EFSA Pilot Project on New Approach Methodologies (NAMs) for Tebufenpyrad Risk Assessment : Part 2. Hazard characterisation and identification of the Reference Point

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This Project was performed to provide an in vitro Point of Departure (PoD) for an Adverse Outcome Pathway (AOP)-informed Integrated Approach to Testing and Assessment (IATA), concerning a potential risk of parkinsonian motor deficits after long-term exposure to Tebufenpyrad. The AOP considered was AOP:3. Assays were performed for Key Event (KE) 1, KE2 (mitochondrial dysfunction) and KE4 of the AOP, based on the use of human dopaminergic neurons (LUHMES cells). KE1 (inhibition of complex I of the mitochondrial respiratory chain) was considered equivalent to the molecular initiating event (MIE). KE4 (dopaminergic cell degeneration) was considered as alternative AO (target cell degeneration). All necessary and linear steps of the AOP (i.e. KE2,3,4) were investigated by experimental test methods. The three major objectives were: (i) generation of potential PoD data from each assay; (ii) evaluation and optimization of the consistency of these data; (iii) selection of a PoD to be used for further risk assessment. During the optimization phase, assay conditions that reflect brain metabolism (MitoMet conditions) were implemented, and degeneration of neurites was considered the most relevant neuropathological endpoint. With this setting, the potential PoD ranged from 6 nM to 45 nM. The selection of the PoD put emphasis on more chronic effects and on the assay closest to the AO. Thus the KE4 assay, measuring neurite degeneration under MitoMet conditions was chosen, and the PoD was 8 nM. This value has a confidence interval of about one log10-fold change from the lowest to the highest estimate (range: 3 nM – 30 nM), based on the experimental variations we observed. Some biokinetics measurements were undertaken to help estimating cell concentrations. These data had a high uncertainty concerning the measurements and the model assumptions. Based on the assumptions we consider most realistic and robust, we suggest a cell/tissue (brain) concentration of 8-40 nM to be associated with a potential onset of toxicity of Tebufenpyrad.

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570 Biowissenschaften, Biologie
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Tebufenpyrad, Point of Departure, neurotoxicity, mitochondrial toxicity, adverse outcome pathway
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ISO 690ALIMOHAMMADI, Mahshid, Birthe MEYBURG, Anna-Katharina ÜCKERT, Anna-Katharina HOLZER, Marcel LEIST, 2023. EFSA Pilot Project on New Approach Methodologies (NAMs) for Tebufenpyrad Risk Assessment : Part 2. Hazard characterisation and identification of the Reference Point. In: EFSA Supporting Publications. Wiley. 2023, 20(1), EN-7794. eISSN 2397-8325. Available under: doi: 10.2903/sp.efsa.2023.EN-7794
BibTex
@article{Alimohammadi2023Pilot-59786,
  year={2023},
  doi={10.2903/sp.efsa.2023.EN-7794},
  title={EFSA Pilot Project on New Approach Methodologies (NAMs) for Tebufenpyrad Risk Assessment : Part 2. Hazard characterisation and identification of the Reference Point},
  number={1},
  volume={20},
  journal={EFSA Supporting Publications},
  author={Alimohammadi, Mahshid and Meyburg, Birthe and Ückert, Anna-Katharina and Holzer, Anna-Katharina and Leist, Marcel},
  note={Article Number: EN-7794}
}
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    <dcterms:abstract xml:lang="eng">This Project was performed to provide an in vitro Point of Departure (PoD) for an Adverse Outcome Pathway (AOP)-informed Integrated Approach to Testing and Assessment (IATA), concerning a potential risk of parkinsonian motor deficits after long-term exposure to Tebufenpyrad. The AOP considered was AOP:3. Assays were performed for Key Event (KE) 1, KE2 (mitochondrial dysfunction) and KE4 of the AOP, based on the use of human dopaminergic neurons (LUHMES cells). KE1 (inhibition of complex I of the mitochondrial respiratory chain) was considered equivalent to the molecular initiating event (MIE). KE4 (dopaminergic cell degeneration) was considered as alternative AO (target cell degeneration). All necessary and linear steps of the AOP (i.e. KE2,3,4) were investigated by experimental test methods. The three major objectives were: (i) generation of potential PoD data from each assay; (ii) evaluation and optimization of the consistency of these data; (iii) selection of a PoD to be used for further risk assessment. During the optimization phase, assay conditions that reflect brain metabolism (MitoMet conditions) were implemented, and degeneration of neurites was considered the most relevant neuropathological endpoint. With this setting, the potential PoD ranged from 6 nM to 45 nM. The selection of the PoD put emphasis on more chronic effects and on the assay closest to the AO. Thus the KE4 assay, measuring neurite degeneration under MitoMet conditions was chosen, and the PoD was 8 nM. This value has a confidence interval of about one log10-fold change from the lowest to the highest estimate (range: 3 nM – 30 nM), based on the experimental variations we observed. Some biokinetics measurements were undertaken to help estimating cell concentrations. These data had a high uncertainty concerning the measurements and the model assumptions. Based on the assumptions we consider most realistic and robust, we suggest a cell/tissue (brain) concentration of 8-40 nM to be associated with a potential onset of toxicity of Tebufenpyrad.</dcterms:abstract>
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