Continuing Education

The Continuing Education (CE) Program offers a wide range of courses which cover established knowledge in toxicology and new developments in toxicology and related disciplines. SOT CE courses can be applied towards numerous different certifying and licensing board requirements both in the United States and around the world. Please be sure to review the specific requirements of your licensing board or certification for details. General courses are intended to provide a broad overview of an area or to assist individuals in learning new techniques or approaches, while courses based on more specialized topics are intended to be of interest to individuals with previous knowledge of the subject who are already working in the field.


All courses will be held on Sunday, March 10, 2019, at the Baltimore Convention Center. Please Note: Each CE course is offered in one of three time blocks:

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

Course books will be provided exclusively in electronic format in 2019.

2019 Courses

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


Sunday, March 10

7:00 AM TO 7:45 AM

SR01: Handling Uncertainties in Evaluating Mixtures: What’s the Difference between a “Similar” and a “Sufficiently Similar” Mixture?

SR01  SUNRISE MINI-COURSE

Course Book

Room:

CC Room 314

Chairperson(s):

Suzanne Fitzpatrick, US FDA, College Park, MD; and Mansi Krishan, Danone North America, Louisville, CO.

Primary Endorser:

In Vitro and Alternative Methods Specialty Section

Other Endorser(s):

Risk Assessment Specialty Section
Women in Toxicology Special Interest Group


Evaluating the safety and potential health risks from exposure to multiple chemicals, such as environmental chemicals, pharmaceuticals, consumer and personal care products, and pesticides and food contaminants, poses one of the major challenges for toxicological research and risk assessment. Significant advances have been made in recent years in better understanding and evaluating chemical mixtures. A key factor in risk assessments of chemical mixtures is the availability of reliable data on the identity, levels of exposure, toxicokinetics, toxicodynamics, and toxicological interactions for the whole mixture or its individual components.  Limited data or lack of data has a direct impact on uncertainty of the risk assessment of mixtures. As a result, risk assessment of chemical mixtures requires a lot of assumptions and uncertainty assessment. The commonly used risk assessment methods for chemical mixtures are whole mixture approaches and component-based approaches. The whole mixture approach is used when toxicological data are available for the mixture itself or toxicity data are available for a similar mixture or a sufficiently similar mixture that can be used as surrogate for the mixture of concern. This CE course will (1) provide an overview of challenges related to whole mixtures risk assessment and highlight approaches for evaluating sufficient similarity among related mixtures, and (2) present recent advances in safety assessment of complex mixtures using an alternative tiered approach, which utilizes in silico and in vitro approaches to identify safety data gaps and inform the need for additional studies. Attendees will be equipped to use similarity and sufficient similarity for whole mixtures, understand the assumptions, and understand how to address the uncertainties. This course would be of interest to scientists who conduct mixtures risk assessment in different sectors, such as occupational health and safety, product safety, public health protection, or regulatory decision-making. This sunrise CE course complements the previous CE courses and sessions at SOT on mixtures and focuses specifically on the uncertainty assessment aspect of similar and sufficiently similar mixtures, which has not be discussed before.


Assessing Human Health Risks from Whole Chemical Mixtures: An Overview. Glenn Rice, US EPA, Cincinnati, OH.

Novel Uncertainty Assessment Approaches for Evaluating Mixture of Concern, Sufficiently Similar Mixtures, or Similar Mixtures Using Case Studies. Amy Roe, Procter & Gamble Company, Cincinnati, OH.

SR02: Publicly Available Exposure Tools to Inform the Toxic Substances Control Act

SR02  SUNRISE MINI-COURSE

Course Book

Room:

CC Room 316

Chairperson(s):

John Wambaugh, US EPA/NCCT, Research Triangle Park, NC; and Kristin Isaacs, US EPA/NERL, Research Triangle Park, NC.

Primary Endorser:

Exposure Specialty Section

Other Endorser(s):

Risk Assessment Specialty Section
Specialty Section Collaboration and Communication Group


Exposure is a key component of chemical risk assessments, as highlighted by the recent amendment to the Toxic Substances Control Act mandating the US Environmental Protection Agency to consider conditions of chemical use, as well as human and ecological exposures across the chemical life cycle. The US EPA Office of Research and Development has many ongoing exposure modeling efforts that may be informative for chemical safety decisions. This sunrise CE course covers how 21st century exposure science tools could be used to inform chemical risk assessments. The first instructor will present a series of databases and models that are both peer reviewed and free to use. The second instructor will cover new, consensus exposure predictions for instances where minimal exposure data are available. Each lecture will provide examples that can be easily modified by course attendees for specific chemical risk assessment applications.


Publicly Available Exposure Data and Models. Kristin Isaacs, US EPA/NERL, Research Triangle Park, NC.

High-Throughput Exposure Forecasting. John Wambaugh, US EPA/NCCT, Research Triangle Park, NC.


8:15 AM TO 12:00 NOON

AM03: Assay Development Principles and Good Research Practices for Rigor and Reproducibility in In Vitro Toxicology

AM03  MORNING COURSE

Course Book

Room:

CC Room 314

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.

AM04: Complex Mixtures and UVCBs: Analysis, Testing, and Risk Assessment

AM04  MORNING COURSE

Course Book

Room:

CC Room 316

Chairperson(s):

Cynthia Rider, NIEHS/NTP, Research Triangle Park, NC; and Mansi Krishan, Danone North America, Louisville, CO.

Primary Endorser:

Mixtures Specialty Section

Other Endorser(s):

Food Safety Specialty Section
Regulatory and Safety Evaluation Specialty Section


A complex mixture, as defined in a 2018 update to the Agency for Toxic Substances and Disease Registry Framework for Assessing Health Impacts of Multiple Chemicals and Other Stressors, has many chemicals (often of different chemical classes), has a composition which may not be fully characterized, and can arise from a single source or multiple sources. The related, but more specifically defined, term, UVCB substances (Chemical Substances of Unknown or Variable Composition, Complex Reaction Products and Biological Materials), has been applied by both the US Environmental Protection Agency (US EPA) in the Toxic Substances Control Act (TSCA) Chemical Substance Inventory and the European Chemicals Agency (ECHA) under the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) regulations. Complex mixtures and UVCBs can include foods and beverages, personal care or consumer products, reaction by-products, emissions, and leachates. They can exhibit a wide array of physicochemical properties and fall under different regulatory jurisdictions. However, there are common principles that can be applied to these substances to gain an understanding of their complex chemistry and evaluate their toxicity and/or safety. Historically, the prevailing dichotomy was to either treat these substances as single entities, thereby ignoring their complex and often dynamic nature, or apply a reductionist approach that only considered a small subset of known constituents (i.e., identified chemical constituents with available toxicity data). Progress in analytical chemistry techniques, untargeted analyses, and in vitro screening tools have allowed for a more comprehensive and holistic approach to complex mixtures. In this course, state-of-the-science approaches for evaluating complex mixtures and UVCBs will be presented. It will begin with a presentation of the regulatory challenges and views of complex mixtures from the perspective of the US Food and Drug Administration (US FDA) Center for Food Safety and Applied Nutrition (CFSAN). Next, recommended methods for chemically analyzing complex mixtures and identifying biologically active constituents will be presented. Untargeted approaches for assessing complex mixtures, such as metabolomics and chemometrics, will be addressed. The use of in vitro assays and alternative animal models in screening complex mixtures will be discussed, with attention on successful applications and pitfalls to avoid. Additionally, available methods and software for combining chemical and biological assay data will be presented. Finally, existing methods for comparing across complex mixtures and determining sufficient similarity of related mixtures will be presented. Presentations will address chemistry, biological activity, and the intersection of the two, with an intentional focus on how these data can be used in safety evaluations of complex mixtures. Throughout the course, speakers will provide terminology and definitions and highlight tools using a diverse array of examples, representing distinct categories of complex mixtures and UVCBs. This course will be useful to those interested in understanding complex mixtures from a product development, research, or regulatory perspective. Course participants will be provided with both big picture context on complex mixtures and specific recommendations learned from application of the presented methods.


A Regulatory Perspective on Complex Mixtures. Brenna Flannery, US FDA/CFSAN, College Park, MD.

Characterization of Complex Mixtures to Enable Safety Assessments. Timothy Baker, Procter & Gamble Company, Cincinnati, OH.

Techniques to Identify Bioactive Constituents from Complex Mixtures: A Biochemometrics Approach. Joshua Kellogg, University of North Carolina, Greensboro, Greensboro, NC.

Evaluating Sufficient Similarity of Complex Mixtures: A Review of Case Studies. Cynthia Rider, NIEHS/NTP, Research Triangle Park, NC.

AM05: Developmental Toxicity of the Skeletal System: Interpretation of Findings in DART Studies and Implications for Risk Assessment

AM05  MORNING COURSE

Course Book

Room:

CC Room 321

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

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.

AM06: Industrial Application of Computational Toxicology in the 21st Century

AM06  MORNING COURSE

Course Book

Room:

CC Ballroom II

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.

AM07: Role of Toxicokinetics in Human Health Safety Assessments

AM07  MORNING COURSE

Course Book

Room:

CC Ballroom I

Chairperson(s):

Sabitha Papineni, Corteva Agriscience, Indianapolis, IN; and Anna Lowit, US EPA, Washington, DC.

Primary Endorser:

Risk Assessment Specialty Section

Other Endorser(s):

Biological Modeling Specialty Section
Comparative and Veterinary Specialty Section


Regulatory toxicity testing and risk assessment paradigms historically have been based on external doses, despite acknowledged scientific advantages in using systemic exposures.  Integrating toxicokinetics (TK) into regulatory toxicity testing provides an opportunity to develop more relevant data by utilizing systemic dose in animals and predicted (modeled) or measured blood levels of chemicals in humans. This provides a foundation for improved evaluation of human relevance, life-stage susceptibility, mode-of-action or adverse outcome pathway, route-to-route extrapolation, and dose selection. In addition, there is increased emphasis on improving toxicity testing and safety assessment in alignment with the Three R’s principles of animal welfare (replace, reduce, refine), and expanded use and collection of TK information reduces the overall use of animals by eliminating unnecessary or redundant tests and provides more humane dose selections, which are less physiologically stressful on the animals. As with any effort, the challenge lies in harmonization of these approaches across the globe. Increased awareness and communication of the benefits of these approaches is key for global harmonization. This course aims to increase knowledge on the principles of TK and will enable students to explore the opportunities that TK offers to risk assessment (all steps: hazard identification, dose-response assessment, exposure assessment, risk characterization) and provide a forum for students to hear from scientists of varying backgrounds and sectors—regulatory, academic, and industry. There have been many advancements in technology and increased emphasis by regulatory agencies to collect TK data. However, the implementation and applicability of this data in regulatory toxicity testing have lagged considerably. The first talk will introduce the topic and present the basic principles of TK, and also will provide an understanding of why and when TK is useful for investigating issues in toxicology. The second presentation will review the experience of integrating and utilizing knowledge of TK in preclinical safety testing of pharmaceuticals. The third presentation will describe the standard testing protocols, technical details, and considerations to integrate TK in standardized guideline studies without use of additional animals and making the guidelines relevant to assessing risks to human health. The fourth presentation will describe the view of the European Food Safety Authority (EFSA) on integration of TK in safety assessments and also will discuss all the available tools, using relevant case studies. The final presentation will provide a regulatory overview of integration of TK into various steps in the risk assessment process, using case studies to demonstrate how TK data have been used in pesticide risk assessment to improve the science underlying regulatory decision-making. Overall, this course will provide the needed background and approaches to implement TK, using practical examples that will enable the attendees to have a better appreciation of its utility in risk assessment of and decision-making regarding chemicals for human health. This course also will highlight the shift toward utilization of high-throughput toxicity screening and nonanimal methods that both are in alignment with 3R principles and offer cost- and resource-effective means to prioritize chemicals. Thus, this course will be of a broad interest to testing laboratories, general toxicologists, and risk assessors across different sectors, including academia, regulatory agencies, and industry.


An Introduction to Toxicokinetics. Curtis Klaassen, University of Kansas College of Medicine, Kansas City, KS.

Pharmaceutical Industry View of Toxicokinetics. Emile Chen, GlaxoSmithKline plc, Chester Springs, PA.

Integration of Toxicokinetics in Toxicity Studies. Sabitha Papineni, Corteva Agriscience, Indianapolis, IN.

Integration of Toxicokinetics in Food and Feed Risk Assessment at the European Food Safety Authority: Principles, Available Tools, and Case Studies. Jean-Lou Dorne, European Food Safety Authority, Parma, Italy.

US EPA Perspective on Implementation of Toxicokinetics in Agrochemical Safety Assessments. Anna Lowit, US EPA, Washington, DC.

AM08: Mechanistic Understanding and Quantitative Risk Assessment in Immunotoxicology

AM08  MORNING COURSE

Course Book

Room:

CC Ballroom IV

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.


1:15 PM TO 5:00 PM

PM09: Applications and Review of Physiologically Based Pharmacokinetic Modeling for Regulatory Risk Assessment

PM09  AFTERNOON COURSE

Course Book

Room:

CC Room 316

Chairperson(s):

Jeffrey Fisher, US FDA/NCTR, Jefferson, AR; and Cecilia Tan, US EPA, Durham, NC.

Primary Endorser:

Risk Assessment Specialty Section

Other Endorser(s):

Biological Modeling Specialty Section
Exposure Specialty Section


Physiologically based pharmacokinetic (PBPK) modeling is widely recognized as a scientifically sound approach to characterize uncertainty in the quantitative relationship between external and internal exposures. The number of regulatory reviews of PBPK models has risen significantly in recent years to support decision-making regarding safety of environmental chemicals and pharmaceutical compounds. For environmental chemicals, PBPK modeling allows for extrapolations across species, life stages, and exposure routes/frequencies, and interpretation of human biomarker measurements. For pharmaceutical compounds, PBPK modeling can be used to identify the need for dose adjustments in subpopulations, the potential for drug-drug interaction, and undesired pharmacokinetics properties such as low bioavailability or rapid clearance. The application of PBPK models to support regulatory risk assessment requires thorough vetting in the context of whether the model’s performance is appropriate for its intended purpose. However, the growing list of applications and different acceptance criteria among agencies and across countries have increased the need for a more standardized approach to both model submission and review processes. To achieve such a goal, this course is designed to provide an overview of how PBPK models might be applied to investigate health outcomes resulting from exposures to environmental or pharmaceutical compounds, as well as to discuss what the key elements being reviewed by different regulatory agencies. This overview will help to promote dialogue among developers, users, and evaluators of PBPK models across government, industry, and academia who seek to establish consistent model submission and review practices. In addition, this course provides training to both modelers and nonmodelers, with the purpose of increasing the pool of potential peer reviewers for regulatory agencies so that they can conduct proper review of models in a timely fashion. To accomplish these training goals, topics to be covered in this course include the principles of pharmacokinetics, fundamental concepts underlying PBPK modeling, data needs, and quality assurance during model development and implementation. The overarching objectives of this course are to highlight opportunities for harmonizing model submission and review processes and to increase the likelihood of model adoption at regulatory agencies. (Disclaimer: The views expressed in this abstract are those of the authors and do not represent Agency policy or endorsement.)


Introduction. Jeffrey Fisher, US FDA/NCTR, Jefferson, AR.

Physiologically Based Pharmacokinetic Modeling and Simulation 101. Andrea Edginton, University of Waterloo, Waterloo, ON, Canada.

Applications of Physiologically Based Pharmacokinetic Models in Clinical Pharmacology. Yuching Yang, US FDA/CDER, Silver Spring, MD.

Physiologically Based Pharmacokinetic Model Construction and Data Needs for Environmental Chemicals. Paul Hinderliter, Syngenta, Greensboro, NC.

Quality Assurance Review of Physiologically Based Pharmacokinetic Models for Regulatory Use. Jordan Smith, Pacific Northwest National Laboratory, Richland, WA.

PM10: Beauty of the Skin Is in the Eye of the Beholder: A Basic Course on Dermal and Ocular Toxicology

PM10  AFTERNOON COURSE

Course Book

Room:

CC Ballroom IV

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.

PM11: Conducting Systematic Review in Toxicology—Why, When, How?

PM11  AFTERNOON COURSE

Course Book

Room:

CC Room 321

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.

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.

PM12: Current Dose-Response Modeling Strategies and Applications in Chemical Risk Assessment

PM12  AFTERNOON COURSE

Course Book

Room:

CC Ballroom II

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.

PM13: Microbiome and Environmental Toxicants: From Study Design and Analysis to Regulatory Guidance

PM13  AFTERNOON COURSE

Course Book

Room:

CC Room 314

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.

PM14: Structural and Functional Alterations of Mitochondria in Chemically Induced Cytotoxicity

PM14  AFTERNOON COURSE

Course Book

Room:

CC Ballroom I

Chairperson(s):

Hilmi Orhan, Ege University, Izmir, Turkey; and Hartmut Jaeschke, University of Kansas Medical Center, Kansas City, KS.

Primary Endorser:

Mechanisms Specialty Section


Mitochondria are critical subcellular organelles, as they provide more than 95% of the energy for biochemical and physiological functions, in addition to playing a critical role in lipid metabolism, steroidogenesis, and programmed cell death. In the context of this course, both structural and functional features of the mitochondria will be addressed. Involvement of mitochondria in health and in drug-induced cellular and subcellular toxicities will be discussed, and the practical applications will be described. In the first lecture of this course, the prominent role of mitochondrial toxicity in adverse outcome pathways (AOPs) mechanistically describing a wide spectrum of organ-specific toxicities will be demonstrated. In the second lecture, the central role of mitochondria in drug-induced programmed necrosis and the impact of adaptive mechanisms such as autophagy and mitochondrial biogenesis on cell survival and regeneration will be highlighted. The third lecture will focus on evaluation of mitochondrial function by confocal and multiphoton microscopy, and measurement of respiration and glycolysis. In the last lecture, the metabolic capacity of mitochondria in terms of local reactive metabolite generation, as well as toxicological outcomes, will be discussed.


Mitochondrial Toxicity: A Frequent Key Event in Adverse Outcome Pathways. Mathieu Vinken, Vrije Universiteit, Brussels, Belgium.

Mitochondria as Critical Regulators of Drug-Induced Organ Toxicity and Recovery. Hartmut Jaeschke, University of Kansas Medical Center, Kansas City, KS.

Assessment of Mitochondrial Dysfunction in Drug- and Oxidant-Induced Cytotoxicity. John Lemasters, Medical University of South Carolina, Charleston, SC.

Local Bioactivation of Drugs and Other Chemicals in Mitochondria: Toxicological Outcomes. Hilmi Orhan, Ege University, Izmir, Turkey.

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