Modeling and assaying dioxin-like biological effects for both dioxin-like and certain non-dioxin-like compounds

Area of Science:

• Environmental Chemistry
• Toxicology
• Computational Chemistry

Background:

• Polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and biphenyls (PCBs) exhibit varying degrees of toxicity, often assessed using Toxic Equivalency Factors (TEFs).
• Accurate TEF assignment is crucial for risk assessment of contaminated sites and food, but many congeners lack defined TEFs.
• Existing methods for determining toxicity can be time-consuming and resource-intensive.

Purpose of the Study:

• To develop and validate Quantitative Spectrometric Data-Activity Relationship (QSDAR) models for predicting TEFs and Relative Potency (REP) values.
• To assess the potential dioxin-like toxicity of congeners with assumed zero TEFs.
• To explore the utility of QSDAR models combined with in vitro assays for efficient screening of chemical toxicity.

Main Methods:

• Correlated 13C NMR data with established TEFs for 29 PCDD, PCDF, and PCB congeners to build QSDAR models.
• Predicted TEFs and REPs for specific congeners, including 1,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 1,2,3,4,7-pentachlorodibenzo-p-dioxin (PeCDD).
• Validated QSDAR predictions using an independent in vitro luciferase gene expression assay in mouse liver cells.

Main Results:

• QSDAR models predicted significant dioxin-like toxicity for TCDD (TEF=0.037, REP=0.115) and PeCDD (TEF=0.004, REP=0.020), challenging their assumed zero TEFs.
• In vitro assays confirmed these findings, yielding REPs of 0.027 for TCDD and 0.013 for PeCDD, showing good agreement with QSDAR predictions.
• The models were applied to predict activity for 108 additional congeners and a dioxin analog, demonstrating broad applicability.

Conclusions:

• QSDAR models, coupled with in vitro assays, offer a powerful and cost-effective approach for predicting dioxin-like toxicity and identifying compounds for further investigation.
• Risk assessments may underestimate toxicity if congeners with non-zero toxicity are incorrectly assigned zero TEFs.
• In silico and in vitro nomination protocols can streamline practical risk assessment for complex mixtures of chemicals with varying toxicities via a common mechanism.