New approach methods (NAMs) supporting read-across: Two neurotoxicity AOP-based IATA case studies

Wanda van der Stel, Giada Carta, Julie Eakins, Johannes Delp, Ilinca Suciu, Anna Forsby, Andrea Cediel-Ulloa, Kristina Attof, Florentina Troger, Hennicke Kamp, Iain Gardner, Barbara Zdrazil, Martijn J Moné, Gerhard F. Ecker, Manuel Pastor, Jose Carlos Gómez-Tamayo, Andrew J. P. White, Erik H.J. Danen, Marcel Leist, Paul WalkerPaul Jennings, Susanne Hougaard Bennekou*, Bob van de Water

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Read-across approaches are considered key in moving away from in vivo animal testing towards addressing data-gaps using new approach methods (NAMs). Ample successful examples are still required to substantiate this strategy. Here we present and discuss the learnings from two OECD IATA endorsed read-across case studies. They involve two classes of pesticides –rotenoids and strobilurins– each having a defined mode-of-action that is assessed for its neurological hazard by means of an AOP-based testing strategy coupled to toxicokinetic simulations of human tissue concentrations. The endpoint in question is potential mitochondrial respiratory chain mediated neurotoxicity, specifically through inhibition of complex I or III. An AOP linking inhibition of mitochondrial respiratory chain complex I to the degeneration of dopaminergic neurons formed the basis for both cases, but was deployed in two different regulatory contexts. The two cases also exemplify several different read-across concepts: analogue versus category approach, consolidated versus putative AOP, positive versus negative prediction (i.e., neurotoxicity versus low potential for neurotoxicity), and structural versus biological similarity. We applied a range of NAMs to explore the toxicodynamic properties of the compounds, e.g., in silico docking as well as in vitro assays and readouts –including transcriptomics– in various cell systems, all anchored to the relevant AOPs. Interestingly, although some of the data addressing certain elements of the read-across were associated with high uncertainty, their impact on the overall read-across conclusion remained limited. Coupled to the elaborate regulatory review that the two cases underwent, we propose some generic learnings of AOP-based testing strategies supporting read-across.
Original languageEnglish
JournalALTEX: Alternatives to Animal Experiments
Volume38
Issue number4
Pages (from-to)615-635
Number of pages21
ISSN1868-596X
DOIs
Publication statusPublished - 2021

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