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
Over the previous funding period, Williams and Baird and their research teams have successfully obtained an FDA IND (#117175) and IRB approvals from the institutions involved. Recruitment opened within the last few months and the interest has been steadily increasing. The researchers have now run the first volunteer through three cycles. Optimization of sample preparation for [14C]-BaP and analysis of plasma and urine sample by ULC-AMS has been performed with [14C]-dibenzo[def,p] chrysene (DBC). The first manuscript using this approach was published in Chemical Research in Toxicology in December, 2013, and selected by the NIEHS Environmental Factor the following month as one of three "papers to watch." The most remarkable finding to date is that researchers are able to identify and quantify polar metabolites of DBC in human plasma as early as 45 minutes post-dosing. This provides researchers with assurance that they will generate a rich pharmacokinetic (PK) dataset for regulatory agencies that includes enzymatic pathways for metabolism and excretion of BaP and metabolites at these micro-doses. With respect to the research team's second specific aim (testing of the RPF approach for risk assessment with PAH mixtures), researchers have obtained (with the assistance of the Community Engagement Core) the smoked salmon and it is undergoing analysis by the Chemistry Core in order to ascertain the amount (probably ½ oz) that will be feed to volunteers in Phase 2 to achieve 10-x the BaP equivalent than the 46 ng [14C]-BaP capsule dose. Any inhibition, induction or synergy of PK parameters will be evidence that the RPF approach cannot be accurately employed at environmentally relevant doses of PAH mixtures. In the last specific aim, the researchers have designed and obtained most of the primers necessary for the genotyping of volunteers for CYP1B1, CYP1A1, EH1, GSTM, GSTT, GSTpi, AKR1C, UGT1A, and other enzymes known to be involved in BaP metabolism. The priority will depend upon the BaP metabolite profile observed and the allelic variants observed with the first dozen or so volunteers examined.