Programs including the ToxCast project have generated large amounts of in vitro high‒throughput screening (HTS) data, and best approaches for the interpretation and use of HTS data, including for chemical safety assessment, remain to be evaluated. To fill this gap, we conducted case studies of two indirect food additive chemicals where ToxCast data were compared with in vivo toxicity data using the RISK21 approach. Two food contact substances, sodium (2-pyridylthio)-N-oxide and dibutyltin dichloride, were selected, and available exposure data, toxicity data, and model predictions were compiled and assessed. Oral equivalent doses for the ToxCast bioactivity data were determined by in-vitro in-vivo extrapolation (IVIVE). For sodium (2-pyridylthio)-N-oxide, bioactive concentrations in ToxCast assays corresponded to low- and no-observed adverse effect levels in animal studies. For dibutyltin dichloride, the ToxCast bioactive concentrations were below the dose range that demonstrated toxicity in animals; however, this was confounded by the lack of toxicokinetic data, necessitating the use of conservative toxicokinetic parameter estimates for IVIVE calculations. This study highlights the potential utility of the RISK21 approach for interpretation of the ToxCast HTS data, as well as the challenges involved in integrating in vitro HTS data into safety assessments.
This work was supported by the IAFNS Food and Chemical Safety Committee 2016 Summer Fellowship.