Exploring the Potential of ToxCast Data in Supporting Read-Across for Evaluation of Food Chemical Safety

The intention of this study was to
determine the utility of high-throughput screening (HTS) data, as
exemplified by ToxCast and Tox21, for application in toxicological
read-across in food-relevant chemicals. Key questions were addressed
on the extent to which the HTS data could provide information enabling
(1) the elucidation of underlying bioactivities associated with apical
toxicological outcomes, (2) the closing of existing toxicological
data gaps, and (3) the definition of the boundaries of chemical space
across which bioactivity could reliably be extrapolated. Results revealed
that many biological targets apparently activated within the chemical
groupings lack, at this time, validated toxicity pathway associations.
Therefore, as means of providing proof-of-principle, a comparatively
well-characterized end pointestrogenicitywas selected
for evaluation. This was facilitated through the preparation of two
exploratory case studies, focusing upon groupings of paraben-gallates
and pyranone-type compounds (notably flavonoids). Within both, the
HTS data were seen to reflect estrogenic potencies in a manner which
broadly corresponded to established structure–activity group
relationships, with parabens and flavonoids displaying greater estrogen
receptor affinity than benzoate esters and alternative pyranone-containing
molecules, respectively. As such, utility in the identification of
out-of-domain compounds was demonstrated, indicating potential for
application in addressing point (3) as detailed above.