Lung https://doi.org/10.1007/s00408-021-00431-z INHALED IRRITANT-INDUCED PULMONARY DISEASE Irritant‑induced Asthma Caused by Aerotoxic Syndrome Jorge Roig1 · Christian Domingo2,3 · Jonathan Burdon4 · Susan Michaelis5 Received: 3 September 2020 / Accepted: 20 February 2021 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021 Abstract Purpose Case series on respiratory features of Aerotoxic Syndrome (AS). The term AS has been coined to describe the spectrum of clinical manifestations after aircraft fume events. Among these manifestations, neurological and respiratory symptoms are the most frequently reported complaints. Methods Three cases of AS with relevant respiratory features are presented. Results Cough and shortness of breath for 6 to12 months were the predominant symptoms in the first two cases. The first case also developed neurological symptoms affecting his central nervous system. In the third case, the patient complained for nine years about an unbearable cough triggered by odors, smells, and a variety of indoor and outdoor irritants, among other symptoms of multiple chemical sensitivity. In all three cases, the respiratory symptoms resolved after appropriate treatment. Conclusion Our report aims at raising awareness on AS and calls for actions to improve the management of patients suffer- ing from this syndrome. Keywords Respiratory symptoms · Fumes · Cough · Aerotoxic syndrome · Asthma · Multiple chemical sensitivity Introduction smell, and onboard fume events [3, 4]. In the USA alone, an average of at least two to three contaminated bleed air events Cabin and flight deck ventilation in most aircraft use outside have been estimated to occur every day [6]. However, these air mixed with air recirculated from the cabin. This unfil- remain underreported [6, 7]. tered outside air comes from the propulsion engine com- The term aerotoxic syndrome (AS) has been coined to pressors and is commonly known as bleed air. Jet engine describe the spectrum of clinical features exhibited after air- oils may leak into the breathing air because seals used in craft fume events exposure. AS encompasses a constellation bleed air systems do not completely prevent low levels of of symptoms and individual susceptibility and variation in contamination from reaching the cabin air in normal flights symptoms are considerable. Of note, the complete list of [1–5]. This phenomenon is known as aircraft fume events. symptoms and clinical findings are not necessarily found There is variability in the reported incidence of smoke, oil in all any individual cases. A study that reported extensive findings from two different cohorts showed that there may be acute and chronic patterns of adverse effects, affecting * Jorge Roig the central nervous system (CNS) and peripheral nervous jroig@separ.es system (PNS) (motor, sensory, and autonomic nervous sys- 1 Department of Pulmonary Medicine, Clínica Creu Blanca, tems involvement), the respiratory and the gastrointestinal Barcelona, Spain tract, and the cardiovascular system. The symptoms of AS 2 Department of Pulmonary Medicine, Corporació Sanitària include neurobehavioural affectation (effects on the neuro- Parc Taulí, Sabadell, Spain logical and cognitive systems); nausea, digestive problems, 3 Department of Medicine, Autonomous University cramps, nasal or throat irritation, cough, wheezing, vari- of Barcelona, Barcelona, Spain able heart rate and blood pressure, joint or muscle pain, per- 4 Consultant Respiratory Physician, St Vincent’s Hospital formance decrease, fatigue, and sensitive skin to irritants Melbourne, Fitzroy, VIC, Australia (chemical sensitivity) [1]. According to previous reports, 5 Occupational and Environmental Health Research Group, the respiratory symptoms after fume events exposure rank School of Health Sciences, University of Stirling, Stirling, only second to neurological symptoms in their frequency UK 13 Vol.:(0123456789) Lung [1, 3–5]. Symptoms, signs, objective measurements, and routine biochemistry were normal and serological tests for diagnoses are usually recorded by medical personnel and HIV were negative. The spirometry test showed a moderate by the affected persons themselves. However, no consist- airway obstruction with a strongly positive bronchodilator ency in diagnosis nor in record keeping have been reached test. A 20% increase of FEV1 was shown after inhalation of so far [8, 9]. the short-acting bronchodilator agent albuterol. The results This could be due to the controversy surrounding AS. of pulmonary function studies performed on the patient are Over the years, there has been a lack of timely and system- summarized in Table 1. Reference values were those of the atic investigation of fume events, which has propelled the European Respiratory Society (ERS) / 2012 Global Lung debate around the contamination sources and components, Initiative (GLI) for the adult population [10]. His diffusion toxicity, consistency of signs and symptoms, and lack of capacity for carbon monoxide ­(DLCO) was normal. causal mechanism [1–9]. Besides, potential contaminants Based on the clinical history and negative microbiology at the time of exposure have not been properly identified. of the patient, a diagnosis of transient irritant asthma related These inadequacies in information have hindered, not only to AS was achieved. An alternative diagnosis of reactive the assessment of measured abnormalities and their relation- airways syndrome (RADS) was ruled out because of the lack ship to clinical symptoms, but also the development and of a positive methacholine test, always required to establish implementation of preventive and therapeutic strategies. such diagnosis. He was prescribed oral steroids, leukotriene Herein, we report three cases of flight crew presenting inhibitors, inhaled long-acting muscarinic agents, and long- symptoms that corresponded to those described for AS. acting beta-adrenergic agents. Respiratory symptoms pro- gressively subsided during the following six months, but he reported a mild worsening of his neurological symptoms. At Summary of Cases that time, extensive blood tests were again normal, including negative immunological studies (ACE, rheumatoid factor, Case 1. A 47-year-old man, international airline pilot, expe- ANA, and ANCA) and MRI examination of head and spine, rienced four episodes of cabin air fume events over two years nerve conduction studies, and EMG were also normal. A during flights. Two of them were oil smell episodes and the blood sample submitted to Duke University showed highly other two were visible smoke events of unknown origin. positive results for autoantibodies against myelin basic pro- None were sufficiently serious to prompt an emergency tein (MBP), neurofilament proteins, microtubule-associated landing. During the last smoke event, the pilot developed a tau proteins, tubulin, and microtubule-associated protein-2 mild cough and shortness of breath that persisted for several (MAP-2), all biomarkers for neuronal degeneration [11]. weeks. He had ceased a mild smoking habit 17 years before Moreover, high levels of autoantibodies against glial fibril- this event. His medical and surgical histories were unre- lary acidic protein and the glial calcium-binding protein markable. Previous spirometry on regular, periodic check- S-100B, both astrocytic markers for brain injury, were also ups had always been normal. The patient was evaluated at observed. Inhaled therapy was eventually withdrawn after our Pulmonary Department one month after the beginning six months of treatment without any relapse on long-term of the fourth episode. He presented with moderate wheezing, follow-up. severe cough productive of a tiny amount of whitish sputum, and moderate dyspnea. He reported some difficulties with Table 1  Pulmonary function studies in case 1: a patient with RADS immediate memory recall and, occasionally, with his fluency related to AS of speech. In addition, he noticed some pain radiating down his arms and slight numbness and tingling in the fingers. Pulmonary function test Measured % Predicted* Cardiopulmonary auscultation revealed bilateral wheezing. TLC, L 7.47 91 Physical examination of the nervous system and brain CT RV, L 2.82 111 scan were normal. His blood pressure was normal, and he FVC, L 5.09 101 was afebrile. The results of a chest X-ray and a thoracic FEV1, L 2.45 63 CT scan did not show any relevant abnormalities and his FEV1/FVC 48 63 sputum microbiology was negative. A PCR test (Film Array FEF25-75, L 0.94 25 Respiratory Panel 2 plus) of nasopharyngeal secretions DLCO, mL/min/mm Hg 25.8 82 was negative for the following microorganisms: adenovi- rus, influenza A and B viruses, parainfluenza, respiratory AS aerotoxic syndrome, DLCO diffusion capacity for carbon monox- ide, FEF25-75 forced expiratory flow 25–75%, FEV1 forced expiratory syncytial, rhinovirus/enterovirus, Chlamydia pneumoniae, volume in one second, FEV1/FVC ratio of FEV1 to FVC, FVC forced Mycoplasma pneumoniae, Bordetella pertussis, metapneu- vital capacity, RADS reactive airway dysfunction syndrome, RV resid- movirus, and coronavirus. ERS, CRP, and total white cell ual volume, TLC total lung capacity count were slightly above the upper limit. The results of *Reference values: ERS for adult population (GLI 2012) 13 Lung Case 2. A 34-year-old woman, international airline Case 3. A 56-year-old woman, international airline pilot, flight attendant, was exposed to a few, repetitive oil smells presented with symptoms of a long-term, unbearable, dry in the cabin during takeoff and landing for two weeks. She cough and symptoms of an upper respiratory tract irrita- complained of non-specific upper respiratory tract irrita- tion. The origin was related to exposure to a variety of envi- tion, a mild but progressive dry cough, and skin itching. ronmental substances or smells. Almost any environmental After a strong smell in the cabin, she developed a skin rash cause triggered coughing. She had to stop wearing perfume that involved particularly her two ears (Fig. 1a) and trunk and using aerosols. Other symptoms included overwhelm- (Fig. 1b); her cough worsened, and she began to complain ing fatigue, mild cognitive impairment, recurrent headaches, about mild dyspnea. She denied having been bitten by an dry eyes, relapsing inflammation of eyelids, pain in her legs insect and was not taking any oral medication. A chest X-ray and shoulders, generalized muscle weakness, dizziness, and performed at the onset of the symptoms was unremarkable. tingling in her fingertips. A few years after the onset of her Her past medical history was unremarkable. No eosino- symptoms she had been forced to stop flying. The psychiat- philia was detected. The rash subsided after a course of oral ric evaluation had never revealed any relevant abnormality steroid therapy, but her moderate shortness of breath and except for some anxiety related to her unpleasant health sta- dry cough persisted. The patient was evaluated at our Pul- tus. The onset of these symptoms, soon after a fume event, monary Department two months after the beginning of the occurred nine years before the evaluation at our Pulmonary first episode. The results of her physical examination were Department. At that time, four passengers of the same flight unremarkable. Baseline spirometry values was normal, but also required medical assistance after showing nausea and bronchodilator testing assessed by inhalation of albuterol shortness of breath. Before that episode, our patient had showed an increase of 11% in FEV1. ­DLCO and thoracic CT never complained about any symptoms that could have scan were normal. Thus, a diagnosis of transient irritant been suggestive of bronchial hyperresponsiveness. Blood asthma related to AS was achieved. The patient was treated tests and neurological evaluation had been normal, except with inhaled therapy (fluticasone furoate and vilanterol). for subtle findings on a brain scan of a low pulsatility of The respiratory symptoms progressively subsided. Inhaled sylvian and thalamic arteries. A blood sample submitted therapy was withdrawn after six months of treatment without to Duke University showed a highly significant increase in any relapse on long-term follow-up. myelin-associated glycoprotein [11]. The results of all her Fig. 1  a, Bilateral erythema and inflammation of ear skin and cartilage (auricular chondritis) after exposure to aircraft fumes. b, Maculo-papular trunk rash after exposure to aircraft fumes 13 Lung chest X-ray had always been normal. Her baseline spirom- Regarding neurological symptoms, the most frequently etry results were within normal limits, but a positive bron- reported features of AS [1], a diffuse pattern is usually chodilator response of 10% in FEV1 was observed following observed. A variety of symptoms involving both CNS and inhalation of albuterol. D ­ LCO was normal. Interestingly, upon PNS have been reported: headache, impaired consciousness; breathing the gas mixture used to perform the diffusion test, trouble speaking; balance problems; visual disturbances; a severe cough episode was triggered. A diagnosis of irritant lack of coordination; dizziness; drowsiness; and shaking, asthma and multiple chemical sensitivity (MCS) related to twitches, tremors, tingling or flushing of extremities; among AS was concluded. The patient was placed on daily inhaled others. Cognitive and neurobehavioral complaints are also therapy with fluticasone furoate and vilanterol. Her cough quite common. Usually, the routine neurological examina- improved but non-respiratory symptoms persisted on long- tions are not sensitive enough to detect the underlying abnor- term follow-up. malities responsible for mild symptoms. Both MRI examina- tion and nerve conduction studies do not demonstrate any relevant abnormalities in AS cases [1]. However, increased Discussion levels of autoantibodies against neuronal and/or glial pro- teins, as found in our cases 1 and 3, would be consistent with Our case series was focused on the respiratory symptoms non-specific chemical-induced nervous system injury [11]. of AS. In the first case, the symptoms, pulmonary evalua- Concerning skin manifestations, dermal folliculitis is the tion, clinical history, and negative microbiology of the air- most frequent feature of AS. However, other skin rashes, line pilot supported a diagnosis of transient irritant asthma as found in our second case, have been also reported in AS related to AS. In the second case, the symptoms, unremark- [20]. They are usually transient but may also be recurring. able results of several tests, and positive outcome of a bron- Our third case, with distinctive symptoms for many years, chodilator test allowed us to achieve, again, a diagnosis of fulfilled the criteria of MCS, also known as idiopathic envi- transient asthma related to AS. Finally, in the third case, the ronmental intolerance, another long-term possible respira- symptoms, clinical history, and the response to a broncho- tory presentation of AS [1, 21]. This syndrome, also con- dilator test resulted in a diagnosis of MCS related to AS. troversial because of the lack of reliable case definitions, is Generally, cough, dyspnea, chest discomfort, and wheez- characterized by complains about sensitivity and heterogene- ing are the usual respiratory features of AS. In some cases, ous, non-specific symptoms when exposed to low concentra- the duration of symptoms may be just a few days or weeks, tions of chemicals commonly present in the environment and but sometimes respiratory complaints may last over many well tolerated by the general population [22]. Some patients months and even longer. Some of these cases could also be, with MCS have also reported intermittent or chronic expo- occasionally, diagnosed as RADS [1]. Previous exposure to sure to low levels of chemicals such as pesticides [23]. an irritating agent, persistent cough and wheezing, absence With respect to AS, the causative agents are also of previous respiratory complaints, duration of symptoms diverse. Fume events in aircrafts are described in a vari- for at least three months, and documented data to support ety of ways [1]. Most have no visual identifying features, bronchial hyperresponsiveness many months after fume such as mist or smoke. Oil fumes are typically described events are the hallmark of RADS, a likely presentation of as smelling like dirty socks/smelly feet, foul, musty or AS [12–14]. Since a positive result in the methacholine test oily odors, while hydraulic fluid is often described as is one of the diagnostic criteria of RADS, this diagnosis acrid. The dirty socks or smelly feet description, often could not be confirmed in our cases. A word of caution has used, is increasingly understood to be related to the ther- been suggested since limits between RADS and irritative mal degradation and hydrolysis of the oil base stocks. In asthma are sometimes quite difficult to be drawn [14]. The most aircraft engine oils, a hazardous substance that can bronchodilator testing for case one fulfilled the classical cri- be found is tricresyl phosphate, a compound with proven teria established by the ATS-ERS statement on spirometry, toxicity [24–27]. Moreover, the high temperatures attained that is, an increase in FEV1 greater than 12% [15, 16]. The in aircraft jet engines may cause thermal pyrolysis able to results of bronchodilator testing for cases two and three were produce potentially toxic, still not well defined, chemical very close to the stringent limits included in this statement. substances [25, 28]. Besides, respiratory, and neurological Other authors have suggested that an increase in FEV1 of toxicity derived from exposure to nanoparticles released more than 8% could also be considered as positive when by bleed air systems in the breathing air of commercial spirometry at baseline is within normal limits [17, 18]. A aircraft has also been reported [29]. Other contamination positive bronchodilator response according to ATS/ERS sources may include hydraulic fluids or flame retardants guidelines requiring both 200 ml and 12% increase in FEV1 emanating from the highly flame-protected environment or FVC after bronchodilator inhalation could be insensitive of airplanes [30]. Minimization of potential contaminat- in those with high or low FEV1 [19]. ing sources and/or improved reduction of pollutants by air 13 Lung cleaning should be mandatory to diminish the risk of AS References [1–9, 24–26]. An important device for air cleaning in air- craft are HEPA filters, and improving their efficacy would 1. Michaelis S, Burdon J, Howard CV (2017) Aerotoxic syndrome: decrease the risk of infection caused by airborne microor- a new occupational disease? Public Health Panorama (WHO) 3:141–356 ganisms such as SARS – CoV 2, A/H1N1 influenza virus, 2. Winder C, Balouet JC (2002) The toxicity of commercial jet and others [1, 31–33] oils. Environ Res 89:146–164. https://​d oi.​o rg/​1 0.​1 006/​e nrs.​ Nowadays, many clinicians are not aware of the exist- 2002.​4346 ence of AS; hence, when patients require medical assis- 3. Howard CV, Michaelis S, Watterson A (2017) The aetiology of ‘aerotoxic syndrome’- A toxico pathological viewpoint. Open tance after a fume event, the lack of a good, standard- Acc J Toxicol 1:555575. https://​doi.​org/​10.​19080/​OAJT.​2017.​ ized protocol precludes general recommendations on the 01.​555575.​002 immediate identification of the implicated chemical toxins, 4. Harrison V, Mackenzie Ross SJ (2016) An emerging concern: on the type of pulmonary and neurological studies to per- toxic fumes in airplane cabins. Cortex 74:297–302. https://​doi.​ org/​10.​1016/j.​cortex.​2015.​11.​014 form, and on the therapeutic management of the disease 5. Hageman G, Pal TM, Nihom J, Mackenzie Ross SJ, van den [1]. Urine and blood samples should be obtained without Berg M (2020) Three patients with probable aerotoxic syn- delay after a fume event and strict technical requirements drome. Clin Toxicol (Phila) 58:139–142. https://​d oi.​o rg/​1 0.​ should be mandatory [1]. A standardized protocol to prop- 1080/​15563​650.​2019.​16160​92 6. Shehadi M, Jones B, Hosni M (2016) Characterization of the erly approach cases suspected of AS is currently drawn frequency and nature of bleed air contamination events in com- up by a team of international experts on the subject [34]. mercial aircraft. Indoor Air 26:478–488. https://​d oi.​o rg/​1 0.​ Besides, since more than two million people fly in com- 1111/​ina.​12211 mercial aircrafts every day all over the world, there is a 7. Liyasova M, Li B, Schopfer LM, Nachon F, Masson P, Furlong C et al (2011) Exposure to tri-o-cresyl phosphate detected in need to raise awareness on this entity [1]. jet airplane passengers. Toxicol Appl Pharmacol 256:337–347. However, not all aircrew or passengers are affected https://​doi.​org/​10.​1016/j.​taap.​2011.​06.​016 by fume events [1]. Probably, individual susceptibility, 8. Schopfer LM, Furlong CE, Lockridge O (2010) Development most likely based on genetic traits such as those related of diagnostics in the search for an explanation of aerotoxic syn- drome. Anal Biochem 404:64–74. https://​doi.​org/​10.​1016/j.​ab.​ to cytochrome P-450 and paraoxonase-1 (PON-1), play a 2010.​04.​032 role in an eventual development of AS after fume events 9. Hageman G, Pal TM, Nihom J, Mackenzie Ross SJ, Berg MVD [35, 36]. In addition, recurrent and cumulative inhalation (2019) Aerotoxic syndrome, discussion of possible diagnostic of tiny concentrations of chemical substances in airplane criteria. Clin Toxicol (Phila) 58:414–416. https://​doi.​org/​10.​ 1080/​15563​650.​2019.​16494​19 cabins could explain why some become ill after long-term 10. Quanjer PH, Stanojevic S, Cole TJ et al (2012) Multi-ethnic exposure [1, 7]. This would have obvious connotations reference values for spirometry for the 3–95-yr age range: the for members of aircrews, maintenance staff, and frequent global lung function 2012 equations. Eur Respir J 40(6):1324– fliers. Besides, some routine medical treatments and even 1343. https://​doi.​org/​10.​1183/​09031​936.​00080​312 11. Abou-Donia MB, Abou-Donia MM, ElMasry EM, Monro JA, dietary factors may also interfere with the metabolic activ- Mulder MF (2013) Autoantibodies to nervous system-specific ity of cytochrome P-450 or PON-1 [35, 37]. At present, proteins are elevated in sera of flight crew members: biomarkers the potential role of underlying diseases in triggering AS for nervous system injury. J Toxicol Environ Health A 76:363– is unknown. 380. https://​doi.​org/​10.​1080/​15287​394.​2013.​765369 12. Shaffo FC, Grodzki AC, Fryer AD, Lein PJ (2018) Mechanisms In conclusion, our report of three cases of AS aims at of organophosphorus pesticide toxicity in the context of air- raising awareness on this unknown disease, particularly on way hyperreactivity and asthma. Am J Physiol Lung Cell Mol the respiratory symptoms, and calls for the implementation Physiol 2018(315):L485–L501. https://​doi.​org/​10.​1152/​ajplu​ng.​ of standardized protocols to manage AS [1–9, 34]. Further 00211.​2018 13. Alberts WM, do Pico GA (1996) Reactive airways dysfunction research is warranted to clarify which chemical substances syndrome. Chest 109:1618–1626. https://​doi.​org/​10.​1378/​chest.​ are potentially causative of this syndrome, which popula- 109.6.​1618 tions are more susceptible, and which preventive and ther- 14. Lemière C, Boulet LP, Cartier A 2020 Reactive airways dys- apeutic measures should ideally be implemented [1, 3–9]. function syndrome and irritant -induced asthma. Section Editor: Barnes PJ (ed) UpToDate Inc, Waltham, MA. https://​www.​uptod​ ate.​com. Accessed 17 Jan 2021 Acknowledgements The authors thank Matías Rey-Carrizo, PhD, from 15. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casa- BCN Medical Writing for providing editorial support buri R et al (2005) Interpretative strategies for lung function tests. Eur Respir J 26:948–968. https://​doi.​org/​10.​1183/​09031​ Declarations 936.​05.​00035​205 16. Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper Conflict of interest Susan Michaelis undertakes limited consultancy BG, Hall GL et al (2019) Standardization of spirometry 2019 work for the Global Cabin Air Quality Executive. Horsham, UK. E- update. An official american thoracic society and european res- mail address: susan@susanmichaelis.com. Jorge Roig, Jonathan Bur- piratory society technical statement. Am J Respir Crit Care Med don, and Christian Domingo declare no conflict of interest. 200:e70–e88. https://​doi.​org/​10.​1164/​rccm.​201908-​1590ST 13 Lung 17. Kaminsky AD (2019) What is a significant bronchodilator of nanoparticles part of the causal mechanism of aerotoxic syn- response? Ann Am Thorac Soc 16:1495–1503. https://​doi.​org/​ drome? J Nanomedicine Nanosci. https://​d oi.​o rg/​1 0.​2 9011/​ 10.​1513/​Annal​sATS.​201908-​604ED JNAN-​139 18. Irwin CG (2020) Pulmonary function testing in asthma. In Barnes 30. Schindler BK, Weiss T, Schütze A, Koslitz S, Broding HC, PJ (ed). UpToDate Inc, Waltham, MA. https://w ​ ww.u​ ptoda​ te.c​ om. Bünger J, Brüning T (2013) Occupational exposure of air crews Accessed 17 Jan 2021 to tricresyl phosphate isomers and organophosphate flame retard- 19. Hansen JE, Dilektasli AG, Porszasz J, Stringer WW, Pak Y, Ros- ants after fume events. Arch Toxicol 87:645–648. https://​doi.​org/​ siter HB et al (2019) A new bronchodilator response grading 10.​1007/​s00204-​012-​0978-0 strategy identifies distinct patient populations. Ann Am Thorac 31. Pombal R, Hosegood I, Powell D (2020) Risk of COVID-19 dur- Soc 16(12):1504–1517. https://​doi.​org/​10.​1513/​Annal​sATS.​ ing air travel. JAMA 324:1798. https://​doi.​org/​10.​1001/​jama.​ 201901-​030OC 2020.​19108 20. Harper A (2005) A survey of health effects in aircrew exposed to 32. Baker MG, Thornley CN, Mills C, Roberts S, Perera S, Peters airborne contaminants. J Occup Health Saf Aust N Z 21:433–439 J et al (2010) Transmission of pandemic A/H1N1 2009 influ- 21. Idiopathic environmental intolerances (1999) American Acad- enza on passenger aircraft: retrospective cohort study. BMJ emy of Allergy, Asthma and Immunology (AAAAI) Board of 21(340):c2424. https://​doi.​org/​10.​1136/​bmj.​c2424 Directors. J Allergy Clin Immunol 103(1 Pt 1):36–40 (PMID: 33. Wilson ME (2020) What goes on board aircraft? . Travel Med 9893182) Infect Dis 33:101572. https://​d oi.​o rg/​1 0.​1 016/j.​t maid.​2 020.​ 22. Tuuminen T (2018) Multiple chemical sensitivity: review of the 101572 state of the art in epidemiology, diagnosis, and future perspec- 34. Heutelbeck AR, Baur X, Belpoggi F, Budnik T, Burdon J, Gee D, tives. J Occup Environ Med 60(8):e429. https://​doi.​org/​10.​1097/​ et al (2017) On the need for a standardized human biomonitoring JOM.​00000​00000​001369 protocol for in-flight incidents (called “fume events”) (Abstract). J 23. Black DW, Temple S (2020) Idiopathic environmental intolerance H & P. 2nd International Conference Pollution in living and work- (multiple chemical sensitivity). Dimsdale J (ed). UpToDate Inc, ing environments and health. DiMoPEx Working Groups Meeting; Waltham, MA. https://​www.​uptod​ate.​com. Accessed 17 Jan 2021 Abstracts Conference Proceedings. S36-S38 24. Furlong CE (2011) Exposure to triaryl phosphates: metabolism 35. Reinen J, Nematollahi L, Fidder A, Vermeulen NP, Noort D, and biomarkers of exposure. J Biol Phys Chem. https://​doi.​org/​ Commandeur JN (2015) Characterization of human cytochrome 10.​4024/​28FU1​1A.​jbpc.​11.​04.​10.​4024/​28FU1​1A.​jbpc.​11.​04 p450s involved in in the bioactivation of tri-ortho-cresyl phos- 25. Megson D, Ortiz X, Jobst KJ, Reiner EJ, Mulder MF, Balouet JC phate (ToCP). Chem Res Toxicol 28:711–721. https://​doi.​org/​10.​ (2016) A comparison of fresh and used aircraft oil for the iden- 1021/​tx500​490v tification of toxic substances linked to aerotoxic syndrome. Che- 36. Costa LG, Giordano G, Cole TB, Marsillach J, Furlong CE (2013) mosphere 158:116–123. https://​doi.​org/​10.​1016/j.​chemo​sphere.​ Paraoxonase 1 (PON1) as a genetic determinant of susceptibility 2016.​05.​062 to organophosphate toxicity. Toxicology 307:115–122. https://d​ oi.​ 26. Baker PE, Cole TB, Cartwright M, Suzuki SM, Thummel KE, Lin org/​10.​1016/j.​tox.​2012.​07.​011 YS et al (2013) Identifying safer anti-wear triaryl phosphate addi- 37. Costa LG, Giordano G, Furlong CE (2011) Pharmacological and tives for jet engine lubricants. Chem Biol Interact 25(203):257– dietary modulators of paraoxonase 1 (PON1) activity and expres- 264. https://​doi.​org/​10.​1016/j.​cbi.​2012.​10.​005 sion: the hunt goes on. Biochem Pharmacol 81:337–344. https://​ 27. Costa LG (2018) Organophosphorus compounds at 80; some old doi.​org/​10.​1016/j.​bcp.​2010.​11.​008 and new issues. Toxicol Sci 162:24–35. https://​doi.​org/​10.​1093/​ toxsci/​kfx266 Publisher’s Note Springer Nature remains neutral with regard to 28. Van Netten C, Leung V (2001) Hydraulic fluids and jet engine jurisdictional claims in published maps and institutional affiliations. oils: pyrolysis and aircraft air quality. Arch Environ Health 56:181–186. https://​doi.​org/​10.​1080/​00039​89010​96040​71 29. Howard CV, Johnson DW, Morton J, Michaelis S, Supplee D, Burdon J (2018) Is a cumulative exposure to a background aerosol 13