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Aerotoxic syndrome, discussion of possible diagnostic criteria

Introduction:

The term aerotoxic syndrome (ATS) was proposed 20 years ago to describe a constellation
of symptoms reported by pilots and cabin crew following exposure to hydraulic fluids, engine oil,
and pyrolysis products during flight. Hydraulic fluids and engine oil contain a large number of potentially
toxic chemicals, including various organophosphate compounds (OPCs). However, ATS is not yet
recognised as a valid diagnosis in aviation or general medicine, because the incidence and aetiology
continues to be debated.

Discussion:

Early studies report findings from symptom surveys or cognitive assessments of small
samples of self-selected aircrew, but objective measures of exposure were lacking. Over the last decade,
researchers have used more sophisticated techniques to measure exposure, such as on board
monitoring studies and biomarkers of exposure (e.g., reduced levels of serum butyrylcholinesterases
[BChE]) and more sophisticated techniques to detect nervous system injuries such as fMRI and autoantibody
testing. Consideration has also been given to inter-individual differences in the ability to
metabolise certain chemical compounds as a result of genetic polymorphisms and exclusion of other
potential causes of ill health.

Conclusions:

We discuss factors which suggest a diagnosis of probable ATS; recommend an assessment
protocol which incorporates the aforementioned techniques; and propose diagnostic criteria for
probable ATS, based on our previously reported findings in aircrew and the results of recent studies.

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AUTOANTIBODIES TO NERVOUS SYSTEM-SPECIFIC PROTEINS ARE ELEVATED IN SERA OF FLIGHT CREW MEMBERS: BIOMARKERS FOR NERVOUS SYSTEM INJURY

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.

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Symptomatische Crewmitglieder nach inhalativer Intoxikation durch kontaminierte
Kabinenluft

Die Luft im Innenraum von Flugzeugen ist im Normalfall von guter Qualität und unterliegt den Anforderungen und
Kontrollen wie die Luft an anderen Innenraumarbeitsplätzen wie beispielsweise Büroarbeitsplätzen. Infolge
unbeabsichtigter technischer Störungen kann es aber zu teilweise auch unangenehmen, geruchlich bemerkbaren
Verunreinigungen kommen. Als Ursache werden am ehesten unbeabsichtigte Verunreinigungen durch Bestandteile aus
Ölen, Hydraulikflüssigkeit oder ähnlichem über die sogenannte Zapfluft diskutiert. Im Zusammenhang mit fume events treten
auch immer wieder Gesundheitsbeschwerden bei Besatzungen und/oder Passagieren auf.

Material und Methode:

In einer retrospektiven Aktenauswertung von Patient/innen unserer Spezialsprechstunde „fume event“, bei denen wir eine
systematische Erfassung der Anamnese durchführen konnten, gingen Symptomatik und die Ergebnisse der (D-ärztlichen)
Erstdiagnostik in die Auswertung ein.

Ergebnis:

Bei 27 Arbeitsunfällen (17 Flugbegleiter/innen (3 männlich, 14 weiblich); 10 Piloten) fanden sich Symptome wie kognitive
Einschränkungen (n=25; 93%), Kopfschmerz (n=24; 89 %), Paraesthesien (n=23; 85%), gastrointestinale Symptomatik
(n=20; 74%), Beschwerden an Schleimhäuten und/oder Atemwegen bzw.(n=21; 78%) und kardiale Beschwerden
(n=13, 48 %). Die Erstversorgung war in 63% beim D-Arzt erfolgt, in erster Linie in Form orientierender Laborwerte
(Leber, Niere, Blutbild), die bei allen weitestgehend unauffällig waren. Blutgasanalysen wurden nur in 26% der Fälle
durchgeführt, nur in 24% der Unfälle mit Atemwegssymptomatik erfolgte eine atemwegsorientierte
Diagnostik. Ebenso wenig erfolgte eine Diagnostik zur Objektivierung der kognitiven Symptomatik (0%), obgleich
diese das Symptomspektrum dominierte.

Schlussfolgerung:

Bei Beschwerden im Zusammenhang mit fume events dominierten neuro- bzw. encephalotoxische sowie lokalirritative
Beschwerden insbesondere an den Atemwegen das Symptomspektrum. Nur ein Teil der Atemwegssymptomatik
wurde in der Erstdiagnostik berücksichtigt, die Dokumentation der neurotoxischen und kardialen Symptomatik blieb
weitestgehend unberücksichtigt. Dies stellt Schwierigkeiten für die Anerkennung der Beschwerden als Folge des Arbeitsunfalls
dar. Insgesamt empfiehlt sich eine Ausweitung des aktuell empfohlenen Vorgehens bei fume events, wie es beispielsweise
von der Berufsgenossenschaft Verkehr (Medizinisches Standardverfahren nach Fume-Events) oder den verschiedenen
Fluggesellschaften vorgeschlagen wird.

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EXPOSURE TO AIRCRAFT BLEED AIR CONTAMINANTS AMONG AIRLINE WORKERS

The outside air supplied to the cabin/flight deck on commercial aircraft (“bleed air”)
may sometimes be contaminated with pyrolyzed engine oil and/or hydraulic fluid. As a result of
this contamination, airline workers may develop acute and/or chronic health effects and seek
attention from health care providers. This document provides information about the health
effects that may result after exposure to aircraft bleed air contaminants, and makes
recommendations regarding treatment methods. The information in this document is largely
based on information that has been published in the medical and scientific literature, and also
relies on the clinical experience of one of the authors (Robert Harrison, MD, MPH) who has
diagnosed and treated airline workers with contaminated bleed air exposure. A more detailed
discussion on the toxicity of tricresylphosphate (TCP) engine oil additives can be found in
Attachment 1. For more information, web links to additional resources and detailed references
are provided at the end of the document.

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Autoantibody markers of neural degeneration are associated with post-mortem
histopathological alterations of a neurologically injured pilot

There are numerous concerns regarding the neurotoxicity of contaminated air inside pressurized aircraft. Neurological symptoms have been seen in many aircrew members who have reportedly been exposed to the breathable, yet potentially toxic, air in airliners. Symptoms allegedly contracted by aircrew and passengers are thought to be caused by a single large exposure or repetitive cumulative low-level exposures to toxic chemicals in the airliner internal air. Genetic variation plays a rôle. We report here the case of a 43-year old airline pilot who presented with neurological deficits and other symptoms. The pilot died without regaining good health. In vivo blood had been collected ante mortem. Analysis of the serum confirmed grossly elevated levels of serum autoantibody biomarkers for neuronal cell degeneration compared with a control group. At autopsy, various tissues underwent histopathological assessment. Brain and spinal tissues exhibited axonal degeneration and demyelination. Peripheral nerves showed T-lymphocyte infiltration and demyelination.
T-lymphocytes had infiltrated the heart muscle tissue. The post-mortem tests and pathological examination of the nervous system confirmed the autoantibody biomarker results. Differential diagnosis showed that the work environment, clinical condition, histopathology and serum biomarkers for nervous system injury are consistent with organophosphate-induced neurotoxicity. The results also indicated that the inferred exposure to organophosphates sensitized the nervous system and heart tissue towards further injury.

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Three patients with probable aerotoxic syndrome

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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Histo-pathological results of four post mortem candidates.

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EVALUATION OF SAMPLES THROUGH ENVIRONMENTAL SCANNING ELECTRON MICROSCOPY INVESTIGATION AND AN X-RAY MICRO- ANALYSIS

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