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New Approach Method...
New Approach Methods (NAMs) Supporting Read-Across : Two Neurotoxicity AOP-based IATA Case Studies
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- van der Stel, Wanda (author)
- Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, Leiden, Netherlands.
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- Carta, Giada (author)
- Vrije Univ Amsterdam, Dept Chem & Pharmaceut Sci, Div Mol & Computat Toxicol, AIMMS, Amsterdam, Netherlands.
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- Eakins, Julie (author)
- Cyprotex Discovery Ltd, Alderley Park, Macclesfield, Cheshire, England.
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- Delp, Johannes (author)
- Univ Konstanz, Dept Inaugurated Doerenkamp Zbinden Fdn, Chair In Vitro Toxicol & Biomed, Constance, Germany.
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- Suciu, Ilinca (author)
- Univ Konstanz, Dept Inaugurated Doerenkamp Zbinden Fdn, Chair In Vitro Toxicol & Biomed, Constance, Germany.;Univ Konstanz, Konstanz Res Sch Chem Biol, Constance, Germany.
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- Forsby, Anna (author)
- Stockholms universitet,Institutionen för biokemi och biofysik,Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.
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- Cediel Ulloa, Andrea (author)
- Uppsala universitet,Miljötoxikologi
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- Attoff, Kristina (author)
- Stockholms universitet,Institutionen för biokemi och biofysik,Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.
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- Troger, Florentina (author)
- Univ Vienna, Dept Pharmaceut Chem, Vienna, Austria.
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- Kamp, Hennicke (author)
- BASF, Ludwigshafen, Germany.
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- Gardner, Iain (author)
- Certara UK Ltd, Sheffield, S Yorkshire, England.
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- Zdrazil, Barbara (author)
- Univ Vienna, Dept Pharmaceut Chem, Vienna, Austria.
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- Moné, Martijn J. (author)
- Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, Leiden, Netherlands.
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- Ecker, Gerhard F. (author)
- Univ Vienna, Dept Pharmaceut Chem, Vienna, Austria.
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- Pastor, Manuel (author)
- Univ Pompeu Fabra, Dept Expt & Hlth Sci, Barcelona, Spain.
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- Gómez-Tamayo, Jose Carlos (author)
- Univ Pompeu Fabra, Dept Expt & Hlth Sci, Barcelona, Spain.
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- White, Andrew (author)
- Unilever, Sharnbrook, Beds, England.
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- Danen, Erik H. J. (author)
- Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, Leiden, Netherlands.
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- Leist, Marcel (author)
- Univ Konstanz, Dept Inaugurated Doerenkamp Zbinden Fdn, Chair In Vitro Toxicol & Biomed, Constance, Germany.
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- Walker, Paul (author)
- Cyprotex Discovery Ltd, Alderley Park, Macclesfield, Cheshire, England.
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- Jennings, Paul (author)
- Vrije Univ Amsterdam, Dept Chem & Pharmaceut Sci, Div Mol & Computat Toxicol, AIMMS, Amsterdam, Netherlands.
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- Bennekou, Susanne Hougaard (author)
- Tech Univ Denmark DTU, Natl Food Inst, Lyngby, Denmark.
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- van de Water, Bob (author)
- Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, Leiden, Netherlands.
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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)
- 2021
- 2021
- English.
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In: Altex. - : ALTEX Edition. - 1868-596X .- 1868-8551. ; 38:4, s. 615-635
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Abstract
Subject headings
Close
- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Keyword
- in vitro
- mitochondrial toxicity
- neurotoxicity
- PBK-modelling
- uncertainty analysis
Publication and Content Type
- ref (subject category)
- art (subject category)
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Altex
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- By the author/editor
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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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show more...
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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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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmacology and ...
- Articles in the publication
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Altex
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Stockholm University
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Uppsala University