Síndrome aerotóxico¿realidad o ficción?

DR. JORDI ROIGNeumología

Aceites sintéticos ✈ Synthetic ester base stock ~95%:

.- Pentaerythritol (PE) + Trimethylpropane (TMP) ✈ Antiwear additive: Triaryl phosphate (OP) ~3%– TCP - includes ortho isomers/TOCP... & TXylilP…

✈ Amine antioxidant: PAN (1%) + contaminants .-β naphthylamine (BNA); phenylnapht. (PBN)

✈ Proprietary substances ✈ Wide variety of pyrolysis substances ✈ Endocrine disruptors (TCP; TButylP; TPhenylP)

Hazardous substances

✈ REACH – Regulation (2006) on “Registration, Evaluation, Authorisation & restriction of Chemicals

✈ CLP - Regulation (2008) on “Classification, Labelling & Packaging of substances and mixtures”

✈ Globally harmonised system – United Nations: harmonised or notified

EU/UN Hazard Classifications (CLP /REACH) Oil , hydraulic, deicing fluids: HAZARDS

TXP – Substance of Very High Concern (SVHC) – REACHMay cause harm to the unborn/Impair fertility

✈ Harmful if swallowed/dermal: ✈ Eye/skin irritant & ? Respiratory irritant

✈ May (suspected) cause damage fertility or harm the unborn child

✈ Skin sensitizer

✈ Single exposure & repeated target organ toxicity - nervous system

✈ Very toxic by inhalation

✈ May cause genetic defects ✈ May cause allergy/asthma or breathing difficulties if inhaled

✈May (Suspected) of causing cancer

✈ May cause drowsiness or dizziness

The Toxicity of Commercial Jet OilsWinder C. Environmental Research 2002

EXPOSURE TO AIRCRAFT BLEED AIRCONTAMINANTS AMONG AIRLINE WORKERS

A GUIDE FOR HEALTH CARE PROVIDERSHarrison R. U.S. Department of Transportation 2009

Aerospace Medical Association annual meeting, Anaheim, California, May 1995.

J Biol Physics Chem 2014;14:117–21

J Biol Physics Chem 2014;14:117–21

J Biol Physics Chem 2014

Routine mechanical causes of aircraft air supply contamination

Ground power unit

Davidson DA. J Biol Physics Chem 2014

Aerospace Information Report AIR 1539 Rev B 2007

Section of Duct 1

Section of Duct 2

Aerospace Information Report AIR 1539 Rev B 2007

Gomez-Seco J et al, Arch de Bronch 2012; 48: 133-136

TOS POR ESTENOSIS SECUNDARIA A ANTRACOFIBROSIS

Antracofibrosis bronquial Cocinas leña Minas

Aire limpio

Humo de biomasa

Fullerton DG, Tropical Med and International Health 2009; 14: 349-354

Electron micrographs of the lining of a portion of unused ducting (duct 1).A - Showing several extruded flattened fibres twisted together and then woven.B - Outer surface of non-woven fabric.

Electron micrographs of the lining of a portion of used ducting taken from an aircraft upon which symptoms of illness had not been reported (duct 2).A - Inner woven fabric.B - Outer non-woven fabric.C - Scrapings of the black deposit on the surface of the ducts.

Electron micrographs of the lining of a portion of used ducting taken from an aircraft upon which symptoms of illness had been reported (duct 3).A - Inner woven fabric.B - Outer non-woven fabric.C - Scrapings of the black deposit on the surface of the ducts.

Sampling "Ginger Jake", April 2, 1932

A comparison of fresh and used aircraft oil for the identification of toxic substances linked to aerotoxic syndrome. Megson D. Chemosphere 2016.

• Fresh and used Mobil Jet Oil II: HRMS study• Fresh: no orthoTCP isomers (< 0.0005%)• Fresh: detectable levels of 4 TCP isomers• Used: alkylated TCPdetected at 0.13-0.69%• Xylenyl and ethylphenyl phospahtes exhibit

similar toxicity to ortho TCP isomers• Future studies should also focus on such

contaminats of used oil (jet engines > 200ºC)

In vitro neurotoxic hazard characterization of different tricresyl phosphate (TCP) isomers and mixtures. Duarte DJ. Neurotoxicology 2016.

• Increase of mitocondrial activity• Decrease neuronal electrical activity• Induce reduction of average neurite length• Effects at non-cytotoxic concentrations• Prolonged and/or repeated exposure to TCPs may

exacerbate the observed neurotoxic effects

Fig. 1 Boxplot of organophosphate metabolite levels for urine from air crews (n = 332) and controls (n = 30 for BCEP, DPP, n = 25 for BCPP, DBP) (Schindler et al. 2009a, b).

Study of reported occurrences in conjunction with cabin air quality in transport aircraft BFU 803.1-14

• Fume events occurred between 2006-2013: 663• Smell cases: 460• Fume cases: 188

Study of reported occurrences in conjunction with cabin air quality in transport aircraft BFU 803.1-14

• Fume events occurred and result in contaminated cabin air• Individual reports indicated health impairment of passengers• No significant reduction of flight safety occur• Different demonstration of compliance of airplanes (CS-25),

engines (CS-E) and APU (CS-APU) are required• All used substances should be considered (ingredients, decay

products, critical values…)

Concentrations of dibutyl phosphate and diphenyl phosphate in the control group from the general population and in pre- and post shift urine samples of aircraft maintenance technicians (N = 5, single values and box plots).

Health risk assessment of exposure to TriCresyl Phosphates (TCPs) in aircraft: A commentary de Ree H.

Exposición de bajo nivel existe

✈ TCP (organophosphate [OP] in oil or hid) in air :-Cranfield 2011 (23%)-IOM 2012 (29%)-TNO 2013 (46% )-ACER (89-95%) -Tri meta isomer of TCP in HEPA filters. Eckels J.Aircraf recirculation filter for air quality and incident assessment. J Aircr 2014- Rosenberger 2013 (17%- TOCP)- OHRCA/ACER 2014 (18%) – No flights had fume events = normal flights

Exposure to tri-o-cresyl phosphate detected in jet airplane passengersLiyasova M. Toxicology and Applied Pharmacology 2011

Activation of tri-ortho-cresyl phosphate to the active metabolite cresyl saligenin phosphate (CBDP) by cytochrome P450; and reaction of CBDP with butyrylcholinesterase (BChE) to yield an adduct on the active-site serine 198.

Exposure to tri-o-cresyl phosphate detected in jet airplane passengersLiyasova M. Toxicology and Applied Pharmacology 2011

EXPOSURE TO AIRCRAFT BLEED AIR CONTAMINANTS AMONG AIRLINE WORKERS A GUIDE FOR HEALTH CARE PROVIDERSHarrison R. U.S. Department of Transportation 2009

EXPOSURE TO AIRCRAFT BLEED AIR CONTAMINANTS AMONG AIRLINE WORKERS A GUIDE FOR HEALTH CARE PROVIDERSHarrison R. U.S. Department of Transportation 2009

Autoantibody markers of neural degeneration are associated with post-mortem histopathological alterations of a neurologically injured pilot. Abou-Donia MB. J Biol Physics Chem 2014;14:34–53

Autoantibody markers of neural degeneration are associated with post-mortem histopathological alterations of a neurologically injured pilot. Abou-Donia MB. J Biol Physics Chem 2014;14:34–53

Table 2. Levels of serum autoantibodies (AA) in controls and the subject and subject’s fold increases relative to healthy controls.

JBPC Vol. 14 (2014)

RADS ↔ S. AEROTOXICO FORMA AGUDA

• Amplia variedad de agentes inhalados– Cloro– Gases inorgánicos,vapores(HCl, SO2, NO2, NH3, H2S)– Productos químicos (isocianatos, ácidos, aldehidos,

gas lacrimógeno, pesticidas, disolventes, …) – Mezclas de difícil identificación (humo incendios,

soldaduras, desechos de combustión de diesel, aerosoles irritantes ...)

Alberts WM, do Pico GA. Chest 1996, 109, 1618-28

WTC 11 September 2001

Reactive Airway Dysfunction Syndrome - RADS

Banauch GI et al. Persistent hyperreactivity and reactive airway dysfunction in firefighters at the World Trade Center. Am J Respir Crit Care Med 2003; 168: 54-62

Tos es síntoma predominante del RADS

RADS – Criterios 1. Ausencia de clínica respiratoria precedente2. Inicio de síntomas después de una única exposición al agente3. Exposición a gas, humos o vapores irritantes en

concentración generalmente importante4. Inicio de síntomas < 24 h después de la exposición5. Persistencia de síntomas durante al menos 3 meses6. Clínica recuerda a asma (tos, disnea, …)7. Puede acompañarse de obstrucción al flujo en estudios

funcionales8. Positividad del test de metacolina9. Exclusión de otras causas

RADS y gravedad del insulto inicial

• Estudios de cohorte no confirman que RADS solo pueda ocurrir después de un insulto inhalatorio grave inicial *

– Kern. ARRD 1991, 144, 1058-64• Derrame de acido acético en un hospital

– Cone et al. Chest 1994, 106, 500-8• Vertido → metano sodio en un rio MITC (CH3NCS)

– Banauch et al. AJRCCM 2003, 168, 54-62• NYFD después del 11S WTC

* Nemery B. (Editorial). AJRCCM 2003, 168, 2-3

– QEESI: Quick Enviromental Exposure Sensivity Inventory • Organofosforados• Disolventes orgánicos• Formaldehido, glutaraldehido• Hidrocarburos aromáticos• Compuestos orgánicos volátiles• Propilenglicol, etilenglicol (anticongelantes)

Sensibilidad Química Múltiple

SQM: “quimiofobia”Intolerancia adquirida (NO alergia) contra niveles bajos de diversas sustancias químicas usuales odoríferas

• Predominio de personas previamente sanas de sexo femenino

• Componente psicógeno muy relevante• Implicaciones laborales reivindicativas• Obliga a un diagnóstico diferencial muy amplio• Una vez establecido el síndrome cualquier producto

aromático puede causar clínica

S Q M ≠ S aerotóxico crónico

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Los pacientes no fueron capaces de distinguir las sustancias químicas irritantes cuando no eran detectables por olfato

Bornschein S, Hausteiner C, Römmelt H, Nowak D, Förstl H, Zilker T. Clin Toxicol (Phila) 2008;46(5):443-9.

Double-blind placebo-controlled provocation study in patients with subjective Multiple Chemical Sensitivity (MCS) and matched control subjects.

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Fugas pequeñas aceite habituales en vuelo normal

✈ Oil seal leakage is reported to occur during certain events such as engine switching, top of descent with chronic engine vapours ‘continuously leak through seals in tiny amounts’De Boer J. TCP and the aerotoxic syndrome of flight crew members. Current gaps in knowledge, Chemosphere 2014

✈ Oil leaking from bearings can be either ‘slowly varying and somewhat continuous or sporadic and quite intermittent.’ – ACER 2013. Airliner Cabin Environment Research. National Air Transportation Center of Excellence for Research in the Intermodal Transport Environment (RITE) ACER Program. Sponsorship of the US Department of Transportation. Funded by the US Federal Aviation Administration Office of Aerospace Medicine

Michaelis S. Oil bearing seals and aircraft cabin air contamination. Sealing Technology ISSN 1350-4789 April 2016

A description of the types of high speed rotary shaft seals in gas turbine engines and the implications for cabin air quality. Flitney KR. J Biol Physics Chem 2014

J Biol Physics Chem 2014

Flitney KR. J Biol Physics Chem 2014

Michaelis S. Oil bearing seals and aircraft cabin air contamination. Sealing Technology ISSN 1350-4789 April 2016

Puntos clave s. aerotóxico

1. Sobrevaloración de orto-TCP2. Infraestimación otras sustancias químicas 3. Exposición inadvertida de bajo grado en vuelos sin incidencias4. Infraestimación incidencia reportada de “fume events” 5. Mayor exposición en tripulación y “frequent flyers”7. Embarazo: riesgo por ciertas sustancias químicas 8. Riesgo en población infantil: EDC ↔ disrupción hormonal9. Riesgo en personas con enfermedad de base10. Papel citocromo P-450↔ interacciones medicamentosas

Negación del s. aerotóxico1. Argumento de pureza conceptual respecto a los requerimientos

ortodoxos de síndrome - enfermedad2. Simplificación del problema en concentración de orto TCP en

aceites sintéticos ya muy bajas en última década3. Estudios aire de concentración de orto TCP no tóxica : “n” baja,

problemas metodología , no biomarcadores, …4. Equiparación ámbito nivel seguridad estándar a cabina aérea5. Nivel bajo = no riesgo → similitud con historia de tabaquismo 6. No existe una identificación etiológica concreta7. Los síntomas son superponibles a quejas múltiples de la

población general sin enfermedad real

Carbon monoxide intoxication: An updated review. Prockop LD. J Neurol Sci 2007

CALL FOR TENDERS N° 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"

• Official notification on 20 Sept. 2016• The European Commission, supported by EASA and

various aviation stakeholders decided to start a new initiative aimed at collecting additional scientific evidence on which to root more robust policies in this subject area

• According to the state of the art, air quality in cabin is generally safe but we still need to demonstrate it

• Prevalence of cardiac disease in female flight attendants was 3.5 times greater than the general population

• Compared to the NHANES population (n =5,713), flight attendants (n = 4,011) had about a 3-fold increase in the age-adjusted prevalence of chronic bronchitis despite considerably lower levels of smoking

• Female flight attendants reported 34% more reproductive cancers

• Conclusions are limited by the cross-sectional design and recall bias

Medidas preventivas y correctoras

1. Estudios detallados productos derivados de pirolisis2. Investigación de nuevos productos exentos toxicidad3. Estudios sobre efectos aditivos y/o sinérgicos4. Adaptación niveles de seguridad a las características de una

cabina aérea5. Filtros sustancias químicas en “bleed air” ≠ sistema PACK6. Mejora tecnológica dispositivos sellado7. Instalación rutinaria de sensores químicos en cabina8. Implementación de nuevos aviones sin sistema “bleed air”

ACKNOWLEDGEMENTS

• Susan Michaelis PhD. Thesis 2010: “Health and Flight Safety Implications From Exposure to Contaminated Air in Aircraft”http://handle.unsw.edu.au/1959-4/50342 http://susanmichaelis.com/caq.html

• Repsol YPF Centro Tecnologia (CTR ), Madrid