Compartmental modeling for the volatile organic compound isoprene in human breath

Der menschliche Atemluft enthält hunderte von flüchtigen Spurenelementen, die entweder im Organismus als Folge von biochemischen und metabolischen Prozessen entstehen, oder von der Umwelt absorbiert werden. Der Quantifizierung von flüchtigen organischen Spurenelementen (VOCs) im menschlichen Atem wird ein diagnostisches Potential zugeschrieben. Atemgasanalyse ist die wissenschaftliche Untersuchung der Atemluft und ihre Hauptmotivation ist die Suche nach Marker-Substanzen, die als Indikatoren von pathophysiologischen Erkrankungen dienen können. Aufgrund ihrer nicht-invasiven Natur haben atemgasanalytische Untersuchungen in den letzten Jahren enorm an Interesse gewonnen. Allerdings ist der nicht-invasive Test noch in Entwicklung und hat in der klinischen Routine noch nicht Eingang gefunden. Neben Problemen bezüglich der Standardisierung der Atemluftabnahme und der Analysemethoden, verhindert das unzureichende Wissen über die Herkunft und die biochemischen Prozesse dieser Substanzen die Anwendung der Atemtests. Die physiologisch basierte mathematische Modellierung spielt bei der quantitativen Analyse der experimentellen Daten eine entscheidende Rolle. Ihre Aufgabe ist es, eine mechanische Beschreibung der zugrundeliegenden physiologischen Phänomene unter Berücksichtigung aller relevanten experimentellen Daten zu liefern. Somit ermöglicht die mathematische Modellierung einerseits ein detailliertes Verständnis der physiologischen Vorgänge und kann andererseits aufgrund dessen bei der Standardisierung und Entwicklung der Atemluftentnahmemethoden eine wichtige Rolle spielen. Die Arbeit konzentriert sich auf Isopren, welches eine der wichtigsten organischen Substanzen in der menschlichen Atemluft ist. Das Ziel der vorliegenden Arbeit war, den quantitativen Zusammenhang zwischen den Atemluftkonzentration und der zugrundeliegenden endogenen Blut/und Gewebekonzentrationen von Isopren zu beschreiben. Um die Kurzzeiteffekte der relevanten physiologischen Faktoren (sowie Blutfluss und Atemfluss) zu bestimmen, wurden Echtzeitmessungen unter Ergometerbelastung durchgeführt. Die herkömmlichen Modelle, die sich hauptsächlich auf die funktionellen Änderungen der Lunge konzentrieren, sind nicht in der Lage, eine physiologisch relevante Beschreibung der experimentellen Daten zu liefern. Im Gegensatz dazu wurde ein neues Modell auf Basis einer peripheren Herkunft von Isopren von unserer Arbeitsgruppe entwickelt. Die neue Hypothese wurde in der vorliegenden Arbeit durch weitere Experimente bekräftigt und das zugrundeliegende Modell verfeinert, was uns zu der Schlussfolgerung führte, dass die Skelettmuskeln eine wichtige Rolle bei der Isoprenformation spielen. Diese Hypothese wirft ein neues Licht auf die bisherigen Untersuchungen und eröffnet neue Diskussions- und Interpretationsmöglichkeiten über die Herkunft von Isopren.The interest in the diagnostic potential of volatile organic compounds (VOCs) in breath increases as a result of constantly improving modern analyzing techniques. Unfortunately, physicians have paid little attention to a causal mathematical description of the underlying physiological processes yet. Even if mathematical models are idealized representations of the reality, their impact on combining all the information and in prediction is undisputable. The emphasis of this work was to derive a mechanical description of the physiological processes governing the gas exchange dynamics of isoprene under physical exercise. Isoprene has been classified in the group of biomarkers and can be seen as a prototypic example of low-soluble substances concerning its gas exchange mechanisms. Modern mass spectrometric techniques allow its online quantification in exhaled breath in real time. Describing short-term effects is crucial to get a deeper understanding of the determining factors of the underlying mechanisms. Changes in physiology occurring during physical exercise, such as increased ventilation and increased cardiac output, offer an opportunity to examine and understand the exchange processes that determine absorption, desorption, and distribution of this important volatile organic compound. Thus, for the present work cycling exercises on a medical ergometer were carried out and an experimental setup allowing parallel and real-time measurements of exhaled isoprene time-courses in conjunction with physiological parameters was used to collect relevant information for modeling purposes. Isoprene concentrations show a distinct peak shaped response to exercise, which has been recognized before by several investigators. The existing model describing exhaled dynamics of isoprene in response to exercise is able to explain its dynamics only on the basis of physiological assumptions, which contradict physiological facts and real-time measurements. As conventional knowledge suggests isoprene is expected to be sensitive to the regional inhomogeneities in the lung due to its low solubility in blood. For this reason, we focused our attention onto various existing lung models first, which take into account regional inhomogeneities of the lung. However, such representations also fail to describe the observed data. On the contrary, experimental evidence suggests a relationship between muscle compartment activity and isoprene excretion. The first known physio\-logical model developed for isoprene exposure studies assumes a production of isoprene in the liver as the solely source of isoprene in the human body and fails to describe its exchange dynamics under physical exercise. Based on this model, we derived a compartment model, which suggests a metabolic activity of the skeletal muscles. The new model is capable to explain the observed isoprene profiles within a range of acceptable parameter sets. Even if further investigations are necessary to consolidate this hypothesis, several findings about isoprene, such as the linkage of its output to age and statin therapy, and the effect of bilateral deficit when switching from two-legged to one-legged exercise appear to fit into this hypothesis

A modeling-based evaluation of isothermal rebreathing for breath gas analyses of highly soluble volatile organic compounds

Isothermal rebreathing has been proposed as an experimental technique for estimating the alveolar levels of hydrophilic volatile organic compounds (VOCs) in exhaled breath. Using the prototypic test compound acetone we demonstrate that the end-tidal breath profiles of such substances during isothermal rebreathing show characteristics that contradict the conventional pulmonary inert gas elimination theory due to Farhi. On the other hand, these profiles can reliably be captured by virtue of a previously developed mathematical model for the general exhalation kinetics of highly soluble, blood-borne VOCs, which explicitly takes into account airway gas exchange as major determinant of the observable breath output. This model allows for a mechanistic analysis of various rebreathing protocols suggested in the literature. In particular, it clarifies the discrepancies between in vitro and in vivo blood-breath ratios of hydrophilic VOCs and yields further quantitative insights into the physiological components of isothermal rebreathing.Comment: 21 page

Modeling-based determination of physiological parameters of systemic VOCs by breath gas analysis: a pilot study

In this paper we develop a simple two compartment model which extends the Farhi equation to the case when the inhaled concentration of a volatile organic compound (VOC) is not zero. The model connects the exhaled breath concentration of systemic VOCs with physiological parameters such as endogenous production rates and metabolic rates. Its validity is tested with data obtained for isoprene and inhaled deuterated isoprene-D5.Comment: 16 page

Physiological modeling of isoprene dynamics in exhaled breath

Human breath contains a myriad of endogenous volatile organic compounds (VOCs) which are reflective of ongoing metabolic or physiological processes. While research into the diagnostic potential and general medical relevance of these trace gases is conducted on a considerable scale, little focus has been given so far to a sound analysis of the quantitative relationships between breath levels and the underlying systemic concentrations. This paper is devoted to a thorough modeling study of the end-tidal breath dynamics associated with isoprene, which serves as a paradigmatic example for the class of low-soluble, blood-borne VOCs. Real-time measurements of exhaled breath under an ergometer challenge reveal characteristic changes of isoprene output in response to variations in ventilation and perfusion. Here, a valid compartmental description of these profiles is developed. By comparison with experimental data it is inferred that the major part of breath isoprene variability during exercise conditions can be attributed to an increased fractional perfusion of potential storage and production sites, leading to higher levels of mixed venous blood concentrations at the onset of physical activity. In this context, various lines of supportive evidence for an extrahepatic tissue source of isoprene are presented. Our model is a first step towards new guidelines for the breath gas analysis of isoprene and is expected to aid further investigations regarding the exhalation, storage, transport and biotransformation processes associated with this important compound.Comment: 14 page

Physiological modeling of isoprene dynamics in exhaled breath

Human breath contains a myriad of endogenous volatile organic compounds (VOCs) which are reflective of ongoing metabolic or physiological processes. While research into the diagnostic potential and general medical relevance of these trace gases is conducted on a considerable scale, little focus has been given so far to a sound analysis of the quantitative relationships between breath levels and the underlying systemic concentrations. This paper is devoted to a thorough modeling study of the end-tidal breath dynamics associated with isoprene, which serves as a paradigmatic example for the class of low-soluble, blood-borne VOCs. Real-time measurements of exhaled breath under an ergometer challenge reveal characteristic changes of isoprene output in response to variations in ventilation and perfusion. Here, a valid compartmental description of these profiles is developed. By comparison with experimental data it is inferred that the major part of breath isoprene variability during exercise conditions can be attributed to an increased fractional perfusion of potential storage and production sites, leading to higher levels of mixed venous blood concentrations at the onset of physical activity. In this context, various lines of supportive evidence for an extrahepatic tissue source of isoprene are presented. Our model is a first step towards new guidelines for the breath gas analysis of isoprene and is expected to aid further investigations regarding the exhalation, storage, transport and biotransformation processes associated with this important compound.Comment: 14 page

A mathematical model for breath gas analysis of volatile organic compounds with special emphasis on acetone

Recommended standardized procedures for determining exhaled lower respiratory nitric oxide and nasal nitric oxide have been developed by task forces of the European Respiratory Society and the American Thoracic Society. These recommendations have paved the way for the measurement of nitric oxide to become a diagnostic tool for specific clinical applications. It would be desirable to develop similar guidelines for the sampling of other trace gases in exhaled breath, especially volatile organic compounds (VOCs) which reflect ongoing metabolism. The concentrations of water-soluble, blood-borne substances in exhaled breath are influenced by: (i) breathing patterns affecting gas exchange in the conducting airways; (ii) the concentrations in the tracheo-bronchial lining fluid; (iii) the alveolar and systemic concentrations of the compound. The classical Farhi equation takes only the alveolar concentrations into account. Real-time measurements of acetone in end-tidal breath under an ergometer challenge show characteristics which cannot be explained within the Farhi setting. Here we develop a compartment model that reliably captures these profiles and is capable of relating breath to the systemic concentrations of acetone. By comparison with experimental data it is inferred that the major part of variability in breath acetone concentrations (e.g., in response to moderate exercise or altered breathing patterns) can be attributed to airway gas exchange, with minimal changes of the underlying blood and tissue concentrations. Moreover, it is deduced that measured end-tidal breath concentrations of acetone determined during resting conditions and free breathing will be rather poor indicators for endogenous levels. Particularly, the current formulation includes the classical Farhi and the Scheid series inhomogeneity model as special limiting cases.Comment: 38 page

Societal acceptance increases Muslim-Gay identity integration for highly religious individuals… but only when the ingroup status is stable

Reconciling religious beliefs with a sexual minority identity can be challenging. After coming out, many gay men report to renounce their religious identity or experience increased identity conflict between their religious and sexual identities. Giving up one’s own identity or identity conflict are known to predict negative wellbeing, and it is important to find ways to reduce this conflict and increase identity integration. In this experiment, we conceptualized identity integration as a social creativity strategy, and we examined whether societal acceptance (vs rejection) and ingroup experience (e.g., whether gay community feels stability or improvement about their status) would alter one’s level of Muslim-gay identity integration. We found that Muslim-gay identity integration was highest among highly religious gay men when societal acceptance was present and ingroup experience was stable. Overall, we discuss our findings by drawing parallels between social identity theory and bicultural identity integration framework, and provide implications to increase identity integration for those with multiple conflicting identities

Physiological modeling for analysis of exhaled breath

There is nothing more practical than a good theory. (David Hilbert 2) Due to its broad scope and applicability, breath gas analysis holds great promise as a versatile framework for general bio-monitoring applications. As a biochemical probe, volatile organic compounds (VOCs) in exhaled breath are unique in the sens