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Differentiating Pathway-Specific From Nonspecific Effects in High-Throughput Toxicity Data: A Foundation for Prioritizing Adverse Outcome Pathway Development.
Toxicol Sci. 2018 06 01; 163(2):500-515.TS

Abstract

The U.S. Environmental Protection Agency's ToxCast program has screened thousands of chemicals for biological activity, primarily using high-throughput in vitro bioassays. Adverse outcome pathways (AOPs) offer a means to link pathway-specific biological activities with potential apical effects relevant to risk assessors. Thus, efforts are underway to develop AOPs relevant to pathway-specific perturbations detected in ToxCast assays. Previous work identified a "cytotoxic burst" (CTB) phenomenon wherein large numbers of the ToxCast assays begin to respond at or near test chemical concentrations that elicit cytotoxicity, and a statistical approach to defining the bounds of the CTB was developed. To focus AOP development on the molecular targets corresponding to ToxCast assays indicating pathway-specific effects, we conducted a meta-analysis to identify which assays most frequently respond at concentrations below the CTB. A preliminary list of potentially important, target-specific assays was determined by ranking assays by the fraction of chemical hits below the CTB compared with the number of chemicals tested. Additional priority assays were identified using a diagnostic-odds-ratio approach which gives greater ranking to assays with high specificity but low responsivity. Combined, the two prioritization methods identified several novel targets (e.g., peripheral benzodiazepine and progesterone receptors) to prioritize for AOP development, and affirmed the importance of a number of existing AOPs aligned with ToxCast targets (e.g., thyroperoxidase, estrogen receptor, aromatase). The prioritization approaches did not appear to be influenced by inter-assay differences in chemical bioavailability. Furthermore, the outcomes were robust based on a variety of different parameters used to define the CTB.

Authors+Show Affiliations

University of Minnesota-Duluth, Biology Department; 1035 Kirby Drive, Swenson Science Building 207, Duluth, MN 55812. CSRA Inc, Science and Engineering, 6201 Congdon Blvd, Duluth, MN 55804.U.S. EPA National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, MN 55804.Badger Technical Services, 6201 Congdon Blvd, Duluth, MN 55804.U.S. EPA National Health and Environmental Effects Research Laboratory, Integrated Systems Toxicology Division, 109 TW Alexander Dr. (MD B105-03), RTP, NC 27711. RTI International, Research Computing Division, 3040 E Cornwallis Rd, Durham, NC 27709.U.S. EPA National Health and Environmental Effects Research Laboratory, Integrated Systems Toxicology Division, 109 TW Alexander Dr. (MD B105-03), RTP, NC 27711.U.S. EPA National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, MN 55804.U.S. EPA National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, MN 55804.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29529260

Citation

Fay, Kellie A., et al. "Differentiating Pathway-Specific From Nonspecific Effects in High-Throughput Toxicity Data: a Foundation for Prioritizing Adverse Outcome Pathway Development." Toxicological Sciences : an Official Journal of the Society of Toxicology, vol. 163, no. 2, 2018, pp. 500-515.
Fay KA, Villeneuve DL, Swintek J, et al. Differentiating Pathway-Specific From Nonspecific Effects in High-Throughput Toxicity Data: A Foundation for Prioritizing Adverse Outcome Pathway Development. Toxicol Sci. 2018;163(2):500-515.
Fay, K. A., Villeneuve, D. L., Swintek, J., Edwards, S. W., Nelms, M. D., Blackwell, B. R., & Ankley, G. T. (2018). Differentiating Pathway-Specific From Nonspecific Effects in High-Throughput Toxicity Data: A Foundation for Prioritizing Adverse Outcome Pathway Development. Toxicological Sciences : an Official Journal of the Society of Toxicology, 163(2), 500-515. https://doi.org/10.1093/toxsci/kfy049
Fay KA, et al. Differentiating Pathway-Specific From Nonspecific Effects in High-Throughput Toxicity Data: a Foundation for Prioritizing Adverse Outcome Pathway Development. Toxicol Sci. 2018 06 1;163(2):500-515. PubMed PMID: 29529260.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differentiating Pathway-Specific From Nonspecific Effects in High-Throughput Toxicity Data: A Foundation for Prioritizing Adverse Outcome Pathway Development. AU - Fay,Kellie A, AU - Villeneuve,Daniel L, AU - Swintek,Joe, AU - Edwards,Stephen W, AU - Nelms,Mark D, AU - Blackwell,Brett R, AU - Ankley,Gerald T, PY - 2018/3/13/pubmed PY - 2019/4/30/medline PY - 2018/3/13/entrez SP - 500 EP - 515 JF - Toxicological sciences : an official journal of the Society of Toxicology JO - Toxicol. Sci. VL - 163 IS - 2 N2 - The U.S. Environmental Protection Agency's ToxCast program has screened thousands of chemicals for biological activity, primarily using high-throughput in vitro bioassays. Adverse outcome pathways (AOPs) offer a means to link pathway-specific biological activities with potential apical effects relevant to risk assessors. Thus, efforts are underway to develop AOPs relevant to pathway-specific perturbations detected in ToxCast assays. Previous work identified a "cytotoxic burst" (CTB) phenomenon wherein large numbers of the ToxCast assays begin to respond at or near test chemical concentrations that elicit cytotoxicity, and a statistical approach to defining the bounds of the CTB was developed. To focus AOP development on the molecular targets corresponding to ToxCast assays indicating pathway-specific effects, we conducted a meta-analysis to identify which assays most frequently respond at concentrations below the CTB. A preliminary list of potentially important, target-specific assays was determined by ranking assays by the fraction of chemical hits below the CTB compared with the number of chemicals tested. Additional priority assays were identified using a diagnostic-odds-ratio approach which gives greater ranking to assays with high specificity but low responsivity. Combined, the two prioritization methods identified several novel targets (e.g., peripheral benzodiazepine and progesterone receptors) to prioritize for AOP development, and affirmed the importance of a number of existing AOPs aligned with ToxCast targets (e.g., thyroperoxidase, estrogen receptor, aromatase). The prioritization approaches did not appear to be influenced by inter-assay differences in chemical bioavailability. Furthermore, the outcomes were robust based on a variety of different parameters used to define the CTB. SN - 1096-0929 UR - https://www.unboundmedicine.com/medline/citation/29529260/Differentiating_Pathway_Specific_From_Nonspecific_Effects_in_High_Throughput_Toxicity_Data:_A_Foundation_for_Prioritizing_Adverse_Outcome_Pathway_Development_ L2 - https://academic.oup.com/toxsci/article-lookup/doi/10.1093/toxsci/kfy049 DB - PRIME DP - Unbound Medicine ER -