Inappropriate Use of Risk Assessment in
Addressing Health Hazards Posed by Civil
Aircraft Cabin Air
Centre for Molecular Biosciences, University of Ulster, UK
Submission:February 12, 2020; Published: December 04, 2020
*Corresponding author: Howard CV, Centre for Molecular Biosciences, University of Ulster, UK
How to cite this article: Howard C. Inappropriate Use of Risk Assessment in Addressing Health Hazards Posed by Civil Aircraft Cabin Air. Open Acc J of Toxicol. 2020; 4(5):555646. DOI: 10.19080/OAJT.2020.04.555646.
Toxicological reviews of data on Aerotoxic Syndrome that have been widely referenced by the airline industry tend to use a toxicological endpoint, Organo-Phosphate Induced Neuropathy (OPIDN), that is acknowledged to be the result of a very high dose of organophosphate exposure. Additionally, the reviews tend to only address one chemical, Tri-Ortho Cresyl Phosphate (TOCP), ignoring the presence of other toxic compounds in a complex mixture. In using this to justify the safety of the continued use of unfiltered engine bleed air to ventilate civil aircraft cabins, this represents a misuse of toxicological risk assessment. The approach totally ignores the scientific literature on repeated low-dose exposure to OPs over extended periods, the constant presence of a complex mixture of OPs in engine bleed air and their overall toxicity and the variable susceptibility of individuals to toxicological damage. This paper lists the above-mentioned studies and reviews a sub-set. We present the scientific literature that should be considered to make a realistic risk assessment of the hazards of aircraft engine bleed air.
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
MOCP 3070ppm in the TCP
DOCP 6ppm in the TCP
TOCP 5ppb (0.005ppm) in the TCP
Using Equivalent toxicity
Ortho TCP content in the oils with TCP at 3% in oils. The
following was published in a 2001conference 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 millionfold, 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 [29-32].
A risk assessment goes through several steps:
Hazard identification: Which requires insight into the
system or process under scrutiny.
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
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.
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 mixtures, etc.
Examples of published risk assessments
There is a pattern in following examples of toxicological
assessment of the health risks (see (Table 3)) from inhalation
of aircraft cabin air. The majority only consider TOCP as the sole
toxic substance. They almost 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.
Three examples of unsustainable statements resulting
from inappropriate risk assessment in the studies
In Table 3. These are representative of the majority of the
studies in Table 3. (Example 1) The CAA Report (2004)  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 (chicken) can be fed 20mg.
kg-1(body weight; BW).day-1 without showing signs of OPIDN.
Signs of toxicity were observed at 60mg.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 0.19μg.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
0.19μg.g-1 ≡ 0.19mg.kg-1 oil ≡ 0.19x10-3 g.Kg-1 (oil) dosage without
OPIDN 20mg.Kg-1.day-1 ≡ 20x10-3 g.Kg-1 (BW). day-1 Therefore, oral
dosage of oil without OPIDN effect is given by 20x10-3 g.Kg-1(oil).day-
1/ 0.19x10-3 g.Kg-1(BW).day-1 = 105Kg(oil).Kg-1(BW).day-1 Assuming
a 70kg body weight for the average human subject. The total dosage
that would not induce OPIDN would be 105x70=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 [34-35].
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 gaseous 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.
Example 2) Dr Pleus  presents a risk assessment based
on the oral dosage hen studies of Freudenthal  in which
they administered oils 0.5%, 1%, or 3% TCP (with 0.4% orthoisomer)
by gavage 5 days per week for 10 weeks . Using the
toxicological endpoint of OPIDN, he directly extrapolates from an
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 7,000mg of oil per cubic metre of cabin air for there to be any
risk of OPIDN in air crew. A grahic is then presented of the Seattle
tower with an LOAEL of oil of 7,000mg/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
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 [38-43]. 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 exposure assessment. 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].
Example 3) De Ree  take a similar approach. Their 2nd
paragraph of Section 4 contains the core of the risk assessment:
“Based on the detection limit of ToCP (0.5ng/m3 ) maximum
uptake via inhalation with a 100% bioavailability would amount
up to 0.02ng/kg body weight per day for a crew member of 70kg
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 1.25mg/
kg/ d after a repeated daily oral dose for 90 days Craig & 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 & Barth ; Johannsen, 1977; Ehrich
& 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 take into account 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
could be of considerable importance, as previously discussed by
Howard . There are widespread reports of illness among
aircrew, which have been categorised by Michaelis . 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 , 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 & 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 for complex mixtures [10,49,50]. It is
clear that the studies listed in Table 3 are of no relevance in the
determination of potential harm to aircrew.
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