@article{VanderStel2021appro-53969,
  year={2021},
  doi={10.14573/altex.2103051},
  title={New approach methods supporting read-across : Two neurotoxicity AOP-based IATA case studies},
  number={4},
  volume={38},
  issn={1868-596X},
  journal={Alternatives to Animal Experimentation : ALTEX},
  pages={615--635},
  author={Van der Stel, Wanda and Carta, Giada and Eakins, Julie and Delp, Johannes and Suciu, Ilinca and Forsby, Anna and Cediel-Ulloa, Andrea and Leist, Marcel and Hougaard Bennekou, Susanne and Van de Water, Bob}
}

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    <dc:creator>Suciu, Ilinca</dc:creator>
    <dcterms:abstract xml:lang="eng">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.</dcterms:abstract>
    <dc:creator>Leist, Marcel</dc:creator>
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    <dc:contributor>Van de Water, Bob</dc:contributor>
    <dc:creator>Van der Stel, Wanda</dc:creator>
    <dc:contributor>Cediel-Ulloa, Andrea</dc:contributor>
    <dc:creator>Hougaard Bennekou, Susanne</dc:creator>
    <dc:creator>Delp, Johannes</dc:creator>
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    <dc:creator>Carta, Giada</dc:creator>
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    <dc:creator>Van de Water, Bob</dc:creator>
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    <dcterms:title>New approach methods supporting read-across : Two neurotoxicity AOP-based IATA case studies</dcterms:title>
    <dc:contributor>Suciu, Ilinca</dc:contributor>
    <dc:creator>Cediel-Ulloa, Andrea</dc:creator>
    <dc:contributor>Eakins, Julie</dc:contributor>
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    <dc:contributor>Carta, Giada</dc:contributor>
    <dc:creator>Eakins, Julie</dc:creator>
    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2021-06-14T11:12:34Z</dc:date>
    <dc:contributor>Van der Stel, Wanda</dc:contributor>
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    <dc:contributor>Leist, Marcel</dc:contributor>
    <dc:contributor>Forsby, Anna</dc:contributor>
    <dc:contributor>Delp, Johannes</dc:contributor>
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    <dc:creator>Forsby, Anna</dc:creator>
    <dc:contributor>Hougaard Bennekou, Susanne</dc:contributor>
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