A comparative dose-related response of several key pro- and antiinflammatory mediators in the lungs of rats, mice, and hamsters after subchronic inhalation of carbon black.
ABSTRACT The objective of this study was to investigate mechanisms underlying species specificity in particle-induced lung inflammation.
Rats, mice, and hamsters exposed to air, 1, 7, or 50 mg/m3 of carbon black for 13 weeks were killed at 1 day, 3 months, and 11 months after exposure. Bronchoalveolar lavage was performed and characterized for cell number, cell type, reactive oxygen and nitrogen species, and cytokine levels. Ex vivo mutational analysis of inflammatory cells was evaluated by coincubating with lung epithelial cells. Lung tissue was evaluated for gene expression of various antiinflammatory mediators.
There was a dose- and time-related effect with all the parameters. Rats demonstrated greater propensity for generating a proinflammatory response, whereas mice and hamsters demonstrated an increased antiinflammatory response.
These differences in pro- and antiinflammatory responses may contribute to the apparent species differences in inflammation and tumorigenesis.
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ABSTRACT: An abnormally high incidence of lung disease has been observed in the residents of Libby, Montana, which has been attributed to occupational and environmental exposure to fibrous amphiboles originating from a nearby contaminated vermiculite mine. The composition of Libby amphibole (LA) is complex and minimal toxicity data are available. In this study, we conduct a comparative particle toxicity analysis of LA compared with standard reference asbestiform amphibole samples. Primary human airway epithelial cells (HAEC) were exposed two different LA samples as well as standard amphibole reference samples. Analysis of the samples included a complete particle size distribution analysis, calculation of surface area by electron microscopy and by gas adsorption and quantification of surface-conjugated iron and hydroxyl radical production by the fibers. Interleukin-8 mRNA levels were quantified by qRT-PCR to measure relative pro-inflammatory response induced in HAEC in response to amphibole fiber exposure. The relative contribution of key physicochemical determinants on the observed pro-inflammatory response were also evaluated. The RTI reference sample contained the longest fibers and demonstrated the greatest potency at increasing IL-8 transcript levels when evaluated on an equal mass basis. The two LA samples and the UICC reference sample consisted of similar particle numbers per milligram as well as similar particle size distributions and induced comparable levels of IL-8 mRNA. A strong correlation was observed between the elongated particle (aspect ratio >=3:1) dose metrics of length and external surface area. Expression of the IL-8 data with respect to either of these metrics eliminated the differential response between the RTI amosite sample and the other samples that was observed when HAEC were exposed on an equal mass basis. On an equal mass basis, LA is as potent as the UICC amosite reference sample at inducing a pro-inflammatory response in HAEC but is less potent than the RTI amosite sample. The results of this study show that the particle length and particle surface area are highly correlated metrics that contribute significantly to the toxicological potential of these amphibole samples with respect to the inflammogenic response induced in airway epithelial cells.Particle and Fibre Toxicology 01/2014; 11(1):2. DOI:10.1186/1743-8977-11-2 · 6.99 Impact Factor
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ABSTRACT: Background Although major concerns exist regarding the potential consequences of human exposures to nanoscale carbon black (CB) particles, limited human toxicological data is currently available. The purpose of this study was to evaluate if nanoscale CB particles could be responsible, at least partially, for the altered lung function and inflammation observed in CB workers exposed to nanoscale CB particles.Methods Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), and Brunauer-Emmett-Teller were used to characterize CB. Eighty-one CB-exposed male workers and 104 non-exposed male workers were recruited. The pulmonary function test was performed and pro-inflammatory cytokines were evaluated. To further assess the deposition and pulmonary damage induced by CB nanoparticles, male BALB/c mice were exposed to CB for 6 hours per day for 7 or 14 days. The deposition of CB and the pathological changes of the lung tissue in mice were evaluated by paraffin sections and TEM. The cytokines levels in serum and lung tissue of mice were evaluated by ELISA and immunohistochemical staining (IHC).ResultsSEM and TEM images showed that the CB particles were 30 to 50 nm in size. In the CB workplace, the concentration of CB was 14.90 mg/m3. Among these CB particles, 50.77% were less than 0.523 micrometer, and 99.55% were less than 2.5 micrometer in aerodynamic diameter. The reduction of lung function parameters including FEV1%, FEV/FVC, MMF%, and PEF% in CB workers was observed, and the IL-1ß, IL-6, IL-8, MIP-1beta, and TNF- alpha had 2.86-, 6.85-, 1.49-, 3.35-, and 4.87-folds increase in serum of CB workers, respectively. In mice exposed to the aerosol CB, particles were deposited in the lung. The alveolar wall thickened and a large amount of inflammatory cells were observed in lung tissues after CB exposure. IL-6 and IL-8 levels were increased in both serum and lung homogenate.Conclusions The data strongly suggests that nanoscale CB particles could be responsible for the lung function reduction and pro-inflammatory cytokines secretion in CB workers. These results, therefore, provide the first evidence of a link between human exposure to CB and long-term pulmonary effects.Particle and Fibre Toxicology 12/2014; 11(1):73. DOI:10.1186/s12989-014-0073-1 · 6.99 Impact Factor
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ABSTRACT: The increased production of nanomaterials has caused a corresponding increase in concern about human exposures in consumer and occupational settings. Studies in rodents have evaluated dose-response relationships following respiratory tract (RT) delivery of nanoparticles (NPs) in order to identify potential hazards. However, these studies often use bolus methods that deliver NPs at high dose rates that do not reflect real world exposures and do not measure the actual deposited dose of NPs. We hypothesize that the delivered dose rate is a key determinant of the inflammatory response in the RT when the deposited dose is constant. F-344 rats were exposed to the same deposited doses of titanium dioxide (TiO2) NPs by single or repeated high dose rate intratracheal instillation or low dose rate whole body aerosol inhalation. Controls were exposed to saline or filtered air. Bronchoalveolar lavage fluid (BALF) neutrophils, biochemical parameters and inflammatory mediator release were quantified 4, 8, and 24 hr and 7 days after exposure. Although the initial lung burdens of TiO2 were the same between the two methods, instillation resulted in greater short term retention than inhalation. There was a statistically significant increase in BALF neutrophils at 4, 8 and 24 hr after the single high dose TiO2 instillation compared to saline controls and to TiO2 inhalation, whereas TiO2 inhalation resulted in a modest, yet significant, increase in BALF neutrophils 24 hr after exposure. The acute inflammatory response following instillation was driven primarily by monocyte chemoattractant protein-1 and macrophage inflammatory protein-2, mainly within the lung. Increases in heme oxygenase-1 in the lung were also higher following instillation than inhalation. TiO2 inhalation resulted in few time dependent changes in the inflammatory mediator release. The single low dose and repeated exposure scenarios had similar BALF cellular and mediator response trends, although the responses for single exposures were more robust. High dose rate NP delivery elicits significantly greater inflammation compared to low dose rate delivery. Although high dose rate methods can be used for quantitative ranking of NP hazards, these data caution against their use for quantitative risk assessment.Particle and Fibre Toxicology 01/2014; 11(1):5. DOI:10.1186/1743-8977-11-5 · 6.99 Impact Factor