1-s2.0-S0165993615000199-main

Trace detection of endogenous human volatile organic compounds forsearch, rescue and emergency applicationsAgapios Agapiou a,*, Anton Amann b,c, Pawel Mochalski b, Milt Statheropoulos d,C.L.P. Thomas e

a Department of Chemistry, University of Cyprus, P.O. Box 20537, Nicosia 1678, Cyprusb Breath Research Institute of the University of Innsbruck, Rathausplatz 4, Dornbirn A-6850, Austriac Univ.-Clinic for Anesthesia and Intensive Care, Innsbruck Medical University, Anichstr, 35, Innsbruck A-6020, Austriad School of Chemical Engineering, National Technical University of Athens (NTUA), Field Analytical Chemistry and Technology Unit, 9 Iroon PolytechniouStr., Athens 157 73, Greecee Department of Chemistry, Centre for Analytical Science, Loughborough University, LE11 3TU, UK

A R T I C L E I N F O

Keywords:BloodBreathChemical patternEmergencyHuman VOCsOdorSkinTrace detectionUrineVolatile organic compound

A B S T R A C T

Since Paulings paper in the 1970s, interest has increased in volatile organic compounds (VOCs) re-leased from different bio-uids, such as blood and urine. A number of VOCs reect internal biochemicalpathways occurring in the human body and their chemical pattern may serve as the chemical platformfor tracing human VOCs. Monitoring endogenous human VOCs is proposed as an alternative method tothe use of canines for search, rescue and emergency applications. Tracing human VOCs requires robust,rapid, reliable and sensitive analytical instruments. Instrumentation currently used to study human VOCbiomarkers (e.g. GC-MS, PTR-MS, SIFT-MS, MCC-IMS, FAIMS and sensor based systems) has signicantclinical potential, but has yet to receive widespread consideration for emergency search applications.

2014 Elsevier B.V. All rights reserved.

Contents

1. Introduction ........................................................................................................................................................................................................................................................ 1582. Trapped human experiment ......................................................................................................................................................................................................................... 1593. Breath .................................................................................................................................................................................................................................................................... 1604. Urine ...................................................................................................................................................................................................................................................................... 1615. Blood ..................................................................................................................................................................................................................................................................... 1636. Skin and sweat ................................................................................................................................................................................................................................................... 1637. Emergency-medicine applications .............................................................................................................................................................................................................. 1648. Analytical instrumentation ............................................................................................................................................................................................................................ 1659. Future work ......................................................................................................................................................................................................................................................... 172

10. Conclusions ......................................................................................................................................................................................................................................................... 172Acknowledgements .......................................................................................................................................................................................................................................... 172References ............................................................................................................................................................................................................................................................ 172

1. Introduction

Humans are thought to have their own distinctive odor, derivedfrom amixture of many low-molecular-weight molecules (18300amu) with associated high vapor pressures and, with the exception

of ammonia, carbon dioxide, water and NO, odor may be consid-ered amixture of volatile organic compounds (VOCs). Humans emithundreds of VOCs associatedwith theirmetabolic processes. At thesame time, other VOCs are formed in the human body throughme-tabolism of food, beverages, drugs [1] or exposure to environmentalVOCs [25]. Human VOC proles are a combination of the VOCs as-sociated with breath, urine, blood and skin; note VOCs from skinare in part produced by cutaneous microorganisms from apocrinesecretion [6]. The tracking of VOCs is interesting for social [7,8], sur-vival,medical [913], forensics [14] and security applications [1517].

* Corresponding author. Tel: +357 22 895432; Fax: +357 22 895466.E-mail address: [email protected] (A. Agapiou).

http://dx.doi.org/10.1016/j.trac.2014.11.0180165-9936/ 2014 Elsevier B.V. All rights reserved.

Trends in Analytical Chemistry 66 (2015) 158175

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The detection and the identication of VOCs in exhaled breathhas attracted most interest for non-invasive, diagnostic applica-tions. Exploitation of the results of signicant effort and progressin this eld is impeded because many studies report large numbersof candidate VOCs, are based on small numbers of participants, anduse different analytical technologies, and standardized approachesto sampling data, normalization and validation have yet to beadopted [18]. The utility of adopting miniaturized, or even hand-held, sensor-based devices [1923] is a matter of debate and manyare skeptical about the feasibility of this approach, given the currentlack of unique or specic markers for certain diseases.

Improvements in the information received from natural and/orman-made disasters have fostered reviews of the state of the artin urban search and rescue (USaR) operations [2426]. The mainfactors that affect USaR operations were reported [27]. Currently,acoustic and optical systems have been widely used to locate ca-sualties trapped in collapsed buildings. Endoscopes using ber optics,infrared and visible cameras have been combined with geo-phones, seismic sensors, andmicrophones tuned to acoustic signals,such as voices, breathing, and heartbeats. In comparison, the useof chemical sensors is limited to carbon dioxide sensing and trainedrescue dogs [28]. The excellent sensing capabilities of canines needto be balanced against their limitations. Dogs may work for a limitedtime only, are easily injured, respond poorly to human distress,become distressed themselves and require time-consuming train-ing [29]. To improve and to enhance the training of canines, adynamic vapor generator that simulates transient odor emissionsof victims entrapped in the voids of collapsed buildings was pre-sented [30]. Although numerous medical data from disasters arerecorded in the literature, information on proles that could con-tribute to casualty detection has been limited [31].

Recently, research addressed this area (www.sgl-eu.org), and thesimulated trapped human experiment indicated that a plume ofhuman metabolites, mainly carbon dioxide, ammonia, acetone andisoprene, capable of travelling through building debris [32], wasformed over a period of up to 6 h. Multi-capillary column ion-mobility spectrometry (MCC-IMS) applied in the same study,subsequently, led to 12 human metabolites being proposed ascandidate signs-of-life markers [33]. In a related study in an attemptto understand the physiology and biochemistry of human sub-jects during entrapment, the injury prole of entrapped victimswas correlated to the VOCs released and their biological source [17].Three types of entrapment were proposed [17], according to victimstatus:

A. people in great anxiety, hyper-alert in panic after the event,with or without minor injuries;

B. persons in intense stress with multiple injuries; and,C. dead victims.

These categories were further subdivided into:

A1, B1. less than 24h of entrapment and,A2, B2. more than 24h.

Tests with a handheld aspiration-type IMS indicated breath VOCs(e.g., propanal, pentanal, acetone, 2-butanone, 2-pentanone4-heptanone, 3-methyl-2-butanone, ethanol, dimethyl disulde,hexanal and octanal) could be detected, indicating potential appli-cations for human detection within the debris eld [34]. Studies onpotential confounding factors addressed the presence of smolder-ing res within the debris by combining audio, video and chemical-data streams; direct imaging was augmented with the analysis ofreected images from metallic surfaces [35]. Further, the chemicalprole of burning patterns of ubiquitousmaterials (e.g., textile, paper,and wood) was examined and data-processing algorithms and

modelling approaches developed [36]. Combustion VOCswere evalu-ated for their potential to mask human VOCs, and the feasibility ofusing them for the remote detection of hidden res for rst re-sponders considered [35,36].

The gold standard for trace-VOC investigations is gaschromatography-mass spectrometry (GC-MS). Alternativetechniques include proton-transfer reaction quadrupole or time-of-ight MS (PTR-Q-MS, PTR-TOF-MS) [37], selected ion ow tube-MS (SIFT-MS) [38] and MCC-IMS [16,39]. Portable and eldapproaches include differential IMS (d-IMS, also known as eld asym-metric IMS, FAIMS) [40,41] and linear IMS, both of which have beensuccessfully coupled to GC.

VOCs are selectively ionized on the basis of the formation ther-modynamics of their ions [e.g., through reactionswith the hydroniumion (H3O+), the nitrosonium ion (NO+) or the dioxygenyl ion (O2+)]and the resulting product ions may identied through their massor ion mobility.

In PTR-MS, compounds may be identied through specic ionswithout requiringpre-separation, allowing for real-timemeasurementof the analytes. However, each method presents specic strengthsandweaknesses. PTR-MS and SIFT-MS provide highly-sensitive, spe-cic data in real time, providing the enthalpy of formation of analyteions is higher than that of the reactant ions used. GC-MS providescomprehensive VOC proles, albeit slowly [12]. None of these MSapproaches comes close to passing eld-operability tests. The elduse of IMShas beenwell established and is acknowledged tobeusefulin safeguarding search and rescue dogs and personnel against ex-posure to toxic chemical agents [42]. Further, IMS has the potentialfor miniaturization but, importantly, it is limited by the selectivityof the ionization chemistry noted above. Other signicant tech-nologies, greatly used in the eld, are novel sensor approaches, suchas chemoresistive sensors, piezoelectric sensors,metal-oxide sensors,and quartz-crystal microbalance (QCM) sensors [1922].

The analytical task for emergency-medicine and USaR opera-tionsmaybe characterization of VOCs and gases that uniquely signifyhuman presence in debris, and specication of the instrumenta-tion to take on USaR deployment. Note that not all VOCs associatedwith humans are candidates {e.g., reduced or low penetration ca-pacity [43,44], time (aging) effects [15], confounding factors relatedto theUSaRenvironment (wastematerials, decomposingbodies, com-bustion products, rodent or insect infestation of the debris eld, andeven emergency medicine and injuries (severe or not)}. It shouldbe stressed that thenatureof this speciceld and the relevant ethicalrestrictions limit research to laboratory-based pilot studies, includ-ing a small number of volunteers (small sample size) and limitedquantitative information (concentration range).

This review evaluates the proposition that current analytical in-strumentation may be used in support of USaR operations.

2. Trapped human experiment

Entrapment under the ruins of collapsed buildings is a severe-ly stressful and painful situation. The victims are entombed inconned spaces, under collapsed structure voids, ghting againsttime for their survival; crush injuries, crush syndrome, acute kidneyfailure and renal damage are the most common medical implica-tions. Triage in situ saves time, resources and lives; however, USaRresources are limited.

According to the rule of four, a victim can survive 4minwithoutair, 4 days without water and 4 weeks without food, so USaR op-erations usually end after 72 h. Nevertheless, several reports haveshown that entrapped victims can survive for longer periods of time[26].

Simulation of this condition is very dicult, if not impossible.Interesting devices capable of mimicking conditions similar to theentrapment scene are body-plethysmography chambers (Ganshorn,

159A. Agapiou et al./Trends in Analytical Chemistry 66 (2015) 158175

Niederlauer, Germany) shown in Fig. 1. Properly adjusted, they canfacilitate study of the changes in human chemical patterns duringentrapment. Moreover, VOCs originating from different sources (e.g.,breath, and skin) can be easily separated and analyzed, as can thephysiological parameters of the individual under study.

Aa an alternative, a controlled environmental chamber was de-signed and built at the University of Loughborough (UnitedKingdom), enabling precise control of ventilation temperature andhumidity. The developed chamber consisted of three main parts:the void simulator; the collapsed building simulator; and, the en-vironmental chamber (Fig. 2). The prototype was tested under realconditions with human volunteers remaining enclosed for 6 h, whilstthe nature and the levels of volatile metabolic markers released byentrapped individuals into collapsed structure voids were moni-tored and detected; the experiment was named Trapped HumanExperiment (THE) and it was an on-going 24 h per day in a ve-day experiment [32,33].

3. Breath

Hippocrates, (ca. 400 BC) noted that the breath aroma of his pa-tients was different to that of normal individuals, and, since theadvent of GC, the origin of the perceived changes in breath odorhave been assigned to numerous trace VOCs (i.e., straight-chain,

methylated and aromatic hydrocarbons, aldehydes, ketones, sulfurand nitrogen compounds) [45,46].

Breathing releases hundreds of endogenous and exogenous VOCs,and biomarkers in exhaled breath have been proposed for diseasediagnosis [18,4549]. Breath gases include inorganic gases, e.g.:

CO2 (respiration); NO (catalyzed by nitric-oxide synthases; involved in vasodila-tion or neurotransmission);

NH3 (protein metabolism); CH4 (gut metabolism of carbohydrates); H2 (gut bacterial metabolism of carbohydrates); H2S (bacterial metabolism of thiol proteins); and, hundreds of VOCs emitted in the low ppbv to pptv region, e.g.: acetone (fatty acid catabolism); isoprene (cholesterol biosynthesis); ethanol (gut bacterial metabolism of sugars); methanol (intestinal bacteria chlora); 2-propanol (product of an enzyme-mediated reduction of

acetone); acetaldehyde (ethanol metabolism, lipid peroxidation); ethane (lipid peroxidation); methanethiol (methionine metabolism); methylamine (protein metabolism); and, n-pentane (lipid peroxidation).

Nevertheless, the biochemical pathway of the majority of VOCsis still a matter in dispute.

Breath is anticipated to be themost prominent source of volatilesin the USaR context due to its continuous nature. Bearing in mindthat entrapped victimsmay drift in and out of sleep or consciousnessover hours and days, it appears reasonable that studies of breathVOCs during sleep are of particular signicance to USaR operations[50].

Real-timemeasurements are of paramount importance in USaRapplications.Mimicking on-site capabilities of canines supposes spa-tiotemporal dynamic detection and identication of the releasedVOCs, soplumemonitoring is a real scientic challenge.A step towardsunderstanding the eld dispersion of VOCs involved the real-timemonitoring of selected VOCs using PTR-TOF-MS. As shown in Fig. 3,the plume of acetone standards over quartz gravels was monitoredin time and space. In the same context, the body-plethysmographychamber (Fig. 1) offers the potential of direct, simultaneous detec-tion of breath and skin metabolites of enclosed volunteers. Sincebreathing is a dynamic, continuous physical process, direct moni-toring of human-oriented VOCs under daily natural activities (e.g.,sleeping and exercising) in associationwith human vital signs opensa uniquewindow for future on-sitemedical applications. This is es-pecially helpful when an entrapped victim is detected under theruins but extrication efforts require several hours.

Acetone and isoprene are the most abundant VOCs in humanbreath and they have been the subject of numerous studies includ-ing mathematical modelling of their dynamics [5153]. In the samecontext, isothermal (same temperature) rebreathing was applied asan experimental technique for estimating the alveolar levels of hy-drophilic VOCs using as prototypic test compounds acetone andmethanol [54].

Victims of severe hydration status were approached through con-tinuous exercise in an ergometer and their specic VOCs weremonitored over time (i.e., methyl acetate, butane, dimethyl suldeand 2-pentanone alongside acetone and isoprene) [55]. These re-vealed associated characteristic rest-to-work transitions in responseto variations in ventilation or perfusion. However, the dynamicdetermination of VOCs introduced a new interesting window on-line measurements using powerful analytical instruments, such asPTR-MS. As a result, isoprene concentrations were shown to increase

Fig. 1. Body-plethysmography chamber for the simultaneous monitoring of breathand skin emanations. {Reproduced with permission from [31]}.

160 A. Agapiou et al./Trends in Analytical Chemistry 66 (2015) 158175

by a factor of 45 during moderate effort (e.g., exercising on a sta-tionary bicycle); probably, isoprene is re-synthesized in the bodyon a time-scale of about 12 h for replenishment of peripheral pools(e.g., in the arms and legs) [56].

Breath ammonia is also widely emitted in the breath of humanindividuals in the concentration range 502000 ppbv. In parallel, ithas been associatedwith variousmedical processes, including kidney,liver, and bacterial infection of either the stomach or mouth (e.g.,hemodialysis, asthma, hepatic encephalopathy, detection ofHelicobacter pylori, and halitosis) [57,58].

It is important to stress that all breath acetone and isoprenestudies were conducted in sterile environments and have many dif-culties in real world real-time applications. In particular, in suchentrapment cases, which are highly inuenced by the surround-ings of the crash site of the building, measuring must be narrowlyconned, allowing the victim to be pinpointed and avoidingconfounding factors, such as the high emission rates of isoprene fromvegetation into the atmosphere.

Sensor-based systems are also considered signicant in breathtesting. In particular, they were used for:

detection of H. pylori infection, as a major cause for gastric cancer(GC) and peptic ulcer disease (PUD) [59];

distinguishing gastric cancer from benign gastric conditions [60];and,

detection of digestive cancer [61].

Furthermore, nanomaterial-based sensors were applied to moni-toring the effect of hemodialysis on exhaled breath VOCs [62].

Finally, therewas an assessment of the exhalation kinetics of VOCslinked with cancer [63].

4. Urine

Human urine is considered one of the best characterized ma-trices for human biomarkers [64,65] and medical diagnosis [66].

Numerous studies have dealt with urine VOCs in medical, toxico-logical, forensic, work-place and environmental exposureapplications. VOCs in human urine originate from three mainsources: dietary, systemic and exogenous (e.g., environmental ex-posure or smoking). Chemical human signatures of VOCs mainlybelong to the rst two categories, although the presence of exog-enous compounds cannot be ignored.

The principal analytical technologies used for headspace anal-ysis of urine VOCs include GC-MS (with or without derivatization)[65,67], SIFT-MS [68], solid-phase extractionwith subsequent thermaldesorption [69] and IMS [70]. The majority of urine-analysis papersfocused on clinical applications, and, as such, the state of the artin urine diagnosis relies on non-eld devices with signicant samplework-up for targeted-compound analysis.

More than 200 different VOCs have been reported in urine byvarious authors [18,71], and, recently, the urine metabolome waspresented [72]. However, such studies have treated urine to enhancethe VOC-extraction process, mainly by salt addition, heating, agi-tation or pH adjustment [71]. Such extensive work is of limitedapplication for USaR applications,where the primary aim is to detectand to identify signs of life, and only spontaneously emitted urine-borne VOCs can be considered as potential markers of humanpresence.Moreover,within theentrapment environment in thedebriseld in conned spaces, temperature and humidity are expected toaffect urination cycles and quantities, as well as volatilization pro-cesses. Also, dehydration and nutrition strongly affects humanphysiology. Consequently, VOCs described in clinical studieswill notnecessarily translate to a USaR context (e.g., many organic acids donot appear in high concentrations in the headspace of urine due totheir lowpKa value). Aside fromwater, urinemainly consists of urea,which therefore serves as the best detectable chemical, as otherorganic chemicals vary substantially and might be harder to relatein such cases.

In a preliminary study, headspace solid-phase microextractionGC-MS (HS-SPME-GC-MS) was employed to create a panel ofspontaneously emitted urinary signs of life [15]. Some 20 healthy

Fig. 2. The trapped human experiment, showing the environmental chamber, (bottom), feeding air to the void simulator and hence to the collapsed building simulator. A Air supply; H Humidier; E In-line Environics air-quality monitoring; T In-line temperature and humidity monitoring; P Thermoelectric heat pump; G CO2, COand O2 gas monitoring; S Sampling point; V Vital signs monitoring; And, F Flow control. 1a 4b: Sampling point locations within the collapsed building simulator.Airow through the experiment is indicated by arrows. {Reproduced with permission from [32]}.


volunteers (9 female, 11 male, mean age 29.5, no special dietaryregimes) provided samples of mid-stream urine that subsequentlyhad their headspaces sampled over a period of four dayswhile theywere stored at room temperature. The inclusion criteria were a de-tectable level in 80% of the samples, and 33 VOCs were detected[15]. Among these compounds, ketones (represented by 10 ubiq-uitous compounds) and aldehydes (7) were the most commonchemical classes. Volatile sulfur compounds (VSCs) were also de-tected. Some17VOCswerepresent in all samples.Methylmercaptane,dimethyl disulde and dimethyl trisuldewere the species showingthe greatest increase in concentration [15].

Moreover, another studywent on to characterize the quantitativepermeation proles of urine VOCs thatwere determined over a 24-hperiod through common building materials, such as brick and con-crete [43]. Some 22 volatiles (based on NIST-standard libraries andretention-timedata fromstandard referencematerials)wereproposedaspotential human-urine indicators fromtheurineof four volunteers;acetone, 2-butanone, 2-pentanone, 4-heptanone,pyrroleanddimethylsuldewere found in all cases, so theywere indicated to be themostpromising biomarkers. TheVOC concentrationswere generally below10 ppb, with the prominent exception of acetone (300600 ppb).Buildingmaterials appeared to affect the permeation proles of theanalytes under study. The more persistent compounds were thosewithgoodsolubility inurine (aldehydes andketones).However, furans

and sulfur compounds presented short residence times, so their use-fulness is limited in the context of UsaR operations. Concrete hada greater effect than brick, drawing out the residence-time prolesto provide clear maxima and strong tailing. Themaximum concen-trations of the aldehydes were relatively unaffected by brick orconcrete and their residence proles also showed strong tailing.

Whilst SPME-GC-MS is effective for building VOC libraries ofhuman indicators, it is not a viable approach for USaR operations,so MCC-IMS [16,44] was used in a follow-up study involving 30 par-ticipants. Two samples were taken, one after fasting and anotherduring a spontaneous urinating event [16], and 23 VOCs were iso-lated from the original panel of 33 VOCs. These 23 compounds servedas a reference library for the MCC-IMS urine studies. Of these po-tential indicators, 11 were identied ubiquitously (using the same80% threshold), of which acetone, 3-methyl-2-butanone, 2-heptanoneand octanal were present in all samples.

Moreover, quantitative aspects of the IMS characterization of urineVOCs were also addressed using 2-heptanone and n-octanal asprototypic VOCs. Their evolution prole wasmapped through a llingchamber lled with varying grain sizes (28 mm) and layers (412 cm) of quartz [44]. Permeation proles of 2-heptanone exhibitedexponential growth and subsequent exponential decay in theheadspace of the chamber. For n-octanal experiments, only expo-nential growth was identied over the full experimental run time

Fig. 3. Spatiotemporal measurements of acetone standards over quartz gravels using proton-transfer reaction time-of-ight mass spectrometry (PTR-TOF-MS) (plume de-tection and monitoring). {The right panel of the gure is reproduced with permission from [31]}.


(12 h), probably because of the limited experimental time, but thework indicated that 2-heptanone permeated four times faster thann-octanal. The 2-fold and 3-fold increases of quartz-sand thick-ness lengthened the permeation times on average 3 and 7 timesfor n-octanal and 3 and 5 times for 2-heptanone, respectively [44].

5. Blood

Headspace analysis of blood VOCs has been studied less thanurine or breath analysis, due to the nature of the sample and in-dividual response. Most of these studies were mainly performed fortoxicological and environmental purposes. However, the close phys-iological link between blood and breath enables small volatilemolecules to pass the alveolar-blood capillary membrane and viceversa. Having in mind the wide presence of isoprene and other hy-drocarbons (i.e., n-alkanes andmethylated alkanes) in human breath,their blood/air partition coecients were studied to improve knowl-edge of their exhalation behavior [73]. It was shown thatpartition-coecient values change exponentially with boiling point,molecular weight and increasing number of carbon atoms. More-over, isoprene solubility in water, human blood and plasma wasdetermined, lling the relevant gap and offering the opportunity tomodel the fate of isoprene in environmental and biological systems[74]. Furthermore, simultaneousmeasurements of blood and breath-borne VOCs were performed in healthy volunteers, enablingendogenous compounds to be distinguished from exogenous com-pounds [46]. Fig. 4 shows the concentration patterns of selected VOCsomnipresent in blood and breath. The colors (or grey-scale pat-terns) correspond to the chemical classes of compounds. Note thatthe VOCs in Fig. 4 are a small set of the compounds found in eitherof the two matrices (breath and blood).

6. Skin and sweat

Skin, next to breath, is a principal source of human VOC con-stituents, as skin is the largest human organ, accounting for almost15% of body weight. Contrary to temporal sources (i.e., blood orurine), skin VOCs are released continuously; however, glandular se-cretion and skin bacteriamay differ considerably between individuals,giving rise to highly disparate VOC proles [75].

A variety of analytical instruments have been employed for thedetermination of skin or sweat emanations, providing on-line mea-surements, such as secondary electrospray ionization atmosphericpressure MS (SESI-API-MS) [76], PTR-MS [77], SIFT-MS [78], MCC-IMS [39], and off-line analytical determinations, including SPME-GC-MS [79,80] and thermally desorbed membranes using TD-GC-MS [81]. Nevertheless, sweat-odor research has mainly focused onstudying certain parts of the body (e.g., mainly axillae, hands andfeet) for their emitted volatiles, while, in parallel, there was wideinterest in deodorants, perfumes and chemical attractants of mos-quitoes [82]. Although human-skin odors are produced in smallamounts, they present high variability due to diet, disease and otherfactors. Nevertheless, in a relevant review, there is a list of the 25most frequently identied VOCs in skin literature [83]. The major-ity of skin VOCs usually comprises oxygenated species, includingaldehydes, alcohols, ketones, acids and esters. Particularly inter-esting compounds are aldehydes and ketones, which are thoughtto be related to oxidative degradation and oxidative stress. Fig. 5shows exemplary measurements of skin-acetone emission from vol-unteers closed in the body-plethysmography chamber. Another verypromising volatile skin compound is NH3 [84], which is releasedin normal and abnormal conditions (e.g., liver or kidney weak-ness, protein breakdown, anidrosia, and low sodium/potassium ratio).All these medical and metabolic implications are also found in

Fig. 4. Concentration patterns of selected omnipresent volatile compounds in blood and breath. The colors correspond to the different chemical classes of compounds:Green, Ketones; Red, Suldes (DMS = Dimethyl sulde, MPS = Methyl propyl sulde); Orange, Terpenoids; Cyan, Hydrocarbons; and, Dark green, Miscellaneous.


entrapped victims, and contribute to higher production of skin NH3.Ammonia and acetone, were identied and detected in the THE[32,33].

The successful coupling of MCC with PTR-TOF-MS resulted inreal-timemonitoring of volatile emanations (aldehydes) from breathand skin [85]. In the same context, selective reagent ionizationtime-of-ight MS with NO+ as the reagent ion [SRI-TOF-MS (NO+) wasapplied for near real-time monitoring of selected skin-bornecompounds. The majority of the detected compounds were alde-hydes (n-propanal, n-hexanal, n-heptanal, n-octanal, n-nonanal, and2 methyl 2-propenal), ketones (acetone, 2-butanone, 3-buten-2-one, and 6-methyl-5-hepten-2-one), a hydrocarbon (2-methyl2-pentene) and a terpene (DL-limonene). The observedmedian emis-sion rates were in the range 0.2844.8 nmol person1 min1

(16 1530 fmol cm2 min1) [86].Furthermore, SPME-GC-MS analysis was applied to monitor the

emission rates of selected VOCs from the skin of healthy volun-teers. The observed median emission rates were in the range 0.554790 fmol cm2 min1, whereas, acetone, 6-methyl-5-hepten-2-one, and acetaldehyde presented high emission rates exceeding 100fmol cm2 min1 [87]. In another study, human-skin and breathvolatiles were simultaneously detected using GC-MS and sensor-based systems [88].

7. Emergency-medicine applications

Patients in emergency-medicine applications (i.e., Intensive CareUnits, ICUs) somehow resemble entrapped victims, as they usuallypresent severe injuries, are multi-fractured and need oxygen supply.Studies denitely require ethical-protocol approval and are per-formed with a limited number of volunteers (small sample size),so the potential and the limitations of such studies were reviewed[9]. In such applications, themost preferred targeted source is expiredair, and, more specically, mechanically ventilated patients [89]. Insuch an application, an ion-molecule-reaction-MS (IMR-MS) wasused for targeted monitoring of acetaldehyde, acetone, ethanol andisoprene [90]. A further step was the breath monitoring of ve an-aesthetized patients, whilst laparoscopic surgery was taking placein the operating theater [91]. SIFT-MS results showed that breathacetone remained almost at a constant level, but the long surgerytime resulted in a slightly raised level because of lipolysis. However,a clear increase in breath isoprene was observed following abdomenination with CO2. The intravenously injected propofol was also de-tected in patients exhaled breath, but it remained constant duringthe whole perioperative period.

Associated work was also carried out in pulmonary diseases. Arecent review, which included data from 73 studies, highlighted the

Fig. 5. Acetone emitted by skin of volunteers in a body-plethysmography chamber, exhaling through a tube leading outside the chamber, not contributing to the concen-tration within the chamber. Different colors refer to different volunteers. The volunteers remained within the chamber for ~60 min. Acetone was measured using proton-transfer reaction time-of-ight mass spectrometry (PTR-TOF-MS) (Ionicon Analytik, Austria) with NO+ as a precursor ion.


VOCs that were correlated with various diseases, such as asthma,chronic obstructive pulmonary disease, cystic brosis, thoracic on-cology (e.g., lung cancer), and acute respiratory distress syndrome[92]. In the same context, the VOCs that are produced by the sixmost abundant and pathogenic bacteria in sepsis (Staphylococcusaureus, Streptococcus pneumoniae, Enterococcus faecalis, Pseudomo-nas aeruginosa, Klebsiella pneumoniae and Escherichia coli) wereidentied and detected [9396]. Sepsis is considered the mostcommon cause of death after crush syndrome.

It should be stressed that ICU patients present many differentcauses that do not necessarily relate to outdoor measurements ofentrapment victims and could span a wide scope of injuries orconditions. However, other emergency applications, such as acutekidney injury, seem closer to the medical conditions of entrappedvictims.

8. Analytical instrumentation

Detection of humans in the eld though their VOC proles ismostly performed by trained canines, often in the context of se-curity applications, criminal investigations, location of missinghumans and/or dead bodies and rescue operations. Rescue dogs havebeen trained and deployed in search and rescue operations to locatecasualties trapped within debris following major structural col-lapses. The apparent speed and delity of canine olfaction in thesesituations often obscures the laborious, dangerous and costly natureof such interventions. Furthermore, the chemical nature and theidentities of the humanmarkers perceived by dogs remain unknown,as does the true sensitivity and selectivity data (Receiver Operat-ing Characteristics, ROC curve: the graphic interpretation of thesensitivity and selectivity that needs to relate to a determined thresh-old). Humans are only aware of the nds, as the false negativesremain unknown. An operational cycle time of 30 min followed by5-h recovery accompanied by exhaustion and injury is the commonway of working of a rescue dog.

GC-MS is a well-established, reliable, standardized analyticalmethod widely applied for the analysis of volatile substances; un-fortunately, the most important aspect of the workow, namelysampling, has yet to achieve the same levels of standardized per-formance. The most effective approaches use adsorbent-basedmaterials {i.e., thermo-desorption tubes [45], needle traps [97] orSPME [46]}, and, with care, signicant enrichment (>104) may beachieved, and miniaturization and integration of such approachesinto portable analytical systems has been demonstrated for remoteenvironmental applications [98] (e.g., International Space Station).

Other container-based approaches that have been developed forhigher concentrations (ppm and above) are straightforward to applybut introduce complexity, instability and dicult-to-characterizeartifacts into measurements, and such approaches would includeglass syringes and polymer bags. Methods developed for monitor-ing VOC exposure in industrial-hygiene applications are more robust(BioVOC) and combine containers with adsorbent traps [99]. Samplereproducibility and storage contaminationmay be addressed throughon-line analytical methods often directly interfaced to a mass spec-trometer (e.g., PTR-MS, and SIFT-MS) due to the complexity of thesample, while others (e.g., MCC-IMS, FAIMS, and sensor arrays) areconsidered more compound-targeted but with high potential forminiaturization.

Table 1Applied analytical methods widely used in the determination of volatile organic compounds (VOCs)

Analytical instrumentation Identication Fast? Small?

Gas Chromatography-Mass Spectrometry (GC-MS) Gold standard; reliable identication and quantication of a wide range of substances Proton Transfer Reaction-Mass Spectrometry (PTR-MS) Limited identication. Fragmentation of compounds. Humidity inuence. Insensitive

to some VOCs (e.g., alkanes)

Proton Transfer Reaction-Time-of-Flight-Mass Spectrometry(PTR-TOF-MS)

High mass resolution m/m ~ 1/5000 often allows separation of isobars. Coupling to aMCC with retention time ~1 min further improves the possibility to separatecompounds, while keeps near-real time capability

Selected Ion Flow Tube-Mass Spectrometry (SIFT-MS) Differentiates and identies substances at the same molecular mass. Less sensitivethan PTR-MS

Laser Spectrometry Detects specic small molecules (e.g., NO, CO, CO2, NH3, carbonyl sulde, ethane). Nota portable technique

Ion Mobility Spectrometry coupled to a multi-capillarycolumn (with retention time ~1 min) (MCC-IMS)

Library of compounds still to be created, insensitive to some VOCs (e.g., alkanes) /

Field Asymmetric Ion Mobility Spectrometry (FAIMS) chip The varying voltage in FAIMS improves the identication of compounds even withoutcoupling to an MCC

Sensors array Multivariate statistical techniques are usually applied to analyze the producedpatterns smell print. Often the sensitivity does not (yet) reach down toconcentrations at 1 ppb.

Fig. 6. An exemplary 3D chromatogram from headspace multi-capillary column ionmobility spectrometer (HS-MCC-IMS) analysis of volatile organic compounds (VOCs)in the headspace of human urine. {Reproduced with permission from [31]}.


Table 2A panel of selected human-borne volatile organic compounds (VOCs) emitted from breath, urine, blood and skin or sweat. Preferentially, median concentrations have been considered from the existing literature, if available

CAS-number Compoundname

Chemicalclass

Chemicalformula

Tentative origin Breath Urine Skin emanations

124-38-9 Carbon dioxide Inorganic CO2 Blood-borne 40000000 ppb healthy [57] || 38000000 ppb healthy [57] || 30000000 ppb healthy [57] || || [83] ||10102-43-9 Nitric oxide Inorganic NO 6.7 ppb healthy [57] || 31 ppb healthy [57] || 20 ppb healthy [57] ||7482-8 Methane Hydrocarbon CH4 Bacterial mean concentration in healthy adult subjects 16.6 ppm and 15.2 ppm [102] || Mean

6.2 ppm [103] ||7484-0 Ethane Hydrocarbon C2H6 Natural or petrol,

product of lipidperoxidation,blood-borne

0.88 0.09 ppb in healthy volunteers [92] || 0.10 (0.250.44) ppb in healthy volunteers[92] || 0.82 0.09 ppb healthy [92] || 1.9 (010.54) ppb in healthy volunteers [92] ||2.9 1.0 pmol/dL healthy [92]

109-66-0 Pentane Hydrocarbon C5H12 Natural, possiblypetrol, product oflipid peroxidation,blood-borne orexogenous

|| Mean 1.8 ppb healthy [46] || 0.21 (0.130.29) ppb healthy [92] || 0.83 (0.611.13) ng/Lhealthy [92] || median 268.0 (107.7462.7) 10-12M healthy [92] || healthy volunteers0.2548.89 ppb, median 5.29 ppb [104] || median 0.12 (0.100.16) nmol/L healthy [92] ||0.57 0.3 (mean SD) nmol/L [105] || healthy mean 40 and median 38 ppbv, 0.3 nmol/L (7ppbv) for a healthy group, healthy populations 13 to 90 ppbv [106] ||

|| Emission rate range (median)[fmol cm2 min1] 2.6913.1(5.19) [87] ||

7879-5 Isoprene Hydrocarbon C5H8 Blood-borne,mevalonatepathway biosynthesis ofcholesterol

|| Range (mean) 31273 (131) ppb healthy [46] || 106 ppb healthy [57] || 58 (44112) ppb[90] || 143 ppb healthy [92] || 105.2 ppb healthy [92] || 70.8 (19.5200.5) ppb healthy [92]|| 81.8 (56.1) ppb healthy [92] || 5.99 (3.538.45) nmol/L healthy [92] || median 21.8 (13.941.4) nmol/m2 healthy [92] || 57.17329.8 healthy volunteers || 40 to 300 ppb healthy,mean 212 ppb, SD 60 ppb [78] || 6 to 275 ppbv (mean: 99 ppbv) healthy [34] || mean (SD)280 (143) ppb non-smokers healthy [107] || healthy volunteers 57.17329.8 ppb, (median104.55 ppb) || 7.05 0.53 (mean SD) nmol/L [105] || range 55121 ppb, mean 89.2 ppb[108] || mean 83 (22234) ppb [108] || median 106 ppb, mean 83 ppb, mean 90 ppb, mean146 42 ppb [109] || median level for young cohort is 37 ppb, geometric standarddeviation (GSD) 2.5, adult cohort of 106 ppb with a GSD of 1.65, mean (SD) for pupilswithin age 710 years (28 24 ppb), 1013 years (40 21 ppb), 1316 years (60 41 ppb)and 1619 years (54 31 ppb), mean 83 ppb (SD 45 ppb) and range 20240 ppb [110] ||mean 118 ppb (SD 68 ppb) and range 0474 ppb, mean 83 ppb, without reported stress(mean 123 ppb) [111]

|| [15] ||[16] ||


67-56-1 Methanol Alcohol CH4O Blood-borne || 461 ppb [57] || 142.0 ppb healthy [92] || mean 502 ppb (SD = 239) healthy, median 444ppb healthy [78] || median value of 460 ppbv healthy [34] || mean (SD) 312 (159) non-smokers healthy ppb [107] || median 461 ppb with geometric standard deviation 1.62[109] ||

64-17-5 Ethanol Alcohol C2H6O Natural, diet,disinfectants,diet/bacteria

|| (1003358) ppb healthy [57] || 123 (108185) ppb healthy [90] || healthy human breath(without consumption of alcohol) < 4.2 ppb [104] || mean 196 ppb (SD = 244), median 153ppb healthy [78] || 188.5 (4.5479.5) ppb healthy [92] || 100200 ppb [103] || mean (SD)130 (213) ppb non-smokers healthy [107] || range 27 153 ppb, mean 86.6 ppb [108] ||median 112 ppb with geometric standard deviation 3.24, mean 115 ppb; mean 90 ppb[109] ||

|| Emission rate range (median)[fmol cm2 min1] 68342773(2005) [87] ||

67-63-0 2-Propanol Alcohol C3H8O Natural,disinfectants

|| 0135 ppb healthy [57] || 3.214.17 ppb healthy [92] || median 94.1 (55.2) ppb healthy[92] || mean 22 ppb (SD = 17) healthy, median 94 ppb healthy [78] || 10 (5) ppb non-smokers healthy [107] || median 18 ppb, mean 22 ppb [109] ||

|| Emission rate range (median)[fmol cm2 min1] 506 [87] ||

104-76-7 2-Ethylhexanol Alcohol C8H18O Contaminant fromtubing material,skin-borne

|| [33] || || 0.70 ppb healthy [39] || >0.05ppb healthy [33] || [83] ||

50-00-0 Formaldehyde Aldehyde CH2O || median 3.0 (1.9 ) ppb healthy [92] || healthy < 10 ppb [78] || healthy volunteers, smokersand lung cancer patients ranged in between 71 nmol/l (1,582 ppb) [112] ||

75-07-0 Acetaldehyde Aldehyde C2H4O Ethanolmetabolism

|| 633 ppb healthy [57] || 63 (4787) ppb healthy [90] || 20 ppb healthy [78] || mean (SD)89 (134) ppb non-smokers healthy [107] || range 2 -5 ppb, mean 3.8 ppb [108] || median22 ppb, range 25 ppb [109] ||

|| 33.3 (SD = 23.5) nmol healthy[77] || Emission rate range(median) [fmol cm2 min1]1643989 (244) [87]

(continued on next page)

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Chemicalclass

Chemicalformula


123-38-6 Propanal Aldehyde C3H6O Natural orindustrial wasteproduct,exogenous orskin-borne

| Range (mean) ) 566 (18.3) ppb healthy [46] || 1.563.44 ppb healthy [92] || 6.9 (5.69.1)ppb healthy [92] ||

|| [15] ||[16] ||[31] ||

|| 7.05 ( SD = 3.32) nmol healthy[77] || || [82] || Emission rate(median) [nmol min-1 person-1]1.23 -19 (4.03) [86] || Emission raterange (median) [fmol cm2 min1] 3.44112 (12.4) [87] ||

7884-2 Propanal,2-methyl- ||Isobutyraldehyde

Aldehyde C4H8O || [113] || || [15] |||| [16] ||[43] ||

[114] [82] || Emission rate range(median) [fmol cm2 min1]5.4817.7 (11.7)[87] || [114] ||

123-72-8 Butanol Aldehyde C4H8O Natural orindustrial wasteproduct, diet, skin-borne

|| 1.351.87 ppb healthy [92] || mean (SD) 9 (5) ppb non-smokers healthy [107] || healthyvolunteers, smokers and lung cancer patients ranged in between 7 pmol/l (161 ppt) [112]||

|| Emission rate range (median)[fmol cm2 min1] 4.6311 (12)[87] ||

590-86-3 Butanol,3-methyl- ||Isovaleraldehyde

Aldehyde C5H10O Skin-borne || 0.32 (0.001.40) nmol/L healthy [92] || || Emission rate range (median)[fmol cm2 min1] 6.0926.9(13.4) [87] || [114] || [115] ||

107-86-8 2-Butenal,3-methyl-

Aldehyde C5H8O Skin-borne || 0.95 ppb healthy [39] || Emissionrate range (median)[fmol cm2 min1] 13.568.7(28.3) [87] ||

110-62-3 Pentanal Aldehyde C5H10O Natural, diet, skin-borne, urine

|| 0.002 (0.0000.011) nmol/L healthy [92] || 4 (2) ppb non-smokers healthy [107] || || [15] |||| [16] ||[43] ||

|| Emission rate range (median)[fmol cm2 min1] 3.7414.9(8.59)[87] ||

66-25-1 Hexanal Aldehyde C6H12O Natural, diet, skin-borne

|| Range (mean) 0.630.67 (0.65) ppb healthy [46] ||1 (1) ppb non-smokers healthy [107] || || [15] |||| [43] ||[16] ||

|| > 0.30 ppb [33] || [83] || 4.9 ppb[85] || Emission rate (median)[nmol min-1 person-1] 1.066.33(1.98) [86] || Emission rate range(median) [fmol cm2 min1]16.8168 (41.9) [87] || [116] ||

124-13-0 n-Octanal Aldehyde C8H16O Natural orindustrial wasteproduct, diet, skin-borne

|| 0.011 (0.0040.028) nmol/L healthy [92] || || [15] |||| [43] ||[16] ||[43] ||[44] ||

|| 1.38 ppb healthy [39] || || >0.10ppb healthy [33] || [82] || [83] || 8.5ppb [85] || Emission rate (median)[nmol min-1 person-1] 0.52.52(0.99) [86] ||Emission rate range (median)[fmol cm2 min1] 22.5150(33.1)[87] || [116] ||

124-19-6 Nonanal Aldehyde C9H18O Possibly natural,skin-borne

|| 0.033 (0.0210.096) nmol/L healthy [92] || || 3.36 ppb healthy [39] || > ppbhealthy [33] || [82] || [83] || 14.4ppb [85] || Emission rate (median)[nmol min-1 person-1] 0.585.22 (1.52) [86] || Emission raterange (median)[fmol cm2 min1] 18.1119(58.9) [87] || [116] ||

112-31-2 Decanal Aldehyde C10H20O Skin-borne || 3.17 ppb healthy [39] || >0.3ppbhealthy [33] || || [82] || [83] || 29.9ppb [85] || [116] ||


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Table 2 (continued)


Chemicalclass

Chemicalformula


107-02-8 2-Propenal ||Acrolein

Aldehyde C3H4O Exogenous || Range (mean) 2.919 (5.9) ppb healthy [46] || (5.109.57) ppb healthy [92] || mean (SD)32 (64) ppb non-smokers healthy [107] ||

|| Emission rate range (median)[fmol cm2 min1] 6.3745(19.5) [87] ||

7885-3 2-Propenal,2-methyl- ||Methacrolein

Aldehyde C4H6O || Range (mean) 0.42.9 (1.2) ppb healthy [46] || || Emission rate (median)[nmol min-1 person-1] 0.220.98 (0.55) [86] ||

100-52-7 Benzaldehyde Aldehyde C7H6O Exogenous, skin-borne

|| Range (mean) 13.4 (1.8) ppb healthy [46] || || 0.47 ppb healthy [39] || Emissionrate range (median)[fmol cm2 min1] 62238 (147)[87] ||

64-19-7 Acetic acid Acid C2H4O2 Natural orindustrial wasteproduct, blood-borne

|| 68 (64) non-smokers healthy ppb [107] || || [82] || 1 ppm healthy (foot odor)[83] || [117] || [118] ||

27960-21-0 trans-3-Methyl-2-hexenoic acid

Acid C7H12O2 || [119] || [120] || [83] || [121] ||[115] || [122] || [6] || [123] ||

58888-76-9 3-Hydroxy-3-methylhexanoicacid

Acid C7H14O3 || [119] || [124] || || [125] || [119] ||[83] || [122] ||

307964-23-4 3-Methyl-3-sulfanylhexan-1-ol

Sulde C7H16OS || [125] || [126] || [100] || [115] ||[122] ||

105-46-4 sec-Butylacetate

Ester C6H12O2 || 0.29 ppb healthy [39] || Emissionrate range (median)[fmol cm2 min1] 6598140(4790) [87] |||

67-64-1 Acetone Ketone C3H6O Blood-borne, fattyacid metabolism

|| Range (mean) 2812525 (950) ppb healthy [46] || 2002000 ppb healthy [57] || 504(152950) ppb healthy [90] || 627.5 ppb healthy [92] || (44.20531.45) ppb healthy [92] ||225.7 (41.6753.4) ppb healthy [92] || 33.2 (20.838.6) nmol/L healthy [92] || median 119(52270) nmol/m2 healthy [92] || (73.11437.14) ppb in healthy volunteers [104] ||median value of 600 ppbv healthy [34] || mouth (101.67 ppb), alveolar (199.19 ppb) [127]|| median concentration (alveolar) 119.19 ppb and (mouth) 101.67 ppb [128] || median212.25 ppb (healthy) [129] || median (mean) 347 (376) ppb healthy, median 327 ppbhealthy, median 263 ppb healthy [103] || mean (SD) 1802 (984) ppb non-smokers healthy[107] ||73.11437.14 ppb (median 145.58 ppb) in the control group [104] || range293 870 ppb, mean 487.4 ppb [108] || median 477 ppb with geometric standarddeviation 1.58, mean 500 ppb; median 520 ppb in controls || young adults 1718 yearsmedian 263 ppb and GSD = 1.61, adults 2060 years median 477 ppb and GSD = 1.58,adults over 60 years median 440 ppb and GSD = 1.57 [130] || geometric mean 477 ppb(GSD 1.58) and range 148 - 2744 ppb, mean 329 ppb (SD 89) and median 318 ppb, mean1130 ppb (SD 763) and median 803 ppb, type-2 diabetes patients greater than 1760 ppbwhereas healthy controls lower than 800 ppb [131] ||

|| [15] ||[43] |||| [16] ||

|| > 2 ppb healthy [33] || Emissionrate (median) [nmol min-

1 person-1] 13.2168 (44.8) [86] ||Emission rate range (median)[fmol cm2 min1] 4933680(1100) [87] ||


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Table 2 (continued)


Chemicalclass

Chemicalformula


7893-3 2-Butanone Ketone C4H8O Diet,environmentalcontaminant,exogenous

|| Range (mean) 0.55 (2.2) ppb healthy [46] || (1.353.18) ppb healthy [92] || mouth (0.32ppb), alveolar (0.24) [127] || median concentration (alveolar) 0.25 ppb and (mouth) 0.32ppb [128] || median 0.38 ppb (healthy) [129] ||

|| [24] ||[34] ||[15] ||[16] ||[43] ||[82] ||

|| Emission rate (median)[nmol min-1 person-1] 2.47.76(3.94) [86] ||Emission rate range (median)[fmol cm2 min1] 3.716.6 (6.4)[87] ||

563-80-4 2-Butanone,3-methyl-

Ketone C5H10O || [24] ||[43] || [15]|| [16] ||

107-87-9 2-Pentanone Ketone C5H10O Blood-borne,natural, diet

|| Range (mean) 0.12.1 (0.62) ppb healthy [46] || (1.804.11) ppb healthy || 4.8 (4.65.1)ppb healthy [92] || mouth (0.11 ppb), alveolar (0.38 ppb) [128] || median concentration(alveolar) 0.38 ppb and (mouth) 0.11 ppb [128] || median 0.38 ppb (healthy) [129] ||

|| [43] ||[15] || [16]|| [82] ||


591-78-6 2-Hexanone Ketone C6H12O Industrial wasteproduct

|| [82] || || Emission rate range (median)[fmol cm2 min1] 1.743.55(2.65)[87] ||

589-38-8 3-Hexanone Ketone C6H12O || [15] ||[43] ||

110-43-0 2-Heptanone Ketone C7H14O || Range (mean) 0.1 ppb healthy [46] || || [44] ||[15] || [43]|| [16] ||


106-35-4 3-Heptanone Ketone C7H14O Natural, drugs,blood-borne

123-19-3 4-Heptanone Ketone C7H14O Blood-borne || Range (mean) 0.020.05 (0.03) ppb healthy [46] || || [32] ||[43] ||

110-93-0 6-Methyl-hept-5-en-2-one

Ketone C8H14O Squalene oxidation,skin-borne

|| 1.04 ppb healthy [39] || [83] ||Emission rate (median)[nmol min-1 person-1] 0.432.54 (0.66) [86] || Emission raterange (median)[fmol cm2 min1] 14918 (133)[87] ||

98-86-2 Acetophenone Ketone C8H8O || > 0.02 ppb healthy [33] ||7783-06-4 Hydrogen

suldeSulde H2S Bacterial || 11.78 ppb [127] || 2 ppb (median) healthy [127] || (mean SD) 115 192 ppb, median 39

ppb [132] || mean concentration 11.78 ppb [128] || median geometric mean/geometric SDmouth 27.5/1.6 ppb [133] ||

75-18-3 Dimethylsulde Sulde C2H6S Blood-borne || Range (mean) 1.428 (5) ppb healthy [46] || 7.58 (5.739.43) healthy [92] || 0.30(0.000.31) nmol/L healthy [92] || 9.3 (5.319.3) ppb healthy [92] || (0.288.09) ppbhealthy volunteers [104] || 20.3 ppb [127] || 4.81 ppb (median) [127] ||(mean SD) = 35 45 ppb, median 20 ppb [132] || mean concentration 20.3 ppb [128] ||median concentration (alveolar) 14.48 ppb and (mouth) 4.29 ppb [128] || median 13.79ppb (healthy) [129] || mean (SD) 17 (10) non-smokers healthy ppb [107] || healthyvolunteers 0.288.09 ppb, median 2.13 ppb [104] || median (geometric mean)/geometricSD ppb mouth 3/1.3 [133] ||

|| [15] ||[43] ||


624-89-5 Sulde, ethylmethyl

Sulde C3H8S Blood-borne || Range (mean) 10.050.06 (0.06 ppb) healthy [46] ||

3877-15-4 Sulde, methylpropyl

Sulde C4H10S Blood-borne, diet || Range (mean) 0.0539 (2.2) ppb healthy [46] ||


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Table 2 (continued)


Chemicalclass

Chemicalformula


10152-76-8 Sulde,allylmethyl

Sulde C4H8S Blood-borne || Range (mean) 0.0912.7 (1.6) ppb healthy [46] || mouth (0 ppb), alveolar (0.10) [127] ||median concentration (alveolar) 0.10 ppb and (mouth) 0 ppb [128] || median 0.08 ppb(healthy) [129] ||


624-92-0 Dimethyldisulde Sulde C2H6S2 || 3920 680 pptv healthy [92] || mouth (0.061 ppb), alveolar (0 ppb) [127] || 0.052 ppb(median) [127] || median concentration (alveolar) 0 ppb and (mouth) 0.061 ppb [128] ||healthy median 0.38 ppb [129] || median geometric mean/geometric SD mouth 5.5/1.3ppb [133] ||

|| [15] ||[16] ||

3658-80-8 Dimethyltrisulde Sulde C2H6S3 || mouth and alveolar (0 ppb) [127] || || [15] ||[16] ||[82] ||

7493-1 Methanethiol ||Methylsulde

Sulde CH4S Bacteria || (1.822.88) ppb healthy volunteers [104] || 9.7 ppb [127] || (mean SD) = 178 193 ppb,median 102 ppb [132] || mean concentration 9.7 ppb [128] || healthy volunteers 1.822.88ppb, median 2.35 ppb [104] || median (geometric mean)/geometric SD ppb: mouth 3.5/1.5[133] ||

|| [16] ||

109-97-7 Pyrrole Heterocyclic C4H5N || Range (mean) 0.090.27 (0.17) ppb healthy [46] || 4 (2) non-smokers healthyppb [107] ||

|| [15] ||[43] ||

110-00-9 Furan Heterocyclic C4H4O Smoking || Range (mean) 0.082.3 (0.42) ppb healthy [46] || 3.7 (3.05.3) ppb non-smokers healthy[92] ||5 (6) non-smokers healthy ppb [107] ||

|| [15] ||[16] ||[43] ||

534-22-5 Furan,2-methyl-

Heterocyclic C5H6O Smoking || Range (mean) 0.13.7 (0.55) ppb healthy [46] || 1 (1) non-smokers healthy ppb [107] || || [43] || || [82] ||

930-27-8 Furan,3-methyl-

Heterocyclic C5H6O Smoking-related,blood-borne

|| Range (mean) 0.050.39 (0.18) ppb healthy [46] || || [16] ||[43] ||

|| [82] || Emission rate range(median) [fmol cm2 min1]0.444.15 (0.9) [87] ||

625-86-5 2,5-Dimethylfuran

Heterocyclic C6H8O Smoking || Range (mean) 0.622.78 (1.6) ppb healthy [46] || mean (SD) 1 (2) non-smokers healthyppb [107] ||


7664-41-7 Ammonia Inorganic NH3 Blood-borne || 502000 healthy [57] || 559639 healthy [57] || 4251800 healthy [57] || | 2002000healthy [57] || 964.4 402.4 ppb, 280 120 ppb healthy subjects [58] || median 688 ppbfor mouth-eNH3 healthy, 34 ppbv for nose-eNH3 healthy, and 21 ppbv for both mouth-and nose-eNH3 healthy after an acidic mouth wash [84] || mean value 854 ppb healthy,median 830 ppb healthy, geometric mean 833 ppb healthy [78] || range 4222389 ppb,mean 1015.4 ppb [108] || median 833 ppb with geometric standard deviation 1.62, mean1000 ppb [109]| geometric mean value 833 ppb and the geometric standard deviation 1.62[134] young adults 1718 years median 317 ppb and GSD = 2.14, adults 2060 yearsmedian 833 ppb and GSD = 1.62, adults over 60 years median 1080 ppb and GSD = 1.71[130] ||

|| A median ammonia mixing ratioin the lower forearm skin gas of 3.4ppbv [84] ||

75-50-3 Trimethylamine Amine C3H9N End stage renalfailure

138-86-3 DL-Limonene Terpene C10H16 Industrial waste(used in foodavorings andcosmetics), blood-borne

|| Range (mean) 0.277.42 (1.46) ppb healthy [46] || || < 0.50 ppb healthy [33] || [83] ||Emission rate (median)[nmol min-1 person-1] 0.212.39 (0.76) [86] || Emission raterange (median)[fmol cm2 min1] 0.88377(8.76) [87] ||

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Fig. 7. Typical mean/median concentrations of selected breath volatile marker compounds in logarithmic scale. Compounds with an asterisk are considered smoking-related compounds (e.g., furan and its methyl derivatives).


Table 1 presents and compares the most widely applied analyt-ical technologies for their performance, on-line capabilities and trendtowards miniaturization [31]. PTR-MS, PTR-TOF-MS, SIFT-MS, IMS,and FAIMS offer on-line monitoring capabilities for human VOCs.Nevertheless, the ion chemistry in the instrument determines thenature of analytes and sample treatment/separation that is needed;this is especially true for atmospheric pressure chemical-ionizationmechanisms. The PTR-Q-MS, PTR-TOF-MS and SIFT-MS techniqueshave been demonstrated to provide rapid, sensitive measure-ments of VOCs in ambient air. MCC-IMS (with GC column) and FAIMS(without GC column) are sensitive instruments with great poten-tial for on-site applications and near real-time capabilities; they areconsidered effective systems for gas detection of biological uidsand situational awareness monitoring.

A number of studies have been proposed to assist USaR teamsin locating entrapped victims under collapsed structures by usinghandheld IMS [16,3234,43]. In this context, Fig. 6 shows an exampleof a 3D chromatogram of urine headspace analysis.

In addition, the advantage of FAIMS is its small size (micro-fabricated), simplicity and compatibility with GC or other samplinginlets. FAIMS is considered much more powerful and informativethan linear IMS, because of the simultaneous detection of positiveand negative ions [100,101].

Table 2 shows a pool of selected human-borne VOCs, which havehigh potential as indicators of life; these were selected from the rel-evant literature with caution. Table 2 presents qualitatively and/or quantitatively the mean or median concentrations of these VOCsoriginating from human breath, blood, urine and/or skin and sweatwith the aim of nally visualizing the human-breath prole basedon the mean/median value results given in the literature. In thiscontext, Fig. 7 represents the typical mean/median concentrationsvalues (from the literature) for selected breath volatile com-pounds in logarithmic scale; the spine-shape gure accumulatesthe selected breath volatiles in a single gure and minimizes thevariations in concentrations of VOCs.

9. Future work

A lot of work needs to be done to solve the puzzle of human VOCsin USaR and emergency applications. Besides the interactions withbuilding materials, other similar interferences include the interac-tion with clothes and the effect of other building materials (e.g., soil,steel, and wood). Another important factor in VOC analysis is theprevailing surface chemistry in the building surfaces of connedspaces; this is believed to be mostly affected by temperature andhumidity. Along with surface chemistry, the porosity of the mate-rial and the type of chemical mechanism (e.g., condensation, andchemical bond) per material is also of paramount importance. Also,an important problem is dust and particulate matter carried in theair, which might strongly affect data collection and interpretationin such sites of building collapse. Finally, VOCs evolved from house-hold animals and plants also need to be taken into consideration.

Since the levels and the types of VOCs tend to evolve depend-ing on victims medical condition, the issue is still open with respectto identication of groups of individuals who resemble the statusof entrapped victims (e.g., people under high stress, and fasting,crush-syndrome, liver-damage, kidney-failure and ICU patients).

Potential breath markers of renal disorder were recently de-tected; trimethylamine (TMA) was measured directly in the breathof individuals next to aliphatic hydrocarbons and sulfur com-pounds [104,135].

Sensor-based systems, such as gold-nanoparticle sensors andsensor arrays based on nanoparticles, were also tested for the de-tection of breath VOCs from renal injury patients [136,137]. Also,FAIMS usage is extending to novel medical applications [138].

While PTR-MS and SIFT-MS are powerful state-of-the-art ana-lytical technologies for the rapid, continuous detection of VOCs, theiruse is mostly beyond consideration in USaR and emergencysituations; their employment for detecting human endogenous VOCsunder debris is relatively unexplored. However, both instrumentsare able to perform on-site dynamicmeasurements. Moreover, MCC-IMS and FAIMS allow near real-time detection and have greatpotential for miniaturization.

10. Conclusions

VOCs are continuously and ubiquitously evolved from humanme-tabolism in a variety of uids, including expired air, sweat, urine,blood, and other biological liquids. These compounds are not nec-essarily unique to human life, as they may be released by othersources. Conned spaces are enriched by VOCs of entrapped victimsdue to breathing, urination, sweating and blood loss (if injured), en-abling their identication after hours and days of entrapment. Thesurvival within ruins of the metabolic plume of VOCs contains tran-sient and dynamic characteristics so it can serve as a chemical signof human presence. State-of-the-art analytical methods (e.g., PTR-MS, SIFT-MS, and MCC-IMS) and novel sensor-based sensorsproviding rapid, real-time, sensitive measurements of VOCs inambient air are considered promising tools for crucial applica-tions in the eld (e.g., detection and identication of entrappedvictims), while portability, robustness and miniaturization (e.g.,FAIMS) remain necessary demands for the success of future on-site operations.

Acknowledgements

The research leading to these results has received funding fromthe European Communitys Seventh Framework Programme (FP7/2007-13) under Grant Agreement No. 217967 (SGL for UsaR Project,Second Generation Locator for Urban Search and Rescue Opera-tions, www.sgl-eu.org). Anton Amann and Pawel Mochalskiappreciate funding from the Austrian Federal Ministry for Trans-port, Innovation and Technology (BMVIT/BMWA, Project 836308,KIRAS). We gratefully appreciate funding from the Oncotyrol-project 2.1.1. The Competence Centre Oncotyrol is funded within thescope of the COMET - Competence Centers for Excellent Technolo-gies through BMVIT, BMWFJ, through the province of Salzburg andthe Tiroler Zukunftsstiftung/Standortagentur Tirol. The COMETProgram is conducted by the Austrian Research Promotion Agency(FFG). P.M. gratefully acknowledges support from the Austrian ScienceFund (FWF) under Grant No. P24736-B23. A.A. and P.M. thank theGovernment of Vorarlberg (Austria) for its generous support.

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