1. ©2010. All rights reserved. GREENBERG TRAURIG, LLP ATTORNEYS AT LAW WWW.GTLAW.COM Nanotechnology, Health and The Environment This presentation is to highlight current efforts by the US Government and Industry in Nanotechnology within Environmental Health & Safety related issues. A special focus is the beneficial effects of technology-based innovation on Human Health and the Environment.

2. Table of Contents 1.Introduction & Overview 2.U.S. Government Efforts in EHS 3.Upside: Beneficial Application of Nanotechnology 4.Potential Downside: EHS Concerns with Nanotechnology 5.Toxicology Concerns and Addressing Them

3. ©2010. All rights reserved. GREENBERG TRAURIG, LLP ATTORNEYS AT LAW WWW.GTLAW.COM Part One: Introduction and Overview

4. What is Nanotechnology? Science has now advanced to the point that those on the cutting edge of research work with individual atoms and molecules. This is the defining characteristic of the new metafield of nanotechnology, which encompasses a broad range of both academic research and industrial development. At this small scale, the familiar classical physics guideposts of magnetism and electricity are no longer dominant; the interactions of individual atoms and molecules take over. At this level—roughly 100 nanometers (a nanometer being a billionth of a meter, and a human hair being 50,000 nanometers wide) and smaller—the applicable laws of physics shift as Newtonian yields to quantum. Nanotechnology holds the promise of advances that exceed those achieved in recent decades in computers and biotechnology. Its applications will have dramatic infrastructural impacts, such as building tremendously faster computers, constructing lighter aircraft, finding cancerous tumors still invisible to the human eye, or generating vast amounts of energy from highly efficient solar cells. Nanotechnology will manifest in innovations both large and small in diverse industries, but the real benefit will accumulate incrementally in small cascades over decades rather than in a sudden, engulfing wave of change. It is not the “Next Big Thing” but rather will be any number of "next large things" after "next large things." Source: “Nanotechnology: Science, Innovation & Opportunity” by Lynn E. Foster, Prentice Hall, 2006

5. Formal Definition of Nanotechnology Nanotechnology is the understanding and control of matter at dimensions between approximately 1 and 100 nanometers, where unique phenomena enable novel applications. Encompassing nanoscale science, engineering, and technology, nanotechnology involves imaging, measuring, modeling, and manipulating matter at this length scale. A nanometer is one-billionth of a meter. A sheet of paper is about 100,000 nanometers thick; a single gold atom is about a third of a nanometer in diameter. Dimensions between approximately 1 and 100 nanometers are known as the nanoscale. Unusual physical, chemical, and biological properties can emerge in materials at the nanoscale. These properties may differ in important ways from the properties of bulk materials and single atoms or molecules. Source: National Nanotechnology Initiative

6. What is nanotechnology? How will it benefit society? What are the concerns with nanotechnology and the environment? Nanotechnology is the control of matter at an atomic level. It encompasses many different areas of research and almost every major industry, and has tremendous potential to help humanity through innovation in a variety of fields from medicine to energy, computing to consumer products, and in biotechnology and information technology. Environmental Health and Safety (EHS) concerns should play an important part in the continued development and commercialization of nanotechnology-based products. This presentation is divided into five parts: (1) An introduction to nanotechnology; (2) a review of the US Government’s EHS efforts; (3) a discussion of beneficial applications of nanotechnology; (4) a review of standards and testing efforts in the field; and (5) a review of current toxicology efforts in nanotechnology. The US Government’s efforts in nanotechnology are lead by the National Nanotechnology Initiative, an interagency entity that has provided over eleven billion dollars for research since 2001. Over 350 million dollars have been dedicated to EHS and toxicology research by Federal Agencies. Non governmental organizations are also addressing the issue. An excellent example is the collaboration between DuPont and the NGO Environmental Defense to develop best practices in EHS issues. Executive Summary

7. Hundreds of consumer products have been developed that employ nanotechnology in some form. Most Fortune 100 companies have either commercial products using nanotechnology or have ongoing research efforts in the field. Hundreds of new consumer products (such as cosmetics and sunscreens) offer improved performance over previous products because of nanotechnology. Nanotechnology has made an impact in the energy field by developing better batteries and more efficient lighting. It also holds the potential to offer green technology solutions in fields like solar energy and the hydrogen economy. It is already making an impact through advances in medicine and computing and holds the potential to impact many more. The largest impact to date has been in advanced materials such as stronger, lighter composite materials and advanced coatings that provide functions that were not available before. The US FDA is very active in evaluating the safety of products utilizing nanotechnology in industries like cosmetics and food. The National Cancer Institute (NCI) considers nanotechnology to be a “disruptive technology” that will drive a new generation of medical products in the early detection of cancer, in-vivo imaging, and therapeutics. NCI has also created the Nanotechnology Characterization Laboratory for cancer researchers in order to speed the regulatory review of nanotechnologies intended for cancer therapies and diagnostics.

8. The beneficial effects of nanotechnology are likely to be dramatic and relatively rapid. In the longer term, nanotechnology-based products will have an impact on cancer, energy, and climate change; in the near term, nanotechnology will very likely have an effect on issues like water filtration and sanitation. Over three million people die annually from water related diseases – nanotechnology will enable new products for water filtration to reduce this impact. Solar energy could easily meet the world’s energy needs if critical bottlenecks in efficiency and energy storage were solved – nanotechnology is considered the key technology for solving those bottlenecks and enabling solar cells capable of providing inexpensive, plentiful electricity. The establishment of common nomenclature and standards are critical to the advancement of nanotechnology research and product development. A number of different standards bodies, including the International Standards Organization (ISO), The American National Standards Institute (ANSI) and ASTM International, are actively developing standards that provide the needed baseline for commerce. A non-profit industry association, the Clean Technology and Sustainable Industries Organization (CTSI), has also been formed to advance the commercialization and global adoption of clean technologies and sustainable industry practices.

9. Understanding the possible downside of nanotechnology is critical to achieving the benefits outlined in this presentation. Some of the early research has focused on the potential risks of nanotechnology-based manufacturing. Although toxicological research for nanotechnology is very much in its infancy, the absence of data is unlikely to limit public debate, NGO scrutiny, and (at some point) regulatory action. Concerns about potential risks to the health and safety of workers, customers, and the public; and (from a business perspective) questions from external stakeholders, discussions with insurers, and emerging regulations will become more common and require solid answers. Questions quite likely will be focused on manufacturing controls for the current and future uses of nanotechnology, the potential risks presented by nanotechnology-based materials and applications, and the requisite safety measures needed (if any). Another area that has begun to gain attention is the environment. What is the fate and transport of nanomaterials in the air, water, and soil? How are nanomaterials being disposed? What does “proper” disposal mean in the context of nanotechnology? What is clear, however, is that the nanotechnology industry must identify and implement the optimum approach for protecting its employees, its customers, and the public. One promising sign is that the research indicates it may be possible to “engineer out” unacceptable levels of toxicity in nanomaterials. If this is true - and there are numerous universities that have embarked on such research programs - then the industry will be able to minimize the human and environmental impact of nanomaterial-based manufacturing and products without extensive government controls or regulations.

10. Nanotechnology is an exciting and rapidly changing field that offers the promise of technology based innovation that will substantially improve the quality of both human life and the natural environment. A sober and scientifically sound approach to the identification, assessment, and mitigation of the EHS risks posed by nanomaterial manufacturing and commercialization will protect both the public, the environment and industry, thereby ensuring that the benefits of nanotechnology are well and widely shared.

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12. Overview of National Nanotechnology Initiative  The NNI is a multi-agency U.S. Government program initiated in 2001 aimed at accelerating the discovery, development, and deployment of nanometer-scale science, engineering, and technology. The NNI is a coordinated program involving nanotechnology-related activities of 26 Federal agencies, 10 of which have budgets for nanotechnology R&D for 2010.  The vision of the NNI is a future in which the ability to understand and control matter on the nanoscale leads to a revolution in technology and industry. The current NNI Strategic Plan specifies four goals aimed at achieving that overall vision: (1) maintain a world-class research and development program aimed at realizing the full potential of nanotechnology; (2) facilitate transfer of new technologies into products for economic growth, jobs, and other public benefit; (3) develop educational resources, a skilled workforce, and the supporting infrastructure and tools to advance nanotechnology; and (4) support responsible development of nanotechnology. Source: NNI Supplement to the President’s FY 2011 Budget

13. NNI Budget Information NNI expenditures* have grown from $464 million in FY ‘01 to an FY ‘11 request of nearly $1.8 billion.** * All numbers shown above are actual spending, except 2010, which is estimated spending for the current year and 2011, which is requested amount for next year (FY ‘09 figure shown here does not include ~$500 million in additional ARRA funding). ** 2011 figure shown here does not include DOD earmarks included in previous yrs. ($117 M ‘09)

14. * Based on allocations ARRA appropriations. Agencies may report additional ARRA funding for SBIR and STTR projects later. ** 2009 and 2010 DOD figures include Congressionally directed funding that is outside the NNI plan ($117 million for 2009). See NNI Supplement to the President’s FY ‘11 Budget for additional details: http://www.nano.gov/NNI_2011_budget_supplement.pdf. Agency 2009 Actual2009 Recovery*2010 Estimated2011 Proposed DOE332.6293.2372.9423.9 NSF408.6101.2417.7401.3 HHS/NIH342.873.4360.6382.4 DOD**459.00.0436.4348.5 DOC/NIST93.443.4114.4108.0 EPA11.60.017.720.0 HHS/NIOSH6.70.09.516.5 NASA13.70.013.715.8 HHS/FDA6.50.07.315.0 DHS9.10.011.7 USDA/NIFA9.90.010.48.9 USDA/FS5.40.05.4 CPSC0.20.00.22.2 DOT/FHWA0.90.03.22.0 DOJ1.20.0 TOTAL1,701.5511.31,781.11,761.6 NNI Budget By Agency

15. Environmental, Health, and Safety (EHS) Budget * Research whose primary purpose is to understand and address potential risks to health and to the environment from nanotechnology, e.g., not including related instrumentation research NNI funding for nanotechnology-related EHS research* has grown much faster than the NNI as a whole ( by fiscal year, in $ millions - FY 2010 is estimated, FY 2011 is requested) 2011

16. NNI EHS Strategy Strategy for Nanotechnology-Related Environmental, Health, and Safety Research (February 2008): http://www.nano.gov/NNI_EHS_research_needs.pdf  Process: 1. Identify priority needs 2. Assess existing research 3. Analyze strengths and weaknesses 4. Periodic updates and revisions  Five research categories: 1. Instrumentation, metrology and analytical methods (NIST lead) 2. Nanomaterials and human health (NIH lead) 3. Nanomaterials and the environment (EPA lead) 4. Human and environmental exposure assessment (NIOSH lead) 5. Risk management methods (FDA and EPA lead)

17. Summary: Recent NNI developments  Cumulative NNI funding for nanoscale science and engineering research, 2001-2011: over $14 billion  Over 60 NNI research centers, networks and user facilities funded  Over $480 million in “primary purpose” EHS R&D, 2005-2011 combined; over $260 million in education and ELSI funding over the same period  Reviews of NNI completed in the past 2 years by President’s Council of Advisors on Science and Technology, National Academies; new PCAST assessment released in March 2010  Current NNI Strategic Plan released Dec. ’07; due for update this year  NNI EHS strategy released Feb. ’08; currently being updated  Broad stakeholder workshops assessing EHS strategy and progress recently conducted in 2009 and 2010; new data call for EHS projects soon  Focus should remain on funding the needed research, as much as on process

18. NNI EHS Strategy Development  Nanotechnology Environmental and Health Implications (NEHI) Working Group formed as informal body in 2003, formalized in 2005  Extraordinary collaboration between research and regulatory agencies  Began with review of respective agencies’ jurisdictions, responsibilities  Industry and non-governmental organizations provided input throughout  Environmental, health, and safety research needs published in September 2006: http://www.nano.gov/NNI_EHS_research_needs.pdf  Public meeting held in January 2007 to gather additional input from research community and public  Interim document for public comment, “Prioritization of Environmental, Health, and Safety Research Needs for Engineered Nanoscale Materials” published in August 2007: http://www.nano.gov/Prioritization_EHS_Research_Needs_Engineered_Nan oscale_Materials.pdf  First comprehensive NNI strategy document published in Feb 2008: http://www.nano.gov/NNI_EHS_research_needs.pdf

19. EHS, Other Regulatory Considerations for Industry  Existing laws, regulations are being applied to nanotechnology-enabled products and processes, primarily on a case-by-case basis, as appropriate with any emerging technology  Regulatory agencies with jurisdiction include:  Environmental Protection Agency (EPA): Toxic Substances Control Act (TSCA); Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA); Clean Water Act, Clean Air Act, etc.  Food and Drug Administration (FDA): Medical devices and biologics require pre-market approval; cosmetics and dietary supplements do not, but can be recalled quickly if there is an adverse event  Consumer Product Safety Commission: No pre-market approvals, but as with all products, industry is liable  Occupational Health and Safety Administration (OSHA): See National Institute for Occupational Safety and Health (NIOSH) for current “best practices” worker protection recommendations  Department of Agriculture: Regulates some aspects of food safety, packaging  Department of Commerce, Department of Defense, Department of State: Exports may require a license if product has potential national security implications

20. NNI EHS Strategy Role of nanotechnology-related EHS research in risk management of nanomaterials* * From Strategy for Nanotechnology-Related Environmental, Health, and Safety Research (February 2008): http://www.nano.gov/NNI_EHS_research_needs.pdf

21. Summary: Approach to EHS, Other Potential Risks  “Bottom-up,” not “top-down” strategy development; input from research community, industry  individual agencies  overall USG strategy  Interagency coordination is essential (see list of agencies, next slide)  Science-based policy development; recommend precautions, just in case, while science results are still pending, especially in workplace settings; NIOSH is leading this effort in the United States  EHS research effort integrated with overall NNI program, including EHS components within many NNI projects (for example, safety and efficacy testing is routine part of late-stage research)  Over $480 million in “primary purpose” EHS R&D, 2005-2011 combined is supplemented by much larger efforts in basic science, materials characterization, understanding of interactions with biosystems, and especially instrumentation, metrology, & standards; total EHS-related investment is much higher counting all this related work  International collaboration is also key: OECD, ISO, bilateral

22. US Government Interagency Highlights in EHS  NIH, FDA, NIST: The Nanotechnology Characterization Lab (NCL) of the National Cancer Institute (NCI) is developing a battery of characterization tests for preclinical evaluation of nanomaterials intended for cancer therapeutics. This work is being done in partnership with FDA and NIST and is aimed at stimulating further development of nanoparticles, development of standards for their characterization, and accelerating transition of these technologies to the clinic.  NIH, FDA, NIOSH: The National Toxicology Program (led by NIEHS) is developing and carrying out research and testing programs addressing health and safety issues in collaboration with NIOSH, the FDA National Center for Toxicological Research, and the NCI Nanotechnology Characterization Lab.  EPA, NSF, USDA/NIFA, EC: EPA’s National Center for Environmental Research (NCER), the National Science Foundation, and USDA’s NIFA will make awards in 2010 through a joint solicitation entitled, “Increasing Scientific Data on the Fate, Transport, and Behavior of Engineered Nanomaterials in Selected Environmental and Biological Matrices.” This solicitation is a collaborative effort with the European Commission.  EPA, NSF, NIH/NIEHS, NIOSH, and DOE: Since 2004 EPA’s STAR grants program has coordinated interagency requests for applications; agencies involved have included NSF, NIEHS, NIOSH, and DOE. The fourth joint research solicitation by EPA’s STAR program was issued in 2007. The solicitation was a collaboration between EPA, NSF, and DOE; over 130 research proposals were received. EPA awarded 15 grants, NSF awarded 6 grants, and DOE awarded 1 grant and made several awards to DOE laboratories. Individual grant awards totaled approximately $9 million. In addition, EPA recently awarded $2 million to study fate and transport in biological systems as part of an NIEHS-led request for applications.

23. US Government Interagency Highlights in EHS  EPA, NSF, NIH/NIEHS, NIOSH, USDA/NIFA, and EC: EPA is leading another interagency solicitation with NSF, NIH/NIEHS, NIOSH, and USDA/NIFA, all in coordination with the European Commission, focused on exposure and safety research data for engineered nanomaterials.  FDA, other agencies, and universities: FDA is planning to establish a CORE program to foster collaborative and interdisciplinary research addressing product characterization and safety. The nanotechnology CORE program supports peer-reviewed research at FDA and in collaboration with academia through grant mechanisms or other approaches. The CORE program focuses on: □ Measurement and detection methods for nanomaterials in FDA-regulated products □ Effects of specific nanomaterial characteristics, such as surface charge, shape, size, and composition, on particle behavior (e.g., distribution in the body) and biological outcomes (e.g., both beneficial effects and toxicities) □ Strategies to better predict, assess, and mitigate potential human health risks  NIST, CPSC: NIST is leading a coordinated research program with the Consumer Product Safety Commission to determine the release of nanoparticle flame retardants from fabrics and foams.  NSF, EPA: To ensure that nanotechnology is developed in a responsible manner, the National Science Foundation and the Environmental Protection Agency continue to fund (over five years, starting in September 2008) two Centers for the Environmental Implications of Nanotechnology (CEIN). Each center works as a network, connected to multiple research organizations, industry, and government agencies, and emphasizes interdisciplinary research and education.

24. January 2008 - EPA launched the Nanoscale Materials Stewardship Program (NMSP)  Basic Program □ Participants are invited to voluntarily report available information on the engineered nanoscale materials they manufacture, import, process or use. □ EPA is not requesting that participants develop additional data, only that participants submit existing data.  In-Depth Program □ Participants will voluntarily develop data, including testing, over a longer time frame. □ Entities or consortia with an interest in developing data for a specific nanoscale material(s) should notify EPA. □ Once potential participants are identified, EPA will facilitate a process leading to data development

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26. Consumer Products  Sporting goods  Paints/coatings  Clothing  Appliances  Cosmetics  Supplements  Food Photos Courtesy of GM Collin Homme, Lancome, Chanel

27. Fortune 100 Sample  General Motors  Ford Motor  General Electric  IBM  Hewlett-Packard  Boeing  Pfizer  Proctor & Gamble  Johnson & Johnson  Dow Chemical  Lockheed Martin  Intel  Delphi  du Pont  Motorola  Honeywell  Caterpiller  Merck

28. Key Industry Segments  Energy  Bio/life sciences  Computers/electronics  Defense/aerospace/automotive  Consumer products

29. Energy  Light, Power, & Efficiency □ Batteries – size, performance □ Catalytic converters (improved performance & emission levels) □ Fuel enhancers □ Lighting  Killer Apps  Solar  Hydrogen economy  Energy transmission Photos Courtesy of Plug Power, LEDtronics

30. Medical – Today’s applications  Wound Care □ Silver-based nanocoating for an antimicrobial effect  Bone restoration  Surgical tool coatings  Drug discovery  Catheters / stents  Filtration □ Virus sortation □ Masks & breathing equipment □ Air filters Photos Courtesy of smith&nephew/Nucrys, Acrymed

31. FDA approved nano therapeutics  Gadolinium chelate for MRI imaging (Gd-DTPA Dimeglumine)  Iron oxide particles for MRI imaging (Feridex)  Products using NanoCrystal technology (Rapamune, Emend)  Liposomes (Doxil, DaunoXome)  Microemulsions (Cyclosporine)  Albumin-bound nanoparticles (Abraxane) Medical – Today’s applications Nakissa Sadrieh, Ph.D., Office of Pharmaceutical Science, CDER, FDA Presentation, Wednesday, May 23, 2007

32. Medicine & Health - Tomorrow  Advanced diagnostics  Targeted drug delivery  Implants  Nanosphere - nucleic acid & protein detection – ultra sensitive  Magforce - Cancer therapies  Nanospectra Biosciences, Inc. – cancer therapies Reference: Jim Heath, California Institute of Technology Photo Courtesy of Nanosphere

33. Computing – Company examples  Nantero □ Nanotube-based/non-volatile Random Access Memory (NRAM) □ Disruptive – replacement for DRAM, SRAM & flash memories  Luxtera □ Optical transceivers fab’ed on single silicon chip □ Enabling cost-viable replacement of copper wiring Photos Courtesy of Nantero, Luxtera

34. Military/Defense/Transportation  Power: portable/long-life  Fuel cells  Protective gear  Coatings  Composites  Communications  Sensors/detection  Explosives  Biological agents Photo Courtesy of DaimlerChrysler

35. Potential Uses of Nanotechnology in Foods  Dietary supplements  Enhance flavor, color and ingredients  Decrease microbial resistant food and improve packaging  Barrier to keep microbes out  Kill microbes directly  Carrier of antimicrobial compounds  Sensor to alert consumer or retailer of potential spoilage  Tracer to identify the source of contamination Source: Dr. Linda M. Katz, Director, Office of Cosmetics and Colors, U.S. Food and Drug Administration Presentation, Monday, May 21, 2007

36. Nanotechnology is a “disruptive technology” which will drive a new generation of cancer diagnostic and therapeutic products, resulting in dramatically improved cancer outcomes  Early detection – highly sensitive and specific sensors  In-vivo imaging – new contrast agents, localization  Therapeutics – local, on-particle delivery Source: Piotr Grodzinski, Ph.D., Director, NCI Nanotechnology Alliance, National Cancer Institute

37. Nanotechnology is an Enabler of New Solutions for Cancer Early detection Imaging Therapy  Molecular imaging and early detection  In vivo imaging  Reporters of efficacy  Multifunctional therapeutics  Prevention and control  Research enablers Focus Areas: Source: Piotr Grodzinski, Ph.D., Director, NCI Nanotechnology Alliance, National Cancer Institute

38.  Nanoparticles □ Quantum dots □ Polymer particles □ Dendrimers □ Magnetic particles □ Nanoshells □ Nanotubes □ Virus engineered particles  Multiple functions –Tissue targeting Tumor-specific binding –Sensing or imaging capability Improved sensitivity Multi-modal imaging –Non-invasive treatment Therapeutic localized delivery Localized cell kill Lower dose administered Improved side effect profile Source: Piotr Grodzinski, Ph.D., Director, NCI Nanotechnology Alliance, National Cancer Institute Clinical Applications Using Nanoparticles

39. Beneficial Nanotechnology: Water Filtration  Over 1 Billion People Worldwide do not have access to a reliable water supply  Over 3.4 Million People die annually from water related diseases  Nanotechnology Applications hold promise in Water Desalination, Water Purification, and Wastewater Treatment to provide dramatic improvements in safe drinking water and sanitation  Nanotechnology Applications for purifying water include Carbon Nanotubes, Nanoscale Membranes, Nanoclays, Nanoscale Metals, and Nanofibers  Nanoscale metals can be used to render inert chemicals including Mercury, Arsenic, Lead and Perchlorate

40.  Sunlight Incident On Earth Produces Enough Energy In 90 Minutes To Meet Global Energy Demands For >1 Year  Solar Power Currently Accounts For <0.1% Of Global Energy  Critical Bottlenecks in Efficiency and Energy Storage Can Be Solved By Nanotechnology  Solar Power Will Not Be Cost Competitive Until Nanotechnology Applications are Developed Alivisatos Research Lab - LBNL, U.C. Berkeley Beneficial Nanotechnology: Solar

41. Today’s Solar Cells:  Material: Silicon  Efficiency 10%-20%  Cost: $5/W  Unsubsidized payback time (CA): 50 Years  Lifetime: 25 Years non-Si SiliconWafer Solar CellSolar Module Ingot 50% Cost25% Cost $1/W for cost effective large scale power Alivisatos Research Lab - LBNL, U.C. Berkeley Solar Energy: The Challenge

42. Plastic Solar Panels  First solar technology capable of generating electricity at costs equivalent to conventional fuels  Key attributes: □ Flexible □ Attractive and colorful □ Transparent □ Low energy, Low temperature… Low-cost manufacturing! □ Any shape and size □ Environment friendly (No toxic or hazardous materials) Photo Courtesy of Solarmer Energy, Inc.

43. The 3 Major Application Areas for Plastic Solar Panels  Building Integrated Photovoltaics □ Windows & Skylights □ Tiles & Shingles □ Walls  Smart Fabrics □ Bags & Backpacks □ Curtains □ Tents & Awnings  Portable Electronics □ Cell Phones □ Digital Cameras □ MP3 Players Photo Courtesy of Solarmer Energy, Inc.

44. The Clean Technology and Sustainable Industries Organization (CTSI)  Public funded research advocacy  Private funded grand challenges  Education & media programs  Technology publication and dissemination  Industry & Policy Leadership programs  Community development and networking  IP and early stage company matching with investment & corporate partners The Clean Technology and Sustainable Industries Organization (CTSI) (www.ct-si.org) is a not-for-profit membership organization. The CTSI’s mission is to advance the commercialization and global adoption of clean technologies and sustainable industry practices through a community of industry, academic, and government leaders committed to a safer, cleaner and more productive world. The CTSI’s core purpose is to provide a cross industry community to promote clean technology development, profitable commercialization and global integration of sustainable industry practices, enabling the transformation of businesses, governments and society towards a more sustainable global economy. The CTSI develops programs and advocacy towards:

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46.  Toxicologists study the potentially harmful effects of chemicals on people.  The practice of toxicology began approximately 500 years ago.  Toxicologists have standard methods, called risk assessments, to evaluate potential hazards of chemicals. The approach is used worldwide.  Two important aspects of the practice of toxicology are the dose and exposure.  Many scientists believe more work needs to be done to adequately address the toxicological issues of nanotechnology. Toxicology “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.” -Paracelsus (1493-1541)

47. Focusing on developing the best science: Ensure properly designed scientific experiments.  Ensuring scientists know what they are testing □ Reporting the physico-chemical parameters of materials being tested (e.g., surface area, size, chemical composition, surface charge, aggregation/agglomeration state). □ Assessing and reporting purity and impurity of the materials being tested. (Something that is 90% pure means that 10% of the material is something other than the tested agent.)  Considerations for in vitro assays □ Does the material interfere with the assay? □ Is the assay appropriate for the material being tested (e.g., cell line)? □ What happens to the physico-chemical parameters once introduced to the test, and is toxicity effected? □ Is the assay relevant to human exposure?  Considerations for in vivo assays □ Consideration of all the points above. □ Is the exposure route relevant? □ How is the preparation of the test sample relevant to human exposure? □ Consideration of the appropriate dose metrics. Toxicology

48.  Research has suggested there are chemical-physical characteristics of nano- objects for us to understand in order to assess their possible harm.  ISO / OECD have developed a list of physico-chemical parameters to be considered when conducting toxicological testing. □ The surface area of a nano-object is one parameter. For example, if one considers the surface area of a tennis ball then considers cutting that one tennis ball into a thousand small balls, the surface area of the small balls is exponentially greater than the regular tennis ball. The surface of a nano-object may have unique toxicological properties. □ Another example of a parameter is size. A nano-object is approximately 1 to 100 nanometers. The size is a parameter that might be important. In general, the smaller the particle is the deeper it can travel into the lungs. Image from V. Murashov, NIOSH, 2007 Toxicology

49. Early Studies: How the surface area of a nano- object creates a greater biological response “…studies with…titanium dioxide (TiO2) particles, …showed …TiO2 (20 nm), when instilled intratracheally into rats and mice, induced a much greater pulmonary-inflammatory neutrophil response…than did…TiO2 (250 nm) when both types of particles were instilled at the same mass dose...” “However, when the instilled dose was expressed as particle surface area, it became obvious that the neutrophil response in the lung for both ultrafine and fine TiO2 fitted the same dose–response curve…suggesting that particle surface area for particles of different sizes but of the same chemistry, such as TiO2, is a better dosemetric than is particle mass or particle number (Oberdörster, 2000).” Emphasis Added Toxicology

50.  Toxicologists have been conducting toxicological risk assessments for over 20 years. The diagram above demonstrates the components of a risk assessment.  A risk assessment provides a frameworks for scientists to think about what might be important for managing human and environmental exposures.  Risk assessments are recognized and conducted by many government organizations.  Risk assessments provide a framework, with appropriate modifications, to assess possible risks from nano-objects.  This paradigm is useful for assessing health risks from nanotechnology. Toxicology

51. Figure adapted from http://www.ami.ac.uk/courses/topics/0109_lct/ Development Manufacture Consumer Use End of use Workers Residents Environmental Workers Residents Environmental Workers Residents Environmental Consumers Workers Residents Environmental □ Entities that can have possible exposures to nano-objects are Workers (people working with a material), Residents (people living near the facility), Consumers (people using products made of nano-objects), and Environment (exposures other than human). □ In general, workers have the greatest potential for exposure. However, when company instigates best practice methods such as materials being produced in a closed system or workers wearing protective equipment, risks of exposures are sharply reduced. □ Consumers can have the potential for greatest exposure when they come into direct contact with a material. For example, if the nano-object is in a cosmetic and applied to the body, a consumer would have potential for greater exposures than if the nano-object was chemically bound (e.g., in the housing of a dishwasher). Note that exposure and toxicity are not synonymous. □ At every step along the lifecycle of a nanomaterial, there exists the ability to control exposures and possibly its toxicity. For example, the concept of green chemistry is to preserve the function of nanomaterial but reduce its toxicity. Lifecycle of Nano-objects

52. Industry, NGOs, and Government Response to EHS Concerns  Many organizations are working to address the possible risks of nanotechnology.  Government organizations work to develop guidance and regulations. (See previous slides.)  Industry develops best practices, An example is the Nano Risk Framework developed by Environmental Defense and DuPont. www.nanoriskframework.com  Some NGOs try to cast light to issues that are not addressed. Some NGOs develop voluntary standards to enhance commerce and protect public and environmental health.

53. The NNI Strategic Plan  The first NNI Strategic Plan was issued in 2004. This one was released in 2007.  The next update is this year, 2010.  The plan “…supports leading edge research…addresses environmental health and societal concerns.” Government

54. The National Cancer Institute (NCI) established the Nanotechnology Characterization Laboratory (NCL) to perform preclinical efficacy and toxicity testing of nanoparticles. The NCL works in concert with the National Institute of Standards and Technology (NIST) and the U.S. Food and Drug Administration (FDA). The NCL serves as a national resource and knowledge base for all cancer researchers to facilitate the regulatory review of nanotechnologies intended for cancer therapies and diagnostics. By providing the critical infrastructure and characterization services to nanomaterial providers, the NCL can accelerate the transition of basic nanoscale particles and devices into clinical applications, thereby reducing suffering and death from cancer. As part of its assay cascade, the NCL will characterize nanoparticles' physical attributes, their in vitro biological properties, and their in vivo compatibilities using animal models. The time required to characterize nanomaterials from receipt through the in vivo phase is anticipated to be one year. The NCL objectives are to: □ Establish a characterization assay cascade for nanoparticles. □ Conduct structured activity-relationships studies. □ Characterize and facilitate regulatory review of nanotech constructs. □ Engage in educational and knowledge sharing efforts. ncl@ncifcrf.gov http://ncl.cancer.gov NCI Nanotechnology Characterization Laboratory Government

55.  NCL has over 20 Materials Transfer Agreements (MTAs) with parties from government, industry, and academia.  As of Feb ’07, 76 nanotechnology strategies are being characterized. Nanoemulsions Nanocrystals TiO 2 FullerenesDendrimers Quantum Dots Gold nanoshells Liposomes Portfolio of Nanoparticles Colloidal gold Polymers Government

56. Nanoparticles submitted to NCL are subject to a three-phase assay cascade for preclinical characterization In Vitro: –Pharmacology –Blood contact properties –Immune cell function –Cytotoxicity –Mechanistic toxicology –Sterility Physicochemical: –Size –Shape –Composition –Molecular weight –Surface chemistry –Identity –Purity –Stability –Solubility In Vivo: –ADME –Safety –Efficacy http://ncl.cancer.gov/assay_cascade.asp NCL Assay Cascade Efficacy & Toxicity Testing Government

57. FDA Activities – Nanotechnology Task Force  Evaluates regulatory approaches with regard to development of safe and effective nanotechnology products  Identifies and determines ways to address knowledge or policy gaps  Held public meeting on October 10, 2006  Task Force Report issued on July 23, 2007 Source: Dr. Linda M. Katz, Director, Office of Cosmetics and Colors, U.S. Food and Drug Administration Government

61.  Several companies in Industry have developed frameworks and practices to protect workers, the public, and the environment.  An example is the Environmental Defense- DuPont Nano Partnership shown at the right.  Initial focus of safety for nanomaterials has been in the workplace, as the worker has the greatest potential for the highest exposures to nanomaterials.  There is an increasing trend in some industries to work at the forefront of developing best practices in a transparent manner. Industry

62.  Nanotechnology standards are important because they: □ encourage the development and commercialization of this technology; □ improve communication among all types of stakeholders; □ foster innovation – encouraging the diffusion of new technologies; □ lower barriers to market entry; □ promote market efficiency; □ protect public health and environment; □ serve as one of the bases for regulations.  Standard Setting Organizations □ The American National Standards Institute's Nanotechnology Standards Panel (ANSI-NSP). They are recognized US representatives to ISO. □ ASTM  Status □ ISO / TC-229 Nanotechnologies: Several initiatives in defining nomenclature, methods, and EHS standards are underway. Because of urgency, two international ISO meetings are held each year. □ First ISO meeting in the US was June 2009 in Seattle. Standards Standards are key to commerce

63. ©2010. All rights reserved. GREENBERG TRAURIG, LLP ATTORNEYS AT LAW WWW.GTLAW.COM Chinh Pham Greenberg Traurig, LLP │ Nanotechnology Practice Chair (617) 310-6000 │ PhamC@gtlaw.comPhamC@gtlaw.com Richard C Pleus, Ph.D. Intertox │ Managing Director (206) 443-2115 │ Rcpleus@intertox.comRcpleus@intertox.com Reed Rubinstein Greenberg Traurig, LLP │ Environmental Law (202) 533-2314 │ RubinsteinR@gtlaw.comRubinsteinR@gtlaw.com Lynn Foster BPT Pharmaceuticals │ CEO FosterL@bptpharma.com