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Andrea L Armstead,1,2 Bingyun Li1–3 1Department of Orthopaedics, School of Medicine, 2School of Pharmacy, West Virginia University, 3Mary Babb Randolph Cancer Center, Morgantown, WV, USA Abstract: As the number of commercial and consumer products containing engineered nanomaterials (ENMs) continually rises, the increased use and production of these ENMs presents an important toxicological concern. Although ENMs offer a number of advantages over traditional materials, their extremely small size and associated characteristics may also greatly enhance their toxic potentials. ENM exposure can occur in various consumer and industrial settings through inhalation, ingestion, or dermal routes. Although the importance of accurate ENM characterization, effective dosage metrics, and selection of appropriate cell or animal-based models are universally agreed upon as important factors in ENM research, at present, there is no “standardized” approach used to assess ENM toxicity in the research community. Of particular interest is occupational exposure to tungsten carbide cobalt (WC-Co) “dusts,” composed of nano- and micro-sized particles, in hard metal manufacturing facilities and mining and drilling industries. Inhalation of WC-Co dust is known to cause “hard metal lung disease” and an increased risk of lung cancer; however, the mechanisms underlying WC-Co toxicity, the inflammatory disease state and progression to cancer are poorly understood. Herein, a discussion of ENM toxicity is followed by a review of the known literature regarding the effects of WC-Co particle exposure. The risk of WC-Co exposure in occupational settings and the updates of in vitro and in vivo studies of both micro- and nano-WC-Co particles are discussed. Keywords: engineered nanomaterial, occupational exposure, lung disease, cancer, toxicity, particle

Andrea L Armstead,1,2 Bingyun Li1–3 1Department of Orthopaedics, School of Medicine, 2School of Pharmacy, West Virginia University, 3Mary Babb Randolph Cancer Center, Morgantown, WV, USA Abstract: Identifying the toxicity of nanoparticles (NPs) is an important area of research as the number of nanomaterial-based consumer and industrial products continually rises. In addition, the potential inflammatory effects resulting from pulmonary NP exposure are emerging as an important aspect of nanotoxicity. In this study, the toxicity and inflammatory state resulting from tungsten carbide–cobalt (WC–Co) NP exposure in macrophages and a coculture (CC) of lung epithelial cells (BEAS-2B) and macrophages (THP-1) at a 3:1 ratio were examined. It was found that the toxicity of nano-WC–Co was cell dependent; significantly less toxicity was observed in THP-1 cells compared to BEAS-2B cells. It was demonstrated that nano-WC–Co caused reduced toxicity in the CC model compared to lung epithelial cell monoculture, which suggested that macrophages may play a protective role against nano-WC–Co-mediated toxicity in CCs. Nano-WC–Co exposure in macrophages resulted in increased levels of interleukin (IL)-1β and IL-12 secretion and decreased levels of tumor necrosis factor alpha (TNFα). In addition, the polarizing effects of nano-WC–Co exposure toward the M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophage phenotypes were investigated. The results of this study indicated that nano-WC–Co exposure stimulated the M1 phenotype, marked by high expression of CD40 M1 macrophage surface markers. Keywords: nanoparticle, nanotoxicity, inflammation, macrophage, lung disease

Andrea L Armstead1–3, Bingyun Li1–31Biomaterials, Bioengineering and Nanotechnology Laboratory, Department of Orthopedics, School of Medicine, West Virginia University, Morgantown, WV; 2Pharmaceutical and Pharmacological Sciences, Health Sciences Center, West Virginia University, Morgantown, WV; 3WVNano Initiative, Morgantown, WV, USAAbstract: Diseases such as tuberculosis, hepatitis, and HIV/AIDS are caused by intracellular pathogens and are a major burden to the global medical community. Conventional treatments for these diseases typically consist of long-term therapy with a combination of drugs, which may lead to side effects and contribute to low patient compliance. The pathogens reside within intracellular compartments of the cell, which provide additional barriers to effective treatment. Therefore, there is a need for improved and more effective therapies for such intracellular diseases. This review will summarize, for the first time, the intracellular compartments in which pathogens can reside and discuss how nanomedicine has the potential to improve intracellular disease therapy by offering properties such as targeting, sustained drug release, and drug delivery to the pathogen's intracellular location. The characteristics of nanomedicine may prove advantageous in developing improved or alternative therapies for intracellular diseases.Keywords: intracellular pathogen, infection, nanomedicine, nanoparticle, drug delivery

Exposure to hard metal tungsten carbide cobalt (WC-Co) "dusts" in enclosed industrial environments is known to contribute to the development of hard metal lung disease and an increased risk for lung cancer. Currently, the influence of local and systemic inflammation on disease progression following WC-Co exposure remains unclear. To better understand the relationship between WC-Co nanoparticle (NP) exposure and its resultant effects, the acute local pulmonary and systemic inflammatory responses caused by WC-Co NPs were explored using an intra-tracheal instillation (IT) model and compared to those of CeO2 (another occupational hazard) NP exposure. Sprague-Dawley rats were given an IT dose (0-500 μg per rat) of WC-Co or CeO2 NPs. Following 24-hr exposure, broncho-alveolar lavage fluid and whole blood were collected and analyzed. A consistent lack of acute local pulmonary inflammation was observed in terms of the broncho-alveolar lavage fluid parameters examined (i.e. LDH, albumin, and macrophage activation) in animals exposed to WC-Co NP; however, significant acute pulmonary inflammation was observed in the CeO2 NP group. The lack of acute inflammation following WC-Co NP exposure contrasts with earlier in vivo reports regarding WC-Co toxicity in rats, illuminating the critical role of NP dose and exposure time and bringing into question the potential role of impurities in particle samples. Further, we demonstrated that WC-Co NP exposure does not induce acute systemic effects since no significant increase in circulating inflammatory cytokines were observed. Taken together, the results of this in vivo study illustrate the distinct differences in acute local pulmonary and systemic inflammatory responses to NPs composed of WC-Co and CeO2; therefore, it is important that the outcomes of pulmonary exposure to one type of NPs may not be implicitly extrapolated to other types of NPs.

Tungsten carbide cobalt (WC-Co) has been recognized as a workplace inhalation hazard in the manufacturing, mining and drilling industries by the National Institute of Occupational Safety and Health. Exposure to WC-Co is known to cause "hard metal lung disease" but the relationship between exposure, toxicity and development of disease remain poorly understood. To better understand this relationship, the present study examined the role of WC-Co particle size and internalization on toxicity using lung epithelial cells. We demonstrated that nano- and micro-WC-Co particles exerted toxicity in a dose- and time-dependent manner and that nano-WC-Co particles caused significantly greater toxicity at lower concentrations and shorter exposure times compared to micro-WC-Co particles. WC-Co particles in the nano-size range (not micron-sized) were internalized by lung epithelial cells, which suggested that internalization may play a key role in the enhanced toxicity of nano-WC-Co particles over micro-WC-Co particles. Further exploration of the internalization process indicated that there may be multiple mechanisms involved in WC-Co internalization such as actin and microtubule based cytoskeletal rearrangements. These findings support our hypothesis that WC-Co particle internalization contributes to cellular toxicity and suggest that therapeutic treatments inhibiting particle internalization may serve as prophylactic approaches for those at risk of WC-Co particle exposure., (Copyright © 2014 Elsevier Inc. All rights reserved.)