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AN INTRODUCTION TO INTERDISCIPLINARY
TOXICOLOGY
AN INTRODUCTION TO
INTERDISCIPLINARY
TOXICOLOGY
FROM MOLECULES TO MAN

Edited by

Carey N. Pope
Regents Professor, Physiological Sciences, College of Veterinary Medicine, Interdisciplinary Toxicology Program,
Oklahoma State University, Stillwater, OK, United States

Jing Liu
Senior Research Scientist, Charles River Laboratories, Reno, Nevada, United States
Academic Press is an imprint of Elsevier
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 Contents

List of contributors xiii II

Foreword xvii
RESPONSES TO CHEMICAL
Preface xix
TOXICANTS

I 4. Toxicant interactions with

GENERAL CONCEPTS macromolecular targets
RUDY J. RICHARDSON

1. History and basic concepts of 4.1 Toxicokinetics and toxicodynamics 45

toxicology 4.2 Toxicokinetics 45
CAREY N. POPE, DANIEL SCHLENK AND
4.3 Toxicodynamics 46
FRÉDÉRIC J. BAUD 4.4 AChE and OP insecticide mechanism and mode of
action 47
1.1 A brief history of toxicology 3 4.5 Mechanism and mode of action of OP inhibitors of
1.2 Important concepts in toxicology 6 AChE 47
References 14 4.6 Toxicodynamic factors for inhibition of AChE by
OP compounds 49
2. Absorption, distribution, and excretion 4.7 Kinetic and equilibrium constants 49
4.8 Determining ki under pseudo-first-order
in complex organisms conditions 50
LARA MAXWELL 4.9 The IC50 and pIC50 51
4.10 Determining the Kd and k2 components of ki 53
2.1 Introduction to xenobiotic disposition 17
4.11 Determining Kd and k2 in the presence of
2.2 Absorption of xenobiotics 22
substrate 53
2.3 Distribution of xenobiotics 24
4.12 Postinhibitory reactions: reactivation and
2.4 Elimination: metabolism and excretion of
aging 54
xenobiotics 26
4.13 Mutant AChE produces insecticide resistance in
References 29
mosquitoes 55
4.14 Conclusion 56
3. Xenobiotic metabolism and References 56
disposition
GUANGPING CHEN 5. Cellular responses to toxicants
LIN LIU
3.1 Introduction 31
3.2 Phase I drug-metabolizing enzymes 32 5.1 Introduction 59
3.3 Phase II drug-metabolizing enzymes 37 5.2 Cell adaptation, injury, and death 59
3.4 Phase III drug transporters 40 5.3 Oxidative stress and cellular protection system 64
3.5 Conclusions 42 5.4 Cellular techniques 66
References 42 Further reading 67

v
vi Contents

6. Disruption of extracellular References 109

signaling Further reading 110
CAREY N. POPE AND KIRSTIN HESTER
9. Epigenetics
6.1 Overview of extracellular signaling 69 JOSEPH PAUL BRESSLER, RICHARD S. LEE AND JAIRUS
6.2 Disruption of extracellular signaling in the PULCZINSKI
expression of toxicity 72
6.3 Conclusions 78 9.1 Historical perspective 111
References 78 9.2 Chromatin remodeling 112
9.3 DNA methylation 112
9.4 Histone modifications 113
7. Disruption of intracellular
9.5 Toxicology and epigenetics 114
signaling 9.6 Cancer as an epigenetic disease 122
ANUMANTHA KANTHASAMY, JIE LUO, 9.7 Pitfalls in epigenetics research 123
DHARMIN ROKAD AND ADHITHIYA CHARLI
References 124
Further reading 124
7.1 Overview of intracellular signaling 81
7.2 Mitochondria-targeted pesticides and mitochondrial
dysfunction 82 10. Microbiome in toxicity and its
7.3 Neuroinflammation 85 modulation
7.4 Oxidative stress 87 KATHLEEN AHLES AND GERWALD KOEHLER
7.5 Concluding remarks and future directions 89
Acknowledgments 90 10.1 Introduction 127
References 90 10.2 Ingested toxicants and the microbiome 129
10.3 Pesticides and the microbiome 132
8. Carcinogenesis 10.4 Environmental toxicants and the
microbiome 133
JAMES E. KLAUNIG
10.5 Toxic metals and the microbiome 134
8.1 Background 97 10.6 Concluding remarks 135
8.2 Definitions 97 References 136
8.3 Mechanisms of chemical carcinogens 99
8.4 Genotoxic/DNA-reactive compounds 100
8.5 Mutation 101 III
8.6 DNA repair 102 ORGAN SYSTEM EFFECTS
8.7 Nongenotoxic carcinogens 102
8.8 Cytotoxicity 103
8.9 Receptor mediated 104 11. Dermal toxicity
8.10 DNA methylation 104 MICHAEL F. HUGHES
8.11 Immunosuppression 104
8.12 Oxidative stress 105 11.1 Introduction 141
8.13 Gap junctional intercellular communication 105 11.2 Histology of skin 142
8.14 Polymorphisms in carcinogen metabolism and 11.3 Dermal absorption of xenobiotics 144
DNA repair 105 11.4 Metabolism 146
8.15 Proto-oncogenes and tumor-suppressor genes 105 11.5 Contact dermatitis 147
8.16 Multistage carcinogenesis 106 11.6 Photosensitivity 147
8.17 Evaluating chemicals for carcinogenicity 108 11.7 Disorders and diseases of skin 148
8.18 Determining human carcinogenic risk 108 11.8 Tattoos 150
 Contents vii
11.9 Conclusions 150 15.3 Classical cardiovascular toxicants and their
References 150 mechanisms of action 201
References 204
12. Hepatic toxicology
ATRAYEE BANERJEE AND SHASHI K. RAMAIAH 16. Introduction to reproductive and
developmental toxicology
12.1 Introduction 153
VICKI SUTHERLAND
12.2 Hepatic structural and functional
organization 153
16.1 Introduction 207
12.3 Cellular components and functions 154
16.2 Hypothalamus and hormones 208
12.4 Mechanism of bile formation and function 154
16.3 Male reproductive system 210
12.5 Types of liver injury 155
16.4 Female reproductive system 212
12.6 Additional mechanisms 160
16.5 Pregnancy and embryo/fetal development 216
12.7 Current state of serum biomarkers to assess liver
16.6 Toxicants 217
damage 160
References 220
12.8 Conclusions 161
Further reading 220
References 161

13. Renal toxicology 17. Organ system effects: endocrine

HYUNG SIK KIM toxicology
NANCY D. DENSLOW AND CHRISTOPHER J. MARTYNIUK
13.1 Structure and function of kidney 163
13.2 Adaptation and susceptibility of kidneys to 17.1 Introduction to hormone systems and endocrine
toxicants 165 toxicology 221
13.3 Site-selective kidney toxicity 167 17.2 General overview of hormone signaling 222
13.4 Evaluation of renal function 170 17.3 Hormone axis and chemical perturbation 223
13.5 Classification of nephrotoxic substances 172 17.4 Comparative endocrinology: insight into endocrine
References 176 toxicology 229
17.5 New directions for the study of endocrine
14. Respiratory toxicology 229
KEVIN N. BAER
Abbreviations 229
References 230
14.1 Introduction 179
14.2 Toxicants affecting the lung following 18. Immunotoxicology
inhalation 181 RANDLE GALLUCCI, LERIN LUCKETT-CHASTAIN AND
14.3 Systemic lung toxicants 185 BERRAN YUCESOY
14.4 Reactive airway dysfunction syndrome 186
References 187 18.1 Introduction 233
18.2 Types of immunotoxicity 233
15. Cardiovascular 18.3 Metals 236
TAMMY R. DUGAS AND KURT J. VARNER 18.4 Pesticides 237
18.5 Polycyclic aromatic hydrocarbons 237
15.1 Overview of cardiovascular physiology 191 18.6 Pulmonary immunotoxicants 238
15.2 Mechanisms of toxicity and disease 18.7 Smoking, alcohol, and drugs of abuse 240
pathogenesis 196 References 241
viii Contents

19. Sensory function 22.5 Conclusion 307

WILLIAM K. BOYES, BENOÎT POUYATOS AND JORDI References 307
LLORENS

19.1 Introduction 245 V

19.2 Vision 245
19.3 Audition 247 TOXICOLOGY AT HOME AND
19.4 Vestibular 252 THE WORKPLACE
19.5 Somatosensory 254
19.6 Olfactory/chemosensory perception 257
19.7 Sensory perception in nonmammalian 23. Toxicology in the home
systems 258 MARION EHRICH
19.8 Conclusion 259
Acknowledgments 259 23.1 Introduction 315
References 259 23.2 Nonprescription drugs 315
23.3 Common prescription drugs 318
20. Nervous system 23.4 Household chemicals 320
Acknowledgments 324
DAVID R. WALLACE AND ALEKSANDRA BUHA
DJORDJEVIC
References 324

20.1 Introduction 261 24. Toxicology in the workplace 327

20.2 Mechanisms and types of neurotoxicity 262 MARIE FORTIN AND MARIE CAPDEVIELLE
20.3 Selected neurotoxicants 265
References 276 24.1 Introduction 327
24.2 Case studies 328
24.3 Managing exposures and protecting workers 334
IV 24.4 Conclusion 336
References 336
MODULATION OF TOXICITY

21. Intrinsic and extrinsic factors that can VI

modify toxicity TOXICOLOGY IN THE
JING LIU AND CAREY N. POPE COMMUNITY
21.1 Intrinsic modifying factors 285
21.2 Extrinsic modifying factors 289 25. Love canal: a classic case study of a
References 291 contaminated community
DUANE A. GILL AND TAMARA L. MIX
22. Influence of dietary factors and
nutritional status on toxicity response to 25.1 Framework and concepts: contamination in the
environmental pollutants context of natural and technological disasters 341
BRENDA J. SMITH AND EDRALIN A. LUCAS
25.2 Love Canal: a historical case study 342
25.3 Sociocultural and psychosocial effects of residing in
22.1 Introduction 295 a contaminated community 347
22.2 Macronutrients 295 25.4 Implications and connections 349
22.3 Micronutrients 300 25.5 Critical connections 350
22.4 Protective effects 306 References 351
 Contents ix
26. “Dear People of Flint”: environmental 28.5 Examples of modes of action of special relevance
justice in a community context, the case of to ecotoxicology 384
28.6 Relating effects from molecular to community
water contamination in Flint, Michigan
levels 384
TAMARA L. MIX AND DUANE A. GILL
28.7 Understanding and measuring exposure in
ecotoxicology 386
26.1 Concepts: environmental inequality and
28.8 Bioconcentration, bioaccumulation, and
justice 353
biomagnification 388
26.2 The case in context: water contamination in Flint,
28.9 Approaches for evaluating the presence of or
Michigan 355
potential for an environmental impact 389
26.3 Environmental inequality and justice intersected:
28.10 Toxicity of mixtures and multiple stressors 391
outcomes in Flint, Michigan 358
28.11 Conclusion 392
26.4 Conclusion 359
References 392
Critical connections 360
References 360
IX
VII NANOTOXICOLOGY
ENVIRONMENTAL EXPOSURES
29. Selected aspects of nanotoxicology
D.B. WARHEIT AND S.C. BROWN
27. Hazardous release: point source
dispersion modeling 29.1 Introduction 397
JOSHUA D. RAMSEY 29.2 Hazard versus risk and regulatory distinctions 399
29.3 Relevant routes of exposure to nanoscale
27.1 Introduction 365 particulate materials—a brief review 400
27.2 Exposure limits 366 29.4 Oral or ingestion exposures 400
27.3 Factors that affect dispersion 368 29.5 Dermal exposures 401
27.4 Dispersion modeling 369 29.6 Toward a future understanding of
27.5 Example problems 374 nanomaterials 404
27.6 Pasquill Gifford dispersion model 29.7 Evaluating the risks associated with nanomaterial
limitations 377 exposures: the NanoRisk Framework 405
27.7 Conclusions 377 29.8 Subchronic inhalation toxicity study in rats with
References 377 carbon nanofibers 407
29.9 Conclusions 407
References 408
VIII
ECOTOXICOLOGY X
CLINICAL TOXICOLOGY
28. Introduction to ecotoxicology
JASON BELDEN
30. Introduction to clinical
28.1 Defining ecotoxicology 381 toxicology
28.2 Goals and challenges of ecotoxicology as FRÉDÉRIC J. BAUD AND PASCAL HOUZÉ
compared to human toxicology 381
28.3 Variability of toxicity between species 382 30.1 The pharmacological basis of clinical
28.4 Toxicity testing using surrogate species 382 toxicology 413
x Contents

30.2 What clinical toxicology actually is? 421

30.3 What does a clinical toxicologist do
XIII
every day? 422 REGULATORY TOXICOLOGY
30.4 Research in clinical toxicology 425
References 428
33. Mammalian cell culture models
THERESA M. FREUDENRICH AND TIMOTHY J. SHAFER
XI 33.1 Basic cell culture laboratory and terminology 463
VETERINARY TOXICOLOGY 33.2 Good cell culture practices 464
33.3 Types of cultures 465
33.4 Use of mammalian cell models for regulatory
31. Introduction to veterinary toxicology 468
toxicology 33.5 Summary 471
RAMESH C. GUPTA Acknowledgments 472
References 472
31.1 Introduction 431
31.2 Classification of poisons 431 34. Toxicity testing: in vitro models in
31.3 Types of poisoning 431 ecotoxicology
31.4 Factors affecting poisoning 432
JUSTIN SCOTT AND MATTEO MINGHETTI
31.5 Diagnostic criteria in animal
poisonings 432 34.1 Overview of the use of animals in toxicology 477
31.6 Toxicology of specific poisons 432 34.2 Alternative methods in regulatory
31.7 Concluding remarks 440 ecotoxicology 479
Acknowledgment 440 34.3 Conclusion 484
References 440 Acknowledgments 485
References 485

XII 35. Toxicology testing: in vivo mammalian

FORENSIC TOXICOLOGY models
K. OLIVIER AND S. KARANTH

32. Introduction to forensic 35.1 Mouse 489

toxicology 35.2 Rat 491
JARRAD R. WAGNER
35.3 Rabbit 495
35.4 Dog 498
32.1 Introduction 445 35.5 Nonhuman primates 499
32.2 History of forensic toxicology 445 References 505
32.3 Human performance testing 446
32.4 Postmortem toxicology 447 36. In vivo ecotoxicology models
32.5 Forensic/workplace drug testing 447 JOSEPH R. BIDWELL
32.6 Fundamental principles of forensic
toxicology 447 36.1 Introduction 507
32.7 Analytical techniques in forensic 36.2 Basic methods for regulatory ecotoxicology
toxicology 449 testing 507
32.8 Quality assurance in forensic 36.3 Alternatives to animal models in ecotoxicity
toxicology 458 testing 520
32.9 Conclusion 458 36.4 Summary 520
Further reading 459 References 521
 Contents xi
37. The zebrafish (Danio rerio) model in 40.4 Future considerations and applications 563
toxicity testing 40.5 Conclusions 566
References 566
STEPHANIE PADILLA AND SCOTT GLABERMAN

37.1 Introduction 525 41. Adverse outcome pathways in

37.2 Using zebrafish for human toxicity ecotoxicology
characterization 526 DANIEL SCHLENK
37.3 Zebrafish in ecotoxicology 527
37.4 Emerging novel technologies 530 41.1 Introduction 569
References 530 41.2 Adverse outcome pathway overview 571
41.3 Examples of adverse outcome pathways in
38. Caenorhabitidis elegans as an animal ecotoxicology 572
model in toxicological studies 41.4 Additional directions for adverse outcome
pathways 576
MARINA LOPES MACHADO, DANIELE CORADINI
ZAMBERLAN, LETICIA PRISCILLA ARANTES, MICHAEL 41.5 Conclusions 577
ASCHNER AND FÉLIX ALEXANDRE ANTUNES SOARES References 578

38.1 Introduction 533

38.2 Neurotoxicology applications 534 XIV
38.3 Heavy metal toxicity 536
38.4 Radiation damage 537 REFERENCE MATERIALS AND
38.5 Pesticide toxicity 539 WEBSITES
38.6 Final remarks—perspectives for C. elegans use in
toxicology 540
Acknowledgments 541 42. Toxicology literature, databases, and
References 541 other online resources
PHILIP WEXLER
39. Principles of risk assessment
ROBINAN GENTRY, ALLISON FRANZEN AND TRACY
42.1 Introduction 583
GREENE 42.2 Books (often available in paper, online, and for e-
readers; check with publisher or Amazon) 583
39.1 Brief historical perspective 545 42.3 Journals (a sampling) 585
39.2 The risk assessment paradigm 546 42.4 Professional societies 586
39.3 Conclusions 557 42.5 US government organizations and laws 587
References 557 42.6 Other organizations 589
42.7 Online databases and other digital tools 590
40. Tox21 and adverse outcome pathways 42.8 The international legal and regulatory
COURTNEY ROPER AND ROBYN LEIGH TANGUAY framework 593
42.9 Social media and blogs 594
40.1 Overview of Tox21 559 42.10 A note about cost of access 595
40.2 Tox21 phases 560
40.3 Data analysis and dissemination 562 Index 597
 List of contributors

Kathleen Ahles Department of Biochemistry and Joseph Paul Bressler Department of

Microbiology, Oklahoma State University Center Environmental Health and Engineering, Kennedy
for Health Sciences, Tulsa, OK, United States; Krieger Institute, Bloomberg School of Public
Present address: Tarrant County College, Hurst, Health, Johns Hopkins University, Baltimore,
TX, United States MD, United States
Leticia Priscilla Arantes Department of S.C. Brown The Chemours Company, Wilmington,
Biochemistry and Molecular Biology, CCNE, DE, United States
UFSM, Santa Maria, Brazil Marie Capdevielle MCD Toxicology Consulting,
Michael Aschner Department of Molecular LLC., Middletown, NJ, United States
Pharmacology, Albert Einstein College of Adhithiya Charli Parkinson’s Disorder Research
Medicine Bronx, New York, NY, United States Laboratory, Iowa Center for Advanced
Kevin N. Baer School of Basic Pharmaceutical and Neurotoxicology, Department of Biomedical
Toxicological Sciences, Waste Management Sciences, Iowa State University, Ames, IA, United
Endowed Professorship in Toxicology, College of States
Pharmacy, University of Louisiana at Monroe, Guangping Chen Department of Physiological
Monroe, LA, United States Sciences, Oklahoma State University, Stillwater,
Atrayee Banerjee Reckitt and Benckiser, Montvale, OK, United States
United States Nancy D. Denslow University of Florida,
Frédéric J. Baud Medical and Toxicological Critical Gainesville, FL, United States
Care Department, Assistance Publique— Aleksandra Buha Djordjevic Department of
Hôpitaux de Paris, Necker Hospital, Paris, Toxicology ‘Akademik Danilo Soldatović’,
France; University Paris Diderot, Paris, France; Faculty of Pharmacy, University of Belgrade,
EA7323 Evaluation of therapeutics and pharma- Belgrade, Serbia
cology in perinatality and pediatrics—University
Tammy R. Dugas Comparative Biomedical
Hospital Cochin—Broca—Hôtel Dieu, Site
Sciences, LSU School of Veterinary Medicine,
Tarnier, University Paris Descartes, Paris, France
Baton Rouge, LA, United States
Jason Belden Department of Integrative Biology, Marion Ehrich Department of Biomedical Sciences
Oklahoma State University, Stillwater, OK, & Pathobiology, Virginia Maryland College of
United States Veterinary Medicine, Virginia Tech, Blacksburg,
Joseph R. Bidwell Department of Biological VA, United States
Sciences, East Tennessee State University, Marie Fortin Early Development Department,
Johnson City, TN, United States Jazz Pharmaceuticals, Philadelphia, PA, United
William K. Boyes Office of Research and States; Rutgers University, Department of
Development, U.S. Environmental Protection Pharmacology and Toxicology, Piscataway, NJ,
Agency, NC, United States United States

xiii
xiv List of contributors

Allison Franzen Ramboll US Corporation, S. Karanth Neuraly, Inc., Germantown, MD,

Monroe, LA, United States United States
Theresa M. Freudenrich Biomolecular and Hyung Sik Kim School of Pharmacy,
Computational Toxicology Division, Center for Sungkyunkwan University, Suwon, Republic of
Computational Toxicology and Exposure (CCTE), Korea
U.S. Environmental Protection Agency, Research James E. Klaunig School of Public Health, Indiana
Triangle Park, NC, United States University, Bloomington, IN, United States
Randle Gallucci Department of Pharmaceutical Gerwald Koehler Department of Biochemistry and
Science, University of Oklahoma Health Science Microbiology, Oklahoma State University Center
Center, Oklahoma City, OK, United States for Health Sciences, Tulsa, OK, United States
Robinan Gentry Ramboll US Corporation, Richard S. Lee Department of Psychiatry and
Monroe, LA, United States Behavioral Sciences, Johns Hopkins University
Duane A. Gill Department of Sociology, School of Medicine, Baltimore, MD, United States
Oklahoma State University, Stillwater, OK, Jing Liu Charles River Laboratories, Reno,
United States Nevada, United States
Scott Glaberman Department of Environmental Lin Liu Department of Physiological Sciences,
Science and Policy, George Mason University, Oklahoma State University, Stillwater, OK,
Fairfax, VA, United States United States
Tracy Greene Ramboll US Corporation, Monroe, Jordi Llorens Department of Physiological
LA, United States Sciences and Institute of Neurosciences, Faculty
Ramesh C. Gupta Toxicology Department, of Medicine and Health Sciences, Universitat de
Breathitt Veterinary Center, Murray State Barcelona, Barcelona, Spain
University, Hopkinsville, KY, United States
Edralin A. Lucas Department of Nutritional
Kirstin Hester Department of Physiological Sciences, Oklahoma State University, Stillwater,
Sciences, College of Veterinary Medicine, OK, United States
Interdisciplinary Toxicology Program, Oklahoma
Lerin Luckett-Chastain Department of
State University, Stillwater, OK, United States
Pharmaceutical Science, University of Oklahoma
Pascal Houzé Laboratory of Biochemistry, Health Science Center, Oklahoma City, OK,
Assistance Publique—Hôpitaux de Paris, United States
Necker Hospital, Paris, France; Laboratory of
Jie Luo Parkinson’s Disorder Research Laboratory,
Analytical Chemistry, Faculty of Pharmacy,
Iowa Center for Advanced Neurotoxicology,
University Paris Descartes, Paris, France;
Department of Biomedical Sciences, Iowa State
Chemical and Biological Technologies for Health
University, Ames, IA, United States
Unit, Paris 5-CNRS UMR8258 Inserm U1022,
Faculty of Pharmacy, University Paris Descartes, Marina Lopes Machado Department of
Paris, France Biochemistry and Molecular Biology, CCNE,
UFSM, Santa Maria, Brazil
Michael F. Hughes U.S. Environmental Protection
Agency, Office of Research and Development, Christopher J. Martyniuk University of Florida,
National Health and Environmental Effects Gainesville, FL, United States
Research Laboratory, Research Triangle Park, Lara Maxwell Department of Physiological
NC, United States Sciences, College of Veterinary Medicine,
Anumantha Kanthasamy Parkinson’s Disorder Oklahoma State University, Stillwater, OK,
Research Laboratory, Iowa Center for Advanced United States
Neurotoxicology, Department of Biomedical Matteo Minghetti Department of Integrative
Sciences, Iowa State University, Ames, IA, United Biology, Oklahoma State University, Stillwater,
States OK, United States
 List of contributors xv
Tamara L. Mix Department of Sociology, Timothy J. Shafer Biomolecular and
Oklahoma State University, Stillwater, OK, Computational Toxicology Division, Center for
United States Computational Toxicology and Exposure (CCTE),
K. Olivier Olivier KOnsulting LLC, Boston, MA, U.S. Environmental Protection Agency, Research
United States Triangle Park, NC, United States
Stephanie Padilla Biomolecular and Brenda J. Smith Department of Nutritional
Computational Toxicology Division, Center for Sciences, Oklahoma State University, Stillwater,
Computational Toxicology and Exposure, U.S. OK, United States
Environmental Protection Agency, Research Félix Alexandre Antunes Soares Department of
Triangle Park, NC, United States Biochemistry and Molecular Biology, CCNE,
Carey N. Pope Department of Physiological UFSM, Santa Maria, Brazil; Department of
Sciences, College of Veterinary Medicine, Molecular Pharmacology, Albert Einstein College
Interdisciplinary Toxicology Program, Oklahoma of Medicine Bronx, New York, NY, United States
State University, Stillwater, OK, United States Vicki Sutherland Division of the National
Benoı̂t Pouyatos Ototoxicity & Neurotoxicity Toxicology Program, National Institute of
Laboratory, National Research and Safety Environmental Health Sciences, Research
Institute for the Prevention of Occupational Triangle Park, NC, United States
Accidents and Diseases (INRS), Vandœuvre, Robyn Leigh Tanguay Sinnhuber Aquatic
France Research Laboratory, Oregon State University,
Jairus Pulczinski Department of Environmental Corvallis, OR, United States
Health and Engineering, Kennedy Krieger Kurt J. Varner Pharmacology and Experimental
Institute, Bloomberg School of Public Health, Therapeutics, LSU Health Sciences Center, New
Johns Hopkins University, Baltimore, MD, Orleans, LA, United States
United States Jarrad R. Wagner School of Forensic Sciences,
Shashi K Ramaiah Pfizer Inc., New York, NY, Oklahoma State University Center for Health
United States Sciences, Tulsa, OK, United States
Joshua D. Ramsey School of Chemical David R. Wallace Department of Pharmacology,
Engineering, Oklahoma State University, School of Biomedical Science, Oklahoma State
Stillwater, OK, United States University Center for Health Sciences, Tulsa, OK,
Rudy J. Richardson Computational Toxicology United States; Interdisciplinary Toxicology
Laboratory, University of Michigan, Ann Arbor, Program, Oklahoma State University, Stillwater,
MI, United States OK, United States
Dharmin Rokad Parkinson’s Disorder Research D.B. Warheit Warheit Scientific LLC, Wilmington,
Laboratory, Iowa Center for Advanced DE, United States
Neurotoxicology, Department of Biomedical Philip Wexler Retired, National Library of
Sciences, Iowa State University, Ames, IA, United Medicine, Bethesda, MD, United States
States Berran Yucesoy Department of Pharmaceutical
Courtney Roper Sinnhuber Aquatic Research Science, University of Oklahoma Health Science
Laboratory, Oregon State University, Corvallis, Center, Oklahoma City, OK, United States
OR, United States Daniele Coradini Zamberlan Department of
Daniel Schlenk Department of Environmental Biochemistry and Molecular Biology, CCNE,
Sciences, University of California, Riverside, CA, UFSM, Santa Maria, Brazil
United States
Justin Scott Department of Integrative Biology,
Oklahoma State University, Stillwater, OK,
United States
 Foreword

Toxicological risk can be defined by the sim- covalent binding or nongenomic alterations,
ple risk equation: RISK 5 INTRINSIC including epigenetic mechanisms, may play a
TOXICITY 3 EXPOSURE. As will be seen in pivotal role.
this volume, this equation encapsulates all At the organ system level, the impacts of
aspects of toxicology, from fundamental defini- toxicants on the hepatic, renal, respiratory, and
tions of toxicology to its many subdisciplines. cardiovascular systems are extensively exam-
Through its comprehensive coverage of this ined. The sensitivity of these systems, includ-
broad field, this work provides a useful and ing the immune and reproductive systems, is
logical description of toxicology in a meaning- appraised. Distribution of receptor systems,
ful and impactful manner. Spanning molecular metabolic capability, enzymatic pathways, and
toxicology, organ systems and organismal toxi- signaling pathways are examined as modula-
cology, ecotoxicology, and ultimately popula- tors of potential toxicity.
tion impact, An Introduction to Interdisciplinary Potentially toxic chemicals can be found
Toxicology covers the waterfront of the disci- almost anywhere, including homes, work-
pline of toxicology. places, and communities. Exposure to potential
Chemical exposure is widely explored in toxicants may vary widely in these different
this text because of its central role in defining environments, but knowledge of exposure sce-
toxicity. From absorption, distribution, metabo- narios and routes of exposure may provide
lism, and elimination of a chemical in an protective strategies for adults and children.
organism to environmental and occupational The principles of ecotoxicology are exam-
exposures, the general principles of chemical ined along with environmental impact of expo-
exposure are systematically examined. The sures to chemicals. The concept of
roles of competing pathways of metabolism, environmental justice is thoroughly examined
including the opportunity for induction of met- and forces that control it are discussed.
abolic enzymes with overall effects to magnify Because wildlife and plant life can be affected,
or lessen the toxicity, are described. the entire ecosystem must be considered. Even
Pathways to toxicity, including receptor the smallest of physico-chemical entities (i.e.,
interaction, intracellular signaling pathways, nanoparticles) are evaluated for their relative
and covalent binding, are thoroughly dis- toxicity profiles compared with more tradi-
cussed in pharmacological and molecular tional forms of those same chemicals.
terms. In many cases, the mechanistic basis for The toxicological world has several branches
a chemical’s toxicity is the disruption of an that are firmly attached to the major trunk of
endogenous biological pathway. Outcomes of the toxicology world. Among those examined
such disruption may be cancer or reproductive are clinical, veterinary, forensic, and regulatory
toxicity, yet other mechanisms such as DNA toxicology, each with its own focus of interest

xvii
xviii Foreword

but all firmly related to general toxicological toxicology provides the basis for understand-
principles. ing the importance of the principles of
Finally, model systems and various risk toxicology.
assessment approaches and tools are presented William Slikker
to strengthen and reinforce the principles of National Center for Toxicological Research,
toxicology. These approaches allow prediction U.S. Food and Drug Administration
and a quantitative definition of the risk associ- 2020 Published by Elsevier Inc.
ated with toxicant exposure. This comprehen-
sive and all-encompassing treatise on
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