An Introduction to Interdisciplinary Toxicology: From Molecules to Man

Cover
An Introduction to Interdisciplinary Toxicology: From Molecules to Man
Copyright
Contents
List of contributors
Foreword
Preface
Part I: General concepts
1 History and basic concepts of toxicology
	1.1 A brief history of toxicology
	1.2 Important concepts in toxicology
		1.2.1 The dose–response relationship
		1.2.2 Time as a factor in the expression of toxicity
		1.2.3 Time as a factor in exposures
		1.2.4 Local versus systemic toxicity
		1.2.5 Interactions
		1.2.6 Adaptations
	References
2 Absorption, distribution, and excretion in complex organisms
	2.1 Introduction to xenobiotic disposition
		2.1.1 Barriers and facilitators of xenobiotic movement
		2.1.2 Uptake, distribution, and elimination in complex organisms
		2.1.3 Ion trapping
		2.1.4 First-order rate constants
		2.1.5 Xenobiotic transporters
		2.1.6 Saturable kinetics
	2.2 Absorption of xenobiotics
		2.2.1 Enteral exposure
		2.2.2 Cutaneous exposure
		2.2.3 Respiratory exposure
	2.3 Distribution of xenobiotics
		2.3.1 Volume of distribution (Vd)
		2.3.2 Factors affecting xenobiotic distribution
		2.3.3 Barriers to distribution
	2.4 Elimination: metabolism and excretion of xenobiotics
		2.4.1 Renal excretion
		2.4.2 Hepatic clearance
		2.4.3 Other
	References
3 Xenobiotic metabolism and disposition
	3.1 Introduction
	3.2 Phase I drug-metabolizing enzymes
		3.2.1 Cytochrome P450s
		3.2.2 Flavin-containing monooxygenases
		3.2.3 Other oxidases and reductases
		3.2.4 Hydrolases
	3.3 Phase II drug-metabolizing enzymes
		3.3.1 UDP-glucuronosyltransferases
		3.3.2 Sulfotransferases
		3.3.3 Glutathione S-transferases
		3.3.4 Other phase II drug-metabolizing enzymes
	3.4 Phase III drug transporters
		3.4.1 Solute carrier transporters
		3.4.2 ATP-binding cassette transporters
	3.5 Conclusions
	References
Part II: Responses to chemical toxicants
4 Toxicant interactions with macromolecular targets
	4.1 Toxicokinetics and toxicodynamics
	4.2 Toxicokinetics
	4.3 Toxicodynamics
	4.4 AChE and OP insecticide mechanism and mode of action
	4.5 Mechanism and mode of action of OP inhibitors of AChE
	4.6 Toxicodynamic factors for inhibition of AChE by OP compounds
	4.7 Kinetic and equilibrium constants
	4.8 Determining ki under pseudo-first-order conditions
	4.9 The IC50 and pIC50
	4.10 Determining the Kd and k2 components of ki
	4.11 Determining Kd and k2 in the presence of substrate
	4.12 Postinhibitory reactions: reactivation and aging
	4.13 Mutant AChE produces insecticide resistance in mosquitoes
	4.14 Conclusion
	References
5 Cellular responses to toxicants
	5.1 Introduction
	5.2 Cell adaptation, injury, and death
		5.2.1 Cell adaptation
		5.2.2 Cell injury
		5.2.3 Cell death
	5.3 Oxidative stress and cellular protection system
		5.3.1 Pro-oxidants: cell injury
		5.3.2 Antioxidants: cell protection
	5.4 Cellular techniques
	Further reading
6 Disruption of extracellular signaling
	6.1 Overview of extracellular signaling
	6.2 Disruption of extracellular signaling in the expression of toxicity
		6.2.1 Toxicants that modulate the levels of signal molecules
		6.2.2 Toxicants that block the extracellular signal at the receptor
		6.2.3 Toxicants that directly mimic the extracellular signal at the receptor
	6.3 Conclusions
	References
7 Disruption of intracellular signaling
	7.1 Overview of intracellular signaling
	7.2 Mitochondria-targeted pesticides and mitochondrial dysfunction
		7.2.1 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
		7.2.2 Rotenone
	7.3 Neuroinflammation
		7.3.1 Manganese
		7.3.2 Dieldrin
	7.4 Oxidative stress
		7.4.1 Manganese
		7.4.2 Lead
	7.5 Concluding remarks and future directions
	References
8 Carcinogenesis
	8.1 Background
	8.2 Definitions
	8.3 Mechanisms of chemical carcinogens
	8.4 Genotoxic/DNA-reactive compounds
	8.5 Mutation
	8.6 DNA repair
	8.7 Nongenotoxic carcinogens
	8.8 Cytotoxicity
	8.9 Receptor mediated
	8.10 DNA methylation
	8.11 Immunosuppression
	8.12 Oxidative stress
	8.13 Gap junctional intercellular communication
	8.14 Polymorphisms in carcinogen metabolism and DNA repair
	8.15 Proto-oncogenes and tumor-suppressor genes
	8.16 Multistage carcinogenesis
	8.17 Evaluating chemicals for carcinogenicity
	8.18 Determining human carcinogenic risk
	References
	Further reading
9 Epigenetics
	9.1 Historical perspective
	9.2 Chromatin remodeling
	9.3 DNA methylation
	9.4 Histone modifications
	9.5 Toxicology and epigenetics
		9.5.1 Case studies of environmental factors that modify the epigenome
		9.5.2 Epigenetic mechanisms control toxicological mechanisms
		9.5.3 Environmental contaminants affect epigenetics
			9.5.3.1 Arsenic
			9.5.3.2 Air contaminants
		9.5.4 Epigenetic mechanisms are targets for toxicants
			9.5.4.1 DNA methylation
			9.5.4.2 Histone modifications
			9.5.4.3 Readers of DNA methylation and histone modifications
			9.5.4.4 Summary
		9.5.5 Toxicological mechanisms that disrupt the epigenome
			9.5.5.1 Reactive oxygen species
			9.5.5.2 Energy metabolism
	9.6 Cancer as an epigenetic disease
	9.7 Pitfalls in epigenetics research
	References
		Author information
		Seminal papers
		Epigenetic mechanisms
	Further reading
		Epigenetic mechanisms
		Toxicants affecting epigenetic mechanisms
10 Microbiome in toxicity and its modulation
	10.1 Introduction
	10.2 Ingested toxicants and the microbiome
		10.2.1 Alcohol
		10.2.2 Artificial sweeteners
		10.2.3 Mycotoxins
	10.3 Pesticides and the microbiome
		10.3.1 Chlorpyrifos
		10.3.2 Glyphosate
	10.4 Environmental toxicants and the microbiome
		10.4.1 Polycyclic aromatic hydrocarbons
		10.4.2 Persistent organic pollutants
	10.5 Toxic metals and the microbiome
		10.5.1 Cadmium
		10.5.2 Mercury
	10.6 Concluding remarks
	References
Part III: Organ system effects
11 Dermal toxicity*
	11.1 Introduction
	11.2 Histology of skin
		11.2.1 Epidermis
		11.2.2 Dermis
	11.3 Dermal absorption of xenobiotics
		11.3.1 Mechanism of absorption and penetration
		11.3.2 Factors affecting absorption and penetration of xenobiotics
		11.3.3 Measurement of absorption and penetration
			11.3.3.1 In vivo
			11.3.3.2 In vitro
	11.4 Metabolism
	11.5 Contact dermatitis
		11.5.1 Irritant
		11.5.2 Allergic dermatitis
	11.6 Photosensitivity
		11.6.1 Phototoxicity
		11.6.2 Photoallergy
	11.7 Disorders and diseases of skin
		11.7.1 Pigment
		11.7.2 Urticaria
		11.7.3 Chloracne
		11.7.4 Cancer
	11.8 Tattoos
	11.9 Conclusions
	References
12 Hepatic toxicology
	12.1 Introduction
	12.2 Hepatic structural and functional organization
	12.3 Cellular components and functions
	12.4 Mechanism of bile formation and function
	12.5 Types of liver injury
		12.5.1 Hepatocellular hypertrophy and CYP enzyme induction
			12.5.1.1 Peroxisome proliferation
			12.5.1.2 Induction via the mixed-function oxidase system
		12.5.2 Drug-induced liver injury
			12.5.2.1 Hepatocellular toxicity
			12.5.2.2 Idiosyncratic hepatotoxicity (drug-induced liver injury type 2)
			12.5.2.3 Metabolic effects and lipid accumulation
			12.5.2.4 Cholestasis and bile-duct hyperplasia
			12.5.2.5 Fibrosis/cirrhosis
			12.5.2.6 Tumors
			12.5.2.7 Immune-mediated hepatotoxicity
			12.5.2.8 Oxidative stress
			12.5.2.9 Mitochondrial impairment
	12.6 Additional mechanisms
	12.7 Current state of serum biomarkers to assess liver damage
	12.8 Conclusions
	References
13 Renal toxicology
	13.1 Structure and function of kidney
		13.1.1 Kidney structure
		13.1.2 Kidney functions
			13.1.2.1 Urine production
			13.1.2.2 Reabsorption and secretion
			13.1.2.3 Other functions
	13.2 Adaptation and susceptibility of kidneys to toxicants
		13.2.1 Adaptation of kidney function
		13.2.2 Susceptibility of the kidney to toxicity
		13.2.3 Acute kidney injury
		13.2.4 Chronic kidney disease
	13.3 Site-selective kidney toxicity
		13.3.1 Proximal tubule injury
		13.3.2 Glomerular injury
		13.3.3 Loop of Henle roof and collecting ducts
		13.3.4 Papilla
	13.4 Evaluation of renal function
		13.4.1 Blood urea nitrogen
		13.4.2 Creatinine
		13.4.3 Glomerular filtration rate
		13.4.4 Renal clearance
		13.4.5 Proteinuria
		13.4.6 Glycosuria
		13.4.7 Urine volume and osmolality
		13.4.8 Secreted enzymes
	13.5 Classification of nephrotoxic substances
		13.5.1 Heavy metals
		13.5.2 Analgesics
		13.5.3 Antibiotics
		13.5.4 Antiviral drugs
		13.5.5 Anticancer drugs
		13.5.6 Halogenated hydrocarbons
		13.5.7 Mycotoxins
		13.5.8 Tetrafluoroethylene
	References
14 Respiratory
	14.1 Introduction
	14.2 Toxicants affecting the lung following inhalation
		14.2.1 Immediate responses
			14.2.1.1 Sulfur dioxide
			14.2.1.2 Formaldehyde
			14.2.1.3 Ammonia
			14.2.1.4 Chlorine
			14.2.1.5 Oxides of nitrogen (silo filler’s disease)
		14.2.2 Delayed and cumulative responses
			14.2.2.1 Toluene diisocyanate
			14.2.2.2 Air pollution
			14.2.2.3 Tobacco smoke
			14.2.2.4 Silicosis
			14.2.2.5 Asbestos
	14.3 Systemic lung toxicants
		14.3.1 Paraquat
		14.3.2 Nitrofurantoin
		14.3.3 Cyclophosphamide
		14.3.4 Amiodarone
	14.4 Reactive airway dysfunction syndrome
	References
15 Cardiovascular
	15.1 Overview of cardiovascular physiology
		15.1.1 Cardiac function
		15.1.2 Vascular function
	15.2 Mechanisms of toxicity and disease pathogenesis
		15.2.1 Shifts in ion homeostasis and calcium overload
		15.2.2 Oxidative stress and mitochondrial toxicity
		15.2.3 Mechanisms involving hypertrophic growth or hyperplasia
			15.2.3.1 Cardiac hypertrophy
			15.2.3.2 Vascular neointimal hyperplasia and atherosclerosis
		15.2.4 Aryl hydrocarbon receptor
	15.3 Classical cardiovascular toxicants and their mechanisms of action
		15.3.1 Cardiac toxicants
		15.3.2 Vascular toxicants
	References
16 Introduction to reproductive and developmental toxicology
	16.1 Introduction
	16.2 Hypothalamus and hormones
	16.3 Male reproductive system
		16.3.1 Testes
		16.3.2 Epididymides
		16.3.3 Seminal vesicles
		16.3.4 Prostate gland
		16.3.5 Cowper’s gland/bulbourethral glands
	16.4 Female reproductive system
		16.4.1 Ovary
			16.4.1.1 Ovarian cycle
		16.4.2 Uterus
			16.4.2.1 Menstrual cycle
	16.5 Pregnancy and embryo/fetal development
	16.6 Toxicants
		16.6.1 Dichlorodiphenyltrichloroethane
		16.6.2 Diethylstilbestrol
		16.6.3 Ethanol
		16.6.4 Metals
		16.6.5 Phthalates
		16.6.6 Polychlorinated biphenyls
		16.6.7 Thalidomide
	References
	Further reading
17 Organ system effects: endocrine toxicology
	17.1 Introduction to hormone systems and endocrine toxicology
	17.2 General overview of hormone signaling
	17.3 Hormone axis and chemical perturbation
		17.3.1 The hypothalamus–pituitary–adrenal axis
		17.3.2 The hypothalamus–pituitary–gonadal axis
		17.3.3 The hypothalamus–pituitary–thyroid axis
		17.3.4 The growth hormone axis
		17.3.5 The gastrointestinal–endocrine system
	17.4 Comparative endocrinology: insight into endocrine toxicology
	17.5 New directions for the study of endocrine toxicology
	Abbreviations
	References
18 Immunotoxicology
	18.1 Introduction
	18.2 Types of immunotoxicity
	18.3 Metals
	18.4 Pesticides
	18.5 Polycyclic aromatic hydrocarbons
	18.6 Pulmonary immunotoxicants
	18.7 Smoking, alcohol, and drugs of abuse
	References
19 Sensory function
	19.1 Introduction
	19.2 Vision
		19.2.1 Physiological basis of vision
		19.2.2 Toxic Effects on the Visual System
		19.2.3 Visual impairments and quality of life
	19.3 Audition
		19.3.1 Physiological basis of hearing
		19.3.2 Toxic effects on the auditory system
		19.3.3 Ototoxic drugs
		19.3.4 Industrial pollutants
		19.3.5 Coexposures
	19.4 Vestibular
		19.4.1 Physiological basis of vestibular perception
		19.4.2 Toxic effects on the vestibular system
		19.4.3 Loss of oculomotor control
		19.4.4 Loss of equilibrium and vestibulospinal reflexes
		19.4.5 Cognitive and physiological consequences
		19.4.6 Vestibular impairments and quality of life
	19.5 Somatosensory
		19.5.1 Physiological basis of somatosensory sensation
		19.5.2 Toxic Effects on the Somatosensory System
		19.5.3 Somatosensory deficits impair the quality of life
	19.6 Olfactory/chemosensory perception
		19.6.1 Physiological basis of olfaction
		19.6.2 Toxic Effects on Olfactory/Chemosensory Function
	19.7 Sensory perception in nonmammalian systems
	19.8 Conclusion
	References
20 Nervous system
	20.1 Introduction
	20.2 Mechanisms and types of neurotoxicity
		20.2.1 Unique absorption, distribution, metabolism, and elimination factors in the nervous system
		20.2.2 Exposure time as a factor in neurotoxicity: chronic versus acute
		20.2.3 Mechanisms of neurotoxicity
	20.3 Selected neurotoxicants
		20.3.1 Metals
			20.3.1.1 Lead
			20.3.1.2 Mercury
			20.3.1.3 Manganese
			20.3.1.4 Aluminum
		20.3.2 Solvents
		20.3.3 Gases and monomers
			20.3.3.1 Carbon monoxide
			20.3.3.2 Hydrogen sulfide
			20.3.3.3 Cyanide
			20.3.3.4 Acrylamide and acrylonitrile
			20.3.3.5 Carbonyl sulfide and carbon disulfide
			20.3.3.6 Styrene and vinyltoluene
		20.3.4 Pesticides
			20.3.4.1 Organophosphates
			20.3.4.2 Organochlorines
			20.3.4.3 Carbamates
			20.3.4.4 Pyrethroids
			20.3.4.5 Neonicotinoids
			20.3.4.6 Other
		20.3.5 Polychlorinated biphenyls and polybrominated diphenyl ethers
	References
Part IV: Modulation of toxicity
21 Intrinsic and extrinsic factors that can modify toxicity
	21.1 Intrinsic modifying factors
		21.1.1 Species
		21.1.2 Strain or breed
		21.1.3 Sex
		21.1.4 Age
		21.1.5 Endogenous regulatory pathways
	21.2 Extrinsic modifying factors
		21.2.1 Diet
		21.2.2 Coexposure to other chemicals
		21.2.3 Voluntary behaviors
	References
22 Influence of dietary factors and nutritional status on toxicity response to environmental pollutants
	22.1 Introduction
	22.2 Macronutrients
		22.2.1 Fats
		22.2.2 Carbohydrates
		22.2.3 Protein
	22.3 Micronutrients
		22.3.1 Vitamins
		22.3.2 Minerals
	22.4 Protective effects
	22.5 Conclusion
	References
Part V: Toxicology at home and the workplace
23 Toxicology in the home
	23.1 Introduction
	23.2 Nonprescription drugs
	23.3 Common prescription drugs
	23.4 Household chemicals
	References
24 Toxicology in the workplace
	24.1 Introduction
		24.1.1 Genesis of occupational toxicology
		24.1.2 Role of the toxicologist in the workplace
		24.1.3 Fundamental concepts
	24.2 Case studies
		24.2.1 Case study 1: Margarita photodermatitis
		24.2.2 Case study 2: Lead neurotoxicity
		24.2.3 Case Study 3: Crystalline silica
		24.2.4 Case Study 4: Popcorn lung
		24.2.5 Case Study 5: Chimney sweep carcinoma
	24.3 Managing exposures and protecting workers
	24.4 Conclusion
	References
Part VI: Toxicology in the community
25 Love canal: a classic case study of a contaminated community
	25.1 Framework and concepts: contamination in the context of natural and technological disasters
	25.2 Love Canal: a historical case study
		25.2.1 Prelude
		25.2.2 The legacy begins
		25.2.3 Initial outcomes
		25.2.4 Love Canal’s legacy continues
	25.3 Sociocultural and psychosocial effects of residing in a contaminated community
	25.4 Implications and connections
	25.5 Critical connections
	References
26 “Dear People of Flint”: environmental justice in a community context, the case of water contamination in Flint, Michigan
	26.1 Concepts: environmental inequality and justice
	26.2 The case in context: water contamination in Flint, Michigan
	26.3 Environmental inequality and justice intersected: outcomes in Flint, Michigan
	26.4 Conclusion
	Critical connections
	References
Part VII: Environmental exposures
27 Hazardous release: point source dispersion modeling
	27.1 Introduction
	27.2 Exposure limits
	27.3 Factors that affect dispersion
	27.4 Dispersion modeling
	27.5 Example problems
	27.6 Pasquill–Gifford dispersion model limitations
	27.7 Conclusions
	References
Part VIII: Ecotoxicology
28 Introduction to ecotoxicology
	28.1 Defining ecotoxicology
	28.2 Goals and challenges of ecotoxicology as compared to human toxicology
	28.3 Variability of toxicity between species
	28.4 Toxicity testing using surrogate species
	28.5 Examples of modes of action of special relevance to ecotoxicology
	28.6 Relating effects from molecular to community levels
	28.7 Understanding and measuring exposure in ecotoxicology
	28.8 Bioconcentration, bioaccumulation, and biomagnification
	28.9 Approaches for evaluating the presence of or potential for an environmental impact
	28.10 Toxicity of mixtures and multiple stressors
	28.11 Conclusion
	References
Part IX: Nanotoxicology
29 Selected aspects of nanotoxicology
	29.1 Introduction
	29.2 Hazard versus risk and regulatory distinctions
	29.3 Relevant routes of exposure to nanoscale particulate materials—a brief review
	29.4 Oral or ingestion exposures
	29.5 Dermal exposures
		29.5.1 Inhalation exposures
	29.6 Toward a future understanding of nanomaterials
	29.7 Evaluating the risks associated with nanomaterial exposures: the NanoRisk Framework
	29.8 Subchronic inhalation toxicity study in rats with carbon nanofibers
	29.9 Conclusions
	References
Part X: Clinical toxicology
30 Introduction to clinical toxicology
	30.1 The pharmacological basis of clinical toxicology
		30.1.1 Pharmacodynamics
		30.1.2 Pharmacokinetics
		30.1.3 Toxicokinetic–toxicodynamic correlation
	30.2 What clinical toxicology actually is?
	30.3 What does a clinical toxicologist do every day?
	30.4 Research in clinical toxicology
		30.4.1 Research in humans
		30.4.2 Research in animals: optimization of antidotal treatment
	References
Part XI: Veterinary toxicology
31 Introduction to veterinary toxicology
	31.1 Introduction
	31.2 Classification of poisons
	31.3 Types of poisoning
	31.4 Factors affecting poisoning
	31.5 Diagnostic criteria in animal poisonings
	31.6 Toxicology of specific poisons
		31.6.1 Metals
			31.6.1.1 Arsenic
			31.6.1.2 Lead
			31.6.1.3 Zinc
		31.6.2 Pesticides
			31.6.2.1 Organophosphates and carbamates
			31.6.2.2 Organochlorines
			31.6.2.3 Pyrethrins and pyrethroids
		31.6.3 Poisonous plants
			31.6.3.1 Cyanogenic
			31.6.3.2 Nitrate and nitrite
			31.6.3.3 Nicotine
			31.6.3.4 Veratrum californicum
		31.6.4 Mycotoxins
			31.6.4.1 Aflatoxins
			31.6.4.2 Fumonisins
		31.6.5 Industrial solvent
			31.6.5.1 Ethylene glycol
	31.7 Concluding remarks
	References
Part XII: Forensic toxicology
32 Introduction to forensic toxicology
	32.1 Introduction
	32.2 History of forensic toxicology
	32.3 Human performance testing
	32.4 Postmortem toxicology
	32.5 Forensic/workplace drug testing
	32.6 Fundamental principles of forensic toxicology
	32.7 Analytical techniques in forensic toxicology
		32.7.1 Specimen types
		32.7.2 Blood
		32.7.3 Common analytes
		32.7.4 Specimen preparation
			32.7.4.1 Dilute and shoot
			32.7.4.2 Liquid–liquid extraction
			32.7.4.3 Solid-phase extraction
		32.7.5 Screening versus confirmation
			32.7.5.1 Screening methods
			32.7.5.2 Confirmation methods
			32.7.5.3 Single mass spectrometry, full scan, and selected ion monitoring
			32.7.5.4 Tandem mass spectrometry, multiple reaction monitoring, and product ion scan
			32.7.5.5 Accurate mass spectrometry
	32.8 Quality assurance in forensic toxicology
	32.9 Conclusion
	Further reading
Part XIII: Regulatory toxicology
33 Mammalian cell culture models
	33.1 Basic cell culture laboratory and terminology
	33.2 Good cell culture practices
	33.3 Types of cultures
		33.3.1 Primary cell cultures
		33.3.2 Clonal cells
		33.3.3 Stem cell-derived models
	33.4 Use of mammalian cell models for regulatory toxicology
	33.5 Summary
	References
34 Toxicity testing: in vitro models in ecotoxicology
	34.1 Overview of the use of animals in toxicology
		34.1.1 Use of animals in scientific research: historic perspective
		34.1.2 Alternatives to animal testing in ecotoxicology
	34.2 Alternative methods in regulatory ecotoxicology
		34.2.1 Fish and amphibian embryos
		34.2.2 Use of isolated fish cells
			34.2.2.1 Primary cultures
			34.2.2.2 Continuous cell lines
			34.2.2.3 New frontiers for in vitro models in ecotoxicology
	34.3 Conclusion
	References
35 Toxicology testing: in vivo mammalian models
	35.1 Mouse
	35.2 Rat
	35.3 Rabbit
	35.4 Dog
	35.5 Nonhuman primates
	References
36 In vivo ecotoxicology models
	36.1 Introduction
	36.2 Basic methods for regulatory ecotoxicology testing
		36.2.1 Standardization of methods and good laboratory practice
		36.2.2 Overview of single-species toxicity tests
		36.2.3 Bioconcentration and bioaccumulation studies
		36.2.4 Common test species
		36.2.5 Problems with single-species tests
		36.2.6 Other approaches in ecotoxicology
	36.3 Alternatives to animal models in ecotoxicity testing
	36.4 Summary
	References
37 The zebrafish (Danio rerio) model in toxicity testing*
	37.1 Introduction
	37.2 Using zebrafish for human toxicity characterization
	37.3 Zebrafish in ecotoxicology
	37.4 Emerging novel technologies
	References
38 Caenorhabitidis elegans as an animal model in toxicological studies
	38.1 Introduction
	38.2 Neurotoxicology applications
	38.3 Heavy metal toxicity
	38.4 Radiation damage
	38.5 Pesticide toxicity
	38.6 Final remarks—perspectives for C. elegans use in toxicology
	References
39 Principles of risk assessment
	39.1 Brief historical perspective
	39.2 The risk assessment paradigm
		39.2.1 Hazard assessment
			39.2.1.1 Systematic review, problem formulation, and scoping
			39.2.1.2 Evidence integration
			39.2.1.3 Mode of action
			39.2.1.4 Relevance to human health
		39.2.2 Dose–response assessment
			39.2.2.1 Dose–response modeling of cancer endpoints
				39.2.2.1.1 Selection of endpoints
				39.2.2.1.2 Extrapolation from animal or epidemiological data to a target population
				39.2.2.1.3 Extrapolation from high to low doses
				39.2.2.1.4 Development of cancer toxicity values
			39.2.2.2 Dose–response modeling of noncancer endpoints
				39.2.2.2.1 Selection of endpoints
				39.2.2.2.2 No observed/lowest observed adverse effect level versus benchmark dose approaches
				39.2.2.2.3 Development of noncancer toxicity values
		39.2.3 Exposure assessment
			39.2.3.1 Identifying potential exposure pathways
			39.2.3.2 Estimating exposure concentrations
		39.2.4 Risk characterization
	39.3 Conclusions
	References
40 Tox21 and adverse outcome pathways
	40.1 Overview of Tox21
		40.1.1 Background
	40.2 Tox21 phases
		40.2.1 Phase I (2005–10)
		40.2.2 Phase II (2011–16)
		40.2.3 Phase III (2014–present)
	40.3 Data analysis and dissemination
		40.3.1 Tox21 toolbox to facilitate data mining, visualization, and integration
		40.3.2 Broader scientific community engagement
	40.4 Future considerations and applications
		40.4.1 Current limitations
		40.4.2 Ultimate goals
		40.4.3 Adverse outcome pathways
	40.5 Conclusions
	References
41 Adverse outcome pathways in ecotoxicology
	41.1 Introduction
	41.2 Adverse outcome pathway overview
	41.3 Examples of adverse outcome pathways in ecotoxicology
		41.3.1 Single molecular initiating event adverse outcome pathways
			41.3.1.1 Aryl hydrocarbon receptor
			41.3.1.2 Estrogen receptor
			41.3.1.3 Aromatase inhibition
		41.3.2 Mixture adverse outcome pathways
	41.4 Additional directions for adverse outcome pathways
		41.4.1 Climate change
	41.5 Conclusions
	References
Part XIV: Reference materials and websites
42 Toxicology literature, databases, and other online resources
	42.1 Introduction
	42.2 Books (often available in paper, online, and for e-readers; check with publisher or Amazon)
	42.3 Journals (a sampling)
	42.4 Professional societies
		42.4.1 American Industrial Hygiene Association (www.aiha.org)
		42.4.2 American Academy of Clinical Toxicology (www.clintox.org)
		42.4.3 American College of Toxicology (www.actox.org)
		42.4.4 Federation of European Toxicologists and European Societies of Toxicology (www.eurotox.com)
		42.4.5 International Union of Toxicology (www.iutox.org)
		42.4.6 Society of Environmental Toxicology and Chemistry (www.setac.org)
		42.4.7 Society for Risk Analysis (www.sra.org)
		42.4.8 Society of Toxicology (www.toxicology.org)
	42.5 US government organizations and laws
		42.5.1 Centers for Disease Control (www.cdc.gov)
		42.5.2 Consumer Product Safety Commission (www.cpsc.gov)
		42.5.3 Environmental Protection Agency (www.epa.gov)
		42.5.4 Food and Drug Administration (www.fda.gov)
		42.5.5 National Institutes of Health (www.nih.gov)
		42.5.6 Occupational Safety and Health Administration (www.osha.gov)
	42.6 Other organizations
		42.6.1 American Association of Poison Control Centers (www.aapcc.org/)
		42.6.2 Toxicology Education Foundation (www.toxedfoundation.org)
		42.6.3 United Nations
		42.6.4 University of Cincinnati College of Medicine, Department of Environmental Health, Risk Science Center (https://med.u...
	42.7 Online databases and other digital tools
		42.7.1 Agency for Toxic Substances and Disease Registry
		42.7.2 Environmental Working Group
		42.7.3 European Chemicals Agency
		42.7.4 European Commission’s Joint Research Centre EU Science Hub
		42.7.5 International Agency for Research on Cancer
		42.7.6 National Center for Toxicological Research
		42.7.7 National Institute of Environmental Health Sciences
		42.7.8 National Library of Medicine (www.nlm.nih.gov)
		42.7.9 National Pesticide Information Center and their Product Research Online Database
		42.7.10 Organisation for Economic Cooperation and Development
		42.7.11 Pesticide Action Network
		42.7.12 State of New Jersey
		42.7.13 US Environmental Protection Agency—ACToR
	42.8 The international legal and regulatory framework
	42.9 Social media and blogs
	42.10 A note about cost of access
Index
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