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Title: Human in Vivo Pharmacokinetics of [ 14 C]Dibenzo[ def,p ]chrysene by Accelerator Mass Spectrometry Following Oral Microdosing

Journal Article · · Chemical Research in Toxicology
DOI:https://doi.org/10.1021/tx5003996· OSTI ID:1167477
;  [1];  [1];  [2]; ;  [2]; ; ; ;
  1. Systems Toxicology & Exposure Science, Pacific Northwest National Laboratory, Richland, Washington 99354, United States
  2. Biology and Biotechnology Research Division, and ¶the Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, Livermore, California 94550, United States
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Dibenzo(def,p)chrysene (DBC), (also known as dibenzo[a,l]pyrene), is a high molecular weight polycyclic aromatic hydrocarbon (PAH) found in the environment, including food, produced by the incomplete combustion of hydrocarbons. DBC, classified by IARC as a 2A probable human carcinogen, has a relative potency factor (RPF) in animal cancer models 30-fold higher than benzo[a]pyrene. No data are available describing the disposition of high molecular weight (>4 rings) PAHs in humans to compare to animal studies. Pharmacokinetics of DBC was determined in 3 female and 6 male human volunteers following oral microdosing (29 ng, 5 nCi) of [14C]-DBC. This study was made possible with highly sensitive accelerator mass spectrometry (AMS), capable of detecting [14C]-DBC equivalents in plasma and urine following a dose considered of de minimus risk to human health. Plasma and urine were collected over 72 h. The plasma Cmax was 68.8 ± 44.3 fg·mL–1 with a Tmax of 2.25 ± 1.04 h. Elimination occurred in two distinct phases: a rapid (α)-phase, with a T1/2 of 5.8 ± 3.4 h and an apparent elimination rate constant (Kel) of 0.17 ± 0.12 fg·h–1, followed by a slower (β)-phase, with a T1/2 of 41.3 ± 29.8 h and an apparent Kel of 0.03 ± 0.02 fg·h–1. In spite of the high degree of hydrophobicity (log Kow of 7.4), DBC was eliminated rapidly in humans, as are most PAHs in animals, compared to other hydrophobic persistent organic pollutants such as, DDT, PCBs and TCDD. Preliminary examination utilizing a new UHPLC-AMS interface, suggests the presence of polar metabolites in plasma as early as 45 min following dosing. Finally, this is the first in vivo data set describing pharmacokinetics in humans of a high molecular weight PAH and should be a valuable addition to risk assessment paradigms.

Research Organization:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Organization:
USDOE Advanced Research Projects Agency - Energy (ARPA-E)
Grant/Contract Number:
AC52-07NA27344; P42ES016465; 8P41 GM103483-14
OSTI ID:
1167477
Alternate ID(s):
OSTI ID: 1263588
Journal Information:
Chemical Research in Toxicology, Journal Name: Chemical Research in Toxicology Vol. 28 Journal Issue: 1; ISSN 0893-228X
Publisher:
American Chemical SocietyCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 18 works
Citation information provided by
Web of Science

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