Fundamentals of Toxicologic Pathology (eBook)

Front Cover 1
Fundamentals of Toxicologic Pathology 4
Copyright Page 5
Contents 6
Preface 20
Acknowledgments 22
CHAPTER 1 PRINCIPLES OF TOXICOLOGY 24
The Effect of the Body on the Chemical 24
Absorption 24
Passage across Membranes 24
Distribution 25
Volume of Distribution 25
Barriers to Distribution 25
Biotransformation 26
Phase I: Metabolism 26
Phase II: Metabolism 27
Enzyme Location in Toxicity 27
Excretion 28
Urinary Excretion 28
Biliary Excretion 28
Pulmonary Excretion 29
Interaction of Chemical and the Body 29
Enzyme Induction and Inhibition 29
Activation, Induction, or Synergism 29
Inhibition 29
Dose Dependency and Site of Action 30
Organ Specificity for Toxicity 30
Site-Specific Interactions and Toxicity 30
Receptors and Enzymes 30
Direct and Cascade Effects 30
Nonspecific Interations and Toxicity 30
Electrophiles and Covalent Binding 30
Free Radicals and Lipid Peroxidation 31
Further Reading 31
CHAPTER 2 MANIFESTATIONS OF TOXIC CELL INJURY: CELL INJURY/DEATH AND CHEMICAL CARCINOGENESIS 32
Section I: Cell Injury, Cell Death and Sequelae 33
Introduction 33
Key Cellular Components in Cell Injury 33
Factors Influencing Injury 33
Reaction of the Body to Injury 34
Adaptation 34
Reversible Cell Injury 36
Cell Swelling 36
Fatty Change 37
Irreversible Injury 38
Oncotic Necrosis 38
Apoptotic Necrosis 42
Sequelae to Irreversible Cell Injury 44
Concluding Comments 46
Section II: Chemical Carcinogenesis 46
Overview 46
Nomenclature of Neoplasms 47
Spectrum of Proliferative Lesions 48
Quantitative Cell Proliferation (Hyperplasia) 48
Qualitative Cell Proliferation 49
Preneoplasia 50
Neoplastic Cell Proliferation 50
Diagnostic Distinction between Preneoplasia, Benign Neoplasia, and Malignant Neoplasia 51
Steps in the Neoplastic Process 51
Initiation 51
Promotion 52
Progression 52
Hypotheses of Mode of Action of Chemical Carcinogens 53
Overview 53
Mutational Genetic Hypothesis of Chemical Carcinogenesis 53
Nonmutational Genetic Hypothesis of Chemical Carcinogenesis 54
Epigenetic Hypothesis of Chemical Carcinogenesis 54
Viral Hypothesis of Carcinogenesis 55
Oncogenes and Tumor Suppressor Genes in Chemical Carcinogenesis 56
Genes and Oncogenes 56
Proto-oncogene Function 56
Proto-oncogene Activation 56
Oncogene Activation in Chemical Carcinogenesis 57
Tumor Suppressor Genes and Carcinogenesis 59
Cell Cycle and Carcinogenesis 59
Cyclins and Cdk Proteins 59
Retinoblastoma Checkpoint 59
p53 Checkpoint 60
Tests for Carcinogenic Potential of Chemicals 60
In Vivo Chronic Rodent Carcinogenesis Studies 60
Additional In Vivo Tests for Carcinogenicity 62
In Vitro Short-term Tests 64
Conclusion 64
Further Reading 64
CHAPTER 3 CLINICAL PATHOLOGY 66
Introduction 66
Hematology 67
Parameters Generally Included in Study Protocols 67
Interpretative Hematology 68
Clinical Chemistry 73
Cholesterol, Triglycerides, and Glucose 73
Serum Proteins 76
Indicators of Hepatic Integrity and Function 77
Indicators of Renal Function 79
Electrolytes 79
Calcium and Inorganic Phosphate 80
Enzymes of Muscle Origin 80
Microsomal Enzyme Induction 80
Urinalysis 81
Interpretation of Clinical Pathology Results 82
Potential Effects of Factors Unrelated to Test Article Treatment 83
Comparators: Concurrent Controls, Reference Ranges 84
Statistical Analyses 85
Direct Versus Indirect Effects 85
Pharmacologic Versus Toxic Effects 86
Biological Importance of Treatment-related Effects 86
Reporting of Clinical Pathology Findings 87
Summary 87
Further Reading 87
CHAPTER 4 NOMENCLATURE: TERMINOLOGY FOR MORPHOLOGIC ALTERATIONS 90
Introduction 90
Basic Terminology 91
Terminology Issues 91
Training 96
Multiple Pathologists 97
Diagnostic Drift 98
Lesion Complexity 98
Standardized Nomenclature 99
Recording Pathology Data 99
Suggested Practices 100
Summary 101
Further Reading 102
CHAPTER 5 TECHNIQUES IN TOXICOLOGIC PATHOLOGY 104
Introduction 104
Factors Influencing Evaluation of Altered Morphology 105
Factors in Collection and Processing of Tissue 107
Factors Intrinsic to the Animal 110
Factors Related to the Environment 113
Factors Related to Nomenclature 114
Further Reading 114
CHAPTER 6 RESPIRATORY SYSTEM 116
Introduction 116
Structure and Cell Biology 117
Macroscopic and Microscopic Anatomy 117
Nasopharyngeal and Laryngeal Regions (Upper Respiratory Tract) 118
Tracheobronchial Region and Bronchioles 119
Pulmonary Region 121
Physiology and Functional Considerations 123
Xenobiotic Exposure, Metabolism, and Excretion 125
Mechanisms of Toxicity 127
Direct Toxicity 128
Metabolic Activation 128
Immune-mediated Toxicity 129
Toxicity and Responses to Inhaled Particles 131
Xenobiotic Interactions 132
Modifying Factors in Toxicity 132
Response to Injury 132
Injury, Regeneration, and Repair 133
Nasopharyngeal and Laryngeal Responses to Injury 134
Airway Response to Injury 136
Pulmonary Parenchymal Response to Injury 141
Edema 142
Inflammation 144
Fibrosis 147
Emphysema 149
Neoplasia 150
Evaluation of Toxicity 151
Methods for Testing 152
In Vitro Methods 152
Lung Cancer Model Systems 153
Pulmonary Function 153
Bronchopulmonary Lavage 153
Biochemical Evaluation 154
Morphologic Evaluation 154
Quantitative Techniques 155
Additional Techniques 155
Animal Models 155
Conclusions 156
Further Reading 156
CHAPTER 7 SKIN AND ORAL MUCOSA 158
Section I: Skin 158
Introduction 158
Structure and Function of Skin 159
Microscopic Anatomy 159
Skin Cell Subpopulations 161
Physiology and Biochemistry 161
Comparative Mechanisms of Cutaneous Toxicity 164
Direct Damage 164
Immunomediated Cutaneous Toxicity 167
Phototoxicity and Photoallergy 169
Response of Skin to Injury 170
Fundamental Non-neoplastic Lesions 170
Neoplastic Lesions 178
Evaluation of Cutaneous Toxicity 179
Skin Irritation Tests 180
Carcinogenesis Bioassays 180
Morphologic Assessment 181
Other Bioassays 181
Transgenic Animal Models 181
In Vitro Testing 182
Section II: Oral Mucosa 182
Introduction 182
Structure and Function of the Oral Mucosa 182
Microscopic Anatomy 182
Physiology 182
Comparative Mechanisms of Mucosal Toxicity 183
Response of Oral Mucosa to Injury 183
Fundamental Non-neoplastic Lesions 183
Carcinogenesis 184
Evaluation of Oral Toxicity 184
Further Reading 184
CHAPTER 8 GASTROINTESTINAL TRACT 186
Introduction 186
Structure and Function of the Gastrointestinal Tract 187
Macroscopic and Microscopic Structure and Function 187
Enteric Lymphoid System 194
Enteric Nervous System 195
Biotransformation 195
Bacterial Metabolism 197
Enterohepatic Circulation 197
Comparative Mechanisms of Gastrointestinal Toxicity 198
Intestinal Barrier Function 198
Intestinal Malabsorption 200
Altered Blood Supply 200
Mucosal Barrier Damage and Cytotoxicity 201
Hypersensitivity 204
Neurotransmitter Effects 206
Perturbation of Microflora 206
Carcinogenicity 206
Response of the Gastrointestinal Tract to Injury 207
Pathophysiological Responses 207
Inflammatory Response 209
Mucosal Response 210
Organ-specific Responses 212
Evaluation of Gastrointestinal Toxicity 214
In Vitro Strategies 214
In Vivo Strategies 215
Molecular Pathology 215
Morphologic Methods 216
Animal Models 217
Further Reading 219
CHAPTER 9 THE LIVER 220
Introduction 220
Structure and Function 220
Gross and Microscopic Anatomy 221
Cell Components 221
Xenobiotic Metabolism 223
Mechanisms of Toxicity 223
Classification of Hepatoxicants 224
Cellular Mechanisms of Toxicity 224
Non-neoplastic Responses to Injury 225
Histologic Types of Hepatic Necrosis 231
Intracellular Accumulations 237
Pathology of Transcription and Translation 241
Cholestasis 242
Hepatocellular Adaptive Responses 242
Hepatocellular Proliferation 243
Bile Ductular Lesions 244
Nonparenchymal Cell Toxicity 247
Hepatitis 248
Hepatic Fibrosis and Cirrhosis 249
Hepatic Neoplasia 251
Hepatocellular Neoplasia 251
Bile Duct Neoplasms 253
Endothelial Neoplasms 254
Küpffer Cell Neoplasms 254
Evaluation of Toxicity 254
Morphologic Evaluation 255
Clinical Chemistry Evaluation 256
Noninvasive Imaging 257
In Vitro Approaches 257
Use of Animals as Models 257
Summary and Conclusions 258
Further Reading 258
CHAPTER 10 PANCREAS 260
Section I: Exocrine Pancreas 260
Introduction 260
Normal Structure of Exocrine Pancreas 261
Gross Anatomy 261
Microscopic Anatomy and Ultrastructure 261
Physiology of Exocrine Pancreas 263
Comparative Mechanisms of Exocrine Pancreatic Toxicity 264
Response of Exocrine Pancreas to Injury 266
Cytotoxic Effects on Acinar Cells 266
Cytotoxic Effects in Ductal and Centroacinar Cells 270
Carcinogenesis 270
Evaluation of Exocrine Pancreatic Toxicity 271
Methods of Testing 272
Morphologic Evaluation of Toxicity 273
Animal Models 273
Summary and Conclusions 273
Section II: Endocrine Pancreas 274
Structure of Endocrine Pancreas 274
Gross Anatomy 274
Microscopic Anatomy and Ultrastructure 274
Physiology of Endocrine Pancreas 275
Mechanisms of Endocrine Pancreatic Toxicity 276
Insulin-dependent Diabetes Mellitus 276
Non-insulin-dependent Diabetes Mellitus 277
Glucose Intolerance 278
Response of Endocrine Pancreas to Injury 279
Apoptosis 279
Necrosis 279
Insulitis 280
Regeneration 281
Carcinogenesis 281
Evaluation of Endocrine Pancreatic Toxicity 281
In Vivo Testing 281
In Vitro Testing 281
Animal Models 281
Summary and Conclusions 281
Further Reading 282
CHAPTER 11 KIDNEY AND LOWER URINARY TRACT 284
Introduction 284
Renal Structure and Function 285
Gross, Microscopic, and Ultrastructural Anatomy 285
Physiology 292
Mechanisms of Toxicity 296
Overview and Classification 296
Glomerular Injury 298
Proximal Tubular Injury 307
Other Sites of Renal Injury 319
Lower Urinary Tract 322
Renal Carcinogenesis 323
Lower Urinary Tract Carcinogenesis 326
Response to Injury 326
Introduction 326
Glomerulus 326
Proximal Tubule and Interstitium 327
Renal Papillary Necrosis 332
Renal Tubular Hyperplasia and Neoplasia 332
Lower Urinary Tract: Non-neoplastic Lesions 333
Lower Urinary Tract Epithelial Neoplasms 336
Evaluation of Toxicity 337
Diagnostic Evaluation of Renal Disease 337
Routine Screening for Nephrotoxicity 337
Special Techniques 338
Evaluation of the Lower Urinary Tract 339
Conclusion 340
Further Reading 340
CHAPTER 12 CARDIOVASCULAR AND SKELETAL MUSCLE SYSTEMS 342
Section I: Heart 343
Introduction 343
Structure and Function 343
Gross and Microscopic Anatomy 343
Cellular and Extracellular Elements of the Heart: Biology and Clinical Relevance 344
Physiology and Functional Considerations 346
Xenobiotic Exposure 347
Mechanisms of Toxicity 347
Physiological Mechanisms of Functional Alterations 347
Biochemical Mechanisms of Cardiotoxicosis 351
Cardiotoxicoses Due to Direct Cellular Injury 352
Cardiotoxicoses Due to Indirect Acting Injury 352
Organellar Localization of Injury 353
Xenobiotic Interactions 354
Response to Injury 354
Developmental Cardiotoxicities 357
Myocardium 358
Endocardium 369
Pericardium 369
Valves 369
Evaluation of Cardiotoxicity 369
Physiologic Evaluation of Toxicity 370
Morphologic Evaluation of Toxicity 372
Biochemical Evaluation of Toxicity 374
Use of Animals as Models 374
Section II: Vessels 374
Introduction 374
Structure and Function 375
Microscopic Anatomy 375
Physiology and Functional Considerations 375
Mechanisms of Toxicity 378
Vasculotoxic Effects of Xenobiotics 378
Vascular Toxicity in Specific Organs 379
Response to Injury 380
Regeneration and Repair 381
Vessel Alterations 381
Evaluation of Vasotoxic Effects 386
Physiologic Methods for Testing 386
Morphologic Evaluation 387
Use of Animals as Models 387
Section III Skeletal Muscle 388
Introduction 388
Structure and Function 388
Gross and Microscopic Anatomy 388
Cells of Skeletal Muscle: Biology and Clinical Relevance 388
Physiologic and Functional Considerations 390
Mechanisms of Toxicity 390
Altered Neurogenic Function 390
Altered Immunologic Function 391
Localized Damage 391
Cell Membrane Alterations 391
Sarcoplasmic Reticulum Alterations 392
Microtubular Alterations 392
Myofilament Alterations 392
Lysosomal Alterations 392
Altered Intracellular Calcium Concentration 392
Altered Protein Synthesis 392
Altered Muscle Cell Differentiation 393
Response to Injury 393
Injury, Regeneration, and Repair 393
Skeletal Muscle Alterations 394
Evaluation of Skeletal Muscle Toxicity 396
Methods for Testing 397
Morphologic Evaluation 397
Use of Animals as Models 399
Further Reading 399
CHAPTER 13 NERVOUS SYSTEM 400
Introduction 400
Structure and Function 401
Macroscopic Structure 401
Microscopic Anatomy 402
Specialized Anatomical Features 404
Select Functions and Neurotoxicity 405
Mechanisms of Disease and Classification of Neurotoxic Diseases 410
Neuronopathies 410
Axonopathies 419
Myelinopathies 421
Toxicants Affecting Vascular Integrity 423
Developmental Neurotoxicants 427
Neurocarcinogens 428
Evaluation of Neurotoxicity 428
Use of Animals as Models 428
Tests of Nervous System Function 428
Morphologic Evaluation 429
In Vitro Systems 432
Conclusions 432
Further Reading 433
CHAPTER 14 BONES AND JOINTS 434
Introduction 434
Skeletal Structure and Composition 435
Formation and Development 435
Composition of Bone 439
Species Differences in Composition and Changes with Age 439
Bone Physiology and Function 440
Modeling and Remodeling of Bone 440
Biomechanics 440
Mineral Homeostasis 441
Regulation of Bone Cell Function 441
Mechanisms of Toxicity 443
Bone Toxicity 443
Joint Toxicity 449
Response of the Skeleton to Toxic Injury 451
Bone 451
Joints 461
Evaluation of Skeletal Toxicity 465
Testing for Skeletal Toxicity 465
Morphologic Evaluation 466
Biochemical Evaluation 470
Animal Models of Skeletal Disease 471
Summary 471
Further Reading 472
CHAPTER 15 IMMUNE SYSTEM 474
Introduction 474
Function and Structure of the Immune System 474
Function of the Immune System 474
Structure of the Immune System 479
Comparative Mechanisms of Immune Toxicity 490
Introduction 490
Examples of Immunotoxic Agents 491
Response of the Immune System to Toxic Injury 500
Decreased Cellularity 501
Increased Cellularity 507
Neoplasia 507
Inflammation in Nonlymphoid Tissues 508
Testing for Immunotoxicity 509
In Vivo and In Vitro Approaches 509
Morphologic Techniques 510
Animal Models 511
Summary 512
Further Reading 512
CHAPTER 16 HEMATOPOIETIC SYSTEM 514
Introduction 514
Phylogeny 514
Ontogeny 515
Structure and Function 515
Gross and Microscopic Anatomy 515
Hematopoiesis 517
Cellular Kinetics 518
Comparative Mechanisms of Toxicity 519
Idiosyncratic Reactions 519
Direct Damage 522
Myelotoxicity 524
Responses of Hematopoietic Tissues to Toxic Injury 526
Changes in Blood 526
Changes in Bone Marrow 528
Hematopoietic Assessment 533
Summary 535
Further Reading 535
CHAPTER 17 ENDOCRINE SYSTEM 536
Introduction 536
Adrenal Cortex 536
Structure and Function 536
Mechanisms of Toxicity 539
Response to Injury 539
Evaluation of Toxicity 546
Adrenal Medulla 546
Structure and Function 546
Mechanisms of Toxicity 546
Response to Injury 546
Evaluation of Toxicity 548
Pituitary Gland 548
Structure and Function 548
Mechanisms of Toxicity 550
Response to Injury 550
Evaluation of Toxicity 553
Thyroid C-cells 553
Structure and Function 553
Mechanisms of Toxicity 554
Response to Injury 554
Thyroid Follicular Cells 555
Structure and Function 555
Mechanisms of Toxicity 559
Response to Injury 561
Evaluation of Toxicity 566
Parathyroid Gland 566
Introduction 566
Structure and Function 567
Mechanisms of Toxicity 569
Response of Parathyroid Chief Cells to Injury 570
Evaluation of Toxicity 573
Further Reading 573
CHAPTER 18 MALE REPRODUCTIVE SYSTEM 576
Introduction 576
Structure and Cell Biology 577
Embryological Derivation of the Reproductive Tract 577
Structure of the Testes 577
Physiology and Functional Considerations of the Testis 581
Structure and Function of the Epididymis and Excurrent Ducts 589
Structure and Function of Accessory Sex Organs 591
Penis and Ejaculation 592
Mechanisms of Toxicity 592
Role of Metabolism 593
Cell-specific Toxicity in the Testis 594
Vascular Effects and Indirect Toxicity to the Testis 596
Epididymal and Sperm Toxicity 598
Secondary Sex Organs 599
Hormone Disruption 599
Toxicity to the Developing Reproductive Tract 600
Responses to Injury 602
Disruption of Spermatogenesis 603
Tubular Dilatation and Tubular Shrinkage 606
Tubular and Testicular Necrosis 606
Leydig Cell Response 608
Disruption of Sperm Maturation 608
Epididymal Response 609
Response to Alterations in Hormone Balance 609
Reversibility 612
Reproductive Toxicity in Domestic Animals 613
Evaluation of Toxicity 616
Detecting Toxicity 616
Characterization of Reproductive Toxicity 616
Functional Characterization 618
Testing for Toxicity of the Developing Reproductive Tract 619
Conclusions 619
Further Reading 620
CHAPTER 19 FEMALE REPRODUCTIVE SYSTEM 622
Introduction 622
Structure and Functional Physiology 623
Structure 623
Functional Physiology 629
Mechanisms of Toxicity 632
General Toxicity 632
Ovary, Uterus, and Vagina as a Unit 632
Local Vaginal Toxicity 636
Carcinogenesis 636
Response to Injury 638
General Responses: Ovary, Uterus, and Vagina as a Unit 638
Local Vaginal Responses 643
Reproductive Toxicity in Domestic Animals 645
Neoplasia 648
Testing for Toxicity 651
General Toxicity 651
Local Vaginal Toxicity 653
Summary 653
Further Reading 653
CHAPTER 20 DEVELOPMENTAL PATHOLOGY 656
Introduction 656
Overview of Fetal Toxicologic Pathology 656
Basic Principles of Developmental Toxicology 657
Incidence of Congenital Anomalies 657
Normal Morphologic Development 657
Fertilization and Blastocyst Formation 658
Gastrulation 658
Organogenesis 658
Histogenesis and Functional Maturation 660
Mechanisms of Toxicity 661
Critical Phases of Intrauterine Development 661
Modifying Factors 662
Response to Injury 665
Death 665
Malformations 666
Intrauterine Growth Retardation 669
Perinatal Toxicology 669
Endocrine Disruption 670
Congenital Neoplasia 670
How Dose Relates to Manifestation of Abnormal Development 671
Selected Malformations 671
Central Nervous System 671
Craniofacial Structures 676
Cardiovascular System 678
Respiratory System 679
Gastrointestinal System 679
Urinary System 679
Reproductive System 680
Skeletal System 681
Developmental Toxicity Testing and Risk Assessment 683
Hazard Identification and Dose-response Analysis 683
Dose–Response Evaluation 687
Field Investigation of Anomalies in Domestic Animals 688
Defining the Individual Incident 688
Defining the Prevalence 689
Defining the Maternal Environment 689
Genetic Analysis 690
Environmental Analysis: An Epidemiological Approach 690
Further Reading 691
Glossary 692
A 692
B 692
C 692
D 692
E 692
F 693
G 693
H 693
I 693
K 693
L 693
M 693
N 693
O 693
P 693
R 694
S 694
T 694
U 694
V 694
W 694
Index 696
A 696
B 697
C 698
D 699
E 700
F 701
G 702
H 702
I 704
J 704
K 705
L 705
M 706
N 708
O 709
P 709
R 711
S 711
T 712
U 713
V 714
W 714
Y 714
Z 714