Environmental Exposure
Conditions
Keywords
Benzo[a]pyrene, Accelerator Mass Spectrometry, Polycyclic Aromatic Hydrocarbons
Brief summary
Evaluation of the pharmacokinetics for \[14C\]-benzo\[a\]pyrene (\[14C\]-BaP) and metabolites in plasma and urine over 48 hours following 4 oral doses of 25, 50, 10 and 250 ng (2.7-27 nCi).
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 25, 50, 100 or 250 ng (2.7-27 nCi). Metabolite profiles and kinetics of elimination over this dose range 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 range (25, 50, 100 and 250 ng)
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
* Inclusion criteria for women: * Age 21-65 (inclusive) * 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) Inclusion criteria for men: * Age 21-65 (inclusive) * 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak Plasma Concentration Cmax | 0-48 hours for each of the 4 dosing cycles with a washout period of 3 weeks between each dosing cycle | Determination of highest concentration 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 peak plasma concentration Cmax. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time at Highest Plasma Concentration Tmax | 0-48 hours for each of the 4 dosing cycles with a washout period of 3 weeks between each dosing cycle | Determination of time at which plasma concentration 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 at highest plasma concentration. |
| Area Under Plasma Concentration Versus Time Curve AUC | 0-48 hours for each of the 4 dosing cycles with a washout period of 3 weeks between each dosing cycle | Integration of concentration 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 (k1e) | 0-48 hours for each of the 4 dosing cycles with a washout period of 3 weeks between each dosing cycle | Determination of constants for rate of elimination 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 k1e. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 25 ng Dose, 50 ng Dose, 100 ng Dose, 250 ng Dose \[14C\]-benzo\[a\]pyrene: Oral micro-dose range (25, 50, 100 and 250 ng)
At least 3 weeks must pass between each capsule dose administration. | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | 25 ng Dose, 50 ng Dose, 100 ng Dose, 250 ng Dose |
|---|---|
| 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 | 3 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 7 |
| other Total, other adverse events | 0 / 7 |
| serious Total, serious adverse events | 0 / 7 |
Outcome results
Primary
Peak Plasma Concentration Cmax
Determination of highest concentration 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 peak plasma concentration Cmax.
Time frame: 0-48 hours for each of the 4 dosing cycles with a washout period of 3 weeks between each dosing cycle
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 25 ng, 50 ng, 100 ng, and 250 ng Doses | Peak Plasma Concentration Cmax | 25 ng [14C]-BaP | 2.51 fg [14C]-BaP/mL plasma | Standard Deviation 2.53 |
| 25 ng, 50 ng, 100 ng, and 250 ng Doses | Peak Plasma Concentration Cmax | 50 ng [14C]-BaP | 5.68 fg [14C]-BaP/mL plasma | Standard Deviation 4.7 |
| 25 ng, 50 ng, 100 ng, and 250 ng Doses | Peak Plasma Concentration Cmax | 100 ng [14C]-BaP | 13.8 fg [14C]-BaP/mL plasma | Standard Deviation 9.52 |
| 25 ng, 50 ng, 100 ng, and 250 ng Doses | Peak Plasma Concentration Cmax | 250 ng [14C]-BaP | 8.99 fg [14C]-BaP/mL plasma | Standard Deviation 7.08 |
Secondary
Area Under Plasma Concentration Versus Time Curve AUC
Integration of concentration 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 the 4 dosing cycles with a washout period of 3 weeks between each dosing cycle
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 25 ng, 50 ng, 100 ng, and 250 ng Doses | Area Under Plasma Concentration Versus Time Curve AUC | 100 ng [14C]-BaP | 88.5 fg [14C]-BaP/mL plasma x hour | Standard Deviation 14.1 |
| 25 ng, 50 ng, 100 ng, and 250 ng Doses | Area Under Plasma Concentration Versus Time Curve AUC | 250 ng [14C]-BaP | 68.6 fg [14C]-BaP/mL plasma x hour | Standard Deviation 60.4 |
| 25 ng, 50 ng, 100 ng, and 250 ng Doses | Area Under Plasma Concentration Versus Time Curve AUC | 25 ng [14C]-BaP | 12.2 fg [14C]-BaP/mL plasma x hour | Standard Deviation 14.5 |
| 25 ng, 50 ng, 100 ng, and 250 ng Doses | Area Under Plasma Concentration Versus Time Curve AUC | 50 ng [14C]-BaP | 19.6 fg [14C]-BaP/mL plasma x hour | Standard Deviation 15.7 |
Secondary
Rate of Elimination (k1e)
Determination of constants for rate of elimination 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 k1e.
Time frame: 0-48 hours for each of the 4 dosing cycles with a washout period of 3 weeks between each dosing cycle
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 25 ng, 50 ng, 100 ng, and 250 ng Doses | Rate of Elimination (k1e) | 250 ng [14C]-BaP | 68.6 hour(-1) | Standard Deviation 64 |
| 25 ng, 50 ng, 100 ng, and 250 ng Doses | Rate of Elimination (k1e) | 100 ng [14C]-BaP | 88.5 hour(-1) | Standard Deviation 14.1 |
| 25 ng, 50 ng, 100 ng, and 250 ng Doses | Rate of Elimination (k1e) | 25 ng [14C]-BaP | 12.2 hour(-1) | Standard Deviation 14.5 |
| 25 ng, 50 ng, 100 ng, and 250 ng Doses | Rate of Elimination (k1e) | 50 ng [14C]-BaP | 19.6 hour(-1) | Standard Deviation 15.7 |
Secondary
Time at Highest Plasma Concentration Tmax
Determination of time at which plasma concentration 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 at highest plasma concentration.
Time frame: 0-48 hours for each of the 4 dosing cycles with a washout period of 3 weeks between each dosing cycle
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 25 ng, 50 ng, 100 ng, and 250 ng Doses | Time at Highest Plasma Concentration Tmax | 25 ng [14C]-BaP | 0.5 hour |
| 25 ng, 50 ng, 100 ng, and 250 ng Doses | Time at Highest Plasma Concentration Tmax | 50 ng [14C]-BaP | 0.5 hour |
| 25 ng, 50 ng, 100 ng, and 250 ng Doses | Time at Highest Plasma Concentration Tmax | 100 ng [14C]-BaP | 0.5 hour |
| 25 ng, 50 ng, 100 ng, and 250 ng Doses | Time at Highest Plasma Concentration Tmax | 250 ng [14C]-BaP | 0.5 hour |