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Research progress of N-nitrosamine detection methods: a review

    Yahui Liu

    Key Laboratory of Consumer Product Quality Safety Inspection and Risk Assessment for State Market Regulation, Institute of Industrial and Consumer Product Safety, Chinese Academy of Inspection and Quarantine, Beijing, 100176, China

    ,
    Xingzhou Guo

    Key Laboratory of Consumer Product Quality Safety Inspection and Risk Assessment for State Market Regulation, Institute of Industrial and Consumer Product Safety, Chinese Academy of Inspection and Quarantine, Beijing, 100176, China

    ,
    Zhijuan Wang

    Key Laboratory of Consumer Product Quality Safety Inspection and Risk Assessment for State Market Regulation, Institute of Industrial and Consumer Product Safety, Chinese Academy of Inspection and Quarantine, Beijing, 100176, China

    ,
    Qing Zhang

    Key Laboratory of Consumer Product Quality Safety Inspection and Risk Assessment for State Market Regulation, Institute of Industrial and Consumer Product Safety, Chinese Academy of Inspection and Quarantine, Beijing, 100176, China

    ,
    Qiang Ma

    Key Laboratory of Consumer Product Quality Safety Inspection and Risk Assessment for State Market Regulation, Institute of Industrial and Consumer Product Safety, Chinese Academy of Inspection and Quarantine, Beijing, 100176, China

    &
    Qing Lv

    *Author for correspondence:

    E-mail Address: Lvqing2009@126.com

    Key Laboratory of Consumer Product Quality Safety Inspection and Risk Assessment for State Market Regulation, Institute of Industrial and Consumer Product Safety, Chinese Academy of Inspection and Quarantine, Beijing, 100176, China

    Published Online:https://doi.org/10.4155/bio-2022-0091

    N-nitrosamines (nitrosamines) are attracting increased attention because of their high toxicity and wide distribution. They have been strictly restricted by regulations in many fields. Researchers around the world have conducted substantial work on nitrosamine detection. This paper reviews the progress of research on nitrosamine detection methods with emphasis on biological-matrix samples. After introducing the category, toxicity, regulatory limit and source of nitrosamines, the paper discusses the most commonly used sample-preparation techniques and instrumental-detection techniques for nitrosamine detection, including some typical application cases.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Crews C. The determination of N-nitrosamines in food. Qual. Assur. Saf. Crops Foods 2(1), 2–12 (2010). • It reviews the detection technology of nitrosamines in food, which provides a guiding role for this paper in the preliminary data collection.
    • 2. Tricker AR, Preussmann R. Volatile and nonvolatile nitrosamines in beer. J. Cancer Res. Clin. Oncol. 117(2), 130–132 (1991).
    • 3. Bellec G, Cauvin JM, Salaun MC et al. Analysis of N-nitrosamines by high-performance liquid chromatography with post-column photohydrolysis and colorimetric detection. J. Chromatogr. A 727(1), 83–92 (1996).
    • 4. Xia B, Xia Y, Wong J et al. Quantitative analysis of five tobacco-specific N-nitrosamines in urine by liquid chromatography-atmospheric pressure ionization tandem mass spectrometry. Biomed. Chromatogr. 28(3), 375–384 (2014).
    • 5. Kubica P. Ultrasound-assisted solvent extraction of a porous membrane packed sample for the determination of tobacco-specific nitrosamines in the replacement liquids for e-cigarettes. Molecules 24(24), 4618 (2019).
    • 6. Roback SL, Kodamatani H, Fujioka T, Plumlee MH. Validation of a novel direct-injection chemiluminescence-based method for N-nitrosamine analysis in advanced-treated recycled water, drinking water, and wastewater. Environ. Sci.: Water Res. Technol. 6, 1106–1115 (2020).
    • 7. Kuhne F, Kappenstein O, Strassgutl S et al. N-nitrosamines migrating from food contact materials into food simulants: analysis and quantification by means of HPLC-APCI-MS/MS. Food Addit. Contam., Part A: Chem., Anal., Control, Exposure Risk Assess. 35(4), 792–805 (2018).
    • 8. Anton P, Bruun KK, Thomsen EM, Borup JN, Pierre Q, Jesper H. Use of N-nitrosodimethylamine (NDMA) contaminated valsartan products and risk of cancer: Danish nationwide cohort study. BMJ Br. Med. J. 362, k3851 (2018).
    • 9. Li R, Liu YH, Wang ZJ, Zhang Q, Bai H, Lv Q. High resolution GC-Orbitrap MS for nitrosamines analysis: method performance, exploration of solid phase extraction regularity, and screening of children's products. Microchem. J. 162(5), 105878 (2021).
    • 10. Abedi G, Talebpour Z. Modified QuEChERS as a novel sample preparation method for analysis of N-nitrosodiethanolamine in shampoo by high performance liquid chromatography. Anal. Methods 9(35), 5165–5173 (2017).
    • 11. Herrmann SS, Duedahl-Olesen L, Granby K. Simultaneous determination of volatile and non-volatile nitrosamines in processed meat products by liquid chromatography tandem mass spectrometry using atmospheric pressure chemical ionisation and electrospray ionisation. J. Chromatogr. A 1330(4), 20–29 (2014).
    • 12. Kim HJ, Shin HS. Determination of tobacco-specific nitrosamines in replacement liquids of electronic cigarettes by liquid chromatography-tandem mass spectrometry. J. Chromatogr. A 1291, 48–55 (2013).
    • 13. Rath S, Reyes F. ChemInform Abstract: nitrosamines. Cheminform 42(52), 421–440 (2011).
    • 14. Herrmann SS, Duedahl-Olesen L, Granby K. Occurrence of volatile and non-volatile N-nitrosamines in processed meat products and the role of heat treatment. Food Control. 48, 163–169 (2015).
    • 15. Roasa J, Liu H, Shao S. An optimised HS-SPME-GC-MS method for the detection of volatile nitrosamines in meat samples. Food Addit. Contam. 36(3), 396–404 (2019).
    • 16. Preussmann R. Occurence and exposure to N-nitroso compounds and precursors. IARC Sci. Publ. 17(57), 3 (1984).
    • 17. Thresher A, Foster R, Ponting DJ, Stalford SA, Thomas R. Are all nitrosamines concerning? A review of mutagenicity and carcinogenicity data. Regul. Toxicol. Pharmacol. 116, 104749 (2020).
    • 18. Thomas R, Thresher A, Ponting DJ. Utilisation of parametric methods to improve percentile-based estimates for the carcinogenic potency of nitrosamines. Regul. Toxicol. Pharmacol. 121, 104875 (2021).
    • 19. International Agency for Research on Cancer (IARC). Vol. 17. Some N-nitroso compounds. In: IARC Monographs on the Evaulation of the Carcinogenic Risk of Chemicals to Humans. IARC Press, Lyon, France (1978).
    • 20. Larsson SC, Bergkvist L, Wolk A. Processed meat consumption, dietary nitrosamines and stomach cancer risk in a cohort of Swedish women. Int. J. Cancer 119(4), 915–919 (2010).
    • 21. Wilkens LR, Kadir MM, Kolonel LN, Nomura A, Hankin JH. Risk factors for lower urinary tract cancer: the role of total fluid consumption, nitrites and nitrosamines, and selected foods. Cancer Epidemiol. Biomarkers Prev. 5(3), 161–166 (1996).
    • 22. Lijinsky W. Chemistry and biology of N-nitroso compounds. Vasc. Pharmacol. 104(2), 395 (1992).
    • 23. Zhao ZX, Chen SZ, Xia ZL et al. High level nitrosamines in rat faeces with colorectal cancer determined by a sensitive GC-MS method. J. Pharm. Biomed. Anal. 210, 114576 (2022).
    • 24. Gushgari AJ, Halden RU. Critical review of major sources of human exposure to N-nitrosamines. Chemosphere 210, 1124–1136 (2018).
    • 25. Wollin KM, Apel P, Chovolou Y et al. Concept for the evaluation of carcinogenic substances in population-based human biomonitoring. Int. J. Environ. Res. Public Health 19(12), 7235 (2022). •• It introduces the concept of carcinogen assessment in population-based human biomonitoring. The thresholds for nitrosamines in biological matrices cannot be defined, but only reference values are given.
    • 26. Apel P, Angerer J, Wilhelm M, Kolossa-Gehring M. New HBM values for emerging substances, inventory of reference and HBM values in force, and working principles of the German Human Biomonitoring Commission. Int. J. Hyg. Environ. Health 220(2), 152–166 (2017).
    • 27. EN 71-12: 2016 Safety of Toys Part 12: N-Nitrosamines and N-Nitrosatable Substances (2016).
    • 28. BS EN 12868: 2017 Child Use and Care Articles – Method for Determining the Release of N-Nitrosamines and N-Nitrosatable Substances from Elastomer or Rubber Teats and Soothers. (2017).
    • 29. Planas C, Palacios O, Ventura F, Rivera J, Caixach J. Analysis of nitrosamines in water by automated SPE and isotope dilution GC/HRMS occurrence in the different steps of a drinking water treatment plant, and in chlorinated samples from a reservoir and a sewage treatment plant effluent. Talanta 76(4), 906–913 (2008).
    • 30. Jakszyn P, Gonzalez CA. Nitrosamine and related food intake and gastric and oesophageal cancer risk: a systematic review of the epidemiological evidence. World J. Gastroenterol. 12(27), 4296 (2006).
    • 31. Hrudey SE, Bull RJ, Cotruvo JA, Paoli G, Wilson M. Drinking water as a proportion of total human exposure to volatile N‐nitrosamines. Risk Anal. 33(12), 2179–2208 (2013).
    • 32. Zhao C, Lu Q, Gu Y, Pan E, Yin L. Distribution of N-nitrosamines in drinking water and human urinary excretions in high incidence area of esophageal cancer in Huai'an, China. Chemosphere 235, 288–296 (2019).
    • 33. Zaitseva NV, Ulanova TS, Nurislamova TV, Suvorov DV. Experience of the Russian federation on development of methods for N-nitrosoamines control in food (children's canned meat products). Vietnam J. Food Control. 1(2), 9–13 (2018).
    • 34. Hecht SS. N-Nitroso compounds and man: sources of exposure, endogenous formation and occurrence in body fluids. Eur. J. Cancer Prev. 6(3), 226–268 (1997).
    • 35. Gushgari AJ, Halden RU. Critical review of major sources of human exposure to N-nitrosamines. Chemosphere 210, 1124–1136 (2018). •• It reviews the sources of human exposure to nitrosamines, which helps readers better understand the sources, toxicity and other hazards of nitrosamines.
    • 36. Stepanov I, Hatsukami DK. Chemical characterization of smokeless tobacco products and relevant exposures in users. Smokeless Tobacco Product 13(6), 121–150 (2020).
    • 37. Bustamante G, Ma B, Yakovlev G et al. Presence of the carcinogen N‘-nitrosonornicotine in saliva of e-cigarette users. Chem. Res. Toxicol. 31(8), 731–738 (2018).
    • 38. Knezevich A, Muzic J, Hatsukami DK, Hecht SS, Stepanov I. Nornicotine nitrosation in saliva and its relation to endogenous synthesis of N'-nitrosonornicotine in humans. Nicotine Tob. Res. 15(2), 591–595 (2013).
    • 39. Park NY, Jung W, Kho Y. Analysis method of N-nitrosamines in human urine by LC-MS/MS system. J. Korean Chem. Soc. 61(2), 51–56 (2017).
    • 40. Mohammadi S, Domeno C, Nerin I et al. Toxic compounds from tobacco in placenta samples analyzed by UPLC-QTOF-MS. J. Pharm. Biomed. Anal. 145, 331–338 (2017).
    • 41. Gerrity D, Pisarenko AN, Marti E et al. Nitrosamines in pilot-scale and full-scale wastewater treatment plants with ozonation. Water Res. 72(1), 251–261 (2015).
    • 42. Zaitseva NV, Ulanova TS, Dolgikh OV, Nurislamova TV, Mal'tseva OA. Diagnostics of early changes in the immune system due to low concentration of N-nitrosamines in the blood. Bull. Exp. Biol. Med. 164(3), 334–338 (2018).
    • 43. Pluym N, Scherer G, Edmiston JS, Jin XC, Sarkar M, Scherer M. Assessment of the exposure to NNN in the plasma of smokeless tobacco users. Chem. Res. Toxicol. 35(4), 663–669 (2022). •• It was cited many times and provided strong technical support for the manuscript in terms of technology and principle.
    • 44. Scherer G, Scherer M, Mütze J, Hauke T, Pluym N. Assessment of the exposure to tobacco-specific nitrosamines and minor tobacco alkaloids in users of various tobacco/nicotine products. Chem. Res. Toxicol. 35(4), 684–693 (2022).
    • 45. Pan J, Song Q, Shi H et al. Development, validation and transfer of a hydrophilic interaction liquid chromatography/tandem mass spectrometric method for the analysis of the tobacco-specific nitrosamine metabolite NNAL in human plasma at low picogram per milliliter concentrations. Rapid Commun. Mass Spectrom. 18(21), 2549–2557 (2004).
    • 46. Lu JN, Li MY, Huang YS et al. A comprehensive review of advanced glycosylation end products and N-nitrosamines in thermally processed meat products. Food Control 131, 108449 (2022).
    • 47. Hotchkiss JH. Analytical methodology for sample preparation, detection, quantitation, and confirmation of N-nitrosamines in foods. J. Assoc. Off. Anal. Chem. 64(5), 1037–1054 (1981).
    • 48. Sen NP, Kubacki SJ. Review of methodologies for the determination of nonvolatile N-nitroso compounds in foods. Food Addit. Contam. 4(4), 357–384 (1987).
    • 49. Parr MK, Joseph JF. NDMA impurity in valsartan and other pharmaceutical products: analytical methods for the determination of N-nitrosamines. J. Pharm. Biomed. Anal. 164, 536–549 (2019).
    • 50. Shaik KM, Sarmah B, Wadekar GS, Kumar P. Regulatory updates and analytical methodologies for nitrosamine impurities detection in sartans, ranitidine, nizatidine, and metformin along with sample preparation techniques. Crit. Rev. Anal. Chem. 52(1), 53–71 (2022).
    • 51. Shah KA, Karnes HT. A review of the analysis of tobacco-specific nitrosamines in biological matrices. Crit. Rev. Toxicol. 40(4), 305 (2010).
    • 52. Akyüz M, Ata Ş, Dinç E. A chemometric optimization of method for determination of nitrosamines in gastric juices by GC-MS. J. Pharm. Biomed. Anal. 117, 26–36 (2016).
    • 53. Stepanov I, Hecht SS. Tobacco-specific nitrosamines and their pyridine-N-glucuronides in the urine of smokers and smokeless tobacco users. Cancer Epidemiol. Biomarkers Prev. 14(4), 885–891 (2005).
    • 54. Kotandeniya D, Carmella SG, Pillsbury ME, Hecht SS. Combined analysis of N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in the urine of cigarette smokers and e-cigarette users. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1007, 121–126 (2015).
    • 55. Krauss M, Hollender J. Analysis of nitrosamines in wastewater: exploring the trace level quantification capabilities of a hybrid linear ion trap/Orbitrap mass spectrometer. Anal. Chem. 80(3), 834 (2008).
    • 56. Li Z, Wang J, Chen X, Hu S, Gong T, Xian Q. A novel molecularly imprinted polymer-solid phase extraction method coupled with high performance liquid chromatography tandem mass spectrometry for the determination of nitrosamines in water and beverage samples. Food Chem. 292, 267–274 (2019).
    • 57. Hu CW, Shih YM, Liu HH, Chiang YC, Chen CM, Chao MR. Elevated urinary levels of carcinogenic N-nitrosamines in patients with urinary tract infections measured by isotope dilution online SPE LC–MS/MS. J. Hazard. Mater. 310(5), 207–216 (2016). • As a developed detection technique for nitrosamines in biological substrate (urine), it plays an important role in this review.
    • 58. Lai FY, Been F, Covaci A, Nuijs A. Novel wastewater-based epidemiology approach based on liquid chromatography–tandem mass spectrometry for assessing population exposure to tobacco-specific toxicants and carcinogens. Anal. Chem. 89(17), 9268–9278 (2017).
    • 59. Chuang YH, Shabani F, Munoz J, Aflaki R, Hammond SD, Mitch WA. Formation of N-nitrosamines during the analysis of municipal secondary biological nutrient removal process effluents by US EPA method 521. Chemosphere 221, 597–605 (2019).
    • 60. Huang MC, Chen HC, Fu SC, Ding WH. Determination of volatile N-nitrosamines in meat products by microwave-assisted extraction coupled with dispersive micro solid-phase extraction and gas chromatographyn–chemical ionisation mass spectrometry. Food Chem. 138(1), 227–233 (2013).
    • 61. Carrizo D, Nerín I, Domeño C, Alfaro P, Nerín C. Direct screening of tobacco indicators in urine and saliva by atmospheric pressure solid analysis probe coupled to quadrupole-time of flight mass spectrometry (ASAP-MS-Q-TOF-). J. Pharm. Biomed. Anal. 124, 149–156 (2016). • It describes in detail the pretreatment methods and detection techniques of biological matrices (urine and gastric juice), which can be of great reference value for the qualitative and quantitative determination of tobacco-specific nitrosamines in biological matrices.
    • 62. Hodgson JA, Seyler TH, McGahee E, Arnstein S, Wang L. A new automated method and sample data flow for analysis of volatile nitrosamines in human urine. Am. J. Analyt. Chem. 7(2), 165–178 (2016).
    • 63. Seo JE, Park JE, Lee JY, Kwon H. Determination of seven N-nitrosamines in agricultural food matrices using GC-PCI-MS/MS. Food Anal. Methods 9(6), 1595–1605 (2016).
    • 64. Grebel JE, Young CC, Suffet IH. Solid-phase microextraction of N-nitrosamines. J. Chromatogr. A 1117(1), 11–18 (2006).
    • 65. Llop A, Borrull F, Pocurull E. Fully automated determination of N-nitrosamines in environmental waters by headspace solid-phase microextraction followed by GC-MS-MS. J. Sep. Sci. 33(23-24), 3692–3700 (2015).
    • 66. Andrade R, Reyes FGR, Rath S. A method for the determination of volatile N-nitrosamines in food by HS-SPME-GC-TEA. Food Chem. 91(1), 173–179 (2005).
    • 67. Rech F, Garrigós MC, Marín ML, Cantó A, Jiménez A. Optimization of parameters for the supercritical fluid extraction in the determination of N-nitrosamines in rubbers. J. Chromatogr. A 963(1-2), 419–426 (2002).
    • 68. Lashgari M, Yamini Y, Basheer C, Lee HK. Ordered mesoporous carbon as sorbent for the extraction of N-nitrosamines in wastewater and swimming pool water. J. Chromatogr. A 1513, 35–41 (2017).
    • 69. Li Z, Qian Z, Hu S, Gong T, Xian Q. Molecularly imprinted solid phase extraction coupled with gas chromatography-mass spectrometry for determination of N-nitrosodiphenylamine in water samples. Chemosphere 212, 872–880 (2018).
    • 70. Zhang Y, Zhao YG, Muhammad N, Ye ML, Zhu Y. Ultrasound-assisted synthesis of clover-shaped nano-titania functionalized covalent organic frameworks for the dispersive solid phase extraction of N-nitrosamines in drinking water. J. Chromatogr. A 1618, 460891 (2020).
    • 71. Deng HM, Tang GL, Fan ZY et al. Use of autoclave extraction-supercritical fluid chromatography/tandem mass spectrometry to analyze 4-(methylintrosamino)-1-(3-pyridyl)-1-butanone and N'-nitrosonornicotine in tobacco. J. Chromatogr. A 1595, 207–214 (2019).
    • 72. Parr MK, Joseph JF. NDMA impurity in valsartan and other pharmaceutical products: analytical methods for the determination of N-nitrosamines. J. Pharm. Biomed. Anal. 164, 536–549 (2019).
    • 73. Ma YJ, Bai RS, Du GR et al. Rapid determination of four tobacco specific nitrosamines in burley tobacco by near-infrared spectroscopy. Anal. Methods 4(5), 1371–1376 (2012).
    • 74. De Mey E, De Klerck K, De Maere H et al. The occurrence of N-nitrosamines, residual nitrite and biogenic amines in commercial dry fermented sausages and evaluation of their occasional relation. Meat Sci. 96(2), 821–828 (2014).
    • 75. Nowak A, Kuberski S, Libudzisz Z. Probiotic lactic acid bacteria detoxify N-nitrosodimethylamine. Food Addit. Contam. Part A Chem. Anal. Control Expo. Risk Assess. 31(10), 1678–1687 (2014).
    • 76. Seyler TH, Kim JG, Hodgson JA, Cowan EA, Blount BC, Wang L. Quantitation of urinary volatile nitrosamines from exposure to tobacco smoke. J. Anal. Toxicol. 37(4), 195–202 (2013).
    • 77. Sun CX, Wang R, Wang TY, Li Q. Primary evaluation of nine volatile N-nitrosamines in raw red meat from Tianjin, China, by HS-SPME-GC-MS. Food Chem. 310, 125945 (2020).
    • 78. Liu J, Xie B, Mai BL et al. Development of a sensitive and stable GC-MS/MS method for simultaneous determination of four N-nitrosamine genotoxic impurities in sartan substances. J. Anal. Sci. Technol. 12(1), 3 (2021).
    • 79. Iavicoli I, Carelli G. Evaluation of occupational exposure to N-nitrosamines in a rubber-manufacturing industry. J. Occup. Environ. Med. 48(2), 195–198 (2006).
    • 80. Stickler DJ, Chawla JC, Tricker AR, Preussmann R. N-nitrosamine generation by urinary tract infections in spine injured patients. Paraplegia 30(12), 855–863 (1992).
    • 81. Luo X, Wang W, Zhao X, Zeng H, Zheng B. A new method for the simultaneous determination of urinary NNAL and cotinine concentrations using HILIC-MS/MS coupled with PRiME HLB SPE. Int. J. Mass Spectrom. 465(3), 116579 (2021). • It developed a method for the simultaneous determination of tobacco-specific nitrosamines in urine by hydrophilic liquid chromatography–MS/MS combined with solid phase extraction, which is reviewed in this article to help readers better understand.
    • 82. Khorolskiy M, Ramenskaya G, Vlasov A, Perederyaev O, Maslennikova N. Development and validation of four nitrosamine impurities determination method in medicines of valsartan, losartan, and irbesartan with HPLC-MS/MS (APCI). Iran. J. Pharm. Res. 20(3), 541–552 (2021).
    • 83. Zhou Y, Zhang H, Wang X et al. Development of a heart-cutting supercritical fluid chromatography-high-performance liquid chromatography coupled to tandem mass spectrometry for the determination of four tobacco-specific nitrosamines in mainstream smoke. Anal. Bioanal. Chem. 411(13), 2961–2969 (2019).
    • 84. Li Z, Wang J, Chen X, Hu S, Gong T, Xian Q. A novel molecularly imprinted polymer-solid phase extraction method coupled with high performance liquid chromatography tandem mass spectrometry for the determination of nitrosamines in water and beverage samples. Food Chem. 292, 267–274 (2019).
    • 85. Yang J, Carmella SG, Hecht SS. Analysis of N'-nitrosonornicotine enantiomers in human urine by chiral stationary phase liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry. J Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1044-1045, 127–131 (2017).
    • 86. Sieira BJ, Carpinteiro I, Rodil R, Quintana JB, Cela R. Determination of N-nitrosamines by gas chromatography coupled to quadrupole-time-of-flight mass spectrometry in water samples. Separations 7(1), 3 (2020).
    • 87. Amelin VG, Bol'shakov DS. Rapid identification and determination of N-nitrosamines in food products by ultra-high-performance liquid chromatography-high resolution quadrupole-time-of-flight mass spectrometry by exact masses of protonated molecules. J. Anal. Chem. 74, 39–46 (2019).
    • 88. Li MP, Li R, Wang ZJ et al. Determination of 16 kinds of N-nitrosamines in water by gas chromatography-quadrapole-orbitrap High Resolution Mass Spectrometry. Chinese J. Anal. Chem. 47(2), 288–296 (2019).
    • 89. Yang J, Marzan TA, Ye W, Sommers CD, Rodriguez JD, Keire DA. A cautionary tale: quantitative LC-HRMS analytical procedures for the analysis of N-nitrosodimethylamine in metformin. AAPS J. 22(4), 89 (2020).
    • 90. Dallinga JW, Pachen DM, Lousberg AH et al. Volatile N-nitrosamines in gastric juice of patients with various conditions of the gastrointestinal tract determined by gas chromatography-mass spectrometry and related to intragastric pH and nitrate and nitrite levels. Cancer Lett. 124(2), 119–125 (1998).
    • 91. Levallois P, Ayotte P, Van Maanen JM et al. Excretion of volatile nitrosamines in a rural population in relation to food and drinking water consumption. Food Chem. Toxicol. 38(11), 1013–1019 (2000).
    • 92. Vermeer IT, Engels LG, Pachen DM, Dallinga JW, Kleinjans JC, van Maanen JM. Intragastric volatile N-nitrosamines, nitrite, pH, and Helicobacter pylori during long-term treatment with omeprazole. Gastroenterology 121(3), 517–525 (2001).
    • 93. Zeng T, Mitch WA. Contribution of N-nitrosamines and their precursors to domestic sewage by greywaters and blackwaters. Environ. Sci. Technol. 49(22), 13158–13167 (2015).
    • 94. Byrd GD, Ogden MW. Liquid chromatographic/tandem mass spectrometric method for the determination of the tobacco-specific nitrosamine metabolite NNAL in smokers' urine. J. Mass Spectrom. 38(1), 98–107 (2003).
    • 95. Kavvadias D, Scherer G, Cheung F, Errington G, Shepperd J, McEwan M. Determination of tobacco-specific N-nitrosamines in urine of smokers and non-smokers. Biomarkers 14(8), 547–553 (2009).
    • 96. Kavvadias D, Scherer G, Urban M et al. Simultaneous determination of four tobacco-specific N-nitrosamines (TSNA) in human urine. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 877(11-12), 1185–1192 (2009).