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ICCVAM Biennial Report 2014-2015

Biennial Progress Report 2014-2015 Interagency Coordinating Committee on the Validation of Alternative Methods

Endocrine Disruptor Testing: NIEHS Activities

Validation of High Throughput Assay for Estrogen-Active Chemicals

NICEATM (National Institute of Environmental Health Sciences) compared the quality and accuracy of a quantitative high throughput screening (HTS) assay to measure estrogen agonist or antagonist activity in human cells with the manual method validated for regulatory use by the U.S. Environmental Protection Agency and described in Test Guideline 455 issued by the Organisation for Economic Co-operation and Development (OECD). The comparison indicated that the performance of the HTS method is equivalent to the manual method.

Curated Database of Rodent Uterotrophic Bioactivity

The uterotrophic assay measures the estrogenic activity of a chemical by assessing the chemical’s effect on the weight of a rodent uterus. To support future validation of in vitro HTS methods and in silico models of estrogenic activity, NICEATM created a comprehensive database of high quality in vivo data from over 1,000 scientific articles describing uterotrophic assay experiments performed using over 2,660 different chemical/study/protocol combinations. These data have potential utility for developing adverse outcome pathways or models of estrogenic activity, prioritizing chemicals for further testing, or evaluating species-specific responses to chemicals. The database is available on the NICEATM website.

Models for Correlation of In Vitro and In Vivo Dosimetry

Using collective results from 16 Tox21 and ToxCast estrogen receptor pathway related assays, NICEATM developed and applied one-compartment or physiologically based pharmacokinetic models to quantitatively correlate in vitro and in vivo dosimetry for estrogen receptor reference chemicals. This approach highlighted the importance of considering the entire process of absorption, distribution, metabolism, and excretion in assessing and ranking endocrine-active chemicals based on in vitro HTS assays. A manuscript describing this project was published in December 2014 in Applied In Vitro Toxicology, and posters describing an approach to optimize parameters in these analyses were presented at the 2015 Society of Toxicology (SOT) Annual Meeting (Chang et al.), 2015 American Society for Cellular and Computational Toxicology (ASCCT) Annual Meeting (Chang et al.), and 2015 SOT FutureTox III meeting (Chang et al.).

Review of Assays to Identify Thyroid-Active Chemicals

NICEATM scientists contributed to development of the report “New Scoping Document on In Vitro and Ex Vivo Assays for the Identification of Modulators of Thyroid Hormone Signalling.” This 2014 report, developed by the OECD Expert Group on Amphibian Testing and the OECD Validation Management Group on Non-animal Testing, provides recommendations for development and use of existing in vitro and ex vivo thyroid assays and identifies data gaps that require development of additional tests.
The scoping document and other OECD documents on endocrine disruptor testing are available on the OECD website.

Computational Methods to Assess Similarity of In Vitro Bioactivity

NICEATM used computational methods to create clusters of tested chemicals based on their activity in ToxCast assays. Clusters containing known toxicants were examined to identify similar in vitro bioactivity patterns in environmental chemicals lacking in vivo data. This work was described in a platform presentation at the 2015 SOT Annual Meeting and is being included as a case study in a manuscript on good read-across practices being prepared in collaboration with the Johns Hopkins University Center for Alternatives to Animal Testing and other partners from industry, government, and academia.

Validation Study of In Vitro Method for Androgen Receptor Activity

NICEATM is collaborating with the test method developer CertiChem, Inc., on a proof-of-concept evaluation of an in vitro test method that uses MDA-Kb2 cells to measure androgen receptor agonist and antagonist activity. Testing of this medium throughput method using a blinded set of chemicals was completed in October 2015. Data are currently being analyzed and a manuscript describing these results is planned.