Trends Trends in Analytical Chemistry, Vol. 28, No.

2, 2009

Commonly used methodologies

for inorganic analysis in international
key comparisons
Yiu-chung Yip, James Chung-wah Lam, Wai-fong Tong

The Consultative Committee for Amount of Substance Metrology in Chemistry (Comite Consultatif pour la Quantite de Matiere,
CCQM) has the task of organizing international key comparisons. The main purpose is to establish a technical basis for mutual
recognition of measurement capabilities among national measurement institutes (NMIs) in the field of chemical measurement.
More importantly, key comparison results provide an effective means of assessing the degree of equivalence of measurement
standards used at different NMIs. Since 1998, the Inorganic Analysis Working Group of CCQM has been identifying and
organizing key comparisons for the determination of analytes, such as elements, inorganic compounds and organo-metallic
compounds in various matrices.
Methodologies, including inorganic mass spectrometry [e.g., isotope dilution mass spectrometry (IDMS) and species-specific
IDMS], inductively coupled plasma atomic emission spectrometry, neutron activation analysis, ion chromatography, high
performance liquid chromatography, X-ray fluorescence spectrometry, flame atomic absorption spectrometry (AAS) and
graphite furnace AAS, have provided satisfactory results in terms of accuracy and precision.
Complex sample matrices examined so far include inorganic solutions and water (e.g., calibration solutions and natural
water), metal and metal alloys (e.g., steel and aluminum alloy), biological fluids, materials and food (e.g., serum, rice, wine,
shellfish, salmon fish, tomato and bovine liver), fuels (e.g., diesel), sediments and soils (e.g., sediments and sewage sludge). The
use of IDMS for elemental analysis has attracted considerable attention.
In this review, we focus on commonly used methodologies for inorganic analysis in CCQM key comparisons between 1998
and 2007, and we suggest potential areas for strategic research and development.
2008 Elsevier Ltd. All rights reserved.

Keywords: CCQM; Elemental analysis; Inductively coupled plasma atomic emission spectrometry; Inorganic analysis; Isotope dilution mass
spectrometry; Key comparison; National measurement institute; Methodology; Neutron activation analysis; Species-specific isotope dilution mass
spectrometry

Yiu-chung Yip*, Wai-fong Tong 1. Introduction purpose of the Convention is to establish

Government Laboratory, Ho a permanent organization for member
Man Tin Government Offices,
Metrology is defined as the scientific study governments to work on matters relating
88 Chung Hau Street, Kowloon,
Hong Kong, Hong Kong Special
of measurement [1]. Kaarls has described to units of measurement. The Convention
Administrative Region, China significant developments in metrology in gives authority to the General Conference
chemistry [2]. Ting et al. paid particular on Weights and Measures (Conference
James Chung-wah Lam attention to the role of metrology in Generale des Poids et Mesures, CGPM),
Center for Coastal Pollution and
chemistry in upholding public health and the International Committee for Weights
Conservation and Centre for
Marine Environmental Research
food safety [3]. The need for measurement and Measures (Comite International des
and Innovative Technology, results that are traceable to the Interna- Poids et Mesures, CIPM) and the Inter-
Department of Biology and tional System of Units (Systeme Interna- national Bureau of Weights and Mea-
Chemistry, City University of tional dUnites, SI) and comparable sures (Bureau International des Poids et
Hong Kong, Kowloon, Hong
worldwide is of concern to analytical lab- Mesures, BIPM) to act in matters of
Kong, Hong Kong Special
Administrative Region, China
oratories, government authorities, indus- metrology (Fig. 1). Nowadays, 20 May is
tries and the public. known as the World Metrology Day to
*
The Convention of the Meter forms the mark this historic occasion.
Corresponding author.
basis of metrology. On 20 May 1875, the In 1960, the CGPM adopted the SI as
Tel.: +852 27623862;
Fax: +852 27151737;
representatives of seventeen nations the practical system of units of mea-
E-mail: ycyip@govtlab.gov.hk signed the Convention in Paris [4]. The surement. The seven base units are as

214 0165-9936/$ - see front matter 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.trac.2008.09.013
Trends in Analytical Chemistry, Vol. 28, No. 2, 2009 Trends

The Convention
of the Meter

CGPM CIPM BIPM

Ensure the propagation Provide worldwide Provide the basis for a

and improvement of SI uniformity in units of single coherent system
measurement of measurement that is
traceable to SI

CCQM

Present activities
concerning primary
methods for measuring
the amount of substance

Organize a series of
international key
comparisons for the
purpose of establishing
the technical basis for
mutual recognition of
measurement
capabilities among
NMIs in the field of
chemical measurement

Figure 1. Organizational structure of The Convention of the Meter, CGPM, CIPM, BIPM and CCQM.

follows: meter (m), kilogram (kg), second (s), ampere
(A), Kelvin (K), mole (mol), and candela (cd) [5].
Among other base units, the mole is of interest to
chemists. The CIPM defined the mole in 1967 and
the CGPM adopted it (1971, Resolution 3) as fol-
lows:
(1) The mole is the amount of substance [6] of a
system that contains as many elementary entities
as there are atoms in 0.012 kg of carbon 12, which
are unbound, at rest and in their ground state [7];
its symbol is mol.
(2) When the mole is used, the elementary entities
must be specified and may be atoms, molecules,
ions, electrons, other particles, or specified groups
of such particles.
The CIPM set up the Consultative Committee for
Amount of Substance Metrology in Chemistry (Comite
Consultatif pour la Quantite de Matiere, CCQM) in 1993.
Two major tasks of the CCQM are:
(i) to present activities concerning primary methods
for measuring the amount of substance; and,
(ii) to organize a series of international key comparisons
for the purpose of establishing a technical basis for
mutual recognition of measurement capabilities
among national measurement institutes (NMIs) in
the field of chemical measurement [8].
Results of key comparisons are intended to support the
statements of Calibration and Measurement Capabilities
(CMCs), as listed in Appendix C of the Mutual Recogni-
tion Arrangement of the International Committee for
Weights and Measures (CIPM MRA) [9]. More impor-
tantly, the results provide an effective means of assessing
the degree of equivalence of measurement standards
used at different NMIs.
In this review, we focus on commonly used meth-
odologies for inorganic analysis in CCQM key com-
parisons between 1998 and 2007 and we suggest
potential areas for strategic research and development.
Moreover, we would like to share the article with
green NMIs and designated institutes (DIs) that are
committed to the development of metrology in chem-
istry.

http://www.elsevier.com/locate/trac 215
Trends Trends in Analytical Chemistry, Vol. 28, No. 2, 2009

Table 1. Measurement service categories and relevant key comparisons

Measurement service Sub-category Key comparison

category
1. High purity chemicals 1.1 Inorganic compounds; 1.2 Organic compounds;
1.3 Metals; 1.4 Isotopics; 1.5 Other
2. Inorganic solutions 2.1 Elemental; 2.2 Anionic; 2.3 Other CCQM-K8 (Mono-elemental calibration solutions of
aluminum, copper, iron and magnesium); CCQM-K29 &
29.1 (Anion calibration solutions)
3. Organic solutions 3.1 PAHs; 3.2 PCBs; 3.3 Pesticides; 3.4 Other
4. Gases 4.1 High purity; 4.2 Environmental; 4.3 Fuel; 4.4
Forensic; 4.5 Medical; 4.6 Other
5. Water 5.1 Fresh water; 5.2 Contaminated water; 5.3 Sea CCQM-K2 (Cadmium and lead in natural water)
water; 5.4 Other
6. pH
7. Electrolytic
conductivity
8. Metal and metal 8.1 Ferrous metals; 8.2 Non-ferrous metals; 8.3 CCQM-K33 (Minor elements in steel); CCQM-K42
alloys Precious metals; 8.4 Other (Constituents of an aluminum alloy)
9. Advanced materials 9.1 Semiconductors; 9.2 Superconductors; 9.3
Polymers and plastics; 9.4 Ceramics; 9.5 Other
10. Biological fluids and 10.1 Blood serum; 10.2 Renal fluids; 10.3 Hair; 10.4 CCQM-K14 (Calcium in human serum); CCQM-K24
materials Tissues; 10.5 Bone; 10.6 Botanical materials; 10.7 (Cadmium in rice); CCQM-K31 (Arsenic in shellfish);
Other CCQM-K43 (Organo-mercury in salmon); CCQM-K45
(Toxic metals in food); CCQM-K49 (Toxic and essential
elements in bovine liver)
11. Food 11.1 Nutritional constituents; 11.2 Contaminants; CCQM-K24; CCQM-K30 (Lead in wine); CCQM-K31;
11.3 GMOs; 11.4 Other CCQM-K43; CCQM-K45; CCQM-K49
12. Fuels 12.1 Coal and coke; 12.2 Petroleum products; 12.3 CCQM-K35 (Sulfur in diesel fuel)
Bio-mass; 12.4 Other
13. Sediments, soils, ores 13.1 Sediments; 13.2 Soils; 13.3 Ores; 13.4 CCQM-K13 & 13.1 (Amount content of cadmium and lead
and particulates Particulates; 13.5 Other in sediment); CCQM-K28 (Tributyltin in sediment);
CCQM-K44 (Trace metals in sewage sludge)
14. Other materials 14.1 Cements; 14.2 Paints; 14.3 Textiles; 14.4
Glasses; 14.5 Thin films; 14.6 Coatings; 14.7
Insulating materials; 14.8 Rubber; 14.9 Adhesives;
14.10 Other

2. Measurement service categories and key
comparisons
Regarding the determination of analytes (e.g., elements,
inorganic compounds and organo-metallic compounds),
the Inorganic Analysis Working Group (IAWG) of CCQM
is responsible for planning and organizing key compar-
isons that cover relevant measurement service categories
(MSCs) in the context of existing or planned CMCs (Table
1).
Each key comparison has its own rationale for
choosing a specific analyte (or several analytes) in a
particular matrix. In view of the complexity of sample
matrices and the difficulty of analyte determination, a
pilot study is sometimes organized to obtain satisfactory
agreement among participants prior to scheduling a
key comparison. Participants are encouraged to employ
their own methods of measurement. Coordinating lab-
oratories are responsible for preparing test samples,
homogeneity and stability tests, distribution of samples
and the technical protocol (i.e. instructions to partici-
pants), calculation of key comparison reference values
(KCRVs) and equivalence statements, and compilation
of final reports. Each KCRV can be calculated as mean,
weighted mean, median, or mixture model median [10].
To facilitate our discussions, we briefly describe below
the rationales of the key comparisons (19982007)
under respective MSCs. Table 2 summarizes details of the
key comparisons.
2.1. Inorganic solutions and water
 CCQM-K2 (Cadmium and lead in natural water; Table
2, Entry 1) [11]: The comparison was a continuation
of CCQM-1 study Lead in Water and focused on the
measurement of Cd and Pb in natural water.
 CCQM-K8 (Mono-elemental calibration solutions of
aluminum, copper, iron and magnesium; Table 2,
Entry 2) [12]: Aqueous mono-elemental solutions
are usually used as calibrants for elemental analysis.
Inaccuracy with respect to declared values and quoted
uncertainties has been found in some commercially
available standards. The comparison provided NMIs
with an opportunity to demonstrate their capabilities
in the measurement of elements in pure solutions
with high accuracy.

216 http://www.elsevier.com/locate/trac
 Trends in Analytical Chemistry, Vol. 28, No. 2, 2009
Table 2. CCQM key comparisons (19982007)

Entry CCQM (Time of Matrix KCRV uncertainty (coverage Sample preparation and measurement Range of relative Coordinating
measurement, factor, k; no. of participants results uncertainties reported by laboratory / Ref.
Status) used for calculating KCRV, n; where participants (coverage
applicable) factor, k; no. of participants
involved, n)
1 CCQM-K2 (1998, Natural water Cd (calculated as mean): Measurement (instrument): Cd: 0.274.6% (k = 2; n = 9) Institute for
approved for (83.49 0.83) nmol/kg (k = 1; n = 9)  IDMS (ICP-MS, ICP-SMS) Reference Materials
equivalence) Pb: (calculated as mean): Pb: 0.464.1% (k = 2; n = 9) and Measurements
(62.79 1.33) nmol/kg (k = 1; n = 9) (IRMM) [11]
2 CCQM-K8 (1999 Calibration Al (gravimetric value): Measurement (instrument): Al: 0.030.60% (k = 1; Swiss Federal
2000, approved for solutions (0.99685 0.00040) g/kg (k = 1)  IDMS (ICP-MS, TIMS) n = 13) Laboratories for
equivalence) Cu (gravimetric  ICP-MS Cu: 0.020.53% (k = 1; Materials Testing
value):(0.98819 0.00003) g/kg  ICP-AES n = 13) and Research
(k = 1)  Titrimetry (EMPA) [12]
Fe (gravimetric  Gravimetry Fe: 0.020.52% (k = 1;
value):(1.01966 0.00010) g/kg  Electrogravimetry n = 13)
(k = 1)  Controlled potential coulometry
Mg (gravimetric Mg: 0.020.67% (k = 1;
value):(1.00428 0.00009) g/kg n = 13)
(k = 1)
3 CCQM-K13 (2000, Sediment Cd (calculated as median): Sample preparation: Cd: 1.15.5% (k: 23; IRMM [25]
approved for (5.41 0.17) lmol/g (k = 2; n = 12)  Microwave digestion / wet ashing / open n = 12)
equivalence) system (HF, HNO3, HCl, HClO4, H2O2)

Pb (calculated as median): Measurement (instrument): Pb: 0.43.7% (k: 22.2;

4 CCQM-K13.1
(2004, approved for
equivalence)
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(169.9 1.6) lmol/g (k = 2; n = 14)
Sediment Cd & Pb: KCRV assigned for CCQM-
K13 was used.
 IDMS (TIMS, Q-ICP-MS, ICP-SMS) n = 14)
 External standard calibration (ICP-SMS)
Sample preparation: Cd: 1.26.1% (k = 2; n = 2) National Institute of
 Microwave digestion (HF, HNO3, HClO4, Standards and
H2O2) Technology (NIST)
[26]
Measurement (instrument): Pb: 0.83.0% (k = 2; n = 2)

 IDMS (ICP-MS, ICP-SMS)

5 CCQM-K14 (2003, Human serum Ca (calculated as weighted mean): Sample preparation: Ca: 0.54.3% (k = 2; n = 9) IRMM [17]
approved for (2.239 0.011) mmol/kg (k = 2;  Microwave digestion / digestion with a
equivalence) n = 9) high pressure asher / digestion with a hot
plate (HF, HNO3, HClO4, H2O2)
 Cation-exchange chromatography
Measurement (instrument):
 IDMS (TIMS, C/RC Q-ICP-MS, ICP-MS
cold plasma, ICP-SMS)
 ICP-AES and AAS

Trends
217

(continued on next page)

218

Trends
Table 2. (continued)

Entry CCQM (Time of Matrix KCRV uncertainty (coverage Sample preparation and measurement Range of relative Coordinating
http://www.elsevier.com/locate/trac

measurement, factor, k; no. of participants results uncertainties reported by laboratory / Ref.

Status) used for calculating KCRV, n; where participants (coverage
applicable) factor, k; no. of participants
involved, n)
6 CCQM-K24 (2001, Rice Cd (calculated as mean): Sample preparation: Cd: 0.42.7% (k: 1.972; IRMM [18]
approved for (14.418 0.087) nmol/g (k = 2;  Microwave digestion / wet digestion (HF, n = 12)
equivalence) n = 12) HNO3, HCl, HClO4, H2O2)
 No sample dissolution / chemical separa-
tion was needed for INAA
Measurement (instrument):
 IDMS (TIMS, Q-ICP-MS, C/RC Q-ICP-MS,
ICP-SMS, MC-ICP-MS)
 INAA comparator method
7 CCQM-K28 (2003, Sediment Tributyltin (calculated as median): Sample preparation: Tributyltin: 2.58.9% (k = 2; Laboratory of
approved for (1.071 0.023) nmol/g TBT+ (k = 2;  Mechanical shaking / sonication / acceler- n = 6) Government
equivalence) n = 6) ated solvent extraction / microwave- Chemist (LGC) and
assisted extraction National Research
 Derivatization Council of Canada
(NRC) [27]
Measurement (instrument):
 Species-specific IDMS (GC-ICP-MS, GC-
ICP-SMS, HPLC-ICP-MS)
 GC-MS
8 CCQM-K29 (2003 Calibration Chloride (gravimetric value): Measurement (instrument) for chloride: Chloride:0.030.74% (k = 2; EMPA [13]
2004, approved for solutions (0.98854 0.00024) g/kg (k = 2)  Coulometry n = 10)

Trends in Analytical Chemistry, Vol. 28, No. 2, 2009

equivalence)  Titrimetry

Phosphate (gravimetric value): Measurement (instrument) for phosphate: Phosphate: 0.061.0%

(1.00447 0.00066) g/kg (k = 2)  Titrimetry (k = 2; n = 10)
 Gravimetry
 ICP-AES
 IC / UV-visible spectrometry
 IC / ICP-AES
 IC
 Ion-exchange chromatography followed
by coulometry

(continued on next page)

9 CCQM-K29.1 Calibration Chloride (gravimetric value): Measurement (instrument) for chloride: Chloride:0.030.48% (k = 2; Slovak Institute of
(2005, approved for solutions (1.00065 0.00024) g/kg (k = 2)  Coulometry n = 2) Metrology (SMU)
equivalence)  Titrimetry [14]
 measurement, factor, k; no. of participants results uncertainties reported by laboratory / Ref.
Status) used for calculating KCRV, n; where participants (coverage
applicable) factor, k; no. of participants
involved, n)

Trends in Analytical Chemistry, Vol. 28, No. 2, 2009

10 CCQM-K30 (2006 Wine Pb (calculated as mean): Sample preparation: Pb: 0.855.5% (k: 1.992.4; LGC [19]
2007, approved for (2.99 0.06) ng/g (k = 2.3; n = 9)  Microwave digestion / water-bath diges- n = 9)
equivalence) tion / digestion with a hot plate / sealed
vessel (HNO3, H2O2)
Measurement (instrument):
 IDMS (Q-ICP-MS, ICP-SMS, MC-ICP-MS)
11 CCQM-K31 (2002 Shellfish As (calculated as mean): Sample preparation: As: 1.915% (k = 2; n = 5) NIST [20]
2003, approved for (0.1117 0.00615) mmol/kg  Microwave digestion (HNO3,H2O2)
equivalence) (k = 2.78; n = 5)  No sample dissolution / chemical separa-
tion was needed for INAA

Measurement (instrument):
 External standard calibration (ICP-MS, C/
RC Q-ICP-MS, Flow injection-hydride
generation-GFAAS)
 Standard addition (GFAAS)
 INAA comparator method
12 CCQM-K33 (2003 Steel Minor elements include: Cr Measurement (instrument): Cr:0.353.6% (k: 22.2; National Metrology
2004, approved for (calculated as median):  IDMS (ICP-MS) n = 8) Institute of Japan
equivalence) (0.5091 0.0030) w % (k = 2; n = 8)  ICP-MS (NMIJ), NIST and
Mn (calculated as median):  ICP-AES Mn: 0.223.5% (k: 22.11; Federal Institute for
(0.5063 0.0016) w % (k = 2; n = 8)  Spectrophotometry n = 8) Materials Research
Ni (calculated as median):  XRF Ni: 0.283.5% (k: 1.972; and Testing (BAM)
(2.5490 0.0123) w % (k = 2; n = 7)  INAA n = 7) [15]
Mo (calculated as median):  Titrimetry Mo: 0.333.7% (k: 22.2;
(1.0393 0.0058) w % (k = 2; n = 8) n = 8)
13 CCQM-K35 (2003 Diesel fuel S (calculated as mixture model Sample preparation: S: 0.614.1% (k: 22.31; NIST [24]
2004, approved for median): (42.17 1.32) lg/g (k = 2;  Microwave digestion / digestion with a n = 4)
equivalence) n = 4) high-pressure asher / digestion with a
Carius tube (HNO3, H2O2)
Measurement (instrument):
 IDMS (TIMS, ICP-SMS)
14 CCQM-K42 (2004 Al alloy Constituents include: Mn (calculated Measurement (instrument): Mn:1.04.6% (k: 2.002.02; BAM [16]
2005, approved for as mean): (0.1084 0.0015) w %  ICP-MS n = 7)
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equivalence) (k = 2; n = 7)  ICP-OES
Cu (calculated as mean):  INAA Cu: 1.34.7% (k: 2.002.05;
(0.1098 0.0009) w % (k = 2; n = 6)  XRF n = 6)
Fe (calculated as mean): Fe: 1.44.7% (k: 2.002.03;
(0.2003 0.0014) w % (k = 2; n = 7) n = 7)
Cr (calculated as mean): Cr: 1.644.5% (k: 2.002.14;
(0.0442 0.0002) w % (k = 2; n = 7) n = 7)
Zn (calculated as mean): Zn: 0.95.6% (k: 1.982.00;
(0.1350 0.0015) w % (k = 2; n = 6) n = 6)
(continued on next page)

Trends
219
220
Table 2. (continued)
Entry CCQM (Time of Matrix KCRV uncertainty (coverage
measurement, factor, k; no. of participants results
http://www.elsevier.com/locate/trac
Status) used for calculating KCRV, n; where
applicable)
15 CCQM-K43 (2005, Salmon fish As: (calculated as mixture model
approved for median): (58.1 1.5) lmol/kg (n = 9)
equivalence) Hg: (calculated as mixture model
median): (0.3884 0.0056) lmol/kg
(n = 8)
Pb: (calculated as mixture model
median): (3.82 0.10) lmol/kg
(n = 5)
Se: (calculated as mixture model
median): (7.32 0.28) lmol/kg
(n = 10)
Methylmercury: (calculated as
mixture model median):
(0.373 0.023) lmol/kg (n = 5)
16 CCQM-K44 (2005, Sewage sludge Trace elements include: Cd and Hg:
measurements 0.510 mg/kg Cr and Ni: 50250 mg/
completed) kg Cu and Pb: 3001000 mg/kg Zn:
10005000 mg/kg
The final report of the comparison
has not been released and the KCRV
for the 7 analytes are not finalized.
Trends
Sample preparation and measurement Range of relative Coordinating
uncertainties reported by laboratory / Ref.
participants (coverage
factor, k; no. of participants
involved, n)
Sample preparation for the analysis of As, Hg, As: 1.35.7% (k = 2; n = 9) IRMM [21]
Pb and Se:
 Microwave digestion / digestion with a Hg: 0.674.8% (k = 2; n = 8)
high-pressure asher (HNO3, HCl, aqua
regia, HClO4, H2O2)
 No sample dissolution / chemical separa-
tion was needed for INAA
Measurement (instrument) for As: Pb: 2.16.3% (k = 2; n = 5)
 External calibration (ICP-MS)
 Standard addition (C/RC Q-ICP-MS)
 Internal standardization (C/RC Q-ICP-MS) Se:1.59.2% (k = 2; n = 10)
 INAA / k0-NAA
Measurement (instrument) for Hg: Methylmercury: 2.36.7%
 IDMS (Q-ICP-MS, C/RC ICP-MS, ICP-SMS, (k = 2; n = 5)
CV-ICP-MS)
Measurement (instrument) for Pb:
 IDMS (TIMS, Q-ICP-MS, C/RC Q-ICP-MS)
 External calibration (ICP-MS)
Measurement (instrument) for Se:
 IDMS (C/RC ICP-MS)
Trends in Analytical Chemistry, Vol. 28, No. 2, 2009
 External calibration (ICP-MS)
 INAA / k0-neutron activation analysis
Sample preparation for the analysis of
methylmercury:
 Extraction (concentrated HCl/NaDDTC,
Protease type XIV, TMAH, KOH/MeOH)
 Derivatization [NaB(C2H5)4, NaB(C3H7)4,
NaB(Ph)4]
Measurement (instrument) for methylmercury:
 Species-specific IDMS (GC-ICP-MS, GC-
ICP-SMS, HPLC-ICP-MS)
 GC-MS
Measurement (instrument): - IRMM
 IDMS (TIMS, Q-ICP-MS)
 External standard calibration (XRF, FAAS,
CVAAS)
 k0-NAA
 measurement, factor, k; no. of participants results
Status) used for calculating KCRV, n; where
applicable)
17 CCQM-K45 (2005, Tomato paste Sn (calculated as mean):
approved for (227.1 2.4) mg/kg (k = 2; n = 4)
equivalence)
18 CCQM-K49 (2006, Bovine Toxic and essential elements include:
report in progress) liver Fe (calculated as mixture model
median): (198.1 2.2) mg/kg (n = 14)
Zn (calculated as mixture model
median): (181.9 1.9) mg/kg (n = 13)
Se (calculated as mixture model
median): (2.056 0.077) mg/kg
(n = 5)
Cd (calculated as mixture model
median): (0.0976 0.0016) mg/kg
(n = 8)
Pb (calculated as mixture model
median): (0.0619 0.0012) mg/kg
(n = 9)
Cr (calculated as mixture model
median): (0.0514 0.0033) mg/kg
(n = 5)
As (calculated as mixture model
median): (0.01965 0.00131) mg/kg
(n = 5)
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221
uncertainties reported by laboratory / Ref.
participants (coverage
factor, k; no. of participants
involved, n)
Trends in Analytical Chemistry, Vol. 28, No. 2, 2009
Sample preparation: Sn: 0.622.6% (k = 2; n = 4) LGC [22]
 Microwave digestion (HNO3, HCl, H2O2)
Measurement (instrument):
 IDMS (Q-ICP-MS, C/RC Q-ICP-MS, ICP-SMS)
Sample preparation for the analysis of Fe, Zn, Se, Fe: 0.35.4% (k: 22.06; NIST [23]
Cd, Pb, Cr and As: n = 14)
 Microwave digestion / digestion in an open
system (HF, HNO3, HClO4, H2O2) Zn:0.55.1% (k: 22.13;
 No sample dissolution / chemical separation n = 13)
was needed for INAA
Measurement (instrument) for Fe: Se: 1.35.3% (k: 22.03;
 IDMS (ICP-MS) n = 5)
 External standard calibration (ICP-MS, ICP-
OES, FAAS) Cd: 0.66.2% (k:22.18;
 Standard additions (ICP-OES) n = 8)
 INAA comparator method Pb: 1.56.8% (k: 22.23;
n = 9)
Measurement (instrument) for Zn: Cr: 3.36.8% (k: 22.3; n =5)
 IDMS (ICP-MS, TIMS) As:4.414.9% (k: 22.4;
 External standard calibration (ICP-MS, ICP- n = 5)
OES,FAAS)
 Standard additions (ICP-OES)
 INAA comparator method
Measurement (instrument) for Se:
 IDMS (ICP-MS)
 External standard calibration (ICP-MS)
 INAA comparator method
Measurement (instrument) for Cd:
 IDMS (ICP-MS, TIMS)
 External standard calibration (ICP-MS)
 Standard additions (ICP-MS)
 RNAA comparator method
Measurement (instrument) for Pb:
 IDMS (ICP-MS)
 External standard calibration (ICP-MS)
 Standard addition (ICP-MS)
Measurement (instrument) for Cr:
 IDMS (ICP-MS)
 External standard calibration (ICP-MS)
 Standard additions (ICP-MS)
 INAA comparator method
Measurement (instrument) for As:
 External standard calibration (ICP-MS)
 Standard additions (ICP-MS, C/RC Q-ICP-MS)
Trends
 RNAA comparator method
Trends
 CCQM-K29 & 29.1 (Anion calibration solutions;
Table 2, Entries 89) [13,14]: Aqueous solutions
of anions are widely used for calibration, particu-
larly in environmental and medicinal investigations.
As deviations up to several percent of the declared
values have been found in some commercially avail-
able standards, it is necessary to develop reliable
methods for certification purposes.
2.2. Metals and metal alloys
 CCQM-K33 (Minor elements in steel; Table 2, Entry
12) [15]: To maintain the production of high quality
steel and steel products, accurate control and determi-
nation of minor elements (e.g., Cr, Mn, Ni and Mo) are
of concern. The amounts of minor elements can affect
product properties (e.g., tensile strength, hardness and
ductility). For example, stainless steel should contain
a minimum of 10% by weight of Cr.
 CCQM-K42 (Constituents of an aluminum alloy; Table
2, Entry 14) [16]: The comparison focuses on the
determination of constituent elements (Mn, Cu, Fe,
Cr and Zn) in aluminum alloy. The availability of a
robust method is important to guarantee the produc-
tion of high quality alloy products. As the final report
of the comparison has not been released, detailed
information is not readily available.
2.3. Biological fluids, materials and food
 CCQM-K14 (Calcium in human serum; Table 2,
Entry 5) [17]: The results of the determination of
Ca in serum samples are usually used for screening
bone diseases or calcium-regulation disorders. In
order to support routine clinical measurements,
there is a need to develop better methodology for
analysis.
 CCQM-K24 (Cadmium in rice; Table 2, Entry 6) [18]:
Cd, a suspected human carcinogen, may cause dys-
functions and reproductive deficiencies in humans.
As rice is the main foodstuff for approximately half
of the worlds population, it is necessary to keep the
contaminant at a level that is toxicologically accept-
able for consumption.
 CCQM-K30 (Lead in wine; Table 2, Entry 10) [19]:
Wine is an important dutiable commodity trading
all over the world. The Office International de la
Vigne et du Vin recommends that the maximum
mass fraction of Pb in wine be 0.2 mg/kg, which is
the threshold value prescribed by the European Com-
mission (EC) Regulation (466/2001). Analysis of toxic
metals (e.g., Pb) in wine is therefore essential for reg-
ulatory control.
 CCQM-K31 (Arsenic in shellfish; Table 2, Entry 11)
[20]: Arsenic is a toxic element and its determination
in shellfish tissues is of public health concern. As iso-
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Trends in Analytical Chemistry, Vol. 28, No. 2, 2009
tope dilution is not applicable to the analysis of mono-
isotopic elements, such as As, it is an analytical chal-
lenge to develop accurate methods based on other
techniques.
 CCQM-K43 (Organo-mercury in salmon fish; Table 2,
Entry 15) [21]: Methylmercury has a higher toxicity
than inorganic Hg and is the major form present in
fish and fish products. In order to protect public
health, it is important to ensure that the level of the
contaminant is below the Hg threshold value of 0.5
mg/kg, as stipulated in the EC Regulation (466/
2001).
 CCQM-K45 (Toxic metals in food; Table 2, Entry
17) [22]: The European Union (EU) regulatory limit
of Sn in food is 200 mg/kg. The scope of the com-
parison was to underpin the capability of NMIs in
the determination of Sn in food samples (e.g., toma-
to paste).
 CCQM-K49 (Toxic and essential elements in bovine
liver; Table 2, Entry 18) [23]: Bovine livers provide
high levels of essential elements (Fe, Zn and Se). How-
ever, toxic elements (Cd, Pb, Cr and As) may be accu-
mulated due to environmental pollution. The IAWG
designated the comparison as an exemplary study,
which requested all NMIs to carry out determination
of Zn and Fe for capability evaluation.
2.4. Fuels
 CCQM-K35 (Sulfur in diesel fuel; Table 2, Entry 13)
[24]: Diesel fuel with a sulfur content of less than
50 lg/g is commonly called ultra-low sulfur diesel
(ULSD). The production of ULSD is costly for both
petroleum industry stakeholders and consumers.
Nonetheless, reduction of sulfur in fuel is expected to
lower significantly atmospheric sulfur oxides, which
are the major pollutants leading to the formation of
acid rain. There is a demand for the provision of cer-
tified reference standards of diesel fuel that contain
sulfur near the EU regulatory limit of 50 lg/g (EURO
IV standard for fuel). Laboratories need reliable stan-
dards to validate the performance of the methods for
the determination of S in diesel fuel. In this regard,
a test sample with a sulfur level of approximately
40 lg/g was used in the comparison.
2.5. Sediments, soils, ores and particulates
 CCQM-K13 & 13.1 (Amount content of cadmium
and lead in sediment; Table 2, Entries 3 and 4)
[25,26]: The sample preparation of sediment is rela-
tively complicated and tedious due to the presence of
highly organic matrices. The comparison was in-
tended to address several challenging issues, includ-
ing analyte losses, higher blank values and matrix
interferences.
Trends in Analytical Chemistry, Vol. 28, No. 2, 2009
 CCQM-K28 (Tributyltin in sediment; Table 2, Entry 7)
[27]: In spite of the ban on the use of tributyltin as an
anti-fouling agent in paints, the high residual levels of
tributyltin in water and marine sediment samples
continue to pose an eco-toxicological threat to the
aquatic environment. Quantification of organotin spe-
cies is difficult because instability of analytes has been
observed during sample extraction. As such, it is nec-
essary to develop robust methods for examination.
 CCQM-K44 (Trace metals in sewage sludge; Table 2,
Entry 16): The EU promotes the use of sewage sludge
as a fertilizer on farmland and has set the concentration
limits for metals such as Cd, Hg, Cr, Ni, Cu, Pb and Zn in
sewage sludge (86/278/EEC Directive). The compari-
son was intended to assess the capabilities of NMIs in
the measurement of metals regulated by the Directive.
Detailed information is not available because the final
report of the comparison has not been released.
3. Methodologies
Methodologies commonly used for inorganic analysis in
CCQM key comparisons include:
(i) inorganic mass spectrometry (e.g., isotope dilution
mass spectrometry (IDMS), species-specific IDMS,
and inductively coupled plasma MS (ICP-MS));
(ii) inductively coupled plasma atomic emission spec-
trometry (ICP-AES); and,
(iii) neutron activation analysis (NAA).
Our evaluation of methodologies primarily focuses on
analytical considerations, advantages and limitations.
We also briefly discuss other methodologies that are less
frequently used [e.g., ion chromatography (IC), high
performance liquid chromatography (HPLC), X-ray fluo-
rescence spectrometry (XRF), flame atomic absorption
spectrometry (FAAS), graphite furnace AAS (GFAAS),
gravimetry, eletrogravimetry, titrimetry and coulometry].
3.1. Isotope dilution mass spectrometry
At present, IDMS is the most extensively used method-
ology in key comparisons for the determination of ele-
ments in various sample matrices.
It is noteworthy that the analytical consideration
given in Section 3.1.1.8 (Weighing) is applicable to all
methodologies that we subsequently discuss.
Table 3. Proposed periods of development for various instruments and typical ranges of precision for IRM
Period Development of instrument
Since 1947 First commercial TIMS available
197883 Initial ICP-MS
198388 Q-ICP-MS
198893 ICP-SMS
19931998 MC-ICP-MS
ICP-TOF-MS
1998present C/RC Q-ICP-MS
Trends
Besides, analytical considerations provided in Sections
3.1.1.9 (Use of cleanrooms) and 3.1.1.10 (Sample dis-
solution with acids/oxidants) should be taken into ac-
count when preventive measures for contamination and
complete sample dissolution are of concern. These two
analytical considerations are also applicable to other
methodologies (e.g., ICP-AES, FAAS and GFAAS).
3.1.1. Analytical considerations
3.1.1.1. Selection of mass spectrometers for isotope ratio
measurements (IRM). Accurate measurement of isotope
ratios is one of the crucial factors for the success of IDMS.
Various mass spectrometers have been employed in key
comparisons, including thermal ionization mass spec-
trometer (TIMS), quadrupole inductively coupled plasma
mass spectrometer (Q-ICP-MS), inductively coupled
plasma sector field mass spectrometer (ICP-SMS; also
known as high resolution ICP-MS or double focusing
ICP-MS), multiple collector inductively coupled plasma
mass spectrometer (MC-ICP-MS), and quadrupole
inductively coupled plasma mass spectrometer with a
collision/reaction cell (C/RCQ-ICP-MS).
Recently, we presented a concise summary of mass
spectrometers currently available in the market for IRM
[28].
Table 3 shows the typical ranges of IRM precision
achievable by various mass spectrometers [29,30]. As
shown in Table 2, both ICP-SMS and Q-ICP-MS with or
without a collision/reaction cell are frequently used for
IDMS analysis.
3.1.1.2. Calibration strategies in IDMS. In a review
about characterization of reference materials by IDMS,
Vogl suggested three major calibration strategies for
analysis: double IDMS, matching IDMS and single IDMS
[31].
In double IDMS, a known amount of an isotopically
enriched spike of an element is added to the sample.
Once equilibration between the analyte isotope and the
spike isotope has been reached, the ratio of the amounts
of the two isotopes will be measured in the sample blend
(blend isotope ratio = amount of analyte isotope/amount
of spike isotope) using a mass spectrometer. Similarly, a
calibration blend is prepared by adding the same amount
of spike to the primary assay standard, whose element
Precision for IRM (RSD) Ref.
0.0050.01% [29]
0.10.5% [29]
0.050.2% [29]
0.0050.02% [29]
0.050.1% [29]
0.070.1% [30]
http://www.elsevier.com/locate/trac 223
Trends
amount content is prepared to match the estimated
element amount content of the sample. The element
amount content of the sample is then calculated from
that of the primary assay standard.
In exact matching IDMS, first proposed by Henrion
[32], an iterative preparation of calibration blends is
needed until an exact match is produced with respect to
both blend isotope ratios and isotope signal intensities.
Several sources of error (e.g., detector dead time and
mass bias) can be negated. An additional advantage is
that the purity of the spike does not make a contribution
to the measurement uncertainty of the final analytical
result. National Measurement Institute, Australia, suc-
cessfully applied the exact matching IDMS approach to
14 international comparisons [33] [e.g., CCQM-P12
(Analysis of Pb in red wine)] [34]. More importantly, it
has been demonstrated to be useful for reference mea-
surements [e.g., Myors et al. presented the IDMS mea-
surement of 10 trace elements (Cd, Cu, Cr, Hg, Mo, Ni,
Pb, Se, Sn and Zn) in a test sample of fortified wheat flour
for the provision of reference values to a proficiency
testing scheme] [35].
In order to simplify time-consuming iterations and
retain the benefits of the full matching procedure,
approximate matching IDMS has been proposed [36]. 3.1.1.4. Optimum blend isotope ratio. In practice, the
Laboratory of Government Chemist, UK, developed an
IDMS protocol for the determination of Ca in human
serum using a quadrupole instrument operated in the
H2-cell mode [37]. An approximate match within
5% was made between the sample blend and the
calibration blend. In addition, in the determination of Pb
in a certified reference material (CRM) (NIST SRM 1547
Peach Leaves) using IDMS, Lam et al. reported the
achievement of satisfactory analytical figures of merit
[recovery: 99%; relative expanded uncertainty (coverage
factor, k = 2): 1.1%] based on the use of approximate
match within 10% [38].
The prerequisite for employing single IDMS is the
availability of a certified spike that has been character-
ized with respect to amount content and isotopic com-
position. The element amount content of the sample can
be calculated directly from that of the certified spike.
3.1.1.3. Equations for quantification. In key comparison
CCQM-K24 (cadmium amount in rice), Equation (1)
describes the measurement procedure of double IDMS
proposed:
" P
my mz K y  Ry  K b  Rb K 0b  R0b  K z  Rz
cx D  cz     P
w  mx m0y K b  Rb  K x  Rx K y  Ry  K 0b  R0b
where cx is the element amount content in the sample
(mol/kg); cz is the element amount content in the pri-
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Trends in Analytical Chemistry, Vol. 28, No. 2, 2009
mary assay standard (mol/kg); my is the mass of the
spike in the sample blend (kg); mx is the mass of
the sample in the sample blend (kg); m0y is the mass of the
spike in the calibration blend (kg); mz is the mass of the
primary assay standard in the calibration blend (kg); Ky
is the mass bias correction factor for the isotope ratio in
the spike; Ry is the isotope ratio in the spike; Kb is the
mass bias correction factor for the isotope ratio in the
sample blend; Rb is the isotope ratio in the sample blend;
Kx is the mass bias correction factor for the isotope ratio
in the sample; Rx is the isotope ratio in the sample; K b0 is
the mass bias correction factor for the isotope ratio in the
calibration blend; Rb0 is the isotope ratio in the calibra-
tion blend; Kz is the mass bias correction factor for the
isotope ratio in the primary assay standard; Rz is the
isotope ratio in the primary assay standard; R(Kxi Rxi) is
the sum of isotope ratios in the sample; R(Kzi Rzi) is the
sum of isotope ratios in the primary assay standard; B is
the procedural blank (mol/kg); D is the digestion factor;
and, w is the fraction dry mass/factor for dry mass cor-
rection.
More details about equations employed for quantifi-
cation purposes have also been reported [39,40].
optimum blend isotope ratio is a compromise between
the error propagation factor, EPFopt, and the ideal 1:1
blend isotope ratio. Furthermore, it should be set in the
range 4:11:4 to maintain reasonable signal intensities
for both analyte and spike isotopes. However, when
samples with high analyte concentrations are examined,
the rule of thumb becomes impractical because a very
large amount of costly spike material is needed. To solve
the problem, Hearn et al. demonstrated the use of a high
blend-isotope ratio (32S/34S) of 14 in the analysis of a
sample of diesel fuel containing approximately 4 mg/g
sulfur [41]. Satisfactory recovery (>99%) was achieved
in the analysis of a CRM (NIST SRM 1624d) when the
blend isotope ratios of the sample and calibration blends
were matched as closely as possible (within 0.5%). The
method demonstrated its suitability for the determina-
tion of sulfur in test samples of diesel fuel for CCQM
comparisons (e.g., CCQM-K35).
3.1.1.5. Detector dead time and mass bias. Precision and
accuracy of IRM are affected by a number of factors [e.g.,
detector dead time, mass bias, instrument blank, spectral
#
K xi  Rxi
B 1
K zi  Rzi
interferences (polyatomic and isobaric interferences)]. In
order to have isotope ratios measured precisely and
Trends in Analytical Chemistry, Vol. 28, No. 2, 2009
accurately, appropriate corrective measures should be
implemented as far as practicable.
In the certification measurement of Pb in a red wine
sample for International Measurement Evaluation Pro-
gramme IMEP-16, Quetel et al. achieved the relative
expanded uncertainty (k = 2) of 1.2% [42]. Q-ICP-MS
was used for IDMS analysis. The uncertainty budget
showed that the contribution from the correction for
detector dead time effects on isotope signal intensities
and the contribution from the measurements performed
to correct for mass bias effects represented 23.1% and
12.3% of the combined standard uncertainty, respec-
tively. To correct for detector dead time effects, the
methods described by Nelms et al. were adopted [43].
Mass bias was corrected by using a certified isotopic
reference material (NIST NBS-982). Note that the same
wine sample (IMEP-16) was used for the other interna-
tional comparison (CCQM-P12).
Generally speaking, there are two ways to correct for
mass bias. External standardization is applicable to ele-
ments whose isotopic abundances are invariant in nat-
ure. To establish mass, a standard solution of known
isotopic composition is analyzed before and after the
measurement of an isotopic blend (standard-sample
bracketing approach). Mass bias correction factor is
calculated according to Eq. (2).
Standard-sample bracketing approach :
Rmeasured Rtrue =K 2 IDMS [51]. Commonly used reagent gases (e.g., H2, NH3
where Rmeasured is the experimental ratio of the isotope
amount fractions measured by a mass spectrometer;
Rtrue is the true ratio of the isotope amount fractions
calculated from the known composition data; and, K is
the mass bias correction factor.
However, internal standardization is recommended for
elements whose isotopic abundances vary naturally (e.g.,
Pb). This requires the addition of an internal standard that
has known isotopic composition. Three approaches are
available for mass bias correction, including linear,
exponential and power law functions [4447]:
Linear law function : Rmeasured Rtrue 1 K 0  DM 3 relative expanded uncertainties reported in the key
0 comparison.
Exponential law function : Rmeasured Rtrue eK DM 4
0 DM
Power law function : Rmeasured Rtrue 1 K 5 (application of a lower radio frequency power to ICP) has
0 been shown to reduce argon-based interferences effec-
where K is the mass bias per mass unit in each of the
functions; and DM is the mass difference between the
isotopes of interest.
3.1.1.6. Instrument blank. Elburg et al. reported that
MC-ICP-MS generally showed a detectable blank for all
elements because of contamination or memory effects in
different parts of the instrument [48]. Moreover, the re-
search team found that the composition of the instrument
blank was often related to the preceding standard or
Trends
sample. In this regard, an empirical method was proposed
for assessing the magnitude of the error introduced by
performing blank corrections on MC-ICP-MS measure-
ments. This was particularly important when samples of
low analyte concentration levels were analyzed.
3.1.1.7. Reduction of spectral interferences. The advance
of collision/reaction cell (C/RC) technology offers an
effective way of reducing certain spectral interferences
based on the proper use of ion-molecule reactions.
Reduction of polyatomic interferences will be achievable
if reactions between interfering ions and reagent gases
are faster than those between analyte ions and reagent
gases. Similarly, separation of isobaric interferences is
feasible when reactions between isobaric ions (or analyte
ions) and reagent gases proceed preferentially.
In a perspective about C/RC in atomic MS, Koppenaal
et al. delivered an overview of ion-molecule reactions,
reagent gases used (H2, O2, CO, NH3, CH4, He, Xe) and
applications of C/RC in the analysis of a range of
matrices (biological, environmental, geological and nu-
clear samples, and high purity reagents) [49].
Later, Olesik presented strategies for using ion-mole-
cule reactions in a reaction cell [50]. Analytical con-
siderations were discussed with respect to the selection of
reagent gases, the adjustment of reaction-cell bandpass
and the optimization of gas flow rates.
Lastly, we reviewed current applications of C/RC in
and CH4) were successfully employed in the determina-
tion of various analytes (Se, selenomethionine, Fe, Ca, Cr
and Cd) in biological and environmental samples.
In the determination of Ca in human serum (CCQM-
K14), Simpson et al. demonstrated that H2 was effective
in reducing possible interferences (26Mg16O+, 40 Ar1 H 2,
26 18 + 27 17 + 28 16 + 43 1 +
40
Ca1 H
2 , Mg O , Al O , Si O and Ca H )
on a pair of isotopes 42Ca and 44Ca chosen for IDMS
analysis [37]. The result submitted by the laboratory
(2.236 0.012 mmol/kg, k = 2) showed excellent
agreement with the mean of all participants results
(2.235 0.035 mmol/kg, k = 2), with one of the lowest
ICP-MS operated under cold plasma conditions
tively [52]. Reduction of intense background peaks
(38Ar1H+, 40Ar+, 40Ar1H+ and 40 Ar1 H 2 ) allowed the
measurement of K and Ca isotopes (39K+, 40K+, 41K+,
40
Ca+ and 42Ca+).
Murphy et al. reported the application of cold
plasma to the IDMS analysis of Ca in the aforementioned
serum sample (CCQM-K14) [53]. The method required
matrix separation using cation exchange chromatogra-
phy before ICP-MS measurements. The results showed
good agreement with other participants results.
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Trends
3.1.1.8. Weighing. Weighing plays a crucial role in not
only IDMS, but also other methodologies. Due caution
should be exercised when weighing test samples that are
hygroscopic. Calibration of analytical balances against
standard weights of appropriate classes should be con-
ducted on schedule. Balances should be placed on
anti-vibration weighing tables. Weighing is preferably
performed in a room that fulfills OIML requirements for
calibration of weights of class E2 (temperature change:
0.7C/h with a maximum of 1C/12 h; range of rel-
ative humidity: 4060% with a maximum of 10%/4 h)
[54].
For IDMS analysis, standard solutions are prepared
gravimetrically and are stored in containers made of
particular materials, such as Teflon perfluoroalkoxy
(PFA) and high-density polyethylene (HDPE). In order to
eliminate electrostatic charges, ionizing blowers are
recommended for use when weighing involves the use of
such containers.
3.1.1.9. Use of cleanrooms. Cleanrooms are classified
according to the size and the number of particles per-
mitted per volume of air [55]. To minimize the risk of
airborne contamination, cleanrooms of ISO Class 4, 5 or
6 (US FED STD 209E equivalent: Class 10, 100 or 1000,
respectively) are suitable for the analysis of samples
having analyte concentrations at trace levels.
For example, Diemer et al. made use of the Ultra-Clean
Chemical Laboratory (Class 10) to perform sample
preparation for the measurement of Cu (220 ng/g) in a
water sample by IDMS [56].
Other activities (e.g., drying of acid-washed Telfon/
HDPE bottles, polyethylene syringes and pipette tips, and
preparation of sub-boiled nitric acid and ultra-pure
water) are often conduced in cleanrooms.
3.1.1.10. Sample dissolution with acids/oxidants. Among
other sample dissolution techniques (e.g., digestion with
a high pressure asher or a Carius tube), microwave-as-
sisted digestion is the most popular method of choice.
Table 4. Criteria for the selection of acids or a combination of acids/oxidants
Acid HNO3 HCl
Property Strong oxidizing Not an oxidizing
agent agent
Suitable for Biological and Certain metal
dissolution of botanical matrices oxides/metals,
sample matrix amines, alkaloids,
some
organometallic
compounds
Can be mixed with H2O2, HCl, HF, Aqua regia
other acids/reagents H2SO4 or HClO4 (HNO3:HCl = 1:3 (v/
v))
Microwave X X
operation
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Trends in Analytical Chemistry, Vol. 28, No. 2, 2009
The criteria for the selection of acids or a combination of
acids/oxidants are summarized in Table 4 [57].
In the certification of Cd, Cu and Pb in a rice material
(IRMM-804) using IDMS, Vassileva et al. compared three
different microwave-assisted digestion procedures
(HNO3, HNO3/H2O2 and HNO3/HF, respectively) [58].
As the rice sample was a complex food matrix that might
contain mineral silicates, the use of HF was found nec-
essary to ensure full solubilization of residual materials
and complete spike equilibration. The optimized diges-
tion conditions (HNO3/HF = 9:1) were eventually ap-
plied to the determination of Cd in the rice sample for
CCQM-K24.
3.1.1.11. Procedural blank analysis. To determine the
procedural blank, Watters Jr. et al. suggested using 1% of
the amount of spike that was added to the analytical
sample [59]. If the blank is 1% of the element amount
content in the sample, it will have the same measured
isotope ratio as the sample blend. The blend isotope ratio
can be achieved with high precision. However, if the
blank is far less than 1%, a much smaller blend isotope
ratio will be obtained with poorer precision. Under cer-
tain circumstances, the procedural blank can be esti-
mated by external calibration [60].
3.1.1.12. Correction for moisture/water content. Accord-
ing to Equation (1), moisture/water content determina-
tion will be necessary for IDMS analysis if the sample in
question is hygroscopic.
In CCQM-K24 (cadmium amount in rice), participants
were requested to equilibrate the test sample of rice with
ambient conditions (successive weights should not differ
more than 0.001 g). The equilibrated sample was
subsequently used for the measurement of moisture
content and Cd amount content. Oven drying at a
temperature of 85 2C was recommended. However,
problems were encountered (e.g., high risk of contami-
nation and difficulty of attaining equilibration due to
changes of relative humidity and temperature). To
HF H2SO4 HClO4
Not an oxidizing agent Not an oxidizing Strong oxidizing
agent agent
Silicate-based materials Almost all organic Organic materials
materials, inorganic
oxides, hydroxides,
alloys, metals, and
ores
HNO3 HNO3 HNO3
X X x (Explosion hazard)
Trends in Analytical Chemistry, Vol. 28, No. 2, 2009
address the influence of the correction for moisture/
water content, IRMM examined three different methods,
namely oven drying, Karl Fischer titration and thermo-
gravimetry, respectively [61]. The examination showed
that the three methods did not give significantly different
values for the Cd amount content.
3.1.1.13. Uncertainty estimation. In the Eurachem/
CITAC Guide [62], Example A7 shows the application of
Kragtens approach to the calculation of uncertainty for
IDMS measurements [63]. This requires tedious estima-
tion of experimental uncertainties of all measurement
parameters that build the model equation [e.g., Eq. (1)].
In order to simplify the work, Magnusson et al.
suggested that only estimates that were >1/5 of the
target value for uncertainty would be used for the
estimation of expanded uncertainty [64]. The simplified
approach for uncertainty estimation was successfully
demonstrated in the determination of Ni in the steel
sample for CCQM-K33 and achieved the relative ex-
panded uncertainty of 1.1% (k = 2), which fulfilled the
target value of 2%.
3.1.2. Advantages
IDMS is a candidate primary method with satisfactory
accuracy and precision. Once equilibration between the
analyte isotope and the spike isotope has been reached,
total recovery of analyte will be unnecessary and the loss
of analyte will not affect the final analytical result. Many
isotopically enriched spikes are commercially available
for the determination of multi-isotopic elements. Any
variations/drifts of instrumental sensitivity have no
influence on the final value of the element amount
content in the sample.
3.1.3. Limitations
Nevertheless, certain limitations are apparent:
 first, resource implications need to be considered, par-
ticularly the high costs of isotopically enriched spikes,
mass spectrometers and training of competent ana-
lysts;
 second, it is necessary to ensure attainment of com-
plete spike equilibration;
 third, the determination of mono-isotopic elements
such as Na and As by IDMS is not possible; and,
 finally, factors that affect the accuracy in the
measurement of isotope ratios (e.g., detector dead
time and mass bias) should be carefully con-
trolled.
3.2. Species-specific isotope dilution mass
spectrometry
Accurate determination of organo-metallic species [e.g.,
methylmercury (MeHg) and tributyltin (TBT)] is a chal-
lenging task. Problems (e.g., instability of analytes and
Trends
derivatized products, low analyte concentration levels,
and poor sample extraction efficiency) are commonly
encountered in speciation analysis. Species-specific IDMS
solves those problems provided that complete equilibra-
tion between the analyte and the spike has been achieved.
It is essential that the spike materials used for analysis
should be isotopically enriched species of MeHg/TBT (i.e.
the analyte and the spike are in the same chemical form).
In their review about potential and limits of speciated
isotope dilution analysis, Monperrus et al. discussed the
possible applications of isotopically enriched species of
MeHg and TBT, particularly in IDMS measurements and
environmental tracer studies [65].
3.2.1. Analytical considerations
3.2.1.1. Extraction, derivatization and separation/detection
methods. A number of methodologies have been dem-
onstrated to give satisfactory results in the analysis of
MeHg in a sample of tuna fish relating to a pilot study
(CCQM-P39) [66]. Each of the participants received a
quartz ampoule containing 202Hg isotopically enriched
CH3HgCl, which was prepared by Institute for Reference
Materials and Measurements (IRMM) for IDMS calibra-
tion. When the separation of MeHg is performed by gas
chromatography, sample preparation always involves a
derivatization step. Several representative methodologies
(extraction derivatization separation/detection) are
summarized as follows:
 Microwave extraction with tetramethylammonium
hydroxide (TMAH) propylation GC-ICP-MS [67]
 Extraction with TMAH and diethyl-dithiocarbamate
(DDTC) Grignard butylation GC-ICP-MS [68]
 Extraction with KOH/MeOH propylation solid-
phase micro-extraction/GC-ICP-MS [69]
 Extraction with concentrated HCl and sodium diethyl-
dithiocarbamate (NaDDTC) Grignard butyla-
tion GC-ICP-MS [70]
Besides, the use of HPLC-ICP-MS offers an alternative
method for examination without derivatization. For
example, Rai et al. developed a method for the mea-
surement of inorganic Hg and MeHg in fish tissues by
enzymatic hydrolysis (Protease type XIV) and HPLC-ICP-
MS [71]. Method accuracy was demonstrated by the
analysis of two reference materials (NRCC DORM-2
Dogfish and NIST RM 50 Albacore tuna). Most of the
mercury in fish tissues examined in the study was
present as MeHg (88100%). In view of the satisfactory
outcome of the pilot study, a follow-up key comparison
(CCQM-K43) was arranged for the examination of a
lower level of MeHg in salmon tissues. Most of the par-
ticipants adopted GC-ICP-MS for analysis and obtained
comparable results.
Two reviews about methodologies for the analysis of
organotin compounds in mussels and sediment are
available in the literature. Pellegrino et al. compared 12
selected extraction methods for the determination of
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Trends
butyltin and phenyltin compounds in mussel samples
[72]. Quevauviller et al. summarized methods suitable
for the monitoring of TBT in mussels and sediment and
reported results obtained in certification campaigns of a
range of reference materials [73].
In order to address the analytical challenge of
organotin speciation, a pilot study (CCQM-P18) for the
determination of TBT in marine sediment was launched
[74]. The Laboratory of Government Chemist (LGC)
provided each participating laboratory with a vial con-
taining a methanolic solution of 117Sn isotopically en-
riched TBTCl for IDMS calibration. GC-ICP-MS and
HPLC-ICP-MS were the popular choices for analysis.
Methodologies based on GC-ICP-MS (extraction
derivatization separation/detection) are shown as fol-
lows:
 Sonication with acetic acid/MeOH ethyla-
tion GC-ICP-MS
 Microwave extraction with acetic acid ethyla-
tion GC-ICP-MS
 Microwave extraction with acetic acid/MeOH/tropo-
lone ethylation GC-ICP-MS
Other methodologies based on HPLC-ICP-MS (extrac-
tion separation/detection) are listed below:
 Accelerated solvent extraction with acetic acid/
MeOH HPLC-ICP-MS
 Microwave extraction with acetic acid HPLC-ICP-
MS
The satisfactory agreement of participants results in
the pilot study encouraged a key comparison (CCQM-
K28) to be scheduled subsequently and permitted the
certification of a new reference material for TBT in
marine sediment (HIPA-1).
There is concern about the performance of separation
(GC versus HPLC) and detection techniques (Q-ICP-MS
versus ICP-SMS) employed for the analysis of TBT. In the
comparison of GC-ICP-MS and HPLC-ICP-MS for the spe-
cies-specific IDMS analysis of TBT in sediment after
accelerated solvent extraction, Wahlen et al. found that
the limit of detection (LOD) of TBT achieved by GC-ICP-MS
(0.03 pg TBT as Sn) was two orders of magnitude better
than that obtained by HPLC-ICP-MS (3 pg TBT as Sn)
[75]. Q-ICP-MS was used for measurement in both cases.
Given the superior sensitivity achievable by GC-ICP-
MS, Yang et al. carried out a performance evaluation
between Q-ICP-MS and ICP-SMS for the determination
TBT in sediment [76]. ICP-SMS was found to provide
better analytical figures of merit, including isotope
ratio measurement precision (ICP-SMS gave a more
than two-fold improvement in precision of measured
120
Sn/117Sn ratios in TBT standards when compared
with Q-ICP-MS) and method detection limit for TBT
(ICP-SMS: 0.4 ng/g; Q-ICP-MS: 0.9 ng/g).
3.2.1.2. Availability of isotopically enriched spikes. Isoto-
pically enriched spikes of both MeHg and TBT are
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Trends in Analytical Chemistry, Vol. 28, No. 2, 2009
conventionally synthesized and characterized by
laboratories according to published methods (e.g.,
[198Hg]MeHgCl [77], [117Sn]TBTCl [78], and
[118Sn]TBTCl [79]). The preparation work requires
skillful analysts, high purity chemicals and reagents,
contamination-free laboratory ware, and suitable mass
spectrometers for characterization. In addition, the
quantification of the element amount content of the
synthesized spike against a primary assay standard
using reverse isotope dilution is needed.
To meet market demand, IRMM initiated a program
for preparation and certification of a spike of 202Hg
isotopically enriched MeHgCl (named ERM-AE670)
[80]. Briefly, the starting material was 202Hg isotopi-
cally enriched HgO. The spike [202Hg]MeHgCl was
synthesized in three steps:
(i) reaction of HgO with Zn in hydrochloric acid to
give HgCl2;
(ii) reaction between HgCl2 and a Grignard reagent of
MeMgCl to form Me2Hg; and,
(iii) comproportionation between Me2Hg and HgCl2 to
produce MeHgCl.
The amount content of MeHg in the spike was
determined by subtracting the inorganic Hg content
from the total Hg content. The Hg isotopic composi-
tion of the spike was checked by Q-ICP-MS. An
isochronous stability study was undertaken for one
year. The relative expanded uncertainty (k = 2) for the
measurement of the amount content of MeHg was
found to be 3.5%, which included a factor account-
ing for potential changes over 2 years shelf life. In-
deed, the certified spike can help laboratories to apply
direct IDMS for MeHg analysis. Fortunately, isotopi-
cally enriched organotin species are also available in
the market [81].
3.2.1.3. Uncertainty contributions to single and double
IDMS. The availability of isotopically enriched spikes
allows the use of single IDMS for measurement. Double
IDMS will be an option if spike materials are synthesized
for intended use.
To compare the performance of the two calibra-
tion strategies, it is essential to take a full uncer-
tainty budget into consideration. Clough et al.
addressed the concern in the determination of MeHg
in fish tissue by HPLC-CV-MC-ICP-MS [82]. MeHg
was separated from inorganic Hg by HPLC, which
was coupled to MC-ICP-MS via a cold vapor gen-
eration system for the measurement of Hg isotope
ratios.
Both single and approximate matching double
IDMS strategies gave comparable accuracy in the anal-
ysis of CRMs (DORM-2 and BCR464).
For single IDMS, two major contributions to the
combined standard uncertainty (uc) were identified:
Trends in Analytical Chemistry, Vol. 28, No. 2, 2009
(i) the standard uncertainty associated with the iso-
tope ratio 200Hg/199Hg in the sample, which was
calculated from IUPAC isotopic abundance data
(58% relative contribution); and,
(ii) the standard uncertainty due to the mass fraction
of the spike [199Hg]MeHgCl (40% relative contribu-
tion).
By contrast, in the double IDMS approach, the largest
contributions to uc resulted from the uncertainty asso-
ciated with the measured isotope ratios in the sample
blend (1443% relative contribution) and the calibration
blend (3474% relative contribution).
3.2.2. Advantages
For the determination of total element amount con-
tent, spike equilibration occurs as a result of sample
dissolution with acids/oxidants. As all isotopes of the
element of interest are reacted to have the same oxi-
dation state, speciation information is lost.
However, species-specific IDMS is a very promising
method that provides information of individual analyte
species when the following three criteria are met:
(i) spike equilibration is attained;
(ii) quantitative extraction methods are used; and,
(iii) appropriate hyphenated techniques (e.g., GC-ICP-
MS and HPLC-ICP-MS) are used.
Once spike equilibration has been achieved, species
transformation (e.g., demethylation of MeHg and deg-
radation of TBT to dibutyltin) will not affect the final
analytical result [65].
3.2.3. Limitations
There are several constraints on species-specific IDMS.
Complicated processes for synthesis and characterization
of isotopically enriched spikes sometimes hinder the
availability of materials. The stability of synthesized spikes
should be closely monitored to check whether decompo-
sition occurs within the anticipated shelf life. Selection of
chromatographic columns with high separation effi-
ciency is critical. Caution should be exercised on the co-
elution of species. It is necessary to choose appropriate
flow rates of carrier gases and proper mobile phases for
GC-ICP-MS and HPLC-ICP-MS examinations, respec-
tively. Incomplete species extraction should be strictly
avoided. When new species/matrices are encountered,
extraction conditions should be thoroughly examined to
ensure that quantitative extraction is achieved.
3.3. Inductively coupled plasma atomic emission
spectrometry
ICP-AES is a robust methodology, and has an impressive
track record of accurate and simultaneous determination
of multi-elements in a wide range of matrices.
However, the following question has been raised: Is it
still possible, necessary and beneficial to perform re-
search in ICP-AES? In a recent perspective article,
Trends
Mermet answered Yes to this question and suggested
five remaining fields of research for consideration:
(i) sample introduction systems (e.g., direct solid anal-
ysis);
(ii) photon collection and detection (e.g., background
noise reduction);
(iii) intelligent software (e.g., automatic selection of
analytical wavelengths);
(iv) analytical performance (e.g., improvement in
LODs); and,
(v) method validation (e.g., uncertainty estimation
and traceability of analytical results to SI) [83].
Similar research fields are also applicable to other
spectrometric techniques (e.g., FAAS, GFAAS and ICP-
MS). It is not surprising to see few publications on the
use of ICP-AES in CCQM exercises in the literature,
because participants often use approved analytical
procedures that may not necessarily show novel sug-
gestions.
3.3.1. Analytical considerations
3.3.1.1. Use of internal standards. The use of internal
standards in ICP-AES measurements has been shown to
achieve satisfactory accuracy and precision. With a view
to determining major inorganic constituents in solution
with relative expanded uncertainties (k = 2) of the order
of 0.1%, Salit et al. reported a novel ICP-AES-calibration
strategy that compared the analyte-to-internal standard
signal ratio measured in an unknown sample to those
ratios measured in mixtures whose amount ratios were
well known [84]. The internal standards used for anal-
ysis included Sc, Mn, Se, In, Sr, Y, Co, Zr and Mo. The
methodology showed satisfactory performance in both
certification and international comparison exercises,
including the certification of 64 different single-element
standard solutions in the NIST SRM 3100 series [85],
the analysis of mono-elemental calibration solutions of
Al, Cu, Fe and Mg (CCQM-K8), and the certification of
major constituents of a refractory alloy (NIST SRM
2175).
3.3.1.2. Matching of matrix elements. The presence of
percentage levels of heavy metals in a sample matrix
often causes difficulties in the determination of ele-
ments of interest at parts-per-million (ppm) levels. In
order to compensate for strong matrix effects, standard
solutions used for calibration should be fortified with
the same matrix elements at levels similar to the
sample.
A typical example is the examination of minor ele-
ments in steel samples. Sheila et al. developed an exact
matching technique for the determination of minor ele-
ments (Mn, Mo, Cr and Ni) in steel by ICP-AES [86].
Three important criteria that should be observed were
as follows:
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Trends
(i) the concentrations of sample and standard were
matched so that the emission intensity ratio of
sample to standard was 1;
(ii) both sample and standard were doped with an
internal standard solution of Au to correct for
instrumental drift; and,
(iii) both sample and standard were matched with re-
spect to the acid strength and the dominant matrix
element of Fe (within 3%).
The method was validated by a CRM (NIST SRM 2171
Low Alloy Steel) and gave a measurement uncertainty of
1% at the 95% confidence interval. The research team
eventually applied the method to a key comparison for
the examination of elements in steel (CCQM-K33) and
achieved satisfactory agreement with other participants
results.
3.3.2. Advantages
Spectrometers for ICP-AES can measure up to 70 ele-
ments simultaneously in a single sample analysis. Dual
viewing of the plasma offers LODs down to parts-per-bil-
lion (ppb) levels (axial viewing) and extends the working
ranges for percentage concentration measurements (ra-
dial viewing). The choice of alternative wavelengths for
the analytes of interest allows analytical results free from
spectral interferences. Modern solid-state detectors (e.g.,
segmented-array charge-coupled device detectors [87])
usually provide uniform resolution at all wavelengths.
Simultaneous background correction can be performed
adjacent to the analytical wavelengths. The technical
difficulty of direct analysis of samples containing organic
solvents has recently been solved by using a special
sample introduction system. For example, Grindlay et al.
designed a microwave-based thermal nebulizer that per-
mitted nebulization of 1040% (w/w) organic solvents
(e.g., formic acid, acetic acid, methanol, ethanol and
propan-2-ol) [88,89].
3.3.3. Limitations
ICP-AES is unsuitable for the analysis of some elements
(e.g., As and Se) because of their high ionization
potentials, thus resulting in poor LODs. Inter-element
interferences may not be completely resolved, even using
the sophisticated detection system. Appropriate correc-
tive measures (e.g., inter-element correction equations
[90] and multi-component spectral fitting [91]) should
be adopted as far as feasible.
3.4. Neutron activation analysis
NAA is a powerful technique for inorganic analysis and
plays an important role in chemical metrology [92,93].
Generally speaking, four major areas of applications
are:
(i) certification of candidate reference materials
[94,95];
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Trends in Analytical Chemistry, Vol. 28, No. 2, 2009
(ii) comparison of NAA with other analytical methods
based on conventional spectrometric techniques
[96,97];
(iii) in vivo analysis of trace elements [98,99]; and,
(iv) accurate determination of element amount con-
tents for various purposes (e.g., international inter-
comparisons, biological studies, environmental
monitoring, geological examinations, and forensic
investigations).
3.4.1. Analytical considerations
The basic principles and instrumentation have been
shown in the literature [100]. As NAA is a less common
technique for ordinary laboratories, we briefly describe
analytical considerations with respect to measurement
process, quantification and classification.
Measurement usually involves three basic steps:
 First, the sample is irradiated with a flux of neutrons.
Neutron fluxes can be divided into three types accord-
ing to their kinetic energies: thermal (<0.5 eV), epi-
thermal (0.5 eV 0.5 MeV) and fast (>0.5 MeV).
Neutron reactors (based on fission of 252Cf), neutron
generators (based on deuterium-tritium or deute-
rium-deuterium fusion reactions) and particle acceler-
ators are the common neutron sources.
 Second, transformation of stable isotopes of a target
element into radioactive isotopes occurs upon neutron
irradiation. Prompt c-rays are emitted from an instan-
taneous decay of radioactive isotopes. Delayed c-rays
are produced according to the characteristic half-lives
of radioactive isotopes varying from seconds to years.
 Finally, characteristic c-radiations of specific energies
are measured and quantified. c-ray spectrometers
equipped with Ge(Li) or hyper-pure Ge semiconductor
detectors are ideal for the measurement of c-rays.
Two quantification approaches are widely used. In the
comparator method, the sample and the standard are
irradiated and measured under identical conditions. The
standard used for calibration contains either an indi-
vidual mono-element or multiple elements. The con-
centration of the sample is calculated according to
Equation (6):
mz Ax
c x cz  6
mx Az
where cx is the element amount content in the sample
(mol/kg); cz is the element amount content in the stan-
dard (mol/kg); mx is the mass of the sample (kg); mz is
the mass of the standard (kg); Ax is the activity of the
sample (Bq or disintegrations per second); and, Az is the
activity of the standard (Bq or disintegrations per sec-
ond).
Furthermore, Zeisler et al. provided a detailed mathe-
matical expression to describe the measurement process
for determination of Cr in a CRM of stainless steel (NIST
SRM 11521a) using instrumental NAA (INAA) [101].
Trends in Analytical Chemistry, Vol. 28, No. 2, 2009 Trends

For k0 method, a single comparator (197Au standard)
is used to determine a k0 normalization factor for all
elements being measured [102].
NAA can be classified into several types with respect
to:
(i) the necessity of carrying out chemical dissolution
of radioactive samples and chemical separation of
radionuclides {radiochemical NAA (RNAA) [103
105] and INAA [106117], which requires no
sample dissolution/chemical separation};
(ii) measurement of c-radiations {prompt gamma NAA
(PGNAA) [118123] and delayed gamma NAA
(DGNAA)};
(iii) use of neutron fluxes for irradiation {thermal NAA
(TNAA), epithermal NAA (ENAA) and fast NNA
(FNAA)}; and,
(iv) measurement conducted inside the body [in vivo
NAA (IVNAA)].
There are no hard and fast rules governing which
type of NAA is best for a new application. Nonethe-
less, a review by Witkowska et al. is a valuable ref-
erence, which describes recent applications of various
types of NAA (TNAA, ENAA, FNAA, IVNAA, PGNAA,
INAA and RNAA) for the study of human and
environmental samples [124]. Furthermore, Fig. 2
shows for reference purposes a periodic table of the
types of NAA for the analysis of specific elements. As
the information is not exhaustive, analysts are
strongly recommended to conduct a literature search
before examination.
3.4.2. Advantages
The methodology is non-destructive (except RNAA) and
can measure many elements simultaneously. It usually
provides the total element amount content of the sample.
As sample dissolution is not needed prior to analysis
(except RNAA), contamination due to acids and reagents
can be avoided. Samples can be in various forms,
including solids, liquids, gases and suspensions/slurries.
The technique is particularly suitable for the examina-
tion of antiques/valuables and samples that are difficult
to be decomposed. Matrix effects are often negligible
because matrix elements (e.g., H, C, O and N) can hardly
form radioactive isotopes during INAA measurements.
Only small quantities of samples (100200 mg) are
needed for analysis. About 70% of the elements shown
in the periodic table (Fig. 2) can be examined by NAA,
which is regarded as complementary to MS techniques.
In view of the advantageous features, NMIs have em-
ployed NAA (mainly INAA and RNAA) for the deter-
mination of As, Cd, Cr, Cu, Fe Mn, Mo, Ni, Se and Zn in
several key comparisons (CCQM-K24, K31, K33, K42,
K43, K44 and K49). Results of NAA are comparable to
those of IDMS in terms of high accuracy and precision.
However, it is imperative to note that mono-isotopic
elements (e.g., As and Mn) are measurable by NAA but
not determinable by IDMS.
3.4.3. Limitations
The use of NAA is limited to a few NMIs because of
huge resource implications, safety concerns about
neutron reactors and the availability of competent
personnel. Another drawback is that several elements
(e.g., Pb) can hardly be determined by NAA. Unless
NAA is combined with chromatographic separation,
speciation information will not be readily available.
Among other nuclear analytical techniques, Chai
et al. highlighted several examples of speciation of Se,
Hg, Cr and I in biological and environmental samples
based on the combination of chromatography (e.g., an-
ion exchange and gel filtration) and NAA (e.g., INAA
and RNAA) [125]. In addition, Shi et al. demonstrated
the use of HPLC-NAA for As speciation in natural water
[126]. However, due to the limited availability of facili-
ties, chromatography combined with NAA is still less
widely used in speciation studies than chromatography

H He
(P)
Li Be B C N O F Ne
(P) (V) (P,V) (P,V) (I)
Na Mg Al Si P S Cl Ar
(I,R,P) (I,R,P) (I,R,P) (P) (I,P,V) (P) (I,R,P)
K Ca Sc Ti V Cr Mn Fe Co Ni Cu Zn Ga Ge As Se Br Kr
(I,V,P) (I,R,P,V) (I,R,P) (I,R,P) (I,R,P) (I,R) (I,R,P) (I,P) (I,R,P) (I,P) (I,R,P) (I,P) (I,R) (R) (I,R) (I,R) (I,R)
Rb Sr Y Zr Nb Mo Tc Ru Rh Pd Ag Cd In Sn Sb Te I Xe
(I) (I,R) (R) (I,R) (I,R) (I,R) (I,R) (I,R) (I) (I,R,P) (I,R) (I,R) (I,R) (I,R) (I,R)
Cs Ba La Hf Ta W Re Os Ir Pt Au Hg Tl Pb Bi Po At Rn
(I,R) (I,R) (I,R) (I,R) (I,R) (I,R) (I,R) (I) (I,R) (I) (I,R) (I,R)
Fr Ra Ac

Ce Pr Nd Pm Sm Eu Gd Tb Dy Ho Er Tm Yb Lu
(I,R) (I,R) (I,R,P) (I,R) (R,P) (I,R) (I,R,P) (I,R) (I,R) (I,R) (I,R) (I,R)
Th Pa U
(I,R) (I,P)

Figure 2. A periodic table showing the types of NAA for the analysis of specific elements (Abbreviations for acronyms are as follows: I: INAA
[106117]; R: RNAA [103105]; P: PGNAA [118124]; and, V: IVNAA [98,99,124]).

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Trends
combined with ICP-MS (i.e. HPLC-ICP-MS and GC-ICP-
MS).
3.5. Ion chromatography/high performance liquid
chromatography (IC/HPLC)
Not long ago, Haddad et al. reviewed recent develop-
ments and emerging directions in ion chromatography
(IC) [127]. Topics of the review included:
(i) new stationary phases;
(ii) miniaturized IC systems;
(iii) expansion of peak capacity in IC; and,
(iv) hyphenated IC systems for speciation analysis and
metallomics.
IC has been traditionally coupled with a range of
detectors (e.g. conductivity, ultraviolet-visible and elec-
trochemical detectors) for the determination of anions
and cations [128].
Nowadays, the hyphenation of IC and MS allows
speciation analysis. Ionization sources, including ICP
and electrospray ionization (ESI), are usually employed
in hyphenated IC systems [129].
Among others, studies of selenium-containing species
[130132] and arsenic-containing species [133,134] in
environmental and biological samples have been the
most extensively developed areas in recent speciation
analysis. New stationary phases developed for IC provide
remarkable efficiency for the separation of a wide range
of complex selenium and arsenic species.
A pilot study (CCQM-P86) relating to the speciation
analysis of selenomethionine (SeMet) in pharmaceutical
yeast tablets is noteworthy [135]. As revealed in the
report, IC-ICP-MS (i.e. HPLC-ICP-MS) was the most fre-
quently used technique for the species-specific IDMS
analysis of SeMet.
We expect key comparisons focusing on selenium/
arsenic speciation to be arranged in the near future.
3.6. X-ray fluorescence spectrometry (XRF)
XRF is a mature technique for elemental analysis and
significant improvements continue to appear. Recent
reviews available [136138] covered the latest devel-
opments [e.g., instrumentation and detectors, matrix
correction and spectrum analysis procedures, total
reflection XRF (TXRF)]. A critical review on TXRF
analysis has also been published [139]. The recent
trends are towards the use of TXRF for metallic con-
tamination control in semiconductor nanotechnology
[140]. Advantages in surface and thin-layer analysis by
TXRF, especially for wafers (thin slices of semiconductor
material) have been discussed [141].
Although XRF has not been widely used in previous
key comparisons (CCQM-K33, K42 and K44), we
anticipate that the technique will be suitable for the
analysis of metal contaminants in advanced materials
(e.g., semiconductors).
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Trends in Analytical Chemistry, Vol. 28, No. 2, 2009
3.7. Flame atomic absorption spectrometry and
graphite furnace atomic absorption spectrometry
The well-established techniques of FAAS and GFAAS are
often used for single-element determinations. These
instruments are less costly than ICP-AES and ICP-MS.
When appropriate accessories are coupled to atomic
absorption spectrometers, hydride generation (HGAAS)
and cold vapor (CVAAS) techniques are suitable for the
analysis of hydride-forming elements (e.g., As and Se)
and Hg, respectively.
Matrix interferences can possibly be overcome in two
ways:
(i) matrix modification (e.g., use of ionization suppres-
sants when analyzing easily ionized elements by
FAAS, addition of matrix modifiers for GFAAS);
and,
(ii) method of standard additions.
AAS based on external standard calibration/standard
additions has provided satisfactory results in some key
comparisons (e.g., CCQM-K14, K31 and K49).
In an account of recent developments in on-line
electrothermal (graphite furnace) AAS, Burguera et al.
evaluated several on-line analyte pre-concentration
systems (e.g., precipitation or co-precipitation/dissolu-
tion reactions, sorption pre-concentration and solvent
extraction) and on-line analyte separation approaches
(e.g., microdialysis separation, electrochemical processes
and chemical vapor generation) [142].
Advancement in on-line techniques allows analysis of
complex samples with low analyte concentrations. More
importantly, the coupling of these techniques to ICP-AES
and ICP-MS can definitely offer a wide range of appli-
cations because of their multi-element measurement
capability.
3.8. Gravimetry, eletrogravimetry, titrimetry and
coulometry
All four methodologies are the oldest techniques in
quantitative analysis. They are regarded as candidate
primary methods of measurement in chemical analysis
[143]. As both theoretical and technical aspects have
been well documented [144], we do not provide addi-
tional information in this review. Although remarkable
analytical methods based on MS are available for inor-
ganic analysis, these methodologies remain active for
standardization processes.
4. The way forward
So far, relevant key comparisons under respective MSCs
have been successfully organized. Three fundamental
issues of chemical metrology are properly addressed:
(i) establishing traceability of analytical results to SI
(i.e. mol and kg);
Trends in Analytical Chemistry, Vol. 28, No. 2, 2009
(ii) enabling worldwide comparability of results; and,
(iii) showing the degree of equivalence of national mea-
surement standards maintained by NMIs.
In addition, laboratories have taken the opportunity to
develop novel methodologies for chemical measure-
ments.
With a view to providing a more comprehensive scope
of measurement services, we suggest including two
additional MSCs, namely Drugs/Medicines and XRF, Mossbauer spectrometry, X-ray absorption spec-
Metalloproteins. trometry, and neutron scattering and diffraction) [148].
Metal-containing drugs/medicines (metallodrugs) are
widely used for chemotherapy purposes. For example,
carboplatin is a chemotherapeutic drug used for the
treatment of ovarian cancer. It comprises Pt and a
bidentate cyclobutane dicarboxylate moiety. The rec-
ommended dosage will be correctly applied to patients
only if the active ingredient of the drug is accurately
determined. This is important to prevent over-dosing
and adverse toxic effects. Species-specific IDMS can be
the method of choice for the accurate quantification of
carboplatin. However, isotopically enriched spikes are
not readily available. In order to rise to the challenge,
Koellensperger et al. reported the first synthesis of 194Pt
isotopically enriched carboplatin [145]. In the quanti-
fication of carboplatin in urine by species-specific IDMS,
both LC-ICP-MS and LC-ESI-TOF-MS (liquid chroma-
tography-electrospray ionization-time-of-flight mass
spectrometry) were found to be effective for analysis. It
was important to note that the LODs achieved by the
two techniques were 0.1 ng/g and 15 ng/g, respec-
tively.
Metalloproteins are responsible for many biological
processes. Some transition metals bind to proteins with
high affinity interactions. Examples of important
metalloproteins (element) include cytochrome oxidase
(Cu), hemoglobin (Fe), glutathione peroxidase (Se),
carboxypeptidase A (Zn) and glutamine synthetase
(Mn). In a recent review, Garcia et al. described trends
in metalloprotein analysis with respect to four areas,
including protein-separation techniques, metal quanti-
fication in proteins, ligand identification and the latest
challenges in metallomics [146]. To explore the feasi-
bility of using species-specific IDMS analysis of metal-
loproteins, Harrington et al. used a Cu-containing
protein, rusticyanin (Rc), as a model system for exam-
ination [147]. The protein is involved in the respiratory
electron transport chain of a bacterium called Acido-
thiobacillus ferrooxidans. Rc containing an enriched
isotope of 65Cu was produced by cell-culture and pro-
tein-expression systems. The isotopically enriched pro-
tein was isolated from the bacterium and characterized
by standard biochemical assays based on UV-visible
spectrometry and electrospray MS. The work showed
that the metal center was stable under the HPLC-ICP-
MS conditions examined and that the approach could
Trends
form the basis of a method for the accurate determi-
nation of metalloproteins by IDMS.
Study of distributions and compositions of all metal-
loproteins in a proteome comprises the scientific field of
metalloproteomics, which has attracted attention to the
development of new methodologies. To this end, Gao
et al. recently evaluated several advanced nuclear ana-
lytical techniques for metalloproteomics (e.g., NAA,
That evaluation clearly described the advantages, the
limitations and the applications of the techniques, so we
do not go into detail about these important aspects.
The advancement of analytical techniques allows the
accurate determinations of metallodrugs and metallo-
proteins. Under the current structure of 14 MSCs (Table
1), the analysis of these two classes of analytes may not
be easily classified into any specific category. It is
therefore desirable to review the present scope of MSCs
and consider the two proposed MSCs. We believe that
this will help promote the development of novel meth-
odologies for the analysis of such important analytes.
International key comparisons focusing on the anal-
ysis of challenging analytes in more complex matrices
attract the development of advanced methodologies for
inorganic analysis. These give benefits to activities such
as certification of materials and the provision of accurate
and SI-traceable reference values of analytes [149].
Analytical field laboratories can validate the methods
that they employ for routine analysis through the use of
matrix-matched CRMs and their participation in inter-
laboratory comparisons (e.g., IMEP), whose independent
reference values (SI-traceable, where possible) are
determined by candidate primary methods (e.g., IDMS).
The efforts of NMIs/DIs eventually enhance the compe-
tence of analytical field laboratories by disseminating
these methods.
Acknowledgements
The authors are indebted to Dr. T.L. Ting (Government
Chemist), Ms. S.Y.K Tam, Dr. W.M. Sin, Dr. C.S. Mok,
Mr. W.C. Sham and Mr. F.W. Lee for their encourage-
ment, advice and help. We sincerely thank Drs. J. Vogl,
D. Schiel, W. Pritzkow, R.E. Sturgeon, L. Yang, C.R.
Quetel, M. Sargent, L.G. Mackay, R.B. Myors, M. van
Son, R.R. Greenberg, K. Chiba, K. Inagaki, E. Hwang,
O.F.X. Donard and E. Krupp for their great support
during the development of protocols for IDMS analysis.
Last but not least, we thank Dr. A.W.L. Leung for
searching relevant information during manuscript
preparation. The contents of this article do not neces-
sarily reflect the views of the Government of the Hong
Kong Special Administrative Region, nor does mention
http://www.elsevier.com/locate/trac 233
Trends
of trade names or commercial products constitute
endorsement or recommendations of use.
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Trends in Analytical Chemistry, Vol. 28, No. 2, 2009
Yiu-chung Yip is a chemist at the Government Laboratory of Hong
Kong. During the preparation of the manuscript, severe natural
disasters happened. He would like to remark: The manuscript is
dedicated to the sufferers and the mother who knelt to protect her
child.
James Chung-wah Lam was formerly a research assistant at the
Government Laboratory of Hong Kong (May 2007 to March 2008)
and is currently a research fellow in the Biology and Chemistry
Department at City University of Hong Kong. His current interest is
focused on the application and the development of advanced tech-
niques and methods to elucidate the impact of pollution on life and
the environment.
Wai-fong Tong is a senior chemist at the Government Laboratory of
Hong Kong. He likes statistics. He is currently the head of the Trace
Elements Section that performs the determination of trace elements for
environmental monitoring programs, litigation as well as food con-
tamination.