Comprehensive Toxicology

Charlene McQueen

BOOK

Comprehensive Toxicology

Charlene McQueen

(2010)

Additional Information

Book Details

ISBN: 978-0-08-046884-6
Edition: 2
Language: English
Pages: 6448
Subjects: Pharmacology
Medical toxicology
Surgical orthopaedics & fractures
Ecological science, the Biosphere
The environment
Computer science

Abstract

An explosive increase in the knowledge of the effects of chemical and physical agents on biological systems has led to an increased understanding of normal cellular functions and the consequences of their perturbations. The 14-volume Second Edition of Comprehensive Toxicology has been revised and updated to reflect new advances in toxicology research, including content by some of the leading researchers in the field. It remains the premier resource for toxicologists in academia, medicine, and corporations.

Comprehensive Toxicology Second Edition provides a unique organ-systems structure that allows the user to explore the toxic effects of various substances on each human system, aiding in providing diagnoses and proving essential in situations where the toxic substance is unknown but its effects on a system are obvious. Comprehensive Toxicology Second Edition is the most complete and valuable toxicology work available to researchers today.

Contents updated and revised to reflect developments in toxicology research
Organized with a unique organ-system approach
Features full color throughout
Available electronically on sciencedirect.com, as well as in a limited-edition print version

Section Title	Page	Action	Price
e9780080468686v1	1
Cover	1
Comprehensive Toxicology	4
Copyright	5
Contents of Volume 1	6
Contents of All Volumes	8
Preface	18
1.01 General Overview of Toxicology	20
Abbreviations	21
1.01.1 Introduction	22
1.01.2 Concepts of Absorption, Distribution, Metabolism, and Excretion	30
1.01.3 Types of Toxic Effect	42
1.01.4 Toxicity Testing in Experimental Animals	58
1.01.5 Risk Assessment and Regulatory Toxicology	62
References	64
1.02 Exposure Science	66
1.02.1 Introduction	66
1.02.2 Basic Principles of Exposure Science	66
1.02.3 Methodologies	69
1.02.4 Environmental Media and Routes of Exposure	71
1.02.5 Biological Markers	72
1.02.6 Data Analysis and Models	74
1.02.7 Exposure Modeling	76
1.02.8 Uncertainties	76
1.02.9 Conclusion	76
Acknowledgments	76
References	76
1.03 Oral Exposure and Absorption of Toxicants	80
Abbreviations	80
1.03.1 Anatomy and Physiology of the Gastrointestinal Tract	80
1.03.2 The Process and Kinetics of Oral Absorption	83
1.03.3 Dose and Dose-Rate Effects	86
1.03.4 Factors Affecting Oral Absorption	87
1.03.5 Gastrointestinal Metabolism	90
1.03.6 Conclusion	91
References	92
1.04 Inhalation Exposure and Absorption of Toxicants	94
Abbreviations	95
1.04.1 Key Terms and Concepts in Inhalation Toxicokinetics	95
1.04.2 Deposition of Inhaled Particles	100
1.04.3 Removal of Particles from the Respiratory Tract	107
1.04.4 Uptake of Gases and Vapors	111
1.04.5 Removal of Gases and Vapors from the Respiratory Tract	119
1.04.6 Conclusions	127
References	127
Relevant Websites	128
1.05 Dermal Exposure and Absorption of Chemicals and Nanomaterials	130
1.05.1 Introduction	130
1.05.2 Structure and Function of Skin	130
1.05.3 Experimental Models to Assess Absorption and Penetration	131
1.05.4 Mathematical Models of Percutaneous Absorption	133
1.05.5 Quantitative Structure Permeability Analyses	136
1.05.6 Nanoparticle Absorption	138
1.05.7 Conclusion	140
References	140
1.06 The Application of ADME Principles in Pharmaceutical Safety Assessment	142
Abbreviations	142
1.06.1 Introduction	143
1.06.2 Study Design	143
1.06.3 Bioanalytical Considerations	147
1.06.4 Metabolite Monitoring	148
1.06.5 Methodology on Metabolite Monitoring	149
1.06.6 Quantitative Comparison of Metabolites Using Radiodetection	149
1.06.7 Toxicokinetic Evaluation	150
1.06.8 Toxicokinetic Evaluation Across Groups	151
1.06.9 When Does Systemic Exposure Fail to Predict Drug Response?	153
1.06.10 Interpretative Use of Toxicokinetic Information	154
1.06.11 Safety Margins	154
1.06.12 Conclusion	155
References	155
1.07 Biotransformation of Toxicants	156
1.07.1 Introduction	156
1.07.2 Enzymology	157
1.07.3 Phase I Metabolism	162
1.07.4 Phase II Metabolism	165
1.07.5 Target Tissue Metabolism	166
1.07.6 Factors Modifying Biotransformation	167
1.07.7 Pharmacogenetics	168
1.07.8 Conclusions	169
References	169
1.08 Modeling of Disposition	172
Abbreviations	172
1.08.1 Introduction	173
1.08.2 Compartmental Toxicokinetic Modeling	173
1.08.3 Physiologically Based Pharmacokinetic Models	180
1.09 Toxicological Interactions of Chemical Mixtures	198
Glossary	198
Abbreviations	198
1.09.1 Introduction	199
1.09.2 Unique Issues Related to Chemical Mixtures	201
1.09.3 Methodological Advances for Assessing Toxicology of Chemical Mixtures	204
1.09.4 PBPK/PD and BRN Modeling in Chemical Mixture Toxicology	207
1.09.5 Biochemical Mechanisms Underlying Chemical Interactions and Modulation of Response due to Chemical Interactions	212
1.09.6 Risk Assessment Issues for Chemical Mixtures	213
1.09.7 Future Perspectives: Nanotoxicology and Its Relevance to Chemical Mixtures	219
Acknowledgment	219
References	219
1.10 Experimental Models for the Investigation of Toxicological Mechanisms	222
1.11 Biomarkers of Exposure, Effect, and Susceptibility	244
Abbreviations	244
1.11.1 Introduction	245
1.11.2 Biomarker Development, Validation, and Application	246
1.11.3 Biomarkers of Exposure: General Principles	246
1.11.4 Biomarkers of Exposure: DNA Adducts	248
1.11.5 Biomarkers of Exposure: Protein Adducts	251
1.11.6 Biomarkers of Effect: Genetic Alterations	253
1.11.7 Biomarkers of Effect: Functional Biomarkers and Molecular Imaging	254
1.11.8 Biomarkers of Effect: Relation to Cancer Risk	255
1.11.9 Biomarkers of Susceptibility	256
1.11.10 Conclusion	259
Acknowledgments	259
References	259
Relevant Website	262
1.12 Cytolethality	264
Abbreviations	264
1.12.1 Introduction	265
1.12.2 Modes of Cell Death	266
1.12.3 Basic Features of Apoptosis and Necrosis	266
1.12.4 Mitochondrial Permeability Transition	268
1.12.5 Molecular Mechanisms in Apoptosis	268
1.12.6 Mitochondrial Proapoptotic Signaling	273
1.12.7 Nucleus	275
1.12.8 Endoplasmic Reticulum	276
1.12.9 Autophagy and Lysosomes	277
1.12.10 Mechanisms Underlying Necrotic Cell Death	277
1.12.11 Conclusion	284
Acknowledgments	284
References	284
1.13 Mitogenesis	288
Abbreviations	288
1.13.1 Introduction	288
1.13.2 Atrophy	289
1.13.3 Hypertrophy	289
1.13.4 Hyperplasia	291
1.13.5 Regeneration	293
1.13.6 Implications of Hyperplasia and Regeneration for Carcinogenesis	294
1.14 Free Radicals and Reactive Oxygen Species	296
Abbreviations	297
1.14.1 Introduction	297
1.14.2 Definitions	299
1.14.3 Biological Sources	303
1.14.4 Chemistries and Reactivities of Radicals	305
1.14.5 Cellular Targets of Free Radicals and Mechanisms Leading to Injury	310
1.14.6 Cell and Tissue Defense Systems	318
1.14.7 Conclusions	323
References	323
1.15 Reactive Electrophiles and Metabolic Activation	328
Abbreviations	328
1.15.1 Chemical Reactivity and Toxicity	328
1.15.2 Concepts of Electrophilicity and Nucleophilicity	329
1.15.3 Enzymes That Bioactivate Xenobiotics to Reactive Metabolites	331
1.15.4 Reactive Electrophiles	333
1.15.5 Conclusions	364
References	364
1.16 DNA-Reactive Agents	368
Abbreviations	368
1.16.1 Introduction	368
1.16.2 US EPA Cancer Guidelines and Incorporation of DNA-Reactive Agents	369
1.16.3 Metabolism of Carcinogens and Formation of DNA Adducts	370
1.16.4 Consequences of DNA Alterations – Gene and Chromosomal Mutations	376
1.16.5 Use of Chemistry and Biology in Risk Assessment	377
1.16.6 Conclusions	378
References	378
1.17 Xenobiotic Receptor-Mediated Toxicity	380
Abbreviations	380
1.17.1 Introduction	381
1.17.2 Estrogen Receptor-Mediated Toxicity	384
1.17.3 Diethylstilbestrol – A History	386
1.17.4 Peroxisome Proliferator-Activated Receptor-Mediated Toxicity/Cancer	394
1.17.5 TCDD Mediates Its Toxicity through the Aryl Hydrocarbon Receptor	401
1.17.6 Conclusions	405
References	405
1.18 Toxicogenomics, Proteomics, and Metabolomics	408
Abbreviations	408
1.18.1 Introduction	409
1.18.2 Genomics Resources for Toxicogenomics	410
1.18.3 Omics Technologies: Shifting the Paradigm from DNA!RNA! Protein to Genomics Protein to Genomics Transcriptomics! Proteomics	411
1.18.4 Specific DNA Analyses: Polymerase Chain Reaction and Microarrays	411
1.18.5 The Genomes: Human, Mouse, and Rat	413
1.18.6 Toxicogenomics and Human Genome Variation	413
1.18.7 Genome Control of Gene Expression: Epigenetics and the Epigenome	415
1.18.8 Transcriptomics: Quantifying Gene Expression by mRNA from Single Genes to the Transcriptome	416
1.18.9 Proteomics	416
1.18.10 Bioinformatics and Toxicogenomics	417
1.18.11 Integrating Toxicogenomics into Investigative Toxicology	417
1.18.12 Systems Toxicology	425
1.18.13 Conclusion	426
References	427
Relavant Websites	429
1.19 Modifications of Mitochondrial Function by Toxicants	430
Abbreviations	431
1.19.1 Mitochondrial Origins, Bioenergetic Function, Morphology, and Fate	432
1.19.2 Mitochondrial Function in Cellular Apoptosis: Endogenous ROS-mediated Cell Death	434
1.19.3 Mitochondrial Endogenous Toxins Formed by Genetic Inborn Errors of Metabolism	437
1.19.4 Mitochondrial Endogenous Toxins Formed by Acquired Diseases or Chemotherapy	440
1.19.5 Drugs or Xenobiotics that Inhibit Mitochondrial Energy Production	451
1.19.6 Conclusions	459
References	460
1.20 Risk Assessment	466
Glossary	466
Abbreviations	467
1.20.1 Introduction	467
1.20.2 Science and Regulation	468
1.20.3 A Brief History of Risk Assessment	474
1.20.4 Methods for Risk Assessment	476
1.20.5 Quantitative Risk Assessment	478
1.20.6 Conclusions	483
References	483
Index to Volume 1	484
e9780080468686v2	500
Cover	500
Comprehensive Toxicology	503
Copyright	504
Contents of Volume 2	505
Contents of All Volumes	509
Preface	519
2.01 Introduction to Molecular Toxicology	521
Glossary	521
Abbreviations	521
2.01.1 Basic Principles	522
Acknowledgment	528
References	528
2.02 A Molecular Perspective on Exposure–Dose–Response	529
Abbreviations	529
2.02.1 Public Health Considerations in Toxicology and Risk Assessment	530
2.02.2 Molecular Toxicology and Dose–Response	535
2.02.3 Conclusions	544
References	545
Relevant Website	546
2.03 Receptor Theory and the Ligand–Macromolecule Complex	547
2.04 Control of Gene Expression	571
Abbreviations	571
2.04.1 Introduction	572
2.04.2 Transcriptional Control of Gene Expression	572
2.04.3 Control of Gene Expression by Pre-mRNA Processing	579
2.04.4 PostTranscriptional Control of Gene Expression	585
2.04.5 Conclusions	588
References	588
2.05 Introduction and Overview of Receptor Systems	591
Abbreviations	591
2.05.1 Introduction	592
2.05.2 Structural Motifs and General Attributes of Nuclear Receptors	593
2.05.3 Basic Helix–Loop–Helix Proteins	594
2.05.4 Nuclear Hormone Receptors	595
2.05.5 C2H2 Zinc Finger Proteins	597
2.05.6 Protein Kinases and Phosphatases	597
2.05.7 Coregulators and Binding Partners	598
2.05.8 Conclusions	599
References	599
2.06 Cell Surface Receptors	601
Abbreviations	601
2.06.1 Introduction	601
2.06.2 General Characteristics of Cell Surface Receptors	602
2.06.3 G-Protein Coupled Receptors	603
2.06.4 Enzyme-Linked Receptors	606
2.06.5 Adhesion Molecules: Mediators of Cell–Matrix and Cell–Cell Interactions	608
2.06.6 Conclusions	610
References	610
2.07 Novel AHR Interactions	613
Abbreviations	613
2.07.1 Body: The AHR and Its Protein Interactions	614
2.07.2 Interactions with the Core AH Receptor Complex	616
2.07.3 Interactions in Inflammation and Oxidative Stress	622
2.07.4 Interactions in Hormone Signaling	624
2.07.5 Interactions in Cell Cycle Regulation	628
2.07.6 Conclusions	631
References	632
2.08 PAS Proteins: Comparative Biology and Proteasomal Degradation	637
2.09 Peroxisome Proliferator-Activated Receptors	665
Glossary	665
Abbreviations	665
2.09.1 Introduction	666
2.09.2 Structure–Function Relationship of PPARs	666
2.09.3 Physiological Roles of PPARs	678
2.09.4 Conclusion	684
References	684
2.10 Constitutive Androstane Receptor	689
Abbreviations	689
2.10.1 Introduction	689
2.10.2 The PB Induction Response	690
2.10.3 The Constitutive Androstane Receptor	693
2.10.4 Cellular Differentiation and Signaling	697
2.10.5 Summary	698
References	698
2.11 Modulation of Soluble Receptor Signaling by Coregulators	703
2.12 Convergence of Multiple Nuclear Receptor Signaling	727
Abbreviations	727
2.12.1 Historical Perspective	728
2.12.2 Regulation of Xenobiotic and Endogenous Compound Metabolism in the Liver	730
2.12.3 Physiological and Pathological Evidence of Cross Talk	733
2.12.4 Mechanisms of Nuclear Receptor Cross Talk	737
2.12.5 Conclusions	746
References	747
2.13 ARNT: A Key bHLH/PAS Regulatory Protein Across Multiple Pathways	751
2.14 Introduction and Overview of Genetic and Epigenetic Determinants of Susceptibility to Environmental Injury	773
2.15 Molecular Biomarkers	787
Abbreviations	787
2.15.1 Introduction	788
2.15.2 Molecular Biomarker Validation Strategies	789
2.15.3 Analytical Considerations for Measuring Molecular Biomarkers	791
2.15.4 Molecular Biomarkers of Carcinogen–DNA Adducts	793
2.15.5 Molecular Biomarkers of Carcinogen–Protein Adducts	798
2.15.6 Molecular Biomarkers of DNA and Protein Adducts for Exploring Cancer Risks	801
2.15.7 Molecular Biomarkers of Aflatoxin as a Paradigm	802
2.15.8 Summary and Perspectives for the Future	811
Acknowledgments	812
References	812
Relevant Website	815
2.16 Inherited Susceptibility to Complex Disease	817
Abbreviations	817
2.16.1 Complex Disease	817
2.16.2 Human Genetic Variation	819
2.16.3 Leading Causes of Death	820
2.16.4 Epigenetics	836
2.16.5 Conclusions	840
References	840
Relevant Website	843
2.17 Modeling Genetic Susceptibility to Disease	845
Abbreviations	845
2.17.1 Models for Toxicology Research	845
2.17.2 Construction of Murine Models of Disease by Gene Targeting	846
2.17.3 Identification of Disease Models Using Phenotypic Screens	852
2.17.4 Future Directions	852
References	853
Relevant Website	853
2.18 Epigenetics	855
Glossary	855
Abbreviations	856
2.18.1 Introduction	857
2.18.2 Epigenetic Mechanisms of Gene Regulation	858
2.18.3 Mechanisms of Epigenetic Disruption Resulting from Toxicant Exposure	866
2.18.4 Methods for Analysis of the Epigenome	871
2.18.5 The Future of Epigenetic Studies in Toxicology	873
References	875
2.19 Chromatin Remodeling	879
Abbreviations	879
2.19.1 Introduction	880
2.19.2 Chromatin Modifications	881
2.19.3 Chromatin Remodeling	884
2.19.4 Summary and Future Directions	892
References	892
2.20 Cellular Responses to DNA Damage	897
Abbreviations	897
2.20.1 Introduction	898
2.20.2 Cell Cycle Checkpoints	898
2.20.3 Repair	900
2.20.4 Mutagenesis	913
2.20.5 Conclusions	918
References	919
2.21 LINE-1	923
Glossary	923
Abbreviations	923
2.21.1 Overview	924
2.21.2 TE Diversity	924
2.21.3 Life Cycle of L1	925
2.21.4 Structure–Function Relationships	927
2.21.5 Reactivation Mechanisms	930
2.21.6 Consequences	935
2.21.7 Concluding Remarks and Perspectives	940
References	941
Relevant Website	946
2.22 Physiological and Pathological Functions of Mammalian MicroRNAs	947
Abbreviations	947
2.22.1 Introduction	948
2.22.2 miRNA Biology	948
2.22.3 Pathological Roles of Human miRNAs	956
2.22.4 miRNAs in Toxicology	961
2.22.5 Perspectives on miRNA-Based Therapeutics	961
Acknowledgments	962
References	962
2.23 Introduction and Overview of Alterations in Cell Signaling	967
Glossary	967
Abbreviations	968
2.23.1 Overview of Cell Signaling	970
2.23.2 Specific Signals	971
2.23.3 The Sensors	974
2.23.4 Signal Transduction Pathways	985
2.23.5 Conclusions	990
References	991
2.24 Protein Kinases	993
Abbreviations	993
2.24.1 Protein Kinases	993
2.24.2 New Frontiers in Protein Kinase Regulation	997
2.24.3 Perturbation of Signaling by Chemical Toxicants	999
2.24.4 Proinflammatory States and Protein Kinase Regulation	1004
2.24.5 State-of-Art Technologies for Characterizing Protein Phosphorylation	1007
2.24.6 Summary	1010
References	1010
2.25 Heavy Metal-Regulated Gene Expression	1015
Nomenclature	1015
Abbreviations	1015
2.25.1 Introduction	1016
2.25.2 Neurotoxicity of Lead	1017
2.25.3 Gene Expression	1026
2.25.4 Lead-Associated Diseases	1035
2.25.5 Conclusions	1036
References	1037
2.26 Antioxidant Induction of Gene Expression	1043
Abbreviations	1043
2.26.1 Antioxidant Induction of Gene Expression in Chemoprevention	1043
2.26.2 Antioxidant Response Element	1044
2.26.3 Nuclear and Cytosolic Factors that Regulate ARE-Mediated Gene Expression	1044
2.26.4 Mechanism of Signal Transduction from Antioxidants and Xenobiotics to Nrf2	1046
2.26.5 Future Perspectives	1047
Acknowledgments	1047
References	1047
2.27 Hypoxia/Ischemia Signaling	1049
Abbreviations	1049
2.27.1 Introduction	1049
2.27.2 Reactive Oxygen Species	1050
2.27.3 Calcium Regulation	1050
2.27.4 Hypoxia-Inducible Factor-1	1051
2.27.5 Endoplasmic Reticulum Stress/Unfolded Protein Response	1053
2.27.6 Inflammation	1054
2.27.7 Chemical Mimetics of Hypoxia/Ischemia	1055
2.27.8 Conclusion	1056
References	1057
2.28 Apoptosis	1063
Abbreviations	1063
2.28.1 History and Evolution of Apoptosis	1064
2.28.2 Caspases	1066
2.28.3 BCL-2 Family Members	1078
2.28.4 Inhibitors of Caspases	1084
2.28.5 Facilitators of Caspase Activation	1086
2.28.6 p53: Tumor Supressor	1087
2.28.7 ATP, Reactive Oxygen Species, and Calcium	1087
2.28.8 Toxicant-Induced Apoptosis	1091
2.28.9 Concluding Remarks	1091
References	1091
Relevant Websites	1098
2.29 Regulation of Xenobiotic Sensor PXR and AhR by NF-and Its Roles in Xenobiotic Detoxification and Inflammation- Associated Carcinogenesis	1099
Abbreviations	1099
2.29.1 Introduction	1099
2.29.2 PXR and Its Roles in Xenobiotic Metabolism and Beyond	1100
2.29.3 Classic and Alternative NF-κB Pathways	1101
2.29.4 AhR and NF- κB Interaction in Lung Inflammation	1102
2.29.5 Cross talk between PXR and NF- κBand Its Role in the Regulation of Xenobiotic Metabolism and Inflammation	1103
2.29.6 Colorectal Cancer and Inflammation: Does PXR–NF- κB Interaction Play a Role?	1104
Acknowledgments	1104
References	1104
2.30 Calcium and Proteases	1107
Abbreviations	1107
2.30.1 Introduction	1108
2.30.2 Components of Intracellular Ca2+ Homeostasis	1109
2.30.3 Components of Intracellular Ca2+ Homeostasis – Ca2+ Channels	1112
2.30.4 Calpains	1118
2.30.5 Conclusion	1127
Acknowledgments	1127
References	1127
2.31 Estrogenic Endocrine Disruptors: Molecular Characteristics and Human Impacts	1129
Abbreviations	1129
2.31.1 Introduction	1129
2.31.2 Endocrine Disruptors and Hormone-Dependent Diseases	1130
2.31.3 Endocrine Disruptors: Chemicals of Concern	1131
2.31.4 Xenoestrogens and Phytoestrogens as SERMs: Implications for Risk Assessment	1133
2.31.5 EDs and their Effects on Male Reproductive Tract Problems	1138
2.31.6 Organochlorine EDs and Breast Cancer	1139
2.31.7 Conclusions	1139
Acknowledgments	1139
References	1139
2.32 Introduction and Overview of Technological Advances and Predictive Assays	1143
Glossary	1143
Abbreviations	1145
2.32.1 Introduction	1145
2.32.2 Bioinformatics	1145
2.32.3 Expressed Sequence Tags	1147
2.32.4 Transcript Profiling	1149
2.32.5 Proteomics	1154
2.32.6 Metabol(n)omics in Toxicology	1154
2.32.7 Data Mining	1155
References	1158
2.33 Genomics, Bioinformatics, and Computational Biology	1161
Abbreviations	1161
2.33.1 Introduction	1161
2.33.2 Computational and Systems Biology	1164
2.33.3 Modeling Cellular Development via Systems Biology	1169
2.33.4 Informatics Infrastructure within a Research Enterprise	1170
2.33.5 The Environment	1171
2.33.6 Solution	1174
2.33.7 Conclusions	1179
Acknowledgments	1180
References	1180
2.34 Interpretation of Toxicogenomics Data	1183
Abbreviations	1183
2.34.1 Introduction	1184
2.34.2 Major Classes of Toxicogenomics Studies	1185
2.34.3 Identification of Differentially Expressed Genes – A Critical Task	1188
2.34.4 Interpretation of Differentially Expressed Genes	1189
2.34.5 Beyond Differentially Expressed Genes	1194
2.34.6 Empowering Toxicogenomics Data Interpretation with Bioinformatics	1197
References	1202
Relevant Websites	1203
2.35 Metabolomics-Edited Transcriptomics Analysis (Meta)	1205
Abbreviations	1205
2.35.1 Introduction	1206
2.35.2 Sample Handling and Preparation	1207
2.35.3 Deciphering AntiCancer Selenite Action in Lung Cancer Cells Using META	1213
2.35.4 Conclusion	1224
Acknowledgments	1224
References	1225
2.36 Nanotoxicology	1227
Abbreviations	1227
2.36.1 History of Nanomaterials	1227
2.36.2 Ultrafine Particles	1228
2.36.3 Effort in Bioengineering and Biocompatibility of Nanomaterials	1228
2.36.4 Why Nanomaterials Are Different from Other Materials?	1229
2.36.5 Applications of Nanomaterials	1229
2.36.6 Challenges of Dosemetrics in Nanotoxicology	1230
2.36.7 Routes of Exposure	1231
2.36.8 Applications of Nanotoxicology in Immunotoxicology	1233
2.36.9 Nanoparticle–Cell Interactions May Follow One or More Precise Pathways	1234
2.36.10 Conclusions	1234
References	1235
2.37 Functional Genomics: Uncovering Cellular and Subcellular Mechanisms of Action	1237
Glossary	1237
Abbreviations	1238
2.37.1 Functional Genomics	1238
2.37.2 Transcriptomic Analyses	1240
2.37.3 Bioinformatic Approaches in Transcriptomic Analyses	1241
2.37.4 Determining Mechanism of Action by Transcript Profiling	1242
2.37.5 Conclusions	1247
References	1248
2.38 Emerging Concepts and Techniques	1251
Abbreviations	1251
2.38.1 Introduction	1251
2.38.2 Overview of Toxicogenomics	1252
2.38.3 Sequencing Technologies and Their Uses	1252
2.38.4 Arrays	1254
2.38.5 Molecular Imaging	1258
References	1260
Index to Volume 2	1263
e9780080468686v3	1275
Cover	1275
Comprehensive Toxicology	1278
Copyright	1279
Contents of Volume 3	1280
Contents of All Volumes	1282
Preface	1292
3.01 Introduction to Toxicology Testing and Evaluation	1294
3.02 Assessing Risks to Human Health	1296
Glossary	1296
Abbreviations	1298
3.02.1 Introduction	1298
3.02.2 Hazard Identification	1298
3.02.3 Dose Response	1300
3.02.4 Exposure Assessment	1303
3.02.5 Risk Characterization	1304
3.02.6 Risk Management	1304
3.02.7 Risk Communication	1305
3.02.8 Current Issues	1305
3.02.9 Sample Risk Calculation – US EPA Approach	1306
References	1307
3.03 Safety Assessment of Pharmaceuticals	1310
Abbreviations	1310
3.03.1 Introduction	1311
3.03.2 The Safety Assessment Process	1311
3.03.3 Regulatory Requirements for Nonclinical Testing	1312
3.03.4 Safety Testing in Context of Clinical Requirements	1314
3.03.5 Summary of Nonclinical Safety Test Requirements	1314
References	1320
3.04 Considerations for the Preclinical Safety Evaluation of Biopharmaceuticals	1322
Abbreviations	1322
3.04.1 Introduction	1323
3.04.2 Background	1324
3.04.3 Key Differences in the Evaluation between Traditional Pharmaceuticals and Biopharmaceuticals Biopharmaceuticals	1325
3.04.4 The ‘Case-by-Case’ Approach	1328
3.04.5 General Principles	1328
3.04.6 Study Design Issues	1329
3.04.7 Identification of General Toxicity	1334
3.04.8 Characterization of Specific Toxicity	1334
3.04.9 Additional Requirements	1339
3.04.10 First-in-Human Dose Selection	1339
3.04.11 Integrated Safety Assessment	1340
3.04.12 Optimization of Animal Use	1340
3.04.13 Risk Evaluation and Mitigation Strategy	1341
3.04.14 Conclusions	1341
References	1343
3.05 Safety Assessment of Nanotechnology Products	1346
Abbreviations	1346
3.05.1 Background on Nanotechnology	1346
3.05.2 Applications	1347
3.05.3 Classification and Metrics	1347
3.05.4 Governmental Involvement	1349
3.05.5 High-Throughput Toxicity Evaluation	1351
3.05.6 Exposure Assessment to ENMs	1352
3.05.7 Path Forward	1353
References	1354
3.06 Occupational Toxicology Testing	1358
Abbreviations	1358
3.06.1 Introduction	1359
3.06.2 Hazard Assessments	1359
3.06.3 Regulatory Requirements	1363
3.06.4 Specific Occupational Toxicology Tests	1371
3.06.5 Further Uses of Occupational Toxicology Data	1374
3.06.6 Future Directions for Occupational Toxicology	1376
3.07 Standards of Good Practice for the Conduct of Regulated Nonclinical Safety Studies	1380
Abbreviations	1380
3.07.1 Introduction	1380
3.07.2 Regulatory History	1380
3.07.3 Good Laboratory Practice Standards	1381
3.07.4 Regulatory Inspections and Audits	1387
3.07.5 Conclusions	1388
References	1388
3.08 Animal Care and Use in Toxicity Testing	1390
Abbreviations	1391
3.08.1 Introduction	1391
3.08.2 The Use of Animals in Toxicity Testing	1391
3.08.3 Regulations and Standards for Animal Care and Use	1393
3.08.4 Associations and Professional Organizations Related to Animal Care and Use	1395
3.08.5 Animal Care and Use Study Requirements in Toxicity Testing	1395
3.08.6 Animal Model Selection	1395
3.08.7 Sources of Experimental Variability in Toxicity Testing due to the Animal Environment	1398
3.08.8 The Use of Alternative Approaches in Toxicology Research and Testing	1402
3.08.9 Challenges for the Future	1406
References	1406
3.09 Carcinogenicity	1410
Abbreviations	1411
3.09.1 Introduction	1411
3.09.2 Definitions	1411
3.09.3 Multistage Carcinogenesis	1412
3.09.4 Mechanisms of Carcinogen Action	1414
3.09.5 Proto-Oncogenes and Tumor-Suppressor Genes	1421
3.09.6 Test Systems for Carcinogenicity Assessment	1423
3.09.7 Application of Bioassay Information to Human Cancer Risk	1427
3.09.8 Mode of Action Approach for Assessing Human Risk to Carcinogens	1429
Relevant Websites	1431
3.10 Genetic Toxicology Testing	1432
Glossary	1432
Abbreviations	1433
3.10.1 Introduction	1433
3.10.2 Definitions and Types of Genetic Damage	1435
3.10.3 General and Safety Considerations	1437
3.10.4 Descriptions of Genetic Toxicity Tests	1438
3.10.5 Testing Schemes – Tiered Battery	1447
3.10.6 Uses/Implications of Test Results	1448
3.10.7 Genetic Toxicity Test Guidelines	1448
3.11 Reproductive and Developmental Toxicity Studies	1452
Abbreviations	1452
3.11.1 Introduction	1452
3.11.2 Definitions of Reproductive Toxicology	1454
3.11.3 Guideline Studies	1455
References	1463
Relevant Websites	1465
3.12 Human Clinical Safety Assessment Procedures	1466
Abbreviations	1466
3.12.1 Introduction	1466
3.12.2 Investigational New Drug Application	1467
3.12.3 New Drug Application	1468
3.12.4 Clinical Trials	1469
3.12.5 Fast Track and Accelerated Approval	1473
3.12.6 ‘Alternate Path Development’	1473
3.12.7 Postmarket Evaluation of Safety	1473
3.12.8 Regulatory Approval and Commercial Distribution	1474
3.12.9 Concluding Remarks	1474
References	1474
Relevant Websites	1474
3.13 Statistical Methods in Toxicology	1476
Abbreviations	1477
3.13.1 Introduction	1477
3.13.2 Basics	1478
3.13.3 Methods	1480
3.13.4 Applications	1484
References	1489
3.14 Ocular and Dermal Local Tissue Tolerance Studies	1492
Abbreviations	1492
3.14.1 Introduction	1492
3.14.2 Dermal Testing	1494
3.14.3 Ocular Testing	1498
References	1502
Relevant Website	1503
3.15 Immunotoxicity Studies	1504
Abbreviations	1504
3.15.1 Introduction	1505
3.15.2 The Immune System and Immune Function	1505
3.15.3 Assessment of the Immune System	1507
3.15.4 Regulations and Guidelines for Evaluating Immune System Toxicity	1514
3.15.5 Risk Assessment of Immune System Toxicity	1515
3.15.6 Conclusions	1515
Acknowledgment	1516
References	1516
Relevant Websites	1516
3.16 Inhalation Toxicology Studies	1518
Abbreviations	1518
3.16.1 Introduction	1519
3.16.2 Reasons for Conducting Inhalation Toxicology Studies	1519
3.16.3 Regulatory Authority and Guidelines	1520
3.16.4 Inhalation Exposure Technology	1522
3.16.5 Dose	1528
3.16.6 Respiratory Tract Toxicity	1531
3.16.7 Considerations for Inhaled Pharmaceuticals	1533
3.16.8 Interpretation of Results of Inhalation Toxicology Studies	1534
3.16.9 Conclusions	1535
References	1535
3.17 Alternatives to Conventional Toxicology Testing	1540
Abbreviations	1540
3.17.1 Why There is Need for Replacement Alternatives	1540
3.17.2 Current Approaches	1542
3.17.3 Possible Approaches in the Future	1546
3.17.4 Conclusions	1551
References	1551
Index to Volume 3	1554
e9780080468686v4	1562
Cover	1562
Comprehensive Toxicology	1565
Copyright	1566
Contents of Volume 4	1567
Contents of All Volumes	1569
Preface	1579
4.01 Biotransformation: Introduction and Historical Perspective	1581
Glossary	1581
Abbreviations	1581
4.01.1 Introduction	1581
4.01.2 History and Identification of Urinary Products	1582
4.01.3 Cancer Epidemiology and Chemical Carcinogenesis	1583
4.01.4 Enzymology	1583
4.01.5 Prelude to Other Chapters	1585
References	1586
Relevant Website	1587
4.02 Enzyme Regulation	1589
Glossary	1589
Abbreviations	1589
4.02.1 Introduction	1591
4.02.2 Regulation by Transcriptional Mechanisms	1591
4.02.3 Regulation by Post-Transcriptional Mechanisms	1603
4.02.4 Regulation by Genetic Polymorphisms	1604
Acknowledgments	1606
References	1606
Relevant Website	1609
4.03 Mechanisms of Enzyme Catalysis and Inhibition	1611
Glossary	1611
Abbreviation	1611
4.03.1 Introduction	1612
4.03.2 General Principles of Transition State Theory	1612
4.03.3 Classical Mechanisms of Catalysis	1613
4.03.4 Kinetics	1614
4.03.5 Cofactors and Prosthetic Groups	1615
4.03.6 General Modes of Catalysis with Key Enzyme Groups	1615
4.03.7 Enzyme Inhibition	1616
4.03.8 Enzyme Stimulation	1617
References	1619
4.04 Cytochrome P450 Enzymes	1621
Glossary	1621
Abbreviations	1623
4.04.1 Historical Perspective	1623
4.04.2 Nomenclature	1630
4.04.3 Gene Organization and Relationships	1631
4.04.4 Polymorphisms	1632
4.04.5 Regulation of Gene Expression	1633
4.04.6 Protein Structure	1635
4.04.7 Catalytic Mechanisms	1638
4.04.8 Catalytic Selectivity of P450s	1644
4.04.9 Roles of P450S in Biotransformation of Toxic Chemicals	1648
4.04.10 Clinical Significance	1650
4.04.11 Future Directions	1652
References	1652
Relevant Website	1656
4.05 Monoamine Oxidases and Flavin-Containing Monooxygenases	1657
Glossary	1657
Abbreviations	1659
4.05.1 General Introduction	1659
4.05.2 Monoamine Oxidase	1660
4.05.3 Flavin-Containing Monooxygenases	1671
4.05.4 Future Directions and Needs in the Field	1683
Acknowledgments	1683
References	1684
Relevant Website	1689
4.06 Alcohol Dehydrogenases	1691
Abbreviations	1691
4.06.1 Introduction	1691
4.06.2 Nomenclature	1691
4.06.3 Gene Organization and Relationships	1693
4.06.4 Regulation of Gene Expression	1694
4.06.5 Major Polymorphisms	1698
4.06.6 Catalytic Mechanism	1699
4.06.7 Protein Structures	1700
4.06.8 Substrate Selectivity	1701
4.06.9 Roles in Toxicity and Clinical Significance	1702
4.06.10 Future Directions and Needs in Field	1706
Acknowledgments	1706
References	1706
Relevant Website	1710
4.07 Aldehyde Dehydrogenases	1711
Glossary	1711
Abbreviations	1712
4.07.1 Introduction and Overview	1712
4.07.2 The ALDH Superfamily: Nomenclature, Gene Organization, and Function	1713
4.07.3 Catalytic Mechanisms of Aldehyde Dehydrogenases	1716
4.07.4 Esterase Activity of Aldehyde Dehydrogenase	1717
4.07.5 Inhibitors of Aldehyde Dehydrogenases	1717
4.07.6 Polymorphisms and Mutational Phenotypes in Humans and Mice	1720
Acknowledgments	1724
References	1724
Relevant Websites	1727
4.08 Aldo-Keto Reductases	1729
Glossary	1729
Abbreviations	1729
4.08.1 Introduction	1730
4.08.2 Nomenclature	1731
4.08.3 Gene Organization and Relationships	1731
4.08.4 Regulation of Gene Expression	1734
4.08.5 Major Polymorphisms	1734
4.08.6 Kinetic and Catalytic Mechanism	1735
4.08.7 Protein Structures (Three-Dimensional)	1738
4.08.8 Substrate Selectivity	1739
4.08.9 Roles in Toxicity and Clinical Significance	1741
4.08.10 Future Directions and Needs in Field	1744
Acknowledgments	1745
References	1745
Relevant Websites	1747
4.09 Peroxidases	1749
Abbreviations	1749
4.09.1 Introduction	1750
4.09.2 Nomenclature	1750
4.09.3 Regulation of Gene Expression	1750
4.09.4 Major Polymorphisms	1752
4.09.5 Catalytic Mechanism	1752
4.09.6 Structure	1754
4.09.7 Substrate Selectivity	1757
4.09.8 Roles in Toxicity and Clinical Significance	1761
References	1762
4.10 Xanthine Oxidoreductase and Aldehyde Oxidase	1765
Glossary	1765
Abbreviations	1767
4.10.1 Introduction	1767
4.10.2 Gene Organization and Relationships	1769
4.10.3 Protein Structure	1772
4.10.4 Catalytic Mechanism	1773
4.10.5 Substrate Specificity	1777
4.10.6 Roles in Toxicity and Clinical Significance	1780
References	1782
4.11 Quinone Reductases	1787
Abbreviations	1787
4.11.1 Background and History	1787
4.11.2 Nomenclature of the NQO Family	1789
4.11.3 Evolutionary Divergence of NQO Genes	1789
4.11.4 Structural Studies of NQO1 and NQO2	1789
4.11.5 Genomic Organization	1790
4.11.6 Regulation of Gene Expression	1790
4.11.7 Catalytic Mechanism	1791
4.11.8 Polymorphisms in NQO1 and NQO2	1791
4.11.9 Quinone Reductases in Cellular Defense	1792
4.11.10 Bioactivation by NQO1 and NQO2	1795
Acknowledgments	1796
References	1796
4.12 Superoxide Dismutase and Catalase	1799
Glossary	1799
Abbreviations	1800
4.12.1 Introduction	1800
4.12.2 Superoxide Dismutases (SOD, EC 1.15.1.1)	1802
4.12.3 Catalases (EC 1.11.1.6)	1803
4.12.4 Clinical Scenarios Related to Changes in SOD and/or Catalase Activity	1804
4.12.5 Future Directions	1806
References	1806
4.13 Glutathione Peroxidases	1809
Glossary	1809
Abbreviations	1810
4.13.1 Introduction	1810
4.13.2 Nomenclature	1811
4.13.3 Gene Organization and Relationships	1813
4.13.4 Regulation of Gene Expression	1815
4.13.5 Major Polymorphisms	1816
4.13.6 Catalytic Mechanism	1817
4.13.7 Protein Structure	1818
4.13.8 Substrate Selectivity	1819
4.13.9 The Peroxiredoxin Family	1819
4.13.10 Roles in Toxicity and Clinical Significance	1820
References	1821
Relevant Websites	1822
4.14 Esterases	1823
Glossary	1824
Abbreviations	1824
4.14.1 Introduction	1825
4.14.2 Nomenclature	1825
4.14.3 How Many Human Esterases Are There?	1826
4.14.4 Tissue Expression of Human Esterases	1828
4.14.5 Gene Organization and Relationships	1830
4.14.6 Major Polymorphisms	1832
4.14.7 Esterase Function	1836
4.14.8 Purification of Proteins	1839
4.14.9 Catalytic Triad	1840
4.14.10 Enzyme Kinetics	1841
4.14.11 Substrate Molecular Recognition	1843
4.14.12 Protein Structures (3-Dimensional)	1846
4.14.13 Substrate Selectivity	1848
4.14.14 Future Directions and Needs in the Field	1850
4.14.15 Conclusions	1850
References	1850
Relevant Websites	1853
4.15 Mammalian Epoxide Hydrolases	1855
Abbreviations	1855
4.15.1 Introduction	1856
4.15.2 Nomenclature	1857
4.15.3 Gene Organization, Relationships, and Transcriptional Regulation	1857
4.15.4 Protein Structures	1859
4.15.5 Catalytic Mechanism	1862
4.15.6 Substrate Selectivity	1865
4.15.7 Major Polymorphisms	1867
4.15.8 Roles in Toxicity and Clinical Significance	1868
4.15.9 Future Directions and Needs in Field	1871
References	1871
Relevant Websites	1874
4.16 Glutathione Transferases	1875
Glossary	1875
Abbreviations	1876
4.16.1 Introduction	1876
4.16.2 Superfamilies and Nomenclature of GSH Transferases	1877
4.16.3 Gene Structure and Regulation	1879
4.16.4 Enzyme Structure	1881
4.16.5 Catalytic Mechanism	1886
4.16.6 GSH Transferases and Human Health	1892
4.16.7 Future Questions	1895
References	1896
4.17 Enzymes Involved in Processing Glutathione Conjugates	1903
Glossary	1904
Abbreviations	1905
4.17.1 Introduction	1905
4.17.2 Enzymes of the Mercapturate Pathway	1906
4.17.3 Interorgan Transport of Mercapturates and Mercapturate Intermediates	1913
4.17.4 Biotransformations of Endogenous Compounds Through the Mercapturate Pathway	1916
4.17.5 Metabolic Pathways Diverging from Mercapturate Biosynthesis	1918
4.17.6 Cysteine S-Conjugate β-Lyases	1922
4.17.7 Major Cysteine S-Conjugate β-Lyases of Mammalian Tissues	1930
4.17.8 Role of the Mercapturate Pathway and Cysteine S-Conjugate β-Lyases in the Bioactivation of Toxic Halogenated Alkenes	1932
4.17.9 Mechanisms Contributing to the Nephrotoxicity of Haloalkene Cysteine S-Conjugates – Toxicant Channeling	1932
4.17.10 Toxic Homocysteine S-Conjugates	1934
4.17.11 Electrophilic Xenobiotics Metabolized through the Mercapturate Pathway	1935
4.17.12 Conclusions	1937
Acknowledgments	1939
References	1939
Relevant Websites	1945
4.18 Sulfotransferases	1947
Glossary	1947
Abbreviations	1947
4.18.1 Introduction	1948
4.18.2 Nomenclature	1950
4.18.3 Gene Organization	1950
4.18.4 Regulation of Gene Expression	1951
4.18.5 Polymorphisms	1952
4.18.6 Protein Structure and Catalysis	1953
4.18.7 Substrate Specificity	1956
4.18.8 Roles in Toxicology and Clinical Significance	1958
4.18.9 Summary and Future Directions	1960
Acknowledgments	1960
References	1960
4.19 Arylamine N-acetyltransferases	1965
Abbreviations	1965
4.19.1 Introduction and Brief Historical Perspective	1966
4.19.2 Nomenclature	1968
4.19.3 Gene Organization and Relationships	1969
4.19.4 Regulation of Gene Expression	1973
4.19.5 Major Polymorphisms in Human NATs	1975
4.19.6 Catalytic Mechanism	1977
4.19.7 Substrate Specificity	1979
4.19.8 NAT Three-Dimensional Structures	1980
4.19.9 Roles in Toxicity and Clinical Significance	1986
4.19.10 Bacterial NAT Enzymes	1987
4.19.11 Future Directions and Needs in the Field	1988
References	1988
Relevant Website	1992
4.20 UDP-Glucuronosyltransferases	1993
Glossary	1993
Abbreviations	1993
4.20.1 Introduction	1994
4.20.2 UDP-Glucuronosyltransferase Nomenclature	1995
4.20.3 UDP-Glucuronosyltransferase Gene Organization	1997
4.20.4 Regulation of UDP-Glucuronosyltransferase Gene Expression	1999
4.20.5 Polymorphisms of UDP-Glucuronosyltransferase Genes	2002
4.20.6 Catalytic Properties of UDP-Glucuronosyltransferases	2004
4.20.7 Structure of UDP-Glucuronosyltransferases	2007
4.20.8 Roles of UDP-Glucuronosyltransferases in Toxicity and Clinical Significance	2008
4.20.9 Future Directions	2010
References	2010
Relevant Websites	2013
4.21 Methyltransferases	2015
Glossary	2015
Abbreviations	2017
4.21.1 Introduction	2017
4.21.2 Catechol O-Methyltransferase	2019
4.21.3 Histamine N-Methyltransferase	2024
4.21.4 Thiol Methyltransferase	2026
4.21.5 Thiopurine Methyltransferase	2028
4.21.6 Summary	2033
Acknowledgments	2034
References	2034
4.22 Enzymology of Amino Acid Conjugation Reactions	2039
Glossary	2040
Nomenclature	2040
Abbreviations	2040
4.22.1 Amino Acid Conjugation in Xenobiotic Metabolism	2040
4.22.2 Mitochondrial Amino Acid Conjugating System	2041
4.22.3 Bile Acid Conjugation	2053
4.22.4 Conclusion	2060
References	2061
4.23 Sulfurtransferase Enzymes Involved in Cyanide Metabolism	2065
Glossary	2065
Abbreviations	2066
4.23.1 Introduction	2066
4.23.2 Cyanide Detoxication Pathways	2066
4.23.3 Enzymes that Catalyze Cyanide Metabolism	2067
4.23.4 Sulfane Sulfur Pool	2068
4.23.5 Thiosulfate: Cyanide Sulfurtransferase (Rhodanese)	2069
4.23.6 3-Mercaptopyruvate Sulfurtransferase	2075
4.23.7 Thiosulfate Reductase	2077
4.23.8 Cystathionase γ-Lyase	2077
4.23.9 Albumin as a Sulfurtransferase	2077
4.23.10 Endogenous Cyanide Generation and the Role of Metabolism	2078
4.23.11 Conclusion	2078
References	2078
4.24 Metallothionein and Intracellular Sequestration of Metals	2081
Abbreviations	2081
4.24.1 Introduction	2081
4.24.2 Discovery, Isolation, and Characterization	2082
4.24.3 Isoforms and Gene Organization	2083
4.24.4 Regulation of MT Biosynthesis	2084
4.24.5 Developmental Changes in Expression and Cellular Localization	2085
4.24.6 Biological Functions	2087
4.24.7 Transgenic Mice Models and Functional Studies	2090
4.24.8 MT Gene Polymorphism and Pathogenic Impact on Human Health	2091
4.24.9 Presence in Human Tumors and Role in Carcinogenesis	2092
4.24.10 Conclusions	2095
References	2095
Relevant Websites	2097
4.25 Uptake Transporters	2099
Glossary	2100
Abbreviations	2102
4.25.1 Introduction	2103
4.25.2 Nomenclature	2103
4.25.3 Gene Organization	2104
4.25.4 Regulation of Gene Expression	2104
4.25.5 Major Polymorphisms	2110
4.25.6 Transport Mechanisms	2116
4.25.7 Protein Structure	2118
4.25.8 Transporters and Substrate Selectivity	2119
4.25.9 Uptake Transporters and Clinical Relevance	2125
4.25.10 Conclusions and Future Perspectives	2128
References	2128
Relevant Websites	2135
4.26 Efflux Transporters	2137
Abbreviations	2138
4.26.1 Historical Perspective	2140
4.26.2 Nomenclature	2140
4.26.3 Protein Structure	2141
4.26.4 Catalytic Mechanism	2147
4.26.5 MDR1/ABCB1	2147
4.26.6 ABCB4	2152
4.26.7 Bile Salt Export Pump (BSEP; ABCB11)	2153
4.26.8 MRP1/ABCC1	2155
4.26.9 MRP2/ABCC2	2159
4.26.10 MRP3/ABCC3	2163
4.26.11 MRP4/ABCC4	2165
4.26.12 MRP5/ABCC5	2167
4.26.13 BCRP/ABCG2	2168
4.26.14 ABCG5 and ABCG8	2171
4.26.15 Future Directions	2173
References	2173
Index to Volume 4	2183
e9780080468686v5	2199
Cover	2199
Comprehensive Toxicology	2202
Copyright	2203
Contents of Volume 5	2204
Contents of All Volumes	2208
Preface	2218
5.01 Overview of the Immune System and Immunotoxicology	2220
Abbreviations	2220
5.01.1 Introduction	2221
5.01.2 Hemopoiesis and Homing	2223
5.01.3 Immune Responses	2226
5.01.4 Lymphocyte Activation	2235
5.01.5 Infection and Tumors	2239
5.01.6 Immunological Tolerance	2239
5.01.7 Autoimmune Disease	2243
5.01.8 Defining Immunotoxicology	2245
5.01.9 Immunotoxicological Investigations	2245
5.01.10 Immunotoxic Lessons Learned from Cytokine Expression	2247
5.01.11 Conclusions	2250
Acknowledgment	2250
References	2250
5.02 B-Cell Development	2254
Abbreviations	2254
5.02.1 Introduction	2255
5.02.2 Immunoglobulin Structure and Function	2255
5.02.3 The Developmental Biology of B Cells	2256
5.02.4 Quality Control for the BCR	2261
5.02.5 Peripheral B-Cell Subsets	2263
5.02.6 Antigen-Driven B-Cell Differentiation	2266
5.02.7 Assays for B-Lineage Cells	2268
5.02.8 Toxicology of B Cells	2270
References	2271
5.03 Natural Killer Cells	2272
Nomenclature	2272
Abbreviations	2273
5.03.1 Introduction	2274
5.03.2 Biology of NK Cells	2275
5.03.3 NK Assays	2286
5.03.4 NK Cell Modulation by Exogenous Agents	2289
5.03.5 Conclusion	2295
References	2296
5.04 Regulatory T Cells	2306
Abbreviations	2306
5.04.1 Introduction	2307
5.04.2 History	2307
5.04.3 Characteristics	2308
5.04.4 The Role of Tregs in Autoimmunity	2311
5.04.5 The Role of Tregs in Transplantation	2311
5.04.6 The Role of Tregs in Infectious Disease	2313
5.04.7 The Role of Tregs in Tumor Immunology	2314
5.04.8 Tregs and Toxicology	2315
5.04.9 Conclusions	2322
References	2322
5.05 Cytotoxic T Cells	2328
Abbreviations	2328
5.05.1 Introduction	2329
5.05.2 General Properties of CTL	2329
5.05.3 Activation and Differentiation of CTL Precursors	2330
5.05.4 Mechanisms of Target Cell Killing by CTL	2331
5.05.5 Methods for Inducing CTL Activity	2332
5.05.6 Methods for Measuring CTLActivity	2339
5.05.7 CTL Assessment in Immunotoxicity Testing	2341
5.05.8 Xenobiotic Effects on CTL Activity	2344
5.05.9 Conclusions	2348
References	2348
5.06 Phagocytes	2352
Abbreviations	2352
5.06.1 Introduction	2353
5.06.2 Neutrophils	2353
5.06.3 Macrophages	2354
5.06.4 The Inflammatory Process	2355
5.06.5 Cytokines	2356
5.06.6 Phagocytes and Tissue Injury	2357
5.06.7 Macrophage-Derived Mediators Implicated in Tissue Injury Mediators Implicated in Tissue Injury and Repair	2359
5.06.8 Conclusions	2366
Acknowledgments	2366
References	2366
5.07 Dendritic Cells	2374
Abbreviations	2374
5.07.1 Introduction	2375
5.07.2 Immune Modulation of DCs by Xenobiotics	2380
5.07.3 Concluding Remarks	2387
References	2387
5.08 Lymphoid Tissue and Pathological Influences of Toxicants	2390
Glossary	2390
Abbreviations	2391
5.08.1 Introduction	2391
5.08.2 Bone Marrow, Thymus, and Mucosal Epithelium	2392
5.08.3 Spleen, Lymphatics, Lymph Nodes, and Mucosa-Associated Lymphoid Tissue	2397
5.08.4 Tertiary Lymphoid Structures	2406
5.08.5 Examples of Toxicant-Induced Pathology and Mechanisms of Toxicity	2406
References	2407
5.09 Pulmonary Immunology	2410
Abbreviations	2410
5.09.1 Introduction	2410
5.09.2 Cells and Tissues of the Immune System	2411
5.09.3 Pulmonary Immune Structures and Orchestration of the Immune Response	2412
5.09.4 Pathologic Consequences of Aberrant Pulmonary Immune Responses	2415
5.09.5 Conclusions	2420
References	2421
5.10 Mucosal Immunity	2422
Abbreviations	2422
5.10.1 Introduction	2422
5.10.2 Gut-Associated Lymphoid Tissues	2423
5.10.3 Immune Cells in the Mucosal Immune System	2423
5.10.4 IgA: The Main Immunoglobulin in Gut Secretions	2428
5.10.5 Oral Tolerance	2430
5.10.6 Food Allergy and Food Intolerance Intolerance Intolerance	2431
References	2431
5.11 Skin Immunology and Immunotoxicity	2436
Abbreviations	2436
5.11.1 Introduction	2436
5.11.2 Response to Environmental Insults	2437
5.11.3 Conclusions	2450
Acknowledgments	2450
References	2450
5.12 Neuroimmunology	2454
Glossary	2454
Abbreviations	2455
5.12.1 Introduction	2455
5.12.2 Evidence that an Interaction Exists Between the Nervous System and the Immune System	2455
5.12.3 Soluble Molecules that Mediate the Neuroimmune Interaction	2457
5.12.4 Clinical Effects Mediated by the Neuroimmune Interaction	2462
5.12.5 Toxicant-Induced Effects on the Neuroimmune Communication	2462
5.12.6 Conclusions	2464
References	2465
5.13 Reproductive and Developmental Immunology	2468
Abbreviations	2468
5.13.1 Introduction	2469
5.13.2 Reproductive Immunology	2469
5.13.3 Developmental Immunology	2475
References	2485
5.14 Leukocyte Trafficking	2490
Abbreviations	2490
5.14.1 Leukocyte Trafficking	2490
5.14.2 Mechanisms of Leukocyte Trafficking	2492
5.14.3 Modulation of Leukocyte Trafficking	2498
5.14.4 Effects of Toxicants on Leukocyte Trafficking	2500
5.14.5 Conclusion	2501
Acknowledgment	2501
References	2501
5.15 Antigen Processing and Presentation	2504
Abbreviations	2504
5.15.1 Introduction	2504
5.15.2 APCs and Molecules of the MHC	2505
5.15.3 Genetics and Nomenclature for the HLA System	2507
5.15.4 Antigen Processing and Presentation	2508
5.15.5 Presentation of Unconventional Antigens	2513
5.15.6 Conclusion	2515
References	2515
Relevant Website	2516
5.16 Inflammation and Organ Failure	2518
Abbreviations	2519
5.16.1 Introduction: Toxic Substances, Inflammation, and Organ Failure	2519
5.16.2 Inflammation and Toxicant-Induced Renal Tissue Damage	2521
5.16.3 Inflammation and Hepatotoxicity	2525
5.16.4 Toxicants, Inflammation, and Lung Injuries	2530
References	2538
Relevant Website	2540
5.17 Antigen-Specific Signal Transduction	2542
Abbreviations	2542
5.17.1 Introduction	2543
5.17.2 Mechanics of B Cell Receptor Signaling	2544
5.17.3 Mechanics of T Cell Receptor Signaling	2551
5.17.4 Signal Strength in the Context of a Dynamic Signaling: A Network Characterized by Negative Feedback and Multiple Inputs and Outputs	2561
5.18 Redox Regulation of Transcription by Cigarette Smoke	2570
Abbreviations	2570
5.18.1 Introduction	2570
5.18.2 Redox Immunotoxicants in Cigarette Smoke	2571
5.18.3 Mechanisms of Redox Transcriptional Regulation	2573
5.18.4 Conclusions	2576
References	2576
5.19 Chemically Induced Allergy and Autoimmunity	2580
Abbreviations	2580
5.19.1 Introduction	2581
5.19.2 Mechanisms of Chemical-Induced T Cell Sensitization	2582
5.19.3 Metabolism and Formation of Reactive Compounds	2586
5.19.4 Cross-Reactivity, Cryptic Epitopes, and Autoimmunity	2586
5.19.5 Immunoregulation and Chemical-Induced T Cell Sensitization	2587
5.19.6 Activation of Innate Immune Responses by Chemicals and Responses by Chemicals and Microbial Factors	2589
5.19.7 Hazard and Risk Assessment of Chemical-Induced Allergy and Autoimmunity – Concluding Remarks	2590
Relevant Website	2593
5.20 Hypersensitivity Reactions in the Respiratory Tract	2594
Abbreviations	2594
5.20.1 Introduction	2594
5.20.2 Allergic Asthma	2598
5.20.3 Allergic Rhinitis	2604
5.20.4 Anaphylaxis	2606
5.20.5 Hypersensitivity Pneumonitis/ Extrinsic Allergic Alveolitis	2608
5.20.6 Chronic Beryllium Disease	2610
5.20.7 Conclusions	2611
References	2611
5.21 Contact Hypersensitivity	2616
Abbreviations	2616
5.21.1 Introduction	2616
5.21.2 Skin Sensitizers (Contact Allergens)	2617
5.21.3 Induction of Contact Sensitization	2618
5.21.4 Elicitation of Contact Sensitization	2621
5.21.5 Conclusions	2626
References	2627
5.22 Autoimmune Models	2632
Glossary	2633
Abbreviations	2634
5.22.1 Introduction	2635
5.22.2 Experimental Models	2635
5.22.3 Mechanisms of Autoimmunity	2644
5.22.4 Models of Chemical-Induced Autoimmunity	2646
5.22.5 Mechanisms of Chemical-Induced Autoimmunity	2651
5.22.6 Conclusions	2653
References	2653
5.23 Environment/Drug-induced Human Autoimmune Disease	2658
Glossary	2658
Abbreviations	2659
5.23.1 Introduction	2659
5.23.2 Definition of Autoimmune Diseases of Humans	2659
5.23.3 Genetic Predisposition	2662
5.23.4 Environmental Agents	2662
5.23.5 Mechanisms	2669
5.23.6 Conclusion Remarks	2670
Acknowledgments	2670
References	2670
5.24 Immunological Aging	2674
Abbreviations	2674
5.24.2 Underlying Causes of AgeRelated Immunosuppression	2677
5.24.1 Aging, Immunosenescence, and Immunotoxicology	2674
5.24.3 Immunosenescence as a Risk Factor for Chemical Immunotoxicity	2680
5.24.4 Diseases Associated with Immunosenescence	2681
5.24.5 Conclusions	2683
References	2683
Relevant Website	2684
5.25 Immunotoxicology of Pesticides and Chemotherapies	2686
Glossary	2686
Abbreviations	2687
5.25.1 Introduction	2687
5.25.2 Pesticides	2687
5.25.3 Chemotherapeutic Agents	2695
5.25.4 Conclusion	2703
References	2703
5.26 Immunotoxicology of Biopharmaceutics	2708
Glossary	2708
Abbreviations	2709
5.26.1 Introduction	2710
5.26.2 Types of Immunotoxicities	2710
5.26.3 Immunogenicity	2731
5.26.4 Tissue Cross-Reactivity	2732
5.26.5 Conclusions	2733
References	2733
5.27 Immunotoxicology of Biological Response Modifiers	2740
Glossary	2740
Abbreviations	2741
5.27.1 Introduction	2741
5.27.2 Immunotoxicity Testing	2743
5.27.3 Conclusions	2747
References	2747
5.28 Stress and Immune Functions	2750
Glossary	2750
Abbreviations	2750
5.28.1 Introduction	2751
5.28.2 Biological Mediators of the Stress–Immune Link	2751
5.28.3 Stress and Immune Function	2755
5.28.4 Refining the Concept of Stress and Its Connections to Immune Function	2758
5.28.5 Stress and Immune Function: Implications for Toxicology	2762
5.28.6 Conclusions	2763
References	2763
5.29 Immunomodulation by Endogenous Stress Response Proteins	2768
Abbreviations	2768
5.29.1 Introduction	2768
5.29.2 Characteristics of Stress Response Proteins	2771
5.29.3 Accessibility of Toxicant-Induced Stress Proteins	2777
5.29.4 Immunomodulatory Effects of Stress Proteins	2778
5.29.5 Conclusion	2781
References	2782
5.30 Methods to Assess Immunotoxicity	2786
Glossary	2786
Abbreviations	2787
5.30.1 Introduction	2787
5.30.2 Evaluation of the Potential to Induce Immunotoxicity	2788
5.30.3 Evaluation of the Potential to Induce Hypersensitivity	2797
5.30.4 Evaluation of the Potential to Influence the Development and/or Progression of Autoimmune Disease	2801
5.30.5 Evaluation of Immunomodulation in the Developing Immune System	2801
5.30.6 Conclusions	2806
References	2807
Index to Volume 5	2810
e9780080468686v6	2828
Cover	2828
Comprehensive Toxicology	2831
Copyright	2832
Contents of Volume 6	2833
Contents of All Volumes	2837
Preface	2847
6.01 Cardiovascular System as a Target of Drug- and Xenobiotic-Induced Toxicity: Overview	2849
6.01.1 Prevalence of Cardiovascular Disease	2849
6.01.2 Risk Factors for Cardiovascular Disease/Toxicity	2849
6.01.3 Objectives of Volume 6	2850
References	2850
6.02 Cardiovascular Development	2851
Glossary	2852
Abbreviations	2852
6.02.1 Introduction	2852
6.02.2 The Chick Embryo as a Model System	2854
6.02.3 Overview of Embryonic Chick Heart Development	2855
6.02.4 Congenital Heart Anomalies	2857
6.02.5 Establishing the Heart-Forming Regions and Cardiac Coelom	2859
6.02.6 Origin of the Endocardium and Myocardium	2861
6.02.7 Fusion of the Heart-Forming Regions	2862
6.02.8 Tubular Heart Morphogenesis	2865
6.02.9 From Tubular Heart to the Four-Chambered Heart	2868
6.02.10 Chamber Septation	2873
6.02.11 Summary and Perspectives	2877
References	2877
6.03 Vascular Physiology and Pharmacology	2883
Abbreviations	2883
6.03.1 Introduction	2884
6.03.2 Endothelium	2885
6.03.3 Vascular Smooth Muscle	2890
6.03.4 Advential Fibroblasts	2894
6.03.5 Conclusions	2895
References	2896
6.04 Cardiac Physiology and Pharmacology	2899
6.04.1 Introduction	2899
6.04.2 Myocardial Excitation and Contraction	2899
6.04.3 Autonomic Regulation of Cardiac Excitation and Contraction	2904
6.04.4 Compartmentation	2906
6.04.5 Classification and Mechanisms of Arrhythmias	2907
6.04.6 Classification and Mechanisms of Action of Antiarrhythmic Agents	2911
References	2914
6.05 In Vitro Vascular Cell Culture Systems – Vascular Smooth Muscle	2917
Nomenclature	2918
Abbreviations	2918
6.05.1 Vascular Smooth Muscle Cell Phenotypic Modulation	2919
6.05.2 VSMC Culture In Vitro	2923
6.05.3 Assays to Study Phenotypic Modulation	2927
6.05.4 Modeling VSMC Phenotypic Modulation In Vitro	2935
6.05.5 Dynamic Models to Study Vascular SM	2941
6.05.6 Conclusion	2942
References	2942
6.06 In Vitro Vascular Cell Culture Systems – Endothelial Cell Culture Systems	2945
Abbreviations	2945
6.06.1 Introduction	2945
6.06.2 Endothelial Heterogeneity	2946
6.06.3 Definition of ECs	2947
6.06.4 Isolation of Primary ECs	2948
6.06.5 Cell Culture Conditions for Primary ECs	2949
6.06.6 Tridimensional cultures of endothelium	2950
6.06.7 Endothelial Culture Systems Under Flow	2952
6.06.8 Immortalized ECs	2954
6.06.9 Conclusions	2955
References	2955
6.07 In Vitro Cultured Cardiomyocytes for Evaluating Cardiotoxicity	2961
Glossary	2961
6.07.1 Introduction	2962
6.07.2 Methods	2964
6.07.3 Applications	2966
6.07.4 Summary	2977
References	2977
6.08 Assessment of Vascular Reactivity	2981
Abbreviations	2981
6.08.1 Introduction	2981
6.08.2 Fundamental Principles and Quantification of Vascular Reactivity	2982
6.08.3 Reactivity in the Vascular Circuit	2983
6.08.4 Methods of Assessing Vascular Reactivity	2984
6.08.5 Alterations in Vascular Reactivity After Particulate Matter Exposure	2986
6.08.6 Vascular Reactivity in Hypertension: Observations and Possible Mechanisms	2986
6.08.7 Vascular Reactivity and Microvascular Dysfunction in the Metabolic Syndrome	2989
6.08.8 Summary	2994
References	2994
6.09 Isolated Heart Preparation	2997
Glossary	2997
Nomenclature	2997
Abbreviations	2997
6.09.1 The Development of the First Completely Isolated-Perfused Mammalian Heart: The Langendorff Heart	2998
6.09.2 The Langendorff Heart: Principles, Advantages, and Applications	2998
6.09.3 Preparation of the Langendorff-Perfused Heart	2999
6.09.4 Experimental Considerations	3000
6.09.5 Sample Studies Using the Langendorff-Perfused Hearts	3005
6.09.6 Concluding Remarks	3006
Acknowledgment	3006
References	3006
6.10 Morphological Evaluation of the Heart and Blood Vessels	3009
Abbreviations	3009
6.10.1 Introduction	3009
6.10.2 Gross Dissection and Examination of the Heart and Vessels	3011
6.10.3 Microscopic Observation	3014
6.10.4 Electron Microscopy	3021
6.10.5 Other Applications – Laser Capture Microscopy	3023
6.10.6 Summary and Conclusion	3024
References	3024
6.11 Systemic Arterial Blood Pressure in Safety Pharmacology	3027
Abbreviations	3027
6.11.1 Scope	3027
6.11.2 Fundamentals (Berne and Levy 1997; Burton 1962; Katz 2005; Opie 2004; Shepherd and Vanhoutte 1979; Wiggers 1949)	3027
6.11.3 Hindrance to Blood Flow	3028
6.11.4 Ventricular Function	3029
6.11.5 High-Pressure Baroreceptors	3029
6.11.6 The Central Arterial Pressure Waveform (McDonald 1974; Milnor 1975; O’Rourke 2005; Pauca et al. 1992)	3030
6.11.7 How Drugs Affect the Waveform	3032
6.11.8 Importance of Arterial Pressure to Myocardial Energetics (Colucci and Braunwald 2005)	3039
6.11.9 Monitoring by Radiotelemetry	3041
6.11.10 Summary	3044
References	3044
6.12 Manganese-Enhanced Magnetic Resonance Imaging: Applications to Preclinical Research	3047
Abbreviations	3047
6.12.1 Introduction	3048
6.12.2 Manganese-Enhanced MRI of Cardiac Research	3049
6.12.3 Manganese-Enhanced MRI of Neuronal Research	3058
6.12.4 Manganese-Enhanced MRI of Cell Labeling	3061
6.12.5 Clinical Manganese-Based Contrast Agent(s)	3062
6.12.6 Conclusion	3064
Acknowledgment	3065
References	3065
6.13 Oxidative Stress and Heart Failure	3069
Abbreviations	3069
6.13.1 Introduction	3070
6.13.2 Clinical Features of Heart Failure	3070
6.13.3 Diseases Leading to Heart Failure	3073
6.13.4 Pathophysiological Basis of Heart Failure	3075
6.13.5 Cellular and Molecular Mechanisms of Heart Failure	3078
6.13.6 Therapeutic Treatment of Heart Failure	3084
References	3086
Relevant Websites	3090
6.14 Oxidants and Endothelial Dysfunction	3091
Abbreviations	3092
6.14.1 Introduction	3092
6.14.2 Generation and Metabolism of ROS in the Vasculature	3093
6.14.3 Endothelial Dysfunction	3098
6.14.4 Effects of ROS on Vascular Cell Physiology and Pathology	3107
6.14.5 Treatments and Therapies for ROS-Mediated Vascular Disease	3112
6.14.6 Conclusions	3116
References	3116
6.15 Mechanical Forces and Vascular Injury	3123
Abbreviations	3123
6.15.1 Introduction	3123
6.15.2 Overview of Mechanical Forces Exerted on the Vascular System	3123
6.15.3 Sensing of Mechanical Forces by Vascular Cells	3125
6.15.4 Response of Vascular Cells and Blood Vessels to Mechanical Stimulation	3127
6.15.5 Contribution of Mechanical Forces to Vascular Injury and Pathologies	3133
6.15.6 Closure	3135
References	3136
6.16 Cardiotoxicity and HIV/AIDS Therapy	3139
Abbreviations	3139
6.16.1 Introduction and Overview	3140
6.16.2 Mitochondrial Toxicity of NRTIs – mtDNA Depletion	3141
6.16.3 Cardiomyopathy in HIV/AIDS – A Clinical Entity	3142
6.16.4 DNA pol-γ as a Subcellular Target in NRTI CM	3144
6.16.5 Biochemical and Cellular Models of NRTI Mitochondrial Toxicity	3144
6.16.6 In Vivo Models with HIV/AIDS, NRTI Toxicity, Mutant DNA pol-γ, and Related Models	3145
6.16.7 Kinases and NRTI Toxicity –TG Models	3146
6.16.8 Models of NRTI Transport and the Development of NRTI CM	3146
6.16.9 mtDNA Mutations and NRTI Toxicity	3147
6.16.10 Toxicogenetic Predisposition to NRTI CM	3147
6.16.11 Problems and Pitfalls with the Working Hypothesis	3148
6.16.12 Oxidative Stress, NRTI Toxicity, and HIV/AIDS CM	3148
6.16.13 Conclusions	3148
Acknowledgment	3149
References	3149
6.17 Transplacental Exposure to Antiretroviral Drugs and Cardiotoxicity in Offspring	3153
Abbreviations	3153
6.17.1 Introduction	3153
6.17.2 Mode of Action of NRTIs as Antiviral Agents and Potential Toxins	3154
6.17.3 Evidence of Mitochondrial Toxicity Resulting from Perinatal NRTI Exposure	3155
6.17.4 Animal Models of Perinatal NRTI Exposure and Mitochondrial Toxicity	3156
6.17.5 Reports of an Association Between Perinatal NRTI Exposure of Children and Clinical Evidence of Mitochondrial Toxicity	3162
6.17.6 Reports of an Association Between Perinatal NRTI Exposure of Children and Molecular Evidence of Mitochondrial Toxicity	3165
6.17.7 Reports of an Association Between Perinatal NRTI Exposure of Children and Echocardiographic Evidence of Mitochondrial Toxicity	3166
6.17.8 Strategies to Prevent NRTI-Induced Cardiotoxicity and Vascular Changes	3167
References	3168
6.18 NSAIDs and Cardiovascular Toxicity	3171
Abbreviations	3171
6.18.1 Background	3171
6.18.2 NSAID Mechanism of Action	3172
6.18.3 Cardiovascular Toxicities	3173
6.18.4 Conclusion	3182
References	3182
Relevant Website	3183
6.19 Drugs of Abuse and Cardiotoxicity	3185
Abbreviations	3186
6.19.1 Introduction	3187
6.19.2 Cardiovascular Toxicity of Cocaine	3187
6.19.3 Amphetamines	3192
6.19.4 Opioids	3195
6.19.5 Phencyclidine and Ketamine	3197
6.19.6 Lysergic Acid Diethylamide	3197
6.19.7 Hallucinogenic Mushrooms	3198
6.19.8 Marijuana	3199
6.19.9 Alcohol (Ethanol) Abuse	3200
6.19.10 Nicotine Abuse	3204
6.19.11 Caffeine Abuse	3205
References	3207
6.20 Iatrogenic QT Prolongation	3213
Glossary	3214
Abbreviations	3214
6.20.1 Introduction	3215
6.20.2 Regulatory Requirements	3216
6.20.3 Hazard Identification –Frontloaded Approach	3222
6.20.4 Risk Assessment – Core Battery Studies	3235
6.20.5 Risk Management and Mitigation – Follow-Up Studies	3238
6.20.6 Integrated Risk Assessment	3240
6.20.7 Predictive Value of Preclinical QT-Related Assays to Humans	3242
6.20.8 Current and Future Challenges	3245
6.20.9 Conclusions	3246
References	3246
Relevant Websites	3250
6.21 Cardiotoxicity Associated with Thiazolidinediones	3251
Abbreviations	3251
6.21.1 Introduction	3251
6.21.2 Thiazolidinediones	3252
6.21.3 Clinical Evidence of Thiazolidinedione-Associated Myocardial Infarction and Chronic Heart Failure	3253
6.21.4 Mechanisms of Thiazolidinedione-Induced Myocardial Infarction and Congestive Heart Failure	3256
6.21.5 Conclusions	3258
References	3259
6.22 Anthracycline, Herceptin, and CV Toxicity	3261
Glossary	3261
Nomenclature	3261
Abbreviations	3261
6.22.1 Introduction	3262
6.22.2 Anthracyclines	3262
6.22.3 Trastuzumab	3269
6.22.4 Diagnostics and Monitoring	3271
6.22.5 Conclusion	3272
References	3272
6.23 Environmentally Induced Heart Malformations	3277
Abbreviations	3277
6.23.1 Introduction	3277
6.23.2 Assessment Tools for Study of Cardiac Teratogens	3278
6.23.3 Key Teratogens and Mechanisms	3280
6.23.4 Future Directions	3290
Acknowledgments	3290
References	3290
Relevant Website	3294
6.24 Metals and Cardiovascular Disease	3295
Abbreviations	3295
6.24.1 Introduction	3295
6.24.2 Overview of Metal Exposures	3296
6.24.3 Mechanisms of Metal Action	3297
6.24.4 Pathogenic Actions of Metals in the Heart	3300
6.24.5 Conclusions	3307
References	3309
6.25 Air Pollution and Cardiovascular Disease	3313
Abbreviations	3313
6.25.1 Introduction	3314
6.25.2 Cardiovascular Toxicity of Gaseous Air Pollutants	3315
6.25.3 Cardiovascular Toxicity of Particulate Air Pollutants	3319
6.25.4 Conclusions	3332
References	3333
6.26 Aldehydes and Cardiovascular Disease	3337
Abbreviations	3337
6.26.1 Introduction	3338
6.26.2 Sources and Levels of Environmentally Important Aldehydes	3339
6.26.3 Cardiovascular Effects of Aldehyde Exposure	3340
6.26.4 Aldehydes and Cardiovascular Disease: From Epidemiology to Exposure Studies	3346
6.26.5 Mechanisms of Aldehyde Action in Cardiovascular Tissues	3347
6.26.6 Cardiovascular Metabolism of Aldehydes	3349
6.26.7 Conclusions and Future Directions	3354
Acknowledgment	3355
References	3356
6.27 1,3-Butadiene and Cardiovascular Disease	3361
Glossary	3361
Abbreviations	3361
6.27.1 Introduction	3361
6.27.2 BD and Cancer	3362
6.27.3 Genotoxicity of BD Metabolites	3363
6.27.4 BD and Cardiovascular Disease: Epidemiology	3364
6.27.5 BD, ETS, and Cardiovascular Disease	3364
6.27.6 BD Inhalation and Atherosclerosis: Experimental	3366
6.27.7 BD-Metabolizing Gene Polymorphisms and Atherosclerosis	3367
6.27.8 Note	3368
References	3368
6.28 Halogenated Aromatic Hydrocarbons and Cardiovascular Disease	3371
Abbreviations	3371
6.28.1 Halogenated Aromatic Hydrocarbons	3372
6.28.2 Human Epidemiology Studies	3373
6.28.3 Animal and Cell Culture Studies	3379
6.28.4 Summary and Future Directions	3382
References	3383
Index to Volume 6	3387
e9780080468686v7	3401
Cover	3401
Comprehensive Toxicology	3404
Copyright	3405
Contents of Volume 7	3406
Contents of All Volumes	3408
Preface	3418
7.01 Functional Anatomy of the Kidney	3420
Abbreviations	3421
7.01.1 Introduction	3421
7.01.2 Overall Structural Organization of the Mammalian Kidney	3422
7.01.3 Nephron Heterogeneity	3424
7.01.4 Renal Vasculature	3424
7.01.5 Glomerulus	3425
7.01.6 Proximal Convoluted Tubule	3428
7.01.7 Proximal Straight Tubule	3430
7.01.8 Thin Descending Limb of Loop of Henle	3430
7.01.9 Thin Ascending Limb of Loop of Henle	3431
7.01.10 Thick Ascending Limb of Loop of Henle	3432
7.01.11 Distal Convoluted Tubule, Connecting Segment, and Initial Collecting Tubule	3433
7.01.12 Cortical Collecting Duct	3434
7.01.13 Outer Medullary Collecting Duct	3436
7.01.14 Inner Medullary Collecting Duct	3437
7.01.15 Papillary Surface Epithelium	3438
Acknowledgment	3439
References	3439
Relevant Websites	3441
7.02 Renal Organic Cation and Anion Transport: From Physiology to Genes	3442
Abbreviations	3443
7.02.1 Introduction	3443
7.02.2 Characteristics of Organic Cation Transport	3446
7.02.3 Organic Cation Transporters	3447
7.02.4 OCTs as Mediators of Toxicity	3450
7.02.5 Characteristics of Organic Anion Transport	3455
7.02.6 Organic Anion Transporters	3456
7.02.7 OATs as Mediators of Toxicity	3460
7.02.8 Conclusions	3466
Note	3466
References	3466
7.03 Renal Xenobiotic Metabolism	3474
Abbreviations	3474
7.03.1 Introduction	3475
7.03.2 Relevance of Renal Structure and Function to Xenobiotic Biotransformation	3475
7.03.3 Phase 1 Xenobiotic Biotransformation Enzymes	3476
7.03.4 Conjugation Reactions (Phase 2 Metabolism)	3484
7.03.5 Conclusions	3492
References	3493
7.04 Mechanisms of Toxicant-Induced Acute Kidney Injury	3500
Abbreviations	3500
7.04.1 Introduction	3501
7.04.2 Susceptibility of Renal Cells to Toxicant-Induced Injury	3501
7.04.3 Toxicant-Specific Renal Cell Injury	3502
7.04.4 General Responses to Toxicant-Induced Acute Kidney Injury: Role of Cell Death	3504
7.04.5 Mechanisms of Nephrotoxicant-Induced Cell Death	3505
7.04.6 Cellular and Biochemical Mediators of Nephrotoxicity	3510
7.04.7 Strategies for Assessment of Mechanisms of Nephrotoxicity	3528
References	3528
7.05 Cytoprotective Systems within the Kidney	3536
Abbreviations	3536
7.05.1 Introduction	3537
7.05.2 Redox Status and Oxidative Stress	3538
7.05.3 GSH Homeostasis and Renal Cellular Function	3540
7.05.4 Other Thiol-Disulfide Redox Protectants	3551
7.05.5 Modulation of Signaling Pathways in Nephroprotection	3554
7.05.6 Modulation of Renal Physiology in Nephroprotection	3561
7.05.7 Summary and Conclusions	3563
References	3563
7.06 Dedifferentiation and Redifferentiation in Epithelial Repair	3570
Glossary	3570
Abbreviations	3571
7.06.1 Introduction	3571
7.06.2 Characteristics of RPTC Dedifferentiation	3571
7.06.3 Renal Proximal Tubule Cell Dedifferentiation Resembles Epithelial Mesenchymal Transition	3572
7.06.4 Signal Transduction in EMT and RPTC Dedifferentiation	3575
7.06.5 Growth Factors and Receptors that Influence RPTC Dedifferentiation	3580
7.06.6 Redifferentiation of Renal Epithelium	3582
7.06.7 Conclusion	3583
References	3583
7.07 Acute Kidney Injury	3588
Glossary	3589
Abbreviations	3589
7.07.1 Introduction	3590
7.07.2 Incidence	3593
7.07.3 Classification and Differential Diagnosis	3593
7.07.4 Diagnosis	3594
7.07.5 Etiology	3595
7.07.6 Pathophysiology of AKI	3598
7.07.7 Management of AKI	3602
7.07.8 Complications of AKI	3604
7.07.9 Prognosis of AKI	3605
7.07.10 Future	3607
7.07.11 Conclusions	3610
References	3610
Relevant Websites	3615
7.08 Biomarkers of Acute Kidney Injury	3616
Abbreviations	3616
7.08.1 Introduction	3617
7.08.2 Urinary Biomarkers for AKI	3619
7.08.3 Conclusions	3627
Acknowledgments	3628
References	3628
7.09 Cell Adhesion Molecules in Renal Injury	3632
Abbreviations	3633
7.09.1 Introduction	3633
7.09.2 Integrins	3633
7.09.3 Cadherins	3639
7.09.4 Distribution of Integrins in the Kidney: Physiology and Pathophysiology	3641
7.09.5 Potential Therapeutic Uses of RGD Peptides	3643
7.09.6 Overview of Leukocyte Trafficking in Host Defense and Inflammation	3647
7.09.7 Regulation of Leukocyte Adhesion by Chemoattractants, Cytokines, and Chemokines	3651
7.09.8 Leukocyte Adhesion Molecules and Kidney Diseases	3654
7.09.9 Future Strategies for Inhibition of Leukocyte Adhesion in Inflammatory Diseases	3658
7.09.10 Conclusions	3659
Acknowledgments	3660
References	3660
7.10 The Glomerulus: Mechanisms of Injury	3664
Abbreviations	3664
7.10.1 Introduction	3665
7.10.2 Diagnosis of Glomerular Dysfunction	3665
7.10.3 Causes and Mechanisms of Injury	3669
7.10.4 Conclusion	3676
References	3677
7.11 In Vivo Methodologies Used to Assess Renal Function and Injury	3682
Glossary	3682
Abbreviations	3683
7.11.1 Introduction	3684
7.11.2 Overview of In Vivo Kidney Methodologies	3684
7.11.3 Assessment of Glomerular Filtration Rate and Renal Blood Flow	3686
7.11.4 Assessment of Tubular Function	3698
7.11.5 Assessment of Glomerular Function	3709
7.11.6 Assessment of Tubular Injury	3710
7.11.7 Assessment of Medullary Function and Injury	3716
7.11.8 Conclusions	3717
References	3717
7.12 Vasoactive Substances As Mediators of Renal Injury	3724
Abbreviations	3725
7.12.1 Introduction	3726
7.12.2 Regulation of Glomerular Filtration Rate	3726
7.12.3 Renin–Angiotensin System	3727
7.12.4 Endothelin	3729
7.12.5 Nitric Oxide	3731
7.12.6 Urotensin II	3732
7.12.7 The Kallikrein–Kinin System	3732
7.12.8 Adenosine	3733
7.12.9 Catecholamines	3734
7.12.10 Natriuretic Peptides	3736
7.12.11 Eicosanoids	3738
7.12.12 Arginine Vasopressin Peptide	3741
7.12.13 Conclusions	3743
References	3743
7.13 Aminoglycoside-Induced Nephrotoxicity	3748
Glossary	3748
Abbreviations	3748
7.13.1 Introduction	3749
7.13.2 Chemistry and Mechanism of Action of Aminoglycosides	3749
7.13.3 Pharmacokinetics of Aminoglycosides	3750
7.13.4 Epidemiology of Aminoglycoside Nephrotoxicity	3751
7.13.5 Risk Factors for Aminoglycoside Nephrotoxicity	3751
7.13.6 Pathology of Aminoglycoside Nephrotoxicity	3752
7.13.7 Renal Transport of Aminoglycosides	3755
7.13.8 Conventional and Once-Daily Regimens	3759
7.13.9 Prevention	3761
References	3762
7.14 Amphotericin B-Induced Nephrotoxicity	3766
Abbreviations	3766
7.14.1 Introduction	3766
7.14.2 Clinical Manifestation of Amphotericin B Nephrotoxicity	3767
7.14.3 Pathological Findings	3770
7.14.4 Mechanisms of Amphotericin B Nephrotoxicity	3770
7.14.5 Approaches Aimed to Reduce Amphotericin B Nephrotoxicity	3772
7.14.6 Conclusion	3774
References	3774
7.15 The Pathogenesis and Prevention of Radiocontrast Medium-Induced Renal Dysfunction	3778
Abbreviations	3778
7.15.1 Introduction	3779
7.15.2 History	3779
7.15.3 Pharmacology and Physiology	3780
7.15.4 Mechanisms of Nephrotoxicity	3782
7.15.5 Renal Metabolism	3787
7.15.6 Animal Models of RCM Nephrotoxicity	3788
7.15.7 Risk Factors for Human RCM Nephropathy	3789
7.15.8 Complications of RCM Procedures	3790
7.15.9 Prophylactic Strategies for Prevention	3791
7.15.10 Summary	3800
References	3800
7.16 Analgesics and Nonsteroidal Anti-Inflammatory Drugs	3806
Abbreviations	3806
7.16.1 Introduction	3806
7.16.2 Arachidonic Acid Metabolism	3807
7.16.3 Effects of Analgesics and NSAIDs on Renal Function	3810
7.16.4 Conclusions	3821
References	3821
7.17 Nephrotoxicity of Lithium and Drugs of Abuse	3824
Abbreviations	3824
7.17.1 Introduction	3824
7.17.2 Lithium Nephrotoxicity	3825
7.17.3 Nephrotoxicity of Drugs of Abuse	3838
7.17.4 Conclusions	3843
References	3843
7.18 Nephrotoxicity of Natural Products: Aristolochic Acid and Fungal Toxins	3852
Abbreviations	3853
7.18.1 Introduction	3853
7.18.2 Aristolochic Acid	3853
7.18.3 Mycotoxins	3859
7.18.4 Mushroom Nephrotoxins	3868
Acknowledgments	3872
References	3872
Relevant Website	3877
7.19 Halogenated Hydrocarbons	3878
Abbreviations	3878
7.19.1 Introduction	3878
7.19.2 Haloalkanes	3878
7.19.3 Haloalkenes	3883
7.19.4 Conclusions	3890
Acknowledgments	3890
References	3890
7.20 Renal Handling and Toxicity of Mercury	3894
Abbreviations	3894
7.20.1 Introduction	3894
7.20.2 Renal Disposition of Mercury	3895
7.20.3 Urinary Excretion of Mercury	3898
7.20.4 Renal Toxicity of Mercury	3899
7.20.5 Renal Cellular Effects Induced by Mercury	3901
7.20.6 Factors that Modify the Renal Toxicity of Mercury	3905
7.20.7 Conclusion	3910
References	3910
7.21 Other Nephrotoxic Metals and Nanometallic Particles	3914
Abbreviations	3914
7.21.1 Introduction	3914
7.21.2 Arsenic	3915
7.21.3 Bismuth	3916
7.21.4 Cadmium	3916
7.21.5 Chromium	3917
7.21.6 Indium	3918
7.21.7 Lead	3918
7.21.8 Platinum	3919
7.21.9 Uranium	3919
7.21.10 Metallic Mixtures	3920
7.21.11 Future Research Needs	3921
References	3922
7.22 α2u-Globulin Nephropathy	3926
Abbreviations	3926
7.22.1 Introduction	3926
7.22.2 Chemical Inducers of α2u-Globulin Nephropathy	3926
7.22.3 Histopathological Characterization of α2u-Globulin Nephropathy	3928
7.22.4 α2u-Globulin	3929
7.22.5 Biochemical Mechanisms of α2u-Globulin Nephropathy	3930
7.22.6 Renal Tubular Tumor Formation in α2u-Globulin Nephropathy	3933
7.22.7 Human Relevance of α2u-Globulin Nephropathy	3934
7.22.8 Risk Assessment for Chemicals Causing α2u-Globulin Nephropathy	3936
References	3937
Index to Volume 7	3942
e9780080468686v8	3954
Cover	3954
Comprehensive Toxicology	3957
Copyright	3958
Contents of Volume 8	3959
Contents of All Volumes	3961
Preface	3971
Preface to Volume 8	3973
8.01 Introduction to Respiratory Toxicology	3975
8.01.1 Definition and Scope of Volume 8	3975
8.01.2 Gross Anatomical Characteristics of the Respiratory System	3976
8.01.3 The Respiratory System as a Target for Toxicants	3976
8.01.4 Overview of Functional Anatomy	3977
8.01.5 Respiratory Tract Response to Injury	3980
8.01.6 Defenses against Toxic Injury	3983
8.01.7 Conclusions	3984
8.02 Nasal Airways	3985
Abbreviations	3985
8.02.1 Nasal Toxicity and Concern for Human Health	3985
8.02.2 Nasal Structure and Function	3986
8.02.3 Nasal Epithelial Injury and Remodeling Induced by Inhaled Toxicants	3994
References	4003
8.03 Tracheobronchial Airways	4007
Abbreviations	4007
8.03.1 Tracheobronchial Airways	4007
8.03.2 Conclusions	4027
Acknowledgments	4027
References	4027
8.04 Alveolar Epithelium in Lung Toxicology	4031
Abbreviations	4031
8.04.1 Introduction	4031
8.04.2 Structure and Functions	4033
8.04.3 Methods for Evaluating Epithelial Integrity	4036
8.04.4 Response to Toxic Exposures	4038
8.04.5 Mechanism of Toxicity	4046
8.04.6 Human Clinical Toxicology and Comparative Toxicity	4054
8.04.7 Isolated and Cultured Type II Cells	4055
8.04.8 Conclusions	4056
References	4056
8.05 Inflammatory Cells of the Lung: Macrophages	4065
Abbreviations	4065
8.05.1 Introduction	4066
8.05.2 Conclusions	4082
References	4083
8.06 Inflammatory Cells of the Lung: Polymorphonuclear Leukocytes	4087
Abbreviations	4087
8.06.1 Introduction	4087
8.06.2 Normal Structure and Function in the Respiratory Tract	4088
8.06.3 Cell Kinetics and Migration	4090
8.06.4 Methods for Evaluating Structure and Function	4093
8.06.5 Markers of Injury	4093
8.06.6 Role in Pulmonary Injury	4094
8.06.7 Acute and Subchronic Responses to Toxic Exposure	4094
8.06.8 Chronic Responses to Toxic Exposure	4095
8.06.9 Human versus Animal Toxicology	4096
8.06.10 In Vitro Systems	4097
References	4098
8.07 Neurogenic Inflammation: TRP Ion Channels in the Lung	4101
Abbreviations	4101
8.07.1 Introduction	4101
8.07.2 Inflammation	4102
8.07.3 Acute Inflammation	4102
8.07.4 Termination and Resolution of Inflammation	4108
8.07.5 Chronic Inflammation	4109
8.07.6 Neurogenic Inflammation	4109
8.07.7 Pulmonary Neurogenic Inflammation	4110
8.07.8 TRP Channels and Neurogenic Inflammation	4111
8.07.9 TRPV1 and Neurogenic Inflammation	4114
8.07.10 Hydrogen Sulfide	4115
8.07.11 Ethanol	4116
8.07.12 Acids and Acidic Environmental Particulate Materials	4116
8.07.13 Toluene Diisocyanate	4117
8.07.14 Neurogenic Inflammation and Other TRP Channels	4118
8.07.15 TRPA1 and Neurogenic Inflammation	4118
8.07.16 Conclusions	4119
References	4119
8.08 Pulmonary Mechanical Function and Gas Exchange	4123
Abbreviations	4123
8.08.1 Introduction	4123
8.08.2 Mechanical Pulmonary Function	4124
8.08.3 Inhaled Air Toxicants and Ventilation	4134
8.08.4 Pulmonary Circulation and Diffusion	4137
8.08.5 Conclusions	4139
Acknowledgment	4140
References	4140
8.09 Biochemical Function of the Respiratory Tract: Metabolism of Xenobiotics	4143
Abbreviations	4143
8.09.1 Introduction	4143
8.09.2 Enzymes Catalyzing the Biotransformation of Xenobiotics in the Respiratory Tract	4144
8.09.3 Conclusions	4149
References	4150
8.10 Carcinogenic Responses of the Respiratory Tract	4153
Abbreviations	4153
8.10.1 Introduction	4153
8.10.2 Nasal	4154
8.10.3 Larynx	4156
8.10.4 Large Airways	4160
8.10.5 Lung	4161
References	4168
8.11 Pulmonary Developmental Responses to Toxicants	4171
Abbreviations	4171
8.11.1 Introduction	4172
8.11.2 Development of Antioxidant and Xenobiotic Metabolizing Enzyme Systems	4178
8.11.3 Exposure to Toxicants	4184
8.11.4 Nutritional Deficiency	4188
8.11.5 Conclusions	4189
References	4189
8.12 Cell Damage and Cell Renewal in the Lung	4195
Abbreviations	4195
8.12.1 Introduction	4195
8.12.2 Defining Cell Damage in the Lung	4196
8.12.3 Methods to Study Cell Kinetics	4197
8.12.4 Kinetics of Lung Cells in Normal Lung	4201
8.12.5 Lung Injury and Cell Proliferation	4201
8.12.6 Conclusions	4210
Acknowledgments	4211
References	4211
8.13 In Vitro Systems for Studying Respiratory System Toxicology	4215
Abbreviations	4215
8.13.1 Introduction	4215
8.13.2 Isolated Subcellular Constituents	4220
8.13.3 Cell Culture Systems	4220
8.13.4 Tissue Sections	4223
8.13.5 Isolated Lung Preparations	4223
8.13.6 Bronchoalveolar Lavage Fluid	4225
8.13.7 Other In Vitro Models	4227
8.13.8 Conclusions	4228
References	4228
8.14 Ozone and Oxygen Toxicity	4233
Abbreviations	4233
8.14.1 General Aspects of Respiratory Health Effects of Ozone	4233
8.14.2 Anatomy and Inflammation	4235
8.14.3 Lung Injury	4236
8.14.4 Setting Standards	4240
References	4244
8.15 Sulfur Oxides	4249
Abbreviations	4249
8.15.1 Introduction	4249
8.15.2 Sources	4249
8.15.3 Atmospheric Concentrations	4250
8.15.4 Dosimetry and Fate	4251
8.15.5 Biomarkers of Exposure	4251
8.15.6 Health Effects	4251
8.15.7 Mechanisms of Toxicity	4258
8.15.8 Conclusions	4260
References	4260
8.16 Aldehydes	4263
Abbreviations	4263
8.16.1 Introduction	4264
8.16.2 Aldehyde Biochemistry and Metabolism	4266
8.16.3 Aldehyde Toxicity	4273
8.16.4 Toxicokinetics and Dosimetry of Aldehydes	4281
8.16.5 Mixtures of Aldehydes	4288
8.16.6 Risk Assessments of Aldehydes	4289
8.16.7 Conclusions	4295
References	4296
8.17 Crystalline Silica and Silicosis	4303
Abbreviations	4303
8.17.1 Introduction	4304
8.17.2 Pathological and Clinical Manifestations of Silicosis	4305
8.17.3 Mechanisms of Crystalline Silica Toxicity and Silicosis	4306
8.17.4 Silicosis and Lung Cancer	4315
8.17.5 Conclusion	4319
References	4320
8.18 Carcinogenic Effects of Cigarette Smoke on the Respiratory Tract	4323
Glossary	4323
Abbreviations	4324
8.18.1 Introduction	4324
8.18.2 Cigarette Smoke As a Cause of Lung Cancer	4324
8.18.3 Tumor Induction by Cigarette Smoke and Its Condensate in Laboratory Animals	4326
8.18.4 Respiratory Carcinogens in Cigarette Smoke	4327
8.18.5 Cigarette Smoke Tumor Promoters and Cocarcinogens	4329
8.18.6 Mechanisms of Lung Tumor Induction by Cigarette Smoke Carcinogens	4330
8.18.7 Biomarkers Specifically Related to Cigarette Smoke Carcinogens	4338
8.18.8 Genetic Factors Affecting Lung Cancer Risk	4340
8.18.9 Chemoprevention of Lung Cancer	4342
8.18.10 Conclusions	4343
References	4344
8.19 Noncarcinogenic Effects of Cigarette Smoke on the Respiratory Tract	4351
Glossary	4351
Abbreviations	4351
8.19.1 Introduction	4352
8.19.2 Chronic Obstructive Pulmonary Disease	4352
8.19.3 Inflammation	4353
8.19.4 Proteases	4355
8.19.5 Oxidants	4356
8.19.6 Environmental Tobacco Smoke and Respiratory Health	4357
8.19.7 Gene–Environment Interactions	4358
References	4360
8.20 Radon	4361
Glossary	4361
8.20.1 Introduction	4361
8.20.2 Sources	4363
8.20.3 Respiratory Dosimetry of Radon	4364
8.20.4 Epidemiologic Studies of Radon and Lung Cancer	4366
8.20.5 Animal Studies of Radon and Lung Cancer	4369
8.20.6 Risk Assessment for Radon and Lung Cancer	4371
8.20.7 Health Effects Other Than Lung Cancer	4373
8.20.8 Conclusions	4374
References	4374
8.21 Toxicity of Airborne Metals	4377
Abbreviations	4377
8.21.1 Introduction	4377
8.21.2 Risk Factors	4378
8.21.3 Exposure Evaluation	4380
8.21.4 Dosimetry	4382
8.21.5 Health Effects Associated with Airborne Metals	4385
References	4390
Relevant Websites	4392
8.22 Particle Toxicities	4393
Abbreviations	4393
8.22.1 Introduction	4393
8.22.2 General Concepts Leading to Site-Specific Particle Effects	4394
8.22.3 Experimental Animal Studies in Evaluating Risk of Particle-Induced Disease	4399
8.22.4 Aerosol Characterization and Relevant Metrics of Exposure	4402
8.22.5 Particles in Occupational Settings	4406
8.22.6 Particles in Ambient Air	4415
8.22.7 Conclusions	4418
Acknowledgment	4419
References	4419
8.23 Nanoparticles in the Lung	4425
Abbreviations	4425
8.23.1 Introduction	4426
8.23.2 Types of Nanoparticles	4429
8.23.3 Lung Exposure to Nanoparticles	4432
8.23.4 Known Nanoparticle Effects in the Lung	4434
8.23.5 Cellular Mechanisms of Nanoparticle Toxicities	4436
8.23.6 Ensuring Nanoparticle Safety	4443
8.23.7 Conclusions	4444
Acknowledgments	4445
References	4445
8.24 The Pulmonary Toxicity of Anticancer Agents	4449
Abbreviations	4450
8.24.1 Introduction	4450
8.24.2 Pathobiological Considerations of Anticancer Drug-Induced Lung Toxicity	4451
8.24.3 Special Case of Anticancer Drug-Induced Pulmonary Fibrosis: The Bleomycin Model	4454
8.24.4 Alkylating Agents	4455
8.24.5 Antimetabolites	4460
8.24.6 Non-Bleomycin Antibiotics	4463
8.24.7 Topoisomerase I Inhibitors	4464
8.24.8 Mitotic Inhibitors	4465
8.24.9 Taxanes	4467
8.24.10 Miscellaneous	4467
8.24.11 Biological Response Modifiers	4468
8.24.12 Molecularly Targeted Therapy	4468
8.24.13 Conclusions	4475
References	4476
Relevant Websites	4482
8.25 Selected Pneumotoxic Agents	4483
Glossary	4483
Abbreviations	4484
8.25.1 General Concepts	4484
8.25.2 Enzyme-Mediated Versus NonEnzyme-Mediated Pulmonary Toxicants	4498
8.25.3 Conclusions	4513
References	4513
Index to Volume 8	4521
e9780080468686v9	4539
Cover	4539
Comprehensive Toxicology	4542
Copyright	4543
Contents of Volume 9	4544
Contents of All Volumes	4548
Preface	4558
9.01 Introduction to the Liver and its Response to Toxicants	4560
Abbreviations	4560
9.01.1 Overview	4560
9.01.2 Hepatic Functional Units	4563
9.01.3 Hepatic Heterogeneity	4564
9.01.4 Chemically Induced Liver Injury	4565
9.01.5 Morphological Responses of the Liver to Chemical Injury	4566
9.01.6 Mechanisms of Liver Injury	4566
9.01.7 Conclusions	4566
References	4567
9.02 Structure and Function of Hepatic Parenchymal Cells	4570
Abbreviations	4570
9.02.1 Introduction	4570
9.02.2 Organization of the Liver	4571
9.02.3 Hepatic Parenchymal Cells: Morphology and Functions	4571
9.02.4 Conclusions	4588
Acknowledgments	4589
References	4589
9.03 Hepatic Sinusoidal Cells: Endothelial Cells, Kupffer Cells, Stellate Cells, and Liver-Associated Lymphocytes	4590
Abbreviations	4590
9.03.1 Introduction	4590
9.03.2 Endothelial Cells	4591
9.03.3 Kupffer Cells	4593
9.03.4 Stellate Cells	4596
9.03.5 Liver-Associated Lymphocytes	4597
9.03.6 Conclusion	4598
References	4598
9.04 Anatomy and Physiology of the Biliary Epithelium	4602
Abbreviations	4603
9.04.1 Introduction	4604
9.04.2 Anatomy	4604
9.04.3 Physiology	4610
9.04.4 Injury, Recovery, Repair	4634
9.04.5 Conclusion	4656
References	4656
9.05 Regulation of Xenobiotic Metabolism in the Liver	4668
Abbreviations	4668
9.05.1 Introduction	4669
9.05.2 Phase I Metabolism	4670
9.05.3 Phase II Metabolism: Conjugation–Deconjugation Reactions	4675
9.05.4 Hepatic Xenobiotic Metabolism and Cofactor Supply	4682
Acknowledgment	4684
References	4684
Relevant Websites	4687
9.06 Evaluation of Hepatotoxicity: Physiological and Biochemical Measures of Hepatic Function in Animals	4688
Abbreviations	4688
9.06.1 Introduction	4689
9.06.2 Serum Enzymes	4689
9.06.3 Hepatic Excretory Function	4692
9.06.4 Liver Content	4693
9.06.5 Mitochondrial Function	4694
9.06.6 Repair and Recovery	4695
9.06.7 Histological Analysis	4697
9.06.8 Summary	4697
References	4698
9.07 Histologic Patterns of Hepatotoxic Injury	4700
Abbreviations	4701
9.07.1 Introduction	4701
9.07.2 Routine Stains Used in Hepatic Histology	4701
9.07.3 Cytoplasmic Changes: Adaptations, Vacuoles, and Inclusions	4702
9.07.4 Nuclear Changes	4708
9.07.5 Acute Injury and Necrosis	4708
9.07.6 Alcoholic Liver Disease	4713
9.07.7 Nonalcoholic Steatohepatitis/Nonalcoholic Fatty Liver Disease	4715
9.07.8 Chronic Hepatic Injury	4716
9.07.9 Cholestatic Liver Disease/Biliary Epithelial Injury	4718
9.07.10 Sinusoidal and Blood Vessel Lesions	4722
9.07.11 Preneoplastic and Neoplastic Lesions	4723
9.07.12 Interactive Hepatotoxicity	4728
9.07.13 Conclusions	4728
References	4728
9.08 Regulation of Hepatobiliary Transporters during Liver Injury	4734
Abbreviations	4735
9.08.1 Introduction	4735
9.08.2 Liver Transporters: Classes, Localization, and Function	4736
9.08.3 Adaptive Changes in Transporters during Liver Injury	4754
9.08.4 Signaling Pathways Underlying Transporter Expression during Liver Injury	4769
9.08.5 Concluding Remarks	4771
References	4772
9.09 Chemicals with Carcinogenic Activity in Rodent Liver	4780
Abbreviations	4780
9.09.1 Introduction	4781
9.09.2 Mechanisms of Carcinogenesis and MOAs of Carcinogens	4781
9.09.3 Categorization of Chemical Hepatocarcinogens	4783
9.09.4 Pathogenesis of Liver Cancer	4784
9.09.5 DNA-Reactive Hepatocarcinogens	4786
9.09.6 Epigenetic Rodent Hepatocarcinogens	4791
9.09.7 Unclassified Hepatocarcinogens	4796
9.09.8 Human Relevance	4799
References	4801
9.10 Mechanisms of Hepatic Steatosis	4810
Abbreviations	4810
9.10.1 Introduction	4811
9.10.2 Regulation of Hepatic Lipid Metabolism	4811
9.10.3 Insulin Resistance and Hepatic Steatosis	4814
9.10.4 Innate Immunity and Hepatic Steatosis	4815
9.10.5 Interactions between Adipose Tissue and Hepatic Steatosis	4816
9.10.6 Hepatic Steatosis: Friend or Foe?	4818
References	4818
9.11 Mechanisms of Liver Fibrosis	4822
Abbreviations	4822
9.11.1 Introduction	4822
9.11.2 Cell Types that Deposit Extracellular Matrix in the Liver During the Genesis of Fibrosis	4823
9.11.3 Mediators of Liver Fibrosis	4825
9.11.4 Role of Other Cell Types in the Pathogenesis of Liver Fibrosis	4830
9.11.5 Summary	4831
References	4832
9.12 The Adaptive Immune System and Liver Toxicity	4834
Abbreviations	4834
9.12.1 Introduction	4835
9.12.2 The Immune System	4835
9.12.3 The Liver as an Immunological Organ	4838
9.12.4 Primary Biliary Cirrhosis	4840
9.12.5 Viral Hepatitis	4842
9.12.6 Alcoholic Liver Disease	4845
9.12.7 Nonalcoholic Fatty Liver Disease	4847
Acknowledgment	4848
References	4849
9.13 Inflammation and Hepatotoxicity	4854
Abbreviations	4854
9.13.1 Introduction	4855
9.13.2 Resident Liver Cells and Inflammation	4856
9.13.3 Extrahepatic Cells and Liver Inflammation	4859
9.13.4 Contribution of Inflammation to Hepatotoxicity	4864
9.13.5 Xenobiotic Interaction with the Inflammatory Response	4868
9.13.6 Conclusions	4871
References	4871
9.14 Antioxidant Defense Mechanisms	4878
Abbreviations	4878
9.14.1 Introduction	4878
9.14.2 Sources of Reactive Oxygen	4879
9.14.3 Antioxidant Defense Mechanisms in the Liver	4884
9.14.4 Pathophysiological Relevance of Antioxidant Defense Mechanisms	4892
References	4893
9.15 Liver Regeneration and Tissue Repair	4898
Abbreviations	4898
9.15.1 Introduction	4899
9.15.2 Biology of Liver Regeneration	4900
9.15.3 Models of Liver Regeneration	4903
9.15.4 Regulation of Liver Regeneration	4905
9.15.5 Liver Regeneration – A Compensatory Response to Injury	4910
9.15.6 Conclusions	4922
References	4923
9.16 Clinical Considerations of Drug-Induced Hepatotoxicity	4928
Abbreviations	4928
9.16.1 Introduction	4929
9.16.2 Signals in Clinical Trials and Monitoring for Liver Injury	4929
9.16.3 Risk Factors for Drug-Induced Liver Injury	4930
9.16.4 Clinical Pathological Characterization	4931
9.16.5 Diagnosis	4936
9.16.6 Treatment	4937
9.16.7 Pitfalls/Special Circumstances	4938
9.16.8 Conclusion	4939
References	4939
9.17 Idiosyncratic Drug-Induced Liver Injury: Mechanisms and Susceptibility Factors	4942
Glossary	4942
Abbreviations	4943
9.17.1 Introduction	4943
9.17.2 Definition and Clinical Hallmarks of Idiosyncratic DILI	4943
9.17.3 Determinants of Idiosyncratic DILI	4945
9.17.4 Mechanisms of Drug Hepatotoxicity (Hazard)	4949
9.17.5 Susceptibility Factors (Risk Modulators)	4952
9.17.6 Novel Animal Models	4956
9.17.7 Prediction of Idiosyncratic DILI	4956
9.17.8 Conclusions	4957
References	4958
9.18 Comparative Hepatotoxicology	4962
Abbreviations	4962
9.18.1 Introduction	4962
9.18.2 Comparative Hepatic Anatomy	4963
9.18.3 Comparative Differences in Hepatic Metabolism	4964
9.18.4 Comparative Hepatic Responses to Injury	4965
9.18.5 Clinical Evaluation of Hepatic Damage by Species	4966
9.18.6 Selected Hepatotoxicants by Species	4968
9.18.7 Relationships Between Hepatic Toxicity and Clinical Signs in Other Organs	4973
9.18.8 Hepatic Cancer Related to Environmental Toxicants	4974
9.18.9 Conclusions	4975
References	4975
9.19 Ethanol-Induced Hepatotoxicity	4980
Abbreviations	4980
9.19.1 Introduction	4981
9.19.2 Ethanol Metabolism and Its Role in ALD	4982
9.19.3 Oxidative Stress	4985
9.19.4 The Role of Inflammation in ALD	4988
9.19.5 New Concepts in ALD	4989
9.19.6 Conclusions	4992
References	4992
9.20 Carbon Tetrachloride-Induced Hepatotoxicity	4996
Abbreviations	4996
9.20.1 Sources	4997
9.20.2 Types of Exposure	4997
9.20.3 Pathophysiological Effects	4997
9.20.4 Mechanisms of Toxicity	4999
9.20.5 Clinical Toxicology	5007
9.20.6 Human versus Animal	5008
9.20.7 Markers of Exposure and Effect	5009
References	5009
9.21 Mechanisms of Acetaminophen Hepatotoxicity	5016
Abbreviations	5016
9.21.1 Introduction	5017
9.21.2 Drug Metabolism and Initiation of Cell Injury	5017
9.21.3 Mitochondrial Dysfunction and Oxidant Stress	5020
9.21.4 DNA Fragmentation	5023
9.21.5 Apoptosis Versus Oncotic Necrosis	5024
9.21.6 Propagation Mechanisms of Cell Injury	5025
9.21.7 Innate Immune Response	5026
9.21.8 Regeneration	5028
9.21.9 Conclusions	5029
References	5029
9.22 Pesticides and Hepatotoxicity	5034
Abbreviations	5034
9.22.1 Introduction	5034
9.22.2 Enzymes	5039
9.22.3 Toxicity	5051
9.22.4 Conclusions	5054
References	5054
Relevant Websites	5059
9.23 Hepatotoxicity of Copper, Iron, Cadmium, and Arsenic	5060
Glossary	5060
Abbreviations	5060
9.23.1 Introduction	5061
9.23.2 Copper	5061
9.23.3 Iron	5067
9.23.4 Cadmium	5071
9.23.5 Arsenic	5077
9.23.6 Conclusions	5081
References	5082
9.24 Hepatotoxic Mycotoxins	5086
Abbreviations	5086
9.24.1 Introduction	5087
9.24.2 Aflatoxins	5088
9.24.3 Fumonisins	5108
References	5120
9.25 α-Naphthylisothiocyanate	5130
Abbreviations	5130
9.25.1 Introduction	5130
9.25.2 Pathophysiological Effects	5130
9.25.3 Hepatotoxicity of ANIT Analogues	5132
9.25.4 Mechanisms of Hepatotoxicity	5133
9.25.5 Conclusion	5137
References	5138
9.26 Hepatotoxicity of Reactive Aldehydes	5140
Abbreviations	5140
9.26.1 Introduction	5140
9.26.2 Characteristics of Specific Aldehydes	5141
9.26.3 Biotransformation and Detoxification Pathways for Aldehydes	5142
9.26.4 Overview of Mechanisms Involved in Hepatic Aldehyde Toxicity	5142
9.26.5 Examples of Aldehyde Toxicity – Aldehydes Produced Endogenously or Derived from Drug/Toxicant Biotransformation	5146
9.26.6 Specific Examples of Aldehyde Toxicity – Aldehydes Produced Endogenously	5150
9.26.7 Conclusions	5151
References	5152
9.27 Pyrrolizidine Alkaloid-Induced Hepatotoxicity	5154
Abbreviations	5154
9.27.1 Introduction	5154
9.27.2 Sources and Exposure	5155
9.27.3 Structure and Metabolism	5160
9.27.4 Pathophysiological Effects	5162
9.27.5 Treatment and Prevention	5165
9.27.6 Conclusions	5167
References	5167
9.28 Endotoxin-Induced Hepatotoxicity	5172
Abbreviations	5172
9.28.1 Endotoxin: Origin	5173
9.28.2 Endotoxin: Structural and Functional Components	5173
9.28.3 Endotoxin Stimulation of Inflammatory Cytokines and Associated Signal Transduction Pathways	5174
9.28.4 Relationship between Endotoxin and Hepatic Neutrophil Infiltration	5176
9.28.5 Endotoxin and Oxidative Stress	5178
9.28.6 Hepatic Circulatory Disturbances as a Result of Endotoxin Exposure	5179
9.28.7 Miscellaneous and Novel Hepatic Effects of Endotoxin	5180
9.28.8 Hepatic Biochemical and Histopathological Manifestations of Endotoxin Exposure	5180
9.28.9 Conclusions	5182
References	5182
9.29 Thioacetamide	5186
Abbreviations	5186
9.29.1 Background	5186
9.29.2 Absorption, Distribution, Metabolism, and Excretion	5187
9.29.3 Toxicokinetics of Thioacetamide	5189
9.29.4 Toxicology	5189
9.29.5 Conclusions	5195
Acknowledgments	5196
References	5196
Index to Volume 9	5198
e9780080468686v10	5218
Cover	5218
Comprehensive Toxicology	5221
Copyright	5222
Contents of Volume 10	5223
Contents of All Volumes	5225
Preface	5235
10.01 Introduction: The Gastrointestinal Tract	5237
10.02 Anatomy and Histology of the Digestive Tract	5239
Glossary	5239
10.02.1 Introduction	5240
10.02.2 Architecture of the Digestive Tract	5240
10.02.3 Overview of Blood and Lymphatic Vessels	5241
10.02.4 Overview of Innervation	5242
10.02.5 Esophagus	5242
10.02.6 Stomach	5243
10.02.7 Small Intestine	5247
10.02.8 Large Intestine	5249
References	5251
10.03 Gastrointestinal System: Overview of Physiology	5253
Abbreviations	5253
10.03.1 General Considerations	5254
10.03.2 Motility	5254
10.03.3 Secretion	5262
10.03.4 Digestion and Absorption	5270
References	5274
10.04 The Gastrointestinal Immune System	5275
Abbreviations	5275
10.04.1 Introduction	5275
10.04.2 Organization of the Mucosal Immune System	5276
10.04.3 Recognition of Microbial Signals and Antigen Uptake	5278
10.04.4 Migration and Homing of Intestinal Lymphocytes	5278
10.04.5 Intraepithelial Lymphocytes	5280
10.04.6 Lamina Propria Cells	5280
10.04.7 Regulation of the Mucosal Immune System	5284
Acknowledgments	5286
References	5287
10.05 Metabolic Barrier of the Gastrointestinal Tract	5289
Glossary	5289
Abbreviations	5289
10.05.1 Introduction	5290
10.05.2 Biotransformation Enzymes	5291
10.05.3 Transport Proteins	5298
10.05.4 Summary	5306
References	5307
10.06 Absorption, Enterohepatic Circulation, and Fecal Excretion of Toxicants	5313
Abbreviations	5313
10.06.1 Introduction	5313
10.06.2 Gastrointestinal Absorption	5314
10.06.3 Uptake into Hepatocytes	5317
10.06.4 Enterohepatic Circulation	5318
10.06.5 Fecal Excretion	5320
10.06.6 Factors Affecting Absorption, Enterohepatic Circulation, and Excretion of Toxicants	5322
10.06.7 Conclusions	5325
References	5325
10.07 Pathologic Response of the Gastrointestinal Tract to Toxicants	5329
Glossary	5329
Abbreviations	5330
10.07.1 Introduction	5330
10.07.2 Normal Anatomy and Histology of the GI Tract	5331
10.07.3 Types of Gastrointestinal Toxicopathologic Lesions	5336
10.07.4 Organ-Specific Responses	5347
10.07.5 Conclusions	5349
References	5349
10.08 Pathophysiological Mechanisms of Gastrointestinal Toxicity	5353
10.08.1 Introduction	5354
10.08.2 Abnormal Conditions	5360
10.08.3 Toxic Mechanisms	5361
10.08.4 Conclusions	5377
References	5377
10.09 Methods for Analysis of Gastrointestinal Toxicants	5381
Abbreviations	5381
10.09.1 Introduction	5381
10.09.2 Analytical Methods	5382
10.09.3 Gastrointestinal Toxicants	5384
10.09.4 Conclusion	5386
References	5386
10.10 Ricin	5389
Abbreviations	5389
10.10.1 Introduction	5389
10.10.2 Gastrointestinal Toxicity	5389
10.10.3 Clinical Toxicology	5392
References	5392
10.11 Nonsteroidal Anti-Inflammatory Drug-Induced Toxicity	5395
Glossary	5395
Abbreviations	5395
References	5397
10.12 Antineoplastic Drugs	5399
Glossary	5399
Abbreviations	5399
References	5400
10.13 Clinical Toxicity: Esophagus	5401
10.13.1 Introduction	5401
10.13.2 Caustic Injuries of the Esophagus	5401
10.13.3 Incidence	5402
10.13.4 Treatment	5403
10.13.5 Medication-Induced Esophageal Injury	5404
10.13.6 Specific Medications	5405
References	5406
10.14 Clinical Toxicology of Common Drugs and Chemicals in Humans: Stomach	5407
Abbreviations	5407
10.14.1 Introduction	5407
10.14.2 General Pathogenesis of Chemical Injury	5408
10.14.3 Specific Etiologic Agents	5409
10.14.4 Conclusions	5414
References	5415
10.15 Clinical Toxicology of Common Drugs and Chemicals: Colon	5417
Abbreviations	5417
10.15.1 Introduction	5417
10.15.2 Functional Abnormalities Induced by Drugs and Chemicals	5418
10.15.3 Specific Colonic Toxicity from Drugs or Chemicals	5421
10.15.4 Conclusions	5427
References	5429
10.16 Comparative Gastrointestinal Toxicity	5431
Abbreviations	5431
10.16.1 Introduction:	5432
Gastrointestinal Toxicology in Animals	5432
10.16.2 Comparative Gastrointestinal Anatomy and Physiology	5432
10.16.3 Mechanisms of Detoxification and Lethal Synthesis in the Rumen	5434
10.16.4 The Role of the Intestines in Gastrointestinal Toxicology	5435
10.16.5 Clinical Evaluation of Gastrointestinal Damage	5435
10.16.6 Gastrointestinal Toxicants Affecting Mucosal Cells	5436
10.16.7 Gastrointestinal Toxicoses Associated with the Neuromuscular System	5438
10.16.8 Gastrointestinal Toxicoses Associated with Alterations in Microbial Flora	5438
10.16.9 Gastrointestinal Toxicoses Associated with Mucosal Metabolism	5439
10.16.10 Other Gastrointestinal Toxicants	5440
10.16.11 Conclusions	5440
References	5440
Index to Volume 10	5443
e9780080468686v11	5449
Cover	5449
Comprehensive Toxicology	5452
Copyright	5453
Contents of Volume 11	5454
Contents of All Volumes	5458
Preface	5468
11.01 Male Reproductive Toxicology	5470
11.01.1 Introduction	5470
11.01.2 Conclusions	5471
References	5472
11.02 Anatomy and Physiology of the Male Reproductive System and Potential Targets of Toxicants	5474
Glossary	5475
Abbreviations	5475
11.02.1 Introduction	5476
11.02.2 Anatomy	5476
11.02.3 Physiology	5494
11.02.4 Normal Sexual Behavior in Males	5522
11.02.5 Conclusions	5523
Acknowledgments	5523
References	5523
11.03 Evaluation of a Male Reproductive Toxicant	5530
Abbreviations	5530
11.03.1 Introduction	5531
11.03.2 Study Designs – Strategies and/or Considerations	5532
11.03.3 Endpoints and Methodologies	5541
11.03.4 Data Interpretation	5550
11.03.5 Conclusions	5552
References	5552
11.04 Evaluation of an Infertile Transgenic Male Animal	5556
Glossary	5556
Abbreviations	5556
11.04.1 Introduction	5557
11.04.2 Determining Fertility	5559
11.04.3 Identifying Causes of Infertility	5561
11.04.4 Conclusions and Future	5562
Directions	5562
Acknowledgments	5563
References	5563
Relevant Websites	5564
11.05 The Sertoli Cell as a Target for Toxicants	5566
Abbreviations	5566
11.05.1 Introduction	5566
11.05.2 Mechanisms and Manifestations	5568
11.05.3 Toxicant Disruption of Sertoli Cell Function During Different Periods of Development	5578
11.05.4 Conclusions	5580
Acknowledgments	5580
References	5580
11.06 The Male Germ Cell as a Target for Toxicants	5584
Abbreviations	5584
11.06.1 Introduction	5584
11.06.2 Sperm Production in the Testis: Germ Cell Stage Specificity	5585
11.06.3 Manifestations of the Effects of Toxicants on Germ Cells	5590
11.06.4 Conclusion	5595
References	5595
Relevant Website	5598
11.07 The Leydig Cell as a Target for Toxicants	5600
Glossary	5600
Abbreviations	5601
11.07.1 Introduction	5602
11.07.2 Leydig Cells	5602
11.07.3 Toxicants with Antiandrogenic Effects on Leydig Cells	5606
11.07.4 Toxicants with Estrogenic Effects on Leydig Cells	5612
Acknowledgments	5613
References	5613
11.08 The Epididymis as a Target for Toxicants	5618
Abbreviations	5618
11.08.1 Introduction	5618
11.08.2 Identification of Direct Versus Indirect Epididymal Toxicity	5619
11.08.3 Impact of Altered Sperm Transit Time on Sperm Quality	5627
11.08.4 Studies on Epididymal Toxicology and the Discovery of a Biomarker of Fertility	5630
11.08.5 The Epididymis as a Target Organ during Reproductive Development	5631
11.08.6 Conclusions	5632
Acknowledgments	5633
References	5633
11.09 Cell Junctions in the Testis as Targets for Toxicants	5636
Abbreviations	5636
11.09.1 Introduction	5637
11.09.2 Cadmium	5637
11.09.3 Flutamide	5642
11.09.4 Vinclozolin	5643
11.09.5 Phthalates and Bisphenol A	5643
11.09.6 Gossypol	5645
11.09.7 CDB-4022	5645
11.09.8 Adjudin	5646
11.09.9 Conclusion and Future Perspectives	5653
Acknowledgments	5653
References	5654
11.10 Immunology of the Testis and Male Reproductive Tract	5658
Abbreviations	5658
11.10.1 Background	5659
11.10.2 The Interface between the Immune System and the Reproductive Tract	5660
11.10.3 Immunological Tolerance	5664
11.10.4 Immunoregulation in the Male Reproductive Tract	5671
11.10.5 General and Toxicological Issues	5687
11.10.6 Conclusions	5689
Acknowledgments	5689
References	5689
11.11 Environmental Endocrine Disruptors and Male Reproductive Toxicology	5700
Abbreviations	5700
11.11.1 Introduction	5701
11.11.2 Estrogen Effects on Males	5705
11.11.3 Environmental Estrogens/ Antiestrogens and Effects on the Hypothalamic-Hypophyseal System	5706
11.11.4 Effects on Wildlife	5707
11.11.5 Disruption of Androgen Signaling by Environmental Chemicals	5708
11.11.6 Endocrine Disruptors and the Testicular Dysgenesis Syndrome	5709
11.11.7 Male Reproductive Effects of Thyroid Hormone Signaling Disruption by Environmental Chemicals	5710
11.11.8 Epigenetic Effects of Environmental Endocrine Disruptors	5710
11.11.9 New Frontiers in Endocrine Disruption	5711
11.11.10 Conclusions and Future Directions	5713
Acknowledgments	5713
References	5713
11.12 Testicular Cancer	5716
Glossary	5716
Abbreviations	5717
11.12.1 Introduction	5717
11.12.2 Terminology, Histopathology, and Gene Expression Profiles of Testicular Neoplasms	5717
11.12.3 Development and Differentiation of the Testis	5721
11.12.4 Toxicological Evidence Linking Endocrine Disruption with Testicular Cancer	5725
11.12.5 Conclusions	5728
References	5729
11.13 Toxic Responses of the Adrenal Cortex	5734
Abbreviations	5734
11.13.1 Introduction	5735
11.13.2 Endocrinology of the Hypothalamo-Pituitary-Adrenocortical (HPA) Axis	5735
11.13.3 Toxic Responses of the Adrenal Cortex	5742
11.13.4 Adrenocortical Response to Toxic Insult	5751
11.13.5 Human Adrenocortical Dysfunction	5752
11.13.6 Environmental Exposures and Adrenal Endocrine Disruption	5754
11.13.7 Conclusions	5755
Acknowledgment	5755
References	5755
Further Reading	5758
11.14 Toxic Responses of the Adrenal Medulla	5760
Glossary	5760
Abbreviations	5760
11.14.1 Introduction	5761
11.14.2 Embryonic Development	5761
11.14.3 Anatomy and Cytology	5762
11.14.4 Histochemistry and Immunohistochemistry	5764
11.14.5 Physiology	5765
11.14.6 Chromaffin Cell Proliferation in the Adult Adrenal Medulla	5768
11.14.7 Adrenal Medullary Lesions in Toxicological Studies	5769
11.14.8 Pheochromocytoma Cell Lines as Models in Toxicological Research	5778
Relevant Website	5780
11.15 Toxicity to the Insulin-Secreting β-Cell	5782
Abbreviations	5782
11.15.1 Introduction	5782
11.15.2 Morphology of the Islets of Langerhans	5783
11.15.3 Insulin Synthesis	5785
11.15.4 Insulin Secretion	5786
11.15.5 β-Cell-Selective Toxic Agents Agents	5788
11.15.6 β-Cell-Selective Cytotoxic Agents: Mechanisms of Action Agents: Mechanisms of Action	5790
11.15.7 Cyproheptadine and Agents: Mechanisms of Action	5798
References	5804
11.16 Female Reproductive Toxicology	5808
Abbreviations	5808
11.16.1 Introduction	5808
11.16.2 Components of Female Reproductive System	5809
11.16.3 Impact of Reproductive Toxicity on Fertility	5810
11.16.4 Risk Assessment	5813
11.16.5 Conclusions	5813
References	5814
11.17 Differentiation and Function of the Female Reproductive System	5816
Abbreviations	5816
11.17.1 Introduction	5817
11.17.2 Genetic Determination of Sex	5817
11.17.3 Differentiation and Development – Prenatal	5818
11.17.4 Sexual Differentiation	5819
11.17.5 Sexual Maturity	5820
11.17.6 Reproduction	5826
11.17.7 Pregnancy	5830
11.17.8 Postnatal Period	5833
11.17.9 Menopause	5834
References	5835
11.18 Neuroendocrine Control of Female Reproduction	5836
Abbreviations	5836
11.18.1 Introduction	5836
11.18.2 Neuroendocrine Control of Female Reproductive Function	5836
11.18.3 Effect of Environmental Toxicants on Hypothalamic Regulation of Pituitary Hormone Secretion	5838
11.18.4 Effect of Environmental Toxicants on Pituitary Hormone Secretion	5845
11.18.5 Conclusions	5846
References	5846
11.19 Ovarian Toxicology	5850
Nomenclature	5850
Abbreviations	5850
11.19.1 Introduction	5851
11.19.2 Embryonic Development of Germ Cells	5851
11.19.3 Primordial Follicle Activation, Growth, and Development	5852
11.19.4 Susceptibility of Follicles to Deleterious Effects by Toxic Compounds: Effects on Female Reproduction and Mechanisms of Action	5857
11.19.5 Techniques for Studying the Effects of Toxicants on Ovarian Follicles	5862
11.19.6 Conclusions and Future Directions	5864
Acknowledgment	5864
References	5864
11.20 Targeting Female Reproductive Function during Follicular Maturation, Ovulation, and Fertilization: Critical Windows for Pharmaceutical or Toxicant Action	5868
Abbreviations	5868
11.20.1 Introduction	5869
11.20.2 Final Preparations in the Ovarian Follicle	5870
11.20.3 Ovulation	5874
11.20.4 Final Preparations in the Oocyte	5878
11.20.5 Fertilization: The Final Orchestration of Events	5882
11.20.6 Conclusion	5883
References	5883
11.21 Embryo–Uterine Interactions during Implantation: Potential Sites of Interference by Environmental Toxins	5888
Abbreviations	5888
11.21.1 Introduction	5889
11.21.2 Development of the Preimplantation Embryo and Its Competency for Implantation	5891
11.21.3 Uterine Changes	5892
11.21.4 Implantation	5898
11.21.5 Environmental Toxins and Embryo Implantation	5901
11.21.6 Environmental Toxins and Uterine Gene Expression	5904
11.21.7 Conclusions	5908
Acknowledgments	5908
References	5908
11.22 Lactation and Contamination of Breast Milk with Xenobiotics	5914
Glossary	5914
Nomenclature	5914
Abbreviations	5914
11.22.1 Introduction	5915
11.22.2 Transfer of Xenobiotics into Milk	5915
11.22.3 Assessing Risk	5918
11.22.4 Special Classes	5922
11.22.5 Effect of Xenobiotics on Milk Production	5922
11.22.6 Practical Methods of Reducing Infant Exposure	5923
References	5923
11.23 Ovarian Metabolism of Xenobiotics	5926
Glossary	5926
Abbreviations	5926
11.23.1 Introduction	5926
11.23.2 Ovarian Metabolism	5927
11.23.3 Two Well-Studied Examples of Ovarian Metabolism	5929
11.23.4 Conclusions	5934
References	5935
11.24 Placental Metabolism of Xenobiotics	5938
Abbreviations	5938
11.24.1 Placental Organization and Function	5939
11.24.2 Placental Enzymes	5939
11.24.3 Mechanisms of Xenobiotic Transport Across the Placenta	5944
References	5948
11.25 Ovarian Cancer and the Environment: Rodent Models	5952
Abbreviations	5952
11.25.1 Introduction	5952
11.25.2 Ovarian Cellular Compartments and Tumor Classification	5953
11.25.3 Germ Cell Tumors	5955
11.25.4 Sex Cord-Stromal and Granulosa Cell Tumors	5956
11.25.5 Tumors of the Ovarian Surface Epithelium	5960
11.25.6 Use of Animal Models of Ovarian Cancer for Toxicology Studies	5963
11.25.7 Conclusions	5965
Acknowledgments	5965
References	5966
11.26 Uterine Tumors and the Environment	5968
Abbreviations	5968
11.26.1 Introduction	5969
11.26.2 Environmental Toxicants and Uterine Tumors in Animal Models	5970
11.26.3 Effects of Specific Environmental Toxicants on Uterine Tumors In Vivo	5971
11.26.4 Transgenerational Effects of Endocrine Disruptors	5976
11.26.5 Uterine Leiomyomas	5976
11.26.6 Environmental Toxicants and Endometrial Cancer	5982
11.26.7 Conclusions	5987
References	5987
11.27 Risk Assessment Studies: Epidemiology	5992
Abbreviations	5992
11.27.1 Introduction	5992
11.27.2 Environmental and Occupational Exposures and Adverse Reproductive Effects	5996
References	6000
11.28 Menopause and Hormone Replacement Therapy	6004
Abbreviations	6004
11.28.1 Introduction	6004
11.28.2 Menopause	6005
11.28.3 Menopausal Therapy	6006
11.28.4 Conclusions	6009
References	6009
11.29 In Vitro Ovarian Model Systems	6012
Glossary	6012
Abbreviations	6012
11.29.1 Introduction	6013
11.29.2 Culturing Intact Ovarian Tissue In Vitro	6014
11.29.3 Ovarian Follicle Cultures In Vitro	6020
11.29.4 Cell Cultures	6026
11.29.5 Perspectives	6027
References	6027
11.30 Genetic Mouse Models for Female Reproductive Toxicology Studies	6030
Abbreviations	6030
11.30.1 Introduction	6031
11.30.2 Endocrine Disrupting Chemicals and Their Impacts on Development and Functions of the Female Reproductive System	6032
11.30.3 Genetic Models Related to the Female Development and Reproduction	6034
11.30.4 Potential Application of Genetic Mouse Models in Reproductive Toxicology	6041
11.30.5 Conclusions	6042
References	6042
Index to Volume 11	6046
e9780080468686v12	6062
Cover	6062
Comprehensive Toxicology	6065
Copyright	6066
Contents of Volume 12	6067
Contents of All Volumes	6069
Preface	6079
12.01 Foreword	6081
12.02 Fundamental Concepts, Current Regulatory Design and Interpretation	6083
Abbreviations	6083
12.02.1 Introduction	6083
12.02.2 Manifestations of Abnormal Development	6083
12.02.3 Principles of Developmental Toxicology	6084
12.02.4 Approaches to Identifying and Regulating Developmental Toxicants	6085
12.02.5 Nonanimal Models to Predict Developmental Toxicity	6087
12.02.6 Known Human Developmental Toxicants	6088
12.02.7 The Future of Developmental Toxicology	6088
Acknowledgements	6088
References	6089
Relevant Websites	6089
12.03 Embryotoxicity: Anatomical, Physiological, and Functional	6091
Abbreviations	6091
12.03.1 Introduction	6091
12.03.2 Case Study: Anatomical Changes	6094
12.03.3 Case Study: Physiological Changes	6098
12.03.4 Case Studies: Functional Changes	6101
12.03.5 Conclusions	6103
References	6104
12.04 Pharmacokinetics and PBPK Models	6107
Abbreviations	6107
12.04.1 Introduction	6107
12.04.2 Pharmacokinetics during Gestation	6108
12.04.3 Pharmacokinetics during Nursing	6117
12.04.4 Pharmacokinetics during Postnatal Development	6121
12.04.5 Conclusions	6133
References	6136
Relevant Websites	6138
12.05 The National Children’s Study: Linking Exposures to Effects in Children’s Environmental Health	6139
Abbreviations	6139
12.05.1 Introduction	6139
12.05.2 History and Rationale	6140
12.05.3 Study Design, Hypotheses, Measures	6141
12.05.4 The Potential for Additional Research	6146
12.05.5 What Does the National Children’s Study Portend for the Field of Developmental Toxicology?	6146
12.05.6 Conclusions	6147
References	6147
12.06 Epigenetics and the Developmental Origins of Health and Disease	6149
Abbreviations	6149
12.06.1 Introduction to Epigenetics	6150
12.06.2 Molecular Mechanisms of Epigenetic Regulation	6150
12.06.3 Epigenetic Regulation during Development	6156
12.06.4 Epigenetic Programming and the Developmental Origins of Health and Disease	6157
References	6165
12.07 Epigenetic Transgenerational Toxicology	6169
Abbreviations	6169
12.07.1 Introduction	6169
12.07.2 Transgenerational Phenotypes	6169
12.07.3 Epigenetics	6170
12.07.4 Epigenetic Transgenerational Phenomena	6172
12.07.5 Summary and Future Directions	6172
References	6173
12.08 The Role of Biotransformation in Developmental Toxicity	6175
Glossary	6175
Abbreviations	6177
12.08.1 Introduction	6177
12.08.2 Maternal Elimination	6180
12.08.3 Bioactivation	6182
12.08.4 Detoxification	6187
12.08.5 Cytoprotection	6189
12.08.6 Molecular Damage	6190
12.08.7 Macromolecular Repair	6191
12.08.8 Reactive Oxygen Species-Mediated Signal Transduction	6192
12.08.9 Conclusions	6192
Acknowledgments	6193
References	6193
12.09 Analysis of Altered Gene Expression in Diabetic Embryopathy	6197
Abbreviations	6197
12.09.1 Introduction	6197
12.09.2 Identification and Validation of Altered Gene Expression	6199
12.09.3 Functional Annotation	6205
12.09.4 Future Challenges	6210
12.09.5 Conclusions	6211
References	6212
Relevant Websites	6213
12.10 Epidemiological Factors in Developmental Toxicology	6215
Abbreviations	6215
12.10.1 Introduction	6215
12.10.2 Sources of Pregnancy Exposure Safety Data	6216
12.10.3 Evaluation of Human Pregnancy Risk for Lithium as an Example of an Exposure with Limited Available Data	6220
12.10.4 Conclusions	6221
References	6223
Relevant Website	6224
12.11 Individual (Personalized) Vulnerabilities	6225
Abbreviations	6225
12.11.1 Introduction	6225
12.11.2 The Science of Pharmacogenomics	6227
12.11.3 Phenylketonuria: A Classic Example of Personalized Nutrition	6232
12.11.4 Multifactorial Regulation of Perinatal Nutritional Requirements	6233
12.11.5 Balancing Needs: When Addressing a Mother’s Disease Endangers the Fetus	6235
12.11.6 Confounding Individualized Therapies: Alteration of Drug Metabolism during Pregnancy	6237
12.11.7 Multigenerational Effects of Altered Perinatal Environment	6238
12.11.8 Conclusion	6238
References	6239
Relevant Websites	6241
12.12 Maternally Mediated Developmental Toxicity	6243
Abbreviations	6243
12.12.1 Introduction	6243
12.12.2 Impact of General Maternal Effects on Prenatal Development	6244
12.12.3 Specific Perturbations of Maternal Physiology and Their Impact on Prenatal Development	6246
12.12.4 Data Evaluation: Unraveling Maternal and Developmental Toxicity Findings	6252
12.12.5 New Concepts on Maternal Toxicity in Safety Evaluation	6254
References	6255
12.13 Developmental Toxicity of Antiepileptic Drugs	6257
Abbreviations	6257
12.13.1 Introduction	6257
12.13.2 Postulated Mechanisms of Developmental Toxicity	6258
12.13.3 Newer Antiepileptic Drugs	6263
12.13.4 Conclusions	6265
References	6266
12.14 Fumonisin, Folate, and Neural Tube Defects	6269
Abbreviations	6269
12.14.1 Introduction	6269
12.14.2 Risk Factors for Neural Tube Defects	6270
12.14.3 Folate Transport and Neural Tube Defects	6272
12.14.4 Fumonisin and Neural Tube Defects	6274
12.14.5 Conclusions	6284
Acknowledgments	6284
References	6285
Relevant Websites	6288
12.15 Metals and Cell Adhesion	6289
Abbreviations	6289
12.15.1 Introduction: Cell Adhesion Molecules at the Nexus of Developmental Biology and Toxicology	6289
12.15.2 The Cadherin Superfamily of Calcium-Dependent Cell Adhesion Molecules	6290
12.15.3 Cadherins as Molecular Targets of Heavy Metal Developmental Toxicants	6291
12.15.4 Calcium-Independent Cell Adhesion Molecules of the Immunoglobulin Superfamily	6294
12.15.5 IgCAMs as Targets of Heavy Metal Developmental Toxicants	6294
12.15.6 Cell Adhesion Molecules as Targets of Organic Solvent Intoxication	6296
12.15.7 Cell Adhesion Molecules as Targets of Insecticides and Other Emergent Environmental Toxicants	6298
12.15.8 Conclusions and Future Directions	6299
Acknowledgments	6300
References	6300
12.16 Alcohol and Cell Death	6303
Abbreviations	6303
12.16.1 Introduction	6304
12.16.2 Alcohol and Cell Death	6305
12.16.3 Mechanisms Underlying Alcohol Cell Death	6306
12.16.4 Prevention or Repair of Alcohol’s Damage	6314
Acknowledgment	6316
References	6316
12.17 Intrauterine Infection	6319
Glossary	6319
Abbreviations	6320
12.17.1 Introduction	6320
12.17.2 Adverse Pregnancy Outcomes after Infection	6324
12.17.3 Examples of Infection during Pregnancy	6328
12.17.4 Immaturity of the Preterm Infant’s Immune System	6334
12.17.5 Effects of Infection on the Pregnant Woman	6335
12.17.6 Conclusions	6335
Acknowledgment	6335
References	6335
12.18 Methods for Detection of Developmental Toxicity	6339
Abbreviations	6339
12.18.1 Background	6339
12.18.2 Introduction	6341
12.18.3 Study of Fertility and Early Embryonic Development to Implantation (ICH 4.1.1)	6343
References	6357
Relevant Website	6358
12.19 Developmental Neurotoxicology	6359
Abbreviations	6359
12.19.1 Introduction	6359
12.19.2 Principles of Developmental Neurotoxicology	6361
12.19.3 Developmental Neurotoxicity Testing	6367
12.19.4 Conclusions	6371
References	6371
12.20 Alternative Methods in Developmental Toxicology	6373
Abbreviations	6373
12.20.1 Introduction	6373
12.20.2 Rodent Postimplantation Whole Embryo Culture	6375
12.20.3 Mouse Embryonic Stem Cell Test	6377
12.20.4 Zebrafish Embryotoxicity Test	6379
12.20.5 Regulatory Implementation of Alternative Tests	6382
References	6383
Relevant Websites	6385
12.21 Computational Toxicology	6387
Glossary	6387
Abbreviations	6388
12.21.1 Introduction	6389
12.21.2 Databases	6390
12.21.3 Informatics Analysis and Predictions	6396
12.21.4 v-EmbryoTM Project	6407
12.21.5 Chemoinformatics Analysis	6407
12.21.6 Conclusions	6415
References	6416
Relevant Websites	6417
12.22 The DevTox Site: Harmonized Terminology and Database	6419
Abbreviations	6419
12.22.1 Introduction	6419
12.22.2 DevTox Information	6420
12.22.3 DevTox Nomenclature	6421
12.22.4 DevTox Database	6423
12.22.5 Outlook	6425
References	6425
Relevant Website	6426
12.23 Virtual Tissues and Developmental Systems Biology	6427
Abbreviations	6427
12.23.1 Introduction	6427
12.23.2 Biological Scale and Complexity	6428
12.23.3 Systems Biology	6431
12.23.4 Future Research	6436
DISCLAIMER	6437
References	6437
Relevant Websites	6438
Index to Volume 12	6439

Comprehensive Toxicology

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