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Continuing Education Course Descriptions

CE Floor Map

Scientific Program Overview (dates and times)

The Continuing Education (CE) Program offers a wide range of courses that cover established knowledge in toxicology, as well as new developments in toxicology and related disciplines. Courses can be applied toward certifying and licensing board requirements and may also be used for recertification with the American Board of Toxicology (ABT). Both Basic and Advanced Course topics are offered. The Basic Course is intended to provide a broad overview of an area or to assist individuals in learning new techniques or approaches. The Advanced Course is intended to be of interest to individuals with previous knowledge of the subject or already working in the field.

All courses will be held on Sunday, March 13, 2016, at the New Orleans Ernest N. Morial Convention Center. Please check the signage in the registration area and at the CE Booth for room assignments. Note: Your course materials will be available in the room immediately prior to the course (they will not be available at the registration area). If you have your course ticket, go directly to the assigned course room. If you have not received your course ticket or have not registered, please go to the registration area on Saturday afternoon/evening or on Sunday morning. If you have misplaced your ticket, please go to a CE Booth at the convention center on Sunday. The booths will be open from 6:30 am–5:30 pm.

Please Note: Each CE Course is offered in one of three time blocks:

Sunrise (7:00 AM–7:45 AM)
AM (8:15 AM–12:00 Noon)
PM (1:15 PM–5:00 PM)

Registration for the Annual Meeting plus a ticket for the CE Course are required.

Live CE Webcasts

SOT is excited to announce two CE courses presented as live webcasts, at the SOT Annual Meeting on Sunday, March 13.

If you are unable to travel to the SOT Annual Meeting, the following webcasts are a great opportunity to virtually attend CE courses on popular and important, topics. Registration for the SOT Annual Meeting is not required to attend these webcasts.

Morning Webcast:
AM03: Adverse Outcome Pathway (AOP) Development and Evaluation
(Webcast begins at 8:15 am US Central Time)

Afternoon Webcast:
PM11: Human Health Risk Assessment: A Case Study Application of Principles
(Webcast begins at 1:15 pm US Central Time)

Each CE course is 195 minutes (3.25 hours) long, excluding a 30-minute break, and webcast attendees will be provided with an electronic copy of the slides.

Audio Broadcast Instructions

Webcast Registration

SOT Member: Postdoctoral (SOT Member or Nonmember):
$220 per webcast $160 per webcast
   
SOT Retired/Emeritus Member: Graduate/Undergraduate Student:
$110 per webcast $115 per webcast
   
Nonmember:  
$370 per webcast  

CE Courses and Books

SR01 Basic Principles and Practices for Applying Epigenetics in Mechanistic Toxicology Basic Book
AM02 Advancing the Detection, Imaging, and Pitfalls in Monitoring Oxidative Stress in Health and Disease Advanced Book
AM03 Adverse Outcome Pathway (AOP) Development and Evaluation Basic Book
AM04 Contribution of Mitochondria to Drug-Induced Organ Toxicities Basic Book
AM05 Discovery and Validation of miRNA Biomarkers Bridging Preclinical and Clinical Toxicity: Lessons Learned from Hepatotoxicity Advanced Book
AM06 Embryology and Developmental Toxicity Testing Basic Book
AM07 Next-Generation Sequencing in Toxicogenomics Advanced Book
PM08 Approaches to Investigate and Assess Risks Associated with Drug-Induced Liver Injury (DILI) Advanced Book
PM09 Exploring Chemical Space in the New Toxicity Testing Paradigm: From Data Curation to Computational Simulations Basic Book
PM10 Genetics and Population Variability in Chemical Toxicity: The What, the How, and So What? Basic Book
PM11 Human Health Risk Assessment: A Case Study Application of Principles Advanced Book
PM12 Unique Approaches to Safety Assessment of Gene, Cell, and Nucleic Acid-Based Therapies Basic Book
PM13 Zebrafish As a Tool in Toxicology and Drug Discovery Screening Basic Book


Basic Principles and Practices for Applying Epigenetics in Mechanistic Toxicology

Sunrise Course (SR01) | CE Basic | 7:00 AM–7:45 AM

Theme:

Molecular Toxicology: Mechanistic Insights and Hazard Assessment

Chairperson(s): Shaun D. McCullough, US EPA, Chapel Hill, NC; and Ronald N. Hines, US EPA, Research Triangle Park, NC.

Endorser(s): In Vitro and Alternative Methods Specialty Section
Mechanisms Specialty Section
Molecular and Systems Biology Specialty Section

The genetic material of every organism exists within the context of regulatory networks that govern gene expression collectively called the epigenome. These epigenetic regulators, chromatin modifications, DNA methylation, and noncoding RNAs, act in concert to shape the way that cells, tissues, and organisms respond to their environment and toxicant exposure. Incorporating epigenetics into both in vitro and in vivo toxicological studies allows for a better understanding of the molecular events underlying the adverse health effects of toxicant exposure, improves our ability to identify vulnerable populations, and facilitates the identification of modifiable risk factors. The goal of this course is to provide toxicologists from a broad range of backgrounds with an overview of the epigenome and general considerations for designing experiments to examine the role of the epigenetics in their toxicological studies. This course will mention noncoding RNAs but focus primarily on participants gaining a fundamental understanding of the role of chromatin and DNA methylation in the regulation of gene expression. The principles and applications of basic experimental techniques, such as chromatin immunoprecipitation (ChIP) and DNA methylation analysis for evaluating epigenetic changes in toxicological studies, will also be discussed. This course will be of broad interest to investigators that are interested in integrating epigenetic approaches into their current or future toxicological studies.

Part 1: Principles of Epigenetics: An Introduction to the Mechanisms of Gene Regulation. Ronald N. Hines, US EPA, Research Triangle Park, NC.

Part 2: Experimental Techniques for Incorporating Chromatin and DNA Methylation Analysis into Mechanistic Toxicology. Shaun D. McCullough, US EPA, Chapel Hill, NC.

View Speaker Biographies

Advancing the Detection, Imaging, and Pitfalls in Monitoring Oxidative Stress in Health and Disease

Morning Course (AM02) | CE Advanced | 8:15 AM–12:00 Noon

Theme:

Health and Environmental Impacts of Manmade and Naturally Released Toxicants
Molecular Toxicology: Mechanistic Insights and Hazard Assessment

Chairperson(s): Maria B. Kadiiska, NIEHS/NIH, Research Triangle Park, NC; and Ronald P. Mason, NIEHS/NIH, Research Triangle Park, NC.

Endorser(s): Immunotoxicology Specialty Section
Mechanisms Specialty Section
Molecular and Systems Biology Specialty Section

Oxidative stress is recognized to play a role in the etiology of numerous diseases as well as in environmental exposures. Exploration of oxidative stress mechanisms is a field of ever-increasing attention, both in science and in commerce. The field is maturing and there is a great effort to study and understand biomarkers at both a chemical and enzymatic molecular-mechanism level. Since increases in oxidative stress are measured using biomarkers, the goal of this course is to convey the most up-to-date knowledge on biomarkers; present novel approaches and advanced methods that can be employed in vivo to measure, predict, and even prevent oxidative stress; and to discuss the methods and pitfalls for distinguishing oxidative stress from systemic toxicities, immunotoxicities and inflammation. Technologically advanced methods, including molecular magnetic resonance imaging, HPLC-MS, spectro(fluoro)metric assays, and immunoassays are potentially rich areas for innovation in systemic oxidative stress research. Consequently, the course outlines the most up-to-date developments in newly emerging methodologies that will enhance the understanding of oxidative stress mechanisms by measuring, detecting, and even imaging it in vivo. The panel of experts evaluates the advantages, applicability, and pitfalls of each method, discusses the most recent data on in vivo and in situ imaging of molecular free radical metabolites with emphasis on both the current state of technology, different areas of toxicology including immunotoxicology, crosstalks with the innate immune mediators, and likely future developments. Because the detection and understanding of oxidative stress could lead to better intervention strategies, output from the course will help identify the most useful applications for a given technique to detect oxidative stress in vivo. Attendees will leave the course with enhanced understanding that measurement of oxidative stress in vivo requires innovative, unconventional methodologies in combination with advanced technologies and often a multidisciplinary approach.

We Detect Free Radicals Not Because It Is Easy but Because It Is Hard. Ronald P. Mason, NIH/NIEHS, Research Triangle Park, NC.

In Vivo, In Situ Imaging of Free Radical Adducts in Animal Disease Models. Rheal A. Towner, Oklahoma Medical Research Foundation, Oklahoma City, OK.

Oxidative Damage Detection in Macromolecules: Free Radical-Innate Immune Crosstalk in Liver Disease. Saurabh Chatterjee, University of South Carolina, Columbia, SC.

Xenobiotic Free Radical Detection in Biological Systems Using HPLC: A Technique for All. Arno G. Siraki, University of Alberta, Edmonton, AB, Canada.

Oxidative Modification of Proteins: Detection and Role in Autoimmunity. M. F. Khan, University of Texas Medical Branch, Galveston, TX.

Validation of Best Detection Methods for Oxidative Stress Biomarkers in Biological Fluids. Maria B. Kadiiska, NIEHS/NIH, Research Triangle Park, NC.

Reinterpreting the Best Biomarker of Oxidative Stress: The 8-iso-PGF2α/PGF2α Ratio Distinguishes Chemical from Enzymatic Lipid Peroxidation. Thomas J. van ‘t Erve, NIEHS/NIH, Research Triangle Park, NC.

View Speaker Biographies

Adverse Outcome Pathway (AOP) Development and Evaluation

Morning Course (AM03) | CE Basic | 8:15 AM–12:00 Noon

Webcast Registration

Theme:

Molecular Toxicology: Mechanistic Insights and Hazard Assessment
Recent Advances in Safety Assessment

Chairperson(s): Stephen Edwards, US EPA, Research Triangle Park, NC; and Andrea Terron, EFSA (European Food Safety Agency), Parma, Italy.

Endorser(s): In Vitro and Alternative Methods Specialty Section
Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section

The Adverse Outcome Pathway provides a construct for assembling mechanistic information at different levels of biological organization in a form designed to support regulatory decision making. In particular, it frames the link between molecular and cellular events that can be measured in high-throughput toxicity testing and the organism or population-level events that are commonly relevant in defining risk. Recognizing the importance of this emerging framework, the Organisation for Economic Co-operation and Development (OECD) launched a program to support the development, documentation, and consideration of AOPs by the international community in 2012. In 2014, a handbook was developed to guide users in the documentation and evaluation of AOPs and their entry into an official knowledgebase. The handbook draws on longstanding experience in consideration of mechanistic data (e.g., mode-of-action analysis) to inform risk assessment. To further assist users, a training program was developed by members of the OECD Extended Advisory Group to teach users the basic principles of AOP development and the best practices as outlined in the OECD AOP handbook. Training sessions began in early 2015, and this course will provide training for interested SOT scientists. Following this course, all participants will be familiar with the core principles of AOP development and assessment and the OECD efforts to support this effort. They will also know how the OECD guidance for AOP development has been implemented in the Wiki module of the AOP Knowledgebase. They will learn how to assemble and evaluate the evidence supporting the AOPs using established best practices from Mode of Action analysis. To reinforce the concepts, they will participate in a live demo where an AOP is developed from a training case study with their assistance and entered into the AOP-Wiki. The value of AOP development will be demonstrated via examples from the European Food Safety Agency and by considering integrated approaches to testing and assessment using the skin sensitization AOP, which was endorsed by the OECD in 2012.

Introduction. Stephen Edwards, US EPA, Research Triangle Park, NC.

Introduction to Adverse Outcome Pathways and International Activities Guiding AOP Development. Kristie Sullivan, Physicians Committee for Responsible Medicine, Washington, DC.

Principles and Best Practices for AOP Development. Dan Villeneuve, US EPA, Duluth, MN.

Weight of Evidence/Confidence Analysis in the Development and Documentation of AOPs. Bette Meek, University of Ottawa, Ottawa, ON, Canada.

Assembling AOP Information in the International AOP Knowledgebase. Carole Yauk, Health Canada, Ottawa, ON, Canada.

Applying AOPs to the Development of Integrated Approaches on Testing and Assessment (IATA). Gavin Maxwell, Unilever, Sharnbrook, United Kingdom.

Implementing the AOP Framework at EFSA. Andrea Terron, EFSA (European Food Safety Agency), Parma, Italy.

View Speaker Biographies

Contribution of Mitochondria to Drug-Induced Organ Toxicities

Morning Course (AM04) | CE Basic | 8:15 AM–12:00 Noon

Theme:

Molecular Toxicology: Mechanistic Insights and Hazard Assessment

Chairperson(s): Varsha G. Desai, National Center for Toxicological Research, US FDA, Jefferson, AR; and Yvonne Will, Pfizer R&D, Groton, CT.

Endorser(s): Drug Discovery Toxicology Specialty Section
Mechanisms Specialty Section
Regulatory and Safety Evaluation Specialty Section

Mitochondria generate more than 90% of energy essential for the cell. Impaired mitochondrial function, therefore, can affect virtually every tissue and organ in the living organism. Tissues with the highest energy needs, such as the heart, brain, liver, kidney, and skeletal muscle are particularly vulnerable to the defects in mitochondrial bioenergetics that can manifest into tissue-specific pathologies. A distinctive feature of mitochondria is that, besides the nucleus, these organelles contain their own genome (mitochondrial DNA). However, coordination between nuclear and mitochondrial genomes is crucial in regulating mitochondrial function. It is also becoming increasingly evident that mitochondria are a prime target of many therapeutic drugs and environmental toxins that can alter their function through different mechanisms, leading to cellular injury, resulting in organ toxicity, and, in the worst case, death. Additionally, mitochondria serve as an important player in the execution of apoptosis (programmed cell death), a process that serves as a major defense mechanism to remove unwanted and potentially dangerous cells. Collectively, these functions highlight a critical role of mitochondria in the life and death of the cell.

This course will provide an in-depth overview of mitochondrial biology and different mechanisms in which drugs can affect mitochondrial function. Particular emphasis is given to mitochondrial toxicity causing heart, liver, and kidney injury. In addition, we will describe novel high-throughput in vitro screening technologies in isolated mitochondria and cell models to elucidate potential mitochondrial toxicity. Several other methodologies will also be discussed that can reveal the mitochondrial target(s) of drug toxicity in different organs. The utility and limitations of these approaches will also be described. This course concludes by providing the participants with in-depth knowledge of basic mitochondrial function and important insights into how subtle changes in mitochondrial activity can progress to overt pathology in tissues and help identify potential biomarkers of early stages of mitochondrial toxicity. Moreover, this course will present how preclinical data on mitochondrial toxicity can help in understanding toxicities in humans.

Contribution of Mitochondria to Drug-Induced Organ Toxicities: An Overview. Varsha G. Desai, National Center for Toxicological Research, US FDA, Jefferson, AR.

Mitochondrial Function and Dysfunction in Disease and Drug-Induced Toxicity. James A. Dykens, EyeCyte Therapeutics, San Diego, CA.

Mitochondrial Toxicity: A Decade of Technology Development, a Decade of Learnings. Yvonne Will, Pfizer R&D, Groton, CT.

Mitochondrial Dysfunction in Acute Kidney Injury. Rick G. Schnellmann, Medical University of South Carolina, Charleston, SC.

Doxorubicin-Induced Mitochondrial Cardiomyopathy. Kendall B. Wallace, University of Minnesota Medical School Duluth, Duluth, MN.

View Speaker Biographies

Discovery and Validation of miRNA Biomarkers Bridging Preclinical and Clinical Toxicity: Lessons Learned from Hepatotoxicity

Morning Course (AM05) | CE Advanced | 8:15 AM–12:00 Noon

Theme:

Molecular Toxicology: Mechanistic Insights and Hazard Assessment
Recent Advances in Safety Assessment

Chairperson(s): Alison Harrill, University of Arkansas for Medical Sciences, Little Rock, AR; and Brian Chorley, US EPA, Research Triangle Park, NC.

Endorser(s): Clinical and Translational Toxicology Specialty Section
Molecular and Systems Biology Specialty Section
Regulatory and Safety Evaluation Specialty Section

Micro(mi)RNAs are small, noncoding RNAs that play an important role in the regulation of biological processes in cells. Owing to recent findings that: (1) miRNA sequences are highly conserved across species, (2) certain miRNAs exhibit tissue-specific expression, and (3) miRNA are highly stable in biological fluids, significant effort has been spent to identify miRNA biomarkers for a variety of toxicological pathologies. However, in addition to basic research and discovery efforts, significant effort must be spent on qualification of biomarkers with regards to specificity for the organ of interest and for the ability of a biomarker to detect comparable injury across species. A major effort is to use miRNA profiles as a “liquid biopsy” that can inform underlying tissue pathology. Thus, the goal of this course is to provide investigators with an overview of the techniques and strategies necessary to progress a biomarker from the discovery stage to practical use in animal and human xenobiotic safety assessment. Well studied biomarkers, such as miR-122, will be used as case studies to demonstrate the path from nonclinical discovery to a validated clinical biomarker.

Introduction. Brian Chorley, US EPA, Research Triangle Park, NC.

Utilizing miRNAs to Assess Organ Specificity: Using miR-122 to Distinguish between Liver and Muscle Injury. Warren Glaab, Merck Research Laboratories, West Point, PA.

Emerging Biomarkers of Liver Injury: From miR-122 to Liquid Biopsies in the Clinic. Jiri Aubrecht, Pfizer Inc., Groton, CT.

Clinical Qualification of a miRNA Biomarker in a Hospital Setting: miR-122 in Acute Liver Failure Patients. Daniel Antoine, University of Liverpool, Liverpool, United Kingdom.

Exosomes and Their miRNA Cargos: Potential Biomarkers for Liver Diseases. Banishree Saha, University of Massachusetts Medical School, Worcester, MA.

View Speaker Biographies

Embryology and Developmental Toxicity Testing

Morning Course (AM06) | CE Basic | 8:15 AM–12:00 Noon

Theme:

Developmental Toxicity: Mechanisms and Evaluation

Chairperson(s): John M. DeSesso, Exponent, Alexandria, VA; and Anthony R. Scialli, Scialli Consulting LLC, Arlington, VA.

Endorser(s): Drug Discovery Toxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section
Reproductive and Developmental Toxicology Specialty Section

Mammalian embryo-fetal development comprises a complex and carefully orchestrated set of activities that can be perturbed by maternal and environmental factors. Perturbations of developing offspring can result in no discernible effect, reduced fetal weights at term, increased prevalence of anatomical variations, congenital defects, and/or the demise of the offspring. This course will focus on preclinical species and will begin by providing an overview of mammalian development, including important gestational milestones, comparative interspecies timelines, and definitions of critical periods in development. Next we will discuss how this information has factored into the design of traditional preclinical studies. The presentation will conclude with a brief introduction to normal variability in some organ systems. This variability is the source of considerable controversy when interpreting traditional developmental toxicity safety tests. Succeeding presentations will discuss two organ systems that are the center of debate among scientists charged with extrapolating results found in safety assessments to potential human risk. The normal embryological development of the first organ system to function, the cardiovascular system, will be described with consideration of normal anatomical variations and nonadverse structural changes. The second organ system to be described is the skeletal system. Particular attention will be paid to its state of maturity at term in various species, the potential influence of maternal toxicity on skeletal maturation, and postnatal development of the skeleton throughout the lactation period. The final presentation will address the development of new testing methods that might be used to prioritize substances for testing or even to replace whole animal testing for developmental toxicity. The presentation will describe basic methods for whole embryo culture, embryonic stem cell test, and a Zebrafish assay, along with various proposed improvements in each. It will finish with some thoughts about integrating the results from multiple assays, and a survey of the regulatory landscape for these emerging methods. Information from the preceding presentations will provide the audience with an understanding of how the biological basis of prenatal developmental toxicity testing and the results of such tests should impact risk assessment and ultimately, the rationale for the design and use of drugs and chemicals that minimizes environmental impact and ensures human health.

Introduction. Anthony R. Scialli, Scialli Consulting LLC, Arlington, VA.

Comparative Embryological Development, Gestational Landmarks, and Their Influence on Test Designs. John M. DeSesso, Exponent, Alexandria, VA.

Details of Skeletal Development and How this Matters When Interpreting Results. John M. Rogers, US EPA, Research Triangle Park, NC.

Normal and Abnormal Development of Heart and Great Vessels: Understanding the Problem and Interpreting the Findings. H. Scott Baldwin, Vanderbilt University School of Medicine, Nashville, TN.

Principles of Validation. Anthony R. Scialli, Scialli Consulting LLC, Arlington, VA.

Developmental Toxicity Testing without Animals: The Big Slippery Mountain. Robert E. Chapin, Pfizer Inc., Groton, CT.

View Speaker Biographies

Next-Generation Sequencing in Toxicogenomics

Morning Course (AM07) | CE Advanced | 8:15 AM–12:00 Noon

Theme:

Molecular Toxicology: Mechanistic Insights and Hazard Assessment
Recent Advances in Safety Assessment

Chairperson(s): Weida Tong, National Center for Toxicological Research, US FDA, Jefferson, Jefferson, AR; and Jos Kleinjans, Maastricht University, Maastricht, The Netherlands.

Endorser(s): Biotechnology Specialty Section
Molecular and Systems Biology Specialty Section
Regulatory and Safety Evaluation Specialty Section

The purpose of toxicogenomics is to study the effects of chemical, biological and physical agents in biological systems at the molecular level and thereby elucidating the molecular mechanisms underlying the expression of toxicity. Recent technology developments in next-generation sequencing (NGS) have opened completely new possibilities for the deep characterization of molecular mechanisms of toxicity at various levels of cellular regulation providing information on substance-induced genomic variations, and on transcriptomic and epigenomic changes. We argue that these developments will strengthen our understanding of toxic mechanisms-of-action and ultimately lead to a systems-wide toxicity analysis thus enabling the development of safer drugs, industrial chemicals, consumer products and improved regulation. This course will discuss various NGS application for an enhanced understanding of underlying mechanisms of toxicity and potential utility in regulatory setting. The discussed topics include but are not limited to  applicability of respective NGS platforms for analyzing mutational spectra, gene expression modifications, and epigenomic alterations induced by toxicants in a range of biological systems, compare their performance with standardized qPCR/microarray techniques, present use cases and highlight future challenges.

Next-Generation Sequencing: Next Wave of Opportunities, Challenges, and Anxiety. Jos Kleinjans, Maastricht University, Maastricht, The Netherlands.

Next-Generation Sequencing: Technology and Bioinformatics. Wenming Xiao, NCTR/US FDA, Jefferson, AR.

DNA-Seq: Toxicant-Induced Mutation Analysis. Florian Caiment, Maastricht University, Maastricht, The Netherlands.

Epigenomics: A New Opportunity in Toxicogenomics. Ralf Herwig, Max-Planck-Institute for Molecular Genetics, Berlin, Germany.

RNA-Seq: Mechanistic and Predictive Toxicology. Weida Tong, NCTR/ US FDA, Jefferson, AR.

RNA-Seq As a Way to Access Transcriptomic Information in Archival Tissues. Susan Hester, National Health and Environmental Effects Research Laboratory, US EPA, Research Triangle Park, NC.

View Speaker Biographies

Approaches to Investigate and Assess Risks Associated with Drug-Induced Liver Injury (DILI)

Afternoon Course (PM08) | CE Advanced | 1:15 PM–5:00 PM

Theme:

Health and Environmental Impacts of Manmade and Naturally Released Toxicants
Recent Advances in Safety Assessment

Chairperson(s): Monicah Otieno, Janssen Pharmaceuticals, Spring House, PA; and Paul Watkins, The UNC Institute for Drug Safety Sciences, Research Triangle Park, NC.

Endorser(s): Drug Discovery Toxicology Specialty Section
Mechanisms Specialty Section

Drug-induced liver injury (DILI) in the clinic is a major cause for drug attrition during development. DILI can be characterized as intrinsic or idiosyncratic. Properties of intrinsic DILI include a dose-response in presentation of injury that may be predicted by animal studies enabling application of safety thresholds and inclusion of liver injury biomarkers for clinical risk assessment. Idiosyncratic DILI (iDILI) is unpredictable and usually occurs following drug exposure in large populations e.g., during Phase III clinical trials or postmarketing. Given that this is a major cause for costly drug withdrawals, there has been significant effort in identifying properties that predispose some compounds to a high risk for iDILI. Both immune and nonimmune mechanisms are hypothesized to contribute to iDILI. This course will discuss DILI hazards that can be used to identify a compound’s potential to cause DILI. A general overview and introduction of DILI will be provided, followed by a clinician’s perspective on DILI focusing on presentation of DILI using examples of key withdrawals. Subsequent presentations will focus on established and emerging science on DILI hazard risks; this will include a presentation on the role of reactive metabolites (RM) and covalent binding in increasing risk for immune or nonimmune mediated DILI. A basic overview on mechanisms of RM formation, methods for detection, and mechanistic studies correlating covalent binding with DILI will be discussed. The relationship between dose, covalent binding thresholds, and DILI also will be addressed. This will be followed by a presentation on hepatic transporters and the role they play in DILI, either through delayed hepatotoxicity resulting from liver accumulation of parent/metabolites and/or inhibition of efflux of toxic bile acids. Mitochondrial toxicity also has been identified as a key hazard for DILI compounds; an overview of mitochondrial toxicity, its role in iDILI, and how interplay with hepatic transport inhibition may increase risk for DILI will be presented. The final presentation will introduce the concept of computational, systems pharmacology approaches integrating all of the mechanisms discussed by the previous speakers along with drug exposure, to put data from various sources into context.

Overview of DILI and Associated Risk Hazards. Monicah Otieno, Janssen Pharmaceuticals, Spring House, PA.

Clinical Perspective Including Risk Identification and Management. Paul Watkins, The UNC Institute for Drug Safety Sciences, Research Triangle Park, NC.

Role of Reactive Metabolites in Immune DILI. Jack Uetrecht, University of Toronto, Toronto, ON, Canada.

Role of Hepatic Transporters in DILI. Kim Brouwer, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Role of Mitochondrial Toxicity in DILI. Yvonne Will, Pfizer Inc., Groton, CT.

Computational Approaches to Integrate DILI Hazards and Predict DILI Potential. Brett Howell, The UNC Institute for Drug Safety Sciences, Research Triangle Park, NC.

View Speaker Biographies

Exploring Chemical Space in the New Toxicity Testing Paradigm: From Data Curation to Computational Simulations

Afternoon Course (PM09) | CE Basic | 1:15 PM–5:00 PM

Theme:

Recent Advances in Safety Assessment

Chairperson(s): Cecilia Tan, US EPA, Research Triangle Park, NC; and Daniel Chang, Chemical Computing Group, Inc., Montreal, QC, Canada.

Endorser(s): Biological Modeling Specialty Section
In Vitro and Alternative Methods Specialty Section
Molecular and Systems Biology Specialty Section

In an effort to determine mechanisms-of-action of toxicants known to induce adverse human health outcomes, traditional toxicity testing focuses on lengthy and costly in vivo animal studies on a chemical-by-chemical basis. In such a paradigm, there is no need to consider chemical space. The accelerated rate of production and distribution of new chemicals in the commercial market precludes such approaches today, and rather, high-throughput in vitro and in silico analyses are encouraged in order to rapidly screen hundreds to thousands of chemicals. The recent advancements in these high-throughput screening approaches, along with computational chemistry and cheminformatics, have provided toxicologists the foundation and opportunity to identify molecular fingerprints that impact each aspect of the source-to-outcome continuum for large amounts of chemicals. Inherent chemical structures and properties are key determinants of exposure potential (based on e.g., function and use), environmental persistence and transformation in environmental and biological systems, and toxicity potential. Computational approaches expand the chemical space through identification of chemicals with similar molecular descriptors capable of influencing these behaviors, thus allowing investigators to predict their toxicity or exposure potential, while foregoing actual testing. Attendees enrolled in this course will learn about the availability of different tools and vast numbers of resources to help them triage in vitro efforts, rationalize mode-of-action information, screen chemicals in a virtual world, and understand the issues of domain of applicability in toxicological studies. Investigators specializing in computational, molecular, and environmental toxicology, as well as those conducting high-throughput analysis for drug discovery or chemical screening, will experience the opportunity to address critical issues regarding evaluation of chemical space along the source-to-outcome continuum through comprehensive lectures and case studies.

Computational Chemistry in Toxicity Testing, Hazard and Risk Assessments. Daniel Chang, Chemical Computing Group, Inc., Montreal, QC, Canada.

Applications of Cheminformatics in the Regulatory Assessment of Chemicals. Andrew Worth, European Commission—Joint Research Centre, Ispra, Italy.

Progress towards Predicting Potential Hazards and Assessing Risk in the Early Stage of Drug Discovery. BinQing Wei, Genentech Inc., South San Francisco, CA.

Advancements in Applying Predictive Computational Tools to Prioritize Environmental Chemicals Investigated in High-Throughput Screening Assays. Jeremy Leonard, North Carolina State University, Raleigh, NC.

The Contributions of Chemistry Standards and Database Tools at the Chemical-Biology Interface. Antony Williams, US EPA, Durham, NC.

Conquering Chemical Space with Cheminformatics Workflow and In Silico Profiling to Complement High-Throughput Screening. Rocky Goldsmith, Chemical Computing Group, Inc., Montreal, QC, Canada.

View Speaker Biographies

Genetics and Population Variability in Chemical Toxicity: The What, the How, and So What?

Afternoon Course (PM10) | CE Basic | 1:15 PM–5:00 PM

Theme:

Health and Environmental Impacts of Manmade and Naturally Released Toxicants
Molecular Toxicology: Mechanistic Insights and Hazard Assessment

Chairperson(s): Ivan Rusyn, Texas A&M University, College Station, TX; and Barbara A. Wetmore, ScitoVation, LLC, Research Triangle Park, NC.

Endorser(s): Drug Discovery Toxicology Specialty Section
Molecular and Systems Biology Specialty Section
Risk Assessment Specialty Section

The US EPA defines “variability” as “the range of toxic response or exposure—for example, the dose that might cause a toxic response can vary from one person to the next depending on factors such as genetic differences, preexisting medical conditions, etc.” What are “genetic differences”? How do toxicologists and regulators estimate “population variability”? What new computational and experimental tools are available to substitute default “uncertainty factor” to account for variation in susceptibility among the members of the human population (i.e., interindividual variability)? This continuing education course is designed to review basics of genetics and demonstrate how appreciation for the role of genetic variability and novel experimental and in silico models can become key elements in human health assessments of chemicals. By superimposing the opportunities that are now afforded by sequencing technologies and novel experimental models and data onto the risk assessment paradigm, this course will be informative to the risk assessment practitioners and the toxicology research community, and increase the scientific impact of the fundamental toxicology studies. In addition, this course is directly responsive to the new SOT Strategic Plan (2015–2018) and the Central Challenge of shaping the future of toxicology in a changing scientific landscape. By using case studies of how the scientific disciplines of genetics and toxicology intertwine, this course will strengthen the impact and relevance of toxicology.

Genetics for Toxicologists: Why Should We Care? Ivan Rusyn, Texas A&M University, College Station, TX.

Basic Concepts in Genetics, Heritability, Genome-Wide Association, and Related Toxicology Study Designs. Fred A. Wright, North Carolina State University, Raleigh, NC.

Pharmacogenomics Tools to Unravel the Genetic Basis of Toxicodynamic Variability. Nancy J. Cox, Vanderbilt University, Nashville, TN.

Strategies to Quantitate Chemical-Specific Toxicokinetic Variability Due to Genetics and Other Factors. Barbara A. Wetmore, ScitoVation, LLC, Research Triangle Park, NC.

Advancing Risk Assessment with Genetic and Population Variability Data. Weihsueh A. Chiu, Texas A&M University, College Station, TX.

View Speaker Biographies

Human Health Risk Assessment: A Case Study Application of Principles

Afternoon Course (PM11) | CE Advanced | 1:15 PM–5:00 PM

Webcast Registration

Theme:

Health and Environmental Impacts of Manmade and Naturally Released Toxicants

Chairperson(s): John C. Lipscomb, US EPA, Cincinnati, OH; and Bette Meek, University of Ottawa, Ottawa, ON, Canada.

Endorser(s): Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section

This advanced, case study application course will build on course content previously presented and archived by the Society of Toxicology through CE courses presented in 2013 (Basic Principles of Human Risk Assessment) and 2014 (Methodologies in Human Health Risk Assessment).  In this course, real world examples from publicly available, peer reviewed, completed risk assessments will be used as teaching aids. Course modules will be organized according to the four components of the Risk Assessment Paradigm: Hazard Characterization, Dose-Response Assessment, Exposure Assessment, and Risk Characterization. The Hazard Characterization component will consist of a guided case study based evaluation of the strength and consistency of available hazard data culminating in a weight of evidence synthesis of hazard information; Dose-response information including default (allometric scaling), pharmacokinetic approaches including a live  benchmark dose application from completed assessments will be presented and discussed; Information documenting actual (measured) exposure and/or data useful in determining a default measure of exposure will be presented and discussed; Risk Characterization will demonstrate the development of drinking water maximum contaminant levels, maximum contaminant level-goals, reference values, and cancer slope factors; as well as methods to estimate risk at a given contaminant level. The course booklet will contain a worksheet on the risk assessment examples, to be completed during the class. Unique to this course, students will be provided a risk assessment problem consisting of fundamental environmental contamination levels and original publications describing toxicity studies and will be asked to characterize the hazard, estimate exposures via soil and water, develop measures of toxic potency, and develop risk values for a hypothetical environmental contaminant. The results will be provided through an open access “drop box” type application.

Introduction. Bette Meek, University of Ottawa, Ottawa, ON, Canada.

Hazard Characterization. Zhongyu (June) Yan, Dow AgroSciences, Indianapolis, IN.

Dose-Response Assessment. Q. Jay Zhao, US EPA, Cincinnati, OH.

Exposure Assessment. Robinan Gentry, Ramboll ENVIRON, Monroe, LA.

Risk Characterization. John C. Lipscomb, US EPA, Cincinnati, OH.

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Unique Approaches to Safety Assessment of Gene, Cell, and Nucleic Acid-Based Therapies

Afternoon Course (PM12) | CE Basic | 1:15 PM–5:00 PM

Theme:

Recent Advances in Safety Assessment

Chairperson(s): Timothy MacLachlan, Novartis, Cambridge, MA; and Joy Cavagnaro, AccessBio, Boyce, VA.

Endorser(s): Biotechnology Specialty Section
Regulatory and Safety Evaluation Specialty Section

The platforms used for therapeutic treatment of disease have been greatly expanding over the last decade beyond the standard small molecule approaches and the now widespread use of proteins and monoclonal antibodies. The prospect of gene therapy began several decades ago with the promise that misfunctioning genes could be simply replaced, but was stunted in its growth with several notable safety events in the clinic. Now gene therapy is making a furious comeback, with several industry and academic groups employing various technologies and racing to catch up. Cell therapy has experienced similar peaks and valleys in interest, with stem cells touted as a platform able to replace entire damaged organ systems. Multiple variants of what one would call a cell therapy now are in development ranging for treatment with fully differentiated somatic cells to naïve cells able to grow and differentiate in vivo. A combination of gene and cell therapy approaches is used in the widely popular T cell immunotherapy approaches for cancer treatment where cells are modified ex vivo to target tumors after reintroduction to the patient. Considering the potency of T cells it is not surprising that safety concerns have limited their target profile. Finally, the concept of knocking down expression of gene expression has gained significant momentum with the introduction of therapeutic RNA interference and most recently with gene editing via a variety of methods. All of these “advanced therapy” platforms require very unique approaches outside of the standards defined by internationally accepted guidance for preclinical safety assessment. Not only does the biopharmaceutical mantra of “case by case” apply, but standard issues such as immunogenicity, tumorigenicity and appropriate animal models take on new meaning when applied to these therapies. With start-up companies being formed and larger pharmaceutical companies investing heavily in these therapeutic areas, there is a growing need for toxicologists to be familiar with these platforms. This course will aim to introduce the audience to each of these four general categories of advanced therapies  as well as provide a regulatory perspective on these modalities and highlight where the standard approaches for safety assessment either do not apply or require unique application.

Toxicological Approaches to Gene Therapy. Joy Cavagnaro, AccessBio, Boyce, VA.

Toxicological Approaches to T-Cell Immunotherapies. Timothy MacLachlan, Novartis, Cambridge, MA.

Toxicological Approaches to Cell Therapies. Cliff Sachs, MedImmune, Gaithersburg, MD.

Toxicological Approaches to Genome Editing. Kathleen Meyer, Sangamo Biosciences Inc., Richmond, CA.

Think Like a Regulator: US FDA Considerations for Preclinical Studies for Cell and Gene Therapy Products. Becky Robinson, Center for Biologics Evaluation and Research, US FDA, Silver Spring, MD.

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Zebrafish As a Tool in Toxicology and Drug Discovery Screening

Afternoon Course (PM13) | CE Basic | 1:15 PM–5:00 PM

Theme:

Health and Environmental Impacts of Manmade and Naturally Released Toxicants
Recent Advances in Safety Assessment

Chairperson(s): Mamta Behl, National Toxicology Program/NIEHS, Research Triangle Park, NC; and Arantza Muriana, BBD Biophoesnix S.L.-Biobide, San Sebastián, Donostia, Spain.

Endorser(s): In Vitro and Alternative Methods Specialty Section
Molecular and Systems Biology Specialty Section
Reproductive and Developmental Toxicology Specialty Section

The zebrafish is a powerful tool to screen compounds, especially for early development since it is a vertebrate, has a high genetic homology with humans, and the assays can be automated to provide relatively high-throughput along with high-content analysis. Adult and developing zebrafish are increasingly being used to assess development, gene expression, and behavior to screen and prioritize compounds for toxicity testing and safety evaluation. Specifically, the zebrafish has proven extremely relevant in the evaluation of acute toxicity and developmental toxicity, as well as organ-specific toxicities, including cardiotoxicity, hepatotoxicity, and neurotoxicity.

The purpose of this course is to bring together experts from the pharmaceutical industry, CROs, academia, and the Government to provide insight on the current developments in the use of zebrafish in the field of toxicology and drug safety and efficacy assessment, and to highlight some ongoing challenges in the field. The course will begin with important basics of zebrafish biology such as selection of strains, husbandry, dose- response and time course, and will highlight its application in toxicology.  The second talk will focus on the recent advancements of zebrafish as a tool to assess developmental toxicity. The third talk will focus on the systematic optimization of variables for efficient screening, and tools for data management, visualization and analysis. Speaker four will highlight the use of zebrafish in drug discovery as a rapid and cost effective method to screen for a number of new molecular entities entering clinical phases. Finally, speaker five will build upon the information presented by the previous speakers to shed light on the utility in screening of drugs for efficacy and safety, and ultimately for acceptance of data for regulatory purposes.

The course will address critical questions on the status of this model in hazard identification and risk assessment for environmental toxicants including progress in the field, loopholes, and data-gaps, novel upcoming developments, and the impact of this model on toxicology research in the 21st century, as well as the impact on safety assessment of drugs.

Introduction and Course Goals. Mamta Behl, National Toxicology Program/NIEHS, Research Triangle Park, NC.

The Ins and Outs of Using Zebrafish for Mechanistic Toxicology Studies. Antonio Planchart, Department of Biological Sciences, North Carolina State University, Raleigh, NC.

Developmental Toxicology Research in Zebrafish. Kimberly Brannen, Merck, West Point, PA.

Optimizing Multi-Dimensional Bioactivity Screening in Zebrafish. Robert Tanguay, Oregon State University, Sinnhuber Aquatic Research Laboratory, Corvallis, OR.

Innovative Zebrafish Hepatotoxicity, Cardiotoxicity, and Neurobehavioral Toxicity Assays for Drug Selection. Arantza Muriana, BBD BioPhenix S.L.-Biobide, San Sebastián, Donostia, Spain.

Recent Developments and Recognition of Zebrafish for Use in Safety Evaluation by the Regulatory Agencies. Gopala Krishna, Supernus Pharmaceuticals, Inc., Rockville, MD.

Zebrafish—Whatever You Ever Wondered About! Additional Discussion with All Panel Speakers

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