Inhalation Studies: Foundations and Techniques

282 Pages·2008·4.37 MB·\282

by  Robert F. Phalen (Author)

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TOXICOLOGY
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about the book… nd

This significantly updated and expanded new edition presents the scientific foundations of
inhalation research essential to the design and conduct of toxicologic studies. It incorporates
Inhalation
I
the major advances that have been made in the field, including recent advances in biology and n
the rapidly increasing global concerns and studies on particulate air pollution.
h
The Second Edition was motivated by:
a
• new developments in the ultrafine particle health effects and concentrated
l
aerosol research a
• advances in understanding postnatal lung growth and the deposition and
t Studies
clearance of inhaled particles i
o
• new techniques in toxicity testing
• the explosion of knowledge in the genetic and molecular realms n
• the introduction of a large number of transgenic animal models
S
• updated ethical guidelines for animal testing
t
• the emergence of aerosol medicine u
• the growing threat of aerosol-related terrorism
d F & t
• increased appreciation of nonpulmonary effects of inhaled substances Foouundnadtioanstionesch niques
i
• use of medical scanning techniques to study respiratory tract structure e
• the introduction of new inhalation exposure systems
s
• the emergence of aerosol concentrators for use in air pollution studies

Second Edition
F and Techniques
about the author... o
u
Robert Phalen, Ph.D., co-directs the Air Pollution Health Effects Laboratory at the University of n
California, Irvine (UCI). He also holds two academic appointments in the College of Health d
Sciences at UCI: Professor in the Department of Community and Environmental Medicine; and a
t
Professor in the Department of Medicine’s Center for Occupational and Environmental Health. i Second Edition
o
He has served as Chair of both the UCI Institutional Review Board (for Human Studies) and the
n
Institutional Animal Care and Use Committee. He is currently a member of the United States s

Environmental Protection Agency’s Clean Air Scientific Advisory Committee—Particulate a
Material, and he is a member of 11 professional scientific associations/societies. n
d
In 1971, he obtained a Ph.D. in biophysics, with specialization in inhalation toxicology, from the

T
University of Rochester (in Rochester, NY). His postdoctoral research was conducted at the e
Inhalation Toxicology Research Institute (now the Lovelace Respiratory Research Institute) in c
Albuquerque, NM. In 1972, Dr. Phalen joined the then College of Medicine at UCI to establish h
the Air Pollution Health Effects Laboratory, which still conducts studies relating to the toxicology n
i
of air pollutants, and trains graduate students and physicians in inhalation toxicology. q
u
His research is in several areas including: predicting doses from inhaled particles; health effects e
of inhaled air pollutants; and applied aerosol physics. He has published over 100 scientific s
papers, and authored and/or edited four previous books on aerosol inhalation topics.
Printed in the United States of America P
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Robert F. Phalen
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Inhalation
Studies
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Inhalation
Studies
Foundations
and Techniques
Second Edition
by
Robert F. Phalen
School of Medicine
University of California, Irvine
Irvine, California, USA
Phalen_978-0849314001_TP.indd 2 9/15/08 9:51:23 AM
9780849314001-FM 8/28/08 2:12 PM Page ii
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Library of Congress Cataloging-in-Publication Data
Phalen, Robert F., 1940-
Inhalation studies: foundations and techniques / by Robert F. Phalen.
— 2nd ed.
p.; cm.
Includes bibliographical references and index.
ISBN-13: 978-0-8493-1400-1 (hardcover: alk. paper)
ISBN-10: 0-8493-1400-3 (hardcover: alk. paper)
1. Gases, Asphyxiating and poisonous—Toxicology—Research—Methodology.
2. Aerosols—Toxicology—Research—Methodology.
3. Air—Pollution—Toxicology—Research—Methodology. 4. Toxicology,
Experimental. I. Title.
[DNLM: 1. Air Pollutants—toxicity. 2. Aerosols—toxicity.
3. Inhalation Exposure—adverse effects. 4. Respiratory
System—physiopathology. WA 754 P534i 2008]
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Preface
The 1984 edition of Inhalation Studies: Foundations and Techniques was a success
because it presented essential information for inhalation toxicologists and other health pro-
fessionals. Prior to preparing the second edition, suggestions were received from a group
of anonymous reviewers. They were unified in recommending that the second edition
should both focus on the essentials, and update the key developments. The author has
learned to take the advice of reviewers.
In the years since the first edition was published, numerous scientific developments
have occurred. Some of the more important to those who perform inhalation studies are:
● the explosion of knowledge in the genetic and molecular realms,
● the introduction of a large number of transgenic animal models,
● the emergence of aerosol medicine,
● the increased threat of aerosol-related terrorism,
● the realization that low levels of ultrafine particles may have health effects,
● the increased appreciation of nonpulmonary effects of inhaled substances,
● the use of medical scanning techniques to study respiratory tract structure,
● the introduction of new inhalation exposure systems,
● the emergence of aerosol concentrators for use in air pollution studies,
● the application of computational fluid dynamics for modeling inhaled aerosols,
● the introduction of new devices for production and characterization of aerosols,
and
● the need for greater security for biomedical laboratories.
As this list is only a sampling of the relevant developments, this edition represents
a significant, as opposed to a minor, update. Several new sections, and hundreds of new
references have been added. Key older references and descriptions of early studies have
been preserved when they still have useful information or show the evolution of modern
concepts.
The topics covered are broad, representing dozens of specialties. The terminology,
symbols, and units of these specialties have been used without any attempt to harmonize
across all chapters.
Countless suggestions were offered by expert reviewers, including William Hinds,
Richard Mannix, Michael Kleinman, Kathryn Osann, and Melanie Fabian. Ms. Leslie Owens
iiiiii
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iv Preface
expertly word-processed and edited the book, and performed many administrative functions;
the author is eternally grateful for her dedication and expertise. Artists Tuan Nguyen,
Robert Olide, and Joshua Bracks contributed to the illustrations. Katherine Phalen checked
the references. Still, the author is solely responsible for inaccuracies and omissions.
This book was possible because of the efforts of scientists who published their work.
They are acknowledged with the deepest gratitude.
Finally, this book is dedicated to Kayla, Joseph, and Samuel, young children who did
not receive all of the attention they deserved from parents and grandparents who worked
on this book: May they have happy and prosperous futures.
Robert F. Phalen, Ph.D
March, 2008
9780849314001-FM 8/28/08 2:12 PM Page v
Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
1 Aerosols and Gases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
The Impact of Aerosols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Size Regimes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Aerosol Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
DIRECT OBSERVATION OF AEROSOL PARTICLES . . . . . . . . . . . . . . . . . . . 5
CIGARETTE SMOKE: A FAMILIAR AEROSOL SYSTEM . . . . . . . . . . . . . . 9
PARTICLE SIZE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
SIZE DISTRIBUTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
AEROSOL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Shape . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Density . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Electrical Charge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Mechanisms of Charging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Attraction of a Charged Particle to a Nearby Conductor . . . . . . . . . . . . . . 17
Charge Distributions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Decay Rate of Charges on Particles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Light Scattering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Hygroscopicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Surface Area . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
AEROSOL DYNAMICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Particle Motion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Gravitational and Buoyant Forces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
The Resistance or Drag Force . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Terminal Settling Velocities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Slip, or Cunningham’s Correction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Brownian Motion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Coagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
PARTICLE SIZE AND TOXICITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Particle Mass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
v
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vi Contents
Aerodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Surface Area . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Other Size-Dependent Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
PROPERTIES OF GASES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Movement from Air into Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Expressing Concentration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
2 The Respiratory Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
POSTNATAL DEVELOPMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
COMPARTMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
GROSS ANATOMY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Nose, Nasopharynx, and Larynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Tracheobronchial Tree . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Trachea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Bronchi and Bronchioles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Respiratory Bronchioles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Parenchyma or Pulmonary Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Subgross Lung Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
CELLS AND TISSUES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Ciliated Mucosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
The Alveolus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
The Macrophage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Mucus-Secreting Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Innervation of the Respiratory System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Bronchial Musculature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
VENTILATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Normal Breathing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Reflex Responses to Inhaled Irritants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
DEPOSITION OF INHALED PARTICLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Aerosol Deposition Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
UPTAKE OF INHALED GASES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
DEFENSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Proximal Airways’Clearance Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Mucociliary Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Alveolar Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
3 Establishing and Controlling Exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
CLEANING AND CONDITIONING THROUGHPUT AIR . . . . . . . . . . . . . . . 69
Contaminants in Supply Air . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Gas Cleaning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Removal of Water Vapor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
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Contents vii
Removal of Unwanted Pollutant Gases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Removal of Unwanted Particles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Air Purification and Conditioning Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
AEROSOL GENERATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Monodisperse Aerosols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Polydisperse Aerosols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Droplet Generators. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Dry Dust Generators. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
GAS GENERATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Common Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Compressed Gas Cylinders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Syringe Injectors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Vaporization and Sublimation Systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Permeation Tubes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Chemical and Physical Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
MIXED AEROSOLS AND GASES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
PRINCIPLES FOR STABILIZING THE EXPOSURE ATMOSPHERE . . . . . . 89
Generator Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Exposure System Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Real-Time Adjustments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
4 Characterizing Exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
THE BREATHING ZONE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
WHAT SHOULD BE MEASURED? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Particle Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Gas Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Environmental Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
INSTRUMENTATION FOR AEROSOL CHARACTERIZATION . . . . . . . . . . 96
Comment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Sampling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Size Analyzers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Isokinetic Sampling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
INSTRUMENTATION FOR GAS CHARACTERIZATION . . . . . . . . . . . . . . . 103
ELIMINATING MEASUREMENT INTERFERENCES . . . . . . . . . . . . . . . . . . 105
General Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Gas/Vapor Denuders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
SAMPLING PROTOCOLS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
5 Methods for Exposing Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
BASIC TYPES OF EXPOSURE SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Chamber Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Head-Only Exposure Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Nose- or Mouth-Only Exposure Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Lung and Partial Lung Exposure Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Intratracheal Instillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129