on Food Safety and Nutrition June 26-28, 28, 2007

Transcription

1 8 th CSL/JIFSAN Joint Symposium on Food Safety and Nutrition June 26-28, 28, 2007 Nanotechnology in Foods and Cosmetics Framework for Systematically Exploring Nanotechnology s Possible Risks Michael Holsapple, Ph.D., A.T.S. Executive Director, HESI

2 Let s s start by clarifying some confusion over my affiliation... ILSI Health and Environmental Sciences Institute (HESI) abstract; ; and ILSI North America list of participants. Let s s consider the differences. Let s s consider the similarities.

3 Differences: ILSI HESI & ILSI NA Specific objectives : ILSI NA: : Advancing the understanding and application of science related to the nutritional quality and safety of the food supply and to health issues related to consumer healthcare products. ILSI HESI: : Providing an international forum to advance the understanding of scientific issues related to human health, toxicology, risk assessment and the environment.

4 Differences: ILSI HESI & ILSI NA Specific objectives. Organizational structure. Global versus regional.

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6 Differences: ILSI HESI & ILSI NA Specific objectives. Organizational structure. Members: ILSI NA: : food, food packaging, beverage, nutrition and consumer health companies. HESI: : pharmaceutical, chemical, petro-chem chem, ag- chem,, biotech & consumer products companies. Each with > 50 members; < 10 overlap.

7 Similarities: ILSI HESI & ILSI NA Non-profit scientific organizations (501c3). Membership-supported supported (some support from gov t). Committed to same principles: Advancing the science of critical issues in public forums. Consensus-building. Results/conclusions are publicly available. Process is as transparent as possible. Tripartite approach (industry + government + academia).

8 Back to today s s presentation... A challenge and some principles A challenge : there is currently no consensus for a framework to explore risks of nanotechnology. Some principles : Properties contributing to applications for nanotech may contribute to the toxicity. Not necessary to develop a framework de novo; ; we can build on extensive work with ultrafine particles, fibers and other products. Risk assessment is a function of hazard + exposure + dose. Characterization of the material being assessed is essential will be especially true for nanomaterials.

9 Nanotechnology Nanoscale science and engineering promise to be as important as the steam engine, the transistor, and the internet and to have the potential to revolutionize other technologies... But the outcome is not guaranteed. Represents multiple technologies. Includes applications of materials with at least one dimension in the <100 nm range. Unique properties & functional applications depend on small size. (Properties can contribute to toxicity) Nanomaterials: : nanoparticles, nanotubes, fullerenes, dendrimers, nanoparticle aggregates.

10 Slide courtesy of Nigel Walker NIEHS/NTP Nanomaterials Single and multi walled nanotubes Fullerenes Metal oxides Dendrimers Quantum dots

11 Relative sizes 18nmx 300nm Tobacco mosaic virus 5nm hemoglobin 5nm wide: Lipid bilayer 2nm x 400nm Carbon nanotubes 120nm HIV 1nm C60 5nm G5 dendrimer 60nm Gold nanoshell 60nm Nano-C60 40nm PEG-Qdot 14 nm x 81nm Rutile nano Ti0 2 1um Slide courtesy of Nigel Walker NIEHS/NTP

12 Nanotechnology Commercial Applications: Information technology. Consumer products: Biotechnology. Cosmetics. Pharmaceuticals. Food Packaging. Novel Medical Delivery Sport equipment. Systems. Clothing. Environmental Remediation.

13 Potential Risks from Nanomaterials Human Health (consumer) Concerns. Worker Health & Safety Considerations. Environmental Impact.

14 Potential Consumer Exposure Risks Textiles & Fabrics Sporting Equipment Cosmetics Electronics

15 Worker Health & Safety Considerations Material Handling. Appropriate Personal Protective Equipment. Acute and Chronic Exposure Implications from Pulmonary and Dermal Exposure.

16 Human Health Concerns As particle size gets smaller, there may be size-specific specific effects on activity. Consider the following: What are the differences in the ADME profile of nanoparticles versus larger particles? Can nanoparticles gain access to the systemic circulation from inhalation, dermal or oral exposure? What preclinical screening tests would be useful to identify potential risks (in( vitro or in vivo)? What are the long-term consequences of exposure to nanomaterials?

17 Human Health Concerns As particle size gets smaller, there may be size-specific specific effects on activity. Consider the following: Will nanoparticles gain access to tissues and cells that normally would be bypassed by larger particles? Once nanoparticles enter tissues, how long will they remain there and how will they be cleared? If nanoparticles enter cells, what effects do they have on cellular and tissue functions? Might nanoparticles cause different effects in different cells types?

18 Potential Environmental Exposure Risks Product Disposal Manufacturing Emissions Ecosystem Impacts Surface & Groundwater Contamination Life-Cycle Impacts? Impacts on Food Chain?

19 Environmental Concerns Can nanoparticles be released into the environment following human and animal use? What methodologies would identify the nature, and quantify the extent, of nanoparticle release in the environment? What might be the environmental impact on other species (animals, fish, plants, microorganisms)?

20 Current Nanoscale Research Efforts (emphasis on Gov t) Basic Nanoscience. Nanoscale characterization and testing. Hazard identification (human health and ecotoxicity). Exposure characterization (human health and environmental endpoints).

21 Prioritizing nanotechnology risk research isn t t rocket science. (2007) Andrew D. Maynard, Ph.D. Chief Science Advisor, Project on Emerging Nanotechnologies, Woodrow Wilson International Center for Scholars, Washington, D.C. 3-part plan: Document what relevant risk research exists. Ensure that agencies responsible for oversight and related research (EPA, FDA, NIEHS, NIOSH, CPSC) are adequately funded. Develop a robust top-down research plan that can be implemented by the U.S. government and used for collaborations with industry and with researchers in other countries.

22 NANOTOXICOLOGY The new kid on the (toxicology( toxicology) block Donaldson et al 2004 (Occup.. Environ. Med. 61: ); first to coin the term, NANOTOXICOLOGY. Dreher 2004 (Toxicol. Sci.. 77:3-5); in a TOXICOLOGICAL HIGHLIGHT, described two papers as the first peer- reviewed comparative toxicological assessments of a specific type of manufactured nanoparticle called SWCNTs. Warheit et al 2004 (Toxicol. Sci. 77: ); 125); Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats. Lam et al 2004 (Toxicol.. Sciences 77: ); 134); Pulmonary toxicity of single-wall carbon nanotubes in mice 7 and 90 days after intratracheal instillation.

23 NANOTOXICOLOGY The new kid on the (toxicology( toxicology) block Warheit et al 2004 (Toxicol. Sci. 77: ); 125); Compared SWCNTs with quartz & carbonyl ion. RESULTS: SWCNTs caused pulmonary granuloma formation in absence of pulmonary inflammation or cellular proliferation. Quartz > SWCNT> Carbonyl ion. Lam et al 2004 (Toxicol.. Sciences 77: ); 134); Compared SWCNTs with quartz & carbon black. RESULTS: SWCNTs caused dose-dependent dependent lung lesions; granuloma formation in alveolar space. SWCNT>Quartz>CB on equal weight basis. These two papers are still some of the most cited in Toxicol. Sci.. Prompted the editorial board to develop a FORUM series on Research Strategies for Safety Evaluation of Nanomaterials.

24 Research Strategies for Safety Evaluation of Nanomaterials (Forum Series for Toxicological Sciences) Article Title / Focus Part I: Evaluating the human health implications of exposure to nanoscale materials. Part II: Toxicological and safety evaluation of nanomaterials: Current challenges & data needs. Part III. Nanoscale technologies for assessing risk and improving public health. Part IV. Emerging issues in risk assessment and risk perception of nanomaterials. Part V. Role of dissolution in biological fate and effects of nanoparticles. Part VI. Characterization of nanoscale materials for toxicological evaluation. Part VII. Nanotechnology and the consumer. Part VIII. International efforts to develop risk-based safety evaluations for nanomaterials. Author(s) K. Thomas and P. Sayre M. Holsapple, W. Farland,, T. Landry, N. Moteiro-Riviere Riviere,, J. Carter; N. Walker and K. Thomas D.M. Balshaw,, M. Philbert and W.A. Suk J. Tsuji, A.D. Maynard, P.C. Howard, J.T. James, C.W. Lam, D.B. Warheit and A.B. Santamaria P. Borm, F.C. Klaessig, T. Landry, B. Moudgill, J. Pauluhn, K. Thomas, R. Trottier and S. Wood, K.W. Powers, S.C. Brown, V.B. Krishna, S.C. Wasdo,, B.M. Moudgil and S.M. Roberts T. Thomas, K. Thomas, N. Sadrich,, N. Savage, P. Adair and R. Bronaugh K., Thomas, P. Aguar,, H. Kawasaki, J. Morris, J. Nakanishi, and N. Savage Publication Date October (2): November (1): December (2): January (1):42-50 February (1): March (2): April (1): June (1):

25 Evaluating Environmental and Human Health Risks from Nanomaterials A Congressional Science Briefing Organized by the SOT September 7, Society of Toxicology

26 Society of Toxicology The SOT is the world s largest professional Society (~5800 members) dedicated to supporting the use of sound scientific information in advancing the health of humans, animals and the environment by reducing uncertainties in the assessment of risk from exposure to chemicals Society of Toxicology

27 SOT Council approves proposal for new Specialty Section on Nanotoxicology 1) To address questions regarding the design of appropriate toxicological studies for evaluating the toxicity of nanomaterials. 2) To develop the most appropriate dosimetrics for evaluating nanomaterials in vitro and in vivo. 3) To develop batteries of screening studies for evaluating the toxicity of nanomaterials and for extrapolating the findings from in vitro assays to the in vivo situation Society of Toxicology

28 SOT Council approves proposal for new Specialty Section on Nanotoxicology 4) To communicate what information is necessary and the types of research that will provide the most comprehensive information for conducting risk assessments of nanomaterials in the future. 5) To conduct programs and educational activities which emphasize current developments and issues in nanotoxicology. 6) To relate the developments in nanotoxicology to the activities of the SOT to stimulate interest and growth in nanotoxicology as it relates to the general science of toxicology Society of Toxicology

29 Risk is function of both the hazard and the exposure Hazard identification Hazard characterisation Exposure assessment Dose-response Slide courtesy of Nigel Walker NIEHS/NTP

30 Definition of HAZARD Hazard the potential to cause harm; it is an intrinsic property of a material. Sulfuric acid, for example, is a hazardous material, by virtue of its chemistry, and nothing can change that potential, short of altering its chemistry to become something else. Understanding Risk Assessment of Nanotechnology by Trudy E. Bell

31 Definition of EXPOSURE Exposure a combination of the concentration of a substance in a medium multiplied by the duration of contact. For example, dilute sulfuric acid that splashes and is quickly washed off is a low-exposure dose that may only redden the skin; whereas concentrated sulfuric acid allowed to sit on the skin is a high exposure dose that is likely to cause serious burns. Understanding Risk Assessment of Nanotechnology by Trudy E. Bell

32 Definition of DOSE Dose the amount of a substance that enters a biological system and can be measured as a systemic dose; the total amount taken up by the biological system; or as the amount in a specific organ (e.g., skin, lung, liver, etc. the so-called target dose). Understanding Risk Assessment of Nanotechnology by Trudy E. Bell

33 Definition of RISK Risk the likelihood of harm occurring; it is a combination of a hazard with the probability of exposure and the magnitude and frequency of doses. Risks, unlike hazards, can be managed and minimized: a hazardous material poses low risk if the chances of exposure and the magnitude and frequency of the dose that might be received through that exposure are low. Understanding Risk Assessment of Nanotechnology by Trudy E. Bell

34 Slide courtesy of Nigel Walker NIEHS/NTP Risk is function of both the hazard and the exposure We can manage the risk by reducing Perceived risk can be the exposure (PPE). managed by educating the public. We can manage the risk by eliminating the exposure. Hazard identification Hazard characterisation We can manage the risk the hazard. risk Exposure by understanding assessment Dose-response

35 Nanomaterial Toxicity Screening Working Group Objective: : to develop the elements of a toxicity screening strategy for nanomaterials (This project was the outgrowth of another project that proposed strategies for short-term term toxicity testing of fibers) ILSI Research Foundation/Risk Science Institute

36 Nanomaterial Toxicity Screening Working Group Members Günter Oberdörster, rster, Chair, University of Rochester Kevin Ausman, Rice University, CBEN Janet Carter, Procter & Gamble Company Vincent Castranova, NIOSH/HELD Ken Donaldson, University of Edinburgh Julie Fitzpatrick, ILSI RF/RSI Barbara Karn, EPA & Woodrow Wilson International Center for Scholars Wolfgang Kreyling, GSF National Research Center of Environment & Health, Institute for Inhalation Biology David Lai, EPA/OPPT Andrew Maynard, Woodrow Wilson International Center for Scholars Nancy Monteiro-Riviere, North Carolina State University Stephen Olin, ILSI RF/RSI David Warheit, DuPont Haskell Laboratory Hong Yang, University of Rochester ILSI Research Foundation/Risk Science Institute

37 Nanomaterial Toxicity Screening Strategy Development Routes of Exposure Considered Oral Dermal Inhalation Injection ILSI Research Foundation/Risk Science Institute

38 Confirmed routes Potential routes Exposure Media Biokinetics of Nano-size Particles Air, Water, Clothes Drug Delivery Air Food, Water Deposition Injection Inhalation Ingestion Uptake Pathways Skin Respiratory tract nasal tracheobronchial alveolar GI tract Translocation and Distribution neurons Lymph CNS PNS neurons neurons Blood (platelets, monocytes, endothelial cells) Lymph Liver Bone Marrow Other sites Kidney Spleen (e.g. muscle, placenta) Heart Excretory Pathways Sweat/Exfoliation Urine Breast Milk Feces Used with permission from Environmental Health Perspectives, Oberdörster3, EHP 2005, 111:

39 Nanomaterial Toxicity Screening Working Group Report Physicochemical Characteristics In Vitro Testing Methods In Vivo Assays ILSI Research Foundation/Risk Science Institute

40 Physicochemical Characteristics Size Distribution Agglomeration State Shape Crystal Structure Chemical Composition Surface Area Surface Chemistry Surface Charge Porosity ILSI Research Foundation/Risk Science Institute

41 In Vitro Testing Methods Portal of Entry Toxicity Lung Skin Mucosal Membranes Target Organ Toxicity Endothelium Blood Spleen Liver Nervous System Heart Kidney ILSI Research Foundation/Risk Science Institute

42 Confirmed routes Potential routes Exposure Media Biokinetics of Nano-size Particles Air, Water, Clothes Drug Delivery Air Food, Water Deposition Injection Inhalation Ingestion Uptake Pathways Skin Respiratory tract nasal tracheobronchial alveolar GI tract Translocation and Distribution neurons Lymph CNS PNS neurons neurons Blood (platelets, monocytes, endothelial cells) Lymph Liver Bone Marrow Other sites Kidney Spleen (e.g. muscle, placenta) Heart Excretory Pathways Sweat/Exfoliation Urine Breast Milk Feces Used with permission from Environmental Health Perspectives, Oberdörster3, EHP 2005, 111:

43 In Vivo Assays Pulmonary (Tier 1 & 2) Oral (Tier 1) Dermal (Tier 1) Injection (Tier 1) ILSI Research Foundation/Risk Science Institute

44 Tier 1 Evaluation In Vivo Assays Markers of Inflammation Oxidant Stress Cell Proliferation Tier 2 Evaluation Deposition, Translocation, and Biopersistence Studies Effects of Multiple Exposures Reproductive Effects (e.g., OECD 422) Alternative Animal Models Mechanistic Studies (e.g., omic techniques) ILSI Research Foundation/Risk Science Institute

45 Principles for Characterizing the Potential Human Health Effects from Exposure To Nanomaterials: Elements of a Screening Strategy Particle and Fibre Toxicology 2005, 2:8 Online Open Access Journal Published by BioMed Central ILSI Research Foundation/Risk Science Institute

46 HESI Nanomaterials Project Committee Evaluating the Human Health Hazards Associated with Exposure to Nanoscale Materials: A Consortium Approach

47 HESI Nanomaterials Project Committee Overall Project Goals: Review the environmental, safety and health aspects of nanomaterials to determine current knowledge-base and research needs. Identify unresolved scientific issues, research needs, and data gaps that would facilitate the development of a comprehensive risk assessment for nanomaterials. Initial focus is to develop a better understanding of the fundamental behavior of nanomaterials.

48 HESI Nanomaterials Project Committee Specific Objectives: Evaluate the distribution and fate of nanomaterials in biological systems. Characterize human physiologic relevance of pulmonary toxicity hazards associated with nanomaterials.

49 HESI Nanomaterials Project Committee Consortium Approach: Evaluate fate of nanomaterials on basis of size ADE studies with nanospheres. Pulmonary toxicity studies. Comparison of relative toxicity associated with 3 routes of exposure in vivo. In vitro toxicity evaluations. Inflammation studies. Genotoxicity studies.

50 HESI Nanomaterials Project Committee Fate and Distribution Objectives: Model and method development. Assess impact of size on translocation from portal of entry. Assess whether route of exposure can impact assumed translocation. Generate basic information on kinetics of elimination. Attempt to generate mass-balance information on a model nanoparticle.

51 HESI Nanomaterials Project Committee Toxicity Studies: Endpoints: Bronchoalveolar Lavage (BAL) Tissue Morphology In Vivo Techniques Intratracheal Instillation Pharyngeal Aspiration Direct Pulmonary Exposure A549 Cell Studies: mrna Expression synthesis of MUC5AC Apoptosis DNA damage inflammatory cell signaling In Vitro Techniques Wistar Rat Carbon Black Titanium Dioxide Carbon Nanotubes Crystalline Silica

52 HESI Nanomaterials Project Committee In vitro Toxicity Studies: Human lung adenocarcinoma cells (A549) examined for sensitivity to nanomaterial-induced induced effect on mrna expression and synthesis of MUC5AC (e.g., predominant mucin expressed by goblet cells). Additionally, in these same cells the effects of nanomaterials on apoptosis, DNA damage and inflammatory cell signalling will be measured.

53 HESI Nanomaterials Project Committee 3M Corporation. Arkema,, Inc. BASF Corporation. Bayer AG. L Oreal Corporation The Dow Chemical Company. The Procter & Gamble Company. Duke University Med. Center East Carolina University National Institute of Environmental Health Sciences. National Institute of Occupational Safety and Health. US Consumer Product Safety Commission. US Environmental Protection Agency. US Food and Drug Administration.

54 Safe handling of nanotechnology. Nature 444(16): Maynard, A.D., Aitken,, R.J., Butz,, T., Colvin, V., Donaldson, K., Oberdorster,, G., Philbert,, M.A., Ryan, J., Seaton, A., Stone, V., Tinkle. S.S., Tran, L., Walker, N.J. and Warheit,, D.B. Five Grand Challenges: Develop instrumentation to measure nanoparticles in air and water. Evaluate the hazards of nanomaterials. Predict the toxicity of emerging nanomaterials with models. Assess the possible impact of nanotechnologies across their lifetime. Develop strategic programs to enable risk-focused research.

55 Summary Bottom Line Should the potential risks associated with nanomaterials cause us to panic? No Is there cause for concern/caution associated with the emerging use of engineered nanomaterials in today s s culture/environment? Yes Is there a quick answer to understanding the risks associated with nanotechnology? No

56 Summary Bottom Line Do we (e.g( e.g,, the scientific and regulatory communities) know what questions to ask? Yes Are the right people asking the (right) questions?? Yes Are we making progress? Yes

57 Final Words Thanks!! Any questions? We welcome your comments. We welcome your participation. Michael P. Holsapple, Ph.D,, ATS PH: (ext 151)