Throughout history, arsenic has been used as an effective and lethal poison. Today, arsenic continues to present a real threat to human health all over the world, as it contaminates groundwater and food supplies. Handbook of Arsenic Toxicology presents the latest findings on arsenic, its chemistry, its sources and its acute and chronic effects on the environment and human health. The book takes readings systematically through the target organs, before detailing current preventative and counter measures. This reference enables readers to effectively assess the risks related to arsenic, and provide a comprehensive look at arsenic exposure, toxicity and toxicity prevention. - Brings together current findings on the effects of arsenic on the environment and human health- Includes state-of-the-art techniques in arsenic toxicokinetics, speciation and molecular mechanisms- Provides all the information needed for effective risk assessment, prevention and countermeasure
Front Cover 1
Handbook of Arsenic Toxicology 4
Copyright Page 5
Contents 6
Foreword 18
Preface 20
Acknowledgements 24
List of Contributors 26
1 Arsenic: Chemistry, Occurrence, and Exposure 30
1.1 Introduction 30
1.2 Chemistry of Arsenic 31
1.2.1 Origin and History 31
1.2.2 Atomic Structure and Bonding 32
1.2.3 Arsenic Oxidation and Reduction 34
1.2.4 Arsenic Methylation 35
1.2.5 Historical and Modern Applications of Arsenic 36
1.3 Arsenic Minerals and Compounds 37
1.3.1 Arsenosulfides 37
1.3.2 Metal Arsenides 39
1.3.3 Arsenites 39
1.3.4 Arsenates 40
1.4 Organoarsenicals 40
1.4.1 Organoarsenicals in the Food Chain 41
1.4.2 Organoarsenicals in Chemical Weapons 42
1.4.3 Methylation in Mammals 42
1.5 Arsenic Mobilization in the Environment 42
1.5.1 Aqueous Chemistry of Arsenic 43
1.5.2 Redox-Dependent Mobilization of Arsenic 45
1.5.3 Microbial-Dependent Mobilization 45
1.6 Sources of Arsenic in the Biosphere 45
1.6.1 Arsenic in Rocks and Soils 46
1.6.2 Arsenic in the Atmosphere 48
1.6.2.1 Arsenic Emission due to Burning of Coal 49
1.6.2.2 Arsenic Dissipation from Fly Ash 49
1.6.3 Arsenic in Various Water Resources 50
1.6.3.1 Rain Water 50
1.6.3.2 River and Lake Water 50
1.6.3.3 Sea and Estuarine Water 51
1.6.3.4 Ground Water 51
1.6.4 Arsenic in Dietary Products 52
1.6.4.1 Plants and Crops 52
1.6.4.2 Rice and Other Food Items 52
1.6.4.3 Tobacco 53
1.7 Arsenic in Hydrothermal and Geothermal Fluids 53
1.7.1 Arsenic Occurrence in Hydrothermal Fluids 53
1.7.2 Arsenic Concentration in Shallow and Deep Hydrothermal Systems 55
1.7.3 Arsenic Occurrence in Geothermal Systems 56
1.7.4 Arsenic Speciation and Deposition in Geothermal Fluids 57
1.7.5 Biogeochemical Fate of Arsenic in Hydro- and Geothermal Systems 58
1.8 Arsenic Release from Mining and Mineral Processing 58
1.8.1 Oxidation of Arsenic Sulfide and Industrial Ore Leaching 58
1.8.2 Chemistry of Arsenic Within Mining Wastes 60
1.8.3 Arsenic Release by Artisanal Mining 61
1.9 Global Occurrence of Arsenic in Ground Water 61
1.9.1 Arsenic Release and Mobility in Natural Water 61
1.9.2 Natural and Anthropogenic Occurrence Globally 62
1.9.2.1 India, Bangladesh, and Nepal 62
1.9.2.2 Latin America 63
1.9.2.3 Argentina, Mexico, and Chile 64
1.9.2.4 Peru 65
1.9.2.5 California 65
1.9.2.6 Central America 65
1.10 Methods of Arsenic Removal from Water 66
1.10.1 Removal via Precipitation 66
1.10.2 Removal via Adsorption 67
1.10.3 Phyto-Remediation 69
1.11 Conclusions 69
References 70
2 Ground Water Arsenic Contamination and Its Health Effects in Bangladesh 80
2.1 Introduction 80
2.2 Arsenic Contamination in Bangladesh Ground Water 81
2.2.1 Reasons for Leaching Arsenic in the Ground Water of Bangladesh 82
2.2.2 Reasons for Variation of Arsenic Concentrations Between the Aquifers 83
2.3 Extent of Arsenic Contamination in Bangladesh 83
2.4 Arsenic in Different Environmental Media of Bangladesh 84
2.4.1 Soil 84
2.4.2 River 84
2.4.3 Food Chain 86
2.5 Health Effects of Arsenic Toxicity in Bangladesh 88
2.6 Epidemiology of Arsenicosis in Bangladesh 95
2.7 Management of Arsenicosis Patients in Bangladesh 95
2.8 Socio-Cultural Aspects of Arsenicosis in Bangladesh 96
2.9 Conclusions 97
References 97
3 Arsenic and Fluorescent Humic Substances in the Ground Water of Bangladesh: A Public Health Risk 102
3.1 Introduction 102
3.2 Materials and Methods 103
3.2.1 Geologic and Demographic Overview 103
3.2.2 Sampling 105
3.2.3 Analysis 105
3.3 Results and Discussion 106
3.3.1 Groundwater Quality 106
3.3.2 Arsenic Poisoning in Ground Water 107
3.3.3 Arsenic in Rice and Vegetables 111
3.3.4 Fluorescence Properties of DOC 114
3.3.5 Molecular Characteristics of Humic Substances 117
3.3.6 Health Risks 117
3.4 Conclusions 119
References 120
4 Arsenic Risk Assessment 124
4.1 Introduction 124
4.2 Arsenic Chemistry 126
4.3 Arsenic Occurrence and Exposure 126
4.4 Hazard Identification 127
4.4.1 Arsenite and Arsenate 127
4.4.1.1 Skin Lesions 127
4.4.1.2 Cancer Effects 128
4.4.1.3 Diabetes 129
4.4.1.4 Cardiovascular Effects 129
4.4.1.5 Neurological Effects 130
4.4.1.6 Pulmonary Effects 130
4.4.1.7 Kidney Effects 131
4.4.1.8 Immune Effects 131
4.4.1.9 Other Effects 131
4.4.1.10 Developmental and Reproduction Effects 131
4.4.2 Hazard Identification—DMA and MMA 132
4.4.3 Hazard Identification—Arsine 132
4.5 Arsenic Metabolism, Mode of Action, and Physiologically Based Pharmacokinetic Modeling 132
4.6 Potential Sources of Susceptibility 135
4.7 Dose–Response Approaches 137
4.8 Risk Characterization 137
4.8.1 Reference Values and Regulatory Standards for Arsenical Compounds 137
4.8.1.1 US EPA 137
4.8.1.1.1 Inorganic Arsenic 137
4.8.1.1.2 Organoarsenicals 138
4.8.1.1.3 Arsine 138
4.8.1.2 ATSDR 138
4.8.1.2.1 Inorganic Arsenic 138
4.8.1.2.2 Organoarsenicals 139
4.8.1.3 RIVM National Institute for Public Health and the Environment 139
4.8.1.4 Other Standards, Regulations, and Guidelines 139
4.8.1.5 World Health Organization (WHO) 139
4.8.1.6 California Environmental Protection Agency 139
Disclaimer 140
References 140
5 Evaluation of Novel Modified Activated Alumina as Adsorbent for Arsenic Removal 150
5.1 Introduction 150
5.2 Materials and Methods 151
5.2.1 Preparation of Sol-Gel Activated Alumina 151
5.2.2 Surface Modifications of Sol-Gel Activated Alumina 151
5.2.2.1 Characterization of Adsorbent Materials 152
5.2.3 Batch Adsorption Experiments 152
5.2.3.1 Breakthrough Column Experiments 153
5.2.3.2 Adsorbent Regeneration 154
5.3 Results and Discussion 154
5.3.1 Adsorbents Properties 154
5.3.2 Arsenic Adsorption Equilibrium 156
5.3.2.1 Solution pH as a Function of Adsorption Time 156
5.3.2.2 As Adsorbent Amount as a Function of pH 157
5.3.2.3 Effect of Initial Concentration on As Removal Efficiency 158
5.3.2.4 Adsorption Equilibrium 159
5.3.3 Breakthrough Column Analysis 161
5.3.4 Adsorbent Regeneration 163
5.4 Conclusions 163
Acknowledgments 164
References 164
6 Health Effects Chronic Arsenic Toxicity 166
6.1 Introduction 166
6.2 Dermatological Manifestations 167
6.2.1 Hyperpigmentation 167
6.2.2 Hypopigmentation 168
6.2.3 Hyperkeratosis 170
6.2.4 Bowen’s Disease 172
6.3 Epidemiological Study of Dermatological Manifestations 173
6.3.1 Systemic Manifestations 175
6.3.2 Respiratory Disease 176
6.3.2.1 Epidemiological Study 177
6.3.2.2 Mortality Studies 180
6.3.3 Gastrointestinal Disease 180
6.3.4 Liver Disease 181
6.3.4.1 Experimental Model for Liver Fibrosis 182
6.3.5 Cardiovascular Disease 182
6.3.6 Diseases of the Nervous System 184
6.3.7 Hematological Effects 186
6.3.8 Diabetes 187
6.3.9 Eye Disease 189
6.3.9.1 Conjunctivitis 189
6.3.9.2 Pterygium 189
6.3.9.3 Cataract 189
6.3.10 Non-Pitting Edema of Limbs 190
6.3.11 Miscellaneous 190
6.3.11.1 Weakness 190
6.3.11.2 Erectile Dysfunction 190
6.3.11.3 Proteinuria 191
6.4 Pregnancy Outcome 191
6.5 Arsenicosis and Cancer 192
6.5.1 Skin Cancer 192
6.5.2 Urinary Bladder Cancer 193
6.5.3 Lung Cancer 193
6.5.4 Other Cancers 194
6.6 Diagnosis 194
6.6.1 Biomarkers with Special Focus on Diagnosis 196
6.7 Treatment 197
6.7.1 Ceasing Drinking of Arsenic-Contaminated Water 197
6.7.2 Specific Therapy 198
References 200
7 Changing Concept of Arsenic Toxicity with Development of Speciation Techniques 208
7.1 Introduction 208
7.2 Conclusions 226
References 226
8 Mechanism for Arsenic-Induced Toxic Effects 232
8.1 Introduction 232
8.2 Biological Consequences of Chronic Arsenic Exposure in Humans 233
8.3 Arsenic Metabolism 234
8.3.1 Biomethylation 234
8.4 Pathophysiology of Arsenic Toxicity 235
8.4.1 Cardiovascular Dysfunction 235
8.4.2 Neurological Disorders 236
8.4.3 Hepatic and Renal Toxicity 237
8.4.4 Testicular Toxicity 238
8.4.5 Arsenic Carcinogenicity 239
8.5 Mechanism for the Toxic Effects of Arsenic 240
8.5.1 Oxidative Stress 240
8.5.2 Signaling Mechanism 241
8.5.3 Role of Transcription Factor 242
8.6 Preventing Arsenic-Induced Toxic Effects by Antioxidants 243
8.6.1 Role of Taurine 244
8.6.1.1 Taurine in Prevention of Arsenic-Induced Cardiac Disorder 244
8.6.1.2 Taurine against As-Induced Hepatic and Testicular Apoptosis 244
8.6.1.3 Taurine against As-Induced Oxidative Cerebral and Renal Disorders 246
8.6.2 Role of N-Acetyl Cysteine 246
8.6.3 Role of Melatonin 246
8.6.4 Role of a-Lipoic Acid 247
8.6.5 Role of Silymarin and Quercetin 247
8.6.6 Herbal Antioxidant 248
8.7 Conclusions and Future Directions 249
References 250
9 Arsenic-Induced Mutagenesis and Carcinogenesis: A Possible Mechanism 262
9.1 Arsenic, a Potent Mutagen and Carcinogen 262
9.2 Epidemiological Perspectives of Arsenic-Induced Human Cancers 263
9.3 Arsenic-Associated Metabolism and Carcinogenesis in Animal Models 264
9.3.1 Arsenic Metabolism and Carcinogenesis 265
9.3.2 Arsenic Metabolism and Free Radical Influences 267
9.3.3 Arsenic May Influence Drug Metabolizing Enzymes 269
9.3.4 Gut Microflora Influences Arsenic Toxicity and Tumorigenesis/Carcinogenesis 270
9.3.5 Arsenic-Induced Carcinogenesis in Animal Models: Role of Signal Transduction 271
9.3.6 Arsenic Induces Cellular Transformation Signaling 271
9.3.7 Arsenic and Epigenetic Modification 273
9.3.8 Arsenic and Tumor/Heat Shock-Associated Proteins 274
9.3.9 Arsenic and Apoptotic Signaling via Transcription Regulation 275
9.4 Human Arsenic Carcinogenesis 280
9.4.1 Genetic/Epigenetic Changes in Arsenic-Associated Human Carcinogenesis 280
9.4.2 Arsenic Affects Cultured Human Cells and Environmentally Exposed Human Populations 282
9.4.3 Arsenic Induces Telomere Instability 283
9.4.4 Arsenic-Associated DNA Damage and Genome Dysfunction in Humans 284
9.4.5 Arsenic and Epigenetic DNA Modification 285
9.4.6 Arsenic-Associated Signal Transduction Processes and Human Carcinogenesis 287
9.5 Conclusions and Future Directions 293
Acknowledgments 294
References 294
10 Arsenic Through the Gastrointestinal Tract 310
10.1 General Aspects 310
10.2 Arsenic in Foods: Household Processing and Toxicological Risk 311
10.3 Role of the Gut in Arsenic Toxicity: Bioavailability and Intestinal Health 312
10.3.1 Gastrointestinal Health 315
10.4 Arsenic-Induced Metabolic/Immune Toxicity 318
10.5 Conclusions and Future Perspectives 320
References 321
11 Cutaneous Toxicology of Arsenic 330
11.1 Introduction 330
11.2 Epidemiology 331
11.3 Clinical Manifestations 332
11.4 Histopathology 333
11.5 Molecular Pathogenesis 333
11.5.1 Oxidative Stress 333
11.5.2 Genotoxicity 334
11.5.3 Disrupted Signal Transduction Pathways 334
11.5.4 Immune Dysfunction and Inflammatory Responses 336
11.6 Treatment 339
References 340
12 Arsenic-Induced Liver Injury 344
12.1 Introduction 344
12.2 Source of Exposure 345
12.3 Biotransformation and Elimination of Arsenic 346
12.4 History of Arsenic-Related Liver Diseases 347
12.5 Hepatoportal Sclerosis 348
12.6 Arsenic-Related Hepatic Fibrosis and Cirrhosis 349
12.7 Epidemiological Study to Assess Arsenic-Related Liver Dysfunction 350
12.8 Animal Studies for Understanding the Pathogenesis 351
12.9 Arsenic and Liver Cancer 358
References 359
13 Arsenic and Respiratory Disease 364
13.1 Introduction 364
13.1.1 Lung Development 365
13.2 Chronic Arsenic Exposure and Respiratory Health 365
13.2.1 Chronic Arsenic Exposure and Respiratory Symptoms 365
13.2.2 Chronic Arsenic Exposure and Lung Function 365
13.2.3 Chronic Arsenic Exposure and Immunosuppression 366
13.2.4 Chronic Arsenic Exposure and Non-Malignant Respiratory Disease 366
13.3 Early Life Arsenic Exposure and Lung Health 367
13.3.1 Early Life Arsenic Exposure, Birth Outcomes, and Growth 367
13.3.2 Early Life Arsenic Exposure and Immune Development 367
13.3.3 Early Life Arsenic Exposure and Non-Malignant Respiratory Disease in Children 368
13.3.4 Early Life Arsenic Exposure and Non-Malignant Respiratory Disease in Adults 369
13.4 Mechanistic Data on Arsenic Exposure and the Lung 370
13.4.1 Mechanistic Data on Early Life Arsenic Exposure 370
13.4.2 Mechanistic Data for Arsenic Exposure and Immune Function 370
13.4.3 Mechanistic Data for Arsenic Exposure and Lung Structure and Function 371
13.5 Conclusions 372
References 372
14 Arsenical Kidney Toxicity 378
14.1 Introduction 378
14.2 Clinical Manifestations of Arsenical Toxicity in Humans 379
14.2.1 Epidemiological Studies 379
14.2.2 Mechanisms of Arsenical Toxicity to Specific Renal Cell Populations 379
14.2.2.1 Renal Blood Vasculature 379
14.2.2.2 Proximal Tubules 380
14.3 Nephrotoxic Arsenical Compounds 380
14.3.1 Arsine 380
14.3.2 Arsenate 380
14.3.3 Arsenite 381
14.4 Mechanisms of Arsenical Toxicity 381
14.4.1 Mitochondrial Effects 381
14.4.1.1 Mitochondrial Respiratory Function 381
14.4.1.2 Heme Biosynthetic Pathway 381
14.4.1.3 Arsenic and Renal Cancer 382
14.4.1.4 Membrane Transport Systems 382
14.4.1.5 Altered Cellular Signaling Pathways 382
14.5 Biomarkers of Nephrotoxicity 383
14.5.1 Omic Biomarkers 383
14.5.2 Altered Gene Expression Patterns (Genomics) 383
14.5.3 Altered Protein Synthesis Patterns (Proteomics) 384
14.5.4 Metabolomics 384
14.5.5 Arsenic-Induced Posttranslational Alterations of Proteins 385
14.5.6 Altered Heme Biosynthesis/Porphyrinuria Patterns 385
14.5.7 Proteinuria Patterns 385
14.6 Arsenical Interactions with Other Nephrotoxic Elements 385
14.6.1 Lead 385
14.6.2 Cadmium 386
14.6.3 Gallium 386
14.6.4 Indium 386
14.7 Summary and Future Research Needs 386
References 386
15 Arsenic-Induced Developmental Neurotoxicity 392
15.1 Introduction 392
15.2 Arsenic Exposure Impairs Intellectual Function in Children 393
15.3 Developmental Neurobehavioral Toxicity in Animals 396
15.4 Arsenic Distribution After Exposure in Early Life 397
15.5 Mechanism of Developmental Neurotoxicity 398
15.5.1 Effects of Arsenic on Neurotransmitter Systems 398
15.5.2 Arsenic and Neurite Growth, Astrocyte, and Myelin 399
15.5.3 Arsenic and Neuron Apoptosis 401
15.5.4 Arsenic and Methylation 402
15.5.5 Arsenic and Nitric Oxide 403
15.5.6 Arsenic and Gene Expression 403
15.6 Neuroprotective Agents Against Arsenic Toxicity 405
15.7 Conclusions 406
References 409
16 Developmental Arsenic Exposure Impacts Fetal Programming of the Nervous System 416
16.1 Introduction 416
16.2 Accumulation of Arsenic in Fetal Brain Tissue 417
16.3 Effect of Arsenic on the Development of the Nervous System 418
16.4 Effect of Arsenic on Neurobehavior 420
16.5 Mechanisms for the Effect of Arsenic on the Nervous System During Development 424
16.5.1 Induction of Oxidative Stress 424
16.5.2 Induction of Apoptosis 425
16.5.3 Effect of Arsenic on the Cell Cycle 426
16.5.4 Effect on Central Neurotransmitters/Neuroendocrine 426
16.5.5 Other Mechanisms 427
16.6 Conclusions and Future Directions 428
References 428
17 Health Effects of Prenatal and Early-Life Exposure to Arsenic 434
17.1 Introduction 434
17.2 Adverse Health Effects Associated with Chronic and Early-Life Arsenic Exposure 435
17.2.1 Health Effects Associated with Chronic Exposure to iAs 435
17.2.2 Health Effects Associated with iAs Exposure during Gestation and Infancy 436
17.2.3 Health Effects of iAs Exposure Observed in Childhood 437
17.2.4 Delayed Health Effects Associated with Chronic and Prenatal Arsenic Exposure 438
17.3 Mechanisms Implicated in Disease Development Associated with Prenatal Exposure 441
17.3.1 Epigenetic Reprogramming as a Potential Key Event in Latent Disease Development 441
17.3.1.1 Epigenetic and Genomic Alterations in Experimental Animals 443
17.3.1.2 Epigenetic and Genomic Alterations in Human Populations 445
17.3.2 Role of Cancer Stem Cells 447
17.3.3 Immunomodulatory Effects 449
17.4 Conclusions and Future Directions 450
References 450
18 Arsenic, Kidney, and Urinary Bladder Disorders 458
18.1 Introduction 458
18.2 Arsenic and Renal Disease 459
18.2.1 Studies in Animals 459
18.2.2 Epidemiological Studies in Humans 460
18.2.3 Early Biomarkers of Arsenic Exposure and Nephrotoxicity 462
18.2.4 Physiopathology 463
18.2.5 Clinical Manifestations of Arsenic-induced Renal Disease 465
18.3 Arsenic and Bladder Disease 465
References 467
19 Developmental Arsenic Exposure: Behavioral Dysfunctions and Neurochemical Perturbations 472
19.1 Introduction 472
19.2 Toxicity 473
19.3 Developmental Toxicity 473
19.3.1 Effects on the Nervous System 474
19.3.1.1 Neurochemical Effects 474
19.3.1.1.1 Neurotransmitter Systems 474
19.3.1.1.2 Oxidative Stress 475
19.3.1.1.3 Neurite Outgrowth 476
19.3.2 Behavioral Effects 476
19.4 Conclusions 478
References 480
20 Arsenic and the Cardiovascular System 488
20.1 Introduction 488
20.2 Cardiovascular System 490
20.3 Arsenic Effects on Blood 491
20.3.1 Erythrocytes 491
20.3.2 Leukocytes 493
20.3.3 Methyltransferases 496
20.4 Arsenic Effects on the Vascular System 497
20.4.1 Clinical Studies 497
20.4.2 Atherosclerosis 499
20.4.3 Genetic Polymorphisms 499
20.4.4 Endothelial Cells 501
20.4.5 Smooth Muscle Cells 502
20.5 Arsenic Effects on the Heart 503
20.5.1 QT Prolongation 503
20.5.2 Ischemic Heart Disease 504
20.5.3 Ion Channels 505
20.5.4 Cellular Signaling 507
20.5.5 Chelation Therapy 510
20.6 Human Pluripotent Stem Cells: Understanding Arsenic Toxicity 510
20.7 Conclusions 512
References 512
21 Immunotoxic Effects of Arsenic Exposure 522
21.1 Introduction 523
21.2 Influence of Nutritional Factors 525
21.3 Effects on Blood Leukocytes 525
21.4 Interruption of Energy Production 525
21.5 Effects on ROS Production 526
21.6 Genotoxic and Carcinogenic Potentials 526
21.7 Hematological Effects on Experimental Animals 527
21.8 Effect on Heme Synthesis 528
21.9 Hepatic Effects and Lipid Peroxidation 528
21.10 Effects on Immune Responses in Fish 529
21.10.1 Innate Immune Response 529
21.10.2 Humoral Immune Response 529
21.11 Effects on Immune Responses in Laboratory Animals 530
21.11.1 Humoral Immune Response 530
21.11.2 Cell-Mediated Immune Response 530
21.12 Effects of Arsenic in Drinking Water on Human Health 531
21.13 Immunotoxic Effects of Organic Arsenicals in Foods 532
21.14 Medicinal Use of Arsenic and Its Mechanism of Action 533
21.15 Effects of Arsenic Compounds on Human Cells in Culture 533
21.15.1 Effects on Growth-Promoting Cytokines and Growth Factors 534
21.15.2 Effects on Human T-Cell Functional Responses 535
21.16 Immunotoxic Effects on Murine and Human Monocytes/Macrophages 535
21.16.1 Effects on Monocyte/Macrophage Functional Responses 537
21.16.2 Impairment of Macrophage-Functional Genes 537
21.17 Immunotoxic Effects on Murine Mononuclear Cells 538
21.18 Decreased Cytokine Production by Human T Cells 538
21.19 Effects of In Utero Exposure on Infant Immune System 539
21.20 Gender-Related Immunotoxic Effects in Human 539
21.21 Effects of Chronic Exposure on Immune Response 540
21.21.1 Effects of Chronic Exposure on Mice and Human Lungs 540
21.21.2 Effects of Chronic Exposure on Humoral Immune Response in Humans 541
21.22 Association with Respiratory Complications and Impaired Immune Responses 541
21.23 Effects of Chronic Exposure on Serum Complement Function 542
21.24 Conclusions 542
References 543
22 Arsenic and Developmental Toxicity and Reproductive Disorders 550
22.1 Introduction 550
22.2 Developmental Toxicity 552
22.2.1 Neural Tube Defects 552
22.2.1.1 Animal Models 552
22.2.1.1.1 Human Studies 553
22.2.1.1.2 Other Birth Defects 553
22.3 Reproductive Toxicity 554
22.3.1 Infant Mortality 554
22.3.2 Birth Weight 554
22.4 Early-Life Exposures and Delayed Health Effects 555
22.5 Reproductive Disorders 556
22.5.1 Male Infertility 556
22.5.1.1 Animal Studies 556
22.5.1.2 Human Studies 556
22.6 Conclusions 557
References 557
23 Arsenic and Cancer 562
23.1 Arsenic and Arsenic-Containing Compounds 562
23.2 Sources of Arsenic and Potential for Human Exposure 564
23.2.1 Arsenic and Drinking Water Contamination 564
23.2.2 Arsenic and Food Contamination 564
23.2.3 Arsenic and Soil Contamination 565
23.2.4 Arsenic and Air Pollution 565
23.2.5 Arsenic Exposure from Medication 566
23.2.6 Occupational Exposure to Arsenic 566
23.3 Molecular Mechanisms of Arsenic-Induced Carcinogenesis 567
23.3.1 Arsenic Perturbation of Keratin Expression 568
23.3.2 Arsenic-Induced Genotoxicity 569
23.3.3 Arsenic-Induced Aberration of Gene Expression 569
23.3.4 Arsenic Dysregulation of Cellular Immune Function 569
23.3.5 Arsenic Distortion of Protein Structure 570
23.3.6 Arsenic Induction of Cell Proliferation 570
23.3.7 Arsenic Dysregulation of Epigenetic Mechanisms 570
23.3.8 Arsenic Cocarcinogenicity 570
23.3.9 Arsenic Interference with Signal Transduction 571
23.3.10 Arsenic Induction of Reactive Oxygen Species 571
23.4 Health Effects Associated with Arsenic Exposure 572
23.4.1 Arsenic and Keratosis 572
23.4.2 Arsenic and Skin Cancer 574
23.4.3 Arsenic and Liver Cancer 575
23.4.4 Arsenic and Kidney Cancer 575
23.4.5 Arsenic and Urinary Bladder Cancer 576
23.4.6 Arsenic and Lung Cancer 576
23.4.7 Arsenic and Gastrointestinal Cancer 577
23.4.8 Arsenic and Brain Cancer 577
23.5 Conclusions 578
Acknowledgments 578
References 578
24 The Association between Chronic Arsenic Exposure and Type 2 Diabetes: A Meta-Analysis 586
24.1 Introduction 586
24.2 Methods and Materials 588
24.2.1 Literature Search 588
24.2.2 Selection of Studies 588
24.2.2.1 Quality of the Studies 588
24.2.2.2 Statistical Analysis 589
24.3 Results 589
24.3.1 Literature Search 589
24.3.2 Quality Scoring 590
24.3.3 Sources of Heterogeneity 590
24.3.4 Meta-Regression and Sensitivity Analysis 596
24.3.5 Influence Analysis 596
24.3.6 Publication Bias 596
24.3.7 Dose–Response 597
24.4 Discussion 597
References 599
25 Arsenic Biosensors: Challenges and Opportunities for High-Throughput Detection 604
25.1 Arsenic: The Toxic Metalloid 604
25.2 Arsenic Biosensors 605
25.2.1 Evolution of a Natural Self-Defense Mechanism—the ars Operon 606
25.2.2 Recombinant Escherichia coli—the Favored Biorecognition Element 606
25.3 Nanosensor Platforms—Towards High-Throughput Detection 610
25.4 Conclusions and Future Directions 614
References 615
26 Medical Countermeasures—Chelation Therapy 618
26.1 Introduction 618
26.2 Clinical Aspects of Arsenic 619
26.3 Diagnosis 620
26.4 Chelation Therapy 621
26.4.1 Concept 621
26.4.2 Chemistry 622
26.4.3 Chemical Considerations 623
26.4.3.1 Thermodynamics of Metal Chelation 623
26.4.3.2 Kinetic Considerations in Metal Chelation 624
26.4.3.3 In Vivo Efficacy of Chelating Agents 624
26.4.4 Toxicokinetics of Chelation 625
26.5 Chelators in Clinical Use 627
26.5.1 Chelating Agents for Arsenic Poisoning 627
26.5.1.1 Dimercaprol (BAL) 627
26.5.1.1.1 Chemistry, Pharmacokinetics, and Pharmacodynamics 627
26.5.1.1.2 Efficacy and Experimental Studies 627
26.5.1.1.3 Mechanism of Action 627
26.5.1.1.4 Human Cases 628
26.5.1.1.5 Drawbacks 629
26.5.1.2 D-Penicillamine (D-PA) 630
26.5.1.2.1 Chemistry, Pharmacokinetics, and Pharmacodynamics 630
26.5.1.2.2 Efficacy and Experimental Studies 630
26.5.1.2.3 Mechanism of Action 630
26.5.1.2.4 Human Studies 630
26.5.1.2.5 Drawbacks 630
26.5.1.3 Meso-2,3-Dimercaptosuccinic Acid (Succimer, DMSA) 631
26.5.1.3.1 Chemistry, Pharmacokinetics, and Pharmacodynamics 631
26.5.1.3.2 Efficacy and Experimental Studies 631
26.5.1.3.3 Mechanism of Action 631
26.5.1.3.4 Human Studies 632
26.5.1.3.5 Drawbacks 632
26.5.1.4 2,3-Dimercaptopropane-1-Sulfonic Acid 633
26.5.1.4.1 Chemistry, Pharmacokinetics, and Pharmacodynamics 633
26.5.1.4.2 Efficacy and Experimental Studies 633
26.5.1.4.3 Mechanism of Action 633
26.5.1.4.4 Human Studies 633
26.5.1.4.5 Drawbacks 634
26.6 Analogues of DMSA as Potential New Arsenic Chelators 634
26.6.1 Monoisoamyl DMSA (MiADMSA) 634
26.6.1.1 Chemistry, Pharmacokinetics, and Pharmacodynamics 634
26.6.1.2 Efficacy and Experimental Studies 635
26.6.1.3 Mechanism of Action 636
26.6.1.4 Drawbacks 636
26.6.2 Monomethyl DMSA (MmDMSA) and Monocyclohexyl DMSA (MchDMSA) 636
26.7 Role of Antioxidants in Preventing Arsenic Toxicity 637
26.7.1 Alpha-Lipoic Acid 638
26.7.2 N-Acetylcysteine 638
26.7.3 Vitamins E and C 639
26.7.4 ß-Carotene 640
26.7.5 Taurine 640
26.7.6 Melatonin 640
26.7.7 Curcumin 641
26.7.8 Essential Metals 641
26.7.8.1 Zinc 641
26.7.8.2 Selenium 642
26.7.9 Herbal Extracts 642
26.8 Newer Strategies 643
26.8.1 Combination Therapy 643
26.8.2 Nanoparticle Carriers to Combat Arsenic Toxicity 644
26.9 Concluding Remarks and Future Directions 647
References 647
27 Biochemical and Molecular Basis of Arsenic Toxicity and Tolerance in Microbes and Plants 656
27.1 Introduction 656
27.1.1 Arsenic: A Threatening Environmental Issue 656
27.1.2 Worldwide Occurrence of Arsenic 657
27.1.3 Arsenic Speciation and Mobilization 658
27.1.4 Arsenic Epidemiology 659
27.2 Arsenic Toxicity and Tolerance in Microbes 660
27.2.1 Arsenic Uptake Pathways 661
27.2.2 Extracellular Immobilization of Arsenic 662
27.2.3 Arsenic Chelation 662
27.2.4 Arsenate Reduction 662
27.2.4.1 Mechanism of Arsenic Detoxification 662
27.2.4.2 Arsenate Respiration or Dissimilatory As(V) Reduction 664
27.2.5 Efflux of As(III) from the Cell 665
27.2.6 Oxidation of As(III) 665
27.2.6.1 Mechanism of As(III) Oxidation 666
27.2.7 Arsenic Biomethylation 668
27.2.7.1 Methylation Pathway 669
27.2.8 Morphological, Physiological, and Biochemical Responses 670
27.3 Arsenic Toxicity and Tolerance in planta 670
27.3.1 Arsenic Uptake and Efflux 671
27.3.1.1 Arsenate Uptake 672
27.3.1.2 Arsenite Uptake 673
27.3.1.3 Uptake of Methylated Arsenic 673
27.3.1.4 Long-Distance Transport 674
27.3.2 Arsenic Toxicity to Plants 674
27.3.2.1 Impact on Morphology, Growth, and Productivity 674
27.3.2.2 Physiological and Biochemical Responses 675
27.3.2.3 Proteomic Responses of Plants to As Stress 675
27.3.3 Mechanism of As Toxicity 676
27.3.3.1 Phosphate Replacement 677
27.3.3.2 Binding Thiol Groups 678
27.4 Mechanisms of As Tolerance and Detoxification 680
27.4.1 Arsenate Reduction 680
27.4.2 Complexation and Sequestration of As 681
27.4.3 Antioxidative Defense System 683
27.4.4 Osmolyte Accumulation 684
27.4.5 Mycorrhization in Crop Plants: the Prospects of Arbuscular Mycorrhizae Symbiosis in Regulation of Plant Defense Resp ... 685
27.5 As Hyperaccumulation and Phytoextraction 686
27.5.1 Mechanisms of As Hyperaccumulation 686
27.6 Summary Points 687
Acknowledgments 688
References 688
28 Arsenic Contents and Its Biotransformation in the Marine Environment 704
28.1 Introduction 704
28.2 Arsenic Concentration in Sea Water 705
28.3 Arsenic Concentration in Marine Sediments 708
28.4 Arsenic Speciation in Marine Ecosystems 710
28.5 Arsenic Cycle in the Marine Environment 712
28.6 Role of Marine Biological Systems in Arsenic Biotransformation 715
28.6.1 Phytoplankton 715
28.6.2 Marine Bacteria 716
28.6.3 Algae 718
28.6.4 Marine Animals 719
28.7 Arsenic in Seafood and Its Toxicity 720
28.8 Future Directions 723
References 723
Index 730
Preface
Swaran J.S. Flora
I have been a chemical toxicologist for nearly 35 years. In this time, I have studied and evaluated the toxicities of toxic metals and the health effects produced by human exposure to metals.
Arsenic, a naturally occurring metalloid, is ubiquitously present in the environment. Arsenic is ranked first among toxicants posing a significant potential threat to human health based on known or suspected toxicity. This naturally occurring metalloid is a known poison, a co-carcinogen, and in lower concentrations has been shown to cause damage to almost all major organs including liver, lungs, bladder and brain. Currently, the permitted concentration of arsenic in water is 10 μg/L (10 ppb). Yet, an estimated 100 million people worldwide are exposed to excessive amounts of arsenic via drinking water (in the ppm, not ppb, range). Many of these individuals obtain drinking water from unregulated sources (wells) or live in regions where arsenic levels are high, such as Bangladesh. Arsenic leaches from rock formations into water sources as the water table recedes, and hence exposure to high amounts of arsenic will continue to persist whilst the demand for clean water increases. This phenomenon particularly affects the Western region of the United States, where it is estimated that certain areas contain up to 3100 μg/L arsenic (31 ppm) in drinking water, on par with levels reported in Taiwan, China, Bangladesh and India.
Although the largest number of people affected worldwide by the arsenic contamination of drinking water are in Bangladesh, the problem is not unique to that area. As early as 1960, scientists reported the link between various forms of cancer and arsenic in drinking water in Taiwan. Communities in North and South America, Europe, Asia and Australia also face the problem of arsenic-contaminated drinking water. The problem of arsenic-contaminated groundwater is found in communities throughout Canada and western USA that use groundwater as their source of drinking water. It is now almost certain that arsenic contamination is a worldwide problem; however, some of the most affected regions lie in the flood plains of the great rivers of Bangladesh, Nepal, and West Bengal, India. In Bangladesh alone, seventy million people are impacted. Problems associated with drinking groundwater were first noticed in Bangladesh by healthcare workers in the early 1990s. While the World Health Organization (WHO) and the Environmental Protection Agency (EPA) regulate water sources of arsenic, lack of strict regulations on food, beverages, and air quality can lead to increased arsenic exposure. Ingestion of arsenic activates metabolic pathways for excretion, resulting in a number of metabolites, some of which are more potent and toxic than the originally ingested inorganic form of arsenic.
Inorganic arsenic exposure of humans, by the inhalation route, has been shown to be strongly associated with lung cancer, while ingestion of inorganic arsenic by humans has been linked to a form of skin cancer and also to bladder, liver, and lung cancer. The EPA has classified inorganic arsenic as a human carcinogen. This explosion of information in the recent years reflects the vast increase in number of researchers studying about the mechanisms of action of arsenic. The specific knowledge of the chemistry, biochemistry, toxicology, and epidemiology of arsenic is far greater than that for any other environmentally-occurring chemical carcinogen.
This book really began over 20 years ago, when I was confronted with the first of scores of instances in Uttar Pradesh, Maharashtra, West Bengal and Bihar in India, where individuals exposed to arsenic subsequently developed symptoms and effects that could notably be explained by the known toxicological effects. In some instances the exposures led to effects far in excess of what would be expected. In others, effects were noted following exposures to extremely low levels of arsenic; in even more instances the body organs targeted were not those known to be impacted by arsenic. I carried out number of studies during these years; a few of them with my colleagues in West Bengal. These studies led to one serious concern: that we do not have a safe, specific and effective chelating drugs in this part of the world, and those drugs available in the developed countries are largely ineffective against arsenic toxicity.
As time progressed, I began to think that the task was too big and a solution remained elusive. The breakthrough came when I got a reprint from Prof. M.M. Jones, Vanderbilt University in which his group synthesized and evaluated the efficacy of number of di- and monoesters of meso 2,3-dimercaptosuccinic acid (DMSA) with limited success against cadmium intoxication. There was a small but an interesting note on the top of the reprints written in red ink, where he asked me to try these esters against arsenic. This led me to my interest in arsenic poisoning and in particular searching for a new chelating agent. A review of the literature and our research group’s own studies highlighted the shortcomings with DMSA, DMPS and BAL, and it was then hypothesized that monoesters of DMSA might be a better option to treat cases of arsenicosis.
I have attempted to bring together as comprehensive a group of scientists as possible in assembling this book. Whilst at first glance, the literature on arsenic toxicology seems exhaustive and systematic, this is not the case. There is no comprehensive and in-depth analysis of its effects on major organs, preventive and therapeutic measures; additionally, there are a few new topics where not much work has been undertaken but could be of potential future interest. This book thus promises to provide a comprehensive coverage of arsenic and its toxic effects, including its toxicokinetics, mode(s) of action, effects on all major organs and medical countermeasures. To my knowledge, this book perhaps is the first in-depth analysis of data on toxicology, risk assessment, and management. Included in these 28 chapters are detailed reviews of the many important mechanistic aspects of arsenic.
Chapters 1 and 2 provide an orientation and introduction to the subject of arsenic. The focus of these chapters is to provide an overview of various critical factors affecting arsenic chemistry, the natural and anthropogenic sources of exposure. The focus of Chapters 3 and 4 are risk assessment following arsenic exposure while Chapter 5 provides data for the removal of arsenic using activated alumina (AA) and modified AA adsorbents. Chapters 5 and 6 provide information on the general health effects of arsenic and the role of arsenic metabolites in the toxic manifestation, respectively. Chapters 7–9 focus on various proposed modes of actions for arsenic, exposure pathways and toxicokinetics, various alterations in mediating genotoxic effects such as altered DNA repair, signal transduction, cellular proliferation, and altered DNA methylation. One of the major mechanisms of arsenic-induced toxic manifestation is oxidative stress. These chapters provide in-depth information regarding alterations at the biochemical level, detailed mechanisms of toxicity and oxidative injury, and the links between arsenic, oxidative stress and cancer. Chapter 10 discusses the gastrointestinal tract as one of the target organs of arsenic and a factor affecting its toxicity and the resultant risk assessments required. The authors suggest that arsenic species with higher toxicity degree than those ingested may appear in the intestinal lumen as a result of interactions with food components and from metabolism by enterocytes and micro biota. Also, the biotransformation may modulate arsenic intestinal absorption and therefore adverse effects.
Although arsenic impacts on the physiological cellular processes in numerous organ systems, the outcomes of its toxicity are usually first seen in the skin. The major focus of Chapter 11 is on skin manifestations from acute toxicity such as flushing, erythema, facial edema, acrodynia, urticarial, alopecia, loss of nails, and Mees lines visible on nails. The liver is the target organ of arsenic and many important various metabolizing reactions take place in liver, rendering it the most susceptible organ to any xenobiotic. Exposure to arsenic leads to various hepatic disorders, which has been discussed in Chapter 12. Arsenic, the only environmental toxicant has been linked to both malignant and non-malignant respiratory disease following ingestion, rather than inhalation, making arsenic a unique toxicant to the respiratory system. Chapter 13 suggests that chronic exposure to arsenic has been associated with the development of respiratory symptoms, impaired lung function and chronic lung disease. Chapter 14 provides an overview of information that arsenic disturbs various vital renal functions such as the excretion of nitrogenous waste products and maintenance of electrolyte balance, which leads to immediate effects on circulating blood and hence whole body. Chapter 15, 16, 17, and 19 make a strong argument for the potential role of arsenic in disrupting the normal functions of the central nervous system, thereby causing impairment of learning, concentration and short term memory. It also alters the release of various neurotransmitters. Since the brain is the most vital organ, it’s important to fully understand the effect of arsenic intoxication and associated neuropathologies, which are discussed here.
Arsenic accumulates in the urinary bladder epithelium, causing activation of specific signaling pathways, leading to increased cell proliferation and increased...
| Erscheint lt. Verlag | 26.12.2014 |
|---|---|
| Sprache | englisch |
| Themenwelt | Medizin / Pharmazie ► Gesundheitsfachberufe |
| Studium ► 2. Studienabschnitt (Klinik) ► Pharmakologie / Toxikologie | |
| Naturwissenschaften ► Biologie ► Ökologie / Naturschutz | |
| Technik | |
| ISBN-10 | 0-12-419955-0 / 0124199550 |
| ISBN-13 | 978-0-12-419955-2 / 9780124199552 |
| Haben Sie eine Frage zum Produkt? |
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