25ho11_.pmd

Workshop summary and conclusions: human sacrifice–road speed–responsibility–economics
Malcolm Hooper*
2 Nursery Close, Sunderland SR3 1PA, UK The major conclusions from this important conference, sharpen the issues surrounding, andshed new light on, the growing concerns about cabin air quality as it affects the health of pilots,cabin crew, and passengers on commercial airlines.
1. HISTORY
early studies were concerned with AChEs and the closely The history of the toxic effects of organophosphates related butyrylcholinesterases (BuChEs), which occur (OPs) goes back to the 1920s and in the UK a significant mainly in blood plasma. Other serine enzymes have now landmark was the report by the Government's then Chief been identified that are more sensitive to OPs. These Scientific Officer, Sir Solly Zuckerman, in 1951 [1]. This report, concerned principally with the spraying of OPs in • Paraoxonase, PON1, which protects against athero- the farming industry, drew on expert testimony from the sclerosis and occurs in plasma and the liver [2–7].
Medical Research Council about the mode of action and • Neuropathy target (toxic) esterase (NTE), which dangers to man of OPs and identified the following as hydrolyses lysophospholipids in the brain [8].
• Acylpeptide hydrolase (APH), which plays key rôles in • Successive small doses . may progressively lower the brain and other tissues [9, 10].
cholinesterase levels without producing symptoms .
A range of novel proteins in the brain were reported rendering individuals increasingly susceptible to further to be very sensitive to OPs [11]; the senior author of that paper has served as a member of the Government • Owing to the slow restoration of cholinesterase to its Committee on Toxicity of Chemicals in Food, Consumer normal level, this susceptibility will persist for a long Products and the Environment (COT) and despite changes time, maybe for some weeks.
in the membership and chairmanship COT has continued • Chronic toxicity and cumulative poisoning may result to resist any recognition of the biomedical effects of OPs, from repeated absorption of parathion.
especially tricresyl phosphates in aerotoxic syndrome • Routes of absorption comprehensively recognized as (AS). Abou-Donia has reviewed the chronic toxicity of inhalation, dermal and ingestion.
OPs [12]. A disturbing development in passenger welfare and made these recommendations: is the recognition that three separate studies now link brain • Working periods to be limited to not longer than 10 development to OP exposure in utero (reviewed in [17]; hours per day and not more than 6 days per week.
this work has recently been extended [18]).
• Supervision providing instruction for employees is 2. THE EVIDENCE
• Precautions to include warnings to general practitioners Much has already been accumulated and extensively and hospitals in areas where spraying is being undertaken.
reported and summarized by Michaelis in her Manual [13] • Protective clothing should be worn.
and recent PhD thesis [14]. Estimates of enforced All this advice has been honoured more in the breach retirement among pilots flying the BAe 146 were reported than the observance. The use of OPs has been extended in one survey as 7.4% with some 25% of cabin crews and with almost total disregard to those warnings despite a pilots reporting significant symptoms [13, 14]. Small number of inquiries into the adverse health effect on numbers of passengers are also reporting AS symptoms farmers after long delays and the Government's (see Furlong's paper1).
enforcement of OPs in sheep dips. Many OPs have, New studies were reported at this conference by however, been withdrawn from use [2].
Passon2 showing up to 25% long term sickness among
Initially, because of the well known action of OPs as those completing the survey and including high levels of inhibitors of acetylcholinesterases (AChEIs), which cancers, peripheral neuropathy and sarcoidosis. Such control cholinergic transmission at nerve synapses, most studies are easy to dismiss for a variety of reasons: small * Emeritus Professor of Medicinal Chemistry, University of Sunderland. E-mail: [email protected] 1 This issue, pp. 165–171.
2 This issue, pp. 201–207.
Journal of Biological Physics and Chemistry 11 (2011) 209–215
2011 Collegium Basilea & AMSI Received 11 October 2011; accepted 30 December 2011 doi: 10.4024/25HO11A.jbpc.11.04 210 M. Hooper Workshop summary and conclusions numbers, self-selecting group etc.) but they do provide SYNDROMES OF UNCERTAIN ORIGINS
hard evidence that contradicts the assertions of all officialgroups, including aerospace and insurance companydoctors and unions, government representatives, panels GULF WAR SYNDROME
MULTIPLE
and committees. In the Lawrence3 case there appear to be
sound grounds for legal action and significant MILITARY ME
compensation claims for mistreatment and false diagnosisand an appalling failure of the duty of care. The Boeingcompensation award to the air hostess Terry Williams SYMPTOMS AND BODILY
[15] for the effects of her exposure to contaminated cabin SYSTEMS AFFECTED:
NEUROLOGICAL—ANS, PNS, CNS
air may well be the tip of an iceberg [16] that will "Considering the extent of the patients'
complaints and disability, the results of
comprehensively expose the failures of all those groups ROUTINE laboratory tests were
responsible for the health and welfare of pilots, cabin strikingly NORMA" (S.E. Straus, 1985)
crews and passengers. The issue of cabin air is now beingraised in hard-hitting TV documentary programmes Figure 1. Complex chronic conditions/syndromes that share a similar constellation of symptoms [20, 21]. Key: OPs, shown in Germany.4
organophosphates (includes aerotoxic syndrome); ME–CFS, The unwillingness of Government to accept any of myalgic encephalomyelitis–chronic fatigue syndrome; GWS/I, these studies and reports as a basis for funding larger Gulf War syndrome/illness; ANS, autonomic nervous system; studies is incomprehensible and suggests a blind ideology PNS, peripheral nervous system; CNS, central nervous system (i.e., brain and spinal cord).
linked to callous and inhumane attitudes that only serve toprotect a wide variety of vested interests.
Table 1. Functional somatic syndrome labels for chronic, Many have seen the development of the Boeing 787, complex conditions and syndromes.
which takes air for the cabin directly from outside, as tacit Functional somatic syndromes: one or many? [22] admission by the industry that the problem of cabin aircontamination is part of a fundamental design flaw in all IBS, non-ulcer dyspepsia PMS, chronic pelvic pain current commercial aircraft [19].
atypical or non-cardiac pain 3. RELATED SYNDROMES/CONDITIONS
Respiratory medicine Infectious disease Several speakers5 referred to the well known constellation
of symptoms associated with OP exposure, AS and other TMJ dysfunction, atypical facial pain emerging chronic complex syndromes and conditions (Figure 1) [13, 14, 20, 21].
The common feature of all these conditions is that Key: IBS, irritable bowel syndrome; PMS, premenstrual despite the obvious complaints and disabilities of syndrome; PVFS, postviral fatigue syndrome; TMJ, temporal sufferers, routine blood test results are usually normal.
mandibular joint; ENT, ear, nose and throat; MCS, multiple The reluctance of physicians and others to engage withthese complex conditions has lead to a great division • Lack any basic similarity to known mental disorders ( i.e., between those who find sound experimental and they are outside of current mental health paradigms).
investigative evidence for underlying biomedical damage • Convert firm knowledge into speculative assertions and defects and those who seek to assert that they are without any critical voices being heard.
somatoform (i.e., psychiatric/psychological) in origin and • Those postulating them typically use evasive arguments label them accordingly. This approach has been applied and have a lamentably poor record of research into across the board by some psychiatrists [22] (Table 1).
causes, particularly where biochemical and environ- Critics of this view emphasize that all these postulated mental factors are concerned. Furthermore, somatoform disorders: • Reclassify bodily symptoms as a mental problem interests seem to be actively influencing the course of (where conventional medicine is at a loss to find an what is ostensibly a scientific discussion. [20, 21, 23–25].
explanation, implying that focused research is needed).
There is ample evidence of inappropriate diagnoses 3 Leonard Lawrence presented his case at the Workshop.
4 Tim van Beveren. http://www.youtube.com/watch?v=ZgQjYdN48vU; http://www.youtube.com/watch?v=mPKSxmiS_AY 5 See especially the paper by Hyde (this issue, pp. 172–179) on myalgic encephalomyelitis/chronic fatigue syndrome.
JBPC Vol. 11 (2011) Workshop summary and conclusions M. Hooper 211 and mistreatment that leads to serious mental and MRS; blood flow SPECT
physical illness in those suffering from such conditions scans (Haley et al.; Julu;
Antibodies for Neuronal
damage; OPIDN–OPICN
(Abou-Donia et al.)
A prominent medical spokesman for the industry firmly aligns himself with the somatoform/psychiatric view of aerotoxic syndrome when he states [30] Esterases – AChE,
The symptoms attributed to cabin air exposure are BuChE, PON1, NTE,
"similar to those seen in a wide range of conditions, including chronic fatigue syndrome, Ross et al.; RACGWVI)
Synergism,
Metabolism,
(Furlong et al.;
Gulf War syndrome, Lyme disease, chronic stress Genetics,
Mackness et al.; La Du
and chronic hyperventilation." Figure 2. Five independent strands of scientific evidence This statement betrays some ignorance and supporting the involvement of organophosphates in aerotoxic obfuscation of the nature of AS by using terms that are syndrome. Key: OPIDN, organophosphate-induced-delayed inexact and confuse rather than clarify. Lyme disease neurotoxicity; OPICN, organophosphate-induced chronic should read chronic Lyme disease, which is associated neurotoxicity; BuChE, butyryl cholinesterases; NTE, with ME-like symptoms [31] and affects only a small neuropathy target esterase; PON1, see text for references.
proportion of those who contract Lyme disease, usually exposure to TCPs. Professor Furlong reported a similar readily treated with established antibiotics. The use of the study with the more sensitive acyl peptide hydrolase misleading term "chronic fatigue syndrome" rather than (APH), present in mouse and human brains.
the more established "myalgic encephalomyelitis" All Furlong's work is in agreement with wider enzyme (classified as a neurological condition by the WHO) studies, especially on paraoxonase (PON1), associated gratuitiously belittles the illness called ME, as fully particularly with GWS/I. OP pesticides and pyridostigmine explained by Hyde and others [27, 32].
bromide (another AchEI) have been causally linked to The attempt to claim that hyperventilation is GWS/I [7]. Using advanced imaging techniques, Haley responsible for the chronic and progressive illness and colleagues have identified hippocampal dysfunction suffered by so many sick cabin crew and pilots defies the associated with regional changes in cerebral blood flow evidence, which includes paralysis and loss of physical and and paradoxical changes in response to cholinergic cognitive functions that persist long after the precipitating challenge in sick Gulf War veterans [35]. This test event and in some cases gives rise to an excess of severe provides diagnostic evidence for profound and extensive neurological diseases such as Parkinson's Disease (PD) damage to the central nervous system following exposure and motor neuron disease (MND, also called Lou Gehrig to acetylcholine esterase inhibitors (AchEIs). The hip- disease in American literature on Gulf War illness/ pocampus is particularly associated with memory processes, syndrome) as well as some cancers.
which are reported as dysfunctional in people with AS.
Using well established tests Mackenzie Ross showed 4. THE SCIENCE
how some neuropsychiatric processes are damaged by Major scientific presentations made at the Workshop low-level exposure to OPs and, building on her recent further established the adverse biomedical effects of paper [36] dealing with farmers exposed to OPs, found organophosphates, particularly tricresylphosphates, known similar deficits in memory, response speed, fine motor to be present in jet engine oils.
control, mental flexibility and strategy-making in sick pilots Figure 2 summarizes five independent strands of even after controlling for the effects of mood. Anxiety and advanced biomedical evidence from internationally depression were badly affected.
acknowledged experts that all point to conclusive Whilst fuller studies are needed it is apparent that evidence that OPs have serious acute and chronic effects.
there is little funding for such work, the results of which The chemistry of the reaction of cresyl saligenin look as though they would completely destroy the official phosphate with the active site of cholinesterases has now commitment to the psychiatric understanding of AS and been published [33] and undergirds the investigations of related conditions.
Furlong who, in a series of papers, developed a specific Figure 2 also draws attention the work of Abou-Donia assay for the identification of key enzymes affected by and his colleagues, which has demonstrated that OPs that are "decorated" with TCP molecules [34]. A synergistic effects of disparate compounds can arise blood test has been developed that can be used immediately when mixtures of chemicals are present [25, 37, 38]. This after any "fume event" to show unambiguous and specific exposes the fallacy that individual exposures to chemicals JBPC Vol. 11 (2011) 212 M. Hooper Workshop summary and conclusions judged to be below the threshold of toxic effects U-shape indicating that the compound may be active at measured for a single compound provide sound grounds concentrations below the threshold of the linear régime for claiming that exposures in complex mixtures of (Figure 3, and briefly reviewed in [25]). Such unexpected chemicals such as those found in engine oils, lubricants responses are outside the old toxicological models used to and antifreeze are "safe" provided the individual assert that threshold values of individual compounds pose compounds are individually present below those thresholds.
no threat to human health. This is now known not to be the Furthermore, the old paradigms in toxicology are no case and the industry needs to take cognizance of these longer valid (Table 2). In particular, many modern dose– new aspects of toxicological science and undertake more response curves are not monotonic; they have an inverted rigorous studies in the light of this information.
Table 2. Changes in toxicology paradigms.
High level contamination overwhelms Low level contamination hijacks control of development detoxification and other defence mechanisms "The dose makes the poison" Non-monotonic dose–response curves are common, in which low level exposure causes effects that disappear at higher levels Only high levels of exposure matter Impacts caused at what had been assumed to be "background" levels Periods of rapid growth and development (prenatal through puberty) are most sensitive to exposure A small number of "bad actors" Many chemicals formerly thought safe are biologically active and capable of interfering with signalling systems Immediate cause and effect Long latencies are common; fetal programming can lead to disease and disabilities decades later Examine chemicals one compound at a time In real life, mixtures are the rule. They can lead to effects at much lower levels than indicated by simple experiments with single chemicals. Synergism is significant Focus on traditional toxicological endpoints like Wide range of health endpoints, including immune system dysfunction (both mutagenesis, carcinogenesis, cell death hyper- and hypo-activity); neurological, cognitive and behavioral effects; reproductive dysfunctions; chronic diseases One-to-one mapping of contaminant to disease or Same contaminants can cause many different effects, depending upon when exposure occurs during development and what signals it disrupts. Multiple contaminants can cause the same endpoint if they disrupt the same developmental process INVERTED-U DOSE–RESPONSE CURVE
FOR CELL SIGNALLING DISRUPTORS
unequivocal evidence of a neurotoxic exposure and isused by sick pilots and cabin crews seeking to,demonstrate the validity of the link between their neurological illnesses and their OP exposure, understand their sickness and support their claims for compensation.
Mulder described his important work of collecting real-time exposure data from pilots, cabin crews and No Effect
passengers. By careful consideration of the biochemicalpathways associated with the production of key neurotransmitter molecules he has also devised a treatment protocol that many sick cabin crew and pilots are Cell signalling disruption range (ppt–ppb) Pharmaceutical range (ppm)
finding useful to alleviate some of the worst symptoms.
TISSUE LEVEL OF AGENT
Figure 3. Very low dose effects below the linear dose–response 5. THE POLITICS, REGULATORS, VESTED INTEREST AND
A further important contribution from Abou-Donia's Government policy seeks and funds research to provide group is the identification of autoantibodies to internal policy-based "evidence" that is in tune with its proteins from damaged neurones; the antibodies are predetermined aims. These aims are in turn influenced by released following OP exposure [39]. This test provides lobbyists for the aero industry, the insurance industry and JBPC Vol. 11 (2011) Workshop summary and conclusions M. Hooper 213 Government departments such as the UK Department bringing air from the engines into the cabin. At the very for Work and Pensions (DWP), which is responsible for least, some kind of contamination monitoring devices sickness benefits. Evidence based on independent science should be retrofitted. The Boeing 787 has already and medicine is ignored or belittled. It has been admitted demonstrated the essential changes needed in future that government funds research to support policy [40].
aircraft design. Furthermore, truth and justice demand that This is evident in the funding for large experimental support for sick pilots, cabin crews and passengers should studies that have failed to address the question of cabin be given without argument or delay.
air contamination or, as in the latest Cranfield study [41],have carried out studies that are at best tangential to the problem. This latter study was very heavily criticized as bad The author thanks Professor Vyvyan Howard for having science lacking the necessary rigour to properly address the provided Fig. 3.
questions associated with cabin air contamination.
The other ploys used by the industry and regulators is to manufacture doubt [42] and call for ever moreexperiments that avoid addressing head-on the question— 1. Zuckerman, S. Toxic Chemicals in Agriculture. Report to the Minister of Agriculture and Fisheries of the Working in this case of cabin air contamination.
Party on Precautionary Measures against Toxic The cryptic phrase "human sacrifice–road speed" in Chemicals used in Agriculture. London: HMSO (1955).
the title of this presentation points to the willingness to 2. Woods, H.F. (Chair). Organophosphates: Committee on sacrifice human life and health in the interests of Toxicity of Chemicals in Food, Consumer Products and the Environment (1999).
economics and profit. A proposal of the present UKGovernment is illustrative: for (unspecified) economic 3. Mackness, B., Durrington, P.N. and Mackness, M.I. Low paraoxonase in Persian Gulf War veterans self-reporting gain, the maximum speed limit on major roads should be Gulf War syndrome. Biochem. Biophys. Res. Comm. 276
raised from 70 to 80 mph [43], which will give rise to an (2000) 729–733.
estimated 20% increase in road deaths [44]. In the same 4. Costa, L.G., Cole, T.B. and Furlong, C.E. Gene-environment way the health and well being of pilots and cabin crews are interactions: paraoxonase (PON1) and sensitivity to organophosphate toxicity. Laboratory Medicine 37 (2008)
being sacrificed at the behest of economic gain and vested corporate interests. Susceptible aircraft passengers are 5. Hotopf, M., Mackness, M.I., Nikolaou, V., Collier, D.A., being similarly sacrificed. It is advisable to listen to the Curtis, C., David, A., Durrington, P., Hull, L., Ismail, K., economists who have challenged the view that "economics Peakman, M., Unwin, C., Wessely, S. and Mackness, B.
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Vested interests and their pressure groups, both of which 6. Haley, R.W., Billecke, S. and La Du, B.N. Association of low are outside the democratic processes of government, must PON1 type Q (type A) arylesterase activity with neurologic be exposed even if, as recently, they involve government symptom complexes in Gulf War veterans. Toxicol. Appl. ministers in what should, more truthfully, be named as Pharmacol. 157 (1999) 227–233.
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7. A comprehensive report to the American congress on the responding to a different economic issue, used the causes of Gulf War illness and the adverse health effects suffered by up to 30% of veterans. Washington: The memorable phrase, "you shall not crucify mankind on a Research Advisory Committee on Gulf War Veterans' Illness cross of gold" [50]. The wilful and knowing sacrifice of (RAC-GWVI) (2008). Downloaded January 2012 from http:/ human health and wellbeing associated with the emerging complex and chronic illnesses deserves the same stricture.
This Workshop has presented incontrovertible and 8. Casida, J.E., Nomura, D.K., Vose, S.C. and Fujioka, K.
Organophosphate-sensitive lipases modulate brain overwhelming scientific evidence in support of AS that lysophospholipids, ether lipids and endocannabinoids.
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aircraft by retrofitting appropriate filters in the ducts 6 The Bill "could benefit Djanogly ‘in multiple ways'…the Justice Minister piloting controversial plans to cut legal aid and curb payouts—a move that could benefit the insurance industry by £1 billion per year . Has investments of at least £1/4 million . as a minority partner in family firm of insurance underwriters" [47]. He "failed to declare that his children were minority shareholders in his brother-in-law's businesses . which advertise ‘no win, no fee' compensation claims" [48]. "Justice minister . criticised for not declaring relative's company which supplied staff to industry he regulates" [49].
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9 July 1896. http://historymatters.gmu.edu/d/5354/ JBPC Vol. 11 (2011)

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