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A systematic comparison of read-across within REACH registration dossiers with Generalised Read-Across (GenRA)
Citation:
Patlewicz, G., P. Karamertzanis, M. Sannicola, K. Friedman, AND I. Shah. A systematic comparison of read-across within REACH registration dossiers with Generalised Read-Across (GenRA). SOT, Salt Lake City, UT, March 10 - 14, 2024. https://doi.org/10.23645/epacomptox.25395493
Impact/Purpose:
Presentation to the Society of Toxicology (SOT) 63rd Annual Meeting and ToxExpo March 2024
Description:
Read-across is a data-gap filling technique utilised to predict the toxicity of a target chemical using data from similar source analogues. Read-across acceptance remains an issue, mainly due to the difficulties of addressing residual uncertainties and because read-across is still often implemented as a subjective expert driven assessment. There have been many efforts to identify the sources of uncertainty in read-across, characterise them consistently and identify practical strategies to address and reduce those uncertainties. Notable of these efforts have been the creation of frameworks to develop, assess and document read-across. Efforts also include transitioning to data driven approaches such as Generalised Read-Across (GenRA) where uncertainties and performance can be quantified. GenRA affords opportunities for New Approach Methodology (NAM) data e.g. metabolic information, reactivity information, as well as biological data, to be incorporated to support the read-across hypothesis and strengthen its justification. A key issue that remains is how to reconcile an expert driven approach with data driven approaches in terms of establishing scientific confidence in the use of NAM data. These issues were investigated through building a database of expert driven read-across assessments that made use of REACH registration data as disseminated in the IUCLID REACH Study Results. Focusing on repeated dose and developmental toxicity by the oral route, a list of ~ 5000 read-across cases was extracted. This dataset was mapped to content within EPA’s Distributed Structure Searchable Toxicity database (DSSTox) to retrieve chemical name, CAS and structural identification information. Content could be mapped to ~3600 of the cases. This dataset was used as a starting point to analyse the similarity between target and the source analogues on the basis of different contexts – from structural similarity using chemical fingerprints to metabolic similarity using predicted metabolic information (using the TIMES expert system). An attempt was made to quantify the relative contribution that each similarity context played relative to the target-source analogue pairings. Finally, a comparison of the predicted toxicities using the GenRA framework was made to the points of departure submitted for each source analogue. We examined which expert analogue groupings appear insufficiently similar, and to what extent other NAM data could be used to refine or support the target-source analogue relationships further. This abstract does not reflect US EPA policy.
URLs/Downloads:
DOI: A systematic comparison of read-across within REACH registration dossiers with Generalised Read-Across (GenRA)
PRESENTATION.PDF (PDF, NA pp, 709.438 KB, about PDF)