Table Of ContentH a y e s
Toxicology
K r u g e r
S IXTH ED IT ION
S IXTH ED IT ION
E D I T E D B Y
Hayes’ Principles and Methods of Toxicology has long been established
as a reliable reference to the concepts, methodologies, and assessments A. Wallace Hayes • Claire L. Kruger
integral to toxicology. The new sixth edition has been revised and updated
while maintaining the same high standards that have made this volume a
benchmark resource in the field. With new authors and new chapters that
address the advances and developments since the fifth edition, the book
presents everything toxicologists and students need to know to understand
hazards and mechanisms of toxicity, enabling them to better assess risk.
The book begins with the four basic principles of toxicology—dose matters,
people differ, everything transforms, and timing is crucial. The contributors
discuss various agents of toxicity, including foodborne, solvents, crop
protection chemicals, radiation, and plant and animal toxins. They examine
various methods for defining and measuring toxicity in a host of areas,
including genetics, carcinogenicity, toxicity in major body systems, and the
environment. This new edition contains an expanded glossary reflecting
significant changes in the field.
New topics in this edition include
• The importance of dose–response
• Systems toxicology
• Food safety
• The humane use and care of animals
• Neurotoxicology
The comprehensive coverage and clear writing style make this volume
an invaluable text for students and a one-stop reference for professionals.
Readers have complimentary access to an online version of the printed book.
H100472
and of
Hayes' Principles Methods Toxicology
SIXTH EDITION
Hayes' Principles
Hayes' Principles
and and
Methods of Toxicology
Methods of Toxicology
S IXTH ED IT ION
Hayes' Principles
and
Methods of Toxicology
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S IXTH ED IT ION
E D I T E D B Y
A. Wallace Hayes • Claire L. Kruger
Boca Raton London New York
CRC Press is an imprint of the
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Hayes' Principles
and
Methods of Toxicology
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Contents
Preface.......................................................................................................................................................................................... ix
Foreword to the Sixth Edition ......................................................................................................................................................xi
Foreword to the Fifth Edition ....................................................................................................................................................xiii
Foreword to the Fourth Edition .................................................................................................................................................. xv
Foreword to the Third Edition ..................................................................................................................................................xvii
Acknowledgments ......................................................................................................................................................................xix
Editors ........................................................................................................................................................................................xxi
Contributors .............................................................................................................................................................................xxiii
Section i Principles of toxicology
Chapter 1 The Wissenschaften of Toxicology: Harming and Helping through Time ............................................................. 3
Richard W. Lane
Chapter 2 Use of Toxicology in the Regulatory Process ....................................................................................................... 35
Barbara D. Beck, Mara Seeley, and Edward J. Calabrese
Chapter 3 Dose–Response: A Fundamental Concept in Toxicology ..................................................................................... 89
Edward J. Calabrese
Chapter 4 Metabolism: A Determinant of Toxicity ..............................................................................................................141
Raymond A. Kemper, Mitchell E. Taub, and Matthew S. Bogdanffy
Chapter 5 Toxicokinetics ..................................................................................................................................................... 215
A. Roberts and Andrew Gordon Renwick
Chapter 6 Physiologically Based Pharmacokinetic and Toxicokinetic Models ................................................................... 247
Harvey J. Clewell III, Rebecca A. Clewell, and Melvin E. Andersen
Chapter 7 Toxicopanomics: Applications of Genomics, Transcriptomics, Proteomics, and Lipidomics in Predictive
Mechanistic Toxicology ...................................................................................................................................... 295
Julia Hoeng, Marja Talikka, Florian Martin, Sam Ansari, David Drubin, Ashraf Elamin, Stephan Gebel,
Nikolai V. Ivanov, Renée Deehan, Ulrike Kogel, Carole Mathis, Walter K. Schlage, Alain Sewer,
Nicolas Sierro, Ty Thomson, and Manuel C. Peitsch
Chapter 8 Toxicologic Assessment of Pharmaceutical and Biotechnology Products .......................................................... 333
Michael A. Dorato, Carl L. McMillian, and Tracy M. Williams
Chapter 9 Statistics and Experimental Design for Toxicologists ......................................................................................... 373
Shayne C. Gad
Chapter 10 Practice of Exposure Assessment ........................................................................................................................ 453
Dennis J. Paustenbach and Amy K. Madl
v
vi Contents
Chapter 11 Epidemiology for Toxicologists ........................................................................................................................... 527
Geary W. Olsen, John L. Butenhoff, and Ralph R. Cook
Chapter 12 Principles of Pathology for Toxicology Studies .................................................................................................. 571
Steven R. Frame, Peter C. Mann, and Jessica M. Caverly Rae
Chapter 13 The Information Infrastructure of Toxicology .................................................................................................... 597
Philip Wexler, Fred Berman, Patricia Nance, Ann Parker, and Jacqueline Patterson
Section ii Agents
Chapter 14 Food Safety and Foodborne Toxicants ................................................................................................................ 621
Claire L. Kruger, Chada S. Reddy, Dietrich B. Conze, and A. Wallace Hayes
Chapter 15 Solvents and Industrial Hygiene .......................................................................................................................... 677
David L. Dahlstrom and John E. Snawder
Chapter 16 Crop Protection Chemicals: Mechanism of Action and Hazard Profles .............................................................711
James T. Stevens, Trent D. Stevens, and Charles B. Breckenridge
Chapter 17 Metals .................................................................................................................................................................. 825
Janis E. Hulla
Chapter 18 Radiation Toxicity ............................................................................................................................................... 883
Roger O. McClellan
Chapter 19 Plant and Animal Toxins ..................................................................................................................................... 957
Frederick W. Oehme, Daniel E. Keyler, and A. Wallace Hayes
Section iii Methods
Chapter 20 Humane Care and Use of Laboratory Animals in Toxicology Research .......................................................... 1023
Dale M. Cooper, Lisa Craig, Christopher N. Papagiannis, Duane W. Poage, Gregory W. Ruppert,
and David G. Serota
Chapter 21 Validation and Regulatory Acceptance of Toxicological Testing Methods and Strategies ...............................1081
William S. Stokes
Chapter 22 Acute Toxicity and Eye Irritancy .......................................................................................................................1117
Ping Kwong (Peter) Chan and A. Wallace Hayes
Chapter 23 Genetic Toxicology .............................................................................................................................................1173
David J. Brusick and Wanda R. Fields
Contents vii
Chapter 24 Short-Term, Subchronic, and Chronic Toxicology Studies ............................................................................... 1205
Daniel T. Wilson, Jerry F. Hardisty, Johnnie R. Hayes, and Nelson H. Wilson
Chapter 25 Carcinogenicity of Chemicals: Assessment and Human Extrapolation ............................................................ 1251
Gary M. Williams, Michael J. Iatropoulos, Harald G. Enzmann, and Ulrich F. Deschl
Chapter 26 Principles of Clinical Pathology for Toxicology Studies .................................................................................. 1305
Robert L. Hall and Nancy E. Everds
Chapter 27 Dermatotoxicology ............................................................................................................................................ 1345
Benjamin B. Hayes, Esther Patrick, and Howard J. Maibach
Chapter 28 Inhalation Toxicology ........................................................................................................................................ 1385
Joseph D. Brain, Wolfgang G. Kreyling, and John J. Godleski
Chapter 29 Detection and Evaluation of Chemically Induced Liver Injury ........................................................................ 1445
Gabriel L. Plaa, Michel Charbonneau, and Isabelle Plante
Chapter 30 Principles and Methods for Renal Toxicology .................................................................................................. 1489
Lawrence H. Lash
Chapter 31 Gastrointestinal Toxicology ...............................................................................................................................1521
Robert W. Kapp, Jr.
Chapter 32 Pathophysiology and Toxicology of the Heart .................................................................................................. 1567
Khalid Almuti, Shahid Rahman, and Daniel Acosta, Jr.
Chapter 33 Neurotoxicology ................................................................................................................................................ 1579
Stephanie J.B. Fretham, Samuel Caito, Ebany J. Martinez-Finley, Gennaro Giordano, Lucio G. Costa,
and Michael Aschner
Chapter 34 Assessment of Male Reproductive Toxicity .......................................................................................................1601
Gary R. Klinefelter and D.N. Rao Veeramachaneni
Chapter 35 Test Methods for Assessing Female Reproductive and Developmental Toxicology ..........................................1637
Raymond G. York, Robert M. Parker, and Lynne T. Haber
Chapter 36 Hormone Assays and Endocrine Function .........................................................................................................1723
Robert M. Parker and Raymond G. York
Chapter 37 Immunotoxicology: The Immune System Response to Toxic Insult .................................................................1793
Robert V. House, Michael I. Luster, Jack H. Dean, and Victor J. Johnson
Chapter 38 Assessment of Behavioral Toxicity ....................................................................................................................1831
Deborah A. Cory-Slechta and Bernard Weiss
viii Contents
Chapter 39 Organelles as Tools in Toxicology: In Vitro and In Vivo Approaches ..............................................................1891
Bruce A. Fowler, Joseph R. Landolph, Jr., Kathleen Sullivan, and A. Wallace Hayes
Chapter 40 Analysis and Characterization of Enzymes and Nucleic Acids Relevant to Toxicology .................................. 1905
F. Peter Guengerich
Chapter 41 Modern Instrumental Methods for Studying Mechanisms of Toxicology ........................................................ 1965
Peter A. Crooks, Howard P. Hendrickson, David R. Worthen, Gary D. Byrd, J. Donald deBethizy,
and William S. Caldwell
Chapter 42 Methods in Environmental Toxicology ............................................................................................................. 2029
Anne Fairbrother, Mace G. Barron, and Mark S. Johnson
Glossary ................................................................................................................................................................................. 2073
Index ........................................................................................................................................................................................2113
Preface
This is the sixth edition of Hayes’ Principles and Methods of principles underlying these methods is not only manageable
Toxicology. It has been revised and updated while maintain- but also essential for the practicing toxicologist, and it is to this
ing the high standards necessary to serve as a reference to the end that this book was conceived and continues in this edition.
concepts, methodologies, and assessments integral to toxicol- “Training is everything. The peach was once a bitter
ogy. As was the case with the frst fve editions of the book, almond; caulifower is nothing but cabbage with a college
new chapters have been added that address the advances and education.” (The Tragedy of Pudd’nhead Wilson and the
developments in the feld of toxicology. These chapters deal Comedy of the Extraordinary Twins—Mark Twain). And
with the importance of dose–response, systems toxicology, thus, we hope to provide in this edition, as before, an experi-
food safety, the humane use and care of animals, and neuro- ence that continues to educate, elucidate, nurture the inquisi-
toxicology. A number of new authors have been added and tive, and foster the motivation to learn. We begin with four
the glossary has been expanded. Every effort has been made basic principles of toxicology—dose matters, people differ,
to maintain this book as a tome useful to both graduate stu- everything transforms, and timing is crucial. The relevance
dents beginning their educational journey as well as the more of these principles is waiting to be discovered, challenged,
seasoned toxicologist. and applied in the following chapters.
In many ways, toxicology remains a paradox. The words
of Paracelsus, the sixteenth-century German-Swiss physician A. Wallace Hayes, PhD, DABT, FATS,
and alchemist, continue to remind us that the line between FIBiol, FACFE, ERT
light and dark, good and evil, poison and medicine is but a Registered Toxicologist (France and EUROTOX registries)
fne one that we as toxicologists have been given the awesome Harvard School of Public Health
responsibility to divine, “Alle Ding’ sind Gift, und nichts Boston, Massachusetts
ohn’ Gift; allein die Dosis macht, daß ein Ding kein Gift ist.”
The frst chapter reminds us of the evolution of toxicology, as Claire Kruger, PhD, DABT
it has matured over the centuries from its genesis as a science Spherix Consulting
focused on the discovery and use of poison as an expedient Division of ChromaDex, Inc.
tool to commit murder to the advances that have resulted in Rockville, Maryland
the use of toxicants to beneft mankind as medicines.
Toxicology is much more than the science of poisons. MATLAB® is a registered trademark of The MathWorks,
Practitioners of toxicology need to understand the hazard and Inc. For product information, please contact:
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