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Feinstaub und Lunge Klinische Aspekte und Aktuelles aus der Forschung Barbara Rothen-Rutishauser Chair BioNanomaterials Adolphe Merkle Institute University of Fribourg Marly, Switzerland BIOCOMBUST Universitt Freiburg, Deutschland -

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Feinstaub und Lunge Klinische Aspekte und Aktuelles aus der Forschung

Barbara Rothen-Rutishauser Chair BioNanomaterials

Adolphe Merkle Institute University of Fribourg Marly, Switzerland

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

The Adolphe Merkle Institute in Fribourg (CH)

Polymer Chemistry & Materials (Weder) BioNanomaterials (Fink/Rothen) Surface Science (2015) Soft Matter Physics (Steiner)

Assembly (Lattuada) Scattering (Balog) Macromolecular Chemistry (Nico Bruns)

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Particulate Matter 10 (PM10)

www.swissinfo.ch

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

What is PM10?

www.eea.europa.eu

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

PM10 limit values – CH/D

Luftqualitätsstandards für PM2,5 Zielwert: 25 µg/m3 als Jahresmittelwert, sollte ab 1.1.2010 erreicht sein Grenzwert Stufe 1: 25 µg/m3 als Jahresmittelwert, der ab 1.1.2015 einzuhalten ist Grenzwert Stufe 2: 20 µg/m3 Jahresmittelwert, der ab 1.1.2020 einzuhalten ist

www.umweltbundesamt.de

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Interaction of PM10 with the lung

http://www.heise.de/ http://www.rudolf-jetter.de http://specialcomm ent.wordpress.com/ http://www.g-o.de/ http://www.spiegel.de/

10µm 8µm 6µm 4µm 2µm 1µm 0.1µm

<1 µm Alveoli Bronchioli Bronchi Trachea Naso- pharynx Particle size Location The smaller the particles and the less water-soluble a gas is the deeper they penetrate into the lung Particles < 30 µm Particles < 10 µm SO2, NO2, Ozon Particles < 2-3 µm NO2, Ozon

  • Dr. P. Straehl, BAFU, Abt. Luft-reinhaltung und NIS and Dr. Regula Rapp, Swiss TPH

http://www.autobild.de/

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

The human lung- Microscopic

Alveoli Interalveolar Septa

  • E. Weibel, Uni Bern
  • P. Gehr, Uni Bern

0.5mm 10µm

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

The human lung- Air-blood barrier

Red blood cell Epithelium (Typ I cell) Endothelium Basal lamina Alveolus (Air) Capillary

  • P. Gehr, Uni Bern

1µm

500 millions alveoli Diameter 1/4mm Gas exchange reion 80-90% Surface 140 m2 Capillary volume 210cm3 Air-blood barrier <1µm

Gehr et al. Resp Physiol (1978) Ochs and Weibel. Fishman´s Pulmonary Diseases and Disorders, New York (2008)

http://www.reinischkogel.at/ http://www.agello.it/

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

The human lung- Clearing mechanisms

Conducting airways Mucociliar transport (fast, minutes) Lung parenchyma The immune system (Slow, days-weeks)

Macrophages: Professional phagocytotic cells Dendritic cells: Professional antigen-presenting cells

  • P. Gehr, Uni Bern

Epithelial cells Dendritic cells

Photos courtesy P. Stumbles / S. Napoli (Blank et al. Exp Rev Resp Med 2008)

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

The human lung- Clearing mechanisms

Boehringer Ingelheim Burkhardt, Pathology, University of Bern Boehringer Ingelheim University of Bern

Healthy and diseased lung

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Translocation of nanoparticles

Nanoparticle can translocate across the lung tissue barrier => secondary organs via the blood circulation ⇒ Liver ⇒ Kidney ⇒ Heart ⇒ Brain ⇒ Fetus

Mills et al. 2009 Nat Clin Pract Cardiovasc Med Muehlfeld et al. 2008 Swiss Med Wkly Semmler-Behnke et al. 2007 Environ Health Perspect Peters et al. 2006 Part Fibre Toxicol Ryman-Rasmussen et al. 2009 Nat Nanotech Wick et al. 2010 Environ Health Perspect

  • P. Gehr, Uni Bern

1µm

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

PM2.5- daily mortality and hospital admissions

A systematic review and meta-analysis of 110 peer-reviewed time series studies => Adverse health effects of short-term exposure to PM2.5: 10 µg/m3 increment associated with 1.04% (95% CI 0.52% to 1.56%) increase in the risk

  • f death

Atkinson et al. Thorax 2014

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

European Study of Cohorts for Air Pollution Effects (ESCAPE)

Association of long-term exposure to ambient air pollution with lung function in adult participants from five cohorts ⇒ 10 µg/m3 increase in NO2 exposure was associated with lower levels of FEV1 ⇒ increase of 10 µg/m3 in PM10 was associated with a lower level

  • f FEV1

Adam et al. EJR 2014 (in press)

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Chronic effects of PM10 exposure

bei 500‘000 Personen der amerikanischen Krebsstudie, 1982-2002

  • 10

10 20 30 Zusätzliche Sterblichkeit pro 1 0 µg Feinstaub in % Alle Ursachen Herz- Lungenkrankheiten Lungenkrebs übrige Todesursachen Pope 2002

+ 6 % + 9% + 14% Pope et al., J. Am. Med. Assoc., 2002

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Chronic effects of PM10 exposure

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Models to study risk assessment of PM10

Epidemiology:

The study of the distribution and determinants of disease frequency in human populations and the application of this study to control health problems

http://publichealth.jbpub.com/ Overview of epidemiologic study design

Animal experiments:

in vivo testing

http://www.aboutanimaltesting.co.uk/using-animals-testing-pros-versus-cons.html

Cell culture experiments:

in vitro testing

Rothen-Rutishauser et al. Exp Opin Drug Metabol Toxicol 2008

german.china.org.cn http://de.wikipedia.org/wiki/Tierversuch

The Ames test:

in vitro testing with bacteria

Ames et al. Proc Nat Acad Sci USA 1973

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Realistic risk assessment systems

Definition of realistic: ”resembling or simulating real life”

dictionary.com www.sott.net

Cell responses

Anatomy, Uni Bern

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Macrophage Dendritic cell Epithelial cells

(A549/16HBE14o-/primary cells)

Rothen-Rutishauser et al. Am J Respir Cell Mol Biol 2005; Blank et al. Am J Respir Cell Mol Biol 2007 Rothen-Rutishauser et al. Review, Exp Opin Drug Metab Toxicol 2008 Lehmann et al. Eur J Pharm Biopharm 2010

3D human epithelial airway barrier model

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Air-liquid cultures

Blank et al. J Aerosol Med 2006; Blank et al. Am J Respir Cell Mol Biol 2007

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Exhaust emission exposure system

  • S. Steiner

Müller et al. Environ Sci Technol 2009 Müller et al. Tox Env Chem 2012

Control measuerement unit

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Flow pattern in the exposure chambers

Müller et al. Environ Sci Technol 2009 Supporting Info FröhlichI et al. lnt. J Mol Sci 2014

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Realistic in vitro dose levels

Ambient urban exposure and occupational exposure

5 mg/m3 (maximum level allowed by Occupational Safety and Health Administration (OSHA)) 3x10-5-5x10-3 μg per h per cm2 of lung tissue 2-300 particles per h per (epithelial) cells

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Particle deposition

2000 4000 6000 8000 10000 12000 14000 16000 18000 1 2 3 4 5 6 7

2 4 6 8 10 12 14

TNF-α in supernatants [ng / mL]

16 18 Control Reference chamber Control Reference chamber DEP Low dose DEP High dose

2-300 Partikel per h per (Epithelial) cell

Paur et al. J Aerosol Sci 2011

1.7 x 107 Particle / cm2 => 134 Particle /cell

Müller et al. Environ Sci Technol 2009; Steiner et al. Tox Letters 2012

*

7.48 x 107 Particle / cm2 => 587 Particle /cell

200µm

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

  • Opel Astra X20DTL, 35 km/h
  • Fuel: low sulfur diesel

(>10mg/kg, Greenergy SA)

  • Lube oil

(V10.237, Motorex)

  • Exhaust dilution 1:10

=> Without filter => With a silicon carbide Diesel particle filter

Filter von Peugeot, Filterhersteller Ibiden

Müller et al. Environ Sci Technol 2009 Steiner et al. Tox Letters 2012

Ohne Filter Mit Dieselpartikelfilter

Effect of non-catalyzed diesel particle filter

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Exhaust characterisation

5 10 15 20 25 30 35 40 CO (ppm) HC (ppm) NOx (ppm) NO2 (ppm) NO (ppm) Verdünnung

Without Filter

Steiner et al. 2013 Atmos Environ

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Exhaust characterisation

5 10 15 20 25 30 35 40 CO (ppm) HC (ppm) NOx (ppm) NO2 (ppm) NO (ppm) Verdünnung

Without Filter With DEP-Filter

Steiner et al. 2013 Atmos Environ

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Particle size distribution

1.00E+00 1.00E+01 1.00E+02 1.00E+03 1.00E+04 1.00E+05 1.00E+06 1.00E+07 1.00E+08 10 100 1000

counts dN/dlog Dp [1/cm3] d [nm]

Particle size distribution

0.5µm

Steiner et al. 2013 Atmos Environ

Without Filter

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Particle size distribution

1.00E+00 1.00E+01 1.00E+02 1.00E+03 1.00E+04 1.00E+05 1.00E+06 1.00E+07 1.00E+08 10 100 1000

counts dN/dlog Dp [1/cm3] d [nm]

Particle size distribution

0.5µm

Steiner et al. 2013 Atmos Environ

Without Filter With DEP-Filter

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Control in the incubator Clean air 6h Without filter 6h With diesel particle filter 6h

No cytotoxicity (LDH assay)

Steiner et al. 2013 Atmos Environ

Cell morphology and cytotoxicity

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Antioxidative response

0.2 0.4 0.6 0.8 1 1.2 Standard Roh-Abgas DPF TBHP Standard Roh-Abgas DPF TBHP

Total reduced glutathione (GSH), an anti-oxidant molecule

Reference Exhaust 2h 6h Without filter With diesel particle filter

=> Oxidative stress

  • S. Steiner

n=3-6

* * * *

Steiner et al. 2013 Atmos Environ

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Pro-inflammatory response

0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 Standard Roh-Abgas DPF LPS Standard Roh-Abgas DPF LPS

Tumor necrosis factor - alpha

2h 6h

=> (pro-)inflammatory reactions

  • S. Steiner

* *

n=3-6

Reference Exhaust Without filter With diesel particle filter

Steiner et al. 2013 Atmos Environ

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Models to study risk assessment of PM10

Epidemiology:

The study of the distribution and determinants of disease frequency in human populations and the application of this study to control health problems

http://publichealth.jbpub.com/ Overview of epidemiologic study design

Animal experiments:

in vivo testing

http://www.aboutanimaltesting.co.uk/using-animals-testing-pros-versus-cons.html

Cell culture experiments:

in vitro testing

Rothen-Rutishauser et al. Exp Opin Drug Metabol Toxicol 2008

german.china.org.cn http://de.wikipedia.org/wiki/Tierversuch

The Ames test:

in vitro testing with bacteria

Ames et al. Proc Nat Acad Sci USA 1973

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Comparison of tests

Ames test (bacteria) Human lung cell model

Steiner et al. Env Sci Technol 2014

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Ames test – human lung cells

Clift et al. Nanotoxicology 2013; Steiner et al. Env Sci Technol 2014

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Conclusions

  • The Ames test in combination with organic extracts is not

a reliable method to assess the risk of exhaust emission

  • Realistic cell culture models combined with a controlled

deposition of nanomaterials at the air-liquid interface of lung cells

  • Stable and reproducible system to study the effect of

exhaust emissions in vitro under realistic conditions

  • => Differentation between gaseous compounds and particles
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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Conclusions

⇒ Diesel particle filter significantly reduces (pro-)inflammation in vitro ⇒ However, the gaseous components also need to be reduced by filter technology

Without filter (Gas and particles) With filter (Gas) Cytotoxicity No No Oxidative stress (GSH and HMOX1) ↑ ↑ Pro-inflammatory reactions (TNFa, IL8) ↑ No

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BIOCOMBUST – Universität Freiburg, Deutschland - 26.11.2014

Outlook: Reliable and versatile system

Two-stroke scooter exhaust Cytotoxicity and pro-inflammatory reactions

Müller et al. 2010 Environ Sci Technol

DEP and CeO2 co-exposures CeO2 reduces oxidative stress effects

  • bserved upon DEP exposure

Steiner et al. 2012 Tox Letters

B0, B20, B100 Reduced cell response only for B20

Steiner et al. 2013 Atmos Environ http://ec.europa.eu/energy/renewables/biofuels/

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Acknowledgments

Institute of Anatomy, University Bern Peter Gehr Former team members EngToxDi Team Jan Czerwinski Pierre Comte Andreas Mayer Norbert Heeb The BioNano-Group Adolphe Merkle Foundation Technion – Israel Institute of Technology Haifa - Israel Josue Sznitman Jana Tenenbaum-Katan

Acknowledgments

Sandro Steiner Loretta Müller