Inhalation studies : foundations and techniques

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 the major advances that have been made in the field, including recent advances in biology and the rapidly increasing global concerns and studies on particulate air pollution.

The Second Edition was motivated by:

new developments in the ultrafine particle health effects and concentrated aerosol research advances in understanding postnatal lung growth and the deposition and clearance of inhaled particles new techniques in toxicity testing the explosion of knowledge in the genetic and molecular realms the introduction of a large number of transgenic animal models updated ethical guidelines for animal testing the emergence of aerosol medicine the growing threat of aerosol-related terrorism increased appreciation of nonpulmonary effects of inhaled substances 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

Author Notes

Robert Phalen, Ph.D., co-directs the Air Pollution Health Effects Laboratory at the University of California, Irvine (UCI)

Preface	p. iii
Introduction	p. xi
1 Aerosols and Gases	p. 1
Introduction	p. 1
The Impact of Aerosols	p. 1
Size Regimes	p. 2
Aerosol Terminology	p. 4
Direct Observation of Aerosol Particles	p. 5
Cigarette Smoke: A Familiar Aerosol System	p. 9
Particle Size	p. 10
Size Distributions	p. 11
Aerosol Properties	p. 13
Shape	p. 13
Density	p. 15
Electrical Charge	p. 16
Mechanisms of Charging	p. 16
Attraction of a Charged Particle to a Nearby Conductor	p. 17
Charge Distributions	p. 18
Decay Rate of Charges on Particles	p. 18
Light Scattering	p. 19
Hygroscopicity	p. 20
Surface Area	p. 20
Aerosol Dynamics	p. 21
Particle Motion	p. 21
Gravitational and Buoyant Forces	p. 22
The Resistance or Drag Force	p. 22
Terminal Settling Velocities	p. 23
Slip, or Cunningham's Correction	p. 23
Brownian Motion	p. 25
Coagulation	p. 26
Particle Size and Toxicity	p. 26
Particle Mass	p. 26
Aerodynamic Properties	p. 27
Surface Area	p. 28
Other Size-Dependent Factors	p. 28
Properties of Gases	p. 29
Movement from Air into Tissues	p. 29
Expressing Concentration	p. 30
Solubility	p. 32
2 The Respiratory Tract	p. 33
Introduction	p. 33
Postnatal Development	p. 34
Compartments	p. 35
Gross Anatomy	p. 37
Overview	p. 37
Nose, Nasopharynx, and Larynx	p. 37
Tracheobronchial Tree	p. 41
Trachea	p. 41
Bronchi and Bronchioles	p. 41
Respiratory Bronchioles	p. 45
Parenchyma or Pulmonary Region	p. 47
Subgross Lung Types	p. 47
Cells and Tissues	p. 49
Ciliated Mucosa	p. 49
The Alveolus	p. 49
The Macrophage	p. 52
Mucus-Secreting Glands	p. 53
Innervation of the Respiratory System	p. 54
Bronchial Musculature	p. 54
Ventilation	p. 54
Normal Breathing	p. 54
Exercise	p. 57
Reflex Responses to Inhaled Irritants	p. 58
Deposition of Inhaled Particles	p. 59
Introduction	p. 59
Aerosol Deposition Models	p. 59
Uptake of Inhaled Gases	p. 62
Defenses	p. 65
Introduction	p. 65
Proximal Airways' Clearance Mechanisms	p. 65
Mucociliary Clearance	p. 66
Alveolar Clearance	p. 66
3 Establishing and Controlling Exposures	p. 69
Introduction	p. 69
Cleaning and Conditioning Throughput Air	p. 69
Contaminants in Supply Air	p. 69
Gas Cleaning	p. 70
Removal of Water Vapor	p. 70
Removal of Unwanted Pollutant Gases	p. 71
Removal of Unwanted Particles	p. 72
Air Purification and Conditioning Systems	p. 73
Aerosol Generation	p. 78
General Considerations	p. 78
Monodisperse Aerosols	p. 78
Polydisperse Aerosols	p. 81
Droplet Generators	p. 81
Dry Dust Generators	p. 83
Gas Generation	p. 85
General Considerations	p. 85
Common Techniques	p. 86
Compressed Gas Cylinders	p. 86
Syringe Injectors	p. 87
Vaporization and Sublimation Systems	p. 87
Permeation Tubes	p. 87
Chemical and Physical Reactions	p. 87
Mixed Aerosols and Gases	p. 88
Principles for Stabilizing the Exposure Atmosphere	p. 89
Generator Stability	p. 89
Exposure System Stability	p. 89
Real-Time Adjustments	p. 90
4 Characterizing Exposures	p. 93
Introduction	p. 93
The Breathing Zone	p. 93
What Should be Measured?	p. 94
Particle Parameters	p. 94
Gas Parameters	p. 94
Environmental Parameters	p. 95
Instrumentation for Aerosol Characterization	p. 96
Comment	p. 96
Sampling	p. 97
Size Analyzers	p. 99
Isokinetic Sampling	p. 103
Instrumentation for Gas Characterization	p. 103
Eliminating Measurement Interferences	p. 105
General Principles	p. 105
Gas/Vapor Denuders	p. 106
Sampling Protocols	p. 107
5 Methods for Exposing Subjects	p. 109
Introduction	p. 109
Basic Types of Exposure Systems	p. 111
Chamber Systems	p. 111
Head-Only Exposure Systems	p. 123
Nose- or Mouth-Only Exposure Systems	p. 126
Lung and Partial Lung Exposure Systems	p. 127
Intratracheal Instillation	p. 129
Aging the Atmosphere	p. 129
Ammonia as a Contaminant	p. 130
Determination of the Inhaled Dose	p. 132
Ethical Responsibilities of the Investigators	p. 133
6 Testing for Toxicity	p. 135
Introduction	p. 135
Quantitation	p. 136
Anatomical Considerations	p. 136
Respiratory Tract Regions and Common Diseases	p. 136
Extrathoracic (Head) Airways	p. 136
Tracheobronchial Airways	p. 137
Pulmonary (Gas Exchange) Airways	p. 138
Morphologic Evaluations	p. 139
Morphometry	p. 141
Pulmonary Function	p. 143
Other Endpoints	p. 146
Pulmonary Defense	p. 146
Lung Development	p. 147
Behavior	p. 148
Biochemical	p. 150
Normal Lung Biochemistry	p. 150
Lung Lavage	p. 151
Detoxification, Activation	p. 151
Extrapulmonary Responses	p. 152
Controls	p. 152
Batteries of Endpoints	p. 153
7 Experimental Designs	p. 155
Introduction	p. 155
Basic Statistical Considerations	p. 155
Two Types of Statistics	p. 155
Type 1 and Type 2 Errors in Hypothesis Testing	p. 156
Some Tests of Significance	p. 157
Group Size	p. 160
The Role of the Statistician	p. 161
Examples of Common Designs	p. 162
Acute Exposures/Dose-Response Relationships	p. 162
Repeated Exposures/Dose Fractionation	p. 164
Chronic Exposures/Carcinogenesis, Mutagenesis, and Teratogenesis	p. 165
Chronic Exposures	p. 165
Carcinogenicity	p. 166
Mutagenicity	p. 167
Teratogenicity	p. 168
Multicomponent Atmospheres	p. 169
8 Facilities and Support Considerations	p. 173
Introduction	p. 173
Facilities Components	p. 174
Laboratory Buildings	p. 174
Exposure Systems	p. 174
Animal Housing	p. 176
Necropsy	p. 178
Data Handling	p. 179
Analytical Support	p. 180
Toxicity Testing	p. 181
Shop Support	p. 182
Conference, Library, and Office Space	p. 184
Facilities Location	p. 185
9 Animal Models	p. 187
Introduction	p. 187
General Considerations	p. 187
Models of Human Diseases	p. 188
Extrapolation from Laboratory Animals to Humans	p. 191
Comparative Dose Distribution	p. 195
Dose and Dose Variability	p. 195
Comparative Minute Ventilation Per Unit Body Mass	p. 198
Comparative Physiology and Anatomy	p. 199
Comparative Pulmonary Function	p. 199
Comparative Airway Anatomy	p. 200
Common Laboratory Animal Models	p. 208
Dogs	p. 208
Ferrets	p. 208
Nonhuman Primates	p. 211
Horses	p. 211
Bovids	p. 212
Rodents	p. 212
Other Mammals	p. 213
10 Regulations and Guidelines	p. 215
Introduction	p. 215
Guidelines Versus Regulations	p. 218
Protection of Laboratory Personnel	p. 218
Protection of Research Subjects	p. 219
Human Subjects	p. 219
Laboratory Animal Subjects	p. 223
Inhalation Toxicity Testing Guidelines	p. 225
References	p. 229
Index	p. 259

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Summary

Summary

Author Notes

Table of Contents