Elsevier

Analytica Chimica Acta

Volume 809, 27 January 2014, Pages 1-8
Analytica Chimica Acta

Accurate determination of ultra-trace levels of Ti in blood serum using ICP-MS/MS

https://doi.org/10.1016/j.aca.2013.10.017Get rights and content

Highlights

  • Novel method for determination of Ti at ultra-trace levels in clinical samples (serum).

  • Novel method based on Ti(NH3)6+ reaction product ion formation and double mass selection using recently introduced ICP-QQQ instrumentation.

  • Lowest limits of detection ever obtained using quadrupole-based instrumentation for Ti.

  • Accurate determination of basal levels of Ti in blood serum.

Abstract

Ti is frequently used in implants and prostheses and it has been shown before that the presence of these in the human body can lead to elevated Ti concentrations in body fluids such as serum and urine. As identification of the exact mechanisms responsible for this increase in Ti concentrations, and the risks associated with it, are not fully understood, it is important to have sound analytical methods that enable straightforward quantification of Ti levels in body fluids (for both implanted and non-implanted individuals). Until now, only double-focusing sector field ICP-mass spectrometry (SF-ICP-MS) offered limits of detection that are good enough to deal with the very low basal levels of Ti in human serum. This work reports on the development of a novel method for the accurate and precise determination of trace levels of Ti in human serum samples, based on the use of ICP-MS/MS. O2 and NH3/He have been compared as reaction gases. While the use of O2 did not enable to overcome all spectral interferences, it has been shown that conversion of Ti+ ions into Ti(NH3)6+ cluster ions by using NH3/He as a reaction gas in an ICP-QQQ-MS system, operated in MS/MS mode, provided interference-free conditions and sufficiently low limits of detection, down to 3 ng L−1 (instrumental detection limit obtained for the most abundant Ti isotope). The accuracy of the method proposed was evaluated by analysis of a Seronorm Trace Elements Serum L-1 reference material and by comparing the results obtained with those achieved by means of SF-ICP-MS. As a proof-of-concept, the newly developed method was successfully applied to the determination of Ti in serum samples obtained from individuals with and without Ti-based implants. All results were found to be in good agreement with those obtained by means of SF-ICP-MS. The typical basal Ti level in human serum was found to be <1 μg L−1, while values in the range of 2–6 μg L−1 were observed for implanted patients.

Introduction

The determination of low levels of Ti in biological fluids has become a hot topic in the last 10–15 years, mainly because of the increased use of Ti in prostheses and dental implants and the awareness that metallic joint replacement devices can interact with the surrounding body fluids and tissues. As all metallic implants are subject to wear over time, increased serum and urine metal concentrations and, eventually, local and systemic metal storage may be the result [1], [2], [3], [4], [5], [6], [7]. Moreover, Ti is also widely used – often under the form of TiO2 nanoparticles – as a white pigment in paints, coatings, plastics, food, toothpaste or in sunscreen [8]. In 2006, the International Agency for Research on Cancer (IARC) has classified TiO2 dust as an IARC Group 2B carcinogen, which means that it is possibly carcinogenic to humans [8]. So far, there is no real evidence on the clinical consequences and potential adverse effects of Ti, released in the human body, but there is a clear need for more systematic research on this topic [9].

Over the years, many authors have reported on the basal Ti levels in human body fluids, with values ranging between 0.200 μg L−1 and 200 μg L−1 [5], [6], [10], [11], [12], [13]. The very large spread on these results, indicates that there is a lot of confusion about the actual basal levels of Ti, which makes it also difficult to obtain reliable information on the possible release of additional Ti in the body. This controversy finds its origin in the fact that most of the analytical methods typically used for trace element determination – such as ETAAS (electrothermal atomization atomic absorption spectrometry) [14], [15], ICP-OES (inductively coupled plasma – optical emission spectroscopy) [16] or ICP-QMS (inductively coupled plasma – quadrupole-based mass spectrometry) [3], [17] – are not sensitive and/or selective enough to allow for an accurate quantification of the ultra-trace levels of Ti in complex matrices, such as human blood (serum). Although, owing to its sensitivity, ICP-MS can generally be seen as the method of choice for the determination of ultra-trace metals in clinical samples, the specific problem for Ti is the occurrence of spectral overlap affecting all Ti isotopes (Table 1) when samples with high Ca, P, S, C and Cl contents (such as clinical samples) have to be analyzed.

Nowadays, the most general way of dealing with spectral interferences is the use of a suited collision/reaction gas in a quadrupole-based ICP-MS instrument (chemical resolution), or of double-focusing sector field (SF)-ICP-MS (higher mass resolution). Sarmiento-González et al. showed that the interferences affecting the Ti isotopes could not be overcome by using H2 or He as reaction/collision gases in an ICP-QMS instrument, equipped with an octopole reaction cell (or octopole reaction system ORS) [17]. Up to now, only by using a double-focusing SF-ICP-MS instrument, operated at a higher mass resolution (R = 3000), a method detection limit of <100 ng L−1 could be obtained [20]. From the above, it must be clear that the shortness in suitable analytical methodologies severely hinders the research concerning Ti release in the body of people with Ti-based implants, particularly considering that the superior robustness and cost-efficiency of quadrupole-based ICP-MS devices makes these instruments to be more prevalent in routine labs than SF-ICP-MS devices.

It can be noted that very recently a new type of quadrupole-based ICP-MS instrument has become commercially available. This instrument is commonly referred to as a triple quadrupole (ICP-QQQ) set-up, although this terminology is not entirely correct. In fact, in such an instrument, an octopole-based collision/reaction cell is located in-between two quadrupole analyzers. This configuration permits to operate an ICP-MS instrument in MS/MS mode [21], [22], which in principle offers superior potential to deal with spectral overlaps. Such instrument should therefore offer improved possibilities for the determination of Ti, although the number of publications reporting on the performance of this spectrometer is still very low and, to the best of the authors’ knowledge, no papers reporting on Ti monitoring have been published yet.

Therefore, the main goal of this work is to explore the capabilities of an ICP-QQQ device and develop a novel analytical method that is both sensitive and selective enough to allow for the accurate determination of Ti concentrations in blood serum of non-exposed and exposed individuals.

Section snippets

Instrumentation

All measurements were carried out with an Agilent 8800 triple-quadrupole ICP-MS instrument (ICP-QQQ/Agilent Technologies, Japan), equipped with a MicroMist nebulizer and a Peltier-cooled (2 °C) scott-type spray chamber for sample introduction. This instrument contains an octopole-based collision/reaction cell, located in-between two quadrupole analyzers. The octopole cell can be vented or pressurized with a collision gas (typically He) or a reaction gas (typically H2, O2 or NH3/He), or a mixture

Selection of the reaction gas and quadrupole mass settings

In a complex sample, such as human blood serum, containing high levels of matrix elements such as C, Ca, Cl, Mg, P and S, the interference-free determination of ultra-trace levels of Ti is a challenging task. It has been shown before [17] that the use of a collision gas, such as He, or a reactive gas, such as H2, in an ORS-ICP-QMS system, is not sufficient to remove all interferences and that such an approach is therefore not suited for this kind of application. However, instead of removing the

Conclusions

In this work, a method has been developed for the accurate determination of ultra-trace levels of Ti in clinical samples by means of ICP-MS/MS. An evaluation of the use of different reaction gases (O2 and NH3/He) showed that accurate results can be obtained with NH3/He as a reaction gas and determination of the Ti+ ions at the m/z of the corresponding Ti(NH3)6+ reaction product ions. The gain of controlling the reaction cell chemistry by operating the instrument in the MS/MS mode has been

Acknowledgements

The authors acknowledge Dr. Luis Rello from the Miguel Servet Universitary Hospital (Zaragoza, Spain) for providing the human serum samples and Dr. Glenn Woods (Agilent Technologies) for his valuable input concerning ICP-MS/MS method development. Also, the funding from the Special Research Fund (BOF) of Ghent University, from the Spanish Ministry of Economy and Competitiveness (Project CTQ2012-33494) and the Aragón Government (Fondo Social Europeo) is acknowledged.

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