Mechanistic Analysis of Repeated Dose Toxicity Studies
Key characteristics of chemical-induced toxicity in the liver, lung, cardiovascular system and kidney
Repeated dose toxicity studies in animals form the basis of chemical safety evaluations. Many parameters can be measured and analysed to assess the potential of the test chemical to cause adverse effects in the test animals and predict potential adverse effects in humans. However, these parameters can be quite general in nature and are not necessarily always helpful in understanding the mechanisms of the toxicities observed. Here we analysed the parameters measured in animal studies and attempted to map these to more mechanistically informative endpoints. The study was conducted by collecting relevant mechanistic data from literature, public and private databases. The scope was limited to the liver, cardiovascular system, kidney and lung, and the oral route of exposure. The ultimate goal was to better understand the nature of chronic toxicity to facilitate and expedite the development of human-centric non-animal prediction models. An extended list of chemical Key Characteristics causing liver, lung, cardiovascular and kidney toxicities in repeat dose exposures were drawn up using both literature and data driven approaches. Case study chemicals, known to cause chronic toxicity helped to generate a shortened list of KCs per organ, giving a rationalisation of the target organ specificity of these chemicals. The approach and the data elaborated should prove helpful in developing methodologies for mechanistic understanding of toxicological data and for designing/optimising new experimental methods.
JENNINGS Paul;
CHANDRASEKARAN Vidya;
HARDY Barry;
LANGEMEIJER Ellen;
DOKTOROVA Tatyana;
MADIA Federica Anna Carla;
PRIETO PERAITA Maria Del Pilar;
2023-05-15
Publications Office of the European Union
JRC132210
978-92-76-99823-5 (online),
1831-9424 (online),
EUR 31427 EN,
OP KJ-NA-31-427-EN-N (online),
https://publications.jrc.ec.europa.eu/repository/handle/JRC132210,
10.2760/824535 (online),
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