Biomonitoring-Based Risk Assessment of Pyrethroid Exposure in the U.S. Population: Application of High-Throughput and Physiologically Based Kinetic Models
Abstract
1. Introduction
2. Materials and Methods
2.1. Problem Definition
- Model Specification: The uncertainty in model specification was addressed by comparing estimations using two reverse dosimetry modeling approaches. Estimates from other available resources (e.g., official databases, publications) were incorporated for exposure comparison.
- Linkage of Pyrethroids and Metabolites: Five downstream metabolites are associated with four upstream pyrethroid exposures. The pyrethroid PBK model quantified the fraction of metabolites formed from a parent compound by calibrated model parameter using human TK data [34]. The high-throughput approach also addresses the stoichiometric fraction of transformation between multiple parent compounds and their metabolites.
- Non-detect Values below the Limit of Detection (LOD): Nondetect values below the LOD introduce uncertainty in exposure estimation. Bayesian inference with the PBK model was used to predict these non-detect values. The high-throughput method assumes that population urine concentrations are log-normally distributed across all compounds, allowing non-detect values to be imputed using the geometric mean and standard deviation of the simulated distribution.
- Short Half-Lives of Pyrethroids and Metabolites: Pyrethroids and their metabolites typically have short half-lives less than 24 h [35], meaning their concentrations change rapidly over a short period. NHANES spot urine samples were used as surrogates for 24-h average urinary concentrations. This may underestimate the daily dose rate due to random sampling times relative to exposure events [36]. Under the same daily exposure dose but with different dosing time intervals, biomonitoring using spot urine samples and 24-h averages can vary widely. Human urinary half-lives of approximately 12 h have been measured for several pyrethroids following oral exposures [37,38]. Kinetic simulations indicate that once-daily exposures lead to within-day peaks in urinary concentration approximately two- to three-fold higher than the steady-state average concentration for compounds with a half-life of 12 h [39]. Additionally, factors such as hydration status, creatinine excretion rate, and metabolism patterns can impact concentrations by a factor of 2 to 3 [40]. The exposure difference from urine concentration to exposure was addressed by quantifying the variation in observed data and intake prediction.
2.2. NHANES Biomonitoring Data
2.3. The Physiologically Based Kinetic Model
2.4. Bayesian Population Modeling
2.5. High-Throughput Model and Other Exposure Prediction Tools
2.6. Exposure Variability
2.7. Bayesian Benchmark Dose Modeling
2.8. Risk Estimates
2.9. Computational Settings and Evaluation
3. Results
3.1. Exploratory Analysis of the Biomonitoring Data
3.2. Model Evaluation
3.3. Exposure Variability, Trend, and Similarity
3.4. Risk Assessment
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
3PBA | 3-Phenoxybenzoic Acid |
BMD | Benchmark Dose |
BMDL | Benchmark Dose Lower Confidence Limit |
DBCA | 3-(2,2-Dibromovinyl)-2,2-Dimethylcyclopropane Carboxylic Acid |
DCCA | 3-(2,2-Dichlorovinyl)-2,2-Dimethylcyclopropane-1-Carboxylic Acid |
DPR | Department of Pesticide Regulation |
EPA | Environmental Protection Agency |
FPBA | 4-Fluoro-3-Phenoxybenzoic Acid |
LOD | Limit of Detection |
MOE | Margin of Exposure |
MOIE | Margin of Internal Exposure |
NHANES | National Health and Nutrition Examination Survey |
NOAEL | No-Observed-Adverse-Effect Level |
PAD | Population-Adjusted Dose |
PBK | Physiologically Based Kinetic |
POD | Point of Departure |
RfD | Reference Dose |
SHEDS | Stochastic Human Exposure and Dose Simulation |
TD | Toxicodynamics |
TK | Toxicokinetics |
USDA | United States Department of Agriculture |
Appendix A
Appendix A.1. Tables
1999–2000 | 2001–2002 | 2007–2008 | 2009–2010 | 2011–2012 | 2013–2014 | 2015–2016 | |
---|---|---|---|---|---|---|---|
3PBA | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 |
FPBA | 0.2 | 0.2 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 |
trans-DCCA | 0.4 | 0.4 | 0.6 | 0.6 | 0.6 | 0.6 | 0.6 |
DBCA | 0.1 | 0.1 | 0.5 | 0.5 | |||
cis-DCCA | 0.1 | 0.1 |
3PBA | FPBA | DBCA | cis-DCCA | Trans-DCCA | |
---|---|---|---|---|---|
Cyfluthrin | x | x | x | ||
Cypermetrhin | x | x | x | ||
Deltamethrin | x | x | |||
Permethrin | x | x | x |
Parameter | Description | Unit | Value | Reference |
---|---|---|---|---|
BW | Body Weight | kg | Observed | |
UrineCreatinine | Urine Creatinine | mg creatinine/dL urine | Observed | |
DailyCreatinine | Daily Creatinine | mg creatinine/day | Estimated | [28] |
DLM_KA | Uptake rate of deltamethrin | /h | 1.51 | [34] |
cisPRM_KA | Uptake rate of cis-permetrhin | /h | 0.52 | [34] |
tranPRM_KA | Uptake rate of trans-permethrin | /h | 1.3 | [34] |
cisCPM_KA | Uptake rate of cis-cypermethrin | /h | 0.52 | [34] |
tranCPM_KA | Uptake rate of trans-cypermethrin | /h | 1.3 | [34] |
cisCYF_KA | Uptake rate of cis-cyfluthrin | /h | 0.52 | [34] |
tranCYF_KA | Uptake rate of trans-cyfluthrin | /h | 1.3 | [34] |
DLM_Kfec | Fecal excretion rate of deltamethrin | /h | 0.59 | [34] |
cisPRM_Kfec | Fecal excretion rate of cis-permetrhin | /h | 0.39 | [34] |
tranPRM_Kfec | Fecal excretion rate of trans-permethrin | /h | 0.85 | [34] |
cisCPM_Kfec | Fecal excretion rate of cis-cypermethrin | /h | 0.39 | [34] |
tranCPM_Kfec | Fecal excretion rate of trans-cypermethrin | /h | 0.85 | [34] |
cisCYF_Kfec | Fecal excretion rate of cis-cyfluthrin | /h | 0.39 | [34] |
tranCYF_Kfec | Fecal excretion rate of trans-cyfluthrin | /h | 0.85 | [34] |
DLM_3PBA | Metabolic fraction of deltamethrin to 3PBA | - | 0.15 | [34] |
DLM_DBCA | Metabolic fraction of deltamethrin to DCCA | - | 0.73 | [34] |
cisPRM_3PBA | Metabolic fraction of cis-permethrin to 3PBA | - | 0.37 | [34] |
cisPRM_DCCA | Metabolic fraction of cis-permethrin to DCCA | - | 0.37 | [34] |
transPRM_3PBA | Metabolic fraction of trans-permethrin to 3PBA | - | 0.85 | [34] |
transPRM_DCCA | Metabolic fraction of trans-permethrin to DCCA | - | 0.61 | [34] |
cisCPM_3PBA | Metabolic fraction of cis-cypermethrin to 3PBA | - | 0.16 | [34] |
cisCPM_DCCA | Metabolic fraction of cis-cypermethrin to DCCA | - | 0.32 | [34] |
transCPM_3PBA | Metabolic fraction of trans-cypermethrin to 3PBA | - | 0.39 | [34] |
transCPM_DCCA | Metabolic fraction of trans-cypermethrin to DCCA | - | 0.57 | [34] |
cisCYF_FPBA | Metabolic fraction of cis-cyfluthrin to FPBA | - | 0.1 | [34] |
cisCYF_DCCA | Metabolic fraction of cis-cyfluthrin to DCCA | - | 0.27 | [34] |
transCYF_FPBA | Metabolic fraction of trans-cyfluthrin to 3PBA | - | 0.23 | [34] |
transCYF_DCCA | Metabolic fraction of trans-cyfluthrin to DCCA | - | 0.35 | [34] |
Parameter Type | No. of Parameter | SD | Truncation (±nxSD) |
---|---|---|---|
Plasma unbound fraction | 1 | 0.1 | 2 |
Partition coefficient | 7 | 0.3 | 3 |
Permeability area cross product | 3 | 0.3 | 3 |
Uptake and fecal excretion rate | 2 | 0.4 | 3 |
Clearance rate | 2 | 0.4 | 3 |
1999–2000 | 2001–2002 | 2007–2008 | 2009–2010 | 2011–2012 | 2013–2014 | 2015–2016 | |
---|---|---|---|---|---|---|---|
3PBA | 68.74 | 77.04 | 65.02 | 72.34 | 91.00 | 88.25 | 95.70 |
FPBA | 3.04 | 0.49 | 6.55 | 4.63 | 15.34 | 10.18 | 13.02 |
trans-DCCA | 33.24 | 28.31 | 15.83 | 11.62 | 7.65 | 24.62 | 37.49 |
DBCA | 0.63 | 0.88 | 1.46 | 1.48 | |||
cis-DCCA | 41.59 | 33.08 |
Appendix A.2. Figures
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Hsieh, N.-H.; Kwok, E.S.C. Biomonitoring-Based Risk Assessment of Pyrethroid Exposure in the U.S. Population: Application of High-Throughput and Physiologically Based Kinetic Models. Toxics 2025, 13, 216. https://doi.org/10.3390/toxics13030216
Hsieh N-H, Kwok ESC. Biomonitoring-Based Risk Assessment of Pyrethroid Exposure in the U.S. Population: Application of High-Throughput and Physiologically Based Kinetic Models. Toxics. 2025; 13(3):216. https://doi.org/10.3390/toxics13030216
Chicago/Turabian StyleHsieh, Nan-Hung, and Eric S. C. Kwok. 2025. "Biomonitoring-Based Risk Assessment of Pyrethroid Exposure in the U.S. Population: Application of High-Throughput and Physiologically Based Kinetic Models" Toxics 13, no. 3: 216. https://doi.org/10.3390/toxics13030216
APA StyleHsieh, N.-H., & Kwok, E. S. C. (2025). Biomonitoring-Based Risk Assessment of Pyrethroid Exposure in the U.S. Population: Application of High-Throughput and Physiologically Based Kinetic Models. Toxics, 13(3), 216. https://doi.org/10.3390/toxics13030216