the Intro- duction 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 respira- tory 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 vari- ous body sizes and for particles of various sizes, densities, shapes, electric charge states, and hygroscopicities are also discussed Sec- tion 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 compart- ments having first-order kinetic relationships Section 7 contains a description of dosimetry models that can be used to calculate radia- tion dose to the epithelium of the naso-oro-pharyngo-laryngeal (NOPL) region, the tracheobronchial (TB) airways region, the pulmo- nary (P) region, and the TB lymph nodes (LN) This Section also 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 specifically identified and sample calcula- tions 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 path- ways, clearance rates and dosimetric data for individual radio- nuclides This information can be revised and expanded to include additional radionuclides as new data become available Lacking spe- cific 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

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 respira- tory tract may be looked upon a s 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 nasopharyn- geal region is changed to the NOPL region to emphasize the differ- ences between nasal and oral modes of breathing The TB and P regions remain essentially a s defined by t h e earlier ICRP Task Group Additionally, the thoracic lymphatic system is included a s a separate region because of its important role in pulmonary clearance and defense against inhaled insoluble toxicants Unless otherwise specified, t h e information provided i n t h i s Section applies to healthy adults

2.1 Anatomy of the Respiratory Tract

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

I t 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 ellip- tical 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 cross-

sectional 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 cili- ated 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

consists of two similar passages separated by a septum These pas- sages 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 epithe- lium covers the surfaces of the main nasal passages except for the olfactory regions at the top of the passages The cilia normally func- tion to move mucus and deposited substances back to the naso- pharynx where they are swept off the posterior wall and swallowed The septum ends at the entrance to the nasopharynx which nar- rows 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 environmen- tal conditions indicate that they vary considerably in cross-sectional opening; this is especially true for the main nasal passages Presum- ably, 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 respiration to a much greater extent, along with the nasal airway, during exercise and nasal blockage (oronasal breathing) 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 fluorogra- phy to be as narrow as 1 cm 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 posi- tioned by muscular action either against the posterior nasopharyn- geal 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 muscle- controlled 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 ai je t in the downstream direc- tion 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

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)

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 mus- cle a larger role in determining airway length and patency The smallest airways of the TB region are collectively called the bronchi- oles, which have no cartilage plates but are supported by smooth muscle Their surfaces have patches of ciliated cells that clear secre- tory fluids toward the epiglottis in the TB airways

2.1.3 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 macro- phages 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,

therefore, to discuss the anatomic features of the lymphatic system that provide an important mode of pulmonary clearance This clear- ance 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 mem- brane, 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 lym- phaticvessels 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 con- sist 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 pro- cesses 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 coordi- nation 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 secre- tions, (4) adjustment of the distribution of blood flow, and (5) provi-

sion 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 a t 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 secre- tion It is clear that the innervation of the respiratory tract is exten- sive and, in fact, present in nearly every region from the nose down

to the alveoli

2.1.6 Cells a t Risk

The respiratory tract appears to contain more than 40 distinct cell types, each with unique and important functions (Breeze and Wheeldon, 1977; Evans, 1982; Jeffery, 1983; Spicer et al., 1983)

It is not yet possible to present a concise description of these cell populations because a variety of techniques have been used to distin- guish 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 char- acterized 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 trans- port 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 bronchi- oles, 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 rough- surfaced endoplasmic reticulum

Other types of cells in the epithelium include brush cells, K cells, squamous cells, oncocytes, lymphocytes, leukocytes and neuroepithe- lial bodies The functions of these cells have not been clearly defined, although the lymphocytes and leukocytes probably contribute to pul- monary 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 I1 cells (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 ves- sels 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

14 / 2 ANATOMYANDMORPHOMETRY

For lower total doses, the major health risk is development of cancer Primary cancers develop from cells that (1) remain in the respiratory tract for a sufficient amount of time to accumulate a significant radiation dose, and (2) undergo cell division to produce viable progeny Thus, it is important to know which cells divide and their locations in the respiratory tract with respect to the source

of radiation

Historically, the target cells for cancer in the bronchial epithelium were considered to be the basal cells and perhaps the Kcells (granule- containing) (Altshuler et al., 1964; Jacobi, 1964; NCRP, 1984b) These were known to divide in response to injury and to replace mature or differentiated cells that are lost by desquamation into the airway lumen Differentiated cells, considered to be incapable of dividing, include ciliated and goblet cells

Epithelial cell renewal in bronchial airways has been described

by Evans (1982), Bowden (1983) and McDowell et al (1984) Cell kinetic studies using tritium-labeled thymidine indicate that basal, intermediate, and some nonciliated secretory cells are capable of cell division (Table 2.1) Thus, these cell types should be considered to

be at risk for developing cancer as a result of exposure to ionizing radiation This is consistent with observations of Trump et al (1978)

that mucus cells of the respiratory epithelium can give rise to epider- moid metaplasia and carcinoma Thus, the cells a t risk are located along all airways from the nasal cavity to the respiratory bronchioles, and from the surface of the epithelium to the basement membrane Studies indicate that the main cells at risk may be the secretory cells (Johnson and Hubbs, 1990) The secretory cell forms the major progenitorial compartment within the rat trachea The continuous secretion of mllcus on to the luminal surface is derived from individ- ual epithelial serous and goblet cells and mucus glands In denuded rat tracheal graRs, the secretory cell is capable of re-establishing a new epithelium composed of basal, secretory and ciliated cells In contrast, the basal cells are capable of only basal and ciliated cell differentiation The secretory cell also has a higher proliferative capacity than the basal cells, which suggests that the basal cells do

TABLE 2.1-Mechanisms for renewal of the pulmonary epithelium

Proeenitor Differentiatine Terminal Region of Lung cells Cells Cell Types

Basal - Intermediate - Mucus

~i1i)ated Terminal bronchiolar Clara - - Type A intermediate Type B intermediate - Ciliated Alveolar Type I1 - Cuboidal intermediate -Type I

not represent the major cell compartment involved in the repair and maintenance of the TB lining (Johnson et al., 1987) Following damage to the tracheal epithelium, it is the secretory cell that contri- butes most of the repair process (Keenan et al., 1982) In the lower

airways, repair of the epithelium occurs in the absence of basal cells (Evans et al., 1976) However, these studies are in contrast to others

that show the basal cell to be the progenitor cell (Inayama et al.,

1988; Ford and Terzhaghi-Howe, 1992) Until the uncertainty about

the identification of the cell at risk in human TB airways is resolved,

it may be appropriate to estimate the combined dose to the secretory cells and the basal cells

In addition to the nasal cavity and TB epithelium, the parenchymal lung should also be considered at risk Bronchioloalveolar adenomas and carcinomas have been reported in dogs and rodents following inhalation of radon progeny The origin of these tumors is either the alveolar Type I1 cells or the Clara cells (Masse, 1980) The alveolar

Type I1 cell has been shown to be the progenitor cell for the parenchy-

mal epithelium (Adamson and Bowden, 1974) The Clara cell has

been shown to be the progenitor cell for the terminal bronchioles,

an area in which basal cells are absent (Evans et al., 1976) Bronchio-

loalveolar tumors, which are a subset of adenocarcinomas, are found

in humans The adenocarcinomas of humans are found in the periph- eral lung and smaller airways and are the predominant tumor type

in nonsmokers (Gazdar and Linnoila, 1988; Kabat and Wynder,

ment, external radiation, chemical carcinogens and substances of unknown origin, then the cells that may give rise to adenocarcino- mas, Type I1 alveolar cells and Clara cells, should be considered

those at risk (NASfNRC, 1988)

In the P region, Type I1 cells, cuboidal intermediate cells, and endothelial cells are thought to be capable of dividing and giving rise to cancers This may also be true for other interstitial cell types; however, more information on the kinetics of these cells is needed

In any event, it appears appropriate to consider radiation dose in the P region as being distributed over the entire mass of cells for the purpose of projecting cancer risk

Inhaled radionuclides may selectively irradiate different regions

of the respiratory tract, depending upon the physical and chemical characteristics of the inhaled material, the anatomy of the airways, and the pattern of breathing Thus, appropriate methods for calculat- ing dose are needed for each region of the respiratory tract Cancers

of the nasal cavity and paranasal sinuses have been induced in rodents and dogs by inhaled and injected alpha- and beta-emitting radionuclides as well as by external x-ray irradiation (Benjamin,

16 / 2 ANATOMY AND MORPHOMETRY

1983) Many of these neoplasms were osteosarcomas, especially in studies when bone-seeking radionuclides 226Ra and 2 3 9 P ~ ) were injected With inhaled radionuclides, a variety of sarcomas and carci- nomas have been reported involving bone and the epithelium of the nasal cavity and sinuses In humans, sinonasal cancers have been reported to result from internally deposited radium and thorium (NASNRC, 1980) These exposures involve irradiation of bone and the epithelium of the nasal sinus cavity Osteosarcomas and carcino- mas of the head and sinus have also been reported

It is important to note that an increased incidence of nasal cancer has not been reported in human populations that had inhaled radio- active substances This is true even for uranium miners who inhaled sufficient quantities of radon and its progeny to cause an easily detected excess of lung cancer (Howe et al., 1986; NAS/NRC, 1980;

NCRP, 1984b; Radford and St Clair Renard, 1984) Similar inhala- tion exposures of laboratory rodents and dogs have resulted in can- cers of the nasal cavity (ICRP, 1979a; 1979b; NCRP, 1978) Cancers

of the nasal cavity have resulted from human inhalation exposures to

a variety of organic compounds, nickel, wood particles and chemicals used in leather, textile and petroleum industries (Hecht et al., 1983; Roush, 1979) Thus, the nasal passages are a target area for cancer development in humans, but it has not been demonstrated that this applies to inhaled radioactive aerosols

The majority of lung cancers in people occur in the central airways (Schlesinger and Lippmann, 1978) and are strongly associated with cigarette smoking Early reports estimated that about 70 percent of these lung cancers occur in ailways between the trachea and segmen- tal bronchi More recent reports (Auerbach and Garfinkel, 1991) indicate a shift in histologic type and location of lung tumors More peripheral tumors (42 percent) were found with a corresponding decrease in centrally originating tumors (60 percent) The incidence

of bronchioloalveolar carcinoma more than doubled to about 20 per- cent The shift in tumor types and location are correlated with a decrease in cigarette smoking in the general population In uranium miners exposed to elevated levels of alpha radiation from radon progeny, about 50 percent of the lung cancers occur in the central ailways and 50 percent in peripheral airways (Archer, 1978) Heavy exposures to cigarette smoke and radon progeny cause significant injury to the epithelium of the central airways; thus, the need for dosimetry calculations applicable to the central ailways of the respi- ratory tract is apparent

Few people have inhaled aerosol particles that contain long-lived radionuclides such that large radiation doses are delivered to cells lining respiratory bronchioles and alveoli However, laboratory

animals exposed to insoluble particles containing long-lived beta- and alpha-emitting radionuclides receive significant radiation doses

to these cells in the P region and develop mainly four types of tumors: bronchioloalveolar carcinoma, squamous cell carcinoma, fibrosar- coma and hemangiosarcoma (ICRP, 1979a; 197913; NAS/NRC, 1980) These types of tumors are also seen in people and laboratory animals exposed to external penetrating radiation

Inhaled insoluble radioactive particles also accumulate in pulmo- nary lymphatic vessels and nodes This leads to high local radiation doses and may result in tissue destruction, loss of immune function and cancers (ICRP, 1979a; 197913) These effects are frequently seen

in animals that received only very high radiation doses, which led

to the conclusion that pulmonary lymphatic cells are relatively resis- tant to ionizing radiation Nonetheless, dosimetry models applicable

to pulmonary lymphatic tissue are included in this Report as an aid

to researchers investigating the potential health effects related to

radiation or toxic chemicals

Radionuclides inhaled in chemical forms that dissolve in lung fluids can readily be absorbed into the blood and transported to other organs beyond the respiratory tract Of these, most significant radiation doses and health effects are then likely to occur in organs that most avidly accumulate and retain the specific chemical species Mathematical models to calculate radiation doses to these organs are subjects of other NCRP and ICRP reports and will not be dis- cussed here However, the rates at which inhaled radionuclides are transferred to blood can be estimated from the models described in this Report

Airway geometry and airflow patterns are important factors that influence the sites of deposition in the respiratory tract for inhaled substances Morphometric measurements of respiratory tract air- ways have been made using gross dissection or sectioning with tomography and with replica casting Parameters of interest to respi- ratory tract modeling obtained using these techniques include air- way cross-sectional areas, lengths, diameters, branching angles and angles of inclination with respect to the direction of gravity These parameters are necessary for constructing mathematical models for predicting regional respiratory tract deposition; however, simplify- ing assumptions are necessary in representing both airway geometry and airflow patterns Morphometric data appear to be satisfactory

18 1 2 ANATOMY AND MORPHOMETRY

for models of the TB and P regions, but airways and airflow patterns

in the NOPL region are so complex that theoretical modeling of inhaled particle deposition is just beginning to become feasible Thus, semi-empirical relationships among airflow, pressure drop, particle size and measured particle deposition are used in this model Unfor- tunately, it is not clear how these empirical relationships extrapolate

to individuals of different body size or health status The overall dimensions of nasal airways are discussed here since they are neces- sary for dosimetry model calculations

2.2.1 Naso-Oro-Pharyngo-Laryngeal Region

The dimensions of the human NOPL airways obtained from mea- surements on cadavers were summarized by Schreider (1983) The airway's dimensions did not include mucus due to the shrinkage of the mucosa after death and it is not known how their dimensions may differ from those in living people

The nares are reported to be about 11 mm + 1.6 mm wide and

20 mm + 3 mm in length (Farkas et al., 1983) The main nasal cavity measures 6 to 10 cm in length from the nares to the posterior

of the hard palate The turbinates protrude into the main nasal cavity, dividing it into narrow channels with high surface to volume ratios This is illustrated by the cross-sectional magnetic resonance (MR) images or tomographs shown in Figure 2.4 (Guilmette et al., 1989; Montgomery et al., 1979) These images begin at the base of the nostrils and continue through the main nasal cavity The shape

of the olfactory region was unclear based on the imaging data and therefore this region was indefinable in the present set of data The airways change markedly along their length, but the areas of all sections were between 0.5 and 3 cm2

Table 2.2 represents cross-sectional areas of the nasal passages

of a male human as a function of distance posterior to the nostril, obtained in vitro from magnetic resonance imaging (MRI) coronal

sections From Table 2.2, a subregion of the posterior nasal passage, including that portion extending to the mid-nasopharynx that is at risk for radiogenic tumors, is used in the retention modeling and dosimetry sections (Sections 6 and 7)

The thicknesses of the mucus layer and epithelium are of great concern when considering radiation doses to the nose These are important because the track length of alpha-emitting radionuclides

is of the same order of magnitude as the thickness of the airways The thickness of the respiratory epithelium of the nasal airways has been estimated in the human, monkey and dog to be about 40 to

Distance

from

et a/ (1 979)

Fig 2.4 Coronal sections obtained by MRI of the nasal airways of a male subject

in normal and decongestive breathing (Guilmette et al., 1989) and of a male cadaver

using computed tomography (Montgomery et al., 1979)

20 1 2 ANATOMY AND MORPHOMETRY

TABLE 2.2-Cross-sectional areas within the nasal passages for the normal male

human (Guilmette et al., 1989)

Sections Normal Airways Decongestive Airways

nose) (nun2) (rnrn2) (rnrnz) (rnrn2)

50 pm (Bond et al., 1988; Harkema et al., 1987; Jafek, 1983) With all of these assumptions for dose modeling, the total mass of the posterior nasal region was 0.4 to 0.5 g Moving toward the outside

of the body, the anterior nose is covered by squamous epithelium typical to any other area of the body Radioactive particles are not expected to cause epithelial tumors in this area and no dimensions are given

The distance to the nostrils was measured by Guilmette et al (1989) using MR images; however, Montgomery et al (1979) did not include measurements but approximations were later made The velocity of airflow through the nasal airways is highest at the nasal valve (the juncture of the vestibule and the main nasal cavity) and along the air channel between the medial and inferior nasal

turbinates (Swift and Proctor, 1977) The nasal airflow pattern is illustrated in Figure 2.5 Detailed morphometry and airflow informa- tion is not available for the nasal airways of people of different body sizes

The dimensions of the oral passage vary greatly depending upon the positions of the lips, jaw, tongue and palate The central passage can be quite narrow during quiet breathing, 1 to 2 cm in the vertical direction, and the cross-sectional area is generally similar to that of the nasal airways (Swift and Proctor, 1977) During exercise, the jaw is usually dropped and the tongue is flattened to increase the airway cross section and reduce the resistance to airflow At rest, the average airflow velocity a t the entrance to the mouth is approxi- mately 1.6 m s-'; during exercise the average velocity is similar due

to opening the mouth

2.2.2 Tracheobronchial Region

The TB region consists of the trachea and the bronchial tree down

to and including the terminal bronchioles The NOPL and TB regions constitute the anatomical dead space of the respiratory tract They also include the major epithelial area of the respiratory tract that

is ciliated and covered with mucus Many morphometric models have been proposed for this region An early model used by Findeisen (1935) and Landahl (1950) consists of only six airway generations

in the TB region I t was widely used for inhaled particle deposition

Fig 2.5 Linear velocity of the inspiratory nasal aidow as derived from model studies The nostril is to the left The size of each dot indicates velocity and the arrows show the direction of the air flow Note the indication of a vortex near the top of the turbinates (Swift and Prodor, 1988)

22 1 2 ANATOMY AND MORPHOMETRY

calculations until the publication of models by Weibel(1964) and by Yeh and Schum (19801, which consist of 16 or 17 airway generations

in the TB region

The early lung models of the human respiratory tract were based upon either a functional concept of structure or an anatomical description (Davies, 1961; Findeisen, 1935; Horsfield and Cumming, 1968; Landahl, 1950; Weibel, 1964; Weibel and Gomez, 1962) These are ordered generation by generation in a tree-like manner Alavi

et al (1970) studied the angle of tracheal bihrcation in humans Olson et al (1970) proposed an average complete asymmetric lung model closely resembling the model of Weibel (1964) Hansen and Ampaya (1975) described a 26-generation lung model by using Weibel's &st 10 model generations and their own analysis of mea- surements of parenchyma

The respiratory tract morphometry model used to calculate the deposition of inhaled substances in this Report was published by Yeh and Schum (1980) It is called the Typical Path Lung Model (TPLM) and includes 16 airway generations between the trachea and the terminal bronchioles and nine more generations to the alveoli (Table 2.3) Data on individual lobes of the human lungs are also available Each generation is represented by a median length (L),

diameter (d), branching angle (8) and the angle with respect to grav- ity (4) These dimensions are based upon measurements obtained from a silicone rubber cast of the lungs in situ of a 60 y male who died of a myocardial infarction Other lung morphometry models published by Weibel (1964), Horsfield and Cumming (1968) and Horsfield et al (1971) are based upon measurements of different lung casts, but they are all sufficiently similar that the use of any

of the models in predicting the deposition of inhaled substances is likely to produce comparable results

Variability in the anatomy of the human upper bronchial tree was studied by Nikiforov and Schlesinger (1985) using replica casts obtained from eight adult males They showed variability in the first eight airway generations for both diameter and length This information is used to quantify the effect of changes in airway dimen- sions on particle deposition calculations using the TPLM

Phalen et al (1985; 1988) measured growth-related changes in airway sizes from in situ casts of children and young adults (male and female) who were between 11 d and 21 y of age and ranged from 48 to 190 cm in height They expressed airway lengths (L,) and diameters (D,) as functions of body height (HI using linear relationships:

L, = a,, H + b,

D, = c , H + d, (2.1)

24 / 2 ANATOMY A N D MORPHOMETRY

where n refers to airway generation number and a,, b,, c, and d, are fitted constants Here, L,, D, and H are all expressed in cm and the constants are summarized in Table 2.4 One should note that the relationship of Equation 2.1 was developed based solely on the right apical lobe of the casts Therefore, there is a n uncertainty in its applicability to the whole lung and it may not extrapolate correctly

to adult lung However, it represents the only available data for children

The airway measurements and relationships to body height

reported by Phalen et al (1985) are similar to those of the mathemati- cal model derived by Hofmann (1982) The latter model related air- way dimensions to age; however, by using a typical relationship between age and height, it can be shown that the two studies gener- ally agree within 30 percent in estimating the dimensions of the conducting airways

The age or body size relationships for infants to adults are shown

in Table 2.5 The Table also contains the dead-space volumes for each age (this volume varies from 2 1 cm3 for the 2 y old to 101 cm3 for the adult) These values should be assumed to be only approximately correct as there is little information available on the variability of human TB dead-space volume

The TB airways are important because most radiogenic cancers occur in the first few generations of the respiratory tract Altshuler

TABLE 2.4-Constants used to describe model airway dimensions for people of

different heights according to Equation 2.1

Airway Length Airway Diameter

TABLE 2.5-Age and body size relationships for United States children as used in the respiratory tract model Tracheal cross-sectional areas are from Griscom and Wohl (1985) TB dead-space volume is the diference between total dead space and airway (mouth, pharynx, larynx) volume from Schum et al (1991) -

TB Dead Age Height Body Mass Racheal Area Space Volume

et al (1964), Gastineau et al (1972), and Wagoner et al (1965)

measured wall thickness of the first few generations from photo- graphs, and found them to be about 40 pm thick However, Mercer

et al (1991) measured the epithelium from the sixth through the

sixteenth airway generations and these results are given in Table 2.6 This Table is used in Section 7 concerning the dosimetry of the respiratory tract

2.2.3 Pulmonary Region

The P region is the area of gas exchange in the lungs It includes the respiratory bronchioles, alveolar ducts, alveolar sacs and alveoli

To extend the model into the P region, Yeh and Schum (1980), based

on Weibel's (1964) morphometric data for the P region, made the following assumptions: about 20 alveoli are associated with each alveolar duct, regular dichotomous branching occurs beyond the ter- minal bronchioles, several generations ofrespiratory bronchioles and alveolar ducts are followed by a single generation of alveolar sacs, the same number of generations of respiratory bronchioles and alveolar ducts are found in the various lobes, the length to diameter ratios

TABLE 2.6-Epithelial thickness of human TB airways (Mercer et al., 1991)

26 1 2 ANATOMY AND MORPHOMETRY

of alveolar sacs is 1.22, either the number or the diameter of alveoli

is known and the total volume of the alveoli is approgmately equal

to 65 percent of the total lung capacity (TLC) at full inspiration The results of these assumptions are included in airway generation numbers 17 through 25 of Table 2.3, but nowhere else in this Report

Physiology of the

Respiratory Tract

The most important physiological parameters required for respira- tory tract dosimetry modeling are those related to ventilation and clearance mechanisms Ventilation affects the amount and distribu- tion of inhaled material that deposits in the respiratory tract The clearance rates and pathways determine the residence time of the deposited material in each respiratory tract locale and the subse- quent dose from deposited material to surrounding tissues

Ventilatory parameters describe the volumes and rates at which air is inhaled and exhaled To determine the amount of an inhaled substance that is available for deposition in the respiratory tract, it

is necessary to know (1) the tidal volume or volume of air in each breath, (2) the breathing frequency, and (3) the functional residual capacity (FRC) or volume of air that remains in the lungs after exhalation To predict deposition for different individuals, it is also necessary to know how these parameters change with body size, physical activity, age and health status Defined fractional divisions

of the respiratory gas volume are illustrated in Figure 3.1 All such

a

INSURATORY CAPACITY

28 / 3 PHYSIOLOGY OF THE RESPIRATORY TRACT

volumes in this Report are given for gas at body temperature (37 OC),

standard pressure (760 mm Hg) and saturated with water vapor

is the anatomical dead-space volume In individuals between 4 and

40 y of age, the anatomical dead-space volume is approximately proportional to body mass, and generally represents 150 to 200 mL

in adult males and 120 to 160 mL in adult females The remainder

of the tidal volume enters the P region where it mixes with the functional residual air or the FRC Not all of this air is equally effective in oxygenating blood; some enters alveoli that are under- perfused with blood The portion of the tidal volume that enters alveoli, but does not take part in gas exchange, is the alveolar dead- space volume This is small in healthy individuals; the total or physi-

ologic dead-space volume (i.e., anatomical dead-space volume plus

alveolar dead-space volume) represents no more than 20 to 30 per- cent of the tidal volume

During expiration, air within the TB tree is expelled along with some alveolar air The alveoli contain a mixture of air from a number

of inspirations Thus, substances inhaled into the P region may be exhaled during several subsequent breaths (Davies et al., 1972) The time available for deposition of airborne substances in the NOPL and TB airways is generally a few seconds or less, but it can be up

to a minute or more in the pulmonary airways

Total ventilation or minute volume is the total volume of air inspired each minute and is equal to the tidal volume times the breathing frequency The average frequency during normal quiet breathing in adults is 11 to 17 breaths per minute; the resting minute ventilation is about 10 L min-l Typical values for these parameters are given in Table 3.1; however, a range of values for minute volume may be obtained with various combinations of tidal volumes and breathing frequencies The minute volume includes anatomical dead- space ventilation and total alveolar ventilation, the latter being the amount of air entering the P region each minute Normal values for ventilation vary with age, gender and body size In humans, body mass correlates well with minute ventilation

30 / 3 PHYSIOLOGY OF THE RESPIRATORY TRACT

3.1.2 Changes in Ventilation with Physical Activity

Changes in ventilation occur as physical activity i s varied (Table 3.1) When increasing physical activity, there is likely to be

a shift from nasal to oronasal breathing (see Table 3.2) This change

in breathing mode occurs partially because, as inspiratory airflow increases, nasal airway flow resistance also increases The shift in mode of breathing occurs at different activity levels in different individuals and acts to reduce total airflow resistance in the NOPL region The maximum level of inspiratory nasal airflow is between

60 to 120 L min-', although the shift from nasal to oronasal breathing occurs at lower flows For normal augmenters, i.e., those who nor- mally breath through their nose, this shift occurs between 30 and

40 L min-' (Niinimaa et al., 1981; Swift and Proctor, 1977) These changes in ventilation can influence deposition in the more distal regions of the respiratory tract (Miller et al., 1988)

The amount that ventilation increases during exercise is deter- mined by several factors, including the rate of COz production, the level at which arterial Pcoz is maintained by respiratory control mechanisms and the ratio of total dead space to tidal volume Maxi- mum voluntary ventilation (i.e., the m h m u m volume of air that can be inhaled per minute) may be increased to more than 10 times the resting ventilation level by increasing both tidal volume and breathing frequency With moderate activity, tidal volume increases largely through an increase in the volume of air inspired (i.e., the tidal volume increases at the expense of the inspiratory reserve volume) With heavy activity, tidal volume increases further through

a decrease in the volume of gas remaining in the lungs a t the end

of expiration (i.e., a t the expense of the expiratory reserve volume) Concurrent with increases in tidal volume, anatomic dead-space volume increases with increasing activity level, but decreases as a fraction of the tidal volume ( v ~ ) A ~ maximal inspiration, anatomic dead-space volume may be as high as 230 mL in males Larger changes in dead-space ventilation associated with changes in breath- ing patterns are due to changes in breathing rate As the frequency of breathing rises with increasing activity level, the time of expiration diminishes while that for inspiration remains relatively constant Respiratory pause (i.e., the time between expiration and inspiration) also changes with activity level Resting individuals may have pauses that can occupy 25 percent of the breathing cycle, but with increasing levels of activity, the pauses become shorter

3.1.3 Effects of Aging

Lung function and the physiologic response to exercise are similar

in children and young adults after adjusting for body size differences

TABLE 3.2-Proportion of airflow entering the nose and the mouth as a function of minute ventilation in normal augmenters and mouth breathers."

Minute Ventilation (L min-')

"Data derived from Niinimaa et al (1981)

However, due to body size differences between children and adults, the contributions of VT and breathing frequency to total ventilation differ In children, the contribution of breathing frequency is greater, and that of VT is less than in adults; these differences gradually decrease as children grow to adult size (Table 3.1)

Ventilatory function improves and then deteriorates with increas- ing age, although the transition between growth and senescence is not well characterized Various models have been proposed to describe the functional deterioration that occurs after peak ventila- tory function is reached between the ages of 20 to 35 y (Buist, 1982) Some models project that after the peak, there is a steady functional decline (i.e., aging is constant throughout adult life) Other models project that after the peak, lung function remains constant for a short period and then decreases beginning in the late 30s to early 40s (i.e., there is a phase in early adult life when there is little or

no age-related deterioration) In some models, pulmonary function changes with aging are independent of body height and there are

no differences in function between individuals within any age groups Other models propose a relationship between height, age and func- tional change In any case, all of the models and clinical measure- ments clearly indicate that, a t some point, there is a decline in lung performance with increasing age (Schlesinger, 1990a)

Changes in lung function with age are the result of changes in lung tissue, 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 dis- ease and chronic or acute exposures to inhaled toxicants Some venti- latory indices are affected by age, while others are not Residual volume as a fraction of TLC increases from 20 to 25 percent in males and females between ages 20 and 37 and to 40 percent by age 60 This is due almost entirely to changes in residual volume, since the TLC a t age 60 is 90 to 100 percent of that a t age 20 Vital capacity decreases with age, but the FRC increases by about 40 percent between the ages of 20 and 60

32 1 3 PHYSIOLOGY OF THE RESPIRATORY TRACT

Aging is also associated with a decrease in the uniformity of p e h - sion, resulting in an increase in alveolar dead space This factor, plus the increase in anatomic dead space, results in an increase in the percentage of the tidal volume that ventilates the total dead space, from 20 to 30 percent by age 20 to 40 percent by age 60 Resting levels of minute volume show no major change with age However, aging does affect the ability of the lungs to respond to increasing activity levels The maximum voluntary ventilation declines by about 30 percent between ages 30 and 70

I t should be noted t h a t most reference values for age-related changes in lung function are derived from population measurements and may not reflect the true aging process, especially since these studies may be measuring the hardiest survivors The best way to avoid possible bias is to examine true aging patterns in longitudinal studies, but these are not available

3.1.4 Other Factors

Ventilation is also affected by inhaled toxicants, altitude, ambient temperature, smoking and state of health However, except for major alterations in lung disease, these factors are considered to be of lesser importance in predicting inhaled particle deposition than is activity level in any given situation (NCRP, 198413)

Retention times and clearance pathways for particles in the respi- ratory tract depend primarily upon the sites of deposition, site- related mechanical clearance rates, and particle dissolution rates During the time that particles are retained in the respiratory tract, some of their mass may be transported to the blood Very soluble material can readily be absorbed from all regions of the respiratory tract, but very insoluble material may have little systemic absorp- tion The amount of a substance reaching the blood is determined

by competitive interaction between mechanical clearance processes that transport material to the gastrointestinal (GI) tract (mucociliary clearance) and lymphatics, and absorption processes that transport substances released from particles directly to blood vessels, or through lymphatic vessels and nodes to the blood On the other hand, whole particles may pass into the blood without dissolving (Gearhart

et al., 1980; Guilmette et al., 1987; Stradling et al., 1978a; 197813) This rarely occurs for large particles [>5 Fm AMAD (activity median

aerodynamic diameter)], but it appears to be enhanced by radiation damage to lung tissue

Particle dissolution plays a major role in determining the amount absorbed, but the rate of dissolution is often difficult to predict in the complex environment of the respiratory tract For example, the particles may remain in contact with mucus or extracellular fluid for a short time, perhaps 1 to 2 h, after they are inhaled After the particles are engulfed by phagocytic cells, their dissolution rate may

be affected by contact with fluids in phagocytic vesicles Prolonged retention of radioactive elements in lung tissue can also occur even when they are inhaled in water-soluble forms, due to binding with tissues (Kanapilly and Goh, 1973) This may also result from precipi- tation of insoluble chemical forms or binding to endogenous ligands Soluble material from all regions of the respiratory tract may be absorbed into the blood with or without passing through lymphatic vessels Macrophages engulf particles in alveoli and transport them

to LN (Harmsen et al., 1985) where they may be retained for long periods of time (Thomas, 1968) Presumably, dissolution of material from particle surfaces also occurs in LN Highly soluble chemical compounds that deposit on alveolar surfaces will rapidly dissolve and pass through lymphatic vessels to the blood circulation (Morrow, 1977) Because of the speed a t which soluble material moves through lymph vessels to blood, it is doubtful that macrophage transport is

an important factor for this pathway

3.2.1 Naso-Oro-Pharyngo-Laryngeal Region

Clearance from the nasal passages occurs by mechanical and absorption processes Except for the most anterior portion, the nasal passages are lined with ciliated epithelium overlaid by mucus The flow of mucus in the ciliated nasal passages is toward the nasophar-

ynx, although the path for mechanical clearance can be circuitous

In the nonciliated region of the anterior nares, mucus flow is forward This clears deposited material to the vestibular area where removal

is by extrinsic means (e.g., sneezing, wiping, blowing) The vestibular area in humans is not ciliated and contains no mucus secreting cells; however, glands originating in more distal areas have long ducts that deposit secretions into the vestibule

There are large variations in nasal mucus flow rates at similar sites in different individuals In addition, there are large variations

in flow rates in different regions of the nasal airways, even in the same individual; the most rapid flow occurs in the mid-portion of the nasal passages Mucus velocities in the main nasal passages of