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DOI | 10.1093/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 |
ISSN | 1096-6080 |
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
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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 |
推荐引用方式 GB/T 7714 | 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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