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The age of a geologic sample is measured on as little as a billionth of a gram of daughter isotopes. Moreover, all the isotopes of a given chemical element are nearly identical except for a very small difference in mass. Such conditions necessitate instrumentation of high precision and sensitivity.

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Accelerator Mass Spectrometry AMS is an ultra-sensitive analytical technique based on the use of an ion accelerator as a powerful mass spectrometer.

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Try out PMC Labs and tell us what you think. Learn More. The use of radioisotopes has a long history in biomedical science, and the technique of accelerator mass spectrometry AMSan extremely sensitive nuclear physics technique for detection of very low-abundant, stable and long-lived isotopes, has now revolutionized high-sensitivity isotope detection in biomedical research, because it Uses of mass spectrometry radioactive dating the direct determination of the amount of isotope in a sample rather than measuring its decay, and thus the quantitative analysis of the fate of the radiolabeled probes under the given conditions.

Since AMS was first used in the early 90's for the analysis of biological samples containing enriched 14 C for toxicology and cancer research, the biomedical applications of AMS to date range from in vitro to in vivo studies, including the studies of 1 toxicant and drug metabolism, 2 neuroscience, 3 pharmacokinetics, and 4 nutrition and metabolism of endogenous molecules such as vitamins.

In addition, a new drug development concept that relies on the ultrasensitivity of AMS, known as human microdosing, is being used to obtain early human metabolism information of candidate drugs.

Instruments and procedures

These various aspects of AMS are reviewed and a perspective on future applications of AMS to biomedical research is provided. The technique utilizes a tandem van de Graaff accelerator in order to generate the potential energy, allowing for separation of elemental isotopes at the single atom level. Therefore, AMS can be applied to quantitating the concentrations of long-lived radioisotopes, such as 14 C, for which decay counting is an inefficient method of quantitation because of its relatively long half-life of years [ 3 ]. However, equivalent discussions refer equally well with changes in chemistry [ 4 ], to several other long-lived isotopes that can be quantitated by AMS: 3 H, 10 Be, 16 Al, 36 Cl, 41 Ca, 56 Ni, 99 Tc, I, and Pu.

Schematic diagram of an accelerator mass spectrometry AMS. Cesium Cs sputter ion source A contains the wheel with the graphite samples under high vacuum. The high-energy ion beam is focused to collide with argon gas electron stripper or a thin carbon foil, 0.

Molecular charged Uses of mass spectrometry radioactive dating such as 13 CH - and 12 CH 2 - do not survive the electron stripping process and are converted to atomic species, and 14 N - ions decay on a femtosecond time-scale.

The positive ions are repelled toward the high-energy exit of the accelerator held at 0 V. The beam currents of relatively abundant 12 C and 13 C are measured with Faraday cups F. The 14 C beam is focused by a quadruple and electrostatic cylinder analyzer and the atoms are counted in a gas ionization detector G. It is possible to optimize the detector to the energy-loss separation of the isotope. The sensitivity of AMS for radiocarbon can be emphasized by its use in geochronology or carbon dating of historical artefacts [ 12 ]. As widely known, small amounts of 14 C are constantly being formed from 14 N by bombardment with cosmic radiation in the upper atmosphere, and this formation gives rise to 14 CO 2 Uses of mass spectrometry radioactive dating, and maintains the atmosphere at a nearly constant radiocarbon concentration of about 1.

Plants fix atmospheric 14 CO 2animals eat the plants and thus all higher living organisms contain 14 C in equilibrium. When an organism dies, there is no longer any carbon exchange, and 14 C decays over time. Thus, the 12 C: 14 C ratio can be correlated with the amount of time elapsed after an organism's death, which is the basis of carbon dating.

Carbon dating now extends beyond 50, years back in time [ 3 ]. The most conventional method for the measurement of radioactivity for biomedical applications is liquid scintillation counting LSCa process known as decay counting. LSC, however, suffers from an innate insensitivity.

In fact, it takes over a billion atoms of 14 C to generate an average of only one disintegration per minute dpm. AMS, on the other hand, allows direct measurement of 12 C and 14 C atoms by physically separating them in an ion beam [ 3 ]. Since the atoms are measured directly, without a necessity to wait for a disintegration event to occur, AMS is about six orders of magnitude more sensitive than LSC.

Nowadays, AMS is the method of choice for carbon dating as well as other LCS-utilized biomedical research because of the technique's sensitivity and precision. The workings of an AMS instrument are outlined elsewhere [ 8 - 10 ]. The use of radioisotopes has a long history in biomedical science.

Isotopic enrichment of xenobiotics with 14 C is routinely used as a method of following their metabolic fate in both animals and humans, and a drug is typically synthesized such that the natural abundance of 14 C is increased from the background level of 1. LSC has been generally used for a long time to detect, follow and quantitate levels of radiotracer in such studies.

There are occasions, however, when the low sensitivity of LSC becomes experimentally limiting, while the technique of AMS has now changed the experimental paradigm because its extremely sensitive detection limit virtually removed the experimental barriers.

The high sensitivity of AMS indeed affects experimental des in several ways. First, the radioisotopic dose can be reduced to inconsequential levels of radiolysis, hazardous waste streams, and human subject exposure.

Secondly, the chemical dose to a biological system, including humans of all ages and health status, is minimized to sub-physiological and sub-toxic doses. This allows a realistic analysis of the effects arising from low chemical doses.

Recent advances in biomedical applications of accelerator mass spectrometry

For example, children and women of child-bearing ages, who are important targets of increased health-related research, are suitable subjects at the low doses afforded by AMS [ 1011 ], since the administration of such low levels of 14 C are considered non-radioactive from a regulatory point of view. Finally, even if the sampled material needs fractionation to specific biomolecules prior to quantitation, the sample sizes are reduced to amounts that can be obtained from well-defined, and often non-invasive procedures.

For a practical AMS measurement, biological samples containing 0.

In a quartz tube, and using excess copper oxide CuOthe sample's biological carbon is oxidized to CO 2. The CO 2 is then reduced to solid carbon by both reduction with titanium hydride and zinc powder and catalyzation with either iron or cobalt. Because this process is independent of the chemical nature of the sample, it eliminates interference or suppression from other sample components. Therefore, AMS provides one piece of information about the sample of carbon measured: the precise 12 C: 14 C ratio.

In AMS, one measures the isotope ratio with respect to that of a well-known external standard in order to produce an absolute isotope concentration for the combusted sample [ 1314 ]. With AMS, experimenters only need the fractional elemental abundance of the sample and the specific activity of the Uses of mass spectrometry radioactive dating compound in order to obtain, in the units most useful for interpretation, the concentration of the tracer in the sampled material. The mechanics of an AMS instrument, the mathematical conversions of the measured values to meaningful "Modern" values, and the comparisons with LSC are well reviewed in the literature [ 31115 - 17 ].

For the first time insensitive and precise quantitation of 14 C was applied to the analysis of biological samples containing enriched 14 C-labeled carcinogens for toxicology and cancer studies by Turteltaub et al. Their research quantified chemical binding of the 14 C-labeled carcinogens to DNA at the level of 1 binding in 10 11 bases.

The benefits of using AMS for the analysis of samples derived from radiotracer studies with humans soon became apparent, since AMS produces very specific quantitation with simple analysis [ 19 ]. Any isotope concentration greater than the known stable natural 14 C background must arise from an introduced isotope label "introduced" includes contamination, which must be carefully controlled and avoided.

In the simplest experimental de, there is only one external radioactive source, perhaps a radiolabeled compound introduced into the biological system at a specific time.

The isotope ratio of the isolated sample is then easily converted to the concentration of the labeled compound and its metabolites per g or ml of the analyte. Not surprisingly, AMS has soon become a tool of choice for pharmacokinetic analyses [ 101116 ]. All the metabolites of the compound that contain the labeled moiety can be directly quantified in chromatographic separations without resorting either to secondary standards or to prior knowledge of metabolic pathways.

Although some fluorescent methods quantitate into the amol levels [ 2021 ], they require derivatization procedures that are not suitable for in vivo tracing, create tracers that are not chemically equivalent, and are less general in applicability across many biological systems. Conversely, AMS is specific only to the labeled compound in any chemical or biological medium.

Accelerator mass spectrometry

Such specificity requires neither prior speciation nor the introduction of either molecular modifications or internal standards. With AMS, it is possible to conduct radiotracer studies in human with the administration of such low levels of 14 C [ 1011 ]. The most recent innovation using AMS technology is the so-called "microdosing" concept [ 10 ]. Choosing a drug for clinical trials from numerous candidates is very much a hit-and-miss business.

Presented with a choice of good candidates, it would be better to take them all into human subjects. This would, however, be prohibitively expensive, as each compound would require a ificant package of toxicological safety testing. At these levels, only a limited toxicology package is required and in vivo human data can be acquired for candidate selection [ 22 ].

Major applications of AMS in various biomedical investigations discussed in the review.

After the first biomedical application of sensitive and precise quantitation of 14 C by AMS in [ 18 ], the technique has been explored for using animals and for fractionating tissues, cells and molecules in the study of metabolism, covalent macromolecule-ligand interactions, and non-covalent macromolecule-ligand interactions with amol sensitivity [ 8 - 10 ].

For example, Phillips et al. They investigated covalent interactions of metabolic products with DNA and proteins, both in animal hosts and in humans. The heterocyclic amines are compounds that are found in cooked meat and are potent carcinogens in rodent models. However, their role in human cancer remains largely unknown. Using AMS, Felton's group at the Lawrence Livermore National Laboratory has identified the metabolites of [2- 14 C]2-aminomethylphenylimidazo [4,5-b]pyridine PhIP in humans and the relationships between the activities of Uses of mass spectrometry radioactive dating enzymes involved in PhIP metabolism and metabolite profiles [ 2425 ].

Through these works, it has been possible to establish the scaling factors between animal hosts and humans for DNA and protein adduct formation, as well as to establish plasma and urinary biomarkers of PhIP exposure. The sensitivity of AMS is required to keep both the chemical and the radiation doses to human volunteers to levels that do not exceed commonly accepted risks.

The work with heterocyclic amine carcinogen has been expanded to the development of chemopreventive strategies for reducing the amount of DNA damage following carcinogen exposure and to the quantitation of the ability of certain dietary agents to reduce the levels of DNA adducts from two heterocyclic amines, PhIP and 2-aminomethylimidazo [4,5-f]quinoline IQ [ 30 ]. It was found that chlorophyllin a stable form of chlorophyll that is found in green leafy vegetables and the isothiocyanate found in broccoli caused the greatest adduct reductions in prostate, liver and colon of rodents, presumably by modifying the metabolic processes leading to the final reactive metabolites.

Accelerator mass spectrometry (ams) dating

Turesky et al. Various animal models were also used to study covalent binding levels of toxic compounds, including a quantitation of chromatin adducts of acrylamide in male germ cells of mice that was related to pre-implantation abnormalities in embryos [ 32 ]. The sample material available for analysis was so small that AMS quantitation could be the only reasonable route for obtaining very pure chromatin.

Very recently, AMS was successfully used to measure the kinetics and repair of DNA adducts formed by two chemotherapeutic compounds, carboplatin and oxaliplatin [ 3334 ]. The kinetics observed for the first time for reaction with genomic DNA revealed that the rate of carboplatin-DNA adduct formation was approximately fold slower than that reported for the more potent analog cisplatin, which may explain the lower toxicity of the compound.