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.
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.
|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 :|
|Bugel, Sean M; Wehmas, Leah C; La Du, Jane K et al. (2016) Phenotype anchoring in zebrafish reveals a potential role for matrix metalloproteinases (MMPs) in tamoxifen's effects on skin epithelium. Toxicol Appl Pharmacol 296:31-41|
|Sadler, Natalie C; Nandhikonda, Premchendar; Webb-Robertson, Bobbie-Jo et al. (2016) Hepatic Cytochrome P450 Activity, Abundance, and Expression Throughout Human Development. Drug Metab Dispos 44:984-91|
|Haggard, Derik E; Noyes, Pamela D; Waters, Katrina M et al. (2016) Phenotypically anchored transcriptome profiling of developmental exposure to the antimicrobial agent, triclosan, reveals hepatotoxicity in embryonic zebrafish. Toxicol Appl Pharmacol 308:32-45|
|Bugel, Sean M; Bonventre, Josephine A; Tanguay, Robert L (2016) Comparative Developmental Toxicity of Flavonoids Using an Integrative Zebrafish System. Toxicol Sci 154:55-68|
|Paulik, L Blair; Smith, Brian W; Bergmann, Alan J et al. (2016) Passive samplers accurately predict PAH levels in resident crayfish. Sci Total Environ 544:782-91|
|Tidwell, Lane G; Allan, Sarah E; O'Connell, Steven G et al. (2016) PAH and OPAH Flux during the Deepwater Horizon Incident. Environ Sci Technol 50:7489-97|
|Garcia, Gloria R; Noyes, Pamela D; Tanguay, Robert L (2016) Advancements in zebrafish applications for 21st century toxicology. Pharmacol Ther 161:11-21|
|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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