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A distributed parameter physiologically-based pharmacokinetic model for dermal and inhalation exposure to volatile
1Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey 08854, USA.
Summary
A new distributed parameter physiologically-based pharmacokinetic (DP-PBPK) model accurately simulates short-term dermal absorption of volatile organic chemicals (VOCs), accounting for time lags and volatilization, unlike simpler models.
Area of Science:
- Toxicology and Environmental Health
- Pharmacokinetics and Exposure Science
Background:
- Traditional dermal dose models assume immediate steady-state flux, which is inaccurate for short-term volatile organic chemical (VOC) exposures.
- Dermal absorption theory highlights the invalidity of steady-state assumptions for short-term VOC exposures.
Purpose of the Study:
- To evaluate a generalized distributed parameter physiologically-based pharmacokinetic (DP-PBPK) model for simulating unsteady-state dermal absorption of VOCs.
- To compare the DP-PBPK model's performance against simpler lumped parameter PBPK models using chloroform as a case study.
Main Methods:
- Developed and parameterized a DP-PBPK model describing unsteady-state dermal mass flux using partial differential equations (Fickian diffusion).
- Compared DP-PBPK model predictions with two lumped parameter PBPK models (ordinary differential equations) for chloroform.
- Validated all models by comparing simulated post-exposure exhaled breath concentrations against experimental data.
Main Results:
- The DP-PBPK model accurately predicted a time-lag in exhaled breath concentrations, consistent with experimental observations.
- DP-PBPK simulations showed significant chloroform volatilization following dermal exposure, a phenomenon not captured by lumped models.
- While end-exposure doses were similar to EPA methods, DP-PBPK predicted a substantially lower net dermal dose due to post-exposure volatilization.
Conclusions:
- The DP-PBPK model provides a more realistic simulation of short-term dermal absorption for VOCs by incorporating time-dependent processes.
- Accounting for dermal absorption time lags and post-exposure volatilization is crucial for accurate net dermal dose estimation.
- Simpler lumped parameter models may underestimate the impact of volatilization, leading to potentially overestimated net dermal doses.