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Integration of New Approach Methodologies for Prospective Selection of Chemicals for Additional Study
Citation:
Paul-Friedman, K. Integration of New Approach Methodologies for Prospective Selection of Chemicals for Additional Study. Society of Toxicology Annual Meeting 2022, San Diego, California, March 27 - 31, 2022. https://doi.org/10.23645/epacomptox.19579081
Impact/Purpose:
Presentation to the Society of Toxicology annual meeting March 2022. The landscape of applied in silico and in vitro models as “new approach methods,” or NAMs, that provide rapid alternatives for the triage and characterization of hundreds to thousands of chemicals of chemicals continues to grow. As the complexity and number of fit-for-purpose tools increase, data practitioners are creating computational toxicology workflows that provide needed examples of context and application, as well as the information necessary to extend these works to new sets of chemicals. In this session, workflows that integrate multiple data streams and lines of information relevant for toxicology will be discussed. In particular, computational workflows that demonstrate how to use NAMs to address questions in regulatory toxicology questions will be a focus. The first presentations highlight rapid assessment approaches to critical components of Global Harmonized System of hazard labeling. The first computational workflow will leverage NAMs for mutagenicity, clastogenicity, and aneugenicity, as well as toxicokinetic approaches, for data-driven points-of-departure for genotoxicity. The second presentation will detail the latest developments of the OECD QSAR Toolbox, which are focused on connectivity with other computational platforms. An example for skin sensitization, including chemical domain of applicability determination, comprises the first extensible workflow that is part of an OECD guideline. Next, two speakers from the Advancing the Pace of Chemical Risk Assessment (APCRA) consortium will present collaborative work aimed at rapid point-of-departure and hazard prediction for chemicals. A prospective approach to rapid chemical assessment for 200 chemicals using several hazard data streams, including targeted biochemical and cell-based assays, high-throughput transcriptomics, and high-throughput phenotypic profiling for putative hazard identification, along with generic high-throughput toxicokinetic models parameterized with chemical-specific data for derivation of points-of-departure, will be discussed. Next, target tissue-based points of departure, based on the high-throughput phenotypic profiling for toxicity prediction (HIPPTox), for liver, lung, and kidney will be presented for the same APCRA chemicals. Finally, rapid triage workflow using a hazard:exposure ratio for thousands of substances with publicly available traditional hazard data and NAMs for near- and far-field models of exposure to demonstrate putative risk will be demonstrated. Presenters from five different countries and organizations, including the Agency for Science, Technology and Research (A*STAR) in Singapore, the Technical University of Denmark (DTU), the European Chemicals Agency, the US Environmental Protection Agency, and Health Canada provide a diverse international perspective on the progress of uptake of computational toxicology tools for regulatory toxicology questions as well as the next generation of work that is needed to increase reproducible utilization of these tools. Attendees will further gain insight into how the capability of the workflows, including their scientific basis and technical operation, and develop a better understanding of the available tools for rapid assessment of environmentally-relevant chemicals. Importantly, this dynamic session will promote greater understanding of the current and future roles for computational workflows that apply NAMs in safety assessment.
Description:
Presentation Description: Use of new approach methodologies (NAMs), including high-throughput, in vitro bioactivity data, in setting a point-of-departure (POD) has the potential to accelerate the pace of human health risk assessments. Combining hazard and exposure predictions as a bioactivity:exposure ratio (BER) for use in risk-based prioritization of substances that may not have a complete data profile represents a prospective approach to employing new approach methodologies (NAMs). Further, NAMs may provide some support for derivation of bioactivity flags, i.e. potential hazards that are of concern for further mechanism-based screening and/or hazard prediction. In this work we describe the first phase of an effort conducted via the Accelerating the Pace of Chemical Risk Assessment initiative, a consortium of international toxicologists and regulatory scientists. This prospective case study involves generation of NAM data for 200 chemicals, with the primary objective of developing reusable and adaptable approach for prioritization of chemicals for additional short-term studies in rats using a combination of the BER and bioactivity-based flags for indication of putative endocrine, developmental, neurological, and immune suppressive effects. Multiple hazard data streams, including targeted biochemical and cell-based assays, high-throughput transcriptomics, and high-throughput phenotypic profiling data, will be used to inform hazard and risk indications, along with generic high-throughput toxicokinetic models parameterized with chemical-specific data. The goal of this case study is to enable regulatory scientists from different international contexts to develop efficient approaches for chemical management, while possibly reducing the need for animal studies by identifying key areas for hazard characterization. This work demonstrates the feasibility, and continuing challenges, of using toxicodynamic and toxicokinetic NAMs in screening level safety assessment. This abstract does not necessarily reflect U.S. EPA, Health Canada, EFSA, ECHA, A*STAR, or JRC policy.
URLs/Downloads:
DOI: Integration of New Approach Methodologies for Prospective Selection of Chemicals for Additional Study
SOT2022_INTEG_OF_NAMS_PROSPECTIVE_SELECTION_CHEMS_032022_V3.PDF (PDF, NA pp, 2251.664 KB, about PDF)