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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