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

Stel, W. van der; Carta, G.; Eakins, J.; Delp, J.; Suciu, I.; Forsby, A.; ... ; Water, B. van de (2021)

Article / Letter to editor

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.

• PBK-modelling
• In vitro
• Mitochondrial toxicity
• Neurotoxicity
• Uncertainty analysis

• All authors: Stel, W. van der; Carta, G.; Eakins, J.; Delp, J.; Suciu, I.; Forsby, A.; Cediel-Ulloa, A.; Attoff, K.; Troger, F.; Kamp, H.; Gardner, I.; Zdrazil, B.; Moné1, M.J.; Ecker, G.F.; Pastor, M.; Gómez-Tamayo, J.C.; White, A.; Danen, E.H.J.; Leist, M.; Walker , P.; Jennings, P.; Hougaard Bennekou, S.; Water, B. van de
• Date: 2021-06-10
• Journal: ALTEX : Alternatives to Animal Experimentation
• Volume: 38
• Advanced Publication: Yes
• DOI: doi:10.14573/altex.2103051
• Link: http://dx.doi.org/10.14573/altex.2103051