Cover

Title Page

Copyright

Contents

List of Contributors

Short CVs of Authors

Preface

Dedication

List of Abbreviations

Chapter 1 Introduction to the Discipline of Toxicology

1.1 Introduction

1.2 The Risk Assessment Process

1.2.1 Hazard Identification

1.2.2 Dose Response and Toxic Potency

1.2.3 Exposure Assessment

1.2.4 Risk Characterization

1.3 Toxicological Evaluation of New and Existing Chemicals

1.3.1 General Requirements for Hazard Identification and Risk Assessment

1.3.2 General Approach for Hazard Identification and Risk Assessment (for details see Chapter 2.1)

1.3.3 Toxicological Issues related to Specific Chemical Classes

1.3.4 Existing Chemicals

1.3.5 Test Guidelines (Chapter 4.1)

1.3.6 Alternatives to Animal Experiments (Chapter 4.5)

1.3.7 Evaluation of Mixtures (Chapter 2.7)

1.3.8 Evaluation of Uncertainties

1.3.9 The Precautionary Principle

1.3.10 The TTC Concept

1.3.11 Classification and Labeling of Chemicals

1.4 Summary

Chapter 2 Principles in Toxicology

2.1 General Concepts of Human Health Risk Assessment

2.1.1 Introduction

2.1.2 Principles of Risk Assessment

2.1.3 Application of Risk Assessment in Setting Exposure Standards and Limits

2.1.4 The Wider Importance of Risk Assessment

2.1.5 Summary

2.2 Toxicokinetics

2.2.1 Definition and Purpose

2.2.2 Absorption, Distribution, and Elimination

2.2.3 Toxicokinetic Models

2.2.4 Summary

2.3 Biotransformation of Xenobiotics

2.3.1 Introduction

2.3.2 Phase I Reactions

2.3.3 Phase II Reactions

2.3.4 Factors that Influence the Biotransformation of Xenobiotics

2.3.5 Role of Bioactivation in Toxicity

2.3.6 Interactions of Reactive Intermediates formed during the Biotransformation

2.3.7 Summary

2.4 Cytotoxicity

2.4.1 Introduction

2.4.2 The Cell

2.4.3 Cellular Targets of Toxins

2.4.4 Mechanisms underlying Cell Death

2.4.5 Summary

2.5 Toxicogenetics

2.5.1 Introduction

2.5.2 Toxicogenetics and Toxicogenomics

2.5.3 Genotype and Phenotype

2.5.4 The Role of Xenobiotic‐metabolising Polymorphisms in Susceptibility to Toxic Agents

2.5.5 Study Numbers and Effect Size

2.5.6 Summary

2.6 Receptor‐mediated Mechanisms

2.6.1 Introduction

2.6.2 Ligand–Receptor Interactions

2.6.3 Biological Consequences of Ligand–Receptor Interactions

2.6.4 Receptor Signal Transduction

2.6.5 Summary

2.7 Mixtures and Combinations of Chemicals

2.7.1 Introduction

2.7.2 Types of Mixed Exposures

2.7.3 Types of Joint Actions and their Role in Safety Evaluation

2.7.4 Role in Safety Evaluation

2.7.5 Summary

2.8 Chemical Carcinogenesis: Genotoxic and Non‐Genotoxic Mechanisms

2.8.1 Introduction

2.8.2 Mechanisms of DNA Damage, Repair, and Carcinogenesis

2.8.3 Cancer Development

2.8.4 Non‐Genotoxic Mechanisms of Carcinogenesis

2.8.5 Implications of Initiation and Promotion for Risk Assessment

2.8.6 Summary

2.9 Threshold Effects for Genotoxic Carcinogens

2.9.1 Introduction

2.9.2 Development of Cancer due to Genotoxic Carcinogens

2.9.3 Cellular Reaction to DNA Damage

2.9.4 Examples of Dose‐dependent Reactions in Cases of Genotoxicity

2.9.5 Summary

2.10 Reproductive Toxicology

2.10.1 Introduction

2.10.2 Characteristics of Reproductive Toxicology

2.10.3 Adverse Effects on Female and Male Fertility

2.10.4 International Test Methods in the Field of Reproductive Toxicology

2.10.5 Pre‐ and Postnatal Toxicology

2.10.6 Effects of Drugs and other Chemicals on Lactation

2.10.7 Endocrine Disrupters

2.10.8 Summary

2.11 Ecotoxicology: More than Wildlife Toxicology

2.11.1 Introduction

2.11.2 Protection Targets

2.11.3 Necessary Information

2.11.4 Risk Assessment

2.11.5 Fast‐track Approaches

2.11.6 Summary

Chapter 3 Organ Toxicology

3.1 The Gastrointestinal Tract

3.1.1 Introduction

3.1.2 Structure and Function

3.1.3 Fate of Xenobiotics in the GI Tract

3.1.4 Toxicology

3.1.5 Summary

3.2 The Liver

3.2.1 Introduction

3.2.2 Structure and Function

3.2.3 Toxicology

3.2.4 Myths of the Liver

3.2.5 Summary

3.3 The Respiratory System

3.3.1 Introduction

3.3.2 Structure

3.3.3 Function

3.3.4 Protective Systems

3.3.5 The Respiratory Tract as a Target for Toxicity

3.3.6 Respiratory Allergy and Asthma

3.3.7 Lung Cancer

3.3.8 Test Systems to Detect the Toxic Effects of Inhaled Materials

3.3.9 Summary

3.4 The Nervous System

3.4.1 Structure and Function of the Nervous System

3.4.2 The Nervous System Site of Attack for Toxins

3.4.3 Clinical Signs and Symptoms induced by Neurotoxins

3.4.4 Summary

3.5 Behavioral Neurotoxicology

3.5.1 Introduction

3.5.2 Exposure Assessment

3.5.3 Methods

3.5.4 Neurobehavioral Effects in Humans

3.5.5 Summary

3.6 The Skin

3.6.1 Structure

3.6.2 Function

3.6.3 Toxicology of the Skin and the Anterior Segment of the Eye

3.6.4 Summary

3.7 Kidney and Urinary Tract

3.7.1 Introduction

3.7.2 Anatomy and Function

3.7.3 Toxicology

3.7.4 Summary

3.8 The Hematopoietic System (Bone Marrow and Blood)

3.8.1 Introduction

3.8.2 Hematopoiesis

3.8.3 The Bone Marrow Niche

3.8.4 Toxicological Features of Circulating Blood Cells

3.8.5 Leucocytes (White Blood Cells)

3.8.6 Platelets (Thrombocytes)

3.8.7 Impairment of Bone Marrow Function

3.8.8 Mechanisms by which Chemicals can Induce Leukemia

3.8.9 Summary

3.9 The Immune System

3.9.1 Introduction: the Innate and Specific Immune System

3.9.2 Antigen Recognition

3.9.3 Activation of T and B lymphocytes

3.9.4 Immunologic Tolerance

3.9.5 Sensitization and Allergy

3.9.6 Risk Assessment of Immunotoxic Effects

3.9.7 Chemical‐induced Autoimmunity

3.9.8 General Immunostimulation by Chemicals

3.9.9 Chemical Immunosuppression

3.9.10 Summary

3.10 The Eye

3.10.1 Introduction

3.10.2 Structure and Function of the Eye

3.10.3 Routes of Delivery of Xenobiotics to the Eye

3.10.4 Specific Toxicology of the Eye

3.10.5 Summary

3.11 The Cardiovascular System

3.11.1 Structure and Function

3.11.2 Toxicology

3.11.3 Summary

3.12 The Endocrine System1

3.12.1 Introduction

3.12.2 Structure and Function

3.12.3 Foetal Development of the Hypothalamus–Pituitary–Gonad Axis

3.12.4 Testing of Sexual Function in Toxicology

3.12.5 Hazard Identification and Risk Assessment of Endocrine Disruptors

3.12.6 Summary

Chapter 4 Methods in Toxicology

4.1 OECD Test Guidelines for Toxicity Tests in vivo

4.1.1 Introduction

4.1.2 Requirements for in vivo Tests

4.1.3 Acute Toxicity

4.1.4 Skin and Eye Irritation

4.1.5 Skin Sensitization

4.1.6 Toxicity after Repeated Dosing

4.1.7 Reproductive Toxicity

4.1.8 Other Test Guidelines

4.1.9 Other Regulatory Bodies

4.1.10 Summary

4.2A In vitro Tests for Genotoxicity

4.2A.1 Introduction

4.2A.2 Bacterial Test Systems

4.2A.3 Test Systems employing Mammalian Cells

4.2A.4 Cell Transformation Assays

4.2A.5 Xenobiotic Metabolism

4.2A.6 Summary

4.2B Mutagenicity tests in vivo

4.2B.1 Introduction

4.2B.2 Chromosomal Mutations in Somatic Cells

4.2B.3 Gene Mutations in Somatic Cells

4.2B.4 Chromosome Mutations in Germ Cells

4.2B.5 Gene Mutations in Germ Cells

4.2B.6 Summary

4.3 Assessment of the Individual Exposure to Xenobiotics (Biomonitoring)

4.3.1 Introduction

4.3.2 Prerequisites for Carrying Out Biomonitoring

4.3.3 Examples of Biomonitoring of Special Substance Groups or Special Biomonitoring Parameters

4.3.4 Summary

4.4 Epidemiology

4.4.1 Introduction

4.4.2 Measures to Describe the Risk

4.4.3 Standardization

4.4.4 Types of Epidemiological Studies

4.4.5 Statistics

4.4.6 Meta‐analysis

4.4.7 Bias, Confounding, Chance, Causality

4.4.8 Summary

4.5 Alternatives to Animal Testing

4.5.1 Introduction

4.5.2 The Birth of Doubt in Animal Experiments

4.5.3 Early Successful Alternatives

4.5.4 The Replacement of Animal Tests is Possible

4.5.5 Validation of Alternative Methods: Animal Welfare must not Trump Patient and Consumer Safety

4.5.6 How Reliable are Animal Tests?

4.5.7 The Animal Test Ban for Cosmetics in Europe as an Engine of Change

4.5.8 “Toxicological Ignorance”: the European REACH Program as a Driver for Alternative Methods

4.5.9 Outlook

4.5.10 Summary

4.6 Omics in Toxicology

4.6.1 Introduction

4.6.2 Concept of Toxicogenomics

4.6.3 Technology Platforms

4.6.4 Bioinformatics and Biostatistics

4.6.5 Applications of Toxicogenomics

4.6.6 Summary

4.7 Introduction to the Statistical Analysis of Experimental Data

4.7.1 Introduction

4.7.2 Descriptive Statistics

4.7.3 Error Propagation

4.7.4 Probability Distribution

4.7.5 Inferential Statistics

4.7.6 Regression Analysis

4.7.7 Probit Analysis

4.7.8 Experimental Designs

4.7.9 Statistical Software

4.7.10 Summary

4.8 Mathematical Models for Risk Extrapolation

4.8.1 Introduction

4.8.2 Basic Approach of Linear Extrapolation

4.8.3 Some Special Methods of Linear Extrapolation

4.8.4 Consideration of Time Aspects

4.8.5 Models of Carcinogenesis

4.8.6 Assumptions and Limits of Extrapolation in Mathematical Models

4.8.7 Summary

Chapter 5 Regulatory Toxicology

5.1 Regulations on Chemical Substances in the European Union

5.1.1 Introduction

5.1.2 Current Legislation in the EU

5.1.3 Risk Issues and Some Definitions in Terms of Chemical Substances

5.1.4 International Co‐operation and Harmonization Supported and Implemented by the EU

5.1.5 EU Legislation on Chemical Substances and Their Uses

5.1.6 Legislation on Chemical Substances in the Environment

5.1.7 Summary

5.2 Regulations Regarding Chemicals and Radionuclides in the Environment, Workplace, Consumer Products, Foods, and Pharmaceuticals in the United States

5.2.1 Introduction

5.2.2 Occupational Health Regulations

5.2.3 Food and Drug Regulations

5.2.4 Environmental Regulations

5.2.5 Consumer Product Regulations

5.2.6 Radionuclides Regulations

5.2.7 Governmental Agencies on Human Health

5.2.8 Centers for Disease Control

5.2.9 Litigation is Nearly as Effective as Regulation in the United States

5.2.10 Summary

5.3 The Concept of REACH

5.3.1 Introduction

5.3.2 Historical Development

5.3.3 Substances, Mixtures and Articles

5.3.4 The Main Elements of REACH

5.3.5 Allocation of Responsibilities and Administration of REACH

5.3.6 Downstream Users

5.3.7 Outlook

5.3.8 Summary

Chapter 6 Specific Toxicology

6.1 Persistent Halogenated Aromatic Hydrocarbons

6.1.1 Introduction

6.1.2 Polychlorinated Dibenzodioxins and Dibenzofurans

6.1.3 Polychlorinated Biphenyls

6.1.4 Dichlorodiphenyltrichloroethane

6.1.5 Hexachlorobenzene

6.1.6 Physico‐chemical Properties

6.1.7 Toxicity

6.1.8 Mechanisms of Action

6.1.9 Metabolism

6.1.10 Enzyme Induction

6.1.11 Kinetics

6.1.12 Summary

6.2 Metals

6.2.1 General Aspects

6.2.2 The Importance of Bioavailability

6.2.3 Acute and Chronic Toxicity as well as Carcinogenicity

6.2.4 Toxicology of Selected Metal Compounds

6.2.5 Summary

6.3 Toxicology of Fibers and Particles

6.3.1 Introduction

6.3.2 Particle Toxicology: Basic Concepts

6.3.3 Particle Properties

6.3.4 Nanoparticles: A Special Case?

6.3.5 Special Particle Effects

6.3.6 Summary

6.4 Principles of Nanomaterial Toxicology

6.4.1 Introduction

6.4.2 Toxicology

6.4.3 Summary

6.5 Endocrine Active Compounds

6.5.1 Introduction

6.5.2 Thyroid Hormone Affecting Compounds

6.5.3 Sex Hormones

6.5.4 Low‐dose, Non‐monotonic Dose‐effect Relation and Additive Effects

6.5.5 Summary

6.6 Assessment of Xenoestrogens and Xenoantiandrogens2

6.6.1 Introduction

6.6.2 Modes of Action and Testing

6.6.3 A Weight of Evidence Approach and Future Improvements

6.6.4 Limited Evidence for Endocrine Disruption

6.6.5 Summary

6.7 Solvents

6.7.1 Introduction

6.7.2 Toxicology of Selected Solvents

6.7.3 Hydrocarbons

6.7.4 Aliphatic Alcohols

6.7.5 Summary

6.8 Noxious Gases

6.8.1 Introduction

6.8.2 Airborne Systemic Poisons

6.8.3 Respiratory Tract Irritants

6.8.4 Irritant Gases

6.8.5 Summary

6.9 Fragrance Materials

6.9.1 Introduction

6.9.2 Evaluation of Toxicity

6.9.3 A Tiered Approach to the Risk Assessment of Fragrances

6.9.4 Summary

6.10 Pesticides

6.10.1 Introduction

6.10.2 Toxicity of Selected Pesticidal Active Substances

6.10.3 Fungicides

6.10.4 Insecticides

6.10.5 Substances of Biological Origin

6.10.6 Insect Growth Regulators

6.10.7 Other Pesticidal Active Substances

6.10.8 Regulatory Toxicology of Pesticidal Active Substances

6.10.9 Toxicological Endpoints

6.10.10 Classification and Cut‐off Criteria

6.10.11 Human Health Risk Assessment

6.10.12 Summary

6.11 Polycyclic Aromatic Hydrocarbons

6.11.1 Introduction

6.11.2 Physico‐chemical Properties

6.11.3 Occurrence in the Environment and in the Workplace

6.11.4 Toxicity

6.11.5 Mechanisms of Action

6.11.6 Evaluation by National and International Organisations

6.11.7 Toxicity Equivalency Factors for PAHs

6.11.8 Summary

6.12 Diesel Engine Emissions

6.12.1 Introduction

6.12.2 Contents of Diesel Engine Emissions

6.12.3 Toxicokinetics

6.12.4 Toxicity

6.12.5 Mechanisms of the Carcinogenic Effects of Diesel Engine Emissions

6.12.6 The Exposure of Humans to Diesel Engine Emissions

6.12.7 Evaluation by International Organizations

6.12.8 Summary

6.13 Animal and Plant Toxins

6.13.1 Introduction

6.13.2 Animal Toxins

6.13.3 Plant Toxins

6.13.4 Summary

Glossary of Important Terms in Toxicology

Index

EULA