Remco Westerink - Toxic presentatie... · metals, flame retardants, electromagnetic fields, drugs Tricresyl phosphates! 5 October 2017 Schiphol . Neurotoxicology Research Group 5

Remco Westerink

Neurotoxicology Research Group, Institute for Risk Assessment Sciences

5 October 2017 Schiphol

IRAS, what is it?

Mission: Education and research into human and veterinary health risks resulting from exposure (environmental, food-related, occupational, intentional) to hazardous compounds

IRAS: Institute for Risk Assessment Sciences (Utrecht University)

- Hazard & Exposure => Risk

Environmental Epidemiology + Veterinary Public Health

Toxicology + Veterinary Pharmacology

Biology

Veterinary Medicine

Pharmaceutical Sciences

Medicine

RIVM

IRAS

NVIC


TNO

Different fields of toxicology

via mechanism-based in vitro research

RISK ASSESSMENT

Toxicology & Veterinary Pharmacology

Neurotoxicology

Endocrine toxicology

Immune toxicology

Alte

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s in to

xicolo

gy

Exp

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Veterinary pharmacology


Neurotoxicology

Neurotransmission = intercellular communication

Any form of (compound-induced) dysfunction of the nervous system

Pesticides, Persistent environmental pollutants, heavy metals, flame retardants, electromagnetic fields, drugs

Tricresyl phosphates!


Neurotoxicology Research Group


Aviation safety from a chemical perspective:

Tricresyl phosphate (TCP), ‘Aerotoxic syndrome’, mechanisms, effects, and biological plausibility

Remco Westerink

Neurotoxicology Research Group, Institute for Risk Assessment Sciences


Toxic cabin air?

Toxic cabin air?

Toxic cabin air?


Tricresyl phosphates

• Different isomers: ToCP, TmCP and TpCP,

often used as mixture

• Additive in engine oil/hydrolic fluid

• Implicated in Aerotoxic Syndrome


Aerotoxic syndrome

- Aerotoxic syndrome is a term describing the alleged short-term and long-term adverse health effects that are attributed to exposure to cabin air that has been contaminated with atomized engine oils and other chemicals.

- Mainly attributed to tricresyl phosphate (TCP), in particular ToCP, a neurotoxic organophosphate used as lubricant in turbine oil.

- Similarity in neurotoxic mechanism of action with organophosporous ester pesticides (parathion etc) and chemical warfare agents (sarin, VX etc)

- No formal causal relationship has been established yet…


Causality and biological plausibility

- Causal relationship:

- Confirmed exposure

- Multiple physical and chemical factors

- Effects

- Effective concentrations

- Biological plausibility

- Sufficient sample size


Exposure: bleed air

- Bleed air, contaminated with oil components


Exposure components and incidence

- Cabin air is by definition contaminated,..

(ng/m3)

TNO measurements of KLM flights

De Ree et al., Neurotoxicology, 2014


- Not only T(o)CP,..

Exposure components and incidence

- Not only chemical exposure(s), but also physical exposure(s): hypoxia, pressure, radiation, humidity, etc.

- Real incidence fume events unknown,..


Exposure and acute effects

• Acute symptoms - Nausea, diarrhea, vomiting

- Breathing difficulties, coughing, irritation of eyes, nose and airways, loss of consciousness

- Blurred/tunnel vision, shaking/tremors, loss of balance, impaired movement, seizures

Smoke and/or stress-related?


Exposure and chronic effects

• Chronic symptoms

Usually vague! (cf sick building syndrome):

- Tired, memory impairment, headache, dizziness, confusion

- Blurred/tunnel vision, shaking/tremors, loss of balance, impaired movement

Ultimately, incapacitation…


Overview of effects

Abou Donia et al., J. Toxicol. Environment. Health, Part A, (2013)

Some similarities, but not identical to either OPDIN or

“painters disease”

Health problems are real and clinical

manifest


Plausibility: Mechanisms & acute effects

- Inhibition of AChE => excess ACh

=> increased excitability (transient)

=> subsequent desensitization

of nACh-receptors (paralyzing)

Usually requires high exposure

Acute effects: (mild) cholinergic syndrome

including tremor, salivation/urination, reduced heart-rate and gastro-intestinal complaints

Symptoms only partly match those of aerotoxic syndrome…?


ToCP is an organophosphate:

Intermediate syndrome

Intermediate syndrome:

- OP-induced

- 24-96h following (high dose) exposure

- Usually muscle weakness, but in severe cases muscle paralysis

- Probably under-diagnosed

- Often recovery 1-2 weeks

Symptoms only partly match those of aerotoxic syndrome…?

Karalliedde et al., Toxicol Rev (2006) 5 October 2017 Schiphol

Plausibility: Mechanisms & chronic effects

control OPIDN

OP-Induced Delayed Neurotoxicity (‘dying back’):

- Inhibition of Neuropathy Target Esterase (NTE)

- NTE interacts with cytoskeleton, ultimately axonopathy

Jokanovic et al., Clin Neurol Neurosurg (2011)

- Usually only upon chronic exposure, possible with single exposure

- Occurs weeks after exposure; pain, muscle weakness, paralysis

- Symptoms poorly/partly match those of aerotoxic syndrome…?

Note; can also result from exposure to solvents (n-hexane) Pellin et al., 1988


Plausibility: Mechanisms & chronic effects

Chronic OP-Induced Neuropsychiatric disorder (COPIND):

- Result of acute poisoning as well as chronic low-dose exposure

- Up to 10% (!) of chronic OP exposures!?

- Symptoms often ‘vague’, include learning/memory, concentration, mood changes, chronic fatigue, tremor, rigidity, etc

- Effects delayed (months) and persistent (years)

Symptoms match those of aerotoxic syndrome…!?

Tan et al., Med Hypotheses (2009) Salvi et al., Toxicol Sci (2003)

Davies et al., Adv Psychiatr Treat (2000a, b)


More plausibility: genetic risk

Organophosphates are metabolized by Cyt P450 to more toxic metabolites.

metabolism

(Cyt P450) OP bioactivated OP

metabolism

(PON-1)

detoxified OP

PON-1-KO mice are more vulnerable to OPs.

The bioactivated OPs are detoxified by PON-1.

Cole et al., Pharmacogenet Genomics, 2005

Risk factors: increased CYP activity (more bioactivation), decreased PON-1 activity (less detoxification)…

Note: PON phenotype not relevant at low OP levels? Coombes et al., Toxicol Lett, 2014


Need for action?

- Bleed air by definition contaminated

- Confirmed exposure

- Symptoms of organophosphate poisoning (partly) match aerotoxic syndrome

- Risk groups (genetic differences in metabolism)

Risk assessment!


Initial TCP Risk Assessment


Step 1


Step 2


Step 3 & 4


Combined step 1-4


More research!


Update TCP Risk Assessment

Not 10x

~25x less

62.5 ng/kg/d

1.5/62,5=0,024 ~1.5

ng/kg/d


Update ToCP Risk Assessment

~2000x less

0.02/62,5=0,00032 ~0.02

ng/kg/d

Not 10x

62.5 ng/kg/d


Causality, plausibility & risk

Yet, so far only at concentrations that are not realistic for human (occupational) exposure… Nonetheless, clinical symptoms are real and appear associated with frequent flying

- Exposure? Effects? Biological plausibility? Yes!

- TCP Risk?? No!

Other chemical, physical and psychological causes

need to be considered…


However, organophosphates/TCPs may have other actions:

- Inhibition of calcium channels (Meijer et al., 2014; 2015)

- Increase mitochondrial activity (Duarte et al., 2016)

- Reduction neuronal activity (Duarte et al., 2016)

- Inhibition glutamatergic signalling (Hausherr et al., 2014; 2016)

Cabin air safety: the way forward?


European Aviation Safety Agency (EASA): - Oil fumes in realistic exposure scenario (part 1) DG-MOVE (European Union): - Oil fumes in realistic exposure scenario (part 2)

Dutch Ministry of Infrastructure & the Environment (I&M): - Hazard characterisation non-ortho TCP isomers • Non-ortho isomers slightly less toxic; • effects only at high concentrations unrealistic for human

exposure

Cabin air safety: integrated readouts

Rat cortex: mixed (GABA/glutamate) neuronal cultures with ~45% astrocytes


http://www.google.nl/url?sa=i&source=images&cd=&cad=rja&uact=8&docid=cNFn6F9NCZNA5M&tbnid=zAzxU_q2WbKfWM:&ved=0CAgQjRw&url=http://www.axionbiosystems.com/applications/applications/&ei=jZrPU_2qGobSOazCgbAN&psig=AFQjCNFL9fqpePsHxl-0x6o9fXs8EUE_Wg&ust=1406200845487777


Cabin air safety: realistic exposure


• Air-Liquid Interface (ALI)

Combined with MEA


Conclusions

Risk Assessment:

Health effects (very) unlikely due to T(o)CP…

Other chemical causes?

• ALI-MEA experiments suggest limited risk (oil), but ongoing…

Further research:

• Additional exposure assessment

• Additional endpoints (e.g. Ca2+ signalling),

• Repeated and/or prolonged exposure

• Other chemical/physical agents

• Other (genetic) risk factors

But clinical symptoms are real so this issue is far from resolved…


Thank you for your attention

Acknowledgements:

Daniel Duarte

Joost Rutten

Harm Heusinkveld


www.neurotoxicology.nl

This presentation represents the personal and professional views and opinions of Dr. Remco H.S. Westerink. They do not necessarily reflect those of Utrecht University or our funding bodies (the Dutch Ministry of Infrastructure and the Environment (I&M), the European Aviation Safety Agency (EASA) and DG-MOVE (European Union).


?? Questions ??

Acknowledgements:

Daniel Duarte

Joost Rutten

Harm Heusinkveld


www.neurotoxicology.nl

This presentation represents the personal and professional views and opinions of Dr. Remco H.S. Westerink. They do not necessarily reflect those of Utrecht University or our funding bodies (the Dutch Ministry of Infrastructure and the Environment (I&M), the European Aviation Safety Agency (EASA) and DG-MOVE (European Union).


Documents

Remco Westerink - Toxic presentatie... · metals, flame retardants, electromagnetic fields, drugs Tricresyl phosphates! 5 October 2017 Schiphol . Neurotoxicology Research Group 5