We examine instrumental and methodological capabilities for microscale (10–50 μg of C) radiocarbon analysis of individual compounds in the context of paleoclimate and paleoceanography applications, for which relatively high-precision measurements are required. An extensive suite of data for 14C-free and modern reference materials processed using different methods and acquired using an elemental-analyzer–accelerator-mass-spectrometry (EA-AMS) instrumental setup at ETH Zurich was compiled to assess the reproducibility of specific isolation procedures. In order to determine the precision, accuracy, and reproducibility of measurements on processed compounds, we explore the results of both reference materials and three classes of compounds (fatty acids, alkenones, and amino acids) extracted from sediment samples. We utilize a MATLAB code developed to systematically evaluate constant-contamination-model parameters, which in turn can be applied to measurements of unknown process samples. This approach is computationally reliable and can be used for any blank assessment of small-size radiocarbon samples. Our results show that a conservative lower estimate of the sample sizes required to produce relatively high-precision 14C data (i.e., with acceptable errors of <5% on final 14C ages) and high reproducibility in old samples (i.e., F14C ≈ 0.1) using current isolation methods are 50 and 30 μg of C for alkenones and fatty acids, respectively. Moreover, when the F14C is >0.5, a precision of 2% can be achieved for alkenone and fatty acid samples containing ≥15 and 10 μg of C, respectively.

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A new instrumental setup, combining laser ablation (LA) with accelerator mass spectrometry (AMS), has been investigated for the online radiocarbon ((14)C) analysis of carbonate records. Samples were placed in an in-house designed LA-cell, and CO2 gas was produced by ablation using a 193 nm ArF excimer laser. The (14)C/(12)C abundance ratio of the gas was then analyzed by gas ion source AMS. This configuration allows flexible and time-resolved acquisition of (14)C profiles in contrast to conventional measurements, where only the bulk composition of discrete samples can be obtained. Three different measurement modes, i.e. discrete layer analysis, survey scans, and precision scans, were investigated and compared using a stalagmite sample and, subsequently, applied to terrestrial and marine carbonates. Depending on the measurement mode, a precision of typically 1-5% combined with a spatial resolution of 100 μm can be obtained. Prominent (14)C features, such as the atomic bomb (14)C peak, can be resolved by scanning several cm of a sample within 1 h. Stalagmite, deep-sea coral, and mollusk shell samples yielded comparable signal intensities, which again were comparable to those of conventional gas measurements. The novel LA-AMS setup allowed rapid scans on a variety of sample materials with high spatial resolution.

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Aim:Although regulatory guidances require human metabolism information of drug candidates early in the development process, the human mass balance study (or hADME study), is performed relatively late. hADME studies typically involve the administration of a 14 C-radiolabelled drug where biological samples are measured by conventional scintillation counting analysis. Another approach is the administration of therapeutic doses containing a 14 C-microtracer followed by accelerator mass spectrometry (AMS) analysis, enabling hADME studies completion much earlier. Consequently, there is an opportunity to change the current drug development paradigm. Materials & methods: To evaluate the applicability of the MICADAScAMS method, we successfully performed: the validation of MICADAS-cAMS for radioactivity quantification in biomatrices and, a rat ADME study, where the conventional methodology was assessed against a microtracer MICADAS-cAMS approach. Results & discussion: Combustion AMS (cAMS) technology is applicable to microtracer studies. A favorable opinion from EMA to complete the hADME in a Phase I setting was received, opening the possibilities to change drug development. Keywords:In the scope of drug development, regulatory guidances encourage the early identification of relevant human metabolites [1][2][3]. A human ADME study that used radiolabeled drugs allows the identification of metabolites and the elucidation of key biotransformation pathways and clearance mechanisms in humans. However, due to the high study cost, the needs for a dosimetry assessment (which include a rat distribution investigation) and for a GMP manufacturing as well as the high attrition rates encountered in drug development, the conventional hADME is generally performed late in drug development (Phase II, see Supplementary Figure 1). The administered dose in a conventional hADME study can contain up to 3.7 mBq of radioactivity which is analysed by scintillation counting. To address the regulatory demands earlier, a first investigation of pharmacokinetics (PK) and excretion routes is typically performed with a radiolabeled drug in rodents. Subsequently, exploratory analysis of potentially relevant metabolites is investigated in early clinical samples (Phase I) without the use of radiolabel [4,5] (Supplementary Figure 1). However, the applied LC-MS methods can fail to identify unknown metabolites. If human-specific metabolites are generated in early clinical samples, these metabolites will not be detected in preclinical species using radiolabeled drug, and will not be discovered in humans until the radiolabeled human mass balance ADME study is completed. To address this gap, we propose to dose a normal, therapeutically relevant dose spiked with very low amounts of a radiotracer to healthy volunteers or patients in a Phase I setting. Thereafter, the mass balance, the excretion routes and levels of circulating metabolites in humans are determined by accelerator mass spectrometry (AMS) as suggested by Lappin and Garner [6,7].AMS is a highly sensit...