Nanotechnology: Risk Assessment and Management
Ronald H. White, M.S.T. R.H. White Consultants, LLC
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?
Woodrow Wilson PEN 2012
Nanomaterials in Consumer Products: What’s In Them?
Woodrow Wilson PEN 2012
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
Van Broekhuizen et al. 2012
Nanomaterial Reference Values
Van Broekhuizen et al. 2012
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
OECD ENV/JM/MONO(2010): Compilation of nanomaterial exposure mitigation guidelines relating to laboratories (2010)
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
OECD ENV/JM/MONO(2010): Compilation of nanomaterial exposure mitigation guidelines relating to laboratories (2010)
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
OECD ENV/JM/MONO(2010): Compilation of nanomaterial exposure mitigation guidelines relating to laboratories (2010)
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