The ongoing developments in chemical risk assessment have led to new concepts building on integration of sophisticated nonanimal models for hazard characterization. Here we explore a pragmatic approach for implementing such concepts, using a case study of three triazole fungicides, namely, flusilazole, propiconazole, and cyproconazole. The strategy applied starts with evaluating the overall level of concern by comparing exposure estimates to toxicological potential, followed by a combination of in silico tools and literature-derived high-throughput screening assays and computational elaborations to obtain insight into potential toxicological mechanisms and targets in the organism. Additionally, some targeted in vitro tests were evaluated for their utility to confirm suspected mechanisms of toxicity and to generate points of departure. Toxicological mechanisms instead of the current “end point-by-end point” approach should guide the selection of methods and assays that constitute a toolbox for next-generation risk assessment. Comparison of the obtained in silico and in vitro results with data from traditional in vivo testing revealed that, overall, nonanimal methods for hazard identification can produce adequate qualitative hazard information for risk assessment. Follow-up studies are needed to further refine the proposed approach, including the composition of the toolbox, toxicokinetics models, and models for exposure assessment.
The research described in this manuscript was financially supported by the Dutch Ministries of Health,
Welfare and Sports and of Economic Affairs; and by the RIVM SPR Program; and by the NanoBio Lab (NBL), the Institute of Bioengineering and Nanotechnology (IBN), the Bioinformatics Institute (BII), and the Innovations in Food and Chemical Safety (IFCS) Programme (grants H18/01/a0/A14 and H18/01/a0/B14) from A*STAR, Singapore.