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Three patients with probable aerotoxic syndrome

DOI:10.1080/15563650.2019.1616092
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Gerard Hageman at Medisch Spectrum Twente
Gerard Hageman
T. M. Pal
T. M. Pal
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Jik Nihom at Medisch Spectrum Twente
Jik Nihom
S. J. MackenzieRoss
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Introduction: “Aerotoxic syndrome” is a debated entity. Regulatory authorities consider long-term health effects to be an unlikely consequence of exposure to contaminated air because several air quality monitoring studies report low concentrations of toxic chemicals in cabin air. We describe two pilots and one flight attendant, who developed ill health during their flying career which improved after cessation of flying. Case details: The most frequently reported symptoms were headache, balance problems, fatigue, gastro-intestinal complaints and cognitive impairment. One of these patients had reduced levels of butyrylcholinesterase after a flight suggesting exposure to organophosphate compounds had occurred. All three were found to have elevated neuronal and glial auto-antibodies, biomarkers of central nervous system injury, and all three had genetic polymorphisms of paraoxonase (PON-1) and two of cytochrome P450, leading to a reduced ability to metabolize organophosphate compound (OPs). Discussion: A similar constellation of symptoms has been described in other studies of aircrew, although objective evidence of exposure is lacking in most of these studies. Reduced levels of butyrylcholinesterases in one of our cases is suggestive of causation and elevated neuronal and glial autoantibodies provide objective evidence of damage to the central nervous system. We consider further research is warranted.
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Clinical Toxicology
ISSN: 1556-3650 (Print) 1556-9519 (Online) Journal homepage: https://www.tandfonline.com/loi/ictx20
Three patients with probable aerotoxic syndrome
G. Hageman, T. M. Pal, J. Nihom, S. J. MackenzieRoss & M. van den Berg
To cite this article: G. Hageman, T. M. Pal, J. Nihom, S. J. MackenzieRoss & M. van den Berg
(2019): Three patients with probable aerotoxic syndrome, Clinical Toxicology
To link to this article: https://doi.org/10.1080/15563650.2019.1616092
Published online: 16 May 2019.
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SHORT COMMUNICATION
Three patients with probable aerotoxic syndrome
G. Hageman
a
, T. M. Pal
b
, J. Nihom
a
, S. J. MackenzieRoss
c
and M. van den Berg
d
a
Medical Spectrum Twente, Hospital Enschede, Enschede, the Netherlands;
b
Occupational Health Physician n.p, Lelystad, the Netherlands;
c
Research Department of Clinical, Educational and Health Psychology, University College London, London, UK;
d
Institute of Risk Assessment
Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
ABSTRACT
Introduction: “Aerotoxic syndrome”is a debated entity. Regulatory authorities consider long-term
health effects to be an unlikely consequence of exposure to contaminated air because several air qual-
ity monitoring studies report low concentrations of toxic chemicals in cabin air. We describe two pilots
and one flight attendant, who developed ill health during their flying career which improved after ces-
sation of flying.
Case details: The most frequently reported symptoms were headache, balance problems, fatigue, gas-
tro-intestinal complaints and cognitive impairment. One of these patients had reduced levels of butyr-
ylcholinesterase after a flight suggesting exposure to organophosphate compounds had occurred. All
three were found to have elevated neuronal and glial auto-antibodies, biomarkers of central nervous
system injury, and all three had genetic polymorphisms of paraoxonase (PON-1) and two of cyto-
chrome P450, leading to a reduced ability to metabolize organophosphate compound (OPs).
Discussion: A similar constellation of symptoms has been described in other studies of aircrew,
although objective evidence of exposure is lacking in most of these studies. Reduced levels of butyryl-
cholinesterases in one of our cases is suggestive of causation and elevated neuronal and glial autoan-
tibodies provide objective evidence of damage to the central nervous system. We consider further
research is warranted.
ARTICLE HISTORY
Received 16 January 2019
Revised 25 April 2019
Accepted 2 May 2019
Published online 15 May
2019
KEYWORDS
CNS/Psychological; aerotoxic
syndrome; cabin crew;
organophosphates; contami-
nated cabin air
Introduction
Over the last two decades, several case studies and health sur-
veys have been published describing health effects of aircrew
and passengers, attributed to exposure to contaminated air
[1]. Hydraulic fluids and engine oils contain a large number of
toxic chemicals, including various organophosphates. The
term “aerotoxic syndrome”(ATS) was proposed in 2000 to
describe the short- and long-term health effects associated
with breathing contaminated cabin air. However, reported
symptoms are nonspecific and cabin air quality studies indi-
cate contaminant levels are below occupational exposure lim-
its and of no concern to human health [2]. Furthermore,
objective evidence of exposure is frequently lacking in previ-
ous case studies and surveys and findings from routine med-
ical and neurological examination (including brain imaging)
are often reported to be normal in symptomatic aircrew. In
this paper, we describe two pilots and one flight attendant,
with neurological, respiratory and gastro-intestinal symptoms
which onset during their flying career and report the findings
of more specialized tests of nervous system injury, metabolic
capacity and biomarkers of exposure to OP compounds.
Case reports
Patient A is a 50-year-old pilot, who worked for two (Dutch)
commercial airline companies for more than 20 years, with
16 years of intercontinental flights. This patient was one of a
case series of 34 flight crew members published in 2013, in
which results of assays to detect auto-antibodies were
described [3]. He was subsequently referred to our depart-
ment for further evaluation of his complaints which onset
gradually over a period of around 14 years. Initial complaints
were burning eyes, migraine-like headaches with visual aura,
position-dependent vertigo, loss of balance, tightness of
chest and hyperventilation. Over time he developed various
gastrointestinal complaints, deterioration of memory and
concentration, confusional episodes and fatigue. Symptoms
improved when he was not at work and worsened when he
returned to flying. He suffered a cardiac dysrythmia following
an intercontinental flight and was admitted to an intensive
care unit and thoroughly investigated (Tables 1–3).
Patient B is a 31-year-old flight attendant. She worked for
4 years on both European and intercontinental flights.
Sometimes she noticed noxious smells in the cabin but she
did not report any fume events. Symptoms onset after 3
years of flying and interfered with her ability to perform
her duties. After 10 months of alternative employment she
felt well enough to return to flying, but her symptoms re-
occurred within a few months of flying and she was referred
to our department for further investigations. Results from
a comprehensive neuropsychological assessment were in
the normal range. Six months after her last flight, com-
plaints persisted, (Tables 1–3).
CONTACT G. Hageman G.Hageman6@kpnplanet.nl Medical Spectrum Twente, Hospital Enschede, P.O. Box 50000, 7500 KA Enschede, the Netherlands
ß2019 Informa UK Limited, trading as Taylor & Francis Group
CLINICAL TOXICOLOGY
https://doi.org/10.1080/15563650.2019.1616092
Patient C is a 30-year-old pilot, who has flown Boeing 737
aircraft for about 3500 hours and whose symptoms onset after
3 years of flying. After a six month period of sick leave she
started flying again and almost immediately her complaints
returned. Following an incident in which oil reservoirs were
overfilled, her symptoms worsened. A cardiologist recorded
periods of tachycardia (>100 b/min), but electro-cardiography
and echocardiography were normal. Over the next six months
of flying her condition deteriorated and she was forced to
retire on ill health grounds. Extensive blood tests, including
serology of Cytomegalovirus and Epstein–Barr virus were nor-
mal. Anti-thyroid peroxidase (TPO) antibodies were mildly
elevated, but there were no signs of hypothyroidism or
Hashimoto’s disease. The only abnormality detected on neuro-
psychological tests were below average scores on tests of
concentration (Tables 1–3for further results). Brain MRI was
not performed. Four years later, an inquiry by telephone
revealed that her condition had improved considerably.
Discussion
The symptoms reported by patients have much in common
with those reported in other case-series and surveys of air-
crew, thought to have been exposed to contaminated air [1].
In patients A and B complaints persisted, in patient C com-
plaints improved. The most frequently reported symptoms
were headache, fatigue, gastro-intestinal complaints, cogni-
tive impairment and balance problems. In patient A onset of
complaints was gradual over a prolonged period of 14 years
of flying, which may seem unusual, but is not uncommon in
neurotoxicological disorders (e.g. painter’s disease) and has
been reported in a previous study of aircrew exposed to con-
taminated air [4]. Delayed onset of symptoms may reflect
the cumulative effects of low level exposure or infrequent
exposure to contaminated air. Patient A had reduced levels
of butyrylcholinesterase (BChE) suggesting exposure to OPs
had occurred. None of our cases reported fume events, but
they did report noxious smells in the aircraft cabin. However,
noxious smells are not necessarily indicative of engine oil
contamination and can be caused by other factors such as
de-icing procedures, insecticides and cleaning products.
Frequently, the source of smell events cannot be identi-
fied [2].
Neuropsychological investigation of aircrew following
exposure to contaminated air demonstrated lower scores on
tests of working memory, processing speed, reaction time
and mental flexibility, not attributable to mood disorder or
malingering [5]. In our case series, only one patient showed
Table 1. Patient data, medical and flying history.
Patient A Patient B Patient C
M/F M F F
Age in years 50 31 30
Pilot/cabincrew pilot flight attendant pilot
Medical history –– –
Medication no no no
Use of alcohol occasionally no no
Flying history 20 years, 10,000 hours 4 years, 2600 hours 4 years, 3500 hours
Aircraft type Dornier 228, Boeing 737, MD-11 Boeing 737 and 747, Airbus A330 Boeing 737
Fume events –– –
Smell events þþ þþ þþ
Onset of symptoms after 14 years after 3 years after 3 years
Exposure time-related þþ þþ þþ
Table 2. Symptoms and diagnostic tests.
Symptoms Patient A Patient B Patient C
Fatigue 
Headache 
GI complaints 
Cognitive impairment 
Balance problems 
Vertigo x
Chest tightness xx
SOB/HV x
Palpitations x x
Muscle pain/cramp x 
Tingling in limbs x x
E,T irritation x
Tremor x x
AChE normal n.a. n.a.
BChE #n.a. n.a.
PON1 activity ###
P450 activity ""n.a.
Neuropsychology NES screening: normal normal Concentration impaired
MRI Brain Imaging normal normal n.a
Neurophysiology EEG, autonomic testing and conduction velocities
of peripheral nerves normal
EEG normal Skin biopsy: no small fibre neuropathy
n.a.: not assessed; GI: gastrointestinal; SOB: shortness of breath.
AChE: acetylcholinesterase; BChE: butyrylcholinesterase.
NES: neuroevaluation system.
2 G. HAGEMAN ET AL.
signs of cognitive impairment. Cholinergic symptoms in our
cases may be gastro-intestinal complaints (A, B and C), palpi-
tations (C), muscle pain and cramp (B and C) and tremor (B).
However, various delayed neurological conditions have been
reported following OP exposure, after the cholinergic symp-
toms have resolved, including cognitive impairment and
increased neuropsychiatric morbidity [6] and several other
noncholinergic mechanisms of OP toxicity have been pro-
posed to account for these such as oxidative stress, impaired
axonal transport, neuroinflammation, release of the neuro-
transmitter L-glutamate, and altered levels of dopamine and
serotonin [7].
Acetylcholinesterase (AChE) was not found to be inhibited
after a fume event in a study of eleven crew members [8];
however, BChE inhibition has been demonstrated in several
case series and surveys, especially in blood samples obtained
24–48 hours after completing a flight [9]. BChE inhibition is
the standard biological test used for OP monitoring, but
should only be considered as a marker of acute exposure.
BChE levels were measured in Patient A in the first 5 days
after a long flight (Table 3) and were noted to be reduced
on days 1 and 2.
A reduced ability to metabolize OPs due to genetic poly-
morphisms may explain why some individuals report ill health
following exposure to contaminated air whilst others do not.
Paraoxonase 1 (PON-1) and Cytochrome P450 are enzymes
involved in the detoxification of OPs and lower activity
levels are associated with specific genetic polymorphisms.
Blood tests in our three patients showed PON-1 192- and
55-polymorphisms [10] and Cytochrome P450 polymorphisms
were identified in patient A and B [11].
Brain reactive autoantibodies are independent of disease
and are present in the vast majority of human sera [12], but
some auto-antibody profiles appear disease-specific. In our
patients MBP, MAP-2 and GFAP were increased in all three,
whereas S-100ẞwas normal in all. Our findings were consist-
ent with those reported in a study of 34 flight crew mem-
bers in which auto-antibodies against MAP-2, tubulin, MBP,
tau and GFAP were markedly elevated, whereas auto-anti-
bodies against S-100 ẞ(a biomarker for traumatic brain
injury) were (almost) normal, as in our cases [3]. Sera of the
12 healthy controls had no or low levels of circulating auto-
antibodies. Our findings provide objective evidence of dam-
age to the central nervous system, but not of causation.
Whether the autoantibody profile is specific to engine oil
emissions needs to be addressed in future studies.
Acknowledgements
We are grateful to Dr. M.F.A. Mulder, MD and Professor M.B. Abou-Donia
MD, PhD for delivering the results of sera autoantibodies of the patients.
Disclosure statement
No potential conflict of interest was reported by the authors.
Table 3. Results of blood and genetic testing.
Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) patient A
Day after flight AChE (Normal value 26.7–50.9 U/l) BChE (Normal value 2300–7000 U/l)
1 30.7 1189
2 32.5 1799
3 30.2 2138
4 33.1 2154
5 38.8 3106
Auto-antibodies to brain specific proteins, compared to healthy controls (Abou-Donia et al., 2013).
Patient A
a
Patient B Patient C
NFP """n
Tau n "" "
Tubulin "nn
MBP """
MAP-2 """"
GFAP """"
S100-B n n n
Genetic testing: (1) paraoxonase (PON-1) gene (patients A, B and C).
Results Effect
PON-1[M55L] and PON-1[Q192R] polymorphisms reduced ability to metabolise organophosphates
Genetic testing: (2) analysis of cytochrome P450 (patients A and B).
Results Effect
CYP1A12A and CYP 1A2C and F polymorphisms overexpression of the enzymes mediating the conversion of organophosphates to its reactive metabolites.
Methods: Red blood cell AChE and plasma BChE were tested using a portable tester (Securetec). Sera samples of our patients were send to prof. M.B. Abou-
Donia, Durham, North Carolina, to measure immunoglobin (IgG) using Western blotting against brain-specific proteins (Abou-Donia et al, 2013). PON-1 192 and
55 determination was performed by PCR amplification and restriction enzyme digestion. Genotyping assays were used to detect single nucleotide CYP 450
polymorphisms.
n: normal; ": increased; "": markedly increased.
a
In patient A, in addition four serum samples were taken to test again for neuronal and glial auto-antibodies at four different time periods, before, during and
after exposure, and showed a temporal relationship with exposure (3).
CLINICAL TOXICOLOGY 3
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4 G. HAGEMAN ET AL.
... Polimanti et al. (2012) describe genetic variation in the cytochrome P450 superfamily. Hageman et al. (2020aHageman et al. ( , 2020b acknowledged this variability, as well as genetic differences in paraoxonase enzyme (PON-1); when tested, those believed to be symptomatic as a result of exposure were found to possess mutations on one or both. Hageman et al. (2020aHageman et al. ( , 2020b suggest that if an individual were to have a low PON 1 activity and high cytochrome P450 action, they might be up to 4000× more susceptible to OP exposure. ...
... Hageman et al. (2020aHageman et al. ( , 2020b acknowledged this variability, as well as genetic differences in paraoxonase enzyme (PON-1); when tested, those believed to be symptomatic as a result of exposure were found to possess mutations on one or both. Hageman et al. (2020aHageman et al. ( , 2020b suggest that if an individual were to have a low PON 1 activity and high cytochrome P450 action, they might be up to 4000× more susceptible to OP exposure. Additionally, elevated autoantibodies indicative of CNS damage have been identified in the blood of ill flight crew by Abou-Donia et al. (2013) and Abou-Donia and Brahmajothi (2020). ...
... The sensitivity of individuals is also a significant concern. Variations in cytochrome p450 superfamily, PON-1, or BChE enzyme reactivity could play an important role in some passengers' sensitivity (Carletti et al., 2011;Chen et al., 2011;Hageman et al., 2020aHageman et al., , 2020b. ...
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Background Airline crew members report adverse health effects during and after inhalation exposure to engine oil fumes sourced to the air supply system onboard commercial and military aircraft. Most investigations into the causal factors of their reported symptoms focus on specific chemical contaminants in the fumes. The adverse health effects reported in aircrew exposed to the aircraft air supply, bled unfiltered off the engine or Auxiliary Power Unit (APU) may be related to particulate exposures, which are widely known to effect health. While oil contaminates the aircraft air supply, some suggest that this will only occur when there is a bearing seal failure, others document that there is low level oil contamination of the air supply during normal engine operation. This brief pilot study explores whether particulate exposure may be associated with the normal engine/APU and air supply operation and to therefore increase the understanding that UFP exposures may have on crew and passengers. Methods An ultrafine particle counter was utilised by an experienced airline captain in the passenger cabin of four short-haul commercial passenger aircraft. All flights were under 90 min on aircraft from two different carriers ranging from 7 months to 14 years old. Results UFP concentrations showed maximum concentrations ranging from 31,300 to 97,800 particles/cm ³ when APU was selected on as a source of air on the ground and with engine bleed air and the air conditioning packs selected on during the climb. In 2 of the 4 flights the peaks were associated with an engine oil smell. Increases in UFP particle concentrations occurred with changes in engine/APU power and air supply configuration changes. Conclusions This study identified increases in UFP concentrations associated with engine and APU power changes and changes in air supply configuration. These results correlated with times when engine and APU oil seals are known to be less effective, enabling oil leakage to occur. The concentrations reached in the passenger cabins exceeded those taken in other ground-based environments. UFP exposures in aircraft cabins during normal flight indicates there will be health consequences for long serving aircrew and some passengers.
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... In recent decades, numerous reports of the adverse health effects caused by fume and smell events in aircrafts, so-called aerotoxic syndrome, have been published [90][91][92][93][94][95][96][97]. Fume and smell events are rare incidents with unpleasant odours or even visible smoke formation in aircraft cabins. ...
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Aerotoxic syndrome: A new occupational disease caused by contaminated cabin air?
Chapter
  • Jul 2022
The term aerotoxic syndrome has been proposed to describe a constellation of symptoms reported by pilots and cabin crew following exposure to possible (neuro)toxic substances in cabin air. Several organ systems are involved. Potentially toxic chemicals emanate from hydraulic fluids and engine oil and include organophosphate compounds, solvents and carbonmonoxide. Oil contamination in the compressor will result in nanoparticles in bleed air under most operating conditions. Overfilling of oil or faulty seals lead to oil leaks which permit ultrafine particles to cross oil seals. Extremely high temperatures in aircraft engines may alter the composition of the original oil and create new toxic compounds. De-icing fluids and the use of insecticides may also contaminate cabin air. Regulatory authorities estimate fume events (incidental smells, smoke or mist inside an airplane) happen on 0.2–0.5% of flights. Objective evidence of exposure is often lacking and indirect proof in the form of biomarkers is scarce. The underlying mechanisms leading to chronic symptoms, extend beyond cholinesterase inhibition. Individual genetic differences in the ability to metabolize solvents and organophosphates may explain why long-term intermittent low-level exposure causes ill health in some people. We discuss the current evidence for central nervous system injury in aerotoxic syndrome and propose diagnostic criteria to argue for its recognition as occupational disorder. Prospective studies and a proactive attitude of authorities are required. Nano-aerosols as vehicles for toxic compounds should stimulate the development of bleedless aircraft. Until then the “aircraft cabin of the future” should have continuous cabin air monitoring and filter technology to make flying safe for everyone.
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Aerotoxic syndrome: A descriptive epidemiological survey of aircrew exposed to incabin airborne contaminants
Article
Full-text available
  • Aug 2002
The term "aerotoxic syndrome" was proposed in 1999 to describe the association of symptoms observed among flight crew and cabin crew who have been exposed to hydraulic fluid or engine oil vapours or mists. A descriptive epidemiological study was conducted to investigate the health effects of aircrew through a questionnaire mail-out. Most of the respondents (88%) reported that symptoms occurred after exposure to engine oil or hydraulic fluid leaks which caused odours and/ or visible contamination in the cabin. Invariably, aircrew directly attributed their symptoms to exposure to in-cabin airborne contaminants. A comparison between 18 respondents from the United States and the 50 Australian respondents shows significant similarities in reported symptoms. There was sufficient commonality in reported symptoms to conclude a symptom basis for aerotoxic syndrome.
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Human genetic variation of CYP450 superfamily: Analysis of functional diversity in worldwide populations
Article
Full-text available
Aim: The present study aimed to investigate the human genetic diversity of the CYP450 superfamily in order to identify functional interethnic differences and analyze the role of CYP450 enzymes in human adaptation. Materials & methods: A computational analysis of genetic and functional differences of the 57 CYP450 genes was performed using the Human Genome Diversity Project and HapMap data; comprising approximately 1694 individuals belonging to 62 human populations. Results: Twenty-six CYP450 SNPs with F-statistics significantly different than the general distribution were identified. Some showed high differentiation among human populations, suggesting that functional interethnic differences may be present. Indeed, some of these are significantly associated with drug response or disease risk. Furthermore, our data highlighted that TBXAS1 and genes in CYP3A cluster may have a role in some processes of human adaptation. Conclusion: Our study provided an analysis of genetic diversity of CYP450 superfamily, identifying functional differences among ethnic groups and their related clinical phenotypes.
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Cognitive function following exposure to contaminated air on commercial aircraft: A case series of 27 pilots seen for clinical purposes
Article
Full-text available
  • Jul 2009
Background. Cabin air on commercial aircraft is sometimes contaminated with hydraulic fluids, synthetic jet engine oils and combusted or pyrolized materials. The incidence of contaminated air events is hard to quantify as commercial aircraft do not have air quality monitoring systems on board. In the UK, around 350 aircrew have advised their union that they may be suffering physical and psychological ill health following exposure to contaminated air. Design. This paper presents a case series of 27 pilots referred for psychological assessment. The general aim of the assessment was to determine whether pilots show evidence of cognitive impairment and whether this relates to exposure history. Materials and method. All pilots underwent neuropsychological and adult mental health assessment, undertaken by 12 examiners, instructed to search for alternative explanations other than exposure to toxic fumes for any symptoms reported. Results. Pilots reported alarming cognitive failures at work such as being unable to retain or confusing numerical information from Air Traffic Control. Nine pilots were excluded from further analysis because they had a medical or psychiatric condition which might otherwise explain these difficulties. In the remaining 18 pilots, language, perceptual skills and general intellectual ability were preserved, but performance on tests of psychomotor speed, attention and executive functioning was below expected levels. Conclusions. The cognitive deficits identified in this cohort of pilots cannot be attributed to factors such as mood disorder or malingering. However, the evidence available in this study does not enable firm conclusions to be drawn regarding a causal link with contaminated air; the cohort of pilots was self‐selected and only crude indices of exposure were available. Further research is warranted given the scientific uncertainty regarding the health effects of inhalation of heated or pyrolized engine oil.
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Exposure to tri-o-cresyl phosphate in jet airplane passengers
Article
Full-text available
The aircraft cabin and flight deck ventilation are supplied from partially compressed unfiltered bleed air directly from the engine. Worn or defective engine seals can result in the release of engine oil into the cabin air supply. Aircrew and passengers have complained of illness following such "fume events". Adverse health effects are hypothesized to result from exposure to tricresyl phosphate mixed esters, a chemical added to jet engine oil and hydraulic fluid for its anti-wear properties. Our goal was to develop a laboratory test for exposure to tricresyl phosphate. The assay was based on the fact that the active-site serine of butyrylcholinesterase reacts with the active metabolite of tri-o-cresyl phosphate, cresyl saligenin phosphate, to make a stable phosphorylated adduct with an added mass of 80 Da. No other organophosphorus agent makes this adduct in vivo on butyrylcholinesterase. Blood samples from jet airplane passengers were obtained 24-48 h after completing a flight. Butyrylcholinesterase was partially purified from 25 ml serum or plasma, digested with pepsin, enriched for phosphorylated peptides by binding to titanium oxide, and analyzed by mass spectrometry. Of 12 jet airplane passengers tested, 6 were positive for exposure to tri-o-cresyl phosphate that is, they had detectable amounts of the phosphorylated peptide FGEpSAGAAS. The level of exposure was very low. No more than 0.05 to 3% of plasma butyrylcholinesterase was modified. None of the subjects had toxic symptoms. Four of the positive subjects were retested 3 to 7 months following their last airplane trip and were found to be negative for phosphorylated butyrylcholinesterase. In conclusion, this is the first report of an assay that detects exposure to tri-o-cresyl phosphate in jet airplane travelers.
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Cabin air quality – Quantitative comparison of volatile air contaminants at different flight phases during 177 commercial flights
Article
Quantitative assessment of human exposure to semi-volatile organic compounds (SVOC), such as tricresyl phosphates (TCP) that may originate from engine oil contamination of the cabin air, during air travel is challenging due to the technical complexity of the air supply in commercial jet aircraft. Normal flight operations involve reduced air exchange before and during takeoff, which results in increased concentrations of potential cabin air pollutants. During cruise, normal ventilation rates (> 20 h- 1) are reestablished and thus lower pollutant concentrations are also reestablished. This relationship between changes in ventilation rate and associated changes in pollutant concentrations during the departure phase is first de-scribed in the present study, although this effect was found by previous studies that investi-gated distinct flight phases. The perception of so-called "smell events" in cabin air does not necessarily indicate the pres-ence of harmful contaminants and TCP-containing oil mist must be clearly distinguished thereof. Thus, aldehydes, VOCs, and organophosphates such as TCP were investigated. In this paper, the occurrence of TCP contamination in a bleed air free Boeing 787 (B787) aircraft is reported for the first time. The results presented here show that there are TCP sources other than bleed air from leaky engines. Furthermore, exceptional release behavior of TCP suggests that a more detailed classification for engine oil-triggered cabin air contamination (CAC) events is necessary. This study evaluated measurement data from 177 flights that were either commissioned by the EASA or conducted as part of studies with the support of Lufthansa, Condor, and British Airways.
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Acetylcholinesterase and neuropathy target esterase activities in 11 cases of symptomatic flight crew members after fume events
Article
  • Dec 2016
In modern aviation, so-called fume events such as exposure to an unknown mixture of chemicals introduced into the aircraft cabin with bleed air drawn off at the engines may occur. Human exposure may result in (neuro)toxic symptoms described as so-called “aerotoxic syndrome.” Currently, among other agents organophosphates (OP) are regarded as a likely cause of the observed adverse effects. After fume events 11 flight crew members (9 female/2 male; ages 23–58 yr) were admitted for a medical examination within 5 d post exposure. Individual acetylcholinesterase (AChE) and neuropathy target esterase (NTE) activities were determined. Anamnesis and clinical findings confirmed prominent symptoms of an intoxication, including headache, cognitive difficulties, and neurological disorders, among others. Patient AChE activities ranged from 37 to 50 U/g hemoglobin (reference values: 26.7–50.9 U/g hemoglobin). Ten individuals showed NTE activities ranging from 3.14 to 6.3 nmol phenyl valerate/(min × mg protein) (reference values: 3.01–24), with one patient exhibiting low NTE activity of 1.4. Biochemical effect monitoring was applied to encompass a broad range of AChE-inhibiting compounds such as OP, carbamates, and isocyanates, or to detect inhibition of NTE. The measured AChE activities indicated a subordinate contribution of OP or related compounds to the observed symptoms. All noted NTE activities were clustered at low levels. Our data suggest a likely inhibition of NTE activities in patients after fume events, which warrants further investigation. The observed symptoms may be linked to known chemical compounds in fume events, and it is not possible to infer a direct correlation between manifestations and AChE -inhibiting compounds at this time.
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Organophosphate Pesticide exposure and neurodegeneration
Article
  • Oct 2015
Organophosphate pesticides (OPs) are used extensively throughout the world. The main sources of contamination for humans are dietary ingestion and occupational exposures. The major concerns related to OP exposure are delayed effects following high level exposures as well as the impact of low level exposures during the lifespan which are suggested to be a risk factor for nervous system chronic diseases. Both high and low level exposures may have a particularly high impact in population subgroups such as aged or genetically vulnerable populations. Apart from the principle action of OPs which involves inhibition of the acetylcholinesterase (AChE) enzyme, several molecular targets, such as hormones; neurotransmitters; neurotrophic factors; enzymes related to the metabolism of beta amyloid protein as well as inflammatory changes have been identified for OP compounds. Here we review the main neurological and/or cognitive deficits described and the experimental and epidemiological relationships found between pesticide exposure and Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis (ALS) diseases. This report also focuses on possible individual differences making groups resilient or vulnerable to these toxicants. A critical discussion of the evidence obtained from experimental models and possible sources of bias in epidemiological studies is included. In particular this review aims to discuss common targets and pathways identified which may underlie the functional deficits associated with both pesticide exposure and neurodegeneration.
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Autoantibodies to Nervous System-Specific Proteins Are Elevated in Sera of Flight Crew Members: Biomarkers for Nervous System Injury
Article
  • Mar 2013
This descriptive study reports the results of assays performed to detect circulating autoantibodies in a panel of 7 proteins associated with the nervous system (NS) in sera of 12 healthy controls and a group of 34 flight crew members including both pilots and attendants who experienced adverse effects after exposure to air emissions sourced to the ventilation system in their aircrafts and subsequently sought medical attention. The proteins selected represent various types of proteins present in nerve cells that are affected by neuronal degeneration. In the sera samples from flight crew members and healthy controls, immunoglobin (IgG) was measured using Western blotting against neurofilament triplet proteins (NFP), tubulin, microtubule-associated tau proteins (tau), microtubule-associated protein-2 (MAP-2), myelin basic protein (MBP), glial fibrillary acidic protein (GFAP), and glial S100B protein. Significant elevation in levels of circulating IgG-class autoantibodies in flight crew members was found. A symptom-free pilot was sampled before symptoms and then again afterward. This pilot developed clinical problems after flying for 45 h in 10 d. Significant increases in autoantibodies were noted to most of the tested proteins in the serum of this pilot after exposure to air emissions. The levels of autoantibodies rose with worsening of his condition compared to the serum sample collected prior to exposure. After cessation of flying for a year, this pilot's clinical condition improved, and eventually he recovered and his serum autoantibodies against nervous system proteins decreased. The case study with this pilot demonstrates a temporal relationship between exposure to air emissions, clinical condition, and level of serum autoantibodies to nervous system-specific proteins. Overall, these results suggest the possible development of neuronal injury and gliosis in flight crew members anecdotally exposed to cabin air emissions containing organophosphates. Thus, increased circulating serum autoantibodies resulting from neuronal damage may be used as biomarkers for chemical-induced CNS injury. The authors thank all of the participants who volunteered to take part in this case study. The technical work of Dr. Hagir B. Suliman and the art work of Sheref M. Abou-Donia are appreciated. This study was supported in part by the Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
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Functional Consequences of Repeated Organophosphate Exposure: Potential Non-Cholinergic Mechanisms
Article
  • Mar 2012
The class of chemicals known as the "organophosphates" (OPs) comprises many of the most common agricultural and commercial pesticides that are used worldwide as well as the highly toxic chemical warfare agents. The mechanism of the acute toxicity of OPs in both target and non-target organisms is primarily attributed to inhibitory actions on various forms of cholinesterase leading to excessive peripheral and central cholinergic activity. However, there is now substantial evidence that this canonical (cholinesterase-based) mechanism cannot alone account for the wide-variety of adverse consequences of OP exposure that have been described, especially those associated with repeated exposures to levels that produce no overt signs of acute toxicity. This type of exposure has been associated with prolonged impairments in attention, memory, and other domains of cognition, as well as chronic illnesses where these symptoms are manifested (e.g., Gulf War Illness, Alzheimer's disease). Due to their highly reactive nature, it is not surprising that OPs might alter the function of a number of enzymes and proteins (in addition to cholinesterase). However, the wide variety of long-term neuropsychiatric symptoms that have been associated with OPs suggests that some basic or fundamental neuronal process was adversely affected during the exposure period. The purpose of this review is to discuss several non-cholinesterase targets of OPs that might affect such fundamental processes and includes cytoskeletal and motor proteins involved in axonal transport, neurotrophins and their receptors, and mitochondria (especially their morphology and movement in axons). Potential therapeutic implications of these OP interactions are also discussed.
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