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DOI10.1093/toxsci/kfy049
Differentiating Pathway-Specific From Nonspecific Effects in High-Throughput Toxicity Data: A Foundation for Prioritizing Adverse Outcome Pathway Development
Fay, Kellie A.1,2; Villeneuve, Daniel L.3; Swintek, Joe4; Edwards, Stephen W.5,6; Nelms, Mark D.5; Blackwell, Brett R.3; Ankley, Gerald T.3
发表日期2018-06-01
ISSN1096-6080
卷号163期号:2页码:500-515
英文摘要

The U.S. Environmental Protection Agency's ToxCast programhas 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.


英文关键词ToxCast;cytotoxic burst;adverse outcome pathway;computational toxicology;in vitro
语种英语
WOS记录号WOS:000434099100019
来源期刊TOXICOLOGICAL SCIENCES
来源机构美国环保署
文献类型期刊论文
条目标识符http://gcip.llas.ac.cn/handle/2XKMVOVA/60806
作者单位1.Univ Minnesota, Dept Biol, 1035 Kirby Dr,Swenson Sci Bldg 207, Duluth, MN 55812 USA;
2.CSRA Inc, Sci & Engn, 6201 Congdon Blvd, Duluth, MN 55804 USA;
3.US EPA, Natl Hlth & Environm Effects Res Lab, Midcontinent Ecol Div, 6201 Congdon Blvd, Duluth, MN 55804 USA;
4.Badger Tech Serv, 6201 Congdon Blvd, Duluth, MN 55804 USA;
5.US EPA, Natl Hlth & Environm Effects Res Lab, Integrated Syst Toxicol Div, 109 TW Alexander Dr,MD B105-03, Res Triangle Pk, NC 27711 USA;
6.RTI Int, Res Comp Div, 3040 E Cornwallis Rd, Durham, NC 27709 USA
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Fay, Kellie A.,Villeneuve, Daniel L.,Swintek, Joe,et al. Differentiating Pathway-Specific From Nonspecific Effects in High-Throughput Toxicity Data: A Foundation for Prioritizing Adverse Outcome Pathway Development[J]. 美国环保署,2018,163(2):500-515.
APA Fay, Kellie A..,Villeneuve, Daniel L..,Swintek, Joe.,Edwards, Stephen W..,Nelms, Mark D..,...&Ankley, Gerald T..(2018).Differentiating Pathway-Specific From Nonspecific Effects in High-Throughput Toxicity Data: A Foundation for Prioritizing Adverse Outcome Pathway Development.TOXICOLOGICAL SCIENCES,163(2),500-515.
MLA 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 163.2(2018):500-515.
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