Cover image for In Vitro Toxicology, Second Edition.
In Vitro Toxicology, Second Edition.
Title:
In Vitro Toxicology, Second Edition.
Author:
Gad, Shayne C.
ISBN:
9780203362815
Personal Author:
Edition:
2nd ed.
Physical Description:
1 online resource (419 pages)
Contents:
Book Cover -- Half-Title -- Title -- Copyright -- Dedication -- Contributors -- Contents -- Preface -- 1 Introduction -- 1.1 DEFINITIONS -- 1.2 LEVELS -- 1.3 HISTORY -- 1.3.1 The Four R's -- 1.4 DRIVING FORCES -- References -- 2 General Principles for In Vitro Toxicology -- 2.1 TEST SYSTEMS: CHARACTERISTICS, DEVELOPMENT, AND SELECTION -- 2.1.1 Considerations in Adopting New Test Systems -- 2.2 TARGET ORGAN TOXICITY MODELS -- 2.3 SENSITIVITY, SPECIFICITY, AND PREDICTIVE VALUE -- 2.4 PROBLEMS IN INTERPRETATION AND EXTRAPOLATION -- 2.5 VALIDATION -- References -- 3 Ocular Toxicity Assessment In Vitro -- 3.1 IN VIVO IRRITATION TESTING -- 3.2 DEVELOPMENT OF ALTERNATIVES -- 3.2.1 Prediction from Preexisting Data -- 3.2.2 In Vitro Approach -- 3.2.3 In Vitro Models -- 3.3 USING ALTERNATIVES -- 3.4 VALIDATION -- 3.5 CONCLUSIONS -- References -- 4 In Vitro Methods to Predict Skin Irritation -- 4.1 CURRENT IN VITRO METHODS -- 4.1.1 Physicochemical Test Methods -- 4.1.2 Cell Culture Techniques -- 4.1.3 Microorganism Studies -- 4.1.4 Human Skin Equivalents -- 4.1.5 Embryonic Testing -- 4.1.6 Computer Modeling/QSAR -- 4.2 HUMAN VOLUNTEER STUDIES -- 4.3 CONCLUSIONS -- References -- 5 Lethality Testing -- 5.1 CELL SYSTEMS -- 5.1.1 Primary Cultures -- 5.1.2 Permanent Cell Lines -- 5.1.3 Clonal Cell Lines -- 5.1.4 Growth Conditions -- 5.1.5 Metabolic Activating Systems -- 5.2 ENDPOINTS -- 5.2.1 Basal Cytotoxicity -- 5.3 VIABILITY -- 5.3.1 Dye Exclusion/Uptake -- 5.3.2 Membrane Leakage -- 5.4 CELL GROWTH -- 5.4.1 Cloning Efficiency -- 5.4.2 DNA Synthesis -- 5.4.3 Mitogenicity -- 5.4.4 Cell-Cycle Kinetics -- 5.5 CELL AND CULTURE MORPHOLOGY -- 5.5.1 Cell Morphology -- 5.5.2 Morphology Indicators of Cytotoxicity -- 5.5.3 Quantification of Morphologic Changes -- 5.6 CELL FUNCTIONS -- 5.6.1 Thermodynamic and Metabolic Function -- 5.6.2 MTT Assay -- 5.6.3 Calcium Ions.

5.7 ASSAY VALIDATION -- 5.7.1 Early Validation Studies -- 5.7.2 Multicenter Studies -- 5.8 THE ROLE OF PHARMACOKINETICS AND STRUCTURE-ACTIVITY RELATIONSHIPS IN MODELING -- 5.8.1 Pharmacokinetics -- 5.8.2 Physiologic Pharmacokinetic Modeling -- 5.8.3 Computer Structure-Activity Relationships Modeling -- 5.9 APPROACHES FOR EVALUATING HUMAN RISK -- References -- 6 In Vitro Genetic Toxicity Testing -- 6.1 BASIC MECHANISMS ASSESSED IN THE GENETIC TOXICOLOGY TESTS MOST FREQUENTLY USED FOR REGULATORY SUBMISSIONS -- 6.1.1 Gene Mutations -- 6.1.2 Chromosomal Mutations -- 6.2 DEVELOPMENT AND APPLICATION OF GENETIC TOXICOLOGY TESTS -- 6.3 HARMONIZED GUIDANCE FOR REGULATORY SUBMISSIONS -- 6.3.1 Organization for Economic Cooperation and Development Screening Information Data Set Guidelines -- 6.3.2 Toxic Substances Control Act Guidelines -- 6.3.3 International Council on Harmonization Guidelines -- 6.4 GENETIC TOXICOLOGY TESTS FOR CURRENT PRODUCT REGISTRATION -- 6.4.1 Reverse Gene Mutations in Bacteria -- 6.4.2 The L5178Y/Thymidine Kinase+/− Gene and Chromosomal Mutation Assay -- 6.4.3 Chromosomal Aberrations: In Vitro -- 6.4.4 Rodent Bone Marrow Chromosomal Effects -- 6.4.5 Chromosomal Aberrations: In Vivo -- 6.4.6 Micronucleus Tests. -- 6.5 ADVANTAGES, DISADVANTAGES, AND PREDICTIVITY OF THE GENETIC TOXICOLOGY TESTS USED FOR CURRENT PRODUCT REGISTRATION -- References -- 7 Pyrogenicity and Muscle Irritation -- 7.1 PYROGENICITY -- 7.1.1 In Vivo -- 7.1.2 In Vitro -- 7.2 IRRITATION OF PARENTERALLY ADMINISTERED AGENTS -- References -- 8 In Vitro Models for Evaluating Developmental Toxicity -- 8.1 PRIMARY CELL CULTURE -- 8.1.1 Nonmammalian Species -- 8.1.2 Mammalian Species -- 8.2 ESTABLISHED CELL LINES -- 8.3 WHOLE-ANIMAL SYSTEMS -- 8.3.1 Nonmammalian Systems -- 8.3.2 Mammalian Whole Embryos -- 8.4 ORGAN CULTURE -- 8.5 CELL-SIGNALING ASSAYS.

8.6 RELATING IN VITRO RESULTS TO RISK FOR THE INTACT ORGANISM -- 8.6.1 In Vitro-In Vivo Dose Conversion -- 8.6.2 Limitations of In Vitro Data for Assessing Health Risks -- 8.7 CONCLUSIONS -- ACKNOWLEDGMENTS -- References -- 9 Neurotoxicology In Vitro -- 9.1 BIOCHEMICAL AND CELLULAR MECHANISMS OF TOXICITY -- 9.2 IN VITRO SYSTEMS IN NEUROTOXICOLOGY -- 9.3 CULTURES OF SPECIFIC CELL TYPES -- 9.3.1 Glia -- 9.3.2 Neurons -- 9.3.3 Use in Physiologic Studies -- 9.4 TISSUE CULTURE METHODOLOGY -- 9.5 ASSAYS OF TOXICITY: CELL CULTURE MODELS -- 9.6 NEUROTOXICOLOGY -- 9.6.1 The Use of More Highly Organized, Multicomponent Systems as a Screening Tool -- 9.7 ISOLATED TISSUE ASSAYS -- 9.7.1 Electrophysiology Methods -- 9.7.2 Neurochemical and Biochemical Assays -- 9.8 THE USE OF GLOBAL MEASURES AS ASSAYS FOR TOXICOLOGIC DAMAGE -- 9.9 SPECIFIC NEUROTOXICOLOGIC STUDIES -- 9.9.1 Phenobarbital, Phenytoin, and Other Anticonvulsant Agents -- 9.9.2 Excitotoxins -- 9.9.3 Heavy Metals -- 9.10 PROBLEMS -- 9.11 PROSPECTS FOR IN VITRO-IN VIVO APPROACHES -- References -- 10 In Vitro Assessment of Nephrotoxicity -- 10.1 ISOLATED PERFUSED KIDNEY -- 10.1.1 Methodology -- 10.1.2 Advantages -- 10.1.3 Limitations -- 10.2 USE OF THE ISOLATED PERFUSED KIDNEY IN RENAL TOXICOLOGY -- 10.2.1 Acetaminophen Nephrotoxicity and Metabolism in the Isolated Perfused Kidney -- 10.2.2 Cisplatin Nephrotoxicity in the Isolated Perfused Kidney -- 10.3 RENAL SLICES -- 10.3.1 Methodology -- 10.3.2 Advantages -- 10.3.3 Limitations -- 10.4 USE OF SLICES IN RENAL TOXICOLOGY -- 10.4.1 Biochemical Mechanisms of Nephrotoxicity: Cephalosporin Antibiotics -- 10.4.2 Site-Selective Nephrotoxic Injury -- 10.5 TUBULE SUSPENSIONS -- 10.5.1 Methodology -- 10.5.2 Advantages -- 10.5.3 Limitations -- 10.6 USE OF RENAL TUBULE SUSPENSIONS IN TOXICOLOGY.

10.6.1 Comparison of Tubular Segments: Proximal Versus Distal Tubules -- 10.6.2 Biochemical Mechanisms of Toxicity: 4-Aminophenol -- 10.7 CELL SUSPENSIONS -- 10.7.1 Methodology -- 10.7.2 Advantages -- 10.7.3 Limitations -- 10.8 USE OF CELL SUSPENSIONS IN RENAL TOXICOLOGY -- 10.8.1 Comparison of Renal Tubular Cells: Proximal Versus Distal Tubular Cells -- 10.8.2 Biochemical Mechanisms of Cytotoxicity: Halogenated Hydrocarbons -- 10.9 CELL CULTURE -- 10.9.1 Methodology -- 10.9.2 Advantages -- 10.9.3 Limitations -- 10.10 USE OF CELL CULTURES IN RENAL TOXICOLOGY -- 10.10.1 Biochemical Mechanisms of Lethal Cell Injury: Halogenated Hydrocarbons -- 10.10.2 Cellular Accumulation and Metabolism: Aminoglycoside Antibiotics -- 10.11 CONCLUDING REMARKS -- References -- 11 Primary Hepatocyte Culture as an In Vitro Toxicologic System of the Liver -- 11.1 ISOLATION OF PRIMARY HEPATOCYTES -- 11.2 CULTURING OF ISOLATED HEPATOCYTES -- 11.3 XENOBIOTIC METABOLISM -- 11.3.1 Phase I Oxidation: P450 Isozymes -- 11.3.2 Phase II Conjugation -- 11.3.3 Species Comparison Studies -- 11.4 TOXICOLOGY -- 11.4.1 Cytotoxicity -- 11.4.2 Genotoxicity -- 11.4.3 Enzyme Induction -- 11.4.4 P450 Induction -- 11.5 HUMAN HEPATOCYTES -- 11.6 INDUSTRIAL APPLICATIONS -- 11.7 CONCLUSIONS -- References -- 12 Application of In Vitro Model Systems to Study Cardiovascular Toxicity -- 12.1 IN VITRO MODEL SYSTEMS IN TOXICITY TESTING -- 12.1.1 Perfused Organ Preparations -- 12.1.2 Isolated Muscle Preparations -- 12.1.3 Organ Culture -- 12.1.4 Tissue Slices -- 12.1.5 Single-Cell Suspensions -- 12.1.6 Cell Culture Systems -- 12.2 CONCLUDING REMARKS -- References -- 13 Gastrointestinal Toxicology: In Vitro Test Systems -- 13.1 TYPES OF GASTROINTESTINAL CELLS AND TOXICITY -- 13.2 IN VITRO MODELS -- 13.3 SPECIFIC ENDPOINT MODELS -- 13.3.1 Irritation -- 13.3.2 Cytotoxicity -- 13.3.3 Malabsorption.

13.3.4 Altered Secretory Activity -- 13.3.5 Altered Motility -- 13.3.6 Neoplasia -- 13.3.7 Symbiotic Population Alteration -- 13.4 SPECIFIC PROBLEMS/LIMITATIONS OF IN VITRO TEST SYSTEMS -- References -- 14 In Vitro Immunotoxicology -- 14.1 GENERAL ORGANIZATION OF THE IMMUNE SYSTEM -- 14.2 TRIGGERING THE IMMUNE RESPONSE -- 14.2.1 Innate Immunity -- 14.2.2 Acquired Immunity -- 14.3 CHEMICAL-INDUCED IMMUNOTOXICITY -- 14.3.1 Immunosuppression -- 14.3.2 Hypersensitivity Reactions -- 14.3.3 Autoimmunity -- 14.4 CULTURING IMMUNE CELLS -- 14.4.1 Origin of the Cells -- 14.4.2 Collection of Cells from Secondary Lymphoid Organs -- 14.4.3 Collection of Cells from Peripheral Blood -- 14.4.4 Conditions of Culturing Immune Cells -- 14.4.5 Differences Between Cells from Human and Animal Origins -- 14.5 IN VITRO MODELS IN IMMUNOTOXICOLOGY: DESCRIPTION, ADVANTAGES, AND LIMITATIONS OF THE DIFFERENT IN VITRO MODELS CURRENTLY USED… -- 14.5.1 Dendritic Cells as a Tool to Evaluate the Sensitizing Potential of Hapten -- 14.5.2 Models to Assess Lymphoproliferation -- 14.5.3 Cytokine Measurement to Assess T Helper or T Helper 2 Lymphocyte Differentiation -- 14.5.4 Evaluation of Apoptosis Induced by Xenobiotics -- 14.5.5 Models to Assess Lymphocyte Cytotoxicity (Innate or Acquired) -- 14.5.6 In Vitro Antibody Production -- 14.6 RELEVANCE OF IN VITRO MODELS -- References -- 15 Strategy and Tactics for Employment -- 15.1 DEFINING TEST OBJECTIVES -- 15.1.1 Objectives Behind Data Generation and Utilization -- 15.2 DESIGNING THE RESEARCH PROGRAM -- 15.2.1 Considerations in Adopting New Test Systems -- 15.2.2 In Vitro Models -- 15.2.3 Short-Term Advances: A Mixed Battery -- 15.2.4 Concept of Screens -- 15.2.5 Far Horizons: How to Get Them -- 15.3 CONCLUSION -- References -- 16 Scientific and Regulatory Considerations in the Development of In Vitro Techniques in Toxicology.

16.1 SHARED GOALS: PREDICTABILITY AND RESPONSIBILITY.
Abstract:
Toxicology has made tremendous strides in the sophistication of the models used to identify and understand the mechanisms of agents that can harm or kill humand and other higher organisms.Non-animals or in vitro models started to gain significant use in the 1960s. As a result of the increased concern over animal welfare, economic factors, and the need for greater sensitivity and understanding of mechanisms, interest in in vitro^n models has risen.This volume demonstrates that there now exists a broad range of in vitro models for use in either identifying or understanding most forms of toxicity. The availability of in vitro models spans both the full range of endpoints (irritation, sensitization, lethality, mutagenicity, and devlopmental toxicity) and the full spectrum of target organ systems (skin, eye, heart, liver, kidney, nervous system, etc.). Chapters are devoted to each of these speciality areas from a perspective of presenting the principal models and their uses and limitations.Chapters that overview the principles involved in the general selection and use of models, and that address the issues of safety concerns and regulatory acceptance of these methods are also included.
Local Note:
Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, 2017. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries.
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