Ultralow Dose PAH Binary Mixture Study

Study Overview
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Brief Summary
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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
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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.

Official Title
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Ultralow Dose PAH Binary Mixture Study

Conditions
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Environmental Exposure

Intervention / Treatment
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* Drug: [14C]-benzo[a]pyrene
* Drug: [14C]-benzo[a]pyrene plus phenanthrene


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 50 ng dose<br>Capsule containing 50 ng (5.4 nCi) [14C]-benzo[a]pyrene (BaP) | Drug: [14C]-benzo[a]pyrene<br>* Oral micro-dose (50 ng) (5.4 nCi)<br>* Other names: Carcinogenic PAH environmental pollutant;|
| Experimental: 50 ng dose plus 1250 ng phenanthrene<br>Capsule containing 50 ng (5.4 nCi) [14C]-benzo[a]pyrene (BaP) and 1250 phenanthrene | Drug: [14C]-benzo[a]pyrene plus phenanthrene<br>* Oral micro-dose of 50 ng (5.4 nCi) [14C]-benzo[a]pyrene plus 1250 ng phenanthrene<br>* Other names: Binary mixture of carcinogenic PAH and non-carcinogenic PAH;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma and urine 14C-BaP and 14C-BaP metabolite levels after oral dose | Plasma and urine levels of 14C-BaP and 14C-BaP metabolites measured by accelerator mass spectrometry | 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak plasma concentration of 14C-BaP Cmax | Determination of highest concentration of 14C-BaP in plasma | 48 hours | 
| Time at highest plasma concentration of 14C-BaP Tmax | Determination of time at which plasma concentration of 14C-BaP is highest | 48 hours | 
| Area under plasma concentration of 14C-BaP versus time curve AUC | Integration of concentration of 14C-BaP in plasma over time | 48 hours | 
| Rate of elimination of 14C-BaP | Determination of constants for rate of elimination of 14C-BaP from plasma | 48 hours | 
| Metabolites of 14C-BaP in plasma | Determination of plasma metabolites of 14C-BaP | 48 hours | 
| Metabolites of 14C-BaP in urine | Determination of urinary metabolites of 14C-BaP | 48 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Benzo[a]pyrene, Accelerator Mass Spectrometry, Polycyclic Aromatic Hydrocarbons, Phenanthrene