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New Approach Methods (NAMs) Supporting Read-Across: Two Neurotoxicity AOP-based IATA Case Studies.

Authors :
van der Stel, Wanda
Carta, Giada
Eakins, Julie
Delp, Johannes
Suciu, Ilinca
Forsby, Anna
Cediel-Ulloa, Andrea
Attoff, Kristina
Troger, Florentina
Kamp, Hennicke
Gardner, Iain
Zdrazil, Barbara
Moné, Martijn J.
Ecker, Gerhard F.
Pastor, Manuel
Gómez-Tamayo, Jose Carlos
White, Andrew
Danen, Erik H. J.
Leist, Marcel
Walker, Paul
Source :
Altex; 2021, Vol. 38 Issue 4, p615-635, 21p
Publication Year :
2021

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
1868596X
Volume :
38
Issue :
4
Database :
Complementary Index
Journal :
Altex
Publication Type :
Academic Journal
Accession number :
153236101
Full Text :
https://doi.org/10.14573/altex.2103051