Publikation:

Protectiveness of NAM-based hazard assessment : which testing scope is required?

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Datum

2024

Autor:innen

Zobl, Walter
Bitsch, Annette
Boei, Jan J.W.A.
Capinha, Liliana
Carta, Giada
Castell, Jose V.
Davoli, Enrico
Drake, Christina
et al.

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oops

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European Union (EU): 101057014
European Union (EU): 964537
European Union (EU): 681002

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EUToxRisk21
RISK-HUNT3R
PARC: Partnership for the Assessment of Risks from Chemicals
Open Access-Veröffentlichung
Open Access Gold
Core Facility der Universität Konstanz

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Titel in einer weiteren Sprache

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Zeitschriftenartikel
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Published

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Alternatives to Animal Experimentation : ALTEX. Springer Spektrum. 2024, 41(2), S. 302-319. ISSN 1868-596X. eISSN 1868-8551. Verfügbar unter: doi: 10.14573/altex.2309081

Zusammenfassung

Hazard assessment (HA) requires toxicity tests to allow deriving protective points of departure (PoDs) for risk assessment irrespective of a compound’s mode of action (MoA). The scope of in vitro test batteries (ivTB) thereby necessitated for systemic toxicity is still unclear. We explored the protectiveness regarding systemic toxicity of an ivTB with a scope, which was guided by previous findings from rodent studies, where examining six main targets, including liver and kidney, was sufficient to predict the guideline scope-based PoD with high probability. The ivTB comprises human in vitro models representing liver, kidney, lung and the neuronal system covering transcriptome, mitochondrial dysfunction and neuronal outgrowth. Additionally, 32 CALUX®- and 10 HepG2 BAC-GFP reporters cover a broad range of disturbance mechanisms. Eight compounds were chosen for causing adverse effects such as immunotoxicity or anemia in vivo, i.e., effects not directly covered by assays in the ivTB. PoDs derived from the ivTB and from oral repeated dose studies in rodents were extrapolated to maximum unbound plasma concentrations for comparison. The ivTB-based PoDs were one to five orders of magnitude lower than in vivo PoDs for six of eight compounds, implying that they were protective. The extent of in vitro response varied across test compounds. Especially for hematotoxic substances, the ivTB showed either no response or only cytotoxicity. Assays better capturing this type of hazard would be needed to complement the ivTB. This study highlights the potentially broad applicability of ivTBs for deriving protective PoDs of compounds with unknown MoA.

Zusammenfassung in einer weiteren Sprache

Fachgebiet (DDC)
570 Biowissenschaften, Biologie

Schlagwörter

NAMs, tiered hazard assessment, qIVIVE, benchmark dose modelling, systemic toxicity

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ISO 690ZOBL, Walter, Annette BITSCH, Jonathan BLUM, Jan J.W.A. BOEI, Liliana CAPINHA, Giada CARTA, Jose V. CASTELL, Enrico DAVOLI, Christina DRAKE, Marcel LEIST, 2024. Protectiveness of NAM-based hazard assessment : which testing scope is required?. In: Alternatives to Animal Experimentation : ALTEX. Springer Spektrum. 2024, 41(2), S. 302-319. ISSN 1868-596X. eISSN 1868-8551. Verfügbar unter: doi: 10.14573/altex.2309081
BibTex
@article{Zobl2024Prote-69149,
  year={2024},
  doi={10.14573/altex.2309081},
  title={Protectiveness of NAM-based hazard assessment : which testing scope is required?},
  number={2},
  volume={41},
  issn={1868-596X},
  journal={Alternatives to Animal Experimentation : ALTEX},
  pages={302--319},
  author={Zobl, Walter and Bitsch, Annette and Blum, Jonathan and Boei, Jan J.W.A. and Capinha, Liliana and Carta, Giada and Castell, Jose V. and Davoli, Enrico and Drake, Christina and Leist, Marcel}
}
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