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Environmental Factor, August 2015

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Groundbreaking EPA testing plan builds on NTP work to replace animal use

By Catherine Sprankle

Headshot of Nicole Kleinstreuer

“The application of these innovative tools … represents the first step in a paradigm shift for chemical safety testing, a practical approach to rapidly screen thousands of environmental chemicals for potential endocrine bioactivity in humans and wildlife, and the first systematic application of ToxCast data in an EPA regulatory program,” wrote Kleinstreuer and her co-authors. (Photo courtesy of Steve McCaw)

Casey and members of the International cooperation

During ASIATOX, Casey, fourth from right, met with members of the International Cooperation on Alternative Test Methods. NICEATM coordinates test method validation activities with its international counterparts through the group, which also includes member organizations from the European Union, Canada, Japan, and South Korea. (Photo courtesy of Warren Casey) (Photo courtesy of Warren Casey)

The U.S. Environmental Protection Agency (EPA) has proposed replacing certain animal tests in its Endocrine Disruptor Screening Program (EDSP) with high-throughput assays and computational methods. In a June 18 press release, EPA said the new approach, which was developed and validated by scientists at EPA and the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), will increase the pace of screening and decrease costs and animal use.

“This is the first proposal for using high-throughput assay data to replace toxicology tests required by law,” noted NICEATM scientist Nicole Kleinstreuer, Ph.D., who helped develop the computational model. She is a co-author of an article in the journal Environmental Science and Technology, which described the new approach in detail. “Using this kind of technology in the EDSP will allow for faster screening of thousands of chemicals,” she said. EPA published a June 19 Federal Register notice asking for comments on the new approach, which focuses on testing for estrogenic activity. Comments will be accepted through August 18.

Screening for estrogenic activity

The screening program is designed to identify chemicals in the environment that may interfere with the normal function of hormones and potentially cause health problems in humans and animals. Chemicals identified in the Tier 1 screening phase as having the potential to interfere with normal hormone function progress to the Tier 2 testing phase.

EPA recently released results for the first 52 chemicals to complete Tier 1 screening under the current protocols, which can take more than five years for any given set of chemicals. Because thousands of chemicals remain to be screened, there is great interest in developing faster and cheaper approaches.

New approach will replace animal tests

Five EDSP Tier 1 assays are used to identify chemicals with potential to interfere with estrogen hormones. The new approach will replace three of these assays, including two that require the use of animals.

To develop the new screening approach, EPA and NICEATM scientists first turned to the EPA program and identified 18 high-throughput assays that represented key events in estrogen hormone function. Data from these assays were used in a computational model of the estrogen receptor pathway to determine the probability that the chemical would interfere with estrogen hormone function.

The accuracy of the model was evaluated by comparing the model’s prediction against existing data curated by NICEATM from both animal and nonanimal tests. “This evaluation was key to ensuring that the new approach will be useful in the EDSP,” explained NICEATM Director Warren Casey, Ph.D., who was also a co-author on the paper. “We used data from well-studied estrogen-active chemicals and compared the model scores with results obtained from methods currently used for regulatory decision-making.”

Casey presented this approach to an EPA advisory panel meeting in December, at which members of industry and animal welfare groups expressed their support.

Citation: Browne P, Judson RS, Casey WM, Kleinstreuer NC, Thomas RS. 2015. Screening chemicals for estrogen receptor bioactivity using a computational model. Environ Sci Technol; doi:10.1021/acs.est.5b02641 [Online 12 June 2015].

(Catherine Sprankle is a communications specialist for ILS, the contractor supporting NICEATM.)

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