Title: Investigating cell type specific mechanisms contributing to acute oral toxicity
Authors: PRIETO PERAITA MARIA DEL PILARGRAEPEL RABEAGERLOFF KIRSTEN BRITTALAMON LARASACHANA MAGDALINIPISTOLLATO FRANCESCAGRIBALDO LAURAPRICE ANNAWORTH ANDREW
Citation: ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION p. 1-24
Publisher: SPEKTRUM AKADEMISCHER VERLAG-SPRINGER-VERLAG GMBH
Publication Year: 2018
JRC N°: JRC111713
ISSN: 1868-596X
URI: https://doi.org/10.14573/altex.1805181
http://publications.jrc.ec.europa.eu/repository/handle/JRC111713
DOI: 10.14573/altex.1805181
Type: Articles in periodicals and books
Abstract: The replacement of animals in acute systemic toxicity testing remains a considerable challenge. Only animal data are currently accepted by regulators, including data generated by reduction and refinement methods. The development of Integrated Approaches to Testing and Assessment (IATA) is hampered by an insufficient understanding of the numerous toxicity pathways that lead to acute systemic toxicity. Therefore, central to our work has been the collection and evaluation of the mechanistic information on eight organs identified as relevant for acute systemic toxicity (nervous system, cardiovascular system, liver, kidney, lung, blood, gastrointestinal system and immune system). While the nervous and cardiovascular systems are the most frequent targets, no clear relationship emerged between specific mechanisms of target organ toxicity and the level (category) of toxicity. From a list of 114 chemicals with acute oral in vivo and in vitro data, 97 were identified with target organ specific effects, of which 94% (91/97) were predicted as acutely toxic by the 3T3 neutral red uptake cytotoxicity assay and 6% (6/97) as non-toxic. Although specific target organ mechanisms of toxicity could in some cases explain the false negative prediction obtained with the cytotoxicity assay, in general it is difficult to explain in vitro misclassifications only on the basis of mechanistic information. This analysis will help to prioritise the development of adverse outcome pathways for acute oral toxicity, which will support the assessment of chemicals using mechanistically informed IATA.
JRC Directorate:Health, Consumers and Reference Materials

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