Fundamentals of Toxicologic Pathology

Front Cover

Fundamentals of Toxicologic Pathology

Copyright Page

Contents

Preface

Acknowledgments

CHAPTER 1 PRINCIPLES OF TOXICOLOGY

The Effect of the Body on the Chemical

Absorption

Passage across Membranes

Distribution

Volume of Distribution

Barriers to Distribution

Biotransformation

Phase I: Metabolism

Phase II: Metabolism

Enzyme Location in Toxicity

Excretion

Urinary Excretion

Biliary Excretion

Pulmonary Excretion

Interaction of Chemical and the Body

Enzyme Induction and Inhibition

Activation, Induction, or Synergism

Inhibition

Dose Dependency and Site of Action

Organ Specificity for Toxicity

Site-Specific Interactions and Toxicity

Receptors and Enzymes

Direct and Cascade Effects

Nonspecific Interations and Toxicity

Electrophiles and Covalent Binding

Free Radicals and Lipid Peroxidation

Further Reading

CHAPTER 2 MANIFESTATIONS OF TOXIC CELL INJURY: CELL INJURY/DEATH AND CHEMICAL CARCINOGENESIS

Section I: Cell Injury, Cell Death and Sequelae

Introduction

Key Cellular Components in Cell Injury

Factors Influencing Injury

Reaction of the Body to Injury

Adaptation

Reversible Cell Injury

Cell Swelling

Fatty Change

Irreversible Injury

Oncotic Necrosis

Apoptotic Necrosis

Sequelae to Irreversible Cell Injury

Concluding Comments

Section II: Chemical Carcinogenesis

Overview

Nomenclature of Neoplasms

Spectrum of Proliferative Lesions

Quantitative Cell Proliferation (Hyperplasia)

Qualitative Cell Proliferation

Preneoplasia

Neoplastic Cell Proliferation

Diagnostic Distinction between Preneoplasia, Benign Neoplasia, and Malignant Neoplasia

Steps in the Neoplastic Process

Initiation

Promotion

Progression

Hypotheses of Mode of Action of Chemical Carcinogens

Overview

Mutational Genetic Hypothesis of Chemical Carcinogenesis

Nonmutational Genetic Hypothesis of Chemical Carcinogenesis

Epigenetic Hypothesis of Chemical Carcinogenesis

Viral Hypothesis of Carcinogenesis

Oncogenes and Tumor Suppressor Genes in Chemical Carcinogenesis

Genes and Oncogenes

Proto-oncogene Function

Proto-oncogene Activation

Oncogene Activation in Chemical Carcinogenesis

Tumor Suppressor Genes and Carcinogenesis

Cell Cycle and Carcinogenesis

Cyclins and Cdk Proteins

Retinoblastoma Checkpoint

p53 Checkpoint

Tests for Carcinogenic Potential of Chemicals

In Vivo Chronic Rodent Carcinogenesis Studies

Additional In Vivo Tests for Carcinogenicity

In Vitro Short-term Tests

Conclusion

Further Reading

CHAPTER 3 CLINICAL PATHOLOGY

Introduction

Hematology

Parameters Generally Included in Study Protocols

Interpretative Hematology

Clinical Chemistry

Cholesterol, Triglycerides, and Glucose

Serum Proteins

Indicators of Hepatic Integrity and Function

Indicators of Renal Function

Electrolytes

Calcium and Inorganic Phosphate

Enzymes of Muscle Origin

Microsomal Enzyme Induction

Urinalysis

Interpretation of Clinical Pathology Results

Potential Effects of Factors Unrelated to Test Article Treatment

Comparators: Concurrent Controls, Reference Ranges

Statistical Analyses

Direct Versus Indirect Effects

Pharmacologic Versus Toxic Effects

Biological Importance of Treatment-related Effects

Reporting of Clinical Pathology Findings

Summary

Further Reading

CHAPTER 4 NOMENCLATURE: TERMINOLOGY FOR MORPHOLOGIC ALTERATIONS

Introduction

Basic Terminology

Terminology Issues

Training

Multiple Pathologists

Diagnostic Drift

Lesion Complexity

Standardized Nomenclature

Recording Pathology Data

Suggested Practices

Summary

Further Reading

CHAPTER 5 TECHNIQUES IN TOXICOLOGIC PATHOLOGY

Introduction

Factors Influencing Evaluation of Altered Morphology

Factors in Collection and Processing of Tissue

Factors Intrinsic to the Animal

Factors Related to the Environment

Factors Related to Nomenclature

Further Reading

CHAPTER 6 RESPIRATORY SYSTEM

Introduction

Structure and Cell Biology

Macroscopic and Microscopic Anatomy

Nasopharyngeal and Laryngeal Regions (Upper Respiratory Tract)

Tracheobronchial Region and Bronchioles

Pulmonary Region

Physiology and Functional Considerations

Xenobiotic Exposure, Metabolism, and Excretion

Mechanisms of Toxicity

Direct Toxicity

Metabolic Activation

Immune-mediated Toxicity

Toxicity and Responses to Inhaled Particles

Xenobiotic Interactions

Modifying Factors in Toxicity

Response to Injury

Injury, Regeneration, and Repair

Nasopharyngeal and Laryngeal Responses to Injury

Airway Response to Injury

Pulmonary Parenchymal Response to Injury

Edema

Inflammation

Fibrosis

Emphysema

Neoplasia

Evaluation of Toxicity

Methods for Testing

In Vitro Methods

Lung Cancer Model Systems

Pulmonary Function

Bronchopulmonary Lavage

Biochemical Evaluation

Morphologic Evaluation

Quantitative Techniques

Additional Techniques

Animal Models

Conclusions

Further Reading

CHAPTER 7 SKIN AND ORAL MUCOSA

Section I: Skin

Introduction

Structure and Function of Skin

Microscopic Anatomy

Skin Cell Subpopulations

Physiology and Biochemistry

Comparative Mechanisms of Cutaneous Toxicity

Direct Damage

Immunomediated Cutaneous Toxicity

Phototoxicity and Photoallergy

Response of Skin to Injury

Fundamental Non-neoplastic Lesions

Neoplastic Lesions

Evaluation of Cutaneous Toxicity

Skin Irritation Tests

Carcinogenesis Bioassays

Morphologic Assessment

Other Bioassays

Transgenic Animal Models

In Vitro Testing

Section II: Oral Mucosa

Introduction

Structure and Function of the Oral Mucosa

Microscopic Anatomy

Physiology

Comparative Mechanisms of Mucosal Toxicity

Response of Oral Mucosa to Injury

Fundamental Non-neoplastic Lesions

Carcinogenesis

Evaluation of Oral Toxicity

Further Reading

CHAPTER 8 GASTROINTESTINAL TRACT

Introduction

Structure and Function of the Gastrointestinal Tract

Macroscopic and Microscopic Structure and Function

Enteric Lymphoid System

Enteric Nervous System

Biotransformation

Bacterial Metabolism

Enterohepatic Circulation

Comparative Mechanisms of Gastrointestinal Toxicity

Intestinal Barrier Function

Intestinal Malabsorption

Altered Blood Supply

Mucosal Barrier Damage and Cytotoxicity

Hypersensitivity

Neurotransmitter Effects

Perturbation of Microflora

Carcinogenicity

Response of the Gastrointestinal Tract to Injury

Pathophysiological Responses

Inflammatory Response

Mucosal Response

Organ-specific Responses

Evaluation of Gastrointestinal Toxicity

In Vitro Strategies

In Vivo Strategies

Molecular Pathology

Morphologic Methods

Animal Models

Further Reading

CHAPTER 9 THE LIVER

Introduction

Structure and Function

Gross and Microscopic Anatomy

Cell Components

Xenobiotic Metabolism

Mechanisms of Toxicity

Classification of Hepatoxicants

Cellular Mechanisms of Toxicity

Non-neoplastic Responses to Injury

Histologic Types of Hepatic Necrosis

Intracellular Accumulations

Pathology of Transcription and Translation

Cholestasis

Hepatocellular Adaptive Responses

Hepatocellular Proliferation

Bile Ductular Lesions

Nonparenchymal Cell Toxicity

Hepatitis

Hepatic Fibrosis and Cirrhosis

Hepatic Neoplasia

Hepatocellular Neoplasia

Bile Duct Neoplasms

Endothelial Neoplasms

Küpffer Cell Neoplasms

Evaluation of Toxicity

Morphologic Evaluation

Clinical Chemistry Evaluation

Noninvasive Imaging

In Vitro Approaches

Use of Animals as Models

Summary and Conclusions

Further Reading

CHAPTER 10 PANCREAS

Section I: Exocrine Pancreas

Introduction

Normal Structure of Exocrine Pancreas

Gross Anatomy

Microscopic Anatomy and Ultrastructure

Physiology of Exocrine Pancreas

Comparative Mechanisms of Exocrine Pancreatic Toxicity

Response of Exocrine Pancreas to Injury

Cytotoxic Effects on Acinar Cells

Cytotoxic Effects in Ductal and Centroacinar Cells

Carcinogenesis

Evaluation of Exocrine Pancreatic Toxicity

Methods of Testing

Morphologic Evaluation of Toxicity

Animal Models

Summary and Conclusions

Section II: Endocrine Pancreas

Structure of Endocrine Pancreas

Gross Anatomy

Microscopic Anatomy and Ultrastructure

Physiology of Endocrine Pancreas

Mechanisms of Endocrine Pancreatic Toxicity

Insulin-dependent Diabetes Mellitus

Non-insulin-dependent Diabetes Mellitus

Glucose Intolerance

Response of Endocrine Pancreas to Injury

Apoptosis

Necrosis

Insulitis

Regeneration

Carcinogenesis

Evaluation of Endocrine Pancreatic Toxicity

In Vivo Testing

In Vitro Testing

Animal Models

Summary and Conclusions

Further Reading

CHAPTER 11 KIDNEY AND LOWER URINARY TRACT

Introduction

Renal Structure and Function

Gross, Microscopic, and Ultrastructural Anatomy

Physiology

Mechanisms of Toxicity

Overview and Classification

Glomerular Injury

Proximal Tubular Injury

Other Sites of Renal Injury

Lower Urinary Tract

Renal Carcinogenesis

Lower Urinary Tract Carcinogenesis

Response to Injury

Introduction

Glomerulus

Proximal Tubule and Interstitium

Renal Papillary Necrosis

Renal Tubular Hyperplasia and Neoplasia

Lower Urinary Tract: Non-neoplastic Lesions

Lower Urinary Tract Epithelial Neoplasms

Evaluation of Toxicity

Diagnostic Evaluation of Renal Disease

Routine Screening for Nephrotoxicity

Special Techniques

Evaluation of the Lower Urinary Tract

Conclusion

Further Reading

CHAPTER 12 CARDIOVASCULAR AND SKELETAL MUSCLE SYSTEMS

Section I: Heart

Introduction

Structure and Function

Gross and Microscopic Anatomy

Cellular and Extracellular Elements of the Heart: Biology and Clinical Relevance

Physiology and Functional Considerations

Xenobiotic Exposure

Mechanisms of Toxicity

Physiological Mechanisms of Functional Alterations

Biochemical Mechanisms of Cardiotoxicosis

Cardiotoxicoses Due to Direct Cellular Injury

Cardiotoxicoses Due to Indirect Acting Injury

Organellar Localization of Injury

Xenobiotic Interactions

Response to Injury

Developmental Cardiotoxicities

Myocardium

Endocardium

Pericardium

Valves

Evaluation of Cardiotoxicity

Physiologic Evaluation of Toxicity

Morphologic Evaluation of Toxicity

Biochemical Evaluation of Toxicity

Use of Animals as Models

Section II: Vessels

Introduction

Structure and Function

Microscopic Anatomy

Physiology and Functional Considerations

Mechanisms of Toxicity

Vasculotoxic Effects of Xenobiotics

Vascular Toxicity in Specific Organs

Response to Injury

Regeneration and Repair

Vessel Alterations

Evaluation of Vasotoxic Effects

Physiologic Methods for Testing

Morphologic Evaluation

Use of Animals as Models

Section III Skeletal Muscle

Introduction

Structure and Function

Gross and Microscopic Anatomy

Cells of Skeletal Muscle: Biology and Clinical Relevance

Physiologic and Functional Considerations

Mechanisms of Toxicity

Altered Neurogenic Function

Altered Immunologic Function

Localized Damage

Cell Membrane Alterations

Sarcoplasmic Reticulum Alterations

Microtubular Alterations

Myofilament Alterations

Lysosomal Alterations

Altered Intracellular Calcium Concentration

Altered Protein Synthesis

Altered Muscle Cell Differentiation

Response to Injury

Injury, Regeneration, and Repair

Skeletal Muscle Alterations

Evaluation of Skeletal Muscle Toxicity

Methods for Testing

Morphologic Evaluation

Use of Animals as Models

Further Reading

CHAPTER 13 NERVOUS SYSTEM

Introduction

Structure and Function

Macroscopic Structure

Microscopic Anatomy

Specialized Anatomical Features

Select Functions and Neurotoxicity

Mechanisms of Disease and Classification of Neurotoxic Diseases

Neuronopathies

Axonopathies

Myelinopathies

Toxicants Affecting Vascular Integrity

Developmental Neurotoxicants

Neurocarcinogens

Evaluation of Neurotoxicity

Use of Animals as Models

Tests of Nervous System Function

Morphologic Evaluation

In Vitro Systems

Conclusions

Further Reading

CHAPTER 14 BONES AND JOINTS

Introduction

Skeletal Structure and Composition

Formation and Development

Composition of Bone

Species Differences in Composition and Changes with Age

Bone Physiology and Function

Modeling and Remodeling of Bone

Biomechanics

Mineral Homeostasis

Regulation of Bone Cell Function

Mechanisms of Toxicity

Bone Toxicity

Joint Toxicity

Response of the Skeleton to Toxic Injury

Bone

Joints

Evaluation of Skeletal Toxicity

Testing for Skeletal Toxicity

Morphologic Evaluation

Biochemical Evaluation

Animal Models of Skeletal Disease

Summary

Further Reading

CHAPTER 15 IMMUNE SYSTEM

Introduction

Function and Structure of the Immune System

Function of the Immune System

Structure of the Immune System

Comparative Mechanisms of Immune Toxicity

Introduction

Examples of Immunotoxic Agents

Response of the Immune System to Toxic Injury

Decreased Cellularity

Increased Cellularity

Neoplasia

Inflammation in Nonlymphoid Tissues

Testing for Immunotoxicity

In Vivo and In Vitro Approaches

Morphologic Techniques

Animal Models

Summary

Further Reading

CHAPTER 16 HEMATOPOIETIC SYSTEM

Introduction

Phylogeny

Ontogeny

Structure and Function

Gross and Microscopic Anatomy

Hematopoiesis

Cellular Kinetics

Comparative Mechanisms of Toxicity

Idiosyncratic Reactions

Direct Damage

Myelotoxicity

Responses of Hematopoietic Tissues to Toxic Injury

Changes in Blood

Changes in Bone Marrow

Hematopoietic Assessment

Summary

Further Reading

CHAPTER 17 ENDOCRINE SYSTEM

Introduction

Adrenal Cortex

Structure and Function

Mechanisms of Toxicity

Response to Injury

Evaluation of Toxicity

Adrenal Medulla

Structure and Function

Mechanisms of Toxicity

Response to Injury

Evaluation of Toxicity

Pituitary Gland

Structure and Function

Mechanisms of Toxicity

Response to Injury

Evaluation of Toxicity

Thyroid C-cells

Structure and Function

Mechanisms of Toxicity

Response to Injury

Thyroid Follicular Cells

Structure and Function

Mechanisms of Toxicity

Response to Injury

Evaluation of Toxicity

Parathyroid Gland

Introduction

Structure and Function

Mechanisms of Toxicity

Response of Parathyroid Chief Cells to Injury

Evaluation of Toxicity

Further Reading

CHAPTER 18 MALE REPRODUCTIVE SYSTEM

Introduction

Structure and Cell Biology

Embryological Derivation of the Reproductive Tract

Structure of the Testes

Physiology and Functional Considerations of the Testis

Structure and Function of the Epididymis and Excurrent Ducts

Structure and Function of Accessory Sex Organs

Penis and Ejaculation

Mechanisms of Toxicity

Role of Metabolism

Cell-specific Toxicity in the Testis

Vascular Effects and Indirect Toxicity to the Testis

Epididymal and Sperm Toxicity

Secondary Sex Organs

Hormone Disruption

Toxicity to the Developing Reproductive Tract

Responses to Injury

Disruption of Spermatogenesis

Tubular Dilatation and Tubular Shrinkage

Tubular and Testicular Necrosis

Leydig Cell Response

Disruption of Sperm Maturation

Epididymal Response

Response to Alterations in Hormone Balance

Reversibility

Reproductive Toxicity in Domestic Animals

Evaluation of Toxicity

Detecting Toxicity

Characterization of Reproductive Toxicity

Functional Characterization

Testing for Toxicity of the Developing Reproductive Tract

Conclusions

Further Reading

CHAPTER 19 FEMALE REPRODUCTIVE SYSTEM

Introduction

Structure and Functional Physiology

Structure

Functional Physiology

Mechanisms of Toxicity

General Toxicity

Ovary, Uterus, and Vagina as a Unit

Local Vaginal Toxicity

Carcinogenesis

Response to Injury

General Responses: Ovary, Uterus, and Vagina as a Unit

Local Vaginal Responses

Reproductive Toxicity in Domestic Animals

Neoplasia

Testing for Toxicity

General Toxicity

Local Vaginal Toxicity

Summary

Further Reading

CHAPTER 20 DEVELOPMENTAL PATHOLOGY

Introduction

Overview of Fetal Toxicologic Pathology

Basic Principles of Developmental Toxicology

Incidence of Congenital Anomalies

Normal Morphologic Development

Fertilization and Blastocyst Formation

Gastrulation

Organogenesis

Histogenesis and Functional Maturation

Mechanisms of Toxicity

Critical Phases of Intrauterine Development

Modifying Factors

Response to Injury

Death

Malformations

Intrauterine Growth Retardation

Perinatal Toxicology

Endocrine Disruption

Congenital Neoplasia

How Dose Relates to Manifestation of Abnormal Development

Selected Malformations

Central Nervous System

Craniofacial Structures

Cardiovascular System

Respiratory System

Gastrointestinal System

Urinary System

Reproductive System

Skeletal System

Developmental Toxicity Testing and Risk Assessment

Hazard Identification and Dose-response Analysis

Dose–Response Evaluation

Field Investigation of Anomalies in Domestic Animals

Defining the Individual Incident

Defining the Prevalence

Defining the Maternal Environment

Genetic Analysis

Environmental Analysis: An Epidemiological Approach

Further Reading

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