Regulatory toxicology

Foreword of the First Edition Preface Acknowledgments Contents About the Editors Contributors Part I: The ``Modus Operandi´´ of Regulatory Toxicology 1 Aims and Mission of Regulatory Toxicology Introduction Components of Risk Assessment Hazard Identification Dose-Response and Toxic Potency Exposure Assessment Risk Assessment Requirements for Toxicological Hazard Identification and Risk Assessment Acute Toxicity, Subchronic Toxicity, and Chronic Toxicity Genotoxicity Carcinogenicity Irritation and Phototoxicity Sensitization Toxicity for Reproduction and Development Toxicokinetics Mode and/or Mechanism of Action Evaluation of Uncertainties Evaluation of Mixtures Classification of Carcinogens The Precautionary Principle The TTC Concept Regulations for Specific Chemical Classes REACH Summary References 2 Working Areas of Regulatory Toxicology Introduction Authorities Industry Universities and Other Basic Research Institutions Contract Research Organizations Advocacy (Lobbying) Expert Witness/Court and Public Inquiry Advisor Work Scientific Societies and Journals Chemical Properties Regulated Areas and Legislature Regulations According to Application Area Ambient Media Understanding Regulations Alarm Systems Working Methods Cross-References References Recommended Reading 3 National and International Collaboration in Regulatory Toxicology Global Chemical Production Milestones in International Chemical Safety International Program on Chemical Safety (IPCS) United Nations Conference for Environment and Development (UNCED) International Forum on Chemical Safety (IFCS) Interorganization Program for the Sound Management of Chemicals (IOMC) World Summit on Sustainable Development (WSSD) The Strategic Approach to International Chemicals Management (SAICM) International Agreements Rotterdam Convention: Convention on the Prior Informed Consent Procedure for Certain Hazardous Chemicals and Pesticides in Int... Stockholm Convention: Convention on Persistent Organic Pollutants (POPs) Basel Convention: Convention on the Control of Transboundary Movements of Hazardous Wastes and Their Disposal Minamata Convention on Mercury ILO Convention Concerning Safety in the Use of Chemicals at Work Chemicals Weapons Convention (CWC): Convention on the Prohibition of the Development, Production, Stockpiling, and Use of Chem... Vienna Convention for the Protection of the Ozone Layer and Montreal Protocol on Substances That Deplete the Ozone Layer International Organizations World Health Organization (WHO) United Nations Environment Program (UNEP) Food and Agriculture Organization of the United Nations (FAO) International Labor Organization (ILO) United Nations Industrial Development Organization (UNIDO) Organization for Economic Cooperation and Development (OECD) World Bank United Nations Development Program (UNDP) Chemical Safety in the European Union (EU) European Chemicals Agency (ECHA) European Chemicals Bureau (ECB) European Food Safety Agency (EFSA) National Chemical Safety German Federal Institute for Risk Assessment (BfR) Federal Office for Consumer Protection and Food Safety (BVL) Federal Institute for Occupational Safety and Health (BAuA) German Federal Environment Agency (UBA) Julius Kühn Institute (JKI: German Federal Research Institute for Cultivated Plants German Federal Institute for Drugs and Medical Devices (BfArM) Cross-References References Resources 4 The Regulatory Process in Toxicology Possibilities of Regulation Threshold Limit Values (TLV) Stock-Taking Profiles of Demand Procedural Steps Historic Developments Types of Organization Cross-References References Recommended Reading 5 Quality Assurance in Toxicology Introduction Quality of Data Quality Management (QM) and Quality Assurance (QA) (QM/QA Systems) First Strategy: Traceability and Transparency of Studies Second Strategy: Reproducibility and Comparability of Data Good Laboratory Practice (GLP) and Other ``GxP´´ Systems Accreditation and Certification ``Codes of Conduct´´ and Quality Assurance Cross-References References Recommended Reading 6 Toxicological Risk Assessment Introduction Why Risk Analysis? Steps in Risk Regulation Risk Assessment Risk Evaluation Risk Management The Process of Risk Assessment Hazard Assessment Hazard Identification: Assessing the Potential to Cause Harm Dose-Response Assessment: The Relation Between Exposure and Effect Exposure Assessment Uncertainty Analysis Risk Characterization: The Synthesis of Risk Information The Need for Harmonization Cross-References References Recommended Reading Part II: Tests and Methods 7 Monoclonal Antibodies: Discovery and Protein Engineering Definitions Introduction Antibody Discovery Fc Engineering to Modulate the Mode of Action Engineering Half-Life of Protein Therapeutics De-risking the Immunogenic Potential of Protein Therapeutics by Protein Engineering A Two-in-One Approach: Bispecific Protein Therapeutics Scaffolds: The Alternative Protein Therapeutics Antibody-Drug Conjugates (ADC): Combining the Best of Two Worlds Cross-References References 8 Characterization of Physicochemical Parameters in Toxicology Introduction Physicochemical Properties and Bioavailability Identification, Content, and Stability of the Test Article Methods Inhalative Toxicology Impurities and Content Guidelines Cross-References References 9 Examination of Acute and Repeated-Dose Toxicity Introduction Aim and Study Protocol Investigated Parameters Reporting Requirements Acute Toxicity Acute Toxic Class Method Long-Term Studies Subacute Studies (28 Day) Performance Ratio Dose-Range Finding Reversibility Subchronic and Chronic Studies Definition of NOAELs Cross-References References 10 Examination of Organ Toxicity Introduction Basic Principles for the Examination of Organ Toxicity Gross Pathology Histopathology Diagnostic Approach, Procedures, and Considerations Clinical Pathology Parameters Results of a Well-Concerted Combination of Anatomical and Clinical Pathology Data Analyses International Activities on Harmonization in the Use of Diagnostic Terms Summary and Future View Cross-References References Resources 11 Specific Toxicity Tests for Neurotoxicity, Immunotoxicity, Allergy, Irritation, Reprotoxicity, and Carcinogenicity Introduction Reproductive Toxicity Testing Genotoxicity Testing Carcinogenicity Testing Neurotoxicity Testing Immunotoxicity Testing Cross-References References 12 Toxicity Testing In Vitro: Regulatory Aspects Introduction Tests with Liver Cell Cultures (Biotransformation and Cytotoxicity) Tests with Mouse Fibroblasts (Phototoxicity) Tests with Isolated Ion Channels (Cardiotoxicity, ECG Changes) Tests with Mammalian Cell Cultures (Genotoxicity) Tests with Incubated Chicken Eggs (Various Parameters) Human Embryonic Stem (hES) Cells for Use in Toxicity Testing, E.g., Early Development Toxicity Testing Possibilities and Limitations of Established In Vitro Toxicity Testing New Developments: Microphysiological Systems (MPS) Cross-References References 13 Integration of Advanced Technologies into Regulatory Toxicology Challenges for Regulatory Testing in the Twenty-First Century Adapting Toxicity Testing to the Challenges of the Twenty-First Century in Europe The US Vision Toxicity Testing in the Twenty-First Century (Tox21) (US NRC 2007) The Adverse Outcome Pathway (AOP) Concept Integrated Approaches to Testing and Assessment (IATA) New Technologies Stem Cells as Advanced Tools in Predictive Toxicology Human-on-a-Chip (Multiorgan-Chip) Technology Applied to Toxicity Testing 3D-Biopriniting Virtual Organ Models Artificial Intelligence (AI) and Machine Learning The Future of Toxicology Is in Vitro Cross-References References 14 Computer-Based Prediction Models in Regulatory Toxicology Introduction into the Principles of Predictive Systems Assessment of Predictive Systems Definitions Use of Predictive Tools in Regulatory Toxicology Future Perspectives Resources Selection of Freely Available Software and Tools References 15 Metabolism Investigations in Drug Development Introduction Profiles and Structure Elucidation In Vitro Test Systems In Vivo Test Systems Structure Elucidation of Metabolites Regulatory Considerations on Metabolites in Safety Testing Investigation of Drug-Drug Interactions Elucidation of Enzymes Involved in the Metabolism of a Drug Enzyme Inhibition Enzyme Induction Regulatory Considerations on DDI (Drug-Drug Interaction) Metabolism of Biotherapeutics Quality Assurance Cross-References References Resources 16 Toxicokinetic Tests Objectives of Toxicokinetic Investigations Extrapolation Across Species and Systems Extrapolation Across Routes Toxicokinetic Data and Risk Assessment Toxicokinetic Readouts Time-Course Changes Selection of Compartment Absorption, Distribution, and Elimination Absorption Absorption from the Skin Gastrointestinal Absorption Pulmonary Deposition, Retention, Clearance, and Absorption Compartmental Pulmonary Biokinetics of Poorly Soluble Particles Kinetic Lung Overload Dissolution and Bioavailability Interdependence of Metrics on Dose Distribution Excretion Toxicokinetic Parameter Time-Course Analyses Volume of Distribution Area Under the Curve Significance of Toxicokinetics in Regulatory Toxicology Future Directions Cross-References References Recommended Reading 17 Toxicodynamic Tests Introduction Isolated Target Molecules Nucleic Acids Proteins/Enzymes Lipids Subcellular Fractions/Organelles Membranes: Cytoplasmic Fraction Receptors Transfer Through Biological Membranes (Ion Channels, Transporters, and Pumps) Mitochondria Nuclei Cells Permanent Cell Lines Primary Cells and Organoids Tissues Isolated Organs Tissue Slices In Silico Methods Adverse Outcome Pathways Experimental Animals Acute Toxicity/Organ Toxicity Chronic Toxicity/Organ Toxicity Other Modes of Action Genotoxic and Carcinogenic Effects Teratogenicity and Developmental and Reproductive Toxicity Alternatives to Animal Tests Investigations in Humans Cross-References References 18 Omics in Toxicology Introduction Toxicogenomics Proteomics Metabolomics Applications of Toxicogenomics in Toxicology Mechanistic Toxicogenomics Predictive Toxicogenomics and Signatures BMD Modeling Weighted Gene Co-expression Network Analysis (WGCNA) ICH(S1) Revision: Potential Use of Transcriptomic Signatures Summary and Conclusion Cross-References References 19 Epidemiological Methods in Regulatory Toxicology Basics Definition Population Exposure and Effect Association Versus Causation Measures of Disease Occurrence and Association Common Epidemiologic Study Designs Descriptive and Analytical Epidemiology Cohort Study Case-Control Study Cross-Sectional Study Panel Study Ecological Study Study Quality Validity Confounding Selection Bias Information Bias {Bias, Information} Effect Measure Modification and Interactions Random Error and Precision Study Planning Statistical Analysis Estimation, Confidence Intervals, and Testing Regression Models Cross-References Recommended Reading 20 Early Clinical Trials Introduction Phase I Studies Safety and Toxicity in Nononcologic Phase I Trials Benefit-Risk Assessments Phase II Studies Phase III Studies Phase IV Studies (Postapproval Studies) Early Clinical Development of Vaccines Important Regulatory Aspects Study Responsibilities and Roles Trial Databases Institutional Review Board (IRB)/Independent Ethics Committee (IEC) Important Documents The Study Protocol The Informed Consent Form The Investigator´s Brochure (IB) Testing of Other Substances Cross-References References 21 Statistical Evaluation Methods in Toxicology Introduction The Falsification Principle Decision Scheme Proof of Hazard Approach Proof of Safety Approach Impact of Sample Size Presentation of Significances The Dunnett Test and Its Modifications Cross-References References 22 Dose-Response Analysis: Identification of Threshold Levels for Chemicals Introduction Toxic Effects on the Individual Level Interaction of Toxicants with Target Molecules in Living Organisms Reversible and Irreversible Damage, Accumulation of Toxic Effects Receptor-Mediated Toxic Effects, Law of Mass Action, and KD-Value Sigmoid Shape of Toxicant-Receptor Binding Curves Toxicant-Receptor Binding and Agonistic and Antagonistic Effects, Intrinsic Activity Characterization of Toxicological Efficacy and Potency Identification of NOEL and LOEL as Toxicological Threshold Levels Problems in Determination of NOEL and LOEL Values Reporting of NOAEL and LOAEL Values Toxic Effects in Collectives Differences in the Individual Sensitivity LD50 and TD50 Distribution of Individual Sensitivity, Therapeutic Range Specific Dose-Effect Relationships Extrapolation of Threshold Levels to Application in Humans Use of More Than One Animal Species Quantification of Exposure Toxic Threshold Levels and Safety Margin in Humans Cross-References References 23 Extrapolation Procedures for Carcinogenic and Noncarcinogenic Compounds Introduction Study Types and Evaluation Principles A Road Map for Extrapolation Choice of Risk Parameters Choice of Risk Measures Dose Extrapolation Risk Assessment Under the Threshold Dose Assumption Risk Assessment Without Threshold Dose Assumption The Limit Risk PoD Based on Benchmark Dose Other PoDs Margin of Exposure (MoE) Cross-References References 24 Probabilistic Methods in Toxicology Background Methods for Quantifying Variability and Uncertainty in Risk Assessment Point Estimates Probabilistic Estimates Sensitivity Analysis Application Potential in Dose-Response Assessment Software for Probabilistic Exposure and Risk Assessment Cross-References References 25 Exposure Analysis for Indoor Contaminants Objectives and Purpose for the Determination of Volatile and Semi-volatile Organic Compounds in Indoor Air Screening Methods Sampling Determination of Organic Pollutants in Indoor Air Limits and Errors of the Determination of Organic Indoor Air Pollutants Influence of Emission Characteristics and Ventilation The Effect of Absorbing Effects (Sinks) Conclusion Cross-References References 26 Benchmark Dose Approach in Regulatory Toxicology Introduction Benchmark-Dose (BMD) Approach Dose-Response Assessment for Risk Characterization Dose-Response Data Types Dose-Response Model (DRM) Before Starting the BMD Approach Data Selection Model Selection and Specification Specification of the Benchmark Response (BMR) Model Fitting and Model Acceptance BMD Modeling in Practice One Data Set A Suite of Models Pragmatic Proposals Frequentist Combining Model Averaging BMD Confidence Interval BMD Modeling with Several Data Sets BMD for Human Data and Presence of Covariate Information BMD Modeling for Different Endpoints Reporting the Results of the BMD Approach Use of the BMDL for Risk Characterization Cross-References References 27 Human Biomonitoring: Its Importance in Toxicological Regulation Introduction Environmental Monitoring Chemicals (Biomarkers of Internal Exposure) Biochemical Effect Monitoring DNA Adducts 8-Hydroxy-2′-deoxyguanosine (8-OHdG) Hemoglobin Adducts (Hb Adducts) Biological Effects (Biomarker of Effect) Other Markers General Population HBM Programs Evaluation of HBM Results (Internal Exposures) Reference Values Reference Value and Risk Assessment Health-Based Values HBM Values Biological Equivalents (BEs) Risk Assessment in Context with Surveys/Tool in Risk Management Cross-References References Resources Part III: Approaches Used 28 Toxicodynamic Models Introduction Requirements for Toxicodynamic Modeling Description and Application of Toxicodynamic Models (TDMs) Toxicodynamic Potency Explanatory and Biologically Based TDMs TDMs for Risk Characterization in Regulatory Toxicology Toxicokinetic-Toxicodynamic Models Chemical-Specific Adjustment Factors Cross-References References 29 Toxicokinetic Models Introduction The Relevance of Toxicokinetics Toxicokinetic Modeling Classical Compartment Open Models Physiologically Based Toxicokinetic (PBTK) Models Cross-References References Recommended Reading 30 Exposure Scenarios in Toxicology Introduction Structure of Exposure Scenarios Characterization of the Source and the Use of the Substance in a Product Categories of Use Release, Distribution, and Disappearance Exposure by Inhalation Typical Scenarios of Inhalation Exposure Dermal Route of Exposure Typical Scenarios of Dermal Exposure Oral Route of Exposure Typical Scenarios Behavior of Populations and Individuals Exposure Estimate Time Budgets Particular Age-Related Behaviors Anthropometric Data Single-Point-Based (Deterministic) Exposure Assessments Distribution-Based (Probabilistic) Exposure Assessment Impact of Exposure Assessment Cross-References Notes References Recommended Reading Resources 31 Quality Criteria for Primary Literature in Toxicology Introduction Data and Data Sources Evaluation of the Reliability of Studies Plausibility of Study Design and Results Plausibility of Results in Relation to the Overall Knowledge on a Given Substance Weighting of Borderline Cases Conclusions Cross-References References Resources 32 Data Mining in Toxicology Introduction Overview of Data Search Methods Using Online Search Engines Portals of Publishing Companies Assessment by a National or International Committee Review Articles Factual Databases Comprehensive Data Searches and Analyses Bibliographical Databases Selection of the Database Searching Strategies Reference Management Databases and Providers Databases and Portals Databases Database Portals Database Portals (Available at a Charge) Databases (Available at a Charge) Portals of Publishing Companies Organizations Statements Explaining Occupational Exposure Limits Cross-References References 33 Principles of Analytical Chemistry for Toxicology Introduction: Historical Summary The Aim and Means of Analytical Chemistry Important Techniques of Pre-analysis Solid-Phase Extraction Liquid-Liquid Extraction Solid-Phase Microextraction Separation Techniques Chromatography HPLC: Including Coupled Techniques LC-MS (Thermospray, Fast Atom Bombardment, Particle Beam) Ionization Techniques Mass Spectrometer LC-MS/MS GC: Including Coupled Techniques Headspace GC GC-MS Thin-Layer Chromatography (TLC) Ion Exchange Chromatography (IEC/IEX) Electrophoresis Atomic Spectroscopy Atomic Absorption Spectroscopy (AAS) Inductively Coupled Plasma Mass Spectrometry (ICP-MS) Selective Analytical Chemistry Sensor Techniques Immunoassays Special Types of Mass Spectrometers (LC)-MALDI-TOF Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR-MS) References 34 Uncertainty Analysis in Exposure Assessment-Relevance for Toxicological Risk Assessment Introduction Development of a Regulatory Status of Uncertainty Analysis Rationale for Characterizing Uncertainty in Exposure Assessment Definition of Assessment Objectives Sources of Uncertainty in Exposure Assessment Scenario Uncertainty Model Uncertainty Parameter Uncertainty Uncertainty in Measurement Data Sources for Model Parameters (Exposure Factors) Evaluating the Total Impact of Uncertainty Model Evaluation Sensitivity Analysis Quantitative Sensitivity Analysis: Identification of Key Sources of Exposure, Uncertainty, and Variability Interpretation of Uncertainty Characterization Results Cross-References References Part IV: Paradigms Used in Risk Evaluation 35 Read-Across Methodology in Toxicological Risk Assessment Introduction Read-Across: Step-by-Step From Problem Formulation to the Initial Read-Across Hypothesis Identify Source Compound(s) Starting with Structure Similarity Source Compound Evaluation Data Gap Filling and Uncertainty Assessment Moving Toward Mechanistic Risk Assessment Using In Vitro and In Silico Models Cross-References Notes References 36 Green and Sustainable Chemistry as Regulatory Levers Introduction Developments Before the Area of Green Chemistry Early Industrial Chemistry Pollution and Accidents (1965-1990) Pollution of Environmental Media Outdoor Air Ozone Hole Surface Water Ground Water Dumping Sites and Soil Indoor Air Consumer Goods Pollutants of Major Concern (1965-1990) Persistent Organic Pollutants (POP) Toxic Metals Polycyclic Aromatic Hydrocarbons Endocrine Disruptors Chlorinated Volatile Solvents Industrial Accidents (Examples) Seveso Bhopal Chernobyl Chemical-Induced Disease Drug Scandals Advances in Chemical Safety Analytical Chemistry and Clinical Chemistry Toxicological Advances Whistle Blowers Information Systems Harmonization of Regulations Green- and Sustainable Chemistry Green Movements ``Green Chemistry´´ Beginning and Mission, Expansion Sustainability Movements The United Nations Sustainable Development Agenda 30 ``Sustainable Chemistry´´ Green Chemistry Methods The Complexity of Sustainable Decisions Toxicology for Sustainable Development Cross-References References 37 Do Carcinogens Have a Threshold Dose? The Pros and Cons Introduction Tumor Promoters Factors Modifying Carcinogenesis Dose, Time, and Cell Fate Heterogeneity Further Examples of Genotoxic Carcinogens Regulatory Aspects on Thresholds or No Thresholds for Genotoxic Carcinogens Conclusions Cross-References References 38 Single Substances Versus Combined Effects: Problems in Mixture Toxicology Introduction Basic Considerations Basic Aspects of the Scientific Evaluation and Regulatory Specifications of Safety Values for Combined Substance Exposures Cross-References References Recommended Reading 39 Biomolecules Versus Smaller Chemicals in Toxicology: ICH, EU, and US Recommendations Introduction Biomolecules Versus Smaller Chemicals in Toxicology ICH Guidelines The Regulatory Environment to Initiate First-in-Human Studies Comparison Between the Nonclinical Assessments of Biologics and New Chemical Entities Pharmacology Pharmacodynamics Safety Pharmacology Pharmacokinetics and Toxicokinetics Toxicology Repeated-Dose Toxicity Genotoxicity and Carcinogenicity Reprotoxicity and Juvenile Animal Studies Immunogenicity and Immunotoxicity The Standard for Exchange of Nonclinical Data (SEND) Format Impact of Manufacturing and Formulation Changes on the Development Process Alternative Methods Including In Silico Evaluation Environmental Risk Assessment (ERA) Conclusion and Recommendations Cross-References References Peer-Reviewed Articles Regulatory Documents 40 Sensitive Humans Versus Average Persons in Toxicology Introduction Genetic Polymorphism Additional Parameters Toxicological Implications Susceptibility in Children Physiological Differences Increased Susceptibility in Fetuses, Babies, and Children Regulatory Considerations Cross-References References 41 Default Factors in Quantitative Risk Assessment Introduction Nomenclature Extrapolations Duration Extrapolation Extrapolation from LOAEL to NAEL Interspecies Extrapolation Intraspecies Extrapolation Consideration of Qualitative Aspects Application Framework Cross-References References Resources 42 Assessment of Background Exposure and Additional Exposure by Human Biomonitoring Introduction Special Issues of HBM Data Assessment for Carcinogens Health-Based Assessment Values Risk-Based Assessment Values Reference Values and Other Descriptive Assessment Values Parameters of Biological and Biochemical Effects Can Thresholds Be Certain? Cross-References References 43 Adverse Effects Versus Non-adverse Effects in Toxicology The Meaning of the Term Adverse Definition of Adverse Effects Dimensions of Adversity Severity of an Effect Detectability Subjective Perception Reversibility Probability and Number of Persons Concerned Groups Concerned Causality Final Remarks References Recommended Reading 44 Health-Based Threshold Values Versus MOS in Toxicology Introduction Health-Based Threshold Values Dose Without (Adverse) Effect Safety Factors/Uncertainty Factors/Assessment Factors Margin of Safety (MOS)/Margin of Exposure (MOE) Exposure Assessment Risk Assessment Cross-References References Resources 45 Precaution Principle Versus Danger Prevention in Toxicology Principle of Hazard Prevention Suspected Threshold of Danger Principle of Precaution Distinction of the Area of Precaution Cross-References References Recommended Reading 46 Hygienic Versus Toxicological Approaches in Regulation Introduction Toxicology Hygiene Example: Pesticide Regulation in the Drinking Water The German Hygiene Philosophy The Philosophy of the WHO Regulation of ``Unknown´´ Substances Cross-References References 47 Protected Property and Protection Level in Regulatory Toxicology Introduction Subjects of Protection Protection Goals and Levels of Protection Complete Protection: Partial Protection Hazard Control: Prevention Substantiation of Protection Goals: Deduction of Standards Cross-References Recommended Reading 48 Ethical Issues in Science: Focus on Regulatory Toxicology Introduction Historical Development Ethical Principles Respect and Protection Informed Consent and Transparency Favorable Risk-Benefit Ratio Fair Participant Selection Scientific Validity Ethical Review Criteria Types of Experiments Animal Welfare Cross-References Recommended Reading Resources Part V: Risk Assessment and Evaluation 49 Teaching Chemical Safety Introduction Chemical Safety at Work Risk Management Substance Information and Labeling Globally Harmonized System of Classification, Labeling, and Packaging of Chemicals (GHS) Hazard Pictograms Hazard (H) and Precautionary (P) Statements Safety Data Sheets (SDS) and Operating Instructions Handling Storage Disposal Implementing Chemical Safety at Work Good Laboratory Practice Summary Cross-References References Recommended Reading 50 Current Role of the Risk Concept in Regulatory Toxicology Introduction History of the Risk Term Dimensions of the Concept of Risk Quantification of Probability Risk Comparison Phantom Risk Dealing with the Concept of Risk Cross-References References Recommended Reading 51 Importance of Physicochemical and Physical Properties for Toxicological Risk Assessment Introduction State of Matter Solid Phase Liquid Phase Gaseous Phase Structural Aspects Small Organic Molecules Organic Macromolecules Biopolymers Particles and Nanoparticles Density Solubility Solubility in Water Hydrophilic Substances Lipophilic Substances Solubility in Lipid Environment n-Octanol/Water Partition Amphiphilic Substances Virtually Insoluble Substances Surface Adsorption Osmotic Activity Volatility, Vapor Pressure, and Vapor Solubility Example Anesthetics Example Mercury Environmental Relevance Viscosity Stability Heat Sensitivity Mechanical Abrasion Photochemical Instability/Reactivity Photosensitivity Isotopic Instability Flammability Kinetics and Reaction Types Toxicokinetics Interaction Types Cross-References References 52 Intrinsic Toxicity of Substances: Aspects for Risk Assessment Introduction Structure-Related Intrinsic Toxicity Toxicokinetic and Toxicodynamic Aspects Corrosive Substances Short-Chain Aldehydes Short-Chain Chlorinated Solvents Nitrosamines Organophosphates Phenylethylamines Aromatic Chlorinated Substances Lectins AB Toxins Dust, Fine, and Ultrafine Particles Metals and Metal Compounds Essential Metals Nonessential Metals Target-Related Toxicity Prologue: Damage and Repair Molecular and Organ Level Membrane Potential and Neuronal Activity Resting Membrane Potential Nerve Conductance Cardiac Long QT Syndrome Neurotransmission Reproductive and Developmental Effects Irritation Sensitization Genotoxicity, Mutagenicity, Carcinogenicity Liver as Target Organ Intrahepatic Cholestasis Drug-Induced Autoimmune Hepatitis Liver Cell Necrosis Fatty Liver Liver Cirrhosis Liver Cancer (Hepatocellular Carcinoma) Hepatic Encephalopathy Role of Individual Susceptibility NSAID-Induced Ulcer Disease Asbestos, Cigarette Smoke, and Lung Cancer Gluten and Celiac Disease Alpha-1 Antitrypsin Deficiency and Lung Function Iron and Iron Storage Disease Age-Dependent Sensitivities Poor Metabolizers Summary Cross-References References Resources 53 Importance of Xenobiotic Metabolism: Mechanistic Considerations Relevant for Regulation Fundamentals Examples of Metabolism Associated Toxicity MeIQx (2-Amino-3,8-Dimethylimadazo[4,5-f]Quinoxaline) Aflatoxin B1 Vinyl Acetate - The Relevance of Practical Thresholds Cross-References References 54 Dose-Response Relationship and Extrapolation in Toxicology: Mechanistic and Statistical Considerations Introduction Dose-Response Curve in Textbook The Logarithm ``Catch´´ Conclusions Continuous Response Variables Linearity as Default Extrapolation for Rates of First-Line Interactions Deviation from Linearity Due to Saturation of Processes that Modulate Biomarker Levels Nonmonotonic Shape if Background Is Reduced at Low Dose Confidence Limits on Low-Dose Effect and Comparison with Background Variation Conclusions Mechanistic Background of Nonmonotonic Dose Response ``Incidence´´ as a Different Type of Response Variable A Dose-Incidence Relationship Reflects Differences in Susceptibility Conclusions Chemical Carcinogenesis and Cancer Incidence Multiplicative Combination of Susceptibility Factors Results in a Lognormal Distribution Extrapolation of a Dose-Cancer Incidence Relationship It Is Time for a Revival of the Lognormal Distribution for Cancer Risk Extrapolation Tolerance Distribution Versus Stochastic Modeling Conclusions How to Incorporate a Nonlinearity of an Experimental Biomarker in a Dose-Incidence Relationship? Monte Carlo Simulations to Differentiate the Dose Response for a Population Average Versus Individuals Conclusions Cross-References References 55 Importance of Exposure Level for Toxicological Risk Assessment Introduction Local Toxicity Irritation Sensitization Local Carcinogenicity Systemic Toxicity Cross-References References 56 Risk Characterization in Regulatory Toxicology Introduction Elements of Risk Characterization Hazard Characterization Uncertainty Factors Other Approaches Exposure Characterization Uncertainty and Variability Weight of Evidence Transparency of the Process Cross-References References Recommended Reading 57 Risk Evaluation in Regulatory Toxicology Introduction Element Foreword of the First Edition Preface Acknowledgments Contents About the Editors Contributors Part I: The ``Modus Operandi ́ ́ of Regulatory Toxicology 1 Aims and Mission of Regulatory Toxicology Introduction Components of Risk Assessment Hazard Identification Dose-Response and Toxic Potency Exposure Assessment Risk Assessment Requirements for Toxicological Hazard Identification and Risk Assessment Acute Toxicity, Subchronic Toxicity, and Chronic Toxicity Genotoxicity Carcinogenicity Irritation and Phototoxicity Sensitization Toxicity for Reproduction and Development Toxicokinetics Mode and/or Mechanism of Action Evaluation of Uncertainties Evaluation of Mixtures Classification of Carcinogens The Precautionary Principle The TTC Concept Regulations for Specific Chemical Classes REACH Summary References 2 Working Areas of Regulatory Toxicology Introduction Authorities Industry Universities and Other Basic Research Institutions Contract Research Organizations Advocacy (Lobbying) Expert Witness/Court and Public Inquiry Advisor Work Scientific Societies and Journals Chemical Properties Regulated Areas and Legislature Regulations According to Application Area Ambient Media Understanding Regulations Alarm Systems Working Methods Cross-References References Recommended Reading 3 National and International Collaboration in Regulatory Toxicology Global Chemical Production Milestones in International Chemical Safety International Program on Chemical Safety (IPCS) United Nations Conference for Environment and Development (UNCED) International Forum on Chemical Safety (IFCS) Interorganization Program for the Sound Management of Chemicals (IOMC) World Summit on Sustainable Development (WSSD) The Strategic Approach to International Chemicals Management (SAICM) International Agreements Rotterdam Convention: Convention on the Prior Informed Consent Procedure for Certain Hazardous Chemicals and Pesticides in Int... Stockholm Convention: Convention on Persistent Organic Pollutants (POPs) Basel Convention: Convention on the Control of Transboundary Movements of Hazardous Wastes and Their Disposal Minamata Convention on Mercury ILO Convention Concerning Safety in the Use of Chemicals at Work Chemicals Weapons Convention (CWC): Convention on the Prohibition of the Development, Production, Stockpiling, and Use of Chem... Vienna Convention for the Protection of the Ozone Layer and Montreal Protocol on Substances That Deplete the Ozone Layer International Organizations World Health Organization (WHO) United Nations Environment Program (UNEP) Food and Agriculture Organization of the United Nations (FAO) International Labor Organization (ILO) United Nations Industrial Development Organization (UNIDO) Organization for Economic Cooperation and Development (OECD) World Bank United Nations Development Program (UNDP) Chemical Safety in the European Union (EU) European Chemicals Agency (ECHA) European Chemicals Bureau (ECB) European Food Safety Agency (EFSA) National Chemical Safety German Federal Institute for Risk Assessment (BfR) Federal Office for Consumer Protection and Food Safety (BVL) Federal Institute for Occupational Safety and Health (BAuA) German Federal Environment Agency (UBA) Julius Kühn Institute (JKI: German Federal Research Institute for Cultivated Plants German Federal Institute for Drugs and Medical Devices (BfArM) Cross-References References Resources 4 The Regulatory Process in Toxicology Possibilities of Regulation Threshold Limit Values (TLV) Stock-Taking Profiles of Demand Procedural Steps Historic Developments Types of Organization Cross-References References Recommended Reading 5 Quality Assurance in Toxicology Introduction Quality of Data Quality Management (QM) and Quality Assurance (QA) (QM/QA Systems) First Strategy: Traceability and Transparency of Studies Second Strategy: Reproducibility and Comparability of Data Good Laboratory Practice (GLP) and Other ``GxP ́ ́ Systems Accreditation and Certification ``Codes of Conduct ́ ́ and Quality Assurance Cross-References References Recommended Reading 6 Toxicological Risk Assessment Introduction Why Risk Analysis? Steps in Risk Regulation Risk Assessment Risk Evaluation Risk Management The Process of Risk Assessment Hazard Assessment Hazard Identification: Assessing the Potential to Cause Harm Dose-Response Assessment: The Relation Between Exposure and Effect Exposure Assessment Uncertainty Analysis Risk Characterization: The Synthesis of Risk Information The Need for Harmonization Cross-References References Recommended Reading Part II: Tests and Methods 7 Monoclonal Antibodies: Discovery and Protein Engineering Definitions Introduction Antibody Discovery Fc Engineering to Modulate the Mode of Action Engineering Half-Life of Protein Therapeutics De-risking the Immunogenic Potential of Protein Therapeutics by Protein Engineering A Two-in-One Approach: Bispecific Protein Therapeutics Scaffolds: The Alternative Protein Therapeutics Antibody-Drug Conjugates (ADC): Combining the Best of Two Worlds Cross-References References 8 Characterization of Physicochemical Parameters in Toxicology Introduction Physicochemical Properties and Bioavailability Identification, Content, and Stability of the Test Article Methods Inhalative Toxicology Impurities and Content Guidelines Cross-References References 9 Examination of Acute and Repeated-Dose Toxicity Introduction Aim and Study Protocol Investigated Parameters Reporting Requirements Acute Toxicity Acute Toxic Class Method Long-Term Studies Subacute Studies (28 Day) Performance Ratio Dose-Range Finding Reversibility Subchronic and Chronic Studies Definition of NOAELs Cross-References References 10 Examination of Organ Toxicity Introduction Basic Principles for the Examination of Organ Toxicity Gross Pathology Histopathology Diagnostic Approach, Procedures, and Considerations Clinical Pathology Parameters Results of a Well-Concerted Combination of Anatomical and Clinical Pathology Data Analyses International Activities on Harmonization in the Use of Diagnostic Terms Summary and Future View Cross-References References Resources 11 Specific Toxicity Tests for Neurotoxicity, Immunotoxicity, Allergy, Irritation, Reprotoxicity, and Carcinogenicity Introduction Reproductive Toxicity Testing Genotoxicity Testing Carcinogenicity Testing Neurotoxicity Testing Immunotoxicity Testing Cross-References References 12 Toxicity Testing In Vitro: Regulatory Aspects Introduction Tests with Liver Cell Cultures (Biotransformation and Cytotoxicity) Tests with Mouse Fibroblasts (Phototoxicity) Tests with Isolated Ion Channels (Cardiotoxicity, ECG Changes) Tests with Mammalian Cell Cultures (Genotoxicity) Tests with Incubated Chicken Eggs (Various Parameters) Human Embryonic Stem (hES) Cells for Use in Toxicity Testing, E.g., Early Development Toxicity Testing Possibilities and Limitations of Established In Vitro Toxicity Testing New Developments: Microphysiological Systems (MPS) Cross-References References 13 Integration of Advanced Technologies into Regulatory Toxicology Challenges for Regulatory Testing in the Twenty-First Century Adapting Toxicity Testing to the Challenges of the Twenty-First Century in Europe The US Vision Toxicity Testing in the Twenty-First Century (Tox21) (US NRC 2007) The Adverse Outcome Pathway (AOP) Concept Integrated Approaches to Testing and Assessment (IATA) New Technologies Stem Cells as Advanced Tools in Predictive Toxicology Human-on-a-Chip (Multiorgan-Chip) Technology Applied to Toxicity Testing 3D-Biopriniting Virtual Organ Models Artificial Intelligence (AI) and Machine Learning The Future of Toxicology Is in Vitro Cross-References References 14 Computer-Based Prediction Models in Regulatory Toxicology Introduction into the Principles of Predictive Systems Assessment of Predictive Systems Definitions Use of Predictive Tools in Regulatory Toxicology Future Perspectives Resources Selection of Freely Available Software and Tools References 15 Metabolism Investigations in Drug Development Introduction Profiles and Structure Elucidation In Vitro Test Systems In Vivo Test Systems Structure Elucidation of Metabolites Regulatory Considerations on Metabolites in Safety Testing Investigation of Drug-Drug Interactions Elucidation of Enzymes Involved in the Metabolism of a Drug Enzyme Inhibition Enzyme Induction Regulatory Considerations on DDI (Drug-Drug Interaction) Metabolism of Biotherapeutics Quality Assurance Cross-References References Resources 16 Toxicokinetic Tests Objectives of Toxicokinetic Investigations Extrapolation Across Species and Systems Extrapolation Across Routes Toxicokinetic Data and Risk Assessment Toxicokinetic Readouts Time-Course Changes Selection of Compartment Absorption, Distribution, and Elimination Absorption Absorption from the Skin Gastrointestinal Absorption Pulmonary Deposition, Retention, Clearance, and Absorption Compartmental Pulmonary Biokinetics of Poorly Soluble Particles Kinetic Lung Overload Dissolution and Bioavailability Interdependence of Metrics on Dose Distribution Excretion Toxicokinetic Parameter Time-Course Analyses Volume of Distribution Area Under the Curve Significance of Toxicokinetics in Regulatory Toxicology Future Directions Cross-References References Recommended Reading 17 Toxicodynamic Tests Introduction Isolated Target Molecules Nucleic Acids Proteins/Enzymes Lipids Subcellular Fractions/Organelles Membranes: Cytoplasmic Fraction Receptors Transfer Through Biological Membranes (Ion Channels, Transporters, and Pumps) Mitochondria Nuclei Cells Permanent Cell Lines Primary Cells and Organoids Tissues Isolated Organs Tissue Slices In Silico Methods Adverse Outcome Pathways Experimental Animals Acute Toxicity/Organ Toxicity Chronic Toxicity/Organ Toxicity Other Modes of Action Genotoxic and Carcinogenic Effects Teratogenicity and Developmental and Reproductive Toxicity Alternatives to Animal Tests Investigations in Humans Cross-References References 18 Omics in Toxicology Introduction Toxicogenomics Proteomics Metabolomics Applications of Toxicogenomics in Toxicology Mechanistic Toxicogenomics Predictive Toxicogenomics and Signatures BMD Modeling Weighted Gene Co-expression Network Analysis (WGCNA) ICH(S1) Revision: Potential Use of Transcriptomic Signatures Summary and Conclusion Cross-References References 19 Epidemiological Methods in Regulatory Toxicology Basics Definition Population Exposure and Effect Association Versus Causation Measures of Disease Occurrence and Association Common Epidemiologic Study Designs Descriptive and Analytical Epidemiology Cohort Study Case-Control Study Cross-Sectional Study Panel Study Ecological Study Study Quality Validity Confounding Selection Bias Information Bias {Bias, Information} Effect Measure Modification and Interactions Random Error and Precision Study Planning Statistical Analysis Estimation, Confidence Intervals, and Testing Regression Models Cross-References Recommended Reading 20 Early Clinical Trials Introduction Phase I Studies Safety and Toxicity in Nononcologic Phase I Trials Benefit-Risk Assessments Phase II Studies Phase III Studies Phase IV Studies (Postapproval Studies) Early Clinical Development of Vaccines Important Regulatory Aspects Study Responsibilities and Roles Trial Databases Institutional Review Board (IRB)/Independent Ethics Committee (IEC) Important Documents The Study Protocol The Informed Consent Form The Investigator ́s Brochure (IB) Testing of Other Substances Cross-References References 21 Statistical Evaluation Methods in Toxicology Introduction The Falsification Principle Decision Scheme Proof of Hazard Approach Proof of Safety Approach Impact of Sample Size Presentation of Significances The Dunnett Test and Its Modifications Cross-References References 22 Dose-Response Analysis: Identification of Threshold Levels for Chemicals Introduction Toxic Effects on the Individual Level Interaction of Toxicants with Target Molecules in Living Organisms Reversible and Irreversible Damage, Accumulation of Toxic Effects Receptor-Mediated Toxic Effects, Law of Mass Action, and KD-Value Sigmoid Shape of Toxicant-Receptor Binding Curves Toxicant-Receptor Binding and Agonistic and Antagonistic Effects, Intrinsic Activity Characterization of Toxicological Efficacy and Potency Identification of NOEL and LOEL as Toxicological Threshold Levels Problems in Determination of NOEL and LOEL Values Reporting of NOAEL and LOAEL Values Toxic Effects in Collectives Differences in the Individual Sensitivity LD50 and TD50 Distribution of Individual Sensitivity, Therapeutic Range Specific Dose-Effect Relationships Extrapolation of Threshold Levels to Application in Humans Use of More Than One Animal Species Quantification of Exposure Toxic Threshold Levels and Safety Margin in Humans Cross-References References 23 Extrapolation Procedures for Carcinogenic and Noncarcinogenic Compounds Introduction Study Types and Evaluation Principles A Road Map for Extrapolation Choice of Risk Parameters Choice of Risk Measures Dose Extrapolation Risk Assessment Under the Threshold Dose Assumption Risk Assessment Without Threshold Dose Assumption The Limit Risk PoD Based on Benchmark Dose Other PoDs Margin of Exposure (MoE) Cross-References References 24 Probabilistic Methods in Toxicology Background Methods for Quantifying Variability and Uncertainty in Risk Assessment Point Estimates Probabilistic Estimates Sensitivity Analysis Application Potential in Dose-Response Assessment Software for Probabilistic Exposure and Risk Assessment Cross-References References 25 Exposure Analysis for Indoor Contaminants Objectives and Purpose for the Determination of Volatile and Semi-volatile Organic Compounds in Indoor Air Screening Methods Sampling Determination of Organic Pollutants in Indoor Air Limits and Errors of the Determination of Organic Indoor Air Pollutants Influence of Emission Characteristics and Ventilation The Effect of Absorbing Effects (Sinks) Conclusion Cross-References References 26 Benchmark Dose Approach in Regulatory Toxicology Introduction Benchmark-Dose (BMD) Approach Dose-Response Assessment for Risk Characterization Dose-Response Data Types Dose-Response Model (DRM) Before Starting the BMD Approach Data Selection Model Selection and Specification Specification of the Benchmark Response (BMR) Model Fitting and Model Acceptance BMD Modeling in Practice One Data Set A Suite of Models Pragmatic Proposals Frequentist Combining Model Averaging BMD Confidence Interval BMD Modeling with Several Data Sets BMD for Human Data and Presence of Covariate Information BMD Modeling for Different Endpoints Reporting the Results of the BMD Approach Use of the BMDL for Risk Characterization Cross-References References 27 Human Biomonitoring: Its Importance in Toxicological Regulation Introduction Environmental Monitoring Chemicals (Biomarkers of Internal Exposure) Biochemical Effect Monitoring DNA Adducts 8-Hydroxy-2′-deoxyguanosine (8-OHdG) Hemoglobin Adducts (Hb Adducts) Biological Effects (Biomarker of Effect) Other Markers General Population HBM Programs Evaluation of HBM Results (Internal Exposures) Reference Values Reference Value and Risk Assessment Health-Based Values HBM Values Biological Equivalents (BEs) Risk Assessment in Context with Surveys/Tool in Risk Management Cross-References References Resources Part III: Approaches Used 28 Toxicodynamic Models Introduction Requirements for Toxicodynamic Modeling Description and Application of Toxicodynamic Models (TDMs) Toxicodynamic Potency Explanatory and Biologically Based TDMs TDMs for Risk Characterization in Regulatory Toxicology Toxicokinetic-Toxicodynamic Models Chemical-Specific Adjustment Factors Cross-References References 29 Toxicokinetic Models Introduction The Relevance of Toxicokinetics Toxicokinetic Modeling Classical Compartment Open Models Physiologically Based Toxicokinetic (PBTK) Models Cross-References References Recommended Reading 30 Exposure Scenarios in Toxicology Introduction Structure of Exposure Scenarios Characterization of the Source and the Use of the Substance in a Product Categories of Use Release, Distribution, and Disappearance Exposure by Inhalation Typical Scenarios of Inhalation Exposure Dermal Route of Exposure Typical Scenarios of Dermal Exposure Oral Route of Exposure Typical Scenarios Behavior of Populations and Individuals Exposure Estimate Time Budgets Particular Age-Related Behaviors Anthropometric Data Single-Point-Based (Deterministic) Exposure Assessments Distribution-Based (Probabilistic) Exposure Assessment Impact of Exposure Assessment Cross-References Notes References Recommended Reading Resources 31 Quality Criteria for Primary Literature in Toxicology Introduction Data and Data Sources Evaluation of the Reliability of Studies Plausibility of Study Design and Results Plausibility of Results in Relation to the Overall Knowledge on a Given Substance Weighting of Borderline Cases Conclusions Cross-References References Resources 32 Data Mining in Toxicology Introduction Overview of Data Search Methods Using Online Search Engines Portals of Publishing Companies Assessment by a National or International Committee Review Articles Factual Databases Comprehensive Data Searches and Analyses Bibliographical Databases Selection of the Database Searching Strategies Reference Management Databases and Providers Databases and Portals Databases Database Portals Database Portals (Available at a Charge) Databases (Available at a Charge) Portals of Publishing Companies Organizations Statements Explaining Occupational Exposure Limits Cross-References References 33 Principles of Analytical Chemistry for Toxicology Introduction: Historical Summary The Aim and Means of Analytical Chemistry Important Techniques of Pre-analysis Solid-Phase Extraction Liquid-Liquid Extraction Solid-Phase Microextraction Separation Techniques Chromatography HPLC: Including Coupled Techniques LC-MS (Thermospray, Fast Atom Bombardment, Particle Beam) Ionization Techniques Mass Spectrometer LC-MS/MS GC: Including Coupled Techniques Headspace GC GC-MS Thin-Layer Chromatography (TLC) Ion Exchange Chromatography (IEC/IEX) Electrophoresis Atomic Spectroscopy Atomic Absorption Spectroscopy (AAS) Inductively Coupled Plasma Mass Spectrometry (ICP-MS) Selective Analytical Chemistry Sensor Techniques Immunoassays Special Types of Mass Spectrometers (LC)-MALDI-TOF Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR-MS) References 34 Uncertainty Analysis in Exposure Assessment-Relevance for Toxicological Risk Assessment Introduction Development of a Regulatory Status of Uncertainty Analysis Rationale for Characterizing Uncertainty in Exposure Assessment Definition of Assessment Objectives Sources of Uncertainty in Exposure Assessment Scenario Uncertainty Model Uncertainty Parameter Uncertainty Uncertainty in Measurement Data Sources for Model Parameters (Exposure Factors) Evaluating the Total Impact of Uncertainty Model Evaluation Sensitivity Analysis Quantitative Sensitivity Analysis: Identification of Key Sources of Exposure, Uncertainty, and Variability Interpretation of Uncertainty Characterization Results Cross-References References Part IV: Paradigms Used in Risk Evaluation 35 Read-Across Methodology in Toxicological Risk Assessment Introduction Read-Across: Step-by-Step From Problem Formulation to the Initial Read-Across Hypothesis Identify Source Compound(s) Starting with Structure Similarity Source Compound Evaluation Data Gap Filling and Uncertainty Assessment Moving Toward Mechanistic Risk Assessment Using In Vitro and In Silico Models Cross-References Notes References 36 Green and Sustainable Chemistry as Regulatory Levers Introduction Developments Before the Area of Green Chemistry Early Industrial Chemistry Pollution and Accidents (1965-1990) Pollution of Environmental Media Outdoor Air Ozone Hole Surface Water Ground Water Dumping Sites and Soil Indoor Air Consumer Goods Pollutants of Major Concern (1965-1990) Persistent Organic Pollutants (POP) Toxic Metals Polycyclic Aromatic Hydrocarbons Endocrine Disruptors Chlorinated Volatile Solvents Industrial Accidents (Examples) Seveso Bhopal Chernobyl Chemical-Induced Disease Drug Scandals Advances in Chemical Safety Analytical Chemistry and Clinical Chemistry Toxicological Advances Whistle Blowers Information Systems Harmonization of Regulations Green- and Sustainable Chemistry Green Movements ``Green Chemistry ́ ́ Beginning and Mission, Expansion Sustainability Movements The United Nations Sustainable Development Agenda 30 ``Sustainable Chemistry ́ ́ Green Chemistry Methods The Complexity of Sustainable Decisions Toxicology for Sustainable Development Cross-References References 37 Do Carcinogens Have a Threshold Dose? The Pros and Cons Introduction Tumor Promoters Factors Modifying Carcinogenesis Dose, Time, and Cell Fate Heterogeneity Further Examples of Genotoxic Carcinogens Regulatory Aspects on Thresholds or No Thresholds for Genotoxic Carcinogens Conclusions Cross-References References 38 Single Substances Versus Combined Effects: Problems in Mixture Toxicology Introduction Basic Considerations Basic Aspects of the Scientific Evaluation and Regulatory Specifications of Safety Values for Combined Substance Exposures Cross-References References Recommended Reading 39 Biomolecules Versus Smaller Chemicals in Toxicology: ICH, EU, and US Recommendations Introduction Biomolecules Versus Smaller Chemicals in Toxicology ICH Guidelines The Regulatory Environment to Initiate First-in-Human Studies Comparison Between the Nonclinical Assessments of Biologics and New Chemical Entities Pharmacology Pharmacodynamics Safety Pharmacology Pharmacokinetics and Toxicokinetics Toxicology Repeated-Dose Toxicity Genotoxicity and Carcinogenicity Reprotoxicity and Juvenile Animal Studies Immunogenicity and Immunotoxicity The Standard for Exchange of Nonclinical Data (SEND) Format Impact of Manufacturing and Formulation Changes on the Development Process Alternative Methods Including In Silico Evaluation Environmental Risk Assessment (ERA) Conclusion and Recommendations Cross-References References Peer-Reviewed Articles Regulatory Documents 40 Sensitive Humans Versus Average Persons in Toxicology Introduction Genetic Polymorphism Additional Parameters Toxicological Implications Susceptibility in Children Physiological Differences Increased Susceptibility in Fetuses, Babies, and Children Regulatory Considerations Cross-References References 41 Default Factors in Quantitative Risk Assessment Introduction Nomenclature Extrapolations Duration Extrapolation Extrapolation from LOAEL to NAEL Interspecies Extrapolation Intraspecies Extrapolation Consideration of Qualitative Aspects Application Framework Cross-References References Resources 42 Assessment of Background Exposure and Additional Exposure by Human Biomonitoring Introduction Special Issues of HBM Data Assessment for Carcinogens Health-Based Assessment Values Risk-Based Assessment Values Reference Values and Other Descriptive Assessment Values Parameters of Biological and Biochemical Effects Can Thresholds Be Certain? Cross-References References 43 Adverse Effects Versus Non-adverse Effects in Toxicology The Meaning of the Term Adverse Definition of Adverse Effects Dimensions of Adversity Severity of an Effect Detectability Subjective Perception Reversibility Probability and Number of Persons Concerned Groups Concerned Causality Final Remarks References Recommended Reading 44 Health-Based Threshold Values Versus MOS in Toxicology Introduction Health-Based Threshold Values Dose Without (Adverse) Effect Safety Factors/Uncertainty Factors/Assessment Factors Margin of Safety (MOS)/Margin of Exposure (MOE) Exposure Assessment Risk Assessment Cross-References References Resources 45 Precaution Principle Versus Danger Prevention in Toxicology Principle of Hazard Prevention Suspected Threshold of Danger Principle of Precaution Distinction of the Area of Precaution Cross-References References Recommended Reading 46 Hygienic Versus Toxicological Approaches in Regulation Introduction Toxicology Hygiene Example: Pesticide Regulation in the Drinking Water The German Hygiene Philosophy The Philosophy of the WHO Regulation of ``Unknown ́ ́ Substances Cross-References References 47 Protected Property and Protection Level in Regulatory Toxicology Introduction Subjects of Protection Protection Goals and Levels of Protection Complete Protection: Partial Protection Hazard Control: Prevention Substantiation of Protection Goals: Deduction of Standards Cross-References Recommended Reading 48 Ethical Issues in Science: Focus on Regulatory Toxicology Introduction Historical Development Ethical Principles Respect and Protection Informed Consent and Transparency Favorable Risk-Benefit Ratio Fair Participant Selection Scientific Validity Ethical Review Criteria Types of Experiments Animal Welfare Cross-References Recommended Reading Resources Part V: Risk Assessment and Evaluation 49 Teaching Chemical Safety Introduction Chemical Safety at Work Risk Management Substance Information and Labeling Globally Harmonized System of Classification, Labeling, and Packaging of Chemicals (GHS) Hazard Pictograms Hazard (H) and Precautionary (P) Statements Safety Data Sheets (SDS) and Operating Instructions Handling Storage Disposal Implementing Chemical Safety at Work Good Laboratory Practice Summary Cross-References References Recommended Reading 50 Current Role of the Risk Concept in Regulatory Toxicology Introduction History of the Risk Term Dimensions of the Concept of Risk Quantification of Probability Risk Comparison Phantom Risk Dealing with the Concept of Risk Cross-References References Recommended Reading 51 Importance of Physicochemical and Physical Properties for Toxicological Risk Assessment Introduction State of Matter Solid Phase Liquid Phase Gaseous Phase Structural Aspects Small Organic Molecules Organic Macromolecules Biopolymers Particles and Nanoparticles Density Solubility Solubility in Water Hydrophilic Substances Lipophilic Substances Solubility in Lipid Environment n-Octanol/Water Partition Amphiphilic Substances Virtually Insoluble Substances Surface Adsorption Osmotic Activity Volatility, Vapor Pressure, and Vapor Solubility Example Anesthetics Example Mercury Environmental Relevance Viscosity Stability Heat Sensitivity Mechanical Abrasion Photochemical Instability/Reactivity Photosensitivity Isotopic Instability Flammability Kinetics and Reaction Types Toxicokinetics Interaction Types Cross-References References 52 Intrinsic Toxicity of Substances: Aspects for Risk Assessment Introduction Structure-Related Intrinsic Toxicity Toxicokinetic and Toxicodynamic Aspects Corrosive Substances Short-Chain Aldehydes Short-Chain Chlorinated Solvents Nitrosamines Organophosphates Phenylethylamines Aromatic Chlorinated Substances Lectins AB Toxins Dust, Fine, and Ultrafine Particles Metals and Metal Compounds Essential Metals Nonessential Metals Target-Related Toxicity Prologue: Damage and Repair Molecular and Organ Level Membrane Potential and Neuronal Activity Resting Membrane Potential Nerve Conductance Cardiac Long QT Syndrome Neurotransmission Reproductive and Developmental Effects Irritation Sensitization Genotoxicity, Mutagenicity, Carcinogenicity Liver as Target Organ Intrahepatic Cholestasis Drug-Induced Autoimmune Hepatitis Liver Cell Necrosis Fatty Liver Liver Cirrhosis Liver Cancer (Hepatocellular Carcinoma) Hepatic Encephalopathy Role of Individual Susceptibility NSAID-Induced Ulcer Disease Asbestos, Cigarette Smoke, and Lung Cancer Gluten and Celiac Disease Alpha-1 Antitrypsin Deficiency and Lung Function Iron and Iron Storage Disease Age-Dependent Sensitivities Poor Metabolizers Summary Cross-References References Resources 53 Importance of Xenobiotic Metabolism: Mechanistic Considerations Relevant for Regulation Fundamentals Examples of Metabolism Associated Toxicity MeIQx (2-Amino-3,8-Dimethylimadazo[4,5-f]Quinoxaline) Aflatoxin B1 Vinyl Acetate - The Relevance of Practical Thresholds Cross-References References 54 Dose-Response Relationship and Extrapolation in Toxicology: Mechanistic and Statistical Considerations Introduction Dose-Response Curve in Textbook The Logarithm ``Catch ́ ́ Conclusions Continuous Response Variables Linearity as Default Extrapolation for Rates of First-Line Interactions Deviation from Linearity Due to Saturation of Processes that Modulate Biomarker Levels Nonmonotonic Shape if Background Is Reduced at Low Dose Confidence Limits on Low-Dose Effect and Comparison with Background Variation Conclusions Mechanistic Background of Nonmonotonic Dose Response ``Incidence ́ ́ as a Different Type of Response Variable A Dose-Incidence Relationship Reflects Differences in Susceptibility Conclusions Chemical Carcinogenesis and Cancer Incidence Multiplicative Combination of Susceptibility Factors Results in a Lognormal Distribution Extrapolation of a Dose-Cancer Incidence Relationship It Is Time for a Revival of the Lognormal Distribution for Cancer Risk Extrapolation Tolerance Distribution Versus Stochastic Modeling Conclusions How to Incorporate a Nonlinearity of an Experimental Biomarker in a Dose-Incidence Relationship? Monte Carlo Simulations to Differentiate the Dose Response for a Population Average Versus Individuals Conclusions Cross-References References 55 Importance of Exposure Level for Toxicological Risk Assessment Introduction Local Toxicity Irritation Sensitization Local Carcinogenicity Systemic Toxicity Cross-References References 56 Risk Characterization in Regulatory Toxicology Introduction Elements of Risk Characterization Hazard Characterization Uncertainty Factors Other Approaches Exposure Characterization Uncertainty and Variability Weight of Evidence Transparency of the Process Cross-References References Recommended Reading 57 Risk Evaluation in Regulatory Toxicology Int