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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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Three patients with probable aerotoxic syndrome
, T. M. Pal
, J. Nihom
, S. J. MackenzieRoss
and M. van den Berg
Medical Spectrum Twente, Hospital Enschede, Enschede, the Netherlands;
Occupational Health Physician n.p, Lelystad, the Netherlands;
Research Department of Clinical, Educational and Health Psychology, University College London, London, UK;
Institute of Risk Assessment
Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
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.
Received 16 January 2019
Revised 25 April 2019
Accepted 2 May 2019
Published online 15 May
syndrome; cabin crew;
nated cabin air
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
. 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 . 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.
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 . 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
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.
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 .
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 . 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-
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 . 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
Chest tightness xx
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  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
Acetylcholinesterase (AChE) was not found to be inhibited
after a fume event in a study of eleven crew members ;
however, BChE inhibition has been demonstrated in several
case series and surveys, especially in blood samples obtained
24–48 hours after completing a flight . 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  and Cytochrome P450 polymorphisms
were identified in patient A and B .
Brain reactive autoantibodies are independent of disease
and are present in the vast majority of human sera , 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 . 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.
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.
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 B Patient C
Tau n "" "
S100-B n n n
Genetic testing: (1) paraoxonase (PON-1) gene (patients A, B and C).
PON-1[M55L] and PON-1[Q192R] polymorphisms reduced ability to metabolise organophosphates
Genetic testing: (2) analysis of cytochrome P450 (patients A and B).
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
n: normal; ": increased; "": markedly increased.
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).
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