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Comparison and Analysis of Toxcast Data with In Vivo Data for Food-Relevant Compounds Using The Risk21 Approach
Citation:
Turley, A., K. Isaacs, B. Wetmore, A. Karmaus, M. Embry, AND M. Krishan. Comparison and Analysis of Toxcast Data with In Vivo Data for Food-Relevant Compounds Using The Risk21 Approach. 2017 SOT Annual Meeting, Baltimore, MD, March 12 - 16, 2017.
Impact/Purpose:
The ToxCast program has generated a great wealth of in vitro high throughput screening (HTS) data on a large number of compounds, providing a unique resource of information on the bioactivity of these compounds. However, analysis of these data are ongoing, and interpretation and use of the ToxCast data such as for safety assessment of food related compounds remains undetermined.
Description:
The ToxCast program has generated a great wealth of in vitro high throughput screening (HTS) data on a large number of compounds, providing a unique resource of information on the bioactivity of these compounds. However, analysis of these data are ongoing, and interpretation and use of the ToxCast data such as for safety assessment of food related compounds remains undetermined. To fill this gap, we conducted a case study of 2 food-related compounds to better understand the ToxCast data and its potential use in chemical safety assessment by comparison between ToxCast and traditional, in vivo toxicology data using the Risk21 approach. Risk21 is an exposure driven flexible risk assessment framework developed by ILSI HESI. Prior work (Karmaus et. al., 2016) looking at all food-relevant compounds in ToxCast showed that food contact substances had high bioactivity in ToxCast assays. To better understand these chemicals based on their indirect food use, exposure and availability of traditional toxicology data, two compounds, dibutyltin dichloride and sodium pyrithione, were selected from a list of the food contact substances with the greatest activity in ToxCast. Exposure and hazard data were compiled and analyzed for both compounds. Comparison between in vitro HTS and in vivo data for sodium pyrithione showed that concentrations that elicited bioactivity in ToxCast assays corresponded to low- and no- observed adverse effect doses in animals. For dibutyltin dichloride, the concentrations that elicited bioactivity in ToxCast were below the doses causing toxicity in animals; however, this is confounded by the extremely conservative pharmacokinetic parameter estimates used in the in-vitro to in-vivo extrapolation calculations due to a lack of pharmacokinetic data. For both compounds, no mode of action was identifiable from the ToxCast data, and exposure data needed for risk assessment were limited. These studies highlight the gaps in knowledge surrounding HTS in- vitro data, including the lack of coverage of biological targets, and the lack of pharmacokinetic data needed for risk assessment. This abstract does not necessarily reflect U.S. EPA policy.
