Toxicokinetics of benzo[a]pyrene in humans: Extensive metabolism as determined by UPLC-accelerator mass spectrometry following oral micro-dosing

Erin Madeen, Lisbeth K. Siddens, Sandra Uesugi, Tammie McQuistan, Richard A. Corley, Jordan Smith, Katrina M. Waters, Susan C. Tilton, Kim A. Anderson, Ted Ognibene, Ken W Turteltaub, David E. Williams

Research output: Contribution to journalArticle

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Abstract

Benzo[a]pyrene (BaP), is a known human carcinogen (International Agency for Research on Cancer (IARC) class 1). The remarkable sensitivity (zepto-attomole 14C in biological samples) of accelerator mass spectrometry (AMS) makes possible, with de minimus risk, pharmacokinetic (PK) analysis following [14C]-BaP micro-dosing of humans. A 46 ng (5 nCi) dose was given thrice to 5 volunteers with minimum 2 weeks between dosing and plasma collected over 72 h. [14C]-BaPeq PK analysis gave plasma Tmax and Cmax values of 1.25 h and 29–82 fg/mL, respectively. PK parameters were assessed by non- compartment and compartment models. Intervals between dosing ranged from 20 to 420 days and had little impact on intra-individual variation. DNA, extracted from peripheral blood mononuclear cells (PBMCs) of 4 volunteers, showed measurable levels (LOD ~ 0.5 adducts/1011 nucleotides) in two individuals 2–3 h post-dose, approximately three orders of magnitude lower than smokers or occupationally-exposed individuals. Little or no DNA binding was detectable at 48–72 h. In volunteers the allelic variants CYP1B1*1/*⁎1, *1/*3 or *3/*3 and GSTM1* 0/0 or *1 had no impact on [14C]-BaPeq PK or DNA adduction with this very limited sample. Plasma metabolites over 72 h from two individuals (one CYP1B1*1/*1 and one CYP1B1*3/*3) were analyzed by UPLC-AMS. In both individuals, parent [14C]-BaP was a minor constituent even at the earliest time points and metabolite profiles markedly distinct. AMS, coupled with UPLC, could be used in humans to enhance the accuracy of pharmacokinetics, toxicokinetics and risk assessment of environmental carcinogens.

Original languageEnglish (US)
Pages (from-to)97-105
Number of pages9
JournalToxicology and Applied Pharmacology
Volume364
DOIs
StatePublished - Feb 1 2019
Externally publishedYes

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Pharmacokinetics
Benzo(a)pyrene
Metabolism
Particle accelerators
Mass spectrometry
Mass Spectrometry
Volunteers
Metabolites
Plasmas
DNA
Environmental Carcinogens
International Agencies
Carcinogens
Risk assessment
Blood Cells
Blood
Nucleotides
Toxicokinetics
Research
Neoplasms

Keywords

  • Accelerator mass spectrometry
  • Benzo[a]pyrene
  • Metabolites
  • Micro-dosing
  • Pharmacokinetics
  • Polycyclic aromatic hydrocarbons

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Toxicokinetics of benzo[a]pyrene in humans : Extensive metabolism as determined by UPLC-accelerator mass spectrometry following oral micro-dosing. / Madeen, Erin; Siddens, Lisbeth K.; Uesugi, Sandra; McQuistan, Tammie; Corley, Richard A.; Smith, Jordan; Waters, Katrina M.; Tilton, Susan C.; Anderson, Kim A.; Ognibene, Ted; Turteltaub, Ken W; Williams, David E.

In: Toxicology and Applied Pharmacology, Vol. 364, 01.02.2019, p. 97-105.

Research output: Contribution to journalArticle

Madeen, E, Siddens, LK, Uesugi, S, McQuistan, T, Corley, RA, Smith, J, Waters, KM, Tilton, SC, Anderson, KA, Ognibene, T, Turteltaub, KW & Williams, DE 2019, 'Toxicokinetics of benzo[a]pyrene in humans: Extensive metabolism as determined by UPLC-accelerator mass spectrometry following oral micro-dosing', Toxicology and Applied Pharmacology, vol. 364, pp. 97-105. https://doi.org/10.1016/j.taap.2018.12.010
Madeen, Erin ; Siddens, Lisbeth K. ; Uesugi, Sandra ; McQuistan, Tammie ; Corley, Richard A. ; Smith, Jordan ; Waters, Katrina M. ; Tilton, Susan C. ; Anderson, Kim A. ; Ognibene, Ted ; Turteltaub, Ken W ; Williams, David E. / Toxicokinetics of benzo[a]pyrene in humans : Extensive metabolism as determined by UPLC-accelerator mass spectrometry following oral micro-dosing. In: Toxicology and Applied Pharmacology. 2019 ; Vol. 364. pp. 97-105.
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abstract = "Benzo[a]pyrene (BaP), is a known human carcinogen (International Agency for Research on Cancer (IARC) class 1). The remarkable sensitivity (zepto-attomole 14C in biological samples) of accelerator mass spectrometry (AMS) makes possible, with de minimus risk, pharmacokinetic (PK) analysis following [14C]-BaP micro-dosing of humans. A 46 ng (5 nCi) dose was given thrice to 5 volunteers with minimum 2 weeks between dosing and plasma collected over 72 h. [14C]-BaPeq PK analysis gave plasma Tmax and Cmax values of 1.25 h and 29–82 fg/mL, respectively. PK parameters were assessed by non- compartment and compartment models. Intervals between dosing ranged from 20 to 420 days and had little impact on intra-individual variation. DNA, extracted from peripheral blood mononuclear cells (PBMCs) of 4 volunteers, showed measurable levels (LOD ~ 0.5 adducts/1011 nucleotides) in two individuals 2–3 h post-dose, approximately three orders of magnitude lower than smokers or occupationally-exposed individuals. Little or no DNA binding was detectable at 48–72 h. In volunteers the allelic variants CYP1B1*1/*⁎1, *1/*3 or *3/*3 and GSTM1* 0/0 or *1 had no impact on [14C]-BaPeq PK or DNA adduction with this very limited sample. Plasma metabolites over 72 h from two individuals (one CYP1B1*1/*1 and one CYP1B1*3/*3) were analyzed by UPLC-AMS. In both individuals, parent [14C]-BaP was a minor constituent even at the earliest time points and metabolite profiles markedly distinct. AMS, coupled with UPLC, could be used in humans to enhance the accuracy of pharmacokinetics, toxicokinetics and risk assessment of environmental carcinogens.",
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AU - Siddens, Lisbeth K.

AU - Uesugi, Sandra

AU - McQuistan, Tammie

AU - Corley, Richard A.

AU - Smith, Jordan

AU - Waters, Katrina M.

AU - Tilton, Susan C.

AU - Anderson, Kim A.

AU - Ognibene, Ted

AU - Turteltaub, Ken W

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