598
Setting the Stage to Advance the Adverse Outcome Pathway Framework through Horizon Scanning
C. LaLone, U.S. EPA / Mid Continent Ecology Division; G.T. Ankley, U.S. EPA / National Health and Environmental Effects Research Laboratory; S.E. Belanger, The Procter & Gamble Company / Environmental Stewardship and Sustainability Organization; M.R. Embry, ILSI Health and Environmental Sciences Institute (HESI); G. Hodges, Unilever / Safety and Environmental Assurance Centre SEAC; D. Knapen, University of Antwerp / Zebrafishlab Dept Veterinary Sciences; S. Munn, European Commission; E.J. Perkins, US Army Engineer Research and Development Center / Environmental Laboratory; M. Rudd, University of York; D.L. Villeneuve, U.S. EPA / National Health and Environmental Effects Research Laboratory; M. Whelan, University of leicester / Geography; C. Willett, the Humane Society of the United States / Animal Research Issues; X. Zhang, Nanjing University / Environmental Science; M. Hecker, University of Saskatchewan / School of the Environment & Sustainability and Toxicology Centre
Recognizing the international interest surrounding the adverse outcome pathway framework, which captures existing information describing causal linkages between a molecular initiating event through levels of biological organization to an adverse outcome of regulatory significance, an effort was undertaken to provide the scientific community the opportunity to engage in determining the direction of the AOP framework. Specifically, a horizon scanning effort was used to solicit questions from the international scientific community asking participants to propose questions that consider key outstanding challenges and/or limitations that must be overcome to advance the AOP framework for both research and regulatory decision making. From March-June, 2016, 340 valid questions were collected from 158 global submissions, spanning all continents, to an online horizon scanning survey. Respondents to the survey self-identified as 35% academia, 35% government, 20% industry, and 5% non-government organizations. Following question solicitation, questions were separated into broad topic areas including, AOP networks, quantitative AOPs, collaboration and communication on AOPs, AOP discovery and development, extrapolation, exposure/toxicokinetics considerations, and AOP application. An expert-ranking exercise was then conducted to identify high-priority questions for each category and from this, four key themes emerged that could aid in guiding future AOP research and regulatory initiatives. These themes were used as workgroup topics for a PellstonTM
their applications; regulatory use of the AOP framework, and expanding awareness of, involvement in; and acceptance of AOPs to support aspects of predictive toxicology and regulatory decision-making. Charge questions for each workgroup were directly modified from those submitted during horizon scanning.
Additionally, from the horizon scanning exercise, frequently asked questions (FAQs) were identified and addressed by experts in the field. Together the horizon scanning approach, expert ranking exercise, and answers to FAQs, were used to set the stage for the SETAC PellstonTM Workshop titled “Advancing the Adverse Outcome Pathway Concept: An International Horizon Scanning Approach,” that took place in Cornwall, Canada during April 2017. The contents of this presentation neither constitute nor necessarily reflect US EPA policy.
599
Adverse Outcome Pathway networks: development, analytics and applications
D. Knapen, University of Antwerp / Zebrafishlab Dept Veterinary Sciences; M. Angrish, US EPA, National Center for Environmental Assessment; M.C. Fortin, Alcami / Environmental and Occupational Health Sciences Institute; I. Katsiadaki, Cefas / Environment and Animal Health; M. Leonard, lOREAL SA; L.
Margiotta-Casaluci, Brunel University London / Institute of Environment, Health and Societies; S. Munn, European Commission; J. O'Brien, Environment and Climate Change Canada / National Wildlife Research Centre; N. Pollesch, US EPA / ORD NHEERL Mid Continent Ecology Division; L. Smith, University of Florida / Physiological Sciences; X. Zhang, Nanjing University / Environmental Science; D.L. Villeneuve, U.S. EPA / National Health and Environmental Effects Research Laboratory
Adverse outcome pathways (AOPs) are an important framework that can help support more effective use of mechanistic, pathway-based, data in risk assessment and regulatory decision-making. AOPs have rapidly evolved from a conceptual paradigm into a formalized framework for organizing biological and toxicological knowledge according to a set of generally accepted principles and guidelines. In response to the recognized need to continue advancing the framework, SETAC sponsored a global horizon scanning exercise to identify major outstanding topics and challenges related to the AOP framework and its application. The development of guidance related to AOP network development and analysis was identified as a critical need. This not only included questions focusing directly on AOP networks, but also on related topics such as mixture toxicity assessment and the
implementation of feedback loops within the AOP framework. This presentation briefly outlines critical concepts concerning the development of AOP networks, how they may be analyzed, and illustrates how information derived from them can be applied. First, derivation of AOP networks is considered in the context of how it differs from development of individual AOP descriptions. Next, the application of filters and layers is discussed, which can be used to refine and enrich derived AOP networks so that they may be tailored to address specific questions of interest. We then introduce a number of analytical and computational approaches that may be used to characterize and analyze the structure of AOP networks to derive information that can guide research and regulatory decision-making. A number of application case studies is used to illustrate concepts underlying development and analysis of AOP networks, and how those concepts tie in with ultimate application. The contents of this presentation represent the personal opinions of the authors and neither constitute, nor necessarily reflect the policies or viewpoints of their employers or institutes.
600
Building and Applying Quantitative Adverse Outcome Pathway Models for Chemical Hazard and Risk Assessment
S. Scholz, Helmholtz Centre for Environmental Research / Department Bioanalytical Ecotoxicology; R. Ashauer, University of York / Environment; R. Conolly, US EPA RTP; B. Landesmann, JRC, European Commission; C. Mackay, Unilever; C. Murphy, Michigan State University / Department of Fisheries and Wildlife; N. Pollesch, US EPA / ORD NHEERL Mid Continent Ecology Division; J. Wheeler, Dow Agrosciences; A. Zupanic, Eawag Swiss Federal Institute of Aquatic Science and Technology / Environmental Toxicology; E.J. Perkins, US Army Engineer Research and Development Center / Environmental Laboratory Quantitative prediction and assessment of chemical impacts on human and environmental health is important in understanding the potential hazards and risks of using, or being exposed to, chemicals. Here we examine how the Adverse Outcome Pathway (AOP) concept and knowledge base can be used to develop quantitative models (qAOPs) to predict and assess hazards and risks of chemicals. Quantitative models can be developed with a clear problem definition and using AOPs as initial conceptual models. Modeling methods range from
semi-quantitative to quantitative modeling approaches or combination of these (e.g. fully mechanistic mathematical /ordinary differential equation based,
individual-based models, statistical, or Bayesian network models). We discuss best practices for choosing modeling approaches, model building and the necessity for transparent and comprehensive documentation in order to gain confidence in the use of a model. Finally, we present examples of how qAOP models can support decision making: a screening level assessment of the health hazards of chemicals and chemical mixtures using a qAOP Bayesian network model of steatosis, the use of qAOPs in a prospective risk assessment context (e.g. in vitro to in vivo
extrapolation using aromatase inhibition as an example) and for extrapolation between species or life stages.
601
Use of Adverse Outcome Pathways to Inform Decisions on Chemical Innovation, Regulation & Stewardship
T. Hill, US EPA NHEERL/ISTD/CB / ORD NHEERL Integrated System Toxicology Division; P. Browne, OECD / OSCP; K.K. Coady, The Dow Chemical Company / Toxicology Environmental Research and Consulting; M.R. Embry, ILSI Health and Environmental Sciences Institute (HESI); T. Hutchinson, School of Biological Sciences, Plymouth University / School of Biological Sciences; E. Lienala, OECD; L. Maslankiewicz, National Institute for Public Health and the Environment (RIVM); T.M. Steeger, U.S. EPA / Office of Chemical Safety and Pollution Prevention
An invited group of scientists participated in a SETAC Pellston WorkshopTM, “Advancing the Adverse Outcome Pathway (AOP) Concept – An International Horizon Scanning Approach,” in April 2017. The workshop addressed key challenges or limitations of AOP constructs as tools for informing research and regulatory decisions that were identified by responses to a global Horizon Scanning survey. This presentation will summarize the findings of Pellston Workgroup 3, which was tasked with the explication of practical considerations for this use of AOP constructs in regulatory decision making. The use of AOPs and related concepts have increased in scientific and regulatory sectors over the past decade, coinciding with pressures to find innovative solutions to evaluate chemical safety in a more efficient and effective manner that better directs resource utilization. This workgroup focused on how AOPs can be a useful tool for chemical decision makers in the government and private sector. At the various points where chemical decision making is employed across the “life” of a chemical – from research and
development within the commercial sector, government registration and regulation, through to post-marketing use/stewardship – AOPs can be used as an organizing principle. Pragmatic evidence is provided for how AOPs can be and are currently being used in chemical decision-making processes. Considerations for evaluating the suitability of AOP for decision makers are discussed, recognizing that the acceptable level of uncertainty varies based upon the nature of the decision and the context in which it is being applied. The presentation provides multiple examples of AOP use and practical considerations for evaluating whether use of AOPs is fit-for-purpose in different circumstances. This abstract does not necessarily
represent the views or policies of the U.S. EPA.
602
Ensuring Long-Term Utility of the AOP Framework and Knowledge for Multiple Stakeholders
G.T. Ankley, U.S. EPA / National Health and Environmental Effects Research Laboratory; A. Carusi, University of Sheffield; H. Davies, WA State Dept of Health / Dept of Ecology; G. De Grandis, Norwegian University of Science and Technology; B. Escher, Helmholtz Centre for Environmental Research GmbH - UFZ / Cell Toxicology; G. Hodges, Unilever Research / Safety and Environmental Assurance Centre; K. Leung, The University of Hong Kong / The Swire Institute of Marine Science and School of Biological Sciences; M. Whelan, University of leicester / Geography; C. Willett, the Humane Society of the United States / Animal Research Issues
The adverse outcome pathway (AOP) framework serves as a knowledge assembly and communication tool to facilitate translation of mechanistic (e.g., molecular, biochemical, histological) data into adverse apical outcomes meaningful to chemical risk assessment. Although initially designed for ecotoxicology applications, the framework has also received extensive attention relative to chemical safety assessments for human health. Moreover, as the AOP concept and associated knowledgebases have evolved, it has become recognized that the potential stakeholder community is broader than scientists and regulators directly involved in chemical safety assessment. For example, the application of AOP-based thinking for addressing biomedical challenges has become increasingly evident. This presentation will identify various stakeholders who currently, or could potentially, benefit from application of the AOP framework and knowledge to specific needs, and describes challenges and strategies to effectively engaging these stakeholders. We also present a “roadmap” on how to maintain a viable, sustainable network to support AOP stakeholders, including recommendations for governance and coordination of AOP development and knowledge dissemination in a multi-stakeholder consortium. The contents of this abstract neither constitute, nor
necessarily reflect, official USEPA policy.
603
Adverse Outcome Pathways: Moving from a scientific concept to a globally accepted framework
M. Hecker, University of Saskatchewan / School of the Environment & Sustainability and Toxicology Centre; C. LaLone, U.S. EPA / Mid Continent Ecology Division
The adverse outcome pathway (AOP) framework has gained significant
international traction as a systematic approach for capturing existing knowledge to transparently link mechanistic data to apical toxicity endpoints as a means to inform research and risk assessment. While the framework has evolved significantly since