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DOI10.1021/acs.est.7b00650
An Intuitive Approach for Predicting Potential Human Health Risk with the Tox21 10k Library
Sipes, Nisha S.1; Wambaugh, John F.2; Pearce, Robert2; Auerbach, Scott S.1; Wetmore, Barbara A.5; Hsieh, Jui-Hua4; Shapiro, Andrew J.1; Svoboda, Daniel3; DeVito, Michael J.1; Ferguson, Stephen S.1
发表日期2017-09-19
ISSN0013-936X
卷号51期号:18页码:10786-10796
英文摘要

In vitro in vivo extrapolation (IVIVE) analyses translating high-throughput screening (HTS) data to human relevance have been limited. This study represents the first report applying IVIVE approaches and exposure comparisons using the entirety of the Tox21 federal collaboration chemical screening data, incorporating assay response efficacy and quality of concentration response fits, and providing quantitative anchoring to first address the likelihood of human in vivo interactions with Tox21 compounds. This likelihood was assessed using a maximum blood concentration to in vitro response ratio approach (C-max/AC(50)), analogous to decision-making methods for clinical drug drug interactions. Fraction unbound in plasma (f(up)) and intrinsic hepatic clearance (CLint) parameters were estimated in silico and incorporated in a three-compartment toxicokinetic (TK) model to first predict C-max for in vivo corroboration using therapeutic scenarios. Toward lower exposure scenarios, 36 compounds of 3925 unique chemicals with curated activity in the HTS data using high quality dose response model fits and >= 40% efficacy gave "possible" human in vivo interaction likelihoods lower than median human exposures predicted in the United States Environmental Protection Agency's ExpoCast program. A publicly available web application has been designed to provide all Tox21-ToxCast dose-likelihood predictions. Overall, this approach provides an intuitive framework to relate in vitro toxicology data rapidly and quantitatively to exposures using either in vitro or in silico derived TIC parameters and can be thought of as an important step toward estimating plausible biological interactions in a high throughput risk-assessment framework.


语种英语
WOS记录号WOS:000411549800057
来源期刊ENVIRONMENTAL SCIENCE & TECHNOLOGY
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/59798
作者单位1.NIEHS, Natl Toxicol Program, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA;
2.US EPA, Natl Ctr Computat Toxicol, 109 TW Alexander Dr, Res Triangle Pk, NC 27711 USA;
3.Sciome, 2 Davis Dr, Res Triangle Pk, NC 27709 USA;
4.Kelly Govt Solut, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA;
5.US EPA, Natl Exposure Res Lab, 109 TW Alexander Dr, Res Triangle Pk, NC 27711 USA
推荐引用方式
GB/T 7714
Sipes, Nisha S.,Wambaugh, John F.,Pearce, Robert,et al. An Intuitive Approach for Predicting Potential Human Health Risk with the Tox21 10k Library[J]. 美国环保署,2017,51(18):10786-10796.
APA Sipes, Nisha S..,Wambaugh, John F..,Pearce, Robert.,Auerbach, Scott S..,Wetmore, Barbara A..,...&Ferguson, Stephen S..(2017).An Intuitive Approach for Predicting Potential Human Health Risk with the Tox21 10k Library.ENVIRONMENTAL SCIENCE & TECHNOLOGY,51(18),10786-10796.
MLA Sipes, Nisha S.,et al."An Intuitive Approach for Predicting Potential Human Health Risk with the Tox21 10k Library".ENVIRONMENTAL SCIENCE & TECHNOLOGY 51.18(2017):10786-10796.
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