Inappropriate Use of Risk Assessment in
Addressing Health Hazards Posed by Civil
Aircraft Cabin Air
C V Howard*
Centre for Molecular Biosciences, University of Ulster, UK
Submission: February 12, 2020; Published: February 27, 2020
*Corresponding author: C V Howard, Centre for Molecular Biosciences, University of Ulster, UK, Email: email@example.com
How to cite this article: C V Howard. Inappropriate Use of Risk Assessment in Addressing Health Hazards Posed by Civil Aircraft Cabin Air. Open Acc J of Toxicol. 2020; 4(2):555634.
Over decades, the airline industry has published considerable documentation on the potential for inhalation exposure to organophosphates and other toxins sourced to engine oil fumes supplied by “bleed air” systems, which are used on most commercial and military aircraft. Case studies on the subsequent development of neurological and other symptoms reported by crewmembers have also been widely documented. However, airline industry reviews tend to define toxicity of engine oil fumes according to a single toxicological endpoint - Organo Phosphate Induced Delayed Neuropathy (OPIDN) – which is acknowledged to be the result of a very high dose of exposure to a specific chemical, Tri-Ortho Cresyl Phosphate (TOCP). Industry reviews typically argue that the low levels of TOCP in aviation engine oils justifies the safety of continuing to use unfiltered engine bleed air to ventilate civil and military aircraft cabins. In fact, this approach ignores the routine presence and toxicity of a complex mixture of OPs in oil fumes supplied by engine bleed air systems and ignores the type of neurological symptoms that crews report (i.e., not OPIDN). The industry approach also ignores the scientific literature on repeated low-dose exposure to OPs over extended periods (particularly relevant for airline crewmembers) and the variable susceptibility of individuals to toxicological damage. This paper reviews the above-mentioned studies and presents the scientific literature that should be considered to make a realistic risk assessment of the hazards of aircraft engine bleed air.
Lubrication oils in gas turbine aero engines require the presence of synthetic lubricants, which include additives, to minimize engine wear at the high temperatures encountered in normal operation [1–3]. The majority of the lubricants utilised in turbine engines add cresyl phosphates, generally termed Tricresyl Phosphate (TCP) at approximately 3%. These cresyl phosphates are organophosphates (OPs) and are toxic [3,4]. TCP / cresyl phosphates contains ortho-, para- and meta- isomers, which can be mono-, di-, or tri- cresyl phosphates as shown in (Figure 1). TCP contains 10 isomers, as shown in (Figure 2). However there are in addition many other compounds in the cresyl phosphate TCP commercial formulations. The TCP commercial formulations utilised consist of a complex mixture of cresols, xylenols and phenols, not just the 10 generally referenced TCP isomers shown in (Figure 1,2) [3–5]. These are generally referred to as Triaryl Phosphates (TAP). This then becomes further complicated by the production of pyrolysis breakdown molecules as the oil ages
during use [2,4,6,7]. Oil utilised in turbine engines is consumed in normal engine operation and a small proportion of this used oil migrates over oil seals used within the engine [8-10]. All current pressurised commercial aircraft, with the exception of the Boing 787, use engine bleed air to ventilate and pressurise the cockpit and the cabin. Because the engine bleed air take-off port is aft of the front engine bearings, fugitive emissions from the engine bearing chambers escape into the cabin breathing air via the oil seals [11,12]. Lower levels of oil can migrate past the seals during transient engine power changes, at low power settings and with changes in air supply configurations as part of normal engine operation. Far less frequently, events such as oil overfill or oil seal failure conditions may occur, leading to higher dose exposure to engine oil fumes. Both scenarios are referred to as ‘fume events’, with the latter scenarios possibly leading to a visible haze in the cabin. However, there is evidence that there is chronic continual low-dose exposure of air-crew and passengers to fugitive engine emissions during normal flying conditions
The toxicity of tricresyl phosphate first came to light in the
‘Ginger Jake’ scandal in the 1920s. Jamaican Ginger was a medicine
(also known as Jake). Because of a price increase of castor oil, one
of the constituents, the manufacturer substituted it with Tri-Ortho
Cresyl Phosphate (TOCP). Consumers of Ginger Jake received
very high doses of TOCP. This proved to be neuro-toxic and caused
paralysis, part of a syndrome that has subsequently become known
as Organo Phosphate Induced Delayed Neuropathy (OPIDN).
Subsequent considerations of the toxicity of cresyl phosphates in
aircraft cabin air have tended to concentrate solely on the TOCP as
the toxic agent and singly on the toxicological endpoint of OPIDN.
This approach ignores a large body of science which considers
the toxicity of other cresyl phosphate congeners [4,14–20] and
toxicological endpoints far more sensitive than OPIDN [21–25]. A
critique of this approach in the consideration of aircraft cabin air
safety is the motive for writing this paper.
If we solely consider the Ortho-Cresyl Phosphate (OCP)
isomers, there are mono- (MOCP), di-(DOCP) and tri- (TOCP)
ortho-isomers present in jet engine oils. TOCP is said to be at
very low levels, however the mono ortho & di-ortho isomers of cresyl phosphate have been generally ignored in toxicological
assessments and are present at higher concentrations.
MOCP is 10 x more toxic than TOCP [3,17,26,27]
DOCP is 5 x more toxic than TOCP [3,17,26,27]
The technical mixture of the commercial formulation of TCP
used in the most widely used engine oil, Mobil Jet Oil II contains
Ortho TCP content in the oils with TCP at 3% in oils. The
following was published in 2001 conference proceedings
in Australia by Winder & Balouet . Therefore, by solely
concentrating on TOCP in deliberating the toxicity of oil in fugitive
jet engine fumes, the toxicity of the ortho-isomers in cresyl
phosphate is being underestimated by about 6 million-fold, as
independently determined by Winder and Balouet. To this the
toxicity of the meta and para isomers of cresyl phosphate would
need to be added alongside the other (generally unspecified)
impurities present in the technical mixture and, additionally, the
pyrolysis products which appear as the oil ages in use (Table 2).
a) Hazard identification – which requires insight into the
system or process under scrutiny.
b) Hazard assessment – which can only be performed on
hazards that have been considered, requires the application
of scientific experimentation (e.g. toxicology) and is therefore
costly and time consuming
c) Exposure assessment - is required when human
exposure to toxic substances is being considered and requires further scientific investigation (e.g. measuring contamination
levels). It can be expensive to perform adequately. The route of
entry of the toxicant(s) is critical to the exposure assessment.
d) Risk assessment – Finally, the information collected
in steps [1–3] can be combined into a risk assessment. The
validity of this final step is totally reliant on the rigour and
completeness of the earlier steps. Incorrect conclusions can
be caused by not choosing the most sensitive toxicological
endpoint, not considering the appropriate route of entry of
the toxicant into the body, failure to address the problem of
There is a pattern in the following examples of toxicological
assessment of the health risks from inhalation of aircraft cabin air.
The majority only consider TOCP as the sole toxic substance. They
all adopt OPIDN as the toxicological endpoint, which is known to
require a very high dosage. The research literature concerning
OPIDN is all based on ingestion studies and not on inhalational
exposure. The publications all consider high dose acute effects
only, there is no mention of chronic repeated low dose exposure
to cabin fumes. There is no mention of the extensive scientific
literature on the mechanisms of low-dose OP exposure toxicity.
These are representative of the majority of the studies in (Table 3). The CAA Report (2004) (33) on page 52 states. "An average man would therefore be able to ingest 7 metric tonnes of pyrolysed oil per day for 74 days without effect." Setting aside the ridiculous nature of this statement, it should be noted that it was made from the following simple linear extrapolation: "Studies of the chronic toxicity of TOCP have shown that the most sensitive species known (chickens) can be fed 20 mg.kg-1(body weight; BW).day-1 without showing signs of OPIDN. Signs of toxicity were observed at 60 mg.kg-1(BW).day-1. Given the TCP content of the pyrolysed oil supplied to Dstl by QQ Pyestock and used in the previous analysis of oil pyrolysate as 0.19 µg.g-1 oil (table1, Appendix A) Assuming all the TCP has the same toxicity as TOCP (over estimating the toxicity by 100 times). TCP content of oil 0.19 µg.g-1 ≡ 0.19 mg.kg-1 oil ≡ 0.19 x 10-3 g.Kg-1 (oil) dosage without OPIDN 20 mg.Kg-1.day-1 ≡ 20 x 10-3 g.Kg-1 (BW).day-1 Therefore, oral dosage of oil without OPIDN effect is given by 20 x 10-3 g.Kg-1(oil).day-1/ 0.19 x 10-3 g.Kg-1(BW).day-1 = 105 Kg(oil).Kg-1(BW).day-1 Assuming a 70 kg body weight for the average human subject. The total dosage that would not induce OPIDN would be 105 x 70 = 7350 Kg.day-1. An average man would therefore be able to ingest 7 metric tonnes
of pyrolysed oil per day for 74 days without effect."
Note that the study was based on an oral dosage study using
chickens. Exposure to air crew is by inhalation, not ingestion, and
therefore this represents a failure of hazard characterisation. All
TCPs are assumed to be of the same toxicity as TOCP. This ignores
the MOCP and DOCP isomers, which are more toxic and more
abundant in jet engine oil, a failure of exposure assessment. The
toxicological endpoint assessed is OPIDN, representing a failure of
hazard identification. Therefore, this approach fails on all three of
the preliminary steps of Risk Assessment.
A further point of interest is that in this CAA Report (2004)
is information about the amount of TOCP found on the sooty
deposits recovered from ventilation ducts on civil aircraft. In
(Table 1) of Appendix A of the report it is shown that, on a weight
basis, the TOCP content of the deposits is hundreds of times higher
than is found in the oil. The majority of particles passing through
such ventilation ducts, during the lifetime of the aircraft, will not
adhere to the duct walls but pass through into the breathing air
in the cabin. The role of OPs adhering to respirable particles
in the aetiology of Aerotoxic Syndrome has been discussed by
Howard et al . The main point is that such adsorbed OPs will
not be detected if the concentration of OPs in air is the only thing
measured. The CAA report makes no mention or provision in their
risk assessment of this further cause of exposure underestimation,
despite their inclusion of the evidence of (Table 1) in Appendix A.
Dr Pleus  presents a risk assessment based on the
oral dosage hen studies of Freudenthal et al.  in which they
administered oils 0.5%, 1%, or 3% TCP (with 0.4% ortho-isomer)
by gavage 5 days per week for 10 weeks .
Using the toxicological endpoint of OPIDN, he directly
extrapolates from a LOAEL in hens of 20 mg/kg TCP. It should be
noted that in the hens in this dosage group, there was an over 60%
inhibition of Neuropathy Target Esterase (NTE), indicating very
high dosing. This oral dosage LOAEL finding is then subjected to
a direct linear scaling to an equivalent human inhalational dose,
taking into account body weight, breathing rate etc. Dr Pleus applies
none of the usual Uncertainty Factors (UFs) commonly applied in
regulatory toxicology (typically 10 for species variability, 10 for
human intra-species variability). This simplistic linear transform
leads Dr Pleus to calculate and opine that there would need to be
7,000 mg of oil per cubic metre of cabin air for there to be any risk
of OPIDN in air crew. A graphic is then presented of the Seattle
tower with an LOAEL of oil of 7,000 mg/m3 equating to a column
of oil reaching the top of the tower, while the oil odour threshold
is <0.45mg/m3 and a visible oil haze is assumed to occur at 7mg/
m3 [35,37], leading to much smaller columns of oil in the graphic.
This is all a total irrelevance, as OPIDN simply doesn’t occur.
It is widely taught in undergraduate toxicology courses that
ingestion of a toxic substance is almost invariably less harmful
than if exposure is by inhalation. There are several reasons for
this. The uptake from the alimentary tract is slower than by
inhalation. Any toxin that is assimilated across the intestinal
wall is taken to the liver by the portal vein. This keeps the initial
bolus of toxin away from the systemic circulation. The liver is the
principal detoxification organ in the body where both Phase 1
and Phase 2 (conjugation) bio-transformations take place. This
makes the toxic substance more soluble and therefore more likely
to be excreted by the kidney. This all leads to a lower sustained
concentration of toxin. Not all orally administered toxin is usually
assimilated and some will pass out with the faeces. The following
US EPA document summarises this very well .
“The only reliable way to characterize inhalation toxicity and
to quantify inhalation risk is through the use of inhalation toxicity
studies. Chemicals tend to be more toxic by the inhalation route
than by the oral route due to rapid absorption and distribution,
bypassing of the liver’s metabolic protection (portal circulation),
and potentially serious portal-of-entry effects, such as irritation,
edema, cellular transformation, degeneration, and necrosis. An
inhalation risk assessment that is based on oral data generally
underestimates the inhalation risk because it cannot account for
Inhalational toxicology usually makes the conservative
assumption that 100% of the inhaled dose is assimilated. Once
across the blood/air barrier the toxic substance is in the systemic
circulation with direct access to the vital organs without the
chance of being detoxified in the liver. This is called the ‘First Pass’
effect. Therefore, Dr Pleus’s approach represents a clear failure of
As with most of the above studies, the assumption of
the toxicological endpoint of OPIDN is a failure of hazard
characterisation. None of the published evidence on Aerotoxic Syndrome [10,13,45] describes anything like OPIDN and indeed it
is safe to say that OPIDN is not seen in air crew. There is a different
set of signs and symptoms that are happening at repeated low
dose exposures. While OPIDN is associated with changes in
cholinesterase levels, the chronic low dose effects in Aerotoxic
Syndrome are not [21,25].
De Ree  takes a similar approach. The 2nd paragraph
of Section 4 contains the core of the risk assessment:“Based
on the detection limit of ToCP (0.5 ng/m3) maximum uptake via
inhalation with a 100% bioavailability would amount up to 0.02
ng/kg body weight per day for a crew member of 70 kg (Step 1),
(Figure 2). This level of exposure was compared with the available
lowest No-Observed Adverse Effect Level (NOAEL) of ToCP that
was established in chickens and amounts to 1.25 mg/kg/ d after a
repeated daily oral dose for 90 days (Craig and Barth) . With
respect to toxicological effects of ToCP it should be noted that
NOAELs and Lowest Observed Adverse Effect Levels (LOAELs) were
determined for two animal species; chicken and cat (reviewed in
Craig and Barth, ; Johannsen, 1977; Ehrich and Jortner, .
For the model, 1 mg/kg body weight per day was used as a NOAEL.
It is recognized that the NOAELs and LOAELs have been obtained
from toxicity studies done several decades ago that focused
exclusively on major clinical symptoms, such as neuropathology,
and not more recently developed neurobehavioral tests. More subtle
neurobehavioral changes are usually seen at lower dose levels than
those associated with neuropathology. Therefore, an Uncertainty
Factor (UF) of 5 was applied to the selected NOAEL. The combined
toxicity studies with two non-rodent animal species – chicken and
cat – indicate a rather close similarity in NOAELs and LOAELs for
ToCP. From a neurotoxicity point of view these two species are
also considered to represent the human sensitivity rather well. It
is therefore not necessary to add an additional uncertainty factor
for comparison with the human situation (UF = 1). This approach is
shown in step 2 in (Figure 2).”
Thus, the regulatory limit they are using to establish safety is
based on hen oral exposure toxicology. For ‘dose’ they assume that
TOCP (and nothing else) is present at the LOD (so they maintain
that is very conservative because no measurements they made
reached LOD) and they assumed 100% assimilation by inhalation,
which is standard toxicology. While the paper does acknowledge
the possibility of lower dose, more subtle, neurological effects
it only assigns an uncertainty factor of 5 to address this. In this
paper we see the same adoption of an unrealistic toxicological
endpoint, OPIDN, based on ingestion rather than inhalation. The
paper ignores the complex mixtures problem. The paper avoids
citing of the latest science on low dose repeat exposure to OPs.
Thus the use of OPIDN as the toxicological endpoint represents,
at best, a failure of hazard assessment and at worst a complete
misunderstanding of the clinical picture presenting in aircrew.
The failures of risk assessment illustrated in these three
examples are repeated in the majority of the other studies listed
in (Table 3).
By failing to consider the increased levels and increased
toxicity of the cresyl phosphate ortho isomers other than TOCP,
the toxicity of the ortho isomers in TCP are underestimated by a
factor of around 6 million. Additionally, toxicity of the non ortho
isomers has been ignored, with a sole focus on OPIDN.
To this should be added the exposure to OPs that are adherent
to the particles in the aerosols in cabin air, which are generally not
measured. This latter source could be of considerable importance,
as previously discussed by Howard et al .
There are widespread reports of illness among aircrew, which
have been categorised by Michaelis et al . The consequences
of repeated low dose exposures to OPs have been reviewed by
Terry . In that review he states “….. 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. 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 neuroinflammation 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 chronic illnesses where these symptoms
are manifested (e.g., Gulf War Illness, Alzheimer’s disease).” This
is precisely the spectrum of symptoms reported for air crew by
Michaelis, Burdon & Howard (2017) , who often achieve
cumulative career-long flying hours exceeding 20,000 hours. The
significance of this pattern of exposure in neurotoxicology has
been highlighted by Harris and Blain .
It is widely acknowledged in toxicological science that
exposure via inhalation is more toxic, dose for dose, than by
ingestion. Inhaled toxicants are assumed to be 100% assimilated.
They pass directly into the systemic circulation, thus avoiding the
liver – the major detoxification organ in the body and having direct
access to the brain and heart, possibly assisted by the presence
of ultrafine particles . The USEPA advice on this is clear and
the failure of the studies in Table 3 to address this represents
a major weakness in their use of toxicology in risk assessment.
The toxicology of mixtures is more or less completely ignored in
the above studies. OPs have been demonstrated to be capable of
acting synergistically . In addition, chronic pre-exposure to
repeated low dose OPs may pre-dispose increased vulnerability
to subsequent higher dose OP exposure . This acute-onchronic
effect is repeatedly seen in the differential rate of referrals
to hospital following fume events on civil aircraft. While a high
proportion of aircrew frequently attend hospital after a fume
event, passengers do not appear to require this. This is consistent
with the published science on the topic.
The use of OELs is inappropriate, they are not meant for
regulating exposure of the public to toxic substances and they
are not appropriate to apply to situations at altitude or complex
mixtures [10,49,50]. It is clear that the studies listed above are of
no relevance in the determination of potential harm to aircrew.
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