Superfund Research Program
PAHs in Humans at Environmental Levels: Pharmacokinetics, Metabolism and Susceptible Individuals
Project Leader: David E. Williams
Grant Number: P42ES016465
Funding Period: 2013-2020
- Project Summary
Project Summary (2013-2020)
This project will analyze pharmacokinetics of the prototypical carcinogenic polycyclic aromatic hydrocarbon (PAH), benzo[a]pyrene (BaP) in humans at environmentally relevant exposures. Currently, regulatory agencies, the Agency for Toxic Substances and Disease Registry (ATSDR), and the International Agency for Research on Cancer (lARC) have to rely on high-dose animal studies for predicting safe lifetime exposure levels. The overall hypothesis of this project is that BaP, given to humans at levels encountered in the environment, will exhibit pharmacokinetics predictable from PBPK models constructed in mice. The research team further hypothesizes that the relative potency factor (RPF) for humans exposed to PAH dietary mixtures will be predictive of risk.
The final aim is exploratory and seeks to identify individuals with greater susceptibility based on a common genetic polymorphism. Human volunteers will be administered a dose of [14C]-BaP an order of magnitude lower than the average daily exposure of a U.S. non-smoker. The use of accelerator mass spectrometry (AMS) allows for micro-dosing of both chemical and radioisotope (5 nCi) and still follows blood and urine levels for three days. Use of newly developed AMS technology permits the researchers to access the levels of parent BaP as well as individual metabolites, a major advance that will contribute to risk assessment.
The U.S. Environmental Protection Agency (EPA) is currently considering the use of a relative potency factor (RPF) approach in risk assessment for PAH mixtures. The research team will conduct a study in which 1-3 ounces of smoked salmon containing ten times the BaPeq, based on the RPF of the PAHs in the salmon, will be co-administered with the [14C]- BaP. By examining pharmacokinetics, metabolite profiles and covalent DNA adducts in blood, the researchers can provide the first test ever of the RPF approach in humans and at environmentally relevant levels. Finally, individuals that exhibit distinct BaP metabolite profiles or levels of BaP-DNA adducts will be genotyped for allelic variants of BaP-metabolizing enzymes in an exploratory gene-environment interaction study. These studies are highly innovative and significant and will markedly advance the field of risk assessment by providing a unique and powerful dataset on pharmacokinetic behavior of PAHs in humans exposed at environmental levels.