Using in vitro high throughput screening assays to identify potential endocrine-disrupting chemicals.
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.


METHODS
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.
Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina, USA.
Daniel M
DM
Rotroff
David J
DJ
Dix
Keith A
KA
Houck
Thomas B
TB
Knudsen
Matthew T
MT
Martin
Keith W
KW
McLaurin
David M
DM
Reif
Kevin M
KM
Crofton
Amar V
AV
Singh
Menghang
M
Xia
Ruili
R
Huang
Richard S
RS
Judson
D000728:Androgens / Q000032:analysis; D052244:Endocrine Disruptors / Q000032:analysis*; D004967:Estrogens / Q000032:analysis; D057166:High-Throughput Screening Assays / Q000379:methods*; D014481:United States; D014484:United States Environmental Protection Agency
D000728:Androgens; D052244:Endocrine Disruptors; D004967:Estrogens