Microchim Acta (2008) 162: 3541 DOI 10.

1007/s00604-007-0909-6 Printed in The Netherlands

Original Paper Metrology in chemistry a rocky road

Heinrich Kipphardt, Ralf Matschat, Ulrich Panne
BAM, Federal Institute for Materials Research and Testing, Berlin, Germany Received 24 August 2007; Accepted 15 November 2007; Published online 31 January 2008 # Springer-Verlag 2008

Abstract. The application of metrology in chemical analysis is today hampered by psychological and practical barriers. The argumentation is based on the differences in physical and chemical metrology, which arises mainly from the objects of the measurements. The term measurement is discussed in the realm of analytical chemistry with a special focus on the inherent relation between chemical identication and determination as well as the consequent use of the concept of traceability and uncertainty.
Keywords: Metrology in chemistry; chemical analysis; traceability; uncertainty

The concept of metrology has been applied to socalled physical measurements for a long time and with great success. However, its application to chemistry is a rather new eld which is considered by many analytical chemists with scepticism and reservation. Acceptance requires understanding, mediation attempts have already been initiated in the early beginning of the debate [1]. Some of the fundamental questions in the realm of metrology in chemistry are: What is metrology and what are chemical measurements about? What is analytical chemistry in the heart of the scientic discipline? What are quantitative and

Correspondence: Heinrich Kipphardt, BAM, Federal Institute for Materials Research and Testing, Richard-Willstaetter Str. 11, 12489 Berlin, Germany, e-mail: heinrich.kipphardt@bam.de

qualitative measurements, and do qualitative measurements without quantitative aspects exist at all? Metrology is the art and science of performing measurements. Quantitative measurements are numerical comparisons of quantities by experiments. Chemical measurements are measurements of quantities, where the chemical identity of the substance matters. Analytical chemistry is the science and art of acquiring information on material systems and their application oriented interpretation [2], however, there are many more denitions possible [3]. Quantitative analysis is typically in the focus of interest of analytical work. However, quantitative aspects are involved in any type of chemical measurement, including qualitative measurements. In this case, often statements are involved such as: Material X does not contain analyte A, or more correctly: Analyte A was not detected in matrix X above a given threshold value when using a certain analytical technique. In the case of discrete classication, for example discriminating genetically modied (GM) foods, the classication statements are given with the corresponding error probabilities, which contain quantitative information [4, 5]. A discrete classication belongs to the case, where namely the uncertainty interval is zero, though the classication was obtained with a certain level of condence or with a certain error probability. The initial focus of activities in chemical metrology was the consultative committee on amount of substance (CCQM, www.bipm.org) of the meter conven-

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tion, founded not before 1993, whereas the consultative committees for other units have been existent at that time for more than 40 years. CCQM with its regional substructure is within the meter convention, which is a diplomatic treaty between governments, the highest metrological authority for chemical measurements worldwide. Its historic development started with gas analysis, electrochemical measurements and the application of IDMS (isotope dilution mass spectrometry) and it covers nowadays virtually all aspects of analytical chemistry, from bio-analysis to classical chemical analysis. Another momentum for introducing metrology in chemistry came from the development in the frame of the ISO-GUM [6], which led to a big impact on all areas of metrology. Metrological activities focus on achieving comparability of measurement results in time and space. Measurement results are usually not an end in itself. They are used in comparison with other values such as specications or (legal) limit values for decision making in virtually all elds of application. Wrong decisions can have far reaching consequences with huge commercial, environmental or medical impact. The objective of this contribution is to provide insights into chemical metrology and its importance for any kind of chemical measurement. Without limiting the generic character of this paper, examples were taken from inorganic analytical chemistry. Quantitative analysis The determination of an analyte (resp. of its content) in a matrix is a measurement, hence containing substantial metrological aspects. If this is true, then why is metrology in chemistry matter of debate at all? Due to historical reasons, and further pushed in the light of modern instrumental techniques, chemists associate the term measurement in many cases only with the nal determination step in the whole analytical process. The outcome of the whole analytical process, which consists of several steps such as sampling, sample preparation, separation, and nally measurement, is understood to be a determination. Sample preparation and sampling are, however, for chemical analysis of signicant importance and inuence for the quality of the measurement result, and typically require the application of specic procedures based on experience and deep understanding of the material under investigation. Sample preparation and sampling are less straightforward and more difcult to control

than e.g. removing obstacles for a length measurement. Disregarding these linguistic ambiguities of the term measurement and determination and naming the whole process a measurement, the question is: Does chemical analysis have a specic characteristic that is different from other measurements? In physical and chemical measurements quantication is performed in most cases via calibration, i.e. comparing the signal size generated from the unknown object to the signal size generated from an object with known property values. For example in the simple operation of weighing, a calibrated mass standard is employed. Concerning calibration there are many different kinds of methods in analytical chemistry. Some of them such as e.g. atomic absorption spectrometry require calibration using the same analyte as intended to be measured. In other cases such as e.g. redox titrimetry calibration is achieved using a different substance than the analyte intended to be measured. And nally there are methods of measurement, that are virtually free of calibration. The later kind of method is sometimes called absolute analysis or primary method of measurement [7]. In this case, the direct calculation of the concentration or amount of the analyte from a single measurement is feasible through knowledge of a fundamental relationship linking a measurable physical quantity to the analyte. Apart from gravimetric or coulometric methods under very dened conditions (e.g. concerning purity of the substances investigated), this approach was not demonstrated completely until today for any instrumental analytical method [810]. All chemical methods of measurement can be jeopardised by several variables, which inuence the measurement when overlooked or not properly taken into account. Although the measurement of physical quantities suffers from the same problem, chemists often argue that chemical analysis is per se difcult due to the huge selection of possible inuencing quantities, which might falsify the result. On top of this, e.g. a balance will never happen to accidentally measure length while in chemical measurements something similar might happen. For example in electrogravimetry, a silver impurity in the sample can accidentally falsify the value measured for the copper content; iron signals observed at  214.445 nm by inductively coupled plasma optical emission spectroscopy (ICP OES) can be accidentally measured instead of cadmium at  214.438 nm due to spectral interference.

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Therefore, in any kind of chemical measurements knowing the identity of the substance measured is of utmost importance. Quantitative as well as qualitative chemical analysis is inherently linked to identication. While this seems trivial for elemental analysis, the challenge becomes more obvious considering current efforts in proteomics research to establish an acceptable condence measure in the assignment of proteins in an unknown sample [11]. This is further reected by the denition of the mole, which is as many entities as there are present in 12 g of 12C in ground state. When the mole is used, the substance needs to be specied, i.e. the identity of the substance is needed. In chemical terms, the substance of interest is called analyte. This causal chain of amount and identity, which is a special parameterisation of the quantity amount of substance, is the most specic characteristic of chemical measurements and a constant challenge of analytical chemistry. Chemical analysis is by nature multivariate, as usually the signal generation for the analyte in a measurement process is not only inuenced by the amount of the analyte but also by the interaction of the analyte with its matrix. As no natural or man-made pure substance exists, every macroscopic material consists of more than a single, individual component. For severe matrix effects, the signal related to concentration or amount of the analyte under study becomes a function of all constituents present in the sample. In chemical analysis in some cases such as e.g. X-ray uorescence analysis calibration is performed in a multivariate way. In most cases however, such as in the case of e.g. ICP OES the difculties arising from the multivariate nature of chemical analysis are overcome by matrix matching or separation. In chemical analysis univariate measurements are possible only under very dened conditions, e.g. extreme dilution of the matrix. In many cases a simple dilution can reduce matrix interferences, but then higher sensitivity of the method might be necessary to solve the analytical problem. This explains the relation between sensitivity and selectivity. In most cases, however, even an apparent univariate determination such as the pH value is modied through the amount and nature of other chemical species present in the sample. This underpins to the importance of selectivity [12] and specicity, which are often used interchangeably and synonymously (see [13] and ref. therein) in chemical metrology, while they have no meaning in physical metrology. A selective method allows determining simultaneous-

ly several components independently from each other, while using a specic analytical method only a single analyte is determined independently from all the other components in the sample. The correct choice of the measurement procedure guarantees that either the interdependency between analyte and its matrix is eliminated through suitable calibration concepts, i.e. a selective method is employed, or a sufcient reduction of the interferences from the matrix leads to a more specic method which can be also t for purpose. Without any doubt, the picture of the accidental measurement of length instead of mass as given above is put to the very extreme and is in its deeper meaning not appropriate for the accidental measurement the amount of iron instead of the amount of cadmium. The amount of cadmium and amount of iron do not relate to different types of quantities, but to quantities of the same class and therefore to the same SI unit (mol or kg of the identied substance). However, the consequences of an accidental measurement of different quantities either of the same class or of different classes are similarly disastrous. Sometimes representatives of other SI units believe that their analogue to chemical analysis is measuring different objects such as the mass of fruits or the mass of steel. However, transferred to chemical analysis fruit and steel describe different kinds of samples only. For the challenge of different analytes and the problems arising from this fact, there seems to be no analogue in the measurements of other quantities. With this in mind, analytical chemistry in its own perception becomes a scientic art where each measurement process has its own specic characteristic. The term measurement, where this specic characteristic is closely related to qualitative aspects, was and is by many chemists seen as a degradation of their art. But if this characteristic is accepted, the corresponding psychological barrier can be put aside. The most important integral qualities of measurement results are traceability and uncertainty, qualities that should be discussed separately. Traceability Traceability is dened by the VIM [14] to be property of the result of a measurement or the value of a standard whereby it can be related to stated references, usually national or international standards, through an unbroken chain of comparisons all having stated uncertainties. Attempts for the application of the trace-

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ability concept to analytical chemistry are given in [1517]. As for other measurements, in chemical analysis stated reference are nally the abstract denitions of the SI, or consequently realised intermediates, that themselves are traceable to the SI. Depending on the actual measurement problem, suitable intermediates can be certied reference materials (CRMs) certied for total purity or certied matrix reference materials, which underpins the importance of these materials. Especially for newer reference materials, the source of traceability and a brief description of the traceability chain must be stated and is integral part of the certicate [18]. To avoid circular reasoning in the certication, only results obtained by calibration with sufciently pure substances of known stoichiometry should be included, whereas the use of existing matrix reference materials for calibration should be disregarded. If calibration using matrix reference materials is included, a prerequisite would be that the uncertainty of the matrix CRM used for calibration is taken fully into account and this uncertainty statement has been proven to be reliable [19]. Especially, the latter is because of lack of transparency in practice hardly feasible. CRMs can be distinguished between matrix reference materials, with analytes in a complex real world matrix, and pure substances used for calibration. It is important to realise, that matrix CRMs can not be achieved without other matrix CRMs or reference to primary pure substances for calibration. Although primary pure materials are in the hierarchy closer to the SI unit, both types of certied reference materials can be a convenient anchor point for the eld laboratories to link their results to the SI. It is the task of the national metrology institutes (NMIs) to provide national standards and primary reference materials. Matrix CRMs and RMs must be linked in the shortest possible way to the SI. This burden must be taken by the producer and does not need to be taken by the eld laboratories; however, it is their responsibility to establish correctly the link between the property of the CRM and the property of the sample measured. The importance of traceability is increasingly recognised by ISO=EN 17025 [20]. Sometimes the consequent use of the mole as reference unit seems to be irritating. The mole is dened via the mass of 12C particles. Therefore, chemists in praxis often report their results in mass of analyte (in g) instead of amount of substance (in mol), but without introducing a fundamental distortion of the

unambiguous traceability statement, although the nature of chemical reactions is based on the particle structure of matter and not on the concept of mass. Mass and amount of substance are convertible through the concept of molar mass. In both cases, however, the identity of the analyte needs to be stated. The objective of the traceability concept is to use common references. It is the task of the NMIs to realise and disseminate these references (e.g. embodied in measurement standards such as CRMs) as laid down in the meter convention. Its nal aim is to enable comparability of measurement results invariant of time, space and borders on a level as general as possible i.e. comparability within quantity subclasses (e.g. within amount of Cd measurements), comparability within quantity classes (e.g. within amount of substance measurements for substances of different identity) and convertibility between different quantity classes through simple and consistent conversion factors (e.g. conversion between amount of substance and a corresponding mass through the concept of molar mass). This guarantees that 1 mol of a substance in one country is not only comparable to 1 mol of the same substance in a different country, but also in the case of chemical analysis comparable to 1 mol of a completely different substance, which is a fundamental prerequisite to make the concept of stoichiometry meaningful applicable. Comparability is not less than the basis to provide national and international binding information on chemical composition. A prerequisite for this approach is, that the NMIs themselves compare on international level their realisations of the SI units and demonstrate their measurement and dissemination capability, and also to create within their countries a structure at least for dissemination of their measurement capability to the eld laboratories. Beyond chemical analysis these structures for dissemination are well established and recognised to be self evident. The quantity value of a calibrated (i.e. validated) mass piece on any balance in any country can always be related through a chain of comparisons to the dened value of the corresponding unit, which in this special case is the value dened by the kgartefact as stored at BIPM (International Bureau of Weights and Measures). To provide a dissemination structure in chemical analysis as depicted in Fig. 1 exemplarily for copper determination is a challenge. Due to the specic characteristic of a huge variety of analytes and matrices, not surprisingly, the current state of the art in disseminating traceability in chem-

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Fig. 1. Dissemination of measurement and calibration capability exemplied for the measurement of copper

istry is limited. Calibration, i.e. matching of the analyte in identity and amount, is an essential tool to achieve traceability. But even today, materials used for calibration are usually not traceable to the SI in a transparent way. Most of the analytical measurement results available are in fact based on nominal purity statements. Nominal purity statements are given by commercial suppliers of high purity materials and include usually only those impurities hat have been measured, typically using a semi-quantitative method of measurement. Often important impurity contributions, especially impurity contributions with nonmetals, are ignored. The problem is that usually the customer wrongly takes the nominal purity synonymous for the total purity. In the case of elemental analysis, an elegant way to solve this problem could be, a system of primary pure substances, that are high purity materials characterised with respect to all possible impurities [17, 21]. Metrological solutions prepared from these materials can then be linked to batches of commercially available solutions in a transparent way to the SI by comparing them with the metrological solutions (compare Fig. 1). A snapshot of the current ability of the NMIs to provide primary pure substances is given in [22]. A snapshot of the ability of the NMIs to determine the concentration of a calibration solution is given in [23]. Measurement uncertainty More than one plain value as sometimes reported as a measurement result, the interval of values that can be attributed due to the inherent imperfections of the

measurement process and the sample material (e.g. representativeness) matters. Knowing this interval is especially important, when the measurement result needs to be compared with other data such as product specications or legal limit vales. A common representation of such an interval is the value measured and its corresponding uncertainty. The term Uncertainty of measurement is dened according to the VIM [14] to be: parameter, associated with the result of a measurement, that characterises the dispersion of the values that could reasonably be attributed to the measurand. The idea is based on the fact, that virtually all inuencing quantities in the measurement equation are known only within a limited uncertainty. Consequently, the measurement result derived from these input quantities must also carry an uncertainty. All uncertainty contributions, those that can be obtained from repeated observation (type A) and those that can be obtained by other means (type B) such as expert knowledge, experience on possible systematic deviation or given on certicates of CRMs, are treated in the same way to nally obtain the so called combined uncertainty uc. This combined uncertainty can be multiplied with coverage factors k to obtain the expanded uncertainty U with higher statistical condence (typically k 2 for 95%) [6]. A graphical example for looking at uncertainties in a measurement process is given in Fig. 2. The uncertainty concept is based in its generic form on an assumed measurement model, as expressed in mathematical language in form of a measurement equation. For this reason, the application of the uncertainty concept turns out to be very difcult for com-

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Fig. 2. Consideration of uncertainty sources exemplied for the measurement of copper after extraction. The individual components can be further split up

plex measurement problems in practice. However, problems with measurement uncertainty are based on problems with proper measurements. If the measurement model is not adequate to the experimental reality or not correctly applied in practice, the measurement result and its uncertainty do not match reality. For inadequate matrix matching, the estimation of the corresponding uncertainty is typically the most relevant problem. From a methodology point of view, matrix inuences can be avoided by separation or their consequences can be reduced by use of the internal standard techniques. If a certied reference material similar to the sample under investigation is available, the uncertainty can be estimated from four components, namely the uncertainty of the CRM, the standard deviations of the measurement of sample and of CRM and the difference between the measured and certied value of the CRM [24]. Although the concept of uncertainty according to ISO-GUM [6] is commonly not fully understood and implemented, the sole consideration of standard deviations or the antiquated concept of systematic errors is no adequate alternative to achieve harmonised data produced in analytical chemistry. Quality assurance and metrology Quality assurance (QA) simply aims to establish the quality of a product through a framework of rules, procedures and through practical measures. Transferred to analytical chemistry, the product is a reliable measurement result. Since metrology is the art and science of performing measurements, quality assurance is a framework which is based on the principles

of metrology. Method validation and verication, transparency, redundancy, symmetry, consistence checks and performance checks as well as other metrological principles are essential elements of QA and metrological practice and have, although not explicitly named in this way, been practice in good laboratories for a long period of time. Conclusion The correct interpretations of the term measurement, the consequent use of the concepts of traceability and uncertainty in combination with the sophisticated art of the analytical chemist including the aspects of quality assurance are and will be the essential elements in obtaining consistent and comparable measurement results. Especially in analytical chemistry, newcomers need to get familiar with the basic metrological concepts and experienced analysts need to step back from the outdated concepts such as the error concept. Hampering psychological and practical barriers are not unconquerable. References
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