Potential of ToxCast Data in the Safety Assessment of Food Chemicals

Abstract

Tox21 and ToxCast are high-throughput in vitro screening programs coordinated by the U.S. National Toxicology Program and the U.S. Environmental Protection Agency, respectively, with the goal of forecasting biological effects in vivo based on bioactivity profiling. The present study investigated whether mechanistic insights in the biological targets of food-relevant chemicals can be obtained from ToxCast results when the chemicals are grouped according to structural similarity. Starting from the 556 direct additives that have been identified in the ToxCast database by Karmaus et al. [Karmaus, A. L., Trautman, T. D., Krishan, M., Filer, D. L., and Fix, L. A. (2017). Curation of food-relevant chemicals in ToxCast. Food Chem. Toxicol. 103, 174-182.], the results showed that, despite the limited number of assays in which the chemical groups have been tested, sufficient results are available within so-called "DNA binding" and "nuclear receptor" target families to profile the biological activities of the defined chemical groups for these targets. The most obvious activity identified was the estrogen receptor-mediated actions of the chemical group containing parabens and structurally related gallates, as well the chemical group containing genistein and daidzein (the latter 2 being particularly active toward estrogen receptor β as a potential health benefit). These group effects, as well as the biological activities of other chemical groups, were evaluated in a series of case studies. Overall, the results of the present study suggest that high-throughput screening data could add to the evidence considered for regulatory risk assessment of food chemicals and to the evaluation of desirable effects of nutrients and phytonutrients. The data will be particularly useful for providing mechanistic information and to fill data gaps with read-across.

Keywords: ToxCast; food chemicals; high-throughput in vitro screening; read-across; risk-benefit.

Figure 1.

Circle pack plot of the defined functional groups and chemical groups. The larger a circle, the more chemicals fall into the group and closely related chemicals are packed more closely together. Tertiary groups (closest related chemicals) are labeled. The legend provides information on the primary chemical groups to which they belong. Details about the composition of the groups can be found in Table 1.

Figure 2.

Heatmaps showing coverage of biological activity for the 102 tertiary chemical groups within the different ToxCast target families. The targets are displayed on the y-axes with ticks, 1 per target. The gradient corresponds to an increasing percentage of chemicals within the chemical group that was active in the different assays of that target. White spots mean that < 3 chemicals were tested in all assays of that target. Gray spots mean that none of the chemicals in the chemical group was active in the assays of that target.

Figure 3.

Heatmaps of the biological activity of the 102 tertiary chemical groups within “DNA binding” and “nuclear receptor” target families. Each target (displayed on the y-axes with labels) is covered by 1–11 assays. The gradient corresponds to an increasing percentage of chemicals within the chemical group that showed activity in the different assays of that target. White spots mean that < 3 chemicals were tested in all assays of that target. Gray spots mean that none of the chemicals in the chemical group was active in the assays of that target. The results for all target families can be interactively viewed through www.https://ilsi.eu/exploitation-of-toxcast-data-on-food-chemicals-for-safety-risk-assessment/ (last accessed January 30, 2020).

Figure 4.

Biological activity of the tertiary chemical groups within the “nuclear receptor” (A–C) and “DNA binding” (D) target families. For each tertiary chemical group, the percent of chemicals that were active in the assays for different target families were calculated and displayed in the colors indicated. The results for all target families can be interactively viewed through www.https://ilsi.eu/exploitation-of-toxcast-data-on-food-chemicals-for-safety-risk-assessment/ (last accessed January 30, 2020).