Perspectives on
FDA’s Regulation
of Nanotechnology:
Emerging
Challenges and
Potential
Solutions
Brianna (MacDonald) Sandoval
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
MS 20090226 Submitted 3/13/2009, Accepted 5/1/2009 . Author Sandoval is
with Covington & Burling LLP. Direct inquiries to author Sandoval (E-mail:
[email protected]).
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
This article was submitted under the direction of Peter Barton Hutt and in sat- supramolecular levels, aimed at creating materials, devices, and
isfaction of the Food and Drug Law Course requirement and third year written
work requirement at Harvard Law School. Ms. Sandoval is currently an Associate systems with fundamentally new molecular organization, properties, and functions.”1 Nanotechnology involves the production
at Covington & Burling LLP, Washington, D.C., U.S.A.
C
R
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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.
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
Characterization and standardization
Any attempt to describe or define nanotechnology with greater particular interest in potential applications for implants and prosspecificity than that provided above immediately reveals at the thetics, drug delivery, and food processing.23
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Perspectives on FDA’s regulation of nanotechnology . . .
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 Conven-
tional 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
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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 frame378
work 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 nanobased 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
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Perspectives on FDA’s regulation of nanotechnology . . .
“‘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 BioIntegrity 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 socalled “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
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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 commer380
cial 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
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3) research toward assessing safety of chemicals, food, drugs ments, and cosmetics. It also considers the potential implications
for nano-based products in each of these product categories.
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 supple-
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
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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-bycase basis, as it did in the case of Emend.119 Each of the nanobased 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
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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
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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 nanobased 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
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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
384
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
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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 nanosized 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 nanobased 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 nanobased 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 FDARegulated 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 FDAregulated 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
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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
386
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-bycase 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
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Perspectives on FDA’s regulation of nanotechnology . . .
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
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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:
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
388
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-february2007.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
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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 3, 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-assessmentessential-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-assessmentessential-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%20
Risk%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 3, at 53. See
also comments of George Kimbrell, representing CTA, FDA Public
Meeting Transcript, endnote 3, at 143.
53
42 U.S.C. §4332(c).
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42 U.S.C. §4332.
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
54
55
390
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.
COMPREHENSIVE REVIEWS IN FOOD SCIENCE AND FOOD SAFETY—Vol. 8, 2009
Perspectives on FDA’s regulation of nanotechnology . . .
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-ofnanotechnology. 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
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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 NanoceuticalsTM Slim Shake
R
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
R
FresherLongerTM product line, as well as refrigSharper Image
R
R
erators 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-agrifoodnanotechnology-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.
392
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
COMPREHENSIVE REVIEWS IN FOOD SCIENCE AND FOOD SAFETY—Vol. 8, 2009
Perspectives on FDA’s regulation of nanotechnology . . .
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.
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