Principles of toxicology

434 Pages·2015·14.38 MB·English

by  Karen E. Stine, Thomas Miller Brown

TOXICOLOGY Stine
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Third Edition
Principles of
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Third Edition
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Reflecting the broad and interdisciplinary nature of toxicology, this third edition of c
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Principles of Toxicology explores the biochemical, physiological, and environmental
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aspects of the subject.
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This new edition is updated and revised to include reference to several major new s

directions in the science of toxicology, including significant changes in thinking about o
cancer and carcinogenesis as well as the rapid expansion of toxicogenomics. The book f

also includes new chapters on topics of timely interest such as radiation, food safety, T
and natural toxins.
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As in previous editions, chapters combine background material in the appropriate
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discipline—which helps readers review and remember the basics—with new
information on toxicology to stress key principles and concepts. Also included is a
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selection of updated case studies through which principles and concepts are applied
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to real-world issues.
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The book features an extensive cross-referencing system linking all sections and
enhancing the integration of material, thus helping readers tie it all together. It also
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includes an appendix of selected toxicants that describes chemical structure, category
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of use, and toxicity. These features make specific information quick and easy to find.
The easy-to-follow format and clear presentation of information in this book will Principles of
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make this one of the most useful references on your shelf.
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TOXICOLOGY
Third
Edition
K14463
Karen E. Stine
6000 Broken Sound Parkway, NW
Suite 300, Boca Raton, FL 33487
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New York, NY 10017 Thomas M. Brown
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www.crcpress.com Abingdon, Oxon OX14 4RN, UK www.crcpress.com
K14463_cover.indd 1 3/12/15 9:24 AM

Third Edition
Principles of
TOXICOLOGY
Karen E. Stine
Department of Biology
Auburn University at Montgomery
Montgomery, Alabama, USA

Thomas M. Brown
GeneCTAr Com LLC
Whitefish, Montana, USA
Boca Raton London New York
CRC Press is an imprint of the
Taylor & Francis Group, an informa business
CRC Press
Taylor & Francis Group
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Boca Raton, FL 33487-2742
© 2015 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
Version Date: 20150311
International Standard Book Number-13: 978-1-4665-0343-4 (eBook - PDF)
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I dedicate this to my parents, Betty and Dale Stine, my
children, Melinda Jacobs and Danny Jacobs, and my
husband, Steve Ballard, as well as to the teachers, colleagues,
and students with whom I have been privileged to work
and who have taught me so much along the way.
—K.E.S.
I dedicate my contributions to this book to my daughter, Annie
May Brown, to my father, Alexander Musgrove Brown, who was
proprietor of Brown’s Corner Drugstore, formerly of Philipsburg,
Pennsylvania, and to the nature of Montana which motivates me.
—T.M.B.

Contents
Preface......................................................................................................................xv
Authors ...................................................................................................................xvii
Chapter 1 Measuring Toxicity and Assessing Risk ..............................................1
Introduction ..........................................................................................1
Chemistry of Toxicants ........................................................................1
Toxicity Testing Methods .....................................................................1
Testing in Animals ..........................................................................2
Human Data and Epidemiology ......................................................3
Factors to be Considered in Planning Toxicity Testing ........................3
Routes of Exposure ..........................................................................3
Determining the Responses to Varying Doses of a Substance .......4
Timing of Exposure .........................................................................5
The LD (Median Lethal Dose) Experiment ......................................5
50
Testing .............................................................................................5
Analysis ...........................................................................................6
Alternative Tests ..............................................................................8
Categories of Toxicity ......................................................................9
No Observed Adverse Effect Levels ....................................................9
Mixtures ...............................................................................................9
Toxicity, Hazard, and Risk .................................................................10
Toxicity and Hazard ......................................................................10
The Role of Laboratory Testing in Estimation of Hazard .............10
Epidemiological Data ....................................................................11
Risk Assessment and Risk Management .......................................12
Case Study: Risk, Perception, and Vaccination .................................13
Bibliography .......................................................................................14
Chapter 2 Toxicokinetics ....................................................................................15
Introduction ........................................................................................15
Pharmacokinetics and Toxicokinetics ...........................................15
Absorption ..........................................................................................16
The Oral Route of Absorption .......................................................17
Respiratory Route of Absorption ...................................................18
Dermal Route of Absorption .........................................................18
Distribution .........................................................................................19
Elimination .........................................................................................20
Toxicokinetic Models .........................................................................20
Mathematical Models of Elimination ............................................20
Complicating Factors .....................................................................23
v
vi Contents
Clearance .......................................................................................24
Absorption and Bioavailability ......................................................24
Contrasting Kinetics of Lipophilic Substances ..................................25
Bibliography .......................................................................................27
Chapter 3 Biotransformation ...............................................................................29
Introduction ........................................................................................29
Primary Biotransformation (Phase I Reactions): Hydrolysis .............30
Serine Hydrolases ..........................................................................31
Paraoxonases .................................................................................34
Epoxide Hydrolase .........................................................................35
Primary Biotransformation (Phase I Reactions): Oxidation ..............35
The Role of Cytochrome P450 ......................................................35
Other Enzymes Carrying Out Oxidation ......................................41
Primary Biotransformation (Phase I Reactions): Reduction ..............43
Secondary Metabolism (Phase II Reactions) .....................................43
Glucuronidation .............................................................................43
Glutathione Conjugation ................................................................45
Acetylation and Other Phase II Reactions .....................................48
Factors That Influence Metabolism ....................................................48
The Role of Metabolism by Gut Flora ...........................................48
Bibliography .......................................................................................49
Chapter 4 Cellular Sites of Action ......................................................................51
Introduction ........................................................................................51
Interaction of Toxicants with Proteins ...............................................52
Effects of Toxicants on Enzymes ..................................................53
Effects of Toxicants on Receptors and Ion Channels ....................59
Effects of Toxicants on Voltage-Activated Ion Channels ..............63
Effects of Toxicants on Transport Proteins ...................................64
Effects of Toxicants on Proteins Involved in the Regulation
of Gene Expression ........................................................................65
Effects of Toxicants on Lipids ............................................................67
Effects of Toxicants on Nucleic Acids ...............................................68
Mechanisms of Cell Death .................................................................70
Apoptosis .......................................................................................70
Necrosis .........................................................................................71
Autophagy .....................................................................................72
Stress, Repair, and Recovery .........................................................73
Case Study: Cyclooxygenase Inhibitors .............................................74
Bibliography .......................................................................................76
Chapter 5 Genomics and New Genetics in Toxicology ......................................79
Introduction ........................................................................................79
Contents vii
The Human Genome Project ..............................................................79
Sorting Out Genes .........................................................................80
Model Organisms and Comparative Genomics.............................80
Toxicogenomics ..................................................................................83
Monitoring Transcription: Gene Expression and Microarrays......83
Other Roles for RNA .....................................................................87
Single Nucleotide Polymorphisms ................................................88
Metabolomics .....................................................................................90
Personalized Susceptibility and Tailored Therapeutics .....................92
Individual Variations in Metabolism and Pharmacogenomics .....93
Race, Ethics, and Genomics ...............................................................94
Systems Toxicology ............................................................................96
Case Study: Using GenBank and Online Tools in Genomics ............96
Bibliography .......................................................................................98
Chapter 6 Carcinogenesis .................................................................................101
Cancer ..............................................................................................101
The Epidemiology of Cancer ...........................................................101
Environmental Factors in Cancer ................................................102
Genetic Factors in Cancer ...........................................................103
Carcinogenesis .................................................................................103
The Mutational Theory of Carcinogenesis ..................................103
Competing Theories ....................................................................104
Oncogenes and Tumor Suppressor Genes ........................................104
The Discovery of Oncogenes ......................................................104
An Example of an Oncogene: The Philadelphia Chromosome .....105
The Role of Proto-Oncogenes in Cell Function ..........................105
Examples of Proto-Oncogenes ....................................................106
Tumor Suppressor Genes .............................................................107
Single Nucleotide Polymorphisms and Cancer ...........................108
Chemical Carcinogens: Initiation .....................................................109
Genetic Carcinogens ....................................................................109
Consequences of Mutagenesis .....................................................111
Chemical Carcinogens: Promotion ..................................................112
Stimulation of Cell Growth and Division ....................................113
Suppression of Cell Death ...........................................................113
Stimulation of Cellular Production of Reactive Compounds ......113
Hormones as Promoters...............................................................114
The Role of Cellular Energetics ..................................................114
Epigenetic Impacts on Genes and Gene Expression ...................114
Other Mechanisms of Promotion ................................................115
Protection against the Development of Cancer ................................115
Testing Compounds for Carcinogenicity ..........................................116
Critiques of Strategies in Cancer Research ......................................117
Carcinogenesis: A Complex Process ................................................118
viii Contents
Case Study: Predicting Carcinogenesis Based upon
Chemistry (QSAR) ...........................................................................118
Bibliography .....................................................................................120
Chapter 7 Reproductive Toxicology and Teratology .........................................123
Introduction ......................................................................................123
Basic Processes in Reproduction and Development: Cell Division ......123
The Cell Cycle and Mitosis .........................................................123
Meiosis .........................................................................................126
Cloning ........................................................................................127
The Male Reproductive System .......................................................128
The Female Reproductive System ....................................................129
The Effects of Toxicants on the Male and Female Reproductive
Systems .............................................................................................131
Protective Mechanism: The Blood–Testis Barrier ......................131
Interference with Cell Division ...................................................131
Cytotoxicity and Infertility ..........................................................132
Endocrine Disrupters and Interference with Hormonal Controls ...133
The Process of Development ............................................................135
Embryogenesis and Developmental Genetics ..................................137
Effects of Toxicants on Development: Teratogens and
Teratogenesis ....................................................................................138
Effects of Dose or Exposure Level on Teratogenicity .................139
Effects of Timing of Exposure on Teratogenicity .......................140
Examples of Teratogens ...............................................................140
Mechanisms of Teratogenicity.....................................................142
Testing for Reproductive and Developmental Toxicity ....................143
Human Assessment .....................................................................143
Testing of Laboratory Animals: General Principles ...................143
Testing In Vitro ............................................................................144
Established Procedures for Testing .............................................144
Case Study: Thalidomide .................................................................145
Bibliography .....................................................................................147
Chapter 8 Respiratory Toxicology ....................................................................149
Function of the Respiratory System .................................................149
Anatomy and Physiology of the Respiratory System .......................149
Respiratory Anatomy ..................................................................149
Pulmonary Ventilation .....................................................................151
Gas Exchange ..............................................................................153
Control of Respiration .................................................................154
Effects of Toxicants on the Respiratory System:
General Principles ............................................................................155
Defense Mechanisms of the Respiratory System .............................156