The SEURAT-1 ab initio case studies : a proof of concept from theory to application
Résumé
SEURAT1 is a research initiative aiming at developing knowledge and technology building blocks required for the development of solutions for the replacement of current repeated dose systemic toxicity testing in vivo used for the assessment of human safety. Within the project a proof of concept study integrating the building blocks is currently ongoing to demonstrate the possibility of addressing the safety assessment of chemicals for systemic toxicity using in silico and in vitro tools. The approach is driven by the needs of the risk assessor to determine a quantitative point of departure for critical decision points and assess this in relation to the applicable exposure scenario for the use case. The quantitative risk assessment or ab initio case study is based on a proof a concept at multiple levels: theoretical, methodological as applied within a toxicological MoA framework. In the scope of SEURAT1, the quantitative assessment of repeated dose toxicity is specifically related to liver hepatotoxicity. Several tools and assays developed within SEURAT1 will be used to qualitatively and quantitatively address 1) the initial critical pathway determination and b) assess the adverse outcome pathways (AOPs) described on liver (Vinken, M. Toxicology. 2013 Oct 4; 312:158-65). Dose response data on applicable in vitro concentrations will be utilised across key in vitro models to determine a relevant biological point of departure for the AOPs and relate this through in vitro to in vivo extrapolation (IVIVE) using derived ADME (administration, distribution, metabolism and excretion) and PBPK models to define a pertinent exposure metric. The approach will be benchmarked with gold compounds that have dose dependant defined toxicities ie low well tolerated dose – and at higher doses increasing incidence of hepatotoxicity. The purpose is to provide an exemplar case study of how to quantitatively translate findings from in vitro and in silico approaches to a chronic systemic exposure relevant for human safety and to identify gaps. The ability to address the uncertainty of adverse risk to consumers under different consumer populations & exposure scenarios and for chronic repeat dose systemic endpoints will also be considered in the ab initio case studies. Work is currently ongoing on three gold compounds: methotrexate, valproic acid and doxorubicin. Preliminary results on these compounds will be discussed.