Ed McCurdy

Inductively coupled plasma mass spectrometry (ICP-MS) instruments can perform low-level elemental analysis in a wide range of sample types, from high-purity chemicals to high matrix digests. But achieving consistently low detection limits requires good control of elemental contamination, as well as spectral interferences. A clean working area, careful selection of reagents, and good sample handling techniques are key to successful trace and ultratrace elemental analysis. In this article, we provide five practical tips for controlling contaminants and minimizing detection limits.

Inductively coupled plasma-mass spectrometry (ICP-MS) instruments offer high sensitivity and low random background, which enables the technique to provide ng/L (ppt) level trace element analysis. But routinely achieving low detection limits requires more than just a sensitive instrument. In industries such as semiconductor manufacturing, experienced analysts develop working practices that minimize the potential for contamination to affect results. The following practical suggestions can be implemented in any laboratory, and will help ensure data quality is not compromised by contamination that could have easily been prevented.

Consider Whether the Laboratory Environment is Suitable for Your Analysis

Analytical laboratories doing trace element analysis in industries such as environmental monitoring, food safety, pharmaceutical manufacturing, and clinical research do not need a special clean laboratory environment to achieve the method detection limits (DLs). But even a normal trace element laboratory should be designed and constructed in a way that minimizes sources of elemental contamination.

In the semiconductor manufacturing and process chemical industries, trace elements are routinely measured at ppt and sub-ppt levels, so laboratories in these industries often install a dedicated cleanroom. Cleanrooms are classified according to the number of particles of various sizes between 0.1 and 5 microns per unit volume of laboratory air. For example, an International Organization for Standardization (ISO) Class 3 laboratory (equivalent to the earlier US Federal Standard 209E [FS209E] Class 1) can contain a maximum of 8 particles of 1 micron and 1000 particles of 0.1 micron per cubic meter of air. An ISO Class 7 laboratory (FS209E Class 10,000) may contain up to 83,200 particles of 1 micron per cubic meter.

However, ISO Class 1 to 4 cleanrooms are expensive to build and maintain, and only retain their rated classification through strict control of access and working practices. A lower cost alternative is to install the ICP-MS in a small Class 10 enclosure located inside a Class 10,000 laboratory or normal trace element laboratory. Another option is to place just the autosampler in a clean enclosure, such as a high efficiency particulate air (HEPA) filtered laminar flow hood. Preparation of samples and standards can also be performed in a similar hood to avoid contamination of vials and solutions while they are open on the bench.

Limit Sources of Particulate Contamination

In a typical laboratory, one of the most problematic sources of sample contamination is airborne particulate material. Consider where contamination may come from and try to eliminate particulate sources from the laboratory.

Common sources of particles in the laboratory include air conditioning units (especially those with overhead vents), corroded bare metal surfaces, printers and personal computers (PCs), and recirculating water chillers, particularly where a fan is used in an air-cooled heat exchanger. Contamination can also arise from dirt and dust brought into the laboratory on people’s shoes, clothing, and personal belongings. Simple steps can remove or reduce the contribution from these sources; for example, by placing the water recirculator in an adjacent service room, or printing to a remote device in a neighboring office. Sticky mats by entrance doors can significantly reduce the amount of dust brought into the laboratory on people’s shoes.

Using appropriate materials during laboratory-based activities can also help to reduce contamination. Gloves are routinely used for safety reasons when handling potentially corrosive acids, and powder free nitrile gloves will help minimize particle contamination.

With a little thought and attention to the way laboratory services, equipment, and personnel are managed, particulate contamination in the laboratory can be minimized without the high costs of installing and operating a dedicated cleanroom.

Avoid Glass! Use Plastic Labware to Minimize Elemental Backgrounds

The following recommendations are appropriate for laboratories that analyze typical ICP-MS sample types prepared and stabilized in dilute acid solutions. If other solvents are used, the details of the cleaning and rinsing protocols will need to be adjusted as appropriate.

Sample vials, pipette tips, and other labware that comes into contact with the sample solution can be a significant source of contamination. Acidic solutions should not be prepared or stored in glassware, even if it has been precleaned, as the acid will extract metal contaminants from the glass. Alkaline solvents such as ammonium hydroxide and tetramethylammonium hydroxide (TMAH) will also extract metals from glass containers. Plastic labware is much cleaner than glass, but brands that contain pigments made with metal additives should be avoided where possible. Clear plasticware made of materials such as polypropylene (PP), low density polyethylene (LDPE), polyethylene terephthalate (PET), or fluoropolymers (PTFE, FEP and PFA) are recommended for the best chemical resistance and lowest levels of contamination. New labware should be acid rinsed to remove surface contamination and manufacturing residues prior to use.

Polypropylene sample vials and centrifuge tubes (15 mL or 50 mL) from brands such as DigiTUBE, Corning, or Nalgene are inexpensive, largely free from metal contamination and are Class A graduated so can be used for volumetric sample preparation. Many laboratories prepare standards and do sample dilution by weight. Conical base DigiTUBEs are available with a skirt to allow them to stand upright on the balance or bench, without needing to be held in an autosampler rack.

Implement Effective Procedures for Cleaning, Storage, and Use of Labware

If the laboratory’s workflow and sample throughput allow, it is good practice to soak sample vials and tubes before use in a covered, clear plastic tank containing ultrapure water (UPW) or dilute acid (for example 0.1% HNO3), as shown in Figure 1. These plastic containers can be purchased at relatively low cost from a normal hardware store. This sort of precleaning approach will help remove manufacturing residues such as mold release agents, which can contain metals, including Al and Zn. More aggressive cleaning may be required to achieve the lowest background levels for ultratrace analysis. Vials and containers should be rinsed three times in UPW prior to use.

Figure 1: Clear plastic containers of various sizes used for cleaning and storage of sample tubes and other consumables.

The same sort of precleaning approach can also be used for soaking pipette tips before use, although clear tips supplied in a covered container will be dust free and do not usually require precleaning except for when ultralow level analysis is required. The rinse baths should not become significantly contaminated, and can usually be used for a year or more before the UPW or acid needs to be changed.

Similar clear plastic storage containers can be used to clean and store ICP-MS sample introduction components, ideally with separate containers for different components, such as standard and inert kits (Figure 2). Sample introduction parts such as the quartz spray chamber and torch can be soaked in an acid bath, then dried before use. Interface cones can be sonicated in UPW or a dilute laboratory cleaning agent such as Citranox, then dried and stored in a sealed container. For very contaminated cones, a fine abrasive polishing powder and a pointed Q-tip can be used, followed by sonication in UPW.

Figure 2: ICP-MS sample introduction components are cleaned and stored in separate containers for different kits, for example standard quartz and PFA inert kit components.

Use Reagents of Appropriate Quality for the Analysis

Good quality deionized water (18 MΩ.cm) is essential to maintain the low background levels required for trace level analysis, particularly for common contaminants such as Na, Al, and Fe. The elements B and Si are more difficult for ion exchange systems to remove, so pay particular attention to the background levels for these elements. An increase in B or Si backgrounds may indicate that the ion exchange cartridge of your ultrapure water system needs to be replaced.

The quality of reagents such as acids should be appropriate for the levels of trace elements being measured but, in general, using better quality acids will reduce the time you have to spend dealing with errors due to contamination. A viable alternative to high purity acids is to purchase reagent grade acids and purify them in the laboratory using sub-boiling distillation.

When using concentrated high purity acids to prepare samples, calibration standards, and quality control standards (QCS), a small volume of acid should be decanted into a micro beaker or the acid bottle lid before pipetting into the sample or standard vials. This will help avoid contaminating the acid in the bottle.

Once empty, the perfluoroalkoxy alkanes (PFA) bottles that high purity acids are supplied in can be rinsed and dried and will then be excellent metal-free containers for subsequent use. These bottles can be used to prepare and store diluents, and can even be used for low-level standard addition analysis with the spikes being added directly into the sample in the reused acid bottle.

These practical tips from experienced ICP-MS analysts have been demonstrated to reduce errors due to contamination. By implementing a few simple procedures and ensuring reagents and consumables are suitable for the intended analysis, ICP-MS users can minimize the possibility of data quality being compromised by trace element contamination.

Bert Woods and Ed McCurdy are with Agilent Technologies, Inc. Direct correspondence to: 

Articles

Inductively coupled plasma mass spectrometry (ICP-MS) instruments can perform low-level elemental analysis in a wide range of sample types, from high-purity chemicals to high matrix digests. But achieving consistently low detection limits requires good control of elemental contamination, as well as spectral interferences. A clean working area, careful selection of reagents, and good sample handling techniques are key to successful trace and ultratrace elemental analysis. In this article, we provide five practical tips for controlling contaminants and minimizing detection limits. 

ICP-MS: Key Steps to Control Contamination and  Achieve Low Detection Limits

Inductively coupled plasma–tandem mass spectrometry (ICP-MS/MS) is a relatively new technique, with the first triple quadrupole ICP-MS (ICP-QQQ) being introduced commercially in 2012. However, the technique has quickly been accepted for a wide variety of applications in industries including, but not limited to, manufacturing, contract analysis, government, research, and academia. In this article, we explain the key steps to setting up an ICP-MS/MS method and address some of the common misconceptions surrounding the technique.

Compared to conventional single quadrupole inductively coupled plasma–mass spectrometry (ICP-MS), the main benefits of ICP-MS/MS include:

the unprecedented ability to resolve spectral interferences using controlled reaction chemistry in the collision reaction cell (CRC);

significantly better separation of adjacent mass, “peak tail” overlaps because of two mass filtering steps; and

improved detection limits through higher sensitivity and lower backgrounds.

The flexibility of ICP-MS/MS has led some people to assume that method development must be more difficult on ICP-MS/MS than on single quadrupole ICP-MS. However, existing single quadrupole methods can usually be transferred to ICP-MS/MS without significant modifications. Also, reaction gas methods run more consistently on ICP-MS/MS, so methods are more universal and operation is simpler.

The following six steps help guide method setup for ICP-MS/MS (Figure 1):

FIGURE 1: Method development steps for ICP-MS/MS.

When developing an ICP-MS/MS method, users may focus on a specific interference that needs to be resolved. However, the starting point for method development on ICP-MS/MS—as with conventional ICP-MS—should consider the wider analytical needs. These needs include several factors that can be easily overlooked.

First, can the instrument handle the sample matrix? Matrix tolerance is important for many ICP-MS applications. Optimizing the plasma to give low CeO

 (<1.5%) ensures that the instrument will easily tolerate typical sample matrix levels. Low CeO/Ce indicates better matrix decomposition, which reduces deposits on the interface and leads to better stability and less maintenance. Low CeO/Ce conditions also increase analyte ionization, improving sensitivity for poorly ionized elements, such as beryllium, arsenic, cadmium, and mercury. Low CeO/Ce indicates better decomposition of molecular species that would otherwise form polyatomic ion overlaps (1).

Second, is the sample composition unknown or variable? The major element levels and sample-to-sample variability can be important factors. Variable sample matrices can give rise to unexpected polyatomic ion overlaps, which a given reaction gas mode may not resolve effectively. In such cases, helium (He) collision mode may provide a simpler, more universal, and more reliable solution (2,3).

Third, which analytes must be measured and at what level? Most ICP-MS applications can be run successfully using He collision mode, but lower analyte levels may require a reaction gas method to further reduce backgrounds and improve detection limits. Similarly, analysis of high-level major elements may require custom tuning or sample dilution if the detector cannot measure the full concentration range.

Finally, how many samples will be analyzed? Many parameters affect analysis speed for large sample batches. ICP-MS/MS systems are compatible with discrete sampling devices to shorten sample analysis times. However, the number of cell gases used—and the time required to switch between cell modes—will also impact throughput.

Step #2: Identify Critical Method Needs—Why is ICP-MS/MS Needed?

Once the basic analytical requirements have been addressed, specific, critical aspects of the analysis should be considered. This stage usually focuses on the most difficult sample types, unusual analytes, or extremely low (or high) concentration levels. In the context of ICP-MS/MS method development, this step should identify analytes that are affected by spectral overlaps.

Step #3: Apply the Simplest Approach to Address Interferences 

ICP-MS/MS offers performance benefits because of the additional quadrupole, Q1, before the CRC, which controls reaction processes in the cell. Reaction gas modes can give extremely effective interference reduction, useful for ultralow level analysis in high purity reagents. However, reaction gas methods may be specific for each overlap being resolved, so multielement methods may require several sets of cell conditions. These conditions may not always be applicable to other sample types.

As mentioned above, many ICP-MS interferences can be addressed using He collision mode. Most spectral overlaps in ICP-MS are caused by polyatomic (molecular) ions. For example, 

 75. Helium mode uses kinetic energy discrimination (KED) to reduce the transmission of polyatomic ions relative to the monatomic analyte ions they overlap (4). As a result, He mode supports multi-element analysis and allows access to secondary (confirmatory) isotopes for many elements, while also practically eliminating the need for unreliable mathematical correction equations.

The major appeal of He mode is that the same cell conditions can be used for multiple analytes across a range of sample types, so method setup is simple and consistent. He mode is the default mode for single quadrupole ICP-MS methods, and can be used in the same way on ICP-MS/MS. Using He mode for most analytes makes it much simpler to develop methods for the remaining analytes that need a reaction gas approach.

Step #4: Identify Analytes or Overlaps that Cannot Be Addressed Using He Mode

Many users employ ICP-MS/MS precisely because their application cannot be performed successfully using single quadrupole ICP-MS, even with well optimized He mode. Usually, the requirements relate to specific spectral interferences or adjacent mass overlaps that can only be resolved using a reaction gas or double mass selection (MS/MS).

ICP-MS/MS can use reaction gas modes to reduce intense spectral overlaps, such as 

S, allowing these previously difficult elements to be measured at a low level. Reaction gas modes can also reduce matrix-based overlaps to lower levels, enabling ultratrace level analysis.

He mode cannot resolve isobaric overlaps, such as 

Pb, and so on. In typical, routine ICP-MS analysis, these overlaps are avoided by measuring an alternative mass (

Pb, in the examples above). However, measurement of the overlapped isotope is required for some applications and provides performance benefits, such as higher sensitivity, in others. In these cases, a reaction gas mode may be able to resolve the overlap.

Doubly charged ion interferences form when an atom loses two electrons in the plasma and forms a doubly charged (M

) ion. A quadrupole mass filter separates ions based on mass to charge ratio (

 ions appear at half their true mass. Most elements form insignificant levels of M

 ions, but some, such as the rare earth elements (REEs), do form a small percentage of M

. Single quadrupole ICP-MS can correct for normal levels of M

 overlap, but this approach is not effective at high levels of interference. For analyses such as trace arsenic and selenium in REE minerals, a reaction gas method is more effective.

Peak tail overlaps affect trace analytes measured next to intense major element peaks. An example is trace manganese (

 55) analysis in an iron or steel matrix (the major isotopes of iron are at 

 54 and 56). Peak tail overlaps are resolved using the double mass selection of MS/MS, as the abundance sensitivity (AS) of a tandem MS is the product of the AS of the two mass filters, so Q1 AS x Q2 AS in the case of ICP-QQQ.

Step #5: Select the Preferred Reaction Gas Mode

For overlaps that cannot be addressed using He mode, an appropriate reaction gas mode is selected, which is not as daunting as new users often assume, because ICP-MS/MS ion–molecule reaction chemistry is well understood and documented. Applications can often be run using the predefined method settings provided with the instrument software. Manufacturers’ application notes (5) and users’ publications (6) document proven methods for many more applications.

ICP-MS/MS users also benefit from unique method development tools, including product ion and precursor ion scans. These are useful for identifying suitable analyte product ions and potential matrix-based product ion overlaps (7).

Step #6: Ensure Control of Cell-Formed Reaction Product Ions 

When reaction gases are used in ICP-MS, new product ions can be formed in the CRC. The creation of potentially interfering product ions is a major downside of reaction gases compared to helium KED mode, but control of product ion formation is a key benefit of a tandem MS configuration. The Q1 mass filter, before the CRC, ensures that only ions at the target mass—that is, the analyte and any on-mass interferences—enter the CRC.

Q1 therefore prevents the formation of product ions from analytes or matrix elements present at other masses. However, product ions can still be created from the reaction gas itself. For example, when 

 is measured in organic matrices, Q1 is set to 

 product ions could react further with the NH

The sequential reactions that form the NH

 product ions can be prevented using either mass discrimination or ion energy discrimination, depending on the ICP-MS/MS cell configuration and operating conditions. The energy discrimination approach is effective because product ions created from the cell gas only have the kinetic energy they derive from the collision. These low-energy product ions have insufficient energy to pass through the gas-filled cell, so they do not appear in the mass spectrum (Figure 2).

FIGURE 2: (a) Overlaid ICP-MS/MS spectra (blank and 1 ppb chromium (Cr) in 1% methanol). (b) Calibration plot for 

Cr. Background <1 ppt confirms cell-formed NH

 52) are removed using energy discrimination.

(2) N. Yamada, J. Takahashi, and K. Sakata, 

(4) E. McCurdy, N. Sugiyama, and S.M. Wilbur, 

(5) “Handbook of ICP-QQQ Applications” (Agilent Technologies, publication 5991–2802EN, 2020).

(6) Agilent ICP-QQQ bibliography https://www.agilent.com/en/promotions/8900icp-qqq-trust.

(7) E. McCurdy, G. Woods, and N. Sugiyama, 

 are with Agilent Technologies Inc. Direct correspondence to: 

Method development for ICP-MS/MS should not be difficult. The six steps here will guide you to success.

Key Steps in Method Development for Inductively Coupled Plasma–Tandem Mass Spectrometry (ICP-MS/MS)

Sulfur (S) is one of a small group of elements that have historically been difficult to analyze at low levels using conventional inductively coupled plasma–mass spectrometry (ICP-MS). Accurate low-level analysis of sulfur is required in applications in life science, clinical research, pharmaceutical development, food safety, environmental monitoring, geochemistry, and petrochemistry. ICP-MS analysis of sulfur is problematic because of the element’s high first ionization potential, which reduces sensitivity. Also, intense polyatomic interferences affect all the isotopes of sulfur. Background levels are also often high, due to the presence of S in many components used in laboratory equipment. ICP-MS fitted with a collision/reaction cell can use oxygen (O

) 48, avoiding the on-mass interferences at 

 32. However, mass 48 can also be affected by interference from 

, as well as from overlapping product ions such as 

. Also, applications such as isotope ratio measurements and isotope dilution mass spectrometry (IDMS) require the accurate determination of a minor isotope, 

S. We describe how tandem mass spectrometry (MS/MS) controls the O

 reaction gas chemistry to resolve multiple spectral overlaps on all the sulfur isotopes. Combined with appropriate selection of instrument components to reduce the sulfur background, MS/MS can provide accurate low-level analysis of sulfur and sulfur isotope ratios in aqueous and organic matrices.

Inductively coupled plasma–mass spectrometry (ICP-MS) is widely used for multielement analysis of trace analytes in a wide variety of sample types. A few elements, including sulfur (S), are difficult to measure using conventional (single)
quadrupole ICP-MS.

Applications that require low level sulfur analysis include petrochemical analysis (1,2), the study of biomolecules (such as proteins) in life science research (3,4), detection of sulfur compounds in foods (5), and development of sulfur-based pharmaceuticals (6,7). Accurate determination of sulfur at low concentrations is affected by several factors:

1.Sulfur has a high first ionization energy (or ionization potential) of 10.36 electron volts (eV), meaning it is only around 10% ionized in a normal ICP plasma. This translates into 10x lower sensitivity than for a fully ionized element.

S, 95.04% abundance) suffers intense background overlap from polyatomic ions including 

, making trace analysis impossible by conventional quadrupole ICP-MS.

S, accounts for only 4.2% of total sulfur, meaning a further reduction in sensitivity by a factor of more than 20. This isotope also suffers from intense background interferences, as does the final potentially useful isotope, 

S (0.75% abundance). The fourth naturally occurring isotope, 

S, is only 0.015% abundant, and is overlapped by a minor isotope of argon. The most significant background polyatomic ions that overlap the isotopes of sulfur are shown in Table I.

4.Sulfur is present in many laboratory reagents and components, causing background contamination.

The commercial development of collision–reaction cells (CRCs) for ICP-MS in 1997 (8) provided analysts with a novel approach to controlling interferences, solving many of the problematic spectral overlaps that had hampered ICP-MS analysis (9,10). However, a small number of analytes, including sulfur, remained difficult to determine at low concentrations.

Approaches to improve the detection of sulfur have included the use of xenon (Xe) cell gas to reduce the intensity of the 

 interference by collisional dissociation and charge transfer (11), and sector field high resolution ICP-MS to mass resolve the O

 (4), However, the use of xenon cell gas does not give low enough detection limits for trace sulfur analysis, and sector field ICP-MS suffers from poor abundance sensitivity (peak tailing), which compromises the separation of the trace 

S+ peak from the much more intense neighboring 

) cell gas can be used in the CRC of a single quadrupole ICP-MS instrument to promote the formation of SO

 cell gas, so S+ can be mass-shifted away from the original O

 product ion masses are overlapped by existing ions, including 

. This approach is therefore not suitable for samples that might contain these other interfering elements, such as high Ca mineral waters and other environmental materials, or organic-based samples in petrochemical and life sciences applications (13).

Analysis of sulfur isotope abundance is of interest in several applications in environmental science, geochemistry, and hydrogeology. Such analysis requires interferences to be resolved on at least one of the minor isotopes of sulfur, 

S isotope. Minor isotopes must also be measured accurately to quantify sulfur using isotope dilution. CRC methods using O

 cell gas with single quadrupole ICP-MS (with or without a bandpass cell) cannot control the formation of interisotope overlaps such as 

, so accurate isotope ratio and isotope dilution analysis that requires analysis of 

S is impossible. Potential matrix-based and interisotope overlaps on the SO

 product ion masses are shown in Table II.

The development of triple quadrupole ICP-MS (ICP-QQQ) in 2012 (14) offered a way to address the limitations of reaction mode methods on single quadrupole and bandpass ICP-MS. ICP-QQQ uses an additional quadrupole mass filter (Q1) before the CRC, allowing tandem mass spectrometry (MS/MS) operation. In MS/MS, Q1 functions as a 1 u mass filter to select the specific mass that is passed to the cell. This excludes any ions that might be present at the mass where analyte product ions would appear (15). As each analyte precursor mass is passed to the CRC while excluding all other masses, ICP-MS/MS also resolves interisotope overlaps so accurate isotope ratio and isotope dilution analysis is straightforward. We investigate the potential interferences on sulfur from several common matrix elements and demonstrate ICP-MS/MS conditions that resolve the interferences on the sulfur isotopes of interest. We compare these results with operating the ICP instrument without MS/MS (Q1 >1 u mass window), and show examples of applications where complete resolution of the interferences is needed.

Measurements were performed using an Agilent 8900 ICP-QQQ (model #100, Advanced Applications configuration). The instrument was fitted with the standard glass concentric nebulizer, quartz spray chamber, quartz torch with 2.5 mm injector, and nickel sampling and skimmer cones. The instrument model used includes an inert, low contamination argon gas flow path, which reduces levels of sulfur (and silicon) in the gas supplied to the plasma torch. The effectiveness of this inert gas flow path is illustrated by the low ng/L (ppt) detection limit that can be achieved for sulfur in high purity semiconductor reagents (16). Samples were introduced via a peristaltic pump with 1.02 mm i.d. pump tubing. Operating conditions are shown in Table III.

Sulfur standards and matrix element solutions were prepared from single element stock standards (Agilent Technologies). Sulfur isotope standards were prepared from sulfur isotope CRMs IAEA-S-1, S-2, and S-3 (National Institute of Standards and Technology [NIST]). Ultrapure water was prepared in the laboratory using a Milli-Q Element system, and acids used for sample stabilization and matrix preparation were Ultra pure Normatom grade (VWR Chemicals).

Comparing MS/MS and Single Quad Mode for Analysis of Sas SO+

The mass-shift approach to resolve interferences has been described extensively (17). To assess the ability of MS/MS to resolve matrix interferences on the sulfur isotopes, mass spectra were acquired covering the region where the S16O+ product ions would appear (

). The same acquisition was performed in MS/MS mode and “single quad” mode, where Q1 is operated as a simple ion guide (no mass filtering). A 10 μg/L (ppb) S standard and separate solutions containing potentially interfering matrix elements Ca, Ti, and C were measured. The overlaid spectra (sulfur standard and matrix solutions) are shown for both modes in Figure 1.

The good isotope template fit and freedom from matrix overlaps for sulfur in MS/MS mode contrasts markedly with the severe overlaps apparent in “single quad” mode. The difference is due to the inability of the single quadrupole to reject the existing Ca

 product ions are measured. In MS/MS, these interfering ions are all rejected by Q1, which is set to pass only the mass of the respective precursor S

Controlling Product Ion Formation with Q1 in MS/MS Mode

With O-atom addition reactions, the large (16 u) mass difference between the precursor and product ion masses means any existing ions at the product ion masses can be rejected, even if Q1 is operated in bandpass mode (mass window > 1 u). However, existing ion overlaps are not the only potential interferences that can affect the accurate measurement of S as SO+. If the sample contains phosphorus (P), 

 48. This is illustrated in Figure 2, where a scan of a sulfur standard (25 μg/L) is shown overlaid with scans of 0.5% H

 and 0.5% HCl. The solutions were measured in MS/MS mode and with Q1 set to pass a 3 u mass window (simulating bandpass operation). In bandpass mode, the P matrix gives rise to an intense interference at 

 32, while MS/MS ensures effective resolution of the 

S+ requires Q1 to operate as a 1 u mass filter (MS/MS mode).

Sulfur Isotope Analysis in Natural Waters

The relative abundance of the stable (non-radiogenic) sulfur isotopes varies a lot in natural materials due to fractionation during redox reactions. The variation in abundances is calculated as a deviation (or delta, δ) in the abundance of the minor isotope (such as δ

S), expressed in per mil (parts per thousand, ‰). Natural materials such as groundwaters, soil, vegetation, and rocks can contain sulfur isotopes with δ

S values ranging from -40‰ to +40‰, and occasionally more (18). This variation enables researchers to study processes such as sedimentary rock formation and biogeochemical cycles. High precision sulfur isotope analysis is usually performed using an isotope ratio mass spectrometer (IRMS), such as a thermal ionization mass spectrometer (TIMS), secondary ionization mass spectrometer (SIMS), or multi-collector ICP-MS. However, the large variation in natural sulfur isotope abundances means that an ICP-MS/MS method with O

 cell gas can measure the differences in S ratios, albeit less precisely.

Determining accurate S isotope abundances by conventional ICP-MS can be affected by errors from interisotope overlaps. Where the mass that enters the CRC is not tightly controlled, multiple sulfur isotopes can react to form product ion overlaps. For example, 

 is excluded from the CRC. As with adjacent mass overlaps (such as 

), resolving inter-isotope overlaps requires Q1 to operate as a 1 u mass filter (MS/MS).

Sulfur isotopes were measured in a range of mineral water, river water, spring water, and seawater samples, using ICP-MS/MS in mass-shift mode with O

 cell gas. Sulfur isotope calibration was based on IAEA-S-1, and bracketing standards were used for mass bias correction. The results are summarized in Figure 3. Excellent δ

 = 10) was obtained. The accuracy of the method was confirmed by the measured δ

S value for NASS 5 seawater (21.5‰), which agreed well with the global average value for oceanic seawater of 21‰ (18).

Sulfur isotope analysis in geochemistry applications may require the measurement of the 

 using ICP-MS, but the large difference in abundance between 

S isotopes can cause errors in the analysis of the minor isotope. In ICP-MS/MS analysis using O

S is measured. This separation can be degraded either by poor Q1 resolution (mass window >1 u), or by poor abundance sensitivity (peak tail of 

S peak would contribute to the signal at the adjacent mass 33, affecting the 

This potential error was assessed by measuring digested sulfide minerals and calculating the mass-independent deviation in the measured abundance of the 

S). Mass independent fractionation of sulfur isotopes rarely occurs naturally, so the defect in 

S x 0.515 should equal zero, assuming equilibrium fractionation (19). A measured value of zero (within experimental error) therefore indicates no contribution from 

S. The results obtained with ICP-MS/MS are shown in Table IV, with a δ

S of -0.1 confirming no contribution from 

product ion masses provides the opportunity to determine sulfur accurately at lower levels than was previously possible by ICP-MS. By allowing only the target S

precursor ion into the CRC, MS/MS eliminates potential interferences from other reactive ions (such as 

) and from existing ions at the product ion masses (such as 

MS/MS also excludes the possibility of inter-isotope overlaps, enabling accurate sulfur isotope analysis in complex sample matrices. These measurements cannot be performed successfully using conventional single quadrupole or bandpass ICP-MS.

B. Bouyssiere, P. Leonhard, D. Profrock, F. Baco, C. L. Garcia, S. Wilbur, and A. Prange, 

J. Heilmann, S.F. Boulyga, and K.G. Heumann, 

J.G. Martinez-Sierra, F.M. Sanz, P.H. Espilez, R. Santamaria-Fernandez, J.M.M. Gayon, and J.I.G. Alonso, 

C.J. Smith, I.D. Wilson, L. Weidolf, F. Abou-Shakra, and M. Thomsen, 

P.J. Turner, T. Merren, J. Speakman, and C. Haines, G. Holland, and S.D. Tanner (eds), 

Plasma Source Mass Spectrometry: Development and Applications

. (The Royal Society of Chemistry, Cambridge, United Kingdom, 28–34,1997).

D. Pröfrock, P. Leonhard, and A. Prange, 

D.R. Bandura, V.I. Baranov, and S.D. Tanner, 

K. De Wolf, L. Balcaen, E. Van De Walle, F. Cuyckens, and F. Vanhaecke,

S.D. Fernandez, N. Sugishama, J.R. Encinar, and A. Sanz-Medel. 

L. Balcaen, G. Woods, M. Resano, and F. Vanhaecke, 

K. Nakano, Ultra-low-level determination of phosphorus, sulfur, silicon and chlorine using the Agilent 8900 ICP-QQQ (Agilent application note 5991-6852EN, 2016).

L. Balcaen, E. Bolea-Fernandez, M. Resano, and F. Vanhaecke, 

T.B. Coplen, J.K. Böhlke, P. De Bièvre, T. Ding, N.E. Holden, J.A. Hopple, H. R. Krouse, A. Lamberty, H. S. Peiser, K. Revesz, S.E. Rieder, K.J.R. Rosman, E. Roth, P.D.P. Taylor, R.D. Vocke Jr., and Y.K. Xiao, 

are withAgilent Technologies LDA (UK) Ltd, in the United Kingdom. 

is with Agilent Technologies International in Japan. Direct correspondence to: 

Combined with appropriate selection of instrument components to reduce the sulfur background, ICP-MS using MS/MS with oxygen reaction cell gas can provide accurate low-level analysis of sulfur and sulfur isotope ratios in aqueous and organic matrices. This is useful in applications in life science, clinical research, pharmaceutical development, food safety, environmental monitoring, geochemistry, and petrochemistry.

Accurate, Low-Level Sulfur Analysis by ICP-MS Using MS/MS with Oxygen Reaction Cell Gas

Collision–reaction cell methods are now almost universally accepted in quadrupole inductively coupled plasma–mass spectrometry (ICP-MS) applications. Helium collision mode provides dramatic improvements in detection limits and accuracy of quantitation for many elements by reducing the relative transmission of polyatomic ions compared to the monatomic analyte ions that they overlap. However, spectral interferences that are not caused by polyatomic ions cannot be controlled effectively using helium collision mode. One important example is isobaric overlaps, where isotopes of two different elements occur at the same mass. Reactive cell gases can provide a solution to isobaric overlaps if a gas is selected that reacts quickly with one of the isobaric elements and slowly, or not at all, with the other. This approach, termed "chemical resolution," allows the target isotope to be resolved from the overlapping isobar. To control the reaction chemistry and to ensure that only the intended product ions are measured, an additional mass selection step (before the collision/reaction cell) is essential. This is achieved using a tandem mass spectrometry system (ICP-MS/MS), such as a triple-quadrupole configuration. In this work, we present application examples where ICP-MS/MS was used to separate isobaric overlaps, allowing accurate analysis to be performed.

	The development of collision–reaction cells in inductively coupled plasma–mass spectrometry (ICP-MS) around 20 years ago transformed the ability of analysts to address spectral interferences. In practical applications, the use of helium (He) collision cell gas and kinetic energy discrimination (KED) has been particularly effective to reduce polyatomic ion overlaps (1). Helium mode has improved the accuracy of ICP-MS results for many previously problematic analytes, such as the first-row transition elements, which suffer from multiple polyatomic overlaps in common sample types.

	However, while He mode may be viewed as a near universal approach to reducing polyatomic ion interferences in ICP-MS (2), it is not at all effective for certain other spectral overlaps. He mode cannot resolve the isobaric (same mass) interferences that occur when two (or more) different elements have an isotope at the same nominal mass (for example, 

 204). These isotopes are much too close to be mass-resolved using sector-field "high-resolution" ICP-MS. The resolution (

) required to separate the Hg/Pb isobars is almost 500,000, whereas sector-field ICP-MS instruments are limited to a resolution of about 10,000 (3). Direct interelement overlaps can also occur because of peak "tailing" from an adjacent mass; for example, boron analysis in organic solvents is affected by the low-mass tail from 

	All naturally occurring elements (except indium) have at least one isotope that is free from direct overlap from an isotope of another element, so isobaric overlaps should theoretically be avoidable. But the "free" isotope is not always the most abundant, and may be severely affected by other interferences, such as matrix-based polyatomic ions. Consequently, there may be analytical benefits to measuring an alternative isotope, even one that has an isobaric overlap, if a method can be devised to avoid or remove the overlapping isotope.

	Also, some applications require the measurement of more than one isotope, for example when isotope dilution is used for quantitative analysis, or where natural variations in isotopic abundances are studied. Isotopic dating (geochronology) studies require the analysis of two or more isotopes of an element to measure the degree of isotopic fractionation or radioactive decay over time. These applications require the accurate measurement of a second isotope, and such secondary isotopes often suffer overlap from isotopes of other elements.

Isobaric Overlaps on Natural and Radiogenic Isotopes

	Methods to address some isobaric overlaps are well-established, such as the use of cool plasma (4) or a reaction gas (5) to remove the interference from the major isotope of argon (

Ar, 99.6%) on the major isotope of calcium (

Ar allows the major Ca isotope to be measured, enabling trace level analysis of Ca in semiconductor process chemicals.

	Other isobaric overlaps are less well-known, but may impact ICP-MS performance for emerging applications. One example is the increasing need to monitor elements arising from high-technology industries and manufacturing. Elements including Ga, Ge, Nb, In, Te, and Ta may be important environmental contaminants, and their behavior and potential toxicological impact are not well understood (6). These elements can be measured using ICP-MS; indeed Ge, In, and Te are commonly used as internal standards. But some of these elements are difficult to measure at low levels and, because their natural background levels in the environment are extremely low, analytical methods must be carefully optimized.

	For example, Te detection limits are degraded by its relatively poor ionization. The first ionization potential of Te is 9.01 eV, similar to other poorly ionized elements, Be, Cd, and Zn, so Te is only about 25% ionized in a normal ICP. Also, the only Te isotope that is free from isobaric overlap is 

Te, so this is the preferred Te isotope for ICP-MS measurements. But 

Te has an isotopic abundance of only 7.07%, so the sensitivity is reduced by almost a factor of five compared to the most abundant Te isotope. To measure Te at low levels in environmental samples, it would be beneficial to be able to measure the more abundant isotopes, 

Te (34.08%). However, both these isotopes suffer isobaric overlaps from Xe (a common trace contaminant in high-purity argon gas), while 

Ba, which may be present at milligram-per-kilogram (part-per-million) levels in natural environmental samples. An ICP-MS/MS method that removes the Xe and Ba isobaric overlaps would significantly improve the trace determination of Te.

	Analysis of non-natural, radiogenic isotopes of interest in the nuclear industry can also be compromised by isobaric overlaps. These elements may need to be monitored following accidental release, or from decommissioning, waste disposal, or weapons testing activities. There is increasing interest in the potential of ICP-MS as a rapid technique for measuring radiogenic isotopes with long half-lives and therefore low specific activity (7). Radiogenic isotopes are frequently overlapped by isotopes of naturally occurring elements, which may be present at much higher concentration than the radiogenic isotope of interest. Examples include 

Eu) (11). Radiometric techniques are ideal for measuring the highly radioactive isotopes (such as 

Cs) that are monitored after an accidental release. But activity-based techniques are less suitable for the lower activity levels of the long-lived radioisotopes that persist in the environment long after the initial release. For these isotopes, the ability of ICP-MS/MS to resolve isobaric overlaps may offer a superior detection capability compared to traditional radiometric approaches.

	Theoretically, the reaction chemistry used to resolve isobaric interferences should be applicable to quadrupole ICP-MS instruments with a simple collision–reaction cell, or a bandpass filter before or in the cell. However, these configurations do not possess a true (1 u) mass filter upstream of the collision–reaction cell, so are unable to selectively pass only one precursor ion mass to the cell. As a result, the reaction chemistry is nonspecific, and the product ions formed are unpredictable, and vary with the sample composition. These errors are eliminated using MS/MS mode on a triple-quadrupole ICP-MS system.

When using a triple-quadrupole ICP-MS system, the increased abundance sensitivity of MS/MS mode makes it possible to measure trace elements using isotopes that would otherwise be affected by peak tailing from an adjacent major element. This approach is illustrated using the example of ultratrace 237Np analysis in the presence of 10 ppm U.

Ed McCurdy

Articles

ICP-MS: Key Steps to Control Contamination and Achieve Low Detection Limits

Key Steps in Method Development for Inductively Coupled Plasma–Tandem Mass Spectrometry (ICP-MS/MS)

Accurate, Low-Level Sulfur Analysis by ICP-MS Using MS/MS with Oxygen Reaction Cell Gas

Using Double Mass Selection and Reaction Cell Gases to Resolve Isobaric Spectral Overlaps in ICP-MS

Supplementary Information: Accurate Measurement of Ultrafine Silica Nanoparticles Using ICP-MS/MS