National Toxicology Program

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 opinions expressed here are those of the author. They do not reflect EPA policy, endorsement, or action.

Please share this post. However, please don't change the title or the content. If you do make changes, don't attribute the edited title or content to EPA or the author.

Evaluating Studies to Understand if a Chemical Causes Cancer

IRIS graphic identifier

By Kacee Deener

When friends ask me what I do, I always mention the Integrated Risk Information System (IRIS) Program and explain that through IRIS, EPA scientists help protect public health by evaluating scientific information on the health effects that may result from exposure to environmental contaminants.  The questions inevitably come up—how do you do that, and what kind of information do you look at?

Scientists around the world contribute to the knowledgebase about the health effects of chemicals.  A particular area of interest has been chemicals’ potential to cause cancer.

Because EPA’s work must be grounded in the best possible science, we recently updated how we consider some of the cancer research of the Ramazzini Institute (RI), a laboratory in Italy known throughout the world for their extensive work in this area, completing cancer studies for more than 200 compounds.

A few years ago, the National Toxicology Program (NTP) identified differences of opinion between their own scientists and those from the Ramazzini Institute in diagnosing certain types of cancers in a study on methanol.  The scientific community—including EPA—was concerned, since Ramazzini data was included in IRIS evaluations.  We reviewed all of our IRIS assessments to determine which, if any, relied substantially on RI data; we found four that did, and we put those assessments on hold.

To follow up, EPA and the National Institute of Environmental Health Sciences cosponsored a group of scientists with expertise in evaluating tissue samples and making disease diagnoses, a Pathology Working Group (PWG), to review several Ramazzini Institute studies. They found some instances where respiratory infections in Ramazzini study animals made definitive diagnoses difficult, and disagreed with some Ramazzini diagnoses, primarily certain leukemias and lymphomas that had been identified. Therefore, EPA decided not to rely on RI data on lymphomas and leukemias in IRIS assessments. There was agreement, though, in diagnosing solid tumors, and EPA decided to continue to consider Ramazzini Institute solid tumor data in IRIS assessments.

This has been an important issue in the world of chemical risk assessment. Last week, this was highlighted once again when a paper authored by EPA scientists, Scientific Considerations for Evaluating Cancer Bioassays Conducted by the Ramazzini Institute, was published in Environmental Health Perspectives.  The article interprets Ramazzini Institute study results and compares their testing protocols with those used by other federal agencies.  The results were consistent with the PWG findings—Ramazzini Institute results for cancer endpoints other than lymphoma and leukemias, and some cases of tumors of the inner ear and cranium, are generally consistent with those of the National Toxicology Program and other laboratories.  The paper also notes that, while differences in Ramazzini Institute testing protocols can complicate the interpretation of study results, they may also provide chemical risk assessors with insights that might not be observed in other laboratories.

The short answer to my friends’ questions is that EPA works to use the best available science—from across the U.S. and around the world—to support IRIS and our other assessments designed to protect public health.

About the Author:  Kacee Deener is the Communications Director in EPA’s National Center for Environmental Assessment, home of the IRIS Program.  She joined EPA 12 years ago and has a Masters degree in Public Health.

Editor's Note: The opinions expressed here are those of the author. They do not reflect EPA policy, endorsement, or action.

Please share this post. However, please don't change the title or the content. If you do make changes, don't attribute the edited title or content to EPA or the author.

Science Wednesday: The Future is Now

Each week we write about the science behind environmental protection. Previous Science Wednesdays.

By Aaron Ferster

When I was a kid one of my favorite shows was a cartoon about a space-age family that tooled around in a flying, spaceship-like car. Cool. “I hope we have that when I’m a dad,” I thought.

While my mode of transportation is earthbound, some of the show’s futuristic gadgets have actually come to pass: I call home with a pocket-sized phone, video conferencing is here, and many of us spend our workdays surrounded by banks of computer screens—even if we don’t make sprockets.

I recently got another glimpse of our emerging high-tech future when EPA joined its research partners from the National Institutes of Environmental Health Sciences (NIEHS) National Toxicology Program, the National Institute of Health (NIH) Chemical Genomics Center, the Food and Drug Administration (FDA), and others to unveil a high-speed robot screening system. The robots are set up to test chemicals for their potential to trigger health problems.

The system consists of robot arms that continually move rectangle “plates” through the toxicity testing process. Each plate contains 1536 small wells that can hold a dab of chemical solution and cells (human and non-human animal), and the arm precisely moves each plate though exposure testing and computer analysis. Take a look at this video to see it in action.

The robot system, housed at the National Institutes of Health Chemical Genomics Center (NCGC) in Rockville, Maryland, was purchased as part of the Tox21 collaboration between the EPA, NIEH’s National Toxicology Program, NCGC, and FDA. Tox21 merges existing resources—research, funding and testing tools—to develop ways to more effectively predict how chemicals will affect human health and the environment.

Tox21 partners have already screened more than 2,500 chemicals for potential toxicity using robots and other innovative chemical screening technologies, such as ToxCast. EPA tapped such technologies to test oil dispersants for potential endocrine disrupting activity following the BP spill in the Gulf of Mexico last year.

The 10,000 chemicals the robot system will screen include those found in industrial and consumer products, food additives, and drugs. Testing results will provide information useful for evaluating if these chemicals have the potential to disrupt human body processes enough to lead to adverse health effects.

While I’m still looking forward to my first flying car, knowing the future should contain fewer potentially harmful chemicals is pretty exciting, too. Especially now that I’m a dad.

About the author: Aaron Ferster is the editor of Science Wednesday and a frequent contributor.

Editor’s Note: The opinions expressed in Greenversations are those of the author. They do not reflect EPA policy, endorsement, or action, and EPA does not verify the accuracy or science of the contents of the blog.

Editor's Note: The opinions expressed here are those of the author. They do not reflect EPA policy, endorsement, or action, and EPA does not verify the accuracy or science of the contents of the blog.

Please share this post. However, please don't change the title or the content. If you do make changes, don't attribute the edited title or content to EPA or the author.