Environmental Exposure
Conditions
Keywords
Benzo[a]pyrene, Accelerator Mass Spectrometry, Polycyclic Aromatic Hydrocarbons, 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.
Interventions
Oral micro-dose (50 ng) (5.4 nCi)
DRUG[14C]-benzo[a]pyrene plus phenanthrene
Oral micro-dose of 50 ng (5.4 nCi) \[14C\]-benzo\[a\]pyrene plus 1250 ng phenanthrene
Sponsors
National Institute of Environmental Health Sciences (NIEHS)
Lawrence Livermore National Laboratory
Pacific Northwest National Laboratory
Oregon State University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Masking description
Deidentified samples will be analyzed by AMS at Lawrence Livermore National Laboratory and the pharmacokinetics determine at Pacific Northwest National Laboratory.
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 50 ng Dose and 50 ng Dose Plus 1250 ng Phenanthrene Capsule containing 50 ng (5.4 nCi) \[14C\]-benzo\[a\]pyrene (BaP). Capsule containing 50 ng (5.4 nCi) \[14C\]-benzo\[a\]pyrene (BaP) and 1250 phenanthrene. At least 3 weeks must pass between each capsule dose administration.
\[14C\]-benzo\[a\]pyrene: Oral micro-dose (50 ng) (5.4 nCi)
\[14C\]-benzo\[a\]pyrene plus phenanthrene: Oral micro-dose of 50 ng (5.4 nCi) \[14C\]-benzo\[a\]pyrene plus 1250 ng phenanthrene | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | 50 ng Dose and 50 ng Dose Plus 1250 ng Phenanthrene |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Region of Enrollment United States | 8 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 5 |
| other Total, other adverse events | 0 / 5 |
| serious Total, serious adverse events | 0 / 5 |
Outcome results
Primary
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.
Time frame: 0-48 hours for each of 2 dosing cycles, with a washout period of 3 weeks between the dosing cycles
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 50 ng Dose and 50 ng Dose Plus 1250 ng Phenanthrene | Peak Plasma Concentration of 14C-BaP Cmax | 50 ng [14C]-BaP | 7.07 fg [14C]-BaP/mL plasma | Standard Deviation 4.89 |
| 50 ng Dose and 50 ng Dose Plus 1250 ng Phenanthrene | Peak Plasma Concentration of 14C-BaP Cmax | 50 ng [14C]-BaP plus 1250 ng phenanthrene | 1.60 fg [14C]-BaP/mL plasma | Standard Deviation 0.86 |
Primary
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.
Time frame: 0-48 hours for each of 2 dosing cycles, with a washout period of 3 weeks between the dosing cycles
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 50 ng Dose and 50 ng Dose Plus 1250 ng Phenanthrene | Time at Highest Plasma Concentration of 14C-BaP Tmax | 50 ng [14C]-BaP | 1.1 hour | Standard Deviation 1.1 |
| 50 ng Dose and 50 ng Dose Plus 1250 ng Phenanthrene | Time at Highest Plasma Concentration of 14C-BaP Tmax | 50 ng [14C]-BaP plus 1250 ng phenanthrene | 1.7 hour | Standard Deviation 1.3 |
Secondary
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.
Time frame: 0-48 hours for each of 2 dosing cycles, with a washout period of 3 weeks between the dosing cycles
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 50 ng Dose and 50 ng Dose Plus 1250 ng Phenanthrene | Area Under Plasma Concentration of 14C-BaP Versus Time Curve AUC | 50 ng [14C]-BaP | 17.88 fg [14C]-BaP/mL plasma x hour | Standard Deviation 9.56 |
| 50 ng Dose and 50 ng Dose Plus 1250 ng Phenanthrene | Area Under Plasma Concentration of 14C-BaP Versus Time Curve AUC | 50 ng [14C]-BaP plus 1250 ng phenanthrene | 10.07 fg [14C]-BaP/mL plasma x hour | Standard Deviation 9.32 |
Secondary
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.
Time frame: 0-48 hours for each of 2 dosing cycles, with a washout period of 3 weeks between the dosing cycles
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 50 ng Dose and 50 ng Dose Plus 1250 ng Phenanthrene | Rate of Elimination of 14C-BaP (Half Life) | 50 ng [14C]-BaP plus 1250 ng phenanthrene | 3.92 hour | Standard Deviation 4.12 |
| 50 ng Dose and 50 ng Dose Plus 1250 ng Phenanthrene | Rate of Elimination of 14C-BaP (Half Life) | 50 ng [14C]-BaP | 4.78 hour | Standard Deviation 4.45 |