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

Regul Toxicol Pharmacol. 2016 Apr;76:102-12. doi: 10.1016/j.yrtph.2015.12.020. Epub 2016 Jan 8.

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 geometric mean value obtained from the inhalation studies (470 mg*hr/L), was used to derive the chronic OEL. A PBPK model for NMP in humans was used to calculate human equivalent concentrations corresponding to the internal dose point of departure values. Application of a net uncertainty factor of 20-21, which incorporates data-derived extrapolation factors, to the point of departure values yields short-term and chronic occupational exposure limit values of 86 and 24 ppm, respectively.

Keywords: Benchmark dose; Developmental toxicity; Occupational exposure limit; PBPK modeling; Window of susceptibility.

Publication types

  • Comparative Study

MeSH terms

  • Abnormalities, Drug-Induced / etiology
  • Animals
  • Animals, Newborn
  • Benchmarking / standards*
  • Birth Weight / drug effects
  • Bone and Bones / abnormalities
  • Bone and Bones / drug effects
  • Dose-Response Relationship, Drug
  • Female
  • Fetal Weight / drug effects
  • Humans
  • Inhalation Exposure / adverse effects
  • Models, Biological*
  • Occupational Exposure / adverse effects
  • Occupational Health / standards*
  • Pregnancy
  • Pyrrolidinones / blood
  • Pyrrolidinones / pharmacokinetics*
  • Pyrrolidinones / toxicity*
  • Rats, Sprague-Dawley
  • Risk Assessment
  • Solvents / pharmacokinetics*
  • Solvents / toxicity*
  • Species Specificity
  • Toxicity Tests / methods*

Substances

  • Pyrrolidinones
  • Solvents
  • N-methylpyrrolidone