Toxicology and Risk Assessment
A Comprehensive Introduction
Herausgeber: Greim, Helmut; Snyder, Robert
Toxicology and Risk Assessment
A Comprehensive Introduction
Herausgeber: Greim, Helmut; Snyder, Robert
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Provides a complete understanding of how our bodies respond to toxicants, and the principles used to assess the health risks of specific exposure scenarios Toxicology and Risk Assessment: A Comprehensive Introduction, Second Edition reflects recent advances in science and technology, and provides the scientific background and methodological issues to enable the reader to understand the basic principles in toxicology and to evaluate the health risks of specific exposure scenarios. Completely updated with the latest information, this book offers a concise introduction to the subject. It is…mehr
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Provides a complete understanding of how our bodies respond to toxicants, and the principles used to assess the health risks of specific exposure scenarios Toxicology and Risk Assessment: A Comprehensive Introduction, Second Edition reflects recent advances in science and technology, and provides the scientific background and methodological issues to enable the reader to understand the basic principles in toxicology and to evaluate the health risks of specific exposure scenarios. Completely updated with the latest information, this book offers a concise introduction to the subject. It is divided into five sections: Principles in Toxicology, Organ Toxicology, Methods in Toxicology, Regulatory Toxicology, and Specific Toxicity. The 2nd Edition adds new chapters that cover recent scientific and technological advances and current topics including the endocrine system, alternatives to animal testing, risk assessment and thresholds for carcinogens, European and international regulation, nanomaterials, fuels, fragrances, and agrochemicals. * Concentrates on the basic concepts of toxicology and provides sufficient information for the reader to become familiar with them in order to understand the principles and to evaluate the risks at given exposures * 30% new chapters cover recent scientific and technological advances including alternatives to animal testing; genotoxic carcinogens; REACH regulations; nanomaterials; fuels; fragrances; PAHs; and agrochemicals * Written by a team of international specialists, and edited by two outstanding scientists in the field Fully updated and expanded, Toxicology and Risk Assessment: A Comprehensive Introduction, Second Edition is an essential text for any student or researcher with an interest in toxicology and related risk assessments.
Produktdetails
- Produktdetails
- Verlag: Wiley
- 2nd edition
- Seitenzahl: 840
- Erscheinungstermin: 5. November 2018
- Englisch
- Abmessung: 257mm x 183mm x 38mm
- Gewicht: 1701g
- ISBN-13: 9781119135913
- ISBN-10: 1119135915
- Artikelnr.: 53690589
- Verlag: Wiley
- 2nd edition
- Seitenzahl: 840
- Erscheinungstermin: 5. November 2018
- Englisch
- Abmessung: 257mm x 183mm x 38mm
- Gewicht: 1701g
- ISBN-13: 9781119135913
- ISBN-10: 1119135915
- Artikelnr.: 53690589
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 xv Short CVs of Authors xix Preface xxix Dedication
xxxi List of Abbreviations xxxiii 1 Introduction to the Discipline of
Toxicology 1 Helmut Greim and Robert Snyder 1.1 Introduction 1 1.2 The Risk
Assessment Process 2 1.2.1 Hazard Identification 2 1.2.2 Dose Response and
Toxic Potency 3 1.2.3 Exposure Assessment 4 1.2.4 Risk Characterization 6
1.3 Toxicological Evaluation of New and Existing Chemicals 6 1.3.1 General
Requirements for Hazard Identification and Risk Assessment 7 1.3.2 General
Approach for Hazard Identification and Risk Assessment (for details see
Chapter 2.1) 12 1.3.3 Toxicological Issues related to Specific Chemical
Classes 13 1.3.4 Existing Chemicals 14 1.3.5 Test Guidelines (Chapter 4.1)
14 1.3.6 Alternatives to Animal Experiments (Chapter 4.5) 15 1.3.7
Evaluation of Mixtures (Chapter 2.7) 15 1.3.8 Evaluation of Uncertainties
16 1.3.9 The Precautionary Principle 16 1.3.10 The TTC Concept 17 1.3.11
Classification and Labeling of Chemicals 17 1.4 Summary 18 2 Principles in
Toxicology 21 2.1 General Concepts of Human Health Risk Assessment 21 Paul
T.C. Harrison, Philip Holmes, and Ruth Bevan 2.1.1 Introduction 21 2.1.2
Principles of Risk Assessment 21 2.1.3 Application of Risk Assessment in
Setting Exposure Standards and Limits 30 2.1.4 The Wider Importance of Risk
Assessment 32 2.1.5 Summary 32 2.2 Toxicokinetics 34 Johannes G. Filser
2.2.1 Definition and Purpose 34 2.2.2 Absorption, Distribution, and
Elimination 35 2.2.3 Toxicokinetic Models 47 2.2.4 Summary 61 2.3
Biotransformation of Xenobiotics 61 Wolfgang Dekant 2.3.1 Introduction 61
2.3.2 Phase I Reactions 64 2.3.3 Phase II Reactions 74 2.3.4 Factors that
Influence the Biotransformation of Xenobiotics 80 2.3.5 Role of
Bioactivation in Toxicity 87 2.3.6 Interactions of Reactive Intermediates
formed during the Biotransformation 90 2.3.7 Summary 94 2.4 Cytotoxicity 98
Daniel Dietrich 2.4.1 Introduction 98 2.4.2 The Cell 102 2.4.3 Cellular
Targets of Toxins 106 2.4.4 Mechanisms underlying Cell Death 115 2.4.5
Summary 120 2.5 Toxicogenetics 122 Lesley A. Stanley 2.5.1 Introduction 122
2.5.2 Toxicogenetics and Toxicogenomics 123 2.5.3 Genotype and Phenotype
123 2.5.4 The Role of Xenobiotic-metabolising Polymorphisms in
Susceptibility to Toxic Agents 127 2.5.5 Study Numbers and Effect Size 135
2.5.6 Summary 139 2.6 Receptor-mediated Mechanisms 140 Jens Schlossmann and
Franz Hofmann 2.6.1 Introduction 140 2.6.2 Ligand-Receptor Interactions 141
2.6.3 Biological Consequences of Ligand-Receptor Interactions 142 2.6.4
Receptor Signal Transduction 144 2.6.5 Summary 147 2.7 Mixtures and
Combinations of Chemicals 148 Hermann Bolt 2.7.1 Introduction 148 2.7.2
Types of Mixed Exposures 148 2.7.3 Types of Joint Actions and their Role in
Safety Evaluation 149 2.7.4 Role in Safety Evaluation 151 2.7.5 Summary 158
2.8 Chemical Carcinogenesis: Genotoxic and Non-Genotoxic Mechanisms 159
Thomas Efferth and Bernd Kaina 2.8.1 Introduction 159 2.8.2 Mechanisms of
DNA Damage, Repair, and Carcinogenesis 160 2.8.3 Cancer Development 171
2.8.4 Non-Genotoxic Mechanisms of Carcinogenesis 181 2.8.5 Implications of
Initiation and Promotion for Risk Assessment 184 2.8.6 Summary 185 2.9
Threshold Effects for Genotoxic Carcinogens 186 Helmut Greim 2.9.1
Introduction 186 2.9.2 Development of Cancer due to Genotoxic Carcinogens
187 2.9.3 Cellular Reaction to DNA Damage 187 2.9.4 Examples of
Dose-dependent Reactions in Cases of Genotoxicity 193 2.9.5 Summary 193
2.10 Reproductive Toxicology 195 Horst Spielmann 2.10.1 Introduction 195
2.10.2 Characteristics of Reproductive Toxicology 196 2.10.3 Adverse
Effects on Female and Male Fertility 197 2.10.4 International Test Methods
in the Field of Reproductive Toxicology 199 2.10.5 Pre- and Postnatal
Toxicology 201 2.10.6 Effects of Drugs and other Chemicals on Lactation 207
2.10.7 Endocrine Disrupters 208 2.10.8 Summary 208 2.11 Ecotoxicology: More
than Wildlife Toxicology 209 Peter Calow and Valery E. Forbes 2.11.1
Introduction 209 2.11.2 Protection Targets 210 2.11.3 Necessary Information
211 2.11.4 Risk Assessment 216 2.11.5 Fast-track Approaches 217 2.11.6
Summary 218 3 Organ Toxicology 221 3.1 The Gastrointestinal Tract 221
Michael Schwenk 3.1.1 Introduction 221 3.1.2 Structure and Function 221
3.1.3 Fate of Xenobiotics in the GI Tract 223 3.1.4 Toxicology 226 3.1.5
Summary 231 3.2 The Liver 231 Jan G. Hengstler 3.2.1 Introduction 231 3.2.2
Structure and Function 232 3.2.3 Toxicology 237 3.2.4 Myths of the Liver
247 3.2.5 Summary 248 3.3 The Respiratory System 248 Florian Schulz 3.3.1
Introduction 248 3.3.2 Structure 249 3.3.3 Function 252 3.3.4 Protective
Systems 254 3.3.5 The Respiratory Tract as a Target for Toxicity 256 3.3.6
Respiratory Allergy and Asthma 261 3.3.7 Lung Cancer 262 3.3.8 Test Systems
to Detect the Toxic Effects of Inhaled Materials 263 3.3.9 Summary 263 3.4
The Nervous System 264 Gunter P. Eckert and Walter E. Müller 3.4.1
Structure and Function of the Nervous System 264 3.4.2 The Nervous System
Site of Attack for Toxins 273 3.4.3 Clinical Signs and Symptoms induced by
Neurotoxins 279 3.4.4 Summary 281 3.5 Behavioral Neurotoxicology 283
Andreas Seeber 3.5.1 Introduction 283 3.5.2 Exposure Assessment 283 3.5.3
Methods 284 3.5.4 Neurobehavioral Effects in Humans 291 3.5.5 Summary 295
3.6 The Skin 296 Brunhilde Blömeke 3.6.1 Structure 296 3.6.2 Function 298
3.6.3 Toxicology of the Skin and the Anterior Segment of the Eye 300 3.6.4
Summary 309 3.7 Kidney and Urinary Tract 311 Helmut Greim 3.7.1
Introduction 311 3.7.2 Anatomy and Function 311 3.7.3 Toxicology 313 3.7.4
Summary 319 3.8 The Hematopoietic System (Bone Marrow and Blood) 320 Robert
Snyder 3.8.1 Introduction 320 3.8.2 Hematopoiesis 321 3.8.3 The Bone Marrow
Niche 323 3.8.4 Toxicological Features of Circulating Blood Cells 323 3.8.5
Leucocytes (White Blood Cells) 326 3.8.6 Platelets (Thrombocytes) 328 3.8.7
Impairment of Bone Marrow Function 328 3.8.8 Mechanisms by which Chemicals
can Induce Leukemia 330 3.8.9 Summary 330 3.9 The Immune System 331 Peter
Griem 3.9.1 Introduction: the Innate and Specific Immune System 331 3.9.2
Antigen Recognition 333 3.9.3 Activation of T and B lymphocytes 334 3.9.4
Immunologic Tolerance 336 3.9.5 Sensitization and Allergy 337 3.9.6 Risk
Assessment of Immunotoxic Effects 342 3.9.7 Chemical-induced Autoimmunity
345 3.9.8 General Immunostimulation by Chemicals 346 3.9.9 Chemical
Immunosuppression 348 3.9.10 Summary 350 3.10 The Eye 351 Ines Lanzl 3.10.1
Introduction 351 3.10.2 Structure and Function of the Eye 351 3.10.3 Routes
of Delivery of Xenobiotics to the Eye 354 3.10.4 Specific Toxicology of the
Eye 355 3.10.5 Summary 363 3.11 The Cardiovascular System 364 Helmut Greim
3.11.1 Structure and Function 364 3.11.2 Toxicology 366 3.11.3 Summary 371
3.12 The Endocrine System 372 Gerlinde Schriever-Schwemmer 3.12.1
Introduction 372 3.12.2 Structure and Function 373 3.12.3 Foetal
Development of the Hypothalamus-Pituitary-Gonad Axis 381 3.12.4 Testing of
Sexual Function in Toxicology 383 3.12.5 Hazard Identification and Risk
Assessment of Endocrine Disruptors 386 3.12.6 Summary 386 4 Methods in
Toxicology 389 4.1 OECD Test Guidelines for Toxicity Tests in vivo 389
Rüdiger Bartsch 4.1.1 Introduction 389 4.1.2 Requirements for in vivo Tests
390 4.1.3 Acute Toxicity 392 4.1.4 Skin and Eye Irritation 394 4.1.5 Skin
Sensitization 397 4.1.6 Toxicity after Repeated Dosing 398 4.1.7
Reproductive Toxicity 401 4.1.8 Other Test Guidelines 406 4.1.9 Other
Regulatory Bodies 407 4.1.10 Summary 407 4.2 Genotoxicity 408 4.2A In vitro
Tests for Genotoxicity 408 Hans-Jörg Martus 4.2A.1 Introduction 408 4.2A.2
Bacterial Test Systems 409 4.2A.3 Test Systems employing Mammalian Cells
411 4.2A.4 Cell Transformation Assays 420 4.2A.5 Xenobiotic Metabolism 420
4.2A.6 Summary 421 4.2B Mutagenicity tests in vivo 422 Ilse-Dore Adler and
Gerlinde Schriever-Schwemmer 4.2B.1 Introduction 422 4.2B.2 Chromosomal
Mutations in Somatic Cells 424 4.2B.3 Gene Mutations in Somatic Cells 427
4.2B.4 Chromosome Mutations in Germ Cells 429 4.2B.5 Gene Mutations in Germ
Cells 433 4.2B.6 Summary 435 4.3 Assessment of the Individual Exposure to
Xenobiotics (Biomonitoring) 440 Thomas Göen 4.3.1 Introduction 440 4.3.2
Prerequisites for Carrying Out Biomonitoring 442 4.3.3 Examples of
Biomonitoring of Special Substance Groups or Special Biomonitoring
Parameters 447 4.3.4 Summary 449 4.4 Epidemiology 450 Kurt Ulm 4.4.1
Introduction 450 4.4.2 Measures to Describe the Risk 450 4.4.3
Standardization 452 4.4.4 Types of Epidemiological Studies 454 4.4.5
Statistics 456 4.4.6 Meta-analysis 457 4.4.7 Bias, Confounding, Chance,
Causality 459 4.4.8 Summary 460 4.5 Alternatives to Animal Testing 461
Thomas Hartung 4.5.1 Introduction 461 4.5.2 The Birth of Doubt in Animal
Experiments 461 4.5.3 Early Successful Alternatives 463 4.5.4 The
Replacement of Animal Tests is Possible 463 4.5.5 Validation of Alternative
Methods: Animal Welfare must not Trump Patient and Consumer Safety 466
4.5.6 How Reliable are Animal Tests? 467 4.5.7 The Animal Test Ban for
Cosmetics in Europe as an Engine of Change 467 4.5.8 "Toxicological
Ignorance": the European REACH Program as a Driver for Alternative Methods
468 4.5.9 Outlook 469 4.5.10 Summary 471 4.6 Omics in Toxicology 472 Laura
Suter-Dick 4.6.1 Introduction 472 4.6.2 Concept of Toxicogenomics 472 4.6.3
Technology Platforms 475 4.6.4 Bioinformatics and Biostatistics 480 4.6.5
Applications of Toxicogenomics 481 4.6.6 Summary 484 4.7 Introduction to
the Statistical Analysis of Experimental Data 486 György Csanády 4.7.1
Introduction 486 4.7.2 Descriptive Statistics 488 4.7.3 Error Propagation
491 4.7.4 Probability Distribution 492 4.7.5 Inferential Statistics 496
4.7.6 Regression Analysis 504 4.7.7 Probit Analysis 506 4.7.8 Experimental
Designs 507 4.7.9 Statistical Software 508 4.7.10 Summary 509 4.8
Mathematical Models for Risk Extrapolation 510 Jürgen Timm 4.8.1
Introduction 510 4.8.2 Basic Approach of Linear Extrapolation 512 4.8.3
Some Special Methods of Linear Extrapolation 514 4.8.4 Consideration of
Time Aspects 515 4.8.5 Models of Carcinogenesis 518 4.8.6 Assumptions and
Limits of Extrapolation in Mathematical Models 521 4.8.7 Summary 523 5
Regulatory Toxicology 525 5.1 Regulations on Chemical Substances in the
European Union 525 Werner Lilienblum and Klaus-Michael Wollin 5.1.1
Introduction 525 5.1.2 Current Legislation in the EU 526 5.1.3 Risk Issues
and Some Definitions in Terms of Chemical Substances 528 5.1.4
International Co-operation and Harmonization Supported and Implemented by
the EU 531 5.1.5 EU Legislation on Chemical Substances and Their Uses 535
5.1.6 Legislation on Chemical Substances in the Environment 552 5.1.7
Summary 556 5.2 Regulations Regarding Chemicals and Radionuclides in the
Environment, Workplace, Consumer Products, Foods, and Pharmaceuticals in
the United States 557 Dennis J. Paustenbach 5.2.1 Introduction 557 5.2.2
Occupational Health Regulations 558 5.2.3 Food and Drug Regulations 561
5.2.4 Environmental Regulations 563 5.2.5 Consumer Product Regulations 568
5.2.6 Radionuclides Regulations 569 5.2.7 Governmental Agencies on Human
Health 570 5.2.8 Centers for Disease Control 571 5.2.9 Litigation is Nearly
as Effective as Regulation in the United States 571 5.2.10 Summary 572 5.3
The Concept of REACH 573 Jörg Lebsanft 5.3.1 Introduction 573 5.3.2
Historical Development 574 5.3.3 Substances, Mixtures and Articles 574
5.3.4 The Main Elements of REACH 575 5.3.5 Allocation of Responsibilities
and Administration of REACH 580 5.3.6 Downstream Users 582 5.3.7 Outlook
583 5.3.8 Summary 583 6 Specific Toxicology 585 6.1 Persistent Halogenated
Aromatic Hydrocarbons 585 Heidrun Greim and Karl K. Rozman 6.1.1
Introduction 585 6.1.2 Polychlorinated Dibenzodioxins and Dibenzofurans 586
6.1.3 Polychlorinated Biphenyls 588 6.1.4 Dichlorodiphenyltrichloroethane
589 6.1.5 Hexachlorobenzene 590 6.1.6 Physico-chemical Properties 591 6.1.7
Toxicity 592 6.1.8 Mechanisms of Action 600 6.1.9 Metabolism 603 6.1.10
Enzyme Induction 603 6.1.11 Kinetics 604 6.1.12 Summary 606 6.2 Metals 607
Andrea Hartwig and Gunnar Jahnke 6.2.1 General Aspects 607 6.2.2 The
Importance of Bioavailability 608 6.2.3 Acute and Chronic Toxicity as well
as Carcinogenicity 609 6.2.4 Toxicology of Selected Metal Compounds 611
6.2.5 Summary 624 6.3 Toxicology of Fibers and Particles 625 Paul J.A. Borm
6.3.1 Introduction 625 6.3.2 Particle Toxicology: Basic Concepts 626 6.3.3
Particle Properties 633 6.3.4 Nanoparticles: A Special Case? 636 6.3.5
Special Particle Effects 637 6.3.6 Summary 640 6.4 Principles of
Nanomaterial Toxicology 641 Thomas Gebel 6.4.1 Introduction 641 6.4.2
Toxicology 643 6.4.3 Summary 648 6.5 Endocrine Active Compounds 649 Volker
Strauss and Bennard van Ravenzwaay 6.5.1 Introduction 649 6.5.2 Thyroid
Hormone Affecting Compounds 651 6.5.3 Sex Hormones 654 6.5.4 Low-dose,
Non-monotonic Dose-effect Relation and Additive Effects 659 6.5.5 Summary
659 6.6 Assessment of Xenoestrogens and Xenoantiandrogens 661 Helmut Greim
6.6.1 Introduction 661 6.6.2 Modes of Action and Testing 662 6.6.3 A Weight
of Evidence Approach and Future Improvements 666 6.6.4 Limited Evidence for
Endocrine Disruption 667 6.6.5 Summary 667 6.7 Solvents 671 Wolfgang Dekant
6.7.1 Introduction 671 6.7.2 Toxicology of Selected Solvents 672 6.7.3
Hydrocarbons 677 6.7.4 Aliphatic Alcohols 680 6.7.5 Summary 685 6.8 Noxious
Gases 686 Kai Kehe and Horst Thiermann 6.8.1 Introduction 686 6.8.2
Airborne Systemic Poisons 686 6.8.3 Respiratory Tract Irritants 692 6.8.4
Irritant Gases 694 6.8.5 Summary 698 6.9 Fragrance Materials 699 Anne Marie
Api 6.9.1 Introduction 699 6.9.2 Evaluation of Toxicity 699 6.9.3 A Tiered
Approach to the Risk Assessment of Fragrances 700 6.9.4 Summary 702 6.10
Pesticides 703 Roland Alfred Solecki and Vera Ritz 6.10.1 Introduction 703
6.10.2 Toxicity of Selected Pesticidal Active Substances 706 6.10.3
Fungicides 709 6.10.4 Insecticides 711 6.10.5 Substances of Biological
Origin 713 6.10.6 Insect Growth Regulators 714 6.10.7 Other Pesticidal
Active Substances 715 6.10.8 Regulatory Toxicology of Pesticidal Active
Substances 716 6.10.9 Toxicological Endpoints 717 6.10.10 Classification
and Cut-off Criteria 718 6.10.11 Human Health Risk Assessment 718 6.10.12
Summary 720 6.11 Polycyclic Aromatic Hydrocarbons 722 Heidrun Greim and
Hermann Bolt 6.11.1 Introduction 722 6.11.2 Physico-chemical Properties 722
6.11.3 Occurrence in the Environment and in the Workplace 723 6.11.4
Toxicity 724 6.11.5 Mechanisms of Action 729 6.11.6 Evaluation by National
and International Organisations 730 6.11.7 Toxicity Equivalency Factors for
PAHs 731 6.11.8 Summary 732 6.12 Diesel Engine Emissions 733 Heidrun Greim
6.12.1 Introduction 733 6.12.2 Contents of Diesel Engine Emissions 734
6.12.3 Toxicokinetics 735 6.12.4 Toxicity 736 6.12.5 Mechanisms of the
Carcinogenic Effects of Diesel Engine Emissions 738 6.12.6 The Exposure of
Humans to Diesel Engine Emissions 740 6.12.7 Evaluation by International
Organizations 740 6.12.8 Summary 741 6.13 Animal and Plant Toxins 742
Thomas Zielker 6.13.1 Introduction 742 6.13.2 Animal Toxins 742 6.13.3
Plant Toxins 751 6.13.4 Summary 759 Glossary of Important Terms in
Toxicology 761 Index 769
xxxi List of Abbreviations xxxiii 1 Introduction to the Discipline of
Toxicology 1 Helmut Greim and Robert Snyder 1.1 Introduction 1 1.2 The Risk
Assessment Process 2 1.2.1 Hazard Identification 2 1.2.2 Dose Response and
Toxic Potency 3 1.2.3 Exposure Assessment 4 1.2.4 Risk Characterization 6
1.3 Toxicological Evaluation of New and Existing Chemicals 6 1.3.1 General
Requirements for Hazard Identification and Risk Assessment 7 1.3.2 General
Approach for Hazard Identification and Risk Assessment (for details see
Chapter 2.1) 12 1.3.3 Toxicological Issues related to Specific Chemical
Classes 13 1.3.4 Existing Chemicals 14 1.3.5 Test Guidelines (Chapter 4.1)
14 1.3.6 Alternatives to Animal Experiments (Chapter 4.5) 15 1.3.7
Evaluation of Mixtures (Chapter 2.7) 15 1.3.8 Evaluation of Uncertainties
16 1.3.9 The Precautionary Principle 16 1.3.10 The TTC Concept 17 1.3.11
Classification and Labeling of Chemicals 17 1.4 Summary 18 2 Principles in
Toxicology 21 2.1 General Concepts of Human Health Risk Assessment 21 Paul
T.C. Harrison, Philip Holmes, and Ruth Bevan 2.1.1 Introduction 21 2.1.2
Principles of Risk Assessment 21 2.1.3 Application of Risk Assessment in
Setting Exposure Standards and Limits 30 2.1.4 The Wider Importance of Risk
Assessment 32 2.1.5 Summary 32 2.2 Toxicokinetics 34 Johannes G. Filser
2.2.1 Definition and Purpose 34 2.2.2 Absorption, Distribution, and
Elimination 35 2.2.3 Toxicokinetic Models 47 2.2.4 Summary 61 2.3
Biotransformation of Xenobiotics 61 Wolfgang Dekant 2.3.1 Introduction 61
2.3.2 Phase I Reactions 64 2.3.3 Phase II Reactions 74 2.3.4 Factors that
Influence the Biotransformation of Xenobiotics 80 2.3.5 Role of
Bioactivation in Toxicity 87 2.3.6 Interactions of Reactive Intermediates
formed during the Biotransformation 90 2.3.7 Summary 94 2.4 Cytotoxicity 98
Daniel Dietrich 2.4.1 Introduction 98 2.4.2 The Cell 102 2.4.3 Cellular
Targets of Toxins 106 2.4.4 Mechanisms underlying Cell Death 115 2.4.5
Summary 120 2.5 Toxicogenetics 122 Lesley A. Stanley 2.5.1 Introduction 122
2.5.2 Toxicogenetics and Toxicogenomics 123 2.5.3 Genotype and Phenotype
123 2.5.4 The Role of Xenobiotic-metabolising Polymorphisms in
Susceptibility to Toxic Agents 127 2.5.5 Study Numbers and Effect Size 135
2.5.6 Summary 139 2.6 Receptor-mediated Mechanisms 140 Jens Schlossmann and
Franz Hofmann 2.6.1 Introduction 140 2.6.2 Ligand-Receptor Interactions 141
2.6.3 Biological Consequences of Ligand-Receptor Interactions 142 2.6.4
Receptor Signal Transduction 144 2.6.5 Summary 147 2.7 Mixtures and
Combinations of Chemicals 148 Hermann Bolt 2.7.1 Introduction 148 2.7.2
Types of Mixed Exposures 148 2.7.3 Types of Joint Actions and their Role in
Safety Evaluation 149 2.7.4 Role in Safety Evaluation 151 2.7.5 Summary 158
2.8 Chemical Carcinogenesis: Genotoxic and Non-Genotoxic Mechanisms 159
Thomas Efferth and Bernd Kaina 2.8.1 Introduction 159 2.8.2 Mechanisms of
DNA Damage, Repair, and Carcinogenesis 160 2.8.3 Cancer Development 171
2.8.4 Non-Genotoxic Mechanisms of Carcinogenesis 181 2.8.5 Implications of
Initiation and Promotion for Risk Assessment 184 2.8.6 Summary 185 2.9
Threshold Effects for Genotoxic Carcinogens 186 Helmut Greim 2.9.1
Introduction 186 2.9.2 Development of Cancer due to Genotoxic Carcinogens
187 2.9.3 Cellular Reaction to DNA Damage 187 2.9.4 Examples of
Dose-dependent Reactions in Cases of Genotoxicity 193 2.9.5 Summary 193
2.10 Reproductive Toxicology 195 Horst Spielmann 2.10.1 Introduction 195
2.10.2 Characteristics of Reproductive Toxicology 196 2.10.3 Adverse
Effects on Female and Male Fertility 197 2.10.4 International Test Methods
in the Field of Reproductive Toxicology 199 2.10.5 Pre- and Postnatal
Toxicology 201 2.10.6 Effects of Drugs and other Chemicals on Lactation 207
2.10.7 Endocrine Disrupters 208 2.10.8 Summary 208 2.11 Ecotoxicology: More
than Wildlife Toxicology 209 Peter Calow and Valery E. Forbes 2.11.1
Introduction 209 2.11.2 Protection Targets 210 2.11.3 Necessary Information
211 2.11.4 Risk Assessment 216 2.11.5 Fast-track Approaches 217 2.11.6
Summary 218 3 Organ Toxicology 221 3.1 The Gastrointestinal Tract 221
Michael Schwenk 3.1.1 Introduction 221 3.1.2 Structure and Function 221
3.1.3 Fate of Xenobiotics in the GI Tract 223 3.1.4 Toxicology 226 3.1.5
Summary 231 3.2 The Liver 231 Jan G. Hengstler 3.2.1 Introduction 231 3.2.2
Structure and Function 232 3.2.3 Toxicology 237 3.2.4 Myths of the Liver
247 3.2.5 Summary 248 3.3 The Respiratory System 248 Florian Schulz 3.3.1
Introduction 248 3.3.2 Structure 249 3.3.3 Function 252 3.3.4 Protective
Systems 254 3.3.5 The Respiratory Tract as a Target for Toxicity 256 3.3.6
Respiratory Allergy and Asthma 261 3.3.7 Lung Cancer 262 3.3.8 Test Systems
to Detect the Toxic Effects of Inhaled Materials 263 3.3.9 Summary 263 3.4
The Nervous System 264 Gunter P. Eckert and Walter E. Müller 3.4.1
Structure and Function of the Nervous System 264 3.4.2 The Nervous System
Site of Attack for Toxins 273 3.4.3 Clinical Signs and Symptoms induced by
Neurotoxins 279 3.4.4 Summary 281 3.5 Behavioral Neurotoxicology 283
Andreas Seeber 3.5.1 Introduction 283 3.5.2 Exposure Assessment 283 3.5.3
Methods 284 3.5.4 Neurobehavioral Effects in Humans 291 3.5.5 Summary 295
3.6 The Skin 296 Brunhilde Blömeke 3.6.1 Structure 296 3.6.2 Function 298
3.6.3 Toxicology of the Skin and the Anterior Segment of the Eye 300 3.6.4
Summary 309 3.7 Kidney and Urinary Tract 311 Helmut Greim 3.7.1
Introduction 311 3.7.2 Anatomy and Function 311 3.7.3 Toxicology 313 3.7.4
Summary 319 3.8 The Hematopoietic System (Bone Marrow and Blood) 320 Robert
Snyder 3.8.1 Introduction 320 3.8.2 Hematopoiesis 321 3.8.3 The Bone Marrow
Niche 323 3.8.4 Toxicological Features of Circulating Blood Cells 323 3.8.5
Leucocytes (White Blood Cells) 326 3.8.6 Platelets (Thrombocytes) 328 3.8.7
Impairment of Bone Marrow Function 328 3.8.8 Mechanisms by which Chemicals
can Induce Leukemia 330 3.8.9 Summary 330 3.9 The Immune System 331 Peter
Griem 3.9.1 Introduction: the Innate and Specific Immune System 331 3.9.2
Antigen Recognition 333 3.9.3 Activation of T and B lymphocytes 334 3.9.4
Immunologic Tolerance 336 3.9.5 Sensitization and Allergy 337 3.9.6 Risk
Assessment of Immunotoxic Effects 342 3.9.7 Chemical-induced Autoimmunity
345 3.9.8 General Immunostimulation by Chemicals 346 3.9.9 Chemical
Immunosuppression 348 3.9.10 Summary 350 3.10 The Eye 351 Ines Lanzl 3.10.1
Introduction 351 3.10.2 Structure and Function of the Eye 351 3.10.3 Routes
of Delivery of Xenobiotics to the Eye 354 3.10.4 Specific Toxicology of the
Eye 355 3.10.5 Summary 363 3.11 The Cardiovascular System 364 Helmut Greim
3.11.1 Structure and Function 364 3.11.2 Toxicology 366 3.11.3 Summary 371
3.12 The Endocrine System 372 Gerlinde Schriever-Schwemmer 3.12.1
Introduction 372 3.12.2 Structure and Function 373 3.12.3 Foetal
Development of the Hypothalamus-Pituitary-Gonad Axis 381 3.12.4 Testing of
Sexual Function in Toxicology 383 3.12.5 Hazard Identification and Risk
Assessment of Endocrine Disruptors 386 3.12.6 Summary 386 4 Methods in
Toxicology 389 4.1 OECD Test Guidelines for Toxicity Tests in vivo 389
Rüdiger Bartsch 4.1.1 Introduction 389 4.1.2 Requirements for in vivo Tests
390 4.1.3 Acute Toxicity 392 4.1.4 Skin and Eye Irritation 394 4.1.5 Skin
Sensitization 397 4.1.6 Toxicity after Repeated Dosing 398 4.1.7
Reproductive Toxicity 401 4.1.8 Other Test Guidelines 406 4.1.9 Other
Regulatory Bodies 407 4.1.10 Summary 407 4.2 Genotoxicity 408 4.2A In vitro
Tests for Genotoxicity 408 Hans-Jörg Martus 4.2A.1 Introduction 408 4.2A.2
Bacterial Test Systems 409 4.2A.3 Test Systems employing Mammalian Cells
411 4.2A.4 Cell Transformation Assays 420 4.2A.5 Xenobiotic Metabolism 420
4.2A.6 Summary 421 4.2B Mutagenicity tests in vivo 422 Ilse-Dore Adler and
Gerlinde Schriever-Schwemmer 4.2B.1 Introduction 422 4.2B.2 Chromosomal
Mutations in Somatic Cells 424 4.2B.3 Gene Mutations in Somatic Cells 427
4.2B.4 Chromosome Mutations in Germ Cells 429 4.2B.5 Gene Mutations in Germ
Cells 433 4.2B.6 Summary 435 4.3 Assessment of the Individual Exposure to
Xenobiotics (Biomonitoring) 440 Thomas Göen 4.3.1 Introduction 440 4.3.2
Prerequisites for Carrying Out Biomonitoring 442 4.3.3 Examples of
Biomonitoring of Special Substance Groups or Special Biomonitoring
Parameters 447 4.3.4 Summary 449 4.4 Epidemiology 450 Kurt Ulm 4.4.1
Introduction 450 4.4.2 Measures to Describe the Risk 450 4.4.3
Standardization 452 4.4.4 Types of Epidemiological Studies 454 4.4.5
Statistics 456 4.4.6 Meta-analysis 457 4.4.7 Bias, Confounding, Chance,
Causality 459 4.4.8 Summary 460 4.5 Alternatives to Animal Testing 461
Thomas Hartung 4.5.1 Introduction 461 4.5.2 The Birth of Doubt in Animal
Experiments 461 4.5.3 Early Successful Alternatives 463 4.5.4 The
Replacement of Animal Tests is Possible 463 4.5.5 Validation of Alternative
Methods: Animal Welfare must not Trump Patient and Consumer Safety 466
4.5.6 How Reliable are Animal Tests? 467 4.5.7 The Animal Test Ban for
Cosmetics in Europe as an Engine of Change 467 4.5.8 "Toxicological
Ignorance": the European REACH Program as a Driver for Alternative Methods
468 4.5.9 Outlook 469 4.5.10 Summary 471 4.6 Omics in Toxicology 472 Laura
Suter-Dick 4.6.1 Introduction 472 4.6.2 Concept of Toxicogenomics 472 4.6.3
Technology Platforms 475 4.6.4 Bioinformatics and Biostatistics 480 4.6.5
Applications of Toxicogenomics 481 4.6.6 Summary 484 4.7 Introduction to
the Statistical Analysis of Experimental Data 486 György Csanády 4.7.1
Introduction 486 4.7.2 Descriptive Statistics 488 4.7.3 Error Propagation
491 4.7.4 Probability Distribution 492 4.7.5 Inferential Statistics 496
4.7.6 Regression Analysis 504 4.7.7 Probit Analysis 506 4.7.8 Experimental
Designs 507 4.7.9 Statistical Software 508 4.7.10 Summary 509 4.8
Mathematical Models for Risk Extrapolation 510 Jürgen Timm 4.8.1
Introduction 510 4.8.2 Basic Approach of Linear Extrapolation 512 4.8.3
Some Special Methods of Linear Extrapolation 514 4.8.4 Consideration of
Time Aspects 515 4.8.5 Models of Carcinogenesis 518 4.8.6 Assumptions and
Limits of Extrapolation in Mathematical Models 521 4.8.7 Summary 523 5
Regulatory Toxicology 525 5.1 Regulations on Chemical Substances in the
European Union 525 Werner Lilienblum and Klaus-Michael Wollin 5.1.1
Introduction 525 5.1.2 Current Legislation in the EU 526 5.1.3 Risk Issues
and Some Definitions in Terms of Chemical Substances 528 5.1.4
International Co-operation and Harmonization Supported and Implemented by
the EU 531 5.1.5 EU Legislation on Chemical Substances and Their Uses 535
5.1.6 Legislation on Chemical Substances in the Environment 552 5.1.7
Summary 556 5.2 Regulations Regarding Chemicals and Radionuclides in the
Environment, Workplace, Consumer Products, Foods, and Pharmaceuticals in
the United States 557 Dennis J. Paustenbach 5.2.1 Introduction 557 5.2.2
Occupational Health Regulations 558 5.2.3 Food and Drug Regulations 561
5.2.4 Environmental Regulations 563 5.2.5 Consumer Product Regulations 568
5.2.6 Radionuclides Regulations 569 5.2.7 Governmental Agencies on Human
Health 570 5.2.8 Centers for Disease Control 571 5.2.9 Litigation is Nearly
as Effective as Regulation in the United States 571 5.2.10 Summary 572 5.3
The Concept of REACH 573 Jörg Lebsanft 5.3.1 Introduction 573 5.3.2
Historical Development 574 5.3.3 Substances, Mixtures and Articles 574
5.3.4 The Main Elements of REACH 575 5.3.5 Allocation of Responsibilities
and Administration of REACH 580 5.3.6 Downstream Users 582 5.3.7 Outlook
583 5.3.8 Summary 583 6 Specific Toxicology 585 6.1 Persistent Halogenated
Aromatic Hydrocarbons 585 Heidrun Greim and Karl K. Rozman 6.1.1
Introduction 585 6.1.2 Polychlorinated Dibenzodioxins and Dibenzofurans 586
6.1.3 Polychlorinated Biphenyls 588 6.1.4 Dichlorodiphenyltrichloroethane
589 6.1.5 Hexachlorobenzene 590 6.1.6 Physico-chemical Properties 591 6.1.7
Toxicity 592 6.1.8 Mechanisms of Action 600 6.1.9 Metabolism 603 6.1.10
Enzyme Induction 603 6.1.11 Kinetics 604 6.1.12 Summary 606 6.2 Metals 607
Andrea Hartwig and Gunnar Jahnke 6.2.1 General Aspects 607 6.2.2 The
Importance of Bioavailability 608 6.2.3 Acute and Chronic Toxicity as well
as Carcinogenicity 609 6.2.4 Toxicology of Selected Metal Compounds 611
6.2.5 Summary 624 6.3 Toxicology of Fibers and Particles 625 Paul J.A. Borm
6.3.1 Introduction 625 6.3.2 Particle Toxicology: Basic Concepts 626 6.3.3
Particle Properties 633 6.3.4 Nanoparticles: A Special Case? 636 6.3.5
Special Particle Effects 637 6.3.6 Summary 640 6.4 Principles of
Nanomaterial Toxicology 641 Thomas Gebel 6.4.1 Introduction 641 6.4.2
Toxicology 643 6.4.3 Summary 648 6.5 Endocrine Active Compounds 649 Volker
Strauss and Bennard van Ravenzwaay 6.5.1 Introduction 649 6.5.2 Thyroid
Hormone Affecting Compounds 651 6.5.3 Sex Hormones 654 6.5.4 Low-dose,
Non-monotonic Dose-effect Relation and Additive Effects 659 6.5.5 Summary
659 6.6 Assessment of Xenoestrogens and Xenoantiandrogens 661 Helmut Greim
6.6.1 Introduction 661 6.6.2 Modes of Action and Testing 662 6.6.3 A Weight
of Evidence Approach and Future Improvements 666 6.6.4 Limited Evidence for
Endocrine Disruption 667 6.6.5 Summary 667 6.7 Solvents 671 Wolfgang Dekant
6.7.1 Introduction 671 6.7.2 Toxicology of Selected Solvents 672 6.7.3
Hydrocarbons 677 6.7.4 Aliphatic Alcohols 680 6.7.5 Summary 685 6.8 Noxious
Gases 686 Kai Kehe and Horst Thiermann 6.8.1 Introduction 686 6.8.2
Airborne Systemic Poisons 686 6.8.3 Respiratory Tract Irritants 692 6.8.4
Irritant Gases 694 6.8.5 Summary 698 6.9 Fragrance Materials 699 Anne Marie
Api 6.9.1 Introduction 699 6.9.2 Evaluation of Toxicity 699 6.9.3 A Tiered
Approach to the Risk Assessment of Fragrances 700 6.9.4 Summary 702 6.10
Pesticides 703 Roland Alfred Solecki and Vera Ritz 6.10.1 Introduction 703
6.10.2 Toxicity of Selected Pesticidal Active Substances 706 6.10.3
Fungicides 709 6.10.4 Insecticides 711 6.10.5 Substances of Biological
Origin 713 6.10.6 Insect Growth Regulators 714 6.10.7 Other Pesticidal
Active Substances 715 6.10.8 Regulatory Toxicology of Pesticidal Active
Substances 716 6.10.9 Toxicological Endpoints 717 6.10.10 Classification
and Cut-off Criteria 718 6.10.11 Human Health Risk Assessment 718 6.10.12
Summary 720 6.11 Polycyclic Aromatic Hydrocarbons 722 Heidrun Greim and
Hermann Bolt 6.11.1 Introduction 722 6.11.2 Physico-chemical Properties 722
6.11.3 Occurrence in the Environment and in the Workplace 723 6.11.4
Toxicity 724 6.11.5 Mechanisms of Action 729 6.11.6 Evaluation by National
and International Organisations 730 6.11.7 Toxicity Equivalency Factors for
PAHs 731 6.11.8 Summary 732 6.12 Diesel Engine Emissions 733 Heidrun Greim
6.12.1 Introduction 733 6.12.2 Contents of Diesel Engine Emissions 734
6.12.3 Toxicokinetics 735 6.12.4 Toxicity 736 6.12.5 Mechanisms of the
Carcinogenic Effects of Diesel Engine Emissions 738 6.12.6 The Exposure of
Humans to Diesel Engine Emissions 740 6.12.7 Evaluation by International
Organizations 740 6.12.8 Summary 741 6.13 Animal and Plant Toxins 742
Thomas Zielker 6.13.1 Introduction 742 6.13.2 Animal Toxins 742 6.13.3
Plant Toxins 751 6.13.4 Summary 759 Glossary of Important Terms in
Toxicology 761 Index 769
List of Contributors xv Short CVs of Authors xix Preface xxix Dedication
xxxi List of Abbreviations xxxiii 1 Introduction to the Discipline of
Toxicology 1 Helmut Greim and Robert Snyder 1.1 Introduction 1 1.2 The Risk
Assessment Process 2 1.2.1 Hazard Identification 2 1.2.2 Dose Response and
Toxic Potency 3 1.2.3 Exposure Assessment 4 1.2.4 Risk Characterization 6
1.3 Toxicological Evaluation of New and Existing Chemicals 6 1.3.1 General
Requirements for Hazard Identification and Risk Assessment 7 1.3.2 General
Approach for Hazard Identification and Risk Assessment (for details see
Chapter 2.1) 12 1.3.3 Toxicological Issues related to Specific Chemical
Classes 13 1.3.4 Existing Chemicals 14 1.3.5 Test Guidelines (Chapter 4.1)
14 1.3.6 Alternatives to Animal Experiments (Chapter 4.5) 15 1.3.7
Evaluation of Mixtures (Chapter 2.7) 15 1.3.8 Evaluation of Uncertainties
16 1.3.9 The Precautionary Principle 16 1.3.10 The TTC Concept 17 1.3.11
Classification and Labeling of Chemicals 17 1.4 Summary 18 2 Principles in
Toxicology 21 2.1 General Concepts of Human Health Risk Assessment 21 Paul
T.C. Harrison, Philip Holmes, and Ruth Bevan 2.1.1 Introduction 21 2.1.2
Principles of Risk Assessment 21 2.1.3 Application of Risk Assessment in
Setting Exposure Standards and Limits 30 2.1.4 The Wider Importance of Risk
Assessment 32 2.1.5 Summary 32 2.2 Toxicokinetics 34 Johannes G. Filser
2.2.1 Definition and Purpose 34 2.2.2 Absorption, Distribution, and
Elimination 35 2.2.3 Toxicokinetic Models 47 2.2.4 Summary 61 2.3
Biotransformation of Xenobiotics 61 Wolfgang Dekant 2.3.1 Introduction 61
2.3.2 Phase I Reactions 64 2.3.3 Phase II Reactions 74 2.3.4 Factors that
Influence the Biotransformation of Xenobiotics 80 2.3.5 Role of
Bioactivation in Toxicity 87 2.3.6 Interactions of Reactive Intermediates
formed during the Biotransformation 90 2.3.7 Summary 94 2.4 Cytotoxicity 98
Daniel Dietrich 2.4.1 Introduction 98 2.4.2 The Cell 102 2.4.3 Cellular
Targets of Toxins 106 2.4.4 Mechanisms underlying Cell Death 115 2.4.5
Summary 120 2.5 Toxicogenetics 122 Lesley A. Stanley 2.5.1 Introduction 122
2.5.2 Toxicogenetics and Toxicogenomics 123 2.5.3 Genotype and Phenotype
123 2.5.4 The Role of Xenobiotic-metabolising Polymorphisms in
Susceptibility to Toxic Agents 127 2.5.5 Study Numbers and Effect Size 135
2.5.6 Summary 139 2.6 Receptor-mediated Mechanisms 140 Jens Schlossmann and
Franz Hofmann 2.6.1 Introduction 140 2.6.2 Ligand-Receptor Interactions 141
2.6.3 Biological Consequences of Ligand-Receptor Interactions 142 2.6.4
Receptor Signal Transduction 144 2.6.5 Summary 147 2.7 Mixtures and
Combinations of Chemicals 148 Hermann Bolt 2.7.1 Introduction 148 2.7.2
Types of Mixed Exposures 148 2.7.3 Types of Joint Actions and their Role in
Safety Evaluation 149 2.7.4 Role in Safety Evaluation 151 2.7.5 Summary 158
2.8 Chemical Carcinogenesis: Genotoxic and Non-Genotoxic Mechanisms 159
Thomas Efferth and Bernd Kaina 2.8.1 Introduction 159 2.8.2 Mechanisms of
DNA Damage, Repair, and Carcinogenesis 160 2.8.3 Cancer Development 171
2.8.4 Non-Genotoxic Mechanisms of Carcinogenesis 181 2.8.5 Implications of
Initiation and Promotion for Risk Assessment 184 2.8.6 Summary 185 2.9
Threshold Effects for Genotoxic Carcinogens 186 Helmut Greim 2.9.1
Introduction 186 2.9.2 Development of Cancer due to Genotoxic Carcinogens
187 2.9.3 Cellular Reaction to DNA Damage 187 2.9.4 Examples of
Dose-dependent Reactions in Cases of Genotoxicity 193 2.9.5 Summary 193
2.10 Reproductive Toxicology 195 Horst Spielmann 2.10.1 Introduction 195
2.10.2 Characteristics of Reproductive Toxicology 196 2.10.3 Adverse
Effects on Female and Male Fertility 197 2.10.4 International Test Methods
in the Field of Reproductive Toxicology 199 2.10.5 Pre- and Postnatal
Toxicology 201 2.10.6 Effects of Drugs and other Chemicals on Lactation 207
2.10.7 Endocrine Disrupters 208 2.10.8 Summary 208 2.11 Ecotoxicology: More
than Wildlife Toxicology 209 Peter Calow and Valery E. Forbes 2.11.1
Introduction 209 2.11.2 Protection Targets 210 2.11.3 Necessary Information
211 2.11.4 Risk Assessment 216 2.11.5 Fast-track Approaches 217 2.11.6
Summary 218 3 Organ Toxicology 221 3.1 The Gastrointestinal Tract 221
Michael Schwenk 3.1.1 Introduction 221 3.1.2 Structure and Function 221
3.1.3 Fate of Xenobiotics in the GI Tract 223 3.1.4 Toxicology 226 3.1.5
Summary 231 3.2 The Liver 231 Jan G. Hengstler 3.2.1 Introduction 231 3.2.2
Structure and Function 232 3.2.3 Toxicology 237 3.2.4 Myths of the Liver
247 3.2.5 Summary 248 3.3 The Respiratory System 248 Florian Schulz 3.3.1
Introduction 248 3.3.2 Structure 249 3.3.3 Function 252 3.3.4 Protective
Systems 254 3.3.5 The Respiratory Tract as a Target for Toxicity 256 3.3.6
Respiratory Allergy and Asthma 261 3.3.7 Lung Cancer 262 3.3.8 Test Systems
to Detect the Toxic Effects of Inhaled Materials 263 3.3.9 Summary 263 3.4
The Nervous System 264 Gunter P. Eckert and Walter E. Müller 3.4.1
Structure and Function of the Nervous System 264 3.4.2 The Nervous System
Site of Attack for Toxins 273 3.4.3 Clinical Signs and Symptoms induced by
Neurotoxins 279 3.4.4 Summary 281 3.5 Behavioral Neurotoxicology 283
Andreas Seeber 3.5.1 Introduction 283 3.5.2 Exposure Assessment 283 3.5.3
Methods 284 3.5.4 Neurobehavioral Effects in Humans 291 3.5.5 Summary 295
3.6 The Skin 296 Brunhilde Blömeke 3.6.1 Structure 296 3.6.2 Function 298
3.6.3 Toxicology of the Skin and the Anterior Segment of the Eye 300 3.6.4
Summary 309 3.7 Kidney and Urinary Tract 311 Helmut Greim 3.7.1
Introduction 311 3.7.2 Anatomy and Function 311 3.7.3 Toxicology 313 3.7.4
Summary 319 3.8 The Hematopoietic System (Bone Marrow and Blood) 320 Robert
Snyder 3.8.1 Introduction 320 3.8.2 Hematopoiesis 321 3.8.3 The Bone Marrow
Niche 323 3.8.4 Toxicological Features of Circulating Blood Cells 323 3.8.5
Leucocytes (White Blood Cells) 326 3.8.6 Platelets (Thrombocytes) 328 3.8.7
Impairment of Bone Marrow Function 328 3.8.8 Mechanisms by which Chemicals
can Induce Leukemia 330 3.8.9 Summary 330 3.9 The Immune System 331 Peter
Griem 3.9.1 Introduction: the Innate and Specific Immune System 331 3.9.2
Antigen Recognition 333 3.9.3 Activation of T and B lymphocytes 334 3.9.4
Immunologic Tolerance 336 3.9.5 Sensitization and Allergy 337 3.9.6 Risk
Assessment of Immunotoxic Effects 342 3.9.7 Chemical-induced Autoimmunity
345 3.9.8 General Immunostimulation by Chemicals 346 3.9.9 Chemical
Immunosuppression 348 3.9.10 Summary 350 3.10 The Eye 351 Ines Lanzl 3.10.1
Introduction 351 3.10.2 Structure and Function of the Eye 351 3.10.3 Routes
of Delivery of Xenobiotics to the Eye 354 3.10.4 Specific Toxicology of the
Eye 355 3.10.5 Summary 363 3.11 The Cardiovascular System 364 Helmut Greim
3.11.1 Structure and Function 364 3.11.2 Toxicology 366 3.11.3 Summary 371
3.12 The Endocrine System 372 Gerlinde Schriever-Schwemmer 3.12.1
Introduction 372 3.12.2 Structure and Function 373 3.12.3 Foetal
Development of the Hypothalamus-Pituitary-Gonad Axis 381 3.12.4 Testing of
Sexual Function in Toxicology 383 3.12.5 Hazard Identification and Risk
Assessment of Endocrine Disruptors 386 3.12.6 Summary 386 4 Methods in
Toxicology 389 4.1 OECD Test Guidelines for Toxicity Tests in vivo 389
Rüdiger Bartsch 4.1.1 Introduction 389 4.1.2 Requirements for in vivo Tests
390 4.1.3 Acute Toxicity 392 4.1.4 Skin and Eye Irritation 394 4.1.5 Skin
Sensitization 397 4.1.6 Toxicity after Repeated Dosing 398 4.1.7
Reproductive Toxicity 401 4.1.8 Other Test Guidelines 406 4.1.9 Other
Regulatory Bodies 407 4.1.10 Summary 407 4.2 Genotoxicity 408 4.2A In vitro
Tests for Genotoxicity 408 Hans-Jörg Martus 4.2A.1 Introduction 408 4.2A.2
Bacterial Test Systems 409 4.2A.3 Test Systems employing Mammalian Cells
411 4.2A.4 Cell Transformation Assays 420 4.2A.5 Xenobiotic Metabolism 420
4.2A.6 Summary 421 4.2B Mutagenicity tests in vivo 422 Ilse-Dore Adler and
Gerlinde Schriever-Schwemmer 4.2B.1 Introduction 422 4.2B.2 Chromosomal
Mutations in Somatic Cells 424 4.2B.3 Gene Mutations in Somatic Cells 427
4.2B.4 Chromosome Mutations in Germ Cells 429 4.2B.5 Gene Mutations in Germ
Cells 433 4.2B.6 Summary 435 4.3 Assessment of the Individual Exposure to
Xenobiotics (Biomonitoring) 440 Thomas Göen 4.3.1 Introduction 440 4.3.2
Prerequisites for Carrying Out Biomonitoring 442 4.3.3 Examples of
Biomonitoring of Special Substance Groups or Special Biomonitoring
Parameters 447 4.3.4 Summary 449 4.4 Epidemiology 450 Kurt Ulm 4.4.1
Introduction 450 4.4.2 Measures to Describe the Risk 450 4.4.3
Standardization 452 4.4.4 Types of Epidemiological Studies 454 4.4.5
Statistics 456 4.4.6 Meta-analysis 457 4.4.7 Bias, Confounding, Chance,
Causality 459 4.4.8 Summary 460 4.5 Alternatives to Animal Testing 461
Thomas Hartung 4.5.1 Introduction 461 4.5.2 The Birth of Doubt in Animal
Experiments 461 4.5.3 Early Successful Alternatives 463 4.5.4 The
Replacement of Animal Tests is Possible 463 4.5.5 Validation of Alternative
Methods: Animal Welfare must not Trump Patient and Consumer Safety 466
4.5.6 How Reliable are Animal Tests? 467 4.5.7 The Animal Test Ban for
Cosmetics in Europe as an Engine of Change 467 4.5.8 "Toxicological
Ignorance": the European REACH Program as a Driver for Alternative Methods
468 4.5.9 Outlook 469 4.5.10 Summary 471 4.6 Omics in Toxicology 472 Laura
Suter-Dick 4.6.1 Introduction 472 4.6.2 Concept of Toxicogenomics 472 4.6.3
Technology Platforms 475 4.6.4 Bioinformatics and Biostatistics 480 4.6.5
Applications of Toxicogenomics 481 4.6.6 Summary 484 4.7 Introduction to
the Statistical Analysis of Experimental Data 486 György Csanády 4.7.1
Introduction 486 4.7.2 Descriptive Statistics 488 4.7.3 Error Propagation
491 4.7.4 Probability Distribution 492 4.7.5 Inferential Statistics 496
4.7.6 Regression Analysis 504 4.7.7 Probit Analysis 506 4.7.8 Experimental
Designs 507 4.7.9 Statistical Software 508 4.7.10 Summary 509 4.8
Mathematical Models for Risk Extrapolation 510 Jürgen Timm 4.8.1
Introduction 510 4.8.2 Basic Approach of Linear Extrapolation 512 4.8.3
Some Special Methods of Linear Extrapolation 514 4.8.4 Consideration of
Time Aspects 515 4.8.5 Models of Carcinogenesis 518 4.8.6 Assumptions and
Limits of Extrapolation in Mathematical Models 521 4.8.7 Summary 523 5
Regulatory Toxicology 525 5.1 Regulations on Chemical Substances in the
European Union 525 Werner Lilienblum and Klaus-Michael Wollin 5.1.1
Introduction 525 5.1.2 Current Legislation in the EU 526 5.1.3 Risk Issues
and Some Definitions in Terms of Chemical Substances 528 5.1.4
International Co-operation and Harmonization Supported and Implemented by
the EU 531 5.1.5 EU Legislation on Chemical Substances and Their Uses 535
5.1.6 Legislation on Chemical Substances in the Environment 552 5.1.7
Summary 556 5.2 Regulations Regarding Chemicals and Radionuclides in the
Environment, Workplace, Consumer Products, Foods, and Pharmaceuticals in
the United States 557 Dennis J. Paustenbach 5.2.1 Introduction 557 5.2.2
Occupational Health Regulations 558 5.2.3 Food and Drug Regulations 561
5.2.4 Environmental Regulations 563 5.2.5 Consumer Product Regulations 568
5.2.6 Radionuclides Regulations 569 5.2.7 Governmental Agencies on Human
Health 570 5.2.8 Centers for Disease Control 571 5.2.9 Litigation is Nearly
as Effective as Regulation in the United States 571 5.2.10 Summary 572 5.3
The Concept of REACH 573 Jörg Lebsanft 5.3.1 Introduction 573 5.3.2
Historical Development 574 5.3.3 Substances, Mixtures and Articles 574
5.3.4 The Main Elements of REACH 575 5.3.5 Allocation of Responsibilities
and Administration of REACH 580 5.3.6 Downstream Users 582 5.3.7 Outlook
583 5.3.8 Summary 583 6 Specific Toxicology 585 6.1 Persistent Halogenated
Aromatic Hydrocarbons 585 Heidrun Greim and Karl K. Rozman 6.1.1
Introduction 585 6.1.2 Polychlorinated Dibenzodioxins and Dibenzofurans 586
6.1.3 Polychlorinated Biphenyls 588 6.1.4 Dichlorodiphenyltrichloroethane
589 6.1.5 Hexachlorobenzene 590 6.1.6 Physico-chemical Properties 591 6.1.7
Toxicity 592 6.1.8 Mechanisms of Action 600 6.1.9 Metabolism 603 6.1.10
Enzyme Induction 603 6.1.11 Kinetics 604 6.1.12 Summary 606 6.2 Metals 607
Andrea Hartwig and Gunnar Jahnke 6.2.1 General Aspects 607 6.2.2 The
Importance of Bioavailability 608 6.2.3 Acute and Chronic Toxicity as well
as Carcinogenicity 609 6.2.4 Toxicology of Selected Metal Compounds 611
6.2.5 Summary 624 6.3 Toxicology of Fibers and Particles 625 Paul J.A. Borm
6.3.1 Introduction 625 6.3.2 Particle Toxicology: Basic Concepts 626 6.3.3
Particle Properties 633 6.3.4 Nanoparticles: A Special Case? 636 6.3.5
Special Particle Effects 637 6.3.6 Summary 640 6.4 Principles of
Nanomaterial Toxicology 641 Thomas Gebel 6.4.1 Introduction 641 6.4.2
Toxicology 643 6.4.3 Summary 648 6.5 Endocrine Active Compounds 649 Volker
Strauss and Bennard van Ravenzwaay 6.5.1 Introduction 649 6.5.2 Thyroid
Hormone Affecting Compounds 651 6.5.3 Sex Hormones 654 6.5.4 Low-dose,
Non-monotonic Dose-effect Relation and Additive Effects 659 6.5.5 Summary
659 6.6 Assessment of Xenoestrogens and Xenoantiandrogens 661 Helmut Greim
6.6.1 Introduction 661 6.6.2 Modes of Action and Testing 662 6.6.3 A Weight
of Evidence Approach and Future Improvements 666 6.6.4 Limited Evidence for
Endocrine Disruption 667 6.6.5 Summary 667 6.7 Solvents 671 Wolfgang Dekant
6.7.1 Introduction 671 6.7.2 Toxicology of Selected Solvents 672 6.7.3
Hydrocarbons 677 6.7.4 Aliphatic Alcohols 680 6.7.5 Summary 685 6.8 Noxious
Gases 686 Kai Kehe and Horst Thiermann 6.8.1 Introduction 686 6.8.2
Airborne Systemic Poisons 686 6.8.3 Respiratory Tract Irritants 692 6.8.4
Irritant Gases 694 6.8.5 Summary 698 6.9 Fragrance Materials 699 Anne Marie
Api 6.9.1 Introduction 699 6.9.2 Evaluation of Toxicity 699 6.9.3 A Tiered
Approach to the Risk Assessment of Fragrances 700 6.9.4 Summary 702 6.10
Pesticides 703 Roland Alfred Solecki and Vera Ritz 6.10.1 Introduction 703
6.10.2 Toxicity of Selected Pesticidal Active Substances 706 6.10.3
Fungicides 709 6.10.4 Insecticides 711 6.10.5 Substances of Biological
Origin 713 6.10.6 Insect Growth Regulators 714 6.10.7 Other Pesticidal
Active Substances 715 6.10.8 Regulatory Toxicology of Pesticidal Active
Substances 716 6.10.9 Toxicological Endpoints 717 6.10.10 Classification
and Cut-off Criteria 718 6.10.11 Human Health Risk Assessment 718 6.10.12
Summary 720 6.11 Polycyclic Aromatic Hydrocarbons 722 Heidrun Greim and
Hermann Bolt 6.11.1 Introduction 722 6.11.2 Physico-chemical Properties 722
6.11.3 Occurrence in the Environment and in the Workplace 723 6.11.4
Toxicity 724 6.11.5 Mechanisms of Action 729 6.11.6 Evaluation by National
and International Organisations 730 6.11.7 Toxicity Equivalency Factors for
PAHs 731 6.11.8 Summary 732 6.12 Diesel Engine Emissions 733 Heidrun Greim
6.12.1 Introduction 733 6.12.2 Contents of Diesel Engine Emissions 734
6.12.3 Toxicokinetics 735 6.12.4 Toxicity 736 6.12.5 Mechanisms of the
Carcinogenic Effects of Diesel Engine Emissions 738 6.12.6 The Exposure of
Humans to Diesel Engine Emissions 740 6.12.7 Evaluation by International
Organizations 740 6.12.8 Summary 741 6.13 Animal and Plant Toxins 742
Thomas Zielker 6.13.1 Introduction 742 6.13.2 Animal Toxins 742 6.13.3
Plant Toxins 751 6.13.4 Summary 759 Glossary of Important Terms in
Toxicology 761 Index 769
xxxi List of Abbreviations xxxiii 1 Introduction to the Discipline of
Toxicology 1 Helmut Greim and Robert Snyder 1.1 Introduction 1 1.2 The Risk
Assessment Process 2 1.2.1 Hazard Identification 2 1.2.2 Dose Response and
Toxic Potency 3 1.2.3 Exposure Assessment 4 1.2.4 Risk Characterization 6
1.3 Toxicological Evaluation of New and Existing Chemicals 6 1.3.1 General
Requirements for Hazard Identification and Risk Assessment 7 1.3.2 General
Approach for Hazard Identification and Risk Assessment (for details see
Chapter 2.1) 12 1.3.3 Toxicological Issues related to Specific Chemical
Classes 13 1.3.4 Existing Chemicals 14 1.3.5 Test Guidelines (Chapter 4.1)
14 1.3.6 Alternatives to Animal Experiments (Chapter 4.5) 15 1.3.7
Evaluation of Mixtures (Chapter 2.7) 15 1.3.8 Evaluation of Uncertainties
16 1.3.9 The Precautionary Principle 16 1.3.10 The TTC Concept 17 1.3.11
Classification and Labeling of Chemicals 17 1.4 Summary 18 2 Principles in
Toxicology 21 2.1 General Concepts of Human Health Risk Assessment 21 Paul
T.C. Harrison, Philip Holmes, and Ruth Bevan 2.1.1 Introduction 21 2.1.2
Principles of Risk Assessment 21 2.1.3 Application of Risk Assessment in
Setting Exposure Standards and Limits 30 2.1.4 The Wider Importance of Risk
Assessment 32 2.1.5 Summary 32 2.2 Toxicokinetics 34 Johannes G. Filser
2.2.1 Definition and Purpose 34 2.2.2 Absorption, Distribution, and
Elimination 35 2.2.3 Toxicokinetic Models 47 2.2.4 Summary 61 2.3
Biotransformation of Xenobiotics 61 Wolfgang Dekant 2.3.1 Introduction 61
2.3.2 Phase I Reactions 64 2.3.3 Phase II Reactions 74 2.3.4 Factors that
Influence the Biotransformation of Xenobiotics 80 2.3.5 Role of
Bioactivation in Toxicity 87 2.3.6 Interactions of Reactive Intermediates
formed during the Biotransformation 90 2.3.7 Summary 94 2.4 Cytotoxicity 98
Daniel Dietrich 2.4.1 Introduction 98 2.4.2 The Cell 102 2.4.3 Cellular
Targets of Toxins 106 2.4.4 Mechanisms underlying Cell Death 115 2.4.5
Summary 120 2.5 Toxicogenetics 122 Lesley A. Stanley 2.5.1 Introduction 122
2.5.2 Toxicogenetics and Toxicogenomics 123 2.5.3 Genotype and Phenotype
123 2.5.4 The Role of Xenobiotic-metabolising Polymorphisms in
Susceptibility to Toxic Agents 127 2.5.5 Study Numbers and Effect Size 135
2.5.6 Summary 139 2.6 Receptor-mediated Mechanisms 140 Jens Schlossmann and
Franz Hofmann 2.6.1 Introduction 140 2.6.2 Ligand-Receptor Interactions 141
2.6.3 Biological Consequences of Ligand-Receptor Interactions 142 2.6.4
Receptor Signal Transduction 144 2.6.5 Summary 147 2.7 Mixtures and
Combinations of Chemicals 148 Hermann Bolt 2.7.1 Introduction 148 2.7.2
Types of Mixed Exposures 148 2.7.3 Types of Joint Actions and their Role in
Safety Evaluation 149 2.7.4 Role in Safety Evaluation 151 2.7.5 Summary 158
2.8 Chemical Carcinogenesis: Genotoxic and Non-Genotoxic Mechanisms 159
Thomas Efferth and Bernd Kaina 2.8.1 Introduction 159 2.8.2 Mechanisms of
DNA Damage, Repair, and Carcinogenesis 160 2.8.3 Cancer Development 171
2.8.4 Non-Genotoxic Mechanisms of Carcinogenesis 181 2.8.5 Implications of
Initiation and Promotion for Risk Assessment 184 2.8.6 Summary 185 2.9
Threshold Effects for Genotoxic Carcinogens 186 Helmut Greim 2.9.1
Introduction 186 2.9.2 Development of Cancer due to Genotoxic Carcinogens
187 2.9.3 Cellular Reaction to DNA Damage 187 2.9.4 Examples of
Dose-dependent Reactions in Cases of Genotoxicity 193 2.9.5 Summary 193
2.10 Reproductive Toxicology 195 Horst Spielmann 2.10.1 Introduction 195
2.10.2 Characteristics of Reproductive Toxicology 196 2.10.3 Adverse
Effects on Female and Male Fertility 197 2.10.4 International Test Methods
in the Field of Reproductive Toxicology 199 2.10.5 Pre- and Postnatal
Toxicology 201 2.10.6 Effects of Drugs and other Chemicals on Lactation 207
2.10.7 Endocrine Disrupters 208 2.10.8 Summary 208 2.11 Ecotoxicology: More
than Wildlife Toxicology 209 Peter Calow and Valery E. Forbes 2.11.1
Introduction 209 2.11.2 Protection Targets 210 2.11.3 Necessary Information
211 2.11.4 Risk Assessment 216 2.11.5 Fast-track Approaches 217 2.11.6
Summary 218 3 Organ Toxicology 221 3.1 The Gastrointestinal Tract 221
Michael Schwenk 3.1.1 Introduction 221 3.1.2 Structure and Function 221
3.1.3 Fate of Xenobiotics in the GI Tract 223 3.1.4 Toxicology 226 3.1.5
Summary 231 3.2 The Liver 231 Jan G. Hengstler 3.2.1 Introduction 231 3.2.2
Structure and Function 232 3.2.3 Toxicology 237 3.2.4 Myths of the Liver
247 3.2.5 Summary 248 3.3 The Respiratory System 248 Florian Schulz 3.3.1
Introduction 248 3.3.2 Structure 249 3.3.3 Function 252 3.3.4 Protective
Systems 254 3.3.5 The Respiratory Tract as a Target for Toxicity 256 3.3.6
Respiratory Allergy and Asthma 261 3.3.7 Lung Cancer 262 3.3.8 Test Systems
to Detect the Toxic Effects of Inhaled Materials 263 3.3.9 Summary 263 3.4
The Nervous System 264 Gunter P. Eckert and Walter E. Müller 3.4.1
Structure and Function of the Nervous System 264 3.4.2 The Nervous System
Site of Attack for Toxins 273 3.4.3 Clinical Signs and Symptoms induced by
Neurotoxins 279 3.4.4 Summary 281 3.5 Behavioral Neurotoxicology 283
Andreas Seeber 3.5.1 Introduction 283 3.5.2 Exposure Assessment 283 3.5.3
Methods 284 3.5.4 Neurobehavioral Effects in Humans 291 3.5.5 Summary 295
3.6 The Skin 296 Brunhilde Blömeke 3.6.1 Structure 296 3.6.2 Function 298
3.6.3 Toxicology of the Skin and the Anterior Segment of the Eye 300 3.6.4
Summary 309 3.7 Kidney and Urinary Tract 311 Helmut Greim 3.7.1
Introduction 311 3.7.2 Anatomy and Function 311 3.7.3 Toxicology 313 3.7.4
Summary 319 3.8 The Hematopoietic System (Bone Marrow and Blood) 320 Robert
Snyder 3.8.1 Introduction 320 3.8.2 Hematopoiesis 321 3.8.3 The Bone Marrow
Niche 323 3.8.4 Toxicological Features of Circulating Blood Cells 323 3.8.5
Leucocytes (White Blood Cells) 326 3.8.6 Platelets (Thrombocytes) 328 3.8.7
Impairment of Bone Marrow Function 328 3.8.8 Mechanisms by which Chemicals
can Induce Leukemia 330 3.8.9 Summary 330 3.9 The Immune System 331 Peter
Griem 3.9.1 Introduction: the Innate and Specific Immune System 331 3.9.2
Antigen Recognition 333 3.9.3 Activation of T and B lymphocytes 334 3.9.4
Immunologic Tolerance 336 3.9.5 Sensitization and Allergy 337 3.9.6 Risk
Assessment of Immunotoxic Effects 342 3.9.7 Chemical-induced Autoimmunity
345 3.9.8 General Immunostimulation by Chemicals 346 3.9.9 Chemical
Immunosuppression 348 3.9.10 Summary 350 3.10 The Eye 351 Ines Lanzl 3.10.1
Introduction 351 3.10.2 Structure and Function of the Eye 351 3.10.3 Routes
of Delivery of Xenobiotics to the Eye 354 3.10.4 Specific Toxicology of the
Eye 355 3.10.5 Summary 363 3.11 The Cardiovascular System 364 Helmut Greim
3.11.1 Structure and Function 364 3.11.2 Toxicology 366 3.11.3 Summary 371
3.12 The Endocrine System 372 Gerlinde Schriever-Schwemmer 3.12.1
Introduction 372 3.12.2 Structure and Function 373 3.12.3 Foetal
Development of the Hypothalamus-Pituitary-Gonad Axis 381 3.12.4 Testing of
Sexual Function in Toxicology 383 3.12.5 Hazard Identification and Risk
Assessment of Endocrine Disruptors 386 3.12.6 Summary 386 4 Methods in
Toxicology 389 4.1 OECD Test Guidelines for Toxicity Tests in vivo 389
Rüdiger Bartsch 4.1.1 Introduction 389 4.1.2 Requirements for in vivo Tests
390 4.1.3 Acute Toxicity 392 4.1.4 Skin and Eye Irritation 394 4.1.5 Skin
Sensitization 397 4.1.6 Toxicity after Repeated Dosing 398 4.1.7
Reproductive Toxicity 401 4.1.8 Other Test Guidelines 406 4.1.9 Other
Regulatory Bodies 407 4.1.10 Summary 407 4.2 Genotoxicity 408 4.2A In vitro
Tests for Genotoxicity 408 Hans-Jörg Martus 4.2A.1 Introduction 408 4.2A.2
Bacterial Test Systems 409 4.2A.3 Test Systems employing Mammalian Cells
411 4.2A.4 Cell Transformation Assays 420 4.2A.5 Xenobiotic Metabolism 420
4.2A.6 Summary 421 4.2B Mutagenicity tests in vivo 422 Ilse-Dore Adler and
Gerlinde Schriever-Schwemmer 4.2B.1 Introduction 422 4.2B.2 Chromosomal
Mutations in Somatic Cells 424 4.2B.3 Gene Mutations in Somatic Cells 427
4.2B.4 Chromosome Mutations in Germ Cells 429 4.2B.5 Gene Mutations in Germ
Cells 433 4.2B.6 Summary 435 4.3 Assessment of the Individual Exposure to
Xenobiotics (Biomonitoring) 440 Thomas Göen 4.3.1 Introduction 440 4.3.2
Prerequisites for Carrying Out Biomonitoring 442 4.3.3 Examples of
Biomonitoring of Special Substance Groups or Special Biomonitoring
Parameters 447 4.3.4 Summary 449 4.4 Epidemiology 450 Kurt Ulm 4.4.1
Introduction 450 4.4.2 Measures to Describe the Risk 450 4.4.3
Standardization 452 4.4.4 Types of Epidemiological Studies 454 4.4.5
Statistics 456 4.4.6 Meta-analysis 457 4.4.7 Bias, Confounding, Chance,
Causality 459 4.4.8 Summary 460 4.5 Alternatives to Animal Testing 461
Thomas Hartung 4.5.1 Introduction 461 4.5.2 The Birth of Doubt in Animal
Experiments 461 4.5.3 Early Successful Alternatives 463 4.5.4 The
Replacement of Animal Tests is Possible 463 4.5.5 Validation of Alternative
Methods: Animal Welfare must not Trump Patient and Consumer Safety 466
4.5.6 How Reliable are Animal Tests? 467 4.5.7 The Animal Test Ban for
Cosmetics in Europe as an Engine of Change 467 4.5.8 "Toxicological
Ignorance": the European REACH Program as a Driver for Alternative Methods
468 4.5.9 Outlook 469 4.5.10 Summary 471 4.6 Omics in Toxicology 472 Laura
Suter-Dick 4.6.1 Introduction 472 4.6.2 Concept of Toxicogenomics 472 4.6.3
Technology Platforms 475 4.6.4 Bioinformatics and Biostatistics 480 4.6.5
Applications of Toxicogenomics 481 4.6.6 Summary 484 4.7 Introduction to
the Statistical Analysis of Experimental Data 486 György Csanády 4.7.1
Introduction 486 4.7.2 Descriptive Statistics 488 4.7.3 Error Propagation
491 4.7.4 Probability Distribution 492 4.7.5 Inferential Statistics 496
4.7.6 Regression Analysis 504 4.7.7 Probit Analysis 506 4.7.8 Experimental
Designs 507 4.7.9 Statistical Software 508 4.7.10 Summary 509 4.8
Mathematical Models for Risk Extrapolation 510 Jürgen Timm 4.8.1
Introduction 510 4.8.2 Basic Approach of Linear Extrapolation 512 4.8.3
Some Special Methods of Linear Extrapolation 514 4.8.4 Consideration of
Time Aspects 515 4.8.5 Models of Carcinogenesis 518 4.8.6 Assumptions and
Limits of Extrapolation in Mathematical Models 521 4.8.7 Summary 523 5
Regulatory Toxicology 525 5.1 Regulations on Chemical Substances in the
European Union 525 Werner Lilienblum and Klaus-Michael Wollin 5.1.1
Introduction 525 5.1.2 Current Legislation in the EU 526 5.1.3 Risk Issues
and Some Definitions in Terms of Chemical Substances 528 5.1.4
International Co-operation and Harmonization Supported and Implemented by
the EU 531 5.1.5 EU Legislation on Chemical Substances and Their Uses 535
5.1.6 Legislation on Chemical Substances in the Environment 552 5.1.7
Summary 556 5.2 Regulations Regarding Chemicals and Radionuclides in the
Environment, Workplace, Consumer Products, Foods, and Pharmaceuticals in
the United States 557 Dennis J. Paustenbach 5.2.1 Introduction 557 5.2.2
Occupational Health Regulations 558 5.2.3 Food and Drug Regulations 561
5.2.4 Environmental Regulations 563 5.2.5 Consumer Product Regulations 568
5.2.6 Radionuclides Regulations 569 5.2.7 Governmental Agencies on Human
Health 570 5.2.8 Centers for Disease Control 571 5.2.9 Litigation is Nearly
as Effective as Regulation in the United States 571 5.2.10 Summary 572 5.3
The Concept of REACH 573 Jörg Lebsanft 5.3.1 Introduction 573 5.3.2
Historical Development 574 5.3.3 Substances, Mixtures and Articles 574
5.3.4 The Main Elements of REACH 575 5.3.5 Allocation of Responsibilities
and Administration of REACH 580 5.3.6 Downstream Users 582 5.3.7 Outlook
583 5.3.8 Summary 583 6 Specific Toxicology 585 6.1 Persistent Halogenated
Aromatic Hydrocarbons 585 Heidrun Greim and Karl K. Rozman 6.1.1
Introduction 585 6.1.2 Polychlorinated Dibenzodioxins and Dibenzofurans 586
6.1.3 Polychlorinated Biphenyls 588 6.1.4 Dichlorodiphenyltrichloroethane
589 6.1.5 Hexachlorobenzene 590 6.1.6 Physico-chemical Properties 591 6.1.7
Toxicity 592 6.1.8 Mechanisms of Action 600 6.1.9 Metabolism 603 6.1.10
Enzyme Induction 603 6.1.11 Kinetics 604 6.1.12 Summary 606 6.2 Metals 607
Andrea Hartwig and Gunnar Jahnke 6.2.1 General Aspects 607 6.2.2 The
Importance of Bioavailability 608 6.2.3 Acute and Chronic Toxicity as well
as Carcinogenicity 609 6.2.4 Toxicology of Selected Metal Compounds 611
6.2.5 Summary 624 6.3 Toxicology of Fibers and Particles 625 Paul J.A. Borm
6.3.1 Introduction 625 6.3.2 Particle Toxicology: Basic Concepts 626 6.3.3
Particle Properties 633 6.3.4 Nanoparticles: A Special Case? 636 6.3.5
Special Particle Effects 637 6.3.6 Summary 640 6.4 Principles of
Nanomaterial Toxicology 641 Thomas Gebel 6.4.1 Introduction 641 6.4.2
Toxicology 643 6.4.3 Summary 648 6.5 Endocrine Active Compounds 649 Volker
Strauss and Bennard van Ravenzwaay 6.5.1 Introduction 649 6.5.2 Thyroid
Hormone Affecting Compounds 651 6.5.3 Sex Hormones 654 6.5.4 Low-dose,
Non-monotonic Dose-effect Relation and Additive Effects 659 6.5.5 Summary
659 6.6 Assessment of Xenoestrogens and Xenoantiandrogens 661 Helmut Greim
6.6.1 Introduction 661 6.6.2 Modes of Action and Testing 662 6.6.3 A Weight
of Evidence Approach and Future Improvements 666 6.6.4 Limited Evidence for
Endocrine Disruption 667 6.6.5 Summary 667 6.7 Solvents 671 Wolfgang Dekant
6.7.1 Introduction 671 6.7.2 Toxicology of Selected Solvents 672 6.7.3
Hydrocarbons 677 6.7.4 Aliphatic Alcohols 680 6.7.5 Summary 685 6.8 Noxious
Gases 686 Kai Kehe and Horst Thiermann 6.8.1 Introduction 686 6.8.2
Airborne Systemic Poisons 686 6.8.3 Respiratory Tract Irritants 692 6.8.4
Irritant Gases 694 6.8.5 Summary 698 6.9 Fragrance Materials 699 Anne Marie
Api 6.9.1 Introduction 699 6.9.2 Evaluation of Toxicity 699 6.9.3 A Tiered
Approach to the Risk Assessment of Fragrances 700 6.9.4 Summary 702 6.10
Pesticides 703 Roland Alfred Solecki and Vera Ritz 6.10.1 Introduction 703
6.10.2 Toxicity of Selected Pesticidal Active Substances 706 6.10.3
Fungicides 709 6.10.4 Insecticides 711 6.10.5 Substances of Biological
Origin 713 6.10.6 Insect Growth Regulators 714 6.10.7 Other Pesticidal
Active Substances 715 6.10.8 Regulatory Toxicology of Pesticidal Active
Substances 716 6.10.9 Toxicological Endpoints 717 6.10.10 Classification
and Cut-off Criteria 718 6.10.11 Human Health Risk Assessment 718 6.10.12
Summary 720 6.11 Polycyclic Aromatic Hydrocarbons 722 Heidrun Greim and
Hermann Bolt 6.11.1 Introduction 722 6.11.2 Physico-chemical Properties 722
6.11.3 Occurrence in the Environment and in the Workplace 723 6.11.4
Toxicity 724 6.11.5 Mechanisms of Action 729 6.11.6 Evaluation by National
and International Organisations 730 6.11.7 Toxicity Equivalency Factors for
PAHs 731 6.11.8 Summary 732 6.12 Diesel Engine Emissions 733 Heidrun Greim
6.12.1 Introduction 733 6.12.2 Contents of Diesel Engine Emissions 734
6.12.3 Toxicokinetics 735 6.12.4 Toxicity 736 6.12.5 Mechanisms of the
Carcinogenic Effects of Diesel Engine Emissions 738 6.12.6 The Exposure of
Humans to Diesel Engine Emissions 740 6.12.7 Evaluation by International
Organizations 740 6.12.8 Summary 741 6.13 Animal and Plant Toxins 742
Thomas Zielker 6.13.1 Introduction 742 6.13.2 Animal Toxins 742 6.13.3
Plant Toxins 751 6.13.4 Summary 759 Glossary of Important Terms in
Toxicology 761 Index 769