Toxicology and Risk Assessment

Helmut Greim, MD, is a toxicologist and former chair of the Institute of Toxicology and Environmental Hygiene at the Technical University of Munich, Germany. His research experience is in drug metabolism, toxicokinetics, mechanisms of carcinogenic agents, and in vitro test systems. Robert Snyder, PhD, is Associate Dean for Research, Ernest Mario School of Pharmacy at the Environmental and Occupational Health Sciences Institute, New Jersey, USA. His research areas are in the toxicology of bone marrow, impact of chemicals on the "niche," mechanisms of benzene toxicology, and leukemogenesis.

• List of Contributors xvShort CVs of Authors xixPreface xxixDedication xxxiList of Abbreviations xxxiii1 Introduction to the Discipline of Toxicology 1Helmut Greim and Robert Snyder1.1 Introduction 11.2 The Risk Assessment Process 21.2.1 Hazard Identification 21.2.2 Dose Response and Toxic Potency 31.2.3 Exposure Assessment 41.2.4 Risk Characterization 61.3 Toxicological Evaluation of New and Existing Chemicals 61.3.1 General Requirements for Hazard Identification and Risk Assessment 71.3.2 General Approach for Hazard Identification and Risk Assessment (for details see Chapter 2.1) 121.3.3 Toxicological Issues related to Specific Chemical Classes 131.3.4 Existing Chemicals 141.3.5 Test Guidelines (Chapter 4.1) 141.3.6 Alternatives to Animal Experiments (Chapter 4.5) 151.3.7 Evaluation of Mixtures (Chapter 2.7) 151.3.8 Evaluation of Uncertainties 161.3.9 The Precautionary Principle 161.3.10 The TTC Concept 171.3.11 Classification and Labeling of Chemicals 171.4 Summary 182 Principles in Toxicology 212.1 General Concepts of Human Health Risk Assessment 21Paul T.C. Harrison, Philip Holmes, and Ruth Bevan2.1.1 Introduction 212.1.2 Principles of Risk Assessment 212.1.3 Application of Risk Assessment in Setting Exposure Standards and Limits 302.1.4 The Wider Importance of Risk Assessment 322.1.5 Summary 322.2 Toxicokinetics 34Johannes G. Filser2.2.1 Definition and Purpose 342.2.2 Absorption, Distribution, and Elimination 352.2.3 Toxicokinetic Models 472.2.4 Summary 612.3 Biotransformation of Xenobiotics 61Wolfgang Dekant2.3.1 Introduction 612.3.2 Phase I Reactions 642.3.3 Phase II Reactions 742.3.4 Factors that Influence the Biotransformation of Xenobiotics 802.3.5 Role of Bioactivation in Toxicity 872.3.6 Interactions of Reactive Intermediates formed during the Biotransformation 902.3.7 Summary 942.4 Cytotoxicity 98Daniel Dietrich2.4.1 Introduction 982.4.2 The Cell 1022.4.3 Cellular Targets of Toxins 1062.4.4 Mechanisms underlying Cell Death 1152.4.5 Summary 1202.5 Toxicogenetics 122Lesley A. Stanley2.5.1 Introduction 1222.5.2 Toxicogenetics and Toxicogenomics 1232.5.3 Genotype and Phenotype 1232.5.4 The Role of Xenobiotic-metabolising Polymorphisms in Susceptibility to Toxic Agents 1272.5.5 Study Numbers and Effect Size 1352.5.6 Summary 1392.6 Receptor-mediated Mechanisms 140Jens Schlossmann and Franz Hofmann2.6.1 Introduction 1402.6.2 Ligand–Receptor Interactions 1412.6.3 Biological Consequences of Ligand–Receptor Interactions 1422.6.4 Receptor Signal Transduction 1442.6.5 Summary 1472.7 Mixtures and Combinations of Chemicals 148Hermann Bolt2.7.1 Introduction 1482.7.2 Types of Mixed Exposures 1482.7.3 Types of Joint Actions and their Role in Safety Evaluation 1492.7.4 Role in Safety Evaluation 1512.7.5 Summary 1582.8 Chemical Carcinogenesis: Genotoxic and Non-Genotoxic Mechanisms 159Thomas Efferth and Bernd Kaina2.8.1 Introduction 1592.8.2 Mechanisms of DNA Damage, Repair, and Carcinogenesis 1602.8.3 Cancer Development 1712.8.4 Non-Genotoxic Mechanisms of Carcinogenesis 1812.8.5 Implications of Initiation and Promotion for Risk Assessment 1842.8.6 Summary 1852.9 Threshold Effects for Genotoxic Carcinogens 186Helmut Greim2.9.1 Introduction 1862.9.2 Development of Cancer due to Genotoxic Carcinogens 1872.9.3 Cellular Reaction to DNA Damage 1872.9.4 Examples of Dose-dependent Reactions in Cases of Genotoxicity 1932.9.5 Summary 1932.10 Reproductive Toxicology 195Horst Spielmann2.10.1 Introduction 1952.10.2 Characteristics of Reproductive Toxicology 1962.10.3 Adverse Effects on Female and Male Fertility 1972.10.4 International Test Methods in the Field of Reproductive Toxicology 1992.10.5 Pre- and Postnatal Toxicology 2012.10.6 Effects of Drugs and other Chemicals on Lactation 2072.10.7 Endocrine Disrupters 2082.10.8 Summary 2082.11 Ecotoxicology: More than Wildlife Toxicology 209Peter Calow and Valery E. Forbes2.11.1 Introduction 2092.11.2 Protection Targets 2102.11.3 Necessary Information 2112.11.4 Risk Assessment 2162.11.5 Fast-track Approaches 2172.11.6 Summary 2183 Organ Toxicology 2213.1 The Gastrointestinal Tract 221Michael Schwenk3.1.1 Introduction 2213.1.2 Structure and Function 2213.1.3 Fate of Xenobiotics in the GI Tract 2233.1.4 Toxicology 2263.1.5 Summary 2313.2 The Liver 231Jan G. Hengstler3.2.1 Introduction 2313.2.2 Structure and Function 2323.2.3 Toxicology 2373.2.4 Myths of the Liver 2473.2.5 Summary 2483.3 The Respiratory System 248Florian Schulz3.3.1 Introduction 2483.3.2 Structure 2493.3.3 Function 2523.3.4 Protective Systems 2543.3.5 The Respiratory Tract as a Target for Toxicity 2563.3.6 Respiratory Allergy and Asthma 2613.3.7 Lung Cancer 2623.3.8 Test Systems to Detect the Toxic Effects of Inhaled Materials 2633.3.9 Summary 2633.4 The Nervous System 264Gunter P. Eckert and Walter E. Müller3.4.1 Structure and Function of the Nervous System 2643.4.2 The Nervous System Site of Attack for Toxins 2733.4.3 Clinical Signs and Symptoms induced by Neurotoxins 2793.4.4 Summary 2813.5 Behavioral Neurotoxicology 283Andreas Seeber3.5.1 Introduction 2833.5.2 Exposure Assessment 2833.5.3 Methods 2843.5.4 Neurobehavioral Effects in Humans 2913.5.5 Summary 2953.6 The Skin 296Brunhilde Blömeke3.6.1 Structure 2963.6.2 Function 2983.6.3 Toxicology of the Skin and the Anterior Segment of the Eye 3003.6.4 Summary 3093.7 Kidney and Urinary Tract 311Helmut Greim3.7.1 Introduction 3113.7.2 Anatomy and Function 3113.7.3 Toxicology 3133.7.4 Summary 3193.8 The Hematopoietic System (Bone Marrow and Blood) 320Robert Snyder3.8.1 Introduction 3203.8.2 Hematopoiesis 3213.8.3 The Bone Marrow Niche 3233.8.4 Toxicological Features of Circulating Blood Cells 3233.8.5 Leucocytes (White Blood Cells) 3263.8.6 Platelets (Thrombocytes) 3283.8.7 Impairment of Bone Marrow Function 3283.8.8 Mechanisms by which Chemicals can Induce Leukemia 3303.8.9 Summary 3303.9 The Immune System 331Peter Griem3.9.1 Introduction: the Innate and Specific Immune System 3313.9.2 Antigen Recognition 3333.9.3 Activation of T and B lymphocytes 3343.9.4 Immunologic Tolerance 3363.9.5 Sensitization and Allergy 3373.9.6 Risk Assessment of Immunotoxic Effects 3423.9.7 Chemical-induced Autoimmunity 3453.9.8 General Immunostimulation by Chemicals 3463.9.9 Chemical Immunosuppression 3483.9.10 Summary 3503.10 The Eye 351Ines Lanzl3.10.1 Introduction 3513.10.2 Structure and Function of the Eye 3513.10.3 Routes of Delivery of Xenobiotics to the Eye 3543.10.4 Specific Toxicology of the Eye 3553.10.5 Summary 3633.11 The Cardiovascular System 364Helmut Greim3.11.1 Structure and Function 3643.11.2 Toxicology 3663.11.3 Summary 3713.12 The Endocrine System 372Gerlinde Schriever-Schwemmer3.12.1 Introduction 3723.12.2 Structure and Function 3733.12.3 Foetal Development of the Hypothalamus–Pituitary–Gonad Axis 3813.12.4 Testing of Sexual Function in Toxicology 3833.12.5 Hazard Identification and Risk Assessment of Endocrine Disruptors 3863.12.6 Summary 3864 Methods in Toxicology 3894.1 OECD Test Guidelines for Toxicity Tests in vivo 389Rüdiger Bartsch4.1.1 Introduction 3894.1.2 Requirements for in vivo Tests 3904.1.3 Acute Toxicity 3924.1.4 Skin and Eye Irritation 3944.1.5 Skin Sensitization 3974.1.6 Toxicity after Repeated Dosing 3984.1.7 Reproductive Toxicity 4014.1.8 Other Test Guidelines 4064.1.9 Other Regulatory Bodies 4074.1.10 Summary 4074.2 Genotoxicity 4084.2A In vitro Tests for Genotoxicity 408Hans-Jörg Martus4.2A.1 Introduction 4084.2A.2 Bacterial Test Systems 4094.2A.3 Test Systems employing Mammalian Cells 4114.2A.4 Cell Transformation Assays 4204.2A.5 Xenobiotic Metabolism 4204.2A.6 Summary 4214.2B Mutagenicity tests in vivo 422Ilse-Dore Adler and Gerlinde Schriever-Schwemmer4.2B.1 Introduction 4224.2B.2 Chromosomal Mutations in Somatic Cells 4244.2B.3 Gene Mutations in Somatic Cells 4274.2B.4 Chromosome Mutations in Germ Cells 4294.2B.5 Gene Mutations in Germ Cells 4334.2B.6 Summary 4354.3 Assessment of the Individual Exposure to Xenobiotics (Biomonitoring) 440Thomas Göen4.3.1 Introduction 4404.3.2 Prerequisites for Carrying Out Biomonitoring 4424.3.3 Examples of Biomonitoring of Special Substance Groups or Special Biomonitoring Parameters 4474.3.4 Summary 4494.4 Epidemiology 450Kurt Ulm4.4.1 Introduction 4504.4.2 Measures to Describe the Risk 4504.4.3 Standardization 4524.4.4 Types of Epidemiological Studies 4544.4.5 Statistics 4564.4.6 Meta-analysis 4574.4.7 Bias, Confounding, Chance, Causality 4594.4.8 Summary 4604.5 Alternatives to Animal Testing 461Thomas Hartung4.5.1 Introduction 4614.5.2 The Birth of Doubt in Animal Experiments 4614.5.3 Early Successful Alternatives 4634.5.4 The Replacement of Animal Tests is Possible 4634.5.5 Validation of Alternative Methods: Animal Welfare must not Trump Patient and Consumer Safety 4664.5.6 How Reliable are Animal Tests? 4674.5.7 The Animal Test Ban for Cosmetics in Europe as an Engine of Change 4674.5.8 “Toxicological Ignorance”: the European REACH Program as a Driver for Alternative Methods 4684.5.9 Outlook 4694.5.10 Summary 4714.6 Omics in Toxicology 472Laura Suter-Dick4.6.1 Introduction 4724.6.2 Concept of Toxicogenomics 4724.6.3 Technology Platforms 4754.6.4 Bioinformatics and Biostatistics 4804.6.5 Applications of Toxicogenomics 4814.6.6 Summary 4844.7 Introduction to the Statistical Analysis of Experimental Data 486György Csanády4.7.1 Introduction 4864.7.2 Descriptive Statistics 4884.7.3 Error Propagation 4914.7.4 Probability Distribution 4924.7.5 Inferential Statistics 4964.7.6 Regression Analysis 5044.7.7 Probit Analysis 5064.7.8 Experimental Designs 5074.7.9 Statistical Software 5084.7.10 Summary 5094.8 Mathematical Models for Risk Extrapolation 510Jürgen Timm4.8.1 Introduction 5104.8.2 Basic Approach of Linear Extrapolation 5124.8.3 Some Special Methods of Linear Extrapolation 5144.8.4 Consideration of Time Aspects 5154.8.5 Models of Carcinogenesis 5184.8.6 Assumptions and Limits of Extrapolation in Mathematical Models 5214.8.7 Summary 5235 Regulatory Toxicology 5255.1 Regulations on Chemical Substances in the European Union 525Werner Lilienblum and Klaus-Michael Wollin5.1.1 Introduction 5255.1.2 Current Legislation in the EU 5265.1.3 Risk Issues and Some Definitions in Terms of Chemical Substances 5285.1.4 International Co-operation and Harmonization Supported and Implemented by the EU 5315.1.5 EU Legislation on Chemical Substances and Their Uses 5355.1.6 Legislation on Chemical Substances in the Environment 5525.1.7 Summary 5565.2 Regulations Regarding Chemicals and Radionuclides in the Environment, Workplace, Consumer Products, Foods, and Pharmaceuticals in the United States 557Dennis J. Paustenbach5.2.1 Introduction 5575.2.2 Occupational Health Regulations 5585.2.3 Food and Drug Regulations 5615.2.4 Environmental Regulations 5635.2.5 Consumer Product Regulations 5685.2.6 Radionuclides Regulations 5695.2.7 Governmental Agencies on Human Health 5705.2.8 Centers for Disease Control 5715.2.9 Litigation is Nearly as Effective as Regulation in the United States 5715.2.10 Summary 5725.3 The Concept of REACH 573Jörg Lebsanft5.3.1 Introduction 5735.3.2 Historical Development 5745.3.3 Substances, Mixtures and Articles 5745.3.4 The Main Elements of REACH 5755.3.5 Allocation of Responsibilities and Administration of REACH 5805.3.6 Downstream Users 5825.3.7 Outlook 5835.3.8 Summary 5836 Specific Toxicology 5856.1 Persistent Halogenated Aromatic Hydrocarbons 585Heidrun Greim and Karl K. Rozman6.1.1 Introduction 5856.1.2 Polychlorinated Dibenzodioxins and Dibenzofurans 5866.1.3 Polychlorinated Biphenyls 5886.1.4 Dichlorodiphenyltrichloroethane 5896.1.5 Hexachlorobenzene 5906.1.6 Physico-chemical Properties 5916.1.7 Toxicity 5926.1.8 Mechanisms of Action 6006.1.9 Metabolism 6036.1.10 Enzyme Induction 6036.1.11 Kinetics 6046.1.12 Summary 6066.2 Metals 607Andrea Hartwig and Gunnar Jahnke6.2.1 General Aspects 6076.2.2 The Importance of Bioavailability 6086.2.3 Acute and Chronic Toxicity as well as Carcinogenicity 6096.2.4 Toxicology of Selected Metal Compounds 6116.2.5 Summary 6246.3 Toxicology of Fibers and Particles 625Paul J.A. Borm6.3.1 Introduction 6256.3.2 Particle Toxicology: Basic Concepts 6266.3.3 Particle Properties 6336.3.4 Nanoparticles: A Special Case? 6366.3.5 Special Particle Effects 6376.3.6 Summary 6406.4 Principles of Nanomaterial Toxicology 641Thomas Gebel6.4.1 Introduction 6416.4.2 Toxicology 6436.4.3 Summary 6486.5 Endocrine Active Compounds 649Volker Strauss and Bennard van Ravenzwaay6.5.1 Introduction 6496.5.2 Thyroid Hormone Affecting Compounds 6516.5.3 Sex Hormones 6546.5.4 Low-dose, Non-monotonic Dose-effect Relation and Additive Effects 6596.5.5 Summary 6596.6 Assessment of Xenoestrogens and Xenoantiandrogens 661Helmut Greim6.6.1 Introduction 6616.6.2 Modes of Action and Testing 6626.6.3 A Weight of Evidence Approach and Future Improvements 6666.6.4 Limited Evidence for Endocrine Disruption 6676.6.5 Summary 6676.7 Solvents 671Wolfgang Dekant6.7.1 Introduction 6716.7.2 Toxicology of Selected Solvents 6726.7.3 Hydrocarbons 6776.7.4 Aliphatic Alcohols 6806.7.5 Summary 6856.8 Noxious Gases 686Kai Kehe and Horst Thiermann6.8.1 Introduction 6866.8.2 Airborne Systemic Poisons 6866.8.3 Respiratory Tract Irritants 6926.8.4 Irritant Gases 6946.8.5 Summary 6986.9 Fragrance Materials 699Anne Marie Api6.9.1 Introduction 6996.9.2 Evaluation of Toxicity 6996.9.3 A Tiered Approach to the Risk Assessment of Fragrances 7006.9.4 Summary 7026.10 Pesticides 703Roland Alfred Solecki and Vera Ritz6.10.1 Introduction 7036.10.2 Toxicity of Selected Pesticidal Active Substances 7066.10.3 Fungicides 7096.10.4 Insecticides 7116.10.5 Substances of Biological Origin 7136.10.6 Insect Growth Regulators 7146.10.7 Other Pesticidal Active Substances 7156.10.8 Regulatory Toxicology of Pesticidal Active Substances 7166.10.9 Toxicological Endpoints 7176.10.10 Classification and Cut-off Criteria 7186.10.11 Human Health Risk Assessment 7186.10.12 Summary 7206.11 Polycyclic Aromatic Hydrocarbons 722Heidrun Greim and Hermann Bolt6.11.1 Introduction 7226.11.2 Physico-chemical Properties 7226.11.3 Occurrence in the Environment and in the Workplace 7236.11.4 Toxicity 7246.11.5 Mechanisms of Action 7296.11.6 Evaluation by National and International Organisations 7306.11.7 Toxicity Equivalency Factors for PAHs 7316.11.8 Summary 7326.12 Diesel Engine Emissions 733Heidrun Greim6.12.1 Introduction 7336.12.2 Contents of Diesel Engine Emissions 7346.12.3 Toxicokinetics 7356.12.4 Toxicity 7366.12.5 Mechanisms of the Carcinogenic Effects of Diesel Engine Emissions 7386.12.6 The Exposure of Humans to Diesel Engine Emissions 7406.12.7 Evaluation by International Organizations 7406.12.8 Summary 7416.13 Animal and Plant Toxins 742Thomas Zielker6.13.1 Introduction 7426.13.2 Animal Toxins 7426.13.3 Plant Toxins 7516.13.4 Summary 759Glossary of Important Terms in Toxicology 761Index 769