Project 1 will analyze pharmacokinetics of the prototypical carcinogenic polycyclic aromatic hydrocarbon (PAH), benzo[a]pyrene (BaP) in humans at environmentally relevant exposures. Currently, regulatory agencies (EPA, FDA) and ATSDR and lARC have to rely on high-dose animal studies for predicting safe lifetime exposure levels. Our overall hypothesis is that BaP, given to humans at levels encountered in the environment, will exhibit pharmacokinetics predictable from PBPK models constructed in mice. We further hypothesize that the relative potency factor (RPF) for humans exposed to PAH dietary mixtures will be predictive of risk.
The final aim i s 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 follow blood and urine levels for three days. Use of newly developed AMS technology permits us to access the levels of parent BaP as well as individual metabolites, a major advance that will contribute to ask assessment. The EPA is currently considering the use of a relative potency factor (RPF) approach in risk assessment for PAH mixtures. We 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, we 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.

Public Health Relevance

PAHs are environmental contaminants prevelant at Superfund Sites and represent 3 top 10 most hazardous substances (ATSDR Priority List of Hazardous Substances). A major obstacle for regulator agencies is lack of human data. We will characterize uptake/elimination of BaP in humans at environmental levels and identify susceptible individuals. This provides critical data for health risk from environmental exposure to PAHs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES016465-06
Application #
8695365
Study Section
Special Emphasis Panel ()
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
6
Fiscal Year
2014
Total Cost
$286,783
Indirect Cost
$90,357
Name
Oregon State University
Department
Type
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97339
Knecht, Andrea L; Truong, Lisa; Simonich, Michael T et al. (2016) Developmental benzo[a]pyrene (B[a]P) exposure impacts larval behavior and impairs adult learning in zebrafish. Neurotoxicol Teratol :
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Zhang, Guozhu; Roell, Kyle R; Truong, Lisa et al. (2016) A data-driven weighting scheme for multivariate phenotypic endpoints recapitulates zebrafish developmental cascades. Toxicol Appl Pharmacol 314:109-117
Truong, Lisa; Bugel, Sean M; Chlebowski, Anna et al. (2016) Optimizing multi-dimensional high throughput screening using zebrafish. Reprod Toxicol 65:139-147

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