Perspectives on FDA's Regulation of Nanotechnology: Emerging Challenges and Potential Solutions

Authors


  • This article was submitted under the direction of Peter Barton Hutt and in satisfaction of the Food and Drug Law Course requirement and third year written work requirement at Harvard Law School. Ms. Sandoval is currently an Associate at Covington & Burling LLP, Washington, D.C., U.S.A.

Abstract

ABSTRACT:  While public attention has been focused on Escherichia coli outbreaks, genetic engineering, and mad cow disease, nanotechnology has quietly taken its place at the forefront of scientific innovation and is poised to revolutionize numerous industries and fields of study. Although nanotechnology has been on the radar of researchers and developers for decades, it is only in the past few years that real-world applications have become a pervasive reality. Some of the most promising applications are in the areas of consumer products regulated by the U.S. Food and Drug Administration (FDA), including new and over-the-counter drugs, medical devices, cosmetics, and food and food packaging. Despite the incredible social and economic potential of nanotechnology, FDA faces numerous hurdles in the regulation of these products. This article explores the current state of our scientific understanding of nanotechnology, human and environmental health and safety concerns, the strengths and weaknesses of FDA's existing regulatory authority, and current efforts to address these and other issues relating to the development, understanding, and promotion of nanotechnology. In addition, the article proposes various regulatory and policy considerations FDA should take into account in addressing nano-based concerns.

Overview

Nanotechnology is a rapidly growing field that will soon have a hand in virtually every aspect of our lives, from household appliances to sporting goods, clothing to food components, and prescription drugs. While the potential benefits of this new field are staggering, the unique properties of nanomaterials present a number of concerns for the federal agencies charged with evaluating and regulating the development, production, marketing, use, and disposal of such materials. This article explores these issues both generally and in the more specific context of FDA's regulation of nano-based products.

After this brief overview, the next section provides an introduction to nanotechnology, a snapshot of the current state of the market, and a discussion of some of the major issues raised by nanotechnology, including characterization and standardization, environmental and human health and safety concerns, public perception, and funding. Section “FDA's Current Product-Based Regulatory Authority” details FDA's current regulatory authority over various product categories, as well as implications for oversight of nano-based products within those categories. Section “FDA's Current Initiatives, and the Other Players Involved” describes FDA's current initiatives relating to nanotechnology and the other players involved in its efforts. Section “Regulatory Options and Recommendations” suggests the regulatory options and possibilities open to FDA as it considers developing a policy position regarding nanotechnology. The last section provides final thoughts and conclusions.

Introduction to Nanotechnology: Problems and Possibilities

Congress has defined nanotechnology as “the science and technology that will enable one to understand, measure, manipulate, and manufacture at the atomic, molecular, and supramolecular levels, aimed at creating materials, devices, and systems with fundamentally new molecular organization, properties, and functions.”1 Nanotechnology involves the production and manipulation of materials at the nanoscale, which lies somewhere in the range of 100 to 200 nanometers or less. A nanometer (nm) is 1 billionth of a meter; for perspective on just how small this is, consider that a human hair is approximately 80,000 nm wide and DNA is approximately 2.5 nm wide.2 At these sizes, materials take on unique properties that are not present when the material is in bulk form. Taking advantage of these unique properties to develop new and improved products and processes is the goal of nanoscientists across the globe.

Nanotechnology has the potential to revolutionize our world through promising applications in fields such as electronics, medicine, materials engineering, and information technology. Even those working to impose strict regulations on nano-based products have recognized the potential benefits of nanotechnology.3 The field also promises incredible financial rewards, particularly for early entrants to the market. Competition to establish international dominance in this field is therefore fierce, as illustrated by Congress’ concern with “accelerating the deployment and application of nanotechnology research and development in the private sector” and “ensuring United States global leadership in the development and application of nanotechnology.”4 Some commentators worry, however, that the government's zeal to secure market dominance may be leading it to push environmental and health concerns to the side.5

A number of products have already reached consumers, though there is some disagreement about the actual size of today's nanotechnology market. The Project on Emerging Nanotechnologies at the Woodrow Wilson Intl. Center for Scholars has created a “Nanotechnology Consumer Products Inventory” that currently contains over 320 manufacturer self-identified products on the market in 17 countries.6 Other groups suggest the numbers are much larger. For example, the Environmental Working Group, a nonprofit public health and environmental research and advocacy organization, says it has identified “nearly 9,800 products containing nano-scale ingredients or ingredients that may contain nano-scale fraction.”7 The problem, of course, with a statistic like this is that the phrase “may contain nano-scale fraction” means that any product that contains an ingredient that is even available in nanoscale was included in the tally, without any determination as to whether or not the ingredient in any particular product is actually in that nanoscale form, as opposed to traditional bulk material.8

Regardless of these discrepancies, it is becoming clear that nanotechnology is poised to be our next industrial revolution. The number of products engineered via nanotechnology or containing nanomaterials has been steadily increasing, with the largest increases coming in the areas of cosmetics, food packaging, and dietary supplements, and more modest increases in drugs and biomedical devices.9 Its impact on consumer products regulated by FDA is inevitable and, in fact, a number of products containing nanomaterials have already entered the market, including sunscreens, cosmetic face creams, and prescription drugs. Unfortunately, the promise of technology usually goes hand in hand with new problems, and nanotechnology is no exception. The following sections provide an overview of some of the most pressing concerns regarding nanotechnology generally, as well as specific hurdles facing FDA. These include characterization and standardization; environmental, health, and safety impacts; public perception; and funding.

Characterization and standardization

Any attempt to describe or define nanotechnology with greater specificity than that provided above immediately reveals at the outset that this is a complicated, uncertain topic. There are numerous definitions of nanotechnology, and little agreement among stakeholders as to how to reconcile these differences. Most U.S. researchers define nanomaterials as those that are 100 nanometers or smaller in any 1 direction. In Japan, however, the nanomaterial designation is reserved for particles of 50 nm or smaller, while 100-nm materials are simply considered “ultrafine.”10 Even within the United States, there is variation, with some organizations classifying particles of up to 200 nm as nanomaterials.11,12

The Natl. Nanotechnology Initiative (NNI)—a federal research and development program established by the U.S. government to coordinate the efforts of government agencies grappling with nanotechnology issues—provides the following description:

Nanotechnology is the understanding and control of matter at dimensions of roughly 1 to 100 nanometers, where unique phenomena enable novel applications. Encompassing nanoscale science, engineering and technology, nanotechnology involves imaging, measuring, modeling, and manipulating matter at this length scale.13

FDA is part of the NNI and participated in the development of this definition, but has not established its own formal definition, nor has it officially adopted NNI's definition for the agency's own regulatory purposes.14

Nanoscale particles can be categorized as natural, incidental, or engineered.15 Naturally occurring nanomaterials include particles in our atmosphere such as volcanic dust; incidental particles result from industrial processes such as diesel exhaust.16 While there are some concerns about incidental and even natural particles (as evidenced by the numerous studies on the human and environmental effects of air pollution), the biggest concerns in the realm of nanotechnology arise from engineered nanoparticles.17 Engineered nanoparticles generally have very regular shapes, which may contribute to their potential toxicity. They can be classified in a number of different ways. The EPA, for example, has divided engineered nanomaterials into 4 categories: carbon-based materials, metal-based materials, dendrimers, and composites.18 The Natl. Academies, on the other hand, created 4 different categories: metal oxides, nanoclays, nanotubes, and quantum dots.19 FDA has not developed its own classification system.

Further complicating the issue is the fact that nanotechnology spans numerous disciplines and is a relatively new field for researchers and academia. As 1 commentator has noted, “‘Nanotechnology’ in many ways is a misnomer. It is not one technology, but many.”20 Indeed, the science of nanotechnology encompasses chemistry, physics, engineering, biology—virtually all technical and scientific fields have the potential to play a role in the development and study of nanotechnology.

So why do all the distinctions about particle size, shape, and classification matter? They matter because science has shown us that materials engineered at the nanoscale can exhibit fundamentally different properties from the same material in bulk form.21 As FDA itself has stated, “such differences include altered magnetic properties, altered electrical or optical activity, increased structural integrity, and increased chemical and biological activity.”22 In fact, these unique properties are what make nanotechnology so thrilling for manufacturers and developers; they allow them to harness the unique physical, chemical, and biological properties of materials that only exist at the nanoscale. FDA has shown particular interest in potential applications for implants and prosthetics, drug delivery, and food processing.23

One point of consensus among virtually all nanotechnology experts is that size matters. In one of the seminal reports on nanotechnology, the Royal Society and Royal Academy of Engineering concluded in 2004 that “chemicals in the form of nanoparticles and nanotubes should be treated separately to those produced in larger form.”24 Over the past few years, consensus has developed around this idea, demonstrated no more clearly than at FDA's October 2006 Public Meeting on Nanotechnology. Nearly every speaker mentioned at one point or another that “size matters.”25 Even representatives from private industry have recognized the importance of understanding the effects of particle size on toxicity.26

Surprisingly, however, FDA's website continues to contain statements that flatly contradict the scientific consensus:

FDA believes that the existing battery of pharmacotoxicity tests is probably adequate for most nanotechnology products that we will regulate. Particle size is not the issue. As new toxicological risks that derive from the new materials and/or new conformations of existing materials are identified, new tests will be required (emphasis added).27

While this statement seems puzzling in light of the widespread consensus among experts that particle size is the issue, it should be noted that FDA itself has made somewhat contradictory statements as to whether or not particle size matters.28 This statement notwithstanding, FDA seems to have acknowledged that particle size is an issue by virtue of the fact that it has embarked on a number of initiatives to determine the appropriate regulatory policy for nano-based products. The continuing presence of the above statement on FDA's website may merely be an oversight, but such statements have been used by consumer groups to suggest that FDA is not giving adequate attention to the possibility of unique safety concerns related to nano-based products. This could prove misleading to consumers, creating mistrust and a negative public perception of FDA's ability and willingness to provide adequate oversight for nano-based products. Public perception issues are addressed subsequently in subsection “Funding” FDA's current efforts with regard to nanotechnology research and policy development will be more fully explored in section “FDA's Current Initiatives, and the Other Players Involved.”

The risks related to particle size were perhaps most pithily captured by Dr. Philippe Martin, who noted the following 3 points during his comments at FDA's Public Meeting: (1) “small is small,” (2) “small is different,” and (3) “small is hard to predict.”29 The 1st point is based on the idea that particles of very small size may, by virtue of their size alone, be able to cross cell membranes or even the blood–brain barrier. This is, of course, both a blessing and a curse, since this property could improve targeted drug therapy but could also lead to unintended cell or organ damage. The 2nd point gets at the earlier referenced idea that materials at such small sizes take on unique properties not present in their conventional bulk form. As Dr. Martin humorously put it, “You take a cat, you shrink it, you shrink again, you shrink it yet again, and it turns into a dog.”30

The 3rd and final point gets at a lingering question among experts—namely, how might variations in the size of a given material, even once it has entered the nanoscale range, also matter? One of the most challenging issues facing scientists today is characterizing the different effects observed in a material as it changes size. Evidence suggests that the properties of many materials change at around 100 nm, while other materials show a steady increase in effects as their size decreases. Predicting how and when materials will change their properties is difficult at best. Take the example of gold, as provided by Dr. Martin.31 Conventional gold is yellow, melts at 1200 degrees and is completely inert. A 1-nanometer particle of gold is blue, has low reactivity, and melts at 200 degrees. A 3-nanometer particle of gold also melts at 200 degrees but has a reddish color and is highly reactive. This is just 1 example of the ways in which nanomaterials are difficult to predict, and thus difficult to characterize and standardize.

Beyond just size, shape and charge can also play a role in how engineered nanomaterials work, how their effects differ from bulk materials, and whether they may pose additional safety risks. Engineered nanomaterials can take on a number of shapes while maintaining the same chemical composition, including spheres, tubes, fibers, rings, and planes; each of these shapes, in turn, may cause the material to exhibit different properties.32 Charge has also been shown to have an impact, as described by Dr. Stacey Harper at FDA's Public Meeting. Dr. Harper described a study in which exposing embryonic zebra fish to positively charged 1.5-nm particles led to mortality, while exposing them to negatively charged particles of the same size had no negative effects.33

As the above discussion illustrates, characterizing the properties of nanomaterials is a daunting task. But it is also a critical one. Standardization and characterization were 2 of the issues most cited by speakers at FDA's Public Meeting on Nanotechnology.34 In an attempt to address international disagreement regarding the definition, classification, and characterization of nanomaterials, a number of national and international standards organizations are coming together to try to develop international standards for the field.35

Although there are major concerns regarding nanotechnology stemming from fears about the implications of reduced particle size, FDA has not yet developed new regulations or guidance to provide industry with standards for adequate safety testing. This can be attributed to a number of factors, including the lack of scientific data on the properties and impacts of nanomaterials and the fact that early evidence suggests that it is impossible to generalize about nanomaterials, given the wide variations in the properties exhibited by different materials—or even by the same materials at different sizes. The current lack of standards not only makes it difficult for FDA to determine when a product is produced through nanotechnology or contains nanomaterials, but it also makes it difficult for industry to know when they have entered nano-territory and therefore may need to consider additional testing based on nanoscale properties. There seems to be a consensus among nanotechnology experts that characterizing the unique properties of nanomaterials—including absorption, distribution, metabolism, and elimination mechanisms—is a critical step in ensuring public safety.36 Expert working groups and consumer groups alike have called on FDA to require a battery of tests for nanomaterials.37

Environmental, health, and safety impacts

Consumer and environmental interest groups have raised numerous concerns about the potential adverse effects of nanotechnology on the environment and human health and safety. Parties in both camps have been guilty of making overgeneralizations about the potential risks of nanomaterials. While both sides concede that the data are equivocal, they take very different positions on what that should mean for regulation. Proponents of nanotechnology argue that the lack of evidence of adverse health impacts and the fact that some studies suggest the safety of certain nanomaterials mean that nanomaterials are generally safe as a class. Their opponents counter that lack of evidence of harm is not the same as proof of safety, and that a handful of animal studies showing adverse effects is enough to suggest that nanomaterials are generally hazardous as a class. Both sides often fail to recognize the subtleties of this technology, such as the fact that the properties of nanomaterials are not consistent from one material to the next. Extrapolating a generalized (and polarizing) position from a handful of studies is unhelpful; it risks jeopardizing public safety in a rush to technology on the one hand and strangling nanotechnology in the crib on the other.

One of the most high-profile illustrations of the debate arose in May 2006, when the Intl. Center for Technology Assessment (CTA) filed a petition with FDA in conjunction with a report on the dangers of nano-sunscreens and nano-cosmetics developed by Friends of the Earth (FOE).38 The petition challenged the agency's purported failure to regulate health threats from nanomaterials.39 CTA's petition relied on scientific studies suggesting the potential hazards of nanotechnology. The Cosmetic, Toiletry, and Fragrance Assn. (CTFA) responded with a brief of its own, in which it described the limits of FDA's regulatory authority in this area, tried to refute CTA's studies, and urged FDA to maintain its current stance with regard to nanotechnology.40 FDA has not yet acted on CTA's petition and is unlikely to do so, at least until FDA's Nanotechnology Task Force develops its findings and recommendations based on the October 2006 Public Meeting.

Another aspect to the larger debate over the potential environmental and health impacts is how to track these effects over the life of the product. U.S. and European experts recently collaborated on a report calling for life-cycle assessment of nano-based products, suggesting that a “cradle-to-grave” look at the environmental and health impacts of nanomaterials and products is necessary to ensure safety, as well as to sustain the commercial viability of nanotechnology.41 The report, which calls for international cooperation and coordination, suggests that existing frameworks such as the Intl. Organization for Standardization (ISO) can be applied to nanotechnology, but cautions that lack of data on nanotoxicity will continue to pose a problem for life-cycle assessment.42 Andrew Maynard, chief scientist for the Project on Emerging Nanotechnology, commented on the importance of developing a risk strategy:

The lack of toxicity data specific to nanomaterials is a repeating theme in this and in other studies related to nanotech environmental, health, and safety concerns. Nanotechnology is no longer a scientific curiosity…But if people are to realize nanotechnology's benefits…the federal government needs an effective risk research strategy and sufficient funding in agencies responsible for oversight to do the job.43

Consumer and industry groups have also begun to advocate life-cycle assessment. In fact, Environmental Defense, an environmental advocacy organization, and DuPont, a private manufacturer of nano-based products, recently joined forces to develop a comprehensive framework for life-cycle analysis and risk management.44 This information-driven framework is modeled on EPA's traditional risk-assessment framework for evaluating new chemicals.45

Life-cycle assessment has the potential to help fill data gaps and guide agency actions, but cooperation between government, academia, industry, and consumer groups is a necessary 1st step. The nature of the U.S. system of administrative agencies compartmentalizes the regulation of products. FDA is responsible for ensuring the safety of certain nano-based consumer products. EPA is charged with addressing potential environmental hazards, and providing guidance on disposal of unused or expired nanoproducts.46 The Natl. Inst. for Occupational Safety and Health (NIOSH) and the Occupational Health and Safety Administration (OSHA) are charged with providing guidance for the protection of workers who may be affected by hazards arising from nanotechnology manufacturing processes. Absent a framework for life-cycle assessment and standardization of nanotechnology, individual agencies may run the risk of making regulatory decisions that do not adequately account for all relevant environmental and health risks.47 As discussed in section “FDA's Current Initiatives, and the Other Players Involved,” cross-agency coordination efforts designed to address these types of concerns are already underway.

Detection is a crucial aspect of developing toxicity and safety protocols, as well as monitoring long-term, postmarketing impacts. The ability to locate nanomaterials in the human body and the environment are crucial to determining the extent of their impact on those systems, but current detection methods for nanomaterials are still in their infancy.48 Neither FDA nor industry has developed any standardized methodologies for detecting nano-based products in the human or natural environment. A related issue involves the labeling of products containing nanomaterials. Since there are currently no labeling requirements, FDA may have difficulty monitoring nano-based products and assessing whether they are giving rise to safety concerns.49 Detection and disclosure of the nanoscale nature of products is imperative for all agencies involved in regulating nanotechnology, and is crucial for adequate and accurate life-cycle assessment.

Environmental impacts Like almost any consumer product, some nano-based products may find their way into the environment.50 Given this possibility, some consumer groups worry that the general public will bear a disproportionate cost of the technology, based on the idea environmental hazards will be borne by everyone, while the benefits will only accrue to direct consumers.51 Some of the critical issues raised by environmental groups involve the durability of nanoscale materials, the possible persistence in excretion of absorbed products, and the fact that at least some materials have shown the potential to bond with and reconfigure DNA, posing a threat to wildlife.52

Under the Natl. Environmental Policy Act of 1969 (NEPA), FDA must consider the environmental impact of any “major federal action,” which includes approval of drugs.53 NEPA was established to ensure that all federal agencies incorporate environmental considerations into their decision-making process by requiring them to prepare an environmental assessment (EA) or an environmental impact statement (EIS) for all major regulatory actions and policies.54 NEPA also established the Council on Environmental Quality (CEQ) to ensure agency compliance with NEPA and coordinate federal environmental efforts across the various agencies.55

In the FDA regulations promulgated to implement NEPA, the agency requires all applicants and petitioners requesting FDA action to prepare an EA when they ask the agency to take a major federal action.56 In this way, FDA has effectively foisted responsibility for conducting environmental assessments onto drug sponsors by requiring the sponsor to include an EA or an EIS in its new drug application (NDA).57 The environmental considerations relating to drug approvals—including nano-based drugs—include toxicity to other organisms as a result of the drug's introduction into the environment through use or disposal.58 On receiving the application, FDA carefully reviews the EA and decides whether the findings are serious enough to require follow-up with an EIS, or whether it is appropriate for the agency to issue a “finding of no significant impact,” or FONSI.59

At 1st glance, it may seem that the current EA/EIS requirement would be sufficient to identify any problems created by nanomaterials. However, there are at least 2 issues that may inhibit the effectiveness of the NEPA requirements in the field of nanotechnology. First, FDA has not yet undertaken or proposed a “major federal action” with regard to a nanotechnology policy that would require it to complete an EIS; to trigger the NEPA requirements, courts have held that an agency must be making an “‘irreversible and irretrievable commitment of resources’ to an action that will affect the environment.”60 In terms of nanotechnology, rather than taking action to promulgate new regulations, FDA has up to this point simply maintained the status quo with regard to its regulatory policies and procedures.

In 2000, FDA was in a similar position with regard to genetically modified foods. The agency had determined that it would presume that foods produced through the rDNA process were generally recognized as safe (GRAS) under the FD&C Act and would therefore not subject them to more stringent regulation, that is, under the food additives category. In Alliance for Bio-Integrity v. Shalala, the plaintiffs challenged FDA's position and argued that their policy constituted major federal action that triggered the NEPA EIS requirement.61 The court rejected the plaintiffs’ arguments and held that FDA's policy did not amount to “major federal action” because the agency had not made any final determinations about whether particular foods would be allowed on the market, and had not taken any particular regulatory actions that could affect the environment.62 Therefore, when FDA decides to regulate products on a case-by-case basis rather than developing a new regulatory policy to cover a new class of products, that decision does not trigger the EIS requirement under NEPA. For nano-based products, this means that, while the environmental effects of individual products may be assessed—for example, through the drug approval process—FDA is not legally required to consider the overall environmental impact of nanotechnology at this time.

The 2nd potential issue with regard to the adequacy of NEPA requirements to bring environmental problems to light arises from the fact that FDA has created a number of categorical exclusions to the EA requirement.63 These exclusions include situations where the approval of a drug will not “increase the use of the active moiety” or, if it does increase the use of the active moiety, then “the estimated concentration at the point of entry into the aquatic environment will be below 1 part per billion.”64 These exclusions do not take into account the fact that a low concentration of nanomaterials may nevertheless have an environmental impact that is different from the impact of the material in bulk, as a result of the small particle size and large surface area of nanomaterials. FDA may need to reconsider—in concert with EPA and the CEQ—whether the categorical exclusion loophole for low concentrations should be changed to reflect the impact of nanomaterials at very low concentrations. Until the agencies have more scientific data by which to evaluate the environmental impact of nano-based products, however, the regulation is unlikely to change.

Human health and safety Nanotoxicity is still a new field, but there is certainly the possibility that some nanomaterials may present a health risk to consumers. Just as size matters when it comes to the physical properties of nanomaterials, it may matter when it comes to entering and interacting with the human body.

Nanomaterials may enter the body through inhalation, ingestion, or skin penetration. Once they have entered the body, many scientists think that they may have the potential to cause serious damage.65 For example, inhaling a large number of nanomaterials might overwhelm the body's natural clearance mechanisms and allow the particles to reach different parts of the respiratory tract.66 Additionally, nanomaterials of less than 100 nm may be able to pass from the lungs to the bloodstream, just like gas molecules.67 If the particle is small enough—smaller than a cell in the body, for instance—it may affect the cell's natural processes.68 Nanomaterials may also enter the liver, spleen, or kidneys through ingestion.69

Skin exposure to nanomaterials has been at the forefront of the nanotechnology debate as it relates to FDA and its regulatory authority, driven largely by the fact that FDA has no authority to require premarket testing of cosmetics and has not indicated whether nano-sized versions of ingredients otherwise approved for use in over-the-counter (OTC) products (such as sunscreens) properly fall under existing OTC monographs. Scientific studies in this area have not provided a definitive answer to the question whether nanoparticles in sunscreen are dangerous and, if so, at what levels of exposure. In vitro studies have suggested that there is little danger, though it is questionable whether in vitro studies are sufficient to provide insight into potential systemic effects.70 Other research suggests that nanomaterials may be able to penetrate the skin and enter the lymphatic system.71 CTFA has urged that the general scientific consensus is that there is no risk to human health, but some commentators suggest that this assertion is based on selective use of the literature and “sets the stage for an ineffective and polarized public dialogue on nanotechnologies risks and benefits.”72

The preceding discussion notwithstanding, it is important to note that the properties that allow nanomaterials to penetrate the body in new ways are not necessarily bad, and in fact may be beneficial, such as in the development of targeted cancer therapies. It is also crucial to bear in mind that not all nanomaterials are created equal—toxicity will likely vary depending not only on the material, but may also vary based on the particle size (that is, whether the material is engineered to 50, 100, 200 nm, and so on).

A number of concerned groups advocate following the so-called “precautionary principle,” urging that a lack of evidence of harm should not be interpreted as an affirmation of the safety of nano-based products.73 Indeed, there are notable historical examples of the detrimental effects of a rush to technology: dangerous pesticides like DDT were initially thought to be safe when they entered the market in the 1950s and 1960s, while regulations addressing their environmental and human health impacts (for example, the Toxic Substances Control Act of 1976) did not emerge until at least a decade later, after the damage was already done.74 Asbestos is another example of the potentially disastrous results of insufficient safety studies and delayed regulation. As a representative of Environmental Defense put it, “There's no reason why we should just be counting bodies and use that as our regulatory system.”75

On the other side of the fence are nanotechnology advocates who suggest that consumer groups are simply sounding their usual alarmist bells, just as they did when genetically modified foods first entered the picture. Proponents of nanotechnology assert that nanoparticles are nothing new to our environment and the human body has developed coping mechanisms to deal with these materials.76 Furthermore, if FDA institutes a moratorium on nano-based products while science plays catch-up, it runs the risk of instilling unwarranted fear in the public that may create unnecessary anxiety and erect a major barrier to diffusion of beneficial nano-based technologies in the future.77 This could prove detrimental for the country both in terms of our economy and our public health. At FDA's public Meeting, Dr. Philbert, representing the Univ. of Michigan, School of Public Health, provided the following insight:

Nano is just a scale. The nanoscale does not per se or of necessity confer any uniform or specific property. Neither does it automatically denote advantageous or adverse health effects…[A]t present the benefits of using nanomaterials greatly outweigh the risks. Any steps in policymaking must be based on a sound foundation of scientific evidence and in my opinion the science does not yet mandate Draconian action.78

While nano may indeed be “just a scale,” there are clearly valid arguments on both sides of that scale. Recognizing the need for additional scientific study and dialogue—as FDA has done—is a step halfway in between that acknowledges the concerns on both sides. Further complicating the issue is the administrative process for formal or notice-and-comment rulemaking, which is time- and resource-consuming. Rushing to judgment in either direction at this point would make it incredibly difficult for FDA to then backtrack and revise its position should future scientific evidence end up dictating a different result.

Public perception of nanotechnology and confidence in FDA

Even if generalized fears about nanotechnology are unfounded, FDA still has to overcome the hurdle of public perception of risk.79 Past experience suggests that transparency and openness with the public may go a long way toward smoothing the road for consumer acceptance of emerging nano-based products. During the biotech revolution, the public became concerned and suspicious about the introduction of genetically modified foods (GMOs), largely due to the fact that biotech companies neglected to engage the public in dialogue about their fears and concerns.80 While some nanotechnology manufacturers have introduced nano-based products to the market without addressing growing concern about the potential risks, there is increasing pressure on companies to disclose the presence of nanomaterials in their products and to take steps to investigate the public's concerns. For example, at FDA's Public Meeting on Nanotechnology, speakers from all sectors—consumer groups, industry, government, and academia—advocated transparency on behalf of manufacturers, as well as FDA. At this point in time, there is no reliable means for identifying products containing nanomaterials; not only does this affect the FDA and frustrate its ability to develop sound policy in this area, but it also frustrates the public, who may feel powerless to exercise their own judgment as to whether to purchase or avoid potentially dangerous nano-based products.

A report describing the results of the most recent national poll on public attitudes toward nanotechnology suggests that, while public awareness of nanotechnology has grown, a majority of Americans still know very little about the technology.81 According to the report, nearly 40% of those polled expressed concern that the risks of nanotechnology might outweigh the benefits.82 Consumer groups have been lobbying for labeling requirements and increased disclosure of the nano-based products currently on the market. Just as many consumers wish to avoid consuming genetically modified food, many consumers may wish to avoid using nano-based products, but will likely feel frustrated by the lack of labeling standards for these products. However, FDA must balance the public's desire for labeling with the very real possibility that such labeling requirements will unnecessarily inhibit the use of highly beneficial products. This is not a new territory for FDA—the agency is currently attempting to revise the labeling requirements for irradiated food, based largely on the fact that such labeling creates a negative perception among consumers and therefore acts as a barrier to the diffusion of food products that may actually be healthier for the consumers, since irradiation kills bacteria and helps reduce the risk of food-borne pathogens.83 In light of this recent history, FDA will likely be wary of creating a similar problem for products containing nanomaterials.

While labeling requirements remain a point of contention between consumer groups and industry, the call for increased publicity about nanotechnology is not confined to its detractors. Industry groups have similarly been calling for more transparency regarding nanotechnology, noting the importance of securing public confidence in their products to maintain their commercial viability. For example, the Food Products Assn. (FPA) and Grocery Manufacturers Assn. (GMA) have urged FDA to educate the public about the potential benefits of nanotechnology and address their concerns about the adequacy of current regulatory standards and procedures.84 Dr. David Rejeski, Director of the Project on Emerging Nanotechnologies at the Woodrow Wilson Intl. Center for Scholars, argues that providing the public with more information and increasing transparency regarding nanotechnology and regulatory oversight will actually increase their support for the technology.85 Public perception is critical to successful diffusion of beneficial nano-based products, particularly prescription drugs and medical devices. If patients do not trust that FDA has exercised adequate oversight, they may be less willing to accept treatments involving nanotechnology, thereby missing out on potentially life-saving advances in medicine.

Unfortunately, the debate and rising public concern over nanotechnology comes at a time when public confidence in FDA is already lower than usual. Historically, the agency has been one of the most trusted and respected agencies in the eyes of the public. In August 2006, however, the Project on Emerging Nanotechnologies conducted a national survey that revealed a dip in public confidence in FDA.86 At the same time, only 12% of respondents trusted companies to self-regulate when it comes to safety monitoring, which is somewhat ironic given that the vast majority of products regulated by FDA are generally monitored by their manufacturers.87 Increasing public awareness of the steps that both the agency and industry are taking to address public concerns will go a long way toward improving public perception and paving the road for the smooth market entry of beneficial new products.

Funding

Both the government and private industry have been pouring billions of dollars into nanotechnology research and development (R&D). According to one research organization, global R&D spending reached $9.6 billion in 2005, and sales of nano-based products reached $32 billion.88 The same firm estimated that venture capital investments in nanotechnology would exceed $650 million in 2006,89 and that products incorporating nanotechnology will account for $2.6 trillion, or 15% of global manufacturing output.90

These projections as to the potentially lucrative size of the nanotechnology market—combined with concerns about understanding potential environmental, health, and safety impacts—have driven the federal government to increase its own awareness of the technology, as well as the funding dedicated to nanotechnology R&D by government agencies and private research groups. At an April 2004 conference sponsored by the NNI, Senator George Allen (R-VA) announced the creation of the 1st Congressional Nanotechnology Caucus.91 The purpose of this initiative has been described by participating congressmen as: “To promote nanotechnology, educate policy makers about this emerging area, and facilitate communications between industrial and academic researchers and the Hill.”92 The NNI itself was officially established in 2001 through President Clinton's budget submission to Congress, in which he raised nanoscale science and technology to the level of a federal initiative.93 NNI noted 3 main categories of government-funded research to understand the environmental, health, and safety impacts of nanotechnology:

  • 1) Basic research to expand knowledge and further understanding of how nanomaterials behave, including in the environment and in the human body;
  • 2) research to develop instrumentation and methods for measuring, characterizing, and testing nanomaterials and for monitoring exposure; and
  • 3) research toward assessing safety of chemicals, food, drugs and medical devices, among other items.94

The 21st Century Nanotechnology Research and Development Act of 2003 established a funding framework for NNI,95 whose 2008 budget is nearly triple the estimated $464 million spent in 2001.96 While this certainly demonstrates “the consistent, strong support of this Administration and of Congress for this program,”97 that financial support does not extend to FDA. The agency does not receive any of NNI's funding, despite its active participation in the program.98 Although Congress explicitly recognized that nanotechnology applications would include advances in the field of medicine, it did not mention FDA in its legislation or in its reports.99

FDA's lack of funding for nanotechnology research is particularly troubling given that it has long been strapped for cash as it is. According to one commentator—a former Deputy Commissioner for Policy at FDA—the agency's annual appropriations have fallen short of its needs for at least a decade, and “FDA's 2006 budget would have to be 49% greater than it is just to maintain its 1996 base level of activity and continue initiatives Congress has directed it to undertake.”100

This long-standing scarcity of resources inhibits FDA's ability to keep up with its traditional duties and operating costs, let alone dedicate additional resources to a new area of study and regulation. Nevertheless, FDA has been an active participant in the dialogue around nanotechnology, even contributing some of the precious resources within its various Centers to studies designed to help the agency “understand the characteristics of nano-materials and nanotechnology processes.”101 It has also established collaborations with other agencies to study, classify, and monitor developments in nanotechnology, as discussed more fully in section “FDA's Current Initiatives, and the Other Players Involved.”

FDA's Current Product-Based Regulatory Authority

Wishful thinking of consumer groups notwithstanding, FDA's mandate is to regulate products, not technologies. The FD&C Act of 1938 provides FDA with authority to regulate specific categories of consumer products: human drugs, biologics, and medical devices (including combination products); cosmetics; food and food additives; dietary supplements; and animal feed and drugs. The scope of FDA's authority varies from category to category, with the agency enjoying strongest authority over new drugs and devices and weakest authority over cosmetics and whole foods.102 Because of these variations in the extent and force of FDA's regulatory authority, the agency's ability to effectively regulate products consisting of or containing nanomaterials, or manufactured through nanotechnology, will depend largely on the category under which the product falls.

FDA has not made any definitive statements with regard to its regulation of nano-based products, instead taking the position—for the time being, at least—that “existing requirements may be adequate for most nanotechnology products that we will regulate,” but that “if new risks are identified, arising from new materials or manufacturing techniques for example, new tests or other requirements may be needed” (emphases added).103 Consumer groups have urged FDA to develop new regulations, or at least issue guidance, with respect to nanotechnology regulation.104 However, the structure of the FD&C Act, as well as the inevitable variations in safety profiles for nano-based products, suggest that a one-size-fits-all approach is neither desirable nor practical. This section explores FDA's existing regulatory authority in the areas of new prescription and OTC drugs, medical devices, combination products, food and food additives, dietary supplements, and cosmetics. It also considers the potential implications for nano-based products in each of these product categories.

New drugs

Existing authority New drugs are subject to a more rigorous regulatory scheme than most other products that fall under FDA's jurisdiction. As such, classification has often been a sticking point for product manufacturers.105 However, government agencies generally enjoy broad discretion in interpreting and applying the statutory terms.106 The FD&C Act provides the following definition of the term “drug:”

(A) Articles recognized in the official United States Pharmacopoeia, official Homeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and

(B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease… ; and

(C) articles (other than food) intended to affect the structure or any function of the body… ; and

(D) articles intended for use as a component of any article specified in [the above clauses].107

All new drugs, whether brand name or generic, must obtain premarketing approval from FDA before they can enter the market.108 To obtain approval, the drug must be proven safe, as well as effective for its intended use. A novel drug must be approved through the NDA process, while a generic version of an existing drug may be approved using an abbreviated NDA (ANDA). Under 21 U.S.C. §355, drug manufacturers must conduct both preclinical (animal) and clinical (human) trials to demonstrate the drug's safety and efficacy. Before clinical trials can proceed, however, the drug company must submit a “Claimed Exemption for an Investigational New Drug” (IND), which includes the results of preclinical research and is designed to ensure the safety of human subjects.109

All information collected by the drug sponsor relating to safety and efficacy must be included in the NDA, along with information about the manufacturing process and provisions for quality assurance.110 The sheer volume of data produced through this process is staggering. According to the House Subcommittee on Science, Research and Technology, each NDA can consist of up to 15 volumes of summary data and 10 to 100 volumes of raw data.111 The sponsor must be able to provide evidence demonstrating the drug's safety “by all methods reasonably applicable to show whether or not such drug is safe for use under the conditions of use prescribed, recommended, or suggested” in the proposed labeling.112

In addition to extensive premarket approval authority, FDA retains a fair measure of postmarket enforcement authority over new drugs. The agency requires manufacturers to report adverse events,113 and also has authority to inspect facilities and records.114 FDA can also choose to revoke approval of an NDA if evidence comes to light that disproves the drug's safety and efficacy.115

Implications for nano-based products One January 2006 report indicated that there are approximately 130 nanotech-based drugs and delivery systems in preclinical, clinical, or commercial development.116 The Project on Emerging Nanotechnologies lists commercialized medical applications for cancer, immunosuppression, hormone therapy, cholesterol, appetite control, bone replacement, chemical substitutes, imaging, drug development, diagnostic tests, and medical tools.117 FDA-approved nano-based products on the market include Abraxane, for the treatment of metastatic breast cancer; Doxil, for the treatment of ovarian cancer and AIDS-related Kaposi's sarcoma; and Emend, an anti-nausea drug designed for chemotherapy patients.118

The FD&C Act and implementing regulations are silent as to how FDA will assess a drug's safety and do not articulate the types of toxicity and safety testing that will suffice to meet FDA's approval. Given the likelihood that nanotechnology will create novel toxicity profiles for new drugs, FDA may need to issue guidance to industry describing appropriate testing protocols for nano-based products. In the alternative, FDA could choose to raise any concerns it might have about particle size on a case-by-case basis, as it did in the case of Emend.119 Each of the nano-based drugs that received FDA approval was subject to FDA's rigorous safety and efficacy testing requirements for new drugs, including toxicity testing in both humans and animals. Studies submitted in support of the NDAs for Abraxane and Doxil show that the nanoformulations of these products actually provide marked improvements over the therapeutic and safety properties of other market leaders utilizing the same compounds.120,121 This is not to say that these drugs do not have negative side effects—the FDA approved package inserts clearly warn patients of a number of risks, such as cardiac toxicity for Doxil—but the side effects seem to be quite similar to those for conventional formulations of the same compounds.122 For example, ongoing studies of patients taking Abraxane have shown “no new or unique toxicities … that were any different than that reported for conventional paclitaxel or Taxol.”123

The extent of FDA's regulatory authority over new drugs prior to market entry suggests that the existing regulations could be applied to drugs containing nanomaterials or manufactured via nanotechnology without necessitating new legislation or regulations. The agency's ability to raise and address safety issues before a product reaches consumers provides an adequate framework for any application—including nanotechnology—provided, of course, that FDA knows what types of safety issues to look out for.

Over-the-counter drugs

Existing authority Although the new drug requirements of the FD&C Act apply to all drugs, FDA has consistently drawn a distinction between prescription and OTC drugs.124 The 1962 Drug Amendments—which added the “effectiveness” requirement to the FD&C Act's mandate regarding approval of new drugs—required FDA to review the safety and effectiveness of all previously approved drugs, including OTC drugs.125 To address this burdensome and time-consuming Congressional mandate, FDA promulgated regulations establishing procedures for classifying OTC drugs as “generally recognized as safe and effective” (GRAS/GRAE) and not misbranded, and for establishing a monograph system to deal with OTC regulation going forward.126 Under these regulations, FDA reviews the safety and effectiveness of the active ingredients in OTC drugs, makes a determination as to whether they are GRAS/GRAE, and publishes a list of all ingredients that can be included in OTC drug formulations.127 The monograph also establishes labeling standards for OTC products. Provided a company formulates its products using only the ingredients approved as GRAS/GRAE and follows the labeling requirements, the OTC drug is not considered a “new drug” and can therefore forego the NDA process.128

Implications for nano-based products Historically, this process has worked efficiently and effectively to handle the regulation of OTC products. However, the rise of nanotechnology has revealed a potential chink in the proverbial armor of FDA's monograph procedure. Although there are a number of products on the market claiming to contain nanomaterials, there is nothing in the current OTC monograph that accounts for variations in particle size. Thus, nano-sized particles of materials listed in the monograph are not subject to any additional testing requirements and legally fall within the definition of those GRAS/GRAE ingredients.129

Given the potential differences in safety profiles based on particle size, ignoring this distinction in the OTC drug context could lead to inappropriate categorization of nano-sized ingredients as GRAS. On the other hand, FDA has the power to amend its monographs if it feels there is an unresolved safety issue about an approved ingredient. If, for example, FDA revises its existing monographs to indicate the particle size of ingredients considered to be GRAS, products containing nano-sized versions of those ingredients would be considered “new drugs” and therefore subject to the NDA process. This would obviously provide an additional layer of consumer protection, but the added burden on manufacturers might inhibit development and market entry of new products whose benefits could outweigh the risks.

Recent controversy surrounding the use of “micronized” and nanoscale titanium dioxide in sunscreens vividly highlights this issue. There are currently at least 13 nano-based sunscreens on the market.130 FDA's sunscreen monograph lists titanium dioxide as an active ingredient, and FDA has stated that “micronized” titanium dioxide falls within the monograph.131 Unfortunately, FDA has not defined the term “micronized,” nor indicated whether nano-sized particles are included in this definition.132

Nanoscaled titanium dioxide is attractive to sunscreen manufacturers—and consumers—because it both blocks harmful UVA light and appears clear on the skin. Despite these attractive qualities, consumer groups are concerned that nanoscale titanium dioxide may pose certain health risks based on a lack of scientific evidence as to whether nano-sized particles might be able to penetrate the skin and give rise to adverse health effects. The aforementioned petition filed by CTA addresses these concerns and calls on FDA to develop nanotechnology regulations generally, and revise its sunscreen monograph specifically.133 For its part, CTFA has reminded FDA that nanoparticles have been incorporated into sunscreens for decades, with no evidence of adverse affects.134 Furthermore, ease of application and the more esthetically pleasing qualities resulting from nanoscale titanium dioxide and zinc oxide may increase consumer use of sunscreens, thereby providing greater overall public health benefits due to reductions in the incidence of skin cancer. FDA is currently collaborating with the Natl. Inst. of Health, Natl. Inst. of Environmental Health Sciences (NIH/NIEHS) and the Natl. Inst. of Standards and Technology (NIST) on studies designed to understand the toxicity and characterize the properties of zinc oxide and titanium dioxide nanoparticles commonly found in sunscreens. The outcome of these studies is likely to inform FDA's new OTC monograph for UVA sunscreens.135

Devices

Existing authority FDA has had authority to regulate medical devices since 1938, but its regulatory power was greatly expanded and elaborated by the Medical Device Amendments of 1976. The amendments created a device classification system that allows FDA to use different approval processes for different classes of devices.136 The 3-tier classification system is based on the level of certainty surrounding a device's safety and effectiveness. Class I devices present the lowest risk and are therefore subject to less burdensome requirements, while Class III devices present the highest risk and are therefore subject to greater scrutiny. Class I and II devices generally must submit a 510(k) for marketing. A 510(k) results in a letter of substantial equivalence from FDA, provided the 510(k) demonstrates the product's substantial equivalence to a device legally marketed before 1976 or to a device FDA has determined to be substantially equivalent to such a device.137 Class III devices must submit a premarket approval application (PMA). The PMA process is much more involved than that 510(k) process, requiring submission of clinical data to support claims about the device. It results in an actual approval of the device, rather than simply a letter of substantial equivalence.138

In addition to the new provisions created by the amendments, all devices remain subject to the general controls created by the 1938 statute.139 As a result, FDA's premarket approval authority of devices is more extensive than its premarket approval authority of most other products. The product sponsor must submit safety and effectiveness data to FDA to obtain approval, and FDA has the authority to require additional clinical testing, which it may well be inclined to do in the case of products consisting of or incorporating novel technology.

Implications for nano-based products As with new drugs, FDA's existing authority over devices is likely to provide a sufficient and substantial framework for the review and approval of nano-based products. According to a report released by NanoBiotech News, as of January 2006 there were approximately 125 devices or diagnostic tests in preclinical, clinical, or commercial development.140 Although developers may attempt to bootstrap their way into approval by suggesting that devices incorporating nanotechnology merely build on previously approved predicate devices, FDA has authority to tailor its approach to each product. If the agency determines that a particular type of product requires greater premarket scrutiny (for example, as a result of potential safety issues), it has discretion to require more rigorous testing. Thus, the existing regulations provide an adequate framework for FDA to regulate devices incorporating or manufactured through nanotechnology; the question is whether it has adequate scientific knowledge and resources to understand which devices merit more intense review.

Combination products

Existing authority In late 2002, FDA established the Office of Combination Products (OCP) pursuant to the Medical Devise User Fee and Modernization Act of 2002.141 The OCP has broad authority over drug-device, drug-biologic, and device-biologic combination products.142 Its primary responsibility, however, is to determine which of FDA's 3 product centers will have jurisdiction over the regulation of a specific product—the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), or the Center for Devices and Radiological Health (CDRH).143 Jurisdiction is generally based on the product's primary mode of action (PMOA)—that is, whether it functions primarily as a drug or primarily as a device; in the absence of an ascertainable PMOA, FDA created an algorithm to assign products to the appropriate center.144

Implications for nano-based products Some commentators have suggested that combination products manufactured through nanotechnology or containing nanomaterials may create a unique regulatory problem for the agency. FDA itself has said that the likelihood that many of the nanotechnology products that “the Agency regulates will be Combination Products” is one of the big issues it expects to face in the course of its regulation of nano-based products.145 For example, if the agency determines that a combination product's PMOA is through its device-like qualities, it will be regulated by the CDRH. These leaves open the possibility that nanomaterials incorporated into the product by virtue of its drug-like qualities may be subject to less rigid scrutiny than if it were regulated by CDER. However, since both drug and device regulations regarding safety testing are already fairly demanding, this may not ultimately create a major issue—at least not one that is any different or more problematic than those already affecting non-nano-based products.

Food and food additives

Existing authority FDA's current authority over food and food additives can be broken down into a number of categories, and the extent of the agency's authority varies widely from one category to another. These categories include whole foods, food additives, GRAS ingredients, prior sanctioned ingredients, and dietary supplements (discussed in subsection “Dietary Supplements”).

Whole foods, for example, are only subject to postmarket oversight. FDA can remove a whole food from the market only if it contains a naturally occurring toxin that makes the food “‘ordinarily injurious’ to health” or if it is “adulterated” by added substances that may make the food “injurious to health.”146

For nonwhole foods, FDA's more rigorous food additives regulations kick in. Food additives include any substances intentionally added to a food, such as natural and artificial flavors, seasonings, and sweeteners.147 Certain additives have been designated GRAS and therefore do not have to undergo premarket approval testing.148 One persistently knotty issue with GRAS exemptions is that a manufacturer is entitled to make its own independent GRAS determination and, when it does, the company is not required to submit the product for review or inform FDA of its plans to market the product.149 FDA can later challenge the company's GRAS determination, but only after the product has already entered the market.150

Food additives other than those designated GRAS are subject to a formal FDA review and approval process.151 In this case, the company must prove to FDA that the proposed food additive shows a “reasonable certainty of no harm.”152 This is a fairly heavy burden for manufacturers and some have argued that it may serve as a barrier to innovation.153 However, the fact that FDA has no authority to require postmarketing surveillance in this area suggests that rigorous ex ante requirements are particularly appropriate and necessary.

Implications for nano-based products Industry groups have suggested that the current regulatory structure is adequate to address nanotechnology concerns related to food products and additives.154 They have also suggested that FDA's policies for dealing with foods derived from biotechnology provide a workable template for the agency's consideration of nanotechnology.155 However, this area of regulation is not without its unique hurdles. As with OTC drug monographs, a potential issue affecting nano-based products is that FDA's GRAS listings do not mention particle size. Thus a nanoscale ingredient would technically be covered by the GRAS exemptions unless FDA amends the regulation to establish particle size parameters. This is a particularly problematic issue considering that the GRAS determinations were likely to have been made in the absence of nanoscale safety evaluations. One example of the problematic nature of the GRAS exceptions is the use of nanoscale titanium dioxide to protect food from exposure to air and moisture.156 FDA's weight-based limits on titanium dioxide may not be adequate to account for the potential impact of nanoscale titanium dioxide since, as already discussed, materials at very small sizes can in fact have a greater effect than the same amount of material at conventional sizes.

Of products currently on the market in this area, only three are actually designated as a “food,” according to the database created by the Project on Emerging Nanotechnologies.157 There appears to be somewhat more activity in the area of food contact products. Food contact products include those used for packaging, storage, or cooking. They account for 17 of the “food and beverage” products in the database.158 A substantial amount of development and marketing activity actually seems to be occurring in the dietary supplement arena, as discussed subsequently. Although the database reveals few food products on the market at this point, a recent report from the Project on Emerging Nanotechnologies predicts a boom in nano-based agriculture and food production.159 A recent study by Helmut Kaiser Consultancy predicts that nanotechnology will be incorporated into approximately $20 billion worth of consumer products in the food industry by 2010.160 If these predictions are correct, FDA may need to consider whether the current regulations are indeed sufficient to ensure the safety of such a huge number of new food products.

One possible regulatory structure that has been suggested to address concerns in this area is a premarket notification system for novel food uses of nanotechnology whereby early food safety evaluations by FDA would be a prerequisite for novel nanotechnology applications.161 This could conceivably require a new statute creating and defining FDA's authority over a new class of product, that is, “novel” food applications. Determining what constitutes a “novel” application in food would be difficult given that FDA may not have adequate information to determine what nanoscale components of food currently exist and whether such ingredients have been adequately substantiated for safety. Such a scheme would also probably require FDA to promulgate a regulation defining “nanotechnology,” which could prove problematic given that FDA has continued to resist defining “nanotechnology” for agency purposes.

Dietary supplements

Existing authority Until the Dietary Supplement Health and Education Act of 1994 (DSHEA), FDA regulated dietary supplements under the same regulations as food additives and therefore had authority to require a manufacturer to go through the premarket approval process if an ingredient in the supplement was not GRAS. The term “dietary supplement” means a product intended to supplement the diet that contains one or more of the following ingredients: a vitamin, a mineral, an herb or other botanical, an amino acid, a dietary substance for use by man to supplement the diet by increasing the total dietary intake, or a concentrate, metabolite, constituent, extract, or combination of any ingredient described above.162 DSHEA, however, dramatically changed FDA's regulatory authority in this area. It is widely believed that DSHEA radically reduced the safety requirements for dietary supplements, although there are also strong arguments suggesting that DSHEA actually may have provided FDA with greater authority over dietary supplements than conventional food.163 Under the FD&C Act as amended by DSHEA, only supplements containing “new” ingredients are subject to premarket notification under DSHEA, and the safety standard seems to be much less burdensome than under the food additive regulations; it merely requires the sponsor to submit information that it believes its product is “reasonably expected to be safe.”164 However, it is also worth noting that a food manufacturer can avoid premarket notification of a new food ingredient by asserting that the ingredient is GRAS, whereas a manufacturer is required to submit premarket notification for any new dietary supplement ingredient that is not derived unchanged from food.165 Thus, while the safety standards appear to be lower for dietary supplements as a result of DSHEA, it is also possible that the Act actually makes it easier for FDA to exercise its regulatory authority in this area.

Implications for nano-based products As noted previously, a number of nano-based supplements are already on the market—16 by the Project on Emerging Nanotechnology's count.166 Once again, nanotechnology presents a potential problem in this area because the statutes are silent as to whether the supplements that use a nanoscale form of vitamins, minerals, herbs, or amino acids would be exempt from the approval process under DSHEA, or whether their unique particle size requires submission of premarket notification. Even if a manufacturer were required to submit premarket notification for a product containing nanomaterials, consumer groups suggest that testing requirements are insufficient to establish the safety of nano-based products. Given that Congress has already decided to tie FDA's hands in this area, it is unlikely that the agency will be able to do much to increase its authority over these products.

Cosmetics

Existing authority The FD&C Act does not provide FDA with any premarket authority over cosmetics, and cosmetics manufacturers are not required to provide FDA with any safety information regarding their products. FDA's only official, legal recourse is to utilize its postmarketing authority to bring an action against unsafe, unlawful, or misbranded products.167 FDA has attempted to use its labeling requirements to implement an additional safeguard in this area. The agency promulgated a regulation stating that products that have not been “adequately substantiated for safety prior to marketing” will be considered misbranded if they do not include the following warning label: “Warning—The safety of this product has not been determined.”168 Few products bear this label and commentators note that the lack of a warning label implies that either manufacturers are ignoring the regulation, or they believe they have adequately substantiated their safety.169 However, FDA has no authority to review the company's safety data to validate this assumption.

Historically, the cosmetic industry has been extremely cooperative with FDA and has implemented voluntary programs that provide FDA with some additional oversight tools, including voluntary safety information disclosure and postmarket reporting systems.170 For example, in 1976, CTFA established the Cosmetic Ingredient Review (CIR) to conduct and publish independent, scientific reviews on the safety of cosmetics ingredients; although funded by CTFA, CIR's review process is independent from CTFA and the cosmetic industry.171 The cosmetic industry has also developed the Voluntary Cosmetic Registration Program (VCRP) to provide FDA with a postmarket reporting system.172 Most recently, CTFA has developed a Consumer Commitment Code whereby cosmetics companies promise to make all safety data available to FDA at its request.173

Implications for nano-based products FDA's limited regulatory authority over cosmetics presents one of the most controversial issues when it comes to nanotechnology. There are already at least 64 nano-based cosmetics products on the market, including multiple products by industry giants Chanel, Dior, Lancome, and L’Oreal.174 Given the uncertainty surrounding adverse effects that may result from skin penetration (as already discussed in relation to sunscreens), the use of nanomaterials in cosmetics has, not surprisingly, generated a fair amount of concern among consumer groups.

Industry stakeholders assert that FDA's current regulatory authority is “significant and adequate to address the issues that are currently before FDA on issues of cosmetics.”175 A major factor underlying this assertion, however, is not related to FDA's actual authority, but to its extensive and historically successful reliance on voluntary reporting and self-regulation programs established in collaboration with industry. Industry is well aware that consumer groups are clamoring for increased agency oversight in this area; recent developments in industry self-regulation policies have sought to assuage public fears while simultaneously protecting industry from the burden of additional regulatory requirements.

CTFA's Consumer Commitment Code has the potential to address many concerns surrounding nanotechnology in this area. The program includes a requirement that companies provide FDA with a “Safety Information Summary” for each of their products upon the agency's request.176 The summary would include a statement that the product's safety has been substantiated, based on an assessment completed by the CIR, the FDA or the regulatory body of another country.177 In order for this voluntary program to prove effective for nano-based products, FDA may need to provide the cosmetic industry with additional guidance on the definition of adequate substantiation of safety. The agency clarified the meaning of “adequately substantiated for safety” in the preamble to the final regulation, stating that a product's safety could be adequately substantiated through “reliance on already available toxicological test data on individual ingredients and on product formulations that are similar in composition to the particular cosmetic” and “performance of any additional toxicological and other tests that are appropriate in the light of such existing data and information.”178 However, it may be necessary for FDA to provide additional guidance as to whether toxicological studies that explicitly consider particle size should be included in a product's safety evaluations.

As the preamble also recognized, “there often is scientific controversy concerning the amount of data necessary to demonstrate the safety of a cosmetic;” therefore, FDA will not require a warning statement “in circumstances where reasonable scientific opinion would regard the available data as adequate.”179 Given the current controversy over the adequacy of safety data for nano-sized particles, FDA may need to voice an opinion on the matter to push industry to undertake additional studies. Ultimately, however, the burden for substantiating safety—and the ramifications for failing to do so adequately—lie with the cosmetic industry, which may be enough to provide sufficient motivation for manufacturers to implement additional toxicological studies.

Although consumer groups often question the wisdom of relying on voluntary programs and industry self-regulation, voluntary programs have played a role in FDA's regulation of consumer products for decades—and with a notably high degree of success. This is largely attributable to the fact that industry has an interest in fostering a cooperative relationship with the agency, and in ensuring that products on the market will not lead to extensive liability for manufacturers. Despite the inevitable detractors, some consumer groups actually support CTFA's efforts. Environmental Working Group, for example, expressed optimism that the Consumer Commitment Code will ensure that nanoscale materials are either removed from products or that adequate safety data will be made available by industry that justify their continued presence on the market.180

While CTFA's program may solve most of the regulatory problems relating to cosmetics, FDA may still need to provide guidance in order for the program to work effectively. For example, it may need to define what is required to adequately substantiate a product's safety. If left to the individual companies, they may ignore nanoscale effects or extrapolate from other safety studies that may not, in fact, be applicable to every product. One potential definition—proposed by Environmental Working Group—would require companies to provide evidence of a “reasonable certainty of no harm from aggregate exposures to the product.”181 This is the same standard of review applied to food additives, but it is questionable whether FDA would—or could—apply that heightened standard of review to cosmetics, albeit on an informal basis.

FDA's Current Initiatives and the Other Players Involved

Many commentators have drawn an analogy between nanotechnology and biotechnology, and suggest that FDA should at the very least issue guidance to provide industry with standards for nanotechnology testing and a sense of how the agency plans to treat nano-based products under the existing regulations. Up to this point, FDA has resisted the call to issue new regulations or guidance addressing nanotechnology. However, FDA has not been passive in the face of this new regulatory dilemma.

The Office of the Commissioner of FDA has established a Nanotechnology Interest Group to coordinate regulation of nano-based products across its various Centers and Offices.182 In August 2006, FDA also formed the Nanotechnology Task Force, which is charged with developing regulatory approaches to nano-based products that will ensure safety and efficacy, while also facilitating beneficial technological innovation.183 According to Task Force co-chairman Randy Lutter, the group has been given 5 main tasks regarding nanotechnology: (1) “assess the current state of scientific knowledge,” (2) “evaluate the effectiveness of the agency's regulatory approaches and authorities to meet any unique challenge that may be presented by the use of nanotechnology materials,” (3) “explore opportunities to foster innovation,” (4) “continue to strengthen FDA's collaborative relationship with other federal agencies,” and (5) “consider appropriate vehicles for communicating with the public.”184

As previously mentioned, FDA's Nanotechnology Task Force held a Public Meeting on Nanotechnology Materials in FDA-Regulated Products on October 10, 2006. According to FDA's announcement of the meeting in the Federal Register, the purpose of the meeting was “help FDA further its understanding of developments in nanotechnology materials that pertain to FDA-regulated products.”185

Speakers at the Public Meeting addressed topics including general science, policy, and use of nanotechnology in FDA-regulated products, as well as specific applications and issues relating to various product categories. Those invited to speak represented a range of viewpoints, from academia to government to consumer groups to industry. Many of their comments have been incorporated in this article's earlier discussion of the problems facing nanotechnology and FDA's current regulatory authority. FDA's public report on the meeting is scheduled to be released in July 2007, and will include the Nanotechnology Task Force's findings and recommendations for the commissioner.186

Because of the potentially widespread implications of nanotechnology, FDA has recognized the need to coordinate with other government agencies through its participation in the Natl. Science and Technology Council's (NSTC) Subcommittee on Nanoscale Science, Engineering and Technology (NSET) and its Nanotechnology Environmental and Health Implications (NEHI) working group, which is chaired by Norris Alderson of FDA.187 NEHI recently prepared a report that was released by the NSTC, entitled Environmental Health and Safety Research Needs for Engineered Nanoscale Materials, that identifies the research and information needs of regulatory agencies in their attempts to assess and manage risks.188 The next step, of course, is for the agencies to figure out exactly how to prioritize the exceptionally broad amount of research needed to fully assess nanotechnology risks. It is a daunting task, but actually identifying the research needs is an important 1st step.

As already mentioned, FDA is also an active participant in the Natl. Nanotechnology Initiative (NNI). The NNI grew out of early efforts to coordinate federal work on nanotechnology that began back in 1996.189 It is charged with coordinating the efforts of its member agencies in area such as environmental, health, and safety research. Coordination is a massive effort, given the large number of participants in the initiative, which include: FDA, EPA, the Consumer Product Safety Commission, the Patent and Trademark Office, the Intl. Trade Commission, the Natl. Science Foundation, the Nuclear Regulatory Commission, the Intelligence Community, NASA, and the Departments of Agriculture, Commerce, Natl. Security, State, Education, Labor, Justice, Energy, Health and Human Services, Transportation, and Treasury.190 As previously noted, however, not every participant receives funding through NNI; only 13 of the agencies listed above are included in NNI's annual budget.191

One of the FDA's most important collaborative efforts is with the Natl. Cancer Inst. (NCI) and the NIST. These 3 groups recently established the Nanotechnology Characterization Laboratory (NCL) to provide preclinical characterization of nanomaterials intended for cancer applications. NCL was developed in response to nationwide concerns voiced by researchers complaining of the difficulty of comparing results between laboratories, determining which parameters of nanoparticles affect toxicity, and perceived uncertainty as to the regulatory process.192 NCL is a national, free resource that is open to researchers in academia, industry, and government.193 A nanoscale material presented as having potential applications for cancer treatment or diagnosis will be subject to physical, in vitro, and in vivo characterization by NCL.194 All of the data collected and developed in the NCL process will be publicly available within approximately 3 mo after NCL relays the information to the vendor.195 Any company considering integrating a nanomaterial into its product can look at the NCL database to determine whether the material has already been characterized. If it has, the company can move forward based on that information; if it has not, the company can submit the proposed particle to NCL for characterization. This revolutionary collaboration between government agencies, academia, and industry has the potential to speed development and approval of beneficial cancer therapies and diagnostics while preserving the private business information of developers.

Nanotechnology is also an international issue. Efforts to develop international standards are underway, and international bodies have been participating in dialogue with the United States regarding FDA's domestic regulation of nano-based products, as well as possibilities for collaboration.196 For example, FDA invited international nanotechnology experts to speak at its Public Meeting. Speakers included Dr. Philippe Martin and Dr. Delara Karkan, who provided perspectives on nanotechnology in the European Union (EU) and Canada, respectively. Other speakers at the conference echoed the sentiments of Drs. Martin and Karkan that international coordination and cooperation on nanotechnology issues is not only desirable, but also perhaps necessary.197 International bodies have also contributed comments to FDA's Public Docket on Nanotechnology.198

Regulatory Options and Recommendations

There is a broad spectrum of possibilities for FDA's treatment of nano-based products, ranging from maintaining the status quo to providing guidance for industry to developing entirely new regulations. Not all of the possibilities are mutually exclusive, and a consistent theme coming from all stakeholders is that we as a society, and FDA as an agency, simply need to know more about nanotechnology.

A number of consumer and environmental groups have urged a recall of all products already on the market that contain nanomaterials, and a moratorium on all nano-based products until comprehensive scientific studies prove their safety and until we have a new regulatory framework for dealing with nanotechnology.199 Realistically, however, this is extremely unlikely to happen, at least through FDA's actions. FDA has authority to regulate individual products and so could deny approval or challenge the marketing of individual nano-based products, but it cannot simply create a blanket regulation for a class of technology. It is possible, however unlikely, that Congress could implement a statutory moratorium on nanotechnology, but this is not something FDA has the power to control. Case-by-case review of products has been the norm since FDA's inception, and this will likely continue to be the case, particularly as more and more scientific evidence points to the fact that generalizations about nanomaterials are both unhelpful and impossible. This does not mean that FDA can ignore nanotechnology—and indeed, it has not—but any guidance provided by FDA would be best suited to providing additional standards and protocols that would support case-by-case product review.

Developing a scheme designed to account for the integration of nanotechnology into FDA-regulated products is problematic at this stage. In a recent symposium article on nanotechnology regulatory policy, Gary Marchant and Douglas Sylvester argue that “it is impossible to predict or recommend substantive regulatory approaches for a technology that is largely hypothetical and uncertain.”200 This is a fair point, but the issue is rapidly becoming less hypothetical as more and more products enter the pipeline and the market. As for uncertainty, this is one of the thorniest issues for FDA and is probably the biggest reason the agency has been hesitant to make definitive policy statements while simultaneously beginning to backtrack from its early assertions that “size is not an issue.” If the efforts of NCL and international standards organizations are any indication, improvements in characterization and testing protocols are around the corner, making it a critical time for FDA to marshal its (admittedly limited) resources to develop a policy perspective that it can communicate to the public.

Not surprisingly, most industry stakeholders believe that FDA's current regulatory authority is perfectly adequate for nano-based products.201 Consumer and environmental advocates, on the other hand, see a “regulatory vacuum.”202 It is true that there are no internationally agreed upon standards or research protocols, few studies on nanotoxicity, little agreement on characterization of nanomaterials, and no labeling requirements. However, there has been substantial progress in this field. FDA—in concert with other agencies, research organizations, and industry—is laying the groundwork for increasing its knowledge base and developing a measured approach to the issue.

Another interesting (and somewhat heretical) proposition was set forth by Dr. Philbert during FDA's Public Meeting. He urged that “there is no such thing as nanotechnology as far as FDA is concerned.”203 Dr. Philbert posits that trying to draw a line to define nanotechnology and label it as such will inevitably be an arbitrary process that misses the bottom line, that is, that what is most important is identifying potential hazards and conducting risk assessment and analysis.204 This does not, however, let FDA off the hook in terms of developing a policy for the regulation of nano-based products. Rather, it suggests that FDA should consider deviating from the current trend of defining nanotechnology based on size alone. A size-based classification might provide a more easily administrable standard for both the agency and industry, but it creates 2 new risks.

First, if such standards are used to label products and advise consumers of their “nano” status, it runs the risk of misleading the public into thinking that all products classified as “nano” involve the same health and safety concerns, whereas variations in the size and type of material are likely to result in vastly different safety profiles. Second, it will almost certainly allow some products to slip through the cracks simply because they are slightly larger than the officially designated size, despite the fact that research has shown that materials above 200 nm—and certainly those above the NNI's definition of 100 nm—can take on the unique properties that give rise to concern.

It may make sense for FDA to take a multi-pronged approach to defining nanotechnology. The agency could consider providing both size parameters and characterization parameters. Size parameters clearly make sense for topically applied products where skin penetration is the biggest concern since, presumably, size is the primary factor. At the same time, FDA could provide characterization parameters for other products, such as food additives, OTC drugs, and dietary supplements. Such parameters could indicate that any engineered material that exhibits properties differing from the same material in bulk form would be considered a “new” ingredient for regulatory purposes. This would allow the agency to account for the uncertainty and variability surrounding the point at which nano-dependent properties become manifest. It would also provide some much-needed clarity for those materials whose conventional forms are currently found on GRAS and OTC monograph listings, but whose nanoscale counterparts have not yet been tested or characterized. Along the same lines, FDA may need to consider revisiting its weigh-based exclusions to NEPA and take particle size and related nano-based properties into account as well.205

At this juncture, it is important to consider some crucial distinctions between nano-based products. There are a vast number of products in the pipeline that FDA will have to deal with down the road, but there are also a number of products already on the market, some of which have been subject to rigorous testing (for example, nano-based drug products like Abraxane, Doxil, and Emend) and some of which may have slipped onto the market without necessarily undergoing sufficient testing with regard to their nano-properties (for example, sunscreens containing nanoparticles of titanium dioxide). FDA's regulatory framework for new drugs and PMA devices seems well equipped to address concerns about nanomaterials—the simple solution would be for FDA to require adequate testing of those materials, as it did for the 3 currently approved nano-based drug products. In the case of 510(k) products, FDA could withhold certification of “substantial equivalence” if it felt that the device's nano-properties required further study. In the case of products such as OTC drugs and GRAS ingredients, however, FDA would need to set a new standard if it wanted manufacturers to specifically consider nano-based safety concerns.206 As for those products already on the market, FDA could revise the monograph and GRAS listings and then provide the manufacturers with a window of time to provide additional data supporting the safety of their products rather than calling for their immediate withdrawal from the market; in particular, this would make sense for products that might fall outside the listings under the new standards, but which have not seemed to create any new safety issues for consumers during their time on the market.

Regardless of the policy position FDA ultimately decides to take, transparency needs to take a front seat. As one speaker at the Public Meeting noted: “Stealth might be great for jet fighters, but it's not the strategy that you want to use for new technology like nanotech…[A]voiding disclosure and transparency is exactly what raises public suspicions and generates mistrust.”207 This extends not only to industry, but also to FDA. If the agency decides not to seek additional authority or implement new regulations, then it is imperative that they communicate exactly how the existing regulations will be applied to nanotechnology, and how they are sufficient to address environmental and human safety concerns related to nano-based products. This is the only way to maintain public confidence in the face of an emerging and uncertain new technological field.

Whether the need for transparency necessarily extends to a need for labeling is less obvious. In terms of labeling, the question really becomes whether there is a valid reason to put information relating to a product's utilization of nanotechnology on the label. In the absence of a sufficiently compelling reason for labeling requirements, such requirements may run up against First Amendment concerns, as illustrated by a case from the mid-1990s in which the dairy industry challenged a Vermont statute requiring labeling of dairy products produced through the use of bovine growth hormone.208 The Second Circuit reversed the district court's decision denying the appellants’ motion for a preliminary injunction against enforcement of the statute on the grounds that the appellants had demonstrated that they would be irreparably harmed by a violation of their First Amendment rights if the statute was allowed to force them to speak, and that consumer curiosity was not a substantial enough state interest to displace the dairy industry's Constitutional rights.209 Thus, any attempts to force the labeling of nano-based products would probably face similar constitutional challenges, and unless advocates can establish a justification for labeling beyond mere consumer desire for information, industry will probably succeed in avoiding statutorily created labeling requirements.

Furthermore, a labeling policy risks creating unwarranted concern among consumers who begin to think there must be something “wrong” with nano if FDA requires such labeling. As mentioned previously, FDA is currently grappling with the negative impact of labeling in the realm of irradiated food, and is attempting to revise its regulations to improve consumer perception of products that are actually beneficial by virtue of the very irradiation consumers seem to fear. If a particular material is scientifically proven to be safe, then it is unclear what the rationale would be for requiring a label on such a product. Since a blanket labeling requirement might inhibit the diffusion and public acceptance of highly beneficial products, a more rational approach would be for FDA to impose labeling requirements only when specific materials or products have questionable or unproven safety profiles.

A valid point raised by a number of commentators is that, while the existing framework for nanotechnology regulation may be adequate, carefully considered implementation of that framework has been sorely lacking.210 Indeed, the current framework has worked for decades and has always managed to adapt to changing technology and novel scientific issues. A common theme at FDA's Public Meeting was that perhaps FDA does not need new regulations for nanotechnology, but rather needs the funding to adequately implement the existing regulations.

Another tool in FDA's arsenal is continued reliance on industry self-regulation and voluntary disclosure. Based on the Project on Emerging Nanotechnologies’ recent survey and focus groups, the public shows “virtually no support of industry self-regulation of a new technology…[or] voluntary programs.”211 But regardless of public mistrust of industry, the fact of the matter is that voluntary measures have strengthened FDA's ability to regulate products over which its statutory authority is weak. Studies suggest that public confidence could be greatly improved by providing for greater transparency, requiring premarket testing, and instituting 3rd party independent testing and research. However, public desire for expanded FDA authority does not necessarily mean it is possible, or even desirable. Furthermore, disclosure and transparency seem to be the most important factors in securing public support; perhaps disclosure and transparency about the considered application of existing regulations and the nature and extent of voluntary programs will suffice to quell the public's fears.

Given the widespread requests from consumer groups, industry, and researchers, FDA will probably be forced to develop nanotechnology standards and policies eventually. The question for FDA, really, is whether it should proceed to set standards now, when the knowledge development process is still young, or later, when there is a greater pool of knowledge that can be applied to products and processes. One scientist has noted that “historically put…the ability to predict impacts at the very early level of scientific discovery doesn't work very well.”212 At the same time, however, “late engagement [can] alienate[] the public.”213 Another option is to wait for international groups, such as the OECD, to develop internationally agreed upon methodologies and standards to manage nano-based products while protecting the public and the environment.214

Even those commentators who fervently urge FDA to expand its regulatory policy to account for the unique issues relating to nanotechnology recognize that such a change will inevitably take time. But they also assert that steps need to be taken in the interim to plug the perceived “gaps” in FDA's oversight of nano-based products.215

Currently, some of the areas most ripe for FDA guidance seem to be in the areas OTC products and food ingredients, where the regulatory status of nanoscale versions of materials included in GRAS and OTC monograph listings is already creating controversy. With so many sunscreens containing nanoparticles already on the market, and with nanotechnology poised to revolutionize the food industry, FDA does not have much time to vacillate on this issue. Similarly, FDA could improve its oversight of dietary supplements—another product area with a number of applications already on the market—by indicating what circumstances are necessary for a nanoscale version of a dietary supplement to be considered a “new” ingredient and therefore subject to new or additional safety substantiation.

Conclusions

Nanotechnology prevents a web of varied and complicated issues that FDA has finally begun taking steps to address. FDA has a rigorous regulatory framework that has served it well over the years, although it is not without its shortcomings. Unfortunately, it seems that FDA's funding crisis will continue for the foreseeable future and will continue to prevent FDA from meeting its evolving regulatory needs as efficiently and effectively as possible. Continued collaboration across agencies and with industry will help fill the gaps left by FDA's own resources and regulatory weaknesses. Public perception should become a greater focus for the agency, as well as industry. Given the extensive calls for disclosure and transparency FDA has been fielding, the agency would be remiss if it did not continue its efforts to engage the public and keep it abreast of policy considerations and developments. Ultimately, the agency has managed to maneuver through the minefields created by new technologies in the past; it will certainly be able to do so again, provided it makes full use of the tools in its regulatory arsenal, admits that the need for some additional clarification in this area is inevitable, and rises to the task of providing it sooner, rather than later.

Acknowledgment

The author thanks Peter Barton Hutt for generously sharing his wisdom and time and for providing guidance throughout this project.

Endnotes

  • 1

    21st Century Nanotechnology Research and Development Act, Pub. L. 108–153, §10, 117 Stat. 1923 (codified at 15 U.S.C. §7509 [2003]).

  • 2

    Nanoscience and Nanotechnologies: Opportunities and Uncertainties—Summary and Recommendations, The Royal Society & the Royal Academy of Engineering (2004). Available from: http://www.nanotec.org.uk/finalreport.htm. Accessed Mar 30, 2007.

  • 3

    See, for example, comments of Carolyn Cairns, representing Consumers Union, FDA's Public Meeting on Nanotechnology Materials in FDA Regulated Products (October 10, 2006), transcript available from: http://www.fda.gov/nanotechnology/meetings/transcript.html. Accessed Apr 9, 2007, [hereinafter FDA's Public Meeting Transcript], at 62: “We recognize the important benefits that these materials can bring to certain product sectors, such as more effective medicines, safer drinking water, and energy savings, but we also know that these benefits depend entirely on responsible development of nanotechnology.”

  • 4

    Pub. L. 108–153, §2, 117 Stat. 1923 (codified at 15 U.S.C. §7501 [2003]).

  • 5

    See, for example, comments of Kathy Jo Wetter, representing ETC Group, FDA's Public Meeting Transcript, endnote 3, at 119: “[T]he US Government has acted as a cheerleader, not a regulator, in addressing the nanotech revolution. In the all out race to secure economic advantage, health and environmental considerations have taken a back seat and socioeconomic impacts are a distant concern.”

  • 6

    The inventory is available from: http://nanotechproject.org/consumerproducts. Accessed Apr 6, 2007.

  • 7

    “A Survey of Ingredients in 25,000 Personal Care Products Reveals Widespread Use of Nano-Scale Materials, Not Assessed for Safety, in Everyday Products,” comments submitted by Environmental Working Group to FDA's Nanotechnology Public Docket. Available for download from: http://www.fda.gov/ohrms/dockets/dockets/06n0107/06n0107.htm. Accessed Apr 9, 2007.

  • 8

    Artificially inflating the numbers in this manner may lead to undue concern on the part of the public, but FDA must be prepared to deal with that concern, whether it is warranted or not. Subsection “Combination Products” addresses this issue in greater detail.

  • 9

    See, for example, comments of Dr. David Rejeski, representing the Project on Emerging Nanotechnologies, FDA's Public Meeting Transcript, endnote 3, at 99.

  • 10

    See Trudy E. Bell, Understanding Risk Assessment of Biotechnology, NNI, available for download from: http://www.nano.gov/Understanding_Risk_Assessment.pdf. Accessed Apr 4, 2007, at 2.

  • 11

    Studies associated with the Natl. Cancer Inst. sometimes refer to particles of up to 200 nm in size as nanoparticles. See, for example, Brightly Fluorescent European Nanoparticles May Improve Cancer Assays, Nanotechwire.com (February 11, 2007), available from: http://www.nanotechwire.com/news.asp?nid=4313&ntid=190&pg=1. Accessed Apr 6, 2007; see also “Nano-targeting” cancer and heart disease, Washington Univ. in St. Louis (May 9, 2003), available from: http://news-info.wustl.edu/tips/page/normal/203.html. Accessed Apr 6, 2007.

  • 12

    In his comments at FDA's Public Meeting, Neil Desai from Abraxis Bioscience Incorporated noted that “of 152 abstracts recently cited, almost 80% actually talk about nanoparticles that are greater than 100 nanometers, not less than 100 nanometers.” FDA's Public Meeting Transcript, endnote 3, at 187.

  • 13

    Nanotechnology Facts: What is Nanotechnology? NNI Website, available from: http://www.nano.gov/html/facts/whatIsNano.html. Accessed Mar 26, 2007.

  • 14

    FDA and Nanotechnology Products: Frequently Asked Questions (FAQs), FDA Website, available from: http://www.fda.gov/nanotechnology/faqs.html. Accessed Mar 26, 2007.

  • 15

    See Bell, endnote 10, at 2.

  • 16

    Id.

  • 17

    Id.

  • 18

    Nanotechnology White Paper, EPA Science Policy Council (December 2, 2005), available from: http://www.epa.gov/osa/pdfs/nanotech/epa-nanotechnology-white-paper-final-february-2007.pdf. Accessed Apr 9, 2007.

  • 19

    See Bell, endnote 10, at 2.

  • 20

    Robin Fretwell Wilson, Nanotechnology: The Challenge of Regulating Known Unknowns, 34 J.L. Med. & Ethics 704 (2006).

  • 21

    This is primarily thought to occur as a result of the extremely large surface area of nanoparticles, which can make them much more reactive than their bulk counterparts. See, for example, Bell, endnote 10, at 2, 3.

  • 22

    71 Fed. Reg. 46232 (August 11, 2006).

  • 23

    71 Fed. Reg. 46232.

  • 24

    Nanoscience and Nanotechnologies: Opportunities and Uncertainties, Royal Society and Royal Academy of Engineering (July 2004), at 79, available for download from: http://www.nanotec.org.uk/finalReport.htm. Accessed Apr 7, 2007.

  • 25

    See generally, FDA's Public Meeting Transcript, endnote 3, available from: http://www.fda.gov/nanotechnology/meetings/transcript.html. Accessed Apr 9, 2007.

  • 26

    For example, DuPont has developed a partnership with Environmental Defense to develop processes for understanding the environmental and health impacts of nanotechnology. See Section “Environmental, health, and safety impacts” of this article for additional information about this effort.

  • 27

    FDA Regulation of Nanotechnology Products, FDA Website, available from: http://www.fda.gov/nanotechnology/regulation.html. Accessed Apr 5, 2007.

  • 28

    For example, FDA's rationale for its October 2006 Public Meeting includes the statement: “Due to their small size and extremely high ratio of surface area to volume, nanotechnology materials often have chemical or physical properties that are different from those of their larger counterparts… because of some of their special properties, they may pose different safety issues than their larger counterparts.” 71 Fed. Reg. 46233 (August 11, 2006).

  • 29

    Comments of Dr. Philippe Martin, representing the European Commission, FDA's Public Meeting Transcript, endnote 3, at 27, 28.

  • 30

    Id. at 27.

  • 31

    Id. at 28.

  • 32

    Two examples include pure carbon, which can take 1 of 3 shapes at the nanoscale (graphite, diamond, and buckyball or fullerene) and titanium dioxide, which can take on at least 2 different shapes. See Bell, endnote 10, at 3.

  • 33

    See comments of Dr. Stacey Harper, representing Oregon State Univ., FDA Public Meeting Transcript, endnote 3, at 80–81.

  • 34

    See, for example, comments of Dr. Celia Merzbacher, representing NNI, FDA Public Meeting Transcript, endnote 3, at 23: “If we can't characterize nanomaterials, then we don't know what we’re testing…researchers and business people alike are clamoring for standards.”

  • 35

    Organizations involved in attempts to establish international standards include ISO, IEC, ANSI, and ASTM. See Bell, endnote 10, at 2.

  • 36

    See, for example, comments submitted by Consumer Union to FDA's Nanotechnology Public Docket, available for download from: http://www.fda.gov/ohrms/dockets/dockets/06n0107/06n0107.htm. Accessed Apr 7, 2007.

  • 37

    Examples include tests for oxidative stress, C-reactive protein, platelet aggregation, and other immune and inflammatory responses, neurotoxicity, and genetic toxicity. See, for example, comments of Consumer Union, submitted to FDA's Nanotechnology Public Docket, available for download from: http://www.fda.gov/ohrms/dockets/dockets/06n0107/06n0107.htm, at 11 (citing various reports from U.S. and European working groups). See also comments of Carolyn Cairns, FDA Public Meeting Transcript, endnote 32, at 62. Accessed Apr 7, 2007.

  • 38

    Citizen Petition to the United States Food and Drug Administration: Petition Requesting FDA Amend its Regulations for Products Composed of Engineered Nanoparticles Generally and Sunscreen Drug Products Composed of Engineered Nanoparticles Specifically (May 16, 2006), available for download from: http://www.icta.org/doc/Nano%20FDA%20petition%20final.pdf. Accessed Apr 9, 2007.

  • 39

    Petitioners included CTA, FOE, Greenpeace Intl., the Action Group on Erosion, Technology and Concentration (ETC Group), Clean Production Action, the Center for Environmental Health (CEH), Our Bodies, Ourselves, and the Silicon Valley Toxics Coalition (SVTC). Id.

  • 40

    Comments of Cosmetic, Toiletry, and Fragrance Association (CTFA) Regarding Scientific and Legal Issues Associated with Nanotechnology in Personal Care Products, submitted in re: Docket Nr 2006P-0210, available for download from: http://www.fda.gov/ohrms/dockets/dockets/06n0107/06n0107.htm. Accessed Apr 9, 2007.

  • 41

    Nanotechnology and Life Cycle Assessment: A Systems Approach to Nanotechnology and the Environment, Project on Emerging Nanotechnologies, Woodrow Wilson Intl. Center for Scholars (March 2007), available for download from: http://www.nanotechproject.org/111/32007-life-cycle-assessment-essential-to-nanotech-commercial-development Accessed Apr 5, 2007.

  • 42

    Id.

  • 43

    Comments of Andrew Maynard, chief scientist for the Project on Emerging Nanotechnologies, quoted in Life Cycle Assessment Essential to Nanotech Commercial Development, Project on Emerging Nanotechnologies, available from: http://www.nanotechproject.org/111/32007-life-cycle-assessment-essential-to-nanotech-commercial-development. Accessed Apr 5, 2007.

  • 44

    S. Walsh and T. Medley, A Framework for Responsible Nanotechnology, Environmental Defense, available from: http://www.environmentaldefense.org/documents/6081_Nano%20Risk%20Framework%20overview%20manuscript-26feb07.pdf. Accessed Apr 5, 2007.

  • 45

    Id.

  • 46

    However, it should be noted that the Natl. Environmental Policy Act (NEPA) requires all federal agencies—including FDA—to consider the environmental effects of any “major federal action” by preparing an Environmental Assessment (EA) or Environmental Impact Statement (EIS). 42 U.S.C. §4332(c).

  • 47

    See, for example, FDA's “Nanotechnology FAQs,” available from: http://www.fda.gov/nanotechnology/faqs.html. Accessed Apr 9, 2007: “Because FDA regulates products based on their statutory classification rather than the technology they employ, FDA's regulatory consideration of an application involving a nanotechnology product may not occur until well after the initial development of that nanotechnology.”

  • 48

    See, for example, comments of Consumer Union, submitted to FDA's Nanotechnology Public Docket, available for download from: http://www.fda.gov/ohrms/dockets/dockets/06n0107/06n0107.htm. Accessed Apr 9, 2007.

  • 49

    Consumer Union suggested that product labeling is “crucial to facilitate exposure assessment and product tracing in the event of unanticipated effects and to enable assessment of cumulative effects that occur from exposure to materials in multiple products.” Id.

  • 50

    For example, products applied topically, such as sunscreens and cosmetics, may enter the water supply through the normal course of washing and bathing; unused prescription drugs may reach the environment after they are tossed in the garbage.

  • 51

    See, for example, comments of Consumer Union, endnote 48.

  • 52

    For example, carbon buckyballs, or fullerenes, have been the subject of studies that show adverse impacts on fish. See, for example, comments of John Balbus, representing Environmental Defense, FDA Public Meeting Transcript, endnote 32, at 53. See also comments of George Kimbrell, representing CTA, FDA Public Meeting Transcript, endnote 32, at 143.

  • 53

    42 U.S.C. §4332(c).

  • 54

    42 U.S.C. §4332.

  • 55

    42 U.S.C. §4342.

  • 56

    21 C.F.R. §24.20.

  • 57

    21 C.F.R. §25.15. See below for additional discussion of the drug approval process.

  • 58

    See “Nanotechnology FAQs,”endnote 47.

  • 59

    21 C.F.R. §25.15.

  • 60

    Wyoming Outdoor Council v. U.S. Forest Service, 165 F.3d 43, 49 (D.C. Cir. 1999) (quoting Mobile Oil Corp. v. FTC, 562 F.2d 170, 173 [2d Cir. 1977]).

  • 61

    Alliance for Bio-Integrity v. Shalala, 116 F. Supp. 2d 166 (D.D.C. 2000).

  • 62

    116 F. Supp. 2d 166, 174.

  • 63

    NEPA entitles FDA to make such exceptions, which have been codified at 21 C.F.R. §31.

  • 64

    21 C.F.R. §25.31.

  • 65

    “Some nanoparticles readily travel throughout the body, deposit in target organs, penetrate cell membranes, lodge in mitochondria, and may trigger injurious responses.” Andre Nel and others, “Toxic potential of materials at the nanolevel,” Science, Vol. 311: No. 5761, 622 (2006).

  • 66

    See Bell, endnote 10, at 4.

  • 67

    Id.

  • 68

    Id.

  • 69

    Id.

  • 70

    See comments of John Balbus, representing Environmental Defense, FDA Public Meeting Transcript, endnote 3, at 53.

  • 71

    See Bell, endnote 10, at 4.

  • 72

    Comments of David Berube, representing Intl. Council on Nanotechnology, FDA Public Meeting Transcript, endnote 3, at 58.

  • 73

    “Lack of evidence of harm should not be a proxy for reasonable certainty of safety.” Comments of Consumers Union, submitted to FDA's Nanotechnology Public Docket (October 6, 2006), available for download from: http://www.fda.gov/ohrms/dockets/dockets/06n0107/06n0107.htm. Accessed Apr 5, 2007.

  • 74

    Id.

  • 75

    Comments of John Balbus, FDA Public Meeting Transcript, endnote 3, at 56.

  • 76

    “We have been surrounded by natural nanoparticles for eons…humans have developed natural response mechanisms to nanoparticles.” Comments of Matthew Jaffee, representing United States Council for Intl. Business, FDA Public Meeting Transcript, endnote 3, at 85.

  • 77

    Despite its potential drawbacks, there is precedent for such a moratorium. Since 2001, FDA has called for a voluntary moratorium on the introduction of food from cloned animals while the agency studies the issue. The agency released a draft risk assessment, a proposed risk management plan, and a draft guidance for industry in December 2006. FDA Issues Draft Documents on the Safety of Animal Clones, FDA News, available from: http://www.fda.gov/bbs/topics/NEWS/2006/NEW01541.html. Accessed May 2, 2007. At the same time, however, the United States successfully challenged the EU's moratorium on genetically modified food under the WTO. See Panel Report, European Communities—Measures Affecting the Approval and Marketing of Biotech Products, WT/DS291/R, WT/DS292/R, WT/DS293/R, Corr.1 and Add.1, 2, 3, 4, 5, 6, 7, 8 and 9, adopted 21 November, 2006.

  • 78

    Comments of Martin Phillbert, FDA Public Meeting Transcript, at 94.

  • 79

    “Even if there are no inherent risks or toxicities associated with nanomaterials, the public's perception of that is not going to be realized until the toxicological studies are promoted in concert transparently with the development of novel materials.” Comments of Stacey Harper, representing Oregon Nanoscience and Microtechnologies Institute, FDA Public Meeting Transcript, at 75.

  • 80

    See, for example, Bell, endnote 10.

  • 81

    Attitudes Toward Nanotechnology and Federal Regulatory Agencies: Report Findings, Peter D. Hart Research Associates, Inc. (September 2006), available for download from: http://www.nanotechproject.org/77. Accessed Apr 9, 2007.

  • 82

    Id. at 5, 7.

  • 83

    72 Fed. Reg. 16291 (April 4, 2007). See also Andrew Bridges, U.S. Seeks to Ease Irradiated Food Label, Forbes.com (April 3, 2007), available from: http://www.forbes.com/feeds/ap/2007/04/03/ap3579512.html. Accessed May 1, 2007.

  • 84

    See comments of FPA and GMA, submitted to FDA's Nanotechnology Public Docket, available for download from: http://www.fda.gov/ohrms/dockets/dockets/06n0107/06n0107.htm. Accessed Apr 7, 2007.

  • 85

    Comments of David Rejeski, FDA Public Meeting Transcript, endnote 3, at 103: “Once people learn about technology, once we give them information, they show very little support for any kind of moratorium on nanotech R&D….They get excited about the applications, especially about the medical applications, which I think has enormous implications for FDA. This is what really excites people in these focus groups, the medical applications of nanotechnology.”

  • 86

    Id. at 100.

  • 87

    Id. at 101. Rejeski also noted that all of the individuals surveyed overestimated the FDA's level of regulatory authority over cosmetics. Id.

  • 88

    Nanotechnology in $32 Billion Worth of Products: Global Funding for Nanotech R&D Reaches $9.6 Billion, Lux Research, Inc., New York (May 8, 2006), available from: http://www.luxresearchinc.com/press/RELEASE_TNR4.pdf. Accessed Apr 3, 2007.

  • 89

    Nanotech Venture Capital to Exceed $650 Million in 2006, Lux Research, Inc., New York (December 4, 2006), available from: http://www.luxresearchinc.com/press/RELEASE_VCreport.pdf. Accessed Apr 3, 2007.

  • 90

    Revenue from Nano-technology Enabled Products to Equal IT and Telecom by 2014, Exceed Biotech by 10 Times, Lux Research, Inc., New York (October 25, 2004), available from: http://www.luxresearchinc.com/press/RELEASE_SizingReport.pdf. Accessed Apr 3, 2007.

  • 91

    Sen. Allen Announces Congressional Nanotechnology Caucus, NNI Website (April 2004), available from: http://www.nano.gov/html/about/NNIConf04.html. Accessed Apr 3, 2007.

  • 92

    See, for example, Wyden, Burr, Gordon, Hall Kick Off Congressional Nanotechnology Caucus, press release from Senator Wyden's website (January 31, 2007), available from: http://wyden.senate.gov/media/2007/01312007_Nanotech.htm. Accessed Mar 26, 2007.

  • 93

    About the NNI: History, NNI Website, available from: http://www.nano.gov/html/about/history.html. Accessed Mar 26, 2007.

  • 94

    NNI Environmental, Health, and Safety Issues, NNI Website, available from: http://www.nano.gov/html/society/EHS.htm. Accessed Apr 9, 2007.

  • 95

    Pub. L. 108-153, 117 Stat. 1923 (codified at 15 U.S.C. §7509 [2003]).

  • 96

    National Nanotechnology Initiative: FY 2008 Budget and Highlights, NNI, available for download from: http://www.nano.gov/NNI_FY08_budget_summary-highlights.pdf. Accessed Apr 9, 2007.

  • 97

    Id.

  • 98

    The agencies entitled to receive a portion of NNI's funding are: NSF, DOD, DOE, DHHS (NIH), DOC (NIST), NASA, EPA, USDA (CSREES), DHHS (NIOSH), USDA/FS, DHS, DOJ, DOT (FHWA). Id.

  • 99

    H.R. Rep. Nr 108–89 (2003), generally, and at 8. See also S. Rep. Nr 108–147 (2003).

  • 100

    Michael R. Taylor, Regulating the Products of Nanotechnology: Does FDA Have the Tools it Needs?, Project on Emerging Nanotechnologies, Woodrow Wilson Intl. Center for Scholars (October 2006), at 14 and 46, available for download from: http://www.nanotechproject.org/82/10506-regulating-the-products-of-nanotechnology. Accessed Mar 26, 2007.

  • 101

    See Nanotechnology FAQs, endnote 14.

  • 102

    See Taylor, endnote 100, at 15.

  • 103

    Nanotechnology FAQs, endnote 14.

  • 104

    See, for example, CTA's Citizen Petition to FDA, endnote 38.

  • 105

    Peter B. Hutt and Richard A. Merrill, Food and Drug Law: Cases and Materials, Second Edition, Foundation Press, New York (1991) at 380.

  • 106

    Chevron, U.S.A., Inc. v. NRDC, Inc., 467 U.S. 837 (U.S. 1984).

  • 107

    21 U.S.C. §321(g)(1).

  • 108

    21 U.S.C. §355(a).

  • 109

    See Hutt and Merrill, endnote 105, at 515.

  • 110

    The Food and Drug Administration's Process for Approving New Drugs, Report of the Subcommittee on Science, Research and Technology of the House Committee on Science and Technology, 96th Congress, 2nd Session (1980), reprinted in Hutt and Merrill, endnote 105, at 519.

  • 111

    Id.

  • 112

    21 U.S.C. §355(d).

  • 113

    21 U.S.C. §355(k)(1). For all approved drugs, “the applicant shall establish and maintain such records, and make such reports to the Secretary, of data relating to clinical experience and other data or information, received or otherwise obtained by such applicant with respect to such drug, as the Secretary may by general regulation, or by order with respect to such application, prescribe on the basis of a finding that such records and reports are necessary in order to enable the Secretary to determine…whether there is or may be grounds for invoking subsection (e) of this section,” where subsection (e) permits FDA to withdraw approval of a previously approved drug. See also FDA regulations promulgated pursuant to this statutory authority and requiring prompt reporting of serious adverse events (21 C.F.R. §314.80) and periodic reporting of all data regarding a drug's safety and efficacy (21 C.F.R. §314.81).

  • 114

    All persons required to keep records under the section, “shall, upon request of an officer or employee designated by the Secretary, permit such officer or employee at all reasonable times to have access to and copy and verify such records.” 21 U.S.C. §355(k)(2).

  • 115

    21 U.S.C. §355(e).

  • 116

    Nanomedicine and Nano Device Pipeline Surges 68%, Nanotechwire.com (January 4, 2006), available from: http://www.nanotechwire.com/news.asp?nid=2743. Accessed Apr 8, 2007.

  • 117

    Database available from: http://nanotechproject.org/87#Tools. It should be noted that not all of these products are marketed or directly available to consumers. Some of the applications included in the database are used by researchers and doctors for drug discovery and imaging, while others require a prescription.

  • 118

    Id.

  • 119

    The approval letter for Emend required the applicant (Merck & Company, Inc.) to commit to providing additional data relating to the nanoparticle formulation, suggesting that FDA was attuned to potential concerns about particle size. Emend Approval Letter(s), CDER Approval Package for Application Number 21-549, available for download from: http://www.fda.gov/cder/foi/nda/2003/21-549_Emend_Approv.pdf. Accessed May 2, 2007.

  • 120

    Both Abraxane and Taxol utilize paclitaxel, but the albumin nanoparticles in Abraxane give it a superior response rate to Taxol, and the maximum tolerated dose of Abraxane is 50% higher than Taxol. Medical Review(s), CDER Approval Package for Application Number 21-660, available for download from: http://www.fda.gov/cder/foi/nda/2005/21660_ABRAXANE_medr.PDF. Accessed May 2, 2007.

  • 121

    Doxil's nanoformulation decreases the toxicity of doxorubicin, an anticancer agent. Vance McCarthy, Pharma Explores Business Opportunities for Nanotech, Nano Science and Technology Inst. (February 22, 2006), available from: http://www.nsti.org/news/item.html?id=43. Accessed May 3, 2007.

  • 122

    Package inserts for each drug can be downloaded from the “Drugs@FDA” section of the FDA website available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed May 2, 2007.

  • 123

    Comments of Dr. Neil Desai, representing Abraxis Bioscience Incorporated, FDA Public Meeting Transcript, endnote 3, at 186.

  • 124

    Hutt and Merrill, endnote 105, at 588.

  • 125

    Pub. L. 87-781, 76 Stat. 780 (October 10, 1962).

  • 126

    21 C.F.R. §330.

  • 127

    Id.

  • 128

    Id.

  • 129

    As previously noted, the FDA made a similar decision to presume that foods produced through the rDNA process were GRAS and therefore not subject them to additional testing requirements. See Alliance for Bio-Integrity, 116 F. Supp. 2d 166.

  • 130

    According to the Project on Emerging Nanotechnology's database of consumer products, available from: http://nanotechproject.org/index.php?id=44&action=advanced. Accessed Apr 5, 2007.

  • 131

    21 C.F.R. §352.

  • 132

    “‘Micronization’ refers to a process of grinding materials down rather than a particle-size classification, and may or may not lead to the production of nanosize particles.” Taylor, endnote 100, at 42.

  • 133

    CTA's Citizen Petition to FDA, endnote 38.

  • 134

    CTFA's comments in response to CTA's Petition to FDA, endnote 40; see also comments of Annette Santamaria, representing CTFA, FDA Public Meeting Transcript, endnote 3, at 168.

  • 135

    National Nanotechnology Initiative: FY 2008 Budget and Highlights, endnote 96; Nanotechnology FAQs, endnote 14.

  • 136

    Pub. L. 94-295, 90 Stat. 539 (1976).

  • 137

    Overview of Regulations, FDA Website, available from: http://www.fda.gov/cdrh/devadvice/overview.html. Accessed Apr 10, 2007.

  • 138

    Id.

  • 139

    “These ‘general controls’ include the basic adulteration and misbranding provisions as well as applicable good manufacturing practice (GMP) regulations, banned device regulations, and notification and repair, replacement, or refund requirements.” Hutt and Merrill, endnote 105, at 749.

  • 140

    Nanomedicine and Nano Device Pipeline Surges 68%, Nanotechwire.com (January 4, 2006), available from: http://www.nanotechwire.com/news.asp?nid=2743. Accessed Apr 8, 2007.

  • 141

    Overview of the Office of Combination Products, USFDA Website, available from: http://www.fda.gov/oc/combination/overview.html. Accessed Mar 29, 2007. See also 21 C.F.R. §3.2(e), for the full definition of “combination product.”

  • 142

    Overview of the Office of Combination Products, endnote 141.

  • 143

    Id.

  • 144

    21 C.F.R. §3.

  • 145

    Nanotechnology FAQs, endnote 14.

  • 146

    Taylor, endnote 100, at 30.

  • 147

    21 U.S.C. §321(s).

  • 148

    Id. Examples include common food ingredients such salt, sugar, flour, and so on.

  • 149

    Taylor, endnote 100, at 34.

  • 150

    21 U.S.C. §331 and §342.

  • 151

    21 U.S.C. §348.

  • 152

    21 C.F.R. §170.3.

  • 153

    Taylor, endnote 100, at 36.

  • 154

    “Regardless of whether the technologies employed are new or conventional, FD&C Act standards remain constant, requiring manufacturers to establish that food is safe and labeling claims are substantiated based on sound scientific evidence…” comments by FPA and GMA submitted to FDA's Nanotechnology Public Docket, available for download from: http://www.fda.gov/ohrms/dockets/dockets/06n0107/06n0107.htm. Accessed Apr 7, 2007.

  • 155

    Id. at 3.

  • 156

    Comments of Kathy Jo Wetter, representing ETC Group, FDA Public Meeting Transcript, endnote 3, at 118.

  • 157

    See database entries for Nanoceuticals™ Slim Shake Chocolate by RBC Life Sciences®, Inc. (U.S.A.), Nanotea by Shenzen Become Industry & Trade Co., Ltd. (China), and Canola Active Oil by Shemen Industries (Israel). The inventory is available from: http://www.nanotechproject.org/44/consumer-nanotechnology. Accessed Apr 9, 2007.

  • 158

    They include, for example, 2 food storage products in the Sharper Image® FresherLonger™ product line, as well as refrigerators by Samsung® and LG®. Id.

  • 159

    Jennifer Kuzma and Peter VerHage, Nanotechnology in Agriculture and Food Production: Anticipated Applications, Project on Emerging Nanotechnologies, Woodrow Wilson Intl. Center for Scholars (September 2006), available for download from: http://www.nanotechproject.org/50/live-webcast-agrifood-nanotechnology-reserach-and-development. Accessed Apr 8, 2007.

  • 160

    Study: Nanotechnology in Food and Food Processing Worldwide 2003-2006-2010-2015, Helmut Kaiser Consultancy, Tübingen, Germany (2006), available from: http://www.hkc22.com/nanofood.html. Accessed Apr 8, 2007.

  • 161

    Id. at 4.

  • 162

    21 U.S.C. §321(ff).

  • 163

    See, for example, Peter Barton Hutt, FDA Statutory Authority to Regulate the Safety of Dietary Supplements, 31 Am. J. L. and Med. 155 (2005).

  • 164

    Pub. L. 103-417, 108 Stat. 4325 (October 25, 1994). See also Taylor, endnote 100, at 32.

  • 165

    See Hutt, endnote 163, at 157.

  • 166

    Database available from: http://www.nanotechproject.org/44/consumer-nanotechnology. Accessed Apr 9, 2007.

  • 167

    21 U.S.C. §361 and §362.

  • 168

    21 C.F.R. §740.10.

  • 169

    See, for example, Taylor, endnote 100, at 28; see also comments of Jane Houlihan, representing Environmental Working Group, FDA Public Meeting Transcript, endnote 3, at 137.

  • 170

    This is often accomplished through the industry's chief trade organization, the Cosmetic, Toiletry, and Fragrance Association (CTFA).

  • 171

    See Cosmetic Ingredient Review Homepage, available from: http://www.cir-safety.org/. Accessed Mar 29, 2007.

  • 172

    See Voluntary Cosmetic Registration Program Homepage, available from: http://www.cfsan.fda.gov/~dms/cos-regn.html. Accessed Mar 29, 2007.

  • 173

    CTFA Consumer Commitment Code, CTFA, available from: http://www.ctfa.org/Content/NavigationMenu/Consumer_Information/Consumer_Commitment_Code/Consumer_Commitment_Code.htm. Accessed Mar 29, 2007.

  • 174

    Database available from: http://www.nanotechproject.org/44/consumer-nanotechnology. Accessed Apr 9, 2007.

  • 175

    Comments of Michael Jaffee, representing the U.S. Council for Intl. Business, FDA Public Meeting Transcript, endnote 3, at 88.

  • 176

    CTFA Consumer Commitment Code, endnote 173.

  • 177

    Id.

  • 178

    40 Fed. Reg. 8912 at 8916 (March 3, 1975).

  • 179

    40 Fed. Reg. 8912 at 8916.

  • 180

    See, for example, comments of Environmental Working Group, submitted to FDA's Nanotechnology Public Docket, available for download from: http://www.fda.gov/ohrms/dockets/dockets/06n0107/06n0107.htm. Accessed Apr 7, 2007.

  • 181

    Id.

  • 182

    FDA Nanotechnology Homepage, available from: http://www.fda.gov/nanotechnology/. Accessed Apr 9, 2007.

  • 183

    FDA Nanotechnology Task Force Homepage, available from: http://www.fda.gov/nanotechnology/nano_tf.html. Accessed Apr 9, 2007.

  • 184

    Co-chairman Lutter's Opening Remarks, FDA Public Meeting Transcript, endnote 3, at 8.

  • 185

    Meeting Notice, 71 Fed. Reg. 56158 (September 26, 2006). The announcement further stated: “FDA is interested in learning about the kinds of new nanotechnology material products under development in the areas of foods (including dietary supplements), food and color additives, animal feeds, cosmetics, drugs and biologics, and medical devices, whether there are new or emerging scientific issues that should be brought to FDA's attention, and any other scientific issues about which the regulated industry, academia, and the interested public may wish to inform FDA concerning the use of nanotechnology materials in FDA-regulated products.”

  • 186

    The report is now available from: http://www.fda.gov/nanotechnology/taskforce/report2007.html. Accessed Apr 9, 2007.

  • 187

    Nanotechnology FAQs, endnote 14.

  • 188

    Statement of Norris Alderson before Committee on Science, House of Representatives, September 21, 2006, available from: http://www.fda.gov/ola/2006/nanotechnology0921.html. Accessed Apr 6, 2007. Report available for download from: http://nano.gov/NNI_EHS_research_needs.pdf. Accessed Apr 6, 2007.

  • 189

    NNI: History, NNI Website, available from: http://www.nano.gov/html/about/history.html. Accessed Apr 9, 2007.

  • 190

    NNI: Participants, NNI Website, available from: http://www.nano.gov/html/about/nniparticipants.html. Accessed Apr 9, 2007.

  • 191

    Funding recipients are: NSF, DOD, DOE, DHHS (NIH), DOC (NIST), NASA, EPA, USDA (CSREES), DHHS (NIOSH), USDA/FS, DHS, DOJ, and DOT (FHWA). National Nanotechnology Initiative: FY 2008 Budget and Highlights, endnote 96.

  • 192

    Comments of Scott McNeil, representing NCL, FDA Public Meeting Transcript, endnote 3, at 219.

  • 193

    NCL Homepage, available from: http://ncl.cancer.gov/. Accessed Apr 9, 2007.

  • 194

    Id.

  • 195

    Id.

  • 196

    In her comments at FDA's Public Meeting, Dr. Celia Merzbacher noted that the Organization for Economic Cooperation and Development (OECD) and the Intl. Organization for Standardization (ISO) are 2 international organizations that have been devoting a great deal of effort to developing 3 areas of standardization: terminology and nomenclature; instrumentation and metrology; and health, safety, and the environment. Comments of Dr. Celia Merzbacher, FDA Public Meeting Transcript, endnote 3, at 23.

  • 197

    Id.

  • 198

    See, for example, comments of the Alliance of Social and Ecological Consumer Organisations (ASECO), submitted to FDA's Nanotechnology Public Docket, available for download from: http://www.fda.gov/ohrms/dockets/dockets/06n0107/06n0107.htm. Accessed Apr 5, 2007.

  • 199

    See, for example, comments of Erich Pica, representing Friends of the Earth, FDA Public Meeting Transcript, endnote 3, at 151.

  • 200

    Gary E. Marchant and Douglas J. Sylvester, Transnational Models for Regulation of Nanotechnology, 34 J.L. Med. & Ethics 714, 715 (2006).

  • 201

    See, for example, comments of Michael Jaffee, FDA Public Meeting Transcript, endnote 3, at 68: “We…strongly encourage FDA to regulate applications that use nanotechnology according to the same guiding scientific principles that have already allowed this agency to effectively protect, promote, and improve public health.”

  • 202

    Comments of Kathy Jo Wetter, FDA Public Meeting Transcript, endnote 3, at 115.

  • 203

    Comments of Dr. Martin Philbert, FDA Public Meeting Transcript, endnote 3, at 125.

  • 204

    Dr. Philbert points out, for example, the absurdity of suggesting that a material of 101 nm no longer presents a risk of toxicity simply because NNI has drawn the line at 100 nm. Id.

  • 205

    See, for example, comments of John Balbus, FDA Public Meeting Transcript, endnote 3, at 56.

  • 206

    In the case of food bioengineering, for example, FDA developed a policy statement for foods derived from new plant materials, and issued guidance for industry to promote early food safety evaluation for new proteins produced through biotechnology and intended for food use. See Statement of Policy: Foods Derived From New Plant Varieties; Notice, 57 Fed. Reg. 22984 (May 29, 1992). See, also, Guidance for Industry: Recommendations for the Early Food Safety Evaluation of New Non-Pesticidal Proteins Produced by New Plan Varieties Intended for Food Use, available from: http://www.cfsan.fda.gov/~dms/bioprgu2.html#ftn1; Notice, 71 Fed. Reg. 35688 (June 21, 2006). Accessed Apr 5, 2007.

  • 207

    Comments of David Rejeski, FDA Public Meeting Transcript, at 104.

  • 208

    International Dairy Foods Ass’n v. Amestoy, 92 F.3d 67 (2d Cir. 1996).

  • 209

    92 F.3d 67.

  • 210

    See, for example, comments of Dr. Philippe Martin and Dr. Michael Taylor, FDA Public Meeting Transcript, endnote 3, at 32, 126, 127.

  • 211

    Comments of David Rejeski, FDA Public Meeting Transcript, endnote 3, at 103.

  • 212

    Comments of Kenneth David, representing Michigan State Univ., FDA Public Meeting Transcript, endnote 3, at 43.

  • 213

    Id. at 73, 74.

  • 214

    “The dynamic and complex nature of nanotechnology makes it imperative that [we] get the framework right….OECD is prepared to play the critical role at this juncture….[it] is ideally placed to develop internationally agreed methodologies [sic], definitions and mechanisms for managing products and for protecting environmental health, human health, and safety.” Comments of Michael Jaffee, FDA Public Meeting Transcript, endnote 3, at 86, 87.

  • 215

    See comments of Michael Taylor, representing the Univ. of Maryland School of Public Health, FDA Public Meeting Transcript, endnote 3, at 110.

Ancillary