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CASARETT AND DOULLS


TOXICOLOGY

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T B S P
HE ASIC CIENCE OF OISONS

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EDITOR
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Curtis D. Klaassen, Ph.D.


Professor of Pharmacology and Toxicology
Department of Pharmacology, Toxicology, and Therapeutics
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University of Kansas Medical Center


Kansas City, Kansas
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McGraw-Hill
MEDICAL PUBLISHING DIVISION
New York Chicago San Francisco Lisbon London Madrid Mexico City Milan
New Delhi San Juan Seoul Singapore Sydney Toronto

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NOTICE

Medicine is an ever-changing science. As new research and clinical experience


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broaden our knowledge, changes in treatment and drug therapy are required. The au-
thor and the publisher of this work have checked with sources believed to be reliable
in their efforts to provide information that is complete and generally in accord with
the standards accepted at the time of publication. However, in view of the possibil-
ity of human error or changes in medical sciences, neither the author nor the pub-
lisher nor any other party who has been involved in the preparation or publication of
this work warrants that the information contained herein is in every respect accurate
or complete, and they disclaim all responsibility for any errors or omissions or for
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the results obtained from use of the information contained in this work. Readers
are encouraged to confirm the information contained herein with other sources. For
example and in particular, readers are advised to check the product information sheet
included in the package of each drug they plan to administer to be certain that the
information contained in this work is accurate and that changes have not been made
in the recommended dose or in the contraindications for administration. This recom-
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mendation is of particular importance in connection with new or infrequently used


drugs.
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CASARETT AND DOULLS TOXICOLOGY: THE BASIC SCIENCE OF POISONS
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Copyright 2001, 1996, 1991, 1986, 1980, 1975, by The McGraw-Hill Companies, Inc. All rights reserved. Printed in the United States of
America. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in
any form or by any means, or stored in a data base or retrieval system, without the prior written permission of the publisher.

1234567890 DOW DOW 0987654321


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ISBN 0-07-134721-6

This book was set in Times Roman by TechBooks, Inc.


The editors were Andrea Seils, Susan R. Noujaim, and Lester A. Sheinis.
The production supervisor was Richard C. Ruzycka.
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The text designer was Marsha Cohen/Parallelogram.


The cover designer was Janice Bielawa.
The indexer was Barbara Littlewood.
R.R. Donnelley & Sons Company was printer and binder.
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This book is printed on acid-free paper.

Library of Congress Cataloging-in-Publication Data is on file for this title at the Library of Congress.

INTERNATIONAL EDITION ISBN 0-07-112453-5


Copyright 2001. Exclusive rights by The McGraw-Hill Companies, Inc., for manufacture and export. This book cannot
be reexported from the country to which it is consigned by McGraw-Hill. The International Edition is not available in
North America.

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This edition of the textbook is dedicated to the memory of Dr. Mary Dr. Amdur made these accomplishments at a time in which
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Amdur, who was a coeditor on editions two through four. science was strongly male-dominated. Her research career was im-
Mary Amdur received her B.S. in Chemistry from the Uni- paired by a number of barriers, because of this environment (Costa
versity of Pittsburgh in 1943, and, in just three years, was awarded and Gordon, Toxicol Sci, 56: 57, 2000). In fact, she never was
the Ph.D. in Biochemistry from Cornell. She spent her academic awarded a tenure position at any of the three academic positions
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career at the Harvard School of Public Health (19491977), Mass- where she did her outstanding research.
achusetts Institute of Technology (19771989), and the Institute of Dr. Amdur received a number of awards throughout her ca-
Environmental Medicine of New York University in Tuxedo Park, reer. These included the 1974 Donald E. Cummings Memorial
New York (19891996). She died in February 1998 while flying Award from the American Industrial Hygiene Association, the
home from a vacation in Hawaii. 1984 Henry F. Smyth Award from the American Academy of In-
Dr. Amdur was a distinguished toxicologist in the area of air dustrial Hygiene, the 1986 Career Achievement Award from the
pollution. Her research accomplishments provided seminal contri- Inhalation Section of the Society of Toxicology, and the 1989
butions to our understanding of the effects of gases and particles Herbert E. Stockinger Award from the American Conference of
on human and animal lungs. She contributed to our knowledge of Governmental Industrial Hygienists. In 1997, she became the
the adverse effects of sulfuric acid mists and mixtures of gases and first woman to receive the Merit Award from the Society of Tox-
particles in the lung. This work had a major role in the establish- icology.
ment of national and international air pollution standards. Her ca- For those of us who were fortunate to work with Mary Am-
reer in toxicology was uniquely distinguished and profound in its dur, we will remember not only her scientific accomplishments but
impact on public policy and public health. also her wit, demeanor, and absolute honesty.

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Copyright 2001 by The McGraw-Hill Companies Retrieved from: www.knovel.com
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CONTRIBUTORS

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Daniel Acosta, Jr., Ph.D. John T. Brandt, M.D.

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Dean and Professor Senior Clinical Research Pathologist
College of Pharmacy Eli Lilly and Company
University of Cincinnati Indianapolis, Indiana
Cincinnati, Ohio Chapter 11
Chapter 18

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James V. Bruckner, Ph.D.
Todd A. Anderson, Ph.D. Professor of Pharmacology and Toxicology
Assistant Section Leader College of Pharmacy
The Institute of Environmental and Human Health (TIEHH) University of Georgia
Associate Professor, Department of Environmental Toxicology Athens, Georgia
Texas Tech dM Chapter 24
Lubbock, Texas
Chapter 29 George A. Burdock, Ph.D., D.A.B.T.
Burdock and Associates, Inc.
Douglas C. Anthony, M.D., Ph.D. Vero Beach, Florida
Associate Professor of Pathology Chapter 30
Harvard Medical School
Department of Pathology Leigh Ann Burns-Naas, Ph.D.
Childrens Hospital Senior Toxicology Specialist
Boston, Massachusetts Health, Environmental, and Regulatory Affairs
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Chapter 16 Dow Corning Corporation


Midland, Michigan
Robert J. Baker, Ph.D. Chapter 12
Adjunct Professor
The Institute of Environmental and Human Health (TIEHH) Louis R. Cantilena, Jr., M.D., Ph.D.
Horn Professor Associate Professor of Medicine and Pharmacology
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Department of Biological Sciences Director, Division of Clinical Pharmacology and Medical Toxicology
Texas Tech University Uniformed Services University of the Health Sciences
Lubbock, Texas Bethesda, Maryland
Chapter 29 Chapter 32

Catherine M. Bens, M.S. Charles C. Capen, D.V.M., Ph.D.


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Senior Research Associate Professor and Chairperson


The Institute of Environmental and Human Health (TIEHH) Department of Veterinary Biosciences
Texas Tech Ohio State University
Lubbock, Texas Columbus, Ohio
Chapter 29 Chapter 21
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John C. Bloom, V.M.D., Ph.D. James A. Carr, Ph.D.


Director, Diagnostic and Experimental Medicine Adjunct Associate Professor
Eli Lilly and Company The Institute of Environmental and Human Health (TIEHH)
Indianapolis, Indiana Associate Professor, Department of Biological Sciences
Chapter 11 Texas Tech University
Lubbock, Texas
William K. Boyes, Ph.D. Chapter 29
Neurophysiological Toxicology Branch
Neurotoxicology Division Enrique Chacon, Ph.D.
National Health and Environmental Effects Research Laboratory Vice President of Business Development
U.S. Environmental Protection Agency Cedra Corporation
Research Triangle Park, North Carolina Austin, Texas
Chapter 17 Chapter 18

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Copyright 2001 by The McGraw-Hill Companies Retrieved from: www.knovel.com
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xii CONTRIBUTORS

Louis A. Chiodo, Ph.D. Yvonne P. Dragan, Ph.D.


Assistant Director Assistant Professor
The Institute of Environmental and Human Health (TIEHH) Ohio State University
Professor of Pharmacology James Cancer Hospital and Solove Research Institute and the
Texas Tech University Health Sciences Center Environmental Molecular Science Institute
Lubbock, Texas Columbus, Ohio
Chapter 29 Chapter 8

Thomas W. Clarkson, Ph.D. David L. Eaton, Ph.D.


J. Lowell Orbison Distinguished Alumni Professor Professor and Associate Dean for Research
Department of Environmental Medicine School of Public Health and Community Medicine

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University of Rochester School of Medicine Department of Environmental Health

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Rochester, New York University of Washington
Chapter 23 Seattle, Washington
Chapter 2
George P. Cobb III, Ph.D.
Division Leader Donald J. Ecobichon, M.D.

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The Institute of Environmental and Human Health (TIEHH) Professor
Associate Professor Department of Pharmacology and Toxicology
Department of Environmental Toxicology Queens University
Texas Tech Kingston, Canada
Lubbock, Texas Chapter 22
Chapter 29
Elaine M. Faustman, Ph.D.
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David E. Cohen, M.D., M.P.H.
Director of Occupational and Environmental Dermatology
Professor
School of Public Health and Community Medicine
Assistant Professor of Dermatology Department of Environmental Health
New York University School of Medicine University of Washington
New York, New York Seattle, Washington
Chapter 19 Chapter 4

Daniel L. Costa, Sc.D. W. Gary Flamm, Ph.D., F.A.C.T., F.A.T.S.


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Chief, Pulmonary Toxicology Branch Flamm Associates


Experimental Toxicology Division Vero Beach, Florida
National Health and Environment Effects Research Laboratory Chapter 30
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina
Chapter 28
Donald A. Fox, Ph.D.
Professor
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Richard L. Dickerson, Ph.D. College of Optometry


Department of Biochemical and Biophysical Sciences, and
Research Scientist, The Institute of Environmental and Human
Department of Pharmacology and Pharmaceutical Sciences
Health (TIEHH)
University of Houston
Associate Professor
Houston, Texas
Department of Environmental Toxicology
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Chapter 17
Texas Tech
Lubbock, Texas
Chapter 29 Lynn T. Frame, Ph.D.
Senior Research Associate
Kenneth R. Dixon, Ph.D. The Institute of Environmental and Human Health (TIEHH)
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Section Leader Texas Tech


The Institute of Environmental and Human Health (TIEHH) Lubbock, Texas
Professor Chapter 29
Department of Environmental Toxicology
Texas Tech Michael A. Gallo, Ph.D.
Lubbock, Texas UMDNJ-Robert Wood Johnson Medical School
Chapter 29 Piscataway, New Jersey
Chapter 1
John Doull, M.D.
Emeritus Professor of Pharmacology and Toxicology Robert A. Goyer, M.D.
Department of Pharmacology Professor Emeritus
University of Kansas Medical Center University of Western Ontario
Kansas City, Kansas London, Ontario, Canada
Appendix Chapter 23

Copyright 2001 by The McGraw-Hill Companies Retrieved from: www.knovel.com


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CONTRIBUTORS xiii

Doyle G. Graham, M.D., Ph.D. Jerold A. Last, Ph.D.


Professor and Chair of Pathology Professor
Department of Pathology Pulmonary/Critical Care Medicine
Vanderbilt University Medical Center School of Medicine
Nashville, Tennessee University of California, Davis
Chapter 16 Davis, California
Chapter 15
Zoltn Gregus, M.D., Ph.D., D.Sc.
Professor Clyde F. Martin, Ph.D.
Department of Pharmacology and Pharmacotherapy Special Assistant
University of Pcs Medical School The Institute of Environmental and Human Health (TIEHH)

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Pcs, Hungary Horn Professor

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Chapter 3 Department of Mathematics and Statistics
Texas Tech University
Naomi H. Harley, Ph.D. Lubbock, Texas
Research Professor Chapter 29
New York University School of Medicine
Department of Environmental Medicine Scott T. McMurry, Ph.D.

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New York, New York Section Leader
Chapter 25 The Institute of Environmental and Human Health (TIEHH)
Assistant Professor
George R. Hoffmann, B.A., M.S., Ph.D. Department of Environmental Toxicology
Anthony and Renee Marlon Professor Texas Tech
Department of Biology dM Lubbock, Texas
Holy Cross College Chapter 29
Worcester, Massachusetts
Chapter 9 B. Jean Meade, D.V.M., Ph.D.
Toxicologist
Michael J. Hooper, Ph.D. National Institute of Occupational Safety and Health
Research Scientist Morgantown, West Virginia
The Institute of Environmental and Human Health (TIEHH) Chapter 12
Associate Professor
Department of Environmental Toxicology Michele A. Medinsky, Ph.D., D.A.B.T.
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Texas Tech
Toxicology Consultant
Lubbock, Texas
Durham, North Carolina
Chapter 29
Chapter 7
Robert J. Kavlock, Ph.D.
Russell B. Melchert, Ph.D.
Director, Reproductive Toxicology Division
Assistant Professor
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National Health and Environmental Effects Research Laboratory


United States Environmental Protection Agency Department of Pharmaceutical Sciences
Research Triangle Park, North Carolina College of Pharmacy
Chapter 10 University of Arkansas for Medical Sciences
Little Rock, Arkansas
Ronald J. Kendall, Ph.D. Chapter 18
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Director
The Institute of Environmental and Human Health (TIEHH)
Richard A. Merrill, L.L.B., M.A.
Professor and Chair Professor of Law
Department of Environmental Toxicology University of Virginia
Texas Tech Charlottesville, Virginia
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Lubbock, Texas Chapter 34


Chapter 29
Thomas J. Montine, M.D., Ph.D.
Curtis D. Klaassen, Ph.D. Associate Professor of Pathology and Pharmacology
Professor of Pharmacology and Toxicology Margaret and George Thorne Professorship in Pathology
Department of Pharmacology, Toxicology, and Therapeutics Department of Pathology
University of Kansas Medical Center Vanderbilt University Medical Center
Kansas City, Kansas Nashville, Tennessee
Chapters 2, 3, 5 Chapter 16

Frank N. Kotsonis, Ph.D., D.A.B.T. Albert E. Munson, Ph.D.


Corporate Vice President, Monsanto Company Director Health Effects Laboratory Division
Worldwide Regulatory Affairs National Institute of Occupational Safety and Health
Skokie, Illinois Morgantown, West Virginia
Chapter 30 Chapter 12

Copyright 2001 by The McGraw-Hill Companies Retrieved from: www.knovel.com


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xiv CONTRIBUTORS

Stata Norton, Ph.D. Robert H. Rice, Ph.D.


Emeritus Professor of Pharmacology and Toxicology Professor
Department of Pharmacology, Toxicology, and Therapeutics University of California/Davis
University of Kansas Medical Center Department of Environmental Toxicology
Kansas City, Kansas Davis, California
Chapter 27 Chapter 19

Gilbert S. Omenn, Ph.D., M.D. John M. Rogers, Ph.D.


Executive Vice President for Medical Affairs Chief
Professor of Internal Medicine, Human Genetics and Public Health Developmental Biology Branch
University of Michigan Reproductive Toxicology Division

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Ann Arbor, Michigan National Health and Environmental Effects Research Laboratory

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Chapter 4 United States Environmental Protection Agency
Research Triangle Park, North Carolina
Andrew Parkinson, Ph.D. Chapter 10
CEO
XENOTECH Karl Rozman, Ph.D.

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Kansas City, Kansas Professor of Pharmacology and Toxicology
Chapter 6 Department of Pharmacology and Toxicology
University of Kansas Medical Center
Reynaldo Patino, Ph.D. Kansas City, Kansas
Section Leader Chapter 5
The Institute of Environmental and Human Health (TIEHH)
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Associate Professor Findlay E. Russell, M.D., Ph.D.
Department of Biological Sciences Department of Pharmacology and Toxicology
Texas Tech University College of Pharmacy
Assistant Unit Leader University of Arizona
Texas Cooperative Fish and Wildlife Research Unit Tucson, Arizona
United States Geological Survey Department of Neurology
Lubbock, Texas University of Southern California
Chapter 29 Los Angeles, California
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Department of Neurological Sciences


Henry C. Pitot III, M.D., Ph.D. Loma Linda University
Professor Emeritus Loma Linda, California
University of Wisconsin Chapter 26
McArdle Laboratory for Cancer Research and the Center for
Environmental Toxicology Rick G. Schnellmann, Ph.D.
Madison, Wisconsin
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Professor and Chair


Chapter 8 Pharmaceutical Sciences
Department of Pharmaceutical Sciences
Alphonse Poklis, Ph.D. Medical University of South Carolina
Professor Charleston, South Carolina
Department of Pathology Chapter 14
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Medical College of Virginia Campus


Virginia Commonwealth University Ernest E. Smith, Ph.D.
Richmond, Virginia Research Scientist
Chapter 31 The Institute of Environmental and Human Health Center
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(TIEHH)
R. Julian Preston, B.A., M.A., Ph.D. Assistant Professor
Director Department of Environmental Toxicology
Environmental Carcinogenesis Division Texas Tech
U.S. Environmental Protection Agency Lubbock, Texas
Research Triangle Park, North Carolina Chapter 29
Chapter 9
Christopher W. Theodorakis, Ph.D.
Kenneth S. Ramos, Ph.D. Assistant Section Leader
Professor The Institute of Environmental and Human Health (TIEHH)
Department of Physiology and Pharmacology Assistant Professor
College of Veterinary Medicine Department of Environmental Toxicology
Texas A&M University Texas Tech
College Station, Texas Lubbock, Texas
Chapter 18 Chapter 29

Copyright 2001 by The McGraw-Hill Companies Retrieved from: www.knovel.com


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CONTRIBUTORS xv

John A. Thomas, Ph.D. Jack Valentine, Ph.D.


Professor Emeritus Research Pharmacokineticist
University of Texas Health Science CenterSan Antonio Research Triangle Institute
Department of Pharmacology Research Triangle Park, North Carolina
San Antonio, Texas Chapter 7
Chapter 20
William M. Valentine, D.V.M., Ph.D.
Michael J. Thomas, M.D., Ph.D.
Associate Professor of Pathology
Assistant Professor Department of Pathology
University of North Carolina School of Medicine Vanderbilt University Medical Center
Division of Endocrinology Nashville, Tennessee

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Chapel Hill, North Carolina Chapter 16

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Chapter 20

Peter S. Thorne, Ph.D. D. Alan Warren, M.P.H., Ph.D


Professor of Toxicology Toxicologist
Professor of Environmental Engineering (secondary) Terra, Inc.
University of Iowa College of Public Health Tallahassee, Florida

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Department of Occupational and Environmental Health Chapter 24
Iowa City, Iowa
Chapter 33 Hanspeter R. Witschi, M.D.
Professor of Toxicology
Mary Treinen-Moslen, Ph.D. Institute of Toxicology and Environmental Health and Department of
William C. Levin Professor of Environmental Toxicology
dM Molecular Biosciences
Toxicology Program School of Veterinary Medicine
University of Texas Medical Branch University of California
Galveston, Texas Davis, California
Chapter 13 Chapter 15
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Copyright 2001 by The McGraw-Hill Companies Retrieved from: www.knovel.com


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PREFACE

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The sixth edition of Casarett and Doulls Toxicology: The Toxicology (Unit 6), and Applications of Toxicology

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Basic Science of Poisons marks its silver anniversary. The (Unit 7).
sixth edition, as the previous five, is meant to serve prima- The sixth edition reflects the marked progress made in
rily as a text for, or an adjunct to, graduate courses in toxi- toxicology the last few years. For example, the importance
cology. Because the five previous editions have been widely of apoptosis, cytokines, growth factors, oncogenes, cell cy-
used in courses in environmental health and related areas, cling, receptors, gene regulation, transcription factors, sig-

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an attempt has been made to maintain those characteristics naling pathways, transgenic animals, knock-out animals,
that make it useful to scientists from other disciplines. This polymorphisms, microarray technology, genomics, proteo-
edition will again provide information on the many facets nomics, etc., in understanding the mechanisms of toxicity
of toxicology and especially on the principles, concepts, and are included in this edition. More information on risk as-
modes of thought that are the foundation of the discipline. sessment is also included. References in this edition include
Mechanisms of toxicity are emphasized. Research toxicol-
dM not only traditional journal and review articles, but, for the
ogists will find this book an excellent reference source to first time, internet sites.
find updated material in areas of their special or peripheral The editor is grateful to his colleagues in academia,
interests. industry, and government who have made useful sugges-
The overall framework of the sixth edition is similar to tions for improving this edition, both as a book and as a
the fifth edition. The seven units are General Principles of reference source. The editor is especially thankful to all
Toxicology (Unit 1), Disposition of Toxicants (Unit 2), the contributors, whose combined expertise has made pos-
Non-Organ-Directed Toxicity (carcinogenicity, muta- sible a volume of this breadth. I especially recognize John
genicity, and teratogenicity) (Unit 3), Target Organ Toxi- Doull, the original editor of this book, for his continued
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city (Unit 4), Toxic Agents (Unit 5), Environmental support.


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Copyright 2001 by The McGraw-Hill Companies Retrieved from: www.knovel.com
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PREFACE TO THE
FIRST EDITION

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This volume has been designed primarily as a textbook for, agents are grouped by chemical or use characteristics. In the

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or adjunct to, courses in toxicology. However, it should also final section (Unit IV) an attempt has been made to illus-
be of interest to those not directly involved in toxicologic ed- trate the ramifications of toxicology into all areas of the
ucation. For example, the research scientist in toxicology will health sciences and even beyond. This unit is intended to
find sections containing current reports on the status of cir- provide perspective for the nontoxicologist in the applica-

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cumscribed areas of special interest. Those concerned with tion of the results of toxicologic studies and a better under-
community health, agriculture, food technology, pharmacy, standing of the activities of those engaged in the various as-
veterinary medicine, and related disciplines will discover the pects of the discipline of toxicology.
contents to be most useful as a source of concepts and modes It will be obvious to the reader that the contents of this
of thought that are applicable to other types of investigative book represent a compromise between the basic, funda-
and applied sciences. For those further removed from the mental, mechanistic approach to toxicology and the desire
field of toxicology or for those who have not entered a spe- to give a view of the broad horizons presented by the sub-
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cific field of endeavor, this book attempts to present a selec-
tively representative view of the many facets of the subject.
ject. While it is certain that the editors selectivity might
have been more severe, it is equally certain that it could have
Toxicology: The Basic Science of Poisons has been or- been less so, and we hope that the balance struck will prove
ganized to facilitate its use by these different types of users. to be appropriate for both toxicologic training and the sci-
The first section (Unit I) describes the elements of method entific interest of our colleague.
and approach that identify toxicology. It includes those prin- L.J.C.
ciples most frequently invoked in a full understanding of tox- J.D.
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icologic events, such as dose-response, and is primarily Although the philosophy and design of this book
mechanistically oriented. Mechanisms are also stressed in the evolved over a long period of friendship and mutual respect
subsequent sections of the book, particularly when these are between the editors, the effort needed to convert ideas into
well identified and extend across classic forms of chemicals reality was undertaken primarily by Louis J. Casarett. Thus,
and systems. However, the major focus in the second section his death at a time when completion of the manuscript was
(Unit II) is on the systemic site of action of toxins. The in- in sight was particularly tragic. With the help and encour-
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tent therein is to provide answers to two questions: What agement of his wife, Margaret G. Casarett, and the other
kinds of injury are produced in specific organs or systems by contributors, we have finished Lous task. This volume is a
toxic agents? What are the agents that produce these effects? fitting embodiment of Louis J. Casaretts dedication to tox-
A more conventional approach to toxicology has been icology and to toxicologic education.
utilized in the third section (Unit III), in which the toxic J.D.
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Copyright 2001 by The McGraw-Hill Companies Retrieved from: www.knovel.com