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Safety and Efficacy of Nanomaterials in Food Products

This chapter summarizes the presentations and discussion that took place during the second session of the workshop. The first presenter, Martin Philbert of the University of Michigan, argued that scientists do not fully understand all of the safety issues associated with nanotechnology. He emphasized that in addition to thinking about the nanosized materials themselves, it is important to consider all of the “things that come along with the nanotechnology.” As examples, he pointed to the biocompatible surfactants often added to nanoparticles as a way to prevent clumping and the metals that are sometimes used during the synthesis of carbon nanotubes: both of these added substances raise potential toxicity issues. It is also important to consider how nanomaterials behave not just in the context of the food matrix (which Aguilera had previously addressed) but also in the context of the biological size scale (i.e., inside the human body). After commenting on some of what is already known about the toxicity of nanomaterials, Philbert briefly described some recent toxicity studies and then identified several key safety issues that remain unresolved.

The second presenter, Laura Tarantino of the U.S. Food and Drug Administration (FDA), provided an overview of the range of FDA authorities over food products and argued that nanotechnology can be viewed as a special case of what the FDA has been doing all along with food. Essentially, the burden of proof is on manufacturers to show that any changes they have made do not affect safety. The challenge is determining what types of testing and data are necessary for determining this. FDA has yet to issue formal guidance for nanotechnology in food, and Tarantino encouraged sponsors who are considering developing nanomaterials-based products to engage in early and frequent consultation with the agency. Not only would early consultation benefit manu-



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3 Safety and Efficacy of Nanomaterials in Food Products This chapter summarizes the presentations and discussion that took place during the second session of the workshop. The first presenter, Martin Philbert of the University of Michigan, argued that scientists do not fully understand all of the safety issues associated with nano- technology. He emphasized that in addition to thinking about the nanosized materials themselves, it is important to consider all of the “things that come along with the nanotechnology.” As examples, he pointed to the biocompatible surfactants often added to nanoparticles as a way to prevent clumping and the metals that are sometimes used during the synthesis of carbon nanotubes: both of these added substances raise potential toxicity issues. It is also important to consider how nanomaterials behave not just in the context of the food matrix (which Aguilera had previously addressed) but also in the context of the biological size scale (i.e., inside the human body). After commenting on some of what is already known about the toxicity of nanomaterials, Philbert briefly described some recent toxicity studies and then identified several key safety issues that remain unresolved. The second presenter, Laura Tarantino of the U.S. Food and Drug Administration (FDA), provided an overview of the range of FDA au- thorities over food products and argued that nanotechnology can be viewed as a special case of what the FDA has been doing all along with food. Essentially, the burden of proof is on manufacturers to show that any changes they have made do not affect safety. The challenge is de- termining what types of testing and data are necessary for determining this. FDA has yet to issue formal guidance for nanotechnology in food, and Tarantino encouraged sponsors who are considering developing nanomaterials-based products to engage in early and frequent consulta- tion with the agency. Not only would early consultation benefit manu- 55

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56 NANOTECHNOLOGY IN FOOD PRODUCTS facturers, by providing them with an indication of what types of testing and data would be required for approval, it would also provide the FDA with information that could be helpful as it develops the necessary guidance. The third and final speaker of this session, Fred Degnan of King & Spaulding, broached some of the same issues that Tarantino did, but as Degnan put it, “from a practicing lawyer’s perspective.” He agreed with Tarantino that the FDA’s statutory authorities provide the agency with the necessary tools for evaluating and regulating the safety of nanomate- rials with novel properties and that the FDA’s existing procedures and systems are adequate to evaluate and regulate nanotechnology in food. In fact, the Food Additive Amendment (FAA) of 1958, which was enacted in response to a post-WWII public health scenario created by the sudden availability of thousands of new synthetic chemicals, was designed to address the very same types of safety issues presented by the use in food of nanomaterials with novel properties. However, he argued that the basis of good regulation is in written guidance, not just “chatting” (to borrow Tarantino’s expression). Any type of written guidance, even if preliminary, would be of enormous benefit, not just for improving indus- try understanding but also for ensuring public confidence that FDA is engaged and focused on nanotechnology issues. This is particularly true of nanomaterials introduced into food products that have previously been exempt from premarket approval because they are Generally Recognized as Safe (GRAS). Again, there was an open discussion period at the end of the session. Most of the questions pertained to issues around toxicology and whether there are any established criteria for how to proceed; how to encourage early industry consultations with the FDA; whether there is an approxi- mate timeline for when the FDA will be providing written guidance per- taining to nanomaterials with novel properties in food products; and under what, if any, circumstances a food designed to deliver nutrients can and should be considered a drug for the purposes of regulation.

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SAFETY AND EFFICACY OF NANOMATERIALS IN FOOD PRODUCTS 57 A BIOLOGICAL PERSPECTIVE ON NANOSTRUCTURES IN FOODS 1 Presenter: Martin A. Philbert 2 Philbert began by remarking: “We are in the realm right now of almost infinite possibilities and very few probabilities.” While it is easy to see in the laboratory or “boutique” commercial setting a variety of interesting, novel nano-structures with all sorts of desirable properties, turning nanotechnology into a “useful iteration that can be safely deployed into a human body is a very different proposition.” There are a wide range of safety issues that need to be considered. Importantly, in addition to thinking about the toxicity of the nanomaterial itself, he said, “We need to pay very close attention to those things that we add in order to deploy the nanotechnology appropriately. And in fact, the nanotech- nology itself may be a bit of a misdirect in that really what we’re looking at is toxicity of things that come along with the nanotechnology.” For example, consider that one of the fundamental properties of nanoparticles is the inverse relationship between particle size and the number of molecules expressed on the surface. As the diameter of a nanoparticle decreases the surface area increases; when particle diameter reaches the nanoscale level (< 100 nm) the ratio of surface molecules expressed increases exponentially. Below 100 nm, forces that are virtu- ally negligible in the bulk scale begin to predominate (e.g., hydrogen bonding, van der Walls forces, and other interactions that tend to drive particles together). Philbert described the results of a study published in Science (Nel et al., 2006) showing more generally how dose metrics be- come more complex as size decreases (i.e., this is true not just of nanoparticles but all types of nanomaterials). 3 For example, when carbon nanotubes are taken out of pristine deionized water and placed in solu- tion, they tend to agglomerate very quickly because of the forces that predominate at these smaller sizes. Biocompatible surfactants can be added as a way to prevent agglomeration, but they present their own set of challenges. 1 This section is a paraphrased summary of Martin Philbert’s presentation. 2 Martin A. Philbert, PhD, is Professor of Environmental Sciences and Associate Dean for Research at University of Michigan’s School of Public Health. 3 A Nel, T Xia, L Mädler, and N Li. 2006. Toxic potential of materials at the nanolevel. Science 311:622-627.

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58 NANOTECHNOLOGY IN FOOD PRODUCTS The addition of biocompatible surfactants is an example of why close attention needs to be directed not just to the toxicity of the nanoma- terial itself (e.g., the carbon nanotube) but also to “those things that we add in order to deploy the nanotechnology appropriately.” Another example, Philbert said, is the use of metals such as indium, vanadium, and sometimes technetium during the synthesis of carbon nanotubes and the consequent, unintended delivery of a very reactive metal during the delivery of the therapeutic to a biological setting. Also in addition to considering the toxicity of all of the various added substances required to deploy a nanotechnology application ap- propriately, one must consider what happens to the nanomaterial in the biological context. Philbert pointed to some very interesting studies com- ing out of Dublin 4 that show how durable carbonaceous materials, when introduced into a high protein environment such as the inside of a cell, can cause abnormal protein fibrillation. (Fibrillation is the formation of fibrils; amyloid protein fibrillation is a type of aggregation phenomena that has been linked to many human diseases.) This may be of some con- sequence in individuals who are either genetically predisposed to or already have the equivalent of familial amyloidosis (a protein-misfolding disease); the nanomaterial may act as a seed around which the amyloid proteins aggregate. Nanomaterials Are Here: Factual and Fanciful From C60 buckminsterfullerenes (spherical structures composed of carbon atoms) to dendrimers (structure with repeatedly branching mole- cules), nanomaterials are here, and they are being used in all sorts of “sublime” but also controversial ways. For example, novel metals and metal oxides are being encapsulated for the enhancement of color and the imparting of beautiful shimmering effects on the surfaces of cars, air- crafts, etc. As another example, nanosized titanium dioxides and zinc oxides are being incorporated into sunscreens, allowing people to stay in the sun 60 times longer than they can with sunscreens with chemical additives, preventing burns and decreasing the likelihood of developing basal cell carcinoma down the line. Philbert noted that the use of these sunscreens raises questions about potential adverse health effects associ- 4 E.g., S Linse, C Cabaleiro-Lago, W-F Xue, I Lynch, S Lindman, E Thulin, SE Radford, and KA Dawson. 2007. Nucleation of protein fibrillation by nanoparticles. Proceedings of the National Academy of Sciences 104:8691-8696.

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SAFETY AND EFFICACY OF NANOMATERIALS IN FOOD PRODUCTS 59 ated with entry of the nanomaterials into the human body. For the home, you can now buy nano-based windows and wood floors. And finally, in health care, nanotechnology is being used to develop targeted delivery of therapeutics; Philbert pointed to the work of Donald Tomalia 5 as one example of an application; targeting therapeutics to cancer cells. One needs to be very careful, Philbert said, about the claims being made about nanotechnology, as these claims very quickly go “from the sublime to the ridiculous.” As just one example, there are “plans afoot” to add a nano-structured robot to the back of a spermatozoon, raising questions about the ethical implication of “subverting normal biological processes and achieving something that nature never intended to occur.” Moreover, not all that claims to be nanotechnology is truly “nano.” There are now more than 800 self-identified nanotechnology products on the market. “Self-identified” is the key word. In fact, it is not really clear how many products on the market actually contain nanomaterials, Philbert said. They range from nanosilver-containing socks that people can wear for seven days without any appreciable odor to stain-resistant pants and ties. But then there are things like the iPod nano, a great exam- ple of a “nano” product that has nothing to do with “nano” except per- haps for the micro-circuitry (which Philbert said is irrelevant from a consumer perspective since consumers are never exposed to it). Of those products that are coming on the market, many contain Nano-Ag0 (“Nano-Silver”) and other nanomaterials designed to come into contact with food. The life cycle of these composite materials is unknown, for example whether repeated dishwashing will “re-liberate” the nanomaterial despite the fact that there are physical forces that pull against that (i.e., once the material is embedded in a resin, it requires a great deal of energy to liberate the nanoparticle as a nanomaterial). Evaluating the Safety of Nanomaterials Philbert differentiated between risk and the perception of risk. He reminded the audience that risk is a product of hazard times exposure, which means that very few people are likely to be exposed to many of these products (especially because these materials are expensive). He showed an image of a person titrating an aerosolized nanomaterial and commented that while the worker is potentially exposed most consumers 5 Tomalia is the Scientific Director of the National Dendrimer and Nanotechnology Center, Central Michigan University, Mt. Pleasant, MI.

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60 NANOTECHNOLOGY IN FOOD PRODUCTS of the product containing this particular nanomaterial aren’t exposed to the actual nanomaterial. Rather, the risk for them is the greater force of impact resulting from a collision with a five-ton truck with nanoengi- neered high-tensile strength bumpers. “Where here is the greater risk?” Philbert asked. The potential health risks extend beyond exposure to the nanomaterial itself and include exposure to the final engineered products as well. He said, “I urge all of us to think more broadly about the impli- cation of the inclusion into materials, not just the hazard associated with limited exposure to material.” Current Knowledge of Nanoscale Material Toxicity Knowledge about physical properties of other materials can be used to predict how nanoparticles will behave and whether they will be toxic in the human body. For example, some formulations of long and thin nanotubes would probably behave like asbestos, depending on the bio- logical and physical context, since both materials have high aspect (length:width) ratios. Other properties with known toxicities include bio- persistence, the presence of reactive surfaces or points (i.e., areas capable of producing reactive oxygen species), certain compositions, and solubil- ity. For example, manganese in welding fume produces an aerosol of particles, most of which are under 100 nm in diameter, and it is well known that many welders develop manganism as a result of this expo- sure. (Manganism is similar to Parkinson disease, with various part’s of the brain that control motor movement degenerating.) As another exam- ple, the cadmium, selenium, and arsenic in quantum dots are soluble at physiological pH; so while a quantum dot may have great functionality, it also serves as a delivery device for super-physiological concentrations of cadmium. While coating some of these potentially toxic materials with biocompatible substances (with dextran, titanium oxide, zinc oxide, or polyethylene glycol) can significantly reduce toxicity, it does not obviate all of the toxicity. Size Is Not Everything Philbert emphasized, “Size is not everything.” There is a tendency to think that all brand new nanomaterials are “bad,” but there are other fac- tors besides size to consider before passing judgment. He described un- published data showing that injecting even a ridiculously high dose of nanomaterial into the tail vein of a rat over the course of an hour, say 500

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SAFETY AND EFFICACY OF NANOMATERIALS IN FOOD PRODUCTS 61 mg per kg, which he likened to injecting “cottage cheese,” has no patho- logical consequences (if the material can be injected without inducing any hydrodynamic changes). However, if the same nanomaterial carrier is used to deliver iron into a different biological context, namely the re- nal cortex and liver, the result is cortical renal necrosis and petechial hemorrhage (a subcutaneous hemorrhage occurring in minute spots) in the liver. So again, size is not the only factor to consider when evaluating safety. Moreover, there is considerable variation in size among nanoparti- cles even in a single system. An carbon nanotube (CN) aerosolized, for example, contains particles ranging in size from smaller than 0.01 µm to greater than 1 µm in diameter. When the aerosol is agitated, the propor- tion of particles smaller than 100 nm increases drastically. Toxicity Studies Philbert described the results of a toxicity study that involved expos- ing mice to a variety of concentrations of aerosolized CNs, demonstrat- ing that CNs can cause inflammatory disease and destruction in the lungs with widespread formation of granulomas. 6 Based on data from studies like this, it is well known now that a variety of nanomaterials interact with the immune system to produce effects ranging from mild stimula- tion of the immune system to severe granulomatous change in, for in- stance, the lung. It is important, however, to make sure that these experiments are done properly and that the properties of the nanomaterial do not, as Philbert said, “defeat the experimental design.” Philbert showed a light micrograph image of lung tissue from a rat exposed to 5 mg/kg of single- walled carbon nanotube (SWCNT). After only a few hours of exposure, the rats in this experiment started dying but not because of pulmonary toxicity; rather, they suffocated because their airways had been mechanically blocked by the SWCNT instillate. So in that case, the death and destruction had “nothing to do with nano.” In fact, if you disperse the SWCNT instillate appropriately, rather than suffocation, you see a progressive granulomatous disease. When “assigning blame in the context of toxicology,” Philbert said, you also have to be very careful about which particle, or rather which 6 The image and graph were Figure 1 in C-W Lam, JT James, R McCluskey, and RL Hunter. 2004. Pulmonary toxicity of single-wall carbon nanotubes in mice 7 and 90 days after intratracheal instillation. Toxicological Sciences 77:126-134.

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62 NANOTECHNOLOGY IN FOOD PRODUCTS particle shape, is the culprit. Even a single nanotube can have multiple morphologies. 7 Is the damage being caused by the smaller nanotubes, the larger ones, or multimers of differently shaped nanotubes? Most com- mercial preparations are mixtures of morphologies, with the goal of increasing tensile strength for less cost, so very rarely are pure samples being prepared in bulk. Despite the lack of clarity around what exactly is causing the dam- age, it appears that some organs, namely the liver, spleen, and lymph nodes, tend to accumulate nanomaterial much more quickly than other organs do. One could inadvertently concentrate a nanomaterial in these organs while targeting other tissues in the body. The liver, for instance, contains Kupffer cells (a specialized type of macrophage located in the liver and forms part of the reticuloendothelial system), which line the sinusoidal wall and are responsible for removing toxins from the blood entering the liver from the gut mesentery. The Kupffer cells normally pick up small viruses and infectious particles, which are in the nano range (i.e., less than 100 nm), and so they presumably pick up other nano-sized substances as well. Philbert mentioned a 2006 study pub- lished in the Proceedings of the National Academy of Science (PNAS) showing that no immediate adverse health effects were found after inject- ing individualized CNs directly into the bloodstream of rabbits. 8 The nanotubes circulated in the blood for more than an hour before being re- moved by the liver. Philbert argued that having “unmodified CNs cleared by the liver” is not necessarily a good thing; while “it is good pharma- cokinetically and maybe even toxicokinetically,” having these long-lived materials in the liver could be harmful. Nanomaterials and the Biological Size Scale Another important feature of nanomaterials with respect to safety is that they fall within the biological size scale. Indeed, this is why they have so many potential applications—nanomaterials can interact with biological components with very high affinity. For example, you can 7 MS Arnold, AA Green, JF Hulvat, SI Stupp, and MC Hersam. 2006. Sorting carbon nanotubes by electronic structure using density differentiation. Nature Nanotechnology 1:60-65. 8 P Cherukuri, CJ Gannon, TK Leeuw, HK Schmidt, RE Smalley, SA Curley, and RB Weisman. 2006. Mammalian pharmacokinetics of carbon nanotubes using intrinsic near- infrared fluorescence. Proceedings of the National Academy of Sciences 103:18882- 18886.

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SAFETY AND EFFICACY OF NANOMATERIALS IN FOOD PRODUCTS 63 now purchase kits for CN-based methods for isolating nucleic acids: the method works because a nucleic acid phospholipid wraps around a car- bon nanotube so readily. 9 But that same affinity can be damaging. For example, work from Philbert’s lab suggests that an array of proteins, in- cluding apolipoprotein A, can readily stick to the surfaces of the coated nanoparticles (e.g., nanoparticles coated with wheat germ agglutinin) that are being developed as a novel mode of drug delivery. Apolipoprotein A is involved with the transport of lipids into the brain and also with some parts of the oxygenation cascade—its attraction to these coated nanopar- ticles, Philbert said, “may or may not lead to inflammatory damage.” Philbert briefly addressed the issue of whether nanomaterials can penetrate the skin. He referred to work on quantum dots being done by Sally Tinkle of the National Institute of Environmental Health Sciences (NIEHS) and Paul Howard and others at the FDA. Tinkle has shown that quantum dots can penetrate flexed and stretched skin; Howard has shown the same with abraded skin. Also, nanoparticles can clearly penetrate cut skin, which Philbert said has implications for kids at the beach who are wearing nanoparticle-based sunscreen—if they have scuffed knees, for example, those nanoparticles are going to enter their bodies. Transloca- tion (of just nanoparticles or both quantum dots and nanoparticles?) across the skin is always to the proximal lymph node, but it is unclear whether there is any lymphadenopathy as a result. There is no evidence yet of lymphadenoapathy, despite a long history of introducing fine and ultra-fine materials into the skin (e.g., tattooing). Unpublished research in Philbert’s lab shows that, as the dose of introduced nanomaterial increases, a greater fraction of that dose resides in “interstitial state” tissue. That is, there are mechanisms that he and his colleagues do not quite yet understand that suggest that introduced nanomaterials are picked up by the liver and other major immune system organs but then diffuse through the tissue(s) such that their exact cellular location cannot be pinpointed. One of these (other) major immune system organs is the gut, specifi- cally the Peyer patches (and M cells, which is where the Peyer patches attach to the gut) and dendritic cells. The M and dendritic cells take part in the constant “sampling” of the microflora of the gut and are involved 9 Y Wu, JS Hudson, Q Lu, JM Moore, AS Mount, AM Rao, E Alexov, and PC Ke. 2006. Coating single-walled carbon nanotubes with phospholipids. Journal of Physical Chemistry B 110:2475-2478.

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64 NANOTECHNOLOGY IN FOOD PRODUCTS with mechanisms that promote a healthy flora. 10 Philbert stated that since “not all guts are ‘normal,’ it would be foolish for us to assume that all interactions of nanomaterials in food are going to be utterly predictable.” Not only is there wide variation in gut microflora, but also there is wide variation in the “tone” of the epithelium of the gut, with the morphology of the gut lining changing with microfloral composition. In conclusion, Philbert summarized the following: • Dosimetry for nanomaterials is not clear. Do we measure mass concentration, surface area, chemical identity, chemical dose, or some complex algorithm that incorporates all of these factors? • We are in “desperate need” of accurate quantitative methods for measuring nanomaterials in complex media such as food. There is an assumption that when we put a nanomaterial in food, it is going to remain a nanomaterial, but we have yet to confirm that this is true. • The long-term stability of nano-enabled products is un- known. We “sort of know intuitively” that our food naturally breaks down into nanomaterials before being absorbed (since the “machines of life” operate at the nanoscale), but we do not know what happens to these nanomaterials as they pass through various media, including after they are eliminated from the body. In fact, environmentally deposited nanomate- rials may be reintroduced into the food chain at a later point; life cycle analysis is important. • Quantitative absorption, distribution, metabolism, and excre- tion (ADME) models are unavailable for most nanomateri- als. Consider the C60 buckyball. If you were to add a hydroxyl group to it, there are 59! [59 factorial = 1 × 2 × 3 × … × 59] possible positions for the next hydroxyl group, 58! for the next, and so on. We will never have the resources or time to do an exhaustive toxicology on all of these new nanomaterials. Philbert said, “We need to put our collective thinking caps on and come up with a rational approach that is resource-appropriate for the identification of hazards and 10 See J-P Kraehenbuhl and M Corbett. 2004. Keeping the gut microflora at bay. Science 303:1624-1625.

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SAFETY AND EFFICACY OF NANOMATERIALS IN FOOD PRODUCTS 65 the establishment of risk and, ultimately, the management of risk.” • We need to know the impact of nanomaterials on non- pulmonary systems and determine whether or not the immune system effects that have been done in non- gastrointestinal (GI) systems translate to these other systems. • We need to better understand both the acute and chronic ef- fects of nanomaterials on the immune system. We are gath- ering data on the former, but virtually nothing is known about the latter. We need to develop better animal models since, if asbestos is an indication, it takes about three dec- ades after initial exposure before mesothelioma begins to manifest in humans. We also need to shift away from high- dose exposure studies and begin studying “more reasonable” exposures. FDA OVERSIGHT OF NANOTECHNOLOGY APPLICATIONS IN FOODS, FOOD PACKAGING, AND NUTRIENT DELIVERY 11 Presenter: Laura M. Tarantino 12 Tarantino began her talk by remarking that many of the questions asked during the first session, coupled with some of the concepts that Philbert broached, served as an excellent lead-in to the issue of regula- tion and the challenge of risk identification. She remarked that the focus of her presentation would be the scope of FDA’s authority and oversight over foods, food ingredients, and nutrients and that she would be provid- ing an overview of the regulatory framework currently in place. Tarantino recommended the FDA Nanotechnology Task Force Report, which was issued in July 2007 as a source of information about the state of the science of biological interactions among nanomaterials (at that time—if the report were written today, its synopsis of the state of the science would be slightly different). The report also includes an analysis and recommendations for science issues and an analysis and recommen- dations for regulatory policy issues. Tarantino remarked that she would not be going into detail about the report but that she did want to highlight 11 This section is a paraphrased summary of Tarantino’s presentation. 12 Laura M. Tarantino, PhD, is Director of the Office of Food Additive Safety in the Center for Food Safety and Applied Nutrition, FDA.

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74 NANOTECHNOLOGY IN FOOD PRODUCTS view. He characterized it as a “remarkably good piece of legislation,” one that is still vibrant and relevant today. Remarkably, the safety issues presented by the use of nanomaterials with novel properties in food are almost identical to those that presented 50 years ago and which led to the passage of the FAA. These issues pre- sented themselves then largely because of the technological and chemis- try developments related to World War II. Synthetic food ingredients were being manufactured very suddenly, and the FDA was confronted with literally thousands of new ingredients whose safety had never been reviewed. The FAA was designed to address a public health scenario with the following: • Potentially thousands of novel substances to be added to food • Only a few such substances specifically tested/reviewed for safety • An existing regulatory system hampered by limited re- sources • Public/private sector concerns about under/over regulation What makes the FAA so vibrant and effective? Degnan noted that the objectives of the FAA are actually twofold: (1) to assure safety and (2) to foster innovation in food technology. Degnan identified three tools that have made it possible to accomplish these dual objectives: 1. Pre–market clearance with burden of proof on the sponsor. 2. A rigorous but non-absolute safety standard (i.e., “reasonable certainty of no harm”). The FAA contains only one absolute binding standard: the Delaney Clause. (The Delaney Clause effectively states that no additive could be deemed safe or given FDA approval if found to cause cancer in humans or experimental animals.) Other than that, as Degnan stated, the statute requires a food additive to be “safe” but does not define in any meaningful way a standard for assessing an additive is “safe.” 3. A broad, comprehensive definition of “food additive” coupled with reasonable expectations, including one flexible, forward- looking exception for substances Generally Recognized as Safe (GRAS).

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SAFETY AND EFFICACY OF NANOMATERIALS IN FOOD PRODUCTS 75 The GRAS Exemption A food additive is defined, in part, as “any substance that directly or indirectly may reasonably become a component of food.” This is a very broad definition and one that led Congress to apply certain exceptions. Pesticide chemical residues, for example, are not considered food addi- tives and instead are regulated under another (nonfood) rubric. The most important exception, however, is for GRAS substances—that is, sub- stances that are generally recognized as safe by qualified experts on the basis of knowledge derived from scientific procedures. Degnan charac- terized the GRAS concept as “the grease, … the element that allows the FAA to work, and it’s been that way since the inception of FDA’s regu- lation of food additives in 1958.” The GRAS provision allows the FDA to prioritize its limited resources and examine only those new and novel substances that demand its attention. And, it provides a flexible way to address food safety concerns in an efficient manner. Degnan briefly described two recent important applications of the GRAS concept: (1) The GRAS provision was critical to the Agency’s ability to implement its transgenic plant policy. The provision allowed FDA to treat as GRAS most transferred genetic materials (primarily nucleic acids) thereby avoiding time-consuming food additive approval and unnecessary restraints on innovative technology. (2) More recent is FDA’s reliance on a voluntary notification process that offers a prompt and thorough review and encourages industry submissions. Under the process industry collects publicly available data with respect to the safety of a given use and assembles a panel of experts to review the information and opine on the safety of the subject compound for a use or set of uses. FDA, in turn, relies on the assembled data and the expert opinions to evaluate whether a question with respect to GRAS status is presented. Degnan emphasized that determining that a substance is GRAS is “not a shortcut or loophole.” He said, “It is far from it. In my view, mak- ing a GRAS determination is harder than making a safety determination, because to be GRAS a substance has to have all of the fundamental proof that would accompany a food additive, and that proof must be publicly available. It’s a demanding standard.” Nanomaterials with Novel Properties and GRAS One of the key regulatory questions with respect to nanomaterials with novel properties is whether they can be considered GRAS. Or,

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76 NANOTECHNOLOGY IN FOOD PRODUCTS because of the practical difficulty involved in establishing general recognition of a novel substance, is it an oxymoron or contradiction to say “GRAS nanomaterials with novel properties?” This is a key issue currently in consideration at the FDA and one that Tarantino and her colleagues must consider in the context of what was done with transgenic plants and, in 1997, with the notification policy. Degnan noted that the issue also relates to a question that Groth asked earlier: Can a line be drawn in the spectrum of differently sized materials such that those materials that fall on one side can be considered GRAS? Degnan remarked that the situation is different with dietary supple- ments. As Tarantino had stated earlier, dietary ingredients in dietary sup- plements qualify as an exemption to the definition of a “food additive,” and thus are not subject to a pre–market approval process. The regulation process for dietary supplements is a post–market approval process, and the only way the FDA can take a dietary supplement off the market is to show that the supplement presents a “significant or unreasonable risk of illness or injury.” This is a difficult burden of proof for FDA to meet. However, there is a pre-market “notification” requirement for certain dietary ingredients. All dietary ingredients not used in dietary supple- ments before October 15, 1994, are considered “New Dietary Ingredi- ents” (NDIs) and, as such, must be the subject of a pre-market notification filed with FDA 75 days before marketing. The notification must contain the basis for the manufacturer’s conclusion that a supple- ment containing an NDI is “reasonably expected to be safe.” Failure to provide that information gives the FDA reason to argue in enforcement action (i.e., post-market action) that an inadequate basis exists to deter- mine whether the general adulteration standard is met. While not the most efficient system, it does provide FDA with a mechanism for evalu- ating a new ingredient, including a nanomaterial with novel properties. Degnan noted a potential complication arises because some sub- stances can be classified as either “food additives” or dietary ingredients, depending on how they are used. Vitamin D added to orange juice, for example, is considered a food additive and is regulated accordingly. On the other hand, vitamin D as an ingredient in a dietary supplement is con- sidered a dietary ingredient and thereby falls under a different regulatory rubric. This variation in how nutrients are regulated, depending on how they are used in or added to foods, “could well in time prove to be an- other significant regulatory issue.” So for dietary ingredients in dietary supplements, the issues are the following:

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SAFETY AND EFFICACY OF NANOMATERIALS IN FOOD PRODUCTS 77 • What criteria will FDA apply for determining whether nanomaterials with novel properties are “new dietary ingre- dients”? Degnan noted that presumably an effort would be made to use the same criteria used for evaluating the safety of a food additive. • What criteria will FDA apply in the “notification” process for evaluating safety of dietary ingredients nanomaterials with novel properties? For other food substances (i.e., food and color additives and GRAS nanomaterials), the issues are the following: • What criteria will FDA apply for evaluating the safety of nanomaterials? Specifically, what are the criteria for (1) sub- stances already holding approved additive status, including both food and color additives; (2) substances already under consideration by regulation or the notification process as GRAS; and (3) nanomaterials for use in new or unapproved substances? • Are there circumstances under which nanomaterials will not be considered to present a safety concern? Degnan identified this issue as “the more driving question.” If the answer is yes, then what factors need to be addressed to reach such a conclusion? • Similarly, what criteria will FDA consider applicable for establishing the GRAS status of nanomaterial substances with novel properties? Concluding Remarks In conclusion, Degnan reiterated four points: 1. FDA’s statutory pre–market authorities provide a comprehensive regulatory framework for assuring the safety of nanomaterials with novel properties for use in food and food packaging. The framework for dietary supplements is not as comprehensive but still provides a mechanism for evaluation by the agency. 2. FDA should author guidances with respect to the criteria to be followed in evaluating the safety of food, food packaging, and

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78 NANOTECHNOLOGY IN FOOD PRODUCTS supplement uses of nanomaterials with novel properties. This is key Degnan said, not only from a public confidence perspective but also from the perspective of industry. Industry needs to have in hand written guidance on the agency’s criteria for showing the safety of nanomaterials of novel properties. 3. FDA should provide leadership, on both the domestic and inter- national fronts, not only in developing guidance but in refining guidance as knowledge evolves. Degnan remarked that FDA is providing this leadership, as evident for example by Tarantino’s encouragement to industry to engage in dialogue with the agency. 4. Industry must conduct research and investigations to substantiate the propriety of the use in food of nanomaterials with novel properties. While FDA needs to take a leadership role, the ulti- mate responsibility is still always going to fall on industry. As a “postscript” to the topic of FDA’s regulation of nanotechnology in the context of food and dietary ingredients, Degnan facetiously commented that the Food, Drug, and Cosmetic Act is “misbranded,” in light of the fact that the Act provides FDA authority to regulate far more than just food, drugs, and cosmetics. His point: “There is a whole universe of products that FDA regulates and each type of product (i.e., drugs, medical devices, cosmetics, etc.) is subject to advancement with nanomaterials with novel properties.” The potentially broad use of nanomaterials with novel properties in FDA regulated products is another reason why the FDA should provide leadership and why there needs to be discussion among the various agency centers involved with developments and ideas concerning nanomaterials and their safety. There are also potential concerns about exposure to nanomaterials from a worker, or Occupational Safety and Health Administration (OSHA) perspective. Finally, Degnan commented that the FDA could also provide leadership on the international front, where current regulatory approaches range from laissez-faire to moratoria on research involving nanomaterials. The basis for providing that leadership role, Degnan reiterated, is written guidance.

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SAFETY AND EFFICACY OF NANOMATERIALS IN FOOD PRODUCTS 79 OPEN DISCUSSION 17 The second session ended with a 15-minute question and answer pe- riod. Most of the questions revolved around the issue of toxicology and testing of nanomaterials. Other topics of discussion included how to en- courage early industry consultation with the FDA (and other regulatory agencies); when to expect written guidance on nanomaterials in food from the FDA; and the difference between foods with targeted delivery capacities and drugs. Toxicology and Testing of Nanomaterials Doyle opened the discussion by commenting on Philbert’s “very in- triguing” comments about how scientists can apply what they already know about physical properties (from having studied other substances, such as asbestos fibers) to nanomaterials. He then asked if there has been any attempt by toxicologists or others to put together some sort of list of the types of things that need to be avoided when developing nanotech- nology related materials. Philbert replied, “There have been various at- tempts.” The problem, however, is that there are very little com- prehensive data available. For example, there are very few published pharmacokinetic studies of nanomaterials. The difficulty lies in not knowing where the nanomaterial ends; it depends on its physical or chemical characteristics. “I think there’s a lot of hand-waving going on. We need more data.” Doyle then asked if this lack of data has any bearing on activity in the area of regulatory approval and whether there won’t be much regula- tory activity until there are more data. Philbert replied, “We in some sense are jumping the gun because we simply don’t know what we’re regulating.” Importantly, however, we are “laying the landscape,” so that when the data do emerge, there is some context for interpreting it. An unidentified workshop attendee remarked that the FDA is at a point where it can only examine each case individually. While doing so, the agency is building the very database in question—one that will allow the Agency to make some generalizations in the future. But it is too soon to be making those generalizations now. 17 This section paraphrases the open discussion that took place at the end of the second session.

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80 NANOTECHNOLOGY IN FOOD PRODUCTS This remark was followed by a question about Degnan’s emphasis on regulatory policies around “nanomaterials with novel properties” and whether the notion of novel properties included those that were unin- tended or unrecognized. Degnan responded by saying that intent in that context is irrelevant. The overriding intent, he said, is the ingredient or the nanomaterial itself, that is, the nanomaterial intended to be a compo- nent of food. He said that as long as that is the case, his remarks apply. Workshop attendee Richard Bruner, WIL Research Laboratories, LLC, Ashland, OH, mentioned his background in preclinical animal test- ing of new drugs and commented on how he had attended this workshop hoping that the panelists would “lay out a platform of animal testing that we could all take back to our laboratories.” He said, “Obviously that’s a daunting task and is not about to happen.” He remarked that animal test- ing is very expensive and that testing even a single nanoparticle in a typical animal profile could exhaust a small company’s entire resources. He suggested that perhaps the “nanotechnology network” join forces and create an organization, much like the Chemistry Industry Institute of Toxicology (CIIT) was formed years ago, which would serve as an inter- face with the FDA and a filtering mechanism for all the small companies who have a need for testing requirements. The group would be a global network of toxicologists, engineers, and other scientists, and it would serve as a source of advice for the FDA and, in turn, a source of informa- tion for the scientific community about how the FDA views nanotech- nology. It would also interface with regulatory agencies in other countries. “Is the pill too large to swallow?” Bruner asked. Degnan responded, “No.” He pointed to work sponsored by the International Life Sciences Institute in the late 1980s and early 1990s on transgenic food safety and conducted by an organization called the International Food Biotechnology Council (IFBC). The IFBC assembled an international array of experts who worked together for a year and a half to produce a template document addressing every aspect of safety through regulatory approval and then circulated the template worldwide for comments. The end product provided a very helpful predicate for and actually prompted FDA to develop its own guidance on transgenic crops (in May 1992). So that approach is one that makes a great deal of sense. Philbert mentioned that the Environmental Defense Fund and DuPont have worked together to develop a set of toxicology tests for use with a wide variety of nanomaterials. However, the set of tests is still “quite expensive” and does not obviate the cost issue, but it does provide a “happy intermediate” in the sense that the toxicity tests have been

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SAFETY AND EFFICACY OF NANOMATERIALS IN FOOD PRODUCTS 81 shown to be very useful for ruling out formulations that are not going to work and are therefore not worth developing further. Bruner remarked that these tests run the risk, however, of being rejected by the FDA. Philbert replied that the idea is to “cherry pick” among tests as a precursor to a Good Laboratory Practice (GLP) study. He said, “I think the days of developing a chemical and then looking at the toxicity are over” and that “involving the toxicologists and the biologists from the outset is the only way to do this.” Tarantino added that toxicologists and biologists from the FDA should be involved from the outset. She reiterated, “Come in before you do all the studies and talk to us, rather than at the end, and we’ll be less likely to reject them.” Early Consultation with the FDA Tarantino’s last comment prompted workshop attendee Bill Jordan of the U.S. Environmental Protection Agency (EPA) to remark that the EPA regulates pesticide products that may contain nanomaterials and, like the FDA, encourages folks who are making those products to engage in dialogue with the EPA in preparation for pre-market review. Based on some of the information presented at this workshop, he observed, “It would seem that there are a lot more folks who should have been doing that than actually have.” Jordan asked if this might also be the case with the FDA. He then asked what regulatory agencies, trade associations, or other organizations can do to encourage people who are developing these technologies to communicate more freely and earlier with the regulatory bodies that have responsibility over those products. Tarantino replied that there have been a few applications and a number of what the FDA calls “pre-submission consultations,” meaning consultations conducted before formal submissions. She would not be surprised if there were some products out there for which manufacturers probably should have approached the FDA but did not. Although again (as Philbert elaborated during his presentation), things labeled “nano” may or may not actually involve nanotechnology or nanomaterials. Tarantino said that she didn’t know how the FDA could encourage earlier consultations. She noted the early and frequent consultations sought by industry when transgenic plants emerged as a regulatory issue, which was very helpful for the FDA. Degnan added that there were a number of factors that motivated the transgenic plant industry’s cooperation and consultation, a large one being consumer acceptance.

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82 NANOTECHNOLOGY IN FOOD PRODUCTS Timeline for FDA Guidance An unidentified workshop attendee asked Tarantino if the FDA knows approximately when it will issue guidance on the topics that Degnan addressed during his presentation and when interim guidances will be available. Tarantino said that she could not provide a date but emphasized that the FDA recognizes the utility of such guidance, particularly with respect to food additives (which is where her office is most involved). With respect to interim guidances, those are done in a “cyclic manner.” She said to expect updates for some of the other guidances (i.e., in addition to the already completed updated guidance for food contact substances) “in the next year or so.” When Does a Food Become a Drug? Workshop attendee Van Hubbard, NIH, commented that nanotech- nology has the ability to target specific tissues. But as scientists begin targeting tissues, where is the point at which this targeting becomes a pharmaceutical delivery? Degnan said that there was a legal response to the question and that the answer hinges on intent: “Foods can tout their effects on the structure and function of the body and do that lawfully. As soon as, however, a food even implies some therapeutic effect—some effect to treat, to mitigate, to cure, prevent or even diagnose disease— … it becomes a drug.” When it becomes a drug, a much more demanding and possibly clearer set of requirements with respect to the testing of both safety and effectiveness come into play. Whether targeted delivery makes something a food or drug depends on intent of the manufacturer, which can be implied and inferred by FDA. Philbert commented on the emergence of Internet communities with their own sense of what foods can do: Manufacturers can now introduce components into their foods knowing that those components (and any implied therapeutic effects) will be discussed in the blogosphere, thereby circumventing the FDA process. He asked if there was any way that the FDA could regulate this type of activity. Tarantino said that part of the answer depends on whether these foods are being advertised as dietary supplements and whether the FDA can take action; and another part de- pends on what sort of claims are being made and whether those claims are supported (i.e., if not, then the FDA can take action). She referred to Hubbard’s original question and said that, in many cases, the line is

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SAFETY AND EFFICACY OF NANOMATERIALS IN FOOD PRODUCTS 83 blurred and will probably become even more blurred in the future as nanomaterials become very effective nutrient delivery vehicles. Degnan pointed out however, that nutrient delivery is in fact a perfectly appropri- ate food and dietary supplement use. A manufacturer can lawfully make claims about nutrients, and there is a rubric for dealing with those claims. Only if that nutrient delivery is used for a therapeutic purpose does one enter “drug territory.”

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