Using in Vitro High Throughput Screening Assays to Identify Potential Endocrine-Disrupting Chemicals

Daniel M. Rotroff,^1,2 David J. Dix,² Keith A. Houck,² Thomas B. Knudsen,² Matthew T. Martin,² Keith W. McLaurin,² David M. Reif,² Kevin M. Crofton,³ Amar V. Singh,⁴ Menghang Xia,⁵ Ruili Huang,⁵ and Richard S. Judson²

¹Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina, USA; ² National Center for Computational Toxicology, and ³National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA; ⁴Lockheed Martin, Research Triangle Park, North Carolina, USA; ⁵National Center for Advancing Translational Sciences, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA


Abstract

Background: Over the past 20 years, an increased focus on detecting environmental chemicals that pose a risk of adverse effects due to endocrine disruption has driven the creation of the U.S. Environmental Protection Agency (EPA) Endocrine Disruptor Screening Program (EDSP). Thousands of chemicals are subject to the EDSP; thus, processing these chemicals using current test batteries could require millions of dollars and decades. A need for increased throughput and efficiency motivated the development of methods using in vitro high throughput screening (HTS) assays to prioritize chemicals for EDSP Tier 1 screening (T1S).


Objective: In this study we used U.S. EPA ToxCast HTS assays for estrogen, androgen, steroidogenic, and thyroid-disrupting mechanisms to classify compounds and compare ToxCast results to in vitro and in vivo data from EDSP T1S assays.


Method: We implemented an iterative model that optimized the ability of endocrine-related HTS assays to predict components of EDSP T1S and related results. Balanced accuracy was used as a measure of model performance.


Results: ToxCast estrogen receptor and androgen receptor assays predicted the results of relevant EDSP T1S assays with balanced accuracies of 0.91 (p < 0.001) and 0.92 (p < 0.001), respectively. Uterotrophic and Hershberger assay results were predicted with balanced accuracies of 0.89 (p < 0.001) and 1 (p < 0.001), respectively. Models for steroidogenic and thyroid-related effects could not be developed with the currently published ToxCast data.


Conclusions: Overall, results suggest that current ToxCast assays can accurately identify chemicals with potential to interact with the estrogenic and androgenic pathways, and could help prioritize chemicals for EDSP T1S assays.


Key words: androgen, endocrine, estrogen, high throughput, in vitro, ToxCast. 


Environ Health Perspect 121:7–14 (2013). http://dx.doi.org/10.1289/ehp.1205065 [Online 28 September 2012]


Address correspondence to R.S. Judson, National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, 109 T.W. Alexander Dr. (B205-01), Research Triangle Park, NC 27711 USA. Telephone: (919) 541-3085. Fax: (919) 541-3513. E-mail: judson.richard@epa.gov


Supplemental Material is available online (http://dx.doi.org/10.1289/ehp.1205065).


The views expressed in this article are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency (EPA). Mention of trade names or commercial products does not constitute endorsement or recommendation for use.


A.V.S. was employed by Lockheed Martin Corporation (Research Triangle Park, NC) as a contractor for the U.S. EPA/National Center for Computational Toxicology. 


The authors declare they have no actual or potential competing financial interests.


Received 6 February 2012; Accepted 28 September 2012; Online 28 September 2012.