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.
(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
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
1.1 Purpose ............................................................................. 2
2
1.2 Scope ................................................................................
1.3 Description of this Report ............................................... 3
2 Anatomy and Morphometry of the Human
Respiratory Tract ...............................................................
2.1 Anatomy of the Respiratory Tract .................................
2.1.1 Naso-Oro-Pharyngo-LaryngealRegion ...............
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-LaryngealRegion ...............
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 ......................................

.

.

.

.

.


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/

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

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 at 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 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


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/

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.

1.2 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


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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 pulmonary (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 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.

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 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.


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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


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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.

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 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.


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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 (granulecontaining) (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 epidermoid metaplasia and carcinoma. Thus, the cells at 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 individual 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.
Region of Lung

-

Proeenitor
cells

Basal
Terminal bronchiolar

Clara

Alveolar

Type I1

-

-

Differentiatine
Cells

Intermediate

Type A intermediate
Type B intermediate

Terminal
Cell Types

Mucus
~i1i)ated

-

Ciliated

Cuboidal intermediate -Type

I


2.1 ANATOMY OF THE RESPIRATORY TRACT

1

15

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 contributes 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 parenchymal 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).Bronchioloalveolar tumors, which are a subset of adenocarcinomas,are found
in humans. The adenocarcinomasof humans are found in the peripheral lung and smaller airways and are the predominant tumor type
in nonsmokers (Gazdar and Linnoila, 1988; Kabat and Wynder,
1984). If the background tumor rate is due in some part to environment, external radiation, chemical carcinogens and substances of
unknown origin, then the cells that may give rise to adenocarcinomas, 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 calculating 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,


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2. ANATOMY AND MORPHOMETRY

1983). Many of these neoplasms were osteosarcomas, especially in
studies when bone-seeking radionuclides

226Ra
and 2 3 9 Pwere
~)
injected. With inhaled radionuclides, a variety of sarcomas and carcinomas 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 carcinomas 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 radioactive 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 inhalation exposures of laboratory rodents and dogs have resulted in cancers 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 segmental 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 percent. 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 respiratory 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


2.2 MORPHOMETRY OF RESPIRATORY TRACT AIRWAYS

1

17

animals exposed to insoluble particles containing long-lived betaand 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, fibrosarcoma 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 pulmonary 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 resistant 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 discussed here. However, the rates at which inhaled radionuclides are
transferred to blood can be estimated from the models described in
this Report.

2.2

Morphometry of Respiratory Tract Airways

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 airways have been made using gross dissection or sectioning with
tomography and with replica casting. Parameters of interest to respiratory tract modeling obtained using these techniques include airway 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, simplifying 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-empiricalrelationships among airflow, pressure drop, particle
size and measured particle deposition are used in this model. Unfortunately, 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 necessary for dosimetry model calculations.

2.2.1

Naso-Oro-Pharyngo-Laryngeal
Region

The dimensions of the human NOPL airways obtained from measurements 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