A Case Study with Triazole Fungicides to Explore Practical Application of Next-Generation Hazard Assessment Methods for Human Health

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.