c

Handbook on the

Toxicology of Metals

Fourth Edition

Volume I: General Considerations

Editors

Gunnar F. Nordberg Department of Public Health and Clinical Medicine,

Umeä University, Sweden

Bruce A. Fowler

Rollins School of Public Health, Emory University, Atlanta, GA,

and Center for Alaska Native Health Research, University of Alaska

Fairbanks, Fairbanks, AK, USA

Monica Nordberg

Institute of Environmental Medicine, Karolinska Institutet,

Stockholm, Sweden

AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO

SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO ELSEVIER Academic Press is an imprint of Elsevier

Füll Contents

Preface

List of Contributors

List of Reviewers

v

xxvii

xxxiii

4.6 Biological Monitoring 4.7 Toxicokinetics and Dosimetry 4.8 Interactions among Metals:

Gene-Environment Interactions 4.9 Risk Assessment

References

11 11

12 12 13

VOLUME I: GENERAL CONSIDERATIONS

C H A P T E R C H A P T E R

Toxicology of Metals: Overview, Definitions, Concepts, and Trends

GUNNAR F. NORDBERG, BRUCE A. FOWLER, AND MONIC A NORDBERG

Metal Exposures and Global Bürden of Disease 3 International Historical Perspectives on Risks of Health Effects of Metals 4 Metal Poisoning and Other Human Health Effects 7 3.1 Metal Poisoning from High-Level

Exposures 7 3.2 Adverse Human Health Effects from

Long-Term Low-Level Exposures 8 3.2.1 Neurotoxicology of Metals 8 3.2.2 Cardiovascular Disease 8 3.2.3 Kidney Effects of Exposure to Metals 8 3.2.4 Metal Carcinogenesis and

Reproductive Toxicology 8 Human Exposures to Metallic Compounds, Risk Assessment, and Prevention 9 4.1 Expanding Current Industrial New

Technological Uses of Metals 9 Toxicity of Metallic Nanoparticles 9 Ecological and Natural Environmental Mobilization Processes 10 Routes of Human Exposure: Release from Implanted Medical Devices; Toxic Metals in Food 10 Essential Metals: Risks from Deficiency and Toxicity 11

4.2 4.3

4.4

4.5

General Chemistry, Sampling, Analytical Methods, and Speciation

DONALD R. SMITH AND MONICA NORDBERG

1 Definition of Metals 16 2 The Periodic Table 16 3 Compounds of Metallic Elements 17

3.1 Covalent and Ionic Bonds 17 3.2 Oxidation Number 18 3.3 Inorganic Compounds 18 3.4 Metal Complexes 18 3.5 Organometallic Compounds 19

4 Solubility 19 5 Properties of Metal Ions 19

5.1 Formation of Metal Ions 19 5.2 Redox Potential 20 5.3 Metal Ions as Lewis Acids 20 5.4 Hydrolysis 20

6 Other Aspects of Metal Chemistry of Biological and Toxicological Interest 21 6.1 Main Group and Transition

Metals 21 6.2 Metal-Containing Biological

Molecules 21 6.2.1 Metalloporphyrins 21 6.2.2 Nonheme Iron

Proteins 22 6.2.3 Cobalt-Containing Biological

Molecules 22 6.2.4 Metalloenzymes and Metal-

Activated Enzymes 22 6.2.5 Metallothioneins 22

xiii

xiv Füll Contents

7 Metallomics, Total Element Analysis, and Elemental Speciation 22

8 Sampling and Sample Preparation 23 8.1 General Considerations 23 8.2 Air, Water, arid Food 24

8.2.1 Air 24 8.2.2 Water 25 8.2.3 Food 25

8.3 Biological Monitoring 26 9 Separation Techniques 27

9.1 Liquid Chromatography 27 9.2 Gas Chromatography 30 9.3 Capillary Electrophoresis 30 9.4 Gel Electrophoresis 30 9.5 Precautionary Measures in Elemental

Speciation 31 10 Detection Methods 32

10.1 General Aspects 32 10.2 Current Methods for the Detection

of Metals 32 10.2.1 Atomic Absorption

Spectrometry 32 10.2.2 Atomic Fluorescence

Spectrometry 33 10.2.3 Atomic Emission

Spectrometry 33 10.2.4 Mass Spectrometry 34 10.2.5 Electrochemical

Methods 36 10.2.6 Spectrophotometry 36 10.2.7 Biosensors for Monitoring

Metal Ions 36 10.2.8 Direct Measurement of Metals

in Solid Samples (Particle Characterization) 36

10.2.9 Neutron Activation Analysis 37

11 Calibration 37 12 Reference Materials 38 13 Quality Assurance 38

13.1 Definitions 39 13.2 Sources of Error 39 13.3 Results of Interlaboratory

Testing 40 13.4 Elements of Quality

Assurance 40 13.5 Statistical Considerations 40 13.6 Reporting of Quality Assurance

Data 40 14 Conclusions 41 References 41

C H A P T E R

Routes of Exposure, Dose, and Toxicokinetics of Metals

ALISON ELDER, GUNNAR F. NORDBERG, AND MICHAEL KLEINMAN

1 Introduction 45 2 Exposure 46

2.1 General Aspects 46 2.2 Exposure by Inhalation 47 2.3 Exposure through Food and

Drinking Water 48 3 Deposition and Absorption 49

3.1 Absorption after Inhalation 49 3.1.1 Absorption of Gases and Vapors 51 3.1.2 Deposition of Particles 51 3.1.3 Clearance of Particles from the

Respiratory System 52 3.2 Absorption after Ingestion 56 3.3 Total Absorption 58

4 Transport, Biotransformation, and Distribution 58

5 Pathways and Mechanisms of Excretion 60 5.1 Gastrointestinal Excretion 60 5.2 Renal Excretion 61 5.3 Excretion Rate: Biological Half-Time 62

6 Toxicokinetic Models and Their Use in Establishing Dose-Response and Dose-Effect Relationships 63 6.1 One-Compartment Model 64

6.1.1 Description 64 6.1.2 Use of the One-Compartment Model

to Describe Toxicokinetics and Convert Biomonitoring Data 64

6.1.3 Use of the One-Compartment Model for Toxicokinetic-Toxicodynamic Modeling of Dose-Response or Dose-Effect Relationships 65

6.2 Multicompartment Models and Physiologically Based Models 66 6.2.1 Description of a Multicompartment

Model for Cadmium 67 6.2.2 Use of Multicompartment and

Physiologically Based Models for Toxicokinetic-Toxicodynamic Modeling 68

7 Use of Indicator Media for Estimating Exposure or Critical Organ Concentration 69

References 70

Füll Contents XV

C H A P T E R 9 Copper and Copper Oxide Nanoparticles 91

4 9.1 Synthesis and Applications 91

4 9.2 In Vitro Toxicity Studies 9.3 In Vivo Toxicity Studies

92 93

Toxicity of Metal and Metal Oxide 10 Nickel and Nickel Oxide Nanoparticles Nanoparticles 93

HANNA L. KARLSSON, MUHAMMET S. TOPRAK, 10.1 Synthesis and Applications 93 AND BENGT FADEEL 10.2 In Vitro Toxicity Studies

10.3 In Vivo Toxicity Studies 94 94

Metal and Metal Oxide Nanoparticles 75 11 Iron Oxide Nanoparticles 95 1.1 Background: Health Effects of Ultrafine 11.1 Synthesis and Applications 95

Particles 75 11.2 In Vitro Toxicity Studies 95 1.2 Technological and Consumer Product 11.3 In Vivo Toxicity Studies 97

Applications 76 12 Titanium Dioxide Nanoparticles 97 1.3 Exposure: Occupational and Consumer or 12.1 Synthesis and Applications 97

Patient Exposure 77 12.2 In Vitro Toxicity Studies 97 1.4 Risk Assessment: Hazard versus Risk: 12.3 In Vivo Toxicity Studies 98

Regulation of Nanomaterials 78 13 Zinc Oxide Nanoparticles 99 Principles of Nanoparticle-Induced Toxicity 78 13.1 Synthesis and Applications 99 2.1 Role of Size, Shape, and Surface Charge 78 13.2 In Vitro Toxicity Studies 99 2.2 Role of Solubility and Metal Ion Release 79 13.3 In Vivo Toxicity Studies 100 2.3 Role of the Biocorona on Nanoparticle 14 Cerium Oxide Nanoparticles 101

Surfaces 80 14.1 Synthesis and Applications 101 2.4 Role of Translocation 81 14.2 In Vitro Toxicity Studies 101 Physicochemical Characterization 81 14.3 In Vivo Toxicity Studies 102 3.1 General Concepts 81 15 Silicon Dioxide or Silica 3.2 Methods for Nanomaterial Nanoparticles 102

Characterization 82 15.1 Synthesis and Applications 102 3.3 Methods for Characterization of 15.2 In Vitro Toxicity Studies 103

Workplace Exposure 84 15.3 In Vivo Toxicity Studies 104 Methods for Toxicity Testing of 16 Semiconductor Nanocrystals 105 Nanoparticles 84 16.1 Synthesis and Applications 105 4.1 Test Methods: In Vitro versus In Vivo 84 16.2 In Vitro Toxicity Studies 106 4.2 High-Throughput Screening and 16.3 In Vivo Toxicity Studies 106

Modeling 84 17 Concluding Remarks 107 Gold Nanoparticles 85 Acknowledgments 108 5.1 Synthesis and Applications 85 References 108 5.2 Toxicity Studies In Vitro 86 5.3 Toxicity Studies In Vivo 87 Silver Nanoparticles 87 C H A P T E R 6.1 Synthesis and Applications 87

5 6.2 In Vitro Toxicity Studies 88 5 6.3 In Vivo Toxicity Studies 88 Platinum and Palladium Nanoparticles 89 Toxicity of Metals Released from Implanted 7.1 Synthesis and Applications 89 Medical Devices 7.2 In Vitro Toxicity Studies 90 RONALD P. BROWN, BRUCE A. FOWLER, SILVIA FUSTINONI, 7.3 In Vivo Toxicity Studies 90 AND MONICA NORDBERG Aluminum and Aluminum Oxide Nanoparticles 90 1 Background 113 8.1 Synthesis and Applications 90 1.1 Toxicological Implications of Metal Ions 8.2 In Vitro Toxicity Studies 90 and Wear Debris Released from Implanted 8.3 In Vivo Toxicity Studies 91 Metallic Devices 114

xvi Füll Contents

2 Toxicological Issues Associated with Metal Release from Specific Types of Implanted Medical Devices 115 2.1 Metallic Neurological Implants 115 2.2 Metallic Cardiovascular Implants 116 2.3 Metallic Orthopedic Implants 117 2.4 Metallic Dental Implants 118

3 Challenges and Future Directions 119 References 121

6 Health-Based Guidance Values and Benchmark Dose (Lower Confidence Limit) for Cadmium, Mercury, Lead, and Arsenic 137

7 Food Contamination from Packaging 138 7.1 Tin 138 7.2 Aluminum 138 7.3 Silver Nanoparticles 138 7.4 Nickel 138

8 Conclusion 138 References 139

C H A P T E R C H A P T E R

Toxic Metals in Food BRUCE A. FOWLER, JAN ALEXANDER, AND

AGNETA OSKARSSON

1 Introduction 2 Cadmium

2.1 Occurrence in the Food Chain 2.1.1 Exposure from Foodstuffs

2.2 Biomonitoring of Exposure 2.3 Toxicity 2.4 Risk Assessment

2.4.1 Flazard Characterization 2.4.2 Risk Characterization Risk Management 2.5

Lead 3.1 Occurrence in the Food Chain

3.1.1 Exposure from Foodstuffs Biomonitoring of Exposure Toxicity Risk Assessment 3.4.1 Hazard Characterization 3.4.2 Risk Characterization Risk Management

Mercury 4.1 Occurrence in the Food Chain

4.1.1 Exposure from Foodstuffs Toxicity Risk Assessment 4.3.1 Hazard Characterization 4.3.2 Risk Characterization Risk Management

Arsenic 5.1 Occurrence in the Food Chain

5.1.1 Exposure from Foodstuffs Toxicity Risk Assessment 5.3.1 Hazard Characterization 5.3.2 Risk Characterization Risk Management

3.2 3.3 3.4

3.5

4.2 4.3

4.4

5.2 5.3

5.4

123 124 124 126 126 127 128 128 128 128 128 129 129 130 130 130 130 131 131 131 131 132 133 133 133 134 134 134 135 135 136 136 136 136 137

Exposure Assessment, Forward and Reverse Dosimetry

PATRICIA RUIZ AND BRUCE A. FOWLER

1 Introduction 1.1 General Background

2 General Principles 3 Physiologically Based Pharmacokinetic

Modeling 4 Biomonitoring and Its Interpretation 5 Human PBPK Tool Kit Development: The

General Approach 5.1 Arsenic 5.2 Cadmium

5.2.1 Modeling Cadmium Biomonitoring Data

5.2.2 Application to Sensitive Subpopulations

5.2.3 Modeling Cadmium Intake Rates in Low- and High-Exposure Areas in Thailand

5.3 Mercury 5.4 Lead 5.5 Human PBPK Toolkit and the Exposome

6 Conclusions References

C H A P T E R

141 141 142

142 143

144 144 145

145

148

148 149 149 151 152 152

8

Biological Monitoring and Biomarkers TIINA SANTONEN, ANTERO AITIO, BRUCE A. FOWLER,

AND MONIC A NORDBERG

1 Introduction 155 2 Sources of Preanalytical and Analytical Error 158 3 Quality Assurance: Reference Materials 158

Füll Contents xvii

4 Specimens in Use 159 2 Interference with the Functions of Essential 4.1 Urine 159 Metals by Toxic Metals 175 4.2 Blood 160 2.1 Introduction 175 4.3 Other Matrices 161 2.2 Calcium 175

5 Reference Values and Biomonitoring 2.3 Zinc 176 Guidance Values 161 2.4 Magnesium 176 5.1 Reference Values 161 2.5 Iron 176 5.2 Biomonitoring Guidance Values 162 2.6 Copper 177

6 Biomarkers of Exposure 163 3 Toxic : Metal-Binding Molecules 177 6.1 Analytical Approaches 163 3.1 Introduction 177 6.2 Speciation in Biomonitoring 163 3.2 Metallothioneins 177 6.3 Kinetics and Sampling: Timing and 3.3 Glutathione 178

Frequency 163 3.4 Summary 179 6.4 Other Challenges Related to the Use of 4 Mutagenic and Genotoxic Effects of Metals 179

Exposure Biomarkers 164 4.1 Introduction 179 7 Biomarkers of Effects 164 4.2 Mutagenicity and Genotoxicity of Nickel

7.1 Renal Toxicity Biomarkers 164 Compounds 179 7.2 Neurotoxicity Biomarkers 165 4.3 Mutagenicity and Genotoxicity of 7.3 Lung Toxicity Biomarkers 165 Chromium Compounds 179 7.4 Biomarkers for Other Target Organs 166 4.4 Mutagenicity and Genotoxicity of 7.5 Genotoxicity Biomarkers 166 Arsenic 180 7.6 Challenges Related to Interpretation of 4.5 Mutagenicity and Genotoxicity of

Effect Biomarker Studies 166 Cadmium 180 8 Ethical Considerations 167 5 Epigenetic Effects of Metal Compounds 180 9 Biomonitoring in Health Risk Assessment 5.1 Introduction 180

and Management 167 5.2 Epigenetic Events in the Development 9.1 Biomonitoring in Occupational Risk of Cancer 181

Assessment 167 5.2.1 DNA Methylation 181 9.2 Biomonitoring in Environmental Health 168 5.2.2 Histone Modifications 181 9.3 Biomonitoring in Risk Management and 5.3 Impacts of Metal Compounds on

Policy Making 169 Epigenetics 182 10 Future Trends 169 5.3.1 Arsenite 182 Acknowledgments 169 5.3.2 Cadmium 183 References 169 5.3.3 Nickel 183

5.3.4 Cobalt 184 6 Effects of Metals on Cell Signaling Pathways

C H A P T E R and Gene Expression 184

9 6.1 Introduction 184

9 6.2 Signal Transduction Pathways Affected

Selected Molecular Mechanisms of Metal by Metal Compounds 6.2.1 Reactive Oxygen Species

184 184

Toxicity and Carcinogenicity 6.2.2 MAPK 185 TODD DAVIDSON, QINDONG KE, AND MAX COSTA 6.2.3 PI3K/Akt

6.2.4 HIF-1 185 185

l Transport of Toxic Metals by Molecular/Ionic 6.2.5 NF-KB 186 Mimicry of Essential Compounds 173 6.2.6 NF-AT 186 1.1 Introduction 173 6.2.7 AP-1 186 1.2 Iron 174 6.3 Impacts of Metal Compounds on Signal 1.3 Zinc 174 Transduction Pathways and Gene 1.4 Phosphate and Sulfate Mimics 174 Expression 187 1.5 Organic Complexes 175 6.3.1 Arsenite 187 1.6 Metal-Anion Complexes 175 6.3.2 Cadmium 188 1.7 Calcium Channels 175 6.3.3 Chromium 189 1.8 Summary 175 6.3.4 Cobalt 189

xviii Füll Contents

6.3.5 Nickel 190 2.2 Influence of Age and Sex on Metal 6.3.6 Other Metals 191 Toxicity 215

References 191 2.2.1 Age 215 2.2.2 Gender 216

2.3 Influence of Other Factors on Metal C H A P T E R Metabolism and Toxicity 217

10 3 Joint Metal-Metal Actions (Noncarcinogenic

10 Effects) 218 3.1 Arsenic and Other Metals 218

General Considerations of Dose-Effect and 3.2 Joint Action of Cadmium and Dose-Response Relationships Other Metals 219 DAPHNE B. MOFFETT, MOIZ M. MUMTAZ, 3.3 Joint Action of Lead and Other Metals 221

DEXTER W. SULLIVAN JR„ AND BRUCE A. FOWLER 3.4 3.5

Mercury and Other Metals Molybdenum-Copper-Zinc Interactions

222 223

l General Aspects of Dose-Response 3.6 Interactions between Thallium and Relationships 197 Potassium 223 1.1 Use of the Terms Effect and Response 197 4 Joint Metal Actions in Carcinogenesis 224 1.2 Interrelationships Among Dose, Effect, 4.1 Arsenic 224

and Response 198 4.2 Chromium 224 1.3 Definitions of Dose and Response 199 4.3 Iron 225

2 Modeling of Dose-Response Relationships 200 4.4 Lead 226 2.1 Shape of Dose-Response Curves: 4.5 Nickel 226

S, Hormesis, and U-Shaped 202 4.6 Selenium 227 2.2 The Sigmoid Curve 202 4.7 Zinc 229 2.3 Hormesis: Inverted U- or J-Shaped 5 Risk Assessment of Mixtures of Metals 230

Curves 203 5.1 Introduction 230 2.4 U-Shaped Curves and Essentiality 203 5.2 Toxicity Assessment of Mixtures 230

3 Modeling the Data 204 5.2.1 Mixture of Concern Approach 230 3.1 Biological Basis for Modeling 207 5.2.2 Similar Mixture Approach 230

4 Species-to-Species Extrapolations 208 5.2.3 Hazard Index Approach 231 5 Risk Assessment and Dose-Response 5.2.4 Target-Organ Toxicity Dose 231

Relationships 209 5.3 A Weight-of-Evidence Method 232 5.1 NOAEL/LOAEL Approach 210 5.3.1 Direction of Interaction 233 5.2 Benchmark Dose Approach 210 5.3.2 Mechanistic Understanding 233 5.3 Data Types and Benchmark Dose 211 5.3.3 Toxicological Significance 234

6 Dose Response in an Era of "Omics" 212 6 Perspectives and Future Needs 234 References 212 References 235

C H A P T E R

11

Interactions and Mixtures in Metal Toxicology

GUNNAR F. NORDBERG, LARS GERHARDSSON, MOIZ M. MUMTAZ, PATRICIA RUIZ, AND

BRUCE A. FOWLER

1 Introduction and General Considerations 213 2 Age, Gender, Drugs, and Other Factors 215

2.1 Influence of Drugs, Alcohol, and Tobacco on Metal Metabolism and Toxicity 215 2.1.1 Drugs 215 2.1.2 Alcohol and Tobacco 215

C H A P T E R

12

Gene-Environment Interactions for Metals

KARIN BROBERG, KARIN ENGSTRÖM, AND SHEGUFTA AMEER

1 Gene-Environment Interactions for Metals 239 1.1 Genes of Concern 240 1.2 Epigenetics of Metals 240 1.3 General Aspects of Gene-Environment

Interaction Studies: Example for Metals 241 1.3.1 Choice of Polymorphisms and

Method of Detection 241 1.3.2 Analysis and Interpretation 241

Füll Contents xix

Interactions of Specific Metals 242 7 Data Analysis and Assessment of the 2.1 Arsenic 242 Benchmark Dose 274

2.1.1 Arsenic (+3 Oxidation State) 7.1 Assessment of Benchmark Dose 275 Methyltransferase 243 7.2 Structural Equation Models 276

2.1.2 Genes Involved in the One-Carbon 8 Inference 277 Metabolism 244 References 278

2.1.3 Glutathione-Related Genes 244 2.1.4 Genes Involved in DNA Repair

and Defense Against Oxidative Stress 245

2.1.5 Other Genes 245 2.1.6 Epigenetic Effects of Arsenic 246

2.2 Beryllium 247 2.3 Cadmium 248

2.3.1 Genetic Influences on Cadmium Toxicokinetics and Toxicodynamics 248

2.3.2 Epigenetic Effects of Cadmium 249 2.4 Cobalt 249 2.5 Lead 250

2.5.1 ALAD 250 2.5.2 VDR 252 2.5.3 HFE and Other Iron Metabolism

Genes 252 2.5.4 Other Genes 253 2.5.5 Epigenetic Effects of Lead 254

2.6 Manganese 254 2.7 Mercury 255

2.7.1 Glutathione-Related and Other Genes and Mercury Toxicokinetics 255

2.7.2 Glutathione-Related and Other Genes and Mercury Toxicodynamics 256

2.7.3 Epigenetic Effects 258 2.8 Nickel 258 2.9 Platinum

3 Conclusions References

C H A P T E R

258 259 259

13

Epidemiological Approaches to Metal Toxicology

PHILIPPE GRANDJEAN AND ESBEN BUDTZ-J0RGENSEN

1 Introduction 2 Epidemiological Terms 3 Study Design 4 Study Population 5 Exposure Assessment 6 Assessment of Effects

265 266 267 268 270 272

C H A P T E R

14

Essential Metals: Assessing Risks from Deficiency and Toxicity

PETER AGGETT, GUNNAR F. NORDBERG, AND MONICA NORDBERG

1 Introduction 281 2 Basic Concepts 283

2.1 Definition of an Acceptable Range of Oral Intake 283 2.1.1 Basic U-Formed Dose-Response

Curve 283 2.1.2 Groups with Special Sensitivity

or Resistance 284 2.2 Other Concepts Used in Risk Assessment

of Essential Metals 285 2.2.1 Toxicological Terms 285 2.2.2 Nutritional Terms: Definitions

and Approaches Used to Assess Individual and Population Requirements for Essential Metals 285

3 Effects of Deficiency and Toxicity 286 3.1 Factors Affecting Dose-Response

Relationships 286 3.1.1 Homeostatic Mechanisms 287 3.1.2 Bioavailability, Speciation, and

Interactions 287 3.2 Basic Principles for Classifying Effect 287 3.3 Examples of Effects of Varying

Severity 289 3.3.1 Lethal Deficiency 289 3.3.2 Deficiency: Clinical Disease 289 3.3.3 Subclinical Biomarkers of

Deficiency with or without Clinical Significance

3.3.4 Lethal Toxic Effects 3.3.5 Toxic Effects with Clinical

Significance 3.3.6 Subclinical Toxic Effects with or

without Functional Significance: Biomarkers of Critical Effect

Summary of the Principles of Human Risk Assessment for Exposures to Essential Metals

289 290

290

290

290

XX Füll Contents

4.1 Application of Principles for the Determination of AROI

5 Estimation of the AROI 6 Conclusions and Recommendations References

C H A P T E R

15

Neurotoxicology of Metals ROBERTO G. LUCCHINI, MICHAEL ASCHNER,

DAVID C. BELLINGER, AND SAMUEL W. CAITO

1 From Neurophysiology to Neurotoxicology 1.1 Ana tomical Organization 1.2 Clinical and Preclinical Neurotoxic Effects 1.3 Central and Peripheral Neurotoxicity of

Metals 2 Central Nervous System Development and

Windows of Vulnerability 2.1 Clinical Effects and Early Signs of

Neurotoxicity 2.1.1 Neurobehavioral Testing

2.2 Neonatal Behavior 2.3 Infant Neurodevelopment 2.4 Intelligence Quotient 2.5 Attention 2.6 Learning and Memory 2.7 Language 2.8 Visuospatial Skills 2.9 Executive Functions 2.10 Motor Skills 2.11 Academic Skills

3 Mechanistic Bases of Metal Neurotoxicity 3.1 Cellular Uptake

5 Cadmium 316 291 6 Chromium 318 292 7 Cobalt 319 295 8 Iron 320 296 8.1 Weiders 320

9 Lead 321 10 Magnesium 321 11 Manganese 323 12 Mercury 324 13 Nickel 325 14 Selenium 326 15 Uranium 327 16 Zinc 327 17 Concluding Remarks 328

299 References 329

299 301

C H A P T E R

301

301

304 304 305 305 305 305 305 305 305 306 306 306 306 306

3.2 Intracellular Sequestration and Transport 307 3.3 Oxidative Stress 3.4 Effects on Mitochondria 3.5 Mechanistic Outcomes of Metal

Exposure References

307 308

308 309

C H A P T E R

16

Cardiovascular Disease BENGT SJÖGREN, CAROLINA BIGERT, AND PER GUSTAVSSON

1 Introduction 2 Aluminum 3 Arsenic 4 Beryllium

313 314 314 315

17

Renal Effects of Exposure to Metals LARS BARREGARD AND CARL-GUSTAF ELINDER

1 Introduction 333 2 Function of the Kidneys and

Indicators of Injury 334 2.1 Glomerular Filtration and Tubulär

Reabsorption 334 2.2 Indicators of Kidney Damage 335 2.3 Urinary Markers of Kidney Injury 335

2.3.1 Albumin 335 2.3.2 Low Molecular Weight Proteins

and Enzymes 336 2.4 Acute and Chronic Effects on Kidneys 336 2.5 Morphological Changes in the Kidneys 337

3 Renal Effects of Exposure to Metals 337 3.1 Lead 337 3.2 Cadmium 340

3.2.1 Glomerular Effects of Cadmium 340 3.2.2 Tubulär Effects 341 3.2.3 Renal Stones 342 3.2.4 Cadmium, Kidney Effects, and

Survival 342 3.3 Mercury 343

3.3.1 Glomerular Effects 343 3.3.2 Tubulär Dysfunction 344 3.3.3 Kidney Effects and Survival 345

3.4 Other Metals 345 3.4.1 Antimony 345 3.4.2 Arsenic 345 3.4.3 Bismuth 346 3.4.4 Chromium 346 3.4.5 Copper 347 3.4.6 Gold 347

Füll Contents xxi

3.4.7 3.4.8

References

Platinum Uranium

C H A P T E R

347 347 348

18

Carcinogenicity of Metal Compounds FREDA LAULICHT, JASON BROCATO, QINGDONG KE, AND

MAX COSTA

1 Principal Metals Showing Carcinogenic Effects 351 1.1 Nickel 352

1.1.1 Epidemiological Observations 352 1.1.2 Animal Models 353 1.1.3 In Vitro Studies 354 1.1.4 Evaluation 354

1.2 Chromium 355 1.2.1 Epidemiological Observations 355 1.2.2 Animal Models 356 1.2.3 In Vitro Studies 357 1.2.4 Evaluation 357

1.3 Arsenic 358 1.3.1 Epidemiological Observations 358 1.3.2 Animal Models 359 1.3.3 In Vitro Studies 360 1.3.4 Evaluation 360

1.4 Cadmium 361 1.4.1 Epidemiological Observations 361 1.4.2 Animal Models 363 1.4.3 In Vitro Studies 363 1.4.4 Evaluation 363

1.5 Beryllium 364 1.5.1 Epidemiological Observations 364 1.5.2 Animal Models 365 1.5.3 Evaluation 365

1.6 Lead 366 1.6.1 Epidemiological Observations 366 1.6.2 Animal Models and In Vitro

Studies 367 1.6.3 Evaluation 367

1.7 Cobalt 368 1.8 Iron 368 1.9 Manganese 369 1.10 Platinum 369 1.11 Titanium 370

2 Potential Mechanisms of Metal Carcinogenesis 370 2.1 Nickel 371 2.2 Chromium 371 2.3 Arsenic 371 2.4 Cadmium 371

3 Epigenetic Effects of Metals 3.1 Nickel 3.2 Arsenic 3.3 Cadmium 3.4 Chromium(VI)

References

C H A P T E R

372 372 373 373 373 374

19

Immunotoxicology of Metals PER HULTMAN AND K. MICHAEL POLLARD

379

379

1 Introduction 1.1 Development of the Concept of Metal

Immunotoxicology 1.2 Overview of Mechanisms in

Immunotoxicology 380 1.3 Dose-Response Considerations in Metal

Immunotoxicology 380 2 Immunosuppression Induced by Metals 381

2.1 General Considerations 381 2.2 In Vitro Studies 381 2.3 In Vivo Studies 381 2.4 Experimental Host Resistance Challenge

Systems 381 2.5 Clinical Immunosuppressive Effects 382

3 Nutritionally Essential Metals and the Immune System 382

4 Hypersensitivity Induced by Metals 383 4.1 General Considerations 383 4.2 Type I Hypersensitivity: Anaphylaxis or

Immediate Hypersensitivity 383 4.3 Type II Hypersensitivity: Antibody-

Mediated (IgG or IgM) Reactions against Cells or Matrix 383

4.4 Type III Hypersensitivity: Immune Complex-Mediated Reactions 383

4.5 Type IV Hypersensitivity: Cell-Mediated Reactions 383

4.6 Relationship between Atopy and Metal Hypersensitivity 384

5 Metals Causing Hypersensitivity Reactions 384 5.1 Beryllium 384 5.2 Chromium 385 5.3 Cobalt 385 5.4 Gold 385 5.5 Mercury 386 5.6 Nickel 387 5.7 Multiple Metal Exposures Related to

Prosthetic Devices 387 5.8 Platinum Group of Elements

(Palladium, Platinum) 388

Füll Contents xxii

6 Interaction between Metals and Proteins 388 6.1 Mechanisms of Interaction between

T Cells and Metal Ions 388 7 Other Interactions between Metals and

Proteins: Implications for Autoimmunity 389 8 Immunostimulation Induced by Metals: The

Examples of Pb, Hg, and Ni 390 9 Metal-Induced Autoimmunity 391 10 Acceleration and Aggravation of

Autoimmunity by Xenobiotics 392 10.1 General Considerations 392 10.2 Acceleration of Spontaneous

Autoimmune Diseases by Mercury 392 10.3 Effect of Cadmium, Lead, and Arsenic on

Spontaneous Autoimmune Diseases 393 10.4 Comments on the Autoimmune Effects

of Metals 393 Acknowledgments 393 References 394

C H A P T E R

20

Effects of Metallic Elements on Reproduction and Development PIETRO APOSTOLI AND SIMONA C ATALANI

1 Introduction 399 2 How to Measure Dose and Effect 400 3 Gender Differences 402 4 Mechanism of Action in Male and Female

Germinal Cells 403 4.1 Direct Mechanism of Spermatogenesis

Alterations 403 4.1.1 Reactive Oxygen Species as Part

of Infertility Assessments 404 4.1.2 Direct Toxicity to the Seminiferous

Tubules or Testis 405 4.1.3 Alteration to DNA-Protamine

Binding 406 4.1.4 Sperm Acrosome Reaction 406

4.2 Direct Effects on the Ovary and Ovarian Production 406

5 The Role of Hormones: Metallic Elements as Endocrine Disruptors 408

6 Conception 410 7 Other Effects on Pregnancy 412 8 Developmental Effects 414

8.1 Developmental Effects of Prenatal Exposure 414 8.1.1 Reactive Oxygen Species 414 8.1.2 Epigenetic Effects 415

8.1.3 Immune Suppression 8.1.4 Effects on Neurotransmitters

8.2 Developmental Effects of Neonatal Exposure

9 Concluding Remarks and the Need for Future Research

References

C H A P T E R

21

Ecotoxicology of Metals—Sources, Transport, and Effects on the Ecosystem

POUL BJERREGAARD, CHRISTIAN B.I. ANDERSEN, AND OLE ANDERSEN

1 Sources of Metal Emissions 1.1 Direct Emissions of Metals into Nature

1.1.1 Emissions to the Atmosphere 1.1.2 Emissions into Water 1.1.3 Emissions to Soil

1.2 Indirect Mobilization of Metals 1.2.1 Acid Rain 1.2.2 Oxygen Depletion 1.2.3 Pyrite Oxidation

2 The Biogeochemical Transport of Metals 2.1 Atmospheric Transport 2.2 Metal Speciation in Water 2.3 Metal Transport in the Ocean 2.4 Transport of Metals in Freshwater and

Estuaries 2.5 Metals in Sediments

3 Uptake and Accumulation of Metals 3.1 Bioavailability, Uptake, Accumulation,

and Elimination 3.2 Metal Transport in Aquatic Food

Chains 4 Defense Against and Storage of Metals

4.1 Metal Toxicity and Defense Systems in Plants

5 Toxicity of Metals in Ecosystems 5.1 Modeling Metal Toxicity 5.2 Overall Assessment of Metal Toxicity

in the Environment 6 Risk Assessment of Metals

6.1 The Aim of Ecotoxicological Risk Assessment

6.2 Integrated Risk Assessment 6.3 Methods of Ecotoxicology 6.4 Practical Risk Management 6.5 Biomarkers as Hazard Indicators in

Ecotoxicological Risk Assessment

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6.6 U.S. Environmental Protection Agency 8.18 Radioactive Metals 454 Ambient Water Quality Criteria 439 8.18.1 Cesium 454

6.7 European Union Water Framework 8.18.2 Polonium 454 Directive 439 8.18.3 Strontium 455

Monitoring Metal Pollution: 8.18.4 Transuranic Metals 455 Biomonitoring 439 References 455 7.1 Mussei Watch 439 7.2 Other Monitoring Organisms 440 Ecotoxicology of Individual Metals 440 C H A P T E R 8.1 Aluminum 440

22 8.2 Antimony 441 22 8.3 Arsenic 441 8.3 Cadmium 442 Risk Assessment

8.3.1 Background Levels GUNNAR F. NORDBERG AND BRUCE A. FOWLER and Emissions 442

8.3.2 Uptake in Organisms 443 1 Introduction 461 8.3.3 Contamination with 2 Exposure and Dose Assessment 462

Cadmium 443 2.1 Exposure and Dose Terminology 462 8.3.4 Cadmium Toxicity in Water 443 2.2 Exposure, Applied/Inhaled Dose, 8.3.5 Cadmium in Agricultural Soil and Daily Intake 463

and Uptake of Cadmium 2.3 Absorbed Dose, Internal Dose 463 into Plants 444 2.4 Dose/Concentration in Critical Organ

8.3.6 Implications for Human and Critical Target 464 Health 444 2.5 Use of Biomarkers for Estimating

8.4 Cobalt 445 Concentration in Critical Organs and the 8.5 Chromium 445 Critical Target Dose 464 8.6 Copper 445 3 Hazard Identification 464 8.7 Iron 446 3.1 Speciation 465 8.8 Lead 446 3.2 Mode of Action; Mechanism

8.8.1 Lead in Ammunition 447 of Action 465 8.8.2 Effects in Birds and Mammals 447 3.2.1 Mechanism of Action 465

8.9 Manganese 447 3.2.2 Mode of Action 466 8.10 Mercury

8.10.1 Background Concentrations, Uses, and Emissions

448

448

3.3 Human Data 3.3.1 Hill's Criteria of Causality 3.3.2 Causality for Cancer: IARC

466 467

8.10.2 The Transformation of Mercury Group 1 467 in Nature 448 3.4 Data from Studies on Acute and Chronic

8.10.3 The Global Mercury Flux 449 Toxicity in Animals, Cells, and Molecular 8.10.4 Uptake of Mercury in Systems In Vitro 467

Organisms and Transport in 3.4.1 In Vivo and In Vitro Data: Food Webs 450 Relevance For Humans 467

8.10.5 Effects of Mercury in 3.4.2 Chronology of Observations Wildlife 450 of Carcinogenicity of Metallic

8.10.6 Implications for Human Compounds 468 Health 451 3.4.3 IARC Group 2 468

8.11 Molybdenum 451 3.5 Classification in the European 8.12 Nickel 451 Union 470 8.13 Selenium 451 3.6 Classification According to the USEPA 8.14 Silver 451 (2014b) 470 8.15 Tin

8.15.1 Inorganic Tin 8.15.2 Tributyltin

452 452 452

3.7 Classification According to the American Conference of Governmental Industrial Hygienists

8.16 Vanadium 454 (ACGIH, 2013) 471 8.17 Zinc 454 3.8 In Vitro and In Silico Data 471

xxiv

4 Dose-Effect and Dose-Response Assessment 471 4.1 Concepts in Quantitative Toxicological

Analysis 471 4.1.1 Dose Effect and Dose Response 471 4.1.2 Critical Concentration, Critical

Organ, Critical Effect, Critical Endpoint, and No Observed Effect Level 472

4.1.3 Benchmark Dose and its Lower Confidence Limit 473

4.1.4 Critical Concentration on a Population Basis 474

4.2 Based on Short-Term and Long-Term Studies in Animals 475 4.2.1 Threshold-Type Critical Effects/

Critical End Points 475 4.2.2 Carcinogenesis and Other

Nonthreshold Effects 476 4.3 Probabilistic Estimation of Dose-

Response Relationships by Toxicokinetic and Toxicodynamic Modeling 478 4.3.1 Deterministic or Threshold-Type

Effects 479 4.3.2 Stochastic or Nonthreshold

Effects 479 4.4 Based on Epidemiological Studies 479

4.4.1 Sensitive Groups 480 4.4.2 Carcinogenic Effects 480

4.5 Newer Approaches to Risk Assessment 480

5 Risk Characterization 480 6 Risk Management and Risk

Communication 481 6.1 Managing Human Exposures by Emission

Control, Substitution, Labeling, or Restrictions in Use 481

6.2 Controlling Human Exposures by Guidelines and Legislated Permissible Exposure Levels 482

6.3 Risk Communication 484 References 484

C H A P T E R

23

Diagnosis and Treatment of Metal Poisoning: General Aspects

LARS GERHARDSSON AND GEORGE KAZANTZIS

1 Clinical Effects 488 1.1 General Considerations 488 1.2 Exposure Pattern and Clinical Effect 488

1.3 Acute Clinical Effects of Metals 489 1.3.1 Gastrointestinal Effects 489 1.3.2 Respiratory Effects 489 1.3.3 Cardiovascular Effects 490 1.3.4 Effects on the Central Nervous

System 490 1.3.5 Renal Effects 490 1.3.6 Hematopoietic Effects 490

1.4 Chronic Clinical Effects of Metal Toxicity 490 1.4.1 Gastrointestinal Effects 490 1.4.2 Hepatic Effects 490 1.4.3 Respiratory Effects 490 1.4.4 Effects on the Nervous System 491 1.4.5 Renal Effects 491 1.4.6 Hemopoietic Effects 491 1.4.7 Allergies 492 1.4.8 Effects on Skin 492 1.4.9 Effects on Bone 492

1.4.10 Cancer 493 Diagnosis of Metal Poisoning 493 2.1 History of Exposure 493 2.2 Clinical Features 494 2.3 Toxicological Analysis 494 2.4 Biochemical Investigation 495 2.5 Physiological Investigation 495 Treatment 495 3.1 Prevention of Further Absorption 495

3.1.1 Removal from Exposure 495 3.1.2 Minimizing Absorption from the

Gastrointestinal Tract 496 3.2 General Supportive Therapy 496

3.2.1 Maintenance of Respiration and Circulation 496

3.2.2 Maintaining Water and Electrolyt e Balance 496

3.2.3 Control of Nervous System Effects 496 3.3 Elimination of Absorbed Poison 497

3.3.1 Diuresis 497 3.3.2 Biliary Excretion 497 3.3.3 Dialysis 497 3.3.4 Exchange Transfusion 497

3.4 Inactivation of the Absorbed Poison 497 3.5 Chelation Therapy 498

3.5.1 Dimercaprol 498 3.5.2 Edetate Calcium Disodium 500 3.5.3 Diethylenetriaminepentaacetic

Acid 501 3.5.4 Penicillamine 501 3.5.5 Tetraethylenetetraamine 501 3.5.6 Deferoxamine 501 3.5.7 Deferiprone 502 3.5.8 Deferasirox 502 3.5.9 Sodium Diethyldithiocarbamate 502

3.5.10 Combinations of Chelating Agents 503

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Füll Contents XXV

3.6 Modification of Response 503 4 Prevention of the Effects of Metal Toxicity 3.6.1 Modification of Tissue Response 503 in the General Environment 517 3.6.2 Modification of Biochemical

Status 503 4.1 General Considerations 4.2 The Unique Vulnerability of Infants and

517

References 503 Children to Poisoning by Metals 517 4.3 Reduction of Environmental

Exposures 518 C H A P T E R 4.3.1 Reduction through Legislative

24 Authority 518

24 4.3.2 Source Control 4.3.3 Routes of Environmental

519

Principles for Prevention of the Toxic Contamination by Metals 519 Effects of Metals 4.4 Environmental Monitoring 520

PHILIP J. LANDRIGAN, ROBERTO G. LUCCHINI, DAVID 4.5 Public Education 520 KOTELCHUCK, AND PHILIPPE GRANDJEAN 4.6 Regulatory Authority 521

5 Perspectives on Precaution and Prevention 521 1 Introduction 508 5.1 Populations at Risk 521 2 General Principles for Prevention of the 5.2 Societal Costs 521

Toxic Effects of Metals 509 5.3 Precautionary Approaches 522 2.1 Hazard Identification 509 References 523

2.1.1 Lead 509 2.1.2 Methylmercury 510 2.1.3 Manganese 510 C H A P T E R

2.2 Reduction of Exposure 510 25 3 Prevention of the Effects of Metal Toxicity

in the Work Environment 511 25

3.1 General Considerations 511 Metal Toxicology in Developing 3.2 Reduction of Exposure 511 Countries

3.2.1 Elimination of Unnecessary Uses and the Substitution of Safer Materials 511

BRUCE A. FOWLER, CANDACE M. PRUSIEWICZ, AND MONICA NORDBERG

3.2.2 Reduced Use of Toxic Metals in Plant and Manufacturing Design 511

1 2 3

Introduction Overview of Public Health Problem Areas Developing Countries as Global Sources

529 530

3.2.3 Other Technical Control Measures 512

of Metals 3.1 Metal Mining Deposits

531 531

3.2.4 Local Exhaust Ventilation 512 3.2 Primary and Secondary Smelting 3.2.5 General Room Ventilation 512 Operations 535 3.2.6 Housekeeping 512 3.3 Recycling of Metal-Containing Products 536 3.2.7 Influence of Personal 3.3.1 Battery Recycling (Lead, Cadmium,

Hygiene on Metal Absorption and Nickel) 536 and Toxicity 513 3.4 E-Waste (Gallium Indium, Gold, and

3.2.8 Reduction of Worker Contact with Arsenic) 537 Toxic Metals, and Personal 4 Artisanal Gold Mining (Mercury—Occupational Protective Equipment 513 Exposures/Subsistence Fishing) 538

3.3 Monitoring of the Work 5 Uranium Mining 540 Environment 513 6 Agricultural Fertilizers 541 3.3.1 Air Sampling Strategy in the

Workplace 514 7 Methods for the Removal of Toxic

Metals from Wastewater Streams in 3.3.2 Sampling Technique 515 Developing Countries 542 3.3.3 Analysis 515 8 Needed Preventive Action and Research 3.3.4 Biological Monitoring 515 into the Toxicity of Metals in Humans 543 3.3.5 Health Examinations 515 References 543

3.4 Education and Training 516 3.5 Authority 516 Index il