Toxicokinetics of benzo[a]pyrene in humans: Extensive metabolism as determined by UPLC-accelerator mass spectrometry following oral micro-dosing.
Toxicol Appl Pharmacol
; 364: 97-105, 2019 02 01.
Article
in En
| MEDLINE
| ID: mdl-30582946
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 46â¯ng (5 nCi) dose was given thrice to 5 volunteers with minimum 2â¯weeks between dosing and plasma collected over 72â¯h. [14C]-BaPeq PK analysis gave plasma Tmax and Cmax values of 1.25â¯h and 29-82â¯fg/mL, respectively. PK parameters were assessed by non- compartment and compartment models. Intervals between dosing ranged from 20 to 420â¯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 2-3â¯h post-dose, approximately three orders of magnitude lower than smokers or occupationally-exposed individuals. Little or no DNA binding was detectable at 48-72â¯h. In volunteers the allelic variants CYP1B1*1/*â1, *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 72â¯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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Mass Spectrometry
/
Benzo(a)pyrene
/
Carcinogens
/
Chromatography, Liquid
Type of study:
Etiology_studies
/
Risk_factors_studies
Limits:
Adult
/
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Toxicol Appl Pharmacol
Year:
2019
Document type:
Article
Affiliation country:
United States