View Article Online / Journal Homepage / Table of Contents for this issue
Analyst, January 1998, Vol. 123 (712)
Published on 01 January 1998. Downloaded on 28/10/2014 14:17:14.
7
Trends in quality assurance of metal determination in
clinical chemistry
K. Byrialsen*, J. Kristiansen and J. M. Christensen
National Institute of Occupational Health, Lers Parkalle 105, DK-2100 Copenhagen, Denmark
A summary is given of the main strategies that can be
used to obtain high quality results in the determination of
metals in clinical chemistry. The trends in quality
assurance of metal analyses are discussed.
Keywords: Quality assurance; metals; clinical chemistry;
human health
Many decisions in a modern society are based on measurement
results. For example, traded goods must meet certain quality
requirements, industrial and agricultural pollution must be
below certain limits, occupational exposure limits must not be
exceeded, etc. Compliance with the desired quality or limit may
be decided by measurement. Furthermore, actions to be taken in
relation to risk assessment and human health and diseases are
often related to measured changes in biomarker concentrations.
Thus, measurement results have large economic, social and
political impact on people and on society, and the reliability of
measurement results is of crucial importance.
Determination of metals is important in both the environ-
mental and occupational health field and in clinical chemistry.
Moreover, metal analysis has a long tradition in the fields
mentioned and strategies for demonstrating the reliability of the
results have been originated and matured within this type of
analytical work.
State-of-the-art
Traditionally, measurement results are considered to be of high
quality if the accuracy (i.e., trueness and precision) of the results
is high.1 Determination of elements in trace amounts in clinical
and environmental specimens poses special problems with
respect to accuracy. For example, trueness may be affected by
contamination or by inappropriate blank correction. Losses and
contamination may occur during the sample pre-treatment
procedure, and matrix interferences may significantly reduce
precision and also affect trueness. Moreover, the matrix of
calibration standards may not match that of the samples or the
calibration standards may be subject to contamination or
element loss during storage. In both cases, trueness of the
measurement results will decrease. In addition, results are also
affected by blunders (gross errors). This type of error is often
underestimated in daily laboratory work, and it is seldomly
subject of systematic investigation. The need for laboratory
personnel to be sufficiently trained and motivated is another
important factor as up to 25% of all operating deficiencies are
directly attributable to operating personnel.2
Laboratories aiming at high quality work must demonstrate
that their measurement results meet the required level of
trueness and precision. Several established quality control
practices are available for the realisation of this goal and most
of them have been thoroughly described in the literature and/or
in standards and guidelines for quality assurance. For example,
the applicability of a given analytical method must be assured
Presented at The Sixth Nordic Symposium on Trace Elements in Human Health and
Disease, Roskilde, Denmark, June 29July 3, 1997.
on the basis of a well designed and carefully performed method
validation study, as described by, e.g., Wernimont3 and
Christensen et al.4 Biased measurement results have to be
corrected on the basis of a method evaluation study, and
inappropriate procedures may be improved resulting in reduced
bias and higher precision.5
Another example of a well-established quality control
practice is internal quality control which includes analysis of
control samples and blank samples. Several standards describe
control charts for data on control samples, for example, the ISO
standards 7870,6 7873,7 79668 and 8258,9 and the IUPAC
guideline on internal quality control procedures.10 The appro-
priate use of internal quality control serves to detect and correct
large non-random changes in accuracy. Such changes will
inevitably arise from changing environmental conditions, wear
of the measuring instrument or parts of it, change of reagents
used in the measurement process, human and technical errors,
etc.
The analysis of certified reference materials (CRMs) can also
be used to demonstrate trueness and precision but because of the
high cost of CRMs and the limited supply, the use of CRMs
should be analysed less often than control samples. Because of
the high degree of trust that can be put in the certified value,
CRMs are particularly valuable in demonstrating the trueness of
measurement results. In this context, the ISO guide 33 describes
how to use CRMs.11
As the understanding and prediction of the impact of trace
elements in the human body has increased, it has become
evident that determination of total element concentrations may
not be adequate. The determination of the abundance, distribu-
tion and toxicity of elements can be understood only in terms of
trace element species. The key to successful determination of
separate trace elements species is preservation of the species
during all acts from sampling to the detection of the analyte.
Therefore, availability of CRMs with certified values of trace
metal species is of crucial importance to improve the analytical
quality. However, great difficulties arise when speciation
CRMs are produced as documentation of all critical parameters
(e.g., homogeneity and stability) must be determined for each
certified species.12
Test results should be mutually agreed across frontiers in
favour of the users, and international cooperation between
national accreditation bodies serves to achieve mutual recogni-
tion of test results. Therefore, test results must be comparable
and participation in external quality assessment (EQA) schemes
serves as an important tool for obtaining comparability.
Laboratories seeking accreditation according to EN 45001 are
requested to participate in EQA schemes.13 In view of use of
EQA results for purposes of accreditation, methods of evalua-
tion of laboratory performance should be comparable and
wherever appropriate harmonized. Unfortunately, at present a
laboratory can be judged differently by different EQA schemes
as a result of differences in performance evaluation proce-
dures.14
The quality control practices mentioned above have been
available in trace element analysis for several years. It is
indisputable that, in general, implementation of good quality
control practices in a laboratory lead to improvement of the
 View Article Online

8 Analyst, January 1998, Vol. 123

quality of the results produced by the laboratory. However, as
the needs of society are changing, so are the demands on the
laboratories and so must the demands on quality control
procedures.
Metrological trend
The most noteworthy trend in quality assurance within the field
of analytical chemistry is the ongoing activities aiming at
establishing a sound metrological basis for analytical measure-
ments. This trend includes introduction of new concepts, such
as traceability and uncertainty. Quality requirements for the
production, certification and use of certified reference materials
are examples of practical implementation of this strategy.15,16
Another example is the International Measurement Evaluation
Programme (IMEP) promoted by the Institute for Reference
Published on 01 January 1998. Downloaded on 28/10/2014 14:17:14.
the BCR guide)15 could be implemented in PC-programs which
may be valuable tools in the certification process, in particular
for small certifying bodies.26 A PC-program specific for
statistical evaluation of certified values and uncertainties on the
basis of data from interlaboratory studies have been developed
for that purpose. The program will generate standardized
reports with full documentation of the evaluation procedure in
accordance with the BCR guide.26
Uncertainty
It is impossible to talk about traceability without referring to
uncertainty, and vice versa. Uncertainty (of measurement) is
defined as parameter, associated with the result of a measure-
ment that characterized the dispersion of the values that could
reasonably be attributed to the measurand.18 In analytical

Materials and Measurements.17 chemistry, the measurand typically is the molar (or mass)
concentration of a substance in a given sample. The wording
dispersion of values that could reasonably be attributed to the
Traceability and certified reference materials
measurand implies that a standard deviation based on repeated
Traceability means that the result of a measurement (or a value measurements does not, in general, satisfy the definition of
of a calibrator) can be related to a stated reference, usually a uncertainty. A standard deviation, e.g., derived under repeata-
national or international standard, through an unbroken chain of bility or reproducibility conditions, is a measure of the
comparisons all having stated uncertainties.18 In analytical laboratory (or a group of laboratories) ability to repeat the
chemistry, the preferred standard of reference would be the SI measurement. However, because the result of the measurement
base unit mole or alternatively, the SI base unit kilogram. Each may be influenced by effects beyond the control of the
step in the comparison chain involves a measurement procedure laboratory (or a group of laboratories), a standard deviation is,
which contributes some uncertainty. Hence, the total un- in general, an underestimate of the uncertainty. In evaluating the
certainty is a quantitative indication of the strength of the uncertainty, the laboratory must assign a value to all relevant
traceability chain . uncertainty components and combine the uncertainty compo-
Certified reference materials (CRMs) play an important role nents to yield an estimate of the uncertainty of the result.27 The
in the practical establishment of traceability. The definition of a principle is illustrated in Fig. 1, where Laboratory A does not
CRM as stated in the international vocabulary of basic and consider the quality of the calibrators purchased from Company
general terms in metrology (VIM)18 implies that CRMs in the A or the systematic effects associated with the measurement
context of traceability are valid standards of reference. The
problems involved in application of CRMs such as the
availability and representativity with respect to matrix and
reference value are well known. Production of well defined
CRMs with expected long-term stability often puts severe
restrictions on the physical form of the material. The necessary
processing of the material runs against the demand for CRMs
with representative matrix and analyte form. For example, solid
materials are often ground and filtered to assure homogeneity,
while liquid materials sometimes are lyophilized to improve the
stability. Sterile filtration is a possible alternative method to
preserve biological fluids, and a CRM for trace elements in
sterile filtered liquid serum is under production.19
The representativity of the CRM is not the only area for
improvement. The database COMAR contains information of
more than 9000 certified reference materials.20 A recent
REMCO status report shows that about 1500 reference
materials are under certification.21 At present, there are no
general requirements to CRM producers to demonstrate their
competence, and therefore it cannot be guaranteed that all
CRMs in the COMAR register warrant the definition of a CRM
and to the demands for strict documentation, as required by,
e.g., the ISO guides 31,22 3423 and 35.24 Guidelines for
production and certification of reference material issued by,
e.g., the Standards, Measurement and Testing Programme
(SM&T, formerly the BCR)15 and the National Institute of
Standards and Technology (NIST)25 may serve as a practical
reference for other minor certifying bodies. The process of
certifying a BCR CRM includes strict adherence to these
guidelines and scrutiny of the certification report by a
certification committee consisting of a panel of expert scien- Fig. 1 Uncertainty estimation. Laboratory A ignores uncertainty asso-
tists. This procedure ensures that CRMs issued by BCR are of ciated to the calibrator and the measurement principle and produces
high quality with respect to documentation and with respect to analytical results far from the true value. Laboratory B takes the uncertainty
metrological quality, i.e., traceability and uncertainty. It has into account and, therefore, the true value is included in the confidence
been suggested that the ISO guides and other guidelines (e.g., interval associated with the analytical result.

principle used by the laboratory when evaluating the un-
certainty. As shown in the figure, the laboratory produces
results far from the given reference value, and the deviation
from the reference value is not accounted for by the reproduci-
bility standard deviation reported by the laboratory. Moreover,
the low reproducibility standard deviation may give the
laboratorys customers a false impression of the laboratorys
performance. On the other hand, Laboratory B is concerned
with all aspects of the measurement. The laboratory concludes
that the values assigned to the calibrators purchased from
Company A are exact, and that bias from the measurement
principle is absent. As no corrections are introduced, Laboratory
B arrives at the same result of measurement as Laboratory A.
However, Laboratory B estimated the calibrators values to be
exact and the measurement principle to be free of bias with
some uncertainty. These uncertainty components are combined
Published on 01 January 1998. Downloaded on 28/10/2014 14:17:14.
with the laboratorys reproducibility to yield a combined
uncertainty of the result of measurement. Contrary to the
reproducibility standard deviation, the uncertainty describes the
deviation from the reference value.
The results produced by Laboratory B will be in agreement
with results produced by other laboratories following the same
principles of uncertainty estimation. An example of uncertainty
evaluation of a method for determination of cobalt in urine is
shown in Fig. 2. More examples of practical applications of the
uncertainty concept within the field of analytical chemistry are
becoming available27,28 and more are needed.
The introduction of the concept of uncertainty (as defined in
the VIM18) in analytical chemistry is not a straightforward task.
One important question is how to handle uncertainty compo-
nents that cannot be evaluated by statistical treatment of data
from repeated measurements, i.e., the so-called Type B
uncertainty components. The uncertainty of defining the
measurand, a significant problem in, e.g., determination of
proteins, cannot easily be attacked by statistical means.
Moreover, in environmental analyses the matrix may differ very
much between samples, and in practice it is difficult to estimate
the matrix interference for all types of samples, although such
an influence is presumed to exist. The uncertainty of such
components can only be evaluated by taking all available
information in consideration. This information could be lit-
erature data, data from a manual, data obtained by other assays,
or judgement carried out by an expert.27 This may seem
forbidden to the chemist who clings to scientific objectivity, but
one must recall that such less objective procedures are already
in use in other scientific fields, e.g., in risk analysis of
chemicals, which involves extrapolation between species and
application of a variety of safety factors in the process. The
scientist must recognize, that the doubt about the exactness of a
measurement result (i.e., the uncertainty) cannot always be
Fig. 2 Example of uncertainty evaluation of a method for the analysis of
cobalt in urine. The relation between the total uncertainty, RSDtot, and the
single uncertainty components, RSDi, is calculated using the equation
(RSDtot )2 = S (RSDi )2 . Major contributions to the total uncertainty in this
example are recovery and matrix effects.
View Article Online
Analyst, January 1998, Vol. 123 9
quantified with the same scientific objectivity as the result itself.
This situation may be acceptable as long as the evaluation of
uncertainty is clearly documented. In the discussion of
uncertainty it must be remembered that the measurement result
is the primary outcome of a measurement and the uncertainty is
a secondary (but not insignificant) outcome.
International measurement evaluation programme
Demonstrating the need for reference measurements, the
Institute for Reference Materials and Measurement (IRMM) in
1988 set up the International Measurement Evaluation Pro-
gramme (IMEP). In IMEP the results from the participating
laboratories are compared with a reference range that contains a
value that is traceable to SI system of measurements in order to
give an objective picture of the state-of-the-art practice of
measurements in field. The reference values are either certi-
fied or assigned, and to qualify as a certified reference value
measurements must have been performed with a primary
method of measurements yielding reference values traceable to
international system of units (SI). All reference values in IMEP
are accompanied by combined uncertainties taking into account
all known sources of uncertainty. With the reference values
traceable to SI, a transparent realisation of international
comparability of results has been performed and presently
IRMM is making preparations for a large study scheduled for
19971998. The starting point is to establish traceable values
for as many of the following inorganic components as possible:
Ca, Cu, Fe, K, Li, Mg, Na, Se, Zn, in human liquid serum.
Furthermore, future rounds of IMEP are planned to evaluate
measurements of Pb and Cd in whole blood, Cd in urine and Al
in serum.17
Trends in standardization
In 1997 the guidance document EAL-G25 was released by
European Cooperation for Accreditation of Laboratories
(EAL).30 The document is a supplement to ISO/IEC Guide 2521
with special emphasis on the accreditation of medical laborato-
ries. As in the ISO/IEC Guide 25 validation of analytical
methods is required. It is stressed that standard or published
methods shall not be taken for granted and their implementation
in the laboratory shall be validated. Validation of new, original
or in-house methods and procedures shall necessary be more
comprehensive. For a measurement procedure, validation shall
include, as appropriate, calibration function, analytical specific-
ity, and sensitivity. It shall also include investigation of useable
calibration materials (e.g., their traceability), estimation of the
uncertainty of measurements (after corrections for known
systematic deviations and based on within and between run
variations) and suitable control systems (control materials,
internal quality control and external quality assessment).
Moreover, the laboratory will have to demonstrate the useful-
ness of the results, e.g., by establishing reference intervals, by
participation in EQA schemes based on human samples and by
establishing the clinical sensitivity and specificity. The total
uncertainty of measurements (including sampling) should be in
accordance with the clinical requirements for accuracy.30
Recognizing the value of intercomparison studies in external
quality control, both ISO and IUPAC have issued guidelines
focusing on interlaboratory studies.32,33 A fertile ground for
harmonization and collaboration among EQA scheme organiz-
ers already exists: in 1996, the European Committee for EQA
Programmes in Laboratory Medicine (EQALM), was estab-
lished. EQALM is a forum for cooperation and exchange of
knowledge about quality-related matters, especially with regard
to external quality assessment. Among other activities, EQALM
intends to organise meetings with scientific or practical themes

10 Analyst, January 1998, Vol. 123
for members and other interested parties, to establish working
groups related to specific scientific matters and to issue
scientific publications. Only organizations or regional EQA
schemes with more than 100 participants can become full
members.34
Serious errors may occur at the state of sampling. Therefore,
sample collection guidelines (technical report) for trace ele-
ments in blood and urine have been issued by IUPAC.35 The
guidelines include the most important elements measured in
occupational and clinical chemistry and embraces harmonized
procedures for collection, preparation, analysis and quality
control.
Recently, it has been decided that the coming revison of ISO/
IEC Guide 25 will be upgraded to international standard and, in
addition to this, the coming revision of EN 45001 will be in
concordance with the revised ISO/IEC Guide 25.36 However,
Published on 01 January 1998. Downloaded on 28/10/2014 14:17:14.
standardization by itself will not result in improvements of the
quality of output. The classical quality management is focused
on corrective actions to be made in order to secure continuous
conformity to the proper standards. A new trend is gradually
introduced in the field of analytical chemistry: total quality
management (TQM) which focuses on continuous quality
improvements. The motivation for improvements will not arise
from standard-regulated activities. Improvements occur when
the analysts are constantly on the lookout for problems, and
have sufficient energy and vitality to improve the quality of
their work. In this context, TQM puts greater weight on attitudes
towards quality than does classical quality management.
As a consequence of the increasing use of laboratory
management systems (LIMS) the U.S. Environmental Protec-
tion Agency, EPA, has developed Good Automated Laboratory
Practices (GALP) which provide the users with principles and
guidance for regulations to assure data integrity in automated
laboratory operations.37 The document includes a guidance for
implementation. The GALPs are developed to assure the
reliability of data prepared by laboratories using LIMS to
acquire, record, manipulate, store and archive data.
Discussion
The reliability and usefulness of any test result depends
critically on the competence of the laboratory carrying out the
test. Laboratory accreditation provides the laboratory with an
independent evaluation and recognition of technical compe-
tence to perform specific tests. The evaluation covers all aspects
of the laboratory operations and is made by technical experts
and quality professionals.
In the near future, accreditation will provide users of test
results with a network of serious and well recognized clinical
laboratories where quality control is a matter of daily routine.
Furthermore, accreditation will increasingly become a demand
from legal authorities as a great advantage from accreditation is
the mutual recognition of test results. ISO 900138 or ISO 900239
certification of A laboratories and certification of personnel are
not expected to attract laboratories performing routine analyses,
but it may be an interesting alternative for laboratories working
with research (ISO 9001). Nomination and accreditation of
national reference laboratories in the field of clinical chemistry
may serve as an enforcing factor to introduce a greater extent of
traceability. Reference laboratories can provide traceability by
participation in international EQA schemes, the IMEP pro-
gramme and by production of CRMs with matrices relevant for
clinical laboratories. The production of speciation CRMs may
be another challenge for the national reference laboratories.
Today most EQA schemes covering metal analyses are not
operated on a metrological basis. Most of the schemes provide
the participants with an evaluation based on consensus values,
trimmed means, etc., which can be sensitive to group bias
View Article Online
among participants. The consensus mean value (if necessary
after exclusion of outliers) may be deemed very reliable if the
EQA scheme involves many laboratories and with representa-
tion of many different methods including definitive methods.
However, the use of an assigned value obtained from concurrent
results from a number of expert laboratories is preferable. Only
few schemes offer traceability together with the assigned value.
This problem should not be solved by using CRMs as control
samples in EQA schemes as stocks of the CRMs soon would run
out. However, the concept of the IMEP programme is a valuable
possibility for obtaining traceability in a EQA scheme and
further initiatives must be encouraged.
The expression of the uncertainty of a result allows
comparison of results with reference values given in specifica-
tions and standards. The accreditation standard EN 45001 and
the ISO Guide 25 call for uncertainty to be reported for
measurement results. Although this demand represents a
significant progress because it recognizes that the quality of
measurement results is important for the use of the data, this
progress is not reflected, in general, in the design of external
quality control schemes or in the guidelines for holding
interlaboratory studies. In other words, the performance of a
laboratory is still judged on the basis of the distance between the
result reported by the laboratory and the target value (calculated
by the scheme organizer). The distance may be deemed
acceptable or not acceptable according to some limits common
to all laboratories. However, these limits do not reflect the
individual uncertainties of the laboratories and it may happen
that a result is denoted unacceptable although it is satisfactory
viewed from the perspective of the laboratory (see Fig. 3).
Introduction of measurement uncertainty in EQA schemes will
allow a more harmonized and up-to-date comparison of the test
result obtained by the laboratories with the target values and
acceptability limits: if the confidence interval of the laboratory
result overlaps the acceptance interval in the EQA evaluation,
the performance should be considered as acceptable. On the
other hand, if the interval is not overlapping, a discrepancy
exists which must be investigated and explained by the
laboratory.
The benefit gained from interlaboratory studies like EQA
schemes depends on the design of the scheme. Critical subjects
are estimation of the target value, sample distribution, commu-
nication and feedback among participants and scheme organizer
and the internal politics of the participating laboratory (Are the
results reviewed and discussed? If necessary, are improvements
initiated?).40 Participation of the laboratories in EQA schemes
is required by the accreditation bodies. In this context, it is
important that scoring results from participation on EQA
schemes are transparent to the laboratories and the accreditation
bodies. Poor performance must be subject to a careful
Fig. 3 Performance evaluation in external quality assessment. When the
laboratory result is outside the acceptance range (shaded area) the
laboratory performance will traditionally be deemed unacceptable.
However, if the EQA evaluation takes notice of the uncertainty of the
laboratory result (illustrated by the normal distribution) the laboratory
performance should rightfully be deemed acceptable.

examination by the laboratory in order to explain what caused
the bad result. The importance of harmonization of existing
schemes with respect to performance score must be stressed as
this factor imposes a major instigation for improvement of
laboratory performance. Further steps in the harmonization of
EQA schemes covering trace elements in clinical chemistry
should involve harmonization of acceptability limits for results
and expected standard deviation for analytes of major concern,
i.e., those for which biological exposure indices have been
established. In view of the importance of EQA schemes in
relation to the accreditation process, the need for organizers of
EQA schemes to adhere to an internationally accepted protocol
and to become either accredited or certified will be adressed in
the future.
Today numerous national EQA schemes exist covering e.g.,
the parameter lead in blood.41 Collaboration among EQA
Published on 01 January 1998. Downloaded on 28/10/2014 14:17:14.
scheme organizers would possibly reduce the number of EQA
schemes with a small number of participants leaving resources
for EQA schemes to cover less common parameters like
different element species.
The visible effect of the quality work applied to analytical
chemistry is unfortunately affected by the unacceptable high
number of human errors. In a recent interlaboratory study we
experienced that approximately 5% out of 2462 reported results
were affected by human errors, mostly simple calculation errors
and reporting of wrong units of measurement. Blunders were
reported by 25% of the participating laboratories. In this
context, the underlying philosophy of continuous quality
improvement from TQM seems to be a valuable step forward. It
may be expected that the number of blunders occurring in
analytical measurements will decrease if the analytical laborato-
ries implement TQM
Conclusion
Future demands of laboratories working in the field of clinical
chemistry are implementation of traceability and uncertainty,
the two indispensable concepts in metrology. Measurement
results are no longer acceptable without a statement of a
standard uncertainty.
Participation in EQA is required in accreditation and,
therefore, EQA scheme organizers should adhere to an
internationally recognized and harmonized protocol thus pro-
viding more transparency in the results to the laboratories and
accreditation bodies. With the implementation of traceability
and uncertainty and with revised evaluation of laboratory
performance in EQA schemes, the field of clinical chemistry
will be entering a new era based on sound metrology rather than
just comparability.
References
1 International Standards Organisation, Accuracy (Trueness and Preci-
sion) of Measurement Methods and Results. Part 1: General
Principles and Definitions, ISO Standard 5725-1, ISO, Geneva,
1994.
2 Broderick, B. E., Cofino, W. P., Cornelis, R., Heydorn, K., Horwitz,
W., Hunt, D. T. E., Hutton, R. C., Kongston, H. M., Muntau, H.,
Baudo, R., Rossi, D., vaan Raaphorst, J. G., Lub, T. T., Schramel, P.,
Smyth, F. T., Wells, D. E., and Kelly, A. G., Mikrochim. Acta, 1991,
II, 523.
3 Wernimont, G. T., Use of Statistics to Develop and Evaluate
Analytical Methods, ed. Spindley, W., Association of Official
Analytical Chemists, Arlington, VA, 1985.
4 Christensen, J. M., Poulsen, O. M., and Anglov, T., in Handbook on
Metals in Clinical and Analytical Chemistry, ed. Seiler, H. G., Sigel,
A., and Sigel, H., Marcel Dekker, New York, 1994, pp. 4546.
5 Christensen, J. M., Mikrochim. Acta, 1996, 123, 231.
View Article Online
Analyst, January 1998, Vol. 123 11
6 International Standards Organisation, Control Charts - General
Guide and Introduction, ISO 7870, ISO, Geneva, 1993.
7 International Standards Organisation, Control Charts for Arithmetic
Means and Warning Limits, ISO 7873, ISO, Geneva, 1993.
8 International Standards Organisation, Acceptance Control Charts,
ISO 7966, ISO, Geneva, 1993.
9 International Standards Organisation, Shewhart Control Charts, ISO
8258, Geneva, 1991.
10 Thompson, M., and Wood, R., Pure Appl. Chem., 1995, 67, 649.
11 International Standards Organisation, Uses of Certified Reference
Materials, ISO Guide 33, ISO, Geneva, 1989.
12 Cornelis, R., Mikrochim. Acta, 1991, III, 37.
13 General criteria for the operation of testing laboratories, Committe
Europeen de Normalisation/Committe Europeen de Normalisation
Electrotechnique, Brussels, EN 45001, 1989.
14 Christensen, J. M., and Olsen, E., Ann. Ist. Super. Sanit`a, 1996, 32,
285.
15 European Commission, Guidelines for the Production and Certifica-
tion of BCR Reference Materials, Doc. BCR/48/93, Commission of
the European Community, Brussels, 1994.
16 Taylor, B. N., and Kuyatt, C. E., Guidelines for evaluating and
expressing the uncertainty of NIST measurement results. NIST
Technical Note 1297, 1994 edn., United States Department of
Commerce, National Institute of Standards and Metrology, Gaithers-
burg, MD.
17 Lamberty, A., Van Nevel, L., Moody, J. R., and De Bievre, P.,
Accred. Qual. Assur., 1996, 1, 71.
18 Bureau International des Poids et Mesures, International Electro-
chemical Commision, International Federation of Clinical Chemistry,
International Organization for Standardization, International Organi-
zation for Pure and Applied Chemistry, International Organization
for Pure and Applied Physics and International Organization of Legal
Metrology, International Vocabulary of Basic and General Terms in
Metrology, ISO, Geneva, 1993.
19 Christensen, J. M., Kristiansen, J., Heydorn, K., Damsgaard, E., and
Cornelis, R., IAEA meeting report, in the press.
20 Klich, H., in Quality Assurance and TQM for Analytical Laborato-
ries, ed. Parkany, M., The Royal Society of Chemistry, Cambridge,
1995, pp. 8085.
21 Rasberry, S., ISO/REMCO, ISO, Geneva, 1995.
22 International Standards Organisation, Contents of Certificates of
Reference Materials, ISO Guide 31, ISO, Geneva, 1981.
23 International Standards Organisation, International Organization for
Standardization, ISO Guide 34, ISO, Geneva, 1996.
24 International Standards Organisation, Certification of Reference
MaterialsGeneral and Statistical Principles, ISO Guide 35, ISO,
Geneva, 1989.
25 Taylor, J. K., Handbook for SRM Users, ed. Trahey, N. M, United
States Department of Commerce, National Institute of Standards and
Metrology, Gaithersburg, MD, 1993.
26 Kristiansen, J., Christensen, J. M., Lillemark, L., Linde, S. A., Merry,
J., Nyeland, B., and Petersen, O., Fresenius J. Anal. Chem., 1995,
352, 157.
27 Bureau International des Poids et Mesures, International Electro-
chemical Commission, International Federation of Clinical Chem-
istry, International Organization of Standardization, International
Union of Pure and Applied Chemistry, International Union of Pure
and Applied Physics and International Organization of Legal
Metrology, Guide to the Expression of Uncertainty in Measurement,
ISO, Geneva, 1993.
28 Kristiansen, J., Christensen, J. M., and Nielsen, J. L., Mikrochim.
Acta, 1996, 123, 241.
29 Kristiansen, J., and Christensen, J. M., Ann. Clin. Biochem., in the
press.
30 European cooperation for Accreditation of Laboratories, European
Confederation of Laboratory Medicine, Publication EAL-G25,
Accreditation for Medical Laboratories, EAL/ECLM, 1997.
31 International Standards Organisastion, General Requirements for the
Competence of Testing and Calibration laboratories, ISO/IEC Guide
25, ISO, Geneva, 1990.
32 Proficiency Testing by Interlaboratory IntercomparisonsPart 1:
Development and Operation of Proficiency Testing SchemesPart
2: Selection and Use of Proficiency Testing Schemes by Laboratory
Accreditation Bodies, ISO, Geneva, 1996.
33 Thompson, M., and Wood, R., Pure Appl. Chem., 1993, 65, 2123.
34 Uldall, A., EQAnews, 1996, 8, 3.
 View Article Online

12 Analyst, January 1998, Vol. 123

35 Cornelis, R., Heinzow, B., Herber, R. F. M., Molin Christensen, J., 39 International Standards Organisation, Quality SystemsModel for
Poulsen, O. M., Sabbioni, E., Templeton, D. M., Thomassen, Y., Quality Assurance in Production, Installation and Servicing, ISO
Vahter, M., and Vesterberg, O., Pure Appl. Chem., 1995, 67, 1575. 9002, ISO, Geneva, 1994.
36 van de Leemput, P. J. H. A. M., Accred. Qual. Assur., 1997, 2, 40 Taylor, A., Mikrochim. Acta, 1996, 123, 251.
263. 41 Taylor, A., Patriarca, M., Menditto, A., and Morisi, G., Ann. Ist.
37 Good Automated Laboratory Practices, U.S. Environmental Protec- Super Sanit`a, 1996, 32, 295.
tion Agency, North Carolina, 1995.
38 International Standards Organisation, Quality SystemsModel for Paper 7/06358J
Quality Assurance in Design, Development, Production, Installation Received September 1, 1997
and Servicing, ISO 9001, ISO, Geneva, 1994. Accepted October 29, 1997
Published on 01 January 1998. Downloaded on 28/10/2014 14:17:14.