Acute Pulmonary Effects of Ultrafine Particles in Rats and Mice

Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, 575 Elmwood Avenue, Box EHSC, Rochester NY 14642, USA.
Research report (Health Effects Institute) 08/2000; 96(96):5-74; disc. 75-86.
Source: PubMed


Ambient fine particles consist of ultrafine particles (< 100 nm) and accumulation-mode particles (approximately 100 to 1,000 nm). Our hypothesis that ultrafine particles can have adverse effects in humans is based on results of our earlier studies with particles of both sizes and on the finding that urban ultrafine particles can reach mass concentrations of 40 to 50 micrograms/m3, equivalent to number concentrations of 3 to 4 x 10(5) particles/cm3. The objectives of the exploratory studies reported here were to (1) evaluate pulmonary effects induced in rats and mice by ultrafine particles of known high toxicity (although not occurring in the ambient atmosphere) in order to obtain information on principles of ultrafine particle toxicology; (2) characterize the generation and coagulation behavior of ultrafine particles that are relevant for urban air; (3) study the influence of animals' age and disease status; and (4) evaluate copollutants as modifying factors. We used ultrafine Teflon (polytetrafluoroethylene [PTFE]*) fumes (count median diameter [CMD] approximately 18 nm) generated by heating Teflon in a tube furnace to 486 degrees C to evaluate principles of ultrafine particle toxicity that might be helpful in understanding potential effects of ambient ultrafine particles. Teflon fumes at ultrafine particle concentrations of approximately 50 micrograms/m3 are extremely toxic to rats when inhaled for only 15 minutes. We found that neither the ultrafine Teflon particles alone when generated in argon nor the Teflon fume gas-phase constituents when generated in air were toxic after 25 minutes of exposure. Only the combination of both phases when generated in air caused high toxicity, suggesting the existence of either radicals on the particle surface or a carrier mechanism of the ultrafine particles for adsorbed gas-phase compounds. We also found rapid translocation of the ultrafine Teflon particles across the epithelium after their deposition, which appears to be an important difference from the behavior of larger particles. Furthermore, the pulmonary toxicity of the ultrafine Teflon fumes could be prevented by adapting the animals with short 5-minute exposures on 3 days prior to a 15-minute exposure. This shows the importance of preexposure history in susceptibility to acute effects of ultrafine particles. Aging of the fresh Teflon fumes for 3.5 minutes led to a predicted coagulation resulting in particles greater than 100 nm that no longer caused toxicity in exposed animals. This result is consistent with greater toxicity of ultrafine particles compared with accumulation-mode particles. When establishing dose-response relationships for intratracheally instilled titanium dioxide (TiO2) particles of the size of the urban ultrafine particles (20 nm) and of the urban accumulation-mode particles (250 nm), we observed significantly greater pulmonary inflammatory response to ultrafine TiO2 in rats and mice. The greater toxicity of the ultrafine TiO2 particles correlated well with their greater surface area per mass. Ultrafine particles of carbon, platinum, iron, iron oxide, vanadium, and vanadium oxide were generated by electric spark discharge and characterized to obtain particles of environmental relevance for study. The CMD of the ultrafine carbon particles was approximately 26 nm, and that of the metal particles was 15 to 20 nm, with geometric standard deviations (GSDs) of 1.4 to 1.7. For ultrafine carbon particles, approximately 100 micrograms/m3 is equivalent to 12 x 10(6) particles/cm3. Homogeneous coagulation of these ultrafine particles in an animal exposure chamber occurred rapidly at 1 x 10(7) particles/cm3, so that particles quickly grew to sizes greater than 100 nm. Thus, controlled aging of ultrafine carbon particles allowed the generation of accumulation-mode carbon particles (due to coagulation growth) for use in comparative toxicity studies. We also developed a technique to generate ultrafine particles consisting of the stable isotope 13C by using 13C-graphite electrodes made in our laboratory from amorphous 13C powder. These particles are particularly useful tools for determining deposition efficiencies of ultrafine carbon particles in the respiratory tracts of laboratory animals and the translocation of particles to extrapulmonary sites. For compromised animals, we used acute and chronic pulmonary emphysema; a low-dose endotoxin inhalation aimed at priming target cells in the lung was also developed. Other modifying factors were age and copollutant (ozone) exposure. Exposure concentrations of the generated ultrafine particles for acute rodent inhalation studies were selected on the basis of lung doses predicted to occur in people inhaling approximately 50 micrograms/m3 urban ultrafine particles. Concentrations that achieved the same predicted lung burden per unit alveolar surface were used in rodents. (ABSTRACT TRUNCATED)

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    • "Results on the influence of primary particle size on pulmonary inflammation after inhalation are rather contradictory. Some studies report increased pulmonary inflammation after exposure to nanoparticles compared to larger micro-sized particles [10,30,31,36,107], while others report no difference [13,37]. As discussed earlier, both the agglomerate size and the primary size of particles affect lung deposition, clearance, and translocation. "
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    ABSTRACT: The increasing manufacture and use of products based on nanotechnology raises concerns for both workers and consumers. Various studies report induction of pulmonary inflammation after inhalation exposure to nanoparticles, which can vary in aspects such as size, shape, charge, crystallinity, chemical composition, and dissolution rate. Each of these aspects can affect their toxicity, although it is largely unknown to what extent. The aim of the current review is to analyse published data on inhalation of nanoparticles to identify and evaluate the contribution of their physicochemical characteristics to the onset and development of pulmonary inflammation. Many physicochemical characteristics of nanoparticles affect their lung deposition, clearance, and pulmonary response that, in combination, ultimately determine whether pulmonary inflammation will occur and to what extent. Lung deposition is mainly determined by the physical properties of the aerosol (size, density, shape, hygroscopicity) in relation to airflow and the anatomy of the respiratory system, whereas clearance and translocation of nanoparticles are mainly determined by their geometry and surface characteristics. Besides size and chemical composition, other physicochemical characteristics influence the induction of pulmonary inflammation after inhalation. As some nanoparticles dissolve, they can release toxic ions that can damage the lung tissue, making dissolution rate an important characteristic that affects lung inflammation. Fibre-shaped materials are more toxic to the lungs compared to spherical shaped nanoparticles of the same chemical composition. In general, cationic nanoparticles are more cytotoxic than neutral or anionic nanoparticles. Finally, surface reactivity correlates well with observed pulmonary inflammation. With all these characteristics affecting different stages of the events leading to pulmonary inflammation, no unifying dose metric could be identified to describe pulmonary inflammation for all nanomaterials, although surface reactivity might be a useful measure. To determine the extent to which the various characteristics influence the induction of pulmonary inflammation, the effect of these characteristics on lung deposition, clearance, and pulmonary response should be systematically evaluated. The results can then be used to facilitate risk assessment by categorizing nanoparticles according to their characteristics.
    Particle and Fibre Toxicology 04/2014; 11(1):18. DOI:10.1186/1743-8977-11-18 · 7.11 Impact Factor
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    • "We see ample evidence of inflammation associated with nanoparticle exposure through the respiratory tract, in terms of elevated WBC, aggregation of alveolar macrophages and neutrophils, and increased cytokines and LDH in the BALF [11, 13, 14]. The degree of inflammation can be affected by the size, concentration, and shape of the nanoparticle, which would alter its surface area, which has emerged to be an important predictor of toxicity [15–18]. "
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    ABSTRACT: Nanotitanium dioxide particle (nTiO2) inhalation has been reported to induce lung parenchymal injury. After inhalation of nTiO2, we monitored changes in 5-lipoxygenase, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) mRNA in rat lung tissue. Lung function parameters include specific airway resistance (SRaw), peak expiratory flow rate (PEF), functional residual capacity (FRC), and lung compliance (Cchord); blood white blood cell count (WBC), nitric oxide (NO), hydrogen peroxide, and lactic dehydrogenase (LDH); and lung lavage leukotriene C4, interleukin 6 (IL6), tumor necrotic factor α (TNF α ), hydroxyl radicals, and NO. Leukotriene receptor antagonist MK571 and 5-lipoxygenase inhibitor MK886 were used for pharmacologic intervention. Compared to control, nTiO2 exposure induced near 5-fold increase in 5-lipoxygenase mRNA expression in lung tissue. iNOS mRNA increased while eNOS mRNA decreased. Lavage leukotriene C4; IL6; TNF α ; NO; hydroxyl radicals; and blood WBC, NO, hydrogen peroxide, and LDH levels rose. Obstructive ventilatory insufficiency was observed. MK571 and MK886 both attenuated the systemic inflammation and lung function changes. We conclude that inhaled nTiO2 induces systemic inflammation, cytokine release, and oxidative and nitrosative stress in the lung. The lipoxygenase pathway products, mediated by oxygen radicals and WBC, play a critical role in the obstructive ventilatory insufficiency induced by nTiO2.
    Oxidative Medicine and Cellular Longevity 02/2014; 2014:485604. DOI:10.1155/2014/485604 · 3.36 Impact Factor
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    • "As a result of the high production volume and extensive applications of powdered TiO 2 , reasonable risks for exposures through inhalation or via other routes are anticipated. TiO 2 -NPs exhibit unique physico-chemical properties associated with their nano-size, which alters their biological behaviors at the cellular, subcellular , and protein levels resulting in adverse health effects (Liu et al., 2009; Nemmar et al., 2011; Oberdorster et al., 2000; Warheit et al., 2007). Thus, a detailed characterization of the tissue-level effects and mechanisms of action of TiO 2 -NPs is required in order to establish acceptable exposure limits. "
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    ABSTRACT: We investigated gene expression, protein synthesis, and particle retention in mouse lungs following intratracheal instillation of varying doses of nano-sized titanium dioxide (nano-TiO2). Female C57BL/6 mice were exposed to rutile nano-TiO2 via single intratracheal instillations of 18, 54, and 162 μg/mouse. Mice were sampled 1, 3, and 28 days post-exposure. The deposition of nano-TiO2 in the lungs was assessed using nanoscale hyperspectral microscopy. Biological responses in the pulmonary system were analysed using DNA microarrays, pathway-specific real-time RT-PCR (qPCR), gene-specific qPCR arrays, and tissue protein ELISA. Hyperspectral mapping showed dose-dependent retention of nano-TiO2 in the lungs up to 28 days post-instillation. DNA microarray analysis revealed approximately 3000 genes that were altered across all treatment groups (±1.3 fold; p < 0.1). Several inflammatory mediators changed in a dose- and time-dependent manner at both the mRNA and protein level. Although no influx of neutrophils was detected at the low dose, changes in the expression of several genes and proteins associated with inflammation were observed. Resolving inflammation at the medium dose, and lack of neutrophil influx in the lung fluid at the low dose, was associated with down-regulation of genes involved in ion homeostasis and muscle regulation. Our gene expression results imply that retention of nano-TiO2 in the absence of inflammation over time may potentially perturb calcium and ion homeostasis, and affect smooth muscle activities.
    Toxicology and Applied Pharmacology 04/2013; 269(3). DOI:10.1016/j.taap.2013.03.018 · 3.71 Impact Factor
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