Objective

Expand our collaborations to develop the next generation of PBPK models capable of predicting target tissue doses of metabolites important for PAH toxicity at potentially susceptible stages of life.

Activities
  • Determine the comparative rates of in vitro metabolism of BaP, DBC and their major metabolites in rat, mouse, and human target tissues and the impact of exposures to PAH mixtures
  • Determine in vivo pharmacokinetics of BaP, DBC, and their major metabolites in mice and rats to confirm in vitro to in vivo scaling of metabolism at different life stages and impact of mixture exposures
  • Determine in vitro and in vivo enzyme activities using a novel activity-based protein profiling (ABPP) approach as a function of species, tissue type, development stage, and PAH exposures.
  • Develop, evaluate and refine life stage-specific PBPK models that describe the impact of BaP, DBC and PAH mixture exposures on metabolite disposition in target tissues of mice, rats and humans
Significance

Project 2 provides the SRP Center with a critical bridge between environmental levels of polycyclic aromatic hydrocarbons (PAHs) found at Superfund Sites and the potential for adverse responses in humans. Human health risks for PAH exposures have historically been based upon studies in animals. However, these studies were generally conducted at high doses or by routes of administration that differ from real human exposures. Furthermore, PAHs may behave differently in humans and animals. Regulatory agencies now recommend physiologically based pharmacokinetic (PBPK) models for extrapolating across species, dose, and exposure route because they integrate chemical-specific processes of absorption, distribution, metabolism and elimination (ADME) with species-specific anatomy and physiology.

Major Accomplishments
  • Developed the first physiologically based pharmacokinetic model for any high-molecular-weight PAH (5rings or more) capable of making cross-species, high-to-low dose, and route-to-route extrapolations of target tissues doses of PAHs.
  • Initiated, with Project 1, the first high-molecular-weight PAH pharmacokinetic study in humans.
  • Initiated, with Project 1, the first study to determine the ontogeny of enzymes active in PAH metabolism in liver, lung, and thymus tissues of fetal mice and humans.
People
  • Jordan Smith, Leader, PNNL
  • Aaron Wright, Co-Investigator, PNNL
  • Denis Mehinagic, Post Bachelor Intern, PNNL
  • Natalie Sadler, Undergrad intern, PNNL
  • Prem Nandhikonda, PostDoc PNNL