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Pharmacokinetics of Benzo[a]Pyrene: Impact of Diet

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03802721
Recruitment Status : Active, not recruiting
First Posted : January 14, 2019
Last Update Posted : April 1, 2020
Sponsor:
Collaborators:
National Institute of Environmental Health Sciences (NIEHS)
Lawrence Livermore National Laboratory
Pacific Northwest National Laboratory
Information provided by (Responsible Party):
David Williams, Oregon State University

Brief 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).

Condition or disease Intervention/treatment Phase
Environmental Exposure Drug: [14C]-benzo[a]pyrene Drug: Brussels sprouts before 50 ng dose Drug: DIM supplement before 50 ng dose Early Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 7 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Masking Description: Deidentified samples will be analyzed by AMS at Lawrence Livermore National Laboratory and the pharmacokinetics determine at Pacific Northwest National Laboratory.
Primary Purpose: Basic Science
Official Title: Pharmacokinetics of Benzo[a]Pyrene: Impact of Diet
Actual Study Start Date : January 1, 2019
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 50 ng dose
Capsule containing 50 ng (5.4 nCi) [14C]-benzo[a]pyrene (BaP)
Drug: [14C]-benzo[a]pyrene
Oral micro-dose (50 ng) (5.4 nCi)
Other Name: Carcinogenic PAH environmental pollutant

Experimental: Brussels sprouts before 50 ng dose
Subjects will consume 50 g (about 1/2 cup) of lightly steamed Brussels sprouts each evening for 7 days prior to taking capsule containing 50 ng (5.4 nCi) [14C]-benzo[a]pyrene (BaP)
Drug: Brussels sprouts before 50 ng dose
Brussels sprouts for 7 days before 50 ng (5.4 nCi) dose of BaP
Other Name: Brussels sprouts and carcinogenic PAH

Experimental: DIM supplement before 50 ng dose
Subjects will consume 300 mg DIM supplement ( 2 capsules of BioResponse DIM® 150) each evening for 7 days prior to taking capsule containing 50 ng (5.4 nCi) [14C]-benzo[a]pyrene (BaP). A 300 mg DIM dose will be co-administrated with the 50 ng BaP dose
Drug: DIM supplement before 50 ng dose
DIM supplement for 7 days before 50 ng (5.4 nCi) dose of BaP and coadministration with DIM supplement
Other Name: Cruciferous vegetable supplement and carcinogenic PAH




Primary Outcome Measures :
  1. Plasma and urine 14C-BaP and 14C-BaP metabolite levels after oral dose [ Time Frame: 48 hours ]
    Plasma and urine levels of 14C-BaP and 14C-BaP metabolites measured by accelerator mass spectrometry


Secondary Outcome Measures :
  1. Peak plasma concentration of 14C-BaP Cmax [ Time Frame: 48 hours ]
    Determination of highest concentration of 14C-BaP in plasma

  2. Time at highest plasma concentration of 14C-BaP Tmax [ Time Frame: 48 hours ]
    Determination of time at which plasma concentration of 14C-BaP is highest

  3. Area under plasma concentration of 14C-BaP versus time curve AUC [ Time Frame: 48 hours ]
    Integration of concentration of 14C-BaP in plasma over time

  4. Rate of elimination of 14C-BaP [ Time Frame: 48 hours ]
    Determination of constants for rate of elimination of 14C-BaP from plasma

  5. Metabolites of 14C-BaP in plasma [ Time Frame: 48 hours ]
    Determination of plasma metabolites of 14C-BaP

  6. Metabolites of 14C-BaP in urine [ Time Frame: 48 hours ]
    Determination of urinary metabolites of 14C-BaP

  7. Metabolites of B-estradiol in urine [ Time Frame: -7 days and 48 hours ]
    Determination of urinary metabolites of B-estradiol

  8. Metabolites of B-estradiol in plasma [ Time Frame: -7 days and 48 hours ]
    Determination of plasma metabolites of B-estradiol

  9. Metabolites of DIM in plasma [ Time Frame: -7 days and 48 hours ]
    Determination of plasma metabolites of DIM

  10. Metabolites of DIM in urine [ Time Frame: -7 days and 48 hours ]
    Determination of urinary metabolites of DIM



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age 21-65 (inclusive)
  • If female, must be post-menopausal or have had surgical sterilization to eliminate any possibility for fetal exposure
  • Willing to defer blood donation for one month before, throughout, and one month after completion of study activities
  • Willing to avoid consuming cruciferous vegetables, I3C or DIM supplements, smoked or cured meat or cheeses, or charcoal-grilled meats for 2 weeks prior to and during each study cycle (gas grilled foods acceptable)
  • Health history review and physical assessment showing general good health, as determined by study physician. Acceptable physical exam may have been conducted as part of protocol 8233 or 8554 if subject has not had significant changes in health status.

Exclusion Criteria:

  • Smoker (tobacco or other substances) or use of smokeless tobacco in past 3 months or living with smoker
  • Regular use of medications that affect gut motility or nutrient absorption (e.g. cholestyramine, sucralfate, orlistat, pro- or anti-motility agents)
  • History of gastrointestinal surgery (e.g. bariatric surgery, cholecystectomy) or gastrointestinal disorder (Crohn's disease, celiac disease, IBS, or colitis)
  • Current or history of kidney or liver disease
  • Prior high-dose 14C exposure from medical tests. (micro-dose 14C exposure not exclusionary)
  • Occupational PAH exposure (e.g. roofers, asphalt pavers, fire-fighters, etc.)
  • Regular use of indole-3-carbinol or DIM dietary supplements
  • Allergy or intolerance to Brussels sprouts or similar foods

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03802721


Locations
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United States, Oregon
Oregon State University
Corvallis, Oregon, United States, 97331
Sponsors and Collaborators
Oregon State University
National Institute of Environmental Health Sciences (NIEHS)
Lawrence Livermore National Laboratory
Pacific Northwest National Laboratory
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Responsible Party: David Williams, Professor, Oregon State University
ClinicalTrials.gov Identifier: NCT03802721    
Other Study ID Numbers: LPI-8789
R01ES028600 ( U.S. NIH Grant/Contract )
First Posted: January 14, 2019    Key Record Dates
Last Update Posted: April 1, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Deidentified samples sent to Lawrence Livermore National Laboratory Deidentified data sent to Pacific Northwest National Laboratory

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by David Williams, Oregon State University:
Benzo[a]pyrene
Accelerator Mass Spectrometry
Polycyclic Aromatic Hydrocarbons
cruciferous vegetable
Brussels sprouts
3,3'-diindolylmethane
DIM
indole-3-carbinol
I3C
PAH