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Differentiating high priority pathway-based toxicity from non-specific effects in high throughput toxicity data: A foundation for prioritizing AOP development.
Citation:
Fay, K., G. Ankley, B. Blackwell, S. Edwards, M. Nelms, AND Dan Villeneuve. Differentiating high priority pathway-based toxicity from non-specific effects in high throughput toxicity data: A foundation for prioritizing AOP development. SETAC North America, Orlando, FL, November 06 - 10, 2016.
Impact/Purpose:
not applicable
Description:
The ToxCast chemical screening approach enables the rapid assessment of large numbers of chemicals for biological effects, primarily at the molecular level. Adverse outcome pathways (AOPs) offer a means to link biomolecular effects with potential adverse outcomes at the level of the individual or population, thus enhancing the utility of the ToxCast effort for hazard assessment. Thus, efforts are underway to develop AOPs relevant to the pathway perturbations detected in ToxCast assays. However, activity (?‘hits’) determined for chemical-assay pairs may reflect target-specific activity relevant to a molecular initiating event of an AOP, or more generalized cell stress and cytotoxicity-mediated effects. Previous work identified a ?‘cytotoxic burst’ phenomenon wherein large numbers of assays begin to respond at or near concentrations that elicit cytotoxicity. The concentration range at which the “burst” occurs is definable, statistically. Consequently, in order to focus AOP development on the ToxCast assay targetswhich are most sensitive and relevant to pathway-specific effects, we conducted a meta-analysis to identify which assays were frequently responding at concentrations well below the cytotoxic burst. Assays were ranked by the fraction of chemical hits below the burst concentration range compared to the number of chemicals tested, resulting in a preliminary list of potentially important, target-specific assays. After eliminating cytotoxicity assays and other generic xenobiotic response assays (e.g., cytochrome P450 induction and pregnane X receptor activation), the resulting list indicated numerous assays with targets previously identified for AOP development (e.g., thyroid peroxidase, peroxisome proliferator-activated receptor ã, estrogen receptor á, aromatase) along with several novel targets (e.g,, matrix metalloproteinase, thyroid hormone receptorá). Additional analyses identified chemicals that consistently were active within the cytotoxic burst region and compared to predictions of their baseline or narcosis toxicity concentrations. Finally, the analysis of assay responses was used to highlight current ToxCast assays of limited discriminatory ability, which either had zero hits among all chemicals tested or were only activated at cytotoxic concentrations.