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
Specific Aim 1: Conduct the first pharmacokinetic study of benzo[a]pyrene (BaP) in humans.
The pharmacokinetics of [14C]-BaP(eq) with multiple dosings over varying time intervals showed low intra-individual variability that was independent of time between exposures. This finding is of significance as it strongly suggests the absorption, metabolism, and excretion of BaP (and perhaps other polyaromatic hydrocarbons, or PAHs) is consistent over time for a given individual and not strongly influenced by extrinsic factors.
Specific Aim 2: Conduct the first evaluation of the Relative Potency Factor (RPF) approach to risk assessment for PAHs in human studies.
Consumption of canned salmon, at an amount equivalent to smoked salmon containing a complex mixture of PAHs at 10-X BaP(eq) as determined by the RPF, showed their previous conclusion regarding the impact of co-exposure on the pharmacokinetics of [14C]-BaP(eq) was not due to the PAHs, but rather to the food matrix. Therefore, the hypothesis that the RPF approach could be used for risk assessment following human dietary exposures to PAH mixtures could not be rejected. This is of significance as in vitro studies with human cell lines and in vivo animal tumor models have called into question the validity of the RPF approach to risk assessment for PAH mixtures.
Specific Aim 3: Conduct the first assessment of gene-environment interactions in humans at environmentally relevant levels of exposure to PAHs.
Covalent DNA adduction has been the most frequently used biomarker for cancer risk assessment of environmental carcinogens including BaP. A time course study has shown that, at a realistic environmental exposure to [14C]-BaP, there is no detectable binding to DNA of peripheral blood mononuclear cells. The question of linearity of this biomarker and its value as a risk assessment tool is still being examined. With the high sensitivity of accelerator mass spectrometry, the researchers can say that following a defined dose of 46 nanograms, the level of peripheral blood mononuclear cell DNA adducts is <1 in 10^11 nucleotides, two to three orders of magnitude lower than reported in lymphocytes of occupationally-exposed populations. As they found no covalent adduction in any subject, relating risk to genotype was not possible.