Development of a QSAR Model for Thyroperoxidase Inhibition and Screening of 72,526 REACH substances

Sine Abildgaard Rosenberg, Nikolai Georgiev Nikolov, Marianne Dybdahl, Steve Simmons, Kevin M. Crofton, Eric D. Watt, Katie Paul Friedmann, Richard S. Judson, Eva Bay Wedebye

Research output: Contribution to conferenceConference abstract for conferenceResearchpeer-review


Thyroid hormones (THs) are involved in multiple biological processes and are critical modulators of fetal development. Even moderate changes in maternal or fetal TH levels can produce irreversible neurological deficits in children, such as lower IQ. The enzyme thyroperoxidase (TPO) plays a key role in the synthesis of THs, and inhibition of TPO by xenobiotics results in decreased TH synthesis. Recently, a high-throughput screening assay for TPO inhibition (AUR-TPO) was developed and used to test the ToxCast Phase I and II chemicals. In the present study, we used the results from AUR-TPO to develop a Quantitative Structure Activity Relationship (QSAR) model for TPO inhibition. The training set consisted of 898 discrete organic chemicals: 134 inhibitors and 764 non-inhibitors. A five times two-fold cross-validation of the model was performed, yielding a balanced accuracy of 78.7%. More recently, an additional ~800 chemicals were tested in the AUR-TPO assay. These data were used for a blinded external validation of the QSAR model, demonstrating a balanced accuracy of 85.7%. Overall, the cross- and external validation indicate a robust model with high predictive performance. Next, we used the QSAR model to predict 72,526 REACH pre registered substances. The model could predict 49.5% (35,925) of the substances in its applicability domain and of these, 8,863 (24.7%) were predicted to be TPO inhibitors. Predictions from this screening can be used in a tiered approach to prioritize potential thyroid disrupting chemical substances for further evaluation.
Original languageEnglish
Publication date2016
Number of pages1
Publication statusPublished - 2016
EventSustain-ATV Conference 2016: Creating Technology for a Sustainable Society - Technical University of Denmark, Kgs. Lyngby, Denmark
Duration: 30 Nov 201630 Nov 2016


ConferenceSustain-ATV Conference 2016
LocationTechnical University of Denmark
CityKgs. Lyngby
Internet address

Bibliographical note

Sustain Abstract U-9
This abstract does not necessarily reflect U.S. EPA policy


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