부산대학교 도서관

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]-BaP eq PK analysis gave plasma T max and C max 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]-BaP eq 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. Highlights • There is little intra-individual variation in T 1/2 , C max or T max of [14C]-benzo[ a ]pyrene. • [14C]-Benzo[ a ]pyrene is rapidly absorbed from GI and eliminated from plasma. • UPLC-accelerator mass spectrometry shows benzo[ a ]pyrene is rapidly metabolized. • Little or no covalent adduction to DNA in PBMCs occurs (<1 in 1011 base pairs). • Two individuals showed marked differences in the profile of metabolites in plasma. [ABSTRACT FROM AUTHOR]