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Tox21

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https://www.readbyqxmd.com/read/28628784/identifying-populations-sensitive-to-environmental-chemicals-by-simulating-toxicokinetic-variability
#1
Caroline L Ring, Robert G Pearce, R Woodrow Setzer, Barbara A Wetmore, John F Wambaugh
The thousands of chemicals present in the environment (USGAO, 2013) must be triaged to identify priority chemicals for human health risk research. Most chemicals have little of the toxicokinetic (TK) data that are necessary for relating exposures to tissue concentrations that are believed to be toxic. Ongoing efforts have collected limited, in vitro TK data for a few hundred chemicals. These data have been combined with biomonitoring data to estimate an approximate margin between potential hazard and exposure...
June 16, 2017: Environment International
https://www.readbyqxmd.com/read/28587163/a-tox21-approach-to-altered-epigenetic-landscapes-assessing-epigenetic-toxicity-pathways-leading-to-altered-gene-expression-and-oncogenic-transformation-in-vitro
#2
REVIEW
Craig L Parfett, Daniel Desaulniers
An emerging vision for toxicity testing in the 21st century foresees in vitro assays assuming the leading role in testing for chemical hazards, including testing for carcinogenicity. Toxicity will be determined by monitoring key steps in functionally validated molecular pathways, using tests designed to reveal chemically-induced perturbations that lead to adverse phenotypic endpoints in cultured human cells. Risk assessments would subsequently be derived from the causal in vitro endpoints and concentration vs...
June 1, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28557712/an-integrated-chemical-environment-to-support-21st-century-toxicology
#3
Shannon M Bell, Jason Phillips, Alexander Sedykh, Arpit Tandon, Catherine Sprankle, Stephen Q Morefield, Andy Shapiro, David Allen, Ruchir Shah, Elizabeth A Maull, Warren M Casey, Nicole C Kleinstreuer
Access to high-quality reference data is essential for the development, validation, and implementation of in vitro and in silico approaches that reduce and replace the use of animals in toxicity testing. Currently, these data must often be pooled from a variety of disparate sources to efficiently link a set of assay responses and model predictions to an outcome or hazard classification. To provide a central access point for these purposes, the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods developed the Integrated Chemical Environment (ICE) web resource...
May 24, 2017: Environmental Health Perspectives
https://www.readbyqxmd.com/read/28531190/real-time-cell-toxicity-profiling-of-tox21-10k-compounds-reveals-cytotoxicity-dependent-toxicity-pathway-linkage
#4
Jui-Hua Hsieh, Ruili Huang, Ja-An Lin, Alexander Sedykh, Jinghua Zhao, Raymond R Tice, Richard S Paules, Menghang Xia, Scott S Auerbach
Cytotoxicity is a commonly used in vitro endpoint for evaluating chemical toxicity. In support of the U.S. Tox21 screening program, the cytotoxicity of ~10K chemicals was interrogated at 0, 8, 16, 24, 32, & 40 hours of exposure in a concentration dependent fashion in two cell lines (HEK293, HepG2) using two multiplexed, real-time assay technologies. One technology measures the metabolic activity of cells (i.e., cell viability, glo) while the other evaluates cell membrane integrity (i.e., cell death, flor). Using glo technology, more actives and greater temporal variations were seen in HEK293 cells, while results for the flor technology were more similar across the two cell types...
2017: PloS One
https://www.readbyqxmd.com/read/28472532/high-throughput-screening-data-interpretation-in-the-context-of-in-vivo-transcriptomic-responses-to-oral-cr-vi-exposure
#5
Julia E Rager, Caroline L Ring, Rebecca C Fry, Mina Suh, Deborah M Proctor, Laurie C Haws, Mark A Harris, Chad M Thompson
The toxicity of hexavalent chromium [Cr(VI)] in drinking water has been studied extensively, and available in vivo and in vitro studies provide a robust dataset for application of advanced toxicological tools to inform the mode of action (MOA). This study aimed to contribute to the understanding of Cr(VI) MOA by evaluating high-throughput screening (HTS) data and other in vitro data relevant to Cr(VI), and comparing these findings to robust in vivo data, including transcriptomic profiles in target tissues. Evaluation of Tox21 HTS data for Cr(VI) identified 11 active assay endpoints relevant to the Ten Key Characteristics of Carcinogens (TKCCs) that have been proposed by other investigators...
May 2, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28441746/high-performance-prediction-of-human-estrogen-receptor-agonists-based-on-chemical-structures
#6
Yuki Asako, Yoshihiro Uesawa
Many agonists for the estrogen receptor are known to disrupt endocrine functioning. We have developed a computational model that predicts agonists for the estrogen receptor ligand-binding domain in an assay system. Our model was entered into the Tox21 Data Challenge 2014, a computational toxicology competition organized by the National Center for Advancing Translational Sciences. This competition aims to find high-performance predictive models for various adverse-outcome pathways, including the estrogen receptor...
April 23, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28440957/the-role-of-high-throughput-screening-in-ecotoxicology-and-engineered-nanomaterials
#7
REVIEW
Andrew Barrick, Amélie Châtel, Mélanie Bruneau, Catherine Mouneyrac
The field of environmental toxicology developed as a result of growing concerns about anthropogenic influences on the environment and how to ameliorate ecological impact. Many governmental bodies are beginning to emphasize prevention rather than mitigation when addressing novel products, leading to more of a focus on identifying potential toxicity prior to release. With the exponential advances in their development and sale, novel metamaterials and biotechnology are set to dramatically outpace the capabilities of current testing strategies...
April 25, 2017: Environmental Toxicology and Chemistry
https://www.readbyqxmd.com/read/28436609/a-semi-automated-approach-to-create-purposeful-mechanistic-datasets-from-heterogeneous-data-data-mining-towards-the-in-silico-predictions-for-oestrogen-receptor-modulation-and-teratogenicity
#8
M Bashir Surfraz, Adrian Fowkes, Jeffrey P Plante
The need to find an alternative to costly animal studies for developmental and reproductive toxicity testing has shifted the focus considerably to the assessment of in vitro developmental toxicology models and the exploitation of pharmacological data for relevant molecular initiating events. We hereby demonstrate how automation can be applied successfully to handle heterogeneous oestrogen receptor data from ChEMBL. Applying expert-derived thresholds to specific bioactivities allowed an activity call to be attributed to each data entry...
April 24, 2017: Molecular Informatics
https://www.readbyqxmd.com/read/28414904/in-silico-prediction-of-chemicals-binding-to-aromatase-with-machine-learning-methods
#9
Hanwen Du, Yingchun Cai, Hongbin Yang, Hongxiao Zhang, Yuhan Xue, Guixia Liu, Yun Tang, Weihua Li
Environmental chemicals may affect endocrine systems through multiple mechanisms, one of which is via effects on aromatase (also known as CYP19A1), an enzyme critical for maintaining the normal balance of estrogens and androgens in the body. Therefore, rapid and efficient identification of aromatase-related endocrine disrupting chemicals (EDCs) is important for toxicology and environment risk assessment. In this study, on the basis of the Tox21 10K compound library, in silico classification models for predicting aromatase binders/nonbinders were constructed by machine learning methods...
April 26, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28350954/integrating-drug-s-mode-of-action-into-quantitative-structure-activity-relationships-for-improved-prediction-of-drug-induced-liver-injury
#10
Leihong Wu, Zhichao Liu, Scott Auerbach, Ruili Huang, Minjun Chen, Kristin McEuen, Joshua Xu, Hong Fang, Weida Tong
Drug-induced liver injury (DILI) is complex in mechanism. Different drugs could undergo different mechanisms but result in the same DILI type, while the same drug could lead to different DILI types via different mechanisms. Therefore, predicting a drug's potential for DILI should take its underlying mechanisms into consideration. To achieve that, we constructed a novel approach by incorporating the drug's Mode of Action (MOA) into Quantitative Structure-Activity Relationship (QSAR) modeling. This MOA-DILI approach was examined using a data set of 333 drugs...
April 24, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28316234/modeling-exposure-in-the-tox21-in-vitro-bioassays
#11
Fabian C Fischer, Luise Henneberger, Maria König, Kai Bittermann, Lukas Linden, Kai-Uwe Goss, Beate I Escher
High-throughput in vitro bioassays are becoming increasingly important in the risk characterization of anthropogenic chemicals. Large databases gather nominal effect concentrations (Cnom) for diverse modes of action. However, the biologically effective concentration can substantially deviate due to differences in chemical partitioning. In this study, we modeled freely dissolved (Cfree), cellular (Ccell), and membrane concentrations (Cmem) in the Tox21 GeneBLAzer bioassays for a set of neutral and ionogenic organic chemicals covering a large physicochemical space...
April 24, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28294544/identification-of-acetylcholinesterase-inhibitors-using-homogenous-cell-based-assays-in-quantitative-high-throughput-screening-platforms
#12
Shuaizhang Li, Ruili Huang, Samuel Solomon, Yitong Liu, Bin Zhao, Michael F Santillo, Menghang Xia
Acetylcholinesterase (AChE) is an enzyme responsible for metabolism of acetylcholine, a neurotransmitter associated with muscle movement, cognition, and other neurobiological processes. Inhibition of AChE activity can serve as a therapeutic mechanism, but also cause adverse health effects and neurotoxicity. In order to efficiently identify AChE inhibitors from large compound libraries, homogenous cell-based assays in high-throughput screening platforms are needed. In this study, a fluorescent method using Amplex Red (10-acetyl-3,7-dihydroxyphenoxazine) and the Ellman absorbance method were both developed in a homogenous format using a human neuroblastoma cell line (SH-SY5Y)...
March 14, 2017: Biotechnology Journal
https://www.readbyqxmd.com/read/28153528/incorporating-toxcast-and-tox21-datasets-to-rank-biological-activity-of-chemicals-at-superfund-sites-in-north-carolina
#13
Sloane K Tilley, David M Reif, Rebecca C Fry
BACKGROUND: The Superfund program of the Environmental Protection Agency (EPA) was established in 1980 to address public health concerns posed by toxic substances released into the environment in the United States. Forty-two of the 1328 hazardous waste sites that remain on the Superfund National Priority List are located in the state of North Carolina. METHODS: We set out to develop a database that contained information on both the prevalence and biological activity of chemicals present at Superfund sites in North Carolina...
April 2017: Environment International
https://www.readbyqxmd.com/read/28006899/in-silico-prediction-of-physicochemical-properties-of-environmental-chemicals-using-molecular-fingerprints-and-machine-learning
#14
Qingda Zang, Kamel Mansouri, Antony J Williams, Richard S Judson, David G Allen, Warren M Casey, Nicole C Kleinstreuer
There are little available toxicity data on the vast majority of chemicals in commerce. High-throughput screening (HTS) studies, such as those being carried out by the U.S. Environmental Protection Agency (EPA) ToxCast program in partnership with the federal Tox21 research program, can generate biological data to inform models for predicting potential toxicity. However, physicochemical properties are also needed to model environmental fate and transport, as well as exposure potential. The purpose of the present study was to generate an open-source quantitative structure-property relationship (QSPR) workflow to predict a variety of physicochemical properties that would have cross-platform compatibility to integrate into existing cheminformatics workflows...
January 9, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/27933809/development-and-validation-of-a-computational-model-for-androgen-receptor-activity
#15
Nicole C Kleinstreuer, Patricia Ceger, Eric D Watt, Matthew Martin, Keith Houck, Patience Browne, Russell S Thomas, Warren M Casey, David J Dix, David Allen, Srilatha Sakamuru, Menghang Xia, Ruili Huang, Richard Judson
Testing thousands of chemicals to identify potential androgen receptor (AR) agonists or antagonists would cost millions of dollars and take decades to complete using current validated methods. High-throughput in vitro screening (HTS) and computational toxicology approaches can more rapidly and inexpensively identify potential androgen-active chemicals. We integrated 11 HTS ToxCast/Tox21 in vitro assays into a computational network model to distinguish true AR pathway activity from technology-specific assay interference...
April 17, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27805829/2015-lush-science-prize
#16
REVIEW
Jenny McCann, Terry McCann
The Lush Prize supports animal-free testing by rewarding the most effective projects and individuals who have been working toward the goal of replacing animals in product or ingredient safety testing. Prizes are awarded for developments in five strategic areas: Science; Lobbying; Training; Public Awareness; and Young Researchers. Should there be a major breakthrough in 21st century toxicology, a Black Box Prize equivalent to the entire annual fund of £250,000 is awarded. A Background Paper is prepared each year, prior to the judging process, to provide the panel with a brief overview of current developments in the field of Replacement alternatives, particularly those relevant to the concept of toxicity pathways...
October 2016: Alternatives to Laboratory Animals: ATLA
https://www.readbyqxmd.com/read/27780885/futuretox-iii-bridges-for-translation
#17
Daland R Juberg, Thomas B Knudsen, Miriam Sander, Nancy B Beck, Elaine M Faustman, Donna L Mendrick, John R Fowle, Thomas Hartung, Raymond R Tice, Emmanuel Lemazurier, Richard A Becker, Suzanne Compton Fitzpatrick, George P Daston, Alison Harrill, Ronald N Hines, Douglas A Keller, John C Lipscomb, David Watson, Tina Bahadori, Kevin M Crofton
Future Tox III, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in November 2015. Building upon Future Tox I and II, Future Tox III was focused on developing the high throughput risk assessment paradigm and taking the science of in vitro data and in silico models forward to explore the question-what progress is being made to address challenges in implementing the emerging big-data toolbox for risk assessment and regulatory decision-making. This article reports on the outcome of the workshop including 2 examples of where advancements in predictive toxicology approaches are being applied within Federal agencies, where opportunities remain within the exposome and AOP domains, and how collectively the toxicology community across multiple sectors can continue to bridge the translation from historical approaches to Tox21 implementation relative to risk assessment and regulatory decision-making...
January 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27773686/differential-modulation-of-fxr-activity-by-chlorophacinone-and-ivermectin-analogs
#18
Chia-Wen Hsu, Jui-Hua Hsieh, Ruili Huang, Dirk Pijnenburg, Thai Khuc, Jon Hamm, Jinghua Zhao, Caitlin Lynch, Rinie van Beuningen, Xiaoqing Chang, René Houtman, Menghang Xia
Chemicals that alter normal function of farnesoid X receptor (FXR) have been shown to affect the homeostasis of bile acids, glucose, and lipids. Several structural classes of environmental chemicals and drugs that modulated FXR transactivation were previously identified by quantitative high-throughput screening (qHTS) of the Tox21 10K chemical collection. In the present study, we validated the FXR antagonist activity of selected structural classes, including avermectin anthelmintics, dihydropyridine calcium channel blockers, 1,3-indandione rodenticides, and pyrethroid pesticides, using in vitro assay and quantitative structural-activity relationship (QSAR) analysis approaches...
December 15, 2016: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/27668830/structure-based-virtual-screening-protocol-for-in-silico-identification-of-potential-thyroid-disrupting-chemicals-targeting-transthyretin
#19
Jin Zhang, Afshan Begum, Kristoffer Brännström, Christin Grundström, Irina Iakovleva, Anders Olofsson, A Elisabeth Sauer-Eriksson, Patrik L Andersson
Thyroid disruption by xenobiotics is associated with a broad spectrum of severe adverse outcomes. One possible molecular target of thyroid hormone disrupting chemicals (THDCs) is transthyretin (TTR), a thyroid hormone transporter in vertebrates. To better understand the interactions between TTR and THDCs, we determined the crystallographic structures of human TTR in complex with perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and 2,2',4,4'-tetrahydroxybenzophenone (BP2). The molecular interactions between the ligands and TTR were further characterized using molecular dynamics simulations...
November 1, 2016: Environmental Science & Technology
https://www.readbyqxmd.com/read/27642585/predictive-modeling-of-estrogen-receptor-binding-agents-using-advanced-cheminformatics-tools-and-massive-public-data
#20
Kathryn Ribay, Marlene T Kim, Wenyi Wang, Daniel Pinolini, Hao Zhu
Estrogen receptors (ERα) are a critical target for drug design as well as a potential source of toxicity when activated unintentionally. Thus, evaluating potential ERα binding agents is critical in both drug discovery and chemical toxicity areas. Using computational tools, e.g., Quantitative Structure-Activity Relationship (QSAR) models, can predict potential ERα binding agents before chemical synthesis. The purpose of this project was to develop enhanced predictive models of ERα binding agents by utilizing advanced cheminformatics tools that can integrate publicly available bioassay data...
March 2016: Frontiers in environmental science
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