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ICCVAM Recommends Non-animal In Vitro Method to Identify Potential Endocrine-active Substances

The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) recently evaluated the usefulness of a non-animal test method that can identify substances with the potential for interacting with the estrogen receptor in vitro. As announced in today's Federal Register, ICCVAM recommended to Federal agencies that this test method, the BG1Luc ER TA, can be used as a screening test to identify substances with in vitro estrogen agonist and antagonist activity.

Chemicals and chemical products that have the potential to interfere with the normal function of hormones in the endocrine system are known as endocrine disruptors or endocrine-active substances. These substances may interact with hormone receptors, potentially leading to abnormal growth, development, or reproduction.

The BG1Luc estrogen receptor (ER) transactivation (TA) test method, also known as the LUMI-CELL® ER test method, was developed to identify substances that can induce or inhibit human ER activity in vitro. Xenobiotic Detection Systems, Inc. (XDS, Durham, NC) developed LUMI-CELL® ER with the support of an NIEHS Small Business Innovation Research grant and nominated the method to ICCVAM for an interlaboratory validation study.

ICCVAM and the Scientific Advisory Committee on Alternative Toxicological Methods (SACATM) recommended the study as a high priority. The National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), which administers ICCVAM, subsequently coordinated an international validation study with counterparts in Japan (the Japanese Center for the Validation of Alternative Methods) and Europe (the European Centre for the Validation of Alternative Methods).

ICCVAM's Interagency Endocrine Disruptor Working Group (EDWG), composed of scientists from ICCVAM member agencies, worked with NICEATM to carry out relevant evaluation activities following completion of the international validation study. A background review document, test method performance standards, and ICCVAM test method recommendations were reviewed by an independent international peer review panel. ICCVAM considered the Panel report and comments from the public, the EDWG, and SACATM in preparing the final test method recommendations.

ICCVAM recommends that the accuracy and reliability of the BG1Luc ER TA test method support its use as a screening test to identify substances that can induce or inhibit human ER activity in vitro. ICCVAM concludes that the accuracy of this assay is at least equivalent to the only ER TA test method currently in a U.S. regulatory test guideline, the Environmental Protection Agency's "OPPTS 890.1300: Estrogen Receptor Transcriptional Activation (Human Cell Line (HeLa- 9903))". In addition, the BG1Luc ER TA test method was found to offer several advantages over the existing ER TA method, including (1) validation for use over a wider concentration range of test substances, (2) potential to detect a wider range of ER-active substances, (3) ability to identify both substances that induce and inhibit the estrogen receptor, and (4) availability of the cell line used for the test from more than one source.

The ICCVAM evaluation is detailed in a report entitled ICCVAM Test Method Evaluation Report: The LUMI-CELL® ER (BG1Luc ER TA) Test Method: An In Vitro Assay for Identifying Human Estrogen Receptor Agonist and Antagonist Activity of Chemicals (NIH Publication No. 11-7850). The report also provides (1) performance standards that can be used to evaluate functionally and mechanistically similar test methods, (2) recommended test method protocols, (3) a final background review document describing the current validation status of this test method, and (4) recommendations for future studies.

The ICCVAM report and recommendations have been transmitted to Federal agencies for their review and response to ICCVAM in accordance with the provisions of the ICCVAM Authorization Act of 2000, which requires agencies to review the recommendations and respond to ICCVAM within 180 days.

The BG1Luc ER TA test method was adapted to a high-throughput format using 1536-well plates by the National Institutes of Health (NIH) Center for Translational Therapeutics (NCTT; formerly the NIH Chemical Genomics Center). Preliminary results are promising, and it is expected that this method will be incorporated into the Tox21 screening paradigm in 2012.

The ICCVAM Test Method Evaluation Report is available on the NICEATM-ICCVAM website here.

The Federal Register notice announcing the ICCVAM recommendations to Federal agencies is available here.

More information about the ICCVAM evaluation of the use of the BG1Luc ER TA test method for identification of potential endocrine-active substances can be found on the NICEATM-ICCVAM website here.

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