Naoki Sugiyama

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: 

Articles

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

Since the launch of the first commercial triple-quadrupole ICP-MS (ICP-MS/MS) instrument in 2012, the technique has become well established in both research and academic institutes, as well as in industrial and commercial laboratories. Users in routine applications wish to benefit from the improved interference removal performance of ICP-MS/MS, without facing the more complex method development inherent in the use of ion-molecule reaction chemistry. In this article, we follow method setup and optimization steps to illustrate how an ICP-MS/MS method can be defined and tested to ensure consistent performance.

	Single-quadrupole inductively coupled plasma–mass spectrometry (ICP-MS) provides performance that meets the needs of most inorganic (metals) analysis laboratories, and exceeds the method requirements for many. The technique offers a unique combination of fast multielement analysis, good elemental coverage, very low detection limits, and the ability to measure major and trace elements in a single acquisition. The development of collision-reaction cells (CRCs) operating in helium collision mode addressed many of the polyatomic interferences that previously hampered accurate analysis of several critical trace elements (1). However, helium mode cannot resolve interferences such as isobaric and doubly charged overlaps. Also, some combinations of analyte and interference require more effective attenuation of the overlap than can be achieved using collision mode and kinetic energy discrimination (KED). For these cases, ion-molecule reaction chemistry using a reactive cell gas may offer a better solution.

	Reactive cell gas methods have been investigated since CRCs were first developed for single-quadrupole ICP-MS in the late 1990s (2). Early work presented the benefits of reaction chemistry for historically problematic analytes that suffer intense spectral overlap (such as selenium, arsenic, iron, calcium, and so on). However, these early applications were often based on the theoretical efficiency of the reaction chemistry to resolve one specific interference, and were illustrated using simple, consistent samples or synthetic solutions. Often, when these methods were applied to more complex and variable natural samples, it became apparent that the reaction processes could be adversely affected by other components in the sample (3,4). An unexpected matrix element or co-existing analyte could react with the cell gas, forming unwanted overlaps on the analyte ion (or product ion). Consequently, a reaction gas method developed for one sample matrix or interference might give erroneous results for a different sample type or combination of analytes.

	The development of triple quadrupole ICP-MS (ICP-MS/MS) in 2012 offered a solution to the inaccurate results observed when using reactive cell gases on single quadrupole instruments (5). ICP-MS/MS has an additional quadrupole mass filter (Q1) before the CRC, in a tandem mass spectrometer (MS/MS) configuration. When Q1 is operated as a true mass filter (1 u mass window), it controls the ions passed to the cell, rejecting all nontarget masses. This means the reaction processes and product ions formed are predictable and consistent, and are unaffected by other analytes or matrix elements in the sample (6).

	In addition to improving data quality, the control of reaction chemistry provided by ICP-MS/MS means that method settings can be applied consistently, even for variable samples. This makes reaction mode method setup easier than on a single quadrupole instrument or a configuration with a bandpass filter (mass window >1 u) before the cell. In this article, we illustrate the information and tools available for ICP-MS/MS to support development and performance testing of a new reaction mode method.

	Reference Methods for Reactive Cell Gas Operation with ICP-MS/MS

	Since the first commercial ICP-MS/MS instrument was released in 2012, many applications have been developed, optimized, and published. In addition to manufacturers' application notes (7), many hundreds of peer-reviewed journal articles detail method settings for both typical and unusual applications.

	The ICP-MS/MS instrument's built-in methods can predefine the typical cell gas mode, analyte and product ion masses, and integration times for common analytes. Where an analyte does not have an established setting predefined in a preset method, the user can easily set up one or more mass pairs for the chosen reaction gas. The choice of reaction gas used to resolve a specific interference can be informed by the literature. Theoretical ion-molecule reaction thermodynamics show which reactions are favored (8,9), while ICP-MS/MS manufacturer's publications show experimental results for various product ion formation rates. Hydrogen (H

) are among the most widely-used reaction gases. For each gas, several common reaction transitions are defined in the literature, and have been confirmed experimentally (10).

	With oxygen cell gas, for example, analytes may be measured on mass (Q2 is set to the same mass as Q1) or mass shifted as the oxide ion (Q2 is set to Q1 + 16 u) or dioxide ion (Q2 is set to Q1 + 32 u). These mass shift transitions, together with equivalent transitions for other reaction gases, are available as preset values in the method setup software, allowing easy selection of the preferred mass shift. Multiple mass shifts can be selected if the user wants to compare results for several product ions or cell gases, and custom mass shifts can be defined, if appropriate.

cell gas, reactions are usually fast and are often sequential, so multiple cluster ions can form from both the analyte ions and any other ions present in the cell. Typical reactions and product ions formed with NH

 cell gas are shown in Table I. MS/MS mode controls the precursor ions that can enter the cell and react, so product ions can only form from ions at the mass of the target analyte ion. However, optimized methods must still be verified to confirm that the chosen reaction product ion is free from overlap by product ions from other sample components present at the same mass as the analyte precursor ion.

	Product ion scanning, which is unique to MS/MS, is a useful method development tool for unfamiliar sample types and unusual combinations of analyte interferences. This mode enables users to check and verify the best product ion(s) to use by identifying product ions that are free from overlap in a given sample type or matrix. This is particularly useful for complex and variable sample matrices, and for the large number of product ions produced when a highly reactive cell gas such as NH

	In a product ion scan, Q1 is set to the mass of the target analyte isotope, and Q2 is scanned across the mass range where useful product ions could appear. It is essential that Q1 is operated at 1 u resolution, so only ions at the target analyte isotope mass enter the cell. A product ion scan is acquired while aspirating a single-element standard of the target analyte, allowing product ions formed from the analyte isotope alone to be identified. A second product ion scan is then acquired while aspirating the unknown sample or synthetic matrix to identify product ions formed from other (nontarget) precursor ions at the target analyte mass. By comparing the spectra from the two scans, analyte product ions that are free from overlap by matrix product ions can easily be identified (11).

	An Agilent 8900 ICP-MS/MS instrument (model #100, Advanced Applications configuration) was used for all measurements. The instrument was fitted with the standard glass concentric nebulizer, quartz spray chamber, quartz torch with 2.5 mm injector, and standard nickel sampling and skimmer cones. Samples were introduced via a peristaltic pump with 1.02-mm i.d. pump tubing. Operating conditions are shown in Table II.

	The hafnium standard was prepared from a single element stock solution, and the rare earth matrix was prepared from a mixed 14-element stock standard (Agilent Technologies). Ultrapure water was prepared in the laboratory using a Milli-Q Element system, and nitric and hydrochloric acids used for sample stabilization were Ultrapure NORMATOM grade (VWR Chemicals).

	Hf and mixed rare earth elements (REE) standards were prepared at 10 ppb and 1 ppm, respectively, in a final diluent of 2% HNO

 and 1% HCl. A spike solution of 10 ppb Hf in 1 ppm REE mix was also prepared.

Choosing Reaction Gas Modes to Resolve Known Interferences

	Theoretical ion-molecule reaction rates can be used to identify potential approaches to resolve a given interference, based on differences in the reactions for the analyte and interfering ion. Figure 1 shows the reactions of all elemental ions with ammonia cell gas (10), displayed in a color-coded periodic table layout. To illustrate how this information can be used, the different reactions of Hg

 are highlighted in the table. Mercury (a Type 3 element) reacts with NH

 cell gas via a charge-transfer reaction leading to the neutralization of the Hg

 ion. In contrast, Pb (a Type 1 element) does not react with NH

, so it can be measured on mass. The difference in reactions of Hg and Pb ions indicates that NH

 could be a suitable cell gas to resolve the 


	Figure 1: Reaction pathways and rates for all analyte ions with NH

 cell gas derived from reference 10. Hg and Pb are highlighted, showing how reaction data can be used to identify the potential to resolve the isobaric overlap from 

	In the case of hafnium analysis in a rare earth element matrix, the reaction data presented in Figure 1 suggests that NH

 cell gas might be able to resolve the Yb and Lu overlaps on Hf. The 

Hf isotope is the preferred isotope for quantitative analysis, but 

Hf is required for some applications such as Hf/Lu and Hf/Hf isotope geochronology. The 

Hf isotope could be considered the worst case in terms of interferences in sample matrices that contain REEs. As well as direct isobaric interferences from 

Dy. Figure 2 shows that Hf (a Type 2b element) reacts with NH

 cell gas, whereas Yb (a Type 1 element) does not. Hafnium will therefore form Hf-NH

 product ions that cannot be overlapped by corresponding NH

 may be a suitable cell gas to resolve Yb and Lu overlaps on Hf (refer to Figure 1 for key to color-coding of NH

	The same principle does not necessarily apply to resolving the 

Hf. Lu is a Type 2a element, so it does react with NH

, and may form product ions that can overlap the Hf-NH

product ions. Also, ion-molecule reaction data does not give specific information about the potential for a given cell gas to resolve polyatomic overlaps, such as the 

Hf. The solution to confirming the suitability of a given reaction gas to resolve such interferences is to verify the performance experimentally by using a product ion scan.

 Product Ions in REE Matrix Using Product Ion Scanning 

	For analytes, interferences, and sample types that are not defined in preset methods or available from reference publications, product ion scanning can identify the best product ion(s) for the application. Product ion spectra were acquired for a 10 ppb Hf standard and a 1 ppm 14-element REE mix. An overlay of the two product ion spectra covering the mass range from 

 175 to 265 is shown in Figure 3. The spectrum comparison facilitates identification of product ions formed from 

 176 precursor ions in the Hf standard but not the REE mix. The most intense interference-free 

 258. This Hf product ion is free from any REE-based overlap-that is, no overlapping NH

 product ions are formed from Lu and GdO/DyO precursor ions present at 

 product ions formed from m/z 176 in Hf standard (gray) and REE mix (pink), showing overlapped and interference-free Hf-NH

	In this example, the REE-based overlaps being investigated were known in advance, so a synthetic standard solution could be prepared, ensuring the creation of the interfering REE-NH

 product ions. For complex sample matrices, which might give rise to unknown product ions, the product ion scan can be performed for a real sample matrix. In this way, potential overlaps from all sample components can be checked and accounted for during method development.

Controlling Product Ion Formation with MS/MS vs. Single Quadrupole or Bandpass

	Product ion scanning-and the MS/MS methods developed using it - rely on Q1 operating at unit mass resolution (1 u mass window). The necessity for this is illustrated in Figure 4, where normal Agilent 8900 MS/MS operation is compared to deliberately "detuned" operation where Q1 has been set to pass a 3 u mass range. This simulates ICP-MS operation with a bandpass filter rather than a unit mass filter before the cell.

 product ions in the mass range around the preferred 

Hf product ion at m/z 258. In (a) MS-MS mode, 

 is free from any REE product ion overlap. (b) In simulated 3 u bandpass mode, 

	The top spectrum in Figure 4 shows the mass range from 

250 to 270 extracted from the full mass product ion spectra in MS/MS mode shown in Figure 3. This includes the preferred, interference-free 

 258. The lower spectrum shows the same mass range for the same product ion scans for the 10 ppb Hf and 1 ppm REE solutions, acquired with 3 u bandpass mode. With a bandpass filter before the cell, adjacent precursor ions are not rejected, so they enter the cell and react. In this example, with Q1 passing a 3 u range of masses around the set mass, 

Lu can enter the cell when the precursor ion mass is set to 

	The example of interferences on Hf product ions in a REE matrix illustrates a general limitation of incomplete rejection of adjacent masses before the cell when using highly reactive cell gases. Any nontarget ions that enter the cell may react to form overlapping product ions, giving errors on the target analyte product ion mass.

	Triple-quadrupole ICP-MS is often perceived as being more complicated and difficult to setup than single-quadrupole ICP-MS. However, the main benefit of the MS/MS tandem mass spectrometer configuration is the superior control it offers with reactive cell gas methods for interference removal. For these reaction gas methods, the ability of MS/MS to select the specific mass that is passed to the cell provides much greater control of the reaction chemistry. Rejecting nontarget, off-mass elements and isotopes using Q1 means these ions cannot enter the cell and affect the reaction processes. As a result, reaction gas methods on ICP-MS/MS are more consistent, more reliable, less matrix dependent, and therefore easier to setup than on single quadrupole ICP-MS.

	(3) L.J. Moens, F.F. Vanhaecke, D.R. Bandura, V.I. Baranov, and S.D. Tanner, 

	(4) F. Vanhaecke, L. Balcaen, I. Deconinck, I. De Schrijver, C. Marisa Almeida, and L. Moens, 

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

	(6) N. Sugiyama, "The accurate measurement of selenium in twelve diverse reference materials using on-line isotope dilution with the 8800 Triple Quadrupole ICP-MS in MS/MS mode" (Agilent publication 5991-0259EN, 2012).

(7) Handbook of ICP-QQQ Applications using the Agilent 8800 and 8900, 

	(9) V.V. Lavrov, V. Blagojevic, G.K. Koyanagi, G. Orlova, and D. K. Bohme, 

	(10) N. Sugiyama and K. Nakano, "Reaction data for 70 elements using O

gases with the Agilent 8800 Triple Quadrupole ICP-MS" (Agilent publication 5991-4585EN, 2014).

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

 are with Agilent Technologies in Stockport, United Kingdom. 

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

Method setup and optimization steps are explored to illustrate how an ICP-MS/MS method can be defined and tested to ensure consistent performance. Users can benefit from improved interference removal performance without the complex method development inherent in the use of ion-molecule reaction chemistry

Naoki Sugiyama

Articles

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

Method Development with ICP-MS/MS: Tools and Techniques to Ensure Accurate Results in Reaction Mode

Direct Analysis of Undiluted Seawater by ICP-MS Using a Novel High Matrix Introduction System