Ab Initio safety assessment case study : Integration of alternative methods in an applied risk assessment for repeated-dose toxicity
Résumé
The SEURAT-1 ("Safety Evaluation Ultimately Replacing Animal Testing") Research Initiative aimed at finding alternative approaches for the safety assessment for repeated-dose toxicity (Gocht et al 2013). Within the SEURAT-1 framework of proof-of-concept case studies for applied safety assessment, the ab initio case study set out to identify and subsequently quantify relevant biological pathway concentration effect levels of a cosmetic ingredient for specific exposure scenarios. Based on the SEURAT-1 conceptual framework for safety assessment (White, Knight 2014), a general workflow was developed in an attempt to structuring knowledge and data in a logical sequence for an integrated safety assessment relying specifically on alternative methods. Considerations included the possible application of the Threshold of Toxicological Concern (TTC) approach and read-across assessment. Physiologically-based pharmacokinetic modelling was applied to identify target organs and internal concentrations. In silico structural alerts and QSAR profilers as well as in vitro information including high throughput assays were used to build a weight of evidence, based on an AOP-anchored mode-of-action hypothesis and supported by in vitro to in vivo extrapolation (IVIVE) modelling and refinement, with the aim of concluding on the safety of use regarding repeated-dose toxicity, focusing on liver toxicity. Piperonyl butoxide (PBO) was selected to illustrate the case study in fictional exposure scenarios as a new ingredient introduced in a shampoo and a daily applied body lotion. The supportive alternative data (in vitro and in silico) were generated in the SEURAT-1 projects or obtained from ToxCast. The case study focusing on alternative approaches highlights the challenge in integrating multiple data streams for safety assessment decisions, points out knowledge gaps and proposes a way forward.