The Superfund Research Program

Our project asks the following questions

What is the role of metabolism in susceptibility for PAH-mediated toxicity and respiratory disease in humans?

PAHs can be metabolized in the human body, forming new chemicals (metabolites). We will use our 3D lung model to determine the extent of PAH metabolism in bronchial epithelial cells. This model provides a unique opportunity to study the role of metabolism and how that may impact the toxicity of PAHs in the body.

Can we predict toxicity and disease phenotype on the basis of biomarkers and pathways that are altered after PAH exposure?

We are very interested in learning how individual PAHs contribute to the overall toxicity of a mixture. We are looking at different components of a mixture, to learn how to predict the toxicity of new mixtures. To do this, we have created several sufficiently similar mixtures from environmental data. Supermix10 is one example of these mixtures. We can then look at the different chemicals in this mixture, which represents environmental data from the Portland Harbor Superfund Site, to determine which chemicals are driving the toxicity of the mixture.

Can current remediation techniques reduce human health hazards?

As Superfund Sites are remediated, there is concern that these techniques may unfortunately increase toxicity by altering PAHs to other chemicals. Therefore, we will test PAH mixtures before and after remediation for toxicity in our 3D lung model.

Do common genetic polymorphisms alter toxicity and subsequent risk to PAH exposure and thereby allow us to identify susceptible individuals?

We are interested in understanding the risk PAHs pose to human health. Certain individuals may be more at risk for adverse health outcomes after inhalation exposure to PAHs given their genetic profile. There are common polymorphisms to the enzymes responsible for metabolizing PAHs (CYP1B1 and GSTM1). We are looking to see if having these polymorphisms makes an individual more susceptible to PAH toxicity.

Collaborations

• We collaborate with the PAH Fate and Exposure project to test environmentally relevant PAHs and mixtures identified at Superfund sites in our lung cells.
• We prioritize testing of PAHs based on zebrafish toxicity screening data from Predicting the Toxicity of Complex PAH Mixtures project and collaborate with the DMAC on benchmark dose modeling of dose-response data.
• We apply activity-based protein proteomics as a measure of enzyme activity and abundance in our lung cell model in collaboration with the Mechanisms of PAH Susceptibility project.
• We track PAH uptake and metabolism in parallel between 3D lung cell and zebrafish models for development of physiologically-based pharmacokinetic (PBPK) models in collaboration with the Mechanisms of PAH Susceptibility and Predicting PAH Mixtures Toxicity projects and the Chemical Mixtures Core.