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Fall Symposium

November 2, 2005

Biological, Toxicological, and Regulatory Assessment of Nano-Materials

National Capital Area Chapter of the Society of Toxicology;

Association of Government Toxicologists; and the

National Capital Area Chapter of the Society for Risk Analysis

Lister Hill Auditorium

National Library of Medicine

Bethesda, MD


Introductory Remarks: Nanotechnology-What’s the Hype?

Celia Merzbacher, Ph.D.

Nanotechnology encompasses the understanding, control, and use of matter at dimensions (roughly 1 to 100 nanometers) at which unique phenomena occur. Nanotechnology falls across a broad range of disciplines, areas of research, applications, and industries, and advances are announced daily by researchers and companies around the world.  Nations and businesses are moving quickly in hopes of reaping the benefits of this emerging technology.  At the same time, concerns have been raised regarding unknown risks associated with the novel materials. Within this dynamic setting, the NNI is working to balance and leverage investments, to stimulate innovation and promote transfer of research to commercial use and public benefit, to assess and manage risks, and to communicate with and engage the public.  This talk will provide an overview of nanotechnology and the NNI.

National Toxicology Program Activities Evaluating the Safety of Nano-scale Materials

Nigel Walker, Ph.D.

Currently there is a paucity of data on the potential toxicity of manufactured nanoscale materials. The unique and diverse physico-chemical properties of nanoscale materials suggest that toxicological properties may differ from materials of similar composition but larger size. The National Toxicology Program (NTP) coordinates toxicology research and testing programs within the federal government and conducts research to provide information about potentially toxic chemicals to health, regulatory, and research agencies, scientific and medical communities, and the public. The NTP is currently engaged in a research program to investigate fundamental questions concerning how nanoscale materials are absorbed and distributed in vivo and whether they can adversely impact biological systems. As part of this research program, the following specific studies are currently ongoing and will discussed: evaluation of the role of size and surface characteristics on the biological fate and disposition of nanoscale crystalline fluorescent semiconductors (“quantum dots”) and titanium dioxide following dermal exposure; evaluation of the in vivo toxicity of fullerene-based nanoscale materials by pulmonary and systemic routes of exposure.

Dermal Penetration of Nano Materials and Possible Toxicity

Robert L. Bronaugh, Ph.D.

Nanoparticles are beginning to be used in cosmetic products as well as other products regulated by FDA. Nanodispersed systems such as liposomes, nanoemulsions, and solid lipid nanoparticles can be used to encapsulate water or lipid soluble ingredients. The flexibility of liposomes and surfactant-based vesicles may aid in their penetration into the skin. More rigid nanoparticles such as polymers are more robust and may have increased stability after application to the skin. The sun blocking agents titanium dioxide and zinc oxide are used in over-the-counter drugs as well as in cosmetic products. The National Toxicology Program is funding a study that could lead to examination of the phototoxicity of nanoparticles of these sunblocking agents. Initial studies have focused on the ability of smaller particles to be absorbed through human, pig and hairless mouse skin. Preliminary results of these studies examining the penetration of quantum dots through skin will be presented.

Pulmonary Toxicity and Impact on Respiratory Health – Particle Size isn’t Everything

David B. Warheit, Ph.D.

The results of several lung toxicology studies in rats have demonstrated that ultrafine or nanoparticles (generally defined as particles in the size range < 100 nm) administered to the lungs produce enhanced inflammatory responses when compared to fine-sized particles of similar chemical composition at equivalent doses. However, the common perception that nanoparticles are always more toxic than fine-sized particles is based upon a systematic comparison of only 2 particle-types, namely, titanium dioxide and carbon black particles. Apart from particle size and corresponding surface area considerations, several additional factors may play more important roles in influencing the pulmonary toxicity of nanoparticles.  These include, but are not limited to: 1) surface treatments/coatings of particles; 2) the aggregation/disaggregation potential of aerosolized particles; 3) the method of nanoparticle synthesis – i.e., whether the particle was generated in the gas or liquid phase (i.e., fumed vs. colloidal/precipitated); 4) translocation potential of the particle; 5) particle shape; and 6) surface charge.  Results of pulmonary bioassay hazard/safety studies will be presented demonstrating that fine-sized quartz particles (1.6 µm) may produce greater pulmonary toxicity (inflammation, cytotoxicity, cell proliferation and/or histopathology) in rats when compared to nanoscale quartz particles (50 nm), but not when compared to smaller nanoquartz sizes (e.g., < 30 nm). In addition, other studies have demonstrated no measurable difference in pulmonary toxicity indices among  particle-types when comparing exposures in rats to 1) fine-sized TiO2 particles (300 nm – 6 m2/g (surface area); 2) TiO2 nanodots (6-10 nm – 169 m2/g); or 3) TiO2 nanorods (25 m2/g).  Finally, studies will be presented which demonstrate that varying surface treatments on fine-sized TiO2 particles influence lung responses.  In summary, some important take-home messages are the following:

1)  Risk is a product of Hazard and Exposure;

2) In general, one cannot assume that nanomaterials have the same chemistry or biology (i.e., toxicity) as their microscale or macroscale counterparts (i.e., either greater than or less than);

3) therefore, the hazards of each particle-type should be tested on a case-by-case basis.

Engineered Nanomaterials and Occupational Health

Andrew Maynard, Ph.D.

Nanotechnology has been hailed by some as the next technological revolution, and is poised to impact on every aspect of our lives.  Through the manipulation of matter at near-atomic scales, the technology is enabling remarkable progress in many fields to produce new materials, structures and devices with unique and truly innovative properties.  Although predominantly at the laboratory and pre-commercial stage, nanotechnology-based commercial products are already available, ranging from cosmetics to stain-resistant clothing.  The future promises significant advances in areas as diverse as next-generation electronics, high efficiency energy conversion and storage, novel sensors and advanced medical diagnostics.

However, as with all new technologies, exploiting the unique behavior of nanomaterials and devices also introduces the potential for unique and unforeseen health and environmental impacts.  Understanding and minimizing possible impacts is a daunting task, and not one that can be undertaken lightly or in isolation.  Central to this task is the need to understand and address possible associations between nanotechnology and occupational health.  While there are many components to assessing and reducing the possible health risk associated with engineered nanomaterials, perhaps one of the most immediate challenges is characterizing exposures – both in the workplace and in toxicity studies.

Characterizing exposures to particulate matter has always carried with it a unique set of challenges.  Unlike bulk materials or gases and vapors, pertinent properties of particles extend beyond the chemistry of the material and encompass physical attributes such as shape and size.  As available information on the toxicity of low solubility nanometer-scale particles and structures increases, it is apparent that we are being faced with a new set of challenges: Particle number, structure, surface area and surface activity as well as size and shape are indicated as potentially relevant properties, questioning the validity of characterizing exposures using mass concentration and bulk chemistry alone for these materials.  As nanotechnology moves closer to widespread commercialization, new methods of characterizing relevant material attributes in toxicity studies and appropriately measuring exposure and dose are required.

This presentation will explore the need for appropriate materials characterization methods as we address the potential health implications of engineered nanomaterials in the workplace, and will discuss recent advances in understanding.

Science Needs for Environmental Decision-Making for Nanotoxicity at the

Environmental Protection Agency

Jeff Morris, Ph.D.

This presentation discusses how EPA currently is evaluating its scientific needs for leveraging the benefits of nanotechnology and assessing the potential impacts of nanomaterials on human health and the environment.  EPA is developing a white paper to discuss science policy issues and research needs related to nanotechnology and the environment.  The presentation will outline the issues being raised and the types of recommendations being proposed in the draft white paper, which is presently undergoing internal agency review.

Characterization of nano particles as part of risk assessment

Scott McNeil, Ph.D.

The Nanotechnology Characterization Laboratory (NCL) conducts preclinical efficacy and toxicity testing of nanoparticles intended for cancer therapeutics and diagnostics. The NCL is a collaborating partnership between NCI, the U.S. Food and Drug Administration and the National Institute of Standards and Technology. As part of its assay cascade, NCL characterizes nanoparticles' physical attributes, their in vitro biological properties, and their in vivo compatibility using animal models. The Laboratory facilitates the rapid transition of basic nanoscale particles and devices into clinical applications by providing the critical infrastructure and characterization services to nanomaterial providers. It is a national resource available to investigators from academia, industry and government. The presentation will provide an overview of the NCL, discuss parameters that are critical to biocompatibility, and present assays used for preclinical characterization of nanoparticles.

FDA’s Current Thinking on the Assessment of Risks From Nano-Materials

Stanley Brown, D. Eng

Dr. Brown has been an FDA delegate to the NSET (Nanoscale Science, Engineering and Technology) subcommittee of the President's Office of Science and Technology Policy for the past 3 years. He is also a member of the FDA OC NanoTechnology Interest Group.  As a result, he has been watching the field develop, paying particular attention to new concepts or devices that would be in the FDA regulatory domain.  Clipping from the literature, from the Web, and from presentations he has heard, Dr. Brown has built a PowerPoint presentation on Nano and FDA.

This seminar will attempt to answer 5 questions:  With whom are we thinking and talking?  What is Nano?  What are the dose metrics?  What are the toxicological issues? Who will regulate products utilizing nanotechnology; what are combination products?  It is presented at a level to help FDA reviewers and toxicologists understand the implications, uniqueness, potential, and hype of nano.  There are also a few off-the-wall examples for a bit of comic relief.





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