Pharmacokinetics of Benzo[a]Pyrene: Impact of Diet
Condition: Environmental Exposure
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Evaluation of the pharmacokinetics for [14C]-benzo[a]pyrene ([14C]-BaP) and metabolites in
      plasma and urine over 48 hours following a 50 ng dose (5.4 nCi) alone, following 7 days'
      consumption of Brussels sprouts, and following 7 days' consumption of a supplement containing
      3,3'-diindolylmethane (DIM).
    

Detailed description: 
      The pharmacokinetics for [14C]-BaP and metabolites will be assessed by UHLPC-Accelerator Mass
      Spectrometry (AMS, Lawrence Livermore National Laboratory) in plasma and urine collected over
      48 hours following oral doses of 50 ng dose (5.4 nCi) alone, following 7 days' consumption of
      Brussels sprouts, and following 7 days' consumption of a supplement containing
      3,3'-diindolylmethane (DIM).

      The investigators hypothesize that pre-administration of Brussels sprouts or DIM will alter
      [14C]-BaP metabolism and increase the rate of elimination consistent with predictions based
      on a previously developed Physiologically-Based Pharmacokinetic (PBPK) model for BaP.
      Briefly, this hypothesis will be tested by dosing individuals with 50 ng [14C]-BaP alone and,
      following a 3-week washout period, ingestion of about 50 g Brussels sprouts or 300 mg of
      3,3'-diindolylmethane (DIM) supplement for 7 days prior to the [14C]-BaP micro-dose. The
      impact of the supplement and the whole food will be assessed with respect to alterations in
      uptake from the GI tract, metabolism and rate of elimination. The consumption of cruciferous
      vegetables will be assessed at the beginning of the study by completion of a dietary
      questionnaire to examine typical eating patterns in the previous 3 months and by collection
      and extraction of blood and urine to assay for DIM by LC/ESI-MS/MS-SRM). In addition, for
      each phase, urine will be assayed for DIM as an estimate of crucifer or DIM supplement
      intake.

      In preclinical and clinical studies, administration of Brussels sprouts or DIM impacts the
      activity of the same enzymes responsible for the phase 1 (CYP1A1 and CYP1B1) and phase 2
      enzymes (GSTM1, UGT, SULT). Monitoring changes in β-estradiol metabolites will confirm the
      mechanism of alteration in the metabolic profile of [14C]-BaP.

      Metabolite profiles and kinetics of elimination are predicted to be consistent with a BaP
      physiologically based pharmacokinetic (PBPK) model developed by Pacific Northwest National
      Laboratory (PNNL). A non-smoker, not exposed occupationally, receives 270-700 ng of BaP
      daily; about 95% dietary. The WHO has set an estimated safe daily lifetime (70 year/70 Kg
      individual, cancer endpoint) exposure to BaP of 42-350 ng. This protocol represents de
      minimus risk.
    

Intervention name(s): [14C]-benzo[a]pyrene; Brussels sprouts before 50 ng dose; DIM supplement before 50 ng dose
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Oral micro-dose (50 ng) (5.4 nCi); Brussels sprouts for 7 days before 50 ng (5.4 nCi) dose of BaP; DIM supplement for 7 days before 50 ng (5.4 nCi) dose of BaP and coadministration with DIM supplement
Other intervention name(s): Carcinogenic PAH environmental pollutant; Brussels sprouts and carcinogenic PAH; Cruciferous vegetable supplement and carcinogenic PAH
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Benzo[a]pyrene; Accelerator Mass Spectrometry; Polycyclic Aromatic Hydrocarbons; cruciferous vegetable; Brussels sprouts; 3,3'-diindolylmethane; DIM; indole-3-carbinol; I3C; PAH