Risk Assessment for Human Metal Exposures

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Mode of Action and Kinetic Approaches

Authors: Gunnar F. Nordberg, Bruce A. Fowler Publisher: Elsevier Science Publication date: 2018 Publication language: Angielski Number of pages: 350 Publication formats: EAN: 9780128042687 ISBN: 9780128042687 Category: Medical toxicology Publisher's index: 9780128042687 Bibliographic note: Dr. Fowler began his scientific career at the National Institute of Environmental Health Sciences prior to becoming Director of the University of Maryland System-wide Program in Toxicology and Professor at the University of Maryland School of Medicine. He then served as Associate Director for Science in the Division of Toxicology and Environmental Medicine at Agency for Toxic Substances and Disease Registry (ATSDR). He is currently a private consultant and Co-owner of Toxicology Risk Assessment Consulting Services (TRACS), LLC. In addition, Dr. Fowler serves as an Adjunct Professor, Emory University Rollins School of Public Health and Presidents Professor of Biomedical Sciences, Center for Alaska Native Health Research (CANHR) at the University of Alaska- Fairbanks. Dr. Fowler, is an internationally recognized expert on the toxicology of metals and has served on a number of State, National and International Committees in his areas of expertise. These include the Maryland Governor’s Council on Toxic Substances (Chair), various National Academy of Sciences / National Research Council Committees, including the 1993 landmark NAS/NRC Report on “Measuring Lead Exposure in Infants Children and Other Sensitive Populations for which he served as the Committee Chair. He has also served on a number of review committees of the National Institutes of Health, the USEPA Science Advisory Board and the Fulbright Scholarship review committee for Scandinavia (Chair, 2000-2001). In 2016, he became an Inaugural Member of the Fulbright 1946 Society and in 2018 became a member of the Fulbright Association Board of Directors. He has also served as a temporary advisor to the World Health Organization (WHO) and on working groups of the International Agency for Research Against Cancer (IARC) for a number of toxicology and risk assessment issues. He is presently appointed as a member of the Joint FAO/WHO Expert Committee on Food Additives (JECFA) for the period 2016-2020. Dr. Fowler has been honored as a Fellow of the Japanese Society for the Promotion of Science (JSPS), a Fulbright Scholar and Swedish Medical Research Council Visiting Professor at the Karolinska Institute, Stockholm, Sweden and elected as a Fellow of the Academy of Toxicological Sciences. His more recent awards include a CDC/ATSDR, Honor Award for Excellence in Leadership Award 2010, The US Pharmacopea (USP) Toxicology Committee 2010-2015 and the USP Elemental Impurities Panel which received the 2014 U.S. Pharmacopea Award for an Innovative Response to Public Health Challenges (Group Award). He is currently appointed to the USP Nanotechnology Subcommittee 2015-. Dr. Fowler was previously elected to the Council of the Society of Toxicology (2005-2007), the Board of Directors of the Academy of Toxicological Sciences (2006-2009), and more recently, to the Council of the Society for Risk Analysis (2014-2017). He is the Federal Legislative and National Active and Retired Federal Employees Association and (NARFE)-PAC Chair for the Rockville Maryland Chapter of NARFE and is currently Chair of the Federal Legislative Committee for the Maryland NARFE Federation. Dr. Fowler is the Past- President of the Rotary Club of North Bethesda, Maryland (2016-2017) and was selected as Rotarian of the Year in 2015 for his work in developing a taxi-based program to help persons with disabilities gain independence via reliable transportation to work. Dr. Fowler is the author of over 260 research papers and book chapters dealing with molecular mechanisms of metal toxicity, molecular biomarkers for early detection of metal-induced cell injury and application of computational toxicology for risk assessment. He has been the editor, co-editor or author of 10 books or monographs on metal toxicology and mechanisms of chemical – induced cell injury, molecular biomarkers and risk assessment and computational toxicology. Dr. Fowler is currently focused on the global problem of electronic waste (e-waste) in developing countries. He serves on the editorial boards of a number of scientific journals in toxicology and is an Associate Editor of the journal Toxicology and Applied Pharmacology and a past Associate Editor of Environmental Health Perspectives (2007-2016).

Description

Risk Assessment for Human Metal Exposures: Mode of Action and Kinetic Approaches examines the current principles of risk assessment in human metal exposures, with a focus on Mode of Action(MOA), Toxicokinetic and Toxicodynamic (TKTD) considerations, and computer models. Derived from the highly respected Handbook on the Toxicology of Metals, Fourth Edition (2014), the book summarizes principles and methods and provides examples of how MOA –TKTD can be used. In addition, it presents tactics on how information generated by such methods can be confirmed by epidemiological data. Furthermore, it demonstrates how epidemiological data can be confirmed and evaluated by the examined models and considerations.

This resource uniquely integrates several important topics, such as risk assessment, characterization, management and communication—the classic risk assessment paradigm—with mode of action, TKTD, and epidemiology, all topics related to human exposure. Written by pioneers in the field, this book is an essential reference for researchers, students and technicians in toxicology and risk assessment.

Covers fundamental risk assessment concerns for the effects of metals on human health
Provides an easy-to-use structure to quickly locate specific methods
Uses case studies to illustrate the methods and theories described
Written to be understood by students, researchers and industry workers who need to conduct risk assessment in metals and human health

Front Cover 2
RISK ASSESSMENT FOR HUMAN METAL EXPOSURES 3
RISK ASSESSMENT FOR HUMAN METAL EXPOSURES: Mode of Action and Kinetic Approaches 5
Copyright 6
DEDICATION 7
CONTENTS 9
AUTHOR BIOGRAPHIES 13
PREFACE 17
One - Metal Exposures and Human Health—Historical Development, Current Importance, and Toxicological Concepts for P ... 19
- 1.1 INTRODUCTION 20
- 1.2 WIDESPREAD EXPOSURE TO METALS CONTRIBUTES TO GLOBAL BURDEN OF DISEASE 21
- 1.3 METAL POISONING—CLINICAL SYMPTOMS AND SIGNS IN OCCUPATIONAL AND ENVIRONMENTAL SETTINGS 22
- 1.4 DETAILED INVESTIGATION IS REQUIRED FOR IDENTIFICATION OF ADVERSE EFFECTS AT LOW-LEVEL METAL EXPOSURES 24
- 1.5 PERSPECTIVES ON HISTORICAL DEVELOPMENT OF CONCEPTS USED IN RISK ASSESSMENT OF METAL EXPOSURES—ROLE OF THE SCIENTIFIC COMMIT 26
- 1.6 CURRENT LONG-TERM LOW-LEVEL EXPOSURES AND RELATED HEALTH EFFECTS 29

Front Cover 2
RISK ASSESSMENT FOR HUMAN METAL EXPOSURES 3
RISK ASSESSMENT FOR HUMAN METAL EXPOSURES: Mode of Action and Kinetic Approaches 5
Copyright 6
DEDICATION 7
CONTENTS 9
AUTHOR BIOGRAPHIES 13
PREFACE 17
One - Metal Exposures and Human Health—Historical Development, Current Importance, and Toxicological Concepts for P ... 19
- 1.1 INTRODUCTION 20
- 1.2 WIDESPREAD EXPOSURE TO METALS CONTRIBUTES TO GLOBAL BURDEN OF DISEASE 21
- 1.3 METAL POISONING—CLINICAL SYMPTOMS AND SIGNS IN OCCUPATIONAL AND ENVIRONMENTAL SETTINGS 22
- 1.4 DETAILED INVESTIGATION IS REQUIRED FOR IDENTIFICATION OF ADVERSE EFFECTS AT LOW-LEVEL METAL EXPOSURES 24
- 1.5 PERSPECTIVES ON HISTORICAL DEVELOPMENT OF CONCEPTS USED IN RISK ASSESSMENT OF METAL EXPOSURES—ROLE OF THE SCIENTIFIC COMMIT 26
- 1.6 CURRENT LONG-TERM LOW-LEVEL EXPOSURES AND RELATED HEALTH EFFECTS 29
  - 1.6.1 Neurotoxicology of Metals 30
  - 1.6.2 Cardiovascular Disease Related to Metals 30
  - 1.6.4 Cancer Induced by Metal Exposures 31
  - 1.6.3 Kidney Effects of Exposure to Metals 31
  - 1.6.5 Reproductive and Developmental Effects of Metal Exposures 32
- 1.7 ISSUES OF CURRENT CONCERN FOR HAZARD ASSESSMENT, RISK ASSESSMENT, AND PREVENTION 32
  - 1.7.1 Expanding Global Industrial Use of Metals 33
  - 1.7.3 Environmental Mobilization Processes 34
  - 1.7.2 Toxicity of Metallic Nanoparticles 34
  - 1.7.4 Toxic Metals in Food and Oral Intake; Other Intake Routes 36
  - 1.7.6 Toxicokinetics and Dosimetry 37
  - 1.7.5 Metal Exposure by Release From Implanted Medical Devices 37
  - 1.7.7 Essential Metals: Deficiency and Toxicity 39
  - 1.7.9 Interactions Among Metals and Gene–Environment Interactions 40
  - 1.7.8 Biological Monitoring 40
  - 1.7.10 Application of MOA TKTD Models, AOPs, or Other Systems Toxicology Approaches to Risk and Hazard Assessment of Metal Expos 41
  - 1.7.11 Applied Hazard- and Risk Assessment—Preventive Action and Management 42
- REFERENCES 44
Two - Exposure, Internal Dose, and Toxicokinetics (TK) 49
- 2.1 INTRODUCTION; TERMINOLOGY 49
- 2.2 EXPOSURE 52
  - 2.2.1 General Considerations 52
  - 2.2.2 Exposure Through Food and Drinking Water 54
  - 2.2.3 Exposure by Inhalation 56
- 2.3 DEPOSITION AND ABSORPTION 58
  - 2.3.1 General Considerations Including an Introduction to Skin Deposition 58
  - 2.3.2 Deposition and Absorption After Ingestion 59
  - 2.3.3 Deposition and Absorption After Inhalation 62
    - 2.3.3.1 Deposition and Absorption of Gases and Vapors 63
    - 2.3.3.2 Deposition of Particles 63
    - 2.3.3.3 Clearance of Particles From the Respiratory System 67
      - 2.3.3.3.1 Tracheobronchial Clearance 67
      - 2.3.3.3.2 Peripheral Lung Clearance and Translocation From the Respiratory Tract 68
    - 2.3.4 Total Absorption 70
  - 2.4 TRANSPORT, BIOTRANSFORMATION, AND DISTRIBUTION 71
  - 2.5 EXCRETION 74
    - 2.5.1 Gastrointestinal Excretion 75
    - 2.5.2 Excretion Through the Kidneys 76
    - 2.5.3 Excretion Rate: Biological Half-Life (Half-Time) 78
  - 2.6 TOXICOKINETIC MODELS 80
    - 2.6.1 One-Compartment Model 81
    - 2.6.2 Multicompartment Models and Physiologically Based Models 83
      - 2.6.2.1 Description of a Multicompartment Model for Cadmium 84
    - 2.7 USE OF INDICATOR MEDIA FOR ESTIMATING CRITICAL ORGAN CONCENTRATION 87
    - REFERENCES 88
  - Three - Biomonitoring, Mode of Action (MOA), Target Dose, and Adverse Outcome Pathways (AOPs) 93
    - 3.1 INTRODUCTION 93
    - 3.2 GENERAL CONSIDERATIONS ON EXPOSURE, ENVIRONMENTAL, AND BIOLOGICAL MONITORING 94
    - 3.3 BIOMONITORING 97
      - 3.3.1 Exposure Biomonitoring: Tissues and Fluids in Use 97
      - 3.3.2 Biomonitoring as a Basis for Estimating Target Dose and Critical Organ Concentration 99
      - 3.3.3 Use of Biomonitoring Data and Toxicokinetic Models to Estimate Dietary Intake 102
      - 3.3.4 Studying Health Outcomes by the Use of Biomarkers: Biomarkers of Effects 102
    - 3.4 MECHANISM OF ACTION, MODE OF ACTION, AND ADVERSE OUTCOME PATHWAYS AS A BASIS FOR HAZARD AND RISK ASSESSMENT 105
      - 3.4.1 Mechanism of Action 105
      - 3.4.2 Mode of Action and the Human Relevance Framework 109
      - 3.4.3 Adverse Outcome Pathways 111
      - 3.4.4 Biomonitoring Equivalents 114
    - REFERENCES 114
    - 3.5 SUMMARY 114
  - Four - Hazard Identification and Assessment 117
    - 4.1 INTRODUCTION 117
    - 4.2 SPECIATION 119
    - 4.3 MECHANISM OF ACTION, MODE OF ACTION, AND ADVERSE OUTCOME PATHWAYS 120
      - 4.3.1 Mechanism of Action 121
      - 4.3.2 Mode of Action 122
      - 4.3.3 Adverse Outcome Pathways 123
    - 4.4 HUMAN DATA 123
      - 4.4.1 General Considerations on Human Data 123
      - 4.4.2 Causality in Epidemiological Studies: Hill's Considerations 124
      - 4.4.3 Requirements for Data and Sources of Human Data 125
      - 4.4.4 Availability of Human Data and Considerations of Causality for Local Irritation Effects, Skin and Respiratory Sensitizatio 126
        
        4.4.4.1 Human Data on Local Corrosive/Irritation Effects on Skin and Mucous Membranes; Skin and Respiratory Sensitization 126
        
        4.4.4.2 Acute Toxicity—Human Data 128
      - 4.4.5 Reproductive and Developmental Toxicity—Human Data 128
      - 4.4.6 Classification of Carcinogenicity Using Human Data; International Agency for Research on Cancer Group 1 129
    - 4.5 DATA FROM STUDIES ON ACUTE AND CHRONIC TOXICITY IN ANIMALS, CELLS, AND MOLECULAR SYSTEMS IN VITRO; COMPUTATIONAL SYSTEMS 130
      - 4.5.1 In Vivo and In Vitro Data: Relevance for Humans—Noncancer Effects 130
      - 4.5.2 In Vitro and In Vivo Data—Mutagenicity and Carcinogenicity 134
        
        4.5.2.2 Carcinogenicity 134
        
        4.5.2.2.1 International Agency for Research on Cancer Classification of Carcinogenicity—Groups 2 and 3 135
        
        4.5.2.1 Mutagenicity 134
        
        4.5.3 Computerized Systems Supporting Hazard Identification and Assessment 136
      - 4.6 OBSERVATIONS OF CARCINOGENICITY OF METALLIC COMPOUNDS DURING 40YEARS 137
      - 4.7 CARCINOGENICITY CLASSIFICATION BY NATIONAL/UNION AUTHORITIES AND BY OTHER ORGANIZATIONS 140
        
        4.7.1 Carcinogenicity Classification in the European Union 140
        
        4.7.1.1 Classification According to SCOEL 140
        
        4.7.1.2 Carcinogenicity Classification According to ECHA (REACH and CLP Regulations) 140
        
        4.7.1.2.1 Category 1: Known or Presumed Human Carcinogens 140
        
        4.7.1.2.2 Category 2: Suspected Human Carcinogens 141
        
        4.7.2 Classification According to the USEPA (2017) 141
        
        4.7.2.1 Hazard Identification for Carcinogenic Effects (USEPA) 141
        
        4.7.3 Classification According to the American Conference of Governmental Industrial Hygienists 142
        
        4.8 ETHICAL CONSIDERATIONS FOR STUDIES OF EFFECTS OF CHEMICAL COMPOUNDS WITH HUMANS OR ANIMALS 143
        
        4.8.1 Studies With Humans 143
        
        4.8.2 Studies With Animals 145
        
        4.8.2.1 Rules in the European Union 145
        
        4.8.2.2 Rules in the United States 147
        
        REFERENCES 148
        
        Five - Dose–Effect and Dose–Response Assessment 151
        
        5.1 CONCEPTS IN QUANTITATIVE TOXICOLOGICAL ANALYSIS 151
        
        5.1.1 Dose–Effect and Dose–Response 151
        
        5.1.2 The S-Shaped or Sigmoid Curve 153
        
        5.1.3 Critical Organ, Critical Concentration, Critical Effect, and No-Observed-Effect Level 154
        
        5.1.4 The Lower Confidence Limit of the Benchmark Dose 157
        
        5.1.5 Population Critical Concentration 159
        
        5.2 ESTIMATING ACCEPTABLE OR RECOMMENDED EXPOSURE LEVELS IN HUMANS BASED ON DOSE–RESPONSE STUDIES IN ANIMALS 161
        
        5.2.1 Threshold-Type Critical Effects 161
        
        5.2.2 Carcinogenesis and Other Stochastic/Nonthreshold Effects 164
        
        5.3 DOSE–RESPONSE RELATIONSHIPS BASED ON MECHANISM OF ACTION, TOXICOKINETIC AND TOXICODYNAMIC MODELING, AND ADVERSE OUTCOME PAT 167
        
        5.3.1 Systemic Effects that are Deterministic/Threshold-Type Effects 168
        
        5.3.1.1 Dose–Response Relationships Based on Known Mechanism of Action And/Or Observations in Humans 169
        
        5.3.2 Toxicokinetic-Toxicodynamic Modeling of Dose–Response or Dose–Effect Relationships Based on the One-Compartment Model 170
        
        5.3.3 Quantitative Toxicokinetic-Toxicodynamic Modeling of Systemic Effects Based on Multicompartment and Physiologically Based 173
        
        5.3.4 Adverse Outcome Pathways 175
        
        5.3.5 Stochastic or Nonthreshold Effects 176
        
        5.4 DOSE–RESPONSE ASSESSMENT BASED ON EPIDEMIOLOGICAL STUDIES 176
        
        5.4.1 Local effects 176
        
        5.4.1.1 Nickel 177
        
        5.4.2 Systemic, Noncarcinogenic Effects 177
        
        5.4.3 Adverse Outcome Pathways and Identification of Sensitive Subpopulations at Risk 178
        
        5.4.3.1 Genetic Variation in the Binding of Lead to ALA-Dehydratase and Susceptibility to Lead-Induced Hypertension 178
        
        5.4.4 Carcinogenic Effects 178
        
        5.4.5 Newer Approaches to Risk Assessment and Developments for the Future 180
        
        REFERENCES 181
        
        Six - Dose–Response for Essential Metals and the Evaluation of Mixed Exposures 185
        
        6.1 ESSENTIALITY OF TRACE METALS 185
        
        6.2 DEFINING AN ACCEPTABLE RANGE OF ORAL INTAKES 188
        
        6.2.1 U-Formed Dose–Response Curve 188
        
        6.2.2 Groups With Special Sensitivity or Resistance 190
        
        6.3 OTHER TERMS AND CONCEPTS USED IN RISK ASSESSMENT OF ESSENTIAL TRACE METALS 191
        
        6.3.1 Terms and Concepts Used in Nutrition Science to Assess Requirements of Essential Trace Metals 191
        
        6.3.1.2 Requirements for Individuals, Basic and Normative Requirements 191
        
        6.3.1.1 Factorial Estimation of Nutrient Requirements 191
        
        6.3.1.3 Population Reference Intake, Recommended Dietary Allowance, Upper Level of Tolerable Intake and Safe Range of Population 192
        
        6.3.2 Toxicological Terms 193
        
        6.4 BASIC MECHANISMS OF HOMEOSTASIS 193
        
        6.5 HEALTH EFFECTS OF DEFICIENCY AND EXCESS 194
        
        6.6 EXAMPLES OF EFFECTS OF VARYING SEVERITY 195
        
        6.6.1 Lethal Deficiency 196
        
        6.6.2 Deficiency: Clinical Disease 196
        
        6.6.3 Subclinical Biomarkers of Deficiency and Their Clinical or Functional Significance 197
        
        6.6.6 Subclinical Toxic Effects or Biomarkers of Such Effects; Their Use as Critical Effects 198
        
        6.6.4 Lethal Toxic Effects 198
        
        6.6.5 Clinical, Nonlethal Poisoning 198
        
        6.7 SUMMARY AND CONCLUSIONS ON THE PRINCIPLES OF RISK ASSESSMENT FOR HUMAN EXPOSURES TO ESSENTIAL TRACE METALS 200
        
        6.8 THE INFLUENCE OF ESSENTIAL METALS ON EFFECTS AND DOSE–RESPONSE RELATIONSHIPS OF TOXIC METALS 202
        
        6.9 THE COMBINED ACTION OF METAL COMPOUNDS, INCLUDING INTERACTIONS, PRINCIPLES, AND METHODS OF ASSESSMENT 204
        
        6.10 THE ACTION OF OTHER FACTORS THAN ESSENTIAL METALS ON THE EFFECTS OF METALLIC COMPOUNDS 206
        
        6.11 GENE–ENVIRONMENT INTERACTIONS 208
        
        6.12 EVALUATION OF EXPOSURE TO MIXTURES 210
        
        6.12.1 Principles and Models for Assessment 210
        
        6.12.2 Summary and Conclusions on Mixtures and Deficiencies 211
        
        REFERENCES 212
        
        Seven - Applied Risk Assessment, Hazard Assessment, and Risk Management 217
        
        7.1 INTRODUCTION 217
        
        7.2 RISK CHARACTERIZATION 218
        
        7.2.1 The Importance of Severity of Critical Effect for Risk Management 219
        
        7.2.2 The Combined Consideration of the Results of Exposure Assessment and Dose–Response Assessment 220
        
        7.2.3 Consideration of Deficiency and Toxicity, Genetic Factors, Joint Action, and Exposure to Mixtures 221
        
        7.2.4 Populations at Risk 222
        
        7.2.5 Hazard Assessment and Hazard Characterization (REACH) 223
        
        7.2.6 Threshold of Toxicological Concern 225
        
        7.3 RISK MANAGEMENT 225
        
        7.3.1 Source Control, Substitution, and Restriction in Use 225
        
        7.3.2 Permissible Exposure Limits and Guidelines 228
        
        7.3.3 Biomonitoring Equivalents 237
        
        7.3.4 Summarizing Comments on Risk Management 237
        
        7.4 RISK COMMUNICATION 239
        
        7.5 ETHICAL ISSUES 240
        
        7.6 EXAMPLES OF SUCCESSFUL PREVENTION OF ADVERSE HEALTH EFFECTS 241
        
        REFERENCES 242
        
        Eight - Examples of Risk Assessments of Human Metal Exposures and the Need for Mode of Action (MOA), Toxicokinetic- ... 245
        
        8.1 ALUMINUM (AL) 246
        
        8.1.1 Properties, Uses, Occurrence and Toxicokinetics 246
        
        8.1.2 Health Effects 248
        
        8.1.3 Human Health Risk Assessments and Exposure Limits 250
        
        8.2 ARSENIC (AS) 251
        
        8.2.2 Production and Uses 251
        
        8.2.3 Environmental Levels and Human Exposures 251
        
        8.2.1 Introduction/Properties 251
        
        8.2.4 Kinetics and Metabolism 252
        
        8.2.5 Mechanism of Action for Arsenical Toxicity 253
        
        8.2.6 Biomonitoring 254
        
        8.2.6.1 Urine 254
        
        8.2.6.2 Blood 254
        
        8.2.6.3 Hair 254
        
        8.2.7 Effects and Dose-–Response Relationships 255
        
        8.2.7.2 Chronic Noncardiovascular Effects 255
        
        8.2.7.3 Chronic Cardiovascular Effects 255
        
        8.2.7.1 Acute and Subacute Effects 255
        
        8.2.7.4 Carcinogenic Effects 256
        
        8.2.7.4.1 Skin Cancer 256
        
        8.2.7.4.2 Lung Cancer 257
        
        8.2.7.4.3 Cancer of the Kidneys and the Bladder (Urothelial Cancer) 257
        
        8.2.7.4.4 Liver Cancer and Other Internal Cancers 258
        
        8.2.8 Risk Assessments and Recommended Preventive Measures Including Exposure Limits Set by International Organizations 258
        
        8.2.9 Arsine 259
        
        8.3 CADMIUM (CD) 259
        
        8.3.1 Introduction/Properties 259
        
        8.3.2 Production and Uses 260
        
        8.3.3 Environmental Occurrence and Human Exposures 260
        
        8.3.4 Toxicokinetics 261
        
        8.3.4.1 Absorption and Uptake 261
        
        8.3.4.3 Excretion, Biological Half-Life 263
        
        8.3.4.2 Transport and Distribution 263
        
        8.3.4.4 Toxicokinetics Model for Cadmium 264
        
        8.3.5 Biomonitoring 264
        
        8.3.5.1 Cadmium in Blood 265
        
        8.3.5.2 Cadmium in Urine 266
        
        8.3.6 Effects and Dose–Response Relationships With Special Reference to Toxicodynamics and Toxicokinetic-Toxicodynamic Relations 267
        
        8.3.6.1 Respiratory Effects 267
        
        8.3.6.2 Kidney Effects 268
        
        8.3.6.3 Bone Effects 269
        
        8.3.6.4 Cancer 270
        
        8.3.6.5 Other Effects 271
        
        8.3.7 Risk Assessments and Recommended Preventive Measures Including Exposure Limits Set by International and National Organizat 271
        
        8.4 COBALT (CO) 273
        
        8.4.2 Production and Uses 273
        
        8.4.2.1 Vitamin B12—An Essential Cobalt-Containing Compound 273
        
        8.4.1 Introduction/Properties 273
        
        8.4.3 Environmental Occurrence and Human Exposures 274
        
        8.4.4 Toxicokinetics 274
        
        8.4.6 Effects and Dose–Response Relationships 275
        
        8.4.5 Biomonitoring 275
        
        8.4.7 Risk Assessment and Recommended Preventive Measures 279
        
        8.5 GALLIUM (GA) 280
        
        8.5.3 Work Environment 280
        
        8.5.6 Biomonitoring 280
        
        8.5.1 Uses 280
        
        8.5.4 Human Exposures 280
        
        8.5.2 Dispersion in the Environment 280
        
        8.5.5 Toxicokinetics 280
        
        8.5.10 Human Risk Assessment 281
        
        8.5.7 Acute Toxicity 281
        
        8.5.9 Carcinogenicity 281
        
        8.5.8 Target Organ System Effects 281
        
        8.5.8.3 Lung 281
        
        8.5.8.1 Kidney 281
        
        8.5.8.4 Irritation 281
        
        8.5.8.2 Immune System 281
        
        8.5.11 Human Health Risks 282
        
        8.6 INDIUM (IN) 282
        
        8.6.3 Work Environment 282
        
        8.6.1 Uses 282
        
        8.6.4 Human Exposures 282
        
        8.6.2 Dispersion in the Environment 282
        
        8.6.6 Biomonitoring 283
        
        8.6.7 Acute Toxicity 283
        
        8.6.5 Toxicokinetics 283
        
        8.6.8 Target Organ System Effects 283
        
        8.6.8.3 Lung 283
        
        8.6.8.1 Kidney 283
        
        8.6.8.4 Irritation 283
        
        8.6.8.2 Developmental Toxicity 283
        
        8.6.10 Human Risk Assessment 284
        
        8.6.11 Human Health Risks 284
        
        8.6.9 Carcinogenicity 284
        
        8.7 THE LANTHANIDES (INCLUDING LANTHANUM, LA; CERIUM, CE; AND GADOLINIUM, GD) 284
        
        8.7.1 Lanthanum (La) 285
        
        8.7.1.1 Production and Uses 285
        
        8.7.1.2 Environmental Levels and Human Exposures 286
        
        8.7.1.3 Toxicokinetics 286
        
        8.7.1.4 Toxicity and Human Health Effects 286
        
        8.7.2 Cerium (Ce) 287
        
        8.7.2.1 Production and Uses 287
        
        8.7.2.2 Human Exposures 287
        
        8.7.2.5 Risk Assessment 288
        
        8.7.2.3 Toxicokinetics 288
        
        8.7.2.4 Acute Toxicity 288
        
        8.7.3 Gadolinium (Gd) 289
        
        8.7.3.2 Environmental Levels and Human Exposures 289
        
        8.7.3.3 Toxicokinetics 289
        
        8.7.3.1 Production and Uses 289
        
        8.7.3.5 Risk Assessment 290
        
        8.7.3.4 Toxicity 290
        
        8.8 LEAD (PB) 291
        
        8.8.1 Introduction/Properties 291
        
        8.8.2 Production and Uses 291
        
        8.8.3 Dispersion in the Environment and Human Exposures 291
        
        8.8.3.1 Work Environment 292
        
        8.8.3.2 Human Exposures 292
        
        8.8.4 Toxicokinetics 292
        
        8.8.7 Target Organ System Effects 293
        
        8.8.7.3 Immune System 293
        
        8.8.7.1 Skeletal System 293
        
        8.8.7.4 Hematopoietic System 293
        
        8.8.7.2 Kidney 293
        
        8.8.5 Biomonitoring 293
        
        8.8.6 Acute Toxicity 293

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