Using physiologically based pharmacokinetic modeling and benchmark dose methods to derive an occupational exposure limit for N-methylpyrrolidone

Regulatory Toxicology and Pharmacology : RTP
Torka S PoetChristopher R Kirman

Abstract

The developmental effects of NMP are well studied in Sprague-Dawley rats following oral, inhalation, and dermal routes of exposure. Short-term and chronic occupational exposure limit (OEL) values were derived using an updated physiologically based pharmacokinetic (PBPK) model for NMP, along with benchmark dose modeling. Two suitable developmental endpoints were evaluated for human health risk assessment: (1) for acute exposures, the increased incidence of skeletal malformations, an effect noted only at oral doses that were toxic to the dam and fetus; and (2) for repeated exposures to NMP, changes in fetal/pup body weight. Where possible, data from multiple studies were pooled to increase the predictive power of the dose-response data sets. For the purposes of internal dose estimation, the window of susceptibility was estimated for each endpoint, and was used in the dose-response modeling. A point of departure value of 390 mg/L (in terms of peak NMP in blood) was calculated for skeletal malformations based on pooled data from oral and inhalation studies. Acceptable dose-response model fits were not obtained using the pooled data for fetal/pup body weight changes. These data sets were also assessed individually, from which the ge...Continue Reading

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Citations

Oct 30, 2016·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Sook-Jin KimHea-Young Cho
Jun 20, 2017·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Miao LiZhoumeng Lin
Feb 1, 2018·Toxicological Sciences : an Official Journal of the Society of Toxicology·Yu-Mei TanJeffrey W Fisher
Jan 25, 2019·Journal of Occupational and Environmental Hygiene·Sandrine F Chebekoue, Kannan Krishnan

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