Sample records for epa toxcast program
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The ToxCast Chemical Landscape - Paving the Road to 21st Century Toxicology
The ToxCast high-throughput screening (HTS) program within the U.S. Environmental Protection Agency (EPA) was launched in 2007. Phase I of the program screened 310 chemicals, mostly pesticides, across hundreds of ToxCast assay endpoints. In Phase II, the ToxCast library was exp...
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The ToxCast Chemical Landscape - Paving the Road to 21st ...
The ToxCast high-throughput screening (HTS) program within the U.S. Environmental Protection Agency (EPA) was launched in 2007. Phase I of the program screened 310 chemicals, mostly pesticides, across hundreds of ToxCast assay endpoints. In Phase II, the ToxCast library was expanded to 1878 chemicals, culminating in public release of screening data at the end of 2013. Concurrently, a larger EPA library of 3726 chemicals (including the Phase II chemicals) was undergoing screening in the cross-federal agency Tox21 HTS project. Four years later, Phase III of EPA’s ToxCast program is actively screening a diverse library consisting of more than 3800 chemicals, 96% of which are also undergoing Tox21 screening. The majority of ToxCast studies, to date, have focused on using HTS results to build biologically based models for predicting in vivo toxicity endpoints. The focus of the present article, in contrast, is on the EPA chemical library underpinning these efforts. A history of the phased construction of EPA’s ToxCast library is presented, considering factors influencing chemical selection as well as the various quality measures implemented. Next, Chemical Abstracts Service Registry Numbers (CASRN), which were used to compile initial chemical nominations for ToxCast testing, are used to assess overlaps of the current ToxCast library with important toxicity, regulatory, and exposure inventories. Lastly, ToxCast chemicals are described in terms of generaliz
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US EPA - ToxCast and the Tox21 program: perspectives
ToxCast is a large-scale project being conducted by the U.S. EPA to screen ~2000 chemicals against a large battery of in vitro high-throughput screening (HTS) assays. ToxCast is complemented by the Tox21 project being jointly carried out by the U.S. NIH Chemical Genomics Center (...
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The U.S. EPA's ToxCast Chemical Screening Program and Predictive Modeling of Toxicity
The ToxCast program was developed by the U.S. EPA's National Center for Computational Toxicology to provide cost-effective high-throughput screening for the potential toxicity of thousands of chemicals. Phase I screened 309 compounds in over 500 assays to evaluate concentration-...
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ToxCast Chemical Landscape: Paving the Road to 21st Century Toxicology.
Richard, Ann M; Judson, Richard S; Houck, Keith A; Grulke, Christopher M; Volarath, Patra; Thillainadarajah, Inthirany; Yang, Chihae; Rathman, James; Martin, Matthew T; Wambaugh, John F; Knudsen, Thomas B; Kancherla, Jayaram; Mansouri, Kamel; Patlewicz, Grace; Williams, Antony J; Little, Stephen B; Crofton, Kevin M; Thomas, Russell S
2016-08-15
The U.S. Environmental Protection Agency's (EPA) ToxCast program is testing a large library of Agency-relevant chemicals using in vitro high-throughput screening (HTS) approaches to support the development of improved toxicity prediction models. Launched in 2007, Phase I of the program screened 310 chemicals, mostly pesticides, across hundreds of ToxCast assay end points. In Phase II, the ToxCast library was expanded to 1878 chemicals, culminating in the public release of screening data at the end of 2013. Subsequent expansion in Phase III has resulted in more than 3800 chemicals actively undergoing ToxCast screening, 96% of which are also being screened in the multi-Agency Tox21 project. The chemical library unpinning these efforts plays a central role in defining the scope and potential application of ToxCast HTS results. The history of the phased construction of EPA's ToxCast library is reviewed, followed by a survey of the library contents from several different vantage points. CAS Registry Numbers are used to assess ToxCast library coverage of important toxicity, regulatory, and exposure inventories. Structure-based representations of ToxCast chemicals are then used to compute physicochemical properties, substructural features, and structural alerts for toxicity and biotransformation. Cheminformatics approaches using these varied representations are applied to defining the boundaries of HTS testability, evaluating chemical diversity, and comparing the ToxCast library to potential target application inventories, such as used in EPA's Endocrine Disruption Screening Program (EDSP). Through several examples, the ToxCast chemical library is demonstrated to provide comprehensive coverage of the knowledge domains and target inventories of potential interest to EPA. Furthermore, the varied representations and approaches presented here define local chemistry domains potentially worthy of further investigation (e.g., not currently covered in the testing library or defined by toxicity "alerts") to strategically support data mining and predictive toxicology modeling moving forward.
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The U.S. EPA ToxCast program is entering its tenth year. Significant learning and progress have occurred towards collection, analysis, and interpretation of the data. The library of ~1,800 chemicals has been subject to ongoing characterization (e.g., identity, purity, stability...
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Using the ToxMiner Database for Identifying Disease-Gene Associations in the ToxCast Dataset
The US EPA ToxCast program is using in vitro, high-throughput screening (HTS) to profile and model the bioactivity of environmental chemicals. The main goal of the ToxCast program is to generate predictive signatures of toxicity that ultimately provide rapid and cost-effective me...
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The US EPA ToxCast program is using in vitro HTS (High-Throughput Screening) methods to profile and model bioactivity of environmental chemicals. The main goals of the ToxCast program are to generate predictive signatures of toxicity, and ultimately provide rapid and cost-effecti...
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The US EPA ToxCast program is using in vitro HTS (High-Throughput Screening) methods to profile and model bioactivity of environmental chemicals. The main goals of the ToxCast program are to generate predictive signatures of toxicity, and ultimately provide rapid and cost-effecti...
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The US EPA ToxCast program is using in vitro, high-throughput screening (HTS) to profile and model the bioactivity of environmental chemicals. The main goal of the ToxCast program is to generate predictive signatures of toxicity that ultimately provide rapid and cost-effective me...
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Predictive Model of Rat Reproductive Toxicity from ToxCast High Throughput Screening
The EPA ToxCast research program uses high throughput screening for bioactivity profiling and predicting the toxicity of large numbers of chemicals. ToxCast Phase‐I tested 309 well‐characterized chemicals in over 500 assays for a wide range of molecular targets and cellular respo...
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Considerations in Use of the EPA’s ToxCast Data for Environmental Toxicology (SETAC)
The US EPA has developed the ToxCast program to prioritize chemicals for selective toxicity testing. ToxCast relies on extensive bioactivity profiling using a panel of biochemical and cellular assays that measure chemicals effects on potential molecular initiating events and key ...
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TOXCAST: A PROGRAM FOR PRIORTITIZING TOXICITY TESTING OF ENVIRONMENTAL CHEMICALS
Evaluating the potential of tens of thousands of chemicals for risk to human health and the environment is beyond the resource limits of the Environmental Protection Agency. The EPA's ToxCast program will explore alternative methods comprising computational chemistry, high-throug...
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High Throughput Prioritization for Integrated Toxicity Testing Based on ToxCast Chemical Profiling
The rational prioritization of chemicals for integrated toxicity testing is a central goal of the U.S. EPA’s ToxCast™ program (http://epa.gov/ncct/toxcast/). ToxCast includes a wide-ranging battery of over 500 in vitro high-throughput screening assays which in Phase I was used to...
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EPA'S TOXCAST PROGRAM FOR PREDICTING TOXICITY AND PRIORITIZING ENVIRONMENTAL CHEMICALS
ToxCast is a research program to predict or forecast toxicity by evaluating a broad spectrum of chemicals and effects; physical-chemical properties, predicted bioactivities, HTS and cell-based assays, and genomics. Data will be interpretively linked to known or predicted toxicol...
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An important goal of toxicology research is the development of robust methods that use in vitro and chemical structure information to predict in vivo toxicity endpoints. The US EPA ToxCast program is addressing this goal using ~600 in vitro assays to create bioactivity profiles o...
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Cheminformatics Analysis of EPA ToxCast Chemical Libraries ...
An important goal of toxicology research is the development of robust methods that use in vitro and chemical structure information to predict in vivo toxicity endpoints. The US EPA ToxCast program is addressing this goal using ~600 in vitro assays to create bioactivity profiles on a set of 320 compounds, mostly pesticide actives, that have well characterized in vivo toxicity. These 320 compounds (EPA-320 set evaluated in Phase I of ToxCast) are a subset of a much larger set of ~10,000 candidates that are of interest to the EPA (called here EPA-10K). Predictive models of in vivo toxicity are being constructed from the in vitro assay data on the EPA-320 chemical set. These models require validation on additional chemicals prior to wide acceptance, and this will be carried out by evaluating compounds from EPA-10K in Phase II of ToxCast. We have used cheminformatics approaches including clustering, data visualization, and QSAR to develop models for EPA-320 that could help prioritizing EPA-10K validation chemicals. Both chemical descriptors, as well as calculated physicochemical properties have been used. Compounds from EPA-10K are prioritized based on their similarity to EPA-320 using different similarity metrics, with similarity thresholds defining the domain of applicability for the predictive models built for EPA-320 set. In addition, prioritized lists of compounds of increasing dissimilarity from the EPA-320 have been produced, to test the ability of the EPA-320
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ToxCast: Using high throughput screening to identify profiles of biological activity
ToxCast, the United States Environmental Protection Agency’s chemical prioritization research program, is developing methods for utilizing computational chemistry and bioactivity profiling to predict potential for toxicity and prioritize limited testing resources (www.epa.gov/toc...
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Predictive In Vitro Screening of Environmental Chemicals – The ToxCast Project
ToxCast, the United States Environmental Protection Agency’s chemical prioritization research program, is developing methods for utilizing computational chemistry and bioactivity profiling to predict potential for toxicity and prioritize limited testing resources (www.epa.gov/toc...
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Biotransformation and ToxCast™
A major focus in toxicology research is the development of in vitro methods to predict in vivo chemical toxicity. Within the EPA ToxCast program, a broad range of in vitro biochemical and cellular assays have been deployed to profile the biological activity of 320 ToxCast Phase I...
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EPAs ToxCast Research Program: Developing Predictive Bioactivity Signatures for Chemicals
The international community needs better predictive tools for assessing the hazards and risks of chemicals. It is technically feasible to collect bioactivity data on virtually all chemicals of potential concern ToxCast is providing a proof of concept for obtaining predictive, b...
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With the development of “high throughput” in-vitro biological assays, screening-level information on potential adverse biological effects is available for a rapidly increasing number of chemicals. The U.S. EPA ToxCast program has now evaluated several thousand chemica...
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The EPA ToxCast research program uses a high-throughput screening (HTS) approach for predicting the toxicity of large numbers of chemicals. Phase-I tested 309 well-characterized chemicals (mostly pesticides) in over 500 assays of different molecular targets, cellular responses an...
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The U.S. Environmental Protection Agency (EPA), through its ToxCast program, is developing predictive toxicity approaches that will use in vitro high-throughput screening (HTS), high-content screening (HCS) and toxicogenomic data to predict in vivo toxicity phenotypes. There are ...
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The US EPAs ToxCast Program for the Prioritization and Prediction of Environmental Chemical Toxicity
To meet the need for evaluating large numbers of chemicals for potential toxicity, the U.S. Environmental Protection Agency has initiated a research project call ToxCast that makes use of recent advances in molecular biology and high-throughput screening. These technologies have ...
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The EPA ToxCast program is using in vitro assay data and chemical descriptors to build predictive models for in vivo toxicity endpoints. In vitro assays measure activity of chemicals against molecular targets such as enzymes and receptors (measured in cell-free and cell-based sys...
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ToxMiner: Relating ToxCast bioactivity profiles to phenotypic outcomes
One aim of the U.S. EPA ToxCast program is to develop predictive models that use in vitro assays to screen and prioritize environmental chemicals for further evaluation of potential toxicity. One aspect of this task is the compilation, quality control and analysis of large amount...
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Predictive Modeling of Apical Toxicity Endpoints Using Data From ToxCast
The US EPA and other regulatory agencies face a daunting challenge of evaluating potential toxicity for tens of thousands of environmental chemicals about which little is currently known. The EPA’s ToxCast program is testing a novel approach to this problem by screening compounds...
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EPA is developing methods for utilizing computational chemistry, high-throughput screening (HTS)and genomic technologies to predict potential toxicity and prioritize the use of limited testing resources.
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High throughput toxicology programs, such as ToxCast and Tox21, have provided biological effects data for thousands of chemicals at multiple concentrations. Compared to traditional, whole-organism approaches, high throughput assays are rapid and cost-effective, yet they generall...
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The US EPA ToxCast program is using in vitro high-throughput screening assays to profile the bioactivity of environmental chemicals, with the ultimate goal of predicting in vivo toxicity. We hypothesize that in modeling toxicity it will be more constructive to understand the pert...
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As part of the chemical screening and prioritization research program of the US EPA, the ToxCast Phase II chemicals were assessed using a vertebrate screen for developmental toxicity. Zebrafish embryos (Danio rerio) were exposed in 96-well plates from late-blastula stage (6hr pos...
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In vitro high-throughput screening (HTS) and in silico technologies have emerged as 21st century tools for chemical hazard identification. In 2007 the U.S. Environmental Protection Agency (EPA) launched the ToxCast Program, which has screened thousands of chemicals in hundreds of...
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In vitro high-throughput screening (HTS) and in silico technologies have emerged as 21st century tools for chemical hazard identification. In 2007 the U.S. Environmental Protection Agency (EPA) launched the ToxCast Program, which has screened thousands of chemicals in hundreds of...
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The ToxCast Chemical Prioritization Program at the US EPA (UCLA Molecular Toxicology Program)
To meet the needs of chemical regulators reviewing large numbers of data-poor chemicals for safety, the EPA's National Center for Computational Toxicology is developing a means of efficiently testing thousands of compounds for potential toxicity. High-throughput bioactivity profi...
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A major focus in toxicology research is the development of new in vitro methods to predict in vivo chemical toxicity. Within the EPA ToxCast program, a broad range of in vitro biochemical and cellular assays have been deployed to profile the biological activity of 320 Phase I che...
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The goal of chemical toxicology research is utilizing short term bioassays and/or robust computational methods to predict in vivo toxicity endpoints for chemicals. The ToxCast program established at the US Environmental Protection Agency (EPA) is addressing this goal by using ca....
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EPAs National Center for Computational Toxicology is developing methods that apply computational chemistry, high-throughput screening (HTS) and genomic technologies to predict potential toxicity and prioritize the use of limited testing resources.
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Endocrine Profiling and Prioritization Using ToxCast Assays
The U.S. EPA's Endocrine Disruptor Screening Program (EDSP) is charged with screening pesticide chemicals and environmental contaminants for their potential to affect the endocrine systems of humans and wildlife (http://www.epa.gov/endo/). The prioritization of chemicals for test...
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EPA is developing methods for utilizing computational chemistry, high-throughput screening (HTS) and various toxicogenomic technologies to predict potential for toxicity and prioritize limited testing resources towards chemicals that likely represent the greatest hazard to human ...
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In Phase II of the ToxCast program, the U.S. EPA and Tox21 partners screened 1,877 chemicals, including pesticides; food, cosmetics and personal care ingredients; pharmaceuticals; and industrial chemicals. Testing used a 782 in vitro assays across 7 technologies and multiple bi...
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ExpoCast: Exposure Science for Prioritization and Toxicity Testing (S)
The US EPA is completing the Phase I pilot for a chemical prioritization research program, called ToxCast. Here EPA is developing methods for using computational chemistry, high-throughput screening, and toxicogenomic technologies to predict potential toxicity and prioritize limi...
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Improved chemical risk management and increased efficiency of chemical prioritization, classification and assessment are major goals within EPA. Towards achieving these goals, EPA's ToxCast™ research program has been designed to rapidly screen hundreds to thousands of chemicals' ...
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Extrapolating toxicity data across species using U.S. EPA SeqAPASS tool
In vitro high-throughput screening (HTS) and in silico technologies have emerged as 21st century tools for chemical hazard identification. In 2007 the U.S. Environmental Protection Agency (EPA) launched the ToxCast Program, which has screened thousands of chemicals in hundreds of...
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EPAs ToxCast Program: From Research to Application
A New Paradigm for Toxicity Testing in the 21st Century. In FY 2009, EPA published the toxicity reference database ToxRefDB, which contains results of over 30 years and $2B worth of animal studies for over 400 chemicals. This database is available on EPA’s website, and increases...
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Screening Chemicals for Estrogen Receptor Bioactivity Using a Computational Model.
Browne, Patience; Judson, Richard S; Casey, Warren M; Kleinstreuer, Nicole C; Thomas, Russell S
2015-07-21
The U.S. Environmental Protection Agency (EPA) is considering high-throughput and computational methods to evaluate the endocrine bioactivity of environmental chemicals. Here we describe a multistep, performance-based validation of new methods and demonstrate that these new tools are sufficiently robust to be used in the Endocrine Disruptor Screening Program (EDSP). Results from 18 estrogen receptor (ER) ToxCast high-throughput screening assays were integrated into a computational model that can discriminate bioactivity from assay-specific interference and cytotoxicity. Model scores range from 0 (no activity) to 1 (bioactivity of 17β-estradiol). ToxCast ER model performance was evaluated for reference chemicals, as well as results of EDSP Tier 1 screening assays in current practice. The ToxCast ER model accuracy was 86% to 93% when compared to reference chemicals and predicted results of EDSP Tier 1 guideline and other uterotrophic studies with 84% to 100% accuracy. The performance of high-throughput assays and ToxCast ER model predictions demonstrates that these methods correctly identify active and inactive reference chemicals, provide a measure of relative ER bioactivity, and rapidly identify chemicals with potential endocrine bioactivities for additional screening and testing. EPA is accepting ToxCast ER model data for 1812 chemicals as alternatives for EDSP Tier 1 ER binding, ER transactivation, and uterotrophic assays.
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Analysis of Pfizer compounds in EPA's ToxCast chemicals-assay space.
Shah, Falgun; Greene, Nigel
2014-01-21
The U.S. Environmental Protection Agency (EPA) launched the ToxCast program in 2007 with the goal of evaluating high-throughput in vitro assays to prioritize chemicals that need toxicity testing. Their goal was to develop predictive bioactivity signatures for toxic compounds using a set of in vitro assays and/or in silico properties. In 2009, Pfizer joined the ToxCast initiative by contributing 52 compounds with preclinical and clinical data for profiling across the multiple assay platforms available. Here, we describe the initial analysis of the Pfizer subset of compounds within the ToxCast chemical (n = 1814) and in vitro assay (n = 486) space. An analysis of the hit rate of Pfizer compounds in the ToxCast assay panel allowed us to focus our mining of assays potentially most relevant to the attrition of our compounds. We compared the bioactivity profile of Pfizer compounds to other compounds in the ToxCast chemical space to gain insights into common toxicity pathways. Additionally, we explored the similarity in the chemical and biological spaces between drug-like compounds and environmental chemicals in ToxCast and compared the in vivo profiles of a subset of failed pharmaceuticals having high similarity in both spaces. We found differences in the chemical and biological spaces of pharmaceuticals compared to environmental chemicals, which may question the applicability of bioactivity signatures developed exclusively based on the latter to drug-like compounds if used without prior validation with the ToxCast Phase-II chemicals. Finally, our analysis has allowed us to identify novel interactions for our compounds in particular with multiple nuclear receptors that were previously not known. This insight may help us to identify potential liabilities with future novel compounds.
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Application of the ToxMiner Database: Network Analysis of ...
The US EPA ToxCast program is using in vitro HTS (High-Throughput Screening) methods to profile and model bioactivity of environmental chemicals. The main goals of the ToxCast program are to generate predictive signatures of toxicity, and ultimately provide rapid and cost-effective alternatives to animal testing. The chemicals selected for Phase I are composed largely by a diverse set of pesticide active ingredients, which had sufficient supporting in vivo data included as part of their registration process with the EPA. Other miscellaneous chemicals of environmental concern were also included. Application of HTS to environmental toxicants is a novel approach to predictive toxicology and health risk assessment, and differs from what is required for drug efficacy screening in that biochemical interaction of environmental chemicals are sometimes weaker than that seen with drugs and their intended targets. Additionally, the chemical space covered by environmental chemicals is much broader compared to that of pharmaceuticals. The ToxMiner database has been created and added to the EPA’s ACToR (Aggregated Computational Toxicology Resource) chemical database. One purpose of the ToxMiner database is to link biological, metabolic and cellular pathway data to genes and in vitro assay data for the initial subset of chemicals screened in the ToxCast Phase I HTS assays. Also included in ToxMiner is human disease information, which correlates with ToxCast assays that tar
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Application of the ToxMiner Database: Network Analysis ...
The US EPA ToxCast program is using in vitro HTS (High-Throughput Screening) methods to profile and model bioactivity of environmental chemicals. The main goals of the ToxCast program are to generate predictive signatures of toxicity, and ultimately provide rapid and cost-effective alternatives to animal testing. The chemicals selected for Phase I are composed largely by a diverse set of pesticide active ingredients, which had sufficient supporting in vivo data included as part of their registration process with the EPA. Other miscellaneous chemicals of environmental concern were also included. Application of HTS to environmental toxicants is a novel approach to predictive toxicology and health risk assessment, and differs from what is required for drug efficacy screening in that biochemical interaction of environmental chemicals are sometimes weaker than that seen with drugs and their intended targets. Additionally, the chemical space covered by environmental chemicals is much broader compared to that of pharmaceuticals. The ToxMiner database has been created and added to the EPA’s ACToR (Aggregated Computational Toxicology Resource) chemical database. One purpose of the ToxMiner database is to link biological, metabolic, and cellular pathway data to genes and in vitro assay data for the initial subset of chemicals screened in the ToxCast Phase I HTS assays. Also included in ToxMiner is human disease information, which correlates with ToxCast assays that ta
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Identification of Chemical Features Linked to Thyroperoxidase Inhibition (SOT)
Disruption of maternal serum thyroid hormone (TH) adversely affects fetal neurodevelopment. Therefore, assay development within the US EPA ToxCast program is ongoing to enable screening for chemicals that may disrupt TH, in support of the Endocrine Disruption Screening Program (E...
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Biological Profiling of Endocrine Related Effects of Chemicals in ToxCast
The Food Quality Protection Act of 1996 mandates that EPA implement a validated screening program for detecting estrogenic chemicals, as well as other endocrine targets deemed appropriate by the Administrator. EPA’s Endocrine Disruptor Screening Program (EDSP) has been developing...
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Biological Profiling of Endocrine Related Effects of Chemicals Using ToxCast
The Food Quality Protection Act of 1996 mandates that EPA implement a validated screening program for detecting estrogenic chemicals, as well as other endocrine targets deemed appropriate by the Administrator. EPA’s Endocrine Disruptor Screening Program (EDSP) has been developing...
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Many high-throughput screening (HTPS) assays are available in the US EPA ToxCast program for estrogen and androgen pathways; only a limited number of assays exist for thyroid pathways. One potential target of thyroid-disrupting chemicals is the active uptake of iodide into the t...
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Cheminformatic Analysis of the US EPA ToxCast Chemical Library
The ToxCast project is employing high throughput screening (HTS) technologies, along with chemical descriptors and computational models, to develop approaches for screening and prioritizing environmental chemicals for further toxicity testing. ToxCast Phase I generated HTS data f...
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THE TOXCAST PROGRAM FOR PRIORITIZING TOXICITY TESTING OF ENVIRONMENTAL CHEMICALS
The United States Environmental Protection Agency (EPA) is developing methods for utilizing computational chemistry, high-throughput screening (HTS) and various toxicogenomic technologies to predict potential for toxicity and prioritize limited testing resources towards chemicals...
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Analysis of Ingredient Lists to Quantitatively Characterize Chemicals in Consumer Products
The EPA’s ExpoCast program is developing high throughput (HT) approaches to generate the needed exposure estimates to compare against HT bioactivity data generated from the US inter-agency Tox21 and the US EPA ToxCast programs. Assessing such exposures for the thousands of...
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A High-Throughput Screening Assay to Detect Thyroperoxidase Inhibitors (Teratology Society)
In support of the Endocrine Disruption Screening Program (EDSP21), the US EPA ToxCast program is developing assays to enable screening for chemicals that may disrupt thyroid hormone synthesis. Thyroperoxidase (TPO) is critical for TH synthesis and is a known target of thyroid-dis...
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Modeling limb-bud dysmorphogenesis in a predictive virtual embryo model
ToxCast is profiling the bioactivity of thousands of chemicals based on high-throughput screening (HTS) and computational methods that integrate knowledge of biological systems and in vivo toxicities (www.epa.gov/ncct/toxcast/). Many ToxCast assays assess signaling pathways and c...
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Applications of high throughput screening to identify profiles of biological activity
ToxCast, the United States Environmental Protection Agency’s chemical prioritization research program, is developing methods for utilizing computational chemistry and bioactivity profiling to predict potential for toxicity and prioritize limited testing resources (www.epa.gov/toc...
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Evaluating the Toxicity Pathways Using High-Throughput Environmental Chemical Data
The application of HTS methods to the characterization of human phenotypic response to environmental chemicals is a largely unexplored area of pharmacogenomics. The U.S. Environmental Protection Agency (EPA), through its ToxCast program, is developing predictive toxicity approach...
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The National Exposure Research Laboratory (NERL) Human Exposure and Atmospheric Sciences Division (HEASD) conducts research in support of EPA mission to protect human health and the environment. HEASD research program supports Goal 1 (Clean Air) and Goal 4 (Healthy People) of EP...
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ToxCast Communications and Outreach Strategy (SETAC)
US EPA's Chemical Safety for Sustainability Research Program has been using in vitro testing methods in an effort to accelerate the pace of chemical evaluations and address the significant lack of health and environmental data on the thousands of chemicals found in commonly used ...
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High Throughput Assays and Exposure Science (ISES annual meeting)
High throughput screening (HTS) data characterizing chemical-induced biological activity has been generated for thousands of environmentally-relevant chemicals by the US inter-agency Tox21 and the US EPA ToxCast programs. For a limited set of chemicals, bioactive concentrations r...
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ToxCast, the United States Environmental Protection Agency’s chemical prioritization research program, is developing methods for utilizing computational chemistry and bioactivity profiling to predict potential for toxicity and prioritize limited testing resources (www.epa.gov/toc...
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Predicting hepatotoxicity using ToxCast in vitro bioactivity and chemical structure
Background: The U.S. EPA ToxCastTM program is screening thousands of environmental chemicals for bioactivity using hundreds of high-throughput in vitro assays to build predictive models of toxicity. We represented chemicals based on bioactivity and chemical structure descriptors ...
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Fun with High Throughput Toxicokinetics (CalEPA webinar)
Thousands of chemicals have been profiled by high-throughput screening (HTS) programs such as ToxCast and Tox21. These chemicals are tested in part because there are limited or no data on hazard, exposure, or toxicokinetics (TK). TK models aid in predicting tissue concentrations ...
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Integrating Biological and Chemical Data for Hepatotoxicity Prediction (SOT)
The U.S. EPA ToxCastTM program is screening thousands of environmental chemicals for bioactivity using hundreds of high-throughput in vitro assays to build predictive models of toxicity. A set of 677 chemicals were represented by 711 bioactivity descriptors (from ToxCast assays),...
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Environmental monitoring and surveillance strategies are essential for identifying potential hazards of contaminant exposure to aquatic organisms. Chemical monitoring is effective for chemicals with well characterized hazards and for which sensitive analytical methods are availa...
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High-Throughput Exposure Potential Prioritization for ToxCast Chemicals
The U.S. EPA must consider lists of hundreds to thousands of chemicals when prioritizing research resources in order to identify risk to human populations and the environment. High-throughput assays to identify biological activity in vitro have allowed the ToxCastTM program to i...
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Modeling Reproductive Toxicity for Chemical Prioritization into an Integrated Testing Strategy
The EPA ToxCast research program uses a high-throughput screening (HTS) approach for predicting the toxicity of large numbers of chemicals. Phase-I tested 309 well-characterized chemicals in over 500 assays of different molecular targets, cellular responses and cell-states. Of th...
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Effects-based monitoring and surveillance is increasingly being utilized in conjunction with chemical monitoring to determine potential biological activity associated with environmental contaminants. Supervised approaches targeting specific chemical activity or molecular pathways...
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An alternative is to perform a set of relatively inexpensive and rapid high throughput screening (HTS) assays, derive signatures predictive of effects or modes of chemical toxicity from the HTS data, then use these predictions to prioritize chemicals for more detailed analysis. T...
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The EPA ToxCast Program: Developing Predictive Bioactivity Signatures for Chemicals
There are tens of thousands of chemicals used in the environment for which little or no toxicology information is known. Current testing paradigms that use large numbers of animals to perform in vivo toxicology are too slow and expensive to apply to this large number of chemicals...
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SeqAPASS to evaluate conservation of high-throughput screening targets across non-mammalian species
Cell-based high-throughput screening (HTS) and computational technologies are being applied as tools for toxicity testing in the 21st century. The U.S. Environmental Protection Agency (EPA) embraced these technologies and created the ToxCast Program in 2007, which has served as a...
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In silico study of in vitro GPCR assays by QSAR modeling
The U.S. EPA is screening thousands of chemicals of environmental interest in hundreds of in vitro high-throughput screening (HTS) assays (the ToxCast program). One goal is to prioritize chemicals for more detailed analyses based on activity in molecular initiating events (MIE) o...
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High Throughput Assays for Exposure Science (NIEHS OHAT Staff Meeting presentation)
High throughput screening (HTS) data that characterize chemically induced biological activity have been generated for thousands of chemicals by the US interagency Tox21 and the US EPA ToxCast programs. In many cases there are no data available for comparing bioactivity from HTS w...
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The Future of Toxicity Testing - the NRC Vision and EPA’s ToxCast Program
The EPA requested the National Research Council (NRC) to develop a vision and strategic plan for toxicity testing in the 21st century. The 2007 report called for transforming toxicology to provide a robust scientific basis for assessing adverse health effects of environmental age...
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Testing of environmental and industrial chemicals for toxicity potential is a daunting task because of the wide range of possible toxicity mechanisms. Although animal testing is one means of achieving broad toxicity coverage, evaluation of large numbers of chemicals is challengin...
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The US EPA's ToxCast program is designed to assess chemical perturbations of molecular and cellular endpoints using a variety of high-throughput screening (HTS) assays. However, existing HTS assays have limited or no xenobiotic metabolism which could lead to a mischaracterization...
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Alginate Immobilization of Metabolic Enzymes (AIME) for High-Throughput Screening Assays (SOT)
Alginate Immobilization of Metabolic Enzymes (AIME) for High-Throughput Screening Assays DE DeGroot, RS Thomas, and SO SimmonsNational Center for Computational Toxicology, US EPA, Research Triangle Park, NC USAThe EPA’s ToxCast program utilizes a wide variety of high-throughput s...
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Developing Predictive Toxicity Signatures Using In Vitro Data from the EPA ToxCast Program
A major focus in toxicology research is the development of in vitro methods to predict in vivo chemical toxicity. Numerous studies have evaluated the use of targeted biochemical, cell-based and genomic assay approaches. Each of these techniques is potentially helpful, but provide...
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Feature Analysis of ToxCast Compounds
ToxCast was initiated by the US Environmental Protection Agency (EPA) to prioritize environmental chemicals for toxicity testing. Phase I generated data for 309 unique chemicals, mostly pesticide actives, that span diverse chemical feature/property space, as determined by quantu...
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The US EPA ToxCast Program: Moving from Data Generation ...
The U.S. EPA ToxCast program is entering its tenth year. Significant learning and progress have occurred towards collection, analysis, and interpretation of the data. The library of ~1,800 chemicals has been subject to ongoing characterization (e.g., identity, purity, stability) and is unique in its scope, structural diversity, and use scenarios making it ideally suited to investigate the underlying molecular mechanisms of toxicity. The ~700 high-throughput in vitro assay endpoints cover 327 genes and 293 pathways as well as other integrated cellular processes and responses. The integrated analysis of high-throughput screening data has shown that most environmental and industrial chemicals are very non-selective in the biological targets they perturb, while a small subset of chemicals are relatively selective for specific biological targets. The selectivity of a chemical informs interpretation of the screening results while also guiding future mode-of-action or adverse outcome pathway approaches. Coupling the high-throughput in vitro assays with medium-throughput pharmacokinetic assays and reverse dosimetry allows conversion of the potency estimates to an administered dose. Comparison of the administered dose to human exposure provides a risk-based context. The lessons learned from this effort will be presented and discussed towards application to chemical safety decision making and the future of the computational toxicology program at the U.S. EPA. SOT pr
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Forecasting Exposure in Order to Use High Throughput Hazard Data in a Risk-based Context (WC9)
The ToxCast program and Tox21 consortium have evaluated over 8000 chemicals using in vitro high-throughput screening (HTS) to identify potential hazards. Complementary exposure science needed to assess risk, and the U.S. Environmental Protection Agency (EPA)’s ExpoCast initiative...
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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 progra...
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The need to develop novel screening methods for developmental neurotoxicity in order to alleviate the demands of cost, time, and animals required for in vivo toxicity studies is well recognized. Accordingly, the U.S. EPA launched the ToxCast research program in 2007 to develop c...
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Across several EPA Program Offices (e.g., OPPTS, OW, OAR), there is a clear need to develop strategies and methods to screen large numbers of chemicals for potential toxicity, and to use the resulting information to prioritize the use of testing resources towards those entities a...
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EPA’s National Center for Computational Toxicology is building capabilities to support a new paradigm for toxicity screening and prediction through harnessing of legacy toxicity data, creation of data linkages, and generation of new in vitro screening data. In association with EP...
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Identification of Chemical Features Linked to Thyroperoxidase ...
Disruption of maternal serum thyroid hormone (TH) adversely affects fetal neurodevelopment. Therefore, assay development within the US EPA ToxCast program is ongoing to enable screening for chemicals that may disrupt TH, in support of the Endocrine Disruption Screening Program (EDSP21). The AUR-TPO assay was recently developed to screen >1,000 ToxCast chemicals for potential thyroperoxidase (TPO) inhibition activity. TPO is critical for TH synthesis and is a known target of thyroid-disrupting chemicals. The bioactivity results from the AUR-TPO assay were used to identify chemical substructures associated with in vitro TPO inhibition. Substructure profiles were generated for each chemical in the ToxCast test set using the publicly-available ToxPrint 2.0 chemotypes. Chemotypes enriched among the putative TPO inhibitors were identified using a cumulative hypergeometric probability (p < 0.01). Of the total 729 chemotypes evaluated, 31 were overrepresented among TPO inhibitors. Examination of those 31 chemotypes revealed four basic pharmacophores that accounted for 70% of the ToxCast chemicals active in the AUR-TPO assay: aromatic alcohols, aromatic amines, thiocarbonyls and phosphothioates. Chemico-structural analysis of AUR-TPO screening results enabled the identification of chemical features that likely drive TPO inhibition in the AUR-TPO assay. This highlights the potential to identify thyroid-disrupting chemicals in silico using structural alerts identified by
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A High-Throughput Screening Assay to Detect ...
In support of the Endocrine Disruption Screening Program (EDSP21), the US EPA ToxCast program is developing assays to enable screening for chemicals that may disrupt thyroid hormone synthesis. Thyroperoxidase (TPO) is critical for TH synthesis and is a known target of thyroid-disrupting chemicals that adversely impact neurodevelopment. The AUR-TPO assay was recently developed to screen >1,900 ToxCast chemicals for potential TPO inhibition activity. Parallel assays were used to determine which AUR-TPO actives were more selective for TPO inhibition. Additionally, the TPO inhibition activities of 150 chemicals were compared between the AUR-TPO assay and an orthogonal peroxidase oxidation assay using guaiacol as substrate to confirm putative TPO inhibition profiles. Bioactivity results from the AUR-TPO assay were used to identify chemical substructures associated with in vitro TPO inhibition. Substructure profiles were generated for each chemical in the ToxCast test set using the publicly-available ToxPrint 2.0 chemotypes. Chemotypes enriched among the putative TPO inhibitors were identified using a cumulative hypergeometric probability (p < 0.01). Of the total 729 chemotypes evaluated, 44 were overrepresented among TPO inhibitors. Another 24 chemotypes were found to be significantly underrepresented among AUR-TPO actives. Examination of these chemotypes revealed four basic pharmacophores that accounted for 70% of the ToxCast chemicals active in the AUR-TPO assay:
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ToxCast: EPAs Contribution to the Tox21 Consortium
The international community needs better predictive tools for assessing the hazards and risks of chemicals. It is technically feasible to collect bioactivity data on virtually all chemicals of potential concern ToxCast is providing a proof of concept for obtaining predictive, b...
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EPA's ToxCast chemical library, currently exceeding 4000 unique chemicals, has successfully captured a broad diversity of chemical use-types, functionality, and structures and features potentially relevant to toxicity and environmental exposure landscapes. Chemical diversity in ...
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Exposure to environmental chemicals adds to the burden of disease in humans and wildlife to a degree that is difficult to estimate and, thus, mitigate. The ability to assess the impact of existing chemicals for which little to no toxicity data are available or to foresee such eff...
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High Throughput Genotoxicity Profiling of the US EPA ToxCast Chemical Library
A key aim of the ToxCast project is to investigate modern molecular and genetic high content and high throughput screening (HTS) assays, along with various computational tools to supplement and perhaps replace traditional assays for evaluating chemical toxicity. Genotoxicity is a...
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The US EPA ToxCast program aims to develop methods for mechanistically-based chemical prioritization using a suite of high throughput, in vitro assays that probe relevant biological pathways, and coupling them with statistical and machine learning methods that produce predictive ...
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TOXCAST, A TOOL FOR CATEGORIZATION AND ...
Across several EPA Program Offices (e.g., OPPTS, OW, OAR), there is a clear need to develop strategies and methods to screen large numbers of chemicals for potential toxicity, and to use the resulting information to prioritize the use of testing resources towards those entities and endpoints that present the greatest likelihood of risk to human health and the environment. This need could be addressed using the experience of the pharmaceutical industry in the use of advanced modern molecular biology and computational chemistry tools for the development of new drugs, with appropriate adjustment to the needs and desires of environmental toxicology. A conceptual approach named ToxCast has been developed to address the needs of EPA Program Offices in the area of prioritization and screening. Modern computational chemistry and molecular biology tools bring enabling technologies forward that can provide information about the physical and biological properties of large numbers of chemicals. The essence of the proposal is to conduct a demonstration project based upon a rich toxicological database (e.g., registered pesticides, or the chemicals tested in the NTP bioassay program), select a fairly large number (50-100 or more chemicals) representative of a number of differing structural classes and phenotypic outcomes (e.g., carcinogens, reproductive toxicants, neurotoxicants), and evaluate them across a broad spectrum of information domains that modern technology has pro
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Comparative Analysis of Predictive Models for Liver Toxicity Using ToxCast Assays and Quantitative Structure-Activity Relationships Jie Liu1,2, Richard Judson1, Matthew T. Martin1, Huixiao Hong3, Imran Shah1 1National Center for Computational Toxicology (NCCT), US EPA, RTP, NC...
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Predictive Modeling of Apical Toxicity Endpoints Using Data ...
The US EPA and other regulatory agencies face a daunting challenge of evaluating potential toxicity for tens of thousands of environmental chemicals about which little is currently known. The EPA’s ToxCast program is testing a novel approach to this problem by screening compounds using a variety of in vitro assays and using the results to prioritize chemicals for further, more detailed testing. Phase I of ToxCast is testing 320 chemicals (mainly pesticide active ingredients) against ~400 cell-based and biochemical assays. In order to anchor these studies, we are using in vivo guideline study data for subchronic, chronic, cancer, reproductive and developmental endpoints. This data is compiled in the EPA toxicity reference database, ToxRefDB. The main goal of ToxCast is the discovery and validation of “signatures” linking in vitro assay data to in vivo toxicity endpoints. These signatures will be collections of assays that are correlated with particular endpoints. These assay collections should also help define molecular-and cellular-level mechanisms of toxicity. This talk will discuss our strategy to use a combination of statistical and machine learning methods, coupled with biochemical network or systems biology approaches. Our initial examples will focus signatures for endpoints from 2 year rodent cancer bioassays. Most of the data we have analyzed is in dose or concentration response series, so to effectively use this data we have developed novel appro
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ToxRefDB - Release user-friendly web-based tool for mining ToxRefDB
The updated URL link is for a table of NCCT ToxCast public datasets. The next to last row of the table has the link for the US EPA ToxCast ToxRefDB Data Release October 2014. ToxRefDB provides detailed chemical toxicity data in a publically accessible searchable format. ToxRefD...
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U.S. EPA’s ToxCast and the related Tox21 projects are employing high-throughput screening (HTS) technologies to profile thousands of chemicals, which in turn serve as probes of a wide diversity of targets, pathways and mechanisms related to toxicity. Initial models relating ToxCa...
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Application of ToxCast to evaluate potential biological effects ...
With the development of “high throughput” in-vitro biological assays, screening-level information on potential adverse biological effects is available for a rapidly increasing number of chemicals. The U.S. EPA ToxCast program has now evaluated several thousand chemicals with more than 800 assays. The original intent of this data was to evaluate potential for human health effects, but it is now being extended to environmental health evaluations. The R package ToxEval was developed as a screening tool to use ToxCast results for evaluation of potential adverse biological effects from trace organic chemicals in water samples. Using ToxEval, trace organic chemical data from water samples and passive samplers collected at 57 Great Lakes tributaries from 2010-2013 were examined to determine the tributaries with the greatest potential for adverse biological effects with prioritization of the most influential contaminants. Results are being used as part of the Great Lakes Restoration Initiative to focus current and future investigations that will help understand likely adverse outcome pathways in biological organisms, and to formulate possible remediation strategies. not applicable
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Evaluation of the Neuroactivity of ToxCast Compounds Using Multi-well Microelectrode Array Recordings in Primary Cortical Neurons P Valdivia1, M Martin2, WR LeFew3, D Hall3, J Ross1, K Houck2 and TJ Shafer3 1Axion Biosystems, Atlanta GA and 2NCCT, 3ISTD, NHEERL, ORD, US EPA, RT...
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Tutorial Video Series: Using Stakeholder Outreach to Increase ...
The limited amount of toxicity data on thousands of chemicals found in consumer products has led to the development of research endeavors such as the U.S. EPA’s Toxicity Forecaster (ToxCast). ToxCast uses high-throughput screening technology to evaluate thousands of chemicals for potential toxicity. At the end of 2013, U.S. EPA released ToxCast chemical data on almost 2,000 chemicals through the interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides public access to the high-throughput screening data that can be used to inform the evaluation of the safety of chemicals. U.S. EPA recognized early in the development of ToxCast that stakeholder outreach was needed in order to translate the complex scientific information featured in the iCSS Dashboard and data, with the goal of educating the diverse user community through targeted efforts to increase data usage and analysis. Through survey feedback and the request of stakeholders, a series of tutorial videos to demonstrate how to access and use the data has been planned, and the first video of the series has been released to guide data usage. This presentation will describe the video tutorial strategy including an overview of: 1) Stakeholder outreach goals and approach; 2) Planning, production, and dissemination of tutorial videos; 3) Overview of Survey Feedback; 4) Overview of tutorial video usage statistics and usage of the ToxCast data. This stakeholder-outreach approach
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21st century tools to prioritize contaminants for monitoring and ...
The webinar focused on ways that ToxCast high throughput screening data and the adverse outcome pathway framework, under development in the CSS program, can be used to prioritize environmental contaminants for monitoring and management. The webinar focused on ways that ToxCast high throughput screening data and the adverse outcome pathway framework, under development in the CSS program, can be used to prioritize environmental contaminants for monitoring and management. The work presented focused on case studies conducted in Region 8, in collaboration with EPA Region 8 and NEIC, as well as other federal (USGS, US FWS) and regional partners (Northern Colorado Plateau Network). The Consortium for Research and Education on Emerging Contaminants (CREEC) is a grass-roots 501(c)(3) non-profit organization comprised of world-class scientists and stakeholders with a shared interest in the source, fate, and physiological effects of contaminants of emerging concern (www.creec.net). As such, they represent an important group of stakeholders with an interest in applying the data, approaches, and tools that are being developed by the CSS program.
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Applying 21st century tools to watersheds of the western US ...
The webinar focused on ways that ToxCast high throughput screening data and the adverse outcome pathway framework, under development in the CSS program, can be used to prioritize environmental contaminants for monitoring and management. The webinar focused on ways that ToxCast high throughput screening data and the adverse outcome pathway framework, under development in the CSS program, can be used to prioritize environmental contaminants for monitoring and management. The work presented focused on case studies conducted in Region 8, in collaboration with EPA Region 8 and NEIC, as well as other federal (USGS, US FWS) and regional partners (Northern Colorado Plateau Network). The Consortium for Research and Education on Emerging Contaminants (CREEC) is a grass-roots 501(c)(3) non-profit organization comprised of world-class scientists and stakeholders with a shared interest in the source, fate, and physiological effects of contaminants of emerging concern (www.creec.net). As such, they represent an important group of stakeholders with an interest in applying the data, approaches, and tools that are being developed by the CSS program.
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EPAs DSSTox Chemical Database: A Resource for the Non-Targeted Testing Community (EPA NTA workshop)
EPA’s DSSTox database project, which includes coverage of the ToxCast and Tox21 high-throughput testing inventories, provides high-quality chemical-structure files for inventories of toxicological and environmental relevance. A feature of the DSSTox project, which differentiates ...
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EPAs National Center for Computational Toxicology is building capabilities to support a new paradigm for toxicity screening and prediction. The DSSTox project is improving public access to quality structure-annotated chemical toxicity information in less summarized forms than tr...
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The iCSS Chemistry Dashboard is a publicly accessible dashboard provided by the National Center for Computation Toxicology at the US-EPA. It serves a number of purposes, including providing a chemistry database underpinning many of our public-facing projects (e.g. ToxCast and Exp...
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Tutorial Video Series: Using Stakeholder Outreach to Increase Usage of ToxCast Data (SOT)
Christina Baghdikian1, Tina Bahadori2, Russell S. Thomas2, Kevin Crofton2 and Monica Linnenbrink2; 1ASPPH Fellow Hosted by U.S. EPA Office of Research and Development, 2U.S. EPA Office of Research and Development, Durham, NCTutorial Video Series: Using Stakeholder Outreach to Inc...
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ToxCast Data Generation: Chemical Workflow
This page describes the process EPA follows to select chemicals, procure chemicals, register chemicals, conduct a quality review of the chemicals, and prepare the chemicals for high-throughput screening.
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Chemical-Gene Interactions from ToxCast Bioactivity Data ...
Characterizing the effects of chemicals in biological systems is often summarized by chemical-gene interactions, which have sparse coverage in the literature. The ToxCast chemical screening program has produced bioactivity data for nearly 2000 chemicals and over 450 gene targets. To evaluate the information gained from the ToxCast project, a ToxCast bioactivity network was created comprising ToxCast chemical-gene interactions based on assay data and compared to a chemical-gene association network from literature. The literature network was compiled from PubMed articles, excluding ToxCast publications, mapped to genes and chemicals. Genes were identified by curated associations available from NCBI while chemicals were identified by PubChem submissions. The frequencies of chemical-gene associations from the literature network were log-scaled and then compared to the ToxCast bioactivity network. In total, 140 times more chemical-gene associations were present in the ToxCast network in comparison to the literature-derived network highlighting the vast increase in chemical-gene interactions putatively elucidated by the ToxCast research program. There were 165 associations found in the literature network that were reproduced by ToxCast bioactivity data, and 336 associations in the literature network were not reproduced by the ToxCast bioactivity network. The literature network relies on the assumption that chemical-gene associations represent a true chemical-gene inte
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Predicting hepatotoxicity using ToxCast in vitro bioactivity and ...
Background: The U.S. EPA ToxCastTM program is screening thousands of environmental chemicals for bioactivity using hundreds of high-throughput in vitro assays to build predictive models of toxicity. We represented chemicals based on bioactivity and chemical structure descriptors then used supervised machine learning to predict their hepatotoxic effects.Results: A set of 677 chemicals were represented by 711 in vitro bioactivity descriptors (from ToxCast assays), 4,376 chemical structure descriptors (from QikProp, OpenBabel, PADEL, and PubChem), and three hepatotoxicity categories (from animal studies). Hepatotoxicants were defined by rat liver histopathology observed after chronic chemical testing and grouped into hypertrophy (161), injury (101) and proliferative lesions (99). Classifiers were built using six machine learning algorithms: linear discriminant analysis (LDA), Naïve Bayes (NB), support vector classification (SVM), classification and regression trees (CART), k-nearest neighbors (KNN) and an ensemble of classifiers (ENSMB). Classifiers of hepatotoxicity were built using chemical structure, ToxCast bioactivity, and a hybrid representation. Predictive performance was evaluated using 10-fold cross-validation testing and in-loop, filter-based, feature subset selection. Hybrid classifiers had the best balanced accuracy for predicting hypertrophy (0.78±0.08), injury (0.73±0.10) and proliferative lesions (0.72±0.09). Though chemical and bioactivity class
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Prioritizing Environmental Chemicals for Obesity and Diabetes ...
Background: Diabetes and obesity are major threats to public health in the US and abroad. Understanding the role chemicals in our environment play in the development of these conditions is an emerging issue in environmental health, although identifying and prioritizing chemicals for testing beyond those already implicated in the literature is a challenge. This review is intended to help researchers generate hypotheses about chemicals potentially contributing to diabetes and obesity-related health outcomes by summarizing relevant findings from the US Environmental Protection Agency (EPA) ToxCast high-throughput screening (HTS) program. Objectives: To develop new hypotheses around environmental chemicals of potential interest for diabetes- or obesity-related outcomes using high throughput screening data. Methods: Identify ToxCast assay targets relevant to several biological processes related to diabetes and obesity (insulin sensitivity in peripheral tissue, pancreatic islet and beta cell function, adipocyte dierentiation, and feeding behavior) and present chemical screening data against those assay targets to identify chemicals of potential interest. Discussion: Results of this screening-level analysis suggest that the spectrum of environmental chemicals to consider in research related to diabetes and obesity is much broader than indicated from research papers and reviews published in the peer-reviewed literature. Testing of hypotheses based on ToxCast data will a
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Chiu, Weihsueh A.; Guyton, Kathryn Z.; Martin, Matthew T.; Reif, David M.; Rusyn, Ivan
2017-01-01
Evidence regarding carcinogenic mechanisms serves a critical role in International Agency for Research on Cancer (IARC) Monograph evaluations. Three recent IARC Working Groups pioneered inclusion of the US Environmental Protection Agency (EPA) ToxCast program high-throughput screening (HTS) data to supplement other mechanistic evidence. In Monograph V110, HTS profiles were compared between perfluorooctanoic acid (PFOA) and prototypical activators across multiple nuclear receptors. For Monograph V112 -113, HTS assays were mapped to 10 key characteristics of carcinogens identified by an IARC expert group, and systematically considered as an additional mechanistic data stream. Both individual assay results and ToxPi-based rankings informed mechanistic evaluations. Activation of multiple nuclear receptors in HTS assays showed that PFOA targets peroxisome proliferator activated and other receptors. ToxCast assays substantially covered 5 of 10 key characteristics, corroborating literature evidence of “induces oxidative stress” and “alters cell proliferation, cell death or nutrient supply” and filling gaps for “modulates receptor-mediated effects.” Thus, ToxCast HTS data were useful both in evaluating specific mechanistic hypotheses and in the overall evaluation of mechanistic evidence. However, additional HTS assays are needed to provide more comprehensive coverage of the 10 key characteristics of carcinogens that form the basis of current IARC mechanistic evaluations. PMID:28738424
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Chiu, Weihsueh A; Guyton, Kathryn Z; Martin, Matthew T; Reif, David M; Rusyn, Ivan
2018-01-01
Evidence regarding carcinogenic mechanisms serves a critical role in International Agency for Research on Cancer (IARC) Monograph evaluations. Three recent IARC Working Groups pioneered inclusion of the US Environmental Protection Agency (EPA) ToxCast program high-throughput screening (HTS) data to supplement other mechanistic evidence. In Monograph V110, HTS profiles were compared between perfluorooctanoic acid (PFOA) and prototypical activators across multiple nuclear receptors. For Monograph V112-113, HTS assays were mapped to 10 key characteristics of carcinogens identified by an IARC expert group, and systematically considered as an additional mechanistic data stream. Both individual assay results and ToxPi-based rankings informed mechanistic evaluations. Activation of multiple nuclear receptors in HTS assays showed that PFOA targets not only peroxisome proliferator activated receptors, but also other receptors. ToxCast assays substantially covered 5 of 10 key characteristics, corroborating literature evidence of "induces oxidative stress" and "alters cell proliferation, cell death or nutrient supply" and filling gaps for "modulates receptor-mediated effects." Thus, ToxCast HTS data were useful both in evaluating specific mechanistic hypotheses and in contributing to the overall evaluation of mechanistic evidence. However, additional HTS assays are needed to provide more comprehensive coverage of the 10 key characteristics of carcinogens that form the basis of current IARC mechanistic evaluations.
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ToxCast Workflow: High-throughput screening assay data processing, analysis and management (SOT)
US EPA’s ToxCast program is generating data in high-throughput screening (HTS) and high-content screening (HCS) assays for thousands of environmental chemicals, for use in developing predictive toxicity models. Currently the ToxCast screening program includes over 1800 unique c...
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Toxcast and the Use of Human Relevant In Vitro Exposures ...
The path for incorporating new approach methods and technologies into quantitative chemical risk assessment poses a diverse set of scientific challenges. These challenges include sufficient coverage of toxicological mechanisms to meaningfully interpret negative test results, development of increasingly relevant test systems, computational modeling to integrate experimental data, putting results in a dose and exposure context, characterizing uncertainty, and efficient validation of the test systems and computational models. The presentation will cover progress at the U.S. EPA in systematically addressing each of these challenges and delivering more human-relevant risk-based assessments. This abstract does not necessarily reflect U.S. EPA policy. Presentation at the British Toxicological Society Annual Congress on ToxCast and the Use of Human Relevant In Vitro Exposures: Incorporating high-throughput exposure and toxicity testing data for 21st century risk assessments .
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The CompTox Dashboard is a publicly accessible database provided by the National Center for Computational Toxicology at the US-EPA. The dashboard provides access to a database containing ~720,000 chemicals and integrates a number of our public-facing projects (e.g. ToxCast and Ex...
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USEPA’s ToxCast program has generated high-throughput bioactivity screening (HTS) data on thousands of chemicals. The ToxCast program has described and annotated the HTS assay battery with respect to assay design and target information (e.g., gene target). Recent stakeholder and ...
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Consensus models to predict endocrine disruption for all ...
Humans are potentially exposed to tens of thousands of man-made chemicals in the environment. It is well known that some environmental chemicals mimic natural hormones and thus have the potential to be endocrine disruptors. Most of these environmental chemicals have never been tested for their ability to disrupt the endocrine system, in particular, their ability to interact with the estrogen receptor. EPA needs tools to prioritize thousands of chemicals, for instance in the Endocrine Disruptor Screening Program (EDSP). Collaborative Estrogen Receptor Activity Prediction Project (CERAPP) was intended to be a demonstration of the use of predictive computational models on HTS data including ToxCast and Tox21 assays to prioritize a large chemical universe of 32464 unique structures for one specific molecular target – the estrogen receptor. CERAPP combined multiple computational models for prediction of estrogen receptor activity, and used the predicted results to build a unique consensus model. Models were developed in collaboration between 17 groups in the U.S. and Europe and applied to predict the common set of chemicals. Structure-based techniques such as docking and several QSAR modeling approaches were employed, mostly using a common training set of 1677 compounds provided by U.S. EPA, to build a total of 42 classification models and 8 regression models for binding, agonist and antagonist activity. All predictions were evaluated on ToxCast data and on an exte
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High Throughput Transcriptomics: From screening to pathways
The EPA ToxCast effort has screened thousands of chemicals across hundreds of high-throughput in vitro screening assays. The project is now leveraging high-throughput transcriptomic (HTTr) technologies to substantially expand its coverage of biological pathways. The first HTTr sc...
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ToxCast, the United States Environmental Protection Agency’s chemical prioritization research program, is developing methods for utilizing computational chemistry, bioactivity profiling and toxicogenomic data to predict potential for toxicity and prioritize limited testing resour...
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20180311 - High Throughput Transcriptomics: From screening to pathways (SOT 2018)
The EPA ToxCast effort has screened thousands of chemicals across hundreds of high-throughput in vitro screening assays. The project is now leveraging high-throughput transcriptomic (HTTr) technologies to substantially expand its coverage of biological pathways. The first HTTr sc...
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TOXCAST: A TOOL FOR THE PRIORITIZATION OF CHEMICALS FOR TOXICOLOGICAL EVALUATION
Due to various legislatiave mandates, the US EPA is faced with evaluating the potential of tens of thousands of chemicals (e.g., high production volume chemicals, pestididal inerts, and drinking water contaminants) to cause adverse human health & environmental effects.
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Biochemical Activities of 320 ToxCast Chemicals Evaluated Across 239 Functional Targets
EPA’s ToxCast research program is profiling chemical bioactivity in order to generate predictive signatures of toxicity. The present study evaluated 320 chemicals across 239 biochemical assays. ToxCast phase I chemicals include 309 unique structures, most of which are pesticide ...
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Endocrine Profiling and Prioritization of Environmental Chemicals Using ToxCast Data
Reif, David M.; Martin, Matthew T.; Tan, Shirlee W.; Houck, Keith A.; Judson, Richard S.; Richard, Ann M.; Knudsen, Thomas B.; Dix, David J.; Kavlock, Robert J.
2010-01-01
Background The prioritization of chemicals for toxicity testing is a primary goal of the U.S. Environmental Protection Agency (EPA) ToxCast™ program. Phase I of ToxCast used a battery of 467 in vitro, high-throughput screening assays to assess 309 environmental chemicals. One important mode of action leading to toxicity is endocrine disruption, and the U.S. EPA’s Endocrine Disruptor Screening Program (EDSP) has been charged with screening pesticide chemicals and environmental contaminants for their potential to affect the endocrine systems of humans and wildlife. Objective The goal of this study was to develop a flexible method to facilitate the rational prioritization of chemicals for further evaluation and demonstrate its application as a candidate decision-support tool for EDSP. Methods Focusing on estrogen, androgen, and thyroid pathways, we defined putative endocrine profiles and derived a relative rank or score for the entire ToxCast library of 309 unique chemicals. Effects on other nuclear receptors and xenobiotic metabolizing enzymes were also considered, as were pertinent chemical descriptors and pathways relevant to endocrine-mediated signaling. Results Combining multiple data sources into an overall, weight-of-evidence Toxicological Priority Index (ToxPi) score for prioritizing further chemical testing resulted in more robust conclusions than any single data source taken alone. Conclusions Incorporating data from in vitro assays, chemical descriptors, and biological pathways in this prioritization schema provided a flexible, comprehensive visualization and ranking of each chemical’s potential endocrine activity. Importantly, ToxPi profiles provide a transparent visualization of the relative contribution of all information sources to an overall priority ranking. The method developed here is readily adaptable to diverse chemical prioritization tasks. PMID:20826373
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EPA’s ToxCast program, the NTP’s HTS initiative, and the NCGC’s Molecular Libraries Initiative into a collaborative research program focused on identifying toxicity pathways and developing in vitro assays to characterize the ability of chemicals to perturb those pathways. The go...
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Translating Computational Toxicology Data Through ...
US EPA has been using in vitro testing methods in an effort to accelerate the pace of chemical evaluations and address the significant lack of health and environmental data on the thousands of chemicals found in commonly used products. Since 2005, EPA’s researchers have generated hazard data using in vitro methods for thousands chemicals, designed innovative chemical exposure prediction models, and created a repository of thousands of high quality chemical structure data. Recently, EPA's ToxCast research effort, released high-throughput screening data on thousands of chemicals. These chemicals were screened for potential health effects in over 700 high-throughput screening assay endpoints. As part of EPA’s commitment to transparency, all data is accessible through the Chemical Safety for Sustainability Dashboard (iCSS). Policy makers and stakeholders can analyze and use this data to help inform decisions they make about chemicals. Use of these new datasets in risk decisions will require changing a regulatory paradigm that has been used for decades. EPA recognized early in the ToxCast effort that a communications and outreach strategy was needed to parallel the research and aid with the development and use of these new data sources. The goal is to use communications and outreach to increase awareness, interest and usage of analyzing and using these new chemical evaluation methods. To accomplish this, EPA employs numerous communication and outreach including t
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High-Throughput Models for Exposure-Based Chemical Prioritization in the ExpoCast Project
The United States Environmental Protection Agency (U.S. EPA) must characterize potential risks to human health and the environment associated with manufacture and use of thousands of chemicals. High-throughput screening (HTS) for biological activity allows the ToxCast research pr...
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Test driving ToxCast: endocrine profiling for1858 chemicals included in phase II
Introduction: Identifying chemicals to test for potential endocrine disruption beyond those already implicated in the peer-reviewed literature is a challenge. This review is intended to help by summarizing findings from the Environmental Protection Agency’s (EPA) ToxCast™ high th...
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The ToxCast program has generated a wealth of in vitro high throughput screening data, and best approaches for the interpretation and use of these data remain undetermined. We present case studies comparing the ToxCast and in vivo toxicity data for two food contact substances us...
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Predictive models of prenatal developmental toxicity from ToxCast high-throughput screening data
EPA's ToxCast™ project is profiling the in vitro bioactivity of chemicals to assess pathway-level and cell-based signatures that correlate with observed in vivo toxicity. We hypothesized that developmental toxicity in guideline animal studies captured in the ToxRefDB database wou...
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An Evaluation of 25 Selected ToxCast Chemicals in Medium-Throughput Assays to Detect Genotoxicity
ABSTRACTToxCast is a multi-year effort to develop a cost-effective approach for the US EPA to prioritize chemicals for toxicity testing. Initial evaluation of more than 500 high-throughput (HT) microwell-based assays without metabolic activation showed that most lacked high speci...
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Defining a predictive model of developmental toxicity from in vitro and high-throughput screening (HTS) assays can be limited by the availability of developmental defects data. ToxRefDB (www.epa.gov/ncct/todrefdb) was built from animal studies on data-rich environmental chemicals...
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Chemically-induced vascular toxicity during embryonic development may cause a wide range of adverse effects. To identify putative vascular disrupting chemicals (pVDCs), a predictive signature was constructed from U.S. EPA ToxCast high-throughput screening (HTS) assays that map to...
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EPA’s National Center for Computational Toxicology is generating data and capabilities to support a new paradigm for toxicity screening and prediction. The DSSTox project is improving public access to quality structure-annotated chemical toxicity information in less summarized fo...
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Biological profiling and dose-response modeling tools, characterizing uncertainty
Through its ToxCast project, the U.S. EPA has developed a battery of in vitro high throughput screening (HTS) assays designed to assess the potential toxicity of environmental chemicals. At present, over 1800 chemicals have been tested in up to 600 assays, yielding a large number...
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HIGH-DIMENSIONAL PROFILING OF TRANSCRIPTION FACTOR ACTIVITY DIFFERENTIATES TOXCAST CHEMICAL GROUPS
The ToxCast™ project at the U.S. EPA uses a diverse battery of high throughput screening assays and informatics models to rapidly characterize the activity of chemicals. A central goal of the project is to provide empirical evidence to aid in the prioritization of chemicals for a...
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Phase I of U.S. Environmental Protection Agency’s ToxCastTM research project is building on three rich data tiers: 309 unique, structurally diverse chemicals (predominantly pesticides), activity and concentration response data from approximately 500 in vitro (cell-based and cell-...
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Aggregated Computational Toxicology Online Resource
Aggregated Computational Toxicology Online Resource (AcTOR) is EPA's online aggregator of all the public sources of chemical toxicity data. ACToR aggregates data from over 1,000 public sources on over 500,000 chemicals and is searchable by chemical name, other identifiers and by chemical structure. It can be used to query a specific chemical and find all publicly available hazard, exposure and risk assessment data. It also provides access to EPA's ToxCast, ToxRefDB, DSSTox, Dashboard and DSSTox data.
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In Vitro Testing of Engineered Nanomaterials in the EPA’s ToxCast Program (WC9)
High-throughput and high-content screens are attractive approaches for prioritizing nanomaterial hazards and informing targeted testing due to the impracticality of using traditional toxicological testing on the large numbers and varieties of nanomaterials. The ToxCast program a...
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EPA Project Updates: DSSTox and ToxCast Generating New ...
EPAs National Center for Computational Toxicology is building capabilities to support a new paradigm for toxicity screening and prediction. The DSSTox project is improving public access to quality structure-annotated chemical toxicity information in less summarized forms than traditionally employed in SAR modeling, and in ways that facilitate data-mining, and data read-across. The DSSTox Structure-Browser, launched in September 2007, provides structure searchability across all published DSSTox toxicity-related inventory, and is enabling linkages between previously isolated toxicity data resources. As of early March 2008, the public DSSTox inventory as been integrated into PubChem, allowing a user to take full advantage of PubChem structure-activity and bioassay clustering features. The most recent DSSTox version of Carcinogenic Potency Database file (CPDBAS) illustrates ways in which various summary definitions of carcinogenic activity can be employed in modeling and data mining. Phase I of the ToxCast project is generating high-throughput screening data from several hundred biochemical and cell-based assays for a set of 320 chemicals, mostly pesticide actives, with rich toxicology profiles. Incorporating and expanding traditional SAR Concepts into this new high-throughput and data-rich would pose conceptual and practical challenges, but also holds great promise for improving predictive capabilities. EPA's National Center for Computational Toxicology is bu
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Evaluation of food-relevant chemicals in the ToxCast high-throughput screening program
There are thousands of chemicals that are directly added to or come in contact with food, many of which have undergone little to no toxicological evaluation. The ToxCast high-throughput screening (HTS) program has evaluated over 1,800 chemicals in concentration-response across ~8...
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Learn by Doing - Phase I of the ToxCast Research Program
In 2007, the USEPA embarked on a multi-year, multi-million dollar research program to develop and evaluate a new approach to prioritizing the toxicity testing of environmental chemicals. ToxCast was divided into three main phases of effort – a proof of concept, an expansion and ...
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Heiger-Bernays, Wendy J; Wegner, Susanna; Dix, David J
2018-01-16
The presence of industrial chemicals, consumer product chemicals, and pharmaceuticals is well documented in waters in the U.S. and globally. Most of these chemicals lack health-protective guidelines and many have been shown to have endocrine bioactivity. There is currently no systematic or national prioritization for monitoring waters for chemicals with endocrine disrupting activity. We propose ambient water bioactivity concentrations (AWBCs) generated from high throughput data as a health-based screen for endocrine bioactivity of chemicals in water. The U.S. EPA ToxCast program has screened over 1800 chemicals for estrogen receptor (ER) and androgen receptor (AR) pathway bioactivity. AWBCs are calculated for 110 ER and 212 AR bioactive chemicals using high throughput ToxCast data from in vitro screening assays and predictive pathway models, high-throughput toxicokinetic data, and data-driven assumptions about consumption of water. Chemical-specific AWBCs are compared with measured water concentrations in data sets from the greater Denver area, Minnesota lakes, and Oregon waters, demonstrating a framework for identifying endocrine bioactive chemicals. This approach can be used to screen potential cumulative endocrine activity in drinking water and to inform prioritization of future monitoring, chemical testing and pollution prevention efforts.
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Metabolomics analysis was performed on the supernatant of human embryonic stem (hES) cell cultures exposed to a blinded subset of 11 chemicals selected from the chemical library of EPA's ToxCast™ chemical screening and prioritization research project. Metabolites from hES cultur...
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Evaluation of High-throughput Genotoxicity Assays Used in Profiling the US EPA ToxCast Chemicals
Three high-throughput screening (HTS) genotoxicity assays-GreenScreen HC GADD45a-GFP (Gentronix Ltd.), CellCiphr p53 (Cellumen Inc.) and CellSensor p53RE-bla (Invitrogen Corp.)-were used to analyze the collection of 320 predominantly pesticide active compounds being tested in Pha...
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An Adherent Cell Differentiation and Cytotoxicity (ACDC) in vitro assay with mouse embryonic stem cells was used to screen the ToxCast Phase I chemical library for effects on cellular differentiation and cell number. The U.S. Environmental Protection Agency (EPA) established the ...
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In silico study of in vitro GPCR assays by QSAR modeling ...
The U.S. EPA is screening thousands of chemicals of environmental interest in hundreds of in vitro high-throughput screening (HTS) assays (the ToxCast program). One goal is to prioritize chemicals for more detailed analyses based on activity in molecular initiating events (MIE) of adverse outcome pathways (AOPs). However, the chemical space of interest for environmental exposure is much wider than this set of chemicals. Thus, there is a need to fill data gaps with in silico methods, and quantitative structure-activity relationships (QSARs) are a proven and cost effective approach to predict biological activity. ToxCast in turn provides relatively large datasets that are ideal for training and testing QSAR models. The overall goal of the study described here was to develop QSAR models to fill the data gaps in a larger environmental database of ~32k structures. The specific aim of the current work was to build QSAR models for 18 G-Protein Coupled Receptor (GPCR) assays, part of the aminergic category. Two QSAR modeling strategies were adopted: classification models were developed to separate chemicals into active/non-active classes, and then regression models were built to predict the potency values of the bioassays for the active chemicals. Multiple software programs were used to calculate constitutional, topological and substructural molecular descriptors from two-dimensional (2D) chemical structures. Model-fitting methods included PLSDA (partial least squares d
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Suspect screening and non-targeted analysis of drinking water using point-of-use filters.
Newton, Seth R; McMahen, Rebecca L; Sobus, Jon R; Mansouri, Kamel; Williams, Antony J; McEachran, Andrew D; Strynar, Mark J
2018-03-01
Monitored contaminants in drinking water represent a small portion of the total compounds present, many of which may be relevant to human health. To understand the totality of human exposure to compounds in drinking water, broader monitoring methods are imperative. In an effort to more fully characterize the drinking water exposome, point-of-use water filtration devices (Brita ® filters) were employed to collect time-integrated drinking water samples in a pilot study of nine North Carolina homes. A suspect screening analysis was performed by matching high resolution mass spectra of unknown features to molecular formulas from EPA's DSSTox database. Candidate compounds with those formulas were retrieved from the EPA's CompTox Chemistry Dashboard, a recently developed data hub for approximately 720,000 compounds. To prioritize compounds into those most relevant for human health, toxicity data from the US federal collaborative Tox21 program and the EPA ToxCast program, as well as exposure estimates from EPA's ExpoCast program, were used in conjunction with sample detection frequency and abundance to calculate a "ToxPi" score for each candidate compound. From ∼15,000 molecular features in the raw data, 91 candidate compounds were ultimately grouped into the highest priority class for follow up study. Fifteen of these compounds were confirmed using analytical standards including the highest priority compound, 1,2-Benzisothiazolin-3-one, which appeared in 7 out of 9 samples. The majority of the other high priority compounds are not targets of routine monitoring, highlighting major gaps in our understanding of drinking water exposures. General product-use categories from EPA's CPCat database revealed that several of the high priority chemicals are used in industrial processes, indicating the drinking water in central North Carolina may be impacted by local industries. Published by Elsevier Ltd.
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ACToR: Aggregated Computational Toxicology Resource (T) ...
The EPA Aggregated Computational Toxicology Resource (ACToR) is a set of databases compiling information on chemicals in the environment from a large number of public and in-house EPA sources. ACToR has 3 main goals: (1) The serve as a repository of public toxicology information on chemicals of interest to the EPA, and in particular to be a central source for the testing data on all chemicals regulated by all EPA programs; (2) To be a source of in vivo training data sets for building in vitro to in vivo computational models; (3) To serve as a central source of chemical structure and identity information for the ToxCastTM and Tox21 programs. There are 4 main databases, all linked through a common set of chemical information and a common structure linking chemicals to assay data: the public ACToR system (available at http://actor.epa.gov), the ToxMiner database holding ToxCast and Tox21 data, along with results form statistical analyses on these data; the Tox21 chemical repository which is managing the ordering and sample tracking process for the larger Tox21 project; and the public version of ToxRefDB. The public ACToR system contains information on ~500K compounds with toxicology, exposure and chemical property information from >400 public sources. The web site is visited by ~1,000 unique users per month and generates ~1,000 page requests per day on average. The databases are built on open source technology, which has allowed us to export them to a number of col
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ToxCast: Developing Predictive Signatures of Chemically Induced Toxicity (S)
ToxCast, the United States Environmental Protection Agency’s chemical prioritization research program, is developing methods for utilizing computational chemistry, bioactivity profiling and toxicogenomic data to predict potential for toxicity and prioritize limited testing resour...
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The iCSS CompTox Dashboard is a publicly accessible dashboard provided by the National Center for Computation Toxicology at the US-EPA. It serves a number of purposes, including providing a chemistry database underpinning many of our public-facing projects (e.g. ToxCast and ExpoC...
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Activation of the nuclear receptor CAR (constitutive active/androstane receptor) is implicated in the control several key biological events such as metabolic pathways. Here, we combined data from literature with information obtained from in vitro assays in the US EPA ToxCast dat...
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The Virtual Liver Project (v-LiverTM) is a US EPA effort to simulate the function of the human liver with sufficient accuracy to predict how environmental exposure to xenobiotic compounds will perturb homeostasis. The better we understand the liver, the better we will understand...
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The Toxicity Data Landscape for Environmental Chemicals
Judson, Richard; Richard, Ann; Dix, David J.; Houck, Keith; Martin, Matthew; Kavlock, Robert; Dellarco, Vicki; Henry, Tala; Holderman, Todd; Sayre, Philip; Tan, Shirlee; Carpenter, Thomas; Smith, Edwin
2009-01-01
Objective Thousands of chemicals are in common use, but only a portion of them have undergone significant toxicologic evaluation, leading to the need to prioritize the remainder for targeted testing. To address this issue, the U.S. Environmental Protection Agency (EPA) and other organizations are developing chemical screening and prioritization programs. As part of these efforts, it is important to catalog, from widely dispersed sources, the toxicology information that is available. The main objective of this analysis is to define a list of environmental chemicals that are candidates for the U.S. EPA screening and prioritization process, and to catalog the available toxicology information. Data sources We are developing ACToR (Aggregated Computational Toxicology Resource), which combines information for hundreds of thousands of chemicals from > 200 public sources, including the U.S. EPA, National Institutes of Health, Food and Drug Administration, corresponding agencies in Canada, Europe, and Japan, and academic sources. Data extraction ACToR contains chemical structure information; physical–chemical properties; in vitro assay data; tabular in vivo data; summary toxicology calls (e.g., a statement that a chemical is considered to be a human carcinogen); and links to online toxicology summaries. Here, we use data from ACToR to assess the toxicity data landscape for environmental chemicals. Data synthesis We show results for a set of 9,912 environmental chemicals being considered for analysis as part of the U.S. EPA ToxCast screening and prioritization program. These include high-and medium-production-volume chemicals, pesticide active and inert ingredients, and drinking water contaminants. Conclusions Approximately two-thirds of these chemicals have at least limited toxicity summaries available. About one-quarter have been assessed in at least one highly curated toxicology evaluation database such as the U.S. EPA Toxicology Reference Database, U.S. EPA Integrated Risk Information System, and the National Toxicology Program. PMID:19479008
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Comparison and Analysis of Toxcast Data with In Vivo Data for ...
The ToxCast program has generated a great wealth of in vitro high throughput screening (HTS) data on a large number of compounds, providing a unique resource of information on the bioactivity of these compounds. However, analysis of these data are ongoing, and interpretation and use of the ToxCast data such as for safety assessment of food related compounds remains undetermined. To fill this gap, we conducted a case study of 2 food-related compounds to better understand the ToxCast data and its potential use in chemical safety assessment by comparison between ToxCast and traditional, in vivo toxicology data using the Risk21 approach. Risk21 is an exposure driven flexible risk assessment framework developed by ILSI HESI. Prior work (Karmaus et. al., 2016) looking at all food-relevant compounds in ToxCast showed that food contact substances had high bioactivity in ToxCast assays. To better understand these chemicals based on their indirect food use, exposure and availability of traditional toxicology data, two compounds, dibutyltin dichloride and sodium pyrithione, were selected from a list of the food contact substances with the greatest activity in ToxCast. Exposure and hazard data were compiled and analyzed for both compounds. Comparison between in vitro HTS and in vivo data for sodium pyrithione showed that concentrations that elicited bioactivity in ToxCast assays corresponded to low- and no- observed adverse effect doses in animals. For dibutyltin dichlori
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High-Throughput/High-Content Screening Assays with Engineered Nanomaterials in ToxCast
High-throughput and high-content screens are attractive approaches for prioritizing nanomaterial hazards and informing targeted testing due to the impracticality of using traditional toxicological testing on the large numbers and varieties of nanomaterials. The ToxCast program a...
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ToxCast Data Expands Universe of Chemical-Gene Interactions (SOT)
Characterizing the effects of chemicals in biological systems is often summarized by chemical-gene interactions, which have sparse coverage in literature. The ToxCast chemical screening program has produced bioactivity data for nearly 2000 chemicals and over 450 gene targets. Thi...
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Background: Chemical toxicity testing is being transformed by advances in biology and computer modeling, concerns over animal use and the thousands of environmental chemicals lacking toxicity data. EPA's ToxCast program aims to address these concerns by screening and prioritizing chemicals for potential human toxicity using in vitro assays and in silico approaches. Objectives: This project aims to evaluate the use of in vitro assays for understanding the types of molecular and pathway perturbations caused by environmental chemicals and to build initial prioritization models of in vivo toxicity. Methods: We tested 309 mostly pesticide active chemicals in 467 assays across 9 technologies, including high-throughput cell-free assays and cell-based assays in multiple human primary cells and cell lines, plus rat primary hepatocytes. Both individual and composite scores for effects on genes and pathways were analyzed. Results: Chemicals display a broad spectrum of activity at the molecular and pathway levels. Many expected interactions are seen, including endocrine and xenobiotic metabolism enzyme activity. Chemicals range in promiscuity across pathways, from no activity to affecting dozens of pathways. We find a statistically significant inverse association between the number of pathways perturbed by a chemical at low in vitro concentrations and the lowest in vivo dose at which a chemical causes toxicity. We also find associations between a small set in vitro ass
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Analysis of ToxCast data for food-relevant compounds by ...
The ToxCast program has generated a wealth of in vitro high throughput screening data, and best approaches for the interpretation and use of these data remain undetermined. We present case studies comparing the ToxCast and in vivo toxicity data for two food contact substances using the RISK21 approach. Available exposure data, toxicity data, and model predictions were analyzed for sodium pyrithione and dibutyltin dichloride. In-vitro to in-vivo extrapolation (IVIVE) was performed to determine oral equivalent doses (OEDs) for the ToxCast data bioactivity. For sodium pyrithione, calculated OEDs corresponded to doses that demonstrated toxicity in animal studies. For dibutyltin dichloride, calculated OEDs were below the doses that demonstrated toxicity in animals, but this was confounded by the conservative estimates used in the IVIVE calculations. These studies highlight the potential of the ToxCast approach while also indicating areas where additional data or predictive tools are needed. We present case studies comparing the ToxCast and in vivo toxicity data for two food contact substances using the RISK21 approach.
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US EPA’s ToxCast research program evaluates bioactivity for thousands of chemicals utilizing high-throughput screening assays to inform chemical testing decisions. Vala Sciences provides high content, multiplexed assays that utilize quantitative cell-based digital image analysis....
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Identifying Structural Alerts Based on Zebrafish Developmental Morphological Toxicity (TDS)
Zebrafish constitute a powerful alternative animal model for chemical hazard evaluation. To provide an in vivo complement to high-throughput screening data from the ToxCast program, zebrafish developmental toxicity screens were conducted on the ToxCast Phase I (Padilla et al., 20...
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Metabolism Retrofit Strategies for ToxCast Assays (BOSC)
The EPA’s ToxCast program utilizes a wide variety of high-throughput screening assays (HTS) to assess chemical perturbations of molecular and cellular endpoints. A limitation of many HTS assays used for toxicity assessment is the lack of xenobiotic metabolism (XM) which precludes...
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Nanomaterial (NM) bioactivity profiling by ToxCast high-throughput screening (HTS)
Rapidly increasing numbers of new NMs and their uses demand efficient tests of NM bioactivity for safety assessment. The EPA’s ToxCast program uses HTS assays to prioritize for targeted testing, identify biological pathways affected, and aid in linking NM properties and potential...
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High-throughput and high-content screens are attractive approaches for prioritizing nanomaterial hazards and informing targeted testing due to the impracticality of using traditional toxicological testing on the large numbers and varieties of nanomaterials. The ToxCast program a...
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Understanding the potential health risks posed by environmental chemicals is a significant challenge driven by the large number of diverse chemicals with generally uncharacterized exposures, mechanisms and toxicities. The U.S. EPA’s ToxCast chemical prioritization research projec...
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ACToR - Aggregated Computational Toxicology Resource ...
There are too many uncharacterized environmental chemicals to test with current in vivo protocols. Develop predictive in vitro screening assays that can be used to prioritize chemicals for detailed testing. ToxCast program requires large amounts of data: In vitro assays (mainly generated by ToxCast program) and In vivo data to develop and validate predictive signatures ACToR is compiling both sets of data for use in predictive algorithms.
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Characterizing the effects of chemicals in biological systems is often summarized by chemical-gene interactions, which have sparse coverage in the literature. The ToxCast chemical screening program has produced bioactivity data for nearly 2000 chemicals and over 450 gene targets....
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Find relationships between bioactivities and NM characteristics or testing conditions. Recommend a dose metric for NMs in vitro studies. Establish associations to in vivo toxicity or pathways identified from testing of conventional chemicals with ToxCast HTS methods. May be abl...
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In Vitro Bioactivity in ToxCast Assays for Fruit and Vegetable Juices (TDS)
The ToxCast and Tox21 programs have generated in vitro screening data for over 1000 chemicals to aid in hazard identification and setting chemical testing priorities. These data, together with in vitro pharmacokinetic data, are used to infer possible toxic responses and external ...
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Chemical toxicity testing is being transformed by advances in biology and computer modeling, concerns over animal use, and the thousands of environmental chemicals lacking toxicity data. The U.S. Environmental Protection Agency’s ToxCast program aims to address these concerns by ...
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Chemical perturbation of vascular development is a putative toxicity pathway which may result in developmental toxicity. EPA’s high-throughput screening (HTS) ToxCast program contains assays which measure cellular signals and biological processes critical for blood vessel develop...
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The USEPA’s ToxCast program is developing a novel approach to chemical toxicity testing using high-throughput screening (HTS) assays to rapidly test thousands of chemicals against hundreds of in vitro molecular targets. This approach is based on the premise that in vitro HTS bioa...
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Endocrine Profiling and Prioritization of Environmental Chemicals Using ToxCast Data
The prioritization of chemicals for toxicity testing is a primary goal of the U.S. EPA’s ToxCast™ program. Phase I of ToxCast utilized a battery of 467 in vitro, high-throughput screening assays to assess 309 environmental chemicals. One important mode of action leading to toxici...
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Quantitative Model of Systemic Toxicity Using ToxCast and ToxRefDB (SOT)
EPA’s ToxCast program profiles the bioactivity of chemicals in a diverse set of ~700 high throughput screening (HTS) assays. In collaboration with L’Oreal, a quantitative model of systemic toxicity was developed using no effect levels (NEL) from ToxRefDB for 633 chemicals with HT...
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Modeling and Predicting Cancer from ToxCast Phase I Data
The ToxCast program is generating a diverse collection of in vitro cell free and cell based HTS data to be used for predictive modeling of in vivo toxicity. We are using this in vitro data, plus corresponding in vivo data from ToxRefDB, to develop models for prediction and priori...
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Currently, little justification is provided for nanomaterial testing concentrations in in vitro assays. The in vitro concentrations typically used may be higher than those experienced by exposed humans. Selection of concentration levels for hazard evaluation based on real-world e...
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Recent Developments in Toxico-Cheminformatics; Supporting ...
EPA's National Center for Computational Toxicology is building capabilities to support a new paradigm for toxicity screening and prediction through the harnessing of legacy toxicity data, creation of data linkages, and generation of new high-content and high-thoughput screening data. In association with EPA's ToxCast, ToxRefDB, and ACToR projects, the DSSTox project provides cheminformatics support and, in addition, is improving public access to quality structure-annotated chemical toxicity information in less summarized forms than traditionally employed in SAR modeling, and in ways that facilitate data-mining and data read-across. The latest DSSTox version of the Carcinogenic Potency Database file (CPDBAS) illustrates ways in which various summary definitions of carcinogenic activity can be employed in modeling and data mining. DSSTox Structure-Browser provides structure searchability across all published DSSTox toxicity-related inventory, and is enabling linkages between previously isolated toxicity data resources associated with environmental and industrial chemicals. The public DSSTox inventory also has been integrated into PubChem, allowing a user to take full advantage of PubChem structure-activity and bioassay clustering features. Phase I of the ToxCast project is generating high-throughput screening data from several hundred biochemical and cell-based assays for a set of 320 chemicals, mostly pesticide actives with rich toxicology profiles. Incorporating
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Kleinstreuer, N.C., E-mail: kleinstreuer.nicole@epa.gov; Smith, A.M.; West, P.R.
2011-11-15
Metabolomics analysis was performed on the supernatant of human embryonic stem (hES) cell cultures exposed to a blinded subset of 11 chemicals selected from the chemical library of EPA's ToxCast Trade-Mark-Sign chemical screening and prioritization research project. Metabolites from hES cultures were evaluated for known and novel signatures that may be indicative of developmental toxicity. Significant fold changes in endogenous metabolites were detected for 83 putatively annotated mass features in response to the subset of ToxCast chemicals. The annotations were mapped to specific human metabolic pathways. This revealed strong effects on pathways for nicotinate and nicotinamide metabolism, pantothenate and CoAmore » biosynthesis, glutathione metabolism, and arginine and proline metabolism pathways. Predictivity for adverse outcomes in mammalian prenatal developmental toxicity studies used ToxRefDB and other sources of information, including Stemina Biomarker Discovery's predictive DevTox Registered-Sign model trained on 23 pharmaceutical agents of known developmental toxicity and differing potency. The model initially predicted developmental toxicity from the blinded ToxCast compounds in concordance with animal data with 73% accuracy. Retraining the model with data from the unblinded test compounds at one concentration level increased the predictive accuracy for the remaining concentrations to 83%. These preliminary results on a 11-chemical subset of the ToxCast chemical library indicate that metabolomics analysis of the hES secretome provides information valuable for predictive modeling and mechanistic understanding of mammalian developmental toxicity. -- Highlights: Black-Right-Pointing-Pointer We tested 11 environmental compounds in a hESC metabolomics platform. Black-Right-Pointing-Pointer Significant changes in secreted small molecule metabolites were observed. Black-Right-Pointing-Pointer Perturbed mass features map to pathways critical for normal development and pregnancy. Black-Right-Pointing-Pointer Arginine, proline, nicotinate, nicotinamide and glutathione pathways were affected.« less
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Tilley, Sloane K.; Reif, David M.; Fry, Rebecca C.
2017-01-01
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. A chemical characterization tool, the Toxicological Priority Index (ToxPi), was used to rank the biological activity of these chemicals based on their predicted bioavailability, documented associations with biological pathways, and activity in in vitro assays of the ToxCast and Tox21 programs. Results The ten most prevalent chemicals found at North Carolina Superfund sites were chromium, trichloroethene, lead, tetrachloroethene, arsenic, benzene, manganese, 1,2-dichloroethane, nickel, and barium. For all chemicals found at North Carolina Superfund sites, ToxPi analysis was used to rank their biological activity. Through this data integration, residual pesticides and organic solvents were identified to be some of the most highly-ranking predicted bioactive chemicals. This study provides a novel methodology for creating state or regional databases of Superfund sites. Conclusions These data represent a novel integrated profile of the most prevalent chemicals at North Carolina Superfund sites. This information, and the associated methodology, is useful to toxicologists, risk assessors, and the communities living in close proximity to these sites. PMID:28153528
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Tilley, Sloane K; Reif, David M; Fry, Rebecca C
2017-04-01
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. 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. A chemical characterization tool, the Toxicological Priority Index (ToxPi), was used to rank the biological activity of these chemicals based on their predicted bioavailability, documented associations with biological pathways, and activity in in vitro assays of the ToxCast and Tox21 programs. The ten most prevalent chemicals found at North Carolina Superfund sites were chromium, trichloroethene, lead, tetrachloroethene, arsenic, benzene, manganese, 1,2-dichloroethane, nickel, and barium. For all chemicals found at North Carolina Superfund sites, ToxPi analysis was used to rank their biological activity. Through this data integration, residual pesticides and organic solvents were identified to be some of the most highly-ranking predicted bioactive chemicals. This study provides a novel methodology for creating state or regional databases of biological activity of contaminants at Superfund sites. These data represent a novel integrated profile of the most prevalent chemicals at North Carolina Superfund sites. This information, and the associated methodology, is useful to toxicologists, risk assessors, and the communities living in close proximity to these sites. Copyright © 2016. Published by Elsevier Ltd.
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Wang, Jun; Hallinger, Daniel R; Murr, Ashley S; Buckalew, Angela R; Simmons, Steven O; Laws, Susan C; Stoker, Tammy E
2018-05-01
Thyroid uptake of iodide via the sodium-iodide symporter (NIS) is the first step in the biosynthesis of thyroid hormones that are critical for health and development in humans and wildlife. Despite having long been a known target of endocrine disrupting chemicals such as perchlorate, information regarding NIS inhibition activity is still unavailable for the vast majority of environmental chemicals. This study applied a previously validated high-throughput approach to screen for NIS inhibitors in the ToxCast phase I library, representing 293 important environmental chemicals. Here 310 blinded samples were screened in a tiered-approach using an initial single-concentration (100 μM) radioactive-iodide uptake (RAIU) assay, followed by 169 samples further evaluated in multi-concentration (0.001 μM-100 μM) testing in parallel RAIU and cell viability assays. A novel chemical ranking system that incorporates multi-concentration RAIU and cytotoxicity responses was also developed as a standardized method for chemical prioritization in current and future screenings. Representative chemical responses and thyroid effects of high-ranking chemicals are further discussed. This study significantly expands current knowledge of NIS inhibition potential in environmental chemicals and provides critical support to U.S. EPA's Endocrine Disruptor Screening Program (EDSP) initiative to expand coverage of thyroid molecular targets, as well as the development of thyroid adverse outcome pathways (AOPs).
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The ToxCast program has generated a great wealth of in vitro high throughput screening (HTS) data on a large number of compounds, providing a unique resource of information on the bioactivity of these compounds. However, analysis of these data are ongoing, and interpretation and ...
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High quality chemical structure inventories provide the foundation of the U.S. EPA’s ToxCast and Tox21 projects, which are employing high-throughput technologies to screen thousands of chemicals in hundreds of biochemical and cell-based assays, probing a wide diversity of targets...
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US EPA’s ToxCast program has screened thousands of chemicals in hundreds of mammalian-based HTS assays for biological activity suggestive of potential toxic effects. These data are being used to prioritize toxicity testing to focus on chemicals likely to lead to adverse health ef...
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ACToR Chemical Structure processing using Open Source ...
ACToR (Aggregated Computational Toxicology Resource) is a centralized database repository developed by the National Center for Computational Toxicology (NCCT) at the U.S. Environmental Protection Agency (EPA). Free and open source tools were used to compile toxicity data from over 1,950 public sources. ACToR contains chemical structure information and toxicological data for over 558,000 unique chemicals. The database primarily includes data from NCCT research programs, in vivo toxicity data from ToxRef, human exposure data from ExpoCast, high-throughput screening data from ToxCast and high quality chemical structure information from the EPA DSSTox program. The DSSTox database is a chemical structure inventory for the NCCT programs and currently has about 16,000 unique structures. Included are also data from PubChem, ChemSpider, USDA, FDA, NIH and several other public data sources. ACToR has been a resource to various international and national research groups. Most of our recent efforts on ACToR are focused on improving the structural identifiers and Physico-Chemical properties of the chemicals in the database. Organizing this huge collection of data and improving the chemical structure quality of the database has posed some major challenges. Workflows have been developed to process structures, calculate chemical properties and identify relationships between CAS numbers. The Structure processing workflow integrates web services (PubChem and NIH NCI Cactus) to d
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The EPA Comptox Chemistry Dashboard: A Web-Based Data ...
The U.S. Environmental Protection Agency (EPA) Computational Toxicology Program integrates advances in biology, chemistry, and computer science to help prioritize chemicals for further research based on potential human health risks. This work involves computational and data driven approaches that integrate chemistry, exposure and biological data. As an outcome of these efforts the National Center for Computational Toxicology (NCCT) has measured, assembled and delivered an enormous quantity and diversity of data for the environmental sciences including high-throughput in vitro screening data, in vivo and functional use data, exposure models and chemical databases with associated properties. A series of software applications and databases have been produced over the past decade to deliver these data but recent developments have focused on the development of a new software architecture that assembles the resources into a single platform. A new web application, the CompTox Chemistry Dashboard provides access to data associated with ~720,000 chemical substances. These data include experimental and predicted physicochemical property data, bioassay screening data associated with the ToxCast program, product and functional use information and a myriad of related data of value to environmental scientists. The dashboard provides chemical-based searching based on chemical names, synonyms and CAS Registry Numbers. Flexible search capabilities allow for chemical identificati
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The EPA CompTox Chemistry Dashboard - an online resource ...
The U.S. Environmental Protection Agency (EPA) Computational Toxicology Program integrates advances in biology, chemistry, and computer science to help prioritize chemicals for further research based on potential human health risks. This work involves computational and data driven approaches that integrate chemistry, exposure and biological data. As an outcome of these efforts the National Center for Computational Toxicology (NCCT) has measured, assembled and delivered an enormous quantity and diversity of data for the environmental sciences including high-throughput in vitro screening data, in vivo and functional use data, exposure models and chemical databases with associated properties. A series of software applications and databases have been produced over the past decade to deliver these data. Recent work has focused on the development of a new architecture that assembles the resources into a single platform. With a focus on delivering access to Open Data streams, web service integration accessibility and a user-friendly web application the CompTox Dashboard provides access to data associated with ~720,000 chemical substances. These data include research data in the form of bioassay screening data associated with the ToxCast program, experimental and predicted physicochemical properties, product and functional use information and related data of value to environmental scientists. This presentation will provide an overview of the CompTox Dashboard and its va
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Use of High Throughput Screening Data in IARC Monograph ...
Purpose: Evaluation of carcinogenic mechanisms serves a critical role in IARC monograph evaluations, and can lead to “upgrade” or “downgrade” of the carcinogenicity conclusions based on human and animal evidence alone. Three recent IARC monograph Working Groups (110, 112, and 113) pioneered analysis of high throughput in vitro screening data from the U.S. Environmental Protection Agency’s ToxCast program in evaluations of carcinogenic mechanisms. Methods: For monograph 110, ToxCast assay data across multiple nuclear receptors were used to test the hypothesis that PFOA acts exclusively through the PPAR family of receptors, with activity profiles compared to several prototypical nuclear receptor-activating compounds. For monographs 112 and 113, ToxCast assays were systematically evaluated and used as an additional data stream in the overall evaluation of the mechanistic evidence. Specifically, ToxCast assays were mapped to 10 “key characteristics of carcinogens” recently identified by an IARC expert group, and chemicals’ bioactivity profiles were evaluated both in absolute terms (number of relevant assays positive for bioactivity) and relative terms (ranking with respect to other compounds evaluated by IARC, using the ToxPi methodology). Results: PFOA activates multiple nuclear receptors in addition to the PPAR family in the ToxCast assays. ToxCast assays offered substantial coverage for 5 of the 10 “key characteristics,” with the greates
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The ToxCast and Tox21 programs have tested ~8,200 chemicals in a broad screening panel of in vitro high-throughput screening (HTS) assays for estrogen receptor (ER) agonist and antagonist activity. The present work uses this large in vitro data set to develop in silico QSAR model...
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Most of the over 2800 nanomaterials (NMs) in commerce lack hazard data. Efficient NM testing requires suitable toxicity tests for prioritization of NMs to be tested. The EPA’s ToxCast program is evaluating HTS assays to prioritize NMs for targeted testing. Au, Ag, CeO2, Cu(O2), T...
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Evaluation of food-relevant chemicals in the ToxCast high-throughput screening program
Thousands of chemicals are directly added to or come in contact with food, many of which have undergone little to no toxicological evaluation. The landscape of the food-relevant chemical universe was evaluated using cheminformatics, and subsequently the bioactivity of food-relevant chemicals across the publicly available ToxCast highthroughput screening program was assessed. In total, 8659 food-relevant chemicals were compiled including direct food additives, food contact substances, and pesticides. Of these food-relevant chemicals, 4719 had curated structure definition files amenable to defining chemical fingerprints, which were used to cluster chemicals using a selforganizing map approach. Pesticides, and direct food additives clustered apart from one another with food contact substances generally in between, supporting that these categories not only reflect different uses but also distinct chemistries. Subsequently, 1530 food-relevant chemicals were identified in ToxCast comprising 616 direct food additives, 371 food contact substances, and 543 pesticides. Bioactivity across ToxCast was filtered for cytotoxicity to identify selective chemical effects. Initiating analyses from strictly chemical-based methodology or bioactivity/cytotoxicity-driven evaluation presents unbiased approaches for prioritizing chemicals. Although bioactivity in vitro is not necessarily predictive of adverse effects in vivo, these data provide insight into chemical properties and cellu
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Ye, Hao; Luo, Heng; Ng, Hui Wen; Meehan, Joe; Ge, Weigong; Tong, Weida; Hong, Huixiao
2016-01-01
ToxCast data have been used to develop models for predicting in vivo toxicity. To predict the in vivo toxicity of a new chemical using a ToxCast data based model, its ToxCast bioactivity data are needed but not normally available. The capability of predicting ToxCast bioactivity data is necessary to fully utilize ToxCast data in the risk assessment of chemicals. We aimed to understand and elucidate the relationships between the chemicals and bioactivity data of the assays in ToxCast and to develop a network analysis based method for predicting ToxCast bioactivity data. We conducted modularity analysis on a quantitative network constructed from ToxCast data to explore the relationships between the assays and chemicals. We further developed Nebula (neighbor-edges based and unbiased leverage algorithm) for predicting ToxCast bioactivity data. Modularity analysis on the network constructed from ToxCast data yielded seven modules. Assays and chemicals in the seven modules were distinct. Leave-one-out cross-validation yielded a Q(2) of 0.5416, indicating ToxCast bioactivity data can be predicted by Nebula. Prediction domain analysis showed some types of ToxCast assay data could be more reliably predicted by Nebula than others. Network analysis is a promising approach to understand ToxCast data. Nebula is an effective algorithm for predicting ToxCast bioactivity data, helping fully utilize ToxCast data in the risk assessment of chemicals. Published by Elsevier Ltd.
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Evaluation of food-relevant chemicals in the ToxCast high-throughput screening program.
Karmaus, Agnes L; Filer, Dayne L; Martin, Matthew T; Houck, Keith A
2016-06-01
Thousands of chemicals are directly added to or come in contact with food, many of which have undergone little to no toxicological evaluation. The landscape of the food-relevant chemical universe was evaluated using cheminformatics, and subsequently the bioactivity of food-relevant chemicals across the publicly available ToxCast highthroughput screening program was assessed. In total, 8659 food-relevant chemicals were compiled including direct food additives, food contact substances, and pesticides. Of these food-relevant chemicals, 4719 had curated structure definition files amenable to defining chemical fingerprints, which were used to cluster chemicals using a selforganizing map approach. Pesticides, and direct food additives clustered apart from one another with food contact substances generally in between, supporting that these categories not only reflect different uses but also distinct chemistries. Subsequently, 1530 food-relevant chemicals were identified in ToxCast comprising 616 direct food additives, 371 food contact substances, and 543 pesticides. Bioactivity across ToxCast was filtered for cytotoxicity to identify selective chemical effects. Initiating analyses from strictly chemical-based methodology or bioactivity/cytotoxicity-driven evaluation presents unbiased approaches for prioritizing chemicals. Although bioactivity in vitro is not necessarily predictive of adverse effects in vivo, these data provide insight into chemical properties and cellular targets through which foodrelevant chemicals elicit bioactivity. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.
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Kavlock, Robert; Dix, David
2010-02-01
Computational toxicology is the application of mathematical and computer models to help assess chemical hazards and risks to human health and the environment. Supported by advances in informatics, high-throughput screening (HTS) technologies, and systems biology, the U.S. Environmental Protection Agency EPA is developing robust and flexible computational tools that can be applied to the thousands of chemicals in commerce, and contaminant mixtures found in air, water, and hazardous-waste sites. The Office of Research and Development (ORD) Computational Toxicology Research Program (CTRP) is composed of three main elements. The largest component is the National Center for Computational Toxicology (NCCT), which was established in 2005 to coordinate research on chemical screening and prioritization, informatics, and systems modeling. The second element consists of related activities in the National Health and Environmental Effects Research Laboratory (NHEERL) and the National Exposure Research Laboratory (NERL). The third and final component consists of academic centers working on various aspects of computational toxicology and funded by the U.S. EPA Science to Achieve Results (STAR) program. Together these elements form the key components in the implementation of both the initial strategy, A Framework for a Computational Toxicology Research Program (U.S. EPA, 2003), and the newly released The U.S. Environmental Protection Agency's Strategic Plan for Evaluating the Toxicity of Chemicals (U.S. EPA, 2009a). Key intramural projects of the CTRP include digitizing legacy toxicity testing information toxicity reference database (ToxRefDB), predicting toxicity (ToxCast) and exposure (ExpoCast), and creating virtual liver (v-Liver) and virtual embryo (v-Embryo) systems models. U.S. EPA-funded STAR centers are also providing bioinformatics, computational toxicology data and models, and developmental toxicity data and models. The models and underlying data are being made publicly available through the Aggregated Computational Toxicology Resource (ACToR), the Distributed Structure-Searchable Toxicity (DSSTox) Database Network, and other U.S. EPA websites. While initially focused on improving the hazard identification process, the CTRP is placing increasing emphasis on using high-throughput bioactivity profiling data in systems modeling to support quantitative risk assessments, and in developing complementary higher throughput exposure models. This integrated approach will enable analysis of life-stage susceptibility, and understanding of the exposures, pathways, and key events by which chemicals exert their toxicity in developing systems (e.g., endocrine-related pathways). The CTRP will be a critical component in next-generation risk assessments utilizing quantitative high-throughput data and providing a much higher capacity for assessing chemical toxicity than is currently available.
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Wetmore, Barbara A.; Wambaugh, John F.; Allen, Brittany; Ferguson, Stephen S.; Sochaski, Mark A.; Setzer, R. Woodrow; Houck, Keith A.; Strope, Cory L.; Cantwell, Katherine; Judson, Richard S.; LeCluyse, Edward; Clewell, Harvey J.; Thomas, Russell S.; Andersen, Melvin E.
2015-01-01
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. PMID:26251325
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New High Throughput Methods to Estimate Chemical ...
EPA has made many recent advances in high throughput bioactivity testing. However, concurrent advances in rapid, quantitative prediction of human and ecological exposures have been lacking, despite the clear importance of both measures for a risk-based approach to prioritizing and screening chemicals. A recent report by the National Research Council of the National Academies, Exposure Science in the 21st Century: A Vision and a Strategy (NRC 2012) laid out a number of applications in chemical evaluation of both toxicity and risk in critical need of quantitative exposure predictions, including screening and prioritization of chemicals for targeted toxicity testing, focused exposure assessments or monitoring studies, and quantification of population vulnerability. Despite these significant needs, for the majority of chemicals (e.g. non-pesticide environmental compounds) there are no or limited estimates of exposure. For example, exposure estimates exist for only 7% of the ToxCast Phase II chemical list. In addition, the data required for generating exposure estimates for large numbers of chemicals is severely lacking (Egeghy et al. 2012). This SAP reviewed the use of EPA's ExpoCast model to rapidly estimate potential chemical exposures for prioritization and screening purposes. The focus was on bounded chemical exposure values for people and the environment for the Endocrine Disruptor Screening Program (EDSP) Universe of Chemicals. In addition to exposure, the SAP
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Computational Modeling and Simulation of Developmental ...
Developmental and Reproductive Toxicity (DART) testing is important for assessing the potential consequences of drug and chemical exposure on human health and well-being. Complexity of pregnancy and the reproductive cycle makes DART testing challenging and costly for traditional (animal-based) methods. A compendium of in vitro data from ToxCast/Tox21 high-throughput screening (HTS) programs is available for predictive toxicology. ‘Predictive DART’ will require an integrative strategy that mobilizes HTS data into in silico models that capture the relevant embryology. This lecture addresses progress on EPA's 'virtual embryo'. The question of how tissues and organs are shaped during development is crucial for understanding (and predicting) human birth defects. While ToxCast HTS data may predict developmental toxicity with reasonable accuracy, mechanistic models are still necessary to capture the relevant biology. Subtle microscopic changes induced chemically may amplify to an adverse outcome but coarse changes may override lesion propagation in any complex adaptive system. Modeling system dynamics in a developing tissue is a multiscale problem that challenges our ability to predict toxicity from in vitro profiling data (ToxCast/Tox21). (DISCLAIMER: The views expressed in this presentation are those of the presenter and do not necessarily reflect the views or policies of the US EPA). This was an invited seminar presentation to the National Institute for Public H
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Inter-Individual Variability in High-Throughput Risk ...
We incorporate realistic human variability into an open-source high-throughput (HT) toxicokinetics (TK) modeling framework for use in a next-generation risk prioritization approach. Risk prioritization involves rapid triage of thousands of environmental chemicals, most which have little or no existing TK data. Chemicals are prioritized based on model estimates of hazard and exposure, to decide which chemicals should be first in line for further study. Hazard may be estimated with in vitro HT screening assays, e.g., U.S. EPA’s ToxCast program. Bioactive ToxCast concentrations can be extrapolated to doses that produce equivalent concentrations in body tissues using a reverse TK approach in which generic TK models are parameterized with 1) chemical-specific parameters derived from in vitro measurements and predicted from chemical structure; and 2) with physiological parameters for a virtual population. Here we draw physiological parameters from realistic estimates of distributions of demographic and anthropometric quantities in the modern U.S. population, based on the most recent CDC NHANES data. A Monte Carlo approach, accounting for the correlation structure in physiological parameters, is used to estimate ToxCast equivalent doses for the most sensitive portion of the population. To quantify risk, ToxCast equivalent doses are compared to estimates of exposure rates based on Bayesian inferences drawn from NHANES urinary analyte biomonitoring data. The inclusion
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Tal, Tamara; Kilty, Claire; Smith, Andrew; LaLone, Carlie; Kennedy, Brendán; Tennant, Alan; McCollum, Catherine W; Bondesson, Maria; Knudsen, Thomas; Padilla, Stephanie; Kleinstreuer, Nicole
2017-06-01
Chemically-induced vascular toxicity during embryonic development may cause a wide range of adverse effects. To identify putative vascular disrupting chemicals (pVDCs), a predictive pVDC signature was constructed from 124 U.S. EPA ToxCast high-throughput screening (HTS) assays and used to rank 1060 chemicals for their potential to disrupt vascular development. Thirty-seven compounds were selected for targeted testing in transgenic Tg(kdrl:EGFP) and Tg(fli1:EGFP) zebrafish embryos to identify chemicals that impair developmental angiogenesis. We hypothesized that zebrafish angiogenesis toxicity data would correlate with human cell-based and cell-free in vitro HTS ToxCast data. Univariate statistical associations used to filter HTS data based on correlations with zebrafish angiogenic inhibition in vivo revealed 132 total significant associations, 33 of which were already captured in the pVDC signature, and 689 non-significant assay associations. Correlated assays were enriched in cytokine and extracellular matrix pathways. Taken together, the findings indicate the utility of zebrafish assays to evaluate an HTS-based predictive toxicity signature and also provide an experimental basis for expansion of the pVDC signature with novel HTS assays. Published by Elsevier Inc.
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Fay, Kellie A; Villeneuve, Daniel L; Swintek, Joe; Edwards, Stephen W; Nelms, Mark D; Blackwell, Brett R; Ankley, Gerald T
2018-06-01
The U.S. Environmental Protection Agency's ToxCast program has 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.
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Evaluation of food-relevant chemicals in the ToxCast high ...
There are thousands of chemicals that are directly added to or come in contact with food, many of which have undergone little to no toxicological evaluation. The ToxCast high-throughput screening (HTS) program has evaluated over 1,800 chemicals in concentration-response across ~820 assay endpoints and continues to grow; with all data completely available to the public, this resource serves as a unique opportunity to evaluate the bioactivity of chemicals in vitro. This study investigated the chemical landscape of the food-relevant chemical universe using cheminformatics analyses, and subsequently evaluated the bioactivity of food-relevant chemicals included in the ToxCast HTS program. Initially, a list of 9,437 food-relevant chemicals was compiled by comprehensively mining publicly available sources for direct food additives, food contact substances, indirect food additives, and pesticides. Of these food-relevant chemicals, 4,638 were associated with curated structure definition files amenable to defining physical/chemical features used to generate chemical fingerprints. Clustering was conducted based on the chemical fingerprints using a self-organizing map approach. This revealed that pesticides, food contact substances, and direct food additives generally clustered apart from one another, supporting that these categories reflect not only different uses but also distinct chemistries. Subsequently, 967 of the 9,437 food-relevant chemicals were identified in the T
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ToxCast Profiling in a Human Stem Cell Assay for ...
Standard practice for assessing disruptions in embryogenesis involves testing pregnant animals of two species, typically rats and rabbits, exposed during major organogenesis and evaluated just prior to term. Under this design the major manifestations of developmental toxicity are observed as one or more apical endpoints including intrauterine death, fetal growth retardation, structural malformations and variations. Alternative approaches to traditional developmental toxicity testing have been proposed in the form of in vitro data (e.g., embryonic stem cells, zebrafish embryos, HTS assays) and in silico models (e.g., computational toxicology). To increase the diversity of assays used to assess developmental toxicity in EPA’s ToxCast program, we tested the chemicals in Stemina’s metabolomics-based platform that utilizes the commecrially available H9 human embryonic stem cell line. The devTOXqP dataset for ToxCast of high-quality based on replicate samples and model performance (82% balanced accuracy, 0.71 sensitivity and 1.00 specificity). To date, 136 ToxCast chemicals (12.8% of 1065 tested) were positive in this platform; 48 triggered the biomarker signal without any change in hESC viability and 88 triggered activity concurrent with effects on cell viability. Work is in progress to complete the STM dataset entry into the TCPL, compare data with results from zFish and mESC platforms, profile bioactivity (ToxCastDB), endpoints (ToxRefDB), chemotypes (DSSTox)
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Predictive Models and Computational Toxicology
Understanding the potential health risks posed by environmental chemicals is a significant challenge elevated by the large number of diverse chemicals with generally uncharacterized exposures, mechanisms, and toxicities. The ToxCast computational toxicology research program was l...
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Classification and Dose-Response Characterization of ...
Thirty years and over a billion of today’s dollars worth of pesticide registration toxicity studies, historically stored as hardcopy and scanned documents, have been digitized into highly standardized and structured toxicity data, within the U.S. Environmental Protection Agency’s (EPA) Toxicity Reference Database (ToxRefDB). The source toxicity data in ToxRefDB covers multiple study types, including subchronic, developmental, reproductive, chronic, and cancer studies, resulting in a diverse set of endpoints and toxicities. Novel approaches to chemical classification are performed as a model application of ToxRefDB and as an essential need for highly detailed chemical classifications within the EPA’s ToxCast™ research program. In order to develop predictive models and biological signatures utilizing high-throughput screening (HTS) and in vitro genomic data, endpoints and toxicities must first be identified and globally characterized for ToxCast Phase I chemicals. Secondarily, dose-response characterization within and across toxicity endpoints provide insight into key precursor toxicity events and overall endpoint relevance. Toxicity-based chemical classification and dose-response characterization utilizing ToxRefDB prioritized toxicity endpoints and differentiated toxicity outcomes across a large chemical set.
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Tiered High-Throughput Screening Approach to Identify ...
High-throughput screening (HTS) for potential thyroid–disrupting chemicals requires a system of assays to capture multiple molecular-initiating events (MIEs) that converge on perturbed thyroid hormone (TH) homeostasis. Screening for MIEs specific to TH-disrupting pathways is limited in the US EPA ToxCast screening assay portfolio. To fill one critical screening gap, the Amplex UltraRed-thyroperoxidase (AUR-TPO) assay was developed to identify chemicals that inhibit TPO, as decreased TPO activity reduces TH synthesis. The ToxCast Phase I and II chemical libraries, comprised of 1,074 unique chemicals, were initially screened using a single, high concentration to identify potential TPO inhibitors. Chemicals positive in the single concentration screen were retested in concentration-response. Due to high false positive rates typically observed with loss-of-signal assays such as AUR-TPO, we also employed two additional assays in parallel to identify possible sources of nonspecific assay signal loss, enabling stratification of roughly 300 putative TPO inhibitors based upon selective AUR-TPO activity. A cell-free luciferase inhibition assay was used to identify nonspecific enzyme inhibition among the putative TPO inhibitors, and a cytotoxicity assay using a human cell line was used to estimate the cellular tolerance limit. Additionally, the TPO inhibition activities of 150 chemicals were compared between the AUR-TPO and an orthogonal peroxidase oxidation assay using
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ToxCast HTS Assay Development and Retrofitting: Strategies ...
A presentation to EC JRC partners on new ToxCast HTS assay methods and strategies to address current limitations to HTS methods Slide presentation to EC JRC partners on new ToxCast HTS assay methods and strategies to address current limitations to HTS methods.
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A predictive model of reproductive toxicity, as observed in rat multigeneration reproductive (MGR) studies, was previously developed using high throughput screening (HTS) data from 36 in vitro assays mapped to 8 genes or gene-sets from Phase I of USEPA ToxCast research program, t...
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EPA’s ToxCast chemical library spans diverse chemical use-types, functionalities, structures and features potentially relevant to toxicity and environmental exposure. However, this structural diversity, along with assay noise and low average hit rates across the varied ToxCast h...
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21st century tools to prioritize contaminants for monitoring and management
The webinar focused on ways that ToxCast high throughput screening data and the adverse outcome pathway framework, under development in the CSS program, can be used to prioritize environmental contaminants for monitoring and management.
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A predictive model for prenatal developmental toxicity using ToxCast Phase I showed the RAR assay set to be the strongest weighting factor (Sipes et al. 2011). Retinoid signaling mediates growth and differentiation of the embryo. ToxCast has 6 reporter assays for trans-activation...
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Tutorial Video Series: Using Stakeholder Outreach to Increase Usage of ToxCast Data (SETAC EU)
The limited amount of toxicity data on thousands of chemicals found in consumer products has led to the development of research endeavors such as the U.S. EPA’s Toxicity Forecaster (ToxCast). ToxCast uses high-throughput screening technology to evaluate thousands of chemicals for...
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High-Throughput Screening in ToxCast/Tox21 (FutureToxII)
Addressing safety aspects of drugs and environmental chemicals relies extensively on animal testing. However, the quantity of chemicals needing assessment and challenges of species extrapolation require development of alternative approaches. The EPA’s ToxCast program addresses th...
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The U.S. EPA’s ToxCast research project was developed to address the need for high-throughput testing of chemicals and a pathway-based approach to hazard screening. Phase I of ToxCast tested over 300 unique compounds (mostly pesticides and antimicrobials). With the addition of Ph...
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The Stemina devTOX quickPredict platform (STM) is a human pluripotent H9 stem cell-based assay that predicts developmental toxicants. Using the STM model, we screened 1065 ToxCast chemicals and entered the data into the ToxCast data analysis pipeline. Model performance was 83.3% ...
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High-Content Screening in Zebrafish Embryos Identifies Butafenacil as a Potent Inducer of Anemia
Leet, Jessica K.; Lindberg, Casey D.; Bassett, Luke A.; Isales, Gregory M.; Yozzo, Krystle L.; Raftery, Tara D.; Volz, David C.
2014-01-01
Using transgenic zebrafish (fli1:egfp) that stably express enhanced green fluorescent protein (eGFP) within vascular endothelial cells, we recently developed and optimized a 384-well high-content screening (HCS) assay that enables us to screen and identify chemicals affecting cardiovascular development and function at non-teratogenic concentrations. Within this assay, automated image acquisition procedures and custom image analysis protocols are used to quantify body length, heart rate, circulation, pericardial area, and intersegmental vessel area within individual live embryos exposed from 5 to 72 hours post-fertilization. After ranking developmental toxicity data generated from the U.S. Environmental Protection Agency's (EPA's) zebrafish teratogenesis assay, we screened 26 of the most acutely toxic chemicals within EPA's ToxCast Phase-I library in concentration-response format (0.05–50 µM) using this HCS assay. Based on this screen, we identified butafenacil as a potent inducer of anemia, as exposure from 0.39 to 3.125 µM butafenacil completely abolished arterial circulation in the absence of effects on all other endpoints evaluated. Butafenacil is an herbicide that inhibits protoporphyrinogen oxidase (PPO) – an enzyme necessary for heme production in vertebrates. Using o-dianisidine staining, we then revealed that severe butafenacil-induced anemia in zebrafish was due to a complete loss of hemoglobin following exposure during early development. Therefore, six additional PPO inhibitors within the ToxCast Phase-I library were screened to determine whether anemia represents a common adverse outcome for these herbicides. Embryonic exposure to only one of these PPO inhibitors – flumioxazin – resulted in a similar phenotype as butafenacil, albeit not as severe as butafenacil. Overall, this study highlights the potential utility of this assay for (1) screening chemicals for cardiovascular toxicity and (2) prioritizing chemicals for future hypothesis-driven and mechanism-focused investigations within zebrafish and mammalian models. PMID:25090246
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The webinar focused on ways that ToxCast high throughput screening data and the adverse outcome pathway framework, under development in the CSS program, can be used to prioritize environmental contaminants for monitoring and management.
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HTTK: R Package for High-Throughput Toxicokinetics
Thousands of chemicals have been profiled by high-throughput screening programs such as ToxCast and Tox21; these chemicals are tested in part because most of them have limited or no data on hazard, exposure, or toxicokinetics. Toxicokinetic models aid in predicting tissue concent...
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tcpl: The ToxCast Pipeline for High-Throughput Screening Data
Motivation: The large and diverse high-throughput chemical screening efforts carried out by the US EPAToxCast program requires an efficient, transparent, and reproducible data pipeline.Summary: The tcpl R package and its associated MySQL database provide a generalized platform fo...
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The US EPA’s ToxCast program is designed to assess chemical perturbations of molecular and cellular endpoints using a variety of high-throughput screening (HTS) assays. However, existing HTS assays have limited or no xenobiotic metabolism which could lead to a mischaracterization...
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High Throughput Assays for Exposure Science (NIEHS OHAT ...
High throughput screening (HTS) data that characterize chemically induced biological activity have been generated for thousands of chemicals by the US interagency Tox21 and the US EPA ToxCast programs. In many cases there are no data available for comparing bioactivity from HTS with relevant human exposures. The EPA’s ExpoCast program is developing high-throughput approaches to generate the needed exposure estimates using existing databases and new, high-throughput measurements. The exposure pathway (i.e., the route of chemical from manufacture to human intake) significantly impacts the level of exposure. The presence, concentration, and formulation of chemicals in consumer products and articles of commerce (e.g., clothing) can therefore provide critical information for estimating risk. We have found that there are only limited data available on the chemical constituents (e.g., flame retardants, plasticizers) within most articles of commerce. Furthermore, the presence of some chemicals in otherwise well characterized products may be due to product packaging. We are analyzing sample consumer products using 2D gas chromatograph (GC) x GC Time of Flight Mass Spectrometry (GCxGCTOF/MS), which is suited for forensic investigation of chemicals in complex matrices (including toys, cleaners, and food). In parallel, we are working to create a reference library of retention times and spectral information for the entire Tox21 chemical library. In an examination of five p
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Analysis of Ingredient Lists to Quantitatively Characterize ...
The EPA’s ExpoCast program is developing high throughput (HT) approaches to generate the needed exposure estimates to compare against HT bioactivity data generated from the US inter-agency Tox21 and the US EPA ToxCast programs. Assessing such exposures for the thousands of chemicals in consumer products requires data on product composition. This is a challenge since quantitative product composition data are rarely available. We developed methods to predict the weight fractions of chemicals in consumer products from weight fraction-ordered chemical ingredient lists, and curated a library of such lists from online manufacturer and retailer sites. The probabilistic model predicts weight fraction as a function of the total number of reported ingredients, the rank of the ingredient in the list, the minimum weight fraction for which ingredients were reported, and the total weight fraction of unreported ingredients. Weight fractions predicted by the model compared very well to available quantitative weight fraction data obtained from Material Safety Data Sheets for products with 3-8 ingredients. Lists were located from the online sources for 5148 products containing 8422 unique ingredient names. A total of 1100 of these names could be located in EPA’s HT chemical database (DSSTox), and linked to 864 unique Chemical Abstract Service Registration Numbers (392 of which were in the Tox21 chemical library). Weight fractions were estimated for these 864 CASRN. Using a
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EPA’s ToxCast project is using high-throughput screening (HTS) to profile and prioritize chemicals for further testing. ToxCast Phase I evaluated 309 unique chemicals, the majority pesticide actives, in over 500 HTS assays. These included 3 human cytochrome P450 (hCYP3A4, hCYP2...
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Toxicity Screening of the ToxCast Chemical Library Using a Zebrafish Developmental Assay
As part of the chemical screening and prioritization research program of the U.S. Environmental Protection Agency, the toxicity of the 320 ToxCast™ Phase I chemicals were assessed using a vertebrate screen of developmental toxicity. Zebrafish embryos/larvae (Danio rerio) were exp...
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The U.S. Environmental Protection Agency’s ToxCast program has 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 ...
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“httk”: EPA’s Tool for High Throughput Toxicokinetics (CompTox CoP)
Thousands of chemicals have been pro?led by high-throughput screening programs such as ToxCast and Tox21; these chemicals are tested in part because most of them have limited or no data on hazard, exposure, or toxicokinetics. Toxicokinetic models aid in predicting tissue concentr...
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Testing of environmental and industrial chemicals for toxicity potential is a daunting task because of the wide range of possible toxicity mechanisms. Although animal testing is one means of achieving broad toxicity coverage, evaluation of large numbers of chemicals is challengin...
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Assessing the Robustness of Chemical Prioritizations Based on ToxCast Chemical Profiling
A central goal of the U.S. EPA’s ToxCast™ program is to provide empirical, scientific evidence to aid in prioritizing the toxicity testing of thousands of chemicals. The agency has developed a prioritization approach, the Toxicological Prioritization Index (ToxPi™), that calculat...
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Framework for a Quantitative Systemic Toxicity Model (FutureToxII)
EPA’s ToxCast program profiles the bioactivity of chemicals in a diverse set of ~700 high throughput screening (HTS) assays. In collaboration with L’Oreal, a quantitative model of systemic toxicity was developed using no effect levels (NEL) from ToxRefDB for 633 chemicals with HT...
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Dose response screening of the Toxcast chemical library using a Zebrafish developmental assay
As part of the chemical screening and prioritization research program of the U.S. Environmental Protection Agency, the toxicity of the 320 ToxCaspM Phase I chemicals was assessed using a vertebrate screen of developmental toxicity. Zebrafish embryos/larvae (Danio rerio) were expo...
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A catalog of putative adverse outcome pathways (AOPs) that ...
A number of putative AOPs for several distinct MIEs of thyroid disruption have been formulated for amphibian metamorphosis and fish swim bladder inflation. These have been entered into the AOP knowledgebase on the OECD WIKI. The EDSP has been actively advancing high-throughput screening for chemical activity toward estrogen, androgen and thyroid targets. However, it has been recently identified that coverage for thyroid-related targets is lagging behind estrogen and androgen assay coverage. As thyroid-related medium-high throughput assays are actively being developed for inclusion in the ToxCast chemical screening program, a parallel effort is underway to characterize putative adverse outcome pathways (AOPs) specific to these thyroid-related targets. This effort is intended to provide biological and ecological context that will enhance the utility of ToxCast high throughput screening data for hazard identification.
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The U.S. EPA’s Endocrine Disruptor Screening Program (EDSP) has been charged with screening thousands of chemicals for their potential to affect the endocrine systems of humans and wildlife. In vitro high throughput screening (HTS) assays have been proposed as a way to prioritize...
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Most nanomaterials (NMs) in commerce lack hazard data. Efficient NM testing requires suitable toxicity tests for prioritization of NMs to be tested. The EPA’s ToxCast program is screening NM bioactivities and ranking NMs by their bioactivities to inform targeted testing planning....
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The U.S. Environmental Protection Agency’s ToxCast program has 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 pote...
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Using uncertainty quantification, we aim to improve the quality of modeling data from high throughput screening assays for use in risk assessment. ToxCast is a large-scale screening program that analyzes thousands of chemicals using over 800 assays representing hundreds of bioche...
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The Environmental Protection Agency has implemented a high throughput screening program, ToxCast, to quickly evaluate large numbers of chemicals for their effects on hundreds of different biological targets. To understand how these measurements relate to adverse effects in an or...
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Research efforts by the US Environmental Protection Agency have set out to develop alternative testing programs to prioritize limited testing resources toward chemicals that likely represent the greatest hazard to human health and the environment. Efforts such as EPA’s ToxCast r...
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The U.S. EPA’s Endocrine Disruptor Screening Program (EDSP) and Office of Research and Development (ORD) are currently developing high throughput assays to screen chemicals that may alter the thyroid hormone pathway. One potential target in this pathway is the sodium iodide...
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Thousands of chemicals have been profiled by high-throughput screening (HTS) programs such as ToxCast and Tox21; these chemicals are tested in part because most of them have limited or no data on hazard, exposure, or toxicokinetics (TK). While HTS generates in vitro bioactivity d...
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In support of the Endocrine Disruptor Screening Program (EDSP), the U.S. EPA’s Office of Research and Development (ORD) is currently developing HTPS approaches to identify chemicals that may alter target sites in the thyroid hormone pathway. One target site is the sodium io...
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Virtual Liver: Evaluating the Impact of Hepatic Microdosimetry for ToxCast Chemicals
The U.S. EPA’s ToxCastTM program uses hundreds of high-throughput, in vitro assays to screen chemicals for potential toxicity. The assays are used to probe in vitro concentrations at which target cellular pathways and processes are perturbed by these chemicals. The U.S. EPA’s Vir...
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The U.S. EPA’s Endocrine Disruptor Screening Program (EDSP) and Office of Research and Development (ORD) are currently developing high throughput assays to screen chemicals that may alter the thyroid hormone pathway. One potential target in this pathway is the sodium iodide sympo...
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The ToxCast Dashboard helps users examine high-throughput assay data to inform chemical safety decisions. To date, it has data on over 9,000 chemicals and information from more than 1,000 high-throughput assay endpoint components.
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Environmental Impact on Vascular Development Predicted by High-Throughput Screening
Judson, Richard S.; Reif, David M.; Sipes, Nisha S.; Singh, Amar V.; Chandler, Kelly J.; DeWoskin, Rob; Dix, David J.; Kavlock, Robert J.; Knudsen, Thomas B.
2011-01-01
Background: Understanding health risks to embryonic development from exposure to environmental chemicals is a significant challenge given the diverse chemical landscape and paucity of data for most of these compounds. High-throughput screening (HTS) in the U.S. Environmental Protection Agency (EPA) ToxCast™ project provides vast data on an expanding chemical library currently consisting of > 1,000 unique compounds across > 500 in vitro assays in phase I (complete) and Phase II (under way). This public data set can be used to evaluate concentration-dependent effects on many diverse biological targets and build predictive models of prototypical toxicity pathways that can aid decision making for assessments of human developmental health and disease. Objective: We mined the ToxCast phase I data set to identify signatures for potential chemical disruption of blood vessel formation and remodeling. Methods: ToxCast phase I screened 309 chemicals using 467 HTS assays across nine assay technology platforms. The assays measured direct interactions between chemicals and molecular targets (receptors, enzymes), as well as downstream effects on reporter gene activity or cellular consequences. We ranked the chemicals according to individual vascular bioactivity score and visualized the ranking using ToxPi (Toxicological Priority Index) profiles. Results: Targets in inflammatory chemokine signaling, the vascular endothelial growth factor pathway, and the plasminogen-activating system were strongly perturbed by some chemicals, and we found positive correlations with developmental effects from the U.S. EPA ToxRefDB (Toxicological Reference Database) in vivo database containing prenatal rat and rabbit guideline studies. We observed distinctly different correlative patterns for chemicals with effects in rabbits versus rats, despite derivation of in vitro signatures based on human cells and cell-free biochemical targets, implying conservation but potentially differential contributions of developmental pathways among species. Follow-up analysis with antiangiogenic thalidomide analogs and additional in vitro vascular targets showed in vitro activity consistent with the most active environmental chemicals tested here. Conclusions: We predicted that blood vessel development is a target for environmental chemicals acting as putative vascular disruptor compounds (pVDCs) and identified potential species differences in sensitive vascular developmental pathways. PMID:21788198
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Use of high-throughput and in vivo data to support read ...
Disrupting normal function of mitochondria can culminate in a variety of organ-level toxicities. A number of mechanisms - such as uncoupling of oxidative phosphorylation and inhibition of the electron transport chain - have been implicated in mitochondrial toxicity. The presence of mitochondrial toxicity has led to a number of drugs being withdrawn from the market highlighting the need to identify potential mitochondrial toxicants within the environment. High-throughput screening (HTS) assays provide a means of rapidly gathering toxicity data for a large number of chemicals; however, information as to the associated in vivo effect is typically unknown. The Adverse Outcome Pathway (AOP) concept provides a valuable scaffold onto which mechanistic data from different levels of biological organisation can be arranged.Information pertaining to mitochondrial toxicity from the U.S. EPA’s ToxCast program were integrated with rodent in vivo data from U.S. EPA’s ToxRefDB to connect the high throughput ToxCast assay results with potential adverse outcome data. Previously developed structural alerts were utilized to profile the chemicals with both in vitro mitochondrial toxicity and in vivo rodent data. Structural similarity guided by the toxicity profile as measured in the ToxCast assay battery was then used to group those chemicals which either were not tested in a mitochondrial toxicity assay or were not considered a “hit” and read-across was performed. Subsequen
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Structure Identification Using High Resolution Mass ...
The iCSS CompTox Dashboard is a publicly accessible dashboard provided by the National Center for Computation Toxicology at the US-EPA. It serves a number of purposes, including providing a chemistry database underpinning many of our public-facing projects (e.g. ToxCast and ExpoCast). The available data and searches provide a valuable path to structure identification using mass spectrometry as the source data. With an underlying database of over 720,000 chemicals, the dashboard has already been used to assist in identifying chemicals present in house dust. This poster reviews the benefits of the EPA’s platform and underlying algorithms used for the purpose of compound identification using high-resolution mass spectrometry data. Standard approaches for both mass and formula lookup are available but the dashboard delivers a novel approach for hit ranking based on functional use of the chemicals. The focus on high-quality data, novel ranking approaches and integration to other resources of value to mass spectrometrists makes the CompTox Dashboard a valuable resource for the identification of environmental chemicals. This abstract does not reflect U.S. EPA policy poster presented at the Eastern Analytical Symposium (EAS) held in Somerset, NJ
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A significant challenge in toxicology is the “too many chemicals” problem. Humans and environmental species are exposed to as many as tens of thousands of chemicals, only a small percentage of which have been tested thoroughly using standard in vivo test methods. This paper revie...
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The field of toxicology is on the cusp of a major transformation in how the safety and hazard of chemicals are evaluated for potential effects on human health and the environment. Brought on by the recognition of the limitations of the current paradigm in terms of cost, time, and...
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The US EPA’s ToxCast program has generated a wealth of data in >600 in vitro assayson a library of 1060 environmentally relevant chemicals and failed pharmaceuticals to facilitate hazard identification. An inherent criticism of many in vitro-based strategies is the inability of a...
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High-Throughput Models for Exposure-Based Chemical ...
The United States Environmental Protection Agency (U.S. EPA) must characterize potential risks to human health and the environment associated with manufacture and use of thousands of chemicals. High-throughput screening (HTS) for biological activity allows the ToxCast research program to prioritize chemical inventories for potential hazard. Similar capabilities for estimating exposure potential would support rapid risk-based prioritization for chemicals with limited information; here, we propose a framework for high-throughput exposure assessment. To demonstrate application, an analysis was conducted that predicts human exposure potential for chemicals and estimates uncertainty in these predictions by comparison to biomonitoring data. We evaluated 1936 chemicals using far-field mass balance human exposure models (USEtox and RAIDAR) and an indicator for indoor and/or consumer use. These predictions were compared to exposures inferred by Bayesian analysis from urine concentrations for 82 chemicals reported in the National Health and Nutrition Examination Survey (NHANES). Joint regression on all factors provided a calibrated consensus prediction, the variance of which serves as an empirical determination of uncertainty for prioritization on absolute exposure potential. Information on use was found to be most predictive; generally, chemicals above the limit of detection in NHANES had consumer/indoor use. Coupled with hazard HTS, exposure HTS can place risk earlie
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Application of High-Throughput In Vitro Assays for Risk-Based ...
Multiple drivers shape the types of human-health assessments performed on chemicals by U.S. EPA resulting in chemical assessments are “fit-for-purpose” ranging from prioritization for further testing to full risk assessments. Layered on top of the diverse assessment needs are the resource intensive nature of traditional toxicological studies used to test chemicals and the lack of toxicity information on many chemicals. To address these challenges, the Agency initiated the ToxCast program to screen thousands of chemicals across hundreds of high-throughput screening assays in concentrations-response format. One of the findings of the project has been that the majority of chemicals interact with multiple biological targets within a narrow concentration range and the extent of interactions increases rapidly near the concentration causing cytotoxicity. This means that application of high-throughput in vitro assays to chemical assessments will need to identify both the relative selectivity at chemicals interact with biological targets and the concentration at which these interactions perturb signaling pathways. The integrated analyses will be used to both define a point-of-departure for comparison with human exposure estimates and identify which chemicals may benefit from further studies in a mode-of-action or adverse outcome pathway framework. The application of new technologies in a risk-based, tiered manner provides flexibility in matching throughput and cos
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20150325 - Application of High-Throughput In Vitro Assays for ...
Multiple drivers shape the types of human-health assessments performed on chemicals by U.S. EPA resulting in chemical assessments are “fit-for-purpose” ranging from prioritization for further testing to full risk assessments. Layered on top of the diverse assessment needs are the resource intensive nature of traditional toxicological studies used to test chemicals and the lack of toxicity information on many chemicals. To address these challenges, the Agency initiated the ToxCast program to screen thousands of chemicals across hundreds of high-throughput screening assays in concentrations-response format. One of the findings of the project has been that the majority of chemicals interact with multiple biological targets within a narrow concentration range and the extent of interactions increases rapidly near the concentration causing cytotoxicity. This means that application of high-throughput in vitro assays to chemical assessments will need to identify both the relative selectivity at chemicals interact with biological targets and the concentration at which these interactions perturb signaling pathways. The integrated analyses will be used to both define a point-of-departure for comparison with human exposure estimates and identify which chemicals may benefit from further studies in a mode-of-action or adverse outcome pathway framework. The application of new technologies in a risk-based, tiered manner provides flexibility in matching throughput and cos
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tcpl: the ToxCast pipeline for high-throughput screening data.
Filer, Dayne L; Kothiya, Parth; Setzer, R Woodrow; Judson, Richard S; Martin, Matthew T
2017-02-15
Large high-throughput screening (HTS) efforts are widely used in drug development and chemical toxicity screening. Wide use and integration of these data can benefit from an efficient, transparent and reproducible data pipeline. Summary: The tcpl R package and its associated MySQL database provide a generalized platform for efficiently storing, normalizing and dose-response modeling of large high-throughput and high-content chemical screening data. The novel dose-response modeling algorithm has been tested against millions of diverse dose-response series, and robustly fits data with outliers and cytotoxicity-related signal loss. tcpl is freely available on the Comprehensive R Archive Network under the GPL-2 license. martin.matt@epa.gov. Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the US.
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High-Throughput Physiologically Based Toxicokinetic Models for ToxCast Chemicals
Physiologically based toxicokinetic (PBTK) models aid in predicting exposure doses needed to create tissue concentrations equivalent to those identified as bioactive by ToxCast. We have implemented four empirical and physiologically-based toxicokinetic (TK) models within a new R ...
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ToxMiner Software Interface for Visualizing and Analyzing ToxCast Data
The ToxCast dataset represents a collection of assays and endpoints that will require both standard statistical approaches as well as customized data analysis workflows. To analyze this unique dataset, we have developed an integrated database with Javabased interface called ToxMi...
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Understanding the Biology and Technology of ToxCast and Tox21 Assays
The ToxCast high-throughput toxicity (HTT) testing methods have been developed to evaluate the hazard potential of diverse environmental, industrial and consumer product chemicals. The main goal is prioritizing the compounds of greatest concern for more detailed toxicological stu...
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ToxCast: One Step in the NRC Vision of 21st Century Toxicology
The international community needs better predictive tools for assessing the hazards and risks of chemicals. It is technically feasible to collect bioactivity data on virtually all chemicals of potential concern ToxCast is providing a proof of concept for obtaining predictive, b...
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EPA’s ToxCast chemical library spans diverse chemical use-types, functionalities, structures and features potentially relevant to toxicity and environmental exposure. However, this structural diversity, along with assay noise and low average hit rates across the varied Tox...
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The Second Phase of ToxCast and Initial Applications to Chemical Prioritization
Tens of thousands of chemicals and other contaminants exist in our environment, but only a fraction of these have been characterized for their potential hazard to humans. ToxCast is focused on closing this data gap and improving the management of chemical risk through a high thro...
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Species-Specific Predictive Signatures of Developmental Toxicity Using the ToxCast Chemical Library
EPA’s ToxCastTM project is profiling the in vitro bioactivity of chemicals to generate predictive signatures that correlate with observed in vivo toxicity. In vitro profiling methods from ToxCast data consist of over 600 high-throughput screening (HTS) and high-content screening ...
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Developing predictions of in vivo developmental toxicity of ToxCast chemicals using mouse embryonic stem cells S. Hunter, M. Rosen, M. Hoopes, H. Nichols, S. Jeffay, K. Chandler1, Integrated Systems Toxicology Division, National Health and Environmental Effects Research Labor...
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20180416 - Understanding the Biology and Technology of ToxCast and Tox21 Assays (SETAC Durham NC)
The ToxCast high-throughput toxicity (HTT) testing methods have been developed to evaluate the hazard potential of diverse environmental, industrial and consumer product chemicals. The main goal is prioritizing the compounds of greatest concern for more detailed toxicological stu...
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ToxCast: One Step in the NRC Vision of 21st Century Toxicology (T)
The international community needs better predictive tools for assessing the hazards and risks of chemicals. It is technically feasible to collect bioactivity data on virtually all chemicals of potential concern ToxCast is providing a proof of concept for obtaining predictive, b...
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ToxCast: One Step in the NRC Vision of 21st Century Toxicology (S)
The international community needs better predictive tools for assessing the hazards and risks of chemicals. It is technically feasible to collect bioactivity data on virtually all chemicals of potential concern ToxCast is providing a proof of concept for obtaining predictive, b...
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Toxcast Profiling in a Human Stem Cell Assay for Developmental Toxicity (SOT)
We correlated the ToxCast library in a metabolic biomarker-based in vitro assay (Stemina devTOXqP) utilizing human embryonic stem (hES) cells (H9 line). This assay identifies the concentration of a chemical that disrupts cellular metabolism in a manner indicative of teratogenic...
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Chemical and HTS Profiling of 63 Cleft Palate Teratogens from ToxCast (FutureTox III)
Cleft palate is a common human birth defect that has been linked to both genetic and environmental factors. To characterize the potential molecular targets and biological processes across mechanistically diverse teratogens that cause cleft palate, we mined the ToxCast high-throug...
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Tox21 and ToxCast Chemical Landscapes: Laying the Foundation for 21st Century Toxicology
The U.S. Environmental Protection Agency’s ToxCast project and the related, multi-Agency Tox21 project are employing high-throughput technologies to screen hundreds to thousands of chemicals in hundreds of assays, probing a wide diversity of biological targets, pathways and mecha...
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Cheminformatics approaches and structure-based rules are being used to evaluate and explore the ToxCast chemical landscape and associated high-throughput screening (HTS) data. We have shown that the library provides comprehensive coverage of the knowledge domains and target inven...
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Safety assessment of drugs and environmental chemicals relies extensively on animal testing. However, the quantity of chemicals needing assessment and challenges of species extrapolation drive the development of alternative approaches. The EPA’s ToxCast and the multiagency Tox21 ...
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EPA’s ToxRefDB contains prenatal guideline study data from rats and rabbits for over 240 chemicals that overlap with the ToxCast in vitro high throughput screening project. A subset of these compounds were tested in Stemina Biomarker Discovery's developmental toxicity platform, a...
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Predicting dermal penetration for ToxCast chemicals using in silico estimates for diffusion in combination with physiologically based pharmacokinetic (PBPK) modeling.Evans, M.V., Sawyer, M.E., Isaacs, K.K, and Wambaugh, J.With the development of efficient high-throughput (HT) in ...
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Evaluation of 1066 ToxCast Chemicals in a human stem cell assay for developmental toxicity (SOT)
To increase the diversity of assays used to assess potential developmental toxicity, the ToxCast chemical library was screened in the Stemina devTOX quickPREDICT assay using human embryonic stem (hES) cells. A model for predicting teratogenicity was based on a training set of 23 ...
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Using high-content imaging data from ToxCast to analyze toxicological tipping points (TDS)
Translating results obtained from high-throughput screening to risk assessment is vital for reducing dependence on animal testing. We studied the effects of 976 chemicals (ToxCast Phase I and II) in HepG2 cells using high-content imaging (HCI) to measure dose and time-depende...
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Angiogenesis is a critical developmental process and a potential target for chemical teratogenesis. Over one-tenth of the Tox21 library of 10,000 compounds have been shown to disrupt mitochondrial function [Attene-Ramos et al., 2015]. Previous studies utilizing ToxCast chemicals ...
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Species-specific predictive models of developmental toxicity using the ToxCast chemical library
EPA’s ToxCastTM project is profiling the in vitro bioactivity of chemicals to generate predictive models that correlate with observed in vivo toxicity. In vitro profiling methods are based on ToxCast data, consisting of over 600 high-throughput screening (HTS) and high-content sc...
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A QSAR Model for Thyroperoxidase Inhibition and Screening ...
Thyroid hormones (THs) are critical modulators of a wide range of biological processes from neurodevelopment to metabolism. Well regulated levels of THs are critical during development and even moderate changes in maternal or fetal TH levels produce irreversible neurological deficits in children. The enzyme thyroperoxidase (TPO) plays a key role in the synthesis of THs. Inhibition of TPO by xenobiotics leads to decreased TH synthesis and, depending on the degree of synthesis inhibition, may result in adverse developmental outcomes. Recently, a high-throughput screening assay for TPO inhibition (AUR-TPO) was developed and used to screen the ToxCast Phase I and II chemicals. In the present study, we used the results from the AUR-TPO screening to develop a Quantitative Structure-Activity Relationship (QSAR) model for TPO inhibition in Leadscope®. The training set consisted of 898 discrete organic chemicals: 134 positive and 764 negative for TPO inhibition. A 10 times two-fold 50% cross-validation of the model was performed, yielding a balanced accuracy of 78.7% within its defined applicability domain. More recently, an additional ~800 chemicals from the US EPA Endocrine Disruption Screening Program (EDSP21) were screened using the AUR-TPO assay. This data was used for external validation of the QSAR model, demonstrating a balanced accuracy of 85.7% within its applicability domain. Overall, the cross- and external validations indicate a model with a high predictiv
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SeqAPASS: Sequence alignment to predict across-species ...
Efforts to shift the toxicity testing paradigm from whole organism studies to those focused on the initiation of toxicity and relevant pathways have led to increased utilization of in vitro and in silico methods. Hence the emergence of high through-put screening (HTS) programs, such as U.S. EPA ToxCast, and application of the adverse outcome pathway (AOP) framework for identifying and defining biological key events triggered upon perturbation of molecular initiating events and leading to adverse outcomes occuring at a level of organization relevant for risk assessment [1]. With these recent initiatives to harness the power of “the pathway” in describing and evaluating toxicity comes the need to extrapolate data beyond the model species. Sequence alignment to predict across-species susceptibilty (SeqAPASS) is a web-based tool that allows the user to begin to understand how broadly HTS data or AOP constructs may plausibly be extrapolated across species, while describing the relative intrinsic susceptibiltiy of different taxa to chemicals with known modes of action (e.g., pharmaceuticals and pesticides). The tool rapidly and strategically assesses available molecular target information to describe protein sequence similarity at the primary amino acid sequence, conserved domain, and individual amino acid residue levels. This in silico approach to species extrapolation was designed to automate and streamline the relatively complex and time-consuming process of co
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EPA DSSTox and ToxCast Project Updates: Generating New ...
EPA’s National Center for Computational Toxicology is generating data and capabilities to support a new paradigm for toxicity screening and prediction. The DSSTox project is improving public access to quality structure-annotated chemical toxicity information in less summarized forms than traditionally employed in SAR modeling, and in ways that facilitate data-mining and data read-across. The DSSTox Structure-Browser provides structure searchability across the full published DSSTox toxicity-related inventory, enables linkages to and from previously isolated toxicity data resources (soon to include public microarray resources GEO, ArrayExpress, and CEBS), and provides link-outs to cross-indexed public resources such as PubChem, ChemSpider, and ACToR. The published DSSTox inventory and bioassay information also have been integrated into PubChem allowing a user to take full advantage of PubChem structure-activity and bioassay clustering features. Phase I of the ToxCastTM project has generated high-throughput screening (HTS) data from several hundred biochemical and cell-based assays for a set of 320 chemicals, mostly pesticide actives, with rich toxicology profiles. DSSTox and ACToR are providing the primary cheminformatics support for ToxCastTM and collaborative efforts with the National Toxicology Program’s HTS Program and the NIH Chemical Genomics Center. DSSTox will also be a primary vehicle for publishing ToxCastTM ToxRef summarized bioassay data for use
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Screening the ToxCast Phase 1 Chemical Library for Inhibition of Deiodinase Type 1 Activity.
Hornung, Michael W; Korte, Joseph J; Olker, Jennifer H; Denny, Jeffrey S; Knutsen, Carsten; Hartig, Phillip C; Cardon, Mary C; Degitz, Sigmund J
2018-04-01
Thyroid hormone (TH) homeostasis is dependent upon coordination of multiple key events including iodide uptake, hormone synthesis, metabolism, and elimination, to maintain proper TH signaling. Deiodinase enzymes catalyze iodide release from THs to interconvert THs between active and inactive forms, and are integral to hormone metabolism. The activity of deiodinases has been identified as an important endpoint to include in the context of screening chemicals for TH disruption. To begin to address the potential for chemicals to inhibit these enzymes an adenovirus expression system was used to produce human deiodinase type 1 (DIO1) enzyme, established robust assay parameters for nonradioactive determination of iodide release by the Sandell-Kolthoff method, and employed a 96-well plate format for screening chemical libraries. An initial set of 18 chemicals was used to establish the assay, along with the known DIO1 inhibitor 6-propylthiouracil as a positive control. An additional 292 unique chemicals from the EPA's ToxCast phase 1_v2 chemical library were screened. Chemicals were initially screened at a single high concentration of 200 µM to identify potential DIO1 inhibitors. There were 50 chemicals, or 17% of the TCp1_v2 chemicals tested, that produced >20% inhibition of DIO1 activity. Eighteen of these inhibited DIO1 activity >50% and were further tested in concentration-response mode to determine IC50s. This work presents an initial effort toward identifying chemicals with potential for affecting THs via inhibition of deiodinases and sets the foundation for further testing of large chemical libraries against DIO1 and the other deiodinase enzymes involved in TH function.
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Sixty-five chemicals in the ToxCast high-throughput screening (HTS) dataset have been linked to cleft palate based on data from ToxRefDB (rat or rabbit prenatal developmental toxicity studies) or from literature reports. These compounds are structurally diverse and thus likely to...
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Inferring Toxicological Responses of HepG2 Cells from ToxCast High Content Imaging Data (SOT)
Understanding the dynamic perturbation of cell states by chemicals can aid in for predicting their adverse effects. High-content imaging (HCI) was used to measure the state of HepG2 cells over three time points (1, 24, and 72 h) in response to 976 ToxCast chemicals for 10 differe...
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Cells adapt to their environment via homeostatic processes that are regulated by complex molecular networks. Our objective was to learn key elements of these networks in HepG2 cells using ToxCast High-content imaging (HCI) measurements taken over three time points (1, 24, and 72h...
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The U.S. Environmental Protection Agency’s ToxCast project and the related, multi-Agency Tox21 project are employing high-throughput technologies to screen hundreds to thousands of chemicals in hundreds of assays, probing a wide diversity of biological targets, pathways and mecha...
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We have used primary cortical neurons grown in multi-well microelectrode array (mwMEA) plates to screen the ToxCast Phase II library of 1055 unique compounds for the ability to cause acute neurotoxicity. Each compound was screened at a single high concentration of 40 µM...
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A central aim of EPA’s ToxCast project is to use in vitro high-throughput screening (HTS) profiles to build predictive models of in vivo toxicity. Where assays lack metabolic capability, such efforts may need to anticipate the role of metabolic activation (or deactivation). A wo...
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Utilizing ToxCast Data and Lifestage Physiologically-Based Pharmacokinetic (PBPK) models to Drive Adverse Outcome Pathways (AOPs)-Based Margin of Exposures (ABME) to Chemicals. Hisham A. El-Masri1, Nicole C. Klienstreur2, Linda Adams1, Tamara Tal1, Stephanie Padilla1, Kristin I...
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20170312 - Adverse Outcome Pathway (AOP) framework for ...
Vascular development commences with de novo assembly of a primary capillary plexus (vasculogenesis) followed by its expansion (angiogenesis) and maturation (angio-adaptation) into a hierarchical system of arteries and veins. These processes are tightly regulated by genetic signals and environmental factors linked to morphogenesis and microphysiology. Gestational exposure to some chemicals disrupts vascular development leading to adverse outcomes. To broadly assess consequences of gestational toxicant exposure on vascular development, an Adverse Outcome Pathway (AOP) framework was constructed that integrates data from ToxCast high-throughput screening (HTS) assays with pathway-level information from the literature and public databases. The AOP-based model resolved the ToxCast library (1065 compounds) into a matrix based on several dozen molecular functions critical for developmental angiogenesis. A sample of 38 ToxCast chemicals selected across the matrix tested model performance. Putative vascular disrupting chemical (pVDC) bioactivity was assessed by multiple laboratories utilizing diverse angiogenesis assays, including: transgenic zebrafish, complex human cell co-cultures, engineered microscale systems, and human-synthetic models. The ToxCast pVDC signature predicted vascular disruption in a manner that was chemical-specific and assay-dependent. An AOP for developmental vascular toxicity was constructed that focuses on inhibition of VEGF receptor (VEGFR2). Thi
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Adverse Outcome Pathway (AOP) framework for embryonic ...
Vascular development commences with de novo assembly of a primary capillary plexus (vasculogenesis) followed by its expansion (angiogenesis) and maturation (angio-adaptation) into a hierarchical system of arteries and veins. These processes are tightly regulated by genetic signals and environmental factors linked to morphogenesis and microphysiology. Gestational exposure to some chemicals disrupts vascular development leading to adverse outcomes. To broadly assess consequences of gestational toxicant exposure on vascular development, an Adverse Outcome Pathway (AOP) framework was constructed that integrates data from ToxCast high-throughput screening (HTS) assays with pathway-level information from the literature and public databases. The AOP-based model resolved the ToxCast library (1065 compounds) into a matrix based on several dozen molecular functions critical for developmental angiogenesis. A sample of 38 ToxCast chemicals selected across the matrix tested model performance. Putative vascular disrupting chemical (pVDC) bioactivity was assessed by multiple laboratories utilizing diverse angiogenesis assays, including: transgenic zebrafish, complex human cell co-cultures, engineered microscale systems, and human-synthetic models. The ToxCast pVDC signature predicted vascular disruption in a manner that was chemical-specific and assay-dependent. An AOP for developmental vascular toxicity was constructed that focuses on inhibition of VEGF receptor (VEGFR2). Thi
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Kleinstreuer, Nicole C; Dix, David J; Houck, Keith A; Kavlock, Robert J; Knudsen, Thomas B; Martin, Matthew T; Paul, Katie B; Reif, David M; Crofton, Kevin M; Hamilton, Kerry; Hunter, Ronald; Shah, Imran; Judson, Richard S
2013-01-01
Thousands of untested chemicals in the environment require efficient characterization of carcinogenic potential in humans. A proposed solution is rapid testing of chemicals using in vitro high-throughput screening (HTS) assays for targets in pathways linked to disease processes to build models for priority setting and further testing. We describe a model for predicting rodent carcinogenicity based on HTS data from 292 chemicals tested in 672 assays mapping to 455 genes. All data come from the EPA ToxCast project. The model was trained on a subset of 232 chemicals with in vivo rodent carcinogenicity data in the Toxicity Reference Database (ToxRefDB). Individual HTS assays strongly associated with rodent cancers in ToxRefDB were linked to genes, pathways, and hallmark processes documented to be involved in tumor biology and cancer progression. Rodent liver cancer endpoints were linked to well-documented pathways such as peroxisome proliferator-activated receptor signaling and TP53 and novel targets such as PDE5A and PLAUR. Cancer hallmark genes associated with rodent thyroid tumors were found to be linked to human thyroid tumors and autoimmune thyroid disease. A model was developed in which these genes/pathways function as hypothetical enhancers or promoters of rat thyroid tumors, acting secondary to the key initiating event of thyroid hormone disruption. A simple scoring function was generated to identify chemicals with significant in vitro evidence that was predictive of in vivo carcinogenicity in different rat tissues and organs. This scoring function was applied to an external test set of 33 compounds with carcinogenicity classifications from the EPA's Office of Pesticide Programs and successfully (p = 0.024) differentiated between chemicals classified as "possible"/"probable"/"likely" carcinogens and those designated as "not likely" or with "evidence of noncarcinogenicity." This model represents a chemical carcinogenicity prioritization tool supporting targeted testing and functional validation of cancer pathways.
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ToxCast chemicals were assessed for induction or suppression of xenobiotic metabolizing enzyme and transporter gene expression using primary human hepatocytes. The mRNA levels of 14 target and 2 control genes were measured: ABCB1, ABCB11, ABCG2, SLCO1B1, CYP1A1, CYP1A2, CYP2B6, C...
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40 CFR 147.801 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.801... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Iowa § 147.801 EPA... administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148...
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40 CFR 147.601 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.601... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Hawaii § 147.601 EPA... administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148...
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40 CFR 147.801 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.801... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Iowa § 147.801 EPA... administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148...
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40 CFR 147.901 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.901... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Kentucky § 147.901 EPA... lands, is administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124...
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40 CFR 147.601 - EPA-administered program.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.601... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Hawaii § 147.601 EPA... administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148...
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40 CFR 147.901 - EPA-administered program.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program. 147.901... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Kentucky § 147.901 EPA... lands, is administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124...
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40 CFR 147.901 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.901... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Kentucky § 147.901 EPA... lands, is administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124...
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40 CFR 147.801 - EPA-administered program.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program. 147.801... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Iowa § 147.801 EPA... administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148...
-
40 CFR 147.901 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.901... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Kentucky § 147.901 EPA... lands, is administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124...
-
40 CFR 147.801 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.801... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Iowa § 147.801 EPA... administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148...
-
40 CFR 147.601 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.601... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Hawaii § 147.601 EPA... administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148...
-
40 CFR 147.601 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.601... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Hawaii § 147.601 EPA... administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148...
-
40 CFR 147.801 - EPA-administered program.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.801... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Iowa § 147.801 EPA... administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148...
-
40 CFR 147.601 - EPA-administered program.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program. 147.601... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Hawaii § 147.601 EPA... administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148...
-
40 CFR 147.901 - EPA-administered program.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.901... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Kentucky § 147.901 EPA... lands, is administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124...
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Identification of Potential Sodium Iodide Symporter (NIS) Inhibitors in ToxCast Phase1_v2 Chemical Library Using in vitro Radioactive Iodide Uptake (RAIU) Assay Jun Wang1,2, Daniel R. Hallinger2, Ashley S. Murr2, Angela R. Buckalew1, Tammy E. Stoker2, Susan C. Laws21Oak Ridge In...
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ToxCast chemicals were assessed for induction or suppression of xenobiotic metabolizing enzyme and transporter gene expression using primary human hepatocytes. The mRNA levels of 14 target and 2 control genes were measured: ABCB1, ABCB11, ABCG2, SLCO1B1, CYP1A1, CYP1A2, CYP2B6, C...
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Differentiating high priority pathway-based toxicity from non ...
The ToxCast chemical screening approach enables the rapid assessment of large numbers of chemicals for biological effects, primarily at the molecular level. Adverse outcome pathways (AOPs) offer a means to link biomolecular effects with potential adverse outcomes at the level of the individual or population, thus enhancing the utility of the ToxCast effort for hazard assessment. Thus, efforts are underway to develop AOPs relevant to the pathway perturbations detected in ToxCast assays. However, activity (?‘hits’) determined for chemical-assay pairs may reflect target-specific activity relevant to a molecular initiating event of an AOP, or more generalized cell stress and cytotoxicity-mediated effects. Previous work identified a ?‘cytotoxic burst’ phenomenon wherein large numbers of assays begin to respond at or near concentrations that elicit cytotoxicity. The concentration range at which the “burst” occurs is definable, statistically. Consequently, in order to focus AOP development on the ToxCast assay targetswhich are most sensitive and relevant to pathway-specific effects, we conducted a meta-analysis to identify which assays were frequently responding at concentrations well below the cytotoxic burst. Assays were ranked by the fraction of chemical hits below the burst concentration range compared to the number of chemicals tested, resulting in a preliminary list of potentially important, target-specific assays. After eliminating cytotoxicity a
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40 CFR 147.1351 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.1351... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Montana § 147.1351 EPA... within the exterior boundaries of the Fort Peck Indian Reservation, is administered by EPA. This program...
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40 CFR 147.1351 - EPA-administered program.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program. 147.1351... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Montana § 147.1351 EPA... within the exterior boundaries of the Fort Peck Indian Reservation, is administered by EPA. This program...
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40 CFR 147.1351 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.1351... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Montana § 147.1351 EPA... within the exterior boundaries of the Fort Peck Indian Reservation, is administered by EPA. This program...
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40 CFR 147.1351 - EPA-administered program.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.1351... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Montana § 147.1351 EPA... within the exterior boundaries of the Fort Peck Indian Reservation, is administered by EPA. This program...
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40 CFR 147.1351 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.1351... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Montana § 147.1351 EPA... within the exterior boundaries of the Fort Peck Indian Reservation, is administered by EPA. This program...
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An Update on ToxCast™ | Science Inventory | US EPA
In its first phase, ToxCast™ is profiling over 300 well-characterized chemicals (primarily pesticides) in over 400 HTS endpoints. These endpoints include biochemical assays of protein function, cell-based transcriptional reporter assays, multi-cell interaction assays, transcriptomics on primary cell cultures, and developmental assays in zebrafish embryos. Almost all of the compounds being examined in Phase 1 of ToxCast™ have been tested in traditional toxicology tests, including developmental toxicity, multi-generation studies, and sub-chronic and chronic rodent bioassays Lessons learned to date for ToxCast: Large amounts of quality HTS data can be economically obtained. Large scale data sets will be required to understand potential for biological activity. Value in having multiple assays with overlapping coverage of biological pathways and a variety of methodologies Concentration-response will be important for ultimate interpretation Data transparency will be important for acceptance. Metabolic capabilities and coverage of developmental toxicity pathways will need additional attention. Need to define the gold standard Partnerships are needed to bring critical mass and expertise.
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40 CFR 147.101 - EPA-administered program.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program. 147.101... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Alaska § 147.101 EPA..., and for all classes of wells on Indian lands, is administered by EPA. This program consists of the UIC...
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40 CFR 147.101 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.101... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Alaska § 147.101 EPA..., and for all classes of wells on Indian lands, is administered by EPA. This program consists of the UIC...
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40 CFR 147.101 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.101... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Alaska § 147.101 EPA..., and for all classes of wells on Indian lands, is administered by EPA. This program consists of the UIC...
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40 CFR 147.101 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.101... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Alaska § 147.101 EPA..., and for all classes of wells on Indian lands, is administered by EPA. This program consists of the UIC...
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Alginate Immobilization of Metabolic Enzymes (AIME) for High ...
Alginate Immobilization of Metabolic Enzymes (AIME) for High-Throughput Screening Assays DE DeGroot, RS Thomas, and SO SimmonsNational Center for Computational Toxicology, US EPA, Research Triangle Park, NC USAThe EPA’s ToxCast program utilizes a wide variety of high-throughput screening (HTS) assays to assess chemical perturbations of molecular and cellular endpoints. A key criticism of using HTS assays for toxicity assessment is the lack of xenobiotic metabolism (XM) which precludes both metabolic detoxification as well as bioactivation of chemicals tested in vitro thereby mischaracterizing the potential risk posed by these chemicals. To address this deficiency, we have developed an extracellular platform to retrofit existing HTS assays with XM activity. This platform utilizes the S9 fraction of liver homogenate encapsulated in an alginate gel network which reduces the cytotoxicity caused by direct addition of S9 to cells in culture. Alginate microspheres containing encapsulated human liver S9 were cross-linked to solid supports extending from a 96-well plate lid and were assayed using a pro-luciferin substrate specific for CYP3A4 (IPA). We demonstrate that S9 was successfully encapsulated and remained enzymatically active post-encapsulation with 5-10X the CYP3A4 activity as compared to 1 µg solubilized human liver S9. Ketoconazole, a known inhibitor of human CYP3A4, inhibited CYP3A4 activity in a concentration-dependent manner (IC50: 0.27 µM) and inhibiti
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40 CFR 147.2751 - EPA-administered program.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.2751... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS American Samoa § 147.2751 EPA-administered program. (a) Contents. The UIC program for American Samoa, including all Indian...
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40 CFR 147.2151 - EPA-administered program.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program. 147.2151... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Tennessee § 147.2151 EPA-administered program. (a) Contents. The UIC program for the State of Tennessee, including all...
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40 CFR 147.1151 - EPA-administered program.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program. 147.1151... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Michigan § 147.1151 EPA-administered program. (a) Contents. The UIC program for the State of Michigan, including all...
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40 CFR 147.1151 - EPA-administered program.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.1151... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Michigan § 147.1151 EPA-administered program. (a) Contents. The UIC program for the State of Michigan, including all...
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40 CFR 147.2801 - EPA-administered program.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program. 147.2801... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Commonwealth of the Northern Mariana Islands § 147.2801 EPA-administered program. (a) Contents. The UIC program for Indian...
-
40 CFR 147.1151 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.1151... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Michigan § 147.1151 EPA-administered program. (a) Contents. The UIC program for the State of Michigan, including all...
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40 CFR 147.1951 - EPA-administered program.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.1951... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Pennsylvania § 147.1951 EPA-administered program. (a) Contents. The UIC program for the State of Pennsylvania, including...
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40 CFR 147.2351 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.2351... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virginia § 147.2351 EPA-administered program. (a) Contents. The UIC program for the State of Virginia, including all...
-
40 CFR 147.2801 - EPA-administered program.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.2801... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Commonwealth of the Northern Mariana Islands § 147.2801 EPA-administered program. (a) Contents. The UIC program for Indian...
-
40 CFR 147.1151 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.1151... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Michigan § 147.1151 EPA-administered program. (a) Contents. The UIC program for the State of Michigan, including all...
-
40 CFR 147.2351 - EPA-administered program.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program. 147.2351... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virginia § 147.2351 EPA-administered program. (a) Contents. The UIC program for the State of Virginia, including all...
-
40 CFR 147.2701 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.2701... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virgin Islands § 147.2701 EPA-administered program. (a) Contents. The UIC program for the Virgin Islands, including all...
-
40 CFR 147.2751 - EPA-administered program.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program. 147.2751... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS American Samoa § 147.2751 EPA-administered program. (a) Contents. The UIC program for American Samoa, including all Indian...
-
40 CFR 147.2351 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.2351... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virginia § 147.2351 EPA-administered program. (a) Contents. The UIC program for the State of Virginia, including all...
-
40 CFR 147.2701 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.2701... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virgin Islands § 147.2701 EPA-administered program. (a) Contents. The UIC program for the Virgin Islands, including all...
-
40 CFR 147.1951 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.1951... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Pennsylvania § 147.1951 EPA-administered program. (a) Contents. The UIC program for the State of Pennsylvania, including...
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40 CFR 147.2404 - EPA-administered program-Colville Reservation.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Colville...) WATER PROGRAMS (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Washington § 147.2404 EPA-administered program—Colville Reservation. (a) The UIC program for the Colville...
-
40 CFR 147.451 - EPA-administered program.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.451... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS District of Columbia § 147.451 EPA-administered program. (a) Contents. The UIC program for the District of Columbia...
-
40 CFR 147.451 - EPA-administered program.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program. 147.451... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS District of Columbia § 147.451 EPA-administered program. (a) Contents. The UIC program for the District of Columbia...
-
40 CFR 147.2751 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.2751... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS American Samoa § 147.2751 EPA-administered program. (a) Contents. The UIC program for American Samoa, including all Indian...
-
40 CFR 147.2801 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.2801... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Commonwealth of the Northern Mariana Islands § 147.2801 EPA-administered program. (a) Contents. The UIC program for Indian...
-
40 CFR 147.451 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.451... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS District of Columbia § 147.451 EPA-administered program. (a) Contents. The UIC program for the District of Columbia...
-
40 CFR 147.2351 - EPA-administered program.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.2351... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virginia § 147.2351 EPA-administered program. (a) Contents. The UIC program for the State of Virginia, including all...
-
40 CFR 147.2751 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.2751... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS American Samoa § 147.2751 EPA-administered program. (a) Contents. The UIC program for American Samoa, including all Indian...
-
40 CFR 147.2404 - EPA-administered program-Colville Reservation.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Colville...) WATER PROGRAMS (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Washington § 147.2404 EPA-administered program—Colville Reservation. (a) The UIC program for the Colville...
-
40 CFR 147.2701 - EPA-administered program.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.2701... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virgin Islands § 147.2701 EPA-administered program. (a) Contents. The UIC program for the Virgin Islands, including all...
-
40 CFR 147.2701 - EPA-administered program.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program. 147.2701... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virgin Islands § 147.2701 EPA-administered program. (a) Contents. The UIC program for the Virgin Islands, including all...
-
40 CFR 147.1951 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.1951... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Pennsylvania § 147.1951 EPA-administered program. (a) Contents. The UIC program for the State of Pennsylvania, including...
-
40 CFR 147.2151 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.2151... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Tennessee § 147.2151 EPA-administered program. (a) Contents. The UIC program for the State of Tennessee, including all...
-
40 CFR 147.2351 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.2351... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virginia § 147.2351 EPA-administered program. (a) Contents. The UIC program for the State of Virginia, including all...
-
40 CFR 147.451 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.451... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS District of Columbia § 147.451 EPA-administered program. (a) Contents. The UIC program for the District of Columbia...
-
40 CFR 147.1951 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.1951... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Pennsylvania § 147.1951 EPA-administered program. (a) Contents. The UIC program for the State of Pennsylvania, including...
-
40 CFR 147.2151 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.2151... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Tennessee § 147.2151 EPA-administered program. (a) Contents. The UIC program for the State of Tennessee, including all...
-
40 CFR 147.2801 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.2801... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Commonwealth of the Northern Mariana Islands § 147.2801 EPA-administered program. (a) Contents. The UIC program for Indian...
-
40 CFR 147.1951 - EPA-administered program.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program. 147.1951... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Pennsylvania § 147.1951 EPA-administered program. (a) Contents. The UIC program for the State of Pennsylvania, including...
-
40 CFR 147.451 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.451... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS District of Columbia § 147.451 EPA-administered program. (a) Contents. The UIC program for the District of Columbia...
-
40 CFR 147.2151 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.2151... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Tennessee § 147.2151 EPA-administered program. (a) Contents. The UIC program for the State of Tennessee, including all...
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40 CFR 147.2701 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.2701... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virgin Islands § 147.2701 EPA-administered program. (a) Contents. The UIC program for the Virgin Islands, including all...
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40 CFR 147.1151 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.1151... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Michigan § 147.1151 EPA-administered program. (a) Contents. The UIC program for the State of Michigan, including all...
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40 CFR 147.2751 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.2751... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS American Samoa § 147.2751 EPA-administered program. (a) Contents. The UIC program for American Samoa, including all Indian...
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40 CFR 147.2801 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.2801... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Commonwealth of the Northern Mariana Islands § 147.2801 EPA-administered program. (a) Contents. The UIC program for Indian...
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40 CFR 147.2151 - EPA-administered program.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.2151... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Tennessee § 147.2151 EPA-administered program. (a) Contents. The UIC program for the State of Tennessee, including all...
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40 CFR 147.3100 - EPA-administered program.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program. 147.3100... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Lands of Certain Oklahoma Indian Tribes § 147.3100 EPA-administered program. (a) Contents. The UIC program for the Indian...
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40 CFR 147.3100 - EPA-administered program.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.3100... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Lands of Certain Oklahoma Indian Tribes § 147.3100 EPA-administered program. (a) Contents. The UIC program for the Indian...
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40 CFR 147.2851 - EPA-administered program.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program. 147.2851... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Trust Territory of the Pacific Islands § 147.2851 EPA-administered program. (a) Contents. The UIC program for Trust Territory of...
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40 CFR 147.1651 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.1651... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS New York § 147.1651 EPA-administered program. (a) Contents. The UIC program for the State of New York, including all...
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40 CFR 147.2851 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.2851... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Trust Territory of the Pacific Islands § 147.2851 EPA-administered program. (a) Contents. The UIC program for Trust Territory of...
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40 CFR 147.2851 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.2851... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Trust Territory of the Pacific Islands § 147.2851 EPA-administered program. (a) Contents. The UIC program for Trust Territory of...
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40 CFR 147.1651 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.1651... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS New York § 147.1651 EPA-administered program. (a) Contents. The UIC program for the State of New York, including all...
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40 CFR 147.3100 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.3100... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Lands of Certain Oklahoma Indian Tribes § 147.3100 EPA-administered program. (a) Contents. The UIC program for the Indian...
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40 CFR 147.1651 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.1651... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS New York § 147.1651 EPA-administered program. (a) Contents. The UIC program for the State of New York, including all...
-
40 CFR 147.2851 - EPA-administered program.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.2851... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Trust Territory of the Pacific Islands § 147.2851 EPA-administered program. (a) Contents. The UIC program for Trust Territory of...
-
40 CFR 147.2851 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.2851... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Trust Territory of the Pacific Islands § 147.2851 EPA-administered program. (a) Contents. The UIC program for Trust Territory of...
-
40 CFR 147.3100 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.3100... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Lands of Certain Oklahoma Indian Tribes § 147.3100 EPA-administered program. (a) Contents. The UIC program for the Indian...
-
40 CFR 147.3100 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.3100... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Lands of Certain Oklahoma Indian Tribes § 147.3100 EPA-administered program. (a) Contents. The UIC program for the Indian...
-
40 CFR 147.1651 - EPA-administered program.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program. 147.1651... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS New York § 147.1651 EPA-administered program. (a) Contents. The UIC program for the State of New York, including all...
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Computer Simulation of Embryonic Systems: What can a ...
(1) Standard practice for assessing developmental toxicity is the observation of apical endpoints (intrauterine death, fetal growth retardation, structural malformations) in pregnant rats/rabbits following exposure during organogenesis. EPA’s computational toxicology research program (ToxCast) generated vast in vitro cellular and molecular effects data on >1858 chemicals in >600 high-throughput screening (HTS) assays. The diversity of assays has been increased for developmental toxicity with several HTS platforms, including the devTOX-quickPredict assay from Stemina Biomarker Discovery utilizing the human embryonic stem cell line (H9). Translating these HTS data into higher order-predictions of developmental toxicity is a significant challenge. Here, we address the application of computational systems models that recapitulate the kinematics of dynamical cell signaling networks (e.g., SHH, FGF, BMP, retinoids) in a CompuCell3D.org modeling environment. Examples include angiogenesis (angiodysplasia) and dysmorphogenesis. Being numerically responsive to perturbation, these models are amenable to data integration for systems Toxicology and Adverse Outcome Pathways (AOPs). The AOP simulation outputs predict potential phenotypes based on the in vitro HTS data ToxCast. A heuristic computational intelligence framework that recapitulates the kinematics of dynamical cell signaling networks in the embryo, together with the in vitro profiling data, produce quantitative pr
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Computational Modeling and Simulation of Developmental ...
Standard practice for assessing developmental toxicity is the observation of apical endpoints (intrauterine death, fetal growth retardation, structural malformations) in pregnant rats/rabbits following exposure during organogenesis. EPA’s computational toxicology research program (ToxCast) generated vast in vitro cellular and molecular effects data on >1858 chemicals in >600 high-throughput screening (HTS) assays. The diversity of assays has been increased for developmental toxicity with several HTS platforms, including the devTOX-quickPredict assay from Stemina Biomarker Discovery utilizing the human embryonic stem cell line (H9). Translating these HTS data into higher order-predictions of developmental toxicity is a significant challenge. Here, we address the application of computational systems models that recapitulate the kinematics of dynamical cell signaling networks (e.g., SHH, FGF, BMP, retinoids) in a CompuCell3D.org modeling environment. Examples include angiogenesis (angiodysplasia) and dysmorphogenesis. Being numerically responsive to perturbation, these models are amenable to data integration for systems Toxicology and Adverse Outcome Pathways (AOPs). The AOP simulation outputs predict potential phenotypes based on the in vitro HTS data ToxCast. A heuristic computational intelligence framework that recapitulates the kinematics of dynamical cell signaling networks in the embryo, together with the in vitro profiling data, produce quantitative predic
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40 CFR 147.60 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands... § 147.60 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Alabama is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.60 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... § 147.60 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Alabama is administered by EPA. This program consists of the UIC program...
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40 CFR 147.651 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands....651 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Idaho is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.60 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands... § 147.60 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Alabama is administered by EPA. This program consists of the UIC program...
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40 CFR 147.353 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands... § 147.353 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Connecticut is administered by EPA. This program consists of the UIC program...
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40 CFR 147.1001 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands....1001 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Maine is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.353 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands... § 147.353 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Connecticut is administered by EPA. This program consists of the UIC program...
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40 CFR 147.205 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... § 147.205 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Arkansas is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.205 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands... § 147.205 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Arkansas is administered by EPA. This program consists of the UIC program...
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40 CFR 147.2205 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands....2205 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Texas is administered by EPA. This program consists of the UIC program...
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40 CFR 147.403 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands... § 147.403 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Delaware is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.353 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands... § 147.353 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Connecticut is administered by EPA. This program consists of the UIC program...
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40 CFR 147.1805 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands....1805 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Ohio is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.353 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... § 147.353 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Connecticut is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.1001 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands....1001 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Maine is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.353 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands... § 147.353 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Connecticut is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.2205 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands....2205 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Texas is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.2205 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands....2205 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Texas is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.1001 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands....1001 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Maine is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.2205 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands....2205 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Texas is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.403 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... § 147.403 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Delaware is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.205 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands... § 147.205 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Arkansas is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.1805 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands....1805 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Ohio is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.403 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands... § 147.403 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Delaware is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.205 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands... § 147.205 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Arkansas is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.651 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands....651 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Idaho is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.2205 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands....2205 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Texas is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.1805 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands....1805 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Ohio is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.403 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands... § 147.403 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Delaware is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.651 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands....651 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Idaho is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.1805 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands....1805 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Ohio is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.1001 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands....1001 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Maine is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.651 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands....651 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Idaho is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.403 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands... § 147.403 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Delaware is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.60 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands... § 147.60 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Alabama is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.205 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands... § 147.205 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Arkansas is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.1805 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands....1805 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Ohio is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.651 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands....651 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Idaho is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.60 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands... § 147.60 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in Alabama is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.1001 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands....1001 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Maine is administered by EPA. This program consists of the UIC program...
-
40 CFR 147.101 - EPA-administered program.
Code of Federal Regulations, 2010 CFR
2010-07-01
... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Alaska § 147.101 EPA-administered program. (a) Contents. The UIC program in the State of Alaska for Class I, III, IV, and V wells, and for all classes of wells on Indian lands, is administered by EPA. This program consists of the UIC...
-
40 CFR 147.151 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.151... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Arizona § 147.151 EPA..., including those on Indian lands, except for Class II wells on Navajo Indian lands for which EPA has granted...
-
40 CFR 147.151 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.151... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Arizona § 147.151 EPA..., including those on Indian lands, except for Class II wells on Navajo Indian lands for which EPA has granted...
-
40 CFR 147.151 - EPA-administered program.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.151... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Arizona § 147.151 EPA..., including those on Indian lands, except for Class II wells on Navajo Indian lands for which EPA has granted...
-
40 CFR 147.751 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.751... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Indiana § 147.751 EPA..., III, IV, and V wells on non-Indian lands in the State of Indiana is administered by the EPA. The...
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40 CFR 147.151 - EPA-administered program.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program. 147.151... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Arizona § 147.151 EPA..., including those on Indian lands, except for Class II wells on Navajo Indian lands for which EPA has granted...
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40 CFR 147.151 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.151... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Arizona § 147.151 EPA..., including those on Indian lands, except for Class II wells on Navajo Indian lands for which EPA has granted...
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40 CFR 147.751 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.751... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Indiana § 147.751 EPA..., III, IV, and V wells on non-Indian lands in the State of Indiana is administered by the EPA. The...
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40 CFR 147.751 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.751... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Indiana § 147.751 EPA..., III, IV, and V wells on non-Indian lands in the State of Indiana is administered by the EPA. The...
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40 CFR 147.3000 - EPA-administered program.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program. 147.3000... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Lands of the Navajo, Ute Mountain Ute, and All Other New Mexico Tribes § 147.3000 EPA-administered program. (a) Contents...
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40 CFR 147.3000 - EPA-administered program.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program. 147.3000... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Lands of the Navajo, Ute Mountain Ute, and All Other New Mexico Tribes § 147.3000 EPA-administered program. (a) Contents...
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40 CFR 147.3000 - EPA-administered program.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program. 147.3000... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Lands of the Navajo, Ute Mountain Ute, and All Other New Mexico Tribes § 147.3000 EPA-administered program. (a) Contents...
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40 CFR 147.3000 - EPA-administered program.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program. 147.3000... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Lands of the Navajo, Ute Mountain Ute, and All Other New Mexico Tribes § 147.3000 EPA-administered program. (a) Contents...
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40 CFR 147.1252 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands... § 147.1252 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Mississippi is administered by EPA. This program consists of the UIC...
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40 CFR 147.1252 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... § 147.1252 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Mississippi is administered by EPA. This program consists of the UIC...
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40 CFR 147.2651 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands... § 147.2651 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the Commonwealth of Puerto Rico is administered by EPA. This program consists of...
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40 CFR 147.553 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... § 147.553 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Georgia is administered by EPA. This program consists of the UIC...
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40 CFR 147.2303 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... § 147.2303 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Vermont is administered by EPA. This program consists of the UIC...
-
40 CFR 147.553 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands... § 147.553 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Georgia is administered by EPA. This program consists of the UIC...
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40 CFR 147.2553 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands... § 147.2553 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Wyoming is administered by EPA. This program consists of the UIC...
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40 CFR 147.1551 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands... § 147.1551 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of New Jersey is administered by EPA. This program consists of the UIC...
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40 CFR 147.1403 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands... § 147.1403 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Nebraska is administered by EPA. This program consists of the UIC...
-
40 CFR 147.2651 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands... § 147.2651 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the Commonwealth of Puerto Rico is administered by EPA. This program consists of...
-
40 CFR 147.1551 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... § 147.1551 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of New Jersey is administered by EPA. This program consists of the UIC...
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40 CFR 147.1752 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... Dakota § 147.1752 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of North Dakota is administered by EPA. This program consists of the...
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40 CFR 147.1451 - EPA administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA administered program-Indian lands... § 147.1451 EPA administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Nevada is administered by EPA. This program consists of the UIC...
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40 CFR 147.2001 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands... Island § 147.2001 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Rhode Island is administered by EPA. This program consists of the...
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40 CFR 147.2453 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands... Virginia § 147.2453 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of West Virginia is administered by EPA. This program consists of the...
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40 CFR 147.2553 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... § 147.2553 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Wyoming is administered by EPA. This program consists of the UIC...
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40 CFR 147.951 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... § 147.951 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Louisiana is administered by EPA. This program consists of the UIC...
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40 CFR 147.1901 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... § 147.1901 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Oregon is administered by EPA. This program consists of the UIC...
-
40 CFR 147.2001 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands... Island § 147.2001 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Rhode Island is administered by EPA. This program consists of the...
-
40 CFR 147.1901 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands... § 147.1901 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Oregon is administered by EPA. This program consists of the UIC...
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40 CFR 147.1501 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands... Hampshire § 147.1501 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of New Hampshire is administered by EPA. This program consists of the...
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40 CFR 147.1703 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands... Carolina § 147.1703 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of North Carolina is administered by EPA. This program consists of...
-
40 CFR 147.1252 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands... § 147.1252 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Mississippi is administered by EPA. This program consists of the UIC...
-
40 CFR 147.1501 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands... Hampshire § 147.1501 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of New Hampshire is administered by EPA. This program consists of the...
-
40 CFR 147.1752 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands... Dakota § 147.1752 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of North Dakota is administered by EPA. This program consists of the...
-
40 CFR 147.1403 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands... § 147.1403 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Nebraska is administered by EPA. This program consists of the UIC...
-
40 CFR 147.951 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands... § 147.951 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Louisiana is administered by EPA. This program consists of the UIC...
-
40 CFR 147.1403 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands... § 147.1403 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Nebraska is administered by EPA. This program consists of the UIC...
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40 CFR 147.2403 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands... § 147.2403 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Washington is administered by EPA. This program, for all Indian lands...
-
40 CFR 147.1501 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... Hampshire § 147.1501 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of New Hampshire is administered by EPA. This program consists of the...
-
40 CFR 147.1752 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands... Dakota § 147.1752 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of North Dakota is administered by EPA. This program consists of the...
-
40 CFR 147.1901 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands... § 147.1901 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Oregon is administered by EPA. This program consists of the UIC...
-
40 CFR 147.2453 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... Virginia § 147.2453 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of West Virginia is administered by EPA. This program consists of the...
-
40 CFR 147.703 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands... § 147.703 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Illinois is administered by EPA. This program consists of the UIC...
-
40 CFR 147.703 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands... § 147.703 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Illinois is administered by EPA. This program consists of the UIC...
-
40 CFR 147.1703 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands... Carolina § 147.1703 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of North Carolina is administered by EPA. This program consists of...
-
40 CFR 147.2403 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands... § 147.2403 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Washington is administered by EPA. This program, for all Indian lands...
-
40 CFR 147.1403 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands... § 147.1403 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Nebraska is administered by EPA. This program consists of the UIC...
-
40 CFR 147.2403 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands... § 147.2403 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Washington is administered by EPA. This program, for all Indian lands...
-
40 CFR 147.1501 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands... Hampshire § 147.1501 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of New Hampshire is administered by EPA. This program consists of the...
-
40 CFR 147.2403 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... § 147.2403 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Washington is administered by EPA. This program, for all Indian lands...
-
40 CFR 147.1303 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands... § 147.1303 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Missouri is administered by EPA. This program consists of the UIC...
-
40 CFR 147.2453 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands... Virginia § 147.2453 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of West Virginia is administered by EPA. This program consists of the...
-
40 CFR 147.2001 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands... Island § 147.2001 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Rhode Island is administered by EPA. This program consists of the...
-
40 CFR 147.1451 - EPA administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA administered program-Indian lands... § 147.1451 EPA administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Nevada is administered by EPA. This program consists of the UIC...
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40 CFR 147.1101 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands... Massachusetts § 147.1101 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Massachusetts is administered by EPA. This program consists of the...
-
40 CFR 147.1703 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... Carolina § 147.1703 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of North Carolina is administered by EPA. This program consists of...
-
40 CFR 147.2303 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands... § 147.2303 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Vermont is administered by EPA. This program consists of the UIC...
-
40 CFR 147.1101 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... Massachusetts § 147.1101 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Massachusetts is administered by EPA. This program consists of the...
-
40 CFR 147.2051 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands... Carolina § 147.2051 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Rhode Island is administered by EPA. This program consists of the...
-
40 CFR 147.1752 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands... Dakota § 147.1752 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of North Dakota is administered by EPA. This program consists of the...
-
40 CFR 147.1101 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands... Massachusetts § 147.1101 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Massachusetts is administered by EPA. This program consists of the...
-
40 CFR 147.1252 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands... § 147.1252 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Mississippi is administered by EPA. This program consists of the UIC...
-
40 CFR 147.1101 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands... Massachusetts § 147.1101 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Massachusetts is administered by EPA. This program consists of the...
-
40 CFR 147.2553 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands... § 147.2553 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Wyoming is administered by EPA. This program consists of the UIC...
-
40 CFR 147.2553 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 40 Protection of Environment 24 2012-07-01 2012-07-01 false EPA-administered program-Indian lands... § 147.2553 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Wyoming is administered by EPA. This program consists of the UIC...
-
40 CFR 147.2453 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands... Virginia § 147.2453 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of West Virginia is administered by EPA. This program consists of the...
-
40 CFR 147.1303 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands... § 147.1303 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Missouri is administered by EPA. This program consists of the UIC...
-
40 CFR 147.2403 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands... § 147.2403 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Washington is administered by EPA. This program, for all Indian lands...
-
40 CFR 147.860 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands... § 147.860 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Kansas is administered by EPA. This program consists of the UIC...
-
40 CFR 147.2051 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... Carolina § 147.2051 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Rhode Island is administered by EPA. This program consists of the...
-
40 CFR 147.2303 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands... § 147.2303 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Vermont is administered by EPA. This program consists of the UIC...
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40 CFR 147.553 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands... § 147.553 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Georgia is administered by EPA. This program consists of the UIC...
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40 CFR 147.1303 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 40 Protection of Environment 24 2013-07-01 2013-07-01 false EPA-administered program-Indian lands... § 147.1303 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Missouri is administered by EPA. This program consists of the UIC...
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40 CFR 147.2303 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA-administered program-Indian lands... § 147.2303 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Vermont is administered by EPA. This program consists of the UIC...
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40 CFR 147.2001 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands... Island § 147.2001 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Rhode Island is administered by EPA. This program consists of the...
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40 CFR 147.1053 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 40 Protection of Environment 23 2014-07-01 2014-07-01 false EPA-administered program-Indian lands... § 147.1053 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Maryland is administered by EPA. This program consists of the UIC...
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40 CFR 147.1451 - EPA administered program-Indian lands.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 40 Protection of Environment 23 2011-07-01 2011-07-01 false EPA administered program-Indian lands... § 147.1451 EPA administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of Nevada is administered by EPA. This program consists of the UIC...
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40 CFR 147.1551 - EPA-administered program-Indian lands.
Code of Federal Regulations, 2010 CFR
2010-07-01
... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program-Indian lands... § 147.1551 EPA-administered program—Indian lands. (a) Contents. The UIC program for all classes of wells on Indian lands in the State of New Jersey is administered by EPA. This program consists of the UIC...