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Spectrochimica Acta Part B 59 (2004) 135–146
Review
Inductively coupled plasma mass spectrometry and electrospray mass
spectrometry for speciation analysis: applications and instrumentation
Amy L. Rosen, Gary M. Hieftje*
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA
Received 15 May 2003; accepted 23 September 2003
Abstract
To gain an understanding of the function, toxicity and distribution of trace elements, it is necessary to determine not only the
presence and concentration of the elements of interest, but also their speciation, by identifying and characterizing the compounds
within which each is present. For sensitive detection of compounds containing elements of interest, inductively coupled plasma
mass spectrometry (ICP-MS) is a popular method, and for identification of compounds via determination of molecular weight,
electrospray ionization mass spectrometry (ESI-MS) is gaining increasing use. ICP-MS and ESI-MS, usually coupled to a
separation technique such as chromatography or capillary electrophoresis, have already been applied to a large number of research
problems in such diverse fields as environmental chemistry, nutritional science, and bioinorganic chemistry, but a great deal of
work remains to be completed. Current areas of research to which ICP-MS and ESI-MS have been applied are discussed, and the
existing instrumentation used to solve speciation problems is described.
䊚 2003 Elsevier B.V. All rights reserved.
Keywords: Speciation; Review; Inductively coupled plasma mass spectrometry (ICP-MS); Electrospray ionization mass spectrometry (ESI-MS)
1. Introduction
It is a well-known fact that the toxicity, bioavailability,
and transport properties of an element are highly dependent upon its chemical form. In the past, total quantification of an element was used to determine potential
health hazards or benefits, but in recent years, more and
more research groups have acknowledged that elemental
quantification alone is not sufficient. To completely
understand the ways in which particular elements will
affect living organisms, it is necessary to determine the
species within which the elements are found, and to
quantify those species. Analysis performed to identify
andyor quantify one or more distinct chemical species
in a sample is known as speciation analysis w1x. Procedures for speciation analysis aimed at determining the
species distribution of a particular element in a sample
involve detection of compounds containing the trace
*Corresponding author. Tel.: q1-812-8552189; fax: q1-81285509588.
E-mail address: hieftje@indiana.edu (G.M. Hieftje).
element of interest, preceded or followed by identification and characterization of those compounds. ‘Hyphenated’ techniques, coupling a separation method with a
sensitive detection method, are often applied to obtain
speciation information for trace metals and metalloids
in biological and environmental systems w2–5x.
It has become common practice in recent years to use
inductively coupled plasma mass spectrometry (ICPMS) for ultra-sensitive detection of trace metal- and
metalloid-containing compounds. For identification of
those compounds that are detected by ICP-MS, electrospray ionization mass spectrometry (ESI-MS) has been
gaining increasing popularity. Because traditional ESIMS reveals only the molecular weight of a compound,
electrospray ionization tandem mass spectrometry (ESIMSyMS) has been increasingly used for structural characterization. ICP-MS, ESI-MS, and ESI-MSyMS
provide complementary information (see Fig. 1), and
when all three techniques are utilized for analysis of a
sample, a complete picture of the species distribution
for a given element within that sample can be obtained.
0584-8547/04/$ - see front matter 䊚 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.sab.2003.09.004
136
A.L. Rosen, G.M. Hieftje / Spectrochimica Acta Part B 59 (2004) 135–146
Fig. 1. Schematic diagram illustrating the contributions of various analytical techniques to the accomplishment of speciation analysis, as well as
relationships between the techniques.
Both ICP and ESI ion sources have been coupled with
a number of different mass analyzers, including quadrupole, ion trap, double focusing, and time-of-flight
mass spectrometers. The quadrupole mass analyzer has
been the most frequently used, although each mass
analyzer has its own advantages.
The field of speciation analysis has come to incorporate a wide variety of analytical techniques applied to
an even wider variety of biological, environmental and
industrial applications. A number of excellent reviews
have been written on various aspects of speciation
analysis w3,5–9x, and entire symposia and journal issues
have been dedicated to the subject. It is by no means
the intention of the present work to provide a review of
the literature from the entire diverse field. Rather, the
intent is to provide a review of those problems within
the field of speciation analysis that have been addressed
by using ICP-MS and ESI-MS, and to provide a brief
overview of ICP-MS and ESI-MS instrumentation as it
is applied to speciation analysis. Although low-power
and reduced-pressure ICP sources have been used by
some researchers, the scope of this paper will be limited
to conventional atmospheric-pressure ICP-MS. Emphasis
will be placed upon the advantages of using ICP and
ESI sources coupled with multidimensional separation
techniques and non-scanning mass analyzers for a wide
variety of applications, and upon recent trends in the
field.
2. Current focal areas in speciation analysis
2.1. General fields of interest
Speciation analysis is becoming increasingly important and necessary in a number of fields w4,10x (see Fig.
2). Applications within environmental chemistry include
the identification of toxic metal- and metalloid-containing species in sites that have been contaminated by
industrial or natural sources, as well as determination of
successful clean-up strategies. Because the bioavailability and thus toxicity of elements such as arsenic and tin
are highly species-dependent, total element determination is not a good indication of the threat that a
contaminated site presents to the public. Identification
of those chemical species that are harmful to living
things is necessary to develop reasonable, chemically
specific regulations for industrial waste w4x, and advances in analytical techniques are necessary to efficiently
monitor this waste for contaminants. Finally, knowledge
of the species present and their chemical behavior is
A.L. Rosen, G.M. Hieftje / Spectrochimica Acta Part B 59 (2004) 135–146
137
Fig. 2. Fields of study within which speciation analysis has had and will continue to have significant impact.
required in order to develop effective strategies to clean
up contaminated sites.
The fields of health and nutrition can also benefit
tremendously from the information that speciation analysis provides w11x. A great number of elements are
known to be essential to human nutrition and survival,
including iron, copper and zinc, which are required at
trace levels, as well as such elements as selenium, cobalt
and manganese, which are necessary in ultra-trace
amounts. Likewise, many elements, such as arsenic,
mercury and lead, are known to be quite toxic to
humans. However, the potential of these elements to be
harmful or beneficial is highly dependent upon their
speciation w11,12x. It is thus of great interest to know
the species of essential and toxic elements that occur
naturally in foods, as well as those that are present in
vitamins and food supplements. Many current standards
issued by the American Food and Drug Administration
(FDA) w13x, and the National Academy of Sciences
Institute of Medicine (IOM) w14x, as well as international health organizations such as the Food and Agriculture
Organization and World Health Organization (FAOy
WHO) w15,16x, rely only on total element concentration
to determine if a particular food or beverage product is
safe to consume. Identification of those particular species that are harmful to humans, as well as improvement
of techniques to accurately and efficiently detect those
species, will foster the development of more appropriate
safety regulations, and will enable the critical evaluation
of natural and synthetic supplements. Furthermore, identification of those particular chemical forms of essential
elements that are easily absorbed and metabolized will
aid in the establishment of more useful nutrition guidelines as well as the development of more effective
supplements.
Finally, advances in speciation analysis will indisputably have a tremendous impact on the field of bioinorganic chemistry w2,3,12x. Once a species enters an
organism, it has the potential to undergo a great many
chemical transformations, some of which may radically
alter its properties. Determination of chemical species
throughout the metabolic pathway and within various
bodily tissues and fluids can provide information about
the biological mechanisms for cellular uptake, transport,
storage and excretion. Furthermore, identification of
species within the body containing toxic elements can
provide information about the ways in which organisms
have adapted to sequester, accumulate, or detoxify otherwise harmful elements. These ideas can be extended
to include therapeutic drugs as well w17x. The identification of drug metabolites is important to understand
the mechanisms of medications already in use and to
aid the development of more effective medications.
2.2. Essential elements
Studies published in the literature regarding detection
and identification of compounds containing essential
elements have focused on trace essential elements, such
as iron, copper and zinc, as well as ultra-trace elements
such as cobalt, manganese and selenium. Major focus
areas have included the identification of metalloproteins
and metalloenzymes, with subsequent analysis of their
structure and function w6,18x, the detection of biological
138
A.L. Rosen, G.M. Hieftje / Spectrochimica Acta Part B 59 (2004) 135–146
metal-complexing ligands w19–21x, and the differentiation between oxidation states of metals such as chromium, for which the 3q oxidation state is essential and
the 6q oxidation state is toxic w11x. Common samples
include foodstuffs, bodily tissues such as liver and
kidney, and bodily fluids such as blood, urine, breast
milk and amniotic fluid w3x. In recent years, a large
number of research groups have turned their focus
towards selenium, and a wealth of literature has become
available on Se speciation. A review on selenium speciation by hyphenated techniques has recently been
published w22x.
The discovery that selenium may help prevent certain
forms of cancer has prompted a pronounced interest in
the mechanisms by which it functions w23–25x. Furthermore, the discovery that individuals in many countries
have a diet deficient in selenium has spurred the introduction of a wide variety of selenium supplements. A
number of research groups have analyzed these supplements w23,24,26–28x as well as natural sources of
selenium w28–30x to determine the species of selenium
present, and others have studied bodily fluids w31–33x
and mammalian tissue w34x to elucidate the mechanisms
by which selenium is metabolized and excreted. In
addition to studies of the utilization of selenium, pathways of toxic action are of interest as well, since the
margin between the nutritionally required and toxic
amounts is very narrow relative to those observed for
other elements w35,36x.
Work performed thus far has identified the amino
acids selenomethionine, selenoethionine, and selenocysteine as likely cancer-preventative species w28x,
although a number of selenoamino acid derivatives,
selenium-containing glutathione derivatives, and smaller
organoselenium species have been detected and identified in selenium-enriched yeast w23,26,27x and in human
urine w31,33x. Improvements in the detection limits of
ICP-MS have resulted in the detection of over 30 distinct
selenium-containing compounds in a single yeast extract.
However, most of these compounds remain unidentified
due to the unavailability of standards and the relatively
poor detection limits of ESI-MS relative to those of
ICP-MS w26x.
2.3. Toxic elements
A great deal of research has been performed to
identify compounds containing metals and metalloids
that are toxic to humans or other organisms. Toxic
elements studied include arsenic, antimony, tin, mercury,
lead, aluminum, chromium, cadmium and mercury, and
studies have focused both on environmental species that
might be ingested, as well as species found in tissue
and bodily fluids. Speciation analysis of tin, lead,
mercury and antimony compounds has focused mainly
on the detection and identification of small organic
derivatives of these metals, as well as detection of the
free metal ion w37–40x. Speciation of aluminum, chromium and cadmium has focused on biologically synthesized proteins and small molecules that act as ligands
to bind and deactivate the toxic metals. Such ligands
discovered so far include citrate, aconitate and malate
ions, transferrin, albumin, ceruloplasmin, metallothionein, and phytochelatins w19,21,41,42x. The latter two
of this list have been studied in detail due to their ability
to bind and sequester a wide variety of toxic metals,
and they will be discussed in a later section. Oxidation
state has been of great interest as well, since the toxicity
of elements such as antimony, arsenic, and chromium
are highly dependent upon oxidation state w11,41x. Just
as the research on essential elements has tended to focus
in recent years on selenium, research on toxic elements
has focused on arsenic, and a wide variety of arseniccontaining species have been discovered.
Arsenic is present in a wide variety of compounds of
vastly differing toxicity. Inorganic arsenic compounds
(arsenite and arsenate) are known to be highly toxic,
while organoarsenic compounds are generally considered
to be non-toxic. Arsenic-containing organic acids such
as dimethylarsinic acid and monomethylarsonic acid are
believed to have intermediate toxicities w43x, and some
phenylarsonic compounds have even been found to be
beneficial in livestock w44x. The speciation of arsenic
has been pursued by a large number of research groups
owing to its disproportionately high concentration in
commonly consumed seafood. The total arsenic concentration in marine plants and animals ranges from 10 to
100 mgyg, but this arsenic is distributed among a large
number of compounds. About half of those arsenic
compounds detected in marine animals have yet to be
identified w45x.
Arsenobetaine, a non-toxic organoarsenic compound,
has been identified as the most abundant arsenic species
in marine animals, and a number of other compounds,
including simple methylated derivatives, arsenocholine,
and a wide variety of arsenic-containing organic acids
have been identified and well-studied w46,47x. Tentative
mechanisms for the metabolism of arsenic by marine
life have been postulated, but the failure to identify
many of the arsenic species present has prevented a
more concrete understanding w47,48x. Analysis of human
urine and serum samples for determination of arsenic
species has been performed as well w49–51x, but the
metabolic pathway of arsenic in humans remains poorly
understood. The increasing application of ESI-MS and
ESI-MSyMS to identify arsenic species will reduce the
current reliance on reference standards, and will aid in
the identification of currently unidentified species.
2.4. Metal sequestration
In studying elements that are toxic to living organisms, it is of great interest to understand the ways in
A.L. Rosen, G.M. Hieftje / Spectrochimica Acta Part B 59 (2004) 135–146
which organisms are capable of protecting themselves.
Plants and animals have developed a number of ways
to sequester or detoxify harmful metals and metalloids.
In some cases, the toxic free element is transformed
enzymatically into a less harmful or completely harmless
organic form which can then be stored or excreted
w36,52x. In other cases, metal or metalloid ions are
complexed by biologically synthesized ligands, which
can be small molecules, peptides, or proteins. In both
plants and animals, chemical species have been identified that are believed to have the sole purpose of binding
metal ions and thus regulating the amount of free metal
in the biological system.
In animals, a class of proteins known collectively as
metallothioneins (MTs) have been detected and characterized. MTs are non-enzymatic, low molecular-weight
proteins (6–7 kDa) that are rich in cystein residues and
lack disulfide bonds. They are thus capable of binding
metals with sulfur affinity and have been shown to play
a role in detoxification of toxic metals (Cd, Hg, Ag),
as well as homeostatic control and metabolism of nontoxic metals (Cu, Zn) w18,20x. The study of MTs is
complicated by the existence of a number of different
isoforms. Furthermore, each MT molecule is capable of
binding up to seven metal atoms. With the variety of
metals that can be bound at each site, a large number
of stoichiometric combinations are possible. Many subisoforms have been identified by means of ESI-MS and
ESI-MSyMS, and stoichiometry has been determined
for some isoforms by acidifying solutions to facilitate
loss of the metals followed by comparison of metallated
and demetallated masses w2,20,53,54x. However, a great
deal of work remains to be done in order to isolate and
detect all of the different sub-isoforms, to determine
their amino-acid sequences, and to identify the metals
bound and stoichiometry under various biological conditions. Improved techniques must also be developed to
detect and characterize the very low concentrations
present in biological organisms in situations where there
is no environmental metal stress to induce increased MT
production w6,19,55x.
Although metallothioneins like those in animals have
not been found in plants, a class of peptides known as
phytochelatins (PCs) has been discovered w56x. Like
MTs, PCs bind metal ions through cysteinyl sulfurs, but
unlike MTs, they are known to be stress-induced and
enzymatically synthesized. PCs have the general structure (g-Glu-Cys)nGly, where n ranges from 2 to 11
(known as PC2, PC3, etc.) w2x. Studies thus far indicate
that PCs detoxify heavy metals and metalloids, including
Cd, Cu, Pb, Zn, and As by sequestration of the PCmetal complex in intracellular vacuoles w18x, although
some research has indicated a more transient role w57x.
Standards exist for the most commonly found PC
ligands, making their detection and determination fairly
straightforward. However, PC-metal complexes are quite
139
labile and to the authors’ knowledge have not successfully been put into the gas phase intact w6x. As a result,
stoichiometric determinations using mass spectrometric
techniques are difficult. Furthermore, mixed-ligand complexes (e.g. PC2 and PC3 in a single complex) have
been detected, but standards do not yet exist for these
complexes and little is known about them w3,21x.
Recent interest in phytochelatins and other metalbinding ligands in plants has centered on hyperaccumulating plants, which are able to absorb and store
unusually large amounts of toxic metals w58,59x. These
plants have the potential to be used in phytoremediation
efforts to detoxify contaminated sites, but the mechanisms by which they are able to sequester toxic metals
at such high concentrations are not well understood
w52,60,61x.
2.5. Drug metabolism
A number of metallocompounds and metallocomplexes have been found to have value as therapeutic drugs.
Included in this category are anti-cancer drugs containing platinum-group elements, gold-containing drugs
used to treat rheumatoid arthritis, lithium carbonate used
to combat manic depression, and vanadium compounds
used as insulin mimetics w62x. In order to fully understand how these metallodrugs behave in vivo, it is
necessary to identify the products of their biotransformation and degradation. Such an analysis includes identification and characterization of chemically transformed
species, as well as complexes of the drug with other
species present in the biological system and with its
target. In many cases, it has been found that the
therapeutically active species is not the administered
drug but rather a metabolite w62,63x. Such discoveries
can potentially help in the development of more effective
or alternative drug products. Furthermore, many metallodrugs are known to have severe side-effects, and the
margin between beneficial and toxic doses can be
narrow, making it necessary to understand mechanisms
of toxicity as well as therapeutic action, and to identify
the toxicologically active species.
The platinum-containing anti-tumor drug cisplatin has
been particularly well studied. The mechanism of action
of cisplatin is known to include a hydration step followed by binding of the hydration product to the
guanosine moieties of DNA w17x. It is believed that
albumin plays a key role in the transport and activation
of cisplatin, although the complex with albumin is itself
inactive, and it is suspected that complexes of cisplatin
with methionine are in part responsible for its toxicity
w17,63,64x. Based upon work done on cisplatin, a number of related compounds have been developed that are
intended to be less toxic and to be effective in cisplatinresistant tumors, although little is understood about
many of them w65x. A great deal of speciation work is
140
A.L. Rosen, G.M. Hieftje / Spectrochimica Acta Part B 59 (2004) 135–146
necessary to better understand these new metallodrugs
and their advantages over cisplatin.
A variety of speciation techniques have been applied
to elucidate the biological mechanisms of metallodrugs,
as well as drugs containing non-metallic heteroatoms
and drugs that do not contain a metal themselves, but
which are known to bind metals in-vivo w62–67x. Most
studies of metallodrug metabolism using hyphenated
techniques have employed standards for compound identification, and thus the utilization of ESI-MS and ESIMSyMS to identify unknown compounds should provide
new insights in the field.
3. Current instrumentation
3.1. Hyphenated techniques
A wide variety of hyphenated techniques have been
developed to tackle the problems of speciation analysis.
Early speciation work found that complex samples could
not be analyzed without the aid of a separation technique, but the most commonly used detectors for separation methods did not provide element-specific
information. The interfacing of gas- and liquid-chromatography instrumentation with element-selective detectors for speciation analysis was pioneered in the late
1970s and 1980s by Van Loon w68x and Suzuki w69x.
Initial configurations employed atomic absorption, atomic fluorescence, and atomic emission spectrometers, but
improvements in atomic mass spectrometric instrumentation have led to the widespread use of mass spectrometry in hyphenated techniques. In particular,
HPLC-ICP-MS has been widely applied and is becoming
routine for speciation studies w8x. Alternative separation
techniques have been employed as well, including gas
chromatography w5x, obviously limited to volatile compounds unless derivatization is employed, capillary electrophoresis (CE) w70–72x, which can be sampled online,
and flatbed electrophoresis w35,73x, which can be coupled offline via techniques such as laser ablation and
electrothermal vaporization. CE has been gaining in
popularity in recent years due to its ultra-high separation
efficiency and the small sample volumes it requires w72x.
A particularly mild separation technique that has been
applied by few researchers for speciation but may have
promise for future investigations is field flow fractionation (FFF), which is known to be capable of separating
macromolecules, colloids and even cells w74,75x.
The wide variety of hyphenated techniques that have
been used for speciation analysis and the applications
for which they have been employed have been reviewed
w2,3,5,7x. In conjunction with HPLC or CE, ICP-MS
has been the most widely used instrument in recent
years for element-specific detection, and ESI-MS has
been the most widely used for compound identification.
Both ionization sources can be coupled in a fairly
straightforward manner to a number of separation techniques, and both have been used with a wide variety of
mass analyzers.
3.2. ICP-MS for elemental detection
ICP-MS has become the most widely used detection
technique for speciation analysis. A number of speciation studies have employed optical spectrometric techniques, including atomic absorption spectroscopy (AA)
and ICP atomic emission spectroscopy (ICP-AES), but
AA does not provide simultaneous multielemental detection, and ICP-AES is in general less sensitive than ICPMS. Routinely achievable sub-ngyl detection limits for
ICP-MS w3x have permitted the detection of ultra-trace
species in biological and environmental matrices. ICPMS can detect trace-element-containing species, even
when a particular trace element is distributed amongst a
large number of species. In particular, improvements in
ICP-MS sensitivity have allowed the detection of more
and more arsenic and selenium compounds in biological
matrices and food supplements w27,76x. In addition to
its low detection limits, the dynamic range of ICP-MS
routinely exceeds six orders of magnitude, allowing
detection of both major constituents and trace components at the same sample dilution. Furthermore, the
multielemental capability of ICP-MS enables the observation of individual isotopes, which permits the use of
isotopic-dilution techniques for internal standardization
and also to monitor species transformations that may
occur during sample pre-treatment or separation w40,77x.
In addition to all of these advantages, there are a
number of difficulties that are often encountered in
using ICP-MS for speciation analysis. A consideration
that is particularly important when ICP-MS is coupled
with HPLC or CE is the solvent composition. It is well
documented that high concentrations of some organic
solvents can result in plasma instability as well as a
build-up of carbon residue on the sampling cone w78x.
These problems can be alleviated to some degree by
addition of oxygen to the nebulizer-gas flow, by increasing the RF power to the plasma, by using a platinum
sampling cone, and by using either a low-flow directinjection nebulizer (DIN) or a nebulizer with an efficient
desolvation unit (such as a membrane desolvator). If
analyte concentrations are high enough, post-column
dilution with water (or dilute HNO3) may also be an
option. The use of solvent gradients can also pose
problems for ICP-MS analysis. A change in solvent
composition alters the plasma temperature and electron
number density, which can result in different ionization
efficiencies and ion energies. If a spray chamber is used,
changing solvent concentrations can also result in memory effects due to solvent adhesion and revolatilization
to and from the spray chamber walls. Thus, if quantifi-
A.L. Rosen, G.M. Hieftje / Spectrochimica Acta Part B 59 (2004) 135–146
cation is desired, solvent gradients should be avoided or
closely monitored w15,65x.
The other common source of difficulties arising from
the coupling of ICP-MS with separation techniques is
the sample matrix. Biological and environmental samples contain very complex matrices, and many HPLC
and CE techniques require the use of a buffer or a
solution of high ionic strength. In the ICP, high salt
concentrations can result in signal suppression due to
increased space-charge effects which defocus the ion
beam w15,79x. Thus, tradeoffs may be required with
respect to separation efficiency and detection sensitivity,
although matrix problems in the ICP can be alleviated
somewhat by performing sample pretreatment, by altering argon flow rates, by modifying interface configurations and voltages, or by post-column dilution w79,80x.
A final potential problem is the appearance of isobaric
overlaps from polyatomic ions occurring at the same
nominal myz as the ions of interest. This problem is
particularly acute when selenium is to be detected, since
its most abundant isotope (80Se) has the same nominal
mass as 40Ar2 w22x. Very high resolution mass analyzers
are capable of overcoming isobaric overlaps to some
degree, and a number of methods have been developed
to either reduce the appearance of the isobaric overlap,
or to move the ion of interest to a different myz via a
chemical reaction w81x.
3.3. ESI-MS for compound identification
Because the ICP is a destructive ionization source,
conventional ICP-MS serves as an ultra-sensitive elemental detector only, and it provides no inherent information about chemical species. Thus, most speciation
studies making use of ICP-MS have employed a separation step and have used standards for compound
identification via matching of retention times. However,
standards are not always available, methods such as CE
produce retention times that are notoriously dependent
on factors such as ionic strength, and it is not always
possible to predict the compounds that one expects to
find. Indeed, progressively lower detection limits for
ICP-MS are providing more and more peaks for newly
detected, unidentified compounds. Standards are not yet
available for the wide variety of metallothionein subisoforms or the minor arsenic- and selenium-containing
species in biological samples w27,55,76x. Furthermore,
the approach based upon retention-time matching of
chromatographic peaks detected by ICP-MS assumes
that complete chromatographic separation has been
achieved and that each peak corresponds to a single
pure compound, which may not be the case. If identification of all compounds containing the metal or metalloid of interest is to be achieved, a technique must be
used that can provide information about the intact
molecular species. One of the most commonly used
141
techniques for this purpose is electrospray ionization
mass spectrometry. The ‘soft’ ionization of ESI produces
molecular ions without any significant fragmentation.
For many heavy compounds, a series of multiply
charged peaks are observed, permitting a very accurate
determination of molecular weight.
In the past, many studies that have focused on
compound identification have made use of nuclear
magnetic resonance (NMR) spectroscopy. ESI-MS
requires significantly smaller sample volumes and less
preliminary purification than are needed by NMR and
has been preferred by most researchers in recent years
w47x. In situations where ESI has proven unsuccessful,
other mass spectrometric methods, including matrix
assisted laser desorption ionization (MALDI), have been
used for molecular weight determination w82x. However,
MALDI has been applied less frequently because its
coupling to separation techniques such as HPLC and
CE is not as straightforward since the sample must be
immobilized.
When one uses ESI-MS or other mass spectrometric
techniques that produce intact molecular ions, structural
information can be obtained by using tandem mass
spectrometry (MSyMS), in which collision-induced dissociation (CID) is used to reproducibly fragment a
selected molecular ion. MSyMS has been used by a
large number of researchers for positive identification
and characterization of detected species w2,46,47,52,76x.
Depending upon instrument configuration, it is often
also possible to remove weakly bound metals from
metallocomplexes by increasing interface potential differences or by post-column acidification. The metalbinding ligand can then be observed on its own, allowing
the determination of its molecular weight and elucidation
of metal:ligand stoichiometry w18,19,83x.
As with any technique, there are some disadvantages
to using ESI-MS. The main disadvantage is its relatively
poor detection limits compared to ICP-MS. Routinely
achievable detection limits for ESI-MS are generally
two to three orders of magnitude poorer than those for
ICP-MS w27x. This discrepancy becomes a problem
when one wishes to identify ultra-trace species that have
been detected by ICP-MS. In fact, most studies aimed
at compound identification in real biological samples
have resorted to preconcentration of chromatographic
fractions preceding analysis by ESI-MS w27,29,52x. The
other major complication that has been observed with
ESI-MS is the suppression of the analyte signal by
complex matrices. The presence of high concentrations
of salts, which may be present in HPLC buffers or CE
electrolytes, has been shown to suppress ionization of
analyte compounds and thus to decrease the observed
signal w27x. Pneumatically assisted ESI, also known as
Ion-spray䉸, has been used by many to overcome these
matrix effects. Ion-spray䉸 is capable of handling a wider
range of solvent compositions than standard ESI,
142
A.L. Rosen, G.M. Hieftje / Spectrochimica Acta Part B 59 (2004) 135–146
although matrix effects can still be a problem w71x.
MALDI-MS has also been applied as an alternative to
ESI-MS in situations where matrix effects were deemed
to be a problem w82x.
3.4. ESI-MS for elemental analysis of small molecules
One of the primary advantages of ESI-MS, as mentioned above, is that it is a ‘soft’ ionization technique,
producing little fragmentation. Most researchers utilizing
ESI-MS have taken advantage of this feature, detecting
intact molecular ions and selecting specific molecular
ions for fragmentation via CID. However, some
researchers have successfully applied ESI-MS for elemental analysis. It has been well demonstrated that the
ions observed in an ESI-MS spectrum are highly dependent upon the conditions imposed within the ESI unit
and the atmosphere-vacuum interface. ‘Mild’ interface
conditions, including moderate desolvation temperatures,
low interface voltages and low curtain-gas flow rates,
have been found to preserve the species found in
solution, while ‘harsh’ interface conditions, including
higher desolvation temperatures, interface voltages and
gas flow rates, have been found to induce declustering
and fragmentation w84x. This fragmentation within the
interface region is believed to result from a collisioninduced dissociation process and has been called by a
number of names, including ‘high-pressure,’ ‘up-front,’
and ‘source’ CID w6,85x.
Several researchers have successfully manipulated
interface conditions to study inorganic and relatively
small organic molecules w85x. Agnes and Horlick have
identified three sets of parameters that result in the
observation of three distinct types of mass spectra for
inorganic solution ions: the ion cluster mode, the metalion mode, and an intermediate mode w84x. A number of
other researchers have applied well-defined interface
conditions to achieve partial fragmentation, complete
fragmentation, and removal of metal ions from relatively
small organometallic compounds, such as ferrocene,
tributyltin, and arsenobetaine w83,86,87x. Despite these
achievements, however, elemental spectra have not been
obtained using ESI-MS for large molecules such as
proteins. Interface conditions have been found under
which non-covalent interactions can be selectively broken, and under which functional groups can be cleaved,
but to the authors’ knowledge complete fragmentation
of a protein molecule to its elements using only an
electrospray source has not been achieved w88,89x.
When compared with ICP-MS, ESI-MS for elemental
analysis has advantageous and disadvantageous features.
ESI-MS in the elemental mode can provide a complete
elemental spectrum free from the spectral interferences
often encountered in ICP-MS w6,87,90x, and it is capable
of providing information about valence state for solution
ions that is unobtainable with conventional ICP-MS
w84,91x. Its use can potentially reduce the cost of
analysis due to decreased sample consumption, lack of
argon consumption, and because elemental and molecular information can be obtained on the same instrument,
although not at the same time w89,90x. The major
shortcoming of ESI-MS relative to ICP-MS is poor
detection limits, which are observed in both molecular
and elemental modes w90x. Additionally, it is difficult to
eliminate oxides without significant loss of signal, highpressure CID is generally difficult to control and can
result in decreased resolution, and optimal interface
parameters vary substantially from element to element,
making
multielement
determinations
difficult
w85,86,90,92x. Finally, and quite importantly for applications in the field of biochemistry, elemental ESI-MS
has not been shown to work for large molecules w89x.
It is clear that elemental ESI-MS may have a promising
future for the analysis of inorganic and small organic
compounds, particularly for those species that are difficult to detect by ICP-MS, but at this point it does not
appear to play a role in the analysis of biomolecules.
3.5. Mass analyzers for mass spectrometric detection
The most common mass analyzer used in conjunction
with ICP and ESI ionization sources in hyphenated
techniques has been the quadrupole mass filter. Its
robustness, modest vacuum requirements, and compact
size have made the quadrupole attractive for routine
analysis. However, current research is turning increasingly toward other types of mass analyzers, including
ion-trap w93x, sector-field w94x, and time-of-flight w95,96x
units. These mass analyzers generally have the advantage of improved resolution, and all have the potential
to detect or extract all ions simultaneously. The elimination of spectral skew afforded by non-scanning instruments permits accurate representation of transient
signals, which is necessary when they are coupled
directly to a chromatographic or electrophoretic separation. With respect to speciation, techniques for simultaneous detection permit identification of species
containing more than one type of metal as well as
determination of stoichiometry within these compounds.
This capability is of particular interest in the study of
metallothioneins, which can bind many different metals
at a number of coordination sites w19,20x. Furthermore,
multielemental detection can allow rapid, simultaneous
speciation analysis of multiple elements in a complex
sample, and can enable the observation of isotopic
patterns for confirmation of metal content in molecular
spectra, and for improved structural analysis capability
in MSyMS w97x. The ability to resolve and simultaneously detect multiple isotopes also enables the use of
isotope-dilution methods w40x for improved quantification. The availability of quadrupole time-of-flight (QTOF) tandem mass spectrometers offers structural
A.L. Rosen, G.M. Hieftje / Spectrochimica Acta Part B 59 (2004) 135–146
analysis without the disadvantages of low-resolution
scanning techniques.
3.6. Multidimensional separation techniques
The need to identify species from increasingly complex mixtures that elute in individual chromatographic
fractions has underscored the difficulty in obtaining
chromatographically pure fractions. An effective and
increasingly popular way of ensuring complete chromatographic (or electrophoretic) separation is to use
multiple orthogonal (complementary) separation techniques in series. Such ‘multidimensional’ approaches
have been recently reviewed with respect to speciation
analysis w97x, and have been applied to the speciation
of arsenic w47,98x and selenium w26x. The most common
combinations incorporate size-exclusion chromatography (SEC) followed by cation-exchange, anionexchange, or reversed-phase HPLC, or CE. The initial
SEC separation facilitates removal of large biological
polymers, partial desalting of analytes, and a rough
fractionation based upon molecular weight w97x. The
separations that follow must be chosen based upon the
analytes of interest, the sample matrix, and the detection
technique to be used. Two- and three-dimensional
approaches are generally sufficient for adequate separation. An additional benefit of multidimensional separation techniques is that they provide a more simplified
matrix, which reduces matrix interferences seen in the
MS detectors.
A critical consideration when one uses separation
techniques is preservation of the original chemical species. If the speciation analysis is to accurately represent
the species distribution in the sample, changes in chemical composition and oxidation state must be minimized
in every step of the procedure, including sample preparation, separation and detection. The separation steps
used for a particular application must be chosen carefully
to minimize interactions with the species of interest, to
maintain appropriate pH, and to minimize loss of analyte. When chemical interactions pose a problem, CE
can be used as an alternative to HPLC, because the lack
of analyte-stationary phase interactions provide less
opportunity for chemical changes w71x. Ion exchange
chromatography has been used by some in place of
more traditional reversed phase chromatography due to
reduced interactions with the matrix w15x. Once again,
the best chromatographic or electrophoretic technique
for a given experiment should be chosen based upon
knowledge of the analytes of interest, the metals or
metalloids they contain, the matrix within which they
exist, and the detection technique to be used.
4. Concluding statements
It is evident from the above overview that although a
great deal of speciation work has been done, a tremen-
143
dous amount of additional information about the speciation of trace metals in biological and environmental
samples must be obtained. Significant advances have
been made in developing instrumentation that has
improved sensitivity and versatility, and can provide
more complete and conclusive information. ICP-MS and
ESI-MS have been applied by a large number of
researchers as complementary techniques, providing elemental and molecular information that together provide
a complete picture of elemental speciation. Future work
in the development of instrumentation for speciation
analysis will include not only improvement of existing
technologies, but also a streamlining of the process.
Instrumental designs have been conceived which allow
the simultaneous use of ICP-MS and ESI-MS instruments in parallel w92x, or the incorporation of ICP and
ESI sources into a single mass spectrometer w99x.
Advances such as these will provide improved speciation
capabilities, and continuing collaboration among the
fields of analytical, bioinorganic, and environmental
chemistry will facilitate the application of new technologies to real-world problems.
Acknowledgments
Supported in part by the US Department of Energy
through grant DOE DE-FG02-98ER14890. Support was
also provided by the US Department of Energy, Office
of Non-proliferation Research and Engineering, through
Pacific Northwest National Laboratory (PNNL). PNNL
is operated by Battelle Memorial Institute for the Department of Energy under contract DE-AC06-76RLO-1830.
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