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Continuing Education

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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. SOT CE Courses can be applied towards numerous different certifying and licensing board requirements both in the United States and around the world. Please be sure to review the specific requirements of your licensing board or certification for details. General courses are intended to provide a broad overview of an area or to assist individuals in learning new techniques or approaches, while courses based on more specialized topics are intended to be of interest to individuals with previous knowledge of the subject or already working in the field.

Course books will be provided exclusively in electronic format in 2018.

 

All courses will be held on Sunday, March 11, 2018, at the Henry B. González Convention Center. Please Note: Each CE Course is offered in one of three time blocks:

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

 

2018 Courses

Registration for the Annual Meeting plus a ticket for the CE Course are required to attend one of the sessions below.


Sunday, March 11

7:00 AM to 7:45 AM

CRISPR-Cas9 for Toxicologists

SR01  SUNRISE MINI-COURSE

Chairperson(s):

Gary W. Miller, Emory University, Atlanta, GA; and Lesa L. Aylward, Summit Toxicology, Falls Church, VA.

Primary Endorser:

Specialty Section Collaboration and Communication Group


Recent advances in genome editing using CRISPR-Cas9 and related technologies have revolutionized the ability to manipulate genes in a rapid, precise, and flexible manner. These advances have spurred an explosion of interest in the possible ways in which genome editing can improve human health. This course will provide an overview of CRISPR-Cas systems, the structure and function of CRISPR-Cas9, the re-purposing of CRISPR-Cas9 for genome engineering, and recent advances in genome editing and the application of these techniques to toxicology. These include its use in screening the genome in different biological systems for gene pathways related to sensitivity or resistance to chemical toxicity, for elucidating the pathways of biological response to chemical stressors, and other applications related to the understanding of mechanisms of gene-environment interactions. The Emerging Science for Environmental Health Decisions (ESEHD) Standing Committee of the National Academies of Science, Engineering, and Medicine serves as an important link between the National Academies and the Society of Toxicology. To foster this collaboration, the ESEHD Committee is pleased to sponsor this course on the use of advanced genome-editing techniques in toxicology, which follows a planned meeting on gene editing in toxicology and environmental health to be held at the National Academies’ Headquarters in January 2018.


The Structure and Function of CRISPR-Cas9. David Taylor, University of Texas, Austin, TX.

Genome-Wide CRISPR Applications in Toxicology. Christopher Vulpe, University of Florida, Gainesville, FL.

The What, When, and How of Using Data from Alternative Testing Methods in Chemical Safety Assessments

SR02  SUNRISE MINI-COURSE

Chairperson(s):

Suzanne C. Fitzpatrick, US FDA, College Park, MD; and Mansi Krishan, ILSI North America, Washington, DC.

Primary Endorser:

In Vitro and Alternative Methods Specialty Section

Other Endorser(s):

Biological Modeling Specialty Section
Food Safety Specialty Section


In the last decade, the fields of toxicology and risk assessment have undergone an extensive shift towards the development of alternative testing methodologies that potentially can be used to assess the safety of chemicals and reduce animal use in toxicological research. New approaches, including molecular biology, computational and systems biology, high-throughput screening (HTS) assays, automated analytical methods, and robotic implementation, are generating toxicological data at unprecedented speeds. Compared to traditional animal toxicity studies, advanced HTS methods, reach-across approaches, in silico tools, and other alternative methodologies hold considerable promise to define biological activity profiles of chemicals. The first step towards better understanding the application of these new methodologies and tools for safety assessment of chemicals is an interdisciplinary approach which: 1) promotes interaction among scientists from diverse backgrounds (e.g., toxicologists, chemists, biologists, mathematicians, programmers, and risk assessors) and 2) provides hands-on-training to demonstrate the utility and challenges associated with the use of these alternative testing methods in different sectors. This course will provide a unique training platform to equip attendees with all the necessary knowledge and know-how to use and apply data from HTS assays, in silico tools, and other emerging technologies, such as virtual embryo, in the safety evaluation of chemicals. It is a learning tool aimed at providing training to scientists interested in applying the latest approaches to the safety assessment of chemicals, as well as students and researchers interested in improving the existing methods and developing new alternative methods for toxicological research. The course will include an overview of each of the methodologies (HTS methods, in silico tools, virtual embryo) and case study exercises to demonstrate the use of data from these methods and the use of tools in different sectors, such as pharmaceuticals, consumer products, food, agricultural products, and environmental toxicants.


Case Studies on the Use of In Vitro Data for Quantitative Evaluation of Dose-Response and Margin of Exposure. Rebecca Clewell, ScitoVation, Research Triangle Park, NC.

Mechanistic Modeling of Developmental Defects through Computational Embryology. Thomas Knudsen, US EPA, Research Triangle Park, NC.


8:15 AM to 12:00 Noon

An Introduction to the Basics of Immunotoxicity Testing

AM03  MORNING COURSE

Chairperson(s):

Jamie DeWitt, East Carolina University, Greenville, NC; and Sarah Blossom, University of Arkansas for Medical Sciences, Little Rock, AR.

Primary Endorser:

Immunotoxicology Specialty Section


The immune system has long been a sensitive target of environmental pollutants, industrial chemicals, and pharmacological agents. For example, several federal laws and guidelines have data requirements for immunotoxicity. However, recent studies by an industry trade association and the the US Environmental Protection Agency Office of Pesticide Programs determined that no clear signs of immunotoxicity may arise from conventional toxicity studies and that additional immunotoxicity testing may only be recommended if “primary indicators” of immunotoxicity arise from conventional toxicity studies. This approach harmonizes with the “weight of evidence” concept that is discussed in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines S8 for human pharmaceuticals and Part 158 for pesticidal substances and certain industrial compounds. This course will provide an overview of the types of immunotoxicity tests often used to meet US data requirements for agents regulated by the US Environmental Protection Agency and the US Food and Drug Administration. The first speaker will set the stage by defining immunotoxicity, discussing the historic aspects of immunotoxicity testing, and highlighting some of the current advances in immunotoxicity assessment, including high-throughput analysis, immunotoxicogenomics, developmental immunotoxicology, and the creation of adverse outcome pathways for immunotoxicity. The second speaker will address the particular data requirements under various laws and guidelines and their applicability to regulatory immunotoxicity. Speaker number three will go into detail about specific required tests under existing laws and guidelines, as well as novel and innovative ways of meeting data requirements. The fourth speaker will provide an overview of the utility of experimental animal models and their predictive value for understanding potential risks toward human health. Finally, the fifth speaker will delve into the information that can be gleaned from human blood samples and how these data can be used to better predict health and disease in exposed/treated humans. Each presentation will include case studies and/or examples of immunotoxicity assessment strategies applied to agents or classes of agents under study, being considered for approval, or under regulatory scrutiny.


An Introduction to Immunotoxicity Testing: Looking to the Past to Inform the Future. Jamie DeWitt, East Carolina University, Greenville, NC.

An Introduction to Immunotoxicity in Risk Assessment. L. Peyton Myers, US FDA, Silver Spring, MD.

Approaches and Methods Used to Generate Useful Immunotoxicity Data. Victor Johnson, Burleson Research Technologies, Inc., Morrisville, NC.

Interpretation of Data from Experimental Animal Studies and Predictive Value for Human Health Risk Assessment. Sarah Blossom, University of Arkansas for Medical Sciences, Little Rock, AR.

Human Immunotoxicology: What Blood and Cells Can Tell Us. Emanuela Corsini, Università degli Studi di Milano, Milan, Italy.

Assessment of Peri- and Prepubertal Developmental and Reproductive Toxicity

AM04  MORNING COURSE

Chairperson(s):

Bethany Hannas, Dow Chemical Company, Midland, MI; and Kary Thompson, Bristol-Myers Squibb, New Brunswick, NJ.

Primary Endorser:

Reproductive and Developmental Toxicology Specialty Section


Perinatal development through the time of puberty can be particularly vulnerable periods to compound exposures resulting in toxicity. Toxicological assessments during these periods include regulatory-required guideline studies, mode-of-action studies, behavioral and functional assessments, and predictive assays/models. Test guideline-driven study designs covering these periods have evolved over time and are subject to additions or variations, depending on what is known about the tested compound. In addition, the field of toxicology is pushing toward increasingly innovative methods and alternative models, coupled with reduction in animal usage in the assessment of a compound, including during vulnerable developmental periods. As such, multiple study designs and models are utilized to support perinatal and juvenile developmental toxicity assessments of pharmaceutical agents, industrial chemicals, pesticides, food additives, and other environmental contaminants. This course will begin with presentations focused on test guideline-driven study designs and case studies of pharmaceutical and environmental chemical safety assessments during early life stages. The next presentation will cover assessment of functional competence and behavior following compound exposures during these vulnerable development periods. Next, the interpretation, reliability, and reproducibility of these studies will be discussed. The course will conclude with a discussion on looking forward for developmental and reproductive toxicity assessments. This course will discuss alternative models for evaluating reproductive and developmental toxicity and focus specifically on using a zebrafish model as a biosensor for early life stage sensitivity. The course will provide an understanding of current approaches to evaluating compound safety during the critical peri- and postnatal periods of development.


Nonclinical Support of Pediatric Drug Development: A Pharmaceutical Industry Perspective. Sarah Campion, Pfizer, Inc., Groton, CT.

Environmental Chemical Assessments: Multi-Generation and Extended One-Generation Studies. Bethany Hannas, Dow Chemical Company, Midland, MI.

Juvenile Toxicology Neurobehavioral Assessments: When and What Should Be Assessed. Charles Vorhees, Cincinnati Children’s Research Foundation and University of Cincinnati, Cincinnati, OH.

Data Interpretation, Reliability, and Reproducibility for DART Studies. Pragati Sawhney Coder, Charles River Laboratories Ashland, LLC, Ashland, OH.

Alternative Models to Detect Developmental and Reproductive Toxicants: Zebrafish as a Case Study. Robert L. Tanguay, Oregon State University, Corvallis, OR.

Biotherapeutic Development: What’s Behind the Curtain?

AM05  MORNING COURSE

Chairperson(s):

Laura Andrews, AbbVie, Worcester, MA; and Mary Ellen Cosenza, MEC Regulatory & Toxicology Consulting, LLC, Moorpark, CA.

Primary Endorser:

Biotechnology Specialty Section

Other Endorser(s):

Regulatory and Safety Evaluation Specialty Section


The approval in 1982 of human recombinant insulin began an expansive growth in biotherapeutics. Great successes were achieved and multiple life-altering therapies were developed. Significant guidance has been released by regulatory agencies in the last two decades to help the rational and scientifically-based development of these complex products. The the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) S6 guidance, adopted in 1997, was the first document to specifically outline best practices for nonclinical approaches to biologic drug development. Additional guidance documents have since been adopted with regular addendums to reflect scientific advances. Despite 36 years of successful biologic drug development, there remain challenges which need to be addressed on a case-by-case basis for each particular therapeutic agent. As the past has taught us, not all safety issues observed nonclinically are relevant to humans. Likewise, not all human safety issues can be identified nonclinically, especially with poorly designed nonclinical studies or irrelevant animal test systems. In addition to addressing the unique aspects of strategies for developing biologics, this will discuss topics such as the selection of relevant species, the role and interpretation of immunogenicity, and the current regulatory challenges. Selection and evaluation of the most relevant species for biologics programs is fundamental. The role of immunogenicity in nonclinical studies continues to confound and cause concern as to interpretability and translatability of these findings to the clinic. A broad overview will be given of how immunogenicity and other immune responses in animals play a role in the interpretation and assessment of toxicology studies. A brief primer will be offered on current regulatory guidance, in addition to highlighting complex issues that are frequently faced when reviewing applications for biopharmaceuticals. Examples from US Food and Drug Administration submissions will be discussed to illustrate these challenges and to present scientific and regulatory strategies that have been used in the design or review of nonclinical programs that support biopharmaceutical drug development. This course will provide an understanding of the considerations of key issues for advancing these therapeutics safely in the clinic. This requires a strong understanding of the biology of the target and also a good comprehension of the caveats and limits of the current nonclinical models and an ability to design fit-for-purpose, creative, nonclinical safety testing funnels adapted to the test agents being developed.


It’s Not Smoke and Mirrors: Demystifying Nonclinical Development Strategies for Biotherapeutics. Jorg Blumel, Genentech, South San Francisco, CA.

Relevant Species Selection: Is It as Easy as Pulling a Rabbit Out of a Hat? Maggie Dempster, GlaxoSmithKline, King of Prussia, PA.

Managing Immunogenicity: Now You See It and Now You Don’t. Robert Caldwell, AbbVie, Worcester, MA.

The Final Curtain: Regulatory Insights on the Development of Biotherapeutics; Where Are We Now? Christopher Ellis, US FDA Center for Drug Evaluation and Research, Silver Spring, MD.

In Vitro Testing: Tales from the Real World

AM06  MORNING COURSE

Chairperson(s):

Kelly Coleman, Medtronic PRL, Minneapolis, MN; and Amy Clippinger, PETA International Science Consortium Ltd., Norfolk, VA.

Primary Endorser:

In Vitro and Alternative Methods Specialty Section

Other Endorser(s):

Medical Device and Combination Product Specialty Section
Regulatory and Safety Evaluation Specialty Section


Advances in science and technology have paved the way for a paradigm shift in toxicity testing. We now have the opportunity to more efficiently evaluate substances and better protect human health and the environment by using approaches grounded in human mechanisms rather than animals. Acute toxicity tests—namely, skin and eye irritation, skin sensitization, and systemic (oral, dermal, and inhalation) toxicity—are commonly conducted on medical devices, pesticides, industrial chemicals, pharmaceuticals, cosmetics, and other substances. Thus, it is important to implement rigorous alternative acute toxicity-testing approaches that will protect human health and the environment while reducing the time, cost, and animal use associated with traditional toxicity testing. The goal of this course is to teach attendees about existing in vitro, in chemico, and in silico acute toxicity tests and how they have been successfully applied in integrated approaches to evaluate the toxicity of a wide range of substances. Other approaches, such as the use of waivers or the Globally Harmonized System of Classification and Labeling of Chemicals (GHS) mixtures equation, will be discussed. The presentations also will highlight the remaining challenges that need to be overcome before alternative methods can be implemented globally and accepted by regulatory agencies. This course will be of interest to toxicologists from diverse sectors, including those from the chemical, pharmaceutical, medical device, and personal care product industries, along with others who want to learn more about currently available non-animal tests and how to use them.


Application of the Reconstructed Human Epidermis (RhE) Model as an In Vitro Skin Irritation Test for Detection of Irritant Activity in Medical Device Extracts. Wim de Jong, Rijksinstituut voor Volksgezondheid en Milieu (RIVM), Bilthoven, Netherlands.

Developing, Testing, and Implementing Novel Testing Strategies for Skin Sensitization Nicole Kleinstreuer, NTP NICEATM, Research Triangle Park, NC.

Replacing Animal Use for Eye Irritation Testing—Once and for All, Let’s Get It Done. David Allen, Integrated Laboratory Systems (ILS), Research Triangle Park, NC.

Opportunities to Implement Alternative Approaches in the Crop Protection Sector. Sean Gehen, Dow AgroSciences, Indianapolis, IN.

Moving Toward Implementation: The Role of International Collaboration, Opportunities, and Challenges. Anna Lowit, US EPA, Washington, DC.

Physiologically-Based Pharmacokinetic Modeling to Support Modernized Chemical Safety Assessment

AM07  MORNING COURSE

Chairperson(s):

Miyoung Yoon, ScitoVation, Research Triangle Park, NC; and Alicia Paini, European Commission Joint Research Centre, Ispra, Italy.

Primary Endorser:

Biological Modeling Specialty Section

Other Endorser(s):

In Vitro and Alternative Methods Specialty Section
Risk Assessment Specialty Section


Physiologically-based pharmacokinetic (PBPK) models have been applied to chemical risk assessment for more than three decades. Extrapolation of animal toxicity findings to humans has been the major application of PBPK models in risk assessment. Under the proposed new toxicity testing paradigm, which relies on data from human-relevant in vitro toxicity assays interpreted through computational approaches, PBPK models have been redefined as a critical translation tool for quantitative in vitro to in vivo extrapolation. The models would link effect concentrations in cell-based assays to equivalent human exposures. PBPK models provide a biologically relevant integration platform to describe the absorption, distribution, metabolism, and excretion of chemicals based on a wide range of in vitro, in silico, and, if available, in vivo information. This course will provide an opportunity to revisit the basic principles of PBPK modeling with a special focus on supporting chemical risk assessment under the new toxicity testing paradigm. In addition to describing the basics of model construction, recent advances in model parametrization, including in vitro to in vivo extrapolation and in silico prediction, will be presented. Evaluation of model performance and reliability along with use of available human data will be discussed. Development and application of the PBPK models to support risk-based decisions in different tiers of risk assessment will be presented. A hands-on demonstration will be provided, using a free online simulation tool (PLETHEM) to demonstrate the workflow of building and parameterizing a PBPK model, simulating different human populations, and applying the model to translate concentration-effect relationships from cell-based assays or in vivo studies to the dose-response relationship in target human populations to support chemical risk assessment. The course will address continuing challenges and future directions in PBPK modeling.


Physiologically-Based Pharmacokinetic Models as a Critical Component in Moving Forward with the New Toxicity Testing Strategies Based on In Vitro and Computational Approaches. Alicia Paini, European Commission Joint Research Centre, Ispra, Italy.

Physiologically-Based Pharmacokinetic Models for Risk and Safety Assessment: Basic Principles and Examples of the Applications in Traditional Risk Assessment. Hugh A. Barton, Pfizer, Inc., Groton, CT.

Parameterization of Physiologically-Based Pharmacokinetic Models with Minimum Reliance on In Vivo Toxicokinetic Studies: Describing Average Person vs. Population. Lisa M. Sweeney, Dayton, OH.

Examples of the Use of Physiologically-Based Pharmacokinetic Models in Support of In Vitro Based Safety Assessment: Hands-On Demonstration of a Work Flow. Miyoung Yoon, ScitoVation, Research Triangle Park, NC.

A Tiered Approach to Incorporate Exposure and Pharmacokinetics Consideration in In Vitro-Based Safety Assessment. Cecilia Tan, US EPA, Research Triangle Park, NC.

Approaches for Evaluation of Non-Animal-Based Physiologically-Based Pharmacokinetic Models Including the Use of Human Biomonitoring Data. Jos Bessems, VITO, Mol, Belgium.

Developmental Neurotoxicity Testing: Current Practices and Latest Advancements

AM08  MORNING COURSE

Chairperson(s):

Kristen Ryan, NIEHS, Research Triangle Park, NC and Susan Makris, US EPA, Washington, DC.

Primary Endorser:

Neurotoxicology Specialty Section


The potential for neurotoxicity in adults and children remains a high public priority due to concerns that recent increases in the prevalence of neurological disorders may in part be due to chemical effects. Guideline developmental neurotoxicity studies in rodents currently remain the gold standard for risk assessment. However, these studies are triggered tests based on evidence of neurotoxicity in standard adult, reproduction, or developmental studies, and as a result, several thousand compounds with unknown neurotoxic potential are never evaluated. Furthermore, many developmental neurotoxicants are still not captured using the current guidelines due to the lack of specific requirements in the guidelines, the subjective nature of these tests causing interlaboratory variability, lack of relevance of some of the assays to human-specific outcomes, and the lack of power to capture subtle deficits. To address some of these issues, concerted efforts have been made in the recent past to advance the science for developmental neurotoxicity testing and to recommend strategies for harmonizing guideline studies for use by regulatory agencies. This course is designed to highlight the current state of the science and recent advancements to identify an integrated strategy for developmental neurotoxicity testing. The course will begin with an introductory talk on the overall practices with current guideline toxicology studies, as well as developments and recommendations for them (US Environmental Protection Agency (US EPA) 870.6300, Organisation for Economic Co-operation and Development (OECD) 426, OECD 443). The next two speakers will focus specifically on the current practices, advancements, and recommendations in neurobehavioral testing (learning, activity, attention) and neuropathology. The subsequent speaker will then highlight how developmental neurotoxicity is assessed in the clinic, provide case examples, and speak on the parallels between human and rodent studies. The last speaker will describe a novel strategy to rapidly screen for compounds with unknown neurotoxic potential to prioritize for further testing and how to incorporate triggers from those screens in further assessment of in vivo developmental neurotoxicity studies.


Introduction and Course Goals. Kristen Ryan, NIEHS, Research Triangle Park, NC.

Introduction to Developmental Neurotoxicity Testing—History, Guidelines, Use in Risk Assessment, and Current Recommendations. Susan Makris, US EPA, Washington, DC.

Assessment of Neurobehavior in Developmental Neurotoxicity Rodent Studies. Larry Sheets, Bayer CropScience, Research Triangle Park, NC.

Histopathology and Morphometry Assessments in Developmental Neurotoxicity Testing. Catherine Picut, Charles River Laboratories International, Inc., Durham, NC.

Tools and Strategies for Assessing Developmental Neurotoxicity in Clinical Research. Kimberly Yolton, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH.

Advancing Developmental Neurotoxicity Testing in the 21st Century: A Potpourri of In Vitro and Guideline Studies. Mamta Behl, NIEHS, Research Triangle Park, NC.


1:15 PM to 5:00 PM

Consumer Products Safety Assessment: Progress in the Use of Alternatives to Animal Models

PM09  AFTERNOON COURSE

Chairperson(s):

Kathryn E. Page, The Clorox Company, Pleasanton, CA; and Thomas Hartung, Johns Hopkins Center for Alternatives to Animal Testing (CAAT), Baltimore, MD.

Primary Endorser:

In Vitro and Alternative Methods Specialty Section

Other Endorser(s):

Risk Assessment Specialty Section
Regulatory and Safety Evaluation Specialty Section


To meet consumer preferences and changes in the regulatory landscape, the use of animals for the safety evaluation of consumer product ingredients and formulas has largely been phased out by cosmetics manufacturers, and other consumer products companies are soon to follow. The purpose of this course is to provide an encompassing overview of the progress in the field of safety evaluation of consumer products ingredients using alternative approaches. The introductory presentation will map the current landscape of alternative methods for assessing consumer product safety, including highlighting the holes still remaining in the field. Occasional resistance to change by regulatory agencies can be frustrating to the industry at large. However, recent government-industry collaboration has shown the potential for helping the process progress. The first presentation will provide insight into the current regulatory landscape of the US Consumer Product Safety Commission (CPSC) animal testing policy, including what methods are approved and recommended, as well as the struggles faced to get there. A roadmap of where testing and regulations are likely headed also will be presented, including what challenges await. Several alternative methods have been developed and validated to assess product safety and are now considered acceptable by regulatory agencies. However, the path to their integration into safety assessments and communication to scientists-at-large is still a work in progress. The second presentation will showcase available options for alternative testing strategies, as well as struggles and triumphs in getting methods accepted by regulatory agencies. The final two presentations will provide case studies of how alternative testing is used in the cosmetics and cleaning products industries, as well as specific examples from L’Oreal as a trendsetter in the field and regarding method development and from Clorox about how to navigate the current regulatory requirements for cleaning products and animal testing. The course will provide a sound understanding of the current and proposed future state of alternatives to animal testing in consumer products safety assessment.


Embracing New Approaches: A Challenging, but Rewarding, Endeavor. Thomas Hartung, Johns Hopkins Center for Alternatives to Animal Testing (CAAT), Baltimore, MD.

The Regulatory Perspective: Approaches for Development, Validation, and Utilization of Alternative Methods for Toxicity Testing. Joanna Matheson, US Consumer Product Safety Commission, Rockville, MD.

Alternative Methods: The How, the Now, and the Future. Allison Hilberer, Institute for In Vitro Sciences, Inc., Gaithersburg, MD.

Cosmetics: A Case Study. Kristin Yamada, L’Oreal, Clark, NJ.

Cleaning Products: A Case Study. Kathryn E. Page, The Clorox Company, Pleasanton, CA.

Evaluation of Leachable Substances from Materials with Applications in Foods and Pharmaceuticals: Science- and Risk-Based Approaches

PM10  AFTERNOON COURSE

Chairperson(s):

Greg L. Erexson, AbbVie, North Chicago, IL; and Kim L. Li, Amgen Inc., Thousand Oaks, CA.

Primary Endorser:

Medical Device and Combination Product Specialty Section

Other Endorser(s):

Risk Assessment Specialty Section


Polymeric materials commonly used in food and pharmaceutical manufacturing and packaging components are known to leach chemical substances into the final products. The leachable substances may present potential safety risks to consumers and patients. The goal of this course will be to provide an overview of scientific and technical considerations relevant to the assessment of leachable substances covering historical and current context on patient safety and product quality, collaboration between chemists and toxicologists, best practices for deriving chemical-specific safety limits, and use of in silico QSAR tools to advance the 3R principle to replace, reduce, and refine animal testing. This course will provide a comprehensive overview of the risk assessment process for leachable compounds from food contact and pharmaceutical materials.


Evaluation of Leachable Substances from Materials with Applications in Foods and Pharmaceuticals: Science- and Risk-Based Approaches. Kim L. Li, Amgen Inc., Thousand Oaks, CA.

Extractables and Leachables Assessment for Patient Safety and Product Quality: Background and Current Context. Greg L. Erexson, AbbVie, North Chicago, IL.

Chemical Characterization of Packaging and Delivery Systems. Cheryl M. Stults, C&M Consulting, LLC, San Mateo, CA.

Safety Evaluation of Leachables/Extractables. Thomas Broschard, Merck KGaA, Darmstadt, Germany.

Use of Computational Approaches to Assess the Toxicity of Extractable and Leachable Substances. Ron Brown, US FDA, Silver Spring, MD.

Lead Optimization of Therapeutic Small Molecules: From Drug Target to Clinical Candidate Selection—Strategies and Decision Making

PM11  AFTERNOON COURSE

Chairperson(s):

Dolo Diaz, Denali Therapeutics Inc., South San Francisco, CA; and Dinah Misner, Alios Biopharma, South San Francisco, CA.

Primary Endorser:

Drug Discovery Toxicology Specialty Section

Other Endorser(s):

In Vitro and Alternative Methods Specialty Section
Cardiovascular Toxicology Specialty Section


From the decision to drug a chosen target with a small or large molecule to the selection of a lead candidate to take into Good Laboratory Practices (GLP) toxicology studies, discovery toxicologists engage an arsenal of tools and strategies with the objective of selecting molecules with a safety profile that provides an optimal chance of clinical success. This is best achieved by early safety involvement in target selection and target de-risking, selection of the best possible chemical matter with minimal off-target effects through lead optimization, and robust safety characterization and investigation of safety issues as they arise. The premise is that robust and thoughtful early safety involvement would reduce attrition in later phases of drug development. This course will provide a comprehensive overview of the strategies and approaches leading from drug target selection to lead identification, optimization, and selection of clinical candidates for first-in-human studies. The first presentation will address the safety considerations in target selection, to ensure that the intended targets are tractable from a safety perspective, and that the relevant questions are addressed and the proper lead optimization paradigms are in place for a particular program. The second presentation will tackle the critical aspects of selectivity for small molecules, including related and unrelated off-targets, and how to ensure that the molecules that are progressed are screened appropriately to ultimately have minimal off-target effects. The next two presentations will focus on two essential aspects of lead optimization: 1) cardiovascular safety and 2) genotoxicity, for which in vitro models have been particularly effective in minimizing liabilities. The session will continue with a presentation focused on particularly promising in vitro models and strategies to minimize hepatotoxicity; these approaches are becoming increasingly important in drug discovery since preclinical in vivo studies poorly identify human-relevant hepatotoxicants. The course will conclude with a presentation that integrates the different aspects of lead optimization discussed previously with in vivo data generated in pilot toxicity studies and will discuss how to incorporate these data into deciding whether to move into GLP toxicology studies. All presentations will focus on the practical aspects of implementing thoughtful de-risking strategies and on how data-driven decisions are made with the data outputs; presenters also will provide relevant examples to illustrate these approaches. The course will provide understanding of how to address safety for small molecules from the inception of a program to candidate selection into investigational new drug (IND)-enabling studies, how to evaluate and integrate relevant data, and how to make good decisions related to compound progression.


Target Safety Assessments: How to Lay the Safety Foundation for a Successful Small Molecule Drug Discovery Program. Rebecca Erickson, Denali Therapeutics Inc., South San Francisco, CA.

Lead Optimization to Increase Selectivity and Minimize Off-Target Effects. Yu (Zoe) Zhong, Genentech, Inc., South San Francisco, CA.

Strategies for Assessment of Cardiovascular Safety during Lead Optimization: How to Avoid Human Safety Risks While Not Throwing Out Babies with the Bathwater. Derek Leishman, Eli Lilly and Company, Indianapolis, IN.

Early Mechanistic Genetic Toxicology Screening: Strategies from Chemical Series to Compound Selection Prevent Late-Stage Attrition of Drug Development Candidates. Maik Schuler, Pfizer, Inc., Groton, CT.

Assessing Hepatotoxicity Risk in Drug Discovery: Practical Strategies and Decision Making. William Proctor, Genentech, Inc., South San Francisco, CA.

Lead Optimization Strategies and Integrated Assessment of In Vitro and In Vivo Toxicology Studies for the Rapid Identification of Clinical Candidates. Mark Fielden, Amgen Inc., Thousand Oaks, CA.

NGS-Based Technologies Enable Biomarker Development and Discovery in Toxicology

PM12  AFTERNOON COURSE

Chairperson(s):

B. Alex Merrick, NIEHS, Research Triangle Park, NC; and Andrew B. Nixon, Duke University Medical Center, Durham, NC.

Primary Endorser:

Biotechnology Specialty Section

Other Endorser(s):

Molecular and Systems Biology Specialty Section
Drug Discovery Toxicology Specialty Section


Next-Generation Sequencing (NGS) represents a series of powerful platforms that have revolutionized DNA and RNA analysis. The simultaneous sequencing of millions of DNA molecules can rapidly provide mechanistic insights into toxicology and biomarker discovery. Evolution of NGS technologies has improved the overall sensitivity and accuracy of these sequencing platforms, allowing for the development of new biomarker assays from tissue, blood, and other biofluids. NGS technologies can identify potential molecular indicators at the cellular and toxicopathological level in response to xenobiotics. The goal of this course is to review NGS-based technologies, demonstrate how they can be used as tools for target discovery in tissue and blood, and suggest best practices for optimal sample acquisition and processing in the toxicology setting. The technological transition from microarray toward NGS platforms in toxicology will be briefly reviewed. In the first presentation, a broad overview will be provided on the development, validation, and implementation of circulating biomarkers from a clinical perspective. Emphasizing lessons learned from the clinical oncology field, where biomarker development is key to disease treatment, the implementation of NGS and its potential use in toxicology will be discussed. The second presentation will describe the roles of non-coding RNAs as potential biomarkers. RNA-Seq data will be presented on long-noncoding RNAs (lncRNAs), recognized as key regulators and potential biomarkers of toxicological responses in humans and animal models. lncRNAs are an exciting and emerging area in toxicology. The third presenter will focus on another type of noncoding RNA, microRNAs (miRNAs), which are small ~22nt RNAs and represent promising new biomarkers; the isolation, NGS analysis, specific cell and tissue localization, and toxicologic responses in vitro in tissues and biofluids will be discussed. The fourth presentation will highlight best practices for optimal sample collection to ensure success with downstream NGS applications, followed by an introduction to whole exome sequencing (WES) in toxicology. WES enriches coding regions of the genome to discover mutations and sequence variants. A new WES platform, which is designed for rats, with future directions toward analysis of circulating, cell-free DNA (ccfDNA) as a potential biomarker for targeting specific biological processes, such as inflammation, will be described. The final presentation will involve NGS methods in epigenetics, using whole-genome bisulfite sequencing (WGBS), as well as other approaches to assess changes in DNA methylation after chemical exposure. Case studies will include the valuable role of zebrafish as an alternative animal model in chemical toxicity screening for NGS-based environmental epigenetics. This course will be of broad interest to investigators in academia, pharma, and government wishing to explore and expand their interest in novel NGS-based approaches with an emphasis on the development and discovery of biomarkers for the detection of xenobiotic toxicity and exposure.


Next-Generation Sequencing Platforms in Toxicology. Bruce A. Merrick, NIEHS, Research Triangle Park, NC.

Biomarker Development and Application to Toxicology. Andrew B. Nixon, Duke University Medical Center, Durham, NC.

Understanding the Regulation of lncRNAs during Toxicological Response Using RNA-Seq. Julia Yue Cui, University of Washington, Seattle, WA.

Next-Generation-Sequencing Applications for MicroRNA Biomarker Discovery in Toxicological Studies. Brian N. Chorley, US EPA, Research Triangle Park, NC.

Whole Exome Sequencing in Toxicology: Principles, Tissue Handling, and a New Rat WES Platform. Julie F. Foley, NIEHS, Research Triangle Park, NC.

Leveraging Illumina-Based Sequencing to Reveal Chemically-Induced Alterations in Genome-Wide Cytosine Methylation. David C. Volz, University of California Riverside, Riverside, CA.

Uncertainty Characterization in 21st-Century Toxicology: Current Practice and Practical Methods Supporting Regulatory Risk Assessment

PM13  AFTERNOON COURSE

Chairperson(s):

Kristi Muldoon-Jacobs, US Pharmacopeial Convention, Rockville, MD; and Andrea Richarz, European Commission Joint Research Centre, Ispra, Italy.

Primary Endorser:

In Vitro and Alternative Methods Specialty Section

Other Endorser(s):

Regulatory and Safety Evaluation Specialty Section
Biological Modeling Specialty Section


Understanding, describing, and, if possible, quantifying uncertainties is an essential part of risk assessment which needs to be communicated clearly to risk managers to support informed decision making. It requires a transparent statement of the likelihood of possible outcomes as a basis of building confidence in decisions taken. This is particularly true for risk assessments that rely on new toxicological methods with which the risk assessment community does not have the benefit of historical experience. The course will clarify the nature and sources of uncertainties and variability and give an overview of existing initiatives and available guidance for uncertainty evaluation for chemical risk assessment in the regulatory context. Current practice in regulatory review will be discussed, as well as challenges in application for the risk assessor/manager (often the same person) in industry. The importance and challenges of communicating uncertainties also will be addressed. A special focus of the course will be the characterization of uncertainties for alternative methods used for chemical hazard and risk assessment, bearing in mind that the incorporation of new toxicological methods into risk assessment is still hampered by lack of knowledge on how to describe and assess the associated different uncertainties. The new methods, for example, combine in silicoin silico, in vitro, and high-throughput toxicokinetics approaches to predict hazards and to provide quantitative estimates of effect levels and are then combined into models to predict in vivo effect levels, such as lowest-observed-adverse-effect levels (LOAELs). Approaches will be shown to quantify uncertainty in these individual inputs, as well as methods to combine uncertainty across all inputs in the final models. Furthermore, uncertainty and variability are compared with those in the in vivo databases that are used as benchmarks for the new models. Another example will include consideration of uncertainties for the non-chemical-specific Threshold of Toxicological Concern (TTC) approach as compared to traditional hazard assessment. The course will further describe state-of-the-art mathematical, statistical, and other methods, such as expert elicitation, to characterize and quantify uncertainty and tiered approaches to handling uncertainty in risk assessment. Examples will illustrate qualitative, deterministic, and probabilistic uncertainty assessment. Two case studies will show how these methods can help risk assessors and support decision making: 1) the use of Bayesian-belief networks to quantify the uncertainty in the potential of a chemical being a skin sensitizer in the light of competing evidence and 2) a mathematical model for an adverse outcome pathway (AOP)-based risk assessment, defined and parameterized using in vitro data sources. Overall, the purpose of the course is to give an overview of the concept of uncertainty and to identify existing resources on uncertainty characterization and reporting in guidance related to hazard assessment, as well as available mathematical methods. Practical examples based on experience from practice in various sectors will emphasize alternative methods supporting hazard assessment. Thus, the course will present concrete methods to characterize uncertainty in the context of chemical risk assessment, in particular how to pragmatically apply them in a tiered approach, while gaining more confidence in assessing alternative methods.


Introduction to Uncertainty: Definitions and Importance for Risk Assessment. Kristi Muldoon-Jacobs, US Pharmacopeial Convention, Rockville, MD.

Considerations of Uncertainty Assessment in Existing Guidance Documents Linked to Chemical Safety Assessment and Current Regulatory Practice. Andrea Richarz, European Commission Joint Research Centre, Ispra, Italy.

Challenges and Opportunities in the Application and Communication of Uncertainty Assessment. Heli M. Hollnagel, Dow Europe GmbH, Horgen, Switzerland.

Using Mathematics to Characterize Uncertainty with Examples from Alternative Approaches in Toxicological Risk Assessments. John Paul Gosling, University of Leeds, Leeds, United Kingdom.

Characterization of Uncertainty in In Silico, In Vitro Assay, and High-Throughput Toxicokinetics Data and Their Combination and Comparison with In Vivo Data Uncertainties. Richard Judson, US EPA, Research Triangle Park, NC.

Xenobiotic Pharmacokinetics during Pregnancy and Lactation

PM14  AFTERNOON COURSE

Chairperson(s):

Natasha Catlin, Pfizer, Inc., Groton, CT; and Angela Slitt, University of Rhode Island, Kingston, RI.

Primary Endorser:

Reproductive and Developmental Toxicology Specialty Section

Other Endorser(s):

Mechanisms Specialty Section
Risk Assessment Specialty Section


Exposure to xenobiotics during pregnancy and lactation is unavoidable and can be either intentional with pharmaceuticals or unintentional as contaminants in air, food, and water. During this critical time period of development, xenobiotic exposure can result in deleterious effects to the developing fetus. A number of critical physiological and molecular changes occur in the pregnant woman or animal that will influence the disposition and toxicity of chemicals, often in a gestational age-dependent manner. These changes range from altered blood flow to changes in metabolic pathways, as well as enhancement of renal filtration. In addition, the placenta is considered a selective barrier to protect the fetus against xenobiotics. However, some pharmaceuticals and toxicants can readily cross this placental barrier through active transport or diffusion, leading to exposure in utero. After birth, lactation represents a new route of xenobiotic exposure for the infant. The goal of this course is to provide participants with an introduction to the maternal and perinatal pharmacokinetics of xenobiotics during pregnancy and lactation. A variety of approaches will be covered, including animal studies, physiologically-based pharmacokinetic (PBPK) modeling, and clinical pharmacology studies in pregnant women. Case study examples also will be discussed in each presentation to illustrate these different approaches. The first presentation will provide an overview of the maternal physiologic changes associated with pregnancy, as well as the metabolic capabilities of fetal and neonatal rodents and humans. The second lecture will discuss placental morphology and the transfer of nutrients and foreign chemicals. The third presentation will cover the application of PBPK modelling to understand how physiological and biochemical processes impact tissue dosimetry of xenobiotics during gestation, fetal, and early-life stage development. The final presentation will describe clinical pharmacology examples of pharmacokinetic changes during pregnancy and the postpartum period and will provide an overview of xenobiotic transfer through breast milk. This course also will cover changes in pharmaceutical drug labeling related to pharmacokinetics and pharmacology during pregnancy and lactation.


Overview of Maternal and Fetal Physiology and Pharmacokinetics. Jamie Moscovitz, Pfizer, Inc., Boston, MA.

Life-Stage Physiologically-Based Pharmacokinetic (PBPK) Models in Humans and Animals. Hisham El-Masri, US EPA, Durham, NC.

Disposition and Toxicity of Xenobiotics in the Placenta throughout Pregnancy. Richard Miller, University of Rochester, Rochester, NY.

Clinical Implications of Pharmacokinetic Changes during Pregnancy and Lactation. Mary Hébert, University of Washington, Seattle, WA.