xvEPA
United States                                    EPA/600/R-10/042
Environmental Protection
Agency
                        Workshop Summary
                               for the
                 EPA Board of Scientific Counselors
                Nanomaterial Case Studies Workshop:
      Developing a Comprehensive Environmental Assessment
          Research Strategy for Nanoscale Titanium Dioxide

                           September 29-30,2009
                            May 2010
               National Center for Environmental Assessment-RTP Division
                       Office of Research and Development
                      U.S. Environmental Protection Agency
                         Research Triangle Park, NC

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                             Disclaimer
     This document has been reviewed in accordance with U.S. Environmental Protection Agency
policy and approved for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
May 2010

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                          Table of Contents
LIST OF TABLES
LIST OF FIGURES
CHAPTER 1. INTRODUCTION
1.1. Background
CHAPTER 2. APPROACH
2.1. Case Studies Document
2.1.1. Rationale and Selection Process for the Case Studies
2.1.2. Comprehensive Environmental Assessment Approach
2.1.3. Contents of the Case Studies Document
2.1.4. Process
2.2. Workshop Objectives and Design
2.2.1 . Choice of Prioritization Method
2.2.2. Identification and Selection of Participants
2.3. Research Needs Ranking Procedure
2.3.1 . Pre-Workshop Review and Rankings
2.3.2. Workshop Procedures
2.3.3. Day 1 Activities
2.3.4. Day 2 Activities
2.3.4.1. Day 2 Breakout Groups
2.4. Nominal Group Technique Process Outcomes
2.4.1. Comparison of Results for Groups A and B
VI
VII
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1-1
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2-3
2-4
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2-9
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2-12
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2-18
CHAPTER 3. PRIORITIZED LIST OF QUESTIONS/TOPICS TO CONSIDER IN A
   COMPREHENSIVE ENVIRONMENTAL ASSESSMENT RESEARCH STRATEGY FOR
   NANO-Ti02	3-1
         3.1. Priority 1: Approaches and Methods for Evaluating the Ecological and Human Effects of
             Nano-Ti02	3-1
             3.1.1.  Breakout Group Members	3-1
             3.1.2.  Short Description	3-1
             3.1.3.  Why this Research/Information is Needed and of High Importance	3-1
             3.1.4.  Extended Description	3-2
             3.1.5.  Other Related Priority Areas	3-2
         3.2. Priority 2: Physico-Chemical Characterization of Nano-Ti02 Throughout the Life Cycle
             Stages, Environmental Pathways, and Fate and Transport	3-2
             3.2.1.  Breakout Group Members	3-2
             3.2.2.  Short Description	3-3
             3.2.3.  Why this Research/Information is Needed and of High Importance	3-3
             3.2.4.  Extended Description	3-3
             3.2.5.  Other Related Priority Areas	3-3
         3.3. Priority 3: Analytical Method Evaluation,  Development and Validation for Analysis of
             nano-Ti02 in Relevant Matrices	3-4
             3.3.1.  Breakout Group Members	3-4
             3.3.2.  Short Description	3-4
             3.3.3.  Why this Research/Information is Needed and of High Importance	3-4
             3.3.4.  Extended Description	3-4
             3.3.5.  Other Related Priority Areas	3-5
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3.4.
3.5.
3.6.
3.7.
3.8.
Priority 4: Nano-Ti02 Product-Focused Physico-Chemical Characterization; Changes
and Possible Effects through the Life Cycle
3.4.1 . Breakout Group Members
3.4.2. Short Description
3.4.3. Why this Research/Information is Needed and of High Importance
3.4.4. Extended Description
3.4.5. Other Related Priority Areas
Priority 5: Exposure Pathways and Life Cycle Analysis
3.5.1. Breakout Group Members
3.5.2. Short Description
3.5.3. Why this Research/Information is Needed and of High Importance
3.5.4. Extended Description
3.5.5. Other Related Priority Areas
Priority 6: Spatial and Temporal Distribution and Magnitude of Anthropogenic and Non-
Anthropogenic Nano-TiO? in the Environment
3.6.1 . Breakout Group Members
3.6.2. Short Description
3.6.3. Why this Research/Information is Needed and of High Importance
3.6.4. Extended Description
3.6.5. Other Related Priority Areas
Priority 7: Using Mechanism of Action (MOA) Information to Drive Toxicity Testing
3.7.1 . Breakout Group Members
3.7.2. Short Description
3.7.3. Why this Research/Information is Needed and of High Importance
3.7.4. Extended Description
3.7.5. Other Related Priority Areas
Priority 8: Long-Term Effects
3.8.1. Breakout Group Members
3.8.2. Short Description
3.8.3. Why this Research/Information is Needed and of High Importance
3.8.4. Extended Description
3.8.5. Other Related Priority Areas
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3-6
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3-7
3-7
3-8
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CHAPTER 4. OBSERVATIONS AND NEXT STEPS	4-1
REFERENCES	R-1
APPENDIX A. NANO-Ti02 CASE STUDIES DOCUMENT	A-1
APPENDIX B. LIST OF QUESTIONS FROM THE NANO-Ti02 CASE STUDIES REPORT	B-1
APPENDIX C. LIST OF REVIEWERS	C-1
APPENDIX D. WEB SITE FORMS AND INFORMATION	D-1
APPENDIX E. BlOSKETCHES OF WORKSHOP PARTICIPANTS	 E-1
APPENDIX F. LIST OF WORKSHOP OBSERVERS	F-1
APPENDIX G. LIST OF NEW AND MODIFIED QUESTIONS	G-1
APPENDIX H. PRE-WORKSHOP RANKING RESULTS	H-1
APPENDIX I. PRE-WORKSHOP HANDOUT: NOMINAL GROUP TECHNIQUE DESCRIPTION	1-1
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APPENDIX J. WORKSHOP AGENDA	J-1
APPENDIX K. RESULTS FROM DAY 1 NOMINAL GROUP TECHNIQUE GROUPS A AND B	K-1
APPENDIX L. RESULTS FROM DAY 2 PLENARY MULTI-VOTING	L-1
APPENDIX M. TEMPLATE AND INSTRUCTIONS FOR BREAKOUT GROUP REPORTS -
  WORD DOCUMENT	M-1
APPENDIX N. TEMPLATE AND INSTRUCTIONS FOR BREAKOUT GROUP REPORTS -
  POWERPOINT PRESENTATION	N-1
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                                    List  of  Tables
Table 2-1. List of Workshop Participants	2-8
Table 2-2. Participant Sector Representation in Day 1 NGT Groups and Overall	2-11
Table 2-3. Participant Expertise Representation in Day 1 NGT Groups and Overall	2-12
Table 2-4. Tally Groupings (by Total Points) of Top-, Middle-, and Bottom-Ranked Research Needs for
         Separate NGT Groups	2-14
Table 2-5. Top-, Middle-, and  Bottom-Ranked Research Needs for Plenary Group	2-15
Table 2-6. Correspondence between top-ranked consolidated issues for Groups A and B	2-18
Table H-1. Pre-Workshop questions in ranked order, beginning with the question awarded the most points	H-6
Table K-1. NGT Group A Results'	K-1
Table K-2. NGT Group B Results	K-4
Table L-1. Plenary Multi-voting1	L-1
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                                  List  of Figures
Figure 2-1. Comprehensive Environmental Assessment Diagram.	2-4
Figure 2-2. Charge to Workshop Participants	2-10
Figure 3-1. Product-Specific Knowledge Highlighted in Priority 4.	3-7
Figure 3-2. Priority Areas Related to Priority 7	3-14
Figure D-1. Background information about the Nanomaterial Case Studies Workshop	D-1
Figure D-2.Web Site Text for Pre-Workshop Activities	D-3
Figure H-1. Ranking Results 1-10.	H-2
Figure H-2. Ranking Results 11-40.	H-3
Figure H-3. Ranking Results 41-70.	H-4
Figure H-4. Ranking Results 71-0.	H-5
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                        Chapter 1. Introduction
      This report describes how the National Center for Environmental Assessment (NCEA)
designed and carried out the "Nanomaterial Case Studies Workshop: Developing a Comprehensive
Environmental Assessment Research Strategy for Nanoscale Titanium Dioxide" in September 2009.
Two case studies focusing on different uses of nanoscale titanium dioxide (nano-TiO2), for water
treatment and for topical sunscreen, were developed around a framework known as comprehensive
environmental assessment (CEA), which is a holistic approach to risk assessment that encompasses
the product life cycle, fate and transport, exposure-dose, and both ecological and human health
effects. The case studies were presented in a draft document to selected reviewers in advance of a
workshop in which they served as participants in a structured process (Nominal Group Technique
[NOT]) to identify and prioritize information or research needed to support a CEA of nano-TiO2.
The results of the ranking process are presented, followed by some brief observations about the
process and a discussion of next steps.
1.1.  Background
      Engineered nanoscale materials (nanomaterials) are conventionally described as having at
least one dimension between 1 and 100 nanometers (nm) and possessing unusual, if not unique,
properties that arise from their small size. Like all technological developments, nanomaterials offer
the potential for both benefits and risks. The assessment of such risks and benefits requires
information, but given the emergent state of nanotechnology, much remains to be learned about the
characteristics and effects of nanomaterials before such assessments can be completed.
      In its 2007 Nanotechnology White Paper (2007, 090564) (p. 89), the U.S. Environmental
Protection Agency (EPA) included the following recommendations regarding the risk assessment of
nanomaterials:

              6.2.7.  Recommendations to Address Overarching Risk Assessment
           Needs - Case Study
              One way to examine how a nanomaterial assessment would fit within
           EPA's overall risk assessment paradigm is to conduct a case study based on
           publicly available information on one or several intentionally produced
           nanomaterials. ... From such case studies and other information, information
Note: Hyperlinks to the reference citations throughout this document will take you to the NCEA HERO database (Health and
Environmental Research Online) at http://epa.gov/hero. HERO is a database of scientific literature used by U.S. EPA in the process of
developing science assessments such as the Integrated Science Assessments (ISAs) and the Integrated Risk Information System (IRIS).
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           gaps may be identified, which can then be used to map areas of research that
           are directly affiliated with the risk assessment process. This has been done in
           the past with research on airborne particulate matter.
              Additionally, a series of workshops involving a substantial number of
           experts from several disciplines should be held to use available information
           and principles in identifying data gaps and research needs that will have to be
           met to carry out exposure, hazard and risk assessments.

      In keeping with these recommendations, the National Center for Environmental Assessment
(NCEA) in EPA's Office of Research and Development (ORD) conducted the "Nanomaterial Case
Studies Workshop: Developing a Comprehensive Environmental Assessment Research Strategy for
Nanoscale Titanium Dioxide" on September 29-30,  2009, in Durham, North Carolina. The
Nanomaterial Case Studies: Nanoscale Titanium Dioxide in  Water Treatment and in Topical
Sunscreen [External Review Draft] (http://cfpub.epa.gov/ncea/cfm/recordisplav.cfm?deid=210206)
was used as a starting point for the workshop, which was conceived as the first of a series of case
study workshops to be used in developing and refining a long-term research strategy for assessing
potential human health and ecological risks of nanomaterials (U.S. EPA, 2009, 225004). A key
feature of the case studies is the comprehensive environmental assessment (CEA) framework, which
takes a holistic view of specific applications of selected nanomaterials beginning with the product
life cycle and encompassing environmental fate and transport, exposure, and ecological as well as
human health implications. The specific objectives of the workshop were to  identify and prioritize
research or information needed to conduct  a CEA of nanoscale titanium dioxide (nano-TiO2). The
present report describes the approach used  in developing the case studies and in designing and
conducting the workshop, as well as some  of the more salient outcomes of the  workshop.
      The Nanomaterial Case Studies Workshop was conducted under the auspices of the EPA Board
of Scientific Counselors (BOSC), an advisory committee of independent scientists and engineers
established by EPA to provide advice, information, and recommendations  concerning practices and
programs of the Office of Research and Development, including ORD's research planning process.
In compliance with the Federal Advisory Committee Act (FACA) (5 U.S.C. App. 2
rhttp://www.archives.gov/federal-register/laws/fed-advisorv-committeel) and related regulations,  the
BOSC announces its meetings in the Federal Register, opens its meetings to the public, and provides
opportunities for public comment on issues before the Board. This summary document is  meant to
serve as an aid to the BOSC in its development of a report that will, among other things, provide
technical feedback and guidance to EPA on the design, implementation, and outcomes of the
workshop.
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      It is important to note that the Nanomaterial Case Studies document and workshop were not
intended to be ends in themselves, even though they may have value or be of interest in their own
right. They were primarily conceived as initial steps in the development and refinement of a long-
range research strategy to support the comprehensive environmental assessment of selected
nanomaterials. Such a strategy will require the examination of other nanomaterial case studies and is
expected to develop in an evolutionary process reflecting adjustments and modifications as
additional nanomaterials are considered and new information becomes available.
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                          Chapter 2. Approach
      Scientific research is a primary means of obtaining information needed for assessing the
potential ecological and human health risks related to nanomaterials, although other types of
information (e.g., production volumes, monitoring data) may also be needed. Determining which
specific information needs are most critical to support assessment efforts can be a complex and
difficult endeavor. The case study workshop approach described here reflects several choices and
assumptions, some of which were based on prior experience with other environmental issues (Davis,
2007,0898031
      Section 2.1 describes the development of the nano-TiO2 case studies document. Section 2.2
discusses the objectives and design of the workshop. Section 2.3 describes the procedure used to
rank research needs. Section 2.4 highlights the main outcomes of the ranking process.
2.1.  Case Studies  Document
     This section provides background information about EPA's nano-TiO2 case studies document
that served as a starting point for the workshop discussions. The section explains the rationale for
using a case study approach and process for selecting the case studies and the CEA approach and
also summarizes the contents of the case studies document and the process of its preparation.

2.1.1. Rationale and Selection Process for the Case Studies
     The complex properties of various nanomaterials make evaluating nanomaterials in the
abstract or with generalizations difficult if not impossible. Thus, EPA decided to use a "bottom-up"
rather than a "top-down" approach and initially focus on specific nanomaterial applications.
     The process for selecting the nanomaterials for the case study involved an EPA workgroup
composed of members from the Office of Research and Development, the Office of Prevention,
Pesticides and Toxic Substances, the Office of Air and Radiation, the Office of Solid Waste and
Emergency Response, the Office of Water, the Office of Environmental Information, and Regional
Offices 3 and 9. The workgroup grew rapidly in size from around 20 persons initially to the
approximately 60 members listed in Section C.I. 3 and in the front matter of the Nanomaterial Case
Studies: Nanoscale Titanium Dioxide in Water Treatment and in  Topical Sunscreen [External Review
Draft] (U.S.  EPA, 2009, 225004).
     In addition to titanium dioxide, several other  candidate nanomaterials were considered and
discussed by the workgroup, especially single-wall  and multi-wall carbon nanotubes, fullerenes,
metals (e.g.,  zero valent iron, silver), and metal oxides (e.g., cerium oxide). Several selection criteria

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were used in deciding which materials to examine as case studies:  (1) "nano-ness," i.e., one or more
properties that distinguish the engineered nanoscale form from its conventional form; (2) potential
exposure for human populations and biota; (3) ecological as well as human health relevance; (4) data
availability; (5) relevance to EPA programs. Limited summaries  of information bearing on these
points were provided for the workgroup to consider, but the evidence pertaining to most of the
selection criteria would be better characterized as "preliminary"  rather than "demonstrated."
     After multiple conference calls and email exchanges over  a period of a couple of months, the
workgroup members were asked to vote for one carbon nanomaterial and one metal/metal oxide
nanomaterial. Although the EPA program offices varied in the number of members on the
workgroup, the top ranked choices were single-wall carbon nanotubes (SWCNTs) and nano-TiO2,
regardless of whether votes were counted on the basis of individual members (34 voted) or
individual program offices (8 voted).
     The next step entailed more in-depth examination of published literature and other sources of
information (e.g., web sites) to  determine which specific applications of the two selected classes of
nanomaterials would be suitable to serve as case studies. Two uses of nano-TiO2 emerged: water
treatment and topical sunscreen. With regard to use of nano-TiO2 for water treatment, several
published studies pointed to the effectiveness of nano-TiO2 in removing arsenic, but eventually we
discovered there was little evidence that it was in fact being routinely used by community water
suppliers. Although this apparent lack of usage might be seen as  contrary to the selection criterion of
exposure potential, we reasoned that if nano-TiO2 were used in the future,  the potential for exposure
would presumably exist at that  time and that our consideration of its implications could be viewed as
proactive rather than reactive. As for the use of nano-TiO2 in topical sunscreen, there was no doubt
that such products were in use by the general population, but some workgroup members questioned
the relevance of these products to EPA programmatic interests, given that sunscreen products were
under the purview of the Food and Drug Administration (FDA).  From a CEA standpoint, however,
the potential for direct and indirect effects on ecological receptors as well as human populations
through multiple pathways provided a cogent reason to focus on the broad environmental
implications of nano-TiO2 in sunscreen.
     Although the literature on SWCNTs appeared to be reasonably robust, it ultimately proved to
be insufficient to develop a compelling scenario for significant exposure of the general population to
SWCNTs. The possibility of substituting a different nanomaterial was explored, but we finally
decided in the face of various resource constraints to limit our efforts to developing the two nano-
TiO2 case studies for the first workshop.
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2.1.2. Comprehensive Environmental Assessment Approach
      The case studies were organized around the concept of comprehensive environmental
assessment (CEA), which combines a product life cycle framework with the risk assessment
paradigm. In essence, CEA expands the risk assessment paradigm by including life-cycle stages and
considering both indirect and direct ramifications of the substance or stressor. Figure 2-1 illustrates
the principal elements in the CEA approach. The first column lists typical stages  of a product life
cycle: feedstocks, manufacturing, distribution, storage, use, and disposal (including reuse or
recycling, if applicable). The second column lists environmental pathways or media (air, water, soil)
to which nanomaterials or associated materials (e.g., manufacturing by-products) might be released
at various stages of the life cycle. Within these media, nanomaterials or associated materials can be
transported and transformed, as well as interact with other substances in the environment, both
natural and anthropogenic. Thus, a combination of primary and secondary contaminants can be
spatially distributed in the environment (column 3).
      The fourth column of Figure 2-1 (Exposure-Dose) goes beyond characterizing the occurrence
of contaminants in the environment, as exposure refers to actual contact between a contaminant and
organisms (i.e., biota as well as human populations). Under the CEA approach, exposure
characterization can involve aggregate exposure across routes (e.g., inhalation, ingestion, dermal);
cumulative exposure to multiple contaminants (both primary and secondary); and various
spatiotemporal dimensions (e.g., activity patterns, diurnal and seasonal changes). Dose is the amount
of a substance that actually enters an organism by crossing a biological barrier. Conceptually, dose
links exposure with the last column of Figure 2-1, which refers to ecological and human health
effects that can result when an effective dose reaches a target cell or organ in a receptor organism  or,
in an ecological context, when a stressor is at a sufficient level  to cause an adverse response in a
receptor. "Effects" encompass both qualitative hazards and quantitative exposure-response
relationships.
      In the present context of research planning and strategy development, CEA is underpinned by
the development and use of analytical methods that  make detection, measurement, and
characterization of nanomaterials in the environment and in organisms possible. A key aspect of
CEA is the use of collective judgment based on diverse technical and stakeholder perspectives, as
will be described later.
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r* L. F- L i A
Cotnpiehensive Environmental Assessment ~
Life Cycle Environmental Fate & Exposure-
Stages Pathways Transport Dose
Feedstocks ^
Manufacture
Air "} Primary ~"\
Distribution [ \ contaminants 1 | Ecosys
f Water f Human
Storage Secondary /af/ons Human
Soil J contaminants} ' J
Use
Disposal J
I 1 1 1
Analytical methods development and application




•terns
Health
I


                                        Source: Modified from Davis (2007, 089803) and Davis and Thomas (2006, 089638)

       Figure 2-1.     Comprehensive Environmental Assessment Diagram.


2.1.3. Contents of the Case Studies Document
      The External Review Draft of Nanomatericil Case Studies: Nanoscale Titanium Dioxide in
Water Treatment and in Topical Sunscreen (U.S. EPA, 2009, 225004) comprised five chapters:  an
introduction, a description of the life cycle stages of both applications, a discussion of the fate and
transport of TiO2 through different environmental media, data regarding potential ecological and
human exposure and dose, and information regarding the known ecological and health effects of
nano-TiO2. Although the document summarized much information relevant to a CEA of nano-TiO2,
it also pointed to many information gaps and listed several unanswered questions at the end of each
chapter or certain sections of the document. These questions, listed in Appendix B of this report,
served as a starting point for the workshop participants to think about the research priorities on
which EPA should focus.

2.1.4. Process
      The case studies were developed through a team effort involving EPA staff, contractors, and
consultants, assisted by several external reviewers and internal EPA Work-group members, all of
whom are listed in Appendix C. In addition to soliciting review comments on the case studies
document from the  workshop participants, EPA also solicited public comment. As of September 23,
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2009, nine public comments had been submitted to the docket.
(http://www.regulations.gov/search/Regs/home.html#docketDetail?R=EPA-HO-ORD-2009-0495)
(Note: check the "public submissions" box on the docket screen to view all nine comments). EPA
plans to address comments from the workshop participants and the public in the final version of the
nano-TiO2 case studies document.

2.2.  Workshop Objectives and Design

      Two key features figured into our thinking about the design and objectives of the Nanomaterial
Case Studies Workshop. One was the importance of going beyond simply generating another list of
nanotechnology research needs. Various "research strategies" and statements of research needs
related to nanotechnology risk assessment have appeared in recent years, including the NNI Strategy
for Nanotechnology-Related Environmental, Health and Safety Research (NEHI, 2008, 598308).
which was criticized by a NRC review panel for, among other things, its "failure to identify
important research needs [and] the lack of rationale for and discussion of research priorities..."
(NRC, 2009, 597919). Although the EPA Nanomaterial  Case Studies Workshop was conceived
before the NRC review had been started, the importance of prioritizing research needs  was a primary
objective from the outset in our plans for a workshop. To satisfy this objective, we felt  that it was
essential to use a more formal or structured decision-support process rather than a typical "free
discussion" workshop discussion format. A second feature of fundamental importance was having a
diverse, multi-disciplinary, and multi-stakeholder group of workshop participants to consider these
issues. This also happened to be consistent with the NRC review in its call for diverse stakeholder
input in developing a research strategy for nanomaterial risk assessment.

2.2.1. Choice of Prioritization Method
      A number of collective judgment and decision-support methods were considered for
identifying and prioritizing research or information needs. In particular, multi-criteria decision
analysis (MCDA) (Linkov et al, 2008, 157531: Seager and Linkov, 2008, 157493) and a variant of
MCDA known as multi-criteria integrated resource assessment (MIRA) (Stahl et al., 2002, 041601).
as well as some form of expert elicitation (Cooke, 1991, 598306; Cooke and Goossens, 2004,
598304; U.S. EPA, 2009, 598301).  were given consideration. In the end, nominal group technique
(NOT) (Delbecq and Van de Ven, 1971, 598309) was selected for the 2009 workshop for various
reasons, including because it seemed more appropriate given the nascent state of the science related
to nanomaterial risk assessment and because it could be implemented more easily in the face of
temporal and other constraints.
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      NOT is a structured process for a set of individuals to identify and rank a number of choices.
Several individuals (nominally a group) are convened and each person is afforded an equal
opportunity to offer his or her view(s) about which choices are highest priority. When a large number
of choices are under consideration, they may be grouped or consolidated into a more manageable
number. A multi-voting process is then used to rank the choices. More details on how NOT was
applied are presented in Section 2.3.2 and in Appendix I.
      Although not necessarily unique to NOT, one feature of NOT that recommended it for this
project was that it allows  for both independence and interaction in judging issues. For example,
participants are free to introduce and argue for any issue they wish, and each participant is accorded
an equal amount of time in a round-robin procedure to make their case. Independent viewpoints are
thus encouraged, while at the same time participants can be exposed to and perhaps influenced by
other points of view. Moreover, interaction occurs during the NGT  consolidation process (Section
2.3.4) when participants discuss and decide whether their respective issues are similar to others'
issues. Independence of judgment is assured in the multi-voting procedure during which all
participants vote simultaneously and essentially anonymously. The  outcome of the voting is a rank
ordering of priorities that reflects a collective judgment of the participants acting individually.
      Since 1992, the National Water Research Institute (http://www.nwri-usa.org/) has used NGT
in numerous workshops for "identifying, prioritizing, and developing approaches to address critical
local, state, and national water issues" (e.g., http://www.nwri-
us a.org/pdfs/OxygenateContaminationworkshopreportSept.2000.pdf). We drew upon our own
individual past experience with the NWRI workshops and more recent informal communications
with NWRI personnel in planning the case studies workshop.

2.2.2. Identification and Selection of Participants
      Several steps were  involved in securing a diverse, multi-disciplinary, and multi-stakeholder
group of workshop participants, and EPA retained a contractor (ICF International) to assist in
organizing and facilitating the workshop. First, a list of candidate participants was developed based
on suggestions from EPA, Internet searches, and other investigation. An initial inquiry was sent via
email to 188 potential  invitees on June 15, 2009, with a link to more information (Section D.I) and a
webform through which they could provide information about their interest in participating in the
workshop, their availability across six different dates in late September, the sector in which they
worked (government, academic, industry, non-government organizations [NGOs], etc.), and their
areas of expertise (Section D.2). On June 22, an additional 97 potential participants were contacted
to ensure an adequate pool of candidates from which to select invited participants. The objective of
the initial inquiry was  to obtain sufficient information to select the dates for the workshop based
upon potential participant availability and to enable an adequate representation and balancing across

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"demographic" factors (i.e., sector affiliation and subject matter expertise). As potential participants
responded to the initial inquiry using a Web-based system (MemberClicks), their information was
stored in a password-protected online database.
      Of the range of proposed dates for the workshop, the dates on which the most potential
participants  were available to attend were September 29 and 30, 2009. Those who were available to
attend the workshop on these dates were then separated into subcategories, first by sector, then by
subject matter expertise. Considerable attention was given to achieving, as much as possible, a
balanced representation of areas of expertise  and sectors (Section 2.3.2 and Tables 2-2 and 2-3).
      A target number of 50 participants was set. The basis for this number is discussed in more
detail in Section 2.3.2. (We also happened to  have roughly 50 demographic categories, but we did
not attempt to  match every such category specifically with a participant.) To reduce travel expenses,
preference was given to potential participants located in North America. In the event any invitees
were unable to complete certain pre-workshop requirements or were unable to attend, a list of 25
alternates, distributed between sectors and subject matter expertise was generated so that
substitutions could be made with minimal impact on the representation balance.
      An invitation was sent to 50 potential participants starting on July 14 with a request to
complete a conflict of interest disclosure and certification form. No conflict of interest concerns  were
identified. Generally, an agreement was executed with the non-federal government participants to
reimburse them for their travel expenses and  pay an honorarium of $1,500 for their services. A legal
agreement and honorarium were used to help ensure that participants would understand that a
commitment of their time and attention was expected and that their services were not being  offered
gratis on their  part.
      The invitees then received a "charge to workshop participants" (Figure 2-2) with guidance for
their review of the case studies. They also received instructions (Section D.3) for submitting
additional or modified information/research needs and for ranking the questions listed in the draft
document using a Web form in advance of the workshop  (discussed further in Section 2.3.1). A small
number of invitees had to decline  or drop out of the process due to  conflicts or emergencies.
Replacements  were identified and retained as time permitted, with 49 invitees ultimately attending.
See Table 2-1 for the list of 49 workshop participants  and Appendix E for the biosketches they
submitted. In addition to the workshop participants, a few other individuals attended the workshop as
observers for varying periods of time; their names and affiliations are listed in Appendix F.
May 2010                                      2-7

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       Table 2-1.  List of Workshop Participants
NAME
David Andrews
Jeff Baker
Brenda Barry
Catherine Barton
Eula Bingham
Pratim Biswas
Jean-Claude Bonzongo
Steven Brown
Mark Bunger
Carolyn Nunley Cairns
Richard Canady
Janet Carter
Elizabeth Gasman
Sylvia Chan Remillard
Shaun Clancy
Ramond David
Joan Denton
Gary Ginsberg
Pertti (Bert) Hakkinen
Jaydee Hanson
Patricia Holden
Paul Howard
Sheila Kaplan
Fred Klaessig
Rebecca  Klaper
Todd Kuiken

John LaFemina
Thomas Lee
Shannon  Lloyd
Christopher Long
Margaret  MacDonell
Fred J. Miller
Nancy Monteiro-Riviere
Paul Mushak
Srikanth Nadadur
Michele Ostraat
Anil Patri

Maria Victoria Peeler
Richard Pleus
John Small
Jeff Steevens
Geoffrey Sunahara
Treye Thomas
John Veranth
Donald Versteeg
Nigel Walker
William Warren-Hicks
Paul Westerhoff
Mark Wiesner
AFFILIATION
Environmental Working Group
TSI Incorporated
American Chemistry Council
DuPont
University of Cincinnati
Washington University in St. Louis
University of Florida
Intel Corporation
Lux Research, Incorporated
Consumers Union
McKenna, Long  & Aldridge LLP
U.S. Occupational Safety and Health Administration
Carnegie Mellon University
HydroQual
Evonik Industries AG
BASF Corporation
California Environmental Protection Agency
Connecticut Department of Public Health
National Institutes of Health (NIH), National Library of Medicine
International Center for Technology Assessment
University of California - Santa Barbara
U.S. Food and Drug Administration
University of California - Berkeley, Graduate School of Journalism
Pennsylvania Bio Nano Systems, LLC
University of Wisconsin, Great Lakes Water Institute
Woodrow Wilson International Center for Scholars, Project on Emerging
    Nanotechnologies
Battelle
Minneapolis Star Tribune
Concurrent Technologies Corporation
Gradient Corporation
Argonne National Laboratory
Independent Consultant
North  Carolina State University
PB Associates
NIH, National Institute of Environmental Health Sciences (NIEHS)
Research Triangle Institute
SAIC  (at NIH, National Cancer Institute, Nanotechnology Characterization
    Laboratory)
Washington State Department of Ecology
Intertox, Incorporated
National Institute for Standards and Technology
U.S. Army Corps of Engineers Research and Development Center
National Research Council - Canada, Biotechnology Research Institute
U.S. Consumer  Product Safety Commission
University of Utah
The Procter & Gamble Company
NIH, NIEHS, National Toxicology Program
EcoStat, Incorporated
Arizona State University
Duke  University	
May 2010
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2.3.  Research  Needs Ranking Procedure

      The 49 selected participants were asked to do several things as part of the process of
identifying and ranking research priorities. Some of these activities were carried out prior to the
workshop, but the workshop itself was the primary venue for the process of ranking research needs.

2.3.1. Pre-Workshop  Review and  Rankings
      In advance of the workshop, the invited participants were asked to review the case studies
document and, using a Web-based form, submit their rankings of research questions by
September 10, 2009. They were instructed to read the case studies and submit their top 10 questions
from the document  in ranked order, an additional 15 questions they felt were important but not
individually ranked, and up to 10 questions they felt were the lowest priorities in laying the
foundation for a CEA of nano-TiO2 (Section D.3). Participants were also encouraged but not
required to submit modifications of existing questions from the  case studies and new questions that
were not originally  included in the document. The responses were collected through a  web form. The
form allowed participants to assign questions: (a) a numerical ranking from 10 down to 1 for the top
10; (b) the classification "high (not ranked)" for the next 15; (c) "low" for the bottom 10; or (d) no
ranking (blank). On a separate page, participants could enter the text of new questions  and indicate
which chapter a question corresponded to or designate it as "multiple" chapters if it had broader
relevance than a single chapter.
      All newly submitted and revised questions were compiled and distributed to the  workshop
participants via email one week before the workshop; also, the questions were included in folders
provided to the participants at the workshop. During the initial plenary session at the workshop, the
facilitators presented the results of the pre-workshop ranking of the questions. The lists of new and
revised questions are shown in Appendix G, and the pre-workshop ranking results and  methodology
used to calculate the results are shown in Appendix H. Thirty-two of the participants submitted new
questions or revisions to existing questions.
      Our objective in having the participants rank the questions in the draft case studies document
prior to the workshop was to help ensure that  they would consider and perhaps even reflect on the
numerous possible questions posed in the document. The fact that several participants  submitted new
or modified questions may indicate that they did in fact give some thought to  issues associated with a
CEA of nano-TiO2,  although some "new" questions were actually redundant with questions already
stated, which suggests that the submitter in those instances might not have  carefully read the
document. Regardless, the pre-workshop ranking exercise presumably helped focus the participants'
attention on issues raised by the document. The results of the pre-workshop ranking process and  the
lists of new and modified questions were provided to participants, albeit only a few days before the

May 2010                                     2-9

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workshop, with the intention of further stimulating their thinking, especially regarding issues the
draft document may have failed to identify or articulate adequately.
                                        Charge to Workshop Participants

                The document you are being asked to review is one step in the development of a research
             strategy for the comprehensive environmental assessment of nanomaterials such as nano-TiO2. It is a
             starting point for the Nanomaterial Case Studies Workshop that will be held on September 29-30,
             2009. Prior to the workshop (by September 10) you should submit your review comments and
             ranking of Questions (research/information needs), as explained below. The preliminary ranking
             results will be provided at the workshop. New questions submitted by September 10 will be
             distributed to workshop participants approximately one week in advance of the meeting.
                The document attempts to take a holistic view of selected uses of nano-TiO2 and the potential
             ecological and health implications of such products across their life cycle. Although much
             information is presented in the document, many questions remain to be answered. Several of these
             questions, which can also be thought of as information or research needs, are listed throughout the
             document. As you review the document, please consider this overarching question:
                "What research or information is most needed in  order to conduct a comprehensive
             environmental assessment of nano-TiO2?"
                You are asked to read the entire document, not just your own areas of expertise or interest. We
             want reviewers to take a "big picture" view and not focus exclusively on a particular chapter or
             section.
                The document is meant to stimulate your thinking about potential release scenarios and
             implications, both direct and indirect. It is a starting point for your thinking, not an end in itself.
                A key aspect of your review is to identify and rank the research or information that is most
             needed in order to conduct a comprehensive environmental assessment of nano-TiO2. Separate
             instructions for the ranking process are provided below and should be read before reviewing the
             document.
                In your review comments, please indicate:
                Is the information presented in the document accurate, objective, and logical? Are statements
             properly supported by references? Note that we have by necessity had to rely on gray literature and
             personal communications at times. If you have better sources to cite for such information, please
             provide them.
                Is information clearly and concisely presented? If not, please suggest alternative wording.
                Is the information complete? Have any important points been omitted? Do you know of other
             information that bears directly or indirectly on the case studies? Can you provide a source (e.g., a
             document, Web site, person) for additional information?

                Thank you for your thoughtful review and participation in this endeavor.
        Figure 2-2.     Charge to Workshop Participants


2.3.2. Workshop  Procedures

       In practice, NOT seems to be applicable to groups no larger than 25-30 persons primarily
because of the amount of time required for every participant to present their views. For example, if
30 participants were each allotted 3 minutes in which to speak, a single round would take a
minimum of 90 minutes. In the EPA workshop, we allowed participants more than one round and
essentially continued until every individual had offered all the issues they wanted to see presented.
Subsequent rounds after the first tend to go more quickly as more and  more participants "pass" when
all of their issues have already been raised. Nevertheless, the total period could easily exceed 3
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hours, which intuitively seems too long to fully engage everyone's attention. And if time were also
included for the participants to move from their seats to a podium (although this practice was not
used in the EPA workshop), the total period could be increased by a third or more. Given these
considerations, we decided to limit the NGT process to 25 persons.
     During the planning process, a question arose about whether one "sample" of 25 individuals
would yield  a substantially different outcome from another group of 25 individuals. Given this
question and the fact that we had on the order of 50 demographic categories (sectors, fields of
expertise), we decided to have a total of 50 participants and run two separate NGT groups of 25
each. (The actual number of participants in attendance was 49; thus, NGT Group A had 24
participants and Group B had 25.)  An effort was made to achieve a rough balance in demographic
characteristics between the two NGT groups (Tables 2-1  and 2-2).
       Table 2-2.  Participant Sector Representation in Day 1 NGT Groups and Overall
Sector
Academia
Industry
NGO
Consulting
Government-State
Government-Federal
Government-
International
Journalist
Total
NGT Group A
5
4
2
5
2
5
0
1
24
NGT Group B
5
5
1
6
1
5
1
1
25
Total
10
9
3
11
3
10
1
2
49
May 2010
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       Table 2-3. Participant Expertise Representation in Day 1 NGT Groups and Overall
Area of Expertise
Manufacturing
Water Treatment
Fate & Transport
Exposure-Dose
Ecology
Health Route
Health Endpoint
Health Method
Evaluation
Risk Management
Other
NGT Group A
3
4
11
14
6
12
8
10
13
16
15
NGT Group B
5
6
12
16
6
13
10
9
14
17
11
Total
8
10
23
30
12
25
18
19
27
33
26
      A description of the NGT procedures was provided to participants in advance of the workshop
so they would know what to expect (Appendix I). The workshop agenda (Appendix J) provides
further detail about how the meeting was conducted. The following sections further elaborate on key
activities during the course of the 2-day meeting.

2.3.3. Day 1 Activities
      Early in the workshop, approximately an hour was devoted to presenting and explaining the
results of the pre-workshop ranking process (Appendix H). Although the results had been provided
to the participants in advance of the meeting, we wanted to provide an opportunity for group
discussion and interaction as a means of further stimulating thought about the relative importance of
different questions. After the workshop protocol and NGT process  was briefly reviewed for all the
participants, two NGT groups (Groups A and B) were assigned separate meeting rooms.
      A period of approximately 20 minutes was allowed for participants to silently consider the lists
of 97 questions (Appendix B) provided in the case study report and of 131  additional questions
(Appendix G) submitted by the participants with their pre-workshop rankings.  The round-robin
procedure allowed each individual up to 3 minutes to present a single research/information need they
deemed of high priority and provide the rationale for selecting that issue in relation to conducting a
CEA. Participants were also given the opportunity to state a new issue in place of choosing  an
existing need or modify the phrasing or content of an existing research question. Each research need
identified by a participant as high-priority was written on a flip-chart sheet of paper and displayed on
the wall for the consideration of the group. After each participant had spoken in support of an issue,,
the round-robin was repeated for two additional rounds, after which the groups indicated that the
research needs of highest priority had been identified. (Many of the participants did not use  all of
May 2010
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their allotted time, which resulted in extra time for additional rounds in both groups.) Altogether,
approximately 82 specific issues were identified as information needs during this stage.
      The second part of the NOT process involved consolidating similar or overlapping research
needs into related research topic areas. Participants were given the opportunity to propose to their
respective group consolidation of two or more research needs, after which those participants who
had nominated the research needs were consulted on whether they agreed that the ideas should be
grouped into a research area. If any one of the participants that had chosen one of the research needs
under consideration for grouping did not agree that the research needs could be consolidated into
one, then the issues were not grouped and each need was considered as  an independent research
priority. Where the participants all agreed that certain research needs should be grouped, the
resulting combination was treated as a single research area, although records were kept of the
individual issues that fed into the consolidated topic area. After completing the consolidation
procedure, Group A had 24 research topic areas and Group B had 26 areas to be ranked.
      The third part of the NGT involved a multi-voting exercise to  develop a ranking of the
consolidated research needs in terms  of their importance for conducting a CEA. Each participant was
given 10 "sticky notes" and instructed to label them 1 to 10 and include their name on each note.
The participants were then asked to rank their top ten research priorities by  giving 10 points to the
research need they deemed most important for conducting the CEA, 9 points to their next highest
priority, and so on, down to 1 point. Only 10 research topics could be ranked by each individual, and
each topic could receive only one ranking per individual. After the voting process, the  results were
tallied and the top research priorities for each group were identified.
      Originally, as described in the pre-workshop NGT handout, our plan was to have the full group
consider the top  10 research priorities from each of the two subgroups,  but it became evident that 10
was an arbitrary  cut point and that it would be better to base the number of top priorities on breaks in
the distribution of scores in the vicinity of the 10th item. For example, as shown in Table 2-3 (and in
greater detail in Appendix K), a gap in the scores from Group A occurred between the  13th- and
14th-ranked items. Therefore, the top 13 research topics from Group A  and the top 12 topics from
Group B were brought forward to a plenary  session on Day 2 (Section 2.3.4) for the entire group of
49 participants to consolidate.
May 2010                                      2-13

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       Table 2-4. Tally Groupings (by Total Points) of Top-, Middle-, and Bottom-Ranked Research
                 Needs for Separate NGT Groups
NGT Group A
Rank
1-4
5-13
14-24
Range of Points1
182-123
76-49
33-0
NGT Group B
Rank
1-6
7-12
13-26
Range of Points1
155-101
70-55
38-0
 Maximum possible number of points, assuming all participants in the group assigned 10 points to a single research need:
NGT Group A: maximum = 240 points
NGT Group B: maximum = 250 points

2.3.4. Day 2 Activities
      To identify the top research priorities collectively among all the participants, each participant
was given the ranked list of top research priorities from both NGT groups (Appendix K) at the start
of day 2. The priorities from each group were labeled according to the group from which they
originated and their ranked order (e.g., question "A. 1" had the most votes from Group A). The
workshop facilitators asked the participants to review the ranked priorities from each group and to
consider whether any of the research priorities ranked by the two groups were similar or
overlapping.
      A consolidation process similar to the one used in the separate NGT groups on Day 1 was
conducted with the plenary group. Participants had the opportunity to nominate research priorities
from either list for consolidation either because the ideas were similar or because one idea was a
component of another. The facilitators then asked the entire group to vote by a show of hands if they
agreed that the two research priorities  could be combined. If the majority of the group agreed, the
priorities were then consolidated. In response to concerns voiced by some participants, the
facilitators emphasized that by consolidating two research priorities, the original questions that made
up those priorities were not lost, but were instead possibly  strengthened by adding more detail and
possibly  a more refined description. During the consolidation process, no questions were altered.
      Following consolidation of similar priorities, the plan was to have multi-voting for the top
priorities by the plenary group using a commercial "audience response" system consisting of
individual remote keypads  and a computerized receiver to tally each participant's weighted vote.
Due to technical problems, however, the facilitators had each person in the plenary group list his/her
top 10 priorities on a sheet of paper, numbering in descending order from 10 down to 1 assigning 10
points to the top priority. The scoring sheets were collected and tallied. During this process, it was
discovered that a  few of the participants had not voted correctly. For example, some participants
assigned points to an item more than once or assigned points to a priority that was not among the set
May 2010
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of top NOT group priorities (e.g., voting for group A's 15th ranked item). If a participant voted for an
issue twice, the lower vote was deleted. Points assigned to non-eligible items were ignored.
      Using the point tallies, the overall top research priorities were identified and then presented to
the group. Rather than limiting consideration to an arbitrary top 10 priorities, the facilitators, with
consensus from the group, chose to rely on break points in the voting results. Table 2-5 shows the
groupings, and Appendix L lists the priorities in ranked order and also indicates which priorities
from the NOT groups were consolidated prior to the final vote. Given the gap between items 8 and 9,
the focus for the remainder of the workshop was on the top 8 priorities.

       Table 2-5.  Top-, Middle-, and Bottom-Ranked Research Needs for Plenary Group
Plenary
Rank
1-5
6-8
9-18
Range of Points1
337-237
185-152
66-0
                        Maximum possible number of points, assuming all participants
                        in the group assigned 10 points to a single research need was
                        480; one participant left early and did not vote.
                        Note: Tally Groupings by Total Points

2.3.4.1.  Day 2 Breakout Groups
      Eight breakout groups corresponding to the top eight research topics were formed by
participants volunteering to work on an issue of their choice (with guidance to limit group sizes to no
more than 7 and no fewer than 5). The groups were given around 3 hours (including lunch) to
develop a short report fleshing out descriptions of the research topic areas, using an MS Word
document template (Appendix M). The written reports are presented in full in Section 3 of this
report. Near the end of Day 2 of the workshop, a spokesperson from each breakout group gave a 5-
minute presentation to the plenary group, using a provided PowerPoint template (Appendix N).
These presentations were meant to briefly summarize each breakout group's written report, with
particular emphasis on the topic's connections to other priority areas. Some time was allowed for the
plenary group to respond to these presentations, especially for the purpose of pointing out additional
connections or relationships between research topic areas.

2.4.  Nominal Group Technique  Process Outcomes

      As explained in Section 2.3.3, on Day 1 Groups A and B considered a set of more than 230
proposed research needs, identified approximately 82 issues as priorities through the round-robin
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procedure, and then consolidated these issues into 24 and 26 high-priority research areas,
respectively. These consolidated research needs were then ranked by the two groups using a multi-
voting process. This resulted in the selection of 13 and 12 highest priority research needs by Groups
A and B, respectively (Appendix K). In a plenary session on Day 2, these 25 research needs were
discussed and consolidated, when possible, resulting in a total of 18 high-priority research areas on
which the plenary group voted to determine the final ranking. The end result of the two-day process
was a set of eight top research priorities (Appendix L).
      The following list of eight priorities contains each of the constituent questions that were
consolidated into the topic areas. Descriptors for the topic areas were developed by the breakout
groups for their written reports, which are presented in Section 3.

      Priority 1: Are current EPA standard testing protocols adequate to determine nano-TiO2
ecotoxicity? If not, what modifications or special considerations, if any, should be made in current
ecological tests? For example, what are the differences in characterization of testing material (as raw
material, in media, and in organisms),  dispersion methods,  and realistic exposure routes between
testing conventional materials and nanomaterials (commercial use)? Are the current EPA harmonized
health test guidelines for assessing toxicity adequate to determine the health effects/toxicity of nano-
TiO2? What criteria, especially associated with an inert colloid particle, should the EPA use when
evaluating harmonized test protocols?  What  set of widely shared reference samples of nano- and
conventional TiO2 would be most useful for integrating the results of different investigators
regarding particle characterization and particle toxicology?

      Priority 2: How do TiO2 properties change from the manufacturing stage, upon its
incorporation into products, during its  use, during storage, upon  release to the environment, upon
environmental aging, and in different compartments? How do various manufacturing processes for
nano-TiO2 affect their physicochemical properties? How do specific physicochemical properties,
including particle surface treatments and aggregation/agglomeration, affect the fate and transport of
nano-TiO2 in various environmental media? Do we have sufficient information to differentiate
decision-critical  characteristics across  the various nano-TiO2 sunscreens or water-formulations?
Have the life cycle flows (intentional and unintentional)  and properties of nano-TiO2 in different
applications been adequately  characterized?

      Priority 3: Are available methods adequate to characterize nano-TiO2 exposure via air,  water,
and food? What  properties of nano-TiO2 should be included in such exposure characterizations? Do
adequate methods exist to  characterize nano-TiO2 in relevant environmental matrices such as soil,
sediment, or biofilms and living organisms?

May 2010                                      2-16

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      Priority 4: How do surface coatings and physical and chemical properties affect
environmental chemistry and toxicity? Do wastewater treatment plant processes affect surface
coatings? What natural particle coatings are added in the environment (e.g., humic and fulvic acids)
and how do these natural coatings influence environmental fate, chemistry, and toxicity? How do
specific physicochemical properties, including particle surface treatments and
aggregation/agglomeration affect the fate and transport of nano-TiO2 in various environmental
media? How can species be described as they move from source to sink? What effect, if any, do
coatings, dopings, carriers, dispersants, and emulsion types have on biopersistence and
bioaccumulation? What factors determine whether and to what extent aggregation or agglomeration
of nano-TiO2 occurs? Emphasize the importance of chemical and physical characterization at a
number of stages in addressing possible toxicity of nanomaterials. What makes one type of
nanoparticle more active or toxic than another?

      Priority 5: Which sources, pathways, and routes pose the greatest exposure potential to nano-
TiO2 for biota and for humans (including children)? At what concentrations? Do particular species of
biota and populations of humans have greater exposure potential (e.g., high-end exposures due to
unusual conditions or atypical consumption)? In particular, do children get a higher exposure and/or
dose? What are the relative  contributions of different stages of life cycles of water treatment,
sunscreen, and other applications and products to environmental levels of nano-TiO2 and associated
contaminants in air, water, and soil?

      Priority 6: What is the global environmental content of nano-TiO2 now  and in the future?
Ecologically is TiO2 a point source or regional exposure problem? If a regional distribution issue,
what are concentration gradients in key media? By region and environmental segment (soil, water,
etc.), what is known about the background concentration and characteristics of nano-TiO2 due to
natural or non anthropogenic processes? Where does nano-TiO2 accumulate in the environment and
in humans? What is the current background level in humans? Does nano-TiO2  bioaccumulate in
humans?

      Priority 7: What might be the primary mechanism(s) of action and dose causing toxic effects
in different species or in different materials? Do nano- and conventional TiO2 have different
toxicological mechanisms of action or  do the two materials simply have a surface-area or surface-
coating  dependent difference in potency? Is the available  biological effects evidence adequate to
support  ecological risk assessment for nano-TiO2? If not,  what is needed? What are the fundamental
May 2010                                      2-17

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biological responses of nano-TiO2 interactions at the cellular level (as dictated by its physical and
chemical characteristics) (Are there dose interactions)?

      Priority 8: What are the effects of long-term exposures in relevant human and ecological
populations for specific nano-mixtures of concern (e.g., neurological, reproductive, integument
[skin])? Need to develop comprehensive health data. How do you prioritize to get specific health
effects data on specific TiO2s of concern, based on levels in the environment or based on short-term
effect data (as with PCBs)? What are the chronic, long-term effects of nano-TiO2 (ecological and
human effects)?

2.4.1. Comparison of Results  for Groups A  and B
      A question that arose during the design and planning of the workshop concerned whether the
results from the two NOT groups would be substantially similar or different. Table L-l (Appendix L)
lists the ranked priority issues for the plenary group and includes a column (Consolidated NGT
Priorities) that indicates the source of the issues that went into the consolidated priority. For
example, Priority 1 in Table L-l indicates that the top-ranked issue by Group A (i.e., A.I) was linked
with the third-ranked issue for Group B  (i.e., B.3). Similarly, Priority 2 comprised issues A.2 and
B.10.  The results are summarized in Table 2-6, examination of which suggests a high
correspondence between the groups in their top 5 priorities but some divergence in rankings
thereafter.
       Table 2-6.  Correspondence between top-ranked consolidated issues for Groups A and B

B.1
B.2
B.3
B.4
B.5
B.6
B.7
B.8
B.9
B.10
B.11a
B.11b
A.1


X









A.2
X











A.3

X










A.4



X








A.5






X





A.6












A.7












A.8












A.9a












A.9b








X



A.11












A.12












A.13




X







May 2010
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Chapter 3.  Prioritized  List of Questions/Topics to
   Consider in a Comprehensive Environmental
  Assessment Research Strategy for Nano-Ti02

    The top eight research priorities identified by the plenary group on Day 2 were further
discussed and articulated in breakout groups of five to seven participants each. As noted above, the
breakout groups were asked to prepare a short report using a standard format (Appendix M). The
format included a section for discussion of how the topic was related to related priority areas; in this
respect, participants were asked to focus only on the topi8 priority areas that had been voted upon
by the full group. Related priorities are referred to by their final rank number, i.e., 1 to 18, as listed in
Appendix L. The following sections present the individual breakout group reports with only minor
editing.

3.1.  Priority  1: Approaches and Methods for Evaluating
the Ecological and Human Effects of Nano-Ti02


3.1.1.  Breakout  Group Members
    Elizabeth Gasman, Raymond David, Carolyn Nunley Cairns, Fred J. Miller, Richard Canady,
and Sheila Kaplan

3.1.2.  Short Description
    It is necessary to understand what makes TiO2 a unique entity, where (if anywhere) it is found
in the environment or in humans, and what effects it may have on humans and the environment. If
information on effects is not garnered early in the assessment process, it may lead to characterizing
aspects of substances and exposures that are not meaningful or are misclassified.

3.1.3.  Why this Research/Information is Needed and of High Importance
    This is crucial to ensure that tests measure effects that are relevant to actual exposures
ecosystems and humans may experience from TiO2 in sunscreens, water treatment, and elsewhere. In
addition, the current problem concerning the lack of comparability among assays and  across test
materials needs to be solved.
May 2010                              3-1

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3.1.4. Extended Description

•     Are current EPA standard testing protocols adequate to determine nano-TiO2
      ecotoxicity? If not, what modifications or special considerations, if any, should be made
      in current ecological tests? For example, what are the differences in characterization of
      testing material (as raw material, in media, and in organisms), dispersion methods, and
      realistic exposure routes between testing conventional materials and nanomaterials,
      surficial aspects including co-transport and protein corona?

•     Are the current EPA harmonized health test guidelines for assessing toxicity adequate to
      determine the health effects/toxicity of nano-TiO2? Additional assays may be needed
      including regenerative cell proliferation, body burden distribution data, bronchoalveolar
      lavage (BAL) for inflammatory mediators. Other batteries of tests may be needed to
      evaluate other endpoints such as neurotoxicity and other possible hazards.

•     This topic applies to nanomaterials across the board and is not unique to nano-TiO2 or
      specific applications.

•     What criteria, especially associated with an inert colloidal particle, should the EPA use
      when evaluating harmonized test protocols?

•     What set of widely shared reference samples of nano- and conventional TiO2 would be
      most useful for integrating the results of different investigators regarding particle
      characterization and particle toxicology?

•     Is it certain that it is nano-TiO2 (or other nanomaterials) being assessed in the
      experiments performed (ecological/human)?

•     Does EPA have standardized research methods and terms to ensure that everyone is
      measuring the same thing, where that is the goal?



3.1.5. Other  Related Priority Areas

     This topic area is underpinned by the related topic areas in Priorities 12 and 15, relating to

standard metrics and reference materials; and Priority 4, relating to characterization. It also affects

Priority 8, effects of long-term exposure.



3.2.  Priority 2:  Physico-Chemical Characterization  of

Nano-Ti02 Throughout the Life Cycle Stages,

Environmental  Pathways, and Fate and Transport



3.2.1. Breakout Group Members

     Pratim Biswas, Jean-Claude Bonzongo, Thomas Lee, Shannon Lloyd, Anil  Patri, Maria

Victoria Peeler, and Sylvia Chan Remillard
May 2010                                  3-2

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3.2.2. Short Description

•      Physico-chemical characterization of nano-TiO2 throughout the life cycle stages,
       environmental pathways, and fate and transport.

•      Nanoscale in this case refers to EPA title rather than American Society for Testing and
       Materials (ASTM) or International Organization for Standardization (ISO) definitions.

•      Life cycle stages include those listed in the nano-TiO2 case study, as well as reuse and
       recycling, and includes both intentional and unintentional aspects of the life cycle stages.



3.2.3. Why this Research/Information is Needed  and of High Importance

•      This will develop an understanding of the real world physical and chemical properties of
       nano-TiO2 in the life cycle stages, environmental pathways, and fate and transport. This
       information will ultimately help to understand the implications on the environment and
       human health.

•      These research goals will eventually help in developing safer nanomaterials.



3.2.4. Extended Description

•      How do nano-TiO2 properties change as a result of the various manufacturing processes,
       upon its incorporation into products (e.g., in sunscreens and water treatment), during its
       use, during storage, upon release to the environment, upon  environmental aging
       (persistent state), and in different compartments?

•      How do specific physico-chemical properties, including particle surface treatments and
       aggregation/agglomeration, affect the fate and transport of nano-TiO2 in various
       environmental media?

•      Do we have sufficient information to identify the important physico-chemical
       characteristics of nano-TiO2 for the relevant stages of a CEA?



3.2.5. Other Related Priority Areas

•      Priority 4 (methods) comes after Priority 2 (characterization) because characterization
       data is required to predict the elements in Priority 4 (methods).

•      Priority 2 comes before Priority 1 (methods for testing health effects/ecotoxicity)
       because it is necessary to characterize and define physical chemical properties of nano-
       TiO2 before exposing organisms.

•      Priority 3 (methods for measuring exposure) must come before Priority 2.

•      Priority 2 identifies the physical and chemical characteristics of nano-TiO2 in Priority 5
       (exposure pathways) and Priority 6 (in the environment).

•      This connects to Priority 1 because thorough characterization is needed to understand the
       mechanisms of interaction of nano-TiO2 with the environment (ecological/human).

•      Priority 2 will provide data for Priority 10 (EPA or other curated databases).
May 2010                                     3-3

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•     Priority 2 relates to Priority 12 (metrics/standards to characterize nano-TiO2).


3.3.  Priority 3:  Analytical  Method Evaluation,
Development and Validation for Analysis of nano-Ti02  in
Relevant Matrices


3.3.1. Breakout Group Members
     Jeff Baker, Steven Brown, Shaun Clancy, John LaFemina, and Paul Westerhoff

3.3.2. Short Description
     Are available methods adequate to characterize nano-TiO2 exposure via air, water, and food?
What properties of nano-TiO2 should be included in such exposure characterizations? Do adequate
methods exist to characterize nano-TiO2 in relevant environmental matrices such as soil, sediment, or
biofilms and living organisms? Actions needed are to evaluate current methods, develop new
methods, and set up validation protocols (with reference materials).

3.3.3. Why this Research/Information is Needed  and of High  Importance
     Quantitative and qualitative characterization of nano-TiO2 is critical for understanding
exposure, dose, and biological and environmental effects. Standardized validated methods are a
critical aspect of comprehensive environmental assessment. Nano-TiO2 is and has been in production
and commerce and released to the environment. Limited analytical methods exist and preliminary
exposure assessments could be conducted for nano-TiO2. With more sophisticated analytical
methods, exposure assessment uncertainty can be reduced.

3.3.4. Extended Description
     This research priority pertains to sunscreen, water treatment, and other uses of nano-TiO2, as
well as for most other metallic-based nanomaterials, and in some case other non-metallic
nanomaterials. The details of methods are chemical-specific, but the need for evaluation,
development, and validation is common among all nanomaterials.
May 2010                                  3-4

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•      Are available methods adequate to characterize nano-TiO2 exposure via air, water, and
       food?

          o   Quantification and characterization needed at environmentally relevant levels.

          o   Terminology needs to differentiate dosage from exposure of nano-TiO2.

•      What properties of nano-TiO2 should be included in such exposure characterizations?

          o   Examples of measurement techniques that are currently available for simple
              matrices (air and water) include, but are not be limited to: size and number
              distribution, aggregates and agglomerates, particle counts (Euro V and Euro VI
              for air emissions), mass concentration, relative surface area, morphology, surface
              chemical properties and reactivity, and surface charge.

          o   Comparisons against reference nano-TiO2 materials are necessary for method
              validation and inter-laboratory comparison.

          o   Develop method/metric to differentiate nano-TiO2 from other  forms of TiO2 (e.g.,
              other sizes, aggregates of nano-TiO2). For example, less than 60 m2/g may be
              used in Germany, and ASTM is developing course/fine/nanomaterials.

•      Do adequate methods exist to characterize nano-TiO2 in relevant environmental and
       biological matrices such as soil, sediment, or biofilms and living organisms?

          o   Dosage needs to be included with exposure.

          o   In-situ measurements are desired.

          o   Food is one type of biological matrix.

          o   Quantification at the organism/organ/cell/sub-cellular level.



3.3.5. Other Related Priority Areas

•      Development of validated reference standards and testing protocols (Priorities 1 and 12).

•      Understanding how properties of nano-TiO2 change spatially and temporally requires
       valid methods (Priority 2).

•      Monitoring the current occurrence and sinks of nano-TiO2 requires valid methods
       (Priority 6).

•      Differentiation of nano-TiO2 to bulk (non-nano) TiO2 requires valid methods (Priority 8).

•      Relates to ALL other priority areas.
May 2010                                     3-5

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3.4.  Priority 4:  Nano-Ti02 Product-Focused Physico-

Chemical Characterization; Changes and Possible Effects

through the Life Cycle



3.4.1. Breakout Group Members

     Mark Bunger, Jaydee Hanson, Fred Klaessig, Richard Pleus, John Small, Treye Thomas, and

Donald Versteeg


3.4.2. Short Description

•     How do surface coatings and physical and chemical properties affect environmental
      chemistry and toxicity? Do wastewater treatment plant processes affect surface coatings?
      What natural particle coatings are added in the environment (e.g., humic and fulvic
      acids) and how do these natural coatings influence environmental fate, chemistry, and
      toxicity?

•     How do specific physico-chemical properties, including particle surface treatments and
      aggregation/agglomeration, affect the fate and transport of nano-TiO2 in various
      environmental media? How can species be described as they move from source to sink?

•     What effect, if any, do coatings, dopings, carriers, dispersants, and emulsion types have
      on biopersistence  and bioaccumulation?

•     What factors determine whether and to what extent aggregation or agglomeration of
      nano-TiO2 occurs?

•     What product-specific knowledge is necessary to conduct a CEA (Figure 3-1)?
May 2010                                 3-6

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           Start with the
                     product
                                      r  -
                                      v  _
What iS it?(ISOTC229WG3/PG5)
  • Agglomeration/Aggregation
  • Chemical composition
  • Size and distribution
  • Shape
  • Solubility / Dispersibility
  • Surface Area
  • Surface Chemistry
  • Surface Charge Chemistry

What do you call it?

What does it look like?

How does it work?

Does it change into another form?
       Figure 3-1.    Product-Specific Knowledge Highlighted in Priority 4.
3.4.3. Why this Research/Information is Needed and of High Importance

•      This work will enable the tests that cover the human and ecological endpoints to be
       related to the nature of the material.

•      The nature of the material will be used at some point in the future to help model and
       therefore predict the various properties and forms of nano-TiO2 in the life cycle.



3.4.4. Extended Description

•      This work is cross-cutting along all areas of environmental health. It is fundamental
       work that allows for identification of specific forms of nano-TiO2 through
       characterization. This work can be useful, in the future, to model and predict potential
       effects.

•      It pertains to all forms of nano-TiO2, rather than to only a specific application of nano-
       TiO2.

•      It pertains to nanomaterials in general, including, but not limited to nano-TiO2.

•      It is necessary to examine typical fate and transport issues, such as bioaccumulation and
       biopersistence.
May 2010
3-7

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3.4.5. Other Related Priority Areas
       Validate or invalidate the protocols, if and when and where they apply to the life cycle
       (Priority 1).

       This work would clearly identify the material in the environment, whether point or non
       point source, background, natural, or anthropogenic. If shown to bioaccumulate or
       biopersist, this work allows for the characterization of the material. This is useful for
       correctly identifying the material and possibly in predictive modeling (Priority 6).

       This work allows for the characterization of forms of nano-TiO2 in food, soil, water, and
       air (as well as other media). It would allow for the determination of different physico-
       chemical parameters that are related to the amount and behavior of forms of nano-TiO2
       (e.g., the difference between a material staying in air or depositing on the ground)
       (Priority 3).

       This work allows for the characterization of forms of nano-TiO2 in various pathways of
       exposure for human or ecological endpoints (Priority 5).

       If measuring toxicity, then it is possible to characterize the form of nano-TiO2. This
       could allow for greater understanding of the mechanism of action, modeling, or
       prediction of possible endpoints (Priority 7).

       Priorities  12 and 15 are essential for the validation of the characterization tests (Priority
       4). There is need for consolidation of Priorities 2, 3, 5-7, 9-11, 14, and 18.

       If ecological effects are discovered, then this work can be used to characterize the forms
       of nano-TiO2 (Priority 8).
3.5.  Priority 5:  Exposure Pathways and Life Cycle
Analysis


3.5.1. Breakout Group Members

     Brenda Barry, Cathie Barton, Janet Carter, Joan Denton, Bert Hakkinen, and Chris Long

3.5.2. Short Description

     This research adopts a life cycle analysis approach to understanding the different sources and
pathways that present the greatest current and future exposures to nano-TiO2 for humans (including
both susceptible and highly exposed populations) and biota. The approach used in this research is
intended to apply to materials beyond nano-TiO2.

3.5.3. Why  this Research/Information is Needed and of High  Importance

     Exposure information is an equal partner with toxicology in assessing and managing potential
risks of [nano-]TiO2. This research is needed to develop epidemiology studies, environmental trend


May 2010                                   3-8

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analyses, and life cycle analyses; realize risk management opportunities; and inform hazard studies

and method development (e.g., sampling, monitoring, analytical).


3.5.4. Extended Description

      While the results may be application-specific, the approach is anticipated to be applicable to a

variety of nanoscale materials. This research applies to specific forms of nano-TiO2 and to those

materials that have similar properties. The life cycle approach is the most holistic way to consider all

potential exposures to nano-TiO2 for  a given application. This research topic includes:

•      Which sources, pathways, and routes pose the greatest exposure potential to nano-TiO2
       for biota and/or humans? At what concentrations?

•      Do particular species of biota and particular human populations have greater exposure
       potential (e.g., receptors with high-end exposures,  and/or sensitive subpopulations, such
       as children, elderly, those with compromised health)?

•      What are the relative contributions at different stages of the life cycle for applications
       such as water treatment, sunscreen use, etc.



3.5.5. Other Related Priority Areas

•      Building databases (Priority 10).

•      Setting up metrics/parameters and standardized exposure protocols (Priority 1).

•      Developing methods for characterization (Priority  3) and changes in properties along the
       life cycle (Priority 2).

•      Setting health effects research priorities (Priority 8).

•      Characterizing worker exposures that are compatible with hazard information including
       concentrations, routes, frequencies, and durations that characterize worker exposures
       across  life cycles and within certain stages of exposure (Priority 13).

•      Evaluating coatings and dopings (Priority 4).

•      Standardizing terminology and nomenclature properties for current and future use
       (Priority 11).
May 2010                                      3-9

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3.6.  Priority 6:  Spatial and Temporal Distribution and
Magnitude of Anthropogenic and Non-Anthropogenic
Nano-Ti02  in the Environment


3.6.1. Breakout Group Members
     David Andrews, Patricia Holden, Todd Kuiken, Michele Ostraat, and Bill Warren-Hicks

3.6.2. Short Description
     This priority area regards where TiO2 originates in the environment at manufacturing,
transport, and use points and its distribution from points of origins at current and future levels of
production and use. This area assumes suitable characterization methods and protocols to detect and
quantify nano-TiO2 concentrations and characteristics in a wide variety of soils, water, air, and biota.
•     What is the global environmental content of nano-TiO2 now and in the future?
•     Ecologically, is TiO2 a point-source or regional-exposure problem? If a regional-
      distribution issue, what are the concentration gradients in key media?
•     By region and environmental segment (soil, water, etc.), what is known about the
      background concentration and characteristics of nano-TiO2 due to natural (non-
      anthropogenic) processes?
•     Does nano-TiO2 bioaccumulate in humans?
•     Where does nano-TiO2 accumulate in the environment and in humans? What is the
      current background level in humans?

3.6.3. Why this Research/Information is Needed and of High  Importance
     This research priority area is central and foundational to any regulatory risk-based decision on
nano-TiO2 because the exposure concentrations will be compared to the human or ecological no-
effects concentrations to determine the magnitude of risk. Background concentrations are critical to
establishing the accountability of the anthropogenic sources and to providing insights into risk
reduction strategies. Establishing future concentrations based on current use activity levels can also
provide insight into potential bioaccumulation rates and extents in biota and humans.

3.6.4. Extended Description
     This area does not pertain to any specific application of nano-TiO2 but provides a general
discussion nano-TiO2 uses. These issues broadly apply to other nanomaterials. The following bullets
May 2010                                  3-10

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provide elaboration on issues associated with the implementation and methodological challenges

associated with the short description provided previously.

•      Background

           o  Requires a sampling system in production, in formulation, in use, in service, and
              in disposal. Actual production levels will be used to bound the mass balance. A
              program for a well-designed survey is required to establish the background
              concentrations and characteristics of nano-TiO2.

•      Current

•      Local / point

           o  Establish the maximum possible amount of nano-TiO2 in the environment based
              upon historical production numbers to place a floor and ceiling on the nano-TiO2
              production levels. This would require:

                 •   Literature searches and information gathering of historical data.

                 •   Establishing a national database of total production of TiO2 and
                     implementation of internal guidance to record relative percent of nano-
                     TiO2.

           o  Conduct spatial sampling adjacent to production/processing  sites and pristine
              sites for comparative analysis. This  sampling requires appropriate
              characterization and protocols to assess nano-TiO2 detection in soils, water, air,
              and biota. This will produce a geospatial concentration gradient throughout the
              United States.

•      Regional

           o  Establish a database that  tabulates nano-TiO2 uses and captures information on
              seasonal and regional uses.

           o  Compare production, formulation, use, service, and disposal amounts to quantify
              point sources for further analysis. Then, extend spatially beyond point sources to
              capture spatial distribution for fate and transport understanding (specially
              focused on emissions issues or accidental release).

•      Future

           o  Implement a long-term monitoring program to capture point-source and regional
              values as well as the environmental  burden in water, soils, air, and biota.

           o  Utilize current information to facilitate the understanding of the long-term
              predictive modeling of fate and transport of nano-TiO2 into and within the
              environment.

                 •   Project changes in production, emissions, and relative percentages in-use
                     to highlight potential environmental  hotspots and  to establish procedures
                     for areas that may require remediation.

                 •   Predict the future spatial and temporal concentrations of nanoTiO2 in soil,
                     water, air, and biota.
May 2010                                      3-11

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                   Use models and monitoring data to identify potential accumulation in the
                   environment, in biota, and up the food chain.
3.6.5. Other Related Priority Areas
      Priority 3 relates to whether or not methods are adequate to characterize exposures and
      are methods adequate to characterize nano-TiO2 in relevant environmental matrices.

      Priority 4 also addresses bioaccumulation and the impact of coatings and other
      formulations.

      Priority 2 involves life cycle issues, a concept highly related to the proposed monitoring
      system discussed above.

      Priority 8 discusses ecological studies of long-term exposures that, together with the
      long-term monitoring, are required to estimate risk.

      Fate and transport modeling concepts for predicting and forecasting concentrations are
      lacking. This needs to be a priority area for funding (Priority not ranked).
3.7.  Priority 7:  Using Mechanism  of Action (MOA)
Information to Drive Toxicity Testing


3.7.1. Breakout Group Members

     Gary Ginsberg, Srikanth Nadadur, Geoffrey Sunahara, Jeffery Steevens, and John Veranth

3.7.2. Short Description

     For a well-defined nano-Ti[O2] material, what are the adverse biological effects across
multiple species, how does it produce these effects (MOA), what is the dose response for the adverse
effects and upstream effects, and how does this relate to dose response for conventional materials?
What is the interpretation of this information for risk assessment at environmentally relevant
concentrations?

3.7.3. Why this Research/Information  is Needed  and of High Importance

     This information needs to be used to develop a toxicity testing paradigm tailored to detect the
types of effects produced by nano-TiO2 materials.
May 2010                                  3-12

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•      Identify key dose metrics for dose-response evaluation using MOA.
•      Identify key response metrics for upstream indicators (i.e., reactive oxygen species
       [ROS], cell signaling).
•      Use metrics to understand if conventional and nano-TiO2 will have same MOA.
•      Predict if interactions will occur (e.g., light, metals, other chemicals).
•      Provide biological basis for [structure-activity relationship] (SAR) approaches.

3.7.4. Extended Description
      Mechanism  of Action. How does nano-TiO2 produce changes at the molecular, cellular,
organism (e.g., skin, lungs, internal organs) and whole-animal level? This may include generation of
ROS, photoactivation, binding to receptors, cell signaling, and gene expression. MOA can be used to
identify key dosimetrics for dose-response evaluation (surface area, particle size, surface charge,
etc.).
•      Dosimetric - what is really doing the damage and how is it measured?
•      Response-metric - identify the most sensitive upstream indicator effects that can be
       plugged into dose-response endpoints.
      Use MOA information to understand whether conventional and nano-TiO2 have the same
MOA and whether  the major distinction is simply in terms of potency.
      Interactions. Use MOA information to understand how nano-TiO2 can interact with light
energy and other toxicants (particularly metals) to produce novel effects. MOA is our bridge to
developing SAR-type approaches for nanomaterials.
      Dose-Response. How do the biological effects and MOA change when going from high dose
to environmentally relevant doses? The dose-response relationship in sensitive species and age
groups is needed for developing estimates of potency used in risk assessment. This dose-response
and mechanistic information needs to be informed by  an up-front literature review and evaluation
that identifies whether risk assessment is possible with the current information and what key data
need to exist to facilitate risk assessment.
      Testing  Strategy. Standard toxicity testing may not capture the effects produced by nano-TiO2
materials. MOA needs to inform toxicity testing (e.g., incorporate photoactivation into testing
protocols) to ensure that nano-Ti[O2] effects are captured.
3.7.5. Other Related Priority Areas
      This priority is related to many other priority areas (Figure 3-2). It will be necessary to start
with physical and chemical characterization (Priority 4). Next, it is necessary to look at
May 2010                                      3-13

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manufacturing processes and products (i.e., what is it?) and relevant form and environmental matrix
(Priorities 2 and 6) to compile databases (Priority 10). Then, aim to determine kinetics and realistic
dose (Priority 9), particularly to sensitive populations (Priority 5), that will cause effects (Priority 1)
using specific endpoints (Priority 8). In order to do these things, the MOA must be known (Priority
7). This research also depends on the development of nomenclature (Priority  11) and
prototype/reference materials (Priority 12).
                        Physical and Chemical Characterization (4)
      Manufacturing
       processes,
   products...what is it?
           (2)
 Relevant Form and
Environmental Matrix
      (3/6)
                    Realistic Dose? (6)
               Sensitive Populations (5)
            Kinetics?
                                      Database (9b)
Is There an Effect?
       (1)

       t

       +
                                                  (7)
                                         What are
                                      Mechanisms of
                                         Action?
                                                                       t
                                                                        i
                                                                        i
              Nomenclature (11) and Prototype/Reference Materials (12)
       Figure 3-2.    Priority Areas Related to Priority 7
3.8.  Priority 8:   Long-Term Effects
3.8.1. Breakout Group Members
      Eula Bingham, Paul Howard, Rebecca Klaper, Margaret MacDonell, Nancy Monteiro-Riviere,
Paul Mushak, and Nigel Walker
May 2010
                3-14

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3.8.2. Short Description
•      What are the long-term human effects following exposure to nanomaterials?
          o  Are in vitro (e.g., high throughput screening assays) appropriate for prioritizing
             specific nano-TiO2 for further long-term evaluation?
          o  Assessment of kinetics of TiO2 in mammalian systems (in vivo).
          o  Long-term exposure outcomes
                 •   human (epidemiology) and animal models (subchronic to chronic).
                 •   oral
                 •   inhalation
                 •   dermal
•      What are the long-term ecological effects following exposure to nanomaterials?
          o  Long-term assays (organism to ecosystem measures).
                 •   Organism/population (key organisms in aquatic, terrestrial, and air).
                 •   Number that survive, kinetics, reproductive problems, other endpoints
                    (e.g., tumors, biomarkers of effect).
          o  Community and ecosystem impacts (functional community, total population).
                 •   Microbial functional community
                 •   Nutrient cycling changes

3.8.3. Why this Research/Information is Needed and of High Importance
     Risk is a combination of exposure and hazard. The work in this area will assess the hazard and
dose response for effects of concern. Both short-term and long-term data are required for proper
assessment of potential risks. If there is no adverse effect, there is no risk. The outcomes of short-
term studies do not necessarily predict long-term effects.

3.8.4. Extended Description
     This topic area is determining the long-term effects of nano-TiO2 on ecosystems and humans,
allowing the determination of risk (hazard X exposure). The descriptions, herein, apply to nano-TiO2
and to other nanomaterials, in general; however, the elements described were developed in view of
the specific case of nano-TiO2.
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      In this risk-assessment document there are limited data on acute effects of TiO2; however,
there is a significant lack of data on long-term effects that would drive the risk assessment models.
To determine long-term human effects for nanomaterial exposure the following is needed:
•      Evaluate the appropriateness of in vitro (e.g., high throughput screening assays) for
       prioritizing specific nano-TiO2 for further long-term evaluation.
•      Assess kinetics of TiO2 in mammalian systems.
•      Generate and collect research data on long-term exposures.
      For the near-term research agenda, this means models of chronic animal exposure. For the
longer-term research agenda, this means data on human epidemiology. One practical solution is to
use assessment of the ecological data to prioritize the materials that will be used to test in humans (as
with PCB's, aquatic bioaccumulation identified the priorities for which PCBs to test).
3.8.5. Other Related Priority Areas
      How can EPA partner with other agencies and industry to better achieve the goals of the CEA
(the priority questions from this workshop)? Although these are all related priorities, [they] should
not all be responsibility of EPA (considering resources, funding, and expertise)? Should there be
collaborations with other agencies, industry, and academia (Priority not ranked)?
      Related priority areas include:
•      Routes of exposure and most sensitive populations (Priority 5).
•      Adequacy of protocol (Priority 1).
•      Characterization methods; if you don't know what you are testing, you don't know how
       it relates to the nanomaterial in environment (Priority 3).
•      Manufacturing, use and release (Priority 2).
•      Coating and modifications, physical chemical properties, and how effect biopersistence
       and bioaccumulation (Priority 4).
•      Spatial, release, sources of exposure (Priority 6).
•      Mechanism of action and dose response (Priority 7).
      Also related are the following:
•      Priority 9 - Is the available ecotoxicity evidence adequate to support ecological risk
       assessment for nano-TiO2? If not, what is needed? What are the sensitive ecological
       endpoints? How do abiotic factors in the environment, such as UV, pH, oxygen level,
       and other chemicals, affect nano-TiO2 and its ecological effects?
May 2010                                      3-16

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       Priority 10 - Should EPA set up comprehensive, user friendly databases with all
       information (such as metrics, toxicity data (current database), characterization, fate, etc.)
       to support comprehensive environmental assessments? What has the EPA learned about
       the quality of the TiO2 data in the open literature as applied to nano-TiO2 and other
       particles?

       Priority 11 - What needs to be standardized as terminology/nomenclature/ properties for
       current and future use? Should the EPA promote a surface chemistry nomenclature
       system for use in particle life cycle analyses? What is nano-TiO2? Is the definition of less
       than 100 nm adequate? Or, should a dimension be derived based on the toxicological
       properties?

       Priority 13 - What parameters should be used to characterize worker (or consumer or
       general human) exposure in a way that is compatible with hazard information.  (Exposure
       matches hazard.) What concentrations, routes,  frequencies, and durations characterize
       worker exposures to nano-TiO2 across the life cycle and within certain stages (e.g.,
       manufacturing)?

       Priorities 12 and 15 - What are the important metrics and standards that we need to use
       to characterize nano-TiO2? What is the role of standard reference materials for
       integrating the results of different investigators regarding particle characterization and
       particle toxicology? What is needed? Can we develop a decision-tree framework and
       best practices to facilitate environmental assessment of individual nanomaterials? Would
       a toxicity - application - exposure - life-cycle assessment - order in a decision tree be
       workable for conducting a CEA for nano-TiO2? How do we integrate analytical methods
       used to characterize risk (mass flow, life cycle) to evaluate and compare environmental
       trade-offs?
May 2010                                     3-17

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        Chapter 4. Observations  and  Next Steps

     The ranking results and breakout group reports presented in this document represent only a
portion of the data provided by the participants in this process. In particular, the specific issues
identified by the individual participants could be examined more extensively to see if some gems
were overlooked or lost in the consolidation and voting process. One unstated hope underlying the
development of the case studies and the review and workshop associated with the case studies was
that bringing a diverse array of technical and stakeholder perspectives to bear on the questions raised
by the selected nanomaterial applications might yield insights that would be useful in averting
unintended consequences of this emerging technology. Closer examination of specific issues and
comments submitted by the participants and other reviewers may still uncover such insights. Also,
more detailed analyses of the ranking data in Appendices K and L remain to be done.
     Various aspects of the workshop could have been done differently and probably improved.
Given that the ranking results of the two NOT groups were similar, it now seems clear that
conducting the workshop with a smaller number of participants would have likely achieved similar
outcomes, particularly for the most highly ranked issues. Apart from the reduced expense of having a
smaller number of participants, the process of consolidating the two groups' issues in a plenary
session could have been avoided and more time freed up for the breakout groups. Many participants
completed workshop evaluations forms and referred to the breakout group discussions as one of the
best features of the meeting. By allowing more time for the breakout groups, we might have enabled
them to develop their thoughts in greater detail or perhaps we could have posed additional questions
and tasks for them to address. Also, more time might have allowed for a more formal consensus
process among the breakout group members in preparing their reports and presentations.
     Some seemingly minor procedural matters may have had some influence on the process and
results. For example, for the round-robin sessions, the NWRI NGT workshops (http://www.nwri-
usa.org/) required participants to come to a lectern and present their views to the group, whereas in
the EPA workshop the facilitators allowed participants to remain seated while speaking to the group.
Although equivalent time limits on individual statements were imposed in both situations, remaining
seated probably saved an appreciable amount of time overall. However, the informality of remaining
seated may have contributed to a more casual attitude on the part of some participants and what
appeared to be, from this author's non-scientific observation, a corresponding lack of incisiveness in
their statements.
     Of course, other differences  between the NWRI and EPA workshops could have also
influenced how the participants approached the round-robin session. It could be that the NWRI
participants were more familiar with the NGT process because of their repeated participation in such
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meetings. The NWRI workshops are more narrowly focused on water-related issues and
intentionally involve experts in that field, so there is a more limited pool of candidates and hence
greater likelihood of repeated participation. Prior experience with the process could lead to more
effective presentations. In contrast, a greater proportion of participants in the EPA workshop may not
have realized the importance of making a cogent argument for their viewpoint, despite (or because
of?) the fairly terse instruction in the pre-workshop handout (Appendix I) to be prepared to offer a
"statement or description of the research/information need and an explanation of why it is a high
priority in relation to a comprehensive environmental assessment of nanoscale titanium dioxide
(nano-TiO2)."
      Another observation on the EPA workshop outcomes is that they tended to reflect a high
degree of consolidation across several individual issues. As listed in Section 2.4, most of the priority
areas subsumed at least 5 questions, and a couple of areas covered 7 questions. This tendency toward
convergence may have reflected a propensity for "lumping" as opposed to "splitting" for a majority
of the participants, but a more likely explanation is that consolidation was a prominent feature of the
workshop and was explicitly encouraged. The problem with too much consolidation is that, at an
extreme, one  ends up with the highest priority question being "What are the risks of nanomaterials?"
- which of course simply begs the question and provides no insight into which specific research
areas warrant the most attention.  For a group made up predominantly of researchers who may tend to
think in terms of specific scientific projects, a push to consolidate related ideas together into a more
broadly stated topic area may be  appropriate. But for a group that is more heterogeneous  in
composition,  especially one that includes a number of persons already inclined (or instructed) to
think about the "big picture," less encouragement to consolidate multiple issues might be
appropriate.
      Among the next steps to be taken to follow up the 2009 EPA workshop are plans to hold
another workshop using a case study focusing on nanoscale silver in spray  disinfectants. At this time,
we presume we will use an NGT process again, although modifications of the process, reflecting
observations made above, are likely. The objective in developing a series of nanomaterial case
studies and holding workshops to identify and prioritize research needs is not simply to see how
different nanomaterials compare to each other. Rather, the ultimate goal is to develop a broad, long-
range strategy for determining where research should be directed to best support efforts to conduct
comprehensive environmental assessments of nanomaterials. This new research strategy will likely
evolve as different case studies are considered and as new information on existing case studies
becomes available. Thus, it will not be a static document, but one that reflects an evolving
understanding of nanomaterials and their (broadly defined) environmental implications. We believe
that however  it evolves, it will benefit from a process that takes advantage of formally tapping the
collective judgments of diverse groups of technical experts and stakeholders.

May 2010                                      4-2

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                                        References
Cooke RM(1991). Experts in uncertainty: opinion and subjective probability in science (Environmental ethics and science
       policy). New York City, NY: Oxford University Press, Inc. 598306

Cooke RM; Goossens LHG (2004). Expert judgement elicitation for risk assessments of critical infrastructures. J Risk Res,
       7: 643-657. 598304

Davis JM (2007). How to assess the risks of nanotechnology: Learning from past experience. J Nanosci Nanotechnol, 7:
       402-409. 089803

Davis JM; Thomas VM (2006). Systematic approach to evaluating trade-offs  among fuel options: The lessons of MTBE.
       AnnN YAcad Sci, 1076: 498-515. 089638

Delbecq AL; Van de Ven AH (1971). A group process model for problem identification and program planning.  J Appl
       Behav Anal, 7: 466-492. 598309

Linkov I; Steevens J; Adlakha-Hutcheon G; Bennett E; Chappell M; Colvin V; Davis JM; Davis T; Elder A; Hansen SF;
       Hakkinen PB; Hussain SM; Karkan D; Korenstein R; Lynch I; Metcalfe C; (2008). Emerging methods and tools for
       environmental risk assessment, decision-making, and policy for nanomaterials: summary of NATO Advanced
       Research Workshop. J Nanopart Res, 11: 513-527. 157531

NEHI (2008). The National Nanotechnology Initiative (NNI) - Strategy for nanotechnology-related environmental, health,
       and safety (EHS) research. The National Nanotechnology Initiative (NNI); Nanotechnology Environmental and
       Health Implications (NEHI) Working Group; Subcommittee onNanoscale Science, Engineering, and Technology
       (NSET); Committee on Technology (CT); National Science and Technology Council (NSTC). Washington,
       DC.http://www.nano.gov/NNI_EHS_Research_Strategy.pdf. 598308

NRC (2009). Review of the federal strategy for nanotechnology-related environmental, health, and safety research.
       National Academies Press. Washington, DC.http://www.nap.edu/openbook.php?record_id=12559&page=Rl.
       597919

Seager TP; Linkov I (2008). Coupling multicriteria decision analysis and life  cycle assessment for nanomaterials. J Ind
       Ecol, 12: 282-285. 157493

Stahl CH; Cimorelli AJ; Chow AH (2002). Anew approach to environmental decision analysis: multi-criteria integrated
       resource assessment (MIRA). Bull Sci Tech Soc, 22: 443-459.  041601

U.S. EPA (2007). Nanotechnology white paper. Science Policy Council, Nanotechnology Workgroup, U.S. Environmental
       Protection Agency. Washington, DC. EPA 100/B-07/001. http://www.epa.gov/osa/pdfs/nanotech/epa-
       nanotechnology-whitepaper-0207.pdf. 090564

U.S. EPA (2009). Expert elicitation task force white paper (external review draft). Sciece Policy Council, U.S.
       Environmental Proteciton Agency. Washington,
       DC .http://yosemite.epa.gov/sab/sabproduct.nsf/368203f97al5308a852574ba005bbd01/F4ACE05D0975F8C68525
       719200598BC7/$File/Expert_Elicitation_White_Paper-January_06_2009.pdf. 598301
U.S. EPA (2009). Nanomaterial case studies: Nanoscale titanium dioxide in water treatment and topical sunscreen (external
       review draft). U.S. Environmental Protection Agency. Research Triangle Park, NC.  EPA/600/R-09/057.
       http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=210206.  225004
Note: Hyperlinks to the reference citations throughout this document will take you to the NCEA HERO database (Health and
Environmental Research Online) at http://epa.gov/hero. HERO is a database of scientific literature used by U.S. EPA in the process of
developing science assessments such as the Integrated Science Assessments (ISAs) and the Integrated Risk Information System (IRIS).
May 2010                                             R-1

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        APPENDIX A. Nano-Ti02 Case Studies  Document

     Nanomaterial Case Studies: Nanoscale Titanium Dioxide in Water Treatment and in Topical
Sunscreen [External Review Draft], U.S. Environmental Protection Agency, National Center for
Environmental Assessment, Research Triangle Park, NC, Report No. EPA/600/R-09/057, July 2009,
is a 222-page document (U.S. EPA, 2009, 225004) that can be accessed at:
http://cfpub.epa.gov/ncea/cfm/recordisplay. cfm?deid=210206
May 2010                                A-1

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       APPENDIX B. List of Questions from the Nano-Ti02

                             Case Studies Report


       Chapter 1 of Nano-TiO2 Case Studies Report: Introduction


             Questions about Characterizing Nanoscale Titanium Dioxide

1-1. To evaluate nano-TiO2 (in these or other applications) or to compare products containing nano-
    TiO2, is further standardization or refinement of terminology needed? If so, is such an effort
    underway and/or what terminology is most important to standardize?

1-2. Have the properties of nano-TiO2 in different applications been adequately characterized? If not,
    is the general problem that methods do not exist or that existing methods have not been widely
    applied? If new methods are needed, what properties should they measure?

1-3. Which coatings, dopings, carriers, dispersants, and emulsion types are most prevalent in
    different applications of nano-TiO2?

1-4. What are the potential implications (e.g., in terms of physical and chemical properties) of
    differences in the composition and mineralogy of different forms of nano-TiO2 (e.g., rutile and
    anatase)?

1-5. How do coatings applied for different purposes (e.g., to disperse particles or to decrease
    photocatalysis) interact or affect other properties of nano-TiO2?

1-6. What factors determine whether and to what extent aggregation or agglomeration of nano-TiO2
    occurs?

1-7. Are data available that indicate the level of agglomeration/aggregation/dispersion of nano-TiO2
    in specific products? If so, what do the data show?

1-8. Is there a difference between the opacity of nano-TiO2 aggregates and conventional TiO2
    particles of nominally similar size (e.g., because of light passing through pores in aggregates)?
    If so, what are the implications of such a difference?

1-9. Regarding the properties of aggregates and agglomerates and proper characterization of particle
    size, what insight is available from study of other nanoparticles?

1-10. What existing or emerging analytical techniques might be relevant or useful for material
    characterization? For example, could field flow fractionation (FFF) be used for characterization
    of particle size and elemental composition?

1-11. Do surface area measurements in air (e.g., BET analysis) correlate to surface area in an
    aqueous environment? If so, what is the extent of their accuracy and precision?

       Chapter 2 of Nano-TiO2 Case Studies Report:
       Life  Cycle  Stages

             Questions about Feedstocks

2.1-1. Are certain feedstocks more relevant to producing nano-TiO2 specifically for water treatment
    or sunscreen applications?
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2.1-2. What contaminants, nanoscale and larger, might be released, and in what quantities, in relation
    to the procurement and processing of feedstocks for nano-TiO2?

              Questions about Manufacturing

2.2-1. How do various manufacturing processes for nano-TiO2 affect their physicochemical
    properties?

2.2-2. How are manufacturing processes likely to evolve with increasing demand for nano-TiO2?

2.2-3. Are certain manufacturing processes used specifically for nano-TiO2 as a water treatment
    agent or as topical sunscreen?

2.2-4. What waste products  or other by-products, both nanoscale and larger, might be released, and
    in what quantities, for nano-TiO2 manufacturing processes?

2.2-5. Where is nano-TiO2 manufactured? What is the potential for general population exposure to
    nano-TiO2 in these areas?

               Questions  about Distribution and Storage

2.3-1. How is nano-TiO2 shipped (i.e., what are the relative frequencies for shipments in bulk, paper
    bags, or drums, or by truck or rail)? How far is it shipped? In what quantities?

2.3-2. Are data available or can they be collected or estimated for accident rates and routine product
    releases associated with various modes of shipping and storage? To what degree could best
    practices reduce such occurrences?

2.3-3. How is nano-TiO2 stored (e.g., in warehouses, sunscreen manufacturing plants, and water
    treatment facilities)?

2.3-4. Does the use of "ventilated paper bags" increase the possibility of accidental spillage during
    shipment and storage? Are any guidelines available on whether protective packaging (e.g.,
    additional polyethylene lining) is warranted?

2.3-5. Could vermin breach storage containers and contribute to environmental releases or become
    part of an environmental exposure pathway?

2.3-6. Would prolonged storage in adverse or less than ideal climates (e.g., cold or humid
    environments) alter nano-TiO2 characteristics and behavior?

2.3-7. How much nano-TiO2 could be released under various routine and accidental scenarios of
    distribution and storage?

               Questions  about Use

2.4-1. To what extent is nano-TiO2 used or could be used for either drinking water or waste water
    treatment? Are data available (e.g., volume of water currently treated in the United States for
    arsenic, amount of TiO2 needed to  treat a given volume of water) that would permit an estimate
    of potential use?

2.4-2. Which water treatment processes use or would use nano-TiO2 and in what quantities? Would
    the  type of process depend on the size of a treatment facility or the size of the population served,
    or both?

2.4-3. What percentage of the nano-TiO2 would settle out in floe or become part of the filter matrix?
    What percentage would be released into finished water? Are measurement or monitoring
    methods adequate to detect such particles?
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2.4-4. Water distribution systems often have substantial biofilm or corrosion development, despite
    the implementation of control practices. Would the presence of nano-TiO2 influence the
    bacterial biofilm community or the occurrence of corrosion?

2.4-5. What is the total quantity of nano-TiO2 used in topical sunscreen products in the United States
    and worldwide?

2.4-6. What is the maximum quantity and frequency of personal sunscreen use in relation to season,
    geographic location, demographics, and other variables?

2.4-7. How much nano-TiO2 enters the environment under different scenarios and conditions of
    sunscreen use (e.g., ambient air and water temperature, swimming, bathing)? Under what
    conditions would nano-TiO2 be released from the sunscreen matrix?

               Questions about Disposal

2.5-1. How much residual nano-TiO2 is present in packaging of the primary material or derived
    products? How is such packaging disposed of?

2.5-2. If nano-TiO2 were to become much more widely used and produced at a much higher volume,
    would packaging and shipping methods of nano-TiO2 change? If so, how would such change
    affect the potential release and exposure during transport, storage, and disposal?

2.5-3. In water treatment, how are filter materials and associated waste/waste water containing nano-
    TiO2 disposed of or recycled?

2.5-4. How are large quantities of sunscreen (e.g., sub-par batches rejected during manufacturing)
    handled?

2.5-5. How much nano-TiO2 is present in sunscreen containers that are discarded? Are there any
    circumstances where such discarded product could enter a microenvironment at significant
    levels?


       Chapter 3  of Nano-TiO2 Case Studies Report:
       Fate and Transport

3-1. What are the relative contributions of different stages of the life cycles of water treatment and
    sunscreen products to environmental levels of nano-TiO2 and associated contaminants in air,
    water, and soil?

3-2. How do specific physicochemical properties, including particle surface treatments and
    aggregation/agglomeration, affect the fate and transport of nano-TiO2 in various environmental
    media?

3-3. Are available fate and transport models applicable to nano-TiO2? If not, can they be adapted, or
    are new models required?

3-4. Is information on environmental  fate and transport of other substances available that might
    provide insights applicable to nano-TiO2?

3-5. If nano-TiO2 production were to increase greatly, the packing and transport methods are likely to
    be changed as well. How would this affect the fate and transport of nano-TiO2?

3-6. How might nano-TiO2 affect the  fate and transport of metals and other potentially toxic
    substances in water or other environmental media?
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3-7. What is the bioavailability of nano-TiO2 in land-applied sludge to both terrestrial and aquatic
    organisms? Is bioavailability likely to change when nano-TiO2 is incorporated into sludge and is
    allowed to "age" (in- situ weathering)?

3-8. What effect, if any, do coatings, dopings, carriers, dispersants, and emulsion types have on
    biopersistence and bioaccumulation?

3-9. Can the photocatalytic properties of nano-TiO2 cause other unintended substances to form, for
    example, degradation products, in various environmental media?

3-10. Will nano-TiO2 affect the efficacy of other major elements of water treatment processes (e.g.,
    chemical disinfection, the coagulant concentration necessary for effective organics removal)?

3-11. What  influence could other drinking water contaminants, including arsenic, have on the
    chemical properties or behavior of nano-TiO2?

3-12. Irradiated photocatalytic nano-TiO2 is  potentially biocidal and antimicrobial. What is the
    potential  for interactions of nano-TiO2 with microbes needed in water treatment systems?

3-13. What are the key environmental factors (e.g., pH, natural organic matter type and
    concentration, temperature) that facilitate or hinder nano-TiO2 stability in the aqueous
    environment? Would humid acids or  other common constituents or contaminants in water
    undergoing treatment affect the fate, including agglomeration/aggregation properties, of TiO2?

3-14. What is  the impact to nutrient and metals cycling and microbial diversity when sludge with
    nano-TiO2 is applied to soils?

3-15. How do sunscreen ingredients affect nano-TiO2 fate and transport?

3-16. Can agglomeration/disagglomeration in the environment be predicted on the basis of physical
    properties of the particle, for example, size, shape, or coating?

3-17. What is  the likelihood that nano-TiO2 in biosolids will become part of the food web and
    ground water contamination?

3-18. What is  the potential for plant uptake of nano-TiO2 from contaminated soil and irrigation
    water?


       Chapter 4 of Nano-TiO2 Case  Studies Report:
       Exposure-Dose Characterization

4-1. Which sources,  pathways, and routes pose the greatest exposure potential to nano-TiO2 for
    biota?  ...  for humans?

4-2. What is the potential for biota and human (both occupational and general population) exposure
    to secondary contaminants (e.g., waste or transformation products) associated with the entire
    life cycle of water treatment or sunscreen applications of nano-TiO2?

4-3. Do  particular species of biota and populations of humans have greater exposure potential (e.g.,
    high-end exposures due to unusual conditions or atypical consumption)? In particular, do
    children get a higher exposure and/or dose?

4-4. What is the total population that could be exposed to nano-TiO2 via drinking water? ... via
    topical sunscreens?

4-5. Approximately how many workers are involved in nano-TiO2 production, distribution, and use?
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4-6. What concentrations, routes, frequencies, and durations characterize worker exposures to nano-
    TiO2 across the life cycle and within certain stages (e.g., manufacturing)?

4-7. What management practices exist to control occupational exposures to nano-TiO2?

4-8. What personal protective equipment do workers use at the various life cycle stages of nano-TiO2
    applications? How effective is such equipment in controlling exposures by all routes?

4-9. Are occupational monitoring methods available or in place for all relevant stages of the life
    cycle for nano-TiO2 applications?

4-10. Are available methods adequate to characterize nano-TiO2 exposure via air, water, and food?
    What properties of nano-TiO2 should be included in such exposure characterizations?

4-11. Given the potential for greater uptake of certain substances in the presence  of nano-TiO2,
    should monitoring and exposure studies include a suite of substances that might interact with
    nano-TiO2?

4-12. What happens when nano-TiO2 is trapped in the stratum corneum and the dead skin flakes off?
    Is there a potential for dead-skin nano-TiO2 to settle around households, or be inhaled? How
    much might accumulate  after a day (or a few days) in the sun (and numerous reapplications)?

4-13. Since nano-TiO2 may increase the uptake of other pollutants, such as arsenic, would nano-TiO2
    be a greater concern for exposure and ecological effects in areas with high concentrations of
    certain pollutants than in other areas? If so, how do we predict or identify such "hot spots?"

4-14. Which,  if any, exposure models have been evaluated for applicability to nano-TiO2?

4-15. Which physiologically-based pharmacokinetic models are optimal for understanding
    absorption, distribution,  and elimination of nano-TiO2 in humans?

4-16. Are exposure-dose models available (and adequate) to quantitatively extrapolate the exposure
    used in animal toxicology studies (by inhalation, instillation, oral, dermal, and in vitro) to the
    human exposure that would result in an equivalent dose to the target of interest?

4-17. What is the potential for nano-TiO2 to transfer to or accumulate in the food web and cause
    adverse effects on ecological  receptors?

4-18. Nano-TiO2 has been shown to attach to the surfaces of algae and fish as well as bioaccumulate
    in fish. Does nano-TiO2 biomagnify?


       Chapter 5 of Nano-TiO2 Case Studies  Report:
       Characterization of Effects

               Questions about Ecological Effects

5.2-1. Are current EPA standard testing protocols adequate to determine nano-TiO2 ecotoxicity? If
    not, what modifications or special considerations, if any, should be made in current ecological
    tests? For example, what are the differences in  characterization of testing material (as raw
    material, in media, and in organisms), dispersion methods, and realistic exposure routes between
    testing conventional materials and nanomaterials?

5.2-2. What are the ecological effects of waste and other by-products of nano-TiO2 manufacturing?

5.2-3. Could ecological effects of pure nano-TiO2 be predictive of effects from products containing
    nano-TiO2 (e.g., containing stabilizers or surfactants)?
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5.2-4. How can contributions of various nano-TiO2 physicochemical properties to nano-TiO2
    ecological effects be identified or compared? For example, could a retrospective analysis of
    many studies and computer modeling identify patterns that would not be evident in individual
    studies? Is  a structure activity relationship (SAR) approach applicable for predicting nano-TiO2
    ecological effects?

5.2-5. What might be the primary mechanism(s) of action of toxic effects in different species?

5.2-6. Are the mechanisms of cellular responses different at low and high concentrations of nano-
    Ti02?

5.2-7. How do abiotic factors in the environment, such as UV, pH, oxygen level, and other
    chemicals,  affect nano-TiO2 and its ecological effects?

5.2-8. How do in vivo biochemical processes alter nano-TiO2 physicochemical characteristics and
    toxicity?

5.2-9. What are the ecological effects of long-term exposure to nano-TiO2?

5.2-10. What are the indirect ecological effects (e.g., on soil or water chemistry) of nano-TiO2?

5.2-11. Nano-TiO2 has anti-bacterial and anti-fungal properties. What are the effects of both
    photocatalytic and photostable nano-TiO2 on the biodiversity of microorganisms?

5.2-12. In addition to arsenic and cadmium, do other compounds show different uptake in the
    presence of nano-TiO2? Are the toxicities of arsenic, cadmium, or other chemicals affected by
    nano-TiO2? Conversely, do other compounds affect the uptake and toxicity of nano-TiO2?

5.2-13. Is the available ecotoxicity evidence adequate to support ecological risk assessment for nano-
    TiO2? If not, what is needed?

               Questions about Health Effects

5.3-1. Are the current EPA harmonized health test guidelines for assessing toxicity adequate to
    determine the health effects/toxicity of nano-TiO2?

5.3-2. Is the current information on nano-TiO2 skin penetration sufficient for risk assessment?

5.3-3. Would nano-TiO2 penetrate into living cells in flexed, "soaked," or damaged skin (such as
    sunburned, scratched, eczematous skin)?

5.3-4. How important is testing nano-TiO2 skin penetration on different races and at different ages?

5.3-5. Do certain formulations of nano-TiO2 sunscreens generate hydroxyl radicals when applied to
    skin?

5.3-6. Given that nano-TiO2 is a good antimicrobial agent,  how does it affect skin flora? Does
    application of sunscreen promote the colonization of skin by potentially harmful bacteria (e.g.,
    staph)?

5.3-7. To what extent do photocatalytic properties of nano-TiO2 contribute to dermal effects?

5.3-8. What kind of studies would provide the most suitable data to understand dose-response of
    nano-TiO2  occupational exposure and health  effects in humans?

5.3-9. What is the potential for reproductive and developmental effects of nano-TiO2?
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5.3-10. Is ingested nano-TiO2 carcinogenic?

5.3-11. Is inhaled nano-TiO2 carcinogenic at exposure levels below those that induce particle
    overload?
May 2010                                       B-7

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                     APPENDIX C. List of Reviewers



C.1.1.   External Reviewers (of November 2007 draft of Case Study 1:
        Water Treatment)

   Pratim Biswas, Washington University
   Bernard Goldstein, University of Pittsburgh
   Judith A. Graham, Private Consultant
   Fred Klaessig, Degussa (now Evonik)
   Rebecca Klaper, University of Wisconsin
   Terry Medley, DuPont (with David Warheit, Gary Whiting, Scott Frerichs, and Brian Coleman)
   Gunter Oberdorster, University of Rochester
   John A. Small, National Institute of Standards and Technology (with Richard Holbrook)
   Jeffrey Steevens, U.S. Army Corps of Engineers
   Mark Wiesner, Duke University (with Christine Robichaud)
   Srikanth Nadadur, National Institute of Environmental Health Sciences

C.1.2.   Interagency Reviewers

   Sarah Gerould, U.S Geological Survey
   Jo Ellen Hinck, U.S. Geological Survey
   Carlos Pefia, Federal Department of Agriculture
   Loretta Schuman, Occupational Safety and Health Administration


C.1.3.   EPA Workgroup Members

   J. Michael Davis (Chair), ORD, NCEA, Research Triangle Park
   Jacqueline McQueen (Co-Chair), ORD, OSP, Washington DC
   Christian Andersen, ORD, NHEERL, Corvallis
   Rochelle Araujo, ORD, NERL, Research Triangle Park
   Fred Arnold, OPPTS, OPPT, Washington DC
   Ayaad Assaad, OPPTS, OPP, Washington DC
   Norman Birchfield, ORD, OSA, Washington DC
   Deborah Burgin, OSWER, OSRTI, Washington DC
   Jim Caldwell, OAR, OTAQ, Washington DC
   David Cleverly, ORD, NCEA, Washington DC
   Michele Conlon, ORD, NERL, Research Triangle Park
   Mary Ann Curran, ORD, NHEERL,  Cincinnati
   Walter Cybulski, ORD, OSP, Washington DC
   Jane Denne, ORD, NERL,  Las Vegas
   Steve Diamond, ORD, NHEERL, Duluth
   Jaimee Dong, OAR, OTAQ, Washington DC
   Kevin Dreher, ORD, NHEERL, Research Triangle  Park
   Jeremiah Duncan, ORD, NCER, Washington DC
   Brian Englert, OW, OST, Washington DC
   Patricia Erickson, ORD, NHEERL, Cincinnati
   Cathy Fehrenbacher, OPPTS, OPPT, Washington DC
   Gina Ferreira, Region 2, New York City
   Kathryn Gallagher, ORD, OSA, Washington DC
   Michael Gill, Region 9, San Francisco
   Michael Gonzalez, ORD, NRMRL, Cincinnati
   Maureen Gwinn, ORD, NCEA, Washington DC
   Kathy Hart, OPPTS, OPPT, Washington DC
   Tala Henry, OPPTS, OPPT, Washington DC
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   Ross Highsmith, ORD, NERL, Research Triangle Park
   Lee Hofmann, OSWER, ORCR, Washington DC
   Marion Hoyer, OAR, OTAQ, Ann Arbor
   Joe Jarvis, ORD, ORMA, Washington DC
   Bernine Khan, ORD, NRMRL, Research Triangle Park
   David Lai, OPPTS, OPPT, Washington DC
   Wen-Hsiung Lee, OPPTS, OPPT, Washington DC
   Laurence Libelo, OPPTS, OPPT, Washington DC
   Diana Locke, OPPTS, OPPT, Washington DC
   Gregory Miller, OPEI, NCEE, Washington DC
   David Meyer, ORD, NRMRL, Cincinnati
   J. Vincent Nabholz, OPPTS, OPPT, Washington DC
   Nhan Nguyen, OPPTS, OPPT, Washington DC
   Carlos Nunez, ORD, NRMRL, Research Triangle Park
   David Olszyk, ORD, NHEERL, Corvallis
   Martha Otto, OSWER, OSRTI, Washington DC
   Scott Prothero, OPPTS, OPPT, Washington DC
   Kim Rogers, ORD, NERL, Las Vegas
   Zubair Saleem, OSWER, ORCR, Washington DC
   Nora Savage, ORD, NCER, Washington DC
   Phil Sayre, OPPTS, OPPT, Washington  DC
   Rita Schoeny, OW, OST, Washington DC
   Walter Schoepf, Region 2, New York City
   Najm Shamim, OPPTS, OPP, Washington DC
   Deborah Smegal, OA, OCHPEE, Washington DC
   Jose Solar, OAR, OTAQ, Washington DC
   Neil Stiber, ORD, OSA, Washington DC
   Timothy Taylor, OSWER, ORCR, Washington DC
   Susan Thorneloe, ORD, NRMRL, Research Triangle Park
   Dennis Utterback, ORD, OSP, Washington DC
   Amy Wang, ORD, NCEA, Research Triangle Park
   Eric Weber, ORD, NERL, Athens
   Randy Wentsel, ORD, IO, Washington DC
   Doug Wolf, ORD, NHEERL, Research Triangle Park
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   Organization Abbreviations:

   IO        Immediate Office
   NCEA    National Center for Environmental Assessment
   NCER    National Center for Environmental Research
   NERL    National Exposure Research Laboratory
   NHEERL National Health and Ecological Effects Laboratory
   NRMRL  National Risk Management Research Laboratory
   OA       Office of the Administrator
   OAR     Office of Air and Radiation
   OCHPEE Office of Children's Health Protection and Environmental Economics
   OPEI     Office of Policy, Economics, and Innovation
   OPP      Office of Pesticide Programs
   OPPT    Office of Pollution Prevention and Toxics
   OPPTS    Office of Prevention, Pesticides, and Toxic Substances
   ORCR    Office of Resource Conservation and Recovery
   ORD     Office of Research and Development
   ORMA    Office of Resource Management and Administration
   OSA     Office of Science Advisor
   OSP      Office of Science Policy
   OSRTI    Office of Superfund Remediation and Technology Innovation
   OST      Office of Science and Technology
   OSWER  Office of Solid Waste and Emergency Response
   OTAQ    Office of Transportation and Air Quality
   OW      Office of Water
May 2010
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             APPENDIX D. Web Site Forms  and  Information
D.1.  Web  Site  Text for Initial Inquiry
                   EPA
                   United States
                   Environmental Protection
                   Agency
Nanomaterial Case Studies Workshop
   x ^* *4Bv      •^'.^•^WBHBlv*' '         - •      ' ''-*.
       -  Developing a Comprehensive Environmental Assessment
             Participant Info  Observers Search  My Profile
                                                                 Welcome.

               Background and Purpose

               The National Center for Environmental Assessment (NCEA) of the U.S.
               Environmental Protection Agency (EPA) is developing a research strategy for
               evaluating potential human health and ecological risks of nanomaterials. As part of
               this effort, case studies focusing on selected applications of nanoscale titanium
               dioxide (nano-TiO2) have been drafted to identify what is known and what needs to
               be known in order to conduct a comprehensive environmental assessment of the
               implications of these products. An essential aspect of this process is a structured
               workshop that comprises a diverse array of technical and stakeholder perspectives.

               The purpose of the Nanomaterial Case Studies Workshop is to:

               review the draft case studies and the research questions identified therein;
               ensure that the research questions listed in the case studies are comprehensive,
               complete, and adequately articulated; and
               generate a prioritized ranking of research directions needed to support a
               comprehensive environmental assessment of nano-TIO2.

               The workshop will be held in late September in the Research Triangle Park area of
               North Carolina. It will be scheduled after considering participant and venue
               availability.


               Please Respond by June 24, 2009

               Click here to indicate your interest in participating in this workshop, subject to your
               availability and EPA's expertise requirements. You will be able to update your
               contact information and provide information on your area(s) of expertise and the
               dates vou are available to attend a workshop.
        Figure D-1.     Background information about the Nanomaterial Case Studies Workshop

D.2.    Demographic Information  Requested  via Web form
      Sector

      Please indicate the sector(s) you represent. Select all that apply.

        Academia

        Industry

        Other

        Government

        NGO
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Based on the sector(s) you selected above, please indicate the applicable descriptor(s) below:

•      Academia: please specify department(s).

•      Government: select... Federal, State and Local, or Other (please describe).

•      Industry:  select...Manufacturer, User, Trade Association, or Other (please describe).

•      NGO: select... Consumer, Labor, Environment / Public Health, or Other (please
       describe).

•      Other: select... Consultant, Journalist, Research Institution, or Miscellaneous (please
       describe).

     Area of Expertise

     Please indicate your primary area(s) of expertise. Select all that apply. Note: Your area of

expertise does not have to be specific to nanoscale titanium dioxide.
     Manufacturing
     Production
     Shipping
     Other (Please describe)

     Water Treatment
     Potable Water
     Wastewater
     Other (Please describe)
     Fate & Transport
     Water
     Air
     Soil
     Other (Please describe)
     Exposure-Dose
     Ecological
     General Population
     Occupational
     Dosimetry/PBPK
     Other (Please describe)
Ecology
Aquatic Effects
Terrestrial Effects
Other (Please describe)

Health Route
Inhalation
Oral
Dermal
Other (Please describe)

Health Endpoint
Neurotoxicology
Immunotoxicology
Reproductive/Developmental
Cancer/Genetox
Other (Please describe)

Health Method
Animal Toxicology
Epidemiology
Human Clinical
Other (Please describe.)
Evaluation
Human Health Risk Assessment
Ecological Risk Assessment
Integrated Risk Assessment
Life cycle Analysis
Industrial
Ecology
Other (Please describe)
Risk Management
Environmental Health & Safety
Public Health
Natural Resources
Green Chemistry
Other Area of Expertise
Analytical Methods
Materials Science
Miscellaneous (Please describe)
May 2010
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D.3.   Instructions for Pre-Workshop Activities
         SEPA
             United States           T
             Environmental Protection
             Agency
'anomaterial Case Studies Workshop
                     Strategy for Nanoscale Titanium Dioxi
                                    Submit Pre-Workshop Input
         Introduction and Objectives

         Please consider this overarching question as you review the EPA Nanomaterial Case Studies document and
         as you rank or add/modify research/information needs.

             What research or information is most needed in order to conduct a comprehensive environmental
         Through this Web form, you can submit (a) your ranking of questions, (b) new/modified questions, and (c)
         your biosketch. All new questions will be distributed in advance to the workshop participants, and
         participants will have an opportunity to discuss their highest priority issues during the workshop. On the
         last page of this Web form, you will be asked to submit a brief biosketch about yourself to be shared with
         all participants at the workshop.

         Be sure to click on the "continue" or "submit" buttons at the end of each session, even if you are not
         finished entering your information. You may come back to this form and finish or revise your work by
         logging in to the workshop Website and going to "Submit Pre-Workshop Input" under the "Participant Info"
         menu.

         If you have trouble using this form, please contact Audrey Turley (aturlevS'icfi.com) for assistance.

         Click Continue to begin.
       Figure D-2.    Web Site Text for Pre-Workshop Activities


Ranking the Questions

Instructions: We are seeking from you the following rankings of the questions presented in the

nano-TiO2 case studies report:

       1.  Ranked list of the top 10 needs: Identify and rank the top 10 priorities by assigning a
           score of 10 to the question you believe is most important of all identified, a score of
           9 to  the question you think is the second most important, a score of 8 for the third
           most important, and so on.

       2.  Top  25 needs: Your top  10 priorities will automatically be included in this group.
           Select an additional 15 questions you believe are among your 25 most important. In
           the Web form, select "High (not ranked)" for these 15 questions.

       3.  The  10 lowest or "zero" priority needs: Identify up to  10 questions that you believe
           are not important or the lowest priority of all of the questions. In the Web form, mark
           these questions as "Low."

      These rankings will be assembled as a starting point for our discussion at the workshop.
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      On the next page of this Web form, you will have the opportunity to submit any new questions
not already contained in the case studies report.
      Note: We recommend using the separate list of questions excerpted from the document to
make notes about your rankings before entering them into the Web form.

Adding New and Modified Questions

Instructions: If there are high priority question(s) that are not already presented in the case studies
report, you can submit them on this form. You can also submit revisions of existing questions.
      You will need to type (or copy  and paste) any new questions in the spaces provided. You
should identify the case studies chapter to which each question belongs:
      Chapter 1: Introduction
      Chapter 2: Life Cycle Stages
      Chapter 3: Fate and Transport
      Chapter 4: Exposure-Dose Characterization
      Chapter 5: Characterization of Effects
      "Multiple": Cross-cutting issues
      If you are modifying an existing question, please indicate the number of the original question
and enter the revised wording. Please limit modifications to questions that are among your top 25.
You should rank the original question if it is among your top 10.
      The Web form can accommodate submittal of up to 10 questions, each with a maximum of
250 characters. If you have more than 10 new research questions, please email your entire list to
Audrey Turley (aturley@icfi.com).
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       APPENDIX E. Biosketches of Workshop Participants

      Dr. David Andrews is a Senior Scientist at the Environmental Working Group. He is utilizing
his background in chemistry and nanomaterials to investigate environmental and human health
issues. Dr. Andrews' recent work has focused on the U.S. reliance on voluntary programs to collect
health and safety information on chemicals, nanomaterials in consumer products, and reviewing
ingredients in cosmetic products. Dr. Andrews holds a B.A. in chemistry from Wesleyan University
and a Ph.D. in chemistry from Northwestern University. He has authored over 10 peer-reviewed
publications and currently has 1 patent pending.

      Jeff Baker is a Regional Manager at TSI, Incorporated, and has over 15 years of experience in
water and air quality. TSI serves a global market by investigating, identifying, and solving
measurement problems. As an industry leader in  the design and production of precision measurement
instruments, TSI partners with research institutions and customers around the world to set the
standard for measurements  relating to aerosol science, air flow, indoor air quality, fluid dynamics,
and biohazard detection. Mr. Baker has published several papers in various journals and has worked
closely with the development of environmental monitoring systems  for nanomaterials.

      Dr. Brenda E. Barry is Senior Director for the Long-Range Research Initiative at the
American Chemistry Council, a program that supports scientific research to advance our
understanding of the effects of chemicals on human health and the environment. Dr. Barry's areas of
expertise include toxicology, nanotechnology, health effects of indoor and outdoor environmental
agents, biosafety, and occupational health and safety. As a senior environmental consultant, Dr.
Barry's recent work focused on strategic business planning activities regarding nanotechnology and
the related human health, environmental, and regulatory concerns. Previously, she was senior project
manager for numerous investigations on indoor and outdoor environmental quality issues and
occupational health concerns. She is the author of two chapters in the recent book, Nanotechnology:
Health and Environmental Risks. Dr. Barry received her doctorate in pathology from Duke
University and completed her post-doctoral studies at the Harvard School of Public Health. She
received her B.S. in zoology and M.S. in biophysics from the University of Rhode Island. Dr. Barry
is a member of the Society  of Toxicology, ASTM International Committee E56 on Nanotechnology,
International Society of Exposure Science, and the American Biological Safety Association where
she is certified as a Registered Biosafety Professional.

      Dr. Catherine Barton has been an Environmental Engineer with DuPont since 1987. Dr.
Barton has been a registered Professional Engineer in the State of Delaware since 1989.  Her
experience at DuPont includes environmental field work (groundwater monitoring well installation
and sampling, air and soil sampling), wastewater treatability testing and system design, regulatory
advocacy, air dispersion modeling, air quality issues and risk, and exposure assessment.  Her risk and
exposure assessment expertise extends from site  specific manufacturing operations to chemical-
specific global assessments. She has taken a life cycle approach to assessing exposure and risk in
multiple assessments, including the assessment used in the DuPont Light Stabilizer Framework
Example in the Nano Risk Framework. She is interested in establishing best practices to establish
exposure information and hazard information that is compatible and therefore usable in assessing
potential risk. She graduated from Virginia Tech  with a B.S. in Civil Engineering and a Masters in
Environmental Engineering. Her Ph.D. is from the University of Delaware, also in Environmental
Engineering.

      Dr. Eula Bingham (IOM) is Professor of Environmental Health at the University of
Cincinnati College of Medicine. Her interests include regulatory toxicology, environmental
carcinogenesis, occupational health, and risk assessment. She was U.S. Assistant Secretary of Labor
for the Occupational Safety and Health Administration (OSHA) from 1977-1981. Throughout her
career, Dr. Bingham has served on numerous national and international advisory groups, including
advisory committees of the Food and Drug Administration, Department of Labor, National Institute
for Occupational Safety and Health, National Institutes of Health, Natural Resources Defense
Council, and the International Agency for Research on Cancer. The  committees addressed issues
concerning research needs in health risk assessment and the potential health effects of environmental
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exposure to chemicals. Dr. Bingham has a Ph.D. from the University of Cincinnati in zoology
(physiology and ecology). She is a member of the NAS Institute of Medicine who has served on
numerous committees of the National Academies.

      Dr. Pratim Biswas is the Stifel and Quinette Jens Professor at Washington DC University in
St. Louis, and the Chair of the newly created Department of Energy, Environmental, and Chemical
Engineering (www.eec.wustl.edu). His expertise is in aerosol science and technology, nanoparticle
technology, particle control and environmentally benign energy production. He was Professor and
Director of the Environmental Engineering and Science Division at the University of Cincinnati
before he moved to Washington DC University  in 2000. He has advised and graduated 35 doctoral
students, and published more than 200 refereed journal papers with them. He has won several
Teaching and Research Awards: was the recipient of the 1991 Kenneth Whitby Award given for
outstanding contributions by the American Association for Aerosol Research; and the Neil
Wandmacher Teaching Award of the College of Engineering in 1994. He was elected as a Fellow of
the Academy of Science, St. Louis in 2003. He  recently finished his term as President of the
American Association for Aerosol Research, and serves on several National and International
Committees. He served on the Review Committee of the National Academy of Science that reviewed
the Nanotechnology Environmental, Health, and Safety Document. Dr. Pratim Biswas received his
B.Tech. degree from the Indian Institute of Technology, Bombay in Mechanical Engineering in 1980;
his M.S. degree from the University of California, Los Angeles in 1981 and his doctoral degree from
the California Institute of Technology in 1985.

      Dr. Jean-Claude J. Bonzongo is an Associate Professor in the Department of Environmental
Engineering Sciences at the University of Florida, Gainesville, Florida. His current research focuses
on aquatic biogeochemistry, remediation of metal-contaminated environments, and mercury in
terrestrial and aquatic systems. Dr. Bonzongo is also interested in environmental fate and
implications of manufactured nanomaterials as  well as sustainable design of nanomaterials. Dr.
Bonzongo received his Ph.D. in Environmental Chemistry and Microbiology from the University of
Rennes I in France.

      Steven Brown is a Certified Industrial Hygienist employed by Intel Corporation and has over
27 years of experience in the field of Industrial  Hygiene, including work in heavy manufacturing
industries, aerospace, and semiconductor fabrication. He is responsible for the development and
implementation of health, safety, and environmental guidelines on the use of nanomaterials within
Intel's global semiconductor manufacturing facilities. Mr. Brown is the Convener of the International
Standards Organization (ISO) Technical Committee #229 Work Group #3 on Nanotechnology. Work
Group #3's mandate is  to develop  ISO Standards on the safe and environmentally benign use of
nanomaterials. The ISO TC229 WG#3 is currently developing over 9 different ISO standards on the
safe use of nanomaterials. He is involved in several industry consortiums focused on promoting the
sound use of nanomaterials such as the International Council on Nanotechnology (ICON) and the
completed Nanotechnology Occupational Safety Health consortium.  Mr. Brown has a Masters of
Science Degree in Industrial Hygiene and a Bachelors of Science Degree in Biology/Chemistry.

      Mark Bunger is a Research Director at Lux Research, with 18 years of business strategy
experience as a management consultant and technology analyst. In this time, he has advised more
than 40 Fortune 500 corporations, led hundreds of engagements, and authored over 60 reports and
other publications. Mr. Bunger joined Lux Research in 2005, and launched and leads Lux Research's
Bioscience Intelligence Service. Mr. Bunger and his work have figured in leading media outlets in
the United States and Europe, including  CNN, PBS, CNBC, NPR, The Wall Street Journal, the
Financial Times, Genetic Engineering and Biotechnology News, American Chemical Society Nano
Letters, and other technical, regional, and trade  publications and channels. Mr. Bunger's business
education was in International Marketing at Malardalen Polytechnic in Sweden, and Market
Research at the University of Texas at Austin. His ongoing technical  education includes extension
courses and lab work in neurology and bioengineering at University of California (Berkeley) and
San Francisco (UCSF), where he currently works in the Desai lab.

      Carolyn Nunley Cairns is  an Environmental Health Scientist and Product Safety Specialist in
the Technical Department's Product Safety and  Health Department at Consumers Union, an
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independent, non-profit organization that publishes Consumer Reports magazine. She leads the
Product Safety program, which includes research and testing to evaluate safety concerns associated
with products containing nano-engineered substances. As an international expert in human health
risk assessment, she has held positions government agencies, private industry, and non-profit
organizations. She holds undergraduate degrees in Chemistry and Government, and a Masters in
Public Health from Yale School of Medicine.

      Dr. Richard A. Canady is an expert in regulatory risk assessment and nanotechnology
regulatory policy having led multidisciplinary teams of policy and technical experts in the resolution
of a wide range of cutting edge health risk management issues over a 20 year career that includes
genomics, nanotechnology, biotechnology, obesity, contaminants in foods and medical products
(including mercury,  dioxins, perchlorate, and  acrylamide), and medical product development. His
experience includes  government regulatory policy for health risk assessment from the executive
level, integrating across product review centers for the FDA Office of the Commissioner and across
Federal Agencies for the Executive Office of the President. His experience includes substantial
international work, leading policy, and technical analysis teams within the Organization for
Economic Cooperation and Development, the World Health Organization, and the Food and
Agriculture Organization as well as in direct bilateral interactions with major U.S. trading partners
on chemical risk management issues  facing FDA. He received a Ph.D. in neurophysiology,
physiology, and behavior from Rockefeller University and a B.S. in psychology and biology from
the University of Michigan. Dr. Canady  is a Diplomat of the American Board of Toxicology
(DABT).

      Janet Carter is a Senior Health Scientist in the Directorate of Standards and Guidance with
the Occupational Safety and Health Administration (OSHA). In addition, she worked for  15 years  at
Procter & Gamble, Inc. as a Respiratory Toxicologist and Study Director researching the
mechanisms of particle-induced pulmonary inflammation/tumorigenesis and nanoparticle toxicity.
She has (co)authored over 35 publications and technical reports with more than 40 presentations and
invited-talks at national and international conferences. In addition, she has participated on numerous
review panels for nanomaterials with the National Academies Institute of Medicine, EPA, NIOSH,
and USD A. She is an active member of the Society of Toxicology (SOT), former Vice-Chair of the
International Life Science Institute/Health and Environmental Science Institutes (ILSI/HESI)
Nanomaterials Safety Committee, and a member of the organizing committee for the SOT
Nanotoxicology Specialty Section. Ms. Carter received a B.S. in Zoology from Miami University,
M.S. in Molecular and Cell Biology from the  University of Cincinnati and currently attends Emory
University Rollin's School of Public  Health in Epidemiology.

      Dr. Elizabeth Gasman is an Associate  Research Professor, in the Department of Engineering
& Public Policy at Carnegie Mellon University. Dr. Gasman is interested in the challenges of
performing risk assessment with incomplete information. She has studied the problem of dealing
with mixed levels of uncertainty in integrated assessment models. She has also developed a
bounding analysis methodology for attributing risks with multiple causative factors. A major new
direction of her research is the risk posed by nanomaterials in the environment. In addition to risk
assessment, she has been involved in a number of health-related projects. With regards to
bioterrorism responses, her recent research has included the following projects: the potential of
urban ecosystems to support rodent-borne plague epidemics, risk communication strategies for
rapidly changing and complex bioterrorism scenarios, rapid detection of covert bio-attacks, the
impact of human behavior on pandemic  influenza epidemics, and the effect of the USAPATRIOT
Act and the Bioterrorism Preparedness Act on microbiological research. She is also interested in
drinking water and health connections in developing countries, watershed management, and
biotechnology policy. She holds a B.S. in Microbiology from Syracuse University, an M.S. in
Microbiology from Northern Arizona University, and a Ph.D. Geography & Environmental
Engineering from The Johns Hopkins University.

      Dr. Sylvia Chan Remillard is an  Environmental Scientist with Golder Associates and
HydroQual Laboratories in Calgary, Alberta. She was awarded an Alberta Ingenuity Industry
Associate working on an Industrial post  doctorate, jointly through Golder Associates and HydroQual
Laboratories Ltd.  She is studying the fate and effects of nanoscale particles on the environment and
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developing a risk based framework to evaluate the products of nanotechnology. She obtained her
Ph.D. in Food Science and Technology from the University of Alberta. Her Ph.D. examined the
ability of dairy derived probiotics and bioactive peptides in altering intestinal microbial ecology in
the treatment of gastrointestinal disorders such as inflammatory bowel disease and colon cancer. She
was nominated for the Governor General Gold Medal Award for her Ph.D. research. She has
received several research grants for her work through the National Research  Council in Canada and
The Natural Sciences and Engineering Research Council of Canada and the Alberta Ingenuity Fund.
She has participated in and presented her current and previous work at numerous international and
local conferences including several SETAC conferences and NATO Advanced Research Workshops.
Dr. Chan Remillard's interest in nanotechnology lie in studying the fate and effects of nanoscale
particle once they have entered into the environment and in developing a suite of nano-compatible
testing methods that are suitable for industry for regulatory compliance.

      Dr. Shaun Clancy heads the Product Regulatory Service group, a Product Stewardship group,
for Evonik Degussa in North America that supports many of the  company's businesses. Areas of
interest outside of nanotechnology include chemical control laws (TSCA, CEPA, FFDCA, FIFRA,
PCPA) as well as topics related to hazard communication and transportation. In nanotechnology he is
interested in all aspects that pertain to EHS topics with a particular interest in the relationship
between material characterization and toxicology. He received his B.S. at the University at Buffalo -
SUNY and completed his doctoral studies at Northwestern.

      Dr. Raymond David is the Manager of Toxicology for Industrial Chemicals in BASF
Corporation. He received his Ph.D. in Pharmacology from the University of Louisville, after which
he was a Postdoctoral Fellow at the Chemical Institute of Toxicology in Research Triangle Park. Dr.
David worked for 8 years at Microbiological Associates in Bethesda, Maryland where he managed
the Inhalation and Mammalian Toxicology Departments. He also spent 14 years at Eastman Kodak
in Rochester New York as Senior Toxicologist before joining BASF in 2006. Dr. David has
experience conducting inhalation, pulmonary, reproductive, and  systemic toxicity studies. He was
responsible for EH&S issues for nanotechnology at Eastman Kodak Company, and is currently
responsible for nanotechnology issues in BASF Corporation.

      Dr. Joan E. Denton is Director of the Office of Environmental Health Hazard Assessment
(OEHHA), a department within the California Environmental Protection Agency. She is responsible
for scientific risk assessments for use in regulation of chemicals  in the environment and
implementing the California Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition
65). Dr. Denton also provides overall scientific guidance and consultation to  the Secretary of the
California Environmental Protection Agency. Dr. Denton earned a B.S. from the University of San
Francisco, a M.S.  from the University of Nevada, Las Vegas, and a Ph.D. in biology from the
University of California, Santa Barbara. In 2005, she was on a Blue Ribbon Panel created in
California to advise  policymakers on increasing the capacity of nanotechnology in the state. OEHHA
staff have expertise in particle toxicology which has resulted in the identification of diesel exhaust as
atoxic air contaminant and state particulate matter standards. OEHHA has also prepared assessments
on metals (including arsenic) in water. Finally, OEHHA is currently funding  a research project
within the University of California San Francisco which will suggest a framework for conducting
risk assessments on nanomaterials.

      Dr. Gary Ginsberg is  a Toxicologist at the Connecticut Department of Public Health within
the Division of Environmental and Occupational Health Assessment. He has  responsibility for
human health risk assessments conducted in the state. Dr. Ginsberg serves as adjunct faculty at the
Yale School of Medicine and is an Assistant Clinical Professor at the University of Connecticut
School of Medicine. He has served on several National Academy of Science  Panels (Biomonitoring
and U.S. EPA risk methods) and has been invited to testify at Congressional hearings on toxics issues
on a number of occasions. He received a Ph.D. in toxicology from the University of Connecticut
(Storrs) and was a post-doctoral fellow in carcinogenesis/mutagenesis at the Coriell Institute for
Medical Research. Dr. Ginsberg's toxicology experience has involved a variety of settings: basic
research, teaching, working within the pesticide and consulting industries, and now working in
public health. He has published in the areas of toxicology, carcinogenesis, physiologically-based
pharmacokinetic modeling, inter-individual variability and children's risk assessment. Dr. Ginsberg
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is also co-author of a book on toxics for the lay public, "What's Toxic, What's Not" Berkley Books,
December 2006.

      Dr. Pertti (Bert) Hakkinen joined the Division of Specialized Information Services, National
Library of Medicine, National Institutes of Health in June 2008 as Senior Toxicologist in the Office
of the Director, and serves as NLM's Toxicology and Environmental Health Science Advisor. As a
member of the SIS staff, Dr. Hakkinen provides leadership on the development of new resources in
toxicology and enhancements to existing NLM resources in this field. He also represents NLM on
various committees, and provides leadership for NLM's participation in national and international
efforts in toxicology-related information.  During his career Dr. Hakkinen has held numerous
leadership positions in the field of toxicology and risk assessment. Dr Hakkinen served on the staff
of the European Commission (EC) at the EC's Institute for Health and Consumer Protection, Joint
Research Centre, in Ispra, Italy from 2003-2006. He has also held positions with Toxicology
Excellence for Risk Assessment (TERA) and Gradient Corporation in the United States, and at the
Procter and Gamble Company in the United States and Japan. He continues to serve as the Vice-
chair of the Scientific Advisory Panel for the Mickey Leland National Urban Air Toxics Research
Center. Dr. Hakkinen earned a B.A. in Biochemistry and Molecular Biology from the University of
California, Santa Barbara, and received his Ph.D. in Comparative Pharmacology and Toxicology
from the University of California, San Francisco. Dr. Hakkinen is a member of the Society of
Toxicology (SOT) and a charter member of the Society for Risk Analysis (SRA) and the
International Society of Exposure Science (ISES). He was a co-editor and co-author of the latest
edition of the Encyclopedia of Toxicology, and of the new edition of the Information Resources in
Toxicology book.  Dr. Hakkinen has authored and co-authored numerous other publications,
including on consumer product-related exposures and risks. He was a work group leader of a 2008
NATO workshop on nanomaterials.

      Jaydee Hanson is Policy Director at the International  Center for Technology Assessment. He
works on issues related to medical, cosmetic, food,  and sunscreen uses of nanotechnology and the
convergence of nanotechnology with other technologies, especially nano-vectors for gene transfer.
He and his colleague, George Kimbrell, coordinated the development of "Principles for the
Oversight of Nanotechnologies and Nanomaterials" with more than 80 groups on six continents. Mr.
Hanson is the US  Co-chair for the Nanotechnology  Taskforce of the Transatlantic Consumers
Dialogue and coordinates an annual meeting of U.S. non-governmental groups working on
nanotechnology policy. He has  degrees from the University of the Pacific and the University of
Hawaii. He has additional course work in bioethics  and environmental ethics. He was an
environmental policy fellow at the East-West Center and is currently a fellow at the Institute on
Biotechnology and the Human Future.

      Dr. Patricia Holden is a Professor of Environmental Microbiology at the Bren School of
Environmental Science & Management at the University of California, Santa Barbara. Dr. Holden's
research surrounds bacteria in the context of environmental water quality, and in the contexts of fate
and transport of pollutants. Dr. Holden's research also involves investigation of microbial ecology of
the vadose zone and sediment environments as context to better understanding the responses of
indigenous microorganisms  to environmental perturbation including pollution. Dr. Holden's
education is in Civil & Environmental Engineering  (B.S., M.S., M.E.) and  in Soil Microbiology
(Ph.D., U.C. Berkeley).

      Dr. Paul Howard is the Director of the Office of Scientific Coordination at the U.S. Food and
Drug Administration's National Center for Toxicological Research (NCTR) (Director, 2009; Deputy
Director 2007-2009) which is responsible for coordinating/administering an interagency agreement
between the National Toxicology Program/NIEHS and NCTR/FDAto conduct toxicological studies
of compounds of regulatory interest to the FDA and NIEHS.  In addition, Dr. Howard is the FDA
Liaison to the National Toxicology Program, is the Acting Director of the NCTR Nanotechnology
Core Facility, and Director of the National Toxicology Program Center for Phototoxicology (at
NCTR). Dr. Howard's research interests include: the biodistribution and toxicity of nanoscale
materials; the phototoxicity  and photocarcinogenicity of chemicals; the toxicity, phototoxicity and
photodecomposition of tattoo and permanent ink constituents; the toxicity and biodistribution and
toxicity of nanoscale materials. Dr. Howard received a Ph.D. in Biochemistry from the University of
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Arkansas for Medical Sciences in 1981. After post-doctoral training in Chemical Carcinogenesis
(NCTR, 1981-1983), he joined the faculty at the Case Western Reserve University (CWRU) School
of Medicine (Assistant Professor, 1983-1989; Associate Professor, 1989-1993. Dr. Howard joined
the staff at NCTR in 1993 as a Staff Scientist in the Division of Biochemical Toxicology.

      Sheila Kaplan is a longtime environmental, science and political j ournalist who works in print
and broadcast media. She is the recipient of numerous national journalism honors, among them: the
John S. Knight Professional Fellowship for Journalists at Stanford University; the Investigative
Reporters and Editors prize for distinguished investigative reporting, the Lowell Mellett prize for
media criticism, and several Emmy nominations. Ms. Kaplan lives in the San Francisco Bay Area
and is currently writing a book on the science and policy issues related to neurotoxicants. The book
is for a general audience and will be published by Basic Books in 2010. She is a fellow at the Nation
Institute, affiliated with The Nation magazine in NYC. Last year, Ms. Kaplan was a lecturer in
political reporting at the University of California, Berkeley, Graduate School of Journalism. She has
worked as a producer for ABC News, MSNBC on the Internet, and the PBS series Frontline. She has
also been a senior writer for U.S. News & World Report, Legal Times and the Hartford Courant. She
is a former investigative editor for Mother Jones magazine. Her freelance work has appeared in
numerous newspapers and  magazines, among them, The Washington DC Post, Discover and The
New Republic.

      Dr. Fred Klaessig is currently with Pennsylvania Bio Nano Systems, a small firm focusing on
reference materials used in investigating chromatographic effects at the nanoscale. In recent years,
he was first the Technical Director for Aerosil & Silanes and later the Business Director for the
Aerosil Business Line, which are currently part  of the Inorganic Materials Business Unit of Evonik
Degussa GmbH. His assignments ranged from commercial overview (Product Management,
Production, Sales) to technical responsibilities involving customer support, new product
introduction, liaison with the R&D Department  in Germany and regulatory matters. AEROSILAฎ is
a trade name for fumed silica, which has been manufactured for 60 years and which is often cited as
an example of a nanoparticle. Fumed silica, fumed titania and other fumed metal oxides are utilized
in many fields for reinforcement, rheology control,  abrasion and UV absorption. In recent years, the
great interest in nanotechnology  has raised safety and registration concerns about materials of this
class. These issues, both everyday technology and EHS, led to his involvement in ASTM (E56), ISO
(TC229) and industry organizations addressing these broader topics. Dr. Klaessig received a B.Sc. in
Chemistry from the University of California, Berkeley and a Ph.D. in Physical Chemistry from
Rensselaer Polytechnic Institute. His earlier industrial experiences were with Bio  Rad Laboratories
as a Quality Control Chemist and various R&D  management positions at Betz Laboratories, now a
division of GE Water Services, where his responsibilities involved scale, corrosion and
microbiological control in many chemical industrial processes.

      Dr. Rebecca Klaper is a tenure-track Associate Scientist at the Great Lakes WATER Institute,
University of Wisconsin-Milwaukee. She uses a combination of genomics and proteomics  with
traditional toxicological measurements to determine the impact of human alterations of the
environment on ecologically relevant species. One of the major areas of her current research
involves examining the impact of emerging contaminants, specifically nanomaterials and
Pharmaceuticals, on environmental and human health. The Klaper laboratory has published several
peer-reviewed articles on the impacts of nanomaterials of differing chemical properties on  the
survival, behavior, and physiology of aquatic species and the potential for uptake  of nanomaterials
by these species. She has served as an invited expert on several technical panels to evaluate
government documents surrounding the issue of nanomaterial risk assessment and the current state
of the science. These include: Technical reviewer for U.S. EPA Office of Research and Development
Research Plan for Nanotoxiology (2008); Nanotechnology Policy Framework Committee for the
State of California (2008);  Invited scientific expert/speaker for the International Organization for
Economic and Cooperative Development (OECD) (2005); Nanotechnology Technical Committee,
Society of Environmental Toxicology and Chemistry (2007-Present); Technical Expert reviewer of
EPA Potential Environmental Impacts of Nanomaterials White Paper (2007).

      Dr. Todd Kuiken is  a research associate with the Foresight and Governance Project and the
Project on Emerging Nanotechnologies at the Woodrow Wilson International Center for Scholars;
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focusing on the environmental health and safety and public policy aspects of nanotechnology. Todd
holds a Ph.D. in environmental science and chemistry from Tennessee Tech University where his
research focused on the air/surface exchange of mercury associated with forest ecosystems. As part
of his dissertation he synthesized these results with other studies associated with mercury cycling,
public health threats, and policy alternatives to bring  attention to the threats and need for an
improved public policy dealing with mercury pollution. After completing his B.S. in Environmental
Management and Technology at Rochester Institute of Technology he worked directly with
renowned scientists on the biogeochemical cycling of mercury at the Department of Energy's Oak
Ridge National Laboratory. He earned an M.A. in Environmental and Resource Policy from The
George Washington DC University concentrating on the scientific, economic and community
development aspects of environmental issues. While there he worked at various environmental non-
profits including the National Wildlife Federation. He worked within the Clean the Rain campaign
that dealt with the environmental and public health threats associated with mercury pollution.

      Dr. John P. LaFemina is the Vice-President and Director of Operations for Toxicology
Northwest, part of the  Battelle Health and Life Sciences Global Business. Dr. LaFemina joined
Battelle from the Pacific Northwest National Laboratory, where he spent 15 years in a variety of
research and executive management positions, including Director of Quality, and leading the
Environmental Management Market Sector. Prior to coming to the Laboratory, Dr. LaFemina was a
Captain in the  United States Army, teaching chemistry and physics at the United States Military
Academy and  serving  as the Deputy Director of the Science Research Laboratory and the Thomas H.
Johnson Photonics Research Center at West Point. Dr. LaFemina earned his Ph.D. in Chemistry at
The Pennsylvania State University under the direction of Professor John P. Lowe in 1985. He has
written or contributed  to than 50 scientific papers and made over 100 presentations on a variety of
scientific and technological topics ranging from the photophysics of polymers to the atomic and
electronic structure of semiconductor and mineral surfaces and interfaces. He was the Series Editor
of "The Chemistry and Physics of Surfaces and Interfaces" published by CRC Press and is a member
of the American Chemical Society.

      Thomas Lee is  a business reporter at the Minneapolis Star Tribune where he covers emerging
and growth companies with a special focus on medical technology and biotechnology. He is also a
freelance writer for China Daily USA and has previously written for the St. Louis Post-Dispatch,
Seattle Times,  the Oregonian, and Newsday. Mr.  Lee was recently awarded a Knight Kavli Science
Journalism Fellowship at the Massachusetts Institute  of Technology. He was one of 15 journalists
across the country who participated in a three day workshop on nanotechnology. Mr. Lee is primarily
interested in the commercialization of nanotechnology and what opportunities/pitfalls this emerging
field poses for companies.

      Dr. Shannon Lloyd is the Sustainability Discipline Director at Concurrent Technologies
Corporation (CTC). She provides technical leadership in developing and applying analytical tools to
assess the economic and environmental implications of policy, process, and technology alternatives.
She has conducted environmental life cycle assessments of products in the automotive, chemical,
nanotechnology, agribusiness, and building construction industries.  Dr. Lloyd recently completed a
study for the Army Environmental Policy Institute (AEPI) that provided recommendations for
evaluating and managing the potential lifecycle risks  of nanomaterials within the U.S. Army. She
received a PhD in Engineering and Public Policy and an M.S. in Civil and Environmental
Engineering from Carnegie Mellon University  and a B.S. in General Engineering from the
University of Illinois at Urbana-Champaign.

      Dr. Christopher Long is a Principal Scientist in Environmental Health & Air Quality with
Gradient, a Massachusetts-based environmental consulting company. His central interests are indoor
and outdoor air quality and health risk assessment, and he has particular expertise in exposure
assessment, air pollution epidemiology and toxicology, air sampling and measurement, and airborne
particulate matter (PM). He has investigated exposures and health risks associated with a number of
airborne PM types, such as ambient PM, diesel exhaust particulates, carbon black, asbestos, and
engineered nanoparticles, as well as a variety of gaseous criteria and hazardous air pollutants. Dr.
Long's practice area includes evaluating product safety, with specific interests in airborne exposures
and engineered nanoparticles. He is co-director of Gradient's Nanotechnology Risk practice  and is  a
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technical editor of Gradient's nanotechnology newsletter "EH&S Nano News."  Dr. Long has a
Sc.D. in Environmental Health from the Harvard School of Public Health and a M.S. in
Environmental Engineering from MIT, and he has prepared a number of peer-reviewed articles in the
general areas of indoor and outdoor air pollution and exposure assessment.

      Dr. Margaret MacDonell is in the Environmental Science Division of Argonne National
Laboratory, where she conducts environmental health risk analyses to support risk management and
communication/educational outreach for federal programs. Projects involve evaluating technologies
and assessing exposures and potential health effects, including fate and susceptibility context, while
integrating toxicity information that extends from acute and short-term to chronic. Activities have
included developing practical approaches for assessing cumulative risk across combined hazards and
exposures. She is also an adjunct professor at Northwestern University  (risk assessment and
environmental impact analysis), member of the National Council on Radiation Protection and
Measurements Scientific Committee on Environmental Radiation and Radioactive Waste Issues, and
fellow of the Society for Risk Analysis. Dr. MacDonell received her B.S. in Biology from the
University of Notre Dame, M.S. in Civil/Environmental Health Engineering from Notre Dame, and
Ph.D. in Civil/Environmental Health Engineering from Northwestern University.

      Dr. Fred  J. Miller is currently an independent consultant in dosimetry and inhalation
toxicology. His  primary research interests include pulmonary toxicology, dosimetry of gases and
particles, extrapolation modeling, and risk assessment. From  1991-2005, Dr. Miller was employed in
various capacities at the  Chemical Industry Institute of Toxicology, serving most recently as Vice
President for Research. During his career as  a U.S. Public Health Service Officer assigned to the
U.S. EPA, Dr. Miller served in  various  leadership positions and was noted for bringing together
interdisciplinary teams of scientists to solve important public health problems. In 1989, Dr. Miller
joined the faculty of Duke University Medical  Center, continuing his long-standing interest in
extrapolation modeling. He is internationally recognized for his research on the dosimetry of reactive
gases and has authored or co-authored more than 160 publications. Dr.  Miller received a number of
Scientific and Technical Achievement awards from EPA and also the  PHS' Outstanding Service
Medal. In 2005, he was awarded the Career Achievement Award by the Inhalation Specialty Section
of the Society of Toxicology (SOT) in recognition for his contributions to the field of inhalation
toxicology. He has served on EPA's Clean Air Science Advisory Committee and on numerous other
peer review panels.

      Dr. Nancy A. Monteiro-Riviere is a Professor of Investigative Dermatology and Toxicology
at the Center for Chemical Toxicology  Research and Pharmacokinetics, North Carolina State
University (NCSU) and in the Joint Department of Biomedical Engineering at UNC-Chapel
Hill/NCSU, as well as a Research Adjunct Professor of Dermatology, School of Medicine at UNC
Chapel Hill. She received her M.S. and Ph.D. in Anatomy and Cell Biology from Purdue University
and a postdoctoral fellowship in toxicology at CUT in Research Triangle Park, NC. She was past-
President of both the Dermal Toxicology and In Vitro Toxicology Specialty Sections of the National
Society of Toxicology. Dr. Monteiro-Riviere is a Fellow in The Academy of Toxicological Sciences,
and in the American College of Toxicology. She serves as Associate Editor for Wiley
Interdisciplinary Reviews in Nanomedicine and Nanobiotechnology and serves on six toxicology
editorial boards. She also serves on several national panels, including many in nanotoxicology, such
as the National Research Council of the National Academies Review of the Federal Strategy to
Address Environmental, Health, and Safety Research Needs for Engineered Nanoscale Materials.
She has published over 200 manuscripts in the field of skin toxicology  and is Editor of the book
"Nanotoxicology: Characterization and Dosing and Health Effects."  Currently, her research interest
is on the mechanisms of nanoparticle cellular uptake in cells and their subsequent translocation
through the body.

      Dr. Paul Mushak is a toxicologist and human health risk assessor, working as a partner in PB
Associates, a consulting practice in Durham, N.C. He is also a visiting professor, Albert Einstein
College of Medicine, Bronx, N.Y. Earlier, he was a faculty member in various capacities from 1971
to 1993 at the University of North Carolina - Chapel Hill School of Medicine, Pathology
Department. He works in the area of contaminant/toxic metals, metalloids, and organometals. His
doctoral (University of Florida, Gainesville) and postdoctoral (Yale University Department of
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Molecular Biophysics and Biochemistry) training were in the areas of metal chemistry, biochemistry,
enzymology, and toxicology. He has more than 40 years of widely published research and advisory
expertise in the areas of exposures and their determinants, analytical pediatric toxicology,
toxicokinetics, modeling and health risk assessments. He has served on numerous peer/advisory
committees of Federal and international agencies and those of the NAS/NRC, chairing several U.S.
Environmental Protection Agency review panels for reports to Congress. He has been qualified as a
testifying expert in the above areas by a number of U.S. Federal and state courts and has testified
before Congress on lead and child health.

      Dr. Srikanth Nadadur is Program Director at National Institute of Environmental Health
Sciences, NIH, overseeing extramural research efforts on environmental cardiovascular and
pulmonary health and health implications of Nanotechnology. Dr. Nadadur received his M.S. and
Ph.D. in molecular physiology from Sri Venkateswara University, India and had postdoctoral
training in molecular biology, cancer chemotherapeutics, and chemical carcinogenesis at Roswell
Park Cancer Institute, Buffalo, NY. Prior to joining NIEHS, Dr. Nadadur worked as Principal
Investigator at ORD, US EPA, where his research efforts were focused on molecular toxicology and
cardiopulmonary health effects of criteria air pollutants. Dr. Nadadur also serves as member of NIH
Nano Taskforce and the organizing committee of National Nanotechnology Initiative Program
Managers Workshop.

      Dr. Michele Ostraat, Senior Director for RTI International's Center for Aerosol Technology,
has expertise in aerosol technology, nanoparticle applications, submicron particle processing, micro-
and nanofiber filtration, portable nanoparticle detection, nanoparticle occupational safety and health,
and inhalation toxicology. She has experience in integrating emerging market needs with technology
capability to define organizational strategies, prioritizing programs for market development, and
commercialization. Before joining RTI, Dr. Ostraat worked at DuPont with primary responsibilities
in aerosol synthesis and characterization of sub-micron and nanoparticles for electronic and
materials applications and was Program Manager  for the Nanoparticle Occupational Safety and
Health Consortium with focus on 1)  developing methods to generate well-characterized aerosols of
solid nanoparticles and measuring aerosol behavior as a function of time; 2) developing air sampling
methodologies and instrumentation;  and 3) measuring barrier efficiency of filter media to specific
engineered aerosol nanoparticles. Prior to joining  DuPont, Dr. Ostraat was a Member of Technical
Staff at Bell Labs and Agere Systems where she examined the synthesis of rare-earth doped aerosol
nanoparticles and investigated the behavior of chalcogenide phase change materials. She earned her
Ph.D. and M.S. degrees in Chemical Engineering  from the California Institute of Technology. She
holds a B.S. Chemistry degree from Trinity University.

      Dr. Anil Patri leads a multi-disciplinary research team in his role as the Deputy Director of
the Nanotechnology Characterization Laboratory (NCL) at the National Cancer Institute at
Frederick. His research is focused on translation of nanotech-derived drugs, diagnostics and imaging
agents to clinic. He interfaces with many sponsors from federal agencies, academia and small
business  on projects related to nanotechnology. He serves as NCL's liaison with NIST and FDA and
facilitates characterization and standards development activities at ASTM and ISO. He directs a
chemistry lab at NCL and collaborates with many ATP labs and intramural NCI investigators on
nanomaterial evaluation. Prior to joining NCL, Dr. Patri served as a research faculty at the Center for
Biologic  Nanotechnology, University of Michigan Medical School, and developed multifunctional
nanomaterial for targeting, imaging,  and drug delivery application for cancer.  He received his Ph.D.
in Chemistry from the University of South Florida. He worked for a pharmaceutical company and as
a lecturer before pursuing a career in research.

      Maria Victoria Peeler is the senior policy specialist responsible for the development and
implementation of the emerging contaminants policy at the Washington DC State Department of
Ecology (Ecology). Ecology has delegated authority from U.S.  EPA for most environmental
regulations, including RCRA and CWA. Ecology has authority under independent state law to
restrict the use, management, and disposal of several PBTs, including mercury, lead and  PBDE.
Emerging contaminants included in the policy  development are pharmaceuticals, biotech and
nanotech. She has worked in the environmental field for over 25 years in areas such as state-owned
land management, utilities and transportation oversight, emergency management, CERCLA and state
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remediation agreements, as well as in-water construction projects, andNEPA/SEPAEIS. Maria
Victoria has undergraduate degrees in biology and chemistry; master's degrees in technical writing,
and environmental engineering (emphasis on engineering management); and is currently attending
the University of Washington DC school of engineering, CEE, researching potential bioassays and
chemical analysis that could be used to properly "designate" engineered nanoparticles that become
waste.

     Dr. Richard C. Pleus, Intertox managing director and toxicologist, has over 25 years
experience assessing the risk to humans exposed to chemical and biological agents via food,
consumer products, therapeutic agents, and the environment. Dr. Pleus' current focus is on
developing environmental health and safety (EHS) standards for nanomaterials and assisting in the
evaluation of EHS risks from exposure to engineered nanoparticles. He is a U.S. delegate on the
International Organization for Standardization (ISO) Technical Committee (TC) 229,
Nanotechnologies. While serving on TC 229, Dr. Pleus is leading the U.S. Technical Advisory Group
(TAG) Working Group 3 to develop a comprehensive list of physical and chemical characterization
parameters of engineered nano-objects for toxicologic assessment. Intertox is also assisting on a
number of product-related nanotechnology issues with companies around the world. Dr. Pleus is a
co-founder of the Nanotechnology Health and Safety Forum. Dr. Pleus has been asked to serve on
the review panel for NIOSH intramural proposals for the NIOSH Nanotechnology Research Center.
Dr. Pleus' credentials include a B.S. in Physiology, with honors, from Michigan State University, an
M.S. and a Ph.D. in Environmental Toxicology from the University of Minnesota, and postdoctoral
research in neuropharmacology at the University of Nebraska Medical Center.

     Dr. John Small is the Division Chief of the Surface and Microanalysis Science Division at  the
National  Institute  for Standards and Technology (NIST). Dr. Small received his B.S. degree in
Chemistry from The College of William and Mary in Virginia in 1971 and his Ph. D. in Chemistry
from the  University of Maryland in  1976 and has worked at NIST, formerly the National Bureau of
Standards (NBS) since that time. During his 32-year career with NBS/NIST, his research has been in
the general area of accuracy in quantitative  analysis of materials focusing on the high spatial
resolution quantitative chemical analysis of individual particles using x-ray microanalytical
techniques. Over the years, his research activities have included the development of a method for  the
quantitative analysis of particles, and the establishment of an accuracy base for the measurement of
environmental asbestos including the production of the first NBS asbestos SRM. Dr. Small served as
the Group leader for the Microscopy Research Group before becoming Division Chief. He is
currently a member of the NIST Nano-Safety committee and he has represented NIST on the Federal
governments interagency Working Group on Nanotechnology Environmental and Health
Implications (NEHI). under the U.S. Nanoscale Science, Engineering, and Technology
Subcommittee.

     Dr. Jeffery A. Steevens is a Research Biologist and Team Leader of the Environmental Risk
Assessment Team at the US Army Engineer Research and Development Center in Vicksburg, MS.
He obtained his bachelors degree in biochemistry from the University of Missouri in 1994 and his
doctorate degree in pharmacology and toxicology from the University of Mississippi in  1999. His
research activities include risk assessment and management of contaminated sediments,
bioavailability, and biological  effects of military-relevant materials (e.g., explosives, nanomaterials,
metals). One of his current responsibilities is leading a multi-disciplinary ERDC research cluster
focusing  on the fate, transport, and ecotoxicology of military relevant nanomaterials. In addition to
his research on nanomaterials, he is also a technical advisor to the World Bank on international
projects,  EPA Superfund Program, and provides expertise on many contaminated sediments projects.
Dr. Steevens has actively published the results of his work and has over 35 peer-reviewed journal
publications and 20 book chapters. He is an active member of the Society of Environmental
Toxicology and Chemistry, American Chemical Society, and Society of Toxicology. Dr.  Steevens is a
Technical Advisor for nanomaterials work group for the Materials of Evolving Regulatory Interest
Team (MERIT), Office of Secretary of Defense.

     Dr. Geoffrey I. Sunahara is a Senior Research Scientist and the Group Leader of Applied
Ecotoxicology at the Biotechnology Research Institute (National Research Council-Canada) in
Montreal, Canada. He has more than 20 years of professional experience in biochemical toxicology
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and environmental risk assessment, having gained this expertise in Canada, the United States and in
Europe. He has more than 200 research publications, proceedings, and presentations. Current
research interests include the ecotoxicological characterization of emerging environmental
contaminants such as nano-biomaterials, as well as recalcitrant soil contaminants such as the
energetic substances (TNT, RDX, and HMX) and their metabolites, using bacteria, plants and
invertebrate toxicity tests, and cultured cell approaches (mutagenicity and cell proliferation). Dr.
Sunaharahas served on several editorial boards, and was the Lead Editor of two ecotoxicology
books. He has participated on expert advisory committees for Environment Canada, U.S. Strategic
Environmental Research and Development Program (SERDP), and U.S.  EPA research projects. Dr.
Sunahara received his Ph.D. in Pharmacology and Toxicology (University of British Columbia,
Canada). He was a Fogarty International Post-doctoral fellow at the NIEHS (North Carolina). He
was a co-recipient of the TTCP Frances Beaupre Award for Environmental Awareness (2005). Dr.
Sunahara holds academic positions at McGill University  and Concordia University.

      Dr. Treye Thomas is a toxicologist and leader of the Chemical Hazards Program team in the
U.S. Consumer Product Safety Commission's (CPSC) Office of Hazard Identification and
Reduction. His duties include establishing priorities and projects to identify and mitigate potential
health risks to consumers resulting from chemical  exposures during product use. Dr. Thomas has
conducted comprehensive exposure assessment studies of chemicals in consumer products and
quantified the potential health risks to consumers exposed to these chemicals. Specific activities
have included conducting exposure and/or health hazard  assessments of flame retardant  (FR)
chemicals, combustion by-products, indoor air pollutants, and compounds used to pressure-treat
wood. Dr.  Thomas is the leader of the  CPSC  nanotechnology team, and is responsible for developing
agency activities for nanotechnology. Dr. Thomas has served as a CPSC representative on a number
of nanotechnology committees including the ILSI/HESI Nanomaterial Environmental, Health, and
Safety Subcommittee, the Federal NSET and NEHI sub-committees, and the International Council
on Nanotechnology (ICON).  Dr. Thomas received a Bachelors degree in Chemistry from the
University of California, Riverside, an MS in Environmental Health Sciences from UCLA, and a
PhD in Environmental Sciences at the University of Texas, Health Science Center, Houston. He
completed a post-doctoral fellowship in Industrial  Toxicology at the Warner-Lambert Corporation
(now Pfizer Pharmaceutical).

      Dr. John Veranth's research over the  past 15 years has evolved from particle formation in
combustion systems to the toxicology  of particles, with an emphasis on the lung. His background is
in mechanical and chemical engineering, but his current position is Research Associate Professor in
the Department of Pharmacology and Toxicology at the University of Utah. His laboratory group
focuses on lung, colon, and vascular cell culture models,  but he has conducted animal inhalation
exposure studies in collaboration with Dr. Kent Pinkerton at U.C. Davis, and was a Visiting Scientist
with Dr. Gunter Oberdorster at University of Rochester. Prior to becoming an academic researcher
Dr. Veranth worked in the energy production, metallurgical, and hazardous waste industries for 25
years. Many of his projects involved air pollution controls. His regulatory experience includes nine
years on the Utah Air Quality Board as the representative of organized environmental groups.
Education: BS Mechanical Engineering, Massachusetts Institute of Technology, 1971, MS ME with
bioengineering emphasis, MIT, 1974, PhD Chemical Engineering, University of Utah, 1997.

      Dr. Donald J. Versteeg is an environmental toxicologist and risk assessor with The Procter &
Gamble Company with 25 years of experience. He received his Ph.D. from Michigan State
University in 1985 and joined P&G as a researcher in the Environmental Science Department. Don
is currently a Principal Research Scientist in  Central Products Safety where he leads an
environmental risk assessment team working to improve  environmental risk assessment  approaches.
Don's research has been diverse including the use  of ecotoxicogenomics to understand mode of
action in fish to the generation of quantitative structure activity relationships to reduce animal usage
in toxicology. Don has over 40 publications in refereed journals on the fate, effects, and
environmental risk assessment of pharmaceuticals, personal care products, and emerging
contaminants. Dr.  Versteeg is a member of the Society of Environmental Toxicology and Chemistry
(SETAC) and serves as an Editor of Aquatic  Toxicology for the journal Environmental Toxicology &
Chemistry.
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      Dr. Nigel Walker is Deputy Program Director for Science for the National Toxicology
Program (NTP) at the National Institute of Environmental Health Sciences (NIEHS), one of National
Institutes of Health (NIH). He received his B.Sc. in Biochemistry in England from the University of
Bath in 1987 and his Ph.D. in Biochemistry from the University of Liverpool in 1993. Following
postdoctoral training in environmental toxicology at the Johns Hopkins School of Hygiene and
Public Health in Baltimore MD, he moved to the NIEHS, where he has been since 1995. He is
currently the lead scientist for the NTP Nanotechnology Safety Initiative that is evaluating the safety
of engineered nanoscale materials. He has over 15 years experience in environmental toxicology,
quantitative dose response modeling, and risk analysis, with particular emphasis on persistent
organic pollutants, has over 80 publications in this area, and has given numerous invited
presentations at national and international workshops and symposia. Dr Walker is on several editorial
boards (Environmental Health Perspectives and Toxicology and Applied Pharmacology), is  a
founding member of the Society of Toxicology Nanotoxicology Specialty Section, an adjunct
associate professor in the  Curriculum in Toxicology at the University of North Carolina at Chapel
Hill, and past-President of the North Carolina Society of Toxicology.

      Dr. William J. Warren-Hicks is CEO of EcoStat, Inc, a small women-owned company
located in Mebane, North Carolina. He holds a Ph.D. from Duke University in environmental
statistics. He has a total of 29 years of experience providing consulting expertise in the areas of risk
analysis, environmental data analysis, uncertainty analysis, Bayesian inference and decision,
probabilistic risk methods, survey design, time-series modeling, messy data analysis, hypothesis
testing, multivariate analyses, and model  validation studies. He has over 120 peer-reviewed
publications, 2 books,  and 8 book chapters in the areas of environmental risk assessment, statistics,
probabilistic modeling, and decision sciences. In a consulting capacity, he has managed over 200
projects for clients in all major Environmental Protection Agency (EPA)  programs. He teaches
courses at Duke University and Elon University to both undergraduate and graduate students.

      Dr. Paul Westerhoff is the Interim Head of the School of Sustainable Engineering and The
Built Environment, and member of the Civil, Environmental and Sustainable Engineering faculty, at
Arizona State University.  He  obtained a Ph.D. from the University of Colorado at Boulder, a MS
from University of Massachusetts and BS from Lehigh University. Westerhoff j oined ASU in August
1995. Westerhoff has a strong publication and research record, has garnered wide recognition for his
work related to treatment  and occurrence  of emerging contaminants in water, and has been active in
multidisciplinary research. He has lead research funded by AWWARF, USEPA, NSF, DOD  and local
organizations investigating the fate of nanomaterials in water, use of nanomaterial-based
technologies for water and reuse treatment, reactions and fate of oxo-anions (bromate, nitrate,
arsenate) during water treatment,  reactivity of natural organic matter, formation of disinfection by-
products, removal of taste and odor micropollutants. He has over 88 peer reviewed journal article
publications and has been involved in over 200 conference presentations. He serves on numerous
voluntary committees for  these organizations. He currently is a member of the AWWARF Expert
Panel on EDC/PPCPs, the WateReuse Foundation Research Advisory Board, and the Water Research
Foundation/AWWARF Public Council.

      Dr. Mark R. Wiesner  serves as Director of the Center for the Environmental Implications of
Nanotechnology (CEINT) headquartered  at Duke, where he holds the James L. Meriam Chair in
Civil and Environmental Engineering with appointments in the Pratt School of Engineering and the
Nicholas School of Environment.  Dr. Wiesner's research has focused on the applications of
emerging nanomaterials to membrane science and water treatment and an examination of the fate,
transport, and impacts  of nanomaterials in the environment. He co-edited/authored the book
"Environmental Nanotechnologies" and serves as Associate Editor of the journal Nanotoxicology.
Before joining the Duke University faculty in 2006, Professor Wiesner was a member of the Rice
University faculty for 18 years where he held  appointments in the Departments of Civil and
Environmental Engineering and Chemical Engineering and served as Associate Dean of
Engineering, and Director of the Environmental and Energy Systems Institute. Prior to  working in
academia, Dr. Wiesner was a Research Engineer with the French company the Lyonnaise des Eaux,
in Le Pecq, France, and a Principal Engineer with the Environmental Engineering Consulting firm of
Malcolm Pirnie, Inc., White Plains, NY. Wiesner received  the 1995 Rudolf Hering medal from the
American Society of Civil Engineers and  the 2004 Frontiers in Research Award from the Association
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of Environmental Engineering and Science Professors. In 2004 Dr. Wiesner was also named a "de
Fermat Laureate" and was awarded an International Chair of Excellence at the Chemical
Engineering Lab of the French Polytechnic Institute and National Institute for Applied Sciences in
Toulouse, France. Professor Wiesner is a Fellow of the American Society of Civil Engineers and
serves on the Board of the Association of Environmental Engineering and Science Professors.
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              APPENDIX F. List of Workshop Observers

             J. Michael Davis       EPA ORD, NCEA
             Jane Denne            EPA ORD, NERL
             Steve Diamond        EPA ORD, NHEERL
             Irish Erickson         EPA ORD, NRMRL
             Maureen Gwinn        EPA ORD, NCEA
             Dorothy Miller        AAAS Fellow with EPA ORD
             Peter Preuss           EPA ORD, NCEA
             Gary Sayler           BOSC / University of Tennessee - Knoxville
             Jo Anne Shatkin        CLF Ventures
             John Vandenberg       EPA ORD, NCEA
             Debra Walsh          EPA ORD, NCEA
             Amy Wang            ORISE Post Doctoral Fellow with EPA ORD, NCEA
             Doug Wolf            EPA ORD, NHEERL

             Abbreviations:
             AAAS       American Association for the Advancement of Science
             BOSC       Board of Scientific Counselors
             EPA        U.S. Environmental Protection Agency
             NCEA       National Center for Environmental Assessment
             NERL       National Exposure Research Laboratory
             NHEERL     National Health and Environmental Effects Research Laboratory
             NRMRL     National Risk Management Research Laboratory
             ORD        Office of Research and Development
             ORISE       Oak Ridge Institute for Science and Education


             Meeting Support Contractor (ICF International) Staff
             Peter Bonner, Lead Facilitator
             Whitney Kihlstrom, Note-taker
             Amalia Marenberg, Note-taker
             Kimberly Osborn, Work Assignment Manager
             Ethan Sanders, Co-facilitator
             Audrey Turley, Meeting Coordinator
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        APPENDIX G. List of New and Modified  Questions



G.1.   New Questions Submitted by Workshop

Participants



G.1.1.  Multiple Chapters:  Cross-Cutting Issues (New Questions)


Mult-A. Are TiO2 particles transferred through the placental barrier or through milk?

Mult-B. Do adequate methods exist to characterize nano-TiO2 in relevant environmental matrices
    such as soil, sediment, or biofilms?

Mult-C. How do surface coatings affect environmental fate, environmental chemistry, particle
    chemistry, and toxicity? Do WWTP processed affect surface coatings? What natural particle
    coatings are added in the environment (e.g., humic & fulvic acids) and how do these natural
    coating influence environmental fate, chemistry, and toxicity?

Mult-D. How do TiO2 properties change from the manufacturing stage, upon its incorporation into
    products, during its use, during storage, upon release to the environment, and upon
    environmental aging?

Mult-E. How do variations in water chemistry (pH,  ionic strength, divalent cation concentration,
    etc.) influence the chemistry and toxicity of nano-TiO2?

Mult-F. How effective are existing management practices to control occupational exposure to nano-
    Ti02?

Mult-G. Is there enough information to quantify the spatial distribution of nano-TiO2 over time?

Mult-H. Is there enough information to quantify the temporal trends in environmental
    concentrations of nano-TiO2?

Mult-I. Just to re-emphasize the importance of chemical and physical characterization at a number
    of stages in addressing possible toxicity of nanomaterials.

Mult-J. Should the EPA promote a surface chemistry nomenclature system for use in particle life
    cycle analyses?

Mult-K. Should the life cycle analysis be product-specific, meaning manufacturing process specific,
    and then combined as a second step for an overall analysis?

Mult-L. Should there be a database of reliable information regarding NPs created and made
    available (the equivalent of the Wikipedia or Google search)?

Mult-M. Should TiO2 particles with coatings and strongly chemisorbed species be evaluated
    separately for the purposes of environmental transport, ecotoxicity, and toxicity?

Mult-N. There should to be a question dealing with  metrology and whether or not the
    instrumentation is available and what needs to be developed in order to do long term field
    monitoring of nanoparticles.
May 2010                                    G-1

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Mult-O. To what degree is sequestration of TiO2 to specific compartments expected to affect fate
    and exposures to receptors (human or ecological)?

Mult-P. What abatement/management practices are recommended to control emissions from
    manufacturing operations that make or use nanomaterials?

Mult-Q. What are each scientific field's roadblocks that currently limit scientific
    reliability/reproducibility and the public's confidence in the resulting risk assessments? What
    are the cross-disciplinary impediments?

Mult-R. What  is the potential for TiO2 particles to accumulate in internal organs and the brain? What
    developmental effects occur in offspring after exposure during pregnancy?

Mult-S. What makes one type of nanoparticle more active or toxic than another?

Mult-T. What set of widely shared reference samples of nano- and conventional TiO2 would be most
    useful for integrating the results of different investigators regarding particle characterization and
    particle toxicology?

Mult-U. While comprehensive studies are underway, and issues being debated (such as in this
    workshop), should a group of experienced individuals (such as in this workshop) try to propose
    "guidelines" for safe use?


G.1.2.  Chapter 1:  Introduction (New Questions)


l-A. By region and environmental segment (soil, water, etc.), what is known about the background
    concentration of nano-TiO2 due to natural or nonanthropogenic processes?

1-B. Do the surface coatings wash off or become diluted when nano-TiO2 is formulated into
    products?

1-C. Do we have comprehensive physicochemical characterization data (non-proprietary) on nano-
    TiO2 used  in sunscreen or water treatment products?

1-D. How can naturally occurring versus engineered NanoTiO2 be differentiated across the
    environment (i.e., in air, water, soil, plants, animals)? How can nano-TiO2 from sunscreens be
    differentiated from nano-TiO2 from waste water processes?

1-E. How reliable are the methods to detect various forms of TiO2 in complex matrices such as
    wastewater? Will there be validated methods?

1-F. Is comprehensive environmental assessment (CEA) the most appropriate framework from which
    to approach the development of a research strategy for assessing nanomaterial risks?

1-G. Is it possible to predict the reactive oxygen species (ROS)-generating potential of nano-TiO2 in
    the lungs from measurements taken on airborne nano-TiO2?

1-H. Morphology is a key determinant of biological interaction of other nanomaterials. Have
    adequate toxicological studies on the effect of morphology been conducted for TiO2
    nanoparticles?

1-1. Should a recommended list of instruments and techniques to characterize nano-TiO2 be
    compiled?

1-J. What are the important metrics that we need to use to characterize nano-TiO2?
May 2010                                      G-2

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1-K. What is nano-TiO2? Is the definition of less than 100 nm adequate? Or, should a dimension be
    derived based on the toxicological properties?

1-L. What is the potential for methods to biomonitor TiO2 in humans?

1-M. What precise definition distinguishes nano-TiO2 from the smallest particles found in
    conventional TiO2 powder mixtures? Is there a continuum between powders deliberately
    enriched in sub-100 nm primary particles and the tail of the size distribution produced as
    conventional TiO2?


G.1.3.  Chapter 2:  Life Cycle  Stages (New Questions)


2-A. Does nano TiO2 settle out in water? (Important for exposure considerations.)

2-B. Highlight high potential areas for use of nano-TiO2. What forms will it be potentially used?

2-C. How can nano TiO2 be removed from water?

2-D. How might the product be misused (intentionally or unintentionally)? How would this change
    the use-phase exposure?

2-E. Is nano-TiO2 even used in any commercial scale drinking water treatment? Is any drinking
    water utility using it in their routine treatment process? [If no, come up with better applications
    to evaluate]

2-F. Is the carbon footprint of supplying and producing nano-TiO2 greater than for conventional
    TiO2?

2-G. Large containers of TiO2 used in sunscreens in storage facilities may change over time and
    could precipitate out. What is the long- term effect? Does size change? Degradation of TiO2
    could occur and it would no longer be the same product that it was. What is the recommendation
    for how long TiO2 will remain stable? Changes in temperature can affect aggregation.

2-H. Radioactive materials are present in ilmenite and natural rutile. Should there be a concern?

2-1. Should we examine data from existing manufacturing facilities for TiO2? Have there been any
    issues or problems? How does this correlate to nano-TiO2, if at all? Are there lessons to be
    learned?

2-J. How much ilmenite is released in the air /environment  during the surface mining process? Has
    this been measured? Would it have inhalation concerns?

2-K. What are the effects of different storage conditions and periods on TiO2 properties related to  it
    as a potential hazard?

2-L. What exposure pathways could potentially be affected if release of these waste products
    occurred?

2-M. What is the proper method of disposal for the by-products generated from the making of TiO2?

2-N. What materials does nano-TiO2 replace in sunscreens and waste water treatment? Is there a net
    positive environmental impact to replacing these materials?
May 2010                                      G-3

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2-O. What size and how much TiO2 can get through the filtration methods? Amounts that get
    through could be harmful. However, there is no discussion or cited reports on the long term
    repetitive oral dosing or oral toxicity studies. How can we decide if TiO2 will be a concern?


G.1.4.   Chapter 3: Fate and Transport (New Questions)


3-A. Are there any data available on the physical and chemical behavior of nano-TiO2 in air or water
    in relationship to its surface chemistry?

3-B. Are there any generalized principles for study of fate and transport of Nanoparticles in the
    environment? What are the important parameters that govern fate and transport of
    Nanoparticles?

3-C. Are there any methods available to measure nano TiO2 particles in diverse matrices?

3-D. By region, what is the background concentration of nanomaterials in wastewater due to
    nonanthropogenic processes?

3-E. Can existing information, perhaps data, regarding uptake and transformation of engineered
    nanoparticles as medium characteristics change, such as sediments from estuarine to marine
    environments?

3-F. Has Ti been analyzed in finished/potable water, and if so how much and can it be attributable to
    Ti02?

3-G. How do natural waters of different solution chemistries affect the physicochemical
    characteristics of nano-TiO2 and its effects on aquatic biota?

3-H. How do TiO2 and other nanomaterials differ from larger scale particles or aggregates of
    nanoparticles or other particles in their fate and transport in the environment and how might
    that affect our ability to use predictive modeling?

3-1. How does nano-TiO2 interact with chlorine in disinfected water supplies? Will it create higher
    levels of disinfection byproducts or novel byproducts?

3-J. Is the use of classic 48-hr, 96-hr, etc. microbiotests  adequate for nano-TiO2 toxicity studies?
    Would the bio-effects be different if exposure times were used?

3-K. Plants and seeds can bioaccumulate TiO2 and other heavy metals. How does this affect the
    edible vegetation? If only less than 1% of the US agricultural land uses treated sewage sludge,
    should we be concerned? This is extremely small.

3-L. What are stabilities of coatings? What is weathered TiO2?

3-M. What are the long-term (centuries to geological timescale) sinks for nano-TiO2?

3-N. What happens to nano-Ti when it is incinerated? Does it agglomerate or does the particles' size
    go down?

3-O. What is the available evidence regarding the likelihood that various TiO2 coatings will be
    degraded under different environmental conditions, and are there coatings that are more
    resistant to environmental degradation?
May 2010                                      G-4

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3-P. What is the current background level of nano-TiO2 in various ecosystems? Recent field flow
    fractionation (FFF) studies have indicated significant amounts of metal-containing nanoparticles
    that appear to be widespread, and may be of natural origin.

3-Q. What knowledge do we have of the potential surface modifications of nano-TiO2 in air, water,
    or biological fluids?


G.1.5.  Chapter 4: Exposure-Dose Characterization (New Questions)


4-A. Are available measurement methods able to adequately discriminate nano-TiO2 from
    conventional TiO2 or other nanoparticles? What suite of methods is currently optimal for
    identifying nano-TiO2?

4-B. Benthopelagic species could potentially be exposed to the settling of TiO2 aggregates; however,
    aggregates are probably larger than some of these species. Therefore, is it a concern?

4-C. Does nano-TiO2 bioaccumulate in humans?

4-D. How do TiO2 and other nanoparticles differ from what we already know about other compounds
    including macroparticles with respect to exposure-dose and how might that affect predictive
    modeling?

4-E. How does the presence of nano-TiO2 cause unique reactions to occur or produce products or
    destroy necessary organisms that have negative environmental implications?

4-F. How much (metric tons) nano-TiO2 is used in sunscreens, cosmetics and other products that are
    contained  in products that may be disposed down the drain? If any of the pigment and other
    TiO2 sources contain a fraction which is nano, this mass should be added into the volume.
    Further, the volume should be split out into different surface coatings, dopings, and size
    fractions.

4-G. What is the concentration of TiO2 in public swimming pools? Eye is a small surface area to be
    affected.

4-H. Fish can take up TiO2 from waste water runoffs and ingest TiO2 along with the prey that has
    been exposed to TiO2. Major Gap is  people then eat the fish which could have bioaccumulated
    the TiO2. What are the health effects in humans after ingestion with TiO2 contaminated fish?
    Remember the mercury situation in large fish.

4-1. If nano-TiO2 is part of the packaging, will it leach into the product?

4-J. Is nano-TiO2 used in any products or packaging for products intended for very young children?

4-K. Is the skin on the forearms (which is used for dermal studies) identical to skin on the face and
    lips (where most of the applications  of TiO2 sunscreen is applied).  (If so, it would appear that
    little TiO2 penetrates the skin surface.)

4-L. Nano-TiO2 on the organism's surface might cause toxicity even if TiO2 does not enter cells?
    Release of other pollutants? Must enter cells or cause damage to cells to exert toxicity, e.g.,
    cross cell membranes.

4-M. Powders  and particles have been produced for many decades in the Industrialized world. Is
    there any epidemiological data from manufacturing sites of particles? Any adverse health data?
May 2010                                      G-5

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4-N. The release of TiO2 from treated products may depend on product use and misuse. How will
    product use/misuse impact release of TiO2 and subsequent exposure to humans and the
    environment?

4-O. What are the relevant exposure metrics for TiO2, and what is their relative importance in terms
    of toxicologic relevance?

4-P. What could be considered as relevant range of nano-TiO2 concentrations in aquatic systems with
    regard to dose-exposure studies using model aquatic organisms?

4-Q. What is nano-TiO2 removal in wastewater treatment? Does wastewater treatment affect
    aggregate size? This should be understood for each of the different surface coatings, dopings,
    and size fractions. Note: there is one published removal study. Additional studies looking at
    other treatment processes are needed.

4-R. What is the effect after repetitive or multiple dosing of TiO2 over time? Could penetrate deeper
    into the skin and be available for systemic absorption.

4-S. What is the potential for inhalation and ingestion exposures to nano-TiO2 from sunscreen? What
    are the dominant sizes of TiO2 aggregates/agglomerates during spraying, and what is the
    potential for inhalation exposure to nano-TiO2 during spraying? What is the potential for hand-
    to-mouth intake of nano-TiO2 from sunscreen usage?

4-T. What is the ultimate sink for nano-TiO2 in the environment? What are surface water, sediment,
    and soil nano-TiO2 concentrations? This should be understood for each of the different surface
    coatings, dopings, and size fractions. Are there background concentrations?  If so, natural nano-
    TiO2 should be fully characterized.


G.1.6.   Chapter 5: Characterization of Effects (New Questions)


5-A. Are the biological responses that have been observed for elevated nano-TiO2 exposures
    different from those elicited for exposures to other small particles? If so, how?

5-B. Are there existing, simple, inexpensive state, Canadian, European Union or other standard
    testing protocols that could do preliminary testing of chronic/sublethal effects with simple end
    points, such as weight?

5-C. How do TiO2 and other nanomaterials differ from larger scale particles, aggregates of
    nanomaterials or other particle types, or solutions of pollutants in their effects on species
    (human and ecological) and how does that affect pharmacokinetics and effects of exposure?

5-D. How relevant are intratracheal installations to humans? Rats are obligatory nose breathers, not
    humans. Forcing large amounts of TiO2 is not a normal scenario.

5-E. If tested on mouse skin, would nano-TiO2 be an initiator, promoter, complete carcinogen, or
    none of the above?

5-F. Is nano-TiO2 toxicity and reactive oxygen species (ROS) generation on the skin enhanced by
    exposure to sunlight?

5-G. Is there any evidence for nano-TiO2 and conventional TiO2 inducing distinctly different
    pathways of cell signaling or gene transcription? Do nano and conventional  TiO2 have different
    toxicological mechanisms of action or do the two materials simply have a surface-area or
    surface-coating dependent  difference in potency?
May 2010                                      G-6

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5-H. Mostly everything including water can cause conjunctivitis of the eye. Very small surface area.
    Is this a concern? Eye protection can be worn during manufacturing etc.

5-1. No long term repetitive oral toxicity studies or sensitization studies have been conducted with
    different concentrations of TiO2, sizes or surface coatings in skin.

5-J. What are the effects of long-term or repeated use of sunscreen containing nano-TiO2?

5-K. What are the fundamental biological responses  of nano-TiO2 interaction(s) at cellular level (as
    dictated by its physical and chemical characteristics)?

5-L. What are the known effects due to exposures to nano TiO2?

5-M. What is the interaction between nano-TiO2 and the various branches of the immune system? Is
    there a threshold for nano-TiO2 perturbation of the immune system?

5-N. What is the potential for TiO2 particles to accumulate in internal organs and the brain? What
    developmental effects occur in offspring after exposure during pregnancy?

5-O. What is the relationship between nano-TiO2 particle size and transport into the central nervous
    system?

5-P. What is the relevance of short-term pulmonary effects observed in animals at high airborne
    concentration levels to human exposures at lower environmental concentration levels? What is
    the real-world relevance of toxicity studies  that rely on sonication, ultrafiltration, and other
    techniques for dispersing TiO2?

5-Q. What properties are most closely tied to the observed biological responses in TiO2 toxicity
    studies, and can we develop predictive models of TiO2 toxicity based on properties data?

5-R. What quantities/concentrations  of TiO2 nanoparticles are unsafe? Is there an LD10, LD50, etc
    for TiO2 nanoparticles?

5-S. Which organisms are most likely to be exposed to each of the sources of nano-TiO2? Which
    organisms are likely to take up particles via endocytosis? Which organisms are likely to be most
    susceptible to free radical effects?


G.2.   Revised Questions  Submitted by Participants



G.2.1.   Chapter 1: Introduction  (Revised  Questions)


1-2. Suggest that the focus be on reasonably foreseeable applications, not "different applications."

1-3. Suggest that this be modified to  include "and other  ingredients."

1-4. (Added text in CAPS.) What are the potential implications (e.g., in terms of physical and
    chemical properties AND RELATED FATE, EXPOSURE, and TOXICITY) of differences in the
    composition and mineralogy of different forms of nano-TiO2 (e.g., rutile and anatase),
    PARTICULARLY FOR CURRENTLY COMMERCIALIZED FORMULATIONS?

1-5. What are the "accepted standard" ways of testing materials today?
May 2010                                     G-7

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1-6. What existing or emerging analytical techniques might be relevant or useful for emissions
    characterization at any stage of the life cycle? For example, could field flow fractionation (FFF)
    be used for characterization of particle size and elemental composition?


G.2.2.  Chapter 2: Life Cycle Stages (Revised Questions)


2.3-3-2.3-6. (These questions could be combined and summarized with 4-8 as follows.) What
    factors are critical to ensure that nanomaterials are contained and remain stable?

2.4-5. Suggest that this be modified from "topical sunscreen products" to "topical sunscreen products
    and other topical personal care products."

2-5-4. How are large quantities of waste (e.g., out of spec nanomaterials, sub-par batches of
    sunscreen) handled?


G.2.3.  Chapter 3: Fate  and Transport (Revised Questions)


3-3. Are available fate and transport models applicable to nanomaterials? If not, can they be adapted,
    or are new models required?

3-4. Is information on environmental fate and transport of other substances available that might
    provide insights applicable to nanomaterials?

3-7. (Added text in CAPS.)  What is the bioavailability of nano-TiO2 in land-applied sludge to
    PLANTS AND terrestrial and aquatic organisms?  Is UPTAKE FROM CONTAMINATED SOIL
    AND WATER POSSIBLE AND IS bioavailability likely  to change when nano-TiO2 is
    incorporated into sludge and is allowed to "age" (in situ weathering) (NOTE: this change is
    intended to combine this question with 3-17 and 18 which is very similar)

3-8. What is their persistence with TiO2 when sunscreen is used?

3-12. (Added text in CAPS.) Irradiated photocatalytic  nano-TiO2 is potentially biocidal and
    antimicrobial. What is the potential for interactions of nano-TiO2 with microbes needed in water
    treatment systems AND ENVIRONMENTAL MEDIA EXPOSED TO WATER AND SLUDGE
    FROM SUCH SYSTEMS? (intended to combine this question with question 3-9)


G.2.4.  Chapter 4: Exposure-Dose Characterization (Revised Questions)


4-1. (Add to existing question)  At what concentrations?

4-6. What parameters should be used to characterize worker (or consumer  or general human)
    exposure in a way that is compatible with hazard information?

4-7. What management practices are recommended to control occupational exposures to
    nanomaterials?

4-8. (Consider changing this question to the following.) What protective equipment are effective in
    containing nanomaterials and what are the factors  most important for ensuring that nano-TiO2 is
    not released and does not expose workers?

4-12. Suggest that this be modified from the focus on inhalation to include potential oral and dermal
    exposures.
May 2010                                    G-8

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4-15. Which physiologically-based pharmacokinetic models are optimal for understanding
    absorption, distribution, and elimination of nanomaterials in humans?


G.2.5.  Chapter 5: Characterization of Effects (Revised Questions)


5.2-1. (Combine with 5.3-1; added text in CAPS.) Are current EPA test protocols adequate to assess
    human and ecological toxicity of nano-TO2, PARTICULARLY FOR COMMERCIALIZED
    FORMULATIONS?

5.2-7. How do abiotic factors in the environment, such as UV, pH, oxygen level, and other
    chemicals, affect nanomaterials and their ecological effects?

5.3-3. This could be worded in a clearer, more comprehensive way to include potential skin hydrated
    conditions that can occur under occluded skin conditions, e.g., from  wearing of diapers,
    feminine hygiene pads, and band aids. (Also need to consider how hydration occurring in patch
    tests could impact penetration, and how such data should be considered in exposure and risk
    assessments.)

5.3-4. Suggest that this question be broadened (or an additional question  created) to include: 1)
    different  disease states and 2) conditions that seek to represent reasonably foreseeable consumer
    product usage and occupational exposure scenarios.

5.3-8. What kind of studies would provide the most suitable data to understand dose-response of
    occupational exposure to nanomaterials and health effects in humans?

5.3-9. (Added text in CAPS.) What is the potential for NEUROLOGICAL, reproductive and
    developmental effects...?

5.3-10. (Combine with 5.3-11.)  Is nano TiO2 carcinogenic? If so, by which routes of exposure?
May 2010                                     G-9

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           APPENDIX H. Pre-Workshop Ranking  Results


     The following steps describe the procedure used to calculate the pre-workshop rankings based

on the rankings received from the participants.

•     Added three placeholder questions so there are a total of 100 questions (to simplify
      presentation of analysis and results).

•     For the ranked questions (top 10 for most participants, although a few submitted only 9),
      converted the score of 10 to 100, score of 9 to 99, score of 8 to 98, etc.

•     For the unranked high questions, assigned a random value between 76 and 90. This was
      done to facilitate calculation of means and standard deviations for the vote tallies for
      each question. The range of random numbers varied depending on how many ranked
      questions the participant submitted.

•     For the unranked low questions, assigned a random value between 1 and 10. Again, this
      range of random numbers may be smaller or larger than 10, depending on how many low
      questions the participant submitted. This range always began at 1.

•     For the ones that were not ranked or selected as high or low (left blank in the Web
      ranking form), assigned a random value between 11 and 75. The placeholder questions
      were included in this group. This range of random numbers varied from participant to
      participant based on how many ranked, low, and high questions were submitted by that
      participant.

•     Calculated total points, mean score, and standard deviation for each question.

•     Ran a Monte Carlo simulation 100 times, storing the total points, mean score, and
      standard  deviation for each run. Only the randomly assigned numbers changed from run
      to run-the ranked questions always kept the same order and points from  100 down to 92
      or 91, depending on how many the participant ranked.

•     Averaged the results of all Monte Carlo simulations to get the final results shown in the
      tables that follow.
May 2010                                   H-1

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                                    Ranking Results (1 -10)
        *Shown in ranked order beginning with question awarded most total points (Question 4-10).
        0
10
Number of Participants Selecting Item
      20             30
40
50
       Figure H-1.    Ranking Results 1 -10.
May 2010
                   H-2

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                                        Ranking Results (11 - 40)
                     'Shown in ranked order beginning with question ranked 11th (Question 2-4-7).
                              10
 Number of Participants Selecting Item
15     20     25      30      35
40
45
50
        Figure H-2.    Ranking Results 11-40.
May 2010
            H-3

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                                       Ranking Results (41 - 70)
                     'Shown in ranked order beginning with question ranked 41st (Question 4-9).
                             10
 Number of Participants Selecting Item
15      20      25      30      35
40
45
50
        Figure H-3.    Ranking Results 41-70.
May 2010
             H-4

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                                       Ranking Results (71 -100)
                    *Shown in ranked order beginning with question ranked 71st (Question 5-2-10).
                             10
                                       Number of Participants Selecting Item
                                     15      20       25      30      35
                                                                            40
                                                                                    45
                                                                                            50
        Figure H-4.    Ranking Results 71-0.
May 2010
H-5

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       Table H-1. Pre-Workshop questions in ranked order, beginning with the question awarded the
                 most points

Rank



1



2



3







4










5






6



Question



4-10



4-1



3-2







5-2-1










1-2






5-3-8


Are available methods adequate to
characterize nano-TiO2 exposure via
air, water, and food? What properties
of nano-TiO2 should be included in
such exposure characterizations?
Which sources, pathways, and routes
pose the greatest exposure potential
to nano-TiO2 for biota? ...for
humans?
How do specific physicochemical
properties, including particle surface
treatments and aggregation/
agglomeration, affect the fate and
transport of nano-TiO2 in various
environmental media?
Are current EPA standard testing
protocols adequate to determine
nano-TiO2 ecotoxicity?
If not, what modifications or special
considerations, if any, should be
made in current ecological tests?
For example, what are the
differences in characterization of
testing material (as raw material, in
media, and in organisms), dispersion
methods, and realistic exposure
routes between testing conventional
materials and nanomaterials?
Have the properties of nano-TiO2 in
different applications been
adequately characterized?
If not, is the general problem that
methods do not exist or that existing
methods have not been widely
applied? If new methods are needed,
what properties should they
measure?
What kind of studies would provide
the most suitable data to understand
dose-response of nano-TiO2
occupational exposure and health
effects in humans?

Total
Points



3,754



3,750



3,734







3,633










3,302






3,249



Mean



76.6



76.5



76.2







74.1










67.4






66.3



Std.
Dev.



25.0



26.3



26.1







27.6










28.0






29.3


Number of Participants Who...
Ranked
in
Top 10


20



21



21







22










15






14


Selected
as High


15



14



13







9










11






10


Selected
as Low


1



1



0







0










1






2


Did
Not
1 WL
Select


13



13



15







18










22






23


May 2010
H-6

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Rank
7
8
9
10
11
12
13
14
15
Question
5-3-1
3-13
3-8
5-3-9
2-4-7
2-2-1
5-3-1 1
1-5
5-2-5
Are the current EPA harmonized
health test guidelines for assessing
toxicity adequate to determine the
health effects/toxicity of nano-TiO2?
What are the key environmental
factors (e.g., pH, natural organic
matter type and concentration,
temperature) that facilitate or hinder
nano-TiO2 stability in the aqueous
environment? Would humic acids or
other common constituents or
contaminants in water undergoing
treatment affect the fate, including
agglomeration/aggregation
properties, of TiO2?
What effect, if any, do coatings,
dopings, carriers, dispersants, and
emulsion types have on
biopersistence and bioaccumulation?
What is the potential for reproductive
and developmental effects of nano-
TiO2?
How much nano-TiO2 enters the
environment under different
scenarios and conditions of
sunscreen use (e.g., ambient air and
water temperature, swimming,
bathing)? Under what conditions
would nano-TiO2 be released from
the sunscreen matrix?
How do various manufacturing
processes for nano-TiO2 affect their
physicochemical properties?
Is inhaled nano-TiO2 carcinogenic at
exposure levels below those that
induce particle overload?
How do coatings applied for different
purposes (e.g., to disperse particles
or to decrease photocatalysis)
interact or affect other properties of
nano-TiO2?
What might be the primary
mechanism(s) of action of toxic
effects in different species?
Total
Points
3,221
3,135
3,134
3,098
3,053
3,043
3,037
3,033
3,013
Mean
65.7
64.0
64.0
63.2
62.3
62.1
62.0
61.9
61.5
Std.
Dev.
30.6
28.0
30.0
28.2
27.2
29.9
29.9
27.7
28.6
Number of Participants Who...
Ranked
in
Top 10
18
11
14
9
6
12
10
9
10
Selected
as High
5
12
9
13
16
10
11
12
9
Selected
as Low
2
0
2
3
0
2
4
0
1
Did
Not
Select
24
26
24
24
27
25
24
28
29
May 2010
H-7

-------

Rank



16





17




18

19


20



21


22


23



24





25




Question



3-1





2-4-3




3-3

5-2-9


5-2-7



5-3-2


5-2-13


4-17



2-2-4





3-7



What are the relative contributions of
different stages of the life cycles of
water treatment and sunscreen
products to environmental levels of
nano-TiO2 and associated
contaminants in air, water, and soil?
What percentage of the nano-TiO2
would settle out in floe or become
part of the filter matrix? What
percentage would be released into
finished water? Are measurement or
monitoring methods adequate to
detect such particles?
Are available fate and transport
models applicable to nano-TiO2? If
not, can they be adapted, or are new
models required?
What are the ecological effects of
long-term exposure to nano-TiO2?
How do abiotic factors in the
environment, such as UV, pH,
oxygen level, and other chemicals,
affect nano-TiO2 and its ecological
effects?
Is the current information on nano-
TiO2 skin penetration sufficient for
risk assessment?
Is the available ecotoxicity evidence
adequate to support ecological risk
assessment for nano-TiO2? If not,
what is needed?
What is the potential for nano-TiO2 to
transfer to or accumulate in the food
web and cause adverse effects on
ecological receptors?
What waste products or other by-
products, both nanoscale and larger,
might be released, and in what
quantities, for nano-TiO2
manufacturing processes?
What is the bioavailability of nano-
TiO2 in land-applied sludge to both
terrestrial and aquatic organisms?
Is bioavailability likely to change
when nano-TiO2 is incorporated into
sludge and is allowed to "age" (in-
situ weathering)?

Total
Points



3,011





2,995




2,983

2,981


2,959



2,929


2,922


2,911



2,910





2,893




Mean



61.5





61.1




60.9

60.8


60.4



59.8


59.6


59.4



59.4





59.0




Std.
Dev.



30.1





28.8




27.9

27.6


26.8



30.5


28.4


27.7



29.2





28.1



Number of Participants Who...
Ranked
in
Top 10


14





8




8

9


7



10


10


6



6





6



Selected
as High


7





14




13

10


11



10


7


13



15





14



Selected
as Low


1





1




1

1


0



4


2


2



3





1



Did
Not
1 WL
Select


27





26




27

29


31



25


30


28



25





28



May 2010
H-8

-------

Rank




26





27


28


29




30






31





32


33




34




Question




4-16





4-6


5-3-10


3-16




4-15






2-4-1





3-6


1-6




4-3



Are exposure-dose models available
(and adequate) to quantitatively
extrapolate the exposure used in
animal toxicology studies (by
inhalation, instillation, oral, dermal,
and in vitro) to the human exposure
that would result in an equivalent
dose to the target of interest?
What concentrations, routes,
frequencies, and durations
characterize worker exposures to
nano-TiO2 across the life cycle and
within certain stages (e.g.,
manufacturing)?
Is ingested nano-TiO2 carcinogenic?
Can agglomeration/ disagglomeration
in the environment be predicted on
the basis of physical properties of the
particle, for example, size, shape, or
coating?
Which physiologically-based
pharmacokinetic models are optimal
for understanding absorption,
distribution, and elimination of nano-
TiO2 in humans?
To what extent is nano-TiO2 used or
could be used for either drinking
water or waste water treatment? Are
data available (e.g., volume of water
currently treated in the United States
for arsenic, amount of TiO2 needed
to treat a given volume of water) that
would permit an estimate of potential
use?
How might nano-TiO2 affect the fate
and transport of metals and other
potentially toxic substances in water
or other environmental media?
What factors determine whether and
to what extent aggregation or
agglomeration of nano-TiO2 occurs?
Do particular species of biota and
populations of humans have greater
exposure potential (e.g., high-end
exposures due to unusual conditions
or atypical consumption)? In
particular, do children get a higher
exposure and/or dose?

Total
Points




2,881





2,848


2,841


2,814




2,812






2,804





2,755


2,730




2,725




Mean




58.8





58.1


58.0


57.4




57.4






57.2





56.2


55.7




55.6




Std.
Dev.




28.1





27.0


29.1


27.4




27.9






29.2





28.1


29.1




26.2



Number of Participants Who...
Ranked
in
Top 10



10





5


8


8




8






8





6


4




4



Selected
as High



6





13


9


8




8






10





11


14




11



Selected
as Low



1





1


4


1




2






2





1


4




0



Did
Not
1 WL
Select



32





30


28


32




31






29





31


27




34



May 2010
H-9

-------

Rank


35


36



37





38




39




40




41


42




43




Question


3-17


5-2-8



1-4





5-2-12




5-3-3




4-13




4-9


1-3




1-10



What is the likelihood that nano-TiO2
in biosolids will become part of the
food web and ground water
contamination?
How do in vivo biochemical
processes alter nano-TiO2
physicochemical characteristics and
toxicity?
What are the potential implications
(e.g., in terms of physical and
chemical properties) of differences in
the composition and mineralogy of
different forms of nano-TiO2 (e.g.,
rutile and anatase)?
In addition to arsenic and cadmium,
do other compounds show different
uptake in the presence of nano-
TiO2? Are the toxicities of arsenic,
cadmium, or other chemicals affected
by nano-TiO2? Conversely, do other
compounds affect the uptake and
toxicity of nano-TiO2?
Would nano-TiO2 penetrate into
living cells in flexed, "soaked," or
damaged skin (such as sunburned,
scratched, eczematous skin)?
Since nano-TiO2 may increase the
uptake of other pollutants, such as
arsenic, would nano-TiO2 be a
greater concern for exposure and
ecological effects in areas with high
concentrations of certain pollutants
than in other areas? If so, how do we
predict or identify such "hot spots?"
Are occupational monitoring methods
available or in place for all relevant
stages of the life cycle for nano-TiO2
applications?
Which coatings, dopings, carriers,
dispersants, and emulsion types are
most prevalent in different
applications of nano-TiO2?
What existing or emerging analytical
techniques might be relevant or
useful for material characterization?
For example, could field flow
fractionation (FFF) be used for
characterization of particle size and
elemental composition?

Total
Points


2,714


2,663



2,659





2,654




2,620




2,613




2,604


2,599




2,597




Mean


55.4


54.3



54.3





54.2




53.5




53.3




53.1


53.0




53.0




Std.
Dev.


26.8


24.9



27.2





27.2




27.5




27.1




25.1


30.0




28.4



Number of Participants Who...
Ranked
in
Top 10

3


3



4





5




5




4




3


7




3



Selected
as High

13


9



10





8




7




10




9


7




12



Selected
as Low

1


0



1





3




3




2




1


4




4



Did
Not
1 WL
Select

32


37



34





33




34




33




36


31




30



May 2010
H-10

-------

Rank


44






45







46



47



48





49




50


51


52


Question


4-18






5-2-4







4-11



5-2-6



3-9





1-1




4-14


2-3-7


2-4-5

Nano-TiO2 has been shown to attach
to the surfaces of algae and fish as
well as bioaccumulate in fish. Does
nano-TiO2 biomagnify?
How can contributions of various
nano-TiO2 physicochemical
properties to nano-TiO2 ecological
effects be identified or compared?
For example, could a retrospective
analysis of many studies and
computer modeling identify patterns
that would not be evident in individual
studies? Is a structure activity
relationship (SAR) approach
applicable for predicting nano-TiO2
ecological effects?
Given the potential for greater uptake
of certain substances in the presence
of nano-TiO2, should monitoring and
exposure studies include a suite of
substances that might interact with
nano-TiO2?
Are the mechanisms of cellular
responses different at low and high
concentrations of nano-TiO2?
Can the photocatalytic properties of
nano-TiO2 cause other unintended
substances to form, for example,
degradation products, in various
environmental media?
To evaluate nano-TiO2 (in these or
other applications) or to compare
products containing nano-TiO2, is
further standardization or refinement
of terminology needed? If so, is such
an effort underway and/or what
terminology is most important to
standardize?
Which, if any, exposure models have
been evaluated for applicability to
nano-TiO2?
How much nano-TiO2 could be
released under various routine and
accidental scenarios of distribution
and storage?
What is the total quantity of nano-
TiO2 used in topical sunscreen
products in the United States and
worldwide?

Total
Points


2,591






2,585







2,568



2,566



2,507





2,494




2,449


2,442


2,439


Mean


52.9






52.8







52.4



52.4



51.2





50.9




50.0


49.8


49.8


Std.
Dev.


26.4






25.9







27.4



24.0



25.5





32.2




27.0


29.8


27.8

Number of Participants Who...
Ranked
in
Top 10

2






4







2



3



3





7




3


1


1

Selected
as High

11






7







11



6



7





8




8


14


11

Selected
as Low

3






1







3



0



0





8




4


7


3

Did
Not
1 WL
Select

33






37







33



40



39





26




34


27


34

May 2010
H-11

-------

Rank


53



54



55


56



57




58



59


60



61




62


63

Question


2-5-3



5-2-1 1



2-2-5


5-3-7



4-8




1-7



3-4


5-2-2



3-12




5-2-3


PH 1
In water treatment, how are filter
materials and associated
waste/waste water containing nano-
TiO2 disposed of or recycled?
Nano-TiO2 has anti-bacterial and
anti-fungal properties. What are the
effects of both photocatalytic and
photostable nano-TiO2 on the
biodiversity of microorganisms?
Where is nano-TiO2 manufactured?
What is the potential for general
population exposure to nano-TiO2 in
these areas?
To what extent do photocatalytic
properties of nano-TiO2 contribute to
dermal effects?
What personal protective equipment
do workers use at the various life
cycle stages of nano-TiO2
applications? How effective is such
equipment in controlling exposures
by all routes?
Are data available that indicate the
level of
agglomeration/aggregation/dispersion
of nano-TiO2 in specific products? If
so, what do the data show?
Is information on environmental fate
and transport of other substances
available that might provide insights
applicable to nano-TiO2?
What are the ecological effects of
waste and other by-products of nano-
TiO2 manufacturing?
Irradiated photocatalytic nano-TiO2 is
potentially biocidal and antimicrobial.
What is the potential for interactions
of nano-TiO2 with microbes needed
in water treatment systems?
Could ecological effects of pure
nano-TiO2 be predictive of effects
from products containing nano-TiO2
(e.g., containing stabilizers or
surfactants)?
Placeholder Question #1

Total
Points


2,418



2,413



2,401


2,393



2,374




2,356



2,343


2,322



2,311




2,289


2,280

Mean


49.3



49.2



49.0


48.8



48.4




48.1



47.8


47.4



47.2




46.7


46.5

Std.
Dev.


26.5



25.6



29.4


24.7



25.8




26.5



27.8


25.4



25.5




22.4


19.0
Number of Participants Who...
Ranked
in
Top 10

3



4



4


2



3




2



1


1



1




1


—
Selected
as High

7



4



8


5



5




7



10


7



7




3


—
Selected
as Low

1



3



6


3



3




3



5


4



3




1


—
Did
Not
Select

38



38



31


39



38




37



33


37



38




44


—
May 2010
H-12

-------
Rank
64
65
66
67
68
69
70
71
72
73
74
75
Question
4-7
PH2
3-14
PH3
4-2
3-10
3-18
5-2-10
1-9
3-15
4-4
2-4-2
What management practices exist to
control occupational exposures to
nano-TiO2?
Placeholder Question #2
What is the impact to nutrient and
metals cycling and microbial diversity
when sludge with nano-TiO2 is
applied to soils?
Placeholder Question #3
What is the potential for biota and
human (both occupational and
general population) exposure to
secondary contaminants (e.g., waste
or transformation products)
associated with the entire life cycle of
water treatment or sunscreen
applications of nano-TiO2?
Will nano-TiO2 affect the efficacy of
other major elements of water
treatment processes (e.g., chemical
disinfection, the coagulant
concentration necessary for effective
organics removal)?
What is the potential for plant uptake
of nano-TiO2 from contaminated soil
and irrigation water?
What are the indirect ecological
effects (e.g., on soil or water
chemistry) of nano-TiO2?
Regarding the properties of
aggregates and agglomerates and
proper characterization of particle
size, what insight is available from
study of other nanoparticles?
How do sunscreen ingredients affect
nano-TiO2 fate and transport?
What is the total population that could
be exposed to nano-TiO2 via drinking
water? ...via topical sunscreens?
Which water treatment processes use
or would use nano-TiO2 and in what
quantities? Would the type of process
depend on the size of a treatment
facility or the size of the population
served, or both?
Total
Points
2,258
2,254
2,248
2,242
2,232
2,224
2,210
2,201
2,187
2,149
2,139
2,134
Mean
46.1
46.0
45.9
45.8
45.6
45.4
45.1
44.9
44.6
43.9
43.7
43.6
Std.
Dev.
27.4
19.2
28.1
19.0
24.3
27.3
27.9
22.8
26.3
23.6
27.6
26.1
Number of Participants Who...
Ranked
in
Top 10
5
—
3
—
2
1
1
2
1
1
4
1
Selected
as High
2
—
6
—
3
8
8
1
6
3
3
5
Selected
as Low
5
—
6
—
2
6
7
3
5
2
7
5
Did
Not
Select
37
—
34
—
42
34
33
43
37
43
35
38
May 2010
H-13

-------
Rank
76
77
78
79
80
81
82
83
84
85
Question
4-5
2-5-5
3-11
1-11
2-1-2
5-3-5
5-3-6
2-2-2
2-4-6
2-3-6
Approximately how many workers are
involved in nano-TiO2 production,
distribution, and use?
How much nano-TiO2 is present in
sunscreen containers that are
discarded? Are there any
circumstances where such discarded
product could enter a
microenvironment at significant
levels?
What influence could other drinking
water contaminants, including
arsenic, have on the chemical
properties or behavior of nano-TiO2?
Do surface area measurements in air
(e.g., BET analysis) correlate to
surface area in an aqueous
environment? If so, what is the extent
of their accuracy and precision?
What contaminants, nanoscale and
larger, might be released, and in what
quantities, in relation to the
procurement and processing of
feedstocks for nano-TiO2?
Do certain formulations of nano-TiO2
sunscreens generate hydroxyl
radicals when applied to skin?
Given that nano-TiO2 is a good
antimicrobial agent, how does it affect
skin flora? Does application of
sunscreen promote the colonization
of skin by potentially harmful bacteria
(e.g., staph)?
How are manufacturing processes
likely to evolve with increasing
demand for nano-TiO2?
What is the maximum quantity and
frequency of personal sunscreen use
in relation to season, geographic
location, demographics, and other
variables?
Would prolonged storage in adverse
or less than ideal climates (e.g., cold
or humid environments) alter nano-
TiO2 characteristics and behavior?
Total
Points
2,123
2,111
2,098
2,030
2,011
2,005
2,003
2,001
1,931
1,909
Mean
43.3
43.1
42.8
41.4
41.0
40.9
40.9
40.8
39.4
39.0
Std.
Dev.
27.3
28.9
26.7
26.5
27.7
23.3
26.3
27.9
25.6
29.4
Number of Participants Who...
Ranked
in
Top 10
2
2
2
1
2
0
2
3
2
2
Selected
as High
5
7
4
4
4
2
2
2
1
5
Selected
as Low
7
9
6
7
9
7
10
9
7
12
Did
Not
Select
35
31
37
37
34
40
35
35
39
30
May 2010
H-14

-------

Rank


86




87




88


89





90





91


92




93




Question


2-2-3




2-4-4




2-5-1


2-5-4





4-12





2-1-1


5-3-4




2-5-2



Are certain manufacturing processes
used specifically for nano-TiO2 as a
water treatment agent or as topical
sunscreen?
Water distribution systems often have
substantial biofilm or corrosion
development, despite the
implementation of control practices.
Would the presence of nano-TiO2
influence the bacterial biofilm
community or the occurrence of
corrosion?
How much residual nano-TiO2 is
present in packaging of the primary
material or derived products? How is
such packaging disposed of?
How are large quantities of
sunscreen (e.g., sub-par batches
rejected during manufacturing)
handled?
What happens when nano-TiO2 is
trapped in the stratum corneum and
the dead skin flakes off? Is there a
potential for dead-skin nano-TiO2 to
settle around households, or be
inhaled? How much might
accumulate after a day (or a few
days) in the sun (and numerous
reapplications)?
Are certain feedstocks more relevant
to producing nano-TiO2 specifically
for water treatment or sunscreen
applications?
How important is testing nano-TiO2
skin penetration on different races
and at different ages?
If nano-TiO2 were to become much
more widely used and produced at a
much higher volume, would
packaging and shipping methods of
nano-TiO2 change? If so, how would
such change affect the potential
release and exposure during
transport, storage, and disposal?

Total
Points


1,870




1,864




1,833


1,785





1,783





1,768


1,766




1,755




Mean


38.2




38.0




37.4


36.4





36.4





36.1


36.0




35.8




Std.
Dev.


24.4




25.9




28.5


24.7





24.8





27.3


25.9




25.7



Number of Participants Who...
Ranked
in
Top 10

1




0




1


1





0





0


1




1



Selected
as High

1




4




5


1





2





5


1




2



Selected
as Low

8




9




13


10





11





14


14




11



Did
Not
1 WL
Select

39




36




30


37





36





30


33




35



May 2010
H-15

-------
Rank
94
95
96
97
98
99
100
Question
2-3-2
3-5
2-3-1
2-3-3
2-3-4
1-8
2-3-5
Are data available or can they be
collected or estimated for accident
rates and routine product releases
associated with various modes of
shipping and storage? To what
degree could best practices reduce
such occurrences?
If nano-TiO2 production were to
increase greatly, the packing and
transport methods are likely to be
changed as well. How would this
affect the fate and transport of nano-
Ti02?
How is nano-TiO2 shipped (i.e., what
are the relative frequencies for
shipments in bulk, paper bags, or
drums, or by truck or rail)? How far is
it shipped? In what quantities?
How is nano-TiO2 stored (e.g., in
warehouses, sunscreen
manufacturing plants, and water
treatment facilities)?
Does the use of "ventilated paper
bags" increase the possibility of
accidental spillage during shipment
and storage? Are any guidelines
available on whether protective
packaging (e.g., additional
polyethylene lining) is warranted?
Is there a difference between the
opacity of nano-TiO2 aggregates and
conventional TiO2 particles of
nominally similar size (e.g., because
of light passing through pores in
aggregates)? If so, what are the
implications of such a difference?
Could vermin breach storage
containers and contribute to
environmental releases or become
part of an environmental exposure
pathway?
Total
Points
1,700
1,619
1,586
1,576
1,406
1,347
934
Mean
34.7
33.0
32.4
32.2
28.7
27.5
19.1
Std.
Dev.
25.5
23.9
24.5
25.2
23.7
24.9
22.0
Number of Participants Who...
Ranked
in
Top 10
1
0
0
0
0
0
0
Selected
as High
1
1
1
2
0
1
0
Selected
as Low
12
13
14
15
18
21
31
Did
Not
Select
35
35
34
32
31
27
18
May 2010
H-16

-------
      APPENDIX  I. Pre-Workshop Handout:  Nominal Group

                             Technique  Description

                          Nanomaterial Case Studies Workshop

             Developing a Comprehensive Environmental Assessment Research Strategy
                               for Nanoscale Titanium Dioxide

                               Nominal Group Technique
     Nominal Group Technique (NOT) is a structured process for a set of individuals to identify
and rank a number of choices. Typically, several individuals (nominally a group) are convened and
each person is afforded an equal opportunity to offer his or her view(s)  about which choices are
highest priority. When a large number of choices are under consideration, they may be grouped or
consolidated into a more manageable number. A multi-voting process is then used to rank the
choices.

     In the U.S. EPA Nanomaterial Case Studies Workshop, the participants will be divided into
two NOT groups of approximately 25 persons each. Each participant will be asked to state their top
priority question (i.e., research or information need) within a 3-minute period (strictly enforced).
This brief oral presentation (without visual aids) should include a statement or description of the
research/information need and an explanation of why it is a high priority in relation to a
comprehensive environmental assessment of nanoscale titanium dioxide (nano-TiO2). As time
permits, additional priorities may also be presented in subsequent rounds. If another participant
precedes you and speaks to the issue you intended to present, you may use your time in support of
the same issue or you may raise a different issue that you consider to also be a high priority.

     Each research/information need will be noted on a large sheet of paper and displayed for the
NGT group. A facilitator will work with the group to determine which questions can be consolidated
into major research areas, thereby reducing the total number of questions to around 20-30. The
consolidation process will be followed by multi-voting, which allows participants to assign weighted
votes to the research areas they deem most important (for supporting a comprehensive environmental
assessment of nano-TiO2). The pre-workshop ranking process used multi-voting for the top 10
questions, and essentially the same process will be used during the workshop.

     After the two NGT groups have ranked their top 10 priorities, the participants will come
together in plenary to compare similarities and differences in their respective rankings. The
combined lists of priorities will undergo multi-voting by the entire group of participants to select a
final top 10 set of priority research areas. The participants will then be divided into 10 breakout
groups, with each group assigned one of the top 10 priorities. The breakout groups will discuss  their
assigned areas and prepare short written summaries  in a format to be provided.

     Finally, the participants will  reconvene in plenary and each of the 10 summaries will be
presented. A primary objective of this final session will be to identify linkages among the 10 research
areas.
May 2010                                     1-1

-------
                        APPENDIX J. Workshop Agenda


                                         vvEPA

                            Nanomaterial Case Studies Workshop

                  Developing a Comprehensive Environmental Assessment Research Strategy
                                  for Nanoscale Titanium Dioxide

                                    September 29 and 30, 2009

                              Doubletree Guest Suites - Raleigh/Durham
                                2515 Meridian Parkway, Durham, NC

                 	Final Agenda	
 Day 1 - Tuesday, September 29, 2009
7:00 - 8:00 AM
8:00 - 9:00 AM
9:00-10:00 AM
10:00-10:15 AM



10:15-10:45 AM


10:45-5:00 PM
Registration / Check In
• Please sign in and receive your meeting
  materials.


Introduction
• Welcome
• Purpose of workshop
• Review agenda
• Brief participant introductions
Presentation of Pre-Workshop Ranking
Results
• Explain pre-workshop ranking of questions
• Present pre-workshop rankings
• Q&A by participants

Explanation of the Nominal Group
Technique (NGT)
Break


NGT Groups Meet
• Individual input from each participant
• Consolidate and prioritize questions
• Groups break for a 1 -hour lunch between
  11:30 and 1:00 PM
• 1/2-hour break in the afternoon at discretion of
  facilitators
            Lobby in front of
        North Carolina Room
        North Carolina Room

       John J. Vandenberg &
            J. Michael Davis,
 U.S. EPA, National Center for
   Environmental Assessment

Peter Bonner, ICF International

        North Carolina Room

Peter Bonner & Audrey Turley,
            ICF International
        North Carolina Room

Peter Bonner, ICF International
Group A: North Carolina Room
      Group B: Durham Room

 Lunch buffet available in hotel
  restaurant Piney Point Grill &
  Seafood Bar ($11.50/person,
             including drink)
5:00-5:30 PM


5:30 PM
Closing for Day 1 & Preview of Day 2

End of Day 1
        North Carolina Room
   May 2010
                      J-1

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 Day 2 - Wednesday, September 30, 2009

7:00 AM - 8:00 AM      Check In
                       • Please sign in.
                                                       Lobby in front of
                                                   North Carolina Room
8:00 AM-9:00 AM




9:00-9:30 AM


9:30-10:00 AM


10:00-10:30 AM




10:30-11:00 AM



11:00 AM-2:45  PM
Presentation of NGT Results
• Review, discuss, and reconcile two NGT
  groups' results

Multi-voting Process

Break

Discussion of Results of Multi-voting
Process
• Assign top 10 results to 10 breakout groups

Organization of Breakout Groups and
Explanation of Charge

Breakout Groups Meet
• Groups break for a 1 -hour lunch sometime
  between 11:30 AM and 1:00 PM; buffet
  available in hotel restaurant Piney Point Grill &
  Seafood Bar ($11.50/person, including drink)
         North Carolina Room
         North Carolina Room
         North Carolina Room
         North Carolina Room
Groups 1, 2, & 3: North Carolina
 Groups 4 & 5: Durham Room A
 Groups 6 & 7: Durham Room B
     Group 8: Raleigh Room 1
     Group 9: Raleigh Room 2
            Group 10: Library
2:45-3:00 PM


3:00-4:45 PM




4:45-5:25 PM




5:25-5:30 PM




5:30 PM
Break

Presentation of Breakout Group Results
• Focus on connections among the 10 research
  areas

Conclusion
• Workshop participants offer final 10 words of
  advice to EPA

Closing Remarks
Workshop Adjourns
         North Carolina Room
         North Carolina Room
            J. Michael Davis,
   U.S. EPA National Center for
    Environmental Assessment
  May 2010
                     J-2

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         APPENDIX K. Results from Day 1 Nominal Group
                          Technique Groups A  and B
       Table K-1. NGT Group A Results
                                    1, 2
  Rank
Points
                         Question(s) - Group A
  A.1
 182
Are current EPA standard testing protocols adequate to determine nano-TiO2
    ecotoxicity? If not, what modifications or special considerations, if any,
    should be made in current ecological tests? For example, what are the
    differences in characterization of testing material (as raw material, in
    media, and in organisms), dispersion methods, and realistic exposure
    routes between testing conventional materials and nanomaterials
    (commercial use)? (5.2-1)

Are the current EPA harmonized health test guidelines for assessing toxicity
    adequate to determine the health effects/toxicity of nano-TiO2? (5.3-1)

What criteria, especially associated with an  inert colloid particle, should the
    EPA use when evaluating harmonized test protocols? (new)

What set of widely shared reference samples of nano- and conventional TiO2
    would be most useful for integrating the results of different investigators
    regarding particle characterization and  particle toxicology? (Mult-T)
  A.2
 136
How do TiO2 properties change from the manufacturing stage, upon its
    incorporation into products, during its use, during storage, upon release
    to the environment, and upon environmental aging (persistent state)?
    (Mult-D)

How do various manufacturing processes for nano-TiO2 affect their
    physicochemical properties? (2.2-1)

How do specific physicochemical properties, including  particle surface
    treatments and aggregation/agglomeration, affect  the fate and transport
    of nano-TiO2 in various environmental media? (3-2)

Do we have sufficient information to differentiate decision-critical
    characteristics across the various nanoscale TiO2  sunscreens or water-
    formulations? (new)
  A.3
 134
Are available methods adequate to characterize nano-TiO2 exposure via air,
    water, and food? What properties of nano-TiO2 should be included in
    such exposure characterizations? (4-10)

Do adequate methods exist to characterize nano-TiO2 in relevant
    environmental matrices such as soil, sediment, or biofilms and living
    organisms? (Mult-B)
1 Strike-outs in the text of the research priorities indicate text the NGT group removed from the original questions; underlined text
 indicates text the NGT group added to the original questions. The original question number is given in parentheses following each
 bulleted questions.

 Two individuals assigned points to an item more than once. In these cases, the larger point quantity was counted and the smaller point
 quantity was ignored.
May 2010
                                 K-1

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  Rank
         Points
                                           Question(s) - Group A
  A.4
          123
                  Which sources, pathways, and routes pose the greatest exposure potential to
                      nano-TiO2 for biota? ...for humans? (4-1)

                  (Add to existing question) At what concentrations?...and for children?
                      (Rev 4-1)

                  Do particular species of biota and populations of humans have greater
                      exposure potential (e.g., high-end exposures due to unusual conditions
                      or atypical consumption)? In particular, do children get a higher exposure
                      and/or dose? (4-3)
  A.5
           76
                  Where does nano-TiO2 accumulate in the environment and in humans? What
                      is the current background level in humans? (new)

                  Does nano-TiO2 bioaccumulate in humans? (4-C)


                  Is the available ecotoxicity evidence adequate to support ecological risk
                      assessment for nano-TiO2? If not, what is needed? (5.2-13)

A.6        74      What are the sensitive environmental endpoints? (new)

                  How do abiotic factors in the environment, such as UV, pH, oxygen level, and
                      other chemicals, affect nano-TiO2 and  its ecological  effects? (5.2-7)
                    What are the key environmental factors (e.g., pH, natural organic matter type
                        and concentration, temperature) that facilitate or hinder nano-TiO2
                        stability in the aqueous environment? Would humid acids or other
                        common constituents or contaminants in water undergoing treatment
                        affect the fate, including agglomeration/aggregation properties, of TiO2?
                        (3-13)
A.7
           67
                    What needs to be standardized as terminology/nomenclature/ properties for
                        current and future use? (new)
  A.8
           65
                  Should the EPA promote a surface chemistry nomenclature system for use in
                      particle life cycle analyses? (Mult-J)

                  What is nano-TiO2? Is the definition of less than 100 nm adequate? Or, should
                      a dimension  be derived based on the toxicological properties? (1-K)
  A.9a
  (tie)
                  Should EPA set up comprehensive, user friendly databases with all
                      information (such as metrics, toxicity data [current database],
                      characterization, fate, etc.) to support comprehensive environmental
           64          assessments? (new)

                  What has the EPA learned about the quality of the TiO2 data in the open
                      literature as applied to nano-TiO2 and other particles? (new)
                    What might be the primary mechanism(s) of action and dose of toxic effects in
                        different species or in different materials? (5.2-5)
  A.9b
  (tie)
           64
                  Is there any evidence for nano-TIO3 and conventional TiO^ inducing distinctly
                      different pathways of cell signaling or gene transcription? Do nano and
                      conventional TiO2 have different toxicological mechanisms of action or do
                      the two materials simply have a surface-area or surface-coating
                      dependent difference in potency? (5-G)
May 2010
                                          K-2

-------
  Rank
         Points
                                Question(s) - Group A
  A.11
           59
       Powders and particles have been produced for many decades in the
            industrialized world. Is there any epidemiological data from
            manufacturing sites of particles? Any adverse health data? (4-M)

       What kind of studies would provide the most suitable data to understand
            dose-response of occupational exposure to nanomaterials and health
            effects in humans? (including  users - e.g., high end) (Rev 5.3-8)
                    What effect, if any, do coatings, dopings, carriers, dispersants, and emulsion
                        types have on biopersistence and bioaccumulation? (3-8)
  A.12
           51
                    Should TiO2 particles with coatings and strongly chemisorbed species be
                        evaluated separately for the purposes of environmental transport,
                        ecotoxicity, and toxicity? (Mult-M)
  A.13
           49
       What are the ecological effects of long-term exposure to nano-TiO2? (5.2-9)
  A.14
           33
       Are available fate and transport models applicable to nano-TiO2? If not, can
           they be adapted, or are new models required? (3-3)
                    What are the relative contributions of different stages of the life cycles of water
                        treatment and sunscreen products to environmental levels of nano-TiO2
                        and associated contaminants in air, water, and soil? (3-1)
  A.15
           25
       What is the maximum quantity and frequency of personal sunscreen use in
            relation to season, geographic location, demographics, and other
            variables? (2.4-6)

       How much (metric tons) nano-TiO2 is used in sunscreens, cosmetics and
            other products that are contained in products that may be disposed down
            the drain? If any of the pigment and other TiO2 sources contain a fraction
            which is nano, this mass should be added into the volume. Further, the
            volume should be split out into different surface coatings, dopings, and
            size fractions (also consumer exposure). (4-F)
                    What are each scientific field's roadblocks that currently limit scientific
                         reliability/reproducibility and the public's confidence in the resulting risk
                         assessments? What are the cross-disciplinary impediments (worker bio
                         monitoring)? (Mult-Q)
A.16
22
  A.17
           18
       What is the concentration of each unique TiO2 material in WWTP effluent,
           sediment near WWTPs, and soils amended with sewage sludge? (new)
                    What are the surface properties, particularly with respect to reactive oxygen
                        species, of various forms of nano-TiO2 in the deep lung, on the skin, and
                        in  drinking water (with respect to chlorine chemistry)? What predictive
                        tests will describe their effects in ways useful for risk assessment? What
                        happens when you burn TiO2? (new)
  A.18
           15
                    What properties drive induction of an adverse response at environmentally
                        and human-relevant levels and are there thresholds in context of
                        "background" body burdens - and accounting for PK: distribution in
                        considering whether/what tissue-specific body burden should be used as
                        the dose metric - and how this can inform a population threshold (toward
                        identifying a 'safe' level)? (new)
May 2010
                                          K-3

-------
Rank
A.19
A.20
A.21
A.22
A.23
A.24
Points
10
9
8
6
5
0
Question(s) - Group A
Do adequate methods exist to char Nano-TiO2 has anti-bacterial and anti-
fungal properties. What are the effects of both photocatalytic and
photostable nano-TiO2 on the biodiversity of microorganisms? (5.2-11)
What is the potential for reproductive and developmental effects of nano-
TiO2? (5.3-9)
To assure appropriate linking of environmental/exposure and internal dose
metrics, what common features should be characterized and
standardized for environmental and human-relevant conditions? (new)
Is dermal penetration a prerequisite to health effects, including immunological
effects? (new)
What properties are most closely tied to the observed biological responses in
TiO2 toxicity studies, and can we develop predictive models of TiO2
toxicity based on properties data? (5-Q)
Do we need to consider comparative ecotox and human risks across
nanomaterials for a specific purpose (e.g., nano-TiO2 and nano-ZnO in
sunscreens)? (new)
         Table K-2.  NGT Group B Results1
Rank
B.1
B.2
Points
155
123
Question(s) - Group B
How do surface coatings and physical and chemical properties affect
environmental chemistry, and toxicity? Do WWTP processes affect
surface coatings? What natural particle coatings are added in the
environment (e.g., humic and fulvic acids) and how do these natural
coatings influence environmental fate, chemistry, and toxicity?
(Mult. C)
How do specific physicochemical properties, including particle surface
treatments and aggregation/agglomeration affect the fate and
transport of nano-TiO? in various environmental media? How can
species be described as they move from source to sink? (3-2)
What effect, if any, do coatings, dopings, carriers, dispersants, and
emulsion types have on biopersistence and bioaccumulation? (3-8)
What factors determine whether and to what extent aggregation or
agglomeration of Nano-TiO2 occurs? (1-6)
Are available methods adequate to characterize nano-TiO2 exposure via
air, water, and food? What properties of nano-TiO2 should be included
in such exposure characterizations? (4-10)
1 Strike-outs in the text of the research priorities indicate text the NGT group removed from the original questions; underlined text
 indicates text the NGT group added to the original questions. The original question number is given in parentheses following each
 bulleted questions.
May 2010
K-4

-------
   Rank
Points
                       Question(s) - Group B
                    Are current E-PA standard testing protocols adequate to determine nano-
                         TiO2 ecotoxicity/health effects? If not, what considerations, if any,
                         should be made in current ecological tests? For example, what are the
                         differences in characterization of testing materials (as raw material, in
                         media, and in organisms), dispersion methods, and realistic exposure
                         routes between testing conventional materials and nanomaterials?
    B.3      111         (5.2-1)

                    Are the current EPA harmonized health test guideline for assessing toxicity
                         adequate to determine the health effects/toxicity of nano-TiO2?  (5.3-1)

                    Are we sure we are assessing TiO2 (or other nanomaterials) in the
                         experiments we  perform (eco/human)? (new)
                    Which sources, pathways and routes pose the greatest exposure potential
                         to nano-TiO2 for biota? For humans? (Epi studies - human and
                         environmental) (4-1)
    B.4
 110
                    What are the relative contributions of different stages of life cycles of water
                         treatment, sunscreen, and other applications and products to
                         environmental levels of nano-TiO2 and associated contaminants in air,
                         water, and soil? (3-1)
                    What are the effects of long-term exposures in relevant human and
                         ecological populations for specific nano-mixtures of concern (e.g.,
                         neurological, reproductive, integument "skin")? Need to develop
                         comprehensive health data, (new)

    B.5      103    How do you prioritize to get specific health effects data on specific TiO2s of
                         concern, based on levels in the environment or based on short-term
                         effect data? (Think PCBs) (new)

                    What are the chronic,  long-term effects of nano-TiO2 (eco and human
                         effects)? (new)
    B.6
 101
    B.7
  70
Just to re-emphasize the importance of chemical and physical
    characterization at a number of stages in addressing possible toxicity
    of nanomaterials.  (Mult. I)

What makes one type  of nanoparticle more active or toxic than another?
    (Mult. S)


What is the global environmental content of nano-TiO2 now and in the
    future? (new)

Ecologically is TiO2 a point source or regional exposure problem? If a
    regional distribution issue, what are concentration gradients in key
    media? (new)

By region and environmental segment (soil, water, etc.), what is known
    about the background concentration and characteristics of nano-TiO2
    due to natural or non  anthropogenic processes? (1 A)
May 2010
                                K-5

-------
   Rank
Points
                       Question(s) - Group B
    B.8
  67
What parameters should be used to characterize worker (or consumer or
    general human) exposure in a way that is compatible with hazard
    information? (Exposure matches hazard) (Rev 4-6)

What concentrations, routes, frequencies, and durations characterize
    worker exposures to nano-TiO2 across the life cycle and within certain
    stages (e.g., manufacturing) (4-6)
    B.9
  60
Is the available biological effects evidence adequate to support ecological
    risk assessment for nano-TiO2? If not, what is needed? (5.2-13)

What are the fundamental biological responses of nano-TiO2 interactions
    at the cellular level (as dictated by its physical and chemical
    characteristics)? (Dose interactions)  (5-K)

What might be the primary mechanisms of action of toxic effects in
    different species? (5.2-5)
    B.10
  59
How do TiO2 properties change from the manufacturing stage, upon its
    incorporation into products, during its use, during storage, upon
    release to the environment, upon  environmental aging, and in different
    compartments? (Mult D)

Have the life cycle flows (intentional and unintentional) and properties of
    nano-TiO2 in different applications been adequately characterized? tf
    not, is the general problem that methods do not exist or that existing
    methods have not been widely applied? If methods are needed, what
    properties should they measure?  (1-2)
   B.11a
    (tie)
  55
What are the important metrics and standards that we need to use to
    characterize nano-TiO2? (1-J)

What is the role of standards or reference materials for integrating the
    results of different investigators regarding particle characterization and
    particle toxicology? What standards or reference materials are
    needed? (MultT, modified)
   B.11b
    (tie)
  55
Can we develop a decision-tree framework and best practices to facilitate
    environmental assessment of individual nanomaterials? (new)

Would a toxicity - application - exposure - LCA- order in a decision tree
    be workable for conducting a CEAfor nano-TiO2? (new)

How do we integrate analytical methods used to characterize risk (mass
    flow, life cycle) to evaluate and compare environmental trade-offs?
    (new)
    B.13
  38
What is the difference between nano-TiO2 and non-nano-TiO2? (new)
   B.14a
    (tie)
  36
Screen nano-mixtures of concern using modern methods in toxicology for
    determining potential adverse effects (human and eco)? (new)

Are there data and methods that allow us to expand nano-scale TiO2
    information into comprehensive chemical computational chemistry,
    toxicology, neurobiology? If not, what do we need to do to achieve
    such a goal?  (new)
May 2010
                                K-6

-------
Rank
B.14b
(tie)
B.16a
(tie)
B.16b
(tie)

B.18
B.19a
(tie)
B.19b
(tie)


BO1 Q
(tie)
B.21b
fi\o\
(i\e)

B.23
Points
36
24
24

20
18
18



17
17


14
Question(s) - Group B
Are available fate and transport models applicable to nano-TiO2? If not,
can they be adapted, or are new models required?
How do abiotic factors in the environment, such as UV, pH, oxygen level,
and other chemicals affect nano-TiO2 and its ecological/human
effects? (5.2-7)
How do different lighting scenarios in different matrices cause coatings,
size, and geometry to affect TiO2 surface reactions? (new)
To what extent do photocatalytic properties of nano-TiO2 contribute to
dermal effects? (5.3-7)
What waste products, feedstocks, or other byproducts, both nanoscale and
larger, might be released, and in what quantities, for nano-TiO2
manufacturing processes? (Collateral damage) (2.2-4)
Can any the photocatalytic properties of or interactions with nano-TiO2
cause other unintended substances to form, for example, degradation
products in various environmental media; or to degrade/destroy (e.g.,
biological activity)? (3-9)
Do we have comprehensive physicochemical characterization data (non-
proprietary) on nano-TiO2 used in sunscreen or water treatment
products? (1-C)
What is the ultimate sink for nano-TiO2 in the environment? What are
surface water, sediment, and soil nano-TiO2 concentrations? This
should be understood for each of the different surface coatings,
dopings, and size fractions. Are there background concentrations? If
so, natural nano-TiO2 should be fully characterized. (4-T)
In addition to arsenic and cadmium, do other compounds, such as metal
organic frameworks (MOFs), show different uptake and/or
bioaccumulation in the presence of nano-TiO2? Are the toxicities
and/or bioaccumulation of arsenic, cadmium and other chemicals
affected by nano-TiO2? Conversely, do other compounds, such as
MOFs, affect the uptake, toxicity, and/or bioaccumulation of nano-
TiO2?(5.2-12)
Is the current information on nano-TiO2 skin permeation sufficient for risk
assessment, in particular, regarding the roles of particle properties
and skin condition or factors affecting skin penetration? (5.3-2)

How can EPA partner with other agencies and industry to better achieve
the goals of the CEA? (new)
May 2010
K-7

-------
Rank
B.24
B.25
B.26
Points
13
9
0
Question(s) - Group B
What materials does nano-TiO2 replace in sunscreens and waste water
treatment? Is there a net positive environmental impact to replacing
these materials? (2-N)
At what level of ecological organization are we concerned given TiO2 is
mildly toxic based on Table 5-3 in the Case Study? (new)
Can we characterize the nano-TiO2 effect as it would respond in a mixture?
(new)
May 2010
K-8

-------
      APPENDIX  L.  Results from  Day 2 Plenary  Multi-Voting
        Table L-1. Plenary Multi-voting
                                       1,2
Research Priority1



















Are current EPA standard testing protocols adequate to
determine nano-TiO2 ecotoxicity? If not, what
modifications or special considerations, if any, should be
made in current ecological tests? For example, what are
the differences in characterization of testing material (as
raw material, in media, and in organisms), dispersion
methods, and realistic exposure routes between testing
conventional materials and nanomaterials (commercial
use)? (5.2-1)
Are the current EPA harmonized health test guidelines for
assessing toxicity adequate to determine the health
effects/toxicity of nano-TiO2? (5.3-1)
What criteria, especially associated with an inert colloid
particle, should the EPA use when evaluating harmonized
test protocols? (new)
What set of widely shared reference samples of nano- and
conventional TiO2 would be most useful for integrating
the results of different investigators regarding particle
characterization and particle toxicology? (Mult-T)
Consolidated
NGT Priorities









A.1
B.3








Points2









00-7
OO /








1 Strike-outs in the text of the research priorities indicate text the NGT group removed from the original questions; underlined text
 indicates text the NGT group added to the original question. The original question number is given in parentheses following each
 bulleted question.

2 A few individuals assigned points incorrectly. They either assigned points to an item more than once or assigned points to an item that
 was not eligible, i.e., lower-ranked items that were not on the slate for voting. In cases where items that received more than one set of
 points, the higher point quantity was counted and the lower point quantity was ignored. Ineligible items assigned points were ignored.
May 2010
L-1

-------
Research Priority1
2
3
How do TiO2 properties change from the manufacturing stage,
upon its incorporation into products, during its use, during
storage, upon release to the environment, upon
environmental aqinq, and in different compartments?
(Mult D)
How do various manufacturing processes for nano-TiO2 affect
their physicochemical properties? (2.2-1)
How do specific physicochemical properties, including particle
surface treatments and aggregation/agglomeration, affect
the fate and transport of nano-TiO2 in various
environmental media? (3-2)
Do we have sufficient information to differentiate decision-
critical characteristics across the various nanoscale TiO2
sunscreens or water-formulations? (new)
Have the life cycle flows (intentional and unintentional) and
properties of nano-TiO2 in different applications been
adequately characterized? (1-2)
Are available methods adequate to characterize nano-TiO2
exposure via air, water, and food? What properties of
nano-TiO2 should be included in such exposure
characterizations? (4-10)
Do adequate methods exist to characterize nano-TiO2 in
relevant environmental matrices such as soil, sediment,
or biofilms and living organisms? (Mult-B)
Consolidated
NGT Priorities
A.2
B.10
A.3
B.2
Points2
274
260
May 2010
L-2

-------
Research Priority1
4
5
How do surface coatings and physical and chemical
properties affect environmental chemistry, and toxicity?
Do VWVTP processes affect surface coatings? What
natural particle coatings are added in the environment
(e.g., humic and fulvic acids) and how do these natural
coatings influence environmental fate, chemistry, and
toxicity? (Mult. C)
How do specific physicochemical properties, including particle
surface treatments and aggregation/agglomeration affect
the fate and transport of nano-TiO2 in various
environmental media? How can species be described as
they move from source to sink? (3-2)
What effect, if any, do coatings, dopings, carriers, dispersants,
and emulsion types have on biopersistence and
bioaccumulation? (3-8)
What factors determine whether and to what extent
aggregation or agglomeration of Nano-TiO2 occurs? (1-6)
Just to re-emphasize the importance of chemical and physical
characterization at a number of stages in addressing
possible toxicity of nanomaterials. (Mult. I)
What makes one type of nanoparticle more active or toxic
than another? (Mult. S)
Which sources, pathways, and routes pose the greatest
exposure potential to nano-TiO2 for biota? ...for humans?
(4-1)
(Add to existing question) At what concentrations?. ..and for
children? (Rev 4-1)
Do particular species of biota and populations of humans
have greater exposure potential (e.g., high-end
exposures due to unusual conditions or atypical
consumption)? In particular, do children get a higher
exposure and/or dose? (4-3)
What are the relative contributions of different stages of life
cycles of water treatment, sunscreen, and other
applications and products to environmental levels of
nano-TiO2 and associated contaminants in air, water, and
soil? (3-1)
Consolidated
NGT Priorities
B.1
B.6
A.4
B.4
Points2
239
237
May 2010
L-3

-------
Research Priority1
6
7
8
What is the global environmental content of nano-TiO2 now
and in the future? (new)
Ecologically is TiO2 a point source or regional exposure
problem? If a regional distribution issue, what are
concentration gradients in key media? (new)
By region and environmental segment (soil, water, etc.), what
is known about the background concentration and
characteristics of nano-TiO2 due to natural or non
anthropogenic processes? (1A)
Where does nano-TiO2 accumulate in the environment and in
humans? What is the current background level in
humans? (new)
Does nano-TiO2 bioaccumulate in humans? (4-C)
What might be the primary mechanism(s) of action and dose
of toxic effects in different species or in different
materials? (5.2-5)

inHiifinn Hi^tinftlv Hiffprpnt mthw^v^ nf ppll ^inmlinn nr
gene transcription? Do nano and conventional TiO2 have
different toxicological mechanisms of action or do the two
materials simply have a surface-area or surface-coating
dependent difference in potency? (5-G)
Is the available biological effects evidence adequate to
support ecological risk assessment for nano-TiO2? If not,
what is needed? (5.2-13)
What are the fundamental biological responses of nano-TiO2
interactions at the cellular level (as dictated by its
physical and chemical characteristics)? (Dose
interactions) (5-K)
What are the effects of long-term exposures in relevant
human and ecological populations for specific nano-
mixtures of concern (e.g., neurological, reproductive,
integument "skin")? Need to develop comprehensive
health data, (new)
How do you prioritize to get specific health effects data on
specific TiO2s of concern, based on levels in the
environment or based on short-term effect data? (Think
PCBs) (new)
What are the chronic, long-term effects of nano-TiO2 (eco and
human effects)? (new)
Consolidated
NGT Priorities
A.5
B.7
A.9b
B.9
A.13
B.5
Points2
185
155
152
May 2010
L-4

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Research Priority1
9a
(tie)
9b
(tie)
11
12
13
14
Is the available ecotoxicity evidence adequate to support
ecological risk assessment for nano-TiO2? If not, what is
needed? (5.2-13)
What are the sensitive ecological endpoints? (new)
How do abiotic factors in the environment, such as UV, pH,
oxygen level, and other chemicals, affect nano-TiO2 and
its ecological effects? (5.2-7)
Should EPA set up comprehensive, user friendly databases
with all information (such as metrics, toxicity data [current
database], characterization, fate, etc.) to support
comprehensive environmental assessments? (new)
What has the EPA learned about the quality of the TiO2 data in
the open literature as applied to nano-TiO2 and other
particles? (new)
What needs to be standardized as terminology/nomenclature/
properties for current and future use? (new)
Should the EPA promote a surface chemistry nomenclature
system for use in particle life cycle analyses? (Mult-J)
What is nano-TiO2? Is the definition of less than 100 nm
adequate? Or, should a dimension be derived based on
the toxicological properties? (1-K)
What are the important metrics and standards that we need to
use to characterize nano-TiO2? (1-J)
What is the role of standard reference materials for integrating
the results of different investigators regarding particle
characterization and particle toxicology? What is
needed? (Mult T, modified)
What parameters should be used to characterize worker (or
consumer or general human) exposure in a way that is
compatible with hazard information. (Exposure matches
hazard) (Rev 4-6)
What concentrations, routes, frequencies, and durations
characterize worker exposures to nano-TiO2 across the
life cycle and within certain stages (e.g., manufacturing)
(4-6)
What are the key environmental factors (e.g., pH, natural
organic matter type and concentration, temperature) that
facilitate or hinder nano-TiO2 stability in the aqueous
environment? Would humid acids or other common
constituents or contaminants in water undergoing
treatment affect the fate, including
agglomeration/aggregation properties, of TiO2? (3-13)
Consolidated
NGT Priorities
A.6
A.9a
A.8
B.11a
B.8
A.7
Points2
66
66
64
61
59
43
May 2010
L-5

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Research Priority1
15
16
17
Can we develop a decision-tree framework and best practices
to facilitate environmental assessment of individual
nanomaterials? (new)
Would a toxicity - application - exposure - LCA- order in a
decision tree be workable for conducting a CEAfor nano-
TiO2? (new)
How do we integrate analytical methods used to characterize
risk (mass flow, life cycle) to evaluate and compare
environmental trade-offs? (new)
Powders and particles have been produced for many decades
in the industrialized world. Is there any epidemiological
data from manufacturing sites of particles? Any adverse
health data? (4-M)
What kind of studies would provide the most suitable data to
understand dose-response of occupational exposure to
nanomaterials and health effects in humans? (Rev 5.3-8)
What effect, if any, do coatings, dopings, carriers, dispersants,
and emulsion types have on biopersistence and
bioaccumulation? (3-8)
Should TiO2 particles with coatings and strongly chemisorbed
species be evaluated separately for the purposes of
environmental transport, ecotoxicity, and toxicity? (Mult-
M)
Consolidated
NGT Priorities
B.11b
A.11
A.12
Points2
38
33
29
May 2010
L-6

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     APPENDIX  M. Template and  Instructions for Breakout
                    Group Reports -Word Document

Nanomaterial Case Studies Workshop - Report from Breakout Group [  ]

Title of priority area (as assigned):

Breakout group members:

Short description:
[Prepare short paragraph, individual sentences, or bullet statements referring to specific questions
subsumed under this priority area.]

Why this research/information is needed and of high importance:
[Explain how it will support comprehensive environmental assessment efforts.]

Extended description (1-3 pages):
[This text should flesh out the topic as fully as possible.
Start with an overview description of the topic area.

Include discussion of the generality/specificity of the topic area, i.e.: Does it pertain to only a
specific application of nano-TiO2? Does it pertain to nano-TiO2 generally but only to nano-TiO2?
Does it pertain to certain nanomaterials other than nano-TiO2 or to nanomaterials in general?

Elaborate on each specific question (research / information need) consolidated under this heading,
explaining how each relates to or supports the general topic.

State the generality/specificity of each specific question, i.e.: Is it limited to a specific application
using nano-TiO2? Does it pertain to nano-TiO2 generally but only to nano-TiO2? Does it pertain to
certain nanomaterials other than nano-TiO2 or to nanomaterials in general?]

Other, related priority areas:
[Refer to any of the other 9 top priority areas and explain how this topic is connected to them (e.g.,
progress in one area will facilitate another, one is logically necessary before the other can be done,
both need to be done simultaneously  or in alternating sequence).]
May 2010                                    M-1

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     APPENDIX N. Template and Instructions for Breakout
            Group  Reports - PowerPoint Presentation

Breakout Group [  ] Summary

Title of priority area:

Members:

Description:
[Short description (sentences or bullet statements referring to specific questions subsumed under
this Priority area]

Why this work is needed and is of high importance:
[One to two sentences saying why this work/information is needed and of high importance]

Other, related priority areas:
[Refer to any of the other 9  top priority areas and briefly explain how this topic is connected]
May 2010                               N-1

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