Memorandum by Dr Clement E Furlong
Comments related to the exposure to tricresyl
phosphate during engine seal failure incidents.
A very brief history of tricresyl phosphate research
Following the cases of paralysis resulting from
the adulteration of ginger extracts during the prohibition era
in the United States, research readily identified the ortho isomer
of tricresyl phosphate (TCP) as the chemical responsible for the
paralyses. It is remarkable that at the time that Henry Ford was
manufacturing the Model A Ford, scientists were able to so readily
identify the ortho isomer of TCP as the agent responsible for
the cases of paralysis.
In the 1950s it became evident that metabolism of TCP was required
to generate the toxic metabolite(s).
In 1961, Casida and co-workers identified the active metabolite
of TCP (Saligenin cyclic o-tolyl phosphate). It is this active
metabolite that causes peripheral neuropathy via inhibition of
neuropathy target esterase.
While some safety considerations consider only the end point of
peripheral neuropathy as being significant, many other physiological
consequences can precede the delayed peripheral neuropathy. If
these exposures are affecting the cognitive capabilities and/or
general health of pilots, crew and passengers, it is important
to know this and take corrective measures to prevent these consequences
Are aircraft occupants being exposed to TCP?
A recent report by van Netten
documents the presence of TCP in a number of aircraft filters,
the flight deck walls and a pilot's trousers. He also describes
the development of a small filter unit that can sample air for
organics as well as CO. The unit is easily activated during an
event. Prof. van Netten also notes the importance of biological
monitoring. Incidence frequencies and incident associated symptoms
are also reported.
Attendance at several cabin air quality conferences,
where the question of whether or not individuals were exposed
to TCP, prompted us to begin development of a blood test that
could determine whether or not an individual was exposed to TCP.
We carried out proof of concept experiments for identifying biomarkers
The proof of concept involved the modification of the active site
of porcine liver carboxylesterase with TCP. The attachment of
monocresyl phosphate to the active site serine was readily apparent
with mass spectrometric analysis. TCP binds initially as a dicresyl
phosphate to the active site serine, then "ages" to
the monocresyl phosphor serine. We have begun the experiments
to adapt this analysis to human blood samples. These analyses
are underway and should be completed before the end of the year
if not sooner.
Other active TCP isomers
The ortho cresyl phosphate content of lubricants
is often reported as the percentage triorthocresyl phosphate (TOCP),
ignoring the content of the mono- (MOCP) and diortho (DOCP) isomers.
Since the monoorthocresyl phosphate may be 10-times as active
as TOCP and DOCP 5-times as active, it is important to consider
the content of these isomers in products.
Synergistic effects of mixed exposures
TCP is a potent inhibitor of carboxyl esterases,
enzymes that are important in the detoxication of other insecticides.
Casida et al. note the potentiation of malathion toxicity by TCP
in their 1961 publication. van Netten (2005) points out the importance
of carboxyl esterases in the detoxication of pyrethroid compounds
in his recent paper. Dr Hodgson's research team has shown that
chlorpyrifos oxon exposure clearly potentiates permethrin toxicity.
Our own recent research has looked at the potentiation of malaoxon
toxicity by chlorpyrifos oxon, diazoxon and paraoxon as well as
the modulation of this potentiation by genetic variability in
the human PON1 gene (Jensen, unpublished results). Thus, spraying
the cabin with what is thought to be a very safe insecticide may
not be so safe if an individual has had a recent exposure to TCP,
parathion, diazinon or chlorpyrifos.
Genetic and developmental factors affecting OP
Another factor to consider in your review is
the presence of highly susceptible individuals among pilots, crew
and passengers, especially, the very young passengers or developing
foetuses. Two of our recent publications deal with the increased
sensitivity of the very young as well as individuals with genetically
determined increased sensitivity to OP exposure.
While much has been learned about genetic factors that affect
sensitivity to some OP compounds, there is still much to learn
about the factors involved in determining sensitivity to specific
I will be pleased to keep you informed on the
progress of our research that is aimed at developing biomarkers
of exposure to TCP. I hope that these comments are useful for
18 June 2007
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