nanotechnology: risk assessment and management

Nanotechnology: Risk Assessment and Management

Ronald H. White, M.S.T. R.H. White Consultants, LLC

[email protected]

Chesapeake AIHA/ASSE Educational Seminar

March 13, 2013

Nanomaterial Definition

• International Standards Organization (ISO) – Nanomaterial: a material with an external dimension in

the nanoscale or having an internal structure or surface structure in the nanoscale

– Nanoscale: size range from approximately 1-100 nm

– Engineered nanomaterial: designed for a specific purpose or function

Classes of Nanoscale Materials

Photo courtesy USEPA

Engineered Nanoparticles

Material Function Applications

Silver Biocide Wound treatment,

prosthesis, odor control

Titanium

Dioxide Photocatalyst: Optical

Cosmetic, sunscreen,

pharmaceutical

Iron Oxide Superparamagnetic Electronics, biomedical

Quantum dots Semiconductor /

Fluorescence Electronics, biology

Carbon

Nanotubes/Fib

ers/Fullerenes

Extraordinary strength,

unique electrical properties,

efficient thermal conductors

Health and fitness,

electronics, automotive,

architecture

Dendrimeres repeatedly

branched molecules

Determined by their

functional groups Drug delivery systems,

tissue engineering?

EPA Nanotechnlogy Definition

“Nanotechnology is defined as: research and technology development at the atomic, molecular, or macromolecular levels using a length scale of approximately one to one hundred nanometers in any dimension; the creation and use of structures, devices and systems that have novel properties and functions because of their small size; and the ability to control or manipulate matter on an atomic scale.” (EPA Nanotechnology White Paper, 2007)

Nanotechnology – Nanotechnology has been incorporated in virtually all

industrial and public sectors, including • Healthcare • Agriculture • Transportation • Energy • Materials • Communication technologies

• Environmental sensors and remediation

Data source: http://www.directionsmag.com

Why Worry About Engineered Nanomaterial Risks?

• Relatively little information on hazard, dose-response, and especially exposure

• Similarities to ultrafine PM (nanoparticles) & asbestos (carbon nanotubes/fibers)

• Novel properties

• Dramatic increase in potential releases and exposures due to exponentially increasing use

Nanomaterial Properties • A material’s surface area / volume ratio increases as its

particles become smaller – Increases interaction with surrounding atoms

– Changes their properties and behavior

• Once particles become small enough, they start to obey the quantum mechanical laws

• Materials at the nano-scale can show different properties to those on the macro-scale, enabling unique applications: – Copper (opaque substance) becomes transparent

– Aluminum (stable material) becomes combustible

– Platinum (inert material) becomes a catalyst

– Silicon (insulator) becomes a conductor

– Gold (solid) turns into liquid at room temperature

Hristozov et al. 2009

World-wide Nanomaterial and Nano-enabled Product Markets

Nanomaterials in Consumer Products

Woodrow Wilson PEN 2012

Nanomaterials in Consumer Products: Where Are They?


Nanomaterials in Consumer Products: What’s In Them?


Nanomaterial Risk Assessment: The Challenges

• How do we define “nanomaterials”? – Size (<100 nm)

– Structure?

– Properties?

– Single particles v. agglomorates/aggregates

– Transformation

• How do we measure exposure? – Units (mass? number? surface area?)

– Low LOD methods

– Distinguish engineered materials from background (e.g., combustion) nano-sized particles

• Lack of fate, transport, and uptake (ADME) data – Impact of solubility, coatings, surface charge, etc. on bioavailability,

translocation and toxic effects

• How do we deal with all this uncertainty and variability?

Potential Occupational and Public Exposure Pathways for Nanomaterials

RS & RAE 2004

Worker v. Consumer-related Nanomaterial Comparison

Pietroiusti 2012

Source Health Impact Framework for ENMs

Smita et al. 2012

Nanomaterial Measurement Metrics

• Volume: Affects alveolar macrophage-mediated lung clearance in rats

• Mass: Dose metric often used in toxicology studies and occupational and environmental exposure monitoring (e.g., airborne mass concentration)

• Number: Dose metric used in toxicology studies and exposure monitoring especially for fibers (e.g., airborne number concentration of structures of specified dimensions) and ultrafine nanoparticles

Nanomaterial Properties and Toxicity

Hristozov et al. 2012

Nanomaterial Properties & Toxicity

• Solubility: Increases or decreases toxicity depending on mode of action

• Surface area: Associated with lung inflammation in rats and mice and

cancer in rats

• Surface reactivity: Alters potency or mode of action

• Size: Affects deposition efficiency to respiratory tract region and target

tissue; may affect translocation and clearance

• Shape: Can influence deposition efficiency by within respiratory tract, biopersistence, target tissue, and response (e.g., fiber effects)

• Volume: Affects alveolar macrophage-mediated lung clearance in rats

• Mass: Dose metric often used in toxicology studies and occupational and

environmental exposure monitoring (e.g., airborne mass concentration)

• Number: Dose metric used in toxicology studies and exposure

monitoring especially for fibers (e.g., airborne number concentration of structures of specified dimensions)

Kuempel et al. 2012

Nanomaterial Toxicity Mechanisms

Linkov et al. 2009

Oxidative Stress Model

“…several NM characteristics can culminate in ROS generation, which is currently the best-developed paradigm for nanoparticle toxicity”

Nel et al., 2006

Potential Pulmonary Toxicity Pathways

• Nanoparticle exposure leads to oxidative stress due to increases in reactive oxygen species (ROS)

• Downstream signaling promotes fibrosis

• Alternative mechanism – increased ROS directly damages DNA, resulting in mutagenicity

Li et al. 2010

Assessing the Toxicity of Nanomaterials

In vivo studies • Increased deposition (by

inhalation)

• Altered clearance

• Inflammation

• Oxidative stress

• Fibrosis and granulomas

• Death

• Translocation to other organs (incl. brain)

• Pre-cancerous lesions

In vitro studies • Genotoxicity

• Oxidative stress

• Inflammatory response

• Increased cell death

• Alterations to cell cycle

• Penetration of barriers (e.g., intestine, skin, placenta)

Are we assessing the right outcomes?

What about more subtle, but potentially harmful affects?

Interactions with DNA or proteins or larger structures?

– Alter gene structure, maintenance, or expression

– Masking or changing conformation of binding sites on proteins

– Altering structures within cells or organisms

Zhao et al. 2005

Summary of Potential Human Effects of Nanoparticles and Nanotubes/Fibers

Tran & Donaldson

Approaches to Addressing Nano Risk Assessment Challenges

• Nanomaterial risk assessment frameworks – Screening life cycle analysis – Comprehensive environmental assessment

• Expert judgment

• Bridging toxicology

• High through-put screening toxicology

• Predictive toxicology – (Q)SAR – Read-across (Nearest analogue)

Nanoparticle Risk Assessment Framework (1)

Tsuji et al. 2006

Nanoparticle Risk Assessment Framework (2)

Kandlikar et al. 2007

Davis 2007

Applying Expert Judgment to Nano Risk Assessment

Morgan 2005

Toxicity Effects Module

Morgan 2005

Applying Expert Judgment to Nano Risk Assessment

Wardak et al. 2008

Nanoparticle Toxicity Testing Challenges

“There is a clear need for validated in vitro assays for nanoparticle evaluation, including assays with meaningful endpoints for genotoxicity tests. In vitro tests should address key properties of the nanoparticles such as biopersistence, free radical generation, cellular toxicity, cell activation and other generic endpoints and provide target cell-specific endpoints.” (SCENIHR 2007)

“…In vitro cellular systems will need to be further developed, standardized, and validated (relative to in vivo effects) in order to provide useful predictive screening data on the relative pulmonary toxicities of inhaled particles” (Warheit et al. 2008)

Nanotox Pulmonary Bioassay Bridging Studies

Carbonyl Iron

Particles

Quartz Particles

PBS Tween Sham

Carbonyl Iron

Particles

Nano Quartz

Particles

Quartz Particles vs vs vs

Inhalation Studies

Intratracheal Instillation Studies

Warheit et al. 2008

Conceptual QSAR Approach to Nanomaterial Biological Effects

Xia et al. 2009

QSAR Approach To Nanoparticle Toxicology

“The successful application of a QSAR approach to nanoparticles is dependent on the ability to derive properties of a new nanoparticle from its atomic and molecular structure, thus providing information for screening and prioritising. Such QSAR models are plausible, but represent a significant challenge in toxicology.” (empahsis added)

(SCENIHR, 2007)

Future Challenges For Nanomaterial Risk Assessment/Risk Management

If current data gaps

for assessing risks from first and second generation nanomaterials continue for future generation nanomaterials, public health and environmental protection policies will be constantly in “catch up” mode

IRGC Nanotechnology Risk Governance 2006

Nanomaterial Risk Assessment: Moving Forward

Key Concepts • Integration of risk assessment frameworks and techniques – e.g.,

“Classic” risk assessment paradigm + Life Cycle Analysis + expert judgment

• Increased emphasis on exposure assessment and development of exposure biomarkers – “No exposure, no risk”

• Develop/refine screening approaches to prioritize hazard assessment (“green nano”), research needs

• Significant investment needed in risk-related data generation

• Consideration of health/societal risk-benefit tradeoffs in risk characterization ?

MANAGING NANOMATERIAL RISKS IN THE WORKPLACE

Weight of Evidence: Nanomaterial Risks v. Benefits

Pietroiusti 2012

Benefit/Exposure and Toxicity/Use Considerations

UCSF 2011

Schulte et al. 2008

* Control evaluation strategies

Potential Workplace Exposures in the Nanomaterial Lifecycle

Schulte et al. 2008

Hierarchy of Workplace Nanomaterial Control Strategies

1. Premarket Testing – Hazard ID

2. Elimination and Substitution – Change form to reduce toxicity or exposure potential

3. Engineering Controls

- Facilities and Process Design

- Local exhaust ventilation

4. Environmental Monitoring - OELs, Nano Reference Values

5. Administrative Controls 6. Personal Protection Equipment 7. Biological Monitoring 8. Medical Screening and Surveillance

Schulte et al. 2008

Control Banding Approach

Schulte et al. 2008

Proposed OELs and DNELs for Nanomaterials

Van Broekhuizen et al. 2012

OEL - Occupational Exposure Limit REL – Recommended Exposure Limit DNEL – Derived No Effect Limit (REACH)

Nano Reference Value Approach • Precautionary-based

alternative to OELs; used in The Netherlands • Provisional, 8-hr TWA exposure •Based on German occupational health institute (IFA) benchmarks • 4 MNM Classes

• Size • Form • Biopersistence • Density

• Target: mass ≤ 0.1 mg/m3


Nanomaterial Reference Values


Institution Guideline title Country Publication date

National Institute of Advanced Industrial Science and

Technology

Guideline for Prevention against Exposure to Nanomaterials Japan 2009

CHS (Center for High-Rate

Nanomanufacturing)

Interim Best Practices for Working with Nanoparticles Organization 2008

DOE (Department of Energy) Nanoscale Science

Research Centers

Approach to Nanomaterial ES&H USA 2008

EPFL (École polytechnique fédérale de Lausanne) Nanoparticles: a security guide Switzerland 2007

Georgia Institute of Technology Nanotechnology Safety Resources USA accessed at 19th Jun

2009

HSE (Health and Safety Executive) Nanotechnology United

Kingdom

2004

Iowa State University Nanomaterials Health and Safety Guidelines USA accessed at 19th Jun

2009

MIT (Massachusetts Institute of Technology) Best Practices for Handling Nanomaterials in Laboratories USA 2008

NASA (National Aeronautics and Space Administration) Nanomaterials Safety and Health Guideline for Carbon-based

nanomaterials

USA 2007

NSF (National Science Foundation) Environmental, Health and Safety guidelines for NSF Nanoscale

Science and Engineering Research Centers

USA accessed at 9th Jul

2009

Laboratory Nanomaterial Guidelines (1)

OECD ENV/JM/MONO(2010): Compilation of nanomaterial exposure mitigation guidelines relating to laboratories (2010)

Laboratory Nanomaterial Guidelines (2)

ORC (Organization Resources Councelors) Guidelines for Safe Handling of Nanoparticles in Laboratories Organization 2005

University of Oklahoma Health Science Center Nanoparticle Handling Guidelines USA accessed at 12th Mar

2009

EHRS (Environmental Health and Radiation Safety),

University of Pennsylvania

Nanoparticle Handling Fact Sheet USA 2008

Delft University of Technology TNW Nanosafety Guidelines Netherlands 2008

University of British Columbia AMPEL Nanofabrication Facility Members' Laboratory Guide Canada 2004

University of California (published as ISO TC 229 WG

3)

Laboratory Management - Draft Health Safety Guidelines

for Nanotechnology research

USA 2004

University of California Irvine Nanotechnology: Guidelines for Safe Research Practices USA 2008

UCSB (University of California Santa Barbara) Laboratory Safety Fact Sheet 32# -Engineered

Nanomaterials: Guidelines for Safe Research Practices

USA accessed at 12th Mar

2009

University of Dayton Nano Technology - Health & Safety USA 2006

VCU (Virginia Commonwealth University) Nanotechnology and Nanoparticles USA 2007


General Workplace Nanomaterial Guidelines (1)

Institution Guideline title Country Publication date

Federal Institute for Occupational Safety and

Health (BAuA) German Chemical Industry

Association (VCI)

Guidance for Handling and Use of Nanomaterials at the

Workplace

Germany 2007

Hallock et al., Journal of Chemical Health & Safety Potential risks of nanomaterials and how to safely handle

materials of uncertain toxicity

2009

Ministry for Economics, Transportation and

State Development for the State of Hessen

Innovationsfördernde Good-Practice-Ansätze zum

verantwortlichen Umgang mit Nanomaterialien

Germany 2008

Hoyt and Mason, Journal of Chemical Health & Safety Nanotechnology - Emerging health issues 2008

HSE (Health and Safety Executive) Risk management of carbon nanotubes United Kingdom 2009

Institut de recherche Robert-Sauvé en santé et en sécurité

du travail.

Best Practices Guide to Synthetic Nanoparticle Risk

Management

Canada 2009


General Workplace Nanomaterial Guidelines (2)

Ministry of Health, Labour and Welfare Measures for Prevention of Exposure to

Nanomaterials at Workplaces

Japan 2009

NanoSafe Australia Network Current OHS Best Practices for the Australian Nanotechnology

Industry

Australia 2007

U.S. National Institute for Occupational Safety and

Health

Approaches to Safe Nanotechnology: Managing the

Health and Safety Concerns

USA 2009

European Agency for Safety and Health at work (OSHA) Workplace exposure to nanoparticles organization 2009, accessed at 5th Jun

2009

Pennsylvania State University Nanomaterials: Potential Risks and Safe Handling Methods USA 2004 (accessed at 3rd Jun

2009)

Safe Work Australia Engineered nanomaterials: evidence on the effectiveness of

workplace controls to prevent exposure

Australia 2009

Schulte et al., Scand J Work Environ Health Sharpening the focus on occupational safety and health in

nanotechnology

2008

University of Surrey, ATI (Advanced Technology

Institute)

Code of practice for working with Nanoparticles United Kingdom 2007


Nanotechnology Occupational Safety and Health Resources

• NIOSH GSP for Working With Engineered Nanomaterials in Research Laboratories (2012)

• NIOSH Approaches to Safe Nanotechnology (2009) • ISO/TR 12885:2008 Nanotechnologies -- Health and safety practices in

occupational settings relevant to nanotechnologies (2008)

• BSI PD6699/2:2007 – Nanotechnologies, Part 2:

Guide to safe handling and disposal of manufactured nanomaterials (2007)

• OECD ENV/JM/MONO(2010)47: Compilation of nanomaterial exposure mitigation guidelines relating to laboratories (2010)

• Good Nano Guide – http://goodnanoguide.org

• Safe Nano – www.safenano.org

POLICY APPROACHES TO NANOMATERIAL RISK MANAGEMENT

“Hard” v. “Soft” Regulation

Hard Regulation

• Toxic Substances Control Act (TSCA)

• Federal Insecticide Fungicide Rodenticide Act (FIFRA)

• Federal Food, Drug and Cosmetic Act (FFDCA)

• Consumer Product Safety Act (CPSA)

• Clean Air Act (CAA)

• Clean Water Act (CWA)

• Resource Conservation and Recovery Act (RCRA)

• Registration, Evaluation, Assessment of Chemicals (REACH)

• Occupational Safety and Health Act (OSHA)

Nanomaterial Life Cycle Regulation

Beaudrie 2010

“Hard” v. “Soft” Regulation

Soft Regulation

• EDF-DuPont NanoRisk Framework

• Responsible Nano Code

• CENARIOS Risk Management

• EU Code of Conduct

• Responsible Care

• NIOSH Current Information Bulletins: Exposure limit guidelines for TiO2, carbon nanotubes

Hard Regulation:

Toxic Substances Control Act

Premanufacture Notices (TSCA §5):

• Since 2005, EPA has received and reviewed over 100 new chemical notices under TSCA for nanoscale materials, including carbon nanotubes

• EPA PMN responses:

– limit the uses of the nanoscale materials

– require the use of personal protective equipment, such as impervious gloves and NIOSH approved respirators,

– limit environmental releases

– require testing to generate health and environmental effects data

Hard Regulation: Toxic Substances Control Act (cont.)

Significant New Use Rule (TSCA §5(a)(2))

• identify existing uses of nanoscale materials based on information submitted under the Agency's voluntary Nanoscale Materials Stewardship Program

• require information on nanoscale materials, such as chemical identification, material characterization, physical/chemical properties, commercial uses, production volume, exposure and fate data, and toxicity data

Hard Regulation: Toxic Substances Control Act (cont.)

Test Rule (TSCA §4) • Require testing for certain nanoscale materials materials

already in commerce and not already tested by other Federal or international organizations

Information Gathering Rule (TSCA §8(a))

• Requires submission of production volume, methods of manufacture and processing, exposure and release information, and available health and safety data

Hard Regulation: FIFRA (2011)

• §6(a)(2) - obtain existing information regarding what nanoscale material is present in a registered pesticide product and its potential effects on humans or the environment

• §3(c)(2)(B) - Obtain information on nanoscale materials in

pesticide products using data call-in notices • new case-by-case determination approach whether a

nanoscale active or inert ingredient is a “new” active or inert ingredient for purposes of FIFRA and the Pesticide Registration Improvement Act, even when an identical, non-nanoscale form of the nanoscale ingredient is already registered

nanotechnology: risk assessment and management

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