목차
Preface v
Foreword: Outlook vii
List of Contributors xxxiii
List of Reviewers xxxix
Introduction---General Considerations and International Perspectives
Gunnar F. Nordberg
Bruce A. Fowler
Monica Nordberg
Lars T. Friberg
Metals and Health---An International Perspective 1
Current Concerns Related to the Toxicology of Metals 4
Expanding Current Industrial New Technological Uses of Metals 4
Ecological and Natural Environmental Mobilization Processes 4
Routes of Exposure 5
Essentiality of Metals 6
Human Health Effects 6
Metal Carcinogenesis and Reproductive Toxicology 7
Toxicokinetics and Metabolism 7
Biological Monitoring 8
Risk Assessment 8
Interactions Among Metals 8
General Chemistry, Sampling, Analytical Methods, and Speciation
Rita Cornelis
Definition of Metals 12
The Periodic Table 12
Compounds of Metallic Elements 13
Covalent and Ionic Bonds 13
Oxidation Number 14
Inorganic Compounds 14
Metal Complexes 15
Organometallic Compounds 15
Solubility 15
Properties of Metal Ions 16
Formation of Metal Ions 16
Redox Potential 16
Metal Ions as Lewis Acids 16
Hydrolysis 16
Other Aspects of Metal Chemistry of Biological and Toxicological Interest 17
Main Group and Transition Metals 17
Metal-Containing Biological Molecules 17
Metalloporphyrins 17
Non-Heme Iron Proteins 18
Cobalt-Containing Biological Molecules 18
Metalloenzymes and Metal-Activated Enzymes 18
Metallothioneins 18
Lead-Containing Biological Molecules 18
Total Element Analysis, Elemental Speciation, and Metallomics 18
Sampling and Sample Preparation 19
General Considerations 19
Air, Water, and Food 20
Air 20
Water 21
Food 21
Biological Monitoring 22
Separation Techniques 22
Liquid Chromatography 22
Gas Chromatography 23
Capillary Electrophoresis 23
Gel Electrophoresis 25
Precautionary Measures in Elemental Speciation 25
Detection Methods 26
General Aspects 26
Current Methods for the Detection of Metals 26
Atomic Absorption Spectrometry 26
Atomic Fluorescence Spectrometry 28
Atomic Emission Spectrometry 28
Mass Spectrometry 28
Electrochemical Methods 29
Spectrophotometry 29
Biosensors for Monitoring Metal Ions 30
Direct Measurement of Metals in Solid Samples (Particle Characterization) 30
Neutron Activation Analysis 30
Spark Source Mass Spectrometry 31
Calibration 31
Reference Materials 32
Quality Assurance 32
Definitions 33
Sources of Error 33
Results of Interlaboratory Testing 33
Elements of Quality Assurance 34
Statistical Considerations 34
Reporting of Quality Assurance Data 34
Conclusions 35
Routes of Exposure, Dose, and Metabolism of Metals
William S. Beckett
Thomas W. Clarkson
Introduction 39
Exposure 40
General Aspects 40
Exposure by Inhalation 41
Exposure Through Food and Drinking Water 42
Deposition and Absorption 42
Deposition and Absorption After Inhalation 43
Absorption of Gases and Vapors 44
Deposition of Particles 44
Clearance of Particles from the Respiratory System 46
Absorption After Ingestion 47
Total Absorption 49
Transport, Biotransformation, and Distribution 49
Pathways and Mechanisms of Excretion 52
Gastrointestinal Excretion 52
Renal Excretion 53
Excretion Rate---Biological Half-Time 54
Toxicokinetic Models and Their Use for Establishment of Dose-Response and Dose-Effect Relationships 55
One-Compartment Model 55
Description 55
Use of One-Compartment Model for Toxicokinetic (TK)---Toxicodynamic (TD) Modeling of Dose-Response or Dose-Effect Relationships 56
Multicompartment Models and Physiologically Based Models 57
Description of a Multicompartment Model for Cadmium 58
Use of Multicompartment and Physiologically Based Models for TK/TD Modeling 59
Use of Indicator Media for Estimation of Exposure or Critical Organ Concentration 59
Biological Monitoring and Biomarkers
Antero Aitio
Alfred Bernard
Introduction 65
Sources of Preanalytical and Analytical Error 67
Quality Assurance; Reference Materials 68
Specimens in Use; Urine Sample Standardization 69
Urine 69
Blood 70
Reference Values 71
Ethical Considerations 71
Biomarkers of Exposure 71
Analytical Approaches 71
Speciation in Biomonitoring 72
Kinetics and Sampling: Timing and Frequency 72
Interpretation of Results 72
Biomarkers of Exposure as a Complement to Industrial Hygiene Measurements 73
Biomarkers of Effects 74
Renal Toxicity Biomarkers 74
Neurotoxicity Biomarkers 75
Lung Toxicity Biomarkers 75
Biomarkers for Other Target Organs 76
Genotoxicity Biomarkers 76
Future Trends 76
Selected Molecular Mechanisms of Metal Toxicity and Carcinogenicity
Todd Davidson
Qingdong Ke
Max Costa
Transport of Toxic Metals by Molecular/Ionic Mimicry of Essential Compounds 79
Introduction 79
Iron 80
Zinc 80
Phosphate and Sulfate Mimics 80
Organic Complexes 80
Metal--Anion Complexes 81
Calcium Channels 81
Summary 81
Interference with the Functions of Essential Metals by Toxic Metals 81
Introduction 81
Calcium 81
Zinc 81
Magnesium 82
Iron 82
Copper 82
Toxic Metal--Binding Molecules 82
Introduction 82
Metallothioneins (MTs) 83
Glutathione 83
Summary 84
Mutagenic and Genotoxic Effects of Metals 84
Introduction 84
Mutagenicity and Genotoxicity of Nickel Compounds 85
Mutagenicity and Genotoxicity of Chromium Compounds 85
Mutagenicity and Genotoxicity of Arsenic 85
Mutagenicity and Genotoxicity of Cadmium 85
Epigenetic Effects of Metal Compounds 86
Introduction 86
Epigenetic Events in the Development of Cancer 86
DNA Methylation 86
Histone Modifications 86
Impacts of Metal Compounds on Epigenetics 87
As 87
Cd 88
Ni 88
Effects of Metals on Cell Signaling Pathways and Gene Expression 89
Introduction 89
Signal Transduction Pathways Affected by Metal Compounds 90
Ros 90
MAPK 90
PI3K/Akt 90
HIF-1 90
NF-kB 91
NFAT 91
AP-1 91
Impacts of Metal Compounds on Signal Transduction Pathways and Gene Expression 91
As 91
Cd 92
Cr 93
Co 94
Ni 94
Other Metals 95
General Considerations of Dose-Effect and Dose-Response Relationships
Daphne B. Moffett
Hisham A. El-Masri
General Aspects of Dose-Response Relationships 101
Use of the Terms Effect and Response 101
Interrelationships Among Dose, Effect, and Response 102
Definitions of Dose and Response 103
Modeling of Dose-Response Relationships 104
The Shape of Dose--Response Curves: S, Hormesis, U-Shaped 105
The Sigmoid Curve 106
Hormesis---Inverted U- or J-Shaped Curves 107
U-Shaped Curves and Essentiality 107
Modeling the Data 108
Biological Basis for Modeling 110
Species-to-Species Extrapolations 112
Risk Assessment and Dose-Response Relationships 113
NOAEL LOAEL 113
Benchmark Dose 113
Data Types and Benchmark Dose 114
Dose-Response in an Era of -Omics 114
Interactions in Metal Toxicology
Lars Gerhardsson
Karin Broberg
Moiz Mumtaz
Patricia Ruiz
Introduction 117
Age, Sex, Drugs, and Some Other Factors 118
Influence of Drugs, Alcohol, and Tobacco on Metal Metabolism and Toxicity 118
Drugs 118
Alcohol and Tobacco 119
Influence of Age and Sex on Metal Toxicity 119
Age 119
Sex 119
Influence of Some Other Factors on Metal Metabolism and Toxicity 120
Gene--Environment Interactions for Metals 120
Genes of Concern 120
Design of Gene--Environment Interaction Studies 121
Interactions for Specific Metals 122
Arsenic 122
Beryllium and Cobalt 123
Cadmium 123
Lead 123
Mercury 126
Nickel 126
Platinum 126
Conclusions 127
Metal--Metal Interactions (Noncarcinogenic Effects) 127
Arsenic and Other Metals 127
Interactions Between Cadmium and Other Metals 128
Interactions Between Lead and Other Metals 129
Hg and Other Metals 130
Molybdenum---Copper-Zinc Interactions 131
Interactions Between Thallium and Potassium 132
Metal---Metal Interactions in Carcinogenesis 132
Arsenic 132
Chromium 132
Iron 133
Lead 133
Nickel 134
Selenium 135
Zinc 136
Risk Assessment of Mixtures of Metals 137
Introduction 137
Toxicity Assessment of Mixtures 137
The Mixture of Concern 137
The Similar Mixture Approach 138
The Hazard Index Approach 138
The Target-Organ Toxicity Dose (TTD) 138
A Weight-of-Evidence (WOE) Method 139
Direction of Interaction 140
Mechanistic Understanding 140
Toxicological Significance 141
Perspectives and Future Needs 141
Epidemiological Methods for Assessing Dose-Response and Dose-Effect Relationships
Tord Kjellstrom
Philippe Grandjean
Epidemiological Measurement of Occurrence of Health Effects 147
Observational Studies and Modeling Studies of Dose-Response Relationships 149
Study Design 151
Data Collection 153
Measurement of Dose 153
Measurement of Effect and Response 155
Data Analysis 157
Inference 159
Essential Metals: Assessing Risks from Deficiency and Toxicity
George C. Becking
Introduction 163
Basic Concepts 164
Definition of an AROI (Acceptable Range of Oral Intake) 164
Groups with Special Sensitivity/Resistance 165
Other Concepts Used in Risk Assessment of Essential Metals 166
Toxicological Terms 166
Nutritional Terms: Definitions and Approaches Used to Assess Individual and Population Requirements for EMs 166
Effects of Deficiency and Toxicity 167
Factors Affecting Dose-Response Relationships 167
Homeostatic Mechanisms 167
Bioavailability, Speciation, and Interactions 167
Basic Principles for Classifying Effect 168
Examples of Effects of Varying Severity 169
Lethal Deficiency 169
Deficiency---Clinical Disease 169
Subclinical Biomarkers of Deficiency with or without Clinical Significance 170
Lethal Toxic Effects 170
Toxic Effects with Clinical Significance 170
Subclinical Toxic Effects with or without Functional Significance---Biomarkers of Critical Effect 170
Summary of Principles for Human Risk Assessment of Exposures to EMs 171
Application of Principles for Determination of AROI 171
Estimation of AROI 172
Conclusions 175
Carcinogenicity of Metal Compounds
George Kazantzis
Principal Metals Showing Carcinogenic Effects 177
Nickel 178
Epidemiological Observations 178
Animal Models 179
Evaluation 180
Chromium 180
Epidemiological Observations 180
Animal Models 181
Short-Term Tests 182
Evaluation 182
Arsenic 182
Epidemiological Observations 182
Animal Models 184
Short-Term Tests 184
Evaluation 185
Cadmium 185
Epidemiological Observations 185
Animal Models 187
Short-Term Tests 187
Evaluation 187
Beryllium 188
Epidemiology Observations 188
Animal Models 189
Evaluation 189
Lead 189
Epidemiological Observations 189
Animal Models and Short-Term Tests 190
Evaluation 190
Cobalt 190
Iron 191
Manganese 191
Platinum 192
Titanium 192
Principal Metals Showing Mutagenic Effects 192
Nickel 193
Chromium 193
Arsenic 193
Cadmium 194
Immunotoxicology of Metals
Per Hultman
Introduction 197
Development of the Concept Metal Immunotoxicology 197
Overview of Mechanisms in Immunotoxicology 198
Dose-Response Considerations in Metal Immunotoxicology 198
Immunosuppression Induced by Metals 199
General Considerations 199
In Vitro Studies 199
In Vivo Studies 199
Experimental Host-Resistance Challenge Systems 199
Clinical Immunosuppressive Effects 199
Essential Metals and the Immune System 200
Hypersensitivity Induced by Metals 200
General Considerations 200
Type I Hypersensitivity (Anaphylacticor Immediate Hypersensitivity) 200
Type II Hypersensitivity (Antibody-Mediated---IgG or IgM---Reactions Against Cells or Matrix) 201
Type III Hypersensitivity (Immune-Complex Mediated Reactions) 201
Type IV Hypersensitivity (Cell-Mediated Reactions) 201
Relation Between Atopy and Metal Hypersensitivity 201
Metals Causing Hypersensitivity Reactions 201
Beryllium 201
Chromium 202
Cobalt 202
Gold 202
Mercury 203
Nickel 203
Multiple Metal Exposure Relatedto Prosthetic Devices 203
The Platinum Group of Elements (Palladium, Platinum, Rhodium) 204
Interaction Between Metals and Proteins 204
Introduction 204
Mechanisms of Interaction Between T Cells and Metal Ions 204
Other Interactions Between Metals and Proteins---Implications for Autoimmunity 205
Nonspecific Immunostimulation Induced by Metals: The Examples of Pb and Hg 205
Metal-Induced Autoimmunity 206
Acceleration and Aggravation of Autoimmunity by Xenobiotics 207
General Considerations 207
Acceleration of Spontaneous Autoimmune Diseases by Hg 207
Acceleration of Spontaneous Autoimmune Diseases by Cadmium and Lead 208
Comments on the Autoimmune Effects of Metals 208
Reproductive and Developmental Toxicity of Metals
Pietro Apostoli
Spomenka Telisman
Polly R. Sager
Introduction 214
Male Reproductive Effects 215
Lead 216
Mercury 218
Cadmium 219
Manganese 220
Chromium 221
Nickel 221
Arsenic 221
Female Reproductive Effects 221
Lead 222
Mercury 224
Cadmium 224
Manganese 225
Chromium 225
Nickel 226
Arsenic 226
Platinum 227
Mixed Metal Exposure 227
Developmental Effects of Prenatal Exposure 228
Lead 229
Mercury 230
Cadmium 233
Chromium 233
Nickel 234
Arsenic 234
Vanadium 234
Uranium 235
Aluminum 235
Lithium 235
Developmental Effects from Neonatal Exposure 235
Lead 236
Mercury 238
Cadmium 240
Nickel 240
Arsenic 240
Aluminum 241
Mixed Metal and Multichemical Exposure 241
Ecotoxicology of Metals---Sources, Transport, and Effects in the Ecosystem
Poul Bjerregaard
Ole Andersen
Sources for Metal Emission 251
Direct Emissions of Metals into Nature 251
Emissions to the Atmosphere 251
Emissions into Water 252
Emissions to Soil 252
Indirect Mobilization of Metals 252
Acid Rain 252
Oxygen Depletion 252
Pyrite Oxidation 252
The Biogeochemical Transport of Metals 252
Atmospheric Transport 252
Metal Speciation in Water 253
Metal Transport in the Ocean 254
Transport of Metals in Freshwater and Estuaries 254
Metals in Sediments 256
Uptake and Accumulation of Metals 256
Bioavailability, Uptake, Accumulation, and Elimination 256
Metal Transport in Aquatic Food Chains 257
Defense Against and Storage of Metals 257
Metal Toxicity and Defense Systems in Plants 258
Toxicity of Metals in Ecosystems 259
Risk Assessment of Metals 260
The Aim of Ecotoxicological Risk Assessment 260
Integrated Risk Assessment 260
Methods of Ecotoxicology 260
Practical Risk Management 261
Biomarkers as Hazard Indicators in Ecotoxicological Risk Assessment 261
Monitoring Metal Pollution---Biomonitoring 262
Mussel Watch 262
Other Monitoring Organisms 263
Ecotoxicology of Individual Metals 263
Alumina 263
Antimony 264
Arsenic 264
Cadmium 265
Background Levels and Emissions 265
Uptake in Organisms 265
Contamination with Cadmium 266
Cadmium's Toxicity in Water 266
Cadmium in Agricultural Soil and Uptake of Cadmium into Plants 266
Implication for Human Health 267
Cobalt 267
Chromium 267
Copper 268
Iron 268
Lead 268
Lead in Ammunition 269
Effects in Birds and Mammals 269
Manganese 269
Mercury 270
Background Concentrations, Uses, and Emissions 270
The Transformation of Mercury in Nature 270
The Global Mercury Flux 271
Uptake of Mercury in Organisms and Transport in Food Webs 272
Effects of Mercury in Wildlife 272
Implications for Human Health 273
Molybdenum 273
Nickel 273
Selenium 273
Silver 273
Tin 274
Inorganic Tin 274
Tributyltin (TBT) 274
Vanadium 276
Zinc 276
Radioactive Metals 276
Cesium 276
Polonium 276
Strontium 277
Transuranic Metals 277
Risk Assessment
Introduction 281
Exposure and Dose Assessment 282
Exposure and Dose Terminology 282
Expoure, Applied/Inhaled Dose, Daily Intake 282
Absorbed Dose, Internal Dose 283
Dose/Concentration in Critical Organ and Critical Target 283
Use of Biomarkers in Estimating Concentration in Critical Organ and Critical Target Dose 283
Hazard Identification 284
Speciation 284
Human Data 285
Data from Studies on Acute and Chronic Toxicity in Animals, Cells, and Molecular Systems In Vitro 285
IARC Group 2 286
IARC Group 2A: The Agent is Probably Carcinogenic to Humans 287
IARC Group 2B: The Agent is Possibly Carcinogenic to Humans 287
Classification According to the European Union 288
Classification According to the USEPA 288
Classification According to the American Conference of Governmental Industrial Hygienists, Inc 288
Dose-Effect and Dose-Response Assessment 289
Concepts in Quantitative Toxicological Analysis 289
Dose Effect and Dose Response 289
Critical Concentration, Critical Organ, Critical Effect, and No-Observed-Effect Level 289
Benchmark Dose 290
The Critical Concentration on a Population Basis 292
Based on Short-Term and Long-Term Studies in Animals 293
Threshold-Type Critical Effects 293
Carcinogenesis and Other Nonthreshold Effects 294
Probabilistic Estimation of Dose-Response Relationships by Toxicokinetic (TK) and Toxicodynamic (TD) Modeling 295
Deterministic or Threshold-Type Effects 295
Stochastic or Nonthreshold Effects 296
Based on Epidemiological Studies 296
Sensitive Groups 296
Carcinogenic Effects 296
Simplified Approach as an Alternative to Risk Assessment 296
Risk Characterization 297
Risk Management and Risk Communication 297
Managing Human Exposures by Emission Control, Substitution, Labeling, or Restrictions in Use 297
Controlling Human Exposures by Guidelines and Legislated Permissible Exposure Levels 298
Risk Communication 300
Diagnosis and Treatment of Metal Poisoning---General Aspects
Clinical Effects 304
General Considerations 304
Exposure Pattern and Clinical Effect 304
Acute Clinical Effects of Metals 305
Gastrointestinal Effects 305
Respiratory Effects 305
Cardiovascular Effects 305
Effects on the Central Nervous System 306
Renal Effects 306
Hemopoietic Effects 306
Chronic Clinical Effects of Metal Toxicity 306
Gastrointestinal Effects 306
Hepatic Effects 306
Respiratory Effects 306
Effects on the Nervous System 307
Renal Effects 307
Hemopoietic Effects 307
Diagnosis of Metal Poisoning 307
History of Exposure 308
Clinical Features 308
Toxicological Analysis 309
Biochemical Investigation 309
Physiological Investigation 309
Treatment 310
Prevention of Further Absorption 310
Removal from Exposure 310
Minimizing Absorption from the Gastrointestinal Tract 310
General Supportive Therapy 310
Maintenance of Respiration and Circulation 311
Maintenance of Water and Electrolyte Balance 311
Control of Nervous System Effects 311
Elimination of Absorbed Poison 311
Diuresis 311
Biliary Excretion 311
Dialysis 311
Exchange Transfusion 312
Inactivation of the Absorbed Poison 312
Chelation Therapy 312
Dimercaprol 312
Calcium Disodium Edetate (Calcium EDTA) 314
Penicillamine (Cuprimine) 315
Triethylene Tetramine (Trien, TETA) 315
Desferrioxamine (DFOA) 315
Deferiprone (L1) 316
Diethylenetriaminepentaacetic Acid (DTPA) 316
Diethyldithiocarbamate (DEDTC) 316
Combinations of Chelating Agents 316
Modification of Response 316
Modification of Tissue Response 316
Modification of Biochemical Status 317
Principles for Prevention of the Toxic Effects of Metals
Philip J. Landrigan
David Kotelchuck
Introduction 319
General Principles for Prevention of the Toxic Effects of Metals 320
Hazard Identification 321
Lead 321
Methylmercury 321
Arsenic 321
Reduction of Exposure 322
Prevention of the Effects of Metal Toxicity in the Work Environment 322
General Considerations 322
Elimination of Unnecessary Uses and Substitution of Safer Materials 322
Reduced Use of Toxic Metals in Plant and Manufacturing Design 323
Other Technical Control Measures 323
Local Exhaust Ventilation 323
General Room Ventilation 323
Housekeeping 324
Influence of Personal Hygiene on Metal Absorption and Toxicity 324
Reduction of Worker Contact with Toxic Metals and Personal Protective Equipment 324
Monitoring of the Work Environment 325
Air Sampling Strategy in the Workplace 325
Sampling Technique 326
Analysis 326
Biological Monitoring 326
Health Examinations 327
Training 327
Authority 327
Prevention of the Effects of Metal Toxicity in the General Environment 328
General Considerations 328
The Unique Vulnerability of Infants and Children to Poisoning by Metals 328
Reduction of Exposure 328
Elimination or Reduction of Use 328
Source Control 329
Routes of Environmental Contamination by Metals 329
Environmental Monitoring 330
Public Education 331
Regulatory Authority 331
Perspectives on Precaution and Prevention 331
Populations at Risk 331
Widening Implications of Subclinical Toxicity 332
Precautionary Approaches 332
Aluminum
Bengt Sjogren
Anders Iregren
Carl-Gustaf Elinder
Robert A. Yokel
Physical and Chemical Properties 339
Methods and Problems of Analysis 339
Production and Use 340
Dietary, Environmental, and Occupational Exposure 341
Metabolism 341
Absorption 341
Distribution 342
Excretion 342
Biological Monitoring 342
Effects 343
Gastrointestinal Symptoms 343
Restrictive Pulmonary Disease 344
Obstructive Pulmonary Disease 345
Central Nervous System 346
Dialysis Encephalopathy 346
Other Medical Aluminum Exposures 346
Neurobehavioral Effects of Occupational Aluminum Exposure 347
Alzheimer's Disease 348
Bone 348
Hematopoietic Tissue 348
Skin 348
Allergic Effects 348
Coronary Heart Disease 349
Carcinogenic Effects 349
Other Aluminum Compounds 349
Recommendations 349
Antimony
Carolyn A. Tylenda
Physical and Chemical Properties 353
Methods and Problems of Analysis 353
Production and Uses 354
Historical Background 354
Production 354
Uses 355
Environmental Levels and Exposures 355
General Environment 355
Food and Daily Intake 355
Air, Soil, and Water 355
Tobacco 356
Working Environment 356
Metabolism 356
Absorption 356
Inhalation 356
Ingestion 357
Distribution 357
Animals 357
Humans 357
Excretion 358
Animals 358
Humans 358
Biological Half-Life 358
Humans 359
Biological Monitoring 359
Effects and Dose-Response Relationships 360
Animals 360
Local Effects and Dose-Response Relationships 360
Systemic Effects and Dose-Response Relationships 360
Humans 361
Local Effects and Dose-Response Relationships 361
Systemic Effects and Dose-Response Relationships 362
Adverse Effects During Antimony Treatment 362
Carcinogenic and Genotoxic Effects 362
Arsenic
C.-H. Selene J. Chou
Robert L. Jones
C.-J. Chen
Physical and Chemical Properties 368
Methods and Problems of Analysis 368
Production and Uses 369
Production 369
Uses 369
Environmental Levels and Exposures 369
Food and Daily Intake 369
Water 370
Soil 371
Air 371
Tobacco 372
Metabolism 373
Absorption 373
Inhalation 373
Ingestion 373
Skin Absorption 373
Transport and Distribution 374
Biotransformation 374
Excretion 375
Biological Half-Time 376
Mechanisms of Arsenical Toxicity 376
Mechanisms of Arsenical Metabolism and Toxicity 376
Metabolism 376
Mechanisms of Arsenical Toxicity 377
Biological Monitoring 380
Organs 380
Urine 380
Blood 381
Hair 381
Effects 382
Lethality 382
Acute and Subacute Effects 383
Chronic Noncardiovascular Effects 383
Dermal Effects 383
Gastrointestinal Effects 383
Neural Effects 384
Hepatic Effects 384
Hematological Effects 384
Respiratory Effects 384
Metabolic Effects 384
Immunological Effects 385
Ophthalmic Effects 385
Chronic Cardiovascular Effects 385
Cardiac Effects 386
Peripheral Vascular Diseases 386
Ischemic Heart Diseases 386
Stroke 387
Carotid Atherosclerosis 387
Hypertension 387
Microcirculation Abnormality 387
Carcinogenic Effects 388
Skin Cancer 388
Lung Cancer 388
Urothelial Cancer 389
Liver Cancer 389
Other Internal Cancers 390
Lifetime Cancer Risk Induced by Arsenic 390
Experimental System Cancer Studies 391
Developmental and Reproductive Effects 391
Genotoxic Effects and Mutagenicity 392
Interaction Between Arsenic and Other Compounds 392
Dose-Effect and Dose-Response Relationship in Arsenic Poisoning 393
Diagnosis, Treatment, and Prognosis 395
Acute Poisoning 395
Inhalation Diagnosis 395
Ingestion Diagnosis 396
Chronic Poisoning 396
Diagnosis 396
Treatment and Prognosis 396
Arsine 397
Experimental Model Studies 397
Barium
Agneta Oskarsson
Andrew L. Reeves
Physical and Chemical Properties 407
Methods and Problems of Analysis 408
Production and Uses 408
Production 408
Uses 408
Environmental Levels and Exposures 408
General Environment 408
Soil, Water, and Air 408
Plants, Animals, and Dietary Intake 409
Working Environment 409
Kinetics 409
Absorption 409
Inhalation 409
Ingestion 409
Parenteral Administration 410
Transport and Distribution 410
Excretion 410
Biological Monitoring 410
Effects and Dose-Response Relationships 411
Humans 411
Acute Effects 411
Chronic Effects 411
Animals 412
Inhalation 412
Ingestion 412
Treatment 413
Beryllium
Marek Jakubowski
Cezary Palczynski
Physical and Chemical Properties 416
Methods and Problems of Analysis 416
Production and Uses 416
Production 416
Uses 417
Environmental Levels and Exposures 417
General Environment 417
Soil, Water, and Air 417
Plants, Animals, and Dietary Intake 418
Estimates of Daily Exposure 418
Working Environment 418
Kinetics 419
Absorption 419
Dermal Exposure 419
Inhalation 419
Ingestion 420
Transport, Distribution, and Excretion 420
Levels in Tissues and Biological Fluids---Biological Monitoring 421
Effects and Dose-Response Relationships 421
Local Effects 422
Skin Contact 422
Inhalation 422
Systemic Effects 423
Acute Effects 423
Chronic Beryllium Disease (CBD, Chronic Pulmonary Granulomatosis, Berylliosis) 423
Other Chronic Systemic Effects 424
Carcinogenic Effects 425
Humans 425
Animals 426
Genotoxic Effects 426
Mechanisms of Toxic Action 427
Biomarkers of Effect 427
Biomarkers of Susceptibility 428
Diagnosis and Treatment 428
Treatment 428
Bismuth
Mary J. Sexton
Physical and Chemical Properties 433
Methods and Problems of Analysis 433
Production and Uses 434
Production 434
Uses 434
Environmental Levels and Exposures 435
General Environment 435
Food 435
Ambient Air, Water, Soil, and Rocks 435
Pharmaceuticals and Cosmetics 435
Working Environment 435
Metabolism 435
Absorption 435
Distribution 435
Excretion 436
Biological Half-Times 436
Biological Monitoring 436
Effects and Dose-Response Relationships 437
Local Effects and Dose-Response Relationships 437
Animals 437
Humans 437
Systemic Effects and Dose-Response Relationships 438
Animals 438
Humans 440
Carcinogenicity, Teratogenicity, and Mutagenicity 441
Treatment of Bismuth Poisoning 441
Cadmium
Koji Nogawa
Physical and Chemical Properties 446
Methods and Problems of Analysis 446
Production and Uses 447
Production 447
Uses 447
Environmental Levels and Exposures 448
General Environment 448
Food and Daily Intake 448
Water and Soil 450
Ambient Air 451
Tobacco 451
Working Environment 451
Toxicokinetics 452
Absorption 452
Inhalation 452
Ingestion 453
Transport and Distribution 453
Systemic Transport 453
Distribution 455
Excretion 457
Biological Half-Life 457
Mathematical Models for Cd Accumulation in Renal Cortex and Other Tissues 458
Biological Monitoring 459
Biomarkers of Exposure 459
Cd in Blood 459
Cd in Urine 460
Cadmium in Placenta 460
Cd in Hair, Feces, and Other Biological Materials 461
Cd in Kidney and Liver, Measured In Vivo, Body Burden 461
Biomarkers of Effects 461
Effects and Dose-Response Relationship 463
Acute Poisoning 463
Inhalation 463
Ingestion 463
Chronic Poisoning 463
General Aspects 463
Pulmonary Disorders 463
Kidney Damage 464
Anemia 465
Blood Pressure 465
Liver Disturbances 466
Effects on Bone 466
Itai-Itai Disease 468
Cadmium and the Central and Peripheral Nervous System 469
Reproductive and Developmental Effects 470
Carcinogenic Effects 471
Genetic Effects 472
Interaction Between Cadmium and Other Metals 472
Cadmium-Zinc-Metallothionein, Iron, and Calcium 472
Interaction Between Arsenic and Cadmium 473
Dose-Response Relationships 473
Critical Concentration in the Kidney and Toxicokinetic Model 473
Direct Observations of Dose-Response and Risk Characterization 474
Life Prognosis 478
Diagnosis, Treatment, Prognosis, and Prevention 479
Acute Poisoning 479
Inhalation 479
Ingestion 479
Chronic Intoxication 479
Diagnosis 479
Treatment, Prognosis, and Prevention 479
Chromium
Sverre Langard
Physical and Chemical Properties 487
Methods of Chemical Analysis 488
Manufacture and Uses 488
Manufacture 488
Uses 489
Concentrations in the Environment 489
Occurrence in Natural Environments and Soil 489
Concentrations in Food 489
Water and Ambient Air 489
Tobacco 489
Daily Intake in Humans 489
Work-Related Exposure 490
Uptake and Metabolism 490
Dietary Intake 490
Inhalation 491
Distribution 491
Excretion and Biological Half-Life 491
Concentrations in Biological Fluids and Tissues 492
Dose and Outcome Effects 492
Local Effects 493
Animals 493
Humans 493
Systemic Effects and Dose-Effect and Dose-Response 494
Animals 494
Humans 495
Carcinogenic, Mutagenic, and Teratogenic Effects 495
Animals 495
Humans 496
Interaction with Other Carcinogenic Factors 505
Mutagenic and Genotoxic Effects 505
Teratogenic Effects 505
Biological Monitoring 506
Biomarkers of Exposure 506
Biomarkers of Effects 506
Cellular Mechanism of Toxicity and Carcinogenicity 506
Molecular Toxicology of Cr 506
Diagnosis, Treatment, Prognosis, and Prevention 507
Cobalt
Dominique Lison
Physical and Chemical Properties 511
Analytical Methods 512
Production and Uses 513
Production 513
Uses 513
Environmental Levels and Exposures 513
General Environment 513
Food and Daily Intake 513
Soil, Ambient Air, and Water 513
Occupational Environment 514
Metabolism 514
Absorption 514