3rd Edition

Practical Toxicology Evaluation, Prediction, and Risk, Third Edition

By David Woolley, Adam Woolley Copyright 2017
    552 Pages 15 B/W Illustrations
    by CRC Press

    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.

    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

    Biography

    Woolley, David; Woolley, Adam