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Published on: August 28, 2019
Quantitative risk analysis for N-methyl pyrrolidone using physiologically based pharmacokinetic and benchmark dose
Torka S Poet1, Chris R Kirman, Michael Bader
1Battelle Pacific Northwest Division, Center for Biological Monitoring and Modeling, Richland, Washington 99352, USA. torka.poet@pnl.gov
Summary
Establishing an occupational exposure limit for N-methyl pyrrolidone (NMP) is crucial. Physiologically based pharmacokinetic models suggest current NMP occupational exposure limits adequately protect workers from developmental toxicity.
Area of Science:
- Toxicology
- Pharmacokinetics
- Occupational Health
Background:
- N-methyl pyrrolidone (NMP) is a widely used industrial solvent.
- Developmental toxicity, specifically decreased fetal/pup body weights, is the most sensitive endpoint for NMP exposure.
- Accurate occupational exposure limits (OELs) are needed to ensure worker safety.
Purpose of the Study:
- To develop physiologically based pharmacokinetic (PBPK) models for NMP in rats and humans to aid in extrapolating toxicity data.
- To establish a scientifically robust point of departure (POD) for NMP-induced developmental toxicity using benchmark dose modeling.
- To estimate human equivalent concentrations (HECs) for NMP to inform OEL derivation.
Main Methods:
- Development of PBPK models in rats and humans, incorporating physiological changes during gestation.
- Application of benchmark dose modeling to rat inhalation studies to determine POD for fetal/pup body weight decrements.
- Estimation of HECs using the rat POD and the human PBPK model.
Main Results:
- PBPK models successfully described NMP pharmacokinetics in rats and humans during gestation.
- Inhalation exposure to NMP vapor resulted in body weight decrements at lower maternal blood concentrations than oral or dermal routes.
- The derived HEC for NMP was 480 ppm, significantly higher than current international OELs (10-20 ppm).
Conclusions:
- Current international OELs for NMP appear sufficiently protective against developmental toxicity.
- PBPK modeling provides a valuable tool for reducing uncertainty in interspecies extrapolation for OEL setting.
- Further research may refine understanding of NMP's developmental toxicity and inform future OEL revisions.
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