THE CHEMICAL BASIS OF LIFE
1 UNDERSTANDING COMBINED EFFECTS FOR METAL CO-EXPOSURE IN ECOTOXICOLOGY 1 Abstract 2 1 Ecotoxicity from Mixture Exposure 2 2 Combination Effect Analysis 6 3 Interactions During Exposure 13 4 Joint Action in Toxicodynamics 17 5 Interaction with Organic Compounds 21 6 Outlook 24 Acknowledgments 25 Abbreviations 25 References 25 2 HUMAN RISK ASSESSMENT OF HEAVY METALS: PRINCIPLES AND APPLICATIONS 27 Abstract 28 1 Introduction 29 2 Principles of Chemical Risk Assessment 29 3 Toxicology of Heavy Metals 34 4 Analytical Techniques and Exposure Assessment of Heavy Metals 39 5 Applications to the Human Risk Assessment of Heavy Metals and Metalloids 43 6 Conclusions and Future Perspectives 53 Acknowledgments 54 Abbreviations and Definitions 54 References 54 3 MIXTURES AND THEIR RISK ASSESSMENT IN TOXICOLOGY 61 Abstract 62 1 Introduction 62 2 Predictions of Toxicity Outcomes 64 3 Weight-of-Evidence Evaluations 66 4 Experimental Validations 68 5 Conclusion 77 Abbreviations 77 References 77 4 METAL IONS AFFECTING THE PULMONARY AND CARDIOVASCULAR SYSTEMS 81 Abstract 82 1 Introduction 83 2 Aluminum 83 3 Arsenic 84 4 Beryllium 85 5 Copper 86 6 Cadmium 87 7 Chromium 89 8 Cobalt 92 9 Lead 93 10 Manganese 95 11 Nickel 97 12 Zinc 98 13 Concluding Remarks 99 References 100 5 METAL IONS AFFECTING THE GASTROINTESTINAL SYSTEM INCLUDING THE LIVER 107 ´ Abstract 108 1 Introduction 108 2 Exposure to Metal Ions in the Gastrointestinal Tract and Liver 110 3 Estimation of Toxicity Associated with Metal Ions in the Gastrointestinal Tract and Liver 117 4 Metal Ion-Molecular Interactions: Effects on Oxidative Damage 123 5 Concluding Remarks and Future Directions 127 Abbreviations 127 References 128 6 METAL IONS AFFECTING THE KIDNEY 133 Abstract 133 1 Introduction 134 2 Exposure to Metal Ions in Air, Food, and Water 134 3 Transport of Metals/Metalloids in the Circulation 135 4 Mechanisms of Metal and Metalloid Uptake by the Kidney 136 5 Effects of Metals/Metalloids on the Kidney 136 6 Mechanisms of Renal Cell Injury 137 7 Renal Biomarkers 137 8 Metal/Metalloid Interactions in the Kidney 138 9 Concluding Remarks and Future Directions 138 Abbreviations 139 References 139 7 METAL IONS AFFECTING THE HEMATOLOGICAL SYSTEM 143 Abstract 144 1 Exposure to Metals and Their Mixtures 144 2 Metals Affecting the Hematological System 145 3 Binary Interactions of Metals and Hematological Effects 147 4 Interaction of Metals with other Chemicals 152 5 Conclusions 153 Abbreviations 153 References 153 8 METAL IONS AFFECTING THE IMMUNE SYSTEM 157 Abstract 157 1 Introduction 158 2 Immunotoxicity and Immunomodulation 159 3 Effect of Heavy Metals on Innate Immunity 160 4 Effect of Heavy Metals on Adaptive Immunity 161 5 Mechanisms of Heavy Metal-Induced Immunotoxic/Immunomodulatory Effects 166 6 Influence of Heavy Metals on the Resistance Toward Infections 170 7 Chronic Inflammation and Autoimmunity 173 8 Concluding Remarks 176 Acknowledgments 177 Abbreviations and Definitions 177 References 178 9 METAL IONS AFFECTING THE SKIN AND EYES 187 Abstract 188 1 Introduction 188 2 Metal Ions and Metal Ion Gradients in the Physiology and Homeostasis of Mammalian Skin 190 3 Xenobiotic Metal Ions 205 4 Carcinogenicity of Metal Ions in the Skin 222 5 The Eye 224 6 General Conclusions 228 Abbreviations 229 References 230 10 METAL IONS AFFECTING THE NEUROLOGICAL SYSTEM 247 Abstract 248 1 Exposure to Metals and Their Mixtures 248 2 Metals Affecting the Neurological System 249 3 Interaction of Metals and Neurological Effects 253 4 Interactions of Metals with Other Chemicals 256 5 Conclusions 259 Abbreviations 260 References 260 11 METAL IONS AFFECTING REPRODUCTION AND DEVELOPMENT 263 Abstract 264 1 Introduction 265 2 Time and Duration of Exposure 267 3 Mechanisms of Action 269 4 Reproductive Effects 270 5 Abortions and Other Pregnancy Effects 280 6 Prenatal Exposure and Developmental Effects 283 7 Early Postnatal Exposure and Developmental Effects 288 8 Concluding Remarks and Needs for Further Research 293 Abbreviations 294 References 295 12 ARE CADMIUM AND OTHER HEAVY METAL COMPOUNDS ACTING AS ENDOCRINE DISRUPTERS? 305 Abstract 306 1 Introduction 306 2 A Model for Estrogen Receptor Activation by Cadmium 307 3 Cadmium Exposure and Cancer Risks in Endocrine- Sensitive Tissues 308 4 In Vivo Studies of Estrogenic Effects of Cadmium 310 5 Cadmium and Other Heavy Metals in In Vitro Cell-Based Assays of Estrogenicity 311 6 Weight of Evidence and Implications for Human Risk Assessment 313 Abbreviations 315 References 315 13 GENOTOXICITY OF METAL IONS: CHEMICAL INSIGHTS 319 Abstract 320 1 Introduction 321 2 Overview of Chemical and Biochemical Processes Leading to Genotoxic Lesions 322 3 Mechanisms of Metal Ion Genotoxicity 330 4 Genotoxic Properties of Selected Metals 336 5 Critical Overview of the Experimental Methods for Studying the Genotoxic Potential of Metals 354 6 Concluding Remarks and Future Directions 357 Acknowledgments 358 Abbreviations 358 References 359 14 METAL IONS IN HUMAN CANCER DEVELOPMENT 375 Abstract 376 1 Introduction 376 2 Known Human Metallic Carcinogens 380 3 Probable and Possible Metallic Carcinogens 388 4 Potential Mechanisms of Metallic Carcinogens 391 5 Periods of Particular Sensitivity to Inorganic Carcinogens 395 6 Future Issues in Metal Carcinogenesis 396 Acknowledgments 397 Abbreviations and Definitions 397 References 397