论文部分内容阅读
Abstract The time-of-flight mass spectrometry （TOF-MS）， one of the mass spectrometry techniques， has been widely applied in the field of rapid screening of food hazard factors as a superior analysis technique because of its wide mass range， high resolution and mass measurement accuracy， high sensitivity and high analysis speed. In this paper， research progresses of TOF-MS on the detection of food additives， food contaminants and residues， illegal additives， pesticide residues， veterinary drug residues and mycotoxin were reviewed， and its probable approaching applications were prospected.
Key words Time-of-flight mass spectrometry; Food; Hazard factor; Screening; Application
Food contaminants and their residues such as pesticide residues， veterinary drug residues， illegal additives and organic pollutants which are generated during food production or from food packaging materials pose a serious threat to food quality and safety. The complexity of food matrices and the variety of food contaminants also place higher requirements on food inspection technologies.
High-resolution time-of-flight mass spectrometry （TOF-MS） has the characteristics of wide mass range， high resolution and mass accuracy and fast analysis speed[1]. Unlike low-resolution mass spectrometry， TOF-MS can obtain the exact mass and possible chemical formula of a compound through a full scan， which greatly improves the anti-interference ability under complex backgrounds and makes the detection results more accurate and reliable. In addition， TOF-MS has a high scanning rate. In theory， there is no upper limit on the number of targets that can be scanned at the same time. It can truly achieve high-throughput detection of hundreds of pesticides at a time. TOF-MS can also establish a database of specific compounds， and perform automatic search and analysis confirmation by software combining with the accurate mass data， retention time， isotope ratio and other information collected from the sample， thereby realizing rapid identification of target compounds without using standards[2-3]. Therefore， TOF-MS is an effective method for the qualitative analysis of trace compounds in complex samples， which can meet the needs of high-throughput rapid screening and quantitative analysis.
Principle of TOF-MS Techique
The TOF-MS mass analyzer is an ion drift tube. The ions generated by an ion source are collected by a collector first. The velocity of all ions becomes zero in the collector. The ions are accelerated by a pulsed electric field， enter the field-free drift tube and fly to an ion receiver at a constant speed. The larger the ion mass is， the longer it takes to reach the receiver; and the smaller the ion mass， the shorter the time to reach the receiver. According to this principle， ions of different masses can be separated according to the m/z value. The classic time-of-flight mass spectrometer is mainly composed of four parts： ion source， cylindrical flight tube， detector and recording system[4-6]. According to the fact that the kinetic energy for ion motion is from the acceleration voltage， we can get：
me=2Vt2s2
Wherein m/e is the mass-to-charge ratio of ions; V is the acceleration voltage， kV; t is the flight time of ions， μs; and s is the flying distance of ions， cm.
The formula shows that the ion mass-to-charge ratio is proportional to the square of time， so the mass-to-charge ratio can be obtained after measuring the flight time of ions. In the detection， the lighter ions have a higher velocity， while the heavier ions have a lower velocity. They reach the detector to produce a signal successively. Generally， the flight time of ions is on the order of microseconds.
Classification of TOF-MS
Both mass spectrometry and chromatography have their own advantages. Combining the two into a set of analysis systems can obtain the best analytical method. TOF-MS can be divided according to the connected chromatograph or spectrometer into liquid chromatography-time-of-flight mass spectrometry （LC-TOF-MS）， gas chromatography-time-of-flight mass spectrometry （GC-TOF-MS）， and full two-dimensional Gas chromatography-time-of-flight mass spectrometry （GC×GC-TOF-MS）， inductively coupled plasma-orthogonal acceleration time-of-flight mass spectrometry （ICP-oa-TOF-MS）， etc.[7]. To connect the LC and MS， the interface technique is the key. According to different interfaces and ionization techniques， TOF-MS can be mainly divided into ESI-TOF-MS composed of electrospray ionization source （ESI） and TOF-MS， APCI-TOF-MS composed of atmospheric pressure chemical ionization source （APCI） and TOF-MS， APPI-TOF-MS composed of atmospheric pressure photoionization source （APPI） and TOF-MS， and MALDI-TOF-MS consisting of matrix-assisted laser desorption ionization （MALDI） and TOF-MS. Multi-stage mass spectrometry can be achieved by tandem mass spectrometry. It is a mass spectrometry technique emerging in the late 1970s. TOF-MS can be classified according to tandem mass spectrometry mainly into Q-TOF-MS composed of quadruple MS and TOF-MS and IT-TOF-MS composed of ion trap mass spectrometry （IT） and TOF-MS.
Performance Characteristic of TOF-MS
Wide mass range
In theory， TOF-MS has no upper limit for mass analysis. Its actual analytical mass range is limited only by the slow flight speed of high-mass ions， insufficient detector response to these ions and limited data storage and memory， but still reaches 300 000 Da， which is much larger than those of quadrupole and ion trap mass spectrometry. Fast analysis
TOF-MS as a pulse-type mass analyzer has a very fast data acquisition speed， up to 4 G/s. Ultra-high-performance liquid chromatography （UPLC）， which has appeared in recent years， can make the retention time and the widths of chromatographic peaks greatly shortened after being collected to TOF， which further increases the speed of sample analysis.
High resolution
TOF-MS belongs to high-resolution mass spectrometry with a resolution of 55 000. Therefore， the molecular weight can be measured to the fourth decimal place， and the elemental composition can be directly analyzed to calculate the molecular formula. Quadrupole and ion trap mass spectrometry belong to low-resolution mass spectrometry， with which only the integer molecular weights of compounds can be measured， and elemental composition analysis cannot be performed.
High mass accuracy
The TOF-MS full-scan detection method has an ion mass accuracy that is more than 100 times higher than that of general mass spectrometry， and the accuracy of accurate mass determination can reach 5 ppm or even lower， while quadrupole and other mass spectrometry are limited to half the mass due to the limitation of the accuracy of the instrument.
High sensitivity
The TOF-MS detector can simultaneously detect ions in the full mass range， and the use of quadrupole focusing ensures the maximum ion transmission rate and greatly improves its sensitivity. The sensitivity under selected ion scanning is lower than that of quadrupole and other mass spectrometry， but the sensitivity under full mass scanning is much higher than that of quadrupole and other mass spectrometry.
Application of TOF-MS in Screening of Food Hazard Factors
Food additives
Food additives are various compounds allowed by the state to be used in foods to improve food quality. The amount of food additives used in Chinese food must strictly comply with the provisions of GB2760-2014 "the National Food Safety Standard： Standards for Food Additive Use"， but the abuse of food additives is still one of the important factors affecting food quality and safety at present. Therefore， it is particularly important to quickly screen and confirm the existence of abuse of additives in food. Chen[3] established a screening method based on LC-TOF-MS for a variety of illegally added colorants and food colorants that are prone to abuse and established a corresponding screening database. The HPLC-Q/TOF-MS method established by Zhao et al.[8] showed a wide screening range and good applicability to foods containing protein， fat and other substrates when screening 29 kinds of illegally added and restricted synthetic pigments in cheese. For food additives commonly used in GB 2760-2014， liquid chromatography or gas chromatography can meet the daily testing requirements for their standard use. When testing or screening certain types of food additives， mass spectrometry such as TOF-MS techniques having the advantages of fast speed， wide screening range and high sensitivity can be used. Food contaminants
Wang et al.[9] established an LC-IT-TOF-MS method for simultaneous determination of 14 heterocyclic amine residues in meat products， and based on this method， developed a method for simultaneous determination of 14 heterocyclic amines in wine. Both methods have a short analysis time and allow rapid screening of heterocyclic amines during food safety testing. Dasgupta et al.[10] established a GC×GC-TOF-MS analysis method for the detection of persistent environmental pollutants such as 12 polychlorinated biphenyls， 12 polycyclic aromatic hydrocarbons， and bisphenol A in grapes and wines. With the GC×GC-TOF-MS analysis method， the detection objects can be well separated， reducing the possibility of false negative results at low residual concentrations. Edible oils and fats may produce organic pollutants such as 3-chloro-1，2-propanediol esters and glycidyl esters during the refining process. Generally， indirect methods are used to detect these two kinds of pollutants， but inconsistent test results are likely to be produced. Haines et al.[11] established an LC-TOF-MS method that can directly detect 3-chloro-1，2-propanediol esters and glycidyl esters in edible fats and oils， and its high resolution can greatly reduce the interference of impurities， thereby improving the detection sensitivity of contaminants in edible fats. Ha et al.[12] established a GC×GC-TOF-MS method for the detection of two trans-oleic acids （18： 1trans-11 and 18： 1trans-9） in meat products and partial hydrogenated edible oils. The GC×GC-TOF-MS method can completely separate the chromatographic peaks of the two trans-fatty acids， so as to obtain the ratio between the two， which is used to judge the source of the trans-fatty acids.
Illegal additives
Lu et al.[13] built a database of 36 illegally added weight-reducing， lipid-lowering and laxative drugs in health foods based on UPLC-IT-TOF-MS， and established a rapid screening and confirmation method， which shortens the time for locking target objects in health food safety inspection and improves inspection efficiency. Hao et al.[14] used IT-TOF-MS to detect the illegal additive rhodamine B in poultry meat and performed multi-stage mass spectrometry analysis. Chen et al.[15] established a method for the analysis of 13 illegal additives in food by using GC×GC-TOF-MS， and quickly and efficiently separated 32 compounds by using GC×GC within 20.5 min， thereby solving the technical difficulty that one-dimensional gas chromatography cannot separate 9 of these compounds from matrix interference components when reducing the detection limit of the method by more than 10 times. Calbiani et al.[16] established a Micro LC-Q-TOF-MS method for the precise detection of four kinds of Sudan red colorants in foods， while Rebane et al.[17] reviewed the various detection methods of Sudan red colorants in foods and compared the minimum detection limits of various methods including the Micro LC-ESI-Q-TOF-MS detection method， and it is concluded that TOF-MS technology has higher sensitivity and resolution. In addition， Soltzberg et al.[18] used MALDI-TOF-MS to identify different types of pigments and dyes， while Djelal et al.[19] used TOF-MS technique to analyze oxidation intermediates of illegally added dyes in foods. Pesticide residues
In the process of crop cultivation， in order to reduce its pests and diseases， relevant pesticides can be used scientifically， but the use of prohibited pesticides or abuse of pesticides has resulted from the lack of strict management of pesticide use in China， which makes the level of pesticide residues in primary agricultural products or pre-packaged foods made from primary agricultural products too high and become a potential food safety hazard. Jiang et al.[20] established a GC×GC-TOF-MS method for the determination of 64 pesticide residues in vegetables. Using this method to detect samples in the market， it was found that two samples contained acephate and cypermethrin residues， the determined values of which were 0.036 and 0.107 mg/kg， respectively. Zhao et al.[21] established a rapid screening method combining QuEChERS with LC-Q-TOF/MS for 281 pesticide residues in apples， tomatoes， and cabbage， the detection limits of which were 0.03-4.47， 0.01-4.49 and 0.02-3.61 μg/kg， respectively. Lacina et al.[22] used ultra high performance liquid chromatography-time-of-flight mass spectrometry （UPLC-TOF-MS） technique combined with QuEChERS pretreatment method to establish a screening method for 212 pesticide residues in plant foods. At a resolution of 10 000 FWHM， more than 96% of the target pesticides were detected in the sample by UPLC-TOF-MS. Ferrer et al.[23] used LC-TOF-MS to analyze 101 pesticides when setting the mass window width to 0.05 Da. They obtained the accurate masses of 101 pesticides in green peppers， and performed accurate screening and confirmation.
Veterinary drug residues
Zhang et al.[24] established a method for the analysis of 19 antibiotics in dairy products using UPLC-Q-TOF-MS combined with a database. The retention time deviation was less than 0.1 min， the mass deviation was less than 5 mDa， and the isotopic peak shape matching degree was not less than 87.4%. Meng et al.[25] established a new method for rapid screening of 8 fluoroquinolones， 5 sulfonamides， and 4 acetylated metabolites in dairy products using UPLC-Q-TOF-MS combined technique. The quantification limits of fluoroquinolones and sulfonamides were 0.5-0.8 and 0.5-13.0 μg/kg， respectively， and the relative standard deviations of the average recoveries were less than 15%. Paschoal et al.[26] also established an analytical method for the detection of such six quinolone drugs as flumequine， oxolinic acid， sarafloxacin， dalfloxacin， enrofloxacin and ciprofloxacin in tilapia using LC-ESI-Q-TOF-MS. Hermo et al.[27] compared the detection sensitivity of LC-TOF-MS， LC-MS and LC-MS/MS to seven quinolones in pig liver. The results showed that the LC-MS/MS method had a limit of quantitation between 0.5 and 1.0 μg/kg， the LC-TOF-MS method has a limit of quantification between 1.5 and 6.0 μg/kg， and the LC-MS has a limit of quantification between 2.0 and 6.0 μg/kg. Mycotoxins
Zhang et al.[10] established an LC-IT-TOF-MS screening method for 10 kinds of mycotoxins （aflatoxin B1， aflatoxin B2， aflatoxin C1， aflatoxin C2， α-zearalenol， β-zearalenol and zearal-enone） in corn liquor dregs. Through accurate mass matching and secondary characteristic fragment ion standard library search， simultaneous qualitative screening and quantitative analysis of different mycotoxins can be achieved. The LC-ESI-Q-TOF-MS method established by Sirhan et al.[29] can detect four aflatoxins in five foods （barley， wheat， corn， peanut， peanut butter， etc.） that are susceptible to contamination by aflatoxin， and the minimum limit of quantification is 0.8 μg/kg. Luo et al.[30] used TOF-MS technique to analyze the structure and toxicity of aflatoxin B1 degradation products in ozone water.
Lei WANG et al. The Development of Time-of-flight Mass Spectrometry （TOF-MS） and Its Applications in Screening Food Hazard Factors
Prospects
TOF-MS， as a mass spectrometry with high resolution， accuracy and sensitivity， shows outstanding technical advantages in trace analysis of food contaminants. It is foreseeable that in the field of food safety research， TOF-MS will become a research and application hotspot in the fields of high-throughput and high-sensitivity rapid screening confirmation analysis of known multi-component trace compounds， separation analysis of complex systems， and screening analysis of unknown compounds and metabolites.
References
[1] WANG CH. Organic mass spectrometry technology and methods[M]. Beijing： China Light Industry Press， 2011： 1-6. （in Chinese）
[2] LI XJ， PENG T， LI CJ. Characteristics of chromatography-time of flight mass spectrometry and its application in food contaminant analysis[J]. Journal of Instrumental Analysis， 2012， 31（5）： 628-632.
[3] CHEN C. Study on the establishment of screening method for colorants in food based on liquid chromatography-time of flight mass spectrometry[D]. Fuzhou：Fujian Agriculture and Forestry University， 2012. （in Chinese）
[4] HE MY. Modern organic and biomass spectrometry[M]. Beijing： Peking University Press， 2006： 1-18. （in Chinese）
[5] SHENG LS， TANG J. Application of liquid chromatography-mass spectrometry in food and drug analysis[M]. Beijing： Chemical Industry Press， 2008： 19-47. （in Chinese）
[6] GROSS JH. Mass spectrometry[M]. Berlin： Springer， 2011： 117-135.
[7] WANG X， WANG SJ， CAI ZW. The latest developments and applications of mass spectrometry in food-safety and quality analysis[J]. Trends in Analytical Chemistry， 2013， （52）： 170-185. [8] ZHAO YS， YANG ML， ZHANG F. Screening of 29 prohibited and restricted synthetic pigments in cheese using liquid chromatography/quadrupole-time of flight mass spectrometry[J]. Chinese Journal of Chromatography， 2011， 29（7）： 631-636. （in Chinese）
[9] WANG M， GUO DH， DING ZP， et al. Determination of 14 heterocyclic aromatic amines in meat products by liquid chromatography-iron trap-time of flight tandem mass spectrometry[J]. Journal of Instrumental Analysis， 2011， 30（12）： 1377-1381. （in Chinese）
[10] DASGUPTA S， BANERJEE K， PATIL SH， et al. Optimization of two-dimensional gas chromatography time-of-flight massspectrometry for separation and estimation of the residues of 160 pesticides and 25 persistent organic pollutants in grape and wine[J]. Journal of Chromatography A， 2010， 1217（24）： 3881-3889.
[11] HAINES TD， ADLAF KJ， PIERCEALL RM， et al. Direct determination of MCPD fatty acid esters and glycidyl fatty acid esters in vegetable oils by LC-TOF-MS[J]. Journal of the American Oil Chemists Society， 2011， 88（1）： 1-14.
[12] HA J， SEO D， SHIN D. Determination of elaidic and vaccenic acids in foods using GC×GC-TOF-MS[J]. Talanta， 2011， 85（1）： 252-258.
[13] LU L， GONG X， FENG YL. Fast screening and identification of 36 illegally added weight-loss， lipid-lowering， cathartic drugs in health products by UPLC-IT/TOF-MS[J]. Central South Pharmacy， 2019， 10（17）： 1667-1676. （in Chinese）
[14] HAO HY， JI FENG， YAO JT， et al. Qualitative detection of rhodamine B in poultry meat by ion hydrazine time of flight tandem mass spectrometry[J]. China Food， 2011（12）： 72-73. （in Chinese）
[15] CHEN Q， HUANG JR， LING Y， et al. Fast qualitative analysis of 32 preservatives and antioxidants in food sample by comprehensive two dimensional gas chromatography coupled time of flight mass spectrometry[J]. Chinese Journal of Analytical Chemistry， 2011， 39（5）： 723-727. （in Chinese）
[16] CALBIANI F， CARERI M， ELVIRI L， et al. Accurate mass measurements for the confirmation of Sudan azo-dyes in hot chilli products by capillary liquid chromatography-electrospray tandem quadrupole orthogonal-acceleration time of flight mass spectrometry[J]. Journal of Chromatography A， 2004， 1058（1-2）： 127-135.
[17] REBANE R， LEITO I， YURCHENKO S， et al. A review of analytical techniques for determination of Sudan I-IV dyes in food matrixes[J]. Journal of Chromatography A， 2010， 1217（17）： 2747-2757.
[18] SOLTZBERG LJ， HAGAR A， KRIDARATIKORN S. MALDI-TOF mass spectrometric identification of dyes and pigments[J]. Journal A merican Society of Mass Spectrometry， 2007， 18（11）： 2001-2006. [19] DIELAL H， CORNEE C， TARTIVEL R， et al. The use of HPLC and direct analysis in real time-of flight mass spectrometry （DART-TOF-MS） for rapid analysis of degradation by oxidation and sonication of an azo dye[J]. Arabian Journal of Chemistry， 2013， 6（2）： 21-31.
[20] JIANG J， LI PW， XIE LH， et al. Rapid screening and simultaneous confirmation of 64 pesticide residues in vegetable using solid phase extraction-comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometer[J]. Chinese Journal of Analytical Chemistry， 2011， 39（1）： 72-76. （in Chinese）
[21] ZHAO ZY， SHI ZH， KANG J， et al. Rapid screening and confirmation of 281 pesticide residues in apples， tomatos and cabbages by liquid chromatography/quadrupole time-of-flight mass spectrometry[J]. Chinese Journal of Chromatography， 2013， 31（4）： 372-379. （in Chinese）
[22] CERVERA MI， PORTOLES T， PITARCH E. Application of gas chromatography time-of-flight mass spectrometry for target and non-target analysis of pesticide residues in fruits and vegetables[J]. Journal of Chromatography A， 2012， 1244： 168-177.
[23] FERRER I， THURMAN EM. Multi-residue method for the analysis of 101 pesticides and their degradates in food and water samples by liquid chromatography/time-of-flight mass spectrometry [J]. Journal of Chromatography A， 2007， 1175（1）： 24-37.
[24] ZHANG J， YAN LJ， PAN CS， et al. Simultaneous analysis of 19 antibiotics in dairy products using ultra-performance liquid chromatography coupled with high resolution time-of-flight mass spectrometry[J]. Chinese Journal of Chromatography， 2012， 30（10）： 1031-1036. （in Chinese）
[25] MENG Z， SHI ZH， LYU YK， et al. Screening of sulfonamides and fluoroquinolones in dairy products by ultra performance liquid chromatography-high-resolution quadrupole time-of-flight mass spectrometry[J]. Chinese Journal of Analytical Chemistry， 2014， 42（10）： 1493-1500. （in Chinese）
[26] PASCHOAL J A， REYES FG. Quantitation and identity confirmation of residues of quinolones in tilapia fillets by LC-ESI-Q-TOF-MS [J]. Anal Bioanal Chem. 2009， 394（8）： 2213-2221.
[27] HERMO MP， BARRON D， BARBOSA J. Determination of multiresidue quinolones regulated by the European union in pig liver samples： high-resolution time-of-flight mass spectrometry versus tandem mass spectrometry detection[J]. Journal of Chromatography A， 2008， 1201（1）： 1-14.
[28] ZHANG F， WANG ML， DAI JY， et al. Rapid screening and confirmation of 10 mycotoxins in corn liquor dregs by QuEChERS clean up coupled with liquid chromatography-ion trap-time of flight tandem mass spectrometry[J]. Jiangsu Agricultural Sciences， 2017， 45（20）： 202-205. （in Chinese）
[29] SIRHAN AY， TAN GH， WONG RCS. Determination of aflatoxins in food using liquid chromatography coupled with electrospray ionization quadrupole time of flight mass spectrometry （LC-ESI-Q-TOF-MS/MS） [J]. Food Control， 2013， 31（1）： 35-44.
[30] LUO XH， WANG R， WANG L， et al. Structure elucidation and toxicity analyses of the degradation products of aflatoxin B1 by aqueous ozone[J]. Food Control， 2013， 31（2）： 331-336.
Key words Time-of-flight mass spectrometry; Food; Hazard factor; Screening; Application
Food contaminants and their residues such as pesticide residues， veterinary drug residues， illegal additives and organic pollutants which are generated during food production or from food packaging materials pose a serious threat to food quality and safety. The complexity of food matrices and the variety of food contaminants also place higher requirements on food inspection technologies.
High-resolution time-of-flight mass spectrometry （TOF-MS） has the characteristics of wide mass range， high resolution and mass accuracy and fast analysis speed[1]. Unlike low-resolution mass spectrometry， TOF-MS can obtain the exact mass and possible chemical formula of a compound through a full scan， which greatly improves the anti-interference ability under complex backgrounds and makes the detection results more accurate and reliable. In addition， TOF-MS has a high scanning rate. In theory， there is no upper limit on the number of targets that can be scanned at the same time. It can truly achieve high-throughput detection of hundreds of pesticides at a time. TOF-MS can also establish a database of specific compounds， and perform automatic search and analysis confirmation by software combining with the accurate mass data， retention time， isotope ratio and other information collected from the sample， thereby realizing rapid identification of target compounds without using standards[2-3]. Therefore， TOF-MS is an effective method for the qualitative analysis of trace compounds in complex samples， which can meet the needs of high-throughput rapid screening and quantitative analysis.
Principle of TOF-MS Techique
The TOF-MS mass analyzer is an ion drift tube. The ions generated by an ion source are collected by a collector first. The velocity of all ions becomes zero in the collector. The ions are accelerated by a pulsed electric field， enter the field-free drift tube and fly to an ion receiver at a constant speed. The larger the ion mass is， the longer it takes to reach the receiver; and the smaller the ion mass， the shorter the time to reach the receiver. According to this principle， ions of different masses can be separated according to the m/z value. The classic time-of-flight mass spectrometer is mainly composed of four parts： ion source， cylindrical flight tube， detector and recording system[4-6]. According to the fact that the kinetic energy for ion motion is from the acceleration voltage， we can get：
me=2Vt2s2
Wherein m/e is the mass-to-charge ratio of ions; V is the acceleration voltage， kV; t is the flight time of ions， μs; and s is the flying distance of ions， cm.
The formula shows that the ion mass-to-charge ratio is proportional to the square of time， so the mass-to-charge ratio can be obtained after measuring the flight time of ions. In the detection， the lighter ions have a higher velocity， while the heavier ions have a lower velocity. They reach the detector to produce a signal successively. Generally， the flight time of ions is on the order of microseconds.
Classification of TOF-MS
Both mass spectrometry and chromatography have their own advantages. Combining the two into a set of analysis systems can obtain the best analytical method. TOF-MS can be divided according to the connected chromatograph or spectrometer into liquid chromatography-time-of-flight mass spectrometry （LC-TOF-MS）， gas chromatography-time-of-flight mass spectrometry （GC-TOF-MS）， and full two-dimensional Gas chromatography-time-of-flight mass spectrometry （GC×GC-TOF-MS）， inductively coupled plasma-orthogonal acceleration time-of-flight mass spectrometry （ICP-oa-TOF-MS）， etc.[7]. To connect the LC and MS， the interface technique is the key. According to different interfaces and ionization techniques， TOF-MS can be mainly divided into ESI-TOF-MS composed of electrospray ionization source （ESI） and TOF-MS， APCI-TOF-MS composed of atmospheric pressure chemical ionization source （APCI） and TOF-MS， APPI-TOF-MS composed of atmospheric pressure photoionization source （APPI） and TOF-MS， and MALDI-TOF-MS consisting of matrix-assisted laser desorption ionization （MALDI） and TOF-MS. Multi-stage mass spectrometry can be achieved by tandem mass spectrometry. It is a mass spectrometry technique emerging in the late 1970s. TOF-MS can be classified according to tandem mass spectrometry mainly into Q-TOF-MS composed of quadruple MS and TOF-MS and IT-TOF-MS composed of ion trap mass spectrometry （IT） and TOF-MS.
Performance Characteristic of TOF-MS
Wide mass range
In theory， TOF-MS has no upper limit for mass analysis. Its actual analytical mass range is limited only by the slow flight speed of high-mass ions， insufficient detector response to these ions and limited data storage and memory， but still reaches 300 000 Da， which is much larger than those of quadrupole and ion trap mass spectrometry. Fast analysis
TOF-MS as a pulse-type mass analyzer has a very fast data acquisition speed， up to 4 G/s. Ultra-high-performance liquid chromatography （UPLC）， which has appeared in recent years， can make the retention time and the widths of chromatographic peaks greatly shortened after being collected to TOF， which further increases the speed of sample analysis.
High resolution
TOF-MS belongs to high-resolution mass spectrometry with a resolution of 55 000. Therefore， the molecular weight can be measured to the fourth decimal place， and the elemental composition can be directly analyzed to calculate the molecular formula. Quadrupole and ion trap mass spectrometry belong to low-resolution mass spectrometry， with which only the integer molecular weights of compounds can be measured， and elemental composition analysis cannot be performed.
High mass accuracy
The TOF-MS full-scan detection method has an ion mass accuracy that is more than 100 times higher than that of general mass spectrometry， and the accuracy of accurate mass determination can reach 5 ppm or even lower， while quadrupole and other mass spectrometry are limited to half the mass due to the limitation of the accuracy of the instrument.
High sensitivity
The TOF-MS detector can simultaneously detect ions in the full mass range， and the use of quadrupole focusing ensures the maximum ion transmission rate and greatly improves its sensitivity. The sensitivity under selected ion scanning is lower than that of quadrupole and other mass spectrometry， but the sensitivity under full mass scanning is much higher than that of quadrupole and other mass spectrometry.
Application of TOF-MS in Screening of Food Hazard Factors
Food additives
Food additives are various compounds allowed by the state to be used in foods to improve food quality. The amount of food additives used in Chinese food must strictly comply with the provisions of GB2760-2014 "the National Food Safety Standard： Standards for Food Additive Use"， but the abuse of food additives is still one of the important factors affecting food quality and safety at present. Therefore， it is particularly important to quickly screen and confirm the existence of abuse of additives in food. Chen[3] established a screening method based on LC-TOF-MS for a variety of illegally added colorants and food colorants that are prone to abuse and established a corresponding screening database. The HPLC-Q/TOF-MS method established by Zhao et al.[8] showed a wide screening range and good applicability to foods containing protein， fat and other substrates when screening 29 kinds of illegally added and restricted synthetic pigments in cheese. For food additives commonly used in GB 2760-2014， liquid chromatography or gas chromatography can meet the daily testing requirements for their standard use. When testing or screening certain types of food additives， mass spectrometry such as TOF-MS techniques having the advantages of fast speed， wide screening range and high sensitivity can be used. Food contaminants
Wang et al.[9] established an LC-IT-TOF-MS method for simultaneous determination of 14 heterocyclic amine residues in meat products， and based on this method， developed a method for simultaneous determination of 14 heterocyclic amines in wine. Both methods have a short analysis time and allow rapid screening of heterocyclic amines during food safety testing. Dasgupta et al.[10] established a GC×GC-TOF-MS analysis method for the detection of persistent environmental pollutants such as 12 polychlorinated biphenyls， 12 polycyclic aromatic hydrocarbons， and bisphenol A in grapes and wines. With the GC×GC-TOF-MS analysis method， the detection objects can be well separated， reducing the possibility of false negative results at low residual concentrations. Edible oils and fats may produce organic pollutants such as 3-chloro-1，2-propanediol esters and glycidyl esters during the refining process. Generally， indirect methods are used to detect these two kinds of pollutants， but inconsistent test results are likely to be produced. Haines et al.[11] established an LC-TOF-MS method that can directly detect 3-chloro-1，2-propanediol esters and glycidyl esters in edible fats and oils， and its high resolution can greatly reduce the interference of impurities， thereby improving the detection sensitivity of contaminants in edible fats. Ha et al.[12] established a GC×GC-TOF-MS method for the detection of two trans-oleic acids （18： 1trans-11 and 18： 1trans-9） in meat products and partial hydrogenated edible oils. The GC×GC-TOF-MS method can completely separate the chromatographic peaks of the two trans-fatty acids， so as to obtain the ratio between the two， which is used to judge the source of the trans-fatty acids.
Illegal additives
Lu et al.[13] built a database of 36 illegally added weight-reducing， lipid-lowering and laxative drugs in health foods based on UPLC-IT-TOF-MS， and established a rapid screening and confirmation method， which shortens the time for locking target objects in health food safety inspection and improves inspection efficiency. Hao et al.[14] used IT-TOF-MS to detect the illegal additive rhodamine B in poultry meat and performed multi-stage mass spectrometry analysis. Chen et al.[15] established a method for the analysis of 13 illegal additives in food by using GC×GC-TOF-MS， and quickly and efficiently separated 32 compounds by using GC×GC within 20.5 min， thereby solving the technical difficulty that one-dimensional gas chromatography cannot separate 9 of these compounds from matrix interference components when reducing the detection limit of the method by more than 10 times. Calbiani et al.[16] established a Micro LC-Q-TOF-MS method for the precise detection of four kinds of Sudan red colorants in foods， while Rebane et al.[17] reviewed the various detection methods of Sudan red colorants in foods and compared the minimum detection limits of various methods including the Micro LC-ESI-Q-TOF-MS detection method， and it is concluded that TOF-MS technology has higher sensitivity and resolution. In addition， Soltzberg et al.[18] used MALDI-TOF-MS to identify different types of pigments and dyes， while Djelal et al.[19] used TOF-MS technique to analyze oxidation intermediates of illegally added dyes in foods. Pesticide residues
In the process of crop cultivation， in order to reduce its pests and diseases， relevant pesticides can be used scientifically， but the use of prohibited pesticides or abuse of pesticides has resulted from the lack of strict management of pesticide use in China， which makes the level of pesticide residues in primary agricultural products or pre-packaged foods made from primary agricultural products too high and become a potential food safety hazard. Jiang et al.[20] established a GC×GC-TOF-MS method for the determination of 64 pesticide residues in vegetables. Using this method to detect samples in the market， it was found that two samples contained acephate and cypermethrin residues， the determined values of which were 0.036 and 0.107 mg/kg， respectively. Zhao et al.[21] established a rapid screening method combining QuEChERS with LC-Q-TOF/MS for 281 pesticide residues in apples， tomatoes， and cabbage， the detection limits of which were 0.03-4.47， 0.01-4.49 and 0.02-3.61 μg/kg， respectively. Lacina et al.[22] used ultra high performance liquid chromatography-time-of-flight mass spectrometry （UPLC-TOF-MS） technique combined with QuEChERS pretreatment method to establish a screening method for 212 pesticide residues in plant foods. At a resolution of 10 000 FWHM， more than 96% of the target pesticides were detected in the sample by UPLC-TOF-MS. Ferrer et al.[23] used LC-TOF-MS to analyze 101 pesticides when setting the mass window width to 0.05 Da. They obtained the accurate masses of 101 pesticides in green peppers， and performed accurate screening and confirmation.
Veterinary drug residues
Zhang et al.[24] established a method for the analysis of 19 antibiotics in dairy products using UPLC-Q-TOF-MS combined with a database. The retention time deviation was less than 0.1 min， the mass deviation was less than 5 mDa， and the isotopic peak shape matching degree was not less than 87.4%. Meng et al.[25] established a new method for rapid screening of 8 fluoroquinolones， 5 sulfonamides， and 4 acetylated metabolites in dairy products using UPLC-Q-TOF-MS combined technique. The quantification limits of fluoroquinolones and sulfonamides were 0.5-0.8 and 0.5-13.0 μg/kg， respectively， and the relative standard deviations of the average recoveries were less than 15%. Paschoal et al.[26] also established an analytical method for the detection of such six quinolone drugs as flumequine， oxolinic acid， sarafloxacin， dalfloxacin， enrofloxacin and ciprofloxacin in tilapia using LC-ESI-Q-TOF-MS. Hermo et al.[27] compared the detection sensitivity of LC-TOF-MS， LC-MS and LC-MS/MS to seven quinolones in pig liver. The results showed that the LC-MS/MS method had a limit of quantitation between 0.5 and 1.0 μg/kg， the LC-TOF-MS method has a limit of quantification between 1.5 and 6.0 μg/kg， and the LC-MS has a limit of quantification between 2.0 and 6.0 μg/kg. Mycotoxins
Zhang et al.[10] established an LC-IT-TOF-MS screening method for 10 kinds of mycotoxins （aflatoxin B1， aflatoxin B2， aflatoxin C1， aflatoxin C2， α-zearalenol， β-zearalenol and zearal-enone） in corn liquor dregs. Through accurate mass matching and secondary characteristic fragment ion standard library search， simultaneous qualitative screening and quantitative analysis of different mycotoxins can be achieved. The LC-ESI-Q-TOF-MS method established by Sirhan et al.[29] can detect four aflatoxins in five foods （barley， wheat， corn， peanut， peanut butter， etc.） that are susceptible to contamination by aflatoxin， and the minimum limit of quantification is 0.8 μg/kg. Luo et al.[30] used TOF-MS technique to analyze the structure and toxicity of aflatoxin B1 degradation products in ozone water.
Lei WANG et al. The Development of Time-of-flight Mass Spectrometry （TOF-MS） and Its Applications in Screening Food Hazard Factors
Prospects
TOF-MS， as a mass spectrometry with high resolution， accuracy and sensitivity， shows outstanding technical advantages in trace analysis of food contaminants. It is foreseeable that in the field of food safety research， TOF-MS will become a research and application hotspot in the fields of high-throughput and high-sensitivity rapid screening confirmation analysis of known multi-component trace compounds， separation analysis of complex systems， and screening analysis of unknown compounds and metabolites.
References
[1] WANG CH. Organic mass spectrometry technology and methods[M]. Beijing： China Light Industry Press， 2011： 1-6. （in Chinese）
[2] LI XJ， PENG T， LI CJ. Characteristics of chromatography-time of flight mass spectrometry and its application in food contaminant analysis[J]. Journal of Instrumental Analysis， 2012， 31（5）： 628-632.
[3] CHEN C. Study on the establishment of screening method for colorants in food based on liquid chromatography-time of flight mass spectrometry[D]. Fuzhou：Fujian Agriculture and Forestry University， 2012. （in Chinese）
[4] HE MY. Modern organic and biomass spectrometry[M]. Beijing： Peking University Press， 2006： 1-18. （in Chinese）
[5] SHENG LS， TANG J. Application of liquid chromatography-mass spectrometry in food and drug analysis[M]. Beijing： Chemical Industry Press， 2008： 19-47. （in Chinese）
[6] GROSS JH. Mass spectrometry[M]. Berlin： Springer， 2011： 117-135.
[7] WANG X， WANG SJ， CAI ZW. The latest developments and applications of mass spectrometry in food-safety and quality analysis[J]. Trends in Analytical Chemistry， 2013， （52）： 170-185. [8] ZHAO YS， YANG ML， ZHANG F. Screening of 29 prohibited and restricted synthetic pigments in cheese using liquid chromatography/quadrupole-time of flight mass spectrometry[J]. Chinese Journal of Chromatography， 2011， 29（7）： 631-636. （in Chinese）
[9] WANG M， GUO DH， DING ZP， et al. Determination of 14 heterocyclic aromatic amines in meat products by liquid chromatography-iron trap-time of flight tandem mass spectrometry[J]. Journal of Instrumental Analysis， 2011， 30（12）： 1377-1381. （in Chinese）
[10] DASGUPTA S， BANERJEE K， PATIL SH， et al. Optimization of two-dimensional gas chromatography time-of-flight massspectrometry for separation and estimation of the residues of 160 pesticides and 25 persistent organic pollutants in grape and wine[J]. Journal of Chromatography A， 2010， 1217（24）： 3881-3889.
[11] HAINES TD， ADLAF KJ， PIERCEALL RM， et al. Direct determination of MCPD fatty acid esters and glycidyl fatty acid esters in vegetable oils by LC-TOF-MS[J]. Journal of the American Oil Chemists Society， 2011， 88（1）： 1-14.
[12] HA J， SEO D， SHIN D. Determination of elaidic and vaccenic acids in foods using GC×GC-TOF-MS[J]. Talanta， 2011， 85（1）： 252-258.
[13] LU L， GONG X， FENG YL. Fast screening and identification of 36 illegally added weight-loss， lipid-lowering， cathartic drugs in health products by UPLC-IT/TOF-MS[J]. Central South Pharmacy， 2019， 10（17）： 1667-1676. （in Chinese）
[14] HAO HY， JI FENG， YAO JT， et al. Qualitative detection of rhodamine B in poultry meat by ion hydrazine time of flight tandem mass spectrometry[J]. China Food， 2011（12）： 72-73. （in Chinese）
[15] CHEN Q， HUANG JR， LING Y， et al. Fast qualitative analysis of 32 preservatives and antioxidants in food sample by comprehensive two dimensional gas chromatography coupled time of flight mass spectrometry[J]. Chinese Journal of Analytical Chemistry， 2011， 39（5）： 723-727. （in Chinese）
[16] CALBIANI F， CARERI M， ELVIRI L， et al. Accurate mass measurements for the confirmation of Sudan azo-dyes in hot chilli products by capillary liquid chromatography-electrospray tandem quadrupole orthogonal-acceleration time of flight mass spectrometry[J]. Journal of Chromatography A， 2004， 1058（1-2）： 127-135.
[17] REBANE R， LEITO I， YURCHENKO S， et al. A review of analytical techniques for determination of Sudan I-IV dyes in food matrixes[J]. Journal of Chromatography A， 2010， 1217（17）： 2747-2757.
[18] SOLTZBERG LJ， HAGAR A， KRIDARATIKORN S. MALDI-TOF mass spectrometric identification of dyes and pigments[J]. Journal A merican Society of Mass Spectrometry， 2007， 18（11）： 2001-2006. [19] DIELAL H， CORNEE C， TARTIVEL R， et al. The use of HPLC and direct analysis in real time-of flight mass spectrometry （DART-TOF-MS） for rapid analysis of degradation by oxidation and sonication of an azo dye[J]. Arabian Journal of Chemistry， 2013， 6（2）： 21-31.
[20] JIANG J， LI PW， XIE LH， et al. Rapid screening and simultaneous confirmation of 64 pesticide residues in vegetable using solid phase extraction-comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometer[J]. Chinese Journal of Analytical Chemistry， 2011， 39（1）： 72-76. （in Chinese）
[21] ZHAO ZY， SHI ZH， KANG J， et al. Rapid screening and confirmation of 281 pesticide residues in apples， tomatos and cabbages by liquid chromatography/quadrupole time-of-flight mass spectrometry[J]. Chinese Journal of Chromatography， 2013， 31（4）： 372-379. （in Chinese）
[22] CERVERA MI， PORTOLES T， PITARCH E. Application of gas chromatography time-of-flight mass spectrometry for target and non-target analysis of pesticide residues in fruits and vegetables[J]. Journal of Chromatography A， 2012， 1244： 168-177.
[23] FERRER I， THURMAN EM. Multi-residue method for the analysis of 101 pesticides and their degradates in food and water samples by liquid chromatography/time-of-flight mass spectrometry [J]. Journal of Chromatography A， 2007， 1175（1）： 24-37.
[24] ZHANG J， YAN LJ， PAN CS， et al. Simultaneous analysis of 19 antibiotics in dairy products using ultra-performance liquid chromatography coupled with high resolution time-of-flight mass spectrometry[J]. Chinese Journal of Chromatography， 2012， 30（10）： 1031-1036. （in Chinese）
[25] MENG Z， SHI ZH， LYU YK， et al. Screening of sulfonamides and fluoroquinolones in dairy products by ultra performance liquid chromatography-high-resolution quadrupole time-of-flight mass spectrometry[J]. Chinese Journal of Analytical Chemistry， 2014， 42（10）： 1493-1500. （in Chinese）
[26] PASCHOAL J A， REYES FG. Quantitation and identity confirmation of residues of quinolones in tilapia fillets by LC-ESI-Q-TOF-MS [J]. Anal Bioanal Chem. 2009， 394（8）： 2213-2221.
[27] HERMO MP， BARRON D， BARBOSA J. Determination of multiresidue quinolones regulated by the European union in pig liver samples： high-resolution time-of-flight mass spectrometry versus tandem mass spectrometry detection[J]. Journal of Chromatography A， 2008， 1201（1）： 1-14.
[28] ZHANG F， WANG ML， DAI JY， et al. Rapid screening and confirmation of 10 mycotoxins in corn liquor dregs by QuEChERS clean up coupled with liquid chromatography-ion trap-time of flight tandem mass spectrometry[J]. Jiangsu Agricultural Sciences， 2017， 45（20）： 202-205. （in Chinese）
[29] SIRHAN AY， TAN GH， WONG RCS. Determination of aflatoxins in food using liquid chromatography coupled with electrospray ionization quadrupole time of flight mass spectrometry （LC-ESI-Q-TOF-MS/MS） [J]. Food Control， 2013， 31（1）： 35-44.
[30] LUO XH， WANG R， WANG L， et al. Structure elucidation and toxicity analyses of the degradation products of aflatoxin B1 by aqueous ozone[J]. Food Control， 2013， 31（2）： 331-336.