Haschek and Rousseaux's Handbook of Toxicologic Pathology Volume 5: Toxicologic Pathology of Organ Systems

4th Edition - February 9, 2025
Imprint: Academic Press
Editors: Wanda M Haschek, Colin G. Rousseaux, Matthew A. Wallig, Brad Bolon
Language: English
Hardback ISBN:
9 7 8 - 0 - 1 2 - 8 2 1 0 4 5 - 1
eBook ISBN:
9 7 8 - 0 - 4 4 3 - 2 3 8 5 0 - 5

Haschek and Rousseaux's Handbook of Toxicologic Pathology, Fourth Edition, Volume Five: Toxicologic Pathology of Organ Systems is a key reference on the integration of structure… Read more

Haschek and Rousseaux's Handbook of Toxicologic Pathology Volume 5: Toxicologic Pathology of Organ Systems

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Haschek and Rousseaux's Handbook of Toxicologic Pathology, Fourth Edition, Volume Five: Toxicologic Pathology of Organ Systems is a key reference on the integration of structure and functional changes in tissues associated with the response to pharmaceuticals, chemicals, and biologics. This book continues coverage of Organ-Specific Toxicologic Pathology and major organ systems not covered in Volume Four, and has been completely revised, making it an essential part of the most authoritative reference on toxicologic pathology for pathologists, toxicologists, research scientists, and regulators studying and making decisions on drugs, biologics, medical devices, and other chemicals, including agrochemicals and environmental contaminants.

Title of Book
Cover image
Title page
Table of Contents
Copyright
Dedication
Contributors
About the Editors
Editors
Associate Editors
Illustrations Editor
Preface
Chapter 1. Cardiovascular System
1 Introduction
Part I: Heart
2 Structure and Function
2.1 Gross and Microscopic Anatomy
2.1.1 Cellular and Extracellular Elements of the Heart
2.2 Physiology and Functional Considerations
2.2.1 Phases of the Cardiac Cycle
2.2.2 Resting and Action Potentials of Cardiac Myocytes
2.2.3 Initiation and Conduction of Cardiac Impulses
2.2.4 Excitation–Contraction Coupling
2.2.5 Myocardial Metabolism
2.2.6 Innervation of the Heart
2.3 Xenobiotic Exposure
3 Evaluation of Toxicity
3.1 Bioactivity Screening for Cardiac Toxicity
3.2 Functional Evaluation of Toxicity
3.2.1 Monitoring Myocardial Contractile Function
3.2.2 Monitoring Myocardial Electrical Activity
3.2.3 Complex In Vitro Modeling Systems
3.2.4 Monitoring Arterial Blood Pressure
3.3 Morphologic Evaluation of Toxicity
3.3.1 Gross Examination
3.3.2 Microscopic Examination
3.3.3 Ultrastructural Examination
3.3.4 Quantification of Morphologic Alterations
3.3.5 Artificial Intelligence and Machine Learning
3.4 Background Alterations, Artifacts, and Spontaneous and Age-Related Lesions
3.5 Biomarkers
3.6 Biochemical Evaluation of Toxicity
4 Responses to Injury
4.1 Developmental Cardiotoxicity
4.2 Cardiac Dysfunction as a Manifestation of Toxicity
4.2.1 Arrhythmias
4.2.2 Changes in Contractility
4.3 Changes in Cardiac Mass as a Response to Toxicity
4.4 Drug-Induced Cardiomyopathies
4.4.1 Alcoholic Cardiomyopathy
4.4.2 Antimicrobial Cardiomyopathy
4.4.3 Antineoplastic Cardiomyopathy
4.5 Cardiomyocellular Injury
4.5.1 Vacuolar Degeneration
4.5.2 Myofibrillar Degeneration
4.5.3 Lipofuscinosis
4.5.4 Phospholipidosis
4.5.5 Cardiomyocyte Necrosis
4.5.6 Myocardial Infarction Associated with Toxic Reactions
4.5.7 Hypersensitivity Myocarditis
4.6 Endocardium
4.6.1 Fibrosis
4.7 Neoplasia
4.8 Valves
4.8.1 Proliferative Valvulopathies
4.8.2 Degenerative/Inflammatory Valvulopathies
4.9 Epicardium
4.9.1 Epicardial Hemorrhage
4.10 Pericardium
5 Mechanisms of Toxicity
5.1 Mechanisms of Altered Cardiac Function
5.1.1 Changes in Rate and Rhythm
5.1.2 Contractility
5.2 Mechanisms of Direct Cellular Injury
5.3 Mechanisms of Indirect Injury
5.4 Cardiotoxicity of Cardiac Drugs
5.5 Hypersensitivity Reactions
5.6 Xenobiotic Interactions
5.7 Modifying Factors in Cardiac Toxicity
6 Cardiotoxicity Issues in Drug Development
6.1 Cardiovascular-Related Drug Development Attrition
6.2 Rodent Progressive Cardiomyopathy
6.3 Animal Models of Human Cardiac Disease
6.4 Clinical Translation of Nonclinical Cardiotoxicity
Part II: Blood Vessels
7 Structure and Function
7.1 Microscopic Anatomy
7.2 Cellular and Extracellular Components of the Vasculature: Biology
7.2.1 Endothelial Cells
7.2.2 Smooth Muscle Cells
7.2.3 Pericytes and Veil Cells
7.2.4 Connective Tissue
7.3 Physiology and Functional Considerations
7.3.1 Blood Circulation and Tissue Perfusion
7.3.2 Endothelial Permeability
7.3.3 Metabolic Activities in Vascular Cells
7.3.4 Vascular Function
8 Evaluation of Toxicity: Vasotoxic Effects
8.1 Physiological Methods for Testing
8.1.1 Noninvasive Measurements of Blood Flow
8.1.2 Invasive Measurements of Blood Flow, Vascular Tone, and Microvasculature
8.2 In Vitro Methods for Detecting Vascular Toxicity
8.2.1 Isolated Vascular Preparations
8.2.2 Cellular Electrophysiological Methods
8.2.3 Cultured Vascular Smooth Muscle Cells
8.2.4 Human-Derived Induced Pluripotent Stem Cells
8.2.5 Emerging Technologies
8.3 Morphologic Evaluation
8.3.1 Gross Examination
8.3.2 Microscopic and Biochemical Evaluation
8.4 Background Alterations, Artifacts, Spontaneous and Age-Related Lesions
8.5 Use of Animals as Models for Vascular Toxicity
8.6 Biomarkers of Vascular Injury
9 Responses to Injury
9.1 Atherosclerosis Acceleration by Toxic Agents
9.2 Medial Proliferation
9.3 Intimal Proliferation
9.4 Calcification
9.5 Aneurysms
9.6 Medial Hemorrhagic Necrosis
9.7 Fibrinoid Necrosis
9.8 Microangiopathy
9.9 Immune-Mediated Vascular Inflammation
9.9.1 Hypersensitivity Vasculitis
9.9.2 Immune Complex-Mediated Vascular Injury
9.9.3 Lupus-Like Syndromes
9.10 Regeneration and Repair
10 Vascular Toxicity in Specific Organs
10.1 Brain
10.2 Lungs
10.3 Heart
10.4 Liver
10.5 Kidney
10.6 Stomach
11 Conclusion
Chapter 2. Kidney
1 Introduction
2 Structure, Function, and Cell Biology
2.1 Renal Ontogeny
2.2 Renal Structure
2.2.1 Gross and Subgross Anatomy
2.2.2 Vasculature and Innervations
2.2.3 Microscopic and Ultrastructural Functional Anatomy
2.2.4 Glomerulus
2.2.5 Proximal Convoluted Tubule
2.2.6 Pars Recta
2.2.7 Thin Limbs of the Loop of Henle
2.2.8 Thick Ascending Limb and Distal Tubule
2.2.9 Juxtaglomerular Apparatus
2.2.10 Distal Convoluted Tubule
2.2.11 Collecting Ducts
2.2.12 Interstitium
2.2.13 Comparative Considerations—Age, Sex, and Species
2.3 Renal Function
2.3.1 Control of Body Water and Electrolytes
2.3.2 Potassium
2.3.3 Calcium and Phosphate
2.3.4 Magnesium
2.3.5 Elaboration of Hormones and Regulatory Peptides
2.3.6 Erythropoietin
2.3.7 Renin
2.3.8 Prostaglandins
2.3.9 Glucose Transporters
2.3.10 Xenobiotic Renal Transporters
2.3.11 Uptake Transporters
2.3.12 Efflux Transporters
2.3.13 Protein and Amino Acid Transport
2.3.14 Control of Acid–Base Balance
2.3.15 Insulin Metabolism
2.3.16 Fatty Acid Utilization
2.3.17 Cholesterol Control
2.3.18 Renal Xenobiotic Metabolism
2.3.19 Renal Clearance and Toxicity
2.4 Renal Cell Biology
3 Evaluation of Toxicity
3.1 Physiologic Considerations
3.1.1 Glomerular Filtration Rate Estimation
3.1.2 Considerations in Pediatric or Neonatal Kidneys
3.1.3 Changes in Aged Kidneys
3.1.4 Hypertrophy
3.2 Biochemical and Biomarker Evaluations
3.2.1 Evaluation of Traditional Biomarkers
3.2.2 Serum Creatinine and Urea Nitrogen
3.2.3 Proteinuria and Albuminuria
3.2.4 Urinary N-acetyl=β-(d)-Glucosaminidase
3.2.5 Urinary Glutathione S Transferases
3.2.6 Evaluation of Novel Biomarkers (See also Biomarkers: Discovery, Qualification, and Application, Vol 1, Chap 14)
3.2.7 Kidney Injury Molecule-1
3.2.8 Neutrophil Gelatinase-Associated Lipocalin
3.2.9 Clusterin
3.2.10 Trefoil Factor 3
3.2.11 Urinary Beta2-Microglobulin
3.2.12 Renal Papillary Antigen
3.2.13 Alternative Biomarkers for Chronic Duration Nonclinical Safety Studies
3.2.14 Cystatin C
3.2.15 Symmetrical Dimethyl Arginine
3.2.16 Dickkopf Homolog 3
3.3 Morphologic Evaluation
3.3.1 Spontaneous Renal Diseases
3.3.2 Chronic Progressive Nephropathy
3.3.3 Common Spontaneous Lesions in Beagle Dogs
3.3.4 Common Spontaneous Lesions in Monkeys
3.3.5 Common Spontaneous Lesions in Minipigs
3.3.6 Common Spontaneous Lesions in Mice and Other Species
3.4 Testing for Renal Carcinogenic Potential
3.5 In Vitro Techniques
3.5.1 In Vitro/Ex Vivo Assay Platforms
3.5.2 Two-dimensional Models
3.5.3 Three-dimensional Models
3.5.4 Microphysiological Systems (Organ-on-a Chip)
3.5.5 Application of In Vitro Assays
3.5.6 3D Bioprinting
3.6 Scoring Schemes
3.7 Computational Pathology
4 Responses to Injury
4.1 Physiologic, Molecular, and Biochemical Response
4.2 Morphologic Response
4.2.1 Glomerulus
4.2.2 Noninflammatory Glomerular Injury
4.2.3 Podocyte Injury
4.2.4 Focal Glomerulosclerosis
4.2.5 Membranous Nephropathy
4.2.6 Amyloidosis
4.2.7 Inflammatory Glomerular Injury
4.2.8 Tubule Injury
4.2.9 Vacuolation
4.2.10 Tubule Dilation and Cysts
4.2.11 Other Types of Tubule Injury
4.2.12 Papillary Injury
4.2.13 Interstitial Injury
5 Mechanisms of Toxicity
5.1 Nephrotoxicity Classification
5.1.1 Functional and Structural Characteristics of Molecules
5.1.2 Subtopographical Targets
5.1.3 Mechanisms of Renal Injury
5.2 Mechanisms of Glomerular Toxicity
5.2.1 Glomerular Podocyte Injury
5.2.2 Glomerular Endothelial Cell Injury
5.2.3 Changes in Polyanionic Binding Sites in the Glomerular Filtration Barrier
5.2.4 Interference in Formation of Crosslinks in Glomerular Basement Membrane Collagen
5.2.5 Perturbation of Renal Hemodynamics
5.2.6 Other Mechanisms of Glomerular Injury
5.3 Mechanisms of Interstitial Injury
5.3.1 Immune-Mediated Interstitial and Glomerular Injury (Biologic Induced Autoimmune Renal Disorders)
5.3.2 Antidrug Antibodies in Animals and Human Patients
5.3.3 Antisense Oligonucleotide Nephropathy and Glomerulonephritis
5.3.4 Renal Safety of Other Novel or Alternative Therapies
5.4 Mechanisms of Proximal Tubular Injury
5.4.1 Direct Perturbation of Cell or Subcellular Organelle Function
5.4.2 Antibiotic Nephrotoxicity
5.4.3 Aminoglycoside Toxicity
5.4.4 Cephalosporin
5.4.5 Nephrotoxicity of Other Antibiotics
5.4.6 Heavy Metals (See also Metals, Vol 3, Chap 10)
5.4.7 Cadmium
5.4.8 Mercury
5.4.9 Lead
5.4.10 Anticancer Drug-Induced Nephrotoxicity
5.4.11 Cisplatin
5.4.12 Molecular Targeted Anticancer Therapies
5.4.13 Immune Checkpoint Inhibitors
5.4.14 Antibody-Drug Conjugates
5.4.15 Xenobiotics that Cause Renal Injury via Metabolic Activation
5.4.16 Organohalides
5.4.17 Organic Acid/Base Transport as a Mechanism for Renal Toxicity
5.4.18 Mycotoxins (See also Mycotoxins, Vol 3, Chap 6)
5.4.19 Xenobiotics Perturbing Endogenous or Nutritive Substrates
5.4.20 Iron Toxicity
5.4.21 Osmotic Vacuolation
5.4.22 Obstructive Nephropathy
5.4.23 Oxalate Crystalluria
5.4.24 Melamine-Related Retrograde Nephropathy
5.4.25 Alpha2μ-Globulin Nephropathy and Hyaline Droplet Nephropathy
5.4.26 Myoglobin and Hemoglobin
5.4.27 Amino Acid Toxicity
5.4.28 Synthetic Diet-induced Nephrocalcinosis
5.4.29 Xenobiotics Inducing Ischemia and/or Hypoxia
5.4.30 Cyclosporine
5.5 Other Sites of Renal Injury
5.5.1 Distal Nephron
5.5.2 2-Amino-4,5-diphenyl Thiazole HCl-related Medullary Cysts
5.5.3 Renal Papillary Injury
5.5.4 NSAID-Related Nephrotoxicity
5.6 Renal Carcinogenesis
5.6.1 Genotoxic Xenobiotics
5.6.2 Heavy Metal Carcinogens
5.6.3 Mechanisms of Nongenotoxic Rodent Renal Carcinogenesis
5.6.4 Lysosomal Enzyme Release
5.6.5 Oxidative Stress/Chronic Inflammation
5.6.6 Sustained Increase of Replicative Rate and Apoptosis
5.6.7 Heritable Change without Direct Xenobiotic Effect on DNA
5.6.8 Exacerbation of CPN and Renal Tumors
5.6.9 Modifying Factors in Renal Tumorigenesis
5.6.10 Nutritional Factors
5.6.11 Hormonal Influence on Renal Carcinogenesis
5.6.12 Aging
6 Issues in Drug Development
6.1 Animal Models
6.1.1 Acute Kidney Injury Models
6.1.2 Ischemia Reperfusion Injury Models
6.1.3 Chemically induced Renal Injury Models
6.1.4 Sepsis-associated Renal Models
6.1.5 Obstructive Uropathy Models
6.1.6 Chronic Kidney Disease Models
6.1.7 Diabetic Kidney Disease Models
6.1.8 Hypertensive Kidney Models
6.2 Adversity
6.2.1 Regulatory Issues
7 Conclusion
Chapter 3. Lower Urinary Tract
1 Introduction
2 Structure, Function, and Cell Biology
2.1 Kidney Pelvis and Papilla
2.2 Ureters
2.3 Urinary Bladder
2.4 Urethra
2.5 Urothelium
3 Evaluation of Toxicity
3.1 Physiologic and Biochemical Evaluation
3.2 Morphologic Evaluation
3.3 Techniques for Evaluation
3.3.1 Urinalysis
4 Responses to Injury
4.1 Acute Injury
4.2 Chronic Injury
4.3 Carcinogenesis
4.4 Morphologic Lesions
4.4.1 Nonneoplastic Lesions
4.4.2 Proteinaceous Plug
4.4.3 Neoplastic Lesions
5 Mechanisms of Toxicity
6 Issues in Drug and Chemical Development
Chapter 4. Respiratory System
1 Introduction
2 Structure, Function, and Cell Biology
2.1 Macroscopic and Microscopic Anatomy
2.2 The Nose
2.2.1 Nasal Epithelium
2.2.2 Nasal-Associated Lymphoid Tissue
2.2.3 Nasal Nerves and Blood Vessels
2.3 The Pharynx and Larynx
2.4 The Trachea, Bronchi, and Bronchioles
2.4.1 Epithelial Cells Lining Tracheobronchial Airways
2.4.2 Bronchus-Associated Lymphoid Tissues
2.5 Gas-Exchange Regions of the Lung
2.5.1 Respiratory Bronchioles
2.5.2 Alveolar Parenchyma of the Lung
2.5.3 Epithelial Cells of the Alveolus
2.5.4 Pulmonary Blood Vessels, Lymphatics, and Nerves
3 Testing for Toxicity
3.1 Methods of Testing
3.1.1 Whole Animal Exposure
3.1.2 Inhalation Exposure
3.1.3 Instillation and Aspiration Exposures
3.1.4 Isolated Perfused Lung
3.1.5 Tissue Sections and Organ Cultures
3.1.6 Isolated Cells and Cell Culture Systems
3.1.7 Pulmonary Function
3.1.8 Bronchoalveolar Lavage
3.1.9 Biochemical Evaluation
3.1.10 Morphological Evaluation
3.2 Background Findings
3.3 Nasopharyngeal and Laryngeal Regions
3.4 Tracheobronchial Airways and Pulmonary Parenchyma
3.5 Animal Models
3.6 Target Liability Assessment and In Vitro Models
3.6.1 In Vitro Methods
3.7 Quantitative Techniques and Lung Imaging Modalities
3.7.1 Molecular Markers
3.7.2 Imaging of Ex Vivo Lung Tissue
3.7.3 Imaging in Animal Models of SARS-COV-2
3.7.4 Lung Injury Caused by Antibody-Based Therapeutics for Targeted Therapy
4 Responses to Injury
4.1 Factors Affecting Toxic Injury and Host Response
4.2 Patterns of Respiratory Tract Injury to Inhaled Toxicants
4.3 Cell-specific Versus Nonspecific Injury
4.4 Cell Proliferation, Regeneration, and Repair Processes
4.5 Nasal, Nasopharyngeal, and Laryngeal Responses to Injury
4.5.1 Nonneoplastic Lesions
4.5.2 Subacute/Chronic Lesions
4.5.3 Nasal Neoplasia
4.6 Tracheobronchial and Pulmonary Responses to Injury
4.6.1 Cell-Specific Injury
4.6.2 Hyperreactive Airway Disease
4.6.3 Chronic Obstructive Pulmonary Disease
4.6.4 Asthma
4.6.5 Proliferative Lesions
4.7 Pulmonary Parenchymal Responses to Injury
4.7.1 Phospholipidosis
4.7.2 Pulmonary Alveolar Proteinosis
4.7.3 Pulmonary Edema
4.7.4 Pulmonary Inflammation
4.7.5 Interstitial Pneumonia
4.7.6 Pulmonary Fibrosis
4.7.7 Pulmonary Emphysema
4.7.8 Pulmonary Neoplasia
4.7.9 Lung Tumors in Mice
5 Mechanisms of Toxicity
5.1 Direct Toxicity
5.2 Metabolic Activation
5.3 Immune-Mediated Toxicity
5.3.1 Inhaled Therapeutic Biologics
5.4 Toxicity and Responses to Inhaled Particles
5.5 Toxicity and Responses to Inhaled Fibers
5.6 Xenobiotic Interactions
5.7 Modifying Factors in Toxicity
5.8 Adversity Considerations
6 Conclusion
Chapter 5. Hematopoietic System
1 Introduction
2 Phylogenesis and Ontogenesis
2.1 Phylogeny
2.1.1 Respiratory Systems
2.1.2 Hemostatic Systems
2.1.3 Immunologic Systems
2.1.4 Hematopoietic Organs
2.2 Mammalian Ontogeny
3 Structure, Function, and Cell Biology
3.1 Anatomy of the Bone Marrow
3.2 Hematopoiesis
3.2.1 The Hematopoietic Microenvironment
3.2.2 Stem Cell Biology
3.2.3 Life Cycles of Blood Cells
4 Evaluation of Hematotoxicity
4.1 Evaluation of Bone Marrow
4.1.1 Histopathology
4.1.2 Cytology
4.1.3 Quantitative Bone Marrow Assessment
4.2 Evaluation of Peripheral Blood
4.2.1 Routine Hematology
4.2.2 Emerging/Advanced Technologies and Biomarkers
4.3 In Vitro Techniques
4.4 Animal Models
5 Responses to Injury
5.1 Changes in Peripheral Blood
5.1.1 Redistribution, Sequestration and Demargination/Margination
5.1.2 Hemolytic Anemia
5.1.3 Blood Loss Anemia
5.1.4 Inflammation
5.2 Changes in Bone Marrow
5.2.1 Changes in Hematopoietic Cells
5.2.2 Physiologic Responses
5.2.3 Nonproliferative Bone Marrow Lesions
5.3 Myeloproliferative Lesions
5.4 Changes in Secondary Hematopoietic Organs
6 Mechanisms of Hematotoxicity
6.1 Direct Nonimmune Injury to Hematopoietic Cells
6.1.1 Injury to Hematopoietic Progenitors
6.1.2 Injury to the Mitotic Pool—Inhibition of DNA Synthesis and Cell Division
6.1.3 Injury to the Maturing Pool—Inhibition of Protein Synthesis
6.2 Direct Nonimmune Injury to Circulating Cells
6.2.1 Oxidative Injury to Circulating Cells
6.2.2 Oxidation of Iron in Hemoglobin: Methemoglobin
6.2.3 Oxidation of Globin
6.3 Immune Injury and Destruction
6.4 Idiosyncratic Reactions
6.5 Altered Blood Cell Function
6.6 Indirect Injury, Secondary Effects, and Modifying Factors
6.6.1 Suppression of Hematopoiesis
6.6.2 Damage to the Bone Marrow Microenvironment
6.6.3 Decreased Cell Lifespan
7 Issues in Drug Development and Regulatory Considerations
7.1 Translatability
7.2 Adversity
7.3 Regulatory Issues
8 Conclusion
Glossary
Chapter 6. Immune System
1 Introduction and Background
2 Function
2.1 Antigen Presentation and Recognition
2.2 Immune Regulation of the Effector Reactions
2.3 Effector Reactions
2.4 Immunological Memory
2.5 Lymphocyte Trafficking and Homing
2.6 Cooperation with Other Organ Systems
3 Development, Structure, and Physiology
3.1 Thymus
3.1.1 Development
3.1.2 Structure/Anatomy
3.1.3 Physiology/Function
3.2 Bone Marrow
3.3 Spleen
3.3.1 Development
3.3.2 Structure/Anatomy
3.4 Physiology/Function
3.5 Lymph Nodes
3.5.1 Development
3.5.2 Structure/Anatomy
3.5.3 Physiology/Function
3.6 Mucosa-Associated Lymphoid Tissue (MALT)
3.6.1 Development
3.6.2 Structure/Anatomy
3.6.3 Physiology/Function
3.7 Tertiary Lymphoid Structures
3.7.1 Development
3.7.2 Structure/Anatomy
3.7.3 Physiology/Function
3.8 Immune-specific Components in Select Organs
3.8.1 Skin
3.8.2 Liver (See also Liver and Gallbladder, Vol 4, Chap 2)
3.8.3 Immune-privileged organs
3.8.4 Serosa-Associated Lymphoid Cluster
4 Physiological Influences on the Immune System Throughout the Lifespan
4.1 Immune Responses to Aging
4.2 Immune Responses to Hormones
4.3 Immune Responses to Stress
5 Immunomodulation, Immune Systems Responses, and Mechanisms of Toxicity
5.1 Defining Immunotoxicology, Immunosuppression, and Immunostimulation
5.2 Biochemical Pathways and Exaggerated Pharmacology in the Immune System
5.3 Perturbations of the Immune System and Recoverability (Relevance to Adversity)
5.4 Nonantigen-Specific Toxicity
5.5 Antigen-specific Toxicity
5.6 Pathophysiological Changes Associated with Therapies Affecting the Immune System
5.6.1 Immunosuppression
5.6.2 Immunostimulation
5.6.3 Immunomodulation
5.7 Recoverability of the Immune System (Acute vs. Chronic Changes, Reversibility)
5.8 Immune Derangements and Neoplasia
6 Evaluation of Changes and Toxicity
6.1 Interpreting Immune System Changes
6.2 Testing for Toxicity
6.3 Anatomic Pathology
6.3.1 Gross Observations
6.3.2 Organ Weights
6.3.3 Microscopic Findings
6.4 Organ-specific Histopathology
6.4.1 Thymus
6.4.2 Bone Marrow
6.4.3 Peripheral Lymphoid Organs: Spleen, Lymph Nodes, and MALT
6.5 Clinical Pathology Evaluation and Considerations
6.6 Immunotoxicology Evaluation and Considerations
6.6.1 Immune Cell Evaluation
6.6.2 Immune Function Evaluation
6.6.3 Biomarkers and Integration of Immune Data
7 Responses to Injury
7.1 Immunosuppression
7.2 Immunostimulation
7.2.1 Tissue-specific Responses
7.2.2 Hypersensitivity and Autoimmunity Changes
8 Preneoplastic Changes and Neoplasia
8.1 Stromal Tumors: Thymoma
8.2 Tumors of Hematopoietic and Lymphopoietic Cells
8.3 Lymphomas
8.4 Histiocytic Sarcoma
9 Best Practices and Regulatory Considerations on Evaluation of Toxicity and Adversity in the Immune System
10 Conclusion
Chapter 7. Integument
1 Introduction
2 Structure and Function
2.1 The Epidermis
2.2 Melanocytes
2.3 Merkel Cells
2.4 Langerhans Cells and Dermal Dendritic Cells
2.5 The Dermal–Epidermal Junction and Dermis
2.6 The Subcutis
2.7 The Adnexa
2.8 The Minipig in Dermal Toxicity Assessment
2.9 Physiology and Biochemistry of the Integument
2.10 Percutaneous Absorption
2.11 Metabolism and the Integument
3 Evaluation of Toxicity
3.1 Physiologic and Morphologic Safety Evaluation Strategies and Techniques
3.1.1 Traditional Test Systems
3.1.2 Draize Scale
3.1.3 Photosafety Testing
3.2 Special Considerations in Design of Topical Dermatologic Studies
3.2.1 Addition of a Sham Control Group
3.2.2 Prevention of Oral Ingestion and Cross Contamination
3.2.3 Application of More than One Test Substance to Same Subject
3.3 Skin Sample Collection Techniques
3.3.1 Preferred Necropsy Collection and Considerations for Sampling Site Selection
3.3.2 Skin Biopsy as a Companion Diagnostic Technique
3.4 Special Techniques
3.4.1 Genetic Toxicity Profiling
3.4.2 Plucked Hair Assessment
3.4.3 In Vivo Microscopy
3.4.4 Label-free Optical Imaging of Skin
3.4.5 Confocal Microscopy
3.4.6 Optical Coherence Tomography
3.4.7 Other Useful In Vivo Tools for Enhanced Physiologic Assessment of Skin
3.4.8 Electron Microscopy
3.5 Three-Dimensional In Vitro Skin Model Systems
4 Responses to Injury
4.1 General Mechanisms of Response to Injury-Cutaneous Immunity
4.2 Special Considerations-Translational Immunology of Skin
4.3 Wound Healing
4.4 Influence of Skin Microbiome on Adaptive Immune Response
4.5 Specific Cutaneous Morphologic Lesions and Patterns of Injury
4.5.1 Nonproliferative Lesions of the Epidermis
4.5.2 Nonproliferative Lesions of the Cutaneous Adnexa
4.5.3 Proliferative Nonneoplastic Lesions of the Epidermis
4.5.4 Proliferative Nonneoplastic Lesions of the Adnexa
4.5.5 Proliferative Nonneoplastic Lesions of the Dermis
4.6 Neoplastic Lesions and Carcinogenesis Models
4.6.1 Carcinogenesis Models
4.6.2 Neoplastic Proliferative Lesions of the Epidermis
4.6.3 Adnexal Neoplastic Lesions
4.6.4 Dermal Neoplastic Lesions
5 Mechanisms of Toxicity
5.1 Direct Cutaneous Toxicity
5.2 Immune-Mediated Cutaneous Toxicity
5.3 Mechanisms of Toxicity: Photosafety
5.3.1 Photosensitivity
5.3.2 Phototoxicity
5.3.3 Photoallergy
5.3.4 Photogenotoxicity
5.3.5 Photocarcinogenicity
5.4 Mechanisms of Toxicity: Photoaging
5.5 Mechanisms of Toxicity: Antisense Oligonucleotides
5.6 Mechanisms of Toxicity: Pigmentation
5.7 Mechanisms of Toxicity: Adnexa—General and Specific Toxicities
6 Conclusion
Chapter 8. Mammary Gland
1 Introduction
2 Mammary Gland Structure and Function
2.1 Stages of Development
2.2 Variation in Development Across Species
2.3 Endocrine and Paracrine Modifiers of Development
2.4 Functional Outcomes
3 Evaluation of Mammary Gland Toxicity
3.1 In Vitro Techniques
3.2 Commonly Used Animal Models
3.3 Physiologic Outcomes
3.4 Morphological Evaluations
3.5 Biochemical Indicators and Biomarkers
4 Responses to Injury
4.1 Physiologic Responses
4.2 Molecular and Biochemical Responses
4.3 Morphological Indicators
5 Mechanisms of Toxicity
6 Conclusion
Appendix: Preparation and Evaluation of Mammary Gland Whole Mounts in Mice and Rats
1 Collection of the Intact Mammary Gland
2 Fixing and Staining Whole Mounts
3 Suggested Evaluation Methods for Mammary Gland Whole Mounts
Chapter 9. Male Reproductive System
1 Introduction
2 Structure, Function, and Cell Biology
2.1 Embryonic Development
2.2 Postnatal Development of the Reproductive Tract
2.2.1 Leydig Cells
2.2.2 Testicular Descent
2.2.3 Morphologic Appearance of the Developing Postnatal Testis
2.3 Structure and Function of the Testis
2.3.1 Capsule and Vasculature
2.3.2 Interstitium
2.3.3 Seminiferous Tubules
2.3.4 Sertoli Cells
2.3.5 Spermatogonia
2.3.6 Spermatocytes
2.3.7 Spermatids
2.4 Spermatogenesis and the Spermatogenic Cycle
2.5 Structure and Function of the Rete Testis, Efferent Ducts, Epididymis, and Vas Deferens
2.5.1 Rete Testis
2.5.2 Efferent Ducts
2.5.3 Epididymis
2.5.4 Vas Deferens
2.5.5 Vasculature
2.6 Structure and Function of the Accessory Sex Organs
2.6.1 Prostate
2.6.2 Seminal Vesicles
2.6.3 Bulbourethral Glands
2.6.4 Preputial Glands
2.7 Hormonal Regulation of Reproductive Function
2.7.1 Gonadotropin-Releasing Hormone
2.7.2 Follicle-Stimulating Hormone
2.7.3 Inhibins and Activins
2.7.4 Luteinizing Hormone
2.7.5 Testosterone
2.7.6 Estrogen
2.7.7 Dihydrotestosterone
2.7.8 Autocrine/Paracrine Regulation of Testicular Function
3 Evaluation of Toxicity
3.1 Physiologic Evaluation
3.1.1 Organ Weights
3.1.2 Sperm Analysis and Spermatid Head Count
3.1.3 Fertility Assessment
3.1.4 Testing for Developmental Toxicity
3.1.5 Measuring Xenobiotic or Metabolite Access and Accumulation in the Testis
3.2 Biochemical and Biomarker Evaluation
3.2.1 Semen Analysis
3.2.2 Hormones
3.2.3 Messenger RNA
3.2.4 miRNA
3.2.5 Toxicogenomics
3.3 Morphologic Evaluation
3.3.1 Importance of Fixation
3.3.2 Importance of Sampling
3.3.3 Stage-Aware Evaluation of Spermatogenesis
3.3.4 Nomenclature and Grading of Lesions
3.4 Special Techniques
3.4.1 Immunohistochemistry
3.4.2 Flow Cytometry
3.4.3 Electron Microscopy
3.4.4 Laser Capture
3.4.5 In Vitro Methods
4 Response to Injury
4.1 Organ Weight Changes
4.2 Morphologic Changes (Nonproliferative)
4.2.1 Germ Cell Degeneration
4.2.2 Germ Cell Depletion
4.2.3 Tubular Degeneration/Atrophy, Testis
4.2.4 Multinucleated Giant Cells
4.2.5 Tubular Necrosis, Testis
4.2.6 Tubular Dilatation, Testis
4.2.7 Tubular Vacuolation
4.2.8 Spermatid Retention
4.2.9 Leydig Cell Atrophy, Apoptosis, or Necrosis
4.2.10 Necrosis/Inflammation, Vascular/Perivascular
4.2.11 Cell Debris, Lumen, Epididymis
4.2.12 Decreased Sperm, Lumen, Epididymis
4.2.13 Single Cell Necrosis/Apoptosis, Epididymis
4.2.14 Vacuolation, Epithelium, Epididymis
4.2.15 Sperm Granuloma, Epididymis
4.2.16 Atrophy: Prostate or Seminal Vesicles
4.2.17 Inflammation and Metaplasia, Prostate or Seminal Vesicles
4.3 Morphologic Changes (Proliferative)
4.3.1 Proliferative Lesions of the Testis
4.3.2 Proliferative Lesions of the Epididymis
4.3.3 Proliferative Lesions of the Accessory Sex Organs
4.4 Recovery and Reversibility of Injury
4.5 Immaturity and Peripuberty as Confounding Factors for Identifying Toxicity
4.5.1 Rodents
4.5.2 Dogs
4.5.3 Nonhuman Primates
4.5.4 Minipigs
4.6 Background Pathology as a Confounding Factor for Identifying Reproductive Toxicity
4.6.1 Rodents
4.6.2 Dogs
4.6.3 Nonhuman Primates
4.6.4 Minipigs
4.7 Stress and Body Weight Loss as a Confounding Factor for Identifying Reproductive Toxicity
5 Mechanisms and Patterns of Toxicity
5.1 Molecular and Biochemical
5.2 Morphologic Patterns of Response to Different Types of Injury
5.2.1 Patterns of Changes Associated with Sertoli Cell Injury
5.2.2 Patterns of Change Associated with Germ Cell-specific Toxicity
5.2.3 Patterns of Change Associated with Anoxia or Ischemia
5.2.4 Patterns of Change Associated with Altered Endocrine Support
5.2.5 Pattern of Change Associated with Disturbance of Fluid Production, Reabsorption, or Efferent Duct Obstruction
5.3 Mechanisms of Developmental Toxicity
5.3.1 Effects via Estrogen Receptors
5.3.2 Effects via the Androgen Receptor
5.3.3 5α-Reductase Inhibition
5.3.4 Steroid Biosynthesis Inhibition
5.3.5 Other Potential Mechanisms: The Example of Di-n-butyl Phthalate
6 Conclusion
Chapter 10. Female Reproductive System
1 Introduction
2 Structure, Function, and Cell Biology
2.1 The Ovary
2.2 The Histology of the Rat Ovary during Prepubertal and Pubertal Development
2.3 The Histology of the Rat Female Reproductive Tract during the Estrous Cycle
2.4 The Histology of the Dog Female Reproductive Tract during the Estrous Cycle
2.5 The Histology of the Cynomolgus Macaque Female Reproductive Tract during the Menstrual Cycle
2.6 The Histology of the Minipig Female Reproductive Tract during the Estrous Cycle
2.7 The Histology of the Rabbit Female Reproductive Tract during the Estrous Cycle
2.8 The Endocrinology of the Estrous and Menstrual Cycles
2.9 Hormonal Events during a Given Reproductive Cycle
2.10 Regulation of Hormonal Secretion
3 Evaluation of Female Reproductive System Toxicity
3.1 Spontaneous Changes in the Female Reproductive System (Table 10.5, Figures 10.24–10.27)
4 Responses to Injury
5 Mechanisms of Toxicity in the Female Reproductive System
5.1 Stress and Negative Energy Balance
5.2 Hyperprolactinemia
5.3 Altered Activity of Sex Steroid Enzymes and Cholesterol Metabolism
5.4 Targeted Cancer Therapies
5.5 Modulation of Central Nervous System Biology
5.6 Toxicity Induced by Constituents of the HPO Axis and Modulators of Nuclear Hormone Receptors
5.7 Toxicity due to Vaginal Irritation
5.8 Study, Interpretative, and Regulatory Issues in Female Reproductive Safety Assessment
6 Carcinogenesis in the Female Reproductive System
6.1 Ovary (Figures 10.32–10.42)
6.2 Uterus (Figures 10.43–10.50)
6.3 Vagina and Cervix (Figures 10.51 and 10.52)
6.4 Clitoral Glands (Figures 10.53–10.55)
7 Conclusion
Chapter 11. Embryo, Fetus, and Placenta
1 Introduction
2 Fundamentals of Developmental Toxicologic Pathology
2.1 Basic Principles
2.2 Critical Phases of Development
2.3 Incidence of Congenital Defects
3 Structure, Function, and Cell Biology—Embryo and Fetus
3.1 Fertilization to Blastocyst Formation
3.2 Implantation
3.3 Gastrulation
3.4 Organogenesis
3.4.1 Induction
3.4.2 Morphogenetic Movements
3.4.3 Morphogen Gradients
3.4.4 Selective Cell Regulation
3.4.5 Programmed Cell Death
3.5 Histogenesis and Functional Maturation
4 Structure, Function, and Cell Biology—Placenta
4.1 Structure
4.2 Cell Biology and Function
4.2.1 Placental Histology
4.2.2 Maternal Endpoints of Developmental Toxicity
5 Evaluation of Toxicity
5.1 Toxicity Testing
5.1.1 In Vitro and Ex Vivo Assays
5.1.2 In Vivo Studies in Animals
5.2 Key Endpoints in Developmental Toxicity Testing
5.2.1 Maternal Endpoints of Developmental Toxicity
5.2.2 Progeny Endpoints of Developmental Toxicity
5.2.3 Differentiating Developmental Toxicity from Maternal Toxicity
6 Responses to Injury
6.1 Death
6.2 Malformations
6.2.1 Central Nervous System
6.2.2 Craniofacial Structures
6.2.3 Cardiovascular System
6.2.4 Respiratory System
6.2.5 Gastrointestinal System
6.2.6 Urinary System
6.2.7 Reproductive System
6.2.8 Skeletal System
6.3 Deformations
6.3.1 Arthrogryposis
6.3.2 Talipes
6.4 Intrauterine Growth Restriction
6.5 In-Life Functional Alterations
6.6 Congenital Neoplasia
7 Mechanisms of Developmental Toxicity
7.1 Excessive Cell Death
7.2 Dysregulated Autophagy
7.3 Interference with Programmed Cell Death (Apoptosis)
7.4 Reduced Cell Proliferation
7.5 Failed Cellular Interactions
7.6 Impeded Morphogenetic Movements
7.7 Reduced Biosynthesis of Essential Components
7.8 Inhibition of Angiogenesis
7.9 Endocrine Disruption
7.10 Oxidative Stress
7.11 Mechanical Disruption
7.12 Intracellular pH Alterations
8 Developmental Toxicity Issues in Product Development
8.1 Biological Factors that Modify Developmental Toxicity
8.1.1 Conceptus
8.1.2 Mother
8.1.3 Father
8.1.4 Placenta
8.2 Study Design Considerations
8.2.1 Hazard Identification and Dose–Response Analysis
9 Regulatory Considerations
9.1 Managing Risk
10 Conclusion
Glossary
Index

Wanda M Haschek

Professor Haschek-Hock has served as president of the Society of Toxicologic Pathology and the Society of Toxicology’s Comparative and Veterinary Specialty Section, as well as Councilor of the American College of Veterinary Pathologists, board member of the American Board of Toxicology; as Associate Editor for Toxicological Sciences and for Toxicologic Pathology; as Editorial Board member for Fundamental and Applied Toxicology, Veterinary Pathology and Toxicologic Pathology. She has served as a member on the USFDA Veterinary Medicine Advisory Committee for the Center for Veterinary Medicine, the EPA’s FIFRA Science Advisory Panel, and National Academy of Sciences Committee. She currently serves on the Board of Directors of the C.L. Davis Foundation for the Advancement of Veterinary and Comparative Pathology. She was awarded the Society of Toxicologic Pathology’s Achievement Award in 2007 and the Midwest Regional Chapter – Society of Toxicology’s Kenneth DuBois Award in 2011.

Affiliations and expertise

Professor Emerita, Dept of Veterinary Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA

Colin G. Rousseaux

Colin G. Rousseaux, BVSc, Ph.D., DABT, FIATP, is also a Fellow of the Royal College of Pathology (FRCPath) and Fellow of the Academy of Toxicological Sciences (FATS). He is a Professor (Adjunct) in the Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, Canada. He has over 35 years of experience in comparative and toxicologic pathology with a research focus on herbal remedies, fetal development and teratology, and environmental pollutants. He has described, investigated, and evaluated numerous toxicologic pathology issues associated with pharmaceuticals, pesticides, and agrochemicals. He has served on the editorial board of Toxicologic Pathology. He is a former President of the STP. Colin served as an Editor for the three editions of the Fundamentals of Toxicologic Pathology and Haschek and Rousseaux’s Handbook of Toxicologic Pathology.

Affiliations and expertise

Adjunct Professor, Department of Pathology and Laboratory Medicine, University of Ottawa Principal, Colin Rousseaux and Associates, Canada

Matthew A. Wallig

Matthew A. Wallig, DVM, Ph.D., DACVP, is Professor Emeritus in the Department of Pathobiology, College of Veterinary Medicine, the Department of Food Science and Human Nutrition, as well as the Division of Nutritional Sciences at the University of Illinois. His research has focused on the chemoprotective properties and mechanisms of phytochemicals in the diet, in particular those in cruciferous vegetables, soy, and tomatoes. His current interests have expanded to include defining morphologic parameters for diagnostic quantitative ultrasound in pancreatitis, pancreatic and hepatic neoplasia, metastatic disease, and chronic hepatic diseases such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Matt has served as an Editor for the last two editions of the Fundamentals of Toxicologic Pathology and Haschek and Rousseaux’s Handbook of Toxicologic Pathology.

Affiliations and expertise

Professor Emeritus, Department of Veterinary Pathobiology, College of Veterinary Medicine University of Illinois at Urbana-Champaign, Urbana, Illinois, USA

Brad Bolon

Brad Bolon, DVM, MS, Ph.D., DAVCP, DABT, FATS, FIATP, FRCPath, has worked [sic] as an experimental and toxicologic pathologist in several settings: academia, a contract research organization, pharmaceutical companies (in both biomolecule and traditional small molecule settings), and private consulting. His main professional interests are the pathology of genetically engineered mice (especially embryos, fetuses, and placentas) and toxicologic neuropathology to assess the efficacy and safety of many therapeutic entities (biomolecules, cell and gene therapies, medical devices, and small molecules). He is a former President of the STP and a Member of the American College of Toxicology (ACT), British Society of Toxicological Pathology (BSTP), and European Society of Toxicologic Pathology (ESTP). Brad served as an Editor for the third edition of the Fundamentals of Toxicologic Pathology and an Associate Editor for the third edition of Haschek and Rousseaux’s Handbook of Toxicologic Pathology.

Affiliations and expertise

President and Pathologist, GEMpath, Inc., Longmont, Colorado, USA

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Wanda M Haschek

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