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研究生(外文):Yi-Chen Sun
論文名稱(外文):Development of a UPLC-MS/MS method to quantitate process-induced nitrogen hazards in SD rat urine samples
指導教授(外文):Hsin-Chang Chen
口試委員(外文):Guor-Jien WeiYu-Fang Huang
外文關鍵詞:Heterocyclic aminesN-nitrosaminesAcrylamideUPLC–MS/MSLow dose animal study
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異環胺、亞硝胺及丙烯醯胺等三類致癌物為生活飲食中常見之食品製程衍生含氮危害物,常於煎、炒、烤、炸、滷等高溫長時間的烹調下生成。據文獻指出,大量攝入這類食品製程衍生含氮危害物可能提升人體罹患大腸癌、膀胱癌及乳癌等多種癌症的風險,故目前已有多數物質被國際癌症研究機構(International Agency For Research On Cancer, IARC)歸類為二級致癌物。然多數文獻僅偏重於單一物質之討論,同時分析三類致癌物之研究較缺乏,且動物試驗大多給與高劑量暴露,與人體實際暴露情形不符。為了解異環胺、亞硝胺及丙烯醯胺在人體內之實際代謝情形並開發尿液之同時監測方法,本研究選用24隻Sprague-Dawley遠交群大鼠(簡稱SD大鼠)進行分組動物實驗,以0.00 (控制組)、0.01、0.05、0.10mg/kg之低劑量將12種異環胺、6種亞硝胺及丙烯醯胺採管餵方式進行單次共同暴露,收集96小時內之大鼠尿液作為後續研究之分析樣品,以模擬人體同時暴露到三類致癌物後在體內之代謝情境並分析之。
本研究以極致液相層析串聯質譜法(Ultra-performance liquid chromatography-tandem mass spectrometry, UPLC-MS/MS)進行尿液中食品加工衍生含氮危害物之定量分析方法開發,於前處理過程中運用酵素水解法還原葡萄醣醛酸之代謝產物以得知總代謝量,同時比較固相萃取法(Solid-Phase Extraction, SPE)及支撐式液相萃取技術(Supported Liquid Extraction, SLE)之淨化效果,並製作基質匹配檢量線針對最低定量極限(Lower limit of quantitation, LLOQ)及低(6 ng/mL)、中(40 ng/mL)、高(80 ng/mL)三個確效濃度點進行方法確效。結果顯示相較於SPE,SLE於分析物之回收率及尿液基質效應的降低皆有更良好的表現,並於酵素水解測試觀察到尿液中異環胺之葡萄醣醛酸代謝產物存在。此方法於多數分析物之定量皆展現良好的靈敏度及穩定性,各物質基質匹配檢量線之決定係數(coefficient of determination, r2)皆大於0.990,顯示其線性關係良好,偵測極限及定量極限介於0.1至2.5 ng/mL及 2至10 ng/mL之間,除丙烯醯胺、一項異環胺 (MeIQ)及一項亞硝胺 (NMOR)等少數物質外,於各確效濃度點皆能獲得良好的同日及異日間之精確度(%RSD 0.0-18.2 %)及準確度(88-126%)。真實樣品除少數亞硝胺外,多數暴露之異環胺、亞硝胺及丙烯醯胺皆能於大鼠尿液中偵測到其濃度,並於暴露後6小時之尿液中達到高峰,與各物質之理論半衰期及過往文獻之相對暴露代謝比例相符。此研究成功建立一套穩定分析尿液中微量異環胺、亞硝胺及丙烯醯胺等食品製程衍生含氮危害物之定量方法,同時比較了SLE及SPE兩萃取技術之適用性,可望提供後續進行生物監測、暴露風險評估等相關研究參考。
Heterocyclic amines (HCAs), N-nitrosamines (NAs) and acrylamide (AA) are three categories of process-induced nitrogen hazards (PINHs) that are commonly found on people’s daily diet. Researchers had indicated that these substances might increase the risk of many cancers, such as colorectal cancer, bladder cancer, and breast cancer by proceeding a lot of animal tests. Consequently, some of HCAs, NAs, and AA had already been classified as Group 2A or 2B carcinogens by the International Agency for Research on Cancer (IARC). However, although a large amount of individual research about HCAs, NAs or AA had been well studied for the past few years, the co-exposure study is still limited, and the usage of the dose was usually very high, which is not in line with the actual exposure situation. To establish a stable method to simultaneously quantify the PINHs in urine, this research utilized 24 male Sprague-Dawley rats (SD rats) which aged at 5 weeks as an animal model and gave the relatively low doses of 0.00 (control), 0.01, 0.05 and 0.10 mg/kg b.w. of twelve HCAs, six NAs, and one AA by oral gavage to obtain the exposed urine sample between 96 h for analysis and simulate the real exposure situation at the same time.
Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS) was used to quantitate PINHs in urine samples. Solid-phase extraction (SPE) and supported liquid extraction (SLE) were used to compare the recovery and matrix effect for pretreating urine samples. To realize the total contents of the PINHs in urine, enzymatic hydrolysis was also conducted before the extraction to hydrolyze glucuronide metabolites. The validation of the method was completed by the establishment of the matrix-matched calibration curve and validated four concentration levels: (lower limit of quantitation) LLOQ, low QC (6 ng/mL), medium QC (40 ng/mL), and high QC (80 ng/mL).
The results indicated that compared to SPE, the SLE technique showed the ideal outcomes in higher recoveries and lower matrix effects. And the glucuronide metabolites of HCAs were also found in rats’ urine through the test of the efficiency of enzymatic hydrolysis. The validated method demonstrated the great sensitives and stability on most of the analytes. Which the matrix-matched calibration curve showed good linearity with the coefficient of determination (r2) greater than 0.990. And the (limits of detection) LODs and LLOQs of most of the PINHs were within the range of 0.03-0.70 ng/mL and 0.10-2.00 ng/mL, respectively. Besides, except for a few analytes (AA, MeIQ, and NMOR), most analytes displayed great within-run and between-run precisions (%RSD 0.0-18.2 % ) and accuracies (88-126%).
When applied the method to SD rat urine samples, except for some of NAs, almost all of the PINHs administrated to SD rats were detected in the exposed urine with the maximal concentrations observed within the samples collected in the first 6 hours after dosing, which matched the half-lives and the relative metabolic ratio of PINHs reported in the previous researches. This study not only successfully simultaneously quantified and compared the extraction efficiency of SPE an SLE of the PINHs in real urine samples by UPLC-MS/MS, but the method also demonstrated the good feasibility and sensitivity for the detection of trace levels (ng/mL) of PINHs. That made this study be a usable reference to conduct further researches such as human biomonitoring or risk assessment of the exposure of PINHs and benefited public health.
誌謝 i
中文摘要 ii
Abstract iv
List of figures ix
List of tables xi
Chapter 1 Introduction 1
1.1 Process-induced nitrogen hazards (PINHs) 1
1.1.1 Heterocyclic amines (HCAs) 2
1.1.2 Nitrosamines (NAs) 7
1.1.3 Acrylamide (AA) 12
1.2 Literature reviews of previous extraction techniques 17
1.2.1 Solid phase extraction (SPE) 17
1.2.2 Supported liquid extraction (SLE) 20
1.3 Literature reviews on detection of PINHs in urine samples 21
1.4 Research motivation 22
Chapter 2 Material and methods 23
2.1 Chemicals and reagents 23
2.2 Animal treatment and sample collection 25
2.3 Parameters of UPLC-MS/MS analysis 26
2.4 Sample pretreatment 27
2.4.1 Enzymatic hydrolysis of the urinary metabolites 27
2.4.2 Extraction of urine samples 27
2.4.3 Extraction of animal supplies 30
2.5 Method validation 31
2.5.1 Calibration curve 31
2.5.2 LODs, LLOQs and quality control (QC) 32
2.5.3 Matrix effects (MEs) 33
2.6 Creatinine analysis 34
2.7 Statistical analyses 34
Chapter 3 Results and discussion 35
3.1 Dose effects on SD rats 35
3.2 Optimization of analytic parameters 35
3.2.1 Optimization of MS 35
3.2.2 Optimization of LC 36
3.3 Optimization of sample pretreatment 37
3.3.1 Extraction efficiency of SPE and SLE 37
3.3.2 Optimization of incubation time for enzymatic hydrolysis 40
3.4 Animal supplies 42
3.5 Validation of the method 44
3.5.1 Calibration curves, LODs, and LLOQs 44
3.5.2 Precision and accuracy 45
3.5.3 Matrix effects (MEs) 47
3.6 Application to SD rat urine samples 48
3.6.1 Heterocyclic amines (HCAs) 48
3.6.2 Nitrosamines (NAs) 50
3.6.3 Acrylamide (AA) 51
Chapter 4 Summary and limitation 52
Chapter 5 Conclusions 54
References 55
Figures 67
Tables 82

List of figures
Figure 1. Structures of urinary PhIP metabolites and metabolic pathways 67
Figure 2. Oxidations of N-nitrosamines to aldehydes and acids 67
Figure 3. Metabolic pathway of acrylamide 68
Figure 4. The flowchart of the developed method in this experiment 69
Figure 5. Statistical analysis of weight changes of SD rats (data and boxplot) 70
Figure 6. Optimization of ion sources (APCI, ESI and USI) 70
Figure 7. Optimization of the mobile phase A (buffer) 71
Figure 8. Optimization of the mobile phase B (organic solvent) 71
Figure 9. Multiple reaction monitoring (MRM) of 12 HCAs, 6 NAs, and AA in MTBE 72
Figure 10. Comparison of MEs of different pretreatment methods 73
Figure 11. Comparison of the recoveries of different SPE methods 73
Figure 12. Comparison of the recoveries of PRiME HLB and SLE 74
Figure 13. Comparison of the extraction efficiency of elution solvents for SLE 74
Figure 14. Optimization of enzymatic hydrolysis procedures (HCAs) 75
Figure 15. Optimization of enzymatic hydrolysis procedures (NAs, AA) 76
Figure 16. PINHs in the animal feed 77
Figure 17. PINHs in animal beddings 77
Figure 18. Recoveries of four validation levels 78
Figure 19. MEs of blank urine samples of four validation levels 79
Figure 20. Multiple reaction monitoring (MRM) of 12 HCAs, 6 NAs, and AA in the urine sample of the control group 80
Figure 21. Trend charts of the quantitative results of the real samples 81

List of tables
Table 1. Summary of the introduction of PINHs 82
Table 2. Molecular structure, name, abbreviation, CAS number and monoisotopic mass of 12 HAAs, 6 NAs and AA 83
Table 3. Summary of the metabolites of PINHs 86
Table 4. Summary of toxicological studies of HCAs and AA 87
Table 5. Summary of toxicological studies of NAs 89
Table 6. Reviews of the SPE techniques applied to PINHs extraction 90
Table 7. Reviews of SLE techniques applied to PINHs extraction 92
Table 8. Solvents gradient of UPLC 93
Table 9. USI-MS/MS parameters 93
Table 10. Optimal voltage parameters with the MRM transition for standards and internal standards of PINHs 94
Table 11. Reviews of enzymatic hydrolysis of the PINHs 95
Table 12. The LODs, LLOQs, calibration range, linear equation and the coefficient of determination of matrix-matched calibration curve 96
Table 13. Precisions and accuracies of four QC levels for the developed method 97
Table 14. Quantitation results of SD rat urine samples (µg/g creatinine) 100
Table 15. Quantitation results of SD rat urine samples (ng/mL) 102
1.Kilcast D, Subramaniam P (2000) The stability and shelf-life of food, vol 15. vol 2. CRC Press LLC, North and South America
2.Gibis M (2016) Heterocyclic aromatic amines in cooked meat products: Causes, formation, occurrence, and risk assessment. Comprehensive Reviews in Food Science and Food Safety 15 (2):269-302
3.Rostkowska K, Zwierz K, Różański A, Moniuszko-Jakoniuk J, Roszczenko A (1998) Formation and metabolism of N-nitrosamines. Polish Journal of Environmental Studies 7 (6):321-325
4.Friedman M, Mottram D (2005) Chemistry and Safety of Acrylamide in Food Advances In Experimental Medicine And Biology 561
5.International agency for research on cancer (2019) List of classifications, volumes 1-123.
6.Nagao M, Honda M, Seino Y, Kawachi T, Sugimura T (1977) Mutagenicities of protein pyrolysates. Cancer Letlers 2 335-340
7.Lee KJ, Lee GH, Kim H, Oh MS, Chu S, Hwang IJ, Lee JY, Choi A, Kim CI, Park HM (2015) Determination of heterocyclic amines and acrylamide in agricultural products with liquid chromatography-tandem mass spectrometry. Toxicol Res 31 (3):255-264
8.Meurillon M, Engel E (2016) Mitigation strategies to reduce the impact of heterocyclic aromatic amines in proteinaceous foods. Trends in Food Science & Technology 50:70-84
9.Alaejos MS, Afonso AM (2011) Factors that affect the content of heterocyclic aromatic amines in foods. Comprehensive Reviews in Food Science and Food Safety 10 (2):52-108
10.Xian Y, Wu Y, Dong H, Chen L, Zhang C, Hou X, Zeng X, Bai W, Guo X (2019) Modified QuEChERS purification and Fe3O4 nanoparticle decoloration for robust analysis of 14 heterocyclic aromatic amines and acrylamide in coffee products using UHPLC-MS/MS. Food Chemistry 285:77-85
11.Borgen E, Solyakov A, Skog K (2001) Effects of precursor composition and water on the formation of heterocyclic amines in meat model systems. Food Chemistry 74 (1):11-19
12.Turesky RJ, Le Marchand L (2011) Metabolism and biomarkers of heterocyclic aromatic amines in molecular epidemiology studies: lessons learned from aromatic amines. Chemical Research in Toxicology 24 (8):1169-1214
13.Kim JK, Gallaher DD, Chen C, Yao D, Trudo SP (2015) Apiaceous vegetable consumption decreases PhIP-induced DNA adducts and increases methylated PhIP metabolites in the urine metabolome in rats. Journal of Nutrition 145 (3):442-451
14.Kobayashi M, Hanaoka T, Tsugane S (2007) Validity of a self-administered food frequency questionnaire in the assessment of heterocyclic amine intake using 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) levels in hair. Mutation Research 630 (1-2):14-19
15.Boobis AR, Lynch AM, Murray S, Torre R, Solans A, Farré M, Segura J, Gooderham NJ, Davies DS (1994) CYP1A2-catalyzed conversion of dietary heterocyclic amines to their proximate carcinogens is their major route of metabolism in humans. Cancer Research 54:89-94
16.Frederiksen H, Frandsen H, Pfau W (2004) Syntheses of DNA-adducts of two heterocyclic amines, 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAαC) and 2-amino9H-pyrido[2,3-b]indole (AαC) and identification of DNA-adducts in organs from rats dosed with MeAαC. Carcinogenesis 25 (8):1525–1533
17.KIEFER F, A. KR ÈODEL, H. JAHN, K. WOLF, BAROCKA A (2000) Harman and norharman plasma levels in weaned alcoholics: correlations with depression and tobacco smoking. Addiction Biology 5: 437-441
18.Fekkes D, Tuiten A, Bom I, Pepplinkhuizen L (2001) Pharmacokinetics of the β-carboline norharman in man. Life Sciences 69:2113–2121
19.Hasegawa R, Juki Kimura, Makoto Yaono, Satoru Takahashi, Toshio Kato, Mitsuru Futakuchi, Masato Fukutake, Kazuo Fukutome, Keiji Wakabayashi, Takashi Sugimura, Nobuyuki Ito, Shirai T (1995) Increased risk of mammary carcinoma development following transplacental and trans-breast milk exposure to a food-derived carcinogen, 2-amino-l-methyl-6phenylimidazo[4,5-b]pyridine (phip), in sprague-dawley rats. Cancer Research 55:4133-4318
20.Dashwood R, Suzui M, Nakagama H, Sugimura T, Nagao M (1998) High frequency of β-catenin (ctnnb1) mutations in the colon tumors induced by two heterocyclic amines in the F344 rat. Cancer Research 58:1127-1129
21.Sugimura T, Wakabayashi K, Nakagama H, Nagao M (2004) Heterocyclic amines: Mutagens/carcinogens produced during cooking of meat and fish. Cancer Science 95:290-299
22.Koda M, Iwasaki M, Yamano Y, Lu X, Katoh T (2017) Association between NAT2, CYP1A1, and CYP1A2 genotypes, heterocyclic aromatic amines, and prostate cancer risk: a case control study in Japan. Environ Health Prev Med 22 (1):72
23.Sinha R (2002) An epidemiologic approach to studying heterocyclic amines. Mutation Research 506–507:197–204
24.Terry PD, Lagergren J, Wolk A, Steineck G, Nyre´n O (2003) Dietary intake of heterocyclic amines and cancers of the esophagus and gastric cardia. Cancer Epidemiology, Biomarkers & Prevention 12:940-944
25.Martinez Gongora V, Matthes KL, Castano PR, Linseisen J, Rohrmann S (2019) Dietary heterocyclic amine intake and colorectal adenoma risk: A systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev 28 (1):99-109
26.Park JE, Seo JE, Lee JY, Kwon H (2015) Distribution oF SEVEN N-nitrosamines in food. Toxicol Res 31 (3):279-288
27.Peto R, Gray R, Brantom P, Grasso P (1991) Dose and time relationships for tumor induction in the liver and esophagus of 4080 inbred rats by chronic ingestion of N-nitrosodiethylamine or N-nitrosodimethylamine. Cancer Research 51:6452-6469
28.Koujitani T, Tamura T, Yasuhara K, Hirose M, Onodera H, Takagi H, Mitsumori K (2002) The utility of N-nitrosamines as initiators for a 26-week rat two-stage nasal carcinogenesis model. Journal of Toxicologic Pathology 15:39–43
29.Herrmann SS, Granby K, Duedahl-Olesen L (2015) Formation and mitigation of N-nitrosamines in nitrite preserved cooked sausages. Food Chem 174:516-526
30.Rostkowska K, Zwierz K, Różański A, Moniuszko-Jakoniuk J, Roszczenko A (1998) Formation and metabolism of N-nitrosamines. Polish Journal of Environmental Studies 7 (6):321-325
31.衛生福利部食品藥物管理署 (2019) 食品添加物使用範圍及限量暨規格標準.
32.Brkić D, Bošnir J, Bevardi M, Bošković AG, Miloš S, Lasić D, Krivohlavek A, Racz A, Ćuić AM, Trstenjak NU (2017) Nitrate in leafy green vegetables and estimated intake. African Journal of Traditional, Complementary and Alternative Medicine 14 (3):31-41
33.Chowdhury G, Calcutt MW, Nagy LD, Guengerich FP (2012) Oxidation of methyl and ethyl nitrosamines by cytochrome P450 2E1 and 2B1. Biochemistry 51 (50):9995-10007
34.CSIRO Advanced Coal Technology Portfolio (2011) Biodegradation, hydrolysis and photolysis testing of nitrosamines in aquatic systems.1-30
35.Sørensen L, Silva EFd, Brakstad OG, Zahlsen K, Booth A (2013) Preliminary studies into the environmental fate of nitrosamine and nitramine compounds in aquatic systems. Energy Procedia 37:683-690
36.Alaneme FO, Maduagwu EN (2004) Pharmacokinetics of biliary excretion of N-nitrosodimethylamine in rats fed diets containing levels of protein. Malawi Medical Journal 16 (1):6-8
37.Šulc M, Hodek P, Stiborová M (2010) The binding affinity of carcinogenic N-nitrosodimethylamine and N-nitrosomethylaniline to cytochromes P450 2B4, 2E1 and 3A6 does not dictate the rate of their enzymatic N-demethylation. General Physiology and Biophysics 29 (2):175-185
38.Veena S, Manu S (2012) N-nitrosodimethylamine as a hazardous chemical toxicant in drinking water. IRJP 3 (3):60-65
39.Minister of Public Works and Government Services (2001) Priority substances list assessment report: N-Nitrosodimethylamine (NDMA). Canadian Environmental Protection Act:1-64
40.Jorquera R, Castonguay A, Schuller HM (1993) Effects of age and ethanol on DNA single-strand breaks and toxicity induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone or n-nitrosodimethylamine in hamster and rat liver. Cancer Letters 74:175-181
41.Bryan NS, Alexander DD, Coughlin JR, Milkowski AL, Boffetta P (2012) Ingested nitrate and nitrite and stomach cancer risk: an updated review. Food and Chemical Toxicology 50 (10):3646-3665
42.Tricker AR, Preussmann R (1991) Carcinogenic N-nitrosamines in the diet: occurrence, formation, mechanisms and carcinogenic potential. Mutation Research 259:277-289
43.Jakszyn P, González CA (2006) Nitrosamine and related food intake and gastric and oesophageal cancer risk: A systematic review of the epidemiological evidence. World Journal of Gastroenterology 12 (27):4296-4303
44.Johnson K, Gorzinski S, Bodner K, Campbell R, Wolf C, Friedman M, Mast R (1986) Chronic toxicity and oncogenicity study on acrylamide incorporated in the drinking water of Fischer 344 rats. Toxicology and Applied Pharmacology 85:154-168
45.Friedman M, Mottram D (2004) Chemistry and safety of acrylamide in food. Advances In Experimental Medicine And Biology 561
46.Consultation RoaJFW (2002) Health implications of acrylamide in food. Food Safety Programme Department Of Protection Of The Human Environment World Health Organization
47.Boekel vMA (2006) Formation of flavour compounds in the Maillard reaction. Biotechnology Advances 24 (2):230-233
48.Franke K, Strijowski U, Reimerdes EH (2009) Kinetics of acrylamide formation in potato powder. Journal of Food Engineering 90 (1):135-140
49.Brathen E, Knutsen S (2005) Effect of temperature and time on the formation of acrylamide in starch-based and cereal model systems, flat breads and bread. Food Chemistry 92 (4):693-700
50.U.S. Food and Drug Administration (2006) Survey data on acrylamide in food: Individual food products.
51.Goodman BA, Yeretzian C (2015) Free Radical Processes in Coffee II—Liquids. In: Processing and impact on active components in food. pp 567-574
52.Wang P, Ji R, Ji J, Chen F (2019) Changes of metabolites of acrylamide and glycidamide in acrylamide-exposed rats pretreated with blueberry anthocyanins extract. Food Chemistry 274:611-619
53.Huang YF, Chen ML, Liou SH, Chen MF, Uang SN, Wu KY (2011) Association of CYP2E1, GST and mEH genetic polymorphisms with urinary acrylamide metabolites in workers exposed to acrylamide. Toxicology Letters 203 (2):118-126
54.Boettcher MI, Angerer J (2005) Determination of the major mercapturic acids of acrylamide and glycidamide in human urine by LC-ESI-MS/MS. Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences 824 (1-2):283-294
55.Kopp EK, Dekant W (2009) Toxicokinetics of acrylamide in rats and humans following single oral administration of low doses. Toxicology and Applied Pharmacology 235 (2):135-142
56.Fennell TR, Sumner SC, Snyder RW, Burgess J, Friedman MA (2006) Kinetics of elimination of urinary metabolites of acrylamide in humans. Toxicological Sciences 93 (2):256-267
57.Wang H, Huang P, Lie T, Li J, Hutz RJ, Li K, Shi F (2010) Reproductive toxicity of acrylamide-treated male rats. Reproductive Toxicology 29 (2):225-230
58.Wilson KM, Giovannucci E, Stampfer MJ, Mucci LA (2012) Dietary acrylamide and risk of prostate cancer. International Journal of Cancer 131 (2):479-487
59.Pelucchi C, Galeone C, Levi F, Negri E, Franceschi S, Talamini R, Bosetti C, Giacosa A, La Vecchia C (2006) Dietary acrylamide and human cancer. International Journal of Cancer 118 (2):467-471
60.Mucci LA, Dickman PW, Steineck G, Adami HO, Augustsson K (2003) Dietary acrylamide and cancer of the large bowel, kidney, and bladder: absence of an association in a population-based study in Sweden. British Journal of Cancer 88 (1):84-89
61.Watzek N, Scherbl D, Feld J, Berger F, Doroshyenko O, Fuhr U, Tomalik-Scharte D, Baum M, Eisenbrand G, Richling E (2012) Profiling of mercapturic acids of acrolein and acrylamide in human urine after consumption of potato crisps, vol 56.
62.Poole CF (2000) Extraction, Solid-Phase Extraction. Encyclopedia of Separation Science:1405-1416
63.Krauss M, Hollender J (2008) Analysis of nitrosamines in wastewater: Exploring the trace level quantification capabilities of a hybrid linear ion trap/orbitrap mass spectrometer. Analytical Chemistry 80:834-842
64.Tran KV, Young MS, Ross E, Hird S (2016) A new sorbent for cleanup of seafood, infant formula, and other fatty matrix extracts . Waters Application Note AN797
65.Zeng M, He Z, Zheng Z, Qin F, Tao G, Zhang S, Gao Y, Chen J (2014) Effect of six Chinese spices on heterocyclic amine profiles in roast beef patties by ultra performance liquid chromatography-tandem mass spectrometry and principal component analysis. Journal of Agricultural and Food Chemistry 62 (40):9908-9915
66.Zeng M, Zhang M, He Z, Qin F, Tao G, Zhang S, Gao Y, Chen J (2017) Inhibitory profiles of chilli pepper and capsaicin on heterocyclic amine formation in roast beef patties. Food Chemistry 221:404-411
67.SUPELCO, Inc (2004) Solid Phase Extraction (SPE) Discovery SPE Tubes. SUPELCO User guide
68.Munch JW (2005) METHOD 521: Determination of nitrosamines in drinking water by solid phase extraction and capillary column gas chromatography with large volume injection and chemical ionization tandem mass spectrometry (ms/ms) US Environmental Protection Agency
69.Dara KR, Mehta TN (2012) Determination of gestodene in human plasma by SLE-LC-MS/MS using a solid core HPLC column Thermo Scientific
70.Biotage (2013) Extraction of acrylamide from fried potato chips (crisps) using ISOLUTE® SLE+ prior to LC-MS/MS analysis. Application Note AN797
71.Zhang L, Xia Y, Xia B, Nicodemus KJ, McGuffey J, McGahee E, Blount B, Wang L (2016) High-throughput and sensitive analysis of urinary heterocyclic aromatic amines using isotope-dilution liquid chromatography-tandem mass spectrometry and robotic sample preparation system. Analytical and Bioanalytical Chemistry 408 (28):8149-8161
72.Shen XC, Zhang YL, Cui YQ, Xu LY, Li X, Qi JH (2017) Simultaneous determination of 9 heterocyclic aromatic amines in pork products by liquid chromatography coupled with triple quadrupole tandem mass spectrometry. IOP Conference Series: Earth and Environmental Science 77
73.Zhao YY, Boyd J, Hrudey SE, Li XF (2006) Characterization of new nitrosamines in drinking water using liquid chromatography tandem mass spectrometry. Environmental Science & Technology 40:7636-7641
74.Ono H, Chuda Y, Ohnishi-Kameyama M, Yada H, Ishizaka M, Kobayashi H, Yoshida M (2003) Analysis of acrylamide by LC-MS and GC-MS in processed Japanese foods, vol 20.
75.Jian SH, Yeh PJ, Wang CH, Chen HC, Chen SF (2018) Analysis of heterocyclic amines in meat products by liquid chromatography – Tandem mass spectrometry. Journal of Food and Drug Analysis
76.CITAC / EURACHEM GUIDE (2002) Guide to quality in analytical chemistry.
77.Association of Official Agricultural Chemists (2010) Standard format and guidance for aoac standard method performance requirement (SMPR) documents
78.U.S. Department of Health and Human Services Food and Drug Administration (2015) Analytical procedures and methods validation for drugs and biologics Pharmaceutical Quality/CMC 1-18
79.Souza-Silva ÉA, Pawliszyn J (2017) Chapter sixteen - recent advances in solid-phase microextraction for contaminant analysis in food matrices. Comprehensive Analytical Chemistry 76 (483-517)
80.Toora BD, Rajagopal G (2002) Measurement of creatinine by Jaffe''s reaction--determination of concentration of sodium hydroxide required for maximum color development in standard, urine and protein free filtrate of serum. Indian journal of experimental biology 40 (3):352-354
81.Treetampinich C, O''Connor AE, MacLachlan V, Groome NP, de Kretser DM (2000) Maternal serum inhibin A concentrations in early pregnancy after IVF and embryo transfer reflect the corpus luteum contribution and pregnancy outcome. Human Reproduction 15 (9):2028-2032
82.Hu CW, Shih YM, Liu HH, Chiang YC, Chen CM, Chao MR (2016) Elevated urinary levels of carcinogenic N-nitrosamines in patients with urinary tract infections measured by isotope dilution online SPE LC-MS/MS. Journal of Hazardous Materials 310:207-216
83.Pozzi R, Bocchini P, Pinelli F, Galletti GC (2011) Determination of nitrosamines in water by gas chromatography/chemical ionization/selective ion trapping mass spectrometry. Journal of Chromatography A 1218 (14):1808-1814
84.LabDiet (2009) Laboratory Rodent Diet 5001.
85.Sauberlich HE, Chang WY, Salmon WD (1953) The amino acid and protein content of corn as related to variety and nitrogen fertilization. The Journal of Nutrition 51 (2):241-250
86.Food And Agriculture Organization Of The United Nations (1992) Maize in human nutrition.
87.Mahboubi A, Linden P, Hedenstrom M, Moritz T, Niittyla T (2015) 13C Tracking after 13CO2 Supply Revealed Diurnal Patterns of Wood Formation in Aspen. Plant Physiol 168 (2):478-489
88.Herraiz T, Guillen H, Aran VJ (2008) Oxidative metabolism of the bioactive and naturally occurring beta-carboline alkaloids, norharman and harman, by human cytochrome P450 enzymes. Chemical Research in Toxicology 21 (11):2172-2180
89.He YH, Friesen MD, Ruch RJ, Schut HA (2000) Indole-3-carbinol as a chemopreventive agent in 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) carcinogenesis: inhibition of PhIP-DNA adduct formation, acceleration of PhIP metabolism, and induction of cytochrome P450 in female F344 rats. Food Chem Toxicol 38 (1):15-23
90.Dashwood R, Liew C (1992) Chlorophyllin-enhanced excretion of urinary and fecal mutagens in rats given 2-amino-3-methylimidazo[4, 5-f]quinoline. Environmental and Molecular Mutagenesis 20 (3):199-205
91.Sjodin P, Wallin H, Alexander J, Jagerstad M (1989) Disposition and metabolism of the food mutagen 2-amino-3,8-dimethylimidazo[4,5-/]quinoxaline (MelQx) in rats. Carcinogenesis 10 1269-1275
92.Kuyooro SE, Adebawo FG, C. OP, Maduagwu EN (2014) Urinary elimination and metabolism of nitrosamines in different dietary protein Wistar rat models. Journal of Pharmacy and Biological Sciences 9:17-21
93.Lakshmi VM, Hsu FF, Zenser TV (2009) Identification of new 2-amino-3-methylimidazo[4,5-f]quinoline urinary metabolites from beta-naphthoflavone-treated mice. Drug Metabolism and Disposition 37 (8):1690-1697
94.Mori Y, Koide A, Kobayashi Y, Furukawa F, Hirose M, Nishikawa aA (2003) Effects of cigarette smoke and a heterocyclic amine, MeIQx on cytochrome P-450, mutagenic activation of various carcinogens and glucuronidation in rat liver. Mutagenesis 18 (1):87-93
95.Stillwell WG, Robert J. Turesky, Sinha R, Tannenbaum SR (1999) N-oxidative metabolism of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in humans: excretion of the n2-glucuronide conjugate of 2-hydroxyamino-MeIQx in urine. Cancer Research 59:5154–5159
96.Turesky RJ (2007) Formation and biochemistry of carcinogenic heterocyclic aromatic amines in cooked meats. Toxicology Letters 168 (3):219-227
97.Novak M, Toth K, Rajagopal S, Brooks M, Hott LL, Moslener M (2002) Reactivity and selectivity of the N-acetyl-Glu-P-1, N-acetyl-Glu-P-2, N-acetyl-MeIQx, and N-Acetyl-IQx nitrenium Ions: comparison to carbocyclic N-arylnitrenium Ions. Journal of the American Chemical Society 124:7972-7981
98.Malfatti MA, Felton JS (2001) N-Glucuronidation of 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) and N-hydroxy-PhIP by specific human UDP-glucuronosyltransferases. Carcinogenesis 22 (7):1087-1093
99.Takahashi E, Marczylo TH, Watanabe T, Nagaib S, Hayatsu H, Negishi T (2001) Preventive effects of anthraquinone food pigments on the DNA damage induced by carcinogens in Drosophila. Mutation Research 480–481:139–145
100.Shiotani B, Ashida H (2004) 3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) triggers apoptosis by DNA double-strand breaks caused by inhibition of topoisomerase I. Carcinogenesis 25 (7):1149-1155
101.de Waziers I, Decloitre F (1984) Effect of glutathione and uridine-5''-diphosphoglucuronic acid on the mutagenicity of tryptophan pyrolysis products (Trp-P-1 and Trp-P-2) by rat-liver and -intestine S9 fraction. Mutation Research 139 (1):15-19
102.Tang Y, LeMaster DM, Nauwelaers G, Gu D, Langouet S, Turesky RJ (2012) UDP-glucuronosyltransferase-mediated metabolic activation of the tobacco carcinogen 2-amino-9H-pyrido[2,3-b]indole. Journal of Biological Chemistry 287 (18):14960-14972
103.Bellamri M, Le Hegarat L, Turesky RJ, Langouet S (2017) MetABOLISM OF THE TOBACCO CARCINOGEN 2-Amino-9H-pyrido[2,3-b]indole (AaC) in primary human hepatocytes. Chem Res Toxicol 30 (2):657-668
104.Turesky RJ, Vouros P (2004) Formation and analysis of heterocyclic aromatic amine-DNA adducts in vitro and in vivo. Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences 802 (1):155-166
105.Hayatsu H (1990) Mutagens in Food. Chemical Rubber Company Press 1:1-296
106.Wei M, Wanibuchi H, Nakae D, Tsuda H, Takahashi S, Hirose M, Totsuka Y, Tatematsu M, Fukushima S (2011) Low-dose carcinogenicity of 2-amino-3-methylimidazo[4,5-f ]quinoline in rats: Evidence for the existence of no-effect levels and a mechanism involving p21(Cip / WAF1). Cancer Science 102 (1):88-94
107.Tavan E, Cayuela C, Antoine JM, Trugnan G, Chaugier C, Cassand P (2002) Effects of dairy products on heterocyclic aromatic amine-induced rat colon carcinogenesis. Carcinogenesis 23 (3):477-483
108.Huang H, Ushijima T, Nagao M, Sugimura T, Ohgaki H (2003) β-Catenin mutations in liver tumors induced by 2-amino-3,4-dimethylimidazo[4,5-f]quinoline in CDF1 mice. Cancer Letters 198 (1):29-35
109.Fujita K, Ohnishi T, Sekine K, Iigo M, Tsuda H (2002) Down-regulation of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) induced CYP1A2 expression is associated with bovine lactoferrin inhibition of MeIQx-induced liver and colon carcinogenesis in rats. Japanese Journal of Cancer Research 93:616–625
110.Suzuki S, Takeshita K, Doi Y, Asamoto M, Takahashi S, Naiki Ito A, Shirai T (2010) 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)-induced hepatocarcinogenesis is not enhanced by CYP1A inducers, alpha- and beta-naphthoflavone: relationship to intralobular distribution of CYP1A expression. Toxicologic Pathology 38 (4):583-591
111.Nakagama H, Ochiai M, Ubagai T, Tajima R, Fujiwara K, Sugimura T, Nagao M (2002) A rat colon cancer model induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, PhIP. Mutation Research 506–507:137–144
112.Steffensen I, Paulsen JE, Alexander J (2002) The food mutagen 2-amino-9H-pyrido[2,3-b]indole (AαC) but not its methylated form (MeAαC) increases intestinal tumorigenesis in neonatally exposed multiple intestinal neoplasia mice. Carcinogenesis 23 (8):1373–1378
113.Hasegawa R, Takahashi S, Shirai T, Iwasaki S, Kim DJ, Ochiai M, Nagao M, Sugimura T, Ito N (1992) Dose-dependent formation of preneoplastic foci and DNA adducts in rat liver with 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alpha C) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Carcinogenesis:13(18):1427-1431.
114.Degawa M, Hanaki K, Sekimoto M (2006) A hepatocarcinogenic tryptophan-pyrolyzate component, Trp-P-1, decreases serum total testosterone level and induces hepatic CYP 1A2 in male mice. Cancer Science 97 (1):32-37
115.Michihito T, Kazuhiro T, Yoshiya A, Kyoko F, Kunitoshi M, Yuzo H (1993) The rat urinary bladder as a new target of heterocyclic amine carcinogenicity: tumor induction by 3-amino-1-methyl-5H-pyrido[4,3-b]indole acetate. Japanese Journal of Cancer Research 84 (8):852-858
116.Suzuki H, Sone H, Kawamura K, Ishihara K (2008) Liver injury due to 3-amino-1-methyl-5h-pyrido [4,3-b] indole (Trp-P-2) and its prevention by miso. Bioscience, Biotechnology, and Biochemistry 72 (8):2236-2238
117.Hiroko O, Hirokazu H, Tamami K, Miki S, Mikiyo U, Shigeaki S, Shozo T, Takashi S (1986) Carcinogenicity in mice and rats of heterocyclic amines in cooked foods. Environmental Health Perspectives 67:129-134
118.Nagao M, Yahagi T, Kawachi T, Sugimura T, Kosuge T, Tsuji K, Wakabayashi K, Mizusaki S (1977) Comutagenic action of norharman and harman. Proceedings of the Japan Academy 2:95-98
119.Nii H (2003) Possibility of the involvement of 9H-pyrido[3,4-b]indole (norharman) in carcinogenesis via inhibition of cytochrome P450-related activities and intercalation to DNA. Mutation Research/Genetic Toxicology and Environmental Mutagenesis 541 (1-2):123-136
120.Beland FA, Mellick PW, Olson GR, Mendoza MC, Marques MM, Doerge DR (2013) Carcinogenicity of acrylamide in B6C3F(1) mice and F344/N rats from a 2-year drinking water exposure. Food and Chemical Toxicology 51:149-159
121.Souliotis VL, John R. Henneman, Carl D. Reed, Saranjit K. Chhabra, Diwan BA, Lucy M. Anderson, Kyrtopoulos SA (2002) DNA adducts and liver DNA replication in rats during chronic exposure to N-nitrosodimethylamine (NDMA) and their relationships to the dose-dependence ofNDMA hepatocarcinogenesis. Mutation Research 500:75–87
122.Jeyabal PV, Syed MB, Venkataraman M, Sambandham JK, Sakthisekaran D (2005) Apigenin inhibits oxidative stress-induced macromolecular damage in N-nitrosodiethylamine (NDEA)-induced hepatocellular carcinogenesis in Wistar albino rats. Molecular Carcinogenesis 44 (1):11-20
123.Wang W, Xu GL, Jia WD, Wang ZH, Li JS, Ma JL, Ge YS, Xie SX, Yu JH (2009) Expression and correlation of hypoxiainducible factor-1α, vascular endothelial growth factor and microvessel density in experimental rat hepatocarcinogenesis. The Journal of International Medical Research 37:417 – 425
124.Michejda CJ, Kroeger-Koepke MB, Kovatch RM (1986) Effects of dairy products on heterocyclic aromatic amine-induced rat colon carcinogenesis. Cancer Research 46:2252-2256
125.Wang M, Lao Y, Cheng G, Shi Y, Villalta PW, Nishikawa A, Hecht SS (2007) Analysis of adducts in hepatic DNA of rats treated with N-Nitrosopyrrolidine. Chemical Research in Toxicology 20:634-640
126.Xie XY, Shen J, Xu LY, Li EM, Shen ZY (2010) Bronchogenic and alveologenic tumors in mice induced by N-nitrosopiperidine. Biochemistry and Cell Biology 88 (4):775-782
127.Cha HJ, Kim NH, Jeong EK, Na YC (2010) Analysis of heterocyclic amines in human urine using multiple solid-phase extraction by liquid chromatography/mass spectrometry. Bulletin of the Korean Chemical Society 31 (8):2322-2328
128.Lee JH, Lee SU, Oh JE (2013) Analysis of nine nitrosamines in water by combining automated solid-phase extraction with high-performance liquid chromatography-atmospheric pressure chemical ionisation tandem mass spectrometry. International Journal of Environmental Analytical Chemistry 93 (12):1261-1273
129.Asami M, Oya M, Kosaka K (2009) A nationwide survey of NDMA in raw and drinking water in Japan. Science of the Total Environment 407 (11):3540-3545
130.Gökmen V, Şenyuva HZ, Acar J, Sarıoğlu K (2005) Determination of acrylamide in potato chips and crisps by high-performance liquid chromatography. Journal of Chromatography A 1088 (1-2):193-199
131.Michalak J, Gujska E, Kuncewicz A (2013) RP-HPLC-DAD studies on acrylamide in cereal-based baby foods. Journal of Food Composition and Analysis 32 (1):68-73
132.Wei X, Brusius M (2015) Acrylamide from coffee using Novum ™ simplified liquid extraction (SLE) tubes and a Synergi ™ Hydro-RP HPLC column. Application of Phenomenex, Inc
133.Humblot C, Murkovic M, Rigottier-Gois L, Bensaada M, Bouclet A, Andrieux C, Anba J, Rabot S (2007) Beta-glucuronidase in human intestinal microbiota is necessary for the colonic genotoxicity of the food-borne carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline in rats. Carcinogenesis 28 (11):2419-2425
134.Armbrecht HJ, Lakshmi VM, Wickstra J, Hsu FF, Zenser TV (2007) Metabolism of a heterocyclic amine colon carcinogen in young and old rats. Drug Metabolism and Disposition 35 (4):633-639
135.Malfatti MA, Kulp KS, Knize MG, Davis C, Massengill JP, Williams S, Nowell S, MacLeod S, Dingley KH, Turteltaub KW, Lang NP, Felton JS (1999) The identification of [2-14C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine metabolites in humans. Carcinogenesis 20:705-713
136.Dietrich CG, de Waart DR, Ottenhoff R, Bootsma AH, van Gennip AH, Elferink RP (2001) Mrp2-deficiency in the rat impairs biliary and intestinal excretion and influences metabolism and disposition of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo. Carcinogenesis 22 (5):805-811
137.Frandsen H, Frederiksen H, Alexander J (2002) 2-Amino-1-methyl-6-(5-hydroxy-)phenylimidazo[4,5-b]pyridine (5-OH-PhIP), a biomarker for the genotoxic dose of the heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Food and Chemical Toxicology 40:1125–1130
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