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4
Risks Associated with Nanotechnology
Several participants noted that nanoparticles are commonly observed;
these particles have both natural and human origins. “There are lots of
nanoparticulates that we are exposed to every day. I am always amazed,
when we think about these engineered nanoparticles as being such
unusual beasts, because they are really not all that unusual,” Dr. Barker
said.
Nonetheless, speakers noted that nanomaterials do pose several types
of potential health risks, including short-term and long-term risks to the
health of those taking nanomedicines, risks to the workers making nano-
medicines, and contamination risks to the environment at large. “If you
are looking at the challenges to nanotechnology, I think they are going to
be about safety, and the agencies of the government need to get together
and work this out,” Dr. Barker said.
DATA COLLECTION: BIODISTRIBUTION AND TOXICOLOGY
Dr. Ferrari and others listed several biological barriers that nano-
medicines might have to surmount in order to reach their targets. These
barriers include the reticuloendothelial system (RES) of the immune sys-
tem, the kidneys, the liver, blood vessel walls, the tumor cell membrane,
the cytosol or the nuclear membrane of a tumor cell, ionic and molecu-
lar pumps within tumor cells, and enzymatic degradation. In addition,
nanomedicines might have to overcome the additional barrier posed by
pressure that builds in tumors because of their leaky blood vessels, which
41
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42 NANOTECHNOLOGY AND ONCOLOGY
large molecules can penetrate. These molecules accumulate and draw
in fluid, building pressure in tumor cells that impedes the entry of even
small molecules, Dr. Li pointed out (see Figure 7).
The properties of nanomaterials make it difficult to predict how they
will penetrate these various biological barriers or be metabolized, which
in turn makes it difficult to assess their biodistribution and toxicity, sev-
eral speakers noted. In most cases, one cannot predict in vivo biodistribu-
tion based on nanostructure physical and chemical properties, such as size
and charge, Dr. Li noted. He added that nanostructures can distribute to
various organs as intact nanoparticles or they can be metabolized or split
up into different pieces, which can enter the cells of various organs and
reside in them for an unknown amount of time before moving to other
organs or being excreted.
“One of the most difficult parts is tracking the multiple components
in vivo over time. Some may stay for a long time, some may stay for a
short time. You don’t even know whether they stay as one whole piece
the whole time. If they stay in the liver, how long are they going to stay,
and what problems are they going to cause in the future?” said Dr. Li.
Dr. McNeil added that “a huge issue that we’ve uncovered is stabil-
ity of the particles. If a nanomaterial is unstable, obviously it will come
apart, and in some cases we’ve seen that within a minute of introducing
Other
Distribution
RES sites
(Local
Barriers)
Target
Liver
Absorption Tissue
Systemic
Circulation
Metabolism
Kidney
Excretion
FIGURE 7 Pharmacokinetics; ADME diagram. ADME stands for absorption, dis-
tribution, metabolism, and excretion: the four biological processes that are as-
sessed when a therapeutic or other systemic or topical drug, device, or biologic
is evaluated for toxicity.
SOURCE: Li presentation (July 12, 2010).
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it intravenously. Other particles are covalently bound and do not cleave,
so the drug, even if it makes it to the tumor, will not come apart. It is not
effective because the drug is not released and cannot interact with its
target enzyme.”
Dr. Ruth Duncan, professor emerita of Cardiff University and visit-
ing professor at the University of Greenwich, stressed that the pharma-
cokinetics (PK) are different for nanoparticles, given that they can enter
cells, and that one needs to show microscopic distribution as well as
macroscopic distribution. “It’s a different kind of paradigm from just
using the old-fashioned cells that we were using for small molecules.
The pharmacokinetics is totally different,” she said. “You need quantita-
tive PK studies on the whole body as well as at the cellular level.” Dr. Li
added, “macroscopic distribution doesn’t imply microscopic distribution.
So even if you have macroscopic imaging, it doesn’t tell us enough of
what is happening in vivo.” Dr. Gaspar stressed assessing both pharma-
cokinetics and pharmacodynamics when evaluating the biological effects
of nanomedicines, and having translational models adapted to the specific
questions that nanomaterials raise.
In addition, Dr. DeSimone cautioned that deformability is a charac-
teristic that needs to be measured for nanomaterials. He described that
deformability is commonly measured in biology: the age of a red blood
cell can be estimated from its deformability and researchers have demon-
strated that metastatic cancer cells are sometimes much more deformable
than their non-cancerous counterparts (Suresh, 2007). In contrast to bio-
logical materials such as red blood cells or cancer cells, deformability has
not been thoroughly explored as a characteristic impacting biodistribution
and toxicity of nanomaterials. He described experiments in which his
lab has begun to look into nanoparticle deformability; intravital micros-
copy—microscopic imaging done on live subjects in vivo—has resulted
in a wealth of data. Results show that deformability can reduce both
formation of aggregates in the lungs and uptake in the liver. In addition,
Dr. DeSimone described how tuning nanoparticle deformability could
help improve intracellular uptake of nanotherapeutics.
Reflecting Dr. Li’s statement that it is difficult to predict nanoparticle
biodistribution and toxicity, Dr. DeSimone pointed out their experiences
when testing the biological effects of PEG-based nanoparticles decorated
with transferrin or antibodies to transferrin receptors (both proteins that
bind transferring receptors); tranferrin receptors are overexpressed in
some types of cancer. DeSimone and colleagues hypothesized that these
nanoparticles could be loaded with anti-tumor drugs, the antibodies
would target cells of interest, thus effecting preferential delivery of drug
to tumor. However, when researchers tested the toxicity of the nanopar-
ticles in the absence of any drug, it was found that the nanoparticles
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44 NANOTECHNOLOGY AND ONCOLOGY
themselves possessed the ability to induce cell death in certain types of
cells (Wang et al., 2010).
Dr. Li pointed out that the route of exposure of nanomaterials will
dictate, to some degree, the specific fate of them in the body. Nanomateri-
als applied via inhalation will have different biodistributions than those
applied to the skin, taken orally, or taken intravenously. “If you inhale
nanotubes versus inject them, you’ll have totally different biodistribution,
toxicity profiles, and so on. Those considerations do not vary as much
with small molecular agents,” Dr. Li said.
Further complicating biodistribution assessments is that the binding
kinetics between nanomaterials and proteins are not well known, nor is
it fully known how different components of nanostructures are metaboli-
cally processed and excreted. “All these special ADME [Absorption, Dis-
tribution, Metabolism, Excretion] considerations for nanomaterials that
are quite distinct from those for small molecular drugs may hinder the
development of nanomedicine, as this is just a partial list of the potential
concerns that we have on different classes of different materials that we
need to define before we get them into the clinic,” Dr. Li concluded, refer-
ring to the concerns shown in Figure 8.
Some effort to fill in these knowledge gaps have been made, Dr. Zhao
noted, especially in regards to toxicity assessments. Studies have docu-
mented to a limited degree such factors as the relationship of response to
nanomaterial dose, degree of aggregation, size, or structure, and methods
have been developed to quantify nanoparticles in vivo, he said. Dr. Zhao
and his colleagues at the Chinese Academy of Sciences have published
about 60 papers in nanotoxicology, as well as completed a 10-volume set
of nanosafety books that was published in Chinese by a scientific press
in Beijing. He noted that there also is a book on nanotoxicology that was
published in English in the United States in 2007 (Zhao and Singh Nalwa,
2006).
Dr. McNeil added that characterizations of more than 200 nanoma-
terials at the Nanotechnology Characterization Laboratory, including 50
animal studies have revealed a few basic principles about nanomaterials
and their effects in the body. These studies indicate that nanoparticles
with high surface charge are cytotoxic regardless of particle type, and
that uncoated nanoparticles will accumulate in the liver and spleen, and
they are more likely to be digested by phagocytes, unlike those that are
PEGylated.
“We found that some of our in vitro results, at least for optimization,
do in fact mimic what we’re seeing in vivo,” Dr. McNeil said. “We can
begin to predict, for example, what PEG length is best for a particular
protein that’s used for a targeting agent, but I can’t look at a nanoparticle
and tell you X amount will go to the liver and X amount to the spleen.
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Nanomaterial
synthesis
Physical Interrelated
characterization
materials properties
Shape Size
Zeta potential
Charge
Hydrophobicity
Chemical
characterization
Surface chemistry:
Functional groups
Protein
interactions
Biological
Cytotoxicity
characterization
Cellular
response
Organ
distribution
Metabolic
pathway
Immuno-suppression/
stimulation
Clearance
Interrelated pharmaco-
kenetic properties
FIGURE 8 Special ADME considerations for nanomedicine.
NOTE: ADME = absorption, distribution, metabolism, excretion.
SOURCES: Li presentation (July 12, 2010) and Fischer and Chan (2007). Reprinted
from Current Opinion in Biotechnology 18(6), H. C. Fischer and W. C. Chan, Nano-
toxicity: The growing need for in vivo study, pp. 565–571, Copyright 2007, with
permission from Elsevier.
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46 NANOTECHNOLOGY AND ONCOLOGY
We can’t provide that level of detail. All we can do is just point out trends
at this point.”
Data at the National Characterization Laboratory show that surface
charge, size, and hydrophobicity influence biocompatibility, he added.
“We know that in our hands, every nanoparticle is unique. Just simply
changing that particle—it’s surface charge or the length of the PEG—
makes it almost a completely different entity, even if it’s still within the
same class,” Dr. McNeil said.
Dr. Kulinowski noted that there are more than 4,000 papers in the
International Council on Nanotechnology database relevant to nanosafety
and nanotoxicology of medical or environmental nanomaterials. But little
of this data is what she termed “regulator-ready” data. “The majority of
the papers are hazard-related rather than exposure-related, and by far the
majority of those are cell culture studies. So the relevance of those papers
that say ‘nanoX kills 50 percent of the cells at this dose’ to a person taking
a drug or using a consumer product is very low. While we might be able
to appreciate that there’s a lot of work being done in this area, we’re not
getting to that next stage yet where we can say what it means for decision
making,” Dr. Kulinowski said.
The International Council on Nanotechnology conducted a workshop
aimed at answering the question how long would it take to develop a
model that would be able to predict nanomaterial behavior in biological
systems and the environment. The outcome of that workshop was that it
would take ten years to understand the dynamic nature of nanomaterials,
Dr. Kulinowski reported. “We need to understand surface interactions
much more than we do now, as well as a variety of other aspects in order
to get to that goal of being able to look at the physical and chemical prop-
erties of a nanomaterial and be able to say, ‘well here’s how it’s going to
interact in a cell, in a biological fluid, in a sand bed, river, etc.’”
So despite the emerging body of knowledge on nanotxoicity, often
multiple studies are needed to characterize complex nanoparticles and
show where they are likely to be distributed in the body when conduct-
ing clinical trials. Some of these studies are rather esoteric, Dr. Desai
pointed out. For example, one might have to do x-ray diffraction to show
the amorphous or crystalline characteristics of the nanoparticle, or elec-
tron microscopy, as well as other tests specific to the construct. “These
can be complex constructs, where you have not just the drug, but you
maybe have polymers, different targeting agents, and many other differ-
ent components. It is very important to understand how all these inter-
act,” Dr. Desai said.
Dr. Gaspar questioned the relevance of in vitro models and certain
animal models when making biodistribution and toxicity assessments of
nanomaterials, and stressed the need for in vivo studies.
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OCCUPATIONAL SAFETY
“Occupational safety is a critical issue,” said Dr. Kulinowski. “No
matter what we’re doing in nanotechnology, that has to be a consider-
ation. Workers, whether they be researchers in the laboratory or produc-
tion workers, are likely to be exposed to nanomaterials in higher quanti-
ties and for longer periods of time than consumers or even patients.”
Dr. Kulinowski noted that although there are numerous journal arti-
cles that touch on nanotechnology occupational safety issues, few address
such practical questions as safe exposure levels for nanotechnology work-
ers. “As a result, we don’t have any occupational exposure limit for
nanoparticles,” Dr. Kulinowski said. She suggested translating the infor-
mation the pharmaceutical industry has acquired on how to safely handle
fine powders with high bioreactivity to workers handling nanomaterials.
She also pointed out that the International Council on Nanotechnology
recently established an open-source website for sharing information about
occupational practices for the safe handling of nanomaterials that they
call the “GoodNanoGuide.” Multiple stakeholders contribute, share, and
discuss information on this site, which is modern, interactive, and up-to-
date.1 “We’re looking at tasks that might be performed in a manufacturing
or research environment and saying ‘here are the potential human expo-
sures, and here are the potential controls that you might want to use,’”
Dr. Kulinowski explained.
She added that there have been discussions about establishing medi-
cal registries and medical surveillance programs to document health risks
in those who work with nanomaterials. The National Institute of Occupa-
tional Safety and Health’s most recent statement about this is that it is pre-
mature to set up a medical surveillance program or registry of workers,
according to Dr. Kulinowski, but she added that the agency continues to
explore this possibility. She noted that it is difficult to identify the demo-
graphics of the nanomaterials worker because nanotechnology is used
in such a wide range of fields, including the chemical industry and the
pharmaceutical industry. “Getting a handle on who they are and what the
tasks are is very difficult,” she said, let alone what types of measurements
and medical tests would be made on these workers.
In his talk, Dr. Zhao stressed the need to distinguish nano-specific risks
from other manufacturing risks. He gave an example of a paper which
linked exposure to nanomaterials of workers to serious lung disease (Song
et al., 2009). This article created a media sensation, with Nature publishing
a news article with the headline “Nanoparticle safety in doubt,” and most
Chinese newspapers reporting that the nanoparticles had killed workers.
1 See http://GoodNanoGuide.org.
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48 NANOTECHNOLOGY AND ONCOLOGY
But the situation was more complex than how it was initially reported.
The patients with lung disease were working in a workshop used to
heat plaster, and the plaster contained some titanium oxide nanoparticles
that were released in the plaster fumes and found in the patients’ lungs.
The nanoparticles were contained within polyacrylate esters. A study in
animals by Dr. Zhao and his colleagues suggested that the lung toxicity
was not due to the nanoparticles, but rather due to the fumes produced
by the heating of the polyacrylate esters. He called for more assessment
technologies and procedures to investigate potential nanotoxicities.
NANOMEDICINE SAFETY
Dr. Curley noted that the long-term toxicities linked to nanoparticles
used in medicine are not known, giving the example of carbon nano-
tubes. “Single-walled carbon nanotubes are fascinating from a physical–
chemical point of view, but they are also incredibly rigid and stable struc-
tures, so are those going to be safe to deliver to a patient over the long
term?” Dr. Curley asked. He said one study found that aerosolized carbon
nanotubes were toxic when delivered to the lungs of rats—they devel-
oped something akin to the black lung disease seen in coal miners. When
asked by Dr. Bahadrasain how to reassure the public that the safety of
nanomedicines is not a problem, Dr. Curley responded, “We need to do
the preclinical and clinical toxicology and toxicity studies that will dem-
onstrate that to the best of our ability, there are no long term effects with
the nanomaterials we are using.
Dr. Duncan noted that the safety issues linked to nanomaterials
depend not only on the material, but how it is used. She pointed out
that using nanomaterials in MRI imaging, in which patients are given a
very low dose of the materials only once or twice, poses different risks
than treating them with a nanomedicine for months or longer. “It’s really
important, when people ask the safety question, that we relate it to a par-
ticular material and a particular use, route of administration, and dose,”
Dr. Duncan stressed. Dr. Curley agreed, noting that “you may be able to
use things like quantum dots in an in vitro diagnostic system that you
would never give to a patient.” Dr. Sackner-Bernstein added, “It doesn’t
mean that carbon nanotubes are not a potential application as medical
devices. It just means you’ve got to make sure that the occupational health
issues are taken care of, and that you’re not using them as an inhaled
device or drug.”
Dr. Libutti pointed out that “there is a lot of fear in the unknown.
One of the biggest challenges for us is to turn the unknown to the known
so we don’t have a lot of unrealistic fears.” Both he and Dr. Barker noted
that this fear of the unknown slowed down the application of recombi-
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nant DNA technology because of the numerous restrictions on how the
technology could be used initially, but eventually those restrictions were
relaxed once its safety was shown. “Because of the natural fears that folks
have and the predilection for watching sci-fi movies, we are going to need
to go through that same evolution with nanotechnology,” he said.
Based on his experience with Abraxane and five other nanomedicines,
Dr. Desai said the standard battery of toxicology studies are sufficient to
establish safety. “Whether you are testing a small molecule or a biologic
or a nano-type construct, the tests are adequate to define the toxicology.
Through the formal toxicology studies which any of you do in the stan-
dard development of drugs, those studies are pretty thorough. You look
histologically at every possible organ, do all the blood chemistries, so if
there is any particular toxicity, whether it be nanoparticle-related or not,
you should be able to find it. I know it has been talked about that nano-
products may have a different toxicology profile, but I think that the pub-
lished papers, and maybe the little bit of hype in the lay press, has prob-
ably been more as a result of occupational exposure in the heavy industry
settings … as opposed to the pharmaceutical applications,” he said. But he
stressed designing and conducting studies to understand the disposition
of the nanomaterial in vivo. “You have to understand the biodistribution,
the metabolism, the excretion, and how these components degrade over
time. These are all very important for the long-term understanding of the
toxicology,” Dr. Desai said.
But Dr. Curley pointed out that Dr. Desai’s experience is with nano-
medicines that have pharmacologic or biologic agents, and may not be
applicable to metallic or semiconducting nanoparticles that may be used
in vivo. Dr. Desai responded, “It is not so much to do with the fact that the
particles we make are albumin and conventional drug molecule versus
magnetic nanoparticles or whatever, but that the way to look at toxicol-
ogy typically has been to take a detailed look at all the possible tissues
and other biofluids. What else could anybody suggest that you look at
that may give you a better idea of some other toxicology profile that isn’t
caught by these kinds of studies?”
Dr. Li then pointed out that the major problem in assessing long-term
toxicity of nanoparticles is that many are not metabolized and excreted,
unlike most other examples of nanomedicines that have been used clini-
cally. He noted that many inhaled particles, such as carbon nanotubes,
might lodge in the lung for the long term, but that potential hazard would
not be discerned in a short-term toxicity study. He said, for example, that
acute toxicity assessments of asbestos would not indicate that it would
cause any problems, but it does cause long-term toxicity. “I don’t think
the acute ADME toxicology studies that we directly deal with using small
molecular drugs would screen for those long term side effects,” Dr. Li
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50 NANOTECHNOLOGY AND ONCOLOGY
said. Dr. Zhao pointed out that his study of the metabolism of nano-
materials has revealed that many bind to proteins in the body, which
impedes their excretion and metabolism. “They can stay there in the body
for a long time—for nine months or longer,” he said. Dr. Curley added
“from an evolutionary point of view, we have not evolved mechanisms to
metabolize, excrete, or otherwise modify fullerenes or solid gold nanopar-
ticles, etc.”
Dr. Desai agreed that one needs to discern if the particles do not
degrade, and if they do accumulate in a particular organ, it raises different
questions that require different studies, “but those aren’t outside of the
realm of what the FDA will ask you for anyway,” he said. Dr. Josephson
added that “The key thing is to make sure that the nanoparticle is gone at
the end of your toxicity study. If it is still there, the interpretation is that
there was no toxicity seen, but the animal didn’t live long enough.” Tak-
ing a lesson from history, he pointed out that gadolinium chelate contrast
agents were shown to be rapidly eliminated by the kidney, and thus were
touted as safe as saline by their manufacturer. But those studies neglected
to look at people whose kidneys did not completely eliminate the com-
pounds. This caused a buildup of gadolinium in their kidneys which
was linked to their developing nephrogenic systemic fibrosis. Avoiding
this syndrome is possible by knowing the renal status of patients prior to
injecting them with the contrast. “But it has heightened the issue of elimi-
nation in nanotechnology—where do things go, how long to they stay,
and can they cause toxicity years and months after they have been given.”
Dr. Barker noted that the safety issues raised by nanomedicines are
not any different than what has been raised by biologics, and the biggest
toxicity issues have not been related to long residence times of the agent
in the body, but rather how these biologics alter factors that cannot be
measured. For example, leukokines have prolonged toxicity that occurs
long after they are administered, she said, for complex reasons that are
currently unknown.
Dr. Duncan stressed “It is up to us as innovators and members of the
public to continue with the regulatory agencies to evolve the process of
safety assessment of nanomedicines, depending on what we are making.”
But Dr. Desai and others cautioned against being overly cautious about
nanomedicines. “It’s important that we don’t create hurdles for ourselves
that make it more difficult in the long run to bring innovative technologies
to the patients,” he said. Dr. Libutti added “We shouldn’t set the bar so
high that it is difficult to cross, especially with respect to cancer therapies,
as we should be so lucky if the patients live long enough to see long-term
toxicities from the therapies. We shouldn’t regulate ourselves out of com-
ing up with innovative therapies, worrying about fantastic toxicities that
may never come to be. Certainly for the development of nanotherapies
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for benign conditions, that may be more of an issue.” He pointed out that
if high toxicity standards were adhered to 50 years ago, there would not
be a single standard chemotherapeutic on the market now.
But Dr. Libutti added that the metrics for toxicity in preclinical trials
may not measure toxicities in patients who are going to live long enough
to manifest them. “It is reassuring and makes you feel comfortable if you
check those boxes off for your toxicity runs, because you are more likely
to get your IND through. But they don’t pretend to encompass as yet
unrealized toxicities that new agents may develop,” he said.
Dr. Heath pointed out that “every application that I know of in nano-
therapeutics that has gone into the people, the net result has been to
decrease toxicity. The headline should be that we have been able to engi-
neer away toxicity to a great extent. That is something that should be
celebrated in this field. We are lowering toxicity of drugs.” Illustrating
the importance of lowering the toxicity of current cancer medicines, Dr.
Curley gave an example of one of his patients, who was a violinist when
he was diagnosed with colorectal cancer metastatic to the liver. Although
he has survived eight years post treatment, he experienced such severe
neurotoxicity from his chemotherapy that he is no longer able to play his
instrument. “We need to look not only at the survival of our patients, but
what is the quality of that survival and what are the long-term effects,” Dr.
Curley said. Dr. Hawk added that lowering the toxicity of cancer preven-
tion agents is the main goal for applying nanotechnology to the cancer
prevention field. “Our biggest challenge is making compounds safer, so
this should be a very exciting future.”
RISK–BENEFIT ASSESSMENTS
Dr. Gaspar suggested that when it comes to nanomedicines, risk–
benefit management is the approach that needs to be taken rather than
risk assessment. “Every medicinal product has a risk. If we start to make
decisions based only on risk assessment, we’ll end up withdrawing the
pipeline of medicinal products as a whole, and not only the nanomedi-
cines in particular,” he said. Dr. Kulinowski added that there is some
social science research that indicates that consumers are willing to take
greater risks for greater benefits. “It’s not just about risk, it’s about risk–
benefit. When the benefit is low, there’s a lower tolerance for risk,” she
said. Dr. Hawk added that risk–benefit assessments will especially under-
lie the usefulness of cancer preventives in a healthy population.
Dr. Sackner-Bernstein noted that FDA takes a risk-based approach
when assessing the safety of medicines and devices, with more scrutiny
given to those products likely to pose the most risk, but that the agency
also considers risk–benefit assessments of those products, including the
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52 NANOTECHNOLOGY AND ONCOLOGY
potential impact on the public and whether there are alternatives that
exist already to the product being considered. “We try to make sure that
when there’s a product that actually has impact, the barriers that it faces
are commensurate with the potential impact,” he said.
Dr. Duncan stressed engaging the public in risk–benefit assessments
of nanotechnologies. “The public decides whether the risk–benefit is
acceptable. As scientists and regulators, we have a duty to our patients
to tell them accurately what the risks and benefits of the technology are,”
she said. Dr. Li agreed that it is important to engage the public in these
assessments, but he expressed concern about the public’s ability to make
the scientific distinctions needed to adequately assess the risks and ben-
efits of nanomedicines. He suggested educating the public about what
nanotoxicology means in the environment or in their food versus what
it means in medicine. He said that public understanding of risk–benefit
is important in order for regulatory agencies to effectively communicate
their work.
