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The use of new approach methodologies (NAMs) to derive extrapolation factors and evaluate developmental neurotoxicity for human health risk assessment (Report)
Citation:
Shafer, T. AND T. Gibson. The use of new approach methodologies (NAMs) to derive extrapolation factors and evaluate developmental neurotoxicity for human health risk assessment (Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/X-22/291, 2022.
Impact/Purpose:
In 2007, the National Research Council’s report on Toxicity Testing in 21st Century: A Vision and a Strategy was published which encouraged a new paradigm in testing that reduces the reliance on using laboratory animals while moving towards in vitro and in silico predictive approaches that are more efficient and human relevant. EPA’s Office of Pesticide Programs (OPP) has developed a strategic vision for implementing the 2007 NRC report on Toxicity Testing in the 21st Century. This strategic vision has multiple components involving a combination of computational and predictive modeling approaches, in vitro techniques, and limited, targeted in vivo testing. To supplement or replace the existing toxicity tests used to support pesticide registration, EPA’s OPP is actively engaged in numerous activities with respect to reducing laboratory animal use and implementing in vitro and computational approaches. Development and implementation of non-animal testing has been supported by the EPA, with the EPA Administrator signing a directive in 2019 that prioritizes efforts to reduce animal testing and a goal to reduce requests for and funding of mammalian studies by 30% by 2025. As new approach methodologies (NAMs) can provide human relevant information that may be challenging to test in whole animals, EPA’s OPP is also interested in using NAMs to reduce the reliance on default assumptions for risk assessment, including the application of 10X default uncertainty factors each for interspecies and intraspecies extrapolations. In line with this, several years ago, OPP began collaborative work with EPA’s Office of Research and Development (ORD), academia, and industry to use the organophosphate pesticides (OPs), as a case study, for the development of NAMs for purposes of using NAM data to inform extrapolation/uncertainty and safety factors in lieu of reliance on default factors. This research is at a point where external peer review and public comment would be useful to specifically inform human health risk assessment for the OP class of insecticides and also as part of confidence building activities needed to implement NAMs in human health risk assessment more broadly. If appropriate, EPA’s OPP may use such NAM information as part of a weight of evidence evaluation for the 10X Food Quality Protection Act (FQPA) Safety Factor. Additionally, in vitro acetylcholinesterase (AChE) inhibition data has been generated for OP compounds. The OPP is considering the potential use of these data to develop interspecies and/or intraspecies data-derived extrapolation factors (DDEFs) in accordance with EPA’s 2014 Guidance for Applying Quantitative Data to Develop DDEFs for Interspecies and Intraspecies Extrapolation.
Description:
To supplement or replace the existing toxicity tests used to support pesticide registration, EPA’s OPP is actively engaged in numerous activities with respect to reducing laboratory animal use and implementing new approach methodologies (NAMs). NAM is a broad term referring to any non-animal technology, methodology, approach, or combination thereof that can be used to provide information on chemical hazard and risk assessment. As NAMs can provide human relevant information that may be challenging to test in whole animals, EPA’s OPP is also interested in using NAMs to reduce the reliance on default assumptions for risk assessment. In line with this, several years ago, the Office of Pesticide Programs (OPP) began collaborative work with the Office of Research and Development (ORD), academia, and industry to use the organophosphate pesticides (OPs) as a case study for the development of NAMs to inform extrapolation/uncertainty and safety factors in lieu of reliance on default factors. Two approaches related to these efforts are presented.
URLs/Downloads:
FINAL REPORT (EPA_600_X-22_291)_508TAGGED.PDF (PDF, NA pp, 4335.847 KB, about PDF)https://www.epa.gov/sap/use-new-approach-methodologies-nams-derive-extrapolation-factors-and-evaluate-developmental