Toxicology of Inhaled Materials: General Principles of Inhalation Toxicology PDF
Preview Toxicology of Inhaled Materials: General Principles of Inhalation Toxicology
Handbook of Experimental Pharmacology Continuation of Handbuch der experimentellen Pharmakologie Vol. 75 Editorial Board G.Y. R.Born,London· A.Farah,Rensselaer,NewYork H. Herken, Berlin' A. D. Welch, Bethesda, Maryland Advisory Board S. Ebashi . E. G. Erdos' V. Erspamer . U. S. von Euler· W S. Feldberg G. B. Koelle' M. Rocha e Silva· J. R. Vane' P. G. Waser Toxicology of Inhaled Materials General Principles of Inhalation Toxicology Contributors I.y. R. Adamson' B. D. Beck' M. R. Becklake . J. D. Brain 1. D. Crapo' R. T. Drew' D. L. Dungworth . A. B. Fisher T. E. Gram' P. 1. Hakkinen . 1. A. Last· M. Lippmann M. G. Mustafa' K. E. Pinkerton' C. E. Plopper . K. M. Reiser S. A. Rooney· B. T. Smith' J. M. Sturgess' W. S. Tyler P. A. Valberg . H. P. Wits chi Editors . H. P. Witschi and 1. D. Brain Springer-Verlag Berlin Heidelberg New York Tokyo IiANSPETER WITSCHI, M.D. Section Head, Toxicology, Biology Division, Oak Ridge National Laboratory, P.O. Box Y, Oak Ridge, TN 37831, USA JOSEPH D. BRAIN, S.D. in Hyg. Professor of Physiology, Director, Respiratory Biology Program, Department of Environmental Science and Physiology, Harvard University School of Public Health, 665 Huntington Ave., Boston, MA 02115, USA With 80 Figures ISBN -13 : 978-3-642-69523-0 e-ISBN -13 : 978-3-642-69521-6 001: 10.1007/978-3-642-69521-6 Library of Congress Cataloging in Publication Data. Main entry under title: Toxicology of inhaled materials. (Handbook of eXJ?Clrimental pharmacology; vol. 75) Bibliography: p. I. Aerosols-Toxicology. 2. Gases, Asphyxiating and poisonous. 3. Toxicology, Experimental. I. Adamson, I. Y. R. II. Witschi, Hanspeter. III. Brain, Joseph D. IV. Series: Handbook of experimental pharmacology; v. 75. [DNLM: I. Environmental Pollutants-toxicity. 2. Respiratory Tract Diseases-chemically induced. 3. Toxicology. WI HA51L v. 75fWA 671 T755] QP905.H3 vol. 75 615'.ls [615.9'11 ~4-20202 [RA1270.A341 ISBN-13 : 978-3-642-69523-0 (U.S.) This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying machine or similar means, and storage in data banks. Under § 54 of the German Copyright Law where copies are made for other than private use, a fee is payable to "Verwertungsgesellschaft Wort", Munich. © by Springer-Verlag Berlin Heidelberg 1985 Softcover reprint of the hardcover 1st edition 1985 The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a st'ecific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product Liability: The publisher can give no guarantee for information about drug dosage and' application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. 2122/3130-543210 List of Contributors I. Y. R. ADAMSON, Department of Pathology, Faculty of Medicine, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba, Canada, R3E OW3 B. D. BECK, Department of Environmental Science and Physiology, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA M. R. BECKLAKE, pepartment of Epidemiology and Health, McGill University, 3775 University Street, Montreal, Quebec, Canada H3A 2B4 J. D. BRAIN, Director, Respiratory Biology Program, Department of Environmental Science and Physiology, Harvard University School of Public Health, 665 Huntington Avenue, Boston, MA02115, USA J.D. CRAPO,. Department of Medicine, Chief, Division of Allergy, Critical Care and Respiratory Medicine, Duke University Medical Center, P.O. Box 3177, Durham, NC 27710, USA R. T. DREW, Medical Department, Brookhaven National Laboratory, Associated Universities, Inc., Upton, L.I., NY 11973, USA D. L. DUNGWORTH, School of Veterinary Medicine, Department of Pathology, University of California, Davis, CA 95616, USA A. B. FISHER, University of Pennsylvania, Department of Physiology, School of Medicine, G-4, 37th & Hamilton Walk, D-404 Richards Bldg., Philadelphia, PA 19104, USA T. E. GRAM, Head, Biochemical Toxicology Section, Laboratory of Medicinal Chemistry and Pharmacology, National Cancer Institute, National Institutes of Health, Bldg. 37, Rm. 6D-28, Bethesda, MD 20205, USA P. J. HAKKINEN, University of Tennessee-Oak Ridge Graduate SchooL of Biomedical Sciences and Biology Division, Oak Ridge National Laboratory, Oak Ridge, TN 37830, USA Present address: The Procter & Gamble Company, Sharon Woods Technical Center, Cincinnati, OH 45241, USA VI List of Contributors J. A. LAST, Department of Internal Medicine, Division of Pulmonary Medicine and California Primate Research Center, University of California, Davis, CA 95616, USA M. LIPPMANN, Department of Environmental Medicine, Institute of Environmental Medicine, New York University Medical Center, 550 First Avenue, New York, NY 10016, USA M. G. MUSTAFA, Division of Environmental and Occupational Health Sciences, School of Public Health, and Division of Pulmonary Disease, Department of Medicine, University of California, Los Angeles, CA 90024, USA K.E. PINKERTON, Department of Pathology, Duke University, Medical Center, P.O. Box 3177, Durham, NC 27710, USA C.E. PLOPPER, Department of Anatomy and California Primate Research Center, University of California, Davis, CA 95616, USA K. M. REISER, Department of Internal Medicine, Division of Pulmonary Medicine and California Primate Research Center, University of California, Davis, CA 95616, USA S. A. ROONEY, Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, P.O. Box 3333, New Haven, CT 06510, USA B. T. SMITH, Joint Program in Neonatology, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA J. M. STURGESS, Warner-LambertJParke-Davis Research Institute, 2270 Speakman Drive, Sheridan Park, Mississauga, Ontario, Canada, L5K IB4 W. S. TYLER, Department of Anatomy and California Primate Research Center, University of California, Davis, CA 95616, USA P. A. VA LBERG, Department of Environmental Science and Physiology, Harvard University School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA H. P. WITscm, Biology Division, Oak Ridge National Laboratory, P.O. Box Y, Oak Ridge, TN 37831, USA Preface This book deals with the methods and scientific basis of inhalation toxicology. It describes devices and facilities needed to expose animals to inhaled particles and gases as well as approaches to estimating or measuring the fraction of the inhaled material that is retained in the respiratory tract. The book then reviews the evergrowing repertoire of techniques that can be used to measure the responses elicited by the exposure. Quantitative and qualitative anatomical, physiological, and biochemical strategies are discussed in detail. We believe that the toxicology of inhaled materials is an important and timely topic for several'reasons. During the past decade, morbidity and mortality attributable to cardiovascular disease have significantly decreased. Progress in combatting cancer, the second most important cause of death, has been slower, and lung cancer actually became the leading cause of death in men and the second leading cause of cancer death in women. In addition, the incidence of non-neo- plastic respiratory diseases such as emphysema, fibrosis, and chronic bronchitis has increased the past decade. In the United States, the National Institutes of Health (NIH) has recently reported that chronic obstructive pulmonary disease affects nearly 10 miliion persons and accounts for 59,000 deaths yearly; indeed, it ranks as the fifth leading cause of death. Because the incidence is increasing, the NIH estimates that it may become the nation's fourth or even third leading cause of death by the year 2000. There is increasing awareness that this rising incidence in respiratory diseases is attributable to the inhalation of particles and gases in urban and work environments and especially to the use of tobacco products. Pulmonary diseases are of concern because they are difficult to treat and because they frequently manifest themselves only after decades of apparently innocuous exposure. For these reasons, the science of inhalation toxicology has emerged as an important specialty. The development of methods that permit the study of human respiratory disease experimentally in animals has gained importance, especially because of increasing concern about environmental lung disease. A consideration of the biological issues also makes it apparent that the science of inhalation toxicology is an important one. The lungs have a unique proximity to the environment not shared by other organs of the body. The same thinness and delicacy that make the air-blood barrier ideal for the efficient exchang~, of oxygen and carbon dioxide reduce its effectiveness as a barrier to inhaled toxic particles and gases. Adults, depending on their size and physical activity, move from 10,000 to 20,000 liters of air daily in and out of their lungs. Inspired air frequently contains particles and gases which are hazardous. Among the purp.oses of this VIII Preface book are to describe various techniques that are used to expose animals to aerosols characteristic of the environment and to explore the diverse physiological and pathological mechanisms which take place as inhaled particles and gases interact with the respiratory tract and the body. Particular emphasis has been placed on quantitative methods that can be used to assess the eventual damage caused in pulmonary tissue by such agents. It is our hope that a better understanding of these mechanisms of lung injury will ultimately permit the design of more effective strategies to prevent and ameliorate respiratory diseases. When we accepted the invitation to edit a handbook on The Toxicology of Inhaled Materials, we were aware of the magnitude of the task. To cover the whole field in detail would be difficult. However, we were convinced it would be extremely valuable to bring together the experience of many different experts. We hope that their collective wisdom will help crystallize the present state of knowledge and facilitate the entry of scientists who want to begin work in this area. The substantial increase in the number and variety of approaches in inhalation toxicology makes it all the more critical that work in this field be evaluated in a comprehensive way. It has been our aim, therefore, to assist scientists in assimilating and evaluating a rapidly growing body of knowledge; thus, the book is intended to be both scholarly and practical. After careful consideration of each major area, we recruited authors who could summarize each topic and anticipate new directions of study. Each contributor has identified central issues against the context of a broad core of published papers. No obligation was felt to mention all the existing literature in the field; rather, the authors were encouraged to be selective. It is our hope that this book will be a chronicle of significant past work, a ~timulus for their rapid and thoughtful application, and a guide for future work. We are indebted to all the authors for their outstanding contributions. HANSPETER WITSClll JOSEPH D. BRAIN Contents Exposure Techniques CHAPTER 1 The Design and Operation of Systems for Inhalation Exposure of Animals R. T. DREW. With 6 Figures A. Introduction . 3 B. Design ...... . 3 I. Facilities . . . 3 II. Simple Systems 4 III. Current Chamber Design . 5 IV. Rooms as Chambers. . 7 V. Isolation Systems ... 8 VI. General Design Features 8 C. Operation . . . . . . 9 I. Static Systems. . . . . 9 II. Dynamic Systems . . . 10 III. Chamber Concentration 11 IV. Airflow . . . . . . . 12 V. Static Pressure . . . . 12 VI. Temperature and Humidity . 13 VII. Exposure Duration 13 VIII. Noise . . . . . 13 IX. Animal Loading. . 14 X. Cages and Racks . 14 D. Limited Exposure Systems 15 E. Summary 18 References. . . . . . . . . 18 CHAPTER 2 Gases and Vapors: Generation and Analysis. M. LIPPMANN With 11 Figures A. Introduction ....... . 23 B. Generation and Atmospheres . 25 I. Static Systems . . 25 II. Dynamic Systems. . . . 27 x Contents C. Monitoring and Control of Concentrations 30 I. Basic Considerations in Monitoring 31 II. Control of Concentration 32 III. Types of Monitors . 33 D. Sampling and Analysis. . 44 I. Sampling Procedures 44 II. Sampling Train. . . 51 III. Analysis of Gases and Vapors 51 E. Calibration and Record Keeping 51 I. Calibration Techniques 51 II. Data Handling 54 F. Summary 55 References. . . . . . 55 CHAPTER 3 Determination of Retained Lung Dose. P. A. VALBERG. With 5 Figures A. General Principles. . . . . . 57 I. Types of Aerosols. . . . . . . . 57 II. Description of the Aerosol . . . . 60 III. Characterization of Retained Dose 63 B. Predicting Dose from Exposure: Determining Factors 64 I. Deposition as Related to Particle Properties 65 II. Pattern of Ventilation . . . 70 III. Respiratory Tract Anatomy 72 IV. Effect of Disease and Age . 72 V. Models of Lung Deposition 73 C. Dose by Measurement of Inspired and Expired Aerosol 75 I. Mass Balance Measurement 75 II. Within-Breath Analysis . . . 75 D. Infectious Particles . . . . . . . 75 E. Techniques Utilizing Radioactivity 76 I. Radiopacity . . . . . . . . 76 II. Whole Body Counting. . . . 76 III. Collimated Detectors and Gamma Cameras 76 IV. Tissue. Samples and Dissection 77 F. Morphological Methods . . . . . 82 I. Measurement at Autopsy. . . 82 II. Light and Electron Microscopy 82 III. Morphometry . . . . . . . 82 G. Magnetopneumography . . . . . 83 I. Retention from Occupational Exposure 83 II. Measurement of Lung Clearance . . . 83 III. Particle Environment Measurements: "Relaxation" 83 H. Tomography: The Imaging Problem. . . . . . . 84 I. Computed X-Ray Transmission Tomography. 84 II. Emission Tomography: ')I-Ray and Positron. 84 III. Nuclear Magnetic Resonance . 84 References. . . . . . . . . . . . . . . . . . . 85 Contents XI General Assessment of Toxic Effects CHAPTER 4 Animal Models. P. J. HAKKINEN and H. P. WITscm A. Introduction . . . . . . . . . . . . . . . 95 B. Advantages and Disadvantages of Different Species 96 I. Mice ... 96 II. Rats. . . 98 III. Hamsters . 100 IV. Rabbits . 101 V. Guinea Pigs 102 VI. Dogs 103 VII. Cats .... 104 VIII. Sheep . . . 104 IX. Horses and Donkeys . 105 X. Goats . 105 XI. Pigs ....... . 105 XII. Cattle '. . . . . . . 106 XIII. Nonhuman Primates. 106 C. Conclusions 106 References. 107 CHAPTER 5 Epidemiologic Studies in Human Populations. MARGARET R. BECKLAKE A. Introduction . . . . . . . . . . . . . . . . . . . . . .. 115 B. Scope . . . . . . . . . . . . . . . . . . . . . . . . " 115 C. Uses of Epidemiology in the General Assessment of the Toxic Effects ofInhaled Materials. . . . . . . . . . . . 117 D. Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . 117 E. Epidemiologic Studies in Human Populations. . . . . . . . . . . 119 I. Definitions, Some Basic Concepts, and the General Assessment of a Problem. . . . . . . . . 119 II. The Elements of a Planned Study 120 F. Design. . . . . . . . . . . 122 I. Experimental Designs . . 122 II. Nonexperimental Designs 123 G. Types of Survey 123 H. Population. . 126 J. Variables 127 K. Measurement. . 129 I. Health Measurements 129 II. Measurements Underlying the Expos~re Variable 133 L. Analysis and Inference. . . . . . . . . . . . . . 135 M. Uses of Epidemiologic Studies in the General Assessment of Toxic Effects of Inhaled Agents 136 I. Identification. . . . . . . . . . . . . . . . . . . . . . . 136
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