44th Summer Meeting Program Overview
The scientific program of The Toxicology Forum’s 44th Annual Summer Meeting features a series of diverse scientific sessions that bring together differing scientific viewpoints from leading government regulators, industry scientists, and academic researchers for dynamic presentations and discussions on emerging topics in toxicology. The format of meeting sessions at The Forum allows for sustained dialogue between speakers and audience members with opportunities not found at other meetings.
Use of Alternative Liver Models for Hepatotoxicity and Disease Progression—The Future of Practical Applications for Evaluating Compound Efficacy and Toxicity▸
Moderated by Esther Haugabrooks, Physician's Council for Responsible Medicine and Miyoung Yoon, ToxStrategies, Inc.
The study of hepatotoxicity in nonanimal models has progressed over recent decades. Uses of alternative liver models are still expanding to cover areas such as in vitro to in vivo extrapolation and disease progression. Moreover, the practical regulatory application of alternative models has not been explored to the extent merited, considering these methodologies have great potential to overcome the well-known, human relevance limitations of the historical models used to study compound efficacy and toxicity. This session will address various approaches, including the incorporation of human data and physiologically based pharmacokinetic modeling, for open discussion of the follow central issues:
· Exploring safety evaluations that utilize in vitro, in silico, and other approaches, discussing lessons learned, and addressing application to regulatory acceptance of modern liver models
· Highlighting practical approaches that overcome species-specific differences in liver pathways while providing more human relevant assessments
Building on the Science: Possible Opportunities to Reduce Toxicity Testing and Better Allocate Resources for Evaluating Ecological Risk▸
Moderated by Thomas Steeger, US EPA
Since publication of the NAS vision/strategy for toxicity testing in the 21st Century, there has been an increased emphasis on moving away from a heavy reliance on whole organism testing. Regulatory programs have relied heavily on such tests given that it is tasked with assessing risk from products which are intended to be toxic. However, the expanding chemical space and limitations on risk assessment resources suggest a growing need for more efficient and reliable testing strategies. While high through-put assays and efforts to delineate Adverse Outcome Pathways have focused on mammalian systems similar efforts for assessing exposure and effects and estimating risk to non-mammalian taxa have lagged. Risk assessors have expressed concerns regarding the extent to which new methods can address uncertainties related to cross-taxa extrapolations, but are examining opportunities to expand the use of new approach methodologies (NAMs) and retrospective analyses of existing data to reduce testing needs. While some program offices within EPA have extensive experience/reliance on predictive approaches (e.g., [quantitative] structure-activity relationships) to support regulatory decisions; there are opportunities to expand the chemical space over which these tools could be applied. This symposium would provide a venue for discussing current obstacles and potential solutions of reducing animal use and adopting NAMs for use in ecological risk assessment.
Integration of Toxicokinetics and the Kinetically-Derived Maximum Dose into Toxicity Testing and Risk Assessment▸
Moderated by Jean Domoradzki, Dow AgroSciences
Absorption, distribution, metabolism and excretion (ADME)/ Toxicokinetic (TK) data are an important aspect of chemical safety assessment and provide insights into in vitro evaluations, IVIVE extrapolations, toxicity testing designs, study interpretation and human health risk assessment.
Integrating TK into toxicity testing (without the use of additional animals) provides data on systemic exposure and any saturation of ADME processes. Saturation of any biological process should be evaluated for its relevance to dose-response relationships relative to human exposure. Systemic dose non-proportionality should not be treated any differently from toxicity findings due to excessive stress indicated by the conventional MTD approach. Determination of whether the onset of TK nonlinearity is well separated from human exposure is increasingly possible given improvements in modeling and biomonitoring analyses supporting human environmental exposure assessments.
Risk assessment is driven by “external doses” administered to animal in toxicity testing strategies. Evaluation of “internal exposure” (TK) alongside toxicodynamic characterization has been supported by numerous publications and regulations. ‘Integration of TK into human health risk assessment’ would describe a framework of benefits of TK in all steps of human health risk assessments from understanding the hazard of a chemical to its relationship with human exposures.
Central Issue to be Addressed:
• Integrating TK into toxicity testing provides data on systemic exposure and any saturation of ADME processes
• Saturation of any biological process should be evaluated for its relevance to dose-response relationships relative to human exposure
• Risk assessment is driven by “external doses” administered to animal in toxicity testing strategies.
• Integration of TK into human health risk assessment’ would describe a framework of benefits of TK in all steps of human health risk assessments from understanding the hazard of a chemical to its relationship with human exposures.
From Bio-Concentration in Aquatic Organisms to Bio-Accumulation in Humans: How the Use of Bio-Concentration Factors (Bcfs) Underestimate PFAS Bio-Accumulation Risks to Humans▸
Moderated by Jamie DeWitt, East Carolina University and Susanne Brander, Oregon State University
Per- and polyfluoroalkyl substances (PFASs) currently are a global focus for agencies charged with protecting public and ecological health, both because of their widespread presence in environmental media, including humans and other biota, and because of awareness of the general public about their potential adverse health effects. Due to the phase out of PFASs that are termed “long-chain,” alternative/novel/replacement chemistries are being implemented into various industrial processes and products. While many of these are environmentally persistent due to the inherent strength of the carbon-fluorine bond, their bioaccumulation potential may be underestimated.
Central Issue to be Addressed:
Appropriate tests for evaluation of bioconcentration/bioaccumulation and toxicity for replacement PFASs
Moderated by Marusia Popovech, ExxonMobil Biomedical Sciences
The safety of food contact materials (FCMs) is evaluated using risk assessment methods, which incorporate both hazard and exposure based assessments. Recent publications (Maffini 2017; Muncke, 2017) have called into question the adequacy of current regulations for evaluating the safety of food contact materials. Alternative toxicology assays and methods for risk assessment, developed over the last few years, are now being proposed for use in regulatory decisions. New recommendations include a focus of risk assessments on finished food contact articles, avoidance of the use of chemicals with unknown toxicity and end use of TTC, toxicologic assessment of migration products or FCM extracts, addition of toxicologic testing on cardiovascular, metabolic, and endocrine endpoints for all FCMs and food contact articles, and use of 3rd party risk assessment. Dialogue on FCM risk assessment among the scientific community is needed in order to come to a consensus on best practices prior to their use for regulatory purposes.
US FDA’s Predictive Toxicology Road Map—A Six-Part Framework for Integrating Predictive Toxicology Methods into Safety and Risk Assessments▸
Moderated by Suzanne Fitzpatrick and Ronald Brown, US FDA
The cumulative effects of globalization, rapidly evolving technologies, and emerging areas of science have created unprecedented opportunities and challenges for the US Food and Drug Administration (US FDA). For example, breakthroughs in many areas of science are generating new tools and methods that are being incorporated into the science of toxicology. During the past decade, US FDA scientists have taken significant steps to upgrade their toxicology toolboxes. However, a comprehensive strategy is needed to evaluate new methodologies and technologies for their potential to expand US FDA’s toxicology predictive capabilities and to potentially reduce the use of animal testing. To ensure that US FDA continues to employ cutting-edge science to assess the safety and effectiveness of its regulated products and to leverage advances being made in toxicology, the US FDA Commissioner tasked the Agency’s Toxicology Working Group with developing a roadmap for integrating predictive toxicology methods into safety and risk assessments.
Central issue(s) to be addressed:
• Description and Goals of the US FDA Predictive Toxicology Roadmap
• Discuss how partnerships with US FDA and its stakeholder can advance predictive toxicology
• Examine different strategies for working with US FDA