Toxicologic Pathology: Nonclinical Safety Assessment

Cover
Half Title
Title Page
Copyright Page
Table of Contents
Preface
Acknowledgments
Editors
Contributors
Section I
: Concepts in Drug Development
	Chapter 1: Overview of Drug Development
		1.1 Scientific History
			1.1.1 Origin of Modern Therapeutic Agents
		1.2 Regulatory History
			1.2.1 Regulatory Aspects of Drug Development
			1.2.2 US Food and Drug Law
			1.2.3 European Drug Law
			1.2.4 Japanese Drug Law
			1.2.5 International Harmonization
			1.2.6 Current Regional Regulatory Differences
			1.2.7 Regulatory Review Process
		1.3 Sequence of Small-Molecule Drug Development
			1.3.1 Selection of Areas for Drug Development
			1.3.2 Scientific Expertise Required for Drug Development
			1.3.3 Stages of Drug Development
			1.3.4 Drug Discovery
			1.3.5 Nonclinical Development
			1.3.6 Clinical Development
			1.3.7 Postmarketing
			1.3.8 Decision Process for Advancement or Termination during Drug Development
			1.3.9 Role and Responsibility of Toxicologic Pathologist in Drug Development
		1.4 Approaches to Drug Development of Biotherapeutics
			1.4.1 Approaches to Drug Development of Oligodeoxynucleotide Therapeutics
		1.4.2 Approaches to Drug Development of Gene Therapy Products
		1.5 Time and Resource Utilization in Drug Development
		1.6 Future Changes in Drug Development
		References
	Chapter 2: Nonclinical Safety Evaluation of Drugs
		2.1 Introduction
		2.2 Lead Optimization Safety Assessment
		2.3 Nonclinical Animal Toxicology Studies for Small Molecules
		2.4 Nonclinical Animal Toxicology Studies for Biopharmaceuticals
		2.5 Reversibility/Recovery of Drug-Induced Pathology in Nonclinical Safety Studies
		2.6 Comparing Biopharmaceuticals to Traditional Small-Molecule Drugs
		2.7 Immunotoxicology
		2.8 Safety Pharmacology
		2.9 Development and Reproductive Toxicology
		2.10 Genetic Toxicology
		2.11 Carcinogenicity Testing
		2.12 Safety Assessment of Oncology Products
		2.13 Challenges with Nonclinical Safety Assessment in the NHP
		2.14 Reporting Pathology Data for the Regulatory Scientist and Clinician
		References
	Chapter 3: Nonclinical Safety Evaluation of Advanced Therapies
		3.1 Introduction
		3.2 Cell-based Therapies
			3.2.1 Types
			3.2.2 Safety Concerns
		3.3 Gene Therapies
			3.3.1 Ex Vivo Gene Therapies/Genetically Modified Cell Therapies
			3.3.2 In Vivo Gene Therapies
			3.3.3 T-Cell Based Immunotherapy
			3.3.4 Genome Editing
			3.3.5 Oncolytic Viruses
		3.4 Expression Knockdown Therapies
			3.4.1 Introduction to Expression Knockdown Therapies
			3.4.2 Accumulation Effects: Basophilic Granules and Vacuolated Macrophages
			3.4.3 Proinflammatory Effects
			3.4.4 Renal Effects
			3.4.5 Liver Toxicity
			3.4.6 Thrombocytopenia
			3.4.7 Newer Generation ASO Modalities
		3.5 US FDA/CBER Regulatory Perspective on Cellular and Gene Therapies
		References
	Chapter 4: Nonclinical Safety Evaluation of Medical Devices
		4.1 Introduction
		4.2 Knowledge Base and Scientific Interactions
		4.3 In Vivo Biological Evaluation of Biomaterials and Medical Devices
		4.4 Terminology
			4.4.1 Biomaterials
			4.4.2 Biocompatibility
			4.4.3 Biomaterial Extractables and Leachables
			4.4.4 Medical Device Definition and Examples
			4.4.5 Combination Products
			4.4.6 Maximum Implantable Dose (MID)
			4.4.7 FDA Title 21 Code of Federal Regulations (21 CFR) Definitions
			4.4.8 Premarket Approval (PMA)
			4.4.9 Premarket Notification 510(k)
			4.4.10 Humanitarian Use Device (HUD)
			4.4.11 Investigational Device Exemption (IDE)
			4.4.12 International Medical Device Regulators Forum (IMDRF)
			4.4.13 Other Terms and Definitions
		4.5 Device Materials and Forms
		4.6 Regulatory Oversight
			4.6.1 Global Medical Device Regulatory Agencies
			4.6.2 Comparison of Global Device Classification Categories
			4.6.3 Global Harmonization Task Force (GHTF) and International Medical Device Regulators Forum (IMDRF)
			4.6.4 FDA Medical Device Risk Assessment Approach
			4.6.5 Standards and Guidelines
				4.6.5.1 Good Laboratory Practices (GLP)
				4.6.5.2 International Organization for Standardization (ISO) Guidelines (www.iso.org)
				4.6.5.3 USP Convention (http://www.usp.org)
				4.6.5.4 American Society for Testing and Materials (ASTM; www.astm.org)
				4.6.5.5 Good Manufacturing Practices (GMPs) and Good Clinical Practices (GCPs)
				4.6.5.6 Conformité Européenne  Marking of Medical Device Products
		4.7 Medical Device Testing Requirements
			4.7.1 Study Design Considerations
				4.7.1.1 Variable Pathways to Biocompatibility and Medical Device Testing
				4.7.1.2 Safety, Efficacy, and Effectiveness of a Device
				4.7.1.3 Engineering Design Failure Modes and Effects Analysis (DFMEA) for Risk Assessment
		4.8 General Principles of Medical Device Testing Program
			4.8.1 In Vitro and In Vivo Testing
				4.8.1.1 Overview of Biocompatibility Evaluation Endpoints
			4.8.2 Preliminary In Vitro and In Vivo Biomaterial and Medical Device Tests
				4.8.2.1 Cytotoxicity
				4.8.2.2 Genotoxicity
				4.8.2.3 Sensitization
				4.8.2.4 Pyrogenicity
				4.8.2.5 Leachables and Extractables
				4.8.2.6 Degradation
				4.8.2.7 Hemocompatibility Studies
			4.8.3 In Vivo Biomaterial and Medical Device Biocompatibility and Preclinical Animal Testing
				4.8.3.1 Alternative Testing Procedures, 3Rs and Ethics of Medical Device Testing
				4.8.3.2 Species Selection
				4.8.3.3 Studies with Histopathology Endpoints
					4.8.3.3.1 Irritation Studies
					4.8.3.3.2 Implantation Studies
					4.8.3.3.3 Acute, Subacute, and Chronic Toxicity Studies
				4.8.3.4 Special In Vivo Studies
					4.8.3.4.1 Safety Pharmacology
					4.8.3.4.2 Immunotoxicity
					4.8.3.4.3 Reproductive and Development Toxicity Studies
					4.8.3.4.4 Carcinogenicity Studies/Tumorigenicity of Biomaterials
		4.9 In-Life Observations
			4.9.1 Clinical Observations, Body Weight, and Food Consumption
			4.9.2 Clinical Pathology
		4.10 Local and Systemic Histopathology Assessment of Medical Devices
			4.10.1 Organ Weights
			4.10.2 Gross Pathology and Sample Collection
			4.10.3 Tissue and Device Histological Preservation and Processing
			4.10.4 Microscopic Pathology Assessment
			4.10.5 Microscopic Tissue Responses to Materials and Medical Devices
			4.10.6 Histochemical and Immunohistochemical Staining
			4.10.7 Specialized and High-Resolution Microscopy Techniques
			4.10.8 Quantitative and Semi-Quantitative Grading
			4.10.9 Morphometry and Stereology
			4.10.10 In Vivo Imaging and Computational Modeling
		4.11 Medical Devices in Pediatric Patients and Juvenile Toxicology Testing
		4.12 Special Biomaterials
			4.12.1 Nanomaterials
			4.12.2 Combination Devices and Drug Delivery Products
			4.12.3 Bioengineering, Regenerative Medicine Products, and 3D Printing
		4.13 Clinical Considerations
		4.14 Conclusion
		References
	Chapter 5: Pathology and the Pathologist in Pharmaceutical Research and Development
		5.1 Introduction
		5.2 Toxicologic Pathology
			5.2.1 Introduction: The Role of the Toxicologic Pathologist in Industry
			5.2.2 The Toxicologic Pathologist and the Toxicity Study
			5.2.3 The Study Pathologist Role
			5.2.4 Study Nomenclature
			5.2.5 Study Results and Interpretation
			5.2.6 Approaches and Challenges of Toxicologic Histopathology
			5.2.7 Toxicologic Pathology Training, Career Directions, Specialization, and Organizations
		5.3 Investigative Pathology in Pharmaceutical R&D
			5.3.1 Introduction
			5.3.2 Selection and Evaluation of Drug Targets
			5.3.3 The Use and Evaluation of Genetically Modified Animals
			5.3.4 Early Evaluation of Drug Effects
			5.3.5 Pathophysiology of the Findings
			5.3.6 Biomarkers
		5.4 The Future of Pathology in R&D
			5.4.1 Introduction
			5.4.2 Advances in Technology
			5.4.3 Data Generation, Handling, and Integration
			5.4.4 Human Systems and Data
			5.4.5 Regulatory (Societal) Environment and Expectations
			5.4.6 The Individual Pathologist in the Future
		References
	Chapter 6: Routine and Special Techniques in Toxicologic Pathology
		6.1 Introduction
		6.2 Routine Techniques
			6.2.1 Necropsy Procedures
				6.2.1.1 Terminal Procedures
					6.2.1.1.1 Euthanasia
						6.2.1.1.1.1  Sodium Pentobarbital An overdose of this injectable anesthetic agent will provide rapid euthanasia. After the animal is no longer responsive to the external stimuli (gauged by toe pinch response, etc.), the chest and abdominal cavities should
						6.2.1.1.1.2  Methoxyflurane or Isoflurane Methoxyflurane and isoflurane are both inhalation anesthetic agents; overdose will provide euthanasia. As with sodium pentobarbital, euthanasia should be followed by exsanguination. Methoxyflurane or isoflurane ma
						6.2.1.1.1.3  Carbon Dioxide Exposure to high concentrations of carbon dioxide followed by exsanguination is a commonly used euthanasia agent for rodents, since it is inexpensive and relatively easy to use. AVMA guidelines on avoidance of prefilled chamber
						6.2.1.1.1.4  Other Methods of Euthanasia Specialized studies may require alternative methods of euthanasia. Cervical dislocation and decapitation are both used in some cases. Both of these methods require extensive training to ensure that the method of eu
					6.2.1.1.2 Blood and Urine Collection
				6.2.1.2 Dissection and Gross Examination
					6.2.1.2.1 External Examination
					6.2.1.2.2 Internal Examination
					6.2.1.2.3 Eyes, Optic Nerves, Harderian/Lacrimal Glands
					6.2.1.2.4 Brain
					6.2.1.2.5 Pituitary
					6.2.1.2.6 Nasal Turbinates and Zymbal’s Glands
					6.2.1.2.7 Skin and Mammary Gland
					6.2.1.2.8 Thoracic Cavity
					6.2.1.2.9 Thoracic Pluck
					6.2.1.2.10 Abdominal Cavity
					6.2.1.2.11 Urogenital Tract
					6.2.1.2.12 Skeletal Muscle and Sciatic Nerve
					6.2.1.2.13 Spinal Cord
				6.2.1.3 Description of Gross Lesions
				6.2.1.4 Organ Weights
				6.2.1.5 Tissue Fixation
					6.2.1.5.1 Neutral Buffered Formalin
					6.2.1.5.2 Bouin’s Fluid
					6.2.1.5.3 Modified Davidson’s Fluid
					6.2.1.5.4 McDowell’s and Trump’s 4F:1G Fixative
					6.2.1.5.5 Alcohol Fixation
					6.2.1.5.6 Fixation Techniques
					6.2.1.5.7 Immersion
					6.2.1.5.8 Inflation
					6.2.1.5.9 Perfusion
			6.2.2 Histology Procedures
				6.2.2.1 Trimming
				6.2.2.2 Processing
					6.2.2.2.1 Dehydration
					6.2.2.2.2 Clearing
					6.2.2.2.3 Infiltration
				6.2.2.3 Embedding
				6.2.2.4 Sectioning (Microtomy)
				6.2.2.5 Staining
					6.2.2.5.1 Routine H&E
					6.2.2.5.2 Special Stains
						6.2.2.5.2.1  Periodic Acid–Schiff Periodic acid–Schiff (PAS) is a staining method most often used to identify the presence of glycogen in tissue sections. The periodic acid oxidizes glucose residues in tissue, creating aldehydes that then react with the S
						6.2.2.5.2.2  Toluidine Blue Toluidine blue (T-blue) is a cationic basic stain that stains the granules in mast cells violet red. T-blue interacts with the acidic heparin in the mast cell granules to produce the characteristic violet red color. T-blue also
						6.2.2.5.2.3  Oil Red O Oil Red O is used to demonstrate the presence of neutral lipids in tissue sections. This technique can only be used on unprocessed (unfixed frozen or formalin-fixed but unprocessed) tissue samples. If the tissue has undergone proces
						6.2.2.5.2.4  Trichrome Many trichrome stains (trichrome means three colors) are available for the differential staining of tissues, with Masson’s trichrome being one of the most commonly used. Masson’s trichrome stains collagen blue, muscle red, and eryth
						6.2.2.5.2.5  Perls’ Iron/Perls’ Prussian Blue Perls’ iron is the classic stain for demonstrating the presence of hemosiderin (ferric iron) in tissue. The iron granules in hemosiderin, as well as other iron deposits (e.g., hemochromatosis), react to form a
						6.2.2.5.2.6  Von Kossa’s Method Von Kossa’s method is used to visualize calcium deposits in tissue sections. Using this method, calcium stains brown to black.
						6.2.2.5.2.7  Luxol Fast Blue A number of specialized stains are used in neuropathology. The luxol fast blue stain for the myelin sheath is one of the most commonly used. The stain reacts with the lipoprotein in myelin. With this stain, myelinated nerve fi
						6.2.2.5.2.8  Fluoro-Jade B Fluoro-Jade B is an anionic fluorescein compound with an affinity for degenerating neurons. With this stain, degenerating neurons appear yellow-green when evaluated with a fluorescent light source and fluorescein isothiocyanate
				6.2.2.6 Coverslipping
				6.2.2.7 Histotechnique Quality Assessment
		6.3 Special Techniques
			6.3.1 Introduction
			6.3.2 Imaging Methods
				6.3.2.1 Electron Microscopy
				6.3.2.2 Fluorescence Microscopy
					6.3.2.2.1 Conventional Wide-Field Fluorescence Microscopy
					6.3.2.2.2 Confocal Microscopy
				6.3.2.3 Digital Microscopy
					6.3.2.3.1 Virtual Slides
					6.3.2.3.2 Quantitative Image Analysis
						6.3.2.3.2.1  Histomorphometry The first step in histomorphometry is to segment the objects of interest from the rest of the specimen. Common measurements include length, perimeter, area, intensity, and number. Some examples include the following: counts o
						6.3.2.3.2.2  Stereology Stereology refers to the statistical derivation of three-dimensional data based on measurements of two-dimensional tissue sections (Weibel et al. 1966). Stereologic assessments require planning prior to necropsy since the entire or
				6.3.2.4 Noninvasive (In Vivo) Imaging
					6.3.2.4.1 Morphologic/Anatomic Imaging Techniques (MRI, CT, and US)
						6.3.2.4.1.1  Magnetic Resonance Imaging MRI uses nuclear magnetic resonance, and the signal is primarily derived from the hydrogen nuclei (protons) of water molecules. The technique uses a powerful magnetic field to align the magnetization of atoms in the
						6.3.2.4.1.2  Computed Tomography In CT, x-rays are emitted from an x-ray source rotating around the subject placed in the center. A detector opposite the x-ray source detects the amount of x-rays that are not absorbed by the tissue, and this absorption is
						6.3.2.4.1.3  Ultrasound US uses high-frequency sound waves emitted from a transducer and analyzes the returning echoes from the tissue to provide an image of the plane being scanned. With higher frequencies, resolution improves but penetration decreases.
					6.3.2.4.2 Functional/Biochemical/Molecular Imaging Techniques (Optical Imaging, PET, and SPECT)
						6.3.2.4.2.1  Optical Imaging In vivo optical imaging includes fluorescence and bioluminescence imaging. Both techniques are highly sensitive (picomolar) at limited depths of a few millimeters; quick and easy to perform (with a high-throughput capability);
						6.3.2.4.2.2  Positron Emission Tomography In PET imaging, a compound (natural biologic molecule or drug) labeled with a positron emitting radioisotope, which generally does not affect the physical or biochemical behavior of the compound, is injected into
						6.3.2.4.2.3  Single-Photon Emission Computed Tomography SPECT imaging mainly detects gamma rays emitted from a radionuclide in the living animal and shares many of the same features as PET imaging, such as the ability to localize and quantify radiolabeled
				6.3.2.5 Digital Image Data and Compliance with GLP Regulations
			6.3.3 In Situ Protein, DNA, and RNA Assays
				6.3.3.1 Immunolabeling (IHC and Immunofluorescence)
					6.3.3.1.1 Antibodies
					6.3.3.1.2 Fixation and Antigen Retrieval (Demasking)
					6.3.3.1.3 Antibody Labeling Methods (Detection Systems)
					6.3.3.1.4 Controls
					6.3.3.1.5 Tissue Cross-Reactivity Studies
				6.3.3.2 Probe Hybridization Labeling (Chromogenic In Situ Hybridization and FISH)
			6.3.4 Laser Microdissection
			6.3.5 Flow Cytometry and Fluorescence-Activated Cell Sorting
			6.3.6 Laser Scanning Cytometry
		References
			Routine Techniques
			Special Techniques
	Chapter 7: Principles of Clinical Pathology
		7.1 Introduction
		7.2 Study Design Factors
			7.2.1 Test Selection
			7.2.2 Test Frequency and Timing
			7.2.3 Sources of Variability
		7.3 Data Interpretation
			7.3.1 Reversibility
			7.3.2 Reference Intervals
		7.4 Interpretation of Hematology Data
			7.4.1 Erythrocytes, Leukocytes, and Platelets
			7.4.2 Increased Red Cell Mass
			7.4.3 Decreased Red Cell Mass
				7.4.3.1 Blood Loss
				7.4.3.2 Hemolysis
				7.4.3.3 Bone Marrow Toxicity
				7.4.3.4 Indirect Causes of Nonregenerative Conditions
			7.4.4 Physiological Leukocytosis
			7.4.5 Stress-Induced Leukocyte Response
			7.4.6 Inflammation
			7.4.7 Miscellaneous Effects on Leukocytes
			7.4.8 Platelets
			7.4.9 Bone Marrow Smear Evaluation
			7.4.10 Coagulation
		7.5 Clinical Chemistry Tests and Interpretation
			7.5.1 Tests of Liver Integrity and Function
				7.5.1.1 Enzymes
				7.5.1.2 Bilirubin
				7.5.1.3 Markers of Liver Function
			7.5.2 Tests of Kidney Function
			7.5.3 Proteins, Carbohydrates, and Lipids
				7.5.3.1 Serum Proteins
				7.5.3.2 Serum Glucose
				7.5.3.3 Serum Lipids
			7.5.4 Minerals and Electrolytes
				7.5.4.1 Serum Calcium and Inorganic Phosphorus
				7.5.4.2 Serum Sodium, Potassium, and Chloride
				7.5.4.3 Miscellaneous Serum Chemistry Tests
		7.6 Urinalysis, Urine Chemistry, and Biomarker Tests, and Interpretation
			7.6.1 Urinalysis
				7.6.1.1 Physicochemical Properties of Urine
				7.6.1.2 Reagent Strip Tests
				7.6.1.3 Microscopic Evaluation of Urine Sediment
			7.6.2 Urine Chemistry Tests
			7.6.3 Urine Biomarkers
		7.7 Safety Biomarkers as Adjunct Tests
			7.7.1 Cardiac Injury Biomarkers
			7.7.2 Protein Biomarkers of Inflammation and Immune Response
			7.7.3 Exploratory Biomarkers for Liver Injury
			7.7.4 Exploratory Biomarkers for Skeletal Muscle Injury
		References
	Chapter 8: Toxicokinetics and Drug Disposition
		8.1 Introduction and Objective
		8.2 Importance of Exposure-Based Interpretation
		8.3 TK or PK Parameters: What They Are, How They Are Derived, and What They Mean
			8.3.1 Plasma Concentration–Time Curves: Where the Numbers Come from
			8.3.2 TK Parameters Derived from Raw Data
			8.3.3 TK Parameters Derived from Transformed Data
			8.3.4 Multiple Dose TK Parameters: Accumulation
		8.4 Importance of Experimental Design and Data Presentation
		8.5 Important Chemical and Biological Factors Governing TK: Absorption, Distribution, Metabolism, Excretion, and Transport
			8.5.1 Factors Governing Oral Absorption
			8.5.2 Species Differences in GI Physiology
			8.5.3 Drug Distribution, Protein Binding, and the Importance of Free (Unbound) Drug and Regulation of Concentrations in Privileged Sites
			8.5.4 Determining Tissue Distribution: Quantitative Whole-Body Autoradiography (QWBA), Microautoradiography (MARG), and Mass Spectrometric Imaging (MSI)
			8.5.5 Examples of Sex and Species Differences in Drug Metabolism
				8.5.5.1 Sex Differences in CYP Metabolism in Rodents
				8.5.5.2 Species Differences in Metabolic Enzymes and Induction
				8.5.5.3 Species Differences in Transporters
		8.6 Summary
		References
	Chapter 9: Toxicogenomics in Toxicologic Pathology
		9.1 Introduction
			9.1.1 –Omics: The Basics
			9.1.2 The –Omics Revolution
			9.1.3 Basic Array Technologies
			9.1.4 The Toxicologic Pathologist’s Role in Toxicogenomics
			9.1.5 Pathway and Network Analyses
			9.1.6 Applications of Toxicogenomics
				9.1.6.1 Phenotypic Anchoring
			9.1.7 Predictive vs Mechanistic Toxicogenomics
			9.1.8 Prediction of Carcinogens Using Toxicogenomics
				9.1.8.1 Genotoxic vs Nongenotoxic
			9.1.9 Toxicogenomics and Risk Assessment
			9.1.10 Toxicogenomic Profiling of Hepatotoxicity
			9.1.11 Toxicogenomic Profiling of Nephrotoxicity
			9.1.12 Toxicogenomic Profiling of Cardiotoxicity
			9.1.13 Toxicogenomic Databases
		9.2 Summary and Conclusions
		Glossary
		References
	Chapter 10: Spontaneous Lesions in Control Animals Used in Toxicity Studies
		10.1 Introduction
		10.2 Rat
		10.3 Mouse
		10.4 Dog
		10.5 Monkey
		10.6 Minipig
		10.7 Summary
		References
Section II
: Organ Systems
	Chapter 11: Gastrointestinal Tract
		11.1 Introduction
		11.2 Embryology
		11.3 Functional Anatomy
			11.3.1 Oral Cavity
			11.3.2 Tongue
			11.3.3 Salivary Glands
			11.3.4 Esophagus
			11.3.5 Stomach
			11.3.6 Small and Large Intestines
			11.3.7 Intestinal Absorption and Secretion
			11.3.8 Biotransformation
			11.3.9 Enterohepatic Circulation
			11.3.10 Bacteria
			11.3.11 Lymphoid Tissue
			11.3.12 Enteric Nervous System
		11.4 Nonproliferative and Proliferative Morphologic Responses
			11.4.1 Oral Cavity and Tongue
				11.4.1.1 Proliferative Changes of Oral Cavity and Tongue
					11.4.1.1.1 Hyperplasia, Squamous Cell
					11.4.1.1.2 Papilloma, Squamous Cell
					11.4.1.1.3 Carcinoma, Squamous Cell
					11.4.1.1.4 Sarcoma
			11.4.2 Salivary Glands
				11.4.2.1 Proliferative Changes of Salivary Glands
					11.4.2.1.1 Hyperplasia
					11.4.2.1.2 Adenoma
					11.4.2.1.3 Adenocarcinoma
					11.4.2.1.4 Squamous Cell Carcinoma
					11.4.2.1.5 Myoepithelioma
					11.4.2.1.6 Tumor, Mixed and Benign
					11.4.2.1.7 Tumor, Mixed Malignant
					11.4.2.1.8 Mesenchymal Tumors, Benign and Malignant
			11.4.3 Esophagus
				11.4.3.1 Proliferative Changes of Esophagus
					11.4.3.1.1 Hyperplasia, Squamous Cell
					11.4.3.1.2 Papilloma, Squamous Cell
					11.4.3.1.3 Carcinoma, Squamous Cell
			11.4.4 Stomach
				11.4.4.1 Nonglandular Stomach
					11.4.4.1.1 Proliferative Changes of Nonglandular Stomach
						11.4.4.1.1.1  Hyperplasia, Squamous Cell—Focal, Multifocal, or Diffuse The hyperplasia at the border of the nonglandular (fore) stomach and glandular stomach (limiting ridge) is normal. Hyperkeratosis alone should be distinguished from hyperplasia. Acanth
						11.4.4.1.1.2  Hyperplasia, Basal Cell Proliferation of basal cells focally or diffusely characterized by increased basophilic staining. Foci of basal cell hyperplasia are not uncommon at the limiting ridge; it is recommended to be recorded as nonglandular
						11.4.4.1.1.3  Papilloma, Squamous Cell—Exophytic, Endophytic Benign tumors are usually exophytic squamous papillomas, with a single or branched connective tissue stalk or multiple papillae, and may arise within the area of epithelial hyperplasia (Fukushim
						11.4.4.1.1.4  Squamous Cell Carcinoma Squamous cell carcinomas display epithelial nests (with or without keratinized cysts) or cords showing true invasion of the submucosa, often arising in the base of papillomas (Figure 11.13c,d). The poorly differentiat
				11.4.4.2 Glandular Stomach
					11.4.4.2.1 Proliferative Changes of Glandular Stomach
						11.4.4.2.1.1  Hyperplasia, Mucosa Focal or Diffuse The oxyntic (fundic) mucosa has deep glands with long cell life span (100+ days) and gastric pits above proliferative zone (life span approximately 6 days). Hypertrophy and hyperplasia can be observed wit
						11.4.4.2.1.2  Neuroendocrine Cells Hyperplasia Neuroendocrine cells (formerly cells of the APUD system) were all thought to originate from the neural crest. However, pancreatic-­gastroenteral endocrine cells are able to proliferate from progenitor cells i
						11.4.4.2.1.3  Neuroendocrine Tumor: Benign/Malignant (Synonym: Gastric Carcinoid) ​Neuroendocrine ECL cells are situated in the basal part of the oxyntic glands and undergo diffuse then focal hyperplasia following prolonged marked hypergastrinemia. Cluste
						11.4.4.2.1.4  Adenoma: Polypoid, Papillary, Sessile The earliest dysplastic lesions seen are altered single basophilic glands with hyperchromatic nuclei (Figure 11.18a) and usually arise in the antral mucosa. Benign exocrine tumors show atypical architect
						11.4.4.2.1.5  Adenocarcinoma Malignancy is based on invasion of muscularis mucosa (Figure 11.18c) or budding into lamina propria. Tumors may be tubular endophytic, nodular, cystic, or solid, composed of either cuboidal cells with varying polarity and roun
						11.4.4.2.1.6  GI Stromal Tumor—Benign/Malignant In humans, nearly all GI stromal tumors (GIST) are classified on the basis of c-kit gene CD117 expression; these soft tissue tumors are believed to derive from the interstitial cells of Cajal, which have bot
						11.4.4.2.1.7  Leiomyoma Leiomyoma is a benign smooth muscle cell tumor, composed of well-circumscribed bundles and whorls of spindle-shaped smooth muscle cells with abundant eosinophilic cytoplasm. Cytoplasm is positive for smooth muscle-specific actin an
						11.4.4.2.1.8  Leiomyosarcoma Leiomyosarcoma is composed of smooth muscle cells derived from mesenchymal stem cells and characterized by the presence of interwoven bundles of eosinophilic spindle cells with cigar-shaped blunt-ended nuclei (Figure 11.14d).
						11.4.4.2.1.9  Sarcoma, NOS (Synonym: Sarcoma Undifferentiated) This is a malignant tumor derived from mesenchymal stem cells comprising poorly differentiated round or spindle cells exhibiting pleomorphism and anaplasia. Differential diagnoses for mesenchy
			11.4.5 Small and Large Intestines
				11.4.5.1 Proliferative Changes of Small and Large Intestines
					11.4.5.1.1 Hyperplasia, Mucosa
					11.4.5.1.2 Atypical Hyperplasia
					11.4.5.1.3 Avillous Hyperplasia
					11.4.5.1.4 Adenoma, Polypoid, Papillary, or Sessile
					11.4.5.1.5 Adenocarcinoma
					11.4.5.1.6 Mucinous Adenocarcinoma
					11.4.5.1.7 Mesenchymal Benign and Malignant Tumors
		11.5 Methods of Evaluation
			11.5.1 Assessment of Structural Integrity and Biomarkers
			11.5.2 Assessment of Proliferation of Mucosal Cells
			11.5.3 Toxicogenomics and Metabonomics
		11.6 Animal Models
			11.6.1 Sjögren’s Syndrome
			11.6.2 Gastritis
			11.6.3 Mucositis
			11.6.4 Inflammatory Bowel Disease
			11.6.5 Models of Colorectal Neoplasia
			11.6.6 Porcine Models in Biomedical Research
		References
	Chapter 12: Liver, Gallbladder, and Exocrine Pancreas
		12.1 Liver
			12.1.1 Introduction
			12.1.2 Hepatocellular Degeneration, Necrosis, and Regeneration
				12.1.2.1 Morphological Patterns of Hepatocellular Necrosis
				12.1.2.2 Clinical Chemistry Biomarkers of Hepatocellular Injury
				12.1.2.3 Differential Diagnosis
				12.1.2.4 Significance in Safety Assessment
			12.1.3 Cellular Adaptations and Accumulations
				12.1.3.1 Alterations in Hepatocyte Size and Number
				12.1.3.2 Cytoplasmic Accumulations and Inclusions (Nonpigment)
				12.1.3.3 Glycogen
				12.1.3.4 Cytokeratin
				12.1.3.5 Drug or Drug Metabolite
				12.1.3.6 Cytoplasmic Pigments
			12.1.4 Nuclear Alterations
				12.1.4.1 Multinucleated Hepatocytes
			12.1.5 Biliary Changes, Nonneoplastic
			12.1.6 Interstitial and Vascular Changes, Nonneoplastic
				12.1.6.1 Hepatic Inflammatory Cells, Kupffer Cells, and Hematopoietic Cells
			12.1.7 Endothelial Cell Response
			12.1.8 Stellate Cell Response
			12.1.9 Hepatic Proliferative Lesions
				12.1.9.1 Hepatocytes
				12.1.9.2 Hepatoblastoma
				12.1.9.3 Bile Duct Epithelium
				12.1.9.4 Endothelial Tumors
				12.1.9.5 Stellate Cell Tumors (Ito Cell Tumors)
				12.1.9.6 Kupffer Cell Tumors
				12.1.9.7 Histiocytic Sarcoma
		12.2 Gallbladder
		12.3 Exocrine Pancreas
			12.3.1 Introduction
			12.3.2 Embryology
			12.3.3 Gross Anatomy
			12.3.4 Microscopic Anatomy
			12.3.5 Immunohistochemical Markers
			12.3.6 Physiology of Secretion
			12.3.7 Pathology of Exocrine Pancreas
				12.3.7.1 Secretory Depletion, Acinar Cells
				12.3.7.2 Increased Zymogen Granules
				12.3.7.3 Vacuolation
				12.3.7.4 Apoptosis, Necrosis, and Regeneration of Acinar Epithelium
				12.3.7.5 Inflammation (Pancreatitis)
				12.3.7.6 Ductular Metaplasia (Tubular Complexes)
				12.3.7.7 Acinar Cell Injury at the Endocrine–Exocrine Interface
				12.3.7.8 Incretin-Based Therapeutics
				12.3.7.9 Metaplasia, Hepatocytic (Pancreatic Hepatocytes)
				12.3.7.10 Pancreatic Proliferative Lesions
			12.3.8 Biomarkers
		References
	Chapter 13: Respiratory System
		13.1 General Introduction
		13.2 Embryology of the Respiratory System
		13.3 Functional Anatomy of the Respiratory System
			13.3.1 Nasal Cavity
			13.3.2 Pharynx
			13.3.3 Larynx
			13.3.4 Trachea and Airways
			13.3.5 Lung
			13.3.6 Alveolar Macrophage
			13.3.7 Mucins and Surfactant in Lungs and Airways
				13.3.7.1 Mucins
				13.3.7.2 Surfactant
		13.4 Ancillary Tests of Respiratory System Function or Damage
		13.5 Nonneoplastic Nasal Cavity Findings
			13.5.1 Atrophy
			13.5.2 Degeneration
			13.5.3 Necrosis
			13.5.4 Eosinophilic Globules (Inclusions, Droplets)
			13.5.5 Erosion/Ulceration
			13.5.6 Regeneration
			13.5.7 Inflammation
				13.5.7.1 Acute Inflammation (Inflammation, Neutrophilic)
				13.5.7.2 Chronic Inflammation (Inflammation, Mononuclear/Lymphohistiocytic)
				13.5.7.3 Chronic Active Inflammation
				13.5.7.4 Granulomatous Inflammation
			13.5.8 Nasal-Associated Lymphoid Tissue
			13.5.9 Vascular Changes
			13.5.10 Hyperplasia
				13.5.10.1 Epithelial (Squamous, Respiratory, Olfactory, Transitional)
				13.5.10.2 Goblet (Mucous) Cell Hyperplasia
				13.5.10.3 Basal Cell Hyperplasia
			13.5.11 Metaplasia
		13.6 Neoplastic Nasal Cavity Changes
			13.6.1 Squamous Cell Papilloma
			13.6.2 Adenoma
			13.6.3 Squamous Cell Carcinoma
			13.6.4 Adenocarcinoma
			13.6.5 Adenosquamous Carcinoma
			13.6.6 Neuroepithelial Carcinoma (Olfactory Neuroblastoma)
		13.7 Larynx, Trachea, and Bronchi
			13.7.1 Epithelial Degeneration and Regeneration of Larynx and Airways
			13.7.2 Necrosis
			13.7.3 Erosion/Ulceration
			13.7.4 Ectasia of Submucosal Glands
			13.7.5 Inflammation
			13.7.6 Hyperplasia
			13.7.7 Squamous Metaplasia
		13.8 Bronchioles
			13.8.1 Club Cell Changes
				13.8.1.1 Club Cell Hypertrophy
				13.8.1.2 Club Cell Inclusions
				13.8.1.3 Club Cell Degeneration/Necrosis
				13.8.1.4 Mucous Cell Metaplasia
				13.8.1.5 Club Cell Proliferation
				13.8.1.6 Club Cell Phospholipidosis
				13.8.1.7 Club Cell Lipid Vacuolation
			13.8.2 Bronchiolar Microlithiasis
			13.8.3 Airway Wall Remodeling
			13.8.4 Bronchiolitis Obliterans
			13.8.5 Bronchiolization
			13.8.6 Neoplastic Changes in Larynx and Trachea and Airways
				13.8.6.1 Papilloma
				13.8.6.2 Squamous Cell Carcinoma
				13.8.6.3 Adenocarcinoma
		13.9 Lung Parenchyma
			13.9.1 Macrophage Reactions
			13.9.2 Foamy Macrophage Reactions
				13.9.2.1 Phospholipidosis
				13.9.2.2 Pulmonary Alveolar Proteinosis
			13.9.3 Pigmented AM Reactions
			13.9.4 Interstitial Macrophage Reactions
			13.9.5 Subpleural/Pleural Macrophage Reactions
			13.9.6 Intravascular Macrophage Reactions
			13.9.7 Reversibility/Adversity of Macrophage Reactions
			13.9.8 Type II Pneumocyte Hypertrophy
			13.9.9 Type II Pneumocyte Hyperplasia
			13.9.10 Surfactant Dysfunction
			13.9.11 Diffuse Alveolar Damage
		13.10 Inflammatory Reactions in the Lung
			13.10.1 Acute Inflammatory Reactions
			13.10.2 Chronic Inflammatory Reactions
			13.10.3 Granulomatous Inflammatory Reactions
			13.10.4 Regional Lymph Node/BALT Reactions
			13.10.5 Pneumonia
			13.10.6 Eosinophilic Crystalline Pneumonia
		13.11 Pulmonary/Pleural Fibrosis
		13.12 Emphysema
		13.13 Alveolar Interstitial Mineralization
		13.14 Alveolar Microlithiasis
		13.15 Vascular Lesions
			13.15.1 Perivascular Eosinophil Accumulation
			13.15.2 Edema
			13.15.3 Embolism
			13.15.4 Alveolar Hemorrhage
			13.15.5 Pulmonary Arteriopathy
			13.15.6 Vascular Mineralization
			13.15.7 Bronchial Arteriopathy
			13.15.8 Congestion
		13.16 Neoplastic Changes in Lungs
			13.16.1 Bronchioloalveolar Adenoma
			13.16.2 Cystic Keratinizing Epithelioma
			13.16.3 Bronchioloalveolar Carcinoma
		Acknowledgments
		References
	Chapter 14: Urinary System
		14.1 Kidney
			14.1.1 Introduction
				14.1.1.1 Functional Anatomy
				14.1.1.2 Embryology
				14.1.1.3 Ancillary Tests of Renal Function or Damage
			14.1.2 Glomerular Changes
				14.1.2.1 Glomerulonephritis
				14.1.2.2 Mesangioproliferative Glomerulopathy
				14.1.2.3 Hyperplasia, Mesangial
				14.1.2.4 Glomerulosclerosis
				14.1.2.5 Hyaline Glomerulopathy
				14.1.2.6 Mesangiolysis
				14.1.2.7 Amyloidosis
			14.1.3 Glomerular Atrophy
				14.1.3.1 Bowman’s Space Enlargement
				14.1.3.2 Metaplasia and Hyperplasia of Bowman’s Capsule
			14.1.4 Tubule Changes
				14.1.4.1 Tubule Degeneration and Tubule Basophilia
				14.1.4.2 Vacuolation
				14.1.4.3 Renal Phospholipidosis
				14.1.4.4 Pigmentation and Inclusion Bodies
				14.1.4.5 Diabetic Nephropathy and Tubule Glycogenosis
				14.1.4.6 Tubule Dilation and Cystic Tubules
				14.1.4.7 Casts
				14.1.4.8 Necrosis
				14.1.4.9 Infarction
				14.1.4.10 Tubule Atrophy
				14.1.4.11 Tubule Regeneration
				14.1.4.12 Karyomegaly
				14.1.4.13 Tubule Hypertrophy
				14.1.4.14 Chronic Progressive Nephropathy
				14.1.4.15 Hyaline Droplets and α-2U-Globulin Nephropathy
				14.1.4.16 Crystalluria, Obstructive Nephropathy, and Retrograde Nephropathy
				14.1.4.17 Papillary Changes
				14.1.4.18 Papillary Necrosis
				14.1.4.19 Pyelonephritis
			14.1.5 Interstitial and Vascular Changes
				14.1.5.1 Interstitial Inflammation and Interstitial Nephritis
				14.1.5.2 Interstitial Fibrosis
				14.1.5.3 Periarteritis and Vasculitis
				14.1.5.4 Lesions of the Renal Pelvis
				14.1.5.5 Hydronephrosis
				14.1.5.6 Miscellaneous Lesions of the Kidney
					14.1.5.6.1 Mineralization
					14.1.5.6.2 Pigmentation
				14.1.5.7 Inclusion Bodies
					14.1.5.7.1 Adipose Aggregates
					14.1.5.7.2 Juxtaglomerular Hyperplasia
					14.1.5.7.3 Congenital Lesions
					14.1.5.7.4 Renal Dysplasia
			14.1.6 Hyperplastic and Neoplastic Changes
				14.1.6.1 Hyperplastic Lesions
				14.1.6.2 Renal Tubule Hyperplasia
				14.1.6.3 Renal Pelvis
				14.1.6.4 Neoplastic Lesions of the Kidney
				14.1.6.5 Renal Tubule Neoplasms
					14.1.6.5.1 Adenoma
					14.1.6.5.2 Carcinoma
					14.1.6.5.3 Familial Adenoma/Carcinoma
				14.1.6.6 Connective Tissue Neoplasms
					14.1.6.6.1 Lipoma/Liposarcoma
					14.1.6.6.2 Renal Mesenchymal Tumor
				14.1.6.7 Embryonic Primordium Neoplasia
					14.1.6.7.1 Nephroblastemosis/Nephroblastoma
				14.1.6.8 Fibrosarcoma/Sarcoma
				14.1.6.9 Hematogenous/Metastatic Neoplasms
				14.1.6.10 Neoplasms of the Renal Pelvis
					14.1.6.10.1 Papilloma
					14.1.6.10.2 Carcinoma
		14.2 Urinary Bladder, Ureters, and Urethra
			14.2.1 Nonneoplastic Lesions of the Lower Urinary Tract
			14.2.2 Hyperplastic Lesions of the Lower Urinary Tract
			14.2.3 Neoplastic Lesions of the Lower Urinary Tract
				14.2.3.1 Papilloma
				14.2.3.2 Carcinoma
				14.2.3.3 Squamous Cell Carcinoma
				14.2.3.4 Adenocarcinoma
				14.2.3.5 Connective Tissue and Smooth Muscle Neoplasms
				14.2.3.6 Mesenchymal Proliferation Lesion
				14.2.3.7 Hematogenous/Metastatic Neoplasms
		References
	Chapter 15: Hematopoietic System
		15.1 Introduction
		15.2 Ontogeny
		15.3 Anatomy and Physiology
			15.3.1 Sites and Macroscopic Appearance
			15.3.2 Microscopic Structure and Cellular Composition
			15.3.3 Cytologic Appearance of Hematopoietic Cells
			15.3.4 Hematopoiesis
		15.4 Bone Marrow Evaluation
			15.4.1 Histopathologic Collection, Processing, and Evaluation
			15.4.2 Cytologic Sample Collection, Processing, and Evaluation
			15.4.3 Additional Bone Marrow Evaluations
		15.5 Alterations in Hematopoiesis
			15.5.1 Generalized Hematopoietic Cell Increases or Decreases
			15.5.2 Increases in Erythroid, Myeloid, and Megakaryocytic Numbers
			15.5.3 Decreases in Erythroid, Myeloid, and Megakaryocytic Numbers
			15.5.4 Hematopoietic Cell Dysplasia
			15.5.5 Reactivity and Inflammation
			15.5.6 Necrosis
			15.5.7 Stromal Alterations and Proliferations
			15.5.8 Fibrosis/Myelofibrosis
			15.5.9 Fibro-Osseous Proliferations
			15.5.10 Focal Lipomatosis
			15.5.11 Serous Atrophy of Fat/Gelatinous Transformation
			15.5.12 Neoplasia
		References
	Chapter 16: The Lymphoid System
		16.1 Introduction
		16.2 Review of the “Best Practice Guideline for the Routine Pathology Evaluation of the Immune System” and the Importance of Compartmental Analysis of Lymphoid Organs
		16.3 Thymus
			16.3.1 Thymus Structure: Historical Perspective
			16.3.2 Thymus Structure: Species Differences
			16.3.3 Thymus: Growth and Development
			16.3.4 Thymus: Function
			16.3.5 Thymus: The Conundrum of Involution versus Pathobiology
		16.4 Spleen
			16.4.1 Spleen: Historical Perspective
			16.4.2 Spleen: White Pulp
				16.4.2.1 PALS and Lymphoid Follicles
				16.4.2.2 Marginal Zone, Mantle Zone, and Marginal Sinus
			16.4.3 Spleen: Red Pulp
				16.4.3.1 Blood Flow and Filtration
			16.4.4 Spleen: Structure Recapitulates Function
				16.4.4.1 Defensive Spleen
				16.4.4.2 Storage Spleen
				16.4.4.3 Intermediate Spleen
				16.4.4.4 Hematopoeisis
				16.4.4.5 Lymphopoiesis
			16.4.5 Spleen: Histopathology
		16.5 Lymph nodes
			16.5.1 Lymph Nodes: Historic Perspective
			16.5.2 Lymph Nodes: Structure and Species Differences
			16.5.3 Lymphoid Follicle: Functional Anatomical Dynamics
			16.5.4 Lymph Node: Histopathology
		16.6 Mucosal Associated Lymphoid Tissue
			16.6.1 Bronchus-Associated Lymphoid Tissue
			16.6.2 Nasal-Associated Lymphoid Tissue
			16.6.3 Gut-Associated Lymphoid Tissue
			16.6.4 GALT: Histopathology
		16.7 Bone Marrow: Lymphopoiesis
		16.8 Immunotoxicity versus Stress, The Hobgoblin of Toxicologic Pathology
		16.9 Lymphoid Neoplasia of Mice and Rats
			16.9.1 Small Lymphocyte: B- or T-Cell Origin
			16.9.2 Follicular/Pleomorphic Lymphoma
			16.9.3 Marginal Zone Lymphoma
			16.9.4 Immunoblastic Lymphoma
			16.9.5 Plasma Cell/Plasmacytic Lymphoma
			16.9.6 Lymphoblastic/Lymphocytic Lymphoma
			16.9.7 LGL Lymphoma (Leukemia)
			16.9.8 Histiocytic Sarcoma (Mononuclear Phagocyte System)
			16.9.9 Myelogenous Leukemia
				16.9.9.1 Granulocytic Leukemia
				16.9.9.2 Erythroid Leukemia
			16.9.10 Thymoma
			16.9.11 Mast Cell Tumor
		ACKNOWLEDGMENTS
		References
	Chapter 17: Bone, Muscle, and Tooth
		17.1 Bone and Joint
			17.1.1 Functional Anatomy
			17.1.2 Species Differences
			17.1.3 Evaluation Methods
			17.1.4 Nonproliferative Lesions of Bone
				17.1.4.1 Increased Bone, Trabeculae, and/or Cortex (Hyperostosis)
				17.1.4.2 Decreased Bone, Trabeculae, and/or Cortex
				17.1.4.3 Increased Eroded Surface
				17.1.4.4 Necrosis
				17.1.4.5 Fracture and Callus Formation
				17.1.4.6 Bone Cyst
				17.1.4.7 Fibrous Osteodystrophy
				17.1.4.8 Fibro-Osseous Lesions
				17.1.4.9 Increased Physeal Thickness, Physeal Dysplasia
				17.1.4.10 Decreased Thickness, Physis
			17.1.5 Proliferative Lesions of Bone
				17.1.5.1 Osteoblast Hyperplasia
				17.1.5.2 Osteoma
				17.1.5.3 Osteoblastoma
				17.1.5.4 Osteosarcoma
				17.1.5.5 Chondroma and Chondrosarcoma
				17.1.5.6 Osteochondroma
				17.1.5.7 Osteogenic Fibrosarcoma
			17.1.6 Nonproliferative Lesions of Joint/Articular Cartilage
				17.1.6.1 Osteoarthritis (Degenerative Joint Disease)
				17.1.6.2 Chondromucinous Degeneration
				17.1.6.3 Cartilage Degeneration
				17.1.6.4 Inflammation
			17.1.7 Proliferative Lesions of Joint/Articular Cartilage
				17.1.7.1 Synovial Hyperplasia
				17.1.7.2 Synovial Sarcoma
		17.2 Skeletal Muscle
			17.2.1 Basic Histology
			17.2.2 Lesions in Muscle
				17.2.2.1 Degeneration, Necrosis, and Regeneration
				17.2.2.2 Hypertrophy
				17.2.2.3 Atrophy
				17.2.2.4 Vacuolation
				17.2.2.5 Infiltrates and Inflammation
				17.2.2.6 Mineralization
				17.2.2.7 Rhabdomyosarcoma
		17.3 Teeth
			17.3.1 Functional Anatomy
			17.3.2 Nonproliferative Lesions of Teeth
				17.3.2.1 Inflammation
				17.3.2.2 Degeneration
				17.3.2.3 Necrosis
				17.3.2.4 Periodontal Pocket
				17.3.2.5 Dentin Niches
				17.3.2.6 Dentin, Decreased (Generalized)
				17.3.2.7 Dentin Matrix Alteration
				17.3.2.8 Dental Dysplasia
				17.3.2.9 Resorption
				17.3.2.10 Denticle(s)
				17.3.2.11 Pulp Concretions
				17.3.2.12 Cyst(s)
				17.3.2.13 Thrombus
			17.3.3 Proliferative Lesions of Teeth
				17.3.3.1 Odontoma
				17.3.3.2 Odontoma, Ameloblastic
				17.3.3.3 Ameloblastoma
				17.3.3.4 Fibroma, Odontogenic
				17.3.3.5 Fibroma, Cementifying/Ossifying
		References
	Chapter 18: The Cardiovascular System
		18.1 Introduction
		18.2 Embryology Structure and Function
		18.3 Extracellular, Cellular, and Subcellular Components
		18.4 Dissection and Methods of Evaluation
		18.5 Spontaneous Heart Lesions in Laboratory Animals
			18.5.1 Murine Progressive Cardiomyopathy
			18.5.2 Valvular Endocardial Myxomatous Change
			18.5.3 Miscellaneous Lesions of the Heart in Rodents
			18.5.4 Lesions of the Heart in Non-Rodents
				18.5.4.1 Non-Human Primates
				18.5.4.2 Miscellaneous Lesions of the Heart in Non-Rodents
				18.5.4.3 Cardiac Weight, Dilation, and Hypertrophy
				18.5.4.4 Drug-Induced Cardiac Hypertrophy
				18.5.4.5 Thiazolidinedione Mechanism of Cardiac Hypertrophy
				18.5.4.6 Tyrosine Kinase (TK)–Induced Cardiotoxicity
				18.5.4.7 Mechanisms of TK Cardiotoxicity
				18.5.4.8 Drug-Induced Myocardial Degeneration and Necrosis, Inflammation, and Fibrosis
				18.5.4.9 Cardiotoxicity Associated with Anti-Cancer Drugs
					18.5.4.9.1 Anthracycline-Induced Myocardial Vacuolation and Degeneration
					18.5.4.9.2 Cyclophosphamide-Induced Cardiomyopathy/Hemorrhagic Myocardial Degeneration
				18.5.4.10 Toxicity of Cardioactive Agents
					18.5.4.10.1 Catecholamine-Induced Cardiotoxicity
				18.5.4.11 Cardiotoxicity of Noncardioactive Agents
					18.5.4.11.1 Mechanism of Action for Selective COX2-Induced Cardiotoxicity
				18.5.4.12 Valvular Lesions
				18.5.4.13 Biomarkers of Mycardial Injury, Remodeling, and Repair
					18.5.4.13.1 Cardiac Tropinins as Biomarkers of Myocardial Injury
					18.5.4.13.2 Heart Fatty Acid-Binding Protein
					18.5.4.13.3 Biomarkers Hypertrophy and Cardiac Remodeling
		18.6 Vascular
			18.6.1 Spontaneous Vascular Injury in Laboratory Animals
				18.6.1.1 Spontaneous Polyarteritis Syndrome in Rats and Mice
				18.6.1.2 Spontaneous Vascular Lesions in Nonrodents
					18.6.1.2.1 Idiopathic Canine Polyarteritis of Beagle Dogs
					18.6.1.2.2 Vascular Lesions in Nonhuman Primates
					18.6.1.2.3 Thrombocytopenia-Associated Arteritis of Minipigs
					18.6.1.2.4 Miscellaneous Findings and Findings Associated with Intravenous Infusion
			18.6.2 Drug-Induced Vascular Injury in Toxicology Studies
			18.6.3 Histopathology Terminology for Drug-Induced Vascular Lesions in Toxicology Studies
				18.6.3.1 Vasodilators and Positive Inotropic Agents
				18.6.3.2 Drug-Induced Vascular Injury in Dogs
					18.6.3.2.1 Cardiotoxicity Related to Exaggerated Pharmacology: Susceptibility and Relevance of the Dog
				18.6.3.3 Implications of Dog Cardiovascular Toxicity and Relevance for Humans
				18.6.3.4 Drug-Induced Vascular Injury in Rats
			18.6.4 Drug-Induced Vascular Injury in Nonhuman Primates
			18.6.5 Drug-Induced Vascular Injury in Swine
			18.6.6 Miscallenous Vascular Lesions at Other Sites
			18.6.7 Vascular Injury or Dysfunction Induced by Biopharmaceutical and Oligonucleotide Therapies
			18.6.8 Morphology of Biopharmaceutical-Related Vascular Injury
			18.6.9 Infusion Reactions and Cytokine-Related Mechanisms of Vascular Alteration
			18.6.10 Vascular Injury Associated with ASO
			18.6.11 Cardiovascular Effects of Cell Therapy
			18.6.12 Differentiating Spontaneous from Drug-Induced Vascular Lesions
			18.6.13 Hypertrophy and Hyperplasia
			18.6.14 Vascular Injury Mode(s) of Action
				18.6.14.1 Direct-Acting Agents
				18.6.14.2 Vasoconstrictor Agents
				18.6.14.3 Mechanism-of-Action for Vasodilator Agent(s)
			18.6.15 Pulmonary Vessels
				18.6.15.1 Pulmonary Hypertension
					18.6.15.1.1 Drug-Induced Pulmonary Vascular Changes
			18.6.16 Aortic Aneurysm
			18.6.17 Biomarkers of Vascular Injury
				18.6.17.1 Physiologic Biomarkers of Vascular Toxicity
					18.6.17.1.1 Heart Rate and Mean Arterial Pressure
					18.6.17.1.2 Regional Blood Flow
				18.6.17.2 Biochemical Biomarkers of Vascular Toxicity
					18.6.17.2.1 Endothelial Cell Biomarkers
				18.6.17.3 Investigational In Vivo Studies
					18.6.17.3.1 MicroRNAs (miRNAs)
			18.6.18 Drug-Induced Vascular Lesions: Implications for Humans
				18.6.18.1 Neoplasia
			18.6.19 Conclusion
		References
	Chapter 19: Endocrine Glands
		19.1 Introduction
		19.2 Pituitary Gland
			19.2.1 Normal Structure and Function
			19.2.2 Nonproliferative Lesions
				19.2.2.1 Atrophy
				19.2.2.2 Hypertrophy
			19.2.3 Proliferative Lesions
				19.2.3.1 Hyperplasia
				19.2.3.2 Neoplasia
		19.3 Thyroid Gland
			19.3.1 Normal Structure and Function
			19.3.2 Thyroid Hormones
			19.3.3 Nonproliferative Lesions
				19.3.3.1 Congenital Lesions
				19.3.3.2 Atrophy/Degeneration
				19.3.3.3 Pigmentation and Accumulations
				19.3.3.4 Inflammatory Lesions
			19.3.4 Proliferative Lesions
				19.3.4.1 Thyroid Follicular Epithelium
				19.3.4.2 Thyroid C-Cells
				19.3.4.3 Mechanisms of Chemically Induced Thyroid Follicular Hyperplasia and Neoplasia
				19.3.4.4 Interference with Thyroid Function by Goitrogenic Compounds
					17.3.4.4.1 Inhibition of Thyroid Hormone Synthesis
					19.3.4.4.2 Inhibition of Thyroid Hormone Secretion
					19.3.4.4.3 Alterations in Thyroid Hormone Metabolism and Clearance
				19.3.4.5 Direct Acting Thyroid Mutagens
		19.4 Parathyroid Gland
			19.4.1 Normal Structure and Function
			19.4.2 Calcitonin and Parathyroid Hormone
			19.4.3 Vitamin D3
			19.4.4 Nonproliferative Lesions
				19.4.4.1 Congenital Lesions
				19.4.4.2 Inflammatory Lesions
				19.4.4.3 Atrophy/Degeneration
			19.4.5 Proliferative Lesions
				19.4.5.1 Chief Cell Hyperplasia
				19.4.5.2 Chief Cell Neoplasms
				19.4.5.3 Alterations of Calcium Homeostasis and Parathyroid Function
					19.4.5.3.1 Primary Hyperparathyroidism
					19.4.5.3.2 Secondary Hyperparathyroidism
					19.4.5.3.3 Pseudohyperparathyroidism (Humoral Hypercalcemia of Malignancy)
				19.4.5.4 Irradiation, Xenobiotics, Heavy Metals, and Alterations in Parathyroid Function
		19.5 Adrenal Glands
			19.5.1 Normal Structure and Function
			19.5.2 Adrenal Cortex
				19.5.2.1 Steroidogenesis in Cortex
				19.5.2.2 Xenobiotics Acting on Hypothalamic-Pituitary-Adrenal Axis
				19.5.2.3 Why Is the Adrenal Gland a Target of Toxicity?
				19.5.2.4 Species Differences
			19.5.3 Nonproliferative Lesions
				19.5.3.1 Hypertrophy
					19.5.3.1.1 Zona Fasciculata Hypertrophy
					19.5.3.1.2 ZG Hypertrophy
					19.5.3.1.3 Atrophy
					19.5.3.1.4 Necrosis
					19.5.3.1.5 Vacuolation
			19.5.4 Proliferative Lesions
				19.5.4.1 Subcapsular Cell Hyperplasia
				19.5.4.2 Focal Hyperplasia, Focal Hypertrophy, and Foci of Cellular Alteration
				19.5.4.3 Adenoma and Carcinoma
				19.5.4.4 In Vitro Methods to Identify Mechanisms of Toxicity
		19.6 Adrenal Medulla
			19.6.1 Normal Structure and Function
			19.6.2 Nonproliferative Lesions
			19.6.3 Proliferative Lesions
		19.7 Pancreatic Islets
			19.7.1 Normal Structure and Function
			19.7.2 Species Differences
			19.7.3 Clinical Chemistry Parameters
			19.7.4 Nonproliferative Lesions
				19.7.4.1 Manifestations of Toxicity
					19.7.4.1.1 Agents that Cause Islet Cell Degeneration/Necrosis/Apoptosis
					19.7.4.1.2 Agents that Cause Islet Cell Functional Abnormalities
			19.7.5 Proliferative Lesions
				19.7.5.1 Pancreatic Islet Cell Carcinogenesis
				19.7.5.2 Animal Models of Diabetes Mellitus
		References
	Chapter 20: Reproductive System and Mammary Gland
		20.1 Introduction
		20.2 Male Embryology and Maturation
			20.2.1 In Utero Development
			20.2.2 Postnatal Development
			20.2.3 Terminology of Sexual Maturation
		20.3 Testis
			20.3.1 Functional Anatomy
				20.3.1.1 Testicular Cell Types
					20.3.1.1.1 Somatic Cells
						20.3.1.1.1.1  Sertoli Cells Sertoli cells are large, post-proliferative cells that make up approximately 10% of cells within the mature seminiferous epithelium and play an essential role in spermatogenesis. They are responsive to follicle stimulating horm
						20.3.1.1.1.2  Leydig Cells Leydig cells reside in the intertubular interstitium and maintain intratesticular androgen levels crucial to germ cell maintenance and development. Histologically, these cells appear in clusters associated with the interstitial
						20.3.1.1.1.3  Peritubular Myoid Cells Peritubular myoid cells encircle the seminiferous tubules and provide propulsive activity for movement of seminiferous fluid and spermatids. The spindloid myoid cells have thin, elongated nuclei, are closely apposed t
					20.3.1.1.2 Germ Cells
						20.3.1.1.2.1  Spermatogonia Spermatogonia are diploid cells, unique in being the sole proliferative cell population within the seminiferous epithelium and in residing outside of the protective blood-testis barrier formed by tight junctions between Sertoli
						20.3.1.1.2.2  Spermatocytes Type B spermatogonia divide to generate preleptotene spermatocytes, which make up the majority of cells in the basal layer at the time of spermiation. Early spermatocytes are moved from the basilar compartment into the sequeste
						20.3.1.1.2.3  Spermatids Round spermatids, still linked by intercellular bridges established among their spermatogonial progenitors, undergo marked morphologic transformation (spermiogenesis) to elongating forms. Spermatids depend on Sertoli cells for suc
					20.3.1.1.3 Spermatogenesis and Staging
					20.3.1.1.4 Hormone Regulation
			20.3.2 Distinguishing Drug-Related Toxicity from Background Pathology and Immaturity
				20.3.2.1 Background Pathology in the Rat and Mouse
				20.3.2.2 Background Pathology in the Dog
				20.3.2.3 Background Pathology in the NHP
				20.3.2.4 Incomplete Maturity in the Rat and Mouse
				20.3.2.5 Incomplete Maturity in the Dog
				20.3.2.6 Incomplete Maturity in the NHP
			20.3.3 Testicular Histopathology
				20.3.3.1 Seminiferous Tubular Changes
					20.3.3.1.1 Stage-Specific Changes
						20.3.3.1.1.1  Germ Cell Degeneration (Apoptosis) Most germ cell death occurs through apoptosis, even though the classic morphological characteristics of apoptotic cells are not always observed (Brinkworth 1995; Lee et al. 1997). Germ cell degeneration is
						20.3.3.1.1.2  Germ Cell Depletion Substantial degeneration of a given germ cell type within a stage results in partial or complete loss of a cell layer. In some cases, absent cells are more obvious because of a residual clear space representing the Sertol
						20.3.3.1.1.3  Spermatid Retention Spermiation, which is the release of mature spermatids into the tubular lumen (rat: step 19; mouse: 16; NHP: 14; dog: 12), normally occurs at rat stage VIII. In rats, when mature spermatids remain attached at the tubular
					20.3.3.1.2 Non-Specific Changes
						20.3.3.1.2.1  Tubular Degeneration/Atrophy Tubular degeneration can include germ cell degeneration, germ cell loss, spermatid retention, vacuolation of Sertoli cell cytoplasm, formation of multinucleated germ cell syncytia, disorder within the germ cell l
						20.3.3.1.2.2  Tubular Vacuolation Compound-mediated effects on Sertoli cells can result in variably sized, small, clear cytoplasmic vacuoles, generally near the basement membrane (Figure 20.23). Larger clear spaces at variable levels within the seminifero
						20.3.3.1.2.3  Multinucleated Germ Cells Through incomplete cytokinesis during mitosis, descendants of early spermatogonia form cohorts of synchronously developing germ cells joined by narrow cytoplasmic bridges, which are maintained by Sertoli cells. Inju
						20.3.3.1.2.4  Necrosis Although apoptotic cell death is usual for germ cells, conditions (e.g., ischemia) resulting in decreased cellular energy can manifest morphologically as necrosis. The term tubular necrosis is applicable where there is extensive los
						20.3.3.1.2.5  Tubular Dilation Changes in tubular seminiferous fluid dynamics can result in increased luminal size or tubular dilation (Figure 20.10a). Decreased resorption of fluid or obstruction within the excurrent duct system (rete testis, efferent du
						20.3.3.1.2.6  Sperm Stasis/Granuloma Impaired intratubular fluid secretion by Sertoli cells, excessive fluid uptake by efferent ductules, or decreased tubular motility due to peritubular myoid cell dysfunction (Yuan et al. 1994) may predispose to impactio
						20.3.3.1.2.7  Germ Cell Exfoliation Individualized, non-degenerate germ cells may appear in the seminiferous tubular lumen, rete testis, and/or epididymis as a result of loss of adherence between germ cells and their supporting Sertoli cells. This finding
				20.3.3.2 Leydig Cell Changes
					20.3.3.2.1 Atrophy
					20.3.3.2.2 Hypertrophy
				20.3.3.3 Vascular Changes
				20.3.3.4 Proliferative Changes
					20.3.3.4.1 Leydig Cell Hyperplasia and Adenoma
					20.3.3.4.2 Rete Testis Hyperplasia, Adenoma, and Carcinoma
					20.3.3.4.3 Mesothelioma
					20.3.3.4.4 Other Testicular Tumors
			20.3.4 Ancillary End Points for Assessing Toxicity
				20.3.4.1 Organ Weights
				20.3.4.2 Sperm Parameters
				20.3.4.3 Clinical Pathology: Hormone Measurements and Biomarkers
				20.3.4.4 Toxicogenomics
				20.3.4.5 Expected Effects of Testicular Toxicity in Other Organs
		20.4 Epididymis and Efferent Ducts
			20.4.1 Functional Anatomy
				20.4.1.1 Efferent Ducts
				20.4.1.2 Epididymides and Vas Deferens
			20.4.2 Efferent Duct and Epididymal Histopathology
				20.4.2.1 Efferent Duct Changes
				20.4.2.2 Epididymal Changes
					20.4.2.2.1 Epithelial Apoptosis
					20.4.2.2.2 Epithelial Vacuolation
					20.4.2.2.3 Epithelial Degeneration
					20.4.2.2.4 Sperm Granulomas
					20.4.2.2.5 Inflammation and Edema
					20.4.2.2.6 Atrophy
					20.4.2.2.7 Luminal Cell Debris/Sloughed Testicular Germ Cells
					20.4.2.2.8 Proliferative Changes
		20.5 Accessory Sex Glands
			20.5.1 Functional Anatomy
				20.5.1.1 Prostate Gland and Coagulating Glands
				20.5.1.2 Seminal Vesicles
			20.5.2 Prostate and Seminal Vesicle Histopathology
				20.5.2.1 Atrophy and/or Decreased Secretory Product
				20.5.2.2 Inflammation
				20.5.2.3 Proliferative Changes
		20.6 Relevance of Male Reproductive System Changes to Humans
		20.7 Female Embryology and Functional Anatomy
			20.7.1 Embryology
			20.7.2 Ovary
			20.7.3 Uterine Tube
			20.7.4 Uterine Body and Horns
			20.7.5 Cervix
			20.7.6 Vagina
		20.8 General Physiology and Maturation
			20.8.1 Rodents
			20.8.2 Dogs
			20.8.3 Nonhuman Primates
		20.9 Hormonal Basis of the Ovarian Cycle
			20.9.1 Rodents
			20.9.2 Dogs
			20.9.3 Nonhuman Primates
		20.10 Histology of the Female Reproductive System
			20.10.1 Rodents
				20.10.1.1 Proestrus
				20.10.1.2 Estrus
				20.10.1.3 Metestrus
				20.10.1.4 Diestrus
			20.10.2 Dogs
				20.10.2.1 Prepubertal/Immature
				20.10.2.2 Proestrus
				20.10.2.3 Estrus
				20.10.2.4 Diestrus
				20.10.2.5 Anestrus
			20.10.3 Nonhuman Primates
				20.10.3.1 Prepubertal/Immature
				20.10.3.2 Follicular Phase
				20.10.3.3 Periovulatory Phase
				20.10.3.4 Luteal Phase
				20.10.3.5 Menstrual Phase
				20.10.3.6 Repair Phase/Early Follicular Phase
			20.10.4 Sampling of the Reproductive Tract for Examination
		20.11 Ancillary End Points for Assessing Toxicity
			20.11.1 Organ Weights
			20.11.2 Vaginal Cytology/Vaginal Swabs
			20.11.3 Follicle Counts
			20.11.4 Hormone Measurements
		20.12 Ovarian Histopathology
			20.12.1 Non-Proliferative Changes
				20.12.1.1 Hypoplasia
				20.12.1.2 Atrophy
				20.12.1.3 Follicular Atresia
				20.12.1.4 Mineralization
				20.12.1.5 Cysts
				20.12.1.6 Polyovular Follicles
				20.12.1.7 Decreased Number/Absence of Recent (Basophilic) Corpora Lutea
				20.12.1.8 Changes in Size/Number of Corpora Lutea
				20.12.1.9 Degeneration and/or Hemorrhage within Corpora Lutea
				20.12.1.10 Interstitial Glands
			20.12.2 Proliferative Changes
				20.12.2.1 Epithelial Proliferative Changes
				20.12.2.2 Sex Cord–Stromal Proliferative Changes
				20.12.2.3 Germ Cell Tumors
				20.12.2.4 Other Proliferative Changes
		20.13 Histopathology of the Uterine Tube
		20.14 Histopathology of the Uterus
			20.14.1 Non-Proliferative Changes
				20.14.1.1 Uterine Atrophy
				20.14.1.2 Uterine Luminal Dilation
				20.14.1.3 Endometrial Glandular Dilation
				20.14.1.4 Inflammation
				20.14.1.5 Anovulatory and Irregular Cycles in Nonhuman Primates
				20.14.1.6 Squamous Metaplasia of the Endometrium
				20.14.1.7 Uterine Adenomyosis
				20.14.1.8 Endometriosis
			20.14.2 Proliferative Changes
				20.14.2.1 Decidual Reaction of the Uterus (Deciduoma)
				20.14.2.2 Endometrial Hyperplasia
					20.14.2.2.1 Cystic Endometrial Hyperplasia in Rodents
					20.14.2.2.2 Endometrial Glandular Hyperplasia in Macaques
					20.14.2.2.3 Endometrial Epithelial Plaques in Macaques
					20.14.2.2.4 Endometrial Stromal Hyperplasia in Rodents
					20.14.2.2.5 Cystic Endometrial Hyperplasia/Pyometra in Dogs
						20.14.2.2.5.1  Diffuse Endometrial Hyperplasia Diffuse cystic endometrial hyperplasia, with or without mucometra, is a common observation in dogs related to repeated progestogenic stimulation that can be exacerbated by a previous estrogenic influence. Adm
						20.14.2.2.5.2  Segmental Endometrial Hyperplasia In dogs, segmental hyperplasia of the endometrium has been described as an unusual spontaneous lesion that is frequently confused with pregnancy or pseudopregnancy. It can occur in young dogs and is occasio
						20.14.2.2.5.3  Pyometra Pyometra is a well-documented condition seen in aging dogs during diestrus as a sequel to persistent cystic endometrial hyperplasia. It is not commonly seen as a spontaneous change in young dogs such as those used in toxicology stu
				20.14.2.3 Endometrial Polyp
				20.14.2.4 Endometrial Adenoma/Adenocarcinoma
				20.14.2.5 Leiomyoma
				20.14.2.6 Stromal Sarcoma
		20.15 Changes in the Cervix and Vagina
			20.15.1 Non-Proliferative Changes
				20.15.1.1 Atrophy
				20.15.1.2 Mucification
				20.15.1.3 Inflammation
				20.15.1.4 Endocervical Squamous Metaplasia
				20.15.1.5 Cysts
			20.15.2 Proliferative Changes
				20.15.2.1 Hyperplasia/Hyperkeratinization
				20.15.2.2 Squamous Papilloma/Carcinoma
				20.15.2.3 Vaginal Polyp
				20.15.2.4 Granular Cell Tumor
		20.16 Relevance of Female Reproductive System Changes to Humans
		20.17 Mammary Gland Embryology and Functional Anatomy
		20.18 Structure of the Mammary Gland
		20.19 Regulation of Mammary Gland Growth and Function
		20.20 Considerations in the Examination of the Mammary Gland
		20.21 Histopathology of the Mammary Gland
			20.21.1 Non-Neoplastic Changes
				20.21.1.1 Atrophy
				20.21.1.2 Sex-Dependent Alterations in the Mammary Gland of the Rat
				20.21.1.3 Inflammation
				20.21.1.4 Dilation of Ducts and Acini
				20.21.1.5 Fibrosis
			20.21.2 Proliferative Changes
				20.21.2.1 Hyperplasia
					20.21.2.1.1 Rat
					20.21.2.1.2 Mouse
					20.21.2.1.3 Dog
					20.21.2.1.4 Nonhuman Primate
				20.21.2.2 Neoplastic Lesions
					20.21.2.2.1 Adenoma
					20.21.2.2.2 Fibroadenoma
					20.21.2.2.3 Carcinoma
					20.21.2.2.4 Fibroma/Fibrosarcoma
					20.21.2.2.5 Benign/Malignant Mixed Mammary Tumors
		20.22 Relevance of Mammary Gland Changes to Humans
		Disclaimer
		References
	Chapter 21: Skin
		21.1 Introduction, Embryology, and Anatomy of Skin
			21.1.1 Introduction
			21.1.2 Embryology
			21.1.3 Functional Anatomy
				21.1.3.1 Epidermis
					21.1.3.1.1 Melanocytes
					21.1.3.1.2 Langerhans Cells
				22.1.3.2 Sensory Receptors in Epidermis and Dermis
					21.1.3.2.1 Low-Threshold Mechanoreceptors
					21.1.3.2.2 Sensory Nerves
				21.1.3.3 Dermis
				21.1.3.4 Subcutis
				21.1.3.5 Hair Follicle
				21.1.3.6 Sweat Glands
				21.1.3.7 Sebaceous Glands
				21.1.3.8 Skin Immunology
		21.2 Dermatologic Drug Development
			21.2.1 Special Considerations in Dermatologic Drug Development
				21.2.1.1 Species Selection
					21.2.1.1.1 Animal Models
					21.2.1.1.2 Hairlessness
				21.2.1.2 Comparative Anatomy (Human, Monkey, Pig, Dog, Rabbit, Rat, and Mouse)
					21.2.1.2.1 Rodent
					21.2.1.2.2 Minipigs
					21.2.1.2.3 Macaques
					21.2.1.2.4 Rabbit
					21.2.1.2.5 Guinea Pig
					21.2.1.2.6 Dogs
				21.2.1.3 Specific Conditions
					21.2.1.3.1 Androgenic Alopecia (Male Pattern Baldness)
					21.2.1.3.2 Radiation Exposure
				21.2.1.4 Methods in Dermatotoxicity Testing
					21.2.1.4.1 In Vitro
					21.2.1.4.2 In Vivo
				21.2.1.5 Criteria for Grading Skin Lesions
				21.2.1.6 Photosafety
					21.2.1.6.1 Basic Principles in Assessing Photosafety
				21.2.1.7 Wound Healing
					21.2.1.7.1 Special Techniques in Assessing Wound Healing
			21.2.2 Role of Excipients in Assessing Dermatotoxicity
				21.2.2.1 Isopropyl Myristate
				21.2.2.2 Sodium Lauryl Sulfate
			21.2.3 Special Techniques in Dermatologic Drug Development
				21.2.3.1 Nanotoxicity
					21.2.3.1.1 Detection of and Response to Nanoparticle Exposure in Skin
				21.2.3.2 Implanted Biomaterials
				21.2.3.3 Carcinogenicity
		21.3 Mechanisms of Dermatotoxicity
			21.3.1 Topical Dermatotoxicity
			21.3.2 Systemic Dermatotoxicity
			21.3.3 Non-Immunologic Dermatotoxicity
			21.3.4 Immunologic Dermatotoxicity
			21.3.5 Idiosyncratic Drug Reactions
				21.3.5.1 Sulfonamide
				21.3.5.2 Nevirapine
			21.3.6 Phototoxicity
				21.3.6.1 Fluoroquinolones
		21.4 Biomarkers of Dermatotoxicity
		21.5 Non-Proliferative Skin Changes
			21.5.1 Pathologic Findings in Dermatotoxicity
				21.5.1.1 Epidermis
					21.5.1.1.1 Clinical Manifestations
					21.5.1.1.2 Clinical Pathology
					21.5.1.1.3 Gross Pathology
					21.5.1.1.4 Histopathology
				21.5.1.2 Dermis
					21.5.1.2.1 Histopathology
				21.5.1.3 Subcutis
					21.5.1.3.1 Histopathology
				21.5.1.4 Adnexa
					21.5.1.4.1 Histopathology
				21.5.1.5 Pigmentation
					21.5.1.5.1 Histopathology
		21.6 Hyperplastic, Preneoplastic, and Neoplastic Skin Changes
			21.6.1 Skin
				21.6.1.1 Epidermis
					21.6.1.1.1 Squamous Cell Hyperplasia
					21.6.1.1.2 Squamous Cell Metaplasia
					21.6.1.1.3 Squamous Cell Papilloma
					21.6.1.1.4 Keratoacanthoma
					21.6.1.1.5 Squamous Cell Carcinoma
					21.6.1.1.6 Basal Cell Tumor (Benign)
					21.6.1.1.7 Basal Cell Carcinoma
				21.6.1.2 Dermis/Subcutis (Mesenchymal)
					21.6.1.2.1 Fibroma
					21.6.1.2.2 Fibrosarcoma
					21.6.1.2.3 Benign Fibrous Histiocytoma
					21.6.1.2.4 Malignant Fibrous Histiocytoma
					21.6.1.2.5 Histiocytic Sarcoma
					21.6.1.2.6 Sarcoma
					21.6.1.2.7 Mast Cell Tumor/Mastocytoma
				21.6.1.3 Melanocytic
					21.6.1.3.1 Nevi
					21.6.1.3.2 Benign Melanoma
					21.6.1.3.3 Malignant Melanoma
			21.6.2 Adnexa
				21.6.2.1 Sebaceous Cell Hyperplasia
				21.6.2.2 Sebaceous Cell Adenoma
				21.6.2.3 Sebaceous Cell Carcinoma
				21.6.2.4 Benign Hair Follicle Tumor (Trichofolliculoma, Pilomatricoma, Trichoepithelioma, and Tricholemmoma)
		References
	Chapter 22: Nervous System
		22.1 Introduction
		22.2 Special Considerations
			22.2.1 Special Consideration #1: Applied Neuroanatomy
				22.2.1.1 Autonomic Components
				22.2.1.2 Circumventricular Organs
				22.2.1.3 Meninges
				22.2.1.4 Cells of the Nervous System
					22.2.1.4.1 Neurons
					22.2.1.4.2 Astrocytes
					22.2.1.4.3 Oligodendrocytes
					22.2.1.4.4 Microglial Cells
					22.2.1.4.5 Ependyma
					22.2.1.4.6 Schwann Cells
					22.2.1.4.7 Satellite Glial Cells
			22.2.2 Special Consideration #2: The “Barriers”
			22.2.3 Special Consideration #3: Sampling
				22.2.3.1 Central Components of the Nervous System
				22.2.3.2 Peripheral Components of the Nervous System
			22.2.4 Special Consideration #4: Timing
		22.3 Evaluation Strategies
		22.4 Diagnostic Neuropathology—Nonproliferative Lesions
			22.4.1 Neurons
			22.4.2 Neuronal Necrosis
			22.4.3 Neuronal Cell Loss
			22.4.4 Neuronophagia
			22.4.5 Chromatolysis
			22.4.6 Vacuolation, Neuronal
			22.4.7 Neuronal Pigments
			22.4.8 Neuronal Inclusions
			22.4.9 Neuronal Heterotopia (Ectopic Neurons)
			22.4.10 Neurons, Binucleate
			22.4.11 Satellitosis
			22.4.12 Axonal Dystrophy/Spheroids
			22.4.13 Axonal Degeneration/Nerve Fiber Degeneration
			22.4.14 Bubbles, Myelin
			22.4.15 Glial Cells
				22.4.15.1 Gliosis, NOS (Not Otherwise Specified)
			22.4.16 Astrocytes
				22.4.16.1 Astrocytosis
				22.4.16.2 Alzheimer Type II Astrocytes
				22.4.16.3 Astrocyte Swelling/Vacuolation
			22.4.17 Microglial Cells
				22.4.17.1 Microgliosis
				22.4.17.2 Microglial Nodules
			22.4.18 Oligodendrocytes and Schwann Cells
				22.4.18.1 Myelinopathy (Demyelination, Altered Myelin/Remyelination), Including Myelin Edema
				22.4.18.2 Schwann Cell Proliferation
			22.4.19 Miscellaneous
				22.4.19.1 Vacuolation/Vacuolation White Matter
				22.4.19.2 Infiltrates vs Inflammation
				22.4.19.3 Hemorrhage
				22.4.19.4 Dilated Ventricles/Central Canal
				22.4.19.5 Infarction
				22.4.19.6 Thrombosis and Vasculitis
				22.4.19.7 Mineralization
				22.4.19.8 Epidermoid Cysts
		22.5 Diagnostic Neuropathology—Proliferative Lesions
			22.5.1 Neuronal Neoplastic Lesions
				22.5.1.1 Medulloblastoma, Malignant (Cerebellar Neuroblastoma, Primitive Neuroectodermal Tumor of Cerebellum)
			22.5.2 Glial Cell Neoplastic Lesions
			22.5.3 Astrocytoma, Malignant (Glioma, Astrocytic)
			22.5.4 Glioma, Mixed, Malignant (Oligoastroglioma)
			22.5.5 Oligodendroglioma, Malignant
			22.5.6 Schwann Cell Neoplasms
				22.5.6.1 Schwannoma (Neurilemmoma, Neurinoma)
			22.5.7 Hamartoma, Lipomatous (Lipoma)
			22.5.8 Granular Cell Tumors
			22.5.9 Meningioma
			22.5.10 Choroid Plexus Tumors
			22.5.11 Ependymoma
			22.5.12 Malignant Reticulosis
		References
	Chapter 23: Special Senses
		23.1 Eye
			23.1.1 Introduction
			23.1.2 Extraocular Tissues
			23.1.3 Cornea
			23.1.4 Conjunctiva
			23.1.5 Sclera and Episclera
			23.1.6 Uvea
			23.1.7 Intraocular Pressure (IOP)
			23.1.8 Lens
			23.1.9 Vitreous Body
			23.1.10 Retina and Optic Nerve
		23.2 Ear
			23.2.1 External Ear
			23.2.2 Middle Ear
			23.2.3 Inner Ear: Auditory System
			23.2.4 Inner Ear: Vestibular System
		References
Index