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New Approach Method...
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van der Stel, WandaLeiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, Leiden, Netherlands.
(författare)
New Approach Methods (NAMs) Supporting Read-Across : Two Neurotoxicity AOP-based IATA Case Studies
- Artikel/kapitelEngelska2021
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2021
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ALTEX Edition,2021
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LIBRIS-ID:oai:DiVA.org:su-199589
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https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-199589URI
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https://doi.org/10.14573/altex.2103051DOI
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-459072URI
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Språk:engelska
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Sammanfattning på:engelska
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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.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Carta, GiadaVrije Univ Amsterdam, Dept Chem & Pharmaceut Sci, Div Mol & Computat Toxicol, AIMMS, Amsterdam, Netherlands.
(författare)
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Eakins, JulieCyprotex Discovery Ltd, Alderley Park, Macclesfield, Cheshire, England.
(författare)
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Delp, JohannesUniv Konstanz, Dept Inaugurated Doerenkamp Zbinden Fdn, Chair In Vitro Toxicol & Biomed, Constance, Germany.
(författare)
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Suciu, IlincaUniv Konstanz, Dept Inaugurated Doerenkamp Zbinden Fdn, Chair In Vitro Toxicol & Biomed, Constance, Germany.;Univ Konstanz, Konstanz Res Sch Chem Biol, Constance, Germany.
(författare)
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Forsby, AnnaStockholms universitet,Institutionen för biokemi och biofysik,Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.(Swepub:su)annaf
(författare)
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Cediel Ulloa, AndreaUppsala universitet,Miljötoxikologi(Swepub:uu)andce270
(författare)
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Attoff, KristinaStockholms universitet,Institutionen för biokemi och biofysik,Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.(Swepub:su)krat6610
(författare)
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Troger, FlorentinaUniv Vienna, Dept Pharmaceut Chem, Vienna, Austria.
(författare)
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Kamp, HennickeBASF, Ludwigshafen, Germany.
(författare)
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Gardner, IainCertara UK Ltd, Sheffield, S Yorkshire, England.
(författare)
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Zdrazil, BarbaraUniv Vienna, Dept Pharmaceut Chem, Vienna, Austria.
(författare)
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Moné, Martijn J.Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, Leiden, Netherlands.
(författare)
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Ecker, Gerhard F.Univ Vienna, Dept Pharmaceut Chem, Vienna, Austria.
(författare)
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Pastor, ManuelUniv Pompeu Fabra, Dept Expt & Hlth Sci, Barcelona, Spain.
(författare)
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Gómez-Tamayo, Jose CarlosUniv Pompeu Fabra, Dept Expt & Hlth Sci, Barcelona, Spain.
(författare)
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White, AndrewUnilever, Sharnbrook, Beds, England.
(författare)
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Danen, Erik H. J.Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, Leiden, Netherlands.
(författare)
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Leist, MarcelUniv Konstanz, Dept Inaugurated Doerenkamp Zbinden Fdn, Chair In Vitro Toxicol & Biomed, Constance, Germany.
(författare)
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Walker, PaulCyprotex Discovery Ltd, Alderley Park, Macclesfield, Cheshire, England.
(författare)
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Jennings, PaulVrije Univ Amsterdam, Dept Chem & Pharmaceut Sci, Div Mol & Computat Toxicol, AIMMS, Amsterdam, Netherlands.
(författare)
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Bennekou, Susanne HougaardTech Univ Denmark DTU, Natl Food Inst, Lyngby, Denmark.
(författare)
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van de Water, BobLeiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, Leiden, Netherlands.
(författare)
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Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, Leiden, Netherlands.Vrije Univ Amsterdam, Dept Chem & Pharmaceut Sci, Div Mol & Computat Toxicol, AIMMS, Amsterdam, Netherlands.
(creator_code:org_t)
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Ingår i:Altex: ALTEX Edition38:4, s. 615-6351868-596X1868-8551
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van der Stel, Wa ...
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Carta, Giada
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Eakins, Julie
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Delp, Johannes
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Suciu, Ilinca
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Forsby, Anna
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Cediel Ulloa, An ...
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Attoff, Kristina
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Troger, Florenti ...
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Kamp, Hennicke
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Gardner, Iain
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Zdrazil, Barbara
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Moné, Martijn J.
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Ecker, Gerhard F ...
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Pastor, Manuel
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Gómez-Tamayo, Jo ...
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White, Andrew
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Danen, Erik H. J ...
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Leist, Marcel
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Walker, Paul
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Jennings, Paul
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Bennekou, Susann ...
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van de Water, Bo ...
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