Trends in Analytical Chemistry: Agapios Agapiou, Anton Amann, Pawel Mochalski, Milt Statheropoulos, C.L.P. Thomas

Trends in Analytical Chemistry 66 (2015) 158175
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Trends in Analytical Chemistry

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t r a c
Trace detection of endogenous human volatile organic compounds for

search, rescue and emergency applications
Agapios 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, Cyprus
Breath Research Institute of the University of Innsbruck, Rathausplatz 4, Dornbirn A-6850, Austria
c
Univ.-Clinic for Anesthesia and Intensive Care, Innsbruck Medical University, Anichstr, 35, Innsbruck A-6020, Austria
d School of Chemical Engineering, National Technical University of Athens (NTUA), Field Analytical Chemistry and Technology Unit, 9 Iroon Polytechniou
Str., Athens 157 73, Greece
e
Department of Chemistry, Centre for Analytical Science, Loughborough University, LE11 3TU, UK
b
A R T I C L E
I N F O
Keywords:
Blood
Breath
Chemical pattern
Emergency
Human VOCs
Odor
Skin
Trace detection
Urine
Volatile organic compound
A B S T R A C T
Since Paulings paper in the 1970s, interest has increased in volatile organic compounds (VOCs) released from different bio-uids, such as blood and urine. A number of VOCs reect internal biochemical
pathways occurring in the human body and their chemical pattern may serve as the chemical platform
for tracing human VOCs. Monitoring endogenous human VOCs is proposed as an alternative method to
the 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 VOC
biomarkers (e.g. GC-MS, PTR-MS, SIFT-MS, MCC-IMS, FAIMS and sensor based systems) has signicant
clinical potential, but has yet to receive widespread consideration for emergency search applications.
2014 Elsevier B.V. All rights reserved.
Contents
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Introduction ........................................................................................................................................................................................................................................................
Trapped human experiment .........................................................................................................................................................................................................................
Breath ....................................................................................................................................................................................................................................................................
Urine ......................................................................................................................................................................................................................................................................
Blood .....................................................................................................................................................................................................................................................................
Skin and sweat ...................................................................................................................................................................................................................................................
Emergency-medicine applications ..............................................................................................................................................................................................................
Analytical instrumentation ............................................................................................................................................................................................................................
Future work .........................................................................................................................................................................................................................................................
Conclusions .........................................................................................................................................................................................................................................................
Acknowledgements ..........................................................................................................................................................................................................................................
References ............................................................................................................................................................................................................................................................
1. Introduction
Humans are thought to have their own distinctive odor, derived
from a mixture of many low-molecular-weight molecules (18300
amu) with associated high vapor pressures and, with the exception
* Corresponding author. Tel: +357 22 895432; Fax: +357 22 895466.

E-mail address: agapiou.agapios@ucy.ac.cy (A. Agapiou).
http://dx.doi.org/10.1016/j.trac.2014.11.018
0165-9936/ 2014 Elsevier B.V. All rights reserved.
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of ammonia, carbon dioxide, water and NO, odor may be considered a mixture of volatile organic compounds (VOCs). Humans emit
hundreds of VOCs associated with their metabolic processes. At the
same time, other VOCs are formed in the human body through metabolism of food, beverages, drugs [1] or exposure to environmental
VOCs [25]. Human VOC proles are a combination of the VOCs associated with breath, urine, blood and skin; note VOCs from skin
are in part produced by cutaneous microorganisms from apocrine
secretion [6]. The tracking of VOCs is interesting for social [7,8], survival, medical [913], forensics [14] and security applications [1517].
A. Agapiou et al./Trends in Analytical Chemistry 66 (2015) 158175
The detection and the identication of VOCs in exhaled breath

has attracted most interest for non-invasive, diagnostic applications. Exploitation of the results of signicant effort and progress
in this eld is impeded because many studies report large numbers
of candidate VOCs, are based on small numbers of participants, and
use different analytical technologies, and standardized approaches
to sampling data, normalization and validation have yet to be
adopted [18]. The utility of adopting miniaturized, or even handheld, sensor-based devices [1923] is a matter of debate and many
are skeptical about the feasibility of this approach, given the current
lack of unique or specic markers for certain diseases.
Improvements in the information received from natural and/or
man-made disasters have fostered reviews of the state of the art
in urban search and rescue (USaR) operations [2426]. The main
factors that affect USaR operations were reported [27]. Currently,
acoustic and optical systems have been widely used to locate casualties trapped in collapsed buildings. Endoscopes using ber optics,
infrared and visible cameras have been combined with geophones, seismic sensors, and microphones tuned to acoustic signals,
such as voices, breathing, and heartbeats. In comparison, the use
of chemical sensors is limited to carbon dioxide sensing and trained
rescue dogs [28]. The excellent sensing capabilities of canines need
to be balanced against their limitations. Dogs may work for a limited
time only, are easily injured, respond poorly to human distress,
become distressed themselves and require time-consuming training [29]. To improve and to enhance the training of canines, a
dynamic vapor generator that simulates transient odor emissions
of victims entrapped in the voids of collapsed buildings was presented [30]. Although numerous medical data from disasters are
recorded in the literature, information on proles that could contribute to casualty detection has been limited [31].
Recently, research addressed this area (www.sgl-eu.org), and the
simulated trapped human experiment indicated that a plume of
human metabolites, mainly carbon dioxide, ammonia, acetone and
isoprene, capable of travelling through building debris [32], was
formed over a period of up to 6 h. Multi-capillary column ionmobility spectrometry (MCC-IMS) applied in the same study,
subsequently, led to 12 human metabolites being proposed as
candidate signs-of-life markers [33]. In a related study in an attempt
to understand the physiology and biochemistry of human subjects during entrapment, the injury prole of entrapped victims
was correlated to the VOCs released and their biological source [17].
Three types of entrapment were proposed [17], according to victim
status:
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.
159
modelling approaches developed [36]. Combustion VOCs were evaluated for their potential to mask human VOCs, and the feasibility of
using them for the remote detection of hidden res for rst responders considered [35,36].
The gold standard for trace-VOC investigations is gas
chromatography-mass spectrometry (GC-MS). Alternative
techniques include proton-transfer reaction quadrupole or timeof-ight MS (PTR-Q-MS, PTR-TOF-MS) [37], selected ion ow tubeMS (SIFT-MS) [38] and MCC-IMS [16,39]. Portable and eld
approaches include differential IMS (d-IMS, also known as eld asymmetric IMS, FAIMS) [40,41] and linear IMS, both of which have been
successfully coupled to GC.
VOCs are selectively ionized on the basis of the formation thermodynamics of their ions [e.g., through reactions with the hydronium
ion (H3O+), the nitrosonium ion (NO+) or the dioxygenyl ion (O2+)]
and the resulting product ions may identied through their mass
or ion mobility.
In PTR-MS, compounds may be identied through specic ions
without requiring pre-separation, allowing for real-time measurement
of the analytes. However, each method presents specic strengths
and weaknesses. PTR-MS and SIFT-MS provide highly-sensitive, specic data in real time, providing the enthalpy of formation of analyte
ions is higher than that of the reactant ions used. GC-MS provides
comprehensive VOC proles, albeit slowly [12]. None of these MS
approaches comes close to passing eld-operability tests. The eld
use of IMS has been well established and is acknowledged to be useful
in safeguarding search and rescue dogs and personnel against exposure to toxic chemical agents [42]. Further, IMS has the potential
for miniaturization but, importantly, it is limited by the selectivity
of the ionization chemistry noted above. Other signicant technologies, greatly used in the eld, are novel sensor approaches, such
as chemoresistive sensors, piezoelectric sensors, metal-oxide sensors,
and quartz-crystal microbalance (QCM) sensors [1922].
The analytical task for emergency-medicine and USaR operations may be characterization of VOCs and gases that uniquely signify
human presence in debris, and specication of the instrumentation to take on USaR deployment. Note that not all VOCs associated
with humans are candidates {e.g., reduced or low penetration capacity [43,44], time (aging) effects [15], confounding factors related
to the USaR environment (waste materials, decomposing bodies, combustion products, rodent or insect infestation of the debris eld, and
even emergency medicine and injuries (severe or not)}. It should
be stressed that the nature of this specic eld and the relevant ethical
restrictions limit research to laboratory-based pilot studies, including a small number of volunteers (small sample size) and limited
quantitative information (concentration range).
This review evaluates the proposition that current analytical instrumentation may be used in support of USaR operations.
2. Trapped human experiment
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-pentanone
4-heptanone, 3-methyl-2-butanone, ethanol, dimethyl disulde,
hexanal and octanal) could be detected, indicating potential applications for human detection within the debris eld [34]. Studies on
potential confounding factors addressed the presence of smoldering res within the debris by combining audio, video and chemicaldata streams; direct imaging was augmented with the analysis of
reected images from metallic surfaces [35]. Further, the chemical
prole of burning patterns of ubiquitous materials (e.g., textile, paper,
and wood) was examined and data-processing algorithms and
Entrapment under the ruins of collapsed buildings is a severely stressful and painful situation. The victims are entombed in
conned spaces, under collapsed structure voids, ghting against
time for their survival; crush injuries, crush syndrome, acute kidney
failure and renal damage are the most common medical implications. Triage in situ saves time, resources and lives; however, USaR
resources are limited.
According to the rule of four, a victim can survive 4 min without
air, 4 days without water and 4 weeks without food, so USaR operations usually end after 72 h. Nevertheless, several reports have
shown 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 the
entrapment scene are body-plethysmography chambers (Ganshorn,
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methylated and aromatic hydrocarbons, aldehydes, ketones, sulfur

and nitrogen compounds) [45,46].
Breathing releases hundreds of endogenous and exogenous VOCs,
and biomarkers in exhaled breath have been proposed for disease
diagnosis [18,4549]. Breath gases include inorganic gases, e.g.:
Fig. 1. Body-plethysmography chamber for the simultaneous monitoring of breath

and skin emanations. {Reproduced with permission from [31]}.
Niederlauer, Germany) shown in Fig. 1. Properly adjusted, they can

facilitate study of the changes in human chemical patterns during
entrapment. Moreover, VOCs originating from different sources (e.g.,
breath, and skin) can be easily separated and analyzed, as can the
physiological parameters of the individual under study.
Aa an alternative, a controlled environmental chamber was designed and built at the University of Loughborough (United
Kingdom), enabling precise control of ventilation temperature and
humidity. The developed chamber consisted of three main parts:
the void simulator; the collapsed building simulator; and, the environmental chamber (Fig. 2). The prototype was tested under real
conditions with human volunteers remaining enclosed for 6 h, whilst
the nature and the levels of volatile metabolic markers released by
entrapped individuals into collapsed structure voids were monitored and detected; the experiment was named Trapped Human
Experiment (THE) and it was an on-going 24 h per day in a veday experiment [32,33].
3. Breath
Hippocrates, (ca. 400 BC) noted that the breath aroma of his patients was different to that of normal individuals, and, since the
advent of GC, the origin of the perceived changes in breath odor
have been assigned to numerous trace VOCs (i.e., straight-chain,
CO2 (respiration);
NO (catalyzed by nitric-oxide synthases; involved in vasodilation 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 VOCs

is still a matter in dispute.
Breath is anticipated to be the most prominent source of volatiles
in the USaR context due to its continuous nature. Bearing in mind
that entrapped victims may drift in and out of sleep or consciousness
over hours and days, it appears reasonable that studies of breath
VOCs during sleep are of particular signicance to USaR operations
[50].
Real-time measurements are of paramount importance in USaR
applications. Mimicking on-site capabilities of canines supposes spatiotemporal dynamic detection and identication of the released
VOCs, so plume monitoring is a real scientic challenge. A step towards
understanding the eld dispersion of VOCs involved the real-time
monitoring of selected VOCs using PTR-TOF-MS. As shown in Fig. 3,
the plume of acetone standards over quartz gravels was monitored
in time and space. In the same context, the body-plethysmography
chamber (Fig. 1) offers the potential of direct, simultaneous detection of breath and skin metabolites of enclosed volunteers. Since
breathing is a dynamic, continuous physical process, direct monitoring of human-oriented VOCs under daily natural activities (e.g.,
sleeping and exercising) in association with human vital signs opens
a unique window for future on-site medical applications. This is especially helpful when an entrapped victim is detected under the
ruins but extrication efforts require several hours.
Acetone and isoprene are the most abundant VOCs in human
breath and they have been the subject of numerous studies including mathematical modelling of their dynamics [5153]. In the same
context, isothermal (same temperature) rebreathing was applied as
an experimental technique for estimating the alveolar levels of hydrophilic VOCs using as prototypic test compounds acetone and
methanol [54].
Victims of severe hydration status were approached through continuous exercise in an ergometer and their specic VOCs were
monitored over time (i.e., methyl acetate, butane, dimethyl sulde
and 2-pentanone alongside acetone and isoprene) [55]. These revealed associated characteristic rest-to-work transitions in response
to variations in ventilation or perfusion. However, the dynamic
determination of VOCs introduced a new interesting window online measurements using powerful analytical instruments, such as
PTR-MS. As a result, isoprene concentrations were shown to increase
161
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, CO
and 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]}.
by a factor of 45 during moderate effort (e.g., exercising on a stationary bicycle); probably, isoprene is re-synthesized in the body
on 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 human
individuals in the concentration range 502000 ppbv. In parallel, it
has been associated with various medical processes, including kidney,
liver, and bacterial infection of either the stomach or mouth (e.g.,
hemodialysis, asthma, hepatic encephalopathy, detection of
Helicobacter pylori, and halitosis) [57,58].
It is important to stress that all breath acetone and isoprene
studies were conducted in sterile environments and have many difculties in real world real-time applications. In particular, in such
entrapment cases, which are highly inuenced by the surroundings of the crash site of the building, measuring must be narrowly
conned, allowing the victim to be pinpointed and avoiding
confounding factors, such as the high emission rates of isoprene from
vegetation into the atmosphere.
Sensor-based systems are also considered signicant in breath
testing. 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 monitoring the effect of hemodialysis on exhaled breath VOCs [62].
Finally, there was an assessment of the exhalation kinetics of VOCs
linked with cancer [63].
4. Urine
Human urine is considered one of the best characterized matrices for human biomarkers [64,65] and medical diagnosis [66].
Numerous studies have dealt with urine VOCs in medical, toxicological, forensic, work-place and environmental exposure
applications. VOCs in human urine originate from three main
sources: dietary, systemic and exogenous (e.g., environmental exposure or smoking). Chemical human signatures of VOCs mainly
belong to the rst two categories, although the presence of exogenous compounds cannot be ignored.
The principal analytical technologies used for headspace analysis of urine VOCs include GC-MS (with or without derivatization)
[65,67], SIFT-MS [68], solid-phase extraction with subsequent thermal
desorption [69] and IMS [70]. The majority of urine-analysis papers
focused on clinical applications, and, as such, the state of the art
in urine diagnosis relies on non-eld devices with signicant sample
work-up for targeted-compound analysis.
More than 200 different VOCs have been reported in urine by
various authors [18,71], and, recently, the urine metabolome was
presented [72]. However, such studies have treated urine to enhance
the VOC-extraction process, mainly by salt addition, heating, agitation or pH adjustment [71]. Such extensive work is of limited
application for USaR applications, where the primary aim is to detect
and to identify signs of life, and only spontaneously emitted urineborne VOCs can be considered as potential markers of human
presence. Moreover, within the entrapment environment in the debris
eld in conned spaces, temperature and humidity are expected to
affect urination cycles and quantities, as well as volatilization processes. Also, dehydration and nutrition strongly affects human
physiology. Consequently, VOCs described in clinical studies will not
necessarily translate to a USaR context (e.g., many organic acids do
not appear in high concentrations in the headspace of urine due to
their low pKa value). Aside from water, urine mainly consists of urea,
which therefore serves as the best detectable chemical, as other
organic chemicals vary substantially and might be harder to relate
in such cases.
In a preliminary study, headspace solid-phase microextraction
GC-MS (HS-SPME-GC-MS) was employed to create a panel of
spontaneously emitted urinary signs of life [15]. Some 20 healthy
162
Fig. 3. Spatiotemporal measurements of acetone standards over quartz gravels using proton-transfer reaction time-of-ight mass spectrometry (PTR-TOF-MS) (plume detection and monitoring). {The right panel of the gure is reproduced with permission from [31]}.
volunteers (9 female, 11 male, mean age 29.5, no special dietary

regimes) provided samples of mid-stream urine that subsequently
had their headspaces sampled over a period of four days while they
were stored at room temperature. The inclusion criteria were a detectable level in 80% of the samples, and 33 VOCs were detected
[15]. Among these compounds, ketones (represented by 10 ubiquitous compounds) and aldehydes (7) were the most common
chemical classes. Volatile sulfur compounds (VSCs) were also detected. Some 17 VOCs were present in all samples. Methyl mercaptane,
dimethyl disulde and dimethyl trisulde were the species showing
the greatest increase in concentration [15].
Moreover, another study went on to characterize the quantitative
permeation proles of urine VOCs that were determined over a 24-h
period through common building materials, such as brick and concrete [43]. Some 22 volatiles (based on NIST-standard libraries and
retention-time data from standard reference materials) were proposed
as potential human-urine indicators from the urine of four volunteers;
acetone, 2-butanone, 2-pentanone, 4-heptanone, pyrrole and dimethyl
sulde were found in all cases, so they were indicated to be the most
promising biomarkers. The VOC concentrations were generally below
10 ppb, with the prominent exception of acetone (300600 ppb).
Building materials appeared to affect the permeation proles of the
analytes under study. The more persistent compounds were those
with good solubility in urine (aldehydes and ketones). However, furans
and sulfur compounds presented short residence times, so their usefulness is limited in the context of UsaR operations. Concrete had
a greater effect than brick, drawing out the residence-time proles
to provide clear maxima and strong tailing. The maximum concentrations of the aldehydes were relatively unaffected by brick or
concrete and their residence proles also showed strong tailing.
Whilst SPME-GC-MS is effective for building VOC libraries of
human indicators, it is not a viable approach for USaR operations,
so MCC-IMS [16,44] was used in a follow-up study involving 30 participants. Two samples were taken, one after fasting and another
during a spontaneous urinating event [16], and 23 VOCs were isolated from the original panel of 33 VOCs. These 23 compounds served
as a reference library for the MCC-IMS urine studies. Of these potential indicators, 11 were identied ubiquitously (using the same
80% threshold), of which acetone, 3-methyl-2-butanone, 2-heptanone
and octanal were present in all samples.
Moreover, quantitative aspects of the IMS characterization of urine
VOCs were also addressed using 2-heptanone and n-octanal as
prototypic VOCs. Their evolution prole was mapped through a lling
chamber lled with varying grain sizes (28 mm) and layers (4
12 cm) of quartz [44]. Permeation proles of 2-heptanone exhibited
exponential growth and subsequent exponential decay in the
headspace of the chamber. For n-octanal experiments, only exponential growth was identied over the full experimental run time
(12 h), probably because of the limited experimental time, but the
work indicated that 2-heptanone permeated four times faster than
n-octanal. The 2-fold and 3-fold increases of quartz-sand thickness lengthened the permeation times on average 3 and 7 times
for n-octanal and 3 and 5 times for 2-heptanone, respectively [44].
5. Blood
Headspace analysis of blood VOCs has been studied less than
urine or breath analysis, due to the nature of the sample and individual response. Most of these studies were mainly performed for
toxicological and environmental purposes. However, the close physiological link between blood and breath enables small volatile
molecules to pass the alveolar-blood capillary membrane and vice
versa. Having in mind the wide presence of isoprene and other hydrocarbons (i.e., n-alkanes and methylated alkanes) in human breath,
their blood/air partition coecients were studied to improve knowledge of their exhalation behavior [73]. It was shown that
partition-coecient values change exponentially with boiling point,
molecular weight and increasing number of carbon atoms. Moreover, isoprene solubility in water, human blood and plasma was
determined, lling the relevant gap and offering the opportunity to
model the fate of isoprene in environmental and biological systems
[74]. Furthermore, simultaneous measurements of blood and breathborne VOCs were performed in healthy volunteers, enabling
endogenous compounds to be distinguished from exogenous compounds [46]. Fig. 4 shows the concentration patterns of selected VOCs
omnipresent in blood and breath. The colors (or grey-scale patterns) correspond to the chemical classes of compounds. Note that
the VOCs in Fig. 4 are a small set of the compounds found in either
of the two matrices (breath and blood).
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6. Skin and sweat

Skin, next to breath, is a principal source of human VOC constituents, as skin is the largest human organ, accounting for almost
15% of body weight. Contrary to temporal sources (i.e., blood or
urine), skin VOCs are released continuously; however, glandular secretion and skin bacteria may differ considerably between individuals,
giving rise to highly disparate VOC proles [75].
A variety of analytical instruments have been employed for the
determination of skin or sweat emanations, providing on-line measurements, such as secondary electrospray ionization atmospheric
pressure MS (SESI-API-MS) [76], PTR-MS [77], SIFT-MS [78], MCCIMS [39], and off-line analytical determinations, including SPMEGC-MS [79,80] and thermally desorbed membranes using TD-GCMS [81]. Nevertheless, sweat-odor research has mainly focused on
studying certain parts of the body (e.g., mainly axillae, hands and
feet) for their emitted volatiles, while, in parallel, there was wide
interest in deodorants, perfumes and chemical attractants of mosquitoes [82]. Although human-skin odors are produced in small
amounts, they present high variability due to diet, disease and other
factors. Nevertheless, in a relevant review, there is a list of the 25
most frequently identied VOCs in skin literature [83]. The majority of skin VOCs usually comprises oxygenated species, including
aldehydes, alcohols, ketones, acids and esters. Particularly interesting compounds are aldehydes and ketones, which are thought
to be related to oxidative degradation and oxidative stress. Fig. 5
shows exemplary measurements of skin-acetone emission from volunteers closed in the body-plethysmography chamber. Another very
promising volatile skin compound is NH3 [84], which is released
in normal and abnormal conditions (e.g., liver or kidney weakness, 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.
164
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 concentration within the chamber. Different colors refer to different volunteers. The volunteers remained within the chamber for ~60 min. Acetone was measured using protontransfer reaction time-of-ight mass spectrometry (PTR-TOF-MS) (Ionicon Analytik, Austria) with NO+ as a precursor ion.
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 in
real-time monitoring of volatile emanations (aldehydes) from breath
and skin [85]. In the same context, selective reagent ionizationtimeof-ight MS with NO+ as the reagent ion [SRI-TOF-MS (NO+) was
applied for near real-time monitoring of selected skin-borne
compounds. The majority of the detected compounds were aldehydes (n-propanal, n-hexanal, n-heptanal, n-octanal, n-nonanal, and
2 methyl 2-propenal), ketones (acetone, 2-butanone, 3-buten-2one, and 6-methyl-5-hepten-2-one), a hydrocarbon (2-methyl
2-pentene) and a terpene (DL-limonene). The observed median emission 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 volunteers. The observed median emission rates were in the range 0.55
4790 fmol cm2 min1, whereas, acetone, 6-methyl-5-hepten-2one, and acetaldehyde presented high emission rates exceeding 100
fmol cm2 min1 [87]. In another study, human-skin and breath
volatiles were simultaneously detected using GC-MS and sensorbased systems [88].
7. Emergency-medicine applications
Patients in emergency-medicine applications (i.e., Intensive Care
Units, ICUs) somehow resemble entrapped victims, as they usually
present severe injuries, are multi-fractured and need oxygen supply.
Studies denitely require ethical-protocol approval and are performed with a limited number of volunteers (small sample size),
so the potential and the limitations of such studies were reviewed
[9]. In such applications, the most preferred targeted source is expired
air, and, more specically, mechanically ventilated patients [89]. In
such an application, an ion-molecule-reaction-MS (IMR-MS) was
used for targeted monitoring of acetaldehyde, acetone, ethanol and
isoprene [90]. A further step was the breath monitoring of ve anaesthetized patients, whilst laparoscopic surgery was taking place
in the operating theater [91]. SIFT-MS results showed that breath
acetone remained almost at a constant level, but the long surgery
time resulted in a slightly raised level because of lipolysis. However,
a clear increase in breath isoprene was observed following abdomen
ination with CO2. The intravenously injected propofol was also detected in patients exhaled breath, but it remained constant during
the whole perioperative period.
Associated work was also carried out in pulmonary diseases. A
recent review, which included data from 73 studies, highlighted the
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Table 1
Applied analytical methods widely used in the determination of volatile organic compounds (VOCs)
Analytical instrumentation
Gas Chromatography-Mass Spectrometry (GC-MS)
Proton Transfer Reaction-Mass Spectrometry (PTR-MS)
Proton Transfer Reaction-Time-of-Flight-Mass Spectrometry
(PTR-TOF-MS)
Selected Ion Flow Tube-Mass Spectrometry (SIFT-MS)
Laser Spectrometry
Ion Mobility Spectrometry coupled to a multi-capillary
column (with retention time ~1 min) (MCC-IMS)
Field Asymmetric Ion Mobility Spectrometry (FAIMS) chip
Sensors array
Identication
Fast?
Small?
Gold standard; reliable identication and quantication of a wide range of substances

Limited identication. Fragmentation of compounds. Humidity inuence. Insensitive
to some VOCs (e.g., alkanes)
High mass resolution m/m ~ 1/5000 often allows separation of isobars. Coupling to a
MCC with retention time ~1 min further improves the possibility to separate
compounds, while keeps near-real time capability
Differentiates and identies substances at the same molecular mass. Less sensitive
than PTR-MS
Detects specic small molecules (e.g., NO, CO, CO2, NH3, carbonyl sulde, ethane). Not
a portable technique
Library of compounds still to be created, insensitive to some VOCs (e.g., alkanes)
The varying voltage in FAIMS improves the identication of compounds even without
coupling to an MCC
Multivariate statistical techniques are usually applied to analyze the produced
patterns smell print. Often the sensitivity does not (yet) reach down to
concentrations at 1 ppb.
VOCs that were correlated with various diseases, such as asthma,

chronic obstructive pulmonary disease, cystic brosis, thoracic oncology (e.g., lung cancer), and acute respiratory distress syndrome
[92]. In the same context, the VOCs that are produced by the six
most abundant and pathogenic bacteria in sepsis (Staphylococcus
aureus, Streptococcus pneumoniae, Enterococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli) were
identied and detected [9396]. Sepsis is considered the most
common cause of death after crush syndrome.
It should be stressed that ICU patients present many different
causes that do not necessarily relate to outdoor measurements of
entrapment victims and could span a wide scope of injuries or
conditions. However, other emergency applications, such as acute
kidney injury, seem closer to the medical conditions of entrapped
victims.
Other container-based approaches that have been developed for

higher concentrations (ppm and above) are straightforward to apply
but introduce complexity, instability and dicult-to-characterize
artifacts into measurements, and such approaches would include
glass syringes and polymer bags. Methods developed for monitoring VOC exposure in industrial-hygiene applications are more robust
(BioVOC) and combine containers with adsorbent traps [99]. Sample
reproducibility and storage contamination may be addressed through
on-line analytical methods often directly interfaced to a mass spectrometer (e.g., PTR-MS, and SIFT-MS) due to the complexity of the
sample, while others (e.g., MCC-IMS, FAIMS, and sensor arrays) are
considered more compound-targeted but with high potential for
miniaturization.
8. Analytical instrumentation
Detection of humans in the eld though their VOC proles is
mostly performed by trained canines, often in the context of security applications, criminal investigations, location of missing
humans and/or dead bodies and rescue operations. Rescue dogs have
been trained and deployed in search and rescue operations to locate
casualties trapped within debris following major structural collapses. The apparent speed and delity of canine olfaction in these
situations often obscures the laborious, dangerous and costly nature
of such interventions. Furthermore, the chemical nature and the
identities of the human markers perceived by dogs remain unknown,
as does the true sensitivity and selectivity data (Receiver Operating Characteristics, ROC curve: the graphic interpretation of the
sensitivity and selectivity that needs to relate to a determined threshold). Humans are only aware of the nds, as the false negatives
remain unknown. An operational cycle time of 30 min followed by
5-h recovery accompanied by exhaustion and injury is the common
way of working of a rescue dog.
GC-MS is a well-established, reliable, standardized analytical
method widely applied for the analysis of volatile substances; unfortunately, the most important aspect of the workow, namely
sampling, has yet to achieve the same levels of standardized performance. The most effective approaches use adsorbent-based
materials {i.e., thermo-desorption tubes [45], needle traps [97] or
SPME [46]}, and, with care, signicant enrichment (>104) may be
achieved, and miniaturization and integration of such approaches
into portable analytical systems has been demonstrated for remote
environmental applications [98] (e.g., International Space Station).
Fig. 6. An exemplary 3D chromatogram from headspace multi-capillary column ion

mobility spectrometer (HS-MCC-IMS) analysis of volatile organic compounds (VOCs)
in the headspace of human urine. {Reproduced with permission from [31]}.
166
Table 2
A 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
Compound
name
Chemical
class
Chemical
formula
Tentative origin
124-38-9
10102-43-9
7482-8
Carbon dioxide
Nitric oxide
Methane
Inorganic
Inorganic
Hydrocarbon
CO2
NO
CH4
7484-0
Ethane
Hydrocarbon
C2H6
109-66-0
Pentane
Hydrocarbon
C5H12
7879-5
Isoprene
Hydrocarbon
C5H8
67-56-1
Methanol
Alcohol
CH4O
Blood-borne
64-17-5
Ethanol
Alcohol
C2H6O
Natural, diet,
disinfectants,
diet/bacteria
67-63-0
2-Propanol
Alcohol
C3H8O
Natural,
disinfectants
104-76-7
2-Ethylhexanol
Alcohol
C8H18O
Contaminant from
tubing material,
skin-borne
50-00-0
Formaldehyde
Aldehyde
CH2O
75-07-0
Acetaldehyde
Aldehyde
C2H4O
Blood-borne
Bacterial
Natural or petrol,
product of lipid
peroxidation,
blood-borne
Natural, possibly
petrol, product of
lipid peroxidation,
blood-borne or
exogenous
Blood-borne,
mevalonate
pathway
biosynthesis of
cholesterol
Ethanol
metabolism
Breath
Urine
Skin emanations
40000000 ppb healthy [57] || 38000000 ppb healthy [57] || 30000000 ppb healthy [57] ||
6.7 ppb healthy [57] || 31 ppb healthy [57] || 20 ppb healthy [57] ||
mean concentration in healthy adult subjects 16.6 ppm and 15.2 ppm [102] || Mean
6.2 ppm [103] ||
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]
|| [83] ||
|| Mean 1.8 ppb healthy [46] || 0.21 (0.130.29) ppb healthy [92] || 0.83 (0.611.13) ng/L
healthy [92] || median 268.0 (107.7462.7) 10-12M healthy [92] || healthy volunteers
0.2548.89 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 (7
ppbv) for a healthy group, healthy populations 13 to 90 ppbv [106] ||
|| 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 (13.9
41.4) 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, (median
104.55 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, mean
146 42 ppb [109] || median level for young cohort is 37 ppb, geometric standard
deviation (GSD) 2.5, adult cohort of 106 ppb with a GSD of 1.65, mean (SD) for pupils
within 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]
|| 461 ppb [57] || 142.0 ppb healthy [92] || mean 502 ppb (SD = 239) healthy, median 444
ppb healthy [78] || median value of 460 ppbv healthy [34] || mean (SD) 312 (159) nonsmokers healthy ppb [107] || median 461 ppb with geometric standard deviation 1.62
[109] ||
|| (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 153
ppb 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] ||
|| 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 nonsmokers healthy [107] || median 18 ppb, mean 22 ppb [109] ||
|| [33] ||
|| Emission rate range (median)

[fmol cm2 min1] 2.6913.1
(5.19) [87] ||
|| median 3.0 (1.9 ) ppb healthy [92] || healthy < 10 ppb [78] || healthy volunteers, smokers
and lung cancer patients ranged in between 71 nmol/l (1,582 ppb) [112] ||
|| 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] || median
22 ppb, range 25 ppb [109] ||
|| [15] ||
[16] ||

[fmol cm2 min1] 0.9917.7
(4.6) [87] ||

[fmol cm2 min1] 68342773
(2005) [87] ||

[fmol cm2 min1] 506 [87] ||
|| 0.70 ppb healthy [39] || >0.05
ppb healthy [33] || [83] ||
|| 33.3 (SD = 23.5) nmol healthy

[77] || Emission rate range
(median) [fmol cm2 min1]
1643989 (244) [87]
(continued on next page)
CAS-number
Table 2 (continued)
CAS-number
Compound
name
Chemical
class
Chemical
formula
Tentative origin
Propanal
Aldehyde
C3H6O
7884-2
Aldehyde
Propanal,
2-methyl- ||
Isobutyraldehyde
C4H8O
123-72-8
Butanol
Aldehyde
C4H8O
590-86-3
Butanol,
3-methyl- ||
Isovaleraldehyde
2-Butenal,
3-methyl-
Aldehyde
C5H10O
Natural or
industrial waste
product, diet, skinborne
Skin-borne
Aldehyde
C5H8O
Skin-borne
107-86-8
Natural or
industrial waste
product,
exogenous or
skin-borne
Urine
Skin emanations
| 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] ||
|| [113] ||
|| [15] ||
|| [16] ||
[43] ||
|| 7.05 ( SD = 3.32) nmol healthy

[77] || || [82] || Emission rate
(median) [nmol min-1 person-1]
1.23 -19 (4.03) [86] || Emission rate
range (median) [fmol cm2
min1] 3.44112 (12.4) [87] ||
[114] [82] || Emission rate range
5.4817.7 (11.7)
[87] || [114] ||
[fmol cm2 min1] 4.6311 (12)
[87] ||
|| 1.351.87 ppb healthy [92] || mean (SD) 9 (5) ppb non-smokers healthy [107] || healthy
volunteers, smokers and lung cancer patients ranged in between 7 pmol/l (161 ppt) [112]
||
|| 0.32 (0.001.40) nmol/L healthy [92] ||
110-62-3
Pentanal
Aldehyde
C5H10O
Natural, diet, skinborne, urine
|| 0.002 (0.0000.011) nmol/L healthy [92] || 4 (2) ppb non-smokers healthy [107] ||
|| [15] ||
|| [16] ||
[43] ||
66-25-1
Hexanal
Aldehyde
C6H12O
Natural, diet, skinborne
|| Range (mean) 0.630.67 (0.65) ppb healthy [46] ||1 (1) ppb non-smokers healthy [107] ||
|| [15] ||
|| [43] ||
[16] ||
124-13-0
n-Octanal
Aldehyde
C8H16O
Natural or
industrial waste
product, diet, skinborne
|| 0.011 (0.0040.028) nmol/L healthy [92] ||
|| [15] ||
|| [43] ||
[16] ||
[43] ||
[44] ||
124-19-6
Nonanal
Aldehyde
C9H18O
Possibly natural,
skin-borne
|| 0.033 (0.0210.096) nmol/L healthy [92] ||
112-31-2
Decanal
Aldehyde
C10H20O
Skin-borne

[fmol cm2 min1] 6.0926.9
(13.4) [87] || [114] || [115] ||
|| 0.95 ppb healthy [39] || Emission
rate range (median)
[fmol cm2 min1] 13.568.7
(28.3) [87] ||
[fmol cm2 min1] 3.7414.9
(8.59)
[87] ||
|| > 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
16.8168 (41.9) [87] || [116] ||
|| 1.38 ppb healthy [39] || || >0.10
ppb healthy [33] || [82] || [83] || 8.5
ppb [85] || Emission rate (median)
(0.99) [86] ||
Emission rate range (median)
[fmol cm2 min1] 22.5150
(33.1)
[87] || [116] ||
|| 3.36 ppb healthy [39] || > ppb
healthy [33] || [82] || [83] || 14.4
ppb [85] || Emission rate (median)
[nmol min-1 person-1] 0.58
5.22 (1.52) [86] || Emission rate
range (median)
[fmol cm2 min1] 18.1119
(58.9) [87] || [116] ||
|| 3.17 ppb healthy [39] || >0.3ppb
healthy [33] || || [82] || [83] || 29.9
ppb [85] || [116] ||
123-38-6
Breath

167
168
Table 2 (continued)
CAS-number
Chemical
class
Chemical
formula
107-02-8
2-Propenal ||
Acrolein
Aldehyde
C3H4O
7885-3
Aldehyde
C4H6O
100-52-7
2-Propenal,
2-methyl- ||
Methacrolein
Benzaldehyde
Aldehyde
C7H6O
Exogenous, skinborne
|| Range (mean) 13.4 (1.8) ppb healthy [46] ||
64-19-7
Acetic acid
Acid
C2H4O2
Natural or
industrial waste
product, bloodborne
|| 68 (64) non-smokers healthy ppb [107] ||
27960-21-0
trans-3Methyl-2hexenoic acid
3-Hydroxy-3methylhexanoic
acid
3-Methyl-3sulfanylhexan1-ol
sec-Butyl
acetate
Acid
C7H12O2
|| [119] || [120] || [83] || [121] ||

[115] || [122] || [6] || [123] ||
Acid
C7H14O3
|| [119] || [124] || || [125] || [119] ||

[83] || [122] ||
Sulde
C7H16OS
|| [125] || [126] || [100] || [115] ||

[122] ||
Ester
C6H12O2
Ketone
C3H6O

rate range (median)
[fmol cm2 min1] 6598140
(4790) [87] |||
|| > 2 ppb healthy [33] || Emission
rate (median) [nmol min-1
1 person ] 13.2168 (44.8) [86] ||
[fmol cm2 min1] 4933680
(1100) [87] ||
58888-76-9
307964-23-4
105-46-4
67-64-1
Acetone
Tentative origin
Exogenous
Breath
Urine
|| Range (mean) 2.919 (5.9) ppb healthy [46] || (5.109.57) ppb healthy [92] || mean (SD)
32 (64) ppb non-smokers healthy [107] ||

[fmol cm2 min1] 6.3745
(19.5) [87] ||
|| Emission rate (median)
0.98 (0.55) [86] ||
rate range (median)
[fmol cm2 min1] 62238 (147)
[87] ||
|| [82] || 1 ppm healthy (foot odor)
[83] || [117] || [118] ||
|| Range (mean) 0.42.9 (1.2) ppb healthy [46] ||
Blood-borne, fatty
acid 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] || median
212.25 ppb (healthy) [129] || median (mean) 347 (376) ppb healthy, median 327 ppb
healthy, 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] || range
293 870 ppb, mean 487.4 ppb [108] || median 477 ppb with geometric standard
deviation 1.58, mean 500 ppb; median 520 ppb in controls || young adults 1718 years
median 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, mean
1130 ppb (SD 763) and median 803 ppb, type-2 diabetes patients greater than 1760 ppb
whereas healthy controls lower than 800 ppb [131] ||
Skin emanations
|| [15] ||
[43] ||
|| [16] ||
Compound
name
Table 2 (continued)
CAS-number
Compound
name
Chemical
class
Chemical
formula
Tentative origin
Urine
Skin emanations
Diet,
environmental
contaminant,
exogenous
|| Range (mean) 0.55 (2.2) ppb healthy [46] || (1.353.18) ppb healthy [92] || mouth (0.32
ppb), alveolar (0.24) [127] || median concentration (alveolar) 0.25 ppb and (mouth) 0.32
ppb [128] || median 0.38 ppb (healthy) [129] ||
|| Emission rate (median)

(3.94) [86] ||
[fmol cm2 min1] 3.716.6 (6.4)
[87] ||
|| 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] ||
|| [24] ||
[34] ||
[15] ||
[16] ||
[43] ||
[82] ||
|| [24] ||
[43] || [15]
|| [16] ||
|| [43] ||
[15] || [16]
|| [82] ||
|| [82] ||
7893-3
2-Butanone
Ketone
C4H8O
563-80-4
2-Butanone,
3-methyl-
Ketone
C5H10O
107-87-9
2-Pentanone
Ketone
C5H10O
Blood-borne,
natural, diet
591-78-6
2-Hexanone
Ketone
C6H12O
Industrial waste
product
589-38-8
3-Hexanone
Ketone
C6H12O
110-43-0
2-Heptanone
Ketone
C7H14O
106-35-4
3-Heptanone
Ketone
C7H14O
123-19-3
4-Heptanone
Ketone
C7H14O
110-93-0
6-Methyl-hept5-en-2-one
Ketone
C8H14O
98-86-2
7783-06-4
Acetophenone
Hydrogen
sulde
Ketone
Sulde
C8H8O
H2S
Bacterial
75-18-3
Dimethylsulde
Sulde
C2H6S
Blood-borne
624-89-5
Sulde, ethyl
methyl
Sulde, methyl
propyl
Sulde
C3H8S
Blood-borne
|| 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 SD
mouth 27.5/1.6 ppb [133] ||
|| 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) ppb
healthy 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 13.79
ppb (healthy) [129] || mean (SD) 17 (10) non-smokers healthy ppb [107] || healthy
volunteers 0.288.09 ppb, median 2.13 ppb [104] || median (geometric mean)/geometric
SD ppb mouth 3/1.3 [133] ||
|| Range (mean) 10.050.06 (0.06 ppb) healthy [46] ||
Sulde
C4H10S
Blood-borne, diet
|| Range (mean) 0.0539 (2.2) ppb healthy [46] ||
3877-15-4
|| Range (mean) 0.1 ppb healthy [46] ||
Natural, drugs,
blood-borne
Blood-borne
|| [15] ||
[43] ||
|| [44] ||
[15] || [43]
|| [16] ||

[fmol cm2 min1] 0.857.56
(1.94) [87] ||
[fmol cm2 min1] 1.743.55
(2.65)
[87] ||

[fmol cm2 min1] 9.0210.3
(9.66) [87] ||
|| [32] ||
[43] ||
Squalene oxidation,
skin-borne
|| 1.04 ppb healthy [39] || [83] ||

Emission rate (median)
2.54 (0.66) [86] || Emission rate
range (median)
[fmol cm2 min1] 14918 (133)
[87] ||
|| > 0.02 ppb healthy [33] ||
|| [15] ||
[43] ||
Breath

[fmol cm2 min1] 0.606.06
(2.52) [87] ||
169
170
Table 2 (continued)
CAS-number
Compound
name
Chemical
class
C4H8S
Tentative origin
Blood-borne
Breath
Sulde,
allylmethyl
624-92-0
Dimethyldisulde Sulde
C2H6S2
3658-80-8
Dimethyltrisulde Sulde
C2H6S3
7493-1
Methanethiol ||
Methylsulde
Sulde
CH4S
109-97-7
Pyrrole
Heterocyclic
C4H5N
110-00-9
Furan
Heterocyclic
C4H4O
Smoking
534-22-5
Furan,
2-methylFuran,
3-methyl-
Heterocyclic
C5H6O
Smoking
|| Range (mean) 0.13.7 (0.55) ppb healthy [46] || 1 (1) non-smokers healthy ppb [107] ||
Heterocyclic
C5H6O
Smoking-related,
blood-borne
Bacteria
|| 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] ||
|| 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 5.5/1.3
ppb [133] ||
|| mouth and alveolar (0 ppb) [127] ||
|| (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 1.822.88
ppb, median 2.35 ppb [104] || median (geometric mean)/geometric SD ppb: mouth 3.5/1.5
[133] ||
|| Range (mean) 0.090.27 (0.17) ppb healthy [46] || 4 (2) non-smokers healthy
ppb [107] ||
|| 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] ||
625-86-5
2,5Dimethylfuran
Heterocyclic
C6H8O
Smoking
|| Range (mean) 0.622.78 (1.6) ppb healthy [46] || mean (SD) 1 (2) non-smokers healthy
ppb [107] ||
7664-41-7
Ammonia
Inorganic
NH3
Blood-borne
|| 502000 healthy [57] || 559639 healthy [57] || 4251800 healthy [57] || | 2002000
healthy [57] || 964.4 402.4 ppb, 280 120 ppb healthy subjects [58] || median 688 ppb
for mouth-eNH3 healthy, 34 ppbv for nose-eNH3 healthy, and 21 ppbv for both mouthand 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, mean
1000 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 years
median 833 ppb and GSD = 1.62, adults over 60 years median 1080 ppb and GSD = 1.71
[130] ||
75-50-3
Trimethylamine
Amine
C3H9N
138-86-3
DL-Limonene
Terpene
C10H16
End stage renal

failure
Industrial waste
(used in food
avorings and
cosmetics), bloodborne
Urine
Skin emanations
[fmol cm2 min1] 0.283.13
(1.73) [87] ||
|| [15] ||
[16] ||
|| [15] ||
[16] ||
[82] ||
|| [16] ||
|| [15] ||
[43] ||
|| [15] ||
[16] ||
[43] ||
|| [43] ||
|| [16] ||
[43] ||
|| [82] ||
|| [82] || Emission rate range
0.444.15 (0.9) [87] ||
[fmol cm2 min1] 0.378.28
(0.55) [87] ||
|| A median ammonia mixing ratio
in the lower forearm skin gas of 3.4
ppbv [84] ||
|| < 0.50 ppb healthy [33] || [83] ||

Emission rate (median)
2.39 (0.76) [86] || Emission rate
range (median)
[fmol cm2 min1] 0.88377
(8.76) [87] ||
10152-76-8
930-27-8
Sulde
Chemical
formula
171
Fig. 7. Typical mean/median concentrations of selected breath volatile marker compounds in logarithmic scale. Compounds with an asterisk are considered smokingrelated compounds (e.g., furan and its methyl derivatives).
172
Table 1 presents and compares the most widely applied analytical technologies for their performance, on-line capabilities and trend
towards 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 the
nature of analytes and sample treatment/separation that is needed;
this is especially true for atmospheric pressure chemical-ionization
mechanisms. The PTR-Q-MS, PTR-TOF-MS and SIFT-MS techniques
have been demonstrated to provide rapid, sensitive measurements of VOCs in ambient air. MCC-IMS (with GC column) and FAIMS
(without GC column) are sensitive instruments with great potential for on-site applications and near real-time capabilities; they are
considered effective systems for gas detection of biological uids
and situational awareness monitoring.
A number of studies have been proposed to assist USaR teams
in locating entrapped victims under collapsed structures by using
handheld IMS [16,3234,43]. In this context, Fig. 6 shows an example
of a 3D chromatogram of urine headspace analysis.
In addition, the advantage of FAIMS is its small size (microfabricated), simplicity and compatibility with GC or other sampling
inlets. FAIMS is considered much more powerful and informative
than linear IMS, because of the simultaneous detection of positive
and negative ions [100,101].
Table 2 shows a pool of selected human-borne VOCs, which have
high potential as indicators of life; these were selected from the relevant literature with caution. Table 2 presents qualitatively and/
or quantitatively the mean or median concentrations of these VOCs
originating from human breath, blood, urine and/or skin and sweat
with the aim of nally visualizing the human-breath prole based
on the mean/median value results given in the literature. In this
context, Fig. 7 represents the typical mean/median concentrations
values (from the literature) for selected breath volatile compounds in logarithmic scale; the spine-shape gure accumulates
the selected breath volatiles in a single gure and minimizes the
variations in concentrations of VOCs.
9. Future work
A lot of work needs to be done to solve the puzzle of human VOCs
in USaR and emergency applications. Besides the interactions with
building materials, other similar interferences include the interaction with clothes and the effect of other building materials (e.g., soil,
steel, and wood). Another important factor in VOC analysis is the
prevailing surface chemistry in the building surfaces of conned
spaces; this is believed to be mostly affected by temperature and
humidity. Along with surface chemistry, the porosity of the material and the type of chemical mechanism (e.g., condensation, and
chemical bond) per material is also of paramount importance. Also,
an important problem is dust and particulate matter carried in the
air, which might strongly affect data collection and interpretation
in such sites of building collapse. Finally, VOCs evolved from household animals and plants also need to be taken into consideration.
Since the levels and the types of VOCs tend to evolve depending on victims medical condition, the issue is still open with respect
to identication of groups of individuals who resemble the status
of 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 detected; trimethylamine (TMA) was measured directly in the breath
of individuals next to aliphatic hydrocarbons and sulfur compounds [104,135].
Sensor-based systems, such as gold-nanoparticle sensors and
sensor arrays based on nanoparticles, were also tested for the detection 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 analytical technologies for the rapid, continuous detection of VOCs, their
use is mostly beyond consideration in USaR and emergency
situations; their employment for detecting human endogenous VOCs
under debris is relatively unexplored. However, both instruments
are able to perform on-site dynamic measurements. Moreover, MCCIMS and FAIMS allow near real-time detection and have great
potential for miniaturization.
10. Conclusions
VOCs are continuously and ubiquitously evolved from human metabolism in a variety of uids, including expired air, sweat, urine,
blood, and other biological liquids. These compounds are not necessarily unique to human life, as they may be released by other
sources. Conned spaces are enriched by VOCs of entrapped victims
due to breathing, urination, sweating and blood loss (if injured), enabling their identication after hours and days of entrapment. The
survival within ruins of the metabolic plume of VOCs contains transient and dynamic characteristics so it can serve as a chemical sign
of human presence. State-of-the-art analytical methods (e.g., PTRMS, SIFT-MS, and MCC-IMS) and novel sensor-based sensors
providing rapid, real-time, sensitive measurements of VOCs in
ambient air are considered promising tools for crucial applications in the eld (e.g., detection and identication of entrapped
victims), while portability, robustness and miniaturization (e.g.,
FAIMS) remain necessary demands for the success of future onsite operations.
Acknowledgements
The research leading to these results has received funding from
the 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 Operations, www.sgl-eu.org). Anton Amann and Pawel Mochalski
appreciate funding from the Austrian Federal Ministry for Transport, Innovation and Technology (BMVIT/BMWA, Project 836308,
KIRAS). We gratefully appreciate funding from the Oncotyrolproject 2.1.1. The Competence Centre Oncotyrol is funded within the
scope of the COMET - Competence Centers for Excellent Technologies through BMVIT, BMWFJ, through the province of Salzburg and
the Tiroler Zukunftsstiftung/Standortagentur Tirol. The COMET
Program is conducted by the Austrian Research Promotion Agency
(FFG). P.M. gratefully acknowledges support from the Austrian Science
Fund (FWF) under Grant No. P24736-B23. A.A. and P.M. thank the
Government of Vorarlberg (Austria) for its generous support.
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Trends in Analytical Chemistry 66 (2015) 158175

Contents lists available at ScienceDirect

Trends in Analytical Chemistry

Trace detection of endogenous human volatile organic compounds for

* Corresponding author. Tel: +357 22 895432; Fax: +357 22 895466.

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

The detection and the identication of VOCs in exhaled breath

These categories were further subdivided into:

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

methylated and aromatic hydrocarbons, aldehydes, ketones, sulfur

Fig. 1. Body-plethysmography chamber for the simultaneous monitoring of breath

Niederlauer, Germany) shown in Fig. 1. Properly adjusted, they can

Nevertheless, the biochemical pathway of the majority of VOCs

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

detection of H. pylori infection, as a major cause for gastric cancer

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

volunteers (9 female, 11 male, mean age 29.5, no special dietary

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

6. Skin and sweat

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

entrapped victims, and contribute to higher production of skin NH3.

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

Gold standard; reliable identication and quantication of a wide range of substances

VOCs that were correlated with various diseases, such as asthma,

Other container-based approaches that have been developed for

Fig. 6. An exemplary 3D chromatogram from headspace multi-capillary column ion

|| Emission rate range (median)

|| Emission rate range (median)

|| Emission rate range (median)

|| Emission rate range (median)

|| 33.3 (SD = 23.5) nmol healthy

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

|| 7.05 ( SD = 3.32) nmol healthy

Natural, diet, skinborne, urine

Natural, diet, skinborne

|| 0.011 (0.0040.028) nmol/L healthy [92] ||

|| 0.033 (0.0210.096) nmol/L healthy [92] ||

|| Emission rate range (median)

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

(continued on next page)

|| Range (mean) 13.4 (1.8) ppb healthy [46] ||

|| 68 (64) non-smokers healthy ppb [107] ||

|| [119] || [120] || [83] || [121] ||

|| [119] || [124] || || [125] || [119] ||

|| [125] || [126] || [100] || [115] ||

|| 0.29 ppb healthy [39] || Emission

|| Emission rate range (median)

|| Range (mean) 0.42.9 (1.2) ppb healthy [46] ||

(continued on next page)

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

|| Emission rate (median)

|| Range (mean) 0.0539 (2.2) ppb healthy [46] ||

|| Range (mean) 0.1 ppb healthy [46] ||

|| Range (mean) 0.020.05 (0.03) ppb healthy [46] ||

|| Emission rate range (median)

|| Emission rate range (median)

|| 1.04 ppb healthy [39] || [83] ||

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

|| Emission rate range (median)

(continued on next page)

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

End stage renal

|| Range (mean) 0.277.42 (1.46) ppb healthy [46] ||