Addressing Nano in Your Food A model for multistakeholder science

1. Addressing Nano in Your Food A model for multistakeholder science TM

2. Overview I) Challenges to developing public health science for food safety II) A project model that can help address these challenges III) Case example: NanoRelease Food Additive project IV) State of the Science on nano in food (Dr. Andrew Bartholomaeus) V) Conclusions & specific next steps, open discussion (feedback on this approach)

3. Challenges in public health science regarding food safety 1) Diminishing public and private funds 2) More disruptive “politicization” of the science • Polarization – Us vs Them • Immediate broad access to information means that more of the uncertain hazard information makes it into general awareness

4. 3) More technical complexity • Explosion of new data types • For assessing biological effect • For monitoring • Technologies in food supply • Nanotech, biotech • Personalized nutrition, functional foods • Information technology • Sheer data volume and need for new decision approaches • Data integration (in silico, computational tox)

5. 4) Failure of the top down or single source approaches to evaluation Bisphenol-A example of how not to develop public policy from science • Health authorities evaluated risks and made announcements • Some members of the public agreed with health authorities, some did not • Press attention to the debate affected perceptions • Decisions were made in public and in private arenas • In the end it seems all sides are asking whether the science was used appropriately and whether public health is improved

6. How can we address these challenges and move forward effectively? We need to publish or produce datain ways that are good science and do not have • Single stakeholder bias • Labels as being from “one side” of the debate The proposed approach is to • Assemble expert stakeholders from opposing views • Build trust between them & establish continuous dialogue • Move forward toward a goal

7. Structure & Flow of project development Step 1: Intellectually invest experts from opposing perspectives in the outcome • Formulate the issue in a way that addresses public health from multiple perspectives • Gather senior experts to form the initial charge for the project • (multi-stakeholder, multinational) • Make it clear that they control the project outcome, all proceedings are public, and that the outcomes (publications, methods) will be public or the intellectual property of the experts of the project. • The core group invites more participants through their networks, becomes the Steering Committee with co-chairs rotating across stakeholder groups and develops the plan of work. • ILSI RF becomes the Secretariat supporting the Steering Committee. The core group is made up of risk managers, not technical experts.

8. Step 2: Build a transparent project run by the experts Secretariat raises funds to support the project, convenes meetings, takes notes of meetings, records project activities and outcomes on a project web site, supports workshops, aids in development of documents as needed. • Steering Committee Invites Experts to Task Groups • Secretariat coordinates Task Groups to address their charges • Steering Committee identifies expert subtopics to be evaluated by Task Groups • (to inform selection of a solution approach) • Steering Committee (risk managers) use the information of the Task Groups to inform “state of the science” or other evaluations regarding the issue. • Task groups independently publish white papers or develop outputs (e.g., methods) Step 3: Make the outputs independent of the funders Task Group experts are invested in the outcome through publications they produce. State of the Science or other evaluations are also independent publications by authors of the group.

9. Incentives for participants • Project participants own and run the project • Leveraged funding • No single entity funds more than 10% of the project • Publications • Extended science policy discussions between stakeholders • Builds trust • Time to talk through the issues (in a trusted forum) • Extended access to key experts in the field • Access to developing science • Publications that fill in gaps in understanding

10. Public-Private Partnerships It’s more than the money ~20 experts on Steering Committee ~50 on 4Task Groups Lower bound estimate of time based on meeting minutes NanoRelease Consumer Products Using a rough estimate of $120/hr, the total value is about $1M

11. Example of agreement across stakeholders There is no good information about what products use nanomaterials/nanotechnology We need to know what is in consumer hands so that we can design the best methods to assure safety The task group experts identified the most used materials based on their own experiences and from purchased market surveys Because we have the experts who are making the materials in industry and who are reviewing the product authorizations at government, we have the best unpublished current information

12. Example of agreement across stakeholders The steering committee is using the project to develop methods to measure what is coming off of real products We need to know what is really coming off of consumer products and test it in toxicity studies Existing hazard data is generally not related to consumer exposure

13. Example of agreement across stakeholders We need to • focus attention on where there is higher release and • have trusted methods for proving the lack of release elsewhere Most of the uses of nanomaterials are safe (because very little is released) • Project experts submitted a “life cycle release scenarios” evaluation that identifies where releases are likely and where proving lack of release is needed • The Steering Committee is using this knowledge to develop the best methods to measure what is coming off of real products

14. More detail on a case example…NanoRelease Food Additiveproject • FOOD SAFETY TOPIC: Nanotechnology in food • CHALLENGES (as stated previously): • 1) Diminishing public and private funds • 2) More disruptive “politicization” of the science • 3) More technical complexity • 4) Failure of the top down or single source approaches to evaluation

15. State of the science on nano in foodDr. Andrew Bartholomaeus

16. the oral pharmacokinetics of particles Dr Andrew Bartholomaeus Professor (Adj) Therapeutic Research Unit, School of Medicine, University of Queensland School of Pharmacy, University of Canberra BartCrofts Scientific Services If you increase the magnification another million times you can see the safety regulations.

17. First we need to understand What are we talking about • Current definitions do not separate new technology from old • Provide no regulatory or research target • Obscure pre-existing knowledge • Largely unhelpful

18. What makes nanoparticles different? • They are small • They might go where larger particles cannot • Protein complexes can be of equivalent size • Biological interactions bridge the chemical/physical boundary • Surface area: volume ratio is large • Surface reactivity is high • Solubility increases • Curvature is high • Influences intermolecular interactions • Potential for engineered novelty • Most of the above really only apply at < 20 or 30 nm and significant around 5 nm

19. HOW NOVEL ARE THEYWhat we can learn from past science Forró L and Schönenberger C. Carbon nanotubes, materials for the future. Europhysics News 2001;32(3).

20. Old wine in a new bottle ? • Those who cannot remember the past are condemned to repeat it1. (1905) • (Colloids)…..this fascinating twilight zone between physics and chemistry2. (1919) • Much of what is presented as new technology is in fact an extension of long standing knowledge and practices, albeit considerably more sophisticated. • George Santayana, Life of Reason, Reason in Common Sense, Scribner's, 1905, page 284 • Jerome Alexander, Colloid Chemistry, D.Van Nostrand Co, NY, 1919

21. “…extending the sphere of interest in this fascinating world between physics and chemistry.”

22. Micelles and Emulsions1 Micelles are dynamic, self assembling nano-structures • The Pharmacists Engler and Dieckhoff discovered they could produce clear solutions of cresol in concentrated aqueous solutions of soaps in in 1898. • .. the small molecules in dilute solutions tend to associate into aggregates (micelles) of equivalent diameters in the 30 to 100 Å (3-10 nm) range….they are called association colloids. Other names are surfactants or surface active agents. 1Remington’s Pharmaceutical Sciences. 15th Ed, Mack Publishing Company, Easton, Pennsylvania. 1975

23. Many food components fit the nanoscale definition

24. Food related applications of nanotechnology

25. Food = Matter Food naturally & traditionally contains particles in the nanometre scale Parrots regularly eat seeds and unripe fruits whose content of alkaloids and other toxins renders them bitter and even lethal to humans and other animals. Because many of these chemicals are positively charged in the acidic conditions found in the stomach, they bind to clay minerals bearing negatively charged cation-exchange sites...“(Jared Diamond)

26. Uses of nanoparticles in food • Traditional • Silicon dioxide (E551) • Homogenised milk (200 to 2000 nm) • New or proposed uses • Nanoencapuslated nutraceuticals: vitamin E, CoQ etc • Nanoencapsulated preservatives • Nanoliposomes in cheese manufacture • Nanoclusters to enhance flavour of a chocolate slimming drink • Phytosterols in canola oil

27. Nanostructures in food Electron micrographs of human breast milk showing casein micelles following centrifugation. Bar = 1 µm in B and 0.2µm in C. [1] Fat globules in ice cream. (A) entire globule with coating of casein subunits, (B) broken globule with collapsed coating of casein subunits, (C) crater left behind by a fat globule, showing casein subunits aligned around periphery. [2] Extruded ice cream [2] 1From: Keenan & Patton. The Structure of milk: Implications for sampling and storage. In, Handbook of milk composition. R.G. Jensen ed. Academic Press. 1995 2. K.G. Berger. Ice Cream. In Food Emulsions. Stig Freiberg ed. Marcel Decker, NY. 1976, 141-210

28. Aerosil – fumed silica dioxide, used in various food, cosmetics, paints and pharmaceutical applications for over half a century Technical Bulletin, Fine Particles, Basic Characteristics of AEROSIL® Fumed Silica Number 11 https://www.aerosil.com/www2/uploads_all/text/SR_11_AE_us_Basic_Characteristics_of_AEROSIL_2006-04.pdf

29. Key Science IssuesPharmacokinetics

30. Pharmacokinetics • Key potential novelty of nanomaterials • Potential for transitional behaviour between particles and chemicals • Size alone is not a sufficient metric to predict pharmacokinetics

31. Absorption of Particles – Is it novel ? • Direct “persorption” of µm size particulates (15-75 µm optimum) across the GI tract wall was first observed in 18441, but some scepticism remains • Particles of starch, charcoal, sulphur, rabbit hair, silica, etc were variously studied in rabbits, dogs or frogs and found to be taken up into blood, bile and urine. • Transport from site of persorbed particles is via chyle or portal blood. • Absorption pathways for nanoparticles may differ to that of microparticles but their absorption is not novel per se. • Volkheimer, G., (2001) The phenomenon of persorption: persorption, dissemination, and elimination of microparticles. In: Old Herborn University Seminar Monograph. 14. Intestinal Translocation. ISBN 3-923022-25-5 • Volkheimer, G (1974) Passage of particles through the wall of the gastrointestinal tract. Environmental Health Perspectives. Vol 9, 215-225

32. Absorption of nano and micro particles is Normal

33. Particulate Persorption as a function of size Florence, T. (1997) The oral absorption of micro and nanomaterials: Neither exceptional nor unusual. Pharmaceutical Research, Vol 14, No 3, 259-266

34. Size dependent routes of absorption • Persorption • Very large particles (5-75 microns) – some contention here • Quantitatively small proportion but numerically significant • Uptake by M cells of the Peyer’s patches • Direct phagocytic immune sampling of gut contents • Favours particles around 1µm • Uptake of particles of smaller or larger dimensions appears less specific • Transcytosis through enterocytes • Generally only significant for nanoparticles with specific ligands promoting receptor mediated endocytosis • Absorption of 500 nm polystyrene beads in rats increased 50 fold by coating with tomato lectin • Paracellular transport • Paracellular pores < 1% of luminal surface • Pore size approx 1 nm in size

35. Uptake 10 into Lymphatic Sysem not Hepatic Portal Vein • Optimum size for lymphatic transport 10-100 nm (Swartz in Advanced Drug Delivery Reviews 50 (2001) 3–20) • Molecules that are smaller than 10 nm are preferentially reabsorbed into the blood capillaries

36. Effect of size and shape on endocytosis Intracellular uptake by HeLa cells, as measured using ICP-AES (inductively coupled plasma atomic emission spectroscopy) Chithrani, B.D. and Chan, W.C. (2007) Nano.Lett 7(6):1542-1550.

37. Tissue distribution Tissue distribution of 20 and 80 nm pegylated gold nanoparticles in nude mice with human squamous carcinoma A431 SC (3/group) 48 h post IV administration Ogawara, K., Furumoto, K., Takakura, Y., Hashida, M., Higaki, K. and Kimura, T. (2001) J Control Release 77(3):191-198. Zhang, G., Yang, Z., Lu, W., Zhang, R., Huang, Q., Tian, M., Li, L., Liang, D. and Li, C. (2009) Biomaterials 30(10):1928-1936.

39. Thank you ?

40. NanoRelease Food Additive project Driving issue: Disagreement on what is nano in foods and whether we are addressing risks Focus: What is the state of the science on methods to measure the oral uptake of nanomaterials? Goal: Establish a widely-accepted set of methods for measuring oral uptake of nanomaterials

41. Early 2012: Steering Committee • Clarified scope, developed task group charges, recruited experts. • Created extensive list/database of relevant studies and projects (80+ references gathered) • Identified nanomaterial characteristics of interest through extensive deliberation and expert input

42. Task Group 1: MATERIAL CHARACTERISTICS What do we need to know about the nanomaterials and the food matrices to predict absorption as particles into the body? Task Group 2: ALIMENTARY CANAL ENVIRONMENT What do we need to know about alimentary tract conditions to understand whether and where a nanomaterial will be absorbed into the body? Task Group 3: ALIMENTARY CANAL MODELS What kinds of models are useful in creating the conditions to measure and understand nanomaterial uptake by the body? Task Group 4: MEASUREMENT METHODS What methods can be used to measure characteristics of materials to understand and predict nanomaterial uptake by the body? Task Group 5: RISK MANAGEMENT CONTEXT Where in the decision process do we most need agreement to such measurement methods?

43. NanoRelease Food Additive Sponsors • The Pew Charitable Trusts • US Food and Drug Administration • ILSI North America, Food and Chemical Safety Committee • Illinois Institute of Technology’s Institute for Food Safety and Health • Health Canada • The Coca Cola Company • Substantial in-kind support is provided by the Nanotechnology Industries Association

44. Participants & Supporting Organizations ILSI branches are participating actively (invited, consulted, included)

45. Regulators dilemma: a) we don’t want to miss anything b) we don’t want to add new regulation to innocuous materials Unintended Nanomaterials Are we ready to re-regulate all the materials that will be roped in? Materials in commerce Targeted Nanomaterials Regulatory definition

46. Are there simple ways of reducing the infinite class of “between 1 and 100 nm” to the risks we are concerned about for oral exposure (through foods)? Proposal: A good start to getting our arms around risks is to see if we can identify the nanomaterials that are likely to be absorbed as particles into the body.

47. Copied from ILSI Europe guideline

48. Hypothetical approach for food nanoparticle evaluation (to prioritize data needs or aid product development) Design products preferably in this range Is it soluble in gastric conditions in adult? In infant? Disease states? Decreasing relative proportion of materials in commerce? Increasing need to apply nanoparticle specific toxicity tests If insoluble, does it aggregate/bind irreversibly to particles greater then 10 micron? Are particles found in tract lining cells in adult? Age/disease variation? Do particles pass to systemic circulation in adult? Age/disease variation?

49. Widely agreed to, robust methods allow sustainable product development and transparent evaluations As a product developer • Can I make it dissolve to non-toxic materials • If no, then can I make it agglomerate or bind irreversibly to particles that pass without absorption? • If no, then can I use a material that results in cell uptake below detection? As a concerned stakeholder • Using a standard test, does the material dissolve? • Is uptake undetectable using standard tests?

50. Outcomes • Trusted dialogue of what is needed to inform safety decisions • Trusted, robust methods that all can use to develop comparable data • Framework for applying methods that • Clarifies risk management and data development decisions • Enables safe product development