Accelerator Mass Spectrometry AMS is a technique for measuring the concentrations of rare isotopes that cannot be detected with conventional mass spectrometers. The original, and best known, application of AMS is radiocarbon dating, where you are trying to detect the rare isotope 14 C in the presence of the much more abundant isotopes 12 C and 13 C.
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The natural abundance of 14 C is about one 14 C atom per trillion 10 12 atoms of 12 C. A nuclear particle accelerator consists essentially of two linear accelerators joined end-to-end, with the join section called the terminal charged to a very high positive potential 3 million volts or higher. Injecting negatively charged carbon ions from the material being analysed into a nuclear particle accelerator based on the electrostatic tandem accelerator principle.
The negative ions are accelerated towards the positive potential. At the terminal they pass through either a very thin carbon film or a tube filled with gas at low pressure the stripper , depending on the particular accelerator. Collisions with carbon or gas atoms in the stripper remove several electrons from the carbon ions, changing their polarity from negative to positive. The positive ions are then accelerated through the second stage of the accelerator, reaching kinetic energies of the order of 10 to 30 million electron volts.
The ion source also inevitably produces negatively charged molecules that can mimic 14 C, viz. These ions are stable, and while of relatively low abundance, are still intense enough to overwhelm the 14 C ions. This problem is solved in the tandem accelerator at the stripper —if three or more electrons are removed from the molecular ions the molecules dissociate into their component atoms. The kinetic energy that had accumulated up to now is distributed among the separate atoms, none of which has the same energy as a single 14 C ion.
It is thus easy to distinguish the 14 C from the more intense "background" caused by the dissociated molecules on the basis of their kinetic energy. Accelerating the ions to high energy has one more advantage. At the kinetic energies typically used in an AMS system it is possible to use well-established nuclear physics techniques to detect the individual 14 C ions as they arrive at a suitable particle detector. The straight line in the log—log plot in Figure 2 indicates that the relation is a power law and the best fit is found as the mean and SD of the ratio of the AMS measure to the direct LSC value 0.
Sub-Modern concentrations of 14 C are validated through radiocarbon dating intercomparisons using LSC systems that are much more advanced than common systems in biochemical or environmental laboratories. The data in Figure 2 mean that AMS has been directly compared with LSC without dilutions or enrichments over six orders of magnitude, except from 1 Modern to Modern.
The urine dilution series spans this region with a reliable linear regression, validating linear AMS quantitation. Thus, AMS is a valuable tool for drug development, during which response may not be well predicted, requiring multiple calibrations of other instruments. With wide range applicability, quantitation is assured even if quantified results fall well outside the range of expected concentrations. Precision and accuracy are individually addressed but are intimately entwined in a quantitative technology for which multiple calibration materials are not widespread.
Precision is a measure of reproducibility from multiple measures of several samples, preferably spanning a period of time and a range of concentrations. Accuracy is assessed from multiple measures of reference materials with well-known concentrations or from direct comparison to already accepted quantitative methods. First, the degree of repeatability of the instrument measurements was found to show that precision and accuracy can be reliably quantified by AMS.
The inherent repeatability of AMS isotope ratio measurement is found by measuring a set of prepared and mounted samples on different occasions, preferably separated by several days under normal operating conditions.
Figure 3 shows repeat normalized measurements of carbon samples derived from human urine that were obtained 10 days apart after the spectrometer had undergone several power cycles and measurement runs for other materials. The samples were removed from the ion source and stored in an argon-filled plastic bag.
Samples are bombarded by caesium metal in the ion source and CsOH forms during removal in air that reacts with CO 2 in the air, incorporating atmospheric 14 C into an exposed sample. For this reason, samples are seldom retained and remeasured after being ceasiated, but samples with high 14 C concentration are minimally affected by absorbed atmospheric CO 2.
Figure 3 shows that normalized measurements of samples from 90 to Modern are reproducibly measured to a median difference of 0. Reproducibility averaged less than 0. The inset shows that the frequency distribution of residuals was not Gaussian. The repeatability of sample combustion, reduction and the routine operation of the spectrometer was demonstrated by measurements of the external standard that was included in every set of samples loaded into the spectrometer . Figure 4 shows the frequency distribution of nearly isotope-ratio measurements on approximately separate samples of commonly used external standard, IAEA C-6 sucrose [ 26 ].
The theoretical ratio of 14 C to 13 C in this material is 1. Figure 4 shows that these measurements made over the course of 2 years have an average raw ratio of 0. The values closely follow a Gaussian distribution with a CV of 2. These measurements were made under a variety of operators, operating conditions and graphite-production sources throughout 2 years, demonstrating the inherent repeatability of the AMS process from combustion to measurement over long periods, despite operator biases or spectrometer variances.
Accelerator mass spectrometry quantifies not only total isotopic label in defined samples of collected tissues or fluids, but also quantifies metabolic profiles and other small biochemical isolates.
Figure 5 exemplifies the repeatability of this entire separation process, followed by sample dilution, combustion, reduction and measurement using separate UPLC runs performed on different days. The tracer level for each fraction is found by subtracting the known 14 C concentration of the diluent carbon from the measured concentration for each fraction. The tracer level is then converted to grams of equivalent drug using the isomolar fraction fraction of molecules containing 14 C of the labeled compound and its molecular weight.
The uncertainties in both the sample isotope ratio and the carrier isotope ratio are propagated to provide a quotable uncertainty in the difference and, hence, in the specific metabolite quantity.
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Thus, AMS provides highly quantitative metabolite profiles with only external standards and no concern about differential ionization, the availability of internal standards, or compound-specific calibration curves. Note, especially, that zero drug equivalent within stated error is within the capability of AMS measurements, since the diluent carbon does have a known level of 14 C. The introduction of a quantitative guidance for toxicity testing of circulating human metabolites of drug candidates emphasized the need for a method that robustly quantifies metabolic products, without resorting to perhaps unpredicted and unavailable internal standards [ 27 ].
The mass of equivalent drug was determined from the 14 C concentration, the specific labeling of the compound and the molecular weight. Error bars represent propagated errors due to measurement of both the fraction and the added carrier compound. The differences between the repeats average 0.
The individual error bars represent 1 SD uncertainty due to both sample and carrier measurement precision and, as such, should overlap at only two thirds of the data points. Only one of six replications do not overlap, however, showing a better than normal repeatability for the procedure. The nonoverlapping elution fraction is at the start of a metabolite peak, where very slight changes in fraction definition have comparatively larger effects.
Accelerator mass spectrometry precision of a single measurement follows closely the Poisson uncertainty of the inverse of the square root of the total 14 C counts [ 28 ]. A single measurement is made to almost any desired precision by obtaining sufficient counts, but the AMS measurement process includes sample aliquoting and conversion, as well as spectrometric quantification.
Figure 1 demonstrated stability and, thus, a precision limit, in measuring multiple aliquots of sera to approximately 2.
Accelerator Mass Spectrometry
Two other materials are frequently measured and provide other data to characterize measurement precision. Biochemical isolations often produce samples that have very low carbon content. The preferred method of presenting the sample in the AMS spectrometer is as a stable reduced carbon solid. Tributyrin is a nonpolar, viscous fluid hydrocarbon at room temperature with low vapor pressure that is highly suitable for such a carrier. When the background materials are low in 14 C, the Poisson nature of AMS counting allows an improvement in background precision and lower LLOQ through longer measurement periods.
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Several hundred measures of the tributyrin carrier had a normal distribution, approximately 8. Very small contaminations of adsorbed Modern CO 2 on sample vessels can add 14 C to produce such a tail. The normal distribution is fit to the primary peak of the frequency distribution and indicates a precision 5.
Higher counting precision is possible for low 14 C samples through longer count times, at a cost of decreased daily throughput. In routine operation, 15—20 samples are measured per hour, but series of carrier-added fractions decrease this to approximately 10—15 per hour. A 9-Modern material was used for assuring that the spectrometer is adjusted for optimal 14 C transmission. The consensus value was found to be 9. More than measurements over a period of 1 year show a near normal distribution with a CV of 2. The measurements have a standard deviation of 2. Determination of AMS accuracy is not needed across the entire range, although multiple trusted calibration materials are being developed.
We discuss accuracy in terms of common materials of known isotope concentration and of direct AMS comparisons with accepted LSC-measured samples. The average atmospheric 14 C concentration is present in recently grown plant materials and reflected in the predose 14 C concentrations of rapidly replaced constituents of living animal hosts and human subjects, such as blood plasma.
This concentration is known and determined with high confidence. The increased industrial use of fossil fuels in the 20th century contributed to a decrease in the atmospheric 14 C isotopic concentration, which was greatest during the intense industrial activity of World War II, as plotted in Figure 8.