Chapter
1.2 WIDESPREAD EXPOSURE TO METALS CONTRIBUTES TO GLOBAL BURDEN OF DISEASE
1.3 METAL POISONING—CLINICAL SYMPTOMS AND SIGNS IN OCCUPATIONAL AND ENVIRONMENTAL SETTINGS
1.4 DETAILED INVESTIGATION IS REQUIRED FOR IDENTIFICATION OF ADVERSE EFFECTS AT LOW-LEVEL METAL EXPOSURES
1.5 PERSPECTIVES ON HISTORICAL DEVELOPMENT OF CONCEPTS USED IN RISK ASSESSMENT OF METAL EXPOSURES—ROLE OF THE SCIENTIFIC COMMIT ...
1.6 CURRENT LONG-TERM LOW-LEVEL EXPOSURES AND RELATED HEALTH EFFECTS
1.6.1 Neurotoxicology of Metals
1.6.2 Cardiovascular Disease Related to Metals
1.6.3 Kidney Effects of Exposure to Metals
1.6.4 Cancer Induced by Metal Exposures
1.6.5 Reproductive and Developmental Effects of Metal Exposures
1.7 ISSUES OF CURRENT CONCERN FOR HAZARD ASSESSMENT, RISK ASSESSMENT, AND PREVENTION
1.7.1 Expanding Global Industrial Use of Metals
1.7.2 Toxicity of Metallic Nanoparticles
1.7.3 Environmental Mobilization Processes
1.7.4 Toxic Metals in Food and Oral Intake; Other Intake Routes
1.7.5 Metal Exposure by Release From Implanted Medical Devices
1.7.6 Toxicokinetics and Dosimetry
1.7.7 Essential Metals: Deficiency and Toxicity
1.7.8 Biological Monitoring
1.7.9 Interactions Among Metals and Gene–Environment Interactions
1.7.10 Application of MOA TKTD Models, AOPs, or Other Systems Toxicology Approaches to Risk and Hazard Assessment of Metal Exposures
1.7.11 Applied Hazard- and Risk Assessment—Preventive Action and Management
Two - Exposure, Internal Dose, and Toxicokinetics (TK)
2.1 INTRODUCTION; TERMINOLOGY
2.2.1 General Considerations
2.2.2 Exposure Through Food and Drinking Water
2.2.3 Exposure by Inhalation
2.3 DEPOSITION AND ABSORPTION
2.3.1 General Considerations Including an Introduction to Skin Deposition
2.3.2 Deposition and Absorption After Ingestion
2.3.3 Deposition and Absorption After Inhalation
2.3.3.1 Deposition and Absorption of Gases and Vapors
2.3.3.2 Deposition of Particles
2.3.3.3 Clearance of Particles From the Respiratory System
2.3.3.3.1 Tracheobronchial Clearance
2.3.3.3.2 Peripheral Lung Clearance and Translocation From the Respiratory Tract
2.4 TRANSPORT, BIOTRANSFORMATION, AND DISTRIBUTION
2.5.1 Gastrointestinal Excretion
2.5.2 Excretion Through the Kidneys
2.5.3 Excretion Rate: Biological Half-Life (Half-Time)
2.6.1 One-Compartment Model
2.6.2 Multicompartment Models and Physiologically Based Models
2.6.2.1 Description of a Multicompartment Model for Cadmium
2.7 USE OF INDICATOR MEDIA FOR ESTIMATING CRITICAL ORGAN CONCENTRATION
Three - Biomonitoring, Mode of Action (MOA), Target Dose, and Adverse Outcome Pathways (AOPs)
3.2 GENERAL CONSIDERATIONS ON EXPOSURE, ENVIRONMENTAL, AND BIOLOGICAL MONITORING
3.3.1 Exposure Biomonitoring: Tissues and Fluids in Use
3.3.2 Biomonitoring as a Basis for Estimating Target Dose and Critical Organ Concentration
3.3.3 Use of Biomonitoring Data and Toxicokinetic Models to Estimate Dietary Intake
3.3.4 Studying Health Outcomes by the Use of Biomarkers: Biomarkers of Effects
3.4 MECHANISM OF ACTION, MODE OF ACTION, AND ADVERSE OUTCOME PATHWAYS AS A BASIS FOR HAZARD AND RISK ASSESSMENT
3.4.1 Mechanism of Action
3.4.2 Mode of Action and the Human Relevance Framework
3.4.3 Adverse Outcome Pathways
3.4.4 Biomonitoring Equivalents
Four - Hazard Identification and Assessment
4.3 MECHANISM OF ACTION, MODE OF ACTION, AND ADVERSE OUTCOME PATHWAYS
4.3.1 Mechanism of Action
4.3.3 Adverse Outcome Pathways
4.4.1 General Considerations on Human Data
4.4.2 Causality in Epidemiological Studies: Hill's Considerations
4.4.3 Requirements for Data and Sources of Human Data
4.4.4 Availability of Human Data and Considerations of Causality for Local Irritation Effects, Skin and Respiratory Sensitization ...
4.4.4.1 Human Data on Local Corrosive/Irritation Effects on Skin and Mucous Membranes; Skin and Respiratory Sensitization
4.4.4.2 Acute Toxicity—Human Data
4.4.5 Reproductive and Developmental Toxicity—Human Data
4.4.6 Classification of Carcinogenicity Using Human Data; International Agency for Research on Cancer Group 1
4.5 DATA FROM STUDIES ON ACUTE AND CHRONIC TOXICITY IN ANIMALS, CELLS, AND MOLECULAR SYSTEMS IN VITRO; COMPUTATIONAL SYSTEMS
4.5.1 In Vivo and In Vitro Data: Relevance for Humans—Noncancer Effects
4.5.2 In Vitro and In Vivo Data—Mutagenicity and Carcinogenicity
4.5.2.2.1 International Agency for Research on Cancer Classification of Carcinogenicity—Groups 2 and 3
4.5.3 Computerized Systems Supporting Hazard Identification and Assessment
4.6 OBSERVATIONS OF CARCINOGENICITY OF METALLIC COMPOUNDS DURING 40YEARS
4.7 CARCINOGENICITY CLASSIFICATION BY NATIONAL/UNION AUTHORITIES AND BY OTHER ORGANIZATIONS
4.7.1 Carcinogenicity Classification in the European Union
4.7.1.1 Classification According to SCOEL
4.7.1.2 Carcinogenicity Classification According to ECHA (REACH and CLP Regulations)
4.7.1.2.1 Category 1: Known or Presumed Human Carcinogens
4.7.1.2.2 Category 2: Suspected Human Carcinogens
4.7.2 Classification According to the USEPA (2017)
4.7.2.1 Hazard Identification for Carcinogenic Effects (USEPA)
4.7.3 Classification According to the American Conference of Governmental Industrial Hygienists
4.8 ETHICAL CONSIDERATIONS FOR STUDIES OF EFFECTS OF CHEMICAL COMPOUNDS WITH HUMANS OR ANIMALS
4.8.1 Studies With Humans
4.8.2 Studies With Animals
4.8.2.1 Rules in the European Union
4.8.2.2 Rules in the United States
Five - Dose–Effect and Dose–Response Assessment
5.1 CONCEPTS IN QUANTITATIVE TOXICOLOGICAL ANALYSIS
5.1.1 Dose–Effect and Dose–Response
5.1.2 The S-Shaped or Sigmoid Curve
5.1.3 Critical Organ, Critical Concentration, Critical Effect, and No-Observed-Effect Level
5.1.4 The Lower Confidence Limit of the Benchmark Dose
5.1.5 Population Critical Concentration
5.2 ESTIMATING ACCEPTABLE OR RECOMMENDED EXPOSURE LEVELS IN HUMANS BASED ON DOSE–RESPONSE STUDIES IN ANIMALS
5.2.1 Threshold-Type Critical Effects
5.2.2 Carcinogenesis and Other Stochastic/Nonthreshold Effects
5.3 DOSE–RESPONSE RELATIONSHIPS BASED ON MECHANISM OF ACTION, TOXICOKINETIC AND TOXICODYNAMIC MODELING, AND ADVERSE OUTCOME PAT ...
5.3.1 Systemic Effects that are Deterministic/Threshold-Type Effects
5.3.1.1 Dose–Response Relationships Based on Known Mechanism of Action And/Or Observations in Humans
5.3.2 Toxicokinetic-Toxicodynamic Modeling of Dose–Response or Dose–Effect Relationships Based on the One-Compartment Model
5.3.3 Quantitative Toxicokinetic-Toxicodynamic Modeling of Systemic Effects Based on Multicompartment and Physiologically Based K ...
5.3.4 Adverse Outcome Pathways
5.3.5 Stochastic or Nonthreshold Effects
5.4 DOSE–RESPONSE ASSESSMENT BASED ON EPIDEMIOLOGICAL STUDIES
5.4.2 Systemic, Noncarcinogenic Effects
5.4.3 Adverse Outcome Pathways and Identification of Sensitive Subpopulations at Risk
5.4.3.1 Genetic Variation in the Binding of Lead to ALA-Dehydratase and Susceptibility to Lead-Induced Hypertension
5.4.4 Carcinogenic Effects
5.4.5 Newer Approaches to Risk Assessment and Developments for the Future
Six - Dose–Response for Essential Metals and the Evaluation of Mixed Exposures
6.1 ESSENTIALITY OF TRACE METALS
6.2 DEFINING AN ACCEPTABLE RANGE OF ORAL INTAKES
6.2.1 U-Formed Dose–Response Curve
6.2.2 Groups With Special Sensitivity or Resistance
6.3 OTHER TERMS AND CONCEPTS USED IN RISK ASSESSMENT OF ESSENTIAL TRACE METALS
6.3.1 Terms and Concepts Used in Nutrition Science to Assess Requirements of Essential Trace Metals
6.3.1.1 Factorial Estimation of Nutrient Requirements
6.3.1.2 Requirements for Individuals, Basic and Normative Requirements
6.3.1.3 Population Reference Intake, Recommended Dietary Allowance, Upper Level of Tolerable Intake and Safe Range of Population Me ...
6.3.2 Toxicological Terms
6.4 BASIC MECHANISMS OF HOMEOSTASIS
6.5 HEALTH EFFECTS OF DEFICIENCY AND EXCESS
6.6 EXAMPLES OF EFFECTS OF VARYING SEVERITY
6.6.2 Deficiency: Clinical Disease
6.6.3 Subclinical Biomarkers of Deficiency and Their Clinical or Functional Significance
6.6.4 Lethal Toxic Effects
6.6.5 Clinical, Nonlethal Poisoning
6.6.6 Subclinical Toxic Effects or Biomarkers of Such Effects; Their Use as Critical Effects
6.7 SUMMARY AND CONCLUSIONS ON THE PRINCIPLES OF RISK ASSESSMENT FOR HUMAN EXPOSURES TO ESSENTIAL TRACE METALS
6.8 THE INFLUENCE OF ESSENTIAL METALS ON EFFECTS AND DOSE–RESPONSE RELATIONSHIPS OF TOXIC METALS
6.9 THE COMBINED ACTION OF METAL COMPOUNDS, INCLUDING INTERACTIONS, PRINCIPLES, AND METHODS OF ASSESSMENT
6.10 THE ACTION OF OTHER FACTORS THAN ESSENTIAL METALS ON THE EFFECTS OF METALLIC COMPOUNDS
6.11 GENE–ENVIRONMENT INTERACTIONS
6.12 EVALUATION OF EXPOSURE TO MIXTURES
6.12.1 Principles and Models for Assessment
6.12.2 Summary and Conclusions on Mixtures and Deficiencies
Seven - Applied Risk Assessment, Hazard Assessment, and Risk Management
7.2 RISK CHARACTERIZATION
7.2.1 The Importance of Severity of Critical Effect for Risk Management
7.2.2 The Combined Consideration of the Results of Exposure Assessment and Dose–Response Assessment
7.2.3 Consideration of Deficiency and Toxicity, Genetic Factors, Joint Action, and Exposure to Mixtures
7.2.4 Populations at Risk
7.2.5 Hazard Assessment and Hazard Characterization (REACH)
7.2.6 Threshold of Toxicological Concern
7.3.1 Source Control, Substitution, and Restriction in Use
7.3.2 Permissible Exposure Limits and Guidelines
7.3.3 Biomonitoring Equivalents
7.3.4 Summarizing Comments on Risk Management
7.6 EXAMPLES OF SUCCESSFUL PREVENTION OF ADVERSE HEALTH EFFECTS
Eight - Examples of Risk Assessments of Human Metal Exposures and the Need for Mode of Action (MOA), Toxicokinetic- ...
8.1.1 Properties, Uses, Occurrence and Toxicokinetics
8.1.3 Human Health Risk Assessments and Exposure Limits
8.2.1 Introduction/Properties
8.2.2 Production and Uses
8.2.3 Environmental Levels and Human Exposures
8.2.4 Kinetics and Metabolism
8.2.5 Mechanism of Action for Arsenical Toxicity
8.2.7 Effects and Dose-–Response Relationships
8.2.7.1 Acute and Subacute Effects
8.2.7.2 Chronic Noncardiovascular Effects
8.2.7.3 Chronic Cardiovascular Effects
8.2.7.4 Carcinogenic Effects
8.2.7.4.3 Cancer of the Kidneys and the Bladder (Urothelial Cancer)
8.2.7.4.4 Liver Cancer and Other Internal Cancers
8.2.8 Risk Assessments and Recommended Preventive Measures Including Exposure Limits Set by International Organizations
8.3.1 Introduction/Properties
8.3.2 Production and Uses
8.3.3 Environmental Occurrence and Human Exposures
8.3.4.1 Absorption and Uptake
8.3.4.2 Transport and Distribution
8.3.4.3 Excretion, Biological Half-Life
8.3.4.4 Toxicokinetics Model for Cadmium
8.3.6 Effects and Dose–Response Relationships With Special Reference to Toxicodynamics and Toxicokinetic-Toxicodynamic Relationships
8.3.6.1 Respiratory Effects
8.3.7 Risk Assessments and Recommended Preventive Measures Including Exposure Limits Set by International and National Organizations
8.4.1 Introduction/Properties
8.4.2 Production and Uses
8.4.2.1 Vitamin B12—An Essential Cobalt-Containing Compound
8.4.3 Environmental Occurrence and Human Exposures
8.4.6 Effects and Dose–Response Relationships
8.4.7 Risk Assessment and Recommended Preventive Measures
8.5.2 Dispersion in the Environment
8.5.8 Target Organ System Effects
8.5.10 Human Risk Assessment
8.5.11 Human Health Risks
8.6.2 Dispersion in the Environment
8.6.8 Target Organ System Effects
8.6.8.2 Developmental Toxicity
8.6.10 Human Risk Assessment
8.6.11 Human Health Risks
8.7 THE LANTHANIDES (INCLUDING LANTHANUM, LA; CERIUM, CE; AND GADOLINIUM, GD)
8.7.1.1 Production and Uses
8.7.1.2 Environmental Levels and Human Exposures
8.7.1.4 Toxicity and Human Health Effects
8.7.2.1 Production and Uses
8.7.3.1 Production and Uses
8.7.3.2 Environmental Levels and Human Exposures
8.8.1 Introduction/Properties
8.8.2 Production and Uses
8.8.3 Dispersion in the Environment and Human Exposures
8.8.7 Target Organ System Effects
8.8.7.4 Hematopoietic System
8.8.7.5 Cardiovascular System
8.8.8 Human Risk Assessment
8.9.1 Introduction/Properties
8.9.2 Production, Uses, Restrictions, and Substitutes
8.9.3 Environmental Occurrence and Human Exposures
8.9.3.1 Geochemical Mercury Cycle, Mercury in Ambient Air, Water, Sediments; Uptake in Biota
8.9.3.2 Human Exposure from Food, Dental Amalgam, and Skin Creams
8.9.3.3 Working Environment
8.9.4 Toxicokinetics and Metabolism
8.9.4.1 Mercury Vapor and Inorganic Divalent Mercury
8.9.6 Effects and Dose–Response Relationships
8.9.6.1 Mercury Vapor and Divalent Mercuric Mercury
8.9.7 Risk Assessments and Recommended Preventive Measures Including Exposure Limits Set by International Organizations
8.10.1 Introduction/Properties
8.10.2 Production and Uses
8.10.3 Environmental Occurrence and Human Exposures
8.10.4.2 Uptake From Food and Drinking Water
8.10.4.3 Transport and Distribution
8.10.4.5 Toxicokinetic Models
8.10.6 Effects and Dose–Response Relationships
8.10.6.2 Pulmonary and Systemic Toxicity
8.10.6.3 Reproductive and Developmental Effects
8.10.6.4 Genotoxicity and Carcinogenicity
8.10.7 Risk Assessments and Recommended Preventive Measures Including Exposure Limits Set by International and National Organizations
8.11.1 Properties and Uses
8.11.2 Dispersion in the Environment and Human Exposure
8.11.3 Toxicokinetics and Biomonitoring
8.11.6 Human Health Risk Assessment
8.12.1 Properties, Uses and Human Exposures
8.12.5 Sensitization and Allergy (Platinosis)
8.12.6 Carcinogenicity, Mutagenicity, and Reproductive Toxicity
8.12.7 Human Health Risk Assessment
GLOSSARY OF TERMS AND ACRONYMS
Risk Assessment for Human Metal Exposures
：Mode of Action and Kinetic Approaches
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