Determination of Sulfur in Bio-Samples by ICP-QMS/QMS with an ORC

Yanbei Zhu^*, Yuko Kitamaki, Megumi Kato, Tomoya Kinumi, Akiharu Hioki and Koichi Chiba

National Metrology Institute of Japan, National Institute of Advanced Industrial Science and Technology, Umezono, Tsukuba, Ibaraki, Japan

*Corresponding Author:

Yanbei Zhu
National Metrology Institute of Japan
National Institute of Advanced Industrial Science and Technology
1-1-1 Umezono, Tsukuba, Ibaraki 305-8563, Japan
Tel: 81-29-861-4130
E-mail: b-zhu@aist.go.jp

Received date: July 25, 2015; Accepted date: September 29, 2015; Published date: October 05, 2015

Citation: Zhu Y, Kitamaki Y, Kato M, Kinumi T, Hioki A, et al. (2015) Determination of Sulfur in Bio-Samples by ICP-QMS/QMS with an ORC. J Anal Bioanal Tech 6:282. doi:10.4172/2155-9872.1000282

Copyright: © 2015 Zhu Y, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

A method for determination of sulfur was investigated using an inductively coupled plasma tandem quadrupole mass spectrometer (ICP-QMS/QMS) with an octopole reaction/collision cell (ORC). It helped to achieve a lower background equivalent concentration (BEC) and a lower detection limit (DL) when 10% HNO3 with 10% ethanol was applied as the rinse solution. Sulfur measurement was carried out by shifting the measured mass from 32S+ to 32S16O+ by reaction with O₂ gas. The introduction of H2 together with O₂ as reaction gases provided a lower DL. The BEC and DL of 32S were 0.83 ng g-1 and 0.03 ng g-1, respectively. The validation of the present method was confirmed by determining sulfur in certified reference materials, NIST SRMs 2773, 2298, and 2299. The results of sulfur in amino-acids and protein indicate that determination of sulfur could be an effective technique for quantification of sulfur-containing amino acids and proteins.

Keywords

ICP-QMS/QMS; Sulphur; ORC; Detection limit; Certified reference material

Introduction

Sulfur is a major target element in metallomics research [1-3]. One of the reasons might be that the sulfur content in human-body is approximately 2%, while two sulfur-containing amino acids cysteine and methionine contribute to the contents of sulfur. Sulfur has four stable isotopes, i.e., ³²S, ³³S, ³⁴S, ³⁶S [4]. Due to the high abundances of ³²S and ³⁴S, respectively ca. 95% and 4%, they are usually analysed for metallomics purpose.

Inductively coupled plasma mass spectrometry (ICP-MS) is one of the most sensitive techniques for elemental measurement due to high temperature of the ICP for ionisation, relatively simple spectra than optical analysis, and wide linearity of the detector. However, the measurement of sulfur isotopes is often challenging for ICPMS with a single quadrupole mass spectrometer (i.e., ICP-QMS) because of the polyatomic spectral interferences, especially ¹⁶O₂⁺ on ³²S⁺.

Many researchers had tried to improve the detection limits of ³²S⁺ by ICP-QMS using O₂ as the reaction cell gas [5-15] to shift ³²S⁺ to ³²S¹⁶O⁺ or Xe gas as the collision gas [15-18] to remove the interferences of ¹⁶O₂⁺. High resolution (HR-) ICPMS [6,19-25] providing a resolution over 1800 could separate the spectrum of ¹⁶O₂⁺ from that of ³²S⁺, which can be calculated from the relative atomic masses of ¹⁶O and ³²S, ca. 15.9949 and 31.9721, respectively [26]. In recent years, an alternative choice for sulfur measurement is an ICP-MS equipped with tandem quadrupole mass spectrometers (ICP-QMS/QMS) along with an octopole reaction/collision cell (ORC) [27-29]. In the measurement by ICP-QMS/QMS, the m/z of 32 was permitted to pass the first QMS and transferred to the ORC for reaction with oxygen gas, after which ³²S⁺ was shift to ³²S¹⁶O⁺ and measured by the second QMS at the m/z of 48.

To the best of the present authors’ knowledge, the best detection limits of ³²S obtained by ICP-QMS with O₂ as reaction cell gas [5] and with Xe as the collision gas [16] were 0.2 ng g^-1 and 3.2 ng g^-1, respectively. The best detection limits obtained by HR-ICP-MS without [19] and with [20] a desolvation unit were 0.6 ng g^-1 and 0.01 ng g^-1, respectively. The improvement of detection limit by using the desolvation unit could be attributed to the removal of oxygen introduction to the HR-ICP-MS, removing the tailing of ¹⁶O₂ + which resulted in a relatively high background signal of ³²S⁺ [20]. The reported detection limit [27-29] obtained by ICPQMS/ QMS was in the range of 0.33 ng g^-1 to 4.3 ng g^-1, which is comparable to the best performance obtained using other approaches but still higher than that obtained by HR-ICP-MS with using a desolvation unit. These facts might indicate that the background signals were not controlled sufficiently in the reports by ICP-QMS/QMS up to date. From the mechanism of spectral interference separation in the ICP-QMS/QMS with and ORC, the present authors speculated that the background signal of sulfur might be achieved at the same level as that obtained by HR-ICP-20MS with using a desolvation unit

In the present work, the authors tried to establish a measurement method for sulfur using ICP-QMS/QMS, where optimisation of the operation conditions was carried out to get a better detection limit (DL). For such purpose, the m/z of the first QMS was set to 32 permitting the pass of ³²S⁺ and ¹⁶O₂⁺ as the majority of the ions; H₂ was additionally used as the reaction gas along with ¹⁶O₂ to prevent the transfer of ¹⁶O₂⁺ to ¹⁶O3 + in the ORC; the m/z of the second QMS was set to 48 for measuring the signal of sulfur as ³²S¹⁶O⁺. In the present work, the precursor ions generating spectral interferences were also investigated, which may provide valuable information for ICP-QMS measurement.

The validity of the present method was confirmed by analysing three certified reference materials, NIST SRMs 2773, 2298, and 2299. The measurement of sulfur content was applied to the quantitation of two sulfur-containing amino acids, cystine and methionine, and a sulfur-containing protein.

Experimental

Instrumentation

An ICP-QMS/QMS with an ORC (Agilent 8800s, Agilent Technologies, Japan) was applied to the measurement of sulfur isotopes and the spectral interferences. The typical operating conditions are summarised in Table 1. The operating condition for each parameter was daily optimised. A microwave digestion instrument (ETHOS 1, Milestone General K.K., Kawasaki, Japan) and TFM® digestion vessels were utilised for the digestion of the certified reference material (CRM) samples. The cleaning of digestion vessels was carried out using an automatic cleaning system (TraceClean system, Milestone General K.K.) and then cleaned with the microwave irradiation whose program is identical to that used for the digestion of the samples.

Table 1: Typical operating conditions of ICP-QMS/QMS.

Chemicals and materials

An elemental standard solution of sulfur (as SO₄^2-, guaranteed by the Japan Calibration Service System, JCSS) was purchased from Kanto Chemical Co., Inc. (Tokyo, Japan). Ultrapur® grade of HNO₃ (13 mol L^-1) for digestion of the samples and making sample solutions was also purchased from Kanto Chemical Co., Inc. Pure water used throughout the present study was prepared using a Millipore purification system (Element, Nihon Millipore Kogyo, Tokyo, Japan). The validity of the present method was confirmed by analysing three CRMs, i.e., NIST SRMs 2773 (bio-diesel), 2298 (high octane gasoline), and 2299 (reformulated gasoline), issued by the National Institute of Standards and Technology (Gaithersburg, USA). The present method was applied to the analysis of three CRMs for sulfur-containing compounds, i.e., two amino acids (NMIJ CRM 6025-a, L-Cystine and NMIJ CRM 6023-a, L-Methionine) and a protein (NMIJ CRM 6202-a, human serum albumin), issued by the National Metrology Institute of Japan (Tsukuba, Japan).

Microwave acid digestion

In microwave acid digestion, 0.5 mL of the sample was taken for each sub-sample and the mass was precisely measured using an electronic balance. After that, 5 mL of Ultrapur® HNO₃ was added and subjected to the microwave irradiation process (ramp: 180°C for 30 min, hold: for 15 min; cool down: for 50 min; 200°C for 30 min, hold: for 15 min; cool down: for 50 min). After the microwave irradiation, pure water was added to each sample to achieve a 50 mL digested solution. At least two blank tests were carried out in each batch of acid digestion, where quantities of HNO₃ equivalent to the samples were added into empty digestion vessels and those were subjected to all of the operations in the acid digestion.

Results and Discussion

Cleaning of the instrument for sulfur measurement

In order to achieve a lower detection limit (DL) for sulfur measurement, the instrument background should be well-controlled. In the present experiment, the instrument was repeatedly washed by introduction of three rinse solutions in turn, i.e., pure water, 10% HNO₃, and 10% HNO₃ with 10% ethanol. The washing was repeated until the background equivalent concentration (BEC) was lower than 2 ng g^-1.

The signal intensities of sulfur obtained with different rinse solution are plotted in Figure 1, where the washing procedure was carried out in the order of “pure water washing 1→10% HNO₃ washing 1→10% HNO₃ with 10% ethanol washing 1→pure water washing 2→”.

Figure 1: Washing profiles of sulfur obtained with three different rinse solutions. (1^st QMS, m/z=32; 2nd QMS, m/z=48; reaction gas, O₂.washing 1;washing 2;washing 3;washing 13;washing 20. (a), pure water; (b), 10 % HNO₃; (c), 10 % HNO₃ with 10 % ethanol).

For each set of washing procedure, it is noted that the signal intensity of sulfur obtained by 10% HNO₃ with 10% ethanol was much lower than that by 10% HNO₃, while the later one was slightly lower than that by pure water. These facts could be attributed to the matrix effect caused by ethanol and HNO₃, respectively. It can be seen that sulfur signal intensity increased in each washing with pure water (except for washing 1) from 0s to 60s, which could be attributed to the matrix transfer from 10% HNO₃ with 10% ethanol to pure water.

In Figure 1, it is notable that the signal intensity of sulfur obtained for “washing 1” of each rinse solution decreased to some extent with the increase of washing time. However, the signal intensity of sulfur after “washing 1” was respectively stable for pure water and 10% HNO₃ in each washing, which indicate that the residual sulfur was difficult to remove by washing with pure water or 10% HNO₃. By contrast, the signal intensity of sulfur apparently decreased in each washing of 10% HNO₃ with 10% ethanol, indicating the effective removal of residual sulfur in the instrument.

Major precursor ions for the spectral interferences of sulfur isotopes

Figure 2 shows the mechanism of the ICP-QMS/QMS for removing the spectral interferences with ³²S⁺ measurement. Oxygen was solely used as the reaction gas in the researches using ICP-QMS/ QMS published up to date [26-28]. In the present research, H₂ was used together with O₂ as the reaction gases.

Figure 2: The mechanism of ICP-QMS/QMS for removing spectral interferences.

The 1^st QMS and the 2^nd QMS could be individually controlled: the instrument permits the mass scan by both QMS’s. In the present work, mass scan was carried out for the 1^st QMS followed by the 2^nd QMS filtering at the m/z 48 for the measurement of ³²S¹⁶O⁺. The flow rate of O₂ as reaction gas was optimised in advance. As the result, 0.3 mL min^-1 of O₂ was found to be the optimum and applied in the following experiments. Mass scan of the 1^st QMS was carried out for the mass range from 2 to 260, using a pair of blank (0.3 mol L^-1 HNO₃) and standard (50 ng g^-1 sulfur in 0.3 mol L^-1 HNO₃) solutions. Since the signal intensities for the mass range lower than 15 and those for the mass range higher than 51 were very low and negligible, the results for the mass range from 16 to 50 are shown in Figure 3 for a clearer comparison.

Figure 3: Mass spectrum observed by the 2^nd QMS at 48 by scanning the mass range from 16 to 50 of the 1^st QMS. (Open bar, 0.3 mol L^-1 HNO₃; solid bar, 50 ng g^-1 sulfur in 0.3 mol L^-1 HNO₃. Reaction gas: (a) 0.3 mL min^-1 of O₂; (b) 0.3 mL min^-1 of O₂ and 1 mL min^-1 of H₂

The results in Figure 3(a) were obtained using O₂ as the reaction gas. Very high signals for m/z of 48 at the 2^nd QMS were obtained when the m/z of the 1^st QMS were 16, 32, 33, 40, and 48. The precursor ions at m/z of 16, 32, 33, and 48 could be attributed to the ions of ¹⁶O⁺, ³²S⁺ (with ¹⁶O₂⁺), ³²S¹H⁺, and ³²S¹⁶O⁺, respectively. The precursor ion at the m/z of 40 has not been reported up to date. One of the possibilities of this precursor ion might be ⁸⁰Kr⁺⁺, which could be the impurities in Ar gas used in ICP-QMS/QMS. A further experiment was carried out by setting the m/z of the 1^st QMS and the 2^nd QMS as 42 and 50, respectively. Signal of 84Kr¹⁶O⁺⁺ was not observed. This result might indicate that either ⁸⁴Kr⁺⁺ was not present in the ions passing through the 1^st QMS or 84Kr++ was not react with ¹⁶O to form 84Kr¹⁶O⁺⁺ ion. Therefore, it could be concluded that the precursor ion at the m/z of 40 in Figure 3(a) was not ⁸⁰Kr⁺⁺. The present authors speculate that the precursor ion at the m/z of 40 was ₄₀Ar⁺ (maybe with minute ⁴⁰Ar₂⁺⁺), which might transfer to ₄₀Ar₂ ¹⁶O⁺⁺ and be observed at the m/z of 48 at the 2^nd QMS. The authors also carried out a measurement by an HR-ICP-MS to check whether the ⁴⁰Ar₂ ¹⁶O⁺⁺ ion was generated in the plasma. The ⁴⁰Ar₂ ¹⁶O⁺⁺ ion was not found in the HR-ICP-MS measurement. This fact indicated that the ⁴⁰Ar₂¹⁶O⁺⁺ ion was not generated in the plasma but generated in the ORC by the reaction with ¹⁶O₂. Another possibility of ⁴⁰Ar⁺ related interferences might be ¹⁶O₃⁺ produced by asymmetric charge transfer. It should be noted that the ionization energies of Ar and O are 15.759 eV and 13.61806 eV, respectively [30]. Therefore, charge transfer from Ar⁺ to O⁺ is an endothermic reaction. Such kind of reactions is possible to happen in the ORC with enough collision energy [31].

Furthermore, it can be seen from Figure 3(b) that the precursor ions at the m/z of 16 and 40 were removed by using H₂ as the reaction gas together with O₂. The signal intensity obtained for the m/z of 32 slightly decreased when H₂ was additionally applied as the reaction gas.

In the measurement of ICP-QMS/QMS with an ORC, the 1^st QMS could be set to permit the pass of ions with m/z of 32 and contributes to the removal of ¹⁶O⁺ and ₄₀Ar⁺ generated in the plasma. However, ₄₀Ar⁺ signal could still be observed at the 2^nd QMS, the reason for which is not clear up to now. The effect of H₂ on removal of ₄₀Ar⁺ was investigated and the results are plotted in Figure 4. As can be seen, apparent ₄₀Ar⁺ signal was observed when H₂ was not introduced as reaction gas.Introduction of 1 mL min^-1 H₂ as the reaction gas was enough to remove the ₄₀Ar⁺ signal. Therefore, H₂ was used as the reaction gas along with O₂ in the present experiment to ensure the removal of ₄₀Ar⁺ related ions.

Figure 4: ⁴⁰Ar⁺ signal intensity observed at different flow rate of H₂ as the ORC gas. (1^st QMS, m/z=32; 2^nd QMS, m/z=40; O₂ flow rate, 0.3 mL min^-1).

Optimisation of H₂ flow rate for the measurement of sulfur

The signal intensities of sulfur in a pair of blank and standard solutions were investigated at different H₂ flow rates from 0 to 5 mL min^-1. The results of ³²S in the blank and standard solutions are plotted in Figure 5(a) and 5(b), while the (standard/blank) signal intensity ratio (S/B) is plotted in Figure 5(c).

Figure 5: Signal intensities of ³²S¹⁶O⁺ in the blank and standard solutions and their ratio observed at different H₂ flow rates. ((a) Blank solution, 0.3 mol L^-1 HNO₃; (b) standard solution, 50 ng g^-1 sulfur in 0.3 mol L^-1 HNO₃; (c) standard to blank signal intensity ratio. 1^st QMS, m/z=32; 2^nd QMS, m/z=48).

It can be seen from Figure 5(a) to 5(c) that the signal intensities of ³²S¹⁶O⁺ in both the blank solution and the standard one decreased gradually when the H₂ flow rate increased from 0 to 1.0 mL min^-1. By contrast, the S/B increased gradually and the maximum ratio was obtained at H₂ flow rate of 1.0 mL min^-1. These results might indicate that the application of H₂ as the reaction gas helped to supress the mass shift from ¹⁶O₂⁺ to ¹⁶O₃⁺ or help to suppress the formation of other spectral interferences induced by ¹⁶O₂⁺. The signal intensities of ³²S¹⁶O⁺ in the blank solution and the standard solution increased to some extent when the H₂ flow rate increased from 1.0 mL min^-1 to 2.0 mL min^-1, while the S/B decreased. When the H₂ flow rate exceeded 2.0 mL min^-1, the signal intensities of ³²S¹⁶O⁺ in the blank solution and the standard solution decreased gradually. At the same time, the S/B increased slightly when the H₂ flow rate increased from 2.0 mL min^-1 to 3.0 mL min^-1, while the S/B was almost stable and independent of the H₂ flow rate when it was over 3.0 mL min^-1.

As it can be seen in Figure 5(c), the maximum S/B was achieved at the H₂ flow rate of 1.0 mL min^-1. This condition provided the best detection limit for sulfur measurement and was applied to the following experiments. The DL(3σ) and BEC of ³²S were 0.03 ng g^-1 and 0.83 ng g^-1, respectively. The calibration curve obtained with 0 ng g^-1, 50 ng g^-1, 100 ng g^-1, and 150 ng g^-1 sulfur in 0.3 mol L^-1 HNO₃ gave a correlation factor with R2=0.9999.

A comparison of the present DL and BEC with those reported with various techniques is summarised in Table 2. As can be seen in Table 2, the present DL is comparable with the best performance reported in Reference [20] obtained by HR-ICP-MS with the assist of a desolvation unit to remove the ¹⁶O₂⁺ interference. The present method provides better DL and BEC than other techniques without using a desolvation unit. The reason could be attributed to the effective removal of spectral interferences by the QMS/QMS system with the ORC using H₂ and O₂ as the reaction gases. The 1^st QMS selecting m/z of 32 permitted the pass of ¹⁶O₂⁺ and ³²S⁺ while blocked ¹⁶O⁺ and reduced the possibility of transference from ¹⁶O⁺ to ¹⁶O₃⁺ in the ORC. The introduction of H₂ as the reaction gas might further reduced the possibility of transference from ¹⁶O₂⁺ to ¹⁶O₃⁺ in the ORC and/or the formation of other spectral interferences induced by ¹⁶O₂⁺. It is noted that the DL in the present work was much lower than those reported in References [27-29] based on the ICP-QMS/QMS technique. These results might indicate that the measurements in References [27-29] were carried out with a relatively higher blank signal, i.e., a higher BEC, as mentioned in Reference [27].

Table 2: The DLs and BECs for measuring ³²S by various techniques. ^a: Not available.

Validity of the method for measurement of sulfur

In order to confirm the validity of the present method, each content of sulfur in three CRMs, NIST SRMs 2773 (bio-diesel), 2298 (high octane gasoline), and 2299 (reformulated gasoline), was measured after acid digestion.

The observed values of sulfur contents in these CRMs are plotted in Figure 6 in comparison to the certified values, along with the expanded uncertainty of each value. It can be seen that the observed value for each CRM agreed with its certified one considering the uncertainty. Because the CRMs were analysed after microwave acid digestion (sample 0.5 g, solution 50 g), the concentration of sulfur in the sample solution of NIST SRM 2298 was approximately 45 ng g^-1. These results showed that the present method is valid for measuring sulfur at 50 ng g^-1 with the expanded uncertainty of approximately 2%.

Figure 6: A comparison of observed and certified values of sulfur in three CRMs. The value following “±” indicates the expanded uncertainty with the coverage factor 2.

Quantitation of sulphur-containing amino acids and sulfur containing proteins by measuring sulfur contents

The present method was applied to the quantitation of sulfurcontaining amino acids (NMIJ CRM 6025-a, L-Cystine and NMIJ CRM 6023-a, L-Methionine) and a protein (NMIJ CRM 6202- a, human serum albumin). The amino acid samples were dissolved in 0.1 mol L^-1 HCl. The protein sample was digested with Ultrapur® HNO₃ in the same way as that used for the NIST SRMs. The samples were further diluted to obtain the analysis solutions containing approximately 50 ng g^-1 of S.

The results are summarized in Table 3 along with the certified values. It can be seen that the observed values were in agreement with the certified values considering the measurement uncertainty. This fact indicates that the measurement of S content could be applied to the quantitation of sulfur-containing compounds.

Table 3: Observed and certified values of sulfur-containing amino acids and protein. ^a: The value following “±” indicates the expanded uncertainty with the coverage factor 2.

Conclusion

ICP-QMS/QMS with an ORC system was investigated to establish a method for the measurement of sulfur in bio-samples. Washing procedure using 10% HNO₃ with 10% ethanol helped to obtain a lower BEC and a lower DL for sulfur measurement. The interference of ¹⁶O₂⁺ with the measurement of ³²S⁺ could be effectively removed by setting the m/z of the 1^st QMS as 32 to permit the pass of ¹⁶O₂⁺ and ³²S⁺, while the ³²S⁺ reacted with O₂ gas and transferred to ³²S¹⁶O⁺ in the ORC and then measured at the m/z of 48 in the 2^nd QMS. The introduction of H₂ gas in the ORC helped to remove ₄₀Ar⁺ related interferences with the measurement of ³²S⁺. The DL and BEC of ³²S in the present work were 0.03 ng g^-1 and 0.83 ng g^-1, respectively. The DL was comparable with that obtained by an HR-ICP-MS with the assist of a desolvation unit and better than those obtained with other techniques. This result could be attributed to the fact that the measurement of ³²S⁺ in the present work was shifted to ³²S¹⁶O⁺ and the transfer from ¹⁶O₂⁺ to ¹⁶O3 + was effectively suppressed by the introduction of H₂; i.e., the measurement by ICP-QMS/QMS with an ORC did not suffer from ¹⁶O₂⁺ signal tailing as that observed in HR-ICP-MS. The validity of the present method was confirmed by analysing sulfur in three NIST SRMs, for which the observed values agreed with their certified values. The results of analysis of sulfur-containing amino acids and protein showed that the measurement of sulfur content could be applied to the quantitation of these compounds.

The analysis in the present work was designed for the quantitation of total sulfur in the sample, which is effective for the quantitation of sulfur-containing compounds of high purity for metrological purpose. Hyphenation of ICP-QMS/QMS with separation techniques such as high pressure liquid chromatography could provide further information for the species of sulfur in the sample.

Acknowledgements

The present research was partly supported by the International Cooperation Project for Research and Standardisation of Clean Energy Technologies (FY2013- 2014). The authors express their sincere gratitude to Drs. Stephen E. Long and John L. Molloy of NIST for their cooperation in the project. The authors also appreciate the technical support for using the ICP-QMS/QMS by Mr. Yasuyuki Shikamori at Agilent Technologies Japan.

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