title: Human in Vivo Pharmacokinetics of [(14)C]Dibenzo[def,p]chrysene by Accelerator Mass Spectrometry Following Oral Microdosing.
abstract: 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 [(14)C]-DBC. This study was made possible with highly sensitive accelerator mass spectrometry (AMS), capable of detecting [(14)C]-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. 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.
authors.forename: Erin
authors.initials: E
authors.lastname: Madeen
authors.affiliation: Systems Toxicology & Exposure Science, Pacific Northwest National Laboratory , Richland, Washington 99354, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Corley
authors.affiliation: Systems Toxicology & Exposure Science, Pacific Northwest National Laboratory , Richland, Washington 99354, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Crowell
authors.affiliation: Biology and Biotechnology Research Division, and ¶the Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory , Livermore, California 94550, United States.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Turteltaub
authors.forename: Ted
authors.initials: T
authors.lastname: Ognibene
authors.affiliation: Biology and Biotechnology Research Division, and ¶the Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory , Livermore, California 94550, United States.
authors.forename: Mike
authors.initials: M
authors.lastname: Malfatti
authors.forename: Tammie J
authors.initials: TJ
authors.lastname: McQuistan
authors.forename: Mary
authors.initials: M
authors.lastname: Garrard
authors.forename: Dan
authors.initials: D
authors.lastname: Sudakin
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001580:Benzopyrenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002273:Carcinogens / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D055815:Young Adult
chemical_list: D001580:Benzopyrenes; D002273:Carcinogens; C041517:dibenzo(a,l)pyrene