Human experimental exposure to N-methyl-2-pyrrolidone (NMP): toxicokinetics of NMP, 5-hydroxy- N-methyl-2-pyrrolidone, N-methylsuccinimide and 2-hydroxy- N-methylsuccinimide (2-HMSI), and biological monitoring using 2-HMSI as a biomarker.
OBJECTIVE
N-methyl-2-pyrrolidone (NMP) is a strong and selective organic solvent with an extensive and increasing use. It has been reported to be a compound that is toxic to the reproductive system. The aim of this study was to evaluate toxicokinetics parameters for NMP and its metabolites, 5-hydroxy- N-methyl-2- pyrrolidone (5-HNMP), N-methylsuccinimide (MSI) and 2-hydroxy- N-methylsuccinimide (2-HMSI), and to develop a method for biological monitoring of NMP exposure that uses 2-HMSI as a biomarker.


METHODS
Six healthy, male volunteers were exposed to NMP in an exposure chamber for 8 h at concentrations of 10, 25 and 50 mg/m(3). In addition, three of the subjects were exposed a second time at 50 mg/m(3). Air levels were monitored by Amberlite XAD-7 sampling and gas chromatography (GC) analysis. Levels of NMP and the metabolites in plasma and urine were analysed by GC or GC with mass spectrometry detection.


RESULTS
The concentration of 2-HMSI in plasma and urine rose during exposure and reached a peak approximately 15 h after the end of exposure. It then decayed according to a one-compartment model with a half-time of about 18 h. There were very close correlations between the NMP air levels, on the one hand, and concentrations of 2-HMSI in plasma (r=0.98) and creatinine-adjusted urinary 2-HMSI levels (r=0.96), on the other. The renal clearances were 0.13, 1.4, 0.12 and 1.2 l/h for NMP, 5-HNMP, MSI and 2-HMSI, respectively. The total clearances were 11.4, 3.2, 8.5 and 1.1 l/h for NMP, 5-HNMP, MSI and 2-HMSI, respectively. The apparent volumes of distribution were 41, 28, 120 and 28 l for NMP, 5-HNMP, MSI and 2-HMSI, respectively.


CONCLUSIONS
Toxicokinetics parameters for NMP, 5-HNMP, MSI and 2-HMSI have been estimated. Furthermore, 2-HMSI is applicable as a biomarker of exposure to NMP, and the levels in plasma and urine may be used to indicate an exposure over three days.
Jönsson
B A G
BA
Department of Occupational and Environmental Medicine, Institute of Laboratory Medicine, University Hospital, 221 85 Lund, Sweden. Bo.Jonsson@ymed.lu.se
Akesson
B
B
D000280:Administration, Inhalation; D000328:Adult; D015415:Biomarkers / Q000097:blood / Q000652:urine; D004784:Environmental Monitoring; D004785:Environmental Pollutants / Q000493:pharmacokinetics* / Q000633:toxicity; D006207:Half-Life; D006801:Humans; D008297:Male; D011760:Pyrrolidinones / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D012997:Solvents / Q000493:pharmacokinetics* / Q000633:toxicity; D013388:Succinimides / Q000097:blood / Q000652:urine
C107901:2-hydroxy-N-methylsuccinimide; C107902:5-hydroxy-N-methylpyrrolidone; D015415:Biomarkers; D004785:Environmental Pollutants; C110990:N-methylsuccinimide; D011760:Pyrrolidinones; D012997:Solvents; D013388:Succinimides; C038678:N-methylpyrrolidone