%0 Journal Article %J Toxicol Appl Pharmacol %D 2023 %T Benzo[a]pyrene toxicokinetics in humans following dietary supplementation with 3,3'-diindolylmethane (DIM) or Brussels sprouts. %A Monica L. Vermillion Maier %A Siddens, Lisbeth K %A Jamie Pennington %A Sandra Uesugi %A Susan C Tilton %A Vertel, Emily A %A Kim A Anderson %A Lane G Tidwell %A Ted J Ognibene %A Kenneth Turteltaub %A Jordan Smith %A Williams, David E %X

Utilizing the atto-zeptomole sensitivity of UPLC-accelerator mass spectrometry (UPLC-AMS), we previously demonstrated significant first-pass metabolism following escalating (25-250 ng) oral micro-dosing in humans of [C]-benzo[a]pyrene ([C]-BaP). The present study examines the potential for supplementation with Brussels sprouts (BS) or 3,3'-diindolylmethane (DIM) to alter plasma levels of [C]-BaP and metabolites over a 48-h period following micro-dosing with 50 ng (5.4 nCi) [C]-BaP. Volunteers were dosed with [C]-BaP following fourteen days on a cruciferous vegetable restricted diet, or the same diet supplemented for seven days with 50 g of BS or 300 mg of BR-DIM® prior to dosing. BS or DIM reduced total [C] recovered from plasma by 56-67% relative to non-intervention. Dietary supplementation with DIM markedly increased T and reduced C for [C]-BaP indicative of slower absorption. Both dietary treatments significantly reduced C values of four downstream BaP metabolites, consistent with delaying BaP absorption. Dietary treatments also appeared to reduce the T and the plasma AUC() for Unknown Metabolite C, indicating some effect in accelerating clearance of this metabolite. Toxicokinetic constants for other metabolites followed the pattern for [C]-BaP (metabolite profiles remained relatively consistent) and non-compartmental analysis did not indicate other significant alterations. Significant amounts of metabolites in plasma were at the bay region of [C]-BaP irrespective of treatment. Although the number of subjects and large interindividual variation are limitations of this study, it represents the first human trial showing dietary intervention altering toxicokinetics of a defined dose of a known human carcinogen.

%B Toxicol Appl Pharmacol %P 116377 %8 2023 Jan 12 %G eng %R 10.1016/j.taap.2023.116377 %0 Journal Article %J Environ Int %D 2022 %T Benzo[a]pyrene (BaP) metabolites predominant in human plasma following escalating oral micro-dosing with [C]-BaP. %A Monica L. Vermillion Maier %A Siddens, Lisbeth K %A Jamie Pennington %A Sandra Uesugi %A Kim A Anderson %A Lane G Tidwell %A Susan C Tilton %A Ted J Ognibene %A Kenneth Turteltaub %A Jordan Smith %A Williams, David E %X

Benzo[a]pyrene (BaP) is formed by incomplete combustion of organic materials (petroleum, coal, tobacco, etc.). BaP is designated by the International Agency for Research on Cancer as a group 1 known human carcinogen; a classification supported by numerous studies in preclinical models and epidemiology studies of exposed populations. Risk assessment relies on toxicokinetic and cancer studies in rodents at doses 5-6 orders of magnitude greater than average human uptake. Using a dose-response design at environmentally relevant concentrations, this study follows uptake, metabolism, and elimination of [C]-BaP in human plasma by employing UPLC - accelerator mass spectrometry (UPLC-AMS). Volunteers were administered 25, 50, 100, and 250 ng (2.7-27 nCi) of [C]-BaP (with interceding minimum 3-week washout periods) with quantification of parent [C]-BaP and metabolites in plasma measured over 48 h. [C]-BaP median T was 30 min with C and area under the curve (AUC) approximating dose-dependency. Marked inter-individual variability in plasma pharmacokinetics following a 250 ng dose was seen with 7 volunteers as measured by the C (8.99 ± 7.08 ng × mL) and AUC (68.6 ± 64.0 fg × hr × mL). Approximately 3-6% of the [C] recovered (AUC) was parent compound, demonstrating extensive metabolism following oral dosing. Metabolite profiles showed that, even at the earliest time-point (30 min), a substantial percentage of [C] in plasma was polar BaP metabolites. The best fit modeling approach identified non-compartmental apparent volume of distribution of BaP as significantly increasing as a function of dose (p = 0.004). Bay region tetrols and dihydrodiols predominated, suggesting not only was there extensive first pass metabolism but also potentially bioactivation. AMS enables the study of environmental carcinogens in humans with de minimus risk, allowing for important testing and validation of physiologically based pharmacokinetic models derived from animal data, risk assessment, and the interpretation of data from high-risk occupationally exposed populations.

%B Environ Int %V 159 %P 107045 %8 2022 Jan 15 %G eng %R 10.1016/j.envint.2021.107045