Table Of ContentHASCHEK AND ROUSSEAUX’S
HANDBOOK OF
TOXICOLOGIC PATHOLOGY
FOURTH EDITION
Volume I: Principles and Practice of Toxicologic Pathology
Editors
WANDA M. HASCHEK
COLIN G. ROUSSEAUX
MATTHEW A. WALLIG
BRAD BOLON
Associate Editors
STACEY L. FOSSEY
JOHN H. VAHLE
Illustrations Editor
BETH W. MAHLER
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Dedication
.
To teach is to learn
(Japanese proverb)
Toourfamilies,teachers,colleagues,andfriendswhohavesupportedusinourjourneysthroughlife,
encouraged us when needed, mentored us in our learning, challenged us in our teaching,
joined us in our passion, followed us in our trailblazing,
.
and inspired us in our scholarly pursuits .
We are grateful for the opportunities we have enjoyed to advance pathology and toxicology as
distinct and blended disciplines, both for our own betterment and in
service to our local and global communities.
Contents
Contributors xxi 2.4. Metabolism:Activation and
Detoxification 24
About the Editors xxiii
2.5. Eliminationof Toxicants 30
Preface to the 4th Edition xxv
2.6. Effectsofthe Microbiomeon Absorption,
Distribution, Biotransformation and
1. Toxicologic Pathology: An Introduction Elimination 34
3. InteractionsofToxicants with Cellularand
WANDAM.HASCHEK,COLING.ROUSSEAUX,
Molecular Targets 35
MATTHEWA.WALLIGANDBRADBOLON
3.1. CovalentModification
1. An Overview of Toxicologic Pathology 1 Chapters3 and 8 35
2. What Is Toxicologic Pathology? 3 3.2. Stress Responses inToxicity 36
3. The BasisofToxicologic Pathology 3 3.3. Altered Gene Expression 38
4. Challenges in Toxicologic Pathology 4 3.4. Mechanisms ofCell Death 40
4.1. CoreChallenges 4 4. Idiosyncratic Mechanisms ofToxicity 42
4.2. Additional Challenges 6 5. Protective Mechanisms, Repair Mechanisms, and
5. Training and Certification in Toxicologic Adaptation orFailure 42
Pathology 8 5.1. Stress Response Constituents and
6. The “Practitioner” ofToxicologic Pathways 42
Pathology 9 5.2. Cell Repairand Adaptation 44
6.1. Industrial Toxicologic Pathology 9 5.3. FailuretoRepairAfterToxicInsult 46
6.2. Toxicologic Pathology Related tothe 6. Summary and Conclusions 47
Environmentand Food Safety 10 References 47
6.3. Diagnostic Toxicologic Pathology 10
6.4. Research in Toxicologic Pathology 11 3. ADME Principles in Small Molecule Drug
6.5. ManagementRoles in Toxicologic Discovery and Development: An Industrial
Pathology 11 Perspective
7. Summary 11
ELLENCANNADY,KISHOREKATYAYANANDNITAPATEL
References 12
1. Introduction 51
PART 1 2. General ADME Principles 52
3. Discovery Overview 54
Principles of Toxicologic Pathology
4. Absorption, Bioavailability, and PK/TK
Studies 55
2. Biochemical and Molecular Basis of
5. Distribution 59
Toxicity
5.1. VolumeofDistribution 59
LOISD.LEHMAN-MCKEEMANAND 5.2. Protein Binding 59
LAURAE.ARMSTRONG 5.3. Transporter Interactions 59
6. Metabolism 61
1. Introduction 15
6.1. Overview ofPhase I and Phase II
2. General Principles of Xenobiotic
Metabolism 61
Disposition 16
6.2. Overview ofReactive Metabolites 61
2.1. General Properties of
6.3. Discovery Metabolism 64
Absorption 16
7. Excretion 65
2.2. Routes ofAbsorption 19
8. PhysiologicallyBased PK Modeling 67
2.3. General Principles of
9. Development 67
Distribution 21
10. MassBalanceStudies 68
vii
viii CONTENTS
11. Tissue Distribution Studies 69 6. ResponseFollowing Chronic Dosing 110
12. DrugMetabolismStudies in 6.1. ReceptorDownregulation 111
Development 71 6.2. Exhaustion of Mediators 111
13. Excretion Studies 71 6.3. Physiological Adaptation 111
14. SpecializedExcretion Studies 73 6.4. Desensitization 111
15. General Timing ofDevelopment ADME 7. Quantitative Modeling for Pharmacokinetic/
Studies 73 Pharmacodynamic andToxicodynamic Data
16. Conclusions 74 Analysis 111
Acknowledgments 74 References 112
References 74
6. Morphologic Manifestations of Toxic Cell
4. BiotherapeuticsADMEandPK/PDPrinciples Injury
DANIELABUMBACAYADAV,KAPILGADKARAND MATTHEWA.WALLIGANDEVANB.JANOVITZ
ISABELFIGUEROA
1. Introduction 113
1. Introduction 77
1.1. Importance of Morphologic Assessment in
1.1. Monoclonal Antibodies 78
Toxicologic Pathology 113
1.2. Antibody-Based Therapeutics 80
1.2. Cell Injury inContextdStructural and
1.3. Beyond Antibody-Based
Functional Components of Cell
Therapeutics 81 Injury 114
2. PharmacokineticsofBiotherapeutics 83 1.3. Host ReactiontoCell Injury 116
2.1. Monoclonal Antibody PK 84 2. Adaptation 116
2.2. PKofAntibody-BasedTherapeutics 90
2.1. Atrophy 116
2.3. PK of Other Biotherapeutic
2.2. Hypertrophy 120
Modalities 92
3. Irreversible versus Reversible Cell
3. PharmacodynamicsofBiotherapeutics 92
Injury 122
4. PKePD Modelingand Interspecies
3.1. CellularSwelling 124
Scaling 95 3.2. Fatty ChangedLipidosis 126
5. Summary 96 4. Irreversible Cell Injury 127
References 96 4.1. Accidental Cell DeathdNecrosis 127
4.2. Programmed Cell Death 133
5. Principles of Pharmacodynamics and
4.3. Consequences ofIrreversible Cell
Toxicodynamics
Injury 139
JINWANGANDDAVIDM.STRESSER 5. Conclusion 146
References 146
1. Introduction: Definitionof Pharmacodynamics
andToxicodynamics 101
7. The Role of Pathology in Evaluation of
2. MechanismofDrug Action andAdverse Drug
Reproductive, Developmental, and Juvenile
Reaction 102
2.1. Physiochemical Property Based 102 Toxicity
2.2. Biochemical Based 102 CHRISTOPHERJ.BOWMANANDWENDYG.HALPERN
3. Types ofAdverse Drug Reaction: Intrinsic (Type
A) Versus Idiosyncratic (Type B) 104 1. Introduction 149
2. Reproductive Toxicity Assessment 150
4. Types ofXenobioticeTarget
2.1. Male Reproductive Toxicity
Interaction 106
Assessment 152
4.1. Reversible,Irreversible,Noncompetitive,and
2.2. Female Reproductive Toxicity
Allosteric Interaction 106
Assessment 159
4.2. Agonist,PartialAgonist, Antagonist, and
2.3. Guidelines 167
Inverse Agonist 106
5. Exposure-Dependent Response 107 3. PregnancyandDevelopmentalToxicity 167
5.1. ReceptorOccupancy Relationship 107 3.1. EmbryoeFetal Development
Studies 168
5.2. Turnover Model 108
3.2. Pre- and Postnatal Development
5.3. QuantalDoseeEffect Model 109
Studies 172
5.4. Nonmonotonic DoseeEffect 109
CONTENTS ix
3.3. Enhanced Pre- and PostnatalDevelopment 3.6. Two-Year National Toxicology Program
Study in the NHP 174 Rodent Carcinogenicity Bioassay 233
3.4. Guidelines 176 3.7. Carcinogenicity Testing 234
4. Juvenile Toxicity Assessment 177 3.8. Current and FutureConsiderations for
4.1. Context for Challenges in Assessingthe Carcinogenicity Testing in
NeonatalPeriod 179 Rodents 235
4.2. Context for Support ofChildren: Weaning 3.9. Conventional RatStrains for
through Puberty 179 Carcinogenicity Testing 237
4.3. Postnatal DevelopmentofSpecific Organ 3.10. MouseModelsofCarcinogenesis 238
Systems 180 3.11. Transgenic Models for Mutagenicity
4.4. Models ofDisease 188 Testing 240
4.5. Practical Species-Specific 3.12. The Tg.rasH2MouseModel 240
Considerations 188 3.13. The Tp53þ/(cid:2) Mouse Model 240
4.6. Guidelinesand Regional 3.14. Hamsters 240
Legislation 190 3.15. Zebrafish 241
5. Conclusions 192 3.16. Organoids 242
Abbreviations 192 3.17. Clinical Pathology 242
References 193 3.18. Histopathology 242
3.19. Carcinogenicity Study Data
8. Carcinogenesis: Mechanisms and Evaluation Interpretation 242
4. Evolving andNew Technologies 244
MARKJ.HOENERHOFF,MOLLYBOYLE,
SHEROYMINOCHERHOMJIANDARUNR.PANDIRI 4.1. Gene Expression Analysis 244
4.2. Next Generation Sequencing to Assess
1. Introduction 206
Mutagenicity andGenome
1.1. ProminentTheories of
Instability 244
Carcinogenesis 207
5. Conclusions 245
1.2. General Features of
Acknowledgments 246
Carcinogenesis 208
References 247
1.3. Cell Growthand Proliferation 210
1.4. Oncogenes andTumor Suppressor
Genes 213
PART 2
1.5. Apoptosis and DNA Damage
Repair 217 Methods in Toxicologic Pathology
1.6. Angiogenesis, Invasion,and
Metastasis 218 9. Basic Approaches in Anatomic Toxicologic
2. Mechanisms of Chemically Induced Pathology
Carcinogenesis 219
TORRIEA.CRABBSANDKEITHNELSON
2.1. GenotoxicCarcinogens 220
2.2. Direct Acting Carcinogens 220 1. Introduction 257
2.3. IndirectActing Carcinogens 220 2. General Considerations inStudy Protocol
2.4. Mechanisms ofHigh-fidelity/Nonmutagenic Development 258
orLow-fidelity/Mutagenic DNA 3. In-Life Evaluations 265
Repair 222 4. Necropsy 268
2.5. DNA Replicationand Repair 5. Fixation and Histologic Procedures 272
Mechanisms 222 6. Specialized Histologic Techniques 275
2.6. Consequences of Genotoxicity 224 7. Histopathologic Evaluation 277
2.7. Nongenotoxic Carcinogens 224 7.1. Cause ofDeath 278
3. Identification ofCarcinogensdTesting Programs 7.2. Nomenclature 279
and Guidelines 231 7.3. SeverityGrading 281
3.1. InVitro Mutagenicity Assays 231 8. Artifacts versusLesions 282
3.2. Chromosomal Aberration Assay 232 9. Diagnostic Challenges inAnatomic
3.3. Micronucleus Test 232 Toxicologic Pathology 284
3.4. Other DNA Based Assays 232 10. Conclusions 289
3.5. TestingProgramsandGuidelines 233 References 290
