AIMT2-TNO: Mechanism-based characterisation of systemic toxicity for RepDose database substances employing in vitro toxicogenomics

Description

Many in vitro toxicogenomics initatives so far focus on the overlap between in vitro mechanistic responses and in vivo toxicity, but are primarily concerned with mechanistic studies and hazard identification. Purpose of this study is to extend this towards applications of toxicogenomics in risk assessment by addressing for selected chemicals from the Fraunhofer RepDose database the following questions:

1. Pathway extrapolation. Is toxicogenomics-based pathway extrapolation from human in vitro models to in vivo possible and do mechanistic data from reported in vivo toxicogenomics datasets corroborate these findings?
2. Between organ potency ranking. Is it possible to reproduce the toxicity potency ranking of three main target organs (liver, kidney, lung) observed in the RepDose database, from in vitro toxicogenomics data, (between organ potency ranking: oral exposure: liver, kidney; inhalation exposure: lung, liver)
3. Within organ potency ranking after oral/inhalation exposure. Is it possible to use in vitro toxicogenomics to predict the within organ potency ranking of substances observed in inhalation and in vivo oral repeated dose toxicity studies, targeting the liver, kidney or lung.
4. Grouping. Is grouping/read-across of chemicals possible based upon in vitro toxicogenomics read-out, in relation to their reported toxicity data and grouping available from the RepDose database from Fraunhofer?
5. Is it possible for selected chemicals used to adress points 1-4 to account for in in vitro–in vivo differences in compound metabolism and target organ dose levels?