Nanotechnologies and Occupational Health

Kai Savolainen

ICOH SCOM International Congress, Amsterdam, The Netherlands

7-8 April 2011

Challenges of nanomaterials and nanotechnologies for occupational health

• Ongoing technological revolution:– engineered nanomaterials (ENM) allow novel technological innovations, already commonplace in consumer and industrial applications

• Huge impact on the economy and the society

• Lack of accepted safety concepts for ENM– Concerns on the effects of ENM on health of workers and consumers

– Toxic effects of ENM have raised concerns among regulators, academia, media and public

• Potential for deleterious impacts on health

Source National Cancer Institute

Scale of things

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1920 1930 1940 1950 1960 1970 1980 1990 2000 2010

Asbestin käyttö, tonnia/vuosi Mesotelioma/vuosi

20th century: The use of asbestos and its association with the incidence of mesotheliomas

Individual studies

The use of asbestos

Incidence of mesotheliomas

Cross section Cancer latency of 30 years

Nanomaterials are already on the market

David Hawkhurst, PENMore than 500 self-identified nanoproducts are on the market today, and the list is growing rapidly, according to the Project on Emerging Nanotechnologies. However, some warn that not all of these claims may hold up to a test of true nano-ness.

Risk assessment required knowledge on effects: what do we know about toxicological and ecotoxicological effects of various ENP

Exposure data is vital for risk assessment: summary of ENP workplace monitoring studies in 2010 – lack of data a major challenge

Diversity of different nanomaterials complicates the assessment of risks of the materials. Schulte et al.J. Occup. Environ. Med. 2009, in press

Actual ENPs

Studied for

Hazard

Generalizability

Universe of Potential ENPs

Challenge: How to use a limited amount of hazard and exposure data to develop risk management guidance?

Issues in Developing Risk Management Guidance for Nanomaterials

• Vast number of nanomaterials

• Limited hazard information

– Few materials studied

– Few long-term studies

• Diverse occupational exposure scenarios

• Workers are currently exposed

Transport

Commercial

Academic

Incorporation in Products

Maintenance of ProductsManipulation of ProductsApplication of Products - Medical Delivery

Disposal / End of Life

Recycling

Research Laboratories

Warehousing/Maintenance

Waste Handling

Start Up/Scale Up Operations

Transport

Warehousing/Maintenance

Warehousing/Maintenance

Transport

Waste Handling

Manufacturing/Production

Schulte P et al,

Sharpening the

focus on

occupational

safety and health

of nano-

technology.

SJWEH (2009)

Metrics of ENM - challenges for the assessment of exposure and effects of ENM

• Due to small size, mass poorly associates with effects of ENM, other choices for metrics:

– surface area, -chemistry, -structure

– shape and size

– chemical composition

– number concentrations

• Measurement of exposure - current technologies do not allow distinction between background nanoparticles and ENM – setting or controlling of OEL not possible

26/04/2011 13

Airborne Monitoring to Distinguish ENM from Incidental Particles for Environmental Health and Safety. Peters et al., J. Occup. Environ. Hyg. 2009, 6:73–81

Kai Savolainen/21/02/2011

Small Amounts of Zinc from Zinc Oxide Particles in Sunscreens Applied Outdoors Are Absorbed through Human Skin. Gulson et al. Toxicol. Sci. 118(1), 140–149 (2010)

What are the exposure-associated hazards we want to control or prevent

• pulmonary inflammation, other inflammatory effects such as effects on the skin

• genotoxic effects

• effects on circulation

• exposure of the brain and possible consequent hazards etc.

• In the following, some examples

CNT and production of ROS, oxidative stress, and associated toxicity

• CNT may induce inflammation, genotoxicity and cancer, which may be associated and even causally linked with each other

• Oxidative stress may be one of the mechanisms explaining the effects of CNT

Inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice

Shvedova et al., Am J Physiol Lung Cell Mol Physiol 289: L698–L708, 2005.

CNT Genotoxicity: DNA damage and micronuclei induced by carbon nanotubes and graphite nanofibres in human bronchial epithelial cells in vitro. Lindberg et al. Toxicol. Lett. 2009, doi:10.1016/j.toxlet.2008.11.019

A single dose of MWCNT induced asbestos-like changes in peritoneal cavity of mice

• Exposure of mouse peritoneum to MWCNT induce asbestos-like fiber-length dependent morphological alterations in the mesothelium; inflammation & granulomas

• Long rather than short (< 5 um) fibers were likely to induce morphological alterations and inflammation (Poland et al., 2008)

Granuloma formation after intra peritoneal exposure to particles/fibers after 7 days

Long amosite(brown asbestos)

Long MWCNTSample 1

Long MWCNTSample 2

Short MWCNTSample 1

Short MWCNTSample 2

Granuloma response7 days post -installation

Long fibersShort fibers

Poland et al. Nature Nanotech. 2008 Jul;3(7):423-8.

Subpleural fibrosis in mice after MWCNT inhalation

saline aerosol-exposed

MWCNT exposed mice 2 weeks after inhalation

Subpleural fibrotic lesion showing MØ with MWCNT

Ryman-Rasmussen et al. Nature

Nanotech. 4(11):747-751 (2009)

Hazard Identification

“Is there reason to believe this

could be harmful?”

Risk Management

“Develop procedures to minimize

exposures.”

Exposure Assessment

“Will there be exposure in real-world

conditions?”

Risk Characterization

“Is substance hazardous and will

there be exposure?”

Key Elements in Worker Protection

Occupational Exposure Limits (OELs)

• Major tool for prevention of occupational disease

• Long history of use

• Some provisional OELs developed for nanomaterials

Available

Toxicity Data

Suggestive

Qualitative or Semi-

quantitative Hazard or Risk Assessment

Reason by Analogy or

SAR

Quantitative Risk

Assessment

Adequate

Insufficient

Determination of OEL

Control Banding

Performance-Based

Exposure Control Limits

Categorical OELs

Proposed OELs for Engineered Nanoparticles

Nanomaterial Parameter OEL References

General 0.004% risk level Mass-based OEL: 15 OECD [2008]

Titanium Dioxide 0.1 risk level particles <100 nm

0.1 mg/m3 NIOSH [2005]

General Dust 3 mg/m3 BAuA [2009]

Photocopier Toner

Tolerable risk2009 acceptable risk2018 acceptable risk

0.6 mg/m3

0.06 mg/m3

0.006 mg/m3

BAuA [2008]

Biopersistent Granular Materials (Metal Oxides, Others)

Density > 6,000 kg/m3 20,000 particles/cm3 IFA [2009]

Biopersistent Granular Materials

Density < 6,000 kg/m3 40,000 particles/cm3 IFA [2009]

CNTs Exposure risk ratio for asbestos

0.01 f/cm3 IFA [2009]

Nanoscale liquid Mass-based OEL IFA [2009]

Fibrous 3:1; length 75,000 nm 0.01 f/cm3 BSI [2007]

CMAR Mass-based OEL: 10 BSI [2007]

Insoluble Not fibrous Mass-based OEL: 15 BSI [2007]

Soluble Not fibrousNot CMAR

Mass-based OEL: 10 BSI [2007]

Hazard Classification forUltrafine (Nanoscale) TiO2<100 nm

• Weight of evidence suggests tumor response in ultrafine TiO2

– Results from secondary genotoxic mechanism

– Related to physical form of inhaled particle(i.e., particle surface) rather than the chemical compound itself

– Rat tumorigenic data are sufficient and appropriate for making preventive recommendations

• Classification– Potential Occupational Carcinogen

Quantitative Risk Assessment (QRA) Methods to DevelopRecommended Exposure Limits for Inhaled ParticlesBased on Kuempel et al. [2006]

Assume equal risk at equivalent dose

Rodent

Determine tissue-specific dose

Calculate benchmark

dose*

Extrapolate

Working lifetime exposure

concentration

Equivalent tissue

dose

Estimate exposures leading to lung dose

Recommended

exposure limit

Technical feasibility of measurement and control

Adjust for species differences

(e.g. lung surface area)*Dose associated with specified level of risk.

Human

Experimental data of exposure andadverse effect

Measure or model

Dose-response modeling

Ultrafine (Nanoscale) TiO2

• Recommended Exposure Limit

– 0.3 mg/m3 (TWA for up to 10 hrs/day for a working lifetime)

– Estimated to reduce risk of lung cancer below1 in 1,000

Fine TiO2

• Recommended Exposure Level• NIOSH used all tumor data when conducting dose-response modeling

• QRA indicates lifetime risk of lung cancer of1 in 1,000 at 2.4 mg/m3 (95% Lower Confidence Limit)

• 2.4 mg/m3 (TWA for up to 10 hrs/day over a working life) to reduce risks of lung cancerbelow 1 in 1,000

CARBON NANOTUBES

• Several animal studies showed pulmonary fibrosis and granulomatous inflammation from carbon nanotube (CNT) exposure

• Associated with both unpurified and purified CNT (raw metal contaminated)

• Effects occurring at relatively low doses

• Ability of CNT to persist and migrate to pleura

• Genotoxicity

Nanocyl[Ma-Hock et al

2009]

NIOSH [CNT CIB 2010]

Bayer [Pauluhn 2010]

AIST Japan [Kobayashi et al

2009]

OEL

(µg/m

3)

15

30

45

3500

5000

MWCNT2.5 µg/m3

CNT & CNF

7 µg/m3

MWCNT 210 µg/m3

MWCNT50 µg/m3

OEL Development Activities for Carbon Nanotubes

OSHA Carbon black PEL

OSHA Graphite PEL (respirable)

BSI—0.01 f/ml [benchmark exposure limit-BEL] high aspect ratio nanomaterials–established at 1/10 asbestos OEL

Views Towards Engineered Nanoparticles

TimeHazard

ClassificationType of Action

Present “As if” Precautionary

Near Future “Likely to be” Due diligence

Farther Future “Is” Institutionalized

Health Hazard Bands: the approach

established in 1980's

• Industry did not have experience establishing very low OELs

• Industry did not have analytical methods to measure these low exposures

• Assign chemicals into “categories” or “bands”

based on their inherent properties

• Facilitates the implementation of “control bands”

TO REMEMBER:

HAZARD X EXPOSURE = RISK

Risk Assessment/Management Paradigms

Traditional

Risk = (HazardExposureControl)

Tait [2005]

Control Banding for Nanomaterials

Maynard, A.D. [2007]. Nanotechnology: the next big thing, or much ado about nothing? Ann Occ Hyg 51(1):1–12.

Steps to Protect Workers from Hazards of an Emerging Technology

Anticipate & identify potential hazards

Take precautions

Assess effectiveness of precautions

Clarify knowledge of hazards

Determine risks

Clarify risk management practices

Establish standard risk management practices

Continually evaluate evidence & approaches

Epidemiologic research

Occupational health surveillance

Establish exposure registries

Physical Form

Task Duration

Quantity

milligrams

kilograms

15 minutes

8 hours

slurry/suspension highly disperseagglomerated

Factors Influencing Control Selection

Engineered Local

Exhaust Ventilation

Closed Systems

Occupational Health Hazardmild /

reversible

severe /

irreversible

THANK YOU FOR YOUR ATTENTION