Organ-Specific Toxicologic Pathology: An Introduction 1(936) Colin G. Rousseaux Wanda M. Haschek Matthew A. Walling Respiratory System Wanda M. Haschek Hanspeter R. Witschi Kristen J. Nikula Introduction 3(1) Structure and Cell Biology 4(25) Macroscopic and Microscopic Anatomy 4(15) Physiology and Functional Considerations 19(5) Xenobiotic Exposure, Metabolism, and Excretion 24(5) Mechanisms of Toxicity 29(7) Direct Toxicity 30(1) Metabolic Activation 31(2) Immune-Mediated Toxicity 33(1) Toxicity and Responses to Inhaled Particles 34(1) Xenobiotic Interactions 35(1) Modifying Factors in Toxicity 36(1) Response to Injury 36(32) Injury, Regeneration, and Repair 37(2) Nasopharyngeal and Laryngeal Responses to Injury 39(7) Airway Response to Injury 46(5) Pulmonary Parenchymal Response to Injury 51(17) Testing for Toxicity 68(17) Methods for Testing 69(3) Evaluation of Toxicity 72(6) Animal Models 78(1) Suggested Reading 79(6) Skin and Oral Mucosa Andres J. P. Klein-Szanto Claudio J. Conti Skin 85(27) Introduction 85(1) Structure and Function of Skin 85(9) Mechanisms of Cutaneous Toxicity 94(4) Response of Skin to Injury 98(11) Evaluation of Cutaneous Toxicity 109(3) Oral Mucosa 112(9) Introduction 112(1) Structure and Function of Oral Mucosa 112(1) Mechanisms of Mucosal Toxicity 113(1) Response of Oral Mucosa to Injury 113(2) Evaluation of Oral Toxicity 115(1) Suggested Reading 116(5) Gastrointestinal Tract T. A. Bertram Introduction 121(1) Structure and Function of the Gastrointestinal Tract 122(21) Macroscopic and Microscopic Structure and Function 122(11) Enteric Lymphoid System 133(2) Enteric Nervous System 135(2) Biotransformation 137(3) Bacterial Metabolism 140(1) Enterohepatic Circulation 141(2) Mechanisms of Gastrointestinal Toxicity 143(12) Intestinal Barrier Function 143(1) Intestinal Malabsorption 144(1) Hypoxia 145(1) Mucosal Barrier Damage and Cytotoxicity 146(4) Hypersensitivity 150(1) Acetylcholinesterase Inhibitors 151(1) Perturbation of Enteric Microflora 151(1) Carcinogenicity 152(3) Response of Gastrointestinal Tract to Injury 155(14) Pathophysiological Response 155(3) Inflammatory Response 158(6) Organ-Specific Response 164(5) Evaluation of Gastrointestinal Toxicity 169(18) In Vitro Strategies 169(1) In Vivo Strategies 170(1) Molecular Pathology 170(1) Morphological Methods 171(7) Animal Models 178(6) Suggested Reading 184(3) Liver Russell C. Cattley James A. Popp Introduction 187(1) Structure and Function 187(3) Gross Anatomy 188(1) Cell Components 188(2) Xenobiotic Metabolism 190(1) Cellular Mechanisms of Toxicity 190(1) Nonneoplastic Responses to Injury 190(22) Histologic Types of Hepatic Necrosis 192(6) Hepatic Lipidosis 198(1) Infiltration and Pigments 199(1) Pathology of Transcription and Translation 200(2) Cholestasis 202(1) Hepatocellular Adaptive Responses 202(2) Hepatocellular Proliferation 204(1) Bile Ductular Lesions 205(4) Nonparenchymal Cell Toxicity 209(2) Hepatitis 211(1) Cirrhosis 211(1) Hepatic Neoplasia 212(6) Hepatocellular Neoplasia 212(3) Bile Duct Neoplasms 215(2) Endothelial Neoplasms 217(1) Kupffer Cell Neoplasms 218(1) Testing for Toxicity 218(4) Whole Animal 218(3) Perfused Liver Preparations 221(1) Cultured Hepatocytes 221(1) Liver Slices 221(1) Use of Animals as Models 222(1) Summary and Conclusions 222(5) Suggested Reading 222(5) Pancreas Daniel S. Longnecker Glenn L. Wilson Overview 227(1) Exocrine Pancreas 227(14) Introduction 227(1) Normal Structure of the Exocrine Pancreas 227(3) Physiology of the Exocrine Pancreas 230(1) Mechanisms of Toxicity in Exocrine Pancreas 230(1) Response of the Exocrine Pancreas to Injury 231(6) Evaluation of Exocrine Pancreatic Toxicity 237(4) Summary and Conclusions 241(1) Endocrine Pancreas 241(14) Structure of Endocrine Pancreas 241(2) Physiology of Endocrine Pancreas 243(1) Mechanisms of Endocrine Pancreatic Toxicity 244(4) Response to Injury 248(3) Evaluation of Endocrine Pancreatic Toxicity 251(1) Summary and Conclusions 252(1) Suggested Reading 252(3) Kidney Kanwar Nasir M. Khan Carl L. Alden Introduction 255(1) Renal Structure and Function 256(15) Gross, Microscopic, and Ultrastructural Anatomy 256(9) Physiology 265(6) Molecular Pathology of the Kidney 271(7) Growth Factors, Protooncogenes, Chemokines, and Heat Shock Proteins 271(1) Molecular Targets of Emerging Novel Therapeutics 272(5) Genetically Modified Rodent Models 277(1) Mechanisms of Toxicity 278(34) Overview and Classification 278(2) Glomerular Injury 280(5) Proximal Tubular Injury 285(17) Other Sites of Injury 302(3) Renal Carcinogenesis 305(7) Response to Injury 312(11) Introduction 312(2) Glomerulus 314(1) Proximal Tubule 315(3) Renal Papilla 318(1) Tubular Hyperplasia and Neoplasia 318(4) Predictors of Carcinogenesis 322(1) Testing for Kidney Toxicity 323(6) Routine Screening of New Chemicals 323(1) Methodology for Refinement of the Risk Assessment 324(3) Spontaneous Renal Disease 327(2) Conclusion 329(8) Suggested Reading 330(7) Lower Urinary Tract Samuel M. Cohen Hideaki Wanibuchi Shoji Fukushima Introduction 337(1) Structure and Function 337(3) Kidney Pelvis 337(1) Ureters 338(1) Urinary Bladder 338(1) Urethra 338(1) Urothelium 339(1) Mechanisms of Toxicity 340(6) Urinary Chemistry 340(1) Urinary Solids 341(3) Chronic Injury 344(1) Carcinogenesis 344(2) Response to Injury 346(6) Nonneoplastic Lesions 346(4) Epithelial Neoplasms 350(1) Urothelial Carcinoma 350(2) Mesenchymal Tumors 352(1) Testing for Toxicity 352(11) Evaluation of Urine 352(4) Morphologic Evaluations 356(2) Animal Models 358(1) Suggested Reading 359(4) Cardiovascular and Skeletal Muscle Systems John F. Van Vleet Victor J. Ferrans Eugene Herman Heart 363(47) Introduction 363(1) Structure and Function 363(10) Mechanisms of Toxicity 373(9) Response to Injury 382(18) Testing for Toxicity 400(10) Vessels 410(19) Introduction 410(1) Structure and Function 410(5) Mechanisms of Toxicity 415(4) Response to Injury 419(6) Evaluation of Vasotoxic Effects 425(4) Skeletal Muscle 429(28) Introduction 429(1) Structure and Function 430(3) Mechanisms of Toxicity 433(2) Response to Injury 435(4) Evaluation of the Effects of Xenobiotics on Skeletal Muscle 439(7) Suggested Reading 446(11) Bones and Joints J. C. Woodard J. E. Burkhardt W. Lee Introduction 457(1) Skeletal Structure and Composition 457(4) Formation and Development 457(3) Blood Supply and Nerves 460(1) Composition of Bone 460(1) Species Differences in Composition and Changes with Age 461(1) Bone Physiology and Function 461(5) Modeling and Remodeling of Bone 461(1) Biomechanics 462(1) Mineral Homeostasis 462(1) Regulation of Bone Cell Function 463(3) Mechanisms of Toxicity 466(10) Bone Toxicity 466(9) Joint Toxicity 475(1) Response of the Skeleton to Toxic Injury 476(18) Bone 476(13) Joints 489(5) Evaluation of Skeletal Toxicity 494(9) Testing for Skeletal Toxicity 494(1) Morphologic Evaluation 495(6) Biochemical Evaluation 501(1) Animal Models of Skeletal Disease 502(1) Summary 503(6) Suggested Reading 503(6) Nervous System David C. Dorman Karrie A. Brenneman Brad Bolon Introduction 509(1) Structure and Function of the Nervous System 510(7) Macroscopic Structure 510(1) Microscopic Anatomy 511(1) Specialized Anatomical Features 512(1) Select Functions 513(4) Mechanisms of Disease and Classification of Neurotoxic Diseases 517(11) Neuronopathies 518(3) Axonopathies 521(2) Myelinopathies 523(2) Toxicants Affecting Vascular Integrity 525(1) Developmental Neurotoxicants 525(2) Neurocarcinogens 527(1) Testing for Neurotoxicity 528(7) Animal Testing 528(6) Use of in Vitro Systems in Neurotoxicity Testing 534(1) Conclusions 535(4) Suggested Reading 535(4) The Eye Herbert E. Whiteley Robert L. Peiffer Introduction 539(1) Development of the Eye 540(2) Structure, Function, and Cell Biology 540(1) Mechanisms of Toxicity 540(2) Cornea 542(11) Structure, Function, and Cell Biology 542(7) Mechanisms of Toxicity 549(4) Lens 553(4) Structure and Function 554(1) Mechanisms of Toxicity 555(2) Retina and Retinal Pigment Epithelium 557(14) Structure and Function 557(4) Mechanisms of Toxicity 561(9) Summary 570(1) Toxicologic, Clinical, and Pathologic Evaluation 571(3) Animal Models: Which Ones? 571(1) Clinical Opthalmic Examination 571(1) Other Clinical Diagnostic Techniques 572(1) Morphologic Evaluation 573(1) Ocular Toxicity Testing 574(3) Ocular Irritation: Draize Test 574(2) Alternative to the Draize Test 576(1) Models of Retinal Toxicity 577(1) Other in Vitro Models 577(1) Conclusions 577(8) Suggested Reading 578(7) Immune System C. Frieke Kuper Emile de Heer Henk Van Loveren Joseph G. Vos Introduction 585(1) Structure and Function of the Immune System 585(19) Function of the Immune System 585(7) Structure of the Immune System 592(12) Mechanisms of Immune Toxicity 604(17) Introduction 604(3) Examples of Immunotoxic Agents 607(13) Immune Derangements and Neoplasia 620(1) Response of Lymphoid Tissue to Toxic Injury 621(14) Decreased Cellularity, Depletion, Atrophy, and Involution 622(10) Increased Cellularity, Hyperplasia, Germinal Center Development, and Macrophage Accumulations 632(3) Neoplasia 635(1) Inflammation in Nonlymphoid Organs: Autoimmune Disease and Allergy 635(6) Testing for Immunotoxicity 641(2) Introduction 641(2) Animal Models 643(1) Summary 643(4) Suggested Reading 644(3) Hematopoietic System V. E. Valli J. P. McGrath I. Chu Introduction 647(1) Phylogeny and Ontogeny of the Hematopoietic and Lymphoid Systems 647(1) Structure and Function 648(14) Gross and Microscopic Anatomy 648(7) Hematopiesis 655(5) Cellular Kinetics 660(2) Hematopoietic Assessment 662(1) Interpreting Changes in Blood and Hematopoietic Tissues 663(9) Maturation Index of Myeloproliferation 666(6) Hematotoxic Agents and Mechanisms 672(5) Summary and Future Direction 677(4) Suggested Reading 677(4) Endocrine System Charles C. Capen Ronald A. DeLellis John T. Yarrington Introduction 681(1) Adrenal Cortex 681(18) Structure and Function 681(5) Mechanisms of Toxicity 686(1) Response to Injury 687(10) Testing for Toxicity 697(2) Use of Animals as Models 699(1) Adrenal Medulla Structure and Function 699(1) Mechanisms of Toxicity 700(1) Response to Injury 701(5) Testing for Toxicity 706(1) Pituitary Gland 706(13) Structure and Function 706(4) Mechanisms of Toxicity 710(3) Response to Injury 713(5) Testing for Toxicity 718(1) Thyroid C Cells Structure and Function 719(2) Mechanisms of Toxicity 721(1) Response to Injury 721(4) Thyroid Follicular Cells 725(30) Structure and Function 725(7) Mechanisms of Toxicity 732(11) Response to Injury 743(7) Evaluation of Toxicity 750(5) Parathyroid Gland 755(30) Introduction 755(1) Structure and Function 755(5) Mechanisms of Toxicity 760(5) Response of Parathyroid Chief Cells to Injury 765(5) Evaluation of Toxicity 770(1) Suggested Reading 771(14) Male Reproductive System Dianne M. Creasy Paul M. D. Foster Introduction 785(1) Structure and Cell Biology 785(23) Embryological Derivation of the Reproductive Tract 785(1) Development of the Reproductive Tract 786(1) Structure of the Testes 787(5) Physiology and Functional Consideration of the Testes 792(13) Structure and Function of the Epididymis and Excurrent Ducts 805(1) Structure and Function of Accessory Sex Organs 806(1) Penis and Ejaculation 807(1) Mechanisms of Toxicity 808(14) Role of Metabolism 809(1) Cell-Specific Toxicity in the Testes 810(6) Vascular Effects and Indirect Toxicity to the Testes 816(1) Epididymal and Sperm Toxicity 817(1) Secondary Sex Organs 818(1) Hormone Disruption 818(2) Toxicity to the Developing Male Reproductive Tract 820(2) Responses to Injury 822(15) Disruption of Spermatogenesis 822(6) Tubular Dilatation and Tubular Shrinkage 828(1) Tubular and Testicular Necrosis 828(1) Leydig Cell Response 828(2) Disruption of Sperm Maturation 830(1) Epididymal Response 830(1) Response to Alternations in Hormone Balance 831(5) Reversibility 836(1) Testing for Toxicity 837(7) Detecting Toxicity 837(1) Characterization of Male Reproductive Toxicity 838(3) Functional Characterization 841(2) Testing for Toxicity of the Developing Male Reproductive Tract 843(1) Conclusions 844(3) Suggested Reading 844(3) Female Reproductive System Yang-Dar Yuan George L. Foley Introduction 847(1) Structure and Functional Physiology 848(17) Structure 848(11) Functional Physiology 859(6) Mechanisms of Toxicity 865(7) General Toxicity: Ovary, Uterus, and Vagina as a Unit 865(5) Local Vaginal Toxicity 870(1) Carcinogenesis 871(1) Response to Injury 872(14) General Responses: Overy, Uterus, and Vagina as a Unit 872(6) Local Inflammation of Vagina 878(2) Neoplasia 880(6) Testing for Toxicity 886(3) General Toxicity 886(2) Local Vaginal Toxicity 888(1) Summary 889(6) Suggested Reading 889(6) Embryo and Fetus Ronald D. Hood Colin G. Rousseaux Patricia M. Blakley Introduction 895(1) Overview of Fetal Toxicologic Pathology 895(1) Basic Principles of Developmental Toxicology 895(1) Incidence of Congenital Anomalies 896(1) Normal Morphologic Development 896(5) Fertilization and Blastocyst Formation 897(1) Gastrulation 897(1) Organogenesis 897(3) Histogenesis and Functional Maturation 900(1) Mechanisms of Toxicity 901(5) Critical Phase of Intrauterine Development 901(1) Modifying Factors 902(4) Response to Injury 906(8) Death 906(1) Malformations 907(3) Intrauterine Growth Retardation 910(1) Perinatal Toxicology 911(1) Endocrine Disruption 912(1) Congenital Neoplasia 912(2) How Dose Relates to Manifestation of Abnormal Development 914(1) Selected Malformations 914(13) Central Nervous System 914(6) Craniofacial Structures 920(2) Cardiovascular System 922(1) Respiratory System 923(1) Gastrointestinal System 924(1) Urinary System 924(1) Reproductive System 925(1) Skeletal System 925(2) Developmental Toxicity Testing and Risk Assessment 927(10) Hazard Identification and Dose-Response Analysis 927(5) Dose---Response Evaluation 932(1) Risk Characterization 933(1) Conclusions 933(1) Suggested Reading 933(4) Index 937
