Superfund Research Program
Elucidating Metabolic and Physicochemical Mechanisms of PAH Susceptibility in Toxicity Test Systems and Humans
Final Progress Reports
Year: 2019 2012
Establishing exposure and cleanup guidelines for polycyclic aromatic hydrocarbons (PAHs) found at Superfund sites have historically relied upon toxicity and carcinogenicity studies conducted in laboratory animals. Unfortunately, little is known about potentially important differences between laboratory animals and humans in how PAHs are handled by the body to produce adverse responses under real-world exposure conditions. Jordan Smith, Ph.D., and his team use in vitro metabolism measurements, activity-based protein profiling, and physiologically based pharmacokinetic (PBPK) modeling to understand how differences in anatomy, physiology, and key biological processes associated with PAH pharmacokinetics relate to target-tissue dose and toxicity.
During this past year, the team achieved a number of accomplishments toward their goal of understanding PAH target-tissue dosimetry. In collaboration with the PAHs in Humans at Environmental Levels: Pharmacokinetics, Metabolism and Susceptible Individuals Project, researchers measured pharmacokinetics of benzo[a]pyrene (BaP) in human volunteers following oral exposures of 46 ng BaP (Madeen et al. 2019). The team utilized activity-based probes developed with this project to measure changes P450 enzymes (Stoddard, in review) of glutathione S-Transferase enzymes following exposure to BaP or mixtures of PAHs in mice as a function of dose and time (Stoddard et al. 2019). Smith and his team utilized results from these studies to refine PBPK models for PAHs including key metabolites as well as species- and life stage-specific changes in anatomy, physiology, and biochemical functions important to predicting the impact of realistic PAH mixture exposures on human health. These models are valuable tools to assess risk of PAH exposures to humans.