Pharmacokinetics of Benzo[a]Pyrene: Impact of Diet

NCT ID: NCT03802721

Last Updated: 2025-06-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 7 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-01-24
• Study Completion Date: 2024-02-01

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).

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.

Conditions

Environmental Exposure

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

50 ng dose; Brussels sprouts before 50 ng dose; DIM supplement before 50 ng dose

Cycle 1: Capsule containing 50 ng (5.4 nCi) [14C]-benzo[a]pyrene (BaP).

Cycle 2: 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).

Cycle 3: 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.

At least 3 weeks will pass between cycles as a washout period.

Group Type: EXPERIMENTAL

[14C]-benzo[a]pyrene

Intervention Type: DRUG

Oral micro-dose (50 ng) (5.4 nCi)

Brussels sprouts before 50 ng dose

Intervention Type: DRUG

Brussels sprouts for 7 days before 50 ng (5.4 nCi) dose of BaP

DIM supplement before 50 ng dose

Intervention Type: DRUG

DIM supplement for 7 days before 50 ng (5.4 nCi) dose of BaP and coadministration with DIM supplement

Interventions

[14C]-benzo[a]pyrene

Oral micro-dose (50 ng) (5.4 nCi)

Intervention Type: DRUG

Brussels sprouts before 50 ng dose

Brussels sprouts for 7 days before 50 ng (5.4 nCi) dose of BaP

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

Carcinogenic PAH environmental pollutant; Brussels sprouts and carcinogenic PAH; Cruciferous vegetable supplement and carcinogenic PAH

Eligibility 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

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Environmental Health Sciences (NIEHS)

NIH

Sponsor Role: collaborator

Lawrence Livermore National Laboratory

OTHER

Sponsor Role: collaborator

Pacific Northwest National Laboratory

FED

Sponsor Role: collaborator

Oregon State University

OTHER

Sponsor Role: lead

Responsible Party

David Williams

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Oregon State University

Corvallis, Oregon, United States

Countries

United States

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

R01ES028600

Identifier Type: NIH

Identifier Source: secondary_id

View Link

LPI-8789

Identifier Type: -

Identifier Source: org_study_id