Is LC-MS suitable for a comprehensive screening of drugs and poisons in clinical toxicology?

This paper reviews the different attempts made to develop efficient LC-MS techniques for systematic toxicologic analysis, or general unknown screening (GUS) of drugs and toxic compounds. Only particle beam interfaces are compatible with electron ionization, but they mainly cover the same range of compounds as GC-MS, i.e. nonpolar, thermally stable molecules. Using the more used electrospray sources, several approaches were used: tandem-mass spectrometry (MS/MS); MS/MS with data-dependent or information-dependent acquisition (DDA or IDA); and single mass spectrometry with in-source collision induced dissociation (CID). The MS/MS strategy is not really compatible with a GUS procedure, as it requires selecting a limited number of ions in the first step, before fragmenting them. DDA or IDA are auto-adaptive MS/MS product-ion scan modes where the m/z ratios the intensity of which is above a given threshold are selected at each unit time. Preliminary studies showed their potential for GUS, but it will probably be necessary to improve the detection of signals of toxicologic interest among background noise. This is also the case for single-MS techniques with in-source CID. Such methods have been proposed by several teams, who demonstrated their repeatability and reproducibility, at least on a same type of instrument and on an intralaboratory basis. Optimized extraction procedures are necessary to recover polar and even hydrophilic drugs, which are those supposed to be detectable by LC-ES-MS and not GC-MS, and such nonselective extraction may be responsible for high chemical noise. Chromatographic conditions and the resulting separation, resolution and signal-to-noise ratio are also probably important determinants of the efficiency of such procedures. Preliminary results using an optimized LC-ES-MS GUS technique showed that it is probably as efficient as GC-MS or HPLC-DAD for the detection of drugs and toxicants in clinical serum samples and that it is complementary to both these techniques.