nanotechnology · •the key issue: what is the risk? •health risk = hazard x exposure...

SASOM-MEDICHEMJOINT CONGRESS 2019

IN SOUTH AFRICA

Nanotechnology

Expand the discussion Nanotechnology and Silica

Best Practice - Availability ofGuides on Occupational Disease

Example Germany - Transfer of knowledge

Murray Coombs

Maren Beth-Hubner

Dirk Pallapies

I declare NO Conflict of Interest


IN SOUTH AFRICA

Best Practice

Definition of best practice

: a procedure that has been shown by research and experience to produce optimal results and that is established or proposed as a standard suitable for widespread adoption

German Guides on Occupational Disease

https://www.bgrci.de/https://www.dguv.de/

https://www.bgrci.de/

https://www.dguv.de/

2 Evaluation of hazards to humans (1/15)

• The key issue: What is the Risk?

• Health Risk =

Hazard x Exposure

• Information gained from

toxicological tests to assess the

hazard and of exposure

measurements provide the basis

for making reasonable and

responsible risk management

decisions.

9-Sep-19 Seite 6Nanotechnology and Cancer Risk, Dr. Maren Beth-Hübner 25.10.2018, 8th World

Congress of Nano-S&T 2018 in Potsdam


9-Sep-19 Seite 7Nanotechnology and Cancer Risk, Dr. Maren Beth-Hübner 25.10.2018, 8th World

Congress of Nano-S&T 2018 in Potsdam

Risk = f (hazard; exposure)

Hazard Exposure

Ris

k

OD Guidance and approach

General principles

General principles – 183 pages

OD Guidance and approach

Silica

Nanotechnology and Cancer Risk

Aspects relevant for Toxicological Evaluation and

Risk Assessment

Dr. Maren Beth-Hübner

Nanotechnology

Nanotechnology and Cancer RiskAspects relevant for Toxicological Evaluation and Risk Assessment

1. Pulmonary toxicity and its mechanisms (32)

2. Evaluation of hazardsto humans (15)

Nanotechnology and Cancer Risk, Dr. Maren Beth-Hübner 25.10.2018, 8th World

Congress of Nano-S&T 2018 in PotsdamSeite 219-Sep-19


• A study which BG RCI initiated in one of

our member companies supports the

hypothesis that exposure to incidental

ultrafine particles pose a greater

respiratory inflammogenic hazard

than the same mass of larger

particles with a similar composition.

• Furthermore the results show the role

of agglomeration and de-

agglomeration in the toxicity of

inhaled nanoparticles.

9-Sep-19Nanotechnology and Cancer Risk, Dr. Maren Beth-Hübner 25.10.2018, 8th World

Congress of Nano-S&T 2018 in PotsdamSeite 22

100 nm

10-15 nm


Therefore it is reasonable

to assume that at

equivalent exposures to

CNT, or other

nanomaterials, workers

may also be at risk of

developing the same

adverse lung effects seen

in experimental animals.




• The amorphous silica fume is formed as a by-product in the process of reduction of SiO2

from quartz sand to Si metal at very high temperatures in an induction furnace.

• BG RCI initiated detailed exposure

characterization (performed by

Professor Wolfgang Koch, Fraunhofer

Institute Toxicology and Experimental

Medicine, Hannover):

• Mass concentration (Respicon®), number concentration (CPC), specific surface area

(BET), mass size distribution (Cascade impactor), morphology (Thermophoretic

sampler/TEM), agglomeration state (SMPS), elemental composition (EDX), crystal

structure, dissolution rate constant (Ringer solution/AAS).




• Results: Fume particles emitted at the smelting furnace are

highly agglomerated structures composed of primary particles

with a wide size range (CMD = 20 nm). The agglomerates are

all in the respirable size range. The number concentration was

parallel to the mass concentration. A mass concentration of 1

mg/m³ was according to a number concentration of 8,500

particles/cm³. The highest concentration of the respirable

fraction of particles directly at the oven was 100 mg/m³.

• In the sacking area the particles have a larger size, the

concentration of respirable particles is very low (two orders of

magnitude lower than at the oven site).



3600

nm

1143

nm

720 nm

1800

nm

720 nm


•The chemical elemental composition showed no

specific reason for the lung effects, whereas 0.5

mass percent of cristobalite = 0.2 mg/m³ as well as

reactive species on the particle surface might be the

underlining cause.

• BG RCI introduced regular workplace exposure measurements as

well as technical, organizational and personal protective measures.

Furthermore the workers at the reactor get regular occupational

medical examinations.

• According to the suitable protective measures employed at the

respective workplace in order to limit the exposure to the respiratory

tract, these examinations did not show any sign of an increased

number of respiratory diseases.



1 Pulmonary toxicity and its mechanisms (6/35)




•BG RCI introduced regular workplace exposure

measurements as well as technical, organizational and

personal protective measures. Furthermore the workers

at the reactor get regular occupational medical

examinations.

•According to the suitable protective measures employed

at the respective workplace in order to limit the exposure

to the respiratory tract, these examinations did not show

any sign of an increased number of respiratory diseases.



Examples Surveillance - Nasterlak


Conclusion from the silica-fume characterization study

• Exposure to non-fibrous, cytotoxic particles such as

silica is more likely to directly affect the alveolar

macrophages due to its surface chemistry and free

radical generation potential (production of oxidative

stress).

• In essence, cells and organs may demonstrate toxic response, even to substances generally

known as non-toxic, when they are exposed in high enough doses to the nano-sized range,

causing overload of particles with a high surface area.

• I there is an addition of iron or other metals these could cause catalytic effects with free-

radical-releasing pro-inflammatory properties.




Conclusion from all presented studies: Grouping of

nanomaterials in 3 categories

1. Nano-GBP (granular biopersistent particles) of no

or low specific toxicity: Prevention in humans was

thought to be possible by maintaining the maximum

workplace concentration GBS (granular

biopersistent dust) of 0.3 mg/m³. However, after the

latest results of the studies with CeO2 with a

LOAEL of only 0.1 mg/m³ this has to be discussed

by the regulatory authorities.




Conclusion from all presented studies: Grouping of

nanomaterials in 3 categories

2. Rigid biopersistent fibrous nanomaterials with a specific

geometry and characteristics (WHO fibers L>5 µm, D<3 µm,

L/D>3/1): Can cause lung cancer and mesotheliomas in

animals. Hazard and risk assessment for humans should be

based on the experiences with asbestos..

3. Nanomaterials for which toxicity is mediated by the specific

chemical properties of its components (released ions,

functional groups on the surface): Evaluation on a case-by-

case basis, depending on their chemical identity.




• Currently no published instances of an actual human disease being caused by manufactured nanomaterials.

• However, the adverse health outcomes related to anthropogenic activity, including inadvertent production of nanoparticles or nanofibers

•Ultrafine particles: Cardiovascular and lung disease•Asbestos: Mesothelioma, cancer•Quartz and mineral dust particles: Interstitial lung disease, silicosis, cancer

•Cationic spray paint particles: Acute lung edema•ZnO and other welding fumes: Metal fume fever confirm that humans can also develop lung inflammation and fibrosis in response to inhaled particles and fibers.




•Health Risk = Hazard x Exposure

•Therefore, to avoid the repetition of the asbestos history, and in

accordance with the Rio Convention 1992 (“… where there are threats

of serious or irreversible damage, lack of scientific certainty shall not

be used as a reason for postponing cost-effective measures to prevent

…”), we must conclude that the principle has to be:

„Better safe than sorry!“




Asbestos repeated?

• The question is: Are carbon nanotubes (CNT) likely to cause

irreparable and fatal effects such as those associated with

asbestos exposure?

• The effects of asbestos include severe lung fibrosis or

scarring, lung cancer, including cancer of the lining of the

lungs or pleura, called mesothelioma.

• CNT is a tubular form of carbon

(like a two dimensional atom-thick graphene sheet rolled into a

cylinder) with a diameter as small as 1 nm and a length of a

few nm to microns.

• Some varieties of CNT are similar in their needle-like shape

to asbestos fibers.




Asbestos repeated?

• In 2005, US-NIOSH researchers showed that aspiration of SWCNT after i.t.

application in mice caused progressive pulmonary fibrosis and granuloma

formation (Shvedova et al., 2005) as well as oxidative stress in the lungs and

cardiovascular system (Lam et al., 2004).

• In May 2008 a study from Scotland (Poland et al., e.g. Ken Donaldson) found that

long MWCNT (≤ 20 µm (≙ ≤ 20,000 nm)) exhibit asbestos-like response in the

form of early stages of mesothelioma of the abdominal cavity after i.p.

application in mice, while short and tangled MWCNT did not.

• Shortly after that a Japanese study (Takagi et al., 2008) reported that MWCNT i.p.

were even more potent in causing abdominal mesothelioma than asbestos in

mice (p 53). Fullerene aggregates did not develop these lesions.




Asbestos repeated?

• Günter Oberdörster interpreted:

The decisive factors for fiber toxicity and carcinogenicity – high

dose, similarity to asbestos fibers, elemental carbon is not soluble and

very biopersistent like asbestos – are part of the fiber carcinogenicity

paradigm of the 3D’s:

Dose, Dimension, and Durability.

• It’s a critical paradigm – like a dogma for

for identifying a tumorigenic fiber.

• WHO Fiber Definition: Length > 5 μm, Diameter < 3 μm, Aspect ratio

L/D > 3/1



Dose, Dimension, and Durability


Asbestos repeated?



CNT 1

CNT 2

CNT 3

Long amositeasbestos

Rittinghausen et al., 2014

(presented by Otto Creutzenberg at the „2nd Joint Symposium on Nanotechnology“ April 6-7, 2017 in Hannover)


Early Warnings – which lessons? (1/2)

• Careful handling: Avoid exposure by inhalation and contamination of skin and clothing.

• Wearing personal protective equipment.

• Handling these materials in closed systems or under appropriately ventilated hoods.

• Exposure measurements.

• Precautionary measures until we know better.




Early Warnings – which lessons? (2/2)

•Studies should serve as a “wake-up call“

•for governmental agencies

•for industry• Oberdörster interpreted these findings within a larger context: “As for other nanoparticles, the issues will be

different. I think that for most of them a risk does not exist or is not as high as many think it is, given

that there will be no or only very low exposures. It is important to consider exposure as a key element

of the risk assessment process. Misunderstanding of risk may be a real “danger” for the future of

nanotechnology.”

• Donaldson concluded: “It’s a good news story, not a bad one. It shows that short or curly carbon

nanotubes did not behave like asbestos, and by knowing the possible dangers of long, thin carbon

nanotubes, we can work to control them."




IN SOUTH AFRICA

SubtitleGuides on Occupational Disease - Achieving Best Practice

Applicability to new HCS Regs in SA

Thank you for your attention!!



Dr. med. Maren Beth-Hübner

Berufsgenossenschaft

Rohstoffe und chemische Industrie

(BG RCI)

(German Social Accident Insurance Institution for the

Raw Materials and Chemical Industry)

Tel.: 06221 5108-28451

Fax: 06221 5108-21199

E-Mail: [email protected]

Internet: http://www.bgrci.de

http://www.medichem.org

Prävention

Kompetenz-Center Gefahrstoffe und

biologische Arbeitsstoffe

Referat Gefahrstoffe, Biostoffe,

Analytik

Secretary General MEDICHEM

Kurfürsten-Anlage 62

D-69115 Heidelberg

Germany

Special thanks to my MEDICHEM

colleagues and in particular our

chair Dr Michael Nasterlak and Dr

Tee Guidotti reminding me that we

always have more to learn in OM.

mailto:[email protected]

http://www.bgrci.de/

http://www.medichem.org/

nanotechnology · •the key issue: what is the risk? •health risk = hazard x exposure...

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