Review Article| Volume 36, ISSUE 4, P635-661, December 2016

Liquid Chromatography–Tandem Mass Spectrometry

An Emerging Technology in the Toxicology Laboratory
Published:October 14, 2016DOI:


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribers receive full online access to your subscription and archive of back issues up to and including 2002.

      Content published before 2002 is available via pay-per-view purchase only.


      Subscribe to Clinics in Laboratory Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Aston F.W.
        • LIX
        The mass-spectra of chemical elements.
        The London, Edinburgh, and Dublin Philosophical Magazine and Journal of Science. 1920; 39: 611-625
        • Thomson J.J.
        The discharge of electricity through gases.
        Charles Scribner's Sons, New York1898
        • Thomson J.J.
        Rays of positive electricity and their application to chemical analysis.
        Longmans Green, London1913
        • Thomson J.J.
        On the appearance of helium and neon in vacuum tubes.
        Science. 1913; 37: 360-364
        • Nier A.O.
        Some reminiscences of mass spectrometry and the Manhattan Project.
        J Chem Educ. 1989; 66: 385-388
        • Rayward W.B.B.
        • Ellen M.
        The history and heritage of scientific and technological information systems: Proceedings of the 2002 conference.
        Information Today, Inc, Medford (NJ)2004
      1. Drew CM, Smith SR. ASTM E-14 Meeting on Mass Spectrometry. San Francisco, May 1955. p. 36.

        • Comisarow M.B.
        • Marshall A.G.
        Fourier transform ion cyclotron resonance spectroscopy.
        Chem Phys Lett. 1974; 25: 282-283
        • Blakley C.R.
        • Carmody J.J.
        • Vestal M.L.
        Liquid chromatograph-mass spectrometer for analysis of nonvolatile samples.
        Anal Chem. 1980; 52: 1636-1641
        • Carroll D.I.
        • Dzidic I.
        • Stillwell R.N.
        • et al.
        Subpicogram detection system for gas phase analysis based upon atmospheric pressure ionization (API) mass spectrometry.
        Anal Chem. 1974; 46: 706-710
        • Yamashita M.
        • Fenn J.B.
        Electrospray ion source. Another variation on the free-jet theme.
        J Phys Chem. 1984; 88: 4451-4459
        • Yost R.A.
        • Enke C.G.
        Selected ion fragmentation with a tandem quadrupole mass spectrometer.
        J Am Chem Soc. 1978; 100: 2274-2275
        • Millington D.S.
        • Kodo N.
        • Norwood D.L.
        • et al.
        Tandem mass spectrometry: a new method for acylcarnitine profiling with potential for neonatal screening for inborn errors of metabolism.
        J Inherit Metab Dis. 1990; 13: 321-324
        • Budzikiewicz H.
        • Schaefer M.
        Mass spectrometry: an introduction.
        6th edition. Wiley-VCH, Weinheim, Germany2012
        • Zeleny J.
        Instability of electrified liquid surfaces.
        Phys Rev. 1917; 10: 1-7
        • Carroll D.I.
        • Dzidic I.
        • Stillwell R.N.
        • et al.
        Atmospheric pressure ionization mass spectrometry. Corona discharge ion source for use in a liquid chromatograph-mass spectrometer-computer analytical system.
        Anal Chem. 1975; 47: 2369-2372
      2. Short LC, SS, Syage JA. APPI: the second source for LC-MS. 2008. Available at: Accessed March 24, 2016.

        • Hanold K.A.
        • Fischer S.M.
        • Cormia P.H.
        • et al.
        Atmospheric pressure photoionization. 1. General properties for LC/MS.
        Anal Chem. 2004; 76: 2842-2851
        • Grebe S.K.
        • Singh R.J.
        LC-MS/MS in the clinical laboratory—where to from here?.
        Clin Biochem Rev. 2011; 32: 5-31
        • Ahmadzai H.
        • Huang S.
        • Hettiarachchi R.
        • et al.
        Exhaled breath condensate: a comprehensive update.
        Clin Chem Lab Med. 2013; 51: 1343-1361
        • Josko D.
        Updates in immunoassays: introduction.
        Clin Lab Sci. 2012; 25: 170-172
        • Ouchterlony O.
        Handbook of immunodiffusion and immunoelectrophoresis. With appendices by three other authorities, and an equipment section.
        Ann Arbor Science Publishers, Ann Arbor (MI)1968
        • Yalow R.S.
        • Berson S.A.
        Immunoassay of endogenous plasma insulin in man.
        J Clin Invest. 1960; 39: 1157-1175
        • McPherson R.
        Henry's clinical diagnosis and management by laboratory methods.
        Elsevier, St. Louis (MO)2011
        • McClatchey K.D.
        Clinical laboratory medicine.
        Lippincott Wiliams & Wilkins, Philadelphia2002
        • George S.
        Position of immunological techniques in screening in clinical toxicology.
        Clin Chem Lab Med. 2004; 42: 1288-1309
        • George S.
        • Braithwaite R.A.
        Use of on-site testing for drugs of abuse.
        Clin Chem. 2002; 48: 1639-1646
      3. Abuelzein E, Institute for New T. Trends in Immunolabelled and Related Techniques. 2012. Available at: Accessed April 20, 2016.

        • Chung H.S.
        • Lee S.T.
        • Lee S.Y.
        Evaluation of Viva-E drug testing system.
        Korean J Lab Med. 2007; 27 ([in Korean]): 330-337
        • Wu A.H.
        • French D.
        Implementation of liquid chromatography/mass spectrometry into the clinical laboratory.
        Clin Chim Acta. 2013; 420: 4-10
        • Kricka L.J.
        Human anti-animal antibody interferences in immunological assays.
        Clin Chem. 1999; 45: 942-956
        • Leung K.S.
        • Fong B.M.
        LC-MS/MS in the routine clinical laboratory: has its time come?.
        Anal Bioanal Chem. 2014; 406: 2289-2301
        • Horie H.
        • Kidowaki T.
        • Koyama Y.
        • et al.
        Specificity assessment of immunoassay kits for determination of urinary free cortisol concentrations.
        Clin Chim Acta. 2007; 378: 66-70
        • Taieb J.
        • Benattar C.
        • Birr A.S.
        • et al.
        Limitations of steroid determination by direct immunoassay.
        Clin Chem. 2002; 48: 583-585
        • Simonick T.F.
        • Watts V.W.
        Preliminary evaluation of the Abbott TDx for screening of D-methamphetamine in whole blood specimens.
        J Anal Toxicol. 1992; 16: 115-118
        • Bertholf R.L.
        Gas chromatography and mass spectrometry in clinical chemistry. Encyclopedia of analytical chemistry.
        John Wiley & Sons, Ltd, Hoboken (NJ)2006
        • James A.T.
        • Martin A.J.
        Gas-liquid chromatography: the separation and identification of the methyl esters of saturated and unsaturated acids from formic acid to n-octadecanoic acid.
        Biochem J. 1956; 63: 144-152
        • Maurer H.H.
        Systematic toxicological analysis of drugs and their metabolites by gas chromatography-mass spectrometry.
        J Chromatogr. 1992; 580: 3-41
        • Maurer H.H.
        Systematic toxicological analysis procedures for acidic drugs and/or metabolites relevant to clinical and forensic toxicology and/or doping control.
        J Chromatogr B Biomed Sci Appl. 1999; 733: 3-25
        • Kraemer T.
        • Theis G.A.
        • Weber A.A.
        • et al.
        Studies on the metabolism and toxicological detection of the amphetamine-like anorectic fenproporex in human urine by gas chromatography-mass spectrometry and fluorescence polarization immunoassay.
        J Chromatogr B Biomed Sci Appl. 2000; 738: 107-118
        • Maurer H.H.
        Role of gas chromatography-mass spectrometry with negative ion chemical ionization in clinical and forensic toxicology, doping control, and biomonitoring.
        Ther Drug Monit. 2002; 24: 247-254
        • Fitzgerald R.L.
        • Rexin D.A.
        • Herold D.A.
        Benzodiazepine analysis by negative chemical ionization gas chromatography/mass spectrometry.
        J Anal Toxicol. 1993; 17: 342-347
        • Maurer H.H.
        Position of chromatographic techniques in screening for detection of drugs or poisons in clinical and forensic toxicology and/or doping control.
        Clin Chem Lab Med. 2004; 42: 1310-1324
        • Schutz H.
        • Gotta J.C.
        • Erdmann F.
        • et al.
        Simultaneous screening and detection of drugs in small blood samples and bloodstains.
        Forensic Sci Int. 2002; 126: 191-196
        • Weinmann W.
        • Renz M.
        • Vogt S.
        • et al.
        Automated solid-phase extraction and two-step derivatisation for simultaneous analysis of basic illicit drugs in serum by GC/MS.
        Int J Legal Med. 2000; 113: 229-235
        • Polettini A.
        • Groppi A.
        • Vignali C.
        • et al.
        Fully-automated systematic toxicological analysis of drugs, poisons, and metabolites in whole blood, urine, and plasma by gas chromatography-full scan mass spectrometry.
        J Chromatogr B Biomed Sci Appl. 1998; 713: 265-279
        • Lacassie E.
        • Dreyfuss M.F.
        • Gaulier J.M.
        • et al.
        Multiresidue determination method for organophosphorus pesticides in serum and whole blood by gas chromatography-mass-selective detection.
        J Chromatogr B Biomed Sci Appl. 2001; 759: 109-116
        • Lacassie E.
        • Marquet P.
        • Gaulier J.M.
        • et al.
        Sensitive and specific multiresidue methods for the determination of pesticides of various classes in clinical and forensic toxicology.
        Forensic Sci Int. 2001; 121: 116-125
        • Maurer H.
        • Pfleger K.
        • Weber A.
        Mass spectral and GC data of drugs, poisons, and their metabolites.
        3rd edition. Wiley-VCH, Deerfield Beach (FL)1985
        • Mills S.
        • Torrance N.
        • Smith B.H.
        Identification and management of chronic pain in primary care: a review.
        Curr Psychiatry Rep. 2016; 18: 22
        • Nahin R.L.
        Estimates of pain prevalence and severity in adults: United States, 2012.
        J Pain. 2015; 16: 769-780
        • Dubois M.Y.
        • Follett K.A.
        Pain medicine: the case for an independent medical specialty and training programs.
        Acad Med. 2014; 89: 863-868
        • Gaskin D.J.
        • Richard P.
        The economic costs of pain in the United States.
        J Pain. 2012; 13: 715-724
        • Mitchell P.B.
        Therapeutic drug monitoring of psychotropic medications.
        Br J Clin Pharmacol. 2001; 52: 45S-54S
        • Mitchell P.B.
        Therapeutic drug monitoring of psychotropic medications.
        Br J Clin Pharmacol. 2000; 49: 303-312
        • Annesley T.
        • Diamandis E.
        • Bachmann L.
        • et al.
        A spectrum of views on clinical mass spectrometry.
        Clin Chem. 2016; 62: 30-36
        • Grund B.
        • Marvin L.
        • Rochat B.
        Quantitative performance of a quadrupole-orbitrap-MS in targeted LC–MS determinations of small molecules.
        J Pharm Biomed Anal. 2016; 124: 48-56
        • Fedorova G.
        • Randak T.
        • Lindberg R.H.
        • et al.
        Comparison of the quantitative performance of a Q-Exactive high-resolution mass spectrometer with that of a triple quadrupole tandem mass spectrometer for the analysis of illicit drugs in wastewater.
        Rapid Commun Mass Spectrom. 2013; 27: 1751-1762
        • Kadar H.
        • Veyrand B.
        • Antignac J.P.
        • et al.
        Comparative study of low- versus high-resolution liquid chromatography-mass spectrometric strategies for measuring perfluorinated contaminants in fish.
        Food Addit Contam Part A. 2011; 28: 1261-1273
        • Morin L.-P.
        • Mess J.-N.
        • Garofolo F.
        Large-molecule quantification: sensitivity and selectivity head-to-head comparison of triple quadrupole with Q-TOF.
        Bioanalysis. 2013; 5: 1181-1193
        • Ferreira C.R.
        • Yannell K.E.
        • Jarmusch A.K.
        • et al.
        Ambient ionization mass spectrometry for point-of-care diagnostics and other clinical measurements.
        Clin Chem. 2016; 62: 99-110