Integrating ion mobility spectrometry into MS-based exposome measurements Perspective
A uthorization and Restriction of Chemicals regulation (contained, e.g., in STOFF-IDENT [71]). The lists used vary widely [54]. The final step in data analysis is nontarget screen-
ing – effectively all the remaining masses in the sample after target and suspect screening. Typically a peak picking step is performed to pick genuine peaks due to chromatographic or other separation, then a grouping step is highly recommended to find associated adduct and isotope peaks. This information provides con- fidence about the mass of the molecular ion and can help determine the molecular formula. To assist in the identification of the structure, fragmentation informa- tion is essential; identification can be performed via library searching or candidate look-up and comparison of predicted and measured fragments. Without a ref- erence standard available, these identifications can be only tentative at best. Communicating the confidence in chemical identi-
fication can be a challenge and several systems exist for small molecules, including
the metabolomics
standards initiative (MSI) [67], an LC-high resolution MS/MS specific set from Eawag [72] and many more. The essences of these are:
• Confirmed identification with two orthogonal matching properties to an authentic reference stan- dard measured in-house (MSI Level 1, Eawag Level 1).
• Probable identification with all evidence indicating only one structure is possible, but authentic stan- dard is not available for confirmation (Eawag Level 2a/b).
• Putative annotation based on physicochemical properties and spectral matching (MSI Level 2, Eawag Level 2a).
• Tentative identification/putative compound class – tentative identification using predictive techniques, multiple structures are possible, or insufficient evi- dence to eliminate other structures; substance class only is clear (MSI Level 3, Eawag Level 3).
• Unknown compounds – molecular formula is unequivocal (Eawag Level 4) or exact mass only (Eawag Level 5; both MSI Level 4). These can be traced in samples and correspond to ‘detected fea- tures’ in the analyses, but the identity remains unclear.
To date, the evidence for coupled chromatographic-
MS systems has been based on the mass spectral infor- mation (exact mass and fragments for MS/MS, EI-MS spectrum for GC-MS) plus retention time information
future science group
(either as retention time or retention indices) as the orthogonal information. However, coupled chromato- graphic systems alone are not ideally suited to high- throughput studies due to the time required per analy- sis. Later in this article, the potential for IMS and CCS to provide orthogonal identification evidence together with (or in place of) the retention time in coupled chromatographic systems is discussed.
Introducing IMS as a new tool for the exposomics toolbox Comprehensive characterization
of exposure is
extremely challenging since individuals are generally subject to thousands of structurally and physicochemi- cally diverse chemical agents per day (e.g., pharma- ceuticals, pesticides, personal care products, industrial chemicals), with various systemic responses to these. Measuring these chemicals in clinical samples is very difficult since they typically occur from picomolar to millimolar concentrations in complex matrices (Figure 2). In addition, many of these molecules trans- form, either in the environment by biotic and abiotic processes, or in vivo due to xenobiotic metabolisms, such that the original chemical is not the final form that may accumulate to detectable levels in the sam- ple of interest. Finally, the parent molecules or their transformation products may be transitory in regard to their detectability in the sample of interest, and there- fore frequent sampling will be required in order to cap- ture their presence. Comprehensive characterization of human exposure with high measurement dynamic range and with throughput sufficient for large, epide- miological studies requiring frequent sampling would transform the search for environmental causes of dis- ease and revolutionize our understanding of the role of the environment and genome in health. An appealing technique for enhancing current expo-
somic methods is the incorporation of IMS [73]. IMS allows ions to be conformationally separated based on the balance of two forces that impact ion movement, namely, the electric field and the drag force from col- lisions with buffer gas molecules. Currently there are many IMS-based platforms such as drift tube IMS (DTIMS), traveling wave IMS (TWIMS), trapped IMS [74], overtone IMS [75,76], differential IMS [77], field asymmetric IMS) [78–80] and transversal modu- lation IMS [81]. However, of these, DTIMS shows the greatest promise in small molecule measurements because it is able to directly determine molecular structural information without the external calibration approaches that are required by other IMS-based plat- forms [82]. In the following sections, we will focus the discussion on the benefits of DTIMS and how it can be used to address the challenges of exposomics.
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