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 14 C in biological samples) of accelerator mass spectrometry (AMS) makes possible, with de minimus risk, pharmacokinetic (PK) analysis following [ 14 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 hours. [ 14 C]-BaP eq PK analysis gave plasma T max and C max values of 1.25 hours and 29-82 fg/mL, respectively. PK parameters were assessed by non-compartment and compartment models. Intervals between dosing ranged from 20-420 days and had little impact on intra-individual

3,3′-Diindolylmethane Exhibits Significant Metabolism after Oral Dosing in Humans

“…The AHR-dependent induction of CYPs 1A1, 1A2 and 1B1 alter the toxicokinetics of BaP in rodent models but at BaP doses orders of magnitude higher than daily human exposure. To examine the potential for DIM supplementation in alteration of the (Madeen et al, 2019). The study reported here was not designed as a DIM pharmacokinetic study although it resembles a previous protocol with I3C (Reed et al, 2006) in which women in a Phase 1 trial were given 200 mg I3C for 4 weeks followed by 4 weeks of 400 mg daily I3C.…”

“…The final version may differ from this version. This research is part of a larger study using UPLC-accelerator mass spectrometry to examine [ 14 C]-benzo[a]pyrene (BaP) toxicokinetics following oral microdosing and the possible effects of dietary intake on kinetics (Madeen et al, 2019). One component of this study involved administration of DIM (BioResponse ® , BR-DIM ® 150) daily for 1 week prior to [ 14 C]-BaP dosing to assess the importance of the blocking mechanism in humans toward an important dietary carcinogen.…”

The safety evaluation of food flavoring substances: the role of genotoxicity studies

“…DNA adducts can be detected at extremely low levels, e.g. the reported limit of detection (LOD) is as low as 1 adduct per 10 11 nucleotides and the limit of quantitation (LOQ) is as low as 5 adducts per 10 11 nucleotides by LC/MS (Zhang et al 2006;Monien et al 2015;Villalta et al 2017;Yang et al 2019) and is even lower by accelerator MS (Hummel et al 2018;Madeen et al 2019). Therefore, it is critical to evaluate whether the level of DNA adducts detected is biologically significant.…”

Radiocarbon Tracers in Toxicology and Medicine: Recent Advances in Technology and Science

“…The moving wire interface was used to measure human plasma and urine metabolism profiles following environmentally relevant exposures to the polycyclic aromatic hydrocarbons, dibenzo[def,p]chrysene (DBC) (Figure 1) [18] and benzo[a]pyrene [19]. Due to their toxicity, doses to healthy human volunteers were required to be kept as low as possible to minimize risk and the metabolite levels recorded following HPLC separation were so low that they could only have been measured as a CO 2 gas.…”

“…At the dose used, BaP was fairly rapidly eliminated from the plasma and very little parent compound was present in the plasma even at the earliest time point examined, indicating extensive metabolism of BaP in these human subjects. The use of the UPLC-AMS together with the on-line gas accepting ion source provided exquisite sensitivity (zepto-mole 14 C in biological samples), allowing for the quantification of BaP plasma metabolites of BaP from exposure levels that were 5 to 15 times lower than the estimated daily exposure to BaP [19].…”