• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of toxsciLink to Publisher's site
Toxicol Sci. Dec 2009; 112(2): 276–296.
Published online Aug 14, 2009. doi:  10.1093/toxsci/kfp188
PMCID: PMC2777075

State of Academic Knowledge on Toxicity and Biological Fate of Quantum Dots

Abstract

Quantum dots (QDs), an important class of emerging nanomaterial, are widely anticipated to find application in many consumer and clinical products in the near future. Premarket regulatory scrutiny is, thus, an issue gaining considerable attention. Previous review papers have focused primarily on the toxicity of QDs. From the point of view of product regulation, however, parameters that determine exposure (e.g., dosage, transformation, transportation, and persistence) are just as important as inherent toxicity. We have structured our review paper according to regulatory risk assessment practices, in order to improve the utility of existing knowledge in a regulatory context. Herein, we summarize the state of academic knowledge on QDs pertaining not only to toxicity, but also their physicochemical properties, and their biological and environmental fate. We conclude this review with recommendations on how to tailor future research efforts to address the specific needs of regulators.

Keywords: ecotoxicology, toxicology, environmental fate, regulatory policy, risk assessment, nanoparticles

Quantum dots (QDs), an important class of emerging nanomaterial, are “among the most promising items in the nanotechnology toolbox” and are widely anticipated to eventually find application in a number of commercial consumer and clinical products (Azzazy et al., 2007). However, before QDs can enter the market, they will likely be subjected to some form of regulatory scrutiny.

The type of regulatory scrutiny QDs will face is currently unknown. Not a single jurisdiction in the world is presently mandating the creation of specific safety-related data for nanomaterials or has declared when and if such requirements can be expected (Pelley and Saner, 2009). At the same time, it is widely expected that nanomaterials, including QDs, will face particular regulatory scrutiny at some point in the near future.

The development of new regulatory requirements is an iterative process. Regulatory data requirements (such as new bioassays) can be a major impediment to innovation and will not be mandated lightly. Instead, such requirements will be developed once the existing scientific understanding suggests that regulators require more information to assess environmental, health, and safety (EHS) risks. In the absence of specific data requirements pertaining to EHS, regulators will have limited access to new information. They will thus find it difficult to arbitrate whether new regulatory measures will lead to overregulation (through an excessive emphasis on “precaution”) or if they are currently underregulating this class of products. The chicken-and-egg problem is best managed by maximizing the accessibility and utility of existing academic knowledge in the regulatory context—which is precisely what we set out to do.

Herein, we build on the seminal literature review on QDs previously published by Hardman (2006). Hardman's review predominantly focused on the toxicity of QDs, however. This is insufficient in the regulatory context, as regulators require knowledge of both the toxicity and the biological fate of substances and products (including the absorption, distribution, metabolism, and excretion (ADME) within a body, and the transportation and transformation within the natural environment). In other words, it is not only the toxicity but also the dosage, the likelihood of that dosage being administered, and the concentrations in the natural environment that matter from a risk perspective.

Aside from updating and reviewing data published since the 2006 review by Hardman, the main contribution of this paper is that it summarizes what has been reported on the biological fate of QDs in the academic literature to date. This approach improves the accessibility of current academic knowledge on QDs for risk assessors who are in the process of developing an approach to the regulation of nanomaterials.

In order to maximize accessibility, our paper is formatted according to the typical structure of a regulatory risk assessment, as depicted in Figure 1 above.

FIG. 1.
The typical structure of a regulatory risk assessment.

What are QDs?

QDs, a heterogeneous class of engineered nanoparticles that are both semiconductors and fluorophores, are rapidly emerging as an important class of nanoparticles with numerous potential applications ranging from medicine to energy. In terms of their basic structure, QD are nanocrystals composed of a semiconductor core encased within a shell comprised of a second semiconductor material. A typical QD has a diameter in the range of 2–10 nm, which is comparable with the size of a large protein.

For biomedical applications, QDs are generally solubilized and require some form of biological “interfacing.” A number of strategies for solubilization and imparting biofunctionality have been devised; these have previously been reviewed by Michalet et al. (2005). A single QD contains a large number (10–100) of potential surface attachment groups, and therefore can readily be conjugated to biomolecules such as biotin, antibodies, oligonucleotides (DNA or RNA), or peptides (illustrated in Fig. 2, below). A standard nomenclature is generally utilized to describe the component parts of various QDs, as follows: Core/Shell-Conjugate. For example, a QD with a cadmium-selenium core and a zinc sulphide shell which has been biotin conjugated would be designated as CdSe/ZnS biotin.

FIG. 2.
Basic structure of a QD.

Key Applications of QDs

The properties of QDs make them potentially useful in a wide variety of settings, including electronics, computing, and various biomedical and clinical imaging applications.

In the field of electronics, researchers are looking to exploit both the semiconductor and luminescent properties of QDs in transistors, to build improved transistor capabilities. The luminescent properties of QDs are being explored for use in next generation versions of light-emitting diodes and diode lasers. QDs are also being explored for potential applications in the emerging field of quantum computing.

The many potential biomedical applications of QDs have been recently and extensively reviewed elsewhere (Azzazy et al., 2007; Delehanty et al., 2008; Hild et al., 2008; Medintz et al., 2008; Michalet et al., 2005; Jamieson et al., 2007; Li et al., 2007; Samia et al., 2006). Biomedical applications exploit the fluorescent properties of QDs, and particularly their advantages over traditional organic dyes, for both diagnostic and clinical applications. The in vitro biomedical and diagnostic applications of QDs include such techniques as the multicolor fluorescent labelling of cell surface molecules and cellular proteins in microscopy and other applications, detection of pathogens and toxins, DNA and RNA technologies, and fluorescence resonance energy transfer. QDs are also being explored for use in whole-body in vivo imaging of normal and tumor tissues. QDs may also find use in therapeutic applications such as targeted drug delivery, photodynamic therapy, and drug discovery.

QDs VIEWED THROUGH A REGULATORY LENS

Governments have traditionally regulated novel technologies on the basis of specific products and their intended uses (e.g., label claim), rather than on the basis of the technology itself. The specific commercial applications of QDs will therefore most likely dictate the approach to regulation, and the perspective of regulators is best served if QDs are classified in a way that is sensitive to the streaming of novel products into existing regulatory frameworks. For the sake of the discussion to follow, we break down the heterogeneous category of all QDs into subcategories based upon specific products or applications likely to be regulated in a similar fashion. We propose the following three regulatory classes of QDs. Note that the rudimentary classification scheme outlined below is intended to be sensitive to the perspective of regulators without presupposing the future emergence of nanotechnology-specific regulatory approaches. It would be premature to be more specific at this time because the regulatory system is currently under development and because terminologies and nuances vary internationally.

Class 1: Consumer products: QDs contained in consumer products, particularly electronics and quantum computing applications.

Class 2: Medical and imaging devices: QDs as in vitro diagnostic agents and as imaging devices used in the biomedical research setting.

Class 3: Pharmaceutical products: QDs as “nanomedicines” and in vivo diagnostic agents, that is, the use of QD in clinical imaging and drug delivery applications.

Closely tied to the regulation of pharmaceutical products is the regulation of food and food products. Any potential applications for QDs in the area of food and food packaging would likely be subject to a similar depth of regulatory attention, if not increased regulatory scrutiny, as compared with pharmaceuticals. Although we are not specifically aware of any research being conducted into the use of QDs in food or food packaging, a 2004 report reporting the use of QDs to specifically detect a strain of Escherichia coli known be a major cause of food borne illness (Su and Li, 2004) suggests that QDs, like other nanoparticles, may eventually find applications in this area.

Beyond the three regulatory product classes of QDs described above, one area in which the specific application of a product does not currently dictate the approach to regulation in a majority of jurisdictions is that of chemical substances. The level of regulatory oversight for chemical substances generally depends on a certain threshold concentration being released into the environment.

In the sections that follow, we will discuss the physicochemical properties, toxicity, and biological fate of QDs in sequence, according to the typical structure of a regulatory risk assessment, as illustrated above in Figure 1.

BASIC PHYSICOCHEMICAL PROPERTIES OF QDs

The health and safety properties of QDs will largely be dependent upon their basic physicochemical properties, such as (1) chemical composition (purity and chemical make-up), (2) shape and size (size may refer both to surface area and to size distribution), and (3) surface properties and solubility (surface reactivity, surface groups, inorganic or organic coatings, etc.). This component of risk assessment requires attention because the justification for novel data requirements hinges to a large extent on the unique behaviours exhibited by materials at the nanoscale.

Chemical Composition

In terms of their chemical composition, QDs are a highly heterogeneous group of products. QDs for biological applications, including those which are currently commercially available from companies such as Invitrogen, are most commonly comprised of cadmium and either selenium or tellurium (CdSe and CdTe QDs) and are frequently coated by a shell comprised of zinc sulphide (ZnS), but there are many other possible combinations.

Cadmium, selenium, and tellurium all have known toxicities in humans, including hepatic, renal, neurologic, and/or genetic toxicities (reviewed in Bertin and Averbeck, 2006; Taylor, 1996; Vinceti et al., 2001). For this reason, it will be important for regulators to know the exact chemical compositions of the both the core and shell structures of the QD.

Size and Shape

The size, or hydrodynamic diameter (HD), of QDs can be characterized by a variety of methods, including transmission electron microscopy (TEM), dynamic light scattering, high-solution atomic force microscopy and gel filtration chromatography. As will be discussed in further detail later, the HD may be predictive of whether or not a particular QD will be cleared from or retained in the body. As the HD of QDs will vary considerably depending upon the organic coating surrounding a QD core, it will be important to report the HD for any new QD formulation undergoing regulatory consideration.

Surface Properties and Solubility

QDs are not inherently water soluble—they are hydrophobic by nature. It is therefore necessary to solubilize QDs for applications in a biological environment by altering the surface properties of the QD. Solubilization can be accomplished in a number of ways, but the most common strategies are silanization and surface exchange with bifunctional molecules (i.e., molecules which possess both a hydrophobic side that can bind to the shell of the QD, and a hydrophilic side that can interact in an aqueous biological environment). For certain applications, it may also be desirable to impart certain functional properties upon the QDs. For example, if the QD is to be targeted to a particular cell structure, cell type, or tissue, then a targeting peptide or antibody may be attached to the surface of the QD. As will be described below, the surface composition and solubility properties of QDs can greatly affect the toxicity and biological fate of QDs. Regulators will therefore be interested in descriptions of the surface composition and measures of the solubility of individual QD preparations.

TOXICITY OF QDs

With notable exceptions, the vast majority of scientific papers reporting on the toxicity of QDs have limited their investigations to cytotoxic effects of QDs observed in short-term, cell culture-based assay systems, rather than addressing the question of how QDs might affect the overall growth, viability, and/or reproductive capacity of humans or other species. Interpretation of the body of evidence relating to the cytotoxic effects of QDs is further complicated as a result of the broad diversity of QDs being tested, as each individual type of QD possesses its own physicochemical properties and due to the diversity of test systems used. The dosage of QDs used and exposure times also vary widely in the literature. Furthermore, it is often unclear how the experimental dosages relate to concentrations associated with real-world commercial applications of QDs. It is therefore difficult to extrapolate the results of such studies in order to form any conclusions regarding the health and safety of QDs. Nonetheless, these studies may provide important insights that will be useful in guiding the eventual design of standardized toxicity tests and protocols.

A Summary of Studies Assessing the Toxicity of QDs

In 2006, Ron Hardman authored a comprehensive review regarding the toxicology of QDs and concluded that the toxicity of QDs was dependent upon their physicochemical properties as well as environmental factors (Hardman, 2006). In this seminal review paper, Hardman included a table summarizing the available literature concerning QD toxicity.

Below, in Table 1, we have adapted and extended Hardman's table to summarize studies that have been published following acceptance of the Hardman review paper in September 2005. We have attempted in this exercise to include all relevant studies up to December 2008. For the sake of completeness, the results of older studies, that is, those which were originally reported by Hardman in 2006, are also summarized below, in Table 2.

TABLE 1
Summary of Quantum Dot Toxicity Studies Published from 2006 to 2008
TABLE 2
Summary of Quantum Dot Toxicity Studies Published Prior to September 2005.

Discussions in the literature relating to the potential toxic effects of nanotechnology applications often point to the fact that the bulk forms of nanomaterials, many of which have been in widespread use for many years, are themselves not toxic. As an example, consider the case of carbon nanotubes, which are nanoforms of carbon.

In the case of QDs, the situation is essentially reversed. The bulk forms of some of the component molecules of QDs—such as cadmium, selenium, and tellurium—are themselves known to be highly toxic. The question therefore becomes one of determining whether in nanoscale format (i.e., in the context of QDs) the toxicity of these substances can be eliminated, or at least drastically reduced.

In 2006, Hardman stated the following regarding the toxicity of QDs: “QD size, charge, concentration, outer coating bioactivity (capping material and functional groups), and oxidative, photolytic, and mechanical stability have each been implicated as determining factors in QD toxicity” (Hardman, 2006). Since 2006, a number of studies have provided further support for this statement. This suggests that the toxicity of QDs can, at least to some extent, be minimized through selection of an appropriate shell coating (Cho et al., 2007; Su et al., 2009), by modulating surface charge (Ryman-Rasmussen et al., 2007) or surface coating (Guo et al., 2007), by selecting a lower overall dosage of QDs (Tang et al., 2008), or by modulating the overall size of the QD (Zhang et al., 2007).

In a number of the toxicity studies summarized in Tables 1 and and22 below and particularly in earlier studies, the presence of free cadmium ions in the QD preparations interferes with extrapolation of the results regarding QD toxicity. This is a major methodological issue which we note is generally being addressed in more recent papers, either through the use of highly purified commercially available QDs or by dialysing QD preparations prior to their use in order to eliminate free cadmium ions. However, although minimizing the presence of free cadmium ions in QD preparations does seem to reduce the toxicity of QDs, this alone does not explain all of the QD toxicity reported in the literature.

Hardman (2006) stated that future research should attempt to evaluate the long-term toxic effects of QDs, as “QD-induced cytotoxicity was generally found in those studies that tended to be longer in nature” (Hardman, 2006). This advice has not been implemented—most of the recent studies (Table 1) relied heavily on the use of short-term in vitro assays, most notably the MTT (otherwise known as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay of cell viability.

We conclude that the progress on the evaluation of the toxicity of QDs has only progressed marginally since Hardman's review. The most noteworthy changes from the perspective of product regulation are the advances made in QD coatings. Hardman's call for long-term toxicity studies—which likely would be echoed by regulators—remains unanswered by current academic research.

BIOLOGICAL FATE OF QDs

In this section, we will summarize the state of academic knowledge up to December 2008 concerning the biological fate (including ADME) of QDs.

For the purposes of the discussion to follow, we use the term “biological fate” to describe any number of the potential outcomes that may befall QDs. We have defined the term broadly, so as to encompass: (1) potential routes of human exposure to QDs; (2) the potential for the degradation of QDs into their component molecules; (3) the tendency of QDs to aggregate, which may affect their biological properties; (4) the question of whether, once exposure has occurred, QDs will accumulate in cells or tissues or whether they will be excreted into the surrounding environment; and finally (5) the question of what might happen to QDs following the excretion or release into the environment. These issues will each be described in detail in the sections that follow.

Potential Routes of Human Exposure to QDs

Central to a discussion of the toxicology and biological fate of QDs is the question of what potential sources of exposure might result in their uptake or absorption by humans. There are a finite number of potential means by which humans can theoretically become exposed to potentially toxic substances: (1) if airborne, substances could potentially be inhaled; (2) substances could be absorbed through the skin or eyes; (3) substances could be ingested; or (4) they could be injected by intravenous, subcutaneous or other injection methods. Below we discuss these four potential routes of exposure and detail and the state of current knowledge regarding the risk of human exposure to QDs through each mechanism.

Quantum Dot Aerosolization and Inhalation

Assessing human exposure to airborne nanomaterials represents a considerable challenge. As recently discussed by Maynard and Aitken (2007), considerations such as particle number, surface area, mass concentration and the basic physicochemical properties of QDs will likely need to be considered. The potential risks associated with the inhalation of QDs are rarely, if ever, discussed. Whether this is due to the fact that QDs do not readily become airborne or whether the potential for aerosolization has simply not yet been evaluated is unclear.

The greatest potential for aerosolization of QDs likely arises during the synthesis and manipulation phases of QD manufacturing, although we cannot rule out the possibility that future clinical applications of QDs could be formulated as aerosols. The conventional synthesis of QDs uses large volumes of high-boiling organic solvents at high temperatures into which aggressive and toxic chemicals must be quickly injected. The synthesis of QDs using microwave irradiation (Li et al., 2005) and chemical aerosol flow synthesis (Didenko and Suslick, 2005) have also been reported. As such, workplace exposure to aerosolized QDs is an area that will require careful consideration by regulators. We are not aware of any attempts in the literature to date which address the potential effects of inhaled QDs experimentally.

Absorption of QDs through the Skin and Eyes

The skin and eyes can both serve as portals of entry for localized or systemic human exposure to potentially toxic materials. Regulators will therefore want to know whether or not it is possible for QDs to enter the human body through dermal or ocular absorption, as well as the probability of exposure to QDs through these routes.

In an in vitro study, Ryman-Rasmussen et al. (2006) have reported that QDs are able to penetrate intact skin. According to their results, QDs with different core/shell shapes (spherical and ellipsoid) and sizes (4.6 nm in diameter and 12 × 6 nm) and with variably charged (neutral, anionic, or cationic) surface coatings were able to penetrate porcine skin within 24 h. In terms of the generalizability of these results to real-world setting, it is notable that the dosage of QDs administered in this study (62.5 pmol/cm2 of skin) was described as “occupationally relevant” by the authors, and that porcine skin is anatomically, physiologically, and biochemically similar to human skin (Ryman-Rasmussen et al., 2006). We are not aware of any in vivo studies on skin absorption nor any study on ocular absorption of QDs.

Ingestion of QDs

To date, the possible toxicity of ingested QDs has not been explored in any great detail. This may be due to the fact that at present, there is little likelihood of QD applications under active development being administered orally or incorporated into food products or food packaging. Notwithstanding this, regulators will need to understand the extent by which QDs could accidentally be ingested by people who work in the manufacturing industry, research laboratories, or diagnostic facilities. Alternatively, QDs could also be ingested by eating or drinking nanoparticle-contaminated food or water.

A recent report examined the possible toxic effects of ingested QDs, using Caco-2 cells as model for the epithelium of the small intestine. The authors of this report also examined the effect of low pH, simulating conditions that would be encountered in the human stomach, on CdSe QD cytotoxicity (Wang et al., 2008). Exposure of QD to low pH conditions in this report resulted in a loss of integrity of the QD structures, release of free cadmium ions, and therefore an increase in QD toxicity. This evidence demonstrates that the toxic effects of QDs could vary considerably depending upon the route of exposure.

The Direct Injection of QDs into Humans

For the vast majority, if not all, of the potential applications of QDs as in vivo nanodiagnostics and nanomedicines, QDs will likely be administered through direct injection into humans and animals. For applications such as sentinel lymph node mapping in animal models, QDs would be injected directly into tumor tissues, whereas intravenous injections are more likely in other clinical applications. A number of studies have looked at the ADME of injected QDs; these will be discussed in further depth below. For the purposes of conducting risk assessments, it will be important to specify the exact method of injection (intravenous, subcutaneous, etc.), as recent reports have suggested that the fate of QDs differs depending upon the mode of injection.

A Summary of Studies Assessing the Biological Fate of QDs

Increasingly, researchers have begun to address the question of what happens to QDs when they are administered in vivo. Do QDs accumulate in tissues and if so, do they preferentially become distributed in certain tissues versus others? Similarly, is it possible to specifically target QDs to particular tissues? This could be useful when using QDs as nanomedicines or in vivo imaging agents; it might, for example, be useful to specifically target tumor cells or affected lymph nodes in order to either diagnose or treat cancer patients. Once administered, are QDs eventually excreted, or do they tend to accumulate in tissues? What is their half-life following administration? These questions are all relevant to determining the ADME of QDs.

To provide a useful reference for regulators and researchers alike, the results of studies addressing the biological fate of administered QDs have been summarized in Table 3, below.

TABLE 3
Summary of Studies Reporting the Biological Fate of QDs

Two basic methodologies have been used in the literature to examine the biological fate of QDs following in vivo administration in lab animals. The first methodology has taken advantage of the fluorescent properties of QDs; researchers determine the biodistribution of QDs following administration by tracking the fluorescent particles. In this regard, QDs offer a considerable advantage over many nanoparticles, in that their luminescent properties render them highly suitable for studies evaluating biological fate.

The second methodology involves generating radiolabeled versions of QDs (e.g., CdTe QDs containing radioactive Te-125m) and using these radioactive variants to track the biodistribution of QDs. One advantage of the radiolabeling methodology is that it allows for the derivation of quantitative data regarding fate. On the other hand, the tracking of radioactivity does not allow for distinguishing between QDs which remain active and those that become inactive, including those which have been degraded into their component molecules. In contrast, only intact QD particles should continue to fluoresce.

As with toxicity, a number of studies have concluded that the pharmacochemical properties of QDs including their size, solubility, aggregation and surface composition may influence the fate of the injected nanoparticles. For this reason, a concerted effort has been made in Table 3 below to report the specific properties of the QDs being assessed in each study, including their chemical composition, emitting wavelength, HD, and overall surface charge.

Of particular interest from a regulatory perspective, it has been suggested that the HD of QDs may influence whether or not they are excreted or will accumulate in tissues (Choi et al., 2007). For this reason, we have included a column to report the HD of the QDs under evaluation in each study.

We have also indicated the concentration, or dosage, of QDs that was utilized in each study. Because dose-response evaluations are a critical feature of the regulatory risk assessment process, we were pleased to note that authors are increasingly taking care to report the number of particles administered (nmol and pmol), rather than the overall mass. In some cases, authors have included observations of in vivo toxicity in their reports; these have been summarized in Table 3 under the column heading “Observations of in vivo toxicity.” Results of studies to date have yielded certain commonalities, but as yet there is no general agreement as to the fate of administered QDs. This will be discussed below under the sections on the accumulation and excretion of administered QDs.

Accumulation of Administered QDs in Organ Tissues

Based on the results of a number of studies looking at the biodistribution (and occasionally pharmacokinetics) of QDs administered in vivo, it is possible to reach a few tentative generalizations regarding the preference of QDs for accumulation in certain target organs.

First, administered QDs are generally completely—and likely also rapidly—cleared from the bloodstream. With respect to the timing of clearance of QDs from the bloodstream, estimates of the half-life of administered QDs in vivo vary from one report to another. Interestingly, one report noted that the blood half-life of a series of QDs varied considerably depending upon the HD of the QDs; aside from varying in terms of their size, the QDs in this series were otherwise physicochemically identical in terms of their composition (Choi et al., 2007). In this report alone, the blood half-life varied from 48 min to 20 h—a rather wide range. However, all of the reports in the literature were unanimous in concluding that QDs show a preference for deposition in organs and tissues and that they do not remain circulating in the bloodstream.

Second, QDs injected intravenously are more likely to accumulate in the liver and spleen. To a lesser extent, QDs injected in this fashion have also been detected in kidneys, lymph nodes, and bone marrow. A subset of the reports summarized in Table 3, for example the 2008 report by Kennel et al. (2008), have attributed the observed migration to the liver and spleen to clearance of QDs by phagocytic cells of the reticuloendothelial (RE) system, which suggests that QDs residing in organ tissues have already been internalized by cells.

When QDs are injected either subcutaneously (Robe et al., 2008; Zimmer et al., 2006), intradermally (Gopee et al., 2007), or directly into animal tumor tissues (Ballou et al., 2007), the pattern of organ deposition is different. QDs injected subcutaneously or into tumors seem to migrate to nearby lymph nodes and remain there. In the one study which looked at intradermal injection, QDs were found in liver, lymph nodes, and kidneys, but the vast majority of the QDs remained at the site of injection. The results of Zimmer et al. (2006) suggest that when the size, or HD, of QDs is above a certain threshold limit (in their study, they estimate this threshold to be approximately 10 nm), this may limit the ability of the QD to migrate further into the lymphatic system or to extravasate from the vasculature. Thus, a likely reason for the dependence upon mode of injection on final fate is that the scope of the migration of QDs in vivo is effectively limited by their size.

It is worth noting that there are no reports to date describing the migration of injected QDs into the brain. Whether this means that QDs are incapable of crossing the blood-brain barrier or whether they are simply cleared too quickly from the circulation by cells of the RE system is a question which, to the best of our knowledge, has not yet been assessed.

Excretion of Administered QDs

In their paper looking at the renal clearance of QDs, Choi et al. (2007) posit that an analysis of bodily fluids, including urine, bile and feces, should be a mandatory part of any human risk assessment following environmental exposure to nanoparticles. Provided that the initial exposure dose is known, such an analysis could help to estimate the total retained dose of nanoparticles.

To date, there have been a few studies in the literature which have looked at the excretion of QDs following their in vivo administration. Results to date have varied, and will be described in further detail below.

Lin et al. (2008) performed in-depth pharmacokinetic and toxicology studies in mice at time points of up to 6 months. According to their results, commercially available Qtracker 705 nontargeted QDs (QD705) injected intravenously into mice accumulated primarily within the liver, spleen, and kidney. The authors could find no evidence of excretion or metabolism of the QD705 nanoparticles within 28 days following dosing. Concerned by the persistence of the QDs, the authors examined the kidneys by TEM at 6-months postdosing, and observed significant renal toxicity in the dosed but not control mice. The “subtle but definitive” cytological changes noted in dosed mice consisted of proximal tubular degeneration, with pronounced changes in mitochondria in the proximal convoluted tubules. Based on these results, the authors caution that the in vivo administration of QD705 may be highly toxic.

In contrast, other studies have demonstrated efficient excretion of QDs by mice. For example, Chen et al. (2008) assessed the biodistribution and excretion paths of water soluble hydroxyl group-modified silica coated CdSeS QDs that were intravenously injected into mice. In contrast to the results described above (Lin et al., 2008), in this study the majority of injected QDs were cleared from mice, via both feces and urine, within 5 days following injection. Only a small amount (approximately 8.6%) of the injected QD dose was retained in the mouse beyond the 5-day time point (although the authors did comment that this remaining dose seemed to resist clearance from the liver, where they seemed to accumulate). Combined with the observed long-term stability of the silica coated CdSeS QDs, the results of Chen et al. seem to indicate few toxic effects linked to the in vivo administration of CdSeS QDs in mice.

From a safety and regulatory perspective, the 2007 report by Choi et al. (2007) opens an interesting avenue. This report demonstrated that, for CdSe/ZnS QDs with a zwitterionic charge and coated with cysteine, there appears to be a threshold HD (in this case less than approximately 5.5 nm) below which QDs are effectively cleared from the body through urine and bile. The authors are justifiably cautious about overinterpretation of their results, pointing out that measurements of diameter are inherently unreliable and therefore should not be substituted in lieu of rigorous testing for clearance from the body. However, these results suggest that it may be possible to optimize QDs for biological applications in such a way as to maximize their excretion from the body. Any toxic effects associated with QD administration to a patient would thereby be minimized. This does exclude, however, the potential of an environmental impact during the subsequent environmental fate.

However, the next logical question becomes: what would happen to QDs following their excretion from the human body? What would be the possible effects of QD accumulation in the environment following excretion? In this vein, the fledgling body of literature regarding the possible food chain transfer and bioaccumulation of QD is summarized below.

Food Chain Transfer and Bioaccumulation of QDs

In a November 2008 report by the UK Royal Commission on Environmental Pollution, the Commission noted that, with respect to nanomaterials, “there is a consensus that mechanisms of toxicity are poorly understood and that, with minor exceptions, appropriate ecological studies have not been undertaken, including studies that address food chain transfer and multigenerational effects” (Royal Commission on Environmental Pollution, 2008). It is therefore noteworthy that among the first reports to appear in the literature regarding the ecotoxicity and food chain transfer of nanoparticles are three publications pertaining to QDs (Bouldin et al., 2008; Gagne et al., 2008; Holbrook et al., 2008).

In one report, the authors examined the toxic effects of cadmium-telluride (CdTe) QDs on freshwater mussels (Gagne et al., 2008). This study concluded that uncoated (i.e., no shell structure) CdTe QDs were immunotoxic to freshwater mussels within 24 h, leading to oxidative stress (lipid peroxidation) in gills and genotoxicity (DNA damage) in the gills and digestive glands. The toxic effects of uncoated QDs are well documented in previous in vitro toxicity studies; this study supports the observed in vitro toxicity of uncoated CdTe QDs in an in vivo model of ecotoxicity.

Another report looked at the effects of commercially available cadmium-selenium QDs coated with a ZnS shell (Qdot 545 ITK Carboxyl QDs) on the freshwater alga Pseudokirchneriella subcapitata and the cladoceran Ceriodaphnia dubia (Bouldin et al., 2008). These model organisms were selected by the authors “because they are established model species in standard toxicological studies and ecological risk assessments,” and because they “provide a simple model for food chain transfer.” In this study, the authors found that aquatic organisms exposed to QDs were able to withstand concentrations of cadmium that were 500-fold or greater higher than was the case for bulk cadmium. This result is contrary to the widely held view that nanoforms of toxic materials (in this case, cadmium) are likely to have toxicological effects at lower concentrations due to their high surface area. Because in QDs, the cadmium is encapsulated by a shell substance, the nanoform of this substance appears to be overall less toxic than its bulk counterpart.

High concentrations of the coated QDs tested in this report were found to have lethal toxicological effects on freshwater algae: the median lethal concentration of QDs on P. subcapitata at 96 h was measured at 37.1 parts per billion (ppb). No lethality was found following 48 h of exposure of C. dubia to QDs at the highest concentrations tested (110 ppb), which suggested that toxic cadmium from the QD core was not bioavailable to the cladoceran species. One note of caution, however, is that this study found that QDs could be transferred up the food chain from dosed algae to C. dubia. Bioaccumulation effects could therefore theoretically result in potential exposure of higher order organisms to concentrations of QDs beyond what could be achieved in this experimental system.

A third report looked at the effects of QDs in an invertebrate rather than aquatic food chain, focusing on representative bacteria (E. coli), ciliate (Tetrahymena pyriformis), and rotifer (Brachionus calyciflorus) species (Holbrook et al., 2008). In this simplified invertebrate food web, the authors did not observe any significant bioconcentration or biomagnifications of QDs. This study utilized commercially available ellipsoid-shaped CdSe/ZnS QDs, and evaluated the effects of both carboxylated and biotinylated QDs. In this experimental system, there was no evidence of QD uptake by individual E. coli bacterial cells. Both carboxylated and biotinylated QDs could become attached to the exterior surface of aggregated E. coli cells, but there was no evidence of ingestion of these bacterial aggregates by the ciliates.

Despite the lack of trophic transfer from bacterial cells to ciliates, the authors did find evidence that QDs in aqueous media could bioconcentrate in ciliate species. Both the biotinylated and carboxylated QDs were taken up by the ciliates (although there were differences noted in the rate of uptake), and biotinylated QDs were furthermore found to be retained more than twice as long as carboxylated QDs. These results suggest that physicochemical properties of QDs, such as surface composition may modulate bioconcentration effects (Holbrook et al., 2008). Trophic transfer of QDs between the ciliates and rotifers was shown to occur, however the rotifers were able to eliminate the QDs. Quantum dot half-lives in rotifers ranged from 14.5 to 23.1 h and appeared to be independent of surface chemistry. This result suggested that although bioconcentration can occur in ciliate species, bioaccumulation resulting from ciliate predation would not be expected to occur in rotifers.

The three studies on the possible environmental effects described above are clearly a step in the right direction. These studies have shown the potential for bioaccumulation in aquatic species, but no evidence of bioaccumulation in an invertebrate food web. Further studies will be required in order to validate and expand upon these preliminary results.

Stability and Aggregation

One component of fate that we have not yet discussed is the potential for QDs to either degrade into their component molecules (i.e., their stability) or to become transformed by aggregation into higher order structures. In the section on toxicity above, we noted that the degradation of QDs and consequent release of free cadmium ions contributed to the overall toxicity of QD. In their report evaluating the biodistribution and metabolism of silica coated QDs, Chen et al. demonstrated that the aggregation state of QDs in vivo influenced their capacity to be excreted from the body, as well as the path by which QD were metabolized (Chen et al., 2008). From a regulatory perspective, the capacity for QDs to degrade or become transformed is therefore of great importance. Below, we will discuss factors which are known to influence the stability and aggregation potential of QDs.

Woodward et al. (2007) recently assessed the chemical stability of radiolabeled CdTe QDs in an aqueous environment. When uncapped CdTe core QD were suspended in aqueous buffer, approximately half of the radioactivity contained within the QDs was released into the environment within 3 days. In contrast, CdTe cores capped with a ZnS shell demonstrated vastly increased stability. In fact, CdTe/ZnS QDs remained stable in aqueous buffer for up to 36 days. This report suggests that the capping of QDs with ZnS significantly enhances their stability in aqueous media.

Researchers have also begun to explore the potential effects of pH on the overall stability of QDs. Chen et al. (2008) looked at the effect of pH (pH 4.8 vs. pH 7.4) on the stability of CdSeS/SiO2 QDs and found that these QD maintained their integrity for up to 5 days in both high and low pH buffers. In fact, they could not detect any leaching of free Cd ions from CdSeS/SiO2 QDs, suggesting that these dots were extremely stable in either pH environment. In contrast, Wang et al. assessed the stability of commercially available polyethylene glycol-coated CdSe/ZnS QDs and concluded that a low pH environment led to a loss of QD integrity and release of free cadmium ions (Wang et al., 2008). Thus the chemical composition of QDs appears to be one factor which influences the stability of QD in a low pH environment.

In a 2004 study, Derfus et al. (2004) demonstrated that exposure of CdSe QDs to air and ultraviolet light led to the degradation of the QD and the consequent release of free cadmium ions. This in turn increased the toxicity of QD that were exposed to air and UV light. The fact that air and UV light can destabilize QDs may not be of particular significance in the context of QDs administered to humans, but it could become a major factor when looking at the potential long-term effects of QDs released into the environment.

Another factor that will be of significant interest in terms of predicting the fate of QDs will be the tendency of the dots to aggregate into higher order structures. Several groups have observed the aggregation of QDs under a variety of conditions. For example, Zhang et al. (2007) recently assessed the stability of CdTe nanoparticles under cell culture conditions and observed the apparent agglomeration of red CdTe nanoparticles over time. The authors additionally noted that this aggregation of QDs was primarily extracellular. Another report looked at the tendency of CdTe QDs to aggregate when dissolved in aquarium water. In this study, it was observed that QD showed a clear tendency to aggregate in the particulate phase, whereas only approximately 15% of QDs were found in the dissolved phase (Gagne et al., 2008). This study suggested that QDs in an ecologically relevant aqueous environment may have a predisposition toward aggregation.

The surface chemistry of various QDs will likely affect their tendency to self-aggregate, and aggregated QDs may have very different health and environmental effects than nonaggregated particles. Research into the tendency of QDs to aggregate has been limited to date; going forward, it will be important to investigate the impacts of aggregation on the stability and biological effects of QDs.

A more complete understanding of both the stability and aggregation potential of QDs will be required in order to further elucidate both the biological and environmental fates of QDs.

FUTURE RESEARCH NEEDS FROM A REGULATORY PERSPECTIVE

At this early stage in the commercial development of QDs, the risk-relevant information available in the academic literature is still limited. Below we will discuss some lessons for regulators and researchers to keep in mind during the iterative process that may (or may not) lead to specific regulatory requirements for QD based products.

The Diversity of QD as a Product Class May Present a Substantial Regulatory Challenge

It is clear that the inherent toxicological potencies of various QDs differ significantly between various QD preparations. The composition of the core, shell, and surface coatings, as well as the overall size and shape of the QD may all impact upon the toxicological profile of different QD. As a result, some detailed and completed case-by-case risk assessments will need to be completed before any attempts at generalizing regulations across a specific group or the full spectrum of QDs might become possible. At this early stage, it is important that researchers continue to report on as many of the properties of the QD preparations that they are using in their studies as possible—this will greatly facilitate any future attempts at generalization. Regulators may want to think about incentives to promote this knowledge transfer. Because of the real possibility that QDs can become degraded, it will be additionally be necessary to report not only on the properties of the overall QD construct, but additionally its component molecules and concentrations. This will be particularly important in the case of QDs which are made up of substances like cadmium, selenium, and tellurium, which have known toxicological properties.

Where Possible, Studies of the Toxicity, and Biological Fate of QD Should Utilize Realistic Dosages

Researchers are making rapid progress in terms of understanding which factors (such as surface coatings and overall size) can be manipulated in order to reduce the overall toxicity of QDs and to improve the rate of their excretion from the human body. Ultimately, however, regulators will be interested in assessments of dose-response relationships. Admittedly, because QDs are as yet still at an early stage in terms of the development of commercial applications, it remains difficult to determine what might be realistic human and environmental exposure levels. However, it remains important to report on dosages and where possible, to utilize meaningful doses in all experimentation. Without an estimation of realistic dose levels to inform dose-response experimentation, it will not be possible for regulators to carry out a meaningful risk assessment.

Toxicity Data to Date are Insufficiently Standardized and based on too Few Endpoints

Research to date has been focused on in vitro assays of cytotoxicity. In vitro studies are very important and can serve as background information to inform the design of in vivo studies, but on their own they provide an insufficient basis for a complete risk assessment. Once the relationship between in vitro and in vivo assays of QDs is better understood, however, regulators may find great utility in rapid, cheap, and highly standardized in vitro assays. We should note that there is considerable pressure from European regulators to improve the utility of in vitro studies and the ability to extrapolate from in vitro to in vivo data in a regulatory context.

Cytotoxicity is an important starting point for beginning to understand the biological effects of QDs, but it is not sufficient as a sole endpoint. For applications of QDs as diagnostic or therapeutic tools, researchers are advised to carefully examine the existing regulatory requirements for pharmaceutical products. These requirements will provide important clues as to which data points regulators may require in order to complete a premarket regulatory risk assessment. The route of administration and the doses used will be key considerations in risk assessments. Data on the biological fate are also required (see below). Studies in the literature have thus far tended to focus on either toxicity or biological fate as endpoints. There would be great merit, moving forward, in designing experiments in such as way as to allow the simultaneous collection of data on both toxicity and biological fate.

Toxicity studies to date have been conducted on a variety of both human and nonhuman cells and cell lines, including the studies described above in the section on the food chain transfer and bioaccumulation of QDs. These data will be helpful in estimating the variance in susceptibilities across different species. Depending upon the location and quantities of QDs that may be found to be released into the environment and their environmental fate, regulators may require data on the toxicity of QDs on indicator species (e.g., water fleas are often used in this context) or other species that are particularly susceptible or exposed. Here, the existing regulatory requirements for the environmental assessment of pharmaceutical products and the assessment of so-called “new substances” under Toxic Substances Control Act in the United States and the Canadian Environmental Protection Act in Canada will provide important clues for researchers about which endpoints regulators may require in the assessment of QDs. The Organization for Economic Co-operation and Development, already an established leader for international testing protocols for new substances, is also leading international efforts in the standardization of regulatory protocols for nanomaterials.

Biological Fate Data are Insufficiently Standardized and based on too Few Endpoints

Our literature survey has shown that the degradation of QDs may be promoted by low pH, air, and ultraviolet light. The QD shell and surface coating may be critical in preventing or delaying this degradation process and, thus, the release of toxic substances such as free cadmium ions from the QD core. This fact will need to be taken into account in the design of studies on toxicity and biological fate. Experimental data suggests that uptake of QDs through the skin is a possible route of human exposure. To date, very little or nothing is known about the likelihood or possibility of QD entry through the eyes, nose or mouth, or via inhalation or ingestion.

Administration of QDs by intravenous injection in model animals has been shown to lead to accumulation of QDs in tissues, and primarily in the liver and spleen. The rate of QD accumulation in the human body will be of critical importance to regulators. Reports such as that by Choi et al. (2007), who reported that QDs below a certain threshold size limit may be efficiently excreted from the body whereas larger QD may accumulate, deserve a great deal of regulatory attention. This study in particular should be extended to examine alternate QD formulations, compositions, and shapes, to help facilitate any future generalizations regarding size thresholds in the regulatory context.

The results from a number of studies have indicated that the placement of molecules such as proteins onto the surface of QDs can greatly impact their pharmacokinetics and biodistribution. Yet, in a number of the in vitro studies summarized in Table 3, there have been no observations on whether animal serum proteins are adsorbed to the surface of the nanoparticles or whether the particles themselves are becoming aggregated. The lack of these observations makes it difficult to compare studies, to understand cause-effect relationships, and to link results from in vitro studies to those observed in vivo.

Research examining the environmental fate of QDs has just begun and interesting results have emerged. However, the existing data on food chain transport, bioaccumulation or biomagnification, and persistence in the natural environment are as yet insufficient to inform a complete environmental risk assessment, even for those products that have been tested. The extrapolation of the environmental risk assessments of one QD to other products is, as mentioned above, another step that will likely require additional data. We should note, however, that the quantity of environmental releases of QDs may eventually be found to be so limited that regulators may judge a complete environmental assessment to be a low priority.

FUNDING

Genome Canada through the Ontario Genomics Institute (grant number 2004-OGI-3-15); and McLaughlin Centre for Molecular Medicine supported A.S.D.

The McLaughlin-Rotman Centre for Global Health, Program on Ethics and Commercialization, is based at the University Health Network and University of Toronto and is primarily supported by Genome Canada through the Ontario Genomics Institute and the Ontario Research Fund, and the Bill and Melinda Gates Foundation. Other matching partners are listed at http://www.mrcglobal.org/.

Acknowledgments

The authors would like to acknowledge the helpful comments by three anonymous reviewers as well as the sources of funding described above. All errors and misconceptions remain our own.

References

  • Akerman ME, Chan WC, Laakkonen P, Bhatia SN, Ruoslahti E. Nanocrystal targeting in vivo. Proc. Natl. Acad. Sci. U. S. A. 2002;99:12617–12621. [PMC free article] [PubMed]
  • Azzazy HME, Mansour MMH, Kazmierczak SC. From diagnostics to therapy: Prospects of quantum dots. Clin. Biochem. 2007;40:917–927. [PubMed]
  • Ballou B, Ernst LA, Andreko S, Harper T, Fitzpatrick JAJ, Waggoner AS, Bruchez MP. Sentinel lymph node imaging using quantum dots in mouse tumor models. Bioconjug. Chem. 2007;18:389–396. [PubMed]
  • Ballou B, Lagerholm BC, Ernst LA, Bruchez MP, Waggoner AS. Noninvasive imaging of quantum dots in mice. Bioconjug. Chem. 2004;15:79–86. [PubMed]
  • Bertin G, Averbeck D. Cadmium: Cellular effects, modifications of biomolecules, modulation of DNA repair and genotoxic consequences (a review) Biochimie. 2006;88:1549–1559. [PubMed]
  • Bouldin JL, Ingle TM, Sengupta A, Alexander R, Hannigan RE, Buchanan RA. Aqueous Toxicity and food chain transfer of quantum dots in freshwater algae and ceriodaphnia dubia. Environ. Toxicol. Chem. 2008;1:1958–1963. [PMC free article] [PubMed]
  • Cai W, Chen K, Li ZB, Gambhir SS, Chen X. Dual-function probe for PET and near-infrared fluorescence imaging of tumor vasculature. J. Nucl. Med. 2007;48:1862. [PubMed]
  • Chen F, Gerion D. Fluorescent CdSe/ZnS nanocrystal-peptide conjugates for long-term, nontoxic imaging and nuclear targeting in living cells. Nano Lett. 2004;4:1827–1832.
  • Chen Z, Chen H, Meng H, Xing G, Gao X, Sun B, Shi X, Yuan H, Zhang C, Liu R, et al. Bio-distribution and metabolic paths of silica coated CdSeS quantum dots. Toxicol. Appl. Pharmacol. 2008;230:364–371. [PubMed]
  • Cho SJ, Maysinger D, Jain M, Roder B, Hackbarth S, Winnik FM. Long-term exposure to CdTe quantum dots causes functional impairments in live cells. Langmuir. 2007;23:1974–1980. [PubMed]
  • Choi HS, Liu W, Misra P, Tanaka E, Zimmer JP, Itty Ipe B, Bawendi MG, Frangioni JV. Renal clearance of quantum dots. Nat. Biotechnol. 2007;25:1165–1170. [PMC free article] [PubMed]
  • Delehanty JB, Mattoussi H, Medintz IL. Delivering quantum dots into cells: Strategies, progress and remaining issues. Anal. Bioanal. Chem. 2008 ePub ahead of print. [PubMed]
  • Delehanty JB, Medintz IL, Pons T, Brunel FM, Dawson PE, Mattoussi H. Self-assembled quantum dot-peptide bioconjugates for selective intracellular delivery. Bioconjug. Chem. 2006;17:920–927. [PMC free article] [PubMed]
  • Derfus AM, Chan WCW, Bhatia SN. Probing the cytotoxicity of semiconductor quantum dots. Nano Lett. 2004;4:11–18.
  • Didenko YT, Suslick KS. Chemical aerosol flow synthesis of semiconductor nanoparticles. J. Am. Chem. Soc. 2005;127:12196–12197. [PubMed]
  • Dubertret B, Skourides P, Norris DJ, Noireaux V, Brivanlou AH, Libchaber A. In vivo imaging of quantum dots encapsulated in phospholipid micelles. Science. 2002;298:1759–1762. [PubMed]
  • Fischer HC, Liu L, Pang KS, Chan WCW. Pharmacokinetics of nanoscale quantum dots: In vivo distribution, sequestration, and clearance in the rat. Adv. Funct. Mater. 2006;16:1299.
  • Gagne F, Auclair J, Turcotte P, Fournier M, Gagnon C, Sauve S, Blaise C. Ecotoxicity of CdTe quantum dots to freshwater mussels: Impacts on immune system, oxidative stress and genotoxicity. Aquat. Toxicol. 2008;86:333–340. [PubMed]
  • Gopee NV, Roberts DW, Webb P, Cozart CR, Siitonen PH, Warbritton AR, Yu WW, Colvin VL, Walker NJ, Howard PC. Migration of intradermally injected quantum dots to sentinel organs in mice. Toxicol. Sci. 2007;98:249. [PMC free article] [PubMed]
  • Guo G, Liu W, Liang J, He Z, Xu H, Yang X. Probing the cytotoxicity of CdSe quantum dots with surface modification. Mater. Lett. 2007;61:1641–1644.
  • Hanaki K, Momo A, Oku T, Komoto A, Maenosono S, Yamaguchi Y, Yamamoto K. Semiconductor quantum dot/albumin complex is a long-life and highly photostable endosome marker. Biochem. Biophys. Res. Commun. 2003;302:496–501. [PubMed]
  • Hardman R. A toxicologic review of quantum dots: Toxicity depends on physicochemical and environmental factors. Environ. Health Perspect. 2006;114:165–172. [PMC free article] [PubMed]
  • Hild WA, Breunig M, Goepferich A. Quantum dots–Nano-sized probes for the exploration of cellular and intracellular targeting. Eur. J. Pharm. Biopharm. 2008;68:153–168. [PubMed]
  • Holbrook RD, Murphy KE, Morrow JB, Cole KD. Trophic transfer of nanoparticles in a simplified invertebrate food web. Nat. Nanotechnol. 2008;3:352–355. [PubMed]
  • Hoshino A, Fujioka K, Oku T, Suga M, Sasaki YF, Ohta T, Yasuhara M, Suzuki K, Yamamoto K. Physicochemical properties and cellular toxicity of nanocrystal quantum dots depend on their surface modification. Nano Lett. 2004a;4:2163–2170.
  • Hoshino A, Hanaki K, Suzuki K, Yamamoto K. Applications of T-lymphoma labeled with fluorescent quantum dots to cell tracing markers in mouse body. Biochem. Biophys. Res. Commun. 2004b;314:46–53. [PubMed]
  • Jaiswal JK, Mattoussi H, Mauro JM, Simon SM. Long-term multiple color imaging of live cells using quantum dot bioconjugates. Nat. Biotechnol. 2003;21:47–51. [PubMed]
  • Jamieson T, Bakhshi R, Petrova D, Pocock R, Imani M, Seifalian AM. Biological applications of quantum dots. Biomaterials. 2007;28:4717–4732. [PubMed]
  • Kennel SJ, Woodward JD, Rondinone AJ, Wall J, Huang Y, Mirzadeh S. The fate of MAb-targeted Cd(125m)Te/ZnS nanoparticles in vivo. Nucl. Med. Biol. 2008;35:501–514. [PubMed]
  • Larson DR, Zipfel WR, Williams RM, Clark SW, Bruchez MP, Wise FW, Webb WW. Water-soluble quantum dots for multiphoton fluorescence imaging in vivo. Science. 2003;300:1434–1436. [PubMed]
  • Li ZB, Cai W, Chen X. Semiconductor quantum dots for in vivo imaging. J. Nanosci. Nanotechnol. 2007;7:2567–2581. [PubMed]
  • Li L, Qian H, Ren J. Rapid synthesis of highly luminescent CdTe nanocrystals in the aqueous phase by microwave irradiation with controllable temperature. Chem. Commun. (Camb). 2005;4:528–530. [PubMed]
  • Lin P, Chen JW, Chang LW, Wu JP, Redding L, Chang H, Yeh TK, Yang CS, Tsai MH, Wang HJ, et al. Computational and ultrastructural toxicology of a nanoparticle, quantum Dot 705, in mice. Environ. Sci. Technol. 2008;42:6264–6270. [PubMed]
  • Lovric J, Bazzi HS, Cuie Y, Fortin GR, Winnik FM, Maysinger D. Differences in subcellular distribution and toxicity of green and red emitting CdTe quantum dots. J. Mol. Med. 2005;83:377–385. [PubMed]
  • Maynard AD, Aitken RJ. Assessing exposure to airborne nanomaterials: Current abilities and future requirements. Nanotoxicology. 2007;1:26–41.
  • Medintz IL, Mattoussi H, Clapp AR. Potential clinical applications of quantum dots. Int. J. Nanomed. 2008;3:151. [PMC free article] [PubMed]
  • Michalet X, Pinaud FF, Bentolila LA, Tsay JM, Doose S, Li JJ, Sundaresan G, Wu AM, Gambhir SS, Weiss S. Quantum dots for live cells, in vivo imaging, and diagnostics. Science. 2005;307:538–544. [PMC free article] [PubMed]
  • Pelley J, Saner M. International Approaches to the regulatory governance of nanotechnology. 2009 Regulation Paper, Regulatory Governance Initiative, Carleton University. Available from: http://www.carleton.ca/regulation/publications/Nanotechnology_Regulation_Paper_April2009.pdf. Accessed 7 July 2009.
  • Robe A, Pic E, Lassalle HP, Bezdetnaya L, Guillemin F, Marchal F. Quantum dots in axillary lymph node mapping: Biodistribution study in healthy mice. BMC Cancer. 2008;8:111. [PMC free article] [PubMed]
  • Royal Commission on Environmental Pollution. Novel materials in the environment: The case of nanotechnology. 2008 Report available online from: http://www.rcept.org.uk/novel%20materials/Novel%20Materials%20report.pdfAccessed 21 January 2009.
  • Ryman-Rasmussen JP, Riviere JE, Monteiro-Riviere NA. Penetration of intact skin by quantum dots with diverse physicochemical properties. Toxicol. Sci. 2006;91:159–165. [PubMed]
  • Ryman-Rasmussen JP, Riviere JE, Monteiro-Riviere NA. Surface coatings determine cytotoxicity and irritation potential of quantum dot nanoparticles in epidermal keratinocytes. J. Invest. Dermatol. 2007;127:143–153. [PubMed]
  • Samia ACS, Dayal S, Burda C. Quantum dot-based energy transfer: Perspectives and potential for applications in photodynamic therapy. Photochem. Photobiol. 2006;82:617–625. [PubMed]
  • Schipper ML, Cheng Z, Lee SW, Bentolila LA, Iyer G, Rao J, Chen X, Wu AM, Weiss S, Gambhir SS. microPET-based biodistribution of quantum dots in living mice. J. Nucl. Med. 2007;48:1511. [PubMed]
  • Shiohara A, Hoshino A, Hanaki K, Suzuki K, Yamamoto K. On the cyto-toxicity caused by quantum dots. Microbiol. Immunol. 2004;48:669–675. [PubMed]
  • Su Y, He Y, Lu H, Sai L, Li Q, Li W, Wang L, Shen P, Huang Q, Fan C. The cytotoxicity of cadmium based, aqueous phase—Synthesized, quantum dots and its modulation by surface coating. Biomaterials. 2009;30:19–25. [PubMed]
  • Su X, Li Y. Quantum dot biolabeling coupled with immunomagnetic separation for detection of Escherichia coli O157:H7. Anal. Chem. 2004;76:4806–4810. [PubMed]
  • Tang M, Xing T, Zeng J, Wang H, Li C, Yin S, Yan D, Deng H, Liu J, Wang M, Chen J, Ruan DY. Unmodified CdSe quantum dots induce elevation of cytoplasmic calcium levels and impairment of functional properties of sodium channels in rat primary cultured hippocampal neurons. Environ. Health Perspect. 2008;116:915–922. [PMC free article] [PubMed]
  • Taylor A. Biochemistry of tellurium. Biol. Trace Elem. Res. 1996;55:231–239. [PubMed]
  • Vinceti M, Wei ET, Malagoli C, Bergomi M, Vivoli G. Adverse health effects of selenium in humans. Rev. Environ. Health. 2001;16:233–251. [PubMed]
  • Voura EB, Jaiswal JK, Mattoussi H, Simon SM. Tracking metastatic tumor cell extravasation with quantum dot nanocrystals and fluorescence emission-scanning microscopy. Nat. Med. 2004;10:993–998. [PubMed]
  • Wang L, Nagesha DK, Selvarasah S, Dokmeci MR, Carrier RL. Toxicity of CdSe nanoparticles in Caco-2 cell cultures. J. Nanobiotechnol. 2008;6:11. [PMC free article] [PubMed]
  • Woodward JD, Kennel SJ, Mirzadeh S, Dai S, Wall JS, Richey T, Avenell J, Rondinone AJ. In vivo SPECT/CT imaging and biodistribution using radioactive Cd125 mTe/ZnS nanoparticles. Nanotechnology. 2007;18:175103.
  • Yang RS, Chang LW, Wu JP, Tsai MH, Wang HJ, Kuo YC, Yeh TK, Yang CS, Lin P. Persistent tissue kinetics and redistribution of nanoparticles, quantum dot 705, in mice: ICP-MS quantitative assessment. Environ. Health Perspect. 2007;115:1339–1343. [PMC free article] [PubMed]
  • Zhang T, Stilwell JL, Gerion D, Ding L, Elboudwarej O, Cooke PA, Gray JW, Alivisatos AP, Chen FF. Cellular effect of high doses of silica-coated quantum dot profiled with high throughput gene expression analysis and high content cellomics measurements. Nano Lett. 2006;6:800–808. [PMC free article] [PubMed]
  • Zhang Y, Chen W, Zhang J, Liu J, Chen G, Pope C. In vitro and in vivo toxicity of CdTe nanoparticles. J. Nanosci. Nanotechnol. 2007;7:497–503. [PubMed]
  • Zimmer JP, Kim SW, Ohnishi S, Tanaka E, Frangioni JV, Bawendi MG. Size series of small indium arsenide-zinc selenide core-shell nanocrystals and their application to in vivo imaging. J. Am. Chem. Soc. 2006;128:2526–2527. [PMC free article] [PubMed]

Articles from Toxicological Sciences are provided here courtesy of Oxford University Press
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...