Reconstructing week-long exposures to volatile organic compounds using physiologically based pharmacokinetic models

Area of Science:

• Environmental Health Sciences
• Toxicology
• Pharmacokinetics

Background:

• Physiologically based pharmacokinetic (PBPK) models and biomarkers offer direct evidence of toxic chemical dose.
• Previous work demonstrated short-term exposure reconstruction for chloroform.
• Long-term exposure reconstruction for volatile organic compounds (VOCs) remains a challenge.

Purpose of the Study:

• To demonstrate the mathematical feasibility of reconstructing long-term exposure to volatile organic compounds (VOCs) using benzene as a model.
• To validate exhaled breath concentration as a suitable biomarker for long-term benzene exposure.
• To utilize a benzene PBPK model to estimate cumulative exposure from simulated data.

Main Methods:

• Utilized a validated benzene PBPK model to simulate long-term exposure scenarios.
• Assessed exhaled breath concentration as a biomarker, noting benzene's accumulation in fat and elimination via breath.
• Employed a maximum likelihood approach to reconstruct exposure from generated 'data' with known error margins.

Main Results:

• Exhaled breath concentration is confirmed as an appropriate biomarker for long-term benzene exposure due to fat accumulation.
• Benzene PBPK modeling indicated fat compartment accumulation for over 10 days, integrating dose.
• Exposure reconstruction estimated cumulative benzene exposure within 40% of actual values, even with unknown exposure profiles.

Conclusions:

• Reconstruction of long-term VOC exposure is mathematically feasible using PBPK models and exhaled breath biomarkers.
• Benzene PBPK models can effectively estimate cumulative exposure, serving as a paradigm for other VOCs.
• While generally accurate, estimated exposure may be an underestimate when constant exposure concentrations are assumed.