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Human in vivo Pharmacokinetics of [¹⁴C]Dibenzo[def,p]chrysene by Accelerator Mass Spectrometry Following Oral Micro-Dosing Public Deposited

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https://ir.library.oregonstate.edu/concern/articles/8p58pf835

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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 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 micro-dosing (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 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 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 dataset describing pharmacokinetics in humans of a high molecular weight PAH and should be a valuable addition to risk assessment paradigms.
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  • Madeen, E., Corley, R. A., Crowell, S., Turteltaub, K. W., Ognibene, T., Malfatti, M., ... & Williams, D. E. (2014). Human in vivo Pharmacokinetics of [¹⁴C]Dibenzo[def,p]chrysene by Accelerator Mass Spectrometry Following Oral Micro-Dosing. Chemical Research in Toxicology. doi:10.1021/tx5003996
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  • 28
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  • 1
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  • This study was funded by PHS grants P42ES016465, K.C. Donnelly Supplement P42ES016465, P41GM103483 and T32ES07060. AMS was performed at the Research Resource for Biomedical AMS which is operated at LLNL under the auspices of the U.S. Department of Energy under contract DE-AC52-07NA27344 and National Institute of General Medical Sciences 8P41 GM103483-14.
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