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Pure Appl. Chem. 75(11/12), 2375-2388, 2003

Pure and Applied Chemistry

Vol. 75, Issues 11-12

Regulatory application of SAR/QSAR for priority setting of endocrine disruptors: A perspective

W. Tong, H. Fang, H. Hong, Q. Xie, R. Perkins, J. Anson, and D. M. Sheehan

FDA ’s National Center for Toxicological Research (NCTR), Jefferson, AR 72079, USA; Logicon ROW Sciences, Jefferson, AR 72079, USA

Abstract: Some seven years have passed since the U.S. legislature mandated the EPA to develop and implement a screening and testing program for chemicals that may disrupt the delicate endocrine system. The envisioned EPA program has evolved to incorporate a tiered scheme of in vitro and in vivo assays, and considered QSAR as a viable method to set testing priorities. At the U.S. FDA's National Center for Toxicological Research (NCTR), the Endocrine Disruptor Knowledge Base Project has developed models to predict estrogen and androgen receptor binding. Our approach rationally integrates various QSAR models into a sequential "Four-Phase" scheme according to the strength of each type of model. In four hierarchical phases, models predict the inactive chemicals that are then eliminated from the pool of chemicals to which increasingly precise but more time-consuming models are subsequently applied. Each phase employs different models selected to work complementarily in representing key activity-determining structure features in order to absolutely minimize the rate of false negatives, an outcome we view as paramount for regulatory use. In this paper, the QSAR models developed at NCTR, and particularly how we integrated these models into the "Four-Phase" system will be discussed for a number of datasets, including 58 000 chemicals identified by the U.S. EPA.

*Report from a SCOPE/IUPAC project: Implication of Endocrine Active Substances for Human and Wildlife (J. Miyamoto and J.Burger, editors). Other reports are published in this issue, pp. 1617-2615.


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