Quadrupole Inductively Coupled Plasma Mass Spectrometry (ICP-Q-MS) combines the high-temperature capabilities of an ICP source with the precision of mass spectrometry to detect trace elements and some non-metals at very low concentrations. The technique involves converting a liquid sample into a mist, ionizing it in an argon plasma, and analyzing the ions produced in a quadrupole mass analyzer based on their mass-to-charge ratios. ICP-MS offers high sensitivity to detect elements at the parts per trillion level and produces a wide spectrum of concentrations quickly in a single analysis run. However, it faces challenges from certain polyatomic ions and matrix effects that affect the results. Equipment costs range from $150,000 to $250,000 USD for entry level systems with ongoing expenses for high-purity argon gas and complex sample preparation. Additionally, ICP-MS requires skilled operators and regular maintenance to produce its accuracy. Despite these challenges, quadrupole ICP-MS is widely used in fields like geology, environmental science, and medicine [114, 115].

High-resolution Inductively Coupled Plasma Mass Spectrometry (HR-ICP-MS) enhances traditional ICP-MS capabilities by incorporating a magnetic sector or double focusing mass spectrometer to separate ions not only by their mass-to-charge ratio but also by energy. This separation significantly improves resolution that allows to distinguish analyte ions and interfering species of identical mass-to-charge ratios. HR-ICP-MS begins similarly to quadrupole ICP-MS but the ionized sample is passed through a magnetic sector field which separates ions based on their momentum. This addition minimizes but not completely removes spectral interferences, including those from polyatomic ions, which produces cleaner spectra and thus provides better trace element quantification.

HR-ICP-MS excels in sensitivity and specificity in being able to detect low-abundance isotopes and elements in complex matrices with minimal interference. It resolves isobaric and polyatomic interferences without chemical resolution, which is useful in fields like environmental monitoring and biomedical research. However, HR-ICP-MS systems are significantly more expensive than ICP-Q-MS with costs typically ranging from $400,000 to $600,000 USD. The instrument’s complexity requires expertise in operation and maintenance, and its higher resolution results from longer analysis times compared to ICP-Q-MS, which reduces throughput. Despite these challenges, HR-ICP-MS has been highly effective in detecting and monitoring metals and non-metals in biological fluids including blood plasma, blood spots, and tissues [116–119].

Triple Quadrupole ICP-MS (ICP-QQQ-MS) is a form of mass spectrometry that utilizes two quadrupole mass analyzers in series separated by a collision/reaction cell [120]. These systems allow for chemical collisions to prevent typical interferences seen in standard ICP-MS [121]. The use of collision-reaction-cells (CRC) and the implementation of a second scanning quadrupole in ICP-QQQ-MS stand out as pivotal developments that effectively eliminate spectroscopic interferences [122].

In ICP-QQQ-MS, the first quadrupole (Q1) selects precursor ions of a specific mass-to-charge ratio, which are then directed into the collision/reaction cell. Within this cell, ions can undergo reactions with a chosen gas, such as removing interferences or inducing predictable reaction products. The second quadrupole (Q2) analyzes the product ions at extremely low concentrations, often in the parts per trillion (ppt) or parts per quadrillion (ppq) range for some elements. By using reaction gases like ammonia or oxygen, ICP-QQQ-MS can break down or transform interfering species. This allows for the accurate quantification of target analytes by mitigating typical ICP-MS interferences like polyatomic or the plasma gas itself [123]. One of the standout features of ICP-QQQ-MS is its versatility in analyzing a wide range of biological samples, including blood, urine, tissue samples, and even complex environmental matrices. Its ability to provide precise and accurate measurements at trace levels makes it particularly valuable in environmental monitoring, clinical research, toxicology, and food safety testing.

With the average cost of an ICP-QQQ-MS system, like an Agilent 8900, typically ranging from $400,000 to $700,000 USD depending on the configuration and application requirements, the complexity of ICP-QQQ-MS systems requiring skilled operators to optimize the reaction cell conditions and interpret the more complex spectra, and having potentially longer analysis for reaction gas optimization, ICP-QQQ-MS has disadvantages for high-throughput or budget-constrained settings.

Time-of-Flight Inductively Coupled Plasma Mass Spectrometry (TOF-ICP-MS) operates on the principle of ionizing sample constituents within a plasma source, accelerating their ions, and measuring their time of flight. This time is inversely proportional to the square root of the mass-to-charge ratio (m/z) and allows for the simultaneous detection of all present isotopes based on their distinct flight times to the detector in a single measurement [124]. This feature makes it particularly suitable for real-time, comprehensive elemental or isotopic overview like in environmental monitoring, food safety, forensic studies, and proteomics. This technique’s high throughput and broad dynamic range facilitate the analysis of biological samples and plant materials, and it provides insight into trace elements and isotopic ratios. Unique to TOF-ICP-MS is its non-scanning operation mode which allows it to excel in applications where rapid, simultaneous multi-element detection is necessary, which offers timesaving and efficiency improvements over other ICP-MS configurations.

With prices ranging from $500,000 to $800,000 USD and being more complex than traditional quadrupole or sector field ICP-MS systems, TOF-ICP-MS systems can be less accessible to labs. Additionally, careful calibration is needed as the broad mass range covered in each measurement can lead to variations in sensitivity across different elements and isotopes.

Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) is an analytical technique that merges the direct solid sampling capability of laser ablation with the sensitivity and selectivity of ICP-MS for trace metal(loids) analysis [125]. It works by focusing a laser beam onto a sample surface to vaporize a minute area (micrograms of mass) that creates an aerosol that is then transported into an ICP-MS system for ionization and mass spectrometric analysis. This process allows for the rapid, in-situ analysis of solid samples with minimal preparation. One of the primary merits of LA-ICP-MS is its ability to perform spatially-resolved analyses to create detailed mapping of elemental distributions within solid biological matrices including human hair, organs, soft tissues, bone, teeth, and others [126–130], which offers insights into historical pollution levels or dietary habits.

LA-ICP-MS can be susceptible to matrix effects where the composition of the sample can influence the ablation process and, consequently, the analytical results. Calibration can also be complex, often requiring matrix-matched standards for accurate quantification. Furthermore, the initial cost and operational expertise required for LA-ICP-MS can be significant barriers to its widespread adoption with costs ranging from $400,000 to $700,000 USD.

Energy Dispersive XRF (EDXRF) uses a detector to discern varying energy levels of characteristic radiation from the sample, creating an XRF spectrum by counting X-rays at each energy level. However, background noise from scattered radiation complicates the detection of low-intensity peaks, which creates some accuracy challenges in trace metal concentrations.

Elemental quantification in EDXRF identifies a sample’s elemental makeup by evaluating X-ray fluorescence intensities from elemental peaks using comparative standards. EDXRF has multiple configurations for the x-ray anode, but all essentially act similarly [132, 133].

Most EDXRF devices can measure most elements accurately, but elements lighter than sodium yield poor results due to their low yield and absorption of photons by air. Lighter elements are better measured using a vacuum or with a helium purge and a specific light element detector. EDXRF is preferred for assessing lead levels in blood samples due to its minimal sample requirement, non-destructive nature, and adaptability. EDXRF spectrometers are compact, cost-effective (prices range from $50,000 to $200,000 USD), and straightforward, which make them a preferred choice over other analytical technologies [2, 63, 66].

Wavelength Dispersive XRF (WDXRF) spectrometers utilize a crystal to separate various energy levels. All radiation emitted from the sample is directed onto the crystal, which then diffracts each energy at different angles [134].

Both EDXRF and WDXRF allow for the direct analysis of solid materials without damaging them. However, particularly for analyzing biological specimens, EDXRF is comparatively more suitable for its efficacy and practicality to WDXRF [135]. The initial setup of a WDXRF spectrometer shares features with the 2D optical and non-secondary EDXRF spectrometers, where the sample is exposed to radiation and is then detected [67, 68]. In WDXRF spectrometry, gas-filled and scintillation detectors are important components due to their effectiveness in detecting different ranges of X-ray energies since neither type is fully efficient across the entire energy spectrum of 1 to 20 keV. WDXRF spectrometers normally consist of a mix of these detectors, including gas-filled, scintillation, and sealed counters, to ensure a broad and effective detection range [70]. Another key distinction between the two methods is that EDXRF systems capture the entire spectrum almost instantly, allowing for the simultaneous determination of a wide array of elements. In contrast, WDXRF systems collect the spectrum through a sequential process. This method is not only more time-intensive but also incurs higher costs because of the limited number of detectors available [136]. Compared with the desktop versions of EDXRF, WDXRF systems can start around $100,000 up to $500,000 USD. These systems were routinely used in air filter analysis but have largely been replaced by smaller, more powerful EDXRF devices [137].

The μ-XRF technique offers a non-destructive method to visualize high-resolution spatial information for each analyzed element [73]. In μ-XRF, the X-ray flux is collimated through an optical arrangement like a pinhole aperture or polycapillary optical system with a micrometer scale diameter and hits the samples. It then emits fluorescence radiation which the detector extracts the sample’s elemental information from the absorbed characteristic X-rays. The projected X-ray beam in this system ranges from 10 μm to 0.1 nm depending on the focusing optics or pinhole used. μ-XRF can also provide 3D elemental profiling through sequential 2D measurements.

μ-XRF can use either synchrotron-based or laboratory-based X-ray production. Synchrotron radiation (SR) generates powerful emissions including ultraviolet, visible, and infrared light, producing radiation levels much higher than those found in typical laboratory X-ray sources, which allow for ultra-low detection limits. The synchrotron beamline essentially reduces the incoming X-rays to a semi-monoenergetic peak which drastically improves the signal-to-noise ratio in spectral counts [73, 138]. SR can assess a broad spectrum of elements in concentrations from 0.01 to 1,000,000 μg/g with high beam alignment accuracy and fine focus, making it ideal for microanalysis. It has been used for elemental profiling of dental, skin, breast, and brain tissues [139–141]. Despite these features, analysis is limited due to their availability and complexities. To resolve this issue, lab-based μ-XRF was developed to provide similar elemental profiling capabilities and fine resolution with different optical systems [73].

The key difference between the benchtop and synchrotron-based μ-XRF is in the spatial resolution and beam flux, which ultimately influences detection limits. Synchrotron facilities use collimators because of the high intensity beams, whereas benchtop systems require mono or polycapillary optical systems. Benchtop μ-XRF fine-tunes elemental detection through voltage adjustments and different filters [142] often employing a separate low-energy detector to detect lighter elements as low as carbon.

The benchtop μ-XRF system has already been applied to analyze a some organ tissues, but not to the same extent that synchrotron has been used [143]. As benchtop μ-XRF continues to develop, it promises to enhance biological and environmental toxicity analysis and exposure assessment by providing high-resolution and sensitive elemental profiling using a lab-based setting. Meanwhile, synchrotron-based systems will continue to provide high precision and sensitivity for trace elemental analysis in biological samples.

Total Reflection XRF (TRXRF) directs a monochromatic X-ray beam at an angle below the critical angle to minimize background scatter and enhance detection capabilities. The beam, focused through a slit, is directed unto the specimen support layer and optimally excites the sample [69, 144]. This technique minimally penetrates the sample support, which significantly reduces background scatter and in turn enhances detection capabilities (ppb or less).

TRXRF has limits of detection (LODs) in the range of 0.1 to 10 ppb for many elements such as lead (Pb), cadmium (Cd), and mercury (Hg), and 10 to 100 ppt for certain elements like arsenic (As) and selenium (Se). However, TRXRF faces challenges related to sample preparation, often requiring dissolution which can damage the sample [145]. The samples typically need to be homogenized and applied to the measurement surface uniformly for unbiased results. While ICP-MS require several milliliters of solution, corresponding to milligrams of a biological sample, TRXRF can achieve comparable detection limits (ppb or even less) using only microliters of solution [146].

Matrix effect removal in TRXRF focuses on minimizing background noise [147]. Biological samples, often containing low-Z elements, can scatter X-rays intensively which affects detection limits. Careful sample preparation allows for direct analysis with TRXRF by requiring only microgram quantities of the sample for multi-element analysis at the same time [76]. This makes TRXRF suitable for low-mass or liquid biological samples [74]. Similarly to other XRF techniques, using light element detectors without windows and performing detection in a vacuum enables accurate measurement of lighter elements down to carbon accurately.