Select Committee on Science and Technology Written Evidence

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.[62] In the 1950s it became evident that metabolism of TCP was required to generate the toxic metabolite(s).[63] 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.[64] 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 of exposure.

Are aircraft occupants being exposed to TCP?

  A recent report by van Netten[65] 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 of exposure.[66] 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.[67]

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.[68] 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 sensitivity

  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.[69] 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 OP compounds.

  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 your review.

18 June 2007

62   See, eg, Smith, MI, Lillie RD 1931. The histopathology of tri-ortho-cresyl-phosphate poisoning. Arch Neurol Psychiat, Chicago 26:976-992. Back

63   Aldridge WN. 1954. Tricresyl phosphates and cholinesterase, Biochem J 56: 185-189; Myers DK, Rebel JBJ, Veeger C, Kemp A, Simons EGL. 1955. Metabolism of triaryl phosphates in rodents, Nature 176: 259-260. Back

64   For a review see, Glynn P 1999, Biochem J, 344: 625-63. Back

65   van Netten C 2005, J Occup Health Safety-Aust NZ 21:460-468. Back

66   Furlong CE, Cole TB, MacCoss M, Richter R, Costa LG. Biomarkers for Exposure and of Sensitivity to Organophosphorus [OP] Compounds. Proceedings of the BALPA Air Safety and Cabin Air Quality International Aero Industry Conference, Imperial College, London, 20-21 April, 2005. Back

67   Henschler D, Bayer H.0H. 1958, Toxicological studies on triphenylphosphate, trixylenylphosphates and triarylphosphates of mixtures of homologous phenols. Naunyn Schmiedebergs Arch Exp Pathol Pharmako, 1958;233(6):512-7, German. Back

68   Choi J, Hodgson E, Rose RL, Inhibition of trans-permethrin hydrolysis in human liver fractions by chloropyrifos oxon and carbary, Drug Metabol Drug Interact, 2004;20(4):233-46. Back

69   Cole TB, RL Jampsa, BJ Walter, TL Arndt, RJ Richter, DM Shih, A Tward, AJ Lusis, RM Jack, LG Costa, and CE Furlong. 2003. Expression of human paraoxonase (PON1) during development, Pharmacogenetics 13:357-364; Furlong C, Holland N, Richter R, Bradman A, Ho A, and B Eskenazi. 2006. PON1 status of farmworker mothers and children as a predictor of organophosphate sensitivity, Pharmacogenetics and Genomics, 16:183-190. Back

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