Pharmacokinetics of [14C]-Benzo[a]pyrene (BaP) in humans: Impact of Co-Administration of smoked salmon and BaP dietary restriction

Abstract

Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH), is a known human carcinogen. In non-smoking adults greater than 95% of BaP exposure is through diet. The carcinogenicity of BaP is utilized by the U.S. EPA to assess relative potency of complex PAH mixtures. PAH relative potency factors (RPFs, BaP = 1) are determined from high dose animal data. We employed accelerator mass spectrometry (AMS) to determine pharmacokinetics of [C]-BaP in humans following dosing with 46 ng (an order of magnitude lower than human dietary daily exposure and million-fold lower than animal cancer models). To assess the impact of co-administration of food with a complex PAH mixture, humans were dosed with 46 ng of [C]-BaP with or without smoked salmon. Subjects were asked to avoid high BaP-containing diets and a 3-day dietary questionnaire given to assess dietary exposure prior to dosing and three days post-dosing with [C]-BaP. Co-administration of smoked salmon, containing a complex mixture of PAHs with an RPF of 460 ng BaP, reduced and delayed absorption. Administration of canned commercial salmon, containing very low amounts of PAHs, showed the impacts on pharmacokinetics were not due to high amounts of PAHs but rather a food matrix effect.

Toxicokinetics of benzo[a]pyrene in humans: Extensive metabolism as determined by UPLC-accelerator mass spectrometry following oral micro-dosing

“…A catheter was placed in an appropriate vein and a time zero blood sample taken prior to swallowing a capsule containing 46 ng (5 nCi) of [7-14 C]-BaP (27 nCi/nmol), with water. The [7-14 C]-BaP was from American Radiolabeled Chemicals, Inc. (St. Louis, MO, custom synthesis) and purified by reverse phase HPLC, capsules prepared and blood (8 mL at each time point) drawn at 0.25 0.5, 0.75, 1.0, 1.5, 2, 2.5, 3, 4, 8, 24, 48 and 72 hours as described in Hummel et al, (2018).…”

“…Aliquots of plasma (0.75 mL or 1.5 ml for metabolic profiles) from each time point were extracted within two hours after collection according to the method of Crowell et al, (2011). The protocol is described in detail in Hummel et al, (2018). Samples were evaporated and flame-sealed in a quartz tube containing Cu(II) and combusted to 900°C, producing CO 2 which was then transferred to a septa sealed glass tube containing Zn and Co and heated to 525°C, producing graphite on the Co catalyst.…”

“…The graphite was loaded into an aluminum sample holder for AMS analysis, performed on the 250 kV single stage AMS, constructed and maintained by the Center for Accelerator Mass Spectrometry at LLNL (ratio of 14 C:C with a precision of 3% and sensitivity of 0.7 attomol 14 C per mg total carbon) . As in previous studies (Madeen et al, 2015;Hummel et al, 2018) biochemical samples are measured 4-10 times with at least 10,000 14 C counts or for 30 seconds (each replicate) (Ognibene et al, 2015).…”

“…Accelerator mass spectrometry (AMS), due to its remarkable sensitivity to 14 C, is finding increasing use in study of environmental carcinogens (Enright et al, 2016;Felton and Turteltabaub, 1994;Ognibene et al, 2004). Human subjects have been dosed with [ 14 C]labeled 2-amino-3-methylimidazo[4,5-f]quinolone (IQ), 2-amino-3,8-dimethylimidazo[4,5b]quinoxaline (MeIQx), 2-amino-3-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), tamoxifen, aflatoxin B 1 , dibenzo [def,p]chrysene (DBC) and BaP (Brown et al, 2006;Enright et al, 2016;Hummel et al, 2018;Jubert et al, 2009;Lightfoot et al, 2000;Madeen et al, 2015;. The majority of these studies with carcinogens have assayed for target organ DNA binding (Lightfoot et al, 2000;Felton and Turteltaub, 1994) (dosing prior to surgical resection) but some have examined pharmacokinetics (Hummel et al, 2018;Madeen et al, 2015;.…”

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.…”