This study aimed to explore if high-throughput screening (HTS) data, as exemplified by ToxCast and Tox21, can be applied in toxicological read-across for food-related compounds. Three main questions were tackled regarding the extent to which the HTS data can provide information for facilitating (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. The results showed that many biological targets activated within the chemical groupings lack, at this time, validated toxicity pathway associations. Thus, for providing proof-of-principle, a comparatively well-characterized end point—estrogenicity—was selected for evaluation in the preparation of two case studies, focusing upon groupings of paraben-gallates and pyranone-type compounds (notably flavonoids). In both cases, 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.
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