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266 Carbon-Based Nanocarriers for Drug Delivery
Anoteworthy discovery was that the expression of calcium-binding proteins exhibited different patterns when exposed to graphene and SWCNT, implying that their
mechanisms of action were distinct.
Subsequently, graphene pristine in nature was discovered for ROS increase
and induced apoptosis in murine RAW 264.7 macrophages, which are crucial
effector cells of the innate immune system [24]. This was thought to be due to
the depletion of mitochondrial membrane potential (MMP) and the activation
of the mitochondrial pathway triggered by ROS. According to this research, the
involvement of both mitogen-activated protein kinases and transforming growth
factor-b (TGF-b) related signaling pathways was associated with the toxicity of
macrophages treated with pristine graphene. The effect of graphene platelets on
human glioblastoma U87 and U118 cells was investigated, with a focus on cell
morphology, mortality, viability, membrane integrity, and the type of cell death
[25]. Graphene platelets were found to localize near the cells but did not penetrate them. Treatment with 100 µg/mL of graphene platelets for 24hours caused
approximately 50% of the cells to die, lose membrane integrity, and undergo
apoptosis. Additionally, when exposed to layered graphene platelets with one to
ten layers at concentrations ≥5 µg/cm2, immortalized human acute monocytic
leukemia cells (THP-1) showed a signicant increase in LDH release, indicating
loss of membrane integrity. The exposure to graphene platelets also resulted in a
decrease in reduced glutathione levels and an increase in the expression of various
cytokines, including monocyte chemotactic protein-1, interleukin-1, macrophage
inammatory protein-1R, and IL-1b.
10.2.1.2 Graphene oxide—In-vitro mammalian cell toxicity
In-vitro toxicity studies have extensively investigated GO as a member of GFNs.
Although the initial comprehensive study on GO toxicity did not show any apparent
effects on cellular uptake or mortality, viability, morphology, and membrane integrity in adenocarcinomic human alveolar basal epithelial (A549) cells, exposure to
GO was found to induce oxidative stress even at a low concentration of 10 mg/mL
[26]. However, this is one of the few instances in which GO exhibited negative cytotoxicity in mammalian cells. Afew months later, Hu etal. (2011) reported that GO
caused concentration-dependent cytotoxicity in the same cell line, which could be
signicantly reduced by incubation with 10% fetal bovine serum, owing to GO’s high
protein adsorption capacity [27]. Subsequently, a wide range of human and animal
cell lines, encompassing immortalized and normal cell lines, stem cells, immune
cells, and blood components, have been explored to appraise the toxicity, genotoxicity, and underlying mechanisms of GO.
The toxicity of GO has been studied in immortalized cells, specically in the
HepG2 cell line. Lammel et al. (2013) examined the cytotoxicity of GO at concentrations ranging from 1 to 16 µg/mL using four assays: 5-carboxyuorescein
diacetate-acetoxymethyl ester (CFDA-AM), Alamar blue assay, neutral red uptake
assay, and uorescamine assay [28]. The CFDA-AM assay showed a dose-dependent
decrease in uorescence intensity, beginning at 4 µg/mL, indicating damage to the
plasma membrane. The strong physical interaction between GO and the phospholipid
bilayer was responsible for the loss of structural integrity of the plasma membrane,
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as per ndings. It was further observed through TEM and scanning electron micrographs that GO could penetrate the plasma membrane, causing changes in cell morphology and an increase in the count of apoptotic cells. Moreover, the increased
ROS levels at concentrations as low as 1 µg/mL and dose-dependent depletion of
the MMP suggested that impaired mitochondrial function may result in intracellular
ROS formation. The authors concluded that plasma membrane damage and oxidative
stress are crucial factors in GO-induced cytotoxicity based on the modes of action
assessed.
In another study, Yuan etal. (2012) utilized iTRAQ-2D LC-MS/MSto evaluate
the cytotoxicity of GO and oxidized SWCNT in HepG2 cells, aiming to characterize
cellular function [29]. Similar to their prior research, treatment with 1 µg/mL of both
GO and oxidized SWCNT led to changes in protein expression involved in metabolic pathways, redox regulation, cytoskeleton formation, and cell growth, with GO
inducing fewer alterations in expression than oxidized SWCNTs. Astudy compared
the cytotoxicity of GO-1 and its repeated KMnO4-H2SO4 oxidation products, GO-2
and GO-3, in HeLa cells using the MTT assay, revealing that GO treatment only
caused a slight reduction in proliferation rate and slightly perturbed cell cycle, and
led to an increase in intracellular ROS levels. GO was found to be less cytotoxic in
HepG2 cells. The lateral sizes of GO-1, GO-2, and GO-3 were reported to be 205.8
nm, 146.8 nm, and 33.78 nm, respectively [30]. At concentrations ranging from 20 to
100 µg/mL, GO-1 induced considerable cytotoxicity, while GO-2 and GO-3 exhibited higher cell viability with enhanced cellular uptake in HeLa cells, indicating that
larger GO sizes inicted more damage to the cell membrane compared to smaller
GOs, according to a study. Another study also found dose-dependent toxicity of GO
in HeLa cells, albeit with a lower cell uptake ratio than CNT and nanodiamonds [31].
Moreover, GO toxicity was observed in human neuroblastoma SH-SY5Y cells at
concentrations ≥80 µg/mL [32].
GO toxicity has also been reported in BEAS-2B human lung cells as well as in
the HBI.F3 human neural stem cell line. In BEAS-2B cells, the MTT assay showed a
signicant decrease in cell viability in a concentration- and time-dependent manner
at concentrations ranging from 10 to 100 µg/mL, along with an increase in both early
and late apoptotic cells compared to the control [33]. Similarly, HBI.F3 cell viability
decreased with increasing GO nano pellet concentration (25–200 µg/mL), as veried
by both the MTT assay and differential pulse voltammetry, which is a microscopic
imaging tool [34].
Compared to previous research, GO was found to have minimal toxicity in spontaneously arising human retinal pigment epithelium (ARPE-19) cells. Various methods, including optical micrography, LDH assay, the CCK-8 assay, and apoptosis
assay, were used to measure toxicity in terms of viability, cell morphology, and
membrane integrity [35]. According to a study, the cells were not affected by the
addition of up to 100 mg/mL GO for 72hours, but some changes in cell morphology were observed after seven days of culture with GO. The release of LDH by
less than 8% of cells at all concentrations suggested minimal damage to the cell
membrane. Therefore, the study indicates that GO has favorable biocompatibility
with retinal pigment epithelium cells and causes only minor effects on cell viability
and morphology.
268 Carbon-Based Nanocarriers for Drug Delivery
10.2.2 ToXic eFFecTs oF carBon nanoTUBes
Due to their unique physicochemical properties, CNTs have proven useful in many
biomedical applications. The population has also been exposed to more CNTs and
CNT-based nanocomposites as a result of improvements in their use across a range
of industries. Although CNTs have several uses, “their toxicity” is the main issue
preventing their widespread use. Researchers frequently struggle to balance the negative effects caused by CNTs’ toxicity with the possible therapeutic effects of these
materials. To determine the toxicity of this nanomaterial, it is essential to choose
an experimental paradigm, whether it be in-vitro or in-vivo [36]. Various variables,
including size, surface charge, administration method, dosage concentration, and
exposure duration, inuence the toxicity of CNTs. In addition to the previously mentioned parameters, the incubating circumstances, such as the exposure dosage, culture period, and type of cell, also directly affect the toxicity of CNTs [37]. For their
in-vivo biological uses, CNTs must rst undergo cytotoxicity testing. The main outcomes of in-vitro experiments focused on cell uptake, cell viability, and ROS.
The cytotoxicity of carbon nanomaterials is closely associated with their size,
shape, dosage, and surface characteristics. In line with this, Zhang etal. (2012) investigated the absorption and toxicity of HeLa cells by MWCNTs, nanodiamonds (ND),
and graphene oxide (GO) [31]. Cellular absorption ratios for the three kinds of carbon
nanomaterials were in the order ND > MWCNTs > GO. However, there was a poor
correlation between the cytotoxicity of these compounds and the cellular uptake ratios.
MWCNTs were taken up by cells more readily than GO, but no differences in their
cytotoxicity were found. ND displayed more excellent biocompatibility with MWCNTs
and GO. SWCNTs are thought to be more hazardous than MWCNTs, according to
studies showing that the mass basis and dosages substantially impact the cytotoxicity
of CNTs. The cell survival of HepG2 broblasts exposed to SWCNTs and graphene
was examined by Yuan etal. (2011) [29]. As a result of activating P53- mediated degradation, the results showed that SWCNTs had a higher level of cytotoxicity, may have
been able to produce oxidative stress, and nally triggered apoptosis [29].
Validating the biocompatibility of CNTs requires toxicological analysis in-vivo
after cytotoxicity investigation. Biomedical studies typically use animal models,
such as mice, zebrash, and rats, to fully understand nanomaterials’ dynamic behaviors and biocompatibility in-vivo. Some researchers have functionalized CNTs using
biocompatible polymers and other biosafety chemicals to boost the biocompatibility
of CNTs [36]. Positron emission tomography was used by Liu etal. (2007) to examine the in-vivo bioavailability of SWCNTs coupled with more accommodative and
hydrophilic PEG [38]. The PEG-functionalized SWCNTs showed prolonged blood
circulation times and low reticuloendothelial system absorption. Mice did not have
any adverse side effects, such as fatigue or weight loss, and no clear toxicity-related
conditions were found. SWCNTs were known to have a high level of cytotoxicity
in the past; however, Xue etal. (2016) found that aggregated SWCNTs signicantly
lessened the behavioral and neurochemical effects of methamphetamine in mice
[39]. Notably, at the dosage levels employed in the study, neither the striatum nor the
midbrain displayed any signs of neuronal toxicity or the mice’s normal behaviors,
including eating, drinking, and moving around.
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The tendency for oxidative stress, generation of free radicals, accumulation of
peroxidative products, DNA fragmentation, and inammation continue to be obstacles to the widespread use of CNTs in the treatment of neurological illnesses, despite
repeated attempts to make them more biocompatible. The fundamental issue with
employing CNTs as an intrinsic medicine for treating neurological disorders is their
safety, particularly regarding brain ejection and disintegration. The functionalization
of CNTs merits considerable research to increase the brain’s breakdown and expulsion of CNTs.
10.2.3 ToXicology oF graphene QUanTUm DoTs
To measure and evaluate the toxicity of living organisms, both in-vitro and in-vivo
experiments are typically conducted in a laboratory setting shown in Figure 10.1.
In-vitro tests utilize living cells from organisms as the test subjects. They are commonly referred to as “cytotoxicity” tests [40]. Conversely, in-vivo tests are performed
on entire living organisms as the test subjects. The toxicity of GQDs, including both
raw and doped varieties (such as nGQDs and bGQDs), has been investigated using
both in-vitro and in-vivo methods. Avariety of human and animal cells have been
utilized in in-vitro testing. HeLa cells (cervical cancer cells) and A549 cells (lung
carcinoma cells) are among the most extensively studied cell types, while MCF-7
cells (breast cancer cells), red blood cells, and stem cells have also been examined.
In terms of in-vivo testing, mice, zebrash, Caenorhabditis elegans, and green gram
sprouts have all been used in these studies.
FIGURE 10.1 Schematic Explanation of In-Vitro and In-Vivo Tests [Reprinted with permis-
sion from Wang et al. (2016)] [40].
270 Carbon-Based Nanocarriers for Drug Delivery
10.2.3.1 In-Vitro Toxicity Analysis of GQDs
In an in-vitro test, cell viability is commonly used to determine cytotoxicity (or
in-vitro toxicity). Widely used assays such as MTT, LDH, or ATP are utilized to
assess cell viability. The test substance is added to the cell culture, and the number
of living cells before and after a specic incubation time (e.g., 24hours) is measured. The ratio between these two numbers represents cell viability. In addition
to cell viability, researchers also observe other indicators such as cell membrane
damage, morphological changes, and the release of certain chemicals (such as lactate
dehydrogenase (LDH), adenosine triphosphate (ATP), and lipid extracts) due to cell
damage. Figure 10.2 depicts the typical results of these cytotoxicity tests, which
reveal that cell viability and the release of common chemicals from cells (such as
LDH) are concentration-dependent [40]. As the concentration of GQDs increases,
cell viability gradually decreases while chemical releases gradually increase. Wu
etal. (2013) conducted an in-vitro toxicity assessment of graphene oxide (GO) and
GQDs on MGC-803 (human gastric cancer) and MCF-7 cells (human breast cancer)
using MTT assays. Their study demonstrated that GO is signicantly more cytotoxic
than GQDs [41].
Additionally, Nurunnabi etal. (2013) conducted a comparison of GQD cytotoxicity among three cancer cell lines: KB (epidermal cancer cells), MDA-MB231, and
FIGURE 10.2 Examples of Results of In-Vitro Tests: (a) Cell Viability for MG-63 Cells, (b)
Cell Viability of MCF-7 Cells and MGC-803 Cells, (c), and (d) Cell Viability and LDH Release
of A549 Cancer Cells. [Reprinted with permission from Wang et al. (2016)] [40].
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A549 [42]. Using yellow-emitting GQDs synthesized by Zhang etal. (2012), it is
possible to image stem cells that are difcult to label with current technology [43].
In toxicity tests, the stem cells retained over 80% viability after being cultured with
GQDs at a concentration of 100 mg mL-1 for 3 days. These results suggest that their
GQDs exhibit low cytotoxicity and are a promising biocompatible agent for labeling stem cells. In addition to testing common GQDs, the cytotoxicity of chemically
doped GQDs was also examined in studies such as those conducted by [44]. In their
study, Wang etal. (2015) investigated the cytotoxicity of graphene oxide (GO) and
nitrogen-doped GQDs on red blood cells (RBCs) [45]. They assessed hemolytic
activity, morphological changes, and the release of ATP in RBCs after being separately exposed to GO and nGQDs. Their results showed that GO caused signicant
hemolysis and released ATP, whereas nGQDs did not cause similar damage to the
RBCs. This indicates that nGQDs exhibit much lower cytotoxicity than GO. Hai
etal. (2015) synthesized boron-doped GQDs and evaluated their biocompatibility
with HeLa cells in their study [46]. In general, based on the majority of in-vitro toxicity tests conducted on different types of cells and GQDs, GQDs appear to have low
cytotoxicity. However, evidence also suggests that the presence of the reactive oxygen species (ROS) mechanism, known to be a toxicity mechanism for other nanomaterials, is not entirely absent in GQDs [47]. Recent research on macrophages further
demonstrated that GQDs could induce apoptosis and autophagy, possibly due to the
generation of ROS.
Moreover, the study indicated that ROS’s effect depends on the concentration of
GQDs. It is worth mentioning that GQDs possess an intrinsic peroxidase-like catalytic activity, which can enhance the antibacterial performance of H2O2 for wound
infections treatment [48]. Despite this, Wu etal. compared the intracellular reactive
oxygen species (ROS) generated by GQDs and GO and found that the level of ROS
induced by their GQDs is lower than that of GO [49]. However, this may not be adequate to eliminate concerns about cytotoxicity when dealing with certain types of
GQDs or cells, particularly in situations with an extremely low tolerance for toxicity.
10.2.3.2 In-Vivo Toxicity Analysis of GQDs
To evaluate the in-vivo behavior of GQDs, a typical experiment involves injecting a
specic dosage of GQDs into a living organism, such as a mouse, and monitoring its
biodistribution, organic accumulation, and excretion over a period of time, typically
24hours. Wu etal. (2013) were the rst to report in-vivo work on GQDs, demonstrating their potential for in-vivo imaging of mice using bottom-up synthesized
GQDs, but did not investigate their toxicity [41]. The rst systematic in-vivo toxicity
study was conducted by Nurunnabi etal. (2013), who examined the in-vivo imaging,
biodistribution, and ex vivo organic imaging of cancer-bearing mice treated with
GQDs synthesized from carbon ber exfoliation [42]. The in-vivo imaging results
indicate that GQDs could be detected in the skin tumor site 12hours after injection
but not in deeper organs, suggesting their potential for supercial tissue imaging
(e.g., skin cancer detection). However, 24hours after injection, no uorescence signal
was detected at the tumor site or any other part of the mouse’s body (Figure10.3a)
[40]. The ex vivo imaging of extracted organs such as the kidney, liver, and heart
revealed that GQDs were distributed throughout the entire body via the circulatory
272 Carbon-Based Nanocarriers for Drug Delivery
FIGURE 10.3 Example of in-vivo toxicity tests: (a) mice, (b) and (c) zebrash, (d) Caenorhabditis
elegans. [Reprinted with permission from Wang et al. (2016)] [40].
system within the rst 12hours, with accumulation varying in different organs. For
instance, during the early stage (two hours), GQDs mainly accumulate in the liver
and heart. The liver accumulation decreased gradually, and after 12 hours, a signicant increase in kidney accumulation was observed. Generally, the uorescence
signal of GQDs weakened at 24hours compared to 12hours, indicating that GQDs
can be easily eliminated through the excretory system. Using a rat model, the authors
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also conducted a comprehensive analysis of complete blood count, serum biochemistry, and histological analysis of tissues. The results showed no signicant difference
between the GQDs-injected group and the control group within 22 days, indicating
low in-vivo toxicity of the GQDs.
Additionally, recent in-vivo studies were conducted with zebrash models by Wang
etal. (2013), who investigated the effect of GQDs on the development of zebrash
embryos [50]. They found that their GQDs mainly accumulated in the intestines and
heart of the zebrash, as shown in Figure10.3b [40]. The concentration of GQDs
was found to determine their impact on zebrash embryos during development. The
growth of embryos was monitored at varying concentrations of GQDs (50, 100, and
200 mg), and it was observed that concentrations exceeding 50 mg mL-1 caused negative effects on the embryos, such as decreased hatch and heart rate, increased mortality, and disgurement. Another study on zebrash embryos showed that GQDs
had difculty entering the circulation system and could be excreted within seven
days. This suggests that the impact of GQDs on zebrash is concentration-dependent,
and their removal from the body is facilitated by the excretory system
(Figure10.3c) [40,41]. The biocompatibility of GQDs was found to be excellent at a
concentration lower than 2 mg mL-1, as there was no discernible difference between
the test group and the control group. Moreover, the possibility of using functionalized GQDs for in-vivo imaging of apoptotic cells to study the apoptosis process was
demonstrated. The contradictory results of the two studies on the in-vivo toxicity for
zebrash could be attributed to the different types of GQDs used in their research.
The former study used GQDs synthesized from cutting graphene oxide, while the
latter utilized GQDs synthesized from hydrothermal treatment of leaf extracts. This
implies that GQDs produced through different methods exhibit distinct toxicity characteristics. Furthermore, research was also conducted on plants. Li etal. (2014) conducted growth experiments on green gram sprouts to compare the in-vivo toxicity of
GQDs with three other carbon materials, including carbon quantum dots (CQDs),
graphene oxides (GO), and single-wall carbon nanotubes (SWCNTs) [51]. The study
results indicated that GQDs exhibited the lowest toxicity among the four materials.
10.2.4 ToXicological aspecTs oF FUllerenes
10.2.4.1 Toxicokinetic
Toxico-kinetic studies are thought to be important for identifying potential target
organs for fullerene toxicity after inhalation and dermal or oral exposure. Overcoming several barriers is necessary to allow fullerenes to be absorbed from the exposure
site and distributed to secondary targets, and if this happens, they can produce toxic
effects throughout the body.
10.2.4.1.1 Absorption
Yamago et al. (1995) found that orally administered radio-labeled 14C fullerene
derivatives (tri-methylene methane) were not efciently absorbed by rats and mice
for a period of 160hours but were rather eliminated in the feces within 48hours [52].
Nevertheless, minute quantities were detected in urine, indicating that certain
274 Carbon-Based Nanocarriers for Drug Delivery
fullerenes were able to cross the intestinal barrier. Folkmann etal. (2009) proposed
that fullerenes are absorbed after oral exposure because oxidative damage in the liver
and lungs was dose-dependent after oral exposure via gavage [53]. The signicance
of these ndings is unclear, as the solvent corn oil demonstrated the same effect and
the presence of fullerenes in these organs was not demonstrated.
Fullerenes (in nano and microparticulate form) were not detected in blood after
inhalation by rats in a study by Baker etal. (2008), indicating that they do not translocate from their respiratory exposure site [54]. The calculated pulmonary deposition
fractions for the C60 fullerene nanoparticle (55 nm, 2.22 mg/m3) group (14.1%) were
50% higher than for the microparticle (0.93 lm, 2.35 mg/m3) group (9.3%). However,
the half-life of fullerene nanoparticles, which was 26 days, was comparable to that of
fullerene microparticles (29 days), indicating that the removal of fullerene from the
lungs involves similar elimination processes, like mucociliary clearance and macrophage absorption. Rats were subjected for 130 and 145 days, respectively, in the
study, which corresponds to the nano- and microparticle exposure times required
to establish steady-state lung loads. In a modied Bronaugh’s diffusion chamber,
Kato etal. (2009) evaluated C60 dissolved in squalane (Lipo-Fullerene, LF-SQ) for
skin permeability for 24hours, and they discovered that C60 was undetectable on
the epidermis and dermis for administration at low doses (2.23 and 22.3 ppm C60
in LF-SQ) [55]. Although C60 was not found in the dermis of a human skin biopsy
after injection at concentrations as high as 223 ppm, it was found to inltrate into the
epidermis. The authors concluded that systemic circulation toxicity need not be taken
into account for C60 dissolved in LF-SQ.
A fullerene-substituted peptide can pass through the epidermal layers via passive
diffusion, as demonstrated by Rouse etal. in 2007 [56]. The rate at which these particles go into the dermis is accelerated by mechanical stresses, such as those brought
on by a repetitive exing motion (such as while walking barefoot, for example).
10.2.4.1.2 Distribution, Metabolism, and Elimination
Due to the low absorption, little information has been found regarding the distribution of fullerenes after inhalation, oral, or cutaneous absorption. Under situations
of lung particle overload and associated inammatory state, translocation of some
nanoparticles from the respiratory tract to secondary organs has been demonstrated
via uptake into pulmonary lymphatics and blood circulation [15]. Following intratracheal instillation (3.3 mg/kg) and inhalation exposure (0.12 mg/m3), a recent study
conducted as part of the NEDO project revealed limited systemic translocation of
fullerenes to the brain (0.17% of lung concentration) and other organs in rats [57].
C60 (agglomerated to a size of about 1 micron) did not spread from the lung to other
tissues until 168hours after being administered through intra-tracheal instillation at
doses of 1 or 5 mg/kg [58]. One milligram per cubic meter of fullerenes (20 nm) was
inhaled for six hours, but no distribution to the liver or spleen, and only minute levels
in the kidneys were discovered. The fact that C60 had poor pulmonary clearance and
a relationship between its disposition and that of 13C indicates that C60 is not being
digested.
Alveolar macrophages in the lungs have been shown to phagocytose fullerenes
[59]. Thus, macrophages perform their function in the host’s defense; yet after
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consuming fullerenes, oxidative or inammatory processes may be triggered (which
requires consideration). Electron microscopic analysis revealed that phagocytosed
fullerenes in alveolar macrophages generated nely scattered granules but were not
converted to organelles or nuclei.
Following intraperitoneal administration, Gharbi etal. (2005) noted a robust macrophagic response and fullerene accumulation (2.5–5 g/kg C60) within Kupffer cells
in the liver [60]. Other cell types, including keratinocytes, epithelial cells, and eye
lens cells, have also been shown to internalize fullerenes in-vitro, frequently with
fatal and damaging effects [56].
It is evident that there is probably only a tiny amount of fullerene absorption after
exposure through physiologically signicant routes. In particular, fullerenes tend to
stay in the lungs and gut, where they can be removed through alveolar macrophages,
the mucociliary escalator, feces, and urine. According to the kind (functionalization)
of fullerene, the solvent employed, and the characteristics of the skin, there is probably little to no absorption of fullerenes via the skin. Due to the scarcity of data, the
study is currently unable to draw broad conclusions about the absorption, distribution, metabolism, and excretion prole of fullerenes and their derivatives.
10.2.4.2 Acute and Repeated Dose Toxicity
During an observation period of up to 14 days following oral administration of a single dose of 2000 mg/kg fullerite (a combination of C60 and C70), no mortality or other
indicators of toxicity in terms of behavior or body weight were seen in rats [61]. Following a single oral treatment of rats with 2500 mg/kg of polyalkylsulfonated (water
soluble) C60, Chen etal. (1998) revealed no effects, and as a result, it was determined
that the substance was not acutely hazardous [62]. Based on these two investigations,
acute no-observed adverse-effect levels (NOAELs) for fullerite (a combination of C60
and C70) and polyalkylsufonated (water soluble) C60 are proposed to be 2000 mg/kg
and 2500 mg/kg, respectively. Nevertheless, because only one dose was evaluated in
each study, and no effects were noted, the actual acute oral NOAEL is likely more
signicant. Fullerenes have relatively low acute oral toxicity; however, there is no
evidence of their long-term effects from repeated oral intake.
The exposure method that is thought to be most responsible for the issue surrounding (airborne) nanoparticles is inhalation. The deposition of discrete NP in the
respiratory tract, where nanoparticles might have local impacts, is determined by the
particle size (aerodynamic diameter). Compared to an equivalent mass of bigger particles, ultrane nanometric particles have been found to cause greater inammation
and to be more tumorigenic. Although it has been demonstrated that some nanoparticles in the lungs are transferred to other organs in the body, no generalizations can
be drawn [15].
When Fischer 344 rats were exposed to fullerenes via nasal inhalation at concentrations of 2.22 mg/m3 (nanoparticle, 55 nm diameter) and 2.35 mg/m3 (microparticle,
0.93mm diameter) for 3 h/day for ten consecutive days, with toxicological assessments carried out up to seven days after exposure, neither inammatory potential nor
toxicity in the lung was observed. Rats exposed to nanoparticles had higher C60 lung
particle loads than rats exposed to microparticles [54]. Rats exposed to nanoparticles
had signicantly higher protein concentrations in their bronchoalveolar lavage uid
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