Medical toxicology Books

Book SynopsisAn essential, 2-volume reference for everyone interested in herpetology—professional herpetologists and their students conducting research in the classroom, at the zoo, and in the field, as well as amateurs.Trade ReviewThe discussion of envenomation identification, grading, and treatment is fascinating and clinically valuable. I was very impressed with the organization and readability of the text. I nearly forgot to mention the wonderful color photographs.... The amount of information packed into these two volumes is truly mindboggling. This is a 'must have' reference for anyone interested in these creatures. -- Grady Calhoun * "The Forked Tongue," The Monthly Newsletter of the Greater Cincinnati Herpetological Society *The information available is overwhelming, yet it is presented in scholarly and clearly understandable fashion, utilizing every available form of still documentation.... The two volumes are indeed a masterful compilation and overview of the venomous reptiles in this geographic region. The volumes are well-produced and published, with sturdy binding, easily readable font size and style, and excellent quality printing of illustrations, colored figures, and the abundant colored photographic plates.... The chapter on 'Venom Poisoning by North American Reptiles' and the following contribution entitled 'Snake Bites in Central and South America: Epidemiology Clinical Features and Clinical Management' offers abundant experiences, observations, and recommendations that often support those currently used by toxicologists and emergency room physicians in North America, yet are diverse enough to highlight some of the controversies and continuing debates on what is most appropriate when and how!... One could easily spend many hours reviewing the clinical recommendations made and observing the excellent documented color photographs of effects and the good-and-bad results from various management procedures.... Just to skim through the illustrations and accompanying text for elaboration opens up a new world for students, herpetologists, zoologists, and veterinary and human toxicologists conducting research in the field or at the zoo, or managing envenomated patients. * Veterinary and Human Toxicology *

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Book SynopsisContributors including epidemiologists, clinicians, risk assessors, experts in air monitoring, microbiologists, and engineers discuss methodologies used in measuring exposures to pollution, strategies for improving indoor air quality, and other issues. They also assess the health effects of specificTrade ReviewHarmful of toxic substances enter the body through the air we breathe, through food or water ingested, or through the skin. This book by two prominent epidemiologists explores the relationship between air pollution and health. The book is well documented and well illustrated and provides a wealth of useful information including epidemiologic results and standards or requirements that influence air quality-both indoor and out. the 17 edited contributions are divided into discussions of (1) sources, (2) health effects, and (3) control and legal aspects. Each chapter is a detailed but readable review, of excellent quality and reliability. Particularly strong are the chapters on indoor air pollution, nitrogen dioxide, wood smoke, formaldehyde, and radon. Worldwide in coverage, this volume successfully provides a review for policy makers, engineers, lawyers, and health professionals, and for students in these disciplines, undergraduate and graduate. M.Gochfeld, Robert Wood Johnson Medical SchoolTable of ContentsContributorsPrefaceAckowledgmentsChapter 1. A Perspective on Indoor and Outdoor Air PollutionPart I. Sources, Concentrations, and ExposureChapter 2. Sources and Concentrations of Indoor Air PollutionChapter 3. Building Dynamics and INdoor Air QualityChapter 4. Assessment of Indoor Air QualityChapter 5. Personal Exposure to Indoor Air PollutionPart II. Health EfectsChapter 6. Environmental Tobacco SmokeChapter 7. Nitrogen DioxideChapter 8. Carbon MonoxideChapter 9. Wood SmokeChapter 10. FormaldehydeChapter 11. Volatile Organic CompoundsChapter 12. Indoor Air Pollution and Infectious DiseasesChapter 13. Biological Agents and Allergic DiseasesChapter 14. Building-related IllnessesChapter 15. RadonPart III. Control and Legal AspectsChapter 16. COntrol StrategiesChapter 17. Legal Aspects of Indoor Air PollutionIndex

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Book SynopsisWith clear scientific explanations and expert advice, The Mold Survival Guide is a valuable resource for anyone worried about a common household problem that can have serious consequences.Trade ReviewWhat molds are, why and where they grow, and how to rid our living spaces of these dangerous fungal microorganisms. The authors furnish clear explanations, examples from actual situations, and valuable advice... A storehouse of knowledge presented in a readable style. Library Journal Mold is a hot issue today, but the problem dates back to biblical times. Jeffrey May, author of My House is Killing Me, is a recognized authority on indoor pollution who focuses here on mold-how it prospers, how it affects one's health, and how it can be remediated. Science News Their handbook delivers both scientific explanations and expert advice. The most common problems can be headed off or corrected once the homeowner understands the life cycle of mold. That alone is worth the price of the book. Boston Globe Magazine A good job on a subject most of us would find less than stimulating... Were I actively listing and selling homes, I would keep this book handy as a reference and I would take every opportunity to see how the issue is playing out at the local level. Home inspectors would obviously be a great source of information, both academic and practical. -- Dr. Kenneth W. Edwards Real Estate Professional 2004 The Mold Survival Guide details mold problems and eradication methods and includes photographs-some in color-that show what water damage and mold infestation look like. -- Jim Watkins Washington Times Mold. It's a scary, mystifying and shudder inducing word... The Mays explore what mold is, where and why it grows, how it flourishes, and how it may or may not cause health problems. Readers learn how to identify mold, how to prevent it from spreading and when to call an expert. Baltimore Sun Recommended particularly for concerned homeowners and renovation architects, The Mold Survival Guide: For Your Home and for Your Health outlines the causes of moisture problems in old and new buildings... Leading you through his most tried-and-true forensic methodologies, Jeff May gives you the tools to root out the causes of the bedeviling musty odors that have forced homeowners to flee their homes. -- Courtney Miller ArchitectureBoston This book will help you make sensible decisions and cut through the 'fear factor' language in a lot of advertising. -- Holly Hayes San Jose Mercury NewsTable of ContentsPrefaceAcknowledgementsPart I: The World of MoldChapter 1. The Indispensable Kingdom of FungiChapter 2. Watering Mold and Spreading SporesChapter 3. How Mold Affects Our HealthChapter 4. Mold Wages Battle: Then and NowPart II: The Search For MoldChapter 5. What Lurks BelowChapter 6. Mold in the MechanicalsChapter 7. The Spaces We Live InChapter 8. The Spaces We Don't Live InChapter 9. Testing for MoldPart III: The CleanupChapter 10. Small-Scale Cleanup JobsChapter 11. Professional RemediationConclusionResource GuideIndex

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Book SynopsisForensic professionals, particularly medical examinersâoften working through heavy caseloadsârequire quick and easy access to reliable sources of information to help interpret toxicology results. While several in-depth resources are available, they are often large, cumbersome, and contain more information than is often needed. The Handbook of Forensic Toxicology for Medical Examiners is a concise handbook referencing the most common toxic substances and their reported non-toxic, toxic, and lethal concentrations, making it an ideal text for quick reference in the lab or autopsy room.Features of the Second Edition: Explains the principles of postmortem toxicology and the factors which must be considered Provides tables of toxicologic data for over 200 commonly encountered substances, including drugs of abuse, poisons, prescription drugs, and over-the-counter medications Includes discussion andTable of ContentsList of Abbreviations 1. How to Use This Book 2. Special Drug Groups 3. Specific Drugs (Alphabetical Listing) Appendix A. Specimen Types and Collection Appendix B. Common Methodologies Appendix C. Normal Values Reference Charts Appendix D. Conversion Chart

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Book SynopsisWritten in 1199 at the request of al-Qadi al-Fadil, the famous counselor and secretary to Saladin, On Poisons and the Protection against Lethal Drugs is distinguished rabbi Moses Maimonides' guide to emergency first aid and readily available antidotes. This book includes critical editions of the medieval Hebrew and Latin translations.

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Book SynopsisCovering areas of drug toxicity which address the major issues including registration requirements of new drugs and pharmacovigilance, this book provides an overview of the methodology and requirements of pre-clinical safety assessment of new medicines. It discusses mechanisms by which drugs cause toxic effects in living organisms.Trade Review'The text is well written, concise and easy to understand with informative and helpful illustrations, figures and tables...it serves as an excellent companion to pharmacology textbooks, dealing with the issues relevant for assessing the safety of new drugs...a good starting point for the novice toxicologist, ambitious undergraduate student or graduate students working in the pharmaceutical sciences.' Irish Pharmacy Journal, November 2006, p418 * Irish Pharmacy Journal *'...this is a great little book...the text is aimed primarily at new PHD students in the pharmaceutical and related sciences but could equally well serve taught postgraduate students on toxicology, clinical pharmacology, drug development and safety or similar courses. The book 'does exactly what it says on the tin' and will definitely whet the appetite of enthusiastic young researchers for toxicology.' Heather M Wallace, Summer 2007 issue of the British Toxicology Society Newsletter -- Heather M Wallace * British Toxicology Society Newsletter *Table of Contents1. General toxicology; 2. Drug metabolism: inactivation and bioactivation of xenobioptics; 3. Molecular and cellular mechanisms of toxicity; 4. Teratology; 5. Genotoxicity; 6. Carcinogenicity of drugs; 7. Liver toxicity; 8. Kidney toxicity; 9. Toxicology in the respiratory system; 10. Immunotoxicity; 11. Clinical toxicology; 12. Safety assessment of pharmaceuticals: regulatory aspects; 13. Pharmacovigilance.

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Book SynopsisClarke's Analysis of Drugs and Poisons is the definitive source of analytical data for drugs and poisons.Trade Review"This continues to be an invaluable reference for pharmaceutical scientists, clinical and forensic toxicologists and environmental chemists...Both the number of substances discussed in the monograph section and the depth of information presented are quite impressive." Randall C. Baselt, Ph.D., Journal of Forensic Science, 2011. -- Randall C. Baselt * Journal of Forensic Science *"Pathologists, clinicians, lawyers and students will find the new Clarke engaging, systematic in its approach and daunting in the massive amount of information provided. It is not until you become accustomed with the layout and logical style of the book that one appreciates the thought that has gone into producing this excellent and essential reference. No toxicologist should be without one!" Dimitri Gerostamoulos, TIAFT Bulletin 41(2), 2011. -- Dimitri Gerostamoulos * TIAFT Bulletin *"The work provides a compilation and easy access to analytical data for numerous compounds that can give an overview without the need of an extensive database search. This is especially true for data of older compounds that cannot be easily found elsewhere...the reader is provided with substantial information making the work an incomparable reference book in drug analysis." Gerhard K.E. Scriba, Department of Pharmaceutical Chemistry, University of Jena, Chromatographia, 10 July 2011. -- Gerhard K.E. Scriba * Chromatographia *Table of ContentsVolume one, part one: methodology and analytical techniques - Contains 44 chapters by leading international scientists covering the practice areas and analytical procedures used in toxicology. Volume two, parts two and three: analytical and toxicological data. Contains 2111 drug and poison monographs detailing physical properties, analytical methods, pharmacokinetic data and toxicity data. Part four: Indexes to analytical data. This part contains indexes of analytical data, including all data for colour tests, chromatography, ultraviolet spectrophotometry, infrared spectrometry and mass spectrometry.

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Book SynopsisAcute toxicology testing constitutes the first line of defense against potentially dangerous chemicals. This book provides a detailed presentation of protocols for each of the common designs, reviews their development and objectives, discusses the types of data they generate, and examines the current status of alternative test designs and models. For each test, applicable U.S. and international guidelines are also presented, and the formulation and selection of vehicles, dosages, and test animals are addressed.

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Book SynopsisAs with the previous editions, Introduction to Toxicology, Fourth Edition, continues to chart the evolution of the field of toxicology, from the use of natural toxins by ancient tribes through the developments established by Paracelsus, and progresses through to the current topics in the public interest. For centuries, the study of toxicology has fascinated students. The book begins with basic toxicological principles, including an historical summary, dose-response relationships (NEW chapter), exposure-response relationships (NEW chapter), disposition, and metabolism of xenobiotic toxic substances. Other important new chapters include target organ toxicity, toxicity of carcinogenic agents and new and updated concepts in toxicity testing, and antidotes and treatment of poisonings. In all, nine new or expanded chapters from the third edition are advanced.Current concerns about the effects of therapeutic drugs, carcinogens, industrial toxins, pesticides, and herbicides onTable of Contents1. Introduction. 2. Dose-Response Relationship. 3. Exposure-Response Relationship. 4. Disposition of Toxic Compounds. 5. Metabolism of Xenobiotic Compounds. 6. Target Organ Toxicity. 7. Carcinogenic and Mutagenic Compounds. 8. Drugs as Toxic Substances. 9. Industry Toxicology. 10. Food Additives and Contaminants. 11. Pesticides and Herbicides. 12. Environmental Pollutants. 13. Natural Products. 14. Commercial and Domestic Products. 15. Fundamentals of Toxicity Testing. 16. Risk Assessment. 17. Antidotes and Treatment of Poisoning. Answers to Chapter Questions. Glossary.

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Book SynopsisGut microbiomes are dynamic communities varying from population to population and throughout life. In Western societies, a toxic metabolic shift of gut microbiomes is a driver and underestimated risk factor for the development of many noncommunicable chronic pathologies. This book identifies the root cause of these deleterious microbial changes. During the last several decades, increased consumption of animal products, coinciding and correlating with global climate change, has been a contributing cause of undesirable gut microbiome changes.Key Features Establishes a connection between poor gut microbiome health and chronic disease and cancer development Demonstrates how animal products and low-fiber diet patterns induce a detrimental metabolic transition of the gut microbiome from a human health-maintaining towards a disease-promoting state Discusses the opportunity of a toxic microbial metabolic signatTable of ContentsTable of Contents Dedication Preface Introduction Chapter 1: Diet related chronic diseases are the most critical health problem of modern societies – how did that happen? Chapter 2: The "industrialized" microbiome - a caution label for a global epidemic Missing microbes - does it matter? Chapter 3: The subtle problems of microbiome research Is the microbiome "oversold"? Is microbiome science heading in the wrong direction? Chapter 4: The gut microbiome: a new perspective Our microbiome is a metabolic organ Functional omes: metabolites over species Finding a new definition for a "healthy" microbiome and "dysbiosis" Chapter 5: Shaping the microbial behavior Diet: the master educator of the gut microbiome Starving the microbial self: a foundation for developing a chronic disease Chapter 6: The toxic microbiome "It’s not the fiber, it’s the animal protein" Protein fermentation Fat toxicity Secondary bile acids Heme iron TMAO: the way to a man’s heart is through his gut microbiota Toxicomicrobiomics A toxic microbiome: useful for predicting chronic diseases? Chapter 7: How to build a healthy gut microbiome and prevent chronic diseases The "true" human diet: are humans really omnivores? "The Paleo diet is a myth" Protein concerns: Do we get enough on plants? Feeding microbes for disease prevention and treatment Chapter 8: "Fixing" the microbiome - Can we restore a healthy microbiome by other means than diet? Probiotics – hype or hope? Fecal microbial transplantation or "The Power of Poop" The "Wild West" of microbiome science: drugging the microbiome and personalized nutrition Glossary Abbreviations Literature

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Book SynopsisEnvironmental issues such as ozone layer depletion, overpopulation, biodiversity loss, global warming, natural resource depletion, and so on affect every organism on the planet somehow. Environmental biotechnology applications can help to protect and restore the quality of the environment. The goal is to use biotechnology with other technologies and safety procedures to prevent, arrest, and reverse environmental degradation. Environmental biotechnology is one of the most rapidly expanding and practically useful scientific fields. Biochemistry, physiology and genetic research of microorganisms can be converted into commercially available technologies for reversing and preventing further deterioration of the earth''s environment. Solid, liquid, and gaseous wastes can be altered either by recycling new by-products or by purifying to make the end product less harmful to the environment. Biotechnology for Toxic Remediation and Environmental Sustainability discusses the remoTable of ContentsPreface. About the Editors. List of Contributors. Recent Literature on Biosorption as a Sustainable Environmental Technology to Remove Pollutants. Production of Biofuels and Value-Added Products Using Anaerobic Digestion of Wastewater. Biodiesel Production by Organic Transformations. An Overview of Green Corrosion Inhibitors. Biochemical, Molecular, and Microbial Ecological Aspects of Bioelectrochemical Systems. Food Microbiome: Ecology, Functions, and Emerging Trends in Food Safety and Security. What We Know and What We Don’t on Antimicrobial Resistance: A Call for Action. Overall Thymoquinone Pharmacological Properties and Its Use as an Anticancer Agent. Function of ZnS Nanoparticles on Stress-Mediated Apoptosis in Mouse Retinal Pigment Epithelial Cells. Index.

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Book SynopsisThis second edition volume expands on the previous edition by exploring the latest advancements in high throughput screening (HTS) in toxicity studies by using in vitro, ex vivo, and in vivo models. This volume also covers the application of artificial intelligence (AI) and data science to curate, manage, and use HTS data. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Cutting-edge and thorough, High Throughput Screening Assays in Modern Toxicology, Second Edition is a valuable resource for scientists pursuing chemical toxicology research. This book will aid scientists and researchers in translating new HTS techniques into standardized chemical toxicology assessment tools that can refine, reTable of ContentsAcknowledgement…Preface…Table of Contents…Contributing Authors…Part I In Vitro Toxicological High Throughput Screening Methods1. Cell-Based Assays to Identify ERR and ERR/PGC ModulatorsCaitlin Lynch, Jinghua Zhao, and Menghang Xia2. Mitochondrial Membrane Potential AssaySrilatha Sakamuru, Jinghua Zhao, Matias S. Attene-Ramos, and Menghang Xia3. Cell-Based hERG Inhibition Assay in a High-Throughput FormatJinghua Zhao, and Menghang Xia 4. Identifying CAR Modulators Utilizing a Reporter Gene AssayCaitlin Lynch, Jinghua Zhao, Hongbing Wang, and Menghang Xia5. Study Liver Cytochrome P450 3A4 Inhibition and Hepatotoxicity Using DMSO-Differentiated HuH-7 CellsYitong Liu6. Acetylcholinesterase Inhibition Assays for High-Throughput ScreeningShuaizhang Li, Andrew J. Li, Michael F. Santillo, and Menghang Xia7. Cell-Based Assays to Identify Modulators of Nrf2/ARE PathwayZhengxi Wei, Jinghua Zhao, Li Zhang, and Menghang XiaPart II In Vitro Toxicological High Content Screening Methods8. Cell-Based Imaging Assay for Detection of PhospholipdosisLi Zhang, Shuaizhang Li, and Menghang Xia9. GFP-LC3 High-Content Assay for Screening Autophagy ModulatorsLi Zhang, Jinghua Zhao, Wen-Xing Ding, and Menghang XiaPart III Three-Dimensional Cell System for Toxicological High Throughput Screening10. Generation of iPSC-Derived Brain Organoids for Drug Testing and Toxicological EvaluationHa Nam NguyenPart IV In Vivo Toxicological High Throughput Screening Methods11. Zebrafish Behavioral Assays in ToxicologySubham Dasgupta, Michael T. Simonich, and Robert L. TanguayPart V In Silico High Throughput Screening Toxicity Data Analysis12. High Throughput Screening Assay Profiling for Large Chemical DatabasesDaniel P. Russo and Hao Zhu13. A Quantitative High Throughput Screening Data Analysis Pipeline for Activity ProfilingRuili Huang14. CurveP Method for Rendering High Throughput Screening Dose-Response Data into Digital FingerprintsAlexander Sedykh15. Accounting for Artifacts in High Throughput Toxicity AssaysJui-Hua Hsieh16. Automatic Quantitative Structure-Activity Relationship Modeling to Fill Data Gaps in High-Throughput ScreeningHeather L. Ciallella, Elena Chung, Daniel P. Russo, and Hao Zhu17. Use In Silico and In Vitro Methods to Screen Hepatotoxic Chemicals and CYP450 Enzyme InhibitorsYitong LiuSubject Index List…

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Book SynopsisExplores the benefits and limitations of the latest high-throughput screening methods With its expert coverage of high-throughput in vitro screening methods for toxicity testing, this book makes it possible for researchers to accelerate and streamline the evaluation and risk assessment of chemicals and drugs for toxicity. Moreover, it enables them to comply with the latest standards set forth by the U.S. National Research Council''s Toxicity Testing in the 21st Century: A Vision and Strategy and the E.U.''s REACH legislation. Readers will discover a variety of state-of-the-science, high-throughput screening methods presented by a group of leading authorities in toxicology and toxicity testing. High-Throughput Screening Methods in Toxicity Testing is divided into five parts: General aspects, including predicting the toxicity potential of chemicals and drugs via high-throughput bioactivity profiling Assessing different cytotoxicTable of ContentsPREFACE ix CONTRIBUTORS xi PART I GENERAL ASPECTS 1 ToxCast: Predicting Toxicity Potential Through High-Throughput Bioactivity Profiling 3 Keith A. Houck, Ann M. Richard, Richard S. Judson, Matthew T. Martin, David M. Reif, and Imran Shah 2 High-Throughput Toxicity Testing in Drug Development: Aims, Strategies, and Novel Trends 33 Willem G.E.J. Schoonen, Walter M.A. Westerink, Femke M. van de Water, and Horbach G. Jean 3 Incorporating Human Dosimetry and Exposure Information with High-Throughput Screening Data in Chemical Toxicity Assessment 77 Barbara A. Wetmore and Russell S. Thomas 4 The Use of Human Embryonic Stem Cells in High-Throughput Toxicity Assays 97 Xin Huang, Dan-yan Zhu, and Yi-jia Lou PART II HIGH-THROUGHPUT ASSAYS TO ASSESS DIFFERENT CYTOTOXICITY ENDPOINTS 5 High-Throughput Screening Assays for the Assessment of Cytotoxicity 109 Andrew L. Niles, Richard A. Moravec, Tracy J. Worzella, Nathan J. Evans, and Terry L. Riss 6 High-Throughput Flow Cytometry Analysis of Apoptosis 129 Francesca de Giorgi and Franc¸ois Ichas 7 High Content Imaging-Based Screening for Cellular Toxicity Pathways 143 Bram Herpers and Bob van de Water 8 The Keratinosens Assay: A High-Throughput Screening Assay to Assess Chemical Skin Sensitization 159 Andreas Natsch 9 High-Throughput Screening Assays to Assess Chemical Phototoxicity 177 Satomi Onoue, Yoshiki Seto, and Shizuo Yamada PART III HIGH-THROUGHPUT ASSAYS TO ASSESS DNA DAMAGE AND CARCINOGENESIS 10 Ames IITM and Ames Liquid Format Mutagenicity Screening Assays 193 Kamala Pant 11 High-Throughput Bacterial Mutagenicity Testing: VitotoxTM Assay 213 Luc Verschaeve 12 Genotoxicity and Carcinogenicity: Regulatory and Novel Test Methods 233 Walter M.A. Westerink, Joe C.R. Stevenson, G. Jean Horbach, Femke M. van de Water, Beppy van de Waart, and Willem G.E.J. Schoonen 13 High-Throughput Genotoxicity Testing: The Greenscreen Assay 271 Jorg Blumel and Nadine Krause 14 High-Throughput Assays to Quantify the Formation of DNA Strand Breaks 285 Marýa Moreno-Villanueva and Alexander Burkle 15 High-Throughput Versions of the Comet Assay 295 Irene Witte and Andre Stang 16 Automated Soft Agar Colony Formation Assay for the High-Throughput Screening of Malignant Cell Transformation 309 Pablo Steinberg 17 High-Throughput Quantification of Morphologically Transformed Foci in Bhas 42 Cells (v-Ha-ras Transfected BALB/c 3T3) Using Spectrophotometry 317 Kiyoshi Sasaki, Ayako Sakai, and Noriho Tanaka PART IV HIGH-THROUGHPUT ASSAYS TO ASSESS REPRODUCTIVE TOXICITY, CARDIOTOXICITY, AND HAEMATOTOXICITY 18 ReProGlo: A New Stem-Cell-Based High-Throughput Assay to Predict the Embryotoxic Potential of Chemicals 343 Frederik Uibel and Michael Schwarz 19 Embryonic Stem Cell Test (EST): Molecular Endpoints Toward High-Throughput Analysis of Chemical Embryotoxic Potential 357 Peter T. Theunissen, Esther de Jong, Joshua F. Robinson, and Aldert H. Piersma 20 Zebrafish Development: High-Throughput Test Systems to Assess Developmental Toxicity 371 Stephanie Padilla 21 Single Cell Imaging Cytometry-Based High-Throughput Analysis of Drug-Induced Cardiotoxicity 385 Min Jung Kim and Joon Myong Song 22 High-Throughput Screening Assays to Evaluate the Cardiotoxic Potential of Drugs 403 Carl-Fredrik Mandenius and Thomas Meyer 23 High-Throughput Screening Assays to Evaluate the Hematotoxic Potential of Drugs 421 Caroline Haglund, Rolf Larsson, and Martin Hoglund PART V HIGH-THROUGHPUT ASSAYS TO ASSESS DRUG METABOLISM AND RECEPTOR-RELATED TOXICITY 24 High-Throughput Enzyme Biocolloid Systems for Drug Metabolism and Genotoxicity Profiling Using LC–MS/MS 433 James F. Rusling and John Schenkman 25 Higher-Throughput Screening Methods to Identify Cytochrome P450 Inhibitors and Inducers: Current Applications and Practice 453 David M. Stresser and George Zhang 26 High-Throughput Yeast-Based Assays to Study Receptor-Mediated Toxicity 479 Johanna Rajasarkka and Marko Virta 27 Evaluating the Peroxisomal Phenotype in High Content Toxicity Profiling 501 Jonathan Z. Sexton and Kevin P. Williams 28 A Panel of Quantitative Calux R Reporter Gene Assays for Reliable High-Throughput Toxicity Screening of Chemicals and Complex Mixtures 519 Bart van der Burg, Sander van der Linden, Hai-yen Man, Roos Winter, Lydia Jonker, Barbara van Vugt-Lussenburg, and Abraham Brouwer 29 DR-Calux R : A High-Throughput Screening Assay for the Detection of Dioxin and Dioxin-Like Compounds in Food and Feed 533 Barbara van Vugt-Lussenburg, Harrie T. Besselink, Bart van der Burg, and Abraham Brouwer INDEX 547

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Book SynopsisAs a guide for pharmaceutical professionals to the issues and practices of drug discovery toxicology, this book integrates and reviews the strategy and application of tools and methods at each step of the drug discovery process. Guides researchers as to what drug safety experiments are both practical and usefulCovers a variety of key topics safety lead optimization, in vitro-in vivo translation, organ toxicology, ADME, animal models, biomarkers, and omics toolsDescribes what experiments are possible and useful and offers a view into the future, indicating key areas to watch for new predictive methodsFeatures contributions from firsthand industry experience, giving readers insight into the strategy and execution of predictive toxicology practicesTable of ContentsLIST OF CONTRIBUTORS xxi FOREWORD xxv PART I INTRODUCTION 1 1 Emerging Technologies and their Role in Regulatory Review 3 Thomas J. Colatsky 1.1 Introduction 3 1.2 safety assessment in Drug Development and Review 4 1.3 The Role of New Technologies in Regulatory Safety Assessment 6 1.4 Conclusions 8 References 8 PART II SAFETY LEAD OPTIMIZATION STRATEGIES 13 2 Small‐Molecule Safety Lead Optimization 15 Donna M. Dambach 2.1 Background and Objectives of Safety Lead Optimization Approaches 15 2.2 Target Safety Assessments: Evaluation of Undesired Pharmacology and Therapeutic Area Considerations 16 2.3 Implementing Lead Optimization Strategies for Small Molecules 16 2.4 Conclusions 23 References 23 3 Safety Assessment Strategies and Predictive Safety of Biopharmaceuticals and Antibody Drug Conjugates 27 Michelle J. Horner, Mary Jane Hinrichs and Nicholas Buss 3.1 Background and Objectives 27 3.2 Target Safety Assessments: Strategies to Understand Target Biology and Associated Liabilities 28 3.3 Strategic Approaches for Biopharmaceuticals and ADCs 29 3.4 Predictive Safety Tools for Large Molecules 33 3.5 Strategies for Species Selection 34 3.6 Strategy for Dose‐Ranging Studies for Safety Evaluation of Biopharmaceuticals 35 3.7 Conclusions 35 References 36 4 Discovery and Development Strategies for Small Interfering Rnas 39 Scott A. Barros and Gregory Hinkle 4.1 Background 39 4.2 Target Assessments 40 4.3 siRNA Design and Screening Strategies 41 4.4 Safety Lead Optimization of siRNA 45 4.5 Integration of Lead Optimization Data for Candidate Selection and Development 48 4.6 Conclusions 49 References 49 PART III BASIS FOR IN VITRO–IN VIVO PK TRANSLATION 53 5 Physicochemistry and the Off‐Target Effects of Drug Molecules 55 Dennis A. Smith 5.1 Lipohilicity, Polar Surface Area, and Lipoidal Permeability 55 5.2 Physicochemistry and Basic ADME Properties for High Lipoidal Permeability Drugs 56 5.3 Relationship between Volume of Distribution (Vd) and Target Access for Passively Distributed Drugs 58 5.4 Basicity, Lipophilicity, and Volume of Distribution as a Predictor of Toxicity (T): Adding The T to ADMET 59 5.5 Basicity and Lipophilicity as a Predictor of Toxicity (T): Separating the D from T in ADMET 60 5.6 Lipophilicity and PSA as a Predictor of Toxicity (T): Adding the T to ADMET 60 5.7 Metabolism and Physicochemical Properties 61 5.8 Concentration of Compounds by Transporters 61 5.9 Inhibition of Excretion Pumps 63 5.10 Conclusions 64 References 65 6 The Need for Human Exposure Projection in the Interpretation of Preclinical In Vitro and In Vivo ADME Tox Data 67 Patrick Poulin 6.1 Introduction 67 6.2 Methodology Used for Human PK Projection in Drug Discovery 67 6.3 Summary of the Take‐Home Messages from the Pharmaceutical Research and Manufacturers of America Cpcdc Initiative on Predictive Models of Human PK from 2011 72 Abbreviations 77 References 77 7 A DME Properties Leading to Toxicity 82 Katya Tsaioun 7.1 Introduction 82 7.2 The Science of ADME 83 7.3 The ADME Optimization Strategy 83 7.4 Conclusions and Future Directions 89 References 90 PART IV Predicting Organ Toxicity 93 8 Liver 95 J. Gerry Kenna, Mikael Persson, Scott Q. Siler, Ke Yu, Chuchu Hu, Minjun Chen, Joshua Xu, Weida Tong, Yvonne Will and Michael D. Aleo 8.1 Introduction 95 8.2 DILI Mechanisms and Susceptibility 96 8.3 Common Mechanisms that Contribute to DILI 98 8.4 Models Systems Used to Study DILI 108 8.5 In Silico Models 114 8.6 Systems Pharmacology and DILI 118 8.7 Summary 119 References 121 9 Cardiac 130 David J. Gallacher, Gary Gintant, Najah Abi‐Gerges, Mark R. Davies, Hua Rong Lu, Kimberley M. Hoagland, Georg Rast, Brian D. Guth, Hugo M. Vargas and Robert L. Hamlin 9.1 General Introduction 130 9.2 Classical In Vitro/Ex Vivo Assessment of Cardiac Electrophysiologic Effects 133 9.3 Cardiac Ion Channels and In Silico Prediction 137 9.4 From Animal Ex Vivo/In Vitro Models to Human Stem Cell‐Derived Cms for Cardiac Safety Testing 140 9.5 In Vivo Telemetry Capabilities and Preclinical Drug Development 141 9.6 Assessment of Myocardial Contractility in Preclinical Models 144 9.7 Assessment of Large Versus Small Molecules in CV SP 147 9.8 Patients do not Necessarily Respond to Drugs and Devices as do Genetically Identical, Young Mature, Healthy Mice! 148 References 152 10 Predictive In Vitro Models for Assessment of Nephrotoxicity and Drug–Drug Interactions In Vitro 160 Lawrence H. Lash 10.1 Introduction 160 10.2 Biological Processes and Toxic Responses of the Kidneys that are Normally Measured in Toxicology Research and Drug Development Studies 163 10.3 Primary Cultures of hPT Cells 164 10.4 Toxicology Studies in hPT Primary Cell Cultures 166 10.5 Critical Studies for Drug Discovery in hpt Primary Cell Cultures 168 10.6 S ummary and Conclusions 168 References 170 11 Predicting Organ Toxicity In Vitro: Bone Marrow 172 Ivan Rich and Andrew J. Olaharski 11.1 Introduction 172 11.2 Biology of the Hematopoietic System 172 11.3 Hemotoxicity 173 11.4 Measuring Hemotoxicity 173 11.5 The Next Generation of Assays 175 11.6 Proliferation or Differentiation? 175 11.7 Measuring and Predicting Hemotoxicity In Vitro 176 11.8 Detecting Stem and Progenitor Cell Downstream Events 177 11.9 Bone Marrow Toxicity Testing During Drug Development 177 11.10 Paradigm for In Vitro Hemotoxicity Testing 178 11.11 Predicting Starting Doses for Animal and Human Clinical Trials 179 11.12 Future Trends 179 11.13 Conclusions 180 References 180 12 Predicting Organ Toxicity In Vitro: Dermal Toxicity 182 Patrick J. Hayden, Michael Bachelor, Mitchell Klausner and Helena Kandárová 12.1 Introduction 182 12.2 Overview of Drug‐Induced Adverse Cutaneous Reactions 182 12.3 Overview of In Vitro Skin Models with Relevance to Preclinical Drug Development 183 12.4 Specific Applications of In Vitro Skin Models and Predictive In Vitro Assays Relevant to Pharmaceutical Development 184 12.5 Mechanism‐Based Cutaneous Adverse Effects 187 12.6 Summary 188 References 189 13 In Vitro Methods in Immunotoxicity Assessment 193 Xu Zhu and Ellen Evans 13.1 Introduction and Perspectives on In Vitro Immunotoxicity Screening 193 13.2 Overview of the Immune System 194 13.3 Examples of In Vitro Approaches 196 13.4 Conclusions 198 References 199 14 Strategies and Assays for Minimizing Risk of Ocular Toxicity during Early Development of Systemically Administered Drugs 201 Chris J. Somps, Paul Butler, Jay H. Fortner, Keri E. Cannon and Wenhu Huang 14.1 Introduction 201 14.2 In Silico and In Vitro Tools and Strategies 201 14.3 Higher‐Throughput In Vivo Tools and Strategies 202 14.4 S trategies, Gaps, and Emerging Technologies 208 14.5 Summary 210 References 210 15 Predicting Organ Toxicity In Vivo—Central Nervous System 214 Greet Teuns and Alison Easter 15.1 Introduction 214 15.2 Models for Assessment of CNS ADRs 214 15.3 S eizure Liability Testing 216 15.4 Drug Abuse Liability Testing 218 15.5 General Conclusions 222 15.5.1 In Vitro 222 15.5.2 In Vivo 223 Abbreviations 223 References 224 16 Biomarkers, Cell Models, and In Vitro Assays for Gastrointestinal Toxicology 227 Allison Vitsky and Gina M. Yanochko 16.1 Introduction 227 16.2 A natomic and Physiologic Considerations 228 16.3 GI Biomarkers 229 16.4 Cell Models of the GI Tract 231 16.5 Cell‐Based In Vitro Assays for Screening and Mechanistic Investigations to Gi Toxicity 235 16.6 Summary/Conclusions/Challenges 236 References 236 17 Preclinical Safety Assessment of Drug Candidate‐Induced Pancreatic Toxicity: From an Applied Perspective 242 Karrie A. Brenneman, Shashi K. Ramaiah and Lauren M. Gauthier 17.1 Drug‐Induced Pancreatic Toxicity 242 17.2 Preclinical Evaluation of Pancreatic Toxicity 245 17.3 Preclinical Pancreatic Toxicity Assessment: In Vivo 247 17.4 Pancreatic Biomarkers 249 17.5 Preclinical Pancreatic Toxicity Assessment: In Vitro 253 17.6 Summary and Conclusions 257 Acknowledgments 258 References 258 PART V A DDRESSING THE FALSE NEGATIVE SPACE—INCREASING PREDICTIVITY 261 18 Animal Models of Disease for Future Toxicity Predictions 263 Sherry J. Morgan and Chandikumar S. Elangbam 18.1 Introduction 263 18.2 Hepatic Disease Models 264 18.3 Cardiovascular Disease Models 268 18.4 Nervous System Disease Models 270 18.5 Gastrointestinal Injury Models 273 18.6 Renal Injury Models 279 18.7 Respiratory Disease Models 282 18.8 Conclusion 285 References 287 19 The Use of Genetically Modified Animals in Discovery Toxicology 298 Dolores Diaz and Jonathan M. Maher 19.1 Introduction 298 19.2 Large‐Scale Gene Targeting and Phenotyping Efforts 299 19.3 Use of Genetically Modified Animal Models in Discovery Toxicology 300 19.4 The Use of Genetically Modified Animals in Pharmacokinetic and Metabolism Studies 303 19.5 Conclusions 309 References 309 20 Mouse Population-Based Toxicology for Personalized Medicine and Improved Safety Prediction 314 Alison H. Harrill 20.1 Introduction 314 20.2 Pharmacogenetics and Population Variability 314 20.3 Rodent Populations Enable a Population‐Based Approaches to Toxicology 316 20.4 Applications for Pharmaceutical Safety Science 320 20.5 Study Design Considerations for Genomic Mapping 322 20.6 Summary 326 References 326 PART VI STEM CELLS IN TOXICOLOGY 331 21 Application of Pluripotent Stem Cells in Drug‐Induced Liver Injury Safety Assessment 333 Christopher S. Pridgeon, Fang Zhang, James A. Heslop, Charlotte M.L. Nugues, Neil R. Kitteringham, B. Kevin Park and Christopher E.P. Goldring 21.1 The Liver, Hepatocytes, and Drug‐Induced Liver Injury 333 21.2 Current Models of Dili 334 21.3 Uses of iPSC HLCs 338 21.4 Challenges of Using ipscs and New Directions for Improvement 339 21.5 Alternate Uses of HLCs in Toxicity Assessment 341 References 342 22 Human Pluripotent Stem Cell‐Derived Cardiomyocytes: A New Paradigm in Predictive Pharmacology and Toxicology 346 Praveen Shukla, Priyanka Garg and Joseph C. Wu 22.1 Introduction 346 22.2 A dvent of hPSCs: Reprogramming and Cardiac Differentiation 347 22.3 iPSC‐Based Disease Modeling and Drug Testing 349 22.4 Traditional Target‐Centric Drug Discovery Paradigm 354 22.5 iPSC‐Based Drug Discovery Paradigm 354 22.6 Limitations and Challenges 358 22.7 Conclusions and Future Perspective 359 Acknowledgments 360 References 360 23 Stem Cell‐Derived Renal Cells and Predictive Renal In Vitro Models 365 Jacqueline Kai Chin Chuah, Yue Ning Lam, Peng Huang and Daniele Zink 23.1 Introduction 365 23.2 Protocols for the Differentiation of Pluripotent Stem Cells into Cells of the Renal Lineage 367 23.3 Renal In Vitro Models for Drug Safety Screening 376 23.4 Achievements and Future Directions 378 Acknowledgments 379 Notes 379 References 379 PART VII CURRENT STATUS OF PRECLINICAL IN VIVO TOXICITY BIOMARKERS 385 24 Predictive Cardiac Hypertrophy Biomarkers in Nonclinical Studies 387 Steven K. Engle 24.1 Introduction to Biomarkers 387 24.2 Cardiovascular Toxicity 387 24.3 Cardiac Hypertrophy 388 24.4 Diagnosis of Cardiac Hypertrophy 389 24.5 Biomarkers of Cardiac Hypertrophy 389 24.6 Case Studies 392 24.7 Conclusion 392 References 393 25 Vascular Injury Biomarkers 397 Tanja S. Zabka and Kaïdre Bendjama 25.1 Historical Context of Drug‐Induced Vascular Injury and Drug Development 397 25.2 Current State of Divi Biomarkers 398 25.3 Current Status and Future of In Vitro Systems to Investigate Divi 402 25.4 Incorporation of In Vitro and In Vivo Tools in Preclinical Drug Development 403 25.5 Divi Case Study 403 References 403 26 Novel Translational Biomarkers of Skeletal Muscle Injury 407 Peter M. Burch and Warren E. Glaab 26.1 Introduction 407 26.2 Overview of Drug‐Induced Skeletal Muscle Injury 407 26.3 Novel Biomarkers of Drug‐Induced Skeletal Muscle Injury 409 26.4 Regulatory Endorsement 411 26.5 Gaps and Future Directions 411 26.6 Conclusions 412 References 412 27 Translational Mechanistic Biomarkers and Models for Predicting Drug‐Induced Liver Injury : Clinical to In Vitro Perspectives 416 Daniel J. Antoine 27.1 Introduction 416 27.2 Drug‐Induced Toxicity and the Liver 417 27.3 Current Status of Biomarkers for the Assessment of DILI 418 27.4 Novel Investigational Biomarkers for DILI 419 27.5 In Vitro Models and the Prediction of Human Dili 422 27.6 Conclusions and Future Perspectives 423 References 424 PART VIII Kidney Injury Biomarkers 429 28 Assessing and Predicting Drug‐Induced Kidney Injury, Functional Change, and Safety in Preclinical Studies in Rats 431 Yafei Chen 28.1 Introduction 431 28.2 Kidney Functional Biomarkers (Glomerular Filtration and Tubular Reabsorption) 433 28.3 Novel Kidney Tissue Injury Biomarkers 435 28.4 Novel Biomarkers of Kidney Tissue Stress Response 436 28.5 Application of an Integrated Rat Platform (Automated Blood Sampling and Telemetry, Abst) for Kidney Function and Injury Assessment 437 References 439 29 Canine Kidney Safety Protein Biomarkers 443 Manisha Sonee 29.1 Introduction 443 29.2 Novel Canine Renal Protein Biomarkers 443 29.3 Evaluations of Novel Canine Renal Protein Biomarker Performance 444 29.4 Conclusion 444 References 445 30 Traditional Kidney Safety Protein Biomarkers and Next‐Generation Drug‐Induced Kidney Injury Biomarkers in Nonhuman Primates 446 Jean‐Charles Gautier and Xiaobing Zhou 30.1 Introduction 446 30.2 Evaluations of Novel Nhp Renal Protein Biomarker Performance 447 30.3 New Horizons: Urinary MicroRNAs and Nephrotoxicity in Nhps 447 References 447 31 Rat Kidney MicroRNA Atlas 448 Aaron T. Smith 31.1 Introduction 448 31.2 Key Findings 448 References 449 32 MicroRNAs as Next‐Generation Kidney Tubular Injury Biomarkers in Rats 450 Heidrun Ellinger‐Ziegelbauer and Rounak Nassirpour 32.1 Introduction 450 32.2 Rat Tubular miRNAs 450 32.3 Conclusions 451 References 451 33 MicroRNAs as Novel Glomerular Injury Biomarkers in Rats 452 Rachel Church 33.1 Introduction 452 33.2 Rat Glomerular miRNAs 452 References 453 34 Integrating Novel Imaging Technologies to Investigate Drug‐Induced Kidney Toxicity 454 Bettina Wilm and Neal C. Burton 34.1 Introduction 454 34.2 Overviews 455 34.3 Summary 456 References 456 35 In Vitro to In Vivo Relationships with Respect to Kidney Safety Biomarkers 458 Paul Jennings 35.1 Renal Cell Lines as Tools for Toxicological Investigations 458 35.2 Mechanistic Approaches and In Vitro to In Vivo Translation 459 35.3 Closing Remarks 460 References 460 36 Case Study: Fully Automated Image Analysis of Podocyte Injury Biomarker Expression in Rats 462 Jing Ying Ma 36.1 Introduction 462 36.2 Material and Methods 462 36.3 Results 463 36.4 Conclusions 465 References 465 37 Case Study: Novel Renal Biomarkers Translation to Humans 466 Deborah A. Burt 37.1 Introduction 466 37.2 Implementation of Translational Renal Biomarkers in Drug Development 466 37.3 Conclusion 467 References 467 38 Case Study: Microrn as as Novel Kidney Injury Biomarkers in Canines 468 Craig Fisher, Erik Koenig and Patrick Kirby 38.1 Introduction 468 38.2 Material and Methods 468 38.3 Results 468 38.4 Conclusions 470 References 470 39 Novel Testicular Injury Biomarkers 471 Hank Lin 39.1 Introduction 471 39.2 The Testis 471 39.3 Potential Biomarkers for Testicular Toxicity 472 39.4 Conclusions 473 References 473 PART IX Best Practices in Biomarker Evaluations 475 40 Best Practices in Preclinical Biomarker Sample Collections 477 Jaqueline Tarrant 40.1 Considerations for Reducing Preanalytical Variability in Biomarker Testing 477 40.2 Biological Sample Matrix Variables 477 40.3 Collection Variables 480 40.4 Sample Processing and Storage Variables 480 References 480 41 Best Practices in Novel Biomarker Assay Fit‐for‐Purpose Testing 481 Karen M. Lynch 41.1 Introduction 481 41.2 Why Use a Fit‐for‐Purpose Assay? 481 41.3 Overview of Fit‐for‐Purpose Assay Method Validations 482 41.4 Assay Method Suitability in Preclinical Studies 482 41.5 Best Practices for Analytical Methods Validation 482 41.6 Species‐ and Gender‐Specific Reference Ranges 486 41.7 Analyte Stability 487 41.8 Additional Method Performance Evaluations 487 References 487 42 Best Practices in Evaluating Novel Biomarker Fit for Purpose and Translatability 489 Amanda F. Baker 42.1 Introduction 489 42.2 Protocol Development 489 42.3 Assembling an Operations Team 489 42.4 Translatable Biomarker Use 490 42.5 Assay Selection 490 42.6 Biological Matrix Selection 490 42.7 Documentation of Patient Factors 491 42.8 Human Sample Collection Procedures 491 42.9 Choice of Collection Device 491 42.10 Schedule of Collections 492 42.11 Human Sample Quality Assurance 492 42.12 Logistics Plan 493 42.13 Database Considerations 493 42.14 Conclusive Remarks 493 References 493 43 Best Practices in Translational Biomarker Data Analysis 495 Robin Mogg and Daniel Holder 43.1 Introduction 495 43.2 Statistical Considerations for Preclinical Studies of Safety Biomarkers 496 43.3 Statistical Considerations for Exploratory Clinical Studies of Translational Safety Biomarkers 497 43.4 Statistical Considerations for Confirmatory Clinical Studies of Translational Safety Biomarkers 498 43.5 Summary 498 References 498 44 Translatable Biomarkers in Drug Development: Regulatory Acceptance and Qualification 500 John‐Michael Sauer, Elizabeth G. Walker and Amy C. Porter 44.1 Safety Biomarkers 500 44.2 Qualification of Safety Biomarkers 501 44.3 Letter of Support for Safety Biomarkers 502 44.4 Critical Path Institute’s Predictive Safety Testing Consortium 502 44.5 Predictive Safety Testing Consortium and its Key Collaborations 504 44.6 Advancing the Qualification Process and Defining Evidentiary Standards 505 References 506 PART X Conclusions 509 45 Toxicogenomics in Drug Discovery Toxicology: History, Methods, Case Studies, and Future Directions 511 Brandon D. Jeffy, Joseph Milano and Richard J. Brennan 45.1 A Brief History of Toxicogenomics 511 45.2 Tools and Strategies for Analyzing Toxicogenomics Data 513 45.3 Drug Discovery Toxicology Case Studies 519 References 525 46 Issue Investigation and Practices in Discovery Toxicology 530 Dolores Diaz, Dylan P. Hartley and Raymond Kemper 46.1 Introduction 530 46.2 Overview of Issue Investigation in the Discovery Space 530 46.3 Strategies to Address Toxicities in the Discovery Space 532 46.4 Cross‐Functional Collaborative Model 533 46.5 Case‐Studies of Issue Resolution in The Discovery Space 536 46.6 Data Inclusion in Regulatory Filings 538 References 538 ABBREVIATIONS 540 CONCLUDING REMARKS 542 INDEX 543

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Book SynopsisA comprehensive and authoritative compilation of up-to-date developments in stem cell research and its use in toxicology and medicine Presented by internationally recognized investigators in this exciting field of scientific researchProvides an insight into the current trends and future directions of research in this rapidly developing new fieldA valuable and excellent source of authoritative and up-to-date information for researchers, toxicologists, drug industry, risk assessors and regulators in academia, industry and governmentTable of ContentsList of Contributors xx Preface xxvi Acknowledgements xxvii PART I 1 1 Introduction 3 Saura C. Sahu References 4 2 Application of Stem Cells and iPS Cells in Toxicology 5 Maria Virginia Caballero, Ramon A. Espinoza‐Lewis, and Manila Candiracci 2.1 Introduction 5 2.2 Significance 6 2.3 Stem Cell (SC) Classification 7 2.4 Stem Cells and Pharmacotoxicological Screenings 8 2.5 Industrial Utilization Showcases Stem Cell Technology as a Research Tool 8 2.6 Multipotent Stem Cells (Adult Stem Cells) Characteristics and Current Uses 9 2.7 Mesenchymal Stem Cells (Adult Stem Cells) 10 2.8 Hematopoietic Stem Cells (Adult Stem Cells) 11 2.9 Cardiotoxicity 12 2.10 Hepatotoxicity 15 2.11 Epigenetic Profile 17 2.12 Use of SC and iPSC in Drug Safety 18 2.13 Conclusions and Future Applications 19 Acknowledgments 19 References 19 3 Stem Cells: A Potential Source for High Throughput Screening in Toxicology 26 Harish K Handral, Gopu Sriram, and Tong Cao 3.1 Introduction 26 3.2 Stem Cells 27 3.3 High Throughput Screening (HTS) 31 3.4 Need for a Stem Cell Approach in High Throughput Toxicity Studies 37 3.5 Role of Stem Cells in High Throughput Screening for Toxicity Prediction 38 3.6 Conclusion 40 Acknowledgement 41 Disclosure Statement 41 Author’s Contribution 41 References 41 4 Human Pluripotent Stem Cells for Toxicological Screening 50 Lili Du and Dunjin Chen 4.1 Introduction 50 4.2 The Biological Characteristics of hPSCs 51 4.3 Screening of Embryotoxic Effects using hPSCs 52 4.4 The Potential of hPSC‐Derived Neural Lineages in Neurotoxicology 55 4.5 The Potential of hPSC ‐Derived Cardiomyocytes in Cardiotoxicity 60 4.6 The Potential of hPSC‐Derived Hepatocytes in Hepatotoxicity 62 4.7 Future Challenges and Perspectives for Embryotoxicity and Developmental Toxicity Studies using hPSCs 65 Acknowledgments 66 References 67 5 Effects of Culture Conditions on Maturation of Stem Cell‐Derived Cardiomyocytes 71 Deborah K. Hansen, Amy L. Inselman, and Xi Yang 5.1 Introduction 71 5.2 Lengthening Culture Time 75 5.3 Substrate Stiffness 76 5.4 Structured Substrates 78 5.5 Conclusions 82 Disclaimer 82 References 83 6 Human Stem Cell‐Derived Cardiomyocyte In Vitro Models for Cardiotoxicity Screening 85 Tracy Walker, Kate Harris, Evie Maifoshie, and Khuram Chaudhary 6.1 Introduction 85 6.2 Overview of hPSC‐Derived Cardiomyocytes 88 6.3 Human PSC‐CM Models for Cardiotoxicity Investigations 90 6.4 Conclusions and Future Direction 112 References 112 7 Disease‐Specific Stem Cell Models for Toxicological Screenings and Drug Development 122 Matthias Jung, Juliane‐Susanne Jung, Jovita Schiller, and Insa S. Schroeder 7.1 Evidence for Stem Cell‐Based Drug Development and Toxicological Screenings in Psychiatric Diseases, Cardiovascular Diseases and Diabetes 122 7.2 Disease‐Specific Stem Cell Models for Drug Development in Psychiatric Disorders 127 7.3 Stem Cell Models for Cardiotoxicity and Cardiovascular Disorders 132 7.4 Stem Cell Models for Toxicological Screenings of EDCs 133 References 135 8 Three‐Dimensional Culture Systems and Humanized Liver Models Using Hepatic Stem Cells for Enhanced Toxicity Assessment 145 Ran‐Ran Zhang, Yun‐Wen Zheng, and Hideki Taniguchi 8.1 Introduction 145 8.2 Hepatic Cell Lines and Primary Human Hepatocytes 146 8.3 Embryonic Stem Cells and Induced Pluripotent Stem‐Cell Derived Hepatocytes 147 8.4 Ex Vivo: Three‐Dimensional and Multiple‐Cell Culture System 148 8.5 In Vivo: Humanized Liver Models 149 8.6 Summary 150 Acknowledgments 150 References 150 9 Utilization of In Vitro Neurotoxicity Models in Pre‐Clinical Toxicity Assessment 155 Karin Staflin, Dinah Misner, and Donna Dambach 9.1 Introduction 155 9.2 Current Models of Drug‐Related Clinical Neuropathies and Effects on Electrophysiological Function 159 9.3 Cell Types that Can Potentially Be Used for In Vitro Neurotoxicity Assessment in Drug Development 162 9.4 Utility of iPSC Derived Neurons in In Vitro Safety Assessment 167 9.5 Summary of Key Points for Consideration in Neurotoxicity Assay Development 170 9.6 Concluding Remarks 172 References 172 10 A Human Stem Cell Model for Creating Placental Syncytiotrophoblast, the Major Cellular Barrier that Limits Fetal Exposure to Xenobiotics 179 R. Michael Roberts, Shinichiro Yabe, Ying Yang, and Toshihiko Ezashi 10.1 Introduction 179 10.2 General Features of Placental Structure 180 10.3 The Human Placenta 180 10.4 Human Placental Cells in Toxicology Research 182 10.5 Placental Trophoblast Derived from hESC 183 10.6 Isolation of Syncytial Areas from BAP‐Treated H1 ESC Colonies 185 10.7 Developmental Regulation of Genes Encoding Proteins Potentially Involved in Metabolism of Xenobiotics 185 10.8 Concluding Remarks 191 Acknowledgments 192 References 192 11 The Effects of Endocrine Disruptors on Mesenchymal Stem Cells 196 Marjorie E. Bateman, Amy L. Strong, John McLachlan, Matthew E. Burow, and Bruce A. Bunnell 11.1 Mesenchymal Stem Cells 196 11.2 Endocrine Disruptors 198 11.3 Pesticides 201 11.4 Alkyl Phenols and Derivatives 206 11.5 Bisphenol A 211 11.6 Polychlorinated Biphenyls 216 11.7 Phthalates 221 11.8 Areas for Future Research 225 11.9 Conclusions 226 Abbreviations 226 References 228 12 Epigenetic Landscape in Embryonic Stem Cells 238 Xiaonan Sun, Nicholas Spellmon, Joshua Holcomb, Wen Xue, Chunying Li, and Zhe Yang 12.1 Introduction 238 12.2 DNA Methylation in ESCs 239 12.3 Histone Methylation in ESCs 240 12.4 Chromatin Remodeling and ESCs Regulation 241 12.5 Concluding Remarks 242 Acknowledgements 243 References 243 PART II 247 13 The Effect of Human Pluripotent Stem Cell Platforms on Preclinical Drug Development 249 Kevin G. Chen 13.1 Introduction 249 13.2 Core Signaling Pathways Underlying hPSC Stemness and Differentiation 250 13.3 Basic Components of In Vitro and Ex Vivo hPSC Platforms 251 13.4 Diverse hPSC Culture Platforms for Drug Discovery 252 13.5 Representative Analyses of hPSC‐Based Drug Discovery 255 13.6 Current Challenges and Future Considerations 257 13.7 Concluding Remarks 260 Acknowledgments 260 References 260 14 Generation and Application of 3D Culture Systems in Human Drug Discovery and Medicine 265 H. Rashidi and D.C. Hay 14.1 Introduction 265 14.2 Traditional Scaffold‐Based Tissue Engineering 266 14.3 Scaffold‐Free 3D Culture Systems 269 14.4 Modular Biofabrication 270 14.5 3D Bioprinting 270 14.6 Tissue Modelling and Regenerative Medicine Applications of Pluripotent Stem Cells 272 14.7 Applications in Drug Discovery and Toxicity 275 14.8 Conclusions 278 References 278 15 Characterization and Therapeutic Uses of Adult Mesenchymal Stem Cells 288 Juliann G. Kiang 15.1 Introduction 288 15.2 MSC Characterization 289 15.3 MSCs and Tissue or Organ Therapy 293 15.4 Conclusions 298 Acknowledgments 298 References 298 16 Stem Cell Therapeutics for Cardiovascular Diseases 303 Yuning Hou, Xiaoqing Guan, Shukkur M. Farooq, Xiaonan Sun, Peijun Wang, Zhe Yang, and Chunying Li 16.1 Introduction 303 16.2 Types of Stem/Progenitor Cell‐Derived Endothelial Cells 304 16.3 EPC and Other Stem/Progenitor Cell Therapy in CVDs 306 16.4 Strategies and Approaches for Enhancing EPC Therapy in CVDs 306 16.5 Concluding Remarks 315 Acknowledgments 316 References 316 17 Stem‐Cell‐Based Therapies for Vascular Regeneration in Peripheral Artery Diseases 324 David M Smadja and Jean‐Sébastien Silvestre 17.1 Sources of Stem Cells for Vascular Regeneration 325 17.2 Canonic Mechanisms Governing Vascular Stem Cells Therapeutic Potential 329 17.3 Stem‐Cell‐Based Therapies in Patients with Peripheral Artery Disease 333 References 337 18 Gene Modified Stem/Progenitor‐Cell Therapy for Ischemic Stroke 347 Yaning Li, Guo‐Yuan Yang, and Yongting Wang 18.1 Introduction 347 18.2 Gene Modified Stem Cells for Ischemic Stroke 348 18.3 Gene Transfer Vectors 354 18.4 Unsolved Issues for Gene‐Modified Stem Cells in Ischemic Stroke 356 18.5 Conclusion 356 Abbreviations 356 Acknowledgments 357 References 357 19 Role of Stem Cells in the Gastrointestinal Tract and in the Development of Cancer 363 Pengyu Huang, Bin Li, and Yun‐Wen Zheng 19.1 Introduction 363 19.2 GI Development and Regeneration 365 19.3 GI Tumorigenesis and Stemness Gene Expression 367 19.4 Toxicants and Other Stress Trigger Epigenetic Changes, Dedifferentiation, and Carcinogenesis 368 19.5 Summary and Perspective 369 Acknowledgments 369 References 370 20 Cancer Stem Cells: Concept, Significance, and Management 375 Haseeb Zubair, Shafquat Azim, Sanjeev K. Srivastava, Arun Bhardwaj, Saravanakumar Marimuthu, Mary C. Patton, Seema Singh, and Ajay P. Singh 20.1 Introduction 375 20.2 Stem Cells and Cancer: Historical Perspective 376 20.3 Cancer Stem Cells 377 20.4 Identification and Isolation of CSCs 382 20.5 Pathological Significance of Cancer Stem Cells 388 20.6 Pathways Regulating Cancer Stem Cells 389 20.7 Therapeutic Strategies Targeting Cancer Stem Cells 394 20.8 Conclusion and Future Directions 399 References 400 21 Stem Cell Signaling in the Heterogeneous Development of Medulloblastoma 414 Joanna Triscott and Sandra E. Dunn 21.1 Brain Tumor Cancer Stem Cells 414 21.2 Medulloblastoma 416 21.3 Hijacking Cerebellar Development 417 21.4 Molecular Classification of MB 420 21.5 Mouse Models and Cell of Origin 424 21.6 Additional Drivers of MB 425 21.7 Repurposing Off‐Patent Drugs 426 21.8 Emerging Therapies for MB 428 21.9 Conclusion 429 Acknowledgments 429 References 429 22 Induced Pluripotent Stem Cell‐Derived Outer-Blood‐Retinal Barrier for Disease Modeling and Drug Discovery 436 Jun Jeon, Nathan Hotaling, and Kapil Bharti 22.1 Introduction 436 22.2 The Outer Blood‐Retinal Barrier 437 22.3 iPSC‐Based Model of the Outer-Blood‐Retinal-Barrier 439 22.4 iPSC Based OBRB Disease Models 442 22.5 Applications of iPSC‐Based Ocular Disease Models for Drug Discovery 448 22.6 Conclusion and Future Directions 451 References 451 23 Important Considerations in the Therapeutic Application of Stem Cells in Bone Healing and Regeneration 458 Hoda Elkhenany, Shawn Bourdo, Alexandru Biris, David Anderson, and Madhu Dhar 23.1 Introduction 458 23.2 Stem Cells, Progenitor Cells, Mesenchymal Stem Cells 459 23.3 Scaffolds 461 23.4 Animal Models in Bone Healing and Regeneration 464 23.5 Conclusions and Future Directions 472 References 472 24 Stem Cells from Human Dental Tissue for Regenerative Medicine 481 Junjun Liu and Shangfeng Liu 24.1 Introduction 481 24.2 Dental Stem Cells 482 24.3 Potential Clinical Applications 488 24.4 Safety 492 24.5 Dental Stem Cell Banking 493 24.6 Conclusions and Perspective 494 References 495 25 Stem Cells in the Skin 502 Hongwei Wang, Zhonglan Su, Shiyu Song, Ting Su, Mengyuan Niu, Yaqi Sun, and Hui Xu 25.1 Introduction 502 25.2 Stem Cells in the Skin 503 25.3 Isolation and the Biological Markers of Skin Stem Cells 506 25.4 Skin Stem Cell Niches 508 25.5 Signaling Control of Stem Cell Differentiation 510 25.6 Stem Cells in Skin Aging 514 25.7 Stem Cells in Skin Cancer 516 25.8 Medical Applications of Skin Stem Cells 518 25.9 Conclusions and Future Directions 520 References 521 Author Index 527 Subject Index 529

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Book SynopsisOver the last ten years the subject of toxicology has changed dramatically, moving from a discipline which was once firmly wedded to traditional (some might say old-fashioned) methods to one which is keen to embrace the innovative techniques emerging from the developing fields of cell culture and molecular biology.Trade Review“Overall, we consider that this book is a useful summary of current and emerging techniques in molecular toxicology.” (BTS Newsletter, 1 March 2015) Table of ContentsForeword xiii Preface xv Acknowledgements xvii Abbreviations xix About the Companion Website xxiii 1 Background to Molecular and Cellular Toxicology 1 1.1 What do we mean by molecular and cellular toxicology? 1 1.2 Tissues and their maintenance 2 1.2.1 Stem cells 3 1.3 Tissue damage 4 1.3.1 Consequences of tissue injury 4 1.3.2 Reversible changes in cells and tissues 6 1.3.3 Irreversible changes in cells and tissues 7 1.4 Tissue responses to injury 7 1.4.1 Oxidative stress 7 1.4.2 Necrosis and apoptosis 10 1.4.3 Neoplasia 13 1.4.4 The initiation–promotion paradigm 13 1.5 Key concepts in toxicology 23 1.5.1 Risk and hazard 23 1.5.2 Variability and uncertainty 25 1.5.3 Threshold and non-threshold dose responses 26 1.5.4 The regulatory context 28 1.5.5 Limitations of whole animal studies 29 1.5.6 Use of human tissues in toxicology 31 1.6 Summing up 33 Self-assessment questions 33 Background Reading 34 References 34 2 Individual Susceptibility to Toxic Chemicals 37 2.1 Introduction 37 2.2 Toxicogenetics and toxicogenomics 38 2.3 Genotyping and phenotyping 39 2.3.1 Genotyping 40 2.3.2 Phenotyping 43 2.3.3 Correlating genotype and phenotype 44 2.4 Polymorphic xenobiotic metabolism 45 2.4.1 Polymorphic xenobiotic metabolising enzymes 49 2.4.2 The role of xenobiotic metabolising polymorphisms in susceptibility to toxic agents 50 2.5 Study numbers and effect size 60 2.6 Recent developments 62 2.6.1 Genome-wide association studies 62 2.6.2 Collaborative programmes 64 2.7 The UK Biobank 69 2.8 Conclusions 71 Self-assessment questions 72 Background Reading 72 References 73 3 ‘Omics Techniques 79 3.1 ‘Omics and bioinformatics 79 3.2 Transcriptomics 80 3.2.1 Methodology 80 3.2.2 Proof of principle 89 3.2.3 Hepatotoxicity 91 3.2.4 Extrahepatic toxicity 96 3.3 Proteomics 97 3.3.1 Methodology 98 3.4 Metabolomics/metabonomics 101 3.4.1 MS-based metabolomics 102 3.4.2 NMR-based metabolomics 106 3.5 Integrating different types of ‘omics data 107 3.5.1 ‘Omics in drug discovery 108 3.5.2 ‘Omics profiles as biomarkers of toxicity 109 3.6 Remaining issues with ‘omics approaches 111 3.7 Conclusions 112 Self-assessment questions 113 Background Reading 113 References 113 4 In Vitro Methods for Predicting In Vivo Toxicity 117 4.1 In vitro toxicology 117 4.2 Tissue culture 117 4.2.1 Primary cell cultures 122 4.2.2 Established cell lines 125 4.3 Acute toxicity in vitro 127 4.3.1 Cytotoxicity testing 127 4.3.2 Choice of cell line 129 4.3.3 Liver 131 4.3.4 Skin 133 4.3.5 Eye 141 4.4 Repeated dose toxicity 144 4.5 Reproductive toxicity 147 4.6 Stem cell-derived systems 149 4.7 Conclusions 151 Self-assessment questions 151 Background Reading 152 References 152 5 In Vitro Methods for Absorption, Distribution, Metabolism and Excretion 159 5.1 Why study ADME in vitro? 159 5.2 Absorption 160 5.2.1 Dermal penetration 160 5.2.2 Gastrointestinal absorption 164 5.3 Distribution 171 5.3.1 Protein binding 172 5.3.2 Blood-brain barrier 172 5.3.3 Other protective barriers 176 5.4 Metabolism 176 5.4.1 Skin 177 5.4.2 Gastrointestinal tract 179 5.4.3 Liver 179 5.5 Excretion 189 5.5.1 Biliary excretion 190 5.5.2 Renal clearance 191 5.6 Conclusions 191 Self-assessment questions 192 References 192 6 In Silico Methods and Structure–Activity Relationships 199 6.1 Why in silico? 199 6.2 Predicting the ADME characteristics of xenobiotics 200 6.2.1 Absorption 200 6.2.2 Distribution 206 6.2.3 Metabolism 207 6.2.4 Excretion 212 6.3 Physiologically based biokinetic modelling 212 6.4 Toxicity 221 6.4.1 Exposure modelling 222 6.4.2 Prediction of toxicity 223 6.5 Conclusions 233 Self-assessment questions 235 References 235 7 Transgenic Animal Models for ADME and Systemic Toxicity 241 7.1 Transgenic models and their use in toxicology 241 7.2 ADME models 242 7.2.1 Nuclear receptor models 244 7.2.2 Xenobiotic metabolism models 251 7.2.3 Drug transporter models 259 7.3 Reporter models 264 7.3.1 LacZ-based models 264 7.3.2 Green fluorescent protein-based models 267 7.3.3 Luciferase-based models 268 7.3.4 Evaluation 273 7.4 Conclusions 273 Self-assessment questions 274 Background Reading 274 References 274 8 Genotoxicity and its Measurement 281 8.1 Genotoxicity testing 281 8.2 Core in vitro tests 282 8.2.1 The Ames test 282 8.2.2 In vitro gene mutation tests using mammalian cells 283 8.2.3 The in vitro chromosome aberration test 284 8.2.4 The in vitro micronucleus assay 287 8.3 Assessment of genotoxicity for regulatory purposes 291 8.4 Novel in vitro methods 292 8.4.1 GreenScreen HC 292 8.4.2 The Reconstructed Skin MicroNucleus assay 293 8.5 Novel in vivo assays for gene mutations 294 8.5.1 The Pig-A assay 294 8.5.2 In vivo assays using transgenic mouse models 295 8.6 DNA damage and its repair 300 8.6.1 DNA damage 300 8.6.2 DNA repair 305 8.7 Thresholds 308 8.8 Conclusions 310 Self-assessment questions 310 References 311 9 Oncogenes and the Identification of Human Carcinogens 317 9.1 Introduction 317 9.2 Identification of human carcinogens 317 9.2.1 The lifetime carcinogenicity bioassay 317 9.2.2 The National Toxicology Program 2-year bioassay 318 9.3 Genetic changes in cancer 321 9.3.1 Methods for detecting activated oncogenes 324 9.3.2 In vitro transformation assays 324 9.3.3 Ras oncogene activation during tumour development 326 9.3.4 Non-ras oncogenes 328 9.3.5 Evaluation 329 9.4 Non-genotoxic carcinogenesis 329 9.4.1 Non-receptor-mediated mechanisms 330 9.4.2 Receptor-mediated mechanisms 331 9.4.3 When is a genotoxic carcinogen not a genotoxic carcinogen? 333 9.5 Transgenic models for short-term carcinogenicity bioassays 335 9.5.1 RasH2 335 9.5.2 Tg.AC 337 9.5.3 p53 models 338 9.5.4 XPC−¨M−, XPA−¨M− and XPA−¨M−/p53+¨M− null mouse models 340 9.5.5 Comparative evaluation of models 340 9.5.6 Regulatory status 341 9.5.7 Limitations of the assays 343 9.5.8 Evaluation 344 9.6 Conclusions 345 Self-assessment questions 346 References 346 10 Emerging Techniques 351 10.1 What’s next? 351 10.2 Novel model organisms 351 10.2.1 The zebrafish 352 10.2.2 Evaluation 358 10.3 Less invasive methods 359 10.3.1 Use of biomarkers 359 10.3.2 Liver 359 10.3.3 Kidney 367 10.3.4 Circulating mRNA biomarkers 371 10.3.5 Evaluation 373 10.4 The systems biology approach 373 10.4.1 Systems biology in toxicology 376 10.5 Collaborative programmes 381 10.5.1 Europe 381 10.5.2 USA 383 10.5.3 Evaluation 384 10.6 Final word 385 Self-assessment questions 385 References 385 Index 391

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Book SynopsisThe hands-on study companion for the most respected, rigorous medical toxicology text availableGoldfrank's Toxicologic Emergencies has long been the go-to guide for accurately diagnosing and effectively treating poisoned and overdosed patients. Now, this practical companion provides everything you need to get even more out of Goldfrankâs.Study Guide for Goldfrank's Toxicologic Emergencies provides 1,400 questions with answers for testing your knowledgeâa process that increases information retention and serves as invaluable practice for board exams. Each chapter has its own question set using both general factual and case-based questions. The guide is ideal for students, nurses, pharmacists, and physicians.Study Guide for Goldfrank's Toxicologic Emergencies covers: General approaches to the poisoned patient Principles of medical toxicology Clinical basis of medical toxicology Poison prevention and eduTable of Contents Historical Principles and Perspectives Toxicologic Misfortunes and Catastrophes in History PART A THE GENERAL APPROACH TO THE PATIENT Initial Evaluation of the Patient: Vital Signs and Toxic Syndromes Principles of Managing the Acutely Poisoned or Overdosed Patient SC1. Principles of Antidote Stocking Decontamination Principles: Prevention of Gastrointestinal Absorption SC2. Decontamination Principles: Prevention of Dermal, ophthalmic and inhalational Absorption A1. Activated Charcoal A2. Whole-Bowel Irrigation and Other Intestinal Evacuants Principles and Techniques Applied to Enhance Elimination Laboratory Principles Principles of Diagnostic Imaging Pharmacokinetic and Toxicokinetic Principles PART B THE FUNDAMENTAL PRINCIPLES OF MEDICALTOXICOLOGY SECTION I BIOCHEMICAL AND MOLECULAR CONCEPTS Chemical Principles Biochemical and Metabolic Principles Fluid, Electrolyte, and Acid–Base Principles Neurotransmitters and Neuromodulators Withdrawal Principles SECTION II PATHOPHYSIOLOGIC BASIS: ORGAN SYSTEMS Cardiologic Principles I: Electrophysiologic and Electrocardiographic Principles Cardiologic Principles II: Hemodynamics Dermatologic Principles SC3. Transdermal Toxicology Gastrointestinal Principles Genitourinary Principles Hema tologic Principles Hepatic Principles Neurologic Principles Oncologic Principles Ophthalmic Principles Otolaryngologic Principles Psychiatric Principles SC4. patient violence Respiratory Principles Thermoregulatory Principles SECTION III SPECIALPOPULATIONS Reproductive and Perinatal Principles Pediatric Principles Geriatric Principles PART C THE CLINICAL BASIS OF MEDICAL TOXICOLOGY SECTION I A. ANALGESICS ANDANTIINFLAMMATORY MEDICATIONS Acetaminophen A3. N-Acetylcysteine Colchicine, Podophyllin, and the Vinca Alkaloids Nonsteroidal Antiinflammatory Drugs Opioids A4. opioid antagonists SC5. Internal Concealment of Xenobiotics SC6. Harm Reduction for Opioid Overdose Salicylates A5. sodium bicarbonate B. Food, Diet, and Nutrition Botulism A6. botulinum antitoxin Food Poisoning Dieting Xenobiotics and Regimens Athletic Performance Enhancers Essential Oils Plant and Animal-Derived Dietary Supplements Vitamins Iron A7. deferoxamine Mary Ann Howland C. pharmaceuticals Pharmaceutical Additives Antidiabetics and Hypoglycemics/Antiglycemics A8. Dextrose(d-Glucose) A9. octreotide Antiepileptics A10. l-carnitine Antihistamines and Decongestants A11. physostigmine salicylate Chemotherapeutics Methotrexate,5-Flourouracil, and Capecitabine A12. folates: leucovorin (Folinic acid) and Folic Acid A13. glucarpidase(carboxypeptidase g2) A14. uridine triacetate SC7. Inadvertent Intrathecal Administration of Xenobiotics SC8. Extravasation of Chemotherapeutics Antimigraine Medications Thyroid and Antithyroid Medications D. Antimicrobials Antibacterials, Antifungals, and Antivirals Antimalarials Antituberculous Medications A15. pyridoxine E. Cardiopulmonary Medications CASE STUDY 4 Antidysrhythmics A16. Magnesium Sulfate Antithrombotics A17. Protein Complex Concentrate and Novel Antithrombotic Antidotes A18. Vitamin k1 A19. protamine β-Adrenergic Antagonists A20. Glucagon

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Book SynopsisA wide-ranging compilation of techniques, Extrapolation Practice for Ecotoxicological Effect Characterization of Chemicals describes methods of extrapolation in the framework of ecological risk assessment. The book, informally known as EXPECT, identifies data needs and situations where these extrapolations can be most usefully applied, making it a practical guide to the application of extrapolation procedures. It focuses on the extrapolation of chemical effects and covers the extrapolation of exposures in the context of interactions between toxicants and the matrix.Table of ContentsExtrapolation in the Context of Criteria Setting and Risk Assessment. Matrix and Media Extrapolation. (Q)SAR and Extrapolation. Extrapolation of Effects Measures Across Levels of Biological Organization in Ecological Risk Assessment. Mixture Extrapolation Approaches. Temporal Extrapolation en Ecological Effect Assessment of Chemicals. Spatial Extrapolation in ecological Effect Assessment of Chemicals. Guidance on the Application of Extrapolation Methods in Ecological Exposure and Effects Characterization of Chemicals. Conclusions. Glossary.

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Book SynopsisWhether you have allergies or asthma, or you just want to avoid exposures to indoor contaminants and allergens, this book will teach you how to have a healthier home. In this thoroughly revised edition of My House Is Killing Me! Jeffrey C. and Connie L. May draw on the dramatic personal stories of their clients to help readers understand the links between indoor environmental conditions and human health. Explaining how air conditioning, finished basements, and other home features affect indoor air quality, the authors offer a step-by-step approach to identifying, controlling, and even eliminating the sources of indoor pollutants and allergens. This new edition includes more than 60 color photographs expanded coverage on the dangers posed by volatile organic compounds (VOCs) produced by such common items as paint, carpet, and household cleaning products up-to-date information on the potential risks of installing spray polyurethane foam (SPF) insulation completely new case studies of pTrade ReviewThe May's continue to be masterful storytellers, using their work with clients to help solve problems and increase education of their indoor spaces.—Healthy IndoorsTable of ContentsForeword, by Jonathan M. Samet, MD, and Elizabeth Matsui, MD, MHSAppreciationIntroduction Part I. The Stage of Our LivesChapter 1. Seeing the InvisibleChapter 2. Cast of Small Characters—Read This Chapter If You Dare!Chapter 3. "Trojan Horse" AllergensChapter 4. Creepy Crawlers (Apologies for the Title!)Chapter 5. The Three Ps—Pets, Pests, and PeopleChapter 6. The SetPart II. Daily LifeChapter 7. Living Rooms, Family Rooms, and Dining AreasChapter 8. Rooms with Water—The BathroomChapter 9. Rooms with Water—The KitchenChapter 10. Rooms with Water—The LaundryChapter 11. BedroomsChapter 12. Attached Garages, Bulkheads, Porches, and DecksChapter 13. The ExteriorChapter 14. Indoor Air Quality in Multi-Unit BuildingsPart III. Below and AboveChapter 15. Unfinished Basements and Crawl SpacesChapter 16. Finished BasementsChapter 17. AtticsPart IV. Heating and CoolingChapter 18. Heating and Cooling with DuctsChapter 19. Heating and Cooling without DuctsChapter 20. More on Heating, Cooling, and FuelPart V. Clean It Up—Inside and OutChapter 21. Renovation and New ConstructionChapter 22. More Environmental HazardsChapter 23. Testing and RemediationChapter 24. CleaningClosing Remarks: Take ChargeNotesGlossaryResource GuideIndex

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Book SynopsisWhether you have allergies or asthma, or you just want to avoid exposures to indoor contaminants and allergens, this book will teach you how to have a healthier home. In this thoroughly revised edition of My House Is Killing Me! Jeffrey C. and Connie L. May draw on the dramatic personal stories of their clients to help readers understand the links between indoor environmental conditions and human health. Explaining how air conditioning, finished basements, and other home features affect indoor air quality, the authors offer a step-by-step approach to identifying, controlling, and even eliminating the sources of indoor pollutants and allergens. This new edition includes more than 60 color photographs expanded coverage on the dangers posed by volatile organic compounds (VOCs) produced by such common items as paint, carpet, and household cleaning products up-to-date information on the potential risks of installing spray polyurethane foam (SPF) insulation completely new case studies of pTrade ReviewThe May's continue to be masterful storytellers, using their work with clients to help solve problems and increase education of their indoor spaces.—Healthy IndoorsTable of ContentsForeword, by Jonathan M. Samet, MD, and Elizabeth Matsui, MD, MHSAppreciationIntroduction Part I. The Stage of Our LivesChapter 1. Seeing the InvisibleChapter 2. Cast of Small Characters—Read This Chapter If You Dare!Chapter 3. "Trojan Horse" AllergensChapter 4. Creepy Crawlers (Apologies for the Title!)Chapter 5. The Three Ps—Pets, Pests, and PeopleChapter 6. The SetPart II. Daily LifeChapter 7. Living Rooms, Family Rooms, and Dining AreasChapter 8. Rooms with Water—The BathroomChapter 9. Rooms with Water—The KitchenChapter 10. Rooms with Water—The LaundryChapter 11. BedroomsChapter 12. Attached Garages, Bulkheads, Porches, and DecksChapter 13. The ExteriorChapter 14. Indoor Air Quality in Multi-Unit BuildingsPart III. Below and AboveChapter 15. Unfinished Basements and Crawl SpacesChapter 16. Finished BasementsChapter 17. AtticsPart IV. Heating and CoolingChapter 18. Heating and Cooling with DuctsChapter 19. Heating and Cooling without DuctsChapter 20. More on Heating, Cooling, and FuelPart V. Clean It Up—Inside and OutChapter 21. Renovation and New ConstructionChapter 22. More Environmental HazardsChapter 23. Testing and RemediationChapter 24. CleaningClosing Remarks: Take ChargeNotesGlossaryResource GuideIndex

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Book SynopsisA behind-the-scenes look inside three key trials involving Monsanto's weed killer Roundup, cancer, and the search for justicewritten by an expert witness medical oncologist who lived it all. For years, Monsanto declared that their product Roundup, the world's most widely used weed killer, was safe. But that all changed in 2015, when the International Agency for Research on Cancer (IARC) analyzed data from scientific studies and concluded that glyphosate, the active ingredient in Roundup, is probably carcinogenic.The Environmental Protection Agency (EPA) disagreed, other regulatory agencies got involved, and scientists clamored to understand the link between glyphosate and cancer. Toxic Exposure tells the true story of numerous patients who developed non-Hodgkin lymphoma, a form of cancer, after using Roundup and their ensuing trials against Monsanto (now owned by Bayer, one of the largest agrochemical companies in the world). Written by Chadi Nabhan, MD, MBA, a cancer specialist, tTrade ReviewThe author describes keeping his compassion for patients front and center despite tough grilling by Monsanto's lawyers and sharpening his resolve by remembering that he was there to help ameliorate suffering.Readers are invited along for the ride: sweating on the witness stand, hanging on the lawyers' every word, hoping for the truth to prevail.—Civil EatsTable of ContentsAuthor's NotePrefaceChapter 1. The Phone CallChapter 2. The First MeetingChapter 3. The EPAChapter 4. Meeting Mr. JohnsonChapter 5. The Night Before the Daubert HearingChapter 6. Coming to AmericaChapter 7. Daubert DayChapter 8. The Johnson Trial BeginsChapter 9. My Trial TestimonyChapter 10. The Johnson VerdictChapter 11. HardemanChapter 12. The Second Trial BeginsChapter 13. VerdictsChapter 14. PilliodsChapter 15. The Third Trial BeginsChapter 16. Another Day in CourtChapter 17. JudgmentChapter 18. EndingsGlossaryResourcesAcknowledgments

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Book SynopsisIn the last decade and a half, great progress has been made in the development of concepts and models for mixture toxicity, both in human and environmental toxicology. However, due to their different protection goals, developments have often progressed in parallel but with little integration. Arguably the first book to clearly link ecotoxicology and classic human toxicology, Mixture Toxicity: Linking Approaches from Ecological and Human Toxicology incorporates extensive reviews of exposure to toxicants, toxicokinetics and toxicodynamics, toxicity of mixtures, and risk assessment.The book examines developments in both fields, compares and contrasts their current state of the art, and identifies where one field can learn from the other. Each chapter provides an essential overview of the state of the art in both human and ecotoxicological mixture risk assessment, focusing on the work published in the last fifteen years. The coverage progresses from exposuTable of ContentsExposure. Introduction. Emission Scenarios. Interactions Affecting Availability and Exposure to Chemical Mixtures. Environmental Fate Modeling. Exposure Scenarios and Monitoring. Summary and Conclusions. Toxicokinetics and Toxicodynamics. Introduction. Fundamental Principles. Toxicokinetics. Toxicodynamics. Toxicity from Combined Exposure to Chemicals. Introduction. Approaches to Mixture Effect Assessment. Mechanisms and mixture effects. The predictability of mixture effects – a brief review. Defining Determinants of Synergistic Mixture Effects. Mixture Effects at Low Levels. What About the Real World? Test Design, Mixture Characterization and Data Evaluation. Introduction. Testing Aims. Concentration Addition and Independent Action: Empirical Modeling. Technical Issues and Pitfalls. Component-Based Approaches, Test Designs and Methods. Whole Mixture Approaches, Test Designs and Methods. Case Studies. Risk Assessment. Introduction. Typical Features of Mixture Assessment. State of the Art in Mixture Assessment. Conceptual Framework for Human and Ecological Risk Assessment of Mixtures. Issues in Human and Ecological Risk Assessment of Mixtures. Appendix. Glossary.

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Book SynopsisThe International Association of Forensic Nurses has developed The Core Curriculum for Forensic Nursing, First Edition, for nurses who aim to work in, and gain certification in the field. The book is well illustrated with full cover photographs and images vital to a solid understanding of forensic nursing. Written by the world's experts in forensic nursing, the Core Curriculum for Forensic Nursing offers a practical organization and writing style to help with subject mastery and retention.

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Book SynopsisThis book bridges the gap between advances in basic biology and chemistry and technological applications in the field of toxicity assessments. It describes areas of progress in the laboratory and clinic and discusses aspects of cellular organelles. It also covers the basic principles and applications of modern toxicological tools such as transcriptomic, proteomic, and metabolomic approaches. The recent developments on molecular modeling and systems biology are described with an eye on the future establishment of virtual cell technology. Finally the clinical implications for the understanding of acute and chronic renal toxicity are studied.Table of ContentsCellular Organelle-based Renal Toxicity. Transcriptomic Approaches. Proteomic Approaches. Metabolomic Approaches. Molecular Modeling – Molecular Design. Systems Biological Approaches. Virtual Cell. Clinical Implication of Renal Toxicology. Molecular Pathology of Renal Fibrosis. Classification of Nephrotoxicants.

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Book SynopsisDrawing on fieldwork in a Chinese toxicology lab that studies the influence of toxins on male reproductive and developmental health, Janelle Lamoreaux investigates how epigenetic research conceptualizes and configures environments.Table of ContentsPreface ix Acknowledgments xv Introduction 1 1. The National Environment 21 2. The Hormonal Environment 35 3. The Dietary Environment 52 4. The Maternal Environment 64 5. The Laboratory Environment 77 Coda 92 Epilogue 97 Notes 103 References 109 Index 129

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Book SynopsisDrawing on fieldwork in a Chinese toxicology lab that studies the influence of toxins on male reproductive and developmental health, Janelle Lamoreaux investigates how epigenetic research conceptualizes and configures environments.Table of ContentsPreface ix Acknowledgments xv Introduction 1 1. The National Environment 21 2. The Hormonal Environment 35 3. The Dietary Environment 52 4. The Maternal Environment 64 5. The Laboratory Environment 77 Coda 92 Epilogue 97 Notes 103 References 109 Index 129

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Book SynopsisThe Environmental and Genetic Causes of Autism delves deep into the full body of past and current research to reveal how genetic predispositions and environmental factors can combine to produce the conditions autism and autism spectrum disorders (ASD).To make this groundbreaking volume, Dr. James Lyons-Weiler combed through the past fifty years of published research on autism, exploring subjects such as genetic variation, mechanisms of neurotoxicity of metals and pesticides, and the central and combined roles of each in causing autism.Lyons-Weiler provides a major overview of all aspects of the condition of autism, reviews changes in diagnoses and treatments, and explains how genetic information can be used to tailor effective treatments, and sometimes reversals, of the symptoms. He also presents practical forward-looking suggestions on how to design future studies to facilitate the discovery of biomarkers for autism risk and how to classify the full range of autism spectrum disorders.Autism is considered one of the most mystifying conditions of our day, and alarmed scientists, doctors, politicians, and parents are desperately trying to understand why the condition is escalating. According to the CDC, rates in the United States have risen from an estimated one in two thousand children in 1980, to one in sixty-eight in 2012, and a new National Health Interview Survey shows a rate of one in forty-five. By the time you read this book, that number may have changed yet again.While most autism researchers focus on either environmental or genetic causes of autism, Lyons-Weiler’s opus demonstrates that to fully understand the condition and to finally put its rate on the decrease, it is essential to pay attention to the science showing how the two classes of factors interact.Trade Review“With nearly one in fifty US children being diagnosed with autism, The Environmental and Genetic Causes of Autism could not come soon enough. The information in this book needs to be read by all medical students, physicians, and parents. I highly recommend this book.”—Dr. David Brownstein, MD, medical director, Center for Holistic Medicine“Dr. Lyons-Weiler is an inspired American scientist. . . . I can say without reservation that this learned person has the ethics of a true teacher, the type idealized from the roots of Western Civilization. He analyzes scientific data for the sake of improving the human condition without monetary influence. . . . His work is encyclopedic.”—Dr. Edward “Ted” Fogarty, MD, chair, Department of Radiology, University of North Dakota School of Medicine and Health Sciences“With over one million new cases per year, a current incidence of one in 45–68 children, and a projected incidence of one in two children within two decades, autism is more than an epidemic—it is a national crisis. At this rate, our entire nation will either be autistic or caring for someone who is. While nearly all efforts and public pronouncements are about management and care, very few are exploring cause. We hear from the medical community that autism is a tragic but inevitable outcome of genetic roulette. Dr. Lyons-Weiler, an impeccably credentialed biologist . . . clearly explains the environmental causes of this terrible spectrum of disorders. In so doing, he provides much-needed hope for its prevention and cure. If you are a parent, health professional, or scientist, this is an essential book to read.”—Michael Gaeta, DAc, MS, CDN, clinician and educator“This book is a Bible for anyone who wants to understand the deep science behind the autism epidemic in America. Dr. Lyons-Weiler shows us convincingly that autism is not a mysterious disease with no known cause and no known treatment: it is the expected outcome when you expose a child with a certain genetic makeup to multiple neurotoxins simultaneously.”—Dr. Stephanie Seneff, senior research scientist at the Massachusetts Institute of Technology (MIT)“[Dr. James Lyons-Weiler’s new book is a call to action] for the pediatric community to ‘awaken from its dogmatic slumber.’ . . . Until our understanding of [autism spectrum disorders] (and their environmental, genetic, and immunological underpinnings) is secure, we must all be willing to evolve as practitioners and scientists and, thusly, light our own candles in the darkness, lest we fall into an abyss.”—Dr. Anthony Kovatch, MD, pediatrician, Pediatric Alliance“Lyons-Weiler has done us all an immense service by putting together this well-documented and highly informative overview of autism. Those who are really seeking answers and a way forward will welcome this book. Those whose interests are threatened will not. Indeed, Lyons-Weiler will be able to measure just how much he has stung big pharma by the number of pharma-paid negative reviews in the media, and by the troll attacks, and the denunciations by the CDC. He should wear all these as a badge of [honor] for ultimately the truth will come out. This book will help the truth emerge.”—Christopher A. Shaw, PhD, author of Neural Dynamics of Neurological Disease“With nearly one in fifty US children being diagnosed with autism, The Environmental and Genetic Causes of Autism could not come soon enough. The information in this book needs to be read by all medical students, physicians, and parents. I highly recommend this book.”—Dr. David Brownstein, MD, medical director, Center for Holistic Medicine“Dr. Lyons-Weiler is an inspired American scientist. . . . I can say without reservation that this learned person has the ethics of a true teacher, the type idealized from the roots of Western Civilization. He analyzes scientific data for the sake of improving the human condition without monetary influence. . . . His work is encyclopedic.”—Dr. Edward “Ted” Fogarty, MD, chair, Department of Radiology, University of North Dakota School of Medicine and Health Sciences“With over one million new cases per year, a current incidence of one in 45–68 children, and a projected incidence of one in two children within two decades, autism is more than an epidemic—it is a national crisis. At this rate, our entire nation will either be autistic or caring for someone who is. While nearly all efforts and public pronouncements are about management and care, very few are exploring cause. We hear from the medical community that autism is a tragic but inevitable outcome of genetic roulette. Dr. Lyons-Weiler, an impeccably credentialed biologist . . . clearly explains the environmental causes of this terrible spectrum of disorders. In so doing, he provides much-needed hope for its prevention and cure. If you are a parent, health professional, or scientist, this is an essential book to read.”—Michael Gaeta, DAc, MS, CDN, clinician and educator“This book is a Bible for anyone who wants to understand the deep science behind the autism epidemic in America. Dr. Lyons-Weiler shows us convincingly that autism is not a mysterious disease with no known cause and no known treatment: it is the expected outcome when you expose a child with a certain genetic makeup to multiple neurotoxins simultaneously.”—Dr. Stephanie Seneff, senior research scientist at the Massachusetts Institute of Technology (MIT)“[Dr. James Lyons-Weiler’s new book is a call to action] for the pediatric community to ‘awaken from its dogmatic slumber.’ . . . Until our understanding of [autism spectrum disorders] (and their environmental, genetic, and immunological underpinnings) is secure, we must all be willing to evolve as practitioners and scientists and, thusly, light our own candles in the darkness, lest we fall into an abyss.”—Dr. Anthony Kovatch, MD, pediatrician, Pediatric Alliance“Lyons-Weiler has done us all an immense service by putting together this well-documented and highly informative overview of autism. Those who are really seeking answers and a way forward will welcome this book. Those whose interests are threatened will not. Indeed, Lyons-Weiler will be able to measure just how much he has stung big pharma by the number of pharma-paid negative reviews in the media, and by the troll attacks, and the denunciations by the CDC. He should wear all these as a badge of [honor] for ultimately the truth will come out. This book will help the truth emerge.”—Christopher A. Shaw, PhD, author of Neural Dynamics of Neurological Disease

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Book SynopsisThe must-have health bible that explains exactly how to stay in radiant, optimal health all year round.Are you confused about what supplements you should be taking? Do you want to know how you can reverse the effects of pollution on your body? Would you like to eat seasonally?Drawing on Dr Jenny Goodman's 20+ years' experience as a medical doctor, lecturer and qualified nutritionist, Staying Alive in Toxic Times sets out exactly what to eat in order to live our healthiest lives, and how to adapt our lifestyle according to the season we are in.Dr Jenny Goodman lays out how to safely and effectively supplement your diet with vitamins and minerals, explains what really works in terms of detoxing your body, and sorts through the confusing myriad of diets and healthy eating fads, using her expertise to myth-bust. Staying Alive in Toxic Times also reveals how to avoid seasonal health hazards, such as indoor pollution, hay fever and SAD.With so many people feeling tired, ill and run-down, this timely guide is what everyone needs to read in order to live vibrant, happy and long lives.

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Book SynopsisIn the first chapter, Yin-Hui Leong, Nurul Izzah Ahmad, and Rahmat Awang, provide an overview of literature on recent progress in aflatoxins research including health effects and human exposure through alimentary or dermal pathways. Next, Mufida Aljicevic MD, PhD, and Damir Ljuboja present a study with the goal to decide whether foods of plant origin have quantifiable concentrations of aflatoxin B1. Additionally, they aimed to examine whether the urine of healthy participants contains measurable aflatoxin B1 in the second chapter. The third chapter by Hsin-Bai Yin, Anup Kollanoor-Johny, and Kumar Venkitanarayanan pinpoints the potential of various natural approaches and their applications in controlling AF contamination at pre- and post-harvest stages of agriculture. During the fourth and final chapter, Edlayne Gonçalez, PhD, Janaina Lara da Silva, MD, Tatiana Emy de Freitas, MD, Christiane Ceriani Aparecido, PhD, Daiane Hansen, PhD, and Joana Darc Felicio, PhD examine the presence of toxigenic species in samples for lactating goats, determining whether this indicates a potential risk of contamination of dairy products.

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