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Human Microdosing with Carcinogenic Polycyclic Aromatic Hydrocarbons:In Vivo Pharmacokinetics of Dibenzo[def,p]chrysene and Metabolites by UPLC Accelerator Mass Spectrometry

Journal Article · · Chemical Research in Toxicology
 [1];  [2];  [3];  [1];  [4];  [1];  [2];  [2];  [5]
  1. Oregon State Univ., Corvallis, OR (United States). Superfund Research Program
  2. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Center for Accelerator Mass Spectrometry
  3. Oregon State Univ., Corvallis, OR (United States). Superfund Research Program; Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
  4. Oregon State Univ., Corvallis, OR (United States)
  5. Oregon State Univ., Corvallis, OR (United States). Superfund Research Program, and Linus Pauling Institute
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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.

Research Organization:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Organization:
USDOE National Nuclear Security Administration (NNSA); Public Health Service (PHS)
Grant/Contract Number:
AC52-07NA27344
OSTI ID:
1787797
Alternate ID(s):
OSTI ID: 1340831
Report Number(s):
LLNL-JRNL--664721; 786111
Journal Information:
Chemical Research in Toxicology, Journal Name: Chemical Research in Toxicology Journal Issue: 10 Vol. 29; ISSN 0893-228X
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
English

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