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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), produces tumors of skin, lung, liver, kidney and stomach in animals, enhances lung cancer in epidemiological studies and is a known human carcinogen. The EPA cancer slope risk factor for oral BaP exposure is 1 per mg/kg-day. The remarkable sensitivity (attomole 14C; precision 0.5-2% in biological samples) of accelerator mass spectrometry (AMS) makes possible [14C]-BaP dosing of humans with de minimus risk. A micro-dose of 46 ng (5 nCi), was given in 3 separate cycles to 5 human volunteers with a minimum 2 weeks between dosing. Blood was collected over 72 hours and BaP and BaP metabolites ([14C]-BaPeq) measured using AMS. [14C]-BaPeq appeared in plasma with an average Tmax of 75 minutes and Cmax 116-326 fM (29-82 fg/mL). Non-compartmental half-lives in plasma ranged from 30.7-114.2 hours and area under the curve values (AUC0-72 hr) 649-2060 fg x hr x mL-1. A two compartmental model yielded first-order rate constants (Ka, K12, K21, Kela and Kelß) of 0.92, 0.49, 0.12, 0.05 and 0.01 fg/hr, respectively. The T1/2a and T1/2ß were 1.14 and 89 hours, respectively. The actual interval between dosing was 20-420 days with no impact on a low intra-individual variation. No covalent [14C]-BaPeq-DNA adducts from peripheral blood mononuclear cellsmore » (PBMCs) were detected (LLOD of 10 fg [14C]-BaPeq adducts/mg DNA) 12-72 hours post-dosing negating the use of this cancer biomarker in risk assessment. We assert that the most relevant model for humans is humans. AMS and micro-dosing could be used to enhance the accuracy of pharmacokinetics and potentially risk assessments.« less

Authors:
; ; ; ; ; ORCiD logo; ; ; ; ; ; ORCiD logo
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1501664
Report Number(s):
PNNL-SA-132492
Journal ID: ISSN 0041-008X
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 364; Journal Issue: C; Journal ID: ISSN 0041-008X
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
pharmacokinetcs, Polycyclic aromatic hydrocarbons

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., 2019. Web. doi: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, 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. doi: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, 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. doi:10.1016/j.taap.2018.12.010.
@article{osti_1501664,
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), produces tumors of skin, lung, liver, kidney and stomach in animals, enhances lung cancer in epidemiological studies and is a known human carcinogen. The EPA cancer slope risk factor for oral BaP exposure is 1 per mg/kg-day. The remarkable sensitivity (attomole 14C; precision 0.5-2% in biological samples) of accelerator mass spectrometry (AMS) makes possible [14C]-BaP dosing of humans with de minimus risk. A micro-dose of 46 ng (5 nCi), was given in 3 separate cycles to 5 human volunteers with a minimum 2 weeks between dosing. Blood was collected over 72 hours and BaP and BaP metabolites ([14C]-BaPeq) measured using AMS. [14C]-BaPeq appeared in plasma with an average Tmax of 75 minutes and Cmax 116-326 fM (29-82 fg/mL). Non-compartmental half-lives in plasma ranged from 30.7-114.2 hours and area under the curve values (AUC0-72 hr) 649-2060 fg x hr x mL-1. A two compartmental model yielded first-order rate constants (Ka, K12, K21, Kela and Kelß) of 0.92, 0.49, 0.12, 0.05 and 0.01 fg/hr, respectively. The T1/2a and T1/2ß were 1.14 and 89 hours, respectively. The actual interval between dosing was 20-420 days with no impact on a low intra-individual variation. No covalent [14C]-BaPeq-DNA adducts from peripheral blood mononuclear cells (PBMCs) were detected (LLOD of 10 fg [14C]-BaPeq adducts/mg DNA) 12-72 hours post-dosing negating the use of this cancer biomarker in risk assessment. We assert that the most relevant model for humans is humans. AMS and micro-dosing could be used to enhance the accuracy of pharmacokinetics and potentially risk assessments.},
doi = {10.1016/j.taap.2018.12.010},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = C,
volume = 364,
place = {United States},
year = {2019},
month = {2}
}

Works referencing / citing this record:

Radiocarbon Tracers in Toxicology and Medicine: Recent Advances in Technology and Science
journal, May 2019

  • Malfatti, Michael A.; Buchholz, Bruce A.; Enright, Heather A.
  • Toxics, Vol. 7, Issue 2
  • DOI: 10.3390/toxics7020027