ToxSci Advance Access published online on December 7, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm294
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Published by Oxford University Press 2007.
Modeling and assaying dioxin-like biological effects for both dioxin-like and certain non-dioxin-like compounds
Division of Systems Toxicology, NCTR, 3900 NCTR Road, Jefferson, AR 72079 USA E-mail address format: firstname.lastname{at}fda.hhs.gov
Division of Genetic and Reproductive Toxicology, NCTR, 3900 NCTR Road, Jefferson, AR 72079 USA E-mail address format: firstname.lastname{at}fda.hhs.gov
Dioxin Group, Arkansas Regional Laboratory, 3900 NCTR Road, Jefferson, AR 72079 USA E-mail address format: firstname.lastname{at}fda.hhs.gov
¶ Division of Biometry and Risk Assessment, NCTR, 3900 NCTR Road, Jefferson, AR 72079 USA E-mail address format: firstname.lastname{at}fda.hhs.gov
* Corresponding author contact information: Jon G. Wilkes, Ph.D. Building 26, HFT-233, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR 72079, Tel: +1 (870) 543-7108, Fax: +1 (870) 543-7686, E-mail: jon.wilkes{at}fda.hhs.gov
Received August 16, 2007; revision received November 9, 2007; accepted December 5, 2007
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Abstract |
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Previous work demonstrated that 13C NMR data could be correlated to Toxic Equivalency Factors (TEFs) of the 29 polychlorinated dioxin-like compounds (PCDDs, PCDFs, or PCBs) for which non-zero TEFs have been defined. Such correlations are called quantitative spectrometric data-activity relationship (QSDAR) models. An improved QSDAR model predicted TEFs of 0.037 and 0.004, respectively, for 1,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 1,2,3,4,7-pentachlorodibenzo-p-dioxin (PeCDD), both of which are among the 390 congeners for which zero value TEFs are assumed. A QSDAR model of Relative Potency (REP) values estimated the corresponding values as 0.115 and 0.020. Results from both models indicated that these two congeners are likely to exhibit significant dioxin-like toxicity. If other such congeners also have non-zero toxicity, TEF-based risk assessments of some dioxin-, furan-, or PCB-contaminated sites or foods may be underestimating toxicity. Both models were extensively cross-validated and the TEF model was externally validated. Validation suggested the advisability of confirming the predictions by an independent, preferably in vitro method. We used a luciferase gene expression assay based on mouse liver cells to determine experimental REPs of 0.027 and 0.013, respectively, for 1,3,7,8-TCDD and 1,2,3,4,7-PeCDD. The corresponding QSDAR-estimated and gene-expression assayed values were in close agreement. We then used the models to estimate biological activity for an applicability domain including 108 non-2,3,7,8 dioxin, furan, or PCB congeners and also 2,3,7,8-tetrachlorophenothiazine, a dioxin analog being proposed as a drug candidate. This study showed that QSDAR prediction followed by a relatively inexpensive in vitro assay could be used to nominate a few candidates among hundreds for expensive in vivo evaluation. Success here suggested that in silico and in vitro nomination protocols may enable practical risk assessment when members of a large chemical family exhibit different degrees of toxicity operating through a common biological mechanism.
Key Words: Risk Assessment - regulatory/policy; Agents - dioxin; Agents - polychlorinated biphenyls; Environmental Toxicology; In Vitro and Alternatives - QSAR; Risk Assessment - biological modeling.