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

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2021
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Van der Stel, Wanda
Carta, Giada
Eakins, Julie
Forsby, Anna
Cediel-Ulloa, Andrea
Hougaard Bennekou, Susanne
Van de Water, Bob
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Alternatives to Animal Experimentation : ALTEX. Springer Spektrum. 2021, 38(4), pp. 615-635. ISSN 1868-596X. eISSN 1868-8551. Available under: doi: 10.14573/altex.2103051
Zusammenfassung

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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ISO 690VAN DER STEL, Wanda, Giada CARTA, Julie EAKINS, Johannes DELP, Ilinca SUCIU, Anna FORSBY, Andrea CEDIEL-ULLOA, Marcel LEIST, Susanne HOUGAARD BENNEKOU, Bob VAN DE WATER, 2021. New approach methods supporting read-across : Two neurotoxicity AOP-based IATA case studies. In: Alternatives to Animal Experimentation : ALTEX. Springer Spektrum. 2021, 38(4), pp. 615-635. ISSN 1868-596X. eISSN 1868-8551. Available under: doi: 10.14573/altex.2103051
BibTex
@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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