Pharmacokinetics of Benzo[a]Pyrene: Impact of Diet

Early Phase 1

Completed

Conditions: Environmental Exposure

Interventions: Drug: [14C]-benzo[a]pyrene
Drug: Brussels sprouts before 50 ng dose
Drug: DIM supplement before 50 ng dose

Registration Number: NCT03802721

Lead Sponsor: 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).

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 7

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
50 ng dose; Brussels sprouts before 50 ng dose; DIM supplement before 50 ng dose	[14C]-benzo[a]pyrene	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.
50 ng dose; Brussels sprouts before 50 ng dose; DIM supplement before 50 ng dose	Brussels sprouts 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.
50 ng dose; Brussels sprouts before 50 ng dose; DIM supplement 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.

Primary Outcome Measures

Name	Time	Method
Peak Plasma Concentration of 14C-BaP Cmax	0-48 hours	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.

Secondary Outcome Measures

Name	Time	Method
Time at Highest Plasma Concentration of 14C-BaP Tmax	0-48 hours	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.
Area Under Plasma Concentration of 14C-BaP Versus Time Curve AUC	48 hours	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.
Rate of Elimination of 14C-BaP (Half Life)	0-48 hours	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.