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E-grāmata: Handbook of Developmental Neurotoxicology

Edited by Merle G. Paule (Division of Neurotoxicology, National Center for Toxicological Research, US FDA, Jefferson, AR, USA), Edited by Cheng Wang (Division of Neurotoxicology, National Center for Toxicolog), Edited by William Slikker Jr. (National Center for Toxicological Research, Jefferson, US FDA, AR, USA)

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Izdošanas datums: 04-Jan-2018
Izdevniecība: Academic Press Inc
Valoda: eng
ISBN-13: 9780128093948

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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. The editors and chapter authors are internationally recognized experts whose collaboration heralds a remarkable advance in the field, bridging developmental neuroscience with the principles of neurotoxicology. The book features eight new chapters with newly recruited authors, making it an essential text for students and professionals in toxicology, neurotoxicology, developmental biology, pharmacology, and neuroscience.

Presents a comprehensive, up-to-date resource on developmental neurotoxicology with updated chapters from the first edition
Contains new chapters that focus on subjects recent to the field
Includes well-illustrated material, with diagrams, charts, and tables
Contains compelling case studies and chapters written by world experts

List of Contributors

xiii

Preface and Acknowledgments

xvii

I Cellular And Molecular Morphogenesis Of The Nervous System

1 Brain Morphogenesis and Developmental Neurotoxicology

Karl F. Jensen

Jeanene K. Olin

I Introduction

(1)

II Man Proposed Computational Models be Integrated Over Three Levels

(1)

III Morphogenetic Features Emerge From Interactions Across Multiple Levels of Biological Organization

(3)

IV Whole Brain Assessment of Larval Zebrafish Reveals Patterns of Connectivity

(2)

V Conclusions: Morphology Informs Predictive Models of Developmental Neurotoxicity

(1)

References

(7)

2 Neural Cell Adhesion Molecules in Normal and Abnormal Neural Development

Cheng Wang

Qi Yin

Tucker A. Patterson

Shuliang Liu

Xuan Zhang

Fang Liu

Merle G. Paule

William Slikker Jr

I Introduction

(1)

II The Expression Levels of NCAM and PSA-NCAM During the Development

(1)

III Regulating PSA-NCAM Expression and Cell Migration

(1)

IV Requirement of PSA-NCAM for Activity-Induced Synaptic Plasticity

(2)

References

(2)

3 Neurite Development and Neurotoxicity

Zhen He

Sherry A. Ferguson

Tucker A. Patterson

Merle G. Paule

I Introduction

(6)

II Conclusions

(1)

References

(4)

4 Myelin: Structure, Function, Pathology, and Targeted Therapeutics

Joseph Hanig

Geeta Negi

I Introduction

(1)

II Myelin Architecture and Assembly: Old and New Perspectives

(2)

III Neuron-Glia Communication and its Regulation

(1)

IV Myelinating Glial Cell Lineages in Peripheral and Central Nervous Systems

(2)

V Chemical Composition of Vertebrate Myelin

(1)

VI Dysmyelination: Myelin Mutant Models for Dysmyelination

(2)

VII Demyelination: Effect of Various Factors on Developmental Myelination

(5)

VIII Remyelination and CNS Disorders: Myelin to Axonal Regeneration

(1)

IX Newer Treatment Strategies for Myelin Disorders

(1)

X Conclusions

(1)

References

(6)

II Developmental Neurobiology/Toxicology

5 Neurotrophic Factors

Jimcy Platholi

Francis S. Lee

I Neurotrophic Factors

(1)

II Expression Pattern and Regulation

(1)

III Neurotrophin Receptors

(1)

IV Neurotrophic Factors in Cell Survival and Cell Death

(1)

V Neurotrophins and Synaptic Plasticity

(1)

VI Neurotrophins and Behavior

(1)

VII Other Neurotrophic Factors

(1)

VIII Clinical Correlates to Neurodegenerative Disorders

(1)

IX Clinical Correlates to Psychiatric Disorders

(1)

X Genetic Polymorphisms

(1)

XI Neurotrophins as Therapeutic Agents

(1)

References

(2)

6 Serotonin Signaling as a Target for Craniofacial Embryotoxicity

Robert M. Greene

Michele M. Pisano

I Introduction-Serotonin and Embryonic Development

(1)

II Serotonin Signal Transduction

(1)

III Role of Serotonin in Development

(5)

IV Conclusions

(1)

References

(3)

7 Neurotoxic and Neurotrophic Effects of GABAergic Agents on the Developing Brain

Julia M. Gohlke

I Introduction

(1)

II The GABAergic System During Development

(1)

III GABAergic Agents and Consequences of Perturbations of GABAergic System Development

(1)

IV Animal Models of GABAergic System Perturbation

(1)

V In Vitro and Cell-Based Models of GABAergic System Perturbation During Neurodevelopment

(1)

VI Bioinformatic and Computational Approaches

(1)

VII Protecting the Developing GABAergic System: Prospects for the Future

(2)

References

(4)

8 Neural Stem Cell Biology and Application to Developmental Neurotoxicity Assessment

Fang Liu

Cheng Wang

I Neural Stem Cells in the Developing Brain

(1)

II Neural Stem Cells in the Adult Brain

(1)

III NSCs-Derived From Embryonic Stem Cells and Induced Pluripotent Stem Cells

(1)

IV Application of NSCs to Developmental Neurotoxicity Assessments

(1)

V Conclusions

(1)

References

(2)

9 Apoptosis as a Mechanism of Developmental Neurotoxicity

Pamela J. Lein

Suangsuda Supasai

Michelle Guignet

I Introduction

(1)

II Molecular Mechanisms of Apoptosis in the Developing Nervous System

(3)

III Physiological Roles of Apoptosis in Neurodevelopment

(1)

IV Chemical-Induced Apoptosis

(10)

V Conclusions

106

(1)

References

106

(7)

10 Periods of Susceptibility: Interspecies Comparison of Developmental Milestones During Ontogenesis of the Central Nervous System

John M. Desesso

Amy L. Williams

I Introduction

113

(1)

II Overview of Central Nervous System Development

114

(6)

III Developmental Milestones

120

(4)

IV Conclusions

124

(1)

References

124

(3)

11 Modeling the Neurovascular Unit In Vitro and In Silico

Katerine S. Saili

Todd J. Zurlinden

Thomas B. Knudsen

I Introduction

127

(1)

II Animal Models of BBB Development and Function

128

(1)

III Cell-Based Models

128

(2)

IV Static Three-Dimensional (3D) Models

130

(1)

V Organotypic Culture Models (OCMs) and Microphysiological Systems(MPS)

131

(2)

VI Implementing In Vitro BBB Models for DNT

133

(4)

VII In Silico Models: BBB Permeability

137

(1)

VIII In Silico Models: Virtual NVU

138

(1)

IX Summary and Conclusions

138

(1)

References

139

(4)

12 Zebrafish as a Model for Developmental Biology and Toxicology

Courtney Roper

Robert L. Tanguay

I Introduction

143

(1)

II Developmental Biology

144

(2)

III Developmental Toxicology

146

(1)

IV Concordance With Mammalian Models

147

(1)

V Conclusions

148

(1)

References

148

(5)

13 Using Caenorhabditis Elegans to Study Neurotoxicity

Margaret M. Sedensky

Philip G. Morgan

I Introduction

153

(1)

II Studies of Specific Neurotoxins

154

(3)

III Anesthetic-Induced Neurotoxicity

157

(1)

IV Conclusions

158

(1)

References

158

(5)

III Synaptogenesis And Neurotransmission

14 Human 3D In Vitro Models for Developmental Neurotoxicity

Lena Smirnova

Thomas Hartung

I Developmental Neurotoxicity Represents a Societal Testing Need

163

(1)

II The Current Testing Approach for DNT In Vivo and In Vitro does not Satisfy Our Needs

164

(1)

III The Process of Developing In Vitro Strategies for DNT

164

(2)

IV The Development of a Reproducible BMPS for Modeling Neurodevelopment and Testing its Perturbation

166

(3)

V Ongoing Developments of the Mini-Brain

169

(1)

VI Conclusions

170

(1)

References

171

(2)

15 Ontogeny of Monoamine Neurotransmitters

Sumit Sarkar

Syed Z. Imam

Jennifer L. Walters

I Introduction

173

(1)

II Innervation of Terminal Fields

174

(1)

III Neurochemical Synaptogenesis

175

(5)

References

180

(3)

16 Developmental Toxicity Within the Central Cholinergic Nervous System

David A. Jett

Michelle Guignet

Suangsuda Supasai

Pamela J. Lein

I Introduction

183

(1)

II The Cholinergic System in CNS Development

184

(1)

III Vulnerable Time Periods of Developmental Neurotoxicity

185

(1)

IV Functional Effects of Developmental Exposure to Anticholinesterases

185

(1)

V Cholinergic Mechanisms of Developmental Neurotoxicity

186

(4)

VI Other Cholinergic Developmental Neurotoxicants

190

(2)

VII Conclusions

192

(1)

References

193

(6)

17 Ontogeny of Second Messenger Systems

Syed Z. Imam

Hector Rosas-Hernandez

Elvis Cuevas

Susan M. Lantz

Sumit Sarkar

Syed F. Ali

Merle G. Paule

I Introduction

199

(1)

II Second Messenger Systems: General and Ontogenic Aspects

199

(2)

III Specific Roles of the Second Messenger System in Brain Development

201

(1)

IV Developmental Neurotoxicants and Second Messenger Systems

202

(2)

V Conclusions

204

(1)

References

204

(3)

18 The NMDA Receptors: Physiology and Neurotoxicity in the Developing Brain

Qiang Gu

Cheng Wang

I Introduction

207

(1)

II Molecular Structure of the NMDA Receptor

208

(1)

III Functional Role &the NMDA Receptor

209

(1)

IV Anatomical Distribution and Developmental Changes in NMDA Receptors in Brain

210

(1)

V Role of the NMDA Receptor in Neurotoxicity During Brain Development

210

(2)

References

212

(5)

IV Nutrient And Chemical Disposition

19 Physiologically Based Pharmacokinetic (PBPK) Models

Jeffrey W. Fisher

Xiaoxia Yang

Charles Timchalk

I Introduction

217

(1)

II Selected PBPK Models for Developmental Neurotoxicology

218

(7)

III Future Directions for Modeling CNS Active Materials

225

(1)

References

225

(4)

20 Blood-Brain Barrier: Physiological and Functional Considerations

Hector Rosas-Hernandez

Elvis Cuevas

Susan M. Lantz

Syed Z. Imam

Merle G. Paule

Syed F. Ali

I Introduction

229

(1)

II Development of the Blood-Brain Barrier

230

(2)

III Disruption of the Blood-Brain Barrier

232

(2)

IV Summary

234

(1)

References

234

(3)

21 Toxicological Mechanisms of Engineered Nanomaterials: Role of Material Properties in Inducing Different Biological Responses

Richard L. Salisbury

Richard Agans

Mary E. Huddleston

Andrew Snyder

Alexandra Mendlein

Saber Hussain

I Introduction

237

(2)

II Manganese NP Toxicity

239

(1)

III The Role of Charge in Gold Nanotoxicity

240

(1)

IV Toxicity of Amorphous Silica Nanoparticles

240

(1)

V Unique Cellular Interactions of Silver Nanoparticles

241

(1)

VI Chronic Toxicity of Nanoparticles in Enhanced Models

242

(1)

VII Impact of Nanoparticles on Cellular Mitochondria

243

(2)

VIII Understanding Molecular Mechanisms of Nanoparticle Toxicity Through Gene-Editing Technology

245

(1)

References

246

(5)

22 Food and Nutrient Exposure Throughout the Life Span: How Does What We Eat Translate Into Exposure, Deficiencies, and Toxicities?

Keli M. Hawthorne

I Introduction

251

(1)

II Nutrient Assessment

252

(1)

III Bioavailability and Beyond

253

(1)

IV Current Nutrient Standards

254

(1)

V Global Causes of Deficiency

254

(1)

VI Global Causes of Toxicity

255

(1)

VII Effects of Deficiency and Excessive Amounts of Selected Nutrients

255

(4)

VIII Approaches to Addressing Micronutrient Deficiencies

259

(1)

IX Further Directions in Research About Lifelong Effects of Nutrition

260

(1)

X Summary

261

(1)

References

261

(4)

23 The Microbiome Gut-Brain Axis

Carl E. Cerniglia

I Introduction

265

(1)

II What is the Human Microbiome?

266

(1)

III What is the Gut-Brain Axis?

267

(1)

IV Current Knowledge on How the Intestinal Microbiota Influences the Gut-Brain Axis

268

(1)

V Intestinal Microbiota-Derived Neuroactive Metabolites

269

(1)

VI Neurological Disorders

269

(1)

VII Conclusions and Research Data Gaps

270

(1)

Definitions for the Gut-Brain Axis

271

(1)

References

271

(4)

24 Drug and Chemical Contaminants in Breast Milk: Effects on Neurodevelopment of the Nursing Infant

Tom Leibson

Prateek Lala

Shinya Ito

I Introduction

275

(1)

II Effects of Breastfeeding on Infant Neurodevelopment

276

(1)

III Exposure of Nursing Infants to Drugs in Breast Milk

277

(1)

IV Effects of Maternal Exposure to Environmental Contaminants on the Nursing Infant

278

(2)

V Drugs and Nonmedicinal Substances

280

(1)

VI Information Resources

280

(1)

VII Conclusions

280

(3)

References

283

(5)

V Behavioral Assessment

25 Behavioral Phenotyping in Developmental Neurotoxicology-Simple Approaches Using Unconditioned Behaviors in Rodents

Devon L. Graham

Jerrold S. Meyer

Gregg D. Stanwood

I Introduction

288

(1)

II Basic Considerations

288

(2)

III Simple Unlearned Behaviors and Other Measures for Assessing Developmental Neurotoxicity

290

(7)

IV Behavioral Test Batteries in Developmental Neurotoxicology

297

(4)

V Conclusions

301

(1)

References

302

(8)

26 Psychometric Tools to Study Cognition, Sensory Functioning, and Social Behavior in Infant and Adolescent Nonhuman Primates

Thomas M. Burbacher

Kimberly S. Grant

I Developmental Assessments for Young Macaque Infants (Birth to 3-4 Months of Age)

310

(2)

II Assessing Cognition in Older Infants and Juveniles

312

(1)

III Methodologies for Measuring Learning and Memory

312

(1)

IV Tests of Cognition Suitable for Infant and Adolescent Monkeys

313

(1)

V Raising the Bar on Difficulty: Measuring Complex Learning Abilities

314

(1)

VI Tools to Measure Vision and Hearing

315

(1)

VII Social Behavior in Play Groups and Mother-Infant Pairs

316

(1)

VIII Concluding Remarks

317

(1)

References

317

(4)

27 Automated Assessment of Cognitive Function in Nonhuman Primates

John C. Talpos

Merle G. Paule

I Introduction

321

(1)

II Measuring Cognition Very Early in Life

321

(1)

III Evaluation of Cognitive Abilities From Late Infancy Into Adulthood

322

(3)

IV Toxicological Testing Using Operant Methods During Development

325

(1)

References

326

(3)

28 Determining the Validity of Preclinical Behavioral Assessments for Extrapolation to a Clinical Setting

John C. Talpos

John J. Chelonis

I Introduction

329

(2)

II Ecological Validity

331

(1)

III Face Validity

332

(1)

IV Convergent Validity

332

(1)

V Construct Validity

333

(1)

VI Predictive Validity

333

(1)

VII Conclusions

334

(1)

References

335

(3)

29 Behavioral Outcome as a Primary Organizing Principle for Mechanistic Data in Developmental Neurotoxicity

Christina Sobin

Mari Golub

I Current Challenges in Risk Assessment

338

(1)

II Organizing Principles for Mechanistic Data in Developmental Neurotoxicity are Needed Because the Brain is a "Complex Adaptive System"

338

(1)

III Changes in Mechanistic Function During Neurodevelopment and Developmental Toxic Exposure May be Indistinguishable

338

(1)

IV Behavior as an Organizing Principle for Mechanistic Data

339

(1)

V Using a Single Behavioral Outcome at a Single Developmental Stage to Develop a Hierarchy of Mechanistic Effects: Rearing in Preadolescent Lead-Exposed Mice

339

(2)

VI Which Mechanisms Have Been Associated With Mouse and Rat Rearing Behavior?

341

(1)

VII Is There Mechanistic Evidence That Lead Exposure Disrupts Cholinergic Transmission?

341

(1)

VIII How do We Understand Other Mechanistic Effects From Lead Exposure Relative to the Cholinergic System Disruption Indicated By Rearing Behavior?

341

(1)

IX Does Evidence Suggest That Disruptions in the Cholinergic System Impact Glutamate/GABA Function?

341

(1)

X What was Gained by Using Rearing Behavior at Preadolescence as a Starting Point for Organizing Extant Mechanistic Data?

342

(1)

XI Limitations

342

(1)

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

342

(1)

XIII Bisphenol A as a Developmental Neurotoxicant

342

(1)

XIV Anxiety as a Domain of Concern in BPA Risk Assessment

343

(1)

XV EPM Anxiety and BPA Effects at Multiple Developmental Stages

343

(1)

XVI What Brain Mechanisms are Relevant to EPM-Assessed Anxiety?

343

(1)

XVII What Mechanism Pathways are Plausible Candidates for Developmental BPA Effects on EPM Anxiety?

343

(2)

XVIII What is Gained by Using Behavior as an Organizing Principle?

345

(1)

XIX Limitations

345

(1)

XX Concluding Remarks

345

(1)

References

345

(6)

VI Clinical Assessment And Epidemiology

30 Evaluation of the Human Newborn Infant

Lilly Bogicevic

Marjolein Verhoeven

Annelqes Van Baar

I Introduction

351

(1)

II A First Impression

352

(1)

III Neurobehavioral Evaluations

353

(3)

IV Neuroimaging

356

(1)

V Neurophysiglogical Assessments

357

(1)

VI Perinatal Riskcores

358

(1)

VII Discussion

359

(1)

References

359

(4)

31 Neuropsychological Assessment of Children in Studies of Developmental Neurotoxicity

David C. Bellinger

Johanna Calderon

I Introduction

363

(1)

II Selecting the Age at Which to Conduct a Neuropsychological Assessment

364

(1)

III Considerations in Designing an Assessment Battery

364

(3)

IV Interpretation

367

(2)

References

369

(2)

32 Neurodevelopmental Assessment of the Older Infant and Child

William J. Barbaresi

Julie Bickel

I Epidemiology of Pediatric Neurodevelopmental and Behavioral Disorders

371

(1)

II Toolkit for Evaluation

372

(4)

References

376

(3)

33 Longitudinal Studies of the Effects of Prenatal Cocaine Exposure on Development and Behavior

Gale A. Richardson

Nancy L. Day

I Methodological Issues in the Study of Prenatal Cocaine Exposure

379

(2)

II A Longitudinal Study of Prenatal Cocaine Exposure: The Maternal Health Practices and Child Development Project

381

(2)

III Results From the Maternal Health Practices and Child Development Project and Other Longitudinal Investigations of Prenatal Cocaine Exposure

383

(1)

IV Conclusions

384

(1)

References

385

(4)

34 Assessment of Case Reports and Clinical Series

Jan M. Friedman

I Introduction

389

(1)

II Recognition of Patterns of Anomalies

389

(1)

III Syndromes of Cognitive or Behavioral Abnormalities

390

(4)

IV Limitations of Pattern Recognition

394

(1)

References

395

(4)

VII Specific Neurotoxic Syndromes

35 Fetal Minamata Disease: A Human Episode of Congenital Methylmercury Poisoning

Alessandra A. Dos Santos

Louis W. Chang

Grace Liejun Guo

Michael Aschner

I Introduction

399

(1)

II Human Episodes

399

(1)

III Neuropathology of Fetal Minamata Disease

400

(4)

IV Concluding Remarks

404

(1)

References

405

(2)

36 The Developmental Neurotoxicity of Cadmium

Ashley J. Malin

Robert O. Wright

I Introduction

407

(1)

II Prenatal and Postnatal Cadmium Exposure

408

(1)

III Mechanisms of Developmental Neurotoxicity

408

(1)

IV Neurobehavioral Outcomes in Animals

409

(1)

V Neurodevelopmental Outcomes in Children and Adolescents

410

(1)

VI Conclusions

411

(1)

References

411

(3)

37 Developmental Neurotoxicology of Lead: Neurobehavioral and Neurological Impacts

Stephen M. Lasley

I Lead Neurotoxicity in Children

414

(4)

II Neurological Effects of Lead Neurotoxicity in Animals: Cognition and Plasticity

418

(5)

References

423

(4)

38 Fetal Alcohol Spectrum Disorder

Irena Nulman

Talya Shulman

Feiyuan Liu

I Introduction

427

(1)

II Epidemiology of Alcohol Consumption in Pregnancy

428

(1)

III Alcohol Mechanism of Action

428

(2)

IV Epigenetics

430

(1)

V Epidemiology of FASD and Economic Burden

430

(1)

VI FASD Diagnosis

430

(2)

VII FASD Disabilities

432

(1)

VIII FASD and Mental Health

433

(1)

IX FASD Challenges and Future Directions

434

(1)

X FASD Prevention

434

(1)

XI Conclusions

435

(1)

References

435

(4)

39 Developmental Neurotoxicity of Nicotine and Tobacco

Edward D. Levin

Yael Abreu-Villaca

I Tobacco and Nicotine Exposure During Pregnancy

439

(1)

II Epidemiological Studies Find Neurobehavioral Dysfunction Associated With Tobacco Exposure in Pregnancy

440

(1)

III Animal Models Show That Nicotine Exposure During Development Causes Neurobehavioral Impairment

441

(2)

IV Nicotine Disrupts Neuronal Development

443

(2)

V Neurotoxicity of Other Compounds in Tobacco

445

(1)

VI Second Hand Smoke

446

(1)

VII Other Nicotinic Compounds

447

(1)

VIII Conclusions

447

(1)

References

448

(5)

40 Developmental Neurobehavioral Neurotoxicity of Insecticides

Yael Abreu-Villaca

Edward D. Levin

I Introduction

453

(1)

II Organochlorines

454

(2)

III Organophosphates

456

(2)

IV Carbamates

458

(1)

V Pyrethroids

459

(1)

VI Neonicotinoids

460

(1)

VII Concluding Remarks

461

(1)

References

462

(5)

41 Developmental Exposure to Polychlorinated Biphenyls Induces Deficits in Inhibitory Control and May Enhance Substance Abuse Risk

Mellessa M. Miller

Helen J.K. Sable

I Introduction

467

(1)

II Developmental Neurobehavioral Neurotoxicity of PCBs

468

(2)

III Developmental PCB Exposure Impairs Dopamine Function

470

(1)

IV Perinatal PCB Exposure Changes the Developing Brain, But Males May Be More Sensitive

471

(1)

V Where Do We Go From Here?

472

(1)

References

472

(5)

42 Developmental Neurotoxicity of General Anesthetics

Jennifer L. Walters

Merle G. Paule

I Introduction

477

(1)

II Classes of Anesthetics and Mechanisms of Action

477

(1)

III Nonclinical Studies of Anesthetic-Induced Neurotoxicity

478

(2)

IV Clinical Studies

480

(2)

V Protective Compounds

482

(1)

VI Conclusions

482

(1)

References

482

(5)

43 Maternal Drug Abuse and Adverse Effects on Neurobehavior of Offspring

Diana Dow-Edwards

I Introduction

487

(2)

II Opiates

489

(2)

III Cocaine

491

(1)

IV Cannabinoids/Marijuana

492

(2)

V Methamphetamine

494

(1)

VI MDMA

494

(1)

VII Transgenerational and Paternal Exposures

495

(1)

VIII Summary

495

(1)

References

495

(4)

44 Developmental Neurotoxicology of Antiepileptic Drugs

Jocelyn M. Lutes

Jolene E. Borchelt

Patricia A. Janulewicz

Jane Adams

I Introduction

499

(1)

II Neurobehavioral Effects of Prenatal Exposure to Monotherapy Treatment

500

(5)

III Putative Underlying Causes of Neuroteratogenic Effects

505

(1)

IV Conclusions

506

(1)

References

507

(4)

VIII Risk Assessment

45 Current Approaches to Risk Assessment for Developmental Neurotoxicity

Susan L. Makris

Andrew D. Kraft

I Introduction

511

(1)

II Risk Assessment Paradigm and General Concepts

512

(1)

III Conduct and Considerations in Developmental Neurotoxicity Risk Assessment

513

(9)

IV Common Data Gaps for DNT Studies of Environmental Chemicals

522

(1)

V Summary

523

(1)

References

524

(3)

46 Animal/Human Concordance

Larry P. Sheets

William Slikker Jr

I Introduction

527

(1)

II Human Conditions

528

(2)

III Assessment of Neurobehavioral Development in Infants and Children

530

(1)

IV Animal Models

530

(4)

V Targeted Testing

534

(1)

VI Newer Models and Approaches

535

(1)

References

536

(3)

47 Physiologically Based Pharmacokinetic Models in the Risk Assessment of Developmental Neurotoxicants

Kannan Krishnan

I Introduction

539

(1)

II Construction and Evaluation of PBPK Models

540

(6)

III Brain Dosimetry in PBPK Models

546

(2)

IV PBPK Modeling of Developmental Neurotoxicants

548

(2)

V Application of PBPK Models in the Risk Assessment of Developmental Neurotoxicants

550

(3)

References

553

(6)

48 Application of Quantitative Dose-Response Data in Risk Assessment and the Incorporation of High-Throughput Data

John C. Lipscomb

I Introduction

559

(1)

II Problem formulation

560

(3)

III Risk Assessment Fundamentals in the Federal Government

563

(2)

IV Defining Adversity

565

(2)

V Data From High-Throughput Assays

567

(1)

VI Risk Quantitation

568

(4)

References

572

(1)

Index

573

Dr. William Slikker, Jr. was the director of FDAs National Center for Toxicological Research (NCTR) before his retirement. He received his Ph.D. in pharmacology and toxicology from the University of California at Davis. Dr. Slikker holds adjunct professorships in the Department of Pediatrics, as well as the Department of Pharmacology and Toxicology at the University of Arkansas for Medical Sciences. He has held committee chairmanships or elected offices in several scientific societies including the Teratology Society (serving as president) and the American Society for Pharmacology and Experimental Therapeutics (chair, Developmental Pharmacology Section and member, Program Committee). Dr. Slikker is also the co-founder and past president of the MidSouth Computational Biology and Bioinformatics Society. He is currently associate editor for NeuroToxicology and associate editor for the Environmental Health” section of Experimental Biology and Medicine. He is the past president of The Academy of Toxicological Sciences and the Society of Toxicology. He is a recipient of the 2014 George H. Scott Memorial Award from The Toxicology Forum and was invited to present the Warkany Lecture at the 2015 annual meeting of the Teratology Society. In early 2019, the Academy of Toxicological Sciences selected Dr. Slikker to receive the prestigious Mildred S. Christian Career Achievement Award. The Society for Birth Defects Research and Prevention selected Dr. Slikker to be the recipient of the 2022 Edward W. Carney Distinguished Service Award.

Dr. Slikker has authored or co-authored over 380 publications in the areas of transplancentalpharmacokinetics, developmental neurotoxicology, neuroprotection, systems biology, and risk assessment. Dr. Slikkers recent research has highlighted the concern for thousands of infants and toddlers who undergo longer-duration general anesthesia. He has performed research with his team and published over 25 peer-reviewed papers outlining the issue of brain-cell death and cognitive-function deficits in animal models that may result from several hours of anesthesia at a critical time of development. He has also, with the use of in vitro and in vivo techniques in rodents and nonhuman primates, defined possible mechanisms of toxicity and protective pathways to prevent the detrimental effects of general anesthesia. Through these and related scientific contributions, he has identified and characterized a host of minimally invasive biomarkers of neurotoxicity including the use of preclinical imaging (MRI, MicroPET/CT), genomic and lipidomic analysis, and modeling approaches to characterize and quantify adult and developmental neurotoxicity. He has also served on several national/international advisory panels for ILSI, HESI, CIIT, EPA, NIEHS, NAS, NIH and WHO. Dr. Paule received his B.S. in Biochemistry and his Ph.D. in Pharmacology and Toxicology at the University of California at Davis. In 1983 he began work at the FDAs National Center for Toxicological Research in Jefferson, Arkansas, where he remains today. He attained certification as one of FDAs Senior Biomedical Research Scientists in 2000 and in 2005 became the Director of the Division of Neurotoxicology at NCTR. Dr. Paule has played a major role in developing an automated system for monitoring multiple complex brain functions in nonhuman primates, children, and rodents. Utilization of similar or identical behavioral tasks across species serves to facilitate the interspecies extrapolation of exposure data and, thus, the risk assessment process. He is past President of the Behavioral Toxicology Society, the Neurobehavioral Teratology Society and the Neurotoxicology Specialty Section of the Society of Toxicology and Associate Editor for the journals NeuroToxicology and Neurotoxicology and Teratology. Dr. Paule has published over 225 research articles and 30 book chapters and holds Adjunct Professorships at the University of Arkansas for Medical Sciences in the Departments of Pharmacology and Toxicology and in Pediatrics. He is an elected Fellow in the Academy of Toxicological Sciences and in the International Behavioral Neuroscience Society. Cheng Wang, M.D., Ph.D. is a Senior Scientist at the National Center for Toxicological Research (NCTR)/US Food and Drug Administration (FDA). He is also an Adjunct Faculty member in the Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences (UAMS). Dr. Wang is the P.I. of protocols (grants) supported by the NCTR/FDA, National Toxicology Program and NICHD. He is currently responsible for leading a research team that provides unique and highly specialized skills in neural toxicology, pharmacology, systems biology and stem cell biology research. Dr. Wang has published more than 80 peer-reviewed research articles in prestigious journals and 20 book chapters. Dr. Wang is a Co-Editor-in-Chief of the book entitled Developmental Neurotoxicology Research: Principles, Models, Techniques, Strategies, and Mechanisms” and Neural Cell Biology”. He also serves as Editor-in-Chief for Journal of Evolving Stem Cell Research (JESR) and Global Journal of Anesthesiology.

Dr. Wang was awarded the Outstanding Performance Award at the Society of Toxicology 44th Annual Meeting and the 2007 FDA Scientific Achievement Award for Excellence in Laboratory Science. He also was awarded a 2008 FDA Group Recognition Award for his participation in the Pediatric Anesthesia Research Group.

Research Interests Neural Stem Cell Biology Application of Systems Biology in Neurotoxicological Studies during Development Activity-induced Synaptic Plasticity and Neural Cell Adhesion Molecule Potential Pediatric Anesthetic-induced Neural Cell Death and the Potential Role of Neurotransmission (Mechanistic Studies) Mitochondrial DNA Damage and Expression Levels of DNA Repair Enzymes

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