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

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  • dc.contributor.author Van der Stel, Wanda
  • dc.contributor.author Pastor Maeso, Manuel
  • dc.contributor.author Gómez-Tamayo, José C.
  • dc.contributor.author Van de Water, Bob
  • dc.date.accessioned 2022-01-13T06:43:20Z
  • dc.date.available 2022-01-13T06:43:20Z
  • dc.date.issued 2021
  • dc.description.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.
  • dc.description.sponsorship This work was supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 681002 (EU-ToxRisk). Parts of this work contributed to two IATA Case Studies Projects “Identification and characterization of parkinsonian hazard liability of deguelin by an AOP-based testing and read across approach” and “Mitochondrial complex-III-mediated neurotoxicity of azoxystrobin – Read-across to other strobilurins” (van der Stel et al., 2020b; Bennekou et al., 2020).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Van 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.2103051
  • dc.identifier.doi http://dx.doi.org/10.14573/altex.2103051
  • dc.identifier.issn 1868-596X
  • dc.identifier.uri http://hdl.handle.net/10230/52201
  • dc.language.iso eng
  • dc.publisher Spektrum Akademischer Verlag
  • dc.relation.ispartof ALTEX. 2021;38(4):615-35
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/681002
  • dc.rights © 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.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword PBK-modelling
  • dc.subject.keyword In vitro
  • dc.subject.keyword Mitochondrial toxicity
  • dc.subject.keyword Neurotoxicity
  • dc.subject.keyword Uncertainty analysis
  • dc.title New approach methods (NAMs) supporting read-across: Two neurotoxicity AOP-based IATA case studies
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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