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Review
. 2005 Jul;113(7):823-39.
doi: 10.1289/ehp.7339.

Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles

Günter Oberdörster  1 , Eva Oberdörster, Jan Oberdörster
Affiliations
Review

Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles

Günter Oberdörster et al. Environ Health Perspect. 2005 Jul.

Erratum in

  • Environ Health Perspect. 2010 Sep;118(9):A380

Abstract

Although humans have been exposed to airborne nanosized particles (NSPs; < 100 nm) throughout their evolutionary stages, such exposure has increased dramatically over the last century due to anthropogenic sources. The rapidly developing field of nanotechnology is likely to become yet another source through inhalation, ingestion, skin uptake, and injection of engineered nanomaterials. Information about safety and potential hazards is urgently needed. Results of older biokinetic studies with NSPs and newer epidemiologic and toxicologic studies with airborne ultrafine particles can be viewed as the basis for the expanding field of nanotoxicology, which can be defined as safety evaluation of engineered nanostructures and nanodevices. Collectively, some emerging concepts of nanotoxicology can be identified from the results of these studies. When inhaled, specific sizes of NSPs are efficiently deposited by diffusional mechanisms in all regions of the respiratory tract. The small size facilitates uptake into cells and transcytosis across epithelial and endothelial cells into the blood and lymph circulation to reach potentially sensitive target sites such as bone marrow, lymph nodes, spleen, and heart. Access to the central nervous system and ganglia via translocation along axons and dendrites of neurons has also been observed. NSPs penetrating the skin distribute via uptake into lymphatic channels. Endocytosis and biokinetics are largely dependent on NSP surface chemistry (coating) and in vivo surface modifications. The greater surface area per mass compared with larger-sized particles of the same chemistry renders NSPs more active biologically. This activity includes a potential for inflammatory and pro-oxidant, but also antioxidant, activity, which can explain early findings showing mixed results in terms of toxicity of NSPs to environmentally relevant species. Evidence of mitochondrial distribution and oxidative stress response after NSP endocytosis points to a need for basic research on their interactions with subcellular structures. Additional considerations for assessing safety of engineered NSPs include careful selections of appropriate and relevant doses/concentrations, the likelihood of increased effects in a compromised organism, and also the benefits of possible desirable effects. An interdisciplinary team approach (e.g., toxicology, materials science, medicine, molecular biology, and bioinformatics, to name a few) is mandatory for nanotoxicology research to arrive at an appropriate risk assessment.

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Figures

Figure 1
Figure 1. Idealized size distribution of traffic-related particulate matter (U.S. EPA 2004). Dp, particle diameter. The four polydisperse modes of traffic-related ambient particulate matter span approximately four orders of magnitude from < 1 nm to > 10 μm. Nucleation- and Aitken-mode particles are defined as UFPs (< approximately 100 nm). Source-dependent chemical composition is not well controlled and varies considerably. In contrast, NPs (1–100 nm) have well-controlled chemistry and are generally monodispersed.
Figure 2
Figure 2. Surface molecules as a function of particle size. Surface molecules increase exponentially when particle size decreases < 100 nm, reflecting the importance of surface area for increased chemical and biologic activity of NSPs. The increased biologic activity can be positive and desirable (e.g., antioxidant activity, carrier capacity for therapeutics, penetration of cellular barriers), negative and undesirable (e.g., toxicity, induction of oxidative stress or of cellular dysfunction), or a mix of both. Figure courtesy of H. Fissan (personal communication).
Figure 3
Figure 3. Hypothetical cellular interaction of NSPs (adapted from Donaldson and Tran 2002). EGFR, epidermal growth factor receptor. Inflammation and oxidative stress can be mediated by several primary pathways: a) the particle surface causes oxidative stress resulting in increased intracellular calcium and gene activation; b) transition metals released from particles result in oxidative stress, increased intracellular calcium, and gene activation; c) cell surface receptors are activated by transition metals released from particles, resulting in subsequent gene activation; or d) intracellular distribution of NSPs to mitochondria generates oxidative stress.
Figure 4
Figure 4. Percentage of neutrophils in lung lavage of rats (A,B) and mice (C,D) as indicators of inflammation 24 hr after intratracheal instillation of different mass doses of 20-nm and 250-nm TiO2 particles in rats and mice. (A,C) The steeper dose response of nanosized TiO2 is obvious when the dose is expressed as mass. (B,D) The same dose response relationship as in (A,C) but with dose expressed as particle surface area; this indicates that particle surface area seems to be a more appropriate dosemetric for comparing effects of different-sized particles, provided they are of the same chemical structure (anatase TiO2 in this case). Data show mean ± SD.
Figure 5
Figure 5. Routes of exposure, uptake, distribution, and degradation of NSPs in the environment. Solid lines indicate routes that have been demonstrated in the laboratory or field or that are currently in use (remediation). Magenta lettering indicates possible degradation routes, and blue lettering indicates possible sinks and sources of NSPs.
Figure 6
Figure 6. NPs have been shown to release oxyradicals [pictured here is the mechanism of C60 as determined by Yamakoshi et al. (2003)], which can interact with the antioxidant defense system. Abbreviations: GPx, glutathione peroxidase; GSH, reduced glutathione; GSSG, oxidized glutathione; ISC, intersystem crossing; R, any organic molecule; SOD, superoxide dismutase. In addition to fullerenes, metals such as cadmium, iron, or nickel quantum dots, or iron from SWNT manufacturing, could also act in Fenton-type reactions. Phase II biotransformation, ascorbic acid, vitamin E, beta carotene, and other interactions are not shown.
Figure 7
Figure 7. Some basic shapes of exposure–response or dose–response relationships. Abbreviations: H, hormetic (biphasic); L, linear (no threshold); S, supralinear; T, threshold. Prerequisites for establishing these relationships for NSPs from in vitro or in vivo studies include a sufficient number of data points, that is, over a wide range of exposure concentrations or doses; knowledge about exposure levels; and information about correlation of exposure with doses at the organismal or cellular level (an exposure is not a dose). Dose–response curves of different shapes can be extrapolated when only response data at high dose levels (indicated by dashed oval) are available. Lack of data in the low—oftentimes the most relevant—dose range can result in severe misinterpretation if a threshold or even a hormetic response is present. Consideration also needs to be given to the likelihood that the shape or slope of exposure–dose–response relationships change for susceptible parts of the population.
Figure 8
Figure 8. Predicted fractional deposition of inhaled particles in the nasopharyngeal, tracheobronchial, and alveolar region of the human respiratory tract during nose breathing. Based on data from the International Commission on Radiological Protection (1994). Drawing courtesy of J. Harkema.
Figure 9
Figure 9. Pathways of particle clearance (disposition) in and out of the respiratory tract. There are significant differences between NSPs and larger particles for some of these pathways (see “Disposition of NSPs in the respiratory tract”). Drawing courtesy of J. Harkema.
Figure 10
Figure 10. In vivo retention of inhaled nanosized and larger particles in alveolar macrophages (A) and in exhaustively lavaged lungs (epithelial and interstitial retention; B) 24 hr postexposure. The alveolar macrophage is the most important defense mechanism in the alveolar region for fine and coarse particles, yet inhaled singlet NSPs are not efficiently phagocytized by alveolar macrophages.
Figure 11
Figure 11. Different forms of caveolae and cellular tight junctions function as translocation mechanisms across cell layers. Depending on particle surface chemistry, NSPs have been shown to transcytose across alveolar type I epithelial cells and capillary endothelial cells (Table 4), but not via cellular tight junctions in the healthy state (A). However, in a compromised or disease state (e.g., endotoxin exposure; B) translocation across widened tight junction occurs as well (Heckel et al. 2004). This indicates that assessing potential effects of NSPs in the compromised state is an important component of nanotoxicology. Adapted from Cohen et al. (2004).
Figure 12
Figure 12. Close proximity of olfactory mucosa to olfactory bulb of the CNS. Inhaled NSP[s], especially below 10 nm, deposit efficiently on the olfactory mucosa by diffusion, similar to airborne “smell” molecules which deposit in this area of olfactory dendritic cilia. Subsequent uptake and translocation of solid NSP[s] along axons of the olfactory nerve has been demonstrated in non-human primates and rodents. Surface chemistry of the particles may influence their neuronal translocation. Copyright © the McGraw-Hill Companies, Inc. Reproduced from Widmaier et al. (2004) with permission from McGraw-Hill.
Figure 13
Figure 13. Occlusion of the right nostril of rats during 6-hr inhalation of nanosized MnO2 particles (~ 30 nm CMD, ~ 450 μg/m3) resulted in accumulation of Mn only in the left olfactory bulb only at 24 hr after dosing. Data are mean ± SD. Data from Feikert et al. (2004).
Figure 14
Figure 14. The epidermis represents a tight barrier against NSP penetration. Quantitatively, dermal translocation will therefore be minimal or nonexistent under normal conditions but increases in areas of skin flexing (Tinkle et al. 2003) and broken skin. Once in the dermis, lymphatic uptake is a major translocation route, likely facilitated by uptake in dendritic cells (epidermis) and macrophages; other potential pathways may include the dense networks of blood circulation and sensory nerves in the dermis. Adapted from Essential Day Spa (2005) with permission from www.essentialdayspa.com.
Figure 15
Figure 15. Risk assessment (NRC 1983) and risk management paradigm for NPs. Risk assessment requires answers to the following questions: Do NPs have adverse effects? What are the dose–response relationships? What are occupational/environmental levels in different media? What is the calculated risk? Once a risk is determined, a risk management decision can be established, including exposure standards and regulations and efforts for effective risk communication. Modified from Oberdörster (1994).
Figure 16
Figure 16. Biokinetics of NSPs. PNS, peripheral nervous system. Although many uptake and translocation routes have been demonstrated, others still are hypothetical and need to be investigated. Translocation rates are largely unknown, as are accumulation and retention in critical target sites and their underlying mechanisms. These, as well as potential adverse effects, largely depend on physicochemical characteristics of the surface and core of NSPs. Both qualitative and quantitative changes in NSP biokinetics in a diseased or compromised organism also need to be considered.
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References

    1. Adams RJ, Bray D. Rapid transport of foreign particles microinjected into crab axons. Nature. 1983;303:718–720. - PubMed
    1. Akerman MA, Chan WCW, Laakkonen P, Bhatia SN, Ruoslahti E. Nanocrystal targeting in vivo. Proc Natl Acad Sci USA. 2002;99:12617–12621. - PMC - PubMed
    1. Amato I. Making the right stuff. Sci News. 1989;136:108–110.
    1. Anderson PJ, Wilson JD, Hiller FC. Respiratory tract deposition of ultrafine particles in subjects with obstructive or restrictive lung disease. Chest. 1990;97:1115–1120. - PubMed
    1. ANSI 2004. Home page. American National Standards Institute. Available: http://www.ansi.org [accessed 16 March 2005].

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