Haschek and Rousseaux's Handbook of Toxicologic Pathology, Volume 2: Safety Assessment Environmental Toxicologic Pathology

Haschek and Rousseaux's Handbook of Toxicologic Pathology, Volume Two, Fourth Edition is a key reference on the integration of structure and functional changes in tissues associated with the response to pharmaceuticals, chemicals and biologics. Sections discuss Toxicologic Pathology in Product Discovery and Safety Assessment, Safety Assessment and Data Interpretation, and Food and the Environment: Selected Toxic Agents. Completely revised with new chapters, this book is 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. Provides new chapters on gene therapy, stem cells, regenerative medicine, genome editing, and in-depth discussions of timely topics in toxicologic pathology Offers high-quality and trusted content in a multi-contributed work written by leading international authorities in all areas of toxicologic pathology Features hundreds of full-color images in both the print and electronic versions of the book to highlight difficult concepts with clear illustrations Front Cover HASCHEK AND ROUSSEAUX’S HANDBOOK OF TOXICOLOGIC PATHOLOGY HASCHEK AND ROUSSEAUX’S HANDBOOK OF TOXICOLOGIC PATHOLOGY Copyright Dedication Contents Contributors About the Editors EDITORS ASSOCIATE EDITORS ILLUSTRATIONS EDITOR Preface 1 - PRODUCT DISCOVERY AND DEVELOPMENT 1 - Overview of Drug Development 1 INTRODUCTION 2 OVERVIEW 2.1 The Stages of the Product Life Cycle Product Development Stages Product Introduction Growth Maturity Decline 2.2 The Scope of Drug Discovery and Development The Challenge Cost, Time, and Risks in Developing New Drugs Time Required to Develop a New Drug The Life Cycle of a Health Product 3 DRUG DISCOVERY AND DEVELOPMENT 3.1 Patents and Intellectual Property 3.2 Discovery Target Identification and Validation Target Validation Lead Generation and Optimization High-Throughput Assays and Quantitative Structure-activity Relationships (QSAR) Mechanistic Studies Innovative Trends in Drug Development Biomarkers Toxicity Assessment 4 DEVELOPMENT 4.1 Drug Substance and Drug Product Development (Quality) Development Pharmaceutics—The Active Pharmaceutical Ingredient Development Pharmaceutics—The Drug Product Manufacture of the Finished Dosage Form Impurities in the Final Drug Product Excipients Packaging Materials Stability Testing of APIs and DPs 4.2 Nonclinical Safety Studies Selection of Doses for Nonclinical Studies Toxicity Tests GENOTOXICITY BACTERIAL MUTATION (AMES) ASSAY CHROMOSOMAL ABERRATION ASSAYS MICRONUCLEUS TEST MUTAGENICITY TEST SINGLE-DOSE TOXICITY REPEATED-DOSE TOXICITY REPRODUCTIVE TOXICITY CARCINOGENIC POTENTIAL 4.3 Animal Efficacy Studies Short-Term Efficacy Studies in Animals BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES DIGESTION AND BALANCE STUDIES Design Considerations for Nonclinical Efficacy Studies ENDPOINTS TIMING OF INTERVENTION ROUTE OF ADMINISTRATION DOSING REGIMEN Risk Mitigation Methods Dose Escalation 5 OTHER HEALTH PRODUCTS 5.1 Biologics 5.2 Medical Devices 5.3 Natural Health Products 5.4 Vaccines 6 CLINICAL TRIALS 6.1 Phase I Clinical Trials 6.2 Phase II Clinical Trials 6.3 Phase III Clinical Trials 6.4 Phase IV Clinical Trials 6.5 Limitations of Clinical Trials 7 POSTMARKETING SURVEILLANCE 7.1 Adverse Drug Events 7.2 Adverse Drug Reactions 7.3 Current Mechanisms and Tools for Identifying and Quantifying ADRs 8 REGULATORY AUTHORITIES 8.1 Overview International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use United States and Canada Europe and the United Kingdom Asia Latin America 8.2 Considerations on Legal Frameworks 9 SUMMARY AND CONCLUSIONS REFERENCES Selected Links to Regulatory Authorities and Issues 2 - Overview of the Role of Pathology in Product Discovery and Development 1 INTRODUCTION 2 DISCOVERY TOXICOLOGY 2.1 Small Molecules 2.2 Nucleic Acid–Based Pharmaceuticals 2.3 Biologics 2.4 Cell and Gene Therapy 3 DEVELOPMENT TOXICOLOGY 3.1 Small Molecules 3.2 Nucleic Acid Pharmaceuticals 3.3 Biologics 3.4 Cell and Gene Therapy 3.5 Anticancer Drugs 3.6 Adversity and Reversibility 3.7 Clinical Dose Setting and Clinical Safety Assessments 3.8 Regulatory Filings 4 NONSTANDARD STUDIES AND END POINTS 4.1 Pharmacology (Efficacy) Studies 4.2 Investigative (Mechanistic) Toxicology Studies 4.3 Standard and Alternative Animal Models 4.3 Standard 4.3 Alternative NONMAMMALIAN MODELS MAMMALIAN MODELS 4.4 Biomarker Considerations 4.5 Interpretation of Unique Findings REFERENCES 3 - Discovery Toxicology and Discovery Pathology 1 INTRODUCTION 1.1 Discovery Toxicology 1.2 Discovery Pathology 2 KNOWLEDGE INTEGRATION AND THE SPANNING OF DISCIPLINES 3 PATHOLOGY TOOLBOX 4 IN VITRO/IN VIVO CORRELATIONS 5 TARGET SELECTION 6 TARGET VALIDATION 7 TRANSLATIONAL MEDICINE 8 HYPOTHESIS GENERATION, EXPERIMENTAL DESIGN, AND THE ROLE OF INVESTIGATIVE STUDIES 9 DISCOVERY STRATEGY FOR BIOLOGICS 10 COMMUNICATIONS 11 PERSONALITY AND BEHAVIORAL TRAITS THAT ARE HELPFUL TO SUCCEED IN DISCOVERY PATHOLOGY AND DISCOVERY TOXICOLOGY 12 SUMMARY REFERENCES 4 - Pathology in Nonclinical Drug Safety Assessment 1 INTRODUCTION 2 DRUG SAFETY AND EFFICACY ARE A CONTINUUM 3 THE PATHOLOGIST'S ROLE IN NONCLINICAL SAFETY ASSESSMENT 3.1 Adverse Effects and Pathology Report 3.2 Reversibility and Delayed Toxicity 3.3 Lexicon and Diagnostic Terminology 3.4 GLP Regulations in Pathology 3.5 Pathology Peer Review 3.6 NOAELs and Study Report 4 PATHOLOGY IN NONCLINICAL SAFETY ASSESSMENT OF SMALL MOLECULES 5 PATHOLOGY IN NONCLINICAL SAFETY ASSESSMENT OF BIOTHERAPEUTICS 5.1 Proteins 5.2 Oligonucleotides 5.3 Gene Therapy 5.4 Cell Therapy 5.5 Stem Cell Therapy 5.6 Vaccines 6 PATHOLOGY IN NONCLINICAL SAFETY ASSESSMENT OF NOVEL FORMULATIONS 6.1 Excipients 6.2 Conjugation 6.3 Nanotechnology 7 DIGITAL PATHOLOGY AND COMPUTATIONAL PATHOLOGY 8 NOVEL INVESTIGATIVE TOOLS IN NONCLINICAL SAFETY ASSESSMENT 9 CONCLUSION REFERENCES REFERENCES 5 - Carcinogenicity Assessment 1 THE PAST, PRESENT, AND POTENTIAL FUTURE OF CARCINOGENICITY ASSESSMENT 1.1 Brief History of Carcinogenicity Assessment 1.2 Food, Drugs, and Cosmetics 1.3 Other Chemicals 1.4 Relevance of Rodent Findings in Carcinogenicity Hazard Identification Studies for Human Risk 1.5 Evolution from Lifetime Bioassays in Two Rodent Species to the Current Standards 1.6 Looking Forward: ICH Guideline S1B Modifications 1.7 New Approaches in Predicting Carcinogenicity Hazards 1.7 In vivo Approaches in Cancer Hazard Assessment 2 PURPOSE, PLANNING, PREREQUISITE INFORMATION, AND TIMING OF LIFETIME CARCINOGENICITY STUDIES 2.1 Prerequisite Data to Design a Carcinogenicity Study Protocol 2.2 Special Protocol Assessment for Carcinogenicity Studies 2.3 Carcinogenicity Study Planning Timeline 3 TWO-YEAR RODENT CARCINOGENICITY STUDIES 3.1 Study Design 3.2 Managing High Mortality in 2-Year Carcinogenicity Studies 3.2 Low Survival in Treated Groups 3.2 Low Survival in the Control Groups 3.2 Low Survival Observed before 12Months 3.3 Pathology Interpretations 3.4 Historical Control Data 4 ALTERNATIVE GENETICALLY MODIFIED MOUSE MODELS 4.1 The Range-Finding Study 4.2 Carcinogenicity Study Design Using Alternative Models 4.3 Conduct of Carcinogenicity Studies Using Alternative Models 5 CARCINOGENICITY ASSESSMENT OF BIOTECHNOLOGY-DERIVED THERAPEUTIC PROTEINS 6 CARCINOGENICITY ASSESSMENT OF NUCLEIC ACID THERAPIES 7 CARCINOGENICITY ASSESSMENT OF STEM CELL–DERIVED THERAPIES 7.1 Safety Concerns for Stem Cell–Derived Therapies 7.2 In vivo Assessment of Teratoma Formation 8 CARCINOGENICITY ASSESSMENT OF MEDICAL DEVICES 9 CONCLUSION REFERENCES 2 - PRODUCT-SPECIFIC PRACTICES FOR SAFETY ASSESSMENT 6 - Protein Therapeutics 1 HISTORY OF PROTEIN THERAPEUTICS 2 TYPES OF PROTEIN THERAPEUTICS: STRUCTURAL AND FUNCTIONAL CONSIDERATIONS 2.1 Key Structural and Functional Elements of Antibodies and Related Products 3 GENERAL NONCLINICAL TOXICITY TESTING STRATEGIES 3.1 General Considerations 3.2 Applicable Regulatory Guidelines 3.3 Target Characterization/Species Selection 4 IMMUNOGENICITY 4.1 Overview 4.2 Effect of Immunogenicity 4.3 Predictivity of Nonclinical Immunogenicity 4.4 Assessing Immunogenicity 4.5 Managing Immunogenicity in Toxicity Studies 5 OFF-TARGET PROFILING 5.1 Overview 5.2 History 5.3 Whether and When to Conduct 5.4 Molecules to Test 5.5 Species to Test 5.6 TCR Strategies Supporting FIH (Only for CDR-Containing Test Articles) 5.7 Impact and Regulatory Considerations 6 GENERAL TOXICITY STUDY DESIGN CONSIDERATIONS 6.1 Overview 6.2 Exploratory (Non-GLP) Studies 6.3 FIH-Enabling Studies 6.4 Post-FIH-Enabling Studies 6.5 Dose Selection 6.6 Dosing Interval 6.7 Route of Administration, Formulation 6.8 Recovery 7 IMMUNOTOXICITY 7.1 Overview 7.2 In Vitro Assays for Assessing Immunotoxicity 7.3 In Vivo Assays for Assessing Immunotoxicity 7.4 Immunosuppression 7.5 Immunostimulation 7.6 Program Strategies and Regulatory Considerations 8 SAFETY PHARMACOLOGY ASSESSMENTS 8.1 Overview 8.2 Strategy and Timing 9 DEVELOPMENTAL AND REPRODUCTIVE TOXICITY STUDIES AND JUVENILE ANIMAL STUDIES 9.1 Overview 9.2 Species to Test and Alternative Models 9.3 Study Design Considerations 9.4 Strategies and Timing 9.5 Nonclinical Pediatric Evaluation 10 GENOTOXICITY 11 CARCINOGENICITY STUDIES 12 ADVANCED CANCER 13 ANTIBODY-DRUG CONJUGATES 13.1 Overview 13.2 Mechanisms of Toxicity 13.3 Nonclinical Safety Assessment 14 MULTISPECIFIC MOLECULES 15 BIOSIMILARS 16 TOXICOLOGIC PATHOLOGY OF PROTEIN THERAPEUTICS—PUTTING IT ALL TOGETHER 16.1 On-Target, Off-Target, and Immunogenicity-Related Effects 16.2 Determining Adversity GLOSSARY Acknowledgments REFERENCES REFERENCES 7 - Nucleic Acid Pharmaceutical Agents 1 INTRODUCTION 2 NUCLEIC ACID PHARMACEUTICALS 2.1 Types of Nucleic Acid Pharmaceuticals 2.1 Antisense Oligonucleotides 2.1 Small Interfering RNA 2.1 MicroRNA 2.2 Advantages of Nucleic Acid Pharmaceuticals over Traditional Therapeutic Modalities 2.3 Specific Indications for Nucleic Acid Pharmaceuticals 2.4 Clinical Trials of Nucleic Acid Pharmaceuticals 3 NUCLEIC ACID PHARMACEUTICAL DESIGN AND DEVELOPMENT 3.1 Chemistry Considerations 3.1 ASOs 3.1 SiRNAs and miRNAs 3.2 Delivery Considerations 3.2 Common Delivery Systems 3.2 Systemic Delivery 3.2 Local Delivery to the Central Nervous System or Peripheral Tissues 3.2 Exploration of Novel Delivery Systems 3.3 Pharmacology Considerations 3.3 Biodistribution 3.3 Detection Methods for Therapeutic Oligonucleotides 4 SAFETY EVALUATION OF NUCLEIC ACID PHARMACEUTICALS 4.1 Regulatory Perspective 4.1 Species Selection for Safety Studies 4.1 Use of Surrogate Sequences 4.1 Genotoxicity Studies 4.1 Reproductive and Developmental Toxicity Studies 4.1 Safety Pharmacology Studies 4.2 Use of Animal Models for Safety Evaluation 4.2 Delivery Models 4.2 Disease-Modifying Models 4.3 Mechanisms of Common Toxicities 4.3 Hybridization-dependent Toxicity 4.3 Hybridization-independent Toxicity 4.3 Tissue Accumulation 5 CONCLUSIONS GLOSSARY REFERENCES 8 - Gene Therapy and Gene Editing 1 INTRODUCTION 2 GENERAL PRINCIPLES OF NONCLINICAL RESEARCH AND DEVELOPMENT FOR GENE THERAPY PRODUCTS 2.1 Pharmacology 2.2 Toxicology 2.3 Biodistribution and Viral Shedding 2.4 Role of Pathologists in the Nonclinical Assessment of Gene Therapy Products 3 IN VIVO GENE THERAPY 3.1 General Concepts of In Vivo Gene Therapy 3.2 AAV as a Model Platform for in vivo Gene Therapy 3.3 Nonclinical Pharmacology and Safety Assessment for in vivo Gene Therapy 3.3 Pharmacology 3.3 Biodistribution 3.3 Toxicology 3.4 Contemporary Toxicities Associated With In Vivo Gene Therapy 3.4 Immunotoxicity Associated With AAV-Based Gene Therapy INNATE IMMUNE RESPONSES TO AAV-BASED GENE THERAPY PRODUCTS ADAPTIVE IMMUNE RESPONSES TO AAV-BASED GENE THERAPY PRODUCTS ASSESSMENT OF IMMUNOTOXICITY IN NONCLINICAL STUDIES 3.4 Acute Liver Injury Associated With High-Dose Gene Therapy 3.4 Dorsal Root Ganglion (DRG) Toxicity Associated With AAV Vectors 3.4 DNA Integration, Hepatocellular Carcinoma, and AAV-Based Gene Therapy 4 EX VIVO GENE THERAPY 4.1 General Concepts of Ex Vivo Gene Therapy 4.1 Autologous Lentiviral Vector–Transduced CD34+ Hematopoietic Stem Cell Ex Vivo Gene Therapy 4.1 Retroviral Vectors Derived from Gamma-Retroviruses and Lentiviruses 4.2 Nonclinical Safety Assessment for Ex Vivo Gene Therapy 4.2 Nonclinical Evaluation Strategies for Ex Vivo Gene Therapy 4.2 Proof-of-Concept Studies for Ex Vivo Gene Therapy 4.2 Biodistribution and Pharmacodynamics for Ex Vivo Gene Therapy 4.2 Toxicity Studies (In Vivo Safety Assessment) for Ex Vivo Gene Therapy 4.2 Experimental Design Features Supporting Ex Vivo Gene Therapy Development ANIMAL MODEL OPTIONS ANIMAL NUMBERS PER GROUP STUDY DURATION CONTROL GROUPS TIME POINTS SOURCE OF CELLS CELL AND VECTOR CHARACTERIZATION ROUTE OF ADMINISTRATION AND DOSING REGIMEN VECTOR COPY NUMBER 4.2 Genotoxicity Studies INTEGRATION SITE ANALYSIS IN VITRO IMMORTALIZATION ASSAY AND SURROGATE ASSAY FOR GENOTOXICITY ASSESSMENT 4.3 Toxicologic Pathology Considerations With Ex Vivo Gene Therapy 4.3 Conditioning Agents in Ex Vivo Gene Therapy CONDITIONING 4.3 Immunogenicity 4.3 Tumorigenicity 5 GENOME EDITING 5.1 Harnessing Cellular DNA Repair 5.1 Zinc-Finger Nucleases 5.1 TALENS 5.1 RNA-Guided Endonucleases (CRISPR/Cas Systems) 5.1 Base Editing 5.2 Genome Editing Strategies 5.2 Loss-of-Function GENE DELETION 5.2 Gain-of-Function GENE INSERTION 5.2 Gene Correction NUCLEASE-MEDIATED CORRECTION 5.3 Nonclinical Safety Assessment for Genome Editing Products 5.3 Exaggerated Pharmacology 5.3 Biodistribution 5.3 Toxicology EFFECTS FROM NANOPARTICLE DELIVERY OF NUCLEIC ACIDS GENOTOXICITY METHODS OF ASSESSING GENOTOXICITY Off-Target Site Discovery Off-Target Site Verification CONSIDERATIONS FOR OFF-TARGET RISK ASSESSMENT CHROMOSOMAL STRUCTURAL VARIATION GENOTOXICITY SUMMARY AND FUTURE DIRECTIONS IMMUNE ACTIVATION 6 CONCLUSION GLOSSARY REFERENCES 9 - Vaccines 1 INTRODUCTION 2 VACCINE IMMUNOLOGY 3 GENERAL CONCEPTS IN VACCINE TOXICOLOGY 3.1 Vaccine Nonclinical Safety Package: Regulatory Expectations 3.2 Immunogenicity Assays 4 VACCINE MODALITIES 4.1 Protein-Based Vaccines 4.1 Protein and Recombinant Protein Vaccines 4.1 Glycoconjugate Vaccines 4.1 Virus-like Particles Nanoparticle or Generalized Modules for Membrane Antigen Based Vaccines 4.2 Nucleic Acid–Based Vaccines 4.2 RNA-Based Vaccines 4.2 DNA Vaccines 4.2 Inactivated and Attenuated Virus Vaccines 4.2 Viral Vectored Vaccines 4.2 Anti-idiotype Vaccines 4.2 Cell-Based Vaccines 4.2 Oncolytic Virus–Based Modalities 5 VACCINE ADJUVANTS 5.1 Mineral Salts 5.2 Surfactant/Emulsion Adjuvants 5.3 Nucleic Acid/Nucleotide Adjuvants 5.3 CpG-ODN 5.3 Double- or Single-Stranded RNA or RNA Analogs 5.4 Lipid Adjuvants 5.5 Adjuvant Systems and Liposome-Based Adjuvants 5.5 Lipid Nanoparticles for Delivery of mRNA-Based Vaccines 5.6 Carbohydrate-Containing Adjuvants 5.7 Toxin-Based Adjuvants 5.8 Other Adjuvants 6 VACCINE PHARMACOLOGY AND OTHER STUDIES 6.1 Immunogenicity and Efficacy Studies 6.1 Immunogenicity Studies 6.1 Efficacy Studies INFECTIOUS DISEASE VACCINES THERAPEUTIC CANCER VACCINES 6.2 Enhanced Disease and Neurovirulence Assessment 6.2 Enhanced Disease 6.2 Neurovirulence Assessments 6.3 Biodistribution and Persistence 6.4 Absorption, Distribution, Metabolism, and Excretion 7 VACCINE SAFETY STUDIES 7.1 Repeat-Dose Toxicity Studies 7.1 Developmental and Reproductive Toxicity Studies 8 VACCINE STUDIES—DESIGN, TECHNICAL CONSIDERATIONS, AND DATA INTERPRETATION 8.1 Species Selection 8.2 Dose Groups 8.3 Technical Considerations Related to Dosing and Dose Administration 8.3 Route of Administration 8.3 Dose Volume 8.3 Animal Husbandry and Dosing 8.3 Injectable Vaccines 8.3 Restraint, Handling, and Dosing 8.4 In-Life Assessments 8.4 Local Toxicity and Reactogenicity 8.5 Clinical Pathology 8.5 Hematology 8.5 Clinical Chemistry 8.5 Coagulation 8.5 Acute Phase Biomarkers 8.5 Therapeutic Vaccine Considerations 8.6 Anatomic Pathology—Post-life Evaluation 8.6 Macroscopic Observations and Sample Collection 8.6 Microscopic Evaluation 8.6 Injection Site—Microscopic Findings 8.6 Draining Lymph Nodes and Spleen 8.6 Other Tissues 8.6 Combined Safety–Efficacy Studies 9 SPECIAL CONSIDERATIONS FOR THERAPEUTIC MODALITIES 9.1 Therapeutic Vaccines 9.2 Other Therapeutic Vaccine Strategies 9.3 Oncolytic Virus-Based Therapeutic Vaccines 10 NONCLINICAL TOXICITY—DETERMINING ADVERSITY 11 NONCLINICAL TOXICITY AND HUMAN TRANSLATION 11.1 Autoimmunity 11.2 Hypersensitivity 11.3 Thrombotic Thrombocytopenia 12 VACCINES AND THE ANTI-VACCINE MOVEMENT 13 CONCLUSIONS 14 GLOSSARY REFERENCES REFERENCES 10 - Stem Cell and Other Cell Therapies 1 INTRODUCTION 2 BIOLOGICAL PRINCIPLES OF CELL THERAPY 2.1 Cell Sources 2.1 Autologous Cells 2.1 Allogeneic Cells 2.1 Xenogeneic Cells 2.2 Classes of Transplantable Cells 2.2 Pluripotent Stem Cells EMBRYONIC STEM CELLS SOMATIC CELL–DERIVED STEM CELLS INDUCED PLURIPOTENT STEM CELLS OTHER SOMATIC-ORIGIN STEM CELLS 2.3 Primary Preclinical Safety Considerations for Cell Therapies 2.3 Test Article–Related Safety Considerations BIODISTRIBUTION OF IMPLANTED CELLS DIFFERENTIATION OF IMPLANTED CELLS PROLIFERATION OF IMPLANTED CELLS 2.3 Procedure-Related Safety Considerations ANIMAL MODELS OF DISEASE IMPLANTATION-RELATED TISSUE INJURY IMMUNOGENICITY TOWARD OR BY IMPLANTED CELLS 3 PRECLINICAL CONSIDERATIONS FOR CELL THERAPIES 3.1 Regulatory Guidance 3.2 Key Endpoints for Preclinical Assessment of Cell Therapies 3.3 Design of Preclinical Safety Studies 3.3 Species Selection 3.3 Group Constitution 3.3 Study Regimen CBMPS AS THERAPEUTIC TEST ARTICLES CBMP AS SUBSTRATES TO DELIVER THERAPEUTIC MOLECULES 3.3 Analytical Design 3.3 Principal Cell Therapy-Related Findings in Tissues EFFECTS DUE TO IMPLANTED CELLS EFFECTS RELATED TO THE IMPLANTATION PROCEDURE 3.4 The Pathologist's Contribution 4 STEM CELL–BASED TOXICITY TESTING 5 SUMMARY GLOSSARY Acknowledgments REFERENCES 3 - DATA INTERPRETATION AND COMMUNICATION 11 - Biomedical Materials and Devices 1 INTRODUCTION 2 DEFINITIONS OF BIOMATERIALS AND BIOMEDICAL DEVICES 2.1 Types of Biomaterials 2.2 Characteristics of Biomaterials and Medical Devices 3 REGULATORY GUIDELINES 3.1 Regulatory Classification of Devices 3.2 Regulatory Standards 4 SAFETY AND FUNCTIONAL ASSESSMENTS OF BIOMATERIALS AND DEVICES 4.1 Biocompatibility 4.2 Safety, Function, and Efficacy 4.3 Integration, Degradation, and Fate of Implanted Medical Materials 4.3 Integration and Degradation of Medical Materials 4.3 Determination of Complete Biodegradation 4.4 Interactions of the Body and the Device, and Biological Fates of Medical Devices 4.4 Body–Device Interactions 4.4 Device–Body Interactions 4.5 Biologic Fate of and Adverse Reactions to Medical Devices 4.6 Immunotoxicology and Immunopathology 4.7 Carcinogenicity 4.7 Metals and Carcinogenicity 4.7 Silicon and Synthetic Silicone 4.8 Histopathologic Assessment of Device/Host Tissue Interactions 4.8 Local Tissue Effects 4.8 Regional Tissue Effects 4.8 Systemic Effects 5 ORGAN SYSTEMS COMMONLY TREATED WITH BIOMATERIALS/MEDICAL DEVICES 5.1 Multisystemic Uses of Devices/Biomaterials 5.2 Cardiovascular 5.2 Vessels 5.2 Catheters 5.3 Musculoskeletal 5.3 Definitions Used in the Evaluation of Interactions of Bone Implants and Bone Substitutes 5.4 Ophthalmic Devices 5.5 Soft Tissue Repair and Wound Management 5.6 Neural and Endocrine Devices 5.7 Oral/Dental 5.8 Bioengineered Implants, Combination Devices, and Delivery Systems Combination Devices 5.9 Other Organ Systems and Devices 6 CONCLUSION REFERENCES REFERENCES 12 - Safety Assessment of Agricultural and Bulk Chemicals 1 INTRODUCTION 2 DEFINITION AND USE OF AGRICULTURAL CHEMICALS 2.1 Different Classes of Agricultural Chemicals 2.2 Screening Strategies for New Compound Classes 3 DEFINITION AND USE OF BULK CHEMICALS 4 SAFETY EVALUATION STRATEGIES 4.1 Regulatory Requirements for Agricultural Chemicals 4.1 North/South America 4.1 Europe 4.1 Asia-Pacific 4.2 Regulatory Requirements for Bulk Chemicals 4.2 North/South America 4.2 Europe 4.2 Asia-Pacific 5 REGULATORY STUDIES FOR REGISTRATION OF AGRO/BULK CHEMICALS 5.1 Toxicity Studies 5.2 Ecotoxicity Studies 6 TOXICOLOGIC PATHOLOGY FINDINGS AND ASSESSMENT 7 SUMMARY AND CONCLUSIONS 8 GLOSSARY REFERENCES 13 - Preparation of the Anatomic Pathology Report for Toxicity Studies 1 INTRODUCTION 2 OBJECTIVE AND AUDIENCE FOR THE ANATOMIC PATHOLOGY REPORT 3 DEVELOPING THE DATA FOR THE ANATOMIC PATHOLOGY REPORT 3.1 Study Protocol 3.2 Importance of Assessing Correlative Data Before Beginning Microscopic Review of the Tissues 3.3 Value of Data from More than One Time Point 4 REVERSIBILITY 4.1 Presentation and Interpretation of Organ Weight Data 4.2 Presentation and Interpretation of Gross Observations 4.3 Presentation and Interpretation of Microscopic Observations 5 TEXT TABLES 6 THE ANATOMIC PATHOLOGY REPORT DISCUSSION 7 THE ANATOMIC PATHOLOGY REPORT CONCLUSION 8 SIGNING THE ANATOMIC PATHOLOGY REPORT 9 EXAMPLES TO BE AVOIDED IN INTERPRETING/PRESENTING DATA IN THE ANATOMIC PATHOLOGY REPORT 10 PEER REVIEW AND PATHOLOGY WORKING GROUPS 11 CONCLUSION REFERENCES REFERENCES 14 - Interpretation of Clinical Pathology Results in Nonclinical Toxicity Testing 1 INTRODUCTION 2 SAMPLE COLLECTION 3 HEMATOLOGY INTERPRETATION (ALSO SEE HEMATOPOETIC SYSTEM, VOL 5, CHAP 5) 3.1 Erythrocytes 3.2 Decreased Red Cell Mass 3.3 Blood Loss 3.4 Hemolysis 3.5 Diminished Erythropoiesis 3.6 Increased Red Cell Mass 3.7 Leukocytes 3.8 Increased Leukocytes 3.9 Decreased Leukocytes 3.10 Platelets 4 INTERPRETATION OF BONE MARROW MORPHOLOGY 5 COAGULATION INTERPRETATION 5.1 Hemostasis 5.1 Primary Hemostasis—Platelets Adhere and Aggregate 5.1 Secondary Hemostasis—Clotting, Soluble Factors Generate Insoluble Fibrin 5.1 Fibrinolysis—Clot Dissolution 5.1 Hypercoagulable and Prothrombotic States 6 CLINICAL CHEMISTRY INTERPRETATION 6.1 Glucose, Cholesterol, and Triglycerides 6.2 Blood Urea Nitrogen (Urea or BUN) and Creatinine 6.3 Total Protein, Albumin, and Albumin/Globulin Ratio 6.4 Calcium and Phosphorus 6.5 Sodium, Chloride, and Potassium 6.6 Markers of Hepatobiliary Injury or Function 6.7 Muscle Injury Markers 7 URINALYSIS AND URINE CHEMISTRY INTERPRETATION 8 NONSTANDARD BIOMARKERS 8.1 Renal Biomarkers 8.2 Hepatobiliary Biomarkers 8.3 Cardiac Biomarkers (see Cardiovascular System, Vol 5, Chap 1) 8.3 Cardiac Troponin 8.3 Creatine Kinase, Aspartate Aminotransferase, Lactate Dehydrogenase 8.3 Atrial and Brain Natriuretic Peptides 8.3 Fatty Acid–Binding Protein and Myosin Light Chain 3 8.4 Inflammatory Biomarkers 8.4 Acute Phase Proteins 8.4 Cytokine/Chemokine Evaluation 8.4 Complement 8.5 Hormones (see Endocrine System, Vol 4, Chap 7) 9 POTENTIAL EFFECTS UNRELATED TO TEST ARTICLE TREATMENT 9.1 Artifacts 9.2 Analytical Methods 9.3 Age/Sex/Genetics 9.4 Anesthesia 9.5 Blood Collection 9.6 Diet/Fasting 9.7 Medications 9.8 Fear/Pain/Stress 9.9 Environment 9.10 Sample Types, Handling, and Stability 9.11 Pregnancy, Neonatal Period, and Estrous Cycle 9.12 In Extremis/Postmortem 10 OVERALL RESULTS INTERPRETATION AND REPORT INTEGRATION 11 COMPARATOR DATA, HISTORICAL CONTROLS, AND STATISTICS 11.1 Comparator Data 11.2 Historical Controls 11.2 Statistics 12 DESCRIPTORS AND BIOLOGIC RELEVANCE 13 REPORT WRITING AND INTEGRATION 13.1 Adversity Reporting in Clinical Pathology 14 CONCLUSIONS REFERENCES 15 - Assigning Adversity to Toxicologic Outcomes 1 INTRODUCTION AND THE NEED FOR QUANTIFYING ADVERSITY 1.1 History: Adversity, Organ Function, and the NOAEL 2 REGULATORY ASSESSMENT OF ADVERSITY IN THE EU, THE UNITED STATES, AND JAPAN 3 ADVERSE REACTIONS, ADAPTATION, AND REVERSIBILITY 3.1 Adaptation and Adversity 3.2 Reversibility and Adversity 3.3 Exacerbation of Spontaneous Pathology, Historical Control Data, and Adversity 4 THE RELATIONSHIP BETWEEN DOSE RESPONSE AND POTENCY THRESHOLDS IN DEFINING ADVERSITY 5 THE ROLE OF PATHOLOGY IN DEFINING ADVERSITY 5.1 Anatomic Pathology 5.1 Anatomic Pathology and Communicating Adversity 5.1 Additional Factors in Anatomic Pathology Influencing Adversity Decisions 5.1 Anatomic Pathology and Function 5.1 Anatomic Pathology and Severity Grading 5.1 Anatomic Pathology Peer Review in Ensuring the Relevance of Adversity Decisions 5.2 Clinical Pathology 5.2 Clinical Pathology and Functional Assessment 5.2 Clinical Pathology and Dose Response 5.2 Clinical Pathology and Reference Intervals 5.2 Clinical Pathology and the Importance of Quantification in Adversity Decisions 5.2 Clinical Pathology and the Speed and Reversibility of Responses 5.2 Clinical Pathology in Dead or Moribund Animals 5.2 Conclusions 6 CASE EXAMPLES OF ASSESSING ADVERSITY 6.1 Introduction 6.2 Thymic Involution 6.3 Liver Weight Changes 6.3 Regulatory Opinion on Adversity and Liver Weight Increases 6.3 Conclusions 6.4 Progressive Cardiomyopathy—Rat 6.4 Pathophysiology of Rodent Progressive Cardiomyopathy 6.5 Alveolar Macrophage Aggregates 6.6 Squamous Metaplasia in Larynx 6.7 Chemically Induced Exacerbation in Retinal Degeneration 6.8 Treatment-Associated Exacerbation of Chronic Progressive Nephropathy 6.9 Exacerbation of Renal Tubular Mineralization 7 GUIDELINES FOR ADVERSITY DECISIONS 8 NEW APPROACHES TO CHARACTERIZING ADVERSITY IN THE 21ST CENTURY? 8.1 The Adverse Outcome Pathway and Its Relevance to Assessing Adversity 8.2 Assessing Adversity Using Bespoke Studies and Alternative Assays 9 CONCLUSIONS REFERENCES 16 - Risk Assessment 1 INTRODUCTION 2 CLASSICAL RISK ASSESSMENT 3 ADVANCES IN CONTEMPORARY RISK ASSESSMENT REFERENCES 17 - Risk Management and Communication: Building Trust and Credibility With the Public 1 DEFINING RISK 2 MANAGING RISK 2.1 General Principles 2.2 Risk Management for Biopharmaceuticals 2.2 Benefit–Risk Principles 2.2 Risk Management in Clinical Development DOSE, SAFETY MARGINS, AND EXPOSURE MULTIPLES DETERMINATION OF HIGHEST RECOMMENDED HUMAN DOSES SAFETY BIOMARKERS ADDITIONAL CLINICAL DEVELOPMENT CONSIDERATIONS 2.2 Risk Management of Approved Therapeutics POSTAPPROVAL SAFETY SURVEILLANCE ENHANCED RISK MANAGEMENT APPROACHES 2.3 Risk Management for Nonpharmaceuticals 2.3 Principles and Considerations 2.3 Risk Management Across Sectors ENVIRONMENTAL CHEMICALS FOOD ADDITIVES AND DIETARY SUPPLEMENTS COSMETICS AND PERSONAL CARE PRODUCTS CONSUMER PRODUCTS MEDICAL DEVICES 3 COMMUNICATING RISK 3.1 General Principles: The Science of Risk Communication 3.1 Challenges and Obstacles to Effective Risk Communication DATA VERSUS INFORMATION EXPECTATIONS OF SCIENCE CONTRADICTORY EXPERT OPINIONS 3.1 The Perception and Acceptance of Risk LIKELIHOOD (SIZE) OF THE ADVERSE EFFECT PERMANENT OR REVERSIBLE NATURE OF THE ADVERSE EFFECT WHO BENEFITS FROM ACCEPTANCE OF A RISK? 3.2 Targeting the Right Audience 3.2 Drug Discovery 3.2 Supporting Clinical Development 3.2 Product Approval and Marketing 3.3 Risk Communication: Pharmaceutical Safety Assessment 3.3 Risk Information for Clinical Trials 3.3 Risk Information for Approved Therapeutic Agents 3.4 Risk Communication: NonPharmaceuticals 3.4 Risk Communication Across Nonpharmaceutical Sectors 4 CONCLUSIONS REFERENCES Index A B C D E F G H I J K L M N O P Q R S T U V Back Cover Haschek and Rousseaux's Handbook of Toxicologic Pathology, recognized by many as the most authoritative single source of information in the field of toxicologic pathology, has been extensively updated to continue its comprehensive and timely coverage. The fourth edition has been expanded to five separate volumes due to an explosion of information in this field requiring new and updated chapters. Completely revised with a number of new chapters, Volume 2: Toxicologic Pathology in Safety Assessment is an essential part of the most authoritative reference on toxicologic pathology principles and techniques for assessing product safety and human risk. Volume 2 describes the integration of product-induced structural and functional changes in tissues and the interpretation of their biological implications. Completely revised with many new chapters, Volume 2 of the Fourth Edition covers product safety assessment from many angles including current and emerging issues in toxicologic pathology for many product classes. Volume 2 of the Handbook of Toxicologic Pathology is a key resource for pathologists, toxicologists, research scientists, and regulators who use toxicologic pathology methods to study and make decisions on product safety. Previous chapters on such topics as drug discovery and development, toxicity and carcinogenicity testing, report preparation, and risk assessment and communication have undergone extensive revision that includes in-depth discussion of new developments in the field New chapters consider fundamental attributes for additional product classes including protein therapeutics, nucleic acid pharmaceutical agents, gene therapy and gene editing, stem cell and other cell therapies, vaccines, agricultural and bulk chemicals, and assigning adversity Chapters dealing with product-specific practices address pathology and regulatory issues Chapters offer high-quality and up-to-date content in a trusted work written by the collaborative efforts of many leading international subject matter experts Hundreds of full-color images and diagrams are featured in both the print and electronic versions of this book to illustrate classic examples and highlight difficult concepts