TitleHuman Microdosing with Carcinogenic Polycyclic Aromatic Hydrocarbons: In Vivo Pharmacokinetics of Dibenzo[def,p]chrysene and Metabolites by UPLC Accelerator Mass Spectrometry.
Publication TypeJournal Article
Year of Publication2016
AuthorsMadeen, EP, Ognibene, TJ, Corley, RA, McQuistan, TJ, Henderson, MC, Baird, WM, Bench, G, Turteltaub, KW, Williams, DE
JournalChem Res Toxicol
Volume29
Issue10
Pagination1641-1650
Date Published2016 10 17
ISSN1520-5010
KeywordsAdult, Aged, Benzopyrenes, Chromatography, High Pressure Liquid, Dose-Response Relationship, Drug, Female, Healthy Volunteers, Humans, Male, Mass spectrometry, Middle Aged, Molecular Structure, Young Adult
Abstract

Metabolism is a key health risk factor following exposures to pro-carcinogenic polycyclic aromatic hydrocarbons (PAHs) such as dibenzo[def,p]chrysene (DBC), an IARC classified 2A probable human carcinogen. Human exposure to PAHs occurs primarily from the diet in nonsmokers. However, little data is available on the metabolism and pharmacokinetics in humans of high molecular weight PAHs (≥4 aromatic rings), including DBC. We previously determined the pharmacokinetics of DBC in human volunteers orally administered a microdose (29 ng; 5 nCi) of [C]-DBC by accelerator mass spectrometry (AMS) analysis of total [C] in plasma and urine. In the current study, we utilized a novel "moving wire" interface between ultraperformance liquid chromatography (UPLC) and AMS to detect and quantify parent DBC and its major metabolites. The major [C] product identified in plasma was unmetabolized [C]-DBC itself (C = 18.5 ±15.9 fg/mL, T= 2.1 ± 1.0 h), whereas the major metabolite was identified as [C]-(+/-)-DBC-11,12-diol (C= 2.5 ±1.3 fg/mL, T= 1.8 h). Several minor species of [C]-DBC metabolites were also detected for which no reference standards were available. Free and conjugated metabolites were detected in urine with [C]-(+/-)-DBC-11,12,13,14-tetraol isomers identified as the major metabolites, 56.3% of which were conjugated (C= 35.8 ± 23.0 pg/pool, T = 6-12 h pool). [C]-DBC-11,12-diol, of which 97.5% was conjugated, was also identified in urine (C = 29.4 ± 11.6 pg/pool, T = 6-12 h pool). Parent [C]-DBC was not detected in urine. This is the first data set to assess metabolite profiles and associated pharmacokinetics of a carcinogenic PAH in human volunteers at an environmentally relevant dose, providing the data necessary for translation of high dose animal models to humans for translation of environmental health risk assessment.

DOI10.1021/acs.chemrestox.6b00169
Alternate JournalChem. Res. Toxicol.
PubMed ID27494294
PubMed Central IDPMC5380438
Grant ListP01 CA090890 / CA / NCI NIH HHS / United States
P41 GM103483 / GM / NIGMS NIH HHS / United States
P42 ES016465 / ES / NIEHS NIH HHS / United States
T32 ES007060 / ES / NIEHS NIH HHS / United States