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

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

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van der Stel, W. (2021) “New approach methods (NAMs) supporting read-across: Two neurotoxicity AOP-based IATA case studies”, ALTEX - Alternatives to animal experimentation, 38(4), pp. 615–635. doi: 10.14573/altex.2103051.

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