Activity profiles of 309 ToxCast™ chemicals evaluated across 292 biochemical targets

Knudsen, Thomas B.; Houck, Keith A.; Sipes, Nisha S.; Singh, Amar V.; Judson, Richard S.; Martin, Matthew T.; Weissman, Arthur D.; Kleinstreuer, Nicole; Mortensen, Holly M.; Reif, David M.; Rabinowitz, James R.; Setzer, R. Woodrow; Richard, Ann M.; Dix, David J.; Kavlock, Robert J.

doi:10.1016/j.tox.2010.12.010

Cited by 127 publications

(114 citation statements)

References 63 publications

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“…These included practical properties such as commercial availability as well as physical properties such as solubility. These properties largely mirror criteria developed for the ToxCast and LIINTOP programs (Knudsen et al 2011;Gomez-Lechon et al 2010) and can be found at the ToxBank Wiki, http://wiki.toxbank. net/wiki/.…”

Section: General Propertiesmentioning

confidence: 89%

“…Promiscuity may be a function of the toxicant, for example, alkylating or redox activity that is relatively indiscriminate with respect to biological target; alternatively, promiscuity may be a property of the biological target, exemplified by receptors that have evolved to present open, hydrophobic binding pockets that are less selective with respect to ligand binding (Azzaoui et al 2007;Nolte et al 1998). In the current effort, identification of promiscuous receptors was guided by data from the ToxCast Phase I screening effort (Knudsen et al 2011;Martin et al 2010). …”

Section: Promiscuitymentioning

confidence: 99%

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SEURAT-1 liver gold reference compounds: a mechanism-based review

et al. 2014

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There is an urgent need for the development of alternative methods to replace animal testing for the prediction of repeat dose chemical toxicity. To address this need, the European Commission and Cosmetics Europe have jointly funded a research program for 'Safety Evaluation Ultimately Replacing Animal Testing.' The goal of this program was the development of in vitro cellular systems and associated computational capabilities for the prediction of hepatic, cardiac, renal, neuronal, muscle, and skin toxicities. An essential component of this effort is the choice of appropriate reference compounds that can be used in the development and validation of assays. In this review, we focus on the selection of reference compounds for liver pathologies in the broad categories of cytotoxicity and lipid disorders. Mitochondrial impairment, oxidative stress, and apoptosis are considered under the category of cytotoxicity, while steatosis, cholestasis, and phospholipidosis are considered under the category of lipid dysregulation. We focused on four compound classes capable of initiating such events, i.e., chemically reactive compounds, compounds with specific cellular targets, compounds that modulate lipid regulatory networks, and compounds that disrupt the plasma membrane. We describe the molecular mechanisms of these compounds and the cellular response networks which they elicit. This information will be helpful to both improve our understanding of mode of action and help in the selection of appropriate mechanistic biomarkers, allowing us to progress the development of animal-free models with improved predictivity to the human situation.

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Section: General Propertiesmentioning

confidence: 89%

Section: Promiscuitymentioning

confidence: 99%

SEURAT-1 liver gold reference compounds: a mechanism-based review

et al. 2014

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“…In total, there are up to 700 assays or assay end-points being used as part of the ToxCast programme. These cover a large range of technologies, including cell-free biochemical assays, assays targeting nuclear and other receptors and other molecular targets, assays measuring downstream integrated cell processes and model organisms (especially zebrafish) [5,6,[13][14][15][16][17][18][19][20][21][22][23][24]. The complete set of assay descriptions can be found at the ToxCast website.…”

Section: Methodsmentioning

confidence: 99%

In Vitro and Modelling Approaches to Risk Assessment from the U.S. Environmental Protection Agency ToxCast Programme

Judson

Houck

Martin

et al. 2014

Basic Clin Pharma Tox

129

101

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A significant challenge in toxicology is the 'too many chemicals' problem. Human beings and environmental species are exposed to tens of thousands of chemicals, only a small percentage of which have been tested thoroughly using standard in vivo test methods. This study reviews several approaches that are being developed to deal with this problem by the U.S. Environmental Protection Agency, under the umbrella of the ToxCast programme (http://epa.gov/ncct/toxcast/). The overall approach is broken into seven tasks: (i) identifying biological pathways that, when perturbed, can lead to toxicity; (ii) developing highthroughput in vitro assays to test chemical perturbations of these pathways; (iii) identifying the universe of chemicals with likely human or ecological exposure; (iv) testing as many of these chemicals as possible in the relevant in vitro assays; (v) developing hazard models that take the results of these tests and identify chemicals as being potential toxicants; (vi) generating toxicokinetics data on these chemicals to predict the doses at which these hazard pathways would be activated; and (vii) developing exposure models to identify chemicals for which these hazardous dose levels could be achieved. This overall strategy is described and briefly illustrated with recent examples from the ToxCast programme.

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“…Some of these new approaches utilise computational approaches such as physiologically based pharmacokinetic (PBPK) modelling to weigh existing toxicity data, while others generate new toxicity data employing a vast array of in vitro approaches such as high-throughput screening (HTS) data. The US EPA have spent millions generating new in vitro HTS data in the ToxCast I, II and III programs (Knudsen et al, 2011;Sipes et al, 2013;Judson et al, 2014) as well developing new tools to integrate all types of data in a meaningful manner (Reif et al, 2010. ToxPi GUI, a computational tool launched by the US EPA is an example of an interface that integrates all types of data from multiple sources into a visual format for chemical prioritisation .…”

Section: State Of the Sciencementioning

confidence: 99%

Integrating emerging technologies into chemical safety assessment: progress since the 2012 report of the expert panel on the integrated testing of pesticides

Ritter

Kacew

Krewski

2017

IJRAM

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Governments need to categorise tens of thousands of data-poor chemicals in order to better inform human health risk assessment. Pesticide active ingredients have contributed considerably to our understanding of the toxicological mechanisms; however, in order to move forward there is a pressing need for testing that is faster and less expensive based upon the chemical specific mode-of-action (MOA). Currently, a comprehensive set of these alternative methods does not yet exist, although the state of the science is rapidly evolving. The next two to ten years will see a global progression towards the use of integrated testing strategies (ITS) in decision-making for both data-rich and data-poor chemicals. Regulatory deployment of integrated approaches to testing and assessment (IATA) will depend upon the types of chemicals and the nature of the decision-making process by regulatory authorities. Regulators need to recognise that adoption of IATA strategies would require the engagement and approval of public stakeholders in order to alleviate concerns regarding potential adverse risks to human health and the environment. The new approach cannot be used to simply streamline processes or sacrifice human and environmental safety for social or economic benefits. Integrating emerging technologies into chemical safety assessment 47

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Activity profiles of 309 ToxCast™ chemicals evaluated across 292 biochemical targets

Cited by 127 publications

References 63 publications

SEURAT-1 liver gold reference compounds: a mechanism-based review

SEURAT-1 liver gold reference compounds: a mechanism-based review

In Vitro and Modelling Approaches to Risk Assessment from the U.S. Environmental Protection Agency ToxCast Programme

Integrating emerging technologies into chemical safety assessment: progress since the 2012 report of the expert panel on the integrated testing of pesticides

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