National Nanotechnology Initiative

EN V I RON M EN TA L ,H E A LT H , A N D S A F E T Y
R E SE A RCH S T R AT E G Y
National Science and Technology Council
Committee on Technology
Subcommittee on Nanoscale Science,
Engineering, and Technology
O C T OBER 2 011

About the National Science and Technology Council
The National Science and Technology Council (NSTC) is the principal means by which the Executive
Branch coordinates science and technology policy across the diverse entities that make up the Federal
research and development enterprise. A primary objective of the NSTC is establishing clear national
goals for Federal science and technology investments. The NSTC prepares research and development
strategies that are coordinated across Federal agencies to form investment packages aimed at accomplishing multiple national goals. The work of the NSTC is organized under committees. Each committee
oversees subcommittees and working groups focused on different aspects of science and technology.
More information is available at http://www.whitehouse.gov/administration/eop/ostp/nstc.

About the Office of Science and Technology Policy
The Office of Science and Technology Policy (OSTP) was established by the National Science andTechnology Policy, Organization, and Priorities Act of 1976. OSTP’s responsibilities include advising thePresident in policy formulation and budget development on questions in which science and technology
are important elements; articulating the President’s science and technology policy and programs; andfostering strong partnerships among Federal, state, and local governments, and the scientific communities in industry and academia. The Director of OSTP also serves as Assistant to the President for Scienceand Technology and manages the NSTC. More information is available at http://www.ostp.gov.

About the Nanoscale Science, Engineering, and Technology Subcommittee
The Nanoscale Science, Engineering, and Technology (NSET) Subcommittee is the interagency body
responsible for coordinating, planning, implementing, and reviewing the National Nanotechnology
Initiative (NNI). It is a subcommittee of the Committee on Technology of the National Science andTechnology Council. The National Nanotechnology Coordination Office (NNCO) provides technicaland administrative support to the NSET Subcommittee and its working groups in the preparation ofmultiagency planning, budget, and assessment documents related to the NNI, including this strategy
document. More information is available at http://www.nano.gov.

About this Document
This document is the NNI’s Environmental, Health, and Safety (EHS) Research Strategy. The NNI EHS
Research Strategy aims to ensure the responsible development of nanotechnology by providing guidance to the Federal agencies that produce the scientific information for risk management, regulatory
decision making, product use, research planning, and public outreach. It describes the NNI’s EHS visionand mission, the state of the science, and the research needed to achieve the vision. This 2011 plan
updates and replaces the 2008 NNI Strategy for Nanotechnology-Related Environmental, Health, andSafety Research.

Copyright Information
This document is a work of the United States Government and is in the public domain (see 17 U.S.C.
§105). Subject to the stipulations below, it may be distributed and copied with acknowledgement to
NNCO. Copyrights to graphics included in this document are reserved by the original copyright holders
or their assignees and are used here under the government’s license and by permission. Requests to
use any images must be made to the provider identified in the image credits or to NNCO if no provider
is identified.
Printed in the United States of America, 2011.

National Nanotechnology Initiative

EN V I RON M EN TA L ,H E A LT H , A N D S A F E T Y
R E SE A RCH S T R AT E G Y
National Science and Technology Council
Committee on Technology
Subcommittee on Nanoscale Science,
Engineering, and Technology

O C T OBER 2 011

National Science and Technology Council
Committee on Technology (CoT)Subcommittee on Nanoscale Science, Engineering, and Technology (NSET)CoT Co-Chairs: Aneesh Chopra, Office of Science and Technology Policy*Vivek Kundra, Office of Management and Budget*Philip Weiser, National Economic Council
CoT Executive Secretary: Pedro Espina, Office of Science and Technology Policy
NSET Subcommittee Co-Chairs:*Travis M. Earles, Office of Science andTechnology Policy
Lewis Sloter, Department of Defense

National Nanotechnology Coordination OfficeDirector and Coordinator for Standards Development:*E. Clayton Teague

NSET Subcommittee Executive Secretary:
Geoffrey M. Holdridge, National Nanotechnology
Coordination Office

National Nanotechnology Coordination Office
Deputy Director and Coordinator for Environment,
Health, and Safety Research:
Sally Tinkle

Department and Agency Representatives to the NSET Subcommittee
Office of Science andTechnology Policy (OSTP)
Travis M. Earles
Office of Management
and Budget (OMB)
Irene B. Kariampuzha
Bureau of Industry
and Security (BIS/DOC)
Matt Borman
Consumer Product Safety
Commission (CPSC)
Mary Ann Danello
Treye A. Thomas
Department of Defense(DOD)
Akbar Khan
Gernot S. Pomrenke
Lewis Sloter
Eric SnowDavid M. Stepp
Department of Education(DOEd)
Krishan Mathur
Department of Energy(DOE)
Harriet Kung
Mihal E. GrossJohn C. Miller
Ravi Prashert
Andrew R. Schwartz
Brian G. Valentine*Affiliations as of April 2011.

Environmental
Protection Agency(EPA)
Jeff Morris
Nora F. Savage
Philip G. Sayre

Department ofHomeland Security(DHS)
Richard T. Lareau
Eric J. Houser
Department of Justice(DOJ)
Joseph Heaps

Food and Drug
Administration(FDA/DHHS)
Carlos Peña
Ritu Nalubola

Department of Labor(DOL)
Janet Carter
Department of State(DOS)
Ken Hodgkins
Chris Cannizzaro

Forest Service(FS/USDA)World L.-S. Nieh
Christopher D. Risbrudt
Theodore H. Wegner

Department ofTransportation(DOT)
Alasdair Cain
Jonathan R. Porter

National Aeronautics
and Space Administration(NASA)
Michael A. Meador
National Institute ofFood and Agriculture(NIFA/USDA)
Hongda Chen

Department of
the Treasury(DOTreas)
John F. Bobalek

National Institutefor Occupational
Safety and Health(NIOSH/CDC/DHHS)
Charles L. Geraci
Vladimir V. Murashov

Director of National
Intelligence(DNI)
Richard Ridgley

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National Instituteof Standards andTechnology(NIST/DOC)
Lloyd J. Whitman
National Institutes of
Health (NIH/DHHS)
Piotr Grodzinski
Lori Henderson
Jeffery A. Schloss
National Science
Foundation (NSF)
Mihail C. RocoParag R. Chitnis
Ian Robertson
T. James Rudd
Nuclear Regulatory
Commission (NRC)
Stuart Richards
U.S. Geological Survey(USGS)
Sarah Gerould
U.S. International Trade
Commission (USITC)
Elizabeth R. Nesbitt
U.S. Patent and Trademark
Office (USPTO/DOC)
Charles Eloshway
Bruce Kisliuk

National Science and Technology Council
Committee on Technology
Subcommittee on Nanoscale Science, Engineering, and Technology
Nanotechnology Environmental and Health Implications (NEHI) Working Group
NEHI Working Group Co-Chairs:
John Howard, National Institute for Occupational
Safety and HealthTreye Thomas, Consumer Product Safety Commission

NEHI Executive Secretary:
Liesl Heeter, National Nanotechnology Coordination
OfficeDepartment and Agency Representatives to the NEHI Working Group
Office of Science and Technology
Policy (OSTP)*Travis M. Earles*Heather Evans
Office of Management and Budget(OMB)
Irene B. Kariampuzha
Consumer Product Safety
Commission (CPSC)
Mary Ann Danello
Treye A. Thomas
Department of Agriculture, Forest
Service (FS/USDA)
World Nieh
Theodore Wagner
Department of Agriculture, National
Institute of Food and Agriculture(NIFA/USDA)
Hongda Chen
Department of Defense (DOD)
T. Matthew Cho
Carole LeBlanc
Igor Linkov*Affiliations as of April 2011.

Department of Energy (DOE)
Jay Larson
Dan Marsick
Kensley Rivera
Paul Wambach

National Institute for Occupational
Safety and Health (NIOSH/CDC/
DHHS)
Charles L. Geraci
Vladimir V. Murashov

Department of Health and Human
Services (DHHS)
Agency for Toxic Substances andDisease Registry (ATSDR)
Candis M. Hunter

National Institute of Standards andTechnology (NIST/DOC)
Debra Kaiser
Laurie Locascio

Department of State (DOS)Chris Cannizzaro
Environmental Protection Agency(EPA)
Jeff Morris
Nora F. Savage
Philip G. Sayre
Food and Drug Administration (FDA/
DHHS)
Ritu Nalubola
Carlos Peña
National Institute of Environmental
Health Sciences (NIEHS/NIH/DHHS)
Nigel Walker
Sri Nadadur
Christopher Weiss

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National Science Foundation (NSF)
Mike Gorman
Barbara Ransom
Mihail C. Roco
Alan Tessier
Occupational Safety and HealthAdministration (OSHA/DOL)
Janet Carter
U.S. Geological Survey (USGS)
Sarah Gerould
International Trade Commission(USITC)Elizabeth R. Nesbitt

N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

Acknowledgements*
The many individuals listed below dedicated considerable time and expertise to write and produce
this strategy.

Writing Team Members
Measurement: Debra Kaiser (NIST), Richard Cavanagh (NIST), Doris Ash (CDC), Rick Davis (NIST),
Matthew Dreyfus (CPSC), Franklin Dunmore (CPSC), Martin Fritts (NIH), Jeffrey Gilman (NIST), Jonathan
Guyer (NIST), Vincent Hackley (NIST), David Holbrook (NIST), Paul Howard (FDA), Laurie Locascio (NIST),
Subhas Malghan (FDA), Kalman Migler (NIST), John Small (NIST), Aleksandr Stefaniak (NIOSH), Sally Tinkle(NIEHS), and Gregory Turk (NIST).
Human Exposure: Cathy Fehrenbacher (EPA), Vladimir Murashov (NIOSH), Charles Geraci (NIOSH),
Maureen Gwinn (EPA), Mark Hoover (NIOSH), Candis M. Hunter (CDC/ATSDR), Anjali Lamba (EPA), Nhan
Nguyen (EPA), Aleks Stefaniak (NIOSH), Treye Thomas (CPSC), David Tobias (AAAS Fellow at EPA), Paul
Wambach (DOE), and Brenda Yamen (OSHA).
Human Health: Sally Tinkle (NIEHS), Carole LeBlanc (DOD), Vince Castranova (NIOSH), Kevin Dreher (EPA),
Matthew Dreyfus (CPSC), Heather Evans (OSTP), Laurie Locascio (NIST), Scott McNeil (NIH), Sri Nadadur(NIEHS), Ryan Tremain (OSHA), Jeanette Van Emon (EPA), Bellina Veronesi (EPA), and Carolyn Wilson (FDA).
Environment: Sarah Gerould (USGS), Phil Sayre (EPA), Alan Tessier (NSF), Dermont Bouchard (EPA),
Michele Conlon (EPA), Jed Costanza (EPA), Jane Denne (EPA), Steve Diamond (EPA), Cathy Fehrenbacher,(EPA), Jeffery Steevens (DOD/USACE), We-Hsiung Lee (EPA), Kim Rogers (EPA), Richard Zepp (EPA), Phil
Sayre (EPA), David Tobias (AAAS Fellow at EPA), and Nora Savage (EPA).
Risk Assessment and Management Methods: Carlos Pena (FDA), Treye Thomas (CPSC), Janet Carter(OSHA), Rick Davis (NIST), Charles Geraci (NIOSH), Jeffrey Gilman (NIST), Maureen Gwinn (EPA), Igor
Linkov (DOD/USARMY), Jeff Morris (EPA), Ritu Nalubola (FDA), Tinh Nguyen (NIST), Phil Sayre (EPA), andSally Tinkle (NIEHS).
Informatics: Martin Fritts (NIH).
Ethical, Legal, and Societal Implications: Jeff Morris (EPA), Vivian Ota Wang (NIH), and Mike Gorman(NSF).
International: Chris Cannizzaro (DOS) and Heather Evans (OSTP).

* Affiliations are as of April 2011.

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Table of Contents
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iv
Table of Contents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .vii
Vision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x
Mission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x
Executive Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
1. Introduction to the 2011 NNI Environmental, Health, and Safety Research Strategy . . . . . 1
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Framing the 2011 NNI EHS Research Strategy . . . . . . . . . . . . . . . . . . . . 2
Process for Developing the 2011 NNI EHS Research Strategy . . . . . . . . . . . . . . 5
Structure of the Research Strategy Document . . . . . . . . . . . . . . . . . . . . 8
2. Nanomaterial Measurement Infrastructure . . . . . . . . . . . . . . . . . . . . 11
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Research Needs as of 2011 . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Comparative Analysis of Projects . . . . . . . . . . . . . . . . . . . . . . . . 14
Rationale for the 2011 Research Needs and Changes from 2008 . . . . . . . . . . . . 15
3. Human Exposure Assessment. . . . . . . . . . . . . . . . . . . . . . . . . . 23
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Research Needs as of 2011 . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Comparative Analysis of Projects . . . . . . . . . . . . . . . . . . . . . . . . 25
Rationale for the 2011 Research Needs and Changes from 2008 . . . . . . . . . . . . 27

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4. Human Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Research Needs as of 2011 . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Comparative Analysis of Projects . . . . . . . . . . . . . . . . . . . . . . . . 38
Rationale for the 2011 Research Needs and Changes from 2008 . . . . . . . . . . . . 40
5. Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Goal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Research Needs as of 2011 . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Comparative Analysis of Projects . . . . . . . . . . . . . . . . . . . . . . . . 54
Rationale for the 2011 Research Needs and Changes from 2008 . . . . . . . . . . . . 54
6. Risk Assessment and Risk Management Methods. . . . . . . . . . . . . . . . . . 65
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Goal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Research Needs as of 2011 . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Comparative Analysis of Projects . . . . . . . . . . . . . . . . . . . . . . . . 67
Rationale for the 2011 Research Needs and Changes from 2008 . . . . . . . . . . . . 69
7. Informatics and Modeling for NanoEHS Research . . . . . . . . . . . . . . . . . . 79
Enhance Quality and Availability of Data . . . . . . . . . . . . . . . . . . . . . 79
Expand Theory, Modeling, and Simulation Capabilities. . . . . . . . . . . . . . . . 80
Build a Collaborative Informatics Infrastructure. . . . . . . . . . . . . . . . . . . 81
Rationale for the 2011 Research Need . . . . . . . . . . . . . . . . . . . . . . 82
8. The Path Forward . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Targeting and Accelerating EHS Research . . . . . . . . . . . . . . . . . . . . . 85
Linking EHS Research Needs and Goals to the NNI Strategic Plan . . . . . . . . . . . . 89
Implementation and Coordination of the NNI EHS Research Strategy . . . . . . . . . . 94
Dissemination of Knowledge . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
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Appendix A. Selected Readings . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Appendix B. International and Domestic Cooperative Activities . . . . . . . . . . . . . 100
International Cooperative Activities . . . . . . . . . . . . . . . . . . . . . . . 100
Domestic Cooperative Activities . . . . . . . . . . . . . . . . . . . . . . . . 105
Appendix C. Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
ISO TC 229 Core Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Appendix D. Comprehensive Chart of 2011 EHS Research Strategy Needs . . . . . . . . . 109
Appendix E. Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

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VisionIn support of the National Nanotechnology Initiative (NNI), the vision for environmental, health, andsafety research in nanotechnology is a future in which nanotechnology provides maximum benefit to
the environment and to human social and economic well-being.

MissionThe NNI agencies serve the public good through the development and deployment of a coordinatednanotechnology environmental, health, and safety research strategy that:rProtects public health and the environmentr

Employs science-based risk analysis and risk managementr

Fosters technological advancements that benefit society

Terminology Used in the NNI Environmental, Health, and Safety Research Strategy
Consistent with the 2006 NNI report Environmental, Health, and Safety Research Needs for Engineered Nanoscale
Materials,1 and for the purposes of this document, the term engineered nanomaterials (or ENMs)* refers to thosematerials that have been purposely synthesized or manufactured to have at least one external dimension of
approximately 1–100 nanometers (nm)—at the nanoscale—and that exhibit unique properties determined bythis size. In this document, when the term nanomaterials is used alone, it refers to engineered nanomaterials.
This definition also applies to nanotechnology-enabled products (NEPs), that is, intermediate engineered
nanoscale products, including ENMs embedded in a matrix material, that exist during manufacture and in
final products. Additional definitions for terms such as agglomerates and aggregates that are used throughout
this strategy document can be found in Appendix C.
NanoEHS is used in this strategtty document as a shorthand term to refer to nanotechnology-related environmental, health, and safety (research, etc.).
* The term engineered nanomaterial is applicable to the NNI 2011 EHS Research Strategy and overall nanotechnology-related EHS research. This term does not necessarily apply to Federal regulatory statutes or policies
relevant to nanotechnology.

1. NSET/NSTC, Washington, DC; http://www.nano.gov/NNI_EHS_research_needs.pdf.

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Executive Summary
Nanotechnology allows scientists to work at the nanoscale to produce technological advances in suchdiverse areas as electronics, energy, environmental remediation, medicine, security, and space. To
promote nanotechnology innovation and economic benefit, the National Nanotechnology Initiative(NNI) was established in 2000 as the Federal Government’s multiagency, multidisciplinary research anddevelopment (R&D) program. The goals of the NNI are fourfold: (1) to advance a world-class nanotechnology R&D program; (2) to foster the transfer of new technologies into products for commercial andpublic benefit; (3) to develop and sustain educational resources, a skilled workforce, and the supporting
infrastructure and tools to advance nanotechnology; and (4) to support responsible development of
nanotechnology.
Environmental, health, and safety (EHS) research is essential to successful achievement of all four NNI
goals; however, it is most closely linked to the goal of responsible development. The NNI agencies collaboratively developed a nanotechnology EHS research strategy that focuses on the use of science-basedrisk analysis and risk management to protect public health and the environment while also fostering
the technological advancements that benefit society. The strategy serves as guidance to the Federal
agencies that produce and use scientific information to develop nanotechnology risk assessments that
inform risk management and regulatory decisions. Given the dynamic nature of research in this area, the
NNI incorporated adaptive management into its first NNI EHS Research Strategy, the 2008 NNI Strategy
for Nanotechnology-Related Environmental, Health, and Safety Research. This document, the 2011 NNI
Environmental, Health, and Safety Research Strategy, is a result of that process and revises and replaces
the 2008 strategy.

Formulating a Science-Based Risk Management Research Framework
The 2011 NNI EHS Research Strategy is grounded in the principles of risk assessment and of productlife cycle analyses. Risk assessment includes understanding the magnitude of the potential exposure
to humans and the environment and the magnitude of the potential hazard or effects presented by
the nanomaterials. Through the risk assessment process, risks and benefits may be compared between
a nanomaterial and other substances, between different nanomaterials, or for a single nanomaterial.
Risk assessment may be conducted at selected points along the life cycle stages of product development, manufacture, commercialization and disposal or end of life. Integration of risk assessment withthe study of life stages of nanotechnology-enabled products (NEPs) permits identification of critical risk
assessment data needs. These data needs have been translated into nanoEHS research needs and organized into core nanoEHS research categories: (1) Nanomaterial Measurement Infrastructure, (2) Human
Exposure Assessment, (3) Human Health, (4) Environment, and (5) Risk Assessment and Risk Management
Methods. The adaptive management process also identified (6) Informatics and Modeling and ethical,
legal, and societal implications (ELSI) of nanotechnology as important additions to the strategy.
In addition to this matrix of research needs, the 2011 NNI EHS Research Strategy was informed bymultiple stakeholder consultations: reviews by the President’s Council of Advisors on Science and

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Technology and the National Academies as well as four multidisciplinary, multi-sector NNI workshopsthat examined the 2008 NNI EHS Research Strategy, the current status of the science, and gaps andbarriers to nanotechnology EHS research.

Structuring the 2011 NNI EHS Research Strategy
The nanoEHS research needs are organized into six chapters (Chapters 2–7), covering each of the core
nanoEHS research categories, followed by a chapter on the means to effectively move nanoEHS researchforward (Chapter 8). Each of the first five research category chapters contains a set of goals, researchneeds to achieve those goals, and an analysis of ongoing research in the category. New in the 2011
NNI EHS Research Strategy are the chapter describing the critical role of informatics and modeling inorganizing the expanding nanoEHS knowledge base and the chapter promoting timely and effective
achievement of strategic NNI nanoEHS goals. ELSI considerations are woven throughout the researchchapters of this document to inform research planning and data and product management at all levels.
(Appendix D provides a comprehensive chart of all the nanoEHS research needs.)

Targeting and Accelerating Research
To move expeditiously toward realization of the vision and goals of the 2011 NNI EHS Research Strategy
and to address several challenges that span all of the research categories, it will be necessary for NNI
agencies and programs to be highly focused and to take advantage of the benefits of collaboration andinformation-sharing among representatives from NNI agencies, academia, industry, nongovernmentalorganizations (NGOs), the general public, and international governance bodies. The Nanoscale Science,
Engineering, and Technology (NSET) Subcommittee and its Nanotechnology Environmental and Health
Implications (NEHI) Working Group will serve as a nexus for communication about and facilitation of thisfocused interagency collaboration. The NEHI Working Group has identified the following key principles
to assist agencies in making strategic decisions about research programs that will efficiently advance
the NNI EHS research agenda while meeting their respective missions:r

Prioritize Nanomaterials for Research. The NEHI Working Group has developed research-focused
criteria to identify and prioritize engineered nanomaterials (ENMs) and nanotechnologyenabled products (NEPs) that may pose a plausible risk to human health and the environment.
These criteria include the risk assessment concepts of the potential for hazard and the likelihoodof exposure and ENM-related properties such as high surface reactivity and biological novelty.

r

Establish Standard Measurements, Terminology, and Nomenclature. Standardized measurements ensure the accuracy, precision, and reproducibility of research results and, thus, provide
a trustworthy knowledge base for evaluating and understanding exposure and hazards tohumans and the environment. Standard terminology and nomenclature are vital to fully characterize and categorize ENMs.

r

Maximize Data Quality. The NEHI agencies recognize the complexity of experimental designand execution of nanoEHS research. Criteria for physico-chemical characterization of ENMs and

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establishment of reliable and reproducible assays, methods, and alternative test methods are
critical for the production of the highest quality data.
r

Stratify Knowledge for Risk Assessment. Depending upon the decision-making context, a qualitative or quantitative risk assessment may be performed. These two types of risk assessment
require different data sets to achieve their respective knowledge thresholds and support thedevelopment of tiered risk management tools.

rPartner to Achieve NNI EHS Research Goals. The NNI agencies recognize the importanceof public–private partnerships with industries, NGOs, and universities to develop thedata for nanoEHS knowledge thresholds. The NNI Nanotechnology Signature Initiatives(http://www.nano.gov/initiatives/government/signature) are examples of such scientific andinvestment collaborations.

rEngage Internationally. The societal challenges for which nanotechnology may provide solutions are global, and as such, provide opportunities for transparent, inclusive, and international
collaboration. International engagement is a priority of the NNI and a critical component of2011 NNI EHS Research Strategy.

Implementing and Coordinating the 2011 NNI EHS Research Strategy
This interagency strategy document will guide programs and investment decisions by the individual
agencies as well as in coordinated interagency activities in the coming years. It should be noted that theagencies have varied missions, and their individual priorities may differ in scope and focus from thoseoutlined in this report. For these reasons, continuous coordination is essential, and agencies will workthrough the NSET Subcommittee, its NEHI Working Group, and the NNCO Coordinator for EHS to ensure
the integration of agency implementation plans.
The NNI, as a program, does not fund research; rather, its funding is the sum of nanotechnology-related
funding allocated by each of the participating agencies. Through its member agencies, the NNI informs
and influences the Federal budget and planning processes.
The 2011 NNI EHS Research Strategy is predicated on both concurrent and sequential progress in all
core nanoEHS research categories. Continuous coordination is essential to ensure the integration of
agency implementation plans. The NSET Subcommittee and its NEHI Working Group’s implementationand coordination framework includes:r

Increasing agency participation in NNI EHS research. As guidance to the NNI agencies, the 2011
NNI EHS Research Strategy identifies research areas that agencies may recognize as aligningwith their missions.

r

Utilizing the NNI EHS Coordinator. The NNI EHS Coordinator facilitates efforts of the NNCO,
NSET Subcommittee, and NEHI Working Group in identifying and leveraging nanoEHS researchcollaborations domestically and internationally; serves as the NNI point-of-contact for stakeholders; and spearheads the 2011 NNI EHS Research Strategy’s implementation, coordination,and evaluation.

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rRefocusing the NEHI Working Group. Through consultation with agency representatives, NEHI
leadership adapted its monthly meeting format to ensure better coordination and assessmentof research to achieve the goals of the 2011 EHS Research Strategy.

r

Implementing media and networking opportunities. The NSET Subcommittee and NEHI Working
Group are exploring new social media opportunities to improve interagency communicationand stakeholder interactions.

rEnabling a broad base of nanoEHS research to support regulatory decision making. The NNI2011 EHS Research Strategy fundamentally depends on sustaining a broad spectrum of basic
and applied research. Support from agencies that investigate the fundamental properties ofnanomaterials and directly apply research for responsible development is critical to achieve
the NNI EHS goals.

r

Coordinating existing and fostering expanded agency efforts to address priority EHS researchneeds and identified gaps. Through monthly meetings and workshops, the NEHI Working Groupwill continue to clarify priorities and identify synergistic opportunities to pursue the goals of
the strategy through collaboration and joint programs.

rFacilitating partnerships with industry. The NEHI Working Group will continue to utilize existing small business programs and explore and develop new mechanisms for NNI agencies topartner with industry.

r

Coordinating standards efforts internationally. Several NNI agencies participate in national
and international efforts to develop standards, nomenclature, and terminology for nanoEHS
research.

r

Adaptively managing the NNI EHS Research Strategy. The NEHI Working Group will periodicallyreview the status of nanoEHS science, progress towards the goals of the 2011 NNI EHS Research
Strategy, and stakeholder concerns. These reviews will inform update of the research needs andpriorities to maintain a dynamic and timely strategy.

Conclusion
Nanotechnology is a multidisciplinary field requiring the engagement of scientists in disciplines asdiverse as materials science, physics, biology, chemistry, engineering, toxicology, clinical practice,social science, and risk assessment, as well as leaders in industry, public health advocacy, healthcare,and participation of the general public. The multicomponent risk management research frameworkthat forms the foundation of this strategy will require focused and sustained coordination by the NEHI
Working Group and regular review by the NNI agencies and stakeholders.

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1. Introduction to the 2011 NNI
Environmental, Health, andSafety Research Strategy
Introduction
Nanotechnology allows scientists to work at the nanoscale to create, explore, and manipulate the biological and material worlds. 1This capability is leading to technological advances across the landscape ofAmerican society in such diverse application areas as electronics, energy, environmental remediation,
medicine, security, and space. To capitalize on the novel material properties that emerge at the nanoscale
to solve critical issues for U.S. citizens, the National Nanotechnology Initiative (NNI) was establishedin 2000 as the Federal Government’s multiagency, multidisciplinary nanotechnology research anddevelopment (R&D) program. Since its establishment, the NNI has served as a locus for communication,
cooperation, and collaboration among participating Federal agencies and has provided a frameworkof shared goals, priorities, and strategies.
The goals of the NNI2 are fourfold: (1) to advance a world-class nanotechnology R&D program; (2)to foster the transfer of new technologies into products for commercial and public benefit; (3) todevelop and sustain educational resources, a skilled workforce, and the supporting infrastructure andtools to advance nanotechnology; and (4) to support responsible development of nanotechnology.
Environmental, health, and safety research is essential to successful achievement of all four NNI goals;
however, it is most closely linked to the goal of responsible development. Responsible developmentof nanotechnology encompasses research to understand the environmental, health, and safety (EHS)
impacts, as well as the ethical, legal, and societal implications (ELSI) of nanotechnology. Responsible
development includes such diverse activities as promoting public outreach and engagement, and theuse of nanomaterials to solve environmental challenges such as ensuring a clean water supply andremediating soil contamination.
To integrate responsible development across the broad spectrum of nanotechnology R&D, manufacturing, and material use activities, the NNI agencies have collaboratively developed a research strategy
specifically focused on environmental, health, and safety aspects of nanotechnology. As a Federal
strategic guidance, this document contains a vision and mission statement for the NNI Environmental,
Health, and Safety Research Strategy, goals and research needs for five of the core nanotechnologyrelated EHS research categories, and evaluations of the status of the science in 2011 and of the Federal
portfolio for nanotechnology-related EHS (nanoEHS) research in Fiscal Year (FY) 2009, the last year forwhich Federal agencies have complete data. Integrated into the strategy are concepts for accelerating
the pace of nanoEHS research, for incorporating product life cycle approaches, and for addressing ethical, legal, and societal issues.
1.
2. NSET/NSTC, NNI Strategic Plan. Washington DC, 2011; http://www.nano.gov

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The NNI EHS Research Strategy provides guidance to the Federal agencies as they develop theiragency-specific nanotechnology EHS research priorities, implementation plans, and timelines. Given
the dynamic nature of research in this area, the NNI incorporated adaptive management into its first
NNI EHS Research Strategy, the 2008 NNI Strategy for Nanotechnology-Related Environmental, Health,and Safety Research3 to allow for modification of the strategy based on research progress, new findings, and product development. This document, the 2011 NNI EHS Research Strategy, is a result of that
adaptive management process and revises and replaces the 2008 strategy. Agencies whose missions
support nanomaterials research are encouraged to use this 2011 document to better understand where
their missions and responsibilities are consistent with those of the NNI EHS Research Strategy, identify
opportunities for collaboration and cooperation, and assist the NNI in achieving U.S. Federal goals fornanotechnology-related environmental, health, and safety research activities. Overall priority is given
to the EHS research that decreases the uncertainty in assessing and managing risk and that addresses
the EHS objectives in the NNI 2011 Strategic Plan. (Table 8-1 in this document sets forth the linkages
between the NNI’s Strategic Plan and its EHS Research Strategy.)
The adaptive management process remains part of the 2011 NNI EHS Research Strategy to ensure proactive, science-based management of engineered nanomaterials (ENMs) into the future. Ongoing evaluation of research progress is conducted by members of the Nanotechnology Environmental and Health
Implications (NEHI) Working Group of the multiagency Nanoscale Science, Engineering, and Technology(NSET) Subcommittee of the National Science and Technology Council’s Committee on Technology. They
will review and evaluate progress on an annual basis to ensure that the NNI EHS Research Strategy andactivities keep pace with the rapid development of nanotechnology and evolving information on theeffects of human and environmental exposure to nanomaterials. Research and development remain
essential to the fundamental understanding and development of tools and materials for nanotechnology. Fundamental research, development of infrastructure, and education will continue to contributeto the knowledge needed for Federal nanoEHS research.

Framing the 2011 NNI EHS Research Strategy
The 2011 NNI EHS Research Strategy aims to ensure the responsible development of nanotechnology byproviding guidance to the Federal agencies that produce and use scientific information to develop risk
assessments that inform decision making. These assessments may compare risks and benefits between
a nanomaterial and other substances, between different nanomaterials, or they may evaluate a single
nanomaterial. The process of risk assessment (Figure 1-1) is comprised of hazard identification, exposure
assessment, dose-response assessment, and risk characterization. Risk characterization, or the systematicand rigorous analysis of available hazard and exposure data, directly informs risk management practices.

3. NSET/NSTC, NNI Strategy for Nanotechnology-Related EHS Research. Washington, DC, 2008;
http://www.nano.gov/NNI_EHS_Research_Strategy.pdf.

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1. INTRODUCTION TO THE 2011 NNI ENVIRONMENTAL, HEALTH, AND SAFETY RESEARCH STRATEGY

Assess Magnitude of Exposure

Identify
HazardCharacterize
Risk
Assess Dose
Response
Relationship

Figure 1-1. Risk assessment process. The risk assessment process is often defined as a mathematical equation
Risk equals Hazard times Exposure, or R = H x E, and indicates that the magnitude of the risk is equal to themagnitude of the hazard measurement (dose-response) made for a material multiplied by the magnitude ofthe exposure.
Source: U.S. EPA.

Figure 1-2 incorporates these key risk assessment components—exposure assessment, hazard identification, and dose–response (left-hand column)—with nanomaterial life cycle stages—from raw materials
through commercialization and end of product life (across the top) and the exposure–effects pathways.
The concentration of nanomaterials in the environment will depend on factors such as the nature andamount of the nanomaterial released, its physical and chemical properties, and time.
As depicted in blue and red in this continuum, nanomaterials released into the environment may
undergo transformation by environmental conditions such as temperature and salinity, biologicalconditions such as habitat, and the presence of co-contaminants. In turn, the transformed nanomaterials may modify atmospheric, soil, or water chemistry. These transformations may alter the form of thenanomaterials that are transported through the environment, and hence, the ENMs to which humans
and ecosystems are exposed. The clustering of nanomaterials into aggregates or agglomerates is an
example of transformations that may alter transport and exposure potential. Biological or environmental
systems may be exposed to these ENMs and respond through systems and pathways designed to buffer
exposures to substances that could perturb human health or adversely impact the environment.

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Product Life Cycle Stages
Research, Design
Commercialization
Raw Materials and Development Production
Disposal or Recycling
Consumer Use

Risk
Assessment
Paradigm

Exposure
Assessment
Transport/
Transform
Concentration
in Env.
External DoseEnvironmental
Pathways

air

water

Transport &Transformation

environmental
conditions

biologicalconditions

Exposure(Biota)aquatic

primary & secondary
contaminants

terrestrial
inhalation

ingestion

Exposure(Human)Hazard ID
Internal Dose& Response

wastewater/
landfills

soil

ecosystems

Effects

dermalabsorption

humansFigure 1-2. The risk assessment paradigm applied across all nanomaterial life cycle stages.
Source: NEHI and N.R. Fuller, Sayo-Art.

These important risk concepts have guided the development of the risk management research framework underpinning the NNI EHS Research Strategy (Figure 1-3). This research framework identifies coreresearch areas to understand and manage risk that provide critical scientific information on (1) nanomaterial measurement infrastructure, (2) human exposure assessment, (3) human health, and (4) theenvironment. Data from these categories are integrated and employed in the core research area, (5) risk
assessment and risk management methods, and are applied to product life cycle, regulatory decision
making, public outreach, and research planning. Also serving in an integrative capacity is (6) informatics
and modeling, an increasingly essential tool for managing and sharing data and for developing andrefining theories, models, and simulations. Ethical, legal, and societal implications of nanotechnology
encircle these research components to highlight the need to include ELSI considerations in the designof all of the core categories of EHS research. The dynamic and iterative nature of the NNI EHS Research
Strategy is captured in Figure 1-3 by feed-forward and feedback loops that indicate how newly developing data inform and modify the research process and risk management decisions.

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1. INTRODUCTION TO THE 2011 NNI ENVIRONMENTAL, HEALTH, AND SAFETY RESEARCH STRATEGYELSI Considerations
Nanomaterials
Synthesis and Use
Potential Release &Disposal

Research toUnderstand andManage Risk

Risk
Assessment

Risk Management

product life cycle
Measurement

Predictive
Modeling

Human Exposure
Human Healthregulatory decision-making
public outreachresearch planning

Environment

Figure 1-3. Risk management research framework for nanotechnology-related risk management, regulatory
decision making, product use, research planning, and public outreach. This research framework identifies coreresearch areas that provide critical scientific information to understand and manage risk. In addition, informatics and predictive modeling are increasingly essential tools for managing and sharing data. Finally, ELSI circles
all components of the framework to highlight the need to include ELSI considerations throughout theframework.
Source: NEHI and N.R. Fuller, Sayo-Art.

Process for Developing the 2011 NNI EHS Research Strategy
This strategy is the product of detailed and collaborative planning efforts. As indicated below, the NNI
agencies established a comprehensive framework to reassess the 2008 NNI EHS Research Strategy. This
included the solicitation, collection, and analysis of relevant information from Federal agencies withresponsibility for the oversight of research, development, manufacture, import, sale, or use of engineered
nanomaterials and nanotechnology-enabled products. It also included the solicitation, collection, andanalysis of input from other stakeholders, including academia, industry, public health advocates, andthe general public. The NEHI Working Group reviewed information obtained from multisector meetingsand individual comments to identify priority research needs, and gaps and barriers to accomplishing
the needed research.

Assessment of Federal EHS Research: Strengths and Weaknesses
Stakeholder consultations included four public workshops, reviews by the National Academies (NA)and the President’s Council of Advisors on Science and Technology (PCAST),4 and other interactions
between government scientists and the public.
Between February 2009 and March 2010, the NEHI Working Group, under the auspices of the NSET
Subcommittee, convened four nanoEHS workshops open to the public to evaluate the 2008 NNI EHS
Research Strategy:
4. PCAST is designated as the National Nanotechnology Advisory Panel and is tasked with biennial reviews of the
NNI.

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1. Human and Environmental Exposure Assessment, February 24–25, 2009 (seehttp://www.nano.gov/events/meetings-workshops/exposure)
2. Nanomaterials and the Environment & Instrumentation, Metrology, and Analytical Methods,
October 6–7, 2009 (see http://www.nano.gov/events/meetings-workshops/environment)
3. Nanomaterials and Human Health & Instrumentation,
Metrology, and Analytical Methods, November 17–18, 2009 (seehttp://www.nano.gov/events/meetings-workshops/humanhealth)
4. Risk Management Methods and Ethical, Legal, and Societal Implications of Nanotechnology,
March 30–31, 2010 (see http://www.nano.gov/events/meetings-workshops/capstone)
At these workshops, representatives from NNI agencies and stakeholder groups reviewed the state of
the science and identified critical gaps and barriers to needed research. This information was significant
to the Federal dialogue to revise the 2008 NNI EHS Research Strategy; the complete workshop reports
are publicly available at http://www.nano.gov.
In 2009, the National Academies conducted a scientific and technical review of the Federal EHS Research
Strategy.5 The NA review committee established a list of elements it considered to be part of an effective
nanotechnology risk-research strategy, evaluated whether the Federal strategy had these elements,
and assessed how the research identified in the strategy would support risk-assessment and riskmanagement needs. Specific NA technical recommendations were considered in the development of
this 2011 strategy.
The most recent PCAST review of the NNI was completed in March 2010. This review included “an assessment of NNI’s performance in helping to orchestrate the identification and management of potential
risks associated with nanotechnology, with particular attention paid to reviewing progress the NNI has
made in following through on recommendations made in the 2008 National Nanotechnology Advisory
Panel review of the NNI.”6 Specifically, the report recommended that the NSET Subcommittee’s NEHI
Working Group:r

Develop clear principles to support the identification of plausible risks associated with the products of nanotechnology. (While principles provide a conceptual framework for considerationof plausible risk, NEHI, in keeping with the more practical guidance provided by the NNI EHS
Research Strategy, has chosen to develop research-focused criteria to identify and prioritize
ENMs and NEPs that might pose a plausible risk to human health or the environment [EHS
Research Strategy Chapter 8].)r

Further develop and implement a cross-agency strategic plan that links EHS research activities with knowledge gaps and decision-making needs within government and industry to
make commercial and regulatory decisions that ensure safe use of nanotechnology products.
(This NNI EHS Research Strategy is directly responsive to the PCAST request to further develop
a cross-agency strategic plan.)

5. Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research (National
Academies Press, Washington, DC, 2009; http://www.nap.edu/catalog.php?record_id=12559).
6. Report to the President and Congress on the Third Assessment of the National Nanotechnology Initiative (PCAST,
Washington, DC, 2010; http://whitehouse.gov/sites/default/files/microsites/ostp/pcast-nni-report.pdf ), p. 7.

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1. INTRODUCTION TO THE 2011 NNI ENVIRONMENTAL, HEALTH, AND SAFETY RESEARCH STRATEGYr

Develop information resources on crosscutting research and nanotechnology EHS issues
that are relevant to businesses, health and safety professionals, researchers, and consumers.
(This recommendation remains a high priority for the NNI agencies. Specifically, Chapter 7in this document addresses the use of informatics tools to aid in the development, analysis,organization, archiving, sharing, and use of data acquired through nanoEHS research projects.)

Additional input to the NNI EHS Research Strategy has come from detailed public responses to a
Request for Information published in the Federal Register and an online dialogue at the NNI Strategy
Portal (http://strategy.nano.gov/), which are further described in Appendix A of the 2011 National
Nanotechnology Initiative Strategic Plan.7
In addition to stakeholder consultation and public comment, the Office of Management and Budget(OMB) requested that NNI agencies provide the NSET Subcommittee with detailed information on EHS
research projects funded in FY 2009 and that the agencies identify the 2008 EHS research category andneed that each project informs. These data were used to identify areas of strength or need when formulating the 2011 NNI EHS Research Strategy. Summaries of the data on these EHS projects are presented
by core EHS research category in Chapters 2–6 of this document, and six examples of research progress
are highlighted in this report. A complete listing of the FY 2009 EHS research projects is available online
at http://www.nano.gov/publications-resources.
The reader should note the difference between the scopes of the research included in the OMBrequested project data reported here for FY 2009 and that reported for environmental, health, safety,
and risk mitigation as a part of Program Component Area 7 in the annual NNI Supplement to the
President’s Budget. The annual budget supplement reports funding for research that is “primarily aimed
at understanding risks posed by nanomaterials.” Data presented online and elsewhere in this report also
include research that supports five of the core EHS research categories but that may not be primarily
aimed at understanding potential risks of engineered nanomaterials; this research is predominantly
in instrumentation and metrology that enables characterization and measurements of ENMs, and in
medical applications research that assesses the safety of nanomaterials being considered for use in thehuman body. Projects focused on risk mitigation and other topics that the NNI EHS Research Strategy
writing teams deemed “not EHS research” are not included in this analysis.

Writing Process
NEHI formed writing teams (over 70 members from 12 NNI agencies; see Acknowledgements) thatanalyzed the Federal portfolio of projects to determine the balance of efforts focused on the priority
research needs and to identify areas of significant investment and under-investment. In addition totabulating the number of projects and total funding in each core EHS research category, the teams
compared the FY 2009 project analysis to the FY 2006 analysis published in the 2008 NNI EHS Research
Strategy in order to gauge progress. In developing the projection of future research needs, the teams
also considered the relationship of the research needs within and across the core research areas, that is,
the sequencing of various kinds of research that depend on results from, or progress in, other researchareas, or the need to develop the capacity for specific types of research. A draft version was posted at
7. NSET/NSTC, NNI Strategic Plan. Washington, DC, 2011; http://www.nano.gov/.

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strategy.nano.gov for public comment (Dec. 1, 2010-Jan. 21, 2011). Where appropriate, this strategy was
updated in response to comments and new information.
The success of the strategy outlined in this document depends on the collective efforts of the NNI agencies and their priorities and resources. The strategy forms one component of the ongoing facilitation andcoordination by the NSET Subcommittee and the NEHI Working Group of a multifaceted, multi-agency
NNI EHS research program.

Structure of the Research Strategy Document
This document provides the concepts, frameworks, research needs, and activities that will assist agencies in making strategic decisions about their nanotechnology EHS research programs. Structurally,
the nanoEHS research needs are organized into six chapters (Chapters 2–6), covering five of the core
nanoEHS research categories — (1) Nanomaterial Measurement Infrastructure, (2) Human Exposure
Assessment, (3) Human Health, (4) the Environment, and (5) Risk Assessment and Management Methods— and a new, sixth core category, informatics and modeling, followed by a final chapter on the means
to effectively move nanoEHS research forward.
These five core research categories are strongly interrelated and synergistic, as illustrated in Figure 1-4.
The risk of nanomaterials to both humans and the environment is the product of exposure and hazard.
Thus, science-based risk assessment and risk management requires data that address research needs inhuman exposure, human health, and the environment. The generation and organization of a vast body ofrequired data that are accurate, precise, and reproducible requires both a comprehensive nanomaterial
measurement infrastructure and predictive modeling and informatics capabilities. This EHS strategy is
predicated on both concurrent and sequential progress in all six research categories.

Predictive Modeling& Informatics

Environment

Human Health

Risk
Assessment& Management

Human
Exposure
Nanomaterial Measurement
Infrastructure

Figure 1-4. Interrelationship of core research areas of the 2011 NNI EHS Research Strategy.
Source: Debra Kaiser, NIST. N.R. Fuller of Sayo-Art provided revised image graphics.
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Each of the five research category chapters contains a set of goals, revised research needs to achieve
those goals, and an analysis of ongoing research in the category. The term “revised research needs” inthese chapters refers specifically to changes made to the research needs in the 2008 NNI EHS Research
Strategy as a result of stakeholder input and analysis of the current state of the science. As part of therevision process, some of the 2011 nanoEHS research needs were reordered to reflect the sequence inwhich the research is conceptualized and accomplished. In response to stakeholder comments, andafter careful consideration, the NEHI Working Group has eliminated the heat diagrams that were usedin the 2008 EHS Research Strategy.8 To be meaningful, prioritization, or timing and staging of research,
are components of an implementation plan and should be developed within agency missions andappropriations, as guided by this NNI EHS Research Strategy.
New in the 2011 NNI EHS Research Strategy is the section (Chapter 7) describing the newly defined
research area of informatics and modeling, and its critical role in organizing the expanding nanoEHS
knowledge base, and the section (Chapter 8) promoting timely and effective achievement of strategic
NNI nanoEHS goals.
Life cycle assessment has an increased emphasis in the 2011 NNI EHS Research Strategy. A life cycle
assessment approach (Figures 1-2, 1-3, and 1-5) presents an opportunity to mitigate potential adverse
human and environmental impacts of nanotechnology. Adding a life cycle approach to the NNI EHS
Research Strategy integrates practical and applied research with the basic research needed to accomplish the goals of the NNI and its EHS Research Strategy.

RecycleConsumer Product
Manufacturing

Raw Material
Production

Consumer
Use
Consumer
Exposure

WorkerExposure

Industrial
Emissions

Product End
of Life
Landfills

Incinerators

WorkerExposure

Human Population and
Ecological Exposure

Figure 1-5. The life cycle perspective on risk assessment. Life cycle assessment supports sound product development, responsible nanomanufacturing (scaling up), and protection of public health.
Source: EPA 100/B07/001, February 2007, http://epa.gov/osa. N.R. Fuller of Sayo-Art provided revised image
graphics.
8. National Nanotechnology Initiative Strategy for Nanotechnology-Related Environmental, Health, and Safety
Research (NSET/NSTC, Washington, DC, 2008; http://www.nano.gov/NNI_EHS_Research_Strategy.pdf ), Figures 3, 5, 7, 9,
and 11 on pages 18, 24, 31, 36, and 42, respectively.

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Also new in the 2011 NNI EHS Research Strategy is the inclusion of ethical, legal, and societal implications of EHS research. ELSI considerations are deeply embedded in the NNI’s commitment to responsible
development of nanotechnology (NNI Strategic Plan Goal 4; see Introduction, p. 2 and Figure 1-2). How
nanotechnology research and applications are introduced into society; how transparent decisions are;how sensitive and responsive policies are to the needs and perceptions of the full range of stakeholders;and how ethical, legal, and social issues, including environmental justice, are addressed will determine
public trust and the future of innovation driven by nanotechnology. The NNI seeks to generate ELSI
knowledge and insights through (1) research in the areas of public perception and understanding of
expected benefits, anticipated risks, and safety that can help society assess potential impacts of nanotechnology and possible responses; (2) scientific meetings and workshops at the local, state, national,
and international levels; and (3) public engagement activities to identify stakeholder perspectives on
nanoEHS and ELSI issues.
ELSI considerations are woven throughout the research chapters of this document to inform researchplanning and data and product management at all levels, and they are linked to the ELSI objectives
outlined in the Goal 4 section of the 2011 NNI Strategic Plan (see also Chapter 8 of this document, Table
8-1). Additionally, EHS research fits within the larger NNI area of societal dimensions, which includes
considerations of who in society is most likely to benefit most from nanotechnology, and who is most
likely to incur any adverse impacts.
The final chapter of this document, Chapter 8, The Path Forward, is aimed at effectively focusing the NNI
agencies’ EHS research efforts. It includes a section on targeting and accelerating research by introducing
criteria for prioritizing nanomaterials for EHS research; expanding standard measurements, terminology,
and nomenclature; defining key concepts to maximize data quality; recognizing approaches to stratify
knowledge for risk assessment; and highlighting the need for partnership and international engagement. These are followed by a section linking the 2011 NNI EHS Research Strategy with the goals andobjectives of the 2011 NNI Strategic Plan. Finally, Chapter 8 addresses implementation and coordinationof the NNI EHS Research Strategy and dissemination of the knowledge gained through the EHS research
efforts of the NNI agencies.

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2. Nanomaterial Measurement Infrastructure
Overview
A comprehensive measurement infrastructure consisting of a suite of complementary tools for accurate,
precise, and reproducible measurements is critical for reliable assessment of exposure and hazards forhumans and the environment across all life cycle stages of engineered nanomaterials (ENMs) and nanotechnology-based, or nanotechnology-enabled, products (NEPs). The 2011 NNI EHS research category
Nanomaterial Measurement Infrastructure (NMI) restructures and expands upon the measurementfocused research category Instrumentation, Metrology, and Analytical Methods (IMA) described in the2008 NNI EHS Strategy. The new category title reflects the foundational role that measurement tools playin supporting and enabling the research needs in the other research categories, such as by evaluating
and understanding effects, processes, and mechanisms related to exposure and hazards.
The “supporting infrastructure and tools,” set out as part of Goal 3 of the NNI Strategic Plan, include
measurement protocols, standards, instruments, models, and data. These measurement tools enable
the accurate, precise, and reproducible measurements essential for science-based risk assessment andmanagement of ENMs and NEPs. Such tools should provide the appropriate level of traceability9 andprecision required for risk-relevant ENM characterization.
The various types of measurement tools covered in this research category are defined as follows:r

Protocols are well-defined procedures, methods, or assays that may require the use of referencematerials and controls, as well as methods for data analysis.

rStandards as used in this document refers to internationally recognized reference materials
and certified reference materials,10 developed by organizations such as the National Institutefor Standards and Technology (NIST), and consensus-based documentary standards publishedby national and international standards development organizations such as the International
Organization for Standardization (ISO) and ASTM International.

rInstruments are new or improved measurement apparatuses that may be broadly transferred
to and adopted by other organizations.

rModels are representations that support interpretation of nanomaterial measurements. Note:
predictive models of effects or structure–activity relationships are covered in other research
categories.

r

Data are “benchmark” data that have been measured using validated protocols and referencematerials (if relevant) or other well-characterized test materials.

9. Traceability is a term to describe the process by which a measurement instrument has been calibrated using areference material and how and the degree to which its property values are traceable to the fundamental units of theInternational System (SI) of units of weight and measure (e.g., the meter for length and the kilogram for mass).
10. ISO Committee on Reference Materials (REMCO), see
http://old.iupac.org/standing/on/remco/ISO_REMCO_for_Teamwork12_July2006.pdf.

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Relevant media for measurement include all media through which humans and the environment could
be exposed, as well as media utilized for in vitro and in vivo testing: environmental matrices (e.g., air,water, soil, sediment, and sludge); biological matrices (e.g., blood, tissue, and other fluids); and buffersand cell culture media. ENM and NEP life cycle stages to be included in measurement activities span
ENM production and NEP manufacture, use, and disposal or recycling.
There are several issues that cut across the five NMI research needs and that pose formidable challenges
for the development of accurate, precise, and reproducible measurement tools for ENMs and NEPs.
These tools are essential for comprehensive characterization of nanomaterials so that measurements
are not questioned and specific studies are not duplicated. Requiring that measurements be performed
in various media adds significant complexity to the design of instruments, the packaging and handlingof reference materials, and the specificity of protocols. Determining the large number of risk-relevant
properties of each ENM-NEP-media system is time-intensive, and can only be made feasible throughthe development of high-throughput, high-content-generating instruments and protocols. Real-time,
in-field testing of exposure media requires new instrumentation concepts and novel approaches tothe development of protocols and reference materials. Significant efforts are needed for national andinternational harmonization and validation of measurement tools. Finally, greater collaboration between
academia, government, and the private sector is essential to establish a comprehensive measurement
infrastructure.
Of the various types of measurement tools, the needs for reference materials (RMs) and protocols areperhaps of greatest immediacy. Because the time and cost associated with certification of RMs is significantly high, there is a short-to-intermediate need for “study” materials that are designed for specificapplications and are well-characterized and widely available, preferably in a centralized repository.
A database that includes all available measurement tools would be a valuable resource for all environmental, health, and safety assessments of ENMs and NEPs.

Goals
r

Develop measurement tools to detect and identify engineered nanoscale materials in products
and relevant matrices and determine their physico-chemical properties throughout all stagesof their life cycles.

r

Develop measurement tools for determination of biological response, and to enable assessmentof hazards and exposure for humans and the environment from engineered nanomaterials andnanotechnology-based products throughout all stages of their life cycles.

Research Needs as of 2011
#1. Develop measurement tools for determination of physico-chemical properties of ENMs in
relevant media and during the life cycles of ENMs and NEPs, focusing on:rPhysical dimensions and morphology: size, size distribution, characteristic dimensions, shaperInternal structure: atomic-molecular, core-shell

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rSurface and interfacial properties: surface charge, zeta potential, surface area and structure,elemental composition, surface-bound molecular coatings and conjugates, reactivityrBulk composition: elemental or molecular composition, crystalline phase(s)rDispersion properties: degree and state of dispersion

r

Mobility and other transport properties: diffusivity and transport in biological and environmental matrices#2. Develop measurement tools for detection and monitoring of ENMs in realistic exposure
media and conditions during the life cycles of ENMs and NEPs, focusing on:r

Sampling and collection of ENMsr

Detecting the presence of ENMsr

Quantity of ENMs: concentration based on surface area, mass, and number concentrationsr

Size and size distribution of ENMsr

Spatial distribution of ENMsr

Discriminating ENMs from ambient nanomaterials such as combustion products and welding
fumes

r

Discriminating multiple types of ENMs, e.g., metals and metal oxides#3. Develop measurement tools for evaluation of transformations of ENMs in relevant media
and during the life cycles of ENMs and NEPs, focusing on:r

Agglomeration and de-agglomerationr

Dissolution and solubilityrAdsorption of natural organic matter and bioconstituentsr

Oxidation and reductionr

Deposition of ENMs on surfaces#4. Develop measurement tools for evaluation of biological responses to ENMs and NEPs in
relevant media and during the life cycles of ENMs and NEPs, focusing on:rAdequacy of existing assaysr

New assays or high-throughput, high-content assaysrCorrelation of biological responses with physico-chemical propertiesr

Surface reactivity at the interfaces between ENMs and biological receptorsrBiomarkers of toxicological response

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N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y#5. Develop measurement tools for evaluation of release mechanisms of ENMs from NEPs in
relevant media and during the life cycles of NEPs, focusing on:r

Release by fire, combustion, and incinerationr

Release by mechanical degradation, such as abrasion, deformation, and impactr

Release by dissolution of matrix materialr

Release by chemical reactions of matrix materialr

Release by photo-induced degradation of matrix materialr

Release by consumer interactions, such as spraying, mouthing, and swallowingr

Release by interactions with biological organisms in the environment

Comparative Analysis of Projects
The NNI agencies reported 78 projects for this research category in the FY 2006 nanoEHS data call and
42 projects in the FY 2009 data call. The restructuring of this research category can partly account for thedecrease in projects; subject matter experts have noted an increase over the past few years in researchon measurement tools, particularly on protocols and reference materials. All of the FY 2009 projects arestrongly relevant to nanoEHS research and represent well the Federal effort in this research category.
The FY 2006 and FY 2009 projects were mapped onto the newly defined research needs; the resulting
distributions by number of projects and funding are presented in Table 2-1.
Although the number of projects and funding for research needs #1–3 apparently decreased between
FY 2006 and FY 2009, the distributions of projects and funding did not change greatly, with most funding distributed between research needs #1 and #2. Measurement tools for evaluation of biologicalresponses to ENMs and NEPs and release mechanisms of ENMs from NEPs were not identified explicitly
in the FY 2006 and FY 2009 data calls; hence, there are few or no projects reported for research needs#4 and #5. However, there is considerable interest within many Federal agencies directed towards theseresearch needs. In addition, measurement tool development is a secondary activity in some projects
reported in other research categories, for example, the Human Health research category.
Two projects reported in the FY 2009 data call were determined to be of benefit to the NMI research
category but did not support a specific research need: (1) an interdisciplinary training program for ENM
characterization; and (2) an approach for independent validation of commercially derived ENM analyses.

Gaps for Future Investment
The underpinning nature and importance of a nanomaterial measurement infrastructure requires asignificant increase in effort by Federal agencies to establish this infrastructure in a comprehensive manner. Elements of such an infrastructure are beginning to be put into place, particularly in some aspectsof research needs #1 and #2, as noted by the funding distribution in Table 2-1. However, significantly
greater emphasis is required to develop the full suite of essential measurement tools in research needs#1 and #2, identified as necessary for science-based risk assessment and management of ENMs and NEPs.

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2 . NA N O M AT E R I A L M E A S U R E M E N T I N F R A S T R U C T U R E

Table 2-1. Analysis of Projects Related to the Nanomaterial Measurement
Infrastructure Category of EHS R&D, FY 2006 & FY 2009*
FY 2006
Research NeedFY 2009

Reported
funding in$K (% oftotal)

ChangeNumberReportedof projects funding in(% of total) $K (% oftotal)

NumberFundingof projects in $K(% of total) (numberof projects

1. Develop measurement tools for determinationof physico-chemical properties of ENMs in relevant
media and during the life cycles of ENMs and NEPs

9,891
(37.4%)

25(32.0%)

4,758(42.2%)

18(42.8%)-5,133(-7)

2. Develop measurement tools for detection andmonitoring of ENMs in realistic exposure media
and conditions during the life cycles of ENMs andNEPs

12,396(46.8%)

36(46.2%)

4,315(38.3%)

14(33.3%)-8,081(-22)

3. Develop measurement tool for evaluation oftransformations of ENMs in relevant media andduring the life cycles of ENMs and NEPs

2,845
(10.7%)

14(17.9%)

1,229(10.9%)

6(14.3%)-1,616(-8)

4. Develop measurement tools for evaluation of
biological responses to ENMs and NEPs in relevant
media and during the life cycles of ENMs and NEPs

---

---

579
(5.1%)

2(4.8%)+579(+2)

5. Develop measurement tools for evaluation of
release mechanisms of ENMs from NEPs in relevant
media and during the life cycles of NEPs

---

---

---

---

Multiple: Projects that capture multiple needs

1,300(4.9%)

2(2.6%)

0

0

-1300
(-2)

Other: Not captured above but of benefit to theresearch category

50(0.2%)

1(1.3%)

400(3.5%)

2(4.8%)+350(+1)

TOTALS

26,482

78

11,281

42-15,201(-36)* Agencies supporting research in this category: EPA, FDA, NIOSH, NIST, NSF

Substantial effort should also be allocated to developing the critical measurement tools for researchneeds #3, #4, and #5, for which there is currently little to no funding. Based on stakeholder inputs fromthe four EHS workshops, the most immediate and greatest need that cuts across all five research needs
areas is the development of protocols and reference materials.

Rationale for the 2011 Research Needs and Changes from 2008
The research needs for the NMI research category have been changed substantially from those in the
IMA research category of the 2008 EHS strategy, as illustrated in Figure 2-1. The rationale for the 2011
NMI research needs is detailed in following subsections.

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2008 Strategy

2011 Strategy

IMA Research Need #1
Develop methods to detectnanomaterials in biological matrices,
the environment, and the workplace

NMI Research Need #1
Develop measurement tools fordetermination of physicochemical properties of ENMs ...

NMI Research Need #2
Develop measurement tools for
detection and monitoring of ENMs ...

IMA Research Need #2
Understand how chemical andphysical modifications affect theproperties of nanomaterials

NMI Research Need #3
Develop measurement tools forevaluation of transformations of
ENMs ...

IMA Research Need #3
Develop methods for standardizing
assessment of particle size, size
distribution, shape, structure, andsurface area

NMI Research Need #4
Develop measurement tools forevaluation of biological responses
to ENMs and NEPs ...

IMA Research Need #4
Develop certified reference materials
for chemical and physicalcharacterization of nanomaterials

NMI Research Need #5
Develop measurement tools
for evaluation of releasemechanisms of ENMs from NEPs ...

IMA Research Need #5
Develop methods to characterize ananomaterial's spatio-chemicalcomposition, purity, and heterogeneity

HH Research Need #2
Develop methods to quantify andcharacterize exposure to nanomaterials
and methods to characterizenanomaterials in biological matrices

HH Research Need #3
Identify or develop appropriate in vitro
and in vivo assays/models to predict invivo human responses to nanomaterial
exposure

Figure 2-1. Comparison of the IMA research needs in the 2008 NNI EHS Research Strategy (left) with the NMI
research needs in the 2011 NNI EHS Research Strategy (right). The arrows indicate mapping of the 2008 IMA
research needs to the 2011 NMI research needs.

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2 . NA N O M AT E R I A L M E A S U R E M E N T I N F R A S T R U C T U R E

rThree of the five IMA research needs concerning physico-chemical properties of ENMs havebeen consolidated into one NMI research need, and the scope of the key properties in this needhas been expanded.

r

The IMA research need concerning detection of ENMs maps to the NMI research need on detection and monitoring, and the scope of the need has been expanded.

r

The IMA research need concerning chemical and physical modifications of ENMs maps to the
NMI research need on transformations, and the scope of the need has been expanded to cover
the key transformation processes.

rSome aspects of the 2008 Nanomaterials and Human Health research needs concerning method
development are included in the NMI research need #4 on biological responses.

r

A new research need on release of ENMs from NEPs was included in the 2011 NMI research
category to address growing awareness and concerns about such releases during manufacture,use, and disposal or recycling of NEPs.

The five 2011 NMI research needs encompass the ENM physico-chemical properties or parameters
identified as essential for EHS assessment by various domestic and international groups, including
the Minimum Information on Nanoparticle Characterization (MinChar) Initiative, the ISO, and theOrganisation for Economic Co-operation and Development (OECD).

Research Need #1: Develop measurement tools for determination of physico-chemical
properties of ENMs in relevant media and during the life cycles of ENMs and NEPs
Overview
Accurate, precise, and reproducible determination of the physico-chemical properties of ENMs in
relevant media has been consistently identified by the nanoEHS community as a high-priority researchneed, and it is the critical initial phase of ENM characterization prior to risk or fate assessment. Insufficient
or inaccurate upstream physico-chemical characterization of ENMs is a significant barrier to understanding the underlying mechanisms of biological response to ENMs and is detrimental to the reproducibility
and accuracy of published toxicity studies. Furthermore, fundamental material properties such as particle
size, shape, and surface chemistry are deterministic with respect to biological response (e.g., cell uptake,toxicity) and fate (e.g., absorption, distribution, metabolism, and excretion [ADME] ecosystem-wide
effects). Therefore, the relevance of this research need is both cross-cutting and integral to the objectivesof the core research categories described elsewhere in this document.
Existing technologies for the measurement of physico-chemical properties are mature and widely
available, but many lack specificity for ENMs or have not been validated for measurement conditions
relevant to EHS applications. Critical needs exist for rapid and high-throughput analysis, validated
protocols for sample preparation and measurement, reference materials relevant to nanoEHS research,and measurement tools applicable to complex biological and environmental matrices over the entire
life cycles of ENMs and NEPs.

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Analysis of Current Projects
The agencies reported 18 projects for this research need in 2009: 16 by NIST, and one each by the
National Science Foundation (NSF) and the National Institute for Occupational Safety and Health(NIOSH). Of these projects, the distribution of projects by sub-research need and measurement tool
type is as follows:r

Physical dimensions and morphology: 3 projects on protocols and reference materials, and 2
projects on high-resolution microscopy methodsrInternal structure: 4 projects on neutron diffraction and scattering, transmission electron
microscopy, and optical methodsrSurface and interfacial properties: 3 projects on electron microscopy, ion mass spectrometry,and Auger electron spectroscopy methodsr

Bulk composition: 3 projects on 3D chemical imaging methods, X-ray microanalysis methods,
and single-particle mass spectrometry instrumentationr

Mobility and other transport properties: 1 project on a single-nanoparticle tracking methodr

Cross-cutting: 2 projects covering reference materials and protocols for two or more subresearch needs

Research Need #2: Develop measurement tools for detection and monitoring of ENMs inrealistic exposure media and conditions during the life cycles of ENMs and NEPs
Overview
Detection and monitoring of ENMs in a specific environment require the collection of samples of realistic
exposure media under exposure conditions, e.g., samples of air from a manufacturing plant or samples
of soil from a disposal site. Similarly, detection of ENMs in humans requires sampling or visualization of
actual biological matrices, e.g., blood or tissue. Quantitative methods for detection and monitoring of
ENMs have been consistently identified by the nanoEHS community as a high-priority research need andthus constitute a vital component of the overall nanoEHS risk assessment approach and a prerequisite
for developing scientifically valid estimates of exposure.
Existing technologies for detection and monitoring of ENMs in the workplace are nonspecific, limited
to airborne measurement, and have limited application beyond the workplace. Similarly, existing
technologies for detection and monitoring of ENMs in humans and the environment lack specificity for
ENMs or have not been validated for relevant measurement conditions. Hence, a critical need exists formeasurement tools to detect and monitor ENMs: for example, real-time or near real-time instruments,
including personal monitors, for specific and sensitive measurement of a range of ENM physico-chemical
properties in relevant media.

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Analysis of Current Projects
The agencies reported 14 projects for this research need in 2009: 5 by NIOSH, 8 by NSF, and one by
NIST. Of these projects, the distribution by sub-research need and measurement tool type is as follows:r

Sampling and collection of ENMs: 1 project on aerosol sampling instrumentsr

Detecting the presence of ENMs: 9 projects on novel instruments and methods in various mediar

Determining the quantity of ENMs: 2 projects on real-time instruments and methods and models
to determine specific surface area and mass in air samplesr

Determining the size and size distribution of ENMs: 1 project on a standard method to measure
ENM size in air samplesr

Determining the spatial distribution of ENMs: 1 project on electron-microscopy-based methods
for imaging the distribution of ENMs in two and three dimensions

Research Need #3: Develop measurement tools for evaluation of transformations of ENMs in
relevant media and during the life cycles of ENMs and NEPs
Overview
Interactions of an ENM with its surrounding media often result in transformations that alter its form andphysico-chemical properties. Transformation processes such as dissolution and agglomeration affectexposure and hazards of the ENMs to humans and the environment. Determination of the extents andrates of transformation processes in realistic exposure media and conditions has been consistently
identified by the nanoEHS community as a critical component of nanoEHS studies.
Assessing ENM transformations requires a thorough evaluation of both ENMs and surrounding media.
Measurement tools for media evaluation are relatively mature and therefore may be readily adapted
to this nanoEHS application. There are some existing technologies to measure the extents and rates oftransformations of micro- to macroscale materials; however, these technologies lack specificity for ENMs
or have not been validated for measurement conditions relevant to EHS applications. Transformationsof ENMs result in changes in physico-chemical properties as a function of time; thus, measurement
tools for evaluating transformations are dependent on the availability of tools for research need #1 onphysico-chemical properties and research need #2 on detection and monitoring. A critical need exists
for measurement tools to detect and monitor the progress of transformations, including real-time
instruments and quantitative methods and reference materials.

Analysis of Current Projects
The agencies reported 6 projects focused primarily on the development of measurement tools forevaluation of transformations: 5 by NIST and 1 by NSF. Of these projects, the distribution by sub-researchneed and measurement tool type is as follows:r

Agglomeration and de-agglomeration: 1 project on advanced, in situ synchrotron and neutron
scattering methods

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N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G YrDissolution and solubility: 2 projects focused on protocols and models for silver nanoparticlesrAdsorption of natural organic matter and bioconstituents: 1 project on microbalance-based
methodsr

Oxidation and reduction: 2 projects on optical and scanned probe microscopy methods

A number of 2009 projects included above for research needs #1 and #2 concern measurement toolsthat are applicable to evaluation of transformations. In addition, a number of projects reported for theEnvironment research category have measurement tool development as a secondary objective or as aprerequisite for the generation of experimental data.

Research Need #4: Develop measurement tools for evaluation of biological responses to
ENMs and NEPs in relevant media and during the life cycles of ENMs and NEPs
Overview
Quantitative assays for the evaluation of toxic responses have been consistently identified by thenanoEHS community as a high-priority research need. The lack of quantitative in vitro and in vivo assays
with specificity for ENMs and relevance to biological systems has been identified as a significant barrier
to understanding human responses to ENMs; determining the mechanisms responsible for toxicity at
the molecular, cellular, tissue, organ, and whole-body levels; and determining ENM uptake, adsorption,and dose effects. In the absence of quantitative assays, the accuracy and reproducibility of publishedtoxicity studies cannot be ascertained. Quantitative assays are also required to evaluate possible beneficial biological responses, e.g., ENMs acting as antioxidants in cells.
Many assays have been developed to evaluate toxic responses to chemicals; however, there are no
methods to test the adequacy and extensibility of these assays for ENMs. Critical needs exist for suchmethods, as well as new high-throughput assays for generating large amounts of information, also
known as high-content assays. The correlation of toxic responses to physico-chemical properties isessential for extrapolating data obtained for one ENM-media system to other similar ENM-NEP-media
systems and for developing predictive models. Determination of surface reactivity, i.e., interactionsof ENMs with proteins and other molecular species in the human body, is critical to the evaluation of
biological response, as are validated biomarkers.

Analysis of Current Projects
The agencies reported 2 projects focused primarily on the development of measurement tools forevaluation of biological responses: one each by NIST and the Food and Drug Administration (FDA). Of
these projects, the distribution by sub-research need and measurement tool type is as follows:r

New assays: 1 project on an assay for photochemical generation of hydroxyl radicalrSurface reactivity: 1 project on mass spectrometry-based methods to assess DNA damage due
to ENMs

It is expected that some projects reported for the Human Health research category have measurement
tool development as a secondary objective or a prerequisite for the generation of experimental data;
these projects are not included here.
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Research Need #5: Develop measurement tools for evaluation of release mechanisms of
ENMs from NEPs in relevant media and during the life cycles of NEPs
Overview
The use of ENMs in NEPs has increased dramatically in recent years. ENMs can be released from NEPs
during manufacturing, use, and disposal or recycling, posing risks of human and environmental exposure
to ENMs. Despite the increased presence of ENMs in commercial intermediates, industrial components,
consumer products, and other NEPs such as medical devices, little is known about the extent to which
ENMs are released from NEPs as a function of use or about the rates of release. These mechanisms include
those active during fire, combustion, or incineration; mechanical degradation; dissolution; chemical
reaction or photo-induced degradation of the NEP matrix containing the ENMs; consumer interactions
with NEPs; and interactions of NEPs with biological organisms. For example, ENMs can be released by aconsumer spraying an ENM-containing aerosol product or by the frictional degradation of ENM-coatedclothing during regular wear. After disposal, NEPs undergo various physico-chemical degradation
processes, such as mechanical crushing of waste, photo-induced breakdown by sunlight, or extractionof ENMs into wastewater by matrix dissolution or chemical reaction, that result in the release of ENMs.

Analysis of Current Projects
More effort is needed for all research in this revised category: research need #5 is a newly defined
research need, so no relevant projects were reported in the FY 2009 data call. However, there is work
underway at NIST and at the Consumer Product Safety Commission (CPSC) to evaluate ENM releasemechanisms from NEPs due to incineration, mechanical degradation, and consumer interactions.

Example of Progress in NanoEHS Research: Gold Nanoparticle Standards
A critical first measurement for all nanoEHS research studies is nanomaterial size, because size affects
physico-chemical and biological properties and thus exposure to and hazards to humans and theenvironment. NanoEHS research has suffered from a lack of reliable nanoscale measurement standards,
both to ensure consistency of data from one lab to the next and to verify the performance of measurement instruments and analytic techniques. In January 2008, the National Institute of Standards andTechnology issued its first reference materials (RMs) for nanomaterials targeted for the nanoEHS andbiomedical research communities—literally “gold standards” for determining the size of nanoparticles(Figure 2-2). The new reference materials, gold spheres nominally 10 nm, 30 nm, and 60 nm in diameter,
were developed in cooperation with the National Cancer Institute’s Nanotechnology Characterization
Laboratory (NCL). The RM dimensions were measured using six independent methods commonly usedby researchers. Over 400 RM units have been sold to industry, government agencies, and universities, including 37 international sales. The RMs have been used in development of NIST-NCL protocols(http://ncl.cancer.gov/working_assay-cascade.asp) and ASTM International consensus standards(http://astm.org/COMMIT/SUBCOMMIT/E56.htm).

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N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

Figure 2-2. (Left) NIST gold nanoparticle reference materials (RMs) 8011–8013. (Right) Atomic force microscopy
image of 60 nm gold reference material nanoparticles.
Source: NIST, http://www.nist.gov/srm/index.cfm. Image: J. Grobelny.

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3. Human Exposure Assessment
Overview
The number of products in commerce and under development that contain nanomaterials has grown
rapidly to include products such as plastics, metals, ceramics, surface coatings, creams, sprays, cosmetics,
electronics, clothing, drugs, medical devices, and medical imaging aids. Exposure potential for nanomaterials can be expected to be strongly dependent on industrial manufacturing and processing methods,
the nanomaterial state and its physico-chemical properties, and the nanomaterial applications. Hence,research on potential exposure must evaluate whether, and to what degree, exposure will occur for eachnanomaterial or NEP at each stage of its life cycle. The 2011 NNI EHS research category Human Exposure
Assessment addresses these and related issues. Characterization of exposure involves use of appropriate methods and tools for measuring or estimating exposure to nanomaterials in various media andorganisms. As described in the Chapter 8 subsection, “Targeting and Accelerating NanoEHS Research,”a life cycle analysis approach may be useful to express the range of exposure likelihoods and potential
areas of focus for research. As the likelihood of exposure for key population segments is determined, careshould be taken in determining what constitutes a “key segment” of the population, who is empowered
to define groups of people, and what implications may arise from placing people in particular categories.
In addition, subpopulations among the “general population” that are disproportionally exposed or more
vulnerable to impacts from exposure should be identified.
Life cycle considerations should include the characterization of exposure to nanomaterials for use in risk
assessment and/or risk management. Where nanomaterials are effectively embedded in the productmatrix, such as computer circuit boards, the potential for exposure during routine use of the product isunlikely because the embedded nanomaterials are not available for exposure. However, potential exposure of workers during the manufacture of such materials, including during any subsequent activities
like milling, machining, sanding, and grinding of the matrix, must still be considered, as should potential
exposure of workers, the general public, and consumers during reasonably foreseeable misuse and as
a result of recycling or disposal at the end of product life.
Because of the relative newness of nanotechnology, very little exposure data related to engineered
nanomaterials, and only a few analyses of workplace exposures based on emission measurements
and consumer exposures based on modeling estimates, have been reported in the scientific literature.
Much of the needed exposure data and analyses will be enabled through linkages to the Nanomaterial
Measurement Infrastructure research needs (Chapter 2), wherein measurement tools are being developed for physico-chemical properties, detection and monitoring, transformations, and releases ofnanomaterials in the workplace and from products.
With untested materials entering commerce, exposure assessment and health surveillance of exposedgroups have added importance for identifying potential hazards that should be studied. Toxicology
and other health studies provide predictions on safe exposure levels that need to be validated throughexposure assessment and health surveillance. This work is complicated by workforce fluctuation. The
production industry is comprised of many startups that either fail or are purchased by larger companies,

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N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

creating difficulties in tracking exposed workers. The rapidly changing nature of the field increases
the difficulty of this task; researchers are continuously finding new and better ways to incorporate
nanomaterials into a large array of products. This means that inferior or less profitable applications
are constantly being phased out, resulting in shifting exposure scenarios. This suggests that industries
that are end-users of nanomaterials might prove to be the best subjects for exposure investigations.
These challenges also make international harmonization of exposure assessment methodologies andinternational collaboration in conducting health surveillance studies critically important.
Specific requirements to achieve significant progress in the Human Exposure Assessment research
category include the following:r

Development of methods or approaches to identify potential sources, characterize the exposure
scenario, and measure actual exposure to nanomaterialsrCollection of data and information on the life cycle and variables that affect exposure tonanomaterialsrCollection and dissemination of data and development of databases for health surveillanceand exposure to nanomaterialsrDevelopment of models to estimate exposures to specific nanomaterials

Goals
r

Identify potential sources, characterize the exposure scenarios, and quantify actual exposuresof workers, the general public, and consumers to nanomaterials.

rCharacterize and identify the health outcomes among exposed populations in conjunction
with information about the control strategies used and exposures to determine practices that
result in safe levels of exposures.

Research Needs as of 2011
#1. Understand processes and factors that determine exposures to nanomaterials:rConduct studies to understand processes and factors that determine exposure to engineered
nanomaterialsrDevelop exposure classifications of nanomaterials and processesrDevelop internationally harmonized and validated protocols for exposure surveys, sample
collection and analysis, and reporting through existing and newly created international frameworksr

Develop comprehensive predictive models for exposures to a broad range of engineered
nanomaterials and processesrCharacterize process- and task-specific exposure scenarios in the workplace

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3. HUMAN EXPOSURE ASSESSMENT#2. Identify population groups exposed to engineered nanomaterials:rSystematically collect and analyze information about nanomaterial manufacture, processing,and direct use in commercial and consumer products over time to discern geographic areas
where engineered nanomaterials may be emitted into the environment, consumed in the formof ingredients of products, and/or disposed of in solid waste, wastewater, etc.

r

Conduct population-based surveys to obtain information on use patterns for consumer productsr

Identify potential subpopulations that are more susceptible to exposure to engineered nanomaterials than othersrDevelop quantitative assessment methods appropriate for target population groups andconduct assessments of those population groups most likely to be exposed to engineered
nanomaterials#3. Characterize individual exposures to nanomaterials:rExpand currently available exposure assessment techniques to facilitate more accurate exposure
assessment for ENMs at benchmark concentration levels using feasible methodsr

Develop new tools through national and international surveys to support effective exposure
characterization of individualsrCharacterize and detect nanomaterials in biological matrices and conduct studies to understandtransformations of nanomaterials during transport in the environment and in human bodiesr

Conduct studies to examine emissions and human contact during normal use and after wear
and tear have degraded a product, as well as during repeated exposuresr

Develop engineered nanomaterials exposure assessment models based on identified critical
exposure descriptorsrDevelop databases to contain the collected data and information#4. Conduct health surveillance of exposed populations:r

Establish a program for the epidemiologic investigation of physician case reports and reportsof suspicious patterns of adverse eventsr

Establish exposure registry and medical surveillance programs for workers

rAnalyze injury and illness reporting in existing programs

Comparative Analysis of Projects
Project data ascribed to the Human Exposure Assessment research category in FY 2006 and FY 2009are shown in Table 3-1. For ease of comparison, FY 2006 projects are shown categorized by the new2011 research needs. A mapping between the 2008 and 2011 needs is provided in Figure 3-1. (The2011 NNI EHS Research Strategy incorporates environmental exposure research into the Environment

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research category, while the 2008 strategy addressed human and environmental exposure together.)Since FY 2006, there was an almost three-fold increase in total funding and in the number of projects
for the Human Exposure Assessment research category and for its individual research needs areas. In
addition, previously unfunded research need #2 and #4 (both the 2008 Human and Environmental
Exposure Assessment category and the 2011 Human Exposure Assessment category) are now supported by agencies.
Table 3-1. Analysis of Projects Related to the Human Exposure Assessment
Category of NanoEHS R&D, FY 2006 & FY 2009*
FY 2006
Research NeedFY 2009

Reported
Funding
in $K (% oftotal)

ChangeNumberReportedof projects Funding(% of total) in $K (% oftotal)

NumberFunding inof projects $K (num(% of total) ber ofprojects)

1. Understand processes and factors that determine exposures to nanomaterials

265
(23%)

3
(60%)

902
(27%)

5
(36%)

+637
(+2)

2. Identify population groups exposed to engineered nanomaterials

--

--

1100
(33%)

1
(7%)

+1,100
(+1)

879
(77%)

2
(40%)

1242
(38%)

7
(50%)

+363
(+5)

4. Conduct health surveillance of exposed
populations

--

--

45
(1%)

1
(7%)

+45
(+1)

Multiple: Projects that capture multiple needs

--

--

--

--

Other: Not captured above but of benefit to theresearch category

--

--

--

--

1,144

5

3,289

14

3. Characterize individual exposures tonanomaterials

Total+2,145(+9)*Agencies supporting research in this category (FY 2009): CPSC, EPA, NIOSH, NSF

Gaps for Future Investment
Research activities in this category remain low relative to the other four NNI EHS research categories.
Therefore, more efforts are needed for all research needs in this category for the specific topics identified in this document. A major remaining gap is the limited funding for research need #4 to conduct
health surveillance of exposed populations. Public health surveillance is an ongoing activity withwell-established methods for collecting both health and exposure data. None of the ongoing exposure
registry and medical surveillance activities is currently targeted to engineered nanomaterials, although
all would be capable of collecting health data from exposed groups. Development of health surveillance
projects with international partners would leverage funding and study populations, thus accelerating
our understanding of human exposures and potential adverse health effects.

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3. HUMAN EXPOSURE ASSESSMENT

Rationale for the 2011 Research Needs and Changes from 2008
In order to reflect research progress achieved in the last three years, incorporate public recommendations, and recognize common challenges across population groups and exposure environments, the2008 Exposure Assessment research needs have been updated as follows:
1. Understand processes and factors that determine exposures to nanomaterials (2008 researchneed #5 was expanded to include the general population and consumers, and reordered as
research need #1)
2. Identify population groups exposed to engineered nanomaterials (2008 research need #2 was
expanded to include workers and reduced to exclude environments, which are covered in theEnvironment research category)
3. Characterize individual exposures to nanomaterials (2008 research needs #3 and #1 have been
merged and refocused on individual exposures)
4. Conduct health surveillance of exposed populations (2008 research need #4 was reduced to
exclude environments, which are covered in the Environment research category)
These changes are shown graphically in Figure 3-1. The ordering of research needs mirrors the sequenceof exposure data generation and prerequisites, rather than priority ranking.
Research in the Human Exposure Assessment category is closely interconnected with research in theother four core EHS research categories. Development of techniques to measure exposure conductedunder the Nanomaterial Measurement Infrastructure category (Chapter 2) is critical for obtaining
exposure data. Environmental exposure information generated under the Human Exposure Assessment
category can be utilized by the Environment category (Chapter 5); likewise, an understanding of environmental fate and transport and transformation is needed to characterize human exposure to nanomaterials from air, water, landfill, and other releases into the environment from industrial, processing, and use
facilities. Exposure data can guide the design of toxicological experiments to generate dose–response
data in the vicinity of possible exposure levels under the Human Health category (Chapter 4), andcorrelations between exposures and health observed in health surveillance programs in the Human
Exposure Assessment category can be investigated through targeted toxicological experiments and assuch, are relevant to the Human Health category. Similarly, mechanistic toxicology studies in the Human
Health category can facilitate exposure characterization with toxicologically relevant metrics. Exposure
assessment data is necessary in risk assessments and can also provide feedback on the effectivenessof the risk mitigation measures conducted under the Risk Assessment and Management Methods
category (Chapter 6).

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N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

2008 Strategy

2011 Strategy

Exposure Research Need #1
Characterize exposure
among workers

Human Exposure
Research Need #1
Understand processes and factorsthat determine exposures to NM

Exposure Research Need #2
Identify population groups andenvironments exposed to ENMs

Human Exposure Research Need #2
Identify population groups exposed
to ENMs

Human Exposure
Research Need #3
Characterize individual
exposures to NM

Exposure Research Need #3
Characterize exposure to thegen.population from industrial
processes & industrial & consumer
products containing NM

Exposure Research Need #4
Characterize health of exposed
populations and environments

Human Exposure Research
Need #4
Conduct health surveillance of
exposed populations

Exposure Research Need #5
Understand workplace processes andfactors that determine exposure tonanomaterials

Environment Research Need #1
Environmental Exposures

Figure 3-1. Comparison of the Human and Environmental Exposure Assessment research needs in the 2008
NNI EHS Research Strategy (left) with the Human Exposure Assessment research needs in the 2011 NNI EHS
Research Strategy (right). The arrows indicate mapping of the 2008 research needs to the 2011 research needs.
Note that several of the 2008 research needs here map to an Environment research need.

Research Need #1. Understand processes and factors that determine exposures tonanomaterials
Overview
Processes and factors that affect exposures to engineered nanomaterials in the workplace can occur atthe macro level (e.g., across industry sectors), mid level (e.g., among organizations in an industry sector),and micro level (e.g., among specific operations). Research gaps include macro-level data on which
sectors to target for exposure monitoring, mid-level data on manufacturing processes and techniquesthat could influence exposures within a sector, and micro-level data on non-carbon nanomaterials
and tasks and activities that produce an intermediate or nanotechnology-enabled product. Factorsthat affect exposures among the general population and consumers are not well understood. Criticalresearch gaps include characterization of process and task-specific exposure in the workplace, data on

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3. HUMAN EXPOSURE ASSESSMENT

emission sources (types, rates, locations, etc.), manufacture of NEPs (processes, types of nanomaterials,etc.), and consumer product use habits (type of use, frequency, etc.). Key barriers for this research needinclude (1) identification, measurement, and characterization of nanomaterials during their life cycles;(2) information on variables that affect exposures; and (3) development and international harmonization of exposure assessment methodologies appropriate for epidemiological studies, studies of theeffectiveness of control technologies, and other research areas.

Recommendations for Changes
The 2008 NNI EHS Research Strategy emphasized three topics for this research need: (1) exposure classification of nanomaterials, (2) exposure classification of processes, and (3) predictive models of workplace exposure. Progress is being made toward understanding these research topics, and new topics
are emerging. Applying a life cycle approach is recommended to make it clear that work to understandprocesses and factors that modify exposures in the workplace, among the general population, andamong consumers is complementary, informs the remaining research needs in the Human Exposure
Assessment research category, and is interdependent with all other research categories.

Analysis of Current Projects
Five FY 2009 projects were identified under research need #1. Two projects, funded by NIOSH, focus
on dustiness that will provide information on the physical behavior of some classes of nanomaterials.
Two projects, funded by the U.S. Environmental Protection Agency (EPA), investigate effects of physicochemical parameters on exposure potential in the environmental media and determinants of exposure
to platinum-containing nanomaterials among the general population. The last project, funded by NSF,
is a supplement to an existing research center devoted to studying exposure pathways of nanoparticles
from synthesis to biological systems, including exposures to people, with a particular focus on aerosolized nanoparticles.

Research Need #2. Identify population groups exposed to engineered nanomaterials
Overview
No projects were identified for this research need in the 2008 NNI Strategy for Nanotechnology-Related
Environmental, Health, and Safety Research. Publicly available studies are underway to identify workers who are potentially exposed to nanomaterials in industrial settings. Over the last two years, there
has been an increasing recognition that consumers may use products that contain or are made using
nanomaterials. Since 2005, the EPA has received over 100 premanufacture notices for nanomaterials
under Section 5 of the Toxic Substances Control Act. In addition to these products, nanomaterials arealso used in a variety of medical products.
Key barriers for identifying population groups exposed to engineered nanomaterials include (1) the difficulties in collecting and disseminating of information on populations potentially exposed to engineered
nanomaterials while protecting confidential business information and personal privacy; (2) the lack ofdata on the life cycles of nanomaterials, including sources, pathways, and routes of potential exposure,and the form of the material to which the person is exposed; and (3) the lack of existing databases toenable the collection and dissemination of information.

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N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

Recommendations for Changes
As described in the report of the February 2009 NNI Human and Environmental Exposure Assessment
Workshop,11 data may already exist with which to begin identifying populations potentially exposed
to engineered nanomaterials. Existing data such as that available in insurance companies, tracking of
consumer use of nanomaterials, information on manufacture and sale of nanomaterials, informationfrom the EPA’s New Chemicals Program, information on patients seeking medical attention, worker
exposure registries, and information from researchers all may prove helpful in identifying or evaluating
consumer and general population exposure scenarios. Collection of this type of information and data
may serve as a mechanism for obtaining relevant data to identify populations potentially exposed
to nanomaterials and to determine whether any segments of the population are disproportionately
susceptible or vulnerable to adverse impacts. While some of this data may be personal or confidential
business information, efforts should be made to make as much information as possible publicly available within established procedures for protecting information. There should be an expectation that theprivate sector will provide adequate information to enable policymakers and members of the public tounderstand and make decisions regarding possible exposures to nanomaterials.

Analysis of Current Projects
One project (funded by EPA) was identified under research need #2. This project is a collaborative
initiative with several United Kingdom partners that proposes integrated model(s) of fate, behavior,bioavailability, and effects; validates and refines the models; and develops methods and tools to detect,assess, and monitor for nanomaterials in biological and environmental samples.

Research Need #3. Characterize individual exposures to nanomaterials
Overview
Since 2008, there has been increasing recognition that consumers may use products that contain or
are made using engineered nanomaterials. In addition to managing worker exposures, understanding
and, where necessary, reducing potential exposures to the general public and consumers from use ofengineered nanomaterials is critical for promoting public health; however, the mechanisms of exposure
to engineered nanomaterials resulting from contact with nanotechnology-enabled products are notfully understood. Although some existing models can be used to predict environmental releases ofnanomaterials and potential worker and general population exposures, such estimates are generic,conservative, or not specific to nanomaterials.
Key barriers to characterizing individual exposures to engineered nanomaterials include:
1. Limitations in existing sampling and analysis methods and the limited availability and usageof instrumentation to measure exposure, including measurement of multiple metrics by useof one instrument

11. Human and Environmental Exposure Assessment: Report of the National Nanotechnology
Initiative Workshop, February 24–25, 2009, Bethesda, Maryland (NSET/NSTC, Washington, DC, 2011;
http://www.nano.gov/publications-resources).

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3. HUMAN EXPOSURE ASSESSMENT

2. Inability to collect, store, and disseminate data useful in characterizing releases of and human
exposures to nanomaterials
3. Limited information on the life cycles of nanomaterials and potential exposure sources andpathways
4. Paucity of data to characterize releases and potential exposures while protecting confidential
business information and personal privacy
5. Lack of standardized protocols for sample collection, analysis, and reporting of results that arenecessary to facilitate intercomparison of study results
6. Few or inadequately tested models for assessing exposure to specific nanomaterials

Recommendations for Changes
As described in the report from the February 2009 NNI Workshop on Human and Environmental
Exposure Assessment, data with which to characterize general population and consumer exposures
are limited, although there are data available with which to begin characterizing worker exposures.
Research is needed to characterize occupational and consumer exposures resulting from repeated use(e.g., abrasion and strain) and reasonably foreseen misuse conditions and accidents (e.g., breakage
and combustion). Some initial work has been done to determine how abrasion can cause the releaseof titanium dioxide and silver nanoparticles from substrates, but more work is needed to address thispotential exposure scenario.
In addition, research is needed to enable characterization of general population exposure from emissions
occurring during manufacture, processing, use, and disposal of nanomaterials. Exposure is also affectedby the cross-cutting issue of aggregation/agglomeration, since exposure to nanomaterials will not simply
be to the primary particle but also to clusters of different-sized particles that could change the relevant
concerns for dermal, oral, or inhalation exposure. In particular, research is needed to examine exposurein vulnerable populations such as children, the elderly, and immunocompromised persons who may be
more susceptible to potential adverse health effects resulting from exposure to nanomaterials.

Analysis of Current Projects
Seven FY 2009 projects were identified under research need #3. Four research projects are being conducted by NIOSH, one is being conducted by CPSC and NIST, and two are being conducted by EPA. These
research projects include workplace monitoring for carbon nanofibers and nanotubes, the feasibility ofindustry-wide studies of workers exposed to nanotubes, a titanium dioxide (TiO2) nanoparticle exposure
study, nanotechnology field evaluations for worker exposure, exposure and fire hazard assessment of
nanoparticles in fire-safe consumer products, investigation of techniques for physical and chemicalevaluation of nanoparticles in the environment, and evaluation of current sampling and analysis of
nanoparticles in the atmosphere.
In FY 2010 CPSC, EPA, and NIOSH developed a collaborative project to investigate the exposure potentialfrom the use of nanosilver-enabled products by the public and workers. The objectives of this work
include the development of protocols for evaluating the presence of nanosilver and the potential

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N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

releases from treated products. For those articles that contain nanosilver, the chemical form andphysico-chemical properties (morphology, size, chemistry) of material released from the products during
simulated use activities will be evaluated using appropriate analytical techniques.

Research Need #4. Conduct health surveillance of exposed populations
Overview
Health surveillance, that is the collection, analysis, and dissemination of health information, is a basic
tool used in Federal, state, and local public health protection activities. The information can be used tocharacterize the extent of health and safety problems, identify opportunities to prevent adverse effects,
plan for delivery of services to mitigate effects, and identify associations between adverse effects andpossible causes that can serve as hypotheses for further research. Integrations of health surveillancedata with exposure assessment data and identification of exposed populations would allow adequate
determination of the impact of ENMs on human health. Key to surveillance is the dissemination to anduse of data by those who need it to protect health and safety. Health surveillance can focus on a specificadverse outcome to identify risk factors (i.e., the NIOSH Adult Blood Lead Epidemiology and Surveillance
Program) or on a specific risk factor to identify adverse outcomes. There are established procedures for
ensuring that personal information is protected in surveillance programs, and those practices mustbe put in place for any such programs instituted for nanomaterials. Also, while certain individuals may
be disproportionately exposed to nanomaterials, so too may specific groups (e.g., certain age groups
utilizing specific products), and surveillance programs should take this into account.
While no fundamental barriers exist to meeting this research need, there are challenges to overcome:(1) attracting the health surveillance community of researchers to nanotechnology, which may requiresignificant outreach; (2) identifying groups with well-defined exposure characteristics or health outcomes known to be associated with exposure, which is needed for most effective surveillance; (3) developing new targeted medical screening tests such as those for cardio-vascular and pulmonary effects;(4) standardizing data collection, format, and terminology to improve efficiency and effectiveness; and(5) collecting information about nanomaterial use in consumer products, which would allow existing
poison control and emergency room surveillance programs to identify opportunities for investigation.

Recommendations for Changes
To overcome these challenges and knowledge gaps, instituting a program for the epidemiologic
investigation of physician case reports and reports of suspicious patterns of adverse events should beconsidered. Recent examples of nanomaterial exposure and unexpected health events reported in
the literature show that astute physicians can identify sentinel events and patterns of events and thatinvestigating the causal factors for these events can provide insight into whether production and useof nanoscale engineered materials are creating undue risks that can be controlled.12

12. Y. Song, X. Li, X. Du, Exposure to nanoparticles is related to pleural effusion, pulmonary fibrosis, and granuloma,
Eur Respir J. 34(3), 559-67 (2009); M. Wu, R.E. Gordon, R. Herbert, M. Padilla, J. Moline, D. Mendelson, V. Litle, W.D. Travis, J.
Gil, Case report: Lung disease in World Trade Center responders exposed to dust and smoke: Carbon nanotubes found in
the lungs of World Trade Center patients and dust samples, Environ Health Perspect. 118(4), 499-504 (2010).

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3. HUMAN EXPOSURE ASSESSMENT

To allow for analysis of the health and exposure data to identify possible associations between the two,
exposure registry and medical surveillance programs for workers should be established. Selected groups
of workers and others who are currently exposed to nanomaterials should be included in an exposure
registry to facilitate medical surveillance of their health over time. Health surveillance in the workplace
can be particularly effective because employment processes already generate records on job duties,
locations, exposures, and health status that can be used to establish exposure registry and medical
surveillance programs. These records may be augmented with special medical and exposure monitoring studies if sufficient data are not already being generated by company safety and health protection
programs. Suspicious health events or patterns of events can be investigated to identify possible associations with exposure. Specific steps to facilitate establishing such registries include (1) characterizing
what nanotechnology workers do, to facilitate creation of exposure registries; (2) providing guidance
as to how companies might develop registries and medical surveillance programs; and (3) initiating a
project to demonstrate the value of routine analyses of health and exposure data.
Evaluation is needed of existing injury and illness reporting programs for consumer exposures to determine the feasibility and utility of their use for identifying adverse outcomes associated with specificnanomaterials. As in occupational exposure reporting, a key question is whether the programs collectinformation that allows for the identification of events associated with nanomaterials. Another potential
resource is risk management programs operated by manufacturers and insurers; these collect loss andclaim data that can identify injuries and illnesses associated with nanotechnology activities. Access tothis information may identify opportunities for further investigation of the likely causes of apparent
associations.

Analysis of Current Projects
At the 2009 NNI exposure assessment workshop, no existing projects to gather health informationfrom nanomaterial-exposed cohorts were identified. However, analysis of FY 2009 projects shows one
funded by NIOSH that provides nanotechnology surveillance and epidemiology for workers exposed
to nanomaterials.

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Example of Progress in NanoEHS Research: Occupational Guidelines
To protect workers and responsibly move nanotechnology forward, NIOSH has developed three parallel
research efforts to (1) conduct foundational toxicology research, (2) measure nanomaterials in workplace air, and (3) evaluate control approaches and personal protective equipment. Findings from field
investigations and laboratory research (e.g., see Figure 3-2) are integrated into the NIOSH guidance,
Approaches to Safe Nanotechnology: Managing the Health and Safety Concerns Associated with Engineered
Nanomaterials (http://www.cdc.gov/niosh/docs/2009-125/). This guidance identifies nanotechnology
occupational safety and health issues; makes recommendations on occupational safety and health bestpractices in the production and use of nanomaterials; facilitates dialogue between NIOSH, industry,labor, and academia; responds to requests for authoritative safety and health guidelines; and identifies
information gaps and areas for future study and research. This document is widely utilized by industry;is cited by trade associations, unions, and other nongovernmental organizations; and has been usedby international organizations as a template for their guidance documents.

Figure 3-2. (Left) A researcher harvests single-walled carbon nanotubes from a carbon arc reactor. (Right) A
TEM image of nanotubes collected in the researcher’s personal breathing zone during nanotube
harvesting.
Source: National Institute for Occupational Safety and Health.

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4. Human Health
Overview
The 2011 Human Health category of EHS research needs is designed to systematically examine exposure,
uptake, distribution, metabolism, excretion, and effects of nanomaterials in in vitro and in vivo models
and relate their physico-chemical properties to nanomaterial biological response at the molecular, cellular, tissue, and whole-organism levels. Data from in vitro and in vivo models will be extrapolated to thehuman response in healthy, vulnerable, and susceptible individuals and populations. When integrated
with data from other sections of the NNI EHS Research Strategy, they will provide the information necessary to understand the human health risk of exposure to nanomaterials and support development ofevidence-based guidance to protect human health.
While there has been progress in understanding human responses to nanomaterials, researchers have
not yet achieved the critical data sets needed to understand fully the risk of exposure and developscience-based nanotechnology-related health and safety guidelines and support for regulatory decision making. To advance this research through an integrated Federal strategy, the NEHI Working Group
reviewed the status of nanotechnology-related human health research and solicited stakeholder comments, leading to the identification of six areas of research needed to achieve the two goals set forth
for human health.
Accurate assessment of physico-chemical properties of engineered nanomaterials is critical to realizing
the human health goals. Through linkages to the Nanomaterials Measurement Infrastructure researchneeds (Chapter 2), measurement tools to determine physico-chemical properties and create reliable
and reproducible assays and methods13 are being developed and applied in human health research tounderstand more precisely the physico-chemical property or subset of properties that regulate absorption, distribution, metabolism, and excretion (ADME) of nanomaterials and cause specific biologicalresponses. An understanding of these property–response or dose–response relationships is essential
for accurate, science-based decision analysis by regulatory agencies and development of robust predictive models that will improve nanomaterial design, maximize biocompatibility, and minimize adverse
health and environmental effects.
This 2011 NNI EHS Research Strategy expands the concept of human health research to include healthy
individuals, vulnerable populations with acute and chronic disease, and developmentally sensitive
populations such as fetuses, children, and the elderly. Airborne particulate research involving sensitiveand vulnerable populations has demonstrated differences in the uptake, metabolism, and excretion
components of the exposure–response paradigm that could shift risk management guidelines forparticular populations. Further explanation is provided in the newly crafted research need #6.
Another cross-cutting thread in the design of nanotechnology-related human health research is theneed to define more accurately the concept of exposure across the life cycles of nanomaterials and
13. The concept and process of validation has scientific discipline-specific definitions and criteria to identify
validated assays and methods. Therefore, the term “reliable and reproducible” is used in place of the term “validated”
when referring to assays and methods in this chapter.

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N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

nanotechnology-enabled products. Human Exposure Assessment (Chapter 3) considers populationbased exposure measurements, whereas the Human Health research needs build on these data at theindividual level by characterizing and analyzing exposure for each exposure route (research need #2) andat and in tissues at the port of entry (research need #4). Transport, biotransformation, and sequestrationof ENMs in secondary tissues are examined in research need #1. Inherent in the life cycle concept andapplicable to all human health research is the longitudinal examination of exposures to nanomaterials
across life cycle stages from R&D material to large-scale production, product incorporation, use, anddisposal.
Furthermore, research on human health often involves complex, interrelated concepts that are investigated most efficiently and effectively by research programs conducted in parallel rather than serially.
This construct challenges the development of a linear series of research needs; however, when woven
together, the Human Health research needs provide the critical framework to provide relevant, highquality data.

Goals
r

Understand the relationship of physico-chemical properties of engineered nanoscale materials
to in vivo physico-chemical properties and biological response.

r

Develop high-confidence predictive models of in vivo biological responses and causal physicochemical properties of ENMs.

Research Needs as of 2011
#1. Identify or develop appropriate, reliable, and reproducible in vitro and in vivo assays andmodels to predict in vivo human responses to ENMs:r

Establish a system to develop and apply reliable and reproducible in vitro and in vivo test
methodsr

Evaluate the degree to which an in vitro response correlates with an in vivo responser

Evaluate the degree to which in vitro and in vivo models predict human responserTranslate structure–activity relationship and other research data into computational models
to predict toxicity in silico#2. Quantify and characterize ENMs in exposure matrices and biological matrices:r

Determine critical ENM measurands in biological and environmental matrices and ensure thedevelopment of tools to measure ENMs in appropriate matrices as neededr

Determine matrix and/or weathering effects that may alter the physico-chemical characteristicsof the ENM measurandsr

Identify key factors that may influence the detection of each measurand in a particular matrix(e.g., sample preparation, detection method, storage, temperature, solvents/solutions)

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4 . H U M A N H E A LT Hr

Characterize and quantify exposure for all exposure routes using in vivo models to identify themost likely routes of human exposurer

Identify biomarkers of exposure and analytical methods for their determination#3. Understand the relationship between the physico-chemical properties of ENMs and theirtransport, distribution, metabolism, excretion, and body burden in the human body:r

Characterize ENM physico-chemical properties and link to mechanisms of transport and distribution in the human bodyr

Understand the relationship of the physico-chemical properties of ENMs to the mechanisms ofsequestration in and translocation of ENMs out of the exposure organ and secondary organs,and to routes of excretion from the human bodyr

Determine the metabolism or biological transformation of ENMs in the human body

#4. Understand the relationship between the physico-chemical properties of ENMs anduptake through the human port-of-entry tissues:rCharacterize ENMs at and in port-of-entry tissues, including nontraditional routes of entry suchas the ear and eye, and identify mechanisms of ENM uptake into tissuesr

Determine the relationship of ENM physico-chemical properties to deposition and uptake underacute exposure conditions and under chronic exposure conditionsrTranslate data on ENM properties and uptake to knowledge that may be used to intentionallyredesign ENMs for optimum human and environmental safety and product efficacy#5. Determine the modes of action underlying the human biological response to ENMs at themolecular, cellular, tissue, organ, and whole-body levels:r

Determine the dose response and time course of biological responses at the primary site of
exposure and at distal organs following ENM exposurer

Understand the mechanisms and molecular pathway(s) associated with ENM biology within
cellular, organ, and whole-organism systemsrLink mechanisms of response with ENM physico-chemical properties and employ this information in the design and development of future ENMsr

Develop translational alternative in vitro testing methods for the rapid screening of future ENMs
based on mechanism(s) of response that are predictive of in vivo biological responses#6. Determine the extent to which life stage and/or susceptibility factors modulate healtheffects associated with exposure to ENMs and nanotechnology-enabled products andapplications:r

Determine the effect of life stage and/or gender on biological response to ENMs

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N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G YrEstablish the role of genetic and epigenetic susceptibility on the biological response to ENMs
in the context of life stage and/or susceptibility factorsrUnderstand mechanistically the influence of preexisting disease on the biological response to
ENMs in the context of life stage and other susceptibility factorsrIdentify exposure conditions that make susceptible individuals more vulnerable to the healtheffects associated with ENMs and nanotechnology-enabled applicationsr

Establish a database that contains published, peer-reviewed literature, occupational andconsumer reports, and toxicological profiles that describe altered responses to ENMs andnanotechnology-enabled applications in susceptible animal models or individuals following
exposureComparative Analysis of Projects
The FY 2009 investment for human health research projects increased by $17.6 million and 17 projects
since FY 2006, with funding from two additional agencies, CPSC and FDA. The average investment per
project has increased from approximately $240,000 per project in FY 2006 to $350,000 per project in
FY 2009. The increase is distributed across the Human Health research needs, with the exception ofresearch need #3 on the distribution and fate of nanomaterials in the body. This decrease is due to achange in agency reporting of nano-biomedical projects that only partially support nanoEHS research.
The increase in funding reflects in part the American Reinvestment and Recovery Act funding acrossmost research needs.
Three projects have broad research scopes that address multiple human health research needs, and 15
are reported as “other” because their research themes are tangentially related to nanoEHS research andprovide some benefit to the general knowledge base. The FY 2006 and FY 2009 projects were mapped
onto the newly defined research needs; the resulting distributions by number of projects and funding
are presented in Table 4-1.

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4 . H U M A N H E A LT H

Table 4-1. Analysis of Projects Related to the Human Health Category of NanoEHS R&D,
FY 2006 & FY 2009*
FY 2006
Research Needs

FY 2009

Reported
funding in$K (% oftotal)

1. Identify or develop appropriate, reliable, andreproducible in vitro and in vivo assays and models
to predict in vivo human responses to ENMs.

NumberReportedof projects funding in(% of total) $K (% oftotal)

ChangeNumberFunding inof projects $K (num(% of total) ber ofprojects)

975
(4%)

6
(6%)

5,170
(12.4%)

17(14.5%)+4,195(+11)

2. Quantify and characterize ENMs in exposure
matrices and biological matrices.

2,895(12.1%)

13
(13%)

7,900
(19%)

19
(16.2%)+5,005(+6)

3. Understand the relationship between thephysico-chemical properties of ENMs and theirtransport, distribution, metabolism, excretion, andbody burden in the human body.

7,758(32.4%)

30
(30%)

2,700
(6.5%)

7(6%)-5,058(-23)

4. Understand the relationship between thephysico-chemical properties of ENMs and uptake
through the human port-of-entry tissues.

2,722(11.4%)

11
(11%)

3,800
(9.1%)

13(11.1%)+1,078(+2)

5. Determine the modes of action underlying thehuman biological response to ENMs at the molecular, cellular, tissue, organ, and whole-body levels.

9,590
(40%)

39
(39%)

17,870(43%)

40(34.2%)+8,280(+1)

6. Determine the extent to which life stage and/or susceptibility factors modulate health effects
associated with exposure to ENMs and nanotechnology-enabled products and applications.

--

--

1,330
(3.2%)

3(2.6%)+1,130(+3)

Multiple: Projects that capture multiple needs

--

--

1,160
(2.8%)

3(2.6%)+1,160(+3)

Other: Not captured above but of benefit to theresearch category

35(0.1%)

1
(1%)

1,680
(4%)

15
(12.8%)+1,680(+14)

TOTALS

23,975100

41,610117+17,635(+17)* Agencies supporting research in this category: DOD, CPSC, EPA, FDA, NIH, NIOSH, NIST, NSF

Gaps for Future Investment
While continued investment across all human health research needs is necessary to achieve the goals
outlined in this chapter, the fate of nanomaterials in the body (research need #3) and the responses ofvulnerable and susceptible populations (research need #6) require near-term attention.

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N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

Rationale for the 2011 Research Needs and Changes from 2008
Against the backdrop of research progress and stakeholder recommendations from the 2009 NNI
Workshop on Nanomaterials and Human Health,14 the Human Health research needs have been revisedin the 2011 NNI EHS Research Strategy as indicated in Figure 4-1. The order of the research needs mirrors
the sequence of research and data generation and prerequisites, rather than priority ranking.
2008 Strategy

2011 Strategy

Humah Health Research Need #1
Understand absorption and transportof NM throughout human body

Human Health Research Need #1
Identify or develop appropriate,
reliable, and reproducible ... assays
and models to predict in vivo human
responses to ENMs

Human Health Research Need #2
Develop methods to quantify &characterize exposure to NM andcharacterize NM in bio matrices

Human Health Research Need #2
Quantify and characterize ENMs in
exposure matrices and biologicalmatrices

Human Health Research Need #3
Identify or develop appropriate invitro & in vivo assays/models to
predict in vivo human responses to
NM exposure

Human Health Research Need #3
Understand relationship between ENM
physico-chem properties and theirtransport, distribution, metabolism,excretion and body burden inhuman body

Human Health Research Need #4
Understand relationship between
properties of NM and uptake

Human Health Research Need #4
Understand relationship between ENM
physico-chem. properties and uptake
on human port-of-entry tissues

Human Health Research Need #5
Determine mechanisms of interaction
between NM and the body at themolecular, cellular, and tissue levels

Human Health Research Need #5
Determine modes of action
underlying human bio response to
ENM at molecular, cellular, tissue,
organ, and whole body levels

Human Health Research Need #6
Determine extent to which life stage
and/or susceptibility factors modulate
health effects from exposure to ENM
and NEPs and applications

NMI Research Need #1
Develop measurement tools fordetermination of physico-chemical
properties of ENMs ...

NMI Research Need #4
Develop measurement tools
for evaluation of biologicalresponses to ENMs and NEPs ...

Figure 4-1. Comparison of the Nanomaterials and Human Health research needs in the 2008 NNI EHS Research
Strategy (left) with the Human Health research needs in the 2011 NNI EHS Research Strategy (right). The arrows
indicate mapping of the 2008 research needs to the 2011 research needs. Note that two of the 2008 researchneeds map in part to the Nanomaterial Measurement Infrastructure (NMI) research category, that 2011 adds
a sixth research need, and that the ordering shifted between 2008 and 2011.
14. Nanomaterials and Human Health & Instrumentation, Metrology, and Analytical Methods,
National Nanotechnology Initiative Workshop, November 17–18, 2009 (NSET/NSTC, Washington, DC, 2011;
http://www.nano.gov/publications-resources).

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Research Need #1. Identify and develop appropriate, reliable, and reproducible in vitro andin vivo assays and models to predict in vivo human responses to ENMs
Overview
In order to predict the behavior of ENMs in humans, it is essential to have in place reliable and reproducible in vitro and in vivo test methods and models that accurately assess ENM distribution and kinetics in
the human body and to develop approaches to translate these data to humans. Developing the ability
to predict with a high confidence level the biological effects of ENMs in exposed humans from in vitro
tests is an iterative process, requiring first the evaluation of the adequacy of traditional in vitro and invivo tests for ENMs, followed by the determination that the in vitro results reflect the in vivo response
quantitatively and qualitatively. This process should culminate in the assessment of the degree to which
the models mimic human exposure conditions and predict the human response to ENMs. Therefore,
efforts should focus on accurate methods of exposure and endpoints that are known to be similar inanimal models and humans. This research need will greatly benefit from the Nanomaterial Measurement
Infrastructure effort (Chapter 2) to develop high-throughput screening methods for in vitro researchthat could reliably replace in vivo systems and from the Human Exposure Assessment research (Chapter3) on dose metrics and routes of exposure.

Recommendations for Changes
At the 2009 NNI human health public workshop, the eight components of the 2008 Human Healthresearch need #3 were found to be redundant within that research need or between other NNI researchneeds. The original eight bullet points have been refocused and consolidated into three bullets anddistributed to Human Health research need #1 in the 2011 NNI EHS Research Strategy.
New test methods and high-throughput screening technologies were incorporated into the 2011 Human
Health research need #1 to emphasize the need to develop and apply a system to establish reliable andreproducible in vitro and in vivo test methods. (Workshop participants considered the developmentof high-throughput screening technologies to be a long-term, lower priority because it will requiresignificant work to develop high-throughput screening technologies that can reliably replace in vivo
systems, and this component was dropped.)
The 2008 research need #3 bullet to evaluate the degree to which in vitro and in vivo models predict
human response is left unchanged in the 2011 research need #1, but it is identified as a long-term andlow priority because animal models only approximate the anatomy and physiology of humans.
Additionally, workshop participants recommended that the term “validate” be avoided due to thepotential for confusion over what criteria and protocols are required to fully validate test methods. In lieu
of “validation,” the 2011 wording is “reliable and reproducible,” to more accurately reflect the desired
properties of these test methods.

Analysis of Current Projects
Seventeen FY 2009 projects were identified as relevant to predicting the behavior of ENMs in humans,
more than double the number of FY 2006 projects under this research need. Using the four 2011 subordinate points identified for Human Health research need #1, almost all of the funded research fits

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currently under the first point to develop and apply a system to establish reliable and reproducible in vitro
and in vivo test methods. Only two projects are relevant to the third point to translate structure–activity
relationships and other research data into computational models to predict toxicity in silico. No projects
were identified as relevant at this time to the second bullet, suggesting that the field has not progressedsufficiently to translate data and models to the prediction of human response. Clearly, this is a critical gap
that needs to be filled in the near term to improve understanding of the relevance of the in vitro and invivo test methods to human health. The outcome of those efforts would inform and drive developmentof the third point, that is, to start building the computational models to predict toxicity in silico.

Research Need #2. Quantify and characterize ENMs in exposure matrices and biologicalmatrices
Overview
Carefully measuring the quantity and properties of ENMs at the site of biological uptake and impact iscritical to identifying and understanding the relationship between exposure, uptake, and biologicallyeffective dose. Measurement data are needed to support an ENM exposure framework for linking
sources to effects. Biomarkers of exposure have been recognized as important tools for understanding
the relationship between exposure, uptake, and disposition in the body.
This priority research need focuses on methods to quantify and characterize ENMs in environmental
matrices that may contact the human body, and to determine the uptake, transport, disposition,and concentration in appropriate human biological compartments. Biological matrices are complex
environments that may change the surface chemistry of nanoparticles; for example, lung surfactant
proteins may be applied to ENMs post-synthesis to prevent agglomeration during use. Technologies
that measure physical properties such as particle size and surface area within an organism are criticalto evaluating exposure, fate, and biological effects over various dose–response paradigms. Analyticalmethods, particularly those that would enable the integration of exposure across exposure routes, need
to be explored. Additionally, it may be insufficient to report only mass measurement of nanomaterials
for data analysis, because other physical and chemical parameters are required to fully understand thebiological behavior of ENMs.

Recommendations for Changes
The 2008 NNI EHS strategy document presented the need for techniques to characterize ENMs in vivo,
and to evaluate the toxicity of these materials in the dose–response paradigm. The results of the 2009
NNI human health workshop emphasized the critical need to understand the relationship between
exposure and dose. Therefore the 2011 EHS Research Strategy has been refocused to include identifying
ENMs in vivo and in matrices outside of the body, such as in air and food, that may subsequently enter
the body and reach target organs, tissues, and cellular components. Current methods that characterize
ENMs in biological or environmental media are unable to measure either physical or chemical transformations of ENMs. Identifying and adequately describing these changes is a key factor in translating
exposure and uptake to biological impact.

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Tools and methods developed under this research need will enable mechanistic studies that can be
performed in vitro and in vivo, as well as support research to determine changes in particle properties
that result from interactions between exposures and biological matrices. Collaboration between physical chemists, physiologists, toxicologists, and pathologists will be important so that diverse scientificapproaches can be applied to characterize multiple types of ENMs in diverse biological matrices.
Applying the tools and methods to catalog transformation of ENMs through time, uses, and microenvironments will enable analysis of measurement uncertainty and production of accurate data. Useof informatics and data transfer tools should be encouraged between measurement researchers andthose studying effects.

Analysis of Current Projects
Nineteen projects were reported in FY 2009 for this research category: 2 by EPA, 4 by NIOSH, 2 by NSF,
and 11 by the National Institutes of Health National Institute of Environmental Health Sciences (NIH/
NIEHS). This represents an increase of six projects since FY 2006. The FY 2009 projects represent a wide
range of approaches, from assessments of toxicity at the cellular level and the properties that impact
observed effects, to projects that use personal sampling for characterizing ENM exposures through nasal
and oral routes. Several studies investigated the relationship between the physico-chemical properties
of ENMs and their observed cellular impact, and one study examined nanomaterial bioavailability andbiopersistence.
While these studies address most of the topics under this research need for one or more nanomaterials,
additional studies will be necessary to fully quantify and characterize the diverse classes and categories
of nanomaterials in biological and exposure matrices. Areas of further study should include development of biomarkers of exposure and high-throughput screening methods for exposure assessment,
the effects of factors such as storage and impact of solvents and solutions during ENM toxicity studies,and route-specific in vivo investigations correlated with biomarkers and biological effects. Models andmethods are needed to determine linkages between exposure sources and health effects. Interactions
between measurement researchers, biologists, and toxicologists should be encouraged to meet thisresearch need.

Research Need #3. Understand the relationship between the physico-chemical properties
of ENMs and their transport, distribution, metabolism, excretion, and body burden in thehuman body
Overview
This research need focuses on the deposition, translocation, and fate of nanomaterials throughout the
body in order to provide information on the bioaccumulation and potential body burden resulting from
repetitive low-level exposures to ENMs. This work will continue to draw upon biomedical and environmental research to examine ENM biokinetics and transport mechanisms, because these applications
provide useful safety data. Projects in this area may investigate, for example, (1) the physico-chemical
properties of ENMs that enhance or impede transport through the biological barriers, blood, cells, andorgans; (2) transport through intracellular compartments and cytoplasm; and (3) the role of ENM–protein

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interactions in the uptake transport of ENMs within these biological systems. This research will provide
critical information on the properties and mechanisms regulating ENM uptake, translocation, and fatein biological systems at the molecular, cellular, and organ levels in order to develop biokinetic models
that predict ENM biological exposure and fate. This research focuses on (1) the transport and distribution of nanomaterials throughout the body, including metabolic pathways and excretion; and (2) bodyburden, including biotransformation, sequestration, and effects of nanomaterial exposure and absorption, especially for sensitive tissues such as the nerves, blood vessels, and bone marrow. Nanomaterials
research in this need area will continue to draw on the experimental and in silico biomedical researchon the design of nanomaterials for improved drug delivery and imaging.

Recommendations for Changes
In 2008, the Nanomaterials and Human Health research need included the absorption and transport ofENMs and did not include research on the distribution, metabolism, excretion, and body burden of ENMs.
Coordination and integration of imaging and analytical methods will allow distinction between ENMs
and their physico-chemical properties and will enhance systematic mass balance analysis over the timecourse from exposure to sequestration, as well as analysis of biological responses. Stable radioactive
isotopic tracing approaches should be employed to enhance sensitivity and selectivity of the imaging
and analytical tools.
Finally, the identification of dose–response, or structure–activity, relationships and the impact of ENMs
on cell function are limited. Little information is currently available on the effect of ENM surface functionalization on metabolism intracellular and intra-organ translocation and dissolution of ENMs into
their component elements/chemicals, and biologically mediated changes in the material properties.
More progress is needed to identify generalized principles of ENM interaction with biological systems,
protein opsonization, and ENM dissolution. The differences in experimental results using in vitro and invivo models and the relationship of data from these experimental systems to human exposures need
to be determined so that in vitro and in vivo data can be interpreted meaningfully.

Analysis of Current Projects
Thirty FY 2006 projects were determined to be in alignment with this research area (2008 EHS Research
Strategy research need #1), for total funding of $7.8 million. Seventeen projects addressed this researchneed directly, and 13 had a relevant research component. Topics included the investigation of ENM
physico-chemical characteristics governing absorption through the respiratory tract; physico-chemical
properties that enhance or impede transport through blood, tissues, intracellular compartments, andcytoplasm; and intracellular and extracellular forces that stabilize or destabilize ENMs and properties
that allow them to coexist benignly with the immune and reticuloendothelial systems.
Only seven FY 2009 projects in the Federal portfolio were identified as aligned with 2011 Human Healthresearch need #3. These projects, funded by NIH (through the National Institute of Environmental
Health Sciences, the National Institute of Child Health and Human Development, and the National
Institute of Dental and Craniofacial Research), NIOSH, and NSF, totaled nearly $2.7 million. Four of the
FY 2009 projects examined sequestration of ENMs in the exposure organ and/or secondary organs,

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and one study characterized distribution of ENMs within alveolar tissue. Another characterized ENM
surface properties and mechanisms of transport in the placenta. The final project addressed general
toxicological assessments for ENMs within the context of the National Toxicology Program. One of the
projects was funded by the American Recovery and Reinvestment Act (ARRA) of 2009, with the resultthat ARRA funds accounted for almost 15 percent of the total investment for this research need for theyear ($350,000). Nevertheless, considerably fewer projects are reported for FY 2009 than for FY 2006,
primarily due to a redistribution and reorganization of research priorities, in particular, as was reported
in the 2008 human health research needs #3 – #5.
There remains significant opportunity for further research to promote understanding of the relationship between the physico-chemical properties of ENMs and their transport, distribution, metabolism,
body burden, and excretion from the human body. There were no studies to address mechanisms oftranslocation of nanomaterials from one organ to a secondary organ, address mechanisms of biotransformation, or examine excretion routes of nanomaterials from the human body. Gastrointestinal andocular exposures also remain understudied.

Research Need #4. Understand the relationship between the physico-chemical properties of
ENMs and uptake through the human port-of-entry tissues
Overview
The research encompassed by research need #4 focuses on the processes by which ENMs enter thehuman body. Developing an understanding of the physico-chemical properties of ENMs that can aid or
prevent uptake is critical to forming a complete picture of ENMs and human health. The term “uptake”
is used in this strategy as an inclusive term to encompass interactions of ENMs at cellular boundaries in
port-of-entry tissues resulting from processes such as deposition, adsorption, and absorption. Researchneed #4 specifically correlates the physico-chemical properties of ENMs with uptake at the cellular levelin relevant biological models and fluids.
The current studies in this research area lack technical specificity on the relationships between nanoparticle characterization, transformation at cellular boundaries, and uptake mechanisms. There has been
considerable attention paid to pulmonary exposure. Although there have been recent advances inaspiration techniques and aerosol generation, historical instillation methods that bypass the upper
respiratory tract are still employed. These instillation methods change the dose rate and distributionof materials in vivo and have limited value for risk assessment. ENM interactions with biological barriers at the port of entry, as well as the effects of biological coatings on ENMs such as surfactants andlipoproteins, should also be studied to understand the influence of these materials on cellular uptake.

Recommendations for Changes
To expand consideration of exposure and uptake in this report, these are divided between researchneeds #3 and #4: research need #3 describes the research associated with physico-chemical propertiesof nanomaterials and their distribution, metabolism, excretion, and body burden, while research need #4
describes the research associated with physico-chemical properties of nanomaterials and their uptake.
There has been more research and progress in the past several years on uptake of nanomaterials than on

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assessment of distribution, metabolism, excretion, and body burden. However, many of the studies of
uptake have been performed in vitro with various cell types that are considered to be models of organ
uptake in the simplest sense.

Analysis of Current Projects
Thirteen projects were identified in the FY 2009 Federal portfolio to align with research need #4.
Compared to the projects listed in the FY 2006 Office of Management and Budget data call, the FY 2009
projects more explicitly seek to connect nanomaterials’ physico-chemical properties with uptake and toleverage that knowledge for design of more biocompatible ENMs and development of biomarkers of
exposure; 8 projects were in this area. Two projects examined the relationship between ENM properties
and acute exposure, deposition, and uptake; 2 focused on intentionally designed ENMs to optimize
safety and efficacy; and 1 focused on the identification of biomarkers of exposure.
Research gaps are evident in the FY 2009 portfolio with respect to research to understand uptake at
port-of-entry tissues. There were no projects identified that studied the relationship between ENM
properties and chronic exposure, deposition, and uptake, nor were there any projects identified to
examine nontraditional port-of-entry tissues such as ear, nose, and eye. Because most of the research
was focused in a single area, there were clear gaps in the portfolio, providing significant opportunities
for further research to promote understanding of the relationship between ENM properties and their
uptake.
The existing, limited studies lack technical specificity on characterization and exposure, such as physicochemical characteristics of the nanomaterials, transformation of ENMs at the interfaces where thenanomaterial meets the cellular border, and mechanisms of the particle’s cellular uptake. Additional
studies are needed on mechanisms of cell-specific uptake in tissues and organs on ports of entry and
ENM interactions, and on the effects of biological molecules covering the nanomaterial surface. Also,
studies are needed on inhalation designed for use in risk assessment. Ultimately, there is a desire for
acute studies to better identify the need for, and inform the design of, studies and risk assessments.

Research Need #5. Determine the modes of action underlying the human biological response
to ENMs at the molecular, cellular, tissue, organ, and whole-body levels
Overview
This research will provide fundamental understanding of the key events and processes that mediate
the biological response and alter function and pathology associated with interaction of ENMs at themolecular, organelle, cellular, and organ/tissue levels of biological organization. By employing physicochemically distinct ENMs, diverse routes of exposure, and dose metrics that reflect realistic human
exposure conditions (Chapter 3), research in this area will enable the identification of common anddiverse molecular mechanism(s) mediating biological responses for similar or different ENMs. Data
from such inquiries will provide cell-, tissue-, and organ-specific responses and will aid in developing a
predictive testing approach based on mechanistic information.
Given the multitude of ENMs under development and the alteration of biological behavior by minutechanges in ENM structure and composition, a high-throughput, high-content assay tool is critical to

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timely evaluation of ENM safety. Development of this tool is described in Nanomaterial Measurement
Infrastructure (NMI) research need #4 (see Chapter 2) and applied to model systems under this researchneed. These methods, combined with in vitro and in vivo systems, will also lead to identification of thebiomarkers that demonstrate biological response to acute or chronic ENM exposure and that link these
exposures and responses to health effects.

Recommendations for Changes
In response to participant input at the November 2009 public NNI Workshop on Human Health andInstrumentation, Metrology, and Analytical Methods and to recent developments in the field, researchneed #5 and supporting specific bullets have been modified from the 2008 NNI EHS Research Strategy.
The research need is refocused to state, “Determine the modes of action underlying the human biological response” to ENMs. The focus of the research was recast to identify critical research endpoints anddistinguish between dose–response relationships and relationships between nanomaterial physicochemical properties and bioactivity. This links biological mechanisms to nanomaterials’ physico-chemical
properties, information that can be employed in the design and development of future nanomaterials.
Emphasis on determining the relationship of biological response, or modes of action, in animal models
to human response was expanded in response to the public workshop recommendations to specify
the routes of exposure that require evaluation and to couple this with specifying the time course for
exposure dose and response. The language in the research need #5 bullets now incorporates thesethree concepts into four bullets and evaluates the biological response to ENMs at the primary site of
exposure and at the distal organ level following pulmonary or dermal exposure, ingestion, or intravenous
administration.

Analysis of Current Projects
The FY 2006 EHS project portfolio was rich in evaluation of nanomaterials for targeted drug delivery
and medical imaging. These studies contributed to the basic foundation for the understanding ofinteractions of nanoparticles with biological fluids, proteins, and cell membranes. In FY 2006, projects
directly evaluating nanotoxicology were in their early stages, and research gaps existed. Review of the
FY 2009 portfolio of Federal projects identified 40 projects related to nanotoxicology research thatexamined dose–response relationships, mechanisms and pathways of biological response, linkage of
mechanisms to ENM physico-chemical properties, and development of alternative testing methods for
rapid screening. Current projects are concentrated primarily on pulmonary and dermal exposure routes,
and evaluate pulmonary, cardiovascular, neurological, reproductive, and dermal endpoints, as well astumorigenesis and mutagenesis. Most of the studies addressing the elucidation of molecular response
pathways are evaluating the role of oxidant generation. Additional projects involve evaluation of particle/
biological matrix interactions, particle/cell interactions, and effects of size, shape, and surface reactivity
on bioactivity. A few projects include methods development for alternative rapid screening tests.
High-priority areas for future investment include the relationship between the structure of ENMs andtheir biological effects; development of EHS predictive capability based on ENM physico-chemical
properties; improved and specific testing regimens, for example, predictive in vitro screening tests ormechanistic information needed to develop biomarkers; the relationship between acute/high-dose-rate

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exposures versus chronic/low-dose-rate exposures; and improved studies of systemic effects of ENMs,
for example, effects of pulmonary or dermal exposure on the carcinogenic potential of ENMs.

Research Need #6. Determine the extent to which life stage and/or susceptibility factors
modulate health effects associated with exposure to ENMs and nanotechnology-enabled
products and applications
Overview
Life stage and host susceptibility factors are critical in regulating all aspects of biological responses
associated with exposure to chemicals and environmental pollutants, including health effects, dosimetry
and biokinetics, mechanism of injury, dose metrics, and dose–response relationships. These factors
play critical roles in susceptibility where young and old individuals with preexisting diseases are mostsusceptible to the adverse health effects associated with environmental exposures. In addition, exposure
to elevated levels of particulate air pollution is associated with adverse developmental effects suchas premature births, birth defects, and low birth weights. There also exists the environmental justiceconcern for people who are disproportionally exposed to pollution and therefore are more vulnerable
to the addition of potential new stressors such as ENMs. Recent studies have shown that some ENMs
(1) enhance the sensitization and exacerbate challenge phases in mouse allergy models, (2) exacerbate
atopic dermatitis, and (3) exacerbate pulmonary and cardiovascular toxicity in older animals.

Recommendations for Changes
Understanding the role that life stages and/or susceptibility factors play in biological response to ENM
exposure is critical to achieving effective protection of the occupational work force and the general public; this is a new research need that was supported by participants at the 2009 NNI Workshop on Human
Health and Instrumentation, Metrology, and Analytical Methods. Research for this new need should
include developmental and health effects associated with all life stages, including pregnancy and preand post-gestational development, and altered susceptibility to exposures that may be associated withpreexisting diseases. The spectrum of research should include dosimetry, biokinetics, dose–response
metrics, and mechanisms of biological responses following different routes of exposure to ENMs.

Analysis of Current Projects
A review of Federally funded projects in FY 2009 to examine nanotechnology-related human healtheffects revealed that 3 out of 117 projects (or 3 percent of projects) were conducting research to identify the extent to which life stage and/or susceptibility factors play a role in modulating health effects
associated with exposure to ENMs and nanotechnology-enabled products. Specifically, the 3 projects
examined the impact that life stage (1 project) or preexisting pulmonary disease (2 projects) have on
the biological response to ENMs. This paucity of research represents a significant gap in our knowledge,
and future nanotechnology health effects research should increase resources to fully understand therelationship of life stage and host susceptibility factors to the human responses to ENM exposure. These
data are essential to allow for effective risk assessment and management decisions that are protectiveof both the occupational work force and the general public.

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Example of Progress in NanoEHS Research: Dermal Exposure to Sunscreens
Early concern about the safety of nanomaterials focused on the use of nanoscale materials in skinproducts, especially in sun block, products that are increasingly used by the general public. Nanoscaletitanium dioxide and zinc oxide, through their ability to act as sunblock agents in sunscreens, can reduceskin cancer from cell damage caused by solar radiation. Concern arose about the ability of nanoscalematerials to penetrate the skin and enter the body. Through a focused research program that examinedboth acute and chronic exposure of skin to sunscreen formulation (with or without nanoparticles, on
intact skin), FDA, the NIEHS National Toxicology Program, and National Cancer Institute Nanotechnology
Characterization Laboratory determined that intact skin provided a barrier to application of a nanomaterial-containing sunscreen formulation (Figure 4-2).

Figure 4-2. Electron microscope image of titanium dioxide particles in stratum corneum following administration of nanoscale TiO2. No significant dermal penetration of titanium dioxide from sunscreen formulations
containing nanometer and submicrometer-size titanium dioxide particles was observed.
Source: N. Sadrieh, A. M. Wokovich, N.V. Gopee, J. Zhen, D. Haines, et al., Lack of significant dermal penetrationof titanium dioxide (TiO2) from sunscreen formulations containing nano- and submicron-size TiO2 particles.
Toxicological Sciences 115, 156-166, 2010.

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5. Environment
Overview
The 2011 Environment EHS research category encompasses research to identify, understand, and control
the potential effects of engineered nanomaterials on both relevant ecological receptors such as fish andthe ecosystems that they occupy, and research on fate and transport of engineered nanomaterials that
leads to a better understanding of the mechanisms by which nanomaterials enter, remain in, degrade,
and are transported through environmental media. Understanding these potential environmental
implications is critical to implementing good product stewardship.
Releases of engineered nanomaterials have the potential to occur at any stage during the product life
cycle. Characterization of physico-chemical properties of specific nanomaterials underpins understanding of how they will move, deposit and accumulate, and transform in environmental matrices and under
the often-changing conditions in which they may be released. Transformation of these materials via
biological and/or photochemical processes, contact with water, or other processes may reduce environmental persistence and help to determine exposure concentrations. These concentrations, along withother modifying factors and the receptors that are present, shape potential exposures.
Effects in exposed organisms again tie back to fundamental physico-chemical properties, as well as
to a host of other factors such as exposure route, detoxification mechanisms in the organism, andsensitivity of the species. Product life cycle offers many potential points of entry into the environment.
Fundamental studies of the potential hazards from nanomaterials, such as those involving single species tests performed for regulatory decision making, should be guided by a view of how nanomaterials
behave in environmental systems. To understand ecosystem-wide effects, the sources (production/use/
disposal), the pathways, and the key environmental receptors need to be understood.
Inventory databases of production and use information should be developed and coupled with
nanoparticle properties of interest, including information on persistence, toxicity, transformations, andphase distributions. Populating such databases implies a shared responsibility and commitment byindustry and government to make information available that, while addressing confidential businessinformation needs, also provides the public with information on how much of what kinds of materials
are being produced for what uses.
Source, pathways, and receptor exposures will be influenced by the fate and transformation of nanoparticles, which can be assessed in microcosms and/or mesocosms. Differences between nanomaterial
behavior in the laboratory and in the environment should be better understood in the near term andshould be correlated with appropriate in-laboratory dosing methods. Testing for adverse effects should
consider not only the parent nanoparticle, but also transformation products and other toxic chemicals
associated with nanoparticles in the environment. Whole effluent testing may be useful to better
understand adverse effects of nanoparticles within a realistic background. Surrogate biomarkers suchas oxidative stress genes can be considered as markers of exposure and effects.

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Technical barriers impede progress in research on environmental fate and effects of ENMs. Methods
or approaches must be developed to identify, characterize, and measure exposure to nanomaterials,
and to follow their path and transformation through the environment and accumulation in organisms.
Approaches may be needed for quantifying nanomaterials in test situations where the concentration
may not be adequate for measurement by conventional means. Improved models for predicting
environmental release and exposure to nanomaterials require more empirical data and mechanistic
understanding of processes. Research on environmental transport is hampered by a limited understanding of particle coating chemistries and formulations used for consumer product applications,and by limited analysis of sources that may release nanomaterials, such as industrial point sources andconsumer non-point sources.
Research in the Environment category provides significant information for other categories. Transport
and transformation research informs the Human Exposure Assessment and Human Health categories, as
it does the environmental exposures and effects on individuals or ecosystems within the Environment
research category. Although research on human health and on effects on individuals of a species often
pursues different paths, the results provide valuable counterpoints to each other. Exposures to workers, consumers, and the general population are included in the Human Exposure Assessment chapter;environmental exposures are included in this chapter.
Progress in overcoming the technical barriers to research progress in this category will be enabledthrough linkages to the Nanomaterial Measurement Infrastructure research needs wherein measurement tools are being developed for physico-chemical properties, detection and monitoring, andtransformations of nanomaterials. The evaluation of exposure depends on understanding of transport,
transformation, and the life cycle of the nanomaterial, as well as on species-specific biological andecological information. Understanding effects on individuals of a species, populations, communities,
and ecosystems (including abiotic effects) depends on understanding how these fate processes altermaterials prior to their interactions with ecosystem receptors. Risk assessment ultimately depends on
information from each of these research areas, and it also informs, in an iterative process, where information gaps exist in each area.

Goalr

Understand the environmental fate, exposure, and ecological effects of engineered nanomaterials, with priority placed on materials with highest potential for release, exposure, and/or hazard
to the environment.

Research Needs as of 2011
#1. Understand environmental exposures through the identification of principal sources of
exposure and exposure routes:r

Manufacturing processes and product incorporationrLife cycle of technology and exposures subsequent to product manufacturing

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Analytical approaches to measure temporal changes in nanoparticle properties throughout
the life cyclerModels to estimate releasesrEnvironmental receptors for exposure assessments#2. Determine factors affecting the environmental transport of nanomaterials:r

Determine key physico-chemical properties affecting transportr

Determine key transport and fate processes relevant to environmental mediar

Develop new tools and adaptations of current predictive tools to accommodate the uniqueproperties of nanomaterials#3. Understand the transformation of nanomaterials under different environmental
conditions:r

Identify and evaluate nanomaterial properties and transformation processes that will reduce
environmental persistence, toxicity, and production of toxic productsr

Determine the rate of aggregation and long-term stability of agglomeration/aggregation andthe long-term stability of these aggregates and agglomeratesrDevelop tools to predict the transformations or degradability of nanomaterials#4. Understand the effects of engineered nanomaterials on individuals of a species and theapplicability of testing schemes to measure effects:r

Test protocolsr

Dose–response characterizationr

Uptake/elimination kinetics, tissue/organ distributionrMode/mechanism of action, predictive toolsrTiered testing schemes/environmental realism#5. Evaluate the effects of engineered nanomaterials at the population, community, andecosystem levels:r

Populationr

Communityr

Other ecosystem-level effectsr

Predictive tools for population-, community-, and ecosystem-level effects

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Comparative Analysis of Projects
The FY 2006 and FY 2009 projects were mapped onto the newly defined research needs; the resulting
distributions by number of projects and funding are presented in Table 5-1.

Gaps for Future Investment
Much of the research in the Environment core EHS research category depends on improvements in theability to quantify and characterize nanomaterials and to differentiate manufactured nanomaterials
from naturally occurring background particles in the environment. Enhancing predictive capabilities will
require investments in databases of nanomaterial properties, environmental modifications, and sources;development/refinement of testing schemes; improved understanding of nanomaterial behavior andfate; and improved understanding of potential receptors, exposures, and effects in individuals andecosystems.

Rationale for the 2011 Research Needs and Changes from 2008
The 2008 research needs have been reordered to reflect the risk assessment process and updated asfollows, and as indicated in the section above, Research Needs as of 2011. Research need #5 in particular
was changed to clarify its scope and incorporate public recommendations from the October 2009 NNI
Workshop on Nanomaterials and the Environment and Instrumentation, Metrology, and Analytical
Methods.15 The sections below on individual research needs describe changes to the bullets. The order ofthe research needs was changed to better reflect the risk assessment process, as indicated in Figure 5-1.
The report from the 2009 NNI Nanomaterials and the Environment & Instrumentation, Metrology, andAnalytical Methods Workshop recommended research to:r

Understand exposure as it relates to determining environmental risk andrConsider life cycle analysis as part of the evaluation of releases from manufacturing sites andother major waste streams in the near and medium term.

15. Nanomaterials and the Environment & Instrumentation, Metrology, and Analytical Methods: Report of the
National Nanotechnology Initiative Workshop, October 6-7, 2009, Arlington, VA (NSET/NSTC, Washington, DC, 2011;
http://www.nano.gov/publications-resources).

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Table 5-1. Analysis of Projects Related to the Environment Category of EHS R&D,
FY 2006 & FY 2009*
FY 2006
Research Need

Reported
Funding($K)
and % of
total

FY 2009% Change

Number of Reported Number ofprojects
projects
Funding($K) and %of total

Funding in$K (number ofprojects)

1. Understand environmental exposures throughthe identification of principal sources of exposure and exposure routes

250
(2%)

1

250‡
(0.6%)

20(+1)

2. Determine factors affecting the environmental
transport of nanomaterials

4,490
(38%)

22

1,315‡(3.0%)

4-3,175(-18)

3. Understand the transformation of nanomaterials under different environmental conditions

2,433
(21%)

9

5,065‡(11.6%)

16+2,632(+7)

4. Understand the effects of engineered
nanomaterials on individuals of a species andthe applicability of testing schemes to measureeffects

351
(3%)

5

715‡
(1.6%)

4

+364
(-1)

5. Evaluate the effects of engineered nanomaterials at the population, community, andecosystem levels

115
(1%)

1

0

1

-115
(0)

36,337+(83.2%)

27+36,337(+27)

Multiple: Projects that capture multiple needs

Other: Not captured in needs above but ofbenefit to the research category

4,089
(35%)

11

0

0

-4,089
(-11)

Total

11,72849

43,68254+31,954(+5)*Agencies supporting research in this category (FY 2009): EPA, NSF, DOD/USAF, NIFA, DOE, NIST
‡ Funding attributable to projects that met the requirement for that research need and no other+ Funding for projects associated with more than one research need

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N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

2008 Strategy

2011 Strategy

Environment Research Need #1
Understand the effects of ENM in
individuals of a species andapplicability of testing schemes tomeasure effects

Environment Research Need #1
Understand the environmental
exposures thru identification ofprincipal sources of exposure andexposure routes

Environment Research Need #2
Understand environmental
exposures through identification ofprinciple sources of exposure andexposure routes

Environment Research Need #2
Determine factors affecting theenvironmental transport of NMs

Environment Research Need #3
Determine factors affecting theenvironmental transport of NM

Environment Research Need #3
Understand the transformation of
NM under different environmental
conditions

Environment Research Need #4
Understand the transformation of
nanomaterials under different
environmental conditions

Environment Research Need #4
Understand the effects of ENM in
individuals of a species and theapplicability of testing schemes tomeasure effects

Environment Research Need #5
Evaluate abiotic and ecosystem-wide
effects

Environment Research Need #5
Evaluate the effects of ENMs at the
population, community, andecosystem levels

Exposure Research Need #4
Characterize health of exposed
populations and environments

Figure 5-1. Comparison of the Nanomaterials and the Environment research needs in the 2008 NNI EHS
Research Strategy (left) with the Environment research needs in the 2011 NNI EHS Research Strategy (right).
The arrows indicate mapping of the 2008 research needs to the 2011 research needs.

Research Need #1. Understand environmental exposures through the identification ofprincipal sources of exposure and exposure routes
Overview
The environmental exposures research need addresses sources of nanomaterials and their routes to theenvironment and environmental exposure, and helps to identify environmental receptors. To understandsources of nanoparticles, exposure pathways, and environmental exposures, the entire life cycle of anano-enabled technology must be considered.
One of the fundamental components in understanding a potential risk is characterizing the exposure
to a stressor. Exposure, uptake, and accumulation of nanomaterials may result in toxicity and other+56 +5. ENVIRONMENT

effects. The variety of nanotechnologies and products gives rise to a wide range of potential releases(both accidental and routine) to the environment throughout product life cycles. While some existingmodels can be applied to predict environmental concentrations of nanoparticles in air, surface water,
groundwater, sediments, and soil, the precision and reliability of such estimates are limited by the lackof nanomaterial-specific laboratory and field validation studies that examine variability in space andtime. Such studies are hampered by the inability of current methods to analyze nanomaterials in environmental samples. To be successful, the integration of life cycle information and exposure assessment
must be coordinated across disciplines and also across organizations (including industry, government,
nongovernmental organizations, and academia), as recommended by the President’s Council of Advisors
on Science and Technology.

Recommendations for Changes
The October 2009 NNI workshop also recommended research to develop models that can predictvarious aspects of engineered nanomaterial fate, distribution, exposure routes, transformations, andinteractions with organisms and ecosystems.
Further discussion identified improved analytical tools, generation of an inventory of nanomaterial
production and use, and routes of waste management as missing in the research topography. In addition
to clarification of these points in the exposures research need, a new bullet was added for identificationof environmental receptors for exposure assessments.

Analysis of Current Projects
Funding associated with the analysis of nanomaterial releases and exposures as part of a technology
or for the analysis in the environment has increased. In 2006, the one project related to environmental
exposures totaled $250,000. In 2009, 2 related projects totaled over $250,000, and 12 more contained
elements that pertained to the research need and are reported in the “Multiple Research Needs” line in
Table 5-1. Although life cycle approaches are an important research requirement, research that directly
addresses this need is minimal.
While several projects focus on analysis of materials, there is limited research on the life cycles of nanomaterials and releases, and no research on manufacture, processing, use, or disposal of manufactured
nanomaterials, including identification of future trends and ways to minimize potentially harmful environmental exposures. Additional gaps include identification of environmental receptors for exposure
assessments and development of cost-effective environmental monitoring approaches. There is one
project with an emphasis on evaluating current modeling capabilities for predicting environmental
releases and exposures.

Research Need #2. Determine factors affecting the environmental transport ofnanomaterials
Overview
Research on transport of nanomaterials through the environment includes consideration of fundamental chemistry and physical properties (formation and stabilization) as well as the contribution ofthese properties to transport and fate in various environmental matrices and scenarios (e.g., aquatic,+

57 +N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

atmospheric, and terrestrial). The physical and chemical properties that govern nanoparticle transportand fate are not always constant, unique values, but rather are best represented as populations of values
that vary over time. Recent research has shown that critical nanoparticle characteristics change overtime and that bioactivity and transport vary with respect to different size classes of nanoparticles. Thesestudies have highlighted the importance of nanomaterial characterization and the dynamic nature ofnanomaterials dispersed in aquatic systems. These complexities in nanomaterial composition complicate
efforts to adapt existing transport models to accommodate the properties of nanoparticles and predict
their movement in the environment.
As the report from the Nanomaterials and the Environment & Instrumentation, Metrology, and Analytical
Methods Workshop (2009) highlights, examination of transport requires understanding of the potential
sources of nanomaterials, or incorporation of a life cycle perspective that considers the sources and theirpoints of entry into the environment.

Recommendations for Changes
The wording of the bullets for the environmental transport research need has been clarified but notchanged substantively.

Analysis of Current Projects
In FY 2006, five agencies funded 22 projects on environmental transport in several relevant environmental media. In FY 2009 there are four research projects to understand key physico-chemical properties
affecting transport being supported by EPA, DOD and the Department of Energy (DOE). Three of these
are characterizing the effect of cerium oxide nanoparticles in diesel fuel additives, commercially available
silver nanoparticles, and suspensions of fullerenes; the use of organic nanoparticles for heavy metals
remediation; and the leaching of silver nanoparticles from consumer products and subsequent transport
through the environment. An additional 9 projects include environmental transport components andare included under “Multiple Research Needs.”
There also is research funded through NSF focusing on the transport and retention of carbon nanotubes
in soils, water, municipal waste water systems, and aquatic ecosystems, and the study of aggregation
behavior, deposition, and sediment infiltration of nanoparticles in lake water, river water, groundwater,and seawater. EPA, NSF, and DOE are funding transport studies on C60 fullerenes, metal oxide nanoparticles, and zero-valent iron in contaminated soils.
Finally, there are research projects involving modification and validation of currently used transportmodels for specific types of nanoparticles being funded by and conducted through EPA, NSF, and DOE.
This research includes modeling of the dissolution of silver nanoparticles in aqueous solutions, analyzing nanoparticle stability and mobility, and modeling of the transport of combusted nanomaterials andtheir effect on regional-scale air quality.

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5. ENVIRONMENT

Research Need #3. Understand the transformation of nanomaterials under different
environmental conditions
Overview
This research need focuses on developing, refining, and evaluating experimental and modeling tools forevaluating the effects of biotic and abiotic transformations on exposure to manufactured nanomaterials
and their absorption by environmental organisms in water, sediments, and soil. The research will reduce
uncertainties in risk assessment by determining and predicting the forms of manufactured nanomaterials to which organisms are exposed.
Transformations play an important role in determining exposure concentrations and the form ofnanomaterials to which organisms are exposed. These transformations may be benign or beneficial
to the environment, as well as deleterious. Biological and/or photochemical processes may transform
nanomaterials by degrading and thus reducing environmental persistence. Engineered nanoparticles,
through transformations, may cause adverse effects, such as the generation of toxic reactive oxygen
species by photochemical transformation of nanoscale titanium dioxide, or nanoparticles may bindenvironmental substances and be used for environmental remediation. Additionally, under certain
environmental conditions, nanomaterials may agglomerate into micrometer-scale particles or partition
into soil and water and display more limited mobility and bioavailability. They may also bind to othercontaminants in the environment.

Recommendations for Changes
The 2008 EHS Research Strategy included three bullets for this research need: key physico-chemical
properties affecting transformation, key transformation processes, and development of predictive tools.
Many of the key physico-chemical properties affecting transformation and the key chemical processes
driving those processes have been identified since 2008. To reflect this progress and incorporate therecommendations of the workshop, the bullets have been refocused as indicated in the Research Needs
as of 2011 section.
Development of tools to predict the transformations or degradability of nanomaterials remains a need.
Such efforts should focus on determining nanomaterial characteristics that make them susceptible
to enzymatic and photo-transformations. These tools should also predict rates of agglomeration andstability, given key nanomaterial characteristics.

Analysis of Current Projects
The nine FY 2006 projects reported in the 2008 NNI strategy document primarily focused on the reactivity of nanomaterials as used for catalysis. In FY 2009, 16 projects were identified by agencies as contributing to this research need, of which 14 were considered applicable to support for transformation andrelated research needs. Three of these projects were focused on the agglomeration of nanomaterials
after release into the environment. These projects focused on transformations ranging from microbial
to photochemical transformations in aquatic systems to those occurring in the atmosphere. One project focused on developing single-walled carbon nanotubes using green chemistry principles. Several
projects focused on developing or optimizing the use of nanomaterials to remediate contaminated

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N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

groundwater and decontaminate drinking water, but they did not evaluate the safety of nanomaterials
to environmental receptors or function; thus, these projects are not relevant to this research need or to
the EHS Research Strategy. Little of the work addresses developing predictive tools for transformation.

Research Need #4. Understand the effects of engineered nanomaterials in individuals of a
species and the applicability of testing schemes to measure effects
Overview
Research in Environment research need #4 focuses on potential adverse effects of engineered nanomaterials on individuals of aquatic and terrestrial species. These include effects in numerous species tested
under current test guidelines and protocols, including freshwater and marine vertebrates and invertebrates, both benthic and pelagic, and a range of metallic and carbon-based engineered nanomaterials.
Endpoints used to assess toxicity range from genomic and molecular, to whole-organism, to mortality
assessed in individuals or as changes in population growth or structure. A key focus of this research area
is evaluating the applicability or adequacy of current test guidelines and protocols for assessing effects
of nanomaterials on individuals of a species. This research area also focuses on nanomaterial uptake,translocation among tissues and organs, elimination, and the kinetics associated with these processes.
Research in this area has revealed generally moderate or low levels of acute toxicity and limited translocation of nanomaterials from potential uptake sites to other organs or tissues. This suggests that
production of reactive oxygen species may be a mechanism of action common to several classes ofnanomaterials. These generalities do not apply for every specific material, test system, or species. Suchexamples illustrate that nanomaterials need to be evaluated on a case-by-case basis.
Research in Environment research need #4, effects on individuals of a species, has focused primarilyon acute effects of ENM exposures in pelagic aquatic species. Less research has been completed on
nonaquatic species, on very early life stages or full life cycle assessments, or on uptake and translocation.
Exposure and effect levels have generally been reported using bulk (concentration) metrics. In addition, the tested materials are predominantly either feedstock materials likely to undergo modification
prior to use or product application, or are specially produced for the effects research being undertaken.
While test results based on these materials are essential for understanding basic questions concerning
nanomaterial behavior in test systems and potential toxicity, it remains unclear how well these materials
represent those that have the greatest potential to reach natural environments. Similarly, acute testingin systems having relatively low complexity is also useful as a starting point for addressing fundamental
toxicity questions, but has limited ability to predict effects or responses in more complex test systems
or over longer exposure periods. While chronic or longer-term testing has received little focus, initialresearch involving biomarkers (including genomics, proteomics, and indicators of oxidative stress) suggests that detectable responses may occur in lower, chronic-level exposures. These responses mightprovide a basis for development of rapid screening approaches; this is a critical need given the large
number of nanomaterials likely to require testing.
The paucity of research in this area can be attributed to the absence of readily available methods or
the requirement for acquisition of such data in existing test guidelines and protocols. Complex test

+

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5. ENVIRONMENT

systems such as microcosms and mesocosms offer more realistic assessment, relative to simple beakeror growth media studies, of the complex and simultaneous fate and biological effects that could occur innatural environments. Some research has focused on high-throughput testing and standard acute andchronic testing protocols. Confirmation of the validity of standard test methods is important, as is highthroughput testing focused on early, initiating events in toxic pathways and early developmental stages.

Recommendations for Changes
In order to reflect research progress achieved in the last three years, to incorporate public recommendations, to better explain the content of the science, and to fill recognized gaps in the research needs,
four modifications have been made to the research need #4 sub-bullets. These are listed in the section
above, Research Needs as of 2011.
The first of these changes is the addition of a specific bullet on uptake/elimination, kinetics, and tissue/
organ distribution. This topic was identified in the 2008 EHS Research Strategy and considered by participants in the October 2009 NNI workshop, Nanomaterials and the Environment & Instrumentation,
Metrology, and Analytical Methods, to be a major component of high-throughput screening in orderto understand tissue dose when evaluating initiating events in toxic pathways. The bullet, “tiered testing schemes,” was modified to “tiered testing schemes/environmental realism” to incorporate testing
nanomaterials in complex systems, such as natural river systems and micro- and mesocosms. This
modification also identifies a major cross-cutting issue within the Environment research category, thatcomplexity in effects testing will require an understanding of transport and transformation processes,
as well as the need to quantify and characterize nanomaterials in complex media. The bullet, “mode ofaction leading to predictive tool development,” has been modified to accommodate a greater focus onalternative testing based on mechanisms of action as well as more traditional mode-of-action endpoints.
Finally, the “test protocols” research need bullet has been reordered and refocused to acknowledge theimportance of identifying and remedying inadequacies in current methods for testing nanomaterials
by development of new test protocols.

Analysis of Current Projects
Four projects in FY 2009 were focused on some aspect of Environment research need #4; funding forthese projects totaled $715,000. In addition, under the “multiple” category, there were four more projects that contributed to this and to other related research needs. Funding was fairly evenly distributed
among the bullets, although uptake/elimination kinetics received about 43% of the total funding,compared with 11% to 17% for research in other sub-needs. It is important to point out that none of
the funding for the Centers for the Environmental Implications of Nanotechnology at Duke University(CEINT; http://ceint.duke.edu), and UCLA (CEIN; http://cein.ucla.edu) is included here; rather, it is included
under the funding category, “Multiple” (see section at the end of this chapter, Projects Capturing Multiple
Needs).
The OMB FY 2009 data call includes research on mechanisms of nanoparticle uptake into cells, tissues,and organs, and research on the effect of nanomaterials on the performance of individual organisms,

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N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

including their reproduction, growth, and survival that contributes to predictive capabilities. Researchsystems include terrestrial (plant-soils-microbes), freshwater (algae-invertebrates-fish), and marine(algae-invertebrates) food webs. Two additional research projects in research need #4 address methods
for characterization and quantification of nanomaterials in environmental media while also focusing
directly on effects of nanomaterials on DNA function.
Funding was fairly evenly distributed among the bullets and suggests that currently funded researchproperly targets many of the needs identified in the October 2009 NNI workshop report.

Research Need #5. Evaluate the effects of engineered nanomaterials at the population,community, and ecosystem levels
Overview
The Environment research need #5 focuses on effects of engineered nanomaterials beyond thosefound in individuals of a species and includes effects on populations, communities, and ecosystems,
including abiotic components and processes. Effects on populations and communities reflect individual
responses but incorporate aspects of population-level and community-level functions (for example,
density-dependent mortality and predation). Research need #5 also encompasses abiotic components
and processes in ecosystems that might be affected by nanomaterial exposure. These might include
interaction of hydrophobic nanomaterials with organic material such as dissolved organic carbon, or
alteration of carbon cycling and energy flow through ecosystems, including effects of photoreactive
nanomaterials in aquatic systems and the influence of natural organic material on the physiologicaleffects of nanomaterials. This research area also includes a focus on higher-level abiotic effects thatmight include alteration of air quality and natural photo-oxidative or catalytic processes.
Limited research indicates that microcosms and/or mesocosms offer more realistic study environments
and can improve understanding of nanomaterial behavior. Studies with greater realism give enhanced
understanding of issues such as receptor exposure in various media, relative sensitivities of different
species of organisms, relative impacts of different nanoparticles in the same system, and selectionof receptors that best indicate ecosystem-wide effects such as impacts on nutrient cycling. Valuable
information will come from comparisons of nanomaterial impacts on individuals (laboratory studies)with community-level results from microcosm, mesocosm, and field studies. Terrestrial systems are infrequently studied, with more research focused on terrestrial mammals than on avian species and plants.
Also understudied are nanoparticle effects on nutrient and water cycling, or on biomass production.

Recommendations for Changes
In response to multiple stakeholder input, an additional bullet on predictive tools has been added. The
section above, Research Needs as of 2011, shows the rewording of the research needs in the Environment
core research category to increase the clarity of the bullets. The pace for much of this research should
be increased in the nearer term relative to that identified in the 2008 NNI EHS Research Strategy.

+

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5. ENVIRONMENT

Analysis of Current Projects
In FY 2006, there was 1 project totaling $115,000 related to this research need. In FY 2009, there was 1
project (Environmental Impacts of Nanomaterials in Engineered Water Systems) focused on this researchneed, and two other large projects supported this and other research needs.

Projects Capturing Multiple Research Needs
Two large projects were within the Centers for the Environmental Implications of Nanotechnology at
Duke University and UCLA. These centers were funded at a total level of $7.8 million in FY 2009. The
work of the centers spans many research needs, including ones within the scope of other chapters. CEIN
funding applies to all five research needs in the Environment chapter as well as to research needs in otherchapters and cannot be compared with totals in the FY 2006 data call. The CEIN research explores theimpact of libraries of engineered nanomaterials on a range of cellular life forms, organisms, and plants interrestrial, fresh water, and seawater environments. Fundamental research on the behavior of nanoscalematerials in laboratory and complex ecosystems covers nanomaterial transport, transformation, fate,exposure, and ecotoxicological impacts and ecosystem functional responses (e.g., biogeochemical
cycling) over a range of length scales and complexity using macrocosms, microcosms, and bench-scale
experiments. The work also characterizes natural and incidental nanomaterials in the environment,
including structural and reactivity differences between natural and synthetic nanomaterials of the samechemical composition, and measurement methods for environmental nanoparticles. Risk assessmentand fate models assess the environmental implications of nanomaterials, including life cycle factors.

Example of Progress in NanoEHS Research: Nanosilver Case Study
In August 2010, the U.S. Environmental Protection Agency released a draft case study document forexternal review, Nanoscale Silver in Disinfectant Spray (http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=226723), organized around a comprehensive environmental assessment framework that
integrates a product life cycle perspective with the risk assessment paradigm and addresses environmental fate and transport, exposure-dose, ecological and human health, and other potential impactsof nanoscale silver in a spray product. The intent of this case study is to describe what is known andunknown about silver nanoparticles in a selected application to help identify and prioritize scientificand technical information that will support long-term assessment efforts. The study notes, for example,
that the behavior of engineered nanoparticles is greatly influenced by the properties of the particles
and the composition and chemistry of the surrounding environment (e.g., see Figure 5-2). This influence
may also extend to the toxicity of nanoparticles; some evidence exists that particle size and surface
properties affect the toxicity of silver nanoparticles. These efforts are helping to refine an integrative,
multidisciplinary strategic approach to research on nanomaterials and may be used to inform decisions
that reduce the risk of unintended consequences from nanotechnology R&D.

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N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

a)

b)

c)

d)

Figure 5-2. TEM images of gram-positive bacteria (Bacillus) cells exposed to silver nanoparticles: (a) unexposed
cells, (b–d) cells exposed to branched polyethyleneimine silver nanoparticles that vary from highly negative
surface charge to highly positive. White arrows indicate silver nanoparticles (b–d); black arrows (b–d) indicate
damage to cell membranes. The positively charged silver nanoparticles exhibited the highest toxicity andcaused bacterial death at all investigated concentrations, whereas the most negatively charged particles
exhibited the least toxicity.
Source: EPA.

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6. Risk Assessment and Risk
Management Methods
Overview
Risk assessment (RA) involves the application of analytical tools, data, and expert knowledge to theevaluation of potential exposure of humans and the environment to nanomaterials and the hazards
that exposure might engender. Risk management methods (RMM) for nanotechnology identify andimplement strategies to address potential hazards.
A number of national and international activities relevant to RA and RMM (combined, RAMM)—the fifth
NNI core EHS research category—are focused on characterizing a set of standard nanomaterials, identifying a standard battery of tests to estimate safety and toxicity, and standardizing a range of approaches
to better inform and quantify potential risks. Most projects are in early stages of development, and theoverall state of the science appears to indicate we are still in the process of learning about nanotechnology, collecting information, and evaluating how best to incorporate findings into risk assessment and risk
management approaches. In addition, research activities to understand and manage risk relevant to (1)nanomaterial measurement infrastructure, (2) human exposure assessment, (3) human health, and (4)the environment are incorporated into RAMM. For example, activities in the physical sciences (including
nanomaterials characterization, environmental transformation, identification of chemical properties,etc.) and in risk assessment and risk management may not be entirely separate; rather, information flows
freely among physical research, risk assessment, and risk management methods. As a result, current
research efforts aim to address these questions across several distinct, yet related, disciplines.
An effective risk management framework involves increasing use of all relevant information to guiderisk-based decisions and management. The risk assessment process incorporates the best available dataon the potential health effects of a nanomaterial and the exposure potential to humans and to the environment; thus, the data needs described in previous chapters and the quality of the results of studies inmeasurement, exposure assessment, human health, and the environment directly impact the reliabilityof risk estimates. In addition to quantifying risk to the extent possible, risk management (1) employs
basic scientific information; (2) uses comparative risk assessments for different nanomaterials with different properties, applications, or intended uses that can affect and result in different risk parametersand decision making; (3) integrates life cycle evaluations; and (4) considers ethical, legal, and societal
implications (ELSI) such as stakeholders’ values, communication needs, and other aspects of decision
analysis. Risk research will play an important role in understanding these factors and integrating theminto an effective risk management schema.
Important inputs from several sources have led to the research need areas outlined in the RAMM
core nanoEHS research category. These sources include the March 2010 NNI capstone workshop, Risk
Management Methods & Ethical, Legal, and Societal Implications of Nanotechnology; other Federally
sponsored environmental, health, and safety workshops; agency missions (including those of regulatory
agencies); input from the public and from a variety of other stakeholders; and input from risk assessors

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N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

and managers in all sectors. In some cases, research needs reflect the ongoing targets from the 2008
EHS Research Strategy, such as the importance of risk characterization information; in other cases, newresearch needs have been identified, such as the integration of risk assessment from multiple scenarios
to aid in decision making. All the research needs incorporate information from the wide variety of sources
and wide range of stakeholders and areas of expertise indicated above.
RAMM is relevant to all research categories within the 2011 NNI EHS Research Strategy, and vice versa.
For example, one significant area of input derives from the NMI focus on developing measurement
tools to determine physico-chemical properties of ENMs in relevant media and during the life cycles
of ENMs and NEPs for risk characterization information. Critical to developing effective strategies tominimize adverse impacts of ENMs to populations and the environment and to manage any potential
undesirable effects of this emerging technology are adequate assessment of the biological effects ofnanomaterials; of the release and fate of the materials in the environment, indoors, and in occupationalsettings; and ultimately, of exposure and uptake into living organisms and humans and the ultimate
risk of harm to these receptors.

Goalr

Increase available information for better decision making in assessing and managing potential
risks from nanomaterials, including using comparative risk assessment and decision analysis;
life cycle considerations; and additional perspectives such as ELSI considerations, stakeholders’values, and additional decision makers’ considerations.

Research Needs as of 2011
#1. Incorporate relevant risk characterization information, hazard identification, exposure
science, and risk modeling and methods into the safety evaluation of nanomaterials:rCharacterization, fate, and release of nanoparticles throughout the life cycles of NEPsr

Development of predictive models on accumulation, migration, and release of nanoparticles
throughout the life cycles of NEPsr

Safety of the nanoparticles throughout the life cycles of the NEPsr

Comprehensive and predictive models to assess the potential risks of nanoparticles during the
manufacturing and life cycles of nanotechnology-enabled products, with inputs from researchon human and environmental exposures and on nanomaterial properties#2. Understand, characterize, and control workplace exposures to nanomaterials:
r

Dissemination and implementation of effective techniques and protocols to measure exposuresin the workplacer

Identification and demonstration of effective containment and control technologies including
for accidents and spills

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6 . R I S K A S S E S S M E N T A N D R I S K M A NAG E M E N T M E T H O D SrDevelopment of an effective industry surveillance systemr

Design and deployment of a prospective epidemiological framework relevant to exposure
sciencer

Systematic approaches for occupational risk modeling#3. Integrate life cycle considerations into risk assessment:r

Establishment of a nanotechnology-specific taxonomy for life cycle stagesrIntegration of risk assessment, life cycle analyses, and decision-making approaches into regulatory decision-making processesrApplication of adaptive management tools based on monitoring/implementation to evaluate
life cycle analysis implementationr

Development of case studies, e.g., green chemistry, nanomaterials selection, nanomaterials
acquisition processes, illustrating application of these risk management methods#4. Integrate risk assessment into decision-making frameworks for risk management:r

Development of comparative risk assessment and formal decision-analytical methods as
opposed to “absolute” risk assessment strategiesrApplication of formal decision-analytical methods to prioritize risk management alternativesr

Use of gap analysis and value of information analysis to identify research needsrIntegration of stakeholder values and risk perceptions into risk management processesrApplication of an integrated decision framework through case studies in risk management
decision making#5. Integrate and standardize risk communication within the risk management framework:r

Development and use of standardized terminology in risk communicationsr

Early information-sharing on hazards and risk among Federal agenciesr

Development of appropriate risk communication approaches for agency-specific needs

Comparative Analysis of Projects
Overall FY 2009 investment in the RAMM research category is primarily focused on risk characterization
information, workplace exposure and exposure of other population subgroups, life cycle assessment,
and informed decision making, with emphasis on standardization and integration of risk communication within the risk management framework. A new research need, integration of risk assessment into
decision making frameworks for risk management, was not identified previously; it represents a newarea for nanoEHS research, because independent research activities need to be thoughtfully combinedin more sophisticated models for evaluation and risk management.

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The FY 2009 research investment tracks closely to the FY 2006 balance of funding reported in the 2008
NNI EHS Research Strategy, but with increased investment in risk characterization information, hazard
identification, exposure science, and risk modeling and methods for the development and evaluation of
nanomaterials. Another area with increased investment is understanding, characterizing, and controlling
workplace exposures to nanomaterials. Investments in FY 2009 comparable to those made in FY 2006
have been made in integrating life cycle considerations into risk assessment and management andintegrating and standardizing risk communication into the risk management framework. The FY 2006
balance of funding identified six projects that capture multiple needs. In contrast, all FY 2009 projects
were categorized within the 2011 strategy’s research needs. The FY 2006 and FY 2009 projects were
mapped onto the newly defined research needs, as shown in Figure 6-1; Table 6-1 presents the resulting
distributions by number of projects and funding.
Table 6-1. Analysis of Projects Related to Risk Assessment andRisk Management Methods Category of NanoEHS R&D, FY 2006 & FY 2009*
FY 2006
Research Needs

FY 2009

ChangeNumberFunding inof projects $K (num(% of total) ber ofprojects)

Reported
Funding
in $K (% oftotal) †Numberof projects(% oftotal)‡

Reported
Funding
in $K (% oftotal)

1. Incorporate relevant risk characterization information, hazard identification, exposure science,and risk modeling and methods into the safety
evaluation of nanomaterials

132
(4%)

1

1,767
(50%)

6

+1,635(+5)

2. Understand, characterize, and control workplace
exposures to nanomaterials

495
(15%)

4

1,267
(36%)

10

+772
(+6)

3. Integrate life cycle considerations into risk
assessment

396
(12%)

2

300
(8%)

4

-96
(+2)

4. Integrate risk assessment into decision-making
frameworks for risk management

—

—

—

—

—

5. Integrate and standardize risk communication
within the risk management framework

231
(7%)

1

200
(6%)

1

-31
(0)

Multiple: Projects that capture multiple needs

2046
(62%)

6

—

—

-2,046(-6)

Other: Not captured in the needs above but ofbenefit to the category

—

—

—

—

—

3300

14

3534

21

+234
(+7)

TOTAL

*Agencies supporting research in this category (FY 2009): EPA, FDA, NIOSH, NSF† Funding estimates track to related research needs in FY 2006
‡ Number of projects track to related research needs in FY 2006

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Gaps for Future Investment
As the use of nanomaterials increases rapidly, it is of vital importance that the risk assessment community understands the complexities of the issues surrounding the manufacture, use, and disposal of
nanomaterials, the potential of environmental and occupational exposure to human populations, as wellas potential adverse health outcomes. For this to happen, it is necessary for the scientific community tounderstand the needs of risk assessors for information such as risk characterization, and what research
will provide that information; also, researchers need to know the decision contexts within which theirresearch findings will be applied. Risk management of nanomaterials requires more information about
the human and ecological effects of exposure to a variety of nanomaterials.

Rationale for the 2011 Research Needs and Changes from 2008
Research focused on the range of uses of a nanomaterial across its life cycle, and the risk assessment
methods and tools used to evaluate each stage of the life cycle, may use different measurement tools.
Also, comparing the use of nanomaterials under different circumstances aids in applying what is learned
to new applications, including predictive modeling for potential exposure and hazard case scenarios.
Due to the wide variety of regulations, legal standards, and other rules pertaining to nanomaterials usedin different products or circumstances, risk assessment and management strategies may need to change
as they focus on various life cycle stages. As a result, the following research needs have been identified
that are general enough to be applied to a variety of nanomaterial uses under different conditions
and environments, and yet specific enough to identify key phases of the life cycles of nanomaterials
during development and use. The research needs presented in the RAMM research category are listed
in the order that reflects steps of risk assessment and management, rather than priority ranking. As
indicated in Figure 6-1, there are changes in the wording and sequence of the 2011 key research needsin risk assessment and risk management methods as compared to 2008, based on multiple inputs fromstakeholders and experts in the field.

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2008 Strategy

2011 Strategy

Risk Mgmt Research Need #1
Understand and develop best
workplace practices, processes, andenvironmental exposure controls

RAMM Research Need #1
Incorporate relevant risk
characterization info,
hazard identification, exposure
science, and risk modeling andmethods into safety eval of NM

RAMM Research Need #2
Understand, characterize, and control
workplace exposures to NM

Risk Mgmt Research Need #2
Examine product of material life cycle
to inform risk reduction decisions

RAMM Research Need #3
Integrate life cycle
considerations intorisk assessment

Risk Mgmt Research Need #3
Develop risk characterization
information to determine and classify
nanomaterials based on physical orchemical properties

RAMM Research Need #4
Integrate risk assessment into
decision making frameworks forrisk management

Risk Mgmt Research Need #4
Develop NM-use and safety-incident
trend information to help focus risk
management efforts

RAMM Research Need #5
Integrate and standardize risk
communication within therisk management framework

Risk Mgmt Research Need #5
Develop specific two-way risk
communication approaches and materials

Figure 6-1. Comparison of the Risk Management Methods research needs in the 2008 NNI EHS Research
Strategy (left) with the Risk Assessment and Risk Management Methods research needs in the 2011 NNI EHS
Research Strategy (right). The arrows indicate mapping of the 2008 research needs to the 2011 research needs.

Research Need #1. Incorporate relevant risk characterization information, hazard
identification, exposure science, and risk modeling and assessment methods into the safety
evaluation of nanomaterials
Overview
RAMM for nanotechnology requires an adequate knowledge of the interactions of nanomaterials withhumans and the environment, not only during the manufacture of nanomaterials, but also during
their life cycles. The 2008 NNI EHS Research Strategy placed a majority of RAMM research emphasis on
airborne particles and controls of inhalation exposures at the workplace. Such emphasis has provided

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valuable data for assessing the potential EHS risks of nanotechnology during the manufacture anduse of engineered nanomaterials. However, nanomaterials are increasingly incorporated into a variety
of product classes and used in a wide range of environments. The fate of these nanomaterials alone
or when used in products, and their EHS effects during the whole life cycle, are largely unknown. For
example, the properties of an ENM influence its behavior in the body and safety profile, whereas slightalterations can fundamentally change both parameters. Observations indicate (1) nanomaterials are
increasingly used in many large-volume industries such as construction, automobiles, and textiles,
and the number of people, including sensitive populations such as children, who are exposed to thesetypes of nanomaterial or products containing such materials is also very high; and (2) long, continuous
human exposure during the entire service life of the products is also an important factor to consider.
Yet, little data currently exist on the use of nanomaterials in products or on the potential risks of nanomaterials during service and post service (e.g., in landfills) in nanotechnology-enabled products. The
lack of such data severely hinders our ability to intelligently assess and manage the potential risks ofnanomaterials; this includes insufficient data on (1) the effects of exposed media on physico-chemical
properties, toxicity, and fate of nanomaterials; and (2) interactions between nanomaterials and theexposed environments (e.g., hydrolysis, photodegradation, thermodegradation, erosion, and abrasion).
For example, in the presence of ultraviolet light, pollutants, water, electrolytes, and oxygen, many typesof nanomaterials are likely to be oxidized, transformed, or modified, which would lead to different EHS
effects, hence potential risks, as compared to their natural states in isolation.

Recommendations for Changes
In 2008, the NNI focused on two areas for this research need: (1) information on flammability and reactivity of nanomaterials, and (2) hazard information for risk management. Progress has been made in thesetwo categories for pristine nanomaterials; however, a comprehensive awareness of potential benefits
and risks of exposure requires similar reliable data for ENMs and NEPs across the entire life cycle using
relevant biological and exposure media. Additional recommended areas of research include:r

Data on characterization, fate, and human and environmental exposure across the product life
cycle

r

Development of models to describe and predict the accumulation, migration, release, andpopulation exposure to nanomaterials from products under different exposure conditionsr

Analysis of toxicity of nanoparticles released during the life cycle of a nanomaterial or NEPrComprehensive models to assess the potential risks of nanomaterials across the product life
cycles, including human and environmental exposure data and release potential

Analysis of Current Projects
Research to provide greater understanding about nanomaterials for better risk assessment has been
substantially increased between FY 2006 and FY 2009. Such research is especially important to developing the rapidly expanding field of risk assessment and management, understanding the evolving
state of scientific knowledge, and applying it to new uses. For example, in FY 2006, only one project on
development of risk characterization information was undertaken among U.S. Federal agencies, but in

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the FY 2009 data call, six projects related to this topic were listed across several government agencies,
including projects focused on the applicability and predictability of genotoxicity of nanomaterials;
release and migration studies in food packaging; explosion hazards of carbonaceous nanoparticles;
incorporating ethical decisions into nanomanufacturing research; development of greener synthesis
strategies for nanomaterials; and efforts relevant to detecting and characterizing nanomaterials inbiological matrices.
Although a stronger emphasis on addressing research need #1 has been made in the past few years, agreater effort should be focused on developing robust data on nanomaterial properties and potential
exposures and hazards for nanomaterials that are used in consumer products and found in the environment during their total life cycles. For example, new developments in the field mean that attention mustbe paid to the emerging science needed to enable nanoEHS efforts to better predict and prepare forthe new types of products that may be seen in the near future. Risk characterization data should offer
sound risk assessment and effective strategies to manage the risks of new nanomaterials.

Research Need #2. Understand, characterize, and control workplace exposures tonanomaterials
Overview
Mitigation of exposure is a key goal of risk management across the life cycle of an engineered nanomaterial. During the manufacture or use of engineered nanomaterials, exposure controls can be in the formof engineering solutions, administrative controls, or procedural approaches. The 2008 NNI EHS Research
Strategy identified the need to gain information on how to identify and better characterize worker
populations with the potential for exposure, develop and refine methods to characterize exposures,and develop tools to control workplace exposures.

Recommendations for Changes
As more nanotechnology-enabled products move to commercialization, there are increasing opportunities to develop knowledge of the nature and scope of the worker population that has the potential to be
exposed. Specific areas that require additional emphasis include developing an epidemiologic framework that can be used to evaluate workers who use nanomaterials; collecting business and industrial
surveillance data to identify and describe the nanomaterials workplace; and incorporating nanomaterialspecific examples into incident investigation, reporting, and tracking systems. Additional research needsin the workplace include developing a streamlined model program for tracking nanomaterials workers;
identifying the control and containment approaches that can be applied to nanomaterials; and useof historical experiences from the pharmaceutical, cosmetics, and dry powder pigment industries to
identify candidate control technologies. Future needs may include identifying and demonstrating theeffectiveness of modern containment technologies for safe handling and transport through the life cycle,
investigating the effectiveness of different work practices for exposure mitigation, and strengthening
current research on personal protective equipment and respiratory protection. Finally, there is a needto develop and disseminate case studies showing the successful containment and control applicationsin nanomaterial facilities in order to identify the best design practices for facilities and processes thatcan engineer out potential exposures.

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Analysis of Current Projects
Key research needs in this area can be divided into two categories: (1) control technologies and (2) industry surveillance.
The 2008 NNI EHS Research Strategy included projects to conduct exposure characterization studies; asthese studies progress, conditions that cause environmental releases and worker exposures are being
identified. The 2009 OMB data call identified 4 projects distributed between NIOSH, EPA, and NSF thatinvestigated various aspects of workplace characterization, environmental impact, risk management
methods, and impact on other population subgroups. One project by NIOSH deployed a team of field
investigators to visit nanomaterial manufacturing and product incorporation sites to gain a better
understanding of actual workplace exposure scenarios and to evaluate the effectiveness of any controlsthat might be in place. Other projects funded by NSF and EPA sponsored centers or workshops that
focused on the high-rate manufacture of nanomaterials. As these nanomanufacturing processes aredeveloped, key information will be captured on their potential for emission of nanomaterial and possible
human or environmental exposure. Knowledge gained on manufacturing processes has been used to
identify opportunities for additional research on mitigating human and environmental exposures andrisks. To meet the need for developing a risk management approach in the absence of complete hazard
data, NIOSH has continued its efforts to explore the utility of applying control banding to nanomaterial
processes. This effort was conducted in parallel with research to evaluate the effectiveness of protective
clothing and respiratory protection equipment. These projects have laid a good foundation for fillingknowledge gaps; however, research is still needed to demonstrate the effectiveness of various types ofcontainment and control technologies for nanomaterial manufacturing processes.
Because nanomaterials are products or key product ingredients, not process contaminants, historicalcontaminant control and removal approaches may not be appropriate. Preliminary investigations haveidentified some conventional controls that are effective, but the number of scenarios evaluated to dateis limited. Research is needed to provide an effective logic model for selecting the most appropriate
type of containment or control based on the material and the processes. More workplace investigations are needed to identify and evaluate containment and control approaches that are effective, as
are laboratory-based studies that evaluate different containment and control schemes and optimize
their performance.
As nanomaterials continue to be developed for commercial application, the number of workers involvedin their manufacture and use will continue to grow and become more diverse. A systematic approach togather and evaluate that information is needed to develop a more realistic view of the potential impactof nanomaterials on the workplace. Developing an effective industry surveillance system to capture thatdata will require collaboration and cooperation between government agencies and the private sector.
Designing and deploying a prospective epidemiological framework, which is described in the Human
Exposure Assessment category, will be needed to evaluate and characterize the exposure experienceof the workers. Applied research that results in the types of guidance and recommendations called forin this research need should be an area for future investment. Project outcomes that have a prospective
impact on reducing emissions and exposures to engineered nanomaterials will support responsible
development of the technology.

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Research Need #3. Integrate life cycle considerations into risk assessment
Overview
Consideration of nanomaterial life cycle has been a standing recommendation, beginning with the 2008
NNI research need to determine the stages of the product’s life cycle that may introduce potential for
EHS risks.16 The 2008 NNI EHS Research Strategy also lists green design as an important consideration,
without linking it to life cycle analysis. In the 2011 revised NNI EHS Research Strategy, life cycle and green
design considerations are linked, and the scope of this research is expanded to include the design ofnanomaterials with maximal benefit and minimal risk to public health and the environment. The limited
information collected over the last several years on nanomaterial risk at different life cycle stages has
highlighted numerous data gaps.

Recommendations for Changes
In the 2008 NNI EHS Research Strategy, this research need focused specifically on risk management
methods for nanomaterials, with no clear discussion of the role of risk assessment or decision making.
Much of the funding has been focused on the overarching issues related to general risk management.
With the research funded since FY 2006, it is now possible to focus future research more precisely
on both risk assessment and risk management, linking them to specific regulatory decision making.
Research priorities in the 2011 NNI EHS Research Strategy have been developed after consideration of
the NNI agency missions, the best use of currently available scientific information, as well as the values
and information expressed by stakeholders and the public.

Analysis of Current Projects
Although NIOSH or NSF funded the FY 2006 projects under this research need, the most recent work
has been funded by EPA and includes risk assessment research. Four FY 2009 projects identified in thiscategory have a component to assess the sustainability of the nanomaterial manufacturing processes
used in the project: three focus on life cycle assessment for specific uses of nanomaterials, and one
focuses on green chemistry use in manufacturing.
The first project is a multicomponent, holistic life cycle assessment for decision support and enhanced
sustainability though the provision of tools that reduce the environmental costs of processes andproducts. The second project, a life cycle assessment case study on lithium ion batteries, is a partnership between two EPA offices, industry, and others to provide specific insights into environmental
improvements in batteries and general insights into how life cycle analysis can be used to design moreenvironmentally benign nanotechnology-enabled products. The third project, a pilot case study, isevaluating a nontraditional approach to assessing sustainability and life cycle implications of nanoscalecarbon fibers in windmill blades. This comparative thermodynamic assessment of a nanocomponent andrelated life cycle inventory, if successful, could be developed for a wide range of applications. The lastongoing project is developing nanoparticle synthesis using a high-efficiency reactor and is intended todemonstrate the use of a continuous process to increase the production efficiency (yield, energy savings,
16. The National Nanotechnology Initiative: Environmental, Health, and Safety Research Needs for Engineered
Nanoscale Materials (NSET/NSTC, Washington, DC, 2006; http://www.nano.gov/NNI_EHS_research_needs.pdf ), p. 54.

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and time savings) of producing nanoparticles. Such a process would also reduce potential releases andtherefore, risks to people and the environment.
Although these projects are focused on life cycle assessment, due to the nature of the research, each is
focused on a single nanomaterial application. The remaining projects expand life cycle assessment toinclude ethical, legal, and societal issues and a core facility that supports this type of assessment of nanomaterials and products. Decision analysis methodology has not been included in some risk assessment
processes and represents a key data gap. The addition of this decision analysis methodology will help
highlight the key data needs for determining risk related to nanomaterial production, use, and disposal.

Research Need #4. Integrate risk assessment into decision-making frameworks for risk
management
Overview
The diversity of nanomaterials in production and use has led to uncertainty about the further development, selection, and application of risk methodologies. There is general agreement among the NNI
stakeholder communities that nanomaterials, for the near term, need to be assessed on a case-by-casebasis—an approach that challenges time and resources. This 2011 RAMM research need aims to integrate risk assessment information with multiple data sources to better inform all stakeholders and help
expedite the evaluation of new applications of nanomaterials.
Whereas the objective of traditional risk assessment is often an absolute risk characterization, a decisiondirected approach emphasizes comparative bases for relative assessment of alternative materials
with varying material properties and life cycle properties. Data needs may be less critical because thedecision-directed approach is comparative and is bounded by the limited number of alternatives anddecision criteria assessed by criteria-specific metrics. Development of comparative risk assessment anddecision-analytical frameworks to assess nanomaterial risks and support management decisions is thus
an important extension of the 2008 Risk Management Methods research category.

Recommendations for Changes
Significant information collection efforts funded by governments and industry worldwide have resulted
in a large volume of data on nanomaterial fates and effects, but their applicability to risk management
and policy decisions has been limited. As this work has progressed, it has become clear that there isa need to focus and prioritize research efforts to evaluate relative risks and benefits associated withnanomaterials. There also exists a growing body of academic literature illustrating application of formal
decision-analytical approaches (e.g., multi-criteria decision analysis) and value-of-information analysis
to nanomaterial risk management, and the 2011 NNI EHS Research Strategy capstone workshop17
specifically discussed the use of these methods for risk management. These developments since 2008
are reflected in the new RAMM research need #4.

17. Risk Management Methods & Ethical, Legal, and Societal Implications of Nanotechnology: Report of the
National Nanotechnology Initiative Workshop, March 30-31, 2010, Arlington, VA (NSET/NSTC, Washington, DC, 2011;
http://www.nano.gov/publications-resources).

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One way to aid nanoEHS research efforts is to recognize synergies available through the integrationof risk assessment and life cycle analyses into decision frameworks. The emergence of new nanomaterials and uncertainties associated with their properties requires integrating technical evaluations ofnanomaterial properties with values and decision-maker objectives as part of this process. Developing
formal decision-analytical methods and tools and their application will focus the gathering of information on risk-based decision needs. Although there are currently no ongoing NNI-funded projects on
the use of decision analysis with nanomaterials, there exists a growing body of academic literatureillustrating the application of formal decision-analytical approaches to nanomaterial risk management.
One example is the Risk Governance Framework of the International Risk Governance Council (IRGC,
http://www.irgc.org/), which developed as a comprehensive risk governance framework tool thatincorporates many societal aspects and communication needs and is aimed at framing nanomaterial
governance as a decision problem. Another example is the 2008 joint North Atlantic Treaty Organization/
EPA and DOD workshop “Nanomaterials: Environmental Risks and Benefits and Emerging Consumer
Products”18 that reviewed multiple risk assessment frameworks and illustrated the application of formal
decision-making tools in multiple settings.
There is a need to integrate stakeholder values in the risk management process in a transparent way. The
emerging risk management tools should be evaluated by stakeholder groups, and value and barriers fortheir applications in different settings should be assessed. Stakeholder engagement and decision analysis could be used for mapping risk perception and tolerance by different stakeholder groups. Decisionmaking approaches could be used to quantify values that stakeholders place on different resources andto integrate these values with technical information to select risk management alternatives.

Analysis of Current Projects
Although currently there are no ongoing NNI-funded projects on the application of decision analysis tonanomaterials, it has been specified as the ultimate goal in several funded projects.
Given the issues specific to nanomaterials, particularly the variability in risks among similar nanomaterials based on their surface coatings, method of production, and specific formulation, decision analysis
frameworks would greatly inform future risk assessments. Case studies incorporating decision analytics
into the risk assessment process will inform the data needed for future risk assessments and will assist
in streamlining data needs for risk assessment. This simplification of data needs will lead to a decreasein extraneous data collection related to specific nanomaterials and move forward risk assessment ofmany nanomaterials.

Research Need #5. Integrate and standardize risk communication within the risk
management framework
Overview
Risk communication is an integral and ongoing process for risk analysis of nanomaterials and is an
essential part of informing stakeholders (e.g., workers, consumers, and the general public) at each stageof the risk assessment and risk management process. Effective risk communication is fundamental for
18. Igor Linkov, Jeffery Steevens, eds., Nanomaterials Risks and Benefits, Proceedings of the NATO Advanced ResearchWorkshop on Nanomaterials: Environmental Risks and Benefits, Faro, Portugal 27–30, April 2008 (NATO Science for Peaceand Security Series C: Environmental Security, Springer, Heidelberg / Dordrecht, 2008).

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developing trust among the various nanotechnology stakeholders and is interconnected with the ELSI
and life cycle considerations for nanotechnology. Risk communication is most effective if undertaken ina systematic and timely way that can be enhanced by using common terminology and by early sharingof risk information among Federal agencies. Risk communication should also be appropriately tailored tothe targeted audience. As a result, different approaches may be used to communicate risk(s) by Federal
and state agencies, academia, and industry stakeholders with the goal of fostering the development ofan effective risk management framework.

Recommendations for Changes
The need for standardized two-way risk communication approaches was identified in the 2008 NNI
EHS Research Strategy. Opportunities for communication are diverse, and different Federal agencies
use a variety of approaches to communicate with and disseminate health and safety information to the
public and other stakeholders, taking into account the needs of target audiences. These approaches
include websites, technical publications, guidances, public meetings, and presentations. Since 2008,
various agencies have initiated risk communication projects, yet there is still limited information among
stakeholders regarding nanotechnology hazards, risks, and benefits. This can be attributed, at least inpart, to a lack of effective risk communications.
The process for enabling and enhancing risk communications across Federal agencies can begin with
developing standardized terminology to describe nanotechnology, promoting early information-sharing
on hazards and risks, and developing risk communication approaches for agency-specific needs. While
the various regulatory agencies have methods available for communicating with stakeholders, specificsectors, such as consumers and industry, can further benefit from understanding agencies’ approaches
in order to evaluate what may be required from them or what is in their best interests. The ultimate
benefit is for stakeholders and agencies to have a better understanding of the risks and benefits fromnanotechnology and of the best ways to manage them.

Analysis of Current Projects
The one FY 2009 research project is funded through NSF. This collaborative research project is investigating the societal aspects of nanoscale science and engineering (NSE), combined with public engagement,
to improve deliberation and decision making about NSE. Its goal is to develop new ways of organizing
the production of knowledge, and to develop and test new processes of anticipatory governance tomeet the emerging promises and challenges of NSE.
Additional gaps remain, and needs have been identified related to risk communication research: identifying location and volume of nanomaterials produced in order to direct where risk communication
efforts are needed; promoting early identification and sharing on hazard and risk; and developing an
integrated approach to research, cooperation, and communication strategies to direct efforts toward
responsible and sustainable growth of nanotechnologies. Progress in this research need will assist thetransparency of other research needs in the RAMM category of nanoEHS research.
Finally, success in communicating ELSI and risk assessment findings will aid in increasing transparency and public understanding of safety issues surrounding the development, use, and disposal of
nanomaterials.

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Example of Progress in NanoEHS Research: Risk Characterization of Nanomaterials in Spray
Products
Government-sponsored risk assessment activities have assessed the safety of nanomaterials in cleaningand disinfecting products. Nanoscale titanium dioxide, when exposed to ultraviolet (UV) light, acts asa photocatalyst to eliminate potentially harmful microorganisms and the accumulation of dirt on thesurfaces of materials such as glass. These products may be used by consumers in the home environmentand by workers who apply these materials, for example, to the surfaces of windows in office buildings.
Through a collaborative effort, NIOSH and CPSC have examined the potential exposure of consumers
and industry workers to nanomaterials released into the air during the use of these products, and thecharacteristics of this exposure. A testing method was developed in 2009 that includes use of a chamber
simulating a controlled indoor environment and incorporating a series of instruments to characterizenanomaterial releases (Figure 6-2). This experimental process addresses the critical need for gatheringrisk characterization information on consumer products, exposure assessment methods, and exposure
data that can be used to evaluate potential health risks that may result from the use of these spray products. This method will be publicly available to guide industry and consumer groups in the development
and evaluation of spray products that may contain nanomaterials.

Figure 6-2. (Left) Nanoparticles-containing spray can aerosol; (Right) Characterization, exposure assessment,
and generator design.
Source: B.T. Chen, A. Afshari, S. Stone, M. Jackson, D. Schwegler-Berry, D.G. Frazer, V. Castranova, T.A. Thomas,
Nanoparticles-containing, spray can aerosol: Characterization, exposure assessment, and generator design,
Inhal. Toxicol. 22, 1072-1082, 2010.

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7. Informatics and Modelingfor NanoEHS Research
To attain the goals of the NNI EHS Research Strategy, an interagency nanoinformatics infrastructure anda strategy for rapidly expanding and integrating that infrastructure are urgently needed. Expanding
informatics capabilities will aid development, analysis, organization, archiving, sharing, and use ofdata that is acquired in nanoEHS research projects in the core categories described in the previous fivechapters. Thus, informatics and modeling have been identified as a sixth core research category. Effective
management of reliable, high-quality data will also help support advanced modeling and simulation
capabilities in support of future nanoEHS R&D and nanotechnology-related risk management. Researchneeds to achieve these informatics and modeling goals are described below.

Enhance Quality and Availability of Data
Data Acquisition
Interlaboratory studies (ILS) have repeatedly emphasized three essential needs for improving data
quality: (1) development and validation of standard protocols having positive and negative controls
to check for interference by the specific nanomaterial being tested; (2) informal interlaboratory testingin development of standard protocols; and (3) formal ILS to establish the uncertainty and traceability19
associated with use of those protocols. Related efforts seek to establish guidelines for minimum reporting requirements regarding the range of quantitative assays used to characterize nanomaterials. In
addition, there is a need to acquire data generated during method development and validation that
establish the robustness and ruggedness of standard protocols. These data provide a measure of thesensitivity of the method to changes in experimental parameters, procedures, and materials, and would
aid in developing more robust methods. Finally, reporting guidelines regarding the extent of validation attained by the laboratory performing the method should be established—whether full or partial
validation was attained, if the result is a single laboratory measurement, or if it has been corroborated
by another laboratory. Until these needs are met, published data will continue to be of limited value,referencing basic techniques and assay types rather than documented protocols, with assays modified
or amended arbitrarily, and without sufficient characterization of the nanomaterial being studied.
Improvements in data reliability and reproducibility can be effected quickly by leveraging the widespread use of wireless and video-enabled devices by the public and by standards development organizations to capture protocol detail through videos and to create training materials for their use. Relatively
modest resources would also be required to establish repositories to store, aliquot, ship, and monitor
the study materials for ILS, and to establish a registry system to provide unique identifiers for each typeand lot of material. The more daunting obstacle is the lack of incentives for participation in the standards
development and ILS processes by academics and by government scientists and regulators. Putting
new incentives in place for participation by all stakeholders, combined with a modest investment ininfrastructure, would provide the means to achieve significantly more reliable and reproducible data.
19. See footnote 9.

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Data Analysis
The need for sensitivity analysis in conjunction with error and uncertainty analysis is urgent for hazard
and exposure estimation and the rational design of nanomaterials. Because the last decade has seen
large improvements in synthesis control and separation techniques, purer and more monodisperse
nanomaterials are becoming available for detailed analysis of the sensitivity of their properties tochanges in their surrounding media and environment. Collaborative multidisciplinary projects todevelop mappings of structure–property spaces for select nanomaterials with monodisperse components would provide design reference data. These efforts would provide focal points for collaborative
efforts in nanomaterial design, including curation of datasets with known uncertainties and errors,
the use of sensitivity analysis to predict changes in nanomaterial properties, and the development ofcomputational models to augment and elucidate experimental data. Identifying regions in which smallchanges in nanomaterial structures lead to large differences in their properties (high sensitivity) and/or large uncertainty and error in the data or models would provide a quantifiable measure of the needfor greater understanding of the underlying mechanisms and help target priority areas for additional
research and funding.

Data Sharing
Improved data sharing is a crucial need to accelerate progress in nanoscience by removing the barriers
presented by the current “siloed” data environment. Because data must be curated by those who havethe most intimate knowledge of how it was obtained and analyzed and how it will be used, a central
repository to facilitate sharing is not an optimal solution. However, federating database systems throughcommon data elements would permit rapid semantic search and transparent sharing over all associated databases, while leaving control and curation of the data in the hands of the experts. The use of
nanomaterial ontologies to define those data elements, together with their computer-readable logicalrelationships, can provide a semantic search capability.
A number of pilot systems and applications have been developed as initial demonstrations of capability to elicit user requirements for database federation. As examples, the NanoParticle Ontology (NPO;
http://nano-ontology.org) provides a consistent mapping among nanoparticle structure and property
data, and nano-TAB (http://is.gd/eaviO) provides a nanotechnology extension to the ISA–TAB format fordata acquisition and sharing. The staged, iterative development of an open-source infrastructure compatible with the current Network for Computational Nanotechnology (NCN; http://www.ncn.purdue.edu/)
and amenable to public/private partnerships should be initiated, with governance of the effort by theparticipating agencies and partners. This would permit the nanotechnology community to improve,
adapt, and extend the pilots and applications that are now available or being developed.

Expand Theory, Modeling, and Simulation Capabilities
Structural Models of Nanomaterials
A nanomaterials data bank is needed to develop, validate, and archive 3D nanomaterial molecular
structures. This data bank would act as an archive and data processing center for freely available

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structural data and would accept structural models from depositors as part of the journal publication
process, provide data-checking and validation services, and archive models. In turn, these models could
be used in blinded validation studies to improve computational models of nanomaterials in different
biological environments. The Collaboratory for Structural Nanobiology (CSN; http://csn.ncifcrf.gov/csn;
see example at the end of this chapter) is such a data bank and includes a 3D model builder to rapidly
develop fully three-dimensional molecular models for complex nanomaterials. The CSN could be used,
together with other available structural database systems, to unify the structural modeling community.

Predictive Models and Simulations
The turnaround times for the development and validation of predictive models is measured in years.
Pilot websites, applications, and tools should be added to the NCN to speed collaborative code development among relevant modeling and simulation disciplines, including the risk modeling community.
The infrastructure should provide for collaborative code development by public and private scientists,
code validation exercises, feedback through interested user communities, and the transfer of validated
code versions to centers such as NanoHUB (http://www.nanohub.org/). Such facilities would provide
the focus for targeting code development resources to the scientific needs of the community whilemarshalling expertise from different agencies and institutions, which would allow development andvalidation of code systems for particularly urgent needs, such as relating exposure to dose for different
nanomaterial types and routes of exposure. Finally, collaborative efforts could supplement nanomaterial
characterization measurements to provide more complete sensitivity information and structure–property relationships.

Build a Collaborative Informatics Infrastructure
The benefits of collaboration are many: the breaking down of data silos; semantic search and sharingof data and models; web-enabled tools for rapid initiation of collaboration across disciplines; andability to gather information regarding similar and different nanomaterials, structures, environments,
mechanisms, and pathways. But the primary advantage is to speed up the rate at which the science canadvance by using digital communication to its fullest possible extent.
The larger problems with setting up a better collaborative informatics infrastructure are based on many
confounding considerations: the policies and practices of different agencies, funding mechanisms, andfunding evaluation schemes for academic research; and intellectual property considerations for industrial research. But initially it is sufficient to allow scientists to interact more effectively scientist-to-scientist,to share appropriate and available data and models, and to begin to gather common requirements
and priorities for more efficient systems. Bringing academia and industry together through alternate
mechanisms such as through nongovernmental organizations is another possibility, as are consortia
for precompetitive partnering.

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Rationale for the 2011 Research NeedTo delineate the research necessary to accomplish these informatics and modeling goals, the following
research need has been established:

Develop computational models of ENM structure–property–activity relationships to support
the design and development of ENMs with maximum benefit and minimum risk to humans
and the environmentr

Validate the predictive capability of in vitro and in vivo assays and employ that subset of assays
in data generation to establish computational models to predict ENM behavior in humans andthe environmentr

Establish a standard set of physical and chemical characterization parameters, dose metrics,
and biological response metricsr

Design and establish structures and ontologies for methods development, data capture, sharing, and analysisr

Evaluate and adapt as necessary existing computational models by beginning with existingmodels for exposure and dosimetry and using data generated from validated assaysr

Use ENM exposure and dosimetry models to develop ENM structure–activity models to predict
ENM behavior in humans and the environmentr

Establish training sets and beta test sites to refine and validate ENM structure–activity modelsr

Disseminate ENM structure–activity models through publicly accessible nanotechnology
websites

Example of Progress in NanoEHS Research: 3D Structural Information about Nanomaterials
Structural information about nanomaterials, including validated 3D models, would improve scientists’understanding of the EHS implications of these materials. The Collaboratory for Structural Nanobiology
was begun in 2007 as a collaboration between researchers at the National Cancer Institute in Frederick,
Maryland, and the University of Talca, Chile. Their goal was to prototype a database to construct, validate, and share molecular models of nanomaterials. Their work has resulted in early predictions of theconformation of two nano-engineered constructs in water, DF1 and DF1 mini, representing dendronizedcarbon fullerene (C60) molecules (see Figure 7-1). These similar constructs have very different physicochemical properties that significantly alter their efficacy and safety in therapeutic medical applications.
Carbon fullerenes have the ability to act as antioxidants and scavenge a large number of hydrogenand oxygen radicals per molecule, making them ideal candidates for the protection of cells sensitive toionizing irradiation during cancer therapy. To design an effective therapy using C60 derivatives, several
challenges must be overcome: induction of cell toxicity, insolubility of the nanoscale material, andreduced protection of the fullerene core from ionizing radiation. Synthesis of C60 with a single molecular
addition was one promising path to solve these problems; however, predictions of C60 properties werelimited by the availability of only 2D models of the structures.

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7 . I N F O R M AT I C S A N D M O D E LI N G F O R NA N O E H S R E S E A R C H

The top half of Figure 7-1 illustrates the similar 2D structures of DF1 and DF1-mini, which differ in that
DF1 has a larger molecular addition than DF1-mini. These 2D models provide no information about
the structure of either construct in water. Exploration of several 3D structural models of these nanomaterials (Figure 7-1, bottom) have verified that, despite their chemical similarity, the structures bear
little resemblance to one another in water and result in markedly dissimilar properties. The DF1-mini
structure is cytotoxic, whereas the dendrons wrapped around the C60 core preserve the benefits of theC60 core as a radical-scavenger, an effect not readily apparent from the 2D structural analysis. The DF1
simulations exemplify the essential use of 3D structures to organize available data and to guide thedesign of engineered nanomaterials.

Figure 7-1. DF1 (left) vs. DF1-mini (right) structural models. Top: 2D rendition. Bottom: The most prevalent 3D
conformations obtained during simulations.
Source: B. Braden et al., Proceedings of the National Academy of Sciences USA, 2000, October 24, 97(22),12193–12197.

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8. The Path Forward
To expeditiously move toward realizing the vision and goals of the NNI EHS Research Strategy, it will benecessary for NNI agencies and programs to be highly focused and to take advantage of the benefitsof collaboration and information-sharing among representatives of NNI agencies, academia, industry,NGOs, the general public, and international governance bodies. This chapter notes near-term opportunities to target and accelerate progress in nanoEHS R&D, to maintain close accord with the overall goals
and objectives of the National Nanotechnology Initiative, and to effectively coordinate agency research
activities and share their results.

Targeting and Accelerating EHS Research
Several issues and challenges span all of the research categories in the NNI EHS Research Strategy andrequire an integrated approach to advance our understanding of nanomaterial risk. Furthermore, the
NNI is committed to a cohesive interagency EHS Research Strategy, with the NSET Subcommittee and its
NEHI Working Group serving as a nexus for communication about and facilitation of nanoEHS researchthrough focused interagency collaboration. The NEHI Working Group has identified the following key
principles to assist agencies in making strategic decisions about research programs that will efficiently
advance the NNI EHS research agenda while meeting their respective missions:r

Prioritize which nanomaterials to researchr

Establish standard measurements, terminology, and nomenclaturer

Maximize data qualityr

Stratify knowledge for risk assessmentrPartner to achieve the NNI EHS research goalsr

Engage internationally

It is expected that the application of these principles, discussed in more detail below, will help theindividual NNI agencies to more effectively target EHS research, accomplish their individual mandates,
and as a group, accelerate the pace and boost the value of their EHS research activities.

Prioritize Nanomaterials for Research
In order to efficiently and effectively identify plausible human and environmental risks associated withnanomaterials exposure, it is necessary to prioritize nanomaterials and nanotechnology-enabled products for study across their life cycles. NEHI, in response to the PCAST recommendation20 and in keepingwith the more practical guidance provided by the NNI EHS Research Strategy, has chosen to develop
research-focused criteria to identify and prioritize ENMs and NEPs that might pose a plausible risk to
20. PCAST, Report to the President and Congress on the Third Assessment of the National Nanotechnology Initiative(PCAST, Washington, DC, 2010; http://www.whitehouse.gov/sites/default/files/microsites/ostp/pcast-nni-report.pdf ),p. 13.

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human health or the environment. In a research modality, the NEHI members propose dual criteria forprioritizing selection of ENMs for research:r

Nanomaterials that may provide a major contribution to the ENM research knowledge base.
These should be chosen for their ability to contribute systematically to a matrix of structure–property–activity relationships, for example, a matrix that includes examination of physicaland chemical characteristics against a defined set of biological responses. This systematic accumulation of data will contribute significantly to identifying the overarching design principles
for new nanomaterials that will guide nanomaterials and nanotechnology–enabled productdevelopment, maximize benefit, and minimize risk.

rNanomaterials and nanotechnology-enabled products that may pose a safety concern tohumans and the environment. Prioritizing the ENMs and NEPs that may pose a safety concern
to workers, consumers, and the environment requires a different set of selection criteria. Many
agencies have established procedures for selecting nanomaterials for safety examination;
however, the NEHI Working Group chose five criteria to be considered collectively when determining priority:rPotential for hazard. This would include nanomaterials that have physical or chemical
characteristics similar to those of known toxicants, or that activate defense mechanisms
and signaling pathways in screening assays. (These criteria might identify, for example,
nanotubes with dimensions matching the long-fiber toxicity paradigm and/or nanomaterials containing heavy metals.)r

Likelihood of exposure. This would include nanomaterials with a high potential for commercialization or that are already produced in large quantities or incorporated into a larger
number of products, or result in exposure of a large number of people or environmental
areas, or are produced by industrial manufacturing and processing methods and/or types
of applications likely to cause exposure.

r

High reactivity. This would include nanomaterials with high potential for biotic and abiotic
transformation in organisms or the environment, ones that change biokinetics, or ones thathave the potential to be manipulated in a biological system by external factors, the resultof which confers increased toxicity.

r

Biological novelty. This would include nanomaterials exhibiting new routes of exposure,sequestration in new biological compartments, biopersistence due to evasion of elimination
pathways due to size, new dose metrics such as surface area and solubility, novel biology
due to size-dependent properties, novel molecular structure, or self-assembly properties.

r

Identified in a health or environmental event. This would include nanomaterials that may
have produced unanticipated human health effects or environmental impacts, which may
require an immediate research effort to evaluate the plausibility of a causal relationshipand the degree of risk.

It should be noted that the criteria used to prioritize nanomaterials for EHS research under this dual track
are consistent with the value-of-information principle that includes the extent to which information

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8 . T H E PAT H F O RWA R D

gained will reduce uncertainty about benefits and risks, lead to broad knowledge about properties andbehavior, and reduce the potential for adverse human and environmental impact.

Establish Standard Measurements, Terminology, and Nomenclature
Confidence in research results on nanomaterials, essential to science-based risk assessment, is achieved
through standardized measurements. Such measurements ensure the accuracy, precision, and reproducibility of research results and thus provide a trustworthy knowledge base for evaluating andunderstanding exposure and hazards to humans and the environment. Reference materials, protocols,and consensus standards (test methods, specifications, and guides) are required for standardized
measurements. Organizations engaged in the research, development, manufacture, and regulation ofengineered nanomaterials and nanotechnology-based products should coordinate and cooperate todevelop reference materials, protocols, and consensus standards for high-priority nanomaterials.
In addition to the need for standardized measurements, there is a need for standardized terminology
and nomenclature to fully characterize and categorize ENMs. NNI agencies should continue active participation in domestic and international terminology and nomenclature activities across government,
industry, and academia.

Maximize Data Quality
The NEHI agencies recognize the complexity of experimental design for EHS research and the importanceof NNI agency support for several critical issues faced by the research community.
Physico-chemical characterization of nanomaterials is critical to understanding the property–structure–
biological activity relationships. The NEHI Working Group strongly recommends that the EHS funding
agencies support minimal characterization requirements. Several scientific communities, such as ISO(http://www.iso.org), the MinChar community of practice (http://characterizationmatters.org), and OECD
(http://www.oecd.org) have developed lists of physical and chemical properties that are necessary tointerpret the toxicological impacts of nanomaterials and to distinguish which characteristics contributeto biological response.
Developing reliable and reproducible EHS data has proven challenging. The NEHI Working Group supports the development of standard methods and techniques with established reliability and reproducibility, and research needs in this strategy reflect this commitment (see also Chapter 7, Informatics andModeling for EHS Research).
The NNI agencies are critically aware of the importance of alternative test methods to reduce or eliminate
the use of animals in research and support the development of alternatives to conventional testing.
While the research needs outlined in this strategy primarily employ in vitro assays and promote thedevelopment of high-throughput screening methods as well as modeling and simulation, animals are
currently necessary to extrapolate biological response and potential risk from in vitro assays to human
response. The NNI agencies promote the reduction of animal use in research by requiring researchers
to follow the guidelines established by their Animal Care and Use Committees.

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Stratify Knowledge for Risk Assessment
Environmental, health, and safety–related decisions rely on risk assessment tiers ranging from relatively
qualitative to relatively quantitative assessments. Each requires different levels of knowledge for the
exposure and hazard identification components of risk assessment analysis. Such tiered approaches
are known for many applications such as consumer products, pesticides, chemicals, and occupationalsafety. For example, a more qualitative approach to managing risks in the workplace is known as control
banding. In control banding, exposure levels are assessed qualitatively, hazards are assigned into hazard
bands, and a limited number of risk mitigating approaches are used. In a more quantitative approach tooccupational risk management, personal exposure levels are measured in the workplace, and risk mitigation measures are implemented to bring those levels below occupational exposure limits according
to a hierarchy of controls. An understanding of the data and modeling needs for both qualitative andquantitative risk assessments will focus the research to achieve these different knowledge thresholds
and to support the development of tiered risk management tools.

Partner to Achieve the NNI EHS Research Goals
The NNI agencies will leverage public–private partnerships with industries, nonprofit foundations, anduniversities to develop the data for nanoEHS knowledge thresholds. These partnerships should include,
where appropriate, joint research solicitations involving nongovernmental organizations and industry.
Additionally, NNI member agencies will continue to identify research questions that address the mission
and needs of multiple agencies and explore mechanisms to issue interagency joint research solicitations.
The NNI Nanotechnology Signature Initiatives (http://www.nano.gov/initiatives/government/signature)are examples of such scientific and investment collaborations.

Engage Internationally
The societal challenges for which nanotechnology may provide solutions are global, and as such, provide
opportunities for transparent, inclusive, and international collaboration. Of immediate concern to all
countries are the potential implications of exposure to nanomaterials and nanotechnology-enabled
products for the environment and human health. International engagement is a priority of the NNI, acritical component of this EHS Research Strategy, and recognized by NNI advisory bodies and external
stakeholders as essential to harmonize EHS methods and generate data critical for risk assessment andrisk management. NNI member agencies engage internationally by:r

Collaborating on nanotechnology-related EHS research via bilateral and multilateral scienceand technology agreements, memoranda of understanding, and joint grant solicitations that
advance common scientific understandingr

Fostering conditions that favor the responsible transfer of nanotechnologies into products forcommercial and public benefit through consensus-based deliberations with other countries,
industry, academia, nongovernmental organizations, and treaty-based organizations regarding
regulation, trade, and standards developmentrSupporting capacity building with our global neighbors, and in particular with developing
countries and economies in transition, to ensure that comprehensive information and bestpractices are available to cultivate awareness of the benefits and risks of nanotechnologies
and nanomaterials+

88 +8 . T H E PAT H F O RWA R D

Appendix B provides specific examples of NNI agency international activities in each of these three areas.

Linking EHS Research Needs and Goals to the NNI Strategic Plan
As stated in the 2011 NNI Strategic Plan and the introduction to this document, responsible developmentof nanotechnology (Goal 4) is central to the advancement of the NNI’s goals: a world-class R&D program(Goal 1), an educated workforce and public and the supporting infrastructure and tools to advancenanotechnology (Goal 3), and all aspects of nanomanufacturing and product commercialization (Goal2). The NNI EHS Research Strategy incorporates many concepts outlined in these three NNI goals, but
it is most specifically linked to the Goal 4 and its related objectives. Table 8-1 provides an overview of
the alignment and integration between the NNI Strategic Plan goals and objectives and those of the
NNI EHS Research Strategy.
Table 8-1. Alignment between Goals/Objectives of the NNI Strategic Plan and the
NNI EHS Research Strategy
Source: NNI Strategic Plan 2011 (NSTC/NSET, Washington, DC, 2011), pp. 23-32.
NNI Strategic Plan Objective
4.1.1.1:
Incorporate safety evaluation of
nanomaterials into the productlife cycle, foster responsible development, and, where appropriate,sustainability across the nanotechnology innovation pipeline,
by developing and applying
measurement and screening tools(defined as protocols, standards,
models, data, and instruments) toassess the physico-chemical properties of nanomaterials and their
biological effects in the environment and on human health andto quantify exposure across thenanotechnology productlife cycle.

NNI EHS Research Strategy Goals:

Explanation of the Relationship:t NMI: Develop measurement tools
to detect engineered nanoscalematerials in relevant media andin products and relevant matrices
and determine their physicochemical properties throughout
all stages of their life cycles.

The NNI EHS Research Strategy goals
and research needs map directly onto
NNI Strategic Plan (SP) objective 4.1.1.1.
The Nanomaterial Measurement
Infrastructure (NMI) goals direct
development of measurement tools todetermine the physico-chemical properties of ENMs in relevant media and in
NEP and for the biological response
across the ENM and NEP life cycles.
The NMI research needs specify thetypes of assays and measurement tools
necessary to achieve the NMI goals, andthe resulting tools are applied in thehuman exposure assessment, humanhealth, and environment categories tomake the quantitative measurementsof exposure and biological effect.
Quantitative measures of exposure
are also consistent with the human
exposure assessment goal to identify,
characterize, and quantify exposuresof workers, the general public, andconsumers to nanomaterials.

t NMI: Develop measurement tools
for determination of biologicalresponse, and to enable assessment of hazards and exposurefor humans and the environment
from engineered nanomaterials and nanotechnology-based
products throughout all stages of
their life cyclest Human Health: Understand therelationship of physico-chemical properties of engineered
nanoscale materials to in vivo
physico-chemical properties andbiological response.
t Human Exposure: Identify
potential sources, characterize theexposure scenarios, and quantify
actual exposures of workers, thegeneral public and consumers tonanomaterials.
t Environment: Understand theenvironmental fate, exposure, andecological effects of engineered
nanomaterials.

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N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

NNI Strategic Plan Objective
4.1.1.2:
Incorporate safety evaluation of
nanomaterials into the productlife cycle, foster responsible development, and, where appropriate,sustainability across the nanotechnology innovation pipeline,
by developing and applying
models, including risk assessment models, to assess safety ofnanomaterials throughout the life
cycle of the material or product.

EHS Research Strategy Goals:t Human Health: Develop highconfidence predictive models ofin vivo biological responses andcausal physico-chemical properties of ENMs.
t Human Health: Understand therelationship of physico-chemical properties of engineered
nanoscale materials to in vivo
physico-chemical properties andbiological response.
t Human Exposure: Characterize
and identify the health outcomesamong exposed populations todetermine benchmark levels of
exposurest Risk Assessment & Risk
Management Methods: Increaseavailable information for better
decision-making in assessing andmanaging risks from nanomaterials, including using comparativerisk assessment and decision
analysis, life cycle considerations
and additional perspectives suchas ELSI considerations, stakeholders’ values, additional decision
makers’ considerations, among
others+90 +Explanation: This SP objective
integrates research derived from severalof the EHS research needs. Models thatpredict biological response will requireprecise data that describe the relationship of physico-chemical properties
of ENMs to biological response in aproperty/structure-activity relationship.
Models of exposure by port-of-entry
tissue will derive from Human Exposure
Assessment exposure measurement
scenarios and Human Health research
on uptake by port-of-entry tissues.
These activity and exposure models
also support the objectives outlined in
SP Goals 1 and 2 as property/structureactivity relationships will inform
nanomaterials R&D as well as technology transfer and product development.
Risk assessment models will incorporate
life cycle considerations and relevantrisk characterization information,
hazard identification, exposure science,and risk modeling and methods into
the development and evaluation of risk
assessment models and management
methods. Resulting data will meet the
Risk Assessment and Risk Management
Methods goal to increase available
information for better decision-making
and risk management, as well as the
SP objective to develop risk assessment
models.

8 . T H E PAT H F O RWA R D

NNI Strategic Plan Objective
4.1.1.3:
Incorporate safety evaluation of
nanomaterials into the productlife cycle, foster responsible development, and, where appropriate,sustainability across the nanotechnology innovation pipeline,
by developing and applying
health surveillance models as
appropriate for the nanotechnology workforce, consumers,
susceptible populations, and theenvironment.

NNI EHS Research Strategy Goal:t Human Exposure: Characterize
and identify the health outcomesamong exposed populations todetermine benchmark levels of
exposures
NNI EHS Research Strategy Needs:t Human Exposure #1: Understandprocesses and factors that determine exposures to NMst Human Exposure #2: Identify
population groups exposed to
ENMst Human Exposure #3: Characterize
individual exposures to ENMst Human Exposure #4: Conduct
health surveillance of exposed
populationst Human Health #4: Understandrelationship between ENM
physico-chemical properties anduptaket Human Health #6: Determine
the extent to which life stage
and/or susceptibility factors
modulate health effects fromexposure to ENMs, NEPs, and theirapplications.

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Explanation: The Human Exposure
Assessment goal and research needs tosupport characterization and identification of health outcomes among
exposed populations will provide data
to determine benchmark levels forhuman exposure. The Human Healthresearch needs investigating mechanisms of uptake and biological response
also contribute to the understanding of
the human health outcomes that might
be measured.

N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

NNI Strategic Plan Objective
4.1.2:NNI EHS Research Strategy
Components and Concepts:

Incorporate safety evaluation of
nanomaterials into the productlife cycle, foster responsible development, and, where appropriate,sustainability across the nanotechnology innovation pipeline,
by creating mechanisms forappropriate and timely information sharing and dissemination
among stakeholders, including
academia, industry, legal entities,
Federal agencies, regulatorycommunities, governments, thegeneral public, and other relevant
stakeholders.

t Informatics Needs for EHS
Researcht The Path Forward: Stratifying
Knowledge for Risk Assessmentt The Path Forward: Disseminationof Knowledge

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Explanation: The SP objective will
create mechanisms for appropriate
and timely research data information
sharing and dissemination among
stakeholders. A robust nanotechnology
knowledge infrastructure will improveresearch outcomes, reduce costs,
increase the availability of resources,
and promote broader collaboration
among a wider range of practitioners
and stakeholders. This will be achieved,in part, through the organization andcollation of available information on
nanomaterial properties, hazards, andexposures, and the dissemination ofdata and ENM property/structure-activity models through publicly accessible
nanotechnology websites. This knowledge infrastructure will also support
the NNI Strategic Plan goals to advancea world-class R&D program and tofoster the transfer of new technologies into products for commercial andpublic benefit. Additionally, the NNI EHS
Research Strategy includes discussionof knowledge thresholds to understanddata and modeling needs for qualitativeand quantitative risk assessments anddissemination of knowledge throughtraditional and newer electronic media.
It should be noted that disseminationof knowledge in this document includes
sharing of safety and hazard information with industry and the general public as well as the scientific community.

8 . T H E PAT H F O RWA R D

NNI Strategic Plan Objective
4.2:
Develop tools and proceduresfor domestic and international
outreach and engagement toassist stakeholders in developing
best practices for communicating
and managing risk.

NNI EHS Research Strategy Goal:t Risk Assessment & Risk
Management Methods: Increaseavailable information for better
decision-making in assessing andmanaging risks from nanomaterials including using comparativerisk assessment and decision
analysis, life cycle considerations
and additional perspectives suchas ELSI considerations, stakeholders’ values, additional decision
makers’ considerations, among
others.
NNI EHS Research Strategy Need:t Risk Assessment & Risk
Management Methods #3:
Integrate and standardize risk
communication within the risk
management framework

Explanation: SP objective 4.2 continues the theme of public engagement.
This theme falls within the scope of the
NNI EHS Research Strategy and aligns
with the risk communication goal as
expressed in the Risk Assessment andRisk Management Methods researchneeds. Specifically, this goal will increase
and integrate available information forassessing and managing risks. The addition of life cycle and ELSI considerations,stakeholders’ values, and additional
decision makers’ perspectives will
ground the risk communication in theneeds of the stakeholders. The Risk
Assessment and Risk Management
Methods research needs direct thedevelopment of processes and information to achieve this objective.

NNI EHS Research Strategy
Concept:t International Engagement
NNI Strategic Plan Objective
4.3.1:
Identify and manage the ethical,
legal and social implications (ELSI)of research leading to nanotechnology-enabled products
and processes, by increasing thecapacity of Federal agencies
to identify andBEESFTT&-4*
issues specific toOBOPUFDIOPMPHZ
by fostering theEFWFMPQNFOUPG
a community ofFYQFSUJTFPO&-4*
issues related toOBOPUFDIOPMPHZ
and by providingBDVSSFOUSFTPVSDF
list of expertsUIBUJTBDDFTTJCMFUP
a broad rangePGVTFSTNNI EHS Research Strategy Goal:t Risk Assessment & Risk
Management Methods: Increaseavailable information for better
decision-making in assessing andmanaging risks from nanomaterials including using comparativerisk assessment and decision
analysis, life cycle considerations
and additional perspectives suchas ELSI, stakeholders’ values,
additional decision makers’
considerations, among others.

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Explanation: The Risk Assessment andRisk Management Methods goal—to
increase available information forassessing and managing risk—again
provides the bridge between the SP
objective and the EHS research needs.
ELSI considerations, as described
previously in this document, provide
a perspective that guides decisions
about types of research needed and risk
analysis and management decisions.
ELSI is presented in this strategy as an
overarching theme and ties directly
to research in the Human Exposure
Assessment, Human Health, andEnvironment chapters and this SP
objective.

N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

Implementation and Coordination of the NNI EHS Research Strategy
This interagency strategy document will guide programs and investment decisions by the individual
agencies as well as in coordinated interagency activities in the coming years. It should be noted that theagencies have varied missions, and their individual priorities may differ in scope and focus from thoseoutlined in this report. For these reasons, continuous coordination is essential, and agencies will workthrough the NSET Subcommittee, its NEHI Working Group, and the NNCO Coordinator for EHS (described
below), to ensure the integration of agency implementation plans.
The NNI, as a program, does not fund research; rather, its funding is the sum of nanotechnology-related
funding allocated by each of the participating agencies. Through its member agencies, the NNI informs
and influences the Federal budget and planning processes. Annual funding by each agency for researchin the EHS program component area since FY 2006 is identified in Table 8-2.
Table 8-2. Agency Investments for NanoEHS Research(in millions of dollars; totals may not add due to rounding*)
Chartered NEHI
Agencies

Actual
FY 2006

FY 2007

FY 2008

FY 2009

FY 2009ARRA

FY 2010

NSF

21.0

26.9

29.2

26.8

3.4

27.1

DOD

1.0

3.8

4.1

DOE

0.5

2.6

3.1

0.2

2.6

DHHS (NIH)

5.2

7.7

11.9

12.0

8.4

20.0

DOC (NIST)

2.4

0.9

1.3

3.5

3.4

EPA

3.7

7.1

11.6

11.1

17.1

USDA (CSREES/NIFA)

0.1

0.1

0.6

0.5

3.7

USDA (FS)

0.0

0.0

0.0

0.0

0.0

DHHS (NIOSH)

3.8

5.6

6.9

6.7

8.5

DHHS (FDA)

6.5

7.3

CPSC

0.2

0.5

TOTAL

37.7

48.3

67.9

74.5

0.0

12.0

90.2

* USDA (FS) did not allocate funding for EHS during FY 2006-FY 2010; DHHS (FDA) and CPSC began allocating EHS
funding in FY 2009.

The framework for implementation of the NNI EHS Research Strategy outlined below describes thevarious activities and coordination that are needed to address the full spectrum of NNI EHS research. It
also provides for participation, interaction, and partnership with non-Federal stakeholders to leverage
efforts and to expedite progress. A tabulation of domestic and international interagency activities thatpertain to this framework is found in Appendix B.
r

Increase agency participation in NNI EHS research. Two NNI/NEHI agencies have developed
research programs and now contribute to the NNI budget crosscut.
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CPSC is meeting identified data needs by supporting interagency collaborations thatdevelop testing methods to adequately address product safety.

−

FDA is supporting agency priorities, including laboratory and product testing capacity,
scientific staff training and development, and collaborative and interdisciplinary research
to address product characterization and safety.

r

Name NNCO EHS Coordinator. Consistent with the PCAST recommendation, OSTP has
named an NNCO Coordinator for EHS to assist agencies in integrating research across thenanoEHS continuum to achieve the objectives presented in the NNI 2011 Strategic Plan. The
new NNCO EHS Coordinator serves on the NSET/NEHI leadership team; leads the NNCO andNSET Subcommittee’s efforts in identifying and leveraging research collaborations domesticallyand internationally; serves as the NNI point of contact for stakeholders with nanoEHS concerns;
and spearheads the NNI EHS Research Strategy’s implementation, coordination, and evaluation.

r

Refocus NEHI. Through consultation with agency representatives, the leadership of the
NEHI Working Group adapted its meeting format to ensure better coordination of research toachieve the goals of the NNI EHS Research Strategy. Four priority areas were identified: ongoing
updates on agency nanoEHS activities; new opportunities for collaboration; research strategy
implementation, coordination, and evaluation; and planning and outreach.

r

Expand media and networking opportunities. NEHI is exploring new social media opportunities to improve interagency communication and stakeholder interactions by:r−

Establishing (Spring 2011) an internal collaborative workspace for NEHI to improve interagency communication and information sharing.

−

Exploiting the new nano.gov website to provide NEHI with opportunities to engage in direct
dialogue with academia, industry, nongovernmental organizations, state and regional entities, and other stakeholders through the use of new social media tools (e.g., blogs, tweets,
and webinars).

−

Exploring opportunities to host webinars 2–3 times a year, to engage stakeholders in discussions on the status of nanotechnology and nanoEHS research, to address stakeholder
concerns, and to exchange information and ideas.

Enable a broad base of nanoEHS research to support regulatory decision making. The NNI
EHS Research Strategy fundamentally depends on sustaining the broad spectrum of basic andapplied research, with support from agencies that investigate the fundamental properties ofnanomaterials and directly apply research for responsible development (including NSF, DOE,
NIST, NIH, and NIOSH). This research effort will support regulatory decision making based on
the best available science. For example, the NIH/NIEHS Centers for Nanotechnology Health
Implications Research are designed to more precisely link the physical and chemical propertiesof nanomaterials to the human biological response and to translate the methods used for thisanalysis into an expanded, nanomaterials-specific risk assessment paradigm.

+

95 +

N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G YrCoordinate existing, and foster expanded, agency efforts to address priority EHS researchneeds and identified gaps. The NEHI Working Group will continue to facilitate coordinationand increased collaboration among the NNI agencies’ research programs by:−

Clarifying priorities and areas of focus to pursue, through collaboration, monthly NEHI
Working Group meetings, and workshops.

−

Identifying synergistic opportunities through annual webinars, workshops, and othermechanisms for information exchange to assess the state of science and current research,and to reassess areas of weakness and gaps.

−

Facilitating development of joint programs among NNI member agencies to fund nanoEHS
research of mutual interest and avoid unproductive redundancy. The Nanotechnology
Signature Initiatives offer NEHI a new mechanism through which to organize and leverageinteragency efforts (http://www.nano.gov/initiatives/government/signature).

r

Facilitate partnerships with industry. The NEHI Working Group will continue to utilize existingFederal Small Business Innovation Research (SBIR)/Small Business Technology Transfer Research(STTR) programs and explore and develop new mechanisms for NNI agencies to partner withindustry. The SBIR/STTR programs support translational research by assisting researchers andsmall businessmen to move research ideas from the laboratory to prototype to commercialization of nanomaterials and nanotechnology enabled products. New programs could support
industry–public partners–agency collaborations on EHS research.

r

Coordinate efforts internationally. Several NNI agencies participate in international efforts
related to EHS research. The OECD Working Party on Manufactured Nanomaterials (WPMN) is
a program to develop internationally accepted nanoEHS research priorities, testing protocols,and predictive tools. ISO and ASTM International are actively developing international standards, nomenclature, and terminology. Additionally, the NEHI Working Group is coordinating a
European Union–United States workshop to bring together EHS scientists, risk assessors, regulators, policy experts, and stakeholders to assess EHS data needs and identify points of contact,
shared research interests, and mechanisms for collaboration. The working group anticipates anannual meeting with international partners.

r

Adaptively manage the NNI EHS Research Strategy. The NEHI Working Group will continue
the adaptive management process that was utilized in the production of this EHS Research
Strategy by conducting periodic progress reviews of Federally funded and international research,
the status of the science, and stakeholder concerns. These reviews will, in turn, provide theinformation necessary to update the research needs and priorities to maintain a dynamic andcurrent NNI EHS Research Strategy.

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8 . T H E PAT H F O RWA R D

Dissemination of Knowledge
Nanotechnology is a multidisciplinary field, requiring the engagement of scientists in disciplines asdiverse as materials science, physics, biology, chemistry, engineering, toxicology, clinical practice, social
science, and risk assessment, as well as leaders in industry, public health advocacy, healthcare, and thegeneral public. To share information among these diverse groups, it is necessary to develop and maintaindata communication infrastructures and organizations. Essential steps include identifying what information is required, who needs the information, how the information should be furnished, and when andwhere. Therefore, the NNI agencies engage in:r

Scientific meetings, workshops, and summits at the local, state, national, and international levelsrDirect communication with stakeholders and research communitiesr

Participation in international standards organizationsr

New media outreach through websites, webcasts, blogs, etc.

r

Creation of data repositories for scientific results

As part of its 2011 revision of the NNI EHS Research Strategy, NNI proposes:rContinuing engagement in traditional scientific forumsr

Building on new-media efforts to engage more stakeholders, for example, in developing prevention strategies, good handling practices, and regulatory standardsrExpanding work in data storage and management (see Section 7, Informatics and Modelingfor NanoEHS Research)r

Creating public engagement events to share information on safety research and efforts tomaximize societal benefits from nanotechnology while minimizing risks. This includes outreachto the general public. Such outreach may be particularly important in considering ethical, legal,
and societal implications of nanotechnology and for risk management and risk mitigation issues.

Conclusion
The vision of this 2011 National Nanotechnology Initiative EHS Research Strategy—a future in which
nanotechnology provides maximum benefit to the environment and to human social and economic
well-being—is a national priority with intense and sustained Federal effort. It complements the NNIStrategic Plan and is critical to achieving many of its objectives. The multicomponent risk management research framework that forms the foundation of this strategy will require focused and sustained
coordination by the NNI agencies and regular review by the agencies and by stakeholders. The Federal
agencies have an essential role to play in defining and coordinating these activities because of the broad
economic, national security, and public health and environmental impacts of nanotechnology andbecause of the diverse science and engineering fields that are needed for its success. The NNI agencies
have a proven track record of working together and will continue to refine mechanisms of collaboration.
Stakeholders have an essential role to play as the researchers, workers, and consumers directly involvedin the development, manufacture, use, and recycling of ENMs and NEPs. As we move forward to achieve
the NNI EHS research goals, agencies, in partnership with stakeholders, accept this responsibility todevelop ENMs and NEPs that maximize benefit and minimize risk to public health and the environment.
+

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1. NNI Environmental, Health, and Safety Research Needs for Engineered Nanoscale Materials(NSTC/NSET, Washington, DC, 2006; http://nano.gov/NNI_EHS_research_needs.pdf ).
2. NNI Prioritization of Environmental, Health, and Safety Research Needs for Engineered
Nanoscale Materials (NSTC/NSET, Washington, DC, 2007;
http://nano.gov/Prioritization_EHS_Research_Needs_Engineered_Nanoscale_Materials.pdf ).
3. NNI Strategy for Nanotechnology-Related Environmental, Safety, and Health Research (NSTC/NSET,
Washington, DC, 2008; http://nano.gov/NNI_EHS_Research_Strategy.pdf ).
4. Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety
Research (National Academies Press, Washington, DC, 2009;http://download.nap.edu/cart/deliver.cgi?record_id=12559).
5. Report to the President and Congress on the Third Assessment of the National Nanotechnology
Initiative (PCAST, Washington, DC, 2010;
http://whitehouse.gov/sites/default/files/microsites/ostp/pcast-nni-report.pdf ).

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Appendix B. International andDomestic Cooperative Activities
International Cooperative Activities
Coordination: The Global Issues in Nanotechnology (GIN) Working Group under the NSET Subcommittee,
with leadership from the U.S. State Department and White House Office of Science & Technology Policy,
coordinates the National Nanotechnology Initiative (NNI) international activities in nanotechnology,
monitors foreign nanotechnology programs, promotes the trade and commercial interests of the UnitedStates, and seeks to broaden international cooperation and communications regarding nanotechnology
R&D. The working group includes representatives from Federal agencies that have active nanotechnology R&D programs, as well as from numerous agencies that have oversight roles in international
affairs. In keeping with the NNI goal of establishing a framework for the safe, secure, and responsible
development of nanotechnology worldwide, international cooperation is important to ensuring thatenvironmental, health, and safety concerns are appropriately addressed by the global scientific community and relevant regulatory agencies.
Activities: Because of their cross-cutting nature, nanotechnology-related efforts within the Organisation
for Economic Cooperation and Development (OECD) are especially significant when evaluating international nanotechnology activities. The United States has played critical leadership roles in both
the OECD Working Party on Manufactured Nanomaterials (WPMN) and the OECD Working Party on
Nanotechnology (WPN), as noted in Box 1.
Box 1. Nanotechnology Activities within the Organisation for
Economic Cooperation and Development
OECD Working Party on Nanotechnology (WPN): The WPN is a forum to advise on emerging policy issues inscience, technology, and innovation related to the responsible development and use of nanotechnology. It is
the premiere multilateral forum that brings governments together to discuss and create policy perspectives
relating to nanotechnology. The U.S. Department of State was the founding chair of the WPN, and continues
to play a critical leadership role on the WPN Bureau. In the current work program, the U.S. FDA is leading aneffort to inventory regulatory frameworks for nanotechnology in food and medical products. Additional
efforts are planned in areas such as business environments and green growth (http://www.oecd.org/sti/nano).
OECD Working Party on Manufactured Nanomaterials (WPMN): The WPMN is leading an international effort
by the OECD member nations and other nonmember nations and organizations to coordinate and collaborate
on approaches for better understanding the environmental, health, and safety impacts and the benefits ofnanotechnology. In 2008, the WPMN embarked on a cooperative international program to conduct testingon 14 nanomaterials types across 59 environmental endpoints. EPA is leading the U.S. effort to sponsor thetesting of many of these materials. NIOSH continues its leadership role in the OECD WPMN steering groupon Cooperation on Exposure Measurement and Exposure Mitigation (http://www.oecd.org/env/nanosafety).

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Activities by NNI member agencies in support of international engagement are summarized in the following three sections: (1) International collaboration in science, technology, and innovation; (2) Fostering
conditions that favor the responsible transfer of nanotechnologies into products for commercial andpublic benefit; and (3) Capacity building with our global neighbors. Tables B1-B3 highlight examples
of supporting activities in each of these areas, with an emphasis on efforts drawn from multiple NNImember agencies. Coordinated activities between NNI agencies and other institutions are reported on
an annual basis in the NNI Supplement to the President’s Budget (available at http://www.nano.gov).

International Collaboration in Science, Technology, and Innovation
The U.S. values robust, rewarding partnerships with other nations that advance our common interestin nanotechnology science, technology, and innovation as well as the responsible development of
nanotechnology. Cooperation under the auspices of bilateral and multilateral science & technology
agreements and memoranda of understanding is an effective mechanism to achieve these goals andshould continue to be pursued. The Federal Government also encourages collaborative research acrossthe international community, for example, by issuing joint grant solicitations between U.S. agencies
and other nations.

International Collaboration on nanoEHS Research
Table B-1. Examples of Activities Supporting International Collaboration in Nanotechnology
FederalAgency(ies)

Partner(s)Activity Description

EPA

United Kingdom Joint funding of research “e-consortia” teams each at $2
million for 4 years.

Type of Activity

Joint research funding
opportunity

EPA, NSF, NIH/ European
NIEHS, NIOSH, Commission
USDA/NIFA

An interagency solicitation with EPA (lead), NSF, NIH/NIEHS,
NIOSH, and USDA/NIFA in coordination with the EC, focuses
on exposure and safety research data for engineered
nanomaterials.

Joint research funding
opportunity

EPA, NSF,
USDA/NIFA

EuropeanCommission

Joint solicitation with EC: “Increasing Scientific Data on theFate, Transport, and Behavior of Engineered Nanomaterials
in Selected Environmental and Biological Matrices”; total
U.S. award est. $4.2 million.

Joint research funding
opportunity

NIH/NCI, NIH/
NIEHS

ChineseAcademy of
Sciences

First Joint U.S. - China Symposium on Nanobiology andNanomedicine in Beijing, October 20-22, 2008; followed up
in Washington, DC in September 16-18, 2010. Exchanged
research experiences, considered possible collaborations.

Symposium; information sharing

NIH/NCI, NIH/
NIEHS

India

1st Indo-U.S. Cancer Nanotechnology Symposium in New
Delhi, Feb 4-6, 2009 brought together NCI researchers with
Indian cancer researchers.

Symposium; information sharing+ 101 +

N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

DOE, NIH,
NIOSH, State
Dept., Exec
Office of the
President,
NSF

RussiaU.S. - Russia Bilateral Presidential Commission(http://www.state.gov/p/eur/rls/fs/130616.htm);
Nanotechnology sub working group under the Science& Technology Working Group is covering Energy andEnvironmental, Health, and Safety R&D.

Research &Development; information sharing

NIH

RussiaU.S.-Russia Biomedical Forum, August 20-21, 2009 held
at NIH on the topic of: “New Directions in Prostate Cancer
Chemotherapy: Natural Products, Synthetic Compounds,
Nanomedicinal Chemistry”

Symposium; information sharing

NIOSH, NIST,
CDC, NIH/NCI

International
Alliance for
NanoEHS
Harmonization(IANH)

IANH coordinates round robin testing of nanomaterials.
It is a peer-group of scientists from around the world thatvoluntarily collaborate on the questions of reproducibility
and standards in the arena of nanobiology and nanosafety.

Research &Development; testing
protocols

NNI agencies(State Dept.
lead)

EU

U.S.-EU Joint Committee Meeting, May 11-12, 2010 brought Research &Development; Policy
together the NNCO director and agency representatives
Coordination
to discuss opportunities and barriers to collaboration. As
a result of discussions that took place in this venue, bothparties proceeded to plan a joint research meeting slated forMarch 2011.

USDA/NIFA,
DOE

CanadaFollowing the successful joint grantees’ meeting with
Canada’s Advanced Food and Materials Network (AFMNet)
held in conjunction with the DOE CINT nanotechnology
user conference in September 2009, USDA/NIFA is planning
for a nanotechnology grantee’s meeting with AFMNet andCanada’s National Institute for Nanotechnology.

Nanomaterial
Measurement
Infrastructure

Symposium

Foster conditions that favor the responsible transfer of nanotechnologies into products forcommercial and public benefit
There is a fundamental shared desire among the U.S. Government agencies for regulation that ensuressafety but does not unjustifiably inhibit innovation, stigmatize new nanotechnologies, or create tradebarriers. The U.S. approach to nanotechnology-related regulation, trade, and standards development
is developed and disseminated through regulatory discussions across the Federal Government withexisting groups and with key international trading partners. Another important component to achieving
favorable nanotechnology transfer is a sustained commitment to voluntary consensus-based standards
development such as globally harmonized data collection, data reporting, and voluntary risk management schemes.

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A P P E N D I X B . I N T E R NAT I O NA L A N D D O M E S T I C CO O P E R AT I V E AC T I V I T I E STable B-2. Examples of Activities Supporting the Responsible Transfer ofNanotechnology into ProductsFederalAgency(ies)

Partner(s)NNI agenciesEUand other USG
agencies (State
Dept., DOC,
and EOP leads)

Activity Description

Type of
ActivityStandards /Transatlantic Economic Council (TEC)
Regulatory /was established in April 2007 under the
Trade
Framework for Advancing Transatlantic
Economic Integration between the U.S. andthe European Union. Activities under the TEC
include: (1) Innovation Action Partnership(http://www.state.gov/p/eur/rt/eu/tec/c34871.htm);(2) High Level Regulatory Cooperation Forum.

EHS Research
Category
Risk Assessment& RiskManagement
Methods

DOD, DOE,
EPA, NIOSH,
NIH/NCI, NIST,
USDA/FS,
USDA/FAS,State Dept.,
DOC, FDA, EOPInternational
Organisation forStandardization(ISO) TC 229

ISO Technical Committee 229 (TC229,
Nanotechnologies) is working to develop
standards in nanotechnology through the U.S.
Technical Advisory Group, which is coordinated by
the American National Standards Institute. ISO has
159 member nations.

Standards
development

Nanomaterial
Measurement
Infrastructure

NIST, EPA, NIH/
NCI, DOD,
NIOSH, FDA

ASTMInternational

ASTM International Technical Committee
E56 (Nanotechnology) develops standards innanotechnology.

Standards
development

Nanomaterial
Measurement
Infrastructure

NIST

International
ElectrotechnicalCommission(IEC)

IEC Technical Committee 113 (Nanotechnology
Standardization for Electrical and Electronics
Products and Systems) develops standards innanotechnology.

Standards
development

Nanomaterial
Measurement
Infrastructure

NIST

Versailles
Project on
Advanced
Materials andStandards(VAMAS)

VAMAS Technical Working Area 34 (Nanoparticle
Standards
Populations Working Group) develops international development
consensus measurement methods.

Nanomaterial
Measurement
Infrastructure

NIST, NIH/NCI

IEEE develops standards in nanotechnology.
Institute ofElectrical andElectronics
Engineers (IEEE)

Standards
development

Nanomaterial
Measurement
Infrastructure

DHS, DOC,
DOD, DOE,
DOT, EOP, EPA,
FDA, OSHA,
USDA, andother agencies

n/aEmerging Technologies Interagency Policy
Coordination Committee (est. 3/2010) is ahigh-level policy group that is anticipated tomake decisions that create and coordinate U.S.
Government - wide policies relating to the safe useof nanotechnology.

Standards/
Regulatory(Policy
coordination)

Risk Assessment& RiskManagement
Methods

NSTC Subcommittee on Standards (est. 4/2010),
co-chaired by NIST and DOJ. This Federal groupfocuses on standards used in support of regulations, procurement, or grant guidance.

Standardsrelated policy
guidance

Targeting and
Accelerating
Researchn/a
CPSC, DHHS,
DHS, DOEd,
DOE, DOJ, State
Dept., DOT,
DoTreas, EPA,
EOP, ITA,ITC,
NASA, NIST,
NSF, USPTO,
and otheragencies+ 103 +

N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

Engage in Capacity Building with our Global Neighbors
The U.S. continues to engage internationally, and with developing countries and economies in transitionin particular, to ensure a balance of the potential benefits and risks of nanotechnologies and nanomaterials. These countries may encounter issues such as inequity, disparate access to safe workplaceenvironments, and an overall dearth of comprehensive information to inform decisions. U.S. participation in international organizations that focus on these issues can facilitate this capacity building. Bestpractices in environmental, health, and safety protocols and approaches (i.e., workplace safety, exposure
assessment, toxicity testing, public engagement, risk assessment, etc.) continue to be identified anddisseminated.
Table B-3. Example Activities Supporting Capacity Building
FederalAgency(ies)

Partner(s)Activity Description

Type of
Activity

NIOSH

International
Council on
Nanotechnology(ICON)ICON’s “Nano Good Practices Wiki”: NIOSH continues toparticipate in the Wiki at http://www.goodnanoguide.org,
a collaboration platform designed to enhance the ability ofexperts to exchange ideas on how best to handle nanomaterials in an occupational setting. Beta sponsors include anumber of Canadian organizations along with ICON and
NIOSH.

Capacity Building;
Information
sharing

NIOSH

World HealthOrganization(WHO)

WHO collaborating centers: NIOSH continues developing
and disseminating best practices globally for working withnanomaterials.

Policy coordination, risk
management

DOS, EPAUNEP / Strategic
Approach toInternational
ChemicalsManagement(SAICM)SAICM supports the achievement of the goal agreed toat the 2002 Johannesburg World Summit on Sustainable
Development of ensuring that, by the year 2020, chemicals
are produced and used in ways that minimize significant
adverse impacts on the environment and human health.

Risk Assessment &Risk Management
Methods; Ethical,
Legal and Societal
Implications

USDA, FDA

Food andAgriculture
Organizationof the United
Nations (FAO)and World HealthOrganization(WHO)

FAO/WHO Expert meeting on “the application of nanotechnologies in the food and agriculture sectors: potential
food safety implications,” June 2009 (see report, publishedin 2010, (http://www.who.int/foodsafety/fs_management/
meetings/nano_june09/en/)). U.S. agencies participatedas experts at the meeting, which was intended to provide
information about applications of nanotechnology andpotential food safety implications, formulate a plan of workfor risk assessment, and analyze ongoing communication
efforts for constructive dialogue.

Risk Assessment &Risk Management
Methods; Ethical,
Legal and Societal
Implications+ 104 +

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Domestic Cooperative Activities
Table B-4. Cooperative Activities Among NEHI Agencies
FederalAgency(ies)

Activity Description

Type of
Activity

EHS Research
Categories

CPSC, NIOSH,EPACPSC to establish interagency agreements with NIOSH and EPA to complete
a literature search and develop experimental procedures to quantify releases ofand consumer exposures to nanosilver intreated consumer products.

RiskManagement;
Ethical, Legaland Societal
Implications

Risk Assessment& RiskManagement
Methods

EPA, NSF, NIH/
NIEHS, NIOSH,
DOE

GrantsSince 2004 EPA’s Science to Achieve
Results (STAR) grants program hascoordinated interagency requests forapplications; agencies involved haveincluded NSF, NIEHS, NIOSH, and DOE.
The fourth joint research solicitation by
EPA’s STAR program was issued in 2007.
The solicitation was a collaboration
between EPA, NSF, and DOE; over 130
research proposals were received. EPA
awarded 15 grants, NSF awarded 6, andDOE awarded one and made several
awards to DOE laboratories. Individual
grant awards totaled approx. $9 million.
In addition, EPA recently awarded $2
million to study fate and transport inbiological systems as part of an NIEHS-led
request for applications.

Environment

There are many classes of products where Research
the FDA is currently the only agency
to conduct research for science‐based
safety and/or risk assessments. While theagency can undertake some self‐initiatedresearch, the scale and range of issues
and expertise involved necessitates collaborations with academic and government labs.

Nanomaterial
Measurement
InfrastructureStandards
Workshop on Enabling Standards for
Nanomaterial Characterization to address development
the urgent need to accelerate standards
development at the pre-standards stage.

Nanomaterial
Measurement
Infrastructure

FDA, otheragencies

NIH/NIEHS, NIST,
NIH/NCI, FDA,
NIOSH

NIH/NCI, NIH/
NIEHS, NIH/NIBIB, NIST

Partner(s)Universities

OregonNanoscience andMicrotechnologies
Institute and
ASTM International

NIH/NCI and NIST held a one-day
workshop to establish an International
Collaboration for NanoEHS Informatics
aimed at development a federated
database system.

+ 105 +

Informatics

Human Health
Risk Assessment& RiskManagement
Methods

Informatics

N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

NIH/NIEHS, EPA

University of
Massachusetts

Conference
International Conference on theEnvironmental Implications andApplications of Nanotechnology, the aimof which was to provide a valuable forum
for scientists, regulators, and policymakers from academia, government, andindustry to interact and share new knowledge on the health and environmental
impacts of nanotechnology, green
nanotechnology, and new environmental
applications, and to help direct future
research and regulatory needs.

Human Health
Environment
Risk Assessment& RiskManagement
Methods

NIOSH, NIST, EPA,NIEHS, FDA andall other NEHI
agencies

NNI 2009-2011 NanoEHS series of four
workshops to provide an open forum
to identify progress, gaps, and barriers
to environmental, health, and safety
research program laid forth in the 2008
NNI EHS Research Strategy.

Workshops

All research
needs

NIOSH, CPSC

Under an interagency agreement
between CPSC and NIOSH, NIOSH
will conduct testing to determine theexposure impact of bathroom spray that
contains engineered nanomaterials .

Research

Risk Assessment& RiskManagement
Methods

NIST, DODNIST and the U.S. Army Corps ofEngineers co-organized a nanosilver
workshop to identify the most pressing
measurements and standards needs,
including the selection of potential formsof nanosilver for international laboratory
studies on nanosilver properties andstability.

Standards
development

Nanomaterial
Measurement
Infrastructure

NIST, CPSCNIST is leading a coordinated research
program with CPSC to determine therelease of nanoparticle flame retardants
from fabrics and foams.

Research

Nanomaterial
Measurement
Infrastructure

These agencies are coordinating thedevelopment of benchmark data,measurement methods, and prototypereference materials for nanosilver forbiomedical applications, including EHS
assessments.

Standards
Development,
Research

NIST, FDA, andEPA+ 106 +

Risk Assessment& RiskManagement
Methods

A P P E N D I X B . I N T E R NAT I O NA L A N D D O M E S T I C CO O P E R AT I V E AC T I V I T I E S

NSF, EPA

GrantsTo ensure that nanotechnology isdeveloped in a responsible manner, NSF
and EPA continue to fund two Centers
for the Environmental Implications ofNanotechnology (CEIN). Led by UCLA andDuke U., the CEINs will study how nanomaterials interact with the environmentand human health, resulting in better risk
assessment and risk mitigation strategies.

+ 107 +All researchneedsAppendix C. Definitions
Nanotechnology is the understanding and control of matter at dimensions between approximately 1
and 100 nanometers, where unique phenomena enable novel applications. Encompassing nanoscalescience, engineering, and technology, nanotechnology involves imaging, measuring, modeling, andmanipulating matter at this length scale. —NNI Strategic Plan, February 2011.

ISO TC 229 Core Terms(ISO/TS 80004-1:2010, available at http://cdb.iso.org/)
Nanoscale is the size range from approximately 1 nm to 100 nm.
Nano-object is a material with one, two, or three external dimensions in the nanoscale.
Nanoparticle or nanoscale particle is a nano-object with all three external dimensions in the nanoscale.
Nanostructured material is a material having internal nanostructure or surface nanostructure.
Nanomaterial or nanoscale material is a material with any external dimension in the nanoscale or having
an internal structure or surface structure in the nanoscale. This generic term is inclusive of nano-object
or nanostructured material.
Engineered nanomaterials are designed for a specific purpose or function.
Manufactured nanomaterial is intentionally produced for commercial purposes to have specific properties or specific composition.
Nanomanufacturing is the intentional synthesis, generation, or control of nanomaterials or fabrication
steps in the nanoscale for commercial purposes.

(ISO/TS 27687:2008, available at http://cdb.iso.org/)
Agglomerate is a collection of weakly bound particles or aggregates or mixtures of the two where theresulting external surface area is similar to the sum of the surface areas of the individual components.
Aggregate is a particle composed of strongly bonded or fused particles where the resulting externalsurface area may be significantly smaller than the sum of calculated surface areas of the individualcomponents.

+ 108 +

Appendix D. Comprehensive Chart of2011 EHS Research Strategy Needs
Table D-1. The Core EHS Research Categories and their Highest-Priority Research Needs (RNs)
Key Research Needs

Subordinate Research Needs

1. Nanomaterial Measurement Infrastructure Research Needs
Develop measurement tools to detect and identify engineered nanoscale materials in products and relevant matrices anddetermine their physico-chemical properties throughout all stages of their life cycles.
Develop measurement tools for determination of biological response and to enable assessment of hazards and exposurefor humans and the environment from engineered nanomaterials and nanotechnology-based products throughout allstages of their life cycles.
RN#1. Develop measurement tools
for determination of physico-chemical
properties of ENMs in relevant media
and during the life cycles of ENMs and
NEPst Physical dimensions and morphology: size, size distribution, characteristic
dimensions, shapet Internal structure: atomic-molecular, core-shellt Surface and interfacial properties: surface charge, zeta potential, surface
structure, elemental composition, surface-bound molecular coatings andconjugates, reactivityt Bulk composition: elemental or molecular composition, crystalline phase(s)t Dispersion properties: degree and state of dispersiont Mobility and other transport properties: diffusivity, transport in biological andenvironmental matrices

RN#2. Develop measurement tools for
detection and monitoring of ENMs inrealistic exposure media and conditions during the life cycles of ENMs
and NEPst Sampling and collection of ENMst Detecting the presence of ENMst Quantity of ENMs—concentration based on surface area, mass, and number
concentrationst Size and size distribution of ENMst Spatial distribution of ENMst Discriminating ENMs from ambient NMs such as combustion products andwelding fumest Discriminating multiple types of ENMs such as metals and metal oxides

RN#3. Develop measurement tools forevaluation of transformations of ENMs
in relevant media and during the life
cycles of ENMs and NEPst Agglomeration and de-agglomerationt Dissolution and solubilityt Adsorption of natural organic matter and bioconstituentst Oxidation and reductiont Deposition of ENMs on surfaces+ 109 +

N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

Key Research Needs

Subordinate Research Needs

RN#4. Develop measurement tools
for evaluation of biological responses
to ENMs and NEPs in relevant media
and during the life cycles of ENMs and
NEPst Adequacy of existing assayst New assays or high-throughput, high content assayst Correlation of biological responses with physico-chemical propertiest Surface reactivity at the interfaces between ENMs and biological receptorst Biomarkers of toxicological response

RN#5: Develop measurement tools
for evaluation of release mechanisms
of ENMs from NEPs in relevant media
and during the life cycles of NEPst Release by fire, combustion, and incinerationt Release by mechanical degradation, such as abrasion, deformation, and impactt Release by dissolution of matrix materialt Release by chemical reactions of the matrix materialt Release by photo-induced degradation of the matrix materialt Release by consumer interactions, such as spraying, mouthing, and swallowingt Release by interactions with biological organisms in the environment

2. Human Exposure Assessment Research Needs
Identify potential sources, characterize the exposure scenarios, and quantify actual exposures of workers, the generalpublic, and consumers to nanomaterials.
Characterize and identify the health outcomes among exposed populations in conjunction with information about thecontrol strategies used and exposures to determine practices that result in safe levels of exposures.
RN#1. Understand processes andfactors that determine exposures tonanomaterialst Conduct studies to understand processes and factors that determine exposure
to engineered nanomaterialst Develop exposure classifications of nanomaterials and processest Develop internationally harmonized and validated protocols for exposure
surveys, sample collection and analysis, and reporting through existing andnewly created international frameworkst Develop comprehensive predictive models for exposures to a broad range ofengineered nanomaterials and processest Characterize process- and task-specific exposure scenarios in the workplace

RN#2. Identify population groups
exposed to engineered nanomaterialst Systematically collect and analyze information about nanomaterial manufacture, processing, and direct use in commercial and consumer products overtime to discern geographic areas where engineered nanomaterials may beemitted into the environment, consumed in the form of ingredients of products,
and/or disposed of in solid waste, wastewater, etc.
t Conduct population-based surveys to obtain information on use patterns for
consumer productst Identify potential subpopulations that are more susceptible to exposure toengineered nanomaterials than otherst Develop quantitative assessment methods appropriate for target populationgroups and conduct assessments of those population groups most likely to be
exposed to engineered nanomaterials+ 110 +

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Key Research Needs

Subordinate Research Needs

RN#3. Characterize individual exposures to nanomaterialst Expand currently available exposure assessment techniques to facilitate moreaccurate exposure assessment for engineered nanomaterials at benchmark
concentration levels using feasible methodst Develop new tools through national and international surveys to support
effective exposure characterization of individualst Characterize and detect nanomaterials in biological matrices and conduct
studies to understand transformations of nanomaterials during transport in
the environment and in human bodiest Conduct studies to examine emissions and human contact during normal use
and after wear and tear have degraded a product, as well as during repeatedexposurest Develop engineered nanomaterials exposure assessment models based on
identified critical exposure descriptorst Develop databases to contain the collected data and information

RN#4. Conduct health surveillance of
exposed populationst Establish a program for the epidemiological investigation of physician casereports and reports of suspicious patterns of adverse eventst Establish exposure registry and medical surveillance programs for workerst Analyze injury and illness reporting in existing programs

3. Human Health Research Needs
Understand the relationship of physico-chemical properties of engineered nanoscale materials to in vivo physico-chemical properties and biological response.
Develop high-confidence predictive models of in vivo biological responses and causal physico-chemical properties of
ENMs.
RN#1. Identify or develop appropriate, t Establish a system to develop and apply reliable and reproducible in vitro andin vivo test methods
reliable, and reproducible in vitro andin vivo assays and models to predict int Evaluate the degree to which an in vitro response correlates with an in vivo
vivo human responses to ENMs
responset Evaluate the degree to which in vitro and in vivo models predict human responset Translate structure-activity relationship and other research data into computational models to predict toxicity in silico
RN#2. Quantify and characterize ENMs t Determine critical ENM measurands in biological and environmental matrices
in exposure matrices and biologicaland ensure the development of tools to measure ENMs in appropriate matrices
matricesas neededt Determine matrix and/or weathering effects that may alter the physico-chemical characteristics of the ENM measurandst Identify key factors that may influence the detection of each measurand in aparticular matrix (e.g., sample preparation, detection method, storage, temperature, solvents/solutions)t Characterize and quantify exposure for all exposure routes using in vivo models
to identify the most likely routes of human exposuret Identify biomarkers of exposure and analytical methods for their determination+ 111 +

N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

Key Research Needs

Subordinate Research Needs

RN#3. Understand the relationshipbetween the physico-chemical properties of ENMs and their transport,
distribution, metabolism, excretion,and body burden in the human bodyt Characterize ENM physico-chemical properties and link to mechanisms oftransport and distribution in the human bodyt Understand the relationship of the physico-chemical properties of ENMs to themechanisms of sequestration in and translocation of ENMs out of the exposureorgan and secondary organs, and to routes of excretion from the human bodyt Determine the metabolism or biological transformation of ENMs in the humanbody

RN#4. Understand the relationshipbetween the physico-chemical properties of ENMs and uptake throughthe human port-of-entry tissuest Characterize ENMs at and in port-of-entry tissues, including nontraditionalroutes of entry such as the ear and eye, and identify mechanisms of ENM
uptake into tissuest Determine the relationship of ENM physico-chemical properties to deposition
and uptake under acute exposure conditions and under chronic exposure
conditionst Translate data on ENM properties and uptake to knowledge that may be used
to intentionally redesign ENMs for optimum human and environmental safety
and product efficacy

RN#5. Determine the modes of action
underlying the human biologicalresponse to ENMs at the molecular,
cellular, tissue, organ, and whole bodylevelst Determine the dose response and time course of biological responses at the
primary site of exposure and at distal organs following ENM exposuret Understand the mechanisms and molecular pathway(s) associated with ENM
biology within cellular, organ, and whole organism systemst Link mechanisms of response with ENM physico-chemical properties andemploy this information in the design and development of future ENMst Develop translational alternative in vitro testing methods for the rapid screening of future ENMs based on mechanism(s) of response that are predictive ofin vivo biological responses

RN#6. Determine the extent to whichlife stage and/or susceptibility factors
modulate health effects associatedwith exposure to ENMs and nanotechnology-enabled products andapplicationst Determine the effect of life stage and/or gender on biological response to ENMs
t Establish the role of genetic and epigenetic susceptibility on the biologicalresponse to ENMs in the context of life stage and/or susceptibility factorst Understand mechanistically the influence of preexisting disease on the biological response to ENMs in the context of life stage and other susceptibility factorst Identify exposure conditions that make susceptible individuals more vulnerable to the health effects associated with ENMs and nanotechnology-enabledapplicationst Establish a database that contains published, peer-reviewed literature, occupational and consumer reports, and toxicological profiles that describe alteredresponses to ENMs and nanotechnology-enabled applications in susceptible
animal models or individuals following exposure+ 112 +

A P P E N D I X D. CO M P R E H E N S I V E C H A R T O F 2 0 1 1 E H S R E S E A R C H S T R AT E G Y N E E D S

Key Research Needs

Subordinate Research Needs

4. Environment Research Needs
Understand the environmental fate, exposure, and ecological effects of engineered nanomaterials, with priority placed onmaterials with highest potential for release, exposure, and/or hazard to the environment.
RN#1. Understand environmental
exposures through the identificationof principal sources of exposure andexposure routest Manufacturing processes and product incorporationt Life cycle of technology and exposures subsequent to product manufacturingt Analytical approaches to measure temporal changes in nanoparticle properties
throughout the life cyclet Models to estimate releasest Environmental receptors for exposure assessment

RN#2. Determine factors affecting
the environmental transport ofnanomaterialst Determine key physico-chemical properties affecting transportt Determine key transport and fate processes relevant to environmental mediat Develop new tools and adaptation of current predictive tools to accommodate
unique properties of nanomaterials

RN#3. Understand the transformation of nanomaterials under different
environmental conditionst Identify and evaluate nanomaterial properties and transformation processes
that will reduce environmental persistence, toxicity, and production of toxic
productst Determine the rate of aggregation and long-term stability of agglomeration/
aggregation and the long-term stability of these aggregates and agglomerates.
t Develop tools to predict the transformations or degradability of nanomaterials

RN#4. Understand the effects of engineered nanomaterials on individuals
of a species and the applicability of
testing schemes to measure effectst Test protocolst Dose-response characterizationt Uptake/elimination kinetics, tissue / organ distributiont Mode/mechanism of action, predictive toolst Tiered testing schemes / environmental realism

RN#5. Evaluate the effects of engit Population
neered nanomaterials at the populat Community
tion, community, and ecosystem levelst Other ecosystem-level effectst Predictive tools for population-, community-, and ecosystem-level effects+ 113 +

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Key Research Needs

Subordinate Research Needs

5. Risk Assessment and Risk Management Methods Research Needs
Increase available information for better decision making in assessing and managing risks from nanomaterials, including
using comparative risk assessment and decision analysis; life cycle considerations; and additional perspectives such as
ELSI considerations, stakeholders’ values, and additional decision makers’ considerations.
RN#1. Incorporate relevant risk
characterization information, hazard
identification, exposure science, andrisk modeling and methods into thesafety evaluation of nanomaterialst Characterization, fate, and release of nanoparticles throughout the life cyclesof nanotechnology-enabled productst Development of predictive models on accumulation, migration, and release of
nanoparticles throughout the life cycles of nanotechnology-enabled productst Safety of nanoparticles throughout the life cycles of the nanotechnologyenabled productst Comprehensive and predictive models to assess the potential risks of nanoparticles during the manufacturing and life cycle of nanoproducts, with inputs fromhuman and environment exposures and on nanomaterial properties

RN#2. Understand, characterize,
and control workplace exposures tonanomaterialst Dissemination and implementation of effective techniques and protocols tomeasure exposures in the workplacet Identification and demonstration of effective containment and control technologies including for accidents and spillst Development of an effective industry surveillance systemt Design and deployment of a prospective epidemiological framework relevant
to exposure sciencet Systematic approaches for occupational risk modelingRN#3. Integrate life cycle considerations into risk assessmentt Establishment of nanotechnology-specific taxonomy for life cycle stagest Integration of risk assessment, life cycle analyses, and decision-making
approaches into regulatory decision making processest Application of adaptive management tools based on monitoring/implementation to evaluate life cycle analysis implementationt Development of case studies, e.g., green chemistry, nanomaterials selection,
nanomaterials acquisition process, illustrating application of these risk management methods

RN#4. Integrate risk assessment into
decision-making frameworks for risk
managementt Development of comparative risk assessment and formal decision-analyticalmethods as opposed to “absolute” risk assessment strategiest Application of formal decision-analytical methods to prioritize risk management alternativest Use of gap analyses and value of information analysis to identify research needst Integration of stakeholder values and risk perceptions into risk management
processest Application of integrated decision framework through case studies in risk
management decision making+ 114 +

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Key Research Needs

Subordinate Research Needs

RN#5. Integrate and standardize
risk communication within the risk
management frameworkt Development and use of standardized terminology in risk communicationst Early information-sharing on hazards and risk among Federal agenciest Development of appropriate risk communication approaches for agencyspecific needs

Informatics and Modeling Research Need
RN#1. Develop computational models t Validate the predictive capability of in vitro and in vivo assays and employ
that subset of assays in data generation to establish computational models toof ENM structure-property-activity
predict ENM behavior in humans and the environment
relationships to support the designand development of ENM witht Establish a standard set of physical and chemical characterization parameters,
maximum benefit and minimum risk
dose metrics, and biological response metrics
to humans and the environmentt Design and establish structures and ontologies for methods development, data
capture, sharing, and analysist Evaluate and adapt as necessary existing computational models by beginningwith existing models for exposure and dosimetry and using data generated
from validated assayst Use ENM exposure and dosimetry models to develop ENM structure-activity
models to predict ENM behavior in humans and the environmentt Establish training sets and beta test sites to refine and validate ENM structure–
activity modelst Disseminate ENM structure-activity models through publicly accessible nanotechnology websites+ 115 +

Appendix E. Glossary
ADME

absorption, distribution, metabolism, and excretion (toxicity parameters)

ARRA

American Recovery and Reinvestment Act

CEIN

Center for the Environmental Implications of Nanotechnology at UCLA

CEINT

Center for the Environmental Implications of Nanotechnology at Duke University

CINT

Center for Integrated Nanotechnologies at Sandia and Los Alamos National
Laboratories

CNST

Center for Nanoscale Science and Technology (NIST)CPSC

Consumer Product Safety Commission

CSN

Collaboratory for Structural Nanobiology

DHS

Department of Homeland Security

DHHS

Department of Health and Human Services

DNI

Director of National Intelligence

DOC

Department of Commerce

DOD

Department of Defense

DOE

Department of Energy

DOEd

Department of Education

DOJ

Department of Justice

DOL

Department of LaborDOS

Department of State

DOT

Department of Transportation

EC

European Commission

EHS

environment(al), health, and safety (aspects of nanotechnology)

ELSI

ethical, legal, and social implications (of nanotechnology)

ENM

engineered nanomaterial

EOP

Executive Office of the President

EPA

Environmental Protection Agency

FAS

Foreign Agricultural Service (USDA)

FDA

Food and Drug Administration (DHHS)+ 116 +

A P P E N D I X E . G L O S S A RY

FHWAFederal Highway Administration (DOT)FS

Forest Service (USDA)

GAO

Government Accountability Office

ILS

interlaboratory studies

IMA

Instrumentation, Metrology, and Analytical Methods (2008 research category)

ISO

International Standards Organization

nanoEHSenvironment(al), health, and safety aspects of nanotechnology

NA

National Academies

NASA

National Aeronautics and Space Administration

NCI

National Cancer Institute (DHHS/NIH)

NCN

Network for Computational Nanotechnology

NEHI

Nanotechnology Environmental and Health Implications Working Group (NSET)

NEP

nanotechnology-enabled product

NIEHS

National Institute of Environmental Health Sciences (DHHS/NIH)NIBIBNational Institute of Biomedical Imaging and Bioengineering (NIH)

NIFA

National Institute of Food and Agriculture (USDA)

NIH

National Institutes of Health (DHHS)NIOSH

National Institute for Occupational Safety and Health (DHHS/CDC)NIST

National Institute of Standards and Technology (DOC)

NM

nanomaterial

NMI

Nanomaterial Measurement Infrastructure (2011 Research Need category)

NNAP

National Nanotechnology Advisory Panel (designated as PCAST)NNCO

National Nanotechnology Coordination Office

NNI

National Nanotechnology InitiativeNSE

nanoscale science and engineering

NSET

Nanoscale Science, Engineering, and Technology Subcommittee of the NSTC Committee
on Technology

NSF

National Science Foundation

NSTC

National Science and Technology Council

OECD

Organisation for Economic Co-operation and Development+ 117 +

N N I E N V I R O N M E N TA L , H E A LT H , A N D S A F E T Y R E S E A R C H S T R AT E G Y

OMBOffice of Management and Budget (Executive Office of the President)

OSHA

Occupational Safety and Health Administration (DOL)

OSTP

Office of Science and Technology Policy (Executive Office of the President)

PBZ

personal breathing-zone

PCAST

President’s Council of Advisors on Science and Technology

ppb

parts per billion

R&D

research and development

RArisk assessment

RAMM

Risk Assessment and Management Methods (2011 Research Need Category)RM

reference material (see also SRM)

RMM

risk management methods

SRM

standard reference material

TEM

transmission electron microscope/y

UNEP

United Nations Environment Programme

USPTO

U.S. Patent and Trademark Office (DOC)

USDA

U.S. Department of Agriculture+ 118 +National Science and Technology Council
Committee on Technology
Subcommittee on Nanoscale Science, Engineering, and Technology
http://www.nano.gov