Fundamentals of Toxicologic Pathology

2. Auflage 2009
ISBN: 978-0-08-091932-4
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 714 Seiten

Toxicologic pathology integrates toxicology and the disciplines within it (such as biochemistry, pharmacodynamics and risk assessment) to pathology and its related disciplines (such as physiology, microbiology, immunology, and molecular biology). Fundamentals of Toxicologic Pathology Second Edition updates the information presented in the first edition, including five entirely new chapters addressing basic concepts in toxicologic pathology, along with color photomicrographs that show examples of specific toxicant-induced diseases in animals. The current edition also includes comparative information that will prove a valuable resource to practitioners, including diagnostic pathologists and toxicologists. - 25% brand new information, fully revised throughout - New chapters: Veterinary Diagnostic Toxicologic Pathology; Clinical Pathology; Nomenclature: Terminology for Morphologic Alterations; Techniques in Toxicologic Pathology - New color photomicrographs detailing specific toxicant-induced diseases in animals - Mechanistic information integrated from both toxicology and pathology discussing basic mechanisms of toxic injury and morphologic expression at the subcellular, cellular, and tissue levels

Autoren/Hrsg.

Inhaltsverzeichnis

1;Front Cover;1
2;Fundamentals of Toxicologic Pathology;4
3;Copyright Page;5
4;Contents;6
5;Preface;20
6;Acknowledgments;22
7;CHAPTER 1 PRINCIPLES OF TOXICOLOGY;24
7.1;The Effect of the Body on the Chemical;24
7.2;Absorption;24
7.2.1;Passage across Membranes;24
7.3;Distribution;25
7.3.1;Volume of Distribution;25
7.3.2;Barriers to Distribution;25
7.4;Biotransformation;26
7.4.1;Phase I: Metabolism;26
7.4.2;Phase II: Metabolism;27
7.5;Enzyme Location in Toxicity;27
7.6;Excretion;28
7.6.1;Urinary Excretion;28
7.6.2;Biliary Excretion;28
7.6.3;Pulmonary Excretion;29
7.7;Interaction of Chemical and the Body;29
7.8;Enzyme Induction and Inhibition;29
7.8.1;Activation, Induction, or Synergism;29
7.9;Inhibition;29
7.10;Dose Dependency and Site of Action;30
7.11;Organ Specificity for Toxicity;30
7.12;Site-Specific Interactions and Toxicity;30
7.12.1;Receptors and Enzymes;30
7.12.2;Direct and Cascade Effects;30
7.13;Nonspecific Interations and Toxicity;30
7.13.1;Electrophiles and Covalent Binding;30
7.13.2;Free Radicals and Lipid Peroxidation;31
7.14;Further Reading;31
8;CHAPTER 2 MANIFESTATIONS OF TOXIC CELL INJURY: CELL INJURY/DEATH AND CHEMICAL CARCINOGENESIS;32
8.1;Section I: Cell Injury, Cell Death and Sequelae;33
8.1.1;Introduction;33
8.1.1.1;Key Cellular Components in Cell Injury;33
8.1.1.2;Factors Influencing Injury;33
8.1.1.3;Reaction of the Body to Injury;34
8.1.1.4;Adaptation;34
8.1.2;Reversible Cell Injury;36
8.1.2.1;Cell Swelling;36
8.1.2.2;Fatty Change;37
8.1.3;Irreversible Injury;38
8.1.3.1;Oncotic Necrosis;38
8.1.3.2;Apoptotic Necrosis;42
8.1.3.3;Sequelae to Irreversible Cell Injury;44
8.1.4;Concluding Comments;46
8.2;Section II: Chemical Carcinogenesis;46
8.2.1;Overview;46
8.2.2;Nomenclature of Neoplasms;47
8.2.3;Spectrum of Proliferative Lesions;48
8.2.3.1;Quantitative Cell Proliferation (Hyperplasia);48
8.2.3.2;Qualitative Cell Proliferation;49
8.2.3.3;Preneoplasia;50
8.2.3.4;Neoplastic Cell Proliferation;50
8.2.3.5;Diagnostic Distinction between Preneoplasia, Benign Neoplasia, and Malignant Neoplasia;51
8.2.4;Steps in the Neoplastic Process;51
8.2.4.1;Initiation;51
8.2.4.2;Promotion;52
8.2.4.3;Progression;52
8.2.5;Hypotheses of Mode of Action of Chemical Carcinogens;53
8.2.5.1;Overview;53
8.2.5.2;Mutational Genetic Hypothesis of Chemical Carcinogenesis;53
8.2.5.3;Nonmutational Genetic Hypothesis of Chemical Carcinogenesis;54
8.2.5.4;Epigenetic Hypothesis of Chemical Carcinogenesis;54
8.2.5.5;Viral Hypothesis of Carcinogenesis;55
8.2.6;Oncogenes and Tumor Suppressor Genes in Chemical Carcinogenesis;56
8.2.6.1;Genes and Oncogenes;56
8.2.6.2;Proto-oncogene Function;56
8.2.6.3;Proto-oncogene Activation;56
8.2.6.4;Oncogene Activation in Chemical Carcinogenesis;57
8.2.6.5;Tumor Suppressor Genes and Carcinogenesis;59
8.2.7;Cell Cycle and Carcinogenesis;59
8.2.7.1;Cyclins and Cdk Proteins;59
8.2.7.2;Retinoblastoma Checkpoint;59
8.2.7.3;p53 Checkpoint;60
8.2.8;Tests for Carcinogenic Potential of Chemicals;60
8.2.8.1;In Vivo Chronic Rodent Carcinogenesis Studies;60
8.2.8.2;Additional In Vivo Tests for Carcinogenicity;62
8.2.8.3;In Vitro Short-term Tests;64
8.2.9;Conclusion;64
8.2.10;Further Reading;64
9;CHAPTER 3 CLINICAL PATHOLOGY;66
9.1;Introduction;66
9.2;Hematology;67
9.2.1;Parameters Generally Included in Study Protocols;67
9.2.2;Interpretative Hematology;68
9.3;Clinical Chemistry;73
9.3.1;Cholesterol, Triglycerides, and Glucose;73
9.3.2;Serum Proteins;76
9.3.3;Indicators of Hepatic Integrity and Function;77
9.3.4;Indicators of Renal Function;79
9.3.5;Electrolytes;79
9.3.6;Calcium and Inorganic Phosphate;80
9.3.7;Enzymes of Muscle Origin;80
9.4;Microsomal Enzyme Induction;80
9.5;Urinalysis;81
9.6;Interpretation of Clinical Pathology Results;82
9.6.1;Potential Effects of Factors Unrelated to Test Article Treatment;83
9.6.2;Comparators: Concurrent Controls, Reference Ranges;84
9.6.3;Statistical Analyses;85
9.6.4;Direct Versus Indirect Effects;85
9.6.5;Pharmacologic Versus Toxic Effects;86
9.6.6;Biological Importance of Treatment-related Effects;86
9.7;Reporting of Clinical Pathology Findings;87
9.8;Summary;87
9.9;Further Reading;87
10;CHAPTER 4 NOMENCLATURE: TERMINOLOGY FOR MORPHOLOGIC ALTERATIONS;90
10.1;Introduction;90
10.2;Basic Terminology;91
10.3;Terminology Issues;91
10.3.1;Training;96
10.3.2;Multiple Pathologists;97
10.3.3;Diagnostic Drift;98
10.3.4;Lesion Complexity;98
10.3.5;Standardized Nomenclature;99
10.3.6;Recording Pathology Data;99
10.4;Suggested Practices;100
10.5;Summary;101
10.6;Further Reading;102
11;CHAPTER 5 TECHNIQUES IN TOXICOLOGIC PATHOLOGY;104
11.1;Introduction;104
11.2;Factors Influencing Evaluation of Altered Morphology;105
11.2.1;Factors in Collection and Processing of Tissue;107
11.2.2;Factors Intrinsic to the Animal;110
11.2.3;Factors Related to the Environment;113
11.2.4;Factors Related to Nomenclature;114
11.3;Further Reading;114
12;CHAPTER 6 RESPIRATORY SYSTEM;116
12.1;Introduction;116
12.2;Structure and Cell Biology;117
12.2.1;Macroscopic and Microscopic Anatomy;117
12.2.2;Nasopharyngeal and Laryngeal Regions (Upper Respiratory Tract);118
12.2.3;Tracheobronchial Region and Bronchioles;119
12.2.4;Pulmonary Region;121
12.2.5;Physiology and Functional Considerations;123
12.2.6;Xenobiotic Exposure, Metabolism, and Excretion;125
12.3;Mechanisms of Toxicity;127
12.3.1;Direct Toxicity;128
12.3.2;Metabolic Activation;128
12.3.2.1;Immune-mediated Toxicity;129
12.3.2.2;Toxicity and Responses to Inhaled Particles;131
12.3.2.3;Xenobiotic Interactions;132
12.3.2.4;Modifying Factors in Toxicity;132
12.3.3;Response to Injury;132
12.3.3.1;Injury, Regeneration, and Repair;133
12.3.3.2;Nasopharyngeal and Laryngeal Responses to Injury;134
12.3.3.3;Airway Response to Injury;136
12.3.3.4;Pulmonary Parenchymal Response to Injury;141
12.3.3.5;Edema;142
12.3.3.6;Inflammation;144
12.3.3.7;Fibrosis;147
12.3.3.8;Emphysema;149
12.3.3.9;Neoplasia;150
12.3.4;Evaluation of Toxicity;151
12.3.4.1;Methods for Testing;152
12.3.4.2;In Vitro Methods;152
12.3.4.3;Lung Cancer Model Systems;153
12.3.4.4;Pulmonary Function;153
12.3.4.5;Bronchopulmonary Lavage;153
12.3.4.6;Biochemical Evaluation;154
12.3.4.7;Morphologic Evaluation;154
12.3.4.8;Quantitative Techniques;155
12.3.4.9;Additional Techniques;155
12.3.4.10;Animal Models;155
12.3.5;Conclusions;156
12.3.6;Further Reading;156
13;CHAPTER 7 SKIN AND ORAL MUCOSA;158
13.1;Section I: Skin;158
13.1.1;Introduction;158
13.1.2;Structure and Function of Skin;159
13.1.2.1;Microscopic Anatomy;159
13.1.2.2;Skin Cell Subpopulations;161
13.1.2.3;Physiology and Biochemistry;161
13.1.3;Comparative Mechanisms of Cutaneous Toxicity;164
13.1.3.1;Direct Damage;164
13.1.3.2;Immunomediated Cutaneous Toxicity;167
13.1.3.3;Phototoxicity and Photoallergy;169
13.1.4;Response of Skin to Injury;170
13.1.4.1;Fundamental Non-neoplastic Lesions;170
13.1.4.2;Neoplastic Lesions;178
13.1.5;Evaluation of Cutaneous Toxicity;179
13.1.5.1;Skin Irritation Tests;180
13.1.5.2;Carcinogenesis Bioassays;180
13.1.5.3;Morphologic Assessment;181
13.1.5.4;Other Bioassays;181
13.1.5.5;Transgenic Animal Models;181
13.1.5.6;In Vitro Testing;182
13.2;Section II: Oral Mucosa;182
13.2.1;Introduction;182
13.2.2;Structure and Function of the Oral Mucosa;182
13.2.2.1;Microscopic Anatomy;182
13.2.2.2;Physiology;182
13.2.3;Comparative Mechanisms of Mucosal Toxicity;183
13.2.4;Response of Oral Mucosa to Injury;183
13.2.4.1;Fundamental Non-neoplastic Lesions;183
13.2.4.2;Carcinogenesis;184
13.2.5;Evaluation of Oral Toxicity;184
13.2.6;Further Reading;184
14;CHAPTER 8 GASTROINTESTINAL TRACT;186
14.1;Introduction;186
14.2;Structure and Function of the Gastrointestinal Tract;187
14.2.1;Macroscopic and Microscopic Structure and Function;187
14.2.2;Enteric Lymphoid System;194
14.2.3;Enteric Nervous System;195
14.2.4;Biotransformation;195
14.2.5;Bacterial Metabolism;197
14.2.6;Enterohepatic Circulation;197
14.3;Comparative Mechanisms of Gastrointestinal Toxicity;198
14.3.1;Intestinal Barrier Function;198
14.3.2;Intestinal Malabsorption;200
14.3.3;Altered Blood Supply;200
14.3.4;Mucosal Barrier Damage and Cytotoxicity;201
14.3.5;Hypersensitivity;204
14.3.6;Neurotransmitter Effects;206
14.3.7;Perturbation of Microflora;206
14.3.8;Carcinogenicity;206
14.4;Response of the Gastrointestinal Tract to Injury;207
14.4.1;Pathophysiological Responses;207
14.4.2;Inflammatory Response;209
14.4.3;Mucosal Response;210
14.4.4;Organ-specific Responses;212
14.5;Evaluation of Gastrointestinal Toxicity;214
14.5.1;In Vitro Strategies;214
14.5.2;In Vivo Strategies;215
14.5.3;Molecular Pathology;215
14.5.4;Morphologic Methods;216
14.5.5;Animal Models;217
14.6;Further Reading;219
15;CHAPTER 9 THE LIVER;220
15.1;Introduction;220
15.2;Structure and Function;220
15.2.1;Gross and Microscopic Anatomy;221
15.2.2;Cell Components;221
15.2.3;Xenobiotic Metabolism;223
15.3;Mechanisms of Toxicity;223
15.3.1;Classification of Hepatoxicants;224
15.3.2;Cellular Mechanisms of Toxicity;224
15.4;Non-neoplastic Responses to Injury;225
15.4.1;Histologic Types of Hepatic Necrosis;231
15.4.2;Intracellular Accumulations;237
15.4.3;Pathology of Transcription and Translation;241
15.4.4;Cholestasis;242
15.4.5;Hepatocellular Adaptive Responses;242
15.4.6;Hepatocellular Proliferation;243
15.4.7;Bile Ductular Lesions;244
15.4.8;Nonparenchymal Cell Toxicity;247
15.4.9;Hepatitis;248
15.4.10;Hepatic Fibrosis and Cirrhosis;249
15.5;Hepatic Neoplasia;251
15.5.1;Hepatocellular Neoplasia;251
15.5.2;Bile Duct Neoplasms;253
15.5.3;Endothelial Neoplasms;254
15.5.4;Küpffer Cell Neoplasms;254
15.6;Evaluation of Toxicity;254
15.6.1;Morphologic Evaluation;255
15.6.2;Clinical Chemistry Evaluation;256
15.6.3;Noninvasive Imaging;257
15.6.4;In Vitro Approaches;257
15.6.5;Use of Animals as Models;257
15.7;Summary and Conclusions;258
15.8;Further Reading;258
16;CHAPTER 10 PANCREAS;260
16.1;Section I: Exocrine Pancreas;260
16.1.1;Introduction;260
16.1.2;Normal Structure of Exocrine Pancreas;261
16.1.2.1;Gross Anatomy;261
16.1.2.2;Microscopic Anatomy and Ultrastructure;261
16.1.3;Physiology of Exocrine Pancreas;263
16.1.4;Comparative Mechanisms of Exocrine Pancreatic Toxicity;264
16.1.5;Response of Exocrine Pancreas to Injury;266
16.1.5.1;Cytotoxic Effects on Acinar Cells;266
16.1.5.2;Cytotoxic Effects in Ductal and Centroacinar Cells;270
16.1.5.3;Carcinogenesis;270
16.1.6;Evaluation of Exocrine Pancreatic Toxicity;271
16.1.6.1;Methods of Testing;272
16.1.6.2;Morphologic Evaluation of Toxicity;273
16.1.6.3;Animal Models;273
16.1.7;Summary and Conclusions;273
16.2;Section II: Endocrine Pancreas;274
16.2.1;Structure of Endocrine Pancreas;274
16.2.1.1;Gross Anatomy;274
16.2.1.2;Microscopic Anatomy and Ultrastructure;274
16.2.2;Physiology of Endocrine Pancreas;275
16.2.3;Mechanisms of Endocrine Pancreatic Toxicity;276
16.2.3.1;Insulin-dependent Diabetes Mellitus;276
16.2.3.2;Non-insulin-dependent Diabetes Mellitus;277
16.2.3.3;Glucose Intolerance;278
16.2.4;Response of Endocrine Pancreas to Injury;279
16.2.4.1;Apoptosis;279
16.2.4.2;Necrosis;279
16.2.4.3;Insulitis;280
16.2.4.4;Regeneration;281
16.2.4.5;Carcinogenesis;281
16.2.5;Evaluation of Endocrine Pancreatic Toxicity;281
16.2.5.1;In Vivo Testing;281
16.2.5.2;In Vitro Testing;281
16.2.5.3;Animal Models;281
16.2.6;Summary and Conclusions;281
16.2.7;Further Reading;282
17;CHAPTER 11 KIDNEY AND LOWER URINARY TRACT;284
17.1;Introduction;284
17.2;Renal Structure and Function;285
17.2.1;Gross, Microscopic, and Ultrastructural Anatomy;285
17.2.2;Physiology;292
17.3;Mechanisms of Toxicity;296
17.3.1;Overview and Classification;296
17.3.2;Glomerular Injury;298
17.3.3;Proximal Tubular Injury;307
17.3.4;Other Sites of Renal Injury;319
17.3.5;Lower Urinary Tract;322
17.3.6;Renal Carcinogenesis;323
17.3.7;Lower Urinary Tract Carcinogenesis;326
17.4;Response to Injury;326
17.4.1;Introduction;326
17.4.2;Glomerulus;326
17.4.3;Proximal Tubule and Interstitium;327
17.4.4;Renal Papillary Necrosis;332
17.4.5;Renal Tubular Hyperplasia and Neoplasia;332
17.4.6;Lower Urinary Tract: Non-neoplastic Lesions;333
17.4.7;Lower Urinary Tract Epithelial Neoplasms;336
17.5;Evaluation of Toxicity;337
17.5.1;Diagnostic Evaluation of Renal Disease;337
17.5.2;Routine Screening for Nephrotoxicity;337
17.5.3;Special Techniques;338
17.5.4;Evaluation of the Lower Urinary Tract;339
17.6;Conclusion;340
17.7;Further Reading;340
18;CHAPTER 12 CARDIOVASCULAR AND SKELETAL MUSCLE SYSTEMS;342
18.1;Section I: Heart;343
18.1.1;Introduction;343
18.1.2;Structure and Function;343
18.1.2.1;Gross and Microscopic Anatomy;343
18.1.2.2;Cellular and Extracellular Elements of the Heart: Biology and Clinical Relevance;344
18.1.2.3;Physiology and Functional Considerations;346
18.1.2.4;Xenobiotic Exposure;347
18.1.3;Mechanisms of Toxicity;347
18.1.3.1;Physiological Mechanisms of Functional Alterations;347
18.1.3.2;Biochemical Mechanisms of Cardiotoxicosis;351
18.1.3.3;Cardiotoxicoses Due to Direct Cellular Injury;352
18.1.3.4;Cardiotoxicoses Due to Indirect Acting Injury;352
18.1.3.5;Organellar Localization of Injury;353
18.1.3.6;Xenobiotic Interactions;354
18.1.4;Response to Injury;354
18.1.4.1;Developmental Cardiotoxicities;357
18.1.4.2;Myocardium;358
18.1.4.3;Endocardium;369
18.1.4.4;Pericardium;369
18.1.4.5;Valves;369
18.1.5;Evaluation of Cardiotoxicity;369
18.1.5.1;Physiologic Evaluation of Toxicity;370
18.1.5.2;Morphologic Evaluation of Toxicity;372
18.1.5.3;Biochemical Evaluation of Toxicity;374
18.1.5.4;Use of Animals as Models;374
18.2;Section II: Vessels;374
18.2.1;Introduction;374
18.2.2;Structure and Function;375
18.2.2.1;Microscopic Anatomy;375
18.2.2.2;Physiology and Functional Considerations;375
18.2.3;Mechanisms of Toxicity;378
18.2.3.1;Vasculotoxic Effects of Xenobiotics;378
18.2.3.2;Vascular Toxicity in Specific Organs;379
18.2.4;Response to Injury;380
18.2.4.1;Regeneration and Repair;381
18.2.4.2;Vessel Alterations;381
18.2.5;Evaluation of Vasotoxic Effects;386
18.2.5.1;Physiologic Methods for Testing;386
18.2.5.2;Morphologic Evaluation;387
18.2.5.3;Use of Animals as Models;387
18.3;Section III Skeletal Muscle;388
18.3.1;Introduction;388
18.3.2;Structure and Function;388
18.3.2.1;Gross and Microscopic Anatomy;388
18.3.2.2;Cells of Skeletal Muscle: Biology and Clinical Relevance;388
18.3.2.3;Physiologic and Functional Considerations;390
18.3.3;Mechanisms of Toxicity;390
18.3.3.1;Altered Neurogenic Function;390
18.3.3.2;Altered Immunologic Function;391
18.3.3.3;Localized Damage;391
18.3.3.4;Cell Membrane Alterations;391
18.3.3.5;Sarcoplasmic Reticulum Alterations;392
18.3.3.6;Microtubular Alterations;392
18.3.3.7;Myofilament Alterations;392
18.3.3.8;Lysosomal Alterations;392
18.3.3.9;Altered Intracellular Calcium Concentration;392
18.3.3.10;Altered Protein Synthesis;392
18.3.3.11;Altered Muscle Cell Differentiation;393
18.3.4;Response to Injury;393
18.3.4.1;Injury, Regeneration, and Repair;393
18.3.4.2;Skeletal Muscle Alterations;394
18.3.5;Evaluation of Skeletal Muscle Toxicity;396
18.3.5.1;Methods for Testing;397
18.3.5.2;Morphologic Evaluation;397
18.3.5.3;Use of Animals as Models;399
18.3.6;Further Reading;399
19;CHAPTER 13 NERVOUS SYSTEM;400
19.1;Introduction;400
19.2;Structure and Function;401
19.2.1;Macroscopic Structure;401
19.2.2;Microscopic Anatomy;402
19.2.3;Specialized Anatomical Features;404
19.2.4;Select Functions and Neurotoxicity;405
19.3;Mechanisms of Disease and Classification of Neurotoxic Diseases;410
19.3.1;Neuronopathies;410
19.3.2;Axonopathies;419
19.3.3;Myelinopathies;421
19.3.4;Toxicants Affecting Vascular Integrity;423
19.3.5;Developmental Neurotoxicants;427
19.3.6;Neurocarcinogens;428
19.4;Evaluation of Neurotoxicity;428
19.4.1;Use of Animals as Models;428
19.4.2;Tests of Nervous System Function;428
19.4.3;Morphologic Evaluation;429
19.4.4;In Vitro Systems;432
19.5;Conclusions;432
19.6;Further Reading;433
20;CHAPTER 14 BONES AND JOINTS;434
20.1;Introduction;434
20.2;Skeletal Structure and Composition;435
20.2.1;Formation and Development;435
20.2.2;Composition of Bone;439
20.2.3;Species Differences in Composition and Changes with Age;439
20.3;Bone Physiology and Function;440
20.3.1;Modeling and Remodeling of Bone;440
20.3.2;Biomechanics;440
20.3.3;Mineral Homeostasis;441
20.3.4;Regulation of Bone Cell Function;441
20.4;Mechanisms of Toxicity;443
20.4.1;Bone Toxicity;443
20.4.2;Joint Toxicity;449
20.5;Response of the Skeleton to Toxic Injury;451
20.5.1;Bone;451
20.5.2;Joints;461
20.6;Evaluation of Skeletal Toxicity;465
20.6.1;Testing for Skeletal Toxicity;465
20.6.2;Morphologic Evaluation;466
20.6.3;Biochemical Evaluation;470
20.6.4;Animal Models of Skeletal Disease;471
20.7;Summary;471
20.8;Further Reading;472
21;CHAPTER 15 IMMUNE SYSTEM;474
21.1;Introduction;474
21.2;Function and Structure of the Immune System;474
21.2.1;Function of the Immune System;474
21.2.2;Structure of the Immune System;479
21.3;Comparative Mechanisms of Immune Toxicity;490
21.3.1;Introduction;490
21.3.2;Examples of Immunotoxic Agents;491
21.4;Response of the Immune System to Toxic Injury;500
21.4.1;Decreased Cellularity;501
21.4.2;Increased Cellularity;507
21.4.3;Neoplasia;507
21.4.4;Inflammation in Nonlymphoid Tissues;508
21.5;Testing for Immunotoxicity;509
21.5.1;In Vivo and In Vitro Approaches;509
21.5.2;Morphologic Techniques;510
21.5.3;Animal Models;511
21.6;Summary;512
21.7;Further Reading;512
22;CHAPTER 16 HEMATOPOIETIC SYSTEM;514
22.1;Introduction;514
22.1.1;Phylogeny;514
22.1.2;Ontogeny;515
22.2;Structure and Function;515
22.2.1;Gross and Microscopic Anatomy;515
22.2.2;Hematopoiesis;517
22.2.3;Cellular Kinetics;518
22.3;Comparative Mechanisms of Toxicity;519
22.3.1;Idiosyncratic Reactions;519
22.3.2;Direct Damage;522
22.3.3;Myelotoxicity;524
22.4;Responses of Hematopoietic Tissues to Toxic Injury;526
22.4.1;Changes in Blood;526
22.4.2;Changes in Bone Marrow;528
22.5;Hematopoietic Assessment;533
22.6;Summary;535
22.7;Further Reading;535
23;CHAPTER 17 ENDOCRINE SYSTEM;536
23.1;Introduction;536
23.2;Adrenal Cortex;536
23.2.1;Structure and Function;536
23.2.2;Mechanisms of Toxicity;539
23.2.3;Response to Injury;539
23.2.4;Evaluation of Toxicity;546
23.3;Adrenal Medulla;546
23.3.1;Structure and Function;546
23.3.2;Mechanisms of Toxicity;546
23.3.3;Response to Injury;546
23.3.4;Evaluation of Toxicity;548
23.4;Pituitary Gland;548
23.4.1;Structure and Function;548
23.4.2;Mechanisms of Toxicity;550
23.4.3;Response to Injury;550
23.4.4;Evaluation of Toxicity;553
23.5;Thyroid C-cells;553
23.5.1;Structure and Function;553
23.5.2;Mechanisms of Toxicity;554
23.5.3;Response to Injury;554
23.6;Thyroid Follicular Cells;555
23.6.1;Structure and Function;555
23.6.2;Mechanisms of Toxicity;559
23.6.3;Response to Injury;561
23.6.4;Evaluation of Toxicity;566
23.7;Parathyroid Gland;566
23.7.1;Introduction;566
23.7.2;Structure and Function;567
23.7.3;Mechanisms of Toxicity;569
23.7.4;Response of Parathyroid Chief Cells to Injury;570
23.7.5;Evaluation of Toxicity;573
23.8;Further Reading;573
24;CHAPTER 18 MALE REPRODUCTIVE SYSTEM;576
24.1;Introduction;576
24.2;Structure and Cell Biology;577
24.2.1;Embryological Derivation of the Reproductive Tract;577
24.2.2;Structure of the Testes;577
24.2.3;Physiology and Functional Considerations of the Testis;581
24.2.4;Structure and Function of the Epididymis and Excurrent Ducts;589
24.2.5;Structure and Function of Accessory Sex Organs;591
24.2.6;Penis and Ejaculation;592
24.3;Mechanisms of Toxicity;592
24.3.1;Role of Metabolism;593
24.3.2;Cell-specific Toxicity in the Testis;594
24.3.3;Vascular Effects and Indirect Toxicity to the Testis;596
24.3.4;Epididymal and Sperm Toxicity;598
24.3.5;Secondary Sex Organs;599
24.3.6;Hormone Disruption;599
24.3.7;Toxicity to the Developing Reproductive Tract;600
24.4;Responses to Injury;602
24.4.1;Disruption of Spermatogenesis;603
24.4.2;Tubular Dilatation and Tubular Shrinkage;606
24.4.3;Tubular and Testicular Necrosis;606
24.4.4;Leydig Cell Response;608
24.4.5;Disruption of Sperm Maturation;608
24.4.6;Epididymal Response;609
24.4.7;Response to Alterations in Hormone Balance;609
24.4.8;Reversibility;612
24.4.9;Reproductive Toxicity in Domestic Animals;613
24.5;Evaluation of Toxicity;616
24.5.1;Detecting Toxicity;616
24.5.2;Characterization of Reproductive Toxicity;616
24.5.3;Functional Characterization;618
24.5.4;Testing for Toxicity of the Developing Reproductive Tract;619
24.6;Conclusions;619
24.7;Further Reading;620
25;CHAPTER 19 FEMALE REPRODUCTIVE SYSTEM;622
25.1;Introduction;622
25.2;Structure and Functional Physiology;623
25.2.1;Structure;623
25.2.2;Functional Physiology;629
25.3;Mechanisms of Toxicity;632
25.3.1;General Toxicity;632
25.3.2;Ovary, Uterus, and Vagina as a Unit;632
25.3.3;Local Vaginal Toxicity;636
25.3.4;Carcinogenesis;636
25.4;Response to Injury;638
25.4.1;General Responses: Ovary, Uterus, and Vagina as a Unit;638
25.4.2;Local Vaginal Responses;643
25.4.3;Reproductive Toxicity in Domestic Animals;645
25.4.4;Neoplasia;648
25.5;Testing for Toxicity;651
25.5.1;General Toxicity;651
25.5.2;Local Vaginal Toxicity;653
25.6;Summary;653
25.7;Further Reading;653
26;CHAPTER 20 DEVELOPMENTAL PATHOLOGY;656
26.1;Introduction;656
26.1.1;Overview of Fetal Toxicologic Pathology;656
26.1.2;Basic Principles of Developmental Toxicology;657
26.1.3;Incidence of Congenital Anomalies;657
26.2;Normal Morphologic Development;657
26.2.1;Fertilization and Blastocyst Formation;658
26.2.2;Gastrulation;658
26.2.3;Organogenesis;658
26.2.4;Histogenesis and Functional Maturation;660
26.3;Mechanisms of Toxicity;661
26.3.1;Critical Phases of Intrauterine Development;661
26.3.2;Modifying Factors;662
26.4;Response to Injury;665
26.4.1;Death;665
26.4.2;Malformations;666
26.4.3;Intrauterine Growth Retardation;669
26.4.4;Perinatal Toxicology;669
26.4.5;Endocrine Disruption;670
26.4.6;Congenital Neoplasia;670
26.4.7;How Dose Relates to Manifestation of Abnormal Development;671
26.5;Selected Malformations;671
26.5.1;Central Nervous System;671
26.5.2;Craniofacial Structures;676
26.5.3;Cardiovascular System;678
26.5.4;Respiratory System;679
26.5.5;Gastrointestinal System;679
26.5.6;Urinary System;679
26.5.7;Reproductive System;680
26.5.8;Skeletal System;681
26.6;Developmental Toxicity Testing and Risk Assessment;683
26.6.1;Hazard Identification and Dose-response Analysis;683
26.6.2;Dose–Response Evaluation;687
26.7;Field Investigation of Anomalies in Domestic Animals;688
26.7.1;Defining the Individual Incident;688
26.7.2;Defining the Prevalence;689
26.7.3;Defining the Maternal Environment;689
26.7.4;Genetic Analysis;690
26.7.5;Environmental Analysis: An Epidemiological Approach;690
26.8;Further Reading;691
26.9;Glossary;692
26.9.1;A;692
26.9.2;B;692
26.9.3;C;692
26.9.4;D;692
26.9.5;E;692
26.9.6;F;693
26.9.7;G;693
26.9.8;H;693
26.9.9;I;693
26.9.10;K;693
26.9.11;L;693
26.9.12;M;693
26.9.13;N;693
26.9.14;O;693
26.9.15;P;693
26.9.16;R;694
26.9.17;S;694
26.9.18;T;694
26.9.19;U;694
26.9.20;V;694
26.9.21;W;694
27;Index;696
27.1;A;696
27.2;B;697
27.3;C;698
27.4;D;699
27.5;E;700
27.6;F;701
27.7;G;702
27.8;H;702
27.9;I;704
27.10;J;704
27.11;K;705
27.12;L;705
27.13;M;706
27.14;N;708
27.15;O;709
27.16;P;709
27.17;R;711
27.18;S;711
27.19;T;712
27.20;U;713
27.21;V;714
27.22;W;714
27.23;Y;714
27.24;Z;714