DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Use of Accelerator Mass Spectrometry in Human Health and Molecular Toxicology

Abstract

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. In conclusion, 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.

Authors:
 [1];  [1];  [2];  [1];  [2];  [1]
  1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  2. UC Davis Medical Center, Sacramento, CA (United States); Accelerated Medical Diagnostics Inc., Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH)
OSTI Identifier:
1367988
Report Number(s):
LLNL-JRNL-696717
Journal ID: ISSN 0893-228X
Grant/Contract Number:  
AC52-07NA27344; HHSN261201000133C; HHSN261201200048C; HHSN261201200084C
Resource Type:
Accepted Manuscript
Journal Name:
Chemical Research in Toxicology
Additional Journal Information:
Journal Volume: 29; Journal Issue: 12; Journal ID: ISSN 0893-228X
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Enright, Heather A., Malfatti, Michael A., Zimmermann, Maike, Ognibene, Ted, Henderson, Paul, and Turteltaub, Kenneth W. Use of Accelerator Mass Spectrometry in Human Health and Molecular Toxicology. United States: N. p., 2016. Web. doi:10.1021/acs.chemrestox.6b00234.
Enright, Heather A., Malfatti, Michael A., Zimmermann, Maike, Ognibene, Ted, Henderson, Paul, & Turteltaub, Kenneth W. Use of Accelerator Mass Spectrometry in Human Health and Molecular Toxicology. United States. https://doi.org/10.1021/acs.chemrestox.6b00234
Enright, Heather A., Malfatti, Michael A., Zimmermann, Maike, Ognibene, Ted, Henderson, Paul, and Turteltaub, Kenneth W. Tue . "Use of Accelerator Mass Spectrometry in Human Health and Molecular Toxicology". United States. https://doi.org/10.1021/acs.chemrestox.6b00234. https://www.osti.gov/servlets/purl/1367988.
@article{osti_1367988,
title = {Use of Accelerator Mass Spectrometry in Human Health and Molecular Toxicology},
author = {Enright, Heather A. and Malfatti, Michael A. and Zimmermann, Maike and Ognibene, Ted and Henderson, Paul and Turteltaub, Kenneth W.},
abstractNote = {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. In conclusion, 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.},
doi = {10.1021/acs.chemrestox.6b00234},
journal = {Chemical Research in Toxicology},
number = 12,
volume = 29,
place = {United States},
year = {Tue Oct 11 00:00:00 EDT 2016},
month = {Tue Oct 11 00:00:00 EDT 2016}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 8 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Applications of accelerator mass spectrometry for pharmacological and toxicological research
journal, January 2005

  • Brown, Karen; Tompkins, Elaine M.; White, Ian N. H.
  • Mass Spectrometry Reviews, Vol. 25, Issue 1
  • DOI: 10.1002/mas.20059

A microdose study of 14C-AR-709 in healthy men: pharmacokinetics, absolute bioavailability and concentrations in key compartments of the lung
journal, June 2013

  • Lappin, G.; Boyce, M. J.; Matzow, T.
  • European Journal of Clinical Pharmacology, Vol. 69, Issue 9
  • DOI: 10.1007/s00228-013-1528-2

Pediatric microdose and microtracer studies using 14 C in Europe
journal, July 2015

  • Turner, Ma; Mooij, Mg; Vaes, Whj
  • Clinical Pharmacology & Therapeutics, Vol. 98, Issue 3
  • DOI: 10.1002/cpt.163

Direct Coupling of an Elemental Analyzer and a Hybrid Ion Source for AMS Measurements
journal, January 2004


Big physics, small doses: the use of AMS and PET in human microdosing of development drugs
journal, March 2003

  • Lappin, Graham; Garner, R. Colin
  • Nature Reviews Drug Discovery, Vol. 2, Issue 3
  • DOI: 10.1038/nrd1037

The resurgence of platinum-based cancer chemotherapy
journal, July 2007

  • Kelland, Lloyd
  • Nature Reviews Cancer, Vol. 7, Issue 8
  • DOI: 10.1038/nrc2167

Comparison of DNA‐adduct and tissue‐available dose levels of MeIQx in human and rodent colon following administration of a very low dose
journal, February 1999


Pharmacokinetic Investigation of Imatinib Using Accelerator Mass Spectrometry in Patients with Chronic Myeloid Leukemia
journal, July 2007


Disposition and Metabolic Profiling of [ 14 C]Cerlapirdine Using Accelerator Mass Spectrometry
journal, September 2014

  • Tse, Susanna; Leung, Louis; Raje, Sangeeta
  • Drug Metabolism and Disposition, Vol. 42, Issue 12
  • DOI: 10.1124/dmd.114.059675

Effective Use of Microdosing and Positron Emission Tomography (PET) Studies on New Drug Discovery and Development
journal, January 2009

  • Sugiyama, Yuichi
  • Drug Metabolism and Pharmacokinetics, Vol. 24, Issue 2
  • DOI: 10.2133/dmpk.24.127

Use of Positron Emission Tomography in Animal Research
journal, January 2001


Microdosing studies using accelerated mass spectrometry as exploratory investigational new drug trials
journal, November 2011


A Single Dose Mass Balance Study of the Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Humans Using Accelerator Mass Spectrometry
journal, May 2011

  • Graham, Richard A.; Lum, Bert L.; Morrison, Glenn
  • Drug Metabolism and Disposition, Vol. 39, Issue 8
  • DOI: 10.1124/dmd.111.039339

Direct measurements of small 14C samples after oxidation in quartz tubes
journal, April 2010

  • Fahrni, S. M.; Gäggeler, H. W.; Hajdas, I.
  • Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, Vol. 268, Issue 7-8
  • DOI: 10.1016/j.nimb.2009.10.031

An interface for the direct coupling of small liquid samples to AMS
journal, October 2015

  • Ognibene, T. J.; Thomas, A. T.; Daley, P. F.
  • Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, Vol. 361
  • DOI: 10.1016/j.nimb.2015.05.018

Systems biology of cisplatin resistance: past, present and future
journal, May 2014


On-line combustion of samples for AMS and ion source developments at ORAU
journal, October 2000

  • Bronk Ramsey, C.; Humm, M. J.
  • Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, Vol. 172, Issue 1-4
  • DOI: 10.1016/S0168-583X(00)00116-6

In vivo pharmacokinetics and pharmacodynamics in drug development using positron-emission tomography
journal, March 2001


Kinetics of Carboplatin−DNA Binding in Genomic DNA and Bladder Cancer Cells As Determined by Accelerator Mass Spectrometry
journal, May 2006

  • Hah, Sang Soo; Stivers, Kristen M.; de Vere White, Ralph W.
  • Chemical Research in Toxicology, Vol. 19, Issue 5
  • DOI: 10.1021/tx060058c

The measurement of cisplatin-DNA adduct levels in testicular cancer patients
journal, January 1988


Platinum-DNA adduct formation in leucocytes of children in relation to pharmacokinetics after cisplatin and carboplatin therapy
journal, December 1997

  • Peng, B.; Tilby, Mj; English, Mw
  • British Journal of Cancer, Vol. 76, Issue 11
  • DOI: 10.1038/bjc.1997.579

Well-Done Meat Intake and the Risk of Breast Cancer
journal, November 1998

  • Zheng, W.; Gustafson, D. R.; Moore, D.
  • JNCI Journal of the National Cancer Institute, Vol. 90, Issue 22
  • DOI: 10.1093/jnci/90.22.1724

Automated Combustion Accelerator Mass Spectrometry for the Analysis of Biomedical Samples in the Low Attomole Range
journal, July 2014

  • van Duijn, Esther; Sandman, Hugo; Grossouw, Dimitri
  • Analytical Chemistry, Vol. 86, Issue 15
  • DOI: 10.1021/ac5015035

Directly Coupled High-Performance Liquid Chromatography–Accelerator Mass Spectrometry Measurement of Chemically Modified Protein and Peptides
journal, March 2013

  • Thomas, Avi T.; Stewart, Benjamin J.; Ognibene, Ted J.
  • Analytical Chemistry, Vol. 85, Issue 7
  • DOI: 10.1021/ac303609n

AFN-1252 in vitro absorption studies and pharmacokinetics following microdosing in healthy subjects
journal, November 2013

  • Kaplan, Nachum; Garner, Colin; Hafkin, Barry
  • European Journal of Pharmaceutical Sciences, Vol. 50, Issue 3-4
  • DOI: 10.1016/j.ejps.2013.08.019

Oxaliplatin-DNA adduct formation in white blood cells of cancer patients
journal, May 2008

  • Pieck, A. C.; Drescher, A.; Wiesmann, K. G.
  • British Journal of Cancer, Vol. 98, Issue 12
  • DOI: 10.1038/sj.bjc.6604387

Retrospective Birth Dating of Cells in Humans
journal, July 2005


Human microdosing for the prediction of patient response
journal, March 2010

  • Henderson, Paul T.; Pan, Chong-xian
  • Bioanalysis, Vol. 2, Issue 3
  • DOI: 10.4155/bio.10.3

Impact of microdosing clinical study — Why necessary and how useful?
journal, June 2011


Approaches using molecular imaging technology — use of PET in clinical microdose studies
journal, June 2011


Early microdose drug studies in human volunteers can minimise animal testing: Proceedings of a workshop organised by Volunteers in Research and Testing
journal, May 2003


Human in Vivo Pharmacokinetics of [ 14 C]Dibenzo[ def,p ]chrysene by Accelerator Mass Spectrometry Following Oral Microdosing
journal, December 2014

  • Madeen, Erin; Corley, Richard A.; Crowell, Susan
  • Chemical Research in Toxicology, Vol. 28, Issue 1
  • DOI: 10.1021/tx5003996

Emerging concepts on drug resistance in bladder cancer: Implications for future strategies
journal, October 2015


Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs
journal, September 2006


The use of isotopes in the determination of absolute bioavailability of drugs in humans
journal, May 2006

  • Lappin, Graham; Rowland, Malcolm; Garner, R. Colin
  • Expert Opinion on Drug Metabolism & Toxicology, Vol. 2, Issue 3
  • DOI: 10.1517/17425255.2.3.419

Intrinsic Erythrocyte Labeling and Attomole Pharmacokinetic Tracing of14C-Labeled Folic Acid with Accelerator Mass Spectrometry
journal, May 1999

  • Buchholz, Bruce A.; Arjomand, Ali; Dueker, Stephen R.
  • Analytical Biochemistry, Vol. 269, Issue 2
  • DOI: 10.1006/abio.1999.4041

Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice
journal, July 2015


Gemcitabine Causes Minimal Modulation of Carboplatin-DNA Monoadduct Formation and Repair in Bladder Cancer Cells
journal, November 2010

  • Wang, Sisi; Zhang, Hongyong; Malfatti, Michael
  • Chemical Research in Toxicology, Vol. 23, Issue 11
  • DOI: 10.1021/tx1003547

Pediatric Microdose Study of [14C]Paracetamol to Study Drug Metabolism Using Accelerated Mass Spectrometry: Proof of Concept
journal, September 2014

  • Mooij, Miriam G.; van Duijn, Esther; Knibbe, Catherijne A. J.
  • Clinical Pharmacokinetics, Vol. 53, Issue 11
  • DOI: 10.1007/s40262-014-0176-8

A Gas Ion Source for Radiocarbon Measurements at 200 kV
journal, January 2007


Chemoprevention with chlorophyllin in individuals exposed to dietary aflatoxin
journal, March 2003


Macromolecular adduct formation and metabolism of heterocyclic amines in humans and rodents at low doses
journal, September 1999


Cellular processing of platinum anticancer drugs
journal, March 2005

  • Wang, Dong; Lippard, Stephen J.
  • Nature Reviews Drug Discovery, Vol. 4, Issue 4
  • DOI: 10.1038/nrd1691

DNA-adduct levels as a predictor of outcome for NSCLC patients receiving daily cisplatin and radiotherapy
journal, March 2000


Platinum—DNA damage in leukocyte DNA of patients receiving carboplatin and cisplatin chemotherapy, measured by atomic absorption spectrometry
journal, January 1991


A microdosing approach for characterizing formation and repair of carboplatin-DNA monoadducts and chemoresistance
journal, March 2011

  • Henderson, Paul T.; Li, Tao; He, Miaoling
  • International Journal of Cancer, Vol. 129, Issue 6
  • DOI: 10.1002/ijc.25814

Bioanalytical Applications of Accelerator Mass Spectrometry for Pharmaceutical Research
journal, July 2000


Platinum-based drugs: past, present and future
journal, February 2016


Accelerator mass spectrometry in the biomedical sciences: applications in low-exposure biomedical and environmental dosimetry
journal, December 1990

  • Felton, J. S.; Turteltaub, K. W.; Vogel, J. S.
  • Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, Vol. 52, Issue 3-4
  • DOI: 10.1016/0168-583X(90)90469-B

Comparative pharmacokinetics between a microdose and therapeutic dose for clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen), and phenobarbital in human volunteers
journal, June 2011

  • Lappin, Graham; Shishikura, Yoko; Jochemsen, Roeline
  • European Journal of Pharmaceutical Sciences, Vol. 43, Issue 3
  • DOI: 10.1016/j.ejps.2011.04.009

Use of Microdosing and Accelerator Mass Spectrometry To Evaluate the Pharmacokinetic Linearity of a Novel Tricyclic GyrB/ParE Inhibitor in Rats
journal, August 2014

  • Malfatti, Michael A.; Lao, Victoria; Ramos, Courtney L.
  • Antimicrobial Agents and Chemotherapy, Vol. 58, Issue 11
  • DOI: 10.1128/AAC.03300-14

Ultrahigh Efficiency Moving Wire Combustion Interface for Online Coupling of High-Performance Liquid Chromatography (HPLC)
journal, December 2011

  • Thomas, Avi T.; Ognibene, Ted; Daley, Paul
  • Analytical Chemistry, Vol. 83, Issue 24
  • DOI: 10.1021/ac202013s

Determining the Pharmacokinetics and Long-Term Biodistribution of SiO 2 Nanoparticles In Vivo Using Accelerator Mass Spectrometry
journal, October 2012

  • Malfatti, Michael A.; Palko, Heather A.; Kuhn, Edward A.
  • Nano Letters, Vol. 12, Issue 11
  • DOI: 10.1021/nl302412f

Significant Human β-Cell Turnover Is Limited to the First Three Decades of Life as Determined by in Vivo Thymidine Analog Incorporation and Radiocarbon Dating
journal, October 2010

  • Perl, S.; Kushner, J. A.; Buchholz, B. A.
  • The Journal of Clinical Endocrinology & Metabolism, Vol. 95, Issue 10
  • DOI: 10.1210/jc.2010-0932

Personalized medicine for targeted and platinum-based chemotherapy of lung and bladder cancer
journal, February 2013

  • Cimino, George D.; Pan, Chong-xian; Henderson, Paul T.
  • Bioanalysis, Vol. 5, Issue 3
  • DOI: 10.4155/bio.12.325

Effects of Chlorophyll and Chlorophyllin on Low-Dose Aflatoxin B 1 Pharmacokinetics in Human Volunteers
journal, December 2009


A gas ion source for radiocarbon measurement at SUERC
journal, June 2007

  • Xu, Sheng; Dougans, Andrew; Freeman, Stewart P. H. T.
  • Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, Vol. 259, Issue 1
  • DOI: 10.1016/j.nimb.2007.01.311

The Dynamics of Folic Acid Metabolism in an Adult Given a Small Tracer Dose of 14C-Folic Acid
book, January 1998

  • Clifford, Andrew J.; Arjomand, Ali; Dueker, Stephen R.
  • Mathematical Modeling in Experimental Nutrition, p. 239-251
  • DOI: 10.1007/978-1-4899-1959-5_15

Detection of 2-amino-1-methyl-6-phenylimidazo [4,5-b]-pyridine (PhIP)–DNA adducts in human pancreatic tissues
journal, January 2006


A Combined Accelerator Mass Spectrometry-Positron Emission Tomography Human Microdose Study with 14C- and 11C-Labelled Verapamil
journal, January 2011


The debate is over: accelerator MS provides the route to better drug-development paradigms/protocols
journal, February 2011


Disposition of the Dietary Mutagen 2-Amino-3,8-dimethylimidazo[4,5- f ]quinoxaline in Healthy and Pancreatic Cancer Compromised Humans
journal, March 2016


Human vitamin B12 absorption measurement by accelerator mass spectrometry using specifically labeled 14C-cobalamin
journal, April 2006

  • Carkeet, C.; Dueker, S. R.; Lango, J.
  • Proceedings of the National Academy of Sciences, Vol. 103, Issue 15
  • DOI: 10.1073/pnas.0601251103

Cisplatin in cancer therapy: Molecular mechanisms of action
journal, October 2014


Chlorophyllin Chemoprevention in Trout Initiated by Aflatoxin B1 Bath Treatment: An Evaluation of Reduced Bioavailability vs. Target Organ Protective Mechanisms
journal, July 1999

  • Breinholt, Vibeke; Arbogast, Dan; Loveland, Pat
  • Toxicology and Applied Pharmacology, Vol. 158, Issue 2
  • DOI: 10.1006/taap.1999.8696

Tissue Platinum Concentration and Tumor Response in Non–Small-Cell Lung Cancer
journal, September 2012


Relationship between the exposure to cisplatin, DNA-adduct formation in leucocytes and tumour response in patients with solid tumours
journal, June 1996

  • Schellens, Jhm; Ma, J.; Planting, ASTh
  • British Journal of Cancer, Vol. 73, Issue 12
  • DOI: 10.1038/bjc.1996.296

Human mass balance study of TAS-102 using 14C analyzed by accelerator mass spectrometry
journal, January 2016

  • Lee, James J.; Seraj, Jabed; Yoshida, Kenichiro
  • Cancer Chemotherapy and Pharmacology, Vol. 77, Issue 3
  • DOI: 10.1007/s00280-016-2965-2

Cisplatin versus carboplatin: comparative review of therapeutic management in solid malignancies
journal, June 2016


Applications of accelerator MS in pediatric drug evaluation
journal, August 2012


Rapid Production of Graphite Without Contamination for Biomedical AMS
journal, January 1992


HPLC−Accelerator MS Measurement of Atrazine Metabolites in Human Urine after Dermal Exposure
journal, August 1999

  • Buchholz, Bruce A.; Fultz, Esther; Haack, Kurt W.
  • Analytical Chemistry, Vol. 71, Issue 16
  • DOI: 10.1021/ac990152g

Long-term kinetic study of β-carotene, using accelerator mass spectrometry in an adult volunteer
journal, November 2000


Works referencing / citing this record:

Synthesis of carbon-14-labelled peptides
journal, August 2019

  • Dell'isola, Antonio; Brown, Rodney T.; Jones, Stuart
  • Journal of Labelled Compounds and Radiopharmaceuticals, Vol. 62, Issue 11
  • DOI: 10.1002/jlcr.3777

Nanotracing and cavity-ring down spectroscopy: A new ultrasensitive approach in large molecule drug disposition studies
journal, October 2018


Nanotracing and cavity-ring down spectroscopy: A new ultrasensitive approach in large molecule drug disposition studies
journal, October 2018