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The liver is among the most frequently targeted organs by noxious chemicals of diverse nature. Liver toxicity testing using laboratory animals not only raises serious ethical questions, but is also rather poorly predictive of human safety towards chemicals. Increasing attention is, therefore, being paid to the development of non-animal and human-based testing schemes, which rely to a great extent on in vitro methodology. The present paper proposes a rationalized tiered in vitro testing strategy to detect liver toxicity triggered by chemicals, in which the first tier is focused on assessing general cytotoxicity, while the second tier is aimed at identifying liver-specific toxicity as such. A state-of-the-art overview is provided of the most commonly used in vitro assays that can be used in both tiers. Advantages and disadvantages of each assay as well as overall practical considerations are discussed.

Original languageEnglish
Article number5038
Pages (from-to)1-45
Number of pages45
JournalInternational Journal of Molecular Sciences
Issue number9
Publication statusPublished - 1 May 2021

Bibliographical note

Funding Information:
This work was supported by grants of the Research Foundation Flanders-Belgium, the Scientific Fund Willy Gepts-Belgium, the Methusalem program of the Flemish government, Cosmetics Europe, the Center for Alternatives to Animal Testing at Johns Hopkins University-USA, the European Research Council (grant 861913 “CONNECT-2-CLINIC), and the Future and Emerging Technologies (grant 858014 “PANACHE”) and Societal Challenges (grant 963845 “ONTOX”) programs of the European Commission.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


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