title: Human Microdosing with Carcinogenic Polycyclic Aromatic Hydrocarbons: In Vivo Pharmacokinetics of Dibenzo[def,p]chrysene and Metabolites by UPLC Accelerator Mass Spectrometry.
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 [14C]-DBC by accelerator mass spectrometry (AMS) analysis of total [14C] 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 [14C] product identified in plasma was unmetabolized [14C]-DBC itself (Cmax= 18.5 ±15.9 fg/mL, Tmax= 2.1 ± 1.0 h), whereas the major metabolite was identified as [14C]-(+/-)-DBC-11,12-diol (Cmax= 2.5 ±1.3 fg/mL, Tmax= 1.8 h). Several minor species of [14C]-DBC metabolites were also detected for which no reference standards were available. Free and conjugated metabolites were detected in urine with [14C]-(+/-)-DBC-11,12,13,14-tetraol isomers identified as the major metabolites, 56.3% of which were conjugated (Cmax= 35.8 ± 23.0 pg/pool, Tmax= 6-12 h pool). [14C]-DBC-11,12-diol, of which 97.5% was conjugated, was also identified in urine (Cmax= 29.4 ± 11.6 pg/pool, Tmax= 6-12 h pool). Parent [14C]-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.
authors: Department of Environmental and Molecular Toxicology, Oregon State University , Corvallis, Oregon 97331, United States.|Superfund Research Program, Oregon State University , Corvallis, Oregon 97331, United States.
authors: Erin P
authors: EP
authors: Madeen
authors: Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory , Livermore, California 94550, United States.
authors: Ted J
authors: TJ
authors: Ognibene
authors: Superfund Research Program, Oregon State University , Corvallis, Oregon 97331, United States.|Systems Toxicology and Exposure Science, Pacific Northwest National Laboratory , Richland, Washington 99354, United States.
authors: Richard A
authors: RA
authors: Corley
authors: Superfund Research Program, Oregon State University , Corvallis, Oregon 97331, United States.
authors: Tammie J
authors: TJ
authors: McQuistan
authors: Department of Environmental and Molecular Toxicology, Oregon State University , Corvallis, Oregon 97331, United States.
authors: Marilyn C
authors: MC
authors: Henderson
authors: Department of Environmental and Molecular Toxicology, Oregon State University , Corvallis, Oregon 97331, United States.|Superfund Research Program, Oregon State University , Corvallis, Oregon 97331, United States.
authors: William M
authors: WM
authors: Baird
authors: Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory , Livermore, California 94550, United States.
authors: Graham
authors: G
authors: Bench
authors: Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory , Livermore, California 94550, United States.|Biology and Biotechnology Research Division, Lawrence Livermore National Laboratory , Livermore, California 94550, United States.
authors: Ken W
authors: KW
authors: Turteltaub
authors: Department of Environmental and Molecular Toxicology, Oregon State University , Corvallis, Oregon 97331, United States.|Superfund Research Program, Oregon State University , Corvallis, Oregon 97331, United States.
authors: David E
authors: DE
authors: Williams
mesh_terms: D000328:Adult; D000368:Aged; D001580:Benzopyrenes / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D015394:Molecular Structure; D055815:Young Adult
chemical_list: D001580:Benzopyrenes; C041517:dibenzo(a,l)pyrene