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
Studies and Results
The researchers are the first to employ the "moving wire" technology in order to interface ULPC with AMS, thus allowing for identification of the chemical form of [14C]. This study is driving the PAHs in Humans at Environmental Levels: Pharmacokinetics, Metabolism and Susceptible Individuals project, supported by P41-RR013461 "Resource for the Development of Biomedical Accelerator Mass Spectrometry (AMS)". With the assistance of a K.C. Donnelly award to trainee Erin Madeen, the researchers have successfully characterized the metabolic profile of a carcinogenic PAH following micro-dosing in humans. This characterization of metabolites is made possible by standards from the PAH repository (Chemistry Core). The Cross-Species and Life Stage Comparisons of PAH Dosimetryproject is analyzing the PK results with the assistance of the Biostatistics and Modeling Core. The researchers will shortly be recruiting volunteers to dose with 46 ng (5 nCi) of [14C]-BaP. The test of the RPF approach for risk assessment with complex PAH mixtures (specific aim 2) and the study of gene-environment interactions following PAH exposures at low doses, are not scheduled to begin until years 2 and 3.
Hundreds of PAHs are present in environmental mixtures. PAHs account for 4 (total PAHs, BaP, benzo[b]fluorine, dibenzo[a,h]anthracene) of the top 10 most hazardous substances on the 2011 ATSDR Priority List of Hazardous Substances [http://www.atsdr.cdc.gov/SPL/index.html]. In the general population the majority of carcinogenic PAH exposure is dietary. The majority of studies on toxicity and carcinogenicity of PAHs have been done with BaP. In animal models, oral exposure to BaP produces cancers of the lung, forestomach, liver, lymphoreticular tissue, esophagus and tongue. Although many studies employed single PAHs, humans are exposed to complex mixtures. EPA is considering regulatory approaches for mixtures based on RPFs with BaP set as 1. This risk assessment is done without data on uptake, metabolism and elimination in humans. The AMS studies with the IARC class 1 human carcinogen, BaP, will provide this critical missing data. The moving wire interface between ULPC and AMS allows us to identify and quantitate PAH metabolites in addition to parent compound. The researchers have provided proof of concept for this approach as a Driving Biomedical Project with the AMS Center at Lawrence Livermore National Laboratory. In specific Aim 2, for the first time ever, the uptake, metabolism and elimination of BaP after oral administration of a complex PAH mixture in a commonly consumed food (smoked salmon), will be measured. BaP, as with many other PAHs in animal models and apparently in humans, is metabolized fairly rapidly by a number of pathways resulting in detoxication or bioactivation. Three main routes of bioactivation follow oral exposure. Peroxidases catalyze 1-e oxidation at carbon 6 to produce a reactive cation, yielding 3,6- and 1,6- quinones. The most studied pathway is CYP-dependent epoxygenation followed by hydrolysis. Epoxygenation a second time by CYP yields BaP-7,8-dihydrodiol-9,10-epoxide (BaPDE, 4 enantiomers). The (+)-anti-BaPDE is the most mutagenic and carcinogenic. The CYP1 family, especially CYP1A1 and CYP1B1, is the most active in carrying out these reactions. The third pathway for bioactivation involves metabolism of the BaP-7,8-DHD to a catechol by aldo-keto reductase (AKR). Catechols readily redox cycle by 1-electron oxidation/reduction reactions through semi-quinones and quinones producing the oxidative stress associated with PAH toxicity. The use of the moving wire technology, along with the BaP metabolite standards available to us, will allow for determination of the metabolic profile of BaP in plasma and urine with time following exposure to an environmentally relevant dose. The gene-environment interaction study in specific aim 3 focuses on a relatively common CYP1B1 genetic polymorphism, CYP1B1*3, associated with increased risk for multiple cancers.