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
		Elements of Risk Evaluation
			Context of the Risk Problem
			Risk Acceptance
			Socio-economic Analysis
			Economic Factors
			Sociopolitical Factors
			Uncertainty and Variability: Scientific and Economic Aspects
		Outlook
		Cross-References
		References
			Recommended Reading
	58 Risk Comparison in Toxicology
		Introduction
		Definitions
		Risk Structures
		Future Risks
		Mortality Risks in the Population
		Acceptance of Risks
		Cross-References
		References
			Recommended Reading
			Resources
	59 Risk-Benefit Considerations in Toxicology
		Introduction
		Risk-Benefit Assessment
		Cost-Benefit Analysis
		Utility Analysis
		Cross-References
		References
			Recommended Reading
	60 Toxicological Risk Assessment in Different Jurisdictions
		Introduction
		Acceptable Risk, Comparison of Risks, and Establishing Acceptable Levels of Risk
		Pharmaceuticals
		Occupational Health
		Indoor and Ambient Air
		Food
		Cosmetics and Consumer Products
		General Chemical Safety
		Radiation Protection
		Cross-References
		Recommended Reading
Part VI: Risk Management and Risk Communication
	61 International Regulation of Toxicological Test Procedures
		Introduction
		International Harmonization of Guidelines for Toxicity Testing
		Validation and Acceptance of New Toxicity Test Methods by the OECD
		Example of Successful Validation and Regulatory Acceptance of New Test Methods
		Implementing of New Concepts for Developing Toxicity Tests During the Last Decade
		Outlook
		Cross-References
		References
	62 Risk Cycles in Toxicology
		Introduction
		A Framework for Risk Evaluation
		Risk-Reduction Cycles
		Product Development Risk
		Life Cycle Cost Risk
		Health Risks
		The Risk Cycle in Toxicology
		Future of Risk-Reduction Cycles
		Cross-References
		References
	63 Risk Minimization in Drug Development: Regulatory Aspects
		Introduction
		Risk and Risk Minimization
			Risk Level
			Unknown Risks
		Strategies for Risk Minimization in Nonclinical Development
			Adaption of Trial Protocols to the Stages of Drug Development
			Chronological Order
			Potential Areas of Risk for Humans
			Extrapolation to Humans
			Feedback of the Results from Early Clinical Trials
			Role of Clinical Development
			Prerequisites for Use in Humans
			Harmonization of Drug Assessment
			Carcinogenicity Studies (ICH S1)
			Reproduction Toxicity Studies (ICH S5)
		Criteria for Inclusion of Volunteers/Patients in Clinical Trials (ICH M3 (R2))
			Men
			Women Not of Childbearing Potential
			Women of Childbearing Potential
			Pregnant Women
			Clinical Trials in Pediatric Populations
		Tolerable/Non-tolerable Risks Using the Example of Safety Pharmacology
			Example QT Interval Prolongation
		Cross-References
		References
	64 Purpose and Methods of Risk Management in Regulatory Toxicology
		Introduction
			Chemical Risk Assessment
		Risk-Reduction Strategy
			Voluntary Agreements and Regulatory Actions
			Thalidomide and Drug Legislation
			Smoke Control and Air Quality Legislation
			DDT, Malaria Control, and Wildlife
		Preventive Measures
		Cross-References
		Recommended Reading
	65 Assessment of Limit Values in Regulatory Toxicology
		Introduction: Types of Exposure
		Criteria to Limit Exposure
		Spheres of Interest When Setting Legal Limit Values
		Rule of Environmental Hygiene (REH)
		REH-Based Criteria for Evaluating Exposure from Chemical Loads
			Framework or Conditions of Social Evaluation: Prevention, Optimization/Acceptance, and Minimization/Tolerance of Exposure
			Holistic Concept for Evaluating Chemical Loads or Exposure in a Triangle of Precautionary Prevention, Rejection, and Acceptanc...
			Concrete Evaluation of Annoyances, Loads, and Risks Within the Triangle of Prevention, Rejection, and Tolerance/Acceptance
		Definition of Precautionary Limit Values According to Origin A-C of Compounds
			Class A, Geogenic/Biogenic: Natural Constituents Without (A1) or After Treatment (A2) of the Resource
			Class B, Anthropogenic: Additives and Their Technically Unavoidable Residues and Side or Transformation Products
			Class C, Anthropogenic: Environmental Contaminants and Their Transformation Products
		Setting and Evaluation of Legal Limit Values by Means of the REH
			Drinking Water Limit Values from the EU as an Example
			Categorization of Legal LVs in Terms of General Precaution, Early Warning, Control of Concern, or Control of Imminent Hazard
				General Precautionary Maximal Values, PVg
				Warning Values, WV
				Threshold of Concern for Adverse Effects, Ea
				Hazard-Linked Action Values, AV
		Summary: A Short Directory to Quantify and Survey Precautionary LVs
		Conclusions
		Cross-References
		Notes
		References
			Recommended Reading
	66 Limit Value Setting in Different Regulatory Areas of Toxicology
		Introduction
		The Setting of Occupational Exposure Limits
		Health-Based Limit Values for Environmental Contaminants
			Air Pollutants
			Water Quality Criteria and Standards
			Soil Values (Contaminated Land)
		Future Perspectives
		Cross-References
		References
			Resources
	67 Registration and Approval in Regulatory Toxicology
		Chemical Regulations
		Introduction
		Pesticides
		Plant Protection Products
		Biocides
		Food Contact Materials
		Toys
		Cosmetics
		Medical Devices
		Medicines
		Cross-References
		References
	68 Health Hazard Classification and Labelling
		Introduction
			Health Hazard Classification
			Health Hazard Labelling
			Safety Data Sheet
			Poisons Centres´ Perspective
		Cross-References
		References
	69 Prohibition and Restrictions in Regulatory Toxicology
		Introduction
		Purpose of Prohibition in Toxicology
		Levels and Origins of Prohibitions and Restrictions
		Drugs
		Addictive Drugs
		Doping Drugs
		Example Alcohol
			US Prohibition
			General Situation Today
		Smoking, Tobacco
		Chemical Weapons
		Mercury
			Technical Uses
			Medical Uses Earlier and Now
			Mercury and the Environment
			Mercury Regulations
		Persistent Organic Pollutants (POP)
		Biocides
		Food, Drinking Water
		Regulations of Emissions and Waste
		Nuclear Weapons
		REACH and Restrictions
		Summary
		Cross-References
		References
	70 Susceptible Population Groups in Regulatory Toxicology
		Introduction
			Are Susceptible Subgroups Protected by the Default Safety Factors?
			Specific Groups and Regulations
		Specific Sensitivity in Different Life Periods
			Prenatal Period
			Age up to Six Months
			Child and Youth
			Elderly (>70 Years of Life)
			Pregnancy
		Influences of Diseases
			Impairment of Excretory Organs
			Other Organs
		Gender-Specific Aspects
		Cross-References
		References
			Recommended Reading
	71 Toxicology Report
		Key Points
		What´s New?
		Expert Requirements
		Report Types
		Report Essentials
		Required Basic Information for Experts
			Reporting Toxicities
			Reporting Standards for Omics in Regulatory Toxicology
		Cause and Effect Relationships
			Occupational and Workplace Issues
			Adverse Drug Effects and Drug-Related Disease
		Work Disability and Reduction in Earning Capacity
		Historical Crosslinks to Regulatory Affairs
		Recommended Internet Sources
		Resources
		Further Reading
		Cross-References
		References
	72 Risk Management in Toxicological Disasters
		Introduction
		Characteristics of Toxicological Disasters
		Preparedness, Regulatory, and Legal Frameworks
		Training, Drill, and Exercises
		Identification of Potential Hazard Sources
		Identification of Hazards Through Emergency Forces
		Detection
		Information on Toxic Substances
		Limits of Exposure
		Physical Protection
		Decontamination
		Drugs
		Centers of Expertise
		Research and Development
		Risk Management
		Summary
		Cross-References
		References
			Recommended Reading
	73 Institutionalized Participation in Regulatory Toxicology
		Introduction
		Why Participation?
		Participatory Risk Management
		Legal Background of Participation
		Rationale and Benefits of Public Participation in Risk Decisions
		Who Should Participate?
		Models of Participation
			Publication of Decision with a Set Period to Submit Objections
			Hearing
			Round Table
			Advisory Board
			Mediation
			Cooperative Discourse
		Evaluation of Participation
		Conclusions
		Cross-References
		References
			Resources
	74 Risk Communication: Challenges for Toxicologists and Other Risk Experts
		Introduction: Issues and Objectives of Good Risk Communication
		Elements of Effective Risk Communication
			Basic Rules of Good Communication
			Important Requirements for Effective Risk Communication
		Contact with News Media (Press, Television, Broadcast)
		Preventive Risk Communication
			Basic Rules for Institutions Involved in Risk Management and Risk Communication
			Public Hearings for Preparing Decisions by Authorities or in Politics
			Risk Communication and Training Preventing Hazardous Incidents and Transport Accidents with Release of Dangerous Substances
		Risk or Hazard Information on Chemical Substances and Products
		Cross-References
		References
			Recommended Reading
			Resources
	75 Dealing with Diseases That Have Been Attributed to Chemical Exposures
		Introduction
		Environmental Health Investigation
		Medical History
		Uncommon Somatic Disorders
		Disorders Not Able to Be Diagnosed by Conventional Medicine
		Social History
		Previous Findings
		Findings
		Blood Sampling
		Monitoring in Environmental Medicine
		Specimen Collection and Processing Procedure
		Evaluation of Results of Human Biomonitoring
		Reference Values for Human Biomonitoring
		Toxicologically Derived Human Biomonitoring Values
		Limitation of Biomonitoring
		Dealing with Environmental Patients from a Psychological and Psychiatric Perspective
		Psychiatric Diagnostics
		Further Models of the Origin of IEI
		Therapy
		Cross-References
		References
			Recommended and Readings
	76 REACH and CLP: Its Role in Regulatory Toxicology
		Introduction
		Objectives, Scope, and Implementation of REACH
		Registration of Chemical Substances: ``No Data - No Market´´
		Information Gathering and Closing of Knowledge Gaps
		Quality Check of Gathered Information
		Hazard Identification and Assessment
		Chemical Safety Assessment (CSA)
		Evaluation
		Authorization and Restriction
		Learnings
		Outlook
		Cross-References
		References
	77 Assessment of Mixtures: Bridging Principles and Other Approaches
		Introduction
		The Additivity Principle
		The Concept of ``Minor Modifications´´
		Bridging Principles
		Weight of Evidence (WOE) Approach and Expert Judgment
		Outlook
		Cross-References
		References
	78 Notification of Hazardous Mixtures and Cosmetic Products for Poisons Centers in the European Union
		Introduction
		Poisons Centers Have an Important Role in Clinical and Regulatory Toxicology
		Notification of Product Information for Poisons Centers Facilitates Rapid Clinical Risk Assessment
			Harmonized Notification of Hazardous Products According to CLP Regulation (EC) No. 1272/2008, Article 45 and Annex VIII
			The Cosmetic Products Notification Portal
		Cross-References
		References
			Resources
			Recommended Reading
Part VII: Regulated Areas
	79 Chemical and Biological Weapons and Their Regulation
		Introduction and History
		Chemical Weapons
			Definitions
			Characteristics of Chemical Weapon Agents (CWAs)
				Nerve Agents
					Clinical Picture
					Toxicodynamic
					Biomonitoring, Bioanalytic, and Verification
					Long-Term Effects
				Vesicants
					Clinical Picture (Short and Long Term)
					Toxicodynamic
					Late Effects
		Biological Weapons
			Definition
			Characteristics of Biological Toxins
		Risk Assessment Aspects
		Risk Management
			Biological Weapons Convention (BWC)
			Chemical Weapons Convention (CWC)
				Organization for the Prohibition of Chemical Weapons (OPCW)
			National Regulations: Installation of Preparedness Standards
				Laboratory Safety
				Risk Management
				Laboratory Standardization Approaches
				Pharmacy
				Decontamination
		Cross-References
		References
			Recommended Reading
	80 Nanoparticles and Their Regulation
		Introduction
		Regulation of Nanomaterials
			Initial Considerations
				Assessing the Risks of ENMs
				How Should ENMs Be Regulated?
				Exposure Paths
			Chemicals: Present Regulatory Status of Nanomaterials
				Regulatory Status at OECD
				EU Definition of Nanomaterials
				Regulatory Framework of European Union
				Regulatory Framework of the USA
				Approaches for Grouping and Categorizing Nanomaterials
		Nanomedicine: Regulatory Status
			Cosmetics: Regulatory Status of Nanomaterials in Europe
			Food/Food Packaging: Regulatory Status of Nanomaterials in Europe
			Exemplary Cases of Nanoparticles Dominant in Commercialization
				Titanium Dioxide (TiO2)
				Silver
				Single-Walled (SWCNT) and Multi-Walled Carbon Nanotubes (MWCNT)
				Graphenes
		Cross-References
		References
	81 Psychoactive Designer Drugs: Classes, Mechanisms, and Regulation
		Introduction
		Designer Drugs and Drug Design
			Types of Designer Drugs
			Drug Design
		Narcotic and Psychoactive Drug Classes
			Terms and Names
			Types and Classes
			Parent Substances and Derivatives
			Novel Psychoactive Substances
			Actions at the Neuronal Synapse
				The Normal Neurotransmission Process
				Interaction with Neurotransmitter Receptors
				Interaction with Neurotransmitter Transport
				Interaction with Neurotransmitter Degradation
			Metabolism and Elimination
			Toxicology and Clinical Toxicology
				Acute Intoxication
				Dose-Response Relationships
				Chronic Toxicity and Dependency
		Central Role of Analytics
		Aspects of Regulation, Control and Health Protection
			National and International Efforts
			The Analogue Principle
				Types and Advantages
			Measures for Health Protection and Control
		Cross-References
		References
			Recommended Reading
			Official Detailed Information and Lists
			Information About Recreational Drugs and Effects
	82 Tobacco and Alternative Nicotine Products and Their Regulation
		Introduction
		Vascular Effects of Tobacco Products and Nicotine
		Respiratory Effects of Tobacco Products and Nicotine
		Cancer from Tobacco Products and Nicotine
		Other Important Diseases Promoted by Tobacco and Nicotine Products
		Effects of Tobacco Products and Nicotine on Fetus and Child
		Addiction
		Guidelines and Regulation on Tobacco Products and Nicotine
		Cross-References
		References
	83 Regulation of Dental Materials
		Introduction
		Development of Safety Regulations
			History
			Legal Framework
			Development of Standardized Testing Procedures
		Clinical Risk Assessment
		Unspecific Versus (Dentally) Specific Tests
		Specific Problems in Dentistry
			Dental Pulp Damage
			Sensitization
			Oral Mucosa
			Nanoparticles
				Nanomaterials and Medical Devices
				Nanoparticles in Dental Materials
			Nanoparticle Exposure from Dental Materials
				Titan (Ti) and Zirconium (Zr) Nanoparticles from Dental Implants
				Protective Measures
		CMR and Systemic Toxicity
			Carcinogenicity of Dental Materials
			Genotoxicity/Mutagenicity of Dental Materials
			Reproductive Toxicity of Dental Materials
			Systemic Toxicity of Dental Materials
		Environment
		Conclusions
		Cross-References
		References
	84 Microplastics: A Novel Suite of Environmental Contaminants but Present for Decades
		Introduction
			Modern Plastics: A Success Story Turned into an Environmental Problem
			Microplastics: A Young Field of Research
			Microplastics: Analysis of Environmental Concentrations
			Microplastics: Environmental Risks
				Ingestion: The Main Entrance Route of Microplastics into Organisms
				Trophic Transfer
				Ingested Microplastic Particles: Possible Effects in the Gastrointestinal Tract
					Effects Caused by Additives
					Effects Caused by Adsorbed Pollutants
					Effects on the Gut Microbiome
			Microplastics: Tissue Translocation
				The Coating of Microplastic Particles: Biofilm, Coronas, and Pathogens
				Effects on Cellular, Tissue, and Physiological Level
				Microplastics: Effects on Morphology, Behavior, Population, and Life History
		Microplastics in Plants: A Fairly New Research Field
		Microplastics Risk to Humans?
		Synopsis
		Cross-References
		References
	85 Regulation of Textiles
		Introduction
		Regulation of Harmful Substances on Textiles
			Regulation of Harmful Substances on Textiles for European Market
			Regulation of Harmful Substances on Textiles for US Market
			Standard 100 by Oeko-Tex
		Regulation of Antimicrobial Textiles
			Registration of Antimicrobial Textiles for European Market
				Registration of Chemicals by REACH
				Registration of Antimicrobial Textiles According to the BPR
			Registration of Antimicrobial Textiles for US Market
		Regulation of Personal Protective Equipment (PPE)
			Regulation of PPE for European Market
			Regulation of PPE for US Market
		Regulation of Medical Textiles
			Regulation of Medical Textiles for European Market
			Regulation of Medical Textiles for US Market
		Conclusion
		Cross-References
		References
	86 Regulation and Mitigation of Greenhouse Gases
		Introduction
		Global Warming and the Greenhouse Effect
			Brief Explanation of the Greenhouse Effect
			Overview of Greenhouse Gases and Their Global Warming Potential
			Global Warming Caused by the Greenhouse Effect
				History
				Future
			Climate Damages and Tipping Points: Why Is It Necessary to Limit Global Warming?
		Current and Future Emissions of Greenhouse Gases
			Scenarios of Future GHG Emissions
			What Would It Take to Stay Within the Limits of the Climate System?
			The Economics of GHG Emissions and Their Mitigation
		Global Regulation of Greenhouse Gas Emissions
			The UN Framework Convention on Climate Change (UNFCCC)
			Regulation from 1995 to 2012 Under the Kyoto Protocol to the UNFCCC
			Regulation Till 2020 Under the Cancún Agreements
			Regulation After 2020 Under the Paris Climate Agreement
			The Link to the UN Sustainable Development Goals (SDG)
		The Great Transition to a Climate-Neutral Global Society
			The Concept of a Great Transition
			The Coronavirus Crisis Recovery as Critical Also for Handling the Climate Crisis
			The European Green Deal as an Integrated Regulatory Approach
		Cross-References
		References
	87 Regulation of Agrochemicals
		Introduction
		Regulation of Agrochemicals
			Data Requirements for Active Substances
			Data Requirements for Plant Protection Products
			Human Health Risk Assessment
				Exposure Assessment
					Dietary Exposure
					Non-Dietary Exposure
				Hazard Assessment
			Authorization of Plant Protection Products
			Approval of Active Substances
				The Glyphosate Controversy
			Co-Formulants
		Cross-References
		References
	88 Biopharmaceuticals: CMC Development ``Points to Consider´´ from a Regulatory Perspective
		Introduction
		Foundations of Drug Development: TPP, Quality TPP, CQAs, and Control Strategy
		Quality Levels for Development and Manufacture of GLP, Phase 1/Phase 2, and Phase 3/Commercial Supplies
		Analytical Development
			Forced Degradation Studies
			Stability
			Comparability
				Early Development Comparability Strategy
				Late Development Comparability Strategy
			Product Characterization: Elucidation of Structure and Impurities
		Manufacturing Material Inputs
			Master and Working Cell Banks
			Raw Materials
		Specifications
		Compatibility
		Viral Clearance
		Conclusions
		Cross-References
		References
	89 Medical Aspects of Traffic Exhaust Regulations
		Introduction
		Air Pollutants
		Health Effects
		Nitrogen Dioxide (NO2)
		Particulate Matter
		Guidance Values Versus Limit Values
		Legal Mechanisms
		Technical Measures
		Non-technical Measure
		Cross-References
		References
	90 Tattooing: Toxicology and Risk Assessment
		Introduction
		Health Risks of Tattoos: Clinical Evidences
		Components
		Risk Assessment
		Conclusion
		Cross-References
		References
	91 Risk Assessment of Food Additives
		Introduction
		Data Required for the Risk Assessment
			Chemical Aspects and Manufacturing
			Toxicokinetics
			Genotoxicity
			Subchronic and Chronic Toxicity and Carcinogenicity
			Reproductive and Developmental Toxicity
			Other Studies
		Derivation of an Acceptable Daily Intake
		Exposure Assessment
		Risk Management Based on Risk Assessments
		Perspective
		Cross-References
		References
			Resources
	92 Risk Assessment of Food Components with Botanical Origin
		Botanicals in Food: An Introduction
		Specifics in the Risk Assessment of Botanicals: Some Examples
			Identity and Specifications
			Interactions of Secondary Plant Components
			Experiences from Human Exposure
		Guidance for Safety Evaluation: An Approach by EFSA
		Legal Background
		Future Perspectives
		Cross-References
		Endnotes
		References
	93 Risk Assessment of Genetically Modified Food and Feed
		Introduction
		Legislation Framing the Use of GMO in the European Union
		Assessment Procedure for Food and Feed from GM Plants
			Hazard Identification and Characterization
				Molecular Characterization
				Comparative Analyses
				Toxicological Assessment
					Newly Expressed Proteins
					New Constituents Other than Proteins
					Altered Levels of Endogenous Constituents
					Assessment of Whole Food and/or Feed Derived from GM Plants
				Assessment of Allergenicity
				Nutritional Assessment
			Exposure Assessment
			Risk Characterization
		Cross-References
		References
	94 Novel and Traditional Foods: Novel Food Regulation in the EU
		Introduction
		Regulation of Novel Foods in the European Union
			Previous History: Situation Before 1 January 2018
			The New Novel Food Regulation (EU) 2015/2283: What Is Actually New?
				Revision of the Novel Food Categories
				Determination of Novel Food Status
				Traditional Foods from Third Countries
				Union List of Generic Authorized Novel Foods
				Transitional Measures
		Authorization Procedure in the EU
			Authorization Procedure for Novel Foods
				Risk Assessment Process
					Introduction and Identity of the Novel Food
					Production Process
					Compositional Data
					Specification
					History of the Novel Food and/or of Its Source
					Proposed Use and Use Levels and Anticipated Intake
					Absorption, Distribution, Metabolism, and Excretion (ADME)
					Nutritional Information
					Toxicological Information
					Allergenicity
			Notification and Application for Authorization of Traditional Foods from Third Countries
				Safety Assessment Procedure for Traditional Foods from Third Countries
					Data from the Experience of Continued Food Use in the Third Country
					Proposed Conditions of Use for the EU Market
		Cross-References
		Notes
		References
	95 Microbiome Product Toxicology: Regulatory View on Translational Challenges
		Introduction
		Regulatory Landscape for Microbiome Products
			Lay Terminology and Regulatory Status
			Global Regulatory Framework in Place
		Stakes and Hurdles of the Toxicological Assessment of Microbiome Products
		Models for Toxicology Assessment
		Toxicological Assessment Strategy
			Distribution, Biodistribution, and Colonization
			Immunogenicity/Immunotoxicity
			Genotoxicity and Tumorigenicity
			Reprotoxicity
			New Nonclinical / Clinical Approach: In Silico Modeling and Simulation
		Bench to Bedside Translation
		Conclusions
		Cross-References
		References
	96 Toxicological Aspects in the Regulation of Gene Therapy Medicinal Products
		Introduction
		Main Gene Therapies and Associated Technologies
			Main Vectors for Gene Therapies (With or Without Ex Vivo Modified Cells)
				Plasmids and Virus-Derived Vectors Overview
					Plasmids
					Recombinant AAV Vectors
					Retroviral/Lentiviral Vectors
			CRIPSR/Cas9 Technology
		Toxicological Aspects in the Regulation of GTMPs
			General Toxicology
			Biodistribution
			Insertional Capability
			Genotoxicity and Tumorigenicity
			Off-Target Toxicological Effects: Case of Genome Editing CRISPR/Cas9 System
			Immunogenicity (Immunotoxicity)
			Reprotoxicity
		Translational Risks from Bench to Clinic
		Benchmark with Approved Gene Therapies
		Definitions and Associated Tests and Assays
			Autologous Versus Allogenic
			Biodistribution, Persistence, Clearance
			CRISPR/Cas9
			Gene Therapy
			Germline Transmission
			Insertional Mutagenesis
			Integrative Versus Nonintegrative Vectors
			NSG Mice
			Replication-Competent Virus (RCV)
			Tumorigenicity
			Vector Mobilization
			Vector Shedding
		Conclusion and Perspectives
		Cross-References
		References
	97 Defence of Biocidal Active Substance Dossiers in the Context of Regulatory Toxicology
		Introduction
		Applied Regulatory Toxicology Using Biocides as an Example
			Overview of the Regulatory Process Toward the Approval of Biocidal Active Substances and Authorization of Biocidal Products
				Approval Process for Biocidal Active Substances
				Evaluation and Defense of Biocidal Active Substances During the Approval Process
				Toxicological Data Requirements of Biocidal Active Substances According to the Provisions of the Biocidal Products Regulation
			Assessment of Potential Endocrine Disruption
				WHO Definition of an Endocrine Disruptor
				Scientific Criteria for the Determination of Endocrine-Disrupting Properties
				Main Elements of the ECHA/EFSA Guidance for the Identification of Endocrine Disruptors
			Derivation of Acceptable Exposure Levels (AELs)/Concentrations (AECs) for Biocidal Active Substances
			Exposure Assessment and Risk Characterization for Biocides
				General Principles on Exposure and Risk Assessment
				Substances of Concern and Cumulative Risk Assessment
		Cross-References
		References
Part VIII: Addendum: Tables and Lists
	98 Checklist: Toxicological Risk Assessment in Practice
		Introduction
		Checklist and Comments
		Cross-References
		References
			Recommended Reading
	99 Limit Values and Guideline Values in Regulatory Toxicology
		Introduction
		Reference Doses
			Acceptable Daily Intake (ADI) Values
			Acute Reference Dose (Acute RfD)
			Contaminants
			Tolerable Absorbed Doses (TRD)
			Reference Dose and Reference Concentration (RfD, RfC)
		Occupational Safety and Health
		Drinking Water
			WHO Guidelines for Drinking Water Quality (WHO-GLDWQ)
			German Regulation on Drinking Water
		Air
			World Health Organization (WHO) Air Quality Guidelines
			Immission Values Based on EU Directives
			Technical Instruction on Air Quality Control (``TA Luft´´)
			Indoor Air Guide Values
		Food
			Maximum Residual Levels (MRLs): International, European, and National Standards and Regulations
			European Maximum Levels for Certain Contaminants in Foodstuffs
		Soil
		Body Burden
		Cross-References
		References
			Resources
			Food
			Occupational Health and Safety
			Body Burden
			Air
			Soil
Appendix
Regulatory Toxicology: Glossary
	References
Index