Abstract

General

Pyrolysed or thermally degraded engine oil and hydraulic fluid fumes contaminating aircraft cabin air conditioning systems have been recognised and well documented since the 1950s. Research suggests that inhalation of these potentially toxic fumes causes ill health. The evidence that fumes can enter the aircraft cabin is not widely accepted, particularly by the airline industry and its regulators. However, there is a documented history spanning decades that associates the onset of ill health with fume exposure in most cases. Evidence suggests that cumulative exposure to regular small doses of toxic fumes is potentially damaging to health and may be exacerbated by a single higher-level exposure. Whilst organophosphates have been the main subject of interest, oil fumes in the air supply also contain ultrafine particles and numerous volatile organic hydrocarbons, which are likely to be damaging to health. Assessment is made more complex because of the limitations of considering the toxicity of individual substances in complex heated mixtures.

The lack of recognition by some, of illness caused by exposure to pyrolysed engine oil, de-icing and hydraulic fluid in aircraft ventilation supply air is likely to be due to lack of knowledge and clinical acumen. The easier finding of more clinically understood diagnoses in unexplained clinical presentations is recognised.

When examined using the Bradford Hill features of evidence and based on a more probable than not approach, the association between fume exposure and ill health leads to the inference that illness caused by fume exposures is a real clinical entity. There is a need for a systematic and consistent approach to diagnosis and treatment of people who have been exposed to toxic fumes in aircraft cabins and education of all professions involved.

This medical protocol has been written by internationally recognised experts and presents a consensus approach to the recognition, investigation and management of people suffering from the toxic effects of inhaling pyrolysed engine oil and other fluids contaminating the air conditioning systems in most aircraft. A best practice medical protocol is outlined including actions and investigations for in flight, immediately post flight and late subsequent follow up.

Introduction

General

Contaminated aircraft cabin air incidents, commonly identified as ‘fume events’, were first described in military aircraft in the 1950s (1-5). The onset of fume events coincided with the introduction of synthetic jet engine oils, used in high performance turbine engines (6), and the practice of supplying the aircraft breathing air directly from the engines without undergoing filtration. Over the following decades, continuing reports describing symptomatic aircrew correlated with fume events (7-14). Subsequently, a number of studies have identified adverse effects reported by aircrew as well as medical findings and diagnoses associated with fume events(15-31).

For several decades, medical diagnostics have been used to check possible functional or organ related impacts that correlate with the reported symptoms. These include both acute and chronic health effects: neuropsychological/neurological (32-39); respiratory (40-43); biomarkers (44, 45); and biomonitoring (46-48). Over the years, there has been a lack of timely and systematic investigation of fume events. There has also been a failure to measure and identify potential contaminants at the time of exposure. The lack of exposure data and documentation have hindered not only the assessment of measured abnormalities and their relationship to clinical symptoms, but also the development and implementation of preventative and therapeutic strategies.

Symptoms, signs, objective measurements and diagnoses are recorded in many cases by initial responders, medical personnel and by those people who have been affected. However, there has been no consistency in the way diagnoses are reached and in record keeping. Thus, there is an urgent need for the development of a consistent, internationally accepted medical protocol to facilitate the recognition of health effects associated with fume exposure in aircraft cabins and cockpits. A medical protocol is needed to establish aircraft-related passenger and, in the context of aircrew, occupationally induced disease (28, 49, 50). The goal is to establish a standardised global basis for better documenting and addressing the health impacts of inhaling these fumes on aircraft.

There has been some effort by the aviation industry and governments to outline medical guidance after fume events (51, 52). Generally, the guidance is not specific and there is inconsistency from region to region and sector to sector in how fume events are recorded. The proposed protocol in this document is a step forward in assembling a uniform database of fume events, their effects (short and long term), diagnostic and treatment options and related outcomes. The proposed protocol is an evidence-based work-in-progress that will be updated as the field progresses.

This document is based on the medical and scientific expertise of a group of international experts and medical centres, including peer-reviewed published findings and grey literature.

Aim of this publication

General

In this protocol, we summarize the data systematically to substantiate the social recognition of illness after cabin air contamination. Its purpose is to document a recommended approach to the observation, measurement and recording of symptoms, signs and treatment (if any), and subsequent management of afflicted persons and their health outcomes. Presentation of health effects are considered in the following timeframes:

• In-flight.
• Immediate post flight (within one to two days).
• Late/subsequent (beyond two days).

The medical management and specific investigations will vary in each case, depending on specific technical and individual contextualfactors. Medical management is related to the presenting symptomology at the time of examination.

Although important in the occupational health and safety context, it is not the intention of this document to address the issue of routine monitoring of aircraft cabin air for the presence of toxic fumes.

Nomenclature

General

Nomenclature for illness resulting from a fume event needs to be agreed upon before proceeding further. In this regard, the term ‘Aerotoxic Syndrome’ (AS), was suggested by Winder et al. in 2000 (11) to describe the constellation of symptoms experienced by people exposed to fume events.

The term Aerotoxic Syndrome has been used for many years, but it has not received broad acceptance for a number of reasons. The term has been widely criticised by the airline industry and others because the term ‘aerotoxic’ could be emotive. Additionally, the term ‘syndrome’ has been questioned because not all the possible clinical manifestations are present in every case. In the medical context, the term ‘syndrome’ is defined as a clinical picture characterised by a certain constellation of signs and symptoms. Not all signs and symptoms are present in every case due to differences in exposure, genetic susceptibility and other factors. ‘Aircraft related illness’ has been suggested elsewhere as a suitable term (53).

Given the above, we submit that the term ‘Aerotoxic Syndrome’ is medically and technically reasonable. We justify our reasons below and note that it is the original term coined by Winder et al. in 2000 (11).

Aircraft air supply

Technical background

In flight, all modern commercial jet transport aircraft, except for the Boeing 787 Dreamliner, use air compressed within the engine as the source of the air used for aircraft ventilation and pressurisation. This air is technically known as ‘bleed air’ because it is bled off the compression section of the engine. On the ground, a small jet engine normally located in the tail of an aircraft, known as an Auxiliary Power Unit (APU) frequently provides the ventilation air. The B787 uses electrically compressed air drawn directly in from outside rather than being sourced from the engine/APU.

As in other indoor air environments, the air supply system is designed to dilute airborne contaminants which are sourced to occupants, systems and surfaces (generated internally or externally) that enter the cabin air when ventilating the cabin with outside air. Outside air is used to dilute contaminants in the air and flush them to the outside of the cabin (54). As such, ventilation exchange rates in aircraft are higher than in other indoor settings.

Fumes within the aircraft cabin can be sourced to the aircraft ventilation air supply or to items within the cabin and/or flight deck (55). These can be seen in Appendices 1A and 1B (55, 56). Such sources within the aircraft cabin may include carry-on baggage, disinfectants, disinsectants or galley equipment. Fume sources from within the ventilation air supply can include engine oil, hydraulic or de-icing fluids, fuel and electrical faults. In this document, we focus on fumes sourced to the aircraft ventilation supply.

Oil and hydraulic fluid fumes

Technical background

It is now increasingly recognised that pyrolysed engine oil, used in jet aircraft engines, leaks at varying levels into the air supply systems in most jet or turbine powered aircraft (52-54). Oil leakage over the engine seals occurs in three main ways:

1. Continual background emissions in normal engine operation, as engine oil seals are not an absolute design.
2. Transient low-level leakage in normal operation with engine power and air supply configuration changes.
3. Less frequent higher-level exposures with certain operational factors or partial or full failure conditions.

The use of engine compressor-generated pressurised air to both seal the oil-bearing chamber and to provide ventilation air for the cabin guarantees that fugitive low-level oil emissions will enter the air supply during normal engine operation (57).

Although contaminants linked to the ventilation air supply may come from a variety of sources, as indicated in Appendices 1A and 1B (55, 56), there has been a particular focus on the oil and hydraulic fumes over many years as highlighted in 2015 by the International Civil Aviation Organization (ICAO): “Of all of these potential contaminants in the cabin and flight deck, particular concerns have been raised regarding the negative impact on flight safety when crew members are exposed to oil or hydraulic fluid fumes or smoke, and experience acute symptoms in flight”(55). With regard to oil seals, “It is accepted that such seals will leak a very small amount of oil vapor during normal service”(57). The oil leakage due to engine operating conditions “pollutes the cabin/cockpit air” (58).

There are two main ways in which exposures may occur (59):

1. Acute high-dose fume events in which there is generally only a detectable odour without a visible haze. This can range from the more common transient lower concentration event during normal operations to the less frequent higher-level event occurring during abnormal operations. Events with symptoms may occur in the absence of an identifiable odour or mist.
2. Chronic repeated low-dose exposure of aircrew on a continual basis to a complex mixture of fugitive jet engine oil emissions. In this scenario most aircrew/persons would not suffer symptoms, but some may.

Fume events

Technical background

Fume events are described in a variety of ways. Most have no visual identifying features, such as mist or smoke. Oil fumes are typically described as smelling like dirty socks/smelly feet, foul, musty or oily odours, while hydraulic fluid is often described as acrid (55). The dirty socks or smelly feet description, often used, is increasingly understood to be related to the thermal degradation and hydrolysis of the oil base stocks creating carboxylic acids (60-62). Odour is subjective, with different people describing the same fumes differently, while olfactory fatigue reduces a person’s ability to detect odours over time (55). After three minutes of exposure to an odorant, the perceived intensity of the odorant is reduced by about 75% (63). Additionally, fumes have often been regarded as a nuisance, with education and training to increase awareness and reporting having only recently been promulgated (55). In some cases, there may be no detectable odour, however, symptoms characteristic of a fume event may be reported at specific stages of flight.

There are neither detection nor warning systems on board aircraft to advise the crew and maintenance staff when the air is or has been contaminated. Furthermore, there are difficulties in identifying the source of fume events during maintenance practices, particularly for the more common lower-level transient events (64-68).

Hazard classifications

Technical background

Aircraft oils and fluids are known to contain hazardous substances and additives, including organophosphates (OPs) (28, 69-74). The hazard classifications related to these fluids listed under the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) (75) (a system established by the United Nations to provide information on hazardous products) include: toxic for reproduction; may damage fertility or the unborn child; suspected of causing cancer; harmful by dermal exposure; specific target organ toxicity – single and repeat exposure; neurotoxicity; eye and skin irritant; skin sensitisation; may cause allergy or asthma or breathing difficulties if inhaled; irritation of the respiratory tract; and, may cause drowsiness or dizziness (28, 73, 74).

Oil and hydraulic fluid compounds

Technical background

Tricresyl phosphate (TCP) is used as an antiwear additive in most engine oils at 2.5-5% concentration. While there has often been a focus on one isomer of TCP, tri-ortho-cresyl phosphate (ToCP), there are nine other ortho, meta and para isomers in TCP. The commercial formulations of TCP used in engine lubricants contain a wide range of cresols, phenols and xylenols (76, 77), including trixylyl phosphate (TXP). Isopropylated phenyl phosphates (3:1) [TIPP/PIP (3:1)] are used in at least one brand of oil rather than TCP and in selected hydraulic fluids. Tributyl phosphate (TBP) is a constituent of most (but not all) hydraulic fluids, ranging from 20-80%, and some oils and hydraulic fluids contain triphenyl phosphate. Amines, such phenyl-α-naphthylamine (PAN) or alkylated diphenylamines are used as antioxidants in a concentration of about 1% in the oils. Beta naphthylamine (BNA), a category 1A carcinogen, is a contaminant of PAN. However, BNA is reported to present at very low levels in the oils and, therefore, not listed on the Material Safety Data Sheets (MSDS) (78). Upon exposure to the very high temperature of the engine, the oil and other fluids are known to generate a thermally degraded or pyrolysed¹ complex mixture of substances (61, 70, 78-81). Therefore, there is exposure to a complex mixture of volatile and semi-volatile hydrocarbons and their degradation products, many of which are known to be hazardous to health.

Complex mixture

Technical background

The complex mixture of jet engine oils and other aircraft fluids have been documented in a variety of studies. However, the approaches undertaken have rarely been systematic nor widely available for review. The contaminants that could be in the aircraft cabin environment relating to oils, fuel, hydraulic and de-icing fluids, anti-corrosion coatings, amongst others, are categorised by the American Society of Heating, Refrigerating and Air-Conditioning Engineers (ASHRAE) as shown in Appendix 1B (60). According to ASHRAE (60), carbon monoxide (CO), ultrafine particles (UFP) (which have diameter of 0.1 µm or less), particulate matter less than 2.5 micrometres in diameter (PM_2.5), aldehydes, OPs, alkanes, amines and esters are consistent with oil and hydraulic fluid contaminants. Carboxylic acids, aromatics and ketones are also linked to oil. Fuel is associated with CO, UFPs, aldehydes, aromatics, alkanes and alcohols. UFP measurements of pyrolysed oil found that “contamination in the compressor will result in a fog of very fine droplets in the bleed air under most operating conditions”(82).

Air quality studies

Technical background

Substances belonging to the categories listed above, have been repeatedly identified in cabin air quality studies (66, 83-88), studies specifically related to the aircraft bleed air supply system in oil contamination (61, 81, 82, 89-93), and oil pyrolysis studies (80, 94-97). The aircraft cabin and bleed air ad hoc studies have generally not been undertaken during fume events. However, in one instance a series of air samples were collected during normal flight in which mild fumes were noticed by some people. TCP and TBP were identified in most of these in most of the samples (88). Sixty-four of the most frequently occurring compounds measured in bleed air are listed in Appendix 1C (89). Ritchie et al. (98) identified kerosene-based jet fuels as an additional source of hydrocarbons. Other contaminants include those related to the black carbonaceous material adhered to the ducting in the air supply, which can contain aluminium, silicon, sulphur and phosphorous that could be released into the cabin air under certain operational conditions (61, 99). These carbonaceous materials and associated chemicals were identified as ‘entirely consistent’ with the products of pyrolysed aircraft engine oils (61). Additionally, one function of the oil is to wash away very small particles such as metal released from the bearings, seals and gears during normal operation (100). Used engine oil evaluation provides further details on the microscopic wear of metals within the engine and oil system (101, 102).

No detection systems specific to oil or hydraulic fluid fumes exist to monitor contaminant levels in the aircraft cabin during a fume event. Available data on potential contaminants present are obtained from a small number of industry sponsored cabin air quality studies, or occasionally from maintenance studies undertaken hours or days after the event (see references above) as described in Chen et al., (87). Levels of contaminants identified in these ad hoc studies are generally reported to be well below occupational exposure limits (OEL). Air monitoring undertaken in Australia when fumes generally considered as ‘normal’ were present, identified low levels of TCP and TBP in most samples, with a pilot medical disqualification noted after repeatedly identifying fumes and adverse effects (88).

Occupational exposure limits

Technical background

Occupational exposure limits or threshold limit values (TLV) are applicable to individual substances but not to all substances. The limits are set to protect most, but not all, workers handling hazardous substances under a specified occupational health and safety condition in the workplace. The limits are not applicable to the general population, which includes pregnant women and children. OELs are not a fine line between safe and dangerous exposures and do not exclude the development of occupationally induced illness. The application of conventional occupational health and safety procedures to the specialised aircraft environment “are inappropriate” (70) and such threshold limits are not applicable to “complex mixtures with many components (e.g., gasoline, diesel exhaust, thermal decomposition products… etc.)” (103).

Individual classical toxicology limits will not be protective for exposure to complex mixtures, such as oil fumes, and especially for aircrew exposed to repeated low doses (57). There is longstanding toxicological knowledge that, with regard to risk assessment, it should be borne in mind that exposure to various substances could occur within a short period of time and, as a result of these mixed loads, an additive or potentiated effect may occur, which does not meet the consideration of the toxicity of the individual substances (104). As stated in an EASA/EU funded pyrolysed oil study, “the conditions in cabin air may differ from standard conditions on which exposure limits are normally based”(80).

Additionally, exposure limits may not reflect the physiological effects of altitude that will be present in an aircraft cabin during flight (105, 106). Environmental changes that arise from altitude include reductions in humidity, temperature and atmospheric pressure and an increase in radiation (particularly over the polar areas). These environmental changes may lead to changes in pulmonary physiology and reduction in oxygenation. The clinical effect of the intake of hazardous substances in an aircraft cabin at altitude has not been well defined, especially in children (107). “No physiological effects due to oxygen deficiency are expected in healthy adults at oxygen partial pressures greater than 132 torr or at elevations less than 5000 feet”(103). At oxygen partial pressures less than 120 torr (5000-7000 feet), “symptoms in unacclimatized workers include increased pulmonary ventilation and cardiac output, incoordination and impaired attention and thinking. “These symptoms are recognized as being incompatible with safe performance of duties)”(103).

¹ . The term pyrolysis has been widely used in association with oils heated to high temperatures within aircraft engines. However, the correct terminology is now recognised to be thermolysis or thermal degradation given that the oils or hydraulic fluids are heated to high temperatures in the presence of air (ASHRAE, 2022). The term pyrolysis will still be used in this report given its wide use, however it is used here to represent thermolysis or thermal degradation.

Reviews of oil fume exposures

Scientific Initiatives

There have been various reviews into new and used engine oils. Reviews have suggested that: it would be almost impossible for a person in an aircraft to receive enough jet oil to cause organophosphate-induced delayed peripheral neuropathy (OPIDN) (77); no toxic effects could be expected, but symptoms of irritation could occur due to pyrolysis of the oils (61); and that pyrolysis of the oils generated 127 different compounds and that there were gaps in knowledge with regards to the effects of exposure to the oils and pyrolysis products (80).

Air monitoring studies

Scientific Initiatives

Air monitoring studies have reported that the concentration levels of the volatile organic compounds (VOCs) identified were similar to other indoor environments (66) that no pollutants in the cabin exceeded available health and safety standards and guidelines (83), and that typical concentrations of VOCs found in the cabin can cause transitory symptoms in healthy individuals (therefore questioning the adequacy of current standards) (108).

Health risk assessments

Scientific Initiatives

Limited health risk assessments and reviews have been undertaken that report that ToCP exposure cannot be the cause of Aerotoxic Syndrome (109), patterns of illness do not conform to OPIDN and ortho-TCP exposures (110) and or that the pattern of clinical signs observed are serious enough to warrant a call for further elucidation (111).

TCP/oil pyrolysis studies

Scientific Initiatives

Limited studies of TCP include in vitro analysis showing impairment of glutamate sensitivity of neurons at very low ToCP levels (112); rat ingestion of a blend of TCP used in engine oils significantly impaired various enzymes (113) and in vitro neurotoxicity studies of various TCP isomers (including non-ortho) found that the different TCP isomers were roughly equipotent and that prolonged or repeated exposure to TCP may exacerbate the observed neurotoxic effects (114). An in vitro neurotoxicity assessment of exposure to pyrolysed engine oils found that neuroactive pyrolysis products were present (80). The study found a modest trend towards increased neuronal activity when the fumes at higher concentrations were passed through an in vitro lung model. When not passed through the lung cells, neuronal activity was significantly increased on an acute basis, and (80) prolonged exposure (48 hours+) markedly decreased neuronal activity was reported raising the need to focus on prolonged and or repeated exposure to pyrolysis products (80). A further in vitro study exposing lung models to simulated pyrolysed oil and hydraulic fumes reported that “exposure to engine oil and hydraulic fluid fumes can induce considerable lung toxicity, clearly reflecting the potential health risks of contaminated aircraft cabin air”(115).

Government and regulator actions and studies

Scientific Initiatives

In 2016 the European Commission and the European aviation regulator outlined a four-stage pathway into the investigation of fume events, effect on people and risk mitigation strategies (116). The study was delayed, with a final report released in late 2021, which identified the study was incomplete, with limited results provided only including those identified by He et al., (115-117). Given the limitations of the study and the inability to answer “the ever evolving questions regarding potential health effects”, further research has been planned (118, 119). A bill was passed into US law under the Federal Aviation Administration 2018 Reauthorization Act (120). The areas addressed included assessment of the health effects on passengers and aircrew exposed to aircraft bleed air constituents, but this research has not taken place to date.

Care pathways

Scientific Initiatives

A fume event guidance document for health care professionals was published in 2009, however, while good, this was not as specific as presented here and not widely utilised (29). The International Air Transport Association (IATA) published guidance for airline health and safety staff on the medical response to cabin air quality events (51). Limited investigations are outlined for ‘high risk exposures’ with neurological and mini mental state examinations reported to be ‘rarely’ required. The UK Civil Aviation Authority (CAA) and National Health Service (NHS) have published an NHS care pathway guideline on how to respond to people exposed to fumes in aircraft (52). The guidelines are not specific and do not provide any suggested investigations. Some airlines and manufacturers are reported to have outlined limited tests that could be undertaken after fume events. The German Social Accident Insurer has published some limited medical procedure guidance for fume events (121). There have been other independent calls for a defined medical protocol to be developed (28, 49, 50). More recently the CEN European Committee for Standardization has issued a Technical Report which recommends medical monitoring at the commencement of aircrew employment and for aircrew and passengers after fume events using a best practice medical protocol (122).

General

Clinical Effects

The medical presentations of people who have been exposed to and inhaled fumes from jet engine oil, hydraulic and other fluids via the air supplied to the aircraft cabin, are variable and well described in the literature (10-43, 45-48, 50, 57, 59, 88, 123-126). In summary, symptoms initially, and consistently, are described as foggy thinking, dizziness, recognising an odour in the cabin (commonly described as a ‘dirty socks’ smell), impaired short-term memory and cognitive thinking, fatigue, headache, nausea, tremor, balance, incoordination, breathing difficulties, chest pain, eye, nose and throat irritation. Many other symptoms, with a delayed onset, have also been reported, but the common factor that binds both the acute and delayed complaints is that they are all consistent with volatile organic hydrocarbon and organophosphate toxicity. The regularity and consistency of presentation demands that this constellation of symptoms deserves identifying nomenclature as previously discussed.

Aerotoxic Syndrome

Clinical Effects

As shown in Appendix 2, Aerotoxic Syndrome encompasses a constellation of symptoms and, as is common in many medical conditions with the ‘Syndrome’ label, the complete list of symptoms and clinical findings is not necessarily found in any individual case. In this regard, it is clear from the experience of medical personnel managing cases of fume event exposures over many years and the accumulated reports in the peer reviewed literature that there is considerable individual susceptibility and variation in symptoms (28). It is likely that this observation is based on various factors, particularly environmental factors, such as the intensity and duration of exposure, exposure conditions, repeated exposures over time versus a single exposure and probably, the duration of the individual’s service in the industry. Also, clinical comorbidities, lifestyle factors (diet, smoking and alcohol use), age, general health, concurrent medication, genetic susceptibility and reproductive status may play a role. In this regard, it is germane to note that it appears to be the total accumulated dose over time that is a key factor. In short, symptoms may be prompted by a single contamination or repeated low-level exposures. It has been suggested that crew members are the most susceptible to the Aerotoxic Syndrome(28, 59, 99, 127).

Symptoms of Aerotoxic Syndrome are recognised to be non-specific and diffuse and, as such, may be dismissed by a clinician who only sees a single or only occasional case (28, 57, 59). However, at the epidemiological or population level, a syndrome can be identified (28). Symptoms and signs are variable and may affect any organ system. There is wide variability between individuals in their capacity to metabolise and detoxify OP compounds (59). The highly variable individual susceptibility to damage by OP exposure is exemplified and has been reported in farmers exposed to OP-containing sheep dips. A study involving individuals who dipped sheep for their job found that those with lower concentrations of liver and plasma enzymes that detoxify OPs were more likely to suffer from ‘dipper’s flu’ (128).

Aircrew, aviation workers and frequent fliers appear to be more susceptible to Aerotoxic Syndrome than individuals who do not fly often (59). However, some passengers who fly infrequently may fall into the susceptible category for reasons set out above.

Misdiagnosis

Clinical Effects

Experience has shown that people suffering from the effects of aircraft fume events are commonly misunderstood and misdiagnosed as being anxious, stressed or experiencing other clinical complaints. Misdiagnosis occurs because the toxic effects of pyrolysed aircraft engine oil are not widely recognised by health care professionals, including airline medical staff, when first consulted by the affected crew members or passengers. Even when the exposure is raised as the cause of their symptoms by the afflicted person, there is frequently a general view that the exposure was not significant enough to cause toxic symptoms. In this regard, health care professionals need to be aware that it is well recognised that toxicity and injury can occur following exposures well below industry accepted standards and that the absence of this form of toxicity from standard reference material does not mean that it does not occur. As in the case of multiple sclerosis, the presenting symptoms take many different forms.

Collection of data

Clinical Effects

Research highlighting adverse effects and outlining possible diagnostic criteria for symptomatic people after cabin air fume events, has led to calls for a clear medical investigation protocol (28, 49, 50). Repeated reports to a poisons unit of noxious fumes released into the aircraft cabin, has led to a call for the aviation regulator to require better safeguards to be put in place to prevent ‘Aerotoxic Syndrome’ (125). Similar calls have been made by public health agencies for better procedures, understanding and collection of data (126).

The need for a well-defined, internationally recognised medical protocol to be used in the management and investigation of people who have been exposed to fumes in an aircraft cabin is therefore provided here. It includes not only clinical information, but also the necessary data to record about the environment in which the event occurred – the what, when, where and how. Only in collecting information in a systematic way can problems associated with fume events be properly addressed with the safety, health and well-being of all people who fly in mind. A clear medical investigation protocol would also protect manufacturers and the airline industry.

General

Documentation

As outlined above, in all reported cases of fume event exposures, or Aerotoxic Syndrome, the onset or continuation of symptoms may follow one of several different time patterns as follows:

• In-flight.
• Immediate post-flight (within one to two days).
• Late/subsequent (beyond two days).

Most individuals report that the onset of symptoms is time correlated with a flight or immediately after, in some cases necessitating medical attention.

As previously discussed, the clinical symptoms reported can differ between individuals and are heterogeneous; symptoms may include functional failure in organs or organ systems, to a greater or lesser degree, as identified in Appendix 2 (28). Typical short and long-term symptoms have been reported elsewhere (29) and are shown in Appendix 3 (27).

Experience over the past decade or so suggests that in many cases symptoms are of short duration, but may take hours, days or weeks to resolve. In some cases, particularly people who have experienced more than one fume event exposure, symptoms can continue for months or years and occasionally full recovery never occurs. A systematic examination of the correlation between the intensity, duration, frequency of exposures, the effect of cumulative exposure over prolonged periods and ill-health has yet to be evaluated and published. It is anticipated that by adopting the medical protocol described in this report on a global basis that data will be accessible to address unanswered questions.

Collation of data

Documentation

The personal information, physiological and pathological data relating to fume events that should be collected and recorded are outlined below. These recommendations are based on the authors’ broad and extensive collective experience in managing flight crew who have been exposed to a fume event of any type and who have developed any of the wide variety of symptoms that have been reported to be associated with the cabin air incidents/Aerotoxic Syndrome (10, 13, 15-19, 21-23, 26-29, 32-43, 45, 46, 125, 129).

Undertaking all of the examinations and special investigations suggested in this protocol may not be possible or medically indicated in every case. Some investigations require specialist laboratories, and there will be practical issues of availability, timing and cost for procedures and tests. Requests for a special investigation should be based on clinical indication in each individual case. Despite these caveats, it is strongly recommended that as much data is collected as is practically possible in every case. Our recommendations for data collection, medical examination and special investigations are set below and formatted to examine each organ system dysfunction individually and are further broken down into time of presentation (In-flight; Immediate post-flight; and Late/subsequent).

Fume events, as discussed in this protocol, are associated with compounds in a gaseous/vapour or particulate/aerosol phase, generally with an odour and are not visible. However, this is not always the case and infrequently a visible mist or smoke may become evident and, less frequently, there may be no detectable odour. Fume events are more commonly cited as being of short duration but sustained more noticeable events are also reported. Some people may be symptomatic to varying degrees, while others may remain symptom-free or experience a delayed onset.

Hospital accident and emergency departments have standard protocols and/or medical triage procedures. The methods described in the medical protocol outlined in this report are, for the most part, based on presenting symptoms, clinical signs or other concerns, such as symptom severity (irritant only or otherwise). Thus, useful information for the ongoing care of the affected individual may not be gathered in the busy milieu of primary care or emergency facilities.

Only with a comprehensive approach in the context of a fume event presentation will this issue be solved. Given that this protocol addresses fume events related to aircraft design in both normal and abnormal operations, the authors hold that a more comprehensive review should be considered, including a toxicological assessment independent of symptomatic presentation alone.

Assessments

Documentation

Initial medical assessments undertaken at the completion of flight duties may also be required for asymptomatic, or relatively asymptomatic, people who have been exposed to fumes in an aircraft cabin. This needs to be considered when decisions are made on an initial medical management approach. Such persons also may be important in the conduct of clinical and epidemiological studies in order to address why some people react poorly to fumes in the aircraft cabin while others do not.

The recommended investigation and management approach suggested upon presentation to a medical facility is outlined below and, in the following flowchart (see Figure 1).

1. In-flight assessment ----> Section 1A.

Recommended to be undertaken for all people exposed to a fume event on an aircraft (in flight/on ground) as appropriate.

2. Immediate post-flight/event ----> Section 1B.

• All occupants:
  • Symptomatic (crew or passengers) – Full medical assessment strongly recommended (1B a, b, c).
  • Asymptomatic (crew or passengers) – Offer medical assessment: brief or full if concerned (strongly recommended for crew members).

Section 1 relates to the general investigations that should be considered after a fume event. Section 2 provides further details on human biomonitoring. Sections 3 to 11 provide relevant information and investigations for specialist areas.

The decision to what extent medical assessment should be undertaken after a fume event, should take into account a variety of factors including: potential exposure to hazardous substances and the duty of care, symptoms may arise at the time of the event, soon after, or on a latent basis. We recommend collecting the data at the time of the incident or at first presentation.

Crew should not be cleared back to fly without an assessment.

In Appendix 4, we summarise our collective experiences using each of the time pattern headings identified above. Appendix 4 has been designed to guide fume-affected people, those who assist them and medical staff who are subsequently consulted. Appendix 5 may provide assistance with regard to documenting symptoms and timing after a fume event.

Figure 1: Recommended investigation and management approach for persons exposed to fume events

SECTION 1: POST-EVENT MEDICAL PROTOCOL

Documentation

SECTION 2: FURTHER INFORMATION ON HUMAN BIOMONITORING

Documentation

SECTION 3: LUNG/HEART

Documentation

SECTION 4: NEUROLOGICAL

Documentation

SECTION 5: IRRITANTS

Documentation

SECTION 6: SENSITISATION

Documentation

SECTION 7: SKIN

Documentation

SECTION 8: GASTROINTESTINAL

Documentation

SECTION 9. OTHER

Documentation

SECTION 10: DIAGNOSTIC CODING

Documentation

SECTION 11: EMERGING ISSUES

Documentation

SECTION 12: CONCLUSIONS

Documentation

1. Kitzes G. Cabin Air Contamination Problems in Jet Aircraft. Aviation Medicine. 1956; 27(1): 53-8. PMCID: 13286221. https://perma.cc/QN4C-CB6R.

2. Gutkowski G, Page R, Peterson M. B-52 Decontamination Program. Seattle: Boeing Airplane Company; 1953. Report No. D-14766-2. https://ca-times.brightspotcdn.com/5e/30 eaf151104b9787942f39d79f87e9/ex.%201%20-%20Decontamination%20Program.pdf. Accessed 1 December 2022.

3. Reddall HA. Elimination of Engine Bleed Air Contamination. SAE Technical Paper 550185. Warrendale, PA, USA: Society of Automotive Engineers; 1955. http://dx.doi.org/10.4271/550185. Accessed 1 December 2022.

4. Loomis T, Krop S. Cabin Air Contamination in RB-57A Aircraft. Maryland, USA: Chemical Corps Medical Laboratory, US Army; 1955. Medical Laboratories Special Report (MLSR) No. 61. https://perma.cc/D6G5-LJG6. Accessed 1 December 2022.

5. AMA. Aviation Toxicology: An Introduction to the Subject and a Handbook of Data. US Aero Medical Association, Committee Aviation Toxicoloy, editors. New York: Blakiston Company; 1953. DOI: 10.1001/jama.1953.02940290066035.

6. Davidson T, Cooley, T. and Way, J. Air Force Experience with Synthetic Gas Turbine Lubricants. SAE Technical Paper 550080. Warrendale, PA, USA: Society of Automotive Engineers; 1955. https://doi.org/10.4271/550080. Accessed 1 December 2022.

7. Gaume J. Analytical Considerations Concerned With Cephalagia On The Dc-10. Long Beach: Aviation Medicine and Safety Research Science Research; McDonnell Douglas Corporation; 1973. https://perma.cc/6HLD-3N4J. Accessed 1 December 2022.

8. Tashkin DP, Coulson AH, Simmons MS, Spivey GH. Respiratory Symptoms Of Flight Attendants During High-Altitude Flight: Possible Relation To Cabin Ozone Exposure. International archives of occupational and environmental health. 1983; 52(2): 117-37. DOI: 10.1007/BF00405416.

9. Rayman R, McNaughton G. Smoke and Fumes in the Cockpit. Aviation, Space and Environmental Medicine. 1983; 54(8): 738-40. PMCID: 6626083. https://pubmed.ncbi.nlm.nih.gov/6626083/.

10. Cone J. Interim Report No. 1 & 2 - Association Of Professional Flight Attendants Health Survey. San Francisco General Hospital Medical Center. Occupational Health Clinic. September 1983, June 1984. San Francisco: San Francisco General Hospital Medical Centre 1984. https://perma.cc/CDG6-HXE5.

11. Winder C, Balouet JC, Aerotoxic Sydrome: Adverse Health Effects Following Exposure to Jet Oil Mist During Commercial Flights. ‘editor’ Eddington I. Towards a Safe and Civil Society: Proceedings of the International Congress on Occupational Health Conference; 2000 4-6 September 2000; Brisbane, Australia: ICOH. https://perma.cc/44EC-EMR4.

12. PCA. Air Safety And Cabin Air Quality in the BAe 146 Aircraft - Report by the Senate Rural and Regional Affairs and Transport References Committee - Final Report. Canberra, Australia: Parliament of the Commonwealth of Australia; October, 2000. http://www.aph.gov.au/binaries/senate/committee/rrat_ctte/completed_inquiries/1999-02/bae/report/report.pdf Accessed 1 December 2022.

13. Montgomery M, Wier GT, Zieve F, Anders MW. Human Intoxication Following Inhalation Exposure to Synthetic Jet Lubricating Oil. Clin Toxicol. 1977; 11(4): 423-6. DOI: 10.3109/15563657708988205.

14. van Netten C. Air Quality and Health Effects Associated with the Operation of BAe 146-200 Aircraft. Applied Occupational and Environmental Hygiene. 1998; 13(10): 733-9. DOI: 10.1080/1047322X.1998.10390150.

15. Winder C, Balouet JC. Aircrew Exposure to Chemicals in Aircraft: Symptoms of Irritation and Toxicity. J of Occup Health and Safety – Austr New Zealand. 2001; 17: 471-83. https://perma.cc/539Z-K2EL.

16. Winder C, Fonteyn P, Balouet JC. Aerotoxic Syndrome: A Descriptive Epidemiological Survey of Aircrew Exposed to In-Cabin Airborne Contaminants. J Occup Health Safety - Aust NZ. 2002; 18(4): 321-38. https://perma.cc/7C6P-V7PL.

17. Cox L, Michaelis S. A Survey of Health Symptoms in BAe 146 Aircrew. J of Occup Health and Safety - Aust NZ. 2002; 18(4): 305-12.

18. Michaelis S. A Survey of Health Symptoms in BALPA Boeing 757 Pilots. Journal of Occupational Health and Safety -Aust and NZ. 2003; 19(3): 253-61.

19. Somers M. Aircrew Exposed to Fumes on the Bae 146: An Assessment of Symptoms. J Occup Health and Safety - Austr New Zealand. 2005; 21(5): 440-9.

20. Abou-Donia MB. Organophosphate Ester Induced Chronic Neurotoxicity,. Journal of Occupational Health Safety-Aust NZ. 2005; 21(5): 408-32.

21. Michaelis S. The 2009 UK BAe 146 /146 RJ Health Survey. Section 4.3.4. In PhD Thesis: Health and Flight Safety Implications From Exposure to Contaminated Air in Aircraft. [PhD]. University of New South Wales: Australia; 2010. http://handle.unsw.edu.au/1959.4/50342. Accessed 1 December 2022.

22. Harper A. A Survey of Health Effects in Aircrew Exposed to Airborne Contaminants. J Occup Health & Safety - Austr and New Zealand. 2005; 21(5): 433-9. https://perma.cc/R4RA-QQNT.

23. Murawski J. Case Study: Analysis of Reported Contaminated Air Events at One Major US Airline in 2009–10. Paper ID: AIAA-2011-5089. Proc 41st Intl Conf on Environ Sys, Am Inst Aeronaut Astronaut, 17–21 July, 2011; Portland. AIAA; 2011. p. 1-11. DOI: 10.2514/6.2011-5089.

24. McNeely E, Gale S, Tager I, Kincl L, Bradley J, Coull B, et al. The Self-Reported Health of US Flight Attendants Compared to the General Population. Environmental Health. 2014; 13(13): 1-11. DOI: 10.1186/1476-069X-13-13.

25. McNeely E, Mordukhovich I, Tideman S, Gale S, Coull B. Estimating the Health Consequences of Flight Attendant Work: Comparing Flight Attendant Health to the General Population in a Cross-Sectional Study. BMC Public Health. 2018; 18(346): 1-11. DOI: 10.1186/s12889-018-5221-3.

26. Passon D. The International Crew Health Survey. J of Biological Physics and Chemistry. 2011; 11: 201-7. DOI: 10.4024/26PA11A.jbpc.11.04.

27. Winder C, Michaelis S. Crew Effects from Toxic Exposures on Aircraft. In: Hocking M, editor. Air Quality in Airplane Cabins and Similar Enclosed Spaces. 4 H. Berlin/Heidelberg, Germany: Springer-Verlag; 2005. p. 223-42. DOI: 10.1007/b107246. ISBN: 978-3-540-25019-7.

28. Michaelis S, Burdon J, Howard CV. Aerotoxic Syndrome : A New Occupational Disease ? Public Health Panorama (WHO). 2017; 3: 198-211. https://apps.who.int/iris/handle/10665/325308.

29. Harrison R, Murawski J, Mcneely E, Guerriero J, Milton D. Exposure to Aircraft Bleed Air Contaminants Among Airline Workers - A Guide for Health Care Providors. San Francisco, CA, USA: Occupational Health Research Consortium in Aviation (OHRCA); 2009. http://www.ohrca.org/medical-protocols-for-crews-exposed-to-engine-oil-fumes-on-aircraft/. Accessed 1 December 2022.

30. Michaelis S. Health and Flight Safety Implications From Exposure to Contaminated Air in Aircraft [PhD thesis]. Sydney, Australia: University of New South Wales; 2010. http://handle.unsw.edu.au/1959.4/50342. Accessed 1 December 2022.

31. Hecker S, Kincl L, McNeely E, van Netten C, Harrison R, Murawski J, et al. Cabin Air Quality Incidents Project Report. Occupational Health Research Consortium in Aviation (OHRCA) and Airliner Cabin Environment Research (ACER); 2014. http://www.ohrca.org/wp-content/uploads/2014/08/finalreport.pdf. Accessed 1 December 2022.

32. Coxon L. Neuropsychological Assessment of a Group of BAe 146 Aircraft Crew Members Exposed to Jet Engine Oil Emissions. J of Occup Health and Safety - Aust and New Zealand. 2002; 18(4): 313-9.

33. Coxon L. Delayed Cognitive Impairment and Pilot Incapacitation Following Contaminated Air Inhalation. Journal of Biological Physics and Chemistry. 2014; 14: 107-10. DOI: 10.4024/13CO14M.jbpc.14.04.

34. Mackenzie Ross S, Harper A, Burdon J. Ill Health Following Exposure to Contaminated Aircraft Air : Psychosomatic Disorder or Neurological Injury? J Occup Health Safety — Aust NZ. 2006; 22(6): 521-8.

35. Mackenzie Ross S. Cognitive Function Following Exposure to Contaminated Air on Commercial Aircraft: A Case Series of 27 Pilots Seen for Clinical Purposes. J Nutritional and Environ Med. 2008; 17(2): 111-26. DOI: 10.1080/13590840802240067.

36. Mackenzie Ross SJ, Harrison V, Madeley L, Davis K, Abraham-Smith K, Hughes T, et al. Cognitive Function Following Reported Exposure to Contaminated Air on Commercial Aircraft: Methodological Considerations for Future Researchers. J Biological Physics and Chemistry. 2011; 11: 180-91. DOI: 10.4024/30MA11A.jbpc.11.04.

37. Reneman L, Schagen SB, Mulder M, Mutsaerts HJ, Hageman G, de Ruiter MB. Cognitive Impairment and Associated Loss in Brain White Microstructure in Aircrew Members Exposed to Engine Oil Fumes. Brain Imaging Behav. 2016; 10(2): 437-44. DOI: 10.1007/s11682-015-9395-3.

38. Heuser G, Auillera O, Heuser S, Gordon R. Clinical Evaluation of Flight Attendants After Exposure to Fumes in Cabin Air. J Occup Health and Safety - Aust NZ. 2005; 21(5): 455-9. https://perma.cc/QJ8Q-XV6V.

39. Pinkerton L, Hein J, Grajewski B, Kamel F. Mortality from Neurodegenerative Diseases in a Cohort of US Flight Attendants. American Journal of Industrial Medicine; 2016. p. 532-7. DOI: 10.1002/ajim.22608.

40. Burdon J, Glanville A. Lung Injury Following Hydrocarbon Inhalation in BAe 146 Aircrew. Journal of Occupational Health and Safety Aust NZ. 2005; 21: 450-4. DOI: 10.1007/b107244.

41. Roig J, Domingo C, Burdon J, Michaelis S. Irritant-Induced Asthma Caused by Aerotoxic Syndrome. Lung. 2021; 199: 165-70. DOI: 10.1007/s00408-021-00431-z.

42. Heutelbeck A. Progress Report: Diagnostics of Health Disorders and Biomonitoring in Aircraft Crewmembers After 'Fume Events' - Preliminary Results After Analysing Patient Files. International Aircraft Cabin Air Conference 2017; 19-20 September 2017; Imperial College, London, England. J Health Pollution; 2019. p. S38-S42. DOI: 10.5696/2156-9614-9.24.191201.

43. Burdon J. Lung Injury Following Hydrocarbon Inhalation in Aircrew. Journal of Biological Physics and Chemistry. 2012; 12: 98-102.

44. Liyasova M, Li B, Schopfer LM, Nachon F, Masson P, Furlong CE, et al. Exposure to Tri-o-cresyl Phosphate Detected in Jet Airplane Passengers. Toxicology and Applied Pharmacology. 2011; 256(3): 337-47. DOI: 10.1016/j.taap.2011.06.016.

45. Abou-Donia MB, Abou-Donia MM, ElMasry Eea. Autoantibodies to Nervous System-Specific Proteins are Elevated in Sera of Flight Crew Members: Biomarkers for Nervous System Injury. J Toxicol Environ Health A. 2013; 76(6): 363-80. DOI: 10.1080/15287394.2013.765369.

46. Heutelbeck ARR, Bornemann C, Lange M, Seeckts A, Müller MM. Acetylcholinesterase and Neuropathy Target Esterase Activities in 11 Cases of Symptomatic Flight Crew Members After Fume Events. Journal of Toxicology and Environmental Health, Part A. 2016; 79(22-23): 1050-6. DOI: 10.1080/15287394.2016.1219561.

47. Hageman G, Pal TM, Nihom J, MackenzieRoss SJ, van den Berg M. Three Patients with Probable Aerotoxic Syndrome. Clinical Toxicology (Phila). 2019; 58(2): 139-42. DOI: 10.1080/15563650.2019.1616092.

48. Schindler BK, Weiss T, Schütze A, Koslitz S, Broding HC, Bünger J, et al. Occupational Exposure of Air Crews to Tricresyl Phosphate Isomers and Organophosphate Flame Retardants After Fume Events. Archives of Toxicology. 2013; 87(4): 645-8. DOI: 10.1007/s00204-012-0978-0.

49. Heutelbeck A, Baur X, Belpoggi F, Budnik LT, Burdon J, Gee D, et al., On the Need for a Standardized Human Biomonitoring Protocol for In-Flight Incidents (Called “Fume Events”). ‘editor’ 2nd International DiMoPEx Conference on “Pollution in Living and Working Environments and Health,” DiMoPEx Working Groups Meeting; 2018. 30-31 October 2017; Cesare Maltoni Cancer Research Center, Ramazzini Institute, Bologna, Italy: Journal of Health and Pollution. DOI: https://doi.org/10.5696/2156-9614.8.17.1.

50. Hageman G, Pal TM, Nihom J, Ross SJM. Aerotoxic Syndrome: Discussion of Possible Diagnostic Criteria. Clin Toxicol. 2019; 58(5): 414-6. DOI: 10.1080/15563650.2019.1649419.

51. IATA. IATA Guidance for Airline Health and Safety Staff on the Medical Response to Cabin Air Quality Events: Smoke, Fumes/Odours. Montreal, Canada: International Air Transport Association; 2015. https://www.iata.org/contentassets/ccbdc54681c24574bebf2db2b18197a5/guidance-medical-response-cabin-air-events.pdf. Accessed 1 December 2022.

52. CAA. Information for Health Professionals on Aircraft Fume Events. Civil Aviation Authority - UK Department for Transport/Division 2017. https://www.caa.co.uk/passengers/before-you-fly/am-i-fit-to-fly/guidance-for-health-professionals/aircraft-fume-events/. Accessed 1 December 2022.

53. EPAAQ. Expert Panel on Aircraft Air Quality (EPAAQ). Contamination of Aircraft Cabin Air by Bleed Air – A Review of the Evidence. Canberra, Australia: Civil Aviation Safety Authority; 2012. https://skybrary.aero/sites/default/files/bookshelf/3595.pdf. Accessed 1 December 2022.

54. NRC. The Airliner Cabin Environment and the Health of Passengers and Crew. US National Reseach Council, editor. Washington, DC: National Academy Press; 2002. DOI: https://doi.org/10.17226/10238. ISBN: 0-309-08289-7.

55. ICAO. Guidelines on Education, Training and Reporting Practices Related to Fume Events. Montréal, Canada: International Civil Aviation Organization; 2015.

56. ANSI/ASHRAE. Standard 161: Air Quality within Commercial Aircraft. Atlanta. GA, USA. American Society of Heating, Refrigerating, and Air Conditioning Engineers. 2007.

57. Howard CV, Johnson DW, Morton J, Michaelis S, Supplee D, Burdon J. Is a Cumulative Exposure to a Background Aerosol of Nanoparticles Part of the Causal Mechanism of Aerotoxic Syndrome ? Nanomedicine and Nanoscience Research. 2018; JNAN-139: 1-8. DOI: 10.29011/JNAN-139. 100039.

58. Lixian LI, Di Matteo M, Hendrick P. Experimental Study to Verify Oil Loss Through the Vent Line of the Aero-Engine Lubrication System. 9ᵀᴴ European Conference For Aeronautics And Space Sciences (EUCASS); 27 June- 1 July; Lille, France. 2022. DOI: 10.13009/EUCASS2022-4391.

59. Howard CV, Michaelis S, Watterson A. The Aetiology of ‘Aerotoxic Syndrome’ - A Toxico-Pathological Viewpoint. Open Acc J of Toxicol. 2017; 1(5): 555575. DOI: 10.19080/OAJT.2017.01.555575.

60. ASHRAE. Guideline 28: Air Quality within Commercial Aircraft. Atlanta, GA, USA: American Society of Heating, Refrigerating, and Air Conditioning Engineers; 2012.

61. CAA. CAA Paper 2004/04: Cabin Air Quality. Gatwick Airport, W. Sussex, England: Civil Aviation Authority, UK Department for Transport 2004. https://publicapps.caa.co.uk/docs/33/CAPAP2004_04.PDF. Accessed 1 December 2022.

62. ExxonMobil. Jet Oil Chemistry and Composition- Considerations for Odor Formation and Risk Assessment. ExxonMobil; 2018.

63. AIHA. Odour Thresholds for Chemicals with Established Occupational Health Standards. Fairfax, VA, USA: American Industrial Hygiene Association; 1989. ISBN: 13: 9780932627346.

64. AAIU. Air Accident Investigation Unit Ireland: AAIU Report No: 2016-013: Boeing 737-8AS, EI-EFB: 18 September 2014. Dublin: Air Accident Investigation Unit (Ireland) 2016. http://www.aaiu.ie/sites/default/files/report-attachments/REPORT%202016-013.pdf. Accessed 1 December 2022.

65. CAA. Health Information for Passengers/Cabin Air Quality. Gatwick: Civil Aviation Authority, Civil Aviation Authority - UK Department for Transport/Division 2017. https://www.caa.co.uk/Passengers/Before-you-fly/Am-I-fit-to-fly/Health-information-for-passengers/Cabin-air-quality/. Accessed 1 December 2022.

66. Schuchardt S, Bitsch A, Koch W, Rosenberger W. EASA Research Project: CAQ Preliminary Cabin Air Quality Measurement Campaign. Final Report EASA_REP_RESEA_2014_4. Cologne, Germany: European Aviation Safety Agency; 2017. https://www.easa.europa.eu/document-library/research-reports/easarepresea20144. Accessed 1 December 2022.

67. Holley J. Reducing Smoke and Burning Odor Events. Boeing Aero Quarterly. QTR-01.09. 2009:6-9. https://www.boeing.com/commercial/aeromagazine/articles/qtr_01_09/article_02_1.html. Accessed 1 December 2022.

68. Overfelt R, Jones B, Loo Sea. Rite-ACER-COE-2012-05. Sensors and Prognostics to Mitigate Bleed Air Contamination Events -2012 Progress Report. Auburn: Airliner Cabin Environment Research; 2012. Report No. RITE-ACER-CoE-2012-05. https://www.faa.gov/data_research/research/med_humanfacs/cer/media/SensorsPrognostics.pdf. Accessed 1 December 2022.

69. Michaelis S. Is it Time to Act? Journal of Biological Physics and Chemistry. 2014; 14(4): 133-5. DOI: 10.4024/19MI14M.jbpc.14.04.

70. Winder C. Hazardous Chemicals on Jet Aircraft: Jet Oils and Aerotoxic Syndrome. Curr Topics Toxicol. 2006; 3: 65-88. http://www.researchtrends.net/tia/abstract.asp?in=0&vn=3&tid=50&aid=2177&pub=2006&type=3.

71. Winder C, Balouet J-C. The Toxicity of Commercial Jet Oils. Environmental Research. 2002; 89(2): 146-64. DOI: 10.1006/enrs.2002.4346.

72. European Commission. Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on Classification, Labelling and Packaging of Substances and Mixtures (CLP). (2009). https://eur-lex.europa.eu/legal-content/EN/LSU/?uri=celex%3A32008R1272.

73. ECHA. CLP Classification and Labelling Database. Helsinki: European Chemicals Agency; 2021. Available from: https://echa.europa.eu/information-on-chemicals/cl-inventory-database. Accessed 1 December 2022.

74. Michaelis S. REACH-CLP Review of Oils Hydraulic & Deicing Fluids: S Michaelis University of Stirling; 2019. https://perma.cc/MD9N-7FM9 Accessed 1 December 2022.

75. UN. Globally Harmonized System of Classification and Labelling of Chemicals (GHS) New York , Geneva: United Nations; 2017. https://unece.org/fileadmin/DAM/trans/danger/publi/ghs/ghs_rev07/English/ST_SG_AC10_30_Rev7e.pdf

www.unece.org/trans/danger/publi/ghs/implementation_e.html.

76. Mackerer C, Ladov E. Mobil Oil Submission (14a): Submission to the Inquiry Into Air Safety - BAe 146 Cabin Air Quality: Vol 3. Canberra, Australia: Parliament of the Commonwealth of Australia; 2000. https://perma.cc/BA88-8XAJ. Accessed 1 December 2022.

77. Mackerer CR, Barth ML, Krueger AJ, Roy TA. Comparison of Neurotoxic Effects and Potential Risks From Oral Administration or Ingestion of Tricresyl Phosphate and Jet Engine Oil Containing Tricresyl Phosphate. Journal of Toxicology and Environmental Health, Part A. 1999; 57(5): 293-328. DOI: 10.1080/009841099157638.

78. PCA. Mobil Oil Australia. Written submission No.13 by Julian Plummer - Inquiry into Air Safety and Cabin Air Quality in the BAe 146 Aircraft. Parliament of the Commonwealth of Australia; 1999 7 October, 1999. https://perma.cc/2D8U-R77V.

79. EASA. A-NPA-2009-10. Cabin Air Quality Onboard Large Aeroplanes. Cologne: European Aviation Safety Agency; 2009. https://www.easa.europa.eu/document-library/notices-of-proposed-amendments/npa-2009-10. Accessed 1 December 2022.

80. Houtzager M, Noort D, Joosen M, Bos J, Jongeneel R, van Kesteren P, et al. Characterisation of the Toxicity of Aviation Turbine Engine Oils After Pyrolysis (AVOIL). Cologne, Germany: European Aviation Safety Agency; 2017. https://www.easa.europa.eu/document-library/research-reports/easarepresea20152. Accessed 1 December 2022.

81. SAE. Air 4766/2- Airborne Chemicals In Aircraft Cabins. Warrendale: Society of Automotive Engineers; 2005. https://www.sae.org/standards/content/air4766/2/. Accessed 1 December 2022.

82. Jones B, Amiri S, Roth J, Hosni M. The Nature of Particulates in Aircraft Bleed Air Resulting from Oil Contamination. LV-17-C046. 2017 ASHRAE Winter Conference; 28 January - 1 February 2017; Las Vegas, NV, USA. American Society of Heating, Refrigerating, and Air Conditioning Engineers; 2017.

83. Crump D, Harrison P, Walton C. Aircraft Cabin Air Sampling Study; Part 1 and 2 of the Final Report. Cranfield, England: Institute of Environment and Health, Cranfield University; 2011. http://dspace.lib.cranfield.ac.uk/handle/1826/5305

http://dspace.lib.cranfield.ac.uk/handle/1826/5306. Accessed 1 December 2022.

84. Rosenberger W, Beckmann B, Wrbitzky R. Airborne Aldehydes in Cabin-Air of Commercial Aircraft: Measurement by HPLC With UV Absorbance Detection of 2,4-Dinitrophenylhydrazones. Journal of Chromatography B. 2016; 1019: 117-27. DOI: 10.1016/j.jchromb.2015.08.046.

85. Spengler J, Vallarino J, Mcneely E, Estephan H. In-Flight/Onboard Monitoring: ACER’s Component for ASHRAE, 1262, Part 2. Boston, MA, USA: Research in the Intermodal Transport Environment/Aircraft Cabin Environment Research; 2012. https://www.faa.gov/data_research/research/med_humanfacs/cer/media/In-FlightOnboardMonitoring.pdf. Accessed 1 December 2022.

86. Schuchardt S, Koch W, Rosenberger W. Cabin Air Quality – Quantitative Comparison of Volatile Air Contaminants at Different Flight Phases During 177 Commercial Flights. Building and Environment. 2019; 148: 498-507. DOI: 10.1016/j.buildenv.2018.11.028.

87. Chen R, Fang L, Liu J, Herbig B, Norrefeldt V, Mayer F, et al. Cabin Air Quality on Non-Smoking Commercial Flights: A Review of Published Data on Airborne Pollutants. Indoor Air. 2021; 31(4): 926-57. DOI: 10.1111/ina.12831.

88. Diamond M. Cabin Air Quality Monitoring – Organophosphates Sampling during Fume Events in Australia. In: Scholz D, editor. Aircraft Cabin Air International Conference 2021; 15-18 March Virtual. 2021. DOI: https://doi.org/10.5281/zenodo.5567739.

89. Fox R, Chase D, Kurlak P, Koerner M, Hagh B, Johnson R, et al., inventors; Honeywell International Inc., assignee. Human Factors Approach to Control Contaminant Concentrations in Aircraft Supply Air from Engine and APU Bleed Air Air and Ground Air Sources, and in Recirculated Air Being Delivered to Aircraft Cabins for the Optimization of User Experience and Energy Consumption. USA patent US9902499B2. 2018. https://worldwide.espacenet.com/patent/search?q=pn%3DUS9902499B2

90. Fox R. Assessing Aircraft Supply Air to Recommend Compounds for Timely Warning of Contamination [PhD]. San Diego, CA, USA: Northcentral University; 2012. https://www.proquest.com/docview/1021859974/2E9451C80D5A4304PQ/1. Accessed 1 December 2022.

91. Space D, Matthews K, Takacs J, Umino P, Salgar A, Roth J, et al. Experimental Determination of the Characteristics of Lubricating Oil Contamination in Bleed Air. Lv-17-C047. 2017 ASHRAE Winter Conference 28 Jan- Feb 1; Las Vegas. ASHRAE; 2017. DOI: xxxx.

92. ASHRAE. ASHRAE Research Project Report 1830-RP: Experimental Characterization of Aircraft Bleed Air Particulate Contamination. Atlanta, GA, USA; 2022.

93. FAA. Aircraft Air Quality and Bleed Air Contamination Detection. William J. Hughes Technical Center; 2022. DOT/FAA/TC-21/45. http://www.tc.faa.gov/its/worldpac/techrpt/tc21-45.pdf. Accessed 1 December 2022.

94. Fox R. Thermal Decomposition Studies of Oils and Fuel Approved for Use in the Honeywell ALF 502/507 Engine - Study Date Dec 2001 - Jan 2002. (Presented to the UK Committee on Toxicity in December 2006). Phoenix, Arizona; 2006 20 October 2006. https://perma.cc/56E3-82FD.

95. Marshman S. Analysis of the Thermal Degradation Products Synthetic Ester Gas Turbine Lubricant. Farnborough, England: UK Ministry of Defence, Defence Evaluation and Research Agency; 2001 29 June 2001. https://perma.cc/435H-R2RW.

96. Havermans J, Houtzager M, Jacobs P. Incident Response Monitoring Technologies for Aircraft Cabin Air Quality Technology Review, Analysis and Performance Testing. Final Report. TNO-060-UTP-2013-00069 /ASHRAE 1306-RP. 2013. Report No. TNO-060-UTP-2013-00069. http://resolver.tudelft.nl/uuid:99b807f8-6993-4ea1-aeb4-d2edf3f2edf9.

97. Mair S, Scherer C, Mayer F. Emissionsverhalten eines Flugzeugmotorenols bei

Thermischer Belastung - (Emission Characteristics of an Aircraft Engine Oil Under Thermal Stress). Gefahrstoffe- Reinhaltung der Luft. 2015; 75(7/8): 295-302. https://publica.fraunhofer.de/handle/publica/242321

98. Ritchie GD, Still KR, Rossi J, Bekkedal MYV, Bobb AJ, Arfsten DP. Biological and Health Effects of Exposure to Kerosene-Based Jet Fuels and Performance Additives. Journal of Toxicology and Environmental Health - Part B: Critical Reviews. 2003; 6(4): 357-451. DOI: 10.1080/10937400306473.

99. Chaturvedi A. Aerospace Toxicology: An Overview. Oklahoma City, OK, USA: Civil Aeromedical Institute, US Federal Aviation Administration; 2009. Report No. DOT/FAA/AM-09/8. https://www.faa.gov/data_research/research/med_humanfacs/oamtechreports/2000s/media/200908.pdf. Accessed 1 December 2022.

100. Linke-Diesinger A. Systems of Commercial Turbofan Engines: An Introduction to Systems Functions: Springer, Berlin, Heidelberg; 2008. DOI: 10.1007/978-3-540-73619-6. ISBN: 978-3-540-73618-9.

101. ExxonMobil. Jet Engine Used Oil Evaluation. ExxonMobil; 2016. Available from: https://www.exxonmobil.com/en/aviation/~/media/files/global/us/aviation/Knowledge-Library/learningandresources_tech-topics_used-oil-evaluation. Accessed 1 December 2022.

102. FAA. FAA-H-8083-32. The Aviation Maintenance Handbook–Powerplant - Vol 2. Oklahoma City: Federal Aviation Administration; 2018. ISBN: 13: 9781490427638. https://www.faa.gov/regulations_policies/handbooks_manuals/aviation/media/FAA-H-8083-32-AMT-Powerplant-Vol-2.pdf

103. ACGIH. TLVs And BEIs - Threshold Limit Values for Chemical Substances and Physical Agents. Cincinnati, Ohio, USA: American Conference of Governmental Industrial Hygienists; 2015. https://www.acgih.org/publications/digital-pubs/#2015tlv. Accessed 2 December 2022.

104. Barnes J, WHO. Toxicité Pour L'homme De Certains Pesticides. Genève: Organisation mondiale de la Santé.; 1954. https://apps.who.int/iris/handle/10665/38801. Accessed 2 December 2022.

105. Lenfant C, Sullivan K. Adaption to High Altitude. New England Journal of Medicine. 1971; 284(23): 1298-309. DOI: 10.1056/NEJM197106102842305.

106. Lockhart A, Saiag B. Altitude and the Human Pulmonary Circulation. Clinical Science. 1981; 60(6): 599-605. DOI: 10.1042/cs0600599.

107. Samuels M. The Effects of Flight and Altitude. Archives of Disease in Childhood. 2004; 89: 448-55. DOI: 10.1136/adc.2003.031708.

108. Weisel CP, Fiedler N, Weschler CJ, Ohman-strickland P, Mohan KR, Mcneil K, et al. Human Symptom Responses to Bioeffluents, Short-Chain Carbonyls/Acids and Long-Chain Carbonyls in a Simulated Aircraft Cabin Environment. Indoor Air. 2017; 27(6): 1154-67. DOI: 10.1111/ina.12392.

109. de Ree H, van den Berg M, Brand T, Mulder GJ, Simons R, Veldhuijzen van Zanten B, et al. Health Risk Assessment of Exposure to Tricresyl Phosphates (TCPs) in Aircraft: A Commentary. Neurotoxicology. 2014; 45: 209-15. DOI: 10.1016/j.neuro.2014.08.011.

110. COT. Position Paper on Cabin Air. London, England: UK Committee Of Toxicity; 2013. https://cot.food.gov.uk/sites/default/files/cot/cotpospapcabin.pdf. Accessed 2 December 2022.

111. de Boer J, Antelo A, van der Veen I, Brandsma S, Lammertse N. Tricresyl Phosphate and the Aerotoxic Syndrome of Flight Crew Members - Current Gaps in Knowledge. Chemosphere. 2015; 119: S58-S61. DOI: 10.1016/j.chemosphere.2014.05.015.

112. Hausherr V, van Thriel C, Krug A, Leist M, Schöbel N. Impairment of Glutamate Signaling in Mouse Central Nervous System Neurons in Vitro by Tri-Ortho-Cresyl Phosphate at Noncytotoxic Concentrations. Toxicol Sci. 2014; 142(1): 274-84. DOI: 10.1093/toxsci/kfu174.

113. Baker PE, Cole TB, Cartwright M, Suzuki SM, Thummel KE, Lin YS, et al. Identifying Safer Anti-Wear Triaryl Phosphate Additives for Jet Engine Lubricants. Chemico-Biological Interactions. 2013; 203(1): 257-64. DOI: 10.1016/j.cbi.2012.10.005.

114. Duarte DJ, Rutten JMM, van den Berg M, Westerink RHS. In Vitro Neurotoxic Hazard Characterization of Different Tricresyl Phosphate (TCP) Isomers and Mixtures. NeuroToxicology. 2017; 59: 222-30. DOI: 10.1016/j.neuro.2016.02.001.

115. He R, Houtzager M, Jongeneel W, Westerink R, Cassee F. In Vitro Hazard Characterization of Simulated Aircraft Cabin Bleed-Air Contamination in Lung Models Using an Air-Liquid Interface (ALI) Exposure System. Environment International. 2021; 156: 106718. DOI: 10.1016/J.ENVINT.2021.106718.

116. European Commission. FACTS - Aircraft Air Quality Study. Brussels, Belgium: European Commission; 2017. Available from: https://www.facts.aero/index.php. Accessed 2 December 2022.

117. European Commission. FACTS: Fresh Aircraft. Deliverable 07 - Final Report: Research Study: Investigation of the Quality Level of the Air Inside the Cabin of Large Transport Aeroplanes and its Health Implication. 2021. https://www.facts.aero/images/Status/FACTS-D7-Final_Report.pdf.

118. EASA. EASA Workshop on Future Cabin Air Quality Research - 30-31 January 2020. Cologne: European Aviation safety Agency; 2020. 2 December 2022. https://www.easa.europa.eu/newsroom-and-events/events/easa-workshop-future-cabin-air-quality-research. Accessed 2 December 2022.

119. EASA. Cabin Air Quality Assessment of Long-Term Effects of Contaminants. Cologne, Germany: European Aviation Safety Agency; 2020. Available from: https://www.easa.europa.eu/research-projects/cabin-air-quality-assessment-long-term-effects-contaminants;https://www.item.fraunhofer.de/en/r-d-expertise/toxicology/cabin-air-quality.html. Accessed 2 December 2022.

120. US Congress. Public Law No: 115-254 (2018): H.R.302 - FAA Reauthorization Act of 2018: Sec. 326. Aircraft Air Quality., (2018). https://www.congress.gov/115/plaws/publ254/PLAW-115publ254.pdf. Accessed 2 December 2022.

121. BG Verkehr. Medizinisches Standardverfahren Nach Fume-Events (Standard medical procedure after fume events). Hamburg: BG Verkehr; 2014. Available from: https://www.bg-verkehr.de/redaktion/medien-und-downloads/informationen/branchen/luftfahrt/standard-verfahren-eng.pdf. Accessed 2 December, 2022.

122. CEN. Cabin Air Quality on Civil Aircraft - Chemical Compounds - Technical Report. Brussels: CEN CENELEC; 2022. PD CEN/TR 17904:2022. https://www.en-standard.eu/pd-cen-tr-17904-2022-cabin-air-quality-on-civil-aircraft-chemical-compounds/.

123. Feuillie V, Onboard Fume Events: Short Term Health Consequences in Aircrew -Air France Medical Department, Occupational Health Services. ‘editor’ EASA Workshop, Cologne, 30-31 January 2020; 2020; Cologne: European Aviation Safety Agency. https://www.easa.europa.eu/en/downloads/113142/en.

124. Michaelis S. Contaminated Aircraft Cabin Air. J Biological Physics and Chemistry. 2011; 11: 132-45. DOI: doi: 10.4024/24MI11A.jbpc.11.04.

125. Bachman G, Santos C, Weiland J, Hon S, Lopez G. Aerotoxic Syndrome: Fuming About Fumes While Flying the Friendly Skies. Clin Toxicol. 2017; 55(7): 773-4. DOI: 10.1080/15563650.2017.1348043.

126. O’Connor L, Boland M. A Series of Three Aircraft Emergency Public Health Alerts at an International Airport Over a Six Week Period due to Suspected Contaminated Cabin Air. Journal of Environmental Science and Public Health. 2020; 4(3): 296-303. DOI: 10.26502/jesph.96120101.

127. Abeyratne R. Forensic Aspects of the Aerotoxic Syndrome. Med Law. 2002; 21(1): 179-99. PMCID: 12017442.

128. Cherry N, Mackness M, Durrington P, Povey A, Dippnall M, Smith T, et al. Paraoxonase (PON1) Polymorphisms in Farmers Attributing Ill Health to Sheep Dip. Lancet. 2002; 359(9308): 763-4. DOI: 10.1016/S0140-6736(02)07847-9.

129. Burdon J. Respiratory Symptoms and Lung Injury After Inhaling Fumes on Aircraft: Toxic Fumes or Hyperventilation? Journal of Biological Physics and Chemistry. 2014; 14(4): 103-6. DOI: 10.4024/21BU14A.jbpc.14.04.

130. Worek F, Schilha M, Neumaier K, Aurbek N, Wille T, Thiermann H, et al. On-site analysis of acetylcholinesterase and butyrylcholinesterase activity with the ChE check mobile test kit—Determination of reference values and their relevance for diagnosis of exposure to organophosphorus compounds. Toxicology Letters. 2016; 249: 22-8. DOI: https://doi.org/10.1016/j.toxlet.2016.03.007. https://www.sciencedirect.com/science/article/pii/S0378427416300431.

131. Ruhnau P, Müller M, Hallier E, Lewalter J. Ein Validiertes Photometrisches Verfahren Für Die Bestimmung Der Neuropathy Target Esterase Aktivität In Humanen Lymphozyten. A Validated Photometric Assay for the Neuropathy Target Esterase Activity in Human Lymphocytes. Umweltmedizin in Forschung und Praxis. 2001; 6: 101-3.

132. ICSC. International Programme On Chemical Safety - N-Phenyl-1-Naphthylamine. Geneva: WHO; 2016. Available from: https://inchem.org/documents/icsc/icsc/eics1113.htm. Accessed 5 December 2022.

133. ExxonMobil. Material Safety Data Sheet: Mobil Jet Oil II. Spring Tx: Exxon Mobil Corporation; 2017. https://perma.cc/MF33-2CDD.

134. Nigg HN, Knaak JB. Blood Cholinesterases as Human Biomarkers of Organophosphorus Pesticide Exposure. Reviews of Environmental Contamination and Toxicology. 2000; 163: 29-111. DOI: 10.1007/978-1-4757-6429-1_2.

135. Aldridge WN. Tricresyl Phosphates and Cholinesterase. Biochem J. 1954; 56(2): 185-9. DOI: 10.1042/bj0560185.

136. Furlong C, Rettie A, Zelter A, McDonald M, MacCoss M, Marsillach J, et al., Have You Been Exposed to Aircraft Engine Oil? Biomarkers Of Exposure. ‘editor’ International Cabin Air Conference; 2021 15-18 March 2021; Virtual. DOI: 10.5281/zenodo.4730424.

137. Furlong CE. Exposure to Triaryl Phosphates: Metabolism and Biomarkers of Exposure. Journal of Biological Physics and Chemistry. 2011; 11: 1-11. DOI: 10.4024/28FU11A.jbpc.11.04.

138. Marsilliach J, Richter RJ, Kim JH, Stevens RC, MacCoss MJ, Tomazela D, et al. Biomarkers of Organophosphorus Exposures on Humans. NeuroToxicology. 2011; 32(5): 656-60. DOI: 10.1016/j.neuro.2011.06.005.

139. Mock DM, Lankford GL, Widness JA, Burmeister LF, Kahn D, Strauss RG. Measurement of Red Cell Survival Using Biotin-Labeled Red Cells: Validation Against 51cr-Labeled Red Cells. Transfusion. 1999; 39(2): 156-62. DOI: 10.1046/j.1537-2995.1999.39299154729.x.

140. Lepage L, Schiele F, Gueguen R, Siest G. Total Cholinesterase in Plasma: Biological Variations and Reference Limits. Clinical Chemistry. 1985; 31(4): 546-50. DOI: 10.1093/clinchem/31.4.546.

141. Carletti E, Colletier J-P, Schopfer LM, Santoni G, Masson P, Lockridge O, et al. Inhibition Pathways of the Potent Organophosphate CBDP With Cholinesterases Revealed by X-Ray Crystallographic Snapshots and Mass Spectrometry. Chemical Research in Toxicology. 2013; 26(2): 280-9. DOI: 10.1021/tx3004505.

142. Lewalter J. Acetylcholinesterase Inhibitors. BAT Value Documentation. 1985; Vol 2. DOI: 10.1002/3527600418.bb0astrinhe0002. 10.1002/3527600418.bb0astrinhe0002.

143. Johnson D, Carter MD, Crow BS, Isenberg SL, Graham LA, Erol HA, et al. Quantitation of Ortho-Cresyl Phosphate Adducts to Butyrylcholinesterase in Human Serum by Immunomagnetic-UHPLC-MS/MS. Journal of Mass Spectrometry. 2015; 50(4): 683-92. DOI: 10.1002/jms.3576.

144. ACGIH. TLV Triorthocresyl Phosphate 78-30-8 - Chemical Substances Documentation Cincinnati: American Conference of Governmental Industrial Hygienists; 2016. https://www.acgih.org/. Accessed 2 December 2022.

145. Casida JE. Specificity of Substituted Phenyl Phosphorus Compounds for Esterase Inhibition in Mice. Biochemical pharmacology. 1961; 5(4): 332-42. DOI: 10.1016/0006-2952(61)90024-7.

146. van Netten C, Leung V. Hydraulic Fluids and Jet Engine Oil: Pyrolysis and Aircraft Air Quality. Archives of Environmental Health. 2001; 56(2): 181-6. DOI: 10.1080/00039890109604071.

147. Budnik LT, Kloth S, Baur X, Preisser AM, Schwarzenbach H. Circulating Mitochondrial DNA as Biomarker Linking Environmental Chemical Exposure to Early Preclinical Lesions Elevation of MtDNA in Human Serum After Exposure to Carcinogenic Halo-alkane-based Pesticides. PLOS ONE. 2013; 8(5): e64413. DOI: 10.1371/journal.pone.0064413.

148. Kloth S, Baur X, Göen T, Budnik LT. Accidental Exposure to Gas Emissions from Transit Goods Treated for Pest Control. Environmental Health. 2014; 13(1): 1-9. DOI: 10.1186/1476-069X-13-110.

149. Morgan MK, Sheldon LS, Jones PA, Croghan CW, Chuang JC, Wilson NK. The Reliability of Using Urinary Biomarkers to Estimate Children's Exposures to Chlorpyrifos and Diazinon. Journal of Exposure Science and Environmental Epidemiology. 2011; 21(3): 280-90. DOI: 10.1038/jes.2010.11.

150. Abou-Donia MB, Nomeir AA, Bower JH, Makkawy HA. Absorption, Distribution, Excretion and Metabolism of a Single Oral Dose of [14C]Tri-o-cresyl phosphate (ToCP) in the Male Rat. Toxicology. 1990; 65(1-2): 61-74. DOI: 10.1016/0300-483X(90)90079-V.

151. Somkuti SG, Abou-Donia MB. Disposition, Elimination, And Metabolism of Tri-o-cresyl phosphate Following Daily Oral Administration in Fischer 344 Male Rats. Archives of Toxicology. 1990; 64(7): 572-9. DOI: 10.1007/BF01971837.

152. Henschler D. Die Trikresylphosphatvergiftung. Experimentelle Klärung von Problemen der Ätiologie und Pathogenese (Tricresyl Phosphate Poisoning. Experimental Clarification of Problems of Etiology and Pathogenesis). Klinische Wochenscrifte. 1958; 36(14): 663-74. DOI: 10.1007/BF01488746 ; https://perma.cc/A465-LDSR.

153. Kurebayashi H, Tanaka A, Yamaha T. Metabolism and Disposition of the Flame Retardant Plasticizer, Tri-p-Cresyl Phosphate, in the Rat. Toxicology and Applied Pharmacology. 1985; 77(3): 395-404. DOI: 10.1016/0041-008X(85)90179-6.

154. Schindler B. Erarbeitung Und Anwendung Einer Analytischen Methode Zur Bestimmung Der Metabolite Von Flammschutzmitteln Auf Der Basis Von Phosphorsäuretriestern In Menschlichen KörperflüSsigkeiten [PhD]: Universität Erlangen-Nürnberg; 2009. https://d-nb.info/995579547/34 Accessed 2 December 2022.

155. Schindler BK, Förster K, Angerer J. Determination of Human Urinary Organophosphate Flame Retardant Metabolites by Solid-Phase Extraction and Gas Chromatography-Tandem Mass Spectrometry. Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences. 2009; 877(4): 375-81. DOI: 10.1016/j.jchromb.2008.12.030.

156. Erdely A, Hulderman T, Salmen R, Liston A, Zeidler-Erdely PC, Schwegler-Berry D, et al. Cross-Talk Between Lung and Systemic Circulation During Carbon Nanotube Respiratory Exposure. Potential Biomarkers. Nano Letters. 2009; 9(1): 36-43. DOI: 10.1021/nl801828z.

157. Kobayashi T, Tsuyoshi I. Diesel Exhaust Particulates Induce Nasal Mucosal Hyperresponsiveness to Inhaled Histamine Aerosol. Toxicological Sciences. 1995; 27(2): 195-202. DOI: 10.1093/toxsci/27.2.195.

158. Lam C-W, James JT, McCluskey R, Hunter RL. Pulmonary Toxicity of Single-Wall Carbon Nanotubes in Mice 7 and 90 Days After Intratracheal Instillation. Toxicological Sciences. 2004; 77(1): 126-34. DOI: 10.1093/toxsci/kfg243.

159. Muller J, Huaux F, Moreau N, Misson P, Heilier JF, Delos M, et al. Respiratory Toxicity of Multi-Wall Carbon Nanotubes. Toxicology and Applied Pharmacology. 2005; 207(3): 221-31. DOI: 10.1016/j.taap.2005.01.008.

160. Shvedova AA, Kisin ER, Mercer R, Murray AR, Johnson VJ, Potapovich AI, et al. Unusual Inflammatory and Fibrogenic Pulmonary Responses to Single-Walled Carbon Nanotubes in Mice. Am J Physiol Lung Cell Mol Physiol. 2005; 289: L698-L708. DOI: 10.1152/ajplung.00084.2005.

161. Meldrum K, Guo C, Marczylo EL, Gant TW, Smith R, Leonard MO. Mechanistic Insight into the Impact of Nanomaterials on Asthma and Allergic Airway Disease. Particle and Fibre Toxicology. 2017; 14(1): 45. DOI: 10.1186/s12989-017-0228-y.

162. AAIB. Report No. U1884. Investigation Report Concerning the Serious Incident to Aircraft Avro 146-RJ100, HB-IXN. Payerne: Swiss Transportation Safety Investigation Board; 2006. https://www.sust.admin.ch/inhalte/AV-berichte/1884_e.pdf.

163. Eastman. Eastman (Tm) Turbo Oil 2380: Safety Data Sheet. Kingsport, TN: Eastman Chemical Company; 2016. https://perma.cc/63PT-74BZ.

164. Carvalho R, Arukwe A, Ait-Aissa Sea. Mixtures of Chemical Pollutants at European Legislation Safety Concentrations: How Safe Are They? Toxicological Sciences. 2014; 141(1): 218-33. DOI: 10.1093/toxsci/kfu118.

165. IGHRC. The Interdepartmental Group on Health Risks From Chemicals. Chemical Mixtures : A Framework for Assessing Risks to Human Health. Cranfield: IEH, Cranfield University; 2009. http://www.iehconsulting.co.uk/IEH_Consulting/IEHCPubs/IGHRC/cr14.pdf. Accessed 2 December 2022.

166. European Commission. European Commission: Something From Nothing? Ensuring the Safety of Chemical Mixtures. Joint Research Centre: European Commission; 2018. https://data.europa.eu/doi/10.2760/618648. Accessed 2 december 2022.

167. Newman KL, Newman LS. Occupational Causes of Sarcoidosis. Current Opinion in Allergy and Clinical Immunology. 2012; 12(2): 145-50. DOI: 10.1097/ACI.0b013e3283515173.

168. Guzman D, Broderick B, Sotolongo A, Osinubi O, Helmer D. A Case of Sarcoidosis in a Veteran With Military-Related Environmental and Occupational Exposure. Chest. 2017; 152(4): A830. DOI: 10.1016/j.chest.2017.08.862.

169. New South Wales Court of Appeal: East West Airlines Limited V Turner [2010] NSWCA 53 - 1 April 2010(2010). http://www.austlii.edu.au/au/cases/nsw/NSWCA/2010/53.html. Accessed 2 December 2022.

170. High Court of Australia: East West Airlines Ltd V Turner [2010] HCATrans 238 (3 September 2010) & Original Decision: Turner V Eastwest Airlines Limited [2009] NSWDDT , 5 May 2009(2010). http://www.austlii.edu.au/au/other/HCATrans/2010/238.html

http://www.austlii.edu.au/au/cases/nsw/NSWDDT/2009/10.html. Accessed 2 December 2022.

171. Zavorsky GS, Hsia CCW, Hughes JMB, Borland CDR, Guénard H, van der Lee I, et al. Standardisation and Application of the Single-Breath Determination of Nitric Oxide Uptake in the Lung. European Respiratory Journal. 2017; 49: 1600962. DOI: 10.1183/13993003.00962-2016.

172. Jensen R, Leyk M, Crapo R, Muchmore D, Berclaz PY. Quality Control of DL,CO Instruments in Global Clinical Trials. European respiratory Journal. 2009; 33(4): 828-34. DOI: 10.1183/09031936.00091208.

173. Roth A, Zellinger I, Arad M, Atsmon J. Organophosphates and the Heart. Chest. 1993; 103(2): 576-82. DOI: 10.1378/chest.103.2.576.

174. Sundaragiri S, Tandur S. Electrocardiographic Profile of Agrochemical Poisoning. International Journal of Contemporary Medical Research. 2016; 3(12): 3539-42.

175. Hung DZ, Yang HJ, Li YF, Lin CL, Chang SY, Sung FC, et al. The Long-Term Effects of Organophosphates Poisoning as a Risk Factor of CVDs: A Nationwide Population-Based Cohort Study. PLoS ONE. 2015; 10(9): e0137632. DOI: 10.1371/journal.pone.0137632.

176. Panikkath R, Nugent K, Perez-Verdia A. Atrial Fibrillation After Inhalational Lung Injury: A Troubling Complication of a Rare Problem. Case Reports in Medicine. 2012; 2012: 302057. DOI: 10.1155/2012/302057.

177. Aggarwal HK, Jain D, Goyal S, Dahiya S, Mittal A. Organophosphate Poisoning Presenting as Bradycardia. El Mednifico Journal. 2014; 2(2): 182. DOI: 10.18035/emj.v2i2.78.

178. Georgiadis N, Tsarouhas K, Tsitsimpikou C, Vardavas A, Rezaee R, Germanakis I, et al. Pesticides and Cardiotoxicity. Where Do We Stand? Toxicology and Applied Pharmacology. 2018; 353: 1-14. DOI: 10.1016/j.taap.2018.06.004.

179. Bar-Meir E, Schein O, Eisenkraft A, Rubinstein R, Grubstein A, Militianu A, et al. Guidelines for Treating Cardiac Manifestations of Organophosphates Poisoning with Special Emphasis on Long QT And Torsades De Pointes. Critical reviews in Toxicology. 2007; 37: 279-85. DOI: 10.1080/10408440601177855.

180. Anand S, Singh S, Nahar Saikia U, Bhalla A, Paul Sharma Y, Singh D. Cardiac Abnormalities In Acute Organophosphate Poisoning. Clin Toxicol. 2009; 47(3): 230-5. DOI: 10.1080/15563650902724813.

181. Abou-Donia MB, Goot FRWVD, Mulder MFA. Autoantibody Markers of Neural Degeneration are Associated with Post-Mortem Histopathological Alterations of a Neurologically Injured Pilot. Journal of Biological Physics and Chemistry. 2014; 14: 34-53. DOI: 10.4024/05AB14A.jbpc.14.03.

182. Old Square Chambers. Anna Roffey Appears in Inquest Concerning the Death of Matthew Bass. 2018. Available from: http://www.oldsquare.co.uk/news-and-media/articles/anna-roffey-appears-in-inquest-concerning-the-death-of-matthew-bass Accessed 2 December 2022.

183. Masuda T, Sawada Y, Tsutsumi K, Tsuchiya N, Yokouchi S, Ohwada T, et al. Toxic Myocarditis Caused by Acute Organophosphate Poisoning. Nihon Kyukyu Igakukai Zasshi. 1993; 4(4): 359-63. DOI: 10.3893/jjaam.4.359.

184. ExxonMobil. Material Safety Data Sheet: Mobil Jet Oil II. Antwerpen, Belgium; 2019. https://perma.cc/6YQ8-XL27.

185. Howard CV. Inappropriate Use of Risk Assessment in Addressing Health Hazards Posed by Civil Aircraft Cabin Air. Open Access Journal of Toxicology. 2020; 4(2): 555634. DOI: 10.19080/OAJT.2020.04.555634.

186. Terry A, Jr. Functional Consequences of Repeated Organophosphate Exposure: Potential Non-Cholinergic Mechanisms. Pharmacol Ther. 2012; 134(3): 355-65. DOI: doi:10.1016/j.pharmthera.2012.03.001.

187. Naughton SX, Terry AV. Neurotoxicity In Acute And Repeated Organophosphate Exposure. Toxicology. 2018; 408: 101-12. DOI: 10.1016/j.tox.2018.08.011.

188. Banks CN, Lein PJ. A Review of Experimental Evidence Linking Neurotoxic Organophosphorus Compounds and Inflammation. NeuroToxicology. 2012; 33(3): 575–84. DOI: 10.1016/j.neuro.2012.02.002.

189. Basheer IA, Hajmeer M. Artificial Neural Networks: Fundamentals, Computing, Design, And Application. Journal of Microbiological Methods. 2000; 43(1): 3-31. DOI: 10.1016/S0167-7012(00)00201-3.

190. Harris J, Blain P. Neurotoxicology: What the Neurologist Needs to Know. Journal of Neurology Neurosurgery Psychiatry. 2004; 75(Suppl 3): iii29 - iii34. DOI: 10.1136/jnnp.2004.046318.

191. Davies R, Ahmed G, Freer T. Chronic Exposure to Organophosphates: Background And Clinical Picture. Advances in Psychiatric Treatment. 2000; 6(3): 187-92. DOI: 10.1192/apt.6.3.187.

192. Abou-Donia MB. Organophosphorus Ester-Induced Chronic Neurotoxicity. Archives of Environmental Health. 2003; 58(8): 484-97. DOI: 10.3200/AEOH.58.8.484-497.

193. Abou-Donia M. Mechanisms of Organophosphorus Ester-Induced Delayed Neurotoxicity: Type-I and Type-II. Annual Review of Pharmacology and Toxicology. 1990; 30: 405-40. DOI: 10.1146/annurev.pa.30.040190.002201

194. Abou-Donia MB. Organophosphorus Ester-Induced Delayed Neurotoxicity. Annual Review of Pharmacology and Toxicology. 1981; 21: 511-48. DOI: 10.1146/annurev.pa.21.040181.002455.

195. Axelrad JC, Howard CV, McLean WG. Interactions Between Pesticides and Components of Pesticide Formulations in an In Vitro Neurotoxicity Test. Toxicology. 2002; 173(3): 259-68. DOI: 10.1016/S0300-483X(02)00036-7.

196. Axelrad JC, Howard CV, McLean WG. The Effects of Acute Pesticide Exposure on Neuroblastoma Cells Chronically Exposed to Diazinon. Toxicology. 2003; 185(1-2): 67-78. DOI: 10.1016/S0300-483X(02)00592-9.

197. Howard CV, Pathogenesis of Non-Specific Neurological Signs and Symptoms in Aircrew on Civil Aircraft. ‘editor’ Aviation Health Conference, London; 2018; London. https://perma.cc/7JWV-578V

198. Cherry N MM, Mackness B, et al. ‘Dippers' Flu’ And Its Relationship to PON1 Polymorphisms. Occupational and Environmental Medicine. 2011; 68(3): 211-7. DOI: doi: 10.1136/oem.2009.052126.

199. Abou-donia MB, Conboy LA, Kokkotou E, Jacobson E, Elmasry EM, Elkafrawy P, et al. Screening for Novel Central Nervous System Biomarkers in Veterans with Gulf War Illness. Neurotoxicology and Teratology. 2017; 61: 36-46. DOI: 10.1016/j.ntt.2017.03.002.

200. Costa LG. Organophosphorus Compounds at 80: Some Old and New Issues. Toxicological Sciences. 2018; 162(1): 24-35. DOI: 10.1093/toxsci/kfx266.

201. Merwin SJ, Obis T, Nunez Y, Re DB. Organophosphate Neurotoxicity to the Voluntary Motor System on the Trail of Environment-Caused Amyotrophic Lateral Sclerosis: The Known, the Misknown, And the Unknown. Archives of Toxicology. 2017; 91(8): 2939-52. DOI: 10.1007/s00204-016-1926-1.

202. Jokanović M. Neurotoxic Effects of Organophosphorus Pesticides and Possible Association with Neurodegenerative Diseases in Man: A Review. Toxicology. 2018; 410: 125-31. DOI: 10.1016/j.tox.2018.09.009.

203. Mostafalou S, Abdollahi M. The Link of Organophosphorus Pesticides with Neurodegenerative and Neurodevelopmental Diseases Based on Evidence and Mechanisms. Toxicology. 2018; 409: 44-52. DOI: 10.1016/j.tox.2018.07.014.

204. Nicholas J, Lackland D, Dosemeci M ea. Mortality Among US Commercial Pilots and Navigators. Journal of occupational and environmental medicine. 1998; 40(11): 980-5. DOI: 10.1097/00043764-199811000-00008.

205. Nicholas JS, Butler GC, Lackland DT, Tessier GS, Mohr J, Hoel DG. Health Among Commercial Airline Pilots. Aviation Space and Environmental Medicine. 2001; 72(9): 821-6. PMCID: 11565817.

206. Pilkington A, Buchanan D, Jamal GA, Gillham R, Hansen S, Kidd M, et al. An Epidemiological Study of the Relations Between Exposure to Organophosphate Pesticides and Indices of Chronic Peripheral Neuropathy and Neuropsychological Abnormalities in Sheep Farmers and Dippers. Occupational and Environmental Medicine. 2001; 58(11): 702-10. DOI: 10.1136/oem.58.11.702.

207. Sommer C, Geber C, Young P, Forst R, Birklein F, Schoser B. Polyneuropathies: Etiology, Diagnosis, and Treatment Options. Deutsches Ärzteblatt International | Dtsch Arztebl Int. 2018; 115: 83-90. DOI: 10.3238/arztebl.2018.083.

208. Devigili G, Tugnoli V, Penza P, Camozzi F, Lombardi R, Melli G, et al. The Diagnostic Criteria for Small Fibre Neuropathy: From Symptoms to Neuropathology. Brain. 2008; 131(7): 1912–25. DOI: 10.1093/brain/awn093.

209. Lauria G, Hsieh ST, Johansson O, Kennedy WR, Leger J, Mellgren S, et al. European Federation of Neurological Societies / Peripheral Nerve Society Guideline on the Use of Skin Biopsy in the Diagnosis of Small Fiber Neuropathy. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society. European Journal of Neurology. 2010; 17: 903-12. DOI: 10.1111/j.1468-1331.2010.03023.x.

210. Devigili G, Rinaldo S, Lombardi R, Cazzato D, Marchi M, Salvi E, et al. Diagnostic Criteria for Small Fibre Neuropathy in Clinical Practice and Research. Brain. 2019; 142(12): 3728–36. DOI: 10.1093/brain/awz333.

211. Sibomana I, Good NA, Hellman PT, Rosado L, Mattie DR. Acute Dermal Toxicity Study of New, Used and Laboratory Aged Aircraft Engine Oils. Toxicology Reports. 2019; 6: 1246-52. DOI: 10.1016/j.toxrep.2019.11.010.

212. Boeing. Boeing MSDS No. 138541. Material Safety Data Sheet- Mil-PRF-23699 (lubricating Oil- Aircraft Turbine Engines- Synthetic Base). Rev 08/09/2007. Seattle: Boeing; 2007. https://perma.cc/KEV6-X6CD.

213. Ladov E. Letter From E Ladov to J Aveni Mobil Oil Corporation- Mobil Jet Oil II. January 24, 1983. New York: Mobil Oil Corporation; 1983. https://perma.cc/Z87P-3TXE.

214. NTP. NTP Chemical Repository (Radian Corporation, August 29, 1991) Tricresyl Phosphate. 1991. https://perma.cc/Z3NY-NTGA.

215. Chemtura. Material Safety Data Sheet- Durad 125 (Tricresyl Phosphate): MSDS Number: 00691. 2006. https://perma.cc/EPJ3-CN38.

216. Mobil. Mobil Jet Oil II Material Safety Data Bulletin -430207-00. Fairfax, Virginia: Mobil Oil Corp; 1999. https://perma.cc/U5GQ-UG99.

217. Eastman. Eastman Turbo Oil 2197 -Oil Can Label. 2018. https://perma.cc/4E8A-M725.

218. ExxonMobil. HYJET IV-A PLUS Hydraulic fluid Safety Data Sheet. Spring, TX: Exxon Mobil Corporation; 2021. https://perma.cc/CDY8-W6EE.

219. Eastman. Skydrol PE-5 - Hydraulic Fluid Safety Data Sheet. Eastman Chemical Company; 2019. https://perma.cc/V5TW-R4VH.

220. Dow. UCAR(TM) PG Aircraft Deicing Fluid Dilute "55/45". Midland, MI: DOW; 2009. https://perma.cc/YFG6-KRKH.

221. Shell. Aeroshell Turbine Oil 560: Safety Data Sheet. 2017. https://perma.cc/C2XG-DN3H.

222. IPCS. Environmental Health Criteria 110 -Tricresyl Phosphate -International programme on Chemical Safety. WHO; 1990. https://inchem.org/documents/ehc/ehc/ehc110.htm. Accessed 2 December 2022.

223. Eastman. Eastman Turbo Oil 2197 Safety Data Sheet. Kingsport, TN: Eastman Chemical Company; 2020. https://perma.cc/R3N2-5WMQ.

224. Esso. Memorandum On The Toxicity Of Synthetic Turbo Oils. Report No. MRD-17N-57; MR.12M.57. April 2, 1957. Esso - Medical Research Division: Esso Research and Engineering Company; 1957. https://perma.cc/VBM5-8VMT.

225. Hooper M. Multiple Chemical Sensitivity: Chapter 50. In: Puri B, Treasaden I, editors. Psychiatry: An Evidence Based Text: Hodder Arnold; 2009. p. 793-820. DOI: https://doi.org/10.1201/b13480https://www.taylorfrancis.com/chapters/mono/10.1201/b13480-58/multiple-chemical-sensitivity-malcolm-hooper-bassant-puri-ian-treasaden?context=ubx&refId=ae471026-2705-4e48-9d73-2fc305541b21

226. Meggs WJ. The Role Of Neurogenic Inflammation In Chemical Sensitivity. Ecopsychology. 2017; 9(2): 83-9. DOI: 10.1089/eco.2016.0045.

227. Winder C. Mechanisms Of Multiple Chemical Sensitivity. Toxicology Letters. 2002; 128(1-3): 85-97. DOI: 10.1016/s0378-4274(01)00536-7

228. Masri S, Miller CS, Palmer RF, Ashford N. Toxicant-Induced Loss of Tolerance for Chemicals, Foods, and Drugs: Assessing Patterns of Exposure Behind a Global Phenomenon. Environmental Sciences Europe. 2021; 33(1). DOI: 10.1186/s12302-021-00504-z.

229. Miller C. The Quick Environmental Exposure and Sensitivity Inventory (QEESI). UT Health ,San Antonio 2021. Available from: https://tiltresearch.org/qeesi-2/. Accessed 2 December 2022.

230. Palmer RF, Jaen CR, Perales RB, Rincon R, Forster JN, Miller CS. Three Questions for Identifying Chemically Intolerant Individuals in Clinical and Epidemiological Populations: The Brief Environmental Exposure and Sensitivity Inventory (BREESI). PLoS One. 2020; 15(9): e0238296. DOI: 10.1371/journal.pone.0238296.

231. ExxonMobil. Mobil Jet Oil II Safety Data Sheet. Spring, TX: Exxon Mobil Corporation; 2020. https://perma.cc/2J6P-DH4D.

232. Buja A, Mastrangelo G, Perissinotto E, Grigoletto F, Frigo AC, Rausa G, et al. Cancer Incidence Among Female Flight Attendants : A Meta-Analysis Of Published Data. 2006; 15(1): 98-105. DOI: 10.1089/jwh.2006.15.98.

233. Goodson WH, Lowe L, Carpenter DO, Gilbertson M, Ali AM, de Cerain Salsamendi AL, et al. Assessing the Carcinogenic Potential of Low-Dose Exposures to Chemical Mixtures in the Environment: The Challenge Ahead. Carcinogenesis. 2015; 36(1): S254-S96. DOI: 10.1093/carcin/bgv039.

234. Otto D. Andrew K Myers: Workers Compensation Board, State of Oregon. WCB Case No. 19-02648 - Opinion and Order. July 31, 2020. Oregon: Workers Compensation Board, State of Oregon; 2020. https://perma.cc/BZ6L-STQL

https://perma.cc/B3PL-R7A7.

235. PCA. Mobil Hansard: Oral Evidence - Inquiry Into Air Safety - BAe 146 Cabin Air Quality. Canberra, Australia; 1 February 2000, 2000. https://perma.cc/8NB7-JT4T.

236. Holgate S, Grigg J, al e. Every Breath We Take: The Lifelong Impact Of Air Pollution. Royal College of Physicians; 2016. https://www.rcplondon.ac.uk/projects/outputs/every-breath-we-take-lifelong-impact-air-pollution. Accessed 2 December 2022.

237. Künzli N, Kaiser R, Medina S, Studnicka M, Chanel O, Filliger P, et al. Public-Health Impact Of Outdoor And Traffic-Related Air Pollution: A European Assessment. Lancet: Lancet Publishing Group; 2000. p. 795-801. DOI: 10.1016/S0140-6736(00)02653-2.

238. Pope CA, Dockery DW. Health Effects of Fine Particulate Air Pollution: Lines That Connect. Journal of the Air & Waste Management Association (1995). 2006; 56(6): 709-42. DOI: 10.1080/10473289.2006.10464485.

239. Zhang J, Chen Z, Shan D, Wu Y, Zhao Y, Li C, et al. Adverse effects of exposure to fine particles and ultrafine particles in the environment on different organs of organisms. Journal of Environmental Sciences. 2022. DOI: 10.1016/j.jes.2022.08.013.

240. Zhang X, Chen X, Zhang X. The Impact of Exposure to Air Pollution on Cognitive Performance. Proceedings of the National Academy of Sciences. 2018; 115(37): 9193-7. DOI: 10.1073/PNAS.1809474115.

241. Lancet Editorial. Air Pollution And Brain Health: An Emerging Issue. The Lancet Neurology. 2018; 17(2): 103. DOI: 10.1016/S1474-4422(17)30462-3.

242. UNICEF. 17 Million Babies Under the Age of 1 Breathe Toxic Air, Majority Live in South Asia UNICEF; 2017 [6 December]. Available from: https://www.unicef.org/press-releases/babies-breathe-toxic-air-south-asia. Accessed 2 December 2022.

243. Carey IM, Anderson HR, Atkinson RW, Beevers SD, Cook DG, Strachan DP, et al. Are Noise and Air Pollution Related to the Incidence of Dementia? A Cohort Study in London, England. BMJ Open. 2018; 8(9): e022404. DOI: 10.1136/bmjopen-2018-022404.

244. Smith RB, Fecht D, Gulliver J, Beevers SD, Dajnak D, Blangiardo M, et al. Impact of London's Road Traffic Air and Noise Pollution on Birth Weight: Retrospective Population Based Cohort Study. BMJ (Online). 2017; 359: j5299. DOI: 10.1136/bmj.j5299.

245. Bonner JC. Nanoparticles as a Potential Cause of Pleural and Interstitial Lung Disease. Proceedings of the American Thoracic Society. 2010; 7(2): 138-41. DOI: 10.1513/pats.200907-061rm.

246. Mudway IS, Dundas I, Wood HE, Marlin N, Jamaludin JB, Bremner SA, et al. Impact of London's Low Emission Zone on Air Quality and Children's Respiratory Health: A Sequential Annual Cross-Sectional Study. The Lancet Public Health. 2019; 4: e28-e40. DOI: 10.1016/S2468-2667(18)30202-0.

247. Leiser CL, Hanson HA, Sawyer K, Steenblik J, Al-Dulaimi R, Madsen T, et al. Acute Effects of Air Pollutants on Spontaneous Pregnancy Loss: A Case-Crossover Study. Fertility and Sterility. 2019; 111(2): 341-7. DOI: 10.1016/j.fertnstert.2018.10.028.

248. Cesaroni G, Forastiere F, Stafoggia M, Andersen ZJ, Badaloni C, Beelen R, et al. Long Term Exposure to Ambient Air Pollution and Incidence of Acute Coronary Events: Prospective Cohort Study and Meta-Analysis in 11 European Cohorts From the Escape Project. BMJ (Online). 2014; 348: f7412. DOI: 10.1136/bmj.f7412.

249. Schraufnagel DE, Balmes JR, Cowl CT, De Matteis S, Jung S-H, Mortimer K, et al. Air Pollution And Noncommunicable Diseases: A Review by the Forum of International Respiratory Societies' Environmental Committee, Part 1: The Damaging Effects of Air Pollution Chest. 2019; 155(2): 409-16. DOI: 10.1016/j.chest.2018.10.042.

250. Schraufnagel DE, Balmes JR, Cowl CT, De Matteis S, Jung SH, Mortimer K, et al. Air Pollution and Noncommunicable Diseases: A Review by the Forum of International Respiratory Societies' Environmental Committee, Part 2: Air Pollution and Organ Systems. Chest. 2019; 155(2): 417-26. DOI: 10.1016/j.chest.2018.10.041.

251. Lavigne E, Lima I, Hatzopoulou M, Van Ryswyk K, van Donkelaar A, Martin RV, et al. Ambient ultrafine particle concentrations and incidence of childhood cancers. Environ Int. 2020; 145: 106135. DOI: 10.1016/j.envint.2020.106135.

252. Liao C-M, Chio C-P, Chen W-Y, Ju Y-R, Li W-H, Cheng Y-H, et al. Lung cancer risk in relation to traffic-related nano/ultrafine particle-bound PAHs exposure: A preliminary probabilistic assessment. Journal of Hazardous Materials. 2011; 190(1): 150-8. DOI: 10.1016/j.jhazmat.2011.03.017.

253. Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, et al. The Epidemiology of Glioma in Adults: a “State of the Science" Review. Neuro Oncol. 2014; 16(7): 896-913. DOI: 10.1093/neuonc/nou087.

254. Wu AH, Fruin S, Larson TV, Tseng C-C, Wu J, Yang J, et al. Association between Airport-Related Ultrafine Particles and Risk of Malignant Brain Cancer: A Multiethnic Cohort Study. Cancer Research. 2021; 81(16): 4360-9. DOI: 10.1158/0008-5472.Can-21-1138.

255. Nawrot TS, Torfs R, Fierens F, De Henauw S, Hoet PH, Van Kersschaever G, et al. Stronger Associations Between Daily Mortality and Fine Particulate Air Pollution in Summer Than in Winter: Evidence From a Heavily Polluted Region in Western Europe. Journal of Epidemiology and Community Health. 2007; 61(2): 146-9. DOI: 10.1136/jech.2005.044263.

256. Wichmann H, Peters A. Epidemiological Evidence of the Effects of Ultrafine Particle Exposure. Trans R Soc Lond. 2000; A358: 2751-69. DOI: 10.1098/rsta.2000.0682.

257. Araujo JA, Barajas B, Kleinman M, Wang X, Bennett BJ, Gong KW, et al. Ambient Particulate Pollutants in the Ultrafine Range Promote Early Atherosclerosis and Systemic Oxidative Stress. Circulation Research. 2008; 102(5): 589-96. DOI: doi:10.1161/CIRCRESAHA.107.164970.

258. Donaldson K, Li XY, MacNee W. Ultrafine (Nanometre) Particle Mediated Lung Injury. Journal of Aerosol Science. 1998; 29(5-6): 553-60. DOI: 10.1016/S0021-8502(97)00464-3.

259. Penttinen P, Timonen KL, Tiittanen P, Mirme A, Ruuskanen J, Pekkanen J. Number Concentration and Size of Particles in Urban Air: Effects on Spirometric Lung Function in Adult Asthmatic Subjects. Environmental Health Perspectives. 2001; 109(4): 319-23. DOI: 10.1289/ehp.01109319.

260. Wåhlin P, Palmgren F, Van Dingenen R, Raes F. Pronounced Decrease of Ambient Particle Number Emissions From Diesel Traffic in Denmark After Reduction of the Sulphur Content in Diesel Fuel. Atmospheric Environment. 2001; 35(21): 3549-52. DOI: 10.1016/S1352-2310(01)00066-8.

261. Donaldson K, Tran L, Jimenez LA, Duffin R, Newby DE, Mills N, et al. Combustion-Derived Nanoparticles: A Review of Their Toxicology Following Inhalation Exposure. Particle and Fibre Toxicology. 2005; 2(10). DOI: 10.1186/1743-8977-2-10.

262. Li N, Sioutas C, Cho A, Schmitz D, Misra C, Sempf J, et al. Ultrafine Particulate Pollutants Induce Oxidative Stress and Mitochondrial Damage. Environmental Health Perspectives. 2003; 111(4): 455-60. DOI: 10.1289/ehp.6000.

263. Harrison RM, Shi JP, Xi S, Khan A, Mark D, Kinnersley R, et al. Measurement of Number, Mass, and Size Distribution of Particles in the Atmosphere. Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences. 2000; 358(1775): 2567-80. DOI: 10.1098/rsta.2000.0669.

264. Hughes LS, Cass GR, Gone J, Ames M, Olmez I. Physical and Chemical Characterization of Atmospheric Ultrafine Particles in the Los Angeles Area. Environmental Science and Technology. 1998; 32(9): 1153-61. DOI: 10.1021/es970280r.

265. Aboh IJK, Henriksson D, Laursen J, Lundin M, Pind N, Lindgren ES, et al. EDXRF Characterisation Of Elemental Contents in PM2.5 in a Medium-Sized Swedish City Dominated by a Modern Waste Incineration Plant. X-Ray Spectrometry. 2007; 36(2): 104-10. DOI: 10.1002/xrs.947.

266. Li Z, Guan J, Yang X, Lin CH. Source Apportionment of Airborne Particles in Commercial Aircraft Cabin Environment: Contributions From Outside and Inside of Cabin. Atmospheric Environment. 2014; 89: 119-28. DOI: 10.1016/j.atmosenv.2014.01.042.

267. Michaelis S, Loraine T, Howard CV. Ultrafine Particle Levels Measured On-Board Short-Haul Commercial Passenger Jet Aircraft. Environmental Health. 2021; 20(89): 1-14. DOI: 10.1186/s12940-021-00770-7.

268. Fushimi A, Saitoh K, Fujitani Y, Takegawa N. Identification of Jet Lubrication Oil as a Major Component of Aircraft Exhaust Nanoparticles. Atmospheric Chemistry and Physics. 2019; 19(9): 6389-99. DOI: 10.5194/acp-19-6389-2019.

269. Lammers A, Janssen NAH, Boere AJF, Berger M, Longo C, Vijverberg SJH, et al. Effects Of Short-Term Exposures To Ultrafine Particles Near An Airport In Healthy Subjects. Environment International. 2020; 141. DOI: 10.1016/j.envint.2020.105779.

270. Bendtsen KM, Bengtsen E, Saber AT, Vogel U. A Review of Health Effects Associated with Exposure to Jet Engine Emissions in and Around Airports. Environmental Health : A Global Access Science Source. 2021; 20(1): 10. DOI: 10.1186/s12940-020-00690-y.

271. Bendtsen KM, Brostrøm A, Koivisto AJ, Koponen I, Berthing T, Bertram N, et al. Airport Emission Particles: Exposure Characterization and Toxicity Following Intratracheal Instillation in Mice. Particle and Fibre Toxicology. 2019; 16(1): 1-23. DOI: 10.1186/s12989-019-0305-5.

272. El Rahman HAA, Salama M, Gad El-Hak SA, El-Harouny MA, ElKafrawy P, Abou-Donia MB. A Panel of Autoantibodies Against Neural Proteins as Peripheral Biomarker for Pesticide-Induced Neurotoxicity. Neurotoxicity Research. 2018; 33(2): 316-36. DOI: 10.1007/s12640-017-9793-y.

273. Wüthrich B. Allergic and Intolerance Reactions to Wine. Allergol Select. 2018; 2(1): 80-8. DOI: 10.5414/alx01420e.

274. Lamba JK, Lin YS, Schuetz EG, Thummel KE. Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev. 2002; 54(10): 1271-94. DOI: 10.1016/s0169-409x(02)00066-2.

275. Lu WJ, Ferlito V, Xu C, Flockhart DA, Caccamese S. Enantiomers of Naringenin as Pleiotropic, Stereoselective Inhibitors of Cytochrome P450 Isoforms. Chirality. 2011; 23(10): 891-6. DOI: 10.1002/chir.21005.

276. Humbert R, Adler DA, Disteche CM, Hassett C, Omiecinski CJ, Furlong CE. The Molecular Basis of the Human Serum Paraoxonase Activity Polymorphism. Nat Genet. 1993; 3(1): 73-6. DOI: 10.1038/ng0193-73.

277. Li WF, Costa LG, Richter RJ, Hagen T, Shih DM, Tward A, et al. Catalytic efficiency determines the in-vivo efficacy of PON1 for detoxifying organophosphorus compounds. Pharmacogenetics. 2000; 10(9): 767-79. DOI: 10.1097/00008571-200012000-00002.

278. Hosokawa M, Endo T, Fujisawa M, Hara S, Iwata N, Sato Y, et al. Interindividual variation in carboxylesterase levels in human liver microsomes. Drug Metabolism and Disposition. 1995; 23(10): 1022. PMCID: 8654188.

279. Delacour H, Dedome E, Courcelle S, Hary B, Ceppa F. Butyrylcholinesterase deficiency. Ann Biol Clin (Paris). 2016; 74(3): 279-85. DOI: 10.1684/abc.2016.1141.

280. Stevens RC, Suzuki SM, Cole TB, Park SS, Richter RJ, Furlong CE. Engineered recombinant human paraoxonase 1 (rHuPON1) purified from Escherichia coli protects against organophosphate poisoning. Proc Natl Acad Sci U S A. 2008; 105(35): 12780-4. DOI: 10.1073/pnas.0805865105.

281. Van Netten C. Analysis and Implications of Aircraft Disinsectants. Science of the Total Environment. 2002; 293: 257-62. DOI: 10.1016/S0048-9697(02)00036-0.

282. Naughton SX, Hernandez CM, Beck WD, Poddar I, Yanasak N, Lin PC, et al. Repeated Exposures to Diisopropylfluorophosphate Result in Structural Disruptions of Myelinated Axons and Persistent Impairments of Axonal Transport in the Brains of Rats. Toxicology. 2018; 406-407: 92-103. DOI: 10.1016/j.tox.2018.06.004.

283. COT. COT Statement 2007/06. Statement on the Review of the Cabin Air Environment, Ill-Health in Aircraft Crews and the Possible Relationship to Smoke/Fume Events in Aircraft. London: Committee Of Toxicity 2007. https://webarchive.nationalarchives.gov.uk/ukgwa/20200803134318/
https://cot.food.gov.uk/cotstatements/cotstatementsyrs/cotstatements2007/cotstatementbalpa0706. Accessed 2 December 2022.

284. European Commission. Call For Tenders No. Move C2/2016-363 -Research Study: Investigation of the Quality Level of the Air Inside the Cabin of Large Transport Aeroplanes and its Health Implication. Tender Specifications. Brussels: European Commission - DG Mobility and Transport 2016. https://perma.cc/2ZLM-R6P2.

285. EPA. Memorandum: Guidance: Waiver Criteria for Multiple-Exposure Inhalation Toxicity Studies. HED SOP 2002.01 August 15, 2002. United States Environmental Protection Agency; 2002. https://perma.cc/D8FS-HS5G.

286. Honeywell. Honeywell Engineering Investigation Report - Customer Bleed Air Testing Engine Model Alf502R-5- Engine Serial Number LF 05311. Report No. 21-11156, 3 March 2000; Including Honeywell Air Quality Test For LF 502 Engine, S/N 5311, Test Cell 956 -December,1999. Phoenix: Honeywell; 2000.

287. SHK. Report Rl 2001: 41e. Incident Onboard Aircraft Se-Dre. Sweden, 12 November 1999. Stockholm, Sweden: Statens Haverikommission (SHK) Board of Accident Investigation; 2001 23 November 2001. https://www.havkom.se/assets/reports/rl2001_41e.pdf. Accessed 5 December 2022.

288. Rosenberger W. Effect of Charcoal Equipped HEPA Filters on Cabin Air Quality in Aircraft: A Case Study Including Smell Event Related In-Flight Measurements. Building and Environment. 2018; 143: 358-65. DOI: 10.1016/j.buildenv.2018.07.031.

289. Houtzager M, Havermans J, Bos J. Onderzoek Naar Aanwezigheid En Concentratie Van Tricresylfosfaten In De Cockpits Van KLM Boeing 737 Toestellen Tijdens Normale Operationele Condities. Investigation of Presence and Concentration of Tricesylphosphates in Cockpits of KLM Boeing 737 Aircraft During Normal Operational Conditions. TNO; 2013. TNO 2013 R11976. https://www.eerstekamer.nl/overig/20140820/tno_rapport_over_onderzoek_naar/document. Accessed 5 December 2022.

290. Kojima H, Takeuchi S, Itoh T, Iida M, Kobayashi S, Yoshida T. In Vitro Endocrine Disruption Potential Of Organophosphate Flame Retardants Via Human Nuclear Receptors. Toxicology. 2013; 314(1): 76-83. DOI: 10.1016/j.tox.2013.09.004.

291. Liu X, Ji K, Choi K. Endocrine Disruption Potentials of Organophosphate Flame Retardants and Related Mechanisms in H295R And MVIN Cell Lines and in Zebrafish. Aquatic Toxicology. 2012; 114-115: 173-81. DOI: 10.1016/j.aquatox.2012.02.019.

292. Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, et al. Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement. Endocrine Reviews. 2009; 30(4): 293-342. DOI: 10.1210/er.2009-0002.

293. Ji X, Li N, Ma M, Rao K, Yang R, Wang Z. Tricresyl phosphate isomers exert estrogenic effects via G protein-coupled estrogen receptor-mediated pathways. Environ Pollut. 2020; 264: 114747. DOI: 10.1016/j.envpol.2020.114747.

294. Bradford Hill A. The Environment and Disease: Association or Causation? Proceedings of the Royal Society of Medicine. 1965; 58(5): 295-300. PMCID: 1898525. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1898525/.

295. Vandenbroucke JP, Broadbent A, Pearce N. Causality and Causal Inference in Epidemiology: The Need for a Pluralistic Approach. International Journal of Epidemiology. 2016; 45(6): 1776-86. DOI: 10.1093/ije/dyv341.

296. Broadbent A, Vandenbroucke JP, Pearce N. Response: Formalism or pluralism? A reply to commentaries on 'Causality and causal inference in epidemiology'. Int J Epidemiol. 2016; 45(6): 1841-51. DOI: 10.1093/ije/dyw298.

297. Gee D. Associations and Causation : A Bradford Hill Approach to Aerotoxic Syndrome. International Aircraft Cabin Air Conference 2017; London. J Health and Pollution; 2019. p. S32-S7. DOI: 10.5696/2156-9614-9.24.191201.

298. Schaumburg HH. Human Neurotoxic Disease. In: Spencer P, Schaumburg H, editors. Experimental and Clinical Neurotoxicology. 2nd ed. Oxford: Oxford University Press; 2000. p. 55-82. ISBN: 9780195084771.

299. Abou-Donia MB, Krengel MH, Lapadula ES, Zundel CG, LeClair J, Massaro J, et al. Sex-Based Differences In Plasma Autoantibodies To Central Nervous System Proteins In Gulf War Veterans Versus Healthy And Symptomatic Controls. Brain Sci. 2021; 11(2): 148. DOI: 10.3390/brainsci11020148.

300. Abou-Donia MB, Lapadula ES, Krengel MH, Quinn E, LeClair J, Massaro J, et al. Using Plasma Autoantibodies of Central Nervous System Proteins to Distinguish Veterans with Gulf War Illness from Healthy and Symptomatic Controls. Brain Sci. 2020; 10(9): 610. DOI: 10.3390/brainsci10090610.

301. Abou-Donia MB, Lieberman A, Curtis L. Neural autoantibodies in patients with neurological symptoms and histories of chemical/mold exposures. Toxicology and Industrial Health. 2018; 34(1): 44-53. DOI: 10.1177/0748233717733852.

302. Abou-Donia MB, Suliman HB, Siniscalco D, Antonucci N, ElKafrawy P, Brahmajothi MV. De Novo Blood Biomarkers in Autism: Autoantibodies Against Neuronal and Glial Proteins. Behavioral Sciences. 2019; 9(5): 47. DOI: 10.3390/bs9050047.

Appendix 1A

International Civil Aviation Organization (ICAO): Examples of potential types of aircraft fumes (55).

Appendix 1B

American Society of Heating, Refrigerating and Air-Conditioning Engineers (ASHRAE) Guideline 28-2012: Air quality within commercial aircraft (60).

Appendix 1C

Frequency of occurrence of contaminants in bleed air samples (89).

Appendix 2

Aerotoxic Syndrome – List of symptoms: Acute & Long-term (28).

Appendix 3

Aerotoxic Syndrome symptoms (27).

Appendix 4: Aircraft Cabin Fume Events – Procedures to follow

Event, clinical history and physical examination

Fume events in aircraft cabins are well recognised and may cause ill health. Clinical illness caused by fume event exposures is increasingly recognised as the Aerotoxic Syndrome.

Most individuals report that the onset of symptoms is time correlated with a flight or immediately after, in some cases necessitating prompt medical examination.

A very broad spectrum of clinical symptoms has been reported to be caused by air supply generated fumes exposure. It is important to recognise and record all symptoms and complaints as they will be helpful to subsequent medical staff who may be consulted.

The onset or recurrence of symptoms may follow one of several different time patterns as follows:

• In flight: Ill health developing during the course of flight.
• Immediate post flight: Ill health developing immediately after a flight.
• Late/subsequent: Ill health developing or continuing days, weeks or even months, years after flight.

This booklet has been designed to assist those persons who have experienced ill health following a fume event and to prompt the recording of what happened, when, individual experiences, symptoms of ill health and other observations. This booklet is intended primarily for use at the time of the fume event or shortly thereafter. For this reason, the prompts related to in-flight and immediately post-flight experiences are highlighted. Longer-term suggested investigations are also listed. Please record all observations and symptoms of ill health in as much detail as possible.

A detailed record of the fume event itself with details of technical and engineering follow up, together with a record of the symptoms and the medical management of afflicted persons are indispensable for longer-term medical management.

Name
Contact
Date of birth
Other

Table 4-1: Contact details

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1A. In flight (air or ground)

• Expected to be undertaken by non-medically trained personnel.
• If medical help is available, also collect and record data listed under 1B – physical examination, as shown below.

Record of environment

Type of aircraft
When did event occur (in-flight, stage of flight, on ground, ascent, descent)?
Where did event occur (where in the aircraft or most likely location)?
How long did the event continue?
What happened (e.g. smell, fumes, smoke)?
If smell or fumes, describe type of smell.
How many persons affected and status (e.g. pilot, cabin crew, passenger? How many (x out of y) affected, when and for how long?
Record air quality monitor recordings (if available) / maintenance history / previous events if known.

Table 4-2: Record of environment

Medical record/first aid response

Record to be made by those assisting the afflicted crew members and other persons.

Clear detailed and careful description and severity of the fume event experienced by the individual.
Record symptoms and progression of symptoms.
Record observations of others (who – important in assessment of affected persons).
Measure and record oximetry, if available, before oxygen administration
Record any treatment given used (e.g. was oxygen used?including flow rate, method of administration e.g. nasal cannula/mask, when and duration) Other first aid?
Record any treatments for past exposures, if known.
Record any unusual behaviour.
Record past medical history in brief (where relevant), medication etc.
Covid 19 exposure history?

Table 4-3: Medical record/first aid response

Clinical examination

It is expected that trained health care professionals will not be present to conduct a medical examination. However, any observations or physical findings or behaviours should be recorded as they will be helpful to future medical carers in guiding ongoing medical management.

If a trained health care professional (doctor, nurse, ambulance personnel) is present, then request this person to undertake a physical examination. It is accepted that in the circumstances surrounding the event that this may be limited in extent.

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1B Immediate post flight/event

Medical history of event

Detailed occupational history of fume event – including time, severity and duration of the fume event and frequency, duration and intensity of previous fume event exposures – see environmental record, 1A
Record total flying hours – actual/estimated – Full-time or % part-time
Medical record of event – see 1A (any additional information)

Table 4-4: Medical history of event

Clinical examination

General appearance (e.g. breathlessness, pallor, agitation)
Record: Blood pressure Heart rate Respiratory rate Oxygen saturation (before and after oxygen administration, flow rate and method of administration (e.g. mask). Monitor if <95% Auscultation heart and lungs General neurological status: (conscious state, balance, muscle weakness, numbness, pupils, muscle reflexes, check for tingling of limbs, muscle cramps, tremor) Mental and cognitive state - clear thinking, problem solving:… (May use Mini-Mental State Examination- ‘MMSE’ - (Orientation for time and place; attention and calculation; memory and processing speed).
Other findings

Table 4-5: Clinical examination

General investigations

It is expected that persons who have experienced ill health during or following a fume event will consult their general practitioner or another medical practitioner, such as the company doctor, accident and emergency department doctor or a medical specialist. It is expected that most doctors will be grateful for guidance regarding appropriate clinical investigations. These tests to complement the clinical examination will give more detailed insight into the symptoms being experienced.

Special investigations should be undertaken as early as possible but should be between two to four hours and three days following exposure to complement the above clinical examination. Some pathological abnormalities will resolve fairly quickly and for this reason blood tests should be undertaken as early as possible after exposure. As an example, blood carbon monoxide levels are reduced by half every two to four hours. Other tests have a two- to three-day window. Many of these tests are routinely available but some may need referral to specialised medical units.

Routinely available:

• Full blood examination: (Hb, WCC and differential count)
• Acute phase reactants (e.g. C-reactive protein, ESR, fibrinogen)
• Routine biochemistry (U&E/Cr, LFTs, LDH)
• Muscle enzymes (e.g. Troponin, CKMM and CKMB, aldolase)
• Blood for cholinesterase (both red cell (AChE) and plasma (BChE) estimations are needed along with later baseline) ^a – see Table 1
• Others, as clinically indicated
• Carboxyhemoglobin (HbCO) Record time since exposure and/or time of last cigarette – maximum two to four hours post flight – short half-life
• Methaemoglobin – maximum two to four hours post flight (short half-life)
• Simplified cognitive assessment – Basic quick (5 min) testing of processing speed using the Symbol Digit Modalities Test (SDMT) (oral and written) and/or digit span forwards and backwards. Follow up with early referral for more detailed neuropsychological testing if required – See section 3C below.
• Other tests as clinically indicated...

Non-routinely available:

(require specialist laboratories, storage, shipping and analysis – more costly) – Table 1 and Table 2

• Bloods for neuro target esterase (NTE) ^a,b
• Urine for organophosphates ^a,b
• Blood for volatile organic hydrocarbons (VOCs) ^b

• Level of OP exposure may not be high enough to show enzyme inhibition or TCP urinary metabolites. Lack of inhibition or metabolites does not indicate that OP exposure did not take place.
• Testing is not routinely available and requires specialist laboratories.

Note: Note that a formal chain of custody should be considered for all samples.

Method	Enzyme	Half-life (days)	Sample 1 (time after incident)	Sample 2 (Baseline) (time after incident)	Sample details
Enzyme assays	AChE - Red blood cell (RBC)	33	Preferably 4 - 48 hours	2-3 months a	Standard protocol**
	BChE - Plasma	12	Preferably 4 – 24 hours	1-2 months a	Standard protocol**
	NTE * (lymphocytic)	5-7		2-3 months. a	Standard protocol* – Only fresh blood can be analysed.

Table 4-6: Acetylcholinesterase (AChE) / butyrylcholinesterase (BChE) / neuro target esterase (NTE) sampling.

* Not routinely available – (require specialist laboratories, storage, shipping and analysis – more costly).

^a. Second sample to be undertaken as a baseline. AChE recovers to normal level after around two to three months, while BChE recovers after around one to two months. If symptoms alleviate before this time, undertake baseline sample before returning to work or when away from further exposures. It is preferable to undertake a baseline before starting flying employment.

** Baseline AChE and BChE values for OP exposures have been generally determined for agricultural exposures, but not for aircraft fume event exposures. Note that there is a wide variation between individual baseline levels and therefore it is the 30-70% inhibition below the individual baseline that is the important reference. Each laboratory will use differing reference levels, which do not take into account the individual variation, which is the most important factor as outlined above.

Note: Refer to main medical protocol report (supplement) for Mass spec AChE and BChE benefits and analysis, which is being undertaken as part of a research project at the University of Washington.

		Sample 1	Further samples	Sample details
Blood	VOCs	As soon as possible after event	If possible 6 and 12 hours later and 1 month later a	5 ml normal EDTA tube. (2 ml transferred asap to coatedheadspace tubes) b
Urine	OPs	As soon as possible after event	If possible, 6 and 12 hours and 1 month later a	20 ml

Table 4-7: Non routinely available*^/** – Blood analysis for VOCs & urine analysis for OPs

* Requires contact with specialist laboratories in advance of testing, storage and shipping – more costly.

** Refer to the main medical protocol report (supplement) for further methodology and limitations.

^a. Last sample to be undertaken one month later as a baseline. VOCs mainly recover to normal levels within hours and OPs probably within two or three days. If symptoms alleviate before this time, undertake baseline sample with at least one week away from flying environment.

(1) 2 ml blood samples have to be transferred as soon as possible to coated headspace tubes for gas chromatography–mass spectrometry (GC–MS) analysis. Contact a specialized laboratory certified for the required analysis

Note: Level of OP exposure may not be high enough to show TCP urinary metabolites- see Section 2 in main medical protocol report (supplement).

Blood analysis for VOCs

Human biomonitoring (HBM) can be undertaken for VOCs, including: aldehydes, aliphatics, aromatics, ketones, alcohols and organics such as n-heptane, n-hexane, benzene, toluene, formaldehyde, acetaldehyde, n-pentane, n-octane and carboxylic acids (valeric acid/pentanoic acid, heptanoic acid, octanoic acid) etc.

Urine analysis for OPs:

HBM can be undertaken for the following OPs: triaryl, trialkyl, triaryl-alkyl organophosphates (OPs). The analysis group for the OPs may include: Tricresyl phosphate (TCP)^a; Trixylyl phosphate (TXP)^a; Tributyl phosphate (TBP)^b; Triphenyl phosphate (TPP)^c, with other potential OPs being: dibutyl phenyl phosphate (DBPP)^b; tri-isobutyl phosphate (TiBP)^b; 2,6-di-tert-butyl-p-cresol (BHT)^b and, isopropylated phenyl, phosphate (3:1) (TIPP/PIP (3:1))^c as well as mixed esters.

Note:

1. Utilised in selected oils.
2. Utilised in selected hydraulic fluids.
3. Utilised in selected oils and hydraulic fluids.

OP metabolites:

Dicresyl phosphates are known to be urinary metabolites of TCP in animal experiments. Three metabolites of tricresyl phosphate isomers—oo -, mm -, pp include dicresyl phosphate (DoCP,DmCP^, DpCP). Dialkyl phosphate metabolites of tributyl phosphate (DBP), and triphenyl phosphate (DPP) may also be assessed. See Section 2 of main protocol for further details.

Note:

Level of OP exposure may not be high enough to show TCP urinary metabolites- see Section 2 in main medical protocol report (supplement).

Autoantibodies against neuronal and glial proteins in blood biomarker testing:

• Not currently available.
• See emerging issues (C), appendix 8 of main medical protocol report (supplement).

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1C: Late/subsequent:

The medical approach is similar to that for earlier presentations.

• Medical history of the event – see Section 1B.
• Clinical examination – see Section 1B.
• Referral for specialist consultation should be considered as appropriate. Refer sections 2- 7 below.

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2. Lung/heart

2A: Immediate post flight /event

• Respiratory and heart rate.
• Auscultation of lung and heart.
• Blood pressure (if measurement and trained personnel available).
• Oxygen saturation SpO₂, (record inspired oxygen concentration, e.g., air, 2L/min by mask etc.).
• Monitor oxygen saturation if <95%.
• Spirometry.
• ECG, if indicated e.g., presence of cardiac irregularity.
• Blood tests as clinically indicated.

Specialist tests within two weeks as required

Respiratory function testing within two weeks

• Detailed lung function tests (spirometry, DLCO and FeNO and/or DLNO (if available)).
  • Check oxygen saturation SpO2.

Consider

• Arterial blood gas analysis breathing room air at rest- undertake earlier if clinical need- see below in notes.
• Expired nitric oxide (FeNO) if available.
• Exercise testing with oxygen saturation or blood gas analysis.
• Exhaled gas analysis (ergospirometry, if available).
• Blood tests (troponin, if indicated e.g., presence of cardiac irregularity).
• ECG – if required.

Notes

• Arterial blood gas analysis is a semi-invasive procedure that perhaps could be avoided in subjects that do not complain about respiratory symptoms or who show an oxygen saturation value >96% at rest and/or during a 6 Minute Walk Test.
• Spirometry is a simple test measuring basic lung volumes that can be easily performed everywhere as it does not require sophisticated equipment. It should be performed promptly because symptoms of respiratory tract irritation may be transitory.
• Measurement of DLCO and/or DLNO are procedures that detect injuries of lung diffusion but are not available in all medical settings. However, these tests should be arranged in persons with respiratory symptoms, such as cough, shortness of breath, oxygen saturation <96% and in all those with abnormal spirometric values. The same approach should be applied for exercise testing or ergospirometry.
• In case the afore-mentioned investigations are not available or in the presence of serious respiratory abnormalities, the patient should be referred immediately to a respiratory specialist or hospital.

2B: Late / subsequent – if symptoms persist over weeks or months

If significant respiratory/cardiac symptoms are present or continue, consider referral to a respiratory specialist/pulmonologist and or cardiologist for an opinion and consideration of the following:

• Repeat routine lung function tests (spirometry, diffusing capacity).
• Static lung volumes.
• Percutaneous oxygen saturation or arterial blood gas analysis, as indicated.
• Appropriate radiology, e.g. chest x-ray, high resolution lung scan (HRCT chest).
• Respiratory orientated exercise test or screen with 6-minute walk test.
• Respiratory muscle strength testing.
• Bronchial provocation (methacholine, mannitol or other agent) testing.
• Blood tests as clinically indicated.
• Specific cardiac function tests as appropriate.
• Exercise testing with oxygen saturation or blood gas analysis.

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3. Neurological

3A: Immediate post flight/event

• Full general medical assessment.
• Detailed neurological assessment and examination.
• Objective assessment of vestibular function.
• MRI brain scan.
• Consider referral to neurologist, severe neurological symptoms and signs.

3B: Late subsequent – if symptoms persist over weeks or months

• Full general medical assessment.
• Detailed neurological assessment and examination.
• Objective assessment of vestibular function.
• MRI – Refer to methodology in Reneman et al. (2016)
• PET/SPECT – Refer to methodology in Heuser et al. (2005)
• EMG/ENG: polyneuropathy.
• Skin biopsy/IENF (intraepidermal nerve fibers) – Small fiber neuropathy – There is an international guideline on how to perform this diagnostic. See Lauriaet al. (2010).

Reneman L, et al. Cognitive Impairment and Associated Loss in Brain White Microstructure in Aircrew Members Exposed to Engine Oil Fumes. Brain Imaging Behav. 2016; DOI: 10.1007/s11682-015-9395-3. Heuser G, et al. Clinical Evaluation of Flight Attendants After Exposure to Fumes in Cabin Air. J Occup Health and Safety - Aust NZ. 2005; 21(5): 455-9. Lauria G, et al. European Federation of Neurological Societies / Peripheral Nerve Society Guideline on the Use of Skin Biopsy in the Diagnosis of Small Fiber Neuropathy. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society. European Journal of Neurology. 2010; DOI: 10.1111/j.1468-1331.2010.03023.x.

3C: Neurocognitive

Neurocognitive adverse effects are reported to include: processing speed (written and oral); attention and concentration; reaction time to stimuli; sequential reaction time; complex problem solving; short and long term visual and verbal memory; cognitive flexibility / capacity to change direction.

Immediate/post flight/event

Neurocognitive testing

• Coding test from WAIS.
  • Symbol Digit Modalities Test (written and oral versions) – see Section 1B.
  • CALCAP – Simple and choice reaction time tests.

Note: All should be able to be administered by medical personnel.

Late subsequent – if symptoms persist over weeks or months

Formal neurocognitive testing

• Test for processing speed such as the Coding Test (WAIS), Symbol Digit Modalities Test (written and oral), Symbol Search (WAIS) and Trail Making test A.
• Tests of New Learning, such as the Austin Maze and the Rey Auditory Verbal Learning Test (RAVLT).
• Memory tests, such as those in the Wechsler Memory Scale, including visual and verbal memory.
• Problem Solving tests, such as the Category Test. The Wisconsin Card Sorting Test and the Stroop Test.
• Fine motor tests, such as the Reitan Finger Tapping Test of manual speed, the Grooved Pegboard Test of manual dexterity and the Dynamometer Grip Strength Test.
• In case of sleep disturbances consider full polysomnography.
• Boston Naming Test of language skills.

Tests available may vary in different countries, however most of the tests listed are universal and come primarily from the United States.

As an example, tests utilised in Germany may include: FAKT-II; RSAT; KVT-C; IGD; CompACT-Vi; Regensburger Wortflüssigkeits-Test.

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4. Other areas of investigation:

To be considered based on clinical need including:

Irritants

Management – Immediate post-flight / Late/subsequent:

• Avoid ongoing exposure to irritants.
• Manage symptoms as appropriate to the organ system involved.

Sensitisation

Management – Immediate post-flight / Late/subsequent:

• Avoid ongoing exposure to irritants.
• Manage symptoms as appropriate to the organ system involved.
• Consider referral to organ system specialist.

Skin

Management – Immediate post-flight / Late/subsequent:

• Avoid ongoing exposure to irritants.
• Consider standard dermatological treatment.
• Manage symptoms as appropriate to the organ system involved.
• Consider referral to dermatologist if recurrent.

Gastrointestinal

Management – Immediate post-flight / Late/subsequent:

• Investigations as clinically indicated.
• Consider referral to gastroenterologist.

Other

Chronic fatigue; chemical sensitivity; reproductive effects; malignancy; susceptibility to infections; sleep disturbances, visual effects and joint aches and pains. Refer main medical protocol report (supplement) for further guidance.

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Diagnostic coding

Many insurance companies and others require a specific formally recognised diagnosis listed in published diagnostic coding systems, such as the International Classification of Diseases (ICD). These can be accessed at https://www.icd10data.com. Some useful ICD10 diagnostic codings are listed below:

• J68.8: Other respiratory conditions due to chemicals, gases, fumes and vapours.
• J68.9: Unspecified respiratory condition due to chemicals, gases, fumes and vapours.
• T52.8: Toxic effects of other organic solvents.
• T52.9 Toxic effects of unspecified organic solvent.
• T65.9: Toxic effect of unspecified substance.
• G64: Other disorders of peripheral nervous system.
• G62.2: Polyneuropathy due to other toxic agents.
• G62.9: Polyneuropathy, unspecified.
• F06.7: Mild cognitive disorder.
• G92: Toxic encephalopathy (If the toxic agent is to be indicated an additional code number should be used such as those listed above)
• J98.8 Other specified respiratory disorders.
• J98.9: Respiratory disorder, unspecified – (respiratory disease (chronic) NOS)

Other areas to consider include: (supplement) for further information)

• Exposure to ultrafine particles.
• Low level repeat exposure to mixtures.
• Autoantibodies against neuronal and glial proteins in blood biomarker testing.
• Chronic low-level exposure to OPs.
• Acute and chronic exposures.
• Dose.
• Endocrine disruptors.
• Causal connection.

Appendix 5: Symptoms during / after a fume event

Symptom (circle specific one where necessary)	YES/NO	Body part/Details	MINOR (-) AVERAGE (✓) MAJOR (+)	Start/ Duration
Headache / pressure in head
Partial / full / impaired consciousness
Tingling (where)
Numbness (where)
Tremors / shaking
Balance problems / erratic movement
Visual problems
Sweating / loss of temperature control / flushing / pallor
Altered taste / metallic taste
Incoordination
Dizziness / light-headedness
Discomfort / disorientation / confusion
Drowsiness / lethargy
Concentration / memory / cognitive problems
Trouble writing / speaking
Diarrhoea
Cramping
Vomiting
Nausea
Breathing problems
Cough / respiratory irritation
Chest discomfort / pains / tightness
Increased heart rate
Palpitations
Eye irritation
Throat irritation / hoarseness
Nose irritation
Sinus problems
Joint / muscle pain / twitching
Weakness / performance decrement
Fatigue
Skin reaction / blisters
Other

Table 4-8: Symptoms during / after a fume event

Appendix 6: Blood and urine testing for VOCs and OPs

		Sample 1	Further samples	Sample details
Blood	VOCs	As soon as possible after event	If possible 6 and 12 hours later and 1 month later a	5 ml normal EDTA. (2 ml transferred asap to coatedheadspace tubes) b
Urine	OPs	As soon as possible after event	If possible, 6 and 12 hours and 1 month later a	20ml

Table 4-9: Blood and urine testing for VOCs and OPs

⁽¹⁾ Last sample to be undertaken 1 month later as a baseline. VOCs mainly recover to normal levels within hours and OPs probably within two or three days. If symptoms alleviate before this time, undertake baseline sample with at least one week away from the flying environment.

⁽²⁾ >2ml blood samples have to be transferred ASAP to coated headspace tubes for Gas Chromatography-Mass spectrometry (GCMS) analysis. Contact a specialized laboratory certified for the required analysis.

Note: Level of OP exposure may not be high enough to show TCP urinary metabolites - see Section 2.

Appendix 7: Supplementary table: Human biomonitoring

Advantage of human biomonitoring (HBM)

It is important not only to identify routes and pathways of exposure, but also to determine that exposure and absorption have occurred. Although there are many ways to quantify the airborne load of dangerous substances in the workplace and the general environment, the measurements of toxins in the air only indicate a potential risk from exposure by inhalation and simply serve to document them. In contrast, human biomonitoring affords the rational possibility of measuring the polluting dose in an organism, providing a relevant estimate of the contamination regardless of the route of exposure.

Subsumed under the term human biomonitoring is an established, standardised analytical procedure for the diagnostic investigation of biological materials with the analytical measurement of biomarkers in specified units of body products (i.e. blood, urine). Biomarkers can be any substances or processes that are measurable and indicate exposure or susceptibility or that predict the incidence or outcome of disease. The combination of exposure biomonitoring and effect biomonitoring can support the clinical diagnosis, strengthening the association between symptoms and the specific causative exposure.

Limitations

One of the important limiting factors with respect to biomonitoring is the lack of knowledge about several chemicals and/or the cumulative effects of various chemicals. For the majority of chemicals, their molecular patho-mechanisms in humans, modes of transport to an affected organ, association with the development of diseases, and modes of elimination from the body are all largely unknown.

There are currently no realistic half-life times for most of the relevant substances. If there are any half-lives, they are derived from animal experiments or a single chemical industry incident. In both cases the half-lives are derived from exposures to extremely high, mostly single substance (in other cases one or two high doses and extrapolate them to lower realistic concentrations, assuming that there is always a linear dose-response). It does not refer to a realistic situation we have with fume events, which is a co-exposure of several substances, some of them in high, some in lower concentrations (this may also differ in a given situation). Note, many chemicals are metabolised through different pathways with different concentrations and also are metabolised differently with co-exposure to other substances (this means that the balance between the metabolites and the parent substance changes).

Human biomonitoring is only of practical value if it employs analytical methods that have been validated with respect to specificity, limit of detection, reliability, and routine use. The biomonitoring analyses must include state-of-the-art internal and external quality assessment, at the same time keeping the pre-analytical and analytical factors as low as possible.

To address the important question of whether the detected low level of a chemical marker is a health hazard, several tests should be combined with clinical occupational medicine anamnesis data and, if possible, with the evaluation of personal susceptibility (acquired and genetic).

Appendix 8: Procedures for Determination of Autoantibodies to Neural Proteins.

Data source: Abou-Donia et al. (45, 299).

The following text and methodology provide additional information for the autoantibodies against neuronal and glial proteins in blood biomarker testing. It was hypothesised that exposure of cabin personnel to chemically contaminated cabin air causes neuronal cell death and the release of their neuronal and glial proteins into circulation across the leaky blood brain barrier. The references cited provide the most detailed methodology and explanation (45, 199, 299-302).

1. Plasma procedures

All sites followed the same protocol; for venipuncture, blood handling, plasma separation, aliquoting and storage at -20°C (preferably -80°C).

2. Western blot assay

Western blot analysis was used to determine autoantibodies against specific proteins in the plasma sample. The assays allowed the determination of the autoantibodies and associated isoforms of the antigen. Each plasma sample was analysed in triplicate (45). All proteins were loaded at 10 ng/lane except for IgG which was loaded as 100 ng/lane. The proteins were denatured and electrophoresed on SDS-PAGE (gradient 4% to 20%) purchased from Invitrogen (Carlsbad, CA). One gel was used for each serum sample. The proteins were transferred to polyvinylidene fluoride (PVDF) membranes (Amersham). Nonspecific binding sites were blocked with Tris-buffered Saline-Tween (TBST) (40 mM Tris [pH 7.6], 300 mM NaCl and 0.1% Tween 20) containing 5% fat-free milk powder for 1 hour at 22 °C. Membranes were incubated with serum samples at 1: 100 dilutions in TBST with 3% non-fat milk powder overnight at 4 °C. After five washes in TBST, the membranes were incubated with a 1:2000 dilution of goat anti-human IgG conjugated to horseradish peroxidase (Amersham). Membranes were developed by enhanced chemiluminescence using the manufacturer's protocol (Amersham) and a Typhoon 8600 variable model recorder. The signal intensity was quantified using Bio-Rad image analysis software (Hercules, California).

3. Specificity of plasma autoantibodies

Previously, the specificity of the plasma and serum autoantibody was checked by performing a peptide/antigen competition assay, in which the serum and plasma were spiked with the target protein or peptide (45, 199). The serum from random healthy controls was mixed with or without tau, MAP2, or MBP. The protein mix was centrifuged at 15,000 rpm to deplete any immune complexes. The supernatants were then carefully removed and used in a western blot. Specificities of autoantibodies against all tested proteins were confirmed in a follow-up study (299-302).

4. Statistics

The pooled data are presented as mean ± SD for continuous variables and the number and percent of participants in each category for categorical variables. Subjects' demographic values were compared to the control groups using Students t-test continuous and chi-square for categorical variables. Mean values of autoantibodies of the subjects were compared using analysis of covariance (ANCOVA). A two-sided p value <0.05 was accepted as statistically significant for all analyses and analyses were not adjusted for multiple comparisons. Analyses were carried out using SAS version 9.4

5. Calculations

Optical density measurement for subjects and controls was divided by the concentration of serum IgG; this value for each subject was normalised to controls and expressed as change from healthy controls. Therefore, the results are expressed as mean triplicate assay values of arbitrary optical density units normalized to IgG optical density as compared to healthy controls.

6. CNS Autoantibody Neurodegeneration Index (NDI)

This index determines the overall neurodegenerative condition of an individual based on the level of autoantibodies in the plasma. It is calculated by adding all of the values of autoantibodies for each neural protein, and then dividing the sum by the number of the autoantibodies used. Finally, the value is multiplied by ten to produce an easy NDI as previously reported (301, 302).

7. Brief methodology

Sera to be isolated using a western blot to estimate immunoglobulin-G (IgG) specific autoantibodies measured against cytoskeletal proteins associated with GFAP, S100B, MBP, MAG, neurofilament, tubulin, MAP-2, TAU, CamK2 and alpha synuclein.

Samples may be collected shortly after a fume event or at a subsequent date (any time post fume event) as chronic exposure is assumed.

Collect a total of 7 ml of blood in a test tube with a red top. Let the sample sit for 20 minutes at room temperature, and then centrifuge the sample to separate the serum. Transfer the serum to another test tube with a red top. The test tube containing serum must be kept frozen (preferably at -80 deg C, but at least -20 deg C), so should be packed in an insulated box containing dry ice.

Contact specialist laboratory for storage and shipping instructions.

Appendix 9A: Hazard classifications associated with substances in oils based on EU CLP inventory database.

Data source:(72-74).

Substance	TCP	Meta / para TCP isomers	ToCP	TXP	P A N	Alkylated diphenyl amines	Base stock – Carboxylic acids	"T I P P
*"
Substance used in product	Oils	Oils	Oils	Oils	Oils	Oils	Oils	Oils
Level in product	1-5%	<3%		0.1-1%	1-<2.5%	1-5%	95%	0-2.5%
Damage to fertility or unborn child	X			X**
Damage to organs - prolonged or repeated exposure	X			X	X
Damage to organs - single exposure	X		X**
Allergic skin reaction / sensitisation	X		X	X	X			X
Allergy or asthma symptoms or breathing					X
difficulties if inhaled
Respiratory irritation					X		X
Harmful if swallowed / in contact with skin	X	X**
Harmful if swallowed
Fatal if inhaled			X
Serious eye irritation	X			X	X	X
Skin irritation					X
Skin burns / eye damage							X
May cause genetic defects			X

*Also known as PIP (3:1) and also used in some newer hydraulic fluids.
**Harmonized classification.

AChE	Acetylcholinesterase
APU	Auxiliary power unit
ASHRAE	American Society of Heating, Refrigerating and Air-Conditioning Engineers
BChE	Butyrylcholinesterase
BNA	Beta naphthylamine
CBDP	Cresyl saligenin phosphate
CNS	Central nervous system
CO	Carbon monoxide
DLCO	Diffusing capacity for carbon monoxide
DLNO	Diffusing capacity for nitric oxide
DOCP	Di-ortho-cresyl phosphate
ED	Endocrine disruptor
FeNO	Fractional concentration exhaled nitric oxide
ICAO	International Civil Aviation Organization
MOCP	Mono-ortho-cresyl phosphate
MSDS	Material safety data sheet
NTE	Neuropathy target esterase
OP	Organophosphate
OPICN	OP-induced chronic neurotoxicity
OPIDN	OP-induced delayed neurotoxicity
PAN	Phenyl-α-naphthylamine
PNS	Peripheral nervous system
TAP	Triaryl phosphate
TBP	Tributyl phosphate
TCP	Tricresyl phosphate
TIPP/PIP (3:1)	Isopropylated phenyl phosphates /
TmCP	Tri-meta-cresyl phosphate
ToCP	Tri-ortho-cresyl phosphate
TpCP	Tri-para-cresyl phosphate
TPP	Triphenyl phosphate
TXP	Trixylyl phosphate
UFP	Ultrafine particles
VOC	Volatile organic compound

Health consequences of exposure to aircraft contaminated air and fume events: A narrative review and medical protocol for the investigation of exposed aircrew and passengers

"Practical guideline prepared by the International Fume Events Task Force (chaired by S. Michaelis) with working groups from the DiMoPEx COST-Action* and Collegium Ramazzini**"

Jonathan Burdon,¹ Lygia Therese Budnik,^{2 ***} Xaver Baur,³ C. Vyvyan Howard,⁴ Gerard Hageman,⁵ Jordi Roig,⁶ Leonie Coxon,⁷, Clement E. Furlong,⁸ David Gee,⁹ Tristan Loraine,¹⁰ Alvin V. Terry Jr.,¹¹ John Midavaine,¹² Hannes Petersen,¹³ Denis Bron,¹⁴ Colin L. Soskolne,¹⁵ Susan Michaelis.¹⁶

1. Consultant Respiratory Physician, St Vincent’s Private Hospital, East Melbourne, Australia.

2. DiMoPEx-Chair, University Medical Center Hamburg-Eppendorf, Institute for Occupational and Maritime Medicine, Hamburg, Germany.

3. European Society for Environmental and Occupational Medicine, President; Emeritus University of Hamburg, Germany.

4. Emeritus Professor, Centre for Molecular Biosciences, University of Ulster, United Kingdom.

5. Department of Neurology, Medical Spectrum Twente, Hospital Enschede, The Netherlands.

6. Department of Pulmonary Medicine. Clínica Creu Blanca, Barcelona, Spain.

7. Clinical and Forensic Psychologist, Mount Pleasant Psychology, Perth, Australia.

8. Departments of Medicine -Div. Medical Genetics and Genome Sciences, University of Washington, Seattle, United States.

9. Visiting Fellow, Centre for Pollution Research and Policy, Brunel University, London.

10. Airline Captain (ret), Technical consultant, Spokesperson for the Global Cabin Air Quality Executive, London, United Kingdom.

11. Regents Professor and Chair, Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta University, Augusta, USA.

12.Sports Doctor (Specialist Orthomolecular Medicine), Lifemedic Bilthoven, The Netherlands.

13.Faculty of Medicine, University of Iceland, Akureyri Hospital, Iceland.

14. Chief Flight Surgeon, Head of Aviation Medicine (AeMC); Federal Department of Defence, Civil Protection and Sport (DDPS); Air Force; Aeromedical Institute (FAI) / AeMC, Switzerland.

15. Professor Emeritus, University of Alberta, Edmonton, Canada.

16. Honorary Senior Research Fellow, Occupational and Environmental Health Research Group, University of Stirling / Michaelis Aviation Consulting, West Sussex, England.

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*Diagnosis, Monitoring and Prevention of Exposure related Noncommunicable diseases, DiMoPEx (www.cost.eu/actions/CA15129) is EU-COST founded action CA 15129, with partners from 27 countries (Late action chair: Lygia Therese Budnik,)

**The Collegium Ramazzini is an independent, international academy founded in 1982 comprising 180 internationally renowned experts in the fields of occupational and environmental health. The mission of the Collegium Ramazzini is to advance the study of occupational and environmental health issues and to be a bridge between the world of scientific discovery and the social and political centers that must act on the discoveries of science to protect public health (www.collegiumramazzini.org).

***The authors recognise Prof. Dr Lygia Therese Budnik for the important part that she played in developing this manuscript. Dr Budnik died on 20 November 2020 [we dedicate this article to her memory].

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Corresponding author: Susan Michaelis: susan@susanmichaelis.com