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

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 [C-14]-DBC. This study was made possible with highly sensitive accelerator mass spectrometry (AMS), capable of detecting [C-14]-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 C-max was 68.8 +/- 44.3 fg.mL(-1) with a T-max of 2.25 +/- 1.04 h. Elimination occurred in two distinct phases: a rapid (alpha)-phase, with a T-1/2 of 5.8 +/- 3.4 h and an apparent elimination rate constant (K-el) of 0.17 +/- 0.12 fg.h(-1), followed by a slower (beta)-phase, with a T-1/2 of 41.3 +/- 29.8 h and an apparent K-el of 0.03 +/- 0.02 fg.h(-1). In spite of the high degree of hydrophobicity (log K-ow 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.