Establishment of a human cell-based in vitro battery to assess developmental neurotoxicity hazard of chemicals

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2023
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Masjosthusmann, Stefan
Bartmann, Kristina
Bendt, Farina
Dönmez, Arif
Kilic, Sadiye
Fritsche, Ellen
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Chemosphere. Elsevier. 2023, 311(Part 2), 137035. ISSN 0045-6535. eISSN 1879-1298. Available under: doi: 10.1016/j.chemosphere.2022.137035
Zusammenfassung

Developmental neurotoxicity (DNT) is a major safety concern for all chemicals of the human exposome. However, DNT data from animal studies are available for only a small percentage of manufactured compounds. Test methods with a higher throughput than current regulatory guideline methods, and with improved human relevance are urgently needed. We therefore explored the feasibility of DNT hazard assessment based on new approach methods (NAMs). An in vitro battery (IVB) was assembled from ten individual NAMs that had been developed during the past years to probe effects of chemicals on various fundamental neurodevelopmental processes. All assays used human neural cells at different developmental stages. This allowed us to assess disturbances of: (i) proliferation of neural progenitor cells (NPC); (ii) migration of neural crest cells, radial glia cells, neurons and oligodendrocytes; (iii) differentiation of NPC into neurons and oligodendrocytes; and (iv) neurite outgrowth of peripheral and central neurons. In parallel, cytotoxicity measures were obtained. The feasibility of concentration-dependent screening and of a reliable biostatistical processing of the complex multi-dimensional data was explored with a set of 120 test compounds, containing subsets of pre-defined positive and negative DNT compounds. The battery provided alerts (hit or borderline) for 24 of 28 known toxicants (82% sensitivity), and for none of the 17 negative controls. Based on the results from this screen project, strategies were developed on how IVB data may be used in the context of risk assessment scenarios employing integrated approaches for testing and assessment (IATA).

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ISO 690BLUM, Jonathan, Stefan MASJOSTHUSMANN, Kristina BARTMANN, Farina BENDT, Xenia DOLDE, Arif DÖNMEZ, Anna-Katharina HOLZER, Sadiye KILIC, Marcel LEIST, Ellen FRITSCHE, 2023. Establishment of a human cell-based in vitro battery to assess developmental neurotoxicity hazard of chemicals. In: Chemosphere. Elsevier. 2023, 311(Part 2), 137035. ISSN 0045-6535. eISSN 1879-1298. Available under: doi: 10.1016/j.chemosphere.2022.137035
BibTex
@article{Blum2023Estab-59156,
  year={2023},
  doi={10.1016/j.chemosphere.2022.137035},
  title={Establishment of a human cell-based in vitro battery to assess developmental neurotoxicity hazard of chemicals},
  number={Part 2},
  volume={311},
  issn={0045-6535},
  journal={Chemosphere},
  author={Blum, Jonathan and Masjosthusmann, Stefan and Bartmann, Kristina and Bendt, Farina and Dolde, Xenia and Dönmez, Arif and Holzer, Anna-Katharina and Kilic, Sadiye and Leist, Marcel and Fritsche, Ellen},
  note={Article Number: 137035}
}
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