Van der Stel, WandaPastor Maeso, ManuelGómez-Tamayo, José C.Van de Water, Bob2022-01-132022-01-132021Van der Stel W, Carta G, Eakins J, Delp J, Suciu I, Forsby A et al. New approach methods (NAMs) supporting read-across: Two neurotoxicity AOP-based IATA case studies. ALTEX. 2021;38(4):615-35. DOI: 10.14573/altex.21030511868-596Xhttp://hdl.handle.net/10230/52201Read-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.application/pdfeng© The Authors, 2021. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is appropriately cited.info:eu-repo/semantics/articlehttp://dx.doi.org/10.14573/altex.2103051PBK-modellingIn vitroMitochondrial toxicityNeurotoxicityUncertainty analysisinfo:eu-repo/semantics/openAccess