FWF project: P24736-B23

Mathematical modeling of trace gas exhalation kinetics and experimental validations


Summary

Endogenous volatile organic compounds (VOCs) are released within the human organism either as a result of normal metabolic activity or due to pathological disorders. They enter the blood stream and are eventually metabolized or excreted via exhalation, skin emission, urine, etc.

Breath sampling presents a golden opportunity for a non-invasive means of extracting information on these topics. Other advantages lie in the possibility to extract breath samples as often as desired, and in the fact that exhalation can be measured in real time, even in breath-to-breath resolution. All together, these factors render breath analysis to be an ideal choice for the purpose of obtaining ongoing information on the current metabolic and physiological state of an individual.

In that process, the identification and quantification of potential disease biomarkers serve as the driving force in that analysis of exhaled breath. Moreover, future applications for medical diagnosis and therapy control with dynamic assessments of normal physiological function or pharmacodynamics are intended. Exogenous VOCs, substances that penetrate the body as a result of environmental exposure, furthermore, can be ultimately utilized to quantify body burden. Finally, breath tests are often based on the ingestion of isotopically labeled precursors, producing isotopically labeled carbon dioxide as well as the possibility of many other labeled metabolites.

Yet, due to a whole host of confounding factors biasing the concentrations of volatiles in the breath, breath sampling currently stands far-removed from the ranks of standardized procedure. These factors are related to both the breath sampling protocols as well as to the complex physiological mechanisms underlying pulmonary gas exchange. Even under resting conditions, exhaled breath concentrations of VOCs can strongly be influenced by specific physiological parameters such as cardiac output and breathing patterns, depending on the physico-chemical properties of the compound under study. Understanding the influence of all these factors and harnessing their control are therefore central to achieving an accurate standardization of breath sample collection and for the correct deduction of the corresponding blood concentration levels, and ultimately paving the way for the routinization of breath sampling.

In this project we developed new and extended our previously developed models and verified them experimentally. These models allow the determination of blood concentrations from their breath concentration. In addition they enable to calculate production rates and metabolic rates from breath concentration.

Furthermore, in a series of investigations the knowledge on the human volatilome was extended:

(i) An investigation of blood and breath volatiles quantified altogether 74 compounds occurring in both types of samples.

(ii) By measuring emissions of volatile organic compounds from skin we created a databank of human-borne volatiles having a high potential as markers of human presence, which could be used for early location of entrapped victims in rescue operations during earthquakes.

(iii) Finally, assessment, origin, and implementation of breath volatile cancer markers were investigated.

Scientific publications / Peer-reviewed publications already published

  1. (pdf), Breath isoprene: muscle dystrophy patients support the concept of a pool of isoprene in the periphery of the human body, J. King, P. Mochalski, K. Unterkofler, G. Teschl, M. Klieber, M. Stein, A. Amann, and M. Baumann, Biochemical and Biophysical Research Communications 423 (2012), 526-530.
  2. Volatile organic compounds in exhaled breath: real-time measurements, modeling, and bio-monitoring applications, J. King, K. Unterkofler, S. Teschl, A. Amann, and G. Teschl, in "The 1st International Workshop on Innovative Simulation for Health Care", W. Backfrieder et al. (eds), Proceedings of IWISH 2012, (2012), 139-144.
  3. Physiological Modeling for Analysis of Exhaled Breath, J. King, H. Koc, K. Unterkofler, G. Teschl, S. Teschl, P. Mochalski, H. Hinterhuber, and A. Amann, in "Volatile Biomarkers - Non-Invasive Diagnosis in Physiology and Medicine", A. Amann and D. Smith (eds), Elsevier, (2013), 27-46.
  4. (pdf) Stability of selected volatile breath constituents in Tedlar, Kynar and Flexfilm sampling bags, P. Mochalski, J. King, K. Unterkofler, and A. Amann, Analyst 138 (2013), 1405-1418.
  5. (pdf) Blood and breath levels of selected volatile organic compounds in healthy volunteers, P. Mochalski, J. King, M. Klieber, K. Unterkofler, H. Hinterhuber, M. Baumann, and A. Amann, Analyst 138 (2013), 2134-2145.
  6. (pdf) Release and uptake of volatile organic compounds by human hepatocellular carcinoma cells (HEPG2) in vitro, P. Mochalski, A. Sponring, J. King, K. Unterkofler, J. Troppmair, and A. Amann, Cancer Cell International 13:72 (2013), 1-9.
  7. (pdf) ABA-Cloud: support for collaborative breath research, I. Elsayed, T. Ludescher, J. King, C. Ager, M. Trosin, U. Senocak, P. Brezany, T. Feilhauer, and A. Amann, J. Breath Res. 7 (2013) 026007.
  8. (pdf) Product ion distributions for the reactions of NO$^{+}$ with some physiologically significant aldehydes obtained using a SRI-TOF-MS instrument, P. Mochalski, K. Unterkofler, P. Spanel, D. Smith, and A. Amann, International Journal of Mass Spectrometry 363 (2014), 23-31.
  9. (pdf) Blood and breath profiles of volatile organic compounds in patients with end-stage renal disease, P. Mochalski, J. King, K. Unterkofler, M. Haas, G. Mayer, and A. Amann, BMC Nephrology 15 (2014), 14p.
  10. (pdf), Monitoring of selected skin-borne volatile markers of entrapped humans by Selective Reagent Ionization Time of Flight Mass Spectrometry (SRI-TOF-MS) in NO$^{+}$ mode, P. Mochalski, K. Unterkofler, H. Hinterhuber, and A. Amann, Analytical Chemistry 86 (2014), 3915-3923.
  11. (pdf), Emission rates of selected volatile organic compounds from skin of healthy volunteers, P. Mochalski, K. Unterkofler, H. Hinterhuber, and A. Amann, Journal of Chromatography B 959 (2014), 62-70.
  12. (pdf) Assessment of the exhalation kinetics of volatile cancer biomarkers based on their physicochemical properties A. Amann, P. Mochalski, V. Ruzsanyi, Y. Y. Broza, and H. Haick, J. Breath Res. 8 (2014) 016003.
  13. (pdf) Product ion distributions for the reactions of NO$^{+}$ with some physiologically significant volatile organosulfur and organoselenium compounds obtained using a selective reagent ionization time-of-flight mass spectrometer P. Mochalski, K. Unterkofler, P. Spanel, D. Smith, and A. Amann, Rapid Commun. Mass Spectrometry 28 (2014), 1683-1690.
  14. (pdf) Quantitative analysis of volatile organic compounds released and consumed by rat L6 skeletal muscle cells in vitro P. Mochalski, R. Al-Zoairy, A. Niederwanger, K. Unterkofler, and A. Amann, J. Breath Res. 8 (2014), 046003 (7pp).
  15. (pdf), Assessment, origin, and implementation of breath volatile cancer markers H. Haick, Y. Y. Broza, P. Mochalski, V. Ruzsanyi, and A. Amann, Chem. Soc. Rev. 43 (2014) 1423-1449.
  16. (pdf) Analysis of volatile organic compounds liberated and metabolized by human umbilical vein endothelial cells (HUVEC) in vitro P. Mochalski, M. Theurl, A. Sponring, K. Unterkofler, R. Kirchmair, and A. Amann, Cell. Biochem. Biophys. 71 (2015), 323-329.
  17. (pdf) Exhaled methane concentration profiles during exercise on an ergometer A. Szabo, V. Ruzsany, K. Unterkofler, A. Mohacsi, E. Tuboly, M. Boros, G. Szabo, and A. Amann, J. Breath Res. 9 (2015) 016009.
  18. (pdf) Modeling-based determination of physiological parameters of systemic VOCs by breath gas analysis: a pilot study K. Unterkofler, J. King, P. Mochalski, M. Jandacka, H. Koc, A. Amann, S. Teschl, and G. Teschl, J. Breath Res. 9 (2015), 036002.
  19. (pdf) Potential of volatiles released by human body for early location of entrapped victims P. Mochalski, K. Unterkofler, G. Teschl, and A. Amann, Trends Anal. Chem. 68 (2015) 88-106.
  20. (pdf) Product ion distributions for the reactions of NO$^{+}$ with some N-containing and O-containing heterocyclic compounds obtained using SRI-TOF-MS P. Mochalski, K. Unterkofler, P. Spanel, D. Smith, and A. Amann, Int. J. Mass Spectrometr 386 (2015) 42-46.
  21. (pdf) Prediction of blood:air and fat:air partition coefficients of volatile organic compounds for the interpretation of data in breath gas analysis C. Kramer, P. Mochalski, K. Unterkofler, A. Agapiou, V. Ruzsanyi, and K. Liedl, J. Breath Res. 10 (2016), 017103.
  22. (pdf) Modeling the dynamic of methane concentration profiles during exercise on an ergometer A. Szabo, K. Unterkofler, P. Mochalski, M. Jandacka, V. Ruzsanyi, M. Boros, G. Teschl, S. Teschl, and J. King, J. Breath Res. 10 (2016), 017105.
 (*) pdfs for scholarly purposes only!