Ultralow Dose PAH Binary Mixture Study

Early Phase 1

Completed

Interventions: Drug: [14C]-benzo[a]pyrene
Drug: [14C]-benzo[a]pyrene plus phenanthrene

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 or with 1250 ng phenanthrene.

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 or with 1250 ng phenanthrene. 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

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)

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

Arm && Interventions

Group	Intervention	Description
50 ng dose and 50 ng dose plus 1250 ng phenanthrene	[14C]-benzo[a]pyrene	Cycle 1: Capsule containing 50 ng (5.4 nCi) \[14C\]-benzo\[a\]pyrene (BaP). Cycle 2: Capsule containing 50 ng (5.4 nCi) \[14C\]-benzo\[a\]pyrene (BaP) and 1250 phenanthrene. At least 3 weeks will pass between cycles as a washout period.
50 ng dose and 50 ng dose plus 1250 ng phenanthrene	[14C]-benzo[a]pyrene plus phenanthrene	Cycle 1: Capsule containing 50 ng (5.4 nCi) \[14C\]-benzo\[a\]pyrene (BaP). Cycle 2: Capsule containing 50 ng (5.4 nCi) \[14C\]-benzo\[a\]pyrene (BaP) and 1250 phenanthrene. 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 for each of 2 dosing cycles, with a washout period of 3 weeks between the dosing cycles	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.
Time at Highest Plasma Concentration of 14C-BaP Tmax	0-48 hours for each of 2 dosing cycles, with a washout period of 3 weeks between the dosing cycles	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.

Secondary Outcome Measures

Name	Time	Method
Area Under Plasma Concentration of 14C-BaP Versus Time Curve AUC	0-48 hours for each of 2 dosing cycles, with a washout period of 3 weeks between the dosing cycles	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 for each of 2 dosing cycles, with a washout period of 3 weeks between the dosing cycles	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.