Pharmacokinetics of Benzo[a]Pyrene: Impact of Diet

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).

Study Overview

• Status: Completed
• Conditions: Environmental Exposure
• Intervention / Treatment: Drug: [14C]-benzo[a]pyrene; Drug: Brussels sprouts before 50 ng dose; Drug: DIM supplement before 50 ng dose

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.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Oregon
    • Corvallis, Oregon, United States, 97331
      • Oregon State University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

Drug: [14C]-benzo[a]pyrene; Oral micro-dose (50 ng) (5.4 nCi); Other Names: Carcinogenic PAH environmental pollutant; Drug: Brussels sprouts before 50 ng dose; Brussels sprouts for 7 days before 50 ng (5.4 nCi) dose of BaP; Other Names: Brussels sprouts and carcinogenic PAH; 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 Names: Cruciferous vegetable supplement and carcinogenic PAH

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak Plasma Concentration of 14C-BaP Cmax	Determination of highest concentration of 14C-BaP in plasma. Blood samples collected at 0 (baseline), 0.25, 0.5, 1, 2, 3, 4, 8, 24, and 48 hour after dosing. All time points were used to determine Cmax.	0-48 hours for each of 3 dosing cycles, with a washout period of 3 weeks between each dosing cycle

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time at Highest Plasma Concentration of 14C-BaP Tmax	Determination of time at which plasma concentration of 14C-BaP is highest. Blood samples collected at 0 (baseline), 0.25, 0.5, 1, 2, 3, 4, 8, 24, and 48 hour after dosing. All time points were used to determine Tmax.	0-48 hours for each of 3 dosing cycles, with a washout period of 3 weeks between each dosing cycle
Area Under Plasma Concentration of 14C-BaP Versus Time Curve AUC	Integration of concentration of 14C-BaP in plasma over time. Blood samples collected at 0 (baseline), 0.25, 0.5, 1, 2, 3, 4, 8, 24, and 48 hour after dosing. All time points were used to determine AUC.	0-48 hours for each of 3 dosing cycles, with a washout period of 3 weeks between each dosing cycle
Rate of Elimination of 14C-BaP (Half Life)	Determination of constants for rate of elimination of 14C-BaP from plasma. Blood samples collected at 0 (baseline), 0.25, 0.5, 1, 2, 3, 4, 8, 24, and 48 hour after dosing. All time points were used to determine half-life.	0-48 hours for each of 3 dosing cycles, with a washout period of 3 weeks between each dosing cycle

Collaborators and Investigators

• Sponsor: Oregon State University
• Collaborators: National Institute of Environmental Health Sciences (NIEHS); Pacific Northwest National Laboratory; Lawrence Livermore National Laboratory

Study record dates

Study Major Dates

• Study Start (Actual): January 24, 2019
• Primary Completion (Actual): January 1, 2024
• Study Completion (Actual): February 1, 2024

Study Registration Dates

• First Submitted: January 10, 2019
• First Submitted That Met QC Criteria: January 10, 2019
• First Posted (Actual): January 14, 2019

Study Record Updates

• Last Update Posted (Actual): June 22, 2025
• Last Update Submitted That Met QC Criteria: June 4, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: PAH; cruciferous vegetable; DIM; 3,3'-diindolylmethane; Benzo[a]pyrene; Accelerator Mass Spectrometry; Polycyclic Aromatic Hydrocarbons; Brussels sprouts; indole-3-carbinol; I3C
• Other Study ID Numbers: LPI-8789; R01ES028600 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Deidentified samples sent to Lawrence Livermore National Laboratory Deidentified data sent to Pacific Northwest National Laboratory

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No