Human in vivo pharmacokinetics of [14C]dibenzo[def,p ]chrysene by accelerator mass spectrometry following oral microdosing

Erin Madeen, Richard A. Corley, Susan Crowell, Ken W Turteltaub, Ted Ognibene, Mike Malfatti, Tammie J. McQuistan, Mary Garrard, Dan Sudakin, David E. Williams

Research output: Contribution to journalArticle

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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 [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. 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.

Original languageEnglish (US)
Pages (from-to)126-134
Number of pages9
JournalChemical Research in Toxicology
Volume28
Issue number1
DOIs
StatePublished - Jan 20 2015
Externally publishedYes

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Pharmacokinetics
Particle accelerators
Mass spectrometry
Mass Spectrometry
Plasmas
Animals
Molecular weight
Polycyclic Aromatic Hydrocarbons
Polycyclic aromatic hydrocarbons
Molecular Weight
DDT
Organic pollutants
Benzo(a)pyrene
Polychlorinated Biphenyls
Hydrophobicity
Metabolites
Hydrocarbons
Urine
Carcinogens
Risk assessment

ASJC Scopus subject areas

  • Toxicology

Cite this

Human in vivo pharmacokinetics of [14C]dibenzo[def,p ]chrysene by accelerator mass spectrometry following oral microdosing. / Madeen, Erin; Corley, Richard A.; Crowell, Susan; Turteltaub, Ken W; Ognibene, Ted; Malfatti, Mike; McQuistan, Tammie J.; Garrard, Mary; Sudakin, Dan; Williams, David E.

In: Chemical Research in Toxicology, Vol. 28, No. 1, 20.01.2015, p. 126-134.

Research output: Contribution to journalArticle

Madeen, E, Corley, RA, Crowell, S, Turteltaub, KW, Ognibene, T, Malfatti, M, McQuistan, TJ, Garrard, M, Sudakin, D & Williams, DE 2015, 'Human in vivo pharmacokinetics of [14C]dibenzo[def,p ]chrysene by accelerator mass spectrometry following oral microdosing', Chemical Research in Toxicology, vol. 28, no. 1, pp. 126-134. https://doi.org/10.1021/tx5003996
Madeen, Erin ; Corley, Richard A. ; Crowell, Susan ; Turteltaub, Ken W ; Ognibene, Ted ; Malfatti, Mike ; McQuistan, Tammie J. ; Garrard, Mary ; Sudakin, Dan ; Williams, David E. / Human in vivo pharmacokinetics of [14C]dibenzo[def,p ]chrysene by accelerator mass spectrometry following oral microdosing. In: Chemical Research in Toxicology. 2015 ; Vol. 28, No. 1. pp. 126-134.
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AU - Ognibene, Ted

AU - Malfatti, Mike

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