Preface ......................................................... V
Foreword: Outlook ............................................. vii
List of Contributors ....................................... xxxiii
List of Reviewers ........................................... xxxix
СHAPTER 1. Introduction-General Considerations and
International Perspectives
GUNNAR F. NORDBERG, BRUCE A. FOWLER, MONICA
NORDBERG, AND LARS T. FRIBERG
1. Metals and Health-An International Perspective ............... 1
2. Current Concerns Related to the Toxicology of Metals ......... 4
2.1. Expanding Current Industrial New Technological Uses
of Metals ............................................... 4
2.2. Ecological and Natural Environmental Mobilization
Processes ............................................... 4
2.3. Routes of Exposure ...................................... 5
2.4. Essentiality of Metals .................................. 6
2.5. Human Health Effects .................................... 6
2.6. Metal Carcinogenesis and Reproductive Toxicology ........ 7
2.7. Toxicokinetics and Metabolism ........................... 7
2.8. Biological Monitoring ................................... 8
2.9. Risk Assessment ......................................... 8
2.10.Interactions Among Metals ............................... 8
CHAPTER 2. General Chemistry, Sampling, Analytical Methods,
and Speciation
RITA CORNELIS AND MONICA NORDBERG
1. Definition of Metals ........................................ 12
2. The Periodic Table .......................................... 12
3. Compounds of Metallic Elements .............................. 13
3.1. Covalent and Ionic Bonds ............................... 13
3.2. Oxidation Number ....................................... 14
3.3. Inorganic Compounds .................................... 14
3.4. Metal Complexes ........................................ 15
3.5. Organometallic Compounds ............................... 15
4. Solubility .................................................. 15
5. Properties of Metal Ions .................................... 16
5.1. Formation of Metal Ions ................................ 16
5.2. Redox Potential ........................................ 16
5.3. Metal Ions as Lewis Acids .............................. 16
5.4. Hydrolysis ............................................. 16
6. Other Aspects of Metal Chemistry of Biological and
Toxicological Interest ...................................... 17
6.1. Main Group and Transition Metals ....................... 17
6.2. Metal-Containing Biological Molecules .................. 17
6.2.1. Metalloporphyrins ............................... 17
6.2.2. Non-Heme Iron Proteins .......................... 18
6.2.3. Cobalt-Containing Biological Molecules .......... 18
6.2.4. Metalloenzymes and Metal-Activated Enzymes ...... 18
6.2.5. Metallothioneins ................................ 18
6.2.6. Lead-Containing Biological Molecules ............ 18
7. Total Element Analysis, Elemental Speciation, and
Metallomics ................................................. 18
8. Sampling and Sample Preparation ............................. 19
8.1. General Considerations ................................. 19
8.2. Air, Water, and Food ................................... 20
8.2.1. Air ............................................. 20
8.2.2. Water ........................................... 21
8.2.3. Food ............................................ 21
8.3. Biological Monitoring .................................. 22
9. Separation Techniques ...................................... 22
9.1. Liquid Chromatography .................................. 22
9.2. Gas Chromatography ..................................... 23
9.3. Capillary Electrophoresis .............................. 23
9.4. Gel Electrophoresis .................................... 25
9.5. Precautionary Measures in Elemental Speciation ......... 25
10.Detection Methods ........................................... 26
10.1.General Aspects ........................................ 26
10.2.Current Methods for the Detection of Metals ............ 26
10.2.1.Atomic Absorption Spectrometry .................. 26
10.2.2.Atomic Fluorescence Spectrometry ................ 28
10.2.3.Atomic Emission Spectrometry .................... 28
10.2.4.Mass Spectrometry ............................... 28
10.2.5.Electrochemical Methods ......................... 29
10.2.6.Spectrophotometry ............................... 29
10.2.7.Biosensors for Monitoring Metal Ions ............ 30
10.2.8.Direct Measurement of Metals in Solid Samples
Particle Characterization) ...................... 30
10.2.9.Neutron Activation Analysis ..................... 30
10.2.10.Spark Source Mass Spectrometry ................. 31
11.Calibration ................................................. 31
12.Reference Materials ......................................... 32
13.Quality Assurance ........................................... 32
13.1.Definitions ............................................ 33
13.2.Sources of Error ....................................... 33
13.3.Results of Interlaboratory Testing ..................... 33
13.4.Elements of Quality Assurance .......................... 34
13.5.Statistical Considerations ............................. 34
13.6.Reporting of Quality Assurance Data .................... 34
14.Conclusions ................................................. 35
CHAPTER 3. Routes of Exposure, Dose, and Metabolism of
Metals
WILLIAM S. BECKETT, GUNNAR F. NORDBERG, AND
THOMAS W. CLARKSON
1. Introduction ................................................ 39
2. Exposure .................................................... 40
2.1. General Aspects ........................................ 40
2.2. Exposure by Inhalation ................................. 41
2.3. Exposure Through Food and Drinking Water ............... 42
3. Deposition and Absorption ................................... 42
3.1. Deposition and Absorption After Inhalation ............. 43
3.1.1. Absorption of Gases and Vapors .................. 44
3.1.2. Deposition of Particles ......................... 44
3.1.3. Clearance of Particles from the Respiratory
System .......................................... 46
3.2. Absorption After Ingestion ............................. 47
3.3. Total Absorption ....................................... 49
4. Transport, Biotransformation, and Distribution .............. 49
5. Pathways and Mechanisms of Excretion ........................ 52
5.1. Gastrointestinal Excretion ............................. 52
5.2. Renal Excretion ........................................ 53
5.3. Excretion Rate-Biological Half-Time .................... 54
6. Toxicokinetic Models and Their Use for Establishment of
Dose-Response and Dose-Effect Relationships ................. 55
6.1. One-Compartment Model .................................. 55
6.1.1. Description ..................................... 55
6.1.2. Use of One-Compartment Model for
Toxicokinetic (TK)-Toxicodynamic (TD)
Modeling of Dose-Response or Dose-Effect
Relationships ................................... 56
6.2. Multicompartment Models and Physiologically Based
Models ................................................. 57
6.2.1. Description of a Multicompartment Model for
Cadmium ......................................... 58
6.2.2. Use of Multicompartment and Physiologically
Based Models for TK/TD Modeling ................. 59
7. Use of Indicator Media for Estimation of Exposure or
Critical Organ Concentration ................................ 59
CHAPTER 4. Biological Monitoring and Biomarkers
ANTERO AITIO, ALFRED BERNARD, BRUCE A.
FOWLER, AND GUNNAR F. NORDBERG
1. Introduction ................................................ 65
2. Sources of Preanalytical and Analytical Error ............... 67
3. Quality Assurance; Reference Materials ...................... 68
4. Specimens in Use; Urine Sample Standardization .............. 69
4.1. Urine .................................................. 69
4.2. Blood .................................................. 70
5. Reference Values ............................................ 71
6. Ethical Considerations ...................................... 71
7. Biomarkers of Exposure ...................................... 71
7.1. Analytical Approaches .................................. 71
7.2. Speciation in Biomonitoring ............................ 72
7.3. Kinetics and Sampling: Timing and Frequency ............ 72
7.4. Interpretation of Results .............................. 72
7.5. Biomarkers of Exposure as a Complement to Industrial
Hygiene Measurements ................................... 73
8. Biomarkers of Effects ....................................... 74
8.1. Renal Toxicity Biomarkers .............................. 74
8.2. Neurotoxicity Biomarkers ............................... 75
8.3. Lung Toxicity Biomarkers ............................... 75
8.4. Biomarkers for Other Target Organs ..................... 76
8.5. Genotoxicity Biomarkers ................................ 76
9. Future Trends ............................................... 76
CHAPTER 5. Selected Molecular Mechanisms of Metal Toxicity
and Carcinogenicity
TODD DAVIDSON, QINGDONG KE, AND MAX COSTA
1. Transport of Toxic Metals by Molecular/Ionic Mimicry
of Essential Compounds ...................................... 79
1.1. Introduction ........................................... 79
1.2. Iron ................................................... 80
1.3. Zinc ................................................... 80
1.4. Phosphate and Sulfate Mimics ........................... 80
1.5. Organic Complexes ...................................... 80
1.6. Metal-Anion Complexes .................................. 81
1.7. Calcium Channels ....................................... 81
1.8. Summary ................................................ 81
2. Interference with the Functions of Essential Metals by
Toxic Metals ................................................ 81
2.1. Introduction ........................................... 81
2.2. Calcium ................................................ 81
2.3. Zinc ................................................... 81
2.4. Magnesium .............................................. 82
2.5. Iron ................................................... 82
2.6. Copper ................................................. 82
3. Toxic Metal-Binding Molecules ............................... 82
3.1. Introduction ........................................... 82
3.2. Metallothioneins (MTs) ................................. 83
3.3. Glutathione ............................................ 83
3.4. Summary ................................................ 84
4. Mutagenic and Genotoxic Effects of Metals ................... 84
4.1. Introduction ........................................... 84
4.2. Mutagenicity and Genotoxicity of Nickel Compounds ...... 85
4.3. Mutagenicity and Genotoxicity of Chromium Compounds .... 85
4.4. Mutagenicity and Genotoxicity of Arsenic ............... 85
4.5. Mutagenicity and Genotoxicity of Cadmium ............... 85
5. Epigenetic Effects of Metal Compounds ....................... 86
5.1. Introduction ........................................... 86
5.2. Epigenetic Events in the Development of Cancer ......... 86
5.2.1. DNA Methylation ................................. 86
5.2.2. Histone Modifications ........................... 86
5.3. Impacts of Metal Compounds on Epigenetics .............. 87
5.3.1. As .............................................. 87
5.3.2. Cd .............................................. 88
5.3.3. Ni .............................................. 88
6. Effects of Metals on Cell Signaling Pathways and Gene
Expression .................................................. 89
6.1. Introduction ........................................... 89
6.2. Signal Transduction Pathways Affected by Metal
Compounds .............................................. 90
6.2.1. ROS ............................................. 90
6.2.2. МАРК ............................................ 90
6.2.3. РIЗК/Akt ........................................ 90
6.2.4. HIF-1 ........................................... 90
6.2.5. NF-kB ........................................... 91
6.2.6. NFAT ............................................ 91
6.2.7. AP-1 ............................................ 91
6.3. Impacts of Metal Compounds on Signal Transduction
Pathways and Gene Expression ........................... 91
6.3.1. As .............................................. 91
6.3.2. Cd .............................................. 92
6.3.3. Cr .............................................. 93
6.3.4. Co .............................................. 94
6.3.5. Ni .............................................. 94
6.3.6. Other Metals .................................... 95
CHAPTER 6. General Considerations of Dose-Effect and Dose-
Response Relationships
DAPHNE B. MOFFETT, HISHAM A. EL-MASRI, AND
BRUCE A. FOWLER
1. General Aspects of Dose-Response Relationships ............. 101
1.1. Use of the Terms Effect and Response .................. 101
1.2. Interrelationships Among Dose, Effect, and Response ... 102
1.3. Definitions of Dose and Response ...................... 103
2. Modeling of Dose-Response Relationships .................... 104
2.1. The Shape of Dose-Response Curves: S, Hormesis,
U-Shaped .............................................. 105
2.2. The Sigmoid Curve ..................................... 106
2.3. Hormesis-Inverted U- or J-Shaped Curves ............... 107
2.4. U-Shaped Curves and Essentiality ...................... 107
3. Modeling the Data .......................................... 108
3.1. Biological Basis for Modeling ......................... 110
4. Species-to-Species Extrapolations .......................... 112
5. Risk Assessment and Dose-Response Relationships ............ 113
5.1. NOAEL/LOAEL ........................................... 113
5.2. Benchmark Dose ........................................ 113
5.3. Data Types and Benchmark Dose ......................... 114
6. Dose-Response in an Era of -Omics .......................... 114
CHAPTER 7. Interactions in Metal Toxicology
GUNNAR F. NORDBERG, LARS GERHARDSSON, KARIN
BROBERG, MOIZ MUMTAZ, PATRICIA RUIZ, AND BRUCE
A. FOWLER
1. Introduction ............................................... 117
2. Age, Sex, Drugs, and Some Other Factors .................... 118
2.1. Influence of Drugs, Alcohol, and Tobacco on Metal
Metabolism and Toxicity ............................... 118
2.1.1. Drugs .......................................... 118
2.1.2. Alcohol and Tobacco ............................ 119
2.2. Influence of Age and Sex on Metal Toxicity ............ 119
2.2.1. Age ............................................ 119
2.2.2. Sex ............................................ 119
2.3. Influence of Some Other Factors on Metal Metabolism
and Toxicity .......................................... 120
3. Gene-Environment Interactions for Metals ................... 120
3.1. Genes of Concern ...................................... 120
3.2. Design of Gene-Environment Interaction Studies ........ 121
3.3. Interactions for Specific Metals ...................... 122
3.3.1. Arsenic ........................................ 122
3.3.2. Beryllium and Cobalt ........................... 123
3.3.3. Cadmium ........................................ 123
3.3.4. Lead ........................................... 123
3.3.5. Mercury ........................................ 126
3.3.6. Nickel ......................................... 126
3.3.7. Platinum ....................................... 126
3.4. Conclusions ........................................... 127
4. Metal-Metal Interactions (Noncarcinogenic Effects) ......... 127
4.1. Arsenic and Other Metals .............................. 127
4.2. Interactions Between Cadmium and Other Metals ......... 128
4.3. Interactions Between Lead and Other Metals ............ 129
4.4. Hg and Other Metals ................................... 130
4.5. Molybdenum-Copper-Zinc Interactions ................... 131
4.6. Interactions Between Thallium and Potassium ........... 132
5. Metal-Metal Interactions in Carcinogenesis ................. 132
5.1. Arsenic ............................................... 132
5.2. Chromium .............................................. 132
5.3. Iron .................................................. 133
5.4. Lead .................................................. 133
5.5. Nickel ................................................ 134
5.6. Selenium .............................................. 135
5.7. Zinc .................................................. 136
6. Risk Assessment of Mixtures of Metals ...................... 137
6.1. Introduction .......................................... 137
6.2. Toxicity Assessment of Mixtures ....................... 137
6.2.1. The Mixture of Concern ......................... 137
6.2.2. The Similar Mixture Approach ................... 138
6.2.3. The Hazard Index Approach ...................... 138
6.2.4. The Target-Organ Toxicity Dose (TTD) ........... 138
6.3. A Weight-of-Evidence (WOE) Method ..................... 139
6.3.1. Direction of Interaction ....................... 140
6.3.2. Mechanistic Understanding ...................... 140
6.3.3. Toxicological Significance ..................... 141
6.4. Perspectives and Future Needs ......................... 141
CHAPTER 8. Epidemiological Methods for Assessing Dose-Response
and Dose-Effect Relationships
TORD KJELLSTROM AND PHILIPPE GRANDJEAN
1. Epidemiological Measurement of Occurrence of Health
Effects .................................................... 147
2. Observational Studies and Modeling Studies of Dose-
Response Relationships ..................................... 149
3. Study Design ............................................... 151
4. Data Collection ............................................ 153
4.1. Measurement of Dose ................................... 153
4.2. Measurement of Effect and Response .................... 155
5. Data Analysis .............................................. 157
6. Inference CHAPTER .......................................... 159
CHAPTER 9. Essential Metals: Assessing Risks from Deficiency
and Toxicity
GEORGE С. BECKING, MONICA NORDBERG, AND GUNNAR
F. NORDBERG
1. Introduction ............................................... 163
2. Basic Concepts ............................................. 164
2.1. Definition of an AROI (Acceptable Range of Oral
Intake) ............................................... 164
2.1.1. Groups with Special Sensitivity/Resistance ..... 165
2.2. Other Concepts Used in Risk Assessment of Essential
Metals ................................................ 166
2.2.1. Toxicological Terms ............................ 166
2.2.2. Nutritional Terms: Definitions and
Approaches Used to Assess Individual and
Population Requirements for EMs ................ 166
3. Effects of Deficiency and Toxicity ......................... 167
3.1. Factors Affecting Dose-Response Relationships ......... 167
3.1.1. Homeostatic Mechanisms ......................... 167
3.1.2. Bioavailability, Speciation, and
Interactions ................................... 167
3.2. Basic Principles for Classifying Effect ............... 168
3.3. Examples of Effects of Varying Severity ............... 169
3.3.1. Lethal Deficiency .............................. 169
3.3.2. Deficiency-Clinical Disease .................... 169
3.3.3. Subclinical Biomarkers of Deficiency with or
without Clinical Significance .................. 170
3.3.4. Lethal Toxic Effects ........................... 170
3.3.5. Toxic Effects with Clinical Significance ....... 170
3.3.6. Subclinical Toxic Effects with or without
Functional Significance- Biomarkers of
Critical Effect ................................ 170
4. Summary of Principles for Human Risk Assessment of
Exposures to EMs ........................................... 171
4.1. Application of Principles for Determination of AROI ... 171
5. Estimation of AROI ......................................... 172
6. Conclusions ................................................ 175
CHAPTER 10.Carcinogenicity of Metal Compounds
QINGDONG KE, MAX COSTA, AND GEORGE KAZANTZIS
1. Principal Metals Showing Carcinogenic Effects .............. 177
1.1. Nickel ................................................ 178
1.1.1. Epidemiological Observations ................... 178
1.1.2. Animal Models .................................. 179
1.1.3. Evaluation ..................................... 180
1.2. Chromium .............................................. 180
1.2.1. Epidemiological Observations ................... 180
1.2.2. Animal Models .................................. 181
1.2.3. Short-Term Tests ............................... 182
1.2.4. Evaluation ..................................... 182
1.3. Arsenic ............................................... 182
1.3.1. Epidemiological Observations ................... 182
1.3.2. Animal Models .................................. 184
1.3.3. Short-Term Tests ............................... 184
1.3.4. Evaluation ..................................... 185
1.4. Cadmium ............................................... 185
1.4.1. Epidemiological Observations ................... 185
1.4.2. Animal Models .................................. 187
1.4.3. Short-Term Tests ............................... 187
1.4.4. Evaluation ..................................... 187
1.5. Beryllium ............................................. 188
1.5.1. Epidemiology Observations ...................... 188
1.5.2. Animal Models .................................. 189
1.5.3. Evaluation ..................................... 189
1.6. Lead .................................................. 189
1.6.1. Epidemiological Observations ................... 189
1.6.2. Animal Models and Short-Term Tests ............. 190
1.6.3. Evaluation ..................................... 190
1.7. Cobalt ................................................ 190
1.8. Iron .................................................. 191
1.9. Manganese ............................................. 191
1.10.Platinum .............................................. 192
1.11.Titanium .............................................. 192
2. Principal Metals Showing Mutagenic Effects ................. 192
2.1. Nickel ................................................ 193
2.2. Chromium .............................................. 193
2.3. Arsenic ............................................... 193
2.4. Cadmium ............................................... 194
CHAPTER 11. Immunotoxicology of Metals
PER HULTMAN
1. Introduction ............................................... 197
1.1. Development of the Concept Metal Immunotoxicology ..... 197
1.2. Overview of Mechanisms in Immunotoxicology ............ 198
1.3. Dose-Response Considerations in Metal
Immunotoxicology ...................................... 198
2. Immunosuppression Induced by Metals ........................ 199
2.1. General Considerations ................................ 199
2.2. In Vitro Studies ...................................... 199
2.3. In Vivo Studies ....................................... 199
2.4. Experimental Host-Resistance Challenge Systems ........ 199
2.5. Clinical Immunosuppressive Effects .................... 199
3. Essential Metals and the Immune System ..................... 200
4. Hypersensitivity Induced by Metals ......................... 200
4.1. General Considerations ................................ 200
4.2. Type I Hypersensitivity (Anaphylacticor Immediate
Hypersensitivity) ..................................... 200
4.3. Type II Hypersensitivity (Antibody-Mediated-IgG or
IgM-Reactions Against Cells or Matrix) ................ 201
4.4. Type III Hypersensitivity (Immune-Complex Mediated
Reactions) ............................................ 201
4.5. Type IV Hypersensitivity (Cell-Mediated Reactions) .... 201
4.6. Relation Between Atopy and Metal Hypersensitivity ..... 201
5. Metals Causing Hypersensitivity Reactions .................. 201
5.1. Beryllium ............................................. 201
5.2. Chromium .............................................. 202
5.3. Cobalt ................................................ 202
5.4. Gold .................................................. 202
5.5. Mercury ............................................... 203
5.6. Nickel ................................................ 203
5.7. Multiple Metal Exposure Relatedto Prosthetic
Devices ............................................... 203
5.8. The Platinum Group of Elements (Palladium, Platinum,
Rhodium) .............................................. 204
6. Interaction Between Metals and Proteins .................... 204
6.1. Introduction .......................................... 204
6.2. Mechanisms of Interaction Between T Cells and Metal
Ions .................................................. 204
7. Other Interactions Between Metals and Proteins-
Implications for Autoimmunity .............................. 205
8. Nonspecific Immunostimulation Induced by Metals: The
Examples of Pb and Hg ...................................... 205
9. Metal-Induced Autoimmunity ................................. 206
10.Acceleration and Aggravation of Autoimmunity by
Xenobiotics ................................................ 207
10.1.General Considerations ................................ 207
10.2.Acceleration of Spontaneous Autoimmune Diseases
by Hg ................................................. 207
10.3.Acceleration of Spontaneous Autoimmune Diseases by
Cadmium and Lead ...................................... 208
10.4.Comments on the Autoimmune Effects of Metals .......... 208
CHAPTER 12. Reproductive and Developmental Toxicity of Metals
PIETRO APOSTOLI, SPOMENKA TELlSMAN, AND POLLY
R. SAGER
1. Introduction ............................................... 214
2. Male. Reproductive Effects ................................. 215
2.1. Lead .................................................. 216
2.2. Mercury ............................................... 218
2.3. Cadmium ............................................... 219
2.4. Manganese ............................................. 220
2.5. Chromium .............................................. 221
2.6. Nickel ................................................ 221
2.7. Arsenic ............................................... 221
3. Female Reproductive Effects ................................ 221
3.1. Lead .................................................. 222
3.2. Mercury ............................................... 224
3.3. Cadmium ............................................... 224
3.4. Manganese ............................................. 225
3.5. Chromium .............................................. 225
3.6. Nickel ................................................ 226
3.7. Arsenic ............................................... 226
3.8. Platinum .............................................. 227
3.9. Mixed Metal Exposure .................................. 227
4. Developmental Effects of Prenatal Exposure ................. 228
4.1. Lead .................................................. 229
4.2. Mercury ............................................... 230
4.3. Cadmium ............................................... 233
4.4. Chromium .............................................. 233
4.5. Nickel ................................................ 234
4.6. Arsenic ............................................... 234
4.7. Vanadium .............................................. 234
4.8. Uranium ............................................... 235
4.9. Aluminum .............................................. 235
4.10.Lithium ............................................... 235
5. Developmental Effects from Neonatal Exposure ............... 235
5.1. Lead .................................................. 236
5.2. Mercury ............................................... 238
5.3. Cadmium ............................................... 240
5.4. Nickel ................................................ 240
5.5. Arsenic ............................................... 240
5.6. Aluminum .............................................. 241
5.7. Mixed Metal and Multichemical Exposure ................ 241
CHAPTER 13. Ecotoxicology of Metals-Sources,Transport, and
Effects in the Ecosystem
POUL BJERREGAARD AND OLE ANDERSEN
1. Sources for Metal Emission ................................. 251
1.1. Direct Emissions of Metals into Nature ................ 251
1.1.1. Emissions to the Atmosphere .................... 251
1.1.2. Emissions into Water ........................... 252
1.1.3. Emissions to Soil .............................. 252
1.2. Indirect Mobilization of Metals ....................... 252
1.2.1. Acid Rain ...................................... 252
1.2.2. Oxygen Depletion ............................... 252
1.2.3. Pyrite Oxidation ............................... 252
2. The Biogeochemical Transport of Metals ..................... 252
2.1. Atmospheric Transport ................................. 252
2.2. Metal Speciation in Water ............................. 253
2.3. Metal Transport in the Ocean .......................... 254
2.4. Transport of Metals in Freshwater and Estuaries ....... 254
2.5. Metals in Sediments ................................... 256
3. Uptake and Accumulation of Metals .......................... 256
3.1. Bioavailability, Uptake, Accumulation, and
Elimination ........................................... 256
3.2. Metal Transport in Aquatic Food Chains ................ 257
4. Defense Against and Storage of Metals ...................... 257
4.1. Metal Toxicity and Defense Systems in Plants .......... 258
5. Toxicity of Metals in Ecosystems ........................... 259
6. Risk Assessment of Metals .................................. 260
6.1. The Aim of Ecotoxicological Risk Assessment ........... 260
6.2. Integrated Risk Assessment ............................ 260
6.3. Methods of Ecotoxicology .............................. 260
6.4. Practical Risk Management ............................. 261
6.5. Biomarkers as Hazard Indicators in Ecotoxicological
Risk Assessment ....................................... 261
7. Monitoring Metal Polluition-Biomonitoring .................. 262
7.1. Mussel Watch .......................................... 262
7.2. Other Monitoring Organisms ............................ 263
8. Ecotoxicology of Individual Metals ......................... 263
8.1. Alumina ............................................... 263
8.2. Antimony .............................................. 264
8.3. Arsenic ............................................... 264
8.3. Cadmium ............................................... 265
8.3.1. Background Levels and Emissions ................ 265
8.3.2. Uptake in Organisms ............................ 265
8.3.3. Contamination with Cadmium ..................... 266
8.3.4. Cadmium's Toxicity in Water .................... 266
8.3.5. Cadmium in Agricultural Soil and Uptake of
Cadmium into Plants ............................ 266
8.3.6. Implication for Human Health ................... 267
8.4. Cobalt ................................................ 267
8.5. Chromium .............................................. 267
8.6. Copper ................................................ 268
8.7. Iron .................................................. 268
8.8. Lead .................................................. 268
8.8.1. Lead in Ammunition ............................. 269
8.8.2. Effects in Birds and Mammals ................... 269
8.9. Manganese ............................................. 269
8.10.Mercury ............................................... 270
8.10.1.Background Concentrations Uses, and
Emissions ...................................... 270
8.10.2.The Transformation of Mercury in Nature ........ 270
8.10.3.The Global Mercury Flux ........................ 271
8.10.4.Uptake of Mercury in Organisms and Transport
in Food Webs ................................... 272
8.10.5.Effects of Mercury in Wildlife ................. 272
8.10.6.Implications for Human Health .................. 273
8.11.Molybdenum ............................................ 273
8.12.Nickel ................................................ 273
8.13.Selenium .............................................. 273
8.14.Silver ................................................ 273
8.15.Tin ................................................... 274
8.15.1.Inorganic Tin .................................. 274
8.15.2.Tributyltin (TBT) .............................. 274
8.16.Vanadium .............................................. 276
8.17.Zinc .................................................. 276
8.18.Radioactive Metals .................................... 276
8.18.1.Cesium ......................................... 276
8.18.2.Polonium ....................................... 276
8.18.3.Strontium ...................................... 277
8.18.4.Transuranic Metals ............................. 277
CHAPTER 14. Risk Assessment
GUNNAR F. NORDBERG AND BRUCE A. FOWLER
1. Introduction ............................................... 281
2. Exposure and Dose Assessment ............................... 282
2.1. Exposure and Dose Terminology ......................... 282
2.2. Expoure, Applied/Inhaled Dose, Daily Intake ........... 282
2.3. Absorbed Dose, Internal Dose .......................... 283
2.4. Dose/Concentration in Critical Organ and Critical
Target ................................................ 283
2.5. Use of Biomarkers in Estimating Concentration in
Critical Organ and Critical Target Dose ............... 283
3. Hazard Identification ...................................... 284
3.1. Speciation ............................................ 284
3.2. Human Data ............................................ 285
3.3. Data from Studies on Acute and Chronic Toxicity
in Animals, Cells, and Molecular Systems In Vitro ..... 285
3.3.1. IARC Group 2 ................................... 286
3.3.2. IARC Group 2A: The Agent is Probably
Carcinogenic to Humans ......................... 287
3.3.3. IARC Group 2B: The Agent is Possibly
Carcinogenic to Humans ......................... 287
3.4. Classification According to the European Union ........ 288
3.5. Classification According to the USEPA ................. 288
3.6. Classification According to the American Conference
of Governmental Industrial Hygienists, Inc ............ 288
4. Dose-Effect and Dose-Response Assessment ................... 289
4.1. Concepts in Quantitative Toxicological Analysis ....... 289
4.1.1. Dose Effect and Dose Response .................. 289
4.1.2. Critical Concentration, Critical Organ,
Critical Effect, and No-Observed-Effect
Level .......................................... 289
4.1.3. Benchmark Dose ................................. 290
4.1.4. The Critical Concentration on a Population
Basis .......................................... 292
4.2. Based on Short-Term and Long-Term Studies in
Animals ............................................... 293
4.2.1. Threshold-Type Critical Effects ................ 293
4.2.2. Carcinogenesis and Other Nonthreshold
Effects ........................................ 294
4.3. Probabilistic Estimation of Dose-Response
Relationships by Toxicokinetic (TK) and
Toxicodynamic (TD) Modeling ........................... 295
4.3.1. Deterministic or Threshold-Type Effects ........ 295
4.3.2. Stochastic or Nonthreshold Effects ............. 296
4.4. Based on Epidemiological Studies ...................... 296
4.4.1. Sensitive Groups ............................... 296
4.4.2. Carcinogenic Effects ........................... 296
4.5. Simplified Approach as an Alternative to Risk
Assessment ............................................ 296
5. Risk Characterization ...................................... 297
6. Risk Management and Risk Communication ..................... 297
6.1. Managing Human Exposures by Emission Control,
Substitution, Labeling, or Restrictions in Use ........ 297
6.2. Controlling Human Exposures by Guidelines and
Legislated Permissible Exposure Levels ................ 298
6.3. Risk Communication .................................... 300
CHAPTER 15. Diagnosis and Treatment of Metal Poisoning-
General Aspects
GEORGE KAZANTZIS
1. Clinical Effects ........................................... 304
1.1. General Considerations ................................ 304
1.2. Exposure Pattern and Clinical Effect .................. 304
1.3. Acute Clinical Effects of Metals ...................... 305
1.3.1. Gastrointestinal Effects ....................... 305
1.3.2. Respiratory Effects ............................ 305
1.3.3. Cardiovascular Effects ......................... 305
1.3.4. Effects on the Central Nervous System .......... 306
1.3.5. Renal Effects .................................. 306
1.3.6. Hemopoietic Effects ............................ 306
1.4. Chronic Clinical Effects of Metal Toxicity ............ 306
1.4.1. Gastrointestinal Effects ....................... 306
1.4.2. Hepatic Effects ................................ 306
1.4.3. Respiratory Effects ............................ 306
1.4.4. Effects on the Nervous System .................. 307
1.4.5. Renal Effects .................................. 307
1.4.6. Hemopoietic Effects ............................ 307
2. Diagnosis of Metal Poisoning ............................... 307
2.1. History of Exposure ................................... 308
2.2. Clinical Features ..................................... 308
2.3. Toxicological Analysis ................................ 309
2.1. Biochemical Investigation ............................. 309
2.5. Physiological Investigation ........................... 309
3. Treatment .................................................. 310
3.1. Prevention of Further Absorption ...................... 310
3.1.1. Removal from Exposure .......................... 310
3.1.2. Minimizing Absorption from the
Gastrointestinal Tract ......................... 310
3.2. General Supportive Therapy ............................ 310
3.2.1. Maintenance of Respiration and Circulation ..... 311
3.2.2. Maintenance of Water and Electrolyte Balance ... 311
3.2.3. Control of Nervous System Effects .............. 311
3.3. Elimination of Absorbed Poison ........................ 311
3.3.1. Diuresis ....................................... 311
3.3.2. Biliary Excretion .............................. 311
3.3.3. Dialysis ....................................... 311
3.3.4. Exchange Transfusion ........................... 312
3.4. Inactivation of the Absorbed Poison ................... 312
3.5. Chelation Therapy ..................................... 312
3.5.1. Dimercaprol .................................... 312
3.5.2. Calcium Disodium Edetate (Calcium EDTA) ........ 314
3.5.3. Penicillamine (Cuprimine) ...................... 315
3.5.4. Triethylene Tetramine (Trien, TETA) ............ 315
3.5.5. Desferrioxamine (DFOA) ......................... 315
3.5.6. Deferiprone (LI) ............................... 316
3.5.7. Diethylenetriaminepentaacetic Acid (DTPA) ...... 316
3.5.8. Diethyldithiocarbamate (DEDTC) ................. 316
3.5.9. Combinations of Chelating Agents ............... 316
3.6. Modification of Response .............................. 316
3.6.1. Modification of Tissue Response ................ 316
3.6.2. Modification of Biochemical Status ............. 317
CHAPTER 16. Principles for Prevention of the Toxic Effects
of Metals
PHILIP J. LANDRIGAN, DAVID KOTELCHUCK, AND
PHILIPPE GRANDJEAN
1. Introduction ............................................... 319
2. General Principles for Prevention of the Toxic Effects
of Metals .................................................. 320
2.1. Hazard Identification ................................. 321
2.1.1. Lead ........................................... 321
2.1.2. Methylmercury .................................. 321
2.1.3. Arsenic ........................................ 321
2.2. Reduction of Exposure ................................. 322
3. Prevention of the Effects of Metal Toxicity in the Work
Environment ................................................ 322
3.1. General Considerations ................................ 322
3.2. Reduction of Exposure ................................. 322
3.2.1. Elimination of Unnecessary Uses and
Substitution of Safer Materials ................ 322
3.2.2. Reduced Use of Toxic Metals in Plant and
Manufacturing Design ........................... 323
3.2.3. Other Technical Control Measures ............... 323
3.2.4. Local Exhaust Ventilation ...................... 323
3.2.5. General Room Ventilation ....................... 323
3.2.6. Housekeeping ................................... 324
3.2.7. Influence of Personal Hygiene on Metal
Absorption and Toxicity ........................ 324
3.2.8. Reduction of Worker Contact with Toxic
Metals and Personal Protective Equipment ....... 324
3.3. Monitoring of the Work Environment .................... 325
3.3.1. Air Sampling Strategy in the Workplace ......... 325
3.3.2. Sampling Technique ............................. 326
3.3.3. Analysis ....................................... 326
3.3.4. Biological Monitoring .......................... 326
3.3.5. Health Examinations ............................ 327
3.4. Training .............................................. 327
3.5. Authority ............................................. 327
4. Prevention of the Effects of Metal Toxicity in the
General Environment ........................................ 328
4.1. General Considerations ................................ 328
4.2. The Unique Vulnerability of Infants and Children
to Poisoning by Metals ................................ 328
4.3. Reduction of Exposure ................................. 328
4.3.1. Elimination or Reduction of Use ................ 328
4.3.2. Source Control ................................. 329
4.3.3. Routes of Environmental Contamination by
Metals ......................................... 329
4.4. Environmental Monitoring .............................. 330
4.5. Public Education ...................................... 331
4.6. Regulatory Authority .................................. 331
5. Perspectives on Precaution and Prevention .................. 331
5.1. Populations at Risk ................................... 331
5.2. Widening Implications of Subclinical Toxicity ......... 332
5.3. Precautionary Approaches .............................. 332
CHAPTER 17. Aluminum
BENGT SJOGREN, ANDERS IREGREN, CARL-
GUSTAF ELINDER, AND ROBERT A. YOKEL
1. Physical and Chemical Properties ........................... 339
2. Methods and Problems of Analysis ........................... 339
3. Production and Use ......................................... 340
4. Dietary, Environmental, and Occupational Exposure .......... 341
5. Metabolism ................................................. 341
5.1. Absorption ............................................ 341
5.2. Distribution .......................................... 342
5.3. Excretion ............................................. 342
5.4. Biological Monitoring ................................. 342
6. Effects .................................................... 343
6.1. Gastrointestinal Symptoms ............................. 343
6.2. Restrictive Pulmonary Disease ......................... 344
6.3. Obstructive Pulmonary Disease ......................... 345
6.4. Central Nervous System ................................ 346
6.4.1. Dialysis Encephalopathy ........................ 346
6.4.2. Other Medical Aluminum Exposures ............... 346
6.4.3. Neurobehavioral Effects of Occupational
Aluminum Exposure .............................. 347
6.4.4. Alzheimer's Disease ............................ 348
6.5. Bone .................................................. 348
6.6. Hematopoietic Tissue .................................. 348
6.7. Skin .................................................. 348
6.8. Allergic Effects ...................................... 348
6.9. Coronary Heart Disease ................................ 349
6.10.Carcinogenic Effects .................................. 349
7. Other Aluminum Compounds ................................... 349
8. Recommendations ............................................ 349
CHAPTER 18. Antimony
CAROLYN A. TYLENDA AND BRUCE A. FOWLER
1. Physical and Chemical Properties ........................... 353
2. Methods and Problems of Analysis ........................... 353
3. Production and Uses ........................................ 354
3.1. Historical Background ................................. 354
3.2. Production ............................................ 354
3.3. Uses .................................................. 355
4. Environmental Levels and Exposures ......................... 355
4.1. General Environment ................................... 355
4.1.1. Food and Daily Intake .......................... 355
4.1.2. Air, Soil, and Water ........................... 355
4.1.3. Tobacco ........................................ 356
4.2. Working Environment ................................... 356
5. Metabolism ................................................. 356
5.1. Absorption ............................................ 356
5.1.1. Inhalation ..................................... 356
5.1.2. Ingestion ...................................... 357
5.2. Distribution .......................................... 357
5.2.1. Animals ........................................ 357
5.2.2. Humans ......................................... 357
5.3. Excretion ............................................. 358
5.3.1. Animals ........................................ 358
5.3.2. Humans ......................................... 358
5.4. Biological Half-Life .................................. 358
5.4.1. Animals ........................................ 358
5.4.2. Humans ......................................... 359
6. Biological Monitoring ...................................... 359
7. Effects and Dose-Response Relationships .................... 360
7.1. Animals ............................................... 360
7.1.1. Local Effects and Dose-Response
Relationships .................................. 360
7.1.2. Systemic Effects and Dose-Response
Relationships .................................. 360
7.2. Humans ................................................ 361
7.2.1. Local Effects and Dose-Response
Relationships .................................. 361
7.2.2. Systemic Effects and Dose-Response
Relationships .................................. 362
7.2.3. Adverse Effects During Antimony Treatment ...... 362
8. Carcinogenic and Genotoxic Effects ......................... 362
CHAPTER 19. Arsenic
BRUCE A. FOWLER, C.-H. SELENE J. CHOU,
ROBERT L. JONES, AND C.-J. CHEN
1. Physical and Chemical Properties ........................... 368
2. Methods and Problems of Analysis ........................... 368
3. Production and Uses ........................................ 369
3.1. Production ............................................ 369
3.2. Uses .................................................. 369
4. Environmental Levels and Exposures ......................... 369
4.1. Food and Daily Intake ................................. 369
4.2. Water ................................................. 370
4.3. Soil .................................................. 371
4.4. Air ................................................... 371
4.5. Tobacco ............................................... 372
5. Metabolism ................................................. 373
5.1. Absorption ............................................ 373
5.1.1. Inhalation ..................................... 373
5.1.2. Ingestion ...................................... 373
5.1.3. Skin Absorption ................................ 373
5.2. Transport and Distribution ............................ 374
5.3. Biotransformation ..................................... 374
5.4. Excretion ............................................. 375
5.2. 5.5. Biological Half-Time ............................. 376
5.6. Mechanisms of Arsenical Toxicity ...................... 376
5.6.1. Mechanisms of Arsenical Metabolism and
Toxicity ....................................... 376
5.6.2. Metabolism ..................................... 376
5.6.3. Mechanisms of Arsenical Toxicity ............... 377
6. Biological Monitoring ...................................... 380
6.1. Organs ................................................ 380
6.2. Urine ................................................. 380
6.3. Blood ................................................. 381
6.4. Hair .................................................. 381
7. Effects .................................................... 382
7.1. Lethality ............................................. 382
7.2. Acute and Subacute Effects ............................ 383
7.3. Chronic Noncardiovascular Effects ..................... 383
7.3.1. Dermal Effects ................................. 383
7.3.2. Gastrointestinal Effects ....................... 383
7.3.3. Neural Effects ................................. 384
7.3.4. Hepatic Effects ................................ 384
7.3.5. Hematological Effects .......................... 384
7.3.6. Respiratory Effects ............................ 384
7.3.7. Metabolic Effects .............................. 384
7.3.8. Immunological Effects .......................... 385
7.3.9. Ophthalmic Effects ............................. 385
7.4. Chronic Cardiovascular Effects ........................ 385
7.4.1. Cardiac Effects ................................ 386
7.4.2. Peripheral Vascular Diseases ................... 386
7.4.3. Ischemic Heart Diseases ........................ 386
7.4.4. Stroke ......................................... 387
7.4.5. Carotid Atherosclerosis ........................ 387
7.4.6. Hypertension ................................... 387
7.4.7. Microcirculation Abnormality ................... 387
7.5. Carcinogenic Effects .................................. 388
7.5.1. Skin Cancer .................................... 388
7.5.2. Lung Cancer .................................... 388
7.5.3. Urothelial Cancer .............................. 389
7.5.4. Liver Cancer ................................... 389
7.5.5. Other Internal Cancers ......................... 390
7.5.6. Lifetime Cancer Risk Induced by Arsenic ........ 390
7.6. Experimental System Cancer Studies .................... 391
7.6.1. Developmental and Reproductive Effects ......... 391
7.6.2. Genotoxic Effects and Mutagenicity ............. 392
7.7. Interaction Between Arsenic and Other Compounds ....... 392
8. Dose-Effect and Dose-Response Relationship in Arsenic
Poisoning .................................................. 393
9. Diagnosis, Treatment, and Prognosis ........................ 395
9.1. Acute Poisoning ....................................... 395
9.1.1. Inhalation Diagnosis ........................... 395
9.1.2. Ingestion Diagnosis ............................ 396
9.2. Chronic Poisoning ..................................... 396
9.2.1. Diagnosis ...................................... 396
9.2.2. Treatment and Prognosis ........................ 396
10.Arsine ..................................................... 397
10.1.Experimental Model Studies CHAPTER .................... 397
CHAPTER 20. Barium
AGNETA OSKARSSON AND ANDREW L. REEVES
1. Physical and Chemical Properties ........................... 407
2. Methods and Problems of Analysis ........................... 408
3. Production and Uses ........................................ 408
3.1. Production ............................................ 408
3.2. Uses .................................................. 408
4. Environmental Levels and Exposures ......................... 408
4.1. General Environment ................................... 408
4.1.1. Soil, Water, and Air ........................... 408
4.1.2. Plants, Animals, and Dietary Intake ............ 409
4.2. Working Environment ................................... 409
5. Kinetics ................................................... 409
5.1. Absorption ............................................ 409
5.1.1. Inhalation ..................................... 409
5.1.2. Ingestion ...................................... 409
5.1.3. Parenteral Administration ...................... 410
5.2. Transport and Distribution ............................ 410
5.3. Excretion ............................................. 410
6. Biological Monitoring ...................................... 410
7. Effects and Dose-Response Relationships .................... 411
7.1. Humans ................................................ 411
7.1.1. Acute Effects .................................. 411
7.1.2. Chronic Effects ................................ 411
7.2. Animals ............................................... 412
7.2.1. Inhalation ..................................... 412
7.2.2. Ingestion ...................................... 412
8. Treatment CHAPTER .......................................... 413
CHAPTER 21. Beryllium
MAREK JAKUBOWSKI AND CEZARY PALCZYNSKI
1. Physical and Chemical Properties ........................... 416
2. Methods and Problems of Analysis ........................... 416
3. Production and Uses ........................................ 416
3.1. Production ............................................ 416
3.2. Uses .................................................. 417
4. Environmental Levels and Exposures ......................... 417
4.1. General Environment ................................... 417
4.1.1. Soil, Water, and Air ........................... 417
4.1.2. Plants, Animals, and Dietary Intake ............ 418
4.1.3. Estimates of Daily Exposure .................... 418
4.2. Working Environment ................................... 418
5. Kinetics ................................................... 419
5.1. Absorption ............................................ 419
5.1.1. Dermal Exposure ................................ 419
5.1.2. Inhalation ..................................... 419
5.1.3. Ingestion ...................................... 420
5.2. Transport, Distribution, and Excretion ................ 420
6. Levels in Tissues and Biological Fluids-Biological
Monitoring ................................................. 421
7. Effects and Dose-Response Relationships .................... 421
7.1. Local Effects ......................................... 422
7.1.1. Skin Contact ................................... 422
7.1.2. Inhalation ..................................... 422
7.2. Systemic Effects ...................................... 423
7.2.1. Acute Effects .................................. 423
7.2.2. Chronic Beryllium Disease (CBD, Chronic
Pulmonary Granulomatosis, Berylliosis) ......... 423
7.2.3. Other Chronic Systemic Effects ................. 424
7.3. Carcinogenic Effects .................................. 425
7.3.1. Humans ......................................... 425
7.3.2. Animals ........................................ 426
7.4. Genotoxic Effects ..................................... 426
7.5. Mechanisms of Toxic Action ............................ 427
7.6. Biomarkers of Effect .................................. 427
7.7. Biomarkers of Susceptibility .......................... 428
8. Diagnosis and Treatment .................................... 428
8.1. Treatment ............................................. 428
CHAPTER 22. Bismuth
BRUCE A. FOWLER AND MARY J. SEXTON
1. Physical and Chemical Properties ........................... 433
2. Methods and Problems of Analysis ........................... 433
3. Production and Uses ........................................ 434
3.1. Production ............................................ 434
3.2. Uses .................................................. 434
4. Environmental Levels and Exposures ......................... 435
4.1. General Environment ................................... 435
4.1.1. Food ........................................... 435
4.1.2. Ambient Air, Water, Soil, and Rocks ............ 435
4.1.3. Pharmaceuticals and Cosmetics .................. 435
4.2. Working Environment ................................... 435
5. Metabolism ................................................. 435
5.1. Absorption ............................................ 435
5.2. Distribution .......................................... 435
5.3. Excretion ............................................. 436
5.4. Biological Half-Times ................................. 436
6. Biological Monitoring ...................................... 436
7. Effects and Dose-Response Relationships .................... 437
7.1. Local Effects and Dose-Response Relationships ......... 437
7.1.1. Animals ........................................ 437
7.1.2. Humans ......................................... 437
7.2. Systemic Effects and Dose-Response Relationships ...... 438
7.2.1. Animals ........................................ 438
7.2.2. Humans ......................................... 440
7.3. Carcinogenicity, Teratogenicity, and Mutagenicity ..... 441
8. Treatment of Bismuth Poisoning ............................. 441
CHAPTER 23. Cadmium
GUNNAR F. NORDBERG, KOJI NOGAWA, MONICA
NORDBERG, LARS T. FRIBERG
1. Physical and Chemical Properties ........................... 446
2. Methods and Problems of Analysis ........................... 446
3. Production and Uses ........................................ 447
3.1. Production ............................................ 447
3.2. Uses .................................................. 447
4. Environmental Levels and Exposures ......................... 448
4.1. General Environment ................................... 448
4.1.1. Food and Daily Intake .......................... 448
4.1.2. Water and Soil ................................. 450
4.1.3. Ambient Air .................................... 451
4.1.4. Tobacco ........................................ 451
4.2. Working Environment ................................... 451
5. Toxicokinetics ............................................. 452
5.1. Absorption ............................................ 452
5.1.1. Inhalation ..................................... 452
5.1.2. Ingestion ...................................... 453
5.2. Transport and Distribution ............................ 453
5.2.1. Systemic Transport ............................. 453
5.2.2. Distribution ................................... 455
5.3. Excretion ............................................. 457
5.4. Biological Half-Life .................................. 457
5.5. Mathematical Models for Cd Accumulation in Renal
Cortex and Other Tissues .............................. 458
6. Biological Monitoring ...................................... 459
6.1. Biomarkers of Exposure ................................ 459
6.1.1. Cd in Blood .................................... 459
6.1.2. Cd in Urine .................................... 460
6.1.3. Cadmium in Placenta ............................ 460
6.1.4. Cd in Hair, Feces, and Other Biological
Materials ...................................... 461
6.1.5. Cd in Kidney and Liver, Measured In Vivo,
Body Burden .................................... 461
6.2. Biomarkers of Effects ................................. 461
7. Effects and Dose-Response Relationship ..................... 463
7.1. Acute Poisoning ....................................... 463
7.1.1. Inhalation ..................................... 463
7.1.2. Ingestion ...................................... 463
7.2. Chronic Poisoning ..................................... 463
7.2.1. General Aspects ................................ 463
7.2.2. Pulmonary Disorders ............................ 463
7.2.3. Kidney Damage .................................. 464
7.2.4. Anemia ......................................... 465
7.2.5. Blood Pressure ................................. 465
7.2.6. Liver Disturbances ............................. 466
7.2.7. Effects on Bone ................................ 466
7.2.8. Itai-Itai Disease .............................. 468
7.2.9. Cadmium and the Central and Peripheral
Nervous System ................................. 469
7.2.10.Reproductive and Developmental Effects ......... 470
7.3. Carcinogenic Effects .................................. 471
7.4. Genetic Effects ....................................... 472
7.5. Interaction Between Cadmium and Other Metals .......... 472
7.5.1. Cadmium-Zinc-Metallothionein, Iron, and
Calcium ........................................ 472
7.5.2. Interaction Between Arsenic and Cadmium ........ 473
8. Dose-Response Relationships ................................ 473
8.1. Critical Concentration in the Kidney and
Toxicokinetic Model ................................... 473
8.2. Direct Observations of Dose-Response and Risk
Characterization ...................................... 474
9. Life. Prognosis ............................................ 478
10.Diagnosis, Treatment, Prognosis, and Prevention ............ 479
10.1.Acute Poisoning ....................................... 479
10.1.1.Inhalation ..................................... 479
10.1.2.Ingestion ...................................... 479
10.2.Chronic Intoxication .................................. 479
10.2.1.Diagnosis ...................................... 479
10.2.2.Treatment, Prognosis, and Prevention ........... 479
CHAPTER 24 Chromium
SVERRE LANGARD AND MAX COSTA
1. Physical and Chemical Properties ........................... 487
2. Methods of Chemical Analysis ............................... 488
3. Manufacture and Uses ....................................... 488
3.1. Manufacture ........................................... 488
3.2. Uses .................................................. 489
4. Concentrations in the Environment .......................... 489
4.1. Occurrence in Natural Environments and Soil ........... 489
4.2. Concentrations in Food ................................ 489
4.3. Water and Ambient Air ................................. 489
4.4. Tobacco ............................................... 489
4.5. Daily Intake in Humans ................................ 489
5. Work-Related Exposure ...................................... 490
6. Uptake and Metabolism ...................................... 490
6.1. Dietary Intake ........................................ 490
6.2. Inhalation ............................................ 491
6.3. Distribution .......................................... 491
6.4. Excretion and Biological Half-Life .................... 491
6.5. Concentrations in Biological Fluids and Tissues ....... 492
7. Dose and Outcome Effects ................................... 492
7.1. Local Effects ......................................... 493
7.1.1. Animals ........................................ 493
7.1.2. Humans ......................................... 493
7.2. Systemic Effects and Dose-Effect and Dose-Response .... 494
7.2.1. Animals ........................................ 494
7.2.2. Humans ......................................... 495
7.3. Carcinogenic, Mutagenic, and Teratogenic Effects ...... 495
7.3.1. Animals ........................................ 495
7.3.2. Humans ......................................... 496
7.3.3. Interaction with Other Carcinogenic Factors .... 505
7.3.4. Mutagenic and Genotoxic Effects ................ 505
7.3.5. Teratogenic Effects ............................ 505
8. Biological Monitoring ...................................... 506
8.1. Biomarkers of Exposure ................................ 506
8.2. Biomarkers of Effects ................................. 506
9. Cellular Mechanism of Toxicity and Carcinogenicity ......... 506
9.1. Molecular Toxicology of Cr ............................ 506
10.Diagnosis, Treatment, Prognosis, and Prevention ............ 507
CHAPTER 25. Cobalt
DOMINIQUE LISON
1. Physical and Chemical Properties ........................... 511
2. Analytical Methods ......................................... 512
3. Production and Uses ........................................ 513
3.1. Production ............................................ 513
3.2. Uses .................................................. 513
4. Environmental Levels and Exposures ......................... 513
4.1. General Environment ................................... 513
4.1.1. Food and Daily Intake .......................... 513
4.1.2. Soil, Ambient Air, and Water ................... 513
4.2. Occupational Environment .............................. 514
5. Metabolism ................................................. 514
5.1. Absorption ............................................ 514
5.1.1. Animal Studies ................................. 514
5.1.2. Humans ......................................... 515
5.2. Distribution .......................................... 516
5.2.1. Animal Studies ................................. 516
5.2.2. Humans ......................................... 516
5.3. Excretion ............................................. 516
5.3.1. Animal Studies ................................. 516
5.3.2. Humans ......................................... 516
6. Biological Monitoring ...................................... 516
7. Effects and Dose-Response Relationships .................... 517
7.1. Local Effects ......................................... 517
7.2. Respiratory Effects ................................... 518
7.2.1. Upper Respiratory Tract ........................ 518
7.2.2. Bronchial Tree ................................. 518
7.2.3. Lung Parenchyma ................................ 519
7.3. Other Systemic Effects ................................ 521
7.3.1. Blood .......................................... 521
7.3.2. Myocardium ..................................... 521
7.3.3. Thyroid Gland .................................. 522
7.4. Mutagenic Effects ..................................... 522
7.4.1. Experimental Data .............................. 522
7.4.2. Human Data ..................................... 523
7.5. Carcinogenic Effects .................................. 523
7.5.1. Animal Data .................................... 524
7.5.2. Human Data ..................................... 524
7.6. Reprotoxicity ......................................... 525
7.6.1. Effects on Reproductive Organs and Fertility ... 525
7.6.2. Developmental Effects .......................... 525
CHAPTER 26 Copper
DAG G. ELLINGSEN, NINA HORN,
AND JAN AASETH
1. Physical and Chemical Properties ........................... 529
2. Methods and Problems of Analysis ........................... 530
3. Production and Uses ........................................ 530
3.1. Production ............................................ 530
3.2. Uses .................................................. 530
4. Environmental Levels and Exposures ......................... 530
4.1. Food and Daily Intake ................................. 530
4.2. Water, Soil, and Ambient Air .......................... 531
4.3. Working Environment ................................... 531
5. Metabolism ................................................. 531
5.1. Absorption ............................................ 532
5.1.1. Inhalation ..................................... 532
5.1.2. Ingestion ...................................... 532
5.2. Distribution .......................................... 532
5.2.1. Interorgan and Intracellular Distribution ...... 532
5.2.2. Molecular Genetics of Intracellular
Transport ...................................... 532
5.2.3. Uptake into the Brain .......................... 534
5.3. Genetic Disorders with a Disturbed Copper
Metabolism ............................................ 534
5.4. Excretion ............................................. 534
5.5. Biological Half-Time .................................. 535
6. Levels in Tissues and Biological Fluids .................... 536
6.1. Biological Monitoring ................................. 536
6.2. Biomarkers of Exposure ................................ 537
7. Effects and Dose-Response Relationships .................... 537
7.1. Local Effects and Dose-Response Relationships ......... 538
7.1.1. Animals ........................................ 538
7.1.2. Humans ......................................... 538
7.2. Systemic Effects and Dose-Response Relationships ...... 539
7.2.1. Laboratory and Domestic Animals ................ 539
7.2.2. Humans ......................................... 540
7.3. Mutagenic, Carcinogenic, and Teratogenic Effects ...... 541
7.4. Biological Interactions ............................... 541
8. Preventive Measures and Treatment .......................... 542
CHAPTER 27. Gallium and Semiconductor Compounds
BRUCE A. FOWLER AND MARY J. SEXTON
1. Physical and Chemical Properties ........................... 547
2. Methods and Problems of Analysis ........................... 547
3. Production and Uses ........................................ 547
3.1. Uses .................................................. 547
4. Environmental Levels and Exposures ......................... 548
4.1. Food and Daily Intake ................................. 548
4.2. Water, Sediments, Soil, and Ambient Air ............... 548
5. Metabolism ................................................. 549
5.1. Absorption ............................................ 549
5.1.1. Inhalation ..................................... 549
5.1.2. Ingestion ...................................... 549
5.2. Distribution .......................................... 549
5.3. Excretion ............................................. 549
5.4. Biological Half-Time .................................. 549
6. Levels in Biological Fluids ................................ 549
7. Effects and Dose-Response Relationships .................... 549
7.1. Animal Studies ........................................ 549
7.2. Human Studies ......................................... 551
7.2.1. Toxicity ....................................... 551
7.2.2. Therapeutic .................................... 552
CHAPTER 28. Germanium
OBAID M. FAROON, L. SAMUEL KEITH, HUGH
HANSEN, AND BRUCE A. FOWLER
1. Physical and Chemical Properties ........................... 557
2. Methods and Problems of Analysis ........................... 558
3. Production and Uses ........................................ 559
3.1. Production ............................................ 559
3.2. Uses .................................................. 559
4. Environmental Levels and Exposures ......................... 559
4.1. Food and Daily Intake ................................. 559
4.1.1. Water, Soil, and Ambient Air ................... 560
4.1.2. Plants, Fishery Products, and Microbial
Organisms ...................................... 560
4.2. Working Environment ................................... 560
5. Toxicokinetics ............................................. 560
5.1. Absorption ............................................ 560
5.1.1. Inhalation ..................................... 560
5.1.2. Ingestion ...................................... 560
5.2. Distribution .......................................... 561
5.3. Excretion ............................................. 561
5.4. Biological Half-Time .................................. 561
6. Levels in Tissues and Biological Fluids-Biological
Monitoring ................................................. 561
7. Effects and Dose-Response Relationships .................... 562
7.1. Inorganic Compounds ................................... 562
7.1.1. Local Effects and Dose-Response
Relationships .................................. 562
7.1.2. Systemic Effects and Dose-Response
Relationships .................................. 562
7.1.3. Humans ......................................... 564
7.2. Organometallic Compounds .............................. 565
7.3. Carcinogenicity, Mutagenicity, and Teratogenicity ..... 565
8. Treatment Trials ........................................... 565
CHAPTER 29. Indium
BRUCE A. FOWLER
1. Physical and Chemical Properties ........................... 569
2. Methods and Problems of Analysis ........................... 569
3. Production and Uses ........................................ 570
3.1. Production ............................................ 570
3.2. Uses .................................................. 570
4. Environmental Levels and Exposures ......................... 571
4.1. Food and Daily Intake ................................. 571
4.2. Water, Soil, and Ambient Air .......................... 571
5. Metabolism ................................................. 571
5.1. Absorption ............................................ 571
5.1.1. Inhalation ..................................... 571
5.1.2. Ingestion ...................................... 571
5.2. Distribution .......................................... 572
5.3. Excretion ............................................. 572
5.4. Biological Half-Time .................................. 573
6. Levels in Tissues and Biological Fluids .................... 573
7. Effects and Dose-Response Relationships .................... 573
7.1. Local Effects and Dose-Response Relationships ......... 573
7.1.1. Animals ........................................ 573
7.1.2. Humans ......................................... 573
7.2. Systemic Effects and Dose-Response Relationships ...... 573
7.2.1. Animals ........................................ 573
7.2.2. Humans ......................................... 574
7.3. Carcinogenicity, Mutagenicity and Teratogenicity ...... 574
7.4. Interactions with Ferric Dextran Thorium Dioxide
Sol, and Gelatin CHAPTER .............................. 575
CHAPTER 30. Iron
PREM PONKA, MILTON TENENBEIN, AND JOHN W. EATON
1. Physical and Chemical Properties ........................... 577
2. Methods and Problems of Analysis ........................... 578
3. Production and Uses ........................................ 578
4. Environmental Levels and Exposures ......................... 578
5. Biological Function and Metabolism ......................... 579
5.1. Overview of Iron Metabolism ........................... 579
5.2. Cellular Iron Acquisition from Transferrin ............ 579
5.3. Iron Export from Cells to Transferrin ................. 582
5.4. Recycling of Hemoglobin Iron .......................... 582
5.5. Iron Absorption ....................................... 582
5.6. Control of Cellular Iron Homeostasis .................. 585
6. Pathophysiology of Iron Metabolism ......................... 585
6.1. Diseases of Iron Deficiency ........................... 585
6.2. Diseases of Iron Overload ............................. 586
6.3. Mechanisms of Tissue Damage in Iron Overload .......... 587
6.3.1. Compensatory Responses to Oxidation/Iron
Overload May Limit Early Damage ................ 588
6.3.2. Iron-Driven Cellular Damage Involves
Oxidative Reactions ............................ 588
6.3.3. Polyunsaturated Fatty Acids .................... 589
6.3.4. DNA ............................................ 589
6.3.5. Proteins ....................................... 589
6.3.6. Iron-Mediated Damage to Mitochondria ........... 589
6.3.7. Iron-Mediated Destabilization of Lysosomal
Membranes ...................................... 590
7. "Carcinogenic" Effects ..................................... 591
7.1. Role of Iron in DNA Synthesis and Cell
Proliferation ......................................... 591
7.2. Evidence That Iron Promotes Carcinogenesis in
Humans Is Lacking ..................................... 591
8. Iron Poisoning ............................................. 592
8.1. Introduction .......................................... 592
8.2. Iron Preparations ..................................... 592
8.3. Pathophysiology ....................................... 592
8.4. Clinical Presentation ................................. 592
8.4.1. Gastrointestinal Toxicity ...................... 593
8.4.2. Relative Stability ............................. 593
8.4.3. Circulatory Shock and Metabolic Acidosis ....... 593
8.4.4. Hepatotoxicity ................................. 593
8.4.5. Gastrointestinal Scarring ...................... 593
8.5. Iron Overdose During Pregnancy ........................ 593
8.6. Laboratory Evaluation ................................. 593
8.7. Treatment ............................................. 594
8.8. Prevention ............................................ 594
9. Conclusions ................................................ 594
CHAPTER 31. Lead
STAFFAN SKERFVING AND INGVAR A. BERGDAHL
1. Background ................................................. 599
2. Inorganic Lead ............................................. 600
2.1. Physical and Chemical Properties ...................... 600
2.2. Methods and Problems of Analysis ...................... 600
2.2.1. Blood Analysis ................................. 600
2.2.2. Air, Water, Soil, and Sediments ................ 601
2.2.3. Specialized Techniques ......................... 601
2.3. Production and Uses ................................... 602
2.4. Exposure .............................................. 602
2.4.1. General Environment ............................ 602
2.4.2. Occupational Environments ...................... 606
2.5. Toxicokinetics ........................................ 606
2.5.1. Absorption ..................................... 606
2.5.2. Distribution ................................... 608
2.5.3. Biotransformation .............................. 610
2.5.4. Elimination .................................... 610
2.5.5. Biokinetics .................................... 611
2.5.6. Gene-Environment Interaction ................... 612
2.6. Biological Monitoring ................................. 613
2.6.1. Biomarkers of Exposure ......................... 613
2.6.2. Biomarkers of Effects .......................... 616
2.6.3. Summary ........................................ 618
2.7. Organ Effects ......................................... 619
2.7.1. Nervous System ................................. 619
2.7.2. Blood and Blood-Forming Organs ................. 621
2.7.3. Kidneys ........................................ 622
2.7.4. Cardiovascular System .......................... 623
2.7.5. Endocrine System ............................... 624
2.7.6. Gastrointestinal Tract ......................... 625
2.7.7. Other Organs ................................... 625
2.8. Immunotoxicology ...................................... 625
2.9. Mutagenicity .......................................... 625
2.10.Cancer ................................................ 626
2.11.Reproduction .......................................... 626
2.11.1.Females and Offspring .......................... 626
2.11.2.Males .......................................... 629
2.12.Overall Assessment of Risk ............................ 629
2.12.1.The Data Sets-Strengths and Limitations ........ 629
2.12.2.Effects and Their Relation to Exposure ......... 630
2.13.Exposure Standards and Classifications ................ 630
2.13.1. Occupational Exposure Limits (OELs) ........... 630
2.13.2. Other Assessments ............................. 631
2.14.Diagnosis, Treatment, and Prognosis of Poisoning
and Medical Surveillance .............................. 631
2.14.1.Diagnosis ...................................... 631
2.14.2.Treatment ...................................... 632
2.14.3.Prognosis ...................................... 632
2.14.4.Medical Surveillance ........................... 633
3. Organic Lead ............................................... 633
3.1. Physical and Chemical Properties ...................... 633
3.2. Methods and Problems of Analysis ...................... 633
3.3. Production and Uses ................................... 633
3.4. Exposure .............................................. 633
3.5. Toxicokinetics ........................................ 634
3.6. Biological Monitoring ................................. 634
3.6.1. Biomarkers of Exposure ......................... 634
3.6.2. Biomarkers of Effects .......................... 634
3.7. Organ Effects ......................................... 635
3.7.1. Nervous System ................................. 635
3.7.2. Other .......................................... 635
3.8. Diagnosis, Treatment, and Prognosis CHAPTER ........... 635
CHAPTER 32. Manganese
MARKO SARIC AND ROBERTO LUCCHINI
1. Physical and Chemical Properties ........................... 646
2. Methods and Problems of Analysis ........................... 646
3. Occurrence, Production, and Uses ........................... 647
3.1. Occurrence and Production ............................. 647
3.2. Uses .................................................. 647
4. Levels and Fate in the Environment and Exposure ............ 648
4.1. General Environment ................................... 648
4.1.1. Ambient Air .................................... 648
4.1.2. Water .......................................... 649
4.1.3. Soil ........................................... 650
4.2. Food .................................................. 650
4.3. Working Environment ................................... 651
5. Toxicokinetics ............................................. 651
5.1. Absorption ............................................ 651
5.1.1. Inhalation ..................................... 651
5.1.2. Ingestion ...................................... 652
5.1.3. Dermal Exposure ................................ 653
5.2. Distribution .......................................... 653
5.3. Metabolism ............................................ 655
5.4. Excretion ............................................. 656
6. Health Effects ............................................. 657
6.1. Manganese Deficiency .................................. 657
6.2. Acute Effects ......................................... 657
6.3. Adverse Effects of Prolonged Exposure ................. 658
6.3.1. Neurotoxic Effect .............................. 658
6.4. Effect on the Lungs ................................... 663
6.4.1. Mode of Action ................................. 663
6.4.2. Human Studies of Lung Impairment ............... 663
6.5. Effects on Other Organs and Systems ................... 664
6.5.1. Reproductive Effects ........................... 664
6.5.2. Cardiovascular Effects ......................... 665
6.5.3. Hematological Effects .......................... 665
6.5.4. Endocrine Effects .............................. 665
6.5.5. Immunological Effects .......................... 665
6.5.6. Genotoxic and Carcinogenic Effects ............. 666
7. Guidelines/Regulations ..................................... 666
8. Manganese Concentrations in Biological Media and
Biomarkers of Exposure and Effects ......................... 667
CHAPTER 33. Mercury
MATHS BERLIN, RUDOLFS K. ZALUPS, AND BRUCE
A. FOWLER
1. Introduction ............................................... 676
2. Physical and Chemical Properties ........................... 677
3. Methods and Problems of Analysis ........................... 677
4. Production and Uses ........................................ 679
4.1. Production ............................................ 679
4.2. Uses .................................................. 680
5. Environmental Levels and Exposures ......................... 680
5.1. General Environment ................................... 680
5.1.1. Food and Daily Intake .......................... 680
5.1.2. Water .......................................... 682
5.1.3. Ambient Air .................................... 682
5.1.4. Soils and Sediments ............................ 682
5.2. Working Environment ................................... 683
6. Metabolism and Toxic Effects of Elemental Mercury and
Inorganic Mercury Compounds ................................ 683
6.1. Elemental Mercury ..................................... 684
6.1.1. Metabolism ..................................... 684
6.1.2. Symptoms and Signs in Poisoning Caused by
Exposure to Mercury Vapor ...................... 686
6.1.3. Indicators of Exposure and Concentration in
the Critical Organ ............................. 689
6.1.4. Dose-Response Relationships .................... 689
6.2. Mercuric Mercury ...................................... 693
6.2.1. Metabolism ..................................... 693
6.2.2. Symptoms and Signs in Poisoning Caused by
Mercuric Salts ................................. 698
6.2.3. Indicators of Exposure and Concentration in
the Critical Organ ............................. 701
6.2.4. Dose-Effect and Dose-Response Relationships
on Exposure to Mercuric Salts .................. 701
6.2.5. Factors Interacting with the Toxicity of
Mercuric Mercury ............................... 702
7. Metabolism and Toxic Effects of Organic Mercury
Compounds .................................................. 703
7.1. Organic Compounds Relatively Stable in the
Mammalian Body ........................................ 703
7.1.1. Metabolism Absorption-Inhalation ............... 703
7.1.2. Toxic Effects and Mechanisms ................... 709
7.1.3. Symptoms and Signs in Poisoning Caused by
Exposure to Alkylmercury ....................... 712
7.1.4. Indicators of Exposure and Concentration in
the Critical Organ ............................. 713
7.1.5. Dose-Response Relationships .................... 713
8. Prevention, Prognosis, and Treatment ....................... 717
8.1. Mercury Vapor ......................................... 718
8.2. Inorganic Mercuric Mercury ............................ 718
8.3. Short-Chain Alkylmercury .............................. 718
8.4. Phenylmercury Compounds or Methoxyethylmercury
Compounds ............................................. 718
8.5. Long-Term Therapy in Chronic Exposed Cases ............ 718
CHAPTER 34 Molybdenum
JUDITH R. TURNLUND AND LARS T. FRIBERG
1. Physical and Chemical Properties ........................... 731
2. Methods and Problems of Analysis ........................... 732
3. Production and Uses ........................................ 732
3.1. Production ............................................ 732
3.2. Uses .................................................. 732
4. Environmental Levels and Exposure .......................... 732
4.1. Food and Daily Intake ................................. 732
4.2. Water, Soil, and Ambient Air .......................... 733
5. Metabolism ................................................. 733
5.1. Absorption ............................................ 733
5.1.1. Inhalation ..................................... 733
5.1.2. Ingestion ...................................... 733
5.2. Distribution .......................................... 733
5.3. Excretion ............................................. 734
5.4. Biological Half-Life .................................. 734
5.5. Molybdenum Deficiency ................................. 734
5.6. Dietary Requirements and Recommendations .............. 735
6. Biological Monitoring ...................................... 736
6.1. Biomarkers of Exposure ................................ 736
6.2. Biomarkers of Effects ................................. 736
7. Effects and Dose-Response Relationships .................... 736
7.1. Local Effects and Dose-Response Relationships ......... 736
7.1.1. Animals ........................................ 736
7.1.2. Humans ......................................... 736
7.2. Systemic Effects and Dose-Response Relationships ...... 737
7.2.1. Laboratory Animals ............................. 737
7.2.2. Livestock ...................................... 737
7.2.3. Humans ......................................... 737
7.3. Interaction with Copper and Sulfur .................... 738
CHAPTER 35. Nickel
CATHERINE KLEIN AND MAX COSTA
1. Physical and Chemical Properties ........................... 743
2. Methods and Problems of Analysis ........................... 743
3. Production and Uses ........................................ 744
3.1. Production ............................................ 744
3.2. Uses .................................................. 744
4. Environmental Exposures .................................... 744
4.1. General Environment ................................... 744
4.1.1. Air, Soil, and Water ........................... 744
4.1.2. Food Intake .................................... 745
4.1.3. Skin Absorption ................................ 745
4.1.4. Tobacco ........................................ 745
4.2. Working Environment ................................... 746
5. Metabolism ................................................. 746
5.1. Essentiality .......................................... 746
5.2. Absorption ............................................ 747
5.3. Transport ............................................. 747
5.4. Excretion ............................................. 747
5.5. Biological Half-Time .................................. 748
6. Biological Monitoring ...................................... 748
6.1. Levels in Human Tissues and Fluids .................... 748
6.2. Biomarkers of Exposure ................................ 748
7. Toxicological Effects ...................................... 749
7.1. General Systemic Effects in Animals and Humans ........ 749
7.2. Inhalation Effects in Animals and Humans .............. 749
7.3. Skin Effects in Animals and Humans .................... 749
7.4. Injection Site Effects in Animals ..................... 750
7.5. Teratogenicity ........................................ 750
8. Genotoxicity and Carcinogenicity ........................... 751
8.1. Genotoxicity and Mutagenicity ......................... 751
8.2. Carcinogenicity in Animals and Humans ................. 752
8.2.1. Animals ........................................ 752
8.2.2. Humans ......................................... 752
9. Effects on Gene Expression and Signaling Pathways .......... 753
10.Epigenetic Effects ......................................... 754
10.1.Effects on DNA Methylation and Epigenetic Silencing ... 754
10.2.Effects on Histone Acetylation ........................ 755
11.Treatment of Nickel Carbonyl Poisoning ..................... 755
CHAPTER 36. Palladium
HIROSHI SATOH
1. Physical and Chemical Properties ........................... 759
2. Methods and Problems of Analysis ........................... 760
3. Production and Uses ........................................ 760
3.1. Production ............................................ 760
3.2. Uses .................................................. 760
4. Environmental Levels and Exposures ......................... 761
4.1. Water, Soil, and Ambient Air .......................... 761
4.2. Food and Daily Intake ................................. 762
4.3. Working Environment ................................... 762
4.4. Iatrogenic Exposure ................................... 762
5. Metabolism ................................................. 763
5.1. Absorption ............................................ 763
5.2. Distribution .......................................... 763
5.3. Excretion ............................................. 763
6. Levels in Tissues and Biological Fluids .................... 763
7. Effects and Dose-Response Relationships .................... 764
7.1. Animals ............................................... 764
7.1.1. Single Exposure ................................ 764
7.1.2. Repeated Exposure .............................. 764
7.1.3. Chronic Exposure ............................... 764
7.1.4. Irritation and Sensitization ................... 764
7.1.5. DNA Interactions and Mutagenicity .............. 764
7.1.6. Carcinogenicity ................................ 765
7.2. Humans ................................................ 765
7.2.1. General Population Exposure .................... 765
7.2.2. Iatrogenic Exposure ............................ 765
7.2.3. Occupational Exposure .......................... 765
7.2.4. Carcinogenicity and Other Effects .............. 766
7.3. Dose-Response Relationships ........................... 766
8. Diagnosis, Treatment, Prognosis, and Prevention ............ 766
CHAPTER 37. Platinum
MIRJA KIILUNEN AND ANTERO AITIO
1. Physical and Chemical Properties ........................... 769
2. Methods and Problems of Analysis ........................... 770
3. Production and Uses ........................................ 770
3.1. Production ............................................ 770
3.2. Uses .................................................. 771
4. Environmental Levels and Exposure .......................... 771
4.1. General Environment ................................... 771
4.2. Working Environment ................................... 771
4.3. Food .................................................. 771
5. Kinetics and Metabolism .................................... 774
5.1. Absorption, Distribution, and Excretion ............... 774
5.2. Reference Values in Tissues and Biological Fluids ..... 774
5.3. Biological Monitoring ................................. 775
6. Effects in Animals and Humans and Dose-Response
Relationships .............................................. 775
6.1. Acute Toxicity ........................................ 775
6.2. Sensitization ......................................... 777
6.3. Carcinogenicity, Mutagenicity, and Reproductive
Effects ............................................... 779
7. Risk Assessment CHAPTER .................................... 779
CHAPTER 38. Selenium
JOHAN HOGBERG AND JAN ALEXANDER
1. Physical and Chemical Properties ........................... 784
2. Methods and Problems of Analysis ........................... 784
3. Production and Uses ........................................ 785
3.1. Production ............................................ 785
3.2. Uses .................................................. 785
4. Environmental Levels and Exposure .......................... 785
4.1. General Environment ................................... 785
4.1.1. Food and Daily Intake .......................... 785
4.1.2. Ambient Air .................................... 785
4.1.3. Water .......................................... 786
4.1.4. Rocks and Soil ................................. 786
4.1.5. Plants ......................................... 786
4.1.6. Tobacco ........................................ 786
4.2. Work Environment ...................................... 786
5. Biological Function and Metabolism ......................... 787
5.1. Biological Functions .................................. 787
5.2. Selenium Deficiency and Diseases Related to
Selenium Status ....................................... 787
5.2.1. Animals ........................................ 787
5.2.2. Selenium and Cardiovascular Diseases ........... 787
5.2.3. Selenium and Cancer ............................ 787
5.2.4. Infectious Diseases ............................ 788
5.2.5. Other Diseases ................................. 789
5.3. Kinetics .............................................. 789
5.3.1. Absorption ..................................... 789
5.3.2. Distribution ................................... 789
5.3.3. Biotransformation .............................. 790
5.3.4. Excretion ...................................... 791
5.3.5. Biological Half-Time ........................... 791
6. Biological Monitoring ...................................... 791
6.1. Levels. in Tissues and Biological Fluids .............. 791
6.2. Biomarkers of Exposure ................................ 792
6.3. Biomarkers of Effect .................................. 792
7. Effects and Dose-Response Relationships .................... 792
7.1. Acute Toxicity ........................................ 792
7.1.1. Laboratory Animals ............................. 792
7.1.2. Humans ......................................... 793
7.2. Chronic Toxicity ...................................... 794
7.2.1. Laboratory Animals ............................. 794
7.2.2. Domestic Animals ............................... 795
7.2.3. Humans ......................................... 795
7.3. Other Diseases Related to Selenium Overexposure ....... 799
7.4. Mutag. enic Effects ................................... 799
7.5. Carcinogenic Effects .................................. 799
7.5.1. Animals ........................................ 799
7.5.2. Humans ......................................... 800
7.6. Reproductive and Developmental Effects ................ 800
7.7. Interactions with Metals .............................. 800
7.7.1. Arsenic ........................................ 801
7.7.2. Bismuth ........................................ 801
7.7.3. Cadmium ........................................ 801
7.7.4. Cobalt ......................................... 801
7.7.5. Copper ......................................... 801
7.7.6. Lead ........................................... 801
7.7.7. Mercury ........................................ 802
7.7.8. Platinum ....................................... 803
7.7.9. Silver ......................................... 803
7.7.10.Tellurium ...................................... 803
7.7.11.Thallium ....................................... 803
8. Prevention, Diagnosis, Prognosis, and Treatment ............ 803
CHAPTER 39 Silver
JAMES S. HOLLER, GUNNAR F. NORDBERG, AND
BRUCE A. FOWLER
1. Physical and Chemical Properties ........................... 809
2. Methods and Problems of Analysis ........................... 809
3. Production and Uses ........................................ 809
3.1. Production ............................................ 809
3.2. Uses .................................................. 810
4. Environmental Levels and Exposures ......................... 810
4.1. General Environment ................................... 810
4.1.1. Food and Daily Intake .......................... 810
4.1.2. Water, Soil, and Ambient Air ................... 810
4.1.3. Tobacco ........................................ 810
5. Metabolism ................................................. 810
5.1. Absorption ............................................ 810
5.1.1. Inhalation ..................................... 810
5.1.2. Ingestion ...................................... 811
5.2. Distribution .......................................... 811
5.3. Excretion ............................................. 811
5.4. Biological Half-Time .................................. 811
6. Levels in Tissues and Biological Fluids-Reference Values ... 811
7. Effects and Dose-Response Relationships .................... 812
7.1. Local Effects and Dose-Response Relationships ......... 812
7.2. Systemic Effects and Dose-Response Relationships ...... 812
7.2.1. Animals ........................................ 812
7.2.2. Humans ......................................... 812
7.3. Interactions with Selenium, Copper and Vitamin E ...... 813
8. Treatment CHAPTER .......................................... 813
CHAPTER 40. Tellurium
LARS GERHARDSSON
1. Physical and Chemical Properties ........................... 816
2. Methods and Problems of Analysis ........................... 816
3. Production and Uses ........................................ 816
3.1. Production ............................................ 816
3.2. Uses .................................................. 816
4. Environmental Levels and Exposures ......................... 817
4.1. General Environment ................................... 817
4.1.1. Food and Daily Intake .......................... 817
4.1.2. Water, Soil, and Ambient Air ................... 817
4.1.3. Plants ......................................... 817
4.2. Working Environment ................................... 817
5. Metabolism ................................................. 817
5.1. Absorption ............................................ 817
5.1.1. Inhalation ..................................... 817
5.1.2. Ingestion ...................................... 817
5.1.3. Skin Absorption ................................ 818
5.2. Distribution .......................................... 818
5.3. Excretion ............................................. 818
5.4. Biological Half-Time .................................. 818
6. Biological Monitoring ...................................... 818
6.1. Levels in Tissues and Biological Fluids ............... 818
6.2. Biomarkers of Exposure ................................ 818
6.3. Biomarkers of Effects ................................. 819
7. Effects and Dose-Response Relationships .................... 819
7.1. Local Effects and Dose-Response Relationships ......... 819
7.1.1. Animals ........................................ 819
7.1.2. Humans ......................................... 819
7.2. Systemic Effects and Dose-Response Relationships ...... 819
7.2.1. Animals ........................................ 819
7.2.2. Humans ......................................... 822
7.2.3. Summary of Systemic Effects .................... 822
8. Carcinogenicity and Mutagenicity ........................... 823
9. Diagnosis, Prevention, and Treatment of Tellurium
Poisoning .................................................. 823
10.Standards-Threshold Limit Values ........................... 823
CHAPTER 41. Thallium
GEORGE KAZANTZIS
1. Physical and Chemical Properties ........................... 827
2. Methods and Problems of Analysis ........................... 828
3. Production and Uses ........................................ 828
4. Environmental Levels and Exposure .......................... 828
4.1. General Environment ................................... 828
4.2. Working Environment ................................... 829
5. Metabolism ................................................. 829
5.1. Absorption ............................................ 829
5.2. Distribution .......................................... 829
5.3. Excretion ............................................. 830
5.4. Biological Half-Time .................................. 830
6. Biological Monitoring ...................................... 831
7. Effects and Dose-Response Relationships .................... 831
7.1. Laboratory Animals .................................... 831
7.2. Domestic and Wild Animals ............................. 832
7.3. Humans ................................................ 832
7.4. Interaction with Potassium and Other Effects .......... 833
8. Diagnosis, Treatment, and Preventive Measures .............. 834
9. Prognosis CHAPTER .......................................... 835
CHAPTER 42. Tin
ELENA A. OSTRAKHOVITCH AND M. GEORGE CHERIAN
1. Physical and Chemical Properties ........................... 839
2. Methods of Analysis ........................................ 840
3. Production and Uses ........................................ 841
3.1. Production ............................................ 841
3.2. Uses .................................................. 841
4. Environmental Levels and Exposures ......................... 842
4.1. General Environment ................................... 842
4.1.1. Food and Daily Intake .......................... 842
4.1.2. Water, Soil, and Air ........................... 843
4.2. Working Environment ................................... 844
5. Metabolism ................................................. 844
5.1. Inorganic Tin ......................................... 844
5.1.1. Absorption ..................................... 844
5.1.2. Distribution ................................... 845
5.1.3. Excretion ...................................... 846
5.1.4. Biological Half-Life ........................... 846
5.1.5. Biotransformation .............................. 846
5.2. Organotin Compounds ................................... 846
5.2.1. Absorption ..................................... 846
5.2.2. Distribution ................................... 847
5.2.3. Excretion ...................................... 847
5.2.4. Biological Half-Life ........................... 848
5.2.5. Biotransformation .............................. 848
6. Levels in Tissue and Biological Fluids ..................... 848
7. Effects and Dose-Response Relationships .................... 849
7.1. Inorganic Tin ......................................... 849
7.1.1. Local Effects and Dose-Response
Relationships .................................. 849
7.1.2. Systemic Effects and Dose-Response
Relationships .................................. 850
7.2. Organotin ............................................. 851
7.2.1. Local Effects and Dose-Response
Relationships .................................. 851
7.2.2. Systemic Effects and Dose-Response
Relationships .................................. 852
7.3. Mechanism of Action ................................... 854
CHAPTER 43. Titanium
TAIYI JIN AND MATHS BERLIN
1. Physical and Chemical Properties ........................... 861
2. Methods and Problems of Analysis ........................... 862
3. Production and Uses ........................................ 862
3.1. Production ............................................ 862
3.2. Uses .................................................. 862
4. Environmental Levels and Exposures ......................... 863
4.1. General Environment ................................... 863
4.1.1. Food and Daily Intake .......................... 863
4.1.2. Water, Soil, and Ambient Air ................... 863
4.2. Working Environment ................................... 863
5. Metabolism ................................................. 864
5.1. Absorption ............................................ 864
5.2. Distribution .......................................... 864
5.3. Biological Half-Time .................................. 864
5.4. Excretion ............................................. 865
6. Levels in Tissues and Biological Fluids .................... 865
7. Effects and Dose-Response Relationships .................... 865
7.1. Local Effects and Dose-Response Relationships ......... 865
7.1.1. Animals ........................................ 865
7.1.2. Humans ......................................... 866
7.2. Systemic Effects and Dose-Response Relationships ...... 867
7.2.1. Animals ........................................ 867
7.2.2. Humans ......................................... 867
7.3. Mutagenicity, Carcinogenicity, Teratogenicity,
and Effects on Reproduction ........................... 867
7.3.1. Animals ........................................ 867
7.3.2. Human CHAPTER .................................. 868
CHAPTER 44. Tungsten
GEORGE KAZANTZIS AND PER LEFFLER
1. Physical and Chemical Properties ........................... 871
2. Methods and Problems of Analysis ........................... 871
3. Production and Uses ........................................ 872
3.1. Production ............................................ 872
3.2. Uses .................................................. 872
4. Environmental Levels and Exposures ......................... 872
4.1. General Environment ................................... 872
4.2. Working Environment ................................... 873
5. Metabolism ................................................. 873
5.1. Absorption ............................................ 873
5.2. Distribution .......................................... 873
5.3. Excretion ............................................. 874
5.4. Biological Half-Time .................................. 874
6. Biological Monitoring ...................................... 874
7. Effects and Dose-Response Relationships .................... 875
7.1. Local Effects and Dose-Response Relationships ......... 875
7.1.1. Animals ........................................ 875
7.1.2. Humans ......................................... 875
7.2. Systemic Effects and Dose-Response Relationships ...... 876
7.2.1. Animals ........................................ 876
7.2.2. Humans ......................................... 877
7.3. Interaction with Molybdenum ........................... 877
CHAPTER 45. Uranium
L. SAMUEL KEITH, OBAID M. FAROON, AND BRUCE
A. FOWLER
1. Physical, Chemical, and Radiological Properties ............ 882
2. Analytical Methods ......................................... 883
3. Production and Uses ........................................ 885
3.1. Production ............................................ 885
3.2. Uses .................................................. 886
4. Environmental Levels and Exposures ......................... 886
4.1. Environmental Levels and Human Exposure ............... 886
4.1.1. Food and Daily Intake .......................... 886
4.1.2. Water .......................................... 886
4.1.3. Soil and Rock .................................. 888
4.1.4. Air ............................................ 888
4.1.5. Other .......................................... 889
4.2. Working Environment ................................... 889
4.3. Remediation ........................................... 889
5. Toxicokinetics ............................................. 889
5.1. Absorption ............................................ 890
5.1.1. Inhalation ..................................... 890
5.1.2. Ingestion ...................................... 890
5.1.3. Dermal Exposure ................................ 891
5.2. Metabolism and Distribution ........................... 891
5.3. Elimination and Excretion ............................. 892
6. Mechanisms of Action ....................................... 892
6.1. Chemical versus Radiological .......................... 893
6.2. Route of Exposure ..................................... 893
6.3. Hepatic Mechanisms .................................... 893
6.4. Immunological Mechanisms .............................. 894
6.5. Pulmonary Mechanisms .................................. 894
6.6. Renal Mechanisms ...................................... 894
6.7. Skeletal Mechanism .................................... 895
6.8. Summary on Mechanisms ................................. 895
7. Effects and Dose-Response Relationships .................... 895
7.1. Organ and Tissue Effects .............................. 896
7.1.1. Cancer ......................................... 896
7.1.2. Dermal Effects ................................. 896
7.1.3. Developmental Effects .......................... 896
7.1.4. Hepatic Effects ................................ 896
7.1.5. Neurological Effects ........................... 897
7.1.6. Pulmonary Effects .............................. 897
7.1.7. Renal Effects .................................. 897
7.1.8. Reproductive Effects ........................... 899
7.2. Health Guidance Values ................................ 899
8. Biomarkers ................................................. 899
8.1. Biomarkers Used to Assess Exposure .................... 899
8.2. Biomarkers Used to Characterize Effect ................ 900
9. Treatment Methods for Reducing Toxic Effects ............... 900
CHAPTER 46. Vanadium
BIRGITTA J-SON LAGERKVIST AND AGNETA OSKARSSON
1. Physical and Chemical Properties ........................... 906
2. Methods and Problems of Analysis ........................... 906
3. Production and Uses ........................................ 907
3.1. Production ............................................ 907
3.2. Uses .................................................. 907
4. Environmental Levels and Exposures ......................... 907
4.1. General Environment ................................... 907
4.1.1. Food ........................................... 907
4.1.2. Air ............................................ 907
4.1.3. Mosses ......................................... 908
4.1.4. Water .......................................... 908
4.1.5. Soil ........................................... 908
4.1.6. Coal and Oil ................................... 909
4.2. Work Environment ...................................... 909
5. Toxicokinetics ............................................. 909
5.1. Absorption ............................................ 909
5.1.1. Inhalation ..................................... 909
5.1.2. Ingestion ...................................... 910
5.1.3. Skin ........................................... 910
5.2. Distribution .......................................... 910
5.2.1. Animal Studies ................................. 910
5.2.2. Human Studies .................................. 911
5.3 Elimination and Biological Half-Time ................ 911
5.3.1. Animal Studies ................................. 911
5.3.2. Human Studies .................................. 911
6. Biological Monitoring ...................................... 912
7. Effects and Dose-Response Relationships .................... 913
7.1. Local Effects and Dose-Response Relationships ......... 913
7.1.1. Human Studies .................................. 913
7.2. Systemic Effects and Dose-Response Relationships ...... 915
7.2.1. Animals ........................................ 915
7.2.2. Humans ......................................... 918
8. Treatment of Vanadium Poisoning ............................ 919
CHAPTER 47. Zinc
HAROLD H. SANDSTEAD AND WILLIAM AU
1. Identity and Physical/Chemical Properties .................. 925
2. Analytical Methods ......................................... 926
3. Sources of Human and Environmental Exposure ................ 926
3.1. Uses .................................................. 926
3.2. General Environment ................................... 926
3.2.1. Atmosphere ..................................... 927
3.2.2. Water .......................................... 927
3.2.3. Soil ........................................... 927
4. Environmental Transport, Distribution, and
Transformation ............................................. 927
4.1. Air ................................................... 927
4.2. Water and Sediment .................................... 927
4.3. Soil .................................................. 927
4.4. Biotransformation ..................................... 928
5. Environmental Levels and Human Exposure .................... 928
5.1. Air ................................................... 928
5.2. Water ................................................. 928
5.3. Soil .................................................. 928
5.4.1. Plants ......................................... 930
5.4.2. Flesh Foods .................................... 930
5.4.3. Dairy Products ................................. 930
5.4.4. Nutritional Supplements ........................ 930
5.5. Work Environment ...................................... 930
5.5.1. Inhalation ..................................... 930
6. Biological Monitoring ...................................... 930
6.1. Direct Indicators of Zn Status ........................ 930
6.1.1. History ........................................ 930
6.1.2. Plasma/Serum Zinc .............................. 930
6.1.3. White Blood Cell Zinc .......................... 931
6.1.4. Hair Zn ........................................ 931
6.1.5. Urine Zinc ..................................... 931
6.2. Indirect Physiological Indicators of Zn Status ........ 931
6.2.1. Alkaline Phosphatase ........................... 931
6.2.2. Ecto 5'-Nucleotidase ........................... 931
6.2.3. Immunity ....................................... 931
6.2.4. Neuropsychological Functions ................... 932
6.2.5. Dark Adaptation ................................ 933
6.2.6. Taste Acuity ................................... 933
6.2.7. Growth and Body Composition .................... 933
6.2.8. Physical Examination ........................... 933
7. Effects on Laboratory Mammals .............................. 934
7.1. Essentiality .......................................... 934
7.2. Deficiency ............................................ 934
7.3. Single Toxic Exposure of Animals ...................... 935
7.4. Short-Term Exposure of Animals ........................ 935
7.5. Long-Term Exposure and Carcinogenicity ................ 935
7.6. Reproductive Toxicity ................................. 935
8. Effects on Humans .......................................... 936
8.1. Absorption ............................................ 936
8.2. Excretion ............................................. 936
8.3. Biological Half-Life .................................. 936
8.4. Zinc Content of Tissues and Blood ..................... 936
8.5. Essentiality and Requirements ......................... 937
8.5.1. Bioavailability ................................ 937
8.5.2. Methods for Determining Requirements ........... 937
8.6. Deficiency ............................................ 939
8.6.1. Dietary (Primary) Deficiency ................... 939
8.6.2. Conditioned (Secondary) Deficiency ............. 939
8.7. Toxicity .............................................. 940
8.7.1. Dietary and Supplement Intakes ................. 940
8.7.2. Reference Dose (RfD) ........................... 941
8.7.3. Poisoning from Ingestion of Zinc-
Contaminated Food, Drink, and Other
Substances ..................................... 941
8.7.4. Poisoning from Inhalation ...................... 941
9. Effects Evaluation ......................................... 942
9.1. Homeostatic Model ..................................... 942
9.2. Risks to Human Health ................................. 942
9.2.1. General Population ............................. 942
9.2.2. Occupational Exposure .......................... 943
9.2.3. Risk of Zn Deficiency .......................... 943
9.2.4. Risk of Excess Zn .............................. 943
9.2.5. Environmental Risk Assessment for Zn ........... 943
Index ..................................................... 949-975
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