Modeling and assaying dioxin-like biological effects for both dioxin-like and certain non-dioxin-like compounds.
13C NMR data have been correlated to Toxic Equivalency Factors (TEFs) of the 29 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 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 may exhibit significant dioxin-like toxicity. If other such congeners have non-zero toxicity, TEF-based risk assessments of some dioxin-, furan-, or PCB-contaminated sites or foods may underestimate toxicity. Both models were extensively cross-validated and the TEF model was externally validated. We confirmed the predictions by an independent in vitro method, a luciferase gene expression assay based on mouse liver cells that found REPs of 0.027 and 0.013, respectively, for 1,3,7,8-TCDD and 1,2,3,4,7-PeCDD. The QSDAR-estimated and gene-expression assayed values agreed. The models were used to predict activity for an applicability domain including 108 non-2,3,7,8 dioxin, furan, or PCB congeners and 2,3,7,8-tetrachlorophenothiazine, a dioxin analog 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 further investigation. It suggested that in silico and in vitro nomination protocols may facilitate practical risk assessment when chemical family members exhibit different degrees of toxicity operating via a common mechanism.
Wilkes
Jon G
JG
Division of Systems Toxicology, Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock 72205-7199, USA. jone.wilkes@fda.hhs.gov
Hass
Bruce S
BS
Buzatu
Dan A
DA
Pence
Lisa M
LM
Archer
Jeffrey C
JC
Beger
Richard D
RD
Schnackenberg
Laura K
LK
Halbert
Mary Kim
MK
Jennings
Lisa
L
Kodell
Ralph L
RL
D000818:Animals; D001681:Biological Assay; D002460:Cell Line; D004147:Dioxins / Q000737:chemistry / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000737:chemistry / Q000633:toxicity*; D005663:Furans / Q000737:chemistry / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008954:Models, Biological; D015394:Molecular Structure; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000633:toxicity*; D021281:Quantitative Structure-Activity Relationship; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000378:metabolism; D015203:Reproducibility of Results; D018570:Risk Assessment; D018675:Toxicity Tests / Q000379:methods*; D014162:Transfection
D004147:Dioxins; D004785:Environmental Pollutants; D005663:Furans; D018336:Receptors, Aryl Hydrocarbon; D011078:Polychlorinated Biphenyls