Sensitivity Of Accelerator Mass Spectrometry Research Articles

Characterization of meteoric 10Be in certified reference materials for use in internal control standards

In recent decades, interest in the measurement of 10Be has increased due to its relevance in various fields of science. Trace amounts of 10Be produced from meteoric sources require sensitive accelerator mass spectrometry (AMS) measurements and robust sample preparation. The extraction, separation, and preparation of the appropriate oxide form for AMS require extensive and careful laboratory processing and certified reference materials to validate the chemical performance of the protocols used and the calibration of the AMS system in the measurement. In this work, the meteoric 10Be concentrations in two certified reference materials are characterized to establish their suitability as internal control standards for laboratory chemical preparation and AMS measurements of this radioisotope in our laboratory and the whole AMS community.

Impact of phenanthrene co-administration on the toxicokinetics of benzo[a]pyrene in humans. UPLC-accelerator mass spectrometry following oral microdosing

Current risk assessments for environmental carcinogens rely on animal studies utilizing doses orders of magnitude higher than actual human exposures. Epidemiological studies of people with high exposures (e.g., occupational) are of value, but rely on uncertain exposure data. In addition, exposures are typically not to a single chemical but to mixtures, such as polycyclic aromatic hydrocarbons (PAHs). The extremely high sensitivity of accelerator mass spectrometry (AMS) allows for dosing humans with known carcinogens with de minimus risk. In this study UPLC-AMS was used to assess the toxicokinetics of [14C]-benzo[a]pyrene ([14C]-BaP) when dosed alone or in a binary mixture with phenanthrene (Phe). Plasma was collected for 48 h following a dose of [14C]-BaP (50 ng, 5.4 nCi) or the same dose of [14C]-BaP plus Phe (1250 ng). Following the binary mixture, Cmax of [14C]-BaP significantly decreased (4.4-fold) whereas the volume of distribution (Vd) increased (2-fold). Further, the toxicokinetics of twelve [14C]-BaP metabolites provided evidence of little change in the metabolite profile of [14C]-BaP and the pattern was overall reduction consistent with reduced absorption (decrease in Cmax). Although Phe was shown to be a competitive inhibitor of the major hepatic cytochrome P-450 (CYP) responsible for metabolism of [14C]-BaP, CYP1A2, the high inhibition constant (Ki) and lack of any increase in unmetabolized [14C]-BaP in plasma makes this mechanism unlikely to be responsible. Rather, co-administration of Phe reduces the absorption of [14C]-BaP through a mechanism yet to be determined. This is the first study to provide evidence that, at actual environmental levels of exposure, the toxicokinetics of [14C]-BaP in humans is markedly altered by the presence of a second PAH, Phe, a common component of environmental PAH mixtures.

The Bucharest 1 MV HVEE Accelerator Mass Spectrometer extended for measurements of hydrogen isotopes

The High Voltage Engineering Europa B.V. (HVEE) 1 MV spectrometer at NIPNE-Bucharest was extended to allow highly sensitive Accelerator Mass Spectrometry (AMS) measurements of tritium (3H). The new established analyzing procedure and a complete AMS experiment with tritium are described in detail.

Determination of IL-23 Pharmacokinetics by Highly Sensitive Accelerator Mass Spectrometry and Subsequent Modeling to Project IL-23 Suppression in Psoriasis Patients Treated with Anti-IL-23 Antibodies

The pro-inflammatory cytokine interleukin (IL)-23 is a key modulator of the immune response, making it an attractive target for the treatment of autoimmune disease. Correspondingly, several monoclonal antibodies against IL-23 are either in development or approved for autoimmune indications such as psoriasis. Despite being a clinical validated target, IL-23 pharmacokinetics (e.g., IL-23 synthesis and elimination rates) and the degree of target suppression (i.e., decrease in free "active" IL-23) associated with clinical efficacy are not well understood, primarily due to its ultra-low circulating levels and the lack of sensitive and accurate measurement methods. In the current work, this issue was overcome by using accelerator mass spectrometry (AMS) to measure the concentration and pharmacokinetics of human recombinant [14C]-IL-23 following an intravenous trace-dose in cynomolgus monkeys. IL-23 pharmacokinetic parameters along with clinical drug exposure and IL-23 binding affinities from four different anti-IL-23 antibodies (ustekinumab, tildrakizumab, guselkumab, and risankizumab) were used to build a pharmacokinetics/pharmacodynamics (PK/PD) model to assess the time course of free IL-23 over oneyear in psoriasis patients following different dosing regimens. The predicted rank order of reduction of free IL-23 was consistent with their reported rank order of Psoriasis Area and Severity Index (PASI) 100 scores in clinical efficacy trials (ustekinumab < tildrakizumab < guselkumab < risankizumab), thus demonstrating the utility of highly sensitive AMS for determining target pharmacokinetics to inform PK/PD modeling and assessing target suppression associated with clinical efficacy.

Adaptation of an Analytical Procedure for Concurrent Determination of Np and Pu in clay samples

AbstractNp and Pu are two important actinides of concern for the safe long-term disposal of nuclear waste. Both actinides are, in addition, constituents of global nuclear fallout. Investigation of their environmental behavior requires ultra-sensitive analytical methods, but current methods for a concurrent determination in clay minerals are lacking. In the present study, a Pu isotope was investigated for use as a non-isotopic yield tracer for Np in extraction, purification, and mass spectrometric determination of Np and Pu isotopes in clay materials. Inductively coupled plasma mass spectrometry was used in this developmental study, but the method is intended for future ultra-trace analysis of global-fallout Np and Pu in clay-rich soil materials by the more sensitive accelerator mass spectrometry. Another field of application may be the investigation of diffusion patterns of actinides in compacted clay liners and potential host rocks for radioactive waste disposal. The analytical procedure includes the following steps: (1) extraction of Np and Pu from clay samples; (2) adjustment of Np and Pu to Np(IV) and Pu(III); (3) pre-concentration of Np and Pu by co-precipitation with iron hydroxide; (4) adjustment of Pu to Pu(IV); (5) extraction chromatographic separation of Pu and Np from iron and matrix elements; and (6) determination of Np and Pu by mass spectrometry. The analytical procedure was applied successfully to spiked montmorillonite and illite test portions of up to 1 g. High chemical yields near 90% were obtained for both Np and Pu. The suitability of Pu as a non-isotopic tracer for Np was indicated by Np/Pu chemical yield ratios close to unity. Accurate pH adjustment during the reductive co-precipitation and short processing times are vital to obtain high chemical yields and Np/Pu yield ratios close to unity.

Multiactinide Analysis with Accelerator Mass Spectrometry for Ultratrace Determination in Small Samples: Application to an in Situ Radionuclide Tracer Test within the Colloid Formation and Migration Experiment at the Grimsel Test Site (Switzerland).

The multiactinide analysis with accelerator mass spectrometry (AMS) was applied to samples collected from the run 13-05 of the Colloid Formation and Migration (CFM) experiment at the Grimsel Test Site (GTS). In this in situ radionuclide tracer test, the environmental behavior of 233U, 237Np, 242Pu, and 243Am was investigated in a water conductive shear zone under conditions relevant for a nuclear waste repository in crystalline rock. The concentration of the actinides in the GTS groundwater was determined with AMS over 6 orders of magnitude from ∼15 pg/g down to ∼25 ag/g. Levels above 10 fg/g were investigated with both sector field inductively coupled plasma mass spectrometry (SF-ICPMS) and AMS. Agreement within a relative uncertainty of 50% was found for 237Np, 242Pu, and 243Am concentrations determined with the two analytical methods. With the extreme sensitivity of AMS, the long-term release and retention of the actinides was investigated over 8 months in the tailing of the breakthrough curve of run 13-05 as well as in samples collected up to 22 months after. Furthermore, the evidence of masses 241 and 244 u in the CFM samples most probably representing 241Am and 244Pu employed in a previous tracer test demonstrated the analytical capability of AMS for in situ studies lasting more than a decade.

Use of Accelerator Mass Spectrometry in Human Health and Molecular Toxicology.

Accelerator mass spectrometry (AMS) has been adopted as a powerful bioanalytical method for human studies in the areas of pharmacology and toxicology. The exquisite sensitivity (10-18 mol) of AMS has facilitated studies of toxins and drugs at environmentally and physiologically relevant concentrations in humans. Such studies include risk assessment of environmental toxicants, drug candidate selection, absolute bioavailability determination, and more recently, assessment of drug-target binding as a biomarker of response to chemotherapy. Combining AMS with complementary capabilities such as high performance liquid chromatography (HPLC) can maximize data within a single experiment and provide additional insight when assessing drugs and toxins, such as metabolic profiling. Recent advances in the AMS technology at Lawrence Livermore National Laboratory have allowed for direct coupling of AMS with complementary capabilities such as HPLC via a liquid sample moving wire interface, offering greater sensitivity compared to that of graphite-based analysis, therefore enabling the use of lower 14C and chemical doses, which are imperative for clinical testing. The aim of this review is to highlight the recent efforts in human studies using AMS, including technological advancements and discussion of the continued promise of AMS for innovative clinical based research.

Verification of the sputter-generated 32SFn− (n = 1–6) anions by accelerator mass spectrometry

Recently, we have performed systematic Secondary Ion Mass Spectrometry (SIMS) measurements at our ion source test set up and have demonstrated that gas phase 32SFn− (n=1–6) anions for all size ‘n’ can be readily generated from a variety of surfaces undergoing Cs+ ion sputtering in the presence of high purity SF6 gas by employing the gas spray-cesium sputter technique. In our SIMS measurements, the isotopic yield ratio 34SFn−/32SFn− (n=1–6) was found to be close to its natural abundance but not for all size ‘n’. In order to gain further insight into the constituents of these molecular anions, ultra sensitive Accelerator Mass Spectrometry (AMS) measurements were conducted with the most abundant 32SFn− (n=1–6) anions, at BARC-TIFR 14 UD Pelletron accelerator. The results from these measurements are discussed in this paper.

Negative ion-gas reaction studies using ion guides and accelerator mass spectrometry I: SrF3−, YF3−, ZrF3−, YF4− and ZrF5− in NO2

Typical accelerator mass spectrometry (AMS) ion sources readily produce useable currents of a wide variety of negative ions, including exotic species, and the sensitivity and dynamic range of AMS can be used for relatively unambiguous ion identification at low count rates. Difficulty producing negative ion currents with high fluxes (ex. when electron binding energies are small) and unambiguous identification of reaction products can be obstacles to negative ion-gas reaction studies. Thus, an AMS setup can be considered to be suitable for certain ion-gas reaction studies. Presented here are preliminary studies on interactions of SrF3−, YF3−, ZrF3−, YF4− and ZrF5− with NO2 gas at <50eV kinetic energies using a prototype radio-frequency quadrupole (RFQ) instrument installed before the accelerator on the low-energy side of an AMS system. The superhalogen anions SrF3−, YF4− and ZrF5− were found to be highly unreactive with NO2, consistent with expected electron binding energies greater than 3.6eV. YF3− and ZrF3− were found to have large overall attenuation cross sections in NO2 of 7.6×10−15±4.4%cm2 and 1.5×10−14±21%cm2 respectively at the ion energies created under the experimental conditions. The major reaction channels were shown to be electron transfer and oxygen capture. A cluster NO2·(YF3−) was also observed.

Mass and abundance 236U sensitivities at CIRCE

The actinides (e.g. 236U and xPu isotopes) are present in environmental samples at the ultra trace level since atmospheric tests of NWs (Nuclear Weapons) performed in the past, deliberate dumping of nuclear waste, nuclear fuel reprocessing, on a large scale and operation of NPPs (Nuclear Power Plants) on a small scale have led to the release of a wide range of radioactive nuclides in the environment. Their detection requires the most sensitive AMS (Accelerator Mass Spectrometry) techniques and at the Center for Isotopic Research on Cultural and Environmental heritage (CIRCE) in Caserta, Italy, an upgraded actinide AMS system, based on a 3-MV pelletron tandem accelerator, has been operated.In this paper the progress made in order to push the 236U mass sensitivity and 236U/238U isotopic ratio down to the natural levels is reported. A uranium contamination mass of about 0.05μg and a 236U/238U isotopic ratio sensitivities at the level of 3.2×10−13 are presently achievable.

Accelerator Mass Spectrometry-Based Signal Generation for Thin Layer Chromatography

A highly sensitive accelerator mass spectrometry (AMS)based assay for determination of the 14 C content in the scraped silica gel after thin layer chromatography (TLC) has been established. In the present study, 14 C-labeled inositol or its cellular derivatives was selected as a model analyte to evaluate the designed assay, since a series of phosphatidyl inositols (PIs) are known to be derived from inositol and to play pivotal roles as precursors or second messengers for several cell signaling processes. After incubating HeLa cells with 14 C-labeled inositol, allowing the dosed 14 C-labeled inositol to be converted to a series of 14 C-labeled PIs and phosphoinositides through biochemical processes, the phospholipids were extracted and separated by the conventional TLC. The resulting TLC plates were scraped and graphitized for AMS measurement. The obtained data demonstrates the intracellular distribution of the phosphatidyl inositols, implying that the developed assay is better and more conv

10Be and 26Al low-energy AMS using He-stripping and background suppression via an absorber

The transmission of the ion beam through a tandem accelerator is a critical parameter for efficient detection of long-lived radionuclides by sensitive accelerator mass spectrometry (AMS). With beam energies at the accelerator terminal of less than 600keV, high transmissions are obtained using He as stripper gas. Here, we discuss Be, B, and Al transmissions in view of their application in the AMS determination of the long-lived radioisotopes 10Be and 26Al with compact facilities. The charge state 2+ of Al and Be shows a high yield, but in both cases an intense background from other nuclides has to be handled. The applicability of a combination of an absorber cell with a gas ionization chamber was tested for suppression of the main background for 10Be2+ (10B2+) and 26Al2+ (13C1+). Energy loss simulations of the involved nuclides confirm the performance observed in the experiments. The findings concerning He stripping and detection methods at low energies may allow the construction of very compact AMS setups for light isotopes.

Progress in Personalizing Chemotherapy for Bladder Cancer

Platinum-based chemotherapy is commonly used for the treatment of locally advanced and metastatic bladder cancer. However, there are currently no methods to predict chemotherapy response in this disease setting. A better understanding of the biology of bladder cancer has led to developments of molecular biomarkers that may help guide clinical decision making. These biomarkers, while promising, have not yet been validated in prospective trials and are not ready for clinical applications. As alkylating agents, platinum drugs kill cancer cells mainly through induction of DNA damage. A microdosing approach is currently being tested to determine if chemoresistance can be identified by measuring platinum-induced DNA damage using highly sensitive accelerator mass spectrometry technology. The hope is that these emerging strategies will help pave the road towards personalized therapy in advanced bladder cancer.

A method for measuring methane oxidation rates using lowlevels of 14C‐labeled methane and accelerator mass spectrometry

We report a new method for methane oxidation rate measurements that uses 103–105 times less 14C‐CH4 than existing measurements by taking advantage of the high sensitivity of accelerator mass spectrometry. Methane oxidation in the marine environment is a microbial process of global importance because it prevents methane released from underlying reservoirs from reaching the ocean and atmosphere. Rate measurements provide a crucial tool for assessing the efficacy of this process across a range of environments, but the current methods use high amounts of radioactive elements (3H‐ or 14C‐CH4), tend to increase methane concentrations in a sample markedly over in situ levels, and are limited by strict health and safety regulations. The low‐level method presented here uses levels of 14C‐CH4 that are below transportation regulations, produce samples that do not require treatment as radioactive waste, and allow for tracer level rate measurements in low methane environments. Moreover, the low‐level method lays the analytical foundation for a below‐regulation rate measurement that could be used broadly and in‐situ. Parallel rate measurements with the low‐level 14C‐CH4 and existing 3H‐CH4 methods are generally consistent with a correlation coefficient of 0.77. However, the low‐level method in most cases yields slower rates than the 3H method possibly due to temperature, priming, and detection limit effects.

Direct radiocarbon analysis of exhaled air

Pharmacokinetic properties of organic substances in humans can be followed by isotopic labeling. For sub-milligram amounts, 14C becomes the preferable isotope and Accelerator Mass Spectrometry (AMS) its most powerful detection method. However, a widespread use of this method is partly impeded by laborious and time consuming sample preparation. We developed a method, which omits any preparation prior to AMS analysis, but allows direct measurement of CO2. The method uses a zeolite molecular sieve for CO2 trapping and requires a small gas interface, which is connected to a gas ion source of the AMS instrument. Based on the method, we developed a kit for CO2 analysis in exhaled air. It can be used to monitor catabolism of labeled compounds to CO2, a seldom studied route of elimination in pharmacokinetic studies. In addition, it provides an easy sampling method for breath tests as the erythromycin breath test, where the analysis with AMS would reduce the required 14C activity by ∼3 orders of magnitude. To demonstrate the potential of the kit in combination with the high sensitivity of AMS, we followed ethanol oxidation in human with a comestible: a brandy of 1964 vintage, enriched in 14C by ∼65% due to atmospheric nuclear bomb testing, could be used as labeled substance with an administered activity of ∼10 Bq14C only.

Use of Accelerator Mass Spectrometry to Measure the Pharmacokinetics and Peripheral Blood Mononuclear Cell Concentrations of Zidovudine

The remarkable sensitivity of accelerator mass spectrometry (AMS) is finding many new applications in pharmacology. In this study AMS was used to measure [14C]-Zidovudine (ZDV) concentrations at the drug's site of action (peripheral blood mononuclear cells, PBMCs) following a dose of 520ng (less than one-millionth of the standard daily dose) to a healthy volunteer. In addition, the pharmacokinetics of this microdose were determined and compared to previously published parameters for therapeutic doses. Microdose ZDV pharmacokinetic parameters fell within reported 95% confidence intervals or standard deviations of most previously published values for therapeutic doses. Blood, urine, stool, saliva, and isolated PBMCs were collected periodically through 96h postdose and analyzed for ZDV and metabolite concentrations. The results showed that ZDV is rapidly absorbed and eliminated, has one major metabolite, and is sequestered in PBMCs. 14C mass balance assessments indicated a significant portion of ZDV remained after 96h with a much prolonged elimination half-life. Results of this study demonstrate the usefulness of microdosing and AMS as a tool for studying the pharmacokinetic characteristics, including PBMC concentrations, of ZDV and underscore the value of AMS as a tool with which to perform pharmacokinetic and mass balance studies using trace amounts of radiolabeled compound.

Long-Term Biokinetics and Radiation Exposure of Patients Undergoing14C-Glycocholic Acid and14C-Xylose Breath Tests

The (14)C-glycocholic acid and (14)C-xylose breath tests are clinically used for the diagnosis of intestinal diseases, such as bacterial overgrowth in the small intestine. The two tests have in earlier studies been thoroughly evaluated regarding their clinical value, but due to the long physical half-life of (14)C and the limited biokinetic and dosimetric data, which are available for humans, several hospitals have been restrictive in their use. The aim of this study was to investigate the long-term biokinetics and dosimetry of the two (14)C compounds in patients and volunteers, using the highly sensitive accelerator mass spectrometry (AMS) technique. Eighteen (18) subjects were included, 9 for each compound. The (14)C content in samples from exhaled air, urine, and, for some subjects, also feces were analyzed with both liquid scintillation counting (LSC) and AMS. The results from the glycocholic acid study showed that, up to 1 year after the administration, 67%+/-6% (mean+/-standard deviation) of the administered activity was recovered in exhaled air, 2.4%+/-0.4% was found in urine, and 7.6% (1 subject) in feces. In the xylose study, the major part was found in the urine (66%+/-2%). A significant part was exhaled (28%+/-5%), and the result from an initial 72-hour stool collection from 2 of the subjects showed that the excretion by feces was insignificant. The absorbed dose to various organs and tissues and the effective dose were calculated by using biokinetic models, based on a combination of experimental data from the present study and from earlier reports. In the glycocholic acid study, the highest absorbed dose was received by the colon (1.2 mGy/MBq). In the xylose study, the adipose tissue received 0.8 mGy/MBq. The effective dose was estimated to 0.5 (glycocholic acid) and 0.07 mSv/MBq (xylose). Thus, from a radiation protection point of view, we see no need for restrictions in using the two (14)C-labeled radiopharmaceuticals on adults with the activities normally administered (0.07-0.4 MBq).

Adduction of DNA with MTBE and TBA in mice studied by accelerator mass spectrometry

Methyl tert-butyl ether (MTBE) is a currently worldwide used octane enhancer substituting for lead alkyls and gasoline oxygenate. Our previous study using doubly (14)C-labeled MTBE [(CH(3))(3) (14)CO(14)CH(3)] has shown that MTBE binds DNA to form DNA adducts at low dose levels in mice. To elucidate the mechanism of the binding reaction, in this study, the DNA adducts with singly (14)C-labeled MTBE, which was synthesized from (14)C-methanol and tert-butyl alcohol (TBA), or (14)C-labeled TBA in mice have been measured by ultra sensitive accelerator mass spectrometry. The results show that the methyl group of MTBE and tert-butyl alcohol definitely form adducts with DNA in mouse liver, lung, and kidney. The methyl group of MTBE is the predominant binding part in liver, while the methyl group and the tert-butyl group give comparable contributions to the adduct formation in lung and kidney.

Disposition of 14C-β-carotene following delivery with autologous triacylglyceride-rich lipoproteins

Following ingestion, a fraction of β-carotene is cleaved into vitamin A in the intestine, while another is absorbed intact and distributed among tissues and organs. The extent to which this absorbed β-carotene serves as a source of vitamin A is unknown in vivo. In the present study we use the attomole sensitivity of accelerator mass spectrometry (AMS) for 14C to quantify the disposition of 14C-β-carotene (930ng; 60.4nCi of activity) after intravenous injection with an autologous triacylglyceride-rich lipoprotein fraction in a single volunteer. Total 14C was quantified in serial plasma samples and also in triglyceride-rich, and low density lipoprotein, subfractions. The appearance of 14C-retinol, the circulating form of vitamin A in plasma, was determined by chromatographic separation of plasma retinol extracts prior to AMS analysis. The data showed that 14C concentrations rapidly decayed within the triglyceride-rich lipoprotein fractions after injection, whereas low density lipoprotein 14C began a significant rise in 14C 5h post dose. Plasma 14C-retinol also appeared at 5h post dose and its concentrations were maintained above baseline for >88 days. Based upon comparisons of 14C-retinol concentrations following an earlier study with orally dosed 14C-β-carotene, a molar vitamin A value of the absorbed β-carotene of 0.19 was derived, meaning that 1mole of absorbed β-carotene provides 0.19moles of vitamin A. This is the first study to show that infused β-carotene contributes to the vitamin A economy in humans in vivo.

A method for optimizing experimental conditions and simulating spectra in the measurement of heavy nuclides in AMS

The sensitivity of accelerator mass spectrometry (AMS) is often limited by interferences from isobars, isotopes and other nuclides. In AMS measurements of heavy nuclides, where a high molecular fragment background can be present, it can be difficult to discriminate the nuclides of interest from the background particles online. In order to solve this problem, a method for optimizing the experimental conditions and simulating spectra in AMS measurements has been developed. Satisfactory agreement has been obtained between calculated and experimental spectra for 26Al, 36Cl, 41Ca and 99Tc measured with the HI-13 AMS system at China Institute of Atomic Energy (CIAE).