BackgroundNanotechnology offers great promise in many industrial applications. However, little is known about the health effects of manufactured nanoparticles, the building blocks of nanomaterials.ObjectivesTitanium dioxide (TiO2) nanoparticles with a primary size of 2–5 nm have not been studied previously in inhalation exposure models and represent some of the smallest manufactured nanoparticles. The purpose of this study was to assess the toxicity of these nanoparticles using a murine model of lung inflammation and injury.Materials and MethodsThe properties of TiO2 nanoparticles as well as the characteristics of aerosols of these particles were evaluated. Mice were exposed to TiO2 nanoparticles in a whole-body exposure chamber acutely (4 hr) or subacutely (4 hr/day for 10 days). Toxicity in exposed mice was assessed by enumeration of total and differential cells, determination of total protein, lactate dehydrogenase (LDH) activity and inflammatory cytokines in bronchoalveolar lavage (BAL) fluid. Lungs were also evaluated for histopathologic changesResultsMice exposed acutely to 0.77 or 7.22 mg/m3 nanoparticles demonstrated minimal lung toxicity or inflammation. Mice exposed subacutely (8.88 mg/m3) and necropsied immediately and at week 1 or 2 postexposure had higher counts of total cells and alveolar macrophages in the BAL fluid compared with sentinels. However, mice recovered by week 3 postexposure. Other indicators were negative.ConclusionsMice subacutely exposed to 2–5 nm TiO2 nanoparticles showed a significant but moderate inflammatory response among animals at week 0, 1, or 2 after exposure that resolved by week 3 postexposure.

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BackgroundThere is increasing interest in the environmental and health consequences of silver nanoparticles as the use of this material becomes widespread. Although human exposure to nanosilver is increasing, only a few studies address possible toxic effect of inhaled nanosilver. The objective of this study was to determine whether very small commercially available nanosilver induces pulmonary toxicity in mice following inhalation exposure.ResultsIn this study, mice were exposed sub-acutely by inhalation to well-characterized nanosilver (3.3 mg/m3, 4 hours/day, 10 days, 5 ± 2 nm primary size). Toxicity was assessed by enumeration of total and differential cells, determination of total protein, lactate dehydrogenase activity and inflammatory cytokines in bronchoalveolar lavage fluid. Lungs were evaluated for histopathologic changes and the presence of silver. In contrast to published in vitro studies, minimal inflammatory response or toxicity was found following exposure to nanosilver in our in vivo study. The median retained dose of nanosilver in the lungs measured by inductively coupled plasma - optical emission spectroscopy (ICP-OES) was 31 μg/g lung (dry weight) immediately after the final exposure, 10 μg/g following exposure and a 3-wk rest period and zero in sham-exposed controls. Dissolution studies showed that nanosilver did not dissolve in solutions mimicking the intracellular or extracellular milieu.ConclusionsMice exposed to nanosilver showed minimal pulmonary inflammation or cytotoxicity following sub-acute exposures. However, longer term exposures with higher lung burdens of nanosilver are needed to ensure that there are no chronic effects and to evaluate possible translocation to other organs.

BackgroundAlthough ZnO nanoparticles (NPs) are used in many commercial products and the potential for human exposure is increasing, few in vivo studies have addressed their possible toxic effects after inhalation. We sought to determine whether ZnO NPs induce pulmonary toxicity in mice following sub-acute or sub-chronic inhalation exposure to realistic exposure doses.MethodsMice (C57Bl/6) were exposed to well-characterized ZnO NPs (3.5 mg/m3, 4 hr/day) for 2 (sub-acute) or 13 (sub-chronic) weeks and necropsied immediately (0 wk) or 3 weeks (3 wks) post exposure. Toxicity was assessed by enumeration of total and differential cells, determination of total protein, lactate dehydrogenase activity and inflammatory cytokines in bronchoalveolar lavage (BAL) fluid as well as measurements of pulmonary mechanics. Generation of reactive oxygen species was assessed in the lungs. Lungs were evaluated for histopathologic changes and Zn content. Zn concentration in blood, liver, kidney, spleen, heart, brain and BAL fluid was measured.ResultsAn elevated concentration of Zn2+ was detected in BAL fluid immediately after exposures, but returned to baseline levels 3 wks post exposure. Dissolution studies showed that ZnO NPs readily dissolved in artificial lysosomal fluid (pH 4.5), but formed aggregates and precipitates in artificial interstitial fluid (pH 7.4). Sub-acute exposure to ZnO NPs caused an increase of macrophages in BAL fluid and a moderate increase in IL-12(p40) and MIP-1α, but no other inflammatory or toxic responses were observed. Following both sub-acute and sub-chronic exposures, pulmonary mechanics were no different than sham-exposed animals.ConclusionsOur ZnO NP inhalation studies showed minimal pulmonary inflammation, cytotoxicity or lung histopathologic changes. An elevated concentration of Zn in the lung and BAL fluid indicates dissolution of ZnO NPs in the respiratory system after inhalation. Exposure concentration, exposure mode and time post exposure played an important role in the toxicity of ZnO NPs. Exposure for 13 wks with a cumulative dose of 10.9 mg/kg yielded increased lung cellularity, but other markers of toxicity did not differ from sham-exposed animals, leading to the conclusion that ZnO NPs have low sub-chronic toxicity by the inhalation route.

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Background The production ban of polychlorinated biphenyl (PCB) technical mixtures has left the erroneous impression that PCBs exist only as legacy pollutants. Some lower-chlorinated PCBs are still being produced and contaminate both indoor and ambient air. Objectives To inform PCB risk assessment, we characterized lung uptake, distribution, metabolism and excretion of PCB11 as a signature compound for these airborne non-legacy PCBs. Methods After delivering [14C]PCB11 to the lungs of male rats, radioactivity in 34 major tissues and 5 digestive matter compartments was measured at 12, 25, 50, 100, 200 and 720 min postexposure, during which time the excreta and exhaled air were also collected. [14C]PCB11 and metabolites in liver, blood, digestive matter, urine and adipose tissues were extracted separately to establish the metabolic profile of the disposition. Results [14C]PCB11 was distributed rapidly to all tissues after 99.8% pulmonary uptake and quickly underwent extensive metabolism. The major tissue deposition of [14C]PCB11 and metabolites translocated from liver, blood and muscle to skin and adipose tissue 200 min postexposure, while over 50% of administered dose was discharged via urine and feces within 12 h. Elimination of the [14C]PCB11 and metabolites consisted of an initial fast phase (t½ = 9-33 min) and a slower clearance phase to low concentrations. Phase II metabolites dominated in liver, blood and excreta after 25 min postexposure. Conclusions This study shows that PCB11 is completely absorbed after inhalation exposure and is rapidly eliminated from most tissues. Phase II metabolites dominated with a slower elimination rate than the PCB11 or phase I metabolites and thus can best serve as urine biomarkers of exposure.

BackgroundHuman exposure to nanoparticles (NPs) and environmental bacteria can occur simultaneously. NPs induce inflammatory responses and oxidative stress but may also have immune-suppressive effects, impairing macrophage function and altering epithelial barrier functions. The purpose of this study was to assess the potential pulmonary effects of inhalation and instillation exposure to copper (Cu) NPs using a model of lung inflammation and host defense.MethodsWe used Klebsiella pneumoniae (K.p.) in a murine lung infection model to determine if pulmonary bacterial clearance is enhanced or impaired by Cu NP exposure. Two different exposure modes were tested: sub-acute inhalation (4 hr/day, 5 d/week for 2 weeks, 3.5 mg/m3) and intratracheal instillation (24 hr post-exposure, 3, 35, and 100 μg/mouse). Pulmonary responses were evaluated by lung histopathology plus measurement of differential cell counts, total protein, lactate dehydrogenase (LDH) activity, and inflammatory cytokines in bronchoalveolar lavage (BAL) fluid.ResultsCu NP exposure induced inflammatory responses with increased recruitment of total cells and neutrophils to the lungs as well as increased total protein and LDH activity in BAL fluid. Both inhalation and instillation exposure to Cu NPs significantly decreased the pulmonary clearance of K.p.-exposed mice measured 24 hr after bacterial infection following Cu NP exposure versus sham-exposed mice also challenged with K.p (1.4 × 105 bacteria/mouse).ConclusionsCu NP exposure impaired host defense against bacterial lung infections and induced a dose-dependent decrease in bacterial clearance in which even our lowest dose demonstrated significantly lower clearance than observed in sham-exposed mice. Thus, exposure to Cu NPs may increase the risk of pulmonary infection.

The mouse trachea is thought to contain two distinct stem cell compartments that contribute to airway repair-basal cells in the surface airway epithelium (SAE) and an unknown submucosal gland (SMG) cell type. Whether a lineage relationship exists between these two stem cell compartments remains unclear. Using lineage tracing of glandular myoepithelial cells (MECs), we demonstrate that MECs can give rise to seven cell types of the SAE and SMGs following severe airway injury. MECs progressively adopted a basal cell phenotype on the SAE and established lasting progenitors capable of further regeneration following reinjury. MECs activate Wnt-regulated transcription factors (Lef-1/TCF7) following injury and Lef-1 induction in cultured MECs promoted transition to a basal cell phenotype. Surprisingly, dose-dependent MEC conditional activation of Lef-1 in vivo promoted self-limited airway regeneration in the absence of injury. Thus, modulating the Lef-1 transcriptional program in MEC-derived progenitors may have regenerative medicine applications for lung diseases.