Analysis, metabolism, effects and biological monitoring of N-methyl-2-pyrrolidone

Abstract: N-methyl-2-pyrrolidone (NMP) is an organic solvent widely used in the industry. Irritation of the eyes and in the respiratory system has been reported after occupational exposure to low air levels of NMP. The EU has also classified it as a developmental toxicant. NMP is easily absorbed in the gastrointestinal tract and airways and through skin. The general aim of this thesis was to develop and evaluate methods for biological monitoring of NMP exposure. For the simultaneous analysis of NMP and its metabolites in plasma and urine, a fast analytical method using liquid chromatography coupled to a tandem mass spectrometer (LC-MS/MS) was developed. The method has high accuracy and precision, good recovery and sufficient detection limits for the analysis of NMP and its metabolites in plasma and urine from occupationally exposed workers. In a study where male and female volunteers were dermally exposed to NMP, no differences in toxicokinetics were found between the sexes. Dermal exposure to an aqueous NMP-solution caused a delay of the peaks for NMP and its metabolites. However, the impact of the delay on the biological levels was small for the metabolite 2-hydroxy-N-methylsuccinimide (2-HMSI). It was concluded that density was preferred over creatinine for adjustment of urinary dilution for some of the compounds. No differences in the total accumulated excretion were found in a study of volunteers after air exposure to dry and humid air, but the individual differences were larger after exposure in humid air, indicating a higher uptake for some of the subjects. However, it was suggested that a large dermal uptake was also present at air exposure. A new NMP metabolite, 2-Pyrrolidone (2-P), was identified. This may be of importance since 2-P has been reported to be developmentally toxic. Significant effects related to the NMP exposure were found for ECP in nasal lavages and for tear film BUT of the eyes. In one study, rats were shown to have a similar metabolism as humans. However, the relative biological levels differed. Thus, the plasma concentrations and area under the curve (AUC) following a developmentally toxic dose were much higher for NMP and 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP), while the levels for 2-HMSI were only about four times the levels found in humans experimentally exposed to 20 mg/m3 for 8 h. Based on the results in this thesis, 2-HMSI is suggested as a biomarker of NMP exposure. Post-shift sampling in the end of the working week, will monitor the last three days of exposure.