10 research outputs found
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MadeenErinEMTHumanInVivo.pdf
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.To the best of our knowledge, one or more authors of this paper were federal employees when contributing to this work. This is the publisher’s final pdf. The published article is copyrighted by the American Chemical Society and can be found at: https://doi.org/10.1021/tx5003996Keywords: accelerator mass spectrometry, human micro-dosing, polycyclic aromatic hydrocarbon, pharmacokinetics, dibenzo(def\, p)chryseneKeywords: accelerator mass spectrometry, human micro-dosing, polycyclic aromatic hydrocarbon, pharmacokinetics, dibenzo(def\, p)chrysen
Recommended from our members
MadeenErinEMTHumanInVivo.pdf
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.To the best of our knowledge, one or more authors of this paper were federal employees when contributing to this work. This is the publisher’s final pdf. The published article is copyrighted by the American Chemical Society and can be found at: https://doi.org/10.1021/tx5003996Keywords: pharmacokinetics, dibenzo(def\, p)chrysene, accelerator mass spectrometry, polycyclic aromatic hydrocarbon, human micro-dosin
Human Microdosing with Carcinogenic Polycyclic Aromatic Hydrocarbons: <i>In Vivo</i> Pharmacokinetics of Dibenzo[<i>def,p</i>]chrysene and Metabolites by UPLC Accelerator Mass Spectrometry
Metabolism is a key
health risk factor following exposures to pro-carcinogenic
polycyclic aromatic hydrocarbons (PAHs) such as dibenzoÂ[<i>def,p</i>]Âchrysene (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 [<sup>14</sup>C]-DBC by accelerator mass spectrometry (AMS) analysis
of total [<sup>14</sup>C] 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 [<sup>14</sup>C] product identified in plasma was unmetabolized [<sup>14</sup>C]-DBC
itself (<i>C</i><sub>max</sub> = 18.5 ±15.9 fg/mL, <i>T</i><sub>max</sub>= 2.1 ± 1.0 h), whereas the major metabolite
was identified as [<sup>14</sup>C]-(+/–)-DBC-11,12-diol (<i>C</i><sub>max</sub>= 2.5 ±1.3 fg/mL, <i>T</i><sub>max</sub>= 1.8 h). Several minor species of [<sup>14</sup>C]-DBC
metabolites were also detected for which no reference standards were
available. Free and conjugated metabolites were detected in urine
with [<sup>14</sup>C]-(+/–)-DBC-11,12,13,14-tetraol isomers
identified as the major metabolites, 56.3% of which were conjugated
(<i>C</i><sub>max</sub>= 35.8 ± 23.0 pg/pool, <i>T</i><sub>max</sub> = 6–12 h pool). [<sup>14</sup>C]-DBC-11,12-diol,
of which 97.5% was conjugated, was also identified in urine (<i>C</i><sub>max</sub> = 29.4 ± 11.6 pg/pool, <i>T</i><sub>max</sub> = 6–12 h pool). Parent [<sup>14</sup>C]-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