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DOI10.1093/toxsci/kfv171
Incorporating High-Throughput Exposure Predictions With Dosimetry-Adjusted In Vitro Bioactivity to Inform Chemical Toxicity Testing
Wetmore, Barbara A.1; Wambaugh, John F.2; Allen, Brittany1; Ferguson, Stephen S.3; Sochaski, Mark A.1; Setzer, R. Woodrow2; Houck, Keith A.2; Strope, Cory L.1; Cantwell, Katherine1; Judson, Richard S.2; LeCluyse, Edward1; Clewell, Harvey J.1; Thomas, Russell S.1,2; Andersen, Melvin E.1
发表日期2015-11-01
ISSN1096-6080
卷号148期号:1页码:121-136
英文摘要

We previously integrated dosimetry and exposure with high-throughput screening (HTS) to enhance the utility of ToxCast HTS data by translating in vitro bioactivity concentrations to oral equivalent doses (OEDs) required to achieve these levels internally. These OEDs were compared against regulatory exposure estimates, providing an activity-to-exposure ratio (AER) useful for a risk-based ranking strategy. As ToxCast efforts expand (ie, Phase II) beyond food-use pesticides toward a wider chemical domain that lacks exposure and toxicity information, prediction tools become increasingly important. In this study, in vitro hepatic clearance and plasma protein binding were measured to estimate OEDs for a subset of Phase II chemicals. OEDs were compared against high-throughput (HT) exposure predictions generated using probabilistic modeling and Bayesian approaches generated by the U.S. Environmental Protection Agency (EPA) ExpoCast program. This approach incorporated chemical-specific use and national production volume data with biomonitoring data to inform the exposure predictions. This HT exposure modeling approach provided predictions for all Phase II chemicals assessed in this study whereas estimates from regulatory sources were available for only 7% of chemicals. Of the 163 chemicals assessed in this study, 3 or 13 chemicals possessed AERs < 1 or < 100, respectively. Diverse bioactivities across a range of assays and concentrations were also noted across the wider chemical space surveyed. The availability of HT exposure estimation and bioactivity screening tools provides an opportunity to incorporate a risk-based strategy for use in testing prioritization.


英文关键词predictive toxicology;ToxCast;in vitro-in vivo extrapolation;dosimetry;exposure assessment
语种英语
WOS记录号WOS:000365547900012
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/58999
作者单位1.Inst Chem Safety Sci, Hamner Inst Hlth Sci, Res Triangle Pk, NC 27709 USA;
2.US EPA, Off Res & Dev, Natl Ctr Computat Toxicol, Res Triangle Pk, NC 27711 USA;
3.ADME, Tox Div Primary & Stem Cell Syst Business Unit, Life Technol, Durham, NC 27703 USA
推荐引用方式
GB/T 7714
Wetmore, Barbara A.,Wambaugh, John F.,Allen, Brittany,et al. Incorporating High-Throughput Exposure Predictions With Dosimetry-Adjusted In Vitro Bioactivity to Inform Chemical Toxicity Testing[J]. 美国环保署,2015,148(1):121-136.
APA Wetmore, Barbara A..,Wambaugh, John F..,Allen, Brittany.,Ferguson, Stephen S..,Sochaski, Mark A..,...&Andersen, Melvin E..(2015).Incorporating High-Throughput Exposure Predictions With Dosimetry-Adjusted In Vitro Bioactivity to Inform Chemical Toxicity Testing.TOXICOLOGICAL SCIENCES,148(1),121-136.
MLA Wetmore, Barbara A.,et al."Incorporating High-Throughput Exposure Predictions With Dosimetry-Adjusted In Vitro Bioactivity to Inform Chemical Toxicity Testing".TOXICOLOGICAL SCIENCES 148.1(2015):121-136.
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