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

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 here by UPLC-AMS.more » 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.« less

Authors:
 [1];  [2];  [3];  [4];  [5]; ORCiD logo [5];  [5];  [1];  [1];  [6];  [7]; ORCiD logo [2]
+ Show Author Affiliations
  1. Oregon State Univ., Corvallis, OR (United States). Dept. of Environmental and Molecular Toxicology. NIEHS Superfund Research Program
  2. Oregon State Univ., Corvallis, OR (United States). Dept. of Environmental and Molecular Toxicology. NIEHS Superfund Research Program. Linus Pauling Inst.
  3. Oregon State Univ., Corvallis, OR (United States). Linus Pauling Inst.
  4. Western Univ. of Health Sciences, Lebanon, OR (United States)
  5. Oregon State Univ., Corvallis, OR (United States). NIEHS Superfund Research Program; Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Chemical Biology and Exposure Science
  6. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Center for Accelerator Mass Spectrometry
  7. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Center for Accelerator Mass Spectrometry. Biology and Biotechnology Research Division
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Oregon State Univ., Corvallis, OR (United States)
Sponsoring Org.:
USDOE; National Inst. of Health (NIH) (United States)
OSTI Identifier:
1515336
Alternate Identifier(s):
OSTI ID: 1636744
Report Number(s):
LLNL-JRNL-744366
Journal ID: ISSN 0041-008X; 899476
Grant/Contract Number:  
AC52-07NA27344; P42ES016465; R01ES028600; T32ES07060; P41 GM103483
Resource Type:
Accepted Manuscript
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 364; Journal ID: ISSN 0041-008X
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; benzo[a]pyrene; pharmacokinetics; polycyclic aromatic hydrocarbons; accelerator mass spectrometry; micro-dosing; metabolites

Citation Formats

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, Kenneth, and Williams, David E. Toxicokinetics of benzo[a]pyrene in humans: Extensive metabolism as determined by UPLC-accelerator mass spectrometry following oral micro-dosing. United States: N. p., 2018. Web. doi:10.1016/j.taap.2018.12.010.
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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, Kenneth, & Williams, David E. Toxicokinetics of benzo[a]pyrene in humans: Extensive metabolism as determined by UPLC-accelerator mass spectrometry following oral micro-dosing. United States. https://doi.org/10.1016/j.taap.2018.12.010
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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, Kenneth, and Williams, David E. Fri . "Toxicokinetics of benzo[a]pyrene in humans: Extensive metabolism as determined by UPLC-accelerator mass spectrometry following oral micro-dosing". United States. https://doi.org/10.1016/j.taap.2018.12.010. https://www.osti.gov/servlets/purl/1515336.
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@article{osti_1515336,
title = {Toxicokinetics of benzo[a]pyrene in humans: Extensive metabolism as determined by UPLC-accelerator mass spectrometry following oral micro-dosing},
author = {Madeen, Erin and Siddens, Lisbeth K. and Uesugi, Sandra and McQuistan, Tammie and Corley, Richard A. and Smith, Jordan and Waters, Katrina M. and Tilton, Susan C. and Anderson, Kim A. and Ognibene, Ted and Turteltaub, Kenneth and Williams, David E.},
abstractNote = {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 here 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.},
doi = {10.1016/j.taap.2018.12.010},
journal = {Toxicology and Applied Pharmacology},
number = ,
volume = 364,
place = {United States},
year = {Fri Dec 21 00:00:00 EST 2018},
month = {Fri Dec 21 00:00:00 EST 2018}
}
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https://doi.org/10.1016/j.taap.2018.12.010
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