Handbook of Developmental Neurotoxicology, Second Edition, provides a comprehensive view of the fundamental aspects of neurodevelopment, the pathways and agents that affect them, relevant clinical syndromes, and risk assessment procedures for developmental neurotoxicants.

Table of Contents

• List of Contributors
• Preface and Acknowledgments
• Part I Cellular and molecular morphogenesis of the nervous system
• Introduction
• Brain Morphogenesis and Developmental Neurotoxicology
• I. Introduction
• II. Marr Proposed Computational Models be Integrated Over Three Levels
• III. Morphogenetic Features Emerge From Interactions Across Multiple Levels of Biological Organization
• A. Sensory Pathways Encode Features of Sense Organs and the Environment
• B. Neurovascular Coupling (NVC) is Essential to Brain Connectivity
• C. Engrams Exist at Multiple Structural Levels
• IV. Whole Brain Assessment of Larval Zebrafish Reveals Patterns of Connectivity
• V. Conclusions: Morphology Informs Predictive Models of Developmental Neurotoxicity
• Acknowledgments
• Abbreviations
• References
• Neural Cell Adhesion Molecules in Normal and Abnormal Neural Development
• I. Introduction
• II. The Expression Levels of NCAM and PSA–NCAM During the Development
• III. Regulating PSA–NCAM Expression and Cell Migration
• IV. Requirement of PSA–NCAM for Activity-Induced Synaptic Plasticity
• Acknowledgments
• References
• Neurite Development and Neurotoxicity
• I. Introduction
• A. Molecular Mechanisms Underlying Neurite Growth
• 1. Applications in Neurotoxicology: Addressing Molecular Mechanisms
• B. Genetic Modulation of Neurite Development
• 1. Examples of Genetic Modulation by Neurotoxicants
• C. Cell Death Mechanisms and Neurite Development
• 1. Relevance to Neurotoxicology: Addressing Cell Death Mechanisms
• D. Stem/Progenitor Cells and Neurite Development
• 1. Applications of Stem Cell Technology for Neurotoxicology
• E. Neurite Growth and State-of-the-Art Techniques
• 1. Overview
• 2. High-Content Imaging
• 3. Applications Using HCI
• 4. Three-Dimensional Approaches
• 5. Nanotechnology and Neurite Development
• 6. Bioengineering and Neurite Development
• II. Conclusions
• Acknowledgment
• References
• Myelin: Structure, Function, Pathology, and Targeted Therapeutics
• I. Introduction
• II. Myelin Architecture and Assembly: Old and New Perspectives
• A. Traditional View of Myelin
• B. Recent Findings: Myelin Structure and Functions
• III. Neuron–Glia Communication and its Regulation
• IV. Myelinating Glial Cell Lineages in Peripheral and Central Nervous Systems
• A. Schwann Cells
• B. Oligodendrocytes
• V. Chemical Composition of Vertebrate Myelin
• VI. Dysmyelination: Myelin Mutant Models for Dysmyelination
• VII. Demyelination: Effect of Various Factors on Developmental Myelination
• A. Malnutrition
• B. Thyroid Deficiency
• VIII. Remyelination and CNS Disorders: Myelin to Axonal Regeneration
• IX. Newer Treatment Strategies for Myelin Disorders
• X. Conclusions
• Acknowledgment
• References
• Part II Developmental neurobiology/toxicology
• Introduction
• Neurotrophic Factors
• I. Neurotrophic Factors
• II. Expression Pattern and Regulation
• III. Neurotrophin Receptors
• IV. Neurotrophic Factors in Cell Survival and Cell Death
• V. Neurotrophins and Synaptic Plasticity
• VI. Neurotrophins and Behavior
• VII. Other Neurotrophic Factors
• VIII. Clinical Correlates to Neurodegenerative Disorders
• IX. Clinical Correlates to Psychiatric Disorders
• X. Genetic Polymorphisms
• XI. Neurotrophins as Therapeutic Agents
• References
• Serotonin Signaling as a Target for Craniofacial Embryotoxicity
• I. Introduction—Serotonin and Embryonic Development
• II. Serotonin Signal Transduction
• A. Serotonin Release and Selective Serotonin Reuptake Inhibitors
• B. Serotonin Receptors and Receptor Antagonists
• III. Role of Serotonin in Development
• A. Placental Transfer of Serotonin
• B. Serotonin and Craniofacial Development
• C. Embryonic Precursors of the Facial Skeleton
• D. Serotonin and Neural Crest Cells
• E. Importance of Proper Orofacial Osteogenesis to Orofacial Development
• F. Serotonin and Bone Development
• IV. Conclusions
• References
• Neurotoxic and Neurotrophic Effects of GABAergic Agents on the Developing Brain
• I. Introduction
• II. The GABAergic System During Development
• III. GABAergic Agents and Consequences of Perturbations of GABAergic System Development
• IV. Animal Models of GABAergic System Perturbation
• V. In Vitro and Cell-Based Models of GABAergic System Perturbation During Neurodevelopment
• VI. Bioinformatic and Computational Approaches
• VII. Protecting the Developing GABAergic System: Prospects for the Future
• References
• Neural Stem Cell Biology and Application to Developmental Neurotoxicity Assessment
• I. Neural Stem Cells in the Developing Brain
• II. Neural Stem Cells in the Adult Brain
• III. NSCs-Derived from Embryonic Stem Cells and Induced Pluripotent Stem Cells
• IV. Application of NSCs to Developmental Neurotoxicity Assessments
• A. Status of Developmental Neurotoxicity Tests
• B. Considerations on the Utilization of NSCs as an In Vitro Model for DNT Assessment
• V. Conclusions
• Acknowledgment
• References
• Apoptosis as a Mechanism of Developmental Neurotoxicity
• I. Introduction
• II. Molecular Mechanisms of Apoptosis in the Developing Nervous System
• III. Physiological Roles of Apoptosis in Neurodevelopment
• IV. Chemical-Induced Apoptosis
• A. Anesthetics
• B. Polychlorinated Biphenyls
• C. Zinc
• V. Conclusions
• References
• Periods of Susceptibility: Interspecies Comparison of Developmental Milestones During Ontogenesis of the Central Nervous System
• I. Introduction
• II. Overview of Central Nervous System Development
• A. Neural Tube Formation
• B. Cellular Components of the Neural Plate
• C. Primary Neurulation
• D. Formation of Cerebral Vesicles
• E. Secondary Neurulation
• F. Intramural Development and Nuclei
• III. Developmental Milestones
• A. Externally Observed Central Nervous System Developmental Milestones
• B. Internally Observed Central Nervous System Developmental Milestones
• C. Developmental Milestones Related to Myelination
• D. Developmental Milestones of Cerebral Cortex
• IV. Conclusions
• References
• Modeling the Neurovascular Unit In Vitro and In Silico
• I. Introduction
• II. Animal Models of BBB Development and Function
• III. Cell-Based Models
• IV. Static Three-Dimensional (3D) Models
• V. Organotypic Culture Models (OCMs) and Microphysiological Systems (MPS)
• VI. Implementing In Vitro BBB Models for DNT
• VII. In Silico Models: BBB Permeability
• VIII. In Silico Models: Virtual NVU
• IX. Summary and Conclusions
• Acknowledgments
• References
• Zebrafish as a Model for Developmental Biology and Toxicology
• I. Introduction
• II. Developmental Biology
• A. Gastrulation
• B. Organogenesis
• C. Neurodevelopment
• D. Neurulation
• E. Neurogenesis
• F. Eye
• G. Brain
• H. Behavior
• III. Developmental Toxicology
• A. Assessments and Chemicals Screened
• B. Advancements
• IV. Concordance With Mammalian Models
• V. Conclusions
• References
• Using Caenorhabditis elegans to Study Neurotoxicity
• I. Introduction
• II. Studies of Specific Neurotoxins
• A. Manganese
• B. Selenium
• C. Methylmercury
• D. Other Toxins
• III. Anesthetic-Induced Neurotoxicity
• IV. Conclusions
• References
• Part III Synaptogenesis and neurotransmission
• Introduction
• Human 3D In Vitro Models for Developmental Neurotoxicity
• I. Developmental Neurotoxicity Represents a Societal Testing Need
• II. The Current Testing Approach for DNT In Vivo and In Vitro does not Satisfy our Needs
• III. The Process of Developing In Vitro Strategies for DNT
• IV. The Development of a Reproducible BMPS for Modeling Neurodevelopment and Testing its Perturbation
• V. Ongoing Developments of the Mini-Brain
• VI. Conclusions
• Acknowledgment
• References
• Ontogeny of Monoamine Neurotransmitters
• I. Introduction
• II. Innervation of Terminal Fields
• A. Ontogeny of Dopaminergic Innervation
• B. Ontogeny of Noradrenergic Innervation
• C. Ontogeny of Serotonergic Innervation
• III. Neurochemical Synaptogenesis
• A. Neurotransmitter Content
• 1. Dopamine
• 2. Norepinephrine
• 3. Serotonin
• B. Biosynthetic Enzymes
• 1. Tyrosine Hydroxylase
• 2. Dopamine β-Hydroxylase (DβH)
• 3. Tryptophan Hydroxylase (TPH)
• C. Reuptake Systems
• 1. High-Affinity DA Uptake
• 2. High-Affinity NE Uptake
• 3. High-Affinity 5-HT Uptake
• D. Monoaminergic Receptors
• 1. Dopaminergic Receptors
• 2. Noradrenergic Receptors
• 3. Serotonergic Receptors
• References
• Developmental Toxicity Within the Central Cholinergic Nervous System
• I. Introduction
• II. The Cholinergic System in CNS Development
• III. Vulnerable Time Periods of Developmental Neurotoxicity
• IV. Functional Effects of Developmental Exposure to Anticholinesterases
• V. Cholinergic Mechanisms of Developmental Neurotoxicity
• VI. Other Cholinergic Developmental Neurotoxicants
• A. Other Insecticides
• B. Nicotine
• C. Lead
• D. Endocrine Disruptors
• VII. Conclusions
• References
• Ontogeny of Second Messenger Systems
• I. Introduction
• II. Second Messenger Systems: General and Ontogenic Aspects
• A. Cyclic Adenosine Monophosphate
• B. Inositol Triphosphate and Diacylglycerol
• C. Calcium
• D. Nitric Oxide
• III. Specific Roles of the Second Messenger System in Brain Development
• A. Neurogenesis and Gliogenesis
• B. Modulation of Apoptosis
• IV. Developmental Neurotoxicants and Second Messenger Systems
• A. Ethanol
• B. Lead
• V. Conclusions
• References
• The NMDA Receptors: Physiology and Neurotoxicity in the Developing Brain
• I. Introduction
• II. Molecular Structure of the NMDA Receptor
• III. Functional Role of the NMDA Receptor
• IV. Anatomical Distribution and Developmental Changes in NMDA Receptors in Brain
• V. Role of the NMDA Receptor in Neurotoxicity During Brain Development
• Acknowledgment
• References
• Part IV Nutrient and chemical disposition
• Introduction
• Physiologically Based Pharmacokinetic (PBPK) Models
• I. Introduction
• II. Selected PBPK Models for Developmental Neurotoxicology
• A. Atrazine
• B. Chlorpyrifos
• C. Deltamethrin
• D. Manganese
• E. Perchlorate and Iodine
• III. Future Directions for Modeling CNS Active Materials
• Acknowledgment
• References
• Blood—“Brain Barrier: Physiological and Functional Considerations
• I. Introduction
• II. Development of the Blood–Brain Barrier
• A. Role of Astrocytes in BBB Development
• B. Role of Pericytes in BBB Development
• C. Signaling Pathways Involved in BBB Development
• III. Disruption of the Blood–Brain Barrier
• A. Drugs of Abuse
• B. Neurodegenerative Diseases
• IV. Summary
• References
• Toxicological Mechanisms of Engineered Nanomaterials: Role of Material Properties in Inducing Different Biological Responses
• I. Introduction
• II. Manganese NP Toxicity
• III. The Role of Charge in Gold Nanotoxicity
• IV. Toxicity of Amorphous Silica Nanoparticles
• V. Unique Cellular Interactions of Silver Nanoparticles
• VI. Chronic Toxicity of Nanoparticles in Enhanced Models
• VII. Impact of Nanoparticles on Cellular Mitochondria
• VIII. Understanding Molecular Mechanisms of Nanoparticle Toxicity Through Gene-Editing Technology
• References
• Food and Nutrient Exposure Throughout the Life Span: How Does What We Eat Translate Into Exposure, Deficiencies, and Toxicities?
• I. Introduction
• II. Nutrient Assessment
• III. Bioavailability and Beyond
• IV. Current Nutrient Standards
• V. Global Causes of Deficiency
• VI. Global Causes of Toxicity
• VII. Effects of Deficiency and Excessive Amounts of Selected Nutrients
• A. Iron
• B. Zinc
• C. Folic Acid
• D. Vitamin A
• E. Vitamin D
• VIII. Approaches to Addressing Micronutrient Deficiencies
• A. Pill Supplementation Programs
• B. Fortification
• C. Multiple Micronutrient Fortified Beverages and Foods
• D. Microencapsulation
• E. Agricultural Enhancement of Micronutrient Content of Foods
• IX. Further Directions in Research About Lifelong Effects of Nutrition
• A. Dietary Intake to Prevent Disease
• B. Neonatal Microbiome
• X. Summary
• References
• The Microbiome Gut—“Brain Axis
• I. Introduction
• II. What is the Human Microbiome?
• III. What is the Gut–Brain Axis?
• IV. Current Knowledge on how the Intestinal Microbiota Influences the Gut–Brain Axis
• V. Intestinal Microbiota-Derived Neuroactive Metabolites
• VI. Neurological Disorders
• VII. Conclusions and Research Data Gaps
• Acknowledgments
• Definitions for the Gut–Brain Axis
• References
• Drug and Chemical Contaminants in Breast Milk: Effects on Neurodevelopment of the Nursing Infant
• I. Introduction
• II. Effects of Breastfeeding on Infant Neurodevelopment
• III. Exposure of Nursing Infants to Drugs in Breast Milk
• A. Mammary Gland Structure
• B. Mechanisms of Xenobiotics Secretion Into Milk
• 1. Ionization Characteristics
• 2. Lipid Solubility
• 3. Plasma Protein Binding
• C. Quantitative Estimation of Infant Drug Exposure Via Breast Milk
• IV. Effects of Maternal Exposure to Environmental Contaminants on the Nursing Infant
• A. Metals and Inorganic Compounds
• 1. Lead
• 2. Methlymercury
• 3. Arsenic
• B. Persistent Organic Pollutants (POP)
• 1. Polychlorinated Dibenzodioxins (Dioxins) and Polychlorinated Dibenzofurans (Furans)
• 2. Polychlorinated Biphenyls
• V. Drugs and Nonmedicinal Substances
• A. Marijuana (Cannabis)
• B. Other Nonmedicinal and Medicinal Substances
• VI. Information Resources
• VII. Conclusions
• References
• Part V Behavioral assessment
• Introduction
• Behavioral Phenotyping in Developmental Neurotoxicology—Simple Approaches Using Unconditioned Behaviors in Rodents
• I. Introduction
• II. Basic Considerations
• III. Simple Unlearned Behaviors and Other Measures for Assessing Developmental Neurotoxicity
• A. Measures of Physical Growth
• B. Appearance of Physical Developmental Landmarks
• C. Sleep–Activity Cycle
• 1. Activity and Circadian Rhythms
• 2. Sleep Cycle
• D. Sensory Function
• 1. Olfactory Orientation
• 2. Auditory Startle Reflex
• 3. Psychophysical Methods
• 4. Other Tests of Sensory Deficits
• E. Motor Development
• 1. Primitive Motor Behaviors
• 2. Other Motor Functions
• F. Activity and Exploratory Behavior
• 1. Activity
• 2. Exploratory Behavior
• 3. Pharmacologically Induced Changes in Locomotor Activity
• G. Species- and Sex-Specific Behaviors
• 1. Grooming
• 2. Reproductive and Parental Behaviors
• 3. Aggressive Behaviors
• 4. Unlearned Social and Play Behaviors
• 5. Ultrasonic Vocalizations
• H. Anxiety- and Depression-Like Behaviors
• IV. Behavioral Test Batteries in Developmental Neurotoxicology
• A. Test Batteries Designed for Rats
• 1. Cincinnati Test Battery
• 2. Collaborative Behavioral Teratology Study Test Battery
• 3. European Collaborative Study
• B. Test Batteries Designed for Mice
• C. Newer Rodent Testing Batteries for Rodents and Design Considerations
• V. Conclusions
• References
• Psychometric Tools to Study Cognition, Sensory Functioning, and Social Behavior in Infant and Adolescent Nonhuman Primates
• I. Developmental Assessments for Young Macaque Infants (Birth to 3–4 Months of Age)
• II. Assessing Cognition in Older Infants and Juveniles
• III. Methodologies for Measuring Learning and Memory
• IV. Tests of Cognition Suitable for Infant and Adolescent Monkeys
• V. Raising the Bar on Difficulty: Measuring Complex Learning Abilities
• VI. Tools to Measure Vision and Hearing
• VII. Social Behavior in Play Groups and Mother–Infant Pairs
• VIII. Concluding remarks
• Acknowledgment
• References
• Automated Assessment of Cognitive Function in Nonhuman Primates
• I. Introduction
• II. Measuring Cognition Very Early in Life
• III. Evaluation of Cognitive Abilities from Late Infancy into Adulthood
• IV. Toxicological Testing Using Operant Methods During Development
• Acknowledgment
• References
• Determining the Validity of Preclinical Behavioral Assessments for Extrapolation to a Clinical Setting
• I. Introduction
• II. Ecological Validity
• III. Face Validity
• IV. Convergent Validity
• V. Construct Validity
• VI. Predictive Validity
• VII. Conclusions
• Acknowledgment
• References
• Behavioral Outcome as a Primary Organizing Principle for Mechanistic Data in Developmental Neurotoxicity
• I. Current Challenges in Risk Assessment
• II. Organizing Principles for Mechanistic Data in Developmental Neurotoxicity are Needed Because the Brain is a “Complex Adaptive System”
• III. Changes in Mechanistic Function During Neurodevelopment and Developmental Toxic Exposure May be Indistinguishable
• IV. Behavior as an Organizing Principle for Mechanistic Data
• A. Approaches for Using Behavior as an Organizing Principle for Mechanistic Data
• B. Examples of Using Behavior as an Organizing Principle for Mechanistic Data
• V. Using a Single Behavioral Outcome at a Single Developmental Stage to Develop a Hierarchy of Mechanistic Effects: Rearing in Preadolescent Lead-Exposed Mice
• VI. Which Mechanisms Have Been Associated With Mouse and Rat Rearing Behavior?
• VII. Is There Mechanistic Evidence That Lead Exposure Disrupts Cholinergic Transmission?
• VIII. How do We Understand Other Mechanistic Effects From Lead Exposure Relative to the Cholinergic System Disruption Indicated by Rearing Behavior?
• IX. Does Evidence Suggest That Disruptions in the Cholinergic System Impact Glutamate/GABA Function?
• X. What was Gained by Using Rearing Behavior at Preadolescence as a Starting Point for Organizing Extant Mechanistic Data?
• XI. Limitations
• XII. Using a Single Behavioral Outcome Measured at Multiple Developmental Stages to Understand the Salience of a Given Mechanism Across a Developmental Trajectory: Elevated Plus Maze (EPM) Performance as a Behavioral Measure of Anxiety
• XIII. Bisphenol A as a Developmental Neurotoxicant
• XIV. Anxiety as a Domain of Concern in BPA Risk Assessment
• XV. EPM Anxiety and BPA Effects at Multiple Developmental Stages
• XVI. What Brain Mechanisms are Relevant to EPM-Assessed Anxiety?
• XVII. What Mechanism Pathways are Plausible Candidates for Developmental BPA Effects on EPM Anxiety?
• A. GABA and Glutamate at One Life Stage
• B. ERβ, Glutamate, and Spine Synapse Density Pathway
• XVIII. What is Gained by Using Behavior as an Organizing Principle?
• XIX. Limitations
• XX. Concluding Remarks
• References
• Part VI Clinical assessment and epidemiology
• Introduction
• Evaluation of the Human Newborn Infant
• I. Introduction
• II. A First Impression
• A. Pregnancy Outcome
• B. Apgar Score
• C. Neonatal Screening Programs
• III. Neurobehavioral Evaluations
• A. Neurologic Examination of the Full-Term Newborn Infant
• B. Neonatal Behavioral Assessment Scale
• C. Bayley Scales of Infant and Toddler Development
• D. Infants With Perinatal Risk Factors
• 1. Neurobehavioral Examinations of the Preterm Infant
• 2. General Movements
• 3. NICU Network Neurobehavioral Scale
• 4. The Assessment for Premature Infant Behavior
• 5. Newborn Individualized Developmental Care and Assessment Program
• 6. Infant Behavioral Assessment–Intervention Program
• 7. Looking Behavior Assessment
• 8. Pain Assessment
• IV. Neuroimaging
• A. Cranial Ultrasound
• B. Magnetic Resonance Imaging
• 1. Diffusion Tensor Imaging
• 2. Functional MRI
• C. Transcranial Doppler
• D. Near-Infrared Spectroscopy
• V. Neurophysiological Assessments
• A. Electroencephalogram
• B. Evoked Potentials
• 1. Auditory Brainstem Responses
• 2. Visual Evoked Potentials
• 3. Somatosensory Evoked Potential
• VI. Perinatal Risk Scores
• A. Clinical Risk for Babies and Score for Acute Neonatal Physiology
• B. Perinatal Risk Inventory and Nursery Neurobiological Risk Score
• C. New Perinatal Risk Scores
• VII. Discussion
• Acknowledgments
• References
• Neuropsychological Assessment of Children in Studies of Developmental Neurotoxicity
• I. Introduction
• II. Selecting the Age at Which to Conduct a Neuropsychological Assessment
• III. Considerations in Designing an Assessment Battery
• IV. Interpretation
• References
• Neurodevelopmental Assessment of the Older Infant and Child
• I. Epidemiology of Pediatric Neurodevelopmental and Behavioral Disorders
• II. Toolkit for Evaluation
• References
• Longitudinal Studies of the Effects of Prenatal Cocaine Exposure on Development and Behavior
• I. Methodological Issues in the Study of Prenatal Cocaine Exposure
• A. Theoretical Model
• B. Sample Selection and Assessment of Substance Use During Pregnancy
• C. Selection of a Comparison Group and Measurement of Covariates
• II. A Longitudinal Study of Prenatal Cocaine Exposure: The Maternal Health Practices and Child Development Project
• A. Sample Selection and Study Design
• B. Pattern of Cocaine Use and Sample Characteristics
• C. Covariates of Cocaine Use
• III. Results From the Maternal Health Practices and Child Development Project and Other Longitudinal Investigations of Prenatal Cocaine Exposure
• A. Growth
• B. Central Nervous System/Cognitive Development
• C. Temperament/Mood
• D. Behavior and Substance Use
• IV. Conclusions
• References
• Assessment of Case Reports and Clinical Series
• I. Introduction
• II. Recognition of Patterns of Anomalies
• III. Syndromes of Cognitive or Behavioral Abnormalities
• IV. Limitations of Pattern Recognition
• References
• Part VII Specific neurotoxic syndromes
• Introduction
• Fetal Minamata Disease: A Human Episode of Congenital Methylmercury Poisoning
• I. Introduction
• II. Human Episodes
• III. Neuropathology of Fetal Minamata Disease
• A. Minamata Cases
• B. Iraqi Cases
• 1. Placental and Mammary Transfer
• 2. Experimental Congenital Mercury Poisoning
• 3. Biomolecular Basis of Neurotoxicity in FMD
• IV. Concluding Remarks
• References
• The Developmental Neurotoxicity of Cadmium
• I. Introduction
• II. Prenatal and Postnatal Cadmium Exposure
• III. Mechanisms of Developmental Neurotoxicity
• IV. Neurobehavioral Outcomes in Animals
• V. Neurodevelopmental Outcomes in Children and Adolescents
• VI. Conclusions
• References
• Developmental Neurotoxicology of Lead: Neurobehavioral and Neurological Impacts
• I. Lead Neurotoxicity in Children
• A. Cognitive Function
• B. Academic Achievement
• C. Specific Mental Domains
• D. Disturbances in Mood and Social Conduct
• E. Summary
• II. Neurological Effects of Lead Neurotoxicity in Animals: Cognition and Plasticity
• A. Lead and Neurotransmitter Release
• B. Lead and Glutamatergic NMDA Receptors
• C. Lead Neurotoxicity and Synaptic Plasticity
• D. Lead Exposure and the Susceptibility to Alzheimer's Disease
• E. Lead and Retinal Function
• F. Neurobehavioral Toxicity of Lead: Schedule-Controlled Behavior
• G. Neurobehavioral Toxicity of Lead: Memory
• H. Lead Neurotoxicity and Structural Synaptic Plasticity
• I. Summary
• References
• Fetal Alcohol Spectrum Disorder
• I. Introduction
• II. Epidemiology of Alcohol Consumption in Pregnancy
• III. Alcohol Mechanism of Action
• A. Provocative Factors
• B. Permissive Factors
• IV. Epigenetics
• V. Epidemiology of FASD and Economic Burden
• VI. FASD Diagnosis
• VII. FASD Disabilities
• VIII. FASD and Mental Health
• IX. FASD Challenges and Future Directions
• X. FASD Prevention
• XI. Conclusions
• References
• Developmental Neurotoxicity of Nicotine and Tobacco
• I. Tobacco and Nicotine Exposure During Pregnancy
• II. Epidemiological Studies Find Neurobehavioral Dysfunction Associated With Tobacco Exposure in Pregnancy
• III. Animal Models Show that Nicotine Exposure During Development Causes Neurobehavioral Impairment
• IV. Nicotine Disrupts Neuronal Development
• V. Neurotoxicity of Other Compounds in Tobacco
• VI. Second Hand Smoke
• VII. Other Nicotinic Compounds
• VIII. Conclusions
• Acknowledgments
• Abbreviations
• References
• Developmental Neurobehavioral Neurotoxicity of Insecticides
• I. Introduction
• II. Organochlorines
• A. Insecticidal Versus Off-Target Acute Toxicity
• B. Developmental Toxicity
• III. Organophosphates
• A. Insecticidal Versus Off-Target Acute Toxicity
• B. Developmental Neurotoxicity
• IV. Carbamates
• A. Insecticidal Versus Off-Target Acute Toxicity
• B. Developmental Neurotoxicity
• V. Pyrethroids
• A. Insecticidal Versus Off-Target Acute Toxicity
• B. Developmental Neurotoxicity
• VI. Neonicotinoids
• A. Insecticidal Versus Off-Target Acute Toxicity
• B. Developmental Neurotoxicity
• VII. Concluding Remarks
• Acknowledgments
• References
• Developmental Exposure to Polychlorinated Biphenyls Induces Deficits in Inhibitory Control and May Enhance Substance Abuse Risk
• I. Introduction
• A. What Are Polychlorinated Biphenyls (PCBs)?
• B. Environmental Toxicology and Bioaccumulation
• II. Developmental Neurobehavioral Neurotoxicity of PCBs
• A. PCBs Cause Inhibitory Control Deficits
• B. PCBs Alter Psychostimulant Behavioral Pharmacology
• III. Developmental PCB Exposure Impairs Dopamine Function
• A. Stimulated Peak Dopamine Release Changes After Developmental PCB Exposure
• B. Developmental PCB Exposure Alters Dopamine Transporter Activity
• C. Dopamine Autoreceptor Sensitivity Increases After Developmental PCB Exposure
• IV. Perinatal PCB Exposure Changes the Developing Brain, But Males May Be More Sensitive
• V. Where Do We Go From Here?
• A. Do PCBs Increase Psychostimulant Addiction Risk?
• B. Future Research
• References
• Developmental Neurotoxicity of General Anesthetics
• I. Introduction
• II. Classes of Anesthetics and Mechanisms of Action
• III. Nonclinical Studies of Anesthetic-Induced Neurotoxicity
• A. General Anesthesia-Induced Apoptotic Neurodegeneration
• B. General Anesthesia-Induced Deficits in Cognitive Function
• C. Dose-Dependent and Duration-Dependent Effects
• D. Combined Exposures
• E. Mechanisms Responsible for Neurocognitive Dysfunction
• IV. Clinical Studies
• V. Protective Compounds
• VI. Conclusions
• Acknowledgment
• References
• Maternal Drug Abuse and Adverse Effects on Neurobehavior of Offspring
• I. Introduction
• II. Opiates
• A. Neonatal Abstinence Syndrome
• B. Neurobehavioral Outcomes for Older Infants/Children
• C. Polydrug
• D. Summary
• III. Cocaine
• A. The Newborn Period
• B. Childhood
• C. Adolescence
• D. Summary
• IV. Cannabinoids/Marijuana
• A. The Newborn Period
• B. Childhood
• C. Adolescence
• D. Summary
• V. Methamphetamine
• A. The Newborn Period
• B. Childhood
• C. Summary
• VI. MDMA
• VII. Transgenerational and Paternal Exposures
• VIII. Summary
• References
• Developmental Neurotoxicology of Antiepileptic Drugs
• I. Introduction
• II. Neurobehavioral Effects of Prenatal Exposure to Monotherapy Treatment
• A. Phenobarbital
• B. Phenytoin
• C. Carbamazepine
• D. Valproic Acid
• E. Lamotrigine
• F. Levetiracetam
• III. Putative Underlying Causes of Neuroteratogenic Effects
• A. Neurogenesis
• B. Migration
• C. Apoptosis
• D. Synaptogenesis
• IV. Conclusions
• References
• Part VIII Risk assessment
• Introduction
• Current Approaches to Risk Assessment for Developmental Neurotoxicity
• I. Introduction
• II. Risk Assessment Paradigm and General Concepts
• III. Conduct and Considerations in Developmental Neurotoxicity Risk Assessment
• A. Hazard Identification
• B. Human Data
• C. Animal Toxicology Data
• 1. Other Study Types
• D. Other Data
• E. Evidence Integration
• F. Dose–Response Analysis
• G. Exposure Assessment
• H. Risk Characterization
• IV. Common Data Gaps for DNT Studies of Environmental Chemicals
• V. Summary
• References
• Animal/Human Concordance
• I. Introduction
• II. Human Conditions
• A. Thyroid Toxicants
• B. Methylmercury
• C. Inorganic Lead
• D. Phenytoin
• E. Fetal Alcohol Spectrum Disorder
• F. Polychlorinated Biphenyls (PCBs)
• III. Assessment of Neurobehavioral Development in Infants and Children
• A. Attention-Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder
• B. Test Batteries for Infants and Children
• IV. Animal Models
• A. General Concepts and Indications
• B. Alternative (Nonmammalian) Species
• 1. Zebrafish (Danio rerio)
• C. Regulatory Guidelines
• 1. Pharmaceuticals: US FDA and ICH Guidelines
• 2. DNT Guidelines (US EPA OCSPP 870.6300 and OECD TG 426)
• 3. Other Guidelines (OECD TG 443)
• D. Apical Tests
• 1. Motor Activity
• 2. Acoustic Startle Response (ASR)
• 3. Neuropathology and Morphometry
• V. Targeted Testing
• A. Neurochemical (AChE and Thyroid Hormone)
• B. Neurologic/Motor Function
• C. Sensory Function
• D. Cognition
• E. Neuropathology and Morphometry
• F. Socio-Sexual and Anxiety-Related Behaviors
• G. In Vitro Test Systems
• VI. Newer Models and Approaches
• A. Imaging as a Biomarker of Developmental Insult and Lasting Effects
• B. The Use of Microphysiological Systems to Simulate the Dynamic Functions
• C. Use of the “Omic” Technologies
• D. Additional Considerations for Assessing DNT
• Abbreviations
• References
• Physiologically Based Pharmacokinetic Models in the Risk Assessment of Developmental Neurotoxicants
• I. Introduction
• II. Construction and Evaluation of PBPK Models
• A. Model Representation
• B. Model Parameterization
• C. Model Simulation
• D. Model Validation and Evaluation
• III. Brain Dosimetry in PBPK Models
• IV. PBPK Modeling of Developmental Neurotoxicants
• V. Application of PBPK Models in the Risk Assessment of Developmental Neurotoxicants
• References
• Application of Quantitative Dose—“Response Data in Risk Assessment and the Incorporation of High-Throughput Data
• I. Introduction
• II. Problem Formulation
• A. Planning and Scoping
• B. Problem Formulation
• III. Risk Assessment Fundamentals in the Federal Government
• A. Maternal Effects
• IV. Defining Adversity
• V. Data From High-Throughput Assays
• VI. Risk Quantitation
• A. Quantifying the Point of Departure
• B. Developing Uncertainty Factor Values
• Acknowledgment
• References