Exploring the potential of ToxCast™ data for mechanism-based prioritization of chemicals in regulatory context: Case study with priority existing chemicals (PECs) under K-REACH

Recent studies have highlighted the potential of the ToxCast™ database for mechanism-based prioritization of chemicals. To explore the applicability of ToxCast data in the context of regulatory inventory chemicals, we screened 510 priority existing chemicals (PECs) regulated under the Act on the Registration and Evaluation, etc. of Chemical Substances (K-REACH) using ToxCast bioassays. In our analysis, a hit-call data matrix containing 298984 chemical-gene interactions was computed for 949 bioassays with the intended target genes, which enabled the identification of the putative toxicity mechanisms. Based on the reactivity to the chemicals, we analyzed 412 bioassays whose intended target gene families were cytochrome P450, oxidoreductase, transporter, nuclear receptor, steroid hormone, and DNA-binding. We also identified 141 chemicals based on their reactivity in the bioassays. These chemicals are mainly in consumer products including colorants, preservatives, air fresheners, and detergents. Our analysis revealed that in vitro bioactivities were involved in the relevant mechanisms inducing in vivo toxicity; however, this was not sufficient to predict more hazardous chemicals. Overall, the current results point to a potential and limitation in using ToxCast data for chemical prioritization in regulatory context in the absence of suitable in vivo data.