The Aetiology of 'Aerotoxic Syndrome'- A Toxico- Pathological Viewpoint-Juniper Publishers
Open Access Journal of Toxicology
Background
The term 'aerotoxic syndrome' was coined in 2000 [1]
to describe a collection of predominantly neurological and respiratory
signs and symptoms found in some commercial aircrew, which includes
pilots and cabin crew. From the 1950's, aircraft were redesigned to
provide pressurized cabin air directly from the compressor stage of the
engine, known as bleed air. This allowed for the fuel consuming turbo
compressors used prior to that date to be dispensed with. However, it
also led to the exposure of aircrew and passengers to fugitive emissions
from aircraft engines. This bleed air remains, to date, supplied to the
cabin unfiltered.
Gas turbine engines require the use of vapors-phase
lubricants, including additives, which can withstand the extremely high
operating temperatures and pressures found in normal use. The most
widely used anti-wear additive is tri- cresylphosphate (TCP), an
organophosphate compound which is neuro toxic. TCP used in gas turbine
lubricating oils is not pure but comes as a technical grade complex
mixture of isomers and other associated triaryl phosphate (TAP)
compounds. The complexity of this mixture is further enhanced by an
ester base stock, amine antioxidants, proprietary ingredients and the
addition of pyrolosis products, as the oil ages through use.
There are two main exposure scenarios:
1. acute higher dose 'fume events’ where there is
generally only a detectable odour and, on occasion, a visible haze.
These are associated with acute irritation of mucosa, primarily of the
respiratory system, eye irritation, breathing problems and nausea. Acute
neurological /neuro behavioral side effects have also been reported,
ranging from mild headache, cognitive problems, dizziness to
incapacitation.
2. chronic repeated low-dose exposure of aircrew on a
day to day basis to a complex mixture of fugitive jet engine emissions.
The current design of the majority of commercial airliners guarantees
this continual background exposure because all oil seals 'weep' small
amounts of lubricant in normal operation [2].
The exposure times can amount cumulatively to thousands of hours per
individual. Frequent flyer passengers would also accumulate large
numbers of hours of exposure, though not to the same extent as
professional aircrew. The symptoms reported are predominantly
neurological and respiratory and tend to be diffuse in nature. They
include inability to concentrate, memory problems, breathing problems,
headache, fatigue, numbness, tingling, confusion, dizziness,
cardiovascular effects and performance decrement. These symptoms setting
out a clear pattern of acute and longer-term effects, in many cases
supported by medical findings and diagnoses, have been reviewed recently
by Michaelis, Burdon and Howard [3].
Currently:
1. On the one hand there are a number of aircrew who
have been acutely impaired in flight incidents, with others becoming
chronically ill, many of whom have had to retire as a result. This is
acknowledged by many aircrew organizations and some doctors and
scientists.
2. On the other hand, arguments are put forward that
the levels of contaminants in aircraft cabin air are too low to be able
to cause the illnesses complained of, which are largely dismissed as
being psychological/psychiatric in nature, common in the general
population or, alternatively, as hyperventilation. This opposed position
is acknowledged by a number of airline operators, aircraft
manufacturers, some scientists and regulatory and airline industry
bodies. It is that conundrum which this paper addresses.
Aetiological Considerations
There is an enormous literature on the acute toxicity
of
organo-phosphate pesticides and nerve gas agents through
acetyl-cholinesterase inhibition, which will already be familiar to the
readership. This aspect was reviewed by the UK Committee on Toxicity in
the context of cabin air quality [4].
They concluded, considering only the one isomer tri-orthocresyl
phosphate (TOCP), that it would not cause organo-phosphate delayed
neuropathy (OPIDN), which is acknowledged to be a sequel of high dose
exposure involving acetyl-cholinesterase inhibition. However, OPIDN is
definitely not the clinical picture observed in Aerotoxic Syndrome [3].
The effect of repeated low dose OP exposure has been reviewed by Terry [5].
He describes a number of mechanisms by which OPs can cause harm at
exposure levels below those required to cause lowering of acetylcholine
esterase. These include covalent binding of OPs to tyrosine and lysine
residues, which suggests that numerous proteins can be modified by OPs.
In addition, the mechanisms of oxidative stress and neuro inflammation
and the known OP targets of motor proteins, neuronal cytoskeleton,
axonal transport, neurotrophins and mitochondria. This type of exposure
has been associated with prolonged impairments in attention, memory, and
other domains of cognition, as well as some chronic illnesses where
these symptoms are manifested, precisely the spectrum of symptoms
reported for air crew by Michaelis et al. [3]. A more recent paper by Terry's group [6],
detected antero grade axonal transport deficits associated with the
oxon metabolite of chlorpyrifos at 0.1nM in vitro, in cultured embryonic
rat neurons, a very low concentration.
The clinical picture is further complicated by at least three factors:
1. the complexity of the mixture to which air crew
are being exposed. Some work has been done on the enhancement of OP
toxicity in mixtures [7] and it is clear that the traditional 'one chemical at a time' toxicology will not suffice.
2. The wide variability between individuals to
metabolize and detoxify OP compounds. A good example of this is provided
by studies on British farm workers who developed 'dippers flu' as a
consequence of handling OP sheep dips. A paper by Cherry et al showed
that R allele at position 192 on PON1 was associated with a higher
probability of illness from dippers flu’s [8].
3. Low dose repeated exposure to OPs has been
demonstrated in vitro to increase the vulnerability of neurons to a
subsequent high dose event [9].
Thus the prospect of an 'acute-on-chronic' mechanism must be
considered, where those cumulatively pre-exposed for hundreds or
thousands of hours would be more vulnerable to harm from a subsequent
high dose fume event.
Discussion
There is no dispute about the fact that fugitive jet
engine emissions are found in aircraft cabin bleed air. The recent
detailed study investigating the pattern of effects, findings and
diagnoses, was supported by maintenance investigations confirming oil
fume leakage in 87% of the identified incident cases with suspected oil
contamination in another 7% [3].
The difficulty in maintenance investigations identifying the oil
leakage sources has been acknowledged within the aviation industry,
along with recognition [10]
of permanent low-level oil leakage with additional discontinuous fume
events sourced to engine oil leakage. However, there is debate about the
significance of this. When there is a differential susceptibility of
various exposure groups to harm then we have to seek an explanation,
this is one of the tenets of occupational medicine. What is observed is
an increased vulnerability of aircrew, when compared with passengers, to
the set of signs and symptoms collectively known as aero toxic
syndrome. This is seen after reported acute fume events as well as in
the absence of high dose events. An Airbus A380 diverted into Vancouver
due to 'toxic gas type fumes', with 25 crew taken to hospital [11].
Fumes on a Boeing 767 with a confirmed oil leak led to crews being
hospitalized with 5 of the 6 crew, including the 2 pilots, no longer
able to fly [12]. Other reports commonly refer to chronic lower-dose exposures [13].
Following the logic of Sir Bradford Hill in
considering causation: Temporality-Aero-toxic syndrome was never
reported prior to the introduction of engine bleed air pressurization
systems, though it was detected soon afterwards [14];
it is biologically plausible that the mixture of chemicals in bleed
air, many of which are known neuro-toxins, could lead to the symptoms
described; animal experimental data supports the diagnosis [5]; there is epidemiological evidence [3]
to support the causation argument. Specificity -The fact that the
symptomatology is rather non-specific is seized upon to explain clinical
findings as being of a psychological/psychiatric nature, rather than an
organic illness. However, consistency of the pattern of symptoms
exists, supporting an organic aetiology [3].
On the balance of probabilities, a causal link
between repeated exposure to a low dose mixture of fugitive turbine
engine oil emissions, based on current scientific knowledge, seems more
likely than not and, in our opinion therefore, to be responsible for
aero-toxic syndrome.
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