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
This FDA IND (#117175) and IRB-approved project allows for dosing volunteers with 46 ng of [14C]-benzo[a]pyrene (BaP), an IARC class 1 known human carcinogen. The researchers have recruited 15 volunteers. Analysis of total [14C]-BaP in blood and urine over a 72-hour period has demonstrated rapid uptake and elimination with only a small amount of [14C]-BaP left in blood or urine at 72 hours. AMS collaborators at Lawrence Livermore National Laboratories recently have built a new 250 KV AMS that will be devoted to biomedical projects such as this. This instrument has a UHLC interface, allowing for the quantification of metabolites rather than just total [14C]. The researchers are currently using this instrument to determine individual metabolism of this important environmental carcinogen as a function of genetics and exposure to other environmental PAHs in complex mixtures. The researchers 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 the assistance of the Chemistry Core and the Community Engagement Core, smoked salmon from the Confederated Tribes of the Umatilla Indian Reservation (CTUIR) was obtained, stored under an FDA approval and analyzed by the Chemistry Core to determine the amount (current batch, 7.5 oz.) that would be fed to volunteers in specific Aim 2 to achieve 10-x the BaPeq 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 employed accurately at environmentally relevant doses of PAH mixtures. The researchers currently are analyzing the results from 3 volunteers to determine whether this PAH mixture in food alters BaP pharmacokinetics. In the last specific aim, the researchers genotyped volunteers for CYP1B1 and GSTM1, known to be involved in bioactivation and detoxication, respectively, of BaP. The researchers are currently correlating CYP1B1*3 and GSTM*0 genotypes with PK constants.