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Analysis of metabolites of N,N-dimethylformamide in urine samples

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Abstract

Aim

To assess the suitability of different methods for biological monitoring of internal dose to N,N-dimethylformamide (DMF) in occupational settings.

Methods

The determination of urinary metabolites of DMF, N-hydroxymethyl-N-methylformamide (HMMF), N-methylformamide (NMF) and N-acetyl-S-(N-methylcarbamoyl) cysteine (AMCC) was carried out by four selected analytical procedures. Two methods solely measured total NMF (HMMF and NMF). The other two methods measured both total NMF and AMCC in one analytical run. All four methods were tested on 34 urine samples from workers exposed to DMF.

Results

Comparison of the four methods for determination of total NMF in urine showed that results were similar for three methods, while the remaining one provided NMF levels significantly lower (by 22%) than the other methods. Thus, all but one of the tested methods for the determination of total NMF can be considered to be suitable for biological monitoring of internal dose to DMF. The two tested methods for the determination of AMCC afforded results that showed high correlation but differed significantly (by 10%).

Conclusion

The choice of the biomonitoring method depends mainly on the purpose for which the measurement is conducted. For evaluation of acute exposures or to assess safety measures in the working area, an updated version of the traditional method of Kimmerle and Eben (1975a, b) for the determination of total NMF in urine is sufficient. For risk assessment after exposure to DMF, the determination of AMCC should be carried out, since AMCC, but not total NMF, is supposed to be related to the toxicity of DMF. However, there is still a need to develop an easier, more sensitive and more selective method for the determination of AMCC in urine until AMCC can be considered for regulatory purposes in occupational settings.

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References

  • ACGIH (2004) TLVs and BEIs, threshold limit values for chemical substance and physical agents and biological exposure indices, Cincinnati

  • Casal-Lareo A, Perbellini L (1995) Biological monitoring of workers exposed to N,N-dimethylformamide. II. Dimethylformamide and its metabolites in urine of exposed workers. Int Arch Occup Environ Health 67:47–52

    CAS  PubMed  Google Scholar 

  • Casal-Lareo A, Perico A, Bavazzano P, Soave C, Perbellini L (1995) Biological monitoring of workers exposed to N,N-dimethylformamide. I. Methods of analysis. Int Arch Occup Environ Health 67:41–46

    CAS  PubMed  Google Scholar 

  • DFG (1997) Deutsche Forschungsgemeinschaft. In: Angerer J, Schaller KH (eds) Analysis of hazardous substances in biological materials, vol 5. Wiley, Weinheim

  • DFG (2004) Deutsche Forschungsgemeinschaft. List of MAK and BAT values 2004. Wiley, Weinheim

  • Fail PA, George JD, Grizzle TB, Heindel JJ (1998) Formamide and dimethylformamide: reproductive assessment by continuous breeding in mice. Reprod Toxicol 12:317–332

    Article  CAS  PubMed  Google Scholar 

  • Gescher A (1993) Metabolism of N,N-dimethylformamide: key to the understanding of its toxicity. Chem Res Toxicol 6:245–251

    CAS  PubMed  Google Scholar 

  • Imbriani M, Maestri L, Marraccini P, Saretto G, Alessio A, Negri S, Ghittori S (2002) Urinary determination of N-acetyl-S-(N-methylcarbamoyl) cysteine and N-methylformamide in workers exposed to N,N-dimethylformamide. Int Arch Occup Environ Health 75:445–452

    Article  CAS  PubMed  Google Scholar 

  • Käfferlein HU, Angerer J (1999a) Simultaneous determination of two human urinary metabolites of N,N-dimethylformamide using gas chromatography-thermionic sensitive detection with mass spectrometric confirmation. J Chromatogr B Biomed Sci Appl 734:285–298

    Article  PubMed  Google Scholar 

  • Käfferlein HU, Angerer J (1999b) Determination of N-acetyl- S-(N-methylcarbamoyl)cysteine (AMCC) in the general population using gas chromatography-mass spectrometry. J Environ Monit 1:465–469

    Article  PubMed  Google Scholar 

  • Käfferlein HU, Angerer J (2001) N-methylcarbamoylated valine of hemoglobin in humans after exposure to N,N-dimethylformamide: evidence for the formation of methyl isocyanate? Chem Res Toxicol 14:833–840

    Article  PubMed  Google Scholar 

  • Käfferlein HU, Göen T, Müller J, Wrbitzky R, Angerer J (2000) Biological monitoring of workers exposed to N,N-dimethylformamide in the synthetic fibre industry. Int Arch Occup Environ Health 73:113–120

    Article  PubMed  Google Scholar 

  • Kawai T, Yasugi T, Mizunuma K, Watanabe T, Cai SX, Huang MY, Xi LQ, Qu JB, Yao BZ, Ikeda M (1992) Occupational dimethylformamide exposure. 2. Monomethylformamide excretion in urine after occupational dimethylformamide exposure. Int Arch Occup Environ Health 63:455–460

    CAS  PubMed  Google Scholar 

  • Kennedy GL Jr (2001) Biological effects of acetamide, formamide, and their mono and dimethyl derivatives: an update. Crit Rev Toxicol 31:139–222

    CAS  PubMed  Google Scholar 

  • Kestell P, Gill MH, Threadgill MD, Gescher A, Howarth OW, Curzon EH (1986) Identification by proton NMR of N-(hydroxymethyl)-N-methylformamide as the major urinary metabolite of N,N-dimethylformamide in mice. Life Sci 38:719–724

    Article  CAS  PubMed  Google Scholar 

  • Kimmerle G, Eben A (1975a) Metabolism studies of N,N-dimethylformamide. I. Studies in rats and dogs. Int Arch Arbeitsmed 34:109–126

    CAS  Google Scholar 

  • Kimmerle G, Eben A (1975b) Metabolism studies of N,N-dimethylformamide. II. Studies in persons. Int Arch Arbeitsmed 34:127–136

    CAS  PubMed  Google Scholar 

  • Lauwerys RR, Kivits A, Lhoir M, Rigolet P, Houbeau D, Buchet JP, Roels HA (1980) Biological surveillance of workers exposed to dimethylformamide and the influence of skin protection on its percutaneous absorption. Int Arch Occup Environ Health 45:189–203

    CAS  PubMed  Google Scholar 

  • Mráz J (1988) Gas chromatographic method for the determination of N-acetyl-S-(N-methylcarbamoyl)cysteine, a metabolite of N,N-dimethylformamide and N-methylformamide, in human urine. J Chromatogr 431:361–368

    PubMed  Google Scholar 

  • Mráz J, Cross H, Gescher A, Threadgill MD, Flek J (1989) Differences between rodents and humans in the metabolic toxification of N,N-dimethylformamide. Toxicol Appl Pharmacol 98:507–516

    PubMed  Google Scholar 

  • Mráz J, Gescher A, Cross H, Shaw AJ, Flek J (1991) New findings in the metabolism of N,N-dimethylformamide—consequences for evaluation of occupational risk. Sci Total Environ 101:131–134

    Article  PubMed  Google Scholar 

  • Mráz J, Nohová H (1992a) Percutaneous absorption of N,N-dimethylformamide in humans. Int Arch Occup Environ Health 64:79–83

    PubMed  Google Scholar 

  • Mráz J, Nohová H (1992b) Absorption, metabolism and elimination of N,N-dimethylformamide in humans. Int Arch Occup Environ Health 64:85–92

    PubMed  Google Scholar 

  • Mráz J, Tureček F (1987) Identification of N-acetyl-S-(N-methylcarbamoyl) cysteine, a human metabolite of N,N-dimethylformamide and N-methylformamide. J Chromatogr 414:399–404

    PubMed  Google Scholar 

  • NIOSH (2003) NIOSH manual of analytical methods. National Institute of Occupational Safety and Health, Cincinnati http://www.cdc.gov/niosh/nmam/

  • NIOSH (2004) Pocket guide to chemical hazards. National Institute of Occupational Safety and Health, Cincinnati http://www.cdc.gov/niosh/npg/npgdname.html

  • OSHA (2003) Occupational Safety and Health Administration, OSHA methods, US Department of Labor, Washington. http://www.osha-slc.gov/dts/sltc/methods/toc.html

  • Perbellini L, Maestri L, Veronese N, Romani S, Brugnone F (2001) Analysis of urinary N-acetyl-S-(N-methylcarbamoyl)cysteine, the mercapturic acid derived from N,N-dimethylformamide. J Chromatogr B 759:349–354

    Article  CAS  Google Scholar 

  • Saillenfait AM, Payan JP, Beydon D, Fabry JP, Langonne I, Sabate JP, Gallissot F (1997) Assessment of the developmental toxicity, metabolism, and placental transfer of N,N-dimethylformamide administered to pregnant rats. Fundam Appl Toxicol 39:33–43

    Article  CAS  PubMed  Google Scholar 

  • Sakai T, Kageyama H, Araki T, Yosida T, Kuribayashi T, Masuyama Y (1995) Biological monitoring of workers exposed to N,N-dimethylformamide by determination of the urinary metabolites, N-methylformamide and N-acetyl-S-(N-methylcarbamoyl) cysteine. Int Arch Occup Environ Health 67:125–129

    CAS  PubMed  Google Scholar 

  • Santoni G, Bavazzano P, Perico A, Colzi A, Benassi S, Medica A, La Morgia R, Giuliano G (1992) High-performance liquid chromatographic determination of N-methylformamide and N-methyl-N-(hydroxymethyl)-formamide in human urine. J Chromatogr 581:287–292

    Article  CAS  PubMed  Google Scholar 

  • Scailteur V, de Hoffmann E, Buchet JP, Lauwerys RR (1984) Study on in vivo and in vitro metabolism of dimethylformamide in male and female rats. Toxicology 29:221–234

    Article  CAS  PubMed  Google Scholar 

  • Scailteur V, Lauwerys R (1984) In vivo metabolism of dimethylformamide and relationship to toxicity in the male rat. Arch Toxicol 56:87–91

    CAS  PubMed  Google Scholar 

  • Scailteur V, Lauwerys RR (1987) Dimethylformamide (DMF) hepatotoxicity. Toxicology 43:231–238

    Article  CAS  PubMed  Google Scholar 

  • Tranfo G, Plebani C, Salerno A, Panebianco AS, Marcelloni AM (1999) High-performance liquid chromatographic determination of N-methylformamide, a biological index for occupational exposure to dimethylformamide. J Chromatogr A 847:19–24

    Article  CAS  PubMed  Google Scholar 

  • WHO (1993) Biomarkers and risk assessment: concepts and principles. Environmental Health Criteria 155. World Health Organization, Geneva

    Google Scholar 

  • WHO (1996) Biological monitoring of chemical exposure in the workplace. Guidelines, vol 1. World Health Organization, Geneva

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Authors and Affiliations

  1. Institut und Poliklinik für Arbeits-, Sozial- und Umweltmedizin, Friedrich-Alexander-Universität Erlangen, Erlangen, Germany

    H. U. Käfferlein, C. Ferstl & J. Angerer

  2. Berufsgenossenschaftliches Forschungsinstitut für Arbeitsmedizin (BGFA), Institut für Arbeitsmedizin, Ruhr-Universität Bochum, Bürkle-de-la-Camp Platz 1, 44789, Bochum, Germany

    H. U. Käfferlein

  3. National Institute of Public Health, Prague, Czech Republic

    J. Mráz

Authors
  1. H. U. Käfferlein
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  2. J. Mráz
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  3. C. Ferstl
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  4. J. Angerer
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Correspondence to H. U. Käfferlein.

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Käfferlein, H.U., Mráz, J., Ferstl, C. et al. Analysis of metabolites of N,N-dimethylformamide in urine samples. Int Arch Occup Environ Health 77, 427–432 (2004). https://doi.org/10.1007/s00420-004-0538-x

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  • DOI: https://doi.org/10.1007/s00420-004-0538-x

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