Practical Toxicology: Evaluation, Prediction, and Risk, Third Edition

Practical Toxicology: Evaluation, Prediction, and Risk, Third Edition shows how to conduct a program of safety evaluation and testing and then to interpret and apply the resulting data and information in the real world, beginning with the basic concepts in toxicology and progressing to the interpretation of the resulting data. Revised and updated chapters on risk assessment guide the reader to setting the foundations necessary for submission to regulatory authorities. In addition, a new chapter in the book reviews the errors in toxicology, mistakes, misuse, mismanagement, and misunderstanding with a view to avoiding these in the future. New Chapters in the Third Edition: Toxicology in silico Errors in Toxicology Safety Assessment of Extractables and Leachables. This new edition follows a practical sequence from introducing the basics of toxicology (including the vital concept of normality in controls) to describing a test program and then interpreting the data and translating that to risk assessment that can be used in a number of real world situations where safety and secure risk assessment are essential. Although written primarily from the perspective of pharmaceutical development, the test designs and toxicological problems encountered in that field are entirely relevant to those with other classes of chemicals, the only difference being the regulatory context. Toxicology is an international discipline and the book has been written to take into account some of the differences in regulatory nuance between the main regions of the world. Completely revised and written in an easily accessible style, the text address several audiences—from students and post-graduates coming to the subject for the first time to established professionals who find themselves needing to learn about toxicology, toxicity testing, interpretation of the results, and risk assessment. It is intended primarily as a textbook, with case studies and information on where to go to ask questions, but can also be used as a practical reference book. It covers all the basics of toxicology and the main aspects of safety evaluation testing and risk assessment while reviewing critically the current state of the discipline. It also provides a foundation for those seeking registration or certification.

Table of Contents:
Introduction to Toxicology: The Necessity of Measurement Introduction The Beginnings Of Toxicological Measurement Toxicology And Toxicity Defined It Is Natural So It Must Be Safe—Everyday Toxicological Conundrums General Objectives Of Toxicological Study Biology And Outcome Of Toxic Reactions Cellular Basis And Consequences Of Toxic Change Expression Of Toxicity Target Organ Expression Of Toxicity Ethics Of Toxicological Assessment The Three Rs: Reduce, Refine, And Replace References　 Normality: Definition and Maintenance Introduction What Is Normality? Normality As A Range Experimental Normality Control Groups As Normality Establishing And Maintaining Normality In Experimental Groups Baseline Data And Historical Controls Summary References Determination of Toxicity: The Basic Principles Introduction Circumstances Of Toxicity Testing Effects Sought In Toxicity Studies Basic Principles Of Toxicological Investigation Toxicokinetic Design Regulatory Framework And Influences Regulation Of Study Conduct—Good Laboratory Practice Summary References Determination of Toxicity: In Vitro and Alternatives Introduction Rationale For In Vitro Toxicology How And When To Use In Vitro Or Alternative Techniques Considerations In Screening Program Design Areas Of Use Of In Vitro Toxicology Considerations In The Development Of In Vitro Tests Validation Of In Vitro Methods Test Systems And Endpoints Target Organ Toxicity Functional Toxicity Testing Pharmacology And Safety Pharmacology In Vitro Metabolism Kinetics Toxicity Testing Carcinogenicity Reproductive Toxicity Sensitization Irritation And Corrosion Phototoxicity Ecotoxicology Pitfalls In In Vitro Toxicology Omics Future Utility Summary Toxicology in silico Introduction (Q)SAR Methodologies Model validity Regulations, QSARs And Experts Case Study: ICH M7 Choosing A (Q)SAR Commercial vs non-commercial Pitfalls In In Silico Toxicology Summary Safety Pharmacology Introduction General Principles Tests To Be Conducted What To Test? Design Test Systems For Safety Pharmacology Safety Pharmacology In Toxicity Studies Tests And Their Conduct Central Nervous System—Modified Irwin Screen Cardiovascular System Respiratory System Gastrointestinal (Gi) Tract Renal Function Pitfalls Of Safety Pharmacology Studies Summary References Determination: General and Reproductive Toxicology General toxicology Test systems for general toxicology Study designs in general toxicology Examinations for specific toxicities Pitfalls in general toxicology Reproductive and developmental toxicology Study designs for reproductive toxicology Pitfalls in reproductive toxicology Summary Determination: Genotoxicity and Carcinogenicity Genotoxicity General Principles in Genotoxicity Test Battery and Study Design Test Systems and Tests Pitfalls in Genotoxicity Genotoxicity Testing In Vitro—Sensitivity and Specificity Carcinogenicity General Principles In Carcinogenicity Test Systems for Carcinogenicity Study Design and Methods of Assessment Choice of Dose Levels Parameters Measured Other Systems for Carcinogenicity Assessment Pitfalls In Carcinogenicity Studies Overview of the Future of Carcinogenicity Assessment Summary Determination: Dermal Toxicity—Sensitization, Irritation, and Corrosion Introduction General principles of dermal toxicology Factors in dermal toxicity Test systems Study design and parameters measured Dermal Irritation and Corrosion Ocular Irritation Irritation by Other Routes Sensitization Allergic Sensitization in Guinea Pigs Allergic Sensitization in Mice (Local Lymph Node Assay) Pitfalls in irritation and sensitization Summary Determination: Environmental Toxicology and Ecotoxicology Introduction Relevance of environmental assessment to chemical development General principles of environmental toxicology and ecotoxicology Pollution, routes of entry, and environmental ADME Factors in testing for environmental effect Test systems and study types for ecotoxicology Ecotoxicology In Vitro Invertebrates Mesocosms and Field Tests and Studies Environmental assessment of agrochemicals Environmental assessment of pharmaceuticals Pitfalls in environmental toxicology Summary References Interpretation: Basic Principles Introduction The Interpretation Challenge The Scope of Interpretation Interpretation as a Dynamic Process Steps In Interpretation Study Design Controls and Expectation Use of Background Data in Interpretation Statistics and Significance in Toxicology Statistical Process Data Treatment and Transformation Assessing Exposure Integration of Exposure Information Toxicokinetics The Reality of Difference—the interpretation of small differences The Reproducibility of Difference Summary Interpretation: Different Data Types Individual Data Sets Safety Pharmacology General Toxicology Toxicokinetics Clinical Pathology Morphological Pathology The Cell Subcellular Organelles Composition Of The Cytoplasm Or Cell Contents Plasma Membrane Changes Hypertrophy And Atrophy Hyperplasia And Metaplasia Changes To Whole Tissues Or Organs Inflammation Changes In Blood Supply Repair And Reversibility Neoplasia Overview Of Interpretation In General Toxicology Reproductive Toxicology Genotoxicity Carcinogenicity Environmental Toxicology And Ecotoxicology Epidemiology And Occupational Toxicology Epidemiology Occupational Toxicology Case Study: Ciprofibrate Summary References Prediction of Hazard Introduction Principles of prediction Steps in the prediction process Prediction from minimal databases Pediction for individuals Summary Background to Risk Due to Toxicity Introduction Overview of risk analysis Levels of risk and factors that affect risk Risk perception Acceptability and tolerability of risk Comparative risk Synthetic versus natural Risk expression and quantification Summary References Risk Assessment in Practice and Setting Exposure Limits Introduction Risk Assessment As A Process Data Quality Data Selection For Risk Assessment Single Effect Versus General Risk Assessment Tools And Models In Risk Assessment Pbpk Models And Scaling Models For Rodent Bioassay Data Target Population, Dose, And Exposure Prediction Of Exposure Measurement Of Exposure Process And Factors In Risk Assessment Physical Form And Formulation Route Of Exposure Bioavailability Dose Response Safety Evaluation And Human Data Purpose And Target Population Setting Safety Factors And Margins Hazard Weighting And Safety Factors Safety Factor Rationale Exposure Limits Dose Level Selection For Starting Risk Assessment Noel And Noael The Benchmark Dose Setting Exposure Limits Use Of The Therapeutic Dose For Setting Wels/Oels For Pharmaceuticals Thresholds Of Toxicological Concern Summary References Safety Assessment of Extractables, Leachables and Impurities Introduction Definitions Regulatory background Toxicological assessment Risk assessment impurities in practice Summary References Risk Assessment and Management in the Workplace Introduction Factors In Workplace Risk Assessment Workplace Risk Assessment Workplace Exposure Assessment Risk Management In The Workplace Summary Risk Assessment: Carcinogenicity, the Environment, Evolution, and Overview of Risk Assessment Introduction Risk Assessment And Carcinogenicity Risk Assessment And The Environment International Management Of Environmental Risks The Evolution Of Risk Assessment Summary Evaluation of Specific Classes of Chemical Introduction Regulatory Influences The Basic Toxicity Test Package Human Pharmaceuticals Veterinary Pharmaceuticals Medical Devices Agrochemicals/Plant Protection Products Biocides Cosmetics General And Industrial Chemicals—Reach Tobacco Products Summary References Errors in toxicology Introduction Errors through the ages A brief history of early regulations Modern mistakes and mismanagement Clinical trials with new medicinal products Contamination Misunderstanding The public and toxicology Summary References The Future of Toxicity Testing and Risk Assessment Introduction Challenges For Toxicology Evolution Of Toxicity Testing Development Of New Test Methods And Models The Future Of Toxicity Testing A New Paradigm For Safety Evaluation What Will The Future Of Testing Look Like? Challenges For Risk Assessment And Management Evolution Of Risk Assessment Summary References