Application of x-ray spectroscopy and density functional theory to toxicology of polychlorinated biphenyls

Abstract

While much is known about the toxicity of polychlorinated biphenyls (PCBs), there are tens of thousands of natural and synthetic chemicals in the environment that can activate the aryl hydrocarbon receptor (AhR) and thus cause toxicity. Since it would be difficult to conduct studies of the toxicity of each and every compound, here is presented a new model based on first-principles taking into account the basic electronic and electron trans- fer characteristics of PCBs, but can be used to predict the toxicities of other AhR-active compounds. The predictive model is based on Density Functional Theory. The model predicts that the energy gap between highest occupied (HOMO) and lowest unoccupied (LUMO) molecular orbitals is the overarching indicator of toxicity of PCBs, but not the only factor. The model explains why chlorination of both para-positions is required for maximum toxic potency. To rank potency of PCBs, the dipole moment in relation to the most chemically active chlorine-sites is critical. The theory is consistent with the accepted toxic equivalency factor (TEF) model for these molecules and is also able to improve on ranking toxic potency of PCBs with similar TEFs. This new model also includes a 13th dioxin-like PCB, PCB 74, not considered in the current TEF model developed by the World Health Organization (WHO). The model was applied to HOMO-LUMO gap mea- surements of a set of PCBs and the measurements are consistent with the model. Values of HOMO-LUMO gap can also be used to predict bio-accumulation of PCBs. The model provides an in silico method to screen a wide range of chemicals to predict their ability to act as an AhR agonist.