June 2011

Green Nanotechnology Challenges And Opportunities

A white paper addressing the critical challenges to advancing greener nanotechnology issued by the ACS Green Chemistry Institute in partnership with the Oregon Nanoscience and Microtechnologies Institute
www.acs.org/greenchemistry

EXEcutIVE SuMMArY
Kira JM Matus, James E Hutchison, Robert Peoples, Skip Rung, Robert L Tanguay

IntroductIon
Nanotechnology is an emerging field. It is an interdisciplinary science whose potential has been widely touted for well over a decade. Despite significant private and public investment, progress moving nanomaterials from the laboratory to industrial production has been slow and difficult. Two challenges that have slowed development have been the poor understanding of the new hazards introduced by nanotechnology and lack of appropriate policies to manage any new risks. Scientists, engineers and entrepreneurs, however, continue to move forward, grappling with challenges that range from the technical to the regulatory and everywhere in between. Just as the concepts of nanoscale invention have required new insights from scientists, they are also demanding new approaches to managing, producing, funding and deploying novel technologies into the larger chemical sector. In this case, there is an unusual opportunity to use science, engineering and policy knowledge to design novel products that are benign as possible to human and environment health. Recognition of this opportunity has led to the development of the green nanoscience concept 1,2.

Green Nanotechnology Challenges And Opportunities

Green nanotechnology has drawn on the field of green chemistry, and the framework of the 12 Principles of Green Chemistry [3] features significantly in work to design new nanotechnologies for joint economic, social, and health/environmental benefit [4]. These efforts have been aided by awareness throughout the nanotech community that they need to address the potential negative impacts of nano from the outset.1 That has not meant, however, that green nanotechnology has gained widespread and popular acceptance in the scientific and business communities. Awareness is still limited in many sectors, and green nanoscience, along with nanoscience more broadly, still faces significant challenges in transitioning from concept to reality.

thE SuMMIt
As part of its mission to advance the implementation of green chemistry throughout the chemical enterprise, the American Chemical Society Green Chemistry Institute (ACS GCI) has begun a process to engage in yearly summits on major issues in the fields of green chemistry and green engineering. In 2010, the first pilot summit was held in conjunction with the Safer Nanomaterials and Nanomanufacturings (SNNI) Fifth Annual Conference in Portland, Oregon.2 ACS GCI engaged a small group of experts,3 and its own project team4 to participate in the conference sessions, in order to develop answers to key questions on four aspects of greener nanoscience: 1. 2. 3. 4. What are the most important technical challenges? What are the challenges to understanding nanotoxicology and the associated informatics challenges? What new policies are necessary to advance greener approaches to nanotechnology? and What the most pressing industrial deployment challenges?

The team was also tasked with identifying important opportunities for green nanotechnology, and to formulate an action plan for ACS GCIs future involvement in advancing the field of green nanoscience.

1 Examples include: Rice Universitys International Council on Nanotechnology, http://icon.rice.edu/; The NNI EHS strategy process http://strategy.nano.gov/blog/generic/page/draft-nni-ehs-strategy and the NIEHS NanoHealth Enterprise 2 GN10: Reducing principles to practice, 16-18 June 2010, Portland, OR. This conference was sponsored by Air Force Research Laboratory under agreement number FA8650-05-1-5041. The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of Air Force Research Laboratory or the U.S. Government. 3 Dr. Jim Hutchison (U. Oregon), Mr. Skip Rung (ONAMI), Dr. Robert Tanguay (OSU) 4 Dr. Robert Peoples (Director, ACS-GCI) and Dr. Kira Matus (LSE)

Green Nanotechnology Challenges And Opportunities

The summit itself drew approximately 120 participants from academia, industry, NGOs and government agencies around the United States. There were three main sessions, each of which began with two keynote speakers. The keynotes were followed by four to five short rapid fire talks. Each session ended with a prolonged group panel discussion session. In this manner, the summit presented a wide range of material to participants, and also encouraged debate and discussion of some key issues in the field. The sessions aligned with the broad areas that the project team and experts had decided were most important for GCI to investigate. The three sessions were: 1. 2. 3. Meeting Characterization Challenges to Support Greener Nanomaterials and Nanomanufacturing, Nanotechnology Innovation and Governance: Moving from Natural Enemies to Partners for Nature, and Advancing Greener Nanomanufacturing: Additive processes and Greener Nanomaterial Production. At the conclusion of the conference, SNNIs expert group and GCIs project team came together to identify the key issues and challenges facing green nanotechnology, along with strategies and opportunities for future GCI involvement in order to help move greener nanotechnologies forward, as part of its broader commitment to supporting the development and implementation of green chemistry throughout the chemical enterprise. The Central Challenge: The challenge of simultaneously developing useful products for the market, advancing the underlying science, and instituting a green nanoscience development and deployment paradigm. One of the most fundamental challenges particular to green nanotechnology is that the science, the testing, the regulatory strategy, and even the processes needed for commercial production are all being developed and deployed at the same time. From this central challenge flow many early stage challenges that were discussed during the course of the workshop. Six key barriers were identified (see Box 1).

Green Nanotechnology Challenges And Opportunities

Box 1- Barriers to the Development and Commercialization of Green Nanotechnology 1. There are no clear design guidelines for researchers in initial discovery phases of green nanoscience; 2. Many green nanomaterials require new commercial production techniques, which increases the need for basic research, engineering research, and coordination of the two between the industrial and research communities; 3. The lack of a deep bench of scientists and engineers with experience developing green nanotechnology; 4. Toxicology and analysis protocols need to be developed and constantly updated to reflect advances in the science; 5. Regulatory uncertainty persists, and green nanotechnologies often face higher regulatory barriers than existing or conventional chemicals; 6. The end-market demand is unclear, especially since there are only a limited number of commercial grade products that can be compared to conventional materials in terms of performance.

thE ActIon AgEndA

Green nanotechnology has been making great forward progress, but the challenges presented above point to an agenda of actions where involvement by the scientific research community, industry and government could bring about changes that would be crucial to supporting a more rapid and effective commercialization of green nanotechnology. Such changes have the potential to reestablish competitive leadership in the field, with positive economic implications for the manufacturing and associated job creation. Specifically, we are proposing that action be taken according the agenda in Box 2 below. In this case, the order of the agenda is important. The first, and most pressing need is for more and better analysis and characterization tools. These are a key input which are required to support the rest of the agenda. They are needed for scientists who wish to understand the mechanisms of the reactions that produce nanomaterials in order to develop better synthesis methods. And they will allow for improved and more complete toxicological studies of green nanomaterials, which are required for better and smarter regulation. Similarly, the second item of the agenda, improved mechanistic understanding, is a key part of the foundation for developing green nanomaterial design guidelines. Finally, new regulations, as well as outreach to regulators must be based on the analysis, understanding, and design concepts that are the result of the first three items.

Green Nanotechnology Challenges And Opportunities

Box 2- The Action Agenda 1. Discover, uncover and provide key analysis and characterization tools ACTORS Federal funding agencies (NIST, NSF, NIH), university researchers, national and government laboratories, industrial nanomaterials practitioners and companies that develop and sell analysis tools ACTIONS o Discover and develop new analytical methods that enable more comprehensive and reliable nanomaterial characterization o Increase efficiency and reproducibility of analytical methods. Accelerate throughput by streamlining sample preparation, data collection and analysis. Reduce costs for analysis. o Develop approaches for real-time monitoring of nanomaterials to support mechanistic investigations and process analytical needs. o Extend the use of existing methods and develop new methods and tools to detect, monitor and track nanomaterials in complex media (eg environmental and biological systems)

2.

Develop, characterize and test precision-engineered nanoparticles for biological and toxicological studies needed to guide greener design o Develop reference libraries of precision engineered nanomaterials that represent materials for basic mechanistic investigations and that are projected for commercial use o Provide the above reference materials to groups that need them for testing. Support the use of those materials with analytical data for each batch and supporting documentation describing best practices for storing and handling the materials o Develop protocols and use these to test the biological and toxicological impacts of materials. Develop hypotheses that help guide redesign of materials that are greener.

NIST and universities, but access to materials and knowledge in firms also required Academic institutions in partnerships with small start-ups that could provide the materials as a service to users. Universities

3.

Investigate and understand reaction mechanisms to support more efficient and precise synthesis and production techniques. o Develop new synthetic methods and conduct research on reaction mechanisms for nanoparticle formation. Use mechanistic knowledge to produce precision-engineered materials and enhance reaction efficiency o Study barriers to reliable and scalable production and develop novel approaches to maintain product integrity as the reaction scale is increased. o Develop design guidelines for commercially producible green nanomaterials. o Aggregate and make available data generated from mechanistic studies, analytical studies and testing, and other sources for use by research community. o Share critical and fundamental knowledge on barriers and engineering hurdles discovered during the scale-up and commercialization process.

Universities

Universities in partnership with companies

Green Nanotechnology Challenges And Opportunities

4.

Develop design guidelines for green nanomaterials o Produce design guidelines for early stage researchers and materials developers to support greener nanomaterial development and production.

Universities

5.

Definition of green criteria for new nanomaterials for fast-track approval by the US EPA. o Implement a fast-track approval route for new nanomaterial innovations that can: demonstrate benefits over existing materials on the market provide basic testing data to demonstrate a reasonable expectation that the material in question poses no additional hazard due to its classification as a nanomaterial1.

US EPA

6.

Education and outreach to regulators to ensure regulatory structures for green nanotechnology reflect accurate knowledge of their intended uses and potential impacts.

Regulatory Agencies: Economic, Scientific and Environmental (Department of Commerce, EPA, FDA, DOE, NIH, etc) Universities, Companies, Regulators

o Agencies need to work together and coordinate so that each can fulfill their mission regarding the development of nanotechnology as an industry. o Agencies need to reach out to experts in science and business to better understand what is needed, and what policies would be effective. o Bring regulators most recent information to help determine rules for the circumstances where nanomaterials may require specialized regulatory approaches instead of being treated like any other new chemical substances. o Provide education on green nano concepts to future generations of scientists, business people and policy makers.

The amount of data required should be tiered according to the level of production of the material.

Nanotechnology presents an opportunity to develop a revitalized, sustainable U.S. chemical and materials manufacturing base. We are at a unique point where we have more understanding of how to go about this than at any time in the past. This new emerging science and associated technologies do not have to follow the typical path of many past innovations in the chemical industry that, despite providing significant benefits, also turned out to have unanticipated costs to human and environment health. The development and commercialization of viable green nanotechnologies is difficult, and the barriers mentioned will require effort from the scientific, research and government communities. But as the presentations at GN10 indicated, there is a pathway forward, and concrete actions that could construct a solid foundation for a profitable and environmentally sustainable future for nanotechnology.

Green Nanotechnology Challenges And Opportunities

SuMMIt rEport
Kira JM Matus, James E Hutchison, Robert Peoples, Skip Rung, Robert L Tanguay

IntroductIon
Nanotechnology is an emerging field. It is an interdisciplinary science whose potential has been widely touted for well over a decade. Despite significant private and public investment, progress moving nanomaterials from the laboratory to industrial production has been slow and difficult. Two challenges that have slowed development have been the poor understanding of the new hazards introduced by nanotechnology and lack of appropriate policies to manage any new risks. Scientists, engineers and entrepreneurs, however, continue to move forward, grappling with challenges that range from the technical to the regulatory and everywhere in between. Just as the concepts of nanoscale invention have required new insights from scientists, they are also demanding new approaches to managing, producing, funding and deploying novel technologies into the larger chemical sector. Nanotechnology, as an emerging technology, presents an important opportunity for the scientific and business community. Nanotech is unlike some other sectors of the chemical industry, where significant capital is already invested in the form of large plants and established supply chains in which production techniques are technologically and culturally embedded. In fact, the need to develop both new nanoproducts, and their equally novel production techniques presents an important opportunity for innovators. In this case, there is an unusual opportunity to use science, engineering and policy knowledge to design novel products that are benign as possible to human and environment health.

Green Nanotechnology Challenges And Opportunities

Recognition of this opportunity has led to the development of the green nanoscience Concept [1,2]. Green nanotechnology has drawn on the field of green chemistry, and the framework of the 12 Principles of Green Chemistry [3] features significantly in work to design new nanotechnologies for joint economic, social, and health/environmental benefit [4]. These efforts have been aided by awareness throughout the nanotech community that they need to address the potential negative impacts of nano from the outset.5 That has not meant, however, that green nanotechnology has gained widespread and popular acceptance in the scientific and business communities. Awareness is still limited in many sectors, and green nanoscience, along with nanoscience more broadly, still faces significant challenges in transitioning from concept to reality. What then, are the main challenges that those practicing greener nanoscience must overcome? How do these differ, if at all, from those being addressed in the wider nano community? Or the chemical industry more generally? And what actions can be taken to drive greener nanoscience forward? Considering nanoscience is an area of rapid development, bold innovation, and significant investment, ensuring that nanotechnologies are designed and deployed to minimize potential harms is of interest to stakeholders throughout academia, industry, government and civil society.

5 Examples include: Rice Universitys International Council on Nanotechnology, icon.rice.edu/; The NNI EHS strategy process strategy.nano.gov/blog/generic/page/draft-nni-ehs-strategy and the NIEHS NanoHealth Enterprise

Green Nanotechnology Challenges And Opportunities

thE SuMMIt
As part of its mission to advance the implementation of green chemistry throughout the chemical enterprise, the American Chemical Society Green Chemistry Institute (ACS GCI) has begun a process to engage in yearly summits on major issues in the fields of green chemistry and green engineering. In 2010, the first pilot summit was held in conjunction with the Safer Nanomaterials and Nanomanufacturings (SNNI) Fifth Annual Conference in Portland, Oregon.6 ACS GCI engaged a small group of experts,7 and its own project team8 to participate in the conference sessions, in order to develop answers to key questions on four aspects of greener nanoscience: 1. 2. 3. 4. What are the most important technical challenges? What are the challenges to understanding nanotoxicology and the associated informatics challenges? What new policies are necessary to advance greener approaches to nanotechnology? And What the most pressing industrial deployment challenges?

The team was also tasked with identifying important opportunities for green nanotechnology, and to formulate an action plan for ACS GCIs future involvement in the field of green nanoscience. The summit itself drew approximately 120 participants from academia, industry, NGOs and government agencies around the United States. There were three main sessions, each of which began with two keynote speakers. The keynotes were followed by four to five short rapid fire talks. Each session ended with a prolonged group panel discussion session. In this manner, the summit presented a wide range of material to participants, and also encouraged debate and discussion of some key issues in the field. The sessions aligned with the broad areas that the project team and experts had decided were most important for GCI to investigate. The three sessions were: 1. 2. 3. Meeting Characterization Challenges to Support Greener Nanomaterials and Nanomanufacturing, Nanotechnology Innovation and Governance: Moving from Natural Enemies to Partners for Nature, and Advancing Greener Nanomanufacturing: Additive processes and Greener Nanomaterial Production.
6 GN10: Reducing principles to practice, 16-18 June 2010, Portland, OR 7 Dr. Jim Hutchison (U. Oregon), Mr. Skip Rung (ONAMI), Dr. Robert Tanguay (OSU) 8 Dr. Robert Peoples (Director, ACS-GCI) and Dr. Kira Matus (LSE)

Green Nanotechnology Challenges And Opportunities

At the conclusion of the conference, the SNNI expert group and GCIs project team came together to identify the key issues and challenges facing green nanotechnology, along with strategies and opportunities for future GCI involvement in order to help move greener nanotechnologies forward, as part of its broader commitment to supporting the development and implementation of green chemistry throughout the chemical enterprise. This report will discuss the challenges for greener nanotechnology that were identified in four key areas: technical, toxicology/analytics, regulations and policy, and industrial implementation. The report will also outline avenues for GCI involvement in shepherding green nanoscience into the mainstream paradigms of the scientific and industrial communities. Box 3- Key Questions about Green Nanotechnology 1. What are the most important technical challenges? 2. What are the challenges to understanding nanotoxicology and the associated informatics challenges? 3. What new policies are necessary to advance greener approaches to nanotechnology? 4. What are the most pressing industrial deployment challenges?

currEnt StAtE
Presentations at the summit underscored two important points. The first is that there are still many factors that contribute to the difficulties in commercializing greener nanotechnology. But the presentations were also demonstrations of how far green nanoscience has progressed over the past decade. There are solid foundations in place, and an important step in moving forward is recognizing the current state of the science, both in terms of nanomaterials and toxicology and analysis. Nanomaterial design, production and analysis During the first decade of nanoscience and nanotechnology development, the science was dominated by the discovery of new materials and properties that fuelled continued interest in the field. Reported research described new properties and novel devices, but for the time being, skipped over some of the key issues related to implementation or commercialization of the technology. New materials were discovered largely by Edisonian (trial and error) approaches, reproducibility of new procedures was often a problem, and characterization was typically functional rather then structural. Materials were often prepared by any means necessary and in quantities just large enough for the studies at hand. What was missing were the structural characterization and reproducible methods needed to reliably relate nanomaterial structure to function. In addition, in the discovery phase, hazards and inefficiencies can be ignored and, for the most part, they were.

Green Nanotechnology Challenges And Opportunities

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Within the last five years, greater emphasis has been placed on structural characterization, synthetic methods development (including mechanistic studies), reliable purification methods and the development of greener production methods. It has been recognized that an appropriate level of characterization, whether for toxicology studies or physical investigation, requires multiple, complementary characterization techniques [3]. A variety of new synthetic approaches and mechanistic studies have been reported. Novel purification approaches have been developed that, in combination with new characterization approaches provide greater confidence in the structures and purities of materials that are being studied[4]. Finally, a variety of greener production methods have been developed, including micro-scale and/or continuous flow reaction systems that provide potentially faster and easier paths for scaling and commercialization of nanomaterial production. Although significant progress has been made, the results from the last decade have also revealed newchallenges. New characterization strategies are needed that are rapid enough to keep pace with (or accelerate) materials development efforts. Analytical methods that identify and provide structural information about nanomaterials embedded within complex matrices (environmental compartments or biological systems) are needed to derive mechanistic insights about nanomaterial/biological system interactions. New synthetic techniques and production methods are needed that allow reproducible production of precision-engineered materials at any scale. Finally, versatile purification methods are needed that make it possible to produce materials of defined purity quickly, economically, and from a range of reaction media. Toxicology and analysis As the excitement of nanotechnology began to grow, the initial approach to address the potential toxicity of engineered nanomaterials was to assume that these novel materials will behave like their bulk counterparts. A strong dismissive tone regarding potential hazard reigned supreme. It was apparent that material scientists were guiding safety assessment in the early stages of this field. Inevitably, biologist and toxicologist became involved and took a new leadership role in the safety evaluations of nanomaterials. Unfortunately, out of the gate there were missteps. Although the toxicology discipline utilizes rigorous well developed methods, the unique properties of nanomaterials were not immediately recognized by this field. Early there was insufficient appreciation for the essential need for material characterization and purity. There were great challenges in defining dosemetrics for nanomaterials. Many of the initial toxicological studies utilized commercially available materials with little or no characterization. Toxicological responses varied by vendor and by batch, and it became clear that at least some of the reported toxicity was actually due to contaminants rather than the nanomaterials themselves [7]. As the funding base for nanotoxicology increased, it became clear that new methodological characterization methods were needed. It also became

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evident that in order to move this field forward material scientists and toxicologist needed to work together to utilize solid science based approaches to guide safer nanotechnology development. The field now agrees that basic nanomaterial characterization must be in place in order to produce interpretable biological response data. Given the many variables in characterization of nanomaterials, including purity and stability as well as their behaviours in biological systems, we currently do not fully understand the nanomaterial characteristics that are important in driving biological activity. Predictive toxicity models that incorporate nanomaterial properties are the current focus. The challenge that we continue to face is the path to follow for nanomaterial hazard identification. The National Academy of Sciences report for

Toxicity Testing in the 21st Century is highly relevant to greener nanoscience [8]. The Academy
recommends that we take bold moves to develop testing strategies that move us toward predictive toxicity models, and away from standard rodent models. It is apparent that it is not advisable to evaluate the toxicity of each new nanomaterial in expensive rodent testing protocols. This one at a time approach has failed for small molecules, and will unquestionably fail for nanoscience. The nearly unlimited variations in the elemental composition, core size, surface functionalization, purity, and synthesis methods indicate that the independent testing of every variation is not feasible. The material needs for this strategy alone is cost prohibitive. Examples of Success One example success is the utilization of the embryonic zebrafish model as a sensitive, dynamic biological testing platform. It is well-established that the fundamental developmental processes are highly conserved across species as are the underlying molecular signalling pathways [9], therefore, the results obtained using zebrafish are highly relevant to humans . The sensitivity of the developmental-stage assay results from the observation that the full repertoire of gene expression is operational. To be clear, in order for a nanomaterial to produce an adverse response, it absolutely must influence the activity or expression of critical biological targets. Developmental life stages thus offer unprecedented access and opportunities to probe the full complement of potential nanomaterial targets. Since perturbation of molecular targets is the only conceivable way in which a nanomaterial can produce toxicological responses; this is an ideal platform to explore the nano/bio interface. There are technical advantages that make zebrafish particularly well-suited for high-throughput screening. Embryos are small, they develop externally, are optical transparent, and they develop is small volumes which greatly reduces the material needs for assessments. To date, this assay has evaluated the biological activity of a few hundred precisely engineered nanomaterials, and most did not produce adverse responses.

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Box 4- The Twelve Principles of Green Chemistry [3] 1. Prevention It is better to prevent waste than to treat or clean up waste after it has been created. 2. Atom Economy Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product. 3. Less Hazardous Chemical Syntheses Wherever practicable, synthetic methods should be designed to use and generate substances that possess little or no toxicity to human health and the environment. 4. Designing Safer Chemicals Chemical products should be designed to effect their desired function while minimizing their toxicity. 5. Safer Solvents and Auxiliaries The use of auxiliary substances (e.g., solvents, separation agents, etc.) should be made unnecessary wherever possible and innocuous when used. 6. Design for Energy Efficiency Energy requirements of chemical processes should be recognized for their environmental and economic impacts and should be minimized. If possible, synthetic methods should be conducted at ambient temperature and pressure 7. Use of Renewable Feedstocks A raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable. 8. Reduce Derivatives Unnecessary derivatization (use of blocking groups, protection/ deprotection, temporary modification of physical/chemical processes) should be minimized or avoided if possible, because such steps require additional reagents and can generate waste. 9. Catalysis Catalytic reagents (as selective as possible) are superior to stoichiometric reagents. 10. Design for Degradation Chemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment. 11. Real-time analysis for Pollution Prevention Analytical methodologies need to be further developed to allow for realtime, in-process monitoring and control prior to the formation of hazardous substances. 12. Inherently Safer Chemistry for Accident Prevention Substances and the form of a substance used in a chemical process should be chosen to minimize the potential for chemical accidents, including releases, explosions, and fires.

To move the field forward it is now possible to systematically investigate the relative influence of core size, surface chemistry, charge, and sample purity on nanomaterial toxicity using precisely engineered gold nanoparticles (AuNPs). Libraries of precisely engineered materials are produced where individual parameters are altered. When zebrafish embryos are exposed to each unique AuNPs, the biological effects were dependent on these parameters. Specifically the surface functionality played the largest role in the driving differential biological responses.

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The foundation is in place to move greener nanotechnology forward as numerous multidisciplinary teams have been built. There is increased evidence that material scientists are working side-by-side with toxicologists, environmental scientists, and educational experts to help identify nanomaterial hazards. There is now a significant amount of data on nanomaterialbiological interactions; however, there is no consensus on the most appropriate test methods for assessing nanomaterial hazard. It is recommended that specific nanomaterial features be identified that influence biological interactions and activity. This will ultimately lead to a framework of structure-activity relationships. It is becoming clear that a much more systematic approach is necessary where the individual nanomaterial features can be isolated to provide informed rules for safer nanoparticle design and synthesis. This approach requires precision engineering and robust, sensitive, rapid-throughput biological testing platforms.

LESSonS LEArnEd About thE bArrIErS to grEEn chEMIStrY

While steady progress has been made in the development of green nanomaterials and the accompanying toxicology and analysis, large-scale commercialization has yet to occur. In some respects, this is not surprising. Almost all new technologies face significant barriers in moving from the laboratory and into the market. This issue has been documented by scholars and business people alike for decades [10]. Furthermore, green chemistry, the principles of which are a core part of green nanotechnology, has also been documented to have its own, distinct challenges in terms of commercialization [11,12]. However, there are some unique aspects to green nanotechnology, as it is an emerging science that must deal with the compounded challenges present in a new area of science, while at the same time breaking new ground on incorporating environmental and health considerations into research and development at the earliest stages.

Generally speaking, innovations face barriers that arise in six different areas: organizational, economic and financial, cultural, regulatory, market, and limitations from previous decisions about investment, development and use of existing technologies (also referred to as path dependence [10,13-23]. Research on green chemistry in particular has found that these barriers do appear, but that in different countries and subsectors, their role and importance vary [11]. For example, in China, path dependence is currently not an element of the major barriers to innovation for green chemistry technologies, largely due to the significant amount of capital investment that is currently taking place, which has so far prevented legacy capital and technology from becoming overly limiting. On the other hand, Chinese green chemistry technologies face special burdens that stem from the particulars of the primacy placed on economic growth over environmental protection, even when the government issues explicitly pro-green technology policies [11].

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Box 5- Barriers to Green Chemistry Innovation9

United States
Economic and Financial Regulatory Technical Organizational Cultural Definition and Metrics

China
Economic and Financial Competing Government Agendas Training Bureaucratic Disincentives Funding Structure for Scientific R&D Engineering Capacity

In the United States, for green chemistry, path-dependency and technology lock-in (when technologies already in use limit the ability to make changes or implement innovations) has been more of a problem, since the chemical industry has a great deal of legacy infrastructure that would be highly costly to replace or radically alter. Within the United States context, many of the challenges reflect the strength of the US in discovery, and the declining focus on domestic manufacture. As a result, cultural barriers that make it difficult to train interdisciplinary science, organizations that are unsure of, or unable to assign the value of green chemistry to their businesses, and the lack of a consensus on how to operationalize the 12 Principles of Green Chemistry into more concrete definitions and metrics are considered to be major roadblocks [11].

9 Adapted from Matus 2009

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Box 6- Dune Sciences: A Case Example of the Challenges Facing Green Nanotechnology In 2006, Dune Sciences (www.dunesciences.com) was founded with the aim of bringing nanotechnology inventions from the University of Oregon to the market. The technologies that Dune Sciences licensed dealt largely with chemical linkers that permitted strong, irreversible binding between a nanoparticle and substrate. Dune Sciences took advantage of this technology to link nanosilver (nanoAg) to surfaces to produce the first nanosilverbased antimicrobial surfaces that permanently bound the particles to the surface, effectively preventing loss of the particles into the environment. The bound particles act as reservoirs of silver and slowly release silver ions that are responsible for the antimicrobial activity. The primary market for these materials is athletic apparel where the antimicrobial activity prevents the development of persistent odor in polyester garments. The development of persistent odor shortens the lifespan of these garments. An anti-odor solution could extend the use of these garments significantly and, as a result, reduce material, energy and water use as well as reducing the use of detergents. Dune estimates that the use of 2.4 kilograms of silver could double the lifespan of a million athletic shirts, preventing the use of the embedded raw materials, energy, water and transportation costs. By way of comparison, over 700,000 kg of silver are currently used each year in industry. In designing this new technology, Dune Sciences applied the principles of green chemistry to product design and process development. The product prevents particle release from the garments and minimizes silver ion release into the environment by using strong linker binding and the minimum silver loading needed for product performance, respectively. The source of nanosilver is a waste stream from another process and the conversion of that wastestream to the active ingredient is an all aqueous process that produces almost no waste. Unfortunately, despite the technical success and exciting social potentialof the product, regulatory barriers prevented the commercialization of the product and uncertainties surrounding possible regulations made it more difficult to attract investors needed to further the development of the technology, and the company had to reduce employment. Because antimicrobial materials are considered pesticides in the U.S. registration of the product with EPA was required. Throughout much of 2009 and 2010 was no path forward to register new products. The argument was made to the EPA OPP and to their Scientific Advisory Panel that if particles are not released from the garment that the potential impacts of these products would be the same as for products that incorporate micro- or macro-scale silver, articles that are already approved. In addition, it was pointed out that articles that the EPA had previously registered have nanosilver within them. Neither of these approaches was successful. As a consequence of these impasses to registration of the product and securing funding needed to continue optimizing the technology, Dune Sciences put this product on hold until a more favourable path to commercialization could be identified. The problems that Dune Sciences faced in getting a commercially viable, efficacious and greener product to the market are a good example of some of the key challenges facing greener nanomaterials, especially in the regulatory arena.

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How does green nanotechnology fit into this broader landscape of innovation? Given its foundation in the concepts of green chemistry, there should be some areas of overlap. However, there are specific aspects of green nanotechnology that would also be expected to present a unique set of challenges. For example, because it is so new, and requires novel commercialization techniques, technological lock-in and path dependency should not yet be a problem. On the flip side, uncertainty surrounding the costs of bringing these products to market, which would include the need to develop these new commercialization technologies and analysis protocols, could increase the financial uncertainty, making them riskier and less attractive investments. From the discussions at GN10, many of the details of the actual barriers that have been faced by entrepreneurs became clear, both in their similarities to, and differences from, other green chemistry innovations, and innovations more broadly.

Like all innovations, the process through which green nanotechnology moves from the laboratory and into the market involves a series of steps, and the involvement of a number of institutions (Figure 1). For green nanotechnology, this process usually involves universities, smaller start-up companies, and finally large companies. In most cases, there are also other groups that become directly or indirectly involved, including government agencies (FDA, EPA, etc), financial backers, consumers, and even NGO and civil society groups.

Figure 1- The Commercialization Process

PRODUCT DEVELOPMENT EXECUTION

GLOBAL MARKET INTELLIGENCE

ORGANIZATIONAL ROLES/NEEDS IN GREEN NANO COMMERCIALIZATION: Universities: scientific discovery, fundamental invention, talent development, shared user facilities. NEED: public and philanthropic funding, enabling regulatory/legal environment Startup companies: pioneering technology and market development of small but disruptive first opportunities. NEED: equity/royalty licenses, large company customers/partners, high-risk (early stage) capital, minimal regulatory/legal burdens Large companies: Manufacturing scale-up and global business development. NEED: large and profitable mainstream markets, low-risk technology options

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Figure 1 is a simplified version of a process that involves these many players, and lots of feedbacks between them. However, it is a good way to understand where in the chain, and how, different barriers emerge between the initial discovery phase, and the eventual entry and use of a marketable product. The Central Challenge: Simultaneously developing useful products for the market, developing the underlying science, and operationalizing a green nanoscience development and deployment paradigm. One of the most fundamental challenges particular to green nanotechnology is that the science, the testing, the regulatory strategy, and even the processes needed for commercial production are all being developed and deployed at the same time. From this central challenge flow many early stage challenges that were discussed during the course of the workshop, including Box 7- Barriers to Development and Commercialization of Green Nanotechnology 1. 2. There are no clear design guidelines for researchers in initial discovery phases of green nanoscience; Many green nanomaterials require new commercial production techniques, which increases the need for basic research, engineering research, and coordination of the two between the industrial and research communities; The lack of a deep bench of scientists and engineers with experience developing green nanotechnology; Toxicology and analysis protocols need to be developed and constantly updated to reflect advances in the science; Regulatory uncertainty persists, and green nanotechnologies often face higher regulatory barriers than existing or conventional chemicals; The end-market demand is unclear, especially since there are only a limited number of commercial grade products that can be compared to conventional materials in terms of performance.

3. 4. 5. 6.

These green nanotechnology-specific barriers can be cross correlated with the general ones from the innovation literature, in terms of whether they contain some aspects of these. It would appear that many of the challenges are the result of organizational problems, as well as some difficulties with the cultural aspect of incorporating concepts like interdisciplinary collaboration and sustainability into stove-piped scientific organizations. More interestingly, the traditional barriers to innovation do not capture some key elements of the challenges described by green nanotechnology innovators. This includes many of the technical and scientific challenges, and the core issue of just how much deeply fundamental research is still required in support of the development and commercialization.

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Table 1-Correlation of Green Nanotechnology Challenges and General Barriers to Innovation General Barriers to Innovation Organizational Economic/ Financial Cultural Regulatory Market PathDependence

Specific Challenges for Green Nanotechnology

Lack of Design Guidelines Coordination and development of new production techniques Experience with development and commercialization Toxicology and analysis protocols Regulatory uncertainty Market uncertainty

X X

X X X

The presentations and discussions during the GN10 workshop provided both greater depth of understanding about how and why these exist, and also about the kinds of policies, actions and approaches that are required to move green nanotechnology forward. These are discussed in more detail below, and together they form a research agenda for the future of green nanoscience and nanotechnology. 1. Lack of Design Guidelines for Discovery-phase Researchers The problem: The choices made by academic researchers as they synthesize new green nanomaterials can have implications throughout the development and commercialization process- but most researchers are unaware of these impacts. There is a need for guidance on what kinds of materials, and processes, will be both commercially viable, and will help to minimize environmental and health impacts.

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Location in the Innovation Chain: This problem is primarily in the research and early development phase, although its impacts reverberate down the chain. Actors Involved: Although the users are mainly academic researchers (especially in chemistry and materials science), they require input from toxicologists, engineers, and others further down the supply chain in order to align their needs and disseminate their knowledge back up the discovery pipeline.

2. Many green nanomaterials require new commercial production techniques, which increases the need for basic research, engineering research, and coordination of the two between the industrial and research communities. The problem: Unlike other chemistry innovations, which can rely largely on proven industrial processes, production of green nanomaterials on a commercial scale requires entirely new methods. This makes it initially more expensive, and more difficult/uncertain to move new technologies out of the laboratory phase and into production. Solving this problem requires involvement from industry, but also by academics in fields like chemical and process engineering and materials science, in order to develop useful new techniques. Because the challenges are not apparent until firms begin to produce in larger quantities, this also requires communication between the industrial and academic communities. Location in the Innovation Chain: This is a problem that is faced by small companies and startups, but is also a challenge for larger firms. Solutions will rely at least partially on work done by the research community. Actors Involved: The development of new production processes falls naturally to small and large manufacturers, who need further support from the community of academic researchers pioneering greener methods.

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3. There is not yet a deep bench of scientists and engineers with experience developing green nanotechnology; The problem: Green nanotechnology, and nanotechnology more broadly, is a new field with relatively few commercialized products. Due to the novelty of production methods, there are very few chemists and engineers in any given organization who have a depth of experience dealing with the particular technical challenges of commercializing green nanotechnologies. In some cases, interns or new employees coming from academia are the most experienced individuals on a project, despite having little or no experience in an industrial setting. There are few, if any, collaborations between industry and academia that could help train experienced industrial chemists and engineers in the new technologies and processes for green nanomaterials. Location in the Innovation Chain: The impacts of this problem are felt most acutely by small and large industrial firms. Actors Involved: This is a problem that is dealt with by small and large industrial firms.

4. Toxicology and analysis protocols need to be developed and constantly updated to reflect advance in the science The problem: Green nanoscience requires new analytical techniques and toxicological protocols in order to fully understand the impacts on people and the environment. These fields need to balance the task of being able to find ways to effectively analyze new technologies as they emerge, and also to develop fundamental understanding of how different properties link to impacts, in order to provide guidance to the discovery community so that they design the most benign products possible from the start. There is also a need to develop in-line process analytical and control techniques for full-scale manufacturing operations. Location in the Innovation Chain: This is a problem that occurs as products come to the market, and need to be tested for potentially harmful impacts. There are also impacts from research that is done earlier in the innovation process, when materials and processes are developed and analyzed for feasibility.

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Actors Involved: This problem involves academic researchers, especially from the toxicology community, but also from nanoscience and engineering. There has also been involvement from national research laboratories that work on impact analysis, standards, and testing protocols, and also from regulators who set rules for what kinds of data and testing will be required for products to enter the market.

5. Regulatory uncertainty persists, and green nanotechnologies often face higher regulatory barriers than existing or conventional chemicals. The problem: Green nanotechnology products face the same regulatory hurdles as other new nanomaterials, but have no advantages over similar, but less green materials already on the market. Depending on their uses, they could fall under the purview of several different agencies, including the FDA and the EPA. The regulation of nanotechnology more broadly is still contested. At this point, it is still not known, with any clarity, whether nano materials are fundamentally more hazardous that conventional chemicals. Given this, there are indications that the EPA, for at least some materials (such as carbon nanotubes and nanoAg) is adapting a stricter stance than they generally have towards new chemical substances. And even for those green nano materials that do not come under specific rules, they still face the pre-manufacture notice (PMN) process under TSCA, which is itself being discussed for major reform in the US Congress. Even under the most lenient of the current regulatory frameworks, producers of green nano materials are at a disadvantage from chemicals already on the market before 1976, which do not have to incur the costs of PMN, or the sometimes more restrictive significant new use rules (SNURs) and consent decrees that the EPA has used to address concerns about certain new materials, or novel uses of those currently on the market (SNURs are the current method for regulating carbon nanotubes). All of these factors add up to uncertainties for firms who face an unknown set of potential future rules, higher regulatory hurdles, or, more positively, potential fast-tracking or lowered costs for greener products if certain elements of the TSCA reform bill are passed. This regulatory uncertainty negatively impacts the availability of investment in green nanotechnologies, both from internal sources in corporations, as well as from early and growthstate sources such as angel investors and venture capital firms. Location in the Innovation Chain: This problem is one faced by small and large industrial firms as they attempt to move green nano technologies into the market place.

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Actors Involved: The main actors involved are small and large manufacturers and the regulatory community- including both government agencies and lawmakers at the federal and state levels.

6. End-market demand is unclear, especially since there are only a limited number of commercial grade products that can be compared to conventional materials in terms of performance and market success, and the applications are often just as innovative as the materials themselves. The problem: Relatively few nanomaterials have been produced at a commercial scale. The discussion is still largely about the promise of green nanotechnology, as opposed to its results. Given many of the other barriers that have been identified, lack of clear market signals, or a detailed understanding of the applications for which green nanotechnology would be particularly advantageous make it difficult for firms to make a strong business case. Smaller start-up firms need to convince investors that they offer attractive ROI despite long payback time frames and high initial costs. Large firms face a similar challenge surmounting internal investment hurdles, and if anything have much lower risk tolerance. All of this sharply limits investment possibilities (e.g. compared to ostensibly more capital-efficient opportunities in social networking and e-tail), which in turn limits the number of products able to make it onto the market. Location in the Innovation Chain: This problem is one that occurs at the point where promising innovations from the laboratory are picked up by industry- either small firms or larger ones, that then have to come up with the funding to get through development and commercialization, and end up with a profitable, marketable product. Actors Involved: The main actors here are the small and large firms, along with their funding infrastructure- incubators, angel investors, venture capitalists, banks, other investors and internal investment mechanisms. There is also some involvement from government programs that fund innovative start-up ventures (i.e. SBIR granting agencies).

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Box 8- Barriers to Green Nano Commercialization Barrier 1. There are no clear design guidelines for researchers in initial discovery phases of green nanoscience; 2. Green nanomaterials require new commercial production techniques, which increases the need for basic research, engineering research, and coordination of the two between the industrial and research communities; 3. There is a lack of deep bench of scientists and engineers with experience developing green nanotechnology; 4. Toxicology and analysis protocols need to be developed and constantly updated to reflect advance in the science; 5. Regulatory uncertainty persists, and green nanotechnologies often face higher regulatory barriers than existing or conventional chemicals; 6. The end-market demand is unclear, especially since there are only a limited number of commercial grade products that can be compared to conventional materials in terms of performance Location in the Innovation Chain Discovery phase; link between academic research and industry Stakeholders Universities

Development and Production phase; Research phase; link between academic research and industry

Universities; Small and large industry

Development and Production phase

Small and large industry

Research phase; link between academic research and industry

Universities, National Laboratories, Regulatory Agencies, Small and large Industry

Commercialization phase

Regulatory Agencies, Small and large Industry, Consumers

Commercialization phase

Small and large industry, consumers, financing mechanisms

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concLuSIonS: thE ActIon AgEndA

Green nanotechnology has been making great forward progress, but the challenges presented above point to an agenda of actions where involvement by the scientific research community, industry and government could bring about changes that would be crucial to supporting a more rapid and effective commercialization of green nanotechnology. Of the challenges that have been previously described, one important common feature is that many of them are the result of issues that occur well in advance of commercialization, i.e. during the design and production process development phases. Improvements in specific characterization and data analysis tools would have an impact on these issues. Further, there is an ongoing need for research into the underlying reaction mechanisms at work in greener nanomaterial synthesis routes. Finally, integrating information from analytical and mechanistic studies is needed to develop design guidelines for greener nanomaterials. Specifically, we are proposing that action be taken in the following areas: Box 9- Action Areas 1. Discover, Uncover and Provide key analysis and characterization tools, 2. Investigate and Understand reaction mechanisms for support of better synthesis and production techniques, 3. Develop design guidelines for commercially producible green nanomaterials, 4. Definition of Green Criteria for new nanomaterials for fast-track approval by the US EPA, 5. Education and outreach to regulators to ensure regulatory structures for green nanotechnology reflect accurate knowledge of their intended uses and potential impacts.

The order of this agenda matters. The first, and most pressing need is for better analysis and characterization tools and protocols. These are a critical enabler for the rest of the agenda. They are required by scientists and engineers who need to understand the mechanisms of the reactions that produce nanomaterials in order to develop better synthesis methods. And they will allow for improved and more complete toxicological studies of green nanomaterials, which are required for better and smarter regulation. Similarly, the second item of the agenda, improved mechanistic understanding, is foundational for developing green nanomaterial design guidelines. Finally, new regulations, as well as outreach to regulators must be based on the analysis, understanding, and design concepts that are the result of the first three items.

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For each area of action, specific recommendations are described below, along with the actors required for each.

Box 10- The Action Agenda 1. Discover, uncover and provide key analysis and characterization tools ACTORS Federal funding agencies (NIST, NSF, NIH), university researchers, national and government laboratories, industrial nanomaterials practitioners and companies that develop and sell analysis tools ACTIONS o Discover and develop new analytical methods that enable more comprehensive and reliable nanomaterial characterization o Increase efficiency and reproducibility of analytical methods. Accelerate throughput by streamlining sample preparation, data collection and analysis. Reduce costs for analysis. o Develop approaches for real-time monitoring of nanomaterials to support mechanistic investigations and process analytical needs. o Extend the use of existing methods and develop new methods and tools to detect, monitor and track nanomaterials in complex media (eg environmental and biological systems)

2. Develop, characterize and test precision-engineered nanoparticles for biological and toxicological studies needed to guide greener design NIST and universities, but access to materials and knowledge in firms also required o Develop reference libraries of precision engineered nanomaterials that represent materials for basic mechanistic investigations and that are projected for commercial use o Provide the above reference materials to groups that need them for testing. Support the use of those materials with analytical data for each batch and supporting documentation describing best practices for storing and handling the materials o Develop protocols and use these to test the biological and toxicological impacts of materials. Develop hypotheses that help guide redesign of materials that are greener.

Academic institutions in partnerships with small start-ups that could provide the materials as a service to users.

Universities

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3. Investigate and understand reaction mechanisms to support more efficient and precise synthesis and production techniques. Universities o Develop new synthetic methods and conduct research on reaction mechanisms for nanoparticle formation. Use mechanistic knowledge to produce precision-engineered materials and enhance reaction efficiency o Study barriers to reliable and scalable production and develop novel approaches to maintain product integrity as the reaction scale is increased. o Develop design guidelines for commercially producible green nanomaterials. o Aggregate and make available data generated from mechanistic studies, analytical studies and testing, and other sources for use by research community. o Share critical and fundamental knowledge on barriers and engineering hurdles discovered during the scale-up and commercialization process.

Universities in partnership with companies

4. Develop design guidelines for green nanomaterials Universities o Produce design guidelines for early stage researchers and materials developers to support greener nanomaterial development and production.

5. Definition of green criteria for new nanomaterials for fast-track approval by the US EPA. US EPA o Implement a fast-track approval route for new nanomaterial innovations that can: demonstrate benefits over existing materials on the market provide basic testing data to demonstrate a reasonable expectation that the material in question poses no additional hazard due to its classification as a nanomaterial2.

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6. Education and outreach to regulators to ensure regulatory structures for green nanotechnology reflect accurate knowledge of their intended uses and potential impacts. Regulatory Agencies: Economic, Scientific and Environmental (Department of Commerce, EPA, FDA, DOE, NIH, etc) o Agencies need to work together and coordinate so that each can fulfill their mission regarding the development of nanotechnology as an industry. o Agencies need to reach out to experts in science and business to better understand what is needed, and what policies would be effective. o Bring regulators most recent information to help determine rules for the circumstances where nanomaterials may require specialized regulatory approaches instead of being treated like any other new chemical substances. o Provide education on green nano concepts to future generations of scientists, business people and policy makers.

Universities, Companies, Regulators

Nanotechnology presents an opportunity to develop a new technology, and a new industry in a sustainable way from the outset. We are at a unique point where we have more understanding of how to go about this than at any time in the past. This new emerging science and associated technologies do not have to follow the path that has been typical of many past innovations in the chemical industry that, despite providing significant benefits, also turned out to have significant, unanticipated costs to human health and the environment. The development and commercialization of viable green nanotechnologies is difficult, and the barriers mentioned will require effort from the scientific, research and government communities. But as the presentations at GN10 indicated, there is a pathway forward, and concrete actions that could construct a solid foundation for an economically profitable and environmentally sustainable future for nanotechnology.

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grEEnEr nAno 2011 SuppLEMEntAL obSErVAtIonS

In an effort to be comprehensive, this short supplement has been added to ensure the most up to date information has been incorporated into this white paper. It is based on the Greener Nano 2011 meeting held in Cupertino, CA May 1-3, 2011. Presentations for Greener Nano 2011 may be found at http://www.greennano.org/GN11_presentations Once again in 2011 there was a major theme around the issue of characterization. If anything the urgency in this area was reinforced as a need for both understanding what is being tested from a toxicology perspective, but also for the ability to implement a consistent and reproducible manufacturing operation. It seems micro reactors may offer an especially attractive approach for process control of nano scale materials. On microreactors for nanoparticle/object production, it might be pointed out that both batch (like Lawrence Berkeley National Laboratorys WANDA) and continuous flow techniques have been reported. It may require a combination of learnings from these two approaches to satisfy industrial cost/efficiency needs in at least some cases [24]. The question of how purification of a nano material influences and in fact changes properties was also raised as a major challenge. In particular methods used to prepare samples for analytical or toxicological testing have the potential to change states of aggregation which may result in significant changes in physico/chemical properties and the resulting interaction with biological systems [25]. The issues of surface area, particle size and especially surface charge continue to receive considerable attention. Sonification is a commonly employed tool for dispersing nano particles, but evidence shows a significant change in states of aggregation and properties may result. This year the element of shape was discussed and how these various characteristics factor into inflammation response and the initiation of apoptosis. The use of coatings may also have a profound impact on the state of aggregation. New insight served as a major development in the fact that nano particles have been in our environment for much longer than we appreciate. The example used was nano silver, and the revelation that silver nanoparticles are readily generated in a humid environment. This raises questions in the context of exposure and toxicity since it appears we have all been exposed through the routine wearing of jewelry, etc. This was discussed in a paper recently submitted to Science.

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 The field of computational toxicology is advancing rapidly and the goal is to move to a predictive capability for use in new risk assessment approaches. The EPA recently held a meeting on their Advancing the Next Generation of Risk Assessment (NexGen) program in Washington, DC to enable movement in this direction [26]. On the regulatory front, there is growing recognition that neither penalty nor data call approaches by regulators are succeeding at the dual goal of advancing innovation and ensuring safety. While there is no consensus on timely alternatives to resolving uncertainty, there may be some openness to consider incentive or fast-track approaches to getting greener nanomaterials with probable net environmental benefit to market faster. Since many of these innovations come from resource-constrained small companies, this remains an urgent agenda item.

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WorKS cItEd
[1] L.C. McKenzie, J.E. Hutchison, Green nanoscience: An integrated approach to greener products, processes, and applications, Chimica Oggi Chemistry Today. (2004) 25. [2] J.A. Dahl, B.L.S. Maddux, J.E. Hutchison, Toward greener nanosynthesis, Chemical Reviews. 107 (2007) 2228-2269. [3] P.T. Anastas, J.C. Warner, Green chemistry : theory and practice, Oxford University Press, Oxford England ; New York, 1998. [4] J.E. Hutchison, Greener nanoscience: a proactive approach to advancing applications and reducing implications of nanotechnology, ACS Nano. 2 (2008) 395-402. [5] E.K. Richman, J.E. Hutchison, The Nanomaterial Characterization Bottleneck, ACS Nano. 3 (2009) 2441-2446. [6] S.F. Sweeney, G.H. Woehrle, J.E. Hutchison, Rapid Purification and Size Separation of Gold Nanoparticles via Diafiltration, J. Am. Chem. Soc. 128 (2006) 3190-3197. [7] M. Kovochich, B. Espinasse, M. Auffan, E.M. Hotze, L. Wessel, T. Xia, et al., Comparative toxicity of C60 aggregates toward mammalian cells: role of tetrahydrofuran (THF) decomposition, Environmental Science & Technology. 43 (2009) 6378-6384. [8] National Research Council (U.S.)., Toxicity testing in the 21st century : a vision and a strategy, National Academies Press, Washington DC, 2007. [9] National Research Council (U.S.), Scientific frontiers in developmental toxicology and risk assessment, National Academy Press, Washington DC, 2000. [10] J. Fagerberg, Innovation: A Guide to the Literature, in: J. Fagerberg, D.C. Mowery, R.R. Nelson (Eds.), The Oxford Handbook of Innovation, Oxford University Press, Oxford, UK, 2006: pp. 1-27. [11] K. Matus, Green Chemistry: A Study of Innovation for Sustainable Development, Harvard University, 2009. [12] M.B. Satterfield, C.E. Kolb, R. Peoples, G.L. Adams, D.S. Schuster, H.C. Ramsey, et al., Overcoming Nontechnical Barriers to the Implementation of Sustainable Solutions in Industry, Environ. Sci. Technol. 43 (2009) 4221-4226. [13] M.L. Tushman, P. Anderson, Technological Discontinuities and Organizational Environments, Administrative Science Quarterly. 31 (1986) 439-465. [14] C. Edquist, Systems of Innovation: Perspectives and Challenges, in: J. Fagerberg, R.R. Nelson, D.C. Mowery (Eds.), The Oxford Handbook of Innovation, Oxford University Press, Oxford, UK, 2005: pp. 181-208. [15] W.E. Bijker, T.P. Hughes, T.J. Pinch, The Social construction of technological systems : new directions in the sociology and history of technology, MIT Press, Cambridge, Mass., 1987. [16] C.J. Dahlman, B. Ross-Larson, L.E. Westphal, Managing Technological Development: Lessons from Newly Industrialized Countries, World Development. 15 (1987) 759-775.

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[17] J.G. March, H.A. Simon, Organizations, Wiley, New York, 1958. [18] S. Lall, C. Pietrobelli, Failing to Compete, Edward Elgar Publishing, Ltd., UK, 2002. [19] D. Archibugi, C. Pietrobelli, The globalization of technology and its implications for developing countries: Windows of opportunity or further burden?, Technological Forecasting & Social Change. 70 (2003) 861-883. [20] V.W. Ruttan, Technology, growth, and development : an induced innovation perspective, Oxford University Press, New York, 2001. [21] H. Gatignon, M.L. Tushman, W. Smith, P. Anderson, A structural approach to assessing innovation: Construct development of innovation locus, type, and characteristics, Management Science. 48 (2002) 1103-1122. [22] G. Gavetti, D. Levinthal, Looking forward and looking backward: Cognitive and experiential search, Administrative Science Quarterly. 45 (2000) 113-137. [23] W. Vincenti, Variationselection in the innovation of the retractable airplane landing gear: the Northrop anomaly, Research Policy. 23 (1994) 575-582. [24] A. Risbud. A robot called Wanda. Berkeley Lab News Center. April 26, 2010. Accessed at: http://newscenter.lbl.gov/feature-stories/2010/04/26/wanda/ on May 25, 2011. [25] L. Truong, T. Zaikova, E. K. Richman, J. E. Hutchison, and R. L. Tanguay. Media ionic strength impacts embryonic responses to engineered nanoparticle exposure. Nanotoxicology. In Press. [26] US EPA. Advancing the Next Generation (NexGen) of Risk Assessment. Accessed at: http:// www.epa.gov/risk/nexgen/ on May 25, 2011.

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