In 2014, SOT and the US FDA Center for Food Safety and Applied Nutrition (CFSAN) began a partnership to present colloquia designed to present high-quality, cutting-edge, future-oriented toxicological science to provide a well-grounded, foundation to inform the work of US FDA employees. These colloquia are open at no cost to all who are interested. Recordings and materials are available after the events and can be found below.
Application of In Vitro to In Vivo Extrapolation in Safety Assessment—December 1, 2016
Chair: Richard A. Becker, PhD, DABT, American Chemistry Council, Washington, DC
Co-Chair: Lisa M. Sweeney, PhD, DABT, Naval Medical Research Unit Dayton, Dayton, OH
Timothy J. Shafer, Chair, US EPA, Research Triangle Park, NC
Jeffrey J. Yourick, Co-Chair, US FDA, Laurel, MD
Development of the nervous system is a complex process that is critically important for normal function and it is vulnerable to both endogenous and exogenous factors. There is increasing awareness among scientists and regulators that neurodevelopment is a critical window of susceptibility for childhood and adult-onset diseases. A growing concern among the general public is that exposures to some environmental factors, dietary components or consumer products may contribute to neurodevelopmental decrements. Novel experimental approaches and scientific concepts are being developed to address the need for more informative and comprehensive testing for the potential developmental neurotoxicity effects of chemicals.
The colloquium will begin with an overview of neurodevelopment and discuss the current state-of-the-art in developmental neurotoxicity assessment. Second, advances in the use of whole-animal alternative models, such as zebrafish, in evaluating developmental neurotoxicity will be discussed. Third, an overview of in vitro alternative models and screening batteries to assess developmental neurotoxicity will be presented. Fourth, the framework of adverse outcome pathways will be used to demonstrate the utility of novel data streams from alternative species and in vitro assays to improve mechanistic understanding of how chemicals elicit developmental neurotoxicity. Finally, the colloquium will conclude with a panel discussion addressing the key issues brought up by the speakers and questions from participants.
Welcome and Introductions
US FDA Welcome and Overview, Mickey Parish, PhD, Acting Director of the Senior Science Advisor Staff, CFSAN, US FDA, College Park, MD
Welcome from SOT and Introductions, Peter Goering, PhD, SOT President, US FDA, Silver Spring, MD
Speaker Introductions, Timothy Shafer, Chair, US EPA, Research Triangle Park, NC
Developmental Neurotoxicity Testing: An Introduction to the State of the Science and Opportunities for Improvement
Charles V. Vorhees, Cincinnati Children’s Hospital Research Foundation, Cincinnati, OH
Zebrafish as an Alternative Species for Developmental Neurotoxicity Testing that can Provide Hazard Identification and Mechanistic Information
Randall T. Peterson, Harvard University, Boston, MA
In Vitro Approaches to Screening Compounds for Developmental Neurotoxicity Hazard
Ellen Fritsche, University of Düsseldorf, Düsseldorf, Germany
Adverse Outcome Pathways for Developmental Neurotoxicity
Anna K. Price, ECVAM, Ispra, Italy
Allen Rudman, Chair, US FDA, CFSAN, College Park, MD
Elaine Faustman, Co-Chair, University of Washington, Seattle, WA
For over a decade we have recognized that children and infants are not simply little adults (WHO Training Report, 2008) and many initiatives and research during life stage have supported this concept. The implications of this statement have had many manifestations. In this colloquium we will focus on early childhood (from birth to 5 years of age) to examine what those general differences are, provide examples of the differences in this age group, and discuss safety assessment approaches that are being used and proposed.
The first presentation will lay the groundwork for this concept and provide an introduction to example case studies that illustrate the importance of safety assessment approaches in early childhood. The second talk will focus on pharmacokinetic considerations that provide a mechanistic basis for our assessments. Critical drug metabolism differences underlie many of the measureable differences for children during early childhood. The speaker will share these new observations and resources to find out information about age dependent metabolism differences. Discussion will include examples from the neonatal, post birth surge in metabolism capabilities as well as slower trajectory of some metabolism capabilities before reaching adult activities. The third talk will provide insight from industry including new models for predicting and modeling responses in early childhood. The current regulatory science behind food safety assessments to protect children during this critical window of susceptibility will be the focus of the concluding presentation. Case studies will be provided and a panel discussion will enhance interaction with the attendees.
Welcome and Introductions
US FDA Welcome and Overview, Suzanne Fitzpatrick, PhD, ATS, CFSAN, US FDA, College Park, MD;
Welcome from SOT, Peter Goering, PhD, DABT, ATS, SOT President, US FDA, Silver Spring, MD
Speaker Introductions, Allen Rudman, PhD, CFSAN, US FDA, College Park, MD
Children Matter: Using a Lifecourse Approach to Understanding Safety Assessment Needs for Children
Elaine Faustman, University of Washington, Seattle, WA
Early Life Development of Pharmacokinetic Pathways: Framework and Case Examples with Implications for Safety Assessment
Gary Ginsberg, Connecticut Department of Public Health, Hartford, CT
Ensuring Safety for Early Life Exposures: Adequacy of Current Methods and Opportunities to Advance the Science
Susan Felter, Procter & Gamble Company, Mason, OH
Toxicology Challenges in Lifestage-Specific Safety Assessments
April Neal-Kluever, US FDA, College Park, MD
Ivan Rusyn, Chair, Texas A&M, College Station, TX
Timothy Adams, Co-Chair, US FDA, College Park, MD
The Threshold of Toxicological Concern (TTC) is a risk assessment approach aimed at deriving a level of human intake or exposure to a chemical that is perceived to be of negligible risk, despite the absence of chemical-specific toxicity data. The original Cramer Decision Tree was proposed in 1978 for the classification of chemical substances of concern and was the basis for the subsequent adoption of the TTC approach. TTC has been originally developed to qualitatively assess the risk of low-level substances in the diet, but is now used frequently to determine whether a comprehensive risk assessment is required for a broad range of chemicals. It also has been a major advance in the prioritization and evaluation of food substances with low exposure scenarios. The application of the TTC approach to a broader universe of chemicals and routes of exposure has been the main focus of recent research, along with a number of proposals for the revision of the Cramer Decision Tree. However, an updated Cramer Decision Tree would require collection and integration of a database of information on species- and sex-specific toxicology, chemistry, dose-dependent metabolism, pharmacokinetics, and mechanism of action for a chemical space related to food exposure.
The objectives of this colloquium include a review of the evolution of the Cramer Decision Tree and TTC approach, presentation of possible revisions to the original Cramer Decision Tree and its impact on TTC levels for other routes of exposure, and a discussion of the possible expansion of the Cramer Decision Tree or other computational approaches to more diverse chemicals, multiple structural classes, and the chemical specificity of questions.
US FDA Welcome and Overview, Mary Torrence, Director, Office of Applied Research and Safety Assessment Laboratories (OARSA), US FDA, College Park, MD; and Welcome from SOT and Introductions, Peter Goering, PhD, SOT President, US FDA, Silver Spring, MD
Threshold of Toxicological Concern Approach in Regulatory Decision-Making: The Past, Present, and Future
Grace Tier, US EPA, Research Triangle Park, NC
Advancements in Food Ingredient Safety Prioritization: An Expanded Cramer Decision Tree Schema
Timothy Adams, US FDA, College Park, MD
In Silico Methods for Threshold of Toxicological Concern Assessment
Andrew Worth, European Commission, Joint Research Centre, Ispra, Italy
Quantitative Prediction of Continuous Toxicity Values using Chemical Structure Information
Jessica Wignall, ICF International, Arlington, VA
Suzanne Fitzpatrick, Chair, US FDA, College Park, MD
Jieun Lee, Co-Chair, Kellogg, Battle Creek, MI
Among the primary goals of a risk assessment are 1) determination of the presence or absence of a cause-effect relationship and 2) quantifying the risk through dose-response analysis. Dose-response data may be derived from in vivo studies in animals or humans, which usually provide the basis for risk characterization, and in vitro studies, which are often related to investigations of mode of action (MOA). MOA information describes key events and processes that would explain the overall process of development of a toxic effect. MOA can also be relevant in considering susceptibility factors within populations and in considering the cumulative effects of exposure to more than a single agent. Over the last several years, advances in our understanding of the ways that chemicals interact with biological systems have yielded several frameworks for evaluating toxicity datasets to determine biologically plausible modes of action and relevance to humans. These frameworks can be used to consider the weight of evidence of hypothesized modes of action in animals and their potential human relevance for both cancer and non-cancer effects. This could result in a move away from defaults to adopt modern knowledge on MOA to improve risk assessments, including the choices for dose-response assessment.
This symposium will include an overview talk about dose-response, including recommendations from the NRC Silver Book; a discussion of mode of action including definition, differences from mechanism of action, and some framework key events; a case study of the choices in dose-response analysis for a mutagenic mode of action; and recommendations from the Risk21 project on the role of key events in deciding on the dose-response analysis.
Welcome and Introductions
Betty Eidemiller, Society of Toxicology, Reston, Virginia, and Elaine Faustman, University of Washington, Seattle, WA
The Role of Mode of Action in Dose-Response Assessments: Recommendations from the 2009 NRC Report “Science and Decisions”
Lauren Zeise, NRC Committee Member, Berkeley, CA
Mode of Action, Distinguishing between Mode and Mechanism of Action, and Some Key Events for MOA
Michael Dourson, TERA, Cincinnati, OH
The Mutagenic Mode of Action and the Choices for the Dose-Response Analysis
Rita Schoeny, US EPA (retired), Washington, DC
Risk21 Quantitative Key Events Dose-Response Framework
J. Craig Rowlands, Dow Chemical Company, Midlands, MI
Roundtable Discussion and Conclusion
Elaine Faustman, University of Washington, Seattle, WA, Moderator
New data types, primarily from in vitro tests, and an ever-increasing plethora of computational tools for in silico modeling have ushered in the era of “big data” in investigative toxicology. Practitioners in the field of human health assessments are transitioning rapidly away from lamenting a lack of data to drowning in a deluge of information. There is a clear opportunity for a paradigm shift toward high-throughput risk assessment and non-traditional data-based regulatory decision-making; however, only very recently has the information from rapid screening, in silico modeling, and prioritization efforts begun to make inroads into human health decisions. This colloquium is following up on the “Contemporary Issues in Risk Assessment” (June 17, 2015) colloquium and extends the discussion to the use of new computational and in vitro science, approaches, and technologies for risk assessment and regulatory decision-making.
Specifically, this session will cover (1) an overview of risk- and hazard-based decision contexts at the US FDA; (2) a case study of replacement of an animal test with a battery of in vitro tests; (3) examples of how in vitro and in silico data aid in developing category and analogue read-across; and (4) the use of in vitro data to fill in data gaps in a traditional cancer hazard assessment. Overall, the learning objective for this session is to demonstrate recent examples of the implementation of the novel information streams from computational and in vitro methods into the practice of risk assessment across a wide array of decision contexts.
US FDA and SOT Welcome and Overview
Suzanne Fitzpatrick, US FDA/CFSAN, College Park, MD
Peter Goering, PhD, SOT President, US FDA, Silver Spring, MD
Development of In Silico Tools at OFAS CFSAN FDA
Patra Volarath, US FDA/CFSAN, College Park, MD
Gaining Confidence in Replacing Animal Tests: A Case Study of the Endocrine Disruption Program at the US EPA
Richard Judson, US EPA/NCCT, Research Triangle Park, NC
Read-Across with Computational and In Vitro Data
Elisabet Berggren (by webinar), Joint Research Centre, European Commission, Ispra, Italy
Use of Computational and In Vitro Data in Cancer Hazard Assessment of Data Rich Chemicals: Examples of IARC Monographs
Ivan Rusyn, Texas A&M University, College Station, TX
The National Academies of Sciences committee that produced a report “Science and Decisions: Advancing Risk Assessment” (NRC, 2009) recommended that “risk assessment should be viewed as a method for evaluating the relative merits of various options for managing risk rather than an end in itself.” How can the federal government best accomplish this goal? This session will focus on recent improvements in the practice of human health assessments. Exciting advances in the methods and best practices, consistent with the advice from the National Academies, have been made in the recent years and implemented by a number of stakeholders. Specifically, this session will cover the lessons learned from (1) problem formulation and protocol development in chemical-specific human health assessments; (2) evidence identification and transparent criteria for inclusion and exclusion of the individual studies in the assessment; (3) harmonization of the cancer and non-cancer dose-response assessments; and (4) the use of the mechanistic data in support of human health assessments. Overall, the learning objective for this session is to demonstrate tangible examples of the implementation of the best practices in risk assessment to illustrate how the field is evolving to meet the needs of various stakeholders.
Welcome, Overview, and Speaker Introduction
Suzanne Fitzpatrick, Colloquium Chair, US FDA Center for Food Safety and Applied Nutrition, College Park, MD
Peter L. Goering, SOT President, FDA, Silver Spring, MD
Ivan Rusyn, Organizing Committee Chair, Texas A&M, College Park, MD
Problem Formulation and Scoping for Human Health Assessments
Juleen Lam, University of California San Francisco, San Francisco, CA
Identification and Selection of the Evidence Base for Human Health Assessments
Kathryn Guyton, International Agency for Research on Cancer Monographs Programme, Lyon, France
Harmonizing Dose-Response Assessment for Cancer and Non-Cancer Endpoints in Human Health Assessments
Weihsueh Chiu, Texas A&M University, College Station, TX
The following Excel® files were used to conduct the case study examples discussed in this presentation, and are provided to help users better familiarize themselves with the approaches described. Specifically, the “BMDS Wizard” files are used to conduct benchmark dose modeling based on US EPA Benchmark Dose Software (BMDS), and the “APROBA” files are used to conduct probabilistic dose-response assessment based on a framework and approach developed by the WHO/IPCS. Execution of the macros in the BMDS wizard files requires that the computer have US EPA BMDS installed.
Deoxynivalenol Case Study—BMDS Wizard file
Deoxynivalenol Case Study—APROBA file
Methyleugenol Case Study using 10% extra risk—BMDS Wizard file
Methyleugenol Case Study using 10% extra risk—APROBA file
Methyleugenol Case Study using 1% extra risk – BMDS Wizard file
Methyleugenol Case Study using 1% extra risk—APROBA file
Note: Case studies using BMDS wizard requires that the computer running the BMDS wizard has BMDS installed.
The focus of this colloquium is on the methods used in safety assessment of substances present in foods that may target the immune system. The immune system is a complex set of cellular, chemical, and soluble mediators that protects the body against foreign substances. Immunotoxicology is the subdiscipline of toxicology that focuses on unintended modulation of the immune system following exposure to environmental chemicals or therapeutics. Adverse effects may include immunosuppression, immunostimulation, allergic hypersensitivity, or autoimmunity, and may result in outcomes such as increased incidences of infectious diseases or neoplastic diseases, allergy/asthma, or autoimmune diseases, respectively. The majority of immunotoxicity testing efforts to date have focused on the potential for xenobiotics to suppress immune function or induce dermal sensitization. With the increased use and development of immune-based or immune-targeted therapeutic proteins, unintended stimulation of the immune system has also become an area of concern. The colloquium will begin with a brief overview of the cells and soluble mediators critical to immune function and the tiered testing strategies used to identify substances that may target immune effectors. Following this introduction, experts will provide a state of the art review of methodological approaches using case studies to elucidate how immunotoxicology data can be used in assessing the safety of ingested materials.
Welcome and Overview
Susan Mayne, PhD, Director, US FDA Center for Food Safety and Applied Nutrition
Peter L. Goering, PhD, SOT Vice President, US FDA
Introduction to Immunology and Immunotoxicology
Dori R. Germolec, PhD, Immunology Discipline Leader, Toxicology Branch, National Toxicology Program, National Institute for Environmental Health Sciences
Immunomodulatory Effects of Perfluoroalkyl Substances in Rodents and Humans
Jamie DeWitt, PhD, Assistant Professor, Department of Pharmacology & Toxicology, Brody School of Medicine, East Carolina University
Toxicology and Food Allergy: Case Study of tBHQ
Cheryl Rockwell, Assistant Professor, Department of Pharmacology & Toxicology, Michigan State University
Dietary Supplement Modulation of Autoimmune Disease
Prakash Nagarkatti, PhD, Vice President for Research, University of South Carolina
The focus of this colloquium is on the application of ADME/PK studies to improve safety assessments for foods and cosmetics. Pharmacokinetic data on the time-course of a chemical in the body can be used to support the key extrapolations that are typically necessary for chemical risk assessments. In the past, the primary concern has been to extrapolate the doses in animal studies showing effects to equivalent doses in the human. With the recent emphasis on in vitro-based risk assessment, pharmacokinetic information is now being used to support the extrapolation from media concentrations associated with effects in vitro to the equivalent in vivo dose. This colloquium will provide a synopsis of the current state of the art for the application of pharmacokinetic data and modeling to risk assessments for foods, food contaminants and cosmetic ingredients. Three case studies will be provided illustrating the process of incorporating pharmacokinetic data in risk assessments based either on traditional or emerging toxicity study approaches. A panel discussion will enhance interaction with the attendees.
US FDA Welcome
Dennis Keefe, PhD, Director, Office of Food Additive Safety Center for Food Safety and Nutrition
Overview: Value of ADME/PK Studies in Safety Assessment
Harvey J. Clewell, PhD, DABT, FATS, Director , Center for Human Health Assessment The Hamner Institutes for Health Sciences
The Importance of ADME/PK to Inform Human Safety Assessments Based on Animal Studies: Example with Furan
Gregory L. Kedderis, PhD, Independent Consultant
The Role of ADME/PK in the Extrapolation of In Vitro Toxicity Results to Equivalent In Vivo Exposures: Where It Started with the Acrylamide Example and Where We Are Now
Bas Blaauboer, Institute for Risk Assessment Sciences, Utrecht University
Consideration of ADME/PK in Safety Assessments for Engineered
William Boyes, PhD, USEPA/NHEERL
Setting the Case Study Framework—An Introduction to PHOs
Martin Ronis, PhD, Professor, Department of Pediatrics, Department of Pharmacology & Toxicology, University of Arkansas for Medical Sciences, Associate Director for Basic Research, Arkansas Children’s Nutrition Cente
Mode of Action and Dose-Response Evaluation of the Effect of Partially
Michael L. Dourson, PhD, DABT, ATS
Dose-Response Assessment Approaches to the Analysis of Non-Cancer Health Effects: Current Practices, Advice from the National Academies, and 2014 WHO/IPCS Guidance
Weihsueh A. Chiu, PhD, Chief, Toxicity Pathways Branch Integrated Risk Information System (IRIS) Division National Center for Environmental Assessment Office of Research and Development US Environmental Protection Agency