New CompTox Approach Targets Thyroid

By Michaela Burns

We are exposed to chemicals everyday— either through chemicals in the environment, in our food or water, or by using consumer products such as shampoos, colognes, and perfumes.  Chemicals help these products to do their jobs—whether cleaning your body or making you smell good. Soap / lotion / shampoo against whiteWorking with industry and other interest groups, EPA evaluates these chemicals and, if necessary, regulates their presence in the environment to help protect our health. Because traditional testing approaches are time-intensive, only a small fraction of chemicals have been evaluated fully for potential human health effects. New methods are needed to rapidly address chemical safety.

To help address this problem, EPA has been developing new computational toxicology methods to prioritize chemicals for testing. One example of this effort is the Endocrine Disruptor Screening Program in the 21st century (EDSP21) which uses the latest computational toxicology methods to evaluate chemicals for potential endocrine disruption.  Recent EPA research in this area is focused on evaluating chemicals for thyroid disruption.

Why is EPA interested in the thyroid? Well, the thyroid, an organ that is located at the front of your neck, is responsible for producing thyroid hormone, a process called thyroid synthesis. Exposure to certain chemicals can interfere with thyroid hormone synthesis, resulting in less thyroid hormone in blood and tissues. In adults, thyroid hormone helps regulate key functions, including metabolism rate and the amount of blood pumped into our heart per minute. When thyroid synthesis is disturbed in the adult body, it can cause reversible symptoms such as depression, fatigue, weight gain, and constipation. Thyroid hormones also help regulate brain development in utero, which means that pregnant mothers and children are populations of concern for thyroid hormone changes. A decrease in thyroid hormone availability during development of a fetus can result in irreversible changes to intelligence, cognitive ability, and motor skills. These potential health effects make it critical that we identify chemicals that may alter thyroid hormone levels.

One of the ways that thyroid hormone synthesis can be decreased is by inhibition of an enzyme called thyroperoxidase. EPA researchers have developed and are using a high-throughput screening assay to detect inhibitors of thyroperoxidase. This high-throughput screening assay can be used to screen thousands of chemicals at a fraction of the time and cost of traditional in vitro and/or whole animal studies.

In 2016 researchers published a scientific paper, Tiered High-Throughput Screening Approach to Identify Thyroperoxidase Inhibitors Within the ToxCast Phase I and II Chemical Libraries (Paul Friedman et al.). This paper describes the results and analysis from screening 1074 chemical samples for potential thyroperoxidase inhibition.

This the largest screening effort to date to identify chemicals that inhibit thyroperoxidase, and it’s only the beginning! This work is part of a larger EPA effort to develop a set of new high-throughput screening assays and other faster computational toxicology approaches to evaluate how chemicals might change thyroid hormone homeostasis. The ultimate goal is to screen chemicals as efficiently as possible in order to make a prediction about whether a chemical may affect thyroid hormones.

And all of EPA’s computational toxicology data, including the data from this paper on screening for thyroperoxidase inhibition, are publicly accessible. You can find and interact with the data through the EPA ToxCast Dashboard and all of the data can be downloaded from the ToxCast data download website.

About the Author: Michaela Burns is an Oak Ridge Associated Universities contractor and writer for the science communication team in EPA’s Office of Research and Development.

Editor's Note: The views expressed here are intended to explain EPA policy. They do not change anyone's rights or obligations. You may share this post. However, please do not change the title or the content, or remove EPA’s identity as the author. If you do make substantive changes, please do not attribute the edited title or content to EPA or the author.

EPA's official web site is www.epa.gov. Some links on this page may redirect users from the EPA website to specific content on a non-EPA, third-party site. In doing so, EPA is directing you only to the specific content referenced at the time of publication, not to any other content that may appear on the same webpage or elsewhere on the third-party site, or be added at a later date.

EPA is providing this link for informational purposes only. EPA cannot attest to the accuracy of non-EPA information provided by any third-party sites or any other linked site. EPA does not endorse any non-government websites, companies, internet applications or any policies or information expressed therein.

The iCSS Chemistry Dashboard – The First Step in Building a Strong Chemistry Foundation for 21st Century Toxicology

By Antony Williams

photo of antony williams

Computational Chemist Antony Williams is the project lead for the iCSS Chemistry Dashboard

EPA has released the Interactive Chemical Safety for Sustainability Chemistry Dashboard—or the iCSS Chemistry Dashboard—a new web application to support scientists in chemical research.

The dashboard is a new app in the armory of computational toxicologists everywhere. It provides data on over 700,000 chemicals including access to nearly 10,000,000 experimental and predicted chemical properties via a website search.  The data are downloadable at the click of a button and are even viewable on your smartphone or tablet. The data and an associated collection of additional resources have been brought together in one application.

The dashboard provides access to the rich and highly curated content that is contained within the Distributed Structure-Searchable Toxicity Database (DSSTox) which was first released in 2002.  The data contained within the DSSTox database has been expanded over the years and now is available via an intuitive website for searching.

For this project, we focused our efforts on building a web application that allows the public to easily search our chemistry data. A number of dashboards and web applications have been built over the years including the Aggregated Computational Toxicology Resource, the ToxCast dashboard, and the Endocrine Disruptor Screening Program dashboard. We were able to take advantage of this previous work and improve the user experience for navigating the data. The resulting web application was released on April 1st, no joke, for beta testing in the real world and to gather initial feedback from the community.

The new chemistry dashboard has been available for only a couple of months and is already garnering positive feedback from its users. New data, functionality, and capabilities are in development to provide regular updates to the application. Much like with Wikipedia’s “crowdsourced feedback”, the application’s users are able to inform us of any issues they see in the data at the individual chemical level to improve the data for all users. As crowdsourced collaboration is increasingly used in the curation of chemistry data, we expect the iCSS Chemistry Dashboard to become one of the primary platforms for environmental chemists and computational toxicologists around the world and form the chemistry foundation for EPA’s efforts in 21st century toxicology.

About the Author: Antony (Tony) Williams is a computational chemist in the National Center for Computational Toxicology and the project leader for the iCSS Chemistry Dashboard. He is an analytical scientist and cheminformatician by training and was one of the original founders for the ChemSpider website. He is widely published with over 150 publications and books/book chapters.

Editor's Note: The views expressed here are intended to explain EPA policy. They do not change anyone's rights or obligations. You may share this post. However, please do not change the title or the content, or remove EPA’s identity as the author. If you do make substantive changes, please do not attribute the edited title or content to EPA or the author.

EPA's official web site is www.epa.gov. Some links on this page may redirect users from the EPA website to specific content on a non-EPA, third-party site. In doing so, EPA is directing you only to the specific content referenced at the time of publication, not to any other content that may appear on the same webpage or elsewhere on the third-party site, or be added at a later date.

EPA is providing this link for informational purposes only. EPA cannot attest to the accuracy of non-EPA information provided by any third-party sites or any other linked site. EPA does not endorse any non-government websites, companies, internet applications or any policies or information expressed therein.

Ushering In a New Generation of Chemical Screening

By Richard Judson

I work with EPA colleagues and other scientists around the world to integrate advances in biology, biotechnology, chemistry, and computer science to evaluate thousands of chemicals. Part of our research is supporting EPA’s Endocrine Disruptor Screening Program, exploring the potential for chemicals to disrupt normal growth and development in humans and other animals.

The work we do is helping usher in a new generation of faster, more efficient, and far less costly chemical screening methods. We use automated technologies, called high-throughput screening assays, to expose cells and proteins to chemicals. We then screen them to identify any that exhibited changes in biological activity that may suggest the potential for endocrine disruption.

My partners and I are excited to announce that we have recently published two papers on results of our work. We used the innovative methods described above to screen chemicals for their potential to mimic normal estrogen hormones, substances that direct development and reproduction. Exposure to chemicals that mimic estrogen pose a range of potential health risks, including birth defects and certain types of cancer.

The first paper, published in Nature Scientific Reports, describes the results of screening approximately 10,500 chemicals. The screening included 88 duplicates of the same chemicals, which validated the reliability of the assays. It also included 39 reference chemicals—those whose estrogen-receptor activity have been well established through traditional testing methods. Using the reference chemicals showed that the assays could accurately identify chemicals that were both positive and negative for their ability to mimic natural estrogens.

Robotic arm moving samples for screening

Robotic arm moves samples for automated chemical screening, part of the Tox 21 collaboration.

This paper is a product of Tox21, a federal collaboration pooling expertise and resources among EPA, the National Toxicology Program (National Institute of Environmental Health Sciences), the Food and Drug Administration, and the National Center for Advancing Translational Sciences (NCATS). Tox21 was established to study how high-throughput screening methods can be used to evaluate thousands of chemicals. These assays were run on the NCATS ultra-high-throughput robotic screening system (pictured).

The second paper (selected by the American Chemical Society’s Environmental Science and Technology journal as an editor’s choice) describes the results of screening 1,814 chemicals (including 36 reference chemicals). The screening was performed using a panel of 13 high-throughput estrogen receptor assays that use a diverse set of cell types and assay technologies.The results indicate that such a panel can accurately predict estrogenic responses. It demonstrates how the resulting data could be used for chemical prioritization as part of the Agency’s Endocrine Disruptor Screening Program.

In December 2013, we publicly released our high-throughput screening data through user-friendly web applications called interactive Chemical Safety for Sustainability (iCSS) Dashboards. I encourage anyone with an interest in this research to take a look at the data and to also participate in EPA’s Second ToxCast Data Summit. The summit is scheduled for September 29-30, 2014 in Research Triangle Park, NC.

The goal of the summit is to bring together the user community (industry, non-governmental organizations, academia, governmental agencies and more) to present their ideas for ways to use the large amount of high-throughput screening data to help inform chemical policy and regulatory decisions.

About the Author: EPA scientist Dr. Richard Judson develops databases and computer applications to model and predict toxicological effects of a wide range of chemicals. He is a member of the EPA Computational Toxicology research team where he leads the effort in bioinformatics. Dr. Judson has a BA in Chemistry and Chemical Physics from Rice University and an MA and PhD in Chemistry from Princeton University.

Information About the Papers

Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway. Ruili Huang, Srilatha Sakamuru, Matt T. Martin, David M. Reif, Richard S. Judson, Keith A. Houck, Warren Casey, Jui-Hua Hsieh, Keith Shockley, Patricia Ceger, Jennifer Fostel, Kristine L. Witt, Weida Tong, Daniel M. Rotroff,2 Tongan Zhao, Paul Shinn, Anton Simeonov, David J. Dix, Christopher P. Austin, Robert J Kavlock, Raymond R. Tice, Menghang Xia. Nature Scientific Reports

Predictive Endocrine Testing in the 21st Century Using in Vitro Assays of Estrogen Receptor Signaling Responses. Daniel M. Rotroff, Matt T. Martin, David J. Dix, Dayne L. Filer, Keith A. Houck, Thomas B. Knudsen, Nisha S. Sipes, David M. Reif, Menghang Xia, Ruili Huang, and Richard S. Judson. Environmental Science & Technology

Editor's Note: The views expressed here are intended to explain EPA policy. They do not change anyone's rights or obligations. You may share this post. However, please do not change the title or the content, or remove EPA’s identity as the author. If you do make substantive changes, please do not attribute the edited title or content to EPA or the author.

EPA's official web site is www.epa.gov. Some links on this page may redirect users from the EPA website to specific content on a non-EPA, third-party site. In doing so, EPA is directing you only to the specific content referenced at the time of publication, not to any other content that may appear on the same webpage or elsewhere on the third-party site, or be added at a later date.

EPA is providing this link for informational purposes only. EPA cannot attest to the accuracy of non-EPA information provided by any third-party sites or any other linked site. EPA does not endorse any non-government websites, companies, internet applications or any policies or information expressed therein.