TitleToxicokinetics of benzo[a]pyrene in humans: Extensive metabolism as determined by UPLC-accelerator mass spectrometry following oral micro-dosing.
Publication TypeJournal Article
Year of Publication2019
AuthorsMadeen, EP, Siddens, LK, Uesugi, S, McQuistan, TJ, Corley, RA, Smith, JN, Waters, KM, Tilton, SC, Anderson, KA, Ognibene, TJ, Turteltaub, K, Williams, DE
JournalToxicol Appl Pharmacol
Volume364
Pagination97-105
Date Published2019 Feb 01
ISSN1096-0333
Abstract

Benzo[a]pyrene (BaP), is a known human carcinogen (International Agency for Research on Cancer (IARC) class 1). The remarkable sensitivity (zepto-attomole C in biological samples) of accelerator mass spectrometry (AMS) makes possible, with de minimus risk, pharmacokinetic (PK) analysis following [C]-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. [C]-BaP PK analysis gave plasma T and C 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/10 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, or and GSTM1 or had no impact on [C]-BaP PK or DNA adduction with this very limited sample. Plasma metabolites over 72 h from two individuals (one CYP1B1 and one CYP1B1) were analyzed by UPLC-AMS. In both individuals, parent [C]-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.

DOI10.1016/j.taap.2018.12.010
Alternate JournalToxicol. Appl. Pharmacol.
PubMed ID30582946
PubMed Central IDPMC6369707
Grant ListP41 GM103483 / GM / NIGMS NIH HHS / United States
P42 ES016465 / ES / NIEHS NIH HHS / United States
R01 ES028600 / ES / NIEHS NIH HHS / United States
T32 ES007060 / ES / NIEHS NIH HHS / United States