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Developing Reference Methods for Nanomaterials

Presentation No 2

Basics of nanotoxicology

Occupational safety and health in practice Example new technologies: nanomaterials

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Imprint

This presentation is a final product of the project NanoValid - project F2268 - and was generated under the lead responsibility of Miriam Baron (Federal Institute for Occupational Safety and Health).The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 263147 (NanoValid – Development of reference methods for hazard identification, risk assessment and LCA of engineered nanomaterials).The responsibility for the contents of this publication lies with the authors.

Copyright © 2015 by the authors

Project monitoring and main author: Miriam BaronFederal Institute for Occupational Safety and Health (BAuA)

With contributions from: Rolf Packroff, Michael Roitzsch, Dag Rother, Aart Rouw, Torsten WolfFederal Institute for Occupational Safety and Health (BAuA)

Shashi SinghCentre for Cellular & Molecular Biology

Damjana DrobneUniversity of Ljubljana

Figures: Miriam BaronFederal Institute for Occupational Safety and Health (BAuA)

Fox / Uwe Völkner

Project support:Elke Kahler-Jenett, Katharina NiesmannFederal Institute for Occupational Safety and Health (BAuA)

Design: Carolin Schneider, eckedesign Berlin

Editing:Johanna Ebbeskotte, Markus FlenderFederal Institute for Occupational Safety and Health (BAuA)

Publisher: Federal Institute for Occupational Safety and Health (BAuA)Friedrich-Henkel-Weg 1-25, 44149 Dortmund, GermanyNöldnerstr. 40-42, 10317 Berlin, GermanyTelephone +49 231 9071-0www.baua.de

NanoValid:Project Coordinator: Rudolf Reuther, Nordmiljö [email protected] +46 563 92253 (Sweden) or +49 170 7011534 (Germany)www.nanovalid.eu

All rights reserved, including photomechanical reproductionand the reprinting of extracts.

First published: July 2015

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Slide 1:

� How large is the Occupational Safety and Health problem regarding nanomaterials from the view of safety ex-perts?

� How does the size of the particles affect the risk? Does the risk end at 100 nm or do we have to consider other ranges?

� Is there only a problem with nanomaterials or do we need to broaden our focus to respirable dusts and fibres? � Are nanomaterials more toxic and carcinogenic and, if yes, how does this change the control strategy?

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Slide 2:


Overview

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Toxicology

Hazard Potential Information gathering

Risk assessment

The complex world of nanomaterials– Challenge for occupational safety

Exposureassessment

Derivation of control strategiesand safe design of workplaces

� In my previous talk, I gave you an insight into the complex world of nanomaterials. Nanomaterials are various. The control strategies for workplaces need to be adapted accordingly.

� Now I will elaborate on the aspect of toxicology. � Toxicology is a strong pillar for risk assessment. � All these factors are required to adequately derive control strategies and safe design of workplaces.

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Slide 3:


Nanotoxicology

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„nano“

Particle toxicology

Route of exposure: Inhalation• Inflammatory responses• Carcinogenicity

Chemical toxicology

Adverse effects, which are specific for nanomaterials, are not known yet.

respirable dusts(granular, biopersistent)

WHO fibres(long, thin,

biopersistent)

Specific toxic effects(CLP criteria forclassification)

Route of exposure: Inhalation, skin

All negative adverse effects of chemicals on health

� We can distinguish between particle toxicology and chemical toxicology. � There is a problem with fibres (if they have a certain size and are biopersistent) � We have exposure routes via inhalation and via the skin. � Until now, no new hazardous effects specific for nanomaterials are known.

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Slide 4:


Toxicokinetics

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Do nanoparticles distribute better in the body than larger particles?

Several exposure routes: dermal (skin), inhalation (lungs), oral (intestine)

Mainly no free primary particles (stick together) :half life of the free particles in inverse ratio to the particleconcentration and proportional tothe particle size (Preining, 1998)

Conc.+

Size

Half life

� Which issues do we need to consider if we talk about potential health risks? What is of particular importance there? The physical structure …

� Are nanoparticles better able to distribute in the body than larger particles? � Several exposure routes: dermal (skin), inhalation (lungs), oral (intestine) � In most cases, there are no free primary particles (stick together) since the half-life of the free particles is in inverse

ratio to the particle concentration and proportional to the particle size (Preining, 1998). � As a general rule, we find aggregates and agglomerates.

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Slide 5:


Distribution of particles: counter-example

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Can nanoparticles systemically distribute through cell membranesand cause damage?

Post mortem samples of stone coal miners(LeFevre et al., Hum Pathol, 1982, 13(12):1121-6)

Stone coal particles, including not nanoscale

Pigments found in liver and spleen

No parallel histopathological changes

Not only nanoparticles show a certain systemic availability anddistribute in the body to a certain extend!

� What if nanomaterials penetrate cells? Can they distribute through cell membranes and cause damage? Maybe this is a new toxicokinetics?

� There are studies on non-nanoparticles regarding the cell penetration topic. One of them is a study with post mortem samples of stone coal miners.

� In this study, a moderate to severe pigment accumulation in liver (10 % of the samples) and spleen (19.5 % of the samples) was found, but there were no parallel histopathological changes in these tissues.

� This means that the coal particles caused no disease in this study. � One can conclude that not only nanoparticles show a certain systemic availability and distribute in the body to a

certain extent – larger particles do this as well.


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Slide 6:


Toxikokinetics: dermal exposure

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Example: Australian study (Gulson et al., 2010), ZnO in sun screen, primaryparticles 19 nm and 110 nm

Experiment: twice a day, 5 days on the beach, Sydney

Measurement: < 0,001 % of the incorporated 68Zn in blood, both formssystemically available, nanoscaled ZnO slightly better presumablydue to better solubility

Conclusion: to a low extent irrelevant dermal uptake

� Example: Australian study (Gulson et al., 2010), ZnO in sun screen, primary particles 19 nm and 110 nm � Experiment: twice a day, 5 days on the beach, Sydney � Measurement: < 0.001% of the incorporated 68Zn in the blood, � The toxicologists say that “both forms are systemically available to a very low extent”. Nanoscaled ZnO particles

are slightly better soluble presumably due to better solubility. � Conclusion: To a low extent, we find irrelevant dermal uptake both from nanoscaled and macroscaled particles.

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Slide 7:


Toxikokinetics: inhalation exposure

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Example: Inhalation study with nanoscaled manganese oxides: primary particles 3 - 8 nm, agglomerates 30 nm

Experiment: rats, 11 - 12 days, 6 h/d

Increase of the tumor necrosis factor alpha in brain

However: parallel experiment with manganese oxides and wellsoluble MnCl2, same result

Manganese oxides not completely insoluble

No particle toxicity: well-known neurotoxic effects of manganese: released ions

� Example: Inhalation study with nanoscaled manganese oxides: primary particles 3 - 8 nm, agglomerates 30 nm � Experiment: rats, 11 - 12 days, 6 h/d � As a matter of fact, an increase of the tumor necrosis factor was found � However: in a parallel experiment with manganese oxides and well soluble MnCl2, a comparable result was ob-

tained. � Manganese oxides are not completely insoluble. � Here, we have no effect attributable to particle toxicity, but rather to the well-known neurotoxic effects of man-

ganese, which released ions.

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Slide 8:


Higher carcinogenic potency than conventional materials?

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Metaanalysis of studies on inhalation carcinogenicity with rats (nano: 3 studies, micro: 4 studies, diesel engine emissions: 11 studies)

Several corrections required, i.e. exposure (h/d, d/week, month) and the total length of the study (tumor development depends on age)

Difference in potency: Carcinogenic potency of

respirable nanoscaled dusts~ 2.5times higher

� Meta-analysis of studies on inhalation carcinogenicity with rats (nano: 3 studies, micro: 4 studies, diesel engine emissions: 11 studies)

� Several corrections required, for instance concerning the duration of exposure (h/d, d/week, month) and the total length of the study (tumor development depends on age)

� Difference in potency: GBD (granular biopersistent dusts) nanomaterials have a carcinogenic potency which is ~ 2.5 times higher than the macroscaled particles

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Slide 9:


How much is 2.5?

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substance Cancer risk4:10000mg/m3

Benzo(a)pyren 0.07

NDMA 0.075

Acrylamide 70

MDA 70

Ethylenoxide 200

Acrylnitrile 260

1,3-Butadien 500

Trichlorethen 33000

Maximal difference in

potency:470000

2.5…… negligible

Regarding the carcinogenic potency, we already find very large differences between different chemicals, that is to say, differences in the order of magnitudes. Compared to this range, 2.5 is, so to speak, almost nothing.

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Slide 10:


Where are the toxicologists worried? 1. Dust effects

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Respirable dust enters the deep airways

Macrophages and their job

Accumulation due to slow removal of biopersistent dusts

Oxidative stress and inflammation

� Why is respirable dust so problematic? � Respirable dust means very fine dust that can enter the deep airways. � Normally, alveolar macrophages have the job to clean material from our deep airways. � In the upper airways, we have cilia, little hairs, which transport the dust out of the airways. There you can swallow

the dust, but in the deep airways, we have only these cells which normally phagocytose bacteria or dusts. � If we inhale a lot of respirable dust, which is biopersistent, it accumulates in the deeper airways, since the removal

is too slow. � The macrophages which are specialised on bacteria, remove the dust. However, if more than 6 % of the volume of

the macrophages is loaded with particles, they react with oxidative stress. � Inflammation processes are the result of an overload of the deep airways. � The inflammation mostly starts at bifurcations where a higher amount of dusts is deposited. � Here we have a general problem with respirable dust which is not restricted to the nanoscale.

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Slide 11:


Where are the toxicologists worried? 1. Fibre effects

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Rigid, insoluble WHO fibres(length > 5 µm, diameter < 3 µm, rigid)

Example: asbestos

Frustrated phagocytosis

External inflammation

Chronic inflammation, tumours

Problem does not stop at the„100 nm size mark“

� If a fibre is rigid, stiff and longer than the alveolar macrophage that takes it up, this causes problems. � Some fibres are so long that if the macrophage tries to phagocytose it, it is not able to do so. This is called “frus-

trated phagocytosis”. Then this macrophage reacts with external inflammation. � This external inflammation leads to lung tissue damage and in case of a chronic inflammation, it may eventually

cause lung tumours. � Also, these fibres have the ability to migrate out of the lung into the mesothelia. The mesothelia are tissues which

align the lung and also our inner organs. In consequence, the fibres can also get stuck in the mesothelia where macrophages can likewise come and try to remove them.

� Since removal of the fibres is not possible, chronic inflammation and, in consequence, tumour development can also occur in the mesothelia.

� This is known as the asbestos problem. However, it is not limited to asbestos. In fact, all rigid nanofibres with similar morphology cause concern.

� Here, we do not have a specific nanomaterial problem, which ends at the “100 nm size mark”. Rather, this issue depends on the biopersistence and the morphology.

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Slide 12:


Conclusions

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As always and for every chemical – there will be open questions left

Many questions already answered

Risk assessment strategies can be developed

It is the respirable (nano-)dust that matters most!

Like for many other chemicals, we still find knowledge gaps regarding thehealth risks. We want to recognize the risks at an early stage.

Scientific knowledge on fine- and ultrafine dusts, fibres and chemicalsubstances is a good starting point.

Nanomaterials can have different hazardous potentials (effect and releasepotential) „Nanoscaled“ cannot be equated with „hazardous“.

For occupational safety, the precautionary approach and the „classical“ dustsafety strategies are a good basis.

� Many relevant questions are answered. � The scientific knowledge on fine- and ultrafine dusts, fibres and chemical substances forms a good starting point

for evaluating the health risks of nanomaterials.

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Slide 13: Thank you!


Thank you for your attention!

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