This talk will cover (for nano in food)

Transcription

1 TM US FDA Nano Guidance for Foods and ILSI RF Research Presented to Netherlands Food and Consumer Product Safety Authority Meeting on risk assessment of nanostructured materials: the case of silica 10 th October, 2013 This talk will cover (for nano in food) Background on the climate in the US and some stakeholder outreach work as US FDA guidance was being developed Overview of FDA policy and guidance releases FDA Position about science and guidance needs (2007) FDA Guidance to gather size data ( ) FDA Not a definition guidance on what triggers attention (2011) FDA Draft Guidance for Manufacturing Process Changes (including Emerging Technologies) (2012) What are the grey areas for predicting risk? Tiered approaches to work through the grey areas TM

2 Preponderance of hazard research in the nano literature International Council on Nanotechnology ( accessed August 6, 2013). As You Sow, April 2013 Report nanomaterials in many foods on supermarket shelves TM

3 Titanium In Common Foods Source: Arizona State University, Paul Westerhoff 2008 Wilson Center/Grocery Manufacturers Association /FDA what if case studies to identify regulatory and science needs Developed hypothetical food contact materials with nanoscale components (some are not so hypothetical any more) Then expert groups ran them through mock regulatory submission to FDA And through this asked: Whether regulations seemed to be asking the right questions Where the science and methods to answer the questions seemed to be lacking

4 The case studies Nano-sanitizer to wrap fresh produce or meat Antimicrobial nanospheres bound to the inner layer of packaging Two Versions: Antimicrobial nisin bound to particles Antimicrobial metal particle releases positive metal ions Packaging film that quantifies microbes Nano-biosensor based on ELISA (enzyme-liked imunoabsorbent assay) incorporated into food contact surface Two Versions Single-walled carbon nanotube Silica or alumina nanotubes Barrier additive to packaging Nanoclay additive to reduce water vapor, oxygen and carbon dioxide permeation The case studies found (my own interpretation) Regulations largely work, with pre-and post-market regulatory authority challenges for all uncertain risks, and some questions about understanding manufacturing changes and GRAS status Science issues regarding what to measure and whether there are valid methods for generating and interpreting exposure and hazard assessment data TM

5 2007 US FDA Task Force Report (not guidance) No size-based inherent hazard (so size definitions that trigger regulation are not warranted) Regulatory coverage no different for nanomaterials than other new materials Some guidance needed on: Data for evaluating size-related properties What is new for regulatory purposes during manufacture Basic science needed for when size affects biology, and how to measure it FDA Guidance to Gather Size Data Chemistry Guidance for: Food Contact Notifications (Dec 2007) Direct Food Additive Petitions (March 2009) Chemical and Technological Guidance for Color Additives for Food, Drugs, Cosmetics or Medical Devices (July 2009) Focus on reporting size and particle characteristics in cases where function related to size Objective: to set expectation that particle data should be generated when it matters to the identity or function of an additive TM

6 TM Ifthe particle size is important for the additive to achieve its intended technical effect, such that the additive is produced or processed using techniques or tools that manipulate the particle size and may contain altered particles that are formed as manufacturing by-products, data on the size (average and distribution), shape, surface area (average and distribution), surface charge (zeta potential), and morphology of the particles, as well as any other size-dependent properties (e.g., agglomeration, aggregation, dispersion) should be included, as appropriate. ncedocuments/foodingredientsandpackaging/ucm htm#intend 2011 Draft Guidance for Industry: Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology No bright line on size to define regulatory status Affirms 2007 task force statement A statement that size-effects will trigger FDA questions Not a definition Questions imply more testing, or new regulatory status Text that looks a lot like a definition Size up to 1 micron, intention, not natural TM

7 2012 Draft FDA Guidance: Assessingthe Effects of SignificantManufacturing Process Changes, including Emerging Technologies, on the Safety and Regulatory Status of Food Ingredients and Food Contact Substances, Including Food Ingredients that are Color Additives Focus on changes to identity and addition of impurities through manufacturing changes that add size-functionality Fingerprint the identity of the material, including particle size Toxicity testing must be validated for the material tested Implicit?: Validate for the material released from the food based on the manufacturing change, so that you do not have an unapproved additive. ngredientsadditivesgraspackaging/ucm htm And a line in the sand on GRAS that underscores the need to measure nano At this time, we are not aware of any food ingredients or FCS intentionally engineered 9 on the nanometer scale for which there are generally available safety data sufficient to serve as the foundation for a determination that the use of a food ingredient or FCS is GRAS. 9 As noted in the 2011 draft guidance, in considering applications of nanotechnology, we distinguish between products that have been engineered to contain nanoscale materials or involve the application of nanotechnology from those products that contain incidental or background levels of nanomaterials or those that contain materials that naturally occur in the nanoscale range. FDA recognizes that conventionally manufactured food substances can sometimes include particles with size distributions that extend into the nanometer range. This draft guidance is not intended to bring into question the regulatory status of such products to the extent that they may have already been determined to be GRAS or approved in response to a food additive petition, color additive petition, or food contact notification. However, as noted in the text, intentional alterations in particle size distribution on the nanometer scale can sometimes be significant manufacturing changes.

8 TM Technical effect examples in the 2012 emerging technology manufacturing process guidance Bioavailability Antimicrobial Humectant Flavoring Surface active agent Stabilizer and thickener Grey area: When do identity or purity significantly change when you are changing size distributions? TM

9 Impurity of size or shape or surface coating is a novel concept when they determine functional properties size size size 100% within range 50% within range 50% impurity? 10% within range 90% impurity? 11/13/ Focus on specification of contains nano from 2011 guidance At this time, when considering whether an FDA-regulated product contains nanomaterials or otherwise involves the application of nanotechnology, FDA will ask: Whether an engineered material or end product has at least one dimension in the nanoscale range (approximately 1 nm to 100 nm); or Whether an engineered material or end product exhibits properties or phenomena, including physical or chemical properties or biological effects, that are attributable to its dimension(s), even if these dimensions fall outside the nanoscale range, up to one micrometer. These considerations apply not only to new products, but also may apply when manufacturing changes alter the dimensions, properties, or effects of an FDA-regulated product or any of its components.

10 Standard wet chemistry is not excluded by the FDA specifications. Large food complexes with nano-substructure are not excluded. Biomolecules are not excluded. Spray dried ingredients and emulsions are not excluded. Is that creamer in your coffee a nanomaterial? It is difficult to say what is not excluded, so FDA will have make case by case decisions. And by the way many food components fit the nanoscale definition, except for the natural exclusion Material Food Product Size(nm) All polysaccharides Edible plant and muscle tissues, ~ milk, eggs, processed foods Glycogen Edible muscle tissue and liver 8 43 Starch granules internal concentric rings Edible plant tissues Starch granules amylopectin clusters Edible plant tissues 5 10 Unsaturated triglyceride Vegetable oils ~3 Cholesterol Animal lipids ~1.5 Myosin Edible muscle tissue diameter, 100 in length Collagen Edible muscle tissue 1.4- to 1.5-wide units Whey Milk 4 6 Enzymes Naturally existing or added 1 10 A, D, E, K, C, thiamin, riboflavin, Naturally existing or added <1 2 niacin, B6, B12, biotin Lycopene Tomatoes ~3 Beta-carotene Carrots, oranges, peaches, peppers ~3 Capsaicin, gingerol, tumerone Capsicum peppers, ginger, turmeric ~1 2 Casein micelle Raw milk

11 US FDA: At least one dimension in the nanoscale range EU: one or more external dimensions is in the size range I nm -l 00 nm. US FDA exhibits properties or phenomena, including physical or chemical properties or biological effects, that are attributable to its dimension(s) is it engineered nano to modify starch structure to reduce its glycemic index? AFM topography image of a pea starch granule showing the blocklet structure within the granule. Grey area: what is the toxic thing that we study in the added nanomaterial? 22

12 A typical nanomaterial can be described by a set of distributions Composition Size Aspect ratio %Coating Surface adherents Transformations will change the distributions that make up the nanomaterial mixture. neat source material in toxicity study in matrix use released from matrix in exposure medium 1

13 How do you keep track of the potent part? What causes the external dose of a given nanomaterial to be toxic? How do you track it across studies or foods? For example, for benzene, it s the benzene you add up across foods in a dietary exposure assessment. For a metal oxide nano-object it could be a functional assay, or uncoated surface area, or coated area, or rutile vs anatase crystal fraction, or size for a certain morphology, or something else. anatase rutile TiO 2 Dose extraction and extrapolation Consider a nanomaterial released to a food matrix from food packaging. If the material does change based on local conditions, what material do you test in toxicity assays? 1. Mono-dispersed material as it was added to the packaging? before packaging or food matrices effects on the nanomaterial? 2. Extract from the packaging under food conditions? before the food matrices? 3. Extract from food matrices? how do you do this in a biologically relevant way? How do you get enough of it? 4. The food itself, with the migrated nanomaterials? how do you get a high enough dose for extrapolation under our usual risk assessment approaches?

14 How do we build weight of evidence for a dynamic mixture? Material variation across studies in the open literature it s often true that no two studies look at the same mixture Vehicle, dispersion, and handling effects Unknown key toxicity we need to group studies for the entity that initiates the mode of action What is the point of reference around which we build WOE for a risk assessment? External dose black box problem How do we maintain consistent external dose metric across assays if we don t know what causes the effect? How do we compare assays using differing media Do matrix effects mean you can only compare same vehicle studies? How do you compare in vitro to in vivo? Do we have principles or hypotheses of common action?

15 So what will FDA do? They will do case by case as usual for new food additives and food contact substances and ask more questions (and may require more proof of validity of testing) where size affects function They have asked for nano data for all submissions and advise (require) specific evaluation of manufacturing change and GRAS determinations where size affects function And, I think, they will apply simplifying principles Simpler to rule out risk than to measure it Use decision trees to sharpen focus to the persistently nanoform materials Do full toxicity assessment only on those materials that need it Similar to what has been proposed by others

16 European Food Safety Authority 2011 Guidance on the risk assessment of the application of nanoscience and nanotechnologies in the food and feed chain Adequate characterisation of ENM is essential for establishing its identity and physico-chemical forms in food/feed products and under testing conditions. The physico-chemical parameters may change in various environments and the characterisation of ENM should ideally be determined in five stages, i.e. as manufactured (pristine state), as delivered for use in food/feed products, as present in the food/feed matrix, as used in toxicity testing, and as present in biological fluids and tissues. Pay attention to the changing form of the material EFSA Guidance Figure 1: Schematic outline for testing and risk assessment of ENM

17 EFSA Guidance Figure 2: Exposure scenarios Engineered Nanomaterial (ENM) ILSI Europe 2012 Approaches to the safety assessment of ENM in food Is the ENM sufficiently characterised regarding physicochemical properties? YES NO Appropriate characterization to be done NO Is ENM readily dissolved under gastric conditions? YES Insoluble / partly insoluble ENM Soluble ENM NO Is the release of components changed (either in time or location) as compared to non-nanoscale formulations? YES Tiered RA addressing potential specific hazards of the ENM Covered by existing RA and/or HOSU Re-evaluation of existing RA with attention on absorption Cockburn, Andrew, Roberta Bradford, Neil Buck, Anne Constable, Gareth Edwards, Bernd Haber, Paul Hepburn et al. "Approaches to the safety assessment of engineered nanomaterials (ENM) in food." Food and Chemical Toxicology 50, no. 6 (2012):

18 Tiered testing to reduce uncertainty for toxicity seem possible Predictive principles are emerging for characteristics of some nanoparticles Interactions of size and charge for crossing barriers (e.g., capillary, cellular, and absorption) Interactions of charge and size with toxicity and distribution/excretion Importance of surface over composition (if insoluble) Biological identity of particles considering adducts and protein corona General principles are just emerging for well-controlled studies of simple and uniform nanomaterials Nanoparticle Biocompatibility % Control Cytotoxicity (+) Cytotoxicity (Surface Reactivity) RES Recognition Low Dose (mg/ml) Zeta Potential 0 Renal Clearance Biliary Clearance? (EPR Effect) Solubility? ( ) 1 nm 220 nm Size (Rigid Core) High Source: Scott McNeil, US NCI/NCL

19 Hypothetical decision sequence for nanoparticle uptake assessment to prioritize data needs or aid product development Does the nanoparticulate nature of the additive persist to the point of ingestion? Is it soluble in gastric conditions in adult? In infant? Disease states? Decreasing relative proportion of materials in commerce? Design products preferably in this range 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? Increasing need to apply nanoparticle specific toxicity tests 37 Try to stay in the safe zone, and if not THEN figure out how to test the ones that we can t rule out For the persistent, absorbed nanoform materials, we seem to need methods to extract or model the material to which we are exposed in the final food Because we can t test it at the levels in food Or assay based approaches to assure applied dose similar to what is delivered in food Or use worst case assumptions based on pristine materials a hazard based approach Assuming that incorporation in food will rarely increase toxicity from the pristine state

20 We already do tiered data needs for food additives, so this is just about developing new rules. Current US FDA Toxicology Guidance Documents: Food Additives Concern Levels (CL) as Related to Human Exposure and Chemical Structure

21 Current US FDA Recommended Toxicological Testing Food Ingredients Toxicity Tests Low (I) Concern Level Intermediate (II) Genetic Toxicity Tests X X X Short-term toxicity tests (rodents) X X X Subchronic toxicity studies (rodents) X X Subchronic toxicity studies (non-rodents) X X High (III) One-year toxicity studies with non-rodents Chronic toxicityor Combined chronic toxicity/carcinogenicity (rodents) X X Carcinogenicity studies (rodents) X Reproduction studies X X Developmental toxicity studies X X Metabolism and Pharmacokinetic studies X X Human studies X Summary Risk assessment works for (many, most?) nanomaterials when structured as tiered decisions to rule out exposure or likelihood of unacceptable risk. The first tiers seem simple and will address the majority of nanoform materials in food now 1. Are the nanoparticles in the finished food? 2. Do they persist in gastric conditions? 3. Are they absorbed (need to define) or do they affect gut lining, or microflora 4. If yes to above, then initial screening tests for toxicity (needs work). 5. If screening does not confidently rule out risk, then Are you sure you need this Prove it is safe

22 Food Additive Standard methods to measure and predict fate of nanoparticles in food and the alimentary tract, so that we can agree which are the obviously benign oral exposures What is the issue being addressed? Nanopowder Dissolved constituent elements (no longer nano) Engineered nanomaterials (ENM) used/being developed for food, beverages, supplements to: -increase nutrition -increase food safety (packaging, shelf life) -change physical/chemical properties Many potential benefits, but advancement is inhibited by potential hazard debates and a lack of methods to measure whether and where for nanomaterials in foods. Methods to measure what nano characteristics affect absorption into the body would greatly clarify the debate of which ENM are potentially hazardous. 44

23 Participant Experts From All Over Note: ILSI Research Foundation is serving as the secretariat on this project. 45 NanoRelease Phased approach Phase 1 (2012) Assemble multi-stakeholder risk manager level Steering Committee, define the overall charge and focus, charge and invite expert groups to collect and evaluate the science supporting the methods needs Phase 2 (2012-present) Assemble expert groups (6) to write white papers and summary issues so that the methods development can focus on the feasible and useful Steering Committee uses the papers to define charge for and invite methods experts to start Phase 3 Phase (July /5) Methods experts write a methods development workplan. Project recruits in-kind laboratory methods development Pilot phase to flesh out the protocol(s) Interlaboratory phase to make the methods rugged, reliable, trusted 46

24 Benefits of the NanoRelease Platform Continuous technical dialogue internationally across key stakeholder expertsabout safe development of nanotech Public-private partnership allows balance of views from academia, industry, government, public interest organizations Secretariat (ILSI Research Foundation) facilitates collaboration in a trusted environment 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 48

25 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 The Coca Cola Company Substantial in-kind support is provided by the Nanotechnology Industries Association Health Canada 49 Thank you Richard Canady, PhD DABT Director, RSIA rcanady@ilsi.org and Libby Tsytsikova ltsytsikova@ilsi.org 50