{ "data": [ { "SessionID": 1, "Title": "Adding Up Chemicals: Component-Based Risk Assessment of Chemical Mixtures", "Year": 2017, "Topic": "Risk Assessment", "Transcription": 0, "Description": " Register/Login

Chairperson(s): Jane Ellen Simmons, US EPA, Research Triangle Park, NC; and Richard Hertzberg, Biomathematics Consulting, Atlanta, GA.

Endorser(s):

Mixtures Specialty Section

Occupational and Public Health Specialty Section

Risk Assessment Specialty Section

The relationship between structure and activity has been exploited in the hazard characterization of chemicals for several decades, including specifically the practice of “reading across” or applying toxicity data from one or more chemicals to another with a similar structure to fill a data gap. Read-across is currently a useful strategy to increase our understanding of chemical hazard without de novo testing. However, expertise, application, and acceptance of the results of a particular read across vary within and among organizations and geographical regions. There are a number of reasons for this, including regulatory or legislative drivers, an increasing motivation to expand the use of non-testing strategies, and minimal consensus around how to weigh evidence and address and express uncertainty. Recently, multiple stakeholder organizations have contributed to active and robust discussions on read across in a variety of venues in an effort to build consensus around these issues. This course will update participants on those efforts and provide practical guidance for conducting read-across for regulatory use, including across different regulatory regions. Speakers will present experience-driven case studies to share best practices and communicate the state-of the-art for structure-based read-across, while looking ahead at how results from New Approach Methodologies including in vitro, “omics,” and high throughput/content methods may be incorporated into a read across to improve its outcome.



Grouping Chemicals for Assessment and Conducting Assessments with the Hazard Index and Related Methods. Jane Ellen Simmons, US EPA, Research Triangle Park, NC.

Mode of Action, Experimental Design, and Model of Combined Action: Is There a Connection? Christopher J Borgert, Applied Pharmacology and Toxicology, Inc., Gainesville, FL.

The Flip Side: Methods for Independent Action, and Hybrid Methods for Interactions and for Mixed Modes. Richard C. Hertzberg, Biomathematics Consulting, Atlanta, GA.

A Case Study: How Mixture Data are Used in Risk Assessments for Genetically-Engineered Crops Expressing Multiple Insecticidal Traits. Steven L. Levine, Monsanto Company, St Louis, MO.


" }, { "SessionID": 3, "Title": "Adverse Outcome Pathway (AOP) Development and Evaluation", "Year": 2016, "Topic": "Regulatory and Safety Evaluation", "Transcription": 0, "Description": " Register/Login

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

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

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

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



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

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

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

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

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

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

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


" }, { "SessionID": 4, "Title": "Alternative In Vitro Toxicology Testing for the 21st Century", "Year": 2012, "Topic": "In Vitro Methods", "Transcription": 1, "Description": " Register/Login

Chairperson: Stephen H. Safe, Texas A&M University, College Station, TX

Endorsed by:
Risk Assessment Specialty Section

Over the last two decades, alternatives to animal testing were strongly driven by animal welfare considerations. A culture of organotypic cell models, quality assurance and validation developed, which resulted in a number of novel approaches for regulatory testing. Progress to replace especially the systemic and chronic types of tests has been limited. Novel programs to assess large number of substances such as existing chemicals (REACH and the emerging TSCA reauthorization), nanoparticles or mixtures, as well as new products such as biologicals and cell therapies now add to the need to move to another approach for toxicity testing. Additionally, interest in health effects like endocrine disruption, developmental neurotoxicity, immunotoxicity, obesity, atherosclerosis or childhood asthma require extensive and new types of testing. This is often referred to as Toxicity Testing for the 21st Century (Tox-21c), after the respective NAS vision document from 2007, which has been made US EPA’s toxicity testing strategy in 2009.The central change is moving from apical “black box” animal models to mechanism or pathway of toxicity (PoT). The biotechnology and bioinformatics revolution of recent years has made it possible to develop systems biology, here systems toxicology, approaches. The experiences from the field of alternative methods now prove to be the most important to implement a new regulatory approach. Standardization and validation of cell cultures is crucial for PoT identification as well as the implementation of high-throughput type of tests based on PoT. The first projects to systematically map the entirety of human PoT, the Human Toxome, have started. The validation of these novel tests represents an enormous challenge. It is proposed to follow the role model of evidence-based medicine. For this purpose, the evidence-based toxicology collaboration was started at SOT 2011 and is currently shaping its procedures and governance.

Alternative In Vitro Toxicology Testing for the 21st Century. Thomas A. Hartung, John Hopkins University Center for Alternatives to Animal Testing (CAAT), Baltimore, MD


" }, { "SessionID": 5, "Title": "An Introduction to the Exposome", "Year": 2015, "Topic": "Exposome", "Transcription": 0, "Description": " Register/Login

Chairperson(s): Gary W. Miller, Emory University, Atlanta, GA; and Martyn T. Smith, University of California Berkeley, Berkeley, CA.

Endorser(s):
Mixtures Specialty Section
Postdoctoral Assembly
Risk Assessment Specialty Section

The exposome has been defined as the totality of our exposures throughout our lifetime. Such a definition defies measurement making it less than useful as a scientific construct. More recently, the concept of the exposome has evolved to represent a measurable entity that encompasses our complex exposures and how our bodies respond to such exposures. The addition of the biological response component to the definition of the exposome positions the field of toxicology to make major contributions to the field. By providing an intellectual foil to the genome-centric framework in biomedical research, the exposome has the potential to elevate the importance of the environment in scientific circles and promote a framework that faithfully integrates the importance of the environment in health and disease. This course will introduce the attendees to the concept of the exposome, explain how it can be used to advance toxicological research by providing a clear translational output, and explain some of the innovative approaches being used to measure the exposome. In order for the exposome to become a useful concept it will be necessary to: (1) capture and quantify the complex exposures, (2) identify and quantify the diverse biological responses, and (3) to integrate these disparate datasets with advanced conceptual thinking and innovative bioinformatic and mathematical approaches. This course was designed to address these three objectives in an informative and interactive setting.



The Exposome: Introduction and Implications for Toxicology. Gary W. Miller, Emory University, Atlanta, GA.

Exposure Pathways, Biomarkers and the Exposome: Predictions, Insight, and Uncertainty. John F. Wambaugh, US EPA, Research Triangle Park, NC.

The Blood Exposome. Martyn T. Smith, University of California Berkeley, Berkeley, CA.

Exposome Bioinformatics: EWAS and Beyond. Chirag J. Patel, Harvard Medical School, Boston, MA.

" }, { "SessionID": 6, "Title": "Applications of Computational Systems Biology for Toxicology", "Year": 2011, "Topic": "Molecular Biology", "Transcription": 0, "Description": "Register/Login

Chairpersons: Melvin E. Andersen, The Hamner Institutes for Health Sciences, Research Triangle Park, NC, and Rory B. Conolly, US EPA, Research Triangle Park, NC

Sponsor: Molecular Biology Specialty Section

Endorsed by:
Biological Modeling Specialty Section

The field of toxicity testing and risk assessment is undergoing a shift from reliance on high-dose animal studies towards increased use of human in vitro systems that promise to provide mechanistic understanding of toxicity for environmentally relevant low-dose exposure. For this fundamental change, toxicologists will need to adopt more integrated experimental and computational approaches to resolve the structures of key signaling pathways, which are composed of functional network motifs, and to understand the consequences of chemical perturbation on the dynamic and steady-state behaviors of these pathways. This course introduces state-of-the-art computational systems biology tools that are being used for organizing and understanding molecular circuits under both physiological and perturbed conditions. A broad overview will first provide a historical context of dose-response studies based on understanding mode of action through cellular pathway perturbation. The course will describe signaling properties of a suite of recurring network motifs, including ultrasensitivity, feedback, and feedforward loops, to appreciate the basic building blocks of complex biochemical pathways and networks. Secondly, focusing on the DNA damage response and cell cycle progression pathways, we will illustrate how these network motifs are organized into molecular circuits to give rise to higher-level cellular functions and if perturbed, how functional aberrations result. Signal transduction networks activated by growth factors are then examined to show how pathway cross-talk and feedback loops define the activation logic of the downstream MAPK, which is a key determinant of cell growth and survival. Finally, we will shows how stochastic gene expression and the resulting non-genetic cell-to-cell variability plays a role in influencing dose response curves using examples such as B cell differentiation and its disruption by dioxin. The course concludes with a short summary and suggestions for applying these computational systems biology tools to future toxicity testing.

Introduction, Melvin E. Andersen, The Hamner Institutes for Health Sciences, Research Triangle Park, NC

Network Signaling Motifs, Qiang Zhang, The Hamner Institutes for Health Sciences, Research Triangle Park, NC

From Dynamics to Decisions: Quantitative Modeling of the Mammalian DNA Damage Response, Jared E. Toettcher, University of California San Francisco, San Francisco, CA

Dynamic Regulation of Growth Factor Signaling Networks, Jason M. Haugh, North Carolina State University, Raleigh, NC

Stochastic Gene Expression and Heterogeneous Cellular Response, Sudin Bhattacharya, The Hamner Institutes for Health Sciences, Research Triangle Park, NC

" }, { "SessionID": 7, "Title": "Approaches to Investigate and Assess Risks Associated with Drug-Induced Liver Injury (DILI)", "Year": 2016, "Topic": "Drug Discovery Toxicology", "Transcription": 0, "Description": " Register/Login

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

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

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

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



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

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

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

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

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

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


" }, { "SessionID": 8, "Title": "Assessment of Ocular Toxicity in Toxicology Studies Conducted for Regulatory Purposes", "Year": 2010, "Topic": "Ocular", "Transcription": 1, "Description": " Register/Login

Chairperson(s): Margaret Collins, Charles River Laboratories, Reno, NV, and Andrea Weir, Charles River Laboratories, Reno, NV

Sponsor: Toxicologic and Exploratory Pathology Specialty Section

Endorsed by: Regulatory and Safety Evaluation Specialty Section Comparative and Veterinary Specialty Section

Ocular toxicity is known to occur following intended or unintended exposure of ocular tissues to xenobiotics. It can occur following local exposure of the eye to an agent or after exposure via oral or other routes of administration. In order to define the risks that pharmaceuticals, pesticides, and other toxic substances pose to the eye, an assessment of ocular toxicity is routinely included in general toxicology studies conducted for regulatory purposes. Because anatomical and physiological differences between species can impact the nature of the ocular effects observed, understanding species differences is important. Although it is possible to detect some ocular effects, such as conjunctivitis, with the naked eye, more sensitive techniques are routinely used to assess ocular toxicity. Slit lamp biomicroscopy and indirect ophthalmoscopy are routinely utilized to more closely evaluate the anterior and posterior chambers of the eye, respectively, during the course of toxicology studies. At the time of necropsy, ocular tissues are collected and processed for histopathological evaluation. More specialized endpoints, such as electroretinography, can be incorporated, as needed. Ocular anatomy and physiology and the assessment of ocular toxicity can be challenging to scientists involved in the safety assessment of pharmaceuticals, pesticides and other agents. This basic course will cover ocular anatomy and physiology in laboratory animals, established methods used to assess ocular toxicity, as well as more novel techniques for toxicity assessment. Examples of ocular toxicity that can occur following different routes of exposure will be discussed.

Introduction and Overview, Margaret Collins, Charles River Laboratories, Reno, NV

Comparative Ocular Anatomy and Physiology in Laboratory Animals, Mark Vezina, Charles River Laboratories, Montreal, Quebec, Canada

Diagnostics in Ocular Toxicology, Robert Munger, Animal Ophthalmology Clinic, Dallas, TX

Diagnostics and Ocular Imaging in the 21st Century, Christopher Murphy, University of California, Davis, CA

Ocular Pathology: Looking at the Eye, Ken Schafer, Vet Path Services, Inc., Greenfield, IN

" }, { "SessionID": 9, "Title": "Basic Embryology and Developmental Toxicity Testing", "Year": 2012, "Topic": "Reproductive and Developmental Toxicology", "Transcription": 0, "Description": " Register/Login

Chairpersons: Christopher J. Bowman, Pfizer Worldwide Research and Development, Groton, CT, and Lori A. Dostal, Exponent, Inc., Farmington Hills, MI

Sponsor:
Reproductive and Developmental Toxicology Specialty Section

Endorsed by:
Regulatory and Safety Evaluation Specialty Section

Embryonic and fetal development in mammalian species is a complex process which is sensitive to the effects of maternal and environmental factors. The timing of development of the major organ systems varies between humans and other animal species, but the basic biology of development is similar in all species thus allowing extrapolation of animal testing results for xenobiotics to humans. The course will begin by providing an overview that highlights developmental biology from fertilization of the gametes to normal maturation of a full term placenta and fetus including examples of developmental toxicants and teratogens with known modes of action. Subsequently, applied toxicology concepts for evaluation of the potential for bio/pharmaceuticals and chemicals to affect pregnancy and embryo-fetal development will be discussed. Global regulatory strategies and requirements to minimize health effects on women and unborn children will also be addressed. Finally, key information will be presented to provide for a better understanding of the biological and toxicological basis of prenatal developmental toxicity testing and the impact of various outcomes on drug development, chemical use, environmental impact, and human health risk.

Introduction. Lori A. Dostal, Exponent, Inc., Farmington Hills, MI

Implantation, Placentation, and Early Embryonic Development. John M. DeSesso, Exponent, Inc., Alexandria, VA

Demystifying Mammalian Embryogenesis. Kathleen K. Sulik, University of North Carolina, Chapel Hill, NC

The Importance of Developmental Toxicity Testing to Pharmaceutical Development. Kimberley A. Treinen, Merck, Summit, NJ

Navigating Developmental Toxicity Testing of Agricultural Molecules and Industrial Chemicals. Reza J. Rasoulpour, Dow Chemical Company, Midland, MI

" }, { "SessionID": 10, "Title": "Basic Principles of Human Risk Assessment ", "Year": 2013, "Topic": "Risk Assessment", "Transcription": 0, "Description": " Register/Login

Theme: Regulatory Science: Advancing New Approaches for Hazard Identification and Risk Assessment

Chairperson(s): Qiyu (Jay) Zhao, US EPA, Cincinnati, OH, and M.E. (Bette) Meek, University of Ottawa, Ottawa, ON, Canada.

Sponsor: Risk Assessment Specialty Section

An overview of the fundamental guiding principles and general methods used in chemical risk assessment will be provided. These principles and methods are addressed in presentations and discussions organized by the four components identified by the National Research Council in the Risk Assessment Paradigm: Hazard Identification and Characterization; Dose- Response Assessment; Exposure Assessment; and Risk Characterization. Guiding principles and key concepts in risk assessment will be illustrated by examples from the literature and sample calculations for dose-response assessment, exposure assessment, and risk characterization will presented.

Introduction to Chemical Risk Assessment. Qiyu (Jay) Zhao, US EPA, Cincinnati, OH.

Hazard Identification and Characterization. Jeffrey Lewis, ExxonMobil Biomedical Sciences, Inc., Annandale, NJ.

Dose-Response Assessment. John C. Lipscomb, US EPA, Cincinnati, OH.

Exposure Assessment. Robinan Gentry, ENVIRON International Corporation, Monroe, LA.

Risk Characterization. M.E. (Bette) Meek, University of Ottawa, Ottawa, ON, Canada.

" }, { "SessionID": 11, "Title": "Best Practices for Developing, Characterizing and Applying Physiologically Based Pharmacokinetic Models in Risk Assessment", "Year": 2011, "Topic": "Risk Assessment/Safety Assessment", "Transcription": 0, "Description": " Register/Login

Chairpersons: M.E. (Bette) Meek, University of Ottawa, Ottawa, Ontario, Canada, and John C. Lipscomb, US EPA, ORD/NCEA, Cincinnati, OH

Sponsor: Risk Assessment Specialty Section

Endorsed by:
Biological Modeling Specialty Section

This course is aimed at increasing confidence in the evaluation and application of PBPK models in quantitative health risk assessments, through systematic consideration of relevant criteria for their development and documentation, based on guidance. These principles (Best Practices for PBPK Modeling Applied to Health Risk Assessment) have been recently collected and expanded upon in guidance published by the WHO International Programme on Chemical Safety (2010), and have been the subject of several other peer-reviewed publications. The course comprises lectures describing the link between mode of action, dose-response characterization and risk assessment, and the role of PBPK models in reducing and characterizing uncertainty and variability. The course will present principles for the development, characterization, and communication and criteria for evaluation of PBPK models for risk assessment applications. A novel inclusion will be a projected demonstration of real-time changes in model outcome that depend on choice of model parameter values (e.g., breathing rate, metabolic activity). The demonstration of user-friendly model development software will be demonstrated in the final lecture. This will show the impact of choices for parameter values, and models will be exercised and the results interpreted to produce quantitative values to be used in place of uncertainty factors in health risk assessments.

Toxicokinetics in Risk Assessment, John C. Lipscomb, US EPA, ORD/NCEA, Cincinnati, OH

Developing a PBPK Model, Hugh Barton, Pfizer, Inc., Groton, CT

Characterizing a PBPK Model, Kannan Krishnan, University of Montreal, Montreal, Québec, Canada

Applying PBPK Models in Risk Assessment, George Loizou, Health and Safety Laboratory, Buxton, United Kingdom

Case Study 1, Bette Meek, University of Ottawa, Ottawa, Ontario, Canada

Case Study 2, Jos Bessems, RIVM, Bilthoven, Netherlands

" }, { "SessionID": 12, "Title": "Combination Products: Toxicology and Regulatory Challenges", "Year": 2014, "Topic": "Combination Products", "Transcription": 0, "Description": " Register/Login

Chairperson(s): Jon Cammack, AstraZeneca Biologics, Gaithersburg, MD, and Chandramallika (Molly) Ghosh, US FDA, Silver Spring, MD.

Sponsor(s):
Career Resource and Development Committee
Drug Discovery Toxicology Specialty Section
Medical Device Specialty Section

Therapeutic and diagnostic products that combine drugs, devices, and/or biological elements are termed and regulated by US Food and Drug Administration (US FDA) as combination products. Technological advances continue to merge product types and blur the historical lines of separation among traditional drugs, biologics, and medical devices. Concomitantly, US FDA’s medical product centers, the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Devices and Radiological Health (CDRH), are employing ever-evolving collaborative efforts to address the regulatory complexities of combination products. Because combination products involve components that would normally be developed and regulated under different types of processes and policies (and frequently submitted to different US FDA Centers), these products raise challenging development, regulatory, and review management questions. Differences in these pathways for each combination product type can impact the processes for all aspects of product development and management (especially preclinical testing), but also clinical investigation, marketing applications, manufacturing and quality control, adverse event reporting, promotion and advertising, and post-approval modifications. Trends and strategies for addressing the impact of overlapping technologies and evolving regulatory processes in developing a successful preclinical evaluation program will be highlighted. A regulatory overview of definitions and combination product examples, as well as a high-level review of US FDA’s final rule (effective July 22, 2013), will be included. A primary focus of the course is discussion of approaches in optimizing a preclinical program for a hypothetical drug-device combination product (e.g., a monoclonal antibody packaged in a prefilled syringe). Additionally, regulatory overview of the preclinical evaluation program will be provided. Future trends in combination product therapies will also be highlighted.

Overview of Combination Products. Thinh Nguyen, US FDA Office of Combination Products, Silver Spring, MD.

Overview of a Development Program for a Hypothetical Combination Product. Jon Cammack, AstraZeneca Biologics, Gaithersburg, MD.

Regulatory Overview of Preclinical Assessment of Combination Products. Chandramallika (Molly) Ghosh, US FDA, Silver Spring, MD.

" }, { "SessionID": 13, "Title": "Comparative Biology of the Lung", "Year": 2010, "Topic": "Inhalation and Respiratory", "Transcription": 0, "Description": " Register/Login

Chairperson(s): Richard Parent, Consultox Ltd., Damariscotta, ME, and Daniel Costa, US EPA, Research Triangle Park, NC

Sponsor: Inhalation and Respiratory Specialty Section

Endorsed by:
Immunotoxicology Specialty Section
Drug Discovery Toxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section

All mammals have evolved respiratory structures to ensure that the principal function of the lung, gas exchange, is met under varying physiological conditions. However, this essential function is achieved despite significant differences in the structural organization, cellular composition, and related functions mediated through the respiratory system and across mammalian species. Translational toxicology requires that one understand these innate differences in fundamental respiratory biology if one is to appropriately interpret and extrapolate findings in animal models. On a gross level, the nasal passages, pleural thickness, vascularity, and connective tissue structure vary between species. Quantitative evaluation of the tracheobronchial airway tree demonstrates few consistent features between species. The epithelial cell populations lining the lung differ in cell type, location, and abundance. The metabolic enzymes, cytokines, chemokines, protease, and anti-oxidant potential, although showing some similarities, also demonstrate vast differences. Similarly, basic immunological functions in laboratory animals must be understood and related to those in humans to enable appropriate species translation. We will illustrate many of these fundamental differences, describe methods for making measurements in different species, and most importantly, focus on the fundamentals of appropriate interpretation of study data derived in animals for human use. Attendees will gain a basic understanding of the value and pitfalls extending from these species differences, which will enable improved study design and extrapolation of research data for efficacy, safety pharmacology, and toxicology studies. This course is intended to provide attendees with a basic understanding of lung structure-function relationships and associated immunological and metabolic functions in laboratory animals that will aid in the extrapolation of inhalation or respiratory data to humans.

Introduction, Richard Parent, Consultox Ltd., Damariscotta, ME, and Daniel Costa, US EPA, Research Triangle Park, NC

Comparative Anatomy of Mammalian Respiratory Systems, Kent Pinkerton, University of California, Davis, CA

Interpretation and Limitations in the Assessment of Lung Function in Laboratory Mammals, Jeffrey Tepper, Tepper Nonclinical Consulting, San Carlos, CA

Metabolism and Enzymatic Balance in the Respiratory Tract, Laura Van Winkle, University of California, Davis, CA

Pulmonary Immune Functions Important for Translational Toxicology and Predictive of Risk in Humans, Gary R. Burleson, BRT—Burleson Research Technologies, Inc., Morrisville, NC

" }, { "SessionID": 14, "Title": "Computational and Experimental Aspects of microRNAs in Toxicology", "Year": 2014, "Topic": "Molecular Biology", "Transcription": 0, "Description": " Register/Login

Theme: Advancing Clinical and Translational Toxicology and Application of Biomarkers

Chairperson(s): Susan C. Tilton, Pacific Northwest National Laboratory, Richland, WA, and Tamara L. Tal, US EPA, Research Triangle Park, NC.

Sponsor(s):
Drug Discovery Toxicology Specialty Section
Mechanisms Specialty Section
Molecular Biology Specialty Section

MicroRNAs (miRNAs) are small noncoding RNAs that function as post-transcriptional regulators of gene expression. miRNAs are increasingly recognized for their importance in regulating mechanisms of disease and exposure, including those associated with nervous system development, cardiac function, metabolism and cancer. miRNAs and their transcriptional targets are highly conserved across species. They are also stable in plasma and urine as biomarkers of tissue-specific damage or response. Furthermore, miRNAs are unique in that not only can they be experimentally measured along with their inhibitory effects on transcript and protein levels, but their post-transcriptional regulation can also be computationally predicted based on sequence specificity and conservation across species. Given the overall importance of miRNAs in toxicology, it is necessary to understand both computational and experimental aspects of miRNAs for accurate miRNA quantification and discovery of the functional consequences of their disruption by chemical or drug exposure. The goal of the course is to provide toxicologists with a better understanding of miRNA biology (biogenesis, sequence, structure, function, and species similarities), the experimental and computational resources available for identification and target prediction and how these resources can be leveraged to identify mechanisms and biomarkers of toxicity.

Background on miRNA Biology and Relationship to Toxicology. Igor Pogribny, US FDA-NCTR, Jefferson, AR.

Experimental Methods for Measuring Circulating RNAs. Kai Wang, Institute for Systems Biology, Seattle, WA.

Computational Resources for miRNA Identification, Target Prediction, and Integration of Co-Expressed miRNAs and mRNAs. Susan C. Tilton, Pacific Northwest National Laboratory, Richland, WA.

Network and Pathway Analysis of miRNA Data. Richard J. Brennan, Sanofi, Waltham, MA.

Strategies for Developing miRNA Biomarkers of Toxicity. Karol L. Thompson, US FDA-CDER, Silver Spring, MD.

" }, { "SessionID": 15, "Title": "Concepts of Green Chemistry and Its Role in the Identification and Design of Safer Chemicals and Products", "Year": 2012, "Topic": "Risk Assessment/Safety Assessment", "Transcription": 1, "Description": " Register/Login

Chairpersons: Pamela J. Spencer, Dow Chemical Company, Midland, MI, and John Warner, Warner Babcock Institute for Green Chemistry, Wilmington, MA

Endorsed by:
Molecular Biology Specialty Section

Hazard identification, dose-response characterization, and exposure potential are the underpinning of product safety assessments. These basic principles help regulatory agencies, manufacturers, and formulators determine the conditions for safe use of chemicals, raw materials, and products for a given application to reduce adverse impacts to human health and the environment. Today, as a part of the growing interest in green chemistry, the pendulum is shifting. The large number of companies engaging in sustainability initiatives coupled with increased consumer demand for greener products is driving a new process where impacts of chemical products and processes are included as design criteria. Reducing intrinsic chemical hazards up front is a strategy used in developing safer alternatives to existing chemicals. Thus green chemistry is raising the bar for chemical safety assessments. Our panel of experts will begin with a background of green chemistry, its basic principles, why it is useful and highlight key certification programs/tools used to identify safer alternatives including their methods and criteria with specific emphasis on the Green Screen for Safer Chemicals alternatives assessment tool. There are unique opportunities for toxicologists to assist molecular designers in reducing the intrinsic hazards of their molecules by providing insight into toxicological mechanisms and data that support the application of green chemistry principles in the design of new chemicals and products. To underscore the importance of this issue, we will illustrate how principles of green chemistry are applied in a consumer products and a chemical company. The caveats and challenges will be addressed by using case studies. The exploration of this topical area will provide an understanding of green chemistry, awareness of the tools and programs immediately available and how to access and use them as well as an appreciation for some of the practical challenges associated with implementing principles of green chemistry into product development and assessments of safer alternatives.

Introduction. Pamela J. Spencer, Dow Chemical Company, Midland, MI

Introduction to the Concepts of Green Chemistry and Its Role in the Design of Safer Chemicals and Products. John Warner, Warner Babcock Institute for Green Chemistry, Wilmington, MA

Using Comparative Hazard Assessments: Green Screen for Safer Chemicals, Lauren Heine, Lauren Heine Group LLC, Juneau, AK

Strategies and Methods for Incorporating Green Chemistry into the Design of Chemicals and Products. Thomas G. Osimitz, Science Strategies, LLC, Charlottesville, VA

Application of the Principles of Green Chemistry in a Chemical Company: Overview and Case Studies. J. Craig Rowlands, Dow Chemical Company, Midland, MI

Application of the Principles of Green Chemistry in a Consumers Products Company: Overview and Case Studies. Donald Versteeg, Procter and Gamble Company, Cincinnati, OH

" }, { "SessionID": 16, "Title": "Contribution of Mitochondria to Drug-Induced Organ Toxicities", "Year": 2016, "Topic": "Mechanisms", "Transcription": 0, "Description": " Register/Login

Theme: Molecular Toxicology: Mechanistic Insights and Hazard Assessment

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

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

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

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



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

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

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

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

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


" }, { "SessionID": 17, "Title": "Current Nonclinical Strategies and Methods for Evaluating Drug-Induced Cardiovascular Toxicity", "Year": 2011, "Topic": "Cardiovascular", "Transcription": 1, "Description": "Register/Login

Chairpersons: Hong Wang, Genentech Inc., South San Francisco, CA, and Dennis J. Murphy, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA

Sponsor: Cardiovascular Toxicology Specialty Section

Endorsed by:
Drug Discovery Toxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section

Cardiovascular (CV) toxicity is among the major causes of withdrawal of drugs or restriction in their labeling and has had an impact on public health and the rising cost of developing new drugs. Early identification and characterization of CV liabilities, better understanding of the predictive values of nonclinical models, and an integrated and iterative approach during drug development could greatly facilitate the development of safe and effective medicines for patients. This course will describe the current in vitro and in vivo methods for evaluation of functional and structural CV liabilities, and discuss the strategies that can be applied at early stages of drug development to help reduce attrition and to avoid unanticipated liabilities at later development stages in either animal studies or in the clinic. Study design and data interpretation will be discussed, as well as the advantages, limitations, and future directions of current methods involving both functional and structural assessments. Specific topics such as integration of functional CV endpoints into repeat-dose toxicity studies, methods for identification and characterization of cardiac arrhythmia, and special considerations for testing oncology and diabetes drugs and biologics will be covered. In addition, case study examples will be provided to highlight how these data can be used to inform decisions at different stages of development. A regulatory perspective on the challenges and gaps of CV safety evaluations and opportunities available to improve the overall CV safety assessment paradigm will also be presented. Overall, this course will provide participants with a broad overview of the types of drug-induced CV liabilities, the current nonclinical strategies and methodologies for early detection of CV liabilities, and a regulatory perspective on the impact of CV toxicity on the drug-development process.

Opening Remarks and Overview of Cardiovascular Toxicity, Dennis J. Murphy, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA

Early Identification of Cardiovascular Functional Liabilities: Role of In Vitro Assays, Derek Leishman, Eli Lilly & Company, Indianapolis, IN

Integrated Assessment of Cardiovascular Functional Liabilities: In Vivo Animal Models, R. Dustan Sarazan, Data Sciences International, St. Paul, MN

Assessment of Cardiovascular Injury: Morphological Evaluations and Biomarkers, Brian Berridge, GlaxoSmithKline Pharmaceuticals, Research Triangle Park, NC

A Regulatory Perspective on Drug-Induced Cardiovascular Liabilities: Challenges, Gaps, and Opportunities, John Koerner, US FDA, Silver Spring, MD

" }, { "SessionID": 18, "Title": "Current Trends in Genetic Toxicology Testing", "Year": 2014, "Topic": "Regulatory and Safety Evaluation", "Transcription": 0, "Description": " Register/Login

Theme: Safety Assessment: Mechanisms and Novel Methods

Chairperson(s): B. Bhaskar Gollapudi, Exponent, Midland, MI, and Stephen Dertinger, Litron Laboratories, Rochester, NY.

Sponsor(s): Regulatory and Safety Evaluation Specialty Section

The scientific discipline of genetic toxicology has played an important role in the safety assessment of existing and new chemicals during the past four decades. This field has undergone significant changes during this time, not only in its regulatory applications, but also in the tools and technologies employed to identify adverse events. While the emphasis during the early years was on protecting germ cells and future generations from the deleterious effects of mutagenic agents, the focus shifted in later years towards identifying carcinogenic chemicals through the use of short-term assays. Furthermore, genetic toxicology tended to operate as a standalone discipline, generating qualitative data and placing little importance on dose-response analysis or integration with other toxicology measurements. The field is now in the midst of a sea change. Regulatory requirements across the globe are being harmonized, with emphasis on “3 Rs.” For example, recent changes to ICH and OECD testing guidelines promote the integration of genetic toxicology endpoints (e.g., Comet, micronucleus, and gene mutation) into repeat-dose general toxicology studies. This integrated approach benefits the interpretation of genotoxic findings by placing them in context with other toxicology data, including pharmacokinetics and pharmacodynamics. Additionally, regulatory initiatives such as REACH stress the importance of germ cell effects as part of a comprehensive assessment of genotoxicity. Guidelines for the study of mutations in germ cells of transgenic animals (OECD 488) have recently been finalized. Rapid advances in molecular biology are facilitating the integration of genomic biomarkers into standard toxicology studies to identify various classes of genotoxic agents (DNA reactive and DNA nonreactive). Finally, genetic toxicology is moving from a qualitative science to the quantitative assessment of dose-responses including the identification of point-of-departure (PoD) metrics to extrapolate effects to realistic human exposure levels. The course is designed to provide a comprehensive overview of recent changes and newly established practices in the field with emphasis on their application in safety assessments.

Introduction. B. Bhaskar Gollapudi, Exponent, Midland, MI.

Integration of Genetic Toxicology Endpoints Into Repeat Dose Studies. Stephen Dertinger, Litron Laboratories, Rochester, NY.

Resurgence of Transgenic Animals in Genotoxicity Testing. Robert H. Heflich, US FDA-NCTR, Jefferson, AR.

Approaches to Genetic Toxicology Testing in the Era of Genomics. Matthew J. LeBaron, The Dow Chemical Company, Midland, MI.

Quantitative Assessment of Dose-Response in Genetic Toxicology Studies. B. Bhaskar Gollapudi, Exponent, Midland, MI.

" }, { "SessionID": 19, "Title": "Cutaneous Toxicity: In Vitro Methods for Toxicity and Safety Evaluation", "Year": 2012, "Topic": "Dermal Toxicology", "Transcription": 0, "Description": " Register/Login

Chairpersons: William G. Reifenrath, Stratacor Inc., Richmond, CA, and Cynthia A. Ryan, Procter & Gamble Company, Cincinnati, OH

Sponsor:
Dermal Toxicology Specialty Section

Endorsed by:
In Vitro and Alternative Methods Specialty Section

Skin is the largest external organ and serves as a living, dynamic protective envelope surrounding the body. As such, it is constantly exposed to environmental hazards, including hazardous compounds; these exposures account for a major portion of all reported industrial illnesses. Skin exposures may also occur from pharmaceuticals or consumer products that are intentionally applied. In vitro methods are important as a first step to estimate skin permeation, and the potential of skin irritation and sensitization for compounds or mixtures of compounds that are directly toxic to the skin or systemically toxic. In exploration of these issues we will provide an overview of the current status of in vitro models for cutaneous toxicity safety evaluations and the regulatory requirements for establishing the nonclinical safety of dermal drug products. This important topic has relevance to toxicologists involved in safety evaluations and risk assessments for chemicals that contact the skin.

Use of the Excised Human Skin Model for Percutaneous Risk Assessment. Thomas J. Franz, Cetero Research, Fargo, ND

Direct Comparison of In Vitro and In Vivo Dermal Absorption of Several Chemicals. Jeffrey J. Yourick, US FDA, Laurel, MD

Specialized Procedures for Lipophilic and Semi-Volatile Compounds and Their Influence on Comparative In Vitro—In Vivo Skin Absorption. William G. Reifenrath, Stratacor, Inc., Richmond, CA

Skin Sensitization: Underlying Mechanisms, Hazard Identification, and a Quantitative Risk Assessment Approach. Cynthia A. Ryan, Procter & Gamble Company, Cincinnati, OH

Skin Irritation: In Vitro Models. John W. Harbell, Mary Kay Inc., Dallas, TX

US Regulatory Requirements for Establishing the Nonclinical Safety of Dermal Drug Products. Marian W. Glynn, Dow Pharmaceutical Sciences, Petaluma, CA

" }, { "SessionID": 20, "Title": "Dealing with the Data Deluge: A Live Data Discovery and Analysis Course", "Year": 2011, "Topic": "Molecular Biology", "Transcription": 0, "Description": " Register/Login

Chairpersons: Marc E. Gillespie, Saint Johns University, Jamaica, NY, and Susan M. Bello, Jackson Laboratory, Bar Harbor, ME

Sponsor: Molecular Biology Specialty Section

Endorsed by: N/A

Using Web based resources and tools to gain novel scientific insights and advance your research is a significant step for all researchers. As the pace of science accelerates, experimental technologies continue to evolve and the quantity of data increases. With the evolution in biological research comes an increasing reliance on database resources and computational analysis tools to parse and integrate this growing mass of biological data. The field of toxicology is not exempt from these challenges. In this course, representatives from a diverse group of data resources have joined their efforts to present a unique series of hands-on tutorials. The tutorials follow a hypothetical researcher through the various stages of experimental design and data analysis, demonstrating how the different workshop resources can be used to facilitate all steps of the research process. Participants will identify orthologous biological information across different species; identify biological trends (pathway, function, phenotype, xenobiotic interactions) within a submitted data set; investigate an individual data set with online resources, identifying supplementary information available across multiple data sets; and gain hands on experience with formatting and submitting data to a diverse set of online data resources.

Today toxicologists must select appropriate model organisms, manage abundant high-throughput data, understand legacy data, and develop pathway-based understanding of environmental factors influencing biological systems. Mastery of these concepts improves toxicity prediction while providing insights into environmentally influenced diseases and phenotypes. A clear understanding of the diverse online data resource aims and limitations equips the researcher with the best combination of resources to effectively address their questions.

NOTE:  This was a unique “hands on” interactive course presented at the 2011 Annual Meeting. AM04 course attendees brought their own laptop computers as well as their own Internet network connection. The interactive nature of this course may be lost for those viewing the course online.

Reactome Knowledgebase, Marc E. Gillespie, Saint Johns University, Jamaica, NY

Comparative Toxicogenomics Database (CTD), Carolyn J. Mattingly, Mount Desert Island Biological Laboratory, Salisbury Cove, ME

PharmGKB, Teri E. Klein and Li Gong, Stanford University Medical Center, Stanford, CA

Mouse Genome Informatics Database, Susan M. Bello, Jackson Laboratory, Bar Harbor, ME

" }, { "SessionID": 21, "Title": "Detecting Cancer Risk in Drugs: Design, Conduct, and Interpretation of Carcinogenicity Studies for Regulatory Approval", "Year": 2017, "Topic": "Drug Discovery Toxicology", "Transcription": 0, "Description": " Register/Login

Chairpersons: Owen McMaster, US FDA Center for Drug Evaluation and Research, Silver Spring, MD; and James Popp, Stratoxon LLC, Morgantown, PA.

Endorsed by: Carcinogenesis Specialty Section and Regulatory and Safety Evaluation Specialty Section

Evaluation of the carcinogenic potential of therapeutic agents is a very complex, multi-step process which is conducted only for drugs which meet certain criteria. Recently, ICH has issued a regulatory notice document regarding proposed changes to rodent carcinogenicity testing of pharmaceuticals. This course is designed to provide an overview of the practical aspects of the design, conduct, and interpretation of the US FDA-required carcinogenicity assessments. This course will be useful for students and investigators who have not had recent, hands-on experience conducting such studies, or who would like to update their knowledge of recent advancements in carcinogenicity assessment. The first talk will provide an overview of the current procedures for evaluating the potential carcinogenicity of a drug to be marketed in the US. The second talk will detail the planning, conduct, and interpretation of the two-year rat carcinogenicity study, the cornerstone of many carcinogenicity assessments. The third talk will detail the planning, conduct, and interpretation of studies using the TgrasH2 mouse model to assess cancer risk. The TgrasH2 has become the most widely used alternative to the two-year mouse carcinogenicity study. This talk will also include a discussion of other alternatives to the two-year bioassay and will end with a case study of a TgrasH2 study. The fourth talk will go into the review of the carcinogenicity assessments from the perspective of an US FDA reviewer. This reviewer will describe the point of view of the Pharmacology/Toxicology review, the review division, and that of CDER's Executive Carcinogenicity Assessment Committee. The fifth talk will discuss an initiative by the ICH S1 Expert Working Group to assess the feasibility of a weight-of-evidence approach as a possible future option for the carcinogenicity testing of pharmaceuticals.

Essentials of Carcinogenicity Testing. Owen McMaster, US FDA Center for Drug Evaluation and Research, Silver Spring, MD.

Specific Aspects and Approaches for Regulatory Evaluation of Pharmaceuticals in 2-Year Rodent Carcinogenicity Studies. James A. Popp, Stratoxon LLC, Morgantown, PA.

The TgrasH2 Assay. Mark Morse, Charles River, Spencerville, OH.

Evaluating Carcinogenicity: The Reviewer’s Perspective. Timothy McGovern, US FDA Center for Drug Evaluation and Research, Silver Spring, MD.

The ICH S1 Carcinogenicity Testing Guideline: Status Report. Todd Bourcier, US FDA Center for Drug Evaluation and Research, Silver Spring, MD.


" }, { "SessionID": 22, "Title": "Embryology and Developmental Toxicity Testing", "Year": 2016, "Topic": "Reproductive and Developmental Toxicology", "Transcription": 0, "Description": " Register/Login

Theme:: Developmental Toxicity: Mechanisms and Evaluation

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

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

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



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

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

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

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

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

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


" }, { "SessionID": 23, "Title": "Epidemiology for Toxicologists: What the Numbers Really Mean", "Year": 2014, "Topic": "Epidemiology", "Transcription": 0, "Description": " Register/Login

Theme: New Science and Perspectives Surrounding Environmental and Occupational Exposures

Chairperson(s): Nancy B. Beck, American Chemistry Council, Washington, DC, and Julie E. Goodman, Harvard School of Public Health and Gradient, Cambridge, MA.

Sponsor(s):
Occupational and Public Health Specialty Section
Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section

Twenty-first Century risk assessment relies on data from multiple lines of evidence. High quality human epidemiology data are generally preferred for regulatory decision-making, but the body of evidence often includes animal toxicity, in vitro, in silico, animal dosimetry, and human exposure data. The quality of individual epidemiology studies can be highly variable and dependent on study design as well as other critical factors that sometimes cannot be controlled for. For risk assessors to fully understand the implications of epidemiology evidence, they must understand how the overall integration of toxicity and mechanistic data with human epidemiology findings facilitates science-informed decision-making. A sufficient understanding of the epidemiology data is a necessary starting point for appropriately integrating all the available information. The course is geared towards the toxicologist who is trying to determine how to appropriately evaluate, use, and integrate epidemiology data in a weight-of-evidence evaluation or risk assessment. Attendees first will be given a basic overview of epidemiology, with a focus on different epidemiology study designs and their strengths and weaknesses. Attendees will also gain an understanding of exposure assessment and biomonitoring, and how this information is used and evaluated in epidemiology studies. Additional learning objectives of the course: How to determine when an association may be supportive of a causal relationship and what confidence intervals mean; how to use trend information; how to evaluate and understand adjustments that are made for potential confounding factors; and how to evaluate several epidemiology studies on the same topic, particularly in light of available toxicity and mechanistic data. Finally, attendees will learn to integrate all types of data streams with a real example. Attendees will leave the course with a stronger understanding of how to interpret and use epidemiology data in their weight-of-evidence analyses and risk assessments, and how epidemiology can help inform regulatory decision-making.

Setting the Stage. Nancy B. Beck, American Chemistry Council, Washington, DC.

Overview of Epidemiologic Studies. Michael Goodman, Emory University, Atlanta, GA.

Exposure Assessment and Biomonitoring in Epidemiologic Studies. Sorina Eftim, George Washington University School of Public Health and Health Services and ICF International, Fairfax, VA.

When an Association Indicates Causation. Julie E. Goodman, Harvard School of Public Health and Gradient, Cambridge, MA.

A Case Study Showing How Toxicology Complements Epidemiology for Informing Human Risk. James S. Bus, Exponent, Midland, MI.

" }, { "SessionID": 24, "Title": "Epigenetics in Toxicology: Introduction, Mechanistic Understanding and Applications in Safety Assessment", "Year": 2011, "Topic": "Molecular Biology", "Transcription": 1, "Description": " Register/Login

Chairpersons: Mayurranjan S. Mitra, Washington University School of Medicine, St. Louis, MO, and Thomas Sussan, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD

Sponsor: Molecular Biology Specialty Section

Endorsed by:
Carcinogenesis Specialty Section
Cardiovascular Toxicology Specialty Section
Mechanisms Specialty Section

Epigenetics refers to molecular mechanisms that cause heritable changes in gene expression without altering the DNA sequence. The most widely studied epigenetic mechanisms encompass DNA methylation, histone modifications, and gene regulation by non-coding RNAs, such as microRNAs. Typically, these mechanisms are required for normal cellular development and differentiation; however, perturbations in them can lead to diseases, notably cancer. Increasing evidence suggest that environmental factors such as diet, stress, and exposure to radiation and xenobiotics can induce heritable changes in the epigenetic status, potentially affecting the health of the present and future generations. Importantly, the long-term and life-threatening consequences of environment/chemical-induced changes in epigenetics, makes this field a critical area for future exploration by toxicologists. The course will begin by introducing the fundamental concepts of epigenetics and reviewing the various underlying mechanisms. Methods to assess epigenetic changes will be discussed, followed by a discussion of the role of DNA cytosine methylation in the regulation of carcinogen-inducible CYP450 genes. Mechanistic understanding of the role of microRNAs in the regulation of cellular toxicity and the influence of environment on epigenetics that cause developmental effects will also be presented. Finally, the future of epigenetics in toxicology and its potential applications for safety assessment will be discussed. Students as well as toxicologists working in academia, federal and pharmaceutical industries, and researchers interested in mechanistic toxicology will benefit from taking this course.

Introduction, Mayurranjan S. Mitra, Washington University School of Medicine, St. Louis, MO

Introduction and Overview of Epigenetics, James G. Herman, The Johns Hopkins School of Medicine, Baltimore, MD

Role of Epigenetics in the Regulation of Carcinogen-Metabolizing Enzymes, Oliver Hankinson, University of California Los Angeles, Los Angeles, CA

Retroelements and MicroRNAs in the Epigenetic Regulation of Cellular Differentiation, Proliferation, and Toxicity, Kenneth S. Ramos, University of Louisville, Louisville, KY

Epigenetic Gene Regulation: Linking Early Developmental Environment to Adult Disease, Dana Dolinoy, University of Michigan, Ann Arbor, MI

What We Need to Know Prior to Incorporating an Epigenetic Evaluation into Safety Assessments, Jay I. Goodman, Michigan State University, East Lansing, MI

" }, { "SessionID": 25, "Title": "Evaluating Toxicity of Engineered Nanomaterials: Issues with Conventional Toxicology Approaches", "Year": 2011, "Topic": "Nanotoxicology", "Transcription": 0, "Description": " Register/Login

Chairpersons: Srikanth S. Nadadur, NIEHS-DERT, Research Triangle Park, NC, and Frank A. Witzmann, Indiana University School of Medicine, Indianapolis, IN

Sponsor: Nanotoxicology Specialty Section

Endorsed by:
Cardiovascular Toxicology Specialty Section
In Vitro and Alternative Methods Specialty Section
Inhalation and Respiratory Specialty Section

Engineered nanomaterials (ENMs) have become an integral part of numerous consumer products, cosmetics, building materials, medical devices, therapeutic agents, and environmental remediation. Global demand for nanomaterials and nano-enabled devices has been projected to surpass $3.1 trillion by 2015. The widespread use of nanotechnology-derived products presents opportunities for intentional and unintentional exposure to ENMs. The size and size-dependent novel physical and chemical properties that make ENMs unique compared to micro-scale products of similar chemical composition makes it difficult to determine their interaction with biological matrices. The recent flood of toxicology literature without proper physical and chemical characterization of ENMs proposes adverse to no health effects for certain common ENMs such as carbon nanotubes and metal oxide nanoparticles. The course will provide an overview of the issues facing nanotechnology that the scientific community must grapple with in regard to predicting toxicity and biological outcomes associated with nanoscale properties and the need to identify and integrate novel approaches for safety of ENMs. To begin, focus will be placed on the importance of incorporating physical and chemical characteristics of ENMs in interpreting biological data; high throughput in vitro approaches using multiple parameters to classify ENMs toxicity profile will then be covered. Altered proteomic profiles in a model in vitro system to understand molecular alterations will be explored. Finally, the interpretation of data from in vivo studies using inhalational routes of exposure will be discussed. The goal of this course is to encourage both the novice and the toxicologist trained in conventional toxicity assessment to think outside the box to design rational toxicology studies in evaluating the safety of ENMs that are currently in use, and to develop models to predict potential toxicity of second and third generation ENMs.

Engineered Nanomaterials (ENMs) Toxicity Evaluation: Issues with Conventional Approaches, Srikanth S. Nadadur, NIEHS-DERT, Research Triangle Park, NC

Importance of Integrating Physicochemical Characterization Information in Toxicity Assessment of Engineered Nanomaterials, Scott McNeil, National Cancer Institute, Bethesda, MD

Emergence of High Content Screening for Assessment of Nanotoxicity,Chris Vulpe, University of California Berkeley, Berkeley, CA

Proteomic Profiling of the Biological Effects of Engineered Nanomaterial Exposure Using In Vitro Models, Frank A. Witzmann, Indiana University School of Medicine, Indianapolis, IN

Correlating In Vitro and In Vivo Nanotoxicity: Limitations and Challenges, Günter Oberdörster, University of Rochester Medical Center, Rochester, NY

" }, { "SessionID": 26, "Title": "Human Health Risk Assessment: A Case Study Application of Principles", "Year": 2016, "Topic": "Risk Assessment", "Transcription": 0, "Description": " Register/Login

Theme: Health and Environmental Impacts of Manmade and Naturally Released Toxicants

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

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

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



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

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

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

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

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


" }, { "SessionID": 27, "Title": "Inhalation Studies: Challenges and Complexities", "Year": 2014, "Topic": "Inhalation and Respiratory", "Transcription": 0, "Description": " Register/Login

Theme: New Science and Perspectives Surrounding Environmental and Occupational Exposures

Chairperson(s): Gregory L. Baker, Battelle, West Jefferson, OH, and Willie J. McKinney, Altria Client Services, Richmond, VA.

Sponsor(s): Inhalation and Respiratory Specialty Section

The successful execution of animal inhalation studies (e.g., acute, subchronic, and chronic) present many challenges and complexities not encountered with other routes of exposure. Five inhalation study challenges will be addressed: 1) Comparison of methods of exposure and potential impact on inhalation studies; 2) Using various test materials, generating simple atmospheres (e.g., exposures to gases, nanoaerosols, bioaerosols, micron-sized aerosols) and mixtures (e.g., semivolatile compounds and particles, tobacco smoke); 3) selection of the appropriate animal species (e.g., species specific dosimetry); 4) incorporating standard and novel toxicological endpoints; 5) deciding which regulatory guidance document or specifications (e.g., US EPA, US FDA, OECD, and NTP) to follow. The diversity of presenters’ backgrounds (government, contract research organization, industry, and academic), and depth of experience, will provide a broad and rich resource for the participants.

Introduction. Willie J. McKinney, Altria Client Services, Richmond, VA.

Comparison of Whole Body vs. Nose-Only Exposure. Robert F. Phalen, University of California Irvine, Irvine, CA.

Test Materials for Inhalation Studies. Gregory L. Baker, Battelle, West Jefferson, OH.

Inhalation Studies—Test Subjects and Dose Predictions. Michael J. Oldham, Altria Client Services, Inc., Richmond, VA.

Toxicological Endpoints in Inhalation Studies. Jack R. Harkema, Michigan State University, East Lansing, MI.

Regulatory Guidance for Inhalation Studies. Mark A. Higuchi, US EPA, Research Triangle Park, NC.

" }, { "SessionID": 29, "Title": "Methodologies in Human Health Risk Assessment", "Year": 2014, "Topic": "Risk Assessment", "Transcription": 1, "Description": " Register/Login

Theme: Enhancing Strategies for Risk Assessment

Chairperson(s): Qiyu (Jay) Zhao, US EPA, Cincinnati, OH, and M.E. (Bette) Meek, University of Ottawa, Ottawa, ON, Canada.

Sponsor(s):
Biological Modeling Specialty Section
Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section

This course provides an overview of more advanced aspects of chemical risk assessment, following up from a successful CE course on basic principles offered at the Annual Meeting in 2013. This new course will focus on methodologies, which incorporate increased use of biological and chemical specific data as a basis to provide more accurate estimates of risk. In addition, it will address evolving areas such as problem formulation as a basis to better target toxicity testing and tailor assessments to the needs of risk management. The course will feature presentations and discussions focusing on the value of mode of action analysis for characterization of hazard, the fundamental tenets of physiologically based pharmacokinetic (PBPK) model development and implementation, use of benchmark dose (BMD) models to identify points of departure, and use of chemical specific adjustment factors to address inter- and intraspecies uncertainty and variability. The principles and key components of these methodologies will be illustrated with applied case examples from the regulatory risk assessment arena.

An Overview of Advanced Aspects of Risk Assessment. M.E. (Bette) Meek, University of Ottawa, Ottawa, ON, Canada.

Mode of Action Analysis. M.E. (Bette) Meek, University of Ottawa, Ottawa, ON, Canada.

Benchmark Dose Modeling. Qiyu (Jay) Zhao, US EPA, Cincinnati, OH.

Physiologically Based Pharmacokinetic and Pharmacodynamic Modeling. Hugh A. Barton, Pfizer, Inc., Groton, CT.

Nondefault Uncertainty Factor Values. John C. Lipscomb, US EPA, Cincinnati, OH.

" }, { "SessionID": 30, "Title": "New Technologies and Approaches in Genetic Toxicology and Their Expanding Role in General Toxicology and Safety Assessment", "Year": 2011, "Topic": "Risk Assessment/Safety Assessment", "Transcription": 1, "Description": " Register/Login

Chairpersons: Jeffrey C. Bemis, Litron Laboratories, Rochester, NY, and Jennifer C. Sasaki, Johnson & Johnson, Raritan, NJ

Sponsor: Regulatory and Safety Evaluation Specialty Section

Endorsed by:
In Vitro and Alternative Methods Specialty Section

For decades, genetic toxicology and the “genetox battery” have been a well-established part of safety testing for pharmaceuticals and other chemical agents. Recent advances in experimental methodologies are contributing to a change in the way that genetic toxicology data are generated and incorporated in the disciplines of toxicology and safety testing. The intention of this course is to illustrate the broader impact that new genetic toxicology approaches are having on drug/chemicals safety assessment and human risk analysis. The structure of the course will provide examples of (1) Early discovery/high-throughput genotoxicity screening of chemical entities; (2) Integration of genetic toxicology assays with repeat-dose in vivo toxicology studies; and (3) New approaches for genotoxicity risk assessment, and conclude with an update on genotoxic impurity management strategies for pharmaceuticals. Speaker presentations will illustrate how genotoxicity testing is evolving from a hazard identification based-discipline to an integrated approach that may ultimately yield quantitative information that can be used for human risk assessment.

This course should be of interest to experienced genetic toxicologists as well as those involved in general toxicology who want to learn about how incorporation of new genotoxicity methods can improve test predictivity, lower costs, reduce animal use, and may ultimately be applied to human risk assessment

Introduction, Jeffrey C. Bemis, Litron Laboratories, Rochester, NY

High-Throughput Genetic Toxicity Screening Assays in Discovery Research & Development, Richard Walmsley, Gentronix, Ltd., and The University of Manchester, United Kingdom

The In Vitro Micronucleus Assay in Mammalian Cells: A High Content Assay, Anthony M. Lynch, GlaxoSmithKline, Hertfordshire, United Kingdom

Genetic Toxicity and Thresholds: State of the Science, B. Bhaskar Gollapudi, The Dow Chemical Company, Midland, MI

Integration of Genetic Toxicology Endpoints into Repeat-Dose Toxicity Studies, Maik Schuler, Pfizer PGRD, Groton, CT

Risk Assessment of Genotoxic Impurities in Pharmaceuticals, Lutz Mueller, Hoffmann La Roche, Inc., Basel, Switzerland

" }, { "SessionID": 31, "Title": "Nonclinical Animal Models Enabling Biopharmaceutical Advances in Translational Medicine", "Year": 2014, "Topic": "Comparative and Veterinary Toxicology", "Transcription": 0, "Description": " Register/Login

Theme: Advancing Clinical and Translational Toxicology and Application of Biomarkers

Chairperson(s): Thomas M. Monticello, Amgen Inc., Thousand Oaks, CA, and Vivek Kadambi, Millennium, Cambridge, MA.

Sponsor(s):
Clinical and Translational Toxicology Specialty Section
Comparative and Veterinary Specialty Section
Toxicologic and Exploratory Pathology Specialty Section

A fundamental theme in drug discovery and nonclinical development is the utilization of appropriate animal models that are predictive for efficacy or adverse events in humans administered a novel biopharmaceutical. The accurate prediction of human adverse effects using nonclinical animal toxicology studies remains a major goal in drug development and relies on appropriate animal models. Essential attributes for an appropriate animal model include similar target distribution, target pharmacology, systemic pharmacokinetics, metabolism, and distribution to those of humans. Utilization of the most appropriate animal model aligns with the 2011 US FDA Strategic Plan to advance regulatory science and modernize toxicology in order to enhance product safety and develop better models of human adverse responses. The Preclinical Safety Leadership Group (PSLG) of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) is creating a contemporary industry-wide database to determine accuracy with which the interpretation of nonclinical safety assessments in animal models correctly predicts human risk. The course will present considerations for the selection of an appropriate animal model for nonclinical safety, the use of animal models of disease in safety testing, emerging use of the minipig in safety testing, data from an industry-wide nonclinical to clinical translational database, and the use of animal safety data in the design and conduct of clinical trials. Output from the course will help identify advances and remaining gaps in the utilization of animal models in biopharmaceutical development.

Introduction. Thomas M. Monticello, Amgen Inc., Thousand Oaks, CA.

What Constitutes a Relative Animal Model in Translational Medicine? Rakesh Dixit, MedImmune Inc., Gaithersburg, MD.

Use of Animal Models of Human Disease for Nonclinical Safety Assessment of Pharmaceuticals. Sherry J. Morgan, Abbvie, North Chicago, IL.

The Minipig As a Nonrodent Species in Nonclinical Safety Testing and Where Are We Now? Niels-Christian Ganerup, Ellegaard Göttingen Minipigs A/S, Dalmose, Denmark.

Nonclinical to Clinical Translational Safety Database Initiative. Vivek Kadambi, Millennium, Cambridge, MA.

Utilization of Nonclinical Animal Data in the Conduct of Human Clinical Trials. John T. Sullivan, Amgen Inc., Thousand Oaks, CA.

" }, { "SessionID": 32, "Title": "Nonclinical Pediatric Drug Development: Considerations, Study Designs, and Strategies", "Year": 2014, "Topic": "Drug Development", "Transcription": 0, "Description": " Register/Login

Theme: Safety Assessment: Mechanisms and Novel Methods

Chairperson(s): Kary E. Thompson, Bristol-Myers Squibb Company, New Brunswick, NJ, and Elise M. Lewis, Charles River Laboratories, Horsham, PA.

Sponsor(s): Reproductive and Developmental Toxicology Specialty Section

Although nonclinical and clinical testing needs for drugs for pediatric populations have been discussed for more than 40 years, there is no default approach to evaluating safety in this age group. Over the last decade there has been a heightened awareness of the differences between the pediatric and adult patient, and these differences are being addressed by the pharmaceutical and healthcare industries, as well as the governmental and regulatory bodies that sanction the development and testing of drugs for children. As regulatory demands evolve for nonclinical safety assessments in juvenile animals, industry leaders are developing innovative ways to meet the regulatory expectations and to overcome the challenges associated with pediatric drug development. Many practical issues regarding nonclinical testing in immature animals have been surmounted, using novel and/or adapted approaches. There are considerations related to the differences in regional guidelines (US FDA, EU, and Japan), therefore development of appropriate information for submission to worldwide agencies is critical. History and experience provide the best scientific arguments as to why juvenile animals can be useful. There are numerous examples of drugs that have identified findings in various species, including information regarding kinetic and toxicity differences that highlight considerations regarding nonclinical testing models. Additionally, there are unique challenges associated with nonclinical juvenile toxicity testing for biopharmaceuticals, including selection of appropriate animal models, immunogenicity, dose selection (toxicity vs. pharmacology), and relevant endpoints. Developing a juvenile animal program requires an appreciation of the complexity of the nonclinical strategies to enable pediatric trials and an overview of the historical perspective and the current approaches to evaluating safety during this unique period of life.

Introduction. Elise M. Lewis, Charles River Laboratories, Horsham, PA.

US FDA Regulatory Perspective on Pediatric Product Development. Karen Davis-Bruno, US FDA, Silver Spring, MD.

EU Pediatric Regulation (EC) No 1901/2006: Impact on Nonclinical Development Plans. Jacqueline Carleer, Belgian Federal Agency for Medicines and Health Products, Brussels, Belgium.

Nonclinical Strategies to Support Pediatric Trials. Kary E. Thompson, Bristol-Myers Squibb Company, New Brunswick NJ.

Juvenile Toxicity Studies: What Can We Do? Susan B. Laffan, GlaxoSmithKline, King of Prussia, PA.

Biologics Juvenile Toxicity Testing: Exploring Options to Address the Challenges. Gary J. Chellman, Charles River Laboratories, Reno, NV.

" }, { "SessionID": 33, "Title": "Overview and Application of the WHO-IPCS Harmonized Guidance for Immunotoxicity Risk Assessment for Chemicals", "Year": 2012, "Topic": "Risk Assessment/Safety Assessment", "Transcription": 0, "Description": " Register/Login

Chairpersons: Andrew A. Rooney, NIEHS, Research Triangle Park, NC, and Henk Van Loveren, National Institute of Public Health and the Environment (RIVM), Bilthoven, Netherlands

Sponsor:
Immunotoxicology Specialty Section

Endorsed by:
Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section

The WHO/IPCS harmonized guidance document is the first compressive guidance document for risk assessment in toxicology. Immunotoxicity risk assessment of chemicals is an evaluation of the potential for unintended effects of chemical exposure on the immune system. These effects manifest as four principal types of immunotoxicity which are categorized as immuno—suppression and stimulation, autoimmunity, and sensitization. We will provide an overview of the methods used to detect and characterize immunotoxicity and the potential consequences of unintended immunomodulation. It is well established that xenobiotic-related immunosuppression can lead to reduced resistance to infections and certain neoplastic diseases. Exposure to xenobiotics has been shown to be associated with development or worsening of autoimmune disease. It has been established that xenobiotics can elicit hypersensitivity responses directly as an allergen, or they can enhance the induction or severity of allergic sensitization to pollen or dust mites. The determination of risk associated with immunostimulation may be more difficult, but unexpected stimulation should not be disregarded as it may result in nonspecific inflammation or the skewing of normally protective immune responses to favor induction or exacerbation of autoimmunity and hypersensitivity. The fundamental concepts of risk assessment as they apply to the evaluation of immunotoxicity as well as the application of the guidance will be highlighted. We will begin by reviewing case studies which include data that focuses on different areas of immunotoxicity—suppression, sensitization, and autoimmunity. The studies will demonstrate application of the guidance, particularly the development of weight of evidence conclusions from the available data. Finally, we will illustrate that risk assessment for a given chemical should consider the full range of immune effects for that chemical, and data should be evaluated separately for evidence of suppression, stimulation, autoimmunity, and sensitization.

Overview of the WHO/IPCS Harmonized Guidance for Immunotoxicity Risk Assessment for
Chemicals. Henk Van Loveren, National Institute of Public Health (RIVM), Bilthoven, Netherlands

Immunotoxicity Risk Assessment. Andrew A. Rooney, NIEHS, Research Triangle Park, NC

Assessment of Immunosuppression, Immunostimulation, and Autoimmunity. Robert W. Luebke, US EPA, Research Triangle Park, NC

Assessment of Sensitization and Allergic Response. Peter Griem, Symrise AG, Holzminden, Germany

Case Study 1: Lead. Michael I. Luster, West Virginia University School of Medicine, Morgantown, WV

Case Study 2: Halogenated Platinum Salts. Peter Griem, Symrise AG, Holzminden, Germany

Case Study 3: Mercury. Andrew A. Rooney, NIEHS, Research Triangle Park, NC

" }, { "SessionID": 34, "Title": "Protecting Human Health: Use of Toxicological and Epidemiological Data in Determining Safe Levels for Human Exposure", "Year": 2011, "Topic": "Risk Assessment/Safety Assessment", "Transcription": 1, "Description": " Register/Login

Chairpersons: Eileen P. Hayes, EP Hayes Toxicology Services LLC, Longmont, CO and Terry Gordon, New York University School of Medicine, Tuxedo Park, NY

Sponsor: Occupational and Public Health Specialty Section

Endorsed by: N/A

Toxicological and epidemiological data are the basis for risk assessment processes used to determine acceptable levels of exposure. This is the case for the general public who may be exposed to pollutants via ambient air and/or drinking water, for workers who may be exposed to chemicals in the workplace, and for patients who may have exposure to both active pharmaceutical ingredients (API) and impurities that may be present in the product. The goal of this course is to provide students with an understanding of the regulatory background and the practical application of both toxicological and epidemiological information in setting exposure levels considered to be protective of public health. The objectives of this course are 1) to describe the regulatory requirements that underlie development of acceptable levels of exposure for either the general population or select populations (workers, patients) via the media described above; and 2) to describe the evaluation of toxicological and epidemiological data in determining acceptable levels of exposure. Case studies of representative compounds will illustrate the processes. The US Environmental Protection Agency (US EPA) has well-defined processes for establishing both National Ambient Air Quality Standards (NAAQS) under the Clean Air Act and drinking water Maximum Contaminant Levels (MCLs) under the Safe Drinking Water Act. The Occupational Health and Safety Administration (OSHA) promulgates permissible exposure limits (PELs) for the workplace. The American Conference of Government Industrial Hygienists (ACGIH), a non-profit, non-governmental organization publishes Threshold Limit Values (TLVs) that are used globally by many public and private-sector employers to protect the health of their employees. Additionally, many employers have established programs to derive acceptable levels of workplace exposure for compounds not specifically regulated by government agencies. Acceptable identification, reporting, and safety thresholds for impurities in drug products are governed under guidance documents issued by the International Committee on Harmonization (ICH), the US Food and Drug Administration and the European Medicines Agency. The course will highlight legal and customary definitions of “acceptable risk,” as well as risk assessment methods for evaluating data to estimate risk levels under these programs. The regulations and/or guidances will be detailed and approaches used to comply with them will be described. This course will begin with a description methods underlying US EPA actions to protect the general public, i.e., establishment of NAAQS and MCLs. The course will then detail requirements, guidance, and processes to protect specific populations, i.e., workers and patients. In each case representative examples will be used to illustrate the processes. The application of toxicological and epidemiological data in these programs will be described.

Introduction, Eileen P. Hayes, EP Hayes Toxicology Services LLC, Longmont, CO

Clean Air Regulation: Science and the Process, Daniel L. Costa, US EPA-ORD, Research Triangle Park, NC

Drinking Water Regulation: Science and the Process, Rita Schoeny, US EPA, Washington, DC

Setting Occupational Exposure Limits, Bruce D. Naumann, Merck & Co., Inc., Whitehouse Station, NJ

Qualification of Impurities in Drug Products, Timothy J. McGovern, SciLucent, LLC, Herndon, VA

" }, { "SessionID": 35, "Title": "Quantitative In Vitro to In Vivo Extrapolation: The Essential Element of In Vitro Assay Based Risk Assessment", "Year": 2011, "Topic": "In Vitro Methods", "Transcription": 1, "Description": " Register/Login

Chairpersons: Harvey J. Clewell, III, The Hamner Institutes for Health Sciences, Research Triangle Park, NC, and Bastiaan Johan Blaauboer, Utrecht University, Utrecht, Netherlands

Sponsor: Risk Assessment Specialty Section

Endorsed by:
Biological Modeling Specialty Section
In Vitro and Alternative Methods Specialty Section
Nanotoxicology Specialty Section

There is increasing recognition of the need to use efficient approaches to assess the risk assessment of high numbers of chemicals in a short time. The reliance on approaches consisting of animal experimentation has its drawbacks in terms of ethical, economical, and—not least—scientific limitations in assessing risks in a high-throughput mode. The quantitative interpretation of toxic effects of compounds in in vitro studies, using in silico approaches such as systems biological descriptions of toxicity pathways and physiologically based pharmacokinetic modeling (PBPK), are a necessary component of the National Academy of Sciences vision on toxicity testing in the 21st Century. The limited studies performed with this approach to date have shown that good predictions for the risk of the use of chemicals can be made. However, a number of limitations have also become clear and more standardization of methods is needed before implementation of quantitative in vitro-in vivo extrapolations (QIVIVE) in risk assessments can be achieved.

In this course, the following elements of the approach for assessing risks on the basis of in vitro toxicity data will be discussed:


The Use of In Vitro Metabolism Data and Biokinetic Modeling to Conduct QIVIVE for Chemicals, Bastiaan Johan Blaauboer, Utrecht University, Utrecht, Netherlands

Characterizing Free Test Chemical Concentration During In Vitro Toxicity Assays, Nynke Kramer, Utrecht University, Utrecht, Netherlands

Particokinetic Modeling to Support QIVIVE for Particle Toxicity Assays, Justin G. Teeguarden, Pacific Northwest National Laboratory, Richland, WA

QIVIVE

" }, { "SessionID": 36, "Title": "Read-Across: Case Studies, New Techniques, and Guidelines for Practical Application", "Year": 2017, "Topic": "Reproductive and Developmental Toxicology Methods", "Transcription": 0, "Description": " Register/Login

Chairpersons:Kristie Sullivan, Physicians Committee for Responsible Medicine, Oakland, CA; and Mark Cronin, Liverpool John Moores University, Liverpool , United Kingdom.

Endorsed by:
Biological Modeling Specialty Section

In Vitro and Alternative Methods Specialty Section

Regulatory and Safety Evaluation Specialty Section

Component-based methods, while least preferred, are most frequently used to conduct mixtures risk assessments (RA), needing only toxicological information on the individual chemicals or pairs. Inherent in component-based methods are assumptions regarding: toxicological similarity (e.g., dose addition) or independent action; the likelihood or relevance of nonadditive interactions; and the appropriate combined action model. This course covers underlying concepts, inherent assumptions, and uncertainties for mixture assessments. Topics include: guidance from regulatory and advisory bodies for component-based mixtures RA; empirical support and biological understanding for concepts of toxicological similarity and independence; existing and emerging methods, such as grouping chemicals for mixtures RA; influence of study design and data analysis on choice of a combined action model; uncertainties from extrapolation of models to untested dose ranges; conceptual differences of individual risk vs population fraction; consequences of forcing effect measures into a pseudo-risk construct; a rubric of criteria for evaluating usefulness of existing interaction studies; and approaches for reducing the uncertainty of, or incorporating nonadditive interactions into, the RA. Three types of component-based methods are considered, based on: toxicological similarity, independent action, and more complex and hybrid concepts. Step-by-step case studies with different mixtures allow the attendee to work through examples with the instructor. A case study is presented that includes toxicological experimentation and environmental RA for an intentional defined mixture of insecticidal proteins that have been commercialized to enhance efficacy against agricultural pests and combat insect resistance by targeting multiple modes of action. The course will help those who conduct component-based mixtures RA for occupational health and safety, product safety, public health protection, or regulatory decision-making and will appeal to toxicologists who conduct component-based mixtures experiments. Attendees will be equipped to use component-based mixture RA methods and understand their assumptions, advantages, and limitations. recht University, Utrecht, Netherlands

The Regulatory Landscape for Read Across. Kristie Sullivan, Physicians Committee for Responsible Medicine, Washington, DC.

Setting the Stage: Forming a Category Using Chemical Structures to Read Across Toxicological Data. Mark Cronin, Liverpool John Moores University, Liverpool, United Kingdom.

Improving Read Across Using Biological Data and Quality Assessment. Nicole Kleinstreuer, National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), Research Traingle Park, NC.

A Framework to Build Scientific Confidence in Read-Across Results. Grace Patlewicz, Environmental Protection Agency, Research Triangle Park, NC.

ECHA’s Approach to Read Across: The Read-Across Assessment Framework (RAAF). Eric Stilgenbauer, European Chemicals Agency, Helsinki, Finland.

Applying the Read-Across Assessment Framework to Identify and Address Uncertainty. Andrea Richarz, European Commission, Joint Research Centre, Ispra (VA), Italy.

Building a Read-Across from the Ground Up. Sharon Buring Stuard, The Procter & Gamble Company, Cincinnati, OH.

" }, { "SessionID": 37, "Title": "Reproductive Toxicity: Challenges and Practical Approaches to Determine Risk in Drug Development", "Year": 2017, "Topic": "Reproductive and Developmental Toxicology Methods", "Transcription": 0, "Description": " Register/Login

Chairpersons: Jeffrey Moffit, Alnylam Pharmaceuticals, Cambridge, MA; and Edward Dere, Brown University, Providence, RI

Endorsed by:
Regulatory and Safety Evaluation Specialty Section

Reproductive and Developmental Toxicology Specialty Section

The goal of this course is intended to provide an overview of reproductive biology, typical mechanisms of toxicity, and provide a path forward to critically evaluate reproductive liabilities for risk/benefit in humans. This course is primarily intended for toxicologists who encounter reproductive toxicity in a drug development setting, but these tools and approaches are equally applicable to assessing consumer products or environmental chemicals. Reproductive toxicity is a major source of compound attrition, representing one of the most difficult toxicities to predict or monitor in humans. The broad description of reproductive toxicity can arise from direct adverse effects on specific reproductive cell types, perturbations in hormonal signaling cascades, or toxicities that may only become evident from adverse effects on the conceptus. Mechanistic insight into reproductive toxicities is often difficult to ascertain, as reproductive tracts are exceedingly complex with many biological unknowns and species-specific differences in biology or maturation. The first two presentations will focus on male and female reproductive toxicity, respectively. These sessions will cover basic reproductive biology, typical types of reproductive toxicity findings, and case studies that provide real-world approaches to developing decision making criteria for evaluating reproductive liabilities. The third talk will describe various in vitro techniques to profile early development candidates for reproductive liabilities or mechanistically investigate toxicities identified in vivo. A final presentation will cover the unique ways in which biologics can cause reproductive toxicities and alternative approaches to investigating these modalities, which differ from small molecules. In summary, this course will give attendees an appreciation for the complexities of reproductive biology, challenges associated with understanding the mechanistic basis of reproductive findings, and provide practical approaches to determining the risk/benefit relationship of these reproductive toxicities.

Introduction. Edward Dere, Brown University, Providence, RI.

Failure to Launch—Challenges and Strategies to Assess Risk in Male Reproductive Toxicity. Jeffrey Moffit, Alnylam Pharmaceuticals, Cambridge, MA.

Female Reproductive Toxicology—Overview of Female Reproductive Biology, Typical Types of Toxicity Pathways/Challenges to Derisking, Case Studies. Kimberly Hatfield, US Food and Drug Administration, Silver Spring, MD.

In Vitro Approaches to Assessing Reproductive Toxicology. Sarah Campion, Pfizer Inc., Groton, CT.

Reproductive Safety Assessment for Biopharmaceuticals. Wendy Halpern, Genentech, South San Francisco, CA.

" }, { "SessionID": 38, "Title": "Segment-Specific Renal Pathology for the Non-Pathologist ", "Year": 2010, "Topic": "Toxicologic and Exploratory Pathology", "Transcription": 1, "Description": " Register/Login

Chairperson(s): Debie Hoivik, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, and Susan G. Emeigh Hart, Auxilium Pharmaceuticals, Inc., Malvern, PA

Sponsor: Toxicologic and Exploratory Pathology Specialty Section

Endorsed by:
Regulatory and Safety Evaluation Specialty Section

The structural and functional complexity of the kidney uniquely predisposes it to be a sensitive target organ for a number of toxicants. By taking a segment-specific approach to the kidney, participants will gain a broad understanding of structure and function, spontaneous changes, the utility of biomarkers for injury, and morphological changes associated with injury. The different segments of the nephron will be reviewed. Species and gender-related differences in renal structure and function will be emphasized, especially where these contribute to differences in nephrotoxic responses. These differences need to be considered when determining the relevance of findings seen in animal studies to humans. We will review some of the more commonly noted spontaneous lesions and their overall incidences, variance by strain (rodents) and age, all of which can impact study outcome. Lesions such as renal amyloidosis in the mouse and chronic progressive nephropathy in the rat are just two examples of spontaneous lesions which may adversely impact the outcome of a study or may be enhanced by chemical administration, often complicating findings and interpretation. Representative examples of segment-specific morphological changes that occur as a direct response to toxicant exposure will be provided, focusing on those changes evident in laboratory animals used for regulatory testing of new chemical entities. For each morphological change, a corresponding control will be provided to clearly depict the nature of the change. Finally, when choosing a biomarker to monitor for kidney effects, it is critical to understand the utility and limitations of traditional and novel serum and urinary markers of renal injury. Participants will gain a broader perspective on selection and implementation of biomarkers, particularly of the newer urinary markers which provide insight into segment specificity or mechanisms of nephrotoxic injury. Moreover, the participants will understand the specificity of each biomarker as a predictor of injury for specific parts of the nephron.

The Kidney: Anatomic and Physiologic Features of Mechanistic Relevance, Susan G. Emeigh Hart, Auxilium Pharmaceuticals, Inc., Malvern, PA

Spontaneous and Background Changes in Laboratory Animals, John Seely, Experimental Pathology Laboratories, Inc., Research Triangle Park, NC

Renal Toxicant Induced Lesions by Nephron Segment, Jim Stoltz, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT

Biomarkers of Renal Injury, Daniela Ennulat, GlaxoSmithKline, King of Prussia, PA

" }, { "SessionID": 39, "Title": "Stem Cells in Toxicology (2014)", "Year": 2014, "Topic": "Stem Cells", "Transcription": 0, "Description": " Register/Login

Theme: Biomarkers for Exposure Assessment, Safety Evaluation, and Translational Medicine

Chairperson(s): Erik J. Tokar, NIEHS, Research Triangle Park, NC, and Michael P. Waalkes, NIEHS, Research Triangle Park, NC.

Sponsor(s): Stem Cells Specialty Section

Stem cells are revolutionizing toxicological research and remain an area with tremendous potential. Recently, research on stem cells has generated tremendous public and professional interest. However, some areas of toxicological research have lagged behind in the integration of stem cells as a concept in toxicant-induced disease etiology. We will describe the utility and suitability of the assorted types of stem cell models (i.e. embryonic, fetal, progenitor, induced pluripotent, immortalized stem cell lines, etc.) for various research purposes, including disease modeling, drug discovery and toxicity testing in order to describe the potential applications of stem cells in toxicological research. This important overview of stem cells will highlight their nomenclature, properties, and their roles in the genesis of various diseases.

Introduction. Erik J. Tokar, NIEHS, Research Triangle Park, NC.

The Concepts and Methods for Stem Cells. Erik J. Tokar, NIEHS, Research Triangle Park, NC.

Stem Cells in Carcinogenesis. Michael P. Waalkes, NIEHS, Research Triangle Park, NC.

Applications of Stem Cells for Toxicology and Regenerative Medicine, Aaron B. Bowman, Vanderbilt University Medical Center, Nashville, TN.

Stem Cells in Safety Testing. Kyle L. Kolaja, Cellular Dynamics International, Montclair, NJ.

" }, { "SessionID": 40, "Title": "Stem Cells in Toxicology (2012)", "Year": 2012, "Topic": "Toxicologic and Exploratory Pathology", "Transcription": 1, "Description": " Register/Login

Chairpersons: Michael P. Waalkes, NIEHS, Research Triangle Park, NC, and Erik J. Tokar, NIEHS, Research Triangle Park, NC

Sponsor:
Stem Cells Specialty Section

Endorsed by:
Biotechnology Specialty Section
Carcinogenesis Specialty Section
Reproductive and Developmental Toxicology Specialty Section

Stem cells are revolutionizing toxicological research and remain an area with tremendous potential. Recently, research on stem cells has generated tremendous public and professional interest. However, some areas of toxicological research have lagged behind in the integration of stem cells as a concept in toxicant-induced disease etiology. We will describe the utility and suitability of the assorted types of stem cell models (i.e. embryonic, fetal, progenitor, induced pluripotent, immortalized stem cell lines, etc.) for various research purposes, including disease modeling, drug discovery and toxicity testing in order to describe the potential applications of stem cells in toxicological research. This important overview of stem cells will highlight their nomenclature, properties, and their roles in the genesis of various diseases.

The Concepts and Methods for Stem Cells. Ying Xia, University of Cincinnati, Cincinnati, OH

Stem Cells in Carcinogenesis. Michael P. Waalkes and Erik J. Tokar, NIEHS, Research Triangle Park, NC

Stem Cells and Regenerative Medicine. R. Clark Lantz, University of Arizona, Tucson, AZ

Stem Cells in Safety Testing. Kyle L. Kolaja, Hoffmann-La Roche, Inc., Nutley, NJ

" }, { "SessionID": 42, "Title": "Stress As a Confounding Factor in Toxicology Studies", "Year": 2009, "Topic": "Stem Cells", "Transcription": 0, "Description": " Register/Login

Chairperson(s): Katie Sprugel, Amgen, Seattle, WA, and Nancy Everds, Amgen, Seattle, WA

Sponsor: Toxicologic and Exploratory Pathology Specialty Section

Endorsed by:
Immunotoxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section
Women in Toxicology Special Interest Group

Stress can confound the interpretation of toxicity studies. The biology of stress includes complex interrelationships between neurologic and endocrine pathways. Stressors can have effects on in-life, clinical pathology, endocrine, and immune system parameters. Effects on any of these systems may be observed during a toxicity study. The challenge in toxicology is to differentiate between primary test article-related changes and secondary changes related to stress. This differentiation is fundamental to the assessment of stress in the regulatory environment. Understanding the pathophysiology of major systems impacted by stress and the potential range of responses is key to assessing the contribution of stress to study findings. Effects of stress in animals and humans, including potential biomarkers, will be discussed. Key references for the understanding of stress-related findings will be provided.

Introduction, Katie Sprugel, Amgen Inc., Seattle, WA

Neurohormonal Aspects of Stress, David Dorman, North Carolina State University, Raleigh, NC

Stress and Clinical Pathology, Nancy Everds, Amgen Inc., Seattle, WA

Stress and Endocrine Organs, George Foley, Schering-Plough, Summit, NJ

Stress and the Immune System, Paul Snyder, Purdue University, West Lafayette, IN

" }, { "SessionID": 43, "Title": "The Biology and Toxicology of the Peri- and Post-Natal Development", "Year": 2011, "Topic": "Reproductive and Developmental Toxicology", "Transcription": 0, "Description": " Register/Login

Chairpersons: Gregg D. Cappon, Pfizer Global Research and Development, Groton, CT, and Gary J. Chellman, Charles River Laboratories, Reno, NV

Sponsor: Reproductive and Developmental Toxicology Specialty Section

Endorsed by: N/A

The susceptibility to toxicity of organ systems during in utero and post-natal development is a concern for both drugs and environmental chemicals. While developmental toxicity can be manifested by death, structural abnormalities, and altered growth, alterations in the functional competence are of special concern during post-natal development. The primary focus in the past has been on functional toxicity to the CNS and reproduction, but the potential for developmental exposure to impact function of other systems such as the cardiovascular, respiratory, immune, endocrine, and digestive systems is now widely recognized. This basic course will begin with a review of post-natal development of major organ systems in humans and how those developmental processes might translate to sensitive periods for toxicity. Focus will be placed on study designs for evaluation of pharmaceuticals during the pre- and post-natal development period and designs for juvenile animal toxicity studies to support pediatric drug development. Next, designs will be presented for assessment of post-natal and juvenile toxicity studies in non-human primates, a rapidly expanding area given the increase in biopharmaceutical research. The course will wrap up with a discussion of multigenerational studies used to assess potential toxicity of environmental chemicals. Attendees will leave this course with an appreciation of the complex biology of pre- and post-natal development periods and an overview of current approaches to evaluating safety during this period.

Post-natal Maturation of Major Organ Systems, Christopher J. Bowman, Pfizer Inc., Groton, CT

Post-natal and Juvenile Toxicity Studies: Basic Study Designs and Practical Approaches, Donald G. Stump, WIL Research Laboratories LLC, Ashland, OH

Post-natal and Juvenile Toxicity Studies in Non-Human Primates, Gary J. Chellman, Charles River Laboratories, Reno, NV

One and Two-Generation Studies for Assessment of Environmental Chemicals, Sue Marty, The Dow Chemical Company, Midland, MI

" }, { "SessionID": 44, "Title": "The Future of Developmental and Reproductive Toxicology—Building a Bridge to the Animal Free Zone", "Year": 2015, "Topic": "Reproductive & Developmental", "Transcription": 0, "Description": " Register/Login

Chairperson(s): Reza J. Rasoulpour, Dow AgroSciences, Indianapolis, IN; and Patrick Allard, University of California Los Angeles, Los Angeles, CA.

Endorser(s):

Regulatory and Safety Evaluation Specialty Section

Reproductive and Developmental Toxicology Specialty Section

In this new age of predictive toxicity, adverse outcome pathways, and replacements for traditional testing designs, the world of developmental and reproductive toxicology is the final frontier. The sheer complexity of a developing mammalian embryo/fetus coupled to, and dependent upon, maternal care to follow the predesigned path towards normal development still holds many mysteries. In the past several years, there have been breakthroughs in our thinking of developmental and reproductive toxicology alternative assays that now take what was once inconceivable to something that is merely on the horizon. The course focus will be to explore several different examples utilizing novel model system approaches to predict reproductive and developmental toxicity endpoints. The course will include an introductory overview on the history of this area and the unique challenges upon finding alternatives for reproductive and developmental assays. Fundamental developmental processes including the roundworm, C. elegans, as a model organism for prediction of germline toxicities, will be presented. The course will explore alternative vertebrate models and gain insight on the opportunities and challenges with the popular zebrafish as an alternative model for evaluating developmental toxicity and novel downstream safety assessment applications. The course will conclude with presentations on how different alternative assays such as whole embryo culture, zebrafish, and embryonic stem cells can be coupled together to develop a fingerprint to predict developmental toxicity and a presentation on about how the interrogation of different developmental pathways can be combined with computational approaches to develop virtual developmental and reproductive toxicity platforms, such as the virtual embryo. Scientists at multiple levels (graduate students to very experienced scientists) in academia, government, or industry who are interested in learning the current state of the science for developmental and reproductive toxicity assessment are encouraged to attend this course. Course learning objectives are (1) The current state of the science for different approaches in understanding potential for developmental and reproductive toxicity; (2) unique challenges and opportunities that exist within the developmental and reproductive toxicity assessment area compared to other disciplines within toxicology; (3) the pros and cons of utilizing single model species tools versus combining multiple species for predictive assays; and (4) steps that are underway for the longterm replacement of these studies with approaches in bioprofiling combined with computational modeling.

Introduction and Overview. Reza J. Rasoulpour, Dow AgroSciences, Indianapolis, IN.

Utilizing C. elegans As a Predictive Model for Germline Disruption. Patrick Allard, University of California Los Angeles, Los Angeles, CA.

Alternative Development Toxicity Assessment Using Zebrafish—Routine Safety Assessment and Applications. Douglas Fort, Fort Environmental Laboratories, Stillwater, OK.

Combining Rodent Whole Embryo Culture, Zebrafish, and Embryonic Stem Cell Assays to Generate Predictive Signatures. Karen Augustine, Bristol-Myers Squibb Company, Pennington, NJ.

Building Cellular Pathways for the Future—The Virtual Embryo. Thomas B. Knudsen, US EPA, Research Triangle Park, NC.


" }, { "SessionID": 45, "Title": "The New World of Cancer Immunotherapy: Challenges in Bench to Bedside Translation", "Year": 2015, "Topic": "Biotechnology, Immunotoxicology", "Transcription": 0, "Description": " Register/Login

Chairperson(s): Rodney Prell, Genentech Inc., South San Francisco, CA; and Rafael A. Ponce, Amgen, Seattle, WA.

Endorser(s):
Biotechnology Specialty Section
Immunotoxicology Specialty Section

The concept of harnessing the immune system to eradicate cancer has been a long-term goal in immunology and oncology. After years of disappointment, the field of cancer immunotherapy (CIT) has gained a strong foothold with the recent approval of two immunotherapies (ipilimumab and sipuleucel-T); and encouraging data emerging from clinical trials testing checkpoint inhibitors, chimeric antigen T cells, oncolytic vaccines, and other modalities. This intensifying effort to identify new CIT targets and/or develop new modalities to harness the immune system presents new challenges for assessing nonclinical safety to support clinical development. For nonclinical safety assessment, understanding the threshold between desired immunological activity (desired pharmacology), and the potential for exaggerated immunologic stimulation is paramount in the clinical dose selection and identifying biomarkers for patient monitoring. Therefore CIT drug development may require creative models and study designs that incorporate extensive immune monitoring that has not been routinely included when testing conventional cancer therapeutics. The course objective is to provide a general overview of the field of cancer immunotherapy, highlight the unique challenges for CIT drug development, and generate discussion with regards to assessing the unique challenges of developing this new oncology therapeutics to ensure patient safety. Presenters will introduce the concept of cancer immunotherapy and summarize the current landscape of the field of CIT drug development, including the various pathways and modalities currently under development, and discuss the scientific limitations of conventional models for evaluating the pharmacology of novel immunotherapeutics, as well as the promise of novel models that may improve translatability of results to the clinical setting. The course will look into the challenges for nonclinical safety assessment of cancer immunotherapy molecules. Case studies from different CIT modalities will illustrate the challenges. Unique clinical challenges of developing CIT molecules, and the regulatory perspective on the need for nonclinical, clinical and regulatory scientists to partner to ensure patient safety when developing CIT molecules, will also be presented.

Introduction into the Transformative World of Cancer Immunotherapy. Rodney Prell, Genentech Inc., South San Francisco, CA.

Developing Novel Nonclinical Models to Improve CIT Drug Development.Keith A. Bahjat, Providence Cancer Center, Portland, OR.

Ipilimumab Nonclinical Safety Assessment: Lessons Learned. Helen G. Haggerty, Bristol-Myers Squibb, New Brunswick, NJ.

Clinical Perspective: Approaches and Challenges to CIT Development. Willem Overwijk, MD Anderson Cancer Center, Houston, TX.

Approaches and Challenges for Cancer Immunotherapy from a Regulatory Perspective. Stacey Ricci, US FDA, Silver Spring, MD.


" }, { "SessionID": 46, "Title": "The Practice and Implementation of Neural Stem Cell-Based Approaches to Neurotoxicology (CME)", "Year": 2013, "Topic": "Stem Cells", "Transcription": 0, "Description": " Register/Login

Jointly Sponsored by: University of Arkansas for Medical Sciences College of Medicine and SOT

CME Task Force: John G. Benitez, MD, MPH (Chair), Dori R. Germolec, PhD (Council Contact), Martin A. Philbert, PhD, Kenneth S. Ramos, MD, PhD, Dr. Richard Y. Wang, MD

Chairperson(s): Timothy J. Shafer, US EPA, Research Triangle Park, NC, and Aaron B. Bowman, Vanderbilt University Medical Center, Nashville, TN.

Sponsor: Neurotoxicology Specialty Section

Endorsed by:
Mechanisms Specialty Section
Metals Specialty Section
Reproductive and Developmental Toxicology Specialty Section
Stem Cells Specialty Section

The availability and use of human pluripotent stem cells (hPSC) and human neural stem cells (hNSC) for toxicology has dramatically increased in the past decade. hNSC are powerful tools for toxicologists and can provide tissue that would otherwise be unobtainable. This includes a renewable source of neural tissue from the same genetic stock that is not transformed or derived from a tumor, a source of normal human nervous system tissue, and sources of nervous system tissue from patients with clinical disease. However, culture and differentiation of hNSC are unique from culture of primary or transformed neural tissue. The course will bring together experts in the culture of various types of neural stem cells, including embryonic human derived neural stem cells, neurospheres, and neural cells derived from hPSC. Each expert will discuss the basic approaches to culturing different types of hNSC, including propagation of the cells in a progenitor status, as well as protocols for differentiation of the cells into different types of neurons. Pitfalls that are both common to the different models as well as unique ones will be described. The goal of the course is to provide the student with knowledge regarding different types of neural stem cell cultures, the techniques to successfully culture and differentiate these models, and application of these model systems to neurotoxicology. The course will conclude with an examination of appropriate outcome measures and discuss the possibility of personalized neurotoxicological assessment.

Accreditation and AMA Designation Statement

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of The University of Arkansas for Medical Sciences (UAMS) College of Medicine and the Society of Toxicology (SOT). The UAMS College of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

The UAMS College of Medicine designates this live activity for a maximum of 3.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Target Audience

Medical Doctors, health professionals and researchers with an interest in stem cell research and neural stem cell based approaches to neurotoxicology, neurology and regenerative medicine.

Statement of Need, Overall Purpose, and Learner Objectives

The novel technology of applying human stem cell models to research in environmental health and medicine means that the challenges and possibilities of this research was not covered in didactic training of most practitioners; this course will provide


Basic background information on the use of appropriate controls and methodologies will be provided to facilitate and improve understanding of the reasonable or practical applications of this technology in answering questions about human disease.

At the conclusion of this activity, participants will acquire an understanding of the application of neural stem cell based approaches to neurotoxicology.

Specifically, participants will be able to


This will ultimately help physicians explain stem cell research and treatments based on stem cell research to their patients.

Disclosure Statement

It is the policy of the University of Arkansas for Medical Sciences (UAMS) College of Medicine to ensure balance, independence, objectivity, and scientific rigor in all sponsored or jointly sponsored educational activities. All individuals who are in a position to control the content of the educational activity (course/activity directors, planning committee members, staff, teachers, or authors of CME) must disclose all relevant financial relationships they have with any commercial interest(s) as well as the nature of the relationship. Financial relationships of the individual’s spouse or partner must also be disclosed, if the nature of the relationship could influence the objectivity of the individual in a position to control the content of the CME. The ACCME describes relevant financial relationships as those in any amount occurring within the past 12 months that create a conflict of interest. Individuals who refuse to disclose will be disqualified from participation in the development, management, presentation, or evaluation of the CME activity.

Special Needs: We are committed to making this CME activity accessible to all individuals. If you need auxiliary aid(s) or service(s) as identified in the Americans with Disabilities Act, or have a dietary restriction, please describe your needs on the registration form. Most requests can be accommodated if notification is received by March 1, 2013.

Introduction. Aaron B. Bowman, Vanderbilt University Medical Center, Nashville, TN.


Cultural and Neural Differentiation of Human ESC-Derived Neural Cells. Steven L. Stice, University of Georgia and ArunA Biomedical, Inc., Athens, GA.

Neurospheres As 3D Cultures for Developmental Neurotoxicity Testing. Ellen Fritsche, Leibniz Research Institute of Environmental Medicine, Düsseldorf, Germany.

Break


Culture and Differentiation of hPSC-Derived Neurons and the Promise of Personalized Toxicology. Aaron B. Bowman, Vanderbilt University Medical Center, Nashville, TN.

Neurotoxicity Test Development and Mechanistic-Based Toxicology Using hNSC. Timothy J. Shafer, US EPA, Research Triangle Park, NC.

" }, { "SessionID": 47, "Title": "The What, When, and How of Nonclinical Support for an IND Submission", "Year": 2013, "Topic": "Drug Discovery", "Transcription": 1, "Description": " Register/Login

Theme: Regulatory Science: Advancing New Approaches for Hazard Identification and Risk Assessment

Chairperson(s): Paul Nugent, Pfizer Worldwide Research and Development, Groton, CT, and Dorothy Colagiovanni, N30 Pharmaceuticals, LLC, Boulder, CO.

Sponsor: Regulatory and Safety Evaluation Specialty Section

Endorsed by:
Cardiovascular Toxicology Specialty Section
Drug Discovery Specialty Section
Toxicologic and Exploratory Pathology Specialty Section

The initiation of dosing of human subjects in a Phase 1 clinical trial represents the culmination of years of drug development, and immediately preceding the start of dosing, months of work to prepare and submit the Investigational New Drug (IND) application (or Clinical Trial Application (CTA)). A critical part of the submission dossier is the sections that describe the nonclinical data and interpretation that underwrite the clinical plan; specifically, the results of studies in pharmacology, pharmacokinetics, and toxicology, and their integration into a coherent argument that justifies the clinical starting dose, escalation of dose, and “stopping criteria” to be used in the clinical trial. The objective of the course is to elucidate the path to a successful IND/CTA submission by outlining what needs to be done (concentrating principally on the toxicology and safety pharmacology studies), the timeline and order of activities, and the presentation of the data and its integration into a coherent risk assessment to support introduction of the investigational compound into the clinic. The focus will be the content of the Nonclinical Overview (NCO), which represents an integrated detailed summary of the nonclinical studies conducted to support the clinical plan for first-in-human (FIH) dosing. The course will address the expectations of the two main “customers” for the NCO: the US FDA pharmacology/toxicology reviewer evaluating the data to determine if it supports the safety considerations of the clinical plan, and the clinician designing the clinical protocol and conducting the FIH trial.

Introduction. Paul Nugent, Pfizer Worldwide Research and Development, Groton, CT.

Overview of the Nonclinical Toxicology Support for Clinical Trials. Paul Nugent, Pfizer Worldwide Research and Development, Groton, CT.

The IND Review Process from the Perspective of the Nonclinical Reviewer. Ronald Wange, US FDA, Silver Spring, MD.

Toxicology Studies in Drug Development and Their Contribution to the NCO. Dorothy Colagiovanni, N30 Pharmaceuticals, LLC, Boulder, CO.

The Content of the Nonclinical Overview (NCO). J. Neil Duncan, Pfizer Worldwide Research and Development, Groton, CT.

Clinical Perspective on the NCO. Drew Rasco, South Texas Accelerated Research Therapeutics (START), San Antonio, TX.


" }, { "SessionID": 48, "Title": "Toxic Effects of Metals", "Year": 2013, "Topic": "Metals", "Transcription": 1, "Description": " Register/Login

Theme: Regulatory Science: Advancing New Approaches for Hazard Identification and Risk Assessment

Chairperson(s): Michael P. Waalkes, NIEHS, Research Triangle Park, NC, and Michael F. Hughes, US EPA, Research Triangle Park, NC.

Sponsor: Metals Specialty Section

Endorsed by:
Risk Assessment Specialty Section
Mechanisms Specialty Section
Neurotoxicology Specialty Section
Stem Cells Specialty Section

Human exposures to metals are a daily occurrence because of their natural presence in the environment—their uses in production of many commercial products—are byproducts of energy production and are found in many hazardous waste sites. The objective of the course is to highlight the fundamentals of metals toxicology. Metals have unique chemical and physical properties that distinguish them from organic-based chemicals. Even though some metals are essential to life, overexposure to these and other metals may result in a toxic effect in one or more organ systems. Upon exposure, metals may be absorbed, distributed throughout the systemic circulation, metabolized, and eliminated. The response of an organism following exposure to metals may be protective (e.g., induction of the metal-binding protein metallothionein), or toxicological by several mechanisms including oxidative stress. Key organ systems such as the central nervous system, the vascular system, as well as the skeleton system are affected by metals including manganese, lead, aluminum, and others. Accumulation of metals in bone has recently gained renewed interest as an eventual source of internal exposure. Noninvasive methods such as neutron activation are now being used to quantitate bone metal levels. Metals can influence gene expression, signal transduction, and epigenetics. Various toxic and carcinogenic metals such as arsenic and chromium alter the epigenetic program in cells; these effects on DNA methylation, histone tail modifications, and microRNA may be involved in metal-induced toxicity. Metals are known to cause cancer by several proposed mechanisms, including oxidative stress and the cancer stem cell hypothesis. Recent evidence suggests that developmental exposure to metals may affect stem cell population dynamics, which could result in adult onset of cancer. Overall, this is intended to be a basic course on metals toxicology, and is ideal to those who desire knowledge on the health effects of metals and useful tools used in metals toxicology research.

Introduction. Michael P. Waalkes, NIEHS, Research Triangle Park, NC.

Essentials of Metals Toxicology. Michael F. Hughes, US EPA, Research Triangle Park, NC.

Metal-Induced Organ Systems Toxicities. Wei Zheng, Purdue University, West Lafayette, IN.

Mode of Metals Toxicities: Example of Epigenetics. Max Costa, New York University School of Medicine, Tuxedo Park, NY.

Metals in Carcinogenesis and Developmental Origins of Adult Disorders. Erik J. Tokar, NIEHS, Research Triangle Park, NC.


" }, { "SessionID": 50, "Title": "Toxicology and Regulatory Considerations for Combination Products", "Year": 2015, "Topic": "Safety Evaluation and Medical Device & Combination Product", "Transcription": 0, "Description": " Register/Login

Theme: Safety Assessment Approaches for Product Development

Chairperson(s): Jon N. Cammack, AstraZeneca Biologics, Gaithersburg, MD; and Chandramallika (Molly) Ghosh, US FDA, Silver Spring, MD.

Endorser(s):
Drug Discovery Toxicology Specialty Section
Medical Device and Combination Product Specialty Section
Regulatory and Safety Evaluation Specialty Section

Therapeutic and diagnostic products that combine drugs, devices, and/or biological elements are termed, and regulated by the US FDA, as combination products. Technological advances continue to merge product types and blur the historical lines of separation between traditional drugs, biologics, and medical devices. Further, the increasing use of absorbable platforms adds another level of complexity to the development and regulation of certain combination products. US FDA’s medical product centers, the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Devices and Radiological Health (CDRH), are utilizing evolving collaborative efforts in order to address the regulatory challenges of combination products. Because combination products involve components that would normally be developed and regulated under different types of processes and policies, and frequently submitted to different US FDA Centers, these products raise challenging development, regulatory, and review management questions. Differences in these pathways for each combination product type can impact the processes for all aspects of product development and management, especially preclinical testing, but also, clinical investigation, marketing applications, manufacturing and quality control, adverse event reporting, promotion and advertising, and post-approval modifications. The 2014 Sunrise Combination Products CE course introduced the emerging topic; the 2015 CE course will provide in-depth detail on the evolving regulatory processes in developing a successful preclinical evaluation program. In addition to examples of product development scenarios (including drug/biologic-device and antibody drug conjugate combination products), US FDA will provide a reviewer perspective on key program considerations.



Regulatory Overview of Combination Products: Introduction, Definitions, Terms, High-Level Review of New FDA GMP Rules. Thinh Nguyen, US FDA, Silver Spring, MD.

Preclinical Development Challenges for a Hypothetical Drug Pump. Kelly P. Coleman, Medtronic, Inc., Minneapolis, MN.

Case Study of a Preclinical Development Program for a mAb Pre-Filled Syringe Biologic-Device Combination Product. Jon N. Cammack, AstraZeneca Biologics, Gaithersburg, MD.

Considerations for Preclinical Development of Antibody-Drug Conjugates. Matthew Dieter, AbbVie, Chicago, IL.

FDA Reviewer Perspective—Considerations for Bench, Biocompatibility, and Animal Testing of Absorbable Drug-Eluting Stents. Jennifer L. Goode, US FDA, Silver Spring, MD.


" }, { "SessionID": 51, "Title": "Toxicology and Risk Assessment of Chemical Mixtures", "Year": 2011, "Topic": "Mixtures", "Transcription": 0, "Description": " Register/Login

Chairpersons: Jane Ellen Simmons, US EPA, Research Triangle Park, NC, and Christopher J. Borgert, Applied Pharmacology Toxicology, Inc., Gainesville, FL

Sponsor: Mixtures Specialty Section

Endorsed by:
Biological Modeling Specialty Section
Occupational Health and Public Health Specialty Section

Assessment of the safety and risk of environmental chemicals, pharmaceuticals, consumer and personal care products, pesticides, and food additives increasingly requires consideration of the potential pharmacological and toxicological interactions that might occur as these agents are encountered as mixtures by patients, consumers, and through environmental exposures (e.g., mixtures present in air, water, soil). Both toxicological evaluations and risk assessments of mixtures of chemicals are complex due to the potential pharmacokinetic and pharmacodynamic mechanisms that might result in nonadditive interactions. While greater than expected toxicity is of most concern for environmental exposures, both less than and greater than additive toxicity are of pharmacological concern. Toxicological evaluation of chemical mixtures necessitates study designs, methods of analysis, and limits on interpretation not required for single chemicals. This course will cover the fundamentals of study design and data analysis for mixtures that apply to all classes and categories of chemicals encountered by humans and animals, regardless of market application. The objectives of this course are to 1) describe the basic principles that underlie modern concepts of the toxicology and risk assessment of chemical mixtures; 2) survey the basic tools and techniques needed to design, conduct, analyze and interpret experimental data with defined or complex mixtures of chemicals; and 3) review the guidance, underlying assumptions, and techniques used in risk assessment of chemical mixtures. This course will be of interest to experimentalists who wish to conduct studies on mixtures that are meaningful for evaluation of risk as well as safety and risk assessors who must evaluate and apply data on mixtures and interactions in assessments.

Basic Principles of Additivity Underyling Methods, Designs, and Techniques for Evaluation of Mixtures, Jane Ellen Simmons, US EPA, Research Triangle Park, NC

The Intersection of Design and Interpretation of Mixtures Data, Christopher J. Borgert, Applied Pharmacology Toxicology, Inc., Gainesville, FL

Pharmacokinetic and Pharmacodynamic Mechanisms of Interactions in Mixtures, Sami Haddad, Université de Montreal, Montreal, Québec

Applications of Mixtures Data in Health Risk Assessment, Moiz Mumtaz, CDC-ATSDR, Atlanta, GA

" }, { "SessionID": 52, "Title": "Translation of Safety Biomarkers in Drug Discovery and Development", "Year": 2009, "Topic": "Drug Discovery", "Transcription": 0, "Description": " Register/Login

Chairperson(s): Kay Criswell, Pfizer Global Research and Development, Groton, CT, and Jennifer Colangelo, Pfizer, Inc., Groton, CT

Sponsor: Regulatory and Safety Evaluation Specialty Section

Endorsed by:
Comparative and Veterinary Specialty Section
Drug Discovery Toxicology Specialty Section

Several major areas prove problematic in translating animal data/biomarkers to humans. This course focuses on translational issues in hematology, clinical chemistry, protein and peptide assays. It concludes with a risk assessment presentation summarizing the realities of implementing the overall process in defining human relevance of safety and efficacy from preclinical data. Preclinical data gathered in laboratory animals is required by regulatory agencies to determine safety in humans prior to marketing of new products. Species-specific differences in routine and esoteric serum biomarkers make the relevance of findings in animals difficult to interpret. Knowledge in this area is beneficial to the safe conduct of clinical trials and the inclusion of relevant biomarkers as effective safety and efficacy endpoints during new product development. Research scientists, industry scientists, laboratory personnel, and pathologists interested in biomarker development, translation, execution and applications from preclinical through clinical trials may be interested. The difference between data obtained in preclinical and clinical circumstances will be covered in this course. Therefore, it may be of interest to anyone in a preclinical research setting through those engaged in clinical trials, as well as those evaluating the safety of industrial chemicals. Course objectives include identification of potential relevance or non-relevance of animal-based hematologic and clinical chemistry biomarkers to humans, identification of methods of overcoming species-specific problems in protein and peptides biomarkers, and understanding human relevance of animal data and the impact of biomarker utilization on speed and decision-making.

Translation of Safety Biomarkers: Introduction, Kay Criswell, Pfizer Global Research and Development, Groton, CT

Does Preclinical Hematology Predict Human Safety? Nancy Everds, Amgen Inc., Seattle, WA

Translation of Clinical Chemistry Biomarkers: Pitfalls and Solutions, Denise Bounous, Bristol-Myers Squibb, Princeton, NJ

Overcoming the Problem of Species-Specific Proteins and Peptides in Assay Development, Jennifer Colangelo, Pfizer Global Research and Development, Groton, CT

Connecting the Dots to Define Human Relevance to Preclinical Data: Implementing Techniques to Enhance Speed of Delivery and Decision Making, Michael R. Bleavins, Michigan Technology and Research Institute, Ann Arbor, MI

" }, { "SessionID": 53, "Title": "Unique Approaches to Safety Assessment of Gene, Cell, and Nucleic Acid-Based Therapies", "Year": 2016, "Topic": "Biotechnology", "Transcription": 0, "Description": " Register/Login

Theme: Recent Advances in Safety Assessment

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

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

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

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

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

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

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

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

" }, { "SessionID": 54, "Title": "Weighing in on Nutrition—Essential Concepts for Toxicologists", "Year": 2013, "Topic": "Cardiovascular Tox", "Transcription": 0, "Description": " Register/Login

Theme: Molecular Basis of Genetic Variability and Susceptibility to Toxicants

Chairperson(s): Daniel M. Wilson, The Dow Chemical Company, Midland, MI, and Angela L. Slitt, University of Rhode Island, Kingston, RI.

Sponsor: Food Safety Specialty Section

Endorsed by:
Cardiovascular Toxicology Specialty Section
Ethical, Legal, and Social Issues Specialty Section
Mechanisms Specialty Section
Women in Toxicology Special Interest Group

There has been an exponential increase in the attention focused on the potential role of nutrition in reducing the risk for numerous health complications, ranging from birth defects to age-associated vascular disease. Underscoring the above is the increasing number of presentations and publications related to this subject, and hallmarks such as the recently revamped Food Pyramid into a Plate Icon. Chronic nutritional diseases are accepted to be a current crisis in our society; three nutrition-related diseases alone, obesity, Metabolic Syndrome, and Type 2 Diabetes, afflict over one-third of the American population. To better understand the components and etiology of nutritional diseases, it’s essential for toxicologists to be well versed in the science of nutrition. A comprehensive understanding of nutrition has broad applications in toxicology, especially considering that many of us have roles in investigating the safety of nutrients, food additives or food ingredients, studying nutritional disease, or designing and interpreting preclinical or clinical studies wherein the need to consider and understand nutritional homeostasis is essential. The potential for intersection of normal nutritional metabolic pathways with adverse outcome pathways is becoming even more important to delineate. This course on general nutrition, the biochemistry of nutritional pathways, the essential role of vitamins, the channeling of nutrients such as carbohydrates, proteins and fats, cellular and molecular details of nutrition, and nutritional aspects of development and reproduction, will heighten awareness of their importance in human and animal health at multiple levels. The focus will be on relevant information, starting with an introduction to nutrition, followed by a review of biochemical and metabolic reactions in nutrition, with an emphasis on their relation to toxicology. How the nutritional status of a woman can modulate the developmental toxicity of a number of diverse toxicants, including alcohol, will be presented, along with a seminar describing the tools and applications of molecular and genetic models of nutritional disease.

Introduction. Daniel M. Wilson, The Dow Chemical Company, Midland, MI

Nutrition 101. Jo Ann S. Carson, University of Texas Southwestern, Dallas, TX.

The Biochemistry of Nutrition. Daniel M. Wilson, The Dow Chemical Company, Midland, MI.

Studying Nutritional Disease in Rodent and Cell-Based Models: Proper Selection of Molecular and Systemic Endpoints. Angela L. Slitt, University of Rhode Island, Kingston, RI.

Nutrition and Pregnancy. Carl L. Keen, University of California Davis, Davis, CA.

" }, { "SessionID": 55, "Title": "CRISPR-Cas9 for Toxicologists", "Year": 2018, "Topic": "Biotechnology", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Gary W. Miller, Emory University, Atlanta, GA; and Lesa L. Aylward, Summit Toxicology, Falls Church, VA.

Endorsed by:
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.

" }, { "SessionID": 56, "Title": "The What, When, and How of Using Data from Alternative Testing Methods in Chemical Safety Assessments", "Year": 2018, "Topic": "In Vitro Methods", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Suzanne C. Fitzpatrick, US FDA, College Park, MD; and Mansi Krishan, ILSI North America, Washington, DC.

Endorsed by:
In Vitro and Alternative Methods Specialty Section
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.

" }, { "SessionID": 57, "Title": "An Introduction to the Basics of Immunotoxicity Testing", "Year": 2018, "Topic": "Immunotoxicology", "Transcription": 0, "Description": "Register/Login

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

Endorsed by:
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.


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

" }, { "SessionID": 58, "Title": "Biotherapeutic Development: What's behind the Curtain?", "Year": 2018, "Topic": "Drug Discovery", "Transcription": 0, "Description": "Register/Login

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

Endorsed by:
Biotechnology Specialty Section
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.

" }, { "SessionID": 59, "Title": "Physiologically-Based Pharmacokinetic Modeling to Support Modernized Chemical Safety Assessment", "Year": 2018, "Topic": "Risk Assessment", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Miyoung Yoon, ScitoVation, Research Triangle Park, NC; and Alicia Paini, European Commission Joint Research Centre, Ispra, Italy.

Endorsed by:
Biological Modeling Specialty Section
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.

" }, { "SessionID": 60, "Title": "Evaluation of Leachable Substances from Materials with Applications in Foods and Pharmaceuticals: Science- and Risk-Based Approaches", "Year": 2018, "Topic": "Safety Assessment", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Greg L. Erexson, AbbVie, North Chicago, IL; and Kim L. Li, Amgen Inc., Thousand Oaks, CA.

Endorsed by:
Medical Device and Combination Product Specialty Section
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.

" }, { "SessionID": 61, "Title": "Lead Optimization of Therapeutic Small Molecules: From Drug Target to Clinical Candidate Selection—Strategies and Decision Making", "Year": 2018, "Topic": "Drug Discovery", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Dolo Diaz, Denali Therapeutics Inc., South San Francisco, CA; and Dinah Misner, Alios Biopharma, South San Francisco, CA.

Endorsed by:
Drug Discovery Toxicology Specialty Section
Cardiovascular Toxicology Specialty Section
In Vitro and Alternative Methods 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.

" }, { "SessionID": 62, "Title": "Uncertainty Characterization in 21st-Century Toxicology: Current Practice and Practical Methods Supporting Regulatory Risk Assessment", "Year": 2018, "Topic": "Risk Assessment", "Transcription": 0, "Description": "Register/Login

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

Endorsed by:
In Vitro and Alternative Methods Specialty Section
Biological Modeling Specialty Section
Regulatory and Safety Evaluation 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 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.

" }, { "SessionID": 63, "Title": "Assay Development Principles and Good Research Practices for Rigor and Reproducibility in In Vitro Toxicology", "Year": 2019, "Topic": "Molecular & Systems Biology", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Shaun D. McCullough, US EPA, Chapel Hill, NC; Menghang Xia, NIH/NCATS, Bethesda, MD; Nathan P. Coussens, NIH/NCATS, Bethesda, MD; and Samantha Faber, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Primary Endorser:
Molecular and Systems Biology Specialty Section

Other Endorser(s):
In Vitro and Alternative Methods Specialty Section
Mechanisms Specialty Section

Toxicological research and testing heavily depends on the application of cell and molecular assays to provide mechanistic insight into the effects of chemical exposures as well as model systems to overcome the constraints of in vivo human and animal exposure studies. Despite being powerful tools, these assays are not immune from the “reproducibility crisis” that has cast a considerable shadow over all fields of biomedical research. Improving the rigor, reproducibility, and physiological relevance of both traditional and high-throughput cellular and molecular methods is critical to protect human health, increase the efficiency of drug and consumer product development, and ensure the reliability of data used in chemical regulation. Recent reports in both the scientific and public literature have revealed a need for increased rigor in preclinical research and highlighted experimental design, reagents (including antibodies and cell lines), and data analysis as key challenges to study reproducibility. The goal of this course is to provide participants with “good research practices” for the rigorous development, optimization, implementation, and interpretation of robust in vitro toxicological assays for reproducible results using physiologically relevant models. Presentations will follow a broadly applicable workflow, starting with the establishment of a verified cell culture model with increased physiological relevance. Participants will learn how understanding the nature of cells in vitro and treating cells as reagents can ensure the design of more reproducible assays. Strategies also will be shared for the successful implementation of high-throughput assays that enable the rapid and high-throughput assessment of both toxicity and efficacy using in vitro models with increased physiological relevance. This will be followed by global gene expression analysis using RNA sequencing, validation, and exploration of target gene expression with quantitative PCR, assessment of protein abundance, and post-translational modification using immunoassays, and evaluation of cumulative effects of exposures on cell physiology and viability. The final presentation will empower participants with the knowledge and tools to utilize innovative statistical measures that were developed specifically to enable reliable assessments about compound properties based on data from in vitro assays. This course will provide attendees with core principles and practices for widely used methods, which will facilitate the design and execution of a broad range of rigorous and reproducible experiments, increased throughput, and improved in-depth interpretation of data from both study findings and published literature. The content of this course will benefit researchers from industry, government, and academic labs who evaluate the safety of experimental compounds and wish to learn more about the latest models, methodologies, and analysis strategies.

Introduction to the Course. Nathan P. Coussens, NIH/NCATS, Bethesda, MD.

Simple Approaches to Improving Relevance and Reproducibility in Cell Culture. Shaun D. McCullough, US EPA, Chapel Hill, NC.

Treating Cells as Reagents to Design Reproducible In Vitro Toxicology Assays. Terry Riss, Promega Corporation, Madison, WI.

In Vitro Toxicological Testing in qHTS Format. Menghang Xia, NIH/NCATS, Bethesda, MD.

Seq-ing the Truth: Principles and Practices for Quantifying Gene Expression Using RNA Sequencing and Quantitative PCR. Elizabeth Martin, NIEHS, Research Triangle Park, NC.

Maximizing Sensitivity, Reproducibility, and Interpretability of Immunoblots and Immunoassays. Kevin Janes, University of Virginia, Charlottesville, VA.

Characterizing Reproducibility and Optimizing Value of In Vitro Screening Methods. Viswanath Devanarayan, University of Illinois at Chicago, Chicago, IL.

" }, { "SessionID": 64, "Title": "Developmental Toxicity of the Skeletal System: Interpretation of Findings in DART Studies and Implications for Risk Assessment", "Year": 2019, "Topic": "Reproductive and Developmental Toxicology", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Michael Garry, Exponent Inc., Seattle, WA; and AtLee Watson, NIEHS/NTP, Research Triangle Park, NC.

Primary Endorser:
Reproductive and Developmental Toxicology Specialty Section Specialty Section

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

Skeletal development represents a period of rapid patterning and specification of tissues that form the basis for subsequent growth in the developing organism. As a result, formation of the skeletal elements (e.g., bone and cartilage) are included as a standard endpoint in prenatal developmental toxicity studies. Abnormal findings are classified as variations or malformations; however, the interpretation of these findings and whether they result in functional deficits in postnatal life can have significant consequences within a regulatory framework for new compounds coming to market. The goal of this course is to provide participants with an introduction to skeletal anatomy and physiology that can facilitate the interpretation of abnormal findings from a toxicological perspective. Speakers from academia, industry, and government with expertise in the fields of skeletal biology and developmental toxicology will provide (1) a fundamental review of skeletal development in animal models currently used in developmental toxicity studies, with an emphasis on differences in developmental course and extrapolation between species; (2) a discussion of current and emerging methods to identify skeletal anomalies in prenatal and postnatal/juvenile developmental toxicity studies, and their relation to overall developmental toxicity, both in the animal models and their potential human relevance; (3) case studies to illustrate the concepts introduced by the first two speakers and specific challenges faced in the interpretation of study results; and (4) context from a regulatory perspective on the interpretation of abnormal skeletal findings and the evolving requirements needed to address skeletal toxicity concerns.

Skeletal Development in Laboratory Mammals and Humans. John DeSesso, Exponent, Alexandria, VA.

Interpretation of Skeletal Anomalies in Laboratory Animals. Athony Scialli, Scialli Consulting, LLC, Washington, DC.

Case Studies of Common Skeletal Findings in Developmental Toxicity Studies. Donald Stump, Charles River Laboratories, Ashland, OH.

Regulatory Perspective on Evaluation and Interpretation of Effects on Skeletal Development, and Outlook for the Future. John Rogers, US EPA, Research Triangle Park, NC.

" }, { "SessionID": 65, "Title": "Industrial Application of Computational Toxicology in the 21st Century", "Year": 2019, "Topic": "Computational Toxicology", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Catrin Hasselgren, Genentech, Inc., South San Francisco, CA; and Alessandro Brigo, F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Primary Endorser:
Computational Toxicology Specialty Section

Other Endorser(s):
In Vitro and Alternative Methods Specialty Section
Risk Assessment Specialty Section

Computational toxicology encompasses the development of computational models and tools applied to datasets of toxicological concern and the use of such methods for various applications. This is a wide field spanning hazard identification, prioritization for experimental testing, optimization of chemical space, and chemical risk assessment. These methods are used in many different industry sectors, such as consumer products, pharmaceuticals, and agrochemicals, as well as being widely used in the environmental sector and in governmental or regulatory organizations. The methods employed vary from simple to complex depending on availability and quality of data, and range from the application of structural alerts to machine-learning models of large-scale biological data and complex systems toxicology modeling. With increased pressure to reduce the number of animal experiments, accelerate the product development cycles, and lower costs, computational toxicology is a continuously developing area with yet-untapped potential. This course will give a short background and introduction to the field, followed by a methods section where different scenarios will be presented that guide the participants in how data is analyzed and models and tools are built, depending on the use case at hand, as well as data limitations. This will be followed by two presentations on practical applications of computational toxicology, the first one focused on consumer products (e.g., food, cosmetics) and the second on examples from the pharmaceutical industry. Both of these presentations will highlight the diversity of use cases within each industry. The course will end with a final presentation discussing the regulatory landscape and examples of how such tools are used to support regulatory safety assessment of various products. The aim of this course is to introduce the discipline of computational toxicology to the nonexpert and provide the participants with a broad understanding of the many benefits of computational toxicology methods, as well as an understanding of the limitations and appropriate use of such methods for successful outcomes in an industrial setting. The learnings from this course are relevant for attendees from all industry sectors as well as from other research-dedicated organizations.

Computational Toxicology—Past, Present, and Future. Catrin Hasselgren, Genentech, Inc., South San Francisco, CA.

Methods and Principles of Computational Toxicology—The Basics. Nigel Greene, AstraZeneca, Waltham, MA.

Computational Methods in Next-Generation Risk Assessment of Consumer Products. Steve Gutsell, Unilever Safety and Environmental Assurance Centre, Sharnbrook, United Kingdom.

Computational Methodologies for the Prediction of Drug Toxicity in the Pharmaceutical Industry. Alessandro Brigo, F. Hoffmann-La Roche Ltd, Basel, Switzerland.

US FDA Experience in the Regulatory Application of Quantitative Structure-Activity Relationshop Modeling. Naomi Kruhlak, US FDA/CDER, Silver Spring, MD.

" }, { "SessionID": 66, "Title": "Mechanistic Understanding and Quantitative Risk Assessment in Immunotoxicology", "Year": 2019, "Topic": "Immunotoxicology", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Emanuela Corsini, Università degli Studi di Milano, Milan, Italy; and Jamie DeWitt, East Carolina University, Greenville, NC.

Primary Endorser:
Immunotoxicology Specialty Section

Considering the important health consequences associated with exposure to immunotoxic compounds, quantitative risk assessment in immunotoxicology is an area of growing interest. The discipline of immunotoxicology has refined several powerful tools to assess the safety of new drugs and other products. Novel approaches for assessment of hypersensitivity and cytokine-based assays to examine chemical-specific effects are moving the field away from the use of animals and providing a path forward for hazard identification and risk assessment. Although the majority of immunotoxicity studies are designed for hazard identification, there is a considerable amount of data demonstrating that a threshold for both immunosuppression and contact sensitization exists, making quantitative risk assessment possible. The purpose of this advanced course is to provide guidance on how to perform risk assessment using immunotoxicology data. Following a brief introduction (first presentation), examples will be given for both immunosuppression (second presentation) and contact hypersensitivity (third presentation). In addition, to support animal-to-human extrapolation, mechanistic understanding is crucial and will be provided in this course (last two presentations). In 21st century toxicology, it also is crucial to integrate all information from in silico and in vitro methods into animal studies. Therefore, in a modern vision of immunotoxicology, integrated strategies will be described and examples provided in each presentation. This course will provide participants with the means and knowledge to conduct quantitative risk assessment using the effect on the immune system as the adverse outcome to protect humans from chemical-induced immunotoxicity and its consequences.

Introduction to the Course. Jamie DeWitt, East Carolina University, Greenville, NC.

Integrated Strategies in Immunotoxicity Risk Assessment. Dori Germolec, NIEHS/NTP, Morrisville, NC.

Quantitative Risk Assessment in Chemical-Induced Skin Sensitization. Frank Gerberick, GF3 Consultancy, LLC, West Chester, OH.

Drug-Induced Systemic Hypersensitivity: Mechanistic Understanding and Early Detection. Jack Uetrecht, University of Toronto, Toronto, ON, Canada.

Cytokine Production from Mechanistic Understanding to Use in Safety Assessment. Wimolnut Manheng, US FDA/CDER, Silver Spring, MD.

" }, { "SessionID": 67, "Title": "Beauty of the Skin Is in the Eye of the Beholder: A Basic Course on Dermal and Ocular Toxicology", "Year": 2019, "Topic": "Dermal Toxicology", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Michael Hughes, US EPA, Research Triangle Park, NC; and Neera Tewari-Singh, University of Colorado at Denver, Aurora, CO.

Primary Endorser:
Dermal Toxicology Specialty Section

Other Endorser(s):
Association of Scientists of Indian Origin Special Interest Group

Every day we use our eyes to see what is going on in the world, while our skin provides key information to our brains by sensing the world around us through touch. Skin also protects our body by regulating our temperature. While the eyes and skin are two distinct organs, they have some commonalities. First, they both provide our bodies with a barrier to the external environment. Although the barrier properties of the skin and cornea are not impermeable or equivalent in their ability to provide protection, they provide a degree of impedance to physical assaults such as sunlight and xenobiotic penetration. Secondly, the outer anatomy of the skin and the eye are epithelial in nature, derived from the ectoderm. These two organs have differences in their physiology, functional purpose, toxicological response, and pathological outcome. Both organs are important to toxicology because they are exposed to the external environment but react differently to toxic insults than internal organs. The purpose of this course is to provide the audience with the fundamentals of dermal and ocular toxicology and methods to assess absorption and toxicity. The first presentation will focus on dermal anatomy and methods to assess dermal absorption. Factors that can affect dermal absorption will be discussed, as well as those learned from in vitro studies (e.g., static, flow-through methods) and in vivo methods to quantitate absorption. The strengths and weaknesses of these methods will be presented. The second presentation will emphasize dermal toxicity. An overview of the manifestations of dermal toxicity, its assessment biomarkers, and useful animal models of chemical-threat agents exposure will be presented. The third presentation will discuss ocular toxicity. The anatomy of the eye and manifestations of ocular injury and toxicity from a variety of drug and chemical classes will be presented. The fourth presentation will highlight toxicology of the cornea. The anatomy of the cornea, absorption of chemicals and drugs through this tissue, and the implications of toxicity on the function of the cornea will be presented. The fifth presentation will cover advances in the field of nonanimal alternatives to toxicity testing for skin sensitization and ocular/dermal irritation. Work to develop and validate integrated testing strategies and progress toward regulatory implementation will be discussed. Overall, by attending this session, the audience will gain basic information to understand the potential toxicological outcome of xenobiotic exposure to the dermal and ocular systems.

Dermal Absorption of Xenobiotics: Skin Anatomy, Factors That Affect Absorption, and Methods to Assess Absorption. Michael Hughes, US EPA, Research Triangle Park, NC.

Dermal Toxicity: Hazardous Chemical Exposure Assessment and Animal Models. Neera Tewari-Singh, Michigan State University, East Lansing, MI.

Ocular Anatomy and Manifestations of Ocular Toxicity. Marion Gordon, Rutgers, The State University of New Jersey, Piscataway, NJ.

Tissue-Specific Aspects of Corneal Injury: The Cornea Is Not Merely a Window to the Soul. Patrick McNutt, US Army Medical Research Institute of Chemical Defense, Fallstom, MD.

Advances in Nonanimal Alternatives to Dermal and Ocular Toxicity Testing. Nicole Kleinstreuer, NIEHS/NICEATM, Research Triangle Park, NC.

" }, { "SessionID": 68, "Title": "Conducting Systematic Review in Toxicology—Why, When, How?", "Year": 2019, "Topic": "Risk Assessment", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Martin Wilks, University of Basel, Basel, Switzerland; and Vickie Walker, NIEHS/NTP, Research Triangle Park, NC.

Primary Endorser:
Risk Assessment Specialty Section

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

Systematic review is gaining interest in the field of toxicology, highlighted by regulatory requirements being globally instituted to conduct systematic review in support of safety assessments of chemicals and foods (e.g., via US Environmental Protection Agency [US EPA] Toxic Substance Control Act [TSCA], US EPA Integrated Risk Information System [IRIS], and European Food Safety Authority [EFSA]). Systematic review refers to the objective and transparent process of collecting and synthesizing scientific evidence for reaching conclusions on specific research questions. While systematic review has been successfully used for decision-making in areas such as clinical medicine for many years, the implementation of systematic review within a toxicological context using established frameworks presents unique challenges. As such, several groups that conduct toxicological research have developed systematic review frameworks that take into consideration the breadth of data relevant to the environmental health and food safety sciences by extending and adapting the approaches developed for clinical medicine. This course will survey available approaches and tools for conducting systematic reviews in toxicology, provide information on the components and conduct of systematic review, and provide instructions on reporting and appraising systematic reviews. Particular emphasis will be placed on determining when a systematic review would be useful and how to determine the specific research question(s), critical appraisal of study quality for human and animal evidence, and structured integration of the evidence across evidence streams. Presenters will highlight and demonstrate tools and other software that can be used for study selection and screening, study quality appraisal, documentation, visualization, and decision-making. The course will provide the opportunity for participants to gain an understanding of why to choose to conduct a systematic review, when it is appropriate to do so, and how to conduct the critical elements of a systematic review, as well as gain an appreciation for the rigor and transparency that a systematic review requires (thus setting it apart from traditional narrative reviews). This course has strong relevance to toxicologists from diverse sectors, including researchers, regulators, risk assessors, consultants, and industry, who may need to use systematic review processes or even consider the results of systematic reviews in their practice.

Systematic Review: An Overview. Daniele Wikoff, ToxStrategies, Inc., Ashville, NC.

Problem Formulation and Protocol Development. Martin Wilks, University of Basel, Basel, Switzerland.

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.

Assessment of Study Quality. Emily Sena, University of Edinburgh, Edinburgh, United Kingdom.

Integrating the Evidence to Develop Hazard Conclusions. Brandiese Beverly, NIEHS/NTP, Research Triangle Park, NC.

Reporting and Critically Appraising Systematic Reviews. Paul Whaley, Lancaster University and Environment International, Lancaster, United Kingdom.

" }, { "SessionID": 69, "Title": "Current Dose-Response Modeling Strategies and Applications in Chemical Risk Assessment", "Year": 2019, "Topic": "Risk Assessment", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Kan Shao, Indiana University, Bloomington, IN; and Allen Davis, US EPA, Cincinnati, OH.

Primary Endorser:
Risk Assessment Specialty Section

Other Endorser(s):
Biological Modeling Specialty Section
Regulatory and Safety Evaluation Specialty Section

Quantifying dose-response relationships to evaluate the toxicity of environmental chemicals is a key step in human health risk assessment and has substantially evolved in recent years. The purpose of this course, to be delivered by a mixed group of experts from government, academia, and industry, is to provide participants an overview of the currently prevailing dose-response modeling methodologies and tools with case studies and applications in chemical risk assessment. The first presentation will introduce basic concepts and terminologies of the benchmark dose (BMD) method, including discussions on the use of US Environmental Protection Agency (US EPA)'s benchmark dose software (BMD), how to model commonly available toxicological data, and how to interpret the results. The second presentation will discuss the categorical regression modeling approach, together with the US EPA CatReg software and its application to chemical risk assessment. The third speaker will present how to apply the BMD methodology in a Bayesian framework to produce probabilistic estimates of interest (e.g., model parameter estimates, single model BMD estimates, and model averaged BMD estimates) to support probabilistic dose-response assessment. While the first three presentations complement each other regarding modeling methodologies, the last speaker will provide an overview to summarize the utilities of the strategies and tools through three case studies in the agrochemical industry to help participants reinforce the knowledge by using real-world relevance and experience.

Introduction on BMD Methodology and US EPA Benchmark Dose Software. Jeff Gift, US EPA, Research Triangle Park, NC.

Categorical Dose-Response Modeling. Allen Davis, US EPA, Cincinnati, OH.

Bayesian BMD Analysis Methodologies and Applications. Kan Shao, Indiana University, Bloomington, IN.

Utilization of Dose-Response Modeling Tools for Product Safety Assessment. Zhongyu (June) Yan, Corteva Agriscience, Indianapolis, IN.

" }, { "SessionID": 70, "Title": "Microbiome and Environmental Toxicants: From Study Design and Analysis to Regulatory Guidance", "Year": 2019, "Topic": "Immunotoxicology", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Sarah Blossom, University of Arkansas for Medical Sciences, Little Rock, AR; and Sangeeta Khare, US FDA/NCTR, Jefferson, AR.

Primary Endorser:
Immunotoxicology Specialty Section

The microbiome consists of indigenous microbial communities and the host environment that they inhabit. Current paradigm-shifting research indicates that the interaction between the host and the microbiome is an important regulator of many diseases and is changing the way that scientists think about the role microbes play in human health. The microbiome includes microbes that are both helpful and potentially harmful, and in a healthy individual, these microbial communities coexist without problems. However, when this balance is disturbed, dysbiosis can occur. One such factor that is emerging as a regulator of this balance is exposure to environmental pollutants that may perturb host-microbiome interactions to promote disease. The microbiome is a rapidly emerging field, and toxicologists from industry, academia, and federal agencies understand the importance of studying the impact of toxicants and pharmaceuticals on gut microbiome dysbiosis and host responses. However, approaching this vast area of study can seem daunting. This course is designed to provide practical information from experts in the field with the latest state-of-the-art tools so that toxicologists can incorporate the study of microbiome and host-associated responses into mechanistic research, risk assessment, and/or therapeutics. Following this course, participants will be familiar with current advances in microbiome research as it pertains to toxicology. An overview of experimental models and case study examples of microbiome toxicity and immunotoxicity will be presented. Further discussion on how xenobiotics change the microbial population and immune status of animals during developmental exposures will be provided. Concepts will be reinforced in a multigenerational toxicology case study that will take the participants through steps of experimental design, data collection, and reporting. The course will provide participants with practical knowledge and tools to conduct microbiome analysis using the metagenomics analysis server (MG-RAST). The latest information related to regulatory aspects for microbiome-based therapeutics approaches will be presented to participants. Overall, this course will provide a comprehensive overview of study design, data analysis, and challenges in biotherapeutics using examples of toxicant-induced intestinal microbiome dysbiosis.

The Microbiome in Immunotoxicology: Current State of the Science. Sarah Blossom, University of Arkansas for Medical Sciences, Little Rock, AR.

Nonanimal and Animal Models to Test the Effect of Xenobiotics on the Intestinal Microbiome and Gut-Associated Immune Responses during Developmental Stages. Sangeeta Khare, US FDA/NCTR, Jefferson, AR.

Microbiome Experimental Design for More Effective Planning and Execution of Multigenerational Toxicology Studies. Kenneth Drake, Seralogix, Inc., Austin, TX.

An Overview of Current Microbiome Analysis Tools. Folker Meyer, Argonne National Laboratory and the University of Chicago, Argonne, IL.

Regulatory Considerations for Microbiome-Based Therapeutics. Paul Carlson, US FDA/CBER, Silver Spring, MD.

" }, { "SessionID": 71, "Title": "Introduction to Open-Access Computational Toxicology Tools", "Year": 2020, "Topic": "Computational Toxicology", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Agnes Karmaus, Integrated Laboratory Systems, Inc.; and Nicole Kleinstreuer, NIEHS/NICEATM.

Primary Endorser:
In Vitro and Alternative Methods Specialty Section

Other Endorser(s):
Mechanisms Specialty Section; Regulatory and Safety Evaluation Specialty Section

Computational toxicology is rapidly accelerating our ability to develop methods for predicting chemical properties and chemical-mediated effects, both in the environmental chemical space and in the area of drug development. With frequently updated tools and approaches, overwhelming feedback suggests that more training is needed to help all toxicologists understand the fundamental approaches, use available tools and databases, and interpret outputs. This CE course is designed to offer an introductory-level foundation for leveraging some widely accepted approaches and demonstrate how to use open-source tools and resources to make use of these methods. Course participants across all sectors, ranging from students to career toxicologists, should walk away with the confidence to use the resources presented for computationally characterizing and predicting chemical-elicited toxicity. In addition to gaining familiarity with basic computational toxicology concepts, participants will gain insight into what makes an approach useful for research projects versus which are ready for potential regulatory applications. The first speaker will help lay a foundation for how chemicals are “interpreted” computationally, explaining how chemical structures are leveraged for subsequent analyses (i.e., fingerprinting and its use for read-across). Building on these concepts, the second speaker will provide a thorough example of how to use the US Environmental Protection Agency (US EPA) CompTox Chemicals Dashboard, which provides data for nearly 900,000 chemicals and drugs. Attendees will learn how to assess the confidence in available data, as well as learn how to use the tools available in the dashboard for predicting chemical toxicity and download pertinent data, including mechanistic information, exposure data, animal toxicity doses, and much more. The third presentation will provide a demonstration to empower course attendees in using the Integrated Chemical Environment (ICE), an interactive tool that contains in vitro to in vivo extrapolation workflows that users can leverage to conduct analyses themselves, as well as provides curated in vivo and in vitro datasets that can be used to evaluate predicted toxicology outcomes. The fourth presentation will steer the course further into the realm of biological interpretation, describing how toxicogenomics data and literature mining underlying the Comparative Toxicogenomics Database (CTD) can be utilized to computationally characterize chemical mode of action and provide insight into toxicity mechanisms. The last speaker will introduce Sysrev, a collaborative computational systematic review tool to extract pertinent data from literature, incorporating approaches such as machine learning and metadata tagging. Overall, course attendees will gain a fundamental understanding of approaches underlying the most widely used computational toxicology methods, as well as learn to use publicly available, open-source tools that apply these methods.

Course Introduction: What Do Computational Toxicology Tools Offer? Nicole Kleinstreuer, NIEHS/NICEATM, Durham, NC.

Cheminformatics 101: Fingerprinting and Read-Across. Mark Cronin, Liverpool John Moores University, Liverpool, United Kingdom.

The US EPA CompTox Chemicals Dashboard. Antony Williams, US EPA/NCCT, Research Triangle Park, NC.

Integrated Chemical Environment (ICE). Shannon Bell, Integrated Laboratory Systems, Inc., Durham, NC.

Comparative Toxicogenomics Database (CTD). Carolyn Mattingly, North Carolina State University, Raleigh, NC.

Sysrev: Collaborative Literature Extraction. Tom Luechtefeld, Insilica, Baltimore, MD.

" }, { "SessionID": 72, "Title": "The Basics of In Vitro Xenobiotic Metabolism and Drug-Drug Interaction Investigations: Applicability to All Xenobiotics", "Year": 2020, "Topic": "In Vitro Toxicology", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Andrew Parkinson, XPD Consulting; and Brian Ogilvie, Sekisui XenoTech LLC..

Primary Endorser:
In Vitro and Alternative Methods Specialty Section

Other Endorser(s):
Drug Discovery Toxicology Specialty Section; Exposure Specialty Section

In the current landscape of drug development and investigation of environmental chemicals, many personnel with toxicology backgrounds find themselves overseeing not only preclinical safety assessments but also in vitro xenobiotic metabolism and interaction studies. Therefore, the goal of this course is to provide attendees with practical perspectives from experts in the field on the approaches and techniques that are available to address the important aspects of xenobiotic metabolism. The first presentation will focus on the experimental design and interpretation of data obtained from studies of in vitro inhibition of cytochrome P450 (CYP) and other xenobiotic-metabolizing enzymes. In contrast, the second presentation will focus on the experimental design and interpretation of data obtained from studies of in vitro induction of CYP and other xenobiotic-metabolizing enzymes. The third talk will broaden considerations of xenobiotic metabolism, including assessment of the toxicological burden of reactive metabolites, and the experimental design and interpretation of data obtained from studies of in vitro reaction phenotyping techniques in human liver microsomes and other test systems derived from humans or toxicologically relevant species. The fourth presentation will discuss in vitro approaches for determining the potential for xenobiotics to be substrates or inhibitors of major transporters that are of regulatory interest and interpretation of the data obtained from these studies. The final presentation will discuss the practical implications of the in vitro approaches discussed and the current regulatory thinking on their applicability to all xenobiotics to which humans are exposed. The overarching objective of this course is to provide attendees with a solid foundation in commonly used methods to enable the design, execution, and interpretation of rigorous and reproducible in vitro xenobiotic metabolism and interaction studies that will withstand regulatory scrutiny and avoid common pitfalls. This course will benefit those whose toxicological interests are expanding to include in vitro xenobiotic metabolism, as well as professionals responsible for appraising or evaluating in vitro xenobiotic metabolism, interaction studies, and other ADME data for internal decision-making, risk assessment, or submission to various regulatory agencies.

Introductory Remarks on Xenobiotic Metabolism and Course Overview. Andrew Parkinson, XPD Consulting, Shawnee, KS.

The Basics of In Vitro CYP Inhibition Studies for Regulatory Submission and Risk Assessment. Brian Ogilvie, Sekisui XenoTech LLC, Kansas City, KS.

The Basics of In Vitro CYP Induction Studies for Regulatory Submission. Diane Ramsden, Alnylam Pharmaceuticals Inc., Cambridge, MA

In Vitro Reaction Phenotyping and the Toxicological Burden of Reactive Metabolites. Jed Lampe, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO.

Xenobiotic Transporter Studies for Regulatory Submission. Caroline Lee, Arena Pharmaceuticals Inc., San Francisco, CA.

The Science of Drug Interactions Is Applicable to All Xenobiotics. Andrew Parkinson, XPD Consulting, Shawnee, KS.

" }, { "SessionID": 73, "Title": "Developing Therapeutics for Ocular Indications: A 20/20", "Year": 2020, "Topic": "Ocular Toxicology", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Kathleen Krenzer, Iuvo BioScience; and Hiromi Hosako, Alcon.

Primary Endorser:
Ocular Toxicology Specialty Section

Other Endorser(s):
Biotechnology Specialty Section; Comparative Toxicology, Pathology, and Veterinary Specialty Section

No longer are eye drops the only way to treat the eye; the emergence of novel therapeutic and development approaches for ocular indications has impacted how we design toxicology assessments, select species, and perform toxicity evaluations. Additionally, the structural complexity of the eye as well as the unique aspects of ocular dose-administration routes require continued refinements of ocular evaluation techniques and assessment strategies. The goal of this course is to provide toxicologists with a broad overview of highly specialized ocular anatomy, current ophthalmic diagnostic techniques, evolving histopathological assessment strategies, and thought-provoking ocular drug development strategies, including case studies. The first speaker will open the session with an detailed overview of ocular anatomy complexity, focusing on unique features of the eye and critical anatomical and physiological features that may influence or impede a drug's efficacy and safety in human patients. The speaker also will discuss novel routes of drug administration in ocular drug development. The second presentation will tune in to gold-standard, in-life ophthalmic diagnostic techniques with selected case examples showing how modern ocular diagnostic equipment can be used to prove multifactorial questions. This presentation also will touch upon recent efforts at harmonization of ocular finding nomenclature and clinical record-keeping lexicon in preparation for SEND (Standard for Exchange of Nonclinical Data) requirements dictating reporting of ocular toxicology studies. The third talk will focus on evolving strategies for histopathological assessment of ocular tissues, which will include key points to consider when processing the eye to ensure a thorough examination of key structures of the globe as well as the effect of factors such as the route of administration and the formulation or character of the therapeutic candidate on effective examination of the eye. The last presentation will highlight unique nonclinical safety challenges and considerations during ocular drug development using case studies to push our assumptions of what is the best way to evaluate the safety of ophthalmic therapeutics.

Do Animals See 20/20? The Spectrum of Ocular Anatomy and Physiology in Animals. S. Eaton, University of Wisconsin–Madison, Madison, WI.

Getting the 20/20 Read: Clinical Evaluation Techniques for Ophthalmic Toxicology. J. T. Bartoe, Northern Biomedical Research Inc., Norton Shores, MI.

20/20 under the Scope: Evolving Strategies for Histopathological Assessment of Ocular Tissues. H. Booler. Genentech Inc., South San Francisco, CA. Sponsor: K. Krenzer.

Using 20/20 Hindsight to Set the Course for Considerations in the Preclinical Development of Ocular Therapeutics in the Future. B. Smith, Allergan, Irvine, CA.

" }, { "SessionID": 74, "Title": "Modern Modeling Strategies to Address Uncertainty and Variability in Dose-Response Assessment", "Year": 2020, "Topic": "Risk Assessment", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Kan Shao, Indiana University; and Weihsueh A. Chiu, Texas A&M University.

Primary Endorser:
Risk Assessment Specialty Section

Other Endorser(s):
Biological Modeling Specialty Section; Regulatory and Safety Evaluation Specialty Section

Quantifying dose-response relationships to evaluate the toxicity of environmental chemicals is a key step in human health risk assessment and has evolved substantially in recent years. In addition to fundamentally developing a dose-response curve and estimating a dose level that results in a predetermined critical effect, recent advances in toxicology and modeling strategies enable dose-response assessment to more comprehensively and quantitatively address uncertainty and human variability. The purpose of this course, to be delivered by a mixed group of experts from academia, government, and industry, is to provide participants an overview of the cutting-edge modeling strategies employed in dose-response assessment to quantify uncertainty and variability. The first presentation will introduce the benchmark dose (BMD) methodology and its utilities to quantify various sources of uncertainty in dose-response modeling with a demonstration of the Bayesian BMD modeling system. The second speaker will present an overview of the principles and recent applications of probabilistic dose-response assessment approaches developed under the WHO/IPCS guidance to address uncertainty and variability in quantitative risk assessment. The third presentation will provide an overview together with case examples of Diversity Outbred (DO) mouse population-based in vitro systems to demonstrate a data-driven probabilistic approach to derive a chemical-specific uncertainty factor for inter-individual variability. The last speaker will introduce how to predict population distributions of toxicokinetic-relevant physiological quantities that NHANES does not measure based on the measured counterparts using the HTTK-Pop R package that incorporates population variability in high-throughput toxicokinetic modeling. Throughout the course, use of and applications to in vitro and high-throughput testing systems will be highlighted, including their relevance to in vitro to in vivo extrapolation (IVIVE).

" }, { "SessionID": 75, "Title": "Harnessing the T Cell for Cancer Immunotherapy: A Course on T Cell Redirection", "Year": 2020, "Topic": "Immunotoxicology", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Jessica Lynch, Janssen Research & Development; and Rafael Ponce, Shape Therapeutics.

Primary Endorser:
Immunotoxicology Specialty Section

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

Cancer immunotherapy is an area that has been of great interest in the last few years as several new therapeutic approaches have shown encouraging results in the clinic and subsequent approvals. The normal immune system has a protective capacity against tumor cells (immunosurveillance), while tumors can employ mechanisms that can result in an insufficient supply of activated and/or antigen-specific T cells within the microenvironment (tumor evasion). To overcome this immune-evasive mechanism, T cells can be redirected and expanded within the tumor microenvironment. CD3 redirection, which leverages protein-based therapeutics to simultaneously bind CD3 on T cells and a tumor associated antigen (TAA) on tumor cells, and engineered T cell–based therapeutics to redirect T cells to TAAs are emerging as powerful ways to harness the immune system to combat malignancies. The goal of this course is to provide the investigator with an overview of T cell redirection technologies and how to design a nonclinical safety strategy to understand safety liabilities. An overview of chimeric antigen receptor (CAR) T cells, T cell receptor (TCR) T cells, CD3 bispecifics, and immune mobilizing monoclonal TCRs against cancer (ImmTac) modalities will be provided. In addition, successful nonclinical safety strategies to support first-in-human clinical trials for these modalities will be shared. Overall, this course will provide a comprehensive overview of T cell redirection platforms, study design, and the challenges associated with these modalities.

" }, { "SessionID": 76, "Title": "The Male Reproductive Tract: Development, Toxicology, and Pathology", "Year": 2020, "Topic": "Reproductive and Developmental Toxicology", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Vicki Sutherland, NIEHS/NTP; and Nicole Principato, Bristol-Myers Squibb Company.

Primary Endorser:
Reproductive and Developmental Toxicology Specialty Section

Other Endorser(s):
Comparative Toxicology, Pathology, and Veterinary Specialty Section; Regulatory and Safety Evaluation Specialty Section

The male reproductive system develops in utero–in rats during mid-gestation and in humans during the second month of pregnancy–but does not fully mature until puberty. Exposure to xenobiotics (e.g., diethylstilbestrol and phthalate exposure) during any stage, particularly during development and maturation, can adversely affect a male's reproductive potential and play a significant role in development of a diseased state. Understanding what normally happens at these critical stages of development can lend clues to determine when an exposure has happened, what tissues are affected, and if functional capabilities will be impacted. Defining potential effects is routinely performed with guideline reproductive and developmental experiments and in academia with focused studies; however, these assessments do not always include histopathology evaluations, and if they do, the rigor needed for select tissues may not be utilized. Inclusion of histopathology, especially during select stages, may help identify a pattern of toxicities, subtle effects of an endocrine-disrupting chemical, or lesions that can lead to future reproductive issues (e.g., infertility). This additional data can expand our capabilities in characterizing potential modes of action that result in functional changes. Thus, a field that did not routinely assess tissues in more than a functional manner is now exploring the utility of pathology evaluations at stages not previously studied (e.g., juvenile assessment of cell populations in the testes) and appreciating that these tools can assist in recognizing patterns of toxicity. Therefore, a full toxicological and histopathology assessment of the male reproductive tract may provide additional information on functional effects, assist in determining which part of the system was targeted and how to mitigate concerns, and, for select issues, provide an early read on potential problems. This course will cover development and maturation of the male reproductive tract, explaining impacts on function at different time periods (in utero, juvenile, and adult) and addressing the potential value of histopathology at both the juvenile and the adult stages. Case studies will be used to highlight the toxicological significance of the effects of xenobiotics on male reproductive system toxicity. Understanding patterns of toxicity (e.g., effects in organ weight linked with findings in other tissues or pathology findings observed in a young animal correlating to outcomes in an adult) and utilizing some of the newer techniques and protocols (e.g., fetal testis explants, biomarkers) will not only provide a better understanding of what endpoints are affected but also may provide us with the tools to design better studies and correlate findings at earlier stages with long-term functional effects. To this end, four speakers, each a world-recognized expert in male anatomy, development, reproduction, and/or pathology, will discuss functional assessments of the male reproductive tract and address the utility of pathology in male reproductive and development evaluations.

" }, { "SessionID": 77, "Title": "An Introduction to New Approach Methodologies (NAMs) and Understanding Their Potential to Support Regulatory Decisions", "Year": 2020, "Topic": "Risk Assessment", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Mansi Krishan, Danone North America; and Suzanne Fitzpatrick, US FDA/CFSAN.

Primary Endorser:
Risk Assessment Specialty Section

Other Endorser(s):
Drug Discovery Toxicology Specialty Section

Recent shifts in the global regulatory landscape to consider the use of nonanimal testing methods have led to significant advances in the development of alternative test methods to replace, reduce, and refine animal use. The term new approach methodologies (NAMs) broadly describes any nonanimal technology, methodology, approach, or combination that can be used to provide information on chemical hazard and risk assessment. With new opportunities comes new challenges, such as validation of test results, understanding their applicability in different sectors and risk assessments, and global regulatory acceptance of these methods. Despite these challenges, the development, use, and acceptance of these predictive toxicology methods is on the rise. There is a wealth of knowledge and data that is being generated with NAMs; however, there are questions on when, how, and where can we use these NAMs. This CE course will provide an overview of NAMs along with case studies where they are being used or could potentially be used for regulatory risk assessment. The speakers will present on (1) chemical-biological data and analysis tools (Tox21/ToxCast) and examples where high-throughput screening (HTS) methods have been approved for use in regulatory decision-making; (2) read-across approaches and their use in regulatory risk assessment; (3) use of evidence maps and systematic reviews and case studies with a focus on application of each to regulatory risk assessment; (4) use of the adverse outcome pathway (AOP) including most well-developed examples of AOP-supported decision processes for evaluating skin sensitizing potential and a computational model to predict the likelihood of reproductive impairment based on aromatase inhibition; and (5) concepts underpinning Integrated Approaches to Testing and Assessment (IATA) and concrete examples for assessing developmental neurotoxicity (DNT) and carcinogenicity of chemicals used in a variety of sectors. Also, updates will be provided on IATA case study projects currently running at the OECD and a set of resources being developed to support IATA development, evaluation, and regulatory uptake. This course will be useful to those interested in understanding the regulatory application of NAMs.

" }, { "SessionID": 78, "Title": "In Vitro Approaches to Assess the Toxicity of Inhaled Substances", "Year": 2020, "Topic": "Inhalation Toxicology", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Amy Clippinger, PETA International Science Consortium Ltd., United Kingdom; and Emily Reinke, Army Public Health Center.

Primary Endorser:
In Vitro and Alternative Methods Specialty Section

Other Endorser(s):
Inhalation and Respiratory Specialty Section; Regulatory and Safety Evaluation Specialty Section

Inhalation is a major route of human exposure to airborne substances, and as such, there are regulatory and nonregulatory needs to assess the potential toxicity of inhaled substances. While the standard regulatory requirement is a rat inhalation toxicity test, anatomical and physiological differences between rodents and humans have led to substantial investment in the optimization of alternative approaches. These alternative approaches can be based on human mechanisms of toxicity, thus better protecting human health while reducing animal use. In this course, speakers from government, contract research organizations, academia, and NGOs, as well as method developers, will discuss progress and challenges associated with various approaches for inhalation toxicity testing. It will include an introductory overview, setting the stage for the remaining talks by discussing the currently used rat inhalation tests and how an alternative approach can be demonstrated to be a valid replacement. Other topics to be covered will be the use of cell culture systems, 3D reconstructed human tissue models, and human precision-cut lung slices, as well as the use of in vitro exposure devices for deposition of test chemicals. The final speaker will present a regulatory perspective on processes in place that allow for acceptance of alternative approaches for inhalation toxicity testing, highlighting a successful example. These presentations will explore the value of the air-liquid interface (ALI) for testing, advantages and limitations of different approaches, and case studies of the use of different model systems in both nonregulatory and regulatory paradigms. Overall, a course attendee should learn about the state-of-the-science of in vitro approaches for respiratory toxicity testing and gain insight into determining which method is most appropriate, depending on the test substance and purpose of the study. This course is aimed at scientists at all levels from industry, government, and academia.

" }, { "SessionID": 79, "Title": "Advances in CRISPR-Cas9 Tools and Applications for Toxicologists", "Year": 2020, "Topic": "Molecular and Systems Biology", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Cheryl Rockwell, Michigan State University; and Elena Demireva, Michigan State University.

Primary Endorser:
Continuing Education Committee

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

CRISPR-Cas-based technologies have revolutionized science by significantly decreasing the time, money, expertise, and labor required to implement gene editing. Thus, this approach is becoming routine in many laboratories as a facile method to alter the genome. And yet, CRISPR-based methodologies continue to evolve. Recent publications demonstrate that CRISPR gene editing can be expanded in new directions to widen the utility and potential applications of this technology. The first presentation in this course will provide an overview of the latest developments in CRISPR-Cas-based techniques, with a focus on new Cas9 variants with new and expanded capabilities. The first presentation also will cover the new field of RNA targeting and the use of pooled CRISPR libraries with single cell transcriptomics to characterize complex phenotypes. The second presentation will focus on the use of CRISPR-Cas9-based screens from a toxicologist's perspective. Specifically, this presentation will discuss how such screens can be used to gain a detailed, mechanistic understanding of a toxicant's effect as well as the role of specific genes. Overall, this course is designed to provide an overview of the most recent advances in CRISPR-based technologies as well to provide some insight into future uses.

" }, { "SessionID": 80, "Title": "Timing Is Everything: Developmental Exposure Alters the Path of Immune Cell Maturation and Function", "Year": 2020, "Topic": "Immunotoxicology", "Transcription": 0, "Description": "Register/Login

Chairperson(s): Alessandro Venosa, University of Utah; and Jamie DeWitt, East Carolina University.

Primary Endorser:
Immunotoxicology Specialty Section

There is compelling evidence that exposure to exogenous agents at different stages of development contributes to disease later in life (and across generations), with animal models supporting this concept in reproductive, metabolic, and neurodegenerative diseases. Two major notions link prenatal and early-life exposure to increased risk of disease later in life–namely, the Barker hypothesis and the hygiene hypothesis–while epigenetic reprogramming may extend this susceptibility across future generations. The immune system represents a unique niche of cells tightly entangled with the parenchyma in every tissue, acting as pro-homeostatic sentinels equipped to mount the appropriate response upon exogenous aggression. While the linkage between developmental immunotoxicity (DIT) and susceptibility to later-life diseases is an accepted paradigm, the mechanisms by which exogenous agents impact the developing immune system and change disease susceptibility are not well established. Clinical evidence suggests that the underlying effects of these agents may be masked until triggered by a later-life event (i.e., infectious exposure or aging itself), at which point the immune response may enact a super-responsive state, favoring disease pathogenesis. Recent evidence highlights myriad variables to take into account to accurately study DIT, including the importance of evaluating the appropriate window of vulnerability; establishing whether the toxicant exerts direct and long-lasting effects on the immunological machinery or reprograms the behavior of bystander parenchymal cells; outlining which pathway each environmental agent will be affecting; and, more recently, determining sex-based outcomes to exposure. With basic and translational researchers facing the challenge of elucidating the molecular mechanisms mediating DIT, it is pivotal that regulatory agencies and industry work in unison toward implementing safety protocols that address these factors. Therefore, this Continuing Education course proposes to (1) inform the attendees on the current advances in the design and execution of DIT studies geared at developing preclinical tools to predict risk of adult-life disease; (2) provide the most recent evidence, spanning multiple phylogenetic species (nonhuman primates, rodents, and fish), of DIT across a wide array of exogenous agents; and (3) provide insights on the impact that studying DIT could provide at the regulatory level.

" }, { "SessionID": 81, "Title": "Chemical Probes: New Tools to Identify Molecular Targets", "Year": 2021, "Topic": "Technology", "Transcription": 0, "Description": "Register/Login

Chairperson(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.

" }, { "SessionID": 82, "Title": "Advances in Single Cell Genomic Analyses for Toxicological Testing", "Year": 2021, "Topic": "Molecular and Systems Biology", "Transcription": 0, "Description": "Register/Login

Chairperson(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.

" }, { "SessionID": 83, "Title": "Applications of In Vitro and In Silico New Approach Methodologies for Predictive and Mechanistic Thyroid Toxicity Testing ", "Year": 2021, "Topic": "Regulatory and Safety Evaluation", "Transcription": 0, "Description": "Register/Login

Chairperson(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.

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

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.

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.

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

" }, { "SessionID": 84, "Title": "Concepts and Approaches for Current and Future Metals Toxicological Research", "Year": 2021, "Topic": "Metals", "Transcription": 0, "Description": "Register/Login

Chairperson(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.

" }, { "SessionID": 85, "Title": "Less Is More: Sustainable Product Development Requires More Toxicological Considerations", "Year": 2021, "Topic": "Sustainable Chemistry", "Transcription": 0, "Description": "Register/Login

Chairperson(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, B&M Associates LLC, New Albany, OH.

" }, { "SessionID": 86, "Title": "Insider Secrets for Design and Analysis of Defined-Mixture Experiments", "Year": 2021, "Topic": "Mixtures", "Transcription": 0, "Description": "Register/Login

Chairperson(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 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.

" }, { "SessionID": 87, "Title": "Development, Toxicology, and Pathology of the Female Reproductive Tract: Interpretation of Findings from the Pathologist and Regulatory Perspectives", "Year": 2021, "Topic": "Reproductive and Developmental Toxicology", "Transcription": 0, "Description": "Register/Login

Chairperson(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, MI.

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

" }, { "SessionID": 88, "Title": "Guidelines for Developing and Implementing Organ-on-a-Chip/Microphysiological Systems for Toxicity Evaluation of Drug Candidates in Drug Development", "Year": 2021, "Topic": "In Vitro and Alternative Methods", "Transcription": 0, "Description": "Register/Login

Chairperson(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.

" }, { "SessionID": 89, "Title": "Navigating New Modalities: A Preclinical Roadmap for Developing Novel Oligonucleotide Safety Strategy", "Year": 2021, "Topic": "Drug Discovery", "Transcription": 0, "Description": "Register/Login

Chairperson(s):
Lauren Lewis, Takeda Pharmaceutical Company Limited; and Samantha Faber, Vicencia Toledo Sales.

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, Vicencia Toledo Sales, Cambridge, MA.

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

" }, { "SessionID": 90, "Title": "Rapid Chemical Assessment Using Open Computational Methods", "Year": 2021, "Topic": "Risk Assessment", "Transcription": 0, "Description": "Register/Login

Chairperson(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:

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:


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

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

An Introduction to Structure-Based Cheminformatics: Data Clustering and Visualization, Read-Across and Predictive Modeling, and Accessing Data through the US EPA CompTox Chemicals Dashboard. Antony Williams, US EPA, Durham, 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, US EPA/CCTE, Research Triangle Park, NC.

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.

" }, { "SessionID": 91, "Title": "Establishing Confidence in Organ-on-a-Chip Systems for Toxicity Testing: Lung-on-a-Chip as an Example", "Year": 2021, "Topic": "In Vitro and Alternative Methods", "Transcription": 0, "Description": "Register/Login

Chairperson(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.

" }, { "SessionID": 92, "Title": "Risk Assessment, DART, and Endocrine Disruption: A World View", "Year": 2021, "Topic": "In Vitro and Alternative Methods", "Transcription": 0, "Description": "Register/Login

Chairperson(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.

" }, { "SessionID": 93, "Title": "Timing Is Everything: Role of Aging in Immune Responses and Toxicological Implications", "Year": 2021, "Topic": "Immunotoxicology", "Transcription": 0, "Description": "Register/Login

Chairperson(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.

" }, { "SessionID": 94, "Title": "Understanding Tox21/ToxCast High-Throughput Screening Data and Application to Modeling", "Year": 2021, "Topic": "Computational Toxicology", "Transcription": 0, "Description": "Register/Login

Chairperson(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., Durham, NC.

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.

" }, { "SessionID": 95, "Title": "Animal-Free Safety Assessment of Consumer Products and Ingredients: A Primer", "Year": 2022, "Topic": "Risk Assessment", "Transcription": 0, "Description": "Register/Login

Chair(s):
Catherine Willett, Humane Society International; and Paul Russell, Unilever Safety and Environmental Assurance Centre, United Kingdom.

Primary Endorser:
In Vitro and Alternative Methods Specialty Section

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

There has been significant progress globally over recent years in advancing the science to underpin nonanimal cosmetic safety assessment. In addition, citizen-led initiatives that prohibit animal testing of cosmetics and cosmetic ingredients are expanding geographically every year. These advances are leading to the need for global capacity building among the regulated and regulatory communities for completely animal-free safety assessment of consumer products. In the European Union, there has been a ban on animal testing of cosmetics since 2004 and a sales ban on cosmetics tested on animals since 2013; nevertheless, because of testing requirements in other sectors or geographies, animal testing of cosmetics continues. To enable confident decision-making regarding the safety of cosmetics and personal care products, it is important to build confidence in the requisite methodologies based on experience. Toward this aim, an in-depth educational program has been developed by the Animal-Free Safety Assessment (AFSA) Collaboration, a partnership of nonprofit organizations and industry. Achieving a confident risk assessment of a consumer product or ingredient without data from new animal testing requires a novel approach to the assessment, as well as integration of several types of in silico and in vitro data. This Continuing Education course will provide a primer on the necessary tools, including understanding the regulatory playing field, risk assessment problem formulation, estimating consumer exposure, in silico and in vitro approaches to filling data gaps, and estimating an in vitro point of departure—plus, a case example demonstrating how to combine all these elements into a well-documented assessment based on the modules developed by the AFSA Collaboration. Each of the presentations, given by a partner representative with the relevant expertise, will include a set of learning objectives to stimulate audience participation; after the presentations and before the open discussion, there will be a short crowdsourced quiz via Slido on the material presented. An open discussion/roundtable will include one to two participants with regulatory experience.

Enabling Animal-Free Safety Assessment of Cosmetics Globally. Catherine Willett, Humane Society International, Washington, DC.

The Global Cosmetics Regulatory Landscape. Jay Ingram, Delphic HSE, Surrey, United Kingdom.

Problem Formulation: Setting the Stage for the Risk Assessment Length. Shashi Donthamsetty, International Flavors & Fragrances Inc., New York, NY.

Estimating Consumer Exposure. Christina Hickey, Firmenich SA, New York, NY.

Internal Exposure. Rebecca Clewell, 21st Century Tox Consulting, Durham, NC.

In Silico and In Vitro Data Generation: Strategies for Addressing Data Gaps to Inform an NGRA. Hans Raabe, Institute for In Vitro Sciences Inc., Gaithersburg, MD.

Integration of New Approach Methodologies for Cosmetic Safety Decision-Making. Matt Dent, Unilever Safety and Environmental Assurance Centre, Bedfordshire, United Kingdom.

" }, { "SessionID": 96, "Title": "Conceptual Models in Immunotoxicology: Leveraging Biological Knowledge, Alternative Approaches, and Computational Strategies for the Future of Risk Assessment", "Year": 2022, "Topic": "Immunotoxicology", "Transcription": 0, "Description": " Register/Login

Chair(s):
Emanuela Corsini, Università degli Studi di Milano, Italy; and Dori R. Germolec, NIEHS.

Primary Endorser:
Immunotoxicology Specialty Section

Over the last several decades, a great deal of progress has been made in the development of alternative methods to assess immunotoxicity, for both inappropriate immunostimulation and immunosuppression. Immunotoxicology hazard identification requires novel approaches and strategies, possibly without the use of animals to be in line with the vision of toxicology in the 21st century. In vitro methods anchored to adverse outcome pathways (AOPs) currently under development or already accepted at the Organisation for Economic Co-operation and Development (OECD) level, associated with identified key characteristics (KCs) of immunotoxicants, and the combination of complementary information, in the context of an Integrated Approaches to Testing and Assessment or a Defined Approach, offer the opportunity to identify the hazard that xenobiotics may pose to the immune system. This Continuing Education course aims to highlight animal-free approaches in immunotoxicology, and participants will learn how to apply these novel strategies to gain an understanding of how and if substances modulate immune processes. The course will present the KCs of immunotoxicants as an approach for hazard identification and will provide examples demonstrating the use of this framework in the characterization of the toxicity of immunotoxic agents. The use of KCs for the design of tests to evaluate the hazards of novel chemicals to complement or replace existing approaches will be emphasized. In the second presentation, the defined approaches for skin sensitization recently adopted at the OECD level will be presented. Defined approaches have been demonstrated to be more reliable and human relevant than stand-alone in vitro tests or the commonly employed in vivo test methods. The third presentation will discuss integrated testing strategies for the identification of xenobiotic-inducing immunosuppression, including high-dimensional profiling pathway analyses and computational approaches to integrating immune-related data and outcomes assessments. Finally, the Universal Immune System Simulator (UISS), a simulation framework to model the immune system, will be introduced. The UISS software is free and has been used for hazard characterization of pharmaceuticals. The application of this software for evaluating environmental contaminants will be demonstrated. The presentation of these novel approaches will enable course participants to gain an understanding of how mechanistic-based testing strategies can be applied to evaluate the adverse effects of chemicals on immunity.

Key Characteristics of Immunotoxicants: The Way Forward? Dori R. Germolec, NIEHS, Morrisville, NC.

OECD and Defined Approaches to Identify Contact Allergy: From Hazard to Quantitative Risk Assessment. Nicole Kleinstreuer, NIEHS, Morrisville, NC.

Integrated Testing Strategy for Immunosuppression. Mark Collinge, Pfizer Inc., Groton, CT.

The Universal Immune System Simulator: An In Silico Model to Predict the Risk Associated with Exposure to Immunotoxicants. Francesco Pappalardo, Università di Catania, Catania, Italy.

" }, { "SessionID": 97, "Title": "Evidence Map, Scoping Review, Rapid Systematic Review, and Systematic Review—And How to Conduct Them", "Year": 2022, "Topic": "Systematic Review", "Transcription": 0, "Description": " Register/Login

Chair(s):
Amy Wang, NIEHS/NTP; and Xabier Arzuaga, US EPA.

Primary Endorser:
Comparative Toxicology, Pathology, and Veterinary Specialty Section

Other Endorser(s):
Carcinogenesis Specialty Section; Risk Assessment Specialty Section

Besides traditional, narrative reviews, other review types are increasingly being used in toxicology and recognized for their strengths. For instance, systematic review has joined the narrative review on the short list in the hasten publication type filter on PubMed. Systematic reviews, a format originating from the clinical research field, offer balanced answers to predefined questions with transparent steps and comprehensive consideration of diverse, including conflicting, results. They are considered the gold standard in many agencies for hazard identification and/or risk assessment of carcinogenic and noncarcinogenic effects from chemical, physical, and biological agents, mixtures, lifestyles, and other scenarios. Evidence map (survey the available research evidence), scoping review (evidence map with a descriptive narrative summary of the results, typically without data extraction or study quality assessment), rapid systematic review (faster completion than a systematic review with or without review shortcuts), umbrella review, and mixed type of review each can fit different needs while requiring fewer resources than a systematic review. This course is designed for toxicologists at all stages of their careers and will explain the review types, how to know which type is right for your question and situation, how to complete selected types of the review, and how to publish them, including interim products, in peer-reviewed journals. Many early steps in the process are highly similar among these highlighted review types, and participants will be able to build knowledge and know-how by following the presentations in the designed order. At the end of the course, the participants will be able to (1) distinguish different types of reviews; (2) prepare an evidence map, scoping review, rapid systematic review, or systematic review that fits their needs; (3) use computational tools to simplify and fasten the process; and (4) write a competitive manuscript to amplify the impact of their work.

Review Types in Toxicology. Amy Wang, NIEHS/NTP, Research Triangle Park, NC.

Fit for Purpose: Scoping Reviews and Systematic Evidence Mapping to Support Decision-Making. Vickie R. Walker, NIEHS/NTP, Research Triangle Park, NC; and Andrew Rooney, NIEHS/NTP, Research Triangle Park, NC.

How to Conduct Systematic Reviews and Rapid Systematic Reviews. Xabier Arzuaga, US EPA, Washington, DC.

Tools to Help Your Review. Ruchir Shah, Sciome LLC, Durham, NC.

Success in Publishing Evidence Reviews: An Editor's Strategy. Paul Whaley, Lancaster University, Lancaster, United Kingdom.

" }, { "SessionID": 98, "Title": "How Advances in Exposure Science and Toxicology Are Changing Assessments of the Effects of Chemical Mixtures on Human Health", "Year": 2022, "Topic": "Exposure Toxicology", "Transcription": 0, "Description": " Register/Login

Chair(s):
Paul Price, Independent Researcher; and Elke Jensen, Dow Chemical Company.

Primary Endorser:
Mixtures Specialty Section

Other Endorser(s):
Exposure Specialty Section; Risk Assessment Specialty Section

The fields of exposure science and toxicology are changing, and these changes have the potential to improve our ability to assess risks from concurrent exposures to multiple chemicals. The changes include advances in exposure monitoring; the development of structure-based predictions of chemical properties relevant to exposure assessment and/or relevant PK modeling of internal doses; the development of new approach methodologies (NAMs); advances in modeling variation and uncertainty in exposure and dose-response; and the creation of curated databases of information on toxicity and exposure. This course presents a review of how these advances can, and likely will, change mixture risk assessments. The course will begin with an overview of the existing approaches for mixture risk assessment, the limitations of these approaches, and the identification of the types of information and tools needed to improve the assessments. The remainder of the course will consist of four talks on how changes in scientific disciplines relevant to mixture toxicology, such as cumulative exposure assessment, toxicokintics, toxicodynamics, and data organization, are helping to address the needs of mixture risk assessors. Each of the talks will describe how advances in the field are improving the ability to assess mixture risks (with case studies) and what could be done in the future. The first talk will focus on how advances in exposure science can be used to improve our ability to rapidly characterize multiple chemical exposures in an individual and how these combined exposures vary across individuals. The second talk will address advances in our understanding and ability to model chemical interactions that involve the toxicokinetics of the chemicals. The third talk will discuss the testing of mixtures of chemicals using in vitro assays to characterize interactions of chemicals in terms of common molecular initiating events, key events, and certain apical effects. The final talk will recast our understanding of the mixture risk assessment process using the concepts of the aggregate exposure pathways (AEP), adverse outcome pathways (AOP), and AEP–AOP networks. This talk will include a description of a proposed taxonomy for chemical interactions that can help organize existing data on mixture toxicity. Together, the talks will describe the relevance of scientific advances to the assessment of risks from exposures to multiple chemicals. The course will discuss assessing risks from exposure to discrete mixtures of chemicals and from exposures to multiple sources (cumulative exposures). While many of the issues discussed apply to ecological effects of mixtures, this course will focus on the effects on human health.

Introduction and Overview of the Key Elements of Mixture Risk Assessment. Richard Hertzberg, Emory University, Atlanta, GA; and Allison Phillips, US EPA, Research Triangle Park, NC.

Advances in Exposure Science and the Improved Characterization of Combined Exposures. Kristin Isaacs, US EPA, Research Triangle Park, NC.

Advances in Pharmacokinetics and Their Implications for Mixture Risk Assessment. Sami Haddad, Université de Montréal, Montreal, QC, Canada.

Surveying the Use of New Approach Methodologies in Component-Based and Whole Mixture Risk Assessment Contexts. Cynthia Rider, NIEHS/NTP, Research Triangle Park, NC.

Organizing Information on Chemical Interactions Using a Framework Based on Networks of Linked Aggregate Exposure Pathways and Adverse Outcome Pathways (AEP-AOP Networks). Paul Price, Independent Researcher, Cedar Rapids, IA.

" }, { "SessionID": 99, "Title": "Importance of Sexual Maturity and Reproductive Senescence in Laboratory Animal Models", "Year": 2022, "Topic": "Reproductive and Developmental Toxicology", "Transcription": 0, "Description": " Register/Login

Chair(s):
Christopher Bowman, Pfizer Inc.; and Pragati S. Coder, Charles River Laboratories Ashland LLC.

Primary Endorser:
Reproductive and Developmental Toxicology Specialty Section

Other Endorser(s):
Comparative Toxicology, Pathology, and Veterinary Specialty Section; Regulatory and Safety Evaluation Specialty Section

Age and reproductive status are often overlooked variables in mammalian nonclinical studies, but they can have a significant impact on the evaluation of the reproductive system, the interpretation of potential experimental- or test article–related findings, and ultimately the risk assessment. The reproductive system of male and female test species undergoes considerable changes as it transitions from immature to puberty and into fully sexually mature. The timing of puberty and sexual maturation varies across species and sexes and is a major variable in acute/subchronic and reproductive toxicity testing. In females, there also is an age-associated decline in reproductive performance, termed reproductive senescence. In chronic toxicity testing, the effects of reproductive aging are not likely to be seen in nonrodents (e.g., dogs, nonhuman primates, and minipigs) because of their relatively long life spans; however, this can be a major complicating factor for female rodents. An appreciation and understanding of these developmental and age-related changes in the reproductive system is critical to study design, execution, and interpretation for a variety of in vivo experimental disciplines, including toxicology (general, juvenile, investigative, DART, etc.), mouse models, and discovery efforts. The objectives for this course are to provide attendees with an overview of the basic biology of sexual maturation in males and females and reproductive aging in females and to review the effects on study design, data interpretation, and extrapolation to humans.

This course will complement the Continuinig Education (CE) course 'The Male Reproductive Tract: Development, Toxicology, and Pathology', which was presented as part of the scientific program during the Virtual 2020 SOT Annual Meeting, and the CE course 'Development, Toxicology, and Pathology of the Female Reproductive Tract: Interpretation of Findings from the Pathologist and Regulatory Perspectives', which was presented as part of the scientific program during the Virtual 2021 SOT Annual Meeting. These courses are available as part of SOT CEd-Tox, the Society's online Continuing Education course program.

Introduction. Christopher J. Bowman, Pfizer Inc., Groton, CT.

Sexual Maturation in the Male and Female Rodent. Wendy Halpern, Genentech Inc., South San Francisco, CA.

Sexual Maturation in Large Animal Species. Justin Vidal, Charles River, Mattawan, MI.

Reproductive Senescence in the Female Rodent. Tammy Stoker, US EPA, Research Triangle Park, NC.

The Art of Senescence—Study Design and Data Interpretation. Pragati S. Coder, Charles River Laboratories Ashland LLC, Ashland, OH.

" }, { "SessionID": 100, "Title": "Safety Evaluation Strategies in Drug Discovery: From Target Assessment to Identification of Drug Candidates", "Year": 2022, "Topic": "Drug Discovery", "Transcription": 0, "Description": " Register/Login

Chair(s):
Marie Lemper, UCB S.A., Belguim; and Satoko Kakiuchi-Kiyota, Genentech Inc.

Primary Endorser:
Drug Discovery Toxicology Specialty Section

Other Endorser(s):
In Vitro and Alternative Methods Specialty Section; Mechanisms Specialty Section

Drug discovery toxicology starts at the very beginning, when a new target is proposed for entry into the portfolio. After confirmation of the target, the discovery toxicologist will serve as an integral member in lead optimization and candidate selection for progression into GLP toxicology studies. A lead candidate is selected through rigorous in silico and in vitro screening and subsequent in vivo pilot toxicology studies that enable a preliminary assessment of safety. In this course, the speakers will provide a comprehensive overview of the target toxicity evaluation, chemical series and compound de-risking strategies, and approaches leading to lead identification and the first in vivo pilot toxicology studies. The identification of any potential liabilities associated with the target and their relevance for the patient population and indication contributes to the decision to invest in the exploration of a particular target. After the decision is made to drug a chosen target, the discovery toxicologist will become a critical member of the early discovery team, where the selection of lead compounds will be discussed to finally enable the identification of a candidate to take into GLP toxicology studies. To select a molecule with a safety profile that provides an optimal chance of clinical success, strategies are developed by selecting a panel of in silico, in vitro, and in vivo experiments. How these in silico and in vitro strategies are developed to provide optimal chemical series and compound de-risking will be discussed. Other presentations will focus on the in vivo experiments where PK/PD modeling and ideally early human dose predictions are needed to drive decisions on dosing frequency and dose selection. Early in vivo pilot toxicology studies will be discussed, with a focus on their design, interpretation, and impact. The course will conclude with an interactive investigative toxicology case study session where different case studies will be discussed with the audience. While this session focuses on strategies for small molecules, the overall concepts, approaches, and technologies are generally informative for biotherapeutics and new chemical modalities.

Target Safety Assessments: Knowledge Is Power. Ruth Roberts, ApconiX, Cheshire, United Kingdom.

Chemical Series and Compound De-risking: What Do We Focus On and Why? Nigel Greene, AstraZeneca, Waltham, MA.

Pharmacokinetics as an Integral Part of Early Drug Development. Sabrinia Crouch, Neurocrine Biosciences Inc., San Diego, CA.

Early In Vivo Pilot Toxicology Studies in Drug Discovery: Study Designs, Strategies, and Objectives. Jonathan Maher, Theravance Biopharma, South San Francisco, CA.

Discovery Toxicology Case Studies: An Interactive Session. Nardos Tassew, Genentech Inc., South San Francisco, CA; and Qin Wang, Takeda Pharmaceutical Company Limited, San Diego, CA.

" }, { "SessionID": 101, "Title": "Best Practices for Successfully Assessing Ototoxicity in Drug Development", "Year": 2022, "Topic": "Drug Development", "Transcription": 0, "Description": " Register/Login

Chair(s):
John Keating, CBSET Inc.; and Donald Hodges, CBSET Inc.

Primary Endorser:
Continuing Education Committee

Hearing loss is a major global health issue affecting 1.5 billion people worldwide. Prevalence is increasing dramatically: in 2050, one in four people will have some hearing impairment. Acquired hearing loss is attributed to different environmental factors, including aging, noise exposure, and intake of ototoxic medicines. Ototoxicity resulting in inner ear damage is a leading cause of acquired hearing loss worldwide. About a billion people are at risk of avoidable hearing loss, according to the World Health Organization (WHO). This could be minimized or avoided by early testing of hearing functions in the preclinical phase. While the assessment of ototoxicity is well defined for drug candidates in the hearing field (i.e., required testing for drugs that are administered by the otic route and expected to reach the middle or inner ear during clinical use), ototoxicity testing is not required for the other therapeutic areas. Unfortunately, this has resulted in more than 200 ototoxic marketed medications. This course will provide an interactive learning opportunity to understand the key considerations for determining a drug candidate's ototoxicity. Discussions will focus on four aspects of ototoxicity: (1) the burden of ototoxicity, the physiopathology of hearing loss, and current therapeutic strategies to treat deafness; (2) why, when, and how to perform preclinical ototoxicity studies; (3) regulatory perspectives; and (4) ototoxicity case studies. The target audience includes toxicologists involved in the development of potentially ototoxic drugs, pharmaceutical companies looking to develop or repurpose drugs for hearing disorders, and those seeking scientific and operational expertise to make sure that drug candidates do not affect auditory mechanisms.

The Global Burden of Ototoxicity: Epidemiology, Physiopathology, and Therapeutic Strategies. Marie-Pierre Pasdelou, CILcare, Lexington, MA.

Nonclinical Ototoxicity Testing Overview and Histopathologic Assessment in Nonclinical Studies. Marie-Pierre Pasdelou, CILcare, Lexington, MA.

Hearing Loss, Ototoxicity, and the Importance of Adequate Testing in Nonclinical Safety Studies: A Regulatory Perspective. Christopher Toscano, US FDA/CDER, Silver Spring, MD.

Evaluating Ototoxic Effects of Medical Devices for Tympanic Membrane Repair. Elaine Horn-Ranney, Tympanogen, Richmond, VA.

How to Select the Best Candidate with Minimal Ototoxicity. Sven Hobbie, Universität Zürich, Zurich, Switzerland.

" }, { "SessionID": 102, "Title": "Juvenile Toxicology Testing: Assessing Pediatric Safety", "Year": 2022, "Topic": "Reproductive and Developmental Toxicology", "Transcription": 0, "Description": " Register/Login

Chair(s):
Susan Laffan, GlaxoSmithKline plc; and Jia Yao, US FDA/CDER.

Primary Endorser:
Reproductive and Developmental Toxicology Specialty Section

This course will focus on the principles of nonclinical pediatric safety assessments. For pharmaceuticals, the ICH S11 Guideline on Nonclinical Safety Testing in Support of Development of Paediatric Pharmaceuticals was recently finalized and outlines a weight of evidence approach to deciding whether a juvenile animal study is warranted. Once it is decided a juvenile animal study is needed, there are many decisions that need to made, as there is no set default study design. The objectives for this course are to provide attendees with an overview of the regulatory rationale to conduct juvenile toxicology studies, the comparative biology of organ systems that develop postnatally, practical study design considerations, and case studies exemplifying data interpretation and risk assessment.

Overview of Juvenile Toxicology. Jia Yao, US FDA/CDER, Washington, DC.

Postnatal Organ System Development across Species. Wendy Halpern, Genentech Inc., South San Francisco, CA.

Designing Juvenile Animal Studies. Susan Laffan, GlaxoSmithKline, Collegeville, PA.

Juvenile Animal Studies: Case Studies and Risk Assessments. Katie Turner, Janssen Research & Development, Spring House, PA.

" }, { "SessionID": 103, "Title": "Leading-Edge Microbiome Methods for Toxicological Applications", "Year": 2022, "Topic": "Microbiome", "Transcription": 0, "Description": " Register/Login

Chair(s):
Anika Dzierlenga, NIEHS; and David Gonzalez, University of California, Los Angeles.

Primary Endorser:
Mechanisms Specialty Section

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

The human microbiome describes the collective genomes, and encoded functions, of the trillions of bacterial cells that live on and in the human body. Host-associated microbiomes produce metabolites that impact human host cells in myriad ways, including interaction with host metabolic and immune signaling. The microbiome's relationship to human health is made more complex when considering its interactions with the environment and the chemicals within. In fact, the role of the microbiome in modulating chemical exposure and the role exposure plays in shaping the microbiome are becoming more critical considerations for mechanistic toxicity studies and chemical evaluations. Recent technological advances that provide a deeper understanding of the microbial milieu are outpacing the incorporation of microbiome analyses in the field of toxicology. The objective of this course is to provide attendees with an overview of reliable and robust approaches for analyzing the microbiome's composition, function, and role as a potential mediator of toxicity. Speakers with expertise in microbiome analysis in the context of exposures will present (1) an overview of the importance of considering the microbiome in the context of toxicology studies; (2) an explanation of cutting-edge technologies currently used to assess changes in microbiome composition and function and their applications to toxicology; (3) examples of the use of in vitro and alternative models for the microbiome and toxicity; (4) guidelines for the use of rodent models in assessing the microbiome as a mechanism of action for toxicity of chemicals; and (5) a summary of current translational approaches for studying the microbiome. Participants will gain an understanding of the utility of available models and methodologies for studying the microbiome, xenobiotic exposure, and human health and toxicity.

Why Consider the Microbiome in the Context of Exposures and Toxicity? Anika Dzierlenga, NIEHS, Durham, NC.

Methods and Approaches to Evaluate the Microbiome. Rob Knight, University of California San Diego, San Diego, CA.

In Vitro and Alternative Models for the Assessment of Chemical-Microbiome Interactions. Tamara Tal, Helmholtz Centre for Environmental Research, Leipzig, Germany.

Rodent Studies to Evaluate the Microbiome as a Mechanism of Toxicity. Sangeeta Khare, US FDA/NCTR, Jefferson, AR.

Translational Approaches for Toxicology, the Microbiome, and Human Health. Yvonne Huang, University of Michigan, Ann Arbor, MI.

" }, { "SessionID": 104, "Title": "Methodological Aspects of Vascular Toxicity", "Year": 2022, "Topic": "Vascular Toxicology", "Transcription": 0, "Description": " Register/Login

Chair(s):
Travis Knuckles, West Virginia University; and Colette Miller, US EPA.

Primary Endorser:
Cardiovascular Toxicology Specialty Section

Other Endorser(s):
Clinical and Translational Toxicology Specialty Section

The vascular network has long been known as a target of toxicity following exposure and absorption. Furthermore, overall health and well-being of the cardiovascular system is highly dependent on a functional vascular network that can respond dynamically to ever-changing physiological demands. However, the difficulty of measuring functional and structural changes in the vascular network can limit toxicological findings. This course will specifically deal with methodology related to quantitating vascular toxicity at the cellular, tissue, and whole-network levels. This course's presentations will describe techniques to elucidate functional vascular outcomes, from cellular to system-wide. After a brief introduction on advanced physiology of the vascular system, including structure, function, fluid dynamics, and pathology, the course will focus on isolated vascular and cellular techniques in rodent models to determine changes in vascular reactivity, vasomotor responses, and barrier integrity in isolated tissue and cells, as well as reactivity of these models to absorbed serum toxicants, followed by a specific discussion of the endothelial cell and vascular remodeling in the cerebrovascular network. Intravital microscopy as a mechanism for functional assessment of intact tissues in a diverse set of vascular beds will be discussed, as will the utilization of ultrasonography to determine in vivo uterine artery blood flow during gestation. In addition, the methodology aspects of endothelial cell function noninvasely, as well as cell harvesting from human volunteers, will be outlined. This course will be of interest to a broad scope of scientists that are increasingly being asked to consider the effects of novel compounds and toxicants on the physiology of the vascular network. Furthermore, this course builds on a 2013 Continuing Education course and a 2019 Platform Session.

Endothelial Cell Role in Mediating Toxicity, Inflammation, and Pathology: Implications for Study Design. Matthew Campen, University of New Mexico, Albuquerque, NM.

Assessing Toxicity in the Cerebral Microvasculature. Amie Lund, University of North Texas, Denton, TX.

Methodological Principles of Microvascular Toxicology. Timothy Nurkiewicz, West Virginia University, Morgantown, WV.

The Role of Uterine Arterial Remodeling in Fetal Development and Adverse Pregnancy Outcomes. Colette Miller, US EPA, Research Triangle Park, NC.

Evaluating Endothelial Cell Function—From Bedside to Bench. Jessica Fettermann, Boston University, Boston, MA.

" }, { "SessionID": 105, "Title": "Next-Level Neurotoxicology: New Technologies to Advance Visualization of Spatial Molecular Alterations and Behavioral Phenotyping", "Year": 2022, "Topic": "Neurotoxicology", "Transcription": 0, "Description": " Register/Login

Chair(s):
Shannah Witchey, NIEHS; and Helena Hogberg, Johns Hopkins University Bloomberg School of Public Health.

Primary Endorser:
Neurotoxicology Specialty Section

Other Endorser(s):
Molecular and Systems Biology Specialty Section; Women in Toxicology Special Interest Group

Neurotoxicological effects following chemical exposure range in structural and functional alterations within the anatomically complex brain. Traditional histological or 'omic techniques used to identify potential toxicity have limitations in specificity or a comprehensive understanding of altered connectivity of the 100 billion interconnected neurons. The objective of this course is to provide toxicologists with a better understanding of novel neuroscience techniques that provide optimized visualization of spatial alterations and behavioral phenotyping that can be applied to and advance neurotoxicology studies. This course is designed to highlight and educate all levels of scientist on the current approaches in neuroscience research that can be used in the field of toxicology to evaluate the context of brain morphogenesis and the significance of toxicant-induced disruption and will demonstrate how the 3D in vitro system can model the complex multicellular brain environment found in vivo. Different approaches to examining intact brain tissue capturing neurocircuit morphology will be discussed, including (1) a novel method to clear the tissue, enabling the visualization and spatial rotation of the regions (or systems) of interest from animals; (2) fMRI methods to provide highly detailed models of neurocircuitry to gain new insights into exposure effects; and (3) proficient behavioral phenotyping models and in vivo neurocircuit visualization to identify neurotoxic chemicals. Many times, the neurochemical effects are unknown and have no targeted system. The course also will discuss spatial profiling on slide-mounted tissue and the capability of choosing a neuronal region of interest to perform genomic profiling; this can distinguish the chemical effects at a genomic level within specific regions of the brain. Providing participants with a comprehensive understanding of the new techniques and their application in neurotoxicology using real-world examples, the course will allow the audience to interact with experts who are currently using the techniques and to ask questions for future application to their own research. While the course focuses on neurotoxicology, these techniques are easily transferred to different areas of research, including neurodegeneration and drug discovery, as well as other organ systems. The five-minute introduction will lay out the agenda of the course, including the overall goals, speaker lineup, and intended outcome. All five speakers will have a total of 30 minutes each, which includes time for questions following each talk. There will be a 10-minute panel discusssion followed by a 10-mininute break after speaker 2. There also will be an additional 20 minutes of panel discussion after the last speaker, providing ample opportunity for participation and Q&A.

Microphysiological Systems of the CNS to Bridge between In Vivo and In Vitro. Helena Hogberg, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.

Exploring 3D Structures and Biomarker Distributions in Intact Transparent Brain and Potential Applications in Neurotoxicology. Sharla White, Clear Light Biotechnologies Inc., San Francisco, CA.

Combined Magnetic Resonance Histology and Light Sheet Whole-Brain Imaging. G. Allan Johnson, Duke University Center for In Vivo Microscopy, Durham, NC.

Overview of Novel Approaches for Neurotoxicological Behavioral Assessment and Neurocircuit Visualization. Jesse Cushman, NIEHS, Durham, NC.

Utilization of Spatial Transcriptomics and Proteomics Analysis of Targeted Neuronal Tissue Microenvironments. Colleen Urben, NanoString, Madison, WI.

" }, { "SessionID": 106, "Title": "Principles and Applications of Read-Across in Human Health Risk Assessment", "Year": 2022, "Topic": "Risk Assessment", "Transcription": 0, "Description": " Register/Login

Chair(s):
Julie Melia, SRC Inc.; and Pam Spencer, ANGUS Chemical Company.

Primary Endorser:
Regulatory and Safety Evaluation Specialty Section

Other Endorser(s):
Sustainable Chemicals through Contemporary Toxicology Specialty Section; Women in Toxicology Special Interest Group

Although read-across approaches have been used for many years to fill data gaps for chemicals lacking experimental toxicology data, recent advances in computational toxicology and the development of new approach methodologies (NAMs) have extended these approaches to allow for better mechanistic understanding. The initial foundation for read-across was based on similarity in chemical structure and physicochemical properties; however, recent approaches also include consideration of toxicokinetic similarity and common toxicologic mode of action. This course will provide important background on read-across principles and will describe the latest computational tools that may assist with toxicological read-across. The importance of applying expert judgment to interpret the output from computational tools will be discussed. Case studies will present a variety of perspectives on current applications of read-across to human health risk assessment (i.e., US and international regulatory agencies, NGOs, industry, and consultants). The course is outlined as follows: The first talk will provide an introduction, focusing on common principles and techniques employed in read-across, regulatory frameworks, and available guidance for best practices. The second talk will then describe available tools used for different aspects of selecting and evaluating analogues in support of a toxicological read-across strategy. The third talk will describe application of the European Chemicals Agency (ECHA) Read-Across Assessment Framework (RAAF) to predict subchronic and developmental health effects for a target chemical. The fourth presentation will expand on the Presentation #3 case study to describe how broadening the use of read-across can help fill multiple data gaps to support selection of safer chemical ingredients. Finally, the fifth talk will discuss the historical and future directions of read-across under Canada's Chemicals Management Plan, including case studies that utilize NAM data. Read-across methods have evolved rapidly during the past several years. This Continuing Education course will provide a thorough overview of existing methods with a view toward the future of incorporating mechanistic NAM data to support read-across approaches. Thus, 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 or risk assessment.

Introduction to Read-Across: Principles, Techniques, and Frameworks. Lucina Lizarraga, US EPA/CPHEA, Cincinnati, OH.

Tools to Assist in Toxicological Read-Across. Mary Kawa, SRC Inc., Syracuse, NY.

Application of the ECHA Read-Across Assessment Framework (RAAF) to Predict Subchronic and Developmental Health Effects of Trometamol. Pam Spencer, ANGUS Chemical Company, Buffalo Grove, IL.

Broadening the Use of Read-Across to Guide the Selection of Safer Chemical Ingredients. Chris Bartlett, ChemFORWARD, Spokane, WA.

Historical and Future Directions of Read-Across under Canada's Chemicals Management Plan: From Structural Similarity to Advances in Incorporating New Approach Methodologies to Support Substance Groupings. Matthew Gagne, Safe Environments Directorate, Ottawa, ON, Canada.

" }, { "SessionID": 107, "Title": "An Introduction to Clinical and Medical Toxicology", "Year": 2023, "Topic": "Clinical and Translational Toxicology", "Transcription": 0, "Description": " Register/Login

Chair(s):
John Benitez, State of Tennessee Department of Health; and William Mattes, Independent Consultant.

Primary Endorser:
Clinical and Translational Toxicology Specialty Section

While all toxicology addresses the adverse effects that agents have on living organisms, clinical and medical toxicology play unique roles not often encountered in traditional toxicology practice or research. These two subsets of toxicology focus on the immediate needs of patients suspected of being poisoned. These fields of toxicology require extensive knowledge of diseases and etiology as well as a thorough understanding of the effects of potential poisons, both of which are commonly used to make diagnoses. Clinical and medical toxicologists must consider three points—the substance involved, the toxic response, and the mechanism by which it occurs—in order to determine the best treatment options for each patient. This course will introduce participants to the basics of clinical and medical toxicology along with new and old tools that may be used by the clinical toxicologist.

Affecting Patient Care—What Are Clinical and Medical Toxicologists? John Benitez and Nena Bowman, State of Tennessee Department of Health, Nashville, TN.

Analytical Detection of Drug Exposure in the Clinical Laboratory: Embracing Novel Technologies and Alternative Matrices. Jennifer Colby, Abbott Laboratories, Chicago, IL.

" }, { "SessionID": 108, "Title": "A Training on the OECD Guidance for Characterizing, Validating, and Reporting Physiologically Based Kinetic Models", "Year": 2023, "Topic": "Biological Modeling", "Transcription": 0, "Description": " Register/Login

Chair(s):
Cecilia Tan, US EPA; and Alicia Paini, esqLABS GmbH, Germany.

Primary Endorser:
Biological Modeling Specialty Section

Other Endorser(s):
Risk Assessment Specialty Section; Women in Toxicology Special Interest Group

Physiologically based kinetic (PBK) modeling predicts internal dose metrics by describing the critical physiological, physicochemical, and biochemical processes that determine the disposition of a chemical in an organism. Here, a general term “kinetic” is considered synonymous with pharmacokinetic (PK), toxicokinetic (TK), or biokinetic (BK). Traditionally, in environmental toxicology, the calibration of parameters in a PBK model and the evaluation of its predictive capability rely heavily on comparing model simulations with in vivo blood or tissue concentration data obtained from laboratory animals. However, the availability of in vivo data is limited to extensively researched chemicals, which impede the broader applications of PBK models by regulatory agencies. The recent paradigm shift toward using new approach methodologies (NAMs) to inform predictive approaches for chemical hazard and risk assessment necessitates the use of PBK models—developed and evaluated without data from live animals—to convert a bioactive concentration observed in cell-based toxicity assays to an equivalent human exposure level. In 2021, in order to keep pace with global efforts to develop and incorporate NAMs in chemical risk assessments, the Organisation for Economic Co-operation and Development (OECD) published a guidance document (GD) on characterizing, validating, and reporting PBK models without the use of animal data. This GD includes contextual information on the characterization and evaluation of PBK models in a regulatory context and highlights common in vitro and in silico approaches to parameterizing the models. The OECD GD provides a model reporting template and model evaluation checklist for evaluating the credibility of PBK models for their intended purposes. Adoption of the OECD PBK model GD is now encouraged when developing OECD Integrated Approaches to Testing and Assessment (IATA). This course offers training on key principles in the OECD GD. After a brief overview of the guidance, common, modern in vitro and in silico approaches for parameterizing a PBK model will be highlighted, as described in the second chapter of the GD. Next, various tools on how to evaluate the context, implementation, and scientific validity of a PBK model without using in vivo data will be presented, as recommended in the third chapter of the GD. At the end of the course, a hands-on exercise will give both novice and expert attendees an opportunity to apply their knowledge in evaluating example PBK packages. This course is designed for those involved in developing, applying, and promoting the acceptance of PBK models and those who seek to reduce/replace animal testing and incorporate more predictive mechanistic data in chemical hazard and risk assessment for human, animal, and environmental health. Attendees enrolled in this course will learn about the fundamental concepts underlying PBK modeling, data needs during model development, and commonly used metrics for model evaluation. These topics will be applicable to PBK models developed for drugs, industrial chemicals, biocides, pesticides, food additives, and chemicals in cosmetics and consumer products. These topics are also applicable to models developed for humans, laboratory test species, farm animals, and species of ecological relevance.

An International Effort to Promote the Regulatory Use of PBK Models: Introduction to the OECD PBK Guidance. Cecilia Tan, US EPA, Research Triangle Park, NC.

Model Conception, Parameterization Using In Silico Methods, and Computational Implementation Michael Lawless, Simulations Plus, Lancaster, CA.

PBK Modeling Parameterization Using In Vitro Methods and Read-Across Workflow. Alicia Paini, esqLABS GmbH, Saterland, Germany.

Uncertainty and Sensitivity Analyses for PBK Modeling Evaluation. Lisa Sweeney, UES Inc., Kettering, OH.

PBK Modeling Assessment Framework for Model Reporting and Evaluation. Bette Meek, University of Ottawa, Ottawa, ON, Canada.

Hands-On Model Evaluation. All Speakers.

" }, { "SessionID": 109, "Title": "Advanced Discovery Toxicology: Integrating Toxicology with Other Functions on the Team", "Year": 2023, "Topic": "Drug Discovery", "Transcription": 0, "Description": " Register/Login

Chair(s):
Satoko Kiyota, Genentech Inc.; and Marie Lemper, UCB S.A. Belgium.

Primary Endorser:
Drug Discovery Toxicology Specialty Section

Other Endorser(s):
Computational Toxicology Specialty Section; Mechanisms Specialty Section

Toxicologists who are fully integrated in early discovery project teams help enable efficient strategic decision-making around lead candidate selection, and are thus quite important. Last year, the Drug Discovery Toxicology Specialty Section hosted a Continuing Education (CE) course in order to focus on an overview of the drug discovery toxicology, from target assessment to identification of drug candidates. This year, the aim of this CE course is to provide an opportunity for toxicologists to gain insights into nonstandard toxicology contents (medicinal chemistry, ADME/pharmacokinetics, formulation development, and machine-learning) that can significantly impact safety outcomes and design of nonclinical safety strategies in the small molecule discovery space.

The first speaker will focus on the link between medicinal chemistry and safety liabilities. While the idea that chemical structures and physicochemical properties can drive safety liabilities has been recognized, toxicologists with limited professional training in medicinal chemistry may not feel empowered to influence medicinal chemistry design. This presentation will enable toxicologists to gain valuable insights into medicinal chemistry approaches in order to mitigate potential toxicophores and help identify chemical series with high potential.

The second speaker will discuss key In Vitro ADME properties and liabilities, which can increase toxicity risks in vivo. Additional focus will be applied to how predicted pharmacokinetic profiles in humans can enable efficient compound triage from a safety perspective before progressing to in vivo toxicity assessments.

The third and fourth speakers will focus on interspecies metabolite comparison and formulation development, which are essential components in the design and conduct of nonclinical in vivo toxicity assessments. To ensure toxicology data from nonclinical species are vital to hazard identification and human risk assessment, the selected species should be relevant to human as far as primary pharmacology and metabolite profile. Additionally, it is imperative that robust exposure is demonstrated to ensure proper toxicological assessments, especially for non-oncology indications. Proper formulation selection is fundamental to address challenging properties of a compound and enable in vivo evaluation with desired exposure levels.

The last speaker will discuss how the emergence of machine learning can enable off-target hypothesis generation for an unexpected toxicity observed in vivo. Toxicologists should promptly identify any causes of unexpected toxicities and propose models to screen out compounds with unfavorable profiles if they are off-target-mediated. However, regardless of considerable time and financial investments, discovering the mechanism of toxicity may not be possible by empirical methods alone. Machine learning may help accelerate the generating of testable hypotheses.

The course will conclude with an interactive session to focus on how toxicologists can achieve diverse ranges of scientific expertise and ensure better decision-making early in the discovery stage. Overall, this course will inform toxicologists of new insights needed to utilize multidisciplinary tools and develop proactive safety paradigms that could reduce project delays and late-stage drug attrition. These concepts and approaches are generally applicable for predictive safety and investigative toxicology in any field, including academic research work.

Model Conception, Parameterization Using In Silico Methods, and Computational Implementation Michael Lawless, Simulations Plus, Lancaster, CA.

Overview of Cross-Functional Aspects of Toxicologists in Drug Development. Dinah Misner, Aligos Therapeutics Inc., South San Francisco, CA.

Making Sense of the Bonds between Chemistry and Toxicology. Graham Smith, AstraZeneca, Cambridge, MA.

Toxicity Prediction from a DMPK Aspect in Drug Discovery. Tomoya Yukawa, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.

A Pragmatic Approach in Utilizing In Vitro Metabolite Identification for Species Selection. Jonathan Maher, Pliant Therapeutics Inc., South San Francisco, CA.

Formulation Fundamentals: From Theory to Practice. Vijay Sethuraman, Genentech Inc., South San Francisco, CA.

Machine-Learning to Enable Off-Target Hypotheses Generation. Yuan Wang, UCB S.A. Belgium, Cambridge, MA.

Interactive Session: How to Efficiently Anchor “Non-toxicology” Discussions to Toxicology. Marie Lemper, UCB S.A. Belgium, Cambridge, MA.

" }, { "SessionID": 110, "Title": "Beyond the Powerhouse: Investigating Mechanisms of Mitotoxicity", "Year": 2023, "Topic": "Molecular and Systems Biology", "Transcription": 0, "Description": " Register/Login

Chair(s):
Katherine Morton, Duke University; and Yvonne Will, Janssen: Pharmaceutical Companies of Johnson & Johnson.

Primary Endorser:
Molecular and Systems Biology Specialty Section

Other Endorser(s):
Mechanisms Specialty Section; Women in Toxicology Special Interest Group

Mitochondria are the central energy-producing organelle in the cells of most eukaryotes, though their roles within the cell expand far beyond bioenergetics. Recent work indicates that this dynamic organelle serves as a regulator of apoptosis, oxidative stress, calcium homeostasis, signal transduction, steroid hormone synthesis, and immunity among other pathways. As a result, mitochondria can alter cell and tissue function, which leads to aging, neurodegenerative disease, cardiovascular disease, inflammatory disorders, and increased cancer severity. However, despite increasing investigations into the non-bioenergetic roles of mitochondria, these areas remain critically understudied and misunderstood. For example, mitochondrial iron uptake plays a critical role in iron homeostasis and related hepatotoxicity. Similarly, mitochondrial dysfunction is increasingly identified as a key factor in Gulf War Illness, suggesting newfound roles in other diseases. This Continuing Education course will explore the wide roles mitochondria play in response to cellular stress and xenobiotics beyond bioenergetic alterations. It will also seek to challenge how researchers traditionally examine and include mitochondrial toxicology in their work. Speakers with expertise in mechanisms and assessment of mitochondrial toxicity will present (1) an introduction to mitochondrial toxicity, which will focus on the need to examine specific mechanisms of toxicity within mitochondria in order to understand the resultant adverse outcomes; three case studies displaying the methods used and mechanisms of mitochondrial toxicity that extend beyond alterations to bioenergetics including (2) mitochondrial iron homeostasis and its role in acetaminophen hepatotoxicity, (3) antiviral medication-induced alterations to heart epigenetic and metabolic landscapes, and (4) the role of mitochondria in function of the innate immune system and inflammation. Next, we will progress from in-depth mitochondrial mechanisms to how this knowledge can be applied by using (5) mitochondria as biomarkers for renal exposures. Finally, in a world with an ever-expanding need for toxicological assessment of new drugs, toxins, and toxicants, we will explore (6) how mitochondrial testing has been improved and conducted in large Pharma and (7) how large Pharma is upscaling mitochondrial toxicity testing in order to meet increased future demand.

Following the session, attendees will have a clear understanding of the dynamic roles mitochondria play within the cell and at tissue and organismal levels, the challenges and current solutions analysis of mitochondrial endpoints presents, and a new perspective on the role of mitochondria in toxicological mechanisms. Further, they will be empowered to assess how these less understood mitochondrial mechanisms may play key roles in their own work, ultimately expanding and improving toxicological evaluations.

Mechanisms of Mitochondrial Toxicity. Joel Meyer, Duke University, Durham, NC.

Mitochondrial Iron Uptake and Release Pathways: Their Role in Hepatotoxicity. Anna-Liisa Nieminen, Medical University of South Carolina, Charleston, SC.

Mitochondrial Impact on the Epigenome and its Relevance to Health and Disease. Janine Santos, NIEHS/NTP, Research Triangle Park, NC.

Mitochondrial Control of Innate Immunity and Inflammation: Implications for Human Disease. A. Phillip West, Texas A&M University, College Station, TX.

Renal Mitochondria as Sentinels for Exposures to Environmental Toxicants and Nephrotoxic Drugs. Lawrence Lash, Wayne State University, Detroit, MI.

Upscaling Mitochondrial Toxicity Testing in Large Pharma.Natalie Mesens, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA.

" }, { "SessionID": 111, "Title": "Nontraditional In Vivo Animal Models in Developmental, Reproductive, and Juvenile Toxicology", "Year": 2023, "Topic": "Reproductive and Developmental Toxicology ", "Transcription": 0, "Description": " Register/Login

Chair(s):
Caren Villano, Boehringer Ingelheim Pharmaceuticals Inc.; and Edward Marsden, Charles River, France.

Primary Endorser:
Reproductive and Developmental Toxicology Specialty Sectionn

Traditionally, rats, mice, and rabbits have been used as preferred animal models (rodent and nonrodent) for nonclinical developmental, reproductive, and juvenile toxicity testing. Published regulatory guidelines recommend the selection of relevant animal models—based on individual project requirements—that may be influenced by systemic exposure and prior systemic toxicity data derived from general toxicology studies. Most compounds use traditional models that are quite effective and widely accepted by international health authorities. Species-specific dose-limiting toxicity, differences in metabolism across test species, and pharmacological relevance may require researchers to investigate nontraditional models including guinea pigs, mini-pigs, and dogs. In addition, certain pharmacological classes (e.g., antibiotics in rabbits) or chemistries may also limit the use of traditional models. Further, in the last year, during the COVID-19 pandemic, a severe shortage of nonhuman primates (particularly sexually mature females needed for ePPND studies) shifted the focus toward nontraditional animal models. This CE course will walk participants through the various considerations for study designs as well as the pros and cons of more common nontraditional mammalian models in DART and juvenile toxicity testing. It will also touch upon the use of rabbits and their limitations in fertility and juvenile animal studies.

The first presentation will describe how collaboration between animal model suppliers, industry, and academia has driven scientific development and expanded the use of the Göttingen Minipig into DART and juvenile toxicology, with specific projects highlighted. The second presentation will focus on the use of beagles in developmental and juvenile toxicity testing, including many critical aspects of study design, associated species differences, and terminology. The third presentation will explore the scientific considerations for the selecting of alternatives to nonhuman primates in order to address embryo-fetal risk and provide examples of how transgenic, knockin and knockout animal models and surrogate molecules can be used to support nonclinical hazard assessment for various biotherapeutics. The course will end with a summary of the current regulatory guidance on DART and juvenile animal toxicity testing, which includes discussion of the use of nontraditional species or models. Following this course, participants will be familiar with a variety of approaches to assessing embryo-fetal risk and juvenile toxicity in animal models not commonly used in DART as well as the current regulatory guidance supporting them.

Introduction to Non-traditional Models for use in DART and Juvenile Toxicology. Caren Villano, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT.

Scientific Development of the Göttingen Minipig in DART and Juvenile Toxicology: Collaborations and Joint Efforts. Andres Eskjær Jensen, Ellegaard Göttingen Minipigs A/S, Dalmose, Denmark.

Use of Beagle Dogs in DART and Juvenile Toxicology. Stephanie Clubb, Charles River, Edinburgh, United Kingdom.

Use of Alternate Models (KO/KI Models, Surrogates, Disease Models) in DART and Juvenile Toxicology. Alan Hoberman, Charles River, Horsham, PA.

Regulatory Guidance on the Use of Non-traditional Species in DART and Juvenile Toxicology. David Klein, US FDA, Silver Spring, MD.

" }, { "SessionID": 112, "Title": "Tools Supporting Open Chemical Evaluations", "Year": 2023, "Topic": "Computational Toxicology", "Transcription": 0, "Description": " Register/Login

Chair(s):
David Reif, North Carolina State University; and Shannon Bell, RTI International.

Primary Endorser:
Regulatory and Safety Evaluation Specialty Section

Other Endorser(s):
Computational Toxicology Specialty Section; Risk Assessment Specialty Section

The rapid expansion of computational and In Vitro methods for the analysis of chemical-biological interactions has evoked a wealth of open-source tools and resources that enable discovery and analysis. This supports increased use of these resources in order to aid chemical assessments and support the finding and generating information for prioritization, study waivers, weight of evidence, and other regulatory applications. Many of these new tools are open access and web-based, which enables broader access.

This session will provide attendees with an understanding of open-source and often web-based tools and resources that can be applied in a context-specific manner for understanding chemical-biological interactions and informing chemical assessments. We will open with an overview of regulatory testing strategies that incorporate the use of nonanimal methods in order to provide a background on how these tools and resources can be used. The next three presentations will provide an overview of resources that contain traditional and NAMs testing data as well as tools that support the assessment needs. Case studies will be used as reference points for participants, who can also work through the course material at their leisure. These presentations will address the following: how can we find existing data for a given chemical or chemicals that are structurally similar, how can we determine whether existing data can be used to fill in gaps of information, and how can computational models be leveraged to generate predictions that increase the weight of evidence?

Our final presentation will highlight various new tools and opportunities to derive narratives of chemical-biological interactions. Together these presentations are intended to inform participants on pertinent resources available and provide a practical guide on when and how to use them.

Objectives: Introduce participants to the mechanisms in which nonanimal approaches can be used to support assessments. Highlight resources for access to data and tools that enable the following applications: waivers; read-across; defined approaches and integrated approaches to testing and assessments (IATA); and QSAR-based modeling. Showcase new resources to complement narratives.

Creating a Narrative for Chemical Effects Using NAMs. Shannon Bell, RTI International, Durham, NC.

National Toxicology Program Tools to Support, Identify, and Explore Data. Scott Auerbach, NIEHS/NTP, Research Triangle Park, NC.

Supporting Chemical Evaluations Using Transparent and Accessible Data. Nisha Sipes, US EPA, Research Triangle Park, NC.

Supporting Chemical Hazard Assessments Using the OECD QSAR Toolbox. Donna Macmillan, Humane Society International, Glasgow, United Kingdom.

Omic-based Tools to Support Chemical Evaluations. Jessica Ewald, McGill University, Montréal, QC, Canada.

Wrap-Up and Synthesis. David Reif, North Carolina State University, Raleigh, NC.

" }, { "SessionID": 113, "Title": "Unique Applications of Systematic Review Methods: Assessment of Ecotoxicity, Environmental Fate, Exposure, Mechanisms, and Comparison of Test Methods ", "Year": 2023, "Topic": "Risk Assessment", "Transcription": 0, "Description": " Register/Login

Chair(s):
Kelly Salinas, SRC Inc.; and Marc Stifelman, US EPA.

Primary Endorser:
Risk Assessment Specialty Section

Other Endorser(s):
Hispanic Organization of Toxicologists Special Interest Group; Women in Toxicology Special Interest Group

Building on courses from previous years, this session seeks to provide members with a brief overview of systematic review (SR) methods and principles, which will be followed by analyses of how these methods can be applied to or interpreted as information beyond traditional human health hazard endpoints (e.g., epidemiology and animal toxicity studies evaluating apical endpoints). SR methods using unbiased, reproducible, transparent approaches have been implemented in order to evaluate data streams. The application to a broader base of evidence is crucial to the practice of risk assessment, given that exposure characterization ecological receptors inform assessment conclusions.

The first talk will provide a brief review of SR principles and be followed by an overview of the translation of principles and techniques of SR across diverse disciplines (i.e., ecotoxicity, environmental fate, exposure, mechanistic, and in vitro/in vivo toxicity testing data). We will then discuss the unique aspects and challenges of applying SR to these disciplines.

The second speaker will discuss how ECOTOXicology Knowledgebase (ECOTOX) literature review and data curation protocols, while ECOTOX-specific, were designed to align with SR methods. Methods were developed to ensure that ecotoxicity data were extracted in sufficient detail in order to support independent evaluation, synthesis, and/or review of ECOTOX data documents ranging from scoping documents to regulatory decision-making.

The focus of the third presentation will be the application of SR methods to environmental fate endpoints, and how the systematic evaluation of these endpoints influences prioritization, assessment, and prediction of human health and ecological hazard and toxicity. The development of a fit-for-purpose evaluation framework to systematically assess data unique to environmental fate endpoints, including field/monitoring data and data estimated from environmental fate and transport models will be described.

The fourth presentation will center on the validation and application of SR methods to environmental exposure data—specifically the data required to estimate daily soil ingestion rates in humans. We will also discuss the application of SR principles, including the development of a Population, Exposure, Comparator, and Outcome (PECO) statement specific to the soil ingestion of contaminants.

The fifth speaker will consider challenges associated with using SR principles in the synthesis and integration of mechanistic data. Adjustments of SR methods needed to evaluate mechanistic data, including a definition of the objective/scope of the use of the data and selection/refinement of an appropriate critical appraisal tool for various types of mechanistic data (e.g., in silico, in vitro, in vivo, and epidemiological data), will be presented. Case studies will be used to demonstrate that these SR adjustments rely on knowledge of standard constructs and methods used in toxicology and/or risk assessment.

The final speaker will consider evidence-based methods forassessing the correlation of in vitro data (from ToxCast) and in vivo data (from standard toxicity studies and human clinical trials) in order to predict human health hazard. A case study will be presented to show how data from these streams were evaluated systematically in order to predict the effects associated with two antidiabetic drugs in humans.

This CE course will demonstrate how SR methods, which are developed to evaluate human health toxicity studies, are being applied to other data streams. The course will provide attendees with the working knowledge base required to assess diverse endpoints using SR methods. Furthermore, this course will appeal to attendees of diverse backgrounds and toxicological disciplines who are interested in studying and applying SR methods, including scientists developing and conducting studies related to ecotoxicity, environmental fate, exposure, mechanistic in vitro/in vivo toxicity testing, and others), along with risk assessment practitioners and regulators.

Background on Systematic Review: Principles, Methods, and Applications. Kris Thayer, US EPA/CPHEA, Research Triangle Park, NC.

Application of Systematic Review Principles to Ecotoxicity Studies: Ecotoxicology Knowledgebase. Jennifer Olker, US EPA/CCTE, Duluth, MN.

Systematic Review Principles Applied to Environmental Fate. Mary Kawa, SRC Inc., North Syracuse, NY.

Application of Systematic Review Principles and Components to Estimate Daily Soil Ingestion Rates for Humans. Marc Stifelman, US EPA, Seattle, WA.

Tailoring Off-the-Shelf Systematic Review Methods to the Identification and Evaluation of Mechanistic Data. Daniele Wikoff, ToxStrategies Inc., Asheville, NC.

Using Evidence-Based Approaches to Compare Toxicological Test Methods: A Case Study Using Troglitazone and Rosiglitazone. Katya Tsaioun, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.

" }, { "SessionID": 114, "Title": "Checking in on Adverse Outcome Pathways: Evolving Development, Evaluation, and Application", "Year": 2023, "Topic": "In Vitro and Alternative Methods", "Transcription": 0, "Description": " Register/Login

Chair(s):
Kristie Sullivan, Physicians Committee for Responsible Medicine; and Bette Meek, University of Ottawa, Canada.

Primary Endorser:
In Vitro and Alternative Methods Specialty Section

Other Endorser(s):
Computational Toxicology Specialty Section; Risk Assessment Specialty Section

Adverse outcome pathways (AOPs) provide convenient integrating organizational constructs for assembling and evaluating mechanistic information at different levels of biological organization, using a form designed to support a range of regulatory applications. These include the development of integrated approaches to testing and assessment (IATA) and chemical-specific assessment to inform predictive inference and mode-of-action analysis. Much experience has been gained in the last 10 years since the introduction of the AOP development program by the Organisation for Economic Co-operation and Development (OECD) and in the more than five years since a similar course was offered to SOT members. Guidance and an associated handbook supports developers in the description and evaluation of AOPs via a publicly available knowledgebase. The program also includes formal peer engagement in the form of coaching for AOP development, external scientific review, and endorsement by parent OECD committees on testing and assessment. Increasing experience in AOP development and application contributes to the continuing evolution of the methodology required to meet regulatory need. Areas of evolution include the more systematic consideration of supporting data, extension of qualitative weight of evidence considerations to quantitation of key event relationships, and increased experience in application. This course builds on training developed within the OECD program on the best practices of documentation and assessment, including updates to the AOP-Wiki in order to encourage the use of common ontologies and delineation of literature analysis strategies and factors that modulate quantitative relationships. Consideration of disease pathways associated with nonchemical stressors also contributes to the expansion of evolving knowledge. The course includes practical demonstration of the Wiki/knowledge base, tips for developers and assessors, an opportunity to use the AOP Wiki to find information within sample use cases, and examples of development and application. Each presentation will cover different aspects of AOP development and application and, using real examples, offer a comprehensive overall learning experience. The first presentation will update attendees on how the available guidance and tools for AOP development have evolved to reflect experience with increasing and expanding content and biological space. The second presentation will emphasize the importance of transparently and efficiently documenting evidence collection and evaluation, which includes sharing tools and effective practices with prospective AOP authors and users. This will lead into a comprehensive demonstration and hands-on activity with the AOP Wiki, including changes to the publicly available interface, which will be of interest to prospective developers as well as those seeking to use currently available AOP information. The remainder of the course will feature a discussion of current and future AOP applications (including the development of IATAs) and a transition to next-generation risk assessment and decision-making using new approach methodologies (NAMs) featuring globally relevant application examples. The course will leave its participants familiar with the most recent developments in efficient practices that support AOP development, assessment, and application. Attendees will also be acquainted with evolving supportive resources within the OECD program and use of the AOP Wiki.

Course Introduction and AOPs in Context. Kristie Sullivan, Physicians Committee for Responsible Medicine, Washington, DC.

The Evolution of Best Practices for the Development and Description of AOPs Suitable to Support Regulatory Application of New Approach Methodologies. Dan Villeneuve, US EPA, Duluth, MN.

Documenting Evidence Identification and Assessment to Support Regulatory Application. Bette Meek, University of Ottawa, Ottawa, ON, Canada.

Wiki Demo and Case Example Walkthrough. Stephen Edwards, RTI International, Research Triangle Park, NC.

Hands-on Activity Using the AOP Wiki. All participants

Walkthrough and Discuss Use Cases. Stephen Edwards, RTI International, Research Triangle Park, NC; and Dan Villeneuve, US EPA, Duluth, MN.

Structuring Integrated Approaches to Testing and Assessment in the Presence and Absence of a Specific Mechanism/Relevant AOP. Georgia Reynolds, Unilever, Bedford, United Kingdom.

Case Studies on the Development and Use of AOPs at the European Food Safety Agency. Andrea Terron, European Food Safety Authority, Parma, Italy.

" }, { "SessionID": 115, "Title": "Immunosafety: Current Considerations and Applications in the Landscape of Immunomodulatory Therapies", "Year": 2023, "Topic": "Immunotoxicology", "Transcription": 0, "Description": " Register/Login

Chair(s):
Tracey Papenfuss, StageBio; and Shermaine Mitchell-Ryan, HESI.

Primary Endorser:
Immunotoxicology Specialty Section

Other Endorser(s):
Comparative Toxicology, Pathology, and Veterinary Specialty Section

Over the last decade, there have been significant advancements in the development of therapies that affect or are specifically designed to target the immune system. Therapies designed to modulate the immune system are being used to treat cancer (immune-oncology), autoimmune diseases, and a wide array of inflammatory or other diseases having an immunopathogenic origin. Immunotoxicology studies the toxic effects of chemicals, drugs, and other xenobiotics on the immune system. However, with the development of a multitude of immunotherapies with nuanced immunomodulatory effects, there is an increasing need to understand immune-related effects that go beyond traditionally recognized toxicity. In light of these immunomodulatory therapies, it can be difficult to determine whether immune-related effects reflect therapeutic efficacy and on-target effects or represent exaggerated pharmacology, overt toxicity, or a combination thereof. The term immunosafety has developed to reflect the integrated approach to evaluating immune system changes (beyond “toxic”) and the therapeutic or safety implications seen with immunomodulatory therapies. Immunosafety evaluation requires an understanding of the complex and dynamic nature of the immune system, therapy mechanism of action, effects within the context of disease, and other patient-related and clinical considerations. The first talk will provide an overview of immunosafety and toxicology considerations within the landscape of immunotherapies. The remaining talks will focus on providing information and practical considerations of immunopathology evaluation, comparative and species-specific concepts, clinical and translational considerations, regulatory considerations, and immunotoxicology assays important for immunosafety.

Immunosafety—History, Basic Background, and Toxicology Considerations in the Current Landscape of Immunomodulatory Therapies. Birgit Fogal, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT.

Pathology of the Immune System and Considerations for Immunosafety and Adversity Determination. Tracey Papenfuss, StageBio, Mount Jackson, VA.

Immunotoxicology Evaluation: Tools and Strategies for Immunosafety. Marie-Soleil Piche, Charles River, Wilmington, MA.

Comparative and Species Considerations for Immunosafety. Ashwini Phadnis-Moghe, Takeda Pharmaceutical Company Limited, Cambridge, MA.

Clinical and Translational Considerations for Immunotherapies. Daniel Weinstock, Independent Consultant, Flemington, NJ.

Regulatory Considerations for Immunosafety. David McMillan, US FDA/CDER, Silver Spring, MD.

" }, { "SessionID": 116, "Title": "In Vitro to In Vivo Extrapolation (IVIVE) Strategy and Guidance across Organ System Toxicities", "Year": 2023, "Topic": "In Vitro and Alternative Methods", "Transcription": 0, "Description": " Register/Login

Chair(s):
Samantha Faber, Takeda Development Center Americas Inc.; and Helena Hogberg-Durdock, NIEHS.

Primary Endorser:
In Vitro and Alternative Methods Specialty Section

Other Endorser(s):
Clinical and Translational Toxicology Specialty Section; Regulatory and Safety Evaluation Specialty Section

In vitro to in vivo extrapolation (IVIVE) efforts are critical for addressing low concordance of preclinical animal models for chemical-induced human toxicity and aligning with global efforts to reduce, refine, or replace animal testing (3Rs). Notably, the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH), Toxicology in the 21st Century (Tox21), and other regulatory initiatives support the development of new approach methodologies (NAMs) and strategies to advance the field of IVIVE. As such, a wave of recently developed, rationally designed in silico models, advanced in vitro systems, 'omics signatures (toxicogenomics, proteomics, epigenomics, metabolomics, and lipidomics), and physiological-based pharmacokinetic (PBPK) modeling approaches demonstrate utility for IVIVE across diverse organ systems. Despite these advancements, there is limited understanding of key concepts related to robust NAM development, validation, and implementation within a regulatory framework to progress IVIVE adoption. Based on gaps in IVIVE guidance, this Continuing Education course will explore successful IVIVE studies across research sectors and highlight important strategies and principles critical for regulatory consideration. Specifically, the course will focus on IVIVE strategy for prominent organ system toxicities, including inhalation toxicity, hepatotoxicity, developmental neurotoxicity, and cardiovascular toxicity. We will begin the course with an overview of IVIVE concepts and utility across academic, government, and industrial toxicological sectors. Our first speaker will highlight the value of IVIVE within the field of inhalation toxicity using IVIVE case studies that connect inhalation exposure to complex mixtures in vitro and tobacco-free nicotine product human risk assessment. Next, speaker two will detail the use of toxicogenomics, PBPK modeling, and publicly available toxicological databases (e.g., TG-GATES) to assess drug-induced liver injury (DILI) IVIVE within a robust compound validation set and describe how these approaches can aid in de-risking hepatotoxicity across research sectors. Speaker three will focus on an integrated approach to testing and assessment (IATA) case study for developmental neurotoxicity (DNT) using a battery of NAMs in order to prioritize a class of compounds. This speaker will also examine how exposure data in humans can be used to interpret this information. Speaker four will provide a balanced viewpoint of the cardiovascular NAM landscape, including 2D and 3D cardiac and vascular toxicity model approaches, challenges, and strategies for IVIVE implementation. The final speaker will conclude the course with a discussion of regulatory considerations and paths forward for the adoption of IVIVE approaches within adverse outcome pathway (AOP) contexts and clinical packages. This course will focus on critical organ systems and provide guidance on pertinent assay parameters (e.g., cell types, model systems, and endpoints) and mechanisms of action shown to affect key toxicities that have the potential for assessment via IVIVE. Also, as experts in their field, the speakers will impart knowledge regarding organ system pathophysiology and offer key insights into in silico, in vitro, and systems biology methodology that are essential for the successful development of IVIVE platforms. Together, the latest developments on assay guidance and strategic IVIVE development can inform participants on the best approaches within the field and help address key challenges and gaps faced by investigators. Along with valuable insights into regulatory considerations and future IVIVE perspectives, this course offers key strategies for the development, implementation, and advancement of IVIVE practices across research sectors.

IVIVE CE Course Overview. Samantha Faber, Takeda Development Center Americas Inc., San Diego, CA.

Evaluation of Inhalation Toxicity IVIVE and Potential Health Impacts of Tobacco-Free Products and Mixtures. Jingjie Zhang, Altria Client Services LLC, Richmond, VA.

IVIVE Approaches to Drug-Induced Liver Injury: Translating Clinical Findings into Knowledge for Drug Safety Evaluation. Zhichao Liu, US FDA/NCTR, Jefferson, AR.

Developing a DNT Battery for Organophosphorus Flame Retardant-Induced Toxicity for Human Health Risk Assessment. Helena Hogberg-Durdock, NIEHS, Research Triangle Park, NC.

Cardiovascular Toxicity Models: Bridging the Gap of the Translatability Challenge. Vicencia Toledo Sales, Takeda Development Center Americas Inc., Cambridge, MA.

Strategies and Guidance for Implementation of IVIVE in Chemical Risk Assessment. Jean-Lou Dorne, European Food Safety Authority, Parma, Italy.

" }, { "SessionID": 117, "Title": "Inhalation Drug Development: Back to Basics", "Year": 2023, "Topic": "Inhalation and Respirtory Toxicology", "Transcription": 0, "Description": " Register/Login

Chair(s):
Simon Moore, Labcorp Drug Development; and Melanie Doyle-Eisele, Lovelace Biomedical.

Primary Endorser:
Inhalation and Respiratory Specialty Section

Inhalation toxicology has always carried an air of mysticism when compared with other routes of administration. This CE course will provide the information necessary for better understanding of this perceived dark art. This course will serve as a take-home introduction for those new to the inhalation toxicology field and provide regulatory guidance to those not so new to inhalation toxicology. It will consist of practical aspects of animal studies regarding the determination of dose and formulation aspects. Further, this course will provide examples and interpretations on what is adverse and not adverse in reference to histopathological findings in the respiratory tract.

Aerosol Generation Systems and Aerosol Characterization Methodology. Jacob McDonald, Lovelace Biomedical and University of New Mexico, Albuquerque, NM.

Optimization of Dosing Methodology for Animals. Simon Moore, Labcorp Drug Development, Huntingdoneshire, United Kingdom.

Inhalation Dose and Respiratory Physiology. Jeffrey Tepper, Tepper Nonclinical Consulting, San Carlos, CA.

Study Design for Respiratory Toxicology (Drug Development Focus). Matthew Reed, Coelus and University of New Mexico, Albuquerque, NM.

Respiratory Pathology—Differences between Inhalation and Non-inhalation Routes. Nicholas Macri, Labcorp Drug Development, Albuquerque, NM.

Roundtable Discussion—Lessons Learned with Inhalation Drug Development. Melanie Doyle-Eisele, Lovelace Biomedical, Albuquerque, NM.

" }, { "SessionID": 118, "Title": "Making the Most of Your Data: How to Build Machine-Learning Models for Toxicology", "Year": 2023, "Topic": "Computational Toxicology", "Transcription": 0, "Description": " Register/Login

Chair(s):
Catrin Hasselgren, Genentech Inc.; and Nigel Greene, AstraZeneca.

Primary Endorser:
Computational Toxicology Specialty Section

Other Endorser(s):
Biological Modeling Specialty Section; Drug Discovery Toxicology Specialty Section

Computational toxicology encompasses the development of machine-learning (ML) and mechanistic models and tools applied to datasets of toxicological concern. Applications of such tools span a wide field, incorporating hazard identification, prioritization for experimental testing, optimization of chemical space and chemical risk assessment. These methods are used in various industry sectors, such as consumer products, pharmaceuticals, cosmetics, and agrochemicals. They are also used in the environmental sector and in governmental and regulatory organizations. The methods employed vary from simple to complex, depending on availability and quality of data, and range from the application of structural alerts to ML models of large-scale biological data and complex systems toxicology modeling. With increased pressure to reduce the number of animal experiments, accelerate the product development cycles, and lower costs, computational toxicology is a continuously developing area with great untapped potential. This course will give a brief introduction to the field of computational toxicology, followed by a series of lectures on methods used in building computational models. The first presentation will focus on the data available for model building and how we normalize, clean, and prepare the experimental data for model building. The second presentation will describe various possible algorithms along with how to select appropriate methods using the data at hand. It will also consider how to split data into training versus test sets. The third presentation will focus on how to appropriately evaluate models so as to understand their utility and application in decision-making. The course will end with an interactive exercise wherein the audience will be asked to vote on the various steps throughout the model building process in order to reinforce the theory presented in the previous three talks. We will jointly evaluate model performance, utility, and lessons learned along the way. The aim of this course is to provide participants with a broad understanding of the many benefits of computational toxicology methods and inform them of the limitations and appropriate use of such methods for successful application depending on the use case. The learnings from this course are relevant for attendees from academic, industry, and government sectors who seek to explore or expand the use of computational models within their organizations.

Computational Toxicology—Introduction. Catrin Hasselgren, Genentech Inc., South San Francisco, CA.

The Importance of Biological Data Evaluation and Preparation. Fjodor Melnikov, Genentech Inc., South San Francisco, CA.

Method Selection and Best Practices in Model Building. Alexander Tropsha, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Approaches for Effective Model Validation and Testing. Timothy Allen, Ladder Therapeutics, Vancouver, BC, Canada.

Case Study—Let’s Build Models Together! Nigel Greene, AstraZeneca, Waltham, MA.

" }, { "SessionID": 119, "Title": "Put Your Science Where Your Mouth Is: Practice Makes Progress in Effective Science Communication", "Year": 2023, "Topic": "Communication", "Transcription": 0, "Description": " Register/Login

Chair(s):
Anne Chappelle, SafeBridge Regulatory & Life Sciences Group; and Barbara L.F. Kaplan, Mississippi State University.

Primary Endorser:
Education and Career Development Committee

Other Endorser(s):
Ethical, Legal, Forensic, and Societal Issues in Toxicology Specialty Section; and Risk Assessment Specialty Section

Training in effective science communication is critical for scientists in all stages of their careers. However, as many of us advance beyond our graduate and postdoctoral training, we have fewer opportunities to convey our communication training to other scientists (both inside and outside our field). The purpose of this Continuing Education (CE) course is to introduce effective science communication, discuss how providing critical feedback helps make you a more effective communicator, and suggest mechanisms by which you can define yourself as a science communicator online. This innovative session will include real-time feedback via mobile devices (i.e., polling) in order to engage the audience. It will also include an interactive session in which participants are required to deliver a 3-minute presentation in small groups (e.g., 5 people) using an oral format or a single slide so as to practice effective communication in a safe space. Attendees will receive constructive comments in real time and during the discussion session. The concluding Q&A session will allow for registrants to use the polling functionality to communicate their experiences from the interactive session. This CE course will be complemented with a Wednesday session in the ToxExpo Hall in the Tiny Tox Theater in which participants and other interested attendees can share how they applied any learned and/or practiced communication skills during the meeting.

This Is Not Your Paracelsus’s CE Course. Barbara L.F. Kaplan, Mississippi State University, Mississippi State, MS.

Communicating Science to the Media and Other Audiences. Emily Copeland, Science Communication Network, Bethesda, MD.

Constructive vs. Destructive Feedback. Anne Chappelle, SafeBridge Regulatory & Life Sciences Group, Chadds Ford, PA.

Getting the Word Out: Communicating Science to the Public. Bill Sullivan, Indiana University School of Medicine

Interactive Session.

Facilitated Q&A.

" }, { "SessionID": 120, "Title": "Plastic Chemical Additives: Determining Human Risk from Microplastic Exposure", "Year": 2024, "Topic": "Exposure", "Transcription": 0, "Description": " Register/Login

Chair(s):
John Norman, American Chemistry Council; and Todd Gouin, TG Environmental Research, United Kingdom.

Primary Endorser:
Exposure Specialty Section

Other Endorser(s):
Nanoscience and Advanced Materials Specialty Section; Risk Assessment Specialty Section

Microplastics, once relatively unknown, have become the focus of local, national, and global interest. Microplastic particles are one subset of plastic debris primarily characterized as having a size of less than five millimeters down to one micrometer; plastic particles smaller than this size are typically termed nanoplastic particles. Together, these particles also may be called NMPs for short (nano- and microplastics). Microplastic particles can either result from the discharge of plastic materials originally manufactured at that size (primary microplastics) or from the degradation of larger plastic debris (secondary microplastics). However, before researchers begin to tackle the question about microplastic risk, you must understand how plastic is manufactured.

Plastic begins as polymers, and through the application of energy (e.g., heat) and incorporation of the desired additives, a plastic material is created. Additives are chemicals intentionally added to plastics to provide a function fit for the purpose to provide, improve, modify, or retain plastic properties such as preventing fire and providing flexibility, durability, or stability during the plastic lifecycle. Additives often are included in plastics because without additives, the plastic materials would have limited applications, be brittle, potentially degrade, and have a very limited shelf life. It is this combination of particle characteristics (e.g., size, shape, polymer type) and the presence of chemical additives that presents toxicologists with a sizable issue.

Another challenge to understand the potential risks of microplastics is the number of potential chemistries used as additives. There is a vast amount of information available through existing regulatory programs; programs like the US Food and Drug Administration’s food contact notification and the Threshold of Toxicological Concern model, coupled with the European Chemicals Agency REACH registration, are sources of valuable exposure and toxicological information. If there is no exposure and toxicological data, scientists can turn to frameworks to predict potential exposures and risks. To reduce the complexity of the issue, scientists might look at human exposure to screen out chemical additives that are low risk due to low exposure potential.

In this course, the first presenter will focus on modeling probabilistic estimates of both direct exposure (e.g., food packaging) and exposure from modifications to an existing numerical bioaccumulation food web model. The second presenter will discuss how risk can be estimated with a newly developed framework when traditional exposure and toxicity data have not been developed, but the molecular structure and chemical tonnage of a chemical is known. These presentations will provide attendees with a new perspective on critical issues toxicologists face studying microplastics and their potential effects on human health.

Microplastics and Chemical Additives: Migration Considerations for Human Exposure. Todd Gouin, TG Environmental Research, Sharnbrook, United Kingdom.

Modeling Chemical Risk without Traditional Exposure or Toxicological Data. Li Li, University of Nevada School of Public Health, Reno, NV.

" }, { "SessionID": 121, "Title": "Advances in Metal Toxicology: From Aging and Disease Causation to Detection and Regulatory Measures", "Year": 2024, "Topic": "Mechanisms", "Transcription": 0, "Description": " Register/Login

Chair(s):
Koren Mann, McGill University; and Johnny Wise, University of Louisville.

Primary Endorser:
Metals Specialty Section<\/p>

Other Endorser(s):
Mechanisms Specialty Section; Occupational and Public Health Specialty Section

Of the 118 elements in the Periodic Table, 95 elements are classified as metals, and 34 of these have been identified to be hazardous to human health. Differing from organic chemicals, metals’ chemical forms may change, but their basic unit is neither created nor destroyed. Thus, a persistent distribution of metals in the ecosystem with no environmental half-life renders the body system susceptible to metal toxicity in every stage of human life. Exposure to metals occurs in daily life through one’s lifestyle, food intake, occupation, or medical treatment. Considering a worldwide growing geriatric population, the possibility of metal exposure in accelerating the aging process has drawn public attention. For the past half century, assessment of total body metal burden and metal toxicity depends largely on conventional techniques such as atomic absorption spectrophotometry and bioassays; however, more recently, real-time analyses and molecular approaches for gene-environment interactions have been implemented. This advanced course invites experts to address interconnected subjects in metal toxicology.

After a general introduction to metals, the first lecture introduces recently developed innovative technologies to determine level of exposure, such as x-ray fluorescence and neutron activation analysis for real-time, noninvasive, nondestructive quantitation of metal levels in bone, nail, hair, and other tissues. The second lecture discusses recent advancements in ’omics-based technologies, such as whole genome and CRISPR-based screens, in understanding the genetic susceptibility that contributes to metal toxicities. The third lecture uses the body as a whole system to address metal toxicity in an aging population from the impact of aging itself on metal toxicity to the impact of metals on aging. The last lecture further discusses the role of the US Food and Drug Administration in the regulation and safety assessment of metals in food additives. Throughout the course, concerns related to human exposure to these metals and potential risk will be raised and discussed with particular emphasis on metals of concern, such as lead, arsenic, manganese, and mercury.

The course serves well for those who desire an advanced knowledge on metal toxicity in lifespan, metal-gene interaction, risk assessment/regulation, and advanced technical approach for metal quantification. The course will be of interest to those engaged in wider aspects of metal toxicology, mechanism of chemical toxicity, neurotoxicology, carcinogenesis, risk assessment, regulatory and safety evaluation, and occupational and public health.

Introduction: Chemical Properties of Metals Determine Unique Metal Toxicology. Wei Zheng, Purdue University, West Lafayette, IN.

Advances in Metal Detection and Quantification in Human Subjects for Risk Assessment. Aaron Specht, Purdue University, West Lafayette, IN.

Using ’Omics to Advance Our Understanding of Metal-Induced Toxicity. Koren Mann, McGill University, Montreal, QC, Canada.

Intersection of Toxicology and Aging: Current Understanding of Metal Exposure and Aging. Johnny Wise, University of Louisville, Louisville, KY.

Safety Assessment and Regulation of Metals in Food Packaging. Laura Markley, US FDA/CFSAN, College Park, MD.

" }, { "SessionID": 122, "Title": "Foundations of Embryonic and Fetal Development and Application to Developmental Toxicity Testing", "Year": 2024, "Topic": "Developmental", "Transcription": 0, "Description": " Register/Login

Chair(s):
Sarah Campion, Pfizer Inc.; and Jessica LaRocca, Corteva Agriscience.

Primary Endorser:
Reproductive and Developmental Toxicology Specialty Section

Other Endorser(s):
Women in Toxicology Special Interest Group

During the pre-implantation period, there are major developmental events that occur, and knowledge of these events is critical for understanding and interpreting potential effects on fertility and early embryonic development. Embryo-fetal development is a complex process that initiates following implantation. The development of the major organ systems during gestation varies in timing across species and drives the design of nonclinical studies conducted to assess the potential human risks of drugs or chemicals. This course will focus on the basic biology of implantation, early embryonic development, and organogenesis, while discussing comparative cross-species timelines and critical periods during development.

In addition to reviewing the key developmental processes and events that occur during the pre-implantation and post-implantation periods, the first two speakers will provide examples of phenotypes that arise following exposures to chemicals or drugs during sensitive developmental periods. The information presented will provide attendees with a basis for interpreting the potential mode of action, as well as interspecies comparison to aid in human risk assessment.

After this critical background information that is the biological basis for prenatal developmental toxicity testing, the succeeding presentations will discuss the design of nonclinical developmental toxicity studies for agrochemicals and pharmaceuticals. These speakers also will present key information on how study outcomes are interpreted and impact human risk assessment. Specific case studies and mode-of-action studies for determining human relevance will provide attendees with real-world examples of how to apply the information presented in this course. Novel approaches for developmental toxicity testing, including the use of comprehensive toxicogenomics data and the use of alternative assays as outlined in ICH S5(R3), also will be discussed, with the aim of providing attendees with a perspective on the evolving future of developmental toxicity testing.

Fertilization to Implantation: Self-Organization of the Mammalian Conceptus. Tristan Frum, University of Michigan Medical School, Ann Arbor, MI.

Comparative Embryo-Fetal Development. Sarah Campion, Pfizer Inc., Groton, CT.

Developmental Toxicity Assessment of Agrochemicals and Using Mode-of-Action Studies to Inform Human Relevance. Kamin Johnson, Corteva Agriscience, Indianapolis, IN.

Developmental Toxicity Testing in Pharma and How Understanding of Embryology Impacts Study Design and Risk Assessment. G. Cappon, ToxStrategies Inc., East Lyme, CT.

" }, { "SessionID": 123, "Title": "High-Throughput In Vitro–In Vivo Extrapolation for Predictive Toxicology", "Year": 2024, "Topic": "In Vitro-In Vivo", "Transcription": 0, "Description": " Register/Login

Chair(s):
John F. Wambaugh, US EPA; and Barbara A. Wetmore, US EPA.

Primary Endorser:
Risk Assessment Specialty Section

Other Endorser(s):
Biological Modeling Specialty Section; Women in Toxicology Special Interest Group

Next-Generation chemical risk assessment (NGRA) aims to replace and expand traditional toxicity testing via new approach methodologies (NAMs) including in vitro screening. Translating in vitro points of departure (PODs) to in vivo contexts requires In Vitro-In Vivo extrapolation (IVIVE) based on toxicokinetics. IVIVE methods for single chemicals were developed and vetted by the pharmaceutical industry. However, NGRA is intended to accelerate the pace of chemical risk assessment, potentially generating in vitro PODs for thousands of chemicals and endpoints. These data require chemical-specific IVIVE to be interpreted as in vivo PODs. To allow higher-throughput IVIVE, higher-throughput toxicokinetic (HTTK) methods are needed. Public health risk chemical prioritization efforts based on HTTK are under consideration at the US Environmental Protection Agency, Health Canada, and the European Food Safety Authority.

This course, which focuses on high-throughput approaches for translating NAMs into PODs, complements but is distinct from fellow 2024 SOT Continuing Education (CE) course “Putting Theory into Practice: Using Computational New Approach Methodologies in Next-Generation Risk Assessment,” which focuses on integrating all NAMs needed for next-generation chemical risk assessment. Further, with its focus on high-throughput IVIVE, it is distinct from previous years’ CE course offerings focused on other aspects of physiologically based kinetic modeling and toxicokinetics.

AHTTK is playing an increasing role in creating more predictive toxicological methods by allowing (1) conversion of external dose metrics (such as mg/kg/day) to internal/tissue dose metrics and (2) relating in vitro PODs to human-relevant doses. With confirmed speakers that include subject matter experts with many years of experience in the development and application of these tools, this course aims to (1) educate researchers to use high-throughput IVIVE to estimate toxicological PODs in their work and (2) allow decision-makers considering the use of NAM-based PODs to be better informed about the capabilities and limitations of high-throughput IVIVE. Attendees of this course will become familiar with the types of data, models, and tools needed to create “bioactivity:exposure ratio” risk-based prioritizations, and other rapid IVIVE techniques. These tools will include SimCyp, httk, and WebICE. While single chemical IVIVE has built a strong foundation, this course will focus on IVIVE to inform models of toxicity that can be applied to large numbers of chemicals. Each of the four main presentations will provide examples that can be easily adapted to the attendees’ research questions and risk assessments.

Introduction: Fifteen Years of High-Throughput Toxicokinetics. Barbara A. Wetmore, US EPA, Research Triangle Park, NC.

High-Throughput in vitro Data and Tools for Toxicokinetics. Hiba Khalidi, Certara Inc., Sheffield, United Kingdom.

R Package httk for High-Throughput IVIVE. Caroline Ring, US EPA, Research Triangle Park, NC.

In Vitro-In Vivo Extrapolation for New Approach Methodologies. Xiaoqing Chang,Inotiv, Research Triangle Park, NC.

Moving toward Next-Generation Risk Assessment with High-Throughput IVIVE. Katie Paul Friedman, US EPA, Research Triangle Park, NC.

" }, { "SessionID": 124, "Title": "Nix the Six: Strategies for Implementing Nonanimal Acute Toxicity Testing", "Year": 2024, "Topic": "In Vitro", "Transcription": 0, "Description": " Register/Login

Chair(s):
Eryn Slankster-Schmierer, Physicians Committee for Responsible Medicine; and Elizabeth Baker, Physicians Committee for Responsible Medicine.

Primary Endorser:
In Vitro and Alternative Methods Specialty Section

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

The acute toxicity of chemicals, mixtures, and formulations has traditionally been assessed with an animal-intensive in vivo battery of tests that in the context of pesticides is collectively referred to as the “six pack.” These tests include methods to address acute oral, dermal, and inhalation toxicity; primary eye irritation; and dermal irritation and sensitization. In light of recent retrospective reviews of in vivo test method performance, the ability of the individual components of the test battery to reliably predict human-relevant responses to chemicals has been in question. In recent years, international collaborations have led to partial and full replacements for several of these endpoints.

In this course, attendees will receive an overview of ongoing efforts and an up-to-date strategy to implement reduction and replacement of animals used for acute toxicity in health hazard and risk assessment of chemicals and end-user product formulations for chemical markets, including drugs, pesticides, and consumer products. The first portion of the course will provide strategies for predicting, waiving, and measuring oral, dermal, and inhalation lethal doses in order to minimize animal use. LD50 tests have been used for nearly a century and still guide regulatory decision-making, with acute oral lethal dose studies the most prevalent, despite poor reproducibility for Globally Harmonized System of Classification and Labelling of Chemicals categorization. The first talk will cover computational approaches to predict acute oral toxicity using the OPERA suite, a free and open-source/open-data suite of QSAR models providing predictions on physicochemical properties, environmental fate, and toxicity endpoints. The second speaker will outline strategies for waiving in vivo acute dermal toxicity tests for US Environmental Protection Agency requirements, including the implementation of bridging principles to leverage data already gathered and reduce additional testing. The third talk will cover human-relevant approaches to overcome the anatomical and physiological respiratory differences that make rodents poor predictors for human inhalation toxicity. The second portion of the course will cover advanced in silico, in vitro, and ex vivo methods for non-lethal acute endpoint studies. The fourth speaker will cover in vitro methods showing improved reliability and human-relevance relative to the Draize test, as well as proposed avenues for the development of a defined approach for dermal irritation. The fifth speaker will cover the methods in the defined approaches for serious eye damage and irritation, offering a full replacement for the Draize eye test in rabbits. Finally, the last talk will round out the six-pack assessment by covering methods within and updates to the defined approach to skin sensitization, including presenting information on the first fully nonanimal defined approach as an effective replacement for the mouse Local Lymph Node Assay and guinea pig maximization tests for dermal sensitization.

In sum, this course will prepare agency and commercial risk and hazard assessment attendees to replace and reduce animal use in acute toxicity testing batteries wherever possible by offering up-to-date guidance on modern nonanimal methods.

Acute Oral Toxicity Predictions for Environmental Safety Assessment Using CATMoS Models. Kamel Mansouri, NIEHS/NICEATM, Research Triangle Park, NC.

Nonanimal Approaches for Dermal Toxicity. Monique Perron, US EPA, Washington, DC.

Nonanimal Methods for Acute Inhalation Toxicity. Clive Roper, Toxicology Consulting Limited, Edinburgh, United Kingdom.

New Approach Methodologies for Primary Dermal Irritation: Implementing Human-Relevant Testing Approaches. Hans Raabe, Institute for In Vitro Sciences, Gaithersburg, MD.

Nonanimal Methods for Eye Irritation. Nathalie Alépée, L’Oréal Research and Innovation, Paris, France.

Defined Approach for Skin Sensitization. Patience Browne, Organisation for Economic Co-operation and Development, Paris, France.

" }, { "SessionID": 125, "Title": "\"Relax, Immune System\", Cell and Gene Therapy Here", "Year": 2024, "Topic": "Immunotoxicology", "Transcription": 0, "Description": " Register/Login

Chair(s):
Ashwini Phadnis Moghe, Takeda Pharmaceutical Company Limited; and Shermaine Mitchell-Ryan, HESI.

Primary Endorser:
Immunotoxicology Specialty Section

Cell and gene therapies have emerged as an exciting breakthrough treatment for liquid and solid tumors in regenerative medicine and for the treatment of rare monogenic disorders as well as a wide range of acquired diseases with limited therapeutic options. While these therapies hold tremendous promise in treating complex diseases, they can be associated with significant immune safety concerns that should be carefully considered during preclinical and clinical development. Such risks may include off-target toxicities, integration-associated genomic toxicities, mutagenic transformation, organ/tissue damage, immunogenicity, and exaggerated activation of the immune system. These therapies also are accompanied by a unique set of challenges where standard safety assessments may not apply and additional testing is warranted, often involving novel de-risking approaches and post-marketing surveillance depending on the therapy in question. Recent advances in the field, along with the sustained momentum in developing safer and more effective next-generation cell and gene therapies, have encouraged a closer examination of the promise and the pitfalls associated with this rapidly evolving class of therapies.

In the first talk of this course, attendees will be guided through the history of these advanced therapies, dating back to the first human gene and cell therapies to the present day approved therapies, along with a description of current nonclinical and clinical strategies designed to overcome hurdles associated with immune-related events. Then, the course will take a deeper dive into immune system considerations for cell and gene therapies with the second talk focusing on the immune barriers to in vivo gene therapies, such as immunogenicity to viral and nonviral (i.e., liposomes, nanoparticles) therapies. This talk also will provide pointers to toxicologists for assessing immunotoxicity issues in gene therapy. The third talk will focus on operational aspects of immune system monitoring during the conduct of a nonclinical study from the contract research organization perspective. The fourth speaker will focus on nonclinical safety assessment for engineered CAR-T therapies, with a focus on immunosafety risks posed by engineered Teff and Treg cells, paving the way for the fifth speaker to discuss the next generation of cellular and gene therapies, including an overview of gene editing to avoid graft vs. host disease.

Historical Overview of the Cellular and Gene Therapy Landscape: The Promise to Revolutionize Treatment of Difficult-to-Treat Diseases and Cancers. Ashwini Phadnis Moghe, Takeda Pharmaceutical Company Limited, Cambridge, MA.

Overcoming the Immune Barriers for In Vivo Gene Therapies. Basel Assaf, Sanofi, Waltham, MA.

Considerations for Immune System Monitoring during the Conduct of Nonclinical Studies for Novel Gene-Modifying Therapies. Brian McIntosh, LabCorp, Madison, WI.

Nonclinical Safety Assessment of Engineered CAR-T Therapies. Herve Lebrec, Sonoma Biotherapuetics, South San Francisco, CA.

Infinite Possibilities!?! The Next Generation of Cellular and Gene Therapies. Kathryn Fraser, Takeda Pharmaceutical Company Limited, Cambridge, MA.

" }, { "SessionID": 126, "Title": "Weight of Evidence Analysis and Problem Formulation for Chemical Risk Assessment: Fundamental Principles and Application through Case Examples", "Year": 2024, "Topic": "In Vitro", "Transcription": 0, "Description": " Register/Login

Chair(s):
Anna Lowit, US EPA; and Gina Hilton, PETA Science Consortium International.

Primary Endorser:
Risk Assessment Specialty Section<

Other Endorser(s):
In Vitro and Alternative Methods Specialty Section; Regulatory and Safety Evaluation Specialty Section

The depth and breadth of information used to characterize hazard and exposure have expanded beyond traditional in vivo studies to encompass ’omics, in vitro, and computational approaches. Interpreting various lines of scientific evidence is rarely unambiguous or straightforward, as the same information can support multiple legitimate interpretations and conclusions. The weight of evidence (WOE) approach is, therefore, essential in toxicology and risk assessment to support decision-making. Although some tools are available to enhance transparency and consistency in WOE, professional judgement remains necessary in almost all cases to evaluate the strengths and limitations of each data source. Subject experts also are expected to provide knowledge-based insights on how various factors, such as experimental design, can influence data comparability. WOE is particularly challenging due to the diverse regulatory and scientific contexts involved in the analysis. Therefore, WOE must be fit for purpose and framed in problem formulation. This course will provide attendees with an understanding of the underlying concepts, principles, and techniques of WOE analysis in the context of chemical risk assessment.

Since the WOE approach is flexible and adaptable (i.e., it can be tailored to fit specific risk assessment contexts or regulatory requirements), this course will use case examples to demonstrate the integration of various lines of scientific evidence generated from both conventional and new approach methods for different purposes, including industrial chemicals, personal care, fragrance, and agrochemical sectors. The case examples will illustrate the concept of fitting WOE to a specific purpose, including optimizing the design of animal toxicity studies (where required), estimating points of departure using nonanimal data, and predicting toxicity of a structurally similar chemical with limited or no toxicity data, as well as merging monitoring data and exposure model predictions.

The introduction will describe the overarching, flexible, and adaptable principles in WOE and problem formulation that will be illustrated throughout the course. The first presentation will cover the fundamental principles in problem formulation, including defining resources and contexts, and computational tools to integrate and evaluate data for fit-for-purpose WOE. A WOE approach using multiple lines of evidence for contemporary study design for regulatory required animal studies to maximize the use of computational modeling, in vitro, and pharmacokinetic data will be shared in the second talk, while the third presenter will discuss a WOE approach for considering the appropriateness of new in vitro inhalation methods for the evaluation of fragrances in risk assessment. The fourth presentation will focus on interpreting multiple lines of evidence using in vitro and computational approaches for safety evaluation of cosmetics. The next presenter will show WOE across in vitro physiologically based kinetic and short-term in vivo data to consider human relevance of particular hazards. The course’s final presentation will focus on exposure assessment and a WOE approach for evaluating and applying measurements and models together in exposure characterization, followed by an interactive session where each presenter will pose a question to test attendee knowledge of fit-for-purpose WOE and problem formulation principles and application.

The learning goals for this course are to (1) understand the value and content of problem formulation; (2) gain knowledge in the concept of fit-for-purpose WOE and its connection to problem formulation; (3) learn how WOE analysis can be used to analyze data and evaluate risks for chemicals that have varying degrees and types of available data; and (4) learn about different types of risk assessments and decision contexts.

Problem Formulation: The Foundation That Supports Any Weight of Evidence Approach. Michelle Embry, HESI, Washington, DC.

Using a Weight of Evidence Approach to Optimize the Design of Animal Toxicity Studies. Cecilia Tan, US EPA, Durham, NC.

Using Weight of Evidence for Inhalation Exposure Safety Evaluation of Fragrances. Nikaeta Sadekar, Research Institute for Fragrance Materials, Mahwah, NJ.

Using Computational Models to Build a Weight of Evidence in Safety Assessments of Cosmetic Ingredients. Alistair Middleton, Unilever, Bedford, United Kingdom.

United Kingdom. Use of Weight of Evidence and Uncertainty Analysis in Hazard Characterization and Risk Assessment of Agrochemicals. Marco Corvaro, Corteva Agriscience, Rome, Italy.

Merging Measurements and Models in a Weight of Evidence Approach for Exposure Estimation. Jon Arnot, ARC Arnot Research and Consulting and University of Toronto, Toronto, ON, Canada.

" }, { "SessionID": 127, "Title": "Benchmark Dose Modeling and Its Applications in Drug, Food, and Chemical Safety Evaluation and Assessment", "Year": 2024, "Topic": "Risk Assessment", "Transcription": 0, "Description": " Register/Login

Chair(s):
Kan Shao, Indiana University; and Antero Vieira da Silva, Karolinska Institutet, Sweden.

Primary Endorser:
Risk Assessment Specialty Section

Other Endorser(s):
Biological Modeling Specialty Section; Regulatory and Safety Evaluation Specialty Section

The rapid expansion of benchmark dose (BMD) modeling methodology has brought it into the spotlight of chemical risk assessment in a variety of applications, including evaluating the safety of substances as diverse as metals, pesticides, nutrients, and pharmaceuticals. This course aims to provide participants with a fundamental understanding of the concepts and principles of BMD modeling methodology and demonstrate its usefulness through a few applications and case studies, covering current practice, issues, and challenges.

The first presentation will provide a general introduction on the BMD modeling methodology and demonstrate its utility to assess dose-response relationships and estimate critical doses using multiple types of data in the recently developed Bayesian benchmark dose modeling (BBMD) system. An application of the BMD modeling approach in drug development for the purposes of safety evaluation, as well as a variety of its advantages over the No-Observed-Adverse-Effect-Level method, will be discussed in the second presentation. Next, a critical issue in BMD modeling, the definition of benchmark response (BMR), will be described by the third presenter, alongside how to standardize, refine, and enrich the BMD approach through the selection of adequate BMR to support prioritizations within food safety. The last presentation will demonstrate an alternative method to derive a human health–protective, point-of-departure value from model organism exposure studies based upon a comprehensive analysis of the transcriptome. Throughout the course, the BMD modeling strategies will be consistently highlighted and demonstrated through cases studies.

Benchmark Dose Modeling Strategies and Tools for Dose-Response Assessment Using Toxicological, Epidemiological, and Genomic Data. Kan Shao, Indiana University, Bloomington, IN.

Benchmark Dose-Response Modeling Is Advantageous for Multiple Endpoints Analysis for Drug Safety Evaluation Purposes. Antero Vieira da Silva, Karolinska Institutet, Stockholm, Sweden.

Standardization, Refinement, and Enrichment of the Benchmark Dose Approach to Support Prioritizations within Food Safety. Salomon Sand, Swedish National Food Agency, Uppsala, Sweden.

Application of a Benchmark Dose–Based Transcriptome Point of Departure in Chemical Safety Assessment. Kamin Johnson, Corteva Agriscience, Indianapolis, IN.

" }, { "SessionID": 128, "Title": "Bridge over Adverse Waters: Integrating Pathology Findings into the Interpretation of Toxicology Studies", "Year": 2024, "Topic": "Drug Discovery", "Transcription": 0, "Description": " Register/Login

Chair(s):
Jonathan Maher, Pliant Therapeutics; and Marie Lemper, UCB S.A., Belgium.

Primary Endorser:
Drug Discovery Toxicology Specialty Section

Other Endorser(s):
Biotechnology Specialty Section; Comparative Toxicology, Pathology, and Veterinary Specialty Section

Although the design and results of a toxicity study follow general guidelines, at certain times, the actual interpretation of a study can be complex. Such interpretation, which encompasses multiple functional areas with an array of different endpoints, ultimately needs to assess whether any findings are detrimental to the animal and whether such a finding poses a risk to human health. One critical piece of the interpretation relies on gross, clinical, and anatomical pathology endpoints. Proper incorporation of these pathology data—and as such communication and exchange between the pathologist and toxicologist—is critical for this integrated analysis. There are many subtleties that are not often appreciated in the equation, including the phase of drug development, duration of the toxicity study, translational aspects, indication and risk/benefit of the therapeutic, and weight of evidence supporting the interpretation.

To address these aspects, this course is designed to first give an overview of toxicology studies and the pathology parameters and assessments during the drug development process. Once that basic understanding is established, the next step is to work through what adversity means in the context of toxicology and some of the challenges and implications of adverse findings. For example, can a finding be harmful to the animal but irrelevant to human health—or vice versa? How and where is such information communicated? When and how do investigational studies or endpoints help? An experienced set of speakers will address some of the best practices in interpreting pathology findings and walk through some challenging scenarios, including weight of evidence approaches that were utilized to contextualize a pathology finding where adversity was unclear. The last portion of the course will feature live polling to allow the audience to experience unique scenarios and make their own interpretations.

Understanding the Aversity to Adversity: Pathologists’ Perspectives on Adversity in Nonclinical Toxicity Studies. Helen Booler, Novartis Institutes for BioMedical Research, Basel, Switzerland.

The Interconnectivity between Pathology and Toxicology. Satoko Kakiuchi-Kiyota, Genentech Inc., South San Francisco, CA.

Integrating Clinical Pathology into the Assessment of Adversity. Paula Katavolos, Bristol Myers Squibb, New Brunswick, NJ.

Pathology Evaluation in Adversity and Weight of Evidence Decisions for Neurotoxic Findings in Nonclinical Studies. Brad Bolon, GEMpath Inc., Longmont, CO.

Alternative Approaches to Routine Histopathology in Drug Development: How Can Alternative Technologies Inform on Overall Risk Profile? Mark Hoenerhoff, Inotiv, Kalamazoo, MI.

How to Efficiently Anchor Pathology Discussions to Toxicology. Marie Lemper, UCB S.A., Belgium, Cambridge, MA.

" }, { "SessionID": 129, "Title": "Harnessing Toxicology in Pregnancy: Traditional and Novel Approaches to Placental Toxicology Research", "Year": 2024, "Topic": "In Vitro", "Transcription": 0, "Description": " Register/Login

Chair(s):
Almudena Veiga-Lopez, University of Illinois at Chicago; and Elana Elkin, San Diego State University.

Primary Endorser:
Reproductive and Developmental Toxicology Specialty Section

Other Endorser(s):
In Vitro and Alternative Methods Specialty Section; Women in Toxicology Special Interest Group

Pregnancy is considered among the most vulnerable life stages, for both the mother and the child. Despite being a critical bridge between the maternal exposome and fetal development, the placenta is an overlooked and severely understudied organ in reproductive toxicology. An appreciation and understanding of the placenta are critical to study design, execution, and interpretation of effects on pregnancy and fetal, and maternal health.

This first-of-its-kind SOT Continuing Education course on the placenta is composed of a diversity of early, mid-career, and established investigators from academia and government with expertise in placental toxicology that spans from basic bench research to human studies that capitalize on placental tissue as the basis for epidemiological work. The objectives for this course are to provide attendees with an overview of the basic biology of placental function and comparative biology across commonly used animal models. The course also will include placental toxicology approaches spanning cell-based techniques, including more traditional/routine approaches, to state-of-the-art approaches, such as placental chemical transfer and microfluidics, and ways to incorporate high-throughput analyses that can ultimately help inform regulatory decisions. The use of animal models in placental toxicology research, sample collection considerations, and study design of human cohort studies also will be covered.

Placental Biology Basics. Elana Elkin, San Diego State University, San Diego, CA.

Current Models for Studying Placental Toxicology. Sean Harris, University of Michigan, Ann Arbor, MI.

Novel Models of Placental Transfer for Toxicological Studies. Phoebe Stapleton, Rutgers, The State University of New Jersey, Piscataway, NJ.

Application of Molecular Epidemiological Approaches to Gain Mechanistic Understanding of How Prenatal Exposures Influence Fetal Development. Alison Paquette, Seattle Children’s Research Institute, Seattle, WA.

Use of High-Throughput Analyses in Placental Toxicological Studies. Bevin Blake, US EPA, Durham, NC.

Capitalizing on 3D and Microfluidic Technologies to Model the Placenta for Toxicological Studies. Almudena Veiga-Lopez, University of Illinois at Chicago, Chicago, IL.

" }, { "SessionID": 130, "Title": "Next-Generation Data Transparency and Open Science Policies: What Toxicologists Need to Know", "Year": 2024, "Topic": "Regulatory & Safety", "Transcription": 0, "Description": " Register/Login

Chair(s):
Paul Whaley, Lancaster University, United Kingdom; and Michelle Angrish, US EPA.

Primary Endorser:
Regulatory and Safety Evaluation Specialty Section

Other Endorser(s):
Continuing Education Committee; Occupational and Public Health Specialty Section

Open science and data transparency policies, particularly implementation of FAIR (Findable, Accessible, Interoperable, and Reusable) data principles in research, have become a major priority of US, national, and global research governance and funding organizations. The purpose of these policies is to make it easier to find, validate, analyze, reproduce, and reuse scientific data in an era when evidence about the health effects of chemical exposures is being generated faster than it can be cataloged and processed.

To help researchers and chemical assessment practitioners prepare for a near future in which open science standards are being implemented, this course will provide a comprehensive primer on what it means for data to be FAIR, a summary of what open science and data policies look like and how they support better regulatory science and public health decision-making, and a practical introduction to the open science workflows that researchers should anticipate engaging with to produce FAIR data. These workflows will include best practices for increasing credibility when working with sensitive or proprietary datasets that cannot be made openly available.

To achieve this, the course will present five expert perspectives on FAIR data and open science practices, with senior figures in research and publishing providing actionable advice aimed at helping participants prepare strategies for benefiting from FAIR data policies rather than being disrupted by them. There also will be a practical exercise that demonstrates how to provide the necessary support materials to make research data, code, and materials FAIR and reproducible. Finally, specific information needs of participants will be addressed through an interactive question-and-answer panel with speakers.

The target audiences for this session include (1) early career researchers who will need to implement open science policies at bench; (2) senior researchers running labs who need to know how to train their PhDs and postdocs in data standards compliance issues; (3) editors who, as the gatekeepers and publishers of research, will need to support scientists and the policy goals of funders and agencies; (4) contract research organizations and research consultancies that may be expected to comply with open data standards but also have to address proprietary concerns; and (6) funders who may want to support the policy goals of organizations such as the National Institute of Environmental Health Science through their independent grant programs.

Participants should note that any opinions expressed in the session reflect those of the individual presenters and not their employers or otherwise affiliated organizations.

Open Data Standards: What They Are and Why They Matter. Charles Schmitt, NIEHS, Durham, NC.

US EPA Plans for Developing, Supporting, and Using Open Data Standards. Michelle Angrish, US EPA, Durham, NC.

Practical Steps for Implementing FAIR Principles in Research. Kaitlyn Hair, University of Edinburgh, Edinburgh, United Kingdom.

An Unexpected Journey through Another Researcher’s Data. Researcher’s Data.

How Journals and Publishers Can Support Open Data Standards. Paul Whaley, Lancaster University, Lancaster, United Kingdom.

Tools to Facilitate Compliance with Open Data Standards. David Mellor, Center for Open Science, Charlottesville, VA.

Panel Q&A: Challenges and Opportunities in Data Standards—Your Questions Answered. All Presenters

" }, { "SessionID": 132, "Title": "Putting Theory into Practice: Using Computational New Approach Methodologies in Next-Generation Risk Assessment", "Year": 2024, "Topic": "Computational", "Transcription": 0, "Description": " Register/Login

Chair(s):
Kristie Sullivan, Institute for In Vitro Sciences Inc.; and Gavin Maxwell, Unilever.

Primary Endorser:
Computational Toxicology Specialty Section

Other Endorser(s):
In Vitro and Alternative Methods Specialty Section; Risk Assessment Specialty Section

Next-Generation risk assessment (NGRA) is an approach to understanding the potential risks of ingredients and chemicals using new approach methodologies (NAMs)—specifically to assess the exposure, bioactivity, and metabolic and kinetic behavior of a chemical for a specified use. Following an NGRA approach for any given chemical or use scenario usually involves building an Integrated Approach to Testing and Assessment, including nonanimal computational and in vitro methods, as well as relevant chemical-specific information. There is a recognized need for increased education about the NGRA approach in general but especially how information sources are selected and the data from them analyzed to decide whether to continue gathering more information or whether a decision can be made. A number of case studies have been published in the literature and reviewed by regulatory authorities in different contexts.

To show how NGRA concepts are being put into practice with a variety of tools and scenarios, this course will offer participants an opportunity to gain in-depth knowledge of the available computational approaches often used as the components of an NGRA through presentation of the basic structure and functional purpose of these approaches, supplemented by real-world application in case examples that have been or will be used in regulatory decision-making contexts. The course will begin with an introduction to NGRA concepts, the state-of-the-science, and the progress toward regulatory acceptance. In the second talk, participants will gain an understanding of key human exposure modeling approaches and how they can be used to estimate consumer and occupational exposure to a variety of ingredients and chemicals. Next, computational methods for deriving a quantitative effect level from in vitro bioactivity information using in vitro-in vivo extrapolation will be discussed, drawing on learnings from Health Canada and collaborative activities. Participants will understand how to integrate the information they have gathered as a weight of evidence and determining whether a safety decision can be made or more testing is needed after the fourth presentation by using case studies. The penultimate talk will discuss innovative activities to increase confidence in the use and acceptance of approaches for NGRA across regions and sectors, with special considerations relevant to computational approaches. Finally, additional educational resources to further the group’s overall knowledge of computational approaches to conduct NGRA will be provided by the last speaker, who also will incorporate audience participation. Together, these talks will help participants put NGRA approaches into daily practice through building a better understanding of how computational NAMs can support all stages of NGRA decision-making and by demonstrating available tools using case studies.

Next-Generation Risk Assessment Overview and Regulatory Landscape. Gavin Maxwell, Unilever, Bedford, United Kingdom.

Use of Computational New Approach Methodologies in Human Exposure Modeling. John Wambaugh, US EPA, Research Triangle Park, NC.

Use of Computational New Approach Methodologies in Bioactivity Characterization. Tara Barton-Mclaren, Health Canada, Ottawa, ON, Canada.

Use of Computational New Approach Methodologies in Next-Generation Risk Assessment Decision-Making. Alistair Middleton, Unilever, Bedford, United Kingdom.

Building Confidence in New Approach Methodologies to Support Next-Generation Risk Assessment. Nicole Kleinstreuer, NIEHS/NICEATM, Durham, NC.

Bridging the Gap: Educational Needs and Resources. Kristie Sullivan, Institute for In Vitro Sciences Inc., Gaithersburg, MD.

" }, { "SessionID": 133, "Title": "Use of New Approach Methodologies for the Assessment of Inhaled Substances: Examples and Case Studies", "Year": 2024, "Topic": "Inhalation", "Transcription": 0, "Description": " Register/Login

Chair(s):
Monita Sharma, PETA Science Consortium International; and Jessica Murray, US EPA.

Primary Endorser:
Inhalation and Respiratory Specialty Section

Other Endorser(s):
In Vitro and Alternative Methods Specialty Section; Women in Toxicology Special Interest Group

New approach methodologies (NAMs) anchored to known mechanisms of human toxicity are increasingly being used to assess the potential toxicity of inhaled substances. Various in silico and in vitro systems can be used to assess respiratory toxicity, and the selection of an appropriate system depends on multiple factors, including the goal of the study, physicochemical properties of the test substance, and biological effects of interest. Despite the need and the growing use, there is an obvious void in NAMs that are accepted for regulatory use related to respiratory toxicity. However, efforts are underway in fulfilling the gap with NAMs that are anchored to known mechanisms of human toxicity and well-characterized, which are critical parameters for their use for risk assessment in support of decision-making.

This course will cover specific examples of methods that are currently available to assess respiratory toxicity, including their technical challenges and refined dosimetry characterizations. This course will discuss case studies of how data are generated using these methods, anchored to adverse outcome pathways, and incorporated into Integrated Approaches to Testing and Assessment for risk assessment and hazard identification of inhaled substances. This course also will explore how to build scientific confidence in such methods to facilitate their use in decision-making and in regulatory acceptance of NAMs.

Establishing Confidence in New Approach Methodologies for Inhalation Toxicity Testing. Dave Allen, Inotiv, Durham, NC.

Human-Derived In Vitro and Ex Vivo Test Systems to Assess Respiratory Toxicity of Chemicals. Holger Behrsing, Institute for In Vitro Sciences Inc., Gaithersburg, MD.

Key Considerations for the Use of In Vitro Systems in the Evaluation of Inhalable Substances for Research and Testing. Shaun McCullough, RTI International, Durham, NC.

Regulatory Use of New Approach Methodologies for Inhalation Risk Assessment. Monique Perron, US EPA, Washington, DC.

Case Study on the Use of an Integrated Approach for Testing and Assessment for New Approach Methodology for Refining Inhalation Risk Assessment from Point-of-Contact Toxicity of the Pesticide Chlorothalonil. Marie Hargrove, Syngenta, Greensboro, NC.

" } ] }