RDT/DART ab initio
Currently, for an enormous proportion of REACH registrations, no safety information is available. This particularly applies to 'lower tonnage' chemicals. Here there is a need to prioritize chemicals based on the likelihood of safety issues. The main objective of the case study is to demonstrate the overall feasibility of high-throughput NAM hazard-based information to identify substances of high-toxicity concern.
The driving hypothesis is that only toxic substances will strongly impact cell biology. This would be reflected by the activation of specific transcriptional networks that will provide mechanistic mode-of-action information. We anticipate that high-throughput NAM approaches could provide this mechanistic insight and thereby allow to rank substances based on their mode-of-action.
To demonstrate the feasibility to prioritize chemicals for further safety assessment, a training set of high tonnage compounds, for which in vivo safety data is available, will be used. These compounds will all be tested in dose-response scenarios in high-throughput test systems to assess the impact on the cell biology, and include: in silico approaches (metabolism, QSAR, target prediction); high-throughput reporter assays; targeted transcriptomics in selected cell types. All compounds will be ranked and we will relate our findings to the available in vivo adversity and potency information.
UL, UKN, BASF, Unilever, BDS, TNO, ITEM, EWC, IRFMN, LUMC, UPF, EMBL-EBI, UNIVIE, HULAFE, CRX, L’Oreal, LHASA, VU, RISE.