Deposition, Retention, and Dosimetry of Inhaled Radioactive Substances: Recommendations of the National Council on Radiation Protection & Measurements (N C R P Report)

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

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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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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

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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

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Clearance

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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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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

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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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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

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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.

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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

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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

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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).

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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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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,

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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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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.

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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.

14

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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,

16

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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

2.2 MORPHOMETRY OF RESPIRATORY TRACT AIRWAYS

Distance from Nostrils

Normal

Decongested

Guilmette et a/. (1989)

1

19

Cadaver

Montgomery et a/. (1979)

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

TABLE2.2-Cross-sectional areas within the nasal passages for the normal male human (Guilmette et al., 1989). Sections (mm from nose)

Normal Airways Right (nun2) (rnrn2) Left

Decongestive Airways Left Right (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

2.2 MORPHOMETRY OF RESPIRATORY TRACT AIRWAYS

1

21

turbinates (Swift and Proctor, 1977). The nasal airflow pattern is illustrated in Figure 2.5. Detailed morphometry and airflow information 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, 1to 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 at the entrance to the mouth is approximately 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 morphometricmodels 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. It 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 measurements 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 gravity (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 dimensions 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 mathematical model derived by Hofmann (1982). The latter model related airway dimensions to age; however, by using a typical relationship between age and height, it can be shown that the two studies generally 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 21 cm3for the 2 y old to 101 cm3for 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 TABLE2.4-Constants used to describe model airway dimensions for people of different heights according to Equation 2.1. Airway Length

na (em)

a. (em)

b, (cm)

Airway Diameter en (cm)

d. (em)

0.0690 0.150 0.010 1 0.0500 0.0886 0.679 0.0069 2 0.0180 0.0046 0.0982 3 0.0070 0.246 0.0033 0.0937 4 0.0053 0.124 0.0017 0.0999 0.196 5 0.0035 0.0014 0.0711 0.113 6 0.0033 0.0012 0.0541 7 0.0022 0.112 0.0007 0.0496 0.133 8 0.0013 0.0004 0.0499 0.152 9 0.0008 0.0003 0.0488 0.130 10 0.0009 0.0002 0.0479 11 0.0007 0.129 0.127 0.0001 0.0461 12 0.0006 0.00009 0.0452 0.125 13 0.0005 0.00006 0.0440 14 0.0004 0.123 0.0429 0.121 0.00004 15 0.0003 0.00002 0.0419 0.120 16 0.0002 "Airway generation numbers were changed numerically from 0 through 15 as presented by Phalen et al. (1985;1988) to 1 through 16 to correspond with those in the rest of the Report.

2.2 MORPHOMETRY OF RESPIRATORY TRACT AIRWAYS

1

25

TABLE2.5-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 (Y)

Height (cm)

Body Mass (kg)

Racheal Area (cm')

Space Volume (m3)

2 4 6 8 10 12 14 16 18

88 104 115 127 138 150 162 170 175

10 16.4 22 27 34 43 54 63 70

0.317 0.488 0.633 0.817 1.012 1.255 1.531 1.734 1.869

21 31 39 49 59 68 85 95 101

et al. (1964), Gastineau et al. (1972), and Wagoner et al. (1965) measured wall thickness of the first few generations from photographs, 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 terminal 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 TABLE2.6-Epithelial

thickness of human TB airways (Mercer et al., 1991).

Airway Diameter (mm)

3 to 5 1 <1 Terminal "Thickness does not include mucus.

Generation (approximate)

6 to 9

13 14 to 15 16

Thickness' (~m)

57 50 15 10

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 respiratory tract dosimetry modeling are those related to ventilation and clearance mechanisms. Ventilation affects the amount and distribution 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 subsequent dose from deposited material to surrounding tissues.

3.1 Ventilation 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

t

4

t

t

t t

INSURATORY CAPACITY

E0

z 5 P

A 3 -I

2 t 0

FUNCTIONAL RESIDUAL CAPACITY

RESIDUAL VOLUME

*

v SPECIAL DlVlSlONS FOR PULMONARY FUNCTION TESTS

Fig. 3.1.

1

- -

PRIMARY SUBDIVISIONS OF LUNG VOLUME

Divisions of the respiratory tract gas volume.

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.

3.1.1 Normal Parameters The amount of air inspired during a normal breath is the tidal volume; it varies with age, body size and the level of physical activity as shown in Table 3.1. Not all of the tidal volume which passes through the mouth or nasal passages, pharynx and larynx reaches the TB airways and the P region. The volume that fills the conducting airways (i.e., NOPL and TB airways in which no gas exchange occurs) 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 underperfused with blood. The portion of the tidal volume that enters alveoli, but does not take part in gas exchange, is the alveolar deadspace volume. This is small in healthy individuals; the total or physiologic dead-space volume (i.e., anatomical dead-space volume plus alveolar dead-space volume) represents no more than 20 to 30 percent 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 11to 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 deadspace 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 is 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 120L min-', although the shift from nasal to oronasal breathing occurs at lower flows. For normal augmenters, i.e., those who normally 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 determined by several factors, including the rate of COz production, the level at which arterial Pcozis maintained by respiratory control mechanisms and the ratio of total dead space to tidal volume. Maximum 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 at the end of expiration (i.e., at 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 ~ inspiration, anatomic fraction of the tidal volume ( v ~ ) . Amaximal dead-space volume may be as high as 230 mL in males. Larger changes in dead-spaceventilation associated with changes in breathing 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.

3.1 VENTILATION

1

31

TABLE 3.2-Proportion of airflow entering the nose and the mouth as a function of minute ventilation in normal augmenters and mouth breathers." 10

1 Nose 0 Mouth 0.7 Mouth breathers Nose 0.3 Mouth "Data derived from Niinimaa et al. (1981).

Normal augmenters

Minute Ventilation (L min-') 20 30 40

60

1 0 0.4 0.6

0.45 0.55 0.3 0.7

1 0 0.47 0.53

0.53 0.47 0.34 0.66

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 increasing 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 ventilatory 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 functional change. In any case, all of the models and clinical measurements 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 disease and chronic or acute exposures to inhaled toxicants. Some ventilatory 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.

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3. PHYSIOLOGY OF THE RESPIRATORY TRACT

Aging is also associatedwith 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. It should be noted that 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).

3.2 Clearance Retention times and clearance pathways for particles in the respiratory tract depend primarily upon the sites of deposition, siterelated 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 absorption. 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 lymphaticvessels 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

3.2 CLEARANCE

1

33

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 1to 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 precipitation 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 nasopharynx, 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

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3. PHYSIOLOGY OF THE RESPIRATORY TRACT

healthy adults are shown in Table 3.3. Overall clearance of material from the ciliated portion of the nasal passages occurs with a mean time of > 1 to 24 mm min-Iwith an average time of 6 mm min-'. Secretions and deposited material in the nonciliated part of the nasal passages are cleared more slowly. Hilding (1963) suggests a flow rate of 1to 2 mm h-' for fluid in this region. Thus, material in the anterior portion of the nasal passages is removed with a halftime estimated to be from 3 to more than 12 h (Fry and Black, 1973; Morrow, 1977). Soluble material deposited on the nasal airways is accessible to underlying cells if it can diffuse through the mucus layer. Since there is a rich vasculature in the main nasal passages, uptake into the blood may occur rapidly. Thus, the nasal mucosa is a potentially important site for absorption of deposited material into the blood circulation. In addition, as was discussed in Section 2.1.6, some soluble materials inhaled by Beagle dogs have shown long-term retention and have produced excess tumors. However, similar phenomena in humans have not been noted for radioactive aerosols. From the trachea, the larynx receives mucus which moves upward and passes over the posterior commissure into the hypopharynx and is swallowed. The vocal cords are lined with squamous epithelium, which interferes with the normal axial flow of mucus. Mucus is probably pulled by traction of the surrounding mucus layer, but a relative slowing of mucus clearance often occurs in this region.

3.2.2 Tracheobronchial Region Airway surfaces from the trachea through the respiratory bronchioles are lined with ciliated epithelium overlaid by mucus; however, the physical structure of the mucus blanket is controversial. It has been described as being relatively continuous (Holma, 1971; TABLE3.3-Measurements of particle clearance velocities in the posterior nasal airwavs.

Measurement Technique

Particle Clearance Velocity (mm min' '1 Mean Range

Inert powder

5

Inert powder I3'I labeled albumin %"Tclabeled resin beads %"Tclabeled resin beads *"Tc labeled polystyrene particles

4.2 6 7 8.4 6.8

3 to 8

Reference

van Ree and van Dishoeck, 1962 1 to 12 Ewert, 1965 4 to 14 Proctor and Wagner, 1965 0 to 15 Quinlan et al., 1969 2 to 24 Andersen et al., 1971 2 to 18 Black et al., 1974

3.2 CLEARANCE

1

35

Sturgess, 1977) or existing as discrete droplets or plaques (Iravani and van As, 1972; van As and Webster, 1974). Nevertheless, mucus in the TB airways is moved toward the oropharynx. In the bronchioles, fluid movement is likely due to ciliary beating as well as surface tension differences between fluids in the bronchioles and alveoli. The velocity of mucus flow is most rapid in the trachea, and it becomes progressively slower in more distal airways. More rapid mucus velocity is expected in the larger airways, since the total internal surface area of each airway generation decreases, beginning at the bronchioles and moving to the trachea. Thus, the velocity of the fluid blanket increases from the distal to proximal airways and this, together with fluid resorption, which may also occur along the airways, prevents fluid pooling (Asmundsson and Kilburn, 1970). The surfaces over which mucus flows are not uniform; there are openings for daughter bronchi and islands of nonciliated cells at bifurcations. The speed at which these obstacles are passed may be dependent upon the traction of the mucus layer, since no cilia are present. Thus, there may be areas of relatively slower flow all along the TB tree. The rate of clearance of insoluble particles deposited in TB airways has been studied using fiberoptic bronchoscopywith visible particles, fluoroscopy with radiopaque particles, and external counting with radioactive particles (Table 3.4). Fiberoptic bronchoscopes have been used to instill small Teflon discs into the lower trachea and to observe their rates of movement along with mucus clearing toward the oropharynx (Santa Cruz et al., 1974; Wood et al., 1975).A similar technique was used by Goodman et al. (1978)to instill radiopaque Teflon discs into the trachea, but their movement was measured using fluoroscopes. The most commonly used technique is to instill or inhale radioactive particles and follow the clearance of boli moving up the trachea by external counting (Camner et al., 1973a; Chopra et al., 1979; Foster et al., 1980; 1982; Yeates et al., 1975).All of these studies measured particle clearance velocities in the trachea, but only one study measured clearance velocities in the major bronchi (Foster et al., 1980). The various empirical and analytical approaches used to estimate transport rates of mucus in TB airways were reviewed by Schlesinger (1985).The use of these different approaches produced wide variability in the measured values, but there are also large differences among individuals, regardless of the technique used. Measured rates of mucus movement in the human trachea range from 4 to 22 mm rnin-', depending upon the experimental technique used (Table 3.4). The use of anesthesia or invasive procedures affects transport and results in measured rates that are apparently slower than normal.

TABLE3.4-Measured clearance velocities for insoluble particles in the trachea and main bronchi of nonnal humans. Technique

Location

Particle Velocity (mm min-')

Reference

Fiberoptic bronchoscopy Midtrachea 20.1 Wood et al., 1975 with Teflon discs Midtrachea 21.5 Santa Cruz et al., (0.68 mm d , 0.13 mm thick) 1974 Goodman et al., Fluoroscopy of instilled Trachea 5.8 to 10.la radiopaque Teflon discs 1978 (1 mm d , 0.8 mm thick) Gamma camera imaging Trachea 15.5 Chopra et al., 1979 of instilled albumin microspheres (3 to 7 pm d ) Gamma camera imaging Trachea 3.6 Yeates et al., 1975 of inhaled albumin microspheres (1.4 pm d , 0.5 pm CMDb) Gamma camera imaging Trachea 5.5 Foster et al., 1982 of inhaled femc oxide (3.63 to 4.38 pm, MMADb) (4.13 to 5.34 pm, Main bronchi 2.4 Foster et al., 1980 MMADb) "Highervalue for individuals <30 y of age; lower value for individuals over 55 y of age. bCMD is count median diameter, MMAD is mass median aerodynamic diameter.

In unanesthetized healthy nonsmokers, average tracheal mucus transport rates of 4 to 6 mm min-I have been found using a noninvasive measurement procedure (Foster et al., 1980;Leikauf et al., 1981; 1984; Yeates et al., 1975; 1981b). It is more difficult to measure mucus velocities in airways distal to the trachea. The mean fluid velocity in the main bronchi was reported in one study to be about 2.4 mm min-' (Foster et al., 1980), but more distal airways of the human bronchial tree have not been directly measured. Transport rates in medium-sized human bronchi have been calculated to be 0.2 to 1.3 mm min-' (Yeates and Aspin, 19781, while those in the most distal ciliated airways may range as low as 0.001 mm min-' (Morrow et al., 1967a; Yeates, 1974; Yeates and Aspin, 1978). Since mucus flow rates in distal airways of humans have not been directly measured, the total duration of the overall clearance of material deposited in the TB region is generally used as an index of clearance function. In healthy nonsmoking humans, most deposited material with very low dissolution and absorption functions will normally be cleared from the TB tree within 24 h (Albert et al., 1969;

3.2 CLEARANCE

/

37

Carnner and Philipson, 1978),but the rate of clearance depends upon the site of deposition. The presence of disease or exposure to irritants may depress mucociliary function and extend the time for clearance beyond 24 h. Other investigators have suggested that bronchial clearance in peripheral airways extends beyond 24 h, even in healthy individuals (Clarke and Pavia, 1980).Svartengren et al. (1981)found a slow phase of clearance for 6 pm AD (aerodynamicdiameter) Teflon particles instilled into the trachea and at the first bifurcation of rabbits; the half-time for the latter region was 39 h. Some recent studies have indicated that a fraction of deposited material may actually be retained within the TB epithelium for prolonged periods of time. Intratracheally instilled material (BaSO, and UOz)has been shown to remain associated with the conducting airway epithelium of rats for at least 30 d after administration (Patrick, 1979; Patrick and Stirling, 1977), but the amount that remained was less than one percent of the total administered. In these cases, damage to the epithelium due to the instillation procedure could have enhanced penetration of the particles into the surrounding tissues. However, there is evidence of a long-term retention in the TB epithelium, even for inhaled particles. Gore and Patrick (1978) found prolonged retention of a small fraction (less than one percent) of inhaled UOz [2.4 to 2.8 pm M W (mass median aerodynamic diameter)] in the trachea and at the filst bifurcation of rats. Watson and Brain (1979) reported that inhaled iron oxide particles (0.15 pm M W ) were taken up by epithelial cells in the trachea and large intrapulmonary bronchi of mice. In both studies, exposure concentrations were high (i.e., 300 mg m-3 and 32 to 70 mg m-3, respectively). The mechanisms by which particles penetrate into the epithelium are unknown. They may include active uptake (i.e., phagocytosis by epithelial cells or airway macrophages, with subsequent translocation into epithelial tissue) or passive movement into the tissue (Gore and Patrick, 1982; Sorokin and Brain, 1975; Stirling and Patrick, 1980; Watson and Brain, 1979). Long-term retention of material in the epithelium of airways may also depend upon the specific characteristics of the particles being studied. In rats, Gore and Patrick (1982)found inhaled U02at 8 to 10 pm beneath the lumenal surface at 7 to 17 d after exposure, and instilled BaS0, at 10 to 15 pm deep 24 h after exposure. Widely variable clearance times in different individuals for the whole of the TB region have been found, largely because clearance is related to the initial site of deposition of particles. Centrally deposited material is cleared faster due to its shorter pathway and the progressive increase in mucus velocity from the peripheral bronchi

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3. PHYSIOLOGY O F THE WSPIRATORY TRACT

to the trachea; coughing may also aid in clearance from the upper TB tree when mucus loading is heavy. Albert et al. (1973)found that in healthy adult nonsmokers, 90 percent of bronchial clearance was completed between 2.5 and 20 h, depending upon the size of the tracer particle (plus resultant deposition site) used. There are no apparent gender-related differences in mucociliary clearance rates based upon measurements of either tracheal mucus velocity or overall TB clearance in males and females. The evidence for age-related differences in mucociliary function in healthy individuals is contradictory.In one study (Goodman et al., 19781, the average tracheal mucus velocity was found to be up to 60 percent slower in a group of elderly nonsmokers (56 to 70 y) when compared to their younger counterparts (19 to 28 y). However, most of the older people had lived in industrial environments and it was difficult to determine whether the age-related decrement in function was due to aging alone, or to long-term,low-level exposures to poIlutants (Wanner, 1977). In another study of nonsmoking adults, no association between tracheal mucus velocity and age was noted for groups of individuals 18to 24 y, 25 to 29 y, or more than 30 y (Yeates et al., 1981a). For bronchial clearance, Pavia et al. (1970) found a weak inverse associationbetween age and clearance rates in subjects that included cigarette smokers. Pnchelle et al. (1979) examined bronchial clearance in nonsmoking males, separated into three age groups, with mean ages of 25 y (21 to 37 y), 45 y (38 to 54 y) and 64 y (55 to 71 y). The amount of clearance that occurred during the measurement period was 35 percent less in the oldest group compared to the youngest group. The amount of clearance in the middle group was less than that in the youngest and greater than that in the oldest group, but it was not significantly different from either. There are few studies of the effect of exercise on mucociliary clearance. Wolff et al. (1977) found increased bronchial clearance rates with exercise (i.e., brisk pedaling on an ergometer for 30 min) compared to clearance measured at rest in nonsmoking healthy adults. Other investigators (Pavia, 1984) found that simple exercise had no effect on bronchial clearance.

3.2.3

Pulmonary Region

Clearance of material deposited in the P region of the lung involves absorptive or nonabsorptive processes occurring simultaneously and with temporal variations (Hatch and Gross, 1964). These are

3.2 CLEARANCE

1

39

summarized in Figure 3.2. Nonabsorptive clearance processes are mediated primarily by pulmonary alveolar macrophages (Harmsen et al., 1985). These large mononuclear cells are in the fluid covering the alveolar epithelium and they isolate, transport and metabolize deposited material. They move by ameboid motion and contact deposited particles, either by chance or via directed motion resulting from chemotactic factors. The efficiency of phagocytosis likely depends on specific properties of the particles, i.e., size, shape, mass and composition. Macrophages may leave the P region by several pathways. One is through mucociliary transport; however, the manner in which the cells reach the mucus blanket is unknown (Ferin, 1976; Sorokin and Brain, 1975). One suggested mechanism involves surface tension gradients (Kilburn, 1968; Scarpelli and Condorelli, 1975). On the other hand, macrophages may propel themselves to the mucus GASTROINTESTINALTRACT

t

TRACHEOBRONCIAL

MUCOCIUARY

MACROPHAGE PHAGOCYTOSIS

Fig. 3.2. Clearance of the alveoli of the lung and surrounding tissue.

40

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3. PHYSIOLOGY OF THE RESPIRATORY TRACT

escalator in a random or a directed manner, perhaps along a density gradient. Another suggested route for macrophages to move to the bronchial airways and mucus escalator is by the pulmonary interstitium (Brundelet, 1965;Green, 1970; 1973;Kilburn, 1974; Tucker et al., 1973).By this hypothesis, macrophages pass through the alveolar epithelial wall into the interstitial spaces and re-enter ciliated airways. Small collections of lymphatic tissue exist a t alveolobronchiolar junctions (Macklin, 1955)and macrophages that pass through the alveolar wall into the lymphatic system may re-enter the airway lumen a t these sites. However, it is possible that cells observed to be following these interstitial clearance pathways were actually interstitial macrophages that ingested particles and passed through the alveolar epithelium. Depending upon their composition and size, free particles may be taken up by alveolar epithelial cells (Bowden and Adamson, 1984; Brody et al., 1981; Lauweryns and Baert, 1974; 1977; Robertson, 1980).Some particles undergo transepithelial transport more readily than others by passing through cells. The likely mechanism for this is endocytosis by Type I pneumocytes, after which particles may be digested in these cells or released into the interstitial space. Endocytosis of toxic particles may result in cell death or desquamation, with subsequent shedding into the alveolar lumen. Hydrophilic molecules (or small molecules of all types) may traverse the epithelium by passive diffusion, both through intercellular junctions and cell membranes. In eertain diseases and with inhalation exposure to irritants, alveolar permeability may increase, enhancing the passage of materials by this route. Once in the interstitium, particles may be engulfed by resident macrophages that may subsequently migrate to a nearby lymphatic channel or be carried with the flow of interstitial fluid toward the lymphatic system, bronchial tree or to perivenous or subpleural sites where they may become trapped. The migration and grouping of particle-laden macrophages may cause a redistribution of inhaled material into focal aggregates in the P region. Trapping of insoluble material in the interstitium may also impede its removal. Thus, inhaled particles that initially may have a diffuse deposition pattern inay subsequently appear in proximal alveoli as focal collections near bronchioles (Heppleston, 1953). Clearance pathways from the P region may also change, depending upon particle loading. Ferin (1977)reported that low exposure concentrations led to particle laden macrophages clearing primarily by way of the mucociliary escalator. With increasing exposure levels, there was a n increase i n translocation of free particles t o the lymphatic system. Even with low particle burdens, however, free

3.2 CLEARANCE

1

41

particles were found in lymphatic vessels. Although the lymphatic clearance pathway was originally believed to be important only for cytotoxic materials, more likely it is a pathway for both cytotoxic and nontoxic particles. Lymphatic clearance is, thus, a primary clearance pathway, but its role appears to vary for unknown reasons. Small particles (<0.010 pm in diameter) in the interstitium may cross the endothelium of alveolar capillaries and enter the blood (Raabe, 1982; Robertson, 1980; Stradling et al., 1978a; 1978b);however, entry into the lymphatic system is more likely. Access to lymphatic vessels is not difficult, since endothelial cells are loosely connected and have wide intercellular junctions (Lauweryns and Baert, 1977). Macrophages and free particles in the "interstitium" may move in either of two directions related to ly~nphaticclearance: (1)to lymphatic vessels that begin in the center of secondary lobules and drain toward the hilum or (2) to lymphaticvessels that lie in the perivenous position around the margins of lobules in subpleural or peribronchial positions and drain toward the hilar nodes. Thus, particles cleared from the alveolar airways may be translocated to TB lymph nodes that become major reservoirs of retained material. Absorptive clearance mechanisms usually begin with particle dissolution. Material that dissolves in alveolar fluid can pass through the epithelium into the lymph or blood (Chinard, 1966; Morrow, 1973). Particles in the interstitium also undergo dissolution and absorption. The factors affecting the rate of dissolution of deposited particles are poorly understood, although dissolution is thought to be influenced by particle surface-volume ratios and other surface properties (Mercer, 1967; Morrow, 1973). On the other hand, material that dissolves from particles in the P region, both inside or outside of cells, may chemicallybind to cells or structural components and remain for very long periods of time. This mechanism is demonstrated in autoradiographs of lung sections taken from animals that inhaled soluble forms of alpha-emitting radionuclides (ICRP, 1980). In lung tissue samples taken from animals that inhaled alphaemitting radionuclides in soluble particulate forms, single alpha tracks are seen to originate from cells in a diffuse pattern. These are distinctly different from the clusters of tracks that originate from undissolved particles. The kinetics of clearance from the pulmonary airways are not fully understood, although it is known that particles in this region remain longer than those deposited in conducting airways. There are few measurements of pulmonary clearance rates in humans, and measurements using laboratory animals vary due to the physical and chemical properties of particles and the species of animal used.

42

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3.

PHYSIOLOGY OF THE RESPIRATORY TRACT

Clearance of insoluble particles by the lymphatic system is slow (Ferin, 1976; Sorokin and Brain, 1975). Pulmonary clearance is often represented by a m~ltiex~one'ntial function, and there have been attempts to relate each component to a specific clearance mechanism. Casarett (1972) related a series of three exponential phases for alveolar clearance from mammalian lungs to specific physiological processes: the initial fast phase having a half-time of two to six weeks is said to represent relatively rapid clearance by macrophages; the intermediate phase was related to slower macrophage clearance having a half-time on the order of months; and the third phase of slow clearance with a half-time of months to years was related to removal by dissolution. Although it is a useful concept to relate clearance half-times to physiologic processes, it is more likely that all phases of clearance involve more than single mechanisms or pathways. In humans, Bohning et al. (1982) found two phases of clearance of inert 3.6 pm mean diameter particles with half-times of 30 and 296 d. The first was ascribed to clearance by macrophages, the second to the passive penetration of the alveolar epithelium. Bailey et al. (19821, using 1.2 and 3.9 pm particles, also found two alveolar clearance phases having half-times of 20 and more than 300 d. Variations in clearance times indicate a strong dependence upon the nature of the particles.

4. Factors Affecting Normal Respiratory Tract Structure and Function Several factors may alter the normal structure and function of the respiratory tract, and thus change the dose fmm inhaled materials as predicted using normal values. For modeling purposes, such changes must be considered. The major altering factors include exposure to inhaled irritants and respiratory tract disease. It should be noted that the doses fmm cigarette smoking are not as clear as they should be. Doses are given in terms of cigarettes1 day, cigaretteslyear, tar weighuday, COlday, respirable particles1 day, benzo(a)pyrenelyear, etc. The reader is cautioned to look up the dose and how it is stated when reviewing this Report. The same is true for sulfur dioxide, nitrogen dioxide and vinyl chloride.

4.1 Tobacco Smoke and Other Irritants There is substantial evidence to associate cigarette smoking with abnormal respiratory tract structure and function. Although the duration and intensity of cigarette smoking strongly influence its deleterious effects, those identified in clinical studies as "smokers" are often considered as a single group, although some individuals will be more or less affected than others. The scientific literature contains many descriptions of structural and physiological changes that accompany both laboratory animal exposures to cigarette smoke and human cigarette smoking (Martonen, 1992). Prolonged exposure to cigarette smoke appears to have two main types of effects: those due to airway irritation and those due to an unusually heavy particle loading. The net effects are to stimulate the secretory apparatus of the airways, to produce accumulations of phagocytic cells, to change t h e numbers and types of epithelial cells, and to alter alveolar morphology. The net result is a strong association between smoke exposure and a degradation of particle clearance efficiency.

44

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4. FACTORS AFFECTING STRUCTURE AND FUNCTION

Lavaging (saline washing) the airways of smoke-exposed laboratory animals and of human smokers yields greatly increased numbers of free cells over those recovered from nonsmoking controls. The cells are predominantly macrophages and tend to be discolored, larger in size, and richer i n cellular inclusions (including proteolytic enzymes) than those recovered from controls. These changes in macrophages have been observed in humans (Brody and Davis, 1982; Warr and Martin, 1978) and in rats, mice and dogs (Jeffery and Reid, 1977; Matulionis, 1984; Zwicker et al., 1978). Histologically, smoke-exposed lungs show accumulations of pigmented macrophages and lymphocytes i n small bronchioles and alveoli (Brody and Davis, 1982; Huber et al., 1981; Matulionis, 1984; Rubin et al., 1992). These cells are also rich i n proteolytic enzymes, suggesting that they may participate in the destruction of small airways and alveoli. Despite the increased numbers of phagocytic cells, their overall efficiency for killing micro-organisms appears to be diminished (Brody and Davis, 1982). Changes are also observed in the bronchial epithelium of smokeexposed laboratory animals and humans. Two types of changes are commonly observed i n the mucus-secreting apparatus: goblet cells increase in number and mucus glands increase in size (Cosio et al., 1980; Jeffery and Reid, 1977). In addition, the epithelium lining the airways exhibits increased numbers of various cell types associated with thickened airway walls (Cosio et al., 1980; Jeffery and Reid, 1977; Zwicker et al., 1978). Deeper in the lung, human autopsy specimens show a dose-related association between cigarette smoking and loss of alveolar tissue, e.g., emphysema (Kuhn et al., 1982). The degree of emphysema in smokers is generally greater than in age-matched nonsmokers. Also, the death rate in human smokers from bronchiolitis and emphysema is estimated to be 16 times that for nonsmokers, and a n 8 to 16 fold increase in the lifetime risk of lung cancer is associated with smoking (Kuhn et al., 1982, NASINRC, 1990). Physiological changes that accompany cigarette smoke exposure are consistent with the anatomical changes. Chronic cough, excess mucus production, decreased TLC, decreased elastic recoil, a n d decreased CO diffusing capacity occur (Huber et al., 1981; Matulionis, 1984; DHHS, 1979). Inhaled irritants affect the pattern of particle deposition by altering ventilatory parameters and airway caliber. Aside from cigarette smoke, few data are available on effects of specific irritants upon subsequent deposition of aerosols. The effects of SOz inhalation has been reported for four human subjects (Lippmann and Altshuler, 1976). I n one, a 78 min exposure to 13 ppm SOzreduced pulmonary

4.1 TOBACCO SMOKE AND OTHER IRRITANTS

1

45

deposition of 4.6 pm diameter particles from 10 to 2 percent and produced a proximal shift in the bronchial deposition pattern. In another subject, a 6 min exposure to 12 ppm SOzreduced pulmonary deposition of 5.9 p,m diameter particles from 18 to 4 percent. Exposures to 5 and 9 ppm SO2 in two other individuals produced no change in regional deposition. The observed effects were presumably due to bronchoconstriction. Thus, other irritants that produce changes in airway caliber would likely cause proximal shifts in aerosol deposition as well. Inhaled particle deposition measurements have been made in smokers (Lippmann et al., 1971).Deposition of 2 to 12 p,m diameter particles in the NOPL airways of adult smokers was more variable than in nonsmokers. As a group, the smokers exhibited higher overall TB deposition, but the data overlapped part of the broad range of the nonsmoking normal population. Due to a proximal shift in particle deposition, smokers exhibited reduced P region deposition in comparison to nonsmokers. Cigarette smoking has been shown to affect bronchial mucociliary transport in humans (Albertet al., 1969; 197la; 1971b; 1975;Camner et al., 1971; Camner and Philipson, 1972; Groth et al., 1990; Pavia et al., 1971; Sanchis et al., 1971). However, the reported effects include both accelerated and slowed clearance. Some confusion may have arisen because of differences in dose and dose rate in studies focused on the short-term effects of smoke exposures. Also, previous chronic smoking can affect airway structure and the capacity of the mucociliary system to respond to further short-term exposures. Since cigarette smoke is a complex mixture, its physical and chemical composition changes rapidly during inhalation. Furthermore, it has a variety of effects on the airways, including bronchoconstriction, increased mucus secretion, reduced ciliary mobility, and desquamation of epithelium. Thus, in considering the effects of smoking on bronchial mucociliary clearance,it is useful to differentiate the shortterm effects produced by recent smoking from the effects resulting from chronic exposure. The short-term effects of inhaled cigarette smoke on people have been described (Albert et al., 1971a). The same observations have been made in studies with donkeys. In human groups of nine nonsmokers and six smokers, exposure to the smoke from two to seven cigarettes resulted in a two-fold reduction in the time required to complete 90 percent of the bronchial clearance (Albert et al., 1975). In three donkeys, exposure to whole fresh smoke from two cigarettes had a similar effect (i.e., a two-fold reduction in the time to complete 90 percent of the bronchial clearance), while short-term exposures to whole smoke from 10 cigarettes produced a slowing of upper

46

1

4. FACTORS AFFECTING STRUCTURE AND FUNCTION

bronchial mucus transport that lasted < I 5 min, and whole smoke from 15 or more cigarettes delayed bronchial clearance by a factor of two or more (Albert et al., 1974).With still higher doses of cigarette smoke in both short- and long-term exposures, clearance can be temporarily stopped (Albert et al., 1971a; 1971b). The time required to complete 90 to 100 percent of the 24 h clearance in humans has been reported to increase (Albert et al., 1971a). This parameter is assumed to represent clearance from the small bronchial airways, but in any case, the difference in this parameter between smokers and nonsmokers may be relatively small. Bronchial clearance has been found to be significantly slower in long-term smokers (Lourencoet al., 1971).A reduction in tracheal mucus velocity in young healthy smokers whose lung mechanics ranged from normal to as low as 20 percent of that of controls has also been reported (Goodman et al., 1978). Specific abnormalities i n mucociliary clearance have been observed in long-term heavy smokers. These include intermittent retrograde mucus flow in the trachea, and intermittent clearance in which periods of stasis alternate with acceleration (Albert et al., 1969; 1971a; 1973). In donkeys, high-level exposure to smoke from 30 cigarettes, three times per week, for six to eight months produced similar abnormalities in clearance (Albert et al., 1971b). In studies using human subjects, it was observed that cigarette smokers who abstained from smoking had significantly slower bronchial clearance than when they smoked a d lib (Camner and Philipson, 1972; Camner et al., 1971; 1973b). Rates of clearance from the P region appear to be reduced in cigarette smokers. Cigarette smoking has been reported to suppress the initial fast clearance phase of a tracer aerosol and increase the half-time of the second slower phase by approximately 15 d per pack per year in individuals who smoked at least one-half to one pack per day for at least 4 y (Bohning et al., 1982). The suppression of a first phase may have been due to the effects of cigarette smoke on alveolar macrophages. The clearance of a magnetic tracer dust from the lungs of heavy smokers (more than one-and-a-half packs per day) has been measured (Cohen et al., 1979). It was reported that by 11 months after dust exposure, about 50 percent of the initial burden was still present, in comparison to only 10 percent in nonsmokers. Numerous inhaled irritants, both gaseous and particulate, have been shown to affect mucociliary clearance hnction in humans and experimental animals (Schlesinger, 1990a; 1990b).Single exposures may either increase or decrease the overall rate of TB clearance, depending upon the exposure concentration and the nature of the

4.2 DISEASE

/

47

inhalant. Although the exposure concentrations used in many of the studies were generally higher than ambient levels, they are oRen consistent with those found in many occupational settings. In addition, the effects of a single irritant may be enhanced by exercise or by co-exposure to other irritants. Single exposures to relatively nontoxic particIes do not appear to significantly alter mucociliary transport. Andersen et al. (1979) showed that there was no significant change in nasal mucociliary clearance rates in people during 5 h exposures to 2,10 or 25 mg m-3 of a plastic dust containing carbon black. Carnner et al. (1973a) showed more rapid bronchial mucociliary transport in people exposed to 20 breaths of carbon particles at 50 mg m-3. Prolonged exposure to wood dust in furniture industry workers has been associated with a reduction in nasal mucociliary transport rate (Black et al., 1974). There are few measurements of effects of acute or chronic exposure to inhaled irritants on clearance in the P region (Schlesinger, 1990b1, although numerous irritants have been shown to impair the functional properties of alveolar macrophages (Gardner, 1984). There is some evidence that pulmonary clearance, like mucociliary clearance, may be accelerated at low exposure concentrations of an inhaled irritant and retarded at high concentrations (Ferin and Leach, 1977; Isawa et al., 1989; Katsnelson and Privalova, 1984; Schlesinger, 1990b). In summary, inhaled irritants have variable and, at times, offsetting effects on particle deposition and clearance. The data on the effects of heavy cigarette smoking are convincing enough to recommend that reduced mechanical clearance rates be used for those individuals smoking more than 10 cigarettes per day. For this population, mechanical clearance rates of half normal in the posterior NOPL, TB and P regions should be considered in the absence of better data. It is recognized, however, that many smokers may exhibit normal clearance.

4.2 Disease Virtually all lung diseases affect structure and function in ways that could alter pollutant deposition and clearance. Goldberg and Lourenco (1973) discussed factors in lung disease that influence particle deposition such as abnormal ventilation and abnormal airway geometry. Abnormal ventilation, including changes in rates of airflow, tidal volumes, breathing frequencies and pauses in the

48

1

4. FACTORS AFFECTING STRUCTURE AND FUNCTION

breathing cycle, occur in diseases such as infectious pneumonia, chronic airway obstruction, bronchial asthma, respiratory distress syndrome, pulmonary thromboembolism, pulmonary fungus infections, emphysema,pulmonary fibrosis (fibrosingalveolitis)and pneumoconioses (Mitchell, 1975; Schlesinger, 1990a). Diseases that alter airway size, shape or caliber include infectious pneumonia, chronic airway obstruction, bronchial asthma, respiratory distress syndrome, hypersensitivity lung diseases (extrinsic allergic alveolitis), pulmonary tuberculosis, pulmonary lung infections, bronchiectasis, lung abscess, emphysema, lung cancer, pulmonary fibrosis and the pneumoconioses (Mitchell, 1975; Schlesinger, 1990a). The data base on inhaled particle deposition in humans with clinically defined disease states is quite limited, except for chronic bronchitis. Heppleston (1963) found that inhaled hematite particles deposited more distally in rats with coal or silica derived pneumoconiosis than in normal animals. Love et al. (1971)found no difference in total deposition of 1 km particles in coal workers with simple pneumoconiosis compared to clinically normal individuals. In a later study, Love and Muir (1976) found no correlation between the presence of simple pneumoconiosis and total inhaled particle deposition, although total deposition did correlate with the degree of airway obstruction. Other studies have shown that airway obstruction in bronchiectasis or bronchitis in humans reduces peripheral lung deposition of aerosols (Lourenco et al., 1972; Pavia et al., 1977; Sanchis et al., 1971; Thomson and Pavia, 1974). Partial or complete airway obstruction in bronchitis, lung cancer, emphysema,fibrosis or atelectasis may reduce or entirely eliminate the deposition of particles in some parts of the lungs (Taplin et al., 1970). Regional deposition may also be altered in disease. Thomson and Short (1969)provided some evidence that bronchitics and asthmatics had greater TB deposition than did normal individuals (Lemarchand et al., 1992; Svartengren et al., 1989b; 1991).Lippmann et al. (1971) examined the deposition of 1to 5 p.m particles in bronchitics. Head deposition in bronchitics was highly variable, but most showed very high deposition in this region. Bronchitics had greatly enhanced TB deposition compared to normals, most of which occurred in airways beyond the trachea. P region deposition was reduced. Also, enhanced TB deposition was seen in this study in some asymptomatic asthmatics, but others have not found such differences (Spektor et al., 1985). Physiological factors that influence clearance rates or pathways are multiple, and include mucus quantity and rheology, epithelial function, macrophage function, lymphatic fluid flow and probably others. Even minor respiratory tract illnesses can drastically affect these factors. As an example, uncomplicated influenza,which usually

4.4 MODELING ASSUMPTIONS

1

49

has a clinical course of about 3 to 5 d, disrupts the upper respiratory tract epithelium to the extent that normal mucociliary clearance ceases (Driessen and Quanjer, 1991; Farquhar et al., 1989;Mortensen et al., 1991; Mussatto et al., 1988; Ols6ni et al., 1992). In this circumstance, clearance of mucus may only be accomplished by frequent coughing. Viral invasion destroys ciliated cells, goblet cells and many bronchial mucus gland cells. In addition, tissue swelling and infiltration by lymphocytes occur. This condition may extend deep into the lung to the level of alveolar ducts. Epithelial recovery may be protracted. A major problem of influenza lies in the severe, often fatal, complications t h a t may follow this disruption of normal defenses. One might also expect the clinical and post-clinical recovery period to greatly predispose the host to the deleterious effects of essentially any airborne material.

4.3 Miscellaneous Factors

Pulmonary function may also be altered by a variety of other factors, including exercise, anxiety, ambient temperature and pharmacologic agents (Bechbacheet al., 1979; Cole et al., 1983; Newman, 1991; Olskni and Wollmer, 1990; Overton, 1990; Spektor et al., 1989; Widdicombe, 1978).

4.4 Modeling Assumptions

In summary, although several factors are associated with abnormal ventilation and clearance, the current state of scientific knowledge makes it difficult to provide quantitative data on the affected variables. Nevertheless, for modeling purposes, it is useful to include the physiologically compromised individual. Unless one has data relating to a specific abnormality, this can be done by assuming that clearance rates are approximately 0.5 to 1times the normal values for the NOPL and TB regions. Use of these slower mechanical clearance rates will, in general, result in significantly elevated doses for the abnormal case in comparison to the normal individual. Other model parameters are assumed to be unchanged in the compromised lung unless specific data are available to provide alternate model values. It should be realized that this 0.5 to 1 times the efficiency factor is somewhat arbitrary and may lead to under- or overestimates of doses for many individuals.

5. Deposition of Inhaled Substances

Several factors can influence the deposition of inhaled substances. These include respiratory tract anatomical structure, physiological parameters, and aerosol and gas properties. Previous sections have dealt with anatomical structure and physiological parameters. In this Section, the properties of aerosol particles, gases and vapors will be reviewed. The general approach to modeling deposition of inhaled substances and models thus obtained will be detailed in this Section. The effect of fiber characteristics will not be reviewed because radioactive material is not likely to be in this form.

5.1 Particles An aerosol is defined as a system of solid or liquid particles that (1)is dispersed in a gaseous medium, (2) is able to remain suspended in the gaseous medium for a long time, relative to the time scale of interest, and (3) has a high surface area to volume ratio. It is usually composed of particles having a wide range of sizes that can be described by mono- or multimodal distributions.

5.1.1

Particle Size Definitions

The geometrical diameters of most naturally occurring aerosols fall within the range of 0.001 to 100 p,m. For a spherical particle, particle size is defined as the geometrical (real) diameter. For nonspherical particles, particle size may be defined by several types of

5.1 PARTICLES

/

51

diameters, as shown in Figure 5.1. The projected area diameter (d,) which is often referred to as the geometric diameter, is most commonly used. There are other important conventions for describing particle size. Most of these are based on aerosol dynamic behavior and the methods used to collect the aerosols. Two conventions are frequently used to describe particle size based on a particle's inertial property: the Stokes' diameter (d,J and the aerodynamic (equivalent) diameter (d,). The Stokes' diameter is defined as the diameter of a

Fig. 5.1. Definitions of nons~hericalparticle geometrical sizes (modifiedfrom Yeh et al., 1976).

52

1

5. DEPOSITION OF INHALED SUBSTANCES

sphere that has the same density and terminal settling velocity (v,) as the nonspherical particle in question;the aerodynamic equivalent diameter is the diameter of a unit density sphere that has the same t,erminal settling velocity as the particle in question. For a spherical particle, the geometric diameter is the Stokes' diameter, and its relationship to the AD is as follows:

where d, is the projected area (or geometric)diameter, pis the particle density, C(d,) is the slip correction factor based on diameter d,, d., is the AD, C(d,,) is the slip correction factor, based on diameter d., and p* is unit density. The slip correction factor is introduced to correct for Stokes' law, when the particle size is small, comparable to the mean free path of air molecules, and the no slip condition at the surface of the particle is no longer satisfied. Raabe (1976)defined an aerodynamic resistance diameter (dm)related to aerosol inertial sampling and sizing instrumentation. Its relationship t o geometric and AD is as follows:

For nonspherical particles, the relationships between the Stokes' diameter, volume equivalent diameter, aerodynamic equivalent diameter, and aerodynamic resistance diameter are as follows:

where K is the dynamic shape factor, d, is the volume equivalent diameter, and C is the appropriate slip correction factor (Raabe, 1976). A third convention for describing particle size is needed for the description of much smaller nonspherical particles. The dynamic behavior of very small particles is dominated by diffusion and their characteristic diameter is more conveniently described by the diffision equivalent diameter. This is defined as the diameter of a sphere having the same diffision coefficient as the particle of interest. Note that, in this definition, particle density and the equivalent volume are not involved. Because almost all aerosols contain particles with a wide range of sizes, an aerosol is usually described by a size distribution function. For an aerosol produced by a single mechanism, the particle size distribution can be satisfactorily represented by a lognormal distribution function and uniquely described by the geometric mean and

5.1 PARTICLES

53

/

geometric standard deviation. Figure 5.2 shows a lognormal distribution of radioactive particles and some of its associated parameters, including the count median diameter (CMD), surface area median diameter (SAMD), mass median diameter (MMD) and AMAD. Depending on the application, one of these parameters with the associated geometric standard deviation (a,)can be used to describe the aerosol. For example, if mass is of interest, as is often the case in inhalation toxicology studies, then MMD or MMAD can be used. Likewise, for radioactive aerosols, the amount of radioactivity is of more concern; thus, the AMAD should be used. For homogeneously radioactive aerosols, the MMAD will be equal to AMAD and, in this case, either MMAD or AMAD will be suitable.

5.1.2 Particle Inhalability Before particles can deposit in the respiratory tract they must be inspired from the ambient air. Particles that do not enter the nose or mouth are unavailable for deposition and if they are included in

-

-

-

DIAMETER OF AVERAGE MASS (0.40 ~ m )

A MAD (1-5

P=3.0

0

0.5

1.O 1.5 PARTICLE DIAMETER (ym)

-2.0

Fig. 5.2. Lognormal distribution of particles with a geometric mean (CMD) of 0.2 pm, geometric standard deviation of 2.0 and density of 3 g ~ m(Yeh - ~et al., 1976). (CMD = count median diameter; SAMD = surface area median diameter; AMAD = activity median aerodynamic diameter; MMD = mass median diameter.)

54

1

5. DEPOSITION OF INHALED SUBSTANCES

dose calculations, the dose estimates may be unrealistic. Inhalability is defined as the fraction of the suspended material in ambient air that actually enters the nose or mouth with the volume of air inhaled. It is a function of several factors, including particle aerodynamic size, inspiratory flow rate, wind speed and wind direction. For lack of specific experimental data pertaining to differences that might result from breathing through the nose and mouth, both are considered equivalent in the following discussion. The limited data that are available on inhalable fractions of particles were summarized by the American Conference of Governmental Industrial Hygienists [ACGIH (1985)l.The inhalable fraction averaged over all wind directions was related to particle aerodynamic size (dae)by the following relationship: for 0 < dae5 100 km where E is the fraction of ambient airborne particles that are inhalable. For particles larger than 100 pm AD, inhalability is unknown. This relationship represents a n average of experimental d a t a obtained using manikins and wind tunnels with different wind speeds and directions (Figure 5.3) to measure particle deposition. For the special case of zero wind speed, measurements have been made in nose-breathing people by Breysse and Swifi (1990);their

AERODY NAMlC DIAMETER (km) Fig. 5.3. ACGIH recommended inspirable particulate mass size-selective criteria for particles up to 100 pm AD (ACGIH, 1985). The available data is averaged over orientation and wind speed. The presentation of the summary data is adapted from Vincent and Armbruster (1981). Data were obtained from Armbruster and Breuer (1982) (O),Ogden and Birkett (1977) (A), and Vincent and Mark (1982) (0).

5.1 PARTICLES

1

55

data are shown in Figure 5.4.Because calm wind conditions cannot be assured, it is recommended that the ACGIH relationship be used to calculate particle inhalability for particles up to 100 pm AD. It is also recommended that 0.50 inhalability be used for larger particles in the absence of relevant data. The effects of body size and breathing pattern on inhalability have not been investigated.

5.1.3

Deposition Mechanisms

There are many mechanisms that cause particles to be deposited in the respiratory airways after they enter the nose or mouth. Figure 5.5 illustrates three important mechanisms by which particles deposit in the respiratory tract. The first mechanism is called inertial impaction. Because particles have mass and therefore inertia, they do not follow the curvature of the air stream exactly and may impact on the airway walls. This mechanism is important for particle sizes larger than about 1 pm AD. The second mechanism, sedimentation, is due to the gravitational force acting on particles. Particles settle

0.0

I 0

\

I

I

I

20

I

40

PARTICLE DIAMETER (pm) Fig. 5.4. Summary of experimental results adapted from Breysse and Swift (1990) on inhalation efficiency when nose breathing in still air at an average minute volume of 15.5 L.

I

56

/

5.

DEPOSITION OF INHALED SUBSTANCES

DIFFUSION

INERTIALIMPACTION SEDIMENTATION Fig. 5.5. Three main particle depositionmechanismsoccurringwithin the respiratory tract (Yeh et al.. 1976).

in air and may deposit on the lower surfaces of airways. This mechanism is important for particle sizes larger than about 0.5 pm AD. The third mechanism is diffusion. When the particle size is small, random (Brownian) motion of the particle, due to collisions with air molecules, may cause it to move across the streamlines and deposit upon contact with the airway wall. This mechanism is important for particle sizes smaller than about 0.5 km diffusion equivalent diameter. Other mechanisms, such as interception and electrostatic attraction due to charge associated with particles, may also cause particle deposition. Interception occurs when the physical size of a particle brings it into direct contact with the airway wall, i.e., when a particle is within a distance from the wall, which is approximately equal to the particle radius. Since respirable aerosols are generally <6 to 10 pm in diameter and the smallest airway size is about 200 p,m in diameter or larger, this mechanism is unimportant and is usually neglected. Aerosols of fibers are one important exception. Electrostatic charge associated with particles may enhance deposition due to electrical attraction, but it is generally believed that this mechanism is important only in the vicinity of nasal hair and only when aerosols are highly charged. Therefore, this mechanism is also neglected in most studies. Another factor associated with aerosols that may affect inhalation deposition is the hygroscopicity of particles. Particles may absorb water and grow within the respiratory airway, enhancing deposition by impaction and sedimentation while reducing diffusion.

5.1 PARTICLES

1

57

5.1.4 Inhaled Particle Deposition Models

Knowledge of the patterns of initial deposition for inhaled particles containing toxic agents within the respiratory tract is essential for determining their clearance and tissue dose patterns. Many factors influence the deposition of inhaled particles; the more important are: (1) the physics of aerosol particles, (2) the anatomy of the respiratory tract, and (3)respiratory physiology (Yehet al., 1976).Mathematical models for predicting inhaled particle deposition should account for the influence of these factors. Because of the complex anatomy and behavior of aerosols within the respiratory tract, most mathematical deposition models incorporate simplifying assumptions related to the structure of the respiratory tract (anatomical lung model), particle deposition on a tube or airway wall, the airflow rate and the breathing pattern (Beeckmans, 1965; Egan et al., 1989; Findeisen, 1935; Landahl, 1950; Taulbee and Yu, 1975;Yeh and Schum, 1980;Yuet al., 1981).Airway parameters that influence particle deposition include airway segment diameter, length, branching angle and angle of inclination to gravity (Yeh et al., 1976). In developing a model for calculating inhaled particle deposition, the respiratory tract is divided into three regions, the NOPL, the TB and the P. The NOPL region consists of the nose, mouth, nasopharynx, oropharynx and larynx. Because of the extreme complexity of the passages within this region, no applicable morphometric description is available. Landahl(1950) suggested a model for this region consisting of four sections in series: (1)external nares having a crosssectional area of 0.75 cm2with hairs of about 100 pm diameter and a passage length of 2 cm, (2) a rectangular tube 1.2 cm high, 0.25 cm wide, and 1em long with bend angle of 30 degrees, (3) a rectangular tube 2 mm wide, 3 cm high and 1cm long with bend angle of 20 degrees, and (4) a section subdivided into two passages, 1mm wide, 4 cm high and 5 cm long with bend angle of 45 degrees and the other one 2 mm wide, 4 cm high and 5 cm long with bend angle of 20 degrees and gravity angle of 45 degrees. The TB and P regions are generally considered together for the purpose of developing an anatomical model. The lung model of Findeisen-Landahl (Landahl, 1950) was used by the TGLDACRP (1966).However, it has been suggested that the low number of airway generations used in this model contributes to the overestimation of pulmonary deposition when compared to experimental data (Thomas and Healy, 1985).Most of the more recent inhaled particle deposition calculations use either the Weibel(1966) or Yeh and Schum (1980)

58

/

5. DEPOSITION OF INHALED SUBSTANCES

anatomical model, with some modification of the mathematical calculations of particle deposition and gas transport. Heyder and Rudolf (1984) recently reviewed the large number of mathematical models of particle deposition in the human respiratory tract that are now available. They classified the models into three formalisms (Findeisen, Altshuler and Taulbee-Yu) based on the mathematical treatment of particle transport to airway surfaces with time and space during breathing. The Findeisen formalism is used for most of the proposed models (Landahl, 1950). It is both spatially and temporally discrete and has been numerically verified (Rudolf, 1984; TGLDACRP, 1966; Yeh and Schum, 1980). In the Altshuler formalism, the lung is regarded as a continuous filter bed (Altshuler et at., 1967). The model, therefore, is a spatially continuous model that is temporally discrete. The model based on this formalism has not been numerically verified and has only been used by Altshuler et al. In theory, the Taulbee-Yu formalism is both temporally and spatially continuous (Taulbee and Yu, 1975). However, due to the discrete nature of the anatomical lung model, numerical verification of models based on this formalism was performed as spatially discrete. In adopting or modifying a model for inhaled particle deposition, several factors are considered. These include (1)adequacy of the anatomical model, (2) realism in calculating particle deposition on airway walls, (3) numerical verification with existing experimental data, and (4) ease in mathematical formulation and calculation so that many people can easily duplicate or perform the calculation. In a comparative study of aerosol deposition in different lung models, Yu and Diu (1982) reported that deposition profiles along the airways from different models show different patterns. They attribute this to the different airway dimensions and number of structures included in the various models. Close examination of their results [where calculated total deposition predictions using four different lung models are compared with data obtained by Heyder et al. (1982) under different breathing conditions and particle size1 revealed that the use of either the Weibel or Yeh and Schum lung model fits the data most satisfactorily. In investigating the contribution to deposition from impaction and sedimentation in the TB tree, Cheng and Yeh (1981) calculated the average tube size (R) (equivalent to the radius of a daughter branch of a single Y-tube, with the bifurcation angle equal to 30 degrees and ratio of the radius of curvature to tube radius equal to four, that will give the same fractional deposition due to impaction as predicted by summing over all TB generations), based os the lung model of Weibel and that of Yeh and Schurn and compared the values with existing in vivo data. Results showed that the calculated values of R are 0.263 cm for the

5.1 PARTICLES

1

59

Weibel lung model A, 0.376 cm for the Yeh and Schum (1980) lung model, as compared with an R value for existing data of 0.367 ? 0.056 cm. Based on the above considerations and the fact that the Yeh and Schum lung model is based on detailed morphometric measurement and includes both the branching angles and inclination with respect to gravity for each airway generation, the anatomic model described by Yeh and Schum will be used here in calculating inhaled particle deposition. With the simplified model of lung airway structure and of airflow patterns, theoretical estimations of particle deposition can be made for any breathing pattern, particle size or particle density.

5.1.5 Naso-Oro-Pharyngo-Laryngeal Deposition Empirical equations are used for calculating inhaled particle deposition in the NOPL region because of the complexity of the structures involved. The TGLDIICRP (1966) used a mathematical relationship for nasal deposition based upon data reported by Pattle (1961).Since that time, many additional measurements of nasal and oral deposition have been reported (Chan and Lippmann, 1980; Foord et al., 1978; Giacomelli-Maltoni et al., 1972; Heyder and Rudolf, 1977; Hounam et al., 1969; 1971; Lippmann, 1970; 1977; Martens and Jacobi, 1974; Stahlhofen et al., 1981). These data were summarized by Yu et al. (1981) who also derived new mathematical functions for nasal deposition during inspiration and expiration, and for oral deposition during inspiration. Their functions related particle deposition efficiency to the logarithm of the impaction parameter (pd2Q) where p is the particle density, d is the particle geometric diameter and Q is the average rate (cm3s-I) of airflow during inhalation or exhalation. For this Report, the same data were fit by log-logistic functions because these functions apply well over the whole range of particle sizes studied and do not require abrupt changes in deposition efficiencies at specific particle sizes. These functions are:

Ni = 1 [l + (pd2Q/4,600)-0.941-1 Ne= 1 [l + (pd2Q/2,300)-1.011-1 Oi

and

(5.5)

1 [l -I-(pd2Q/30,000)-1~371-1 0. = Oi (if there is no other information) =

where Ni is the nasal deposition efficiency during inhalation, Neis the nasal deposition efficiency during exhalation, and Oi and 0, the oral deposition efficiency during inhalation and exhalation,

60

/

5. DEPOSITION OF INHALED SUBSTANCES

respectively. These relationships are illustrated in Figures 5.6, 5.7 and 5.8. The empirical equations, Equation 5.5, for deposition in the NOPL region were derived from experiments using particles larger than 0.2 pm in diameter and, thus, are valid only for particles larger than 0.2 pm. In the previous ICRP model (TGLDIICRP, 19661, the nose or mouth deposition for particles <0.2 pm was assumed to be zero. However, recent studies indicated that this is not the case. For particles C0.2 pm geometrical diameter, the diffusion deposition mechanism dominates the NOPL region. Detailed nasal and oral deposition measurements of ultrafine particles (0.005 to 0.2 pm), using a human nasal and oral cast, were reported by Cheng et al. (1988; 1990; 1993) and Yamada et al. (1988). For children, studies with hollow nasal models indicate that for a given level of physical exertion, aerosol deposition efficiency is similar to that of adults. Therefore, correction factors are applied to Equation 5.5 to account for the lower flow rates of children. For computation, the model uses a correction factor to multiply the lower ventilation rate for children in order to obtain an adult ventilation rate that produces an

LANDAHL et a/. (1951)

V PATTLE (1961) LIPPMANN (1970; 1977)

A

A HOUNAMet a/. (1971)

0GIACOMELLI-MALTONIet al. (19721 . ,

VA

A MARTIN AND JACOB1 (1972) 0 HEYDER AND RUDOLF (1977)

Fig. 5.6. Deposition of particles in the head for nose inspiration as a function of pdZQ.

5.1 PARTICLES

1

61

0 SUBJECT A SUBJECT

V

1 3 SUBJECT 5 SUBJECT 6

Fig. 6.7. Deposition of particles in the head for nose expiration as a function of pd2Q.

equivalent deposition efficiency. The following equations, used to calculate the scaling factors, are not required for the TB model. APN, = 0.00482 Q1.79 ~ P N=, 0.00345 Q1.'' D o i = 0.00453 Q1.85 APq = 0.00849 Q1.16

(5.6)

62

/

5. DEPOSITION OF I N W D SUBSTANCES

UPPMANN (1977)

V FOORD et a/.(1978) 0 CHAN AND LIPPMANN (1980) A STAHLHOFEN et a/.(1980)

Fig. 5.8. Deposition of particles in the head for mouth inspiration as a function of pd2Q.

and

Ni

= =

1 - exp(-12.8DmQ-I") 1 - exp( - 18.2 D m &-IB)

QinLmin-I Q in cm3s-l

5.1 PARTICLES

1

63

where AP is the pressure drop (in Pa) across the nose or mouth during inhalation or exhalation,D cm2s-I is the diffusion coefficient of the particle and subscripts i, e, n and o are used to indicate inhalation, exhalation, nose breathing and oral breathing, respectively. Equation 5.6 shows the pressure drop-flow rate relationship. It should be noted that the resistance in oral breathing shown in Equation 5.6 was closer to the reported values for spontaneous oral breathing. Therefore, the oral deposition efficiency shown in Equation 5.7 should apply only to spontaneous oral breathing. When the mouth was open widely, such as in heavy exercise or in the case of using a mouth tube during an experiment, zero deposition may be assumed. Figures 5.9a, 5.9b, and 5.10a and 5.10b illustrate the deposition of ultrafine particles in the NOPL region as a function of particle size (as described by the diffusion coefficient)and flow rate. Deposition efficiency of inspired particles in the NOPL region during inhalation is:

where ai is the fraction of air inspired through the nose. Deposition efficiency of inspired particles in the NOPL region during exhalation is: NOPL,

=

a, N,

+ (1 - a,) 0,

(5.9)

where a, is the fraction of air expired through the nose. Total deposition of inspired particles in the NOPL region is given by:

-

NOPL NOPLT = (5.10) NOPLi + NOPL, [(I - NOPLi) - (TB' + P' )I = NOPLi + NOPL, (1- NOPLi) [ l - (TB' + Pf)(l- V ~ T ) I where NOPLi and NOPL, are obtained from Equations 5.8 and 5.9 for inhalation and exhalation, respectively. TB' and P' represent fractional deposition in the TB and P regions, respectively, relative to the number of particles entering the trachea, V, is the volume of the NOPL region and VTis the tidal volume. In the following default calculations, it is assumed that V, is equal to 50 cm3,and that there is no pause between inhalation and exhalation. Deposition in TB and P regions becomes: TB

=

(1 - NOPLJ (1 - V,/vT)TB'

(5.11)

The empirical equations (Equations 5.5through 5.7) for deposition in the NOPL region were derived from experimental data instead of theoretical models because of the highly complex geometry within

64

1

5. DEPOSITION OF INHALED SUBSTANCES

1.o 0 CHENG et a/. (1sEa)

SWIFT efal. (1992)

a8

ti i? 0.6 Z

Y

W

Z

0

0.4

g W 0

0.2

0.0 0.0001

0.0100

0.0010

0.1 000

1.0000

10.0000

1.0000

10.0000

uln~"",(cm~/s)'~ (~lmin jl" 1.o 0 YAMADA et al. (1988)

CHENG st a/.(1993)

0.8

6Z w

0.6 Y

W

Z

0

k 0.4

rn

2 W 0

0.2

0.0 0.0001

0.0010

0.0100 0.1 000 Din O-im , ( ~ m ~ / s(~Irnin ) ' ~ jM

Fig. 5.9. Nasal deposition efficiency during (a) inspiration (Cheng et al., 1988; Swift et al., 1992) and (b) expiration (Cheng et al., 1993; Yamada et al., 1988) as a function of diffusion coefficient and flow rate.

5.1 PARTICLES

/

65

1.o 0 CHENG et sf. (1990)

CHENG et 81. (1993)

>

0.8

Y!!!

2 0.6 Y

W

z

0

E 0.4 cn 2Y n

0.2

0.0 0.0001

0.0010

0.0100

0.1000

1.moo

10.0000

D ' ~ " ~ , ( e r n ~ / s()~ ' "l m ijim n

Fig. 5.10. Oral deposition efficiency during (a) inspiration (Cheng et al., 1993) and (b)expiration(Chengetal., 1990) as a functionof diffusion coefficient and flow rate.

66

1

5. DEPOSITION OF INHALED SUBSTANCES

the NOPL region. In the case of children, it is assumed for the model that the regional deposition fraction is equal to that for the adult a t comparable states of rest or exercise. 5.1.6

Tracheobromhial and Pulmonary Deposition

To calculate TB' and P', the lung model of Yeh and Schum (1980) was used along with a method of calculation similar to that of Findeisen (1935) and Landahl (1950). This method was modified to accommodate an adjustment of lung volume and substitution of reaiistic deposition equations. Briefly, airway dimensions were adjusted to conform to the normal lung volume, i.e., FRC plus onehalf of VT,assuming (1)FRC = 0.4 TLC or actual FRC value, if available, (2) conductingairway diameters expand as the square root of volume expansion, and (3) both diameters and lengths of airways in the respiratory region are proportional to the cube root of the lung volume (Schum and Yeh, 1980).Fractional aerosol deposition in each generation was calculated using deposition equations due to inertial impaction, sedimentation and diffusion. These equations, including both the entrance length effect (Equation 5.13) and the effect due to entrance configuration (e.g,, tube branching) (Equation 5.17) are listed in Table 5.1 (Schurn and Yeh, 1980).Adjustments were made in the calculations to compensate for depositionin previous generations and for the fraction of tidal air not penetrating to the generation under consideration. Cohen et al. (1990), based on their deposition study of ultrafine particles in a TB cast, reported that the measured diffusional deposition was about twice that predicted, such as in Equation 5.13 in Table 5.1. Because the TB cast used has less than 10 generations with incomplete branches, rather than using their empirical equation, we used the correction factor for entrance configuration (f,) which has a value between 1.4 and 2.4, based on branching angles listed in Table 2.3. No consideration is given in the current deposition model for possible enhanced penetration due to axial streaming as predicted by Briant (1988)for higher frequency ventilation. However, the enhanced diffusion deposition of submicrometer or ultrafine particles as compared to laminar tube flow conditions due to airway branching, as observed by Cohen (1987) and Cohen and Asgharian (1990),has been taken into account as shown in Equation 5.17 ofTable 5.1 (Yeh, 1974).We choose to use Equation 5.17, instead of the empirical equation of Cohen and Asgharian because Equation 5.17 ties to branching angle, airway segment diameter and length. It can be applied to all generations within the conducting airways. The equation of Cohen and Asgharian was fitted

5.1 PARTICLES

TABLE5.1-Deposition equations for the TB and P regions. A. Deposition by Diffusion For laminar flow where

PD = diffusion deposition probability D = diffusion coefficient of particles, ema s-' R = radius of tube or airway, cm C = mean flow velocity, cm s-' L = length of tube or airway segment, cm x

=

E

2R2C For turbulent flow

* *

2.828xm(1 - 0.314~"~ +...)

PD = +(I-2-+...)= R

9R

where t = time for flow to pass through the tube or airway segment For a pause

=

Ll;

where t = pause time K = Boltzmann constant T = temperature in OK C = Cunningham slip correction factor r, = radius of the particle p = viscosity of fluid p = pause Effect of entrance configurations (Yeh, 1974) f , = 1 + Cl(2RIL) for LIR > 10 where f, = factor for correcting the effect of entrance configuration C, = (281~)(13- 1281~) 0 = bend angle or branching angle (in radians)

B. Deposition by Sedimentation

where

P.

= sedimentation deposition probability 6 = density of the particle 4 = inclination angle relative to gravity (4 = 0 degree for horizontal tube). For a pause, Llu is replaced by t (the pause time) in Equation 5.18.

C. Deposition by Inertial Impaction P,= 1 -2c o s - l ( ~ s t ) + Lsin[2 c o s - l ( ~ ~ t ) for ~ O S ~< 1 -

?r

PI= 1

for0StZl

where

P, = impaction deposition probability 0 = bend angle or branching angle (in radians)

1

67

/

68

5. DEPOSITION OF INHALED SUBSTANCES

to limited data obtained mainly from a few upper generations of the conducting airways. For a given breathing frequency, equal time was allocated for inspiration and expiration with no pause. The regional depositions TB and P were obtained from Equations 5.11 and 5.12 with appropriate NOPLi for either nasal breathing or mouth breathing.

5.1.7

Regional Deposition of Inhaled Particles

Table 5.2 (also see Figure 9.1) shows the result of the inhaled particle deposition calculations for unit density spheres using tidal volumes of 770, 1,300 and 2,400 cm3 and a breathing frequency of 13,15 and 25 breaths per minute, respectively. Comparison between the present results and available experimental data is shown in Figures 5.11 through 5.13. Figure 5.11 shows the total respiratory tract deposition calculated using the present model for nasal breathing for tidal volumes of 750 and 1,450cm3with 15 breaths per minute and the data of Giacomelli-Maltoni et al. (1972) and Heyder and Rudolph (1977). An acceptable level of agreement between these data is evident. In Figures 5.12 and 5.13, the experimental results obtained by various investigators for mouth breathing and a variety of respiratory frequencies and tidal volumes in human subjects are compared with the calculated deposition of particles entering the trachea. The data and deposition predictions agree reasonably well despite the fact that the calculated values do not take into account the amount of particles deposited in the mouth region, including possible loss in the mouthpiece. TABLE5.2-Calculated fractional deposition of unit density spheres during nose breathing. Particle Diameter, km

VT andfh

770 cm" f = 13

Region

0.01

0.06

0.20

0.60

1.0

2.0

3.0

4.0

6.0

10.0

NOPL 0.161 0.040 0.018 0.071 0.169 0.401 0.535 0.611 0.685 0.708 TB 0.570 0.151 0.049 0.024 0.026 0.044 0.061 0.071 0.078 0.063 P 0.117 0.330 0.162 0.102 0.127 0.208 0.218 0.182 0.098 0.020

1,300cm3 NOPL 0.141 0.036 0.017 0.128 0.283 0.546 0.646 0.697 0.742 0.734 = 15 TB 0.518 0.116 0.037 0.019 0.021 0.034 0.044 0.049 0.050 0.038 P 0.235 0.414 0.187 0.113 0.135 0.202 0.193 0.149 0.071 0.014

f

2,400cm3 NOPL 0.119 0.033 0.048 0.323 0.569 0.775 0.805 0.812 0.804 0.758 f = 25 TB 0.361 0.066 0.021 0.015 0.020 0.033 0.037 0.038 0.032 0.019 P 0.441 0.377 0.143 0.075 0.079 0.090 0.073 0.051 0.019 0.002 "f = breaths per minute without pause and FRC = 0.4 TLC.

5.1 PARTICLES

"

I

0.1

I

I

I

0.5 1.0 5 AERODYNAMIC DIAMETER (pm)

1

69

I

10

Fig.5.11. Total respiratorytract deposition during nasal breathing. GiacamelliMaltoni et al. (1972), 12 breaths per minute, 1,000 em3VT; Giacomelli-Maltoni et al. (19721, 8 to 19 breaths per minute, 400 to 1,500 cmT'VT;o Giacomelli-Maltoni et al. (1972), 12 breaths per minute, 750 c m V T ; 0 Giacomelli-Maltoni et al. (1972), 12 breaths per minute, 1,850 cm3VT;A Heyder et al. (1975), 500 em3VT; Heyder et al. (1975); 1,000 cm3 VT.Curves: present model -750 cmYVT,- - - - 1,450 cm3 VT with 15 breaths per minute.

70

1

5. DEPOSITION OF INHALED SUBSTANCES

I

0.1

I

I

0.5 1.0 5 AERODYNAMIC DIAMETER @m)

I

10

I 20

Fig. 5.12. Total respiratory tract deposition during mouth breathing. GiacommeliMaltoni et al. (1972); o Lippmann (1977); Landahl(l950); V Altshuler et al. (1967); 0 Lever (1974); A Heyder et al. (1975), 500 em3VT;A Heyder et al. (1975), 1,000 cm3 VT.Curves: present model -750 cm3VT,- - - - 1,450 cm3VTwith 15 breaths per minute and unit density spheres.

5.2 Gases and Vapors Radioactive elements and compounds exist in the form of gases and vapors, and are accessible to the body via the respiratory tract in this form. Being in the gaseous state, these and unit density spheres' physical behaviors are described by the kinetic theory of gases and the physicochemical principles of vapor-liquid partitioning. By definition, gases and vapors differ in that, at the temperature of consideration, gases are noncondensible while vapors can be in

5.2 GASES AND VAPORS

0.1

1

71

5 I 0 20 AERODYNAMIC DIAMETER (pm)

Fig. 5.13. Pulmonary deposition during mouth breathing. Lippmann (1977); Altshuler et al. (1967). Curves: present model -750 cm3VT,- - 1,450 cm3 V, with 15 breaths per minute and unit density spheres.

--

equilibrium with their liquid phase. This difference plays no essential role in the respiratory behavior of these substances. The gaseous forms of these substances are dispersed as individual atoms or molecules, most often in the presence of other gaseous mixtures, such as air, water vapor and their trace gas constituents. They shall be denoted as "gases" in what follows. Because gases are molecularly dispersed, they are not subject to gravitational and inertial forces to the degree that particles are and, thus, do not deposit on surfaces by inertia and sedimentation (illustrated in Figure 5.5). Gas molecules do undergo kinetic motion and are capable of deposition by passive diffusion, as is the case with

72

1

5. DEPOSITION OF INHALED SUBSTANCES

ultrafine particles. Because gas molecules are in random motion, net diffusive transport of gas species within a gaseous medium or to a gas-liquid boundary can only occur when a concentration gradient of the gas species exists. When such a concentration gradient exists, the transport is in the direction of decreasing concentration, and is commonly described by Fick's Law of Diffusion:

-~ Where F = flux of gas, moles ~ r n s-' D = gas diffusivity, cm2 s-' c = gas concentration, moles X = distance along axis of transport, cm The flux is defined as the net number of moles of gas crossing an area of 1cm2perpendicular to the gradient axis per unit time. The diffusivity of a gas species in a gaseous medium depends upon the molecular properties of the diffusing and stationary gas species and the gas temperature. Values for specific gases in air can be found in handbooks [e-g.,CRC Handbook of Chemistry and Physics (Weast et al., 198811 or estimated from molecular properties by methods described by Chapman and Cowling (1970). In the following sections, gas deposition in the respiratory tract will be described first in terms of gas-phase transport mechanisms, then in terms of the conditions a t the gas-liquid interface and finally in terms of liquid transport of species. The implications of these principles for deposition in the three respiratory regions will be considered next, followed by a consideration of the deposition of specific radioactive gases.

5.2.1

Gas-Phase Transport Mechanisms

Within the gas phase itself, net motion of gaseous species present as constituents of gas mixtures may occur as a result of two mechanisms: convection and diffusion. Convective transport of gas species is the result of bulk motion of the entire gas mixture (fluid motion of air in and out of the respiratory tract). Convective motion of gases has two principal modes: laminar flow, in which adjacent fluid parcels slide as sheets (or "lamina") and turbulent flow, characterized by chaotic, randomly and rapidly varying velocities. This turbulent convection is described in terms of a mean velocity distribution (in general, composed of more than one cartesian component) and a fluctuating component whose properties lead to rapid mixing of fluid

5.2 GASES AND VAPORS

1

73

elements within the bulk of the flow field except for a laminar layer adjacent to a phase boundary (gas-solid or gas-liquid). Molecular diffusive transport within the gas phase, as discussed above, occurs when concentration gradients of a species exist and are described quantitatively by a diffusive flux (F)as in Equation 5.21. It is common for both convection and molecular diffision to be important in gas-phase transport but, in some cases, one mechanism is dominant over most of the flow field, which makes the analysis oftransport simpler. The relative importance of convection and diffusion in gas transport is quantitatively expressed by the dimensionless Peclet number (Pel, which is given by:

where u

=

characteristic fluid velocity (It-l)

x = characteristic system dimension (1) D = gas diffusivity (12t-l) (1 = length and t = time)

The relative importance of convection and diffusion as a mechanism for gas transport varies greatly from the proximal to the distal portion of the respiratory tract. For water vapor transport in the trachea at a constant flow rate of 500 cm s-', the Pe is 940, indicating that convection dominates, except for a narrow zone at the airway-liquid interface. By contrast, in the acinar airway proximal to the alveoli, the Pe is 0.0074, indicating dominance of diffusive transport for gases having diffusivity similar to that for water vapor (0.24 cm2s-I).

5.2.2

Gas-Phase Transport and Conditions a t the Phase Boundary

Since an understanding of gas deposition upon the fluid boundaries of the respiratory tract is sought, the transport rates at these boundaries are of primary importance, and transport elsewhere in the gas phase is only important t o the extent that it influences local transport to the boundaries. It is a well-establishedprinciple of fluid mechanics that tangential and normal convective velocities decrease approaching a boundary (gas-solid or gas-liquid), the former because of the effect of fluid viscosity and the latter because convective flow does not take place through the boundary. Thus, over a certain gas layer thickness, normal transport of a gas is dominated by diffusion. In laminar one dimensional flow, transport to the walls normal to the

74

1

5. DEPOSITION OF INHALED SUBSTANCES

flow direction is described by a concentration profile, which changes over the entire flow cross section. Thus, gases differ from particles in their transport to airway boundaries in that particles can move to boundaries by inertial motion and external forces (e.g., gravity), whereas gases do not exhibit such movement and depend on molecular diffusion (implying a concentration gradient or difference across the boundary layer) for deposition. For a gas of given initial concentration and diffusivity, the transport flux depends on the boundary thickness (6) the difference between the bulk, or ''free stream," gas concentration ( C G ) and the gas concentration a t the boundary (CB).For many situations, the Fick equation (Equation 5.21) can be rewritten in simplified form as:

where the gradient has been replaced by the concentration difference divided by the gas-phase boundary thickness over which concentration changes in an assumed linear manner from the free stream concentration to that at the boundary. The problem of gas deposition onto the boundary is thus reduced to determining 6 and CBat the gas-liquid (mucus) boundary. The boundary thickness can be approached in a different fashion by rewriting Equation 5.23 in terms of a phenomenological mass transfer coefficient (kc):

The mass transfer coefficient (kc) is of great interest for the solution of interphase transfer problems and has been treated extensively in transport phenomena texts, e.g., Bird et al. (1960), where it is shown that kGis a function of system geometry, gas properties and fluid flow regime (laminar or turbulent). The mass transfer coefficienthas been measured for a number of simple systems, such as flow in cylinders, which can be used to estimate transport in the approximately cylindrical portions of the bronchial region. For a fuller treatment of this approach the reader is referred to Lightfoot (1974). The gas concentration at the boundary (CB)depends upon several factors, including the physicochemical interaction of the gas with the surface fluid, underlying tissue and blood supply to the tissue. This is another feature of gas deposition, which is more complex

5.2

GASES ANDVAPORS

1

75

than the corresponding situation for ultrafine (particlediffusion controlled) aerosol deposition. In the case of aerosol deposition by diffusion, the interface between gas and liquid can be treated as an infinite sink, i.e., every particle that strikes the liquid surface "sticks." This corresponds to the condition that CBequals zero, so that there is always an aerosol concentration difference between the gas phase and the boundary, whose magnitude is CG,until concentration in the gas phase is reduced to zero. The physicochemical interaction of a gas with the surface fluid can be characterized in terms of its liquid solubility and chemical reactivity. The solubility of a gas in a liquid and the resultant gasphaselliquid-phase equilibrium (or partition) is given for a number of gases by Henry's Law, which is a linear approximation and only valid at low concentrations:

where PG = partial pressure of gas (atm) CL= dissolved gas concentration in liquid (g ~ m - ~ ) H = Henry's Law constant (atm g-' cm3) The value of the Henry's Law constant varies widely among gases, e.g., for HCl the value of H is 0.0031, while for CH,, the value of H is 5.0 X lo4. When gas is absorbed into the surface liquid, it is accessible to the underlying epithelial tissue and its attendant blood supply, which cany the dissolved gas away. If the gas is highly soluble and transport to tissue and blood is rapid enough, the gas concentration at the gas-liquid boundary is very low, and the overall transport is limited by transport on the gas side. In this instance, the interface concentration of gas approaches zero, corresponding to the liquid and tissue acting as an infinite sink. The other case in which the gas concentration at the interface approaches zero is when the gas rapidly and irreversibly reacts with the liquid and the reactants are likewise carried away from the interface by tissue and blood transport. Some pollutant gases, such as 03, are not highly soluble in water, but react with constituents of the respiratory secretion, thus, providing a means of removal from the gas-liquid interface. Studies of uptake of O3in the NOPL region (discussed later in this Section) demonstrate removal that is more extensive than would occur from solubility alone. If the gas has both low water solubility and has low chemical reactivity, the gas concentration at the interface is almost as great as the gas concentration in the bulk of the gas phase. In this instance, the flux of gas at the interface is significantly smaller than for a soluble orreactive gas, according to Equation 5.22, and the deposition

76

1

5. DEPOSITION OF INHALED SUBSTANCES

for a given segment of the respiratory tract can be significant only for a very large area, such as the surface of the entire P region.

5.2.3 Gas Transport on the Liquid Side of the Interface

As discussed previously, the behavior of gas in the airway liquid layer and epithelial tissue has a significant influence on the deposition rate from the gas phase. In general, as with gas-phase transport, dissolved gas can be transported both by convection of liquid and by molecular diffusion. However, in most instances in the respiratory airways, liquid convectivevelocity (usually parallel to the interface) is very small and the movement of dissolved gases in the liquid phase is dominated by molecular diffusion in a direction normal to the interface. The diffusivity of dissolved gases in water is very much less than gas diffisivity in the gaseous phase. Based on literature values, Davidson and Schroter (1983) took an average value of diffusivity of gases in water to be cm2 s-l, which is approximately four orders of magnitude smaller than diffisivity in gas. Nevertheless, when the gas is highly soluble in the surface fluid, the rate of transport of gas through the liquid layer to the underlying epithelial tissue is sufficiently rapid so that the overall transport from the gas phase to the blood perfusing the epithelium is controlled by the gas-phase boundary zone. The thickness of the liquid and tissue layers varies significantly from the upper airways to the alveolar spaces. In airways surrounded by ciliated and mucus secreting cells, the fluid thickness is of the order of 10 pm (0.001 cm), while the tissue thickness was estimated by DuBois and Rogers (1968) to vary from 0.09 cm (trachea) to 0.003 cm (terminal bronchiole). In the alveolar spaces, the liquid layer thickness has been estimated as 0.3 pm and the tissue thickness as 0.36 to 2.5 pm (Meessen, 1960). Removal of gases in the liquid layer or tissues by chemical reaction, as mentioned above, is a second mechanism for enhancing liquid side transport, and in the limiting case, providing essentially a zero concentration of gas at the interface. Some pollutant gases, such as NH3, 0, or NO2 are known to react rapidly with water, the constituents of secretions or tissue components. The behavior of such gases in the respiratory tract has been treated theoretically by McJilton

5.2 GASESANDVAPORS

1

77

et al. (1972) and Overton and Miller (1985) in a model represented diagrammatically in Figure 5.14. 5.2.4 Gas Deposition in the Naso-Oro-Pharyngo-Laryngeal Region All experimental studies in humans and other animals of regional gas deposition have been carried out in the NOPL region, primarily because it is easy to isolate this region and sample its inflow and outflow for gas concentration. This is accomplished either by drawing gas-laden air through the nose and out the mouth (in humans) or by drawing such a mixture through the nasal passage, pharynx and larynx of an experimental animal and out through a transected tracheal airway. The nasal removal of SOz in humans was measured by Speizer and Frank (1966) for a concentration of 16 ppm and found to be essentially 100 percent. In view of its very high water solubility, this result is not surprising, and suggests that the gas concentration at the interface was at or near zero. Recent experimental studies of deposition of ultrafine aerosols in human nasal and oral replicate models (Cheng et al., 1988) indicate deposition approaching 50 percent for 5 nrn particles and are consistent with the quantitative removal of highly soluble or reactive gases when breathed either by nose or mouth. Deposition studies of other gases demonstrating NOPL uptake between 10 and 100 percent have been carried out in experimental animals by several other investigators; these include 03,NOz,NO, acetone, formaldehyde, propionaldehyde, acrolein and

I

LUMEN OF AIRWAY

-

O

R

GAS -

-

r

I

1

LIQUID LINING

Gf S

TISSUE V GAS

I

-

REACTANTS

REA~ANTS

GAS

PRODUCTS ++ REACTANTS PRODUCTS

b PRODUCTS

Fig. 5.14. Gas deposition model for air flow into and out of a lung airway.

78

1

5. DEPOSITION OF INHALED SUBSTANCES

acetaldehyde. The general conclusion of these studies is that percent uptake varies directly with solubility or reactivity and decreases somewhat at increasing flow rate. Detailed patterns of deposition are not described in any study. 5.2.5

Gas Deposition in the Tracheobronchial and Pulmonary Regions

Overall respiratory tract uptake for several of the gases listed above have been measured by several investigators in experimental animals, as reported by Overton et al. (1987). Mathematical models of gas uptake in the TB and P regions have been reported by McJilton et al. (1972), Miller et al. (1978) and Davidson and Schroter (1983). All of these simplified models were devised to predict the effect of gas properties and breathing parameters on the generation specific deposition of a specific gas (03),or absorbing gases in general, specified by their Henry's Law constants. Generally, these models demonstrate distribution of deposition throughout the bronchial airways and alveolar region for less soluble gases, such that specific dose per unit area of airway surface does not vary greatly. More soluble gases, which penetrate the NOPL region, tend to demonstrate higher doses in the more proximal airways with little penetration to the P region, as illustrated by the calculation of McJilton for SO,. 5.2.6

Predicted Deposition of Specific Radioactive Gases

Six gases are considered in this Section, representative of a larger number of radioactive substances, which can occur in the gaseous state. These are krypton, radon, xenon, iodine (Iz), ruthenium tetraoxide, and uranium hexafluoride. The diffusion coefficient and available Henry's Law constants of these gases are shown in Table 5.3. Both xenon and krypton are used as lung ventilation agents in the field of nuclear medicine. As such, their respiratory distribution has been of interest, because if they can be shown to have significant deposition in a particular respiratory region, their use would be limited to the visualization of the region. Studies of inhalation of xenon and krypton (Aldersonand Line, 1980)demonstrate that these gases exist in the P region because of their low solubility in airway secretions in the NOPL and TB regions. Because of the similarity of water solubility of radon gas to xenon and krypton and its chemical inertness, it can be predicted that radon gas will also be deposited only in the P region.

5.2 GASES AND VAPORS

1

79

TABLE5.3-Physical properties of selected gases a t 25 "C. Henrv's Law constant (atm g-' cm-*)

Molecular Mass

Diffusivity

Radon

222

0.056

22.4 x 10"

Xenon

131

0.18

2.0 X 10"

Iodine (12)

254

0.07

2.08

Ruthenium tetroxide

166

0.15

-

Uranium hexafluoride "Data are not available

352

0.07

-

Gas

(cm2 see-')

Conversely, the other three gases, because of the very high solubility (iodine)or reactivity (ruthenium tetroxide) will be quantitatively removed in the NOPL region. This has been demonstrated in the case of ruthenium tetroxide for canine exposure (Snipes, 1981) and there is no reason to expect the behavior of this and the other similar gases to be different in the human respiratory tract.

6. Respiratory Tract Clearance This Section contains a description of the clearance of particles deposited in the respiratory tract. Most of the information summarized here was derived from studies using human subjects; however, results of studies using laboratory animals are included because many needed measurements cannot be made using human subjects and because it is important to compare respiratory tract clearance in humans and animals for the purposes of toxicology and human health risk assessment. The majority of studies on respiratory tract clearance have been done using inhaled radioactive particles. The reported measurements of retention include radionuclides t h a t remained associated with the particles, as well as radionuclides that may have dissociated from the particles. Such measurements of retention are used to determine radiation dose to nearby tissues. However, when chemically toxic substances are inhaled, it should be remembered that injury of tissues may result from the inhaled compound or from associated metabolic products. Thus, measurements of the clearance of radioactive compounds from the respiratory tract may not provide all of the pertinent information needed. The first model of respiratory tract clearance recommended by the ICRP (1959) for radiation dosimetry calculations described retention patterns for the two particle classifications of relatively soluble compounds and all other compounds. All inhaled particles were considered t o deposit i n the upper and lower respiratory passages, respectively. For soluble materials, 25 percent of the inhaled material was deposited in the lung and immediately transported to blood. Of material which was deposited in the upper respiratory passages, 50 percent, was subsequently swallowed. The remaining 25 percent was assumed to be exhaled. For insoluble materials (also called "other compounds"), 25 percent was deposited in the lung, half was assumed to be cleared to the GI tract over a 24 h period, and the other half would remain in the lung with a biological half-time (TB) of 120 d. The exceptions to this rule were all isotopes of plutonium (Tg = 1 y) and isotopes of thorium (TB = 4 y). This model was revised by the TGLDACRP (1966) to include information on regional deposition and clearance of particles in the respiratory tract. The

6. RESPIRATORY TRACT CLEARANCE

/

81

estimation of clearance of particles to the GI tract, blood or LN was modified to account for dissolution rates reflected by half-times of days, weeks and years. Individual compounds were assigned to a clearance class based upon experimental data (when available) and on a knowledge of the physicochemical form of the deposited material when experimental data were not available. Since 1966, new studies have shown that respiratory tract clearance pathways and rates are markedly influenced by inhaled particle size, surface area, previous temperature treatment, the overall composition of the particle matrix and decay rate for high-LET radiations. The ICRP model published in 1966 (TGLDIICRP, 1966)was generally applied in a conservative manner when formulating exposure control guidelines. That is, dose estimates for respiratory tract tissues were often overestimated as a result of the practice of using clearance half-times representing the slowest clearing fractions of the inhaled radionuclides observed in studies of exposed humans or laboratory animals. Single half-times were used even though a substantial portion of the deposited radioactivity may have been absorbed into blood more rapidly. This practice may be satisfactory for making recommendations on how best to protect the respiratory tract, but it may lead to underestimating radiation exposures to other internal organs and to misinterpretation of bioassay information from accidentally exposed people. The constraint that respiratory tract clearance pathways follow first order kinetic processes is unduly restrictive for general application of the model. Clearance rates may change with time and users of the models described in this Report are encouraged to derive specific clearance information from measurements obtained on exposed humans or laboratory animals. An important assumption underlying this modeling approach is that, for a given chemical, the rate for transfer of particles into the blood is the same throughout the entire respiratory tract and is similar in different mammalian species (even though mucociliary clearance rates are known to be species dependent). If information on systemic absorption of specificradionuclide forms is not available from inhalation studies, then f i s t approximations of clearance rate parameters may be derived from studies of the dissolution of particles placed in solvents in vitro. Although in vitro systems do not strictly resemble the environment of particles in lung tissue, they are generally reliable for distinguishing between particles that readily dissolve in aqueous media and particles that dissolve very slowly. This approach presumes that, for most of the material deposited in the respiratory tract, dissolution from particles takes place before absorption to blood and that dissolution is the main rate-controlling step. Finally, if no experimental information

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6. RESPIRATORY TRACT CLEARANCE

is available for a particular radionuclide form, then values for model parameters that control systemic absorption may be selected by reference to the previous Task Group clearance classifications of days, weeks and years (TGLDDCRP, 1966). The mathematical aspects of the models of respiratory tract clearance described in this Report are more complex than those used prior to 1994. The new models can be applied to new types of exposure and dosimetry evaluations. The models must be adjusted to represent the specific inhaled material and individual characteristics of breathing patterns and body size. To facilitate the use of the models described in this Report, sample calculations are provided and computer programs are available.

6.1 Concepts of Respiratory Tract Clearance

The rates and pathways by which deposited substances are cleared from the respiratory tract depend mainly upon the sites of deposition and chemical interactions between the substances and components of the surrounding tissues. As discussed in Section 5, the sites of deposition are influenced by: (1)aerosol particle size, shape and density, (2) respiratory parameters, including breathing frequency (VT)and residual air volume, (3) airway morphology, and (4) breathing mode (nasal or oral). Chemical factors that influence the rates of clearance of specific substances include: (1)their physical/chemical form and that of the total particle matrix, (2) their rates of elution from the particle surfaces, (3) their dissolution rates, (4) their reactions with constituents of lung fluids, especially those influencingdissolution, and (5)their chemical binding to cellular and extracellular tissue components. The interactions of these factors are complex, so that predicting inhaled particle deposition and clearance for toxicity evaluations requires extensive information on the specific inhaled material along with model calculations. The respiratory tract clearance model is subdivided into the NOPL airways, TB airways, P region and LN (Figure 6.1). In all regions beyond the anterior nasal airways, clearance is described in terms of competing mechanical and absorptive processes. Mechanical clearance processes move deposited substances toward the pharynx, where they are swallowed, or to the P lymph nodes. Absorptive processes transfer substances from the respiratory tract and LN to the blood. Absorption mainly occurs for substances after they dissolve or elute from particle surfaces; however, these substances may still react with tissue constituents and remain in the respiratory tract for a long time.

6.1 CONCEPTS OF RESPIRATORY TRACT CLEARANCE

1

83

NASO-ORO-PHARYNGO-LARYNGEAL REGION

Fig. 6.1. The respiratory tract lung model is based on four regions: NOPL, TB, P and LN. The extrinsic and intrinsic clearance rates are represented by arrows. Transfer to blood U(t) = absorption function], transfer to the TB region and GI tract [M(t) = mechanical clearance rate function] and transfer to the lymph nodes (LN = 0.0001 (1-') serve as model inputs. The output of the model contains estimations of deposition and clearance suitable for calculating dose to the respiratory tract.

Conversely, a small fraction of the deposited particles may pass intact into the blood and translocate to other organs or be excreted (Gearhart et al., 1980; Stradling et al., 1978a; 1978b).This rarely occurs for particles larger than 0.1 p,m in diameter, but may be more common for smaller particles. The absorptive processes described in the respiratory tract model represent the net transfer of material from the respiratory tract to blood, regardless of the mechanism. Most of the airway surfaces from the nasal passages through the terminal bronchioles are lined with ciliated epithelium and covered

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1

6. RESPIRATORY TRACT CLEARANCE

by mucus. Except for the most anterior area in the nose, substances depositing in these airways are effectively moved by mucociliary action toward the oropharynx. The velocity of mucus movement is more rapid in the larger airways and becomes progressively slower in the smaller distal airways (see Tables 3.3 and 3.4). Mucus flow patterns are probably complicated, especially in very convoluted airways and near bifurcations; however, simple linear flow in regular shaped tubes is assumed in the following discussions. In some studies using laboratory animals, a small fraction of the inhaled particles has been shown to be retained in the nasal and TB epithelium for several weeks after exposure (Benjamin et al., 1979; Gore and Patrick, 1978; Watson and Brain, 1979). The mechanisms by which particles penetrate into the epithelium are unknown, but they may include pinocytosis by epithelial cells, phagocytosis by macrophages with subsequent translocation into epithelial tissues, passive movement along normal fluid clearance pathways, trapping in areas where clearance mechanisms have been damaged and others. The importance of such focal accumulations of potentially toxic material in relation to the high average doses to tissues in other areas of the respiratory tract is uncertain. However, tumors of the nasal airways have been observed in some studies of laboratory animals and humans who inhaled specific carcinogenic substances (Boecker et al., 1986) and tumors of the central bronchial airways are the most common sites for lung cancer in cigarette smokers (Schlesinger and Lippmann, 1978). Clearance of particles from the P region appears to depend on their size, shape and composition. Deposited particles smaller than 1 pm and down to molecular sizes are found in almost all types of cells (Lauweryns and Baert, 1977). They can be taken into cells by phagocytosis, pinocytosis and endocytosis, and cleared to the lymphatic vessels, TB airways or blood circulation (Figure 6.2a). Larger particles are mainly taken up by phagocytic cells and cleared to the TB airways or lymphvessels (Figure 6.2b), although soluble material leaving the surfaces of the particles can pass directly into the blood. Most likely, cells phagocytize the particles in the alveolar lumen and move to the TB airways or through the epithelium and interstitial spaces to lymphatic vessels (Harmsen et al., 1985). Fibers >5 to 10 pm in length that deposit in the P region are cleared very slowly (Morgan et al., 1982;Roggli et al., 1987;Vincent et al., 1985).Because they may be too large for cells to ingest and move along the pathways described above, dissolution with absorption into the circulating blood and mechanical penetration of whole fibers toward the lung pleura appear to be the main factors affecting clearance (if they clear at all).

6.2 MECHANICAL CLEARANCE OF PARTICLES

1

85

Fig. 6.2. Clearance pathways for material deposited in the P region: (a) probable pathways for submicrometer particles and (b) probable pathways for larger particles.

The location and state of particles in the P region change with time after deposition, and so will their availability for clearance through different pathways. The time course over which these changes in location and state occur is not precisely known, but probably depends upon particle characteristics. The fractional clearance rate for deposited material generally decreases with time, making it difficultto use simple first order kinetic relationships in predicting the lung burdens and doses to tissues at risk for inhaled toxic substances. Thus, the mathematical model discussed below makes use of variable clearancerates that are expressed in terms of the fractions of the remaining tissue burdens cleared per day.

6.2 Mechanical Clearance of Particles 6.2.1 Particle Clearance in the Naso-Oro-Pharyngo-Laryngeal Airways

To describe the clearance of deposited substances, the nasal airways may be divided into the anterior and posterior areas (Figure 2.1). In the anterior area, clearance is toward the nostrils

86

1

6. RESPIRATORY TRACT CLEARANCE

and the cleared material may remain in the nasal vestibule for many hours because it is only removed by extrinsic means such as wiping or blowing with clearance estimated (for the purpose of this model) to be effectively completed in 1h (Proctor et al., 1977). Direct absorption of dissolved substances from the anterior area is assumed to be a t a much slower rate than the rate of absorption from the posterior region because most of this area is lined with squarnous epithelium similar to skin (Swift and Proctor, 1977). Because mucus flow is very slow in the anterior nasal region and extrinsic removal is unpredictable (Hounam, 1975;Hounamet al., 1983),the selection of a n average retention time accounting for the cleaning of the anterior nose is arbitrary. For the healthy person, use of a retention time of 1h is recommended. Substances that deposit in the posterior area of the nasal airways are cleared to the oropharynx where they are rapidly swallowed. Absorption from the posterior region to blood can be significant, probably due to its moist surface and rich vascular perfusion. Cuddihy and Ozog (1973) and Stather and Howden (1975) have studied nasal absorption in Syrian hamsters and rats (Table 6.1). Approximately 70 percent of the mass of soluble isotopes of Cs, Sr or Ba was absorbed into the blood from the posterior region of the nasal airways, compared to only 10 percent absorption for soluble isotopes of Ce and Pu. Default conditions in the model include 50 percent absorption in this region for soluble isotopes up to the lanthanides and 10 percent absorption for soluble isotopes having higher atomic numbers. Studies with Beagle dogs have shown that a portion of soluble isotopes deposited in the nose is retained in that region for a considerable length of time, perhaps 100 d or more (Benjamin et al., 1979; Boecker and Cuddihy, 1974; Cuddihy, 1978; Cuddihy and Boecker, 1970; Cuddihy and Griffith, 1972; Cuddihy et al., 1974). If this is TABLE6.1-Nasal

absorption in hamsters and rats following intranasal intubation. Measured Absorptions

239Pu nitrate

75% 77% 61% 4% 10%

239h citrate

15%

13?Cs 90Sr l"Ce

Estimated Absorptionb

1

70% 10%

"Data from hamsters (Cuddihy and Ozog, 1973) and rats (Stather and Howden, 1975) are available; data from humans are not available. bThe average Cs, Sr and Ba are for monovalent and divalent compounds and Ce and Pu for trivalent and higher compounds. This is a default option because assigning too much weight to these numbers from hamsters and rats could be misleading since human data are not available.

6.2 MECHANICAL CLEARANCE OF PARTICLES

1

87

shown to be the case with humans, the model will have to be changed in the future. Quantitative measurements of the NOPL clearance of inhaled particles in the nasal airways of human subjects were reported by Lippmann (1970) and Fry and Black (1973). The particles were between 0.8 and 10 pm AD and the resting subjects breathed normally. In both studies, most of the deposited particles were in the forward portion of the nasal passages. About 40 percent of the total nasal deposits cleared within 3 h (as expected for deposition in the posterior area); 60 percent showed prolonged retention, which is assumed to be associated with the anterior area. Model studies reported by Itoh et al. (1985) and Swift and Proctor (1986) indicate a shift in deposition toward the posterior nasal area for particles (0.5 p,m in diameter. For such particles, it is reasonable to assume 50 percent deposition in each of the anterior and posterior areas. Measurements of effective particle clearance velocity in the posterior nasal airways were presented in Table 3.3. Most of these measurements are focused on the posterior area, beginning just forward of the nasal turbinates. Particle clearance velocities were reported between 0 and 24 mm m i d ; a median value of 6 rnrn min-Iis assumed for the clearance model described in this Report. Because the posterior nasal area is about 6 cm long, the effective retention time for inhaled particles in this area is about 10 min (Fry and Black, 1973). Some studies using radioactive aerosols inhaled by laboratory animals have shown prolonged retention of material in the area of the nasal turbinates (Boecker et al., 1986). For example, significant concentrations of inhaled "4CeC13were observed to remain for more than 30 d after exposure and probably played a significant role in the subsequent development of nasal cancers in some animals. Such prolonged retention of inhaled radioactivity in the nasal turbinate area is not often observed and it may be caused by trauma to the epithelium and chemical binding to tissues. It is not known if prolonged retention of material in the nasal airways is a factor causing the observed increase in nasal cancer risk among workers in the furniture, leather or asbestos industries, but this is an important area for further research (Acheson, 1976; Lane and Anderson, 1977; Stell and McGill, 1973). Given the absence of additional data in the human, the model provided in this Report does not include a slowly clearing compartment in this region. No details of local deposition and clearance characteristics for particles in the oral passages have been reported. The likely sites for deposition are just inside of the entrance to the mouth and at the oropharyngeal bend. Clearance of insoluble particles is by swallowing, which occurs frequently, and expectorating. Tissues of the

88

1

6. RESPIRATORY TRACT CLEARANCE

mouth may have the capacity for rapid systemic absorption of soluble material, but it is not likely that chemical binding can cause longterm retention. However, these issues are not resolved. Pharyngeal clearance of insoluble particles is also by swallowing, coughing and expectorating.The larynx is cleared toward the epiglottis by mucociliary action, but not all of the epithelial surface of the larynx is ciliated. Exposure of the larynx is from; (1) directly deposited particles on inhalation (2)particles deposited in the upper respiratory tract, and (3) particles that are deposited elsewhere in the TB airways but are cleared through the trachea. Material that is deposited or cleared passes over the laryngeal walls on its way to being swallowed. The velocity of movement of particles in the larynx is assumed here to be equal to that in the trachea.

6.2.2

Particle Clearance in TracheobronchialAirways

Measured clearance rates for insoluble particles deposited in the TB region are summarized in Table 3.4. In most of these studies, particle clearance velocities were measured in the trachea only, but in one study, the velocities were actually measured in the major bronchi. The effective particle clearance velocity in the trachea is assumed to be 5.5 mm min-' for the purpose of dosimetry modeling in this Report. Transport rates in medium-sizehuman bronchi have been calculated to be 0.2 to 1.3 mm min-' (Foster et al., 19821, and those in the most distal ciliated airways were calculated to be 0.001 to 0.6 mm min-I (Morrow et al., 1967a; Yeates, 1974; Yeates and Aspin, 1978). Since direct measurements of mucus flow rates in the distal airways of humans are very difficult to make, the time pattern for clearance of material deposited in the thorax is generally used as an index of mucus flow rates. Measurements of thoracic clearance of insoluble radioactive particles, beginning immediately after inhalation, show a rapid clearance phase during the first 20 to 40 h followed by a slow clearance phase lasting hundreds of days (Figure 6.3). The rapid phase is mainly due to clearance of particles deposited in the TB region and the prolonged phase to clearance from the P region (Bair and Willard, 1963; Hatch and Gross, 1964; Lippmann and Albert, 1969).In healthy, nonsmoking humans, material has been reported to clear from the TB region within 24 h (Albert et al., 1969; Camner and Philipson, 1978),but the presence of disease or exposure to irritants may depress mucociliary function and extend the time for clearance well beyond 24 h. Other investigators have suggested that bronchial clearance in peripheral airways extends

6.2 MECHANICAL CLEARANCE OF PARTICLES

20

40 60 80 HOURS AFTER INHALATION

1

89

100

Fig. 6.3. Illustration of early thoracic clearance pattern for inhaled insoluble particles and assignment of deposited fractions to the TB airways and P region. It is assumed that most of the rapidly cleared material is deposited in the TB region, and that most of the slowly cleared material is deposited in the P region.

beyond 24 h, even in healthy individuals (Clarke and Pavia, 1980). Svartengren et al. (1981)reported a slow phase of clearance for 6 Fm Teflon particles instilled into the trachea and at the first bifurcation of rabbits; the clearance half-time at the latter site was 39 h. Effective particle clearance velocities can be estimated for individual bronchial airway generations by usinginformation on respiratory tract airway dimensions, inhaled particle deposition fractions for individual airways and thoracic clearance measurements. The first detailed attempt to estimate effective particle clearance velocities for individual airways was reported by Altshuler et al. (1964) and was later extended by Harley and Pasternack (1972).These analyses were based upon particle clearance studies reported by Albert and Arnett (1955) and considerations of mucus thickness in the TB airways. Using new clearance data for monodisperse aerosols (7.9 Fm AD) and the Weibel A anatomic model, Lee et al. (1979) also calculated effective airway particle clearance velocities. The results of calcuIations using both of the models are summarized in Table 6.2. The third set of model calculations shown in Table 6.2, the NCRP analysis, was obtained from analyses of particle deposition and clearance studies reported by Stahlhofen et al. (1980). For these

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6. RESPIRATORY TRACT CLEARANCE

TABLE6.2-Effective particle cleamnce velocities calculated for TB airways of the

Airway Generation

1 trachea 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 (terminal brunchioles)

human lung. Effective Clearance Velocities (mm min-l) Harley and Lee et al., Pasternack, 1979 1972

15 8 2.5 2.5 0.9 0.9 0.9 0.25 0.25 0.25 0.01 0.01 0.01 0.01 0.01 0.01

5.5 4.1 3 2.2 1.4 0.88 0.55 0.34 0.21 0.13 0.074 0.044 0.025 0.015 0.0082 0.0046

NCRP Analysis

5.5 4

2 1.3 1 0.9 0.7 0.6 0.4 0.3 0.2 0.1 0.04 0.02 0.005 0,001

calculations, three nonsmoking males used two different breathing patterns to inhale monodisperse aerosols (monodisperseaerosols are made with one particle size only) of between 1.1and 9.5 pm AD. In this analysis, particle deposition was calculated for each airway generation using the model of Yeh and Schum (1980). The corresponding particle sizes and breathing patterns were incorporated into the calculations to produce a cumulative deposition curve (as a function of airway generation) as illustrated by the upper curve and left ordinate in Figure 6.4. The measured clearance in the exposed individual is illustrated by the lower curve and right ordinate. The time for clearance of each airway generation was then calculated, as indicated for generation 12 by the dashed lines connecting the left (airway generation) and right (clearance time) ordinates. These clearance times were divided into the typical airway lengths reported by Yeh and Schum to obtain effective particle clearance velocities for each airway generation (Figure 6.5 and Table 6.2). Although the vast majority of material that deposits in the TB airways clears to the GI tract within 40 h, a small amount may be retained for much longer periods of time. Attention was focused on this question after reports indicated that human autopsy specimens from smokers showed greater concentrations of 210Poat bronchial airway bifurcations than in other bronchial tissue (Cohen et al., 1979; Little et al., 1965; 1985; Martell, 1974; 1975). Also, studies with relatively insoluble uranium dioxide particles instilled or

6.2 MECHANICfL CLEARANCE OF PARTICLES

/

91

20 40 60 80 100 PERCENT OF TRACHEOBRONCHIAL DEPOSITION

Fig. 6.4. Relationship between the calculated cumulative deposition of inhaled particles in TB airway generations (upper curve and left ordinate) and time for clearance of the deposited particles (lower curve and right ordinate). The method of estimating the time for clearance of each airway generation (ATJ is indicated for generation 12 by the solid and dashed lines connecting the left and right ordinates.

inhaled into the airways of rats showed prolonged retention in the trachea and bronchi (Patrick, 1979).Gore and Patrick (1978)estimated that the concentration of uranium in tissues of the bronchial airways was 57 percent of that in pulmonary tissue for more than 35 d. Autoradiography studies showed that most of the bronchial 235U02 was located under the bronchial epithelium. Although quantitative measurements of this retention pathway are not as yet sufficient for purposes of dosimetry modeling, it is useful to note that portions of the bronchial airway epithelium may receive radiation doses comparable to pulmonary tissues, even when least expected, as with inhaled relatively insoluble alpha-emitting radionuclides. For more penetrating radiations, beta and gamma, the doses to bronchial airways are almost always similar to those received by pulmonary tissues. Even though focal areas of long-term retention of radionuclides in TB airways are likely to occur, their impact on dose calculations is expected to be small. The clearance half-times in Table 6.2 were used and the long half-time for clearance in the

92

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6. RESPIRATORY TRACT CLEARANCE

I

I

I

2

4

I

I

I

I

6 8 10 12 AIRWAY GENERATION

I

I

14

16

Fig. 6.5. Relationship between effective particle clearance velocity ( f SD) and TB airway generation beginning with the trachea (measuredvalue) and ending with the terminal bronehioles.

TB airways was not used because there was not enough supporting evidence.

6.2.3 Particle Clearance in the Pulmonary Region Due to the absence of mucociliary clearance mechanisms, clearance of insoluble particles from the P region is considerably slower

6.2

MECHANICAL CLEARANCE OF PARTICLES

/

93

than clearance of insoluble particles deposited in nasal or TB airways. Particles depositing in the P region are likely to be engulfed by phagocytes within hours (Sanders, 1969), but they may remain in alveolar cells, interstitial spaces or cells, cells lining blood or lymphatic vessels and LN for hundreds of days thereafter. Particles slowly move to the ciliated airways and LN through mechanisms that usually involve pulmonary macrophages (Harmsen et al., 1985). At the same time, some of this material may disperse in surrounding fluids and be absorbed into the systemic circulation. Because of these complex interactions, pulmonary clearance is most simply modeled in terms of particle clearance processes representing material passing to the TB airways or LN, and competing absorption processes representing material passing into the blood circulation. The rates at which particles are cleared to the TB airways and GI tract must be determined from inhalation studies of humans exposed to very insoluble aerosol particles. To be most useful, the studies should also furnish quantitative information on the slow absorption of material from the P region to blood over very long periods of time. Because the fractional long-term clearance rate for d-I, absorption of particles in the P region is only about 1 x respirable size particles, which generally occurs at very slow rates, would introduce considerable uncertainty in the estimates of particle clearance rates unless information is provided to correct for this effect. Only two long-term studies meet this requirement: Bailey et al. (1985) measured the retention of 85Sr-and 8T-labeled fused aluminosilicate particles in 12 adult males for 372 to 533 d and Philipson et al. (1985) measured the retention of 51Cr-labeledTeflon particles in six adult males for 300 d. In both studies, the long-term rate of dissolution of the radioactive label was similar to the rate of particle clearance. However, measurements of in vitro solubility and urinary excretion were provided so that appropriate corrections could be made in calculating the rates of particle clearance. Other clearance studies in humans can also be used for the early time periods (e.g., 4 0 0 d) during which particle clearance rates are much larger than rates of absorption of the radioactive label into the blood circulation (Bohning et al., 1982; Newton et al., 1978; Stahlhofen et al., 1980). A summary of information on particle clearance rates from the P region of humans is shown in Figure 6.6. At early times, the daily d-', corresponding to a clearance rate is approximately 6 x half-time of 115 d. By 200 d after inhalation exposure, this decreases d-l, corresponding to a half-time to a daily value of about 1 x of 700 d. A mathematical fbnction representing the fractional daily clearance rate for particles in the P region of humans is:

94

/

A

2 5 10 -

* =3W

6. RESPIRATORY TRACT CLEARANCE I I

*TEFLON \ 1'

8-

# t

-- ----

-----P

u

B

I

1

I

I

I

200

100

I

I

300

I

400

DAYS AFTER INHALATION Fig. 6.6. Calculated fractional daily clearance rate [M(t)l, for humans in the P region based on experimental measurements using inhaled Teflon (Philipson et al., 1985), iron oxide (Stahlhofen et al., 1980), fused aluminosilicate (Bailey et al., 1988) and polystyrene particles (Bohning et al., 1982).

The rates at which insoluble particles are cleared from the P region varies markedly among different species (Bailey et al., 1989;Cuddihy, 1978; Snipes et al., 1984; Thomas, 1972). Mathematical functions representing particle clearance to the TB airways (Equations 6.2 to 6.7) are compared in Figure 6.7. Similar aerosols (radiolabeledfused aluminosilicate particles) were used in the studies from which these fmctions were derived. Clearance in mice and rats is notably faster, while clearance in dogs is slower than in humans. The reasons for these differences in particle clearance are not understood, but they may result from species differences in airway structure between the terminal bronchioles and alveoli. M(t) = 0.02e-0.0Mt+ 0.0015 mice (CD-1)

(6.2)

M(t) = 0.02e-0.07t+ 0.001

rats (Fisher-344)

(6.3)

HRT rats

(6.4)

hamsters

(6.5)

M(t)

=

0.02e-0.013t + 0.001

M(t) = 0.007e-0.0044t +0 M(t)

=

0.004e-0.04"+ 0.0005 beagle dogs

M(t) = 0.005e-0,02t+ 0.001 humans

(6.6) (6.7)

1

6.2 MECHANICAL CLEARANCE OF PARTICLES

95

MICE (CD-1) RAT (FISHER 344) HAMSTER RAT (HRT) MAN

DOG (BEAGLE)

0

50

100 150 DAYS AFTER INHALATION

200

250

Fig. 6.7. Fractional clearance rate per day [M(t)l, from the P region to the TB region estimated from laboratory studies using inhaled insoluble particles (Bailey et al., 1985; Cuddihy, 1978; Snipes et al., 1984).

6.2.4

Particle Clearance to Pulmonary Lymph Nodes

The rates oftransport ofinsolubleparticles from the P region to LN has not been studied quantitatively in humans. Thomas presented analyses of experimental measurements of transfer rate constants to suggest that this rate is relatively independent of animal species d-' for the daily fractional transfer and derived a value of 1 x rate constant (Thomas, 1972).This value is similar to those derived for inhaled niobium oxide in dogs (Cuddihy, 1978)and inhaled fused aluminosilicateparticles in dogs and guinea pigs (Snipeset al., 1984). Therefore, 1 x 10-* d-' is used in this Report to represent a constant daily transfer of particles from the P region to pulmonary LN in humans.

96

1

6. RESPIRATORY TRACT CLEARANCE

6.3 Absorption into the Blood

The rate at which material deposited in the respiratory tract is absorbed into the blood depends upon many factors, even for particles of similar chemical form. These include particle surface area, chemical structure, previous temperature treatment, radionuclide specific activity and, probably, other factors. Mercer (1967) suggested that particle dissolution is a major determinant controlling the rate of absorption for material retained in the respiratory tract, and that for simple materials, dissolution rate is proportional to particle surface area and a characteristic dissolution rate constant. This concept provides an excellent basis for mathematical modeling of lung clearance if (1) all factors controlling particle dissolution are known, (2) sufficient data are available to project dissolution rates for different substances in biological fluids, and (3) dissolution is the only factor controllingabsorption of substances from the respiratory tract. To date, scientific information is not available to adequately model these factors. Thus, a more pragmatic approach to predicting absorption is described here that uses experimental observations of clearance rates for specific substances that are inhaled by humans or laboratory animals. For this approach to be successful, it is necessary to assume that systemic absorption functions for material deposited in the respiratory tract are similar among different species. If differences exist among species, they are not likely to be detected for highly soluble or insoluble particles. Likewise, the related errors in dosimetry calculations are not apt to be significant when absorption functions derived from data on laboratory animals are used for humans. The largest difficulties arise with inhaled particles that have intermediate rates of dissolution and with substances that are incorporated into particles having a mixed chemical composition. Experimental measurements of the rates of absorption of inhaled cerium from the lungs of dogs, mice, rats and hamsters indicate that cerium chloride and cerium oxalate have similar absorption functions (Cuddihyet al., 1979).Also, absorption functions for cesium incorporated into fused aluminosilicate particles and deposited in the lungs of dogs, guinea pigs, rats and mice were reported to be independent of species (Snipes et al., 1983a). An extensive interspecies comparison to test this hypothesis has been completed using cobalt oxide aerosols inhaled by rats, mice, dogs, baboons and humans (Bailey et al., 1989). Without huinan data, the best estimation of the monodispersed cobalt oxide aerosol clearance kinetics is the absorption function combined with mechanical clearance

6.3 ABSORPTION INTO THE BLOOD

1

97

function from animals, but the uncertainty in animals and humans must be kept in mind. At present, several hundred radionuclide inhalation studies are available in the scientific literature. Absorption functions can be derived from many of these studies. Ideal studies for this purpose provide information on radionuclide contents of the head airways, lungs (including the trachea and bronchi), GI tract, body tissues and organs and excreta as a function of time after inhalation exposure. Measurements should also be provided for absorption in the GI tract and endogenous fecal excretion of material after absorption into the blood circulation. Because few studies report such complete kinetic information for inhaled aerosols, values for some model parameters must be assumed or estimated from separate studies using the same or similar radionuclides and chemical forms. For radioactive particles, the most useful experimental measurements for respiratory tract dosimetry modeling are of thoracic radioactivity as a function of time after inhalation exposure [TR(t)l.Such measurements generally include radioactivity in the TB airways, P region and LN. The decrease in thoracic radioactivity results from (1)clearance of material through the TB region to the GI tract, (2) absorption into the blood circulation, and (3) radioactive decay. After correcting for radioactive decay, mathematical functions are fit to the measurements of thoracic radioactivity and the derivatives of the functions are obtained. The overall daily fractional clearance rate [FC(t)l, can then be calculated:

This process is illlistrated in Figure 6.8. For modeling purposes, the total daily fractional clearance rate for the thorax is composed of clearance rates to the GI tract, Mit) as given above, and to the blood circulation [A(t)l. In using this relationship to calculate A(t), it is assumed that (1)the rate of absorption or clearance to the blood circulation is similar for all material retained in the thorax (including that in the P region, TI3 region and LN) and (2) Ait) is independent of species so that absorption functions calculated from studies in laboratory animals can be directly applied to model calculations for humans. To ascertain if the derived function for absorption of radioactivity into the blood circulation is reasonable, further evaluation using information for radionuclide uptake by internal body organs and excreta is useful (Cuddihy, 1978; Cuddihy and Griffith, 1972). The amount of

98

1

6. RESPIRATORY TRACT CLEARANCE

DAYS AFTER INHALATION

(b)

DAYS AFTER INHALATION Fig. 6.8. Illustration of a method for estimating the absorption function [A(t)l, using (a) measurements of TR(t) over long periods of time and (b) the derivative of TR(t) expressed as a fraction of the remaining radioactive material.

6.4 COMPARISON OF MODEL VERSUS EXPERIMENTAL

1

99

radionuclide absorbed from the respiratory tract into the blood O~BSRT),, between the exposure and time, t, is calculated from the expression: (6.10) W3SRT), =X (internal organ burdens), +Z, (urine + endogenous feces) - GI absorption Here, radioactivityis summed over all organs (exceptthe respiratory and GI tracts) at time, t, and for urinary and endogenous fecal excretion from the time of exposure to time, t. The amount of radioactivity absorbed from the GI tract is deducted from the sums. This amount of radioactivity calculated to be absorbed from the respiratory tract should also be equal to the integrated product of the fractional absorption function and amount of radioactivity remaining in the respiratory tract: where HR(t) is the amount of radioactivity retained in the head airways. This application of radionuclide kinetic informationis illustrated in Figure 6.9. With a calculator or computer model readout, the following variables are given:

- NOPL region NOPL (posterior) TB (generations 2-16 or any combinations) - TB region P - P region LN - LN region These variables may be retrieved in several combinations depending on how the respiratory tract is structured. They are given in days for any length of time desired.

6.4 Comparison of Clearance Model Projections with Experimental Measurements

The mathematical model of respiratory tract deposition and clearance was formulated by combining particle deposition calculations described by Yeh and Schum (1980),TB clearance represented by a series of 16 airway generations having effective particle clearance velocities as summarized in Table 6.2, and pulmonary clearance represented by the daily fractional rate functions, M(t) and A(t). Projections were made for the clearance of inhaled insoluble particles having an AD of 4 p,m, and inhaled with a tidal volume of 1,000 cm" and frequency of 7.5 min-l. The results are compared with shortterm clearance measurements in three subjects reported by Stahlhofen

100

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6. RESPIRATORYTRACTCLEARANCE

DAYS AFTER INHALATION

TOTAL ABSORBED

FROM RESPIRATORY TRACT

7

DAYS AFTER INHALATION Fig. 6.9. Illustration of a method for estimating the amount of an inhaled substance that is absorbed from the respiratory tract using (a) measurements of the cumulative urine and endogenous fecal excretion and internal organ contents and (b) calculated absorption of the substance in the GI tract.

6.4 COMPARISON O F MODEL VERSUS EXPERIMENTAL

/

101

et al. (19.80) and long-term clearance measurements reported by Bailey et al. (1985) and Philipson et al. (1985). These are shown in Figure 6.10. In general, there is agreement between the model projections and experimental measurements. This is not surprising considering that these and other similar measurements formed the basis for the model formulation. The composite deposition and clearance model tended to overestimate the amount of early clearance for inhaled particles <7 p,m AD and to underestimate the amount of early clearance for larger particle sizes. Long-term clearance projected by the model was corrected for dissolution and absorption of the radioactive label, which accounted for 20 to 30 percent of the daily fractional clearance beyond 200 d after inhalation. Finally, model projections were made for respiratory tract clearance of AmOzinhaledby humans. Americium deposited in lung tissue is slowly absorbed into blood where it transfers to bone and liver or is excreted in urine. Several sets of data obtained from studies of accidental human exposures were summarized by Mewhinney and Griffith (1982) and are shown in Figure 6.11. Thoracic retention is expressed as a percent of the measured or calculated burden at 4 d after inhalation. The model projection used a fractional daily absorption function [A(t)l,expressed by the function: A(t)

=

0.03e-0.016t + 0.0014.

(6.12)

This was derived from the results of inhalation studies using dogs. All other parameters used in the model projection are described previously. The agreement between model calculations and measurements of clearancein humans supports the use of absorption function information derived from studies with laboratory animals. Although the model described earlier was based mainly on studies using radioactive cations, many of its features apply equally well to projecting clearance of a variety of inhaled chemical substances. Unless chemical toxicity or mass loading alters the clearance mechanisms, virtually all respirable size particles should be cleared in a similar manner. Dissociation of more complex chemical compounds from particles will likewise control their absorption into the blood circulation and this may be determined from studies usinglaboratory animals. However, chemical changes induced by metabolism and the importance of these changes in estimating dose to target tissues are unique to each type of inhaled substance. These factors are beyond the model calculations described here, but they must be taken into account when estimating chemical dose.

102

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6. RESPIRATORY TRACT CLEARANCE

1.o

0.8

0.6 MODEL PROJECTION SAME AS LOWER LIMIT OF RANGE

0

1

I

0

20

1

I

I

I

I

40 40 6 0 1 0 0 1 2 0 HOURS AFTER INHALATION

MODEL PROJECTION FUSED ALUMINOSILICATE

-

0

'I 0

I

I

I

100 200 300 DAYS AFrER INHALKrION

1 400

Fig. 6.10. Comparison of (a) short-term thoracic clearance of inhaled particles measured by Stahlhofenet al. (1981)and (b)long-termpulmonaryclearance measured by Bailey et al. (1985)and Philipson et al. (1985),with mathematical model projections. All measurements used particles having ADS of about 4 pm.

6.4 COMPARISON OF MODEL VERSUS EXPERIMENTAL

1

103

J

5 t

0

z_

0 CASE A

1

*)

MODEL PREDICTION

Jeanmarie and Ballada (1971)

Edvardssen and Lindgren (1976) Sanders (1974)

0 1

I

0

I

100 200 DAYS AFTER INHALATION

1

300

Fig. 6.11. Comparison of measured thoracic clearance of americium oxide in humans with clearance for humans as modeled by Equation 6.9.

7. Lung Model for Exposure to Radioactive Particles The deposition model is based on the morphometry of the lung as presented by Yeh and Schum (1980) and the descriptions of the NOPL, TB, P and LN regions given in this Report. The application of the model to a wide variety of humans and situations requires that model parameters are scalable to different ages, body sizes, activity levels, and to nose and mouth breathing (Cuddihy and Yeh, 1988; Cuddihy et al., 1988). The properties of the aerosol, such as AD and density, need to be specified as well. The calculation of the deposition fraction in the NOPL airways and the different generations of airways in the TB region and lung includes the three mechanisms of diffusion, impaction and sedimentation. The main innovations are the new NOPL, TB and P models, and incorporation of the recent data sets for deposition of ultrafine particles (c0.2 pm M W ) in the oral and nasal passes (Cheng et al., 1988; 1990; Yamada et al., 1988). The focus of the clearance calculations in this model is on the respiratory tract. Burdens and doses in other organs in the body are not calculated explicitly. The main change compared to previous models is caused by the introduction of experimental data for mucociliary clearance velocities and the clearance function to blood. Each of the 16 generations of the upper TB airways (not shown in this model) is considered as a separate compartment. Using the geometrical information and values for the mucociliary transport velocities, the burden in each compartment in the airways is calculated as a function of time.

7.1 Deposition 7.1.1 Naso-Oro-Pharyngo-Laryngeal Airways Deposition in the NOPL airways is calculated by using empirical functions of particle diameter (d),particle density ( p ) and average during inhalation or exhalation as main parameters. airflow rate (Q)

7.1 DEPOSITION

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105

For particles larger than 0.2 ym, the log-logistic function is used to parameterize the deposition probability P,: where a,and b, are experimental parameters depending on the index ( q ) that differentiates between inhalation or exhalation, as well as between mouth breathing and nose breathing (Table 7.1). For particles <0.2 ym, the general function for turbulent diffusion in a cylinder gives a good representation of the data,

Here, c, is another parameter fitted to experimental data (Table 7.1). The diffusion coefficient (D), is given by:

where, k is the Boltzmann constant, T the absolute temperature, q the dynamic viscosity coefficient for air and the Knudsen number K is given by

where h (6.53 x pm for air at one atmosphere) is the mean free path of the gas particles. The h is the only quantity that introduces a strong dependence on atmospheric pressure into Equations 7.2 to 7.4. The expression in the square bracket of Equation 7.3 is the Cunningham slip correction factor (Fuchs, 1989). The numerical constants used are those appropriate for spherical and near-spherical particles. With these functions, deposition for nasal and oral breathing during the inhalation and exhalation phases can be calculated for particle diameters from about 100 pm down to the sizes of about 60 nm. For nasal deposition during inhalation with an average flow rate of 20 L min-', the deposition probability is shown in Figure 9.1 or TABLE7.1-Numerical values of the fitted parameters for nasal and oral deposition during inhalation and exhalation.' Q, b, Cq Nasal Inhalation 4,600 0.94 40.3 Exhalation 2,300 1.01 48.7 Oral Inhalation 30,000 1.37 40.2 Exhalationb 30,000 1.37 34.3 "Forthese values of the parameters, the flow rate Q must be given in cmhs-',the density ping ~ m -the ~ ,particle diameter in pm, and the diffusion constant in cm2s-'. baqand b, are assumed to be equal to inhalation values. Organ

Phase

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7. LUNG MODEL FOR EXPOSURE TO RADIOACTIVE PARTICLES

Table 5.2. The deposition decreases to almost zero below 1 p,m and then rises again to high values for the sizes of particles down to 0.001 pm. Nasal deposition during exhalation and oral deposition during both breathing phases yield similar curves.

7.1.2 Tracheobronchial Tree and Pulmonary Region The morphometric model of Yeh and Schum is summarized in Table 2.3.For each of the 16generations, a geometricalcharacterization is given, consisting of the median length (L)and diameter (dl of each cylindrical tube, the branching angle 8 at the top of each tube, the angle of the tube axis with respect to the direction of gravity (for a lung in the vertical position) and the number of elements in each generation. These data permit us to calculate anumber of auxiliary quantities, such as the cross-sectional area and the volume of each generation, as well as the cumulative volume up to that generation. This set of data is used to model the physical processes along a typical lung path. Both in the TB airways and in the lung, particle deposition is modeled by impaction, diffusion and sedimentation in properly oriented, cylindrical tubes and for diffusion,the appropriate entrance correction for the bifurcation is applied (Yeh, 1974). The result is a deposition rate or a total one-time deposition in the four NOPL airway compartments (anterior and posterior nose, oral and pharyngeal regions) and each one of the 16 compartments of the TB tree and the lung.

+

7.2 Clearance 7.2.1 Model Characteristics The NOPL model has three independent compartments, anterior and posterior compartments of the nose and the oral region. The anterior region of the nose is cleared periodically toward the exterior; whereas the posterior region clears toward the pharynx. The oral region also clears toward the pharyngeal region during swallowing. The pharyngeal region, fed from the trachea, the posterior nasal compartment and the mouth, discharges its burden to the GI tract during swallowing. The TB airways consist of 16 compartments, corresponding to a generation of bronchi, each clearing upward to the next compartment

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and to the blood. The lung clears to the lung-associated LN, the blood and the TB airway. Whereas clearance to the lung-associated LN occurs a t a constant rate, clearance to the TB airway and to the blood compartment is given by two functions of time, M(t) and A(t). The clearance functionA(t) couples almost all compartments to each other (Figure 6.1).

7.2.2

Clearance Functions M(t) and A(t)

Mechanical clearance from the lung to the base of the TB airway can be described by a function M(t) for the fractional daily clearance rate, which is independent of the particle diameter, Equation 6.1. This function, which describes the clearance from the generations of the TB airway to the upper parts of the respiratory tract, is independent of radioisotope and chemical form in which it appears in the aerosol. Figure 7.1 shows the pulmonary retention function or lung burden TR(t) for the time after inhalation. Its differential with regard to time is plotted in Figure 7.2 as the fractional clearance rate [FC(t)l. After the fractional mechanical clearance rate [M(t)l is subtracted, what remains is the fractional clearance rate to blood [A(t)l. For each radioisotope and each chemical compound, a different function A(t) will result. A typical example is shown in Figure 7.2 where the lung burden of a one-time exposure to a n aerosol of 140BaC12 is given as a function of time (Cuddihy and Griffith, 1972). Integral data derived from the burdens stored in other organs of the body and in excreta can be used to verify the derivation.

7.2.3

System of Differential Equations

There are 22 compartments in the clearance model, 17 for lung and the TB airway, one for the lymphatic system, and four for the head airways. Two additional compartments, the blood and the GI tract serve merely as sinks for particles or their radioactivity. No mass burdens are calculated for the latter compartments. Note that the clearance to blood introduces a n additional coupling between the equations. The general structure of the differential equations for clearance of such a system is given by the expression:

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7. LUNG MODEL FOR EXPOSURE TO RADIOACTIVE PARTICLES

l4'sa Cl,

0.001 0

20

40

60

70

DAYS AFTER INHALATION Fig. 7.1. Lung burden (LB)of '40BaCI,in dog after inhalation [measurements including the spread of the data are in Cuddihy and Griffith (197211. Three exponential functions are needed to parameterize the data, which are normalized to the initial lung burden ( 100 percent) a t t = 0.

where Qi(t) is the burden in compartment i, fij(t)is the transfer rate function between compartment i and j and Di(t)is the direct input rate for compartment i. For the system of differential equations depicted, many of the transfer rate functions are either constant or

1

7.2 CLEARANCE

0.01

1

I

I

20 40 DAYS AFTER INHALATION

109

I

I

60

70

Fig. 7.2. Relative absorption coefficients [A(t)l in percent per day, for I4OBaCl2in the entire respiratory system. In this case, the process results in two exponentials and a constant.

zero. With the exception ofthe transfer to blood, most of the equations have a sequential structure, i.e., the two sums in Equation 7.5 have only one term each. The transfer rate to blood has 20 terms and this Equation provides a general coupling between the sequential equations:

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7. LUNG MODEL FOR EXPOSURE TO RADIOACTIVE PARTICLES

To simplify this set of equations, the assumption is made that fractional clearance rate [A(t)]applies to each compartment separately. Each compartment contributes to the transfer to blood according to its burden.

7.3 Dose Calculations The calculation of accumulated dose from the instantaneous burden in each compartment is based on the application of dose-rate conversion factors for each radiation type and energy. The basic approach employed here is to develop tables of specific absorbed fractions in tissue from imbedded point, plane and cylindrical radiation sources and to use these fractions to calculate absorbed dose to tissues in the lungs or the upper airways. These dose calculations can be expanded to include the usual dose to entire organs. They can be somewhat focused to allow for regional doses to large parts of the organ (such as the lung and the TB tree or the two nose compartments), or they can be restricted to calculations at the local level (small structural parts of organs, such as a particular generation of bronchi). The choice of volume over which to perform this range of dose calculations depends largely on the type of radiation and, to a lesser degree, on its energy. For high-LET radiation, such as alpha particles emitted by radioisotopes with energies below 10 MeV, the range in tissue (
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radiation, therefore, only organ-averagedoses will be used. The relevant dose parameters are taken from Medical Internal Radiation Dose (MIRD) Committee tabulations (Snyder et al., 1969). For charged, low-LET radiations, such as beta rays, the argument of a range greater than the dimensions of the structure can again be made for emissions having initial energy >25 eV and a range of a fraction of a millimeter to a few millimeters in tissue. For such emissions in this energy range, instead of local or regional doses, global doses will again be calculated by using parameters supplied in the MIRD tabulations. The model may also be used to calculate deposition and retention of chemical.toxicants, although additional deposition and absorption mechanisms may have to be modeled. In addition, much less is known quantitatively about the retention of chemical toxicants in the body, and the dosimetry may be quite different, particularly when metabolites, rather than the agents inhaled are involved in damaging critical tissues. Both data sets and models have to be developed before calculations at the level of this model are possible. The calculation of deposition, retention and absorbed dose can be extended to include children. To calculate the absorbed dose in children, the morphological data table (Table2.3) must be adjusted to present airway sizes appropriate for the age of the child. In addition, different retention functions may be needed for children, and possibly even a different mechanical clearance function. Similar changes would be needed for an extension ofthis model to laboratory animals, where a more detailed model is needed for the interpretation of experimental data.

7.3.1 Absorbed Dose from Photons, Electrons and Alphas Dose to the tissues at risk, resulting from inhaled radionuclides, is calculated for each of the four regions of the respiratory tract which are composed of epithelial tissue of the NOPL region, epithelial tissue of the TB region, epithelial and endothelial tissue of the P region, and lymphatic tissue of the lung and pleural cavity. The absorbed dose delivered to the target tissue is calculated by applying geometric algorithms to tables and/or relations of point isotropic specific absorbed fraction for photon-emitting radioactivity (Brownell et al., 1968; C[h]risty and Eckerman, 1987; Ellett and Humes, 1970, beta radioactivity (Berger, 1971) and alpha radioactivity (Taner and Eckerman, 1985). The output of the dose calculations for the respective tissues will be the absorbed dose from photons, the absorbed dose from alpha

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particles and the absorbed dose from beta radiation. Absorbed dose (D) is calculated as the ratio of the mean energy imparted to a unit mass of tissue by ionizing radiation. Absorbed dose has units of joules per kg (J kg-') and 1J kg-l is equal to 1 Gy. The absorbed dose for photons, electrons and alpha particles in tissue can be used to calculate quantities relevant to radiation protection. The absorbed dose (D) will be calculated from the absorbed dose rate (D) (Figure 7.3). The input of the clearance model to these calculations will be the total alpha, beta and gamma activity, yield per decay, and initial energy of each radiation, as a function of time in each compartment of the lung model. The absorbed dose rate to a tissue element is given by:

where k is a constant created to account for conversion of units, A is the activity of the source, a point source in the case ofEquation 7.8, Y is the yield per disintegration, E, is the initial energy of the ionizing radiation that is released, and @(r,E,)is the point isotropic specific absorbed fraction. Absorbed dose rate has units of Gy per unit time. The point isotropic specific absorbed fraction, @(r,Eu)has units of kg-' and is a function of the distance from the point source (r) and the initial energy of the ionizing radiation (E,). The absorbed dose at a distance (r), from a point source is calculated by integrating the absorbed dose rate over time. The average absorbed dose to tissues within a defined volume (V)can be calculated by integrating the absorbed dose over a volume and dividing by the total volume. The point isotropic specific absorbed fraction [@(r,Eo)lis a direct function of the total mass stopping power [S,(E,)] as indicated in the following equation:

The point isotropic specific absorbed fraction [@(r,E,)I changes inversely as the square of the distance (r) from the source, inversely as the initial energy (E,) of radiation being emitted from the source, and directly as the total mass stopping power [S,(E,)I. The proposed approach for calculating absorbed dose to tissues in the four regions of the respiratory tract (NOPL, TB, P and LN) or to subcomponents of these regions is to tabulate the specific absorbed fraction according to the four geometric conditions (also given in Table 7.2): 1. the absorbed fraction for a uniform distribution of photon emitters in an ellipsoid of revolution,

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NEAR

LINE SOURCE

Absorbed Dose

=

kAc Y Eo@,(r, R, Ed)

-1

am,

rmax

= 5

Fig. 7.3. Specific absorbed fraction @(r,R,E,)for a point located a perpendicular distance ( r )from the surface of an isotropic cylindrical source of radius (R)and zero (0)wall thickness. The equation for @(r,R,E,)includes the contribution of infinitely thin line sources, O(r,E,), compromising the "far" and "near" surfaces defined by whether or not the radiation traverses a portion of the tissue prior to reaching the point of estimated absorption. This relation, based on tabulated values of the point source, isotropic specific absorbed fraction, @(r,E.), is used in all subsequent cylindricalsource, absorbed-dose calculations.

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2. the absorbed fraction for a uniform distribution of photon emitters in a lung-shaped volume, 3. specific absorbed fractions from planar and cylindrical isotropic sources of electron emitters, and 4. specific absorbed fractions from planar and cylindrical isotropic sources of alpha par-ticle emitters. Available, published tables of point isotropic specific absorbed fraction [@(r,E,)]for photons, alphas and betas will form the basis for the calculations in this current lung model. The basic approach is presented in Table 7.2 and Figure 7.3. The published tables are produced by solving for the total mass stopping power [S,(E,)I at a given distance (r) from the source which, in turn, requires knowing what the remaining energy of the radiation is at that point. The key to all of the calculations in this lung model is experimental measurements on the total mass stopping power of the material for each type of ionizing radiation. The total mass stopping power is defined as the ratio of the energy lost by charged particles per unit distance in traversing a small distance in material and has units of J m2kg-l (if the energy lost is expressed in electron volts, then the units are eV m2kg-I).

7.3.1.1 Estimating Dose from Photon-Emitting Radiation. For photons, the total amount of activity contained in the TB tree, P region and lymphatic tissue of the pulmonary cavity will be combined. The absorbed dose will be calculated assuming a uniform distribution of activity over the entire combined tissue mass. The point isotropic specific absorbed fraction for such a distributed source of gamma radiation has been integrated over the volume and general shape of lungs scaled from child to adult (Cblristy and Eckerman, 1987). These fractions are listed in Table 7.3 as a function of photon energy and lung size. The point isotropic specific absorbed fraction for a distributed source has also been integrated over the volume of small spheres and ellipsoids (Ellett and Humes, 1971). These calculations were made for different masses of tissue and photon energies. An example of these calculations for small ellipsoids of axes ratio 1:2:4is shown in Table 7.4. The absorbed dose rate can be calculated as shown in Equation 7.8. The specific absorbed fraction will be used for calculating the absorbed dose from activity in each of the regions, TB, P and LN. Calculation of absorbed dose from photons in the NOPL region will be done by first assigning a volume or mass to the NOPL region. For this region the geometry will be assumed to be an elongated

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TABLE7.4-Absorbed fractions (fractions absorbed in an object) of photon energy for uniformly distributed sources in a small unit-density ellipsoid surrounded by scattering medium (azes 1:2:4) (Ellett and Humes, 1971). Mass

Photon Energy (MeV) 0.10 0.14 0.364

(g)

0.03

0.04

0.06

0.08

1 2 4 6 8 10 20 40 60 80 100

0.045 0.058 0.073 0.082 0.092 0.100 0.125 0.155 0.192 0.229 0.244

0.021 0.027 0.035 0.040 0.045 0.049 0.063 0.081 0.101 0.121 0.131

0,010 0.013 0.017 0.020 0.022 0.024 0.032 0.042 0.052 0.063 0.069

0.008 0.011 0.014 0.016 0.018 0.020 0.026 0.034 0.043 0.051 0.056

0.008 0.011 0.014 0.016 0.018 0.019 0.025 0.032 0.040 0.049 0.053

0.009 0.011 0.014 0.016 0.018 0.020 0.025 0.032 0.041 0.049 0.053

0,010 0.013 0.016 0.018 0.021 0.022 0.028 0.035 0.044 0.053 0.057

0.662

1.46

2.75

0.010 0.013 0.016 0.018 0.020 0.022 0.028 0.035 0.044 0.052 0.056

0.009 0.011 0.014 0.016 0.018 0.019 0.024 0.030 0.037 0.045 0.049

0.007 0.009 0.012 0.012 0.015 0.016 0.020 0.025 0.031 0.037 0.040

ellipsoid with axis 1:2:4. Absorbed fractions for this geometry are listed in Table 7.4. The absorbed dose to the NOPL region from photon emitting radioactivity is calculated from the summation of activity and tissue mass in the subcompartments. The mass of the tissue of the NOPL region is assumed to consist of all tissue from the airway surface to the basement membrane. Given the calculated mass and the photon energy, the absorbed fraction in an ellipsoid of revolution, having an aspect ratio of 1:2:4, can be extrapolated from Table 7.4. The absorbed dose from photon emitting radioactivity in the TB region is calculated from the cumulative activity in each generation of the conducting airway. Given the combined mass of the TB and P and LN regions, the absorbed fraction in a lung shaped object can be extrapolated from Table 7.3. This is not the case in the absorbed dose calculations for alpha and beta radiation, since D can be directly estimated in J kg-I(Gy). For the purpose of estimating the dose from photons, the mass of the NOPL region is calculated by estimating the surface area (the default value is taken to be 100 cm2in adults as discussed in Section 2) and multiplying it by the assumed average depth to the basement membrane (default value equals 0.1 mm). 7.3.1.2 Estimating Dose from Alpha Radiation. In the pulmonary and lymphatic tissue, the alpha radiation is assumed to be uniformly distributed throughout the tissues and the energy from each decay is assumed to be completely absorbed. In the TB region, tables of the point isotropic specific absorbed fraction for alphas must be used to estimate the absorbed dose to epithelial and other tissues surrounding the airways (Table 7.5). These calculations will be made

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7. LUNG MODEL FOR EXPOSURE TO RADIOACTniTE PARTICLES

TABLE7.5-Plane source, isotropic specific absorbed fraction for 4, 6 and 8 MeV alpha radiation in tissue. E,, (MeV) r(max), (cmP r 1 r(rnax)

0.01 0.02

4 0.00275

6.303+ 02 5.60E + 02

"Range of the alpha particle.

6 0.0048

specific absorbed fraction (cmag-')

3.313 +02 2.953 + 02

8 0.00774

2.07E + 02 1.85E + 02

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for each of the first 16 generations because of the availability (from the clearance model) of the activity as a function of time for each generation. The point isotropic specific absorbed fraction for alpha energies of 4, 6 and 8 MeV is tabulated in Tables 7.6a through 7.6h as a function of the fraction of maximum path length in tissue. Absorbed dose to an annular cylinder of tissue surrounding each airway is calculated assuming concentric cylindrical sources, each having an annular thickness of 3 pm. The cylindrical isotropic specific absorbed fraction is calculated using values of the isotropic specific absorbed fraction for a line source imbedded in tissue, for alpha particles that travel directly through tissue, and values of the isotropic specific absorbed fraction for a line source surrounded by a cylinder of air, for alpha particles on the cylindrical source that travel first through air and then through tissue before reaching the target site. Tables 7.6a through 7.6h contain values of the cylindrical isotropic specific absorbed fraction. The absorbed dose from alpha particles in the NOPL region is calculated assuming two stacks of parallel planar sources separated by an average distance (R) (default = 1.0 mm). The tissue has a surface area and minimum depth as indicated above for adults.

7.3.1.3 Estimating Dose from Beta Radiation. The calculations for the absorbed dose of electrons will use the same equations and default conditions as used in calculating the dose for alpha particles. The calculated absorbed dose to the tissues surrounding the conducting airways will be increased by the respective absorbed dose from the P region for electrons with energies >25 keV. The specific absorbed fraction from planar and cylindrical sources of electron radiation are listed in Tables 7.7 and 7.8a through 7.8h. The specific absorbed fractions listed in these two tables are based on the point source specific absorbed fraction for electrons as reported by Berger (1971). Berger gives the specific absorbed fraction for a point source for electrons in an infinite water medium. As shown in Figure 7.3, the specific absorbed fraction from a cylindrical source of electrons is calculated assuming that it is a stockade of very thin line sources. Absorbed dose from a planar source is taken to be the same as from a cylindrical source of infinite radius (Moss and Eckerman, 1991).

7.3.2. Sample Calculations of Dose The purpose of this Section is to demonstrate the use of the model through an example. In so doing, an accident is described in detail. The application of the model is then presented to show how the

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TABLE7.6a-Cylindrical source, isotropic specific absorbed fraction for 4, 6 and 8 MeV alpha particles in tissue (cylinder radius R = 0.03 cm). En,(MeV) 4 6 8 r(max), (cm)

0.00275

0.00498 specific absorbed fraction (cmQgl)

2.813 + 02 2.553 +02

0.00774

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TABLE7.6b-Cylindrical source, isotropic specific absorbed fraction for 4, 6 and 8 MeV alpha particles in tissue (cylinder radius R Eo,(MeV) drnax), (em) r

0.05 cm).

6 0.00498 specific absorbed fraction (emz g-'1

8 0.00774

6.13E +02 5.50E 02 5.00E 02

2.983 + 0 2 2.723 02 2.643 + 02

1.76E+02 1.60E + 0 2 1.57E+ 02

l r(max)

0.01 0.02 0.04

=

4 0.00275

+ +

+

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7. LUNG MODEL FOR EXPOSURE TO RADIOACTIVEPARTICLES

TABLE7.6~-Cylindrical source, isotropic specific absorbed fraction for 4, 6 and 8 MeV alpha particles in tissue (cylinder radius, R = 0.07 em). E,, (MeV) r(max), (cm) r 1 r(max)

0.01 0.02

4

0.00275

6.30E + 02 5.483 + 02

6 0.00498 specific absorbed fraction (cm2g-')

3.09E + 02 2.823 + 02

8 0.00774

1.83E + 02 1.67E + 02

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TABLE7.6d-Cylindrical source, isotropic specific absorbed fraction for 4, 6 and 8 ~ e ~ a l particles ~ h a in tissue (c&in&r radius, R-= 0.10 cm). Eo. (MeV

4

0.00275

6 0.00498

specific absorbed fraction (emag-'1

9 0.00774

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7. LUNG MODEL FOR EXPOSURE TO RADIOACTIVEPARTICLES

TABLE7.6e-Cylindrical source, isotropic specific absorbed fraction for 4, 6 and 8 MeV alpha particles in tissue continued (cylinder radius, R = 0.20 cm). E,, (MeV) rfmax), (cm) r l r(max)

4 0.00275

0.01 0.02

6.353 + 02 5.483 +02

6 0.00498

8 0.00774

specific absorbed fraction (cm2g-')

3.353 + 02 2.883 + 02

2.04E + 02 1.80E +02

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TABLE7.6f-Cylindrical source, isotropic specific absorbed fiaction for 4, 6 and 8 MeV alpha particles in tissue (cylinder radius, R = 0.30 cm). E,, (MeV) dmax),(cm) r l dmax)

0.01 0.02

4

0.00275

6.353 + 02 5.483 + 02

6

0.00498 specificabsorbed fraction (cm2 g-')

3.333 + 02 2.883 + 02

8 0.00774

+

2.093 02 1.803 + 02

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7 . LUNG MODEL FOR EXPOSURE TO RADIOACTIVE PARTICLES

TABLE7.6g-Cylindrical source, isotropic specific absorbed fraction for 4, 6 and 8 MeV alpha particles in tissue (cylinder radius, R = 0.40 cm).

".

En. (MeV) ,. dmax), (cm) r / r(max)

4

fi

R

0.00275

0.00498

0.00774

specific absorbed fraction (em2g ')

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TABLE7.6h-Cylindrical source, isotropic specific absorbed fraction for 4, 6 and 8 MeV alpha particles in tissue (cylinder radius, R = 0.50 em). E.. -",

(.-M -- e n,

r(max), (cm) r / rtmax)

4

fi

8

0.00275

0.00498

0.00774

specific absorbed fraction (cm2g-')

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parameters are defined for calculating dose, how the calculation is performed, and what the output of the model provides. In the example accident scenario, a health physicist is asked to estimate the absorbed dose, out to 200 d, for a worker exposed to plutonium dioxide. The worker was removing material from a glove box at the end of a plutonium oxide production line. An approximately 15 min inhalation exposure occurred during the transfer process. According to personal samplers, approximately 100 Bq of activity was inhaled with an AMAD of 1 p,m. To use the lung model to estimate absorbed dose in this example, the tables in Section 5 would be used to estimate the deposition fraction in the different compartments of the lung model. The clearance times for the amount deposited in each compartment would be estimated from the tables and figures of Section 6. A table of the average amount of activity remaining in each compartment of the lung model, as a function of discrete time intervals, can then be constructed so that the equations and tables of Section 7 can be used to estimate absorbed dose. An integrated modeling package (computer program1) has been developed and includes two entry screens on the computer. The first screen requires the user to input the parameters necessary for computing fractions of total inhaled radioactive material deposited in the respiratory tract (see Table 7.9, computer Table A). The second screen requires the input of infonnation necessary for computing the dose as a function of time (see Table 7.9, computer Table B). The first three parameters shown on screen one are (1)breathing frequency (breaths per minute), (2) VT (cm3),and (3) FRC (cm3).These parameters describe the physical status of the individual and can be varied depending on the age, body size and physical activity level. In our example the individual was working as reflected in the tidal volume. The next two parameters, (4)particle diameter (km), and (5) particle density (grn ~ m - ~ ) , describe aerosol properties of the substances. If the AD is used as input the density is input as one. The next parameter, (6) atmospheric pressure [in atmospheres (atm)], is input because large changes in atmospheric pressure will alter aerosol behavior, especially for ultrafine particles and, therefore change the probability of deposition. The seventh parameter (7) is the pause between breaths. Because breathing patterns can differ for an individual and among individuals, this parameter offers the option of considering pauses between breaths. The current computer software permits pauses to occur only between exhalation and inhalation. 'Information on availability of this program can be obtained by contacting Dr. Richard Cuddiiy, 7511 LaMadera Road, NE, Albuquerque, NM 87109.

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TABLE7.9-Summary of data required to calculate respimtoy tmct burdens. Parameter

Value

Relevant Table/Figure/etc.

Output

Deposition (computer Table A) Breathing freq./min VT~ FRCa

Densityb Atmospheric pressure Pause Nose breathing Mouth breathing Body height

1 g em-" 1 atm 0.5 s 100% 0% 175 cm

Deposition efficiencies in the NOPL, TB and P regions

Table 3.2 Table 3.2

Clearance and dosimetry (computer Table B) Initial point Cumulative point Break point M(t)

Total inhaled activity Lung mass TB tissue depth dose

0d 200 d 20 0.005 exp (- 0.02t) + 0.001 0.0016 exp ( - 0.02t) + 0.0001 100 Bq 1,000g 10 to 50 pm

-

Equation 6.1 Appendix A

Clearance and dose in the NOPL, TB, P and LN regions

Absorbed Deposition dose in gray after 200 D fraction Total 0.477 NOPL 0.339 (Posterior nose) 1.6 X TBd 0.019 5.4 x P 0.119 1.2 x lo-4 LN 0.000 8.4 x lo-5 "The parameter units will appear as cc on the screen. the example, AMAD was known, therefore unit density was input; if the real diameter and density are known, they should be used. 'Breakpoints refer to the selectable number of equal intervals for which dose is reported by the software. Results computer Table C )

dThedeposition reported in this example is for TB generations 2 through 6 inclusive, as this is the region of interest for cancer development.

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The eighth (8)and ninth parameters (9) allow the user to adjust for oral breathing. Because the breathing mode can shift from nose breathing to nose and mouth breathing with an increasing level of physical activity, these parameters provide the option of considering a different breathing mode. The tenth parameter (10) allows users to specify whether the subject is an adult or a child, and to adjust for height. For children, the NOPL volume is scaled downward in proportion to the tracheal cross section. These options also allow model calculations to account for age and height related differences in the size of the TB region airways. Similarly, this option can be used to make adjustments for females by modeling them as males having the same body height as the female under consideration. All of this information is, in turn, used to compute the particle deposition fractions (using the deposition Equations 5.5 and 5.7 and Table 5.1). The deposition fractions are stored in an intermediate file and used to compute cumulative exposure and absorbed doses in gray (Gy). Deposition fractions are multiplied by the inspirability to account for the fraction of airborne material that is actually inhaled, which is particle size, but (assumed) not age dependent. On the second screen, the first three parameters, initial point, cumulative point and break point are for a time period of days. Absorbed dose is calculated as a function of time from 0 to 200 d, in this example. The number of breakpoints, 20, indicates to the software that the initial absorbed dose summary table need only contain 20 rows or cumulative dosimetry calculations for every tenth day. The next choices are the mechanical clearance function [M(t)l and absorption function [A(t)l which depend on previous studies and are available in the computer table or in Appendix A. The absorption hnction (or dissolution rate depending on how it is measured) can vary greatly depending on the chemical form and other factors. The computer program, through a built-in table (or Appendix A) offered in the program, allows the user to create a file for other radionuclides and chemical forms by entering parameters for mechanical clearance, absorption, half-life, radiation type, radiation yield, and energy. Total inhaled activity in Bq is entered to calculate absorbed doses in each compartment of the lung model. The next parameter is lung mass, which has a default value of 1,000 g for a 70 kg adult. For a child, a smaller lung mass (m,)can be entered by using the scaling law:

where M, is the body mass and m, the lung mass for the standard adult and M, is the body mass of the child. The next parameter is

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for tissue depths of cells at risk. The default depth for the NOPL and TB regions is 50 pm. The depth for cells at risk can be changed for each region of the lung, including each generation of the conducting airways. The depth of the cells at risk can vary from 10 to 100 (*3n. The dose would vary depending upon the thickness of the epithelium, if that is known with greater accuracy. The cumulative activity in each region of the lung model over time (t) can be calculated by computer or by hand. In either case, the differential equations (Equations 7.6 and 7.7) are expanded in tabular form and the activity accumulated. The clearance of the initial burden in each compartment is calculated by having one differential equation for each of the 24 regions of the respiratory tract. Numerical solutions are obtained on the computer by using a simulation language to describe the physical and biokinetic behavior of t h e material. The computer program output includes particle deposition fractions and absorbed dose. Deposition fractions of the total airborne aerosol inhaled are provided for various regions of the total respiratory tract, NOPL, TB, P and LN regions. Absorbed dose measured in Gy is provided for the NOPL, TB, P and LN regions in the example. Doses are output for each of the time points that were determined by selecting the initial time, the final time point, and the number of equal intervals (breakpoints). For the TB region, output is printed for generations 2 through 6, 7 through 11, and 12 through 16, in addition to generation by generation. In the example given in Table 7.9 only TB generations 2 through 6 are shown because this has been the zone in which bronchial cancer has been observed in humans. A summary of typical radionuclides that may provide a dose estimation is given in Table 7.10. Additional sample dose calculations for plutonium dioxide, americium dioxide, cerium chloride, barium chloride and cobalt oxide (the radionuclides in Table 7.10) for time intervals out to 50 y are given in Table 7.11. In these examples, a resting minute ventilation (lower VT)has been used. 7.3.3 Modifying Factors Age, smoking and disease states that increase or decrease the rate of clearance of material from these regions will influence the calculation because the delivered dose is directly proportional to the time the material remains in the region of cells at risk. These are not directly included in the computer program. 7.3.3.1 Influence ofAge. The main influence of age in this dosimetry model will be an increase in clearance times. The dosimetry

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TABLE7.11-Results of sample dose calculations for humans for different inhaled radionuclides giving the tissues at risk" (calculated for 100 Bq). Tissue at Risk Radionuclide Form

Plutonium dioxide 2:j9pU

Americium dioxide 241Am

Cerium chloride I44Ce

Barium chloride lroBa

Cobalt oxide 57Co

(50 y dose commitment)

GY

Posterior nose TB ( 2 to 6 ) TB (12 to 16) P LN Posterior nose TB ( 2 to 6 ) TB (12 to 16) P LN Posterior nose TB ( 2 to 6 ) TB (12 to 16) P LN Posterior nose TB ( 2 to 6 ) TB (12 to 16) P LN Posterior nose TB ( 2 to 6 ) TB (12 to 16) P

"Sample deposition values for: 15 breaths per minute, 750 cmWT,FRC is 2,225.6 cm3, 1 atm, 1 pm particles, 1 g ~ r n - no ~ , pause between breaths, 100 percent nose breaths. Deposition fractions: Total deposition = 0.332, NOPL = 0.192, TB = 0.025, P = 0.114. Dose for 10 to 50 pm depth in tissue.

calculations will be dependent on the subsequent changes in these values as calculated and discussed in Section 6.

7.3.3.2 Effect of Tobacco Smoking. Smoking can change the rates of mechanical clearance. This change will reflect a reduction in clearance rate and half-time, and thus, short-term dose to the tissues lining the conducting airways. The user might use a modifying factor for altered mechanical clearance rate (for example, one-half, as described in Section 4.1). 7.3.3.3 Effect of Disease States. The influence of disease states on the dosimetry calculations deals mainly with the change in the volume and thickness of the related tissues. The normal condition is taken as the default condition for calculations. The depth of integration of the absorbed fraction can be changed by the user to meet specific cases.

8. Consideration for Nonradioactive Substances Although the primary objective of this Report is to provide a summary of scientific information and models to describe the deposition, retention and dosimetry of inhaled radioactive substances, much of the same information can be applied to inhaled nonradioactive substances. However, there are additional factors, not emphasized in the preceding sections, that commonly influence exposure-doseeffect relationships for inhaled chemically toxic substances. These are discussed below.

8.1 Deposition of Inhaled Chemical Toxicants As discussed in Section 5, the regional deposition pattern for inhaled aerosols depends upon the morphology of the respiratory tract, the breathing pattern, and particle size, shape, density, hygroscopicity and electric charge. Because these characteristics are not uniquely different for radioactive and nonradioactive particles, the information given on inhaled particle deposition generally applies to all aerosols. Although radioactive particles are self-charging to a degree, this does not significantly influence their respiratory tract deposition patterns, except in very rare cases involving substances that have extremely high specific activity. The pattern of respiratory tract deposition of inhaled vapors and gases is discussed in Section 5.2. Inhalation exposures to radioactive gases or vapors generally occur a t low concentrations in the inhaled air and for short periods of time. Thus, significant accumulation of absorbed gases or vapors does not generally occur. Conversely, with exposure to some nonradioactive gases or vapors, significant accumulation may occur, and the tissue processes illustrated in Figure 5.14 may control the regional uptake and clearance in such cases.

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8.2 Respiratory Tract Clearance of Chemical Toxicants Compared to the abundance of quantitative information on the clearance of radioactive cations from the respiratory tract, much less is known about the clearance of nonradioactivechemical compounds. This imbalance probably results from the relative ease with which radioactive elements can be measured in the body. More difficult analyses are frequently necessary to quantify the kinetic behavior of inhaled chemical compounds and their metabolic products. For example, Bond et al. (1986) compared the rates at which several organic compounds were cleared from the lungs of rats after being inhaled in different chemical forms. A summary of such measurements for benzo(a)pyrene (BaP) is shown in Figure 8.1. The inhaled particles were composed of pure BaP or BaF' associated with carbonaceous diesel exhaust particles, organic coal tar particles, and inorganic gallium oxide particles. It is clear that the association of BaP with particles, especially carbon particles, markedly reduced its rate of clearance and absorption into blood. Similar results were reported for inhaled nitropyrene (Bond et ad., 1986). The rates at which organic compounds are absorbed from the respiratory tract may be predicted from measurements of their lipophilicity (Bond, 1987; Bond et al., 1985; Medinsky et al., 1986). Lipophilicity has been quantified using the octanollwater partition coefficient and related to the half-time for long-term retention of organic compounds in the respiratory tract. Results of studies to date indicate that lipophilic compounds are absorbed more slowly by blood. However, additional work is needed before quantitative models can be developed. The clearance studies with radioactive aerosols described in Section 6 generally involved tens to hundreds of micrograms of deposited particles. In other reported studies designed to assess the chemical toxicity of substances, much higher aerosol concentrationshave often been used, and these resulted in pulmonary burdens exceeding 1mg of particles per gram of lung tissue. For example, studies have been done with rats chronically exposed to diesel engine exhaust at concentrations of particles up to 7 mg m - h f air (Strom et al., 1988; Vostal et al., 1982; Wolff et al., 1987). The long-term clearance of particles from the lower respiratory tract was impaired and nearly ceased after about 12 months of exposure. This pattern of particle accumulation is illustrated in Figure 8.2. The exposure to whole diesel engine exhaust began at four months of age. An important conclusion to be drawn from these studies is that the use of high aerosol concentrations in toxicology experiments may not result in the same exposure-dose relationships or mechanisms

8.2 RESPIRATORY TRACT CLEARANCE OF CHEMICAL TOXICANTS

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-

BaPlCOALTAR

0.01

I 0

I

I

I

4 8 12 DAYS AFTER INHALATION

I 16

Fig. 8.1. Clearance of radiolabeled BaP from the lungs of rats that received a single inhalation exposure to BaP alone and BaP associated with particles of diesel engine exhaust, gallium oxide and coal tar (from Bond et al., 1986).

of injury as observed in studies using lower aerosol concentrations (Morrow, 1992). It is interesting to note that long-term respiratory tract clearance in most human cigarette smokers is not impaired to the same extent as observed in the rats exposed to diesel engine exhaust, even though heavy smokers inhale more than 1 g of tar each day (Bohning et al., 1982). This could result from cigarette smoke tar being absorbed from the lungs more rapidly than carbonaceous diesel soot particles, but further information is needed to resolve this question.

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0

6

12 18 MONTHS OF EXPOSURE

24

Fig.8.2. Accumulated lung burdens of diesel engine exhaust particles in the lungs of rats exposed daily to air concentrations of 0.35 (low), 3.5 (medium) and 7 (high) mg m-3. Pulmonary clearance of particles appeared to cease after 12 to 18 months of inhalation exposure.

8.3 Chemical Dose to Cells at Risk One of the greatest challenges faced by toxicologists in developing exposure-dose-risk relationships is identifying the most appropriate expressions of dose. For studies of ionizingradiation, there is general agreement that the total energy deposited in the cells a t risk is the best representation of dose. However, identifying the most appropriate expressions of dose is more difficult when the exposures involve chemically toxic agents. Here, the tissue concentration of the chemical, the time integrated concentration or the peak concentration may all represent appropriate dose parameters. Also, the concentrations of metabolites of the chemical agent or the amount of a chemical or one of its metabolites bound to cellular DNA (DNA adduds) may be important measures of dose. Even greater uncertainty in estimating appropriate doses arises when the exposures involve complex mixtures of toxic chemicals, e.g., inhaled cigarette smoke or atmospheric pollutants. The concept of chemical dose is most easily understood for inhaled gases. In particular, studies of the toxicity of nitrogen oxides, sulfur oxides, oxygen, ozone and formaldehyde have well-defined respiratory tract dose patterns. However, the concept of chemical dose from

8.3 CHEMICAL DOSE TO CELLS AT RISK

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inhaled particles is less developed. Models have been described to project dose a t the cellular level after inhalation of relatively insoluble particulate matter; these specifically address the unique association of particles with phagocytes. It is generally expected t h a t nonradioactive particles contained within the vacuoles of phagocytes may not directly interact with other cells in the respiratory tract. However, the direct effect of such particles on the lysosomalvacuoles may produce a secondary response resulting in cellular damage far greater than the primary response in the macrophage itself. Direct exposure of epithelial, interstitial and endothelial cells of the lung to toxic particles may have consequences quite distinct from exposure to the chemicals after phagocytosis. It appears that inhaled particles may be divided into two classes; one that is biologically reactive and one that is relatively nonreactive. Within the biologically reactive class are particles with fibrogenic, irritant and carcinogenic potential. A third component of lung disease uniquely associated with inhaled chemicals is sensitization reactions. Toxicity of many chemicals results from transformation products formed from the chemical rather than the chemical itself; asthma is one example of this. Carcinogenesis and fibrotic reactions, along with reactions that sensitize the pulmonary immune system, represent the primary categories of lung diseases generally associated with inhalation of toxic chemicals in particulate form. The nonreactive class of particles may still impair lung function or clearance as was described previously for inhaled diesel exhaust. Because the toxicity or carcinogenicity of some chemicals results from the metabolic products rather than from the chemicals themselves, dose-risk relationships based upon the concentrations of the chemicals in the affected tissues may not be suitable. Such risks are better related to the tissue concentrations or rates of formation of the metabolite. One illustration of the importance of metabolites in deriving dose-risk relationships is seen with exposures to vinyl chloride (Gehring et al., 1978). Exposure to high concentrations of vinyl chloride can cause hepatic angiosarcomas, but this appears to be related to its metabolic products, chloroethylene oxide and chloroacetaldehyde. Maltoni and Lefemine (1975) determined the incidence of hepatic angiosarcomas in studies with rats exposed to vinyl chloride by chronic inhalation. Analyses of these data by Gehring et al. (1978) resulted in the relationships illustrated in Figure 8.3. When related to the exposure concentration of vinyl chloride in air, the incidence of liver tumors remained constant or actually decreased with increasing dose in the three highest exposure groups. When related to the rate of metabolism of vinyl chloride transformation, the incidence

1

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8. CONSIDERATION FOR NONRADIOACTIVE SUBSTANCES

01 .+,

0.01 0

1 2 3 LOG V.C. AIR CONCENTRA'TION

4

1

0

I

II

I

I

1

2 3 4 LOG V.C. TRANSFORMATION

Fig. 8.3. Percentage of rats with liver tumors expressed as a function of the log of the vinyl chloride concentration in air (left) and the log of the vinyl chloride transformation (right).

of liver tumors increased uniformly over the entire range of exposures. The rate of formation of metabolites of vinyl chloride was assumed to follow Michaelis-Menton type kinetics (Mantel and Bryan, 1961). This analysis was then used to predict liver cancer risk in human exposure situations by adjusting for differences between rats and humans in exposure level and body surface area. The latter parameter was used as an index of the relative rates of metabolism of vinyl chloride in rats and humans. With regard to carcinogenesis in well-defined target tissues, it appears that specific molecular lesions may be identified for some types of chemical carcinogens. The formation of DNA adducts is often considered to be an indicator of effective dose after exposures to organic chemicals. In recent years, there has been a consistent observation that many fibrogenic materials may react through an oxygen radical intermediate. Reactive oxygen intermediates, including superoxide free radicals, are thought to be critical chemical intermediates affecting cell damage and cell death. Such free radicals are produced by chemical interactions with biological targets and are similar to free radicals thought to play an important role in the biological actions of ionizing radiation.

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Regardless of the biological outcome, pharmacokinetics and metabolism play a critical role in determining the chemically significant dose from xenobiotic agents. Although similar concerns are important for inhaled radionuclides, it is not unusual to identie specific chemical compounds whose toxicity is primarily manifest due to metabolites. The applicability of pharmacodynamic principles in estimating the chemically significant dose to target tissue within the respiratory tract must be emphasized.

9. Summary This Report provides a summary of scientific information and mathematical models that describe respiratory tract deposition, clearance and dosimetry for radioactive substances inhaled by humans. It is intended for use in estimating and assessing exposure of radiation workers and the public, and in evaluating accidental exposures of individuals. The models can be applied to people having different body sizes and levels of physical activity. Recommendations are also made on how the model calculations may be altered to account for the potential effects of cigarette smoking and compromised respiratory health status. Measurements of the deposition and clearance of inhaled radionuclides derived from studies of exposed people are emphasized in this Report. Data derived from studies using laboratory animals are also included because they provide most of the available information on rates of absorption of deposited radionuclides from the respiratory tract to blood. In this Report, the respiratory tract is subdivided into four main regions. These are the NOPL, TB, P and LN regions. All regions are represented in the model presented because they may receive significant doses from deposited radionuclides. The deposition, clearance and dose resulting from inhaled radionuclides are calculated separately for each region of the respiratory tract, including the pulmonary LN. Clearance data pertaining to specific physical-chemical forms of individual radionuclides are provided in Appendix A. These data summarize most of the applicable published information for each radionuclide form and are intended to indicate the range of clearance rates that might be observed following an accidental human exposure. Recommended clearance rates are also given as a beginning point for dosimetry evaluations related to forms that are most likely to be encountered by humans.

9.1 Anatomy and Morphometry of the Respiratory Tract Although the anatomical structures comprising the NOPL region are well-known, little quantitative information is available on the

9. SUMMARY

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151

internal dimensions of the airways during normal respiration. Also, most of the available information pertains to adult Caucasian males, and virtually no information is available pertaining to people of other races, women or children of either sex. The nasal passages are relatively narrow, but they have enhanced surface area that provide for rapid transfer of heat and moisture to the inspired air. The dimensions of their lumina are quite variable and they depend on the amount of blood perfusion in the surrounding tissues and the thickness of the mucus covering. The nasal valves (Figure 2.1) are the narrowest part of the respiratory tract through which all of the inspired air may flow. Beyond the nasal valves, the passages open abruptly causing turbulence in the flow of inspired air. This can result in high local deposition of inhaled particles in the area from the nares to the beginning of the nasal turbinates. In the forward portion of this region, clearance of deposited substances is generally toward the nares. ThereaRer, mucociliary flow transports deposited substances toward the pharynx. These characteristics of inhaled particle deposition and clearance subdivide the nasal airways into the anterior and posterior subregions. The configuration of the mouth and pharynx during oral breathing is also highly variable. Opening the mouth lessens the resistance to air flow and reduces the local deposition of inhaled particles or gases. However, when the mouth is only slightly opened for respiration, oral deposition of inhaled substances appears similar to that in the nasal airways. Little quantitative information is available on the ranges of dimensions of the oral passages in adults or in children of any race. Clearance of substances deposited in the mouth is rapid and normally occurs by swallowing. The lumen of the larynx is approximately cylindrical except where the vocal cords narrow the opening. The position of the vocal cords is variable and they cause turbulence in the air flowing through and beyond the larynx. This results in deposition ofparticlesimmediately downstream. Little is known about the configuration of the larynx during normal respiration in adults and children or about the local clearance rate of deposited substzlces. This is unfortunate because the larynx is a site where tumors are known to devehp in people. These tumors may result from the substances that deposit in or clear through this structure. The distal end of the larynx marks the end of the NOPL region. The TB region (Figure 2.2) begins just below the larynx and ends with the terminal bronchioles. It consists of a series of branching airways that are approximately cylindrical in shape. The dimensions and orientations of these airways have been estimated from measurements made on casts obtained from the lungs of adults and

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SUMMARY

children after accidental deaths (without respiratory airway disease). The numbers and sizes of the airways in various paths from the trachea to alveoli vary considerably. A typical pathway which represents the average of all the path lengths and angles for each generation from the trachea to the terminal bronchioles was selected for the initial model calculations of TB deposition and clearance in this Report. This typical pathway can be scaled in dimensions for calculating doses to children. The scaling constants are based on measurements of lung casts. As a model concept, the TB region is considered to end a t the level of the terminal bronchioles where the mucus-secreting cells and ciliated cells become infrequent. Almost all of the inhaled material that deposits proximally to the terminal bronchioles is presumed to rapidly transport toward the trachea by mucociliary action in healthy people. For such individuals, clearance from the TB region may require up to 20 to 40 h. Material that remains in the thorax after 40 h clears more slowly and, for the purpose of the clearance model in this Report, is assigned to the P region. The model of the P region lumps all structures from the respiratory bronchioles to the alveoli in a single model compartment. Human adults have approximately 300 million alveoli. The epithelium in the airways of the P region contains few ciliated cells, and is covered with a thin layer of serous fluid. Clearance of insoluble particles from the P region is probably largely mediated through the action of macrophages, and is much slower than clearance from other regions of the respiratory tract. The TB and P regions can be defined by their hnctional characteristics, Figure 6.3. This is based on the use of observed clearance rates by dividing the total amount of inhaled material that deposits in the thorax into TB and P fractions. This is a useful concept for mathematical modeling, even though a small portion of the material in the bronchial airways may not clear within 2 d and a portion of the material that deposits beyond the respiratory bronchioles may clear more rapidly. An alternative approach is to define fast and slow clearing fractions that are consistent with the clearance measurements. This approach is technically accurate, but it is less conventional. It introduces two new terms, a fast clearing deposition fraction and a slow clearing deposition fraction. This is in place of the terms TB deposition fraction and P deposition fraction. The NCRP decision is to continue use of the terms TB and P deposition fractions. 9.2 Cells at Risk from Inhaled Radioactive Aerosols

There are more than 40 different types of cells in the respiratory tract. The cells which are most critical with respect to radiation-

9. SUMMARY

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153

induced injury are thought to be cells that remain in respiratory tract tissues for a sufficient time to accumulate significant dose and then divide. Ciliated cells in the epithelium of the NOPL and TB airways normally do not divide and they are not likely to give rise to respiratory tract tumors. Recently, the secretory cells were shown to be the likely progenitors of basal and ciliated cells in these airways. Also, the basal cells were shown to be progenitors for ciliated cells. Thus, all cells may be important when acute injuries occur to the respiratory tract epithelium, but the secretory and basal cells are probably the most important cells at risk for development of tumors in the NOPL and TB regions. In the P region, Type I1 alveolar cells are the progenitors for Type I alveolar cells; the latter cells are probably terminally differentiated. Thus, Type 11cells are likely to be important cells at risk for radiationinduced tumors in the P region, but other types of cells may also give rise to lung cancers. These include fibroblasts and endothelial cells of the lymphatic system and blood vessels. Macrophages, cells in pulmonary LN, circulating blood and lymphatic cells have not been implicated as cells that transform to produce respiratory tract tumors.

9.3 Physiological Factors Related to Deposition and Clearance Breathing frequency, tidal volume and functional residual capacity are the ventilatory factors used in this Report to model the deposition of inhaled substances. Typical values for these parameters are given in Table 3.1. They are related to body height and three levels of physical activity: low activity (tidal volumes of about 750 cm3), light exertion (about 1,450 cm3), and heavy exertion (about 2,150 cm3). Approximate corresponding values for age, body mass and height are also included, but these should not be used to select breathing parameters for an individual in preference to using known ventilatory values. Clearance of substances from all regions of the respiratory tract is considered to result from competitive mechanical and absorptive processes. Mechanical clearance in airways of the NOPL and TB regions results from mucociliary action. This is represented in the model as a series of escalators, all moving toward the glottis (except for clearance in the anterior portion of the nose). Each airway is assigned an effective clearance velocity. In the posterior area of the

nasal airways, the effective clearance velocity is 6 mm min-l (see Table 3.3); in the TB airways, the effective clearance velocity varies from 5.5 to 0.001 mm min-l (see Table 6.2). Clearance of substances deposited in the P region may require several hundred days or more. This can be represented by fractional daily clearance rates to the TB region, pulmonary LN, and blood. Fractional mechanical clearance to the TB region is modeled as 0.006 d-'initially, but this decreases to about 0.001 d-l by200 d after the inhalation exposure. Clearance of particles to the pulmonary LN is mediated by lung macrophages and takes place a t a fractional rate of about 0.0001 d-l. The rates for transfer of radionuclides to the blood depend mainly on their rate of dissolution in water and lung lipids. Highly soluble compounds may be absorbed within minutes, whereas relatively insoluble particles are likely to remain for hundreds of days and be cleared to the LN or TB region. Because little information is available on absorption functions for radionuclides in people, most of this information must be derived from studies using laboratory animals. A fundamental assumption used in this Report is that the rates for absorption of radionuclides into the blood are the same in all regions of the respiratory tract and that they can be estimated from laboratory studies using mammalian species as a prediction and then moving on to humans as more data become available.

9.4 Regional Deposition of Inhaled Particles The sampling efficiency, or inhalability (formerly called inspirability), of airlnorne particles of a certain aerodynamic diameter (d) is the initial input to the deposition calculations. The ACGIH (1985) definition for inhalability (0, shown below, is recommended:

I = 50 [l + exp (-0.06 dl1 for 0 < d

I : 100

(~m

(9.1)

Fractional deposition of the inhaled aerosols in the airways of the NOPL region is projected from empirical relationships based on particle diameter and flow rate (Figure 5.3). Other relationships based on pressure drop in the nasal airways during inhalation have been proposed. More research effort is needed to verify the existing relationships for predicting deposition in the NOPL region or to develop new relationships based on physical principles, including anatomical and physiological parameters.

Particle deposition in the TB and P regions is projected from model calculations based on geometrical or aerodynamic particle diameter and physical mechanisms includingimpaction, sedimentation, interception and diffusion. These calculations are based on air flow information and idealized morphometry (the typical pathway model mentioned previously).Although this approach simplifies many complex factors that may act on inhaled particles, it provides a means t o estimate deposition along typical airway generations and requires only modest computer resources that are available to almost everyone. Thus, exposure-dose relationships can be obtained quickly for specific individuals and exposure circumstances. Typical deposition fractions for an average adult male breathing various sizes of particles are summarized in Figure 9.1.

9.5 Regional Solubility of Inhaled Gases and Vapors Regional solubilityof inhaled gases and vapors is difficult to project from model calculations. A major factor that increases the complexity of the calculation is the vapor pressure exerted by substances after their dissolution in the airway mucus lining or epithelium of the airway. The net rate of dissolution is influenced by the concentration TIDAL VOLUME 770 mL 2400 mL

-----

Fig. 9.1. Relation of particle diameter to calculated regional deposition for spheriNot corrected for inhalability. cal particles of density 1g

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of the vapor or gas in the airways, its concentration and solubility in the mucus lining, its rate of metabolism or reaction, and its rate of transport to blood. Little is known about these factors for most radioactive gases and vapors. Thus, solubility of inhaled gases and vapors are projected for only two general cases. These are for gases and vapors whose solubilities, rates of metabolism or chemical reactivities are either low or high. In the first case, solubility in the NOPL and TI3 regions is low; however, the large surface area of the P region can result in a significant fractional uptake of such gases in this region. In the case of highly soluble or reactive gases, uptake in the NOPL and TB region is further increased. Examples of radioactive gases that have low solubility in the respiratory tract airways are radon, xenon and krypton. When inhaled, they distribute rather uniformly throughout the respiratory air tract and irradiate all regions almost equally. Examples of substances that have high solubility efficiencies in the respiratory tract are iodine and ruthenium oxide vapors. These mainly deposit in the NOPL and TB regions where the majority of the dose is delivered.

9.6 Respiratory Tract Clearance of Particles

Much of the appropriate information to summarize clearance of radioactive substances from the respiratory tract is included with the earlier discussions on anatomy, morphometry and physiology. This has resulted because clearance characteristics were used to subdivide the respiratory tract into different regions (Figure 9.2). The nose is divided into two parts, the anterior nasal cavity which clears mucus toward the nares and the posterior nasal cavity which clears mucus back to the pharynx. The anterior cavity clears by external mechanical means such as wiping or blowing and effective clearance takes about 1h. In the posterior region of the nose, clearance requires about 12 min. The mouth is cleared by swallowing. Material from the nose and mouth collect a t the back of the pharynx and merge with material on its way from the larynx to the stomach. The TB region clears by the mucociliary escalator. The trachea clears most rapidly, followed by the second through the sixteenth generations of the TI3 region. The mucus flow rate (or velocity) ranges from 5.5 m m min-l in the trachea to 0.001 mm min-l in the terminal bronchioles, requiring about 2 d to get from the bottom to the top of the escalator. Information on the absorption function [A(t)l, the mechanical clearance function [M(t)l and the mechanics of LN uptake and clearance can be obtained from studies using laboratory animals. The

9. SUMMARY

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NASO-ORO-PHARYNGO-LARYNGEAL REGION

Fig. 9.2. The respiratory tract model is based on four regions, NOPL, TB,P and LN. The extrinsic and intrinsic clearance rates are represented by arrows. Transfer to blood M(t) = absorption function], transfer to the TB region and GI tract [M(t) = mechanical clearance rate function], and transfer to the lymph nodes (LN = 0.0001 d-') serve as model inputs. The output of the model contains estimations of deposition and clearance suitable for calculating dose to the respiratory tract.

mechanical clearance mechanisms in mice, rats, hamsters, guinea pigs, dogs, baboons and people are somewhat similar; however, mechanical clearance rates in people are closer to those of the baboon and dog rather than to those of mice or rats. The P region is cleared by three main processes: mechanical clearance through the TB airways, absorption into the blood, and transfer to the LN. The relative mechanical clearance rate of the TB airways for humans is described as:

The fractional clearance rate of material from the P region: FC(t)

=

A(t)

+ M(t)

(9.3>2

The LN were not studied in detail for people. In animal studies, the rate of transfer of particles to the LN was 0.0001 d-l irrespective of the aerosol form or radionuclides. Absorption functions [A(t)l for inhaled radionuclides deposited in lungs passing into blood were examined in detail from animal studies and a few human studies. The absorption functions were constantly changing with respect to time and two examples of their calculations are compared. The respiratory tract variables, chemical forms, radionuclide characteristics and the doses to the NOPL, TB, P and LN regions are given for your judgement or change. The respiratory tract model can provide results for periods from 1d to 100 y depending on the radionuclide involved and the lifespan of the people exposed. When the radionuclide kinetics meet the data for the exposed individuals then the problem is solved. Examples are given in Section 7 and Appendix A.

9.7 Calculation of Dose from Inhaled Radionuclides

Methods are given to calculate doses for subjects that inhale radioactive particles of inhalable size. These may be used for computer or hand calculation, but the former is preferreda3The dose calculations are for the four regions of the respiratory tract, NOPL (anterior and posterior), TB, P and LN. Calculations of dose to other organs, blood and GI tract, are not included. The model input values for the deposition calculation include: breaths per minute, tidal volume, functional residual capacity, activity medium aerodynamic diameter, density, atmospheric pressure, pause between breaths, nose and mouth breathing parameters, and body heights. Other parameters, such as a numerical parameter for the nasal and oral partitioning of air flow, are in the computer program or in tables. The values are put into equations to determine the deposition to the NOPL, TB and P regions. Other model input parameters include: number of airway tubes, lengths, diameters, 'In these equations, time is measured in days. 3A computer program based on this model has been developed by Dr. Richard Cuddihy and colleagues. Information on availability of this program can be obtained by contacting Dr. Cuddihy, 7511 La Madera Road, NE, Albuquerque, NM 87109.

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159

volumes, total volume, and air velocities during inspiration and expiration. The values used for calculation of total clearance rate are: mechanical clearance rate [M(t)l, absorption [A(t)l, total amount inhaled, activity, lung weight and tissue depth. Clearances rates are given as a function of time in days. Values inside the program are the absorbed dose rate in Gy s-', given as D = MYE, @ (r, R, E,)

(9.4)

where k is the value of all the constants, A is the activity (Bq), Y is the yield per disintegration, E, is the initial energy of the radiation (MeV) and @ (r, R, E,) is the point source isotropic specific absorbed fraction (kg-I). The program output is the fraction of the lung burden in the NOPL, TB, P and the LN in units of Bq and dose in Gy. As an example of how this model can be used, the disposition of activities and respective doses are given for plutonium dioxide, americium dioxide, cerium-praseodymium chloride, barium-lanthanum chloride and cobalt chloride. In each case, diseases which affect deposition and clearance, and subsequently dose, are also reviewed.

9.8 Chemically Toxic Inhaled Substances

Several additional factors must be considered when the proposed dosimetry models are applied to nonradioactive toxic substances. First, nonradioactive materials are more difficult to detect in intact animals, so less is known regarding their deposition and clearance. Second, chemicals so often exert their effects after they are transformed by metabolism. This transformation must be understood. In addition, nonradioactive substances are commonly encountered in amounts sufficient to produce physiological changes that distort normal deposition and clearance phenomena. The following examples demonstrate some of these complicating factors. The gas and vapor deposition model is one of the more complicated models. A gas or vapor enters the TB region and passes through the liquid lining, tissue and blood interface. A unique aspect of inhaled gases and vapors is that deposition is influenced by their concentration in the surrounding fluids. High concentrations can slow deposition or reverse the direction of diffusion back into tidal air. In addition, irritants can produce reflex changes in breathing patterns that can alter both deposition sites and doses. The association of absorbed chemicals with particles changes their rates of clearance and absorption into the blood. Lipophilicity of

organic compounds influences their absorption functions from the respiratory tract. Long-term clearance of particles from diesel engine exhaust is impaired in rats by high particle accumulation in the lower respiratory tract. This overload effect of high levels of particles in the lung may or may not also occur in people. Carcinogenesis and the fibrotic reaction, as well as reactions that sensitize the pulmonary immune system, are seen with inhalation of toxic chemicals in particulate form. The toxicity of some chemicals may result from metabolic products. In such cases, the dose-risk relationships are best related to tissue concentrations or rates of formation of the metabolite. An example of this is seen with exposures to vinyl chloride, where the incidence of liver tumors remains constant or decreases with increasing dose, yet, a t the same time can be shown to increase uniformly over the entire range of exposure when related to vinyl chloride metabolism rate.

APPENDIX A

Clearance Data Clearance information applied to the physical, chemical and biological forms for individual radionuclides are provided in ascending atomic number. The standard aerosol and breathing pattern to which they were all normalized to is: Particle size = 1 pm MMAD Particle density = 1g ~ m - ~ Atmospheric pressure = 1atm Breathing frequency = 13 min-' Tidal volume = 770 cm3 Functional residual capacity = 2,659 cm3 Deposition in the NOPL = 40 percent TB = 10 percent P = 50 percent The needed information for a given exposure to a radionuclide is: Element Atomic number Isotope (With the same atomic number, one can vary the neutrons so long as the half-life is not too much longer than the isotope studied.) Half-life (Authors may have used a different half-life because it was not known accurately at the time. Some examples are given.) Compound (studied) Absorption [M(t) at t = 01 {Compoundswere all adjusted externally and internally to 100 percent absorption. That portion deposited externally was neglected and that portion deposited internally and taken into the GI tract or blood is determined by nasal absorption (Table 6.1), mechanical clearance [M(t)l and the absorption function [A(t)l as the simulation begins.} Absorption function (Different for each element and chemical form. For different isotopes of the same element, half-life is the controlling factor.)

162

/

APPENDIXA

Summaries are included for most of the published information for each radionuclide form and are intended to indicate the range of clearance functions that might be observed following an accidental human exposure. Recommended clearance rates are given as a beginning point related to those most likely to be encountered by people. When human studies are sot available then primates and dogs are used. When humans, primates or dogs are not available then rodents or the TGLD model (TGLDACRP, 1966) are used.

A1 Manganese Atomic number: 25 Isotope used: 54Mn Half-life4:312.5 d Compound: Manganese dioxide (Mn02)and manganese chloride (MnCl,)

0

100 200 3b DAYS AFTER INHALATION

400

Fig. kl. Percentage of the initial lung burdens of manganese dioxide and manganese chloride in humans (Morrow et al., 1967a; 1967b), beagle dogs (Morrow et al., 1964) and macaque (Newland et al., 1987) as a function of time in days. 4Thisinformation is adapted from Morrow et al. (1964; 1967b) who used a physical half-life of 290 d.

A.l MANGANESE

/

163

DAYS AFTER INHALATION

Fig.A.2. Relative absorption functions [A(t)]for manganese dioxide and manganese chloride in humans, beagle dogs and macaques with time in days.

TABLEA.1-Recommended absorption functions (at t

= 0) for humans as a fraction of the initial deposit and going through the various pathways.

NOPL TB P

Cleared Internally to:

Cleared Externally

GI Tract

Blood

0.20 -

0.18 0.10

0.02 -

-

+

n !in

-

Recommended absorption function for manganese dioxide: A(t) = 0.75e-0.5t+ 0.02 (human)

(A.1)

0.25e-0.5t+ 0.05 (beagle)

(A.2)

A(t)

=

Recommended absorption functions for manganese chloride: A(t) = 0.6e-0.5t+ 0.02e-0.015t + 0.0045 (macaque)

(A.3)

A2 Cobalt Atomic number: 27 Isotope used: 57Co Half-life: 270.9 d 'j°Co Half-life: 5.271 y Compound: Cobalt oxide (COOand C0304) TABLEA.2-Recommended absorption functions (at t

= 0) for humans as a fraction of the initial deposit and going through the various pathways.

Cleared Externally

NOPL TB P

0.20 -

Cleared Internally to:

GI Tract

Blood

0.18 0.09

0.02

c

-

0.50

+

Recommended absorption functions for cobalt oxide: A(t) = 0.022e-0.05t+ 0.002 (human) A(t) = 0.033e-0,07t+ 0.0035 (baboon) ~ ( t=) 0.2e-0.1t + 0.01 (beagle)

(A.4) (A.5) (A.6)

Information in Figure A.5 gives 75Colung burden versus time for guinea pigs, SPF rats, Sprague-Dawley rats, HRT rats, CBAIH mice and DSN hamsters.

0

200

400 600 800 DAYS AFTER INHALATION

1000

1200

Fig. k 3 . Percentage of the initial lung burdens of cobalt oxides in humans (Bailey et al., 1989; Foster et al., 1989; Gupton and Brown, 1972; Hegde et al., 1979; Newton and Rundo, 1971; Pearman et al., 1989), baboons (Andre et al., 1989) and beagle dogs (Barnes et al., 1976; Kreyling et al., 1989) as a function of time in days.

1

A.2 COBALT I

165

I

I

Co OXIDES

-

HUMAN

0.001

I

0

I

I

I

200

400 600 800 DAYS AFTER INHALATION

-

I

I000

1200

Fig. A.4. Relative absorption functions [A(t)] cobalt oxides in humans, baboons and beagle dogs with time in days.

I

I

I

I

-

"CO OXIDES

-

7

-

-

0.01

HRT RAT

I

0

I

1

-

I

100 200 300 400 DAYS AFTER INHALATION

500

Fig. A.5. Percentage of initial lung burdens of cobalt oxides in guinea pigs (Collier et al., 1989a), SPF Fisher rats (Patrick et al., 1989),Sprague-Dawley rats (Drosselmeyer et al., 1989),HRT rats (Collieret al., 1989b), CBAIH mice (Talbot and Morgan, 1989) and DSN hamster (Collier et al., 1989a) as a function of time in days.

166

/

APPENDIXA

A3 Yttrium Atomic number: 39 Isotope used: 90Y Half-life: 64 h Compound: Yttrium in fused aluminosilicate particles TABLE A.3-Recommended absorption functions (at t = 0) for humans as a fraction of the initial d e ~ o s i and t eoing through the various ~ a t h w a v s . Cleared Externallv

NOPL TB

P

Cleared Internally to:

GI Tract

Blood

0.18 0.09

0.02

0.20 -

-

0.50

c

4

Recommended absorption function for yttrium in fused aluminosilicate particles: A(t) = 0.003

(beagle)

(A.7)

Fig. k 6 . Percentage of the initial lung burden ofyttrium in fused aluminosilicate in beagle dogs (Barnes et al., 1972) as a function of time in days.

1

A.4 NIOBIUM I

0.01

I

I

I

167

I

I

"IFAP

-

-

-

-

-

T

DOG

-

-

0.001

I

0

2

I I I I 6 8 1 0 1 4 DAYS AFTER INHALATION

I

2

1

4

Fig. A.7. Relative absorption functions [A(t)] for yttrium in fused aluminosilicate in beagle dogs with time in days.

A4 Niobium Atomic number: 41 Isotope used: 95Nb Half-life: 35.15 d Compound: Niobium oxide [Nb,(V)O51 TABLE A.4-Recommended absorption functions (at t

= 0) for humans as a fraction of the initial deposit and going through the various pathways.

Cleared Externally

NOPL TB P

Cleared Internally to:

GI Tract

Blood

0.20

-

Recommended absorption function for niobium oxide: A(t)

=

0.00016e-~0.04t + 0.0001

(beagle)

168

/

APPENDIXA

b

Nb OXALATE

0.1

I

0

I

I

I

I

1 I

I

I

40 80 120 DAYS AFTER INHALATION

Fig. A.8. Percentage of the initial lung burdens of niobium oxide and niobium oxalate (Cuddihy, 1978; Moskalev et al., 1964) in beagle dogs as a function of time in days.

I

I

-

DOG NbOXALATE

0.001 0.0001

DOG Nb OXIDE

-

I

0

-

--

0.00001

-

I

I

40 80 120 DAYS AFTER INHALATION

160

Fig.k g . Relative absorption functions [A(t)Jfor niobium oxide and niobium oxalate in beagle dogs with time in days.

/

A4 NIOBIUM

I

I

100

169

I

5 P u

3

*Q

10-

z

-

Nb OXALATE

3 A

4

t z

-

!-

5 0

1-

u

W I I

Nb OXALATE

0.1

I

0

I

I

40 80 120 DAYS AFTER INHALATION

160

Fig. k10. Percentage of the initial lung burdens of niobium oxalate (Thomas et al., 1967)in rats as a function o f time in days.

Compound: Niobium oxalate [Nb(V)Oxzl TABLE A.5-Recommended absorption functions (at t

= 0) for humans as a fraction of the initial deposit and going through the various pathways.

Cleared Externally

NOPL

TB P

0.20

-

Cleared Internally to:

GI Tract

Blood

0.18 0.09

0.02 0.01

c

0.50

-t

Recommended absorption function for niobium oxalate: A(t) = 1.7e-2t+ 0.05e-0.01t + 0.004

(beagle)

(A.9)

Information in Figure A.10 gives 95% lung burden as a function of time in rats for Nb oxalate and carrier free oxalate.

170

/

APPENDJX A

A5 Ruthenium Atomic number: 44 Isotope used: l0%u Half-life: 39.28 d Compound: Unknown chemical form TABLE A.6-Recommended absorption functions (at t

= 0) for humans as a fraction of the initial deposit and going through the various pathways.

Cleared Internally to:

Cleared Externally

NOPL

TB P

GI Tract

Blood

0.18 0.09

0.02 0.01

0.20 -

-

0.50

-t

Recommended absorption functions for ruthenium mixed form: A(t)

=

0.005

(human)

(A.10)

Fig. All. Percentage of the initial lung burdens of ruthenium in the mixed form (Pusch, 1968)in humans as a function of time in days.

A.5 RUTHENIUM

/

171

Isotope used: Half-life: 368 d Compound: Ruthenium tetroxide (RuOJ TABLEA.7-Recommended absorption finctions (at t

= 0)for humans as a fraction of the initial deposit and going through the variozs pathways.

Cleared Internally to:

Cleared Externally

NOPL

GI Tract

0.45

-

0.40 0.05

-

TB P

Blood

0.10

C

+

Recommended absorption function for ruthenium tetroxide: NOPL = 85e-lt + 0.03e-0.ma

I

(beagle)

I

HUMAN Ru-MIXED OXIDE

-

-

0

40 80 120 DAYS AFTER INHALATION

1

I

I

Fig. k12. Relative absorption functions [A(t)l for ruthenium in the mixed form in humans with time in days.

I

I

I

I

-

lMRu 0,

A

-

c

-

4

P c z W

0.1

z

-

RAT

-

-

W 0.

DOG

-

NOPL

0.01 0

I

I

I

I

I

100

200

300

400

500

600

DAYS AFTER INHALATION

Fig. A.13. Percentage of the nasal burden of ruthenium tetroxide in beagle dogs (Snipes, 1981;Snipes and Kanapilly, 1983)and rats (Runkelet al., 1980)as a function of time in days.

A6 Cesium Atomic number: 55 Isotope used: 13'Cs Half-life5:30 y Compound: Cesium in fused aluminosilicate particles TABLEA.8-Recommended

absorption functions (at t = 0) for humans a s a fraction of the initial &posit and going through the various pathways. Cleared Externally

NOPL TB

P

0.20

-

-

Cleared Internally to: GI Tract

Blood

0.13 0.09

0.07 0.01

-

0.50

-t

Recommended absorption function for cesium in fused aluminosilicate particles:

A(t) = 0 ~ j e - O+ . ~0.011e-0.0085t ~ + 0.0005

(beagle) (A.12)

SThisinformation is adapted from Boecker (1972)who used a physical half-life of 26.6 y.

/

A.6 CESIUM

173

Fig.k14. Percentageof the initiallung burdens of cesium in fused aluminosilicate (Boecker et al., 1974) and cesium chloride in beagle dogs (Boecker, 1969a; 1969b; Boecker et al., 1974) as function of time in days. 1

0.1

g

0.01

I

I

-

-

-

-

-

CI

I

I

-

D

O

-

G

-

-

-

-

-

0.001 -

DOG

0.0001

' 3 7 FAP ~ ~

I

0

I

I

-

-

I

I000 2000 DAYS AFTER INHALATION

Fig. k 1 5 . Relative absorption functions [A(t)]for cesium in fused aluminosilicate and cesium chloride in beagle dogs with time in days.

174

/

APPENDIXA

Fig. k l 6 . Percentage of initial lung burdens of cesium oxides in albino rats (Lie, 1964; Thomas and Thomas, 1968) as a function of time in days.

Compound: Cesium chloride (CsCl) TABLEA.9-Recommended absorption functions (at t

= Oj for humans as a fraction of the initial deposit and going through the various pathways.

Cleared Externally

NOPL

TB P

Cleared Internally to:

GI Tract

Blood

-

0.10 0.05

0.10 0.05

-

c

0.20

0.50

+

Recommended absorption function for cesium chloride:

+ 0.015 A(t) = 0.01e-0.15t

(beagle)

(A.13)

Information in Figure A.16 gives 137Cs versus time for albino rats.

A.7 BARIUM

1

175

A7 Barium Atomic number: 56 Isotope used: 140Ba Half-life: 12.74 d Compound: Barium chloride (BaC12) TABLE A.lO-Recommended absorption functions (at t

= 0) for humans a s a fmction ofthe initial deposit and going through the various pathways.

Cleared Internally to:

Cleared Externally

NOPL

0.20

-

TB P

GI Tract

Blood

0.10 0.05

0.10 0.05 0.50

c

+

Recommended absorption function of barium chloride: A(t) = 6.6e-0.75t+ 0.75e-0.23t+ 0.052 (beagle) (A.14) Isotope used: 133Ba Half-life? 10.74 Compound: Barium fused aluminosilicate particles and unheated and heated barium sulfate (BaS04) I

I

I

I

I

I

-

'"B~CI~

z W

K 3

m

e

l.o-

3 4 4

5 t

-

10-

n

-

-

-

-

L

-

-

I-

-

-

a

-

-

z

0.1

z0 g

0.01-

-

0.001

DOG I

0

I

I

I

I

-

I

20 40 60 DAYS AFTER INHALATION

70

Fig. k l 7 . Percentage of the initial lung burdens of barium chloride in beagle dogs (Cuddihy and Griffith, 1972) as a function of time in days. 'This information is adapted from Cuddihy et al. (1974) who used a physical halflife of 7.2 y.

176

/

APPENDIXA

TABLE A.ll-Recommended absorption functions fat t

= 0) for humans as a fraction of the initial deposit and going through the various pathways.

Cleared Internally to:

Cleared Externally

NOPL TB P

GI Tract

0.20

Blood

-

0.20 0.10

-

0.50

c

4

Recommended absorption function of barium in fused aluminosilicate particles:

+ 0.0016 A(t) = 0.018e-0,12t

(beagle)

(A.15)

Recommended values for barium sulfate (heated and unheated): A(t) = 0.35e-0,15t + -(Unheated) A(t) = 0.18e-0-15t (Heated)

(beagle) (beagle)

(A.16) (A.17)

Barium-133 sulfate, which was unheated or heated, did not have enough data to extend beyond 16 d for the absorption function [A(t)l. The goal of the experiment was done for a different purpose. I

I

I

140

BaC12

-

h

3

DOG

0.01

I

0

I

I

I

I

I

20 40 60 DAYS AFTER INHALATION

70

Fig.A.18. Relative absorption functions [A(t)]for barium chloride in beagle dogs with time in days.

A.7 BARIUM

-

!-

z W

1

177

-

BaS04

0

B

-

-

P

DOG BaC12

1

I

0

l"1

1

I

I

1016 100 300 500 DAYS AFTER INHALATION

Fig. A.19. Percentage of the initial lung burdens for barium in fused aluminosilicate, barium sulfate and barium chloride in beagle dogs (Cuddihy et al., 1974) as a function of time in days.

BaCI,

DOG Ba FAP

0

10 16 100 300 500 DAYS AnER INHALATION

Fig. A.20. Relative absorptionfunctions [A(t)]for barium in fused aluminosilicate, barium sulfate and bai-ium chloride in beagle dogs with time in days.

Isotope used: 133Ba Half-life7:10.74 y Compound: Barium chloride (BaCl,) Recommended absorption functions and absorption function for barium chloride is developed from 140BaC12because in this experiment the lung burden received special measurement as opposed to 133BaC12.

A8 Lanthanum Atomic number: 57 Isotope used: I4OLa Half-life: 40.272 h Compound: Lanthanum chloride (LaC13)

DAYS AFTER INHALATION

Fig. A.21. Percentage of the initial lung burdens of lanthanum chloride in beagle dogs (Cuddihy and Boecker, 1970) as a function of time in days.

'This information is adapted &om Cuddihy et al. (1974) who used a physical halflife of 7.2 y.

/

A.8 LANTHANUM

179

1 2

0.1 0

8

6

4

10

DAYS AFTER INHALATION

Fig. k22. Relative absorption functions [A(t)l for lanthanum chloride in beagle dogs with time in days.

TABLE A.12-Recommended absorption functions (at t

= 0) for humans as a fraction of the initial deposit and going through the various pathways.

NOPL TB P

Cleared Internally to:

Cleared Externally

GI Trad

Blood

0.20 -

0.18 0.09

0.02 0.01

-

c

0.50

+

Recommended absorption function for lanthanum chloride: A(t)

=

8.5e-I"

+ 0.45

(beagle)

(A.18)

180

/

APPENDIXA

A9 Cerium Atomic number: 58 Isotope used: 144Ce Half-life: 284.3 d Compound: Cerium in fused aluminosilicate particles TABLEA.13-Recommended

absorption functions (at t = 0) for humans as a fraction of the initial deposit and going through the various pathways. Cleared Internally to:

Cleared Externally

GI Tract

Blood

0.20 -

0.18 0.09

0.02 0.01

NOPL

TB

-

-

P

0.50

4

Recommended absorption function for cerium in fused aluminosilicate particles: A(t)

=

0.0045

(beagle)

(A.19)

Compound: Cerium chloride (CeC13) TABLEA.14-Recommended absorption functions (at t

= 0) for humans as a fraction of the initial deposit and going through the various pathways.

0.1

)

I

0

200

I

I

400 600 DAYS AFTER INHALATION

I 800

I

1000

Fig. k 2 3 . Percentage of the initial lung burdens of cerium fused aluminosilicate, cerium chloride (Boecker and Cuddihy, 1974) and cerium oxide (McClellan et al., 1970) in beagle dogs as a function of time in days.

1

A.9 CERIUM I

I

I

I

I

I

181

I

-

-

-

-

-

$

0.1-

-

0.01

-

-

DOG Ce FAP

0.001

I

I

1

I

I

WG CeC13 I

-

I

200 400 600 DAYS AFTER INHALATION

0

-

800

Fig. A.24. Relative absorption functions [A(t)l for cerium fused aluminosilicate and cerium chloride in beagle dogs with time in days.

Cleared Externally

NOPL

0.20

-

TB P

-

Cleared Internally to: GI Tract

Blood

0.10 0.05

0.10 0.05

c

0.50

-

Recommended absorption function for cerium chloride:

A(t)

=

4.2e-1.4t+ 0.012e-0.01t + 0.0015

(beagle) (A.20)

182

/

APPENDIXA

A10 Polonium

Atomic number: 84 Isotope used: 210Po Half-life: 138.38 d Compound: Polonium chloride (gas) TABLEA.15-Recommended absorption functions (at t = 0)for humans as a fiaction of the initial deposit and going through the various pathways. Cleared Externallv

NOPL TB P

Cleared Internally to: GI Tract

Blood

0.18 0.09

0.02 0.01

0.20 -

0.50

c

4

Recommended absorption function for polonium chloride (gas): A(t) = 0.024

(beagle)

(A.21)

DAYS AFTER INHALATION

Fig. k25. Percentage of the initial lung burdens of polonium chloride in beagle dogs (Smith et al., 1961) as a function of time iil days.

/

A . l l URANIUM I

0.1

I

I

I

I

I

183

I

PoCI,

-

-

-

%

-

-

DOG

0.01

I

0

20

I I I I I 40 60 80 100 120 DAYS AFTER INHALATION

I

140

160

Fig. k26. Relative absorption functions burdens IA(t)l of polonium chloride in beagle dogs with time in days.

A l l Uranium Atomic number: 92 Isotope used: 235U Half-life: 7.038 x lo8y Compound: Uranium dioxide (UOJ and uranium trioxide (UOJ TABLEA.16-Recommended absorption functions (at t

= 01 for humans as a fraction of the initial deposit and going through the various pathways.

Cleared Externally

NOPL

0.20

TI3

P

-

Cleared Internally to: GI Tract

Blood

0.18 0.09

0.02 0.01

c

0.50

-.L

Recommended absorption function for uranium dioxide: A(t) = 0.13e-0.14t+ 0.0027

(beagle)

(A.22)

Recommended absorption function for uranium trioxide: A(t) = 0.17e-O.lt + 0.02

(beagle)

(A.23)

Compound: Uranium hexifluoride (UFs)and uranium dioxide difluoride (U0,F2)

184

/

APPENDIX A I

I

DOG 235

uo2

-

7

-

DOG 235

uos

0.1

I

0

I

I

I

50 100 150 200 DAYS AFTER INHALATION

250

Percentage of the initial lung burdens of uranium dioxide, uranium Fig. A.27. trioxide, uranium hexifluoride, and uranium dioxide difluoride in beagle dogs (Hodge et al., 1973; Leach et al., 1970;1973;Morrow et al., 1964; 1966;1972; 1982) as a function of time in days.

Fig.A.28. Relative absorption functions [A(t)]for uranium dioxide,uranium trioxide, uranium hexifluoride, and uranium dioxide difluoride in beagle dogs with time in days.

1

A.ll URANIUM

185

TABLEA.17-Recommended absorption functions (at t

= 0) for humans as a fraction of the initial deposit and going through the various pathways.

Cleared Externally

NOPL

0.20 -

TB P

Cleared Internally to:

GI T ~ a e t

Blood

0.10 0.05

0.10 0.05

-

-

0.50

+

Recommended absorption function for uranium hexafluoride and uranium dioxide difluoride:

A(t)

=

1.2e-0.53t+ 0.09

(beagle)

(A.24)

Information in Figure A.29 gives uranium lung burden as a function of time in rats for uranium oxide, uranium floride and mixtures thereof in rats. I

RAT 234-we

u02

-

RAT

-

UF4

0.1 0

I I I I 200 400 600 800 DAYS AFTER INHALATION

1000

Fig. k29. Percentage of the initial lung burdens for uranium oxide, fluorides and mixtures thereof in rats (Ballou et al., 1986; Briant and Sanders, 1987; Galibin and Parfenov, 1970; Morris et al., 1989; Stradling et al., 1985a; 1985b) as a function of time in days.

186

/

APPENDIXA

A12 Plutonium Atomic number: 94 Isotope used: 2 3 9 P ~ Half-life: 24,065 y 2381?u Half-life: 87.74 y Compound: Plutonium dioxide (PuOz),nitrates [Pu(N03)J and citrates

TABLEA.18-Recommended absorption functions (at t = 0) for humans as a fraction of the initial deposit and going through the various pathways. Cleared Internally to:

Cleared Externally

NOPL TB P

0.20 -

Blood

0.18 0.09

0.02 0.01 0.50

c

I

100

GI Tract

I

I

I

I

I

+

I

-

-

-

E

W

P

-

==puo2 0.1

I 0

I 3000 DAYS AFTER INHALATION I

1000

I

2d00

I

I

4000

Fig.A.30. Percentage of the initial lung burdens of plutonium dioxide (Bair and Thompson, 1974;Ballou et al., 1972; Diel and Lundgren, 1982; Guilmette et al., 1984; 1987; Park et al., 1972), plutonium nitrates (Ramsden et al., 1970) and plutonium citrates (Dagle et al., 1983) i n baboons (LaBauve et al., 1980; Metivier et al., 1978) and beagle dogs (Mewhinney and Diel, 1983; Morrow et al., 1 9 6 7 ~as ) a function of time in days.

A.12 PLUTONIUM I

0.1

0.01 h

T

I

I

I

I

I

I

-

-

DOG ,"~PUCITRATE

-

DOG "'PUO~

-

DOG250~u02

-

BABOON 2 s ~ ~ 0 2 DOG 2 a ~ u ~ Z

I

0

-

-

0.00001

187

-

0.001 -

0.0001

1

I

I

I

I

I

200 400 600 DAYS AFTER INHALKI'ION

I

800

Fig. A.31. Relative absorption functions [A(t)]for plutonium dioxide, plutonium nitrates, and plutonium citrates in baboons and beagle dogs with time in days.

DAYS AFTER INHALATION

Fig. A.32. Percentage of the initial lung burdens of plutonium dioxides in hamsters (Smith et al., 1980), rats (Rhoads et al., 1986; Sanders et al., 1976; 1977), and mice (Bair et al., 1961) as a function of time in days.

Recommended absorption functions for plutonium dioxide: A(t) = 0.0016e-0.02t+ 0.0001 (baboon) (A.25) A(t) = 0.0014e-0.07t+ 0.00004 (beagle) (A.26) A(t) = 0.0023e-0.017t + 0.0004 (beagle) (A.27) Recommended absorption function for plutonium nitrates: A(t) = 0.0005 (beagle) (A.28) Recommended absorption function for plutonium citrates: (beagle) (A.29) A(t) = 0.073e-0.073t+ 0.0045 Information in Figure A.32 gives plutonium lung burden as a function of time for 238h or 2 3 9 Pdioxide ~ particles inhaled by Syrian hamsters, Wistar rats and mice.

A13 Americium Atomic number: 95 Isotope used: 241Am Half-life8: 432.2 y Compound: Americium dioxide (AmOz)

DAYS AFTER INHALATION

Fig. k33. Percentage of the initial lung burdens of americium dioxide in beagle dogs (Craig et al., 1979; Mewhinney and Griffith, 1982; 1983) as a function of time in days. RThisinformation is adapted from Craig et al. (1979) and Mewhinney and Griffith (1982) who used a physical half-life of 458 d.

A.13 AMERICIUM

0

200

400 600 800 DAYS AFTER INHALATION

1

189

1000

Fig. k34. Relative absorption functions [A(t)l for americium dioxide in beagle dogs with time in days.

TABLEA.19-Recommendxd absorption functions (at t

= 0)for humans as a fraction of the initial deposit and going through the uarious pathways.

Cleared Externally '

NOPL TB P

0.20 -

Cleared Internally to:

GI Tract

Blood

0.18 0.09

0.02 0.01

+

0.50

4

Recommended absorption functions for americium dioxide:

A(t)

=

0.048e-0.028t + 0.002

(beagle)

(A.30)

A14 Curium Atomic number: 96 Isotope used: 244Cm Half-lifeg: 18.11 y Compound: Curium chloride (CmC13), curium dioxide (Cm203)and curium nitrate [Cm(N0,)3] TABLEA.20-Recommended absorption functions (at t

= 0) for humans as a fraction of the initial deposit and going through the various pathways.

Cleared Internally to:

Cleared Externally

NOPL TB P

0.20 -

-

GI Tract

Blwd

0.18 0.09

0.02 0.01 0.50

c

4

Recommended absorption functions of plutonium dioxide: A(t)

= I

100

0.06e-0.046t+ 0.02 I

I

I

(beagle) I

I

(A.31)

I

Cm OXIDE & CHLORIDE

-

-

z W 0

a

2

-

S 3 5

IO-

-

z

-

-

J

c I-

z W

0

5P

DOG

1

I

0

I

I

I

I

I

200 400 600 DAYS AFTER INHALATION

I

800

Fig. A.35. Percentage of the initial lung burdens of curium chloride and curium dioxide in beagle dogs (Guilmette and Kanapilly, 1988; McClellan et al., 1972) as a function of time in days.

'This information is adapted from Guilmette and Kanapilly (1988)who used a physical half-life of 17.7 y.

1

A.14 CURIUM 0.1 I

I

I

I

I

I

I

191

I

Cm OXIDE & CHLORIDE

-

-

-

?

-

0.01

DOG

I

0

I

I

I

I

I

400 600 DAYS AFTER INHALATION

200

-

I

800

Fig. A.36. Relative absorption functions [A(t)] for curium chloride and curium dioxide in beagle dogs with time in days.

Glossary absorbed dose: the quotient of de by dm where de is the mean energy imparted by ionizing radiation to the matter in a volume element and dm is the mass of the matter in that volume element, i.e., the absorbed dose D = dddm. The unit of absorbed dose is the gray (Gy). absorption functions [A(t)]:dissolution and absorption functions of radionuclides found in the lung after deposition (functions can be exponential, polynomial or constant relationships). acinus: minute sac-like beginnings of the alveolar gland, a n air cell of the lung. activity median aerodynamic diameter (AMAD): the diameter in a n aerodynamic particle size distribution for which the total activity above and below this size are equal. A log-normal distribution of particle sizes is usually assumed. aerodynamic (equivalent)diameter (AD): the diameter of a unit density sphere having the same settling velocity as the particle of interest. aerosol: a suspension of solid or liquid particles in a gas. alveoli:terminal air sacs of the lung that provide for oxygen-carbon dioxide gas exchange and consist of Type I cells, Type I1 cells, and macrophages. alveolar dead space: portion of the tidal volume that enters the alveoli but does not take part in gas exchange. anatomical dead space: volume of the airways of the lung in which no gas exchange occurs. annual reference level of intake (ARLI): activity of a radionuclide that, taken into a body during a year, would provide a committed effective dose to a person, represented by Reference Man, equal to 20 mSv (ARLI is expressed in becquerels, Bq). atelectasis: collapse of the alveoli of the lung or portion of the lung due to pressure of a pleural effusion or blockage of the small bronchial tubes. basal cell: cells that form a single row along basement membrane and are responsible for the pseudostratified appearance of the epithelium. basement membrane: very thin membrane beneath the epithelium.

GLOSSARY

/

193

branching angle: angle of change in direction of the bulk air-flow moving &om the parent airway segment into the daughter segment. breathing frequency number of breaths per unit time. breathing mode: fraction of inhalation and exhalation of air through the nose and mouth (air passing each way, such as 10010 percent, 50150 percent, etc). bronchial asthma: allergic reaction characterized by a narrowing of the lumen of the bronchial tubes from spasms of the muscles in the walls or a congestive swelling of the bronchial mucous membrane. bronchioloalveolaradenoma: benign lung neoplasm arising from the epithelium lining bronchioles or alveoli. bronchioloalveolarcarcinoma: malignant lung neoplasm arising from the epithelium lining the bronchioles or alveoli. bronchus: one of the two main branches arising from the trachea at its bifurcation, one going to each lung. brush cell: tall cells that rest on the basement membrane and have a prominent tuft on the luminal surface scattered among the epithelium of the trachea, bronchi and bronchioles. carina:ridge-likestructure formed by the bifurcation of the trachea, at the distal end where it branches into the main bronchi. ciliated cell: roughly columnar cell type having "hairlike structures" or cilia on its upper surface; a major cell type in all airway epithelium. Clara cell: nonciliated secretory cell that is one of the two major cell types in the bronchiolar epithelium. clearance pathway routes by which material deposited in the lungs can move into the blood, lymph nodes or bronchi. convection: fluid motion of air into and out of the respiratory tract in terms of (1)laminar flow in which adjacent fluid parcels slide as sheets and (2) turbulent flow characterized by rapidly varying velocities. count median diameter (CMD):particle size for which there are equal numbers of particles above and below this value. cricoid cartilage: lower-most cartilage of the larynx which is shaped like a signet ring. cytotoxicity:ability of a substance to induce degenerative changes in cells that may lead to cell death. deoxyribonucleic acid (DNA): the genetic material of cells; a complex molecule of high molecular weight consisting of deoxyribose, phosphoric acid, and four bases which are arranged as two long chains that twist around each other to form a double helix joined by bonds between the complementary components.

194

/

GLOSSARY

derived reference air concentrations (DRAC): the ARLI of a radionuc1;de divided by the volume of air inhaled by Reference Man in a working year (i.e., 2.4 X 103m3)(the DRAC is given in Bq m-3). diffision:Brownian or random motion of particles due to collisions with surrounding molecules resulting in movement from a region of higher to one of lower concentration. diffusion equivalent diameter: diameter of a sphere having the same rate of diffusion (or diffusion coefficient) as the particle in question. dissolution rate: rate of change of a solid to a liquid form by immersion in a fluid of suitable character. DNA adduct: a chemical covalently bound to DNA. elastic recoil:the ability to return to the original shape after bouncing off an object. electrostatic attraction (or repulsion): affinity for attraction (or repulsion) due to electrostatic charges associated with particles. emphysema:abnormal dilation of the pulmonary air spaces (alveoli) accompanied by destruction of respiratory tissue. endothelial blood capillary cells: layer of flat cells lining the inside blood vessels and capillaries. epiglottis: saddle-shaped plate of cartilage, covered with mucous membrane at the root of the tongue, that folds back over the aperture of the larynx, closing it during the act of swallowing. epithelial serous cell: found in the trachea and extrapulmonary bronchi of the rat (the function of this cell is unknown although it might contribute to the periciliary liquid layer found beneath the tracheobronchial mucus). esophagus: portion of the digestive canal between the pharynx and the stomach where it extends from the lower border of the cricoid vertebra to the cardiac orifice of the stomach. expiratory reserve volume: largest amount of air that can be forced out of the lungs after a normal breath has been let out; includes the tidal volume expired down to the residual volume. fiberoptic bronchoscopy:use of a flexible material (glass or plastic) that transmits light to obtainvisual images ofthe lung airways. fibrosarcoma: a malignant neoplasm with characteristics of fibrous tissue. Fick's law of diffusion: the flux of a gas is equal to the gas diffusion coefficient multiplied by the gas concentration divided by the distance along the axis of transport. first-orderkineticrelationship:solution of an equation with independent and dependant variables that are related to functions of the first order of time.

GLOSSARY

1

195

free radicals: highly reactive molecules containing an odd number of electrons. functional residual capacity (FRC): a i r in t h e lung which remains after the tidal air is exhaled. fused aluminosilicate particles (FAP):particles composed of heat-treated montmorillonite clay. gas exchange (respiratory):process by which inhaled air supplies molecules of oxygen to the body and exhaled air removes molecules of carbon dioxide to the outside air. gas-phaseboundary zone: distance above a reactive or absorbing surface within which transfer of gas or vapor from an air stream to the surface is occurring. (Distance depends on the diffusion coefficient of the gas or vapor, temperature difference between the stream and surface and turbulent mixing in the gas stream.) geometric mean diameter:median diameter of a lognormal distribution of particle diameters. geometric standard deviation: for a log normal distribution it is the exponential of the standard deviation of the associated normal distribution (always 2 1). goblet cells: epithelial cells that are distended with mucin so as to have a goblet shape (mucin is capable of being discharged upon the epithelial surface). gray (Gy): SI unit of absorbed dose, kerma and specific energy imparted (1 Gy = 1 J kg-I = 100 rad). hemangiosarcoma: malignant neoplasm originating from blood vessels and involving endothelial and fibroblastic tissue. Henry's law: the solubility of a gas in a liquid is proportional to the partial pressure of the gas, i.e., by doubling the pressure, twice as much gas passes into solution. hilar area or nodes: depression or recess a t entrance or exit of vessels to an organ; the root of the lung and its lymph nodes. hydrophilic molecule: molecule that readily absorbs moisture; bibulous. hygroscopicity: degree of absorption and retention of moisture. hypopharynx: lowermost portion of the pharynx that leads to the larynx and esophagus. inertial impaction of particles: fraction of particles that may contact ailway walls because of their inertia (particles do not follow the curvature of the airstream exactly) inhalability (inspirable particulate mass): fraction of the suspended material in ambient air that enters the nose or mouth with the volume of air inhaled. inspiratory capacity: index of the maximum volume of a i r breathed in during inhalation; includes the tidal volume and inspiratory reserve volume.

196

/

GLOSSARY

interception: process by which the physical size of an inhaled particle (equal to the particle radius) brings it into direct contact with the airway wall. K cell: a granule-containing cell type residing in the tracheobronchial epithelium that could be involved in pulmonary circulation that closely resembles the gastrointestinal Kultschitzky cell. lamina propria: connective tissue layer of the mucous membrane in humans. larynx: organ structure of the muscle and cartilage at the upper end of the human trachea containing the vocal cords. lavage: washing out of an organ (i.e., stomach, intestinal tract, sinuses or lung). linear energy transfer (LET): energy lost by a charged particle, due to collisions with electrons, in traversing a distance through matter. lipophilicity: affinity for fat. lymphatic system: complex network of capillaries, vessels, valves, ducts and organs involved in producing, filtering, and conveying lymph and producing various blood cells. magnetic resonance imaging (MRI):an imaging technique based on the magnetic properties of biological molecules. These images provide detailed anatomical views for diagnostic purposes. mass median aerodynamicdiameter (MMAD):the aerodynamic diameter of a particle having median mass, i.e., the masses of particles above and below this value are equal. mass median diameter (MMD): the particle diameter for which there is an equal mass particles above and below this size. mass stopping power [Sp(E,)]: ratio of the average energy lost by a charged particle in traversing a distance in a material to the density of the material. mass transfer coefficient: proportionality factor for mass transfer due to mass concentration gradient of the gas. mast cell: cells of the subepithelial source of the globule leukocytes that contain substances (e.g., histamine) which mediate allergic reactions. mean diameter: average diameter of the particles (sum of all diameters divided by the number of particles). mechanical clearance function [M(t)]:rate of movement of particles, either phagocytized or unphagocytized, from the lung or tracheobronchial airways up the tracheobronchial tree. Medical Internal Radiation Dose (MIRD) Committee: a committee of the Society of Nuclear Medicine responsible for the internal dosimetry of radiopharmaceuticals used diagnostically.

GLOSSARY

1

197

molecular diffusion: the spreading out of molecules or ions in a fluid, in a direction tending to result in uniform concentrations in all portions of the system. monodisperse aerosol:aerosol composed of particles having a single size or a very small range of sizes. mucociliary clearance velocity (mucousflow rates):time rate of movement for particles up the mucus escalator of the tracheobronchial airways. mucous escalator: mucus flow moving up the tracheobronchial airways due to ciliary action. mucus cells or mucus glands: cells or glands secreting a viscid fluid consisting of mucin, inorganic salts, and water that are present in the bronchi. nasal septum: wall or septum between the two nasal cavities. nasal turbinates: three scroll-like bones coming from the outer walls of the superior, middle, and inferior passages in the main nasal cavity that provide filtration, temperature control and aeration in the nose. nasal valve: smallest part of the nasal airway forming the anteriorposterior portion of the nose that filters the incoming air. naso-oro-pharyngo-laryngeal(NOPL)region: nasal, oral, pharyngeal and laryngeal portion of the upper respiratory tract. olfactory region:membranes in the upper part of the nasal cavities that contain the olfactory receptors for the sense of smell. oronasal breathing. respiratoly intake of air either by nose andl or mouth. oropharynx: central portion of the pharynx lying between the soft palate and upper portion of the epiglottis. osteosarcoma: malignant tumor of the connective tissue of the bone. particle clearance velocity: speed of clearance of particles deposited in the respiratory tract by mucous clearance, phagocytosis or dissolution and absorption. particle dissolution rate: rate a t which the change from a solid to a liquid form takes place. phagocytic cells: cells with the ability to engulf solid material. pharynx: passageway for air from the nasal cavity to the larynx and for food from the mouth to the esophagus and also acts as a resonating cavity for sound. (The upper portion is lined with pseudostratified ciliated columnar epithelium, middle portion with stratified columnar epithelium, and the lower portion with stratified squamous epithelium). photon energy (MeV):a quantity of electromagnetic energy whose value in ergs is the product of its frequency in cycles per second and Planck's constant.

198

/

GLOSSARY

physical-chemical form: form relating to the physics and chemistry of its source. pleura: serous membrane enveloping the lungs and lining the walls of the thoracic cavity. point isotropic specific absorbed fraction:fraction of the energy emitted by a point isotropic source that is absorbed per gram a t a distance from the source. polydisperse aerosols:aerosols composed of particles with a range of sizes. pneumoconiosis: disease of the lungs, characterized by fibrosis and caused by the chronic inhalation of mineral dusts, especially silica and asbestos. pulmonary fibrosis: formation of scar tissue within the connective tissue of the lungs following pulmonary disease or inflammation. pulmonary lymph nbdes: lymph nodes found in the pulmonary parenchyma, usually a t bifurcations of bronchi and bronchioles. pulmonary (P)region: gas exchange region of the lungs; consists of alveoli and respiratory bronchioles. pulmonary thromboembolism: blockage of a blood vessel in the lungs, usually by a clot in the heart that has become detached from its site of formation. pulmonary tuberculosis: infectious disease of the lung caused by tubercle bacillus and characterized pathologically by inflammatory infiltrations, formation of tubercles, caseation, necrosis, abscesses, fibrosis, and calcification. residual volume: air that remains in the lung following maximum exhalation. respiratory tract: consists of the naso-oro-pharyngo-laryngeal region, tracheobronchial region and pulmonary region, common to humans and animals. retention times: specific times of retention of a substance that has been inhaled or injected in an organ or organs of the body. rheology: study of the flow of matter embracing elasticity, viscosity, and plasticity. scaling law: a principle for estimating a secondary measurement based on a primary measurement of size, weight, mass, volume, length, etc. secretory cell: low ciliated and taller nonciliated secretory cells comprising the main portion of the epithelium of the terminal bronchus. sedimentation:process by which a particle deposits on the wall of a tube in the lung due to gravitational settling. specific activity: total radioactivity of a given isotope per unit mass or volume of the compound.

GLOSSARY

/

199

surface area median diameter (SAMD): diameter of particles having a median surface area, i.e., 50 percent of particles have a surface area above and 50 percent below this diameter. surfactant: agent that lowers surface tension. Task Group on Lung Dynamics (TGLD): an ICRP task group that promulgated revised models for deposition and retention of inhaled materials in the human respiratory tract in 1966. thoracic lymphatic system: structures involved in the lymph system which include lymph capillaries, lacteals, lymph nodes, lymph vessels and main lymph ducts. tidal volume: volume of air that enters and leaves the lung during normal breathing. tissue depth: depth of tissues lining the respiratory tract including the mucus and cells lining the trachea, main bronchus or bronchial airway. tissues at risk: cells endangered from exposure to radionuclides in the air. tomography: x-ray technique designed to show detailed images of structures in a selected plane of tissue by blurring images of structures in all other planes. trachea: air tube extending from the larynx to the major bronchi whose membranous wall contains cartilage and muscular fibers. trach;?obronchial (TB) region: area of the trachea and bronchi down to the terminal bronchioles which functions in gas transport. Type I cells: large, flattened cells that line the alveoli covering about 97 percent of the surface; they maintain the barrier between the air and blood of the lung. Type I1 cells: cuboidal cells of the alveoli that synthesize, secrete and recycle components of pulmonary surfactant. Typical Path Lung Model (TPLM): lung model using a single unique pathway to represent either the total lung or a portion of the lung. vital capacity: maximum amount of air breathed in during inspiration.

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Currently, the following subgroups are actively engaged in formulating recommendations: SC 1

SC 9 SC 46

SC 57

SC 64

SC 66 SC 72 SC 75 SC 85 SC 86 SC 87

SC 88 SC 89

Basic Criteria, Epidemiology, Radiobiology and Risk SC 1-4 Extrapolation of Risk from Non-Human Experimental Systems to Man SC 1-5 Uncertainty in Risk Estimates SC 1-6 Basis for the Linearity Assumption SC 1-7 Information Needed to Make Radiation Protection Recommendations for Travel Beyond Low-Earth Orbit Structural Shielding Design and Evaluation for Medical Use of X Rays and Gamma Rays of Energies Up to 10 MeV Operational Radiation Safety SC 46-8 Radiation Protection Design Guidelines for Particle Accelerator Facilities SC 46-10 Assessment of Occupational Doses from Internal Emitters SC 46-11 Radiation Protection During Special Medical Procedures SC 46-13 Design of Facilities for Medical Radiation Therapy Dosimetry and Metabolism of Radionuclides SC 57-9 Lung Cancer Risk SC 57-10 Liver Cancer Risk SC 57-14 Placental Transfer SC 57-15 Uranium SC 57-16 Uncertainties in the Application of Metabolic Models SC 57-17 Radionuclide Dosimetry Models for Wounds Radionuclides in the Environment SC 6417 Uncertainty in Environmental Transport in the Absence of Site Specific Data SC 64-18 Risks from Space Applications of Plutonium SC 64-19 Historical Dose Evaluation SC 64-20 Contaminated Soil SC 64-21 Decontamination and Decommissioning of Facilities Biological Effects and Exposure Criteria for Ultrasound Radiation Protection in Mammography Guidance on Radiation Received in Space Activities Risk of Lung Cancer from Radon Hot Particles in the Eye, Ear or Lung Radioactive and Mixed Waste SC 87-1 Waste Avoidance and Volume Reduction SC 87-2 Waste Classification Based on Risk SC 87-3 Performance Assessment SC 87-4 Management of Waste Metals Containing Radioactivity Fluence a s the Basis for a Radiation Protection System for Astronauts Nonionizing Electromagnetic Fields SC 89-1 Biological Effects of Magnetic Fields SC 89-3 Extremely Low-Frequency Electric and Magnetic Fields SC 89-4 Modulated Radiofrequency Fields SC 89-5 Biological Effects and Exposure Criteria for Radiofrequency Electromagnetic Fields

THE NCRP SC 91

SC 92 SC 93

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Radiation Protection in Medicine SC 91-1 Precautions in the Management of Patients Who Have Received Therapeutic Amounts of Radionuclides SC 91-2 Dentistry Policy Analysis and Decision Making Radiation Measurement

In recognition of its responsibility to facilitate and stimulate cooperation among organizations concerned with the scientific and related aspects of radiation protection and measurement, the Council has created a category of NCRP Collaborating Organizations. Organizations or groups of organizations that are national or international in scope and are concerned with scientific problems involving radiation quantities, units, measurements and effects, or radiation protection may be admitted to collaborating status by the Council. Collaborating Organizations provide a means by which the NCRP can gain input into its activities from a wider segment of society. At the same time, the relationships with the Collaborating Organizations facilitate wider dissemination of information about the Council's activities, interests and concerns. Collaborating Organizations have the opportunity to comment on draft reports (at the time that these are submitted to the members of the Council). This is intended to capitalize on the fact that Collaborating Organizations are in an excellent position to both contribute to the identification of what needs to be treated in NCRP reports and to identify problems that might result from proposed recommendations. The present Collaborating Organizations with which the NCRP maintains liaison are as follows: American Academy of Dermatology American Academy of Environmental Engineers American Academy of Health Physics American Association of Physicists in Medicine American College of Medical Physics American College of Nuclear Physicians American College of Occupational and Environmental Medicine American College of Radiology American Dental Association American Industrial Hygiene Association American Institute of Ultrasound in Medicine American Insurance Services Group American Medical Association American Nuclear Society American Pharmaceutical Association American Pediatric Medical Association American Public Health Association American Radium Society American Roentgen Ray Society

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THENCRP

American Society of Health-System Pharmacists American Society of Radiologic Technologists American Society for Therapeutic Radiology and Oncology Association of University Radiologists Bioelectromagnetics Society Campus Radiation Safety Officers College of American Pathologists Conference of Radiation Control Program Directors Council on Radionuclides and Radiopharmaceuticals Defense Special Weapons Agency Electric Power Research Institute Electromagnetic Energy Association Federal Communications Commission Federal Emergency Management Agency Genetics Society of America Health Physics Society Institute of Nuclear Power Operations International Brotherhood of Electrical Workers National Aeronautics and Space Administration National Association of Environmental Professionals National Electrical Manufacturers Association National Institute of Standards and Technology Nuclear Energy Institute Office of Science and Technology Policy Oil, Chemical and Atomic Workers Union Radiation Research Society Radiological Society of North America Society of Nuclear Medicine United States Air Force United States Army United States Coast Guard United States Department of Energy United States Department of Housing and Urban Development United States Department of Labor United States Department of Transportation United States Environmental Protection Agency United States Navy United States Nuclear Regulatory Commission United States Public Health Services Utility Workers Union of America

The NCRP has found its relationships with these organizations to be extremely valuable to continued progress in its program. Another aspect of the cooperative efforts of the NCRP relates to the Special Liaison relationships established with various governmental organizations that have an interest in radiation protection and measurements. This liaison relationship provides: (1)an opportunity for participating organizations to designate an individual to provide liaison between the organization and the NCRP; (2) that the individual designated will receive copies of draft NCRP reports (at the time that these are submitted to the members of the Council) with an

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invitation to comment, but not vote; and (3) that new NCRP efforts might be discussed with liaison individuals as appropriate, so that they might have an opportunity to make suggestions on new studies and related matters. The following organizations participate in the Special Liaison Program: Australian Radiation Laboratory Commissariat a 1'Energie Atomique (France) Commission of the European Communities Health Council of the Netherlands International Commission on Non-Ionizing Radiation Protection Japan Radiation Council Korea Institute of Nuclear Safety National Radiological Protection Board (United Kingdom) National Research Council (Canada) Russian Scientific Commission on Radiation Protection South African Forum for Radiation Protection Ultrasonics Institute (Australia)

The NCRP values highly the participation of these organizations in the Special Liaison Program. The Council also benefits significantly from the relationships established pursuant to the Corporate Sponsor's Program. The program facilitates the interchange of information and ideas and corporate sponsors provide valuable fiscal support for the Council's program. This developing program currently includes the following Corporate Sponsors: Amersham Corporation Commonwealth Edison Consolidated Edison Duke Power Company Landauer, Inc. 3M New York Power Authority Southern California Edison Westinghouse Electric Corporation

The Council's activities are made possible by the voluntary contribution of time and effort by its members and participants and the generous support of the following organizations: Agfa Corporation Alfred P. Sloan Foundation Alliance of American Insurers American Academy of Dermatology American Academy of Health Physics American Academy of Oral and Maxillofacial Radiology

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THE NCRP

American Association of Physicists in Medicine American Cancer Society American College of Medical Physics American College of Nuclear Physicians American College of Occupational and Environmental Medicine American College of Radiology American College of Radiology Foundation American Dental Association American Healthcare Radiology Administrators American Industrial Hygiene Association American Insurance Senices Group American Medical Association American Nuclear Society American Osteopathic college of Radiology American Pediatric Medical Association American Public Health Association American Radium Society American Roentgen Ray Society American Society of Radiologic Technologists American Society for Therapeutic Radiology and Oncology American Veterinary Medical Association American Veterinary Radiology Society Association of University Radiologists Battelle Memorial Institute Canberra Industries, Inc. Chem Nuclear Systems Center for Devices and Radiological Health College of American Pathologists Committee on Interagency Radiation Research and Policy Coordination Commonwealth of Pennsylvania Consumers Power Company Council on Radionuclides and Radiopharmaceuticals Defense Nuclear Agency Duke Power Company Eastman Kodak Company Edison Electric Iostitute Edward Mallinckrodt, Jr. Foundation EG&G Idaho, Inc. Electric Power Research Institute Federal Emergency Management Agency Florida Institute of Phos~hateResearch Florida Power Corporation Fuji Medical Systems, U.S.A., Inc. Genetics Society of America Health Effects Research Foundation (Japan) Health Physics Society Institute of Nuclear Power Operations James Picker Foundation Martin Marietta Corporation Motorola Foundation National Aeronautics and Space Administration National Association of Photographic Manufacturers

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National Cancer Institute National Electrical Manufacturers Association National Institute of Standards and Technology Nuclear Energy Institute Picker International Public Sewice Electric and Gas Company Radiation Research Society Radiological Society of North America Richard Lounsbery Foundation Sandia National Laboratory Siemens Medical Systems, Inc. Society of Nuclear Medicine Society of Pediatric Radiology United States Department of Energy United States Department of Labor United States Environmental Protection Agency United States Navy United States Nuclear Regulatory Commission Victoreen, Inc.

Initial funds for publication of NCRP reports were provided by a grant from the James Picker Foundation. The NCRP seeks to promulgate information and recommendations based on leading scientificjudgment on matters of radiation protection and measurement and to foster cooperation among organizations concerned with these matters. These efforts are intended to serve the public interest and the Council welcomes comments and suggestions on its reports or activities from those interested in its

NCRP Publications NCRP publications are distributed by the NCRP Publications Office. Information on prices and how to order may be obtained by directing an inquiry to: NCRP Publications 7910 Woodmont Avenue Suite 800 Bethesda, MD 20814-3095 or visit the NCRP website a t http://wmv.ncrp.com. The currently available publications are listed below. NCRP Reports No.

Title

Control and Removal ofRadioactive Contamination in Laboratories (1951) Maximum Permissible Body Burdens and Maximum Permissible Concentrations of Radionuclides in Air and i n Water for Occupational Exposure (1959) [Includes Addendum 1 issued in August 19631 Measurement of Neutron Flux and Spectra for Physical and Biological Applications (1960) Measurement of Absorbed Dose of Neutrons, and ofMixtures of Neutrons and Gamma Rays (1961) Stopping Powers for Use with Cavity Chambers (1961) Safe Handling of Radioactive Materials (1964) Radiation Protection in Educational Institutions (1966) Dental X-Ray Protection (1970) Radiation Protection i n Veterinary Medicine (1970) Precautions i n the Management of Patients Who Have Received Therapeutic Amounts of Radionuclides (1970) Protection Against Neutron Radiation (1971) Protection Against Radiation from Brachytherapy Sources (1972)

NCRP PUBLICATIONS

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Specification of Gamma-Ray Brachytherapy Sources (1974) Radiological FactorsAffecting Decision-Making in a Nuclear Attack (1974) Krypton-85 in the Atmosphere-Accumulation, Biological Significance, and Control Technology (1975) Alpha-Emitting Particles i n Lungs (1975) Tritium Measurement Techniques (1976) Structural Shielding Design and Evaluation for Medical Use of X Rays and Gamma Rays of Energies Up to 20 MeV (1976) Environmental Radiation Measurements (1976) Radiation Protection Design Guidelines for 0.1-100 MeV Particle Accelerator Facilities (1977) Cesium-137 from the Environment to Man: Metabolism and Dose (1977) Medical Radiation Exposure of Pregnant and Potentially Pregnant Women (1977) Protection of the Thyroid Gland in the Event of Releases of Radioiodine (1977) Instrumentation and Monitoring Methods for Radiation Protection (1978) A Handbook ofRadioactivity Measurements Procedures, 2nd ed. (1985) Operational Radiation Safety Program (1978) Physical, Chemical, and Biological Properties of Radiocerium Relevant to Radiation Protection Guidelines (1978) Radiation Safety Training Criteria for Industrial Radiography (1978) Tritium in the Environment (1979) Tritium and Other Radionuclide Labeled Organic Compounds Incorporated in Genetic Material (1979) Influence of Dose and Its Distribution i n Time on DoseResponse Relationships for Low-LET Radiations (1980) Management of Persons Accidentally Contaminated with Radionuclides (1980) Radiofrequency Electromagnetic Fields-Properties, Quantities and Units, Biophysical Interaction, and Measurements (1981) Radiation Protection in Pediatric Radiology (1981) Dosimetry of X-Ray and Gamma-Ray Beams for Radiation Therapy i n the Energy Range 10 keV to 50 MeV (1981) Nuclear Medicine-Factors Influencing the Choice and Use of Radionuclides in Diagnosis and Therapy (1982)

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NCRP PUBLICATIONS

Operational Radiation Safety-Training (1983) Radiation Protection and Measurement for Low-Voltage Neutron Generators (1983) Protection in Nuclear Medicine and Utrasound Diagnostic Procedures i n Children (1983) Biological Effects of Ultrasound: Mechanisms and Clinical Implications (1983) Iodine-129: Evaluation of Releases from Nuclear Power Generation (1983) Radiological Assessment: Predicting the Transport, Bioaccumulation, and Uptake by Man of Radionuclides Released to the Environment (1984) Exposures from the Uranium Series with Emphasis on Radon and Its Daughters (1984) Evaluation of Occupational and Environmental Exposures to Radon and Radon Daughters i n the United States (1984) Neutron Contamination from Medical Electron Accelerators (1984) Induction of Thyroid Cancer by Ionizing Radiation (1985) Carbon-14 in the Environment (1985) S I Units i n Radiation Protection and Measurements (1985) The Experimental Basis for Absorbed-Dose Calculations i n Medical Uses of Radionuclides (1985) General Concepts for the Dosimetry of Internally Deposited Radionuclides (1985) Mammography-A User's Guide (1986) Biological Effects and Exposure Criteria for Radiofrequency Electromagnetic Fields (1986) Use ofBioassay Procedures for Assessment ofInternal Radionuclide Deposition (1987) Radiation Alarms and Access Control Systems (1986) Genetic Effects from Internally Deposited Radionuclides (1987) Neptunium: Radiation Protection Guidelines (1988) Public Radiation Exposure from Nuclear Power Generation in the United States (1987) Ionizing Radiation Exposure of the Population of the United States (1987) Exposure of the Population i n the United States and Canada from Natural Background Radiation (1987) Radiation Exposure of the U.S. Population from Consumer Products and Miscellaneous Sources (1987) Comparative Carcinogenicity of Ionizing Radiation and Chemicals ( 1989)

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Measurement of Radon and Radon Daughters i n Air (1988) Guidance on Radiation Received i n Space Activities (1989) Quality Assurance for Diagnostic Imaging (1988) Exposure of the U.S. Population from Diagnostic Medical Radiation (1989) Exposure of the U.S. Population from Occupational Radiation (1989) Medical X-Ray, Electron Beam and Gamma-Ray Protection for Energies Up to 50 MeV (Equipment Design, Performance and Use) (1989) Control of Radon in Houses (1989) The Relative Biological Effectiveness of Radiations of Different Quality ( 1990) Radiation Protection for Medical and Allied Health Personnel (1989) Limit for Exposure to "Hot Particles" on the Skin (1989) Implementation of the Principle of As Low As Reasonably Achievable (ALARA) for Medical and Dental Personnel (1990) Conceptual Basis for Calculations of Absorbed-Dose Distributions (1991) Effects of Ionizing Radiation on Aquatic Organisms (1991) Some Aspects of Strontium Radiobiology (1991) Developing Radiation Emergency Plans for Academic, Medical or Industrial Facilities (1991) Calibration of Survey Instruments Used i n Radiation Protection for the Assessment of Ionizing Radiation Fields and Radioactive Surface Contamination (1991) Exposure Criteria for Medical Diagnostic Ultrasound:I. Criteria Based on Thermal Mechanisms (1992) Maintaining Radiation Protection Records (1992) Risk Estimates for Radiation Protection (1993) Limitation of Exposure to Ionizing Radiation (1993) Research Needs for Radiation Protection (1993) Radiation Protection i n the Mineral Extraction Industry (1993) A Practical Guide to the Determination of Human Exposure to Radiofrequency Fields (1993) Dose Control at Nuclear Power Plants (1994) Principles and Application of Collective Dose in Radiation Protection (1995) Use of Personal Monitors to Estimate EffectiveDose Equivalent and Effective Dose to Workers for External Exposure to Low-LET Radiation (1995)

238 123 124 125

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NCRP PUBLICATIONS

Screening Models for Releases of Radionuclides to Atmosphere, Surface Water, and Ground (1996) Sources and Magnitude of Occupational and Public Exposures from Nuclear Medicine Procedures (1996) Deposition, Retention a n d Dosimetry of Inhaled Radioactive Substances (1997)

Binders for NCRP reports are available. Two sizes make it possible to collect into small binders the "old series" of reports (NCRP Reports Nos. 8-30)and into large binders the more recent publications (NCRP Reports Nos. 32-125). Each binder will accommodate from five to seven reports. The binders carry the identification "NCRP Reports" and come with label holders which permit the user to attach labels showing the reports contained in each binder. The following bound sets of NCRP reports are also available: Volume I. NCRP Reports Nos. 8, 22 Volume 11. NCRP Reports Nos. 23,25,27, 30 Volume 111. NCRP Reports Nos. 32, 35, 36, 37 Volume IV. NCRP Reports Nos. 38,40,41 Volume V. NCRP Reports Nos. 42,44,46 Volume VI. NCRP Reports Nos. 47,49,50,51 Volume VII. NCRP Reports Nos. 52,53, 54, 55, 57 Volume VIII. NCRP Report No. 58 Volume M. NCRP Reports Nos. 59,60, 61, 62,63 Volume X. NCRP Reports Nos. 64, 65,66,67 Volume XI.NCRP Reports Nos. 68,69, 70,71, 72 Volume XII. NCRP Reports Nos. 73, 74, 75, 76 Volume XIII. NCRP Reports Nos. 77, 78, 79, 80 Volume XIV. NCRP Reports Nos. 81,82,83,84,85 Volume XV.NCRP Reports Nos. 86, 87,88,89 Volume XVI. NCRP Reports Nos. 90, 91, 92, 93 Volume XVII. NCRP Reports Nos. 94,95,96, 97 Volume XVIII. NCRP Reports Nos. 98, 99, 100 Volume XM. NCRP Reports Nos. 101,102, 103, 104 Volume XX.NCRP Reports Nos. 105, 106, 107,108 Volume XXI. NCRP Reports Nos. 109,110,111 Volume XXII. NCRP Reports Nos. 112,113,114 Volume XXIII. NCRP Reports Nos. 115,116,117,118 Volume XXIV. NCRP Reports Nos. 119, 120, 121, 122 Volume XXV.NCRP Reports No. 1231 and 123II (Titles of the individual reports contained in each volume are given above.)

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NCRP Commentaries No.

Title

1

Krypton-85 in the Atmosphere-With Specific Reference to the Public Health Significance of the Proposed Controlled Release at Three Mile Island (1980) Screening Techniques for Determining Compliance with Environmental Standards-Releases of Radionuclides to the Atmosphere (1986),Revised (1989) Guidelines for the Release of Waste Water from Nuclear Facilities with Special Reference to the Public Health Significance of the Proposed Release of Treated Waste Waters at Three Mile Island (1987) Review of the Publication, Living Without Landfills (1989) Radon Exposure of the U.S. Population-Status of the Problem (1991) Misadministration of Radioactive Material in MedicineScientific Background (1991) Uncertainty in NCRP Screening Models Relating to Atmospheric Transport, Deposition and Uptake by Humans (1993) Considerations Regarding the Unintended Radiation Exposure of the Embryo, Fetus or Nursing Child (1994) Advising the Public about Radiation Emergencies: A Document for Public Comment (1994) Dose Limits for Individuals Who Receive Exposure from Radionuclide Therapy Patients (1995) Radiation Exposure and High-Altitude Flight (1995) An Introduction to Eflicacy i n Diagnostic Radiology and Nuclear Medicine (Justification of Medical Radiation Exposure) (1995) A Guide for Uncertainty Analysis i n Dose and Risk Assessments Related to Environmental Contamination (1996)

Proceedings of the Annual Meeting No.

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Perceptions of Risk, Proceedings of the Fifteenth Annual Meeting held on March 14-15,1979(includingTaylor Lecture No. 3) (1980)

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NCRP PUBLICATIONS

Critical Issues in Setting Radiation Dose Limits, Proceedings of the Seventeenth Annual Meeting held on April 8-9, 1981 (including Taylor Lecture No. 5) (1982) R a d i a t i o n Protection and New Medical Diagnostic Approaches, Proceedings of the Eighteenth Annual Meeting held on April 6-7, 1982 (including Taylor Lecture No. 6) (1983) Environmental Radioactivity, Proceedings of the Nineteenth Annual Meeting held on April 6-7,1983 (including Taylor Lecture No. 7) (1983) Some Issues Important in Developing Basic Radiation Protection Recommendations, Proceedings of the Twentieth Annual Meeting held on A p d 4-5,1984 (including Taylor Lecture No. 8) (1985) Radioactive Waste, Proceedings of the Wenty-first Annual Meeting held on April 3-4,1985 (includingTaylor Lecture No. 9) (1986) Nonionizing Electromagnetic Radiations and Ultrasound, Proceedings of the Twenty-second Annual Meeting held on April 2-3, 1986 (including Taylor Lecture No. 10) (1988) New Dosimetry at Hiroshima and Nagasaki and Its Implications for Risk Estimates, Proceedings of the Twenty-third Annual Meeting held on April 8-9, 1987 (including Taylor Lecture No. 11)(1988) Radon, Proceedings of the Twenty-fourth Annual Meeting held on March 30-31, 1988 (including Taylor Lecture No. 12) (1989) Radiation Protection Today-The NCRP at Sixty Years, Proceedings of t h e Twenty-fifth Annual Meeting held on April 5-6, 1989 (including Taylor Lecture No. 13) (1990) Health and Ecological Implications of Radioactively Contaminated Environments, Proceedings of the Twenty-sixth Annual Meeting held on April 4-5, 1990 (including Taylor Lecture No. 14) (1991) Genes, Cancer and Radiation Protection, Proceedings of the Twenty-seventh Annual Meeting held on April 3-4, 1991 (including Taylor Lecture No. 15) (1992) Radiation Protection in Medicine, Proceedings of the Twentyeighth Annual Meeting held on April 1-2, 1992 (including Taylor Lecture No. 16) (1993) Radiation Science and Societal Decision Making, Proceedings of the Twenty-ninth Annual Meeting held on April 7-8, 1993 (including Taylor Lecture No. 17) (1994)

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Lauriston S. Taylor Lectures No.

Title

1

The Squares of the Natural Numbers in Radiation Protection by Herbert M. Parker (1977) Why be Quantitative about Radiation Risk Estimates? by Sir Edward Pochin (1978) Radiation Protection-Concepts and Trade Offs by Hymer L. Friedell (1979) [Available also in Perceptions of Risk, see abovel From "Quantity of RadiationJ' and "Dose" to "Exposure" and "Absorbed DoseJ'-An Historical Review by Harold 0. Wyckoff (1980) How Well Can We Assess Genetic Risk? Not Very by James F. Crow (1981) [Available also in Critical Issues in Setting Radiation Dose Limits, see abovel Ethics, Trade-offs and Medical Radiation by Eugene L. Saenger (1982) [Available also in Radiation Protection and New Medical Diagnostic Approaches, see abovel The Human Environment-Past, Present and Future by Merril Eisenbud (1983) [Available also in Environmental Radioactivity, see above] Limitation and Assessment in Radiation Protection by Harald H. Rossi (1984) [Available also in Some Issues Important i n Developing Basic Radiation Protection Recommendations, see abovel Truth (and Beauty) in Radiation Measurement by John H. Harley (1985) [Available also in Radioactive Waste, see abovel Biological Effects ofNon-ionizing Radiations: Cellular Properties and Interactions by Herman P. Schwan (1987) [Available also i n Nonionizing Electromagnetic Radiations and Ultrasound, see abovel How to be Quantitative about Radiation Risk Estimates by Seymour Jablon (1988) [Available also in New Dosimetry at Hiroshima and Nagasaki and its Implications for Risk Estimates, see above] How Safe is Safe Enough? by Bo Lindell(1988) [Available also in Radon, see abovel Radiobiology and Radiation Protection: The Past Century and Prospects for the Future by Arthur C. Upton (1989) [Available also in Radiation Protection Today, see abovel Radiation Protection and the Internal Emitter Saga by

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J. Newel1 Stannard (1990) [Available also in Health and Ecological Implications of Radioactively Contaminated Environments, see abovel When is a Dose Not a Dose? by Victor P. Bond (1992) [Available also in Genes, Cancer and Radiation Protection, see abovel Dose and Risk in Diagnostic Radiology: How Big? How Little?by Edward W. Webster (1992)[Availablealso in Radiation Protection in Medicine, see above1 Science, Radiation Protection and the NCRP by Warren K. Sinclair (1993)[Available also in Radiation Science and Societal Decision Making, see abovel Mice, Myths and Men by R.J. Michael Fry (1995) Symposium Proceedings

No.

Title

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The Control of Exposure of the Public to Ionizing Radiation in the Event ofAccident or Attack, Proceedings of a Symposium held April 27-29, 1981 (1982) Radioactive and Mixed Waste-Risk as a Basis for Waste Classification, Proceedings of a Symposium held November 9, 1994 (1995)

NCRP Statements No.

Title

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"Blood Counts, Statement of the National Committee on Radiation Protection," Radiology 63, 428 (1954) "Statements on Maximum Permissible Dose from Television Receivers and Maximum Permissible Dose to the Skin of the Whole Body," Am. J. Roentgenol., Radium Ther. and Nucl. Med. 84, 152 (1960) and Radiology 75, 122 (1960) X-Ray Protection Standards for Home Television Receivers, Interim Statement of the National Council on Radiation Protection and Measurements (1968) Specification of Units of Natural Umnium and Natural Thorium, Statement of the National Council on Radiation Protection and Measurements (1973) NCRP Statement on Dose Limit for Neutrons (1980) Control of Air Emissions of Radionuclides (1984) The Probability That a Particular Malignancy May Have Been Caused by a Specified Irradiation (1992)

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Other Documents The following documents of the NCRP were published outside of the NCRP report, commentary and statement series: Somatic Radiation Dose for the General Population, Report of the Ad Hoc Committee of the National Council on Radiation Protection and Measurements, 6 May 1959, Science, February 19, 1960, Vol. 131, No. 3399, pages 482-486 Dose Effect Modifying Factors in Radiation Protection, Report of Subcommittee M-4 (Relative Biological Effectiveness) of the National Council on Radiation Protection and Measurements, Report BNL 50073 (T-471)(1967) Brookhaven National Laboratory (National Technical Information Service Springfield, Virginia) The following documents are now superseded andlor out of print:

NCRP Reports No.

Title X-Ray Protection (1931) [Superseded by NCRP Report No. 31 Radium Protection (1934) [Superseded by NCRP Report No. 41 X-Ray Protection (1936) [Superseded by NCRP Report No. 61 Radium Protection (1938) [Superseded by NCRP Report No. 131 Safe Handling of Radioactive Luminous Compound (1941) [Out of Print] Medical X-Ray Protection Up to Two Million Volts (1949) [Superseded by NCRP Report No. 181 Safe Handling of Radioactive Isotopes (1949) [Superseded by NCRP Report No. 301 Recommendations for Waste Disposal of Phosphorus-32 and Iodine-131 for Medical Users (1951) [Out of Print1 Radiological Monitoring Methods and Instruments (1952) [Superseded by NCRP Report No. 571 Maximum Permissible Amounts of Radioisotopes i n the Human Body and Muximum Permissible Concentrations in Air and Water (1953) [Superseded by NCRP Report No. 221 Recommendations for the Disposal of Carbon-14 Wastes (1953) [Superseded by NCRP Report No. 811

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Protection Against Radiations from Radium, Cobalt-60 and Cesium-137 (1954) [Superseded by NCRP Report No. 241 Protection Against Betatron-Synchrotron Radiations Up to 100 Million Electron Volts (1954) [Superseded by NCRP Report No. 511 Safe Handling of Cadavers Containing Radioactive Isotopes (1953) [Superseded by NCRP Report No. 211 Radioactive-Waste Disposal in the Ocean (1954) [Out of Print] Permissible Dose from External Sources of Ionizing Radiation (1954) including Maximum Permissible Exposures to Man, Addendum to National Bureau of Standards Handbook 59 (1958) [Superseded by NCRP Report No. 391 X-Ray Protection (1955) [Superseded by NCRP Report No. 261 Regulation of Radiation Exposure by Legislative Means (1955) [Out of Print] Protection Against Neutron Radiation Up to 30 Million Electron Volts (1957) [Superseded by NCRP Report No. 381 Safe Handling of Bodies Containing Radioactive Isotopes (1958) [Superseded by NCRP Report No. 371 Protection Against Radiations from Sealed Gamma Sources (1960) [Superseded by NCRP Reports No. 33,34 and 401 Medical X-Ray Protection Up to Three Million Volts (1961) [Superseded by NCRP Reports No. 33,34,35 and 361 A Manual of Radioactivity Procedures (1961) [Superseded by NCRP Report No. 581 Exposure to Radiation in a n Emergency (1962) [Superseded by NCRP Report No. 421 Shielding for High-Energy Electron Accelerator Installations (1964) [Superseded by NCRP Report No. 511 Medical X-Ray and Gamma-Ray Protection for Energies Up to 10 MeV-Equipment Design and Use (1968) [Superseded by NCRP Report No. 1021 Medical X-Ray and Gamma-Ray Protection for Energies Up to 10 MeV-Structural Shielding Design and Evaluation Handbook (1970) [Superseded by NCRP Report No. 491 Basic Radiation Protection Criteria (1971) [Superseded by NCRP Report No. 911 Review of the Current State ofRadiation Protection Philosophy (1975) [Superseded by NCRP Report No. 911 Natural Background Radiation in the United States (1975) [Superseded by NCRP Report No. 941 Radiation Protection for Medical and Allied Health Personnel (1976) [Superseded by NCRP Report No. 1051

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Review ofNCRPRadiation Dose Limit for Embryo and Fetus in Occupationally-Exposed Women (1977) [Out of Printl Radiation Exposure from Consumer Products and Miscellaneous Sources (1977) [Superseded by NCRP Report No. 951 A Handbook of Radioactivity Measurements Procedures, 1st ed. (1978) [Superseded by NCRP Report No. 58,2nd ed.1 Mammography (1980) [Out of Printl Recommendations on Limits for Exposure to Ionizing Radiation (1987) [Superseded by NCRP Report No. 1161

NCRP Commentaries No. 2

Title

Preliminary Evaluation of Criteria for the Disposal of Transuranic Contaminated Waste (1982) [Out of Printl

NCRP Proceedings No. 2

Title

Quantitative Risk in Standards Setting, Proceedings of the Sixteenth Annual Meeting held on April 2-3, 1980 [Out of Printl

Index Absorbed dose (Dl 110-112, 117, 119, 137, 140 for alphas 111 for electrons 111 for photons 111 rate 112 Absorption 32, 33, 36, 41, 81, 82, 86, 96, 99, 101, 107, 111, 139 A(t) 107, 139 functions 101 mechanisms 111 to blood 81, 99 Activity (A) 104, 112 Activity median aerodynamic diameter (AMAD)53, 137 Aerodynamic (equivalent) diameter (d.,) 51 Aerodynamic resistance diameter (d,) 52 Aerosol deposition 45, 60 Aerosols 3, 50, 82 density 82 particle size 82 shape 82 Age 27, 30, 104, 137, 140 Airflow rate 104 Airway 1, 22,40, 58,66, 90 branching 66 flow patterns 1 generations 22, 90 lumen 40 shapes 1 walls 58 Alpha particles 110 range 110 Alpha radiation 117 dose 117 Altitude 32 Altshuler formalism 58 Alveolar 16, 28, 44,47, 93 cells 93 macrophage 47 Alveolobronchiolar junctions 40

Ameboid motion 39 Anatomical lung model 57 Anatomy of the human respiratory tract 5, 6, 21, 24, 25, 28, 32, 50 alveoli 25 alveolar ducts 25 alveolar sacs 25 bronchioles 25 dead-space 21, 24, 28, 32 upper airways 6 Anesthesia 35 Annual reference levels 1 Anterior nasal areas 82, 86 clearance 82 Anxiety 49 ApicaI lobe 24 Aqueous media 81 Asthma 147 Atmospheric pressure 105, 137 Atomic numbers 86 Baboons 96 Basement membrane 12 Beagle dog 34, 86, 94 Becquerel (Bq) 139 Beta radiation 119 dose 119 Bifurcation angle 58 Bioassay measurements 2 80 Biological half-time (TB) Blood 9, 28, 32, 33, 41, 75, 76, 81, 93, 96, 107, 144 capillary 9 circulation 33, 93, 96 oxygenation 28 perfusing 76 transport 75 vessels 32 Body mass 28 Body size 30, 55, 104, 137 Boltzmam constant (m 67, 105 Branching angle 66, 67

INDEX

Breakpoints 139 Breathing cycle (mode) 30,59, 66, 82, 139 frequency 66 mode 82 Breathing rate 30, 90, 137 patterns 90 Bronchial asthma 48 Bronchial clearance 38, 44, 46, 90 epithelium 91 mucociliary transport 44 tissue 90 Bronchiolitis 44 Bronchoconstriction 45 Brownian motion 56 Cancer (neoplasm) 14, 15, 16, 17, 147 bronchioloalveolar adenomas 15 bronchioloalveolar carcinomas 15 fibrosarcoma 16 hemangiosarcoma 17 osteosarcomas 16 squamous cell carcinoma 17 risk 15 Carbon dioxide production 30 Cell membranes 40 Cells 11, 12, 13, 15, 44, 49 basal cells 12 brush cells 13 Clara cells 12, 15 endothelial cells 13, 15 glandular mucus cells 12 goblet cells 12, 44, 49 intermediate cells 12 interstitial cells 13 K cells 13 lymphocytes 13, 49 mast cells 13 neuroepithelial bodies 13 oncocytes 13 phagocytic cells 11 secretory cells 12 serous cells 12 squamous cells 13 Type 1cells 13 Type 11cells 12, 15

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Cells at risk 140 Chemical binding 82, 87, 96 structure 96 Chemical irritants 1, 2, 75, 77 reaction 77 reactivity 75 Chemically toxic substances 80, 111 Chemical composition 96 mixed 96 Cigarette smoking 16, 43, 84, 145 Ciliated epithelium 83 Clearance 32, 37, 40, 46, 81, 89, 90, 91, 96,104, 106, 144 bronchial clearance 37, 46 half-time 89, 91 long-term 144 mechanical 32 mucociliary 32 processes 32 rates 81, 96 times 90 to blood 104 Coal tar particles 144 Convection 73, 76 velocity 76 Count median diameter (CMD)53 Cunningham slip correction factor 67, 105 Cytotoxic material 41 Density 52, 59, 104, 137 Deposition of inhaled substances 50, 76 rate 76 Deposition mechanisms 55 Diesel exhaust particles 144 carbonaceous 144 Differential equations 107, 140 Diffusing capacity (COA 44 Diffusion 40, 52, 56, 60, 63, 66, 73, 76, 104, 105 coefficient 52, 63, 105 deposition mechanism 60 equivalent diameter 52 flux 73 gases 73, 76 passive 40

248

1

INDEX

Dissolution rate 32, 41, 81, 93, 101, 139 Donkeys 45 Dose rate conversion factors 110 Dosimetry 1,45,88, 91 dose 45 dose rate 45 modeling 88, 91 Dynamic viscosity coefficient 105 Effective particle clearance velocity 87 Elastic recoil 44 Electrostatic attraction 56 Emphysema 44 Endocytosis 40, 84 Endogenous ligands 33 Energy (Eo) 112, 139 Entrance configuration 67 Epithelial surface 88 Epithelium (ciliated) 9, 18 squamous epithelium 18 Escalator 40 mucus 40 Esophagus 83 Exercise 21, 38 Exhalation 105 Expectorating 88 Expiration 59, 68 Fecal excretion 97 Fibers 56, 84 Fiberoptic bronchoscopy 35 Fibrotic reactions 147 Fick's Law of Diffusion 69 Findeisen formalism 58 First order kinetic relationships 85 Flow rate 63 Fluid 35, 73 blanket 35 mechanics 73 pooling 35 resorption 35 Flux of gas 72, 75 Free particles 41, 44

Free radicals 148 Functional residual capacity (FRC) 27,66,137 Fused aluminosilicate particles (FAP) 93 Gallium oxide 144 Gamma camera imaging 36 Gas deposition 72, 74 Gas diffusivity 72 Gas exchange 13, 28 Gas-liquid boundary 72, 73, 75 interface 75 Gas-phase transport mechanisms 72 Gas-solid boundary 73 Gas transport 9, 58, 76 Gaseous state 69 Gases 70, 76, 78, 143 concentration 75 molecules 71 uptake 78 Gastrointestinal tract 81, 90 Geometrical (real) diameter 50, 60 Geometric mean 52 Geometric standard deviation 53 Gravitational force 55 Gray (Gy) 112, 139 Guinea pigs 95 Half-life 139 Half-time 34, 81 Health status 27 Henry's Law (H) 75, 78 Hilar nodes 41 Hilum 41 Human exposures 2, 94, 96, 101, 104,148 Human health risk assessment 80 Hydrophilic molecules 40 Hygroscopicity 56 Hypopharynx 34 Impaction 58, 59, 104 parameter 59

INDEX

Inertial impaction 55, 66 Inertial motion 74 Infectious pneumonia 48 Inhalability 53 Inhalation 105 Inhalation studies (humans) 93 Inhaled particles 1, 2, 21, 40, 48, 80, 81, 84, 111, 143 chemical toxicant 143 deposition 48 gases and vapors 1 nonradioactive substances 2 radioactive substances 1, 111 size 81 surface area 81 temperature treatment 8 1 Inhaled toxic materials 31, 85 chemicals 143 irritants 47 Inspiration 59, 68 Inspiratory flow rate 54 Insoluble particles 32, 33, 90, 94, 96 chemical forms 33 Inspiratory airflow 30 Inspirability 54, 139 Interception 56 Interspecies comparison 96 Iron oxide particles 94 Isotopes 85 51Cr (Teflon) 93 54MnC12(manganese chloride) 162 54Mn02(manganese dioxide) 162 57C00(cobalt oxide) 140, 164 @ C'o304 (cobalt oxide) 164 =Sr (fused aluminosilicate particles) 93 90Sr(fused aluminosilicate particles) 93 88Y (fused aluminosilicate particles) 93 T (fused aluminosilicate particles) 166 "Nbz(V)05 (niobium oxide) 95, 168 95Nb(niobium oxalate) 16, 168

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249

lo3Ru(mixed oxide) 170 137Cs(fused aluminosilicate particles) 172 137CsCl(cesium chloride) 86, 174 133BaS04(barium sulfate) 86, 176 133Ba(fused aluminosilicate particles) 177 140BaC12(barium chloride) 107, 140,175 l4LaCl3 (lanthanum chloride) 178 14*CeC13(cerium chloride) 86, 96, 140, 180 (fused aluminosilicate particles) 180 210PoC12(polonium chloride) 90, 182 2"U0. (uranium oxide) 90, 183 235UFf10zFz(uranium hexifluorideluranium dioxide difluoride) 183 2 3 8 P ~ (plutonium 02 dioxide) 186 239h02 (plutonium dioxide) 137, 140, 186 WSfi(N03)4 (plutonium nitrate) 186 239Pu (nitrate and citrate) 86 "lAmOz (americium dioxide) 101, 140, 188 24CmC13(curium chloride) 190 244Cm203 (curium dioxide) 190 244Cm(N03)3 (curium nitrate) 190 Isotropic specific absorbed fraction 112, 115, 119 cylindrical sources 119 line sources 119 planar sources 115 point sources 112

Kinetic processes 81 first order 81 Kinetic theory of gases 70 Knudsen number (K) 105

250

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INDEX

Lamina propria 13 Laminar flow 66,73 Larynx 8, 57, 77, 88 Lavaging 44 Lipophilicity 144 Liquid layer 76 Liver tumors 147 Log-!ogistic functions 59, 105 Lognormal distribution function 52 Long-term retention 91, 101 Lung 9, 22, 31, 32, 46, 66, 78, 80, 82, 96,104, 137,139, 144 clearance 96 disease 32 fluids 82 function 31 mass 139 mechanics 46 models 22, 66, 104, 137, 139 tissue 144 volume 66 ventilation 78 Lung cancer 16, 44 lifetime risk 44 Lymphatic nodes 40, 97, 107 system 40, 107 Lymphocytes 44 Lymphoid tissue 7, 11, 32, 41, 81, 84,107, 111 hilar area 11 cells 11 nodes 11, 81,107 pleura 11 vessels 32, 41, 84 Lysosomal vacuoles 147

Macrophage 39, 44,147 Macrophage transport 33 Magnetic resonance (MR) 18 cross-section 18 Magnetic resonance imaging (MRI) 18 Mass median diameter (MMD) 53 Mass stopping power 112 Mass transfer coefficient 74

Mathematical models 58, 85, 93 function 93 Maximum path length in tissues 119 Mean free path of air molecules 52, 105 Mechanical clearance 82, 85, 96, 107, 111, 139 M(t) 107, 139 for children 111 of particles 85 Mechanical processes 33, 47 clearance rate 47 Medical Internal Radiation Dose (MIRD) Committee 111 Mice 37, 94 Michaelis-Menton type kinetic 148 Model formulation 101 Molecular diffusion 73, 76 Molecular mass 79 Monodisperse aerosols 89, 90, 96 Morphometry of the human respiratory tract 5, 17, 22, 106 Type I cells 9 Type I1 cells 9 macrophage 9 Mouth 5,6, 31,57, 68, 104 breathing 5, 31, 68, 104 Mucociliary clearance 37, 39, 47, 104 function 37 mechanisms 92 transport 39 transport velocities 104 Mucosa 7 Mucus 9, 18, 33, 34, 35, 37, 39, 46, 76, 84, 88, 89 blanket 39 flow patterns 84, 88 glands 9 layer 34 secreting cells 76 thickness 89 transport 46 velocity 33, 37 Mucus-secreting epithelium 6, 7, 9

ciliated 7 goblet cells 9 Multiexponential function 42 Nasal absorption 86 Nasal airways 6, 15, 18, 20, 30, 33, 77, 86 cavity 15 passages 33, 77, 86 valve 20 Nasal breathing 68 Nasal deposition 59, 105 efficiency 59 Nasal hair 56 Nasal mucociliary transport 47, 86, 87 Nasal vestibule 86 turbinate 87 Nasal tumors 84, 87 cancers 87 Naso-oro-pharyngo-laryngeal region (NOPL) 5-8, 18, 28, 33, 49, 57, 63, 77, 85, 104, 111 nasal cilia 9 upper airways 6 Nasopharynx 7,33,57 Nervous system 11,12 Nitrogen oxide 76, 77 dioxide 76, 77 Nitropyrene 144 Nonradioactive materials 16, 43, 44, 47,143, 147 Benzo(a)pyrene (BaP) 143 leather 16 nickel 16 nitrogen dioxide 43 organic compounds 16 petroleum 16 sulfur dioxide 43, 44 vinyl chloride 43, 147 wood dust 16, 47 Nose 5, 6, 7, 18, 57, 60, 85, 104 breathing 5, 60, 104 nasal hairs 6 nasal valves 6 nostrils 6, 18, 85 septum 7

turbinate 7 vestibular area 6 Obstacles 35 Olfactory region 7, 18 Oral breathing 63, 139 Oral deposition 59 efficiency 59 Oral passage 21, 83, 87 cavity 83 lips, jaw, tongue, palate 21 Organic compounds 77, 78 acetone, formaldehyde, acrolein, etc. 77 krypton, radon, xenon, iodine, ruthenium tetroxide, uranium hexafluoride 78, 79 Oronasal breathing 6 Oropharynx 7, 35, 57 Ozone (0,)76 Particle deposition 44, 57 Partial pressure 75 of gas 75 Particle radius 56 Particles 32, 34, 43, 47, 50, 88, 92, 95, 96, 104, 137 clearance 47, 88, 92, 95 clearance efficiency 43 clearance velocity 34 density 104 deposition 47 diameter 104, 137 dissolution 96 insoluble 32 loading 40, 43 soluble 32 Particles size 32, 36, 37, 50, 90, 101 activity median aerodynamic diameter (AMAD) 32 aerodynamic diameter (AD) 36 mass median aerodynamic diameter (MMAD) 37 Particle transport 58, 90 clearance velocity 90

252

1

INDEX

Passive diffusion 71 Pause 63, 68, 137 Peclet number 73 Phagocytic cells 43 vessels 33 Phagocytosis 37, 84, 147 Pharynx 6, 77, 106 Pharyngeal clearance 88 Pharmacologic agents 49 Photon-emitting radiation 115 Pharmacokinetics 149 Physical activity 27, 30 exertion 60 Physicochemical from 81 Physiology 27, 44, 50 breathing frequency 27 functional residual capacity (FRC) 27 tidal volume 27 ventilation 27 Pinocytosis 84 Plastic dust 46 Pleural cavity 111 Pneumoconioses 48 Polystyrene particles 94 Posterior nasal airways 83, 86 region 86 Pressure drop 63 Projected area diameter 51 Proteolytic enzymes 44 Pulmonary clearance 47, 93 Pulmonary deposition 22 Pulmonary fibrosis 48 Pulmonary interstitium 40 Pulmonary (P) region 9, 10, 25, 28, 38, 57, 66, 78, 84, 92, 93, 97, 104,111, 115 acinus branches 9 alveolar sac 10 alveoli 9 bronchioles 9 cavity 115 macrophage 93 surfactant 9 terminals bronchioles 9 Rabbits 37, 89 Radiation 1, 3, 80, 110-113, 139 annual limits on intake 3

charged particles 110 dose 80 guidelines for workers 3 high-LET 110 low-LET 111 photons (gamma rays) 110 protection 2 type 139 workers 1 yield 139 Radioactive gases 72 Radioactive particles 35, 53, 80, 96, 104,144 inhaled 80, 144 specific activity 96 Radionuclides 1 barium (Ba) 37 radon (Rn) (progeny) 16 uranium (U) 16 Radiosensitivities 1 Rats 37, 86, 91, 94, 144, 148 Respiratory gas volume 27 expiratory reserve volume 27 functional residual capacity 27 inspiratory capacity 27 reserve volume 27 tidal volume 27 total lung capacity 27 vital capacity 27 Respiratory parameters 82 breathing frequency 82 residual air volume 82 Respiratory tract 1, 2, 3, 13, 30, 32,43, 68, 69, 70, 72, 73, 75, 76, 80, 81, 82, 84,96, 97, 144 bronchial region 2 bronchiolar region 2, 13 clearance 2, 32, 80, 82, 144 decay 97 deposition 1, 2, 68, 69, 70 dosimetry 2, 3, 97 mathematical models 2 pause 30 perfusion 32 retention 1, 2 secretion 75 tissues 8 1

INDEX

Respiratory tract model 1, 3, 83 default parameters 3 Resting minute ventilation 140 Sedimentation 55, 58, 66, 104 Silicone rubber cast 22 Simulation language 140 Siip correction factor 52 Smoking humans 32, 36,44, 90 nonsmoking humans 36,44 Soluble particles 32, 96 isotopes 86 materials 80 Specific absorbed fractions 111, 112, 113, 115, 116, 117, 119, 120-136 Spherical particle 50 Squamous epithelium 6, 7, 34 Stokes' diameter 51, 67 number 67 Sulfur dioxide (SO.,) 77 Surface area 96 Surface area median diameter (SAMD) 53 Surface tension gradients 39 Surfactant 12 Swallowing 88, 106 Syrian hamsters 86 Systemic absorption 81,93 circulation 93 Task Group on Lung Dynamics (TGLD) 82 Taulbee-Yu formalism 58 Teflon discs 35, 37, 89, 94 particles 89, 94 Temperature 49, 96, 105 treatment 96 Terminal settling velocity 52 Thoracic radioactivity 10, 97, 101 lymphatic system 10 retention 101 Tidal air 66 Tidal volume 63, 68, 128 Tissues a t risk 85, 111 Tobacco smoke 43, 142

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253

Tomography 17 Total lung capacity (TLC) 27. 66 Trachea 7, 21, 35, 63, 88 Tracheobronchial (TB) region 8, 21, 28, 34, 45, 49, 57, 66, 78, 84, 88, 90, 97, 104, 111 c-shaped cartilages 8 carina 9 smooth muscle 9 terminal bronchioles 8, 21 thoracic cavity 9 Transfer rate constants 95 Tube branching 66 Turbinate 20 inferior 20 medial 20 Turbulent flow 67, 72 Typical airway length 90 Typical Path Lung Model (TPLM) 22, 106 Ultrafine particles 60, 66, 72, 77, 104,137 aerosols 77 Unit density sphere 52,68 Uranium miners 16 Urinary excretion 93 Vapor-liquid partitioning 70 Vapors 70, 143 Velocity 20 airflow 20 Ventilation 30 Vital capacity 31 Vocal cords 34 Volume equivalent diameter 52 Water solubility 75, 78 Wind 54 direction 54 speed 54 tunnels 54 Xenobiotic agents 149 Yield per disintegration 112