High-Throughput Screening in ToxCast/Tox21 (FutureToxII)

EPA Science Inventory

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...

Biotransformation and ToxCast™

EPA Science Inventory

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...

Probabilistic prediction of outbreaks of meningococcus W-135 infections over the next few years in Spain

NASA Astrophysics Data System (ADS)

Acedo, L.; Burgos, C.; Cortés, J.-C.; Villanueva, R.-J.

2017-11-01

The genogroups of meningococcal and other bacteria are in competition in the ecosystem they form with the human hosts. Changes in vaccination strategies, prophylactic measures or usual habits, may also change the distribution of the genogroups in the ecosystem but, usually, this competition is ignored in most epidemiological models, despite it can be highly influential in the evolution of infection diseases and outbreaks. Our goal is to propose a susceptible-carrier-susceptible (SCS) epidemiological model to determine the percentage of carriers in the population, and introduce a fractional Lotka-Volterra competition model to describe the evolution of the meningococcal genogroups in Spain among the carriers. Using data from the distribution of the genogroups in Spain in 2011 and 2012, we find the model parameters and their uncertainties according to a probabilistic fitting approach. On this basis, we predict the evolution of the carriers of the different genogroups over the next few years and, in particular, the percentage of carriers of meningococcus W-135 with a 95% confidence interval. Then, we estimate the probability of having a possible outbreak of meningococcus W-135 in Spain over the next few years. According to our model and, under the present conditions, the risk of a serious outbreak of W-135 in Spain in the next 3 years is below 0 . 3%.

Quantitative Model of Systemic Toxicity Using ToxCast and ToxRefDB (SOT)

EPA Science Inventory

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...

Chemical-Gene Interactions from ToxCast Bioactivity Data ...

EPA Pesticide Factsheets

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

[Epidemic meningitis in 2013 in Republic of Guinea: Nesseria meningitidis W135 emergence].

PubMed

Traoré, F A; Sako, F B; Sylla, D; Kader, D S; Bangoura, M; Traoré, M; Keita, A; Sidibé, A; Keita, S; Barry, M; Cisse, M; Touré, A

2016-12-01

A prospective study conducted from 1 January to 31 December 2013 described a meningitis epidemic in Republic of Guinea. The identification of the germs was based on Gram stain, latex agglutination and culture. During the study period, 480 suspected cases of meningitis were reported by 21 health districts. The average age was 18±8 years and 62.5% were men. The vaccination status was unknown in all patients. The largest attack rates were found in Siguiri (3.2 per 10,000), Kankan (2.6 per 10,000) and Dabola (3.9 per 10,000). The locality of Kintinian in Siguiri was the only one to cross the epidemic threshold. The identified microorganisms were Haemophilus influenzae (1 time), Pneumococcus (2 times), Neisseria meningitidis A (4 times) and W135 (10 times) with a total of 17 positive samples. All of these germs were sensitive to chloramphenicol, ceftriaxone and ciprofloxacin. The average hospital stay was 6.5±2 days. The lethality was 13.8%. This meningitis epidemic was characterized by the emergence of Neisseria meningitidis W135. The monitoring of this serogroup should be increased and future vaccination strategies must include it presence.

Tox21 and ToxCast Chemical Landscapes: Laying the Foundation for 21st Century Toxicology

EPA Science Inventory

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...

Using the ToxMiner Database for Identifying Disease-Gene Associations in the ToxCast Dataset

EPA Science Inventory

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...

Tox21 Enricher: Web-based Chemical/Biological Functional Annotation Analysis Tool Based on Tox21 Toxicity Screening Platform.

PubMed

Hur, Junguk; Danes, Larson; Hsieh, Jui-Hua; McGregor, Brett; Krout, Dakota; Auerbach, Scott

2018-05-01

The US Toxicology Testing in the 21st Century (Tox21) program was established to develop more efficient and human-relevant toxicity assessment methods. The Tox21 program screens >10,000 chemicals using quantitative high-throughput screening (qHTS) of assays that measure effects on toxicity pathways. To date, more than 70 assays have yielded >12 million concentration-response curves. The patterns of activity across assays can be used to define similarity between chemicals. Assuming chemicals with similar activity profiles have similar toxicological properties, we may infer toxicological properties based on its neighbourhood. One approach to inference is chemical/biological annotation enrichment analysis. Here, we present Tox21 Enricher, a web-based chemical annotation enrichment tool for the Tox21 toxicity screening platform. Tox21 Enricher identifies over-represented chemical/biological annotations among lists of chemicals (neighbourhoods), facilitating the identification of the toxicological properties and mechanisms in the chemical set. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Computational Analysis and Characterization of RC-135 External Aerodynamics

DTIC Science & Technology

2012-03-22

date date date AFIT/GAE/ENY/12-M06 Abstract Both the RC-135V/W Rivet Joint (RJ) and the RC-135U Combat Sent (CS) aircraft are United States Air...Page 1.1. RC-135V/W Rivet Joint [1] . . . . . . . . . . . . . . . . . . . . 2 1.2. RC-135U Combat Sent [1] . . . . . . . . . . . . . . . . . . . . . 2...1.3. RC-135V/W Rivet Joint BL9 antenna locations [2] . . . . . . . 3 1.4. RC-135U Combat Sent showing LCS with louver installed over exhaust [1

Toxicity ForeCaster (ToxCast™) Data

EPA Pesticide Factsheets

Data is organized into different data sets and includes descriptions of ToxCast chemicals and assays and files summarizing the screening results, a MySQL database, chemicals screened through Tox21, and available data generated from animal toxicity studies.

Use of ToxPrint chemotypes for exploring chemical feature enrichments across the ToxCast chemical-assay landscape

EPA Science Inventory

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...

A knowledge-informed chemotype approach to mining the ToxCast/Tox21 chemical-data landscape (WC9)

EPA Science Inventory

ToxCast and Tox21 chemical libraries currently exceed 2000 and 8000 unique chemicals, respectively, and span a broad diversity of chemical use-types, functionality, and toxicity mechanism and endpoint space. These libraries function as mechanism probes across hundreds of high-th...

Application of the ToxMiner Database: Network Analysis ...

EPA Pesticide Factsheets

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

Correlation of microstructure and low cycle fatigue properties for 13.5Cr1.1W0.3Ti ODS steel

NASA Astrophysics Data System (ADS)

He, P.; Klimenkov, M.; Möslang, A.; Lindau, R.; Seifert, H. J.

2014-12-01

Reduced activation oxide dispersion strengthened (ODS) steels are prospective structural materials for the blanket system and first wall components in Tokamak-type fusion reactors. Under the pulsed operation, these components will be predominantly subjected to cyclic thermal-mechanical loading which leads to inevitable fatigue damage. In this work, strain controlled isothermal fatigue tests were conducted for 13.5Cr1.1W0.3Ti ODS steel at 550 °C. The total strain range varied from 0.54% to 0.9%. After thermomechanical processing, 13.5CrWTi-ODS steel exhibits a remarkable lifetime extension with a factor of 10-20 for strain ranges Δε ⩽ 0.7%. 13.5Cr ODS steel shows no cyclic softening at all during the whole testing process irrespective of the strain range. TEM observations reveal ultrastable grain structure and constant dislocation densities around 1014 m-2, independent of the number of cycles or the applied strain amplitude. The presence of the stabilized ultrafine Y-Ti-O dispersoids enhances the microstructural stability and therefore leads to outstanding fatigue resistance for 13.5Cr1.1W0.3Ti-ODS steel.

Application of the ToxMiner Database: Network Analysis Linking the ToxCast Chemicals to Known Disease-Gene Associations

EPA Science Inventory

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...

The ToxCast Chemical Landscape - Paving the Road to 21st ...

EPA Pesticide Factsheets

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

ToxMystery

MedlinePlus

Accessibility - This is a link to an external javascript file that searchs for a flash browser plug-in and what version of the browser is being used. The javascript is functional ToxMystery uses Adobe Flash Player. If you cannot install Flash Player, please use ...

ToxCast: EPAs Contribution to the Tox21 Consortium

EPA Science Inventory

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...

20180311 - Use of ToxPrint chemotypes for exploring chemical feature enrichments across the ToxCast chemical-assay landscape (SOT)

EPA Science Inventory

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...

Exploration of ToxCast/Tox21 bioassays as candidate bioanalytical tools for measuring groups of chemicals in water.

PubMed

Louisse, Jochem; Dingemans, Milou M L; Baken, Kirsten A; van Wezel, Annemarie P; Schriks, Merijn

2018-06-14

The present study explores the ToxCast/Tox21 database to select candidate bioassays as bioanalytical tools for measuring groups of chemicals in water. To this aim, the ToxCast/Tox21 database was explored for bioassays that detect polycyclic aromatic hydrocarbons (PAHs), aromatic amines (AAs), (chloro)phenols ((C)Ps) and halogenated aliphatic hydrocarbons (HAliHs), which are included in the European and/or Dutch Drinking Water Directives. Based on the analysis of the availability and performance of bioassays included in the database, we concluded that several bioassays are suitable as bioanalytical tools for assessing the presence of PAHs and (C)Ps in drinking water sources. No bioassays were identified for AAs and HAliHs, due to the limited activity of these chemicals and/or the limited amount of data on these chemicals in the database. A series of bioassays was selected that measure molecular or cellular effects that are covered by bioassays currently in use for chemical water quality monitoring. Interestingly, also bioassays were selected that represent molecular or cellular effects that are not covered by bioassays currently applied. The usefulness of these newly identified bioassays as bioanalytical tools should be further evaluated in follow-up studies. Altogether, this study shows how exploration of the ToxCast/Tox21 database provides a series of candidate bioassays as bioanalytical tools for measuring groups of chemicals in water. This assessment can be performed for any group of chemicals of interest (if represented in the database), and may provide candidate bioassays that can be used to complement the currently applied bioassays for chemical water quality assessment. Copyright © 2018. Published by Elsevier Ltd.

Application of the ToxMiner Database: Network Analysis of ...

EPA Pesticide Factsheets

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

FutureTox III: Bridges for Translation | Science Inventory | US ...

EPA Pesticide Factsheets

The present document describes key discussion points and outcomes of a Society of Toxicology (SOT) Contemporary Concepts in Toxicology (CCT) Workshop, entitled FutureTox III1,2 that was held in Crystal City, Virginia, November 19-20, 2015. The workshop built on the many lessons learned from the first 10 years of TT21 and the first two workshops in the FutureTox series (for summary of FutureTox II see (Knudsen et al., 2015); for summary of FutureTox I see (Rowlands et al., 2014)). FutureTox III was attended in person and via webcast by more than 300 scientists from government research and regulatory agencies, research institutes, academia, and the chemical and pharmaceutical industries in Europe, Canada, and the United States. The meeting materials for FutureTox III, currently available to meeting registrants at http://www.toxicology.org/events/shm/cct/meetings.asp#upcoming-pnl-open, will be open to the public on November 29, 2016. At this workshop, participants reviewed and discussed the state of the science in toxicology and human risk and exposure assessment with a focus on moving TT21 science into the arena of regulatory decision-making. This manuscript describes the outcome of the FutureTox III 'contemporary concepts in toxicology' conference of the Society Toxicology, held November 2015 in Crystal City VA.

Overview of ToxCast™ | Science Inventory | US EPA

EPA Pesticide Factsheets

In 2007, EPA launched ToxCast™ in order to develop a cost-effective approach for prioritizing the toxicity testing of large numbers of chemicals in a short period of time. Using data from state-of-the-art high throughput screening (HTS) bioassays developed in the pharmaceutical industry, ToxCast™ is building computational models to forecast the potential human toxicity of chemicals. These hazard predictions will provide EPA regulatory programs with science-based information helpful in prioritizing chemicals for more detailed toxicological evaluations, and lead to more efficient use of animal testing. 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. ToxRefDB, a relational database being created to house this information, will contain nearly $1B worth of toxicity studies in animals when completed. ToxRefDB is integrated into a more comprehensive data management system developed by NCCT called ACToR (Aggregated Computational Toxicology

eMolTox: prediction of molecular toxicity with confidence.

PubMed

Ji, Changge; Svensson, Fredrik; Zoufir, Azedine; Bender, Andreas

2018-03-07

In this work we present eMolTox, a web server for the prediction of potential toxicity associated with a given molecule. 174 toxicology-related in vitro/vivo experimental datasets were used for model construction and Mondrian conformal prediction was used to estimate the confidence of the resulting predictions. Toxic substructure analysis is also implemented in eMolTox. eMolTox predicts and displays a wealth of information of potential molecular toxicities for safety analysis in drug development. The eMolTox Server is freely available for use on the web at http://xundrug.cn/moltox. chicago.ji@gmail.com or ab454@cam.ac.uk. Supplementary data are available at Bioinformatics online.

ToxCast Dashboard

EPA Pesticide Factsheets

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.

RapidTox Dashboard

EPA Pesticide Factsheets

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.

ToxMiner: Relating ToxCast bioactivity profiles to phenotypic outcomes

EPA Science Inventory

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...

ADME-Tox profiles of some food additives and pesticides

NASA Astrophysics Data System (ADS)

Craciun, Dana; Modra, Dorina; Isvoran, Adriana

2015-12-01

Within this study we compute the Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME-Tox) profiles of several commonly used food additives and some pesticides. As expected, all the food additives considered in this study provided to be safe, their ADME-Tox profiles indicating that they have a good oral bioavailability and they do not produce phosphoslipidosis. The ADME-Tox profiles of the pesticides indicate that, with a few exceptions, they are highly toxic (some of them being not approved in the EU, but still used in other countries) and may cause many diseases. Our results are in good agreement with published data concerning the considered food additives and pesticides revealing that the ADME-Tox profiling method may be successfully used to test other chemicals than drug candidates.

ToxCast HTS Assay Development and Retrofitting: Strategies ...

EPA Pesticide Factsheets

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.

Application of the ToxMiner Database: Network Analysis of Linkage between ToxCast Phase I Chemicals and Thyroid Related Disease Outcomes

EPA Science Inventory

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...

DSSTox ToxCast and Tox21 Chemical Inventories: Laying the Foundation for the U.S. EPA’s Computational Toxicology Research Programs

EPA Science Inventory

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...

ToxCast Chemical Landscape: Paving the Road to 21st Century Toxicology.

PubMed

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

Environmental signals modulate ToxT-dependent virulence factor expression in Vibrio cholerae.

PubMed

Schuhmacher, D A; Klose, K E

1999-03-01

The regulatory protein ToxT directly activates the transcription of virulence factors in Vibrio cholerae, including cholera toxin (CT) and the toxin-coregulated pilus (TCP). Specific environmental signals stimulate virulence factor expression by inducing the transcription of toxT. We demonstrate that transcriptional activation by the ToxT protein is also modulated by environmental signals. ToxT expressed from an inducible promoter activated high-level expression of CT and TCP in V. cholerae at 30 degrees C, but expression of CT and TCP was significantly decreased or abolished by the addition of 0.4% bile to the medium and/or an increase of the temperature to 37 degrees C. Also, expression of six ToxT-dependent TnphoA fusions was modulated by temperature and bile. Measurement of ToxT-dependent transcription of genes encoding CT and TCP by ctxAp- and tcpAp-luciferase fusions confirmed that negative regulation by 37 degrees C or bile occurs at the transcriptional level in V. cholerae. Interestingly, ToxT-dependent transcription of these same promoters in Salmonella typhimurium was relatively insensitive to regulation by temperature or bile. These data are consistent with ToxT transcriptional activity being modulated by environmental signals in V. cholerae and demonstrate an additional level of complexity governing the expression of virulence factors in this pathogen. We propose that negative regulation of ToxT-dependent transcription by environmental signals prevents the incorrect temporal and spatial expression of virulence factors during cholera pathogenesis.

ASTRONAUT YOUNG, JOHN W. - ZERO-GRAVITY (ZERO-G) - KC-135

NASA Image and Video Library

1978-12-15

S79-30347 (31 March 1979) --- Taking advantage of a brief period of zero-gravity afforded aboard a KC-135 flying a parabolic curve, the flight crew of the first space shuttle orbital flight test (STS-1) goes through a spacesuit donning exercise. Astronaut John W. Young has just entered the hard-material torso of the shuttle spacesuit by approaching it from below. He is assisted by astronaut Robert L. Crippen. The torso is held in place by a special stand here, simulating the function provided by the airlock wall aboard the actual shuttle craft. The life support system is mated to the torso on Earth and remains so during the flight, requiring this type of donning and doffing exercise. Note Crippen?s suit is the type to be used for intravehicular activity in the shirt sleeve environment to be afforded aboard shuttle. The suit worn by Young is for extravehicular activity (EVA). Young will be STS-1 commander and Crippen, pilot. They will man the space shuttle orbiter 102 Columbia. Photo credit: NASA

OpenTox predictive toxicology framework: toxicological ontology and semantic media wiki-based OpenToxipedia.

PubMed

Tcheremenskaia, Olga; Benigni, Romualdo; Nikolova, Ivelina; Jeliazkova, Nina; Escher, Sylvia E; Batke, Monika; Baier, Thomas; Poroikov, Vladimir; Lagunin, Alexey; Rautenberg, Micha; Hardy, Barry

2012-04-24

The OpenTox Framework, developed by the partners in the OpenTox project (http://www.opentox.org), aims at providing a unified access to toxicity data, predictive models and validation procedures. Interoperability of resources is achieved using a common information model, based on the OpenTox ontologies, describing predictive algorithms, models and toxicity data. As toxicological data may come from different, heterogeneous sources, a deployed ontology, unifying the terminology and the resources, is critical for the rational and reliable organization of the data, and its automatic processing. The following related ontologies have been developed for OpenTox: a) Toxicological ontology - listing the toxicological endpoints; b) Organs system and Effects ontology - addressing organs, targets/examinations and effects observed in in vivo studies; c) ToxML ontology - representing semi-automatic conversion of the ToxML schema; d) OpenTox ontology- representation of OpenTox framework components: chemical compounds, datasets, types of algorithms, models and validation web services; e) ToxLink-ToxCast assays ontology and f) OpenToxipedia community knowledge resource on toxicology terminology.OpenTox components are made available through standardized REST web services, where every compound, data set, and predictive method has a unique resolvable address (URI), used to retrieve its Resource Description Framework (RDF) representation, or to initiate the associated calculations and generate new RDF-based resources.The services support the integration of toxicity and chemical data from various sources, the generation and validation of computer models for toxic effects, seamless integration of new algorithms and scientifically sound validation routines and provide a flexible framework, which allows building arbitrary number of applications, tailored to solving different problems by end users (e.g. toxicologists). The OpenTox toxicological ontology projects may be accessed via the OpenTox

Bicarbonate increases binding affinity of Vibrio cholerae ToxT to virulence gene promoters.

PubMed

Thomson, Joshua J; Withey, Jeffrey H

2014-11-01

The major Vibrio cholerae virulence gene transcription activator, ToxT, is responsible for the production of the diarrhea-inducing cholera toxin (CT) and the major colonization factor, toxin coregulated pilus (TCP). In addition to the two primary virulence factors mentioned, ToxT is responsible for the activation of accessory virulence genes, such as aldA, tagA, acfA, acfD, tcpI, and tarAB. ToxT activity is negatively modulated by bile and unsaturated fatty acids found in the upper small intestine. Conversely, previous work identified another intestinal signal, bicarbonate, which enhances the ability of ToxT to activate production of CT and TCP. The work presented here further elucidates the mechanism for the enhancement of ToxT activity by bicarbonate. Bicarbonate was found to increase the activation of ToxT-dependent accessory virulence promoters in addition to those that produce CT and TCP. Bicarbonate is taken up into the V. cholerae cell, where it positively affects ToxT activity by increasing DNA binding affinity for the virulence gene promoters that ToxT activates regardless of toxbox configuration. The increase in ToxT binding affinity in the presence of bicarbonate explains the elevated level of virulence gene transcription. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Bicarbonate Increases Binding Affinity of Vibrio cholerae ToxT to Virulence Gene Promoters

PubMed Central

Thomson, Joshua J.

2014-01-01

The major Vibrio cholerae virulence gene transcription activator, ToxT, is responsible for the production of the diarrhea-inducing cholera toxin (CT) and the major colonization factor, toxin coregulated pilus (TCP). In addition to the two primary virulence factors mentioned, ToxT is responsible for the activation of accessory virulence genes, such as aldA, tagA, acfA, acfD, tcpI, and tarAB. ToxT activity is negatively modulated by bile and unsaturated fatty acids found in the upper small intestine. Conversely, previous work identified another intestinal signal, bicarbonate, which enhances the ability of ToxT to activate production of CT and TCP. The work presented here further elucidates the mechanism for the enhancement of ToxT activity by bicarbonate. Bicarbonate was found to increase the activation of ToxT-dependent accessory virulence promoters in addition to those that produce CT and TCP. Bicarbonate is taken up into the V. cholerae cell, where it positively affects ToxT activity by increasing DNA binding affinity for the virulence gene promoters that ToxT activates regardless of toxbox configuration. The increase in ToxT binding affinity in the presence of bicarbonate explains the elevated level of virulence gene transcription. PMID:25182489

Tox21 and ToxCast Chemical Landscapes: Laying the Foundation for 21st Century Toxicology - Application of the Strategy to Chemical Testing

EPA Science Inventory

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...

Understanding the Biology and Technology of ToxCast and Tox21 Assays

EPA Science Inventory

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...

Using the ToxMiner Database for a Network Analysis of Linkage between ToxCast Phase I Chemicals and Thyroid Related Disease Outcomes

EPA Science Inventory

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...

Applying network analysis and Nebula (neighbor-edges based and unbiased leverage algorithm) to ToxCast data.

PubMed

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.

OpenTox predictive toxicology framework: toxicological ontology and semantic media wiki-based OpenToxipedia

PubMed Central

2012-01-01

Background The OpenTox Framework, developed by the partners in the OpenTox project (http://www.opentox.org), aims at providing a unified access to toxicity data, predictive models and validation procedures. Interoperability of resources is achieved using a common information model, based on the OpenTox ontologies, describing predictive algorithms, models and toxicity data. As toxicological data may come from different, heterogeneous sources, a deployed ontology, unifying the terminology and the resources, is critical for the rational and reliable organization of the data, and its automatic processing. Results The following related ontologies have been developed for OpenTox: a) Toxicological ontology – listing the toxicological endpoints; b) Organs system and Effects ontology – addressing organs, targets/examinations and effects observed in in vivo studies; c) ToxML ontology – representing semi-automatic conversion of the ToxML schema; d) OpenTox ontology– representation of OpenTox framework components: chemical compounds, datasets, types of algorithms, models and validation web services; e) ToxLink–ToxCast assays ontology and f) OpenToxipedia community knowledge resource on toxicology terminology. OpenTox components are made available through standardized REST web services, where every compound, data set, and predictive method has a unique resolvable address (URI), used to retrieve its Resource Description Framework (RDF) representation, or to initiate the associated calculations and generate new RDF-based resources. The services support the integration of toxicity and chemical data from various sources, the generation and validation of computer models for toxic effects, seamless integration of new algorithms and scientifically sound validation routines and provide a flexible framework, which allows building arbitrary number of applications, tailored to solving different problems by end users (e.g. toxicologists). Availability The OpenTox toxicological

Analysis of ToxCast data for food-relevant compounds by ...

EPA Pesticide Factsheets

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.

ToxReporter: viewing the genome through the eyes of a toxicologist.

PubMed

Gosink, Mark

2016-01-01

One of the many roles of a toxicologist is to determine if an observed adverse event (AE) is related to a previously unrecognized function of a given gene/protein. Towards that end, he or she will search a variety of public and propriety databases for information linking that protein to the observed AE. However, these databases tend to present all available information about a protein, which can be overwhelming, limiting the ability to find information about the specific toxicity being investigated. ToxReporter compiles information from a broad selection of resources and limits display of the information to user-selected areas of interest. ToxReporter is a PERL-based web-application which utilizes a MySQL database to streamline this process by categorizing public and proprietary domain-derived information into predefined safety categories according to a customizable lexicon. Users can view gene information that is 'red-flagged' according to the safety issue under investigation. ToxReporter also uses a scoring system based on relative counts of the red-flags to rank all genes for the amount of information pertaining to each safety issue and to display their scored ranking as an easily interpretable 'Tox-At-A-Glance' chart. Although ToxReporter was originally developed to display safety information, its flexible design could easily be adapted to display disease information as well.Database URL: ToxReporter is freely available at https://github.com/mgosink/ToxReporter. © The Author(s) 2016. Published by Oxford University Press.

ToxRefDB: Classifying ToxCast™ Phase I Chemicals Utilizing Structured Toxicity Information

EPA Science Inventory

There is an essential need for highly detailed chemicals classifications within the ToxCast™ research program. In order to develop predictive models and biological signatures utilizing high-throughput screening (HTS) and in vitro genomic data, relevant endpoints and toxicities m...

Cheminformatic Analysis of the US EPA ToxCast Chemical Library

EPA Science Inventory

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...

The ToxCast Chemical Landscape - Paving the Road to 21st Century Toxicology

EPA Science Inventory

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...

Building predictive models of developmental toxicity from ToxRefDB and ToxCast

EPA Science Inventory

EPA’s ToxCast™ project is profiling the in vitro bioactivity of chemical compounds to assess pathway-level and cell-based signatures that are highly correlated with observed in vivo toxicity. We hypothesize that cell signaling pathways underlying development are primary targets f...

Application of ToxCast to evaluate potential biological effects ...

EPA Pesticide Factsheets

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

The Role of TOX in the Development of Innate Lymphoid Cells.

PubMed

Seehus, Corey R; Kaye, Jonathan

2015-01-01

TOX, an evolutionarily conserved member of the HMG-box family of proteins, is essential for the development of various cells of both the innate and adaptive immune system. TOX is required for the development of CD4(+) T lineage cells in the thymus, including natural killer T and T regulatory cells, as well as development of natural killer cells and fetal lymphoid tissue inducer cells, the latter required for lymph node organogenesis. Recently, we have identified a broader role for TOX in the innate immune system, demonstrating that this nuclear protein is required for generation of bone marrow progenitors that have potential to give rise to all innate lymphoid cells. Innate lymphoid cells, classified according to transcription factor expression and cytokine secretion profiles, derive from common lymphoid progenitors in the bone marrow and require Notch signals for their development. We discuss here the role of TOX in specifying CLP toward an innate lymphoid cell fate and hypothesize a possible role for TOX in regulating Notch gene targets during innate lymphoid cell development.

Overview of ToxCast™

EPA Science Inventory

In 2007, EPA launched ToxCast™ in order to develop a cost-effective approach for prioritizing the toxicity testing of large numbers of chemicals in a short period of time. Using data from state-of-the-art high throughput screening (HTS) bioassays developed in the pharmaceutical i...

Release of ToxCastDB and ExpoCastDB databases

EPA Science Inventory

EPA has released two databases - the Toxicity Forecaster database (ToxCastDB) and a database of chemical exposure studies (ExpoCastDB) - that scientists and the public can use to access chemical toxicity and exposure data. ToxCastDB users can search and download data from over 50...

Framework for a Quantitative Systemic Toxicity Model (FutureToxII)

EPA Science Inventory

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...

Analysis of Pfizer compounds in EPA's ToxCast chemicals-assay space.

PubMed

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.

An Update on ToxCast™

EPA Science Inventory

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, transcripto...

ToxCast Profiling in a Human Stem Cell Assay for ...

EPA Pesticide Factsheets

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)

Modeling and Predicting Cancer from ToxCast Phase I Data

EPA Science Inventory

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...

Incorporating ToxCast and Tox21 Datasets to Rank Biological Activity of Chemicals at Superfund Sites in North Carolina

PubMed Central

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

Incorporating ToxCast and Tox21 datasets to rank biological activity of chemicals at Superfund sites in North Carolina.

PubMed

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.

Vibrio cholerae ToxR downregulates virulence factor production in response to cyclo(Phe-Pro).

PubMed

Bina, X Renee; Taylor, Dawn L; Vikram, Amit; Ante, Vanessa M; Bina, James E

2013-08-27

Vibrio cholerae is an aquatic organism that causes the severe acute diarrheal disease cholera. The ability of V. cholerae to cause disease is dependent upon the production of two critical virulence determinants, cholera toxin (CT) and the toxin-coregulated pilus (TCP). The expression of the genes that encode for CT and TCP production is under the control of a hierarchical regulatory system called the ToxR regulon, which functions to activate virulence gene expression in response to in vivo stimuli. Cyclic dipeptides have been found to be produced by numerous bacteria, yet their biological function remains unknown. V. cholerae has been shown to produce cyclo(Phe-Pro). Previous studies in our laboratory demonstrated that cyclo(Phe-Pro) inhibited V. cholerae virulence factor production. For this study, we report on the mechanism by which cyclo(Phe-Pro) inhibited virulence factor production. We have demonstrated that exogenous cyclo(Phe-Pro) activated the expression of leuO, a LysR-family regulator that had not been previously associated with V. cholerae virulence. Increased leuO expression repressed aphA transcription, which resulted in downregulation of the ToxR regulon and attenuated CT and TCP production. The cyclo(Phe-Pro)-dependent induction of leuO expression was found to be dependent upon the virulence regulator ToxR. Cyclo(Phe-Pro) did not affect toxR transcription or ToxR protein levels but appeared to enhance the ToxR-dependent transcription of leuO. These results have identified leuO as a new component of the ToxR regulon and demonstrate for the first time that ToxR is capable of downregulating virulence gene expression in response to an environmental cue. The ToxR regulon has been a focus of cholera research for more than three decades. During this time, a model has emerged wherein ToxR functions to activate the expression of Vibrio cholerae virulence factors upon host entry. V. cholerae and other enteric bacteria produce cyclo(Phe-Pro), a cyclic dipeptide

Meningococcal quadrivalent (serogroups A, C, W135 and Y) tetanus toxoid conjugate vaccine (Nimenrix™).

PubMed

Croxtall, Jamie D; Dhillon, Sohita

2012-12-24

Nimenrix™ (MenACWY-TT) is a quadrivalent meningococcal conjugate vaccine, comprising the polysaccharide serogroups A, C, W135 and Y, and tetanus toxoid (TT) as carrier protein. It is the first quadrivalent vaccine (administered as a single dose) to be approved in Europe for active immunization of individuals aged ≥ 12 months against invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, W135 and Y. Administration of a single dose of Nimenrix™ elicited a strong immune response against all four vaccine serogroups in healthy toddlers aged 12-23 months, children and adolescents aged 2-17 years and adults aged 18-55 years in randomized, multicentre, phase III trials. In toddlers, Nimenrix™ was noninferior to Meningitec® in terms of seroresponse rates against meningococcal serogroup C 42 days post-vaccination. In children, adolescents and adults, Nimenrix™ was noninferior to Mencevax™ in terms of vaccination response rates against all four serogroups 1 month post-vaccination. Furthermore, several phase II studies and a phase III trial showed that the immune response elicited by Nimenrix™ in all age groups persisted for 7-42 months after the primary vaccination (when evaluated by rabbit serum bactericidal activity), with the vaccine also inducing immune memory in toddlers. In addition, several randomized, multicentre, phase III, noninferiority trials showed that when coadministered with other childhood vaccines or a seasonal flu vaccine, the immunogenicity of Nimenrix™ or that of the coadministered vaccine was generally not altered. Nimenrix® was generally well tolerated in all age groups whether administered as a single vaccine or coadministered with other routine vaccines. The incidence of grade 3 local or systemic solicited adverse events during the first 4 days following vaccination and of serious adverse events over an extended follow-up period of up to 6 months was low (<4.5%). Although protective effectiveness and longer

Transient transcriptional activation of the Vibrio cholerae El Tor virulence regulator toxT in response to culture conditions.

PubMed

Medrano, A I; DiRita, V J; Castillo, G; Sanchez, J

1999-05-01

Vibrio cholerae El Tor require special in vitro culture conditions, consisting of an initial static growth period followed by shift to shaking (AKI conditions), for expression of cholera toxin (CT) and toxin coregulated pili (TCP). ToxT, a regulator whose initial transcription depends on the ToxR regulator, positively modulates expression of CT and TCP. To help understand control of CT and TCP in El Tor vibrios, we monitored ctxAB and ToxR-dependent toxT transcription by time course primer extension assays. AKI conditions stimulated CT synthesis with an absence of ctxAB transcription during static growth followed by induction upon shaking. ToxR-dependent toxT transcription was induced at the end of the static growth period but was transient, stopping shortly after shaking was initiated but, interestingly, also if the static phase was prolonged. Immunoblot assays showed that ToxR protein levels were not coincidentally transient, implying a protein on/off switch mechanism for ToxR. Despite the transient activation by ToxR, transcription of ctxAB was maintained during shaking. This finding suggested continued toxT expression, possibly through relay transcription from another promoter. The 12.6-kb distant upstream tcpA promoter responsible for expression of the TCP operon has been proposed to provide an alternate toxT message by readthrough transcription. Activation of the tcpA promoter is supported by increased expression of TcpA protein during the shaking phase of the culture. Readthrough transcription of toxT from tcpA would be compatible with reverse transcription-PCR evidence for a toxT mRNA at times when ToxR-dependent transcription was no longer detectable by primer extension.

CompTox Chemistry Dashboard webinar

EPA Pesticide Factsheets

The CompTox Chemistry Dashboard is part of a suite of dashboards developed by EPA to help evaluate the safety of chemicals. The dashboard provides access to a variety of information on over 700,000 chemicals currently in use. Within the application, users

Chemical and HTS Profiling of 63 Cleft Palate Teratogens from ToxCast (FutureTox III)

EPA Science Inventory

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...

Endocrine Profiling and Prioritization of Environmental Chemicals Using ToxCast Data

EPA Science Inventory

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...

Intracellular expression of a host-selective toxin, ToxA, in diverse plants phenocopies silencing of a ToxA-interacting protein, ToxABP1

USDA-ARS?s Scientific Manuscript database

Pyrenophora tritici-repentis is a necrotophic, fungal pathogen whose ability to cause tan spot of wheat (Triticum aestivum) is dependent on the production of host-selective toxins. One of these toxins, Ptr ToxA, is a protein that is only toxic to genotypes of wheat carrying the Tsn1 locus. The prot...

An Introduction to ToxCast™

EPA Science Inventory

ToxCast™ is a chemical prioritization research program to develop the ability to forecast toxicity using bioactivity profiling. The point is to use results in a variety of in vitro and rapid non-mammalian in vivo assays to explore effects at different toxicity targets. The desi...

20180416 - Understanding the Biology and Technology of ToxCast and Tox21 Assays (SETAC Durham NC)

EPA Science Inventory

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...

EPA DSSTox and ToxCast Project Updates: Generating New ...

EPA Pesticide Factsheets

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

Biochemical Activities of 320 ToxCast Chemicals Evaluated Across 239 Functional Targets

EPA Science Inventory

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 ...

Assessing the Robustness of Chemical Prioritizations Based on ToxCast Chemical Profiling

EPA Science Inventory

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...

Predictive Model of Rat Reproductive Toxicity from ToxCast High Throughput Screening

EPA Science Inventory

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...

Feature Analysis of ToxCast Compounds

EPA Science Inventory

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...

ToxCast: Developing Predictive Signatures of Chemically Induced Toxicity (Developing Predictive Bioactivity Signatures from ToxCasts HTS Data)

EPA Science Inventory

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...

ToxCast Workflow: High-throughput screening assay data processing, analysis and management (SOT)

EPA Science Inventory

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...

An Update on ToxCast™ | Science Inventory | US EPA

EPA Pesticide Factsheets

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.

An Evaluation of ToxCast Angiogenic Disruptors for Effects on ...

EPA Pesticide Factsheets

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 have shown a correlation between vascular disruption in Tg(kdrl:EGFP)mitfab692 zebrafish embryos and mitochondrial disruption reported in literature [McCollum et al., submitted]. To more closely examine this correlation, we culled ToxCast data for mitochondrial translocator protein (TSPO; NovaScreen) and mitochondrial membrane potential (MMP) and biomass (Tox21 and Apredica) for a total of 192 chemicals tested for adverse effects on vascular development in transgenic zebrafish embryos [McCollum et al., submitted; Tal et al., submitted]. This set included 40 compounds that disrupted vascular development in zebrafish embryos (zVDC) and 152 compounds that did not. The zVDC set displayed consistent in vitro bioactivity on mitochondrial membrane potential (with a Pearson Chi-Square value of 16.92, p < 0.0001), but did not have consistent effects on mitochondrial biomass (0.4; p = 0.527) or translocator protein ligand binding (0.05; p = 0.823). The effect on MMP is consistent with the hypothesis that disruption of the mitochondrial respiratory complexes is a potential mode of action of angiogenic disruptors (complex I for pyridaben, fenpyroxymate, tebufenpyrad, and rotenone; complex III for py

Species-Specific Predictive Signatures of Developmental Toxicity Using the ToxCast Chemical Library

EPA Science Inventory

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 ...

Predictive models of prenatal developmental toxicity from ToxCast high-throughput screening data

EPA Science Inventory

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...

In Vitro Bioactivity in ToxCast Assays for Fruit and Vegetable Juices (TDS)

EPA Science Inventory

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 ...

AMBIT RESTful web services: an implementation of the OpenTox application programming interface.

PubMed

Jeliazkova, Nina; Jeliazkov, Vedrin

2011-05-16

The AMBIT web services package is one of the several existing independent implementations of the OpenTox Application Programming Interface and is built according to the principles of the Representational State Transfer (REST) architecture. The Open Source Predictive Toxicology Framework, developed by the partners in the EC FP7 OpenTox project, aims at providing a unified access to toxicity data and predictive models, as well as validation procedures. This is achieved by i) an information model, based on a common OWL-DL ontology ii) links to related ontologies; iii) data and algorithms, available through a standardized REST web services interface, where every compound, data set or predictive method has a unique web address, used to retrieve its Resource Description Framework (RDF) representation, or initiate the associated calculations.The AMBIT web services package has been developed as an extension of AMBIT modules, adding the ability to create (Quantitative) Structure-Activity Relationship (QSAR) models and providing an OpenTox API compliant interface. The representation of data and processing resources in W3C Resource Description Framework facilitates integrating the resources as Linked Data. By uploading datasets with chemical structures and arbitrary set of properties, they become automatically available online in several formats. The services provide unified interfaces to several descriptor calculation, machine learning and similarity searching algorithms, as well as to applicability domain and toxicity prediction models. All Toxtree modules for predicting the toxicological hazard of chemical compounds are also integrated within this package. The complexity and diversity of the processing is reduced to the simple paradigm "read data from a web address, perform processing, write to a web address". The online service allows to easily run predictions, without installing any software, as well to share online datasets and models. The downloadable web application

AMBIT RESTful web services: an implementation of the OpenTox application programming interface

PubMed Central

2011-01-01

The AMBIT web services package is one of the several existing independent implementations of the OpenTox Application Programming Interface and is built according to the principles of the Representational State Transfer (REST) architecture. The Open Source Predictive Toxicology Framework, developed by the partners in the EC FP7 OpenTox project, aims at providing a unified access to toxicity data and predictive models, as well as validation procedures. This is achieved by i) an information model, based on a common OWL-DL ontology ii) links to related ontologies; iii) data and algorithms, available through a standardized REST web services interface, where every compound, data set or predictive method has a unique web address, used to retrieve its Resource Description Framework (RDF) representation, or initiate the associated calculations. The AMBIT web services package has been developed as an extension of AMBIT modules, adding the ability to create (Quantitative) Structure-Activity Relationship (QSAR) models and providing an OpenTox API compliant interface. The representation of data and processing resources in W3C Resource Description Framework facilitates integrating the resources as Linked Data. By uploading datasets with chemical structures and arbitrary set of properties, they become automatically available online in several formats. The services provide unified interfaces to several descriptor calculation, machine learning and similarity searching algorithms, as well as to applicability domain and toxicity prediction models. All Toxtree modules for predicting the toxicological hazard of chemical compounds are also integrated within this package. The complexity and diversity of the processing is reduced to the simple paradigm "read data from a web address, perform processing, write to a web address". The online service allows to easily run predictions, without installing any software, as well to share online datasets and models. The downloadable web application

20180312 - Profiling the ToxCast library with a pluripotent human (H9) embryonic stem cell assay (SOT)

EPA Science Inventory

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% ...

FutureTox III: Bridges for Translation

EPA Science Inventory

The present document describes key discussion points and outcomes of a Society of Toxicology (SOT) Contemporary Concepts in Toxicology (CCT) Workshop, entitled FutureTox III1,2 that was held in Crystal City, Virginia, November 19-20, 2015. The workshop built on the many lessons l...

Correlation between serum bactericidal activity against Neisseria meningitidis serogroups A, C, W-135 and Y measured using human versus rabbit serum as the complement source.

PubMed Central

CJ, Gill; S, Ram; JA, Welsch; L, DeTora; A, Anemona

2014-01-01

The surrogate of protection against invasive meningococcal disease is the presence of serum bactericidal activity (SBA) at a titer ≥4 in an assay using human serum as the complement source (hSBA). However, for various practical and logistical reasons, many meningococcal vaccines in use today were licensed based on a modified SBA assay that used baby rabbit serum as the complement source (rSBA). To assess the strength of correlation between the two assay systems for serogroups A, C, W-135 and Y, we analyzed a subset of samples from adolescent subjects enrolled in a Phase II study of Novartis’ MenACWY-CRM conjugate vaccine vs. an ACWY polysaccharide vaccine; samples were analyzed in parallel using hSBA and rSBA. We compared geometric mean titers (GMTs), calculated Pearson correlation coefficients between paired hSBA and rSBA results, and calculated sensitivity/specificity and likelihood ratios for an rSBA ≥8 or ≥128 for classifying hSBA ≥4, taking hSBA as the ‘gold standard’. Correlations between hSBA and rSBA ranged from 0.46 to 0.78 for serogroup C, but were weaker for serogroups A, W-135 and Y (range -0.15 to 0.57). In post vaccination samples, nearly all subjects had rSBA titers ≥8, though up to 15% remained seronegative by hSBA. In post vaccination settings, rSBA titers at ≥8 or ≥128 was highly sensitive for an hSBA titer ≥4, but non-specific. In conclusion, results generated by rSBA did not accurately classify serostatus according to hSBA for serogroups A, W-135 and Y. PMID:22075087

“httk”: EPA’s Tool for High Throughput Toxicokinetics (CompTox CoP)

EPA Science Inventory

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...

Species-specific predictive models of developmental toxicity using the ToxCast chemical library

EPA Science Inventory

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...

ToxPi Graphical User Interface 2.0: Dynamic exploration, visualization, and sharing of integrated data models.

PubMed

Marvel, Skylar W; To, Kimberly; Grimm, Fabian A; Wright, Fred A; Rusyn, Ivan; Reif, David M

2018-03-05

Drawing integrated conclusions from diverse source data requires synthesis across multiple types of information. The ToxPi (Toxicological Prioritization Index) is an analytical framework that was developed to enable integration of multiple sources of evidence by transforming data into integrated, visual profiles. Methodological improvements have advanced ToxPi and expanded its applicability, necessitating a new, consolidated software platform to provide functionality, while preserving flexibility for future updates. We detail the implementation of a new graphical user interface for ToxPi (Toxicological Prioritization Index) that provides interactive visualization, analysis, reporting, and portability. The interface is deployed as a stand-alone, platform-independent Java application, with a modular design to accommodate inclusion of future analytics. The new ToxPi interface introduces several features, from flexible data import formats (including legacy formats that permit backward compatibility) to similarity-based clustering to options for high-resolution graphical output. We present the new ToxPi interface for dynamic exploration, visualization, and sharing of integrated data models. The ToxPi interface is freely-available as a single compressed download that includes the main Java executable, all libraries, example data files, and a complete user manual from http://toxpi.org .

Endocrine Profiling and Prioritization of Environmental Chemicals Using ToxCast Data

PubMed Central

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

Comparison of diverse nanomaterial bioactivity profiles based on high-throughput screening (HTS) in ToxCast™ (FutureToxII)

EPA Science Inventory

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....

High Throughput Prioritization for Integrated Toxicity Testing Based on ToxCast Chemical Profiling

EPA Science Inventory

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...

Considerations in Use of the EPA’s ToxCast Data for Environmental Toxicology (SETAC)

EPA Science Inventory

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 ...

75 FR 43162 - Tetrahedron, Inc., with Subcontractors: Syracuse Research Corporation; Tox Path, Inc; and...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-23

... Subcontractors: Syracuse Research Corporation; Tox Path, Inc; and Pathology Associates; Transfer of Data AGENCY... information that may have been claimed as confidential business information (CBI) by the submitter, will be transferred to Tetrahedron, Inc., and its subcontractors: Syracuse Research Corporation, Tox Path, Inc., and...

Computational toxicology using the OpenTox application programming interface and Bioclipse

PubMed Central

2011-01-01

Background Toxicity is a complex phenomenon involving the potential adverse effect on a range of biological functions. Predicting toxicity involves using a combination of experimental data (endpoints) and computational methods to generate a set of predictive models. Such models rely strongly on being able to integrate information from many sources. The required integration of biological and chemical information sources requires, however, a common language to express our knowledge ontologically, and interoperating services to build reliable predictive toxicology applications. Findings This article describes progress in extending the integrative bio- and cheminformatics platform Bioclipse to interoperate with OpenTox, a semantic web framework which supports open data exchange and toxicology model building. The Bioclipse workbench environment enables functionality from OpenTox web services and easy access to OpenTox resources for evaluating toxicity properties of query molecules. Relevant cases and interfaces based on ten neurotoxins are described to demonstrate the capabilities provided to the user. The integration takes advantage of semantic web technologies, thereby providing an open and simplifying communication standard. Additionally, the use of ontologies ensures proper interoperation and reliable integration of toxicity information from both experimental and computational sources. Conclusions A novel computational toxicity assessment platform was generated from integration of two open science platforms related to toxicology: Bioclipse, that combines a rich scriptable and graphical workbench environment for integration of diverse sets of information sources, and OpenTox, a platform for interoperable toxicology data and computational services. The combination provides improved reliability and operability for handling large data sets by the use of the Open Standards from the OpenTox Application Programming Interface. This enables simultaneous access to a variety

ProTox: a web server for the in silico prediction of rodent oral toxicity

PubMed Central

Drwal, Malgorzata N.; Banerjee, Priyanka; Dunkel, Mathias; Wettig, Martin R.; Preissner, Robert

2014-01-01

Animal trials are currently the major method for determining the possible toxic effects of drug candidates and cosmetics. In silico prediction methods represent an alternative approach and aim to rationalize the preclinical drug development, thus enabling the reduction of the associated time, costs and animal experiments. Here, we present ProTox, a web server for the prediction of rodent oral toxicity. The prediction method is based on the analysis of the similarity of compounds with known median lethal doses (LD50) and incorporates the identification of toxic fragments, therefore representing a novel approach in toxicity prediction. In addition, the web server includes an indication of possible toxicity targets which is based on an in-house collection of protein–ligand-based pharmacophore models (‘toxicophores’) for targets associated with adverse drug reactions. The ProTox web server is open to all users and can be accessed without registration at: http://tox.charite.de/tox. The only requirement for the prediction is the two-dimensional structure of the input compounds. All ProTox methods have been evaluated based on a diverse external validation set and displayed strong performance (sensitivity, specificity and precision of 76, 95 and 75%, respectively) and superiority over other toxicity prediction tools, indicating their possible applicability for other compound classes. PMID:24838562

Domain-Specific QSAR Models for Identifying Potential Estrogenic Activity of Phenols (FutureTox III)

EPA Science Inventory

Computational tools can be used for efficient evaluation of untested chemicals for their ability to disrupt the endocrine system. We have employed previously developed global QSAR models that were trained and validated on the ToxCast/Tox21 ER assay data for virtual screening of a...

The U.S. EPA ToxCast Program: Moving from Data Generation to Application (SOT Tox21 update symposium presentation)

EPA Science Inventory

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...

CalTOX (registered trademark), A multimedia total exposure model spreadsheet user's guide. Version 4.0(Beta)

DOE Office of Scientific and Technical Information (OSTI.GOV)

McKone, T.E.; Enoch, K.G.

2002-08-01

CalTOX has been developed as a set of spreadsheet models and spreadsheet data sets to assist in assessing human exposures from continuous releases to multiple environmental media, i.e. air, soil, and water. It has also been used for waste classification and for setting soil clean-up levels at uncontrolled hazardous wastes sites. The modeling components of CalTOX include a multimedia transport and transformation model, multi-pathway exposure scenario models, and add-ins to quantify and evaluate uncertainty and variability. All parameter values used as inputs to CalTOX are distributions, described in terms of mean values and a coefficient of variation, rather than asmore » point estimates or plausible upper values such as most other models employ. This probabilistic approach allows both sensitivity and uncertainty analyses to be directly incorporated into the model operation. This manual provides CalTOX users with a brief overview of the CalTOX spreadsheet model and provides instructions for using the spreadsheet to make deterministic and probabilistic calculations of source-dose-risk relationships.« less

46 CFR 7.135 - Point Sur, CA to Cape Blanco, OR.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Pacific Coast § 7.135 Point Sur, CA to Cape Blanco, OR. (a) A line drawn from Monterey Harbor Light “6” to latitude 36°36.5′ N. longitude 121°53.2′ W. (Monterey Harbor Anchorage Buoy “A”); thence to the... 46 Shipping 1 2010-10-01 2010-10-01 false Point Sur, CA to Cape Blanco, OR. 7.135 Section 7.135...

46 CFR 7.135 - Point Sur, CA to Cape Blanco, OR.

Code of Federal Regulations, 2014 CFR

2014-10-01

... Pacific Coast § 7.135 Point Sur, CA to Cape Blanco, OR. (a) A line drawn from Monterey Harbor Light “6” to latitude 36°36.5′ N. longitude 121°53.2′ W. (Monterey Harbor Anchorage Buoy “A”); thence to the... 46 Shipping 1 2014-10-01 2014-10-01 false Point Sur, CA to Cape Blanco, OR. 7.135 Section 7.135...

46 CFR 7.135 - Point Sur, CA to Cape Blanco, OR.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Pacific Coast § 7.135 Point Sur, CA to Cape Blanco, OR. (a) A line drawn from Monterey Harbor Light “6” to latitude 36°36.5′ N. longitude 121°53.2′ W. (Monterey Harbor Anchorage Buoy “A”); thence to the... 46 Shipping 1 2013-10-01 2013-10-01 false Point Sur, CA to Cape Blanco, OR. 7.135 Section 7.135...

46 CFR 7.135 - Point Sur, CA to Cape Blanco, OR.

Code of Federal Regulations, 2012 CFR

2012-10-01

... Pacific Coast § 7.135 Point Sur, CA to Cape Blanco, OR. (a) A line drawn from Monterey Harbor Light “6” to latitude 36°36.5′ N. longitude 121°53.2′ W. (Monterey Harbor Anchorage Buoy “A”); thence to the... 46 Shipping 1 2012-10-01 2012-10-01 false Point Sur, CA to Cape Blanco, OR. 7.135 Section 7.135...

ProTox: a web server for the in silico prediction of rodent oral toxicity.

PubMed

Drwal, Malgorzata N; Banerjee, Priyanka; Dunkel, Mathias; Wettig, Martin R; Preissner, Robert

2014-07-01

Animal trials are currently the major method for determining the possible toxic effects of drug candidates and cosmetics. In silico prediction methods represent an alternative approach and aim to rationalize the preclinical drug development, thus enabling the reduction of the associated time, costs and animal experiments. Here, we present ProTox, a web server for the prediction of rodent oral toxicity. The prediction method is based on the analysis of the similarity of compounds with known median lethal doses (LD50) and incorporates the identification of toxic fragments, therefore representing a novel approach in toxicity prediction. In addition, the web server includes an indication of possible toxicity targets which is based on an in-house collection of protein-ligand-based pharmacophore models ('toxicophores') for targets associated with adverse drug reactions. The ProTox web server is open to all users and can be accessed without registration at: http://tox.charite.de/tox. The only requirement for the prediction is the two-dimensional structure of the input compounds. All ProTox methods have been evaluated based on a diverse external validation set and displayed strong performance (sensitivity, specificity and precision of 76, 95 and 75%, respectively) and superiority over other toxicity prediction tools, indicating their possible applicability for other compound classes. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Toxicology in the 21st Century (Tox21)

EPA Pesticide Factsheets

Tox21 researchers aim to develop better toxicity assessment methods to quickly and efficiently test whether certain chemical compounds have the potential to disrupt processes in the human body that may lead to negative health effects.

ToxPi GUI: an interactive visualization tool for transparent integration of data from diverse sources of evidence.

PubMed

Reif, David M; Sypa, Myroslav; Lock, Eric F; Wright, Fred A; Wilson, Ander; Cathey, Tommy; Judson, Richard R; Rusyn, Ivan

2013-02-01

Scientists and regulators are often faced with complex decisions, where use of scarce resources must be prioritized using collections of diverse information. The Toxicological Prioritization Index (ToxPi™) was developed to enable integration of multiple sources of evidence on exposure and/or safety, transformed into transparent visual rankings to facilitate decision making. The rankings and associated graphical profiles can be used to prioritize resources in various decision contexts, such as testing chemical toxicity or assessing similarity of predicted compound bioactivity profiles. The amount and types of information available to decision makers are increasing exponentially, while the complex decisions must rely on specialized domain knowledge across multiple criteria of varying importance. Thus, the ToxPi bridges a gap, combining rigorous aggregation of evidence with ease of communication to stakeholders. An interactive ToxPi graphical user interface (GUI) application has been implemented to allow straightforward decision support across a variety of decision-making contexts in environmental health. The GUI allows users to easily import and recombine data, then analyze, visualize, highlight, export and communicate ToxPi results. It also provides a statistical metric of stability for both individual ToxPi scores and relative prioritized ranks. The ToxPi GUI application, complete user manual and example data files are freely available from http://comptox.unc.edu/toxpi.php.

Identification of Vibrio parahaemolyticus Strains at the Species Level by PCR Targeted to the toxR Gene

PubMed Central

Kim, Yung Bu; Okuda, Jun; Matsumoto, Chiho; Takahashi, Naoki; Hashimoto, Satoru; Nishibuchi, Mitsuaki

1999-01-01

The DNA colony hybridization test with the polynucleotide probe for Vibrio parahaemolyticus toxR gene was performed. All 373 strains of V. parahaemolyticus gave positive results, and the strains belonging to four other Vibrio species including Vibrio alginolyticus gave weakly positive results, suggesting that toxR sequence variation may reflect the phylogenetic relationships of Vibrio species. We then established a toxR-targeted PCR protocol for the specific detection of V. parahaemolyticus. PMID:10074546

Cheminformatics Analysis of EPA ToxCast Chemical Libraries ...

EPA Pesticide Factsheets

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

Characteristics of the ToxRefDB In Vivo Datasets from Chronic, Reproductive and Developmental Assays

EPA Science Inventory

ToxRefDB was developed to store data from in vivo animal toxicity studies. The initial focus was populating ToxRefDB with pesticide registration toxicity data that has been historically stored as hard-copy and scanned documents by the Office of Pesticide Programs. A significant p...

Tutorial Video Series: Using Stakeholder Outreach to Increase Usage of ToxCast Data (SETAC EU)

EPA Science Inventory

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...

Intersection of toxicogenomics and high throughput screening in the Tox21 program: an NIEHS perspective.

PubMed

Merrick, B Alex; Paules, Richard S; Tice, Raymond R

Humans are exposed to thousands of chemicals with inadequate toxicological data. Advances in computational toxicology, robotic high throughput screening (HTS), and genome-wide expression have been integrated into the Tox21 program to better predict the toxicological effects of chemicals. Tox21 is a collaboration among US government agencies initiated in 2008 that aims to shift chemical hazard assessment from traditional animal toxicology to target-specific, mechanism-based, biological observations using in vitro assays and lower organism models. HTS uses biocomputational methods for probing thousands of chemicals in in vitro assays for gene-pathway response patterns predictive of adverse human health outcomes. In 1999, NIEHS began exploring the application of toxicogenomics to toxicology and recent advances in NextGen sequencing should greatly enhance the biological content obtained from HTS platforms. We foresee an intersection of new technologies in toxicogenomics and HTS as an innovative development in Tox21. Tox21 goals, priorities, progress, and challenges will be reviewed.

The toxR Gene of Vibrio (Listonella) anguillarum Controls Expression of the Major Outer Membrane Proteins but Not Virulence in a Natural Host Model

PubMed Central

Okuda, Jun; Nakai, Toshihiro; Chang, Park Se; Oh, Takanori; Nishino, Takeshi; Koitabashi, Tsutomu; Nishibuchi, Mitsuaki

2001-01-01

To examine the hypothesis that the ancestral role of the toxR gene in the family Vibrionaceae is control of the expression of outer membrane protein (OMP)-encoding genes for adaptation to environmental change, we investigated the role of the toxR gene in Vibrio anguillarum, an important fish pathogen. The toxR gene of V. angullarum (Va-toxR) was cloned from strain PT-87050 isolated from diseased ayu (Plecoglossus altivelis), and the sequence was analyzed. The toxR sequence was 63 to 51% identical to those reported for other species of the family Vibrionaceae. Distribution of the Va-toxR gene sequence in V. anguillarum strains of various serotypes was confirmed by using DNA probe and PCR methods. An isogenic toxR mutant of V. anguillarum PT-24, isolated from diseased ayu, was constructed by using an allelic exchange method. The wild-type strain and the toxR mutant did not differ in the ability to produce a protease(s) and a hemolysin(s) or in pathogenicity for ayu when examined by the intramuscular injection and immersion methods. A 35-kDa major OMP was not produced by the toxR mutant. However, a 46-kDa OMP was hardly detected in the wild-type strain but was produced as the major OMP by the toxR mutant. For the toxR mutant, the MICs of two β-lactam antibiotics were higher and the minimum bactericidal concentration of sodium dodecyl sulfate was lower than for the wild-type strain. Analysis of the N-terminal amino acid sequences of the 35- and 46-kDa OMPs indicated that these proteins are the porin-like OMPs and are related to the toxR-regulated major OMPs of the family Vibrionaceae. The results indicate that the toxR gene is not involved in virulence expression in V. anguillarum PT-24 and that toxR regulation of major OMPs is universal in the family Vibrionaceae. These results support the hypothesis that the ancestral role of the toxR gene is regulation of OMP gene expression and that only in some Vibrio species has ToxR been appropriated for the regulation of a

Predicting hepatotoxicity using ToxCast in vitro bioactivity and ...

EPA Pesticide Factsheets

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

The EPA CompTox Chemistry Dashboard - an online resource ...

EPA Pesticide Factsheets

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

Evaluation of ToxA and Vibrio parahaemolyticus lysate on humoral immune response and immune-related genes in Pacific red snapper.

PubMed

Reyes-Becerril, Martha; Maldonado-García, Minerva; Guluarte, Crystal; León-Gallo, Amalia; Rosales-Mendoza, Sergio; Ascencio, Felipe; Hirono, Ikuo; Angulo, Carlos

2016-09-01

Immunogenicity of ToxA and Vibrio parahaemolyticus lysate was evaluated in a double immunostimulation scheme in Pacific red snapper after V. parahaemolyticus infection. Three groups of Pacific red snapper were intraperitonealy (i.p.) injected with phosphate-buffered saline (PBS group), ToxA of V. parahaemolyticus (ToxA-Vp group) or V. parahaemolyticus lysate (lysate-Vp group) (first injection, day 1; second injection, day 7). Fish were subsequently infected with live V. parahaemolyticus. Humoral immune parameters in skin mucus and serum were evaluated on days 1, 7, 8 and 14 days post-immunostimulation and 7 days post-infection. Moreover expression of immune-related genes was quantified by real time PCR in head-kidney leukocytes, spleen, liver, and intestine. The ToxA-Vp-treated group showed a higher anti-protease and catalase activity in skin mucus when compared with the PBS group. Measurements of SOD and CAT activities showed an increment in both activities a day after the second boost with ToxA-Vp or lysate-Vp. Interestingly, IgM levels in mucus and transcripts were enhanced followed the ToxA-Vp treatment even after challenge. Furthermore, IL-1β was strongly expressed in all analyzed cell or tissues followed ToxA-Vp or Vp-lysate treatments. Finally, SOD and CAT gene expression was up-regulated in fish immunostimulated with either treatment ToxA-Vp or lysate-Vp, mainly after infection in head-kidney leukocytes and intestine. This is the first study where the effects of ToxA from V. parahaemolyticus in the immune system of Pacific red snapper was evaluated. These results suggest that ToxA-Vp would positively affect humoral immune response and up-regulate expression of genes involved in the immune system function; and could help in the control of V. parahaemolyticus infection in Pacific red snapper Lutjanus peru, an economic important fish in Mexico. Copyright © 2016 Elsevier Ltd. All rights reserved.

Predicting Developmental Toxicity of ToxCast Phase I Chemicals Using Human Embryonic Stem Cells and Metabolomics

EPA Science Inventory

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...

ToxCast Assay Network (TCAN) Viewer: A Visualization Tool for High-throughput Assay Chemical Data (SOT)

EPA Science Inventory

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 ...

Quantitative variation in effector activity of ToxA isoforms from Stagonospora nodorum and Pyrenophora tritici-repentis

USDA-ARS?s Scientific Manuscript database

ToxA is a proteinaceous necrotrophic effector produced by Stagonospora nodorum and Pyrenophora tritici-repentis. In this study, all eight mature isoforms of the ToxA protein were purified and compared. Circular dichroism spectra indicated that all isoforms were structurally intact and had indistingu...

PanDaTox: A tool for accelerated metabolic engineering

DOE Office of Scientific and Technical Information (OSTI.GOV)

Amitai, Gil; Sorek, Rotem

2012-07-18

Metabolic engineering is often facilitated by cloning of genes encoding enzymes from various heterologous organisms into E. coli. Such engineering efforts are frequently hampered by foreign genes that are toxic to the E. coli host. We have developed PanDaTox (www.weizmann.ac.il/pandatox), a web-based resource that provides experimental toxicity information for more than 1.5 million genes from hundreds of different microbial genomes. The toxicity predictions, which were extensively experimentally verified, are based on serial cloning of genes into E. coli as part of the Sanger whole genome shotgun sequencing process. PanDaTox can accelerate metabolic engineering projects by allowing researchers to exclude toxicmore » genes from the engineering plan and verify the clonability of selected genes before the actual metabolic engineering experiments are conducted.« less

EPA's ToxCast Project: Lessons learned and future directions for use of HTS in predicting in vivo toxicology -- A Chemical Perspective

EPA Science Inventory

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...

Metabolism Retrofit Strategies for ToxCast Assays (BOSC)

EPA Science Inventory

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...

Building 1204, oblique view to west, 135 mm lens. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Building 1204, oblique view to west, 135 mm lens. - Travis Air Force Base, Squadron Operations & Readiness Crew Facility, W Street, Armed Forces Special Weapons Project Q Area, Fairfield, Solano County, CA

Highlight report: Launch of a large integrated European in vitro toxicology project: EU-ToxRisk.

PubMed

Daneshian, Mardas; Kamp, Hennicke; Hengstler, Jan; Leist, Marcel; van de Water, Bob

2016-05-01

The integrated European project, EU-ToxRisk, proudly sees itself as "flagship" exploring new alternative-to-animal approaches to chemical safety evaluation. It promotes mechanism-based toxicity testing and risk assessment according to the principles laid down for toxicology for the twenty-first century. The project was officially launched in January 2016 with a kickoff meeting in Egmond aan Zee, the Netherlands. Over 100 scientists representing academia and industry as well as regulatory authorities attended the inaugural meeting. The project will integrate advances in in vitro and in silico toxicology, read-across methods, and adverse outcome pathways. EU-ToxRisk will continue to make use of the case study strategy deployed in SEURAT-1, a FP7 initiative ended in December 2015. Even though the development of new non-animal methods is one target of EU-ToxRisk, the project puts special emphasis on their acceptance and implementation in regulatory contexts. This €30 million Horizon 2020 project involves 38 European partners and one from the USA. EU-ToxRisk aims at the "development of a new way of risk assessment."

Evaluation of 1066 ToxCast Chemicals in a human stem cell assay for developmental toxicity (SOT)

EPA Science Inventory

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 ...

KC-135 Survivability in a War in Europe

DTIC Science & Technology

1989-05-01

IIESEARCHlRPR KC-135 SURVIVA~BILITY IN4 A WA~R IN EUROPE 6T COL joHN EKWALL 3.989c ei-.T ..... , t =T’ p \\47 MR JIVERSI~r UAIRE s’rAT AIR FORCE ...MAWEIJL AIR FORCE BASbAB AIR WAR COLLEGE AIR UNIVERSITY KC-135 SURVIVABILITY IN A WAR IN EUROPE by John Ekwall Lieutenant Colonel, USAF A DEFENSE...ANALYTICAL STUDY SUBMITTED TO THE FACULTY IN FULLFILLMENT OF THE CURRICULUM REQUIREMENT Advisor: Colonel Frank W. Anderson, Jr. MAXWELL AIR FORCE BASE

Building 931, oblique view to southeast, 135 mm lens. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Building 931, oblique view to southeast, 135 mm lens. - Travis Air Force Base, Central Battery Charging Building, North of W Street, Armed Forces Special Weapons Project Q Area, Fairfield, Solano County, CA

Toxicology Testing in the 21st Century (Tox21)

EPA Pesticide Factsheets

Tox21 researchers aim to develop better toxicity assessment methods to quickly and efficiently test whether certain chemical compounds have the potential to disrupt processes in the human body that may lead to negative health effects.

The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing.

PubMed

Kohonen, Pekka; Benfenati, Emilio; Bower, David; Ceder, Rebecca; Crump, Michael; Cross, Kevin; Grafström, Roland C; Healy, Lyn; Helma, Christoph; Jeliazkova, Nina; Jeliazkov, Vedrin; Maggioni, Silvia; Miller, Scott; Myatt, Glenn; Rautenberg, Michael; Stacey, Glyn; Willighagen, Egon; Wiseman, Jeff; Hardy, Barry

2013-01-01

The aim of the SEURAT-1 (Safety Evaluation Ultimately Replacing Animal Testing-1) research cluster, comprised of seven EU FP7 Health projects co-financed by Cosmetics Europe, is to generate a proof-of-concept to show how the latest technologies, systems toxicology and toxicogenomics can be combined to deliver a test replacement for repeated dose systemic toxicity testing on animals. The SEURAT-1 strategy is to adopt a mode-of-action framework to describe repeated dose toxicity, combining in vitro and in silico methods to derive predictions of in vivo toxicity responses. ToxBank is the cross-cluster infrastructure project whose activities include the development of a data warehouse to provide a web-accessible shared repository of research data and protocols, a physical compounds repository, reference or "gold compounds" for use across the cluster (available via wiki.toxbank.net), and a reference resource for biomaterials. Core technologies used in the data warehouse include the ISA-Tab universal data exchange format, REpresentational State Transfer (REST) web services, the W3C Resource Description Framework (RDF) and the OpenTox standards. We describe the design of the data warehouse based on cluster requirements, the implementation based on open standards, and finally the underlying concepts and initial results of a data analysis utilizing public data related to the gold compounds. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Building 904, oblique view to southeast, 135 mm lens. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Building 904, oblique view to southeast, 135 mm lens. - Travis Air Force Base, Base Spares Warehouse No. 1, Dixon Avenue & W Street, Armed Forces Special Weapons Project Q Area, Fairfield, Solano County, CA

Building 904, oblique view to northwest, 135 mm lens ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Building 904, oblique view to northwest, 135 mm lens - Travis Air Force Base, Base Spares Warehouse No. 1, Dixon Avenue & W Street, Armed Forces Special Weapons Project Q Area, Fairfield, Solano County, CA

Improving the human hazard characterization of chemicals: a Tox21 update.

PubMed

Tice, Raymond R; Austin, Christopher P; Kavlock, Robert J; Bucher, John R

2013-07-01

In 2008, the National Institute of Environmental Health Sciences/National Toxicology Program, the U.S. Environmental Protection Agency's National Center for Computational Toxicology, and the National Human Genome Research Institute/National Institutes of Health Chemical Genomics Center entered into an agreement on "high throughput screening, toxicity pathway profiling, and biological interpretation of findings." In 2010, the U.S. Food and Drug Administration (FDA) joined the collaboration, known informally as Tox21. The Tox21 partners agreed to develop a vision and devise an implementation strategy to shift the assessment of chemical hazards away from traditional experimental animal toxicology studies to one based on target-specific, mechanism-based, biological observations largely obtained using in vitro assays. Here we outline the efforts of the Tox21 partners up to the time the FDA joined the collaboration, describe the approaches taken to develop the science and technologies that are currently being used, assess the current status, and identify problems that could impede further progress as well as suggest approaches to address those problems. Tox21 faces some very difficult issues. However, we are making progress in integrating data from diverse technologies and end points into what is effectively a systems-biology approach to toxicology. This can be accomplished only when comprehensive knowledge is obtained with broad coverage of chemical and biological/toxicological space. The efforts thus far reflect the initial stage of an exceedingly complicated program, one that will likely take decades to fully achieve its goals. However, even at this stage, the information obtained has attracted the attention of the international scientific community, and we believe these efforts foretell the future of toxicology.

The Vibrio parahaemolyticus ToxRS Regulator Is Required for Stress Tolerance and Colonization in a Novel Orogastric Streptomycin-Induced Adult Murine Model

PubMed Central

Whitaker, W. Brian; Parent, Michelle A.; Boyd, Aoife; Richards, Gary P.

2012-01-01

Vibrio parahaemolyticus, a marine bacterium, is the causative agent of gastroenteritis associated with the consumption of seafood. It contains a homologue of the toxRS operon that in V. cholerae is the key regulator of virulence gene expression. We examined a nonpolar mutation in toxRS to determine the role of these genes in V. parahaemolyticus RIMD2210633, an O3:K6 isolate, and showed that compared to the wild type, ΔtoxRS was significantly more sensitive to acid, bile salts, and sodium dodecyl sulfate stresses. We demonstrated that ToxRS is a positive regulator of ompU expression, and that the complementation of ΔtoxRS with ompU restores stress tolerance. Furthermore, we showed that ToxRS also regulates type III secretion system genes in chromosome I via the regulation of the leuO homologue VP0350. We examined the effect of ΔtoxRS in vivo using a new orogastric adult murine model of colonization. We demonstrated that streptomycin-treated adult C57BL/6 mice experienced prolonged intestinal colonization along the entire intestinal tract by the streptomycin-resistant V. parahaemolyticus. In contrast, no colonization occurred in non-streptomycin-treated mice. A competition assay between the ΔtoxRS and wild-type V. parahaemolyticus strains marked with the β-galactosidase gene lacZ demonstrated that the ΔtoxRS strain was defective in colonization compared to the wild-type strain. This defect was rescued by ectopically expressing ompU. Thus, the defect in stress tolerance and colonization in ΔtoxRS is solely due to OmpU. To our knowledge, the orogastric adult murine model reported here is the first showing sustained intestinal colonization by V. parahaemolyticus. PMID:22392925

An Evaluation of ToxCast Angiogenic Disruptors for Effects on Mitochondrial Bioactivity Profiles (Teratology Society Annual Meeting)

EPA Science Inventory

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 ...

Solution NMR Structures of Pyrenophora tritici-repentis ToxB and Its Inactive Homolog Reveal Potential Determinants of Toxin Activity*

PubMed Central

Nyarko, Afua; Singarapu, Kiran K.; Figueroa, Melania; Manning, Viola A.; Pandelova, Iovanna; Wolpert, Thomas J.; Ciuffetti, Lynda M.; Barbar, Elisar

2014-01-01

Pyrenophora tritici-repentis Ptr ToxB (ToxB) is a proteinaceous host-selective toxin produced by Pyrenophora tritici-repentis (P. tritici-repentis), a plant pathogenic fungus that causes the disease tan spot of wheat. One feature that distinguishes ToxB from other host-selective toxins is that it has naturally occurring homologs in non-pathogenic P. tritici-repentis isolates that lack toxic activity. There are no high-resolution structures for any of the ToxB homologs, or for any protein with >30% sequence identity, and therefore what underlies activity remains an open question. Here, we present the NMR structures of ToxB and its inactive homolog Ptr toxb. Both proteins adopt a β-sandwich fold comprising three strands in each half that are bridged together by two disulfide bonds. The inactive toxb, however, shows higher flexibility localized to the sequence-divergent β-sandwich half. The absence of toxic activity is attributed to a more open structure in the vicinity of one disulfide bond, higher flexibility, and residue differences in an exposed loop that likely impacts interaction with putative targets. We propose that activity is regulated by perturbations in a putative active site loop and changes in dynamics distant from the site of activity. Interestingly, the new structures identify AvrPiz-t, a secreted avirulence protein produced by the rice blast fungus, as a structural homolog to ToxB. This homology suggests that fungal proteins involved in either disease susceptibility such as ToxB or resistance such as AvrPiz-t may have a common evolutionary origin. PMID:25063993

High Throughput Pharmacokinetics for Environmental Chemicals (FutureToxII)

EPA Science Inventory

Pharmacokinetic (PK) models are critical to determine whether chemical exposures produce potentially hazardous tissue concentrations. For bioactivity identified in vitro (e.g. ToxCast) – hazardous or not – PK models can forecast exposure thresholds, below which no significant bio...

EPAs ToxCast Program: From Research to Application

EPA Science Inventory

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...

Characteristics and Applications of the ToxRefDB In Vivo Datasets from Chronic, Reproductive and Developmental Assays

EPA Science Inventory

ToxRefDB was developed to store data from in vivo animal toxicity studies. The initial focus was populating ToxRefDB with pesticide registration toxicity data that has been historically stored as hard-copy and scanned documents by the Office of Pesticide Programs. A significant p...

Improving the Human Hazard Characterization of Chemicals: A Tox21 Update

PubMed Central

Austin, Christopher P.; Kavlock, Robert J.; Bucher, John R.

2013-01-01

Background: In 2008, the National Institute of Environmental Health Sciences/National Toxicology Program, the U.S. Environmental Protection Agency’s National Center for Computational Toxicology, and the National Human Genome Research Institute/National Institutes of Health Chemical Genomics Center entered into an agreement on “high throughput screening, toxicity pathway profiling, and biological interpretation of findings.” In 2010, the U.S. Food and Drug Administration (FDA) joined the collaboration, known informally as Tox21. Objectives: The Tox21 partners agreed to develop a vision and devise an implementation strategy to shift the assessment of chemical hazards away from traditional experimental animal toxicology studies to one based on target-specific, mechanism-based, biological observations largely obtained using in vitro assays. Discussion: Here we outline the efforts of the Tox21 partners up to the time the FDA joined the collaboration, describe the approaches taken to develop the science and technologies that are currently being used, assess the current status, and identify problems that could impede further progress as well as suggest approaches to address those problems. Conclusion: Tox21 faces some very difficult issues. However, we are making progress in integrating data from diverse technologies and end points into what is effectively a systems-biology approach to toxicology. This can be accomplished only when comprehensive knowledge is obtained with broad coverage of chemical and biological/toxicological space. The efforts thus far reflect the initial stage of an exceedingly complicated program, one that will likely take decades to fully achieve its goals. However, even at this stage, the information obtained has attracted the attention of the international scientific community, and we believe these efforts foretell the future of toxicology. PMID:23603828

Identification of Fusarium virguliforme FvTox1-Interacting Synthetic Peptides for Enhancing Foliar Sudden Death Syndrome Resistance in Soybean

PubMed Central

Wang, Bing; Swaminathan, Sivakumar; Bhattacharyya, Madan K.

2015-01-01

Soybean is one of the most important crops grown across the globe. In the United States, approximately 15% of the soybean yield is suppressed due to various pathogen and pests attack. Sudden death syndrome (SDS) is an emerging fungal disease caused by Fusarium virguliforme. Although growing SDS resistant soybean cultivars has been the main method of controlling this disease, SDS resistance is partial and controlled by a large number of quantitative trait loci (QTL). A proteinacious toxin, FvTox1, produced by the pathogen, causes foliar SDS. Earlier, we demonstrated that expression of an anti-FvTox1 single chain variable fragment antibody resulted in reduced foliar SDS development in transgenic soybean plants. Here, we investigated if synthetic FvTox1-interacting peptides, displayed on M13 phage particles, can be identified for enhancing foliar SDS resistance in soybean. We screened three phage-display peptide libraries and discovered four classes of M13 phage clones displaying FvTox1-interacting peptides. In vitro pull-down assays and in vivo interaction assays in yeast were conducted to confirm the interaction of FvTox1 with these four synthetic peptides and their fusion-combinations. One of these peptides was able to partially neutralize the toxic effect of FvTox1 in vitro. Possible application of the synthetic peptides in engineering SDS resistance soybean cultivars is discussed. PMID:26709700

Investigation Into The Needs of Part 135 Operators to Access Airports Restricted Under FAR Part 135 Sections 135.213, 135.219 and/or 135.225

NASA Technical Reports Server (NTRS)

Eckert, Clifford A.; Stough, H. P. (Technical Monitor)

2002-01-01

NASA and the FAA have joint interests and responsibilities for developing guidelines and standards for cockpit displays of Flight Information Services (FIS) information and for developing enhancements to the planned FAA Data Link (FISDL) services. NASA and the FAA have established responsibilities in connection with development tasks for enhancements to the FISDL project. This report is the result of NASA Task 2, "Weather Support Concept- Part 135 Operations." The objective of the task was to determine the needs of Part 135 operators as they relate to FAA Part 135 Sections 135.213, 135.219 and 135.225, which pertain to weather reporting requirements at destination airports. This report discusses the results of two questionnaires completed by volunteer Part 135 operators that questioned their operations, their needs for flying to airports without weather reporting compatibilities, and suggestions for modifying FARs 135.213, 135.219 and 135.225. The operators pointed out airports in areas of the CONUS that were needed for IFR operations but lacked weather reporting capabilities and they offered practical suggestions for changes to the FARs. Related to operators's needs, and discussed in this report, were the Fractional Ownership NPRM and the possible impact of GPS WAAS and LAAS approaches.

Structure Identification Using High Resolution Mass Spectrometry Data and the EPA’s CompTox Chemistry Dashboard (EAS)

EPA Science Inventory

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...

Biological profiling of the ToxCast Phase II Chemical Library in Primary Human Cell Co-Culture Systems

EPA Science Inventory

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...

Extending the Derek-Meteor Workflow to Predict Chemical-Toxicity Space Impacted by Metabolism: Application to ToxCast and Tox21 Chemical Inventories

EPA Science Inventory

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...

ToxCast: Developing Predictive Signatures of Chemically Induced Toxicity (S)

EPA Science Inventory

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...

ToxRefDB 2.0: Improvements in Capturing Qualitative and Quantitative Data from in vivo Toxicity Studies (SOT)

EPA Science Inventory

The Toxicity Reference Database (ToxRefDB) is a publicly accessible resource that contains 40+ years of in vivo dose-response toxicological studies. ToxRefDB provides curated in vivo toxicity data for systematic evaluation of a continuously expanding catalog of chemicals, and co...

A ToxA-like protein from Cochliobolus heterostrophus induces light-dependent leaf necrosis and acts as a virulence factor with host selectivity on maize.

PubMed

Lu, Shunwen; Gillian Turgeon, B; Edwards, Michael C

2015-08-01

ToxA, the first discovered fungal proteinaceous host-selective toxin (HST), was originally identified in 1989 from the tan spot fungus Pyrenophora tritici-repentis (Ptr). About 25years later, a homolog was identified in the leaf/glume blotch fungus Stagonospora nodorum (Parastagonospora nodorum), also a pathogen of wheat. Here we report the identification and function of a ToxA-like protein from the maize pathogen Cochliobolus heterostrophus (Ch) that possesses necrosis-inducing activity specifically against maize. ChToxA is encoded by a 535-bp open reading frame featuring a ToxA-specific intron with unusual splicing sites (5'-ATAAGT…TAC-3') at conserved positions relative to PtrToxA. The protein shows 64% similarity to PtrToxA and is predicted to adopt a similar three-dimensional structure, although lacking the arginyl-glycyl-aspartic acid (RGD) motif reported to be required for internalization into sensitive wheat mesophyll cells. Reverse-transcriptase PCR revealed that the ChTOXA gene expression is up-regulated in planta, relative to axenic culture. Plant assays indicated that the recombinant ChToxA protein induces light-dependent leaf necrosis in a host-selective manner on maize inbred lines. Gene deletion experiments confirmed that ChtoxA mutants are reduced in virulence on specific ChToxA-sensitive maize lines, relative to virulence caused by wild-type strains. Database searches identified potential ChToxA homologues in other plant-pathogenic ascomycetes. Sequence and phylogenetic analyses revealed that the corresponding ToxA-like proteins include one member recently shown to be associated with formation of penetration hypha. These results provide the first evidence that C. heterostrophus is capable of producing proteinaceous HSTs as virulence factors in addition to well-known secondary metabolite-type toxins produced biosynthetically by polyketide synthase megaenzymes. Further studies on ChToxA may provide new insights into effector evolution in host

High-Throughput Exposure Potential Prioritization for ToxCast Chemicals

EPA Science Inventory

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...

Value of shared preclinical safety studies - The eTOX database.

PubMed

Briggs, Katharine; Barber, Chris; Cases, Montserrat; Marc, Philippe; Steger-Hartmann, Thomas

2015-01-01

A first analysis of a database of shared preclinical safety data for 1214 small molecule drugs and drug candidates extracted from 3970 reports donated by thirteen pharmaceutical companies for the eTOX project (www.etoxproject.eu) is presented. Species, duration of exposure and administration route data were analysed to assess if large enough subsets of homogenous data are available for building in silico predictive models. Prevalence of treatment related effects for the different types of findings recorded were analysed. The eTOX ontology was used to determine the most common treatment-related clinical chemistry and histopathology findings reported in the database. The data were then mined to evaluate sensitivity of established in vivo biomarkers for liver toxicity risk assessment. The value of the database to inform other drug development projects during early drug development is illustrated by a case study.

High-Throughput Physiologically Based Toxicokinetic Models for ToxCast Chemicals

EPA Science Inventory

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 ...

Activation of both acfA and acfD transcription by Vibrio cholerae ToxT requires binding to two centrally located DNA sites in an inverted repeat conformation.

PubMed

Withey, Jeffrey H; DiRita, Victor J

2005-05-01

The Gram-negative bacterium Vibrio cholerae is the infectious agent responsible for the disease Asiatic cholera. The genes required for V. cholerae virulence, such as those encoding the cholera toxin (CT) and toxin-coregulated pilus (TCP), are controlled by a cascade of transcriptional activators. Ultimately, the direct transcriptional activator of the majority of V. cholerae virulence genes is the AraC/XylS family member ToxT protein, the expression of which is activated by the ToxR and TcpP proteins. Previous studies have identified the DNA sites to which ToxT binds upstream of the ctx operon, encoding CT, and the tcpA operon, encoding, among other products, the major subunit of the TCP. These known ToxT binding sites are seemingly dissimilar in sequence other than being A/T rich. Further results suggested that ctx and tcpA each has a pair of ToxT binding sites arranged in a direct repeat orientation upstream of the core promoter elements. In this work, using both transcriptional lacZ fusions and in vitro copper-phenanthroline footprinting experiments, we have identified the ToxT binding sites between the divergently transcribed acfA and acfD genes, which encode components of the accessory colonization factor required for efficient intestinal colonization by V. cholerae. Our results indicate that ToxT binds to a pair of DNA sites between acfA and acfD in an inverted repeat orientation. Moreover, a mutational analysis of the ToxT binding sites indicates that both binding sites are required by ToxT for transcriptional activation of both acfA and acfD. Using copper-phenanthroline footprinting to assess the occupancy of ToxT on DNA having mutations in one of these binding sites, we found that protection by ToxT of the unaltered binding site was not affected, whereas protection by ToxT of the mutant binding site was significantly reduced in the region of the mutations. The results of further footprinting experiments using DNA templates having +5 bp and +10 bp

ToxCast Data Expands Universe of Chemical-Gene Interactions (SOT)

EPA Science Inventory

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...

The global regulator of pathogenesis PnCon7 positively regulates Tox3 effector gene expression through direct interaction in the wheat pathogen Parastagonospora nodorum.

PubMed

Lin, Shao-Yu; Chooi, Yit-Heng; Solomon, Peter S

2018-05-03

To investigate effector gene regulation in the wheat pathogenic fungus Parastagonospora nodorum, the promoter and expression of Tox3 was characterised through a series of complementary approaches. Promoter deletion and DNase I footprinting experiments identified a 25 bp region in the Tox3 promoter as being required for transcription. Subsequent yeast one-hybrid analysis using the DNA sequence as bait identified that interacting partner as the C2H2 zinc finger transcription factor PnCon7, a putative master regulator of pathogenesis. Silencing of PnCon7 resulted in the down-regulation of Tox3 demonstrating that the transcription factor has a positive regulatory role on gene expression. Analysis of Tox3 expression in the PnCon7 silenced strains revealed a strong correlation with PnCon7 transcript levels, supportive of a direct regulatory role. Subsequent pathogenicity assays using PnCon7-silenced isolates revealed that the transcription factor was required for Tox3-mediated disease. The expression of two other necrotrophic effectors (ToxA and Tox1) was also affected but in a non-dose dependent manner suggesting that the regulatory role of PnCon7 on these genes was indirect. Collectively, these data have advanced our fundamental understanding of the Con7 master regulator of pathogenesis by demonstrating its positive regulatory role on the Tox3 effector in P. nodorum through direct interaction. This article is protected by copyright. All rights reserved. © 2018 John Wiley & Sons Ltd.

Building 909, oblique view to southeast, 135 mm lens. Building ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Building 909, oblique view to southeast, 135 mm lens. Building 908 at extreme right for context. - Travis Air Force Base, Handling Crew Building, North of W Street, Armed Forces Special Weapons Project Q Area, Fairfield, Solano County, CA

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury

MedlinePlus

... News Information Resources Glossary Abbreviations SEARCH THE LIVERTOX DATABASE Search for a specific medication, herbal or supplement: ... About Us . Disclaimer. Information presented in the LiverTox database is derived from the scientific literature and public ...

Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics

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

Persistence of immune responses after a single dose of Novartis meningococcal serogroup A, C, W-135 and Y CRM-197 conjugate vaccine (Menveo®) or Menactra® among healthy adolescents.

PubMed

Gill, Christopher J; Baxter, Roger; Anemona, Alessandra; Ciavarro, Giuseppe; Dull, Peter

2010-11-01

The persistence of human bactericidal activity (hSBA) responses in adolescents was assessed 22 months after vaccination with one dose of Menveo® (MenACWY-CRM; Novartis) or Menactra® (MCV4) (sanofi pasteur). The proportion of subjects with hSBA titers ≥8 was significantly higher among recipients of MenACWY-CRM than MCV4 for serogroups A, W-135 and Y.

Profiling 976 ToxCast Chemicals across 331 Enzymatic and Receptor Signaling Assays

PubMed Central

2013-01-01

Understanding potential health risks is a significant challenge due to the large numbers of diverse chemicals with poorly characterized exposures and mechanisms of toxicities. The present study analyzes 976 chemicals (including failed pharmaceuticals, alternative plasticizers, food additives, and pesticides) in Phases I and II of the U.S. EPA’s ToxCast project across 331 cell-free enzymatic and ligand-binding high-throughput screening (HTS) assays. Half-maximal activity concentrations (AC50) were identified for 729 chemicals in 256 assays (7,135 chemical–assay pairs). Some of the most commonly affected assays were CYPs (CYP2C9 and CYP2C19), transporters (mitochondrial TSPO, norepinephrine, and dopaminergic), and GPCRs (aminergic). Heavy metals, surfactants, and dithiocarbamate fungicides showed promiscuous but distinctly different patterns of activity, whereas many of the pharmaceutical compounds showed promiscuous activity across GPCRs. Literature analysis confirmed >50% of the activities for the most potent chemical–assay pairs (54) but also revealed 10 missed interactions. Twenty-two chemicals with known estrogenic activity were correctly identified for the majority (77%), missing only the weaker interactions. In many cases, novel findings for previously unreported chemical–target combinations clustered with known chemical–target interactions. Results from this large inventory of chemical–biological interactions can inform read-across methods as well as link potential targets to molecular initiating events in adverse outcome pathways for diverse toxicities. PMID:23611293

LimTox: a web tool for applied text mining of adverse event and toxicity associations of compounds, drugs and genes

PubMed Central

Cañada, Andres; Rabal, Obdulia; Oyarzabal, Julen; Valencia, Alfonso

2017-01-01

Abstract A considerable effort has been devoted to retrieve systematically information for genes and proteins as well as relationships between them. Despite the importance of chemical compounds and drugs as a central bio-entity in pharmacological and biological research, only a limited number of freely available chemical text-mining/search engine technologies are currently accessible. Here we present LimTox (Literature Mining for Toxicology), a web-based online biomedical search tool with special focus on adverse hepatobiliary reactions. It integrates a range of text mining, named entity recognition and information extraction components. LimTox relies on machine-learning, rule-based, pattern-based and term lookup strategies. This system processes scientific abstracts, a set of full text articles and medical agency assessment reports. Although the main focus of LimTox is on adverse liver events, it enables also basic searches for other organ level toxicity associations (nephrotoxicity, cardiotoxicity, thyrotoxicity and phospholipidosis). This tool supports specialized search queries for: chemical compounds/drugs, genes (with additional emphasis on key enzymes in drug metabolism, namely P450 cytochromes—CYPs) and biochemical liver markers. The LimTox website is free and open to all users and there is no login requirement. LimTox can be accessed at: http://limtox.bioinfo.cnio.es PMID:28531339

Analysis of ToxCast data for food-relevant compounds by comparison with in vivo data using the RISK21 approach

EPA Science Inventory

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...

Predicting hepatotoxicity using ToxCast in vitro bioactivity and chemical structure

EPA Science Inventory

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 ...

Enhancing high throughput toxicology - development of putative adverse outcome pathways linking US EPA ToxCast screening targets to relevant apical hazards.

EPA Science Inventory

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...

Evaluation of food-relevant chemicals in the ToxCast high-throughput screening program

EPA Pesticide Factsheets

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

EPAs ToxCast Research Program: Developing Predictive Bioactivity Signatures for Chemicals

EPA Science Inventory

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...

Structure of Vibrio cholerae ToxT reveals a mechanism for fatty acid regulation of virulence genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lowden, Michael J.; Skorupski, Karen; Pellegrini, Maria

2010-03-04

Cholera is an acute intestinal infection caused by the bacterium Vibrio cholerae. In order for V. cholerae to cause disease, it must produce two virulence factors, the toxin-coregulated pilus (TCP) and cholera toxin (CT), whose expression is controlled by a transcriptional cascade culminating with the expression of the AraC-family regulator, ToxT. We have solved the 1.9 {angstrom} resolution crystal structure of ToxT, which reveals folds in the N- and C-terminal domains that share a number of features in common with AraC, MarA, and Rob as well as the unexpected presence of a buried 16-carbon fatty acid, cis-palmitoleate. The finding thatmore » cis-palmitoleic acid reduces TCP and CT expression in V. cholerae and prevents ToxT from binding to DNA in vitro provides a direct link between the host environment of V. cholerae and regulation of virulence gene expression.« less

The cysteine rich necrotrophic effector SnTox1 produced by Stagonospora nodorum triggers susceptibility of wheat lines harboring Snn1

USDA-ARS?s Scientific Manuscript database

The gene encoding SnTox1, a necrotrophic effector from Stagonospora nodorum that causes necrosis of wheat lines expressing Snn1, has been verified by heterologous expression in Pichia pastoris. SnTox1 encodes a 117 amino acid cysteine rich protein with the first 17 amino acids predicted as a signal ...

Causal Inferences from Mining ToxCast Data and the Biomedical Literature for Molecular Pathways and Cellular Processes in Cleft Palate (SOT)

EPA Science Inventory

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...

LimTox: a web tool for applied text mining of adverse event and toxicity associations of compounds, drugs and genes.

PubMed

Cañada, Andres; Capella-Gutierrez, Salvador; Rabal, Obdulia; Oyarzabal, Julen; Valencia, Alfonso; Krallinger, Martin

2017-07-03

A considerable effort has been devoted to retrieve systematically information for genes and proteins as well as relationships between them. Despite the importance of chemical compounds and drugs as a central bio-entity in pharmacological and biological research, only a limited number of freely available chemical text-mining/search engine technologies are currently accessible. Here we present LimTox (Literature Mining for Toxicology), a web-based online biomedical search tool with special focus on adverse hepatobiliary reactions. It integrates a range of text mining, named entity recognition and information extraction components. LimTox relies on machine-learning, rule-based, pattern-based and term lookup strategies. This system processes scientific abstracts, a set of full text articles and medical agency assessment reports. Although the main focus of LimTox is on adverse liver events, it enables also basic searches for other organ level toxicity associations (nephrotoxicity, cardiotoxicity, thyrotoxicity and phospholipidosis). This tool supports specialized search queries for: chemical compounds/drugs, genes (with additional emphasis on key enzymes in drug metabolism, namely P450 cytochromes-CYPs) and biochemical liver markers. The LimTox website is free and open to all users and there is no login requirement. LimTox can be accessed at: http://limtox.bioinfo.cnio.es. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Nanomaterial (NM) bioactivity profiling by ToxCast high-throughput screening (HTS)

EPA Science Inventory

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...

Predictive Modeling of Apical Toxicity Endpoints Using Data From ToxCast

EPA Science Inventory

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...

Prediction of metabolites of epoxidation reaction in MetaTox.

PubMed

Rudik, A V; Dmitriev, A V; Bezhentsev, V M; Lagunin, A A; Filimonov, D A; Poroikov, V V

2017-10-01

Biotransformation is a process of the chemical modifications which may lead to the reactive metabolites, in particular the epoxides. Epoxide reactive metabolites may cause the toxic effects. The prediction of such metabolites is important for drug development and ecotoxicology studies. Epoxides are formed by some oxidation reactions, usually catalysed by cytochromes P450, and represent a large class of three-membered cyclic ethers. Identification of molecules, which may be epoxidized, and indication of the specific location of epoxide functional group (which is called SOE - site of epoxidation) are important for prediction of epoxide metabolites. Datasets from 355 molecules and 615 reactions were created for training and validation. The prediction of SOE is based on a combination of LMNA (Labelled Multilevel Neighbourhood of Atom) descriptors and Bayesian-like algorithm implemented in PASS software and MetaTox web-service. The average invariant accuracy of prediction (AUC) calculated in leave-one-out and 20-fold cross-validation procedures is 0.9. Prediction of epoxide formation based on the created SAR model is included as the component of MetaTox web-service ( http://www.way2drug.com/mg ).

Mass-Spectrometry Based Structure Identification of "Known-Unknowns" Using the EPA's CompTox Dashboard (ACS Spring National Meeting) 4 of 7

EPA Science Inventory

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...

ToxCast: Using high throughput screening to identify profiles of biological activity

EPA Science Inventory

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...

Predictive In Vitro Screening of Environmental Chemicals – The ToxCast Project

EPA Science Inventory

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...

Vibrio parahaemolyticus ToxRS regulator is required for stress tolerance and colonization in a novel orogastric streptomycin-induced adult murine model

USDA-ARS?s Scientific Manuscript database

Vibrio parahaemolyticus, a marine bacterium, is the causative agent of gastroenteritis associated with the consumption of seafood. It contains a homologue of the toxRS operon that in V. cholerae is the key regulator of virulence gene expression. We examined a non-polar mutation in toxRS to determi...

Zebrafish Developmental Screening of the ToxCast™ Phase I Chemical Library

EPA Science Inventory

Zebrafish (Danio rerio) is an emerging toxicity screening model for both human health and ecology. As part of the Computational Toxicology Research Program of the U.S. EPA, the toxicity of the 309 ToxCast™ Phase I chemicals was assessed using a zebrafish screen for developmental ...

Learn by Doing - Phase I of the ToxCast Research Program

EPA Science Inventory

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 ...

High-Throughput/High-Content Screening Assays with Engineered Nanomaterials in ToxCast

EPA Science Inventory

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...

Evaluation of food-relevant chemicals in the ToxCast high-throughput screening program.

PubMed

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.

Multivariate analysis of toxicity experimental results of environmental endpoints. (FutureToxII)

EPA Science Inventory

The toxicity of hundreds of chemicals have been assessed in laboratory animal studies through EPA chemical regulation and toxicological research. Currently, over 5000 laboratory animal toxicity studies have been collected in the Toxicity Reference Database (ToxRefDB). In addition...

Curation of food-relevant chemicals in ToxCast.

PubMed

Karmaus, Agnes L; Trautman, Thomas D; Krishan, Mansi; Filer, Dayne L; Fix, Laurel A

2017-05-01

High-throughput in vitro assays and exposure prediction efforts are paving the way for modeling chemical risk; however, the utility of such extensive datasets can be limited or misleading when annotation fails to capture current chemical usage. To address this data gap and provide context for food-use in the United States (US), manual curation of food-relevant chemicals in ToxCast was conducted. Chemicals were categorized into three food-use categories: (1) direct food additives, (2) indirect food additives, or (3) pesticide residues. Manual curation resulted in 30% of chemicals having new annotation as well as the removal of 319 chemicals, most due to cancellation or only foreign usage. These results highlight that manual curation of chemical use information provided significant insight affecting the overall inventory and chemical categorization. In total, 1211 chemicals were confirmed as current day food-use in the US by manual curation; 1154 of these chemicals were also identified as food-related in the globally sourced chemical use information from Chemical/Product Categories database (CPCat). The refined list of food-use chemicals and the sources highlighted for compiling annotated information required to confirm food-use are valuable resources for providing needed context when evaluating large-scale inventories such as ToxCast. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Identifying known unknowns using the US EPA's CompTox Chemistry Dashboard.

PubMed

McEachran, Andrew D; Sobus, Jon R; Williams, Antony J

2017-03-01

Chemical features observed using high-resolution mass spectrometry can be tentatively identified using online chemical reference databases by searching molecular formulae and monoisotopic masses and then rank-ordering of the hits using appropriate relevance criteria. The most likely candidate "known unknowns," which are those chemicals unknown to an investigator but contained within a reference database or literature source, rise to the top of a chemical list when rank-ordered by the number of associated data sources. The U.S. EPA's CompTox Chemistry Dashboard is a curated and freely available resource for chemistry and computational toxicology research, containing more than 720,000 chemicals of relevance to environmental health science. In this research, the performance of the Dashboard for identifying known unknowns was evaluated against that of the online ChemSpider database, one of the primary resources used by mass spectrometrists, using multiple previously studied datasets reported in the peer-reviewed literature totaling 162 chemicals. These chemicals were examined using both applications via molecular formula and monoisotopic mass searches followed by rank-ordering of candidate compounds by associated references or data sources. A greater percentage of chemicals ranked in the top position when using the Dashboard, indicating an advantage of this application over ChemSpider for identifying known unknowns using data source ranking. Additional approaches are being developed for inclusion into a non-targeted analysis workflow as part of the CompTox Chemistry Dashboard. This work shows the potential for use of the Dashboard in exposure assessment and risk decision-making through significant improvements in non-targeted chemical identification. Graphical abstract Identifying known unknowns in the US EPA's CompTox Chemistry Dashboard from molecular formula and monoisotopic mass inputs.

NanoE-Tox: New and in-depth database concerning ecotoxicity of nanomaterials.

PubMed

Juganson, Katre; Ivask, Angela; Blinova, Irina; Mortimer, Monika; Kahru, Anne

2015-01-01

The increasing production and use of engineered nanomaterials (ENMs) inevitably results in their higher concentrations in the environment. This may lead to undesirable environmental effects and thus warrants risk assessment. The ecotoxicity testing of a wide variety of ENMs rapidly evolving in the market is costly but also ethically questionable when bioassays with vertebrates are conducted. Therefore, alternative methods, e.g., models for predicting toxicity mechanisms of ENMs based on their physico-chemical properties (e.g., quantitative (nano)structure-activity relationships, QSARs/QNARs), should be developed. While the development of such models relies on good-quality experimental toxicity data, most of the available data in the literature even for the same test species are highly variable. In order to map and analyse the state of the art of the existing nanoecotoxicological information suitable for QNARs, we created a database NanoE-Tox that is available as Supporting Information File 1. The database is based on existing literature on ecotoxicology of eight ENMs with different chemical composition: carbon nanotubes (CNTs), fullerenes, silver (Ag), titanium dioxide (TiO2), zinc oxide (ZnO), cerium dioxide (CeO2), copper oxide (CuO), and iron oxide (FeO x ; Fe2O3, Fe3O4). Altogether, NanoE-Tox database consolidates data from 224 articles and lists altogether 1,518 toxicity values (EC50/LC50/NOEC) with corresponding test conditions and physico-chemical parameters of the ENMs as well as reported toxicity mechanisms and uptake of ENMs in the organisms. 35% of the data in NanoE-Tox concerns ecotoxicity of Ag NPs, followed by TiO2 (22%), CeO2 (13%), and ZnO (10%). Most of the data originates from studies with crustaceans (26%), bacteria (17%), fish (13%), and algae (11%). Based on the median toxicity values of the most sensitive organism (data derived from three or more articles) the toxicity order was as follows: Ag > ZnO > CuO > CeO2 > CNTs > TiO2 > FeO x . We

High Throughput Genotoxicity Profiling of the US EPA ToxCast Chemical Library

EPA Science Inventory

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...

Probing the ToxCast Chemical Library for Predictive Signatures of Developmental Toxicity

EPA Science Inventory

EPA’s ToxCast™ project is profiling the in vitro bioactivity of chemical compounds to assess pathway-level and cell-based signatures that correlate with observed in vivo toxicity. We hypothesize that cell signaling pathways are primary targets for diverse environmental chemicals ...

Periodic Leg Movements during Sleep Are Associated with Polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD

PubMed Central

Moore, Hyatt; Winkelmann, Juliane; Lin, Ling; Finn, Laurel; Peppard, Paul; Mignot, Emmanuel

2014-01-01

Study Objectives: To examine association between periodic leg movements (PLM) and 13 single nucleotide polymorphisms (SNPs) in 6 loci known to increase risk of restless legs syndrome (RLS). Setting: Stanford Center for Sleep Sciences and Medicine and Clinical Research Unit of University of Wisconsin Institute for Clinical and Translational Research. Patients: Adult participants (n = 1,090, mean age = 59.7 years) from the Wisconsin Sleep Cohort (2,394 observations, 2000-2012). Design and Interventions: A previously validated automatic detector was used to measure PLMI. Thirteen SNPs within BTBD9, TOX3/BC034767, MEIS1 (2 unlinked loci), MAP2K5/SKOR1, and PTPRD were tested. Analyses were performed using a linear model and by PLM category using a 15 PLM/h cutoff. Statistical significance for loci was Bonferroni corrected for 6 loci (P < 8.3 × 10-3). RLS symptoms were categorized into four groups: likely, possible, no symptoms, and unknown based on a mailed survey response. Measurements and Results: Prevalence of PLMI ≥ 15 was 33%. Subjects with PLMs were older, more likely to be male, and had more frequent RLS symptoms, a shorter total sleep time, and higher wake after sleep onset. Strong associations were found at all loci except one. Highest associations for PLMI > 15/h were obtained using a multivariate model including age, sex, sleep disturbances, and the best SNPs for each loci, yielding the following odds ratios (OR) and P values: BTBD9 rs3923809(A) OR = 1.65, P = 1.5×10-8; TOX3/BC034767 rs3104788(T) OR = 1.35, P = 9.0 × 10-5; MEIS1 rs12469063(G) OR = 1.38, P = 2.0 × 10-4; MAP2K5/SKOR1 rs6494696(G) OR = 1.24, P = 1.3×10-2; and PTPRD(A) rs1975197 OR = 1.31, P = 6.3×10-3. Linear regression models also revealed significant PLM effects for BTBD9, TOX3/BC034767, and MEIS1. Co-varying for RLS symptoms only modestly reduced the genetic associations. Conclusions: Single nucleotide polymorphisms demonstrated to increase risk of RLS are strongly linked to increased

Profiling of the Tox21 Chemical Collection for Mitochondrial ...

EPA Pesticide Factsheets

Mitochondrial dysfunction has been implicated in the pathogenesis of a variety of disorders including cancer, diabetes, and neurodegenerative and cardiovascular diseases. Understanding how different environmental chemicals and drug-like molecules impact mitochondrial function represents an initial step in predicting exposure-related toxic effects and defining a possible role for such compounds in the onset of various diseases. OBJECTIVES: To identify individual chemicals and general structural features associated with the disruption of mitochondrial membrane potential (MMP). METHODS: We used a multiplexed quantitative high throughput screening (qHTS) approach combined with informatics tools to screen the Tox21 10,000 compound library (~8300 unique chemicals) at 15 concentrations in triplicate to identify chemicals and structural features that are associated with changes in MMP in HepG2 cells. RESULTS: In the primary screening, approximately 11% of the compounds (913 unique compounds) decreased the MMP after 1 h of treatment without affecting cell viability. Additionally, 309 compounds decreased MMP over a concentration range that also produced measurable cytotoxicity [half maximal inhibitory concentration (IC50) in MMP assay/IC50 in viability assay) ≤ 3, p<0.05]. Over 11% of the structural clusters that constitute the Tox21 library (76 of 651 clusters) were significantly enriched for compounds that decreased the MMP. CONCLUSIONS: Our multiplexed qHTS approach

Evaluation of the Triage TOX Drug Screen Assay for Detection of 11 Drugs of Abuse and Therapeutic Drugs.

PubMed

Bang, Hae In; Jang, Mi Ae; Lee, Yong Wha

2017-11-01

The demand for rapid and broad clinical toxicology screens is on the rise. Recently, a new rapid toxicology screening test, the Triage TOX Drug Screen (Alere Inc., USA), which can simultaneously detect 11 drugs of abuse and therapeutic drugs with an instrument-read cartridge, was developed. In the present study, we evaluated the efficacy of this new on-site immunoassay using 105 urine specimens; the results were compared with those obtained by using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-TMS). Precision was evaluated according to the CLSI EP12-A2 for analyte concentrations near the cutoff, including C₅₀ and±30% of C₅₀, for each drug using standard materials. The C₅₀ specimens yielded 35-65% positive results and the±30% concentration range of all evaluated drugs encompassed the C₅-C₉₅ interval. The overall percent agreement of the Triage TOX Drug Screen was 92.4-100% compared with UPLC-TMS; however, the Triage TOX Drug Screen results showed some discordant cases including acetaminophen, amphetamine, benzodiazepine, opiates, and tricyclic antidepressants. The overall performance of the Triage TOX Drug Screen assay was comparable to that of UPLC-TMS for screening of drug intoxication in hospitals. This assay could constitute a useful screening method for drugs of abuse and therapeutic drugs in urine. © The Korean Society for Laboratory Medicine.

Novel topical BoNTA (CosmeTox, toxin type A) cream used to treat hyperfunctional wrinkles of the face, mouth, and neck.

PubMed

Chajchir, I; Modi, P; Chajchir, A

2008-09-01

This study aimed to compare the effect of the stabilized novel topical botulinum neurotoxin type A (BoNTA) cream (CosmeTox) and a placebo cream on subjects, to compare clinician-reported outcomes, and to assess the safety and utility of the novel topical BoNTA cream for treating the entire upper face, chin, and neck areas. This study randomized 40 female subjects to receive either topical BoNTA (CosmeTox) cream (2 U/ml) or an identical placebo cream (without BoNTA) on the face, chin, and neck areas. The subjects were followed for 12 weeks. The main outcome measures were the Facial Line Outcomes questionnaire scores and results from the Self-Perception of Age instrument, which assesses age of appearance relative to actual age. The BoNTA topical cream (CosmeTox) treatment produced significant improvements in the Facial Lines Outcome scores, which were maintained throughout the study period and lasted more than 3 months. The BoNTA topical cream treatment also reduced the age of appearance for a majority of subjects. The placebo had no effect on any measure. No serious adverse events occurred during the entire study period. Topical treatment with the stabilized BoNTA cream (CosmeTox) to the entire upper facial lines resulted in significantly improved facial features and age appearance, as measured by the subjects and clinicians. The BoNTA cream (CosmeTox) resulted in a significantly younger, more satisfying, relaxed appearance.

W. W. "Mo" Cleland: a catalytic life.

PubMed

Dunaway-Mariano, Debra; Holden, Hazel M; Raushel, Frank M

2013-12-23

Professor W. Wallace Cleland, the architect of modern steady-state enzyme kinetics, died on March 6, 2013, from injuries sustained in a fall outside of his home. He will be most remembered for giving the enzyme community Ping-Pong kinetics and the invention of dithiothreitol (DTT). He pioneered the utilization of heavy atom isotope effects for the elucidation of the chemical mechanisms of enzyme-catalyzed reactions. His favorite research journal was Biochemistry, in which he published more than 135 papers beginning in 1964 with the disclosure of DTT.

The Second Phase of ToxCast and Initial Applications to Chemical Prioritization

EPA Science Inventory

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...

Mining hidden knowledge for drug safety assessment: topic modeling of LiverTox as a case study

PubMed Central

2014-01-01

Background Given the significant impact on public health and drug development, drug safety has been a focal point and research emphasis across multiple disciplines in addition to scientific investigation, including consumer advocates, drug developers and regulators. Such a concern and effort has led numerous databases with drug safety information available in the public domain and the majority of them contain substantial textual data. Text mining offers an opportunity to leverage the hidden knowledge within these textual data for the enhanced understanding of drug safety and thus improving public health. Methods In this proof-of-concept study, topic modeling, an unsupervised text mining approach, was performed on the LiverTox database developed by National Institutes of Health (NIH). The LiverTox structured one document per drug that contains multiple sections summarizing clinical information on drug-induced liver injury (DILI). We hypothesized that these documents might contain specific textual patterns that could be used to address key DILI issues. We placed the study on drug-induced acute liver failure (ALF) which was a severe form of DILI with limited treatment options. Results After topic modeling of the "Hepatotoxicity" sections of the LiverTox across 478 drug documents, we identified a hidden topic relevant to Hy's law that was a widely-accepted rule incriminating drugs with high risk of causing ALF in humans. Using this topic, a total of 127 drugs were further implicated, 77 of which had clear ALF relevant terms in the "Outcome and management" sections of the LiverTox. For the rest of 50 drugs, evidence supporting risk of ALF was found for 42 drugs from other public databases. Conclusion In this case study, the knowledge buried in the textual data was extracted for identification of drugs with potential of causing ALF by applying topic modeling to the LiverTox database. The knowledge further guided identification of drugs with the similar potential and most

Mining hidden knowledge for drug safety assessment: topic modeling of LiverTox as a case study.

PubMed

Yu, Ke; Zhang, Jie; Chen, Minjun; Xu, Xiaowei; Suzuki, Ayako; Ilic, Katarina; Tong, Weida

2014-01-01

Given the significant impact on public health and drug development, drug safety has been a focal point and research emphasis across multiple disciplines in addition to scientific investigation, including consumer advocates, drug developers and regulators. Such a concern and effort has led numerous databases with drug safety information available in the public domain and the majority of them contain substantial textual data. Text mining offers an opportunity to leverage the hidden knowledge within these textual data for the enhanced understanding of drug safety and thus improving public health. In this proof-of-concept study, topic modeling, an unsupervised text mining approach, was performed on the LiverTox database developed by National Institutes of Health (NIH). The LiverTox structured one document per drug that contains multiple sections summarizing clinical information on drug-induced liver injury (DILI). We hypothesized that these documents might contain specific textual patterns that could be used to address key DILI issues. We placed the study on drug-induced acute liver failure (ALF) which was a severe form of DILI with limited treatment options. After topic modeling of the "Hepatotoxicity" sections of the LiverTox across 478 drug documents, we identified a hidden topic relevant to Hy's law that was a widely-accepted rule incriminating drugs with high risk of causing ALF in humans. Using this topic, a total of 127 drugs were further implicated, 77 of which had clear ALF relevant terms in the "Outcome and management" sections of the LiverTox. For the rest of 50 drugs, evidence supporting risk of ALF was found for 42 drugs from other public databases. In this case study, the knowledge buried in the textual data was extracted for identification of drugs with potential of causing ALF by applying topic modeling to the LiverTox database. The knowledge further guided identification of drugs with the similar potential and most of them could be verified and

Extracorporeal Membrane Oxygenation (ECMO) for Severe Toxicological Exposures: Review of the Toxicology Investigators Consortium (ToxIC).

PubMed

Wang, G S; Levitan, R; Wiegand, T J; Lowry, J; Schult, R F; Yin, S

2016-03-01

Although there have been many developments related to specific strategies for treating patients after poisoning exposures, the mainstay of therapy remains symptomatic and supportive care. One of the most aggressive supportive modalities is extracorporeal membrane oxygenation (ECMO). Our goal was to describe the use of ECMO for toxicological exposures reported to the American College of Medical Toxicology (ACMT) Toxicology Investigators Consortium (ToxIC). We performed a retrospective review of the ACMT ToxIC Registry from January 1, 2010 to December 31, 2013. Inclusion criteria included patients aged 0 to 89 years, evaluated between January 2010 through December 2013, and received ECMO for toxicological exposure. There were 26,271 exposures (60 % female) reported to the ToxIC Registry, 10 (0.0004 %) received ECMO: 4 pediatric (< 12 years), 2 adolescent (12-18 years), and 4 adults (>18 years). Time of initiation of ECMO ranged from 4 h to 4 days, with duration from 15 h to 12 days. Exposures included carbon monoxide/smoke inhalation (2), bitter almonds, methanol, and several medications including antihistamines (2), antipsychotic/antidepressant (2), cardiovascular drugs (2), analgesics (2), sedative/hypnotics (2), and antidiabetics (2). Four ECMO patients received cardiopulmonary resuscitation (CPR) during their hospital course, and the overall survival rate was 80 %. ECMO was rarely used for poisoning exposures in the ACMT ToxIC Registry. ECMO was utilized for a variety of ages and for pharmaceutical and non-pharmaceutical exposures. In most cases, ECMO was administered prior to cardiovascular failure, and survival rate was high. If available, ECMO may be a valid treatment modality.

Evaluation of the on-site immunoassay drug-screening device Triage-TOX in routine forensic autopsy.

PubMed

Tominaga, Mariko; Michiue, Tomomi; Maeda, Hitoshi

2015-11-01

Instrumental identification of drugs with quantification is essential in forensic toxicology, while on-site immunoassay urinalysis drug-screening devices conveniently provide preliminary information when adequately used. However, suitable or sufficient urine specimens are not always available. The present study evaluated the efficacy of a new on-site immunoassay drug-screening device Triage-TOX (Alere Inc., San Diego, CA, USA), which has recently been developed to provide objective data on the one-step automated processor, using 51 urine and 19 pericardial fluid samples from 66 forensic autopsy cases, compared with Triage-Drug of Abuse (DOA) and Monitect-9. For benzodiazepines, the positive predictive value and specificity of Triage-TOX were higher than those of Triage-DOA; however, sensitivity was higher with Monitect-9, despite frequent false-positives. The results for the other drugs with the three devices also included a few false-negatives and false-positives. These observations indicate the applicability of Triage-TOX in preliminary drug screening using urine or alternative materials in routine forensic autopsy, when a possible false-negative is considered, especially for benzodiazepines, providing objective information; however, the combined use of another device such as Monitect-9 can help minimize misinterpretation prior to instrumental analysis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Test driving ToxCast: endocrine profiling for1858 chemicals included in phase II

EPA Science Inventory

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...

In Vitro Screening of 1877 Industrial and Consumer Chemicals, Pesticides and Pharmaceuticals in up to 782 Assays: ToxCast Phase I and II (SOT)

EPA Science Inventory

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...

Critical appraisal of a quadrivalent CRM(197) conjugate vaccine against meningococcal serogroups A, C W-135 and Y (Menveo) in the context of treatment and prevention of invasive disease.

PubMed

Bröker, Michael; Cooper, Brian; Detora, Lisa M; Stoddard, Jeffrey J

2011-01-01

Worldwide, invasive meningococcal disease affects about 500,000 people annually. Case fatality in developed countries averages 10%, and higher rates are reported in less prosperous regions. According to the World Health Organization, the most important pathogenic serogroups are A, B, C, W-135, X, and Y. Clinical features of invasive meningococcal disease make diagnosis and management difficult. Antibiotic measures are recommended for prophylaxis after exposure and for treatment of invasive meningococcal disease cases; however, resistant strains may be emerging. Vaccines are generally regarded as the best preventative measure for invasive meningococcal disease. Polysaccharide vaccines against serogroups A, C, W-135, and Y using protein conjugation technology have clear advantages over older plain polysaccharide formulations without a protein component. The first quadrivalent meningococcal conjugate vaccine (MenACWY-D) was licensed in the US in 2005. More recently, MenACWY-CRM (Menveo(®)) was licensed in Europe, the US, the Middle East, and Latin America. MenACWY-CRM uses cross-reactive material 197, a nontoxic mutant of diphtheria toxin, as the carrier protein. MenACWY-CRM offers robust immunogenicity in all age groups, with a tolerability profile similar to that of a plain polysaccharide vaccine. Given its potential for protecting persons from infancy to old age, MenACWY-CRM offers the opportunity to protect broad populations against invasive meningococcal disease. The most optimal strategy for use of the vaccine has to be assessed country by country on the basis of local epidemiology, individual health care systems, and need.

Seroprevalence and placental transmission of maternal antibodies specific for Neisseria meningitidis Serogroups A, C, Y and W135 and influence of maternal antibodies on the immune response to a primary course of MenACWY-CRM vaccine in the United Kingdom.

PubMed

Blanchard-Rohner, Geraldine; Snape, Matthew D; Kelly, Dominic F; O'Connor, Daniel; John, Tessa; Kibwana, Elizabeth; Parks, Hannah; Ford, Karen; Dull, Peter M; Pollard, Andrew J

2013-07-01

Maternal antibodies give neonates some protection against bacterial infection. We measured antibodies against Neisseria meningitidis serogroups A, C, Y and W135 in mothers and their 2-month-old infants at study enrollment. We also assessed the impact of maternal antibody present at 2 months of age on the immune response to a primary course of quadrivalent meningococcal conjugate vaccine (MenACWY-CRM197) given at 2 and 4 months of age. This was a single-center, open-label, randomized study undertaken in Oxford, United Kingdom. Two hundred sixteen healthy infants were enrolled in the study and vaccinated with MenACWY-CRM197 at 2 and 4 months of age. Blood was obtained from all mothers, in a subset of infants at 2 months and all infants at 5 months. Antibody and memory B-cell responses at 5 months were correlated with maternal antibodies. Mothers had low IgG antibodies against serogroups C, W135 and Y polysaccharides, but high serogroup A antibody, whereas 61-78% had protective human complement serum bactericidal activity (hSBA) (≥1:4) for serogroups C, W135 and Y but only 31% for serogroup A. Only 9%, 32%, 45% and 19% of 2-month-old infants had hSBA ≥1:4 for serogroups A, C, W135 and Y, respectively. Maternal antibody had little association on responses to MenACWY-CRM197, except a moderate negative association between MenC-specific bactericidal antibody at 2 and 5 months (r = -0.5, P = 0.006, n = 28) and between carrier-specific IgG antibody at 2 months and MenC-specific hSBA/IgG antibody at 5 months (r = -0.4, P = 0.02 and 0.04, n = 32 and 23). Nonetheless, 90% of infants achieved protective MenC-hSBA titers after vaccination at 2 and 4 months of age. The levels of serogroup-specific meningococcal antibodies were low in mothers and 2-month-old infants. Immunizing mothers before or during pregnancy with meningococcal conjugate vaccines might increase antibody levels in early infancy and provide protection against infection due to N. meningitidis.

Toxicity Screening of the ToxCast Chemical Library Using a Zebrafish Developmental Assay

EPA Science Inventory

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...

ToxCast: One Step in the NRC Vision of 21st Century Toxicology

EPA Science Inventory

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...

Virtual Liver: Evaluating the Impact of Hepatic Microdosimetry for ToxCast Chemicals

EPA Science Inventory

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...

An Investigation Into Criteria Commonly Used by the FAA to Grant Relief to Part 135 Operators Under FAR Sections: 135.213, 135.219, and/or 135.225

NASA Technical Reports Server (NTRS)

Williams, Louis J.; Heck, Michael L.; Burgess, Malcolm A.; Stough, H. P. (Technical Monitor)

2002-01-01

The objective of this study was to determine the criteria commonly used by the FAA to grant waivers, exemptions, or deviations to FAR Part 135, Sections 135.213, 135.219, and 135.225 and the potential impact on Flight Information Services Data Link (FISDL) implementation. These aviation regulations address the requirements for the use of weather reports or forecasts when conducting operations under FAR Part 135. In this study a literature search was conducted to obtain historical records of requests for relief from the 3 FAR sections under consideration. The exemption request records were then analyzed in order to determine the reasons given by the FAA for either granting or denying the request. In addition, FAA personnel and Part 135 operators were interviewed to determine the procedures used for satisfying the requirements of the 3 FAR sections.

Evaluation of food-relevant chemicals in the ToxCast high-throughput screening program

EPA Science Inventory

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...

Chemical effects in biological systems (CEBS) object model for toxicology data, SysTox-OM: design and application.

PubMed

Xirasagar, Sandhya; Gustafson, Scott F; Huang, Cheng-Cheng; Pan, Qinyan; Fostel, Jennifer; Boyer, Paul; Merrick, B Alex; Tomer, Kenneth B; Chan, Denny D; Yost, Kenneth J; Choi, Danielle; Xiao, Nianqing; Stasiewicz, Stanley; Bushel, Pierre; Waters, Michael D

2006-04-01

The CEBS data repository is being developed to promote a systems biology approach to understand the biological effects of environmental stressors. CEBS will house data from multiple gene expression platforms (transcriptomics), protein expression and protein-protein interaction (proteomics), and changes in low molecular weight metabolite levels (metabolomics) aligned by their detailed toxicological context. The system will accommodate extensive complex querying in a user-friendly manner. CEBS will store toxicological contexts including the study design details, treatment protocols, animal characteristics and conventional toxicological endpoints such as histopathology findings and clinical chemistry measures. All of these data types can be integrated in a seamless fashion to enable data query and analysis in a biologically meaningful manner. An object model, the SysBio-OM (Xirasagar et al., 2004) has been designed to facilitate the integration of microarray gene expression, proteomics and metabolomics data in the CEBS database system. We now report SysTox-OM as an open source systems toxicology model designed to integrate toxicological context into gene expression experiments. The SysTox-OM model is comprehensive and leverages other open source efforts, namely, the Standard for Exchange of Nonclinical Data (http://www.cdisc.org/models/send/v2/index.html) which is a data standard for capturing toxicological information for animal studies and Clinical Data Interchange Standards Consortium (http://www.cdisc.org/models/sdtm/index.html) that serves as a standard for the exchange of clinical data. Such standardization increases the accuracy of data mining, interpretation and exchange. The open source SysTox-OM model, which can be implemented on various software platforms, is presented here. A universal modeling language (UML) depiction of the entire SysTox-OM is available at http://cebs.niehs.nih.gov and the Rational Rose object model package is distributed under an open

Measurements of the Fuel Mileage of a KC-135 Aircraft with and Without Winglets

NASA Technical Reports Server (NTRS)

Temanson, G. E.

1982-01-01

The KC-135A Winglet Flight Research and Demonstration Program was a joint effort of the Air Force, NASA and the Boeing Military Airplane Company to flight test winglets on the KC-135A. The primary objective of the program was to verify the cruise performance improvements predicted by analysis and wind tunnel tests. Flight test data were obtained for winglets positioned at 15 deg cant/-2 deg incidence, 0 deg cant/-4 deg incidence, 15 deg cant/-4 deg incidence and for winglets off (baseline). Both fuel mileage and drag measurements were obtained. The 15 deg cant/-4 deg incidence winglet configuration provided the greatest performance improvement. The flight test measured fuel mileage improvement for a 0.78 Mach number was 3.1 percent at 8 x 10(5) pounds W/delta and 5.5 percent at 1.05 x 10(6) pounds W/delta. Correcting the flight measured data for surface pressure differences between wind tunnel and flight resulted in a fuel mileage improvement of 4.4 percent at 8 x 10(5) pounds W/delta and 7.2 percent at 1.05 x 10(6) pounds W/delta. The agreement between the fuel mileage and drag data was excellent.

Predictive Signatures from ToxCast Data for Chronic, Developmental and Reproductive Toxicity Endpoints

EPA Science Inventory

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...

Using the US EPA's CompTox Dashboard to support identification and screening of emerging organic contaminants in the environment (ACS Spring National meeting) 2 of 7

EPA Science Inventory

The US EPA’s iCSS CompTox Dashboard is a curated, publicly accessible resource provided by the National Center for Computational Toxicology (https://comptox.epa.gov). The Dashboard provides support for toxicology and risk assessment within and external to the EPA (including ToxC...

The U.S. EPA's ToxCast Chemical Screening Program and Predictive Modeling of Toxicity

EPA Science Inventory

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-...

ToxCast: One Step in the NRC Vision of 21st Century Toxicology (T)

EPA Science Inventory

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...

ToxCast: One Step in the NRC Vision of 21st Century Toxicology (S)

EPA Science Inventory

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...

In Vitro Screening of Environmental Chemicals for Targeted Testing Prioritization: The ToxCast Project

EPA Science Inventory

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 ...

Predictive Signatures of Developmental Toxicity Modeled with HTS Data from ToxCast™ Bioactivity Profiles

EPA Science Inventory

The EPA ToxCast™ research program uses a high-throughput screening (HTS) approach for predicting the toxicity of large numbers of chemicals. Phase-I contains 309 well-characterized chemicals which are mostly pesticides tested in over 600 assays of different molecular targets, cel...

Overview of the ToxCast Research Program: Applications to Predictive Toxicology and Chemical Prioritization

EPA Science Inventory

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...

Heavy Metals in ToxCast: Relevance to Food Safety (SOT) ...

EPA Pesticide Factsheets

Human exposure to heavy metals occurs through food contamination due to industrial processes, vehicle emissions and farming methods. Specific toxicity endpoints have been associated with metal exposures, e.g. lead and neurotoxicity; however, numerous varieties of heavy metals have not been systematically examined for potential toxicities. We describe results from testing a large set of heavy metal-containing compounds in extensive suites of in vitro assays to suggest possible molecular initiating events in toxicity pathways. A broad definition of heavy metals that includes As, Se and organometallics or inorganic salts containing metals in Group III or higher (MW > 40) was used to identify 75 different compounds tested in the EPA’s ToxCast assays encompassing biochemical, cellular and model organism assays. These 75, plus an additional 100 metal-containing compounds, were tested in Tox21 quantitative high-throughput screening (qHTS) assays covering nuclear receptor and stress pathways. Known activities were confirmed such as activation of stress pathways and nuclear receptors (RXR, PPARg) as well as overt cytotoxicity. Specifically, organotin and organomercury were among the most potent of over 8K chemicals tested. The HTS results support known toxicities, including promiscuous GPCR activity for mercury compounds consistent with the neuropsychiatric effects seen in mercury poisoning (Mad Hatter’s Syndrome). As such, HTS approaches provide an efficient method

Evaluation of food-relevant chemicals in the ToxCast high ...

EPA Pesticide Factsheets

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

Developing Methods Using ToxCast Data for the Classification and Prioritization of Antimicrobials and Inerts

EPA Science Inventory

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' ...

High content screening of ToxCast compounds using Vala Sciences’ complex cell culturing systems (SOT)

EPA Science Inventory

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....

A genetic polymorphism in TOX3 is associated with survival of gastric cancer in a Chinese population.

PubMed

Zhang, Xiaojing; Zhu, Haixia; Wu, Xiaomin; Wang, Meilin; Gu, Dongying; Gong, Weida; Xu, Zhi; Tan, Yongfei; Gong, Yongling; Zhou, Jianwei; Tang, Cuiju; Tong, Na; Chen, Jinfei; Zhang, Zhengdong

2013-01-01

Recently, genetic polymorphism (rs3803662C>T) in TOX3 was reported to induce the risk of breast cancer. In this study, we hypothesized that rs3803662 could influence gastric cancer survival outcomes. With multiplex SNaPshot method, we genotyped TOX3 rs3803662 in 880 gastric patients with surgical resection. The association between genotype and survival outcomes was performed by the Kaplan-Meier method, Cox regression analysis models and the log-rank test. There was no association in the analyses of rs3803662 and survival of gastric cancer. However, the stratified analysis by histology showed that rs3803662 CT/TT genotype was associated with a significantly better survival for diffuse-type gastric cancer (log-rank p = 0.030, hazard ratio [HR]  = 0.67, 95% confidence interval [CI]  = 0.46-0.96), than the CC genotype. In addition, this favorable effect was especially obvious among gastric cancer patients with tumor size >5 cm, T3 and T4 depth of invasion, lymph node metastasis, no drinking, no distant metastasis, no chemotherapy and gastric cardia cancer. TOX3 rs3803662 might play an important role in the prognostic outcome and treatment of gastric cancer, especially perhaps further help in explaining the reduced risk of death associated with diffuse-type gastric cancer.

Evaluation of Compatibility of ToxCast High-Throughput/High-Content Screening Assays with Engineered Nanomaterials

EPA Science Inventory

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...

In Vitro Testing of Engineered Nanomaterials in the EPA’s ToxCast Program (WC9)

EPA Science Inventory

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...

Overview of the ToxCast Research Program: Applications to Predictive Toxicology and Chemical Prioritization (SETAC)

EPA Science Inventory

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...

Using high-content imaging data from ToxCast to analyze toxicological tipping points (TDS)

EPA Science Inventory

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...

ToxPlorerTM: A Comprehensive Knowledgebase of Toxicity Pathways Using Ontology-driven Information Extraction

EPA Science Inventory

Realizing the potential of pathway-based toxicity testing requires a fresh look at how we describe phenomena leading to adverse effects in vivo, how we assess them in vitro and how we extrapolate them in silico across chemicals, doses and species. We developed the ToxPlorer™ fram...

Critical appraisal of a quadrivalent CRM197 conjugate vaccine against meningococcal serogroups A, C W-135 and Y (Menveo®) in the context of treatment and prevention of invasive disease

PubMed Central

Bröker, Michael; Cooper, Brian; DeTora, Lisa M; Stoddard, Jeffrey J

2011-01-01

Worldwide, invasive meningococcal disease affects about 500,000 people annually. Case fatality in developed countries averages 10%, and higher rates are reported in less prosperous regions. According to the World Health Organization, the most important pathogenic serogroups are A, B, C, W-135, X, and Y. Clinical features of invasive meningococcal disease make diagnosis and management difficult. Antibiotic measures are recommended for prophylaxis after exposure and for treatment of invasive meningococcal disease cases; however, resistant strains may be emerging. Vaccines are generally regarded as the best preventative measure for invasive meningococcal disease. Polysaccharide vaccines against serogroups A, C, W-135, and Y using protein conjugation technology have clear advantages over older plain polysaccharide formulations without a protein component. The first quadrivalent meningococcal conjugate vaccine (MenACWY-D) was licensed in the US in 2005. More recently, MenACWY-CRM (Menveo®) was licensed in Europe, the US, the Middle East, and Latin America. MenACWY-CRM uses cross-reactive material 197, a nontoxic mutant of diphtheria toxin, as the carrier protein. MenACWY-CRM offers robust immunogenicity in all age groups, with a tolerability profile similar to that of a plain polysaccharide vaccine. Given its potential for protecting persons from infancy to old age, MenACWY-CRM offers the opportunity to protect broad populations against invasive meningococcal disease. The most optimal strategy for use of the vaccine has to be assessed country by country on the basis of local epidemiology, individual health care systems, and need. PMID:21904459

Neurospora crassa tox-1 Gene Encodes a pH- and Temperature-Tolerant Mini-Cellulase.

PubMed

Xiao, Yue; Zhang, Qiongsi; Luo, Yiquan; Zhang, Ying; Luo, Xi; Wang, Yuchuan; Cao, Weiguo; Pinto, Vito De; Liu, Qiuyun; Li, Gang

2016-06-15

Cellulases that endure extreme conditions are essential in various industrial sectors. This study reports a mini-cellulase gene tox-1 from Neurospora crassa. The gene tox-1 was cloned in Escherichia coli after chimerization with the YebF gene and substitutions of certain isoleucine and valine with leucine residues. The yeast transformants could grow on rice straw-agar medium. The 44-amino acid peptide and its two mutant variants displayed potent cellulase activities in Congo Red assay and enzymatic assays. Conservative replacements with leucine have substantially increased the stabilities and half-lives of the peptides at alkaline pH and low and high temperatures and also the tolerance to organic solvents and surfactants, on the basis of activities toward cellose. The small size of the mini-cellulase would allow for commercially viable automatic chemical peptide synthesis. This work suggests that conservative leucine replacements may serve as a general strategy in the engineering of more robust enzymes with special features with little loss of activities.

20170824 - A New Tox21 Strategic Plan and the Integration of EPA Science (WC10)

EPA Science Inventory

The predominant focus of Tox21 collaboration has been on developing and applying high-throughput in vitro screening to hazard identification and dose-response. To remain relevant, the interagency collaboration must broaden its focus to developing new predictive toxicology testing...

FORUM - FutureTox II: In vitro Data and In Silico Models for Predictive Toxicology

EPA Science Inventory

FutureTox II, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in January, 2014. The meeting goals were to review and discuss the state of the science in toxicology in the context of implementing the NRC 21st century vision of predicting in vivo resp...

Evaluating ToxCast™ High-Throughput Assays For Their Ability To Detect Direct-Acting Genotoxicants

EPA Science Inventory

A standard battery of tests has been in use for the several decades to screen chemicals for genotoxicity. However, the large number of environmental and industrial chemicals that need to be tested overwhelms our ability to test them. ToxCast™ is a multi-year effort to develop a ...

Use of Chemotypes for Profiling and Exploring the ToxCast Chemical-Assay Landscape (ACS Spring meeting)

EPA Science Inventory

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 ...

Identifying Toxicity Pathways with ToxCast High-Throughput Screening and Applications to Predicting Developmental Toxicity

EPA Science Inventory

Results from rodent and non-rodent prenatal developmental toxicity tests for over 300 chemicals have been curated into the relational database ToxRefDB. These same chemicals have been run in concentration-response format through over 500 high-throughput screening assays assessin...

Probing the ToxCastTM Chemical Library for Predictive Signatures of Developmental Toxicity -NLTO Poster

EPA Science Inventory

EPA’s ToxCast™ project is profiling the in vitro bioactivity of chemical compounds to assess pathway-level and cell-based signatures that correlate with observed in vivo toxicity. We hypothesize that cell signaling pathways are primary targets for diverse environmental chemicals ...

Validation, acceptance, and extension of a predictive model of reproductive toxicity using ToxCast data

EPA Science Inventory

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...

The US EPAs ToxCast Program for the Prioritization and Prediction of Environmental Chemical Toxicity

EPA Science Inventory

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 ...

Chemical and Biological Profiling Approaches for Exploring Mutagenicity and Carcinogenicity of EPA ToxCast Chemicals

EPA Science Inventory

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-...

Prioritizing Environmental Chemicals for Obesity and Diabetes Outcomes Research: A Screening Approach Using ToxCast™ High-Throughput Data.

PubMed

Auerbach, Scott; Filer, Dayne; Reif, David; Walker, Vickie; Holloway, Alison C; Schlezinger, Jennifer; Srinivasan, Supriya; Svoboda, Daniel; Judson, Richard; Bucher, John R; Thayer, Kristina A

2016-08-01

Diabetes and obesity are major threats to public health in the United States and abroad. Understanding the role that 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 challenging. This review is intended to help researchers generate hypotheses about chemicals that may contribute to diabetes and to obesity-related health outcomes by summarizing relevant findings from the U.S. Environmental Protection Agency (EPA) ToxCast™ high-throughput screening (HTS) program. Our aim was to develop new hypotheses around environmental chemicals of potential interest for diabetes- or obesity-related outcomes using high-throughput screening data. We identified ToxCast™ assay targets relevant to several biological processes related to diabetes and obesity (insulin sensitivity in peripheral tissue, pancreatic islet and β cell function, adipocyte differentiation, and feeding behavior) and presented chemical screening data against those assay targets to identify chemicals of potential interest. The 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 by research papers and reviews published in the peer-reviewed literature. Testing hypotheses based on ToxCast™ data will also help assess the predictive utility of this HTS platform. More research is required to put these screening-level analyses into context, but the information presented in this review should facilitate the development of new hypotheses. Auerbach S, Filer D, Reif D, Walker V, Holloway AC, Schlezinger J, Srinivasan S, Svoboda D, Judson R, Bucher JR, Thayer KA. 2016. Prioritizing environmental chemicals for obesity and diabetes outcomes research: a screening approach using ToxCast™ high-throughput data. Environ

Herbal medicine Inchin-ko-to (TJ-135) prevents liver fibrosis and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet.

PubMed

Sakaida, Isao; Tsuchiya, Masako; Kawaguchi, Kotarou; Kimura, Teruaki; Terai, Shuji; Okita, Kiwamu

2003-06-01

The herbal medicine Inchin-ko-to (TJ-135), extract power from three herbs, has recently been reported possessing anti-apoptotic activity. The aim of this study was to investigate whether TJ-135 has any influence on the development of preneoplastic lesions as well as liver fibrosis. The effects of the TJ-135 were examined using the choline-deficient L-amino acid-defined diet-induced liver fibrosis model. In addition, the effect of TJ-135 on mitogen-activated protein (MAP) kinase, type III procollagen mRNA expression and the medium N-terminal procollagen III propeptide (PIIINP) concentration in a hepatic stellate cell line (LI90) were examined. TJ-135 prevented fibrosis in a dose-dependent manner up to 1.5% (w/w). TJ-135 also reduced the expression of type III procollagen mRNA in the liver, as well as the number of activated stellate cells. Furthermore, TJ-135 reduced the area of preneoplastic lesions in the liver. With LI90 cells, TJ-135 reduced MAP kinase (ERK and JNK but not P38) activities resulting in reduced type III procollagen mRNA and PIIINP concentrations in the medium in a dose-dependent manner. These results indicate that although TJ-135 has anti-apoptotic activity, TJ-135 does not increase preneoplastic lesions but significantly reduces liver fibrosis through the inhibition of stellate cell activation without a reduction of hepatocyte cell death.

Assessment of ToxCast Phase II for Mitochondrial Liabilities Using a High-Throughput Respirometric Assay

PubMed Central

Wills, Lauren P.; Beeson, Gyda C.; Hoover, Douglas B.; Schnellmann, Rick G.; Beeson, Craig C.

2015-01-01

Previous high-throughput screens to identify mitochondrial toxicants used immortalized cell lines and focused on changes in mitochondrial membrane potential, which may not be sufficient and do not identify different types of mitochondrial dysfunction. Primary cultures of renal proximal tubule cells (RPTC) were examined with the Seahorse Extracellular Flux Analyzer to screen 676 compounds (5 μM; 1 h) from the ToxCast Phase II library for mitochondrial toxicants. Of the 676 compounds, 19 were classified as cytotoxicants, 376 were electron transport chain (ETC) inhibitors, and 5 were uncouplers. The remaining 276 compounds were examined after a 5-h exposure to identify slower acting mitochondrial toxicants. This experiment identified 3 cytotoxicants, 110 ETC inhibitors, and 163 compounds with no effect. A subset of the ToxCast Phase II library was also examined in immortalized human renal cells (HK2) to determine differences in susceptibility to mitochondrial toxicity. Of the 131 RPTC ETC inhibitors tested, only 14 were ETC inhibitors in HK2 cells. Of the 5 RPTC uncouplers, 1 compound was an uncoupler in HK2 cells. These results demonstrate that 73% (491/676) of the compounds in the ToxCast Phase II library compounds exhibit RPTC mitochondrial toxicity, overwhelmingly ETC inhibition. In contrast, renal HK2 cells are markedly less sensitive and only identified 6% of the compounds as mitochondrial toxicants. We suggest caution is needed when studying mitochondrial toxicity in immortalized cell lines. This information will provide mechanisms and chemical-based criteria for assessing and predicting mitochondrial liabilities of new drugs, consumer products, and environmental agents. PMID:25926417

Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX)

Integrated Risk Information System (IRIS)

Hexahydro - 1,3,5 - trinitro - 1,3,5 - triazine ( RDX ) ; CASRN 121 - 82 - 4 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health

Identifying Functionally Linked Gene Modules Within Biological Pathways Assessed by ToxCast In Vitro Assays

EPA Science Inventory

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...

Developing predictions of in vivo developmental toxicity of ToxCast chemicals using mouse embryonic stem cells.

EPA Science Inventory

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...

Chemical-Gene Interactions from ToxCast Bioactivity Data Expands Universe of Literature Network-Based Associations (SOT)

EPA Science Inventory

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....

Application of ToxCast to evaluate potential biological effects from organic contaminants in Great Lakes tributaries

EPA Science Inventory

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...

20180318 - Using the US EPA's CompTox Chemistry Dashboard for structure identification and non-targeted analyses (ACS Spring)

EPA Science Inventory

The CompTox Chemistry Dashboard provides access to data for ~760,000 chemicals. High quality curated data and rich metadata facilitates mass spec analysis. “MS-Ready” processed data enables structure identification.

STS_135_Landing

NASA Image and Video Library

2011-07-21

NASA astronaut Chris Ferguson, STS-135 commander, examines the thermal tiles of the orbiter after the space shuttle Atlantis landed at the Kennedy Space Center in Florida completing STS-135, the final mission of the NASA shuttle program, on Thursday, July 21, 2011. ( NASA Photo / Houston Chronicle, Smiley N. Pool )

Building an Adverse Outcome Pathway Framework through HTS Data and Literature Mining Integration (FutureToxII)

EPA Science Inventory

Interpreting EPA’s ToxCast in vitro assay data in the context of Adverse Outcome Pathway (AOP) development is a significant challenge. While chemical activation in these assays may shed light on the molecular initiating event, the downstream effect of these activities at higher ...

Extrapolation of mammalian-based ToxCast assay results to non-mammalian species to evaluate endocrine disruption

EPA Science Inventory

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...

Profiling Developmental Toxicity of 387 Environmental Chemicals using EPA’s Toxicity Reference Database (ToxRefDB)

EPA Science Inventory

EPA's Toxicity Reference Databases (ToxRefDB) was developed by the National Center for Computational Toxicology in partnership with EPA's Office of Pesticide Programs, to store data derived from in vivo animal toxicity studies [www.epa.gov/ncct/toxrefdb/]. The initial build of To...

Prioritizing Environmental Chemicals for Obesity and Diabetes Outcomes Research: A Screening Approach Using ToxCast™ High-Throughput Data

PubMed Central

Auerbach, Scott; Filer, Dayne; Reif, David; Walker, Vickie; Holloway, Alison C.; Schlezinger, Jennifer; Srinivasan, Supriya; Svoboda, Daniel; Judson, Richard; Bucher, John R.; Thayer, Kristina A.

2016-01-01

Background: Diabetes and obesity are major threats to public health in the United States and abroad. Understanding the role that 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 challenging. This review is intended to help researchers generate hypotheses about chemicals that may contribute to diabetes and to obesity-related health outcomes by summarizing relevant findings from the U.S. Environmental Protection Agency (EPA) ToxCast™ high-throughput screening (HTS) program. Objectives: Our aim was to develop new hypotheses around environmental chemicals of potential interest for diabetes- or obesity-related outcomes using high-throughput screening data. Methods: We identified ToxCast™ assay targets relevant to several biological processes related to diabetes and obesity (insulin sensitivity in peripheral tissue, pancreatic islet and β cell function, adipocyte differentiation, and feeding behavior) and presented chemical screening data against those assay targets to identify chemicals of potential interest. Discussion: The 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 by research papers and reviews published in the peer-reviewed literature. Testing hypotheses based on ToxCast™ data will also help assess the predictive utility of this HTS platform. Conclusions: More research is required to put these screening-level analyses into context, but the information presented in this review should facilitate the development of new hypotheses. Citation: Auerbach S, Filer D, Reif D, Walker V, Holloway AC, Schlezinger J, Srinivasan S, Svoboda D, Judson R, Bucher JR, Thayer KA. 2016. Prioritizing environmental chemicals for obesity and diabetes outcomes research

ToxPi GUI: An interactive visualization tool for transparent integration of data from diverse sources of evidence

EPA Science Inventory

Motivation: Scientists and regulators are often faced with complex decisions, where use of scarce resources must be prioritized using collections of diverse information. The Toxicological Prioritization Index (ToxPi™) was developed to enable integration of multiple sources of evi...

14 CFR 135.201 - Applicability.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Applicability. 135.201 Section 135.201 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR CARRIERS... Limitations and Weather Requirements § 135.201 Applicability. This subpart prescribes the operating...

14 CFR 135.201 - Applicability.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Applicability. 135.201 Section 135.201 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR CARRIERS... Limitations and Weather Requirements § 135.201 Applicability. This subpart prescribes the operating...

14 CFR 135.201 - Applicability.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false Applicability. 135.201 Section 135.201 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR CARRIERS... Limitations and Weather Requirements § 135.201 Applicability. This subpart prescribes the operating...

14 CFR 135.201 - Applicability.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false Applicability. 135.201 Section 135.201 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR CARRIERS... Limitations and Weather Requirements § 135.201 Applicability. This subpart prescribes the operating...

14 CFR 135.201 - Applicability.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Applicability. 135.201 Section 135.201 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR CARRIERS... Limitations and Weather Requirements § 135.201 Applicability. This subpart prescribes the operating...

NCCT ToxCast Program for Nanomaterial Prioritization: High-Throughput Screening, Consideration of Exposure, and Bioactivity Profiling/Modeling

EPA Science Inventory

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...

ToxCast Phase I

EPA Pesticide Factsheets

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

Toxicity Screening of the ToxCast Phase II Chemical Library Using a Zebrafish Developmental Assay (SOT)

EPA Science Inventory

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...

Human Pluripotent Stem Cell-Based Assay Predicts Developmental Toxicity Potential of ToxCast Chemicals (ACT meeting)

EPA Science Inventory

Worldwide initiatives to screen for toxicity potential among the thousands of chemicals currently in use require inexpensive and high-throughput in vitro models to meet their goals. The devTOX quickPredict platform is an in vitro human pluripotent stem cell-based assay used to as...

Tox21: Putting a Lens on the Vision of Toxicity Testing in the 21st Century

EPA Science Inventory

In response to the release of the NRC report on "Toxicity Testing in the 21st Century, a Vision and Strategy" (NRC, 2007), two NIH institutes and EPA formed a collaboration (Tox21) to 1) identify mechanisms of chemically induced biological activity, 2) prioritize chemicals for mo...

Phase I/II, open-label trial of safety and immunogenicity of meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine in human immunodeficiency virus-infected adolescents.

PubMed

Siberry, George K; Williams, Paige L; Lujan-Zilbermann, Jorge; Warshaw, Meredith G; Spector, Stephen A; Decker, Michael D; Heckman, Barbara E; Demske, Emily F; Read, Jennifer S; Jean-Philippe, Patrick; Kabat, William; Nachman, Sharon

2010-05-01

Quadrivalent meningococcal polysaccharide conjugate vaccine (MCV4) is routinely recommended for healthy youth in the United States, but there are no data about its use in HIV-infected people. P1065 is a Phase I/II trial of MCV4 safety and immunogenicity in HIV-infected children and youth performed at 27 US sites of the IMPAACT network. All youth (11-24 years old) received 1 dose of open-label MCV4 at entry. Standardized questionnaires were used to evaluate safety. Baseline protective immunity was defined as rabbit serum bactericidal antibody (rSBA) titer > or = 1:128. Immunogenic response was defined as a > or = 4-fold rise in rSBA against each meningococcal serogroup. Multivariable logistic regression analysis was used to evaluate the association of demographic and clinical characteristics on immunogenic response to serogroup C. Among 319 subjects who received MCV4, 10 (3.1%) reported immediate adverse events which were local and mild, and 7 (2.2%) experienced Grade > or = 3 adverse events, unrelated to vaccine. The 305 subjects with serologic data had a median age of 17 years and were 59% male, 50% Black, and 38% Latino. Subjects were stratified by entry CD4%: 12%, CD4 <15%; 40%, 15% to 24%; and 48%, > or = 25%. Baseline protective immunity varied by serogroup: A, 41%; C, 11%; W-135, 15%; Y, 35% The immunogenic response rates to serogroups A, C, W-135, and Y were 68%, 52%, 73%, and 63%, respectively. In multivariable logistic regression models, lower entry CD4%, higher entry viral load, and CDC Class B/C diagnosis were associated with significantly lower odds of response to serogroup C. Many HIV-infected youth naturally acquire meningococcal immunity. MCV4 is safe and immunogenic in HIV-infected youth, but response rates are lower than in healthy youth, particularly for those with more advanced HIV clinical, immunologic, and virologic status.

14 CFR 121.135 - Contents.

Code of Federal Regulations, 2010 CFR

2001-01-01

... 14 Aeronautics and Space 2 2001-01-01 2001-01-01 false Contents. 121.135 Section 121.135 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (Continued) AIR CARRIERS..., FLAG, AND SUPPLEMENTAL OPERATIONS Manual Requirements § 121.135 Contents. (a) Each manual required by...

28 CFR 115.135 - [Reserved

Code of Federal Regulations, 2012 CFR

2012-07-01

... 28 Judicial Administration 2 2012-07-01 2012-07-01 false [Reserved] 115.135 Section 115.135 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) PRISON RAPE ELIMINATION ACT NATIONAL STANDARDS Standards for Lockups Training and Education § 115.135 [Reserved] Screening for Risk of Sexual Victimization...

28 CFR 115.135 - [Reserved

Code of Federal Regulations, 2014 CFR

2014-07-01

... 28 Judicial Administration 2 2014-07-01 2014-07-01 false [Reserved] 115.135 Section 115.135 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) PRISON RAPE ELIMINATION ACT NATIONAL STANDARDS Standards for Lockups Training and Education § 115.135 [Reserved] Screening for Risk of Sexual Victimization...

28 CFR 115.135 - [Reserved

Code of Federal Regulations, 2013 CFR

2013-07-01

... 28 Judicial Administration 2 2013-07-01 2013-07-01 false [Reserved] 115.135 Section 115.135 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) PRISON RAPE ELIMINATION ACT NATIONAL STANDARDS Standards for Lockups Training and Education § 115.135 [Reserved] Screening for Risk of Sexual Victimization...

Reserch of the gene polymorphism TOX3 / LOC643714 and the risk of breast cancer development in persons exposed to ionizing radiation after Chornobyl disaster.

PubMed

Polinyk, S I; Rybchenko, L A; Klimyk, B T

2017-12-01

The objective of this work was to identify and compare the polymorphism of the rs3803662 polymorphism of the TOX3/LOC643714 gene in breast cancer patients who have undergone ionizing radiation due to the Chornobyl accident and in patients without ionizing radiation (IR) in the history. The determination of the rs3803662 polymorphism of the TOX3/LOC643714 gene was per formed by polymerase chain reaction (PCR) in 83 patients with breast cancer: 42 subjects who were exposed to ion izing radiation due to the Chornobyl accident, 41 people without ionizing radiation in history and 17 controls in Ukraine without cancer pathology. In order to compare the obtained data on spontaneous and radiation associated breast cancer and to calculate the differences in the frequencies of alleles and the risk of oncopathology, data from literature on control groups of the populations of the Russian Federation, Sweden, and the United Kingdom were used. Comparing with the literature data and the group of exposed subjects, the homozygous carriers of the minor alleles of the TOX3/LOC643714 ТТ gene revealed an increased risk of developing breast cancer: OR = 2.89, p = 0.02 (CI 95% 1.17 7,16). In subjects without the influence of IR in history, the carrier of homozygous minor axis of the gene TOX3/LOC643714 ТТ is also associated with the risk of breast cancer: OR = 3.83, p = 0.0002 (CI 95% 0.82-14.14). In the homozygous carriers of the minor alleles of the TOX3 / LOC643714 gene exposed to IR, there was no increase in the risk of developing breast cancer (OR = 0.65, p = 0.46, CI 95% 0.21-2.04) compared with the con trol group of Ukrainian population. The carrier of homozygous minor alleles of the TOX3/LOC643714 gene is not a risk factor for the devel opment of breast cancer under conditions of exposure to ionizing radiation in the study group of the Ukrainian population. S. I. Polinyk, L. A. Rybchenko, B. T. Klimyk.

STS_135_CEIT

NASA Image and Video Library

2011-04-07

JSC2011-E-040358 (7 April 2011) --- NASA astronaut Doug Hurley, STS-135 pilot, exits the hatch of the space shuttle Atlantis during the STS-135 Crew Equipment Interface Test (CEIT) in the Orbiter Processing Facility at NASA?s Kennedy Space Center, Florida on April 7, 2011. Photo credit: NASA Photo/Houston Chronicle, Smiley N. Pool

33 CFR 135.101 - Purpose.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 2 2011-07-01 2011-07-01 false Purpose. 135.101 Section 135.101 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE POLLUTION FINANCIAL RESPONSIBILITY AND COMPENSATION OFFSHORE OIL POLLUTION COMPENSATION FUND Levy of Fees § 135.101...

33 CFR 135.101 - Purpose.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Purpose. 135.101 Section 135.101 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE POLLUTION FINANCIAL RESPONSIBILITY AND COMPENSATION OFFSHORE OIL POLLUTION COMPENSATION FUND Levy of Fees § 135.101...

33 CFR 135.101 - Purpose.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 33 Navigation and Navigable Waters 2 2014-07-01 2014-07-01 false Purpose. 135.101 Section 135.101 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE POLLUTION FINANCIAL RESPONSIBILITY AND COMPENSATION OFFSHORE OIL POLLUTION COMPENSATION FUND Levy of Fees § 135.101...

33 CFR 135.101 - Purpose.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 33 Navigation and Navigable Waters 2 2013-07-01 2013-07-01 false Purpose. 135.101 Section 135.101 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE POLLUTION FINANCIAL RESPONSIBILITY AND COMPENSATION OFFSHORE OIL POLLUTION COMPENSATION FUND Levy of Fees § 135.101...

33 CFR 135.101 - Purpose.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 33 Navigation and Navigable Waters 2 2012-07-01 2012-07-01 false Purpose. 135.101 Section 135.101 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE POLLUTION FINANCIAL RESPONSIBILITY AND COMPENSATION OFFSHORE OIL POLLUTION COMPENSATION FUND Levy of Fees § 135.101...

Mechanism-based genotoxicity screening of metal oxide nanoparticles using the ToxTracker panel of reporter cell lines.

PubMed

Karlsson, Hanna L; Gliga, Anda R; Calléja, Fabienne M G R; Gonçalves, Cátia S A G; Wallinder, Inger Odnevall; Vrieling, Harry; Fadeel, Bengt; Hendriks, Giel

2014-09-02

The rapid expansion of manufacturing and use of nano-sized materials fuels the demand for fast and reliable assays to identify their potential hazardous properties and underlying mechanisms. The ToxTracker assay is a recently developed mechanism-based reporter assay based on mouse embryonic stem (mES) cells that uses GFP-tagged biomarkers for detection of DNA damage, oxidative stress and general cellular stress upon exposure. Here, we evaluated the ability of the ToxTracker assay to identify the hazardous properties and underlying mechanisms of a panel of metal oxide- and silver nanoparticles (NPs) as well as additional non-metallic materials (diesel, carbon nanotubes and quartz). The metal oxide- and silver nanoparticles were characterized in terms of agglomeration and ion release in cell medium (using photon cross correlation spectroscopy and inductively coupled plasma with optical emission spectroscopy, respectively) as well as acellular ROS production (DCFH-DA assay). Cellular uptake was investigated by means of transmission electron microscopy. GFP reporter induction and cytotoxicity of the NPs was simultaneously determined using flow cytometry, and genotoxicity was further tested using conventional assays (comet assay, γ-H2AX and RAD51 foci formation). We show that the reporter cells were able to take up nanoparticles and, furthermore, that exposure to CuO, NiO and ZnO nanoparticles as well as to quartz resulted in activation of the oxidative stress reporter, although only at high cytotoxicity for ZnO. NiO NPs activated additionally a p53-associated cellular stress response, indicating additional reactive properties. Conventional assays for genotoxicity assessment confirmed the response observed in the ToxTracker assay. We show for CuO NPs that the induction of oxidative stress is likely the consequence of released Cu ions whereas the effect by NiO was related to the particles per se. The DNA replication stress-induced reporter, which is most strongly

5 CFR 838.135 - Settlements.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Settlements. 838.135 Section 838.135 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) COURT... § 838.135 Settlements. (a) OPM must comply with the terms of a properly filed court order acceptable for...

22 CFR 135.30 - Changes.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Changes. 135.30 Section 135.30 Foreign... AGREEMENTS TO STATE AND LOCAL GOVERNMENTS Post-Award Requirements Changes, Property, and Subawards § 135.30 Changes. (a) General. Grantees and subgrantees are permitted to rebudget within the approved direct cost...

FORUM - FutureTox II: In vitro Data and In Silico Models for ...

EPA Pesticide Factsheets

FutureTox II, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in January, 2014. The meeting goals were to review and discuss the state of the science in toxicology in the context of implementing the NRC 21st century vision of predicting in vivo responses from in vitro and in silico data, and to define the goals for the future. Presentations and discussions were held on priority concerns such as predicting and modeling of metabolism, cell growth and differentiation, effects on sensitive subpopulations, and integrating data into risk assessment. Emerging trends in technologies such as stem cell-derived human cells, 3D organotypic culture models, mathematical modeling of cellular processes and morphogenesis, adverse outcome pathway development, and high-content imaging of in vivo systems were discussed. Although advances in moving towards an in vitro/in silico based risk assessment paradigm were apparent, knowledge gaps in these areas and limitations of technologies were identified. Specific recommendations were made for future directions and research needs in the areas of hepatotoxicity, cancer prediction, developmental toxicity, and regulatory toxicology. This article reports on the outcome of FutureTox II1,2, the second in a series of Society of Toxicology (SOT) Contemporary Concepts in Toxicology (CCT) Workshops, which was attended by invitees and participants from governmental and regulatory agencies, research institutes, academ

21 CFR 135.3 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Definitions. 135.3 Section 135.3 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION FROZEN DESSERTS General Provisions § 135.3 Definitions. For the purposes of this part, a...

STS-135_VMS

NASA Image and Video Library

2011-03-02

JSC2011-E-040204 (2 March 2011) --- NASA astronaut Chris Ferguson, STS-135 commander, prepares for departure from Moffett Field in a T-38 trainer home to Houston after the crew of STS-135 trained in the Vertical Motion Simulator (VMS) at NASA's Ames Research Center in Mountain View, Calif. on March 2, 2011, Photo credit: NASA Photo/Houston Chronicle, Smiley N. Pool

STS_135_CEIT

NASA Image and Video Library

2011-04-08

JSC2011-E-040366 (8 April 2011) --- Close-up photo of tools taken during the STS-135 crew members' inspection of the equipment they will use in space. The inspection was part of the STS-135 Crew Equipment Interface Test (CEIT) conducted April 8, 2011 at NASA?s Kennedy Space Center in Florida. Photo credit: NASA Photo/Houston Chronicle, Smiley N. Pool

The SED-TOX: Toxicity-directed management tool to assess and rank sediments based on their hazard -- concept and application

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bombardier, M.; Bermingham, N.

1999-04-01

This article introduces the sediment Toxicity (SED-TOX) Index for the assessment and ranking of toxic hazards in sediment. Major features include expression of toxicity responses on a single scale of measurement (dry weight-based toxic units), consideration of multiple routes of exposure (pore water, organic extract, wet sediment, and whole sediment), application of differential treatments to toxicity data depending on the level of response, and use of weighting factors to discriminate sediment exposure phases and effect endpoints on the basis of sensitivity. A battery of seven bioassays with four test species (Vibrio fischeri, Escherichia coli, Lytechinus pictus, and Amphiporeia virginiana) wasmore » conducted on 49 marine sediment samples collected from six sites at Anse-a-Beaufils and Cap-aux-Meules, which are in the Gulf of St. Lawrence. The SED-TOX scores were calculated for each sampling station and compared with sediment contaminant concentrations. Results indicate that physico-chemical characterization is not sufficient to assess contaminated-sediment hazard for organisms; furthermore, using several exposure phases and test species belonging to various trophic levels increases the possibility of correctly identifying toxic sediments. The results of this study indicate that the SED-TOX approach is valuable as a toxicity assessment and ranking tool for sediments. It could easily be combined with other measures of ecosystem disturbance to discriminate between polluted and unpolluted sites.« less

40 CFR 135.1 - Purpose.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 22 2014-07-01 2013-07-01 true Purpose. 135.1 Section 135.1 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS PRIOR NOTICE OF CITIZEN SUITS Prior Notice Under the Clean Water Act § 135.1 Purpose. (a) Section 505(a)(1) of the Clean Water...

40 CFR 135.1 - Purpose.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 22 2011-07-01 2011-07-01 false Purpose. 135.1 Section 135.1 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS PRIOR NOTICE OF CITIZEN SUITS Prior Notice Under the Clean Water Act § 135.1 Purpose. (a) Section 505(a)(1) of the Clean Water...

40 CFR 135.1 - Purpose.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 21 2010-07-01 2010-07-01 false Purpose. 135.1 Section 135.1 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS PRIOR NOTICE OF CITIZEN SUITS Prior Notice Under the Clean Water Act § 135.1 Purpose. (a) Section 505(a)(1) of the Clean Water...

40 CFR 135.1 - Purpose.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 23 2012-07-01 2012-07-01 false Purpose. 135.1 Section 135.1 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS PRIOR NOTICE OF CITIZEN SUITS Prior Notice Under the Clean Water Act § 135.1 Purpose. (a) Section 505(a)(1) of the Clean Water...

49 CFR 213.135 - Switches.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 49 Transportation 4 2012-10-01 2012-10-01 false Switches. 213.135 Section 213.135 Transportation... TRANSPORTATION TRACK SAFETY STANDARDS Track Structure § 213.135 Switches. (a) Each stock rail must be securely seated in switch plates, but care shall be used to avoid canting the rail by overtightening the rail...

49 CFR 213.135 - Switches.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 49 Transportation 4 2013-10-01 2013-10-01 false Switches. 213.135 Section 213.135 Transportation... TRANSPORTATION TRACK SAFETY STANDARDS Track Structure § 213.135 Switches. (a) Each stock rail must be securely seated in switch plates, but care shall be used to avoid canting the rail by overtightening the rail...

49 CFR 213.135 - Switches.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 4 2014-10-01 2014-10-01 false Switches. 213.135 Section 213.135 Transportation... TRANSPORTATION TRACK SAFETY STANDARDS Track Structure § 213.135 Switches. (a) Each stock rail must be securely seated in switch plates, but care shall be used to avoid canting the rail by overtightening the rail...

Inferring Toxicological Responses of HepG2 Cells from ToxCast High Content Imaging Data (SOT)

EPA Science Inventory

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...

Building Structure Feature-based Models for Predicting Isoform-specific Human Cytochrome P-450 (hCYP 3A4, 2D6 and 2C9) Inhibition Assay Results in ToxCast

EPA Science Inventory

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...

STS_135_STA

NASA Image and Video Library

2011-05-31

JSC2011-E-059480 (31 May 2011) --- NASA astronaut Sandy Magnus, STS-135 mission specialist, is seen on May 31 in the rear station of a T-38 which had been piloted by astronaut Doug Hurley, STS-135 pilot, and is now sitting just off the runway following arrival at NASA?s Kennedy Space Center in Florida. Photo credit: NASA Photo/Houston Chronicle, Smiley N. Pool

Public Access to Environmental Chemistry Data via the CompTox Chemistry Dashboard (ACS Fall Meeting 6 of 12)

EPA Science Inventory

The National Center for Computational Toxicology (NCCT) has assembled and delivered an enormous quantity and diversity of data for the environmental sciences through the CompTox Chemistry Dashboard. These data include high-throughput in vitro screening data, in vivo and functiona...

The ToxCast Pathway Database for Identifying Toxicity Signatures and Potential Modes of Action from Chemical Screening Data

EPA Science Inventory

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 ...

Linking ToxCast Signatures with Functional Consequences: Proof-of-Concept Study using Known Inhibitors of Vascular Development

EPA Science Inventory

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...

STS_135_NBL

NASA Image and Video Library

2011-03-10

JSC2011-E-040220 (10 March 2011) --- NASA astronaut Rex Walheim (left), STS-135 mission specialist, and astronaut Mike Fossum are aided by divers as they work in a mock-up of the space shuttle's payload bay as the crew of STS-135 trains for a spacewalk in the Neutral Buoyancy Laboratory near NASA?s Johnson Space Center on March 10, 2011. Photo credit: NASA Photo/Houston Chronicle, Smiley N. Pool

STS_135_NBL

NASA Image and Video Library

2011-03-10

JSC2011-E-040218 (10 March 2011) --- NASA astronaut Rex Walheim, STS-135 mission specialist, is aided by divers as he works with astronaut Mike Fossum in a mock-up of the space shuttle's payload bay as the crew of STS-135 trains for a spacewalk in the Neutral Buoyancy Laboratory near NASA?s Johnson Space Center on March 10, 2011. Photo credit: NASA Photo/Houston Chronicle, Smiley N. Pool

(ENVIRONMENTAL SCIENCE and TECHNOLOGY) An Intuitive Approach for Predicting Human Risk with the Tox21 10k Library

EPA Science Inventory

In vitro to in vivo extrapolation (IVIVE) analyses translating high-throughput screening (HTS) data to human relevance have been limited. This is the first time IVIVE approaches and exposure comparisons have explored the entire Tox21 federal collaboration’s 10,000 chemi...

Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics

EPA Science Inventory

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...

IRIS Toxicological Review of Hexahydro-1,3,5-Trinitro-1,3,5 ...

EPA Pesticide Factsheets

On March 10, 2016, the public comment draft Toxicological Review of Hexahydro-1,3,5-trinitro-1,3,5-triazine and the draft charge to external peer reviewers were released for public review and comment. The Toxicological Review and charge were reviewed internally by EPA and by other federal agencies and White House Offices before public release. Consistent with the May 2009 IRIS assessment development process, all written comments on IRIS assessments submitted by other federal agencies and White House Offices are made publicly available. Accordingly, interagency comments and the interagency science consultation materials provided to other agencies, including interagency review drafts of the IRIS Toxicological Review of Hexahydro-1,3,5-trinitro-1,3,5-triazine and the charge to external peer reviewers, are posted on this site. EPA is undertaking an update of the Integrated Risk Information System (IRIS) health assessment for RDX. The outcome of this project is an updated Toxicological Review and IRIS Summary for RDX that will be entered into the IRIS database.

STS_135_Return

NASA Image and Video Library

2011-07-22

JSC2011-E-068761 (22 July 2011) --- A small portion of a large Ellington Field crowd is seen on July 22, 2011 through a door bearing a STS-135 sticker on its window. A short while later the crew of the space shuttle Atlantis' mission used this door for its entrance during a welcome home ceremony. STS-135 is the final mission of the NASA Space Shuttle Program. Photo credit: NASA Photo/Houston Chronicle, Smiley N. Pool

STS_135_Landing

NASA Image and Video Library

2011-07-21

JSC2011-E-067995 (21 July 2011) --- NASA astronaut Chris Ferguson, STS-135 commander, makes a public statement as, from left, NASA Administrator Charles Bolden, along with NASA astronauts Rex Walheim, Sandy Magnus and Doug Hurley look on after the space shuttle Atlantis landed on July 21 at the Kennedy Space Center in Florida. The landing completed STS-135, the final mission of the NASA Space Shuttle Program. Photo credit: NASA Photo/Houston Chronicle, Smiley N. Pool

Comparative Analysis of Predictive Models for Liver Toxicity Using ToxCast Assays and Quantitative Structure-Activity Relationships (MCBIOS)

EPA Science Inventory

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...

Building Scientific Confidence in the Development and Evaluation of Read-Across Using Tox21 Approaches (SOT Annual Meeting)

EPA Science Inventory

Acceptance of read-across is an ongoing challenge and several efforts are underway to identify and address major uncertainties associated with read-across. Several approaches have been proposed but to date few case studies if any have evaluated how Tox21 approaches may be instruc...

Virtual Liver: Estimating Proliferation and Apoptosis of Hepatocytes Exposed to Environmental Chemicals Using ToxCastTM Data

EPA Science Inventory

The U.S. EPA’s ToxCastTM program has screened over a thousand chemicals for potential toxicity using hundreds of high-throughput, in vitro assays. The U.S. EPA’s Virtual Liver (v-Liver™) is a cellular systems model of hepatic tissues that enables the estimation of in vivo effects...

Alternative Testing Strategy Example: Bioactivity Profilign of Diverse Engineering Nanomaterials via High-throughput Screening in ToxCast

EPA Science Inventory

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...

14 CFR 121.135 - Manual contents.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Manual contents. 121.135 Section 121.135 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR CARRIERS..., FLAG, AND SUPPLEMENTAL OPERATIONS Manual Requirements § 121.135 Manual contents. (a) Each manual...

33 CFR 175.135 - Existing equipment.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 2 2011-07-01 2011-07-01 false Existing equipment. 175.135 Section 175.135 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) BOATING SAFETY EQUIPMENT REQUIREMENTS Visual Distress Signals § 175.135 Existing equipment. Launchers...

33 CFR 175.135 - Existing equipment.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 33 Navigation and Navigable Waters 2 2012-07-01 2012-07-01 false Existing equipment. 175.135 Section 175.135 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) BOATING SAFETY EQUIPMENT REQUIREMENTS Visual Distress Signals § 175.135 Existing equipment. Launchers...

33 CFR 175.135 - Existing equipment.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 33 Navigation and Navigable Waters 2 2014-07-01 2014-07-01 false Existing equipment. 175.135 Section 175.135 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) BOATING SAFETY EQUIPMENT REQUIREMENTS Visual Distress Signals § 175.135 Existing equipment. Launchers...

33 CFR 175.135 - Existing equipment.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 33 Navigation and Navigable Waters 2 2013-07-01 2013-07-01 false Existing equipment. 175.135 Section 175.135 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) BOATING SAFETY EQUIPMENT REQUIREMENTS Visual Distress Signals § 175.135 Existing equipment. Launchers...

33 CFR 175.135 - Existing equipment.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Existing equipment. 175.135 Section 175.135 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) BOATING SAFETY EQUIPMENT REQUIREMENTS Visual Distress Signals § 175.135 Existing equipment. Launchers...

14 CFR 135.229 - Airport requirements.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false Airport requirements. 135.229 Section 135.229 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Operating Limitations and Weather Requirements § 135.229 Airport requirements. (a) No certificate holder may...

14 CFR 135.229 - Airport requirements.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Airport requirements. 135.229 Section 135.229 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Operating Limitations and Weather Requirements § 135.229 Airport requirements. (a) No certificate holder may...

14 CFR 135.229 - Airport requirements.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false Airport requirements. 135.229 Section 135.229 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Operating Limitations and Weather Requirements § 135.229 Airport requirements. (a) No certificate holder may...

14 CFR 135.229 - Airport requirements.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Airport requirements. 135.229 Section 135.229 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Operating Limitations and Weather Requirements § 135.229 Airport requirements. (a) No certificate holder may...

14 CFR 135.229 - Airport requirements.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Airport requirements. 135.229 Section 135.229 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Operating Limitations and Weather Requirements § 135.229 Airport requirements. (a) No certificate holder may...

Chemical landscape analysis with the OpenTox framework.

PubMed

Jeliazkova, Nina; Jeliazkov, Vedrin

2012-01-01

, the method is implemented as part of an existing open source Ambit package and could be accessed via an OpenTox API compliant web service and via an interactive application, running within a modern, JavaScript enabled web browser. Combined with the functionalities already offered by the OpenTox framework, like data sharing and remote calculations, it could be a useful tool for exploring chemical landscapes online.

22 CFR 135.44 - Termination for convenience.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Termination for convenience. 135.44 Section 135.44 Foreign Relations DEPARTMENT OF STATE MISCELLANEOUS UNIFORM ADMINISTRATIVE REQUIREMENTS FOR GRANTS..., Retention, and Enforcement § 135.44 Termination for convenience. Except as provided in § 135.43 awards may...

22 CFR 135.22 - Allowable costs.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Allowable costs. 135.22 Section 135.22 Foreign Relations DEPARTMENT OF STATE MISCELLANEOUS UNIFORM ADMINISTRATIVE REQUIREMENTS FOR GRANTS AND COOPERATIVE AGREEMENTS TO STATE AND LOCAL GOVERNMENTS Post-Award Requirements Financial Administration § 135.22 Allowable...

22 CFR 135.22 - Allowable costs.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Allowable costs. 135.22 Section 135.22 Foreign Relations DEPARTMENT OF STATE MISCELLANEOUS UNIFORM ADMINISTRATIVE REQUIREMENTS FOR GRANTS AND COOPERATIVE AGREEMENTS TO STATE AND LOCAL GOVERNMENTS Post-Award Requirements Financial Administration § 135.22 Allowable...

22 CFR 135.22 - Allowable costs.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Allowable costs. 135.22 Section 135.22 Foreign Relations DEPARTMENT OF STATE MISCELLANEOUS UNIFORM ADMINISTRATIVE REQUIREMENTS FOR GRANTS AND COOPERATIVE AGREEMENTS TO STATE AND LOCAL GOVERNMENTS Post-Award Requirements Financial Administration § 135.22 Allowable...

22 CFR 135.22 - Allowable costs.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Allowable costs. 135.22 Section 135.22 Foreign Relations DEPARTMENT OF STATE MISCELLANEOUS UNIFORM ADMINISTRATIVE REQUIREMENTS FOR GRANTS AND COOPERATIVE AGREEMENTS TO STATE AND LOCAL GOVERNMENTS Post-Award Requirements Financial Administration § 135.22 Allowable...

29 CFR 1910.135 - Head protection.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 29 Labor 5 2012-07-01 2012-07-01 false Head protection. 1910.135 Section 1910.135 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR OCCUPATIONAL SAFETY AND HEALTH STANDARDS Personal Protective Equipment § 1910.135 Head protection. (a) General...

STS_135_Launch

NASA Image and Video Library

2011-07-08

JSC2011-E-067589 (8 July 2011) --- The space shuttle Atlantis launches for the STS-135 mission to the International Space Station in the final mission of the Space Shuttle Program at NASA?s Kennedy Space Center in Florida. Liftoff was at 11:29 a.m. (EDT) on July 8, 2011. Onboard are NASA astronauts Chris Ferguson, STS-135 commander; Doug Hurley, pilot; Sandy Magnus and Rex Walheim, both mission specialists. Photo credit: NASA Photo/Houston Chronicle, Smiley N. Pool

STS_135_Launch

NASA Image and Video Library

2011-07-09

JSC2011-E-067644 (8 July 2011) --- The space shuttle Atlantis launches for the STS-135 mission to the International Space Station in the final mission of the Space Shuttle Program at NASA?s Kennedy Space Center in Florida. Liftoff was at 11:29 a.m. (EDT) on July 8, 2011. Onboard are NASA astronauts Chris Ferguson, STS-135 commander; Doug Hurley, pilot; Sandy Magnus and Rex Walheim, both mission specialists. Photo credit: NASA Photo/Houston Chronicle, Smiley N. Pool

STS_135_Launch

NASA Image and Video Library

2011-07-08

JSC2011-E-067612 (8 July 2011) --- The space shuttle Atlantis launches for the STS-135 mission to the International Space Station in the final mission of the Space Shuttle Program at NASA?s Kennedy Space Center in Florida. Liftoff was at 11:29 a.m. (EDT) on July 8, 2011. Onboard are NASA astronauts Chris Ferguson, STS-135 commander; Doug Hurley, pilot; Sandy Magnus and Rex Walheim, both mission specialists. Photo credit: NASA Photo/Houston Chronicle, Smiley N. Pool

STS_135_Launch

NASA Image and Video Library

2011-07-08

JSC2011-E-067590 (8 July 2011) --- The space shuttle Atlantis launches for the STS-135 mission to the International Space Station in the final mission of the Space Shuttle Program at NASA?s Kennedy Space Center in Florida. Liftoff was at 11:29 a.m. (EDT) on July 8, 2011. Onboard are NASA astronauts Chris Ferguson, STS-135 commander; Doug Hurley, pilot; Sandy Magnus and Rex Walheim, both mission specialists. Photo credit: NASA Photo/Houston Chronicle, Smiley N. Pool

STS_135_Launch

NASA Image and Video Library

2011-07-09

JSC2011-E-067640 (8 July 2011) --- The space shuttle Atlantis launches for the STS-135 mission to the International Space Station in the final mission of the Space Shuttle Program at NASA?s Kennedy Space Center in Florida. Liftoff was at 11:29 a.m. (EDT) on July 8, 2011. Onboard are NASA astronauts Chris Ferguson, STS-135 commander; Doug Hurley, pilot; Sandy Magnus and Rex Walheim, both mission specialists. Photo credit: NASA Photo/Houston Chronicle, Smiley N. Pool

Overview of Provisional Peer-Reviewed Toxicity Values (PPRTVs), Alternative Methods in Human Health Risk Assessment, and the RapidTox Dashboard

EPA Science Inventory

This poster provides an overview of three key lines of ongoing work at EPA/ORD/NCEA-CIN: Provisional Peer-Reviewed Toxicity Values (PPRTVs), Alternative Methods in Human Health Risk Assessment, and the RapidTox Dashboard collaboration.

33 CFR 135.307 - Notification contents.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Notification contents. 135.307 Section 135.307 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE POLLUTION FINANCIAL RESPONSIBILITY AND COMPENSATION OFFSHORE OIL POLLUTION COMPENSATION FUND Notification of Pollution Incidents § 135.307...

47 CFR 24.135 - Frequency stability.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 47 Telecommunication 2 2013-10-01 2013-10-01 false Frequency stability. 24.135 Section 24.135... SERVICES Narrowband PCS § 24.135 Frequency stability. (a) The frequency stability of the transmitter shall... battery operated equipment, the equipment tests shall be performed using a new battery without any further...

47 CFR 24.135 - Frequency stability.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 47 Telecommunication 2 2012-10-01 2012-10-01 false Frequency stability. 24.135 Section 24.135... SERVICES Narrowband PCS § 24.135 Frequency stability. (a) The frequency stability of the transmitter shall... battery operated equipment, the equipment tests shall be performed using a new battery without any further...

47 CFR 24.135 - Frequency stability.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 2 2010-10-01 2010-10-01 false Frequency stability. 24.135 Section 24.135... SERVICES Narrowband PCS § 24.135 Frequency stability. (a) The frequency stability of the transmitter shall... battery operated equipment, the equipment tests shall be performed using a new battery without any further...

47 CFR 24.135 - Frequency stability.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 47 Telecommunication 2 2014-10-01 2014-10-01 false Frequency stability. 24.135 Section 24.135... SERVICES Narrowband PCS § 24.135 Frequency stability. (a) The frequency stability of the transmitter shall... battery operated equipment, the equipment tests shall be performed using a new battery without any further...

47 CFR 24.135 - Frequency stability.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 47 Telecommunication 2 2011-10-01 2011-10-01 false Frequency stability. 24.135 Section 24.135... SERVICES Narrowband PCS § 24.135 Frequency stability. (a) The frequency stability of the transmitter shall... battery operated equipment, the equipment tests shall be performed using a new battery without any further...

34 CFR 300.135 - Written affirmation.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 34 Education 2 2010-07-01 2010-07-01 false Written affirmation. 300.135 Section 300.135 Education....135 Written affirmation. (a) When timely and meaningful consultation, as required by § 300.134, has occurred, the LEA must obtain a written affirmation signed by the representatives of participating private...

12 CFR 13.5 - Customer information.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 12 Banks and Banking 1 2013-01-01 2013-01-01 false Customer information. 13.5 Section 13.5 Banks... PRACTICES § 13.5 Customer information. Prior to the execution of a transaction recommended to a non... obtain information concerning: (a) The customer's financial status; (b) The customer's tax status; (c...

22 CFR 135.41 - Financial reporting.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Financial reporting. 135.41 Section 135.41... Enforcement § 135.41 Financial reporting. (a) General. (1) Except as provided in paragraphs (a) (2) and (5) of...) Submitting financial reports to Federal agencies, or (ii) Requesting advances or reimbursements when letters...

23 CFR 1.35 - Bonus program.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 23 Highways 1 2011-04-01 2011-04-01 false Bonus program. 1.35 Section 1.35 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION GENERAL MANAGEMENT AND ADMINISTRATION GENERAL § 1.35 Bonus program. (a) Any agreement entered into by a State pursuant to the provisions of section 12 of the...

23 CFR 1.35 - Bonus program.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 23 Highways 1 2014-04-01 2014-04-01 false Bonus program. 1.35 Section 1.35 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION GENERAL MANAGEMENT AND ADMINISTRATION GENERAL § 1.35 Bonus program. (a) Any agreement entered into by a State pursuant to the provisions of section 12 of the...

23 CFR 1.35 - Bonus program.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 23 Highways 1 2010-04-01 2010-04-01 false Bonus program. 1.35 Section 1.35 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION GENERAL MANAGEMENT AND ADMINISTRATION GENERAL § 1.35 Bonus program. (a) Any agreement entered into by a State pursuant to the provisions of section 12 of the...

23 CFR 1.35 - Bonus program.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 23 Highways 1 2013-04-01 2013-04-01 false Bonus program. 1.35 Section 1.35 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION GENERAL MANAGEMENT AND ADMINISTRATION GENERAL § 1.35 Bonus program. (a) Any agreement entered into by a State pursuant to the provisions of section 12 of the...

20 CFR 401.135 - Other laws.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 20 Employees' Benefits 2 2013-04-01 2013-04-01 false Other laws. 401.135 Section 401.135 Employees' Benefits SOCIAL SECURITY ADMINISTRATION PRIVACY AND DISCLOSURE OF OFFICIAL RECORDS AND INFORMATION Disclosure of Official Records and Information § 401.135 Other laws. When the FOIA does not apply, we may not...

20 CFR 401.135 - Other laws.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 20 Employees' Benefits 2 2011-04-01 2011-04-01 false Other laws. 401.135 Section 401.135 Employees' Benefits SOCIAL SECURITY ADMINISTRATION PRIVACY AND DISCLOSURE OF OFFICIAL RECORDS AND INFORMATION Disclosure of Official Records and Information § 401.135 Other laws. When the FOIA does not apply, we may not...

20 CFR 401.135 - Other laws.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 20 Employees' Benefits 2 2012-04-01 2012-04-01 false Other laws. 401.135 Section 401.135 Employees' Benefits SOCIAL SECURITY ADMINISTRATION PRIVACY AND DISCLOSURE OF OFFICIAL RECORDS AND INFORMATION Disclosure of Official Records and Information § 401.135 Other laws. When the FOIA does not apply, we may not...

20 CFR 401.135 - Other laws.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 20 Employees' Benefits 2 2014-04-01 2014-04-01 false Other laws. 401.135 Section 401.135 Employees' Benefits SOCIAL SECURITY ADMINISTRATION PRIVACY AND DISCLOSURE OF OFFICIAL RECORDS AND INFORMATION Disclosure of Official Records and Information § 401.135 Other laws. When the FOIA does not apply, we may not...

10 CFR 26.135 - Split specimens.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 1 2011-01-01 2011-01-01 false Split specimens. 26.135 Section 26.135 Energy NUCLEAR REGULATORY COMMISSION FITNESS FOR DUTY PROGRAMS Licensee Testing Facilities § 26.135 Split specimens. (a) If the FFD program follows split-specimen procedures, as described in § 26.113, the licensee testing...

10 CFR 26.135 - Split specimens.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Split specimens. 26.135 Section 26.135 Energy NUCLEAR REGULATORY COMMISSION FITNESS FOR DUTY PROGRAMS Licensee Testing Facilities § 26.135 Split specimens. (a) If the FFD program follows split-specimen procedures, as described in § 26.113, the licensee testing...

20 CFR 401.135 - Other laws.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Other laws. 401.135 Section 401.135 Employees' Benefits SOCIAL SECURITY ADMINISTRATION PRIVACY AND DISCLOSURE OF OFFICIAL RECORDS AND INFORMATION Disclosure of Official Records and Information § 401.135 Other laws. When the FOIA does not apply, we may not...

10 CFR 26.135 - Split specimens.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 1 2013-01-01 2013-01-01 false Split specimens. 26.135 Section 26.135 Energy NUCLEAR REGULATORY COMMISSION FITNESS FOR DUTY PROGRAMS Licensee Testing Facilities § 26.135 Split specimens. (a) If the FFD program follows split-specimen procedures, as described in § 26.113, the licensee testing...

10 CFR 26.135 - Split specimens.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 1 2014-01-01 2014-01-01 false Split specimens. 26.135 Section 26.135 Energy NUCLEAR REGULATORY COMMISSION FITNESS FOR DUTY PROGRAMS Licensee Testing Facilities § 26.135 Split specimens. (a) If the FFD program follows split-specimen procedures, as described in § 26.113, the licensee testing...

10 CFR 26.135 - Split specimens.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 1 2012-01-01 2012-01-01 false Split specimens. 26.135 Section 26.135 Energy NUCLEAR REGULATORY COMMISSION FITNESS FOR DUTY PROGRAMS Licensee Testing Facilities § 26.135 Split specimens. (a) If the FFD program follows split-specimen procedures, as described in § 26.113, the licensee testing...

22 CFR 135.41 - Financial reporting.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Financial reporting. 135.41 Section 135.41... Enforcement § 135.41 Financial reporting. (a) General. (1) Except as provided in paragraphs (a) (2) and (5) of...) Submitting financial reports to Federal agencies, or (ii) Requesting advances or reimbursements when letters...

KC-135 on ramp

NASA Technical Reports Server (NTRS)

1958-01-01

The Boeing KC-135 Stratotanker, besides being used extensively in its primary role as an inflight aircraft refueler, has assisted in several projects at the NASA Dryden Flight Research Center, Edwards, California. In 1957 and 1958, Dryden was asked by what was then the Civil Aeronautics Administration (later absorbed into the Federal Aviation Administration (FAA) in 1958) to help establish new approach procedure guidelines on cloud-ceiling and visibility minimums for Boeing's first jet airliner, the B-707. Dryden used a KC-135 (the military variant of the 707), seen here on the runway at Edwards Air Force Base, to aid the CAA in these tests. In 1979 and 1980, Dryden was again involved with general aviation research with the KC-135. This time, a special wingtip 'winglet', developed by Richard Whitcomb of Langley Research Center, was tested on the jet aircraft. Winglets are small, nearly vertical fins installed on an airplane's wing tips to help produce a forward thrust in the vortices that typically swirl off the end of the wing, thereby reducing drag. This winglet idea was tested at the Dryden Flight Research Center on a KC-135A tanker loaned to NASA by the Air Force. The research showed that the winglets could increase an aircraft's range by as much as 7 percent at cruise speeds. The first application of NASA's winglet technology in industry was in general aviation business jets, but winglets are now being incorporated into most new commercial and military transport jets, including the Gulfstream III and IV business jets, the Boeing 747-400 and MD-11 airliners, and the C-17 military transport. In the 1980's, a KC-135 was used in support of the Space Shuttle program. Since the Shuttle was to be launched from Florida, researchers wanted to test the effect of rain on the sensitive thermal tiles. Tiles were mounted on special fixtures on an F-104 aircraft and a P-3 Orion. The F-104 was flown in actual rain conditions, and also behind the KC-135 spray tanker as it

Probing the ToxCastTM Chemical Library for Predictive Signatures of Developmental Toxicity - Poster at Teratology Society Annual Meeting

EPA Science Inventory

EPA’s ToxCast™ project is profiling the in vitro bioactivity of chemical compounds to assess pathway-level and cell-based signatures that correlate with observed in vivo toxicity. We hypothesize that cell signaling pathways are primary targets for diverse environmental chemicals ...

Screening ToxCast™ Phase I Chemicals in a Mouse Embryonic Stem Cell Adherent Cell Differentiation and Cytotoxicity (ACDC) Assay

EPA Science Inventory

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 ...

High Throughput Assays for Exposure Science (NIEHS OHAT Staff Meeting presentation)

EPA Science Inventory

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...

Modeling Biotransformation Using In Vitro Data on Parent-Metabolite Pairs within the ToxCast Phase I Chemical Set

EPA Science Inventory

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...

Learning Boolean Networks in HepG2 cells using ToxCast High-Content Imaging Data (SOT annual meeting)

EPA Science Inventory

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...

A randomized study to assess the immunogenicity, antibody persistence and safety of a tetravalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine in children aged 2–10 years

PubMed Central

Vesikari, Timo; Forstén, Aino; Boutriau, Dominique; Bianco, Véronique; Van der Wielen, Marie; Miller, Jacqueline M.

2012-01-01

Incidence of meningococcal diseases is high in children, and effective vaccines are needed for this age group. In this phase II, open, controlled study, 309 children aged 2–10 y from Finland were randomized (3:1) into two parallel groups to receive one dose of meningococcal ACWY-tetanus toxoid conjugate vaccine (ACWY-TT group; n = 231) or a licensed meningococcal ACWY polysaccharide vaccine (Men-PS group; n = 78). Serum bactericidal activity using rabbit complement (rSBA) was evaluated up to three years post-vaccination. Exploratory comparisons suggested that rSBA vaccine response rates and geometric mean titers (GMTs) for each serogroup at one month post-vaccination and rSBA GMTs for serogroups A, W-135 and Y up to three years post-vaccination were higher in the ACWY-TT compared with Men-PS group, but did not detect any difference between groups in terms of rSBA-MenC GMTs at three years post-vaccination; this is explained by the higher proportion of children from the Men-PS group who were excluded because they were re-vaccinated with a monovalent meningococcal serogroup C vaccine due to loss of protective antibody levels against this serogroup. Although there was a higher incidence of local reactogenicity in the ACWY-TT group, general and unsolicited symptoms reporting rates were comparable in both groups. This study showed that MenACWY-TT was immunogenic with a clinically acceptable safety profile in children aged 2–10 y. MenACWY-TT induced higher functional antibody titers for all serogroups, which persisted longer for serogroups A, W-135 and Y, than the MenACWY polysaccharide vaccine. This study has been registered at www.clinicaltrials.gov NCT00427908. PMID:23032168

31 CFR 1.35 - Information forms.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 31 Money and Finance: Treasury 1 2013-07-01 2013-07-01 false Information forms. 1.35 Section 1.35... § 1.35 Information forms. (a) Review of forms. Except for forms developed and used by constituent... developed and used by the Department of the Treasury to collect information from and about individuals. The...

LuminoTox as a tool to optimize ozone doses for the removal of contaminants and their associated toxicity.

PubMed

Marshall, Meghan; Yargeau, Viviane

2018-03-01

New treatment technologies and quality monitoring tools are needed for Contaminants of Emerging Concern (CECs) in wastewater. The purpose of this work was to assess the LuminoTox as a monitoring tool for CEC-associated toxicity in municipal wastewater during ozone treatment, and to evaluate the impact of different ozone feed concentrations at equivalent ozone doses for removing toxicity. The LuminoTox was sensitive at monitoring changes in toxicity of atrazine (ATZ) in synthetic wastewater (SWW) and in a 14 CECs mix in secondary effluent (SE) during ozone treatment. In both experiments, a decrease in toxicity was observed with increasing transferred ozone dose, which corresponded to a decrease in CEC concentration. For ATZ in SWW, a 5 ppm ozone feed showed better toxicity removal, up to 25% and 35% inhibition for LuminoTox algae biosensors SAPS I and SAPS II, respectively, for statistically equivalent ozone dose pairs of 43 mg (5 ppm ozone feed) and 36 mg (15 ppm ozone feed). The opposite was true for the 14 CECs in SE; the 15 ppm ozone feed showed better toxicity removal, up to a reduction of 37% and 40% for SAPS I and SAPS II inhibition, respectively, for statistically equivalent ozone dose pairs of 42 mg (5 ppm ozone feed) and 42 mg (15 ppm ozone feed). Different feed applications had an impact on the efficiency of toxicity removal for equivalent ozone doses; this efficiency appears to depend on the type of contaminants and/or wastewater matrix. Copyright © 2017 Elsevier Ltd. All rights reserved.

STS_135_ MEDIA

NASA Image and Video Library

2011-06-30

JSC2011-E-060794 (30 June 2011) --- NASA astronaut Chris Ferguson, STS-135 commander, points to acknowledge a reporter while greeting the media along with NASA astronauts Doug Hurley, pilot, and Sandy Magnus and Rex Walheim, both mission specialists, during the STS-135 crew media briefing at NASA?s Johnson Space Center June 30, 2011. The press conference provided the last scheduled opportunity for a large group of press to speak with the crew before the final launch on July 8. Photo credit: NASA Photo/Houston Chronicle, Smiley N. Pool

21 CFR 135.160 - Water ices.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 2 2011-04-01 2011-04-01 false Water ices. 135.160 Section 135.160 Food and Drugs... CONSUMPTION FROZEN DESSERTS Requirements for Specific Standardized Frozen Desserts § 135.160 Water ices. (a) Description. Water ices are the foods each of which is prepared from the same ingredients and in the same...

21 CFR 135.160 - Water ices.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Water ices. 135.160 Section 135.160 Food and Drugs... CONSUMPTION FROZEN DESSERTS Requirements for Specific Standardized Frozen Desserts § 135.160 Water ices. (a) Description. Water ices are the foods each of which is prepared from the same ingredients and in the same...

46 CFR 133.135 - Rescue boats.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 4 2012-10-01 2012-10-01 false Rescue boats. 133.135 Section 133.135 Shipping COAST... Requirements for All OSVs § 133.135 Rescue boats. (a) Each OSV must carry at least one rescue boat. Each rescue boat must be approved under approval series 160.156 and equipped as specified in table 133.175 of this...

46 CFR 133.135 - Rescue boats.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 4 2013-10-01 2013-10-01 false Rescue boats. 133.135 Section 133.135 Shipping COAST... Requirements for All OSVs § 133.135 Rescue boats. (a) Each OSV must carry at least one rescue boat. Each rescue boat must be approved under approval series 160.156 and equipped as specified in table 133.175 of this...

46 CFR 133.135 - Rescue boats.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Rescue boats. 133.135 Section 133.135 Shipping COAST... Requirements for All OSVs § 133.135 Rescue boats. (a) Each OSV must carry at least one rescue boat. Each rescue boat must be approved under approval series 160.056 and equipped as specified in table 133.175 of this...

46 CFR 133.135 - Rescue boats.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 4 2011-10-01 2011-10-01 false Rescue boats. 133.135 Section 133.135 Shipping COAST... Requirements for All OSVs § 133.135 Rescue boats. (a) Each OSV must carry at least one rescue boat. Each rescue boat must be approved under approval series 160.156 and equipped as specified in table 133.175 of this...

46 CFR 133.135 - Rescue boats.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 4 2014-10-01 2014-10-01 false Rescue boats. 133.135 Section 133.135 Shipping COAST... Requirements for All OSVs § 133.135 Rescue boats. (a) Each OSV must carry at least one rescue boat. Each rescue boat must be approved under approval series 160.156 and equipped as specified in table 133.175 of this...

21 CFR 135.160 - Water ices.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 2 2014-04-01 2014-04-01 false Water ices. 135.160 Section 135.160 Food and Drugs... CONSUMPTION FROZEN DESSERTS Requirements for Specific Standardized Frozen Desserts § 135.160 Water ices. (a) Description. Water ices are the foods each of which is prepared from the same ingredients and in the same...

21 CFR 135.160 - Water ices.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 2 2012-04-01 2012-04-01 false Water ices. 135.160 Section 135.160 Food and Drugs... CONSUMPTION FROZEN DESSERTS Requirements for Specific Standardized Frozen Desserts § 135.160 Water ices. (a) Description. Water ices are the foods each of which is prepared from the same ingredients and in the same...

21 CFR 135.160 - Water ices.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 2 2013-04-01 2013-04-01 false Water ices. 135.160 Section 135.160 Food and Drugs... CONSUMPTION FROZEN DESSERTS Requirements for Specific Standardized Frozen Desserts § 135.160 Water ices. (a) Description. Water ices are the foods each of which is prepared from the same ingredients and in the same...

Cross-species extrapolation of mammalian-based ToxCast Data using Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS)

EPA Science Inventory

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...

KC-135 and Other Microgravity Simulations

NASA Technical Reports Server (NTRS)

2005-01-01

This document represents a summary of medical and scientific evaluations conducted aboard the KC-135 from June 23, 2004 to June 27, 2005. Included is a general overview of KC-135 activities manifested and coordinated by the Human Adaptation and Countermeasures Office. A collection of brief reports that describe tests conducted aboard the KC-135 follows the overview. Principal investigators and test engineers contributed significantly to the content of the report describing their particular experiment or hardware evaluation. This document concludes with an appendix that provides background information concerning the KC-135 and the Reduced-Gravity Program.

CompNanoTox2015: novel perspectives from a European conference on computational nanotoxicology on predictive nanotoxicology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bañares, Miguel A.; Haase, Andrea; Tran, Lang

A first European Conference on Computational Nanotoxicology, CompNanoTox, was held in November 2015 in Benahavís, Spain with the objectives to disseminate and integrate results from the European modeling and database projects (NanoPUZZLES, ModENPTox, PreNanoTox, MembraneNanoPart, MODERN, eNanoMapper and EU COST TD1204 MODENA) as well as to create synergies within the European NanoSafety Cluster. This conference was supported by the COST Action TD1204 MODENA on developing computational methods for toxicological risk assessment of engineered nanoparticles and provided a unique opportunity for crossfertilization among complementary disciplines. The efforts to develop and validate computational models crucially depend on high quality experimental data andmore » relevant assays which will be the basis to identify relevant descriptors. The ambitious overarching goal of this conference was to promote predictive nanotoxicology, which can only be achieved by a close collaboration between the computational scientists (e.g. database experts, modeling experts for structure, (eco) toxicological effects, performance and interaction of nanomaterials) and experimentalists from different areas (in particular toxicologists, biologists, chemists and material scientists, among others). The main outcome and new perspectives of this conference are summarized here.« less

CompNanoTox2015: novel perspectives from a European conference on computational nanotoxicology on predictive nanotoxicology.

PubMed

Bañares, Miguel A; Haase, Andrea; Tran, Lang; Lobaskin, Vladimir; Oberdörster, Günter; Rallo, Robert; Leszczynski, Jerzy; Hoet, Peter; Korenstein, Rafi; Hardy, Barry; Puzyn, Tomasz

2017-09-01

A first European Conference on Computational Nanotoxicology, CompNanoTox, was held in November 2015 in Benahavís, Spain with the objectives to disseminate and integrate results from the European modeling and database projects (NanoPUZZLES, ModENPTox, PreNanoTox, MembraneNanoPart, MODERN, eNanoMapper and EU COST TD1204 MODENA) as well as to create synergies within the European NanoSafety Cluster. This conference was supported by the COST Action TD1204 MODENA on developing computational methods for toxicological risk assessment of engineered nanoparticles and provided a unique opportunity for cross fertilization among complementary disciplines. The efforts to develop and validate computational models crucially depend on high quality experimental data and relevant assays which will be the basis to identify relevant descriptors. The ambitious overarching goal of this conference was to promote predictive nanotoxicology, which can only be achieved by a close collaboration between the computational scientists (e.g. database experts, modeling experts for structure, (eco) toxicological effects, performance and interaction of nanomaterials) and experimentalists from different areas (in particular toxicologists, biologists, chemists and material scientists, among others). The main outcome and new perspectives of this conference are summarized here.

Open Source Bayesian Models. 1. Application to ADME/Tox and Drug Discovery Datasets.

PubMed

Clark, Alex M; Dole, Krishna; Coulon-Spektor, Anna; McNutt, Andrew; Grass, George; Freundlich, Joel S; Reynolds, Robert C; Ekins, Sean

2015-06-22

On the order of hundreds of absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) models have been described in the literature in the past decade which are more often than not inaccessible to anyone but their authors. Public accessibility is also an issue with computational models for bioactivity, and the ability to share such models still remains a major challenge limiting drug discovery. We describe the creation of a reference implementation of a Bayesian model-building software module, which we have released as an open source component that is now included in the Chemistry Development Kit (CDK) project, as well as implemented in the CDD Vault and in several mobile apps. We use this implementation to build an array of Bayesian models for ADME/Tox, in vitro and in vivo bioactivity, and other physicochemical properties. We show that these models possess cross-validation receiver operator curve values comparable to those generated previously in prior publications using alternative tools. We have now described how the implementation of Bayesian models with FCFP6 descriptors generated in the CDD Vault enables the rapid production of robust machine learning models from public data or the user's own datasets. The current study sets the stage for generating models in proprietary software (such as CDD) and exporting these models in a format that could be run in open source software using CDK components. This work also demonstrates that we can enable biocomputation across distributed private or public datasets to enhance drug discovery.

Inroads to predict in vivo toxicology-an introduction to the eTOX Project.

PubMed

Briggs, Katharine; Cases, Montserrat; Heard, David J; Pastor, Manuel; Pognan, François; Sanz, Ferran; Schwab, Christof H; Steger-Hartmann, Thomas; Sutter, Andreas; Watson, David K; Wichard, Jörg D

2012-01-01

There is a widespread awareness that the wealth of preclinical toxicity data that the pharmaceutical industry has generated in recent decades is not exploited as efficiently as it could be. Enhanced data availability for compound comparison ("read-across"), or for data mining to build predictive tools, should lead to a more efficient drug development process and contribute to the reduction of animal use (3Rs principle). In order to achieve these goals, a consortium approach, grouping numbers of relevant partners, is required. The eTOX ("electronic toxicity") consortium represents such a project and is a public-private partnership within the framework of the European Innovative Medicines Initiative (IMI). The project aims at the development of in silico prediction systems for organ and in vivo toxicity. The backbone of the project will be a database consisting of preclinical toxicity data for drug compounds or candidates extracted from previously unpublished, legacy reports from thirteen European and European operation-based pharmaceutical companies. The database will be enhanced by incorporation of publically available, high quality toxicology data. Seven academic institutes and five small-to-medium size enterprises (SMEs) contribute with their expertise in data gathering, database curation, data mining, chemoinformatics and predictive systems development. The outcome of the project will be a predictive system contributing to early potential hazard identification and risk assessment during the drug development process. The concept and strategy of the eTOX project is described here, together with current achievements and future deliverables.

33 CFR 135.201 - Applicability.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Applicability. 135.201 Section 135.201 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE POLLUTION FINANCIAL RESPONSIBILITY AND COMPENSATION OFFSHORE OIL POLLUTION COMPENSATION FUND...

33 CFR 135.201 - Applicability.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 33 Navigation and Navigable Waters 2 2014-07-01 2014-07-01 false Applicability. 135.201 Section 135.201 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE POLLUTION FINANCIAL RESPONSIBILITY AND COMPENSATION OFFSHORE OIL POLLUTION COMPENSATION FUND...

33 CFR 135.201 - Applicability.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 33 Navigation and Navigable Waters 2 2012-07-01 2012-07-01 false Applicability. 135.201 Section 135.201 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE POLLUTION FINANCIAL RESPONSIBILITY AND COMPENSATION OFFSHORE OIL POLLUTION COMPENSATION FUND...

33 CFR 135.215 - Certification.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Certification. 135.215 Section 135.215 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE POLLUTION FINANCIAL RESPONSIBILITY AND COMPENSATION OFFSHORE OIL POLLUTION COMPENSATION FUND...

33 CFR 135.215 - Certification.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 2 2011-07-01 2011-07-01 false Certification. 135.215 Section 135.215 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE POLLUTION FINANCIAL RESPONSIBILITY AND COMPENSATION OFFSHORE OIL POLLUTION COMPENSATION FUND...

33 CFR 135.215 - Certification.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 33 Navigation and Navigable Waters 2 2012-07-01 2012-07-01 false Certification. 135.215 Section 135.215 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE POLLUTION FINANCIAL RESPONSIBILITY AND COMPENSATION OFFSHORE OIL POLLUTION COMPENSATION FUND...

33 CFR 135.201 - Applicability.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 33 Navigation and Navigable Waters 2 2013-07-01 2013-07-01 false Applicability. 135.201 Section 135.201 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE POLLUTION FINANCIAL RESPONSIBILITY AND COMPENSATION OFFSHORE OIL POLLUTION COMPENSATION FUND...

33 CFR 135.215 - Certification.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 33 Navigation and Navigable Waters 2 2014-07-01 2014-07-01 false Certification. 135.215 Section 135.215 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE POLLUTION FINANCIAL RESPONSIBILITY AND COMPENSATION OFFSHORE OIL POLLUTION COMPENSATION FUND...

33 CFR 135.201 - Applicability.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 2 2011-07-01 2011-07-01 false Applicability. 135.201 Section 135.201 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE POLLUTION FINANCIAL RESPONSIBILITY AND COMPENSATION OFFSHORE OIL POLLUTION COMPENSATION FUND...

33 CFR 135.215 - Certification.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 33 Navigation and Navigable Waters 2 2013-07-01 2013-07-01 false Certification. 135.215 Section 135.215 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE POLLUTION FINANCIAL RESPONSIBILITY AND COMPENSATION OFFSHORE OIL POLLUTION COMPENSATION FUND...

Assessing cross species conservation of ToxCast Assay targets using Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS)

EPA Science Inventory

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...

7 CFR 966.135 - Appeals.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Appeals. 966.135 Section 966.135 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE TOMATOES GROWN IN FLORIDA Rules and...

IRIS Toxicological Review of Hexahydro-1,3,5-Trinitro-1,3,5 ...

EPA Pesticide Factsheets

EPA is developing an Integrated Risk Information System (IRIS) assessment of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and has released the draft assessment for public comment. When final, the assessment will appear on the IRIS database. EPA is undertaking an update of the Integrated Risk Information System (IRIS) health assessment for RDX. The outcome of this project is an updated Toxicological Review and IRIS Summary for RDX that will be entered into the IRIS database.

7 CFR 1956.131-1956.135 - [Reserved

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 14 2010-01-01 2009-01-01 true [Reserved] 1956.131-1956.135 Section 1956.131-1956.135...) PROGRAM REGULATIONS (CONTINUED) DEBT SETTLEMENT Debt Settlement-Community and Business Programs §§ 1956.131-1956.135 [Reserved] ...

STS_135_FDF

NASA Image and Video Library

2011-06-24

JSC2011-E-059611 (24 June 2011) --- NASA astronaut Sandy Magnus, STS-135 mission specialist, leans out around pilot Doug Hurley, left, to confer with commander Chris Ferguson (out of frame) as the crew of the final space shuttle mission participates in the STS-135 Flight Data File (FDF) review at NASA?s Johnson Space Center June 24, 2011. The review involves examining and annotating more than 200 procedure books and cue cards that comprise all of the detailed technical steps that will be performed during the mission. Photo credit: NASA Photo/Houston Chronicle, Smiley N. Pool

14 CFR 135.149 - Equipment requirements: General.

Code of Federal Regulations, 2010 CFR

2010-01-01

.... 135-1, 44 FR 26737, May 7, 1979; Amdt. 135-34, 54 FR 43926, Oct. 27, 1989; Amdt. 135-38, 55 FR 43310... REQUIREMENTS: COMMUTER AND ON DEMAND OPERATIONS AND RULES GOVERNING PERSONS ON BOARD SUCH AIRCRAFT Aircraft and...

14 CFR 135.149 - Equipment requirements: General.

Code of Federal Regulations, 2014 CFR

2014-01-01

.... 135-1, 44 FR 26737, May 7, 1979; Amdt. 135-34, 54 FR 43926, Oct. 27, 1989; Amdt. 135-38, 55 FR 43310... REQUIREMENTS: COMMUTER AND ON DEMAND OPERATIONS AND RULES GOVERNING PERSONS ON BOARD SUCH AIRCRAFT Aircraft and...

14 CFR 135.149 - Equipment requirements: General.

Code of Federal Regulations, 2013 CFR

2013-01-01

.... 135-1, 44 FR 26737, May 7, 1979; Amdt. 135-34, 54 FR 43926, Oct. 27, 1989; Amdt. 135-38, 55 FR 43310... REQUIREMENTS: COMMUTER AND ON DEMAND OPERATIONS AND RULES GOVERNING PERSONS ON BOARD SUCH AIRCRAFT Aircraft and...

14 CFR 135.149 - Equipment requirements: General.

Code of Federal Regulations, 2012 CFR

2012-01-01

.... 135-1, 44 FR 26737, May 7, 1979; Amdt. 135-34, 54 FR 43926, Oct. 27, 1989; Amdt. 135-38, 55 FR 43310... REQUIREMENTS: COMMUTER AND ON DEMAND OPERATIONS AND RULES GOVERNING PERSONS ON BOARD SUCH AIRCRAFT Aircraft and...

14 CFR 135.149 - Equipment requirements: General.

Code of Federal Regulations, 2011 CFR

2011-01-01

.... 135-1, 44 FR 26737, May 7, 1979; Amdt. 135-34, 54 FR 43926, Oct. 27, 1989; Amdt. 135-38, 55 FR 43310... REQUIREMENTS: COMMUTER AND ON DEMAND OPERATIONS AND RULES GOVERNING PERSONS ON BOARD SUCH AIRCRAFT Aircraft and...

50 CFR 86.135 - [Reserved

Code of Federal Regulations, 2010 CFR

2010-10-01

... 50 Wildlife and Fisheries 6 2010-10-01 2010-10-01 false [Reserved] 86.135 Section 86.135 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR (CONTINUED) FINANCIAL ASSISTANCE-WILDLIFE SPORT FISH RESTORATION PROGRAM BOATING INFRASTRUCTURE GRANT (BIG) PROGRAM How...

40 CFR 1037.135 - Labeling.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 34 2012-07-01 2012-07-01 false Labeling. 1037.135 Section 1037.135 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR POLLUTION CONTROLS CONTROL OF... identify other emission standards that the vehicle meets or does not meet (such as European standards). You...

40 CFR 1037.135 - Labeling.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 33 2014-07-01 2014-07-01 false Labeling. 1037.135 Section 1037.135 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR POLLUTION CONTROLS CONTROL OF... that the vehicle meets or does not meet (such as European standards). You may also add other...

40 CFR 1037.135 - Labeling.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 34 2013-07-01 2013-07-01 false Labeling. 1037.135 Section 1037.135 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR POLLUTION CONTROLS CONTROL OF... identify other emission standards that the vehicle meets or does not meet (such as European standards). You...

K-12 Students Flock To ToxTown In San Diego: Results of an SOT K-12 Education Outreach Workshop

EPA Science Inventory

Just prior to the start of the 2015 Annual Meeting in San Diego, hundreds of K-12 students, teachers, and science enthusiasts visited the ToxTown booth at the annual San Diego Festival of Science and Engineering grand finale event, EXPO Day. Over 20,000 attendees participated in ...

Hazard assessment of a simulated oil spill on intertidal areas of the St. Lawrence River with SPMD-TOX

USGS Publications Warehouse

Johnson, B. Thomas; Petty, J.D.; Huckins, J.N.; Lee, Kenneth; Gauthier, J.

2004-01-01

Phytoremediation in a simulated crude oil spill was studied with a “minimalistic” approach. The SPMD-TOX paradigm—a miniature passive sorptive device to collect and concentrate chemicals and microscale tests to detect toxicity—was used to monitor over time the bioavailability and potential toxicity of an oil spill. A simulated crude oil spill was initiated on an intertidal freshwater grass-wetland along the St. Lawrence River southwest of Quebec City, Quebec, Canada. Several phytoremediation treatments were investigated; to dissipate and ameliorate the spill, treatments included nutrient amendments with inorganic nitrogen sources (ammonium nitrate and sodium nitrate) and phosphate (super triple phosphate) with and without cut plants, with natural attenuation (no phytoremedial treatment) as a control. Sequestered oil residues were bioavailable in all oil-treated plots in Weeks 1 and 2. Interestingly, the samples were colored and fluoresced under ultraviolet light. In addition, microscale tests showed that sequestered residues were acutely toxic and genotoxic, as well as that they induced hepatic P450enzymes. Analysis of these data suggested that polycyclic aromatic hydrocarbons were among the bioavailable residues sequestered. In addition, these findings suggested that the toxic bioavailable fractions of the oil spill and degradation products dissipated rapidly over time because after the second week the water column contained no oil or detectable degradation products in this riverine intertidal wetland. SPMD-TOX revealed no evidence of bioavailable oil products in Weeks 4, 6, 8, and 12. All phytoremediation efforts appeared to be ineffective in changing either the dissipation rate or the ability to ameliorate the oil toxicity. SPMD-TOX analysis of the water columns from these riverine experimental plots profiled the occurrence, dissipation, and influence of phytoremediation on the bioavailability and toxicity of oil products (parent or degradation products).

KC-135 and Other Microgravity Simulations

NASA Technical Reports Server (NTRS)

Skinner, Noel C.

1999-01-01

This document represents a summary of medical and scientific evaluations conducted aboard the KC-135 from June 20, 1998 to June 20, 1999. Included is a general overview of KC-135 activities manifested and coordinated by the Life Sciences Research Laboratories. A collection of brief reports that describes tests conducted aboard the KC-135 follows the overview. Principal investigators and test engineers contributed significantly to the content of the report describing their particular experiment or hardware evaluation. Although this document follows general guidelines, each report format may vary to accommodate differences in experiment design and procedures. This document concludes with an appendix that provides background information concerning the KC-135 and the Reduced-Gravity Program.

KC-135 and Other Microgravity Simulations

NASA Technical Reports Server (NTRS)

Skinner, Noel C.; Schlegel, Todd T. (Technical Monitor)

2001-01-01

This document represents a summary of medical and scientific evaluations conducted aboard the KC-135 from January to June 15, 2001. Included is a general overview of KC-135 activities manifested and coordinated by the Human Adaptation and Countermeasures Office. A collection of brief reports that describes tests conducted aboard the KC-135 follows the overview. Principal investigators and test engineers contributed significantly to the content of the report describing their particular experiment or hardware evaluation. Although this document follows general guidelines, each report format may vary to accommodate differences in experiment design and procedures. This document concludes with an appendix that provides background information concerning the KC-135 and the Reduced-Gravity Program.

14 CFR 135.203 - VFR: Minimum altitudes.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false VFR: Minimum altitudes. 135.203 Section 135.203 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Operating Limitations and Weather Requirements § 135.203 VFR: Minimum altitudes. Except when necessary for...

14 CFR 135.205 - VFR: Visibility requirements.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false VFR: Visibility requirements. 135.205 Section 135.205 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... Operating Limitations and Weather Requirements § 135.205 VFR: Visibility requirements. (a) No person may...

14 CFR 135.215 - IFR: Operating limitations.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false IFR: Operating limitations. 135.215 Section 135.215 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Operating Limitations and Weather Requirements § 135.215 IFR: Operating limitations. (a) Except as provided...

14 CFR 135.215 - IFR: Operating limitations.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false IFR: Operating limitations. 135.215 Section 135.215 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Operating Limitations and Weather Requirements § 135.215 IFR: Operating limitations. (a) Except as provided...

14 CFR 135.205 - VFR: Visibility requirements.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false VFR: Visibility requirements. 135.205 Section 135.205 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... Operating Limitations and Weather Requirements § 135.205 VFR: Visibility requirements. (a) No person may...

14 CFR 135.203 - VFR: Minimum altitudes.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false VFR: Minimum altitudes. 135.203 Section 135.203 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Operating Limitations and Weather Requirements § 135.203 VFR: Minimum altitudes. Except when necessary for...

14 CFR 135.215 - IFR: Operating limitations.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false IFR: Operating limitations. 135.215 Section 135.215 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Operating Limitations and Weather Requirements § 135.215 IFR: Operating limitations. (a) Except as provided...

14 CFR 135.203 - VFR: Minimum altitudes.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false VFR: Minimum altitudes. 135.203 Section 135.203 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Operating Limitations and Weather Requirements § 135.203 VFR: Minimum altitudes. Except when necessary for...

14 CFR 135.205 - VFR: Visibility requirements.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false VFR: Visibility requirements. 135.205 Section 135.205 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... Operating Limitations and Weather Requirements § 135.205 VFR: Visibility requirements. (a) No person may...

14 CFR 135.215 - IFR: Operating limitations.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false IFR: Operating limitations. 135.215 Section 135.215 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Operating Limitations and Weather Requirements § 135.215 IFR: Operating limitations. (a) Except as provided...

14 CFR 135.215 - IFR: Operating limitations.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false IFR: Operating limitations. 135.215 Section 135.215 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Operating Limitations and Weather Requirements § 135.215 IFR: Operating limitations. (a) Except as provided...

14 CFR 135.291 - Applicability.

Code of Federal Regulations, 2014 CFR

2014-01-01

... AND ON DEMAND OPERATIONS AND RULES GOVERNING PERSONS ON BOARD SUCH AIRCRAFT Crewmember Testing... checks required for pilot and flight attendant crewmembers and for the approval of check pilots in... chapter who meet the requirements of §§ 135.337 and 135.339 to conduct training, testing, and checking...

14 CFR 135.291 - Applicability.

Code of Federal Regulations, 2013 CFR

2013-01-01

... AND ON DEMAND OPERATIONS AND RULES GOVERNING PERSONS ON BOARD SUCH AIRCRAFT Crewmember Testing... checks required for pilot and flight attendant crewmembers and for the approval of check pilots in... chapter who meet the requirements of §§ 135.337 and 135.339 to conduct training, testing, and checking...

14 CFR 135.291 - Applicability.

Code of Federal Regulations, 2012 CFR

2012-01-01

... AND ON DEMAND OPERATIONS AND RULES GOVERNING PERSONS ON BOARD SUCH AIRCRAFT Crewmember Testing... checks required for pilot and flight attendant crewmembers and for the approval of check pilots in... chapter who meet the requirements of §§ 135.337 and 135.339 to conduct training, testing, and checking...

14 CFR 135.291 - Applicability.

Code of Federal Regulations, 2011 CFR

2011-01-01

... AND ON DEMAND OPERATIONS AND RULES GOVERNING PERSONS ON BOARD SUCH AIRCRAFT Crewmember Testing... checks required for pilot and flight attendant crewmembers and for the approval of check pilots in... chapter who meet the requirements of §§ 135.337 and 135.339 to conduct training, testing, and checking...

14 CFR 135.291 - Applicability.

Code of Federal Regulations, 2010 CFR

2010-01-01

... AND ON DEMAND OPERATIONS AND RULES GOVERNING PERSONS ON BOARD SUCH AIRCRAFT Crewmember Testing... checks required for pilot and flight attendant crewmembers and for the approval of check pilots in... chapter who meet the requirements of §§ 135.337 and 135.339 to conduct training, testing, and checking...

10 CFR 71.135 - Quality assurance records.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 2 2010-01-01 2010-01-01 false Quality assurance records. 71.135 Section 71.135 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) PACKAGING AND TRANSPORTATION OF RADIOACTIVE MATERIAL Quality Assurance § 71.135 Quality assurance records. The licensee, certificate holder, and applicant for a CoC...

47 CFR 87.135 - Bandwidth of emission.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 5 2010-10-01 2010-10-01 false Bandwidth of emission. 87.135 Section 87.135 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AVIATION SERVICES Technical Requirements § 87.135 Bandwidth of emission. (a) Occupied bandwidth is the width of a frequency...

14 CFR 135.217 - IFR: Takeoff limitations.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false IFR: Takeoff limitations. 135.217 Section 135.217 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Operating Limitations and Weather Requirements § 135.217 IFR: Takeoff limitations. No person may takeoff an...

14 CFR 135.217 - IFR: Takeoff limitations.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false IFR: Takeoff limitations. 135.217 Section 135.217 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Operating Limitations and Weather Requirements § 135.217 IFR: Takeoff limitations. No person may takeoff an...

14 CFR 135.217 - IFR: Takeoff limitations.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false IFR: Takeoff limitations. 135.217 Section 135.217 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Operating Limitations and Weather Requirements § 135.217 IFR: Takeoff limitations. No person may takeoff an...

14 CFR 135.217 - IFR: Takeoff limitations.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false IFR: Takeoff limitations. 135.217 Section 135.217 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Operating Limitations and Weather Requirements § 135.217 IFR: Takeoff limitations. No person may takeoff an...

14 CFR 135.217 - IFR: Takeoff limitations.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false IFR: Takeoff limitations. 135.217 Section 135.217 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED... Operating Limitations and Weather Requirements § 135.217 IFR: Takeoff limitations. No person may takeoff an...

Cheminformatics and Data Mining Approaches for Exploring the Alternatives Testing Landscsape: Case Studies in ToxCast and Skin Sensitization (BOSC CSS)

EPA Science Inventory

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...

32 CFR 13.5 - Policies.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 1 2010-07-01 2010-07-01 false Policies. 13.5 Section 13.5 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE MILITARY COMMISSIONS RESPONSIBILITIES OF THE CHIEF... or the General Counsel of the Department of Defense. 1 Available at http://www.dtic.mil/whs...

32 CFR 13.5 - Policies.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 1 2013-07-01 2013-07-01 false Policies. 13.5 Section 13.5 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE MILITARY COMMISSIONS RESPONSIBILITIES OF THE CHIEF... or the General Counsel of the Department of Defense. 1 Available at http://www.dtic.mil/whs...

32 CFR 13.5 - Policies.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 1 2011-07-01 2011-07-01 false Policies. 13.5 Section 13.5 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE MILITARY COMMISSIONS RESPONSIBILITIES OF THE CHIEF... or the General Counsel of the Department of Defense. 1 Available at http://www.dtic.mil/whs...

ISS during STS-135 Approach

NASA Image and Video Library

2011-07-10

S135-E-006777 (10 July 2011) --- This is one of a series of images showing the International Space Station photographed by a crewmember onboard the space shuttle Atlantis as the two spacecraft performed rendezvous and docking operations on the STS-135 mission's third day in Earth orbit. Photo credit: NASA

ISS during STS-135 Approach

NASA Image and Video Library

2011-07-10

S135-E-006784 (10 July 2011) --- This is one of a series of images showing the International Space Station photographed by a crewmember onboard the space shuttle Atlantis as the two spacecraft performed rendezvous and docking operations on the STS-135 mission's third day in Earth orbit. Photo credit: NASA

ISS during STS-135 Approach

NASA Image and Video Library

2011-07-10

S135-E-006700 (10 July 2011) --- This is one of a series of images showing the International Space Station photographed by a crewmember onboard the space shuttle Atlantis as the two spacecraft performed rendezvous and docking operations on the STS-135 mission's third day in Earth orbit. Photo credit: NASA

ISS during STS-135 Approach

NASA Image and Video Library

2011-07-10

S135-E-006698 (10 July 2011) --- This is one of a series of images showing the International Space Station photographed by a crewmember onboard the space shuttle Atlantis as the two spacecraft performed rendezvous and docking operations on the STS-135 mission's third day in Earth orbit. Photo credit: NASA

ISS during STS-135 Approach

NASA Image and Video Library

2011-07-10

S135-E-006702 (10 July 2011) --- This is one of a series of images showing the International Space Station photographed by a crewmember onboard the space shuttle Atlantis as the two spacecraft performed rendezvous and docking operations on the STS-135 mission's third day in Earth orbit. Photo credit: NASA

40 CFR 135.4 - Service of complaint.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 22 2011-07-01 2011-07-01 false Service of complaint. 135.4 Section 135.4 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS PRIOR NOTICE OF CITIZEN SUITS Prior Notice Under the Clean Water Act § 135.4 Service of complaint. (a) A...

40 CFR 135.4 - Service of complaint.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 21 2010-07-01 2010-07-01 false Service of complaint. 135.4 Section 135.4 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS PRIOR NOTICE OF CITIZEN SUITS Prior Notice Under the Clean Water Act § 135.4 Service of complaint. (a) A...

40 CFR 135.4 - Service of complaint.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 23 2012-07-01 2012-07-01 false Service of complaint. 135.4 Section 135.4 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS PRIOR NOTICE OF CITIZEN SUITS Prior Notice Under the Clean Water Act § 135.4 Service of complaint. (a) A...

40 CFR 135.12 - Contents of notice.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 22 2011-07-01 2011-07-01 false Contents of notice. 135.12 Section 135.12 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS PRIOR NOTICE OF CITIZEN SUITS Prior Notice Under the Safe Drinking Water Act § 135.12 Contents of notice. (a...

40 CFR 135.12 - Contents of notice.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 21 2010-07-01 2010-07-01 false Contents of notice. 135.12 Section 135.12 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS PRIOR NOTICE OF CITIZEN SUITS Prior Notice Under the Safe Drinking Water Act § 135.12 Contents of notice. (a...

Performance of 100-W HVM LPP-EUV source

NASA Astrophysics Data System (ADS)

Mizoguchi, Hakaru; Nakarai, Hiroaki; Abe, Tamotsu; Nowak, Krzysztof M.; Kawasuji, Yasufumi; Tanaka, Hiroshi; Watanabe, Yukio; Hori, Tsukasa; Kodama, Takeshi; Shiraishi, Yutaka; Yanagida, Tatsuya; Soumagne, Georg; Yamada, Tsuyoshi; Yamazaki, Taku; Okazaki, Shinji; Saitou, Takashi

2015-08-01

At Gigaphoton Inc., we have developed unique and original technologies for a carbon dioxide laser-produced tin plasma extreme ultraviolet (CO2-Sn-LPP EUV) light source, which is the most promising solution for high-power high-volume manufacturing (HVM) EUV lithography at 13.5 nm. Our unique technologies include the combination of a pulsed CO2 laser with Sn droplets, the application of dual-wavelength laser pulses for Sn droplet conditioning, and subsequent EUV generation and magnetic field mitigation. Theoretical and experimental data have clearly shown the advantage of our proposed strategy. Currently, we are developing the first HVM light source, `GL200E'. This HVM light source will provide 250-W EUV power based on a 20-kW level pulsed CO2 laser. The preparation of a high average-power CO2 laser (more than 20 kW output power) has been completed in cooperation with Mitsubishi Electric Corporation. Recently, we achieved 140 W at 50 kHz and 50% duty cycle operation as well as 2 h of operation at 100 W of power level. Further improvements are ongoing. We will report the latest status and the challenge to reach stable system operation of more than 100 W at about 4% conversion efficiency with 20-μm droplets and magnetic mitigation.

Evaluation of the Neuroactivity of ToxCast Compounds Using Multi-well Microelectrode Array Recordings in Primary Cortical Neurons

EPA Science Inventory

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...

Xenobiotic Metabolizing Enzyme and Transporter Gene Expression in Primary Cultures of Human Hepatocytes Modulated by ToxCast Chemicals

EPA Science Inventory

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...

22 CFR 135.33 - Supplies.

Code of Federal Regulations, 2010 CFR

2010-04-01

... supplies exceeding $5,000 in total aggregate fair market value upon termination or completion of the award... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Supplies. 135.33 Section 135.33 Foreign... Supplies. (a) Title. Title to supplies acquired under a grant or subgrant will vest, upon acquisition, in...

Identification of Estrogen-Related Receptor α Agonists in the Tox21 Compound Library.

PubMed

Lynch, Caitlin; Zhao, Jinghua; Huang, Ruili; Kanaya, Noriko; Bernal, Lauren; Hsieh, Jui-Hua; Auerbach, Scott S; Witt, Kristine L; Merrick, B Alex; Chen, Shiuan; Teng, Christina T; Xia, Menghang

2018-02-01

The estrogen-related receptor α (ERRα) is an orphan nuclear receptor (NR) that plays a role in energy homeostasis and controls mitochondrial oxidative respiration. Increased expression of ERRα in certain ovarian, breast, and colon cancers has a negative prognosis, indicating an important role for ERRα in cancer progression. An interaction between ERRα and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) has also recently been shown to regulate an enzyme in the β-oxidation of free fatty acids, thereby suggesting that ERRα plays an important role in obesity and type 2 diabetes. Therefore, it would be prudent to identify compounds that can act as activators of ERRα. In this study, we screened ∼10,000 (8311 unique) compounds, known as the Tox21 10K collection, to identify agonists of ERRα. We performed this screen using two stably transfected HEK 293 cell lines, one with the ERRα-reporter alone and the other with both ERRα-reporter and PGC-1α expression vectors. After the primary screening, we identified more than five agonist clusters based on compound structural similarity analysis (e.g., statins). By examining the activities of the confirmed ERRα modulators in other Tox21 NR assays, eliminating those with promiscuous NR activity, and performing follow-up assays (e.g., small interfering RNA knockdown), we identified compounds that might act as endocrine disrupters through effects on ERRα signaling. To our knowledge, this study is the first comprehensive analysis in discovering potential endocrine disrupters that affect the ERRα signaling pathway. Copyright © 2018 Endocrine Society.

Open Source Bayesian Models. 1. Application to ADME/Tox and Drug Discovery Datasets

PubMed Central

2015-01-01

On the order of hundreds of absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) models have been described in the literature in the past decade which are more often than not inaccessible to anyone but their authors. Public accessibility is also an issue with computational models for bioactivity, and the ability to share such models still remains a major challenge limiting drug discovery. We describe the creation of a reference implementation of a Bayesian model-building software module, which we have released as an open source component that is now included in the Chemistry Development Kit (CDK) project, as well as implemented in the CDD Vault and in several mobile apps. We use this implementation to build an array of Bayesian models for ADME/Tox, in vitro and in vivo bioactivity, and other physicochemical properties. We show that these models possess cross-validation receiver operator curve values comparable to those generated previously in prior publications using alternative tools. We have now described how the implementation of Bayesian models with FCFP6 descriptors generated in the CDD Vault enables the rapid production of robust machine learning models from public data or the user’s own datasets. The current study sets the stage for generating models in proprietary software (such as CDD) and exporting these models in a format that could be run in open source software using CDK components. This work also demonstrates that we can enable biocomputation across distributed private or public datasets to enhance drug discovery. PMID:25994950

40 CFR 135.3 - Contents of notice.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 22 2011-07-01 2011-07-01 false Contents of notice. 135.3 Section 135.3 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS PRIOR NOTICE OF CITIZEN SUITS Prior Notice Under the Clean Water Act § 135.3 Contents of notice. (a) Violation of...

40 CFR 135.3 - Contents of notice.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 21 2010-07-01 2010-07-01 false Contents of notice. 135.3 Section 135.3 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS PRIOR NOTICE OF CITIZEN SUITS Prior Notice Under the Clean Water Act § 135.3 Contents of notice. (a) Violation of...

40 CFR 135.3 - Contents of notice.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 23 2012-07-01 2012-07-01 false Contents of notice. 135.3 Section 135.3 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS PRIOR NOTICE OF CITIZEN SUITS Prior Notice Under the Clean Water Act § 135.3 Contents of notice. (a) Violation of...

40 CFR 135.4 - Service of complaint.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 22 2014-07-01 2013-07-01 true Service of complaint. 135.4 Section 135.4 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS PRIOR NOTICE OF CITIZEN SUITS Prior Notice Under the Clean Water Act § 135.4 Service of complaint. (a) A citizen...

40 CFR 135.3 - Contents of notice.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 22 2014-07-01 2013-07-01 true Contents of notice. 135.3 Section 135.3 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS PRIOR NOTICE OF CITIZEN SUITS Prior Notice Under the Clean Water Act § 135.3 Contents of notice. (a) Violation of standard...

40 CFR 135.13 - Timing of notice.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 21 2010-07-01 2010-07-01 false Timing of notice. 135.13 Section 135.13 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS PRIOR NOTICE OF CITIZEN SUITS Prior Notice Under the Safe Drinking Water Act § 135.13 Timing of notice. No action...

40 CFR 135.13 - Timing of notice.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 22 2011-07-01 2011-07-01 false Timing of notice. 135.13 Section 135.13 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS PRIOR NOTICE OF CITIZEN SUITS Prior Notice Under the Safe Drinking Water Act § 135.13 Timing of notice. No action...

17 CFR 230.135a - Generic advertising.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 17 Commodity and Securities Exchanges 2 2012-04-01 2012-04-01 false Generic advertising. 230.135a Section 230.135a Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION GENERAL RULES AND REGULATIONS, SECURITIES ACT OF 1933 General § 230.135a Generic advertising. (a) For the purposes only of...

17 CFR 230.135a - Generic advertising.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 17 Commodity and Securities Exchanges 2 2013-04-01 2013-04-01 false Generic advertising. 230.135a Section 230.135a Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION GENERAL RULES AND REGULATIONS, SECURITIES ACT OF 1933 General § 230.135a Generic advertising. (a) For the purposes only of...

17 CFR 230.135a - Generic advertising.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 17 Commodity and Securities Exchanges 2 2011-04-01 2011-04-01 false Generic advertising. 230.135a Section 230.135a Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION GENERAL RULES AND REGULATIONS, SECURITIES ACT OF 1933 General § 230.135a Generic advertising. (a) For the purposes only of...

17 CFR 230.135a - Generic advertising.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 17 Commodity and Securities Exchanges 2 2010-04-01 2010-04-01 false Generic advertising. 230.135a Section 230.135a Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION GENERAL RULES AND REGULATIONS, SECURITIES ACT OF 1933 General § 230.135a Generic advertising. (a) For the purposes only of...

17 CFR 230.135a - Generic advertising.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 17 Commodity and Securities Exchanges 3 2014-04-01 2014-04-01 false Generic advertising. 230.135a Section 230.135a Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION GENERAL RULES AND REGULATIONS, SECURITIES ACT OF 1933 General § 230.135a Generic advertising. (a) For the purposes only of...

36 CFR 223.135 - Effect of listing.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 36 Parks, Forests, and Public Property 2 2010-07-01 2010-07-01 false Effect of listing. 223.135 Section 223.135 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE SALE AND DISPOSAL OF NATIONAL FOREST SYSTEM TIMBER Suspension and Debarment of Timber Purchasers § 223.135 Effect of...

14 CFR 135.209 - VFR: Fuel supply.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false VFR: Fuel supply. 135.209 Section 135.209 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR CARRIERS... Limitations and Weather Requirements § 135.209 VFR: Fuel supply. (a) No person may begin a flight operation in...

14 CFR 135.209 - VFR: Fuel supply.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false VFR: Fuel supply. 135.209 Section 135.209 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR CARRIERS... Limitations and Weather Requirements § 135.209 VFR: Fuel supply. (a) No person may begin a flight operation in...

14 CFR 135.209 - VFR: Fuel supply.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false VFR: Fuel supply. 135.209 Section 135.209 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR CARRIERS... Limitations and Weather Requirements § 135.209 VFR: Fuel supply. (a) No person may begin a flight operation in...

14 CFR 135.209 - VFR: Fuel supply.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false VFR: Fuel supply. 135.209 Section 135.209 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR CARRIERS... Limitations and Weather Requirements § 135.209 VFR: Fuel supply. (a) No person may begin a flight operation in...

14 CFR 135.23 - Manual contents.

Code of Federal Regulations, 2010 CFR

2010-01-01

... in command in the briefing under § 135.117; (l) Flight locating procedures, when applicable; (m... § 135.123; (n) En route qualification procedures for pilots, when applicable; (o) The approved aircraft...

OpenVirtualToxLab--a platform for generating and exchanging in silico toxicity data.

PubMed

Vedani, Angelo; Dobler, Max; Hu, Zhenquan; Smieško, Martin

2015-01-22

The VirtualToxLab is an in silico technology for estimating the toxic potential--endocrine and metabolic disruption, some aspects of carcinogenicity and cardiotoxicity--of drugs, chemicals and natural products. The technology is based on an automated protocol that simulates and quantifies the binding of small molecules towards a series of currently 16 proteins, known or suspected to trigger adverse effects: 10 nuclear receptors (androgen, estrogen α, estrogen β, glucocorticoid, liver X, mineralocorticoid, peroxisome proliferator-activated receptor γ, progesterone, thyroid α, thyroid β), four members of the cytochrome P450 enzyme family (1A2, 2C9, 2D6, 3A4), a cytosolic transcription factor (aryl hydrocarbon receptor) and a potassium ion channel (hERG). The toxic potential of a compound--its ability to trigger adverse effects--is derived from its computed binding affinities toward these very proteins: the computationally demanding simulations are executed in client-server model on a Linux cluster of the University of Basel. The graphical-user interface supports all computer platforms, allows building and uploading molecular structures, inspecting and downloading the results and, most important, rationalizing any prediction at the atomic level by interactively analyzing the binding mode of a compound with its target protein(s) in real-time 3D. Access to the VirtualToxLab is available free of charge for universities, governmental agencies, regulatory bodies and non-profit organizations. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

The US EPA CompTox Chemistry Dashboard as a source of data to fill data gaps for chemical sources of risk

EPA Science Inventory

Chemical risk assessment is both time-consuming and difficult because it requires the assembly of data for chemicals generally distributed across multiple sources. The US EPA CompTox Chemistry Dashboard is a publicly accessible web-based application providing access to various da...

Predicting dermal penetration for ToxCast chemicals using in silico estimates for diffusion in combination with physiologically based pharmacokinetic (PBPK) modeling.

EPA Science Inventory

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 ...

46 CFR 160.135-5 - Incorporation by reference.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Polyester, High Strength, Flexible, (May 13, 1997), IBR approved for §§ 160.135-7 and 160.135-15. (“A-A... Specification for Carbon Structural Steel, (approved May 15, 2008), IBR approved for §§ 160.135-7 and 160.135-15 (“ASTM A 36”). (2) ASTM A 276-08a, Standard Specification for Stainless Steel Bars and Shapes, (approved...

46 CFR 160.135-5 - Incorporation by reference.

Code of Federal Regulations, 2012 CFR

2012-10-01

... Polyester, High Strength, Flexible, (May 13, 1997), IBR approved for §§ 160.135-7 and 160.135-15. (“A-A... Specification for Carbon Structural Steel, (approved May 15, 2008), IBR approved for §§ 160.135-7 and 160.135-15 (“ASTM A 36”). (2) ASTM A 276-08a, Standard Specification for Stainless Steel Bars and Shapes, (approved...

21 CFR 135.115 - Goat's milk ice cream.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 2 2012-04-01 2012-04-01 false Goat's milk ice cream. 135.115 Section 135.115... Goat's milk ice cream. (a) Description. Goat's milk ice cream is the food prepared in the same manner prescribed in § 135.110 for ice cream, and complies with all the provisions of § 135.110, except that the...

21 CFR 135.115 - Goat's milk ice cream.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 2 2013-04-01 2013-04-01 false Goat's milk ice cream. 135.115 Section 135.115... Goat's milk ice cream. (a) Description. Goat's milk ice cream is the food prepared in the same manner prescribed in § 135.110 for ice cream, and complies with all the provisions of § 135.110, except that the...

21 CFR 135.115 - Goat's milk ice cream.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 2 2014-04-01 2014-04-01 false Goat's milk ice cream. 135.115 Section 135.115... Goat's milk ice cream. (a) Description. Goat's milk ice cream is the food prepared in the same manner prescribed in § 135.110 for ice cream, and complies with all the provisions of § 135.110, except that the...

21 CFR 135.115 - Goat's milk ice cream.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 2 2011-04-01 2011-04-01 false Goat's milk ice cream. 135.115 Section 135.115... Goat's milk ice cream. (a) Description. Goat's milk ice cream is the food prepared in the same manner prescribed in § 135.110 for ice cream, and complies with all the provisions of § 135.110, except that the...

14 CFR 135.209 - VFR: Fuel supply.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false VFR: Fuel supply. 135.209 Section 135.209... AND ON DEMAND OPERATIONS AND RULES GOVERNING PERSONS ON BOARD SUCH AIRCRAFT VFR/IFR Operating Limitations and Weather Requirements § 135.209 VFR: Fuel supply. (a) No person may begin a flight operation in...

VirtualToxLab — A platform for estimating the toxic potential of drugs, chemicals and natural products

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vedani, Angelo, E-mail: angelo.vedani@unibas.ch; Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel; Dobler, Max

The VirtualToxLab is an in silico technology for estimating the toxic potential (endocrine and metabolic disruption, some aspects of carcinogenicity and cardiotoxicity) of drugs, chemicals and natural products. The technology is based on an automated protocol that simulates and quantifies the binding of small molecules towards a series of proteins, known or suspected to trigger adverse effects. The toxic potential, a non-linear function ranging from 0.0 (none) to 1.0 (extreme), is derived from the individual binding affinities of a compound towards currently 16 target proteins: 10 nuclear receptors (androgen, estrogen α, estrogen β, glucocorticoid, liver X, mineralocorticoid, peroxisome proliferator-activated receptormore » γ, progesterone, thyroid α, and thyroid β), four members of the cytochrome P450 enzyme family (1A2, 2C9, 2D6, and 3A4), a cytosolic transcription factor (aryl hydrocarbon receptor) and a potassium ion channel (hERG). The interface to the technology allows building and uploading molecular structures, viewing and downloading results and, most importantly, rationalizing any prediction at the atomic level by interactively analyzing the binding mode of a compound with its target protein(s) in real-time 3D. The VirtualToxLab has been used to predict the toxic potential for over 2500 compounds: the results are posted on (http://www.virtualtoxlab.org). The free platform — the OpenVirtualToxLab — is accessible (in client–server mode) over the Internet. It is free of charge for universities, governmental agencies, regulatory bodies and non-profit organizations. -- Highlights: ► In silico technology for estimating the toxic potential of drugs and chemicals. ► Simulation of binding towards 16 proteins suspected to trigger adverse effects. ► Mechanistic interpretation and real-time 3D visualization. ► Accessible over the Internet. ► Free of charge for universities, governmental agencies, regulatory bodies and NPOs.« less

Rotational band properties of 173W

NASA Astrophysics Data System (ADS)

Wang, H. X.; Zhang, Y. H.; Zhou, X. H.; Liu, M. L.; Ding, B.; Li, G. S.; Hua, W.; Zhou, H. B.; Guo, S.; Qiang, Y. H.; Oshima, M.; Koizumi, M.; Toh, Y.; Kimura, A.; Harada, H.; Furutaka, K.; Kitatani, F.; Nakamura, S.; Hatsukawa, Y.; Ohta, M.; Hara, K.; Kin, T.; Meng, J.

2012-10-01

High-spin states in 173W have been studied using the 150Nd(28Si,5n)173W reaction at beam energies of 135 and 140 MeV. The previously known bands associated with the 7/2+[633], 5/2-[512], and 1/2-[521] configurations are extended significantly, and the unfavored signature branch of the 1/2-[521] band is established for the first time. The band properties, such as level spacings, band-crossing frequencies, alignment gains, and signature splittings, are discussed with an emphasis on the low-spin signature inversion observed in the 5/2-[512] band. By comparing the experimental B(M1)/B(E2) ratios with the theoretical values, we conclude that the configuration of the 5/2-[512] band is quite pure at low spins without appreciable admixture of the 5/2-[523] orbit, in conflict with the particle rotor model calculated results.

Application of Targeted Functional Assays to Assess a Putative Vascular Disruption Developmental Toxicity Pathway Informed By ToxCast High-Throughput Screening Data

EPA Science Inventory

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...

Real-time prediction of Physicochemical and Toxicological Endpoints Using the Web-based CompTox Chemistry Dashboard (ACS Fall meeting) 10 of 12

EPA Science Inventory

The EPA CompTox Chemistry Dashboard developed by the National Center for Computational Toxicology (NCCT) provides access to data for ~750,000 chemical substances. The data include experimental and predicted data for physicochemical, environmental fate and transport and toxicologi...