PNNL

Abstract

N-Methyl pyrrolidone (NMP) is a widely used solvent which exhibits toxicity only in high dose animal studies. Due to its widespread use, establishing an occupational exposure limit (OEL) for NMP is important. Based on studies in rodents, the most sensitive endpoint is a decrease in fetal/pup bodyweights after exposures of the dams. The most sensitive route of exposure, and the most relevant to workers, is via inhalation. To reduce the uncertainty of rat to human extrapolations, PBPK models were developed that described the pharmacokinetics of NMP in rat and humans. Since in utero exposures are of concern, the models were used to describe major physiological changes occurring in the dam or mother over the course of gestation. In addition, benchmark dose (BMD) modeling was used to better define a point of departure for fetal/pup body weight changes by using the dose-response information from the key studies. The BMD modeling was applied to the internal maternal blood AUC from the key studies as determined using the rat PBPK model. The human PBPK model was then used to estimate human equivalent exposure concentrations (HEC) to quantitatively extrapolate a safe exposure concentration in the workplace. The geometric mean point of departure based upon two studies was estimated to be 350 mg*hr/L (expressed in terms of internal dose), which correspond to a human equivalent concentration (HEC) of 480 ppm (occupational exposure of 8 hours/day, 5 days/week). The HEC determined in this study is ~5-50x higher than the international OELs currently in place (1-100 or just compare to 10?), indicating that the international OELs currently in effect are expected to be protective of worker exposures to NMP.