Continuing Education

The Continuing Education (CE) Program offers a wide range of courses that cover established knowledge in toxicology and new developments in toxicology and related disciplines. SOT CE courses can be applied toward numerous certifying and licensing board requirements 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 who are already working in the field.

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Please expand the course detail for specific information on the timing of each Continuing Education course.

2021 Virtual Meeting Courses


Friday, March 12

CE01  

Live Course Presentation Time:

9:30 AM–10:30 AM (US EST, UTC -5)

Chair(s):

Jordan N. Smith, Pacific Northwest National Laboratory; and Aaron T. Wright, Pacific Northwest National Laboratory.

Primary Endorser:

Mechanisms Specialty Section

Other Endorser(s):

Drug Discovery Toxicology Specialty Section

Chemical biology is an emerging scientific discipline that utilizes synthetic chemical probes to functionally identify and measure reactive biological molecules. Researchers design and synthesize small molecule chemical probes to functionally target and covalently label enzymes, receptors, and nucleic acids based on catalytic activities or selective affinities. Using fluorescent or mass spectrometry–based readouts, chemical probe platforms facilitate rapid and quantitative screening of cells, tissues, and biological fluids from microbes, animal models, and humans. Compared with conventional transcriptomics and proteomics, chemical probes provide measurements of functional activity rather than total abundance of transcripts, proteins, or nucleic acids. As such, chemical probes have recently gained popularity among research toxicologists and drug developers as tools to measure enzymatic activity important in metabolism and identify novel molecular binding targets of toxicants and drugs.

This course will highlight innovative methods using chemical probes in the field of toxicology. The first presenter will cover how chemical probes can measure enzyme activity and resulting consequences of enzyme variability, induction, and ontogeny and impacts on chemical metabolism. The next presenter will demonstrate how chemical probes can be used to identify novel targets of organophosphates beyond acetylcholinesterase inhibition. Finally, the last presenter will discuss how chemical probes can reveal chemically induced damage to DNA and resulting mutations.


Activity-Based Protein Profiling to Better Understand, Measure, and Translate Metabolism. Jordan N. Smith, Pacific Northwest National Laboratory, Richland, WA.

Activity-Based Protein Profiling for Identifying and Translating Organophosphate Targets across Animal Models. Vivian S. Lin, Pacific Northwest National Laboratory, Richland, WA.

Next-Generation DNA Damage Sequencing. Shana J. Sturla, Eidgenössische Technische Hochschule Zürich, Zurich, Switzerland.

CE02  

Live Course Presentation Time:

11:00 AM–2:45 PM (US EST, UTC -5)

Chair(s):

Justin Colacino, University of Michigan; and Sudin Bhattacharya, Michigan State University.

Primary Endorser:

Molecular and Systems Biology Specialty Section

Other Endorser(s):

Computational Toxicology Specialty Section; Mixtures Specialty Section

In recent years, single cell genomic analyses have provided a foundational new understanding of development and disease. While these novel and exciting technologies are being adopted across many fields in biology, their usage in the toxicological sciences is not yet widespread. This Continuing Education course will highlight the applications and current best practices for single cell genomics analyses in toxicology. The lectures will describe experimental design and analytic considerations for single cell experiments, define best practices and an overview of analytic methods for single cell RNA-sequencing and single cell chromatin profiling with ATAC-seq, and identify the state-of-the art computational methods for integrated single cell multi-’omics analyses and new machine-learning techniques to best apply single cell technologies in toxicology studies. The content of the course will benefit researchers from industry, government, and academia who evaluate mechanisms of action and safety of experimental compounds, consumer products, and environmental exposures and want to learn more about emerging technologies in this rapidly evolving area.


Experimental Considerations and Best Practices for Single Cell Analyses in Toxicology. Justin Colacino, University of Michigan, Ann Arbor, MI.

Application of Single Cell Transcriptomics to Mechanistic Toxicology. Peer Karmaus, NIEHS, Research Triangle Park, NC.

Epigenetic Profiling and Chromatin Confirmation Analysis with Single Cell ATAC-Seq. Poudyal Rosha, 10x Genomics, Pleasanton, CA.

A Practical Guide for Single Cell Data Analysis. Lana Garmire, University of Michigan, Ann Arbor, MI.

CE03  

Live Course Presentation Time:

11:00 AM–2:45 PM (US EST, UTC -5)

Chair(s):

Jessica LaRocca, Corteva Agriscience; and Edward LeCluyse, LifeNet Health.

Primary Endorser:

Mechanisms Specialty Section

Other Endorser(s):

Regulatory and Safety Evaluation Specialty Section

Understanding disruption of thyroid signaling pathways and thyroid homeostasis following exposure to environmental, agricultural, and industrial chemicals is both an evolving and an increasingly important challenge in the global regulatory community. This session will focus on innovative new approach methodologies (NAMs), such as 3D microtissues, organ-on-a-chip, hepatic thyroxine clearance models, and computational approaches, that are being developed for predictive and mechanistic thyroid toxicology testing approaches. There is currently a heavy reliance on traditional animal testing approaches to evaluate the potential for a chemical to induce adverse thyroid effects, which are time and resource intensive. In fact, several in vivo guideline studies were recently updated to include additional thyroid-related apical endpoints, such as thyroxine and thyroid-stimulating hormone measurements. There is an opportunity to harness new transformative approaches, such as in silico screening and organotypic in vitro models, to replace animal-intensive testing programs to identify thyroid disrupting toxicants and elucidate the mode of action and human relevance. Embracing NAMs can both provide valuable information to aid in molecule design from a predictive safety standpoint and provide guidance for targeted toxicological testing strategies. With continual progress in screening assays for thyroid hormone disruption as demonstrated by recent publications and new releases of data, and with endocrine-disruptor identification in the EU being dependent on such assays to identify points of chemical interaction with the thyroid pathway, this session will provide a timely update on the data and tools available for rapidly evaluating in vitro activity relevant to the thyroid adverse outcome pathway network. To this end, experts from industry, the United States government, and the European Commission will discuss the current state-of-the-science and how these approaches are being utilized for predictive and mechanistic studies as well as regulatory toxicology applications. Each speaker will discuss opportunities for NAMs to be integrated in chemical safety evaluation. After the presentations, a Q&A will engage attendees to enable deeper understanding of the current state-of-the-art approaches for addressing chemical-induced thyroid-related bioactivities. The target audience would be those interested in understanding how these tools are being leveraged in real-world regulatory testing paradigms. They also will gain insight into the strengths, limitations, and future development opportunities of in vitro, in silico, and alternative models for predictive and mechanistic thyroid toxicity assessments.


Integration of In Vitro and Aquatic Embryo Models to Predict Direct and Indirect Thyroid Toxicity Modes of Action. Jessica LaRocca, Corteva Agriscience, Indianapolis, IN.

Development of Novel In Vitro Assay Technologies for Human Thyroid Screening. Chad Deisenroth, US EPA/CCTE, Research Triangle Park, NC.

Mechanistic Nonanimal Methods for the Detection of Thyroid Disruptors in the EU Regulatory Context. Sharon Munn, European Commission, Lombardy, Italy.

In Vitro Methods to Address Species Differences in Liver-Mediated Thyroid Toxicity. Remi Bars, Bayer SAS, Valbonne, France.

State-of-the-Science: ToxCast and Tox21 Assays and Approaches to Screening for Potential Thyroid Hormone Disruption. Katie Paul-Friedman, US EPA/CCTE, Research Triangle Park, NC.

CE04  

Live Course Presentation Time:

11:00 AM–2:45 PM (US EST, UTC -5)

Chair(s):

Wei Zheng, Purdue University; and Edward Levin, Duke University.

Primary Endorser:

Metals Specialty Section

Other Endorser(s):

Mechanisms Specialty Section; Neurotoxicology Specialty Section

Advancement of metal toxicology, from a historical perspective, relies on innovation in science and technology. Discovery of atomic absorption spectrophotometry in the 19th century made it possible to quantify metals in the environment and human body, representing a turning point in understanding metals’ effects on human health. Since then, a variety of animal models have been developed—ranging from drosophila, C. elegans, and zebrafish to rodents and nonhuman primates—for in vivo metal toxicity evaluation. Recent advances in specific fluorescent metal-binding ligands have further allowed tracing of the subcellular trafficking of metals by live imaging in cells and tissues. For mechanistic investigation, the CRISPR technology permits impeccable gene editing, lending itself to an effective, precise, and affordable method for identification of modes of metal toxicity. Moreover, big data algorithms and artificial intelligence (AI) offer advantages not only by the machine learning for fast processing of existing data, but more importantly through learning, it maximizes the chances of successful choices for better prediction of metal’s health impact. Achievements notwithstanding, application of these technologies—especially AI in infotechnology and CRISPR in biotechnology, two leading technology breakthroughs—in basic metal toxicological research remains in its infancy. This basic course is designed to introduce essential concepts and new technologies in the metal toxicology research field. The first lecture will review the history of metal toxicology in the context of historical technology advancement, followed by identifying gaps in the field and the future direction of trace element research. The second lecture will introduce the principles in metal quantification, with a focus on using genetic- and protein-based biomarkers for assessment of metals in cells and tissues; the speaker also will discuss fluorescent reporters and high-tech imaging and spectroscopy in metal research. The third lecture will discuss the concepts, general approaches, and applications of CRISPR for precise mechanistic study of metal toxicity; the speaker will teach this revolutionary technology from his own experience on the ideal procedure for investigation of metal-induced neurotoxicities. The fourth lecture will focus on the essential framework and considerations for choosing the most informative animal model to study modes of metal toxicity, neurotoxic risk, and therapeutic treatment. Finally, the last lecture will introduce the basic concept and general practice of AI in health research, followed by integrative examples of how to use AI to interpret chemical toxicities as well as the policy regulation. Each lecture captures the most up-to-date knowledge and development in the field and discusses the concepts and technologies with details specific to metals that have particular human environmental and occupational health relevance, such as lead (Pb), manganese (Mn), cadmium (Cd), arsenic (As), silver (Ag), and mercury (Hg). The course will benefit those who desire to learn basic knowledge on technologies for mechanistic interpretation, novel concepts of machine-assisted prediction of metal or chemical toxicities, and technical approaches in utilizing widely available CRISPR and cellular imaging technologies that can be used to support research in metal toxicology. As the course introduces these techniques that are equally applicable to other fields, such as neurotoxicology, nanotoxicology, carcinogenesis, risk assessment, and occupational health, researchers engaged in these wider aspects of toxicological sciences shall benefit by attending this basic course and learning the knowledge beyond metals.


Brief History of Metal Toxicology: Propelled by Discovery and Technology Innovation. Wei Zheng, Purdue University, West Lafayette, IN.

Concepts and Applications of Metal Detection and Measurement Technology for Cellular, Tissue, and Organism Exposure Assessments. Aaron Bowman, Purdue University, West Lafayette, IN.

Introduction of CRISPR Technology and Its Uses in Studying Metal Neurotoxicity. Somshuvra Mukhopadhyay, University of Texas at Austin, Austin, TX.

Basic Considerations for Choosing Optimal Animal Models for Assessing Metal-Induced Neurobehavioral Toxicity. Edward Levin, Duke University, Durham, NC.

Artificial Intelligence in Regulatory Toxicology: Concept, Strategy, and Possible Application in Metal Toxicity Assessment. Weida Tong, US FDA/NCTR, Little Rock, AR.

CE05  

Live Course Presentation Time:

10:00 AM–1:45 PM (US EST, UTC -5)

Chair(s):

Mansi Krishan, Becton, Dickinson and Company; and Brittany Baisch, Henkel Corporation.

Primary Endorser:

Sustainable Chemicals through Contemporary Toxicology Specialty Section

Other Endorser(s):

Ethical, Legal, Forensics, and Societal Issues Specialty Section; Women in Toxicology Special Interest Group

Developing sustainable products with less impact on the environment and human health requires additional considerations and legwork by toxicologists. Performing the appropriate risk assessments for consumer product goods and pharmaceuticals is of paramount importance, but there are many added layers if the product has sustainable attributes. Sustainable products are those that address current-day challenges of depletion of natural resources, high energy consumption, and release of chemicals and waste into the environment. Furthermore, sustainable products also are those for which consumers hold high expectations of having more transparency about the ingredients and containing fewer ingredients overall, yet also anticipate a certain level of satisfaction and product performance. Global regulatory agencies, academicians, product developers, and manufacturers have been working toward developing such sustainable, innovative, safe, efficacious, and cost-effective solutions for consumers. With advances in substituting existing substances and processes with greener alternatives, there is a need for holistic methodologies that ensure that the substituted products and processes leave a smaller environmental footprint throughout their life cycle. Toxicologists must integrate all these considerations into their product safety risk assessments. The Organisation for Economic Co-operation and Development (OECD) publication Fostering Innovation for Green Growth highlights how the chemical industry and chemical management serve as examples of a scientific discipline that influences innovation in green technologies. As the demand for sustainable products increases, there is a need to integrate the elements of green and sustainable chemistry, such as green engineering, with toxicology early in the product development process. The field of “green toxicology” expands on the principles of green chemistry to develop products that not only are safe for use but also result in reduced human exposure, waste, or environmental impact; address climate change; and are not resource intensive. The US EPA Toxics Release Inventory and Safer Choice Program and USDA Biobased certifications highlight the shift toward ingredient safety and transparency, as well as the incorporation of 21st-century toxicological principles and advances with green chemistry to develop sustainable alternatives. This shift emphasizes the need for toxicologists to provide guidance on the requirements in the development of sustainable alternatives, how to perform substitutions, how to conduct risk assessments on alternatives, and how to meet sustainability-related certifications and claims. This CE course will provide an overview of the role of the safety assessment toxicologist in bringing sustainable solutions to the market, with case studies from different sectors. The speakers will present (1) the key principles of green chemistry and how they intersect with toxicology, and key opportunities for toxicologists to be engaged with the selection of more sustainable ingredients; (2) US EPA programs such as the Toxics Release Inventory and Safer Choice, the national analyses that demonstrate the use of databases and assessment tools by toxicologists to identify and prioritize specific chemicals that, if replaced, can reduce the impact on waste streams in various industries; (3) the importance of understanding consumer expectations and how regulatory toxicology, external certifications, and safety-related product claims converge to inform the safety assessment of a sustainable product, demonstrated with a laundry detergent case study; (4) strategies for the application of in silico, in vitro, and targeted in vivo tests within the stage gate development process to satisfy regional and pseudo-regulatory requirements from retailers to produce more sustainable personal care products; and (5) the toxicological assessment considerations in the design and manufacturing of pharmaceuticals. Attendees of this CE course will be equipped to apply the key principles of green toxicology, use different tools and approaches, and navigate certifications to build safety assessments for sustainable products, particularly for consumer products and pharmaceuticals. In addition, this CE course provides the opportunity for attendees to learn about a transdisciplinary field, capitalize on scientific advancements in safety assessment, and discover the robust role of toxicologists in innovating sustainable products and practicing product stewardship.


Green Toxicology Approaches toward Sustainable Environmental Quality. Bryan W. Brooks, Baylor University, Waco, TX.

The Toxics Release Inventory and Considerations for the Design of Safer, Sustainable Commercial Chemicals. Stephen C. DeVito, US EPA/OCSPP, Washington, DC.

Sustainability Adds Complexity to Product Safety Assessments: A Laundry Detergent Case Study. Brittany Baisch, Henkel Corporation, Trumbull, CT.

Sustainable Personal Care Ingredients and New Product Development—How to Optimize Safety Assessments That Meet Regional Requirements. Pamela J. Spencer, ANGUS Chemical Company, Buffalo Grove, IL.

Integration of New Testing Methods and Strategies in Pharmaceutical Product Development toward Green Toxicology: Where Are We Today? Brinda Mahadevan, Abbott, Mumbai, India.

Friday, March 19

CE06  

Live Course Presentation Time:

9:30 AM–10:30 AM (US EDT, UTC -4)

Chair(s):

Jane Ellen Simmons, US EPA/CPHEA; and Richard Hertzberg, Emory University.

Primary Endorser:

Mixtures Specialty Section

Other Endorser(s):

Risk Assessment Specialty Section; Women in Toxicology Special Interest Group

Design, conduct, analysis, and interpretation of mixtures experiments are daunting challenges. Frequently, defined-mixture experiments investigate whether the response of a mixture is predictable from the dose-responses curves of the component chemicals. Experimental toxicologists have found that guideline study designs, while extremely valuable for intended purposes, are often not useful for investigation of consistency or lack of consistency with various definitions and forms of additivity (e.g., dose/concentration addition, response addition). Not typically taught in toxicology courses, individuals seeking knowledge on experimental design for mixtures generally sort through sometimes bewildering literature, where sources seemingly, or actually, contradict one another. There is a long history of poorly designed and analyzed studies; the ability to use available literature to understand the potential for nonadditive interactions is hampered by these design and analysis issues. This sunrise course will shed light on the poorly illuminated topic of mixture experimental design. Attendees will leave the course informed on fundamental factors and important elements to consider when constructing defined-mixture experiments. Benefits of incorporating multidisciplinary expertise (the essential trio) will be discussed. The advantages of working with a qualified data analyst before executing the experiment will be contrasted with the inefficiency of statistical consultation only after data are in hand. Areas of focus will be the low-dose/low-effect region, particularly important when concerned with environmental agents; designs useful when higher-dose regions are of interest, such as combinations of pharmaceutical agents; and ensuring utility of results for risk assessment, risk management, and regulatory decision-making. Both frequently used and less common but important designs with associated analysis strategies will be covered, as will those that allow insight into biologically interpretable dose-response models. Key factors requiring consideration during construction of the design will be emphasized, including power, overall experimental size, dose level spacing, and placement of experiment units within dose groups. The design impact(s) of testing for greater-than additive versus less-than additive outcomes will be covered. The concepts and strategies covered apply to traditional in vivo, traditional in vitro (e.g., Salmonella mutational assays), and new approach methodology (NAM) experiments. Attendees will be provided a curated, annotated bibliography for future reference. Example mixtures covered in the course and/or the annotated bibliography include mixtures of chemicals known or thought to act either by a common mechanism/mode of action/adverse outcome pathway or by dissimilar mechanisms/modes/pathways. While design and statistical considerations will be illustrated with mixtures relevant to occupational, pharmaceutical, and environmental exposures, the concepts are broadly and generally applicable. At the conclusion of the course, attendees will be better equipped to answer the perennially vexing question: What is the optimal defined-mixture experiment for my goals? Attendees will acquire a foundation of knowledge equipping them to participate more fully in selection or construction of experiments suitable to the goal(s) of the study, yielding data that meet the criteria for appropriate statistical analyses. In addition to toxicologists interested in defined-mixture experiments, this course will be of value to those who evaluate or use the results of such experiments. Because of the multidisciplinary collaboration required for fit-for-purpose, high-quality defined-mixture experimentation, the presentation will be given jointly (in true mixtures fashion).


Toxicology and Experimenter Perspective. Jane Ellen Simmons, US EPA/CPHEA, Research Triangle Park, NC.

Statistical and Risk Assessment Perspective. Richard Hertzberg, Emory University, Atlanta, GA.

CE07  

Live Course Presentation Time:

11:00 AM–2:45 PM (US EDT, UTC -4)

Chair(s):

AtLee Watson, Integrated Laboratory Systems Inc.; and Aileen Keating, Iowa State University.

Primary Endorser:

Reproductive and Developmental Toxicology Specialty Section

Other Endorser(s):

Regulatory and Safety Evaluation Specialty Section

The development, maturation, and function of the female reproductive system is a complex, dynamic process in humans and laboratory animals and is sensitive to perturbation following exposure to a range of environmental and pharmacological agents. As a result, preclinical studies involving therapeutics intended for use in the female population or agents with potential widespread human exposure often require toxicologic and histopathologic assessments of female reproductive endpoints to demonstrate safety. Evaluation of these endpoints in laboratory animals necessitates an understanding of considerations that include developmental timing, concordance of clinical and histopathological correlates, species differences, and the translational relevance of animal findings to the broader human population. The objective for this advanced CE course is to provide attendees with an overview of the development and maturation of the female reproductive system, study design considerations, and pathology and regulatory perspectives to facilitate interpretation of abnormal findings observed in in vivo animal studies. Speakers from academia, industry, and government (research and regulatory) with expertise in the fields of female reproductive and developmental toxicology will provide attendees with (1) a concise review of the development of the female reproductive tract, highlighting species differences and known targets; (2) current toxicologic and histopathologic methods to assess effects on female reproductive function and cyclicity; (3) distinct mechanisms of toxicity in adult female rats, including the onset of sexual maturity, cycling, and reproductive senescence; and (4) a regulatory perspective that will cover recent draft guidance from the US Food and Drug Administration and other regulatory bodies and include relevant case examples to illustrate specific issues encountered when reviewing preclinical toxicity packages for small molecules and biologics. Note: this course will complement the CE course “The Male Reproductive Tract: Development, Toxicology, and Pathology,” presented as part of the scientific program during the 2020 SOT Virtual Meeting. The course “The Male Reproductive Tract: Development, Toxicology, and Pathology” is available as part of the SOT CEd-Tox, the Society’s online continuing education course program.


Unscrambling Female Reproductive Toxicology. Aileen Keating, Iowa State University, Ames, IA.

Methods and Approaches to Evaluate the Female Reproductive Tract. Darlene Dixon, NIEHS/NTP, Research Triangle Park, NC.

Mechanisms and Patterns of Toxicity in the Female Reproductive System: A Pathologist’s Perspective. Justin Vidal, Charles River, Mattawan, WI.

Regulatory Considerations for Reproductive Toxicity Testing of Pharmaceuticals. Andrew McDougal, US FDA/CDER, Silver Spring, MD.

CE08  

Live Course Presentation Time:

11:00 AM–2:45 PM (US EDT, UTC -4)

Chair(s):

Jason Ekert, GlaxoSmithKline plc; and Anthony Bahinski, GlaxoSmithKline plc.

Primary Endorser:

In Vitro and Alternative Methods Specialty Section

Other Endorser(s):

Drug Discovery Toxicology Specialty Section; Mechanisms Specialty Section

Drug failures in clinical trials are mainly due to the poor translational relevance and clinical predictive power of existing preclinical models, which include human cell-based in vitro and animal models. Microphysiological systems (MPS) (or organs-on-chips [OOC]) bring together advances in stem cell/organoid biology, biomaterials, tissue engineering, and biosensors to generate healthy and diseased models, where these human organ biomimetics more closely model the organ’s physiology and pathophysiology. There is a clear need to enhance predictability of toxicities that may be encountered in human subjects. Human MPS models may assist to better identify early potential toxicity and elucidate the mechanism of toxicity once identified. The goal of the course will be to outline general principles and considerations of the appropriate use of OOC/MPS models in drug development for safety evaluation and highlight advantages/limitations in the current models. The first talk will give an overview and history of OOC/MPS. The tissue chip developer will discuss how to leverage MPS technology for generating toxicity assays and will give several examples of systems that have been used to evaluate toxicological events. The second presentation will focus on the characterization and validation of linked organ chip systems that could be utilized for PK/PD modeling and for a predictive way to model human drug toxicity. The third presentation will give insights and recommendations from a pharma perspective when implementing 3D/MPS for early toxicology testing and for later-stage toxicology investigations in a drug discovery setting. The final presentation will be given from a regulatory perspective that will inform the audience about performance criteria, standardizing the evaluation of MPS, and the importance of utilizing human cellular material and will present cardiac and liver MPS case studies. This course should be of broad interest to laboratories considering using 3D/OOC/MPS platforms as a mechanistic approach to predicting and understanding human organ system toxicities.


Organ-on-a-Chip/Microphysiological Systems to Improve Culture and Assaying of In Vitro Tissue for Toxicological Testing. Joseph Charest, Charles Stark Draper Laboratory Inc., Cambridge, MA.

Quantitative Prediction of Human Pharmacokinetic Responses to Drugs via Fluidically Coupled Vascularized Organ Chips. Rachelle Prantil-Baun, Wyss Institute for Biologically Inspired Engineering at Harvard University, Cambridge, MA.

Considerations When Developing and Implementing 3D/MPS Models for Safety Testing and Investigative Toxicology in Pharmaceutical Drug Development. Jason Ekert, GlaxoSmithKline plc, Collegeville, PA.

Evaluation of Cardiac and Hepatic Cellular Microsystems for Drug Development. Alexandre Ribeiro, US FDA/CDER, Silver Spring, MD.

CE09  

Live Course Presentation Time:

11:00 AM–2:45 PM (US EDT, UTC -4)

Chair(s):

Lauren Lewis, Takeda Pharmaceutical Company Limited; and Samantha Faber, Takeda Pharmaceutical Company Limited.

Primary Endorser:

Drug Discovery Toxicology Specialty Section

Other Endorser(s):

Clinical and Translational Toxicology Specialty Section; Regulatory and Safety Evaluation Specialty Section

New chemical modalities (such as RNA-based or oligonucleotide gene therapies) represent a paradigm shift in drug discovery and toxicology. While these molecules were initially developed as therapeutics more than 30 years ago, novel sequences, chemistries, and delivery mechanisms have introduced unknown safety risks that require toxicologists to expand beyond the traditional small molecule chemical space and think more broadly when assessing potential hazards and how toxicological effects will impact meaningful therapies for patients. This Continuing Education course will serve as a roadmap for how to approach evaluating safety concerns for novel oligonucleotides starting in early drug discovery phases through regulatory development, and will detail approaches to design oligonucleotide-based gene therapies with safety in mind. The course will begin with an overview that explores the advances of oligonucleotide platforms over the last three decades and outlines the obstacles faced by toxicologists to evaluate safety for novel oligonucleotide sequences. Our first speaker will delve into chemical and structural sequence alterations associated with toxicity as well as share a case study that highlights the importance of sequence selection for optimizing tolerability. The next speaker will explore several studies that emphasize the importance of in vitro assays for predicting oligonucleotide-dependent toxicity and the utility of 3D microphysiological systems for de-risking oligonucleotide platforms. The third speaker will focus on available preclinical in vivo models for oligonucleotide toxicity studies and concerns regarding cross-species differences in response. The fourth speaker will discuss the preclinical and clinical oligonucleotide therapy landscape and findings from a meta-analysis study detailing the main adverse events driving attrition of oligonucleotide candidates in the clinic. The final speaker will conclude the course with discussion of regulatory approaches for novel oligonucleotide gene therapies and the advantage of pre-IND discussions to ensure successful development of novel compounds. Navigating a new chemical modality space can be challenging, especially when no defined regulatory pathway exists; therefore, this course offers a guide for the development of novel RNA-based therapeutic platforms from chemical toxicology through drug development. As experts in their field, the speakers offer key insights into drug discovery and toxicological parameters that are essential for successful development of oligonucleotide therapy platforms and will aid in advancing our understanding of unforeseen drug-induced toxicological endpoints for improved human health and safety.


Strategic Thinking in Early Drug Discovery for RNA-Based Therapeutics. Lauren Lewis, Takeda Pharmaceutical Company Limited, Cambridge, MA.

Chemical Toxicology Approaches to Selecting Oligonucleotides. Andrew Burdick, Pfizer Inc., Cambridge, MA.

In Vitro Approaches for Oligonucleotide Safety Profiling. Sebastien Burel, Ionis Pharmaceuticals, Cambridge, MA.

Preclinical Toxicity Models for Oligonucleotide Development. Patrik Andersson, AstraZeneca, Gothenburg, Sweden.

Drawing Strategies from Tragedies: A Meta-Analysis of Clinical Trial Data on Oligonucleotides. Samantha Faber, Takeda Pharmaceutical Company Limited, Cambridge, MA.

Regulatory Aspects Involved in Developing INDs for Novel Oligonucleotides and Strategies for Product Development. James Wild, US FDA/CDER, Silver Spring, MD.

CE10  

Live Course Presentation Time:

11:00 AM–2:45 PM (US EDT, UTC -4)

Chair(s):

Michelle Angrish, US EPA; and Shannon Bell, Integrated Laboratory Systems Inc.

Primary Endorser:

Risk Assessment Specialty Section

Other Endorser(s):

Computational Toxicology Specialty Section; In Vitro and Alternative Methods Specialty Section

Traditional chemical assessments are time-intensive, manual efforts requiring large amounts of human and experimental data. There are times, though, when a quick assessment of health impacts for a chemical is needed. Literature-based chemical assessments paired with computational and open-access (free) software applications (tools) can provide a quick, evidence-based solution. Human expertise supported by these tools can allow you to go from zero information to a preliminary hazard level without setting foot in the lab. Many freely available tools and workflows exist to support this process without adding on the cost for new software.

This course will provide an overview of the types of chemical health safety assessments and their information requirements, setting the stage for how tools can support rapid chemical evaluations. It will close with an example of how structured data extractions are deposited into US Environmental Protection Agency (US EPA) dashboards.

The format of the course follows the risk assessment process, as follows:

  • Identifying chemical information using literature search: No/little information on a chemical? Learn how to conduct a literature search for chemical data. Focus will be on search strategy, identifying studies with information of interest, and results prioritization.
  • Expanding the dataset using chemical similarity: Are the data for the chemical of interest limited, but rich for a structurally similar neighbor? Learn how to expand your chemical search for data-poor chemicals using structural similarity or apply new approach methods in chemical assessment while considering other key data.
  • Using in vitro evidence for toxicokinetic modeling: Is the evidence so limited (i.e., no information available at all) that a purely in vitro/in silico approach should be considered? Learn how to use in vitro to in vivo extrapolation to calculate in vivo measurements, even ones tailored to susceptible populations. This will help you go from internal concentrations (or close estimates) to external/applied exposure concentrations/doses.
  • Calculation of point of departure: Use the concentration response information from various data sources, including in vitro, in vivo, and in silico, to develop the point of departure (POD). You’ll need the POD to develop toxicity reference values that you can use to estimate safe exposure levels.

Course materials will include listing of additional resources, a walk-through of highlighted tools discussed, and example datasets. At the end of this course, participants will be able to:

  • Explore and prioritize data needed for rapid chemical assessment
  • Expand searches for data-poor chemicals using chemical analog toxicity information
  • Extrapolate in vitro bioactivity to in vivo exposure scenarios
  • Apply approaches for calculating POD

Welcome and Introduction. Michelle Angrish, US EPA, Durham, NC.

Identifying Data on Your Chemical. Neepa Choksi, Integrated Laboratory Systems Inc., Durham, NC.

Structure-Based Cheminformatics: Data Clustering and Visualization, Read-Across, AI/ML, and 3D Docking. Denis Fourches, North Carolina State University, Raleigh, NC.

httk and HTTK-Pop: Open-Source Software for Simulation of Population Variability in High-Throughput Toxicokinetic Modeling for In Vitro to In Vivo Extrapolation and Rapid Chemical Prioritization. Caroline Ring, ToxStrategies Inc., Austin, TX.

Open-Source Approaches to Calculating a Point of Departure. Lyle Burgoon, Raptor Pharm & Tox Ltd., Apex, NC.

Use of Specialized Software to Improve the Efficiency of Conducting Chemical Assessments and Interoperability with the US EPA CompTox Chemicals Dashboard. Kristina Thayer, US EPA, Durham, NC.

Use of Specialized Software to Improve the Efficiency of Conducting Chemical Assessments and Interoperability with the US EPA CompTox Chemicals Dashboard. Antony Williams, US EPA, Durham, NC.

Friday, March 26

CE11  

Live Course Presentation Time:

11:00 AM–2:45 PM (US EDT, UTC -4)

Chair(s):

Robert Moyer, Battelle Memorial Institute; and Jennifer Harris, Los Alamos National Laboratory.

Primary Endorser:

In Vitro and Alternative Methods Specialty Section

Other Endorser(s):

Drug Discovery Toxicology Specialty Section; Inhalation and Respiratory Specialty Section

Over the past several decades, there has been a disturbing trend of declining efficiency in drug research and development. This trend has led to unsustainable cost growth for pharmaceutical research and highlights a significant risk for the development of new drugs. One of the most compelling explanations is that the conventional “brute force” methods of drug discovery are reaching a point of diminishing returns. Animal tests are too slow and expensive to keep pace with increasing demands for innovation and often fail to predict human responses because traditional animal models frequently do not accurately mimic human physiology. Organ-on-a-chip systems have the potential to address these concerns and meet the growing need for rapid, affordable, and replicable preclinical models. They offer the benefits of using human cells to recreate functions of living human organs, thus bridging the gap between extensively studied animal models and human clinical trials. As with any model, some level of confidence in the results provided is necessary for the successful implementation of organ-on-a-chip models, and widespread agreement in the field on approaches for the validation of organs-on-a-chip will be essential. This course will present considerations for the validation of organ-on-a-chip models for toxicity assessment from the perspectives of regulatory, industry, and academic stakeholders, with lung-on-a-chip as an example. The course Co-Chairs will begin the session with a brief introduction of the topic and the speakers. The first two speakers will be representatives of US government agencies. The first speaker, a representative from the US Food and Drug Administration, will discuss regulatory compliance and application requirements that significantly impact the use of organs-on-a-chip technologies for drug discovery and development. She also will describe current thinking on use of nonanimal alternatives in efficacy and toxicology testing. The second speaker, representing NIEHS and ICCVAM, will focus on the challenges and lessons learned from past and current validation efforts. The next three speakers, including representatives from academia, government, and industry, will present the perspectives of laboratories that conduct organ-on-a-chip research, development, and validation efforts. The third speaker will present the development and validation of a multi-organoid “body-on-a-chip” platform for testing drug toxicity and developing countermeasures for toxic agents. Next, the fourth speaker will describe the applications for and validation efforts with a multi-bioreactor platform that recapitulates bronchiolar and alveolar aspects of the human lung. Finally, the last talk will be a collaborative presentation describing the design and validation of a breathing lung-on-a-chip that integrates reliable and reproducible application of test aerosols at the air-liquid interface. This course includes a diverse group of speakers and topics that will translate well to the target audience of scientists and practicing toxicologists. Attendees from academic institutions, government, and industry alike will be well represented and have sincere interest in the overall discussion. Attendees will leave the session with a greater understanding of the regulatory considerations, lessons learned, and potential next steps for the validation of organ-on-a-chip systems for toxicity testing.


Implementing New Testing Approaches at the US Food and Drug Administration. Suzanne Fitzpatrick, US FDA/CFSAN, College Park, MD.

Organ-on-a-Chip Validation Efforts: Challenges and Lessons Learned. Warren Casey, NIEHS/NICEATM, Durham, NC.

Body-on-a-Chip. Anthony Atala, Wake Forest School of Medicine, Winston-Salem, NC.

PuLMo: A National Laboratory Perspective of the Development and Validation of Lung-Organ-Systems-on-a-Chip. Jennifer Harris, Los Alamos National Laboratory, Los Alamos, NM.

A New Breathing Lung-on-Chip Aerosol Exposure System. Janick Stucki, AlveoliX AG, Bern, Switzerland.

A New Breathing Lung-on-Chip Aerosol Exposure System. Tobias Krebs, VITROCELL Systems GmbH, Waldkirch, Germany.

CE12  

Live Course Presentation Time:

11:00 AM–2:45 PM (US EDT, UTC -4)

Chair(s):

Bethany Hannas, Corteva Agriscience; and Natasha Catlin, Pfizer Inc.

Primary Endorser:

Reproductive and Developmental Toxicology Specialty Section

Protection of humans from excessive exposures to chemicals and pharmaceuticals associated with toxicity can be managed through risk assessment. Developmental and Reproductive Toxicity/Endocrine Disruption (DART/ED) hazard identification (ID) is a critical component of the risk assessment process. DART/ED hazard ID also is used independent of exposure assessment considerations to label compounds with DART or ED properties and, in some cases, limit or prevent sales in certain geographies. Although risk assessment or hazard ID applications can differ across sectors and geographies, scientists often collaborate on best practices for methods and interpreting endpoints within DART and endocrine-specific toxicity studies. This course will therefore provide a view of the regulatory landscape for DART/ED assessments, focusing on specific case studies as examples of applying DART/ED data to the end goal of protection of human health through risk assessment. The first talk will focus on the application of DART data for regulatory decision-making in the pharmaceutical sector. The second talk will then cover specific pharmaceutical case studies with DART data from nonclinical studies and the determination of human risk. The third talk will give an overview of endocrine disruption and how DART data apply to ED-specific requirements for chemicals across geographies, with examples of regulatory decisions based on existing datasets. The fourth talk will provide an overview of the US perspective on application of DART and ED data to the risk assessment process for chemicals, with a specific example focused on thyroid assessments. Finally, the fifth talk will introduce alternative approaches for DART/ED assessments and the vision for application of alternative approaches to regulatory decision-making. This will be a crash course on the current regulatory approach to use of DART/ED data, with a view to the future, considering alternatives to animal testing approaches. As such, this course will offer broad appeal to audience members of different backgrounds and may be of interest to trainees interested in a career in regulatory toxicology.


Introduction. Bethany Hannas, Corteva Agriscience, Newark, DE.

DART in Risk Assessment for Pharmaceuticals. Ilona Bebenek, US FDA/CDER, Silver Spring, MD.

Case Studies of Regulatory Decision-Making Based on DART Data for Pharmaceuticals. Natasha Catlin, Pfizer Inc., Groton, CT.

Sufficiency of Pesticides DART Data Package for Endocrine Disruption Assessments: A Global Perspective on Regulatory Requirements for Human Health. Bethany Hannas, Corteva Agriscience, Newark, DE.

Thyroid Hormone Assessment: Implications for Developmental and Reproductive Toxicology. Elizabeth Mendez, US EPA, Washington, DC.

Application of Alternative Approaches for DART/ED to Regulatory Decisions. George Daston, Procter & Gamble, Mason, OH.

CE13  

Live Course Presentation Time:

11:00 AM–2:45 PM (US EDT, UTC -4)

Chair(s):

Emanuela Corsini, Università degli Studi di Milano, Italy; and Florence Burleson, Burleson Research Technologies.

Primary Endorser:

Immunotoxicology Specialty Section

Two major features in the process of aging of the human immune system are immunosenescence and inflammaging. Immunosenescence refers to the gradual deterioration of the immune system by natural age advancement and is one of the potential reasons for the increase in the incidence of infections. The term “inflammaging” was coined to combine the processes of inflammation and aging, since chronic, low-grade, systemic inflammation is associated with aging, contributing significantly to age-related diseases and mortality risk in the elderly. With age, the immune system undergoes adaptations and modifications, with important consequences for both communicable and noncommunicable diseases, for which the contribution of chemical exposure is not fully understood. This Continuing Education course aims to cover mechanisms of inflammaging and immunosenescence, their consequences, and implications in terms of response to vaccination, drugs, and immunotoxic compounds, which is timely and relevant in the era of COVID-19.

The first speaker will introduce the audience to the current understanding of the biology underlying immunosenescence and inflammaging, and their contribution to age-related diseases. The second speaker will cover the problems associated with an effective vaccination and discuss how the understanding of immunosenescence will help in the design of more effective vaccines for the elderly. The third speaker will discuss the merits of animal models and their usefulness in the study of immunosenescence and drug-induced liability in a growing older population. Finally, the last speaker will cover the role of age in chemical-induced immunotoxicity and how the understanding of the mechanism of action underlying chemical toxicity is central to define an increased risk—or not—in the elderly. Overall, this course aims to contribute to the understanding of physiological aging in the response to vaccines, drugs, and chemicals, which is considered of fundamental importance in light of an increasingly older population.


Role of Immunosenescence in the Development of Age-Related Diseases. Tamas Fulop, Université de Sherbrooke, Sherbrooke, QC, Canada.

Aging and the Immune System: Impact on Infections and Vaccine Immunogenicity. Claudia Wrzesinski, US FDA/CBER, Silver Spring, MD.

Nonhuman Primate Models of Immunosenescence in Preclinical Biotherapeutic Testing. Padma Kumar Narayanan, Janssen: Pharmaceutical Companies of Johnson & Johnson, San Diego, CA.

Impact of Immunosenescence on Immunotoxicity: From Mechanistic Understanding to Susceptibility to Immunotoxicants. Emanuela Corsini, Università degli Studi di Milano, Milan, Italy.

CE14  

Live Course Presentation Time:

11:00 AM–2:45 PM (US EDT, UTC -4)

Chair(s):

Ruili Huang, NIH/NCATS; and Menghang Xia, NIH/NCATS.

Primary Endorser:

Women in Toxicology Special Interest Group

There is a large number of chemicals in the environment that lack adequate toxicological characterization necessary for the assessment of their exposure risk and subsequent regulatory decision-making. In order to generate toxicity profiles effectively on large sets of compounds, the US Tox21 and US Environmental Protection Agency (US EPA) ToxCast programs have developed in vitro assays to test thousands of environmental compounds in a high-throughput screening (HTS) format. To date, more than 100 million data points have been generated from these screens and made publicly available. These datasets can aid in the identification of previously uncharacterized toxicants as well as the development of computational models for toxicity prediction. However, there are technical aspects and caveats associated with these HTS assays that are not well understood by the end users, creating a gap between data generation and data interpretation. To bridge this gap, this Continuing Education course will provide an explanation and guidance on the understanding of Tox21/ToxCast HTS data to be applied more efficiently to toxicological modeling. The course will start with a presentation that describes various HTS assays used in the Tox21/ToxCast screening programs, followed by presentations describing different data processing methods and activity definitions dealing with biological and technological artifacts, a presentation comparing these data analysis methods, and finally a presentation on example applications to computational modeling. Live demos of the databases containing the results from different analysis pipelines will be included in some presentations. The content of this course will benefit researchers in the toxicology field, especially computational scientists who wish to develop models using the screening data and learn more about the assay technologies and data analysis methodologies.


Application of Various Assay Technologies for Tox21 Screening. Menghang Xia, NIH/NCATS, Rockville, MD.

A Quantitative High-Throughput Screening Data Analysis Pipeline for Activity Profiling. Ruili Huang, NIH/NCATS, Rockville, MD.

Analyzing and Interpreting Tox21 Quantitative High-Throughput Screening (qHTS) Data from a Data Science Perspective. Jui-Hua Hsieh, NIEHS/NTP, Durham, NC.

An Update on the ToxCast Data Pipeline: New Features for Dataset Development. Katie Paul-Friedman, US EPA/CCTE, Durham, NC.

Concentration-Response Modeling in High-Throughput Transcriptomics. Richard Judson, US EPA/CCTE, Durham, NC.

Interpreting the Tox21 Data Analysis Methods toward a Consensus. Agnes Karmaus, Integrated Laboratory Systems Inc.

Use of Tox21 Data for QSAR Modeling of Different Minimum Potency Levels for Aromatase Inhibition and PPAR-Gamma Activation in the H2020 FREIA Project. Eva Wedebye, DTU Fødevareinstituttet, Danmarks Tekniske Universitet, Lyngby, Denmark.